Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33].C(N(C(C)C)CC)(C)C.Br[CH2:50][CH2:51][CH2:52][C:53]#[N:54]>C(#N)C>[C:53]([CH2:52][CH2:51][CH2:50][NH:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33])#[N:54]
Reactant: N#CCCCBr
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](NCCCC#N)c3ccccc3)c2=O)c1F
Yield: 93.9 %

Procedure:
Compound 1f (110 mg, 0.2 mmol) was dissolved in acetonitrile (5 mL) and diisopropylethyl amine (52 mg, 0.4 mmol) was added, followed by the addition of 4-bromobutyronitrile (90 mg, 0.6 mmol). The reaction mixture was refluxed for 16 hours. Volatiles were evaporated and the residue was purified by flash chromatography (silica, 5% MeOH/CH2Cl2) to give compound 3a (115 mg, 94%). MS (CI) m/z 613.3 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][C:20]2[N:21]=[C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]3[CH:29]=2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:37]=[O:38]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][C:20]2[N:21]=[C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]3[C:29]=2[CH:37]=[O:38])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccn2cc(C=Cc3ccc([N+](=O)[O-])c(OCc4ccccc4)c3)nc2c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccn2c(C=O)c(C=Cc3ccc([N+](=O)[O-])c(OCc4ccccc4)c3)nc2c1

Procedure:
A solution of 2-[2-(3-benzyloxy-4-nitrophenyl)vinyl]-7-methylimidazo[1,2-a]pyridine (9.00 g) in N,N-dimethylformamide (50 ml), was added dropwise to a solution of phosphorus oxychloride (6.36 ml) in N,N-dimethylformamide (90 ml) at ambient temperature with stirring. After the mixture was stirred for 6 hours, the solvent was evaporated in vacuo. The residue was mixed with water (200 ml) and dichloromethane (300 ml) and made basic with aqueous potassium carbonate. The resulting precipitate was collected, washed with water and recrystallized from a mixture of methanol, chloroform and dioxane to give 2-[2-(3-benzyloxy-4-nitrophenyl)vinyl]-3-formyl-7-methylimidazo[1,2-a]pyridine (5.15 g).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9](O)(=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].Cl.[OH-].[Na+]>O>[CH2:25]([C:26]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: Nc1ccccc1N
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCCc1nc2ccccc2[nH]1
Temperature: 15 °C
Reaction time: 5 h

Procedure:
Into a four-necked flask of 2 l capacity were charged 54.0 g (0.5 mol) of o-phenylenediamine, 142 g (0.5 mol) of stearic acid and 500 ml of 4N-hydrochloric acid, and a reaction was effected for 5 hours while refluxing the reaction solution. Then, 500 ml of water was added to the reaction mass, and the resulting solution was neutralized up to a pH of 9.2 at a temperature of not higher than 15° C. with a 20% aqueous solution of sodium hydroxide. Then, the resulting mixture was stirred at a temperature of not higher than 15° C. for 1 hour, and then filtered. The filter cake was washed with water to obtain the aimed 2-heptadecylbenzimidazole in an yield of 139.5 g (78.4%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[C:16](=O)[C:15]2[C:14]([C:18]([O:20]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][CH:8]1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1.O.[NH2:34][NH2:35]>CO>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[C:16]2=[N:34][NH:35][C:18](=[O:20])[C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([C:15]=32)[NH:9][CH:8]1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccc(C(F)(F)F)cc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: Cn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
A mixture of ethyl 3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (150 mg, 0.34 mmol) in 85% hydrazine monohydrate (4 ml) and methanol (6 mL) was stirred at room temperature for 2 h. The mixture was filtered and washed with water to give the title compound (25 mg, yield: 18%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.46 (s, 3H), 4.81 (d, J=10.8 Hz, 1H), 5.07 (d, J=10.8 Hz, 1H), 6.82 (s, 1H), 6.97 (d, 1H), 7.16 (d, J=8 Hz, 1H), 7.41 (d, J=7.6 Hz, 2H), 7.58-7.69 (m, 5H), 12.22 (d, 1H); LC-MS (ESI) m/z: 412 (M+1)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:9]=[N:10][N:11]([C:22]2[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][N:23]=2)[C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)(=O)=O.Cl.[CH3:31][NH:32][CH3:33].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:31][N:32]([CH3:33])[CH2:6][CH2:7][C:8]1[CH:9]=[N:10][N:11]([C:22]2[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][N:23]=2)[C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1
Reactant: CNC
Reactant: CS(=O)(=O)OCCc1cnn(-c2cc(C#N)ccn2)c1OCc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)CCc1cnn(-c2cc(C#N)ccn2)c1OCc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
To a solution of 2-[1-(4-cyanopyridin-2-yl)-5-[(4-fluorophenyl)methoxy]pyrazol-4-yl]ethyl methanesulfonate (42 mg, 0.1 mmol) and dimethylamine hydrochloride (41 mg, 0.5 mmol) in ACN (3 mL) was added K2CO3 (276 mg, 2 mmol) and KI (62 mg, 0.4 mmol) at rt. The reaction mixture was heated to 80° C. and stirred overnight. Filtered, solvent removed and purified by prep-HPLC to give the title compound (16 mg, 44%). 1H NMR (400 MHz, CDCl3): δ 2.45 (6H, s), 2.56-2.61 (2H, m), 2.69-2.73 (2H, m), 5.16 (2H, s), 7.03-7.07 (2H, m), 7.35-7.41 (3H, m), 7.53 (1H, s), 8.03 (1H, s), 8.64 (1H, d, J=4.8 Hz). [M+H] Calc'd for C20H20FN5O, 366. Found, 366.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.Cl.[C:12]1(C)[CH:17]=[CH:16][C:15]([NH:18]N)=[CH:14][CH:13]=1>C(O)(=O)C>[CH:13]1[CH:12]=[CH:17][CH:16]=[C:15]2[C:14]=1[C:1]1[C:2]([CH:3]=[C:4]3[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]3)=[N:18]2
Reactant: O=C1Cc2ccccc2C1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CC(=O)O
Product: C1=c2ccccc2=C2C1=Nc1ccccc12
Temperature: 25 °C

