Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+:2].C(O)C.[C:6]1([CH:12]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:13]2[CH2:18][CH2:17][N:16]([C:19]([C@@H:21]([NH:26][C:27]([C@@H:29]3[O:31][C@H:30]3[C:32]([O:34]CC)=[O:33])=[O:28])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C>[C:6]1([CH:12]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:13]2[CH2:18][CH2:17][N:16]([C:19]([C@@H:21]([NH:26][C:27]([C@@H:29]3[O:31][C@H:30]3[C:32]([O-:34])=[O:33])=[O:28])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1.[Na+:2]
Reactant: CCOC(=O)[C@@H]1O[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)C[C@H](NC(=O)[C@@H]1O[C@H]1C(=O)[O-])C(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
Under cooling with ice, a 0.48N sodium hydroxide-ethanol solution (54.2 ml) was added dropwise to an ethanol solution (70 ml) of ethyl trans-3-[(s)-1-(4-diphenylmethylpiperazine-1-yl carbonyl)-3-methylbutyl carbamoyl]oxirane-2-carboxylate (13.2 g) obtained above. After stirring at room temperature for 3 hours, the solvent was removed by distillation under reduced pressure, and the reaction mixture was further dried under reduced pressure to yield 12.4 g of sodium trans-3-[(s)-1-(4-diphenylmethylpiperazine-1-yl carbonyl)-3-methylbutylcarbamoyl]oxirane-2-carboxylate as a light yellow powder (yield: 95%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[O:26][CH3:27])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:35][C:36]([F:51])([F:50])[C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[C:40](Cl)=[O:41].C(=O)([O-])O.[Na+]>ClCCl.O>[F:35][C:36]([F:50])([F:51])[C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:46]([F:49])([F:47])[F:48])[CH:45]=1)[C:40]([N:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][CH:13]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=1[O:26][CH3:27])=[O:41]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1cccc(CC2CN(C(=O)OCc3ccccc3)CCN2)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cccc(CC2CN(C(=O)OCc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1OC
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a mixed solution of 1-(benzyloxycarbonyl)-3-(2,3-dimethoxybenzyl)piperazine (0.65 g) and triethylamine (0.293 ml) in dichloromethane (17 ml) was added dropwise a solution of 3,5-bis(trifluoromethyl)benzoyl chloride (0.534 g) in dichloromethane (2.5 ml) under ice-cooling. After being stirred at the same temperature for 2 hours, the reaction mixture was poured into a mixed solvent of water (40 ml) and dichloromethane (25 ml) and the whole was adjusted to pH 9 with aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (10 g) using a mixed solvent of n-hexane and ethyl acetate (2:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give 1-[3,5-bis(trifluoromethyl)benzoyl]-4-(benzyloxycarbonyl)-2-(2,3-dimethoxybenzyl)piperazine (0.84 g).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH2:10][CH2:9]4)[CH:6]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][C@H:27]3[CH2:31][S:32][CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:40])([F:39])[F:38])[CH2:5][C:4]=2[CH:3]=1.[BH4-].[Na+]>>[F:42][C:36]([F:41])([C:37]([F:38])([F:39])[F:40])[CH2:35][CH2:34][CH2:33][S:32][CH2:31][C@@H:27]1[CH2:28][CH2:29][CH2:30][N:26]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C@@H:6]1[CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:19]=[CH:18][C:17]=2[C@@H:16]2[C@@H:7]1[C@H:8]1[C@@:12]([CH2:14][CH2:15]2)([CH3:13])[C@@H:11]([OH:20])[CH2:10][CH2:9]1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC(CCCCCN4CCC[C@H]4CSCCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCC[C@H]4CSCCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CC[C@@H]2O
Yield: 64.8 %

