Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3].C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:30][CH2:31][CH:32]2[CH2:33][CH2:34]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][N:27]([C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[5-acetyl-2-(cyclopropylmethoxy)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f55) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[Si:12]([O:19][C@@H:20]([C@H:22]1[C:30](=[O:31])[N:29]2[C@@H:23]1[CH2:24][C:25](=[O:45])[CH2:26][CH:27]=[C:28]2[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])[CH3:21])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>ClCCl>[C:8]([O:45][C:25]1[CH2:24][C@H:23]2[N:29]([C:30](=[O:31])[C@@H:22]2[C@H:20]([O:19][Si:12]([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:14])[CH3:13])[CH3:21])[C:28]([C:32]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=2)=[O:33])=[CH:27][CH:26]=1)(=[O:10])[CH3:9]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCC(=O)C[C@H]12
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1=CC=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2C1
Reaction time: 0.08 h
Yield: 77.6 %

Procedure:
Triethylamine (1.1 ml, 7.5 mmol) followed by acetyl chloride (0.295 ml, 4.1 mmol) were added to a solution of 4-nitrobenzyl (7R,8S)-8-[(1R)-1-(tert-butyldimethylsilyloxy)-ethyl]-5,9-dioxo-1-azabicyclo[5.2.0]non-2-ene-2-carboxylate (1.67 g, 3.4 mmol) in anhydrous dichloromethane (220 ml) cooled with an ice bath. After 5 minutes, the reaction mixture was washed with water and dried over magnesium sulphate. The solvent was evaporated and the residue purified by flash chromatography, eluting with dichloromethane/ethyl acetate (95:5) to give 4-nitrobenzyl (7R,8S)-5-acetoxy-8-[(1R)-1-(tertbutyldimethyl-silyloxy)ethyl]-9-oxo-1-azabicyclo[5.2.0]non-2,4-diene-2-carboxylate (1.4 g, 77%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:26](=[O:30])[N:27]([CH3:29])[CH3:28])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.CC(C)=O>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:26](=[O:30])[N:27]([CH3:28])[CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(Nc2ncc3cc(C(=O)N(C)C)n(C4CCCC4)c3n2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Temperature: 45 °C
Reaction time: 12 h
Yield: 80.7 %

Procedure:
To a suspension of methyl 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinate (2.0 g, 4.9 mmol) in THF (6 mL) was added 1M LiOH (aq) (6 mL, 1.2 equiv) and the slurry stirred at 45° C. for 12 hours (the slurry became clear). After cooling to room temperature, the THF was evaporated and the reaction mixture was treated with 1N HCl until pH=1-2. The resulting precipitate was filtered and the filtrate extracted with 20% Isopropanol/CH2Cl2 (3×100 mL), the combined organic layers dried, filtered, and concentrated to a tan solid. The tan solid was triturated in acetone giving the desired product as a tan solid (1.56 g, 73% yield) which was used without further purification. MS: (M+H)=395.5
Reaction SMILES: [CH2:1]([N:5]([CH2:22][CH2:23][CH2:24][CH3:25])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:26]([C:28]1[C:29](=[C:36]([C:39]#[N:40])[C:37]#[N:38])[O:30][C:31]([CH3:35])([CH3:34])[C:32]=1[CH3:33])#[N:27].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:22]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[CH:33][C:32]3[C:31]([CH3:34])([CH3:35])[O:30][C:29](=[C:36]([C:37]#[N:38])[C:39]#[N:40])[C:28]=3[C:26]#[N:27])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)cc2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)cc2)cc1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
In an ethanol/tetrahydrofuran mixed solvent were dissolved 180 mg (0.54 mmol) of 4-[2-(4-dibutylaminophenyl)vinyl]benzaldehyde and 118 mg (0.59 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene]propanedinitrile. To this mixture, 46 mg (0.60 mmol) of ammonium acetate was added, and the mixture was stirred at room temperature. The solvent was evaporated off. The residue was purified by silica gel column chromatography and washed with ethanol to give 245 mg of a black crystal having a mp of 224-226° C. (yield: 88.4%).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[C:3]=1[F:13].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>>[Cl:20][CH2:21][CH2:22][CH2:23][N:6]1[C:5]2[CH:11]=[CH:12][C:2]([F:1])=[C:3]([F:13])[C:4]=2[O:9][CH2:8][C:7]1=[O:10]
Reactant: ClCCCI
Reactant: O=C1COc2c(ccc(F)c2F)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1COc2c(ccc(F)c2F)N1CCCCl
Yield: 93.2 %

