Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=O.[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25][NH2:26]>C1(C)C=CC=CC=1>[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25]/[N:26]=[CH:1]/[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2C=O)CC1
Reactant: CC(C)(C)CCN
Solvent: Cc1ccccc1
Product: CC(C)(C)CC/N=C/c1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of tert-butyl 4-(2-formylphenyl)piperidine-1-carboxylate (229 mg, 0.79 mmol) in toluene (4 mL) was added 3,3 dimethylbutylamine (88.09 mg, 117.1 μL, 0.8705 mmol) and 4 Å molecular sieves. The resulting suspension was stirred at rt overnight. Filtered out molecular sieves and concentrated the mixture with a flow of N2 to give 282 mg of tert-butyl 4-(2-((E)-(3,3-dimethylbutylimino)methyl)phenyl)piperidine-1-carboxylate as an thick off-white oil which was used without further purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:35]4[CH:36]=[N:37][C:38]([Cl:41])=[CH:39][CH:40]=4)([NH:25]CC4C=CC(OC)=CC=4)[C:19]4[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:42][CH:43]3[CH2:45][CH2:44]3)[C:10](=[O:46])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:25][C:18]([C:35]1[CH:36]=[N:37][C:38]([Cl:41])=[CH:39][CH:40]=1)([C:19]1[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=1)[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:42][CH:43]1[CH2:44][CH2:45]1)[C:10](=[O:46])[CH:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: COc1ccc(CNC(c2ccc(Cl)nc2)(c2ccc3c(c2)c(-c2cccc(Cl)c2)cc(=O)n3CC2CC2)c2cncn2C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cncc1C(N)(c1ccc(Cl)nc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1

Procedure:
To a solution of the title compound of Example 48 (the slower moving enantiomer), (−)4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-(4-methoxy-benzyl-amino)-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one (1.07 g, 1.64 mmol) in dichloromethane (6.5 ml) was added trifluoroacetic acid (TFA, 6.5 ml) slowly at 0° C. The reaction mixture was stirred at ambient temperature for 80 minutes after which time it was diluted with DCM (10 ml) and was poured into a chilled aqueous solution of potassium carbonate. After separation, the organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to give the crude product. It was chromatographed on silica gel with MeOH—CHCl3—NH4OH (1.5:98.5:0.15) as the eluents to afford the title compound as a white solid ( 0.588 g, 1.11 mmol, 68% yield). It is the faster eluting enantiomer of 6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one with >99% optical purity.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]([Si:13]([CH3:25])([CH3:24])[O:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[CH:20][NH:21]2)=[CH:17][CH:16]=1)([CH3:12])([CH3:11])[CH3:10]>ClCCl>[C:9]([Si:13]([CH3:25])([CH3:24])[O:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([Cl:1])=[CH:20][NH:21]2)=[CH:17][CH:16]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc[nH]c2c1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(Cl)c[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution of N-chlorosuccinimide (270 mg, 2 mmol) in dichloromethane (4 ml) is added within 30 min to a solution of 6-(tert-butyl-dimethyl-silanyloxy)-1H-indole (500 mg, 2 mmol) in dichloromethane (10 ml) at 0° C. under an argon atmosphere. The solution was naturally warmed to ambient temperature and stirred for 2 h. Ice water was added and the mixture was extracted two times with tert-butyl methyl ether. The combined extracts were dried over sodium sulfate and the solvent was removed under reduced pressure to give 560 mg (1.98 mmol, 98%) of the title compound as red solid which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:9]([CH2:10][CH2:11][C:12]3[C:13]4[C@:20]([CH3:28])([CH2:21][CH2:22][C:23]=32)[C@@H:16]([C@H:17]([OH:19])[CH3:18])[CH2:15][CH:14]=4)[C:8]1([CH3:30])[CH3:29])[CH3:5])[CH3:2].CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:55](Br)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>O.C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:9]([CH2:10][CH2:11][C:12]3[C:13]4[C@:20]([CH3:28])([CH2:21][CH2:22][C:23]=32)[C@@H:16]([C@H:17]([O:19][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH3:18])[CH2:15][CH:14]=4)[C:8]1([CH3:30])[CH3:29])[CH3:5])[CH3:2]
Reactant: CCOC(C)O[C@H]1CC[C@]2(C)C3=C(CC[C@H]2C1(C)C)C1=CC[C@H]([C@@H](C)O)[C@@]1(C)CC3
Reactant: BrCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(C)O[C@H]1CC[C@]2(C)C3=C(CC[C@H]2C1(C)C)C1=CC[C@H]([C@@H](C)OCc2ccccc2)[C@@]1(C)CC3
Temperature: 70 °C

