Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[C:14]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[N+:19]([O-])=O.[H][H]>[OH-].[Na+].[Ni]>[NH2:19][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([S:15](=[O:18])(=[O:17])[NH2:16])[C:6]=1[NH:5][CH2:4][CH2:3][O:2][CH3:1])[C:10]([OH:12])=[O:11]
Reactant: [H][H]
Reactant: COCCNc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: COCCNc1c(N)cc(C(=O)O)cc1S(N)(=O)=O

Procedure:
4-(2-Methoxyethylamino)-3-nitro-5-sulphamyl-benzoic acid (3.2 g) was dissolved in 1N sodium hydroxide (10 ml) and hydrogenated after addition of moist Raney-Nickel (1 g). When the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the resulting 3-amino-4-(2-methoxyethylamino)-5-sulphamyl-benzoic acid was precipitated from the filtrate by addition of 4N hydrochloric acid until pH 3. After recrystallization from water, the melting point was 209°-211°C.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.CCN(C(C)C)C(C)C>CS(C)=O.O>[O:16]=[C:3]1[C:2]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[NH:4]1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCC3)nc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (200 mg, 0.84 mmol) in DMSO (2 mL) was added pyrrolidine (90 mg, 1.27 mmol) and DIEA (163 mg, 1.26 mmol). After stirring overnight at 70° C., the reaction mixture was dissolved in water (50 mL), then filtered to afford methyl 2-oxo-3-(pyrrolidin-1-yl)-1,2-dihydroquinoxaline-6-carboxylate as a light yellow solid (200 mg, 87%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:16]=[C:17]([CH3:19])[CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][C@H:3]1[O:20][CH3:21].[Cl:22][C:23]1[N:24]=[C:25]([C:30](O)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:22][C:23]1[N:24]=[C:25]([C:30]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([CH:16]=[C:17]([CH3:19])[CH:18]=3)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][C@H:3]2[O:20][CH3:21])=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)c1cc(C)cc(N2CC[C@H](N)[C@H](OC)C2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)cc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)c1
Yield: 76.4 %

Procedure:
The same operation as in Example (1g) was performed using ethyl cis(±)-3-(4-amino-3-methoxypiperidin-1-yl)-5-methylbenzoate obtained in Example (259g) (about 0.24 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (37 mg, 0.21 mmol), WSC hydrochloride (134 mg, 0.70 mmol), HOBT (47 mg, 0.35 mmol), dichloromethane (1.5 mL) and DMA (1.5 mL), to obtain 72 mg of the title compound as a colorless oily substance (75%).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20]2>>[CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=[C:20]2[C:19]3[C:23](=[CH:24][CH:25]=[C:17]([F:16])[CH:18]=3)[NH:22][C:21]2=[O:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: COc1ccc(C=O)cc1C1CCCC1
Product: COc1ccc(C=C2C(=O)Nc3ccc(F)cc32)cc1C1CCCC1

Procedure:
3-Cyclopentyl-4-methoxybenzaldehyde was condensed with 5-fluoro-2-oxindole to give 0.25 g of 3-(3-cyclopentyl-4-methoxybenzylidene)-5-fluoro-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([N:10]1[CH:14]=[CH:13]N=C1)=[S:9].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1CCN.C(OCC)(=O)C>CN(C)C=O>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:13][CH2:14][NH:10][C:8]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[S:9]
Reactant: NCCc1ccccc1Cl
Reactant: S=C(Nc1ccccn1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: S=C(NCCc1ccccc1Cl)Nc1ccccn1
Temperature: 25 °C
Yield: 14.4 %

