Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=2.[CH2:15](OC(OCC)CBr)[CH3:16].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C1COCC1>[Cl:1][C:2]1[C:3]2[N:4]([CH:15]=[CH:16][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=2
Reactant: Cc1cc2nc(N)c(Cl)nc2cc1C
Reactant: CCOC(CBr)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2nc(Cl)c3nccn3c2cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
To a stirred suspension of 3-chloro-6,7-dimethyl-quinoxalin-2-ylamine (30.9 g, 0.16 mol) in water/THF 1:1 (540 mL) at room temperature was added bromoacetaldehyde diethyl acetal (94.6 g, 0.48 mol) and 5 g of PPTS in one portion. After stirring at room temperature for 1 h, the mixture was heated to reflux for 3 h under stirring and then stirred for an additional 15 h at room temperature. The pH value of the mixture was adjusted to pH 8 by addition of solid sodium carbonate. The precipitate formed was filtered off to give 25 g of the title compound. 1H-NMR (300 MHz, d6-DMSO): δ=8.85 (1H, s), 8.19 (1H, s), 7.73 (1H, bs), 7.80 (1H, bs), 3.60 (6H, s) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].C[Al](C)C.N#N.[NH:21](/[C:25](/[CH3:31])=[CH:26]\[C:27](OC)=[O:28])[C:22]([CH3:24])=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:27](=[O:28])[CH:26]=[C:25]([CH3:31])[N:21]=[C:22]2[CH3:24])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Agent: N#N
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.1 %

Procedure:
To a solution of 3-fluoro-4-morpholinoaniline (11.0 g, 56 mmol) in CH2Cl2 (200 mL) was added trimethylaluminium (168 mL, 168 mmol, 1 M in heptane) dropwise carefully under N2. The mixture was stirred at rt for 20 min, followed by the addition of a solution of methyl 3-acetaminocrotonate (10.57 g, 67 mmol) in CH2Cl2 (30 mL). The reaction was stirred at rt for 5 h, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2. The combined organic phases were washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was recrystallized from EtOAc to give the title compound as a pale yellow solid (11.39 g, 67%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C(OC(C1ON=C(C2C=CC(N)=CC=2)C=1)=O)C.[CH2:18]([O:20][C:21]([C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-])=O)[CH:29]=2)[CH:24]=1)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[CH:29]=2)[CH:24]=1)=[O:22])[CH3:19]
Reactant: CCOC(=O)c1cc(-c2cccc([N+](=O)[O-])c2)no1
Agent: CCOC(=O)c1cc(-c2ccc(N)cc2)no1
Product: CCOC(=O)c1cc(-c2cccc(N)c2)no1

Procedure:
The title compound was prepared according to the procedure as set forth in Example 1 for the preparation of 3-(4-amino-phenyl)-isoxazol-5-carboxylic acid ethyl ester, except that 3-(3-nitro-phenyl)-isoxazole-5-carboxylic acid ethyl ester was used in place of 3-(4-nitro-phenyl)-isoxazole-5-carboxylic acid ethyl ester. The crude product was purified by flash chromatography with 15% EtOAc in light petroleum. Mass (ES+), 233 (M++1), 255 (M++Na); IR (KBr): 3460, 3369, 1727, 1615, 1431; 1H NMR (CDCl3) 1.43 (t, 3H), 3.83 (s, 2H), 4.45 (q, 2H), 6.78 (m, 1H), 7.13-7.19 (m, 4H).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:31])=O.CN(C=O)C>ClCCl>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:31])=[O:10])=[C:7]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)O)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Cl)CC1
Reaction time: 0.5 h

