Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)C>[CH2:17]([CH:24]1[CH2:29][CH2:28][N:27]([C:13](=[O:15])[C:12]([NH:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([SH:1])[NH:3][C:4]=3[CH:10]=2)=[O:16])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)C(=O)Nc1ccc2nc(S)[nH]c2c1
Solvent: CCOCC
Product: O=C(Nc1ccc2nc(S)[nH]c2c1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from N-(2-mercapto-3H-benzimidazol-5-yl)-oxalamic acid and 4-benzyl-piperidine according to the method described in Example 1c. Melting Point: 277-281° C. (diethylether)
Reaction SMILES: FC1C=CC=CC=1NC(=S)NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(O)=O)C3)=CC=1.[CH3:35][CH:36]([CH3:69])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][CH:62]=4)=[S:59])=[CH:53][CH:52]=3)[CH:48]=2)[C:43]1=[O:68])[C:38]([O:40]C)=[O:39]>>[CH3:35][CH:36]([CH3:69])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:62]=[CH:63][C:64]([CH3:67])=[CH:65][CH:66]=4)=[S:59])=[CH:53][CH:52]=3)[CH:48]=2)[C:43]1=[O:68])[C:38]([OH:40])=[O:39]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccc(C)cc4)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Product: Cc1ccc(NC(=S)Nc2ccc(-c3ccc4c(c3)CN([C@H](C(=O)O)C(C)C)C4=O)cc2)cc1
Yield: 75 %

Procedure:
The compound of example 275 was prepared analogous to compound of example 257 by hydrolysis of compound of example 274.
Reaction SMILES: ClC1N2N=C(C)C=C2N=C(NC(=O)[C:14]2C=[CH:18][C:17]([C:20](O)(C)C)=[N:16][CH:15]=2)C=1.N1CC[CH:28](NC(=O)C)[CH2:27][CH2:26]1>CN1C(=O)CCC1>[CH:27]([N:16]([CH2:15][CH3:14])[CH:17]([CH3:18])[CH3:20])([CH3:28])[CH3:26]
Reactant: CC(=O)NC1CCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)nc3)cc(Cl)n2n1
Solvent: CN1CCCC1=O
Product: CCN(C(C)C)C(C)C
Yield: 114.3 %

Procedure:
In a 2 ml microwave vial was placed N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-6-(2-hydroxypropan-2-yl)nicotinamide (11C, 75 mg, 0.21 mmol) and N-(piperidin-4-yl)acetamide (31 mg, 0.21 mmol). To the sealed vial was then added NMP (1 ml) and then N,N-diisopropylethylamine (0.042 ml, 0.24 mmol) to give a dark yellow solution. The mixture was then heated in the microwave at 100° C. for 10 minutes. After cooling to room temperature, the crude product mixture was purified by preparatory HPLC (20-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the collected fractions gave the titled product (77 mg, 79% yield) as an off white powder. 1H NMR (DMSO-d6) δ: 11.07 (s, 1H), 9.00 (dd, J=2.4, 0.9 Hz, 1H), 8.33 (dd, J=8.3, 2.3 Hz, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.75 (dd, J=8.3, 0.8 Hz, 1H), 7.26 (s, 1H), 6.11 (d, J=0.5 Hz, 1H), 4.28 (br. s., 2H), 3.76-3.90 (m, 2H), 3.11-3.21 (m, 2H), 2.32 (s, 4H), 1.80-1.90 (m, 3H), 1.76 (s, 3H), 1.51 (d, J=8.8 Hz, 3H), 1.41 (s, 6H); ESI-MS: m/z 452.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:38])=[C:5]([C:22]([O:24][CH2:25][CH2:26][N:27]2C(=O)C3=CC=CC=C3C2=O)=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].O.NN>>[CH3:1][C:2]1[NH:3][C:4]([CH3:38])=[C:5]([C:22]([O:24][CH2:25][CH2:26][NH2:27])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2C(=O)c3ccccc3C2=O)C1c1cccc([N+](=O)[O-])c1
Agent: NN
Solvent: O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCN)C1c1cccc([N+](=O)[O-])c1

