Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19](=[O:28])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19](=[O:28])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CCCCCCCNC(=O)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCNC(=O)Oc1ccc2c(c1)CCCN2

Procedure:
A nitrogen flushed mixture of heptyl-carbamic acid 1-benzyl-1, 2, 3, 4-tetrahydro-quinolin-6-yl ester (0.378 g., 1 mmol) and 10% Pd—C (0.02 g.) in absolute ethanol (20 ml) was shaken in a par apparatus at room temperature (38° C.) under 55 psi pressure of hydrogen for 4 hours. Pd—C was then discarded through filtration. The reaction mixture was concentrated under reduced pressure and the residue was chromatographed with methanol: dichloromethane (1:99) to give 2b; yield: 0.25 g. (84.6%), m.p.: 67° C., C17H26N2O2; 1H NMR δ ppm (CDCl3): 0.88 (bs, 3H), 1.20-1.30 (m, 7H, 1.56 (bs, 3H), 1.88-1.93 (m, 2H), 2.74 (t, 2H), 3.23-3.28 (m, 4H), 3.66-3.76 (m, 1H), 4.89 (bs, 1H), 6.40-6.44 (m, 1H), 6.68-6.71 (m, 2H); IR vmax (KBr) (cm−1): 561, 665, 768, 815, 887, 976, 1149, 1223, 1308, 1353, 1506, 1621, 1699, 2362, 2857, 2930, 3763.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][CH2:12][CH2:13][CH2:14][C:15]2([S:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[S:19][C:18](=[O:20])[NH:17][C:16]2=[O:21])=[C:6]([CH3:33])[CH:5]=1.[OH-].[Li+].O>C1COCC1.CO>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([S:22]([C:15]2([CH2:14][CH2:13][CH2:12][C:11]#[C:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:34])=[O:2])=[CH:5][C:6]=3[CH3:33])[S:19][C:18](=[O:20])[NH:17][C:16]2=[O:21])(=[O:23])=[O:24])=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(C#CCCCC2(S(=O)(=O)c3ccc(OC)cc3)SC(=O)NC2=O)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)C2(CCCC#Cc3ccc(C(=O)O)cc3C)SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-{5-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-1-ynyl}-3-methylbenzoic acid methyl ester (Example 160)(0.29 g, 0.536 mmol) in THF (30 ml plus sufficient methanol to dissolve the substrate) was added lithium hydroxide (0.75 ml of 1.0M in water), and this solution was stirred at room temperature for 3 days. Dilution with water and acidification gave a solid which was crystallized from hexane-ethyl acetate to give the title compound as a light yellow solid mp 182-184° C. THEORY: C, 56.66, H, 4.34, N, 2.87. FOUND: C, 56.39, H, 4.60, N, 2.80.
Reaction SMILES: [OH-].[Ca+2:2].[OH-].[Cl:4][C:5]1[CH:34]=[CH:33][C:8]([O:9][CH:10]([CH3:32])[CH2:11][O:12][N:13]=[C:14]([CH:18]2[C:23](=[O:24])[CH2:22][CH:21]([CH:25]3[CH2:30][CH2:29][CH2:28][S:27][CH2:26]3)[CH2:20][C:19]2=[O:31])[CH2:15][CH2:16][CH3:17])=[CH:7][CH:6]=1>CO>[Ca:2].[Cl:4][C:5]1[CH:34]=[CH:33][C:8]([O:9][CH:10]([CH3:32])[CH2:11][O:12][N:13]=[C:14]([CH:18]2[C:23](=[O:24])[CH2:22][CH:21]([CH:25]3[CH2:30][CH2:29][CH2:28][S:27][CH2:26]3)[CH2:20][C:19]2=[O:31])[CH2:15][CH2:16][CH3:17])=[CH:7][CH:6]=1
Reactant: [Ca+2]
Agent: CCCC(=NOCC(C)Oc1ccc(Cl)cc1)C1C(=O)CC(C2CCCSC2)CC1=O
Agent: [OH-]
Solvent: CO
Product: [Ca]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of calcium hydroxide (0.2 g) in 30 ml of methanol was added to a solution of 2-{1-[2-(4-chlorophenoxy)propyloximino]butyl}-5-tetrahydrothiopyran-3-ylcyclohexane-1,3-dione (2.5 g) in 80 ml of methanol with vigorous stirring. The mixture was subsequently stirred for 5 hours at room temperature, whereupon the solvent was removed in vacuo. Yield: 2.6 g of calcium salt.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(O)CCCCC1.[C:14]([O:17]CC)(=[O:16])[CH3:15]>>[C:14]([O:17][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:16])[CH3:15]
Reactant: c1ccccc1
Reactant: CCOC(C)=O
Solvent: OC1CCCCC1
Product: CC(=O)OC1CCCCC1
Reaction time: 28 h

