Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH2:5])=O>C1COCC1.O>[F:1][C:2]([F:12])([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][NH2:5]
Reactant: NC(=O)C(F)(F)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: NCC(F)(F)c1ccccc1
Temperature: 0 °C
Yield: 59.3 %

Procedure:
Following the procedures described in Middleton and Bingham J. Org. Chem., 1980, 45, 2883, 500 mg portion of 7-5 (4.826 mmol) was dissolved in 25 ml of THF and cooled to 0° C. via ice bath. To this stirred solution was added 30 ml (30 mmol) of 1M Borane·THF complex dropwise over ten mintes via syringe. The reaction mixture was aged until the ice bath expired. Upon expiration of the ice bath, the reaction mixture was heated to 70° C. overnight. The reaction mixture was diluted with water and concentrated in vacuo. The residue was diluted with chloroform and washed with 10% sodium carbonate. Three chloroform extractions were performed on the aqueous layer. The organic layers were combined, dried (sodium sulfate), and concentrated in vacuo to give 450 mg of a yellow oil. The oil was purified using a 30mm column, 5 inches of silica gel, and a 1:1 ethyl acetate to hexane solvent system to give 7-6 (Wade and Kheribet J. Org. Chem, 1980, 45, 5333) as a yellow oil: H1NMR CDCl3): δ 3.15 (t, 2H, 14.6 Hz), 7.4-7.49 (m, 5H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:20]=1.[OH:21]CC1C=CC2CCC3C=CC=CC=3SC=2C=1>>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:9]=3[S:8](=[O:21])[C:7]=2[CH:20]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C=Cc1ccc(CO)cc1S2
Reactant: OCc1ccc2c(c1)Sc1ccccc1CC2
Product: O=[N+]([O-])c1ccc2c(c1)C=Cc1ccc(CO)cc1S2=O

Procedure:
Repeat the process of Example 2, substituting an equivalent quantity of 3-hydroxymethyl-8-nitro-dibenzo[b,f]thiepin for the 3-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin, to obtain the title product.
Reaction SMILES: [S:1]1(=[O:10])(=[O:9])[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH2:3][CH2:2]1.C([Li])CCC.[C:16](=[O:18])=[O:17]>C1COCC1.CCCCCC.CCOCC>[S:1]1(=[O:10])(=[O:9])[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH2:3][CH:2]1[C:16]([OH:18])=[O:17]
Reactant: O=C=O
Reactant: O=S1(=O)CCc2ccsc21
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)C1Cc2ccsc2S1(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47 %

Procedure:
2,3-Dihydrothieno[2,3-b]thiophene-1,1-dioxide (35.5 g, 0.204 mol) in THF (300 mL) was cooled to -78° C. under a nitrogen atmosphere. A solution of n-butyllithium in hexane (82.7 mL, 2.47M) was added dropwise over a period of 1 hour. The dark red solution was stirred for an additional 15 minutes and poured over dry ice (2 L) in ether (2 L). The reaction was allowed to warm to room temperature and the product partitioned between aqueous sodium hydroxide and ether. The aqueous phase was extracted twice with ethyl acetate, then rendered acidic (pH 1) with concentrated HCl. The resulting yellow suspension was extracted into ethyl acetate. The ethyl acetate solution was washed with saturated brine and dried over magnesium sulfate, filtered, and the solvent removed in vacuo to provide an 8:2 mixture of carboxylic acids. The solid was triturated with 5% acetonitrile in ether and collected by filtration. This was repeated a total of four times to remove most of the undesired minor product. The filtrates from the washings were combined to give approximately 1:1 mixture of carboxylic acids (17.6 g, 39%), which could be separated by column chromatography on silica gel with 10% acetic acid in chloroform. The filtered product was a light tan powder which was dried in a vacuum oven at 20° C. under house vacuum overnight to provide the title compound (21.3 g, 47%) in >95% purity.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:29]=[CH:28][C:10]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40]Cl>C(OCC)(=O)C>[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)[CH2:17][CH2:18]2)=[CH:28][CH:29]=1
Reactant: CN(C)CCCl
Reactant: Oc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 42.6 %