Procedure:
A mixture of 2-indanone (51.0 g, 0.39 mol) and p-tolylhydrazine hydrochloride (61.4 g, 0.39 mol) is dissolved in glacial acetic acid (525 mL) and is vigorously stirred and heated to reflux. The mixture turns red and is heated for 2 h. After cooling to room temperature, it is poured into ice water (1 L). The precipitate is filtered to afford a solid, which is washed with water (about 1 L). The solid is dissolved in ethyl acetate (1.4 L), activated charcoal is added, and the mixture is gently warmed. The mixture is then cooled and filtered over a pad of Celite. The filtrate is dried over Na2SO4 filtered, and is then concentrated to 450 mL and cooled to −30° C. for 3 days. The crystalline solid is filtered and washed with chilled (−78° C.) hexanes (2×500 mL). The beige solid is collected and dried under vacuum (47.1 g, 56%).
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][OH:5].[Br:6][C:7]1[CH:24]=[CH:23][C:10]([NH:11][C:12]2[C:13]([C:20](O)=[O:21])=[CH:14][N:15]([CH3:19])[C:16](=[O:18])[CH:17]=2)=[C:9]([F:25])[CH:8]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CO>[Br:6][C:7]1[CH:24]=[CH:23][C:10]([NH:11][C:12]2[C:13]([C:20]([NH:1][O:2][CH2:3][CH2:4][OH:5])=[O:21])=[CH:14][N:15]([CH3:19])[C:16](=[O:18])[CH:17]=2)=[C:9]([F:25])[CH:8]=1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)cc1=O
Reactant: NOCCO
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: Cn1cc(C(=O)NOCCO)c(Nc2ccc(Br)cc2F)cc1=O
Yield: 38 %

Procedure:
2-(Aminooxy)ethanol, 4-(4-bromo-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and DMT-MM were reacted in MeOH as outlined in example 33, step D. Further purification by flash chromatography on silica gel (EtOAc followed by 10% MeOH/CH2Cl2) gave 4-(4-bromo-2-fluoroanilino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (38%); m.p. (EtOAc/Hexane) 124-128° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.64 (br s, 1H), 9.50 (br s, 1H), 8.13 (s, 1H), 7.69-7.65 (m, 1H), 7.47-7.41 (m, 2H), 5.53 (d, J=0.7 Hz, 1H), 4.78 (s, 1H), 3.91 (t, J=5.0 Hz, 2H), 3.61 (t, J=5.0 Hz, 2H), 3.36 (s, 3H). LCMS (ACPI−) 400 (80%), 398 (100%). Anal. Calcd for C15H15BrFN3O4.0.25 H2O: C, 44.5; H, 3.9; N, 10.4. Found C, 44.3; H, 3.5; N, 10.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[CH2:15][CH2:16][CH2:17][N:18]1[C:23](=[O:24])[C:22]([CH3:25])=[CH:21][N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]1=[O:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][N:18]2[C:23](=[O:24])[C:22]([CH3:25])=[CH:21][N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[C:19]2=[O:34])[CH2:10][CH2:9]1
Reactant: Cc1cn(COCC[Si](C)(C)C)c(=O)n(CCCCl)c1=O
Reactant: Clc1ccccc1N1CCNCC1
Product: Cc1cn(COCC[Si](C)(C)C)c(=O)n(CCCN2CCN(c3ccccc3Cl)CC2)c1=O