Procedure:
7,8-Difluoro-4H-benzo[1,4]oxazin-3-one (81MF2082a) (0.119 g, 0.64 mmol), Cs2CO3 (0.314 g, 0.96 mmol) and 3-chloro-1-iodopropane (0.144 g, 0.70 mmol) were mixed according to GP5 giving the crude title compound (0.156 g); 1H NMR (CDCl3) d 6.89-6.82 (m, 1H), 6.78-6.74 (m, 1H), 4.68 (s, 2H), 4.08 (t, J=7.2 Hz, 2H), 3.63 (t, J=6.4 Hz, 2H), 2.18-2.10 (m, 2H); 13CNMR (CDCl3) d 163.5, 147.7 (q, J=245.6 Hz, J=10.4 Hz), 141.0 (q, J=249.4 Hz, J=15.7 Hz), 135.5, 126.2, 109.9 (d, J=18.4 Hz), 108.6 (q, J=7.6 Hz, J=4.2 Hz), 67.8, 42.3, 39.4, 30.0.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O>O1CCCC1>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1c(-c2ccccc2)ccnc1Cl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: OCc1c(-c2ccccc2)ccnc1Cl
Yield: 71.7 %

Procedure:
To a solution of 2-chloro-4-phenylnicotinic acid (22.4 g) in tetrahydrofuran (200 ml) was added thionyl chloride (21 ml), and the mixture was heated under reflux for 3 hrs. The solvent was evaporated under reduced pressure, and the precipitated solid was collected by filtration and washed with hexane. The obtained powdery solid was dissolved in tetrahydrofuran (200 ml), and lithium aluminum hydride (4.5 g) was added by small portions while cooling in a dry ice-acetone bath. The mixture was stirred under cooling for 5 min. and water was added to quench the reaction. The precipitated solid was filtered off, and the filtrate was concentrated and extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (15.1 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:6]=2[CH:19]=1.[Cl:20][CH2:21][CH2:22][N:23]=[C:24]=[O:25]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:24]([NH:23][CH2:22][CH2:21][Cl:20])=[O:25])[CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:6]=2[CH:19]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCCN2
Reactant: O=C=NCCCl
Solvent: ClCCl
Product: O=C(NCCCl)N1CCN=C(c2ccccc2Cl)c2cc(Cl)ccc21

Procedure:
25 Parts of 7-chloro-5-(o-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine is dissolved in 250 parts by volume of methylene chloride. To this solution 15 parts of 2-chloroethylisocyanate is slowly added with stirring. The resultant mixture is stirred at ambient temperature for about 90 minutes. The resulting dark brown solution is filtered through a layer of activated magnesium silicate, the filtrate dried and treated with charcoal. After removal of charcoal by filtration the solvent is removed from the resultant filtrate to affort an oil. This oil is dissolved in about 100 parts by volume of ether and the resultant solution cooled to give 7-chloro-N-(2-chloroethyl)-5-(o-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine-1-carboxamide as crystalline solid melting at about 150°-153° C. This compound is represented by the following formula ##STR19##
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6].[CH2:13](O)[CH2:14][CH2:15][OH:16]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:16][CH2:15][CH2:14][CH2:13][O:6]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: OCCCO
Product: O=[N+]([O-])c1ccc(C2OCCCO2)cc1O
Yield: 94.9 %

Procedure:
3-Hydroxy-4-nitro-benzaldehyde (7.5 g, 44.9 mmol) is treated with 1,3-propanediol (5.1 g, 67.3 mmol) according to the procedure of Example 1 to give 2-(3-hydroxy-4-nitro-phenyl)-1,3-dioxane (9.6 g, 95% yield) oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([N+:9]([O-])=O)[CH:8]=1)[NH2:5].[ClH:12].[H][H]>[Rh].O>[ClH:12].[ClH:12].[CH3:1][CH:2]1[CH2:3][CH:4]([NH2:5])[CH2:6][CH:7]([NH2:9])[CH2:8]1
Reactant: Cc1cc(N)cc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Rh]
Agent: Cl
Solvent: O
Product: CC1CC(N)CC(N)C1
Temperature: 100 °C
Yield: 98.2 %

