Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>C(OCC)(=O)C>[O:25]([C:2]1[C:3]2[N:10]([CH2:11][CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(Cn1ccc2ncnc(Cl)c21)OCC
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(Cn1ccc2ncnc(Oc3ccccc3)c21)OCC
Temperature: 140 °C
Yield: 94.7 %

Procedure:
A mixture of 4-chloro-5-(2,2-diethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine (1 g), phenol (420 mg), potassium carbonate (617 mg) and 1-methyl-2-pyrrolidone (6.74 mL) was stirred with heating at 140° C. for 6 hrs. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with water (80 mL). The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→40/60) to give the title compound (1.15 g) as a yellow oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH:8]([C:31]([O:33]CC1C=CC=CC=1)=[O:32])[CH2:9][C@@H:10]([C:21]([O:23]CC1C=CC=CC=1)=[O:22])[NH:11][C:12](=[O:20])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][CH2:6][Cl:7]>CN(C=O)C.[Pd]>[Cl:1][CH2:2][CH2:3][N:4]([CH:8]([C:31]([OH:33])=[O:32])[CH2:9][C@@H:10]([C:21]([OH:23])=[O:22])[NH:11][C:12](=[O:20])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][CH2:6][Cl:7]
Reactant: O=C(Nc1ccccc1)N[C@@H](CC(C(=O)OCc1ccccc1)N(CCCl)CCCl)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)N[C@@H](CC(C(=O)O)N(CCCl)CCCl)C(=O)O

Procedure:
A solution of the intermediate dibenzyl 4-[N,N-bis(2-chloroethyl)amino]-phenylcarbamoyl-L-glutamate (1.138 g) in DMF (15 ml) was hydrogenated over 10% Pd/C for 16 hours. After filtration and evaporation in vacuo, the residue was dissolved in CHCl3 (20 ml). After 18 hours the crystalline precipitate was filtered off and dried in vacuo to obtain 4-[N,N-bis-(2-chloroethyl)amino]phenylcarbamoyl-L-glutamic acid. Yield, 730 mg (93%). After recrystallisation from acetone/CHCl3 microscopic rods formed m.p. 116°-118° C. NMR (CD3COCD3): δ8.0(s)1H; 7.2(d)2H; 6.6(d)2H; 6.2(d)2H NH; 4.4(m)1H; 3.6(m)8H; 2.5-1.9(m)4H.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.C([Li])CCC.[CH:30](=[O:32])[CH3:31]>C1COCC1>[CH2:16]([CH:15]([NH:14][C:11]1[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([O:6][C:5]2[C:21]([CH3:23])=[CH:22][C:2]([CH:30]([OH:32])[CH3:31])=[CH:3][C:4]=2[CH3:24])[C:12]=1[CH3:13])[CH2:18][CH3:19])[CH3:17]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C(C)O)cc2C)c1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butyllithium at −78° C. After stirring at −78° C. for 10 min, acetaldehyde was added and the resulting mixture was stirred at −78° C. for 30 min, the dry-ice bath was removed. After stirring for 5 min, the mixture was quenched with brine and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated to dryness. The residue was purified through silica gel chromatography to give the title compound. 1H NMR(CDCl3) d 7.06(s,2H), 4.84(m,1H), 6.08(s,1H), 3.73(d,1H), 3.35(m,1H), 2.14(s,3H), 2.12(s,3H), 2.11(s,6H), 1.4–1.7(m,4H), 1.51(d,3H), 0.96(t,6H) ppm.
Reaction SMILES: Cl.[C:2]([O:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[C:17]([O:21][C:22](=[O:33])[CH2:23][CH:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:25](O)=[O:26])([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C1COCC1>[CH2:31]([O:30][C:28](=[O:29])[CH:24]([C:25](=[O:26])[NH:7][O:6][C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:23][C:22]([O:21][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:33])[CH3:32]
Reactant: CC(C)(C)ON
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCOC(=O)C(CC(=O)OC(C)(C)C)C(=O)NOC(C)(C)C
Temperature: 0 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
To a stirring solution of O-tert-butyl hydroxylamine hydrochloride (3.67 g, 29.3 mmol) in dry THF (30 mL) at room temperature was added diisopropylethyl amine (3.60 g, 27.9 mmol). To the resulting mixture was transferred the compound of example 58 (6.87 g, 27.9 mmol), as a solution in dry THF (30 mL), followed by HOBt (5.35 g, 27.9 mmol). The mixture was cooled to 0° C. and EDC (5.35 g, 27.9 mmol) was added in one portion. The reaction mixture was then allowed to warm to room temperature and was stirred for 24 h. The solvent was evaporated and the residue was taken-up into 500 ml of ethyl acetate and subsequently washed with a 5% aqueous solution of KHSO4 (2×200 mL), with a 5% aqueous solution of NaHCO3 (2×200 mL), and finally with water. After drying (anhydrous MgSO4) and evaporation, the crude product was purified by flash chromatography (SiO2, 60% hexane-40% ethyl acetate) to afford 5.93 g (66.0% yield) of the desired product: 1H NMR (CDCl3, 400 MHz) 8.61 (s, 1H), 4.20 (q, 2H), 3.55 (t, 1H), 2.93 (d, 3H), 1.43 (s, 9H), 1.28 (s, 9H); 13C NMR (CDCl3, 400 MHz) 195.8, 171.2, 169.7, 83.1, 81.9, 62.4, 46.8, 34.1, 28.4, 26.6, 14.5.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.Cl.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH2:25][CH2:24][N:23]([CH2:3][C:4]3[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=3)[CH2:22][CH:21]=2)=[CH:16][CH:15]=1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Reactant: Cc1ncc(CCl)c(N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CC=C(c3ccc(F)cc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.8 %