Procedure:
A solution of 1-[(2-pyridyl)thiocarbamoyl]imidazole (1.02 g, 5.0 mmol) and 2-(2-chlorophenyl)ethylamine (0.81 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 24 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant oil was purified by chromatography on silica gel to provide 0.21 g (14%) of the titled product as a yellow solid:
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C@H:7]([N:10]([CH2:18][C@H:19]([OH:28])[CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][OH:9])=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37](O)=[O:38].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[OH:9][CH2:8][C@@H:7]([N:10]([CH2:18][C@H:19]([OH:28])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:37]([C:33]2[N:32]([CH3:31])[CH:36]=[CH:35][CH:34]=2)=[O:38])=[CH:30][CH:29]=1
Reactant: Cn1cccc1C(=O)O
Reactant: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccccc1)[C@H](CO)Cc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1cccc1C(=O)Nc1ccc(C[C@@H](CO)N(C[C@H](O)COc2ccccc2)C(=O)OC(C)(C)C)cc1
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a solution of tert-butyl N-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate (200 mg) in N,N-dimethylformamide (2.0 ml) was added successively 1-methyl-1H-pyrrole-2-caroxylic acid (72.1 mg) and 1-hydroxybenzotriazole hydrate (77.9 mg). To the mixture was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (110 mg) at room temperature and the mixture was stirred overnight. The mixture was diluted with ethyl acetate (20 ml) and washed with water (20 ml×2), a saturated aqueous sodium hydrogencarbonate solution (20 ml×1) and brine (20 ml×1) successively. The organic solution was dried over magnesium sulfate, filtered, and evaporated to give a yellow solid. The crude product was purified by a recycling preparative high pressure liquid chromatography equipped with a gel permeation chromatography column (eluent: chloroform) to give tert-butyl N-[(1S)-2-hydroxy-1-[4-[[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino]benzyl]ethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate (163 mg) as a white foam.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([Cl:13])[CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=2)[CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[Cl:13][C:7]1[CH:8]=[C:9]([OH:12])[CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=1)[CH:3]=[C:2]2[C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1
Reactant: Oc1cc(Cl)c2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cc(-c3ccc(O)c(F)c3)nc3c(Cl)cc(O)cc23)cc1
Yield: 97 %

Procedure:
This compound was prepared from 45a using 4-methoxyphenylboronic acid according to method P. Orange solid; Yield: 97%; mp 140-142° C.; 1H-NMR (400 MHz, DMSO-d6) δ 3.87 (s, 3H), 7.09 (dd, J=8.8, 8.8 Hz, 1H), 7.11 (d, J=2.7 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.51 (d, J=2.6 Hz, 1H), 7.53 (d, J=8.8 Hz, 2H), 7.93 (s, 1H), 8.02 (dd, J=8.5, 1.7 Hz, 1H), 8.14 (dd, J=13.1, 2.1 Hz, 1H), 10.21 (s, 1H), 10.27 (s, 1H); 19F-NMR (400 MHz, DMSO-d6) δ −136.48 (dd, J=13.0, 9.7 Hz); MS (ESI) m/z 394/396 ([M−H]−), 396/398 ([M+H]+); Anal. Calcd for C22H15ClFNO3: C, 66.76; H, 3.82; N, 3.54. Found: C, 66.05; H, 4.01; N, 3.19.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[NH:20][CH2:19][C:17]2=[C:18]3[C:13](=[C:14]([CH2:21][C:22](=[O:24])[NH2:23])[CH:15]=[CH:16]2)[CH:12]=[CH:11][N:10]3[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O:26][C:27](=O)[C:28]([C:30]1[C:40]2=[C:41]3[C:36](=[CH:37][CH:38]=[CH:39]2)[CH2:35][CH2:34][C:33]([CH3:43])([CH3:42])[N:32]3[CH:31]=1)=O>>[C:1]([O:5][C:6]([CH:8]1[NH:20][CH2:19][C:17]2=[C:18]3[C:13](=[C:14]([C:21]4[C:22](=[O:24])[NH:23][C:27](=[O:26])[C:28]=4[C:30]4[C:40]5=[C:41]6[C:36](=[CH:37][CH:38]=[CH:39]5)[CH2:35][CH2:34][C:33]([CH3:42])([CH3:43])[N:32]6[CH:31]=4)[CH:15]=[CH:16]2)[CH:12]=[CH:11][N:10]3[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1Cn2ccc3c(CC(N)=O)ccc(c32)CN1
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2(C)C
Product: CC(C)(C)OC(=O)C1Cn2ccc3c(C4=C(c5cn6c7c(cccc57)CCC6(C)C)C(=O)NC4=O)ccc(c32)CN1