Procedure:
N,N-Dimethylformamide (2.5 ml) was added to 1-[1-(4-hydroxyphenethyl)piperidin-4-yl]indoline (0.1 g), potassium carbonate (0.081 g) and 2-dimethylaminoethyl chloride hydrochloride (0.078 g) followed by stirring at 80° C. overnight (12 hr). After allowing to cool, the resultant mixture was mixed with ethyl acetate (200 ml) and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (0.052 g) as a brown oil (yield: 27.0%).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[C:8]([I:19])=[C:9]([C:13]([I:18])=[C:14]([NH2:17])[C:15]=1[I:16])[C:10]([Cl:12])=[O:11])=[O:6])[CH:2]=[CH2:3].[C:20]([OH:23])(=[O:22])[CH3:21].[C:24]([OH:27])(=[O:26])[CH3:25].[C:28]([OH:31])(=[O:30])[CH3:29].[O:32]=[C:33](Cl)[C@H:34]([C@@H:36]([CH2:38]O)O)O>CC(N(C)C)=O.C(OCC)(=O)C>[C:20]([O:23][CH:36]([CH2:38][O:30][C:28](=[O:31])[CH3:29])[CH:34]([O:26][C:24](=[O:27])[CH3:25])[C:33](=[O:32])[NH:17][C:14]1[C:13]([I:18])=[C:9]([C:10]([Cl:12])=[O:11])[C:8]([I:19])=[C:7]([C:5](=[O:6])[NH:4][CH2:1][CH:2]=[CH2:3])[C:15]=1[I:16])(=[O:22])[CH3:21]
Reactant: O=C(Cl)[C@@H](O)[C@H](O)CO
Reactant: CC(=O)O
Reactant: C=CCNC(=O)c1c(I)c(N)c(I)c(C(=O)Cl)c1I
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: C=CCNC(=O)c1c(I)c(NC(=O)C(OC(C)=O)C(COC(C)=O)OC(C)=O)c(I)c(C(=O)Cl)c1I
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.2 %

Procedure:
3-Allylcarbamoyl-5-amino-2,4,6-triiodo-benzoyl chloride (7) (20 g, 32.4 mmol) was dissolved in dry DMA (50 mL) and threonic acid chloride triacetate (18) (18.22 g, 64.8 mmol) was added. The reaction was stirred for 3 days at room temperature with nitrogen bubbling through. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with ice-water (5×20 mL). The organics were collected, dried over MgSO4, filtered and evaporated to dryness under reduced pressure. The solid was adsorbed onto silica gel and purified by column chromatography eluting with DCM: ethyl acetate (0-100%, SiO2, 750 g, 10 CV) to give acetic acid 2,3-diacetoxy-1-(3-allylcarbamoyl-5-chlorocarbonyl-2,4,6-triiodo-phenylcarbamoyl)-propyl ester as a yellow solid (15.1 g, 54%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH2:19]([O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CO>[CH2:19]([O:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:24][CH:23]=1)[CH3:20]
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: CCOc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCOc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 90 °C

Procedure:
A mixture of 0.3 g (1.173 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine (for preparation see German Auslegeschrift no. 1 061 788 [published 23.07.1959]), and 0.483 g (3.52 mmol) 4-ethoxyaniline is heated for 30 min at 90° C. The cooled reaction mixture is distributed with thorough stirring between a dichloromethane/methanol mixture (18:1) and saturated aqueous sodium carbonate solution. The organic phase washed with water and brine is dried over anhydrous sodium sulfate and evaporated under vacuum. Title compound is obtained after recrystallization of the residue from acetate/methanol and acetonitrile; m.p. 223-224° C.; ESI-MS: (M+H)+=357.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH:7]=[CH:6][CH:5]=2.[CH3:23][NH:24][CH3:25].[CH2:26]=O>C(O)(=O)C.O1CCCC1>[CH3:23][N:24]([CH2:26][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:3][C:2]=1[CH3:1])[CH3:25]
Reactant: Cc1cc2c(/C=C/C(=O)OCc3ccccc3)cccc2[nH]1
Reactant: CNC
Reactant: C=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1[nH]c2cccc(/C=C/C(=O)OCc3ccccc3)c2c1CN(C)C

Procedure:
Treatment of benzyl (E)-3-(2-methyl-1H-indol-4-yl)-2-propenoate (6.20 g) with dimethylamine (3.2 ml of 33% solution in methylated spirit), and formaldehyde (1.68 ml of 40% aqueous solution) in acetic acid (13 ml) and tetrahydrofuran (15 ml) according to the method of Preparation 12 gave thetitle compound as a foam (7.45 g), Rf. 0.3(SS3).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:26][C@@H:27]([C:29]([OH:31])=[O:30])[CH3:28]>>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([S:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][C@H:27]([CH3:28])[C:29]([OH:31])=[O:30])=[O:7]
Reactant: C[C@@H](N)C(=O)O
Reactant: CCCCOC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O
Product: C[C@@H](NC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O)C(=O)O