Procedure:
substituting 1-(2-chlorophenyl)piperazine and 3-(3-chloropropyl)-5-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-2,4(1H,3H)-pyrimidinedione gave 3-{3-[4-(2-chlorophenyl)piperazin-1-yl]propyl}-5-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-2,4(1H,3H)-pyrimidinedione;
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=2)[N:3]=1.O[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33]C)=[O:32])=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH-].[Na+].Cl>CO.O1CCCC1.O.ClCCl>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][O:21][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:25][CH:24]=3)=[CH:18][CH:19]=2)[N:3]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: Cc1cc(-c2ccccc2)n(Cc2ccc(CO)cc2)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(-c2ccccc2)n(Cc2ccc(COc3ccc(CCC(=O)O)cc3)cc2)n1
Temperature: 25 °C
Yield: 42.2 %

Procedure:
To a mixture of {4-[(3-methyl-5-phenyl-1H-pyrazol-1-yl)methyl]phenyl}methanol (139 mg, 0.5 mmol), methyl 3-(4-hydroxyphenyl)propanoate (90 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol) and dichloromethane (3 mL) was added dropwise diethyl azodicarboxylate (40% toluene solution, 435 mg, 1.0 mmol) with stirring at room temperature, and the mixture was stirred at room temperature for 1 hr. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography (hexane:ethyl acetate=19:1-1:2) to give a yellow oil. The yellow oil was dissolved in methanol (3 mL) and tetrahydrofuran (3 mL), and 1 N aqueous sodium hydroxide solution (2 mL) was added. The mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water, and neutralized with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (Manufactured by Wako. Pure Chemical Industries, Ltd.), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1-1:4) to give the title compound (90 mg, yield 42%, 2 steps) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=O)=[C:24]([O:32][CH3:33])[CH:23]=2)[N:17]=1.[F:34][CH:35]([F:43])[C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14])=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([NH:39][C:38]3[CH:40]=[CH:41][CH:42]=[C:36]([CH:35]([F:43])[F:34])[CH:37]=3)=[O:28])=[C:24]([O:32][CH3:33])[CH:23]=2)[N:17]=1
Reactant: Nc1cccc(C(F)F)c1
Reactant: COC(=O)c1ccc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)F)c1

Procedure:
The title compound was prepared according to the procedure described in step-6 of Intermediate-26 by using methyl 4-(3-(2-chloro-5-((2,2,2-trifluoroacetamido)methyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-5 of Intermediate-26, 0.100 g, 0.20 mmol), 3-(difluoromethyl)aniline (Intermediate-29, 0.045 g, 0.30 mmol), trimethyl aluminium (2M solution in toluene) (1.0 mL) and dry toluene (5.0 mL) to afford 0.080 g of crude product which was triturated with methanol:DCM:ether to afford 0.080 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 3.95 (s, 3H), 4.47 (d, J=5.7 Hz, 2H), 7.05 (m, 1H), 7.30 (m, 1H), 7.50 (d, J=7.8 Hz, 2H), 7.70 (m, 3H), 7.80 (d, J=6.3 Hz, 3H), 8.08 (s, 1H), 10.11 (br s, 1H), 10.28 (s, 1H), 12.72 (br s, 1H); MS (m/z): 596.12 (M+H)+.
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:18][NH:19][CH:20]([CH3:22])[CH3:21]>CO>[CH:20]([N:19]([CH2:17][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:18])([CH3:22])[CH3:21]
Reactant: c1ccc(-c2ccccc2OCC2CO2)cc1
Reactant: CNC(C)C
Solvent: CO
Product: CC(C)N(C)CC(O)COc1ccccc1-c1ccccc1