Procedure:
Beginning with 7-Carbamoylmethyl-3,4-dihydro-1H-[1,4]diazepino[6,7,1-hi]indole-2-carboxylic acid tert-butyl ester and (4,4-Dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-oxo-acetic acid methyl ester, the title compound was prepared essentially as Example 1.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([CH2:14][N+:15]34CN5CN(CN(C5)C3)C4)[O:11][N:10]=2)=[CH:5][CH:4]=1.Cl>CO>[NH2:15][CH2:14][C:12]1[O:11][N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[CH:13]=1
Reactant: Clc1ccc(-c2cc(C[N+]34CN5CN(CN(C5)C3)C4)on2)cc1
Agent: Cl
Agent: [Br-]
Solvent: CO
Product: NCc1cc(-c2ccc(Cl)cc2)no1

Procedure:
A 205 g. portion of the product of Example 5 was dissolved in 1.5 l. of methanol and 250 ml. of concentrated hydrochloric acid was added. The mixture was stirred at reflux temperature overnight, and the solvent was then evaporated under vacuum. The residue was neutralized with aqueous sodium hydroxide and the product was extracted from the aqueous mixture with methylene dichloride and was purified by evaporating the solvent and recrystallizing the residue from ethanol-petroleum ether. The product was 78 g. of 5-aminomethyl-3-(4-chlorophenyl)isoxazole, m.p. 81°.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1.Cl.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[CH2:31][CH2:32][NH2:33]>>[OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:33][CH2:32][CH2:31][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)=[O:13])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: COc1cc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccn1
Reactant: NCCC1CCCCO1
Agent: Cl
Product: COc1cc(-c2cnn(-c3ccc(C(=O)NCCC4CCCCO4)cn3)c2O)ccn1

Procedure:
The title compound was prepared in a manner similar to Example 198 using 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazol-1-yl)nicotinic acid and 2-(tetrahydro-2H-pyran-2-yl)ethanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.19 (m, 1 H) 1.31-1.43 (m, 3 H) 1.52 (d, J=12.9 Hz, 1 H) 1.58 (q, J=7.1 Hz, 2 H) 1.65-1.75 (m, 1H) 3.18-3.25 (m, 2 H) 3.29-3.38 (m, 2 H) 3.81 (m, J=2.0 Hz, 4 H) 7.34 (br. s., 1 H) 7.42 (d, J=5.1 Hz, 1 H) 7.98 (d, J=5.6 Hz, 1 H) 8.26-8.34 (m, 1 H) 8.37 (br. s., 1 H) 8.52 (br. s., 1 H) 8.59 (t, J=5.4 Hz, 1 H) 8.82 (s, 1 H) 13.45 (br. s., 1 H). MS m/z 424 [M+H]+.
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[N+:9]([C:12]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])=[CH:17][C:13]=1[C:14](Cl)=[O:15])([O-:11])=[O:10].C(#N)C.[OH-].[Na+]>O>[CH2:2]([O:4][C:5]([CH2:6][NH:7][C:14](=[O:15])[C:13]1[CH:17]=[C:18]([O:21][C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:30])[F:31])=[CH:24][C:23]=2[Cl:33])[CH:19]=[CH:20][C:12]=1[N+:9]([O-:11])=[O:10])=[O:8])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: O=C(Cl)c1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CNC(=O)c1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 95.7 %

Procedure:
7 g of aminoacetic acid ethyl ester chloride, 20.7 g of 2-nitro-5-(2,6-dichloro-4-trifluoromethyl-phenoxy)-benzoic acid chloride and 180 ml of acetonitrile were initially introduced into the reaction vessel. 4 g of sodium hydroxide, dissolved in 10 ml of water, were added dropwise at -10° to -5° C. The reaction mixture was then poured onto water and adjusted to pH 10 and the crystalline product was filtered off. 23 g (95% of theory) of 5-(2,6-dichoro-4-trifluoromethyl-phenoxy)-2-nitro-benzoic acid (ethoxycarbonylmethyl)-amide with a melting point of 146° C. were obtained.
Reaction SMILES: [OH-].[K+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.I[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CN(C)C=O>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: c1ccc(CNCc2ccccn2)nc1
Reactant: CCCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCCN(Cc1ccccn1)Cc1ccccn1
Reaction time: 16 h
Yield: 72.8 %

