Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][Na].Cl[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[CH2:7]>CO>[CH3:1][O:2][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[CH2:7]
Reactant: CO[Na]
Reactant: C=C(CCl)c1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: C=C(COC)c1ccc([N+](=O)[O-])cc1

Procedure:
To a CH3ONa-solution from 6.9 g (0.3 gramatom) Na and 600 ml absolute CH3OH are added 59.3 g (0.3 Mol) 4(1-chloromethyl-ethenyl)-nitrobenzene, the reaction mixture heated under reflux for 2 hours and then evaporated to dryness. The residue is digested with diethylether, the ethereal solution filtered and the filtrate concentrated by evaporation. The residue is then chromatographed on silica gel (eluant n-hexane/diethylether 1:1) to give the title compound in analytically pure form (Rf=0.37 on silica gel with CHCl3).
Reaction SMILES: [Na:1].COC1OCC([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])CO1.[CH3:31][C:32]1([CH2:40]CO)[O:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][O:33]1>>[Na:1].[CH3:30][C:13]1[C:14]([CH2:18][S:19]([C:21]2[NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)=[O:20])=[N:15][CH:16]=[CH:17][C:12]=1[O:11][CH2:10][CH2:31][C:32]1([CH3:40])[O:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][O:33]1
Reactant: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Reactant: CC1(C)COC(C)(CCO)OC1
Agent: [Na]
Product: Cc1c(OCCC2(C)OCC(C)(C)CO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 7.2 %

Procedure:
The same procedure as in the steps (6b) to (6f) of Example 6 was repeated using 2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethanol obtained in the step (34a) to obtain the title compound (196 mg, total yield: 7.2%) as a light yellow solid.
Reaction SMILES: [NH:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4[CH2:16][CH2:17][CH2:18][CH:5]([C:6]=42)[O:4][CH2:3][C:2]1=[O:19])[CH:12]=[CH:11][CH:10]=[CH:9]3.[CH3:20]C(C)([O-])C.[K+].CI>O1CCCC1.O.C(OCC)C>[CH3:20][N:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4[CH2:16][CH2:17][CH2:18][CH:5]([C:6]=42)[O:4][CH2:3][C:2]1=[O:19])[CH:12]=[CH:11][CH:10]=[CH:9]3
Reactant: CC(C)(C)[O-]
Reactant: O=C1COC2CCCc3nc4ccccc4c(c32)N1
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)COC2CCCc3nc4ccccc4c1c32
Yield: 46.3 %

Procedure:
To a solution of 1,3,4a,5,6,7-hexahydro-2H-quino[4,3,2-ef][1,4]-benzoxazepin-2-one (4.09 g) in tetrahydrofuran (100 ml) was added potassium t-butoxide (2.17 g) followed by methyl iodide (1.25 ml). The reaction mixture was stirred in water/ethyl ether, the precipitate was collected and dried to give 2.0 g (46%) of 1,3,4a,5,6,7-hexahydro-1-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.
Reaction SMILES: [CH2:1]([C:3]([C:22]1[CH:35]=[CH:34][C:25]([O:26][CH2:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:24]([CH3:36])[CH:23]=1)([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[C:8]([CH3:21])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH3:37][O:38][C:39](=[O:48])[CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[C:45](Br)[CH:46]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[CH3:37][O:38][C:39](=[O:48])[CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[C:45]([C:9]2[CH:10]=[CH:11][C:6]([C:3]([C:22]3[CH:35]=[CH:34][C:25]([O:26][CH2:27][C:28](=[O:33])[C:29]([CH3:30])([CH3:31])[CH3:32])=[C:24]([CH3:36])[CH:23]=3)([CH2:1][CH3:2])[CH2:4][CH3:5])=[CH:7][C:8]=2[CH3:21])[CH:46]=1
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 140 °C
Yield: 85.3 %

