Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH:13](=[N:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(CN)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(CN=Cc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12.0 g of 2,4-dimethoxybenzylamine hydrochloride is added to 100 ml of 1N sodium hydroxide solution and the mixture is extracted with 125 ml of ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and stripped of solvent to give 10.2 g of 2,4-dimethoxybenzylamine as an oil. This amine is dissolved in 150 ml of benzene; 6.47 g of benzaldehyde and 0.6 g of p-toluenesulfonic acid monohydrate are added. The mixture is heated under reflux removing water with a Dean-Stark separator and in two hours the calculated amount of water (1.1 ml) separates out. The mixture is cooled to room temperature. Upon further cooling the benzene solution deposits some precipitate. Benzene is removed under reduced pressure and 60 ml of petroleum ether is added to the residue. An oily layer separates out with more precipitate. Benzene (10 ml) is added to make the layers homogeneous and the remaining precipitate is filtered. The filtrate is stripped of solvent to give 14.2 g of the title compound as an oil.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[C:27]([F:42])=[CH:28][C:29]([F:41])=[C:30]([S:32]([NH:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])(=[O:34])=[O:33])[CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[C:27]([F:42])=[CH:28][C:29]([F:41])=[C:30]([S:32]([NH:35][CH2:36][CH2:37][N:38]([CH3:39])[CH3:40])(=[O:34])=[O:33])[CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN(C)CCNS(=O)(=O)c1cc(Br)c(F)cc1F
Product: CN(C)CCNS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (337 mg, 1.0 mmol) and 5-bromo-N-(2-dimethylamino-ethyl)-2,4-difluoro-benzenesulfonamide (example B.36) (446 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (300 mg, 50%). MS (ISP) 600.2 [(M+H)+]; mp 165-166° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(OC(=O)[NH:20][C@@H:21]1[CH2:25][CH2:24][NH:23][CH2:22]1)(C)(C)C>>[NH2:20][C@@H:21]1[CH2:25][CH2:24][N:23]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:22]1
Reactant: N#Cc1ccc2nccc(Br)c2c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Product: N#Cc1ccc2nccc(N3CC[C@@H](N)C3)c2c1

Procedure:
Starting from 4-bromo-6-cyanoquinoline (commercial) and (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (commercial) the title compound was prepared according to procedure F followed by procedure E and was isolated as a yellow solid (330 mg, 65% over two steps).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24]C(=O)OC(C)(C)C)[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]=2[N:19]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:1][C:2]1[N:3]([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6]([O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:5]=2[N:19]=1
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCCCNC(=O)OC(C)(C)C)c2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(Oc2ccccc2)c2nc(C)n(CCCCN)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A solution of tert-butyl 4-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butylcarbamate (6.70 g, 15.8 mmol) in dichloromethane (50 mL) was slowly added to a chilled (0° C.) mixture of trifluoroacetic acid (60 mL) and dichloromethane (100 mL). The reaction mixture was allowed to warm to ambient temperature and then left overnight. The reaction mixture was concentrated under reduced pressure to provide a brown oil. The oil was dissolved in dichloromethane and the solution was made basic (pH 14) with 5% aqueous sodium hydroxide. The layers were separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate and then concentrated under reduced pressure to provide 4.50 g of 4-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butylamine as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[C@@H:16]3[C@@H:14]([CH2:15]3)[C@@H:13]([OH:17])[C@H:12]2[OH:18])=[C:4]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[C:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]#[CH:35])[CH:22]=2)[N:3]=1.ClC1N=C2C(N=CN2[C@@H]2[C@@H]3[C@@H](C3)[C@@H](O)[C@H]2O)=C(NCC2C=CC=C(C#CCCCC3[N:68]=[N:69][N:70]([C:72]4[CH:77]=[CH:76][C:75]([F:78])=[C:74]([N+:79]([O-:81])=[O:80])[CH:73]=4)C=3)C=2)N=1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[C@@H:16]3[C@@H:14]([CH2:15]3)[C@@H:13]([OH:17])[C@H:12]2[OH:18])=[C:4]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[C:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]3[N:68]=[N:69][N:70]([C:72]4[CH:77]=[CH:76][C:75]([F:78])=[C:74]([N+:79]([O-:81])=[O:80])[CH:73]=4)[CH:35]=3)[CH:22]=2)[N:3]=1
Reactant: C#CCCCCCC#Cc1cccc(CNc2nc(Cl)nc3c2ncn3[C@H]2[C@H](O)[C@H](O)[C@@H]3C[C@@H]32)c1
Reactant: O=[N+]([O-])c1cc(-n2cc(CCCC#Cc3cccc(CNc4nc(Cl)nc5c4ncn5[C@H]4[C@H](O)[C@H](O)[C@@H]5C[C@@H]54)c3)nn2)ccc1F
Product: O=[N+]([O-])c1cc(-n2cc(CCCCCC#Cc3cccc(CNc4nc(Cl)nc5c4ncn5[C@H]4[C@H](O)[C@H](O)[C@@H]5C[C@@H]54)c3)nn2)ccc1F
Yield: 91 %

