Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH3:18][C:19]1[O:20][C:21]([CH3:27])=[CH:22][C:23]=1[C:24](O)=[O:25]>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:24]([C:23]3[CH:22]=[C:21]([CH3:27])[O:20][C:19]=3[CH3:18])=[O:25])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: Cc1cc(C(=O)O)c(C)o1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: Cc1cc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OC[C@@H]3F)c2)c(C)o1

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 2,5-dimethyl-furan-3-carboxylic acid (CAS 636-44-2) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=364.3 [M+H]*.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH:35]([CH3:37])[CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:38][O:39][C:40]1[CH:46]=[C:45]([CH2:47][CH2:48][N:49]2[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]2)[CH:44]=[CH:43][C:41]=1[NH2:42]>>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[CH:44][C:45]([CH2:47][CH2:48][N:49]4[CH2:50][CH2:51][N:52]([CH3:55])[CH2:53][CH2:54]4)=[CH:46][C:40]=3[O:39][CH3:38])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH:35]([CH3:37])[CH3:36]
Reactant: COc1cc(CCN2CCN(C)CC2)ccc1N
Reactant: CC(C)Oc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Product: COc1cc(CCN2CCN(C)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC(C)C)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Yield: 51 %

Procedure:
The title compound (0.092 g, 0.12 mmol, 51%) was prepared from 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-[(1-methylethyl)oxy]benzamide (Intermediate Example 7) and 2-(methyloxy)-4-[2-(4-methyl-1-piperazinyl)ethyl]aniline (Example 131, step D) in an analogous manner to that described for Example 26, step E. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (d, J=5.9 Hz, 6H), 2.13 (s, 3H), 2.26-2.35 (m, 3H), 2.38-2.45 (m, 3H), 2.52 (d, J=8.8 Hz, 4H), 2.66-2.75 (m, 2H), 3.82 (s, 3H), 4.82-4.91 (m, 1H), 6.63 (d, J=5.1 Hz, 1H), 6.76 (dd, J=8.3, 1.7 Hz, 1H), 6.92-7.03 (m, 2H), 7.19 (t, J=7.9 Hz, 2H), 7.30 (d, J=8.8 Hz, 1H), 7.34-7.40 (m, 1H), 7.44 (dd, J=8.4, 6.2 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.67-7.77 (m, 2H), 8.07 (d, J=2.2 Hz, 1H), 8.27 (d, J=5.1 Hz, 1H), 8.49 (s, 1H), 9.36 (d, J=6.2 Hz, 1H), 9.70 (s, 1H). MS (M+H, ES+) 733.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:12])[C:10]=1[CH3:11])[CH2:7][CH2:6][CH2:5]2.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC([N+](C(OCC)=O)=[N-])=O)C>ClCCCl>[OH:1][C:2]1[C:3]([C@@H:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:4]2[C:8](=[C:9]([CH3:12])[C:10]=1[CH3:11])[CH2:7][CH2:6][CH2:5]2
Reactant: Cc1c(O)cc2c(c1C)CCC2
Reactant: COC(=O)CCCCC[C@H](O)c1ccc(F)cc1
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(O)c(C)c(C)c2c1CCC2
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To a solution of 5-hydroxy-6,7-dimethylindan (0.96 g, 5.9 mmol), methyl (S)-7-(4-fluorophenyl)-7-hydroxyheptanoate (0.30 g, 1.2 mmol) and triphenylphosphine (0.46 g, 1.8 mmol) in 1,2-dichloroethane (15 ml) was added dropwise a solution of 95% diethyldiazodicarboxylate (DEAD) (0.33 ml) in 1,2-dichloroethane (3 ml) at 10° C. taking 30 minutes. The mixture was stirred for one hour at the same temperature range, then the solvent was distilled off under reduced pressure. The residue was subjected to a silica gel coluann chromatography to give 0.18 g of methyl (R)-7-(5-hydroxy-6,7-dimethylindan-4-yl)-7-(4-fluorophenyl)heptanoate. Likewise, Compound 1, 5-8 and 10-17 were prepared.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH2:14][CH2:15][C:16]([OH:18])=[O:17].Cl>CC(C)=O.[OH-].[Na+].O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1ccc(S(=O)(=O)NCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Ex-26A: To a solution of 4-acetylbenzenesulfonyl chloride (0.50 g, 2.3 mmol) in acetone (7.5 mL) was added a solution of glycine (0.42 g, 5.7 mmol) in 5% aqueous sodium hydroxide (2.5 mL) and the reaction was stirred for 30 min at room temperature. The mixture was diluted with water (10 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with brine (2×20 mL), dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting solid was dried in vacuo to afford 0.55 g (94%) of (4-acetylbenzenesulfonylamino)acetic acid as a white solid, mp 213–215° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.28 (t, 1H, J=5.4 Hz), 8.12 (d, 2H, J=8.4 Hz), 7.92 (d, 2H, J=8.4 Hz), 3.64 (d, 2H, J=5.1 Hz), 2.64 (s, 3H). Anal. Calcd. for C10H11NO5S: C, 46.69; H, 4.31; N, 5.44; S, 12.46; Found: C, 46.76; H, 4.43; N, 5.39; S, 12.16.