Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[C:8]([CH2:14][CH2:15][C:16]([OH:18])=O)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]>C(Cl)(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]([CH2:14][CH2:15][C:16]([Cl:3])=[O:18])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(CCC(=O)O)cc1Br
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCC(=O)Cl)cc1Br

Procedure:
A solution of 102.4 g (0.86 mol) of thionyl chloride is added to a solution of 51.8 g (0.2 mol) of 3-(3-bromo-4-methoxyphenyl)propanoic acid in 700 ml of chloroform. The mixture is heated at reflux for 4 hours, and the solvent is then evaporated off. 53 g are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].O[C@@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]1)#[N:2]
Reactant: COC(=O)[C@H]1CC[C@@H](O)CC1
Reactant: N#Cc1cccc(O)c1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1CC[C@H](Oc2cccc(C#N)c2)CC1

Procedure:
3-Cyanophenol (3.00 g, 25.2 mmol) and methyl cis-4-hydroxycyclohexanecarboxylate (2.66 g, 16.8 mmol) were dissolved in toluene (80 mL), and cyanomethylenetributylphosphorane (6.6 mL, 25.2 mmol) was added thereto, and then, the resulting mixture was heated to reflux under a nitrogen atmosphere for 2.5 hours.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([CH:25]([CH3:28])[CH2:26][OH:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([CH:25]([CH3:28])[CH2:26][O:27][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Reactant: CC(CO)c1ccccc1
Product: CC(COC(=O)NC(=O)C(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 131° C. and MS: m/e=373.5 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and (RS)-2-phenyl-propan-1-ol.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:12]1[N:13]=[CH:14][C:15]([C:18]2[N:19]=[C:20]([N:28]3[CH2:33][CH2:32][C@H:31]([NH:34][C:35]([C:37]4[NH:38][C:39]([CH3:44])=[C:40]([Cl:43])[C:41]=4[Cl:42])=[O:36])[C@H:30]([O:45][CH3:46])[CH2:29]3)[S:21][C:22]=2[C:23]([O:25]CC)=[O:24])=[N:16][CH:17]=1.Cl>O1CCCC1.C(#N)C>[Cl:42][C:41]1[C:40]([Cl:43])=[C:39]([CH3:44])[NH:38][C:37]=1[C:35]([NH:34][C@@H:31]1[CH2:32][CH2:33][N:28]([C:20]2[S:21][C:22]([C:23]([OH:25])=[O:24])=[C:18]([C:15]3[CH:14]=[N:13][C:12]([O:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:17][N:16]=3)[N:19]=2)[CH2:29][C@@H:30]1[O:45][CH3:46])=[O:36]
Reactant: OCCN1CCCC1
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1-c1cnc(Cl)cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CO[C@H]1CN(c2nc(-c3cnc(OCCN4CCCC4)cn3)c(C(=O)O)s2)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 44.1 %

Procedure:
To a stirred solution of 2-(pyrrolidine-1-yl)ethanol (0.102 mL, 0.872 mmol) in dry tetrahydrofuran (20 mL) was added sodium hydride (70 mg, 1.771 mmol) at 0° C. The reaction mixture was heated to 80° C. After 10 min, ethyl 4-(5-chloropyrazin-2-yl)-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate (Example 59, 250 mg, 0.436 mmol) was added to the reaction mixture at 80° C. and further maintained at 80° C. for 10 min. After the completion of the reaction, the reaction mixture was cooled and carefully quenched by adding ice pieces. The aqueous layer was extracted with ethyl acetate (2×50 mL) to get rid of any organic impurities and discarded. The aqueous layer was acidified to pH=2 using 2N HCl solution and was extracted with 10% methanol/dichloromethane (2×100 mL). The organic layer was dried and concentrated under reduced pressure to yield the product. The obtained product was stirred in acetonitrile (10 mL). The solid was filtered and dried to obtain 120 mg (45%) of 2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-{5-[2-(pyrrolidin-1-yl)ethoxy]pyrazin-2-yl}-1,3-thiazole-5-carboxylic acid as yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: CO
Reactant: O=C(O)c1ccc(I)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(I)c([N+](=O)[O-])c1
Yield: 77 %

