Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:32])=[CH:4][C:5]2[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[CH2:9][C:8]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:29]5[CH:28]=[CH:27][N:26]=[CH:25][C:24]=5[N:23]=[C:22]4[CH3:30])=[CH:17][CH:16]=3)=[N:7][C:6]=2[CH:31]=1.Cl.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]1[C:3]([CH3:32])=[CH:4][C:5]2[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[CH2:9][CH:8]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:29]5[CH:28]=[CH:27][N:26]=[CH:25][C:24]=5[N:23]=[C:22]4[CH3:30])=[CH:17][CH:16]=3)[NH:7][C:6]=2[CH:31]=1
Reactant: Cc1cc2c(cc1C)-n1ccnc1CC(c1ccc(-n3c(C)nc4cnccc43)cc1)=N2
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: ClCCl
Product: Cc1cc2c(cc1C)-n1ccnc1CC(c1ccc(-n3c(C)nc4cnccc43)cc1)N2
Reaction time: 16 h

Procedure:
A solution of 8,9-dimethyl-5-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-4H-imidazo[1,2-a][1,5]-benzodiazepine (100 mg, 0.24 mmol) in dichloromethane was stirred with an excess of ethereal hydrogen chloride until precipitation was complete. The solid was filtered and dissolved in dry methanol (5 ml) to which was added sodium cyanoborohydride (20 mg 0.32 mmol). After stirring for 16 hours, the solution was acidified with dilute hydrochloric acid then adjusted to pH 8 by addition of sodium bicarbonate solution. The mixture was extracted with ethyl acetate which was dried over magnesium sulphate. Evaporation left a colourless gum.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[C:5]#[N:6].Cl[Sn]Cl.[NH4+].[OH-]>C(O)(=O)C.Cl>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([NH2:10])=[C:2]([CH3:1])[CH:3]=1)#[N:6]
Reactant: Cc1cc(C#N)ccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1cc(C#N)ccc1N
Reaction time: 3 h
Yield: 90.7 %

Procedure:
4-Cyano-2-methylaniline was synthesized as previously described (J. Med. Chem. (1991), 34, 3295): To a solution of 3-methyl-4-nitrobenzonitrile (2.0 g, 12.34 mmol) in acetic acid (20 L) was added dropwise a solution of SnCl2 (9.6 g, 49.38 mmol) in conc. HCl (20 mL). After stirring for 3 h, the mixture was added carefully to a saturated NH4OH solution (120 mL) at 0° C. The resulting mixture was extracted with EtOAc (4×30 mL). The combined organic layers were sequentially washed with H2O (30 mL) and a saturated NaCl solution (30 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (10% EtOAc/hex) to give 4-cyano-2-methylaniline as a white solid (1.48 g, 92%): TLC (30% EtOAc in hexane) Rf0.23. This material was used without further purification.
Reaction SMILES: [S:1]1[C:5]2[C:6]([S:10]([OH:13])(=[O:12])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+].C[N:25]([CH3:28])[CH:26]=O>>[S:1]1[C:5]2[C:6]([S:10]([N:3]3[CH2:4][CH2:5][CH2:28][NH:25][CH2:26][CH2:2]3)(=[O:12])=[O:13])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=S(=O)(O)c1cccc2ncsc12
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: O=S(=O)(c1cccc2ncsc12)N1CCCNCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To 12 g of 7-benzothiazolesulfonic acid were added 120 ml of thionyl chloride and 1.2 ml of dimethylformamide. The resultant mixture was heated under reflux for 3 hours and the thionyl chloride was removed by distillation under reduced pressure to obtain a residue. The thus obtained residue was dissolved in 100 ml of ice water and adjusted to a pH of 6 with a saturated aqueous sodium carbonate solution. The resultant solution is subjected to extraction with 100 ml of dichloromethane, followed by separation of a dichloromethane phase. The dichloromethane phase was dropwise added to 100 ml of a dichloromethane solution containing 16.8 g of homopiperazine over 30 minutes while cooling with ice. The resultant mixture was stirred at a temperature of 0° C. to 5° C. for 1 hour to carry out a reaction. After completion of the reaction, the resultant mixture was washed with 200 ml of water and dried over anhydrous magnesium sulfate. Then, solvent removal was conducted by distillation under reduced pressure to obtain a residue. The thus obtained residue was subjected to purification by means of a chromatography column packed with 600 g of silica gel (Wakogel C-200, manufactured and sold by Wako Pure Chemical Industries, Ltd., Japan), using a mixed solvent of methanol and chloroform (5 to 10% methanol) as an eluent, to thereby obtain 10.8 g of 1-(7-benzothiazolesulfonyl)homopiperazine (yield: 65%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.[C:59]([N:66]1[CH2:71][CH2:70][CH:69]([NH2:72])[CH2:68][CH2:67]1)([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60]>CN(C=O)C.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([NH:72][CH:69]6[CH2:68][CH2:67][N:66]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:71][CH2:70]6)=[O:27])=[CH:28][CH:29]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(-c3ccc4nnn(Cc5ccc6ncccc6c5)c4n3)cc2)CC1
Reaction time: 0.08 h
Yield: 42.3 %