Procedure:
Prepared in analogy to Example A-63 g) by reacting 4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester with D-alanine MS-(−)-ion: M−1=367.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:18]([F:34])=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[C:18]=2[F:34])[C:24]([C:25]#[N:26])([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(F)cc1
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(F)cc1
Yield: 72.7 %

Procedure:
In a manner similar to the method described in Example 1c, [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (1.1 g, 5 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-fluoro-phenyl)-acrylonitrile (1.25 g, 4.5 mmol) prepared in Example 55a, AgF (1.6 g, 13 mmol), and triethylamine (1.6 g, 16 mmol) in dichloromethane (100 mL) at room temperature for 5 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.6 g, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH2:4].ClC(Cl)(O[C:14](=[O:20])OC(Cl)(Cl)Cl)Cl.[CH3:22][C@H:23]1[CH2:28][NH:27][C@H:26]([CH3:29])[CH2:25][N:24]1[C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([F:38])[CH:31]=1.C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:14]([N:27]1[CH2:28][C@@H:23]([CH3:22])[N:24]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([F:38])[CH:31]=2)[CH2:25][C@@H:26]1[CH3:29])=[O:20]
Reactant: Nc1ccc(Br)cc1Br
Reactant: C[C@@H]1CN(c2ccc(C#N)c(F)c2)[C@@H](C)CN1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)Nc2ccc(Br)cc2Br)[C@@H](C)CN1c1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 300 mg portion of 2,4-dibromoaniline was dissolved in 10 ml of THF, and the solution was mixed with 153 mg of triphosgene under ice-cooling and then stirred at room temperature for 4 hours. Next, to this was added dropwise 5 ml of THF solution containing 427 mg of trans-4-(2,5-dimethylpiperazin-1-yl)-2-fluorobenzonitrile synthesized in Reference Example 1-1 and 460 mg of triethylamine, and the mixture was further stirred for 1 hour. After evaporation of the solvent, the thus obtained residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and saturated brine in that order and then dried over sodium sulfate. After evaporation of the solvent under reduced pressure, the residue was purified by a silica gel column chromatography to obtain 390 mg of the title compound from chloroform-hexane (1:1, v/v) eluate as a light yellow product.
Reaction SMILES: Br[C:2]1[N:16]([Si](C(C)(C)C)(C)C)[C:15]2[C:24]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([CH3:25])[CH2:7][N:6]1[CH3:26].C([Li])(C)(C)C.CCCCCC.O>C1(C)C=CC=CC=1>[CH3:26][N:6]1[C@H:5]2[C@@H:10]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:24]=3[C:3]([CH2:4]2)=[CH:2][NH:16]4)[CH:9]=[C:8]([CH3:25])[CH2:7]1
Reactant: CC1=C[C@@H]2c3cccc4c3c(c(Br)n4[Si](C)(C)C(C)(C)C)C[C@H]2N(C)C1
Agent: [Li]C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: CC1=C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: -90 °C
Reaction time: 5 h