Procedure:
When a benzene solution containing 15 mmols of cyclohexanol, 5 mmols of ethyl acetate and 0.05 mmols of complex 1 was refluxed under argon atmosphere, GC analysis after 28 hrs showed that all of the ethyl acetate disappeared and cyclohexyl acetate was formed as a single product (Table 30, entry 1). 1H NMR and GC-MS of the isolated product were identical to cyclohexyl acetate prepared by refluxing neat acetic anhydride with cyclohexanol.
Reaction SMILES: CS[C:3]1[C:4]2[C:5](=[CH:14][S:15][CH:16]=2)[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.[CH2:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH3:18]>C(O)(=O)C>[CH2:17]([N:19]1[CH2:24][CH2:23][N:22]([C:3]2[C:4]3[C:5](=[CH:14][S:15][CH:16]=3)[NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]=2)[CH2:21][CH2:20]1)[CH3:18]
Reactant: CCN1CCNCC1
Reactant: CSC1=Nc2ccccc2Nc2cscc21
Solvent: CC(=O)O
Product: CCN1CCN(C2=Nc3ccccc3Nc3cscc32)CC1

Procedure:
A mixture comprising 2.5 g. of 10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine (U.S. Pat. No. 3,951,981 -- Ex. 2), 11.4 g. of N-ethylpiperazine and 3 drops of acetic acid is stirred and refluxed overnight. The mixture is evaporated. The residue is slurried in water and then the residue is dissolved in 50 ml. of 2N acetic acid, filtered and the filtrate is made alkaline with ammonium hydroxide. The mixture is cooled and filtered. The solid is recrystallized twice from ethanol giving 10-(4-ethyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=O)[CH2:2][C:3]#[CH:4].[CH3:13][C:14]1([CH3:37])[O:19][C:18]2[CH:20]=[CH:21][C:22]([C@@H:24]([OH:36])[CH2:25][NH:26][C@@H:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:28][OH:29])=[CH:23][C:17]=2[CH2:16][O:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CCOC(C)=O.C(=O)(O)[O-].[Na+]>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:26]([C@@H:27]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:28][OH:29])[CH2:25][C@@H:24]([C:22]1[CH:21]=[CH:20][C:18]2[O:19][C:14]([CH3:13])([CH3:37])[O:15][CH2:16][C:17]=2[CH:23]=1)[OH:36])[CH2:2][C:3]#[CH:4]
Reactant: C#CCCOCCCCCC=O
Reactant: CC1(C)OCc2cc([C@@H](O)CN[C@H](CO)c3ccccc3)ccc2O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: C#CCCOCCCCCCN(C[C@H](O)c1ccc2c(c1)COC(C)(C)O2)[C@H](CO)c1ccccc1
Reaction time: 48 h
Yield: 79 %