Procedure:
To a solution of example 8 (0.200 g, 0.524 mmol) in DMF (1 ml), HOBT (0.084 g, 0.629 mmol), EDC-HCl (0.250 g, 1.31 mmol) and triethylamine (0.2 ml, 1.57 mmol) were added and stirred for 5 min. 1-Boc-4-aminopiperidine (0.210 g, 1.04 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as an off-white solid (0.125 g, 42%). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.69 (d, J=8.7 Hz, 1H), 8.40 (d, J=7.8 Hz, 1H), 8.38 (d, J=8.5 Hz, 1H), 8.33 (d, J=8.5 Hz, 2H), 8.20 (d, J=8.7 Hz, 1H), 8.03-7.99 (m, 4H), 7.84 (dd, J=8.7, 1.8 Hz, 1H), 7.53 (dd, J=8.3, 4.1 Hz, 1H), 6.22 (s, 2H), 3.99 (m, 3H), 2.87 (m, 2H), (d, J=9.9 Hz, 2H), 1.45-1.37 (m, 11H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH:22]2[CH2:24][CH2:23]2)[C:9]2[N:10]=[CH:11][C:12]3[N:17]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]([F:38])([F:37])[O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:19]([NH:18][C:16]1[S:15][C:13]2[N:14]=[C:9]([N:8]([CH:22]3[CH2:24][CH2:23]3)[C:4]3[CH:3]=[C:2]([NH:1][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][CH:36]=[C:28]([O:27][C:26]([F:25])([F:37])[F:38])[CH:29]=4)[CH:7]=[CH:6][CH:5]=3)[N:10]=[CH:11][C:12]=2[N:17]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1nc2cnc(N(c3cccc(N)c3)C3CC3)nc2s1
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(N(c3cccc(NC(=O)c4cccc(OC(F)(F)F)c4)c3)C3CC3)nc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A solution of N-{5-[(3-aminophenyl)(cyclopropyl)amino][1,3]thiazolo[5,4-d]pyrimidin-2-yl}acetamide (120 mg, 353 μmol) produced in Example D21(v), 3-(trifluoromethoxy)benzoic acid (77 mg, 371 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (161 mg, 424 μmol) in pyridine (3 mL) was stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→98/2), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (134 mg, 71%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]2=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3.[CH:24](=O)[CH3:25].[BH4-].[Na+].O>C(O)C>[CH2:24]([NH:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]2=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[CH3:25]
Reactant: CC=O
Reactant: COc1ccc2ccn3c(N)c(-c4ccccc4C)nc3c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNc1c(-c2ccccc2C)nc2c3cc(OC)ccc3ccn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5.0 g of 3-amino-9-methoxy-2-(2-methylphenyl)imidazo[2,1-a]isoquinoline (Compound 26) in 100 ml of ethanol was added 3.0 ml of acetaldehyde, and the mixture was stirred at room temperature for 3 hours. After 3.3 g of sodium borohydride was added to the mixture and refluxed for 2 hours, the reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The crude crystal was recrystallized from petroleum ether/ethyl acetate to give 5.0 g of the title compound as colorless needles.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([NH2:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].O=[CH:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21]>O>[CH2:4]([C@H:3]1[C:11](=[O:12])[NH:13][CH:17]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])[NH:2]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)COC(=O)CCC=O
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)COC(=O)CCC1NC(=O)[C@H](Cc2ccccc2)N1
Yield: 19.7 %

