Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([C:18]2[C:19]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]3)=[N:22][CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.C([BH3-])#[N:45].[Na+]>C(OCC)(=O)C>[NH2:45][CH:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:20]=[C:19]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]3[CH:4]=[C:3]([C:2]([F:40])([F:41])[F:1])[CH:8]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:6]=3)([CH3:39])[CH3:38])=[CH:23][N:22]=2)[CH2:25][CH2:26]1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2CCC(=O)CC2)cc1-c1ccccc1Cl
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2CCC(N)CC2)cc1-c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 63.6 %

Procedure:
To a solution of 752 mg (1.26 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-oxo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide in 7 ml methanol 970 mg (12.6 mmol) ammonium acetate were added at room temperature. The mixture was stirred 5 minutes at this temperature, cooled to 0° C. and treated with 119 mg (1.89 mmol) sodium cyanoborohydride. The reaction mixture was allowed to slowly warm to room temperature during 5 h, followed by dilution with 20 ml ethyl acetate, washing with 10 ml brine and extraction with 20 ml ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 480 mg (64%) of the title compound as a white foam.
Reaction SMILES: O[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:20])=O>CCOCC>[Cl:20][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1noc2ccccc12
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Clc1noc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Hydroxy benzisoxazole 11 (1.03 gr, 6.25 mmol), triethylarnine (632 mg, 6.25 mmol) and phosphorousoxychloride (1.92 gr, 12.5 mmol) were heated in a sealed tube at 150° C. for 18 h. After this time the reaction was cooled to room temperature and diluted with ether and carefully quenched with excess ice/water. The resulting mixture was stirred for 15 min then the organic layer was washed with water (2×), brine (1×), dried with magnesium sulfate, filtered and evaporated to afford 12 as a white solid after column chromatography (hexanes/ethyl acetate, 97:3); 1H-NMR (CDCl3, 500 MHz) δ 7.65-7.63 9 m, 2H), 7.42 (dd, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:20][CH:21]3[O:23][CH2:22]3)=[CH:16][CH:17]=2)[O:12][C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:38]=[CH:37][C:29]([CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:28][CH:27]=1>C(O)C>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:20][CH:21]([OH:23])[CH2:22][N:34]3[CH2:33][CH2:32][N:31]([CH2:30][C:29]4[CH:37]=[CH:38][C:26]([Cl:25])=[CH:27][CH:28]=4)[CH2:36][CH2:35]3)=[CH:16][CH:17]=2)[O:12][C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: O=c1cc(OCc2ccccc2)c2ccc(OCC3CO3)cc2o1
Solvent: CCO
Product: O=c1cc(OCc2ccccc2)c2ccc(OCC(O)CN3CCN(Cc4ccc(Cl)cc4)CC3)cc2o1
Yield: 62.3 %

Procedure:
A mixture of 4-benzyloxy-7-(2,3-epoxypropyloxy)coumarin (8.48 g; 0.026 mole), 1-(4-chlorobenzyl)piperazine (6.20 g; 0.0295 mole) and ethanol (50 ml) were refluxed together for 90 mins and allowed to cool. Evaporation of the solvent in vacuo gave an oily residue which crystallized on trituration with petrol ether. Recrystallization from methanol gave 8.67 g (62%) of title compound of m.p. 130°-133° C., νmax (mull) 1720, 1615 cm-1 ; δ (CDCl3) 2.55 (10H, m); 3.20 (1H, m); 3.48 (2H, s); 4.07 (3H broad s); 5.20 (2H, s); 5.68 (1H, s); 6.89 (2H, m); 7.30 (4H, s); 7.45 (5H, s); 7.77 (1H, d, J 10 Hz). (Found: C, 67.72; H, 6.00; N, 5.29; Cl, 7.21; C30H31N2ClO5 requires; C, 67.34; H, 5.84; N, 5.24; Cl, 6.63%).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.CCOCC.O>[OH-].[Na+]>[C:22]([O:21][C:19]([NH:18][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:10][CH:11]=1)[C:3]([OH:26])=[O:2])=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)C(Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Reaction time: 3 h

Procedure:
(S)-2-(t-butoxycarbonylamino-3-(biphenyl-4-yl)-propionic acid methyl ester (4.1 g, 11.5 mmol) is dissolved at room temperature in methanolic 1N sodium hydroxide (60 mL). The solution is stirred for 3 hours. Ether (30 mL) and water (30 mL) are added. The aqueous layer is separated and acidified with concentrated hydrochloric acid, then extracted with ether (2×20 mL) and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gives (S)-2-(t-butoxycarbonylamino)-3-(biphenyl-4-yl)-propionic acid as a white solid, m.p. 122°-123°.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[O:6]([CH2:13][CH:14]([OH:17])[CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[S:1]([O:16][CH2:15][CH:14]([O:17][S:1](=[O:4])(=[O:3])[NH2:2])[CH2:13][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: OCC(O)COc1ccccc1
Reactant: NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NS(=O)(=O)OCC(COc1ccccc1)OS(N)(=O)=O
Reaction time: 0.75 h

Procedure:
To the above sulfamoyl chloride solution in acetonitrile was added dropwise with stirring a solution of 8.4 g (0.05 mole) of 3-phenoxy-1,2-propanediol (95% purity obtained from Aldrich Chem. Co., Inc.) and 20.2 g (0.2 mole) of triethylamine in 50 ml of acetonitrile at such a rate that the temperature did not exceed 12° C. over a 45 min period. The cooling bath was removed and the mixture was stirred for 2 hr and treated with 100 ml of ethyl acetate and 50 ml of water. The mixture was vigorously stirred for 5 min and the layers were separated. The organic layer was washed with 50 ml of water and 100 ml of salt brine, dried over sodium sulfate and concentrated to give a gum as residue. The gum was purified by column chromatography on 350 g of silica gel. Fractions eluted with 15% acetone in methylene chloride were combined and concentrated to give a clear gum as residue. The gum was triturated with petroleum ether (b.p. 30°-60° C.) to give crystalline solid. The solid was collected by filtration and recrystallized from benzene-acetonitrile to yield 4.2 g (26% yield) of white solid title compound, mp 116°-118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C-]#N.[K+]>CO.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([CH:6]([C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[OH:7])=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(c1ccc(Cl)cc1)C(O)c1ccc(Cl)cc1
Yield: 76.7 %