Procedure:
v)—A mixture of (3β,5α,20R)-3-[(1-ethoxyethyl)oxy]-4,4-dimethylpregna-8,14-dien-20-ol (19b; 0.80 g), dry toluene (56 ml), potassium t-butoxide (2.76 g), 18-crown-6 (0.48 g) and benzyl bromide (1.13 ml) was heated at 70° C. for 1 h. After cooling, the reaction mixture was poured into water and the product extracted into ethyl acetate. The combined organic phases were washed with water and with brine, dried over sodium sulfate, and concentrated under reduced pressure to give (3β,5α,20R)-3-[(1-ethoxyethyl)oxy]-4,4-dimethyl-20-(phenylmethoxy)pregna-8,14-diene (compound 20b; 1.92 g), which was used in the following step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:18])([CH3:17])[C:12](OCC)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.[NH2:20][NH2:21]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:18])([CH3:17])[C:12]([NH:20][NH2:21])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NN
Reactant: CCOC(=O)C(C)(C)c1ccc(OC)c(OC)c1
Solvent: O
Solvent: CO
Product: COc1ccc(C(C)(C)C(=O)NN)cc1OC
Reaction time: 12 h
Yield: 102.5 %

Procedure:
A solution of ethyl 2-(3,4-dimethoxyphenyl)-2-methylpropanoate (2.84 g, 11.26 mmol) and hydrazine hydrate (7.00 mL, 112.56 mmol) in MeOH (15 mL) was heated at 110° C. in a sealed tube. After 12 h, additional hydrazine hydrate (10 mL) was added to the reaction mixture, which then was heated for additional 6 h. The cooled mixture was concentrated to afford 2-(3,4-dimethoxyphenyl)-2-methylpropanehydrazide (2.75 g, quant) as a liquid. 1H NMR (400 MHz, CDCl3) δ 6.94-6.91 (m, 1H), 6.87-6.81 (m, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.69 (br s, 3H), 1.56 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[CH:10]([CH3:11])[C:9]2[C:4](=[C:5]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+].[O:22]1CCOCC1>O>[NH2:3][C:4]1[C:5]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[CH:6][CH:7]=[CH:8][C:9]=1[CH:10]([CH3:11])[C:2]([OH:22])=[O:1]
Reactant: CC1C(=O)Nc2c(Oc3ccccc3Cl)cccc21
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)c1cccc(Oc2ccccc2Cl)c1N

Procedure:
A mixture of 2-oxo-3-methyl-7-(2-chlorophenoxy)indoline (4 g.), sodium hydroxide (2.4 g.), dioxane (25 ml.) water (25 ml.) was refluxed under heating for 5 days with stirring. After cooling, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. To the residue was added water and the mixture was washed with diethyl ether. Ethyl acetate was added to the aqueous solution and adjusted to pH 4 to 5 with 5% sulfuric acid. The ethyl acetate layer was separated, washed with water and dried over magnesium sulfate and the solvent was distilled off under reduced pressure to give oily 2-[2-amino-3-(2-chlorophenoxy)phenyl]propionic acid (2.4 g.). This compound was dissolved in an aqueous solution of sodium bicarbonate and filtered. The filtrate was concentrated to dryness under reduced pressure and the residue was dissolved in ethyl acetate and filtered. The filtrate was evaporated under reduced pressure, and the residue was dissolved in water and lyophilized to give light brown powder of the captioned compound (1.6 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][CH2:32][N:33]3C(=O)C4=CC=CC=C4C3=O)[C:6]=2[CH:44]=1.O.NN.O.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][CH2:32][NH2:33])[C:6]=2[CH:44]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCCN3C(=O)c4ccccc4C3=O)c3cc(Cl)ccc32)cn1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCCN)c3cc(Cl)ccc32)cn1
Yield: 127.2 %