Procedure:
A solution of 1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one (Example 30-(2); 0.06 g, 0.12 mmol), (5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 42.0 mg, 0.18 mmol), tetrakistriphenylphosphine palladium (19.6 mg, 0.017 mmol) and potassium phosphate (38.7 mg, 0.18 mmol) in N,N-dimethylformamide (0.3 mL) was stirred with microwave heating at 140° C. for 10 minutes. The reaction mixture was filtered through cotton plug, and the mixture was purified by silica gel chromatography (40% ethyl acetate/hexane) to give the title compound (52.8 mg, 83%).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([NH2:21])[CH:15]=[CH:14]2)=[O:10])C1C=CC=CC=1.CC(O)C.[OH-].[K+]>O>[NH2:21][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:9]([OH:10])=[O:8])[CH:12]=2)[N:17]=1
Reactant: Nc1ccc2cc(C(=O)OCc3ccccc3)ccc2n1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Nc1ccc2cc(C(=O)O)ccc2n1
Reaction time: 12 h
Yield: 95 %

Procedure:
A mixture of 2-amino-quinoline-6-carboxylic acid benzyl ester (15.63 g, 0.0562 moles), 2-propanol (235 mL), water (15.6 mL) and potassium hydroxide (6.3 g, 0.112 moles) was heated to reflux, 80° C. to 85° C., for 2 to 4 hours. The reaction mixture was then cooled to 20° C. to 25° C., vacuum concentrated (volume of 160 mL) and granulated at 20° C. to 25° C. for 8 to 16 hours. The product was isolated by filtration (12.08 g, 0.0534 moles, 95% yield).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:12]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>CC(N(C)C)=O.O>[CH:12]1([NH:17][C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC1CCCC1
Reactant: Nc1nc2cccc(Br)n2n1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1nc2cccc(NC3CCCC3)n2n1
Temperature: 180 °C

Procedure:
To a solution of 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.5 g, 2.35 mmol) in dimethylacetamide (2 mL), cyclopentylamine (2.3 mL, 23.5 mmol) was added and the solution was heated under microwave irradiation (180° C., 180 min). The resulting mixture was diluted with water and extracted into ethyl acetate. The organics were washed with water then brine, and dried over magnesium sulfate. The solid (0.5 g) was used without further purification. LCMS1: 2.84 min, 218 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:28])[C:11]=1[C:12]([N:14]1[C:22]2[CH:21]=[CH:20][N:19]=[C:18]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[C:17]=2[CH:16]=[CH:15]1)=[O:13])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:28])[C:11]=1[C:12]([N:14]1[C:22]2[CH:21]=[CH:20][N:19]=[C:18]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[C:17]=2[CH:16]=[CH:15]1)=[O:13])[C:5]([OH:7])=[O:6]
Reactant: CCC(=O)Nc1nccc2c1ccn2C(=O)c1c(Cl)cc(C(=O)OC)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)Nc1nccc2c1ccn2C(=O)c1c(Cl)cc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
A mixture of methyl 3,5-dichloro-4-{[4-(propanoylamino)-1H-pyrrolo[3,2-c]pyridin-1-yl]carbonyl}benzoate (250 mg, 0.59 mmol) and sodium hydroxide (23 mg, 0.59 mmol) in tetrahydrofuran and water (1:1) was stirred at room temperature for about 1 hour. Tetrahydrofuran was removed in vaccuo and aqueous layer was diluted with water (5 mL) and acidified with hydrochloric acid (2N, up to pH 2). The solid thus obtained was filtered and dried to afford 3,5-dichloro-4-{[4-(propanoylamino)-1H-pyrrolo[3,2-c]pyridin-1-yl]carbonyl}benzoic acid (170 mg, 70%). The material was taken as such for the next step.
Reaction SMILES: [CH3:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH3:10])[CH2:5]1>C(O)(C)(C)C>[C:2]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH:2]([CH3:1])[CH2:3][N:4]2[CH2:9][CH2:8][CH2:7][CH:6]([CH3:10])[CH2:5]2)=[CH:17][CH:16]=1)([CH3:11])([CH3:3])[CH3:1]
Reactant: CC1CCCN(CC(C)Cc2ccccc2)C1
Solvent: CC(C)(C)O
Product: CC1CCCN(CC(C)Cc2ccc(C(C)(C)C)cc2)C1