Procedure:
The 3-methyl-5-nitroaniline (10.0 g, 65.7 mmol) was added to water (146 ml) and treated with 6N HCl (22.5 ml, 135.0 mmol) and 5% Rhodium on Alumina (1.9 g, 0.9 mmol). The mixture was charged to 105 atm of Hydrogen and heated to 100° C. for 19 hours. The reaction was cooled and filtered through celite and concentrated to dryness to give 5-methylcyclohexane-1,3-diamine dihydrochloride (12.9 g, 64.5 mmol) as a racemic mixture. The salt (6.5 g, 32.5 mmol) was dissolved in isopropyl alcohol (100 ml) and acetonitrile (100 ml) and treated with potassium carbonate (25.2 g, 182.0 mmol). The mixture was stirred at room temperature overnight, filtered thru celite, and concentrated in vacuo to afford 2.2 g of 5-methylcyclohexane-1,3-diamine as a racemic brown oil: LCMS RT=0.41 (M+1) 128.9.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH:1][C@H:2]2[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)[C@@H]1CC[C@H](N)C1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(F)cc2F)cc1
Product: COC(=O)[C@@H]1CC[C@H](NS(=O)(=O)c2ccc(-c3ccc(F)cc3F)cc2)C1

Procedure:
Using a method analogous to Method A, using (1R,3S)-methyl 3-aminocyclopentanecarboxylate and 2′,4′-difluorobiphenyl-4-sulphonyl chloride, the title compound was obtained as a pale yellow gum.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:10](N1C=CC=CC1=O)([N:12]1C=CC=CC1=O)=[S:11].N.CO>C(Cl)Cl>[NH:1]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[C:10]([NH2:12])=[S:11]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CNC(N)=S
Reaction time: 18 h

Procedure:
To a magnetically stirred suspension of tert-butyl 2-aminoacetate (11.2 g, 85 mmol) in CH2Cl2 (200 mL) under nitrogen is added 1,1′-thiocarbonyldipyridin-2(1H)-one (21 g, 90 mmol) and the resulting mixture is stirred at room temp. for 18 h. The solvent is removed in vacuo, the residue treated with 2M ammonia in methanol (600 mL, 1200 mmol) and stirred at room temperature for 45 min. The solvent is removed in vacuo and dried under high vacuum to give the title compound as a reddish oil that is used “as is” without further purification in the next step. LC/MS (Condition A): ret. T=2.19 min, (M+H)+ 191—actually see (M−55) 134.95 (this is characteristic of BOC fragmentation pattern).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C@@H:5]([NH:7][CH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[N:11]=[CH:12][CH:13]=[N:14]2)[CH3:6])[CH3:2].[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37]([NH:39][C@@H:40]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=3)[C:41](O)=[O:42])=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1>>[C:52]([O:51][C:48]1[CH:47]=[CH:46][C:45]([CH2:44][C@H:40]([NH:39][C:37](=[O:38])[O:36][CH2:35][CH:33]2[C:34]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:41]([N:7]([C@@H:5]([CH3:6])[CH:4]([O:19][CH2:20][CH3:21])[O:3][CH2:1][CH3:2])[CH2:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[N:11]=[CH:12][CH:13]=[N:14]3)=[O:42])=[CH:50][CH:49]=1)([CH3:55])([CH3:53])[CH3:54]
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2nccnc12
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2nccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 48.3 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, (S)-1,1-diethoxy-N-(quinoxalin-5-ylmethyl)propan-2-amine (Compound IX-8) 1.93 g (6.65 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid 3.36 g (7.31 mmol) and purified on Buch silica gel column chromatography (chloroform:methanol=100:0 to 98:2) to obtain the title compound 2.35 g (48%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].Cl.[CH:15]12[NH:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][CH2:17][CH2:16]2.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH:19]12[N:22]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=3[C:10]([F:13])([F:12])[F:11])[CH:15]([CH2:21][CH2:20]1)[CH2:16][CH2:17][CH2:18]2
Reactant: C1CC2CCC(C1)N2
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2C3CCCC2CC3)c(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
4-Fluoro-3-(trifluoromethyl)benzonitrile (1.35 g, 7.14 mmol), 8-aza-bicyclo[3.2.1]octane hydrochloride (1.26 g, 8.57 mmol), and N,N-diisopropylethylamine (1.79 g, 13.8 mmol) were combined in DMSO (15 mL) and heated at 120° C. for 24 hours. The mixture was allowed to cool to ambient temperature and partitioned between diethyl ether and saturated NaHCO3 solution. The separated aqueous phase was extracted with diethyl ether and the combined organic layers were washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10][C@@H:11]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[CH:13]([C:14](=O)[CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C:20]2=[O:30])[CH2:12]1)=[O:4].Cl.[NH2:35][OH:36]>>[F:32][C:2]([F:33])([F:1])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10][C@@H:11]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[CH:13](/[C:14](=[N:35]/[OH:36])/[CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C:20]2=[O:30])[CH2:12]1)=[O:4]
Reactant: NO
Reactant: C[C@]12CC[C@@H](SCCCCNC(=O)C(F)(F)F)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Product: C[C@]12CC[C@@H](SCCCCNC(=O)C(F)(F)F)CC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 40 %