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C([N:8]([C:23]([O:25][CH2:26]C1C=CC=CC=1)=O)[C:9]1[CH:10]=[C:11]([CH:15]=C(C2OC=CN=2)C=1)[C:12]([OH:14])=[O:13])C=C>O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:1]([NH:4][C:9]1[CH:10]=[C:11]([CH:15]=[C:23]([O:25][CH3:26])[N:8]=1)[C:12]([OH:14])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cc(C(=O)O)cc(-c2ncco2)c1
Reactant: C=CCN
Agent: [Cu+2]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: C=CCNc1cc(C(=O)O)cc(OC)n1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
A mixture of 3.97 ml (52 mmol, 10 eq) allylamine, 0.97 g (5.2 mmol, 1 eq) 2-chloro-6-methoxy-isonicotinic acid (see building block A3) and 1.29 g (5.2 mmol, 1 eq)-copper(II) sulfate pentahydrate in 10 ml water is heated in a closed vessel during 2.5 h at a bath temperature of 160° C. After cooling to rt the mixture is diluted with 400 ml aq 10% citric acid and extracted with EtOAc. The extracts are washed with water and brine, dried over sodium sulfate and the solvents are evaporated at reduced pressure. The residue is dissolved in about 20 ml hot DCM/MeOH (2/1). On addition of about 25 ml of hexane, partial evaporation of the solvents to a volume of about 20 ml and keeping at 4° C. for 4 h the product precipitates and is filtered off and dried in vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([S:15][CH3:16])[C:4]=1/[CH:17]=[C:18](\[CH3:24])/[C:19]([O:21]CC)=[O:20].COC1C2C(=CC=CC=2)C(OC)=CC=1/C=C(\C)/C(O)=O>CCOC(C)=O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([S:15][CH3:16])[C:4]=1/[CH:17]=[C:18](\[CH3:24])/[C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)/C(C)=C/c1c(SC)c(OC)c2ccccc2c1OC
Agent: COc1cc(/C=C(\C)C(=O)O)c(OC)c2ccccc12
Solvent: CCOC(C)=O
Product: COc1c(/C=C(\C)C(=O)O)c(SC)c(OC)c2ccccc12

Procedure:
Compound 99h was prepared from 98h (0.165 g, 0.476 mmol) as described above for 29a to give 0.181 g (0.568 mmol, 118%) of the product as a orange solid following flash chromatography (1:3 EtOAc:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](O)=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].C([N:38](CC)CC)C.O>C(#N)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:12])[NH2:38])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Reactant: CCN(CC)CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 92.2 %

Procedure:
188 mg (1.16 mmol) of N,N'-carbonyldiimidazole were added to a suspension of 381 mg (0.84 mmol) of N-(2-t-butyl-5-carboxyphenyl)-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Preparation 7) in 8 ml of acetonitrile, and the resulting mixture was stirred at room temperature for 40 minutes, after which 282 mg (4.18 mmol) of ammonium chloride and 0.59 ml (4.23 mmol) of triethylamine were added thereto. The reaction mixture was then stirred for 2 hours, after which water was added, and the aqueous mixture was freed from acetonitrile by distillation under reduced pressure. The resulting residue was extracted with ethyl acetate, and the extract was washed with 2 N aqueous hydrochloric acid, with a saturated aqueous solution of sodium hydrogencarbonate, with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 50 g of silica gel, using ethyl acetate as the eluent, to give 352 mg (yield 93%) of the title compound as crystals, melting at 151-152° C. (from a mixture of hexane and ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[C:11]([Cl:19])=[N:12][C:13]([S:17][CH3:18])=[N:14][C:15]=1[Cl:16])[OH:9]>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:11]([Cl:19])=[N:12][C:13]([S:17][CH3:18])=[N:14][C:15]=1[Cl:16])=[O:9]
Reactant: CSc1nc(Cl)c(C(O)c2ccccc2Cl)c(Cl)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CSc1nc(Cl)c(C(=O)c2ccccc2Cl)c(Cl)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 16.3 %