Procedure:
Prepared by a method analogous to that of Example 1(b) from 20.78 g (40 mmol) of 1,4-dihydro-2,6-dimethyl-3-ethoxycarbonyl-4-(3-nitrophenyl)-5-(2-phthalimidoethoxy)carbonyl-pyridine and 5.83 ml (120 mmol) of hydrazine hydrate. 13.39 g (86%) of yellow crystals, melting point 137°-139° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[C:4]([NH:11][S:12]([C:15]2([CH2:18][C@@H:19]3[CH2:23][O:22]C(C)(C)[O:20]3)[CH2:17][CH2:16]2)(=[O:14])=[O:13])[C:5]([O:9][CH3:10])=[CH:6][C:7]=1[F:8]>C1COCC1.Cl>[F:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[C:4]([NH:11][S:12]([C:15]2([CH2:18][C@@H:19]([OH:20])[CH2:23][OH:22])[CH2:17][CH2:16]2)(=[O:13])=[O:14])[C:5]([O:9][CH3:10])=[CH:6][C:7]=1[F:8]
Reactant: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1NS(=O)(=O)C1(C[C@@H]2COC(C)(C)O2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1NS(=O)(=O)C1(C[C@@H](O)CO)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude (R)—N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)cyclopropane-1-sulfonamide was dissolve in a mixture of THF (1 mL) and HCl (1.2N, 0.15 ml) and stirred overnight at room temperature. The solvents were removed under reduced pressure and the residue dissolved in ethyl acetate. The organic phase was washed with aqueous NaHCO3, dried (Na2SO4), and concentrated to afford (R)—N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide (1.4 mg, crude).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH:6]([C:12]([O:14]C)=O)[NH:7]2>C(N)CCC>[CH2:6]([NH:7][C:12]([CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[NH:7]1)=[O:14])[CH2:5][CH2:4][CH3:3]
Reactant: COC(=O)C1Cc2c(cccc2OC)N1
Solvent: CCCCN
Product: CCCCNC(=O)C1Cc2c(cccc2OC)N1