Procedure:
Following the reaction conditions described in Example 1 and starting from 3α-(4-trifluoroacetamidobutylthio)androstane-6,17-dione and hydroxylamine hydrochloride, 3α-(4-trifluoroacetamidobutylthio)-6-(E)-hydroxyiminoandrostane-17-one (238 mg, 40%) was obtained. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.35 (1H, s), 9.40 (1H, t), 3.20 (4H, m), 2.55-0.90 (25H, m), 0.76 (3H, s), 0.67 (3H, s).
Reaction SMILES: ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:23][C:24]1[CH:25]=[C:26]([C:41]2[CH:42]=[CH:43][C:44]([CH2:47]O)=[N:45][CH:46]=2)[CH:27]=[C:28]([NH:30][C:31]2[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][N:32]=2)[CH:29]=1.C(Br)(Br)(Br)[Br:50]>S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:50][CH2:47][C:44]1[N:45]=[CH:46][C:41]([C:26]2[CH:27]=[C:28]([NH:30][C:31]3[N:36]=[C:35]([C:37]([F:38])([F:40])[F:39])[CH:34]=[CH:33][N:32]=3)[CH:29]=[C:24]([CH3:23])[CH:25]=2)=[CH:42][CH:43]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(CO)nc2)c1
Reactant: BrC(Br)(Br)Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(CBr)nc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dichloromethane (3.24 mL) and triphenylphosphine (0.459 g, 1.75 mmol) was added to [5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]methanol (0.35 g, 0.971 mmol). Carbon tetrabromide (0.451 g, 1.36 mmol) was added slowly to the reaction mixture and stirred for 8 hours at room temperature. The reaction mixture was diluted with 10% sodium thiosulfate (5.00 mL) and the organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to yield N-{3-[6-(bromomethyl)pyridin-3-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine. MS APCI calc'd for C18H15BrF3N4 [M+H]+ 423 and 425. found 423 and 425.
Reaction SMILES: [S:1]1[C:5]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[N:4][N:3]=[N:2]1.[CH3:14][N:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16](Cl)=[O:17]>>[S:1]1[C:5]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][C:16](=[O:17])[N:15]([CH3:14])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][CH:12]=2)=[N:4][N:3]=[N:2]1
Reactant: Oc1ccc(Nc2nnns2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(Nc2nnns2)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-(1,2,3,4-thiatriazol-5-ylamino)phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (10%, light brown solid material). HPLC-MS: m/z=328.0 (M+1); Rt: 3.69 min, purity 81%.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)=[C:2]=[S:3].C(N(C(C)C)CC)(C)C.Cl.[NH:23]([CH2:25][C:26](OCC)=[O:27])[NH2:24]>ClCCl>[NH2:24][N:23]1[CH2:25][C:26](=[O:27])[N:1]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=2)[C:2]1=[S:3]
Reactant: CCOC(=O)CNN
Reactant: O=C(O)c1ccc(N=C=S)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NN1CC(=O)N(c2ccc(C(=O)O)cc2)C1=S
Yield: 52.5 %