Procedure:
800 mg of 2-bromo-1-(tert-butyldimethylsilyl)-8,9-didehydro-6,8-dimethylergoline was dissolved in 50 ml of anhydrous toluene; the solvent was distilled off under vacuum and the mixture taken up in 75 ml of anhydrous, freshly distilled toluene under an argon atmosphere. To this solution was added 1 ml of anhydrous tetramethylethylenediamine and the mixture was cooled to -90° C. Then the mixture was combined with 6.0 ml of 1.4-molar tert-butyllithium solution in hexane (8.4 mmol) and agitated for 5 hours. Water was then added, the mixture was extracted with methylene chloride, the organic phase was dried with sodium sulfate and evaporated. In a quantitative yield, 8,9-didehydro-6,8-dimethylergoline was isolated. The desired 8,9-didehydro-6,8-dimethyl-2-trimethylsilylergoline could not be detected by NMR.
Reaction SMILES: [C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([C:22]([OH:24])=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O>CN(C)C=O.C(Cl)CCl>[C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([C:22]([O:24][C:13]3[CH:14]=[CH:15][C:10]([NH:9][C:1](=[O:8])[CH3:2])=[CH:11][CH:12]=3)=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCc2c(c3ccccc3n2C(=O)c2ccccc2)C1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(=O)Nc1ccc(OC(=O)C2CCc3c(c4ccccc4n3C(=O)c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 9.6 g. of 9-benzoyl-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 15 ml. of thionyl chloride and two drops of dry dimethylformamide in 100 ml. of ethylene dichloride was stirred at room temperature for 7 hours. The mixture was evaporated to dryness under reduced pressure, at room temperature, and to the resulting residue was added a solution of 6 g. of 4-acetamidophenol in 50 ml. of dry pyridine. The solution was stirred at room temperature for 30 minutes and diluted with water. The resulting solid was collected by filtration to give 6.74 g. of the title compound; m.p. 166°-168°C. (ethyl alcohol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[O:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.Cl.[SH:18][C:19]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:20]=1[NH2:21]>CO.O>[CH:12]1([O:11][C:4]2[CH:5]=[C:6]([C:7]3[S:18][C:19]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:20]=4[N:21]=3)[CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1cc(F)ccc1S
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc(-c2nc3cc(F)ccc3s2)cc1OC1CCCC1
Reaction time: 8 h
Yield: 72.8 %

Procedure:
A mixture of (440 mg, 2 mmoles) 4-methoxy-3-cyclopentyloxy benzaldehyde and (400 mg, 2.1 mmoles) 2-mercapto-5-fluoroaniline hydrochloride was heated on a steam bath for 15 minutes. The resulting thick orange oil was cooled and dissolved in 5 ml of 10% FeCl3 in methanol and allowed to stir overnight. The reaction was diluted with water and extracted with CH2Cl2. The CH2Cl2 layer was dried and evaporated to give 760 mg of crude product which was purified on silica gel with CH2 Cl2 to give 500 mg of product. Recrystallization from isopropanol gave 140 mg of product. M.P.: 96°-97° C. Elemental Analysis Calc'd for C19H18O2NSF : Calc'd: C, 66.45; H, 5.28; N, 4.08. Found: C, 66.44; H. 5.13; N. 4.06.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][NH2:5].[CH2:11](C(CC)(CC)C([O-])([O-])[O-])[CH3:12]>C(O)C>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]2[C:3]=1[CH2:4][NH:5][C:11]([CH3:12])=[N:1]2
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: NCc1c(N)cccc1F
Solvent: CCO
Product: CC1=Nc2cccc(F)c2CN1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
A solution of 2-amino-6-fluorobenzylamine (1.1 g, 7.86 mmol) and triethylorthoacetate (1.58 mL, 8.64 mmol) in ethanol (30 mL) was heated at 80° C. for 14 h. The reaction mixture was allowed to cool to room temperature and evaporated in vacuo. The yellow oil was triturated with diethyl ether to give the title compound as white solid (0.74 g, 57%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:28]=[CH:27][C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH3:26])[CH:20]=3)[CH2:14][CH2:15][C:9]=2[CH:8]=1>N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:28]=[CH:27][C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][S:2]([CH3:1])(=[O:4])=[O:3])=[C:21]([CH3:26])[CH:20]=3)[CH2:14][CH2:15][C:9]=2[CH:8]=1)(=[O:4])=[O:3]
Reactant: Cc1cc(OCCN2CCc3ccc(N)cc3CC2)ccc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1cc(OCCN2CCc3ccc(NS(C)(=O)=O)cc3CC2)ccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methanesulphonyl chloride (0.18 ml) was added dropwise to a solution of 7-amino-3-[2-(4-amino-3-methylphenoxy)ethyl]-1,2,4,5-tetrahydro-3H-3-benzazepine (0.36 g) in pyridine (30 ml) cooled to 0°, and the mixture was then stirred at room temperature for 72 hours. The solvent was evaporated in vacuo and the residue was taken up in methylene chloride and washed three times with saturated aqueous sodium bicarbonate and three times with brine. The organic layer was dried (Na2SO4), filtered and evaporated in vacuo to give an oil which was triturated with methylene chloride to give a solid. Recrystallisation of the solid from ethanol/ethyl acetate gave the title compound, yield 0.28 g, m.p. 173°-174°.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:12](=[O:13])[CH:11]=[N:10][C:9]2[CH:14]=[CH:15][C:16]([N:18]3[CH:22]=[N:21][CH:20]=[N:19]3)=[N:17][C:8]1=2.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].[OH-].[Na+]>C(OCC)(=O)C.O>[O:13]=[C:12]1[N:7]([CH2:6][CH:2]=[O:1])[C:8]2[N:17]=[C:16]([N:18]3[CH:22]=[N:21][CH:20]=[N:19]3)[CH:15]=[CH:14][C:9]=2[N:10]=[CH:11]1
Reactant: O=c1cnc2ccc(-n3cncn3)nc2n1CC1OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: O=CCn1c(=O)cnc2ccc(-n3cncn3)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 143.5 %

