Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]=1[O:14][CH3:15])[CH2:10][C:9]([CH3:22])=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.C1COCC1.[Cl:33][Si:34](Cl)([CH3:36])[CH3:35]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]2[C:11]([CH:10]=[C:9]([CH3:22])[CH:8]2[Si:34]([Cl:33])([CH3:36])[CH3:35])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]=1[O:14][CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(Cl)Cl
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)CC(C)=C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)C=C(C)C2[Si](C)(C)Cl
Temperature: -20 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a solution of 16.2 g (55.4 mmol) of 5-tert-butyl-6-methoxy-2-methyl-7-phenyl-1H-indene in 300 ml of toluene, 22.2 ml (55.5 mmol) of 2.5 M nBuLi in hexanes was added at room temperature. The resulting viscous solution was stirred for 2 h, and then 15 ml of THF was added. The formed suspension was stirred for 12 h at room temperature, ca. 2 h at 60° C., then cooled to −20° C., and 35.8 g (277 mmol) of dichlorodimethylsilane was added in one portion. The resulting solution was warmed to 60° C. and stirred for 1 h at this temperature. The resulting mixture was evaporated to ca. ½ of its volume, then filtered through glass frit (G3). The precipitate was additionally washed by 20 ml of toluene. The combined filtrate was evaporated to dryness to give 21.2 g (99%) of viscous yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:19].[OH-].[Na+]>>[Cl:19][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([Cl:1])[C:11]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:10][C:5]=2[N:6]=1
Reactant: O=c1[nH]c2cc(Cl)c(OC(F)(F)F)cc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)Oc1cc2nc(Cl)[nH]c2cc1Cl
Temperature: 25 °C
Yield: 96 %

Procedure:
Thoroughly dried 5-chloro-6-trifluoromethoxy-1,3-dihydro-benzoimidazol-2-one (154.6 g, 0.61 mol, 1.0 equiv.) was suspended in POCl3 (450 mL, 8.0 equiv.). The reaction solution was heated to reflux temperature for 6 hours and cooled to room temperature. The solution was poured into crushed ice/water (˜3 L) slowly with sufficient stirring. The solution was neutralized to pH=6.0 with NaOH. The precipitated solid was collected by filtration, washed with water, and dried to afford the title compound (159.97 g, 96%). The crude product was used in the following reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH:10]3[CH2:19][CH2:18][CH2:17][CH:16]4[C:11]3([CH2:12][CH2:13][NH:14][CH2:15]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:20](Br)[CH:21]=[CH2:22].C(=O)([O-])[O-].[K+].[K+]>>[CH2:22]([N:14]1[CH2:13][CH2:12][C:11]23[C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=4[O:9][CH:10]2[CH2:19][CH2:18][CH2:17][CH:16]3[CH2:15]1)[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: COc1cccc2c1OC1CCCC3CNCCC231
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCN1CCC23c4cccc(OC)c4OC2CCCC3C1

Procedure:
Thus, 9-methoxy-2,3,4,4a,5,6,7,7a-octahydro-1H-benzo[4,5]furo[3,2-e]isoquinoline, when treated with allyl bromide in the presence of a base such as potassium carbonate, gives 3-allyl-9-methoxy-2,3,4,4a,5,6,7,7a-octahydro-1H-benzo[4,5]furo[3,2-e]isoquinoline (R1 =CH2CH=CH2 ; R2 =MeO; R3, R4, R5 =H). Also, thienyl or furyl carbonyl chlorides followed by reduction with lithium aluminum hydride give 3-(2-thienylmethyl or 2-furylmethyl-9-methoxy-2,3,4,4a,5,6,7,7a-octahydro-1H-benzo[4,5]furo[3,2-e]isoquinoline ##STR81##
Reaction SMILES: [CH3:1][C@:2]1([NH:34]C(=O)OC(C)(C)C)[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[C:24]([O:32][CH3:33])[CH:25]=[C:26]([F:31])[CH:27]=5)[N:22]=4)=[N:19][N:20]=3)[CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:3]1.Cl>C(Cl)Cl.O1CCOCC1>[CH3:1][C@:2]1([NH2:34])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[C:24]([O:32][CH3:33])[CH:25]=[C:26]([F:31])[CH:27]=5)[N:22]=4)=[N:19][N:20]=3)[CH:17]=2)[C:8]([F:10])([F:9])[F:11])[CH2:3]1
Reactant: COc1cc(F)cc2ccc(-c3nnc4ccc([C@H](N5CC[C@](C)(NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(F)cc2ccc(-c3nnc4ccc([C@H](N5CC[C@](C)(N)C5)C(F)(F)F)cn34)nc12
Reaction time: 2.5 h
Yield: 92.4 %