Procedure:
To a solution of 7-chloro-5-(2-phthalimidoethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.26 g) in ethanol (10 ml) is added hydrazine hydrate (0.04 ml), and the mixture is refluxed for 2 hours, and cooled. Water is added to the reaction solution, and the mixture is made acidic with diluted hydrochloric acid, and washed with diethyl ether. Aqueous sodium hydroxide solution is added to the aqueous layer in order to make it basic, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-aminoethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.26 g) as colorless amorphous.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CC([O-])(C)C.[Na+]>CC1C=CC=CC=1C.O.[Pd]>[N:11]1([C:2]2[C:10]3[NH:9][CH:8]=[N:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Brc1cccc2nc[nH]c12
Reactant: C1CNCCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: c1cc(N2CCCNCC2)c2[nH]cnc2c1
Temperature: 120 °C

Procedure:
A suspension of 4-bromobenzimidazole (42 mmol), homopiperazine (256 mmol) and NaOt-Bu (59 mmol) in dry o-xylene, under N2, is treated with a catalytic amount of Pd (OCOCH3)2·P(t-Bu)3 (P/Pd=4), heated at 120° C. for 3 hr, cooled to room temperature and diluted with water. The aqueous mixture is extracted with ethyl acetate. The extracts are combined, dried over MgSO4 and concentrated in vacuo to give a residue. The residue is purified by flash chromatography to give 4-(homopiperazin-1-yl)benzimidazole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[CH3:12].[NH2:13][CH2:14][C:15]([O-:17])=[O:16].[Na+:18]>CN(C=O)C.O>[Na+:18].[Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([NH:13][CH2:14][C:15]([O-:17])=[O:16])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: NCC(=O)[O-]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1Br
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(NCC(=O)[O-])c([N+](=O)[O-])cc1Br
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-bromo-5-fluoro-4-nitrotoluene (1.662 g, 7.102 mmol, as prepared above) in DMF (7.0 mL) at 70° C., was added, dropwise, a solution of sodium glycinate (0.690 g, 7.11 mmol, Aldrich, used as received) in water (7.0 mL). The resulting suspension was stirred overnight at 70° C. The suspension was cooled to room temperature and the red solid was filtered, washed with acetone, and dried under vacuum to give 0.932 g (45%) of the pure (1H NMR) title compound as a red powder; 1H NMR (DMSO-d6): δ 2.306 (s, 3H), 3.452 (d, 2H, J=3.9 Hz), 6.874 (s, 1H), 8.125 (s, 1H), 8.779 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1)=[O:11].Br[C:26]1[C:31]([F:32])=[CH:30][C:29]([Cl:33])=[CH:28][N:27]=1>>[Cl:33][C:29]1[CH:30]=[C:31]([F:32])[C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)=[O:11])=[N:27][CH:28]=1
Reactant: Fc1cc(Cl)cnc1Br
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(Cl)cc2F)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone and 2-bromo-5-chloro-3-fluoropyridine. ESI-MS (m/z): 456 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[C:15](Cl)[C:10]=1[C:11]([NH:13][NH2:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](OC1C=CC(C(NN)=O)=C(CC)C=1Cl)[C:29]1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[C:15]([CH2:28][CH3:29])[C:10]=1[C:11]([NH:13][NH2:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1c(C(=O)NN)ccc(OCc2ccccc2)c1Cl
Reactant: NNC(=O)c1c(Cl)cc(OCc2ccccc2)cc1OCc1ccccc1
Product: CCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1C(=O)NN