Procedure:
1-[3-(p-tert.butyl-phenyl)-2-methyl-propyl]-3-methyl-piperidine, b.p. 116° C./0.02 Torr is prepared from 1-(2-methyl-3-phenyl-propyl)-3-methyl-piperidine and tert.butanol;
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].FC1C=CC(CBr)=CC=1.[Na].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18]1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CCOC(=O)C1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)OC1=O
Agent: Fc1ccc(CBr)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1C[C@@H]([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)OC1=O
Reaction time: 16 h

Procedure:
10.2 g of 5(S)-[1(S)-(Boc-amino)-2-cyclohexylethyl]-3(R,S)-ethoxycarbonyl-dihydrofuran-2-(3H)-one are reacted at RT with 5.39 g of p-fluorobenzyl bromide (Fluka, Buchs, Switzerland) and 0.68 g of sodium in 180 ml of ethanol. Because, according to TLC, not all of the lactone has reacted after 1.5 h, a further 0.2 g of sodium and 0.7 g of p-fluorobenzyl bromide are added. After 16 h, the batch is poured onto a mixture of 10% citric acid and ice and extracted 3 times with ether. The organic phases are washed twice with water and twice with brine, dried with Na2SO4 and concentrated by evaporation. After the addition of hexane/ethyl acetate, some of the oily crude product crystallises out under the effect of ultrasound to give the title compound (ratio of diastereoisomers 4:1). Column chromatography (SiO2, hexane/ethyl acetate 4:1) of the mother liquor yields more title compound (ratio of diastereoisomers approximately 1:4). TLC Rf (C)=0.29; FAB-MS (M+H)+ =492.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13](C=O)[CH2:12][CH2:11]2)[N:7]=[C:6]([N:18]2[CH2:23][CH2:22][S:21](=[O:24])[CH2:20][CH2:19]2)[C:5]=1[N+:25]([O-:27])=[O:26])[CH3:2].[OH-].[Na+].O>CO>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[N:7]=[C:6]([N:18]2[CH2:19][CH2:20][S:21](=[O:24])[CH2:22][CH2:23]2)[C:5]=1[N+:25]([O-:27])=[O:26])[CH3:2]
Reactant: CCOc1nc(N2CCN(C=O)CC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOc1nc(N2CCNCC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]

Procedure:
1.2 gm (3 millimols) of 6-ethoxy-2-(N-formyl-piperazino)-5-nitro-4-(1-oxido-thiomorpholino)-pyrimidine (m.p. 209°-211°C) were refluxed together with 1.2 gm (30 millimols) of sodium hydroxide in 80 ml of methanol for 3 hours. The reaction mixture was then poured into water, and the aqueous mixture was extracted with chloroform. The chloroform phase was dried with sodium sulfate, and the chloroform was removed in vacuo. Yield: 1 gm (89.6% of theory), m.p. 222°-223°C (ethanol).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:17][CH:16]2[N:18]([CH2:19][CH2:20]O)[CH:13]([CH2:14][CH2:15]2)[CH:12]=1.CS([Cl:26])(=O)=O.CCN(CC)CC.C(Cl)Cl>O>[Cl:26][CH2:20][CH2:19][N:18]1[CH:16]2[CH2:15][CH2:14][CH:13]1[CH:12]=[C:11]([C:2]1[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=1)[CH2:17]2
Reactant: CS(=O)(=O)Cl
Reactant: OCCN1C2C=C(c3ccc4ccccc4c3)CC1CC2
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCCN1C2C=C(c3ccc4ccccc4c3)CC1CC2
Yield: 50 %

Procedure:
2-[3-(2-Naphthyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]ethanol (0.95 g, 3.40 mmol), 0.42 g (3.70 mmol) MsCl, 0.71 mL (515 mg, 5.10 mmol) Et3N and 20 mL CH2Cl2 are stirred at 23 C in for 12 h. The reaction mixture is poured into 200 mL of H2O and extracted with 3×50 mL CH2Cl2. The combined organics are washed with H2O (3×100 mL,) brine (1×100 mL), dried over MgSO4, filtered, and the volatiles are evaporated. Flash chromatography on SiO2 gel, eluting with EtOAc/MeOH (20/1 to 10/1), gives 0.50 g (1.68 mmol, a 50% yield) of the title compound as a tan solid. mp: 122-123° C.; MS (ES) m/z 298 (MH)+.
Reaction SMILES: [CH2:1]([C:8]([OH:15])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO>[CH:2]1([CH2:1][C:8]([OH:15])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][OH:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CCCCC(O)(CO)Cc1ccccc1
Solvent: CO
Product: CCCCC(O)(CO)CC1CCCCC1
Yield: 91.7 %

Procedure:
A solution of the product from Example 19B (1.07 g, 5.19 mmol) was reduced using hydrogen gas at 4 atm in the presence of Rh/alumina in methanol to provide 1.02 g (92%) of the title compound.
Reaction SMILES: [F:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[S:13]1[C:17]2=[CH:18][CH:19]=[CH:20][C:21]([S:22]([NH:25][C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=3)(=[O:24])=[O:23])=[C:16]2[N:15]=[CH:14]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1([OH:10])[CH2:5][CH2:6][N:7]([C:30]([C:29]2[CH:28]=[CH:27][C:26]([NH:25][S:22]([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]4[S:13][CH:14]=[N:15][C:16]=34)(=[O:24])=[O:23])=[CH:34][CH:33]=2)=[O:31])[CH2:8][CH2:9]1
Reactant: CC(C)(F)CC1(O)CCNCC1
Reactant: O=C(O)c1ccc(NS(=O)(=O)c2cccc3scnc23)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(F)CC1(O)CCN(C(=O)c2ccc(NS(=O)(=O)c3cccc4scnc34)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round-bottom flask was added with 4-(2-fluoro-2-methylpropyl) piperidin-4-ol (25 mg 0.143 mmol), 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (47 mg, 0.143 mmol), DIPEA (110 mg, 0.85 mmol), HATU (54 mg, 0.143 mmol), and DCM (5 mL). The mixture was stirred at r.t. for 16 hours. After washing with satd. NaHCO3, brine, the combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Purification by a standard method gave the desired compound. 1H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.19 (dd, J=8.1, 0.8 Hz, 1H), 8.10 (dd, J=7.5, 1.1 Hz, 1H), 7.93 (s, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.16-7.23 (m, J=8.3 Hz, 2H), 7.05-7.15 (m, J=8.3 Hz, 2H), 4.19-4.47 (m, 1H), 3.46 (d, J=15.6 Hz, 1H), 3.35 (d, J=15.3 Hz, 2H), 1.89 (s, 3H), 1.84 (s, 3H), 1.49-1.55 (m, 3H), 1.46 (s, 3H). LC-MS: m/z 492.65 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH2:16])[CH:10]=1.[CH2:17]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH2:30][CH:29]([C:33](Cl)=[O:34])[CH2:28]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>ClCCl.CN(C1C=CN=CC=1)C>[CH2:17]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH2:30][CH:29]([C:33](=[O:34])[NH:16][C:11]2[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:14]=[C:13]([CH3:15])[N:12]=2)[CH2:28]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccccc1-c1cc(N)nc(C)n1
Reactant: O=C(Cl)C1CCCN(C(=O)OCc2ccccc2)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1-c1cc(NC(=O)C2CCCN(C(=O)OCc3ccccc3)C2)nc(C)n1
Reaction time: 3 h
Yield: 114.5 %