Procedure:
To a solution of tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(3-(6-fluoro-8-methoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.900 g, 1.57 mmol) in DCM (8 mL) was added 4M HCl in dioxane (2 mL) and the reaction stirred for 2.5 hours. The reaction was diluted DCM (100 mL) and washed with saturated Na2CO3 (25 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by normal phase chromatography (5% [10% NH4OH]/DCM) to give (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(3-(6-fluoro-8-methoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-amine (0.690 g, 1.45 mmol, 92.8% yield) MS APCI (+) m/z 475 (M+1) detected.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:3][CH2:2]1.[O:22]1[CH2:25][C:24](=O)[CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]1([N:4]([CH:24]2[CH2:25][O:22][CH2:23]2)[CH2:5][CH2:6][CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1ccc(NCCCNC2CC2)c([N+](=O)[O-])c1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(NCCCN(C2CC2)C2COC2)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 308A (314 mg) in dichloromethane (5 mL) was added oxetan-3-one (72 mg) followed by sodium triacetoxyborohydride (318 mg). The mixture was stirred overnight. The mixture was diluted with dichloromethane (300 mL) and washed with aqueous NaHCO3, water and brine and dried over Na2SO4. After filtration, evaporation of the solvent gave the crude title compound.
Reaction SMILES: [BrH:1].[CH3:2][C:3]1[N:4]=[C:5]2[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][N:6]2[CH:14]=1.[H][H]>CO.[Pd]>[BrH:1].[NH2:11][C:10]1[C:5]2[N:6]([CH:14]=[C:3]([CH3:2])[N:4]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: Cc1cn2cccc([N+](=O)[O-])c2n1
Agent: [Pd]
Agent: Br
Solvent: CO
Product: Cc1cn2cccc(N)c2n1

Procedure:
A solution of 16.5 g 2-methyl-8-nitro-imidazo[1,2-a]pyridine-hydrobromide in 800 ml methanol is saturated with hydrogen at room temperature at low pressure for 8 hours after addition of a catalytic amount of commercial Pd/C-catalyst. The catalyst is then filtered off and the filtrate evaporated until dry. After recrystallization from acetronitrile 11.9 g of the title compound of m.p. 237°-238° C. is obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].[N:13]1([C:18]2[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[N:14]1>>[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:22][C:21]1[CH:20]=[CH:19][C:18]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:25][CH:24]=1
Reactant: COC(=O)CCCCCCN
Reactant: O=Cc1ccc(-n2cccn2)cc1
Agent: Cl
Product: COC(=O)CCCCCCNCc1ccc(-n2cccn2)cc1