Procedure:
The required starting material, 4-iodo-3-nitrobenzoic acid, can be prepared as described in Tetrahedron, 61, 2005, 10113-10121, or by any other suitable method. The conversion of 4-iodo-3-nitrobenzoic acid to its methyl ester using sulfuric acid and methanol is described in U.S. 2007/0135485 A1 (section [0255], page 30). The method involves reacting a methanolic solution of 4-iodo-3-nitrobenzoic acid with sulfuric acid, neutralizing the acid with sodium bicarbonate, removal of methanol, diluting with water and extracting with diethyl ether, to obtain an oily product, which was subjected to chromatography to get 4-iodo-3-nitro benzoic methyl ester as a solid in 77% yield. Diethyl ether is not a suitable solvent on an industrial scale because of its high inflammability. Also column chromatography for purification in large scale is not desirable. Hence, we have modified the reported procedure. We have found that methyl tert-butyl ether (MTBE) is a better solvent for extraction which gives the product as a solid directly without any need for chromatographic purification (98.5% HPLC) and in high yield (85%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[CH:31][C:27]=1[C:28]([OH:30])=O.C(N(CC)CC)C.Cl.[O:55]1[CH2:59][CH2:58][CH2:57][CH:56]1[CH2:60][O:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C)C=O>[F:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[CH:31][C:27]=1[C:28]([N:65]1[CH2:66][CH2:67][CH:62]([O:61][CH2:60][CH:56]2[CH2:57][CH2:58][CH2:59][O:55]2)[CH2:63][CH2:64]1)=[O:30]
Reactant: C1COC(COC2CCNCC2)C1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OCC2CCCO2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
O-Benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (509 mg, 1.34 mmol) was added, in one portion, to 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (200 mg, 0.67 mmol) and triethylamine (0.206 mL, 1.48 mmol) in N,N-dimethylformamide (2.5 mL), at 25° C. under an air atmosphere. The resulting solution was stirred at 25° C. for 10 minutes. A solution of 4-((tetrahydrofuran-2-yl)methoxy)piperidine hydrochloride (164 mg, 0.74 mmol) and triethylamine (0.206 mL, 1.48 mmol) in N,N-dimethylformamide (1 mL) was then added dropwise and the resulting solution stirred at 25° C. for 10 hours. The crude mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound as a solid (238 mg, 76%); 1H NMR (400.132 MHz, DMSO) δ 1.01 (2H, dt), 1.31-1.37 (1H, m), 1.43-1.50 (1H, m), 1.51-1.58 (1H, m), 1.68-1.73 (1H, m), 1.74-1.93 (4H, m), 3.00-3.07 (1H, m), 3.17-3.18 (1H, m), 3.39 (2H, d), 3.53-3.59 (1H, m), 3.70-3.75 (1H, m), 3.90 (2H, ddd), 4.33 (2H, s), 7.21 (1H, t), 7.33-7.35 (1H, m), 7.39-7.43 (1H, m), 7.83 (1H, td), 7.89 (1H, td), 7.97 (1H, d), 8.27 (1H, dd), 12.56 (1H, s) m/z (LC-MS, ESI+), RT=1.71 (M+H 466.5).
Reaction SMILES: C[O-].[Na+].[SH:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]([CH3:13])[N:6]=1.Cl[CH2:15][C:16](=[O:28])[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>CO.O>[NH2:12][C:11]1[C:10]2[C:5](=[N:6][C:7]([CH3:13])=[CH:8][CH:9]=2)[S:4][C:15]=1[C:16](=[O:28])[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(C#N)c(S)n1
Reactant: O=C(CCl)CS(=O)(=O)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc2c(N)c(C(=O)CS(=O)(=O)c3ccc(Cl)cc3)sc2n1
Yield: 67.2 %

Procedure:
To a mixture of 5.4 g (0.1 mol) of sodium methoxide and 7.5 g (0.05 mol) of 2-mercapto-3-cyano-6-methyl pyridine in 100 ml methanol was slowly added 13.3 g (0.05 mol) of 3-chloro-1-(4-chloro-phenylsulfonyl)-2-propanone. The reaction mixture was refluxed for 7 hours. It was then cooled, diluted with water and filtered to give 15.5 g of crude product which was crystallized from acetonitrile to give 12.8 g of pure product, m.p. 265°-7° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9].[H-].[Na+].Cl[C:17]1[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=1.O>CN(C)C=O>[Cl:23][C:22]1[C:17]([N:6]2[C:2]([CH3:1])=[C:3]([C:7]([F:13])([F:12])[C:8]([F:10])([F:9])[F:11])[N:4]=[CH:5]2)=[N:18][CH:19]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:21]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Cc1[nH]cnc1C(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(F)(F)C(F)(F)F)ncn1-c1ncc(C(F)(F)F)cc1Cl
Reaction time: 0.17 h
Yield: 43.9 %