Procedure:
A suspension of 27.2 g (0.14 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride, 29.8 g (0.14 mol) of 4-(4-fluoro-phenyl)-1,2,3,6-tetrahydropyridine hydrochloride and 42 g (0.30 mol) of dry potassium carbonate in 200 ml of dimethyl-formamide was stirred at room temperature for 18 hours. The mixture was suction filtered, the filter cake was washed with dichloromethane, the filtrate was completely freed from the solvents and the residue was crystallized twice from ethyl acetate/cyclohexane. 11.6 g (28%) of 5-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-2-methyl-pyrimidin-4-ylamine were obtained as yellowish crystals; m.p. 176°-178°.
Reaction SMILES: [OH:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([O-:23])=[O:22].Cl>CN(C)C1C=CN=CC=1.ClCCl>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([S:30]([O:1][C@H:2]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]([O:5][CH3:6])=[O:4])(=[O:32])=[O:31])=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: COC(=O)[C@H](O)c1ccccc1Cl
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](OS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
0.72 g (6 mmoles; 0.1 equivalent) of 4-dimethylaminopyridine, 12.0 g (60 mmoles; 1 equivalent) of methyl(R)-2-hydroxy-2(2-chlorophenyl)acetate and 7.8 g (78 mmoles; 1.3 equivalent) of triethylamine and 20 ml of dichloromethane were added to a dry reaction flask. The colorless solution obtained was cooled to 0° C. and then, operating at this temperature, 13.14 g (60 mmoles; 1 equivalent) of 4-nitrobenzenesulfonyl chloride as a solution in 30 ml of dichloromethane was added. The reaction mixture was stirred for 3 hours at 0° C. and 240 ml of 1N hydrochloric acid and 240 ml of dichloromethane was added drop wise, while stirring this mixture. After decanting, the dichloromethane phase is washed with dilute hydrochloric acid and then with water, before being concentrated under reduced pressure. An analytically pure sample is obtained after purifying on a silica column. In this manner, methyl(R)-2-(4-nitrophenylsulfonyloxy)-2(2-chlorophenyl)acetate is obtained: Yield: 98%. Optical purity: 99%.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([Cl:15])[CH:3]=1.[CH3:16][C:17]1(C)[C:21](C)(C)OB(C(C)=C)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:15][C:4]1[CH:3]=[C:2]([C:17]([CH3:21])=[CH2:16])[CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)c1ccc(C(=O)OC(C)(C)C)c(Cl)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a solution of tert-butyl 4-bromo-2-chlorobenzoate (1.0 g, 3.43 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (588 mg, 3.50 mmol) in 1,4-dioxane (40 mL) and water (10 mL) were added sodium carbonate (742 mg, 7.0 mmol) and tetrakis(triphenylphosphine)palladium (40 mg, 0.035 mmol). The resultant reaction mixture was stirred at 90° C. overnight under nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was concentrated. The residue was purified by pre-HPLC to get tert-butyl 2-chloro-4-(prop-1-en-2-yl)benzoate (800 mg, 92.3%) as a yellow oil. LRMS (M+H+) m/z: calcd 253.09. found 253.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][SH:25])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1>C(Cl)Cl>[ClH:10].[ClH:10].[CH:1]1([NH:7][C:8](=[SH:25][CH2:24][CH2:23][CH2:22][N:19]2[CH2:20][CH2:21][N:16]([CH2:15][C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:27][CH:26]=3)[CH2:17][CH2:18]2)[OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C=NC1CCCCC1
Solvent: ClCCl
Product: Cl
Product: OC(NC1CCCCC1)=[SH]CCCN1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
A mixture of 1.0 g of cyclohexyl isocyanate, 2.1 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol and 10 ml of methylene chloride was stirred at room temperature overnight and then concentrated in vacuo. The residue crystallized upon standing. The product was recrystallized from aqueous ethanol, dissolved in ether, and the ethanol solution was dried (magnesium sulfate). The salt was then precipitated with ethereal hydrochloric acid and recrystallized twice from aqueous ethanol to give 1.2 g (30% of theory) of N-cyclohexyl-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. >165° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]([CH3:13])[CH:11]=[N:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][N:24]1[CH2:29][CH2:28][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][NH:37][C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1.C(N(CC)CC)C>>[CH3:23][N:24]1[CH2:25][CH2:26][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][N:37]([C:20]([C:17]5[CH:18]=[CH:19][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[N:12]([CH3:13])[CH:11]=[N:10][CH:9]=7)=[CH:7][C:2]=6[CH3:1])=[CH:15][CH:16]=5)=[O:21])[C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:28][CH2:29]1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: Cc1cc(-c2cncn2C)ccc1-c1ccc(C(=O)O)cc1
Solvent: CCN(CC)CC
Product: Cc1cc(-c2cncn2C)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1
Reaction time: 18 h
Yield: 38.6 %