Procedure:
22.7 g (0.1 mole) of 2,3-epoxy-1-(2-phenylphenoxy)-propane is dissolved in 30 ml of methanol. Then 15 ml (0.2 moles) of methylisopropylamine is added to the reaction mixture slowly while stirring. The mixture is refluxed over a steam bath for 48 hr after which time the solvent and excess amine are evaporated under reduced pressure. The residue remaining is dissolved in 200 ml of ether and the solution washed with water. The ether phase is extracted with 5% aqueous hydrochloric acid and the aqueous extracts washed once with ether. The aqueous phase is neutralized with ammonium hydroxide, then extracted with methylene chloride. The methylene chloride extract is dried over anhydrous potassium carbonate and the solvent evaporated under reduced pressure to afford 1-(N-isopropyl-N-methylamino)-3-(2-phenylphenoxy)-propan-2-ol, as a blue-green oil.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].C[N:8]1[CH2:13][CH2:12][C:11](=[C:14]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH2:18][CH2:17][C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]2=3)[CH2:10][CH2:9]1>C1C=CC=CC=1>[C:4]([N:8]1[CH2:9][CH2:10][C:11](=[C:14]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH2:18][CH2:17][C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]2=3)[CH2:12][CH2:13]1)([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)Cl
Reactant: CN1CCC(=C2c3ccccc3CCc3cccnc32)CC1
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC(=C2c3ccccc3CCc3cccnc32)CC1
Temperature: 25 °C

Procedure:
To a solution of 10.9 g (0.1 mole) of ethylchloroformate in 300 ml of anhydrous benzene is added dropwise, with stirring at room temperature, a solution of 14.5 g (0.05 M) of 11-(N-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo-[5,6]-cyclohepta-[1,2-b]-pyridine (hereinafter referred to as Compound IA) in 200 ml of benzene. The solution is stirred and is heated under reflux overnight (16-20 hrs.). The mixture is cooled and is poured into ice water and the organic layer is separated, washed with water, dried, and then concentrated to dryness. The residue is triturated with petroleum ether and a white solid having a melting point of 106°-107° C. is recrystallized from isopropyl ether after decolorization with decolorizing carbon.
Reaction SMILES: C([N:8]([C@H:33]1[CH2:38][CH2:37][C@H:36]([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:41][CH:40]=2)[CH2:35][CH2:34]1)[CH2:9][C@H:10]([OH:32])[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([O:24]CC2C=CC=CC=2)=[C:17]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:18]=1)C1C=CC=CC=1>C(O)C.[Pd]>[C:42]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:43]=[CH:44][C:39]([C@H:36]2[CH2:37][CH2:38][C@H:33]([NH:8][CH2:9][C@H:10]([OH:32])[CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:16]([OH:24])=[C:17]([NH:19][S:20]([CH3:23])(=[O:21])=[O:22])[CH:18]=3)[CH2:34][CH2:35]2)=[CH:40][CH:41]=1
Reactant: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(-c4ccccc4)cc3)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN[C@H]2CC[C@H](c3ccc(-c4ccccc4)cc3)CC2)ccc1O
Reaction time: 4 h

Procedure:
A mixture of 0.16 g of trans-N-[5-[((2S)-3-{benzyl[4-(1,1′-biphenyl-4-yl)cyclohexyl]amino}-2-hydroxypropyl)oxy]-2-(benzyloxy)phenyl]methanesulfonamide (0.23 mmol) and of 0.1 g of 10% palladium-on-charcoal (50% in water) in ethanol (6 ml) is placed under a hydrogen atmosphere and stirred for 4 hours. The reaction mixture is filtered through celite. The solvents are evaporated under reduced pressure and trans-N-{5-[((2S)-3-{[4-(1,1′-biphenyl-4-yl)cyclohexyl]amino}-2-hydroxypropyl)oxy]-2-hydroxyphenyl}methanesulfonamide is obtained in the form of a white solid (0.08 g, 68%) after purification on silica gel (eluent: dichloromethane/methanol, 99/1 to 85/15 gradient in 30 minutes).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][CH2:38][N:39]3[CH:43]=[CH:42][N:41]=[CH:40]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][CH2:38][N:39]3[CH:43]=[CH:42][N:41]=[CH:40]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccc(OCCCn3ccnc3)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(C)ccc(OCCCn3ccnc3)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-7-[3-(imidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:7][C@@:8]12[C@H:18]3[CH2:19][CH2:20][C@:21]4([CH3:31])[C@@:25]5([O:30]C(=O)CC5)[CH2:24][CH2:23][C@H:22]4[C@@H:17]3[CH:16]=[CH:15][C:14]1=[CH:13][C:11](=[O:12])[CH2:10][CH2:9]2.C[Si](Cl)(C)C>C(Cl)Cl.CCOCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:9]1[C@@:8]2([CH3:7])[C:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:18]2[CH2:19][CH2:20][C@@:21]2([CH3:31])[C@H:22]3[CH2:23][CH2:24][C:25]2=[O:30])=[CH:13][C:11](=[O:12])[CH2:10]1
Reactant: C=CCCCBr
Reactant: C[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@@]21CCC(=O)O1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@]12C(=CC(=O)C[C@@H]1CCCCCBr)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.25 h
Yield: 7 %