Procedure:
To a solution of 0.6 g (3 m mol) of 5-methyl-4-pentafluoroethylimidazole in 5 ml of N,N-dimethyl formamide was added slowly 120 mg (3 m mol) of an oily sodium hydride (60%) while cooling with ice, followed by stirring at the same temperature for 10 minutes. After the reaction was completed, to the reaction mixture was added dropwise 0.65 g (3 m mol) of 2,3-dichloro-5-trifluoromethylpyridine, followed by stirring at room temperature for 9 hours. After the reaction was completed, the reaction mixture was poured into water, and extracted with ethyl acetate. Further, then the residue was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 0.5 g of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-5-methyl-4-pentafluoroethylimidazole.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:17]([NH:19][CH3:20])=[O:18].CCN(C(C)C)C(C)C>C1COCC1>[Cl:10][C:6]1[N:5]=[C:4]([S:11][CH3:12])[N:3]=[C:2]([NH:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:17]([NH:19][CH3:20])=[O:18])[C:7]=1[C:8]#[N:9]
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Reactant: CNC(=O)c1ccc(C)c(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(C)c(Nc2nc(SC)nc(Cl)c2C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbonitrile (2.19 g, 10 mmol), 3-amino-4,N-dimethyl-benzamide (1.64 g, 10 mmol), and DIEA (1.40 g, 18.8 mmol) were mixed in THF (20 mL). The resulting mixture was stirred at room temperature for overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was concentrated and the crude product was purified by flash chromatography to obtain 3-(6-chloro-5-cyano-2-methylsulfanyl-pyrimidin-4-ylamino)-4,N-dimethyl-benzamide (2.78 g, 80%). MS (m/z): 348 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([CH2:10][N:11]2[C:17](=[O:18])[C@@H:16]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH:32]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[NH:30][C:29]4=[O:39])[CH2:24][CH2:23]3)=[O:21])[CH2:15][NH:14][C@H:13]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:12]2)[CH2:9][CH2:8]1.[CH2:46](Br)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CC(C)=O>[CH2:46]([N:14]1[CH2:15][C@@H:16]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[CH:32]=[C:31]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:30][C:29]3=[O:39])[CH2:24][CH2:23]2)=[O:21])[C:17](=[O:18])[N:11]([CH2:10][CH:7]2[CH2:9][CH2:8]2)[CH2:12][C@@H:13]1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: BrCc1ccccc1
Reactant: O=C(N[C@H]1CN[C@H](c2ccccc2)CN(CC2CC2)C1=O)N1CCC(n2cc(-c3ccccc3)[nH]c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(N[C@@H]1CN(Cc2ccccc2)[C@@H](c2ccccc2)CN(CC2CC2)C1=O)N1CCC(n2cc(-c3ccccc3)[nH]c2=O)CC1
Reaction time: 18 h
Yield: 77.3 %

Procedure:
Potassium carbonate (6.4 mg, 0.05 mmol) was added to a solution of N-[(3R,6S)-1-(cyclopropylmethyl)-7-oxo-3-phenyl-1,4-diazepan-6-yl]-4-(2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)piperidine-1-carboxamide (12.2.0 mg, 0.023 mmol) and benzyl bromide (14 □L, 0.12 mmol) in acetone (0.5 mL). After 18 h, the mixture was concentrated. Purification by silica gel chromatography (1% methanol/dichloromethane→5% methanol/dichloromethane) gave the title compound (11 mg). MS 619.3 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:9])([CH3:8])[C:5]([OH:7])=[O:6].[Si:10]([O:17][C@H:18]1[CH2:27][C@H:26](O)[C@H:25]2[C:20]([CH:21]=[CH:22][C@H:23]([CH3:46])[C@@H:24]2[CH2:29][CH2:30][C@H:31]2[O:36][C:35](=[O:37])[CH2:34][C@H:33]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:32]2)=[CH:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>>[Si:10]([O:17][C@H:18]1[CH2:27][C@H:26]([O:6][C:5](=[O:7])[C:4]([CH2:3][O:2][CH3:1])([CH3:9])[CH3:8])[C@H:25]2[C:20]([CH:21]=[CH:22][C@H:23]([CH3:46])[C@@H:24]2[CH2:29][CH2:30][C@H:31]2[O:36][C:35](=[O:37])[CH2:34][C@H:33]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:40])[CH3:41])[CH2:32]2)=[CH:19]1)([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:12])[CH3:11]
Reactant: COCC(C)(C)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: COCC(C)(C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 35 %