Procedure:
To 15 ml of N,N-dimethylformamide, 0.85 g potassium hydroxide, 1.0 g di(2-picolyl)amine, and 0.99 g 1-iodopentane were successively added. The mixture was stirred under nitrogen at 35 C for 2.5 hours before an additional 0.99 g 1-iodopentane were added. The mixture was then stirred for 16 hrs at 35 C under nitrogen. The reaction was quenched with 90 ml of water and extracted with two 50 ml portions of ethyl acetate. The combined organic layers were washed with two 25 ml portions of water, dried over anhydrous magnesium sulfate, and filtered. Following solvent removal, the orange oil obtained was purified by silica gel chromatography using a methanol/ethyl acetate mixed solvent system that was ramped from 0% to 10% methanol by volume during the course of the elution. An orange oil (0.98 g) was obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.Cl.[N:12]([O-])=O.[Na+].C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[NH4+].[NH4+]>CO.O.[Zn]>[NH2:12][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[CH3:1]
Reactant: CC1Cc2ccccc2N1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Product: CC1Cc2ccccc2N1N
Temperature: 15 °C

Procedure:
140 g of 2-methylindoline was dissolved in 1 liter of methanol. About 95 ml of concentrated hydrochloric acid was added and the solution was cooled to 15° C. Then a 25% solution of sodium nitrite (73 g) in water was added dropwise at 5°-10° C. The pH of the solution was adjusted to about 7.5 with sodium bicarbonate and 156 g of zinc dust was added to form a mixture thereof. Keeping the mixture at about 5° C., a solution of 264 g of ammonium carbonate in 1 liter of water was added over a period of about 1.5 hours. The mixture was then stirred at 5°-10° C., warmed to 40° C., and filtered. The residual was washed with toluene. The combined filtrate and washes were separated and the aqueous layer was discarded. The toluene was removed in vacuo and the residue recrystallized from heptane to give 1-amino-2-methylindoline. TLC test confirmed the identity of the product compound. (ANALTECH Silica Gel plate; chloroform/acetic acid:9/1).
Reaction SMILES: [ClH:1].[F:2][C:3]1[C:4]([C:18]2[N:19]=[N:20][C:21]([N:24]([CH3:35])[CH:25]3[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]3)=[CH:22][CH:23]=2)=[C:5]([OH:17])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([O:15]C)[CH:10]=2)[CH:8]=1.Cl.N1C=CC=CC=1.Cl>CO.CS(C)=O>[ClH:1].[F:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)[CH:6]=[C:5]([OH:17])[C:4]=1[C:18]1[N:19]=[N:20][C:21]([N:24]([CH3:35])[CH:25]2[CH2:30][C:29]([CH3:31])([CH3:32])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)=[CH:22][CH:23]=1
Reactant: COc1cc(-c2cc(O)c(-c3ccc(N(C)C4CC(C)(C)NC(C)(C)C4)nn3)c(F)c2)ccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: CO
Product: CN(c1ccc(-c2c(O)cc(-c3cc[nH]c(=O)c3)cc2F)nn1)C1CC(C)(C)NC(C)(C)C1
Yield: 30.7 %