Procedure:
To a solution of 4-chlorobenzaldehyde (240 g, 1.707 mol) in 144 mL of methanol was added 2.40 g of potassium cyanide in 4.8 mL water over 6 min. The mixture was refluxed for another 50 min (mixture became deep red), cooled, then concentrated under reduced pressure. The red residue was taken up in 1500 mL of hexane-ethyl acetate (1:1), and washed successively with water (1×150 mL), 20% sodium bisulfite (6×150 mL), brine (1×150 mL) and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the product was boiled in 400 mL of hexane to remove small amounts of 4-chlorobenzaldehyde. The mixture was cooled and the white solid was collected by suction filtration to give 183.94 g of 4,4′-dichlorobenzoin (76%). This procedure was adapted from Lutz et al. J. Am. Chem. Soc. 1949, 71, 478.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:22]C)=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[O:11])[S:7][C:6]=2[C:18]=1[N+:19]([O-:21])=[O:20].N1C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>C(OCC)(=O)C>[OH:22][C:3]1[C:2]([OH:1])=[C:18]([N+:19]([O-:21])=[O:20])[C:6]2[S:7][C:8]([C:10]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)=[O:11])=[CH:9][C:5]=2[CH:4]=1
Reactant: COc1cc2cc(C(=O)N3CCOCC3)sc2c([N+](=O)[O-])c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(c1cc2cc(O)c(O)c([N+](=O)[O-])c2s1)N1CCOCC1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
(6-Hydroxy-5-methoxy-7-nitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone (1.0 g) was dissolved in ethyl acetate (11 ml) and pyridine (14 ml) added into. Next aluminum trichloride (0.47 g) was gradually added into the solution. The reaction mixture was refluxed for 2 hours at 110° C. To the warm reaction (60° C.) solution was added the mixture of ice and concentrated hydrochloric acid (1:1) and then it was stirred at room temperature for one hour. The solid was filtered, washed with water and treated with diethyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:22]=[C:12]3[N:13]=[C:14]([C:17]([O:19]CC)=[O:18])[CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:5][CH:4]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:22]=[C:12]3[N:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccn2nc(-c3ccc(OC)cc3)cc2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cc3nc(C(=O)O)ccn3n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylate (485 mg; 1.63 mmol) in THF (10 mL) and water (3 mL) was added lithium hydroxide hydrate (206 mg; 4.9 mmol) and the mixture was stirred at room temperature for 3 hours. Concentrated hydrochloric acid was then slowly added (ca. 0.5 mL) until pH reached 1 and the mixture was concentrated under reduced pressure. The resulting solid was dissolved in methylene chloride, filtered, concentrated and dried under high vacuum. The crude product was used directly in the next step. LCMS m/z 270.1 (M+H)+, ret. time=2.20 min.
Reaction SMILES: [OH:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]=3[C:29]([F:32])([F:31])[F:30])[O:15][N:14]=2)=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C[N:61]1CC[O:64][CH2:63][CH2:62]1.NCCO>CN(C=O)C>[OH:1][C:2]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:17]=[C:16]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:19]=3[C:29]([F:30])([F:32])[F:31])[O:15][N:14]=2)=[CH:11][CH:12]=1)([CH3:6])[C:3]([NH:61][CH2:62][CH2:63][OH:64])=[O:5]
Reactant: CN1CCOCC1
Reactant: CC(O)(C(=O)O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: NCCO
Product: CC(O)(C(=O)NCCO)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 14.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid (Int-XV, 30 mg, 0.067 mmol), BOP (29.8 mg, 0.067 mmol), 4-methylmorpholine (27.3 mg, 0.269 mmol), and 2-aminoethanol (6.17 mg, 0.101 mmol) were added to DMF (1 mL). The reaction mixture was stirred for 1 h and then purified by prep HPLC (PHENOMENEX® 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=30.0 min) to provide (R/S)-2-hydroxy-N-(2-hydroxyethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanamide (6 mg, 9.83 μmol, 14.59% yield): LCMS=489.0 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.10-8.21 (2 H, m), 7.53-7.92 (7 H, m), 3.60 (2 H, td, J=5.61, 3.74 Hz), 3.33-3.43 (2 H, m), 1.80 (3 H, s); HPLC peak RT=9.0 min (Method A).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:10]=[C:9]([CH:11]=[CH2:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].C(=O)(O)[O-].[Na+].Cl.[NH2:21][OH:22]>CC(O)C.C(OCC)(=O)C>[OH:22][N:21]=[C:5]([NH2:6])[C:4]1[CH:7]=[CH:8][C:9]([CH:11]=[CH2:12])=[CH:10][C:3]=1[C:2]([F:14])([F:13])[F:1]
Reactant: NO
Reactant: C=Cc1ccc(C#N)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: C=Cc1ccc(C(N)=NO)c(C(F)(F)F)c1
Temperature: 85 °C
Yield: 87.6 %

Procedure:
To a mixture of 2-(trifluoromethyl)-4-vinylbenzonitrile (450 mg, 2.282 mmol) and sodium bicarbonate (767 mg, 9.13 mmol) in 2-propanol (10 mL) was added hydroxylamine hydrochloride (317 mg, 4.56 mmol). The reaction mixture was heated at 85° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with H2O. The organic layer was dried with MgSO4, filtered, and concentrated to give 460 mg of N′-hydroxy-2-(trifluoromethyl)-4-vinylbenzimidamide. MS (m+1)=231. HPLC Peak RT=0.78 minutes (Analytical Method B).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=2)[CH:3]=1.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>CN1C(=O)CCC1.C(OCC)(=O)C>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]2[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: Cc1cc(C)cc(Nc2cc(Cl)nnc2C(N)=O)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)c1
Temperature: 140 °C
Reaction time: 7 h
Yield: 41.5 %

Procedure:
To a solution of 6-chloro-4-(3,5-dimethylphenylamino)pyridazine-3-carboxamide (44 mg, 159 μmol) in NMP (530 μL) was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (68.2 mg, 318 μmol) and the mixture heated to 140° C. for 20 h. Additional tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (68.2 mg, 318 μmol) was then added and heating continued for a further 7 h. Finally, another portion of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (34.1 mg, 159 μmol) was added and the mixture heated for 16 h. The reaction mixture was cooled, and then diluted with ethyl acetate. The phases were separated and the organic phase then washed with water and brine. The organic phase was collected, concentrated in vacuo, and the residue obtained was purified by chromatography (silica, 30 to 70% ethyl acetate in hexanes) to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(3,5-dimethylphenylamino)pyridazin-3-ylamino)cyclohexylcarbamate (30 mg, 66.0 μmol, 42%) as a brown oil. MS (EI/CI) m/z: 455.2 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH:13][C:14]([O:16][CH3:17])=[O:15])[CH2:10][C@@H:9]1[C@H:18]1[O:22][C:21]([CH3:24])([CH3:23])[N:20]([C:25](=[O:27])[CH3:26])[C@H:19]1[CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:10][C@@H:9]1[C@H:18]1[O:22][C:21]([CH3:24])([CH3:23])[N:20]([C:25](=[O:27])[CH3:26])[C@H:19]1[CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: COC(=O)C=C1C[C@H]([C@H]2OC(C)(C)N(C(C)=O)[C@H]2Cc2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC1C[C@H]([C@H]2OC(C)(C)N(C(C)=O)[C@H]2Cc2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1

Procedure:
Combine (R)-2-[(4S,5S)-3-Acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-[1-methoxycarbonyl-methylidene]-pyrrolidine-1-carboxylic acid tert-butyl ester (as mixture of isomers Z/E) (0.010 g, 0.02 mmol), 10% palladium on carbon (4 mg) and methanol (2 mL) and stir for 3 hours under 1 atmosphere of hydrogen. Add filter agent, filter and concentrate under reduced pressure to provide the desired compound as a mixture of cis and trans isomers, (0.01 g, 98%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:25][C@@:23]3([CH3:24])[C@@H:19]([CH2:20][C@@H:21]([CH3:31])[C@@H:22]3[C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C@H:18]3[C:9]2=[C:10]2[C:15]([CH2:16][CH2:17]3)=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:38]1[CH:43]=[N:42][CH:41]=[CH:40][N:39]=1)CCC>>[CH:28]1([C:26]([C@H:22]2[C@H:21]([CH3:31])[CH2:20][C@H:19]3[C@H:18]4[C:9]([C@@H:8]([C:5]5[CH:6]=[CH:7][C:2]([C:38]6[CH:43]=[N:42][CH:41]=[CH:40][N:39]=6)=[CH:3][CH:4]=5)[CH2:25][C@:23]23[CH3:24])=[C:10]2[C:15](=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)[CH2:16][CH2:17]4)=[O:27])[CH2:29][CH2:30]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(Br)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(-c4cnccn4)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Temperature: 135 °C
Yield: 35 %

Procedure:
According to the procedure described in example 8, (11β,16α,17β)-11-(4-bromophenyl)-17-cyclopropylcarbonyl-16-methylestra-4,9-dien-3-one and 2-tributylstannylpyrazine were heated in a microwave at 135° C. (150 W, 25 minutes) to give the title compound (35% yield). 1H NMR (400 MHz, CDCl3): δ 0.33 (s, 3H), 0.84-2.86 (m, 24H), 4.47 (d, J=7 Hz, 1H), 5.81 (s, 1H), 7.30-7.34 (m, 2H), 7.92-7.96 (m, 2H), 8.49 (d, J=3 Hz, 1H), 8.61 (dd, J=3 and 1 Hz, 1H), 9.01 (d, J=1 Hz, 1H).
Reaction SMILES: N#N.C(OC([C@@:13]1([C:30]([NH2:32])=[O:31])[CH2:17][C@@H:16]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][N:14]1[C:26]([CH3:29])([CH3:28])[CH3:27])=O)C1C=CC=CC=1>C(O)C.[Pd]>[C:22]([O:21][C:19]([NH:18][C@H:16]1[CH2:15][N:14]([C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:13]([C:30]([NH2:32])=[O:31])[CH2:17]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(C(C)(C)C)[C@@](C(N)=O)(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(N)=O)N(C(C)(C)C)C1
Yield: 106.6 %

Procedure:
0.25 g of N2 -(benzyloxycarbonyl)-4(R)-(tert.butoxyformamido)-N1 -tert.butyl-L-prolinamide was dissolved in ethanol and hydrogenated over 0.1 g of 10% palladium-on-carbon at room temperature and under atmospheric pressure for 4 hours. The catalyst was filtered off and the filtrate was evaporated to give 0.17 g of 4(R)-(tert-butoxyformamido)-N1 -tert.butyl-L-prolinamide as a glass which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]([CH3:23])([CH3:22])[CH2:20][NH2:21])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][C:3]=1[O:24][CH3:25].N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]([CH3:23])([CH3:22])[CH2:20][NH:21][S:33]([CH3:32])(=[O:35])=[O:34])[NH:11][C:12]=2[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(-c2nc(C(C)(C)CN)[nH]c2-c2ccncc2)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2nc(C(C)(C)CNS(C)(=O)=O)[nH]c2-c2ccncc2)ccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
A solution of Example 2 (178 mg, 0.5 mmol) in dichloromethane (10 ml) containing pyridine (0.12 ml, 1.5 mmol) at 0° C. was treated with a solution of methanesulfonyl chloride (57.3 mg, 0.5 mmol) in dichloromethane (1 ml). The solution was stirred at 0° C. for 1 hour followed by 30 min at room temperature before being diluted with dichloromethane and saturated sodium hydrogen carbonate solution. The aqueous layer was then separated and extracted with additional dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulphate, filtered and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with dichloromethane/methanol/0.880 ammonia solution (8:1:0.1) to give the title compound (85 mg, 40%) as a pale yellow solid; MS(ES+) m/e 435/437 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15](O)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[CH3:20][N:21]1[C:25]([Sn](CCCC)(CCCC)CCCC)=[CH:24][CH:23]=[N:22]1.[Li+].[Cl-]>CN(C)C=O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([C:25]3[N:21]([CH3:20])[N:22]=[CH:23][CH:24]=3)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1CN(C(=O)C(F)(F)F)CCc2cc(-c3ccnn3C)ccc21
Reaction time: 4 h

Procedure:
To a solution of N-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, O-trifluoromethanesulfonate (100 mg, 0.25 mmol) in dimethylformamide (2 mL) was treated with (2-methyl-2H-pyrazol-3-yl)-tri-n-butyltin (138 mg, 0.37 mmol), LiCl (21 mg, 0.50 mmol), Pd(PPh3)2Cl2 (35 mg, 0.05 mmol) and stirred at 100 C for 4 hours. The product mixture was diluted with EtOAc (20 mL), washed twice with water (10 mL), once with brine (10 mL), dried with Na2SO4 and concentrated. Flash chromatography (30% EtOAc in hexane, silica) resulted in 80 mg of a clear oil. MS calculated for C17H18F3N3O+H: 338, observed: 338.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:15][C:14](=[O:16])[N:13]2[N:17]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=[C:12]2[CH:11]=1.[CH2:26]=O.[Na]>CO>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:15][C:14](=[O:16])[N:13]2[N:17]=[C:18]([CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:19]=[C:12]2[CH:11]=1
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2Cl)cc2nc(C3CCNCC3)nn12
Reactant: C=O
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)[nH]c(=O)n3n2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., 500 mg (1.25 mmol) of 7-(2,4-dichlorophenyl)-2-(piperidin-4-yl)[1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one hydrochloride were initially charged in methanol (4 ml), and 3 Å molecular sieve (50 mg), formalin (210 μl, 7.50 mmol) and sodium cyanoborhydride (470 mg, 7.50 mmol) were added. The mixture was stirred at 0° C. for 1 h and then stirred at RT for another 12 h. The reaction mixture was filtered, and dichloromethane (100 ml) and water (75 ml) were added to the filtrate. The mixture was extracted and the organic phase was dried (magnesium sulfate) and concentrated. This gave 274 mg (58% of theory) of the crude product.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8]CC2C=CC(OC)=CC=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])F.BrC1C=C(C(F)F)[C:26](Cl)=[N:27]C=1>>[NH2:8][C:5]1[CH:4]=[C:3]([CH:18]([F:20])[F:21])[C:2]([C:26]#[N:27])=[N:7][CH:6]=1
Reactant: COc1ccc(CNc2cnc(Cl)c(C(F)(F)F)c2)cc1
Reactant: FC(F)c1cc(Br)cnc1Cl
Product: N#Cc1ncc(N)cc1C(F)F

Procedure:
The title compound was synthesized as described in Intermediate 1 (Steps 3-5) using 5-bromo-2-chloro-3-(difluoromethyl)pyridine as the starting material. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, 1H), 7.28-7.01 (m, 2H), 6.80 (s, 2H). LCMS [M+H]+ 170.1.