Procedure:
Compound 216 (91%) was synthesized from compound 213 following the same procedure as for compound 214. 1H NMR (CD3OD, 400 MHz) δ 8.56-8.54 (m, 1H), 8.40 (s, 1H), 8.13-8.18 (m, 2H), 7.60 (t, J=8.8 Hz, 1H), 7.37 (s, 1H), 7.30 (d, J=6.8 Hz, 1H), 7.24-7.21 (m, 2H), 4.79 (s, 1H), 4.72-4.69 (m, 3H), 3.90 (d, J=6.4 Hz, 1H), 2.84 (t, J=7.2 Hz, 2H), 2.45 (t, J=6.8 Hz, 2H), 2.01-1.95 (m, 1H), 1.86-1.79 (m, 2H), 1.68-1.58 (m, 5H), 1.33-1.30 (m, 1H), 0.82-0.72 (m, 1H). HRMS calculated for C33H32ClFN9O4 (M+H)+: 672.2250. Found 672.2245.
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH:4]([CH3:9])[CH2:5][CH:6]([CH3:8])[N:7]=1.Cl(O)(=O)(=O)=O.CO[CH:17](OC)[CH2:18][CH:19](OC)OC>>[CH3:8][CH:6]1[CH2:5][CH:4]([CH3:9])[N:3]2[CH:17]=[CH:18][CH:19]=[N:1][C:2]2=[N:7]1
Reactant: CC1CC(C)NC(N)=N1
Reactant: COC(CC(OC)OC)OC
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC1CC(C)N2C=CC=NC2=N1

Procedure:
0.66 g 2-amino-4,6-dimethyl-1,4,5,6-tetrahydropyrimidine was refluxed to boiling point in a methanolic solution with the addition of perchloric acid with an equimolar amount of 1,1,3,3-tetramethoxypropane. Removing the solvent and coating the residue with a layer of diethyl ether yielded the 2,4-dimethyl-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidine hydroperchlorate, which was filtered off and dried in a vacuum.
Reaction SMILES: [N:1]([C@H:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C@H:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N+]=[N-]>C(O)(C)C.[Pd]>[CH3:15][O:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C@@H:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:4]([NH2:1])[CH2:13][CH2:12]2
Reactant: COc1ccc2c(c1)CC[C@H](N=[N+]=[N-])[C@@H]2c1ccccc1
Agent: [Pd]
Solvent: CC(C)O
Product: COc1ccc2c(c1)CC[C@H](N)[C@@H]2c1ccccc1

Procedure:
The azido-tetrahydronaphthalene 31 obtained above (1.3 g) was dissolved in isopropanol (50 mL) and this solution was hydrogenated at 50 psi over 10% palladium on carbon (0.2 g) at room temperature for 18 h. The catalyst was removed by filtration and the solvent was evaporated in vacuo to afford crude cis-1,2,3,4-tetrahydro-6-methoxy-1-phenyl-2-naphthalenamine 32 as an oil, which was used in the subsequent step without purification (FIG. 10). MS m/e (MH+) 254.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[C:6]([N+:16]([O-])=O)[C:5]=1[S:19][C:20]#[N:21].N>C(O)(=O)C.O.[Fe]>[CH3:1][O:2][C:3]([C:4]1[C:5]2[S:19][C:20]([NH2:21])=[N:16][C:6]=2[CH:7]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:9]=1)=[O:22]
Reactant: COC(=O)c1cc(-c2cccnc2)cc([N+](=O)[O-])c1SC#N
Agent: [Fe]
Agent: N
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(-c2cccnc2)cc2nc(N)sc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.2 %