Procedure:
Under the conditions of Example 8, 500 mg of 3-hydroxy-7 -(5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]-pentyl)-estra-1,3,5(10)-trien-17-one is reduced with 100 mg of sodium borohydride. 325 mg of the title compound is obtained as oil. [α]D22 =-8.7°(c=0.510 in methanol).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>COCCOC>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)N
Solvent: COCCOC
Product: CC(=O)Nc1ccc(S(=O)(=O)NC(C)(C)C)cc1
Reaction time: 4 h
Yield: 68.8 %

Procedure:
To a suspension of 4-acetylaminobenzenesulfonyl chloride (10 g, 43 mmol) in DME (103 mL) is added, at 0° C., tert-butylamine (9 mL, 86 mmol) in DME (103 mL). Next, the reaction mixture is stirred for 4 h at reflux. The solvent is removed and CHCl3 is added. The resulting suspension is filtered and the solid is washed with CHCl3, H2O and Et2O. The solid obtained is dried in vacuo to give 8.0 g of the product as a white solid (yield: 68%).
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[N:4][CH2:3]1>C1C2C(CCCC2)CCC1.[Pd]>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1
Reactant: CC1CN=Cc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: C1CCC2CCCCC2C1
Product: Cc1cncc2cc([N+](=O)[O-])ccc12
Reaction time: 8 h
Yield: 41.9 %

Procedure:
A mixture of 3,4-dihydro-4-methyl-7-nitroisoquinoline (14.63 g) and palladium black (4 g) in decahydronaphthalene (170 ml) was refluxed for 6 hours with stirring. The reaction mixture was allowed to stand overnight at ambient temperature, and then filtered and the residue on a filter was washed with chloroform. The filtrate was extracted with 2N hydrochloric acid (70 ml×3). Aqueous sodium hydroxide was added slowly to the combined aqueous layer, under dryice-acetone cooling. The light brown solid was collected, washed with water and dried. The crude product was chromatographed on silica gel column using chloroform as an eluent to give 4-methyl-7-nitroisoquinoline (6.06 g).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:10]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([Br:17])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(=O)CC>[CH2:1]([O:16][C:15]1[CH:14]=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCOc1ccc(Br)cc1
Reaction time: 10 h
Yield: 66.8 %

Procedure:
A reaction vessel was charged with 22.3 g of octyl bromide, 20 g of p-bromophenol, 33.3 g of potassium carbonate and 200 ml of 2-butanone (MEK), and the mixture was reacted under reflux and agitation for 10 hours. The reaction liquid was poured into diluted hydrochloric acid and the mixture was extracted with benzene. The extract was washed with an aqueous solution of edible salt and dried over Glauber's salt. The solvents were distilled off and the residue was distilled under reduced pressure to obtain 22.0 g (66.8%) of 4-octyloxybromobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:14]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][N:12]([C:20](Cl)=[O:21])[CH:11]3[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[F:30])[C:5]2=[CH:4][CH:3]=1.[CH3:32][N:33]1[CH:37]=[CH:36][C:35]([CH2:38][NH2:39])=[N:34]1>C(N(CC)CC)C>[CH3:32][N:33]1[CH:37]=[CH:36][C:35]([CH2:38][NH:39][C:20]([N:12]2[CH2:13][CH:14]([CH2:15][C:16]([CH3:19])([CH3:17])[CH3:18])[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:31])[CH:11]2[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[F:30])=[O:21])=[N:34]1
Reactant: CC(C)(C)CC1CN(C(=O)Cl)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: Cn1ccc(CN)n1
Solvent: CCN(CC)CC
Product: Cn1ccc(CNC(=O)N2CC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)n1