Procedure:
Methyl 4-methoxyindoline-2(R/S)-carboxylate (0.89 g, 4.3 mmol) was dissolved in butylamine (40 ml) under nitrogen and the solution was then stirred at reflux for three hours. After cooling the mixture, the remaining butylamine was removed under vacuum. The crude product was recrystallized from diethyl ether in order to give an off-white solid.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1([C:9]([OH:11])=O)[CH2:8][CH2:7]1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][CH:21]([F:23])[F:22])[NH2:16].Cl>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH3:12][C:13]1[CH:14]=[C:15]([NH:16][C:9]([C:6]2([CH3:5])[CH2:8][CH2:7]2)=[O:11])[CH:17]=[CH:18][C:19]=1[O:20][CH:21]([F:22])[F:23]
Reactant: CC1(C(=O)O)CC1
Reactant: Cc1cc(N)ccc1OC(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)C2(C)CC2)ccc1OC(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
To a mixture of toluene (50 ml) and pyridine (4.2 g) cooled at 0° C., thionyl chloride (1.3 g) was added, and a solution of 1-methylcyclopropanecarboxylic acid (1.0 g) in toluene was dropwise added thereto while stirring. A solution of 3-methyl-4-difluoromethoxyaniline (1.75 g) in toluene was dropwise added thereto. After the dropwise addition was completed, stirring was continued at room temperature for 3 hours. The reaction mixture was admixed with 5% hydrochloric acid (20 ml). The organic solvent layer was separated, washed with 1% sodium hydroxide solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give crude crystals (2.2 g). The crude crystals were recrystallized from ethanol to give N-(3-methyl-4-difluoromethoxyphenyl)-1-methylcyclopropanecarboxamide (1.8 g). M.P., 68°-69° C.
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N+:34]([O-:36])=[O:35])=[C:19]([CH:21]([O:29][Si](C)(C)C)[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:20]=1>C(O)C.O>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N+:34]([O-:36])=[O:35])=[C:19]([CH:21]([OH:29])[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:20]=1
Reactant: CCOC(=O)CCC(O[Si](C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCC(O)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
Citric acid (0.51 g) was added to a solution of ethyl 4-(5-chloro-2-nitrophenyl)-4-(trimethylsilyloxy)butanoate (4.76 g) in ethanol (25 mL) and water (5 mL) and stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Subsequently, the solvent was distilled off and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1→10:1) to obtain 3.8 g of ethyl 4-(5-chloro-2-nitrophenyl)-4-hydroxybutanoate.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([NH2:36])=[CH:29][C:28]=2[CH:37]([CH3:39])[CH3:38])=[O:25])[C:6]1=[O:40])[CH2:2][CH2:3][CH3:4].[CH:41](=O)[C:42]1[CH:47]=[CH:46][CH:45]=[N:44][CH:43]=1.Cl.[BH4-].[Na+]>CO.O>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([NH:36][CH2:41][C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[CH:29][C:28]=2[CH:37]([CH3:39])[CH3:38])=[O:25])[C:6]1=[O:40])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(N)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Reactant: O=Cc1cccnc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(NCc3cccnc3)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To a solution of N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-(2,6-diisopropyl-4-aminophenyl)urea (450 mg, 0.727 mmol) in methanol (5 ml) are added nicotinaldehyde (0.137 ml, 1.45 mmol) and conc. hydrochloric acid (0.12 ml, 1.44 mmol) at room temperature. Then, the mixture is cooled under ice-cooling, and thereto is added sodium borohydride (68.6 mg, 1.09 ml), and the mixture is stirred at room temperature for 5 hours. To the mixture is added water, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with an aqueous sodium hydrogen carbonate solution and then dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound (475 mg, 0.654 mmol) as colorless amorphous.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27](=O)[CH2:28][C@@H:29]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([S:45]([NH2:48])(=[O:47])=[O:46])=[CH:41][C:40]=2[S:49]([C:52]([F:55])([F:54])[F:53])(=[O:51])=[O:50])[CH2:30][S:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:23][CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1.N.CO>[Si:1]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C@@H:29]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([S:45]([NH2:48])(=[O:46])=[O:47])=[CH:41][C:40]=2[S:49]([C:52]([F:54])([F:53])[F:55])(=[O:50])=[O:51])[CH2:30][S:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:23][CH2:22]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCCN1CCN(C(=O)C[C@H](CSc2ccccc2)Nc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CC1)(c1ccccc1)c1ccccc1
Agent: B
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCN1CCN(CC[C@H](CSc2ccccc2)Nc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
(R)-4-(4-(4-(2-(tert-Butyldiphenylsilyloxy)ethyl)piperazin-1-yl)-4-oxo-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 21, 0.98 g, 1.15 mmol) was dissolved in THF (4.6 ml), under a nitrogen atmosphere, and a solution of borane-THF complex (1M in THF; 6.93 ml, 6.93 mmol) was added. The mixture was diluted with NH3 in MeOH (7N, 20 ml) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (75 ml), washed with water (40 ml), and dried (Na2SO4). Evaporation of the volatiles under reduced pressure afforded a concentrate, which was purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→100% EtOAc/hexanes) to provide the title compound (245 mg, yield: 25%).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([CH:29]1[CH2:32]C[CH2:30]1)[O:26][CH2:27]C)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.F[C:43](F)(F)C1C=C(C=C(C(F)(F)F)C=1)CN(CC1C=C(C(F)(F)F)C=CC=1C=O)C1N=NN(C)N=1.C([Mg]Cl)(C)(C)C.CI>>[CH3:27][O:26][CH:25]([C:16]1[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=1[CH2:14][N:7]([CH2:6][C:5]1[CH:33]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:35]=[C:3]([C:2]([F:41])([F:40])[F:1])[CH:4]=1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1)[C:29]([CH3:43])([CH3:32])[CH3:30]
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C=O)n1
Reactant: CCOC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCC1
Agent: CC(C)(C)[Mg]Cl
Solvent: CI
Product: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C(C)(C)C