Procedure:
2'-Methyl-4'-(1-methylimidazol-5-yl)biphenyl-4-carboxylic acid (D93, 300 mg, 1.0 mmol) was heated at reflux in thionyl (15 ml) for 1 hour, cooled and evaporated in vacuo. The residue was redissolved in dry THF (10 ml) and treated with 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8, 250 mg, 1.0 mmol) and triethylamine (143 ul, 1.0 mmol) then stirred for 18 hours. The reaction mixture was evaporated in vacuo, partitioned between water and CHCl3 (3 times) and the organic extracts combined. The organics were dried over Na2SO4 and evaporated in vacuo to an orange gum. The gum was purified by flash silica gel chromatography (eluting with 3% MeOH/CHCl3) to yield the title compound as a pale yellow gum (200 mg, 38%) which was converted to the hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([C:17]4[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=4)[C:11]=3[C:10](=[O:23])[NH:9]2)=[CH:4][CH:3]=1.Cl[C:25]1[CH:26]=[C:27]([CH3:35])[C:28]2[N:29]([C:31]([CH3:34])=[N:32][N:33]=2)[N:30]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([C:17]4[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=4)[C:11]=3[C:10](=[O:23])[N:9]2[C:25]2[CH:26]=[C:27]([CH3:35])[C:28]3[N:29]([C:31]([CH3:34])=[N:32][N:33]=3)[N:30]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(Cl)nn2c(C)nnc12
Reactant: Cc1nn(-c2ccnn2C)c2c1C(c1ccc(Cl)cc1)NC2=O
Product: Cc1nn(-c2ccnn2C)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3n1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 110 using 4-(4-chlorophenyl)-3-methyl-1-(1-methyl-1H-pyrazol-5-yl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 114.2) and 6-chloro-3,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine (Step 111.2). The crude material was first purified by silica gel column chromatography (CH2Cl2/MeOH 1-5%), followed by preparative achiral SFC (column NH2, gradient 9-14% in 6 min_total 11 min) and trituration in Et2O. tR: 4.37 min (HPLC 1); tR: 1.01 min (LC-MS 2); ESI-MS: 474 [M+H]+ (LC-MS 2); ESI-MS: 472 [M−H]− (LC-MS 2); Rf=0.45 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.05 (s, 3H) 2.53 (s, 3H) 2.56 (s, 3H) 3.85 (s, 3H) 6.60 (s, 1H) 6.65 (d, J=2.0 Hz, 1H) 7.39 (d, J=8.2 Hz, 2H) 7.54-7.60 (m, 3H) 8.02-8.05 (m, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[NH2:33][C:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[O:36][C:35]=1[C:43]([NH:45][C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][N:47]=1)=[O:44]>ClCCl.O>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][C:16]([NH:33][C:34]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[O:36][C:35]=2[C:43]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][N:47]=2)=[O:44])=[O:18])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(C(=O)Nc2ccc(Cl)cn2)oc2ccccc12
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Yield: 260 %