Procedure:
In a manner similar to the method described in Example 9, rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carbonyl chloride prepared in Example 8 (57 mg, 0.12 mmol) was reacted with (1-methyl-1H-pyrazol-3-yl)methylamine (Oakwood) (20 mg, 0.18 mmol) and triethylamine to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid (1-methyl-1H-pyrazol-3-ylmethyl)-amide as a white solid (Yield, 18 mg, 27%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[NH:17][C:18]2[CH:24]=[C:23]([C:25]([OH:27])=O)[CH:22]=[CH:21][C:19]=2[N:20]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)[CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42]2[CH:43]=[CH:44][C:45]([NH:48][C:25]([C:23]3[CH:22]=[CH:21][C:19]4[NH:20][C:16]([C:3]5[CH:4]=[C:5]([C:8]6[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=6)[CH:6]=[CH:7][C:2]=5[OH:1])=[N:17][C:18]=4[CH:24]=3)=[O:27])=[CH:46][CH:47]=2)[CH2:36][CH2:35]1
Reactant: Nc1ccc(CCN2CCN(c3ccccn3)CC2)cc1
Reactant: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ncccc1-c1ccc(O)c(-c2nc3cc(C(=O)Nc4ccc(CCN5CCN(c6ccccn6)CC5)cc4)ccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
To a solution of 2-[2-hydroxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-3H-benzoimidazole-5-carboxylic acid (containing 1 equivalent of DMA, 44 mg, 0.1 mmol), 4-[2-(4-pyridin-2-yl-piperazin-1-yl)-ethyl]-phenylamine (28.2 mg, 0.1 mmol) and HATU (38 mg, 0.1 mmol) in DMF (1.2 mL) was added DIEA (45 mg, 0.35 mmol). The reaction mixture was stirred at room temperature for 2 h and heated at 60° C. for 3 h, and then evaporated under reduced pressure. The residue was diluted with DMSO (1.5 mL), filtered and then purified with using HPLC (TFA/H2O/CH3CN) to afford the title compound (26.6 mg, 39%). 1H NMR (MeOH-d4) δ 3.10-4.01 (12H), 3.98 (s, 3H), 6.87 (m, 1H), 7.04-7.12 (2H), 7.21 (d, J=9 Hz, 1H), 7.36 (d, J=6 Hz, 2H), 7.72-7.83 (5H), 7.89 (d, J=6 Hz, 1H), 8.09 (d, J=6 Hz, 1H), 8.17 (t, J=3 Hz, 2H), 8.26 (s, 1H), 8.37 (s, 1H). ESI-MS m/z 626.5 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([F:12])[CH:5]=1)([O-])=O.C(O)(=O)C>[Fe].C(OCC)(=O)C>[NH2:1][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([F:12])[CH:5]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#Cc1ccc(N)cc1F
Yield: 96 %

Procedure:
A mixture of 4-nitro-2-fluorobenzonitrile (1.83 g, 5 mmol) and iron (1.68 g, 6 mmol) M a mixture of acetic acid (40 ml) and ethyl acetate (40 ml) was refluxed for 2 hours. The solid was filtered off and the filtrate was washed with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated and chromatographed (dichloromethane:acetone, 95:5) to yield 4-amino-2-fluorobenzonitrile (54a) (0.653 g, 4.8 mmol, 96%).
Reaction SMILES: [O:1]=[C:2]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH:3]([CH2:9]N1CCCCC1)[CH2:4][C:5]([O:7][CH3:8])=[O:6]>C(O)C.Cl.O1CCOCC1>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:2]([C:3](=[CH2:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6])=[O:1])[CH:17]=1
Reactant: COC(=O)CC(CN1CCCCC1)C(=O)c1cccnc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: C=C(CC(=O)OC)C(=O)c1cccnc1
Yield: 80.7 %

Procedure:
A solution of methyl 4-oxo-3-(piperidylmethyl)-4-(3-pyridyl)butanoate (4 g) in ethanol (10 mL) and 4N HCl/dioxane (4.0 mL) was heated at 80° C. for 12 hrs. The reaction mixture was concentrated and purified on flash chromatography (SIO2, CHCl3: MeOH: CH3COOH=10: 1:0.5) to give 2.28 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[CH:17]=O.CC(OC(C)=O)=O.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.CO>[CH3:25][O:24][C:20]1[CH:19]=[C:16]([CH:17]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([OH:11])=[O:10])[CH:15]=[C:14]([O:13][CH3:12])[C:21]=1[O:22][CH3:23]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C=C(C(=O)O)c2ccc(F)cc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.6 %

