Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](B(O)O)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:13]1[CH:14]=[N:15][N:16]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=[CH:26][C:19]=23)[CH:17]=1.C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C:7]([C:13]2[CH:14]=[N:15][N:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=[CH:26][C:19]=34)[CH:17]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(B(O)O)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-n3cc(Br)cn3)ccnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: C=C(c1ccccc1)c1cnn(-c2ccnc3c2ccn3COCC[Si](C)(C)C)c1
Temperature: 100 °C

Procedure:
A mixture of (1-phenylvinyl)boronic acid (24.0 mg, 0.000162 mol) and 4-(4-bromo-1H-pyrazol-1-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (50.0 mg, 0.000127 mol) in toluene (2.00 mL, 0.0188 mol) and ethanol (0.50 mL, 0.0086 mol) was treated with potassium carbonate (35 mg, 0.00025 mol) in water (1.00 mL, 0.0555 mol). The mixture was degassed by bubbling nitrogen. Tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.00001 mol) was added and nitrogen was bubbled for 3 min. The reaction was heated in a sealed tube in the microwave at 100° C. for 30 min. The reaction was allowed to cool to rt and partitioned between ethyl acetate and water. The combined organic layer was dried over MgSO4, filtered and concentrated to give the crude material The crude product was purified by FCC on silica gel eluting with EtOAc/Hexanes (1:5) to give 4-[4-(1-phenylvinyl)-1H-pyrazol-1-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]-pyridine as a solid residue, LC/MS (M+H)+: 417.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.[C:18]1([CH3:27])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>>[CH3:27][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2
Reactant: Cc1ccccc1B(O)O
Reactant: BrC=C1c2ccccc2CCc2ccccc21
Product: Cc1ccccc1C=C1c2ccccc2CCc2ccccc21

Procedure:
Combine 5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.5 g, 1.75 mmol) and o-tolylboronic acid (0.238 g, 1.75 mmol) using procedures essentially as described in Example 219, below. Pass through a plug of silica gel equilibrated with hexanes. Concentrate the filtrate to give the title product: MS (m/e) 296 (M+); Analysis for C23H20: Calcd: C, 93.19 H, 6.80. Found: C, 93.42 H, 6.79.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:47]=[CH:46][C:12]2[N:13]([CH:16]([C:22]3[N:23](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:24]=[CH:25][N:26]=3)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:14]=[N:15][C:11]=2[CH:10]=1)#[N:2].C(O)=O.[H-].[Na+].Br[CH2:54][C:55]([O:57][CH2:58][CH3:59])=[O:56]>CCOCC.O.CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:47]=[CH:46][C:12]2[N:13]([CH:16]([C:22]3[N:23]([CH2:54][C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH:24]=[CH:25][N:26]=3)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:14]=[N:15][C:11]=2[CH:10]=1)#[N:2]
Reactant: CCOC(=O)CBr
Reactant: CCCCCC(c1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)n1cnc2cc(-c3ccccc3C#N)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: O=CO
Product: CCCCCC(c1nccn1CC(=O)OCC)n1cnc2cc(-c3ccccc3C#N)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
2-[1-[5-(2-Cyanophenyl)-1H-benzimidazol-1-yl]hexyl]-1-trityl-1H-imidazole (3.44 moles, 2.1 g) was dissolved in 200 ml ether, 240 ml formic acid, and 24 drops of water. The solution was stirred for 1 hour at room temperature and concentrated. Ethyl acetate was added. The ethyl acetate solution was washed with water, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in 50 ml DMF. Sodium hydride (3.8 mmoles, 152 mg of 60% in mineral oil) was added. The reaction was stirred at room temperature for 2 hours. Ethyl bromoacetate (3.8 moles, 0.634 g.) in 50 ml DMF was added. The reaction was stirred for 1 hour, poured into ice water, and extracted with ethyl acetate. The organic solution was washed with brine, dried over sodium sulfate, and concentrated. The intermediate was purified by chromatography over silica gel eluted with ethyl acetate to give 830 mg of ethyl 2-[1-[5-(2-cyanophenyl)1H-benzimidazol-1-yl]hexyl]-1H-imidazole-1-acetate. (MS)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)[CH:5]=O.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[C:23]=1[NH2:29]>>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[C:23]=3[N:29]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1
Reactant: Cc1cccc(N)c1N
Reactant: CN1CCN(CCCOc2ccc(C=O)cc2F)CC1
Product: Cc1cccc2[nH]c(-c3ccc(OCCCN4CCN(C)CC4)c(F)c3)nc12
Yield: 100 %

Procedure:
This compound was prepared by the method described in Example 1, using 3-fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde (94 mg, 0.34 mmol, 1.0 equiv), 3-methyl-benzene-1,2-diamine (42 mg, 0.34 mmol, 1.0 equiv), and Na2S2O5 (84 mg, 0.44 mmol, 1.3 equiv) in General Procedure 3. Purification by Method 2 afforded 130 mg (100%) of the title compound. MS (electrospray): mass calculated for C22H27FN4O, 382.22; m/z found, 383.2 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.86-7.78 (m, 2H), 7.40-7.37 (m, 1H), 7.12-6.97 (m, 3H), 3.99 (t, J=6.1 Hz, 2H), 3.00-2.30 (m, 13H), 2.25 (s, 3H), 1.94-1.90 (m, 2H).
Reaction SMILES: C([BH3-])#N.[Na+].[CH:5](=[N:12][NH:13][C:14]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>CO.C1COCC1.O>[CH2:5]([NH:12][NH:13][C:14]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)c1cc(Cl)ccc1NN=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Cl)ccc1NNCc1ccccc1
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
A solution of sodium cyanoborohydride (780 mg) in methanol (20 ml) was added to a stirred solution of 2-(benzylidenehydrazino)-5-chlorobenzoic acid (2.7 g) in THF (20 ml) containing a few milligrams of the indicator Congo Red. A methanolic solution of hydrogen chloride was added dropwise until the indicator in the reaction solution turned blue. Stirring was continued for 15 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and evaporated to give 2-(2-benzylhydrazino)-5-chlorobenzoic acid as a solid (2.5 g) which was used without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH2:16])=O)[CH:6]=[CH:5]2.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]#[N:16])[CH:6]=[CH:5]2
Reactant: Cc1ccc2nc(-c3ccccc3C(N)=O)ccc2c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Product: Cc1ccc2nc(-c3ccccc3C#N)ccc2c1
Yield: 45 %

Procedure:
15 ml of pyridne were added to 2.05 g (7.82 mmol) of 2-(6-methylquinolin-2-yl)benzamide obtained in Reference Example 7 and the mixture was stirred. Were, 1.49 g (7.82 mmol) of p-toluenesulfonyl chloride were added thereto and stirred at room temperature for 2 hours. After further stirring the mixture at 40° C. for 2 hours, the reaction mixture was poured into 30 ml of water and extracted with 50 ml of methylene chloride. The resulting extract was dried over magnesium sulfate followed by filtration. The filtrate was concentrated and the concentrate was subjected to silica gel chromatography using a mixed solvent of hexane and ethyl acetate (7/1) to obtain 0.86 g of 2-(6-methylquinolin-2-yl)benzonitrile.
Reaction SMILES: Cl.[CH:2]1([NH:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.N/[C:10](/[CH3:14])=[CH:11]\[C:12]#[N:13]>C(O)C>[CH:2]1([N:7]2[C:12]([NH2:13])=[CH:11][C:10]([CH3:14])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NNC1CCCC1
Reactant: C/C(N)=C/C#N
Agent: Cl
Solvent: CCO
Product: Cc1cc(N)n(C2CCCC2)n1

