Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=23)=[N:5]1.C(N(CC)CC)C.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C)C=O>[CH2:38]([O:37][C:35]([CH2:34][NH:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=23)=[N:5]1)=[O:36])[CH3:39]
Reactant: CCOC(=O)CBr
Reactant: NCCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CNCCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of 3-[2-(2-aminoethyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]-pyridine (1.5 g), triethylamine (1.5 ml), and N,N-dimethylformamide (15 ml) was added ethyl 2-bromoacetate (0.60 ml), and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated, and the residue was partitioned between chloroform and water. The organic layer was separated, washed with sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated. Purification of the residue by column chromatography on silica gel (gradient elution, using 50:1 and 25:1 mixture of chloroform and methanol) gave 3-[2-{2-(ethoxycarbonylmethylamino)ethyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.90 g).
Reaction SMILES: [Pd:1](Br)Br.O.[CH2:5]1[CH2:9][O:8][CH:7]([N:10]2[C:16](=[O:17])[NH:15][C:13](=[O:14])[C:12]([F:18])=[CH:11]2)[CH2:6]1>[OH-].[NH4+]>[Pd:1].[CH2:5]1[CH2:9][O:8][CH:7]([N:10]2[C:16](=[O:17])[NH:15][C:13](=[O:14])[C:12]([F:18])=[CH:11]2)[CH2:6]1
Reactant: Br[Pd]Br
Agent: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: [Pd]
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
Palladium dibromide (0.377 g) is dissolved in 30% aqueous ammonium hydroxide (50 g) in a 250-mL flask equipped with a magnetic stir bar. Deionized water (60 g) is added to the solution, followed by addition of TS-1 (30 g, 2.12 wt. % titanium) over a 5 minute period. The slurry is stirred at 23° C. for 0.5 hr, then the solvent is removed by rotoevaporation at 55° C. The solids are dried in a vacuum oven (1 torr) at 50° C. for 4 hrs. The catalyst (Catalyst 3) analyzed for 0.5 wt % palladium, 2.1 wt % titanium, 0.7 wt % bromine and 0.37 wt % nitrogen.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([CH2:15][OH:16])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:23](Cl)([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>N1C=CC=CC=1>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([CH2:15][O:16][S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1CCCN(CC(c2ccccc2)c2ccccc2)C1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN(CC(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(2,2-Diphenylethyl)-3(S)-hydroxymethyl-piperidine (1.01 g, 3.41 mmol) was dissolved in dry pyridine (25 mL) and tosyl chloride (0.684 g, 3.58 mmol) was added to the solution After stirring at ambient temperature for 18 hr, the solution was concentrated, the residue taken up in EtOAc, washed with sat. NaHCO3 solution, H2O, brine, and dried (MgSO4). Filtration and concentration gave the title compound without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[N:11]=[C:12]([C:20]2[CH:21]=[C:22]([C:42]([F:45])([F:44])[F:43])[C:23]([O:26][CH2:27][CH2:28][O:29][C@@H:30]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]3)=[N:24][CH:25]=2)[C:13]2[CH:18]=[CH:17][N:16]([CH3:19])[C:14]=2[N:15]=1)#[N:9].C(#N)C.C(Cl)[Cl:50]>>[ClH:50].[CH3:19][N:16]1[C:14]2[N:15]=[C:10]([C:8]#[N:9])[N:11]=[C:12]([C:20]3[CH:25]=[N:24][C:23]([O:26][CH2:27][CH2:28][O:29][C@@H:30]4[CH2:34][CH2:33][NH:32][CH2:31]4)=[C:22]([C:42]([F:44])([F:45])[F:43])[CH:21]=3)[C:13]=2[CH:18]=[CH:17]1
Reactant: ClCCl
Reactant: Cn1ccc2c(-c3cnc(OCCO[C@@H]4CCN(C(=O)OC(C)(C)C)C4)c(C(F)(F)F)c3)nc(C#N)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cl
Product: Cn1ccc2c(-c3cnc(OCCO[C@@H]4CCNC4)c(C(F)(F)F)c3)nc(C#N)nc21
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl(3R)-3-(2-{[5-(2-cyano-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)pyridin-2-yl]oxy}ethoxy)pyrrolidine-1-carboxylate (240 mg) in CH2Cl2 (4 mL)-acetonitrile (1 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. After the reaction mixture was concentrated under reduced pressure, CH2Cl2 (4 mL) and a 4 M solution of hydrogen chloride in EtOAc (0.4 mL) were added to the residue at room temperature. The reaction mixture was concentrated under reduced pressure, and diisopropyl ether was added to the residue. The precipitate was collected by filtration, whereby 7-methyl-4-[6-{2-[(3R)-pyrrolidin-3-yloxy]ethoxy}-5-(trifluoromethyl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile monohydrochloride (208 mg) was obtained as a solid.