Procedure:
A mixture of 4-fluoro phenyl acetic acid (2 g, 13 mmol), 3,4,5 trimethoxybenzaldehyde (2.5 g, 13 mmol), Ac2O (10 mL) and DIPEA (2.9 mL, 16.8 mmol) was stirred at room temperature for 12 hours. Upon completion, as monitored by TLC using DCM:MeOH (9:1) as the eluent, 10% aqueous HCl (10 mL) was added to the reaction mixture; the precipitate formed was filtered and dissolved in DCM (100 mL). The organic layer was washed with 10% aqueous NaOH (3×50 mL) and the basic aqueous solution was acidified with 10% aqueous HCl to pH 3. The precipitate formed was filtered, washed with 100 mL water and dried to get the product (2.4 g, 56% yield).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([N:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:17]([O:19][CH3:20])=[O:18])=O)C1C=CC=CC=1.C1COCC1>[Pd].C(O)(C)C>[CH3:20][O:19][C:17](=[O:18])[C@@H:16]([N:21]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[C:28]2[C:33]1=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:15][CH2:14][CH2:13][CH2:12][NH2:11]
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)n1c2ccccc2c2ccccc21
Agent: [Pd]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCCCN)n1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
10% Pd/C (0.100 g) was added in one portion to a stiffed solution of (S)-Methyl 6-benzyloxycarbonylamino-2-carbazol-9-yl-hexanoate 3 (1.06 g, 2.47 mmol) in a (1:1) mixture of THF (10 mL) and isopropanol (10 mL) under nitrogen atmosphere. The reaction mixture was subsequently stirred under hydrogen atmosphere for 4 h at room temperature. The reaction mixture was filtrated through a celite pad and the filtrate was evaporated under reduced pressure to get (S)-6-amino-2-carbazol-9-yl-hexanoic methyl ester 4 (0.640 g, 85%) as off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[CH3:10][C:11]([CH3:13])=O>>[F:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[N:1]=[C:11]([CH3:13])[CH3:10]
Reactant: CC(C)=O
Reactant: Nc1ccc(O)cc1F
Product: CC(C)=Nc1ccc(O)cc1F

Procedure:
Using the procedure for Example 13, 4-amino-3-fluoro-phenol Compound 14a was refluxed with acetone to provide 3-fluoro-4-isopropylideneamino-phenol Compound 14b in quantitative yield. MS (ESI) m/z: 168 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([Cl:20])=[CH:22][CH:23]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)cc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.7 %

Procedure:
Commercially available 6-chloro-nicotinic chloride (56.8 mmol, 10 g) was dissolved in 50 ml of anhydrous CH2Cl2 and added dropwise to a solution of diisopropylethylamine (DIEA) (1.2 equivalents, 68.2 mmol, 11.67 ml) and 4-chloroaniline (1.2 equiv., 68.2 mmol, 8.70 g) in 50 ml CH2Cl2 at O° C. The mixture was stirred at room temperature for 20 h, then diluted with CH2Cl2 (200 ml) and washed with water (1×200 ml) and brine (1×100 ml). The organic layer was dried over sodium sulphate and concentrated. The crude was crystallized from diethyl ether to give 13 g of a white solid. Yield=86%. 1H NMR (CDCl3, 200 MHz) δ 7.35 (2H, d, J=8.8 Hz), 7.47 (1H, d, J=8.2 Hz), 7.58 (2H, d, J=8.8 Hz), 7.88 (1H, bs), 8.16 (1H, dd, J=8.4 Hz, J′=2.8 Hz), 8.84 (1H, d, J=2.4 Hz)
Reaction SMILES: Cl.Cl.[C:3]([C:5]([C:9]1[CH:10]=[CH:11][C:12]([O:29]C)=[C:13]([CH:28]=1)CN[C@H]1CCCN[C@H]1C1C=CC=CC=1)([C:7]#N)[CH3:6])#[N:4].I[CH:32]([CH3:34])[CH3:33].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O.CCOC(C)=O>[CH:32]([O:29][C:12]1[CH:11]=[CH:10][C:9]([C:5]([CH3:7])([CH3:6])[C:3]#[N:4])=[CH:28][CH:13]=1)([CH3:34])[CH3:33]
Reactant: CC(C)I
Reactant: COc1ccc(C(C)(C#N)C#N)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(C(C)(C)C#N)cc1
Yield: 96.8 %