Procedure:
To a stirring solution of 4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoic acid (4.0 g, 10.6 mmol) in dichloromethane (20 mL) at 0° C., was added oxalyl chloride (13 mmol), followed by a small amount of DMF. After 30 min, the solvents were removed in vacuo and the residue was dissolved in dichloromethane to make a solution of the title compound, approximately 0.1 g/mL.
Reaction SMILES: N#N.[F:3][C:4]1[CH:5]=[C:6]([C:10]2[O:14][C:13]([CH3:15])=[N:12][C:11]=2[C:16]([OH:18])=O)[CH:7]=[CH:8][CH:9]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:33]([Si:37]([CH3:54])([CH3:53])[O:38][CH:39]([C:41]1[O:42][C:43]([CH2:46][N:47]2[N:51]=[C:50]([NH2:52])[CH:49]=[N:48]2)=[CH:44][N:45]=1)[CH3:40])([CH3:36])([CH3:35])[CH3:34]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[C:33]([Si:37]([CH3:54])([CH3:53])[O:38][CH:39]([C:41]1[O:42][C:43]([CH2:46][N:47]2[N:51]=[C:50]([NH:52][C:16]([C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=3)=[O:18])[CH:49]=[N:48]2)=[CH:44][N:45]=1)[CH3:40])([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)o1
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ncc(N)n2)o1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: Cc1nc(C(=O)Nc2cnn(Cc3cnc(C(C)O[Si](C)(C)C(C)(C)C)o3)n2)c(-c2cccc(F)c2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(3-fluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid (34 mg, 0.16 mmol) in CH2Cl2 (1.0 mL) was treated at rt with HOBt (25 mg, 0.19 mmol), EDC (74 mg, 0.38 mmol), DMAP (5 mg, 0.04 mmol) and the resulting mixture was stirred at rt for 30 min. 2-{2-[1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl}-2H-[1,2,3]triazol-4-ylamine (50 mg, 0.16 mmol) in CH2Cl2 (0.6 mL) was then added and the resulting mixture was stirred at rt for 16 h. CH2Cl2 (20 mL) followed by water (15 mL) were added and the aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with water, brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a brown oil. LC-MS-conditions 02: tR=1.22 min, [M+H]+=527.5.
Reaction SMILES: [C:1]1([C:7]([NH:10][C:11]2[O:12][C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:20]=[C:19]4B3OC(C)(C)C(C)(C)O3)=[N:14][N:15]=2)([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:45]1[N:50]=[CH:49][CH:48]=[CH:47][N:46]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]1([C:7]([NH:10][C:11]2[O:12][C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:26])=[O:27])[CH:20]=[C:19]4[C:45]3[N:50]=[CH:49][CH:48]=[CH:47][N:46]=3)=[N:14][N:15]=2)([CH3:8])[CH3:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)(C)c5ccccc5)o4)ccc32)cc1
Reactant: Brc1ncccn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncccn3)c3cc(-c4nnc(NC(C)(C)c5ccccc5)o4)ccc32)cc1
Temperature: 120 °C
Yield: 42.7 %

Procedure:
N-(2-Phenylpropan-2-yl)-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (757.3 mg, 1.265 mmol), 2-bromopyrimidine (221 mg, 1.392 mmol) (Aldrich), potassium phosphate (806 mg, 3.80 mmol) (Sigma-Aldrich), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (36.2 mg, 0.076 mmol) (Strem Chemicals), and Pd2(dba)3 (34.8 mg, 0.038 mmol) (Strem Chemicals) were weighed into a 20 mL glass microwave tube, and the tube was purged with argon. The solids were treated with dioxane (8 mL) and water (0.800 mL), the tube was sealed and the contents were heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 20 min. The mixture was treated with water, extracted with EtOAc (3×50 mL), dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (30-100% EtOAc in Hex) to give N-(2-phenylpropan-2-yl)-5-(3-(pyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (297.4 mg, 0.540 mmol, 42.7%). MS (ESI, pos. ion) m/z: 551.2 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([F:8])([F:7])[F:6].O.[NH2:11][NH2:12]>CO>[F:6][C:5]([F:8])([F:7])[CH2:4][C:3]([NH:11][NH2:12])=[O:2]
Reactant: COC(=O)CC(F)(F)F
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)CC(F)(F)F
Yield: 57.8 %

Procedure:
A solution of 3,3,3-trifluoro-propionic acid methyl ester (24.6 g, 173 mmol) in methanol (173 mL) was treated with hydrazine hydrate (8.4 mL, 173 mmol). The resulting mixture was then heated under reflux for 16 h and filtered. The filtrate was adsorbed on silica, evaporated and chromatographed (SiO2, dichloromethane:methanol=95:5 to 90:10). The title compound (14.2 g, 58%) was obtained as a white solid. MS: m/e=142.1 [M]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[CH3:14])([CH3:3])[CH3:2].Cl.[C:16]1([CH:22]2[O:27][C:26]3([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH2:25][NH:24][C:23]2=[O:33])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([N:30]2[CH2:29][CH2:28][C:26]3([CH2:25][NH:24][C:23](=[O:33])[CH:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:27]3)[CH2:32][CH2:31]2)=[O:11])=[CH:7][C:6]=1[CH3:14])([CH3:2])[CH3:3]
Reactant: O=C1NCC2(CCNCC2)OC1c1ccccc1
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2CCC3(CC2)CNC(=O)C(c2ccccc2)O3)ccc1OC(C)C
Reaction time: 16 h
Yield: 40.1 %