Procedure:
To a solution of (2-chlorophenyl)-(4,6-dichloro-2-methylsulfanylpyrimidin-5-yl)-methanol (8.6 g, 25.6 mmol) in toluene (300 mL) was added manganese (IV) oxide (Aldrich) (22.3 g, 10 eq), and the resulting mixture was heated to reflux with stirring for a total of 5 hours. The reaction was cooled to room temperature and then filtered through a 3.5 cm pad of Celite and the filtrate was concentrated to give 8.84 g of a crude product. Purification by Flash Column Chromatography on Silica Gel eluting with a gradient starting with pure hexanes and progressing to 2% ethyl acetate in hexanes and finally 5% ethyl acetate in hexanes gave the title compound as an off-white powder (1.388 g, (M+H)+=333).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][C:20]([CH2:29][CH2:30][OH:31])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:19][CH2:18]2)=[O:16])[C:12]([Cl:32])=[CH:11][C:10]=1[F:33])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(C)=O.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][C:20]([CH2:29][CH:30]=[O:31])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:19][CH2:18]2)=[O:16])[C:12]([Cl:32])=[CH:11][C:10]=1[F:33])(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1cc(C(=O)N2CCC(CCO)(c3ccccc3)OC2)c(Cl)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1cc(C(=O)N2CCC(CC=O)(c3ccccc3)OC2)c(Cl)cc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of N-(tert-butyl)-4-chloro-2-fluoro-5-{[6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-3-yl]carbonyl}benzenesulfonamide (25.2 mg, 0.05 mmol) in dimethyl sulfoxide (71 μL, 1 mmol), diisopropylethylamine (53 μL, 0.30 mmol) and 1 mL CH2Cl2 was added SO3.pyr in one portion. The reaction mixture was stirred for 2 h at 0° C., saturated aqueous NaHCO3 was added, and the aqueous layer was extracted with CHCl3. After evaporation, the resultant crude N-(tert-butyl)-4-chloro-2-fluoro-5-{[6-(2-oxoethyl)-6-phenyl-1,3-oxazinan-3-yl]carbonyl}benzenesulfonamide was obtained and used in the next step without further purification.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[OH:12][CH2:13][CH:14]([CH2:16]O)[OH:15].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CC1C=CC=CC=1.O>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)[O:15][CH:14]([CH2:13][OH:12])[CH2:16][O:4]1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: OCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: OCC1COC(CBr)(c2ccc(Cl)cc2)O1