Procedure:
To a stirred solution of Compound 39 (500 mg, 3.10 mmol) and 2-Iodopropane (0.930 ml, 9.30 mmol) in acetone (8 ml) was added Cs2CO3 (4.55 g, 14.0 mmol), and refluxed for 2 h. The mixture was filtered over celite and washed with acetone. The filtrate was concentrated to give crude Compound 40. This was diluted with AcOEt, washed with water and brine, dried (MgSO4), and concentrated. This was purified by a column chromatography on silica gel to give Compound 40 (610 mg, 97%) as a colorless oil.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([CH2:11][CH3:12])[CH2:9][C@H:8]2[C@H:13]3[C:22](=[CH:23][CH2:24][C@:6]12[CH3:7])[C:21]1[CH2:20][CH2:19][C:18](=[O:25])[CH2:17][C:16]=1[CH2:15][CH2:14]3)(=[O:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1.C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@H:10]([CH2:11][CH3:12])[CH2:9][C@H:8]2[C@H:13]3[C:22]([CH:23]=[CH:24][C@:6]12[CH3:7])=[C:21]1[C:16](=[CH:17][C:18](=[O:25])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3)(=[O:3])[CH3:2]
Reactant: CC[C@@H]1C[C@H]2[C@@H]3CCC4=C(CCC(=O)C4)C3=CC[C@]2(C)[C@H]1OC(C)=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3C=C[C@]2(C)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
3.2 g of 17β-acetoxy-16α-ethyl-5(10),9(11)-estradien-3-one is dissolved in 120 ml of toluene and 40 ml of methylene chloride and combined at room temperature dropwise with a solution of 5.5 g of dichlorodicyano-p-benzoquinone in 80 ml of toluene and 20 ml of methylene chloride. The mixture is stirred for 16 hours at room temperature, filtered over neutral aluminum oxide, and concentrated. After crystallization from diethyl ether, 2.8 g of 17β-acetoxy-16α-ethyl-4,9,11-estratrien-3-one is obtained, m.p. 95°-98° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][NH:8][CH2:7][CH2:6]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([C:15](=[O:17])[CH3:16])[CH2:7][CH2:6]2
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(cc1OC)CNCC2
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)CN(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a stirred solution of 6,7-dimethoxy-1,2, 3,4-tetrahydroisoquinoline (3.00 g, 15.4 mmol, 1.00 equiv) in anhydrous pyridine (100 mL) under argon at room temperature was added acetic anhydride (14.5 mL, 154 mmol, 10.0 equiv) over 15 min. The resulting mixture was stirred at room temperature for 2 h, and then at reflux for 6 h. The volatiles were removed by rotary evaporation at 80° C. under high vacuum. The residue was flash chromatographed on silica gel (MeOH-CH2Cl2 8:92) to afford 3.21 g (89%) of viscous brown oil. The 1H NMR spectrum reflected the presence of two slowly interconverting conformers in a ratio of 1.2 :1 at room temperature. 1H NMR (300 MHz, CDCl3) for conformer 1: δ 2.18 (s, 3 H), 2.83 (t, J=5.9 Hz, 2 H), 3.67 (t, J=5.9 Hz, 2 H), 3.86 (s, 3 H), 3.87 (s, 3 H), 4.66 (s, 2 H), 6.63 (s, 1 H), 6.65(s, 1 H). For conformer 2:δ 2.19 (s, 3 H), 2.77 (t, J=5.9 Hz, 2 H), 3.81 (t, J=5.9 Hz, 2 H), 3.86 (s, 3 H), 3.87 (s, 3 H), 4.56 (s, 2 H), 6.59 (s, 1 H), 6.63 (s, 1 H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[C:4]2[CH:5]=[N:6][N:7]([CH3:13])[C:8]=2[C:9](=[O:12])[C:10]=1[Cl:11].[CH:15]1([NH2:18])[CH2:17][CH2:16]1>C(O)C>[Cl:11][C:10]1[C:9](=[O:12])[C:8]2[N:7]([CH3:13])[N:6]=[CH:5][C:4]=2[C:3](=[O:14])[C:2]=1[NH:18][CH:15]1[CH2:17][CH2:16]1
Reactant: NC1CC1
Reactant: Cn1ncc2c1C(=O)C(Cl)=C(Cl)C2=O
Solvent: CCO
Product: Cn1ncc2c1C(=O)C(Cl)=C(NC1CC1)C2=O