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 960 mg of 2-methoxymethyl-2-methylpropionic acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 423 mg of the title compound as a colorless foam.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12](=[O:29])[N:13]([C:15]1[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=1)[CH3:14]>CO.CN(C=O)C.[Pd]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:11][C:12](=[O:29])[N:13]([C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:16]=2)[CH3:14])[CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=O)N(C)c1cc(NC(=O)OC(C)(C)C)ncn1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(N)cc1NC(=O)N(C)c1cc(NC(=O)OC(C)(C)C)ncn1
Reaction time: 20 h

Procedure:
A solution of tert-butyl {6-[3-(2-methyl-5-nitro-phenyl)-1-methyl-ureido]-pyrimidin-4-yl}-carbamate (330 mg, 0.82 mmol) in a mixture of methanol (20 ml) and DMF (50 ml) is hydrogenated in the presence of 10% palladium on charcoal (500 mg) at atmospheric pressure. After 20 h the hydrogenation is complete and the catalyst is filtered off. The filtrate is evaporated to dryness. The residue obtained is triturated with ether, filtered off, and vacuum dried to afford a gray powder: HPLC: tR=5.38 min (purity: 97%, gradient A), ESI-MS: 373.4 [MH]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[CH2:12]([NH2:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:20][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: NCCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCCC1NCCc1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 38.6 %

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (3.00 g, 19.2 mmol) in ethanol (20 mL) was treated with phenethylamine (2.41 mL, 19.2 mmol), sodium cyanoborohydride (2.42 g, 38.4 mmol), and glacial acetic acid (10 drops) and stirred for 16 h at 50° C. After cooling to 25° C. the solvent was removed in vacuo, the crude material was redissolved in ethyl acetate (100 mL and washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was discarded and the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was discarded, 1.0 M aqueous sodium hydroxide solution (75 mL) was added and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the desired product, 2-phenethylamino-cyclopentanecarboxylic acid ethyl ester (1.94 g, 7.42 mmol, 38.6%), as a light yellow solid. LC-MS (ESI) calcd for C16H23NO2 261.17, found 262.2 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]=[C:18]=S)=[C:6]([CH:16]=1)[CH2:7][O:8][Si](C(C)(C)C)(C)C.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:30]=1[CH:29]([NH2:31])[CH2:28][CH2:27]2>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]=[C:18]([NH:31][CH:29]3[C:30]4[C:26](=[CH:25][CH:24]=[CH:23][C:22]=4[O:21][CH3:20])[CH2:27][CH2:28]3)[O:8][CH2:7][C:6]=2[CH:16]=1
Reactant: COc1cccc2c1C(N)CC2
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1N=C=S
Product: COc1cccc2c1C(NC1=Nc3ccc(Br)cc3CO1)CC2
Yield: 66.7 %