Procedure:
An analogous preparation procedure also gives 2,4-dibenzyloxy-6-chlorobenzohydrazide: yield 61%, m.p. 166-1670, and 4-benzyloxy-3-chloro-2-ethylbenzohydrazide: yield 85%, m.p. 182-1840.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([O:8][CH3:9])=[N:6][N:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:4]=1.[F:20][C:21]([F:28])([F:27])[C:22]1[CH:26]=[CH:25][NH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:9][O:8][C:7]1[C:3]([CH2:2][N:24]2[CH:25]=[CH:26][C:22]([C:21]([F:28])([F:27])[F:20])=[N:23]2)=[N:4][N:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:6]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: COc1nn(-c2ccc(C(F)(F)F)cc2)nc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nn(-c2ccc(C(F)(F)F)cc2)nc1Cn1ccc(C(F)(F)F)n1
Temperature: 55 °C
Reaction time: 1.25 h

Procedure:
To a solution of 4-(bromomethyl)-5-methoxy-2-[4-(trifluoromethyl)phenyl]-2H-1,2,3-triazole (i.e. the product of Example 1, Step D) (0.25 g, 66 weight %, 0.5 mmol) in N,N-dimethylformamide (2 mL total), was added 3-(trifluoromethyl)pyrazole (0.082 g, 0.6 mmol) and anhydrous potassium carbonate (0.21 g, 1.5 mmol). The mixture was heated to 55° C. and stirred for 75 min. The reaction mixture was cooled to 23° C., diluted with water (20 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL) and saturated aqueous sodium chloride solution (10 mL), dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel eluting with 0 to 40% ethyl acetate in hexanes to afford the title compound (0.098 g) as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][Cl:35])=[CH:26][CH:25]=2)=[C:16]([Cl:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][Cl:35])=[CH:28][CH:29]=2)=[C:16]([Cl:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: ClCCCCOc1ccc(C(=C(Cl)c2ccccc2)c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1ccc(C(=C(Cl)c2ccccc2)c2ccc(OCCCCCl)cc2)cc1
Reaction time: 1.5 h

Procedure:
Combine 1-(4-benzyloxyphenyl)-1-(4-(4-chlorobutyloxy) phenyl)-2-chloro-2-phenyl ethylene (0.1 g, 0.20 mmol), 5% palladium-on-carbon (30 mg), and ethyl acetate (1.5 mL). Treat with hydrogen at atmospheric pressure. After 1.5 hours, filter using a 0.45 micron membrane. Concentrate the filtrate in vacuo to give 1-(4-hydroxyphenyl)-1-(4-(4-chlorobutyloxy)phenyl)-2-chloro-2-phenyl ethylene.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[F:14])=[O:5])#[N:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[C:1]([C:3](=[CH:17][N:18]([CH3:20])[CH3:19])[C:4]([NH:6][C:7]1[C:8]([F:14])=[CH:9][CH:10]=[CH:11][C:12]=1[F:13])=[O:5])#[N:2]
Reactant: COC(OC)N(C)C
Reactant: N#CCC(=O)Nc1c(F)cccc1F
Product: CN(C)C=C(C#N)C(=O)Nc1c(F)cccc1F

Procedure:
As for Example 1, 2-cyano-2',6'-difluoroacetanilide as colorless crystals, m.p. 180°-181° C. (prepared by the procedure described in U.S. Pat. No. 3,116,312), is heated with N,N-dimethylformamide dimethylacetal to yield 2-cyano-3-dimethylamino-2', 6'-difluoroacrylanilide as colorless crystals, m.p. 158°-159.5° C.
Reaction SMILES: O.OO.N[C:5]([NH2:7])=[O:6].[OH-].[Na+].[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([N:21]2[CH2:46][CH2:45][C:24]3([CH2:27][N:26]([C@H:28]4[C:36]5[C:31](=[CH:32][C:33]([C:37]6[CH:44]=[CH:43][C:40](C#N)=[CH:39][N:38]=6)=[CH:34][CH:35]=5)[CH2:30][CH2:29]4)[CH2:25]3)[CH2:23][CH2:22]2)=[O:20])=[N:16][CH:17]=1>CCO>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([N:21]2[CH2:22][CH2:23][C:24]3([CH2:27][N:26]([C@H:28]4[C:36]5[C:31](=[CH:32][C:33]([C:37]6[CH:44]=[CH:43][C:40]([C:5]([NH2:7])=[O:6])=[CH:39][N:38]=6)=[CH:34][CH:35]=5)[CH2:30][CH2:29]4)[CH2:25]3)[CH2:45][CH2:46]2)=[O:20])=[N:16][CH:17]=1
Reactant: NC(N)=O
Reactant: COc1ccc(CC(=O)N2CCC3(CC2)CN([C@@H]2CCc4cc(-c5ccc(C#N)cn5)ccc42)C3)nc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(CC(=O)N2CCC3(CC2)CN([C@@H]2CCc4cc(-c5ccc(C(N)=O)cn5)ccc42)C3)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 2.8 %