Procedure:
A mixture of 6-(but-3-ynyloxy)hexanal (434 mg) and (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[(1S)-2-hydroxy-1-phenylethyl]amino}ethanol (WO0196278 A2) (710 mg) in chloroform (10 ml) was treated at 20° C. with sodium triacetoxyborohydride (866 mg) and stirred under nitrogen for 2 days. The mixture was diluted with EtOAc and aqueous sodium bicarbonate solution. The organic phase was separated and washed with sodium bicarbonate solution, brine, dried and purified on a silica Bond Elut cartridge (10 g) eluting with dichloromethane, Et2O and finally EtOAc to give the title compound (810 mg): LCMS RT=2.69 min, ES+ve m/z 496 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C@@:22]([OH:33])(CCO)[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].F[C:52](F)(F)[C:53]([O:55][C:56](=[O:61])[C:57](F)(F)F)=O.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[C:56]([O:55][CH2:53][CH2:52][C@:22]([OH:33])([C@@H:21]([C:19](=[O:20])[NH:18][C@H:13]([C:14]([O:16][CH3:17])=[O:15])[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:11][CH:10]=1)/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:23]([OH:25])=[O:24])(=[O:61])[CH3:57]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)OC)cc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC(C)=O)C(=O)O)C(=O)OC)cc1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
To a mixture of No. 5217614, tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoate (150 mg, 0.214 mmol) and dichloromethane (15 mL) were added trifluoroacetic acid anhydride (TFAA, 36 μL, 0.258 mmol), triethylamine (89 μL, 0.642 mmol), and DMAP (1.3 mg, 0.0107 mmol), and the mixture was stirred at room temperature. After being stirred for 3 hours, trifluoroacetic acid anhydride (72 μL, 0.516 mmol) was added again. After confirming the consumption of No. 5217614 tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoate by LCMS, formic acid (5 mL) was added and the mixture was stirred overnight. The solvent was distilled off under reduced pressure. THF (5 mL) and a saturated aqueous solution (0.5 mL) of NaHCO3 were then added and the mixture was stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure. The residue was then purified by preparative HPLC. The purified fraction was freeze-dried to obtain the title compound (67 mg, 48% yield, yellow oil).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17]I)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C-:19]#[N:20].[Na+].O.Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:19]#[N:20])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: [C-]#N
Reactant: O=c1[nH]c2cc(Br)cc3c2n(c1=O)C(CI)CC3
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Temperature: 40 °C
Yield: 24.4 %

Procedure:
A mixture of 9-bromo-5-iodomethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (Example 36) (632 mg, 1.5 mmol) and sodium cyanide (147 mg, 3 mmol) in DMF (5 mL) was heated at 40° C. for 14.5 h. The mixture was poured into water, acidified by addition of 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with ethyl acetate to 1% acetic acid/ethyl acetate to give 117 mg of the title compound (24%): mp>280° C.; 1H NMR (270 MHz, DMSO-d6) δ12.10 (bs, 1H), 7.23 (s, 1H), 7.16 (s, 1H), 4.97~5.07 (m, 1H), 2.74~3.10 (m, 4H), 2.20 (dm, 1H, J=13.5 Hz), 1.87~2.03 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O.ON1C2C=CC=CC=2N=N1.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([N:19]1[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]1)=[O:7]
Reactant: CN1CCNCC1
Reactant: COc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C(=O)N2CCN(C)CC2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
2-Methoxy-3-nitro-benzoic acid (1.20 g, 6.09 mmol), 1-Methylpiperazine (1.01 mL, 9.13 mmol) N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1750 mg, 9.13 mmol, 1-hydroxybenzotriazole hydrate (1.45 g, 9.13 mmole) and N,N-Dimethylformamide (40.4 mL) were combined into a vial and stirred at room temperature for 1 hour. LCMS showed complete conversion to product. Diluted reaction mixture with saturated NaHCO3 and filtered off resulting ppt. The solid was filtered and washed with water. The solid was dried under vacuum overnight to give (2-Methoxy-3-nitro-phenyl)-(4-methyl-piperazin-1-yl)-methanone as a white solid (0.70 g, 44%)
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][C:8]2[NH:13][N:12]=[CH:11][C:10](=O)[CH:9]=2)[CH:4]=[CH:5][N:6]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:10]1[CH:9]=[C:8]([CH2:7][N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])[N:13]=[N:12][CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nccn1Cc1cc(=O)cn[nH]1
Product: Cc1nccn1Cc1cc(Cl)cnn1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 72.5 %