Reaction SMILES: [C:1]([CH:9]=[C:10]([CH3:21])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:22][CH2:23][C:24]([OH:26])=[O:25]>>[C:1]([CH2:9][C:10]([S:22][CH2:23][C:24]([OH:26])=[O:25])([CH3:21])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=CC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(O)CS
Product: CC(CC(=O)c1ccccc1)(SCC(=O)O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
As for Example 76, 1-(3-benzoyl-2-methylacryloyl)-L-proline is reacted with mercaptoacetic acid to give the product of the example as a glass.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12]([Cl:17])=[CH:11][CH:10]=1.[CH2:18]([OH:21])[C:19]#[CH:20].O>[Cu](I)I.C(OCC)(=O)C>[Cl:17][C:12]1[CH:11]=[CH:10][C:9]([C:20]#[C:19][CH2:18][OH:21])=[N:14][C:13]=1[O:15][CH3:16]
Reactant: C#CCO
Reactant: COc1nc(Br)ccc1Cl
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1nc(C#CCO)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
Triethylamine (70 mL) and bistriphenylphosphinepalladium(II) dichloride (756 mg) were added to 6-bromo-3-chloro-2-methoxypyridine (12.1 g), 2-propyn-1-ol (4.0 g) and copper iodide (210 mg) in a nitrogen atmosphere, and the mixture was stirred at room temperature for four hours. Water and ethyl acetate were added to the reaction solution, followed by filtration. The aqueous layer was adjusted to pH 3 or less with 1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3→5:5) to give the title compound as a light brown powder (8.60 g, 80%).
Reaction SMILES: C1N(COCCO)[C:4]2N=C(N)N=C(O)[C:3]=2N=1.[C:17]([NH:27][C@H:28]([C:33]([OH:35])=[O:34])[C@H:29]([CH2:31][CH3:32])[CH3:30])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:3]([O:34][C:33](=[O:35])[C@H:28]([C@H:29]([CH2:31][CH3:32])[CH3:30])[NH:27][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH3:4]
Reactant: Nc1nc(O)c2ncn(COCCO)c2n1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)CC
Temperature: 25 °C
Reaction time: 96 h
Yield: 61.4 %

Procedure:
A mixture of acyclovir (1.0 g, 4.4. mmol; Burroughs Wellcome Co.), 4-dimethylaminopyridine (74 mg, 0.6 mmol; Aldrich Chemical Co. and Chem. Ber. 89 2921-33 [1956]), 1,3-dicyclohexylcarbodiimidide (1.6 g, 8.0 mmol; Aldrich Chemical Co. and U.S. Pat. No. 2,656,383), N-carbobenzoxy-L-isoleucine (1.8 g, 6.6 mmol; Sigma Chemical Co. and Bull. Chem. Soc. Jap (1966) 39 947 or Tetrahedron 40 (24) 5207-11 [1984]), and molecular sieves (0.3 g, Davison type 3A; Fisher Scientific, Co.) in dry N,N-dimethylformamide (80 ml) was stirred at room temperature under nitrogen. After 4 days, additional 1,3-dicyclohexylcarbodiimide (1.6 g, 8.0 mmol) and N-carbobenzoxy-L-isoleucine (1.8 g, 6.6 mmol) were added. Stirring at room temperature was continued for 7 days. The resulting mixture was filtered and the clear filtrate was concentrated in vacuo to a semi-solid residue. Elution of the residue from silica gel 60 (EM, 230-400 mesh; 8.5×14 cm) with 2.5-5% methanol/methylene chloride gave 2-[2-Amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl-N-[(benzyloxy)carbonyl]-L-isoleucinate 0.8 g, 45%) as a white solid; mp 155°-157° C.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:6].C(N(CC)CC)C.[C:24](Cl)(=[O:27])[CH2:25][CH3:26].[OH-].[Na+]>O.CC(C)=O>[C:24]([C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:6])(=[O:27])[CH2:25][CH3:26]
Reactant: CCC(=O)Cl
Reactant: Nc1cccc(C(=O)Nc2ccccn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCC(=O)c1cccc(C(=O)Nc2ccccn2)c1
Temperature: 25 °C
Yield: 91.7 %

Procedure:
To a mixture of 2-aminopyridine (28.2 g), triethylamine (45 ml) and acetone (600 ml), 3-nitrobenzoyl chloride (55.8 g) was gradually added with stirring under ice cooling. The mixture was stirred for 30 minutes under the same condition, then for one hour at room temperature. Thereafter, the reaction solution was poured into 3 liters of water, and the resulting crystal was collected by filtration, washed with water, and recrystallized from methanol to provide 58.5 g of 3-nitro-N-2-pyridylbenzamide as a colorless acicular crystal (yield: 80%, m.p. 156°-157° C.). Hydrogen was bubbled into a mixture of the 3-nitro-N-2-pyridylbenzamide (15.9 g), 10% palladium-carbon (1.5 g) and ethanol (300 ml). After a stoichiometric amount of hydrogen was absorbed, the catalyst was removed, the reaction mixture was concentrated under vacuum, and the residue was recrystallized from ethanol to provide 7.2 g of a colorless acicular crystal of 3-amino-N-2-pyridylbenzamide (yield: 52%, m.p. 113°-115° C.). To a mixture of the 3-amino-N-2-pyridylbenzamide (6.4 g), triethylamine (4.5 ml) and acetone (60 ml), propionic acid chloride (2.8 g) was gradually added with stirring at room temperature. After one hour of stirring, the reaction mixture was poured into 200 ml of water which was then made weakly alkaline by gradually adding a 10% solution of sodium hydroxide. The resulting crystal was collected by filtration, washed with water and recrystallized from methanol to provide 7.0 g of 3-propionyl-N-2-pyridylbenzamide as a colorless acicular crystal (compound 1) (yield: 87%, m.p. 128°-129° C.).
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([C:16](Cl)=[O:17])=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C>CO.O>[CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([CH2:16][OH:17])=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1cccc2c1CCCc1ccccc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: OCc1cccc2c1CCCc1ccccc1-2

Procedure:
The reaction of 6,7-dihydro-5H-dibenzo[a,c]cycloheptene-4-carbonyl chloride (3.5 grams, 0.014 mole), lithium aluminum hydride (0.6 grams, 0.016 mole), and diethyl ether (100 ml) gave a yellow oil. The oil was dissolved in methanol/water, and the solution was extracted with diethyl ether. The extract was dried over anyhydrous magnesium sulfate and filtered. The filtrate was evaporated to give 6,7-dihydro-5H-dibenzo[a,c]cycloheptene-4-methanol as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5](=O)[CH:6]([CH3:10])[C:7](=O)[CH3:8])[CH3:2].C(=O)(O)[O-].[C:19]1([NH:25][C:26]([NH2:28])=[NH2+:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH3:10][C:6]1[C:5]([CH:4]([O:12][CH2:13][CH3:14])[O:3][CH2:1][CH3:2])=[N:27][C:26]([NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:28][C:7]=1[CH3:8]
Reactant: NC(=[NH2+])Nc1ccccc1
Reactant: CCOC(OCC)C(=O)C(C)C(C)=O
Agent: O=C([O-])O
Solvent: CCO
Product: CCOC(OCC)c1nc(Nc2ccccc2)nc(C)c1C
Temperature: 75 °C
Yield: 114.6 %

Procedure:
A mixture of 44 g (purity about 50%, about 0.11 mol) of 1,1-diethoxy-3-methylpentane-2,4-dione (crude product, Example 2a) and 35 g (0.175 mol) of phenylguanidinium bicarbonate in 300 ml of ethanol was heated at 70-80° C. for about 3 hours. The reaction mixture was then concentrated and the residue was filtered, with suction, through silica gel using methyl tert-butyl ether. The solvent was evaporated. Less volatile components were distilled off under a pressure of 0.3 mbar, at a bath temperature of 150° C. The residue obtained was 38 g (quantitative yield) of the title compound as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH2:9][C:10](=[O:13])[NH:11][N:12]=2)=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:24][Br:25])=[O:23])=[CH:18][CH:17]=1>C(O)C>[Br-:25].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:24][N+:1]2[CH:2]=[CH:3][C:4]([C:7]3[S:8][CH2:9][C:10](=[O:13])[NH:11][N:12]=3)=[CH:5][CH:6]=2)=[O:23])=[CH:18][CH:17]=1
Reactant: O=C1CSC(c2ccncc2)=NN1
Reactant: COc1ccc(C(=O)CBr)cc1
Solvent: CCO
Product: COc1ccc(C(=O)C[n+]2ccc(C3=NNC(=O)CS3)cc2)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-(4-Pyridyl)-4H,6H-1,3,4-thiadiazin-5-one (1.88 g, 9.74 mmol) and 4'-methoxyphenacyl bromide (2.23 g, 9.74 mmol) were dissolved in absolute ethanol (40 ml) and stirred at room temperature for one day. The resultingprecipitate was collected by filtration and washed with absolute ethanol toobtain the titled compound (3.84g) as yellow powder.