Procedure:
Cp2ZrHCl (206 mg, 0.80 mmol, 2.0 eq.) was added to a stirred, room temperature, solution of 5-bromo-1-pentene (0.12 mL, 1.0 mmol, 2.5 eq.) in CH2Cl2 (0.40 mL) under an argon atmosphere. After stirring for about 15 min, the resulting clear yellow solution was transferred via syringe over about 1 min to a clear colourless stirred solution of CuOTf-ligand complex (30.0 mg, 0.040 mmol, 0.10 eq.) in Et2O (2.0 mL) under an argon atmosphere. The resulting dark mixture was allowed to stir for an additional 10 min before Canrenone (136.0 mg, 0.40 mmol, 1.0 eq.) and TMSCl (0.26 mL, 2.00 mmol, 5.0 eq.) were added sequentially dropwise via syringe. Stirring at room temperature was continued arbitrarily for 15 h before the reaction was quenched by the addition of Et2O (ca 3 mL) and NH4Cl (1 M aq., ca 1.5 mL). The mixture was partitioned between the aqueous and Et2O layers and the former phase was extracted with Et2O (3×10 mL). The combined organic phase was washed with NaHCO3 (sat. aq., ca 10 mL), dried (Na2SO4), filtered and concentrated in vacuo to give an oil. Flash column chromatography of the yellow residue (30:70 EtOAc/petrol; SiO2) gave major diastereomer (4) (+)-7α-(5-bromopentyl)-17α-hydroxy-3-oxo-pregn-4-ene-21-carboxylic acid γ-lactone (64 mg, 0.13 mmol, 33%) and minor diastereomer (4a) (+)-1α-(5-bromopentyl)-4-androstene-3,17-dione (14 mg, 0.028 mmol, 7%). Diastereomeric ratio was determined by integration of 1H NMR spectra.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[C:24]([CH3:25])=[CH:23][C:16]([O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][C:14]=2[CH3:26])(=[O:12])=[O:11])=[C:5]([N+:27]([O-])=O)[CH:4]=1>C(OCC)(=O)C.[Ni].[Pt]=O>[NH2:27][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[NH:9][S:10]([C:13]1[C:24]([CH3:25])=[CH:23][C:16]([O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][C:14]=1[CH3:26])(=[O:12])=[O:11]
Reactant: COC(=O)COc1cc(C)c(S(=O)(=O)Nc2ccc(OC)cc2[N+](=O)[O-])c(C)c1
Agent: O=[Pt]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: COC(=O)COc1cc(C)c(S(=O)(=O)Nc2ccc(OC)cc2N)c(C)c1
Yield: 104.1 %

Procedure:
Methyl [4-(4-methoxy-2-nitrophenyl)aminosulfonyl-3,5-dimethylphenoxy]acetate (Intermediate A2, 8.1 g, 0.019 mol) in 200 mL ethyl acetate was stirred with Raney nickel (0.75 g) for 30 min and filtered through a celite pad with the aid of an additional 100 mL of ethyl acetate. The filtrate was mixed with platinum oxide (0.40 g, 0.0018 mol) and hydrogenated to give 7.8 g (100%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:38]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:37][N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[C:26]([C:29]6[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=6)[CH:25]=[CH:24]5)=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>Cl.O1CCOCC1>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:38]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:37][N:21]4[N:22]=[C:27]5[C:28]([CH:23]=[CH:24][CH:25]=[C:26]5[C:29]5[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=5)[C:35]#[N:36])=[C:20]4[N:19]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cc(-c6cccc(C#N)c6)ccc5nn4cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2cccc3c2nn2cc(-c4ccccc4)c(-c4ccc(C5(N)CCC5)cc4)nc32)c1
Yield: 22.3 %

Procedure:
172 mg (0.21 mmol) (1-{4-[9-(3-Cyanophenyl)-3-phenylpyrimido[1,2-b]indazol-2-yl]phenyl}cyclobutyl)carbamic acid tert-butyl ester in 12 mL 4M hydrogen chloride in dioxane were stirred over night at room temperature. The solvent was evaporated and the residue was treated with saturated sodium bicarbonate solution. After extraction with dichloromethane (three times) the combined organic extracts were washed with brine, dried (sodium sulfate) and filtrated. The solvent was removed and the crude residue (117 mg) was purified by HPLC yielding 23 mg of the title compound.