Procedure:
To 4-isopropoxy-3-methyl-benzoic acid (114 mg, 0.59 mmol), 4-phenyl-5-oxa-2,9-diazaspiro[5.5]undecan-3-one hydrochloride salt (166 mg, 0.59 mmol) and HATU (223 mg, 0.59 mmol) in DMF (0.5 mL) was added diisopropylethylamine (228 mg, 307 μL, 1.76 mmol) and the reaction mixture was stirred for 16 hours. The reaction mixture was concentrated in vacuo, diluted with methanol and purified by prep LCMS (1-99% ACN/H2O, 5 mM HCl modifier) to give 3-(4-isopropoxy-3-methyl-benzoyl)-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-9-one (100 mg, 40%) as a yellow foam. ESI-MS m/z calc. 422.2. found 423.5 (M+1)+; Retention time: 1.61 minutes (3 min run).
Reaction SMILES: NC1C=CC(C2CCC(C(OC)=O)C2)=CC=1.[N+](C1C=CC(C2CCC(C(OC)=O)C2)=CC=1)([O-])=O.[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([C@@H:42]2[CH2:46][CH2:45][C:44](=[CH:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:43]2)=[CH:38][CH:37]=1>>[NH2:35][C:36]1[CH:37]=[CH:38][C:39]([C@@H:42]2[CH2:46][CH2:45][CH:44]([CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:43]2)=[CH:40][CH:41]=1
Reactant: CCOC(=O)C=C1CC[C@@H](c2ccc(N)cc2)C1
Agent: COC(=O)C1CCC(c2ccc(N)cc2)C1
Agent: COC(=O)C1CCC(c2ccc([N+](=O)[O-])cc2)C1
Product: CCOC(=O)CC1CC[C@@H](c2ccc(N)cc2)C1

Procedure:
Following the procedure described for methyl 3-(4-aminophenyl)cyclopentanecarboxylate, replacing methyl 3-(4-nitrophenyl)cyclopentanecarboxylate (Intermediate 84(ii)) with ethyl [(3R)-3-(4-aminophenyl)cyclopentylidene]acetate, the title compound was obtained; 1H NMR δ 1.18 (t, 3H), 1.21-1.76 (m, 2H), 1.80-2.12 (m, 2H), 2.23-2.48 (m, 2H), 2.80-3.01 (m, 1H), 3.16-3.30 (m, 2H), 4.06 (q, 2H), 4.79 (s, 2H), 6.45-6.51 (m, 2H), 6.84-6.91 (m, 2H); MS m/e M+MeCN 289.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([CH:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]([OH:22])=[O:21])[C:3]=1[CH3:28].BrC1C2C(=CC=CC=2)C(C2C=CC(Cl)=CC=2)=C([C@@H](O)C(OC)=O)C=1C>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:4]([C@@H:19]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:20]([OH:22])=[O:21])[C:3]=1[CH3:28]
Reactant: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1Br
Agent: COC(=O)[C@H](O)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Product: Cc1c([C@@H](OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1Br

Procedure:
(R)-2-(4-Bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (150A) was prepared in a similar manner to 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid of Example 124, except using (R)-methyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate, giving the title compound (parent form). 1H NMR (400 MHz, CD3OD) δ 8.38 (d, J=8.6 Hz, 1H), 7.63-7.47 (m, 4H), 7.38-7.20 (m, 3H), 5.30 (s, 1H), 2.69 (s, 3H), 1.00 (s, 9H). LCMS-ESI− (m/z): [M—CO2—H]− calcd for C22H21BrClO: 415.2; Found: 415.0.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[CH2:27]([OH:31])[CH2:28][C:29]#[CH:30]>>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:30][CH2:29][CH2:28][CH2:27][OH:31])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCCO
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(Br)cc12
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(CCCCO)cc12

Procedure:
6-(4-hydroxy-butyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime was prepared in 17% overall yield using the methods described in examples 83A and 83B, starting from 6-bromo-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (tert-butyl protected oxime of example 66) and But-3-yn-1-ol. The title compound was isolated as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)(O)[C:20]4[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=4)[CH:17]=[CH:18][C:13]=3[N:12]([CH3:34])[C:11](=[O:35])[CH2:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:38])=O>>[Cl:38][C:19]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)([C:20]1[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=1)[C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH3:34])[C:11](=[O:35])[CH2:10][N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:14]=2[CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: CN1C(=O)CN=C(c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc21
Product: CN1C(=O)CN=C(c2cccc(Cl)c2)c2cc(C(Cl)(c3ccc(Cl)cc3)c3cncn3C)ccc21
Temperature: 5 °C
Reaction time: 6 h