Procedure:
The title compound was prepared in the same manner as described for intermediate 19 using cyclopentylhydrazine hydrochloride (2 g, 14.64 mmol), (2Z)-3-amino-2-butenenitrile (1.202 g, 14.64 mmol) and ethanol (20 mL). The final product was collected as 0.57 g (24%). LCMS E-S (M+H)=166.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.60-1.69 (m, 2H), 1.86-1.95 (m, 2H), 1.99-2.09 (m, 4H), 2.19 (s, 3H), 3.46 (br. s., 2H), 4.38 (quin, J=7.89 Hz, 1H), 5.36 (s, 1H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[S:13]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)(=[O:15])=[O:14].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH:3]=[O:2])=[C:7]([S:13]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)(=[O:14])=[O:15])[CH:8]=1
Reactant: COC(=O)CCc1ccc(F)cc1S(=O)(=O)N1CCOCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: O=CCCc1ccc(F)cc1S(=O)(=O)N1CCOCC1
Temperature: -70 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
The solution of the product of example 87 (830 mg, 2.5 mmol) in toluene (5 ml) was cooled down to −70° C. DIBAL-H (1 mol/l in toluene, 3.12 ml) was added dropwise. After completion of addition, the mixture was stirred at −70° C. for one hour. Then the reaction was quenched by adding MeOH (2 ml), after which it was warmed to room temperature. The mixture was dissolved in EA, washed with brine, dried and evaporated under reduced pressure. The residue was purified by column chromatography (PE:EA=3:2) to afford the title compound (355 mg, 47% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[F:32][C:33]([F:47])([F:46])[C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:37][NH2:38]>>[F:32][C:33]([F:46])([F:47])[C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([C:42]([F:45])([F:43])[F:44])[CH:41]=1)[CH2:37][NH:38][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([C:16]2[CH:15]=[N:14][C:10]3[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:28]([F:30])([F:31])[F:29])[C:9]=3[CH:17]=2)=[CH:19][CH:20]=1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 3,5-bis(trifluoromethyl)benzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=672.90 (M+H+); retention time=1.11 minutes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([CH:15]=[C:16](Br)Br)[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23]>>[C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][C:22](=[O:23])[N:21]([CH3:25])[CH3:20])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C=C(Br)Br)CC1
Reactant: CN(C)C(=O)Cl
Product: CN(C)C(=O)C#C[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1

Procedure:
In a similar way as described in example 26.5, trans-[4-(2,2-Dibromo-vinyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester and dimethylcarbamoyl chloride gave trans-(4-Dimethylcarbamoylethynyl-cyclohexyl)-methyl-carbamic acid tert-butyl ester, mp: 115-117° C.; MS: 309 (MH+).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Li]CCCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:27]=[N:26][N:25]([CH3:28])[C:24]=2[CH:29]=[O:30])=[CH:19][CH:18]=1>C1COCC1>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[N:27]=[N:26][N:25]([CH3:28])[C:24]=2[CH:29]([OH:30])[CH2:1][C:2]2[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=2)=[CH:21][CH:22]=1
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(CC(O)c2c(-c3ccc(F)cc3)nnn2C)sc1C(=O)O
Temperature: -75 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
To a suspension of 2,4-dimethylthiazole-5-carboxylic acid (236 mg, 1.5 mmol) in THF (12 mL) was added dropwise n-BuLi (1.6 M in hexanes, 1.88 mL, 3.0 mmol) under Ar at −75° C. The brown suspension was stirred at −75° C. for 2 h and then a solution of 5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazole-4-carbaldehyde (308 mg, 1.50 mmol) in THF (4.5 mL) was added at −75° C. and the brown suspension was stirred at −75° C. for 2 h. The mixture was then quenched with an aqueous solution of citric acid (5%, 15 mL), allowed to warm to room temperature. The mixture was then poured into saturated ammonium chloride solution and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 30% methanol in dichloromethane) afforded 2-{2-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-2-hydroxy-ethyl}-4-methyl-thiazole-5-carboxylic acid (417 mg, 77%) as a yellow foam. The acid was then dissolved in methanol (4 mL) and diethylether (2 mL) and trimethylsilyldiazomethane (2M in diethylether, 5×0.38 mL, 3.75 mmol) added dropwise. The reaction was quenched with a few drops of AcOH and evaporated. To the brown oil was added sodium hydroxide (1 N, 20 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, 0 to 30% methanol in dichloromethane) afforded the title compound (214 mg, 38%) as a light brown foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[C:16]([NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[N+:13]([C:3]1[CH:4]=[C:5]([C:8]2[NH:12][N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]=1[N:27]1[CH2:26][CH2:25][CH:24]([NH:23][C:16](=[O:17])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:29][CH2:28]1)([O-:15])=[O:14]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=[N+]([O-])c1cc(-c2ccn[nH]2)ccc1Cl
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(-c3ccn[nH]3)cc2[N+](=O)[O-])CC1

