Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])[CH3:2].N1CCCCC1.[C:27]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([OH:29])=[O:28]>C1C=CC=CC=1>[C:16]([O:15][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[C:6](=[O:7])/[C:5](/[C:4]([O:3][CH2:1][CH3:2])=[O:20])=[CH:34]/[C:33]1[CH:36]=[CH:37][C:30]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CCOC(=O)/C(=C\c1ccc(C(=O)O)cc1)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 75.8 %

Procedure:
To a solution of tert-butyl (2S)-2-(3-ethoxy-3-oxopropanoyl)-1-pyrrolidinecarboxylate (5.0 g, 17.5 mmol) in benzene (50 ml) and piperidine (0.3 ml, 3 mmol) was added 4-carboxybenzaldehyde (2.63 g, 17.5 mmol), and the mixture was refluxed for 3 h. The cooled solution was washed with 0.1 N HCl twice. The aqueous layer was extracted three times with ether. The combined organic phases were dried (Na2SO4) and concentrated to give C as a tan solid (5.54 g, 76% yield). LCMS m/z 416 (M−H), 833 (2M−H).
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:9]([O:11][P:12]([O:16]CC)[O:13][CH2:14][CH3:15])[CH3:10]>>[CH2:9]([O:11][P:12]([CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])([O:13][CH2:14][CH3:15])=[O:16])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)C(C)Br
Product: CCOC(=O)C(C)P(=O)(OCC)OCC

Procedure:
Ethyl 2-bromopropanoate (30.0 g.) and triethylphosphite (70.0 g) were heated overnight at 150° C. under an air condenser. The resulting crude mixture was purified by distillation, the ethyl 2-(diethylphosphono)propanoate was collected at 66°-68° C. at 0.3-0.5 mm.Hg.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH2:18].C(N(CC)CC)C>ClCCl>[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH:18][C:11]([NH:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:12]
Reactant: COC(=O)CN
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a suspension of 3-nitrophenyl isocyanate (10 g, 61 mmol) and glycine methyl ester hydrochloride (8.4 g, 67 mmol, 1.1 equiv.) in dichloromethane (250 mL) was added triethylamine (10 mL, 72 mmol, 1.2 equiv.) at 0° C. The resulting solution was stirred at room temperature overnight. The resulting dark brown solution was concentrated and triturated in water to give a light yellow suspension. The suspension was filtered and the filter cake was washed with water and air-dried to give [[[(3-nitrophenyl)amino]carbonyl]aminoacetic acid methyl ester (15 g) in quantitative yield.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.[CH:19]1[N:23]=[CH:22][N:21]([C:24](N2C=NC=C2)=O)[CH:20]=1.CN(C)CCN>>[CH3:22][N:21]([CH3:24])[CH2:20][CH2:19][NH:23][C:14]([C:7]1([CH3:17])[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=2[CH3:18])[O:8]1)=[O:16]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: CN(C)CCN
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCN(C)C)O2
Yield: 75.9 %

Procedure:
Following the amide coupling procedure described in protocol A, 1.03 g 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (4.11 mmol), 0.712 g CDI (4.39 mmol) and 704 mg N,N-dimethylethylenediamine (7.99 mmol) produced 1 g of N-(2-(dimethylamino)ethyl)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide as a white crystalline solid.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:39]=[CH:38][CH:37]=[CH:36][C:11]=2[C:12]([NH:14][CH:15]([C:17]2[N:22]=[N:21][C:20]([NH:23][C:24]3[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=3)=[N:19][CH:18]=2)[CH3:16])=O)[CH:6]=[CH:7][CH:8]=1.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:16][C:15]1[N:14]=[C:12]([C:11]2[CH:36]=[CH:37][CH:38]=[CH:39][C:10]=2[NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:41])([F:40])[F:1])[CH:4]=2)[N:22]2[C:17]=1[CH:18]=[N:19][C:20]([NH:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=1)=[N:21]2
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3Nc3cccc(C(F)(F)F)c3)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccccc4Nc4cccc(C(F)(F)F)c4)n3n2)cc(OC)c1OC
Yield: 46.9 %

Procedure:
In a similar manner as described for Example 9, 2-{[3-(trifluoromethyl)phenyl]amino}-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 40) (276 mg, 0.48 mmol), and 1,2,4-triazole (200 mg, 2.91 mmol) in pyridine (3 mL) and phosphorous oxychloride (0.14 mL, 1.5 mmol) gave 5-methyl-7-(2-{[3-(trifluoromethyl)phenyl]amino}phenyl)-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (124 mg, 48%) as a yellow solid. 1H NMR (CDCl3): δ9.53 (s, 1H), 8.83 (s, 1H), 8.39 (dd, J=7.87 and 1.28 Hz, 1H), 7.45 (d, J=8.06 Hz, 1H), 7.32 (t, J=7.78 Hz, 2H), 7.23 (m, 2H), 7.12 (d, J=7.51 Hz, 1H), 7.01 (t, J=7.32 Hz, 1H), 6.92 (s, 1H), 6.90 (s, 2H), 3.83 (s, 3H), 3.79 (s, 6H), 2.63 (s, 3H). MS m/z 550 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:9][C:10]1([F:16])[CH2:13][CH:12]([C:14]#[N:15])[CH2:11]1.C1(C)C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>CCOC(C)=O.O>[Cl:8][C:7]1[C:2]([C:12]2([C:14]#[N:15])[CH2:13][C:10]([F:16])([F:9])[CH2:11]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: N#CC1CC(F)(F)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#CC1(c2ncccc2Cl)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a 100 mL round bottom flask was added 2,3-dichloropyridine (2.9 g, 20 mmol), 3,3-difluorocyclobutanecarbonitrile (2.1 g, 18 mmol), and toluene (50 mL). The mixture was cooled to ° C. and sodium hexamethyldisilazide (NaHMDS, 2.0 M in THF, 11 mL, 22 mmol) was added. The reaction mixture was warmed to rt and stirred for 2 h. The mixture was then diluted with EtOAc (20 mL) and water (20 mL). The aqueous layer was extracted with EtOAc and the combined organic phases were washed with brine, dried over Na2SO4, and concentrated to provide the desired product (3.4 g) as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[N:2]1.C([N-]C(C)C)(C)C.[Li+].[CH:23]12[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[C:24]1=[O:33])[CH2:30]2.O>O1CCCC1>[OH:33][C:24]1([CH:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:3]2[N:4]=[CH:5][NH:1][N:2]=2)[CH:23]2[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]1[CH2:26]3)[CH2:30]2
Reactant: N#Cc1ccc(Cc2nc[nH]n2)cc1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C(c2nc[nH]n2)C2(O)C3CC4CC(C3)CC2C4)cc1
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
5 g of 4-[1-(1,2,4-triazolyl)methyl]benzonitrile is dissolved in 100 ml of tetrahydrofuran and combined at -50° with 19.8 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour, further stirred with 4.25 g of adamantanone for 1 hour at -70°, and heated to 25°. Then water is added, the mixture is extracted twice with ethyl acetate, washed neutral with water, dried over sodium sulfate, and concentrated to dryness under vacuum, yielding 9 g of crude 4-(2-hydroxyadamant-2-yl-1(1,2,4-triazolyl)methyl]benzonitrile.
Reaction SMILES: C(OC([N:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[C:28]([F:29])=[CH:27][C:26]([F:30])=[C:25]([NH:31][CH2:32][CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36])[C:21]=3[C:22](=[O:24])[CH:23]=2)=[CH:14][C:13]=1[F:38])COC)=O)(C)(C)C.S(=O)(=O)(O)O.O>C(O)C>[NH2:8][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[C:28]([F:29])=[CH:27][C:26]([F:30])=[C:25]([NH:31][CH2:32][CH2:33][CH:34]=[C:35]([CH3:36])[CH3:37])[C:21]=3[C:22](=[O:24])[CH:23]=2)=[CH:14][C:13]=1[F:38]
Reactant: COCN(C(=O)OC(C)(C)C)c1ccc(-c2cc(=O)c3c(NCCC=C(C)C)c(F)cc(F)c3o2)cc1F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CC(C)=CCCNc1c(F)cc(F)c2oc(-c3ccc(N)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
1.03 g (1.94 mmol) of the above 2-[4-[N-(tert-butoxycarbonyl)-N-methoxymethylamino]-3-fluorophenyl]-6,8-difluoro-5-(4-methyl-3-pentenylamino)-4H-1-benzopyran-4-one was dissolved in 80 mL of ethanol, 20 mL of 50% sulfuric acid was added and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with an aqueous saturated solution of sodium bicarbonate, once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:2-2:1) to give 520 mg of Compound 137 (yield: 69%).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([N+]([O-])=O)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([Cl:20])[N:8]=2)[CH2:3][CH2:2]1.Cl[C:22]1C2C(=C([N+]([O-])=O)C=CC=2)C=C(Cl)N=1.N1CCSCC1>C(OCC)(=O)C>[S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([CH3:22])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([Cl:20])[N:8]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccc2c(Cl)nc(Cl)cc12
Reactant: O=[N+]([O-])c1cccc2c(N3CCSCC3)nc(Cl)cc12
Agent: C1CSCCN1
Solvent: CCOC(C)=O
Product: Cc1cccc2c(N3CCSCC3)nc(Cl)cc12

Procedure:
1-Thiomorpholino-3-chloro-5-nitro-isoquinoline, m.p. 163°-165°C (from ethyl acetate), was prepared from 1,3-dichloro-5-nitro-isoquinoline [see M. D. Nair and S. R. Mehta, Indian J. Chem. 5, 403 (1967); m.p. 176°-177°C] and thiomorpholine.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:13]=[C:12]([S:14]C(OCC)=S)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].Cl.C(=O)([O-])O.[Na+]>O.CCO.S(=O)(=O)(O)O.CO>[Cl:3][C:4]1[CH:13]=[C:12]([SH:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCOC(=S)Sc1ccc(C(=O)OC)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Solvent: CO
Product: COC(=O)c1ccc(S)cc1Cl
Temperature: 70 °C

Procedure:
8 g of methyl 4-amino-2-chlorobenzoate was dissolved in 16 mL of MeOH, 8 mL of H2O and 8 mL of concentrated hydrochloric acid and was then cooled to 0 C. A solution of 3.9 g of sodium nitrite in 15 mL of H2O was added dropwise over 30 min. The reaction was stirred at 0° C. for an additional 1 h. The cold diazonating mixture was added to a solution of 13.8 g of potassium ethyl xanthate in 10 mL of H2O at 50˜60° C. The reaction was heated to 65° C. for 2 h and monitored by TLC until complete. The mixture was cooled to 25° C. and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. Purified by silica gel chromatography (0-10% ethyl acetate/hexane) to afford methyl 2-chloro-4-(ethoxycarbonothioylthio)benzoate. A solution of 2.6 g of sodium hydroxide in 20 mL of H2O was added to 5.9 g of methyl 2-chloro-4-(ethoxycarbonothioylthio)benzoate in 40 mL of EtOH The reaction mixture was heated to 70° C. for 1 h. Upon completion, the mixture was cooled to 25° C., and then acidified to pH 3 by the addition of 10 N HCl. The solid was filtered and washed with H2O to give 2-chloro-4-mercaptobenzonic acid. 3.8 g of 2-chloro-4-mercaptobenzonic acid in 40 mL of 5% sulfuric acid-methanol was refluxed under nitrogen atmosphere for 3 h. After concentration of the reaction mixture, 10 mL of H2O was added and the resulting mixture was made alkaline with sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated to yield methyl 2-chloro-4-mercaptobenzoate. 80 mg of isobutylene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford methyl 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoate. 190 mg of methyl 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoate was hydrolyzed via Procedure M to give 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoic acid. 160 mg of 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoic acid was reacted via procedure R to give 2-chloro-4-(2-hydroxy-2-methylpropylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to 2-chloro-4-(2-hydroxy-2-methylpropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2-methylpropylsulfonyl)benzamide. MS (Q1) 479.1 (M)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>CO>[C:1]([C:5]1[CH:10]=[C:9]([S:11][C:17]2([S:11][C:9]3[CH:8]=[C:7]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: O=C1CCCC1
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(SC2(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CCCC2)cc(C(C)(C)C)c1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of 2,6-di-t-butyl-4-mercaptophenol (600 mg, 1.04 mmol) in methanol (10 mL) was added cyclopentanone (1.5 mL) and a catalytic amount of concentrated hydrochloric acid. The mixture was heated and stirred at 60° C. overnight. The solvent was distilled off from the reaction mixture, and the resulting residue was purified by a flash column chromatography (filler: manufactured by Kanto Kagaku, K.K., 60Nmesh40-100, developing solvent:n-hexane/ethyl acetate (volume ratio)=1/0 to 100/1) to give bis(3,5-di-t-butyl-4-hydroxyphenylthio)cyclopentane (yield 485 mg and 67%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5]([N:13]2[CH:17]=[N:16][N:15]=[C:14]2[SH:18])=[CH:4][CH:3]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C1COCC1.O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5]([N:13]2[CH:17]=[N:16][N:15]=[C:14]2[S:18][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc2c(C)ccc(-n3cnnc3S)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)CSc1nncn1-c1ccc(C)c2ccc(C)cc12
Temperature: 60 °C
Yield: 86.4 %