Procedure:
A solution of 3-Nitro-5-pyridin-3-yl-2-thiocyanato-benzoic acid methyl ester (1.1 g, 3.49 mmol) in glacial acetic acid (23 ml) was treated with iron powder (0.97 g, 17.5 mmol) and stirred at ambient temperature for 16 h. The resultant mixture was diluted with water (200 ml) and made alkaline by the addition of concentrated ammonia solution. The mixture was filtered and the filtrate extracted with ethyl acetate (3×200 ml). The filtered solid was extracted with boiling ethanol (3×250 ml) and the combined organic fractions evaporated to dryness to give 2-Amino-5-pyridin-3-yl-benzothiazole-7-carboxylic acid methyl ester as an off-white solid (0.46 g, 46%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:10](OC(OCC)OCC)(=O)C>C1CCCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[N:9][N:8]=2)[CH:7]=1
Reactant: CCOC(OCC)OC(C)=O
Reactant: NNc1ccc(F)cn1
Solvent: C1CCCCC1
Product: Fc1ccc2nncn2c1

Procedure:
(5-Fluoro-pyridin-2-yl)-hydrazine (500 mg, 3.93 mmol) in diethoxymethyl acetate (5 mL) was stirred at RT for 2 h. The resulting precipitate was diluted with cyclohexane (5 mL) and filtered to give Intermediate Fa (379 mg, 70%). NMR (400 MHz, CDCl3): 7.25 (1H, m), 7.84 (1H, m), 8.09 (1H, t, J=2.5 Hz), 8.84 (1H, s).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[S:42]([NH2:45])(=[O:44])=[O:43]>>[CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:45][S:42]([C:33]3[CH:34]=[CH:35][C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:32]=3)(=[O:43])=[O:44])=[O:31])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1ccc2ccccc2c1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc3ccccc3c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 18) and 2-naphtylsulfonamide.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[C:15]([C:33](=[O:35])[NH2:34])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]>C(O)(C(F)(F)F)=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)[C:15]([C:33]([NH2:34])=[O:35])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCN(C(=O)OC(C)(C)C)CC3)n2)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCNCC3)n2)c1
Yield: 59.2 %

Procedure:
A solution of tert-butyl 4-((2-(3-acetamidophenylamino)-5-carbamoylpyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (100 mg, 0.207 mmol) in TFA (3 mL) was stirred at room temperature for 30 min. TFA was removed in vacuo. The residue was purified by HPLC to give the titled compound (47 mg). MS 384.4 (M+H); UV 200.0, 248.6 nm.
Reaction SMILES: ClC1C=CC=CC=1Cl.[Cl:9][C:10]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=1[NH2:12].[F:20][C:21]([F:33])([F:32])[C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>N1C=CC=CC=1>[Cl:9][C:10]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=1[NH:12][S:28]([C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:32])[F:33])[CH:23]=1)(=[O:30])=[O:29]
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: Clc1ccccc1Cl
Product: O=[N+]([O-])c1ccc(NS(=O)(=O)c2cccc(C(F)(F)F)c2)c(Cl)c1
Temperature: 25 °C

Procedure:
In a 400 ml flask, 200 ml of o-dichlorobenzene, 1 ml of pyridine and 1.7 g (0.01 mole) of 2-chloro-4-nitroaniline were charged. While stirring the contents at room temperature, 2.5 g (0.01 mole) of 3-trifluoromethylbenzenesulfonylchloride was added gradually over 30 minutes. Thereafter, the reaction mixture was heated and stirred for 8 hours under reflux (175°-180° C.) to complete the reaction. After cooling the reaction mixture to room temperature, it was thoroughly washed first with dilute hydrochloric acid and then with water. Subsequent to its dehydration with sodium sulfate, o-dichlorobenzene was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (eluent: benzene) to isolate the intended Compound 1. m.p. 126°-127° C., yield 1.9 g (50%).
Reaction SMILES: [OH:1][CH:2]([CH2:8][C:9](=[O:11])[O-:10])[CH2:3][N+:4]([CH3:7])([CH3:6])[CH3:5].[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14].CC(C)=O>FC(F)(F)C(O)=O>[C:12]([C:2]([CH2:8][C:9](=[O:10])[O-:11])([CH2:3][N+:4]([CH3:7])([CH3:5])[CH3:6])[OH:1])(=[O:16])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)C(=O)Cl
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)C(O)(CC(=O)[O-])C[N+](C)(C)C
Reaction time: 4 h
Yield: 57.6 %

Procedure:
To a solution of carnitine (3 grams; 0.015 mole) in trifluoroacetic acid (5 cc), isobutyryl chloride (10 cc; 0.096 moles) was added dropwise. The resulting mixture was kept at 45° C. for 4 hours, acetone was added thereto and the residual carnitine was filtered off. Anhydrous ethyl ether was added to the solution and the desired product (2 grams; yield 66%) was obtained by precipitation.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[O:9]=[C:10]1[NH:14][C:13]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([CH2:15][O:16][CH2:17][CH:18]=[CH2:19])[C:12](=[O:27])[N:11]1[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:29]=1>CN(C=O)C>[O:9]=[C:10]1[N:14]([CH3:1])[C:13]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)([CH2:15][O:16][CH2:17][CH:18]=[CH2:19])[C:12](=[O:27])[N:11]1[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([C:36]([F:38])([F:39])[F:37])[CH:29]=1
Reactant: O=C([O-])[O-]
Reactant: C=CCOCC1(c2ccc(F)cc2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCOCC1(c2ccc(F)cc2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
325 mg of potassium carbonate and 0.25 mL of iodomethane are added to a solution of 0.85 g of 4-[2,5-dioxo-4-(4-fluorophenyl)-4-[(2-prop enyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethylbenzonitrile obtained in step 4, dissolved in 3 mL of DMF. The mixture is stirred at rt for 4 hours under argon atmosphere, evaporated to dryness, diluted with water and brine and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and evaporated to provide the desired product.
Reaction SMILES: [F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([O:21]C2CCCCO2)=[CH:13][C:12]=1[CH2:11][CH2:10]3.C(O)(=O)C(O)=O>CO.O>[F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([OH:21])=[CH:13][C:12]=1[CH2:11][CH2:10]3
Reactant: C[C@]12CC[C@@H]3c4ccc(OC5CCCCO5)cc4CC[C@H]3[C@@H]1CCC2=C(F)F
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=C(F)F
Yield: 47.1 %

Procedure:
1.3 g of crude 17-difluoromethylene-3-(tetrahydro-pyran-2-yl-oxy)-estra-1,3,5(10)-trien in 30 ml of methanol and 3 ml of water are suspended with 1.3 g of oxalic acid for 1 hour at a bath temperature of 100° C. Then, it is added to water, extracted three times with dichloromethane, washed neutral, dried on sodium sulfate and evaporated to dryness in a vacuum. 1.0 g of crude 17-difluoromethylene-estra-1,3,5(10)-trien-3-ol, which is chromatographed on silica gel with hexane/ethyl acetate, is obtained. 480 mg of pure 17-difluoromethylene-estra-1,3,5(10) -trien-3-ol is obtained as colorless crystals with a melting point of 154-156° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([NH2:21])=[O:20])[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].[CH:22]1([NH2:26])[CH2:25][CH2:24][CH2:23]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH:22]1([NH:26][CH:1]([C:4]2[CH:9]=[CH:8][C:7]([C:10]3[NH:14][C:13]4[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([NH2:21])=[O:20])[C:12]=4[N:11]=3)=[CH:6][CH:5]=2)[CH3:2])[CH2:25][CH2:24][CH2:23]1
Reactant: NC1CCC1
Reactant: CC(=O)c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(NC1CCC1)c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of EXAMPLE 1A (0.07 g, 0.3 mmol) and cyclobutylamine (0.34 mL, 4.8 mmol) in methanol (1 mL) was treated with sodium cyanoborohydride (0.016 g, 0.3 mmol) and acetic acid (0.2 mL). The mixture was stirred at ambient temperature for 48 hours then concentrated. The residue was purified by chromatography on a silica gel column with 0-10% methanol/dichloromethane/0.1% ammonium hydroxide to provide the title compound. 1H NMR (DMSO-d6) δ 9.34 (s, 1H), 8.19 (d, J=7.7 Hz, 2H), 7.86 (d, J=7.7 Hz, 1H), 7.72 (d, J=8.0 Hz, 2H), 7.57 (d, J=7.7 Hz, 2H), 7.34 (t, J=7.7 Hz, 1H), 3.97 (s, 1H), 3.16 (d, J=5.2 Hz, 4H), 2.09 (s, 1H), 1.88 (s, 2H), 1.75 (s, 1H), 1.60 (s, 1H), 1.52 (s, 1H), 1.36 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:12])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][CH2:45][CH2:46]Cl>CC(=O)CC.C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1/[N:10]=[C:11]1\[S:12][CH2:44][CH2:45][CH2:46][N:13]\1/[N:14]=[CH:15]/[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:32]=3)[N:23]=2)=[CH:20][CH:21]=1)([CH3:3])[CH3:2]
Reactant: ClCCCBr
Reactant: CC(C)c1ccccc1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CC(C)c1ccccc1/N=C1\SCCCN1/N=C/c1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 60 °C
Yield: 13.2 %