Procedure:
3-Fluoro-5-(2-methoxypyridin-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol hydrochloride salt (Example 40-1, 10 mg, 0.02 mmol) and pyridine hydrochloride (50 mg, 0.43 mmol) were heated at 170° C. for 15 minutes in a Biotage® Initiator microwave reactor. The reaction mixture was diluted with MeOH/DMSO, and purified via reverse phase preparative HPLC (10 to 45% acetonitrile in water, 0.1% trifluoroacetic acid as modifier). The appropriate fractions containing product were free based by catch and release using SiliaBond Propylsulphonic Acid® (4 eq, methanol as eluent and a 2 N ammonia solution in MeOH to release the material). The solvent was concentrated in vacuo and the resulting solid was suspended in CH3CN/H2O (3/1 mL). 1 M aqueous HCl (3 equivalents) was added and solvent was concentrated in vacuo to afford the title compound as a yellow solid (3 mg, 26%). LCMS Rt=0.47 min [Method Q]; [M+H]: 452.3; 1H NMR (400 MHz, MeOD) δ 8.28 (d, J=10.0 Hz, 1H), 8.07 (d, J=10.0 Hz, 1H), 7.69 (d, J=6.5 Hz, 1H), 7.25 (dd, J=11.0, 1.5 Hz, 1H), 7.19 (s, 1H), 6.89 (s, 1H), 6.85 (dd, J=6.5, 1.5 Hz, 1H), 5.07 (bs, 1H), 3.21 (s, 3H), 2.20-2.00 (m, 4H), 1.66 (s, 6H), 1.59 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CCO.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:24]1([CH2:23][CH2:22][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)Cc1ccc(O)cc1
Reactant: ClCCN1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(OCCN2CCOCC2)cc1

Procedure:
A solution of 1 g of ethyl (4-hydroxyphenyl)acetate in 20 ml of EtOH is admixed with 2.5 g of K2CO3, 1.68 g of 4-(2-chloroethyl)morpholine hydrochloride and 0.01 g of tetrabutylammonium iodide and then heated at reflux for 5 hours. After cooling to AT, the K2CO3 is filtered off and washed with EtOH and the filtrate is concentrated under vacuum. The residue is taken up in water and extracted with AcOEt, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated under vacuum. This gives 1.5 g of the expected compound in the form of a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][NH:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[K+].C(O)C.O.Cl>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1ccc(NCc2ccc(OC)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(CNc2ccc(C(=O)O)cc2)cc1

Procedure:
A mixture of 15 g. of ethyl p-[(p-methoxybenzyl)amino]benzoate, (prepared as described in Example 14) 15 g. of potassium hydroxide and 200 ml. of ethanol-water (9:1) are refluxed for 3 hours, acidified while hot with concentrated hydrochloric acid, diluted with water, cooled, filtered and the solid is washed with water to give tan crystals, m.p. 208°-210° C. Recrystallization from ethanol gives off-white crystals, m.p. 209°-210° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1([CH2:26][O:27]CC2C=CC=CC=2)[CH2:10][O:9][C:8](=[O:11])/[C:7]/1=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:3])[CH3:2].B(Cl)(Cl)Cl>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1([CH2:26][OH:27])[CH2:10][O:9][C:8](=[O:11])/[C:7]/1=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCC/C=C1\C(=O)OCC1(COCc1ccccc1)COC(C)=O
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCC/C=C1\C(=O)OCC1(CO)COC(C)=O
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A solution of 14b (0.324 g, 0.685 mmol) in CH2Cl2 (20 mL) was cooled to -78° C., treated with boron trichloride (1.0M in dichloromethane, 2.74 mL, 2.74 mmol), and stirred for 1 h at that temperature. The reaction mixture was quenched with saturated NaHCO3 solution (3.0 mL), and immediately partitioned between chloroform and a pH 7 buffer solution. The organic layer was washed with water, dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography over silica gel with EtOAc/hexane (1:1) as eluant to give 14c (0.252 g, 96%) as a white solid: mp 48° C.; IR (KBr) 3489 (OH), 1735 (C=O) and 1667 cm-1 (C=C); 1H NMR (CDCl3) δ 0.86 (distorted t, 3 H, CH3), 1.10-1.50 (m, 22 H, >C=CHCH2 (CH2)11CH3), 2.08 (s, 3 H, CH3CO), 2.60-2.90 (m, 2 H, >C=CHCH2), 3.59 (AB m, 2 H, CH2OH), 4.18 (2 AB multiplets, 4 H, H-5, CH2OAc), 6.28 (t, 1 H, J=7.6 Hz, 1 H, >C=CH); 13C NMR (CDCl3) δ 14.11, 20.72, 22.68, 27.61, 29.06, 29.24, 29.35, 29.41, 29.55, 29.64, 31.91, 47.58, 64.42, 65.34, 69.86, 126.06, 147.72, 169.69, 171.19; FAB MS m/z 383 (MH+, 100). Anal. Calcd for C22H38O5 : C, 69.07; H, 10.01. Found: C, 69.06; H: 10.03.
Reaction SMILES: [CH3:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2(C=O)[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2CC[C@@]2(C)[C@H]1CCC2=O.O[C@@]1(C)CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(C=O)C(=CC(=O)CC1)C=C3.O[C@@]1(C#CC)CC[C@H]2[C@H]3[C@H:65](CC[C@]12C)[C@:62]1([CH:63]=[O:64])[C:57](=[CH:58][C:59](=[O:68])[CH2:60][CH2:61]1)[CH:56]=[CH:55]3.C[C@]12CC[C@H]3[C@@H](C=CC4[C@]3(C=O)CCC(=O)C=4)[C@@H]1CCC2=O>>[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][CH2:17][C@@:16]2([CH3:15])[C:3]=1[CH2:4][C@@H:5]([CH3:6])[C@@H:58]1[C@:59]2([OH:68])[CH2:60][CH2:61][C@@:62]2([CH3:65])[C@H:57]1[CH2:56][CH2:55][C@@H:63]2[OH:64]
Reactant: CC1=C2C=C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C=O)CCC1=O
Reactant: CC#C[C@]1(O)CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(C=O)[C@H]3CC[C@@]21C
Agent: C[C@]1(O)CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(C=O)[C@H]3CC[C@@]21C
Agent: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@]43C=O)[C@@H]1CCC2=O
Product: CC1=C2C[C@@H](C)[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@]3(O)[C@@]2(C)CC[C@@H]1O