Procedure:
The title compound of Step A was prepared from 7-amino-heptanoic acid methyl ester hydrochloride, of Preparation 1, and 4-pyrazol-1-yl-benzaldehyde, of Preparation 42, using the method described in Example 1, Step A. 1H NMR (400 MHz, CDCl3) δ 7.90 (m, 1H), 7.70 (d, 1H), 7.63 (d, 2H), 7.39 (d, 2H), 6.45 (m, 1H), 3.80 (s, 2H), 3.65 (s, 3H), 2.61 (t, 2H), 2.29 (t, 2H), 1.63-1.32 (m, 4H), 1.25 (m, 4H); MS 316 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[CH:36]=2)[CH:30]=1)=[O:28])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-ethoxy-phenyl)-carbamic acid tert-butyl ester (Example J25) (215 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (280 mg, 71%).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:17]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:20]=[C:19]([S:28][CH3:29])[N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:4]([O:3][C:1]([NH:8][C:9]1[CH:10]=[C:11]([NH:15][C:21]2[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][N:18]=[C:19]([S:28][CH3:29])[N:20]=2)[CH:12]=[CH:13][CH:14]=1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(SC)nc1Nc1cccc(NC(=O)OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A mixture of N-Boc-m-phenylenediamine (50a, prepared according to the procedures reported in: Duceppe, J.-S. et al. Org. Process. Res. Dev. 2009, 13, 1156-1160) (280 g, 1.35 mol) and ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (Sigma-Aldrich; 303.7 g, 1.32 mol) in DMF (200 mL) at RT was treated with K2CO3 (361 g, 2.6 mol). The mixture was stirred at 80° C. in an oil bath overnight. It was cooled to RT and treated with ice water. The resulting white suspension was filtered and washed with water. The white solid was collected and dried to afford crude ethyl 4-((3-((tert-butoxycarbonyl)amino)phenyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (50c) (450 g, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.44 (s, 1H), 8.72 (s, 1H), 7.90 (s, 1H), 7.35-7.33 (m, 1H), 7.28-7.24 (m, 1H), 7.14-7.12 (m, 1H), 4.38-4.33 (q, 2H), 2.51 (s, 3H), 1.48 (s, 9H), 1.35 (t, 3H). m/z (ESI, +ve ion) 405.0 (M+1)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[C:16]([C:20]1[CH:33]=[CH:32][C:23]([CH2:24][N:25]2[CH2:29][CH2:28]OS2(=O)=O)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([CH2:24][NH:25][CH2:29][CH2:28][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]3[CH2:10][CH2:9]3)[CH:3]=2)=[CH:32][CH:33]=1)([CH3:18])([CH3:17])[CH3:19]
Reactant: Brc1cccc(C2CC2)c1
Reactant: CC(C)(C)c1ccc(CN2CCOS2(=O)=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CNCCc2cccc(C3CC3)c2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
To a solution of m-bromophenylcyclopropane (synthesized as described in J. Org. Chem. 1976, 41, 2262-2266) (100 mg, 0.51 mmol) in dry THF (3 ml) at −78° C. was added nBuLi (317 μl, 1.6M solution in hexane, 0.51 mmol) dropwise. The reaction mixture was stirred at −78° C. for 10 min and then a solution of 3-(4-tert-butylbenzyl)-[1,2,3]oxathiazolidine 2,2-dioxide (109 mg, 0.41 mmol) in THF (1 ml) was added dropwise. The reaction mixture was warmed to 0° C. over 3 hours and then quenched with 5 ml 20% (v/v) H2SO4. The reaction mixture was warmed to 60° C. overnight and then cooled to RT and poured into water. The aqueous phase was made basic with 1N NaOH and then extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography to give (4-tert-butylbenzyl)-[2-(3-cyclopropylphenyl)-ethyl]-amine (72 mg, 58%) as a colorless oil. MS (ISP) 308.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:9]=1)[CH:7]=O.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1.N1CCCC1>CO>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21](=[CH:7][C:6]3[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1cc(Cl)ccc1OCC(F)(F)F
Solvent: CO
Solvent: C1CCNC1
Product: O=C1Nc2cc(Cl)ccc2C1=Cc1cc(Cl)ccc1OCC(F)(F)F
Temperature: 70 °C
Yield: 71.7 %