Procedure:
To (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (200 mg, 0.393 mmol) and potassium carbonate (217 mg, 1.57 mmol) in butanone (10 ml) in a 25 mL vial equipped with a stir bar and vigruex column was added 1-bromo-3-chloropropane (0.047 ml, 0.472 mmol). The reaction was heated to 60° C. overnight. The reaction was determined to be complete by LCMS. The reaction mixture was diluted with DCM and washed with water. The aqueous layer was extracted with DCM. The organic layers were poured through a phase separator and concentrated. Purification by flash column chromatography provided two compounds. The minor compound was dried overnight under house vacuum providing the title compound 87C (2Z,NE)-2-((2-isopropylphenyl)imino)-N-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)-1,3-thiazinan-3-amine (28.5 mg, 13%) as a yellow solid: mp 187-189° C.; 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 8.66 (s, 1H), 8.21 (d, J=8.3 Hz, 2H), 7.92 (d, J=8.4 Hz, 2H), 7.81 (t, J=10.2 Hz, 4H), 7.30-7.26 (m, 2H), 7.17-7.04 (m, 1H), 6.83 (d, J=6.4 Hz, 1H), 3.96 (t, J=6.1 Hz, 2H), 3.13 (heptet, J=6.9 Hz, 1H), 2.97-2.90 (m, 2H), 2.47-2.38 (m, 2H), 1.25 (d, J=7.5 Hz, 6H); ESIMS m/z 550 (M+H). The major compound was recrystallized with MeOH. The solid was filtered, washed with MeOH and dried at 50° C. under vacuum. The solid was then azeotroped with acetone (3×) and the resultant solid was dried at 50° C. under vacuum providing the title compound 179C (Z)-3-(2-isopropylphenyl)-2-((E)-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazono)-1,3-thiazinane as a yellow solid (92.3 mg, 0.168 mmol, 43%): mp 212-213° C.; 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 8.15 (d, J=8.4 Hz, 2H), 8.06 (s, 1H), 7.91 (d, J=8.5 Hz, 2H), 7.79 (d, J=8.6 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.38 (dd, J=7.8, 1.6 Hz, 1H), 7.33 (td, J=7.5, 1.4 Hz, 1H), 7.29-7.23 (m, 1H), 7.18 (dd, J=7.8, 1.4 Hz, 1H), 3.78-3.72 (m, 1H), 3.59-3.48 (m, 1H), 3.18-3.04 (m, 3H), 2.40-2.30 (m, 2H), 1.26-1.20 (m, 6H); ESIMS m/z 550 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C@H:15]([NH:33][S@](C(C)(C)C)=O)[CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:5][CH:4]=1>CO>[ClH:2].[NH2:33][C@@H:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=1)[CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1
Reactant: CCOC(=O)c1ccc(N2CCC([C@@H](N[S@@](=O)C(C)(C)C)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1ccc(N2CCC([C@@H](N)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 215 %

Procedure:
HCl (1.16 ml, 4.63 mmol, 4.0 M in dioxane) was added to a solution of ethyl 4-(4-((R)-(4′-chlorobiphenyl-2-yl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidin-1-yl)benzoate (INTERMEDIATE 128, 0.128 g, 0.23 mmol) in MeOH (3.5 ml) and the reaction mixture was stirred at r.t. for 3 hours. The reaction mixture was concentrated under reduced pressure and dried under vacuum to provide (R)-ethyl 4-(4-(amino(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoate hydrochloride salt (INTERMEDIATE 133, STEP 1, 0.12 g), which was used in the preparation of INTERMEDIATE 133, STEP 2 without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][S:10][C:11]2[O:12][C:13]3[C:18]([C:19](=[O:22])[C:20]=2[CH3:21])=[C:17](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F-:36].[K+]>C1COCC1>[C:1]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][S:10][C:11]2[O:12][C:13]3[C:18]([C:19](=[O:22])[C:20]=2[CH3:21])=[C:17]([F:36])[CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc3oc(SCc4ccc(C(C)(C)C)cc4)c(C)c(=O)c23)cc1
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(SCc2ccc(C(C)(C)C)cc2)oc2cccc(F)c2c1=O
Temperature: 25 °C

Procedure:
2-(4-tertbutylbenzylmercapto)-3-methyl-5-tosyloxy chromen-4-one (200 mg, 0.39 mmol) is dissolved in THF in a 15 mL round bottom flask and potassium fluoride (0.39 mmol) and Kryptofix (0.39 mmol) are added to it. The solution is heated to reflux for 3 hours after which it is cooled to room temperature. The reaction mixture is then concentrated and the crude residue obtained is purified by silica gel flash chromatography to obtain the above product.