Procedure:
6-(2-Methyl-imidazol-1-ylmethyl)-1H-pyridazin-4-one (3.9 g, 20.5 mmol)) was treated with phosphorus oxychloride (18 ml, 205 mmol) under argon. The mixture was stirred in a 60° C. oilbath for 1.5 hours. The solvent was removed in vacuo and the residue was dissolved in water (100 ml) under icebath cooling. The brown solution was neutralized with solid NaHCO3 and the aqueous layer was extracted with MeCl2 (6×50 ml). The combined extracts were dried over Na2SO4, filtered and the solvent was removed in vacuo to provide 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine (3.1 g, 73%) as a brown solid, MS: m/e=209.3 (M+H+).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[CH:15]=[CH:14][C:13](O)=[C:12]([CH2:17][CH3:18])[CH:11]=1>CN(C=O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([O:4][CH3:1])=[C:12]([CH2:17][CH3:18])[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CCc1cc(Br)ccc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCc1cc(Br)ccc1OC
Reaction time: 16 h
Yield: 67.5 %

Procedure:
Potassium carbonate (3.9 g, 28.3 mmol) and methyl iodide (0.59 mL, 9.43 mmol) were added to a solution of 4-Bromo-2-ethyl-phenol (1.9 g, 9.43 mmol, from step 1 of Example A(22)) dissolved in DMF (10 mL). The mixture was stirred for 16 h under N2 and then partitioned between 1 N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a yellow oil. The oil was purifed by silica gel chromatography to give the title compound as a clear oil (1.37 g, 68%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[N+:12]([O-:14])=[O:13].[N:15]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[NH:18][CH2:17][CH2:16]2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:12]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([N:18]1[CH:19]3[CH2:22][CH2:23][N:15]([CH2:21][CH2:20]3)[CH2:16][CH2:17]1)=[CH:11]2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc2cc(Br)cnc12
Reactant: C1CN2CCC(CC2)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc2cc(N3CCN4CCC3CC4)cnc12
Temperature: 85 °C
Yield: 71.9 %

Procedure:
1.54 g (6.1 mmol) of 3-bromo-8-nitro_quinoline, 0.7 g (5.5 mmol) of 1,4-diazabicyclo—[3.2.2]nonane, 0.05 g (0.22 mmol) of palladium diacetate, 2.5 g (7.7 mmol) of cesium carbonate and 0.137 g (0.22 mmol) of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, in 30 ml of tetrahydrofuran and 10 ml of toluene, are introduced consecutively into a 100 ml three-necked round-bottomed flask and the reaction mixture is heated at 80-90° C. for 24 h. The inorganic products are separated by filtration and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on a silica gel column, with the elution being carried out using a 95/5/0.5, and then a 90/10/1, mixture of dichloromethane, methanol and ammonia. 1.18 g of solid are obtained, with this solid then being recrystallized in methanol.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]1[CH:25]=[CH:24][C:11]([O:12][CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=1)(=O)=O.[N:26]1([C:31]2[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=2)[CH:30]=[CH:29][N:28]=[CH:27]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:26]1([C:31]2[CH:36]=[CH:35][C:34]([O:5][CH2:6][CH2:7][C:8]3[CH:25]=[CH:24][C:11]([O:12][CH2:13][C:14]4[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=4[C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=3)=[CH:33][CH:32]=2)[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: COC(=O)c1ccccc1COc1ccc(CCOS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccccc1COc1ccc(CCOc2ccc(-n3ccnc3)cc2)cc1
Temperature: 75 °C
Yield: 113.7 %