Procedure:
t-Butyl 4-hydroxy-1-piperidinecarboxylate (175 mg) and triphosgene (90 mg) are dissolved in dichloromethane (5 ml), and thereto is added pyridine (77 μl) with stirring under ice-cooling. The reaction solution is stirred at room temperature for 3 hours, and then cooled again with ice. To the mixture is added 3-amino-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide (250 mg) obtained in Reference Example 74, and the mixture is stirred for several minutes. Pyridine (105 μl) is added to the mixture, and the mixture is stirred at room temperature for 3 hours. The reaction solution is poured into water, and the mixture is extracted with chloroform. The organic layer is washed successively with 5% aqueous citric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution and a saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1, then 5/1) to give the title compound (406 mg).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[C:12]2[O:11][CH:10]=[CH:9][C:8]=2[C:7]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[CH3:28][O:29][CH2:30][CH2:31][C:32](O)=[O:33]>>[F:3][C:4]1[C:12]2[O:11][CH:10]=[CH:9][C:8]=2[C:7]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]3[CH2:22][CH2:23][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH2:30][O:29][CH3:28])[CH2:25][CH2:26]3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3ccc(F)c4occc34)CC2)CC1
Reactant: COCCC(=O)O
Agent: Cl
Product: COCCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3ccc(F)c4occc34)CC2)CC1

Procedure:
The title compound, white solid (60 mg, 56%), MS (ISP) m/z=431.5 [(M+H)+], mp 177° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(7-fluoro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate C) (104 mg, 0.25 mmol) and 3-methoxypropionic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:12]([N:15]1[CH2:20][CH2:19][N:18]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:17][CH2:16]1)([CH3:14])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: CC(C)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 16 h
Yield: 90.6 %

Procedure:
A mixture of 4-nitrobenzylchloride (4.1 g, 23.90 mmol), N-isopropylpiperazine (3.6 g, 28.67 mmol, 1.2 equiv), potassium carbonate (6.5 g, 47.79 mmol, 2 equiv) and acetone (82 ml) was stirred for 16 h at reflux. The reaction mixture was allowed to cool, was then filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH+1% NH3aq, 9:1) to afford 5.7 g of the title compound: ESI-MS: 264.1 [M+H]+; TLC: tR=1.73 min (System 1); TLC: Rf=0.34 (DCM/MeOH+1% NH3aq, 9:1).
Reaction SMILES: Cl.[OH:2]C1N=CC(NC(C2C=CC=CN=2)=O)=CC=1.[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21].N12CCN(CC1)CC2.O>CN(C)C=O.ClCCl>[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](=[O:2])[OH:21]
Reactant: O=C(Nc1ccc(O)nc1)c1ccccn1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)O)c1ccccc1
Yield: 126.3 %