Procedure:
6-(2-Methoxy-phenyl)-2-methyl-pyrimidin-4-ylamine (XXXVI) (0.111 g, 0.512 mmol) was taken in 3 ml of dry dichloromethane, DMAP (0.075 g, 0.614 mmol) and a solution of 3-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (XXV) (0.155 g, 0.563 mmol) in dichloromethane (1 ml) were added dropwise at room temperature and the reaction mixture was stirred for 3 hours. Then water was added to the reaction mixture followed by extraction with dichloromethane. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to provide 0.270 g of 3-[6-(2-methoxy-phenyl)-2-methyl-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XXXVII).
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:26]=[CH:25][C:9]2[N:10]([CH2:13][C:14]3[CH:24]=[CH:23][C:17]4[N:18]=[C:19]([S:21][CH3:22])[S:20][C:16]=4[CH:15]=3)[CH:11]=[N:12][C:8]=2[CH:7]=1.[C:27]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C>[CH3:27][N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:26]=[CH:25][C:9]3[N:10]([CH2:13][C:14]4[CH:24]=[CH:23][C:17]5[N:18]=[C:19]([S:21][CH3:22])[S:20][C:16]=5[CH:15]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)=[N:4]1
Reactant: O=C([O-])[O-]
Reactant: CSc1nc2ccc(Cn3cnc4cc(-c5nn[nH]n5)ccc43)cc2s1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1nc2ccc(Cn3cnc4cc(-c5nnn(C)n5)ccc43)cc2s1
Temperature: 60 °C
Reaction time: 4 h
Yield: 38.5 %

Procedure:
To a stirred mixture of 6-((5-(2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (796 mg, 2.1 mmol), Cs2CO3 (673 mg, 2.1 mmol), and DMF (10 mL) was added iodomethane (129 μL, 2.1 mmol). The mixture was heated at 60° C. for 6 h. Additional iodomethane (30 μL, 0.5 mmol) was added and the mixture was stirred at 60° C. for an additional 4 h. The mixture was cooled to rt and partitioned between EtOAc (200 mL) and 0.5 M aq Na2CO3 (100 mL). The organic layer was separated and washed with brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with 2% MeOH in CH2Cl2, to afford 6-((5-(2-methyl-2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (318 mg, 39%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (500 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.31 (s, 1H), 8.03 (s, 1H), 7.93 (dd, J=1.0, 8.4 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.46 (dd, J=1.2, 8.4 Hz, 1H), 5.66 (s, 2H), 4.41 (s, 3H), 2.76 (s, 3H); LCMS (ESI) m/z 394 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C([O:45][C:46](=[O:49])[CH2:47]Br)C.COC(C)(C)C>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:1]([O:8][C@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][CH:10]1[O:11][CH2:47][C:46]([OH:49])=[O:45])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: O=C(O)COC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture that consists of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-mannopyranose, 1.7 g (5 mmol) of tetrabutylammonium hydrogen sulfate and 24 g (600 mmol) of fine-powder sodium hydroxide in 350 ml of toluene is cooled to 0° C. At 0° C., 29.3 g (150 mmol) of bromoacetic acid ethyl ester is added in drops over 10 minutes while being stirred vigorously. It is stirred for one hour at 0° C. 250 ml of MTB (methyl-tert-butyl ether) is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of ethanol/50 ml of water. 60 ml of 50% aqueous sodium hydroxide solution is added, and it is refluxed for four hours. It is cooled to 0° C., set at pH 8 with 10% aqueous hydrochloric acid, and the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water and 500 ml of ethyl acetate, and the pH of the aqueous phase is set at 2 while being stirred (10% aqueous hydrochloric acid). The organic phase is separated, and the aqueous phase is extracted once more with 200 ml of ethyl acetate. The combined organic phases are dried on magnesium sulfate, the solvent is distilled off in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are evaporated, dissolved in 400 ml of ethyl acetate, and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([S:9]([CH3:12])(=[O:11])=[O:10])[CH2:5][CH2:4]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]2[C@:22]3([C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:31])[CH2:21]2)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C@H:20]2[C@@:22]3([C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH2:2][CH:3]4[CH2:8][CH2:7][N:6]([S:9]([CH3:12])(=[O:11])=[O:10])[CH2:5][CH2:4]4)[C:23]3=[O:31])[CH2:21]2)=[CH:18][CH:19]=1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Reactant: CS(=O)(=O)N1CCC(CCl)CC1
Product: CS(=O)(=O)N1CCC(CN2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)CC1