Procedure:
Methyl 2-[(4-{2-[(methylsulfonyl)oxy]ethyl}phenoxy)methyl]benzoate (0.2 g, 0.55 mmol) and 4-(1H-imidazol-1-yl)phenol (0.11 g, 0.66 mmol) was dissolved in acetonitrile (10 ml) and potassium carbonate (0.09 g, 0.66 mmol) was added. The mixture was stirred over night at 75° C. Remove the acetonitrile by evaporation, dilute with EtOAc (10 ml) and wash the organic phase with Brine three times, dry (MgSO4) and evaporate. This gave 0.268 g of methyl 2-[(4-{2-[4-(1H-imidazol-1-yl)phenoxy]ethyl}phenoxy)methyl]benzoate (yield 90%).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([OH:12])[CH:3]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:55][N:56](C)C=O>[C-]#N.[Zn+2].[C-]#N.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:9]([C:5]1[C:4]([OH:12])=[CH:3][C:2]([C:55]#[N:56])=[C:7]([CH3:8])[CH:6]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)c1cc(C)c(Br)cc1O
Reactant: CN(C)C=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(=O)c1cc(C)c(C#N)cc1O
Temperature: 120 °C
Yield: 98 %

Procedure:
The 1-(4-bromo-2-hydroxy-5-methylphenyl)ethanone (8.5 g, 37 mmol, Alfa Aesar catalog#H29125) was combined with zinc cyanide (8.7 g, 74 mmol) in N,N-dimethylformamide (75 mL) degassed with nitrogen and the tris(dibenzylideneacetone)dipalladium(0) (Aldrich Catalog No. 328774) (1.0 g, 1.1 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (Aldrich Catalog No. 526460) (1.5 g, 2.6 mmol) were added. The reaction was degassed again with nitrogen and heated to 120° C. and monitored by LC/MS. After heating for 18 hrs the reaction was complete, the reaction was allowed to cool to room temperature, taken up in ethyl acetate and washed with water (2×), brine, dried over magnesium sulfate and concentrated to give the crude product as a dark amber oil. The product was purified by FCC on silica gel eluting hexane:ethyl acetate gradient to give 4-acetyl-5-hydroxy-2-methylbenzonitrile as a solid (6.3 g, 98%). LCMS calculated for C10H10NO2(M+H)+: m/z=176.1; found: 176.2.
Reaction SMILES: S([O-])(O)=O.[Na+].C([O:8][C:9]([C:11]1[NH:12][C:13]([CH3:19])=[C:14]([CH:17]=O)[C:15]=1[CH3:16])=[O:10])C.[NH2:20][C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][C:34]=1[NH2:35])[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[C:24]([C:23]1[CH:32]=[CH:33][C:34]2[N:35]=[C:17]([C:14]3[C:15]([CH3:16])=[C:11]([C:9]([OH:8])=[O:10])[NH:12][C:13]=3[CH3:19])[NH:20][C:21]=2[CH:22]=1)(=[O:25])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1[nH]c(C)c(C=O)c1C
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(C(=O)O)c(C)c1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Temperature: 120 °C
Reaction time: 10 h
Yield: 84.9 %

Procedure:
Sodium hydrogensulfite (1.0 g) and 3,5-dimethyl-4-formylpyrrole-2-carboxylic acid ethyl ester (1.5 g) were added to an N,N-dimethylacetamide (20 ml) solution of 3,4-diaminobenzophenone (1.6 g), and the mixture was heated to 120° C. and stirred for 10 hours. After the mixture was allowed to cool to room temperature, a 5% sodium carbonate (60 g) was added and stirred at room temperature, and the precipitate was collected by filtration and washed with water. The obtained solid was dissolved in ethanol (15 ml) and tetrahydrofuran (15 ml), and a 4 N sodium hydroxide aqueous solution (20 ml) was added and heated under reflux for 12 hours. After the starting material was disappeared, the reaction mixture was allowed to cool to room temperature, and neutralized with a 1 N hydrochloric acid solution. The precipitate was collected by filtration to afford 4-(5-benzoylbenzimidazol-2-yl)-dimethylpyrrole-2-carboxylic acid (2.3 g, 90%) as a light yellow solid.
Reaction SMILES: C1(S([CH2:9][N:10]2[C:14]([NH:15][C:16](=[O:25])[CH:17](Cl)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:12]=[N:11]2)=O)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCCC1>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:13]1[N:12]=[N:11][N:10]2[CH:9]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16](=[O:25])[NH:15][C:14]=12
Reactant: O=C(Nc1c(-c2ccccc2F)nnn1CS(=O)c1ccccc1)C(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: O=c1[nH]c2c(-c3ccccc3F)nnn2cc1-c1ccccc1
Reaction time: 1.5 h
Yield: 64 %