Procedure:
5-Chloro-2-(2,2,2-trifluoro-ethoxy)-benzaldehyde (4 g, 16 mmol) and 6-chlorooxindole (2.8 g, 16 mmol) were mixed in anhydrous methanol (20 mL). Then pyrrolidine (1.32 mL, 16 mmol) was added slowly at r.t. The mixture was heated to 70° C. for 3 h and cooled to room temperature. The precipitate was collected by filtration to give title compound as a yellow solid (Yield: 4.45 g, 72%).
Reaction SMILES: C([N:3](CC)CC)C.C(OC(Cl)=O)C(C)C.[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][O:28][CH3:29])[CH:23]=[CH:22][C:21]=1[CH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([OH:38])=O)[CH2:31]1.N>O1CCCC1>[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][O:28][CH3:29])[CH:23]=[CH:22][C:21]=1[CH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([NH2:3])=[O:38])[CH2:31]1
Reactant: COCOc1ccc(C2CCCC(C(=O)O)C2)c(OCOC)c1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: COCOc1ccc(C2CCCC(C(N)=O)C2)c(OCOC)c1
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Triethylamine (16 μl) and isobutylchloroformate (14 μl) were added to a stirred solution of (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexanecarboxylic acid in anhydrous tetrahydrofuran (2 ml) at 0° C. under argon. After 30 min, aqueous ammonia solution (0.5 ml, 28% w/w) was added. The reaction mixture was partitioned between water (20 ml) and ethyl acetate (50 ml). The aqueous layer was extracted with ethyl acetate (2×20 ml) and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give the title compound (26 mg, 87%) as a mixture of diastereoisomers; m/z (ES+) 324 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C@@H:13]2[CH2:15][C@@H:14]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]1=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].C(O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C@@H:13]2[CH2:15][C@@H:14]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@H]1C1CCN(Cc2ccccc2)C1=S
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@H]1C[C@H]1C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To 50 ml of an ethanol solution of 1.19 g (3.59 mmol) of 1-benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine-2-thione (isomer B) was added 10 ml of Raney nickel, followed by stirring at room temperature for 30 minutes. The insoluble matter was filtered off, and the solvent was evaporated under reduced pressure. Chloroform was added to the residue, and the mixture was washed with 10% aqueous ammonia. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 929.0 mg (85.8%) of the title compound as a pale yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([C:25]3[N:26]=[N:27][NH:28][N:29]=3)[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]4[N:26]=[N:27][NH:28][N:29]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c(-c3nn[nH]n3)cccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cccc(-c3nn[nH]n3)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-(2H-tetrazol-5-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([C@H:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][C@@H:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=[CH2:3].I[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][OH:39])=[CH:32][CH:31]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:11]([O:10][C:8]([NH:7][C@H:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5][C@H:4]([CH2:1]/[CH:2]=[CH:3]/[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][OH:39])=[CH:32][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: C=CC[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: OCCCc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](C/C=C/c1ccc(CCCO)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of di-tert-butyl (4S)-4-allyl-N-(tert-butoxycarbonyl)-L-glutamate (940 mg, 2.53 mmol) in 5 mL acetonitrile under an argon atmosphere was added 3-(4-iodophenyl)propan-1-ol (740 mg, 2.82 mmol), triethylamine (394 μl, 2.82 mmol), and palladium(II) acetate (106 mg, 0.47 mmol). The mixture was stirred in a pressure tube at 80° C. for 2 h. After cooling to room temperature, the solvent was removed under reduced pressure and the crude material was purified on silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7]([CH3:13])([CH3:12])[CH:8]=[CH:9]2)=[CH:4][CH:3]=1.[Cu][C:15]#[N:16].C(N)CN>CN1CCCC1=O>[C:15]([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7]([CH3:13])([CH3:12])[CH:8]=[CH:9]2)=[CH:4][CH:3]=1)#[N:16]
Reactant: N#C[Cu]
Reactant: CC1(C)C=Cc2cc(Br)ccc2C1
Solvent: NCCN
Solvent: CN1CCCC1=O
Product: CC1(C)C=Cc2cc(C#N)ccc2C1
Yield: 96 %

Procedure:
A solution of 7-bromo-3,3-dimethyl-3,4-dihydronaphthalene (6.2 g) and copper (1) cyanide (3.5 g) in N-methylpyrrolidone (60 ml) was heated under reflux for 2 hours. After cooling, the mixture was poured into 10% aqueous ethylenediamine (200 ml) and extracted into ethyl acetate. The combined extracts were washed with water, and dried over magnesium sulphate. Solvent and drying agent were removed and the residue chromatographed on silica gel using ether-pentane (1:10) as eluant gave the dihydronaphthalene as a white crystalline solid (4.6 g), having mp 50°-52° C.;
Reaction SMILES: CS(O)(=O)=O.[CH3:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=[O:13].[N-:14]=[N+]=[N-].[Na+]>COCCOC>[CH3:6][CH:7]1[NH:14][C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC1CCCCC1=O
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: COCCOC
Product: CC1CCCCC(=O)N1
Temperature: 23 °C
Reaction time: 20 h