Procedure:
The title compound was prepared in analogy to Example 70 starting from 4-chloromethyl-1-methanesulfonyl-piperidine (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C23H25ClN2O35: 444, observed (M+H)+: 445.1 1HNMR (400 MHz, DMSO-d6) δppm 1.23-1.41 (m, 2 H) 1.66-1.78 (m, 2 H) 1.84-1.98 (m, 1 H) 2.02 (dd, J=9.09, 4.80 Hz, 1 H) 2.30 (dd, J=7.71, 4.67 Hz, 1 H) 2.67 (t, J=11.75 Hz, 2 H) 2.83 (s, 3 H) 3.11 (t, J=8.46 Hz, 1 H) 3.56 (d, J=12.13 Hz, 2 H) 3.71 (d, J=7.33 Hz, 2 H) 6.12 (d, J=7.33 Hz, 1 H) 6.66-6.80 (m, 1 H) 7.10-7.20 (m, 2 H) 7.25-7.34 (m, 2 H) 7.34-7.43 (m, 2 H).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][O:27][Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C=O)C.[CH2:43](Br)[C:44]#[CH:45]>CCOCC>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:45][C:44]#[CH:43])[C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][O:27][Si:28]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:35]([CH3:37])[CH3:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CCBr
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CO[Si](C(C)C)(C(C)C)C(C)C)[nH]c2c1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C#CCn1c(-c2ccccc2CO[Si](C(C)C)(C(C)C)C(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To an ice cooled solution of methyl 3-cyclohexyl-2-(2-{[(triisopropylsilyl)oxy]methyl}phenyl)-1H-indole-6-carboxylate in DMF (0.13 M) NaH (2 eq.) was added. After 20 min. propargyl bromide (80% solution in toluene) (1.5 eq.) was added and the mixture stirred at 0° C. for 1 h, diluted with Et2O, washed with sat aq. NH4Cl and brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The residual material was subjected to flash chromatography (PE:EtOAc, 20:1). After evaporation of the solvents the product was obtained as yellow oil (67%). MS (ES+): 558.7 (M+H+).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1>>[OH:38][C:36]([CH3:39])([CH3:37])[CH2:35][N:32]1[CH:33]=[CH:34][C:30]([NH:29][C:8](=[O:10])[CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[CH2:6][CH2:1][CH2:5][CH2:4][CH2:3][CH3:2])=[N:31]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc3ccccc23)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CCCCCCC(C(=O)Nc1ccn(CC(C)(C)O)n1)n1ncc(Oc2cccc3ccccc23)cc1=O
Yield: 11 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(naphthalen-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 38) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(naphthalen-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-octanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide as a white solid (0.15 g, 11%); ES+-HRMS m/e calcd for C29H33N5O4 [M+H+] 516.2606 found 516.2604. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.10-1.20 (br.s., 7H), 1.22-1.83 (m, 8H), 1.93 (m, 1H), 2.29 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.45 (m, 1H), 5.63 (s, 1H), 6.40 (s, 1H), 7.44-7.74 (m, 5H), 7.87-8.16 (m, 3H), 8.29 (s, 1H), 10.79 (s, 1H).