Procedure:
To 98 mg of 4-(1,3-dioxolan-2-ylmethyl)-6-(1H-1,2,4-triazol-1-yl)pyrido(2,3-b)pyrazin-3(4H)-one, 3 mL of an 80% aqueous trifluoroacetic acid solution was added, and the mixture was stirred at room temperature for 6 hours 30 minutes. Thereto were added water and ethyl acetate, and the mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and an aqueous sodium hydroxide solution. The organic layer was separated, and sodium chloride was added to the aqueous layer, and the mixture was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.12 g of (3-oxo-6-(1H-1,2,4-triazol-1-yl)pyrido(2,3-b)pyrazin-4(3H)-yl)acetaldehyde as a light red solid.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)[CH2:9][CH3:10].S(Cl)([Cl:22])=O>N1C=CC=CC=1>[CH2:8]([C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([Cl:22])=[O:19])[CH2:13][CH2:12]1)[CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCC[C@H]1CC[C@H](C(=O)Cl)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Toluene (1,000 ml) was added to trans-4-propylcyclohexanecarboxylic acid (1) (500.0 g) in a reaction vessel under an atmosphere of nitrogen, and the mixture was heated to 50° C. Pyridine (0.70 ml) and thionyl chloride (360.0 g) were then added, and the stirring was continued for 3 hours. The unreacted thionyl chloride and the toluene were distilled off at atmospheric pressure. The residue was distilled under reduced pressure (83° C., 3 mmHg) to give trans-4-propylcyclohexanecarboxylic acid chloride (2) (531.7 g) in 98% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:51]=[CH:52][CH:53]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:40]([C:43]3[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[CH:13]=2)[C:8]([CH3:50])=[N:7]1.[ClH:54]>CO.O1CCOCC1>[ClH:54].[F:1][C:2]1[CH:3]=[C:4]([CH:51]=[CH:52][CH:53]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:40]([C:43]3[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=3)(=[O:41])=[O:42])[CH:13]=2)[C:8]([CH3:50])=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Yield: 93.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (example 40 step 1) (232 mg, 0.315 mmol) was deprotected in methanol (5 ml), HCl in dioxane (5 ml). This afforded 198 mg (93.8% yield) of the titled compound. MS: m/z=651.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1([CH2:22][CH2:23][CH3:24])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[C:17](Br)[C:16]([F:20])=[CH:15][C:14]=3[CH3:21])[CH3:2].[C:26]([Cu])#[N:27]>CN1CCCC1=O.O>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1([CH2:22][CH2:23][CH3:24])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[C:17]([C:26]#[N:27])[C:16]([F:20])=[CH:15][C:14]=3[CH3:21])[CH3:2]
Reactant: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)cc(F)c(Br)c21
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)cc(F)c(C#N)c21
Temperature: 220 °C
Yield: 93.9 %

Procedure:
5-Bromo-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester (496 mg, 1.20 mmol) and CuCN (162 mg, 1.81 mmol) was dissolved in N-methyl-2-pyrrolidinone (6 mL) and the solution was divided into the 2 microwave reaction vessels (3.0 mL each). The reaction vessels were heated in microwave at 220° C. for 15 minutes. The reaction mixtures in 2 vessels were combined and then diluted with water (10 mL). The crude mixture was extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (silica, 25% EtOAc in hexanes) to give 404 mg (94%) of title compound as a white solid. 1H NMR (DMSO): 300 MHz δ 12.02 (bs, 1H), 11.33 (bs, 1H), 7.00 (d, J=9.00 Hz, 1H), 3.96 (m, 2H), 2.95 (d, J=10.3 Hz, 1H), 2.83 (t, J=3.9 Hz, 1H), 2.72 (d, J=10.3 Hz, 1H), 2.54 (s, 3H), 1.99 (m, 2H), 1.28 (m, 1H), 0.85 (m, 1H), 0.79 (t, J=5.41 Hz, 3H).