Procedure:
Prepared from (5-bromo-2-isothiocyanato-benzyloxy)-tert-butyl-dimethyl-silane (Example 32, step B) (4.0 g, 11.2 mmol) and the rac-7-methoxy-indan-1-ylamine (Example 10, step A) (1.82 g, 11.2 mmol) according to the procedure described for Example 1. Obtained the title compound as a white solid (2.79 g, 67%), m.p. 151° C.; MS (ISP) m/e=375.1 [(M+H)+].
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21](O)=[O:22])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([NH:38][C:21]([C:20]2[N:11]([CH2:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[C:12](=[O:31])[C:13]3[C:18]([C:19]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][C:16]([Br:30])=[CH:15][CH:14]=3)=[O:22])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reactant: NC1CCCCC1
Product: O=C(NC1CCCCC1)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 249 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg) and cyclohexylamine. Colorless crystals (130 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]([S:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[N:5][CH:6]=[C:7]([CH3:9])[CH:8]=1)#[N:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[C:1]([C:3]1[C:4]([S:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[N:5][CH:6]=[C:7]([CH2:9][Br:20])[CH:8]=1)#[N:2]
Reactant: Cc1cnc(Sc2ccc([N+](=O)[O-])cc2)c(C#N)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: N#Cc1cc(CBr)cnc1Sc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 60.00 g (0.221 mol) of 3-cyano-2-(4-nitrophenylthio)-5-methylpyridine, 39.37 g (0.221 mol) of N-bromosuccinimide, 3.0 g of benzoyl peroxide and 60 mL of benzene was refluxed for 16 hours while being irradiated with a 275-W sunlamp. The solvent was removed under reduced pressure and the residue was shaken with a mixture of 1 L of water and 1 L of methylene chloride. The organic layer was separated, washed with 1 L of water, dried over anhydrous magnesium sulfate, and filtered. Removal of the solvent by evaporation under reduced pressure yielded 3-cyano-2-(4-nitrophenylthio)-5-bromomethylpyridine which can be used in the following step without further purification.
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH2:30][CH2:31][NH:32][CH2:33][CH:34]3[CH2:36][CH2:35]3)[CH:25]=[CH:24]4)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.[BH4-].[Na+]>CO.C(O)(=O)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH2:30][CH2:31][N:32]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH2:33][CH:34]3[CH2:35][CH2:36]3)[CH:25]=[CH:24]4)=[N:17][CH:18]=2)=[CH:11][CH:12]=1
Reactant: O=CC1CC1
Reactant: Clc1ccc(-c2ccc(C#Cc3ccc4c(ccn4CCNCC4CC4)c3)nc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Clc1ccc(-c2ccc(C#Cc3ccc4c(ccn4CCN(CC4CC4)CC4CC4)c3)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
36 μL (0.47 mmol) cyclopropanecarbaldehyde are added to a solution of 100 mg (0.24 mmol) (2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethyl)-cyclopropylmethyl-amine in 20 mL MeOH at RT and 15 min later 59 mg (0.94 mmol) NaBH4 and one drop of glacial acetic acid are added. The mixture is stirred for 1 h at RT, evaporated down i.vac., the residue is taken up in dilute K2CO3 solution, extracted exhaustively with EtOAc and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is triturated with PE, suction filtered and dried.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:17]2[CH:16]=[C:15]([CH:18]([CH2:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:19]([NH:21][C:22]3[S:23][CH:24]=[C:25]([CH2:27][C:28]([O:30]CC)=[O:29])[N:26]=3)=[O:20])[CH:14]=[CH:13][C:12]=2[S:11](=[O:41])(=[O:40])[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.Cl>O1CCCC1.O>[CH3:3][N:4]1[C:17]2[CH:16]=[C:15]([CH:18]([CH2:33][CH:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[C:19]([NH:21][C:22]3[S:23][CH:24]=[C:25]([CH2:27][C:28]([OH:30])=[O:29])[N:26]=3)=[O:20])[CH:14]=[CH:13][C:12]=2[S:11](=[O:40])(=[O:41])[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: CCOC(=O)Cc1csc(NC(=O)C(CC2CCOCC2)c2ccc3c(c2)N(C)c2ccccc2S3(=O)=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1c2ccccc2S(=O)(=O)c2ccc(C(CC3CCOCC3)C(=O)Nc3nc(CC(=O)O)cs3)cc21
Temperature: 25 °C

Procedure:
At room temperature and with stirring, 0.25 ml of 2M NaOH are added to a suspension of 25.0 mg of ethyl {2-[2-(10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-3-(tetrahydropyran-4-yl)propionylamino]thiazol-4-yl}acetate in 5 ml of tetrahydrofuran and 2 ml of water, and the mixture is stirred at room temperature for 12 hours. The reaction mixture is then neutralized by addition of 1M HCl. The solvents are removed under reduced pressure, and the residue is taken up in 20 ml of ethyl acetate and washed three times with in each case 10 ml of water. The organic phase is dried with MgSO4 and concentrated under reduced pressure. The residue is purified by RP-HPLC. This gives 22.5 mg of {2-[2-(10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-3-(tetrahydropyran-4-yl)propionylamino]thiazol-4-yl}acetic acid as a lyophilisate.