Procedure:
A mixture of 2-bromo-1-(4-chlorophenyl)ethanone (1.47 mol), glycerine (3.5 mol) and 4-methylbenzenesulfonic acid (0.25 mol) in methylbenzene (3000 ml) was stirred and refluxed for 24 hours, using a water separator. The reaction mixture was poured out into an aqueous NaHCO3 solution and stirred for a while. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 485 g (93%; oil) of (cis +trans)-2-(bromomethyl)-2-(4-chlorophenyl)-1,3-dioxolane-4-methanol (interm. 8a).
Reaction SMILES: [C:1]1([C:10]#[N:11])[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.I[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:23][CH2:24][O:25][CH3:26])[CH:14]=1.C([O-])(=O)C.[K+].O>CN1CCCC1=O>[C:10]([C:1]1[CH:2]=[C:3]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:23][CH2:24][O:25][CH3:26])[CH:14]=2)[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2)#[N:11]
Reactant: COCOc1cc(I)ccc1C(=O)OC
Reactant: N#Cc1ccn2ccccc12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COCOc1cc(-c2cc(C#N)c3ccccn23)ccc1C(=O)OC
Temperature: 100 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
To a solution of indolizine-1-carbonitrile (0.20 g) in N-methylpyrrolidone (5 mL) were added methyl 4-iodo-2-methoxymethoxybenzoate (0.5 g), dichlorobis (triphenylphosphine) palladium (II) (0.05 g), potassium acetate (0.28 g) and water (0.05 mL), and the mixture was stirred at 100° C. for 1 hour. After cooling to room temperature, to the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=100/0-0/100) to give methyl 4-(1-cyanoindolizine-3-yl)-2-methoxymethoxybenzoate (0.17 g). To a mixed solution of the obtained compound (0.17 g) in tetrahydrofuran (4.5 mL), ethanol (1.5 mL) and water (1.5 mL) was added lithium hydroxide monohydrate (0.10 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/L hydrochloric acid (1.5 mL), and the mixture was stirred at 50° C. overnight. After cooling to room temperature, to the reaction mixture was added water. The precipitated solid was collected by filtration, washed with water and n-hexanc, and dried under reduced pressure at 50° C. to give the title compound (0.11 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21](O)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:47][C:48]1[N:53]=[CH:52][C:51]([CH2:54][NH2:55])=[CH:50][CH:49]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21]([NH:55][CH2:54][C:51]3[CH:52]=[N:53][C:48]([CH3:47])=[CH:49][CH:50]=3)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CN)cn1
Reactant: O=C(O)c1cc(C(=O)N2CCCC2)cc(-c2ccc(Br)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(CNC(=O)c2cc(C(=O)N3CCCC3)cc(-c3ccc(Br)cc3)c2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-bromo-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (1.65 g, 4.41 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.7 g, 8.8 mmol), 1-hydroxybenzotriazole hydrate (0.20 g, 1.3 mmol), and CH2Cl2 (50 mL) were added (6-methylpyridin-3-yl)methanamine (0.81 g, 6.6 mmol) and N,N-diisopropylethylamine (1.5 mL, 8.8 mmol). The mixture was stirred at room temperature overnight and then washed with water, dried (Na2SO4), and concentrated. The residue was purified by silica gel column (0-15% MeOH/CH2Cl2) and analytical sample was purified by preparative HPLC (100×20.2 mm, C18 column; 30-80% CH3CN-water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[O:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)COC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)COC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 64 %

Procedure:
A mixture of crude ethyl di-(4-chlorophenyl)methyloxyacetate (9 g.), sodium hydroxide (5 g.), ethanol (150 ml.) and water (5 ml.) was heated under reflux for 16 hours. The mixture was evaporated and the residue was diluted with water (100 ml.) and ether (30 ml.). The ether extracts were discarded and the aqueous phase was acidified to pH 2-3 with 20% v/v hydrochloric acid. The mixture was extracted with ether and the extracts were dried (MgSO4) and evaporated. The residual solid obtained was crystallised from a mixture of ethyl acetate and petrol to give di-(4-chlorophenyl)methyloxyacetic acid, m.p. 108°-110°, in 64% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[Br:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1>>[Br:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([O:23][C@@:9]2([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12][C@@H:13]3[C@H:8]2[CH2:7][CH2:6][N:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1ccc(Br)cc1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-brom-benzoic acid to yield (3aR,4S,7aR)-methyl 4-(4-bromobenzoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester elimination ion); RT=7.705 min; LC-MS Method II
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[C:3](O)=[O:4].O.[NH2:15][NH2:16]>CO.S(=O)(=O)(O)O>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[C:3]([NH:15][NH2:16])=[O:4]
Reactant: NN
Reactant: COc1ccc(C(O)C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COc1ccc(C(O)C(=O)NN)cc1
Reaction time: 1 h