Procedure:
To a solution of water (30 mL) and urea hydrogen peroxide (165 mg, 1.70 mmol) was added sodium hydroxide (39.8 mg, 0.99 mmol) and the reaction was stirred at room temperature. Once a clear solution was obtained, the reaction was placed in an ice bath and fitted with an addition funnel. A solution of 6-((R)-1-{7-[2-(5-methoxy-pyridin-2-yl)-acetyl]-2,7-diaza-spiro[3.5]non-2-yl}-indan-5-yl)-nicotinonitrile (11-1c, 379 mg, 0.85 mmol) in 1 mL of EtOH was added dropwise via the funnel over a period of 30 minutes. The solution became cloudy and was stirred overnight while warming to room temperature. After 18 hours, the reaction was concentrated. The crude product was purified on a Biotage (Biotage Inc.) 10 g reverse phase column, eluting with 0-50% acetonitrile in water to give the title compound 12 mg (8%). MS (ES+) 512.0 (M+H)+. 1H NMR (CD3OD) δ 1.61-1.75 (m, 4H), 1.90 (td, 1H), 2.24 (ddd, 1H), 2.83-2.94 (m, 1H), 3.05-3.17 (m, 1H), 3.20-3.27 (m, 2H), 3.48-3.56 (m, 5H), 3.83 (s, 4H), 3.85 (s, 2H), 4.04 (dd, 1H), 7.21-7.29 (m, 1H), 7.30-7.38 (m, 1H), 7.46 (d, 1H), 7.81-7.88 (m, 1H), 7.89-7.95 (m, 2H), 8.13 (d, 1H), 8.27 (dd, 1H), 9.05 (dd, 1H).
Reaction SMILES: [CH3:1][Li].Cl[C:4]1[C:14]2[C:13]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=3[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:10][CH2:9][C:8]=2[N:7]=[C:6]([CH3:26])[N:5]=1>CCOCC.O.S>[Cl:19][C:17]1[CH:16]=[CH:15][C:13]2[C:14]3[C:4]([CH3:1])=[N:5][C:6]([CH3:26])=[N:7][C:8]=3[CH2:9][N:10]=[C:11]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:12]=2[CH:18]=1
Reactant: [Li]C
Reactant: Cc1nc(Cl)c2c(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2
Agent: S
Solvent: O
Solvent: CCOCC
Product: Cc1nc(C)c2c(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dropwise 13.2 ml (18.5 mmol) of a 1.4M ether solution of methyl lithium was added to a suspension of 1.7 g (8.9 mmol) of cuprous iodide in 50 mL of ether which was cooled to 0°. A solution of 0.8 g (2.2 mmol) of 1,9-dichloro-3-methyl-7-phenyl-5H-pyrimido[4,5-d][2]benzazepine in 30 mL of ether was added dropwise to the ether solution of lithium dimethylcuprate which was further cooled to -25°. The mixture was stirred at -25° for 1 hr, warmed to room temperature, diluted with water and saturated with hydrogen sulfide. The resulting precipitate was removed by filtration over celite and the filtrate was concentrated at reduced pressure. Purification of the residue by column chromatography (silica gel, 10 g; eluent, 20% ether in methylene chloride) gave an oil which was crystallized from a mixture of ether and petroleum ether to give off-white needles, mp 121°-124°.
Reaction SMILES: COCCOC[O:7][CH:8]([C:10]1[S:14][C:13]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:12][C:11]=1[S:19]([CH3:22])(=[O:21])=[O:20])[CH3:9].S(=O)(=O)(O)O>CO.O>[OH:7][CH:8]([C:10]1[S:14][C:13]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:12][C:11]=1[S:19]([CH3:22])(=[O:20])=[O:21])[CH3:9]
Reactant: COCCOCOC(C)c1sc(S(N)(=O)=O)cc1S(C)(=O)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: CC(O)c1sc(S(N)(=O)=O)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.9 %