Procedure:
To a solution of 4-(4,7-Dimethylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (0.2 g, 0.783 mmol) in THF (3.1 mL) was added Ethyl 2-bromoacetate (87 μL, 0.783 mmol) and Potassium carbonate (0.216 g, 1.57 mmol), then heated to 60° C. for 1 hour. Additional DMF (1 mL) was added and the mixture heated at 60° C. for 18 hours. Water (3 mL) was added and the mixture extracted with ethyl acetate (3×3 mL). The combined organic extracts were dried over sodium sulfate, filtered, concentrated and Purified by SGC (0-100% EtOAc/Hexanes) to afford ethyl 2-(4-(4,7-dimethylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate as a clear oil (0.231 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.BrC1C=CC(OC)=CC=1.[Mg].Cl.Br[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Cl-].[Ni+2].C(OC)(C)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: Brc1ccncc1
Agent: [Ni+2]
Agent: COc1ccc(Br)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: COc1ccc(-c2ccncc2)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 4-methoxyphenylmagnesium bromide, prepared from 4-bromoanisole (150 g 0.80 mol) and magnesium (20 g, 0.83 mol) in dry tetrahydrofuran (300 mL) is filtered, cooled to −10° C. and added cautiously to a stirred mixture of bis-(triphenylphosphine)nickel (II) chloride (1.5 g. 2.25 mmol) and 4-bromopyridine hydrochloride (65 g, 0.334 mol) in dry tetrahydrofuran (300 mL) at 10° C. under an argon atmosphere. After 50% of the Grignard reagent had been added a vigorous, exothermic reaction sets in and the temperature of the mixture is maintained between 50 and 60° C. throughout the rest of the addition by employing an ice-methanol cooling bath. When the addition is complete the mixture is stirred for 60 min at 50° C. The solvent is evaporated off under reduced pressure to yield a residue which is treated with t-butylmethylether (500 mL) and extracted with hydrochloric acid (3×300 mL of 5M). The combined extracts are washed (t-butylmethylether), basified (aqueous NaOH) and extracted with t-butylmethylether (4×300 mL). The combined extracts are dried (Na2SO4) and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from t-butylmethylether-cyclohexane to give 4-(4-methoxyphenyl)pyridine as a colourless Crystalline solid, m.p. 94-96° C.
Reaction SMILES: [CH3:1][N:2]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=1)[CH2:3][C:4]([F:7])([F:6])[F:5]>C(O)C.[Pd]>[CH3:1][N:2]([CH2:3][C:4]([F:7])([F:5])[F:6])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][N:9]=1
Reactant: CN(CC(F)(F)F)c1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CN(CC(F)(F)F)c1ccc(N)cn1
Yield: 100.3 %

Procedure:
A solution of methyl-(5-nitro-pyridin-2-yl)-(2,2,2-trifluoro-ethyl)-amine (80 mg, 0.34 mmol) in ethanol (10 mL) in the presence of 10% palladium on carbon (10 mg) was shaken under hydrogen with a pressure of 50 psi at room temperature for 2 hours. After the reaction was complete, the reaction mixture was filtered through a plug of celite and the filtration pad was washed with ethanol. The organic layers were combined and concentrated to give N2-methyl-N2-(2,2,2-trifluoro-ethyl)-pyridine-2,5-diamine (70 mg, crude) as a brown oil, which was directly used in the next step without further purification. LCMS calcd for C8H10F3N3 (m/e) 205, obsd 206 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:27])[C:5]2[C:10]([C:11]#[C:12][CH2:13][CH2:14][OH:15])=[CH:9][N:8]([CH2:16][C:17]3[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=3)[C:6]=2[N:7]=1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>N1C=CC=CC=1.C(Cl)Cl>[CH2:32]([O:31][C:29](=[O:30])[NH:1][C:2]1[N:3]=[C:4]([Cl:27])[C:5]2[C:10]([C:11]#[C:12][CH2:13][CH2:14][O:15][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:9][N:8]([CH2:16][C:17]3[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=3)[C:6]=2[N:7]=1)[CH3:33]
Reactant: CCOC(=O)Cl
Reactant: COc1c(C)cnc(Cn2cc(C#CCCO)c3c(Cl)nc(N)nc32)c1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1nc(Cl)c2c(C#CCCOC(=O)OCC)cn(Cc3ncc(C)c(OC)c3C)c2n1
Temperature: 0 °C

Procedure:
A suspension of 4-[2-Amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-but-3-yn-1-ol (see example 2) (0.73 g) in anhydrous pyridine (5 mL) and DCM (25 mL) was treated with ethyl chloroformate (1 mL) at rt for 30 min. The mixture was cooled to 0° C., treated with addition EtOCOCl (1 mL), and the temperature was allowed to slowly reach rt overnight. The reaction mixture was diluted with DCM (30 mL) and washed sequentially with H2O, NH4OH 1M, and brine. The DCM was evaporated, but not the residual pyridine, Addition of MeOH (20 mL) induced crystallization of the product, as white needles. HPLC Rt=6.28 min.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH:4]([C:7]1([CH3:27])[C:11](=[O:12])[NH:10][C:9]([C:13]2[C:21]3[N:20]=[C:19]([CH3:22])[N:18]([CH3:23])[C:17]=3[CH:16]=[CH:15][C:14]=2[C:24]([OH:26])=[O:25])=[N:8]1)([CH3:6])[CH3:5].C(O)(=O)C>CCOCC.CO>[CH:4]([C:7]1([CH3:27])[C:11](=[O:12])[NH:10][C:9]([C:13]2[C:21]3[N:20]=[C:19]([CH3:22])[N:18]([CH3:23])[C:17]=3[CH:16]=[CH:15][C:14]=2[C:24]([O:26][CH3:3])=[O:25])=[N:8]1)([CH3:6])[CH3:5]
Reactant: Cc1nc2c(C3=NC(C)(C(C)C)C(=O)N3)c(C(=O)O)ccc2n1C
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)c1ccc2c(nc(C)n2C)c1C1=NC(C)(C(C)C)C(=O)N1
Yield: 28.9 %

Procedure:
A solution of diazomethane in ether is added dropwise to a solution of the 4-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-1,2-dimethyl-5-benzimidazolecarboxylic acid (2.50 g, 7.61 mmol) in methanol until the yellow color persists. The reaction mixture is neutralized with acetic acid and concentrated in vacuo. Preparative HPLC (silica gel, ethyl acetate eluent) affords the title product as off-white crystals (0.750 g, 28.9%), mp 240°-242° C.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][NH:18][CH:19]=3)[N:12]3[CH:20]=[CH:21][N:22]=[C:11]3[CH:10]=2)[CH:6]=[N:5]1)([CH3:3])[CH3:2].[C:23]([CH:25]=[C:26]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]1)#[N:24]>>[C:23]([CH2:25][C:26]1([N:17]2[CH:16]=[C:15]([C:13]3[N:12]4[CH:20]=[CH:21][N:22]=[C:11]4[CH:10]=[C:9]([C:7]4[CH:6]=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=4)[N:14]=3)[CH:19]=[N:18]2)[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]1)#[N:24]
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Reactant: CC(C)n1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Product: CC(C)n1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(C(=O)OC(C)(C)C)C4)c3)n2)cn1
Yield: 64 %

Procedure:
7-(1-isopropyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Example 34, Step B) was reacted in the same manner as Example 34, Step C, replacing 3-cyclopropylacrylonitrile with tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (Preparation F, Step A) to obtain tert-butyl 3-(cyanomethyl)-3-(4-(7-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (0.090 g, 0.1846 mmol, 64% yield). MS (apci) m/z=488.3 (M+H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[CH2:21][CH2:22][CH:23]=O)[CH2:3]1.Cl.Cl.[CH3:27][N:28]([CH3:34])[CH:29](C)[CH2:30][O:31][NH2:32]>>[CH3:27][N:28]([CH3:34])[CH2:29][CH2:30][O:31]/[N:32]=[CH:23]/[CH2:22][CH2:21][C@H:11]1[CH2:10][CH2:9][C@H:8]2[C@H:7]3[C@H:16]([CH2:15][CH2:14][C@:12]12[CH3:13])[C@:17]1([CH3:20])[C:4]([CH2:3][C@@H:2]([OH:1])[CH2:19][CH2:18]1)=[CH:5][CH2:6]3
Reactant: CC(CON)N(C)C
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2CCC=O
Agent: Cl
Product: CN(C)CCO/N=C/CC[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
The compound (I-k) (0.22 g) was obtained as a white solid, containing 10% of Z isomer from 0.30 g of 3-(3β-hydroxyandrost-5-en-17β-yl)propionaldehyde (prep. 4) and 2-dimethylaminopropoxyamine dihydrochloride using the same method as that described in Ex. 1.