Procedure:
To a solution of hydroxy-(4-methoxy-phenyl)-acetic acid (45 g, 0.25 mol) in 300 ml of methanol are added 30 drops of concentrated sulfuric acid at room temperature and the resulting mixture is heated to reflux for 4 hours. Subsequently the mixture is cooled and evaporated in vacuo. The remainder is taken up in water and extracted with ethyl acetate. The combined organic layer isn washed with brine, dried over magnesium sulfate and evaporated. The residue, which is hydroxy-(4-methoxy-phenyl)-acetic acid methyl ester, is dissolved in 350 ml of diethyl ether. Hydrazine monohydrate (47 ml, 0.95 mol) is added dropwise at room temperature and the mixture is stirred for 1 hour. The reaction mixture is poured on water and extracted with ethyl acetate. The combined organic layer is washed with brine, dried over magnesium sulfate and evaporated, the remaining hydroxy-(4-methoxy-phenyl)-acetic acid hydrazide is sufficiently pure to be used directly in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][CH:9]=[C:10]([CH:12]=[CH:13][CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)[N:11]=1>[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[N:11]=1
Reactant: O=C1c2ccccc2C(=O)N1CCC=Cc1csc(-c2ccccn2)n1
Agent: [Pd]
Product: NCCCCc1csc(-c2ccccn2)n1
Reaction time: 2 h
Yield: 135.8 %

Procedure:
Using the procedure of Stage B of Preparation 32, 7.22 g of the product of Stage F and 1.5 g of palladium on activated charcoal were hydrogenated for 2 hours under 1800 mbars to obtain 6.33 g of the expected product melting at 119-121° C.
Reaction SMILES: C(OC([N:8]1[C@@H:15]([C:16](=[O:32])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]3=[O:30])=[CH:20][C:19]=2[F:31])[C:14]2[CH:13]=[N:12][N:11]([CH3:33])[C:10]=2[CH2:9]1)=O)(C)(C)C.CCOC(C)=O>Cl.O1CCOCC1>[F:31][C:19]1[CH:20]=[C:21]([N:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]2=[O:30])[CH:22]=[CH:23][C:18]=1[NH:17][C:16]([C@H:15]1[C:14]2[CH:13]=[N:12][N:11]([CH3:33])[C:10]=2[CH2:9][NH:8]1)=[O:32]
Reactant: Cn1ncc2c1CN(C(=O)OC(C)(C)C)[C@H]2C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1ncc2c1CN[C@H]2C(=O)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
A solution of (R)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-1-methyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (258 mg) in 1 ml 4M HCl/dioxane was stirred 18 h at rt. The reaction mixture was portionned between AcOEt and 1M NaOH/ice. The organic layers were washed with brine, dried over magnesium sulfate and evaporated to deliver a white residue (115 mg) of the title compound. MS: 354.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[S:7])=[CH:4][CH:3]=1.[F:12][CH:13]([F:23])[O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[S:7][CH:17]([C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[O:14][CH:13]([F:12])[F:23])[NH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NNC(=S)c1ccc(Cl)cc1
Reactant: O=Cc1ccccc1OC(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)Oc1ccccc1C1NN=C(c2ccc(Cl)cc2)S1
Reaction time: 0.17 h

Procedure:
To a heterogeneous mixture of 4-chloro-thiobenzoic acid hydrazide (0.107 mmol) in CH2Cl2 (1 mL) is added 2-difluoromethoxy-benzaldehyde (0.128 mmol) and DIEA (0.128 mmol). After 10 minutes the mixture become homogenous and the reaction is complete by TLC and LCMS to give 5-(4-chloro-phenyl)-2-(2-difluoromethoxy-phenyl)-2,3-dihydro-[1,3,4]thiadiazole which is used in the next step without evaporation of the solvent.
Reaction SMILES: [C:1]([C:4](=[C:10](SCC1C=CC=CC=1)[S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].[CH3:27][NH:28][NH2:29]>C(#N)C>[CH3:27][N:28]1[C:10]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:1]([CH3:2])=[N:29]1
Reactant: CNN
Reactant: CCOC(=O)C(C(C)=O)=C(SCc1ccccc1)SCc1ccccc1
Solvent: CC#N
Product: CCOC(=O)c1c(C)nn(C)c1SCc1ccccc1
Yield: 77.2 %

Procedure:
In 60 ml of acetonitrile is dissolved 10.0 g of ethyl 2-acetyl-3,3-bis(benzylthio)acrylate. To the solution is added dropwise, while stirring at room temperature (15° C.), 1.2 g of methyl hydrazine over a period of 10 minutes, followed by heating for 3 hours under reflux. Then, the solvent is distilled off under reduced pressure. The residue is purified by means of silica gel column chromatography (eluent, n-hexane:ethyl acetate=8/1) to give 5.8 g of the title compound as white crystals, m.p. 55° to 56° C.