Procedure:
Methanesulfonic acid (15 mL) was added to a solution of 2-methylcyclohexanone (2-1, 6.00 g, 53.5 mmol, 1 equiv) in DME (20 mL) at −40° C. Sodium azide (8.69 g, 134 mmol, 2.50 equiv) was added in four equal portions over 1 h as cooling was maintained. The cold bath was then removed and the reaction mixture was warmed to 23° C. and stirred for 20 h. The mixture was diluted with DME (20 mL) and basified to pH 9 with concentrated aqueous ammonium hydroxide solution. The resulting mixture was partitioned between brine (200 mL) and ethyl actetate (4×200 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 7-methylazepan-2-one (2-2) as a pasty white solid. 1H NMR (300 MHz, CDCl3) δ 5.50 (br s, 1H), 3.50 (m, 1H), 2.43 (m, 2H), 2.05-1.30 (m, 6H), 1.21 (d, 3H,J=7.1 Hz).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].[CH2:6](Br)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].C(N(CC)CC)C>C(OCC)(=O)C>[O:8]=[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][O:4][C:1](=[O:5])[CH2:2][OH:3]
Reactant: O=C(O)CO
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CO)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 61 %

Procedure:
A mixture of 7.61 g of glycolic acid, 19.90 g of phenacylbromide and 13.9 ml of triethylamine in 300 ml of ethyl acetate was stirred for 20 hours at room temperature. Then, the mixture was filtered. The filtrate was washed with 2N HCl, saturated sodium bicarbonate, and brine. Then, the filtrate was dried, filtered again, and evaporated to dryness. The resulting white solid was purified by recrystallization to yield 11.85 g of colorless crystals.
Reaction SMILES: ClC(Cl)C.[CH3:5][O:6][C:7]1[CH:44]=[CH:43][C:10]([CH2:11][N:12]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:13]2[N:18]=[CH:17][C:16]([C:19]3[C:20]4[CH2:33][CH2:32][NH:31][C:21]=4[N:22]=[C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:24]=3)=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[I:45][C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([N:52]=[C:53]=[O:54])[CH:47]=1>CN(C1C=CN=CC=1)C.ClCCl>[I:45][C:46]1[CH:47]=[C:48]([NH:52][C:53]([N:31]2[C:21]3[N:22]=[C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:24]=[C:19]([C:16]4[CH:15]=[N:14][C:13]([N:12]([CH2:11][C:10]5[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:44][CH:43]=5)[CH2:34][C:35]5[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=5)=[N:18][CH:17]=4)[C:20]=3[CH2:33][CH2:32]2)=[O:54])[CH:49]=[CH:50][CH:51]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: O=C=Nc1cccc(I)c1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)Nc3cccc(I)c3)cn2)cc1
Temperature: 25 °C

Procedure:
To a dichloroethane solution (10 ml) of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (540 mg), DMAP (12.2 mg) and 1-iodo-3-isocyanato-benzene (490 mg) were added, followed by refluxing for 17 hours. This was cooled to room temperature, and dichloromethane (40 ml) was added. After washing with saturated aqueous ammonium chloride solution (30 ml), the organic layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off under reduced pressure, followed by silica gel column chromatography (hexane/dichloromethane/ethyl acetate=4/4/1 to 1/2/1), to obtain the desired compound as a crude product (404 mg, 51%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Cl)[N:19]=1>C1COCC1>[Cl:17][C:18]1[N:19]=[C:20]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Cl)n2)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
To a stirred solution of 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.63 g, 8.1 mmol) in THF (20 mL), NaH (0.40 g, 10.1 mmol)) was added and stirred at 60° C. for 0.5 h. 2,6-dichloropyridine (1.0 g, 6.75 mmol) was added and stirred at room temperature for 3-4-h. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was concentrated in vacuo and the resultant residue was purified by flash column chromatography to yield tert-butyl 4-((6-chloropyridin-2-yl)oxy)piperidine-1-carboxylate as a pale yellow solid (0.98 g, 48%); MS: 335.1 (M+23)