Procedure:
5,6-Dichloro-1-methyl-1H-indazole-4,7-dione (10 grams prepared as in Example I) and cyclopropylamine (10 grams) in ethanol (50 milliliters) were stirred together at room temperature for 30 minutes. The precipitate formed was filtered off and dried to yield the desired product as a red solid having a melting point of 175°-176° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7].[Br:16]N1C(=O)CCC1=O.C(OOCC1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:2]([F:14])([F:15])[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(C(F)(F)F)c1
Agent: c1ccc(COOCc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(C(F)(F)F)c1
Yield: 87.8 %

Procedure:
A reactor is charged with 1 g (4.6 mmol) of the compound obtained in step 1, 0.97 g (5.5 mmol) of N-bromosuccinimide, 133 mg (0.55 mmol) of benzyl peroxide and 25 ml of carbon tetrachloride. The mixture is heated for 4 hours at reflux. The solvent is evaporated under reduced pressure and 100 ml of a saturated sodium bicarbonate solution is added. The solution obtained is extracted with 3*30 ml ethyl acetate. The organic phases are combined, dried on sodium sulphate and evaporated under reduced pressure to give the expected product (1.2 g, 88%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:20]#[N:21])=[CH:8][N:9]2[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:4][C:3]=1[N+:23]([O-:25])=[O:24].[NH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(#N)C>[N:29]1([CH2:28][CH2:27][NH:26][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:22])[C:7]([C:20]#[N:21])=[CH:8][N:9]3[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:4][C:3]=2[N+:23]([O-:25])=[O:24])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c(=O)c2cc([N+](=O)[O-])c(Cl)cc21
Reactant: NCCN1CCOCC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1cc(C#N)c(=O)c2cc([N+](=O)[O-])c(NCCN3CCOCC3)cc21
Yield: 62 %

Procedure:
A mixture of 1.25 g (3.29 mmol) of 7-chloro-6-nitro-4-oxo-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1,4-dihydro-3-quinolinecarbonitrile and 1.07 g (8.2 mmol) of 4-(2-aminoethyl)-morpholine in 21 mL of acetonitrile is heated at reflux temperature for 17 hours. After cooling, the mixture is concentrated under reduced pressure and the residue is partitioned between methylene chloride and brine. The separated organic layer is dried over sodium sulfate and filtered. Removal of the solvent yields a residue which is flash chromatographed (elution with methylene chloride, then a gradient of 99:1 to 98:2 methylene chloride/methanol), giving 966 mg (61.9%) of the product as a yellow solid, mp 294–216° C.