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].[CH3:4][C:5]([CH3:10])([CH3:9])[C:6](Cl)=[O:7]>C(OCC)C>[N+:1](=[CH:3][C:6](=[O:7])[C:5]([CH3:10])([CH3:9])[CH3:4])=[N-:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: CC(C)(C)C(=O)C=[N+]=[N-]
Reaction time: 16 h
Yield: 100 %

Procedure:
To the diazomethane solution at 0° C. was added a solution of 1.23 mL (1.21 g, 10 mmol, Aldrich) of trimethylacetyl chloride in 1 mL of diethyl ether dropwise with stirring. The resulting mixture was kept at 0° C. for 16 h. The solution was sparged with argon to remove the excess diazomethane and diethyl ether was removed under reduced pressure to give 1.33 g (10 mmol, 100%) of crude 1-diazo-3,3-dimethyl-2-butanone as a yellow liquid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:13]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]=3)[NH:14]2)[CH:10]=[CH:11][CH:12]=1>N1C=CC=CC=1>[CH3:23][C:22]1([CH3:24])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]=2)[NH:14][CH:13]1[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Solvent: c1ccncc1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
In a round-bottomed flask, methanesulfonyl chloride (0.07 mL, 0.84 mmol) was added dropwise to a solution of 2-(3-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (0.1 g, 0.34 mmol) in dry pyridine (2 mL) was allowed to stir at room temperature for 1 h. The pyridine was removed under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=1:1) to afford 3,3-dimethyl-2-(3-(methylsulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid (27 mg, yield: 21.3%); MS (ES+APCI) M+1=375.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:19])[CH:3]=1.[H-].[Na+].BrC=[CH:24][CH2:25][CH3:26].[CH2:27]1COCC1>>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:27][C:25]([CH3:24])=[CH2:26])[C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)[CH:5]=[C:4]([CH3:19])[CH:3]=1
Reactant: Cc1cc(Cl)nc(Nc2ccc(C(F)(F)F)cc2)c1
Reactant: C1CCOC1
Reactant: CCC=CBr
Agent: [H-]
Agent: [Na+]
Product: C=C(C)CN(c1ccc(C(F)(F)F)cc1)c1cc(C)cc(Cl)n1
Yield: 68 %

Procedure:
To a solution of (6-chloro-4-methyl-pyridin-2-yl)-(4-trifluoromethyl-phenyl)-amine (290 mg, 1.0 mmol) in THF (10 mL) was added NaH (60%, 80 mg, 2.0 mmol) and 1-bromo-3-methylpropene (150 mg, 1.1 mmol). The mixture was microwaved 20 minutes at 120° C. and concentrated. The residue was purified by chromatography on silica gel (10-30% CH2Cl2 in heptane) to give the product as a colorless oil (230 mg, 68%). 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J=8.29 Hz, 2H), 7.34 (d, J=8.67 Hz, 2H), 6.59 (s, 1H), 6.45 (s, 1H), 4.81 (d, J=15.07 Hz, 2H), 4.55 (s, 2H), 2.18 (s, 3H), 1.76 (s, 3H). MS m/e 341.1 (M+H),
Reaction SMILES: [CH:1]([N-]C(C)C)([CH3:3])[CH3:2].[Li+].[Cl:9][C:10]1[CH:31]=[CH:30][C:13]2[C:14]3[C:15](=[CH:26][NH:27][C:28]=3[CH3:29])[CH2:16][N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:12]=2[CH:11]=1.C(Br)C#C.O>O1CCCC1.C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:31]=[CH:30][C:13]2[C:14]3[C:15](=[C:26]([CH2:3][C:1]#[CH:2])[NH:27][C:28]=3[CH3:29])[CH2:16][N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:12]=2[CH:11]=1
Reactