Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[O:5][CH2:6][CH:7]1[C:12]2([C:13]3[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=3)[CH:8]1[CH2:9][N:10]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:11]2.[NH:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[O:5][CH2:6][CH:7]1[C:12]2([C:13]3[CH:18]=[CH:17][C:16]([N:31]4[CH2:35][CH2:34][CH2:33][C:32]4=[O:36])=[CH:15][CH:14]=3)[CH:8]1[CH2:9][N:10]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:11]2
Reactant: CC(C)(C)OC(=O)N1CC2C(COc3ccc(Cl)c(Cl)c3)C2(c2ccc(Br)cc2)C1
Reactant: O=C1CCCN1
Product: CC(C)(C)OC(=O)N1CC2C(COc3ccc(Cl)c(Cl)c3)C2(c2ccc(N3CCCC3=O)cc2)C1

Procedure:
The title compound was prepared from tert-butyl 6-((3,4-dichlorophenoxy)methyl)-1-(4-bromophenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylate obtained in Step 1 of Example XXXV and 2-pyrrolidinone using the method described for Step 1 (Example XXXIII)
Reaction SMILES: O[Li].O.[C:4]([O:8][C:9]([NH:11][C@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([F:25])[CH:19]=1)[C:13]([O:15]C)=[O:14])=[O:10])([CH3:7])([CH3:6])[CH3:5].C1COCC1>O>[C:4]([O:8][C:9]([NH:11][C@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([F:25])[CH:19]=1)[C:13]([OH:15])=[O:14])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: COC(=O)[C@@H](Cc1ccc(Cl)c(F)c1)NC(=O)OC(C)(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)c(F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
LiOH—H2O (0.6246 g, 14.88 mmol) was added to a solution of (R)-methyl 2-(tert-butoxycarbonylamino)-3-(4-chloro-3-fluorophenyl)propanoate (1.646 g, 4.961 mmol) in 1:1 THF:H2O (26 mL). The reaction mixture was stirred at room temperature for 2 hours, after which it was diluted with H2O and washed with EtOAc. The aqueous layer was then acidified with solid KHSO4 and extracted with DCM. The combined extracts were dried (Na2SO4), filtered, concentrated, and then re-concentrated from DCM/hexanes to give (R)-2-(tert-butoxycarbonylamino)-3-(4-chloro-3-fluorophenyl)propanoic acid (1.31 g, 83.10% yield) as a white powder. LCMS (APCI−) m/z 316 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:3]=1.Br[C:28]1[S:32][C:31]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:30][CH:29]=1>>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([C:28]3[S:32][C:31]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:30][CH:29]=3)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(B(O)O)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3ccc(S(N)(=O)=O)s3)c2)n1

Procedure:
The title compound was prepared from 3-[6-methyl-4-(4-trifluoromethyl-phenyl)pyridin-2-yl]-benzeneboronic acid (example G.9) (0.40 g, 1.1 mmol) and commercially available 5-bromo-thiophene-2-sulfonic acid amide (0.478 g, 2.4 mmol) according to the general procedure VI. Obtained as a white solid (0.180 g, 42%). MS (ISP) 475.2 [(M+H)+]; mp 215° C.
Reaction SMILES: CO.[C:3]1([CH3:13])[CH:8]=[CH:7][C:6](S(O)(=O)=O)=[CH:5][CH:4]=1>C1(C)C=CC=CC=1>[C:3]1([C:13]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH2:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: C=C(c1ccccc1)c1ccccc1
Yield: 36321.4 %

Procedure:
Into a 1-liter reaction flask were introduced 200.23 g of the crude carbinol, 400 ml of toluene, and 1 g of p-toluenesulfonic acid (PTSA). Azeotropic dehydration was conducted for 2 hours with toluene refluxing (94-116° C.). After cooling, this reaction mixture was washed with water, with 2% aqueous soda ash solution, and then with water, dried with magnesium sulfate, and concentrated to obtain 190.09 g of crude 1,1-diphenylethylene (9a; R1 =R2 =H). This crude 1,1-diphenylethylene (9a) was distilled with a Claisen flask equipped with a vigreux, giving 174.06 g of 1,1-diphenylethylene (9a). b.p., 103° C./1 mmHg
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH2:12][CH:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.[CH3:19][C:20]([CH3:22])=[O:21].Cl>O1CCCC1>[C:13]1([C:10]23[CH2:9][CH:8]([O:21][C:20]2([CH3:22])[CH3:19])[N:7]([CH3:6])[CH2:12][CH2:11]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)=O
Reactant: CN1CC=C(c2ccccc2)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC2(c3ccccc3)CC1OC2(C)C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (15 ml of 1.5M solution in hexane) was added under nitrogen to a solution of 4.7 g of commercially available 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (II: R1 =Me; R2, R3 =H; R4 =phenyl) in 50 mL of tetrahydrofuran, kept at -10°. The deep red solution was stirred at -10° for 15 min and then transferred in a slow stream into a stirred mixture of 15 mL of acetone and 25 mL of tetrahydrofuran and kept at -70°. Excess 10% hydrochloric acid was added after stirring at -70° for 5 min; the mixture was allowed to come to room temperature, and then washed with toluene. The aqueous layer was made basic with sodium hydroxide and extracted with methylene chloride. Removal of the solvent from the dried solution and short-path distillation of the residue (90°-135° bath temperature, 5×10-4 mm Hg [0.07 Pa]) gave 2.79 g of 5-phenyl-2,6,6-trimethyl-7-oxa-2-azabicyclo[3.2.1]octane (III: R1, R5, R6 =Me; R2, R3 =H, R4 =phenyl) as an oil of ca. 85% purity.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f15) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[CH:9]=[CH:8]2)[CH3:2].[O:14]1CCOCC1>O>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH:13]=[O:14])[CH:9]=[CH:8]2)[CH3:2]
Reactant: CCc1cccc2ccc(C)nc12
Reactant: C1COCCO1
Solvent: O
Product: CCc1cccc2ccc(C=O)nc12
Temperature: 25 °C
Yield: 85.8 %

Procedure:
A solution of 8-ethyl-2-methylquinoline (3.34 g, 19.5 mmol) in dioxane (150 mL) and water (1.5 mL) was added SeO2 (2.60 g, 23.4 mmol) and the mixture was stirred at reflux for 2 hours. After cooling to ambient temperature, the solid was removed by filtration and washed with DCM. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (1:1 hexane/DCM) to give 8-ethylquinoline-2-carbaldehyde (3.1 g, 85.8%) as a solid.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])=[CH:10][CH:9]=1
Reactant: C=C1CC(=O)O1
Reactant: Nc1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 25.72 mL (336 mmol) of diketene in 100 mL of toluene is added dropwise at 90° C. to a solution of 51.0 g (288 mmol) of 4-bromoaniline in 200 mL of toluene and the reaction mixture is kept for 5 hours at this temperature. The reaction solution is cooled in the ice bath, and the precipitate formed is filtered and then washed with toluene until the product is virtually colorless. Subsequently it is dried at 50° C. in the circulating air dryer until the weight is constant. Yield: 50.0 g (68% of theoretical); C10H10BrNO2 (M=256.096); calc.: molpeak (M+H)+: 256/258 (Br); found: molpeak (M+H)+: 256/258 (Br); HPLC-MS: 4.7 min (method B).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[N:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1>CN(C=O)C>[CH3:21][S:20][C:16]1[N:17]=[C:18]([N:7]2[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH2:1])[C:10]=3[N:9]=[N:8]2)[CH:19]=[CH:14][N:15]=1
Reactant: CSc1nccc(Cl)n1
Reactant: Nc1cccc2[nH]nnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(-n2nnc3c(N)cccc32)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.5 %

Procedure:
Dry DMF (100 mL) was cooled under N2 in an ice bath. To this was added 4-amino-1H-benzotriazole (9.0 g), and the mixture stirred for 10 min. To this was added NaH (60%, 2.95 g), and the mixture stirred on the ice bath for 15 min. Finally, 4-chloro-2-methylsulfanyl-pyrimidine (11.00 g) was added, the ice bath removed, the mixture allowed to warm to RT, and then heated to 85° C. for 1 h. The reaction mixture was then cooled to RT, and diluted with ice water. The fine yellow precipitate was filtered, washed with cold water, and titurated with EtOAc to provide 1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-benzotriazol-4-ylamine (13.43 g, 78% yield).
Reaction SMILES: C([C:3]1([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[Cl:22])[CH2:9][CH2:8][CH2:7][CH2:6][C:5](=[CH:10]N(C)C)[C:4]1=O)C.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([NH:45][C:46]([NH2:48])=[NH:47])[CH:36]=[CH:37][C:38]=1[N:39]1[CH:43]=[C:42]([CH3:44])[N:41]=[CH:40]1>>[Cl:22][C:16]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=1[CH:3]1[C:4]2[N:48]=[C:46]([NH:45][C:35]3[CH:36]=[CH:37][C:38]([N:39]4[CH:43]=[C:42]([CH3:44])[N:41]=[CH:40]4)=[C:33]([O:32][CH3:31])[CH:34]=3)[N:47]=[CH:10][C:5]=2[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CCC1(c2cc(Cl)ccc2Cl)CCCCC(=CN(C)C)C1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(c2cc(Cl)ccc2Cl)CCCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from crude ethyl 2-(2,5-dichloro-phenyl)-7-[1-dimethylamino-methylidene]-cycloheptanone (197 mg, ca. 0.61 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (169 mg, 0.45 mmol) using in analogous manner the procedure described in example 45b). Obtained as a pale-yellow solid (163 mg, 73%). MS ISP (m/e): 494.0 [(M+H)+]. mp 218-220° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:19](OCC)=[O:20])=[N:4][C:5]2[C:6]=1[C:7]([CH3:18])=[C:8]1[C:16]([CH:17]=2)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]2)=[N:9]1.[K+].[Br-]>C(CN)O>[OH:20][CH2:19][CH2:3][NH:4][C:19]([C:3]1[C:2]([CH3:1])=[C:6]2[C:5]([N:4]=1)=[CH:17][C:16]1[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[C:7]2[CH3:18])=[O:20]
Reactant: CCOC(=O)C1=Nc2cc3c(c(C)c2=C1C)N=c1ccccc1=3
Agent: [Br-]
Agent: [K+]
Solvent: NCCO
Product: CC1=c2c(cc3c(c2C)N=c2ccccc2=3)N=C1C(=O)NCCO

Procedure:
Ethyl 3,4-dimethylpyrrolo[3,2-b]carbazole-2-carboxylate (1.00 g, 3.26 mmol) was suspended in ethanolamine (5 ml) and heated at reflux (giving an orange solution) under nitrogen for 1.5 hours, by which time TLC showed no remaining starting material. The excess ethanolamine was removed in vacuo and the yellow residue was triturated with DCM. The resulting solid was recrystallised from ethanol/water to give the product (two crops combined) (0.383 g, 36.5%) with m.p. 270° C. (decomp.). δH [2 H6 ]-DMSO 10.90 (1H, br s, 1-NH), 10.59 (1H, s, 5-NH), 8.09 (1H, d, J 9, 9-H), 7.89 (1H, t, J 5, amide NH), 7.85 (1H, s, 10-H), 7.29-7.45 (2H, m, 6-H, 7-H), 7.08 (1H, t, J 7.5, 8-H), 4.80 (1H, t, J 5,O-H) 3.60 (2H, quartet, J 6, 2'-CH2), 3.23-3.50 (2H, m, 1'-CH2), 2.92 and 2.86 (2×3H, 2×s, 3-CH3 and 4-CH3); m/z (%) 321 (87, M+), 303 (72), 260 (100), 231 (64), 69 (67); νmax (KBr disc)/cm-1 3334, 1587, 1543, 1309, 1250.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N:9]([O-])=O.[Na+].[F:13][B-:14]([F:17])([F:16])[F:15].[Na+]>O.Cl>[F:13][B-:14]([F:17])([F:16])[F:15].[Cl:1][C:2]1[CH:3]=[C:4]([N+:5]#[N:9])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=N[O-]
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Product: N#[N+]c1cccc(Cl)c1
Reaction time: 0.17 h
Yield: 74.1 %

Procedure:
3-Chloroaniline (2.0 g) was dissolved in a mixed solvent of water (30 ml) and concentrated hydrochloric acid (3.5 ml), and sodium nitrite (1.30 g) was added under ice cooling to stir the mixture for 10 minutes. After concentrated hydrochloric acid (5.3 ml) and sodium tetrafluoroborate (6.90 g) were added to the reaction mixture to stir the mixture for 30 minutes under ice cooling, precipitate was collected by filtration and washed with water, methanol and diethyl ether to obtain the title compound (2.63 g). This compound was used in the next reaction as it was.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])[CH2:24][CH2:23]1.Cl>C(O)C>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:7][C:2]([NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:28]([N:25]3[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]3)[CH:29]=2)=[N:3][CH:4]=1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCN(c2cccc(N)c2)CC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccccc1Nc1nc(Nc2cccc(N3CCN(C)CC3)c2)ncc1Cl
Temperature: 95 °C
Reaction time: 24 h
Yield: 97.9 %

Procedure:
Ethyl 2-[(2,5-dichloro-4-pyrimidinyl)amino]benzoate (10.2 g, 32.8 mmol) and 3-(4-methyl-1-piperazinyl)aniline (6.6 g, 34.4 mmol) were combined in a vessel with ethanol (200 mL) and concentrated HCl (3.2 mL, 38.4 mmol, 12N). The vessel was sealed and heated with stirring at 95° C. for 24 h. The reaction was cooled to room temperature and poured onto water (1.3 L). The aqueous layer was extracted with ethyl acetate (2×250 mL) and neutralized to pH 7 by the slow addition of 6N NaOH. The precipitated solid was filtered off and washed with water and ethyl ether to afford the product (15.0 g, 98% yield) as a tan solid. MS: M(C24H27ClN6O2)=466.97, (M+H)+=467.2 and 469.2.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]([NH2:19])=[O:18]>>[OH:8][C:4]1[CH:3]=[C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([NH2:19])=[O:18])[CH:7]=[CH:6][CH:5]=1
Reactant: NC(=O)Nc1ccccc1Br
Reactant: Oc1cccc(O)c1
Product: NC(=O)Nc1ccccc1-c1cccc(O)c1

Procedure:
3-Hydroxy phenol and 2-bromophenyl urea were reacted under Suzuki cross coupling conditions in a similar manner as described for the preparation of Example 294 to provide 1-(3′-hydroxybiphenyl-2-yl)urea.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:8]2[N:7]3[CH2:18][CH2:19][NH:20][C:21](=[O:22])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[H-].[Na+].I[CH3:26]>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:8]2[N:7]3[CH2:18][CH2:19][N:20]([CH3:26])[C:21](=[O:22])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: CI
Reactant: O=C1NCCn2c1cc1cc(F)cc(-c3ccc(F)cc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c(cc3cc(F)cc(-c4ccc(F)cc4)c32)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
To a stirred solution of 8-fluoro-6-(4-fluoro-phenyl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 18) (0.05 g, 0.17 mmol) in DMF (1.1 ml) was added at room temperature sodium hydride (8.78 mg, 0.2 mmol), and the mixture was allowed to stir at room temperature for 30 min. Afterwards iodomethane (23.8 mg, 10.5 μl, 0.17 mmol) was added and the reaction mixture was allowed to stir at room temperature for 16 h. The mixture was poured into ice/water (30 ml) and extracted with ethyl acetate (2×25 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO4) and evaporated. The crude product (50 mg) was further purified by flash chromatography on silica gel [dichloromethane-dichloromethane/MeOH 9:1 (0-50%)] to yield the title compound as a white solid (21 mg, 40%), MS (ISP) m/z=313.4 [(M+H)+], mp 212° C.
Reaction SMILES: O=[C:2]1[C@@:19]2([CH3:20])[C:6]([NH:7][CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][CH2:13]2)=[CH:5][C:4](=[O:21])[CH:3]1CCC1CCCCC1.CC[O:32][CH2:33][CH3:34]>>[O:32]=[C:33]([C@H:13]1[CH2:12][CH2:11][C@H:10]2[C@H:9]3[C@H:18]([CH2:17][CH2:16][C@:14]12[CH3:15])[C@:19]1([CH3:20])[C:6](=[CH:5][C:4](=[O:21])[CH2:3][CH2:2]1)[NH:7][CH2:8]3)[CH2:34][CH:2]1[CH2:19][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOCC
Reactant: C[C@@]12CCC[C@H]1[C@@H]1CNC3=CC(=O)C(CCC4CCCCC4)C(=O)[C@]3(C)[C@H]1CC2
Product: C[C@]12CC[C@H]3[C@@H](CNC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CC1CCCCC1

Procedure:
A solution of 17β-carboxy-6-t-butoxycarbonyl-6-azaandrost-4-en-3-one (260 mg, 0.62 mmol), example 1, part F, is dissolved in toluene (10 mL) and treated with pyridine (3 eq) and catalytic dimethylformamide, cooled to 0° C., and thionyl chloride added (80 mL, 1.10 mmol). The reaction is then allowed to warm to room temperature and stir for 1 hr. The solids are then removed by filtration, the solution concentrated, the resulting crude acrid chloride dissolved in THF (6 mL), Cul added (120 mg, 0.62 mmol), cooled to -78° C. and treated with methylenecyclo-hexylmagnesium bromide (2.0M in diethyl ether, 0.5 mL, 1 mmol). The reaction is allowed to warm to room temperature, stir for 30 min, is quenched with saturated NaHSO4, extracted with ethyl acetate (2×25 mL), dried over MgSO4, concentrated and chromatographed on silica gel (25% ethyl acetate/hexane) to give 17β-(1-oxo-2-(cyclohexylethyl))-6-t-butoxycarbonyl-6-azaan-drost-4-en-3-one; yield: 302 mg (98%). This material may be deprotected as described in example 1, part G above to give, on crystallization from ether, 17β-(1-oxo-2-(cyclohexylethyl)-6-azaandrost-4-en-3-one; yield: 121 mg (50%); m.p. 214°-216° C. Anal. Calcd. for C26H39 NO2. 1/2H2O; C, 76.80; H, 9.92; N, 3.44. Found: C, 76.61; H, 9.89; N, 3.49.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6](C=O)=[CH:5][CH:4]=1)#[N:2].[N:11]1([CH:17]=O)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(O)=O.Cl>C(O)C>[N:11]1([CH2:17][C:6]2[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: O=CN1CCNCC1
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cl
Solvent: O=CO
Solvent: CCO
Product: N#Cc1ccc(CN2CCNCC2)cc1
Reaction time: 0.17 h

Procedure:
A mixture of 13.1 g. of p-cyanobenzaldehyde and 15 ml. of piperazine-1-carboxaldehyde was heated to 100° C. Over 10 minutes, 6 g. of 99% formic acid were added. The mixture was heated for 3 hours, then 200 ml. of 3.6 N hydrochloric acid in ethanol were added and the mixture was refluxed for 4 hours. The solid was collected, washed with ether and suspended in water. 10 N Sodium hydroxide extracted with three 100 ml. portions of chloroform and the combined extracts were evaporated. The residue was suspended in a mixture of 6 N hydrochloric acid and chloroform and filtered. The filtrate was adjusted to pH>7 with 10 N sodium hydroxide, extracted with chloroform, and the extract dried and evaporated to an oil which was distilled, giving α-(1-piperazinyl)-p-tolunitrile as a colorless liquid, b.p. 207°-209° C. (15 mm.).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:41])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[C:36]4[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([C:37]#[N:38])[CH:35]=4)[N:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[CH:12]=1.S(OC)(O[CH3:46])(=O)=O>C1COCC1.CN(C=O)C>[CH3:46][N:17]([C:13]1[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=1)[C:18](=[O:41])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([C:37]#[N:38])[CH:35]=3)[N:30]=[CH:29][CH:28]=2)=[CH:24][CH:25]=1
Reactant: COS(=O)(=O)OC
Reactant: COc1cc2nccc(Oc3ccc(CC(=O)Nc4cccnc4)cc3)c2cc1C#N
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(CC(=O)N(C)c4cccnc4)cc3)c2cc1C#N
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
Under an atmosphere of argon, a 1M solution of lithium hexamethyldisilazane in THF (0.27 ml) was added dropwise to a stirred solution of N-(3-pyridyl)-2-[4-(6-cyano-7-methoxyquinolin-4-yloxy)phenyl]acetamide (0.1 g) in DMF (2 ml) that had been cooled to −5° C. After 5 minutes, a solution of dimethyl sulphate (0.026 ml) in DMF (0.5 ml) was added dropwise and the resultant mixture was stirred at 0° C. for 30 minutes. The mixture was evaporated and the residue was purified by preparative HPLC using a Waters ‘Xterra’ reversed-phase column (5 microns silica) using decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. There was thus obtained the title compound (0.04 g); 1H NMR: (CDCl3) 3.34 (s, 3H), 3.52 (s, 2H), 4.08 (s, 3H), 6.51 (d, 1H), 7.07 (d, 2H), 7.18 (d, 2H), 7.42 (m, 1H), 7.53 (br s, 2H), 8.5 (br s, 1H), 8.65 (br s, 1), 8.67 (d, 1H), 8.69 (s, 1H); Mass Spectrum: M+H+ 425.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[C:34](B(O)O)=[N:35][CH:36]=[CH:37][CH:38]=1>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:34]3[C:33]([F:32])=[CH:38][CH:37]=[CH:36][N:35]=3)[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: OB(O)c1ncccc1F
Product: Cn1ncc(NC(=O)c2csc(-c3ncccc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3-fluoropyridin-2-yl)boronic acid gave 237. LCMS (ES+) m/z 435 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[C:15]([NH:19][NH2:20])(=O)[CH2:16][CH3:17]>C(O)CCC>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([C:15]([CH2:16][CH3:17])=[N:19][N:20]=3)[N:4]=2)=[CH:9][CH:10]=1
Reactant: CCC(=O)NN
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Solvent: CCCCO
Product: CCc1nnc2ccc(-c3ccc(Cl)cc3)nn12

Procedure:
A mixture of 9.0 g. of 3-chloro-6-(p-chlorophenyl)pyridazine (prepared as in Example 16), 7.4 g. of propionic acid hydrazide and 60 ml. of butyl alcohol is stirred at reflux temperature for 48 hours. The mixture is chilled, filtered and the solid is washed with petroleum ether and with water. The material is recrystallized from 50 ml. of ethyl alcohol to afford the product of the example as crystals, m.p. 197°-199° C.
Reaction SMILES: [N:1]1([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][C:4](=O)[CH2:3][C:2]1=[O:8].[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH2:18].O>CC1CCCO1>[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH:18][C:4]1[CH2:5][CH2:6][N:1]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:2](=[O:8])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: O=C1CCN(N2CCCCC2)C(=O)C1
Solvent: O
Solvent: CC1CCCO1
Product: O=C1C=C(Nc2ccc(Cl)cc2Cl)CCN1N1CCCCC1
Temperature: 25 °C
Yield: 77 %

Procedure:
1,1′-bipiperidine-2, 4-dione (1,000 g, 4,739 mmol) and 2,4-dichloroaniline (0.921 g, 5.687 mmol) were dissolved in 2-methyltetrahydrofuran (10 ml) and the reaction mixture was boiled under reflux for 22 h whilst the water formed was removed using a Dean and Stark apparatus. Upon cooling to rt the product precipitated and was collected by filtration to yield a white solid (1.490 g, 92%).