Procedure:
The title compound was prepared in an analogous manner to that described for the preparation of (3,5-bis-trifluoromethyl-benzyl)-[2-(cyclobutyl-ethoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)amine from 2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzaldehyde by the addition of tert-butylmagnesium chloride followed by O-methylation with methyl iodide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12].[CH2:14](O)[CH3:15]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=C(O)/C=C/c1cc(O)ccc1Br
Reactant: CCO
Product: CCOC(=O)/C=C/c1cc(O)ccc1Br
Yield: 90 %

Procedure:
A solution of acrylic acid 8 (4.35 g, 18.0 mmol) in dry ethanol (50 mL) with a small quantity of acid resine DOWEX™ (300 mg) was refluxed for 24 h. The reaction mixture was filtered, the solvent was evaporated in vacuo and the crude reaction product was purificated by means of chromatography on silica gel (hexane/AcOEt 10:1) to give 4.36 g of ester 9 as a white solid. Yield 90%. 1H RMN (300 MHz, CD3COCD3) δ ppm: 8.82 (br s, 1H), 7.94 (d, J=16.1 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.28 (d, J=2.9 Hz, 1H), 6.88 (dd, J1=8.7 Hz, J2=2.9 Hz, 1H), 6.45 (d, J=16.1 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H); 13C RMN (75 MHz, CD3COCD3) δ ppm: 167.5, 159.1, 144.0, 136.7, 135.9, 123.0, 121.3, 116.2, 115.8, 62.1, 15.6; HRMS (EI) m/z: calcd for C11H11BrO3: 269.9892. found: 269.9886; mp: 96-98° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[N:15]=[CH:14]3)=[C:6]([CH:9]=1)[C:7]#[N:8].[ClH:21]>CO.[OH-].[OH-].[Pd+2]>[ClH:21].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[N:15]=[CH:14]3)=[C:6]([CH:9]=1)[CH2:7][NH2:8]
Reactant: Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: Cn1ncc2cc(Oc3ccc(F)cc3CN)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (4t) (0.32 g, 1.22 mmol) in MeOH (20 mL) was purged with nitrogen and treated with 20% Pd(OH)2/C catalyst (15% wt, 180 mg) followed by concentrated HCl (0.3 mL, 3.6 mmol). After purging further with nitrogen, a balloon containing hydrogen was placed on top of the flask. After stirring at room temperature for 18 hours, the LC indicated no more starting material was present. The catalyst was filtered through a plug of silica gel/celite/sand and washed with MeOH. The solvent was evaporated in vacuo and the residue co-evaporated from ether. The resulting pale yellow foam (5t) was stored under N2, 0.34 g (91% isolated yield). 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=7.8 Hz, 1H), 7.17 (dd, J=7.8, 1.6 Hz, 1H), 7.13 (d, J=1.6 Hz, 1H), 5.19-5.18 (m, 1H), 4.51-4.44 (m, 1H), 4.43-4.36 (m, 1H), 2.53-2.45 (m, 1H), 2.36-2.30 (m, 1H); MS (ESI+) m/z 272 (M+H) detected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([CH:27]=O)[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([CH2:27][N:33]5[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]5)[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2cc1CN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.053 g (0.13 mmole) of 4-(3-chloro-phenyl)-2-(6-formyl-5-methoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.46a), 0.030 mL of N-methylpiperazine, 0.050 g of sodium triacetoxyborohydride and 5 mL of dichloromethane was stirred at room temperature for 16 hours. The mixture was partitioned between 50 mL of dilute aqueous potassium carbonate solution and 50 mL of dichlormethane. The organic layer was separated and the aqueous layer was extracted three times with 20 mL of dichloromethane. The combined organic layers were washed with 30 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 15:85-20:80) to give 0.016 g of 4-(3-chloro-phenyl)-2-[5-methoxy-6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.46) as a pink solid. MH+/Z=497
Reaction SMILES: [CH3:1][N:2]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[C:24]([CH3:32])[CH:23]=2)=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([OH:10])=O.[NH2:33][OH:34]>>[OH:34][NH:33][C:8]([C@@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[N:2]([CH3:1])[S:11]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[C:24]([CH3:32])[CH:23]=2)=[CH:18][CH:19]=1)(=[O:13])=[O:12])=[O:10]
Reactant: NO
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@H]3CCC[C@H]3C(=O)O)cc2)c2ccccc2n1
Product: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@H]3CCC[C@H]3C(=O)NO)cc2)c2ccccc2n1
Yield: 97 %