Procedure:
Substituting 4-methyl-4,6-androstadiene-3,17,19-trione, 17β-hydroxy-17α-methyl-4,6-androstadiene-3,19-dione and 17β-hydroxy-17α-propinyl-4,6-androstadiene-3,19-dione for the 4,6-androstadiene-3,17,19-trione above results in the formation of 4,7α-dimethyl-4-androstene-3β,17β,9-triol, 7α,17α-dimethyl-4-androstene-3β,17β,19-triol and 7α-methyl-17α-propinyl-4-androstene-3β,17β,19-triol, respectively.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)=[C:13]=[S:14]>CCO>[Br:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[NH:1][C:13](=[S:14])[N:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:4]2=[O:6]
Reactant: S=C=Nc1ccccn1
Reactant: Nc1c(Br)cccc1C(=O)O
Solvent: CCO
Product: O=c1c2cccc(Br)c2[nH]c(=S)n1-c1ccccn1
Temperature: 25 °C
Yield: 28.5 %

Procedure:
A mixture of 2-amino-3-bromobenzoic acid (705 mg, 3.26 mmol, Sigma Aldrich) and 2-isothiocyanatopyridine (800 mg, 5.87 mmol, 415a) in EtOH (19.6 mL) was set stirring at RT, and TEA (0.68 mL, 4.90 mmol) was added dropwise. It was sealed and heated to 100° C. for 16 h. The mixture was concentrated under reduced pressure to a residue that was taken up in DCM. Silica was added, and the crude reaction was adsorbed. It was purified on 24 g SiO2 (eluent: 0-100% EtOAc/hexanes over 30 min, RediSep Gold). The product fractions were combined and concentrated under reduced pressure to give a yellow-orange solid (311 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.18 (1H, br. s.) 8.60 (1H, d, J=4.69 Hz) 8.39 (1H, d, J=4.11 Hz) 8.11 (1H, d, J=6.85 Hz) 7.83-7.93 (1H, m) 7.78 (1H, dd, J=7.82, 1.37 Hz) 7.44-7.53 (2H, m). m/z (ESI, +ve) 333.8 (M+H)+.