Procedure:
179 mg (1 mmol) of 4-isothiocyanatobenzoic acid and 523 μl (3 mmol) of diisopropylethylamine were stirred in 8 ml of dichloromethane and then with 155 mg (1 mmol) of ethyl hydrazinoacetate hydrochloride at room temperature for 96 hours. After the solvent was concentrated, the mixture was partitioned between ethyl acetate and 30% acetic acid. The aqueous layer was extracted with ethyl acetate again, and the organic layers were combined, washed with water and then with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The resulting solid was mixed with a 190:10:0.8 liquid mixture of ethyl acetate, methanol and acetic acid, and the insoluble was dried to obtain 132 mg of the desired product (yield 53%).
Reaction SMILES: N(C(C)C)[CH:2](C)C.[Li]CCCC.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[CH:17]=[C:16]([Cl:26])[N:15]=1.CI>C1COCC1>[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[C:17]([CH3:2])=[C:16]([Cl:26])[N:15]=1
Reactant: COc1ccc2cc(Cl)nc(Cl)c2c1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc2c(C)c(Cl)nc(Cl)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
To a solution of i-Pr2NH (1.95 g, 19.3 mmol) in anhydrous THF (40 mL) was added dropwise n-BuLi (7.72 mL, 19.3 mmol, 2.50 M in hexane) at −78° C. under N2 atmosphere. After 30 minutes, 1,3-dichloro-7-methoxyisoquinoline (described in step 2 of Intermediate 12) (4.00 g, 17.5 mmol) in anhydrous THF (20 mL) was added to the reaction. After 15 minutes, MeI (4.97 g, 35.0 mmol) was added dropwise. The resulting mixture was warmed to 25° C. and allowed to stir for 16 hours. The reaction was quenched with H2O (150 mL) followed by an ethyl acetate extraction/workup to give the crude product, which was purified by prep-HPLC (0.1% TFA as additive). Most of CH3CN was removed under reduced pressure and extracted with EtOAc (50 mL×3). The combined organic layers were washed with H2O (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 1,3-dichloro-7-methoxy-4-methylisoquinoline (2.0 g, yield 47%) as an off-white solid.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][CH2:2][NH:1]2)=[CH:6][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccc2c(c1)NCCC2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(Oc2ccc3c(c2)NCCC3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 6.6 %

Procedure:
To a solution of 0.15 g (1.01 mmol) 1,2,3,4-tetrahydro-quinolin-7-ol in 10 ml dichloromethane were added 0.19 g (1.56 mmol) phenylboronic acid, 0.27 g (1.49 mmol) copper(II) acetate, a spatula end of 4 Å molecular sieves and 0.64 ml (5.03 mmol) triethylamine. The reaction mixture was stirred at room temperature for 72 hours and then filtered through celite, washing with dichloromethane. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, ethyl acetate/heptane gradient) to afford 15 mg (7%) of the title compound as a light yellow oil. MS (ISP): 226.3 ([M+H]+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:14])([F:13])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6].[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[CH:18][N:17]=1>C1COCC1.CCOC(C)=O>[Cl:15][C:16]1[CH:21]=[C:20]([O:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([F:13])([F:14])[F:3])[N:19]=[CH:18][N:17]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OC(c1ccccc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)C(Oc1cc(Cl)ncn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.9 %

Procedure:
NaH (60%, 120 mg, 3.0 mmol) was added to a solution of 2,2,2-trifluoro-1-phenyl-ethanol (350 mg, 2.03 mmol) in 5 ml of THF. The mixture was stirred for 20 minutes at room temperature. 4,6-Dichloro-pyrimidine (300 mg, 2.03 mmol) was added and then the reaction mixture was heated at 70° C. for 1 hour. After cooling, the THF was evaporated to provide a residue, which was dissolved in 15 ml of EtOAc, and then washed with water, and dried over sodium sulfate. The solvent was removed by rotovap to give 550 mg of 4-chloro-6-(2,2,2-trifluoro-1-phenyl-ethoxy)-pyrimidine, yield 95%.