Procedure:
According to the procedure of Example 10, Step 2, the reaction of 222 mg (0.39 mmol) of cis-2-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylic acid with hydroxylamine provided 183 mg of cis-N-hydroxy-2-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxamide in 97% yield. MS: 470.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)=[O:3].N1CCC(NC2C=C(C=CC=2)C#N)CC1>>[NH:14]1[CH2:13][CH2:12][CH:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:2]([NH2:1])=[O:3])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C(N)=O)CC1
Agent: N#Cc1cccc(NC2CCNCC2)c1
Product: NC(=O)c1ccccc1NC1CCNCC1

Procedure:
The title compound was prepared from 1,1-dimethylethyl 4-{[2-(aminocarbonyl)phenyl]amino}-1-piperidinecarboxylate (D19) using a method similar to that described for D6 in Description 6.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[NH:7]1)=[O:5])[CH3:2].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[N:7]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@H](C(=O)O)N1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C1CCC(C(=O)O)N1C(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 0.75 h

Procedure:
To an aqueous solution of trans-2,5-pyrrolidine dicarboxylic acid monoethyl ester (4.8 g, 0.25 m) at 5° C. was simultaneously added benzyl chloroformate (4.8 ml, 0.032 m) and a solution of sodium carbonate (5.4 g, 0.05 m) in water (20 ml). The mixture was stirred at 5° C. for 45 minutes and then extracted with ether. The aqueous mixture was acidified to pH 3 with dilute hydrochloric acid and extracted with diethyl ether. The combined extracts were washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to yield the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[C@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=2)=[CH:4][CH:3]=1.[CH:27](O)=[O:28]>>[CH:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[C@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=2)=[CH:4][CH:3]=1)=[O:28]
Reactant: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(N)cc1
Reactant: O=CO
Product: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(NC=O)cc1

Procedure:
2,1 g of cis-6-(4-aminophenyl)-8,9-dimethoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6] naphthyridine are heated to 100° for 21/2 hours in 50 ml of 90% formic acid. The reaction solution is evaporated to dryness in a vacuum, the resulting residue is made alkaline with a dilute potash solution and this aqueous phase is extracted with methylene chloride. After drying and concentrating the organic phase by evaporation, the title compound is obtained as a yellow oil and crystallizes after the addition of ethanol in the form of yellowish prisms having a melting point of 140°-145°.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][C:18]=2[CH3:27])[C:12]2[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:11]=2[NH:10][CH2:9]1)(C)(C)C.[ClH:35]>O1CCOCC1>[ClH:35].[NH2:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][C:18]=2[CH3:27])[C:12]2[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:11]=2[NH:10][CH2:9]1
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2cc(C#N)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](N)CNc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.15 %

Procedure:
To a solution of [(S)-7-cyano-1-(2-methyl-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-carbamic acid tert-butyl ester (Intermediate 9) (400 mg, 0.877 mmol) in 1,4 dioxane (3 mL) at 0° C. was added 4 N HCl in dioxane solution (0.7 mL) dropwise. The mixture was stirred for 16 h at RT. The mixture was concentrated and the residue was triturated with diethyl ether to provide (S)-3-amino-1-(2-methyl-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile hydrochloride (310 mg, 90.15%) obtained as an off white solid. LC-MS: 357.2 (M+H).