Procedure:
To a solution of L-phenylalaninamide hydrochloride (20 g, 0.1 mol) in water (200 ml), adjusted to pH 8.2 with 10% sodium hydroxide (about 35 ml), was added isobutyl 4-oxobutanoate (16 g, 0.1 mol). The solution was refluxed for 24 hours. After cooling, the solution was extracted with dichloromethane (4×200 ml). The organic phase was dried and evaporated to dryness under vacuum. The residue was chromatographed over silica gel (dichloromethanemethanol 9:1) to afford 6 g (20%) of the title compound, as an oil, which was characterized as the hydrochloride, m.p. 152°-155° C. (with decomposition) (after crystallization from ethanol-diethyl ether). NMR (DMSO-d6, CDCl3): deltaH =9.25 (b.s., 1H, CONH); 7.6-7.1 (c.a., 5H, PhH), 4.90 (t, J=6.1 Hz, 1H, NHCHNH); 4.17 (t, J=6.1 Hz, 1H, CHCH2Ph); 3.84 (d, J=6.9 Hz, 2H, COOCH2CH); 3.35 (c.a., 2H, CH2Ph); 2.50-1.60 (c.a., 5H, CH2CH2COO, CH2CH(CH3)2. MS (E.I., 70 eV, 1.5 mA) m/z=304 (M+), 213 M-C7H7)+, 84 (C3H4N2O)+.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=1>>[C:1]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:13]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: CCCC(=O)Cl
Product: CCCC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Yield: 63.8 %

Procedure:
In a manner similar to that described in Example 3, butyryl chloride (0.033 g, 0.00031 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.042 g of 4-[4-(butyrylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+264.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]2[N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:10]=[C:11]([CH2:12][CH3:13])[C:3]=12.N.[Na+].[Cl-]>ClCCl.[Zn]>[Cl:8][C:6]1[N:5]=[C:4]2[N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:10]=[C:11]([CH2:12][CH3:13])[C:3]2=[CH:2][N:7]=1
Reactant: CCc1nn(-c2ccccc2)c2nc(Cl)nc(Cl)c12
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CCc1nn(-c2ccccc2)c2nc(Cl)ncc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of 4,6-dichloro-3-ethyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (300 mg, 1.03 mmol, 1.00 equiv) in dichloromethane (10 mL) at room temperature. To the resulting mixture was then added Zn (400 mg, 6.15 mmol, 6.00 equiv), in portions at room temperature, followed by NH3/NaCl (10 mL), in portions at room temperature. The resulting solution was stirred overnight at 60° C. The solids were filtered out. The resulting solution was extracted with dichloromethane (2×50 mL) and the organic layers combined. The resulting mixture was washed with sodium chloride (3×50 mL). The resulting mixture was dried over anhydrous sodium sulfate and the solids were filtered out. The resulting mixture was concentrated under vacuum to yield 6-chloro-3-ethyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine as a yellow solid. MS (m/z): 258 [MH+].
Reaction SMILES: C([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@@H:11]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)[C:12]2[CH:24]=[CH:23][C:15]([C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)[C@@H:6]([CH3:32])[CH2:5]1)C=C.C(O)(=O)C1C(=CC=CC=1)S>O1CCCC1.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:32][C@H:6]1[CH2:5][NH:4][C@H:9]([CH3:10])[CH2:8][N:7]1[C@@H:11]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=1)[C:12]1[CH:24]=[CH:23][C:15]([C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1
Reactant: C=CCN1C[C@H](C)N([C@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(O)c2)C[C@H]1C
Agent: O=C(O)c1ccccc1S
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)NC[C@@H]2C)cc1
Yield: 103.6 %

Procedure:
A solution of 4-[(R)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-hydroxyphenyl)-methyl]-N,N-diethylbenzamide (10.89 g, 25 mmol) and thiosalicylic acid (4.63 g, 30 mmol) in anhydrous tetrahydrofuran (50 mL) was stirred with a catalyst solution prepared by dissolution of bis(dibenzylidineacetone)palladium (0.718 g, 1.25 mmol) and 1,4-bis(diphenylphosphino)butane (0.533 g, 1.25 mmol) in tetrahydrofuran (10 mL) at room temperature under nitrogen for 1.5 hours. (J.P. Genet, S. Lemaire-Audoire, M. Savignac, Tetrahedron Letters, 36, 1267-1270 (1995)). The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (150 mL) and aqueous sodium carbonate solution. The layers were separated and diethyl ether (250 mL) was added to the organic layer. This was extracted with 5% sodium carbonate solution (2×150 mL). The organic layer was diluted with pentane (500 mL) and extracted with 3 M hydrochloric acid (6×30 mL). The aqueous solution was adjusted to pH 9-10 with saturated aqueous sodium carbonate solution and extracted with methylene chloride (3×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to yield 4-[(R)-((2S,5R)-2,5-dimethyl-1-piperazinyl)(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide as a brittle pale yellow foam (10.24 g). The product showed a single peak on HPLC (Zorbax C-8, isocratic 40% 0.01 M NH4OAc in MeOH, 3 min; linear gradient to 100% MeOH, 45 min; isocratic MeOH, 5 min; 1.0 mL/min; λobs =210 nm, Rt=19.24 min). Calc. for C24H33N3O2 0.1 EtOAc 0.4 CH2Cl2: %C, 67.96; H, 7.96; N, 9.59. Found: %C, 67.90; H, 8.03; N, 9.54. 1H NMR (CDCl3, 300 MHz): δ 7.42 (d, J=8.1 Hz, 2H); 7.26 (d, J=8.3 Hz, 2H); 7.11 (t, J=7.8 Hz, 1H); 6.72 (d, J=8.1 Hz, 1H); 6.65 (s, 1H); 6.59 (d, J=7.6 Hz, 1H); 5.16 (s, 1H); 4.93 (v br s, 2H); 3.51 (br m, 2H); 3.27 (br m, 2H); 3.02-2.97 (m, 1H); 2.92 (d, J=10.5 Hz, 1H); 2.66 (br d, J=8.5 Hz, 2H); 2.60-2.45 (m, 1H); 1.84 (dd, J=11.3, 8.3 Hz, 1H); 1.27-1.15 (m, 3H); 1.10 (d, J=6.1 Hz, 3H overlapping with m, 3H); 1.02 (d, J=6.1 Hz, 3H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10](/[C:13](=[CH:22]\[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)/[C:14]([NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[O:15])=[CH:9][CH:8]=1>C(Cl)Cl>[OH:6][C:7]1[CH:12]=[CH:11][C:10](/[C:13](=[CH:22]\[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)/[C:14]([NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[O:15])=[CH:9][CH:8]=1
Reactant: COc1ccc(/C(=C\C2CCOCC2)C(=O)Nc2nccs2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(Nc1nccs1)/C(=C/C1CCOCC1)c1ccc(O)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
BBr3 (2.5 mL of a 1.0M solution in CH2Cl2, 2.5 mmol) was added to a stirred solution of (E)-2-(4-methoxyphenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylacrylamide (EXAMPLE 13, 340 mg, 984 μmol) in anhydrous CH2Cl2 (20 mL) at −78° C. After 1 h, the mixture was allowed to warm to 20° C. over a period of 24 h. CH2Cl2 (100 mL) was added, then the mixture was washed with H2O (20 mL) and brine (20 mL), before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (CH2Cl2-MeOH, 50:1) furnished the title compound: RTB=1.27 min; m/z (ES+)=331.0 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C([O-])(O)=O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(=O)=O>O.C1(C)C=CC=CC=1>[C:16]([N:5]1[CH2:6][C@H:2]([OH:1])[CH2:3][C@@H:4]1[C:7]([OH:9])=[O:8])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)[C@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 96 %

Procedure:
Cis-4-hydroxy-D-proline 8 (10.0 g, 76.3 mmol) was dissolved in H2O (165 mL) containing NaHCO3 (16.0 g, 190 mmol). Benzyl chloroformate (12.5 mL, 15.0 g, 87.7 mmol) in toluene (40 mL) was added to this stirring solution at room temperature over 30 minutes using a dropping funnel. The reaction was stirred for 16 h. By this time, CO2 evolution had ceased, and the two phases were separated. Excess benzyl chloroformate was removed from the aqueous layer by washing with ether (3×50 mL). The aqueous phase was cooled in an ice bath and acidified to pH2 with concentrated HCl, causing precipitation of the oily product. This oil was extracted from the aqueous layer by repeated washings with ethyl acetate (5×50 mL). Further acidification of the aqueous layer produced no more precipitate, indicating the extraction was complete. The combined organic layers were washed with brine, dried (MgSO4), and concentrated to a colorless viscous oil, which crystallized upon standing at room temperature to provide 19.42 g (96%) of N-CBZ-cis-4-hydroxy-D-proline: mp 110°-111° C. (lit. 19 mp 110.5°-111.5° C.); [α]25d +24.4° (c 1.0, CHCl3) ]lit. 19 [α25D +26.3° (c 1.0, CHCl3)].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[F:21])=[CH:9][C:8]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:7]([O:30][CH3:31])[CH:6]=2.Cl[C:33](OC(Cl)(Cl)Cl)=[O:34].C([O-])([O-])=O.[Na+].[Na+].O>ClCCl.CCN(C(C)C)C(C)C>[CH2:23]([O:22][C:8]1[C:7]([O:30][CH3:31])=[CH:6][C:5]2[N:4]=[CH:3][C:2]3[NH:1][C:33](=[O:34])[N:12]([C:13]4[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=4[F:21])[C:11]=3[C:10]=2[CH:9]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncc(N)c(Nc3ccc(C#N)cc3F)c2cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COc1cc2ncc3[nH]c(=O)n(-c4ccc(C#N)cc4F)c3c2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
4-(3-Amino-6-benzyloxy-7-methoxyquinolin-4-ylamino)-3-fluorobenzonitrile (2.99 g, 7.2 mmol) was dissolved in dichloromethane (69 ml) together with Hünig's base (iPr2EtN, 1.43 ml). The solution obtained was subsequently added dropwise with ice-bath cooling to a mixture of trichloromethyl chloroformate (diphosgene, 938 μl, 7.72 mmol) and dichloromethane (42 ml). When the addition was complete, the mixture was stirred at room temperature for a further 30 min. Saturated Na2CO3 (30 ml) and water (170 ml) were subsequently added. After stirring for a further 30 min, the mixture was extracted twice with ethyl acetate (225 ml each time). The combined organic phases were washed once with water (150 ml), dried over Na2SO4, filtered and evaporated to dryness in vacuo. The residue was chromatographed over flash silica gel (solvent gradient ethyl acetate/0-17% by vol. of ethanol), giving 4-(8-benzyloxy-7-methoxy-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)-3-fluorobenzonitrile (1.87 g, 4.3 mmol) as solid. MS: 441.1 (M+H+), TLC (HPTLC): Rf=0.44 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: Cl.[SH:2][C@@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1.[OH-].[Na+].[CH:13]1([C:19]2[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(O)C>C(Cl)(Cl)Cl>[CH:13]1([C:19]2[CH:26]=[CH:25][C:22]([CH2:23][S:2][C@@H:3]3[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4]3)=[CH:21][CH:20]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: ClCc1ccc(C2CCCCC2)cc1
Reactant: O=C(O)[C@@H]1C[C@H](S)CN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=C(O)[C@@H]1C[C@H](SCc2ccc(C3CCCCC3)cc2)CN1
Temperature: 0 °C
Yield: 90.3 %

Procedure:
To (4S)-4-mercapto-L-proline hydrochloride (300 mg) is added 2 N sodium hydroxide (1.6 ml) aqueous solution, and the mixture is stirred at 0° C. A solution of 4-cyclohexylbenzyl chloride (340 mg) in a mixed solvent of ethanol (5 ml)/chloroform (1 ml) is added thereto, and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure, and deposited crystals are filtered off. The crystals are washed with water, ethanol and diethyl ether successively to give 470 mg (91%) of the titled compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH2:27]([NH:30][CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29]>C(#N)C>[CH3:26][S:23]([C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][CH:13]([CH2:12][N:30]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29])[O:14]2)=[CH:19][CH:18]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCCNCCC
Solvent: CC#N
Product: CCCN(CCC)CC1CCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), N-propylpropan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 325 (M+, 1), 296 (7), 131 (4), 115 (10), 114 (bp), 86 (6).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[CH:9]=2)[NH:4][N:3]=1.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[CH2:33]([O:32][C:30]([NH:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[CH:9]=2)[NH:4][N:3]=1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CSc1nccc(-c2cc3c(N)n[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1
Reactant: O=C(Cl)OCc1ccccc1
Product: CSc1nccc(-c2cc3c(NC(=O)OCc4ccccc4)n[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1

Procedure:
Following a similar procedure to that described in example 245, but starting from 3-amino-5-[2-(methylsulfanyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine (obtained in example 123) and benzyl chloroformate, the desired compound was obtained.