Procedure:
5-(3-chlorophenyl)-7-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (see Example B8) (0.0075 mol) was added portionwise at 5° C. to thionyl chloride (40 ml). The mixture was stirred at 5° C. for 6 hours. The solvent was evaporated till dryness. The product was used without further purification, yielding 7-[chloro(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-5-(3-chlorophenyl)-1,3dihydro-1-methyl-2H-1,4-benzodiazepin-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][C:15]([CH3:17])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:15]([CH3:17])[CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(N2CCNCC2)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)N1CCN(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
To a mixture of 1-(4-bromophenyl)piperazine (1.20 g, 5 mmol) and acetone (1.47 mL, 20 mmol) in DCE/THF (45 mL/15 mL) was added NaBH(OAc)3 (1.38 g, 6.5 mmol), followed by AcOH (0.5 mL). After addition, the resulting mixture was stirred O/N at rt. The reaction as quenched with NaHCO3 (10 mL) and H2O (10 mL), and was extracted with EtOAc (60 mL×2). The solvents were removed in vacuo to give the crude title compound as a white solid (1.40 g, 99%). 1H NMR (400 MHz, DMSO-d6) δ 7.45 (d, J=7.2 Hz, 2H), 7.21 (d, J=7.2 Hz, 2H), 3.64-3.55 (m, 2H), 3.44 (s, 2H), 2.68 (d, J=11.6 Hz, 2H), 1.75 (t, J=11.0 Hz, 2H), 1.54 (d, J=6.0 Hz, 6H); MS ESI 282.9 [M+H]+, calcd. for [C13H19BrN2+H]+ 283.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1Cl.[NH2:12][CH2:13][CH2:14][CH2:15][OH:16]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:12][CH2:13][CH2:14][CH2:15][OH:16]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: NCCCO
Solvent: CCCCO
Product: O=[N+]([O-])c1cccc(Cl)c1NCCCO

Procedure:
A mixture of 100 parts of 1,2-dichloro-3-nitrobenzene, 95 parts of 3-amino-1-propanol and 200 parts of butanol is stirred and refluxed overnight. The reaction mixture is cooled and evaporated. The residue is taken up in water and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated, yielding 115 parts of 3-[(2-chloro-6-nitrophenyl)amino]-1-propanol as a residue.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=1)([O-])=O.C(Cl)Cl>CO.[C].[Pd]>[N:10]1([C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][N:7]=2)[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=[N+]([O-])c1ccnc(N2CCCC2)c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccnc(N2CCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
4-Nitro-2-(pyrrolidin-1-yl)pyridine (560 mg, 2.90 mmol) was dissolved in methanol (21 mL) and methylene chloride (8.3 mL) and the solution was added with palladium carbon (50% aqueous, 560 mg), followed by stirring at room temperature for 1 hour under hydrogen atmosphere. After filtering off the insoluble matter of the reaction mixture, the solvent was evaporated under reduced pressure to obtain 2-(pyrrolidin-1-yl)pyridin-4-ylamine (474 mg, 91%).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH3:31])[CH2:15][N:16]2[CH:20]=[C:19]([Cl:21])[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([Cl:30])[CH:23]=3)=[N:17]2)=[O:12])[NH:8][N:7]=1)(=[O:5])[CH3:4].Cl>C(O)C.O>[Cl:21][C:19]1[C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([Cl:30])[CH:23]=2)=[N:17][N:16]([CH2:15][C@@H:14]([NH:13][C:11]([C:9]2[NH:8][N:7]=[C:6]([CH:3]([OH:5])[CH3:4])[CH:10]=2)=[O:12])[CH3:31])[CH:20]=1
Reactant: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2cc(Cl)c(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(O)c1cc(C(=O)N[C@@H](C)Cn2cc(Cl)c(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 51 %