Procedure:
The 5-[1-(methoxyethoxymethoxy)ethyl]-4-methylsulfonylthiophene-2-sulfonamide (5.94 g, 0.0159 mol) was dissolved in 50/50 methanol/water (30 ml) with warming and concentrated sulfuric acid (15 ml) was added. The solution was cooled to ambient temperature and stirred for 1 hour. The methanol was removed in vacuo and the aqueous acid was diluted with water (50 ml). The product was extracted into ethyl acetate. The extract was washed with saturated NaHCO3 solution, water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. A colorless oil was obtained which solidified to a white solid. Several recrystallizations from water gave pure product (1.04 g, 23%), m.p. 121-127° C. NMR supported the structure and HPLC confirmed the purity.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([NH:8][CH3:9])[CH:7]=1.[CH3:13][C:14]1[CH:15]=[C:16]([OH:24])[CH:17]=[C:18]([CH3:23])[C:19]=1[N+:20]([O-:22])=[O:21].CC(C)([O-])C.[K+].Cl>CN(C)C(=O)C>[CH3:23][C:18]1[CH:17]=[C:16]([CH:15]=[C:14]([CH3:13])[C:19]=1[N+:20]([O-:22])=[O:21])[O:24][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([NH:8][CH3:9])[CH:7]=1
Reactant: CNc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CNc1cc(Oc2cc(C)c([N+](=O)[O-])c(C)c2)ccc1[N+](=O)[O-]
Temperature: 125 °C
Reaction time: 0.75 h
Yield: 80.4 %

Procedure:
To a solution of N-(5-chloro-2-nitrophenyl)-N-methylamine (0.86 g) and 3,5-dimethyl-4-nitrophenol (0.76 g) in N,N-dimethylacetamide (12 ml) was added potassium t-butoxide (0.554 g) at room temperature, and the resulting mixture was stirred successively at the same temperature for 20 minutes, at 100° C. for 10 minutes, at 125° C. for 45 minutes, and at 140° C. for 1 hour. After cooling the reaction mixture to 0° C., the reaction mixture was adjusted to a pH of about 3 with 3N hydrochloric acid. The crystalline solid precipitated was collected by filtration, washed successively with 3N hydrochloric acid and water and air-dried for 3 days to afford the title compound (1.16 g, yield: 80%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[Br-].[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:11])=[O:10]>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:9]([OH:11])=[O:10]
Reactant: O=C(O)CCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccs1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCC=Cc1cccs1
Yield: 46 %

Procedure:
This compound was synthesized from 2-thiophenecarboxaldehyde (2.24 g, 20 mmol) and 9-carboxynonyltriphenylphosphonium bromide (10.27 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization (hexanes-ethyl acetate) afforded the product (2.45 g, 46%) as white crystals (mp 61-62° C.); IR: 3450-2500, 1715 cm-1 ; 1H-NMR: 1.31 (m, 8H), 1.45 (m, 2H), 1.65 (m, 2H), 2.34 (t, 2H), 2.38 (t, 2H), 5.55 (m, 1H), 6.50 (d, 1H), 6.95 (m, 2H), 7.23 (d, 2H), 10.05 (bs, 1H). Anal. Calcd. for C15H22O2S: C, 67.63, H, 8.32%; Found: C, 67.60, H, 8.34%. Z:E=19:81.