Procedure:
Method 1 was followed using 5-(4-chloro-3-nitrophenyl)-1H-pyrazole (1.0 eq), 4-(N-Boc-amino) piperidine (1.1 eq), and TEA (2.0 eq) at 55° C. for 24 hours yielding tert-butyl 1-(2-nitro-4-(1H-pyrazol-5-yl)phenyl)piperidin-4-ylcarbamate. LCMS (m/z): 388.1 (MH+); LC Rt=2.84 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH:17][C:18]2[CH:19]=[N:20][N:21]([CH3:40])[C:22]=2[N:23]2[CH2:29][C:28]([F:31])([F:30])[CH2:27][CH:26]([NH:32]C(=O)OC(C)(C)C)[CH2:25][CH2:24]2)=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[N:6][CH:7]=1.Cl>O1CCOCC1>[NH2:1][C:2]1[C:3]([C:15]([NH:17][C:18]2[CH:19]=[N:20][N:21]([CH3:40])[C:22]=2[N:23]2[CH2:24][CH2:25][CH:26]([NH2:32])[CH2:27][C:28]([F:31])([F:30])[CH2:29]2)=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[N:6][CH:7]=1
Reactant: Cn1ncc(NC(=O)c2nc(-c3ccccc3F)ncc2N)c1N1CCC(NC(=O)OC(C)(C)C)CC(F)(F)C1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3F)ncc2N)c1N1CCC(N)CC(F)(F)C1

Procedure:
tert-butyl 1-(4-(5-amino-2-(2-fluorophenyl)pyrimidine-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6,6-difluoroazepan-4-ylcarbamate (157 mg) was stirred with 4N HCl in dioxane (6 mL) at room temperature for 1 h. The reaction mixture was concentrated to dryness, basified with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate 3×. Combined organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified on reversed phase HPLC to give 237. MS (ESI) m/z: 461.1 [M+H+].
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9](CO)[OH:10])[OH:8])[OH:6])[OH:4].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>O>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Yield: 1 %

Procedure:
Streptomyces sp. ATCC 21175 was grown under aerobic submerged fermentation conditions at a pH of 7 in a presterilized aqueous medium containing 1 percent sorbitol, 0.75 percent dextrose, sufficient corncob hydrolysate to provide 1 percent xylose, 4 percent steep water at 29° C. and 0.024 percent cobaltous ion. The fermentation was carried out at 30° C., an airflow of 1 volume of air per volume of medium per minute and a back pressure of 10 p.s.i. The fermenting broth was mechanically stirred at 200 r.p.m. and after 65 hours 4 percent filter aid was admixed into the broth and the cellular material harvested from the broth by filtration with suction. The filter cake was washed with demineralized water, broken into small pieces and dried for 5 hours in a forced-air oven at an air temperature of 140° F. The activity of the air-dried filter cake was 660 GIU/g.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[C:10]2[S:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].CI.[C:29](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[N:12]([CH3:29])[N:11]=[C:10]2[S:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OCCCl)cccc12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(S(=O)(=O)c2cccc3ccccc23)c2cccc(OCCCl)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.7 g, 1.8 mmoles), methyl iodide (0.28 mL, 2.17 mmoles), and potassium carbonate (0.29 g, 2.17 mmoles) in DMF (10 mL) was stirred together in a round bottom flask at room temperature for 2 hours. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC using as eluent 30% EtOAc/hexane to afford the title compound as an off-white solid, 0.55 g, 1.375 mmoles.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4](=[S:7])[N:3]1[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[N+:18]([C:21]1[CH:22]=[C:23]([C:27]2[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=2)[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].C(O)(=O)C.C(O)(=O)C.C(N)CN.S([O-])(O)=O.[Na+]>CO>[N+:18]([C:21]1[CH:22]=[C:23]([C:27]2[O:31][C:30]([CH:32]=[C:6]3[S:5][C:4](=[S:7])[N:3]([NH:8][C:9]4[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=4[C:11]([OH:13])=[O:12])[C:2]3=[O:1])=[CH:29][CH:28]=2)[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: O=Cc1ccc(-c2cccc([N+](=O)[O-])c2)o1
Reactant: O=C(O)c1ccccc1NN1C(=O)CSC1=S
Agent: O=S([O-])O
Agent: [Na+]
Solvent: NCCN
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1NN1C(=O)C(=Cc2ccc(-c3cccc([N+](=O)[O-])c3)o2)SC1=S
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.5 %