Procedure:
Into a 0° C. solution containing sodium tetrahydroborate (0.022 g, 0.580 mmol) dissolved in ethanol (1 ml), (S)-3-acetyl-N-(1-(4-chloro-3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide (0.125 g, 0.290 mmol) of Example 224 dissolved in 2 ml of ethanol was added slowly. The mixture was stirred at 0° C. for a few minutes after which the mixture was allowed to warm to RT and the stirring was continued for 4.5 h. A few drops of water was added slowly. The pH was adjusted below 4 with 2 M HCl. The solvent was evaporated and the residue extracted with DCM/water. Organic phase was isolated with phase separator and evaporated. The product was purified by recrystallization from ethanol. Yield 51.0%. 1H-NMR (400 MHz; DMSO-d6): δ 1.14 (d, 3H), 1.38 (d, 3H), 4.23-4.37 (m, 2H), 4.40-4.50 (m, 1H), 4.75-4.83 (m, 1H), 5.40 (d, 1H), 6.40 (s, 1H), 8.00 (dd, 1H), 8.04 (dd, 1H), 8.05-8.14 (m, 3H), 13.03 (s, 1H).
Reaction SMILES: [CH2:1]1[N:17]2[C:18]3[C:10]([C:11]4[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=42)=[CH:9][CH:8]=[CH:7][C:6]=3[CH2:5][CH2:4][NH:3][CH2:2]1.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH2:1]1[N:17]2[C:18]3[C:10]([CH:11]4[CH:16]2[CH2:15][CH2:14][CH2:13][CH2:12]4)=[CH:9][CH:8]=[CH:7][C:6]=3[CH2:5][CH2:4][NH:3][CH2:2]1
Reactant: c1cc2c3c(c1)c1c(n3CCNCC2)CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: c1cc2c3c(c1)C1CCCCC1N3CCNCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution 2,3,4,5,9,10,11,12-octahydro-1H-[1,4]diazocino[7,8,1-jk]carbazole (0.20 g, 0.80 mmole) in acetic acid (50 mL) was added sodium cyanoborohydride (0.30 g, 4.5 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue was diluted with ethyl acetate (300 mL) and washed with saturated aqueous sodium bicarbonate (150 mL) and saturated aqueous sodium chloride (150 mL), dried (sodium sulfate) and concentrated in vacuo. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 3:2) provided 0.12 g of the title compound as an oil. This compound was treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 169-171° C. MS (ESI) m/z 243 ([M+H]+).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].ClCCl.[C:8]([O:12][C:13]([NH:15][CH2:16][C:17]1[S:18][C:19]([CH2:22]O)=[CH:20][N:21]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>N1C=CC=CC=1>[C:1]([O:4][CH2:22][C:19]1[S:18][C:17]([CH2:16][NH:15][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])=[N:21][CH:20]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)NCc1ncc(CO)s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1cnc(CNC(=O)OC(C)(C)C)s1
Reaction time: 17 h

Procedure:
A 6 ml portion of anhydrous acetic acid was added to a mixed solution of 10 ml of dichloromethane and 20 ml of pyridine containing 2.17 g of 2-(N-t-butoxycarbonylamino)methyl-5-hydroxymethylthiazole, and the mixture was then allowed to stand at room temperature for 17 hours. Under reduced pressure, the solvent was distilled off, and the resulting residue was dissolved in 120 ml of chloroform. The solution was washed once with water and twice with a 10% saline solution, dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under reduced pressure to obtain 2.47 g of 5-acetoxymethyl-2-(N-t-butoxycarbonylamino)methylthiazole.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([SH:17])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)=O>C(O)C.O>[CH2:18]([S:17][C:11]1[CH:10]=[CH:9][C:8]([CH3:7])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc(S)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(SCc2ccccc2)c(C(=O)O)c1
Yield: 89 %

Procedure:
To a solution of 4.15 g. (0.030 moles) of potassium carbonate in 50 ml. of water is successively added 100 ml. of ethanol, 5.05 g. (0.030 moles) of 5-methyl-2-mercaptobenzoic acid, and 3.8 g. (0.030 moles) of benzyl chloride. After the evolution of carbon dioxide ceases (about 10 minutes), the mixture is refluxed on a steam bath for one hour. The mixture is cooled, and the major portion of the solvent is evaporated under reduced pressure. The cloudy, white liquid residue is diluted to a volume of about 600 ml. with water. The mixture is filtered, cooled, and acidified with 6 N hydrochloric acid. The white precipitate which forms is separated, filtered, and triturated with about 400 ml. of water. Filtration and drying under high vacuum provides 6.9 g. (89 percent yield) of 2-benzylthio-5-methylbenzoic acid, m.p. 169°-171°C. sint. 167°C.