Procedure:
A solution of pyridine-2-carboxylic acid (6-hydroxy-pyridin-3-yl)-amide hydrochloride (0.50 g, 1.99 mmol), N-methyl-N-phenylcarbamoyl chloride (0.44 g, 2.59 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.54 g, 4.81 mmol) in dimethylformamide (15 mL) was stirred at room temperature for 1 hour. Water was added and the solids were isolated by suction, re-dissolved in dichloromethane. The solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 50:50) yielding the title compound (0.38 g, 55% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[N:8][C:6]=2[N:7]=1.[I:17]I.C[Si]([N-][Si](C)(C)C)(C)C.[K+].O>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:5]2[S:10][C:9]([I:17])=[N:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2scnc2n1
Reactant: II
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1nc(N2CCOCC2)c2sc(I)nc2n1
Temperature: -50 °C
Reaction time: 8 h

Procedure:
4-(5-Chlorothiazolo[4,5-d]pyrimidin-7-yl)morpholine 16 was dissolved in tetrahydrofuran and iodine (3 eq) was added. The solution was cooled to −50° C. and potassium bis(trimethylsilyl)amide (1.2 eq of 0.5M solution in toluene) was added over a period of 10 minutes. The solution was warmed to room temperature and stirred overnight. Water was added to quench the reaction and the tetrahydrofuran was removed in vacuo. The residue was brought up in methylene chloride, washed with saturated sodium bicarbonate solution and dried with magnesium sulfate. The solution was concentrated a purified by silica gel chromatography to yield 4-(5-chloro-2-iodothiazolo[4,5-d]pyrimidin-7-yl)morpholine 27.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[CH3:10][C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][C:12]=1[CH2:22][CH2:23]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:23][CH2:22][C:12]1[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:15][C:11]=1[CH3:10]
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: Cc1cccc(C)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(C)c1OCCc1nc(-c2ccccc2)oc1C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
1.1 g of 2,6-Dimethylphenol, 2.01 g of 2-(5-methyl-2-phenyl-oxazole-4yl)-ethanol 2.6 g of triphenylphosphin were dissolved in 30 ml THF and treated at 0° with 1.6 ml DEAD (Diethyl azodicarboxylate). The reaction mixture was kept overnight at RT. Water was added. Twofold extraction with AcOEt, washing with brine, drying over sodium sulfate, and evaporation of the solvents provided a crude product, which was purified by chromatography (SiO2; ether/cyclohexane) to yield 0.89 g of the title compound as a slightly yellow oil.
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][O:7]C2CCCCO2)=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]2[O:29][C:30]3[C:35]([Cl:36])=[CH:34][C:33]([S:37]([O-:39])=[O:38])=[CH:32][C:31]=3[C:25]=2[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[Li+]>>[Cl:36][C:35]1[C:30]2[O:29][C:26]3[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:22])[CH2:24][C:25]=3[C:31]=2[CH:32]=[C:33]([S:37]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][OH:7])=[CH:14][CH:15]=2)(=[O:39])=[O:38])[CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)[O-])cc3c2C1
Reactant: Ic1ccc(COC2CCCCO2)cc1
Agent: [Li+]
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)c4ccc(CO)cc4)cc3c2C1
Yield: 7 %

Procedure:
The product of step A was coupled with lithium 2-(tert-butoxycarbonyl)-6-chloro-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine-8-sulfinate following the procedure of Example 50, step A. The crude product was purified by flash column chromatography (SiO2, 7:3 hexanes/ethyl acetate) to give tert-butyl 6-chloro-8-((4-(hydroxymethyl)phenyl)sulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (30 mg, 7%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 8.02-7.89 (m, 3H), 7.82 (s, 1H), 7.53 (d, J=8.1 Hz, 2H), 4.77 (d, J=5.4 Hz, 2H), 4.56 (s, 2H), 3.83 (t, J=5.7 Hz, 2H), 2.97-2.85 (m, 2H) 1.50 (s, 9H).