Procedure:
To a cold (−78° C.), stirred solution of N-[3-benzenesulfinylmethyl-5-(2-fluorophenyl)-3H-1,2,3-triazol-4-yl]-2-chloro-2-phenylacetamide (850 mg, 1.81 mmol) in dry tetrahydrofuran (50 ml) was added a solution of potassium bis(trimethylsilyl)amide (8.44 ml, 0.752 M in toluene, 6.34 mmol) and the reaction stirred for 90 minutes. The reaction was then transferred to a −20° C. bath and stirred for 15 minutes. The reaction was quenched by pouring into water (200 ml) and stirring for 10 minutes. The aqueous mixture was acidified with citric acid (10% aqueous) and extracted with ethyl acetate (2×200 ml). The combined organic extracts were washed with water (100 ml), brine (100 ml), dried (Na2SO4) and concentrated iin vacuo to about 10 ml total volume. 3-(2-Fluorophenyl)-6-phenyl-4H-1,2,3-triazolo[1,5-α]pyrimidin-5-one (355 mg, 64%) thus obtained was collected by filtration and washed with diethyl ether. The title product was used in subsequent reactions without further purification. δH (400 MHz, DMSO) 7.32-7.39 (6H, m, ArH, 7.70-7.74 (3H, m, ArH), 9.17 (1H, s, PhC═CH), 12.70 (1H, br s, NH); m/z (ES+) 307 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:13][CH2:12][O:11][C:10]2=O)[CH2:5][CH2:4]1.[OH-].[NH4+:16]>C(O)C>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:13][CH2:12][NH:16][C:10]2=[O:11])[CH2:5][CH2:4]1
Reactant: COC1CCC(C2CCOC2=O)CC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: COC1CCC(C2CCNC2=O)CC1

Procedure:
Heat a mixture of 3-(4-methoxycyclohexyl)-dihydro-furan-2-one (0.91 g), ammonium hydroxide (20 mL) and ethanol (20 mL) at 230° C. in a sealed steel bottle for 12 hours. Cool the reaction and remove the solvent in vacuo. Partition the residue with ethyl acetate (100 mL) and HCl (1N, 60 mL). Dry the organic over sodium sulfate. After filtration and concentration, recrystallize with 1:3 ethyl acetate:hexane to afford 0.71 gram of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N+:24]([O-])=O)[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1>C1COCC1.CO.[Ni]>[NH2:24][C:12]1[C:13]([CH:21]2[CH2:23][CH2:22]2)=[CH:14][C:15]2[C:10]([CH:11]=1)=[N:9][N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:16]=2[C:17]([NH:19][CH3:20])=[O:18]
Reactant: CNC(=O)c1c2cc(C3CC3)c([N+](=O)[O-])cc2nn1-c1ccc(Cl)cc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1c2cc(C3CC3)c(N)cc2nn1-c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-nitro-2H-indazole-3-carboxamide (127 mg, 0.34 mmol) in THF (2.5 mL) and MeOH (7.5 mL) was added Raney nickel (20 mg) and the reaction was stirred vigorously under an atmosphere of hydrogen at 60° C. for 2 h. The reaction mixture was diluted with MeOH (40 mL), filtered and then concentrated to dryness to give 6-amino-2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-2H-indazole-3-carboxamide as a tan solid (97 mg, 83%).