Procedure:
A mixture of 2-(4-oxo-2-thioxo-thiazolidin-3-ylamino)-benzoic acid (0.092 g, 0.34 mmol), 5-(3-nitrophenyl)furan-2-carbaldehyde (0.071 g, 0.33 mmol) (purchased from Aldrich Chemical Company) and ethylenediamine diacetate (0.059 g, 0.033 mmol) in methanol (10 mL) was stirred at room temperature for 18 h. The reaction mixture was poured into stirred 0.6 N aq sodium hydrogensulfite (50 mL). The mixture was vigorously stirred for 30 min. The solid product was filtered off and washed on funnel successively with 0.6 N aq sodium hydrogensulfite (1 mL), water (2×2 mL), acetonitrile (1 mL), ether (2×2 mL) and acetonitrile (1 mL). The material was dried in a vacuum oven at 65° C. for 17 h to afford 2-{5-[1-[5-(3-Nitro-phenyl)-furan-2-yl]-methylidene]-4-oxo-2-thioxo-thiazolidin-3-ylamino}-benzoic acid (115 mg, 72%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 6.62 (1H, m), 6.90 (1H, m), 7.37 (1H, m), 7.44 (1H, d, J=3.6 Hz), 7.64 (1H, d, J=3.6 Hz), 7.80 (1H, s), 7.88 (1H, m), 7.92 (1H, m), 8.28 (2H, m), 8.65 (1H, m), 10.2 (1H, bs). LC/MS: APCI 466.7, HPLC 96.5%
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11](Cl)=[O:12].O>C1(C)C=CC=CC=1>[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:12]
Reactant: O=C(Cl)c1cccs1
Reactant: C1CCNC1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(c1cccs1)N1CCCC1

Procedure:
Pyrrolidine (47 ml) was added to 2-thiophene carbonyl chloride (40 g) in toluene below 10°. After 11/2 hr, water was added. The product was extracted with ethyl acetate, crystallised from toluene and recrystallised from light petroleum (b.p. 60°-80°)/ethyl acetate to give white crystals (40 g) m.p. 66°-68°; TLC silica/ethyl acetate Rf 0.5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:26](Br)[CH2:27][CH2:28][CH2:29][CH3:30]>CN(C)C=O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Combine 1-t-butoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.8 g, 2.5 mmol) in dimethylformamide (10 mL). Add sodium hydride (0.13 g, 60% in oil, 3.25 mmol) portionwise. After about 30 minutes, when the gas evolution ceases, add pentyl bromide (0.34 mL, 2.74 mmol). Heat to 80° C. After 18 hours, cool the reaction mixture and dilute with dichloromethane (150 mL) and extract with brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-t-butoxycarbonyl-4-(1-pentyl-1H-benzimidazol-2-yl)[1,4]diazepane: Rf =0.87 (silica gel, 5% methanol/dichloromethane/0.05% concentrated aqueous ammonia). Combine 1-t-butoxycarbonyl-4-(1-pentyl-1H-benzimidazol-2-yl)[1,4]diazepane (0.7 g, 1.8 mmol) and ethanol (5 mL). Add aqueous hydriodic acid (5 mL, 57%). Heat to reflux. After 1 hour, cool to ambient temperature and dilute with diethyl ether (250 mL) and stir to give a solid. Collect the solid by filtration, rinse with diethyl ether, and dry to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)[C:7](=O)[CH2:6][CH2:5]2.[NH2:22][C:23]1[CH:31]=[C:27]([C:28]([OH:30])=[O:29])[C:26]([OH:32])=[CH:25][CH:24]=1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>>[C:28]([C:27]1[CH:31]=[C:23]([N:22]2[C:7]3[CH2:6][CH2:5][C:4]4[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=4[C:8]=3[CH:12]=[C:13]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:24]=[CH:25][C:26]=1[OH:32])([OH:30])=[O:29]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C(CC1C(=O)CCc2cc(Cl)ccc21)c1ccccc1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2cc(Cl)ccc2-3)ccc1O

Procedure:
A mixture of 10.1 g. (0.03 mole) of 6-chloro-1-phenacyl-2-tetralone, 4.5 g. (0.03 mole) of 5-aminosalicylic acid and 30 ml. of glacial acetic was heated under reflux for 70 minutes, cooled and filtered. The collected solid was washed with acetic acid and petroleum ether and recrystallized from acetonitrile to give 4.3 g. (59%) of colorless crystals, m.p. 249°-251°.