Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[CH2:18][C:19]([C:21]1[S:22][C:23]([Br:26])=[CH:24][CH:25]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Br:26][C:23]1[S:22][C:21]([C:19](=[O:20])[CH2:18][O:16][C:3]2[C:2]([I:1])=[CH:11][C:10]3[C:9]([CH3:12])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=3[CH:4]=2)=[CH:25][CH:24]=1
Reactant: O=C(CBr)c1ccc(Br)s1
Reactant: CC1(C)CCC(C)(C)c2cc(I)c(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC1(C)CCC(C)(C)c2cc(OCC(=O)c3ccc(Br)s3)c(I)cc21

Procedure:
A solution of 3-iodo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ol (4 g, 12.1 mmol), 2-bromoacetyl-5-bromothiophene (3.44 g, 12.1 mmol) and potassium carbonate (1.8 g, 13.3 mmol) in methyl ethyl ketone (100 ml), was heated under reflux for 3 h. The reaction medium was filtered and then concentrated in a rotary evaporator, and water and ethyl ether were added. After stirring and decantation, the organic phase was washed twice with water, dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[C:4]([CH2:24][CH3:25])[CH:3]=1.[CH3:26]B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[F-].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCCC1>[CH2:24]([C:4]1[CH:3]=[C:2]([CH3:26])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:15])=[O:16])[CH2:10][CH2:9]1)[CH3:25]
Reactant: CB(O)O
Reactant: CCc1cc(Br)ccc1N1CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(C)ccc1N1CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Yield: 114.2 %

Procedure:
A mixture of 4-bromo-2-ethylaniline (1.4 mL), diisopropylethylamine (4.4 mL) and N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (3 g) was refluxed for 5 hr. After cooling, the solvent was evaporated, and the residue was purified by column chromatography (chloroform) to give 1-(4-bromo-2-ethylphenyl)-4-(toluene-4-sulfonyl)piperazine (3 g). To a mixture of 1-(4-bromo-2-ethylphenyl)-4-(toluene-4-sulfonyl)piperazine (3 g), methylboronic acid (1.2 g), palladium acetate (112 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (411 mg) and potassium fluoride (2.3 g) was added tetrahydrofuran (30 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 1-(2-ethyl-4-methylphenyl)-4-(toluene-4-sulfonyl)piperazine (2.9 g). A mixture of 1-(2-ethyl-4-methylphenyl)-4-(toluene-4-sulfonyl)piperazine (2.9 g), hydrobromic acid (16 mL) and acetic acid (16 mL) was refluxed for 8 hr. After cooling, the reaction mixture was alkalified with 1N aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. 4N hydrogen chloride/ethyl acetate (3 mL) was added and the mixture was filtered to give 1-(2-ethyl-4-methylphenyl)piperazine hydrochloride (1.7 g). To a mixture of 4-bromo-2-methanesulfonylbenzoic acid (1.1 g), 1-(2-ethyl-4-methylphenyl)piperazine hydrochloride (963 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (1.5 g) were added chloroform (6 mL), methanol (6 mL) and N-methylmorpholine (440 μL), and the mixture was stirred at room temperature overnight. After evaporation of the solvent, the residue was purified by column chromatography (chloroform) to give the title compound (1.8 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[CH3:26][O:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][O:33][CH3:34]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](=[O:13])[N:30]([CH2:31][CH2:32][O:33][CH3:34])[CH2:29][CH2:28][O:27][CH3:26])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1)=[O:25]
Reactant: COCCNCCOC
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1C(=O)Nc1ccncc1
Product: COCCN(CCOC)C(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1

Procedure:
Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with bis-(2-methoxy-ethyl)-amine gives “A89”; method 1: HPLC/MS: 1.30 min, [M+H]=450;
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH:9]=[C:8]([CH2:23][O:24]C(=O)C)[N:7]=1)(=O)C.C(OCC1C=C(CCC2C=CC([N+]([O-])=O)=CC=2)C=C(C)N=1)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[OH:24][CH2:23][C:8]1[CH:9]=[C:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH:11]=[C:6]([CH2:5][OH:4])[N:7]=1
Reactant: CC(=O)OCc1cc(CCc2ccc([N+](=O)[O-])cc2)cc(COC(C)=O)n1
Agent: CC(=O)OCc1cc(CCc2ccc([N+](=O)[O-])cc2)cc(C)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(CCc2cc(CO)nc(CO)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Diacetate (7) (12.0 g, 34.1 mmol), was dissolved in 50 ml of ethanol. To this solution stirred at RT, sodium hydroxide 5 H, 20 ml was added at once. After 10 min, when the TLC test for the substrate was negative, the mixture was neutralized with citric acid, and partitioned between sat. sodium hydrogen carbonate and ethanol/chloroform 1:1. The extraction was repeated three times using 100 ml of organic solvent for each extraction. The combined extracts were evaporated and the residual mixture was flash chromatographed using finally 8% ethanol/ chloroform as a solvent. The appropriate pure fractions were collected and evaporated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH3:30])=[O:18].Br[C:32]1[S:33][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][CH:36]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:32]2[S:33][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][CH:36]=2)[CH:5]=[CH:4][C:3]=1[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH3:30])=[O:18]
Reactant: CS(=O)(=O)c1ccc(Br)s1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2ccc(S(C)(=O)=O)s2)cc1F
Yield: 78 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure A using [2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-[2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-methanone (458 mg, 1.1 mmol) and 2-Bromo-5-methanesulfonyl-thiophene (CAS 2160-61-4) (255 mg, 1.0 mmol) to give 350 mg (78% yield). MS (ES+) 451.2 (M+H)+
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1.CCN(C(C)C)C(C)C.[CH3:19][NH:20][CH2:21][CH2:22][O:23][CH3:24]>C1COCC1>[CH3:24][O:23][CH2:22][CH2:21][N:20]([CH2:3][C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1)[CH3:19]
Reactant: CNCCOC
Reactant: Nc1nc(CCl)cs1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCN(C)Cc1csc(N)n1

Procedure:
4-(chloromethyl)thiazol-2-amine hydrochloride (Intermediate I) (1 meq) was suspended in THF (20 ml) and DIEA (2 eq.) was added followed by addition of N-methyl-methoxyethylamine (1 eq.). The reaction was heated at reflux overnight. The reaction was concentrated by evaporation to solid residue.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=2)[N:12]=[CH:11][N:10]=1>C(O)(C)C>[C:2]1([NH:1][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Reactant: Nc1ccccc1
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc2ncnc(Nc3ccccc3)c2c1

Procedure:
Aniline or derivatized aniline (1 equivalent) is reacted with 4-chloro-6-nitroquinazoline (3.5 equivalents), in a polar solvent such as iso-propylalcohol. The product, 4-(phenylamino)-6-nitroquinazoline, is obtained after filtration.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[C:16]([NH2:22])[N:15]=2)[N:6]=1.Cl[C:28]([O:30][CH3:31])=[O:29]>N1C=CC=CC=1>[CH3:31][O:30][C:28](=[O:29])[NH:21][C:17]1[C:16]([NH2:22])=[N:15][C:14]([N:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[C:5]([CH2:4][C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[F:1])=[N:6]2)=[N:19][C:18]=1[NH2:20]
Reactant: COC(=O)Cl
Reactant: Nc1nc(-n2nc(Cc3ccccc3F)c3ncccc32)nc(N)c1N
Solvent: c1ccncc1
Product: COC(=O)Nc1c(N)nc(-n2nc(Cc3ccccc3F)c3ncccc32)nc1N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
200 mg (0.57 mmol) of 2-[3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidine-4,5,6-triamine from example 8 are dissolved in 10 ml of pyridine. The solution is cooled to 0° C., and 81 mg (0.86 mmol) of methyl chloroformate are added. The reaction mixture is stirred at RT overnight and then concentrated in vacuo, mixed with ethyl acetate and washed twice with water and with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated in vacuo. The residue is purified by preparative HPLC to result in 125 mg (54% of theory) of the title compound as a pale beige solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].[I-].[CH3:20]OC(CCCCCCCCCC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O.C[O-].[Na+].C(=O)CC(C)C.C(=O)CCCC>C(N(C)C)=O>[CH3:1][CH:2]([CH3:18])[CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:20])=[O:16]
Reactant: CC(C)C/C=C\CCCCCCCCCC(=O)O
Reactant: COC(=O)CCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)CC=O
Agent: C[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCCCC=O
Product: COC(=O)CCCCCCCCC/C=C\CC(C)C
Yield: 83 %

Procedure:
(Z)-14-Methyl-11-pentadecenoic acid. 10-(Methoxycarbonyl)-decyltriphenylphosphonium iodide having a melting point of 126°-129° (N. Petragnani and G. Schill, Chem. Ber., 97, 3293, (1964)), was treated with NaOMe and HCONMe2 to give Ph3PCH(CH2)9 --COOMe. It was then treated with isovaleraldehyde ((CH3)2CHCH2CH=O)(as with valeraldehyde in the Pentragnani et al. process) to give methyl (Z)-14-methyl-11-pentadecenate (83% yield) as a yellow oil; PMR (CDCl3) δ 5.44 m (CH=CH), 3.70s (COOCH3), 0.90d (Me2C, J = 6.0 Hz). The ester, without distillation, still contained 5% triphenylphosphine oxide. Saponification afforded 78% of (Z)-14-methyl-11-pentadecenoic acid, free of Ph3PO. A sample was distilled, bp 134°-136° (0.003 mm), mp 12.5°.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1>C(O)(=O)C>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[N:4]1[CH:12]=[CH:16][CH:15]=[CH:14]1
Reactant: Cc1ccc(N)c(Br)c1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: Cc1ccc(-n2cccc2)c(Br)c1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
2-Bromo-4-methylaniline (15.0 g), 2,5-dimethoxytetrahydrofuran (10.7 g) and acetic acid (81 ml) were combined under nitrogen atmosphere. The reaction mixture was stirred at 90° C. for 1.5 hours. After being cooled to room temperature, the reaction mixture was concentrated in vacuo with toluene. n-Hexane (300 ml) was added to the residue, and the suspension was filtered through Celite. Then silica gel was added to the filtrate with stirring until the colour of the solution disappeared. The suspension was filtered and the filtrate was concentrated in vacuo to give 1-(2-bromo-4-methylphenyl)pyrrole (16.1 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([C:14]3([CH2:18][C:19]#[N:20])[CH2:17][NH:16][CH2:15]3)[CH:13]=2)[CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>ClCCl>[Cl:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([C:14]3([CH2:18][C:19]#[N:20])[CH2:17][N:16]([S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH2:15]3)[CH:13]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CCS(=O)(=O)Cl
Reactant: N#CCC1(n2cc(-c3ccnc(Cl)n3)cn2)CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ccnc(Cl)n3)cn2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-ylacetonitrile hydrochloride (1.42 g, 0.00456 mol) in dichloromethane (30 mL) was added triethylamine (1.59 mL, 0.0114 mol) followed by ethanesulfonyl chloride (0.497 mL, 0.00525 mol) at 0° C. The reaction was stirred at room temperature for 1 h, quenched with 1N HCl. The organic layer was separated, washed with aqueous sodium bicarbonate, dried over sodium sulfate, and evaporated to dryness. The crude product was used directly in next step (1.26 g, 75.3%). LCMS (M+H) 367.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)[CH2:6]Cl.[Na+].[CH3:15][S:16]([O-:18])=[O:17].O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][S:16]([CH3:15])(=[O:18])=[O:17])[CH:8]=[CH:9][C:10]=1[NH2:11]
Reactant: COc1cc(CCl)ccc1[N+](=O)[O-]
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(CS(C)(=O)=O)ccc1N
Temperature: 80 °C
Yield: 83.4 %

Procedure:
To a solution of 3-methoxy-4-nitrobenzyl chloride (2.76 g, 13.7 mmol) in 20 mL of absolute ethanol was added methanesulphinic acid sodium salt (1.0 g, 27.4 mmol). The reaction was heated to 80° C. for 16 h. The reaction was cooled to room temperature and poured into water and the aqueous layer was extracted with ethyl acetate. Combined organics were dried over anhydrous MgSO4, filtered, concentrated onto silica gel and purified by flash chromatography with ethyl acetate/hexanes as the eluent. The fractions containing the desired product were concentrated to dryness, then redisolved in absolute ethanol and 10% Palladium on carbon (500 mg) was added and the reaction was placed on the Fischer-Porter hydrogenation apparatus and treated with 50 psi of H2 gas overnight to afford 2-(methyloxy)-4-[(methylsulfonyl) methyl]aniline (2.46 g, 83%). 1H NMR (400 MHz, CDCl3) δ ppm 6.80 (d, J=1.7 Hz, 1H), 6.68 (d, J=8.0, 1.6 Hz, 1H), 6.57 (d, J=8.1, 1H), 4.82 (s, 2H), 4.21 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=O)[C:10]([CH3:24])([CH3:23])[N:9]=1.[H-].[Na+].[C:27]([NH:30][NH2:31])(=O)[CH3:28]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]2[C:27]([CH3:28])=[N:30][N:31]=[C:11]2[C:10]([CH3:24])([CH3:23])[N:9]=1
Reactant: CC(=O)NN
Reactant: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1F)=NC2(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
55.25 g (0.16 mol) of 5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one, dissolved in 800 ml of tetrahydrofuran, are treated portionwise and while stirring at room temperature with 9.7 g of a 55 to 60 percent sodium hydride dispersion and the mixture is stirred at 50° C. for a further 60 minutes. 100 g (0.39 mol) of dimorpholinochlorophosphate are added to the cooled solution and the mixture is stirred at room temperature for 24 hours. After the addition of 50 g (0.67 mol) of acetic acid hydrazide, the mixture is stirred at room temperature for a further 45 hours and concentrated in vacuo. The residue is taken up in methylene chloride; the organic phase is washed with water and the solvent is removed. The residue is treated with 1.2 liters of n-butanol and heated to boiling under reflux. After distilling off 350 ml of solvent, the mixture remaining is heated at reflux for a further 1 hour and concentrated in vacuo. The residue is dissolved in 250 ml of hot ethanol. After cooling to -10° C., there is obtained crystalline 6-(o-fluorophenyl)-1,4,4-trimethyl-8-nitro-4H-s-triazolo[4,3-a][1,4]benzodiazepine of melting point 195° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][CH:8]2[OH:11])=[CH:4][CH:3]=1.[CH2:12]([C:14]1[CH:19]=[CH:18][C:17]([Mg]Br)=[CH:16][CH:15]=1)[CH3:13]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][OH:7])=[C:9]([CH:8]([C:17]2[CH:18]=[CH:19][C:14]([CH2:12][CH3:13])=[CH:15][CH:16]=2)[OH:11])[CH:10]=1
Reactant: CCc1ccc([Mg]Br)cc1
Reactant: OC1OCc2ccc(Br)cc21
Solvent: C1CCOC1
Product: CCc1ccc(C(O)c2cc(Br)ccc2CO)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
Step 2) To a solution of compound 145 (2.1 g, 9.77 mmol) in tetrahydrofuran (40.0 mL) was slowly added 4-ethylphenylmagnesium bromide (39 mL, 0.5M solution in THF) at 0° C., and the reaction mixture was stirred for 12 h at room temperature. The resulting mixture was quenched with sat. NH4Cl, diluted with EtOAc and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude was purified by silica gel column chromatography to provide (5-bromo-2-(hydroxymethyl)phenyl)(4-ethylphenyl)methanol (146, 1.53 g, 49%) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=2.0 Hz, 1H), 7.42 (dd, J=8.0, 2.0 Hz, 1H), 7.26-7.17 (m, 5H), 5.97 (s, 1H), 4.58 (d, J=12.8 Hz, 1H), 4.43 (d, J=12.4 Hz, 1H), 2.65 (q, J=7.6 Hz, 2H), 1.23 (t, J=7.6 Hz, 3H).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:15][N:16]1[C:20]([C:21]2[NH:22][C:23]3[C:28]([N:29]=2)=[C:27]([NH2:30])[N:26]=[CH:25][N:24]=3)=[C:19]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:18]=[CH:17]1.[CH:37]1(O)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH:37]1([N:22]2[C:21]([C:20]3[N:16]([CH3:15])[CH:17]=[N:18][C:19]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[N:29][C:28]3[C:23]2=[N:24][CH:25]=[N:26][C:27]=3[NH2:30])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: Cn1cnc(-c2ccccc2)c1-c1nc2c(N)ncnc2[nH]1
Reactant: OC1CCCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1cnc(-c2ccccc2)c1-c1nc2c(N)ncnc2n1C1CCCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 11 %

Procedure:
Diisopropyl azodicarboxylate (0.1 mL) was added to a solution of 8-(1-methyl-4-phenyl-1H-imidazol-5-yl)-9H-purin-6-amine (Example 3) (75 mg), cyclohexanol (0.07 mL) and triphenylphosphine (0.14 g) in THF (4 mL) under an inert atmosphere. After stirring at ambient temperature for 48 hours the reaction mixture was heated at 40° C. for 48 hours and then at 55° C. for 24 hours. The solvent was then evaporated in vacuo to give a brown oil. Purification by preparative LCMS gave the title compound as a white solid (11 mg, 11%);
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:19])([CH3:18])[CH:5]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6](OC)=[O:7].[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[C:14]([O:13][C:11](=[O:12])[NH:10][CH:5]([CH2:6][OH:7])[C:4]([CH3:19])([CH3:18])[CH2:3][OH:2])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CO)C(C)(C)CO
Temperature: -78 °C
Reaction time: 16 h
Yield: 29.1 %

Procedure:
1-methyl ester and 3-tert-butoxycarbonylamino-2,2-dimethyl-succinic acid dimethyl ester (0.47 g, 1.53 mmol) was dissolved in dichloromethane (3 mL) and cooled to −78° C. Diisobutylaluminum hydride (3.4 mL of a 1M dichloromethane solution, 3.4 mmol) was slowly added. The reaction mixture was warmed to room temperature with stirring over 16 h. Additional diisobutylaluminum hydride (a total of 6.8 mL of a 1M solution, 6.8 mmol) was added portionwise over the next 24 h until thin layer chromatography indicated the starting material was consumed. Aqueous ammonium chloride solution and ethyl acetate were added to the reaction, the layers were separated and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 104 mg (29%) of (3-hydroxy-1-hydroxymethyl-2,2-dimethyl-propyl)-carbamic acid tert-butyl ester.
Reaction SMILES: Cl.[C:2]1([C:8]#[C:9][C:10]2[S:14][C:13]([C:15]3[N:16]=[C:17]4[CH:22]=[N:21][CH:20]=[CH:19][N:18]4[C:23]=3[NH2:24])=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:27](Br)[CH3:28].CC(=O)OCC.C(Cl)Cl>CN(C=O)C>[CH2:27]([NH:24][C:23]1[N:18]2[CH:19]=[CH:20][N:21]=[CH:22][C:17]2=[N:16][C:15]=1[C:13]1[S:14][C:10]([C:9]#[C:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:11][CH:12]=1)[CH3:28]
Reactant: Nc1c(-c2ccc(C#Cc3ccccc3)s2)nc2cnccn12
Reactant: CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCNc1c(-c2ccc(C#Cc3ccccc3)s2)nc2cnccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
395 mg (1.25 mmol) of 2-(5-phenylethynyl-thiophen-2-yl)-imidazo[1,2-a]pyrazin-3-ylamine hydrochloride (Example 83) were dissolved in DMF (8 ml). After addition of 100 mg (2.5 mmol) of sodium hydride (60% dispersion in mineral oil), the mixture was stirred at RT for 1 h. A solution of 74 μl (0.8 mmol) of ethyl bromide in DMF (2 ml) was then added dropwise. The reaction solution was stirred at RT for 16 h, quenched with water (10 ml) and extracted with EA (2×50 ml). The combined organic phases were dried over MgSO4, filtered and evaporated under a vacuum. 253 mg (0.74 mmol, 58% of theoretical) of ethyl-[2-(5-phenylethynyl-thiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-amine were obtained by means of column chromatography (silica gel, EA/DCM 4:1).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[Si:5]([O:12][C@H:13]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:15](=[CH:16][CH2:17][C@@H:18]3[C@@H:27]2[CH2:26][CH2:25][C@@:23]2([CH3:24])[C@H:19]3[CH:20]=[CH:21][C:22]2=[O:32])[CH2:14]1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]>C1COCC1>[CH2:1]([C@H:20]1[C@H:19]2[C@H:18]3[C@H:27]([CH2:26][CH2:25][C@:23]2([CH3:24])[C:22](=[O:32])[CH2:21]1)[C@:28]1([CH3:31])[C:15]([CH2:14][C@@H:13]([O:12][Si:5]([C:8]([CH3:11])([CH3:9])[CH3:10])([CH3:7])[CH3:6])[CH2:30][CH2:29]1)=[CH:16][CH2:17]3)[CH3:2]
Reactant: CC[Mg]Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)C=C[C@@H]32)C1
Agent: *CC*
Solvent: C1CCOC1
Product: CC[C@@H]1CC(=O)[C@@]2(C)CC[C@H]3[C@@H](CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@]43C)[C@H]12
Temperature: -22 °C
Reaction time: 1.5 h

Procedure:
Cuprous chloride (CuCl, 0.7611 g, 7.689 mmol) is slurried in THF (40 mL) under nitrogen and then chilled to −22° C. with a dry ice/tetrachloroethylene bath. Ethylmagnesium chloride solution (2.00 M in ether; 22.0 mL, 44.0 mmol) is added to the cold cuprous chloride slurry and the dark solution is stirred for 90 minutes. A solution of 3β-t-butyldimethylsilyloxy-androst-5,15-dien-17-one (from Example 28C;) in THF (50 mL) is added dropwise via polyethylene cannula to the organometallic solution over 10 minutes, followed by a THF rinse (20 mL). The reaction mixture is stirred for 2 hours at −22° C. and then allowed to warm to ambient temperature over 30 minutes, followed by addition of saturated aqueous NH4Cl (50 mL). The biphasic mixture is extracted with EtOAc (2×40 mL) and the combined organic layers are washed with brine (50 mL), dried over MgSO4, filtered and evaporated to dryness. Purification by flash chromatography gives 15β-ethyl-3β-t-butyldimethylsilyloxy-androst-5-en-17-one, which is deprotected as in Example 19C to give the corresponding 3-alcohol, which is then oxidized as in Example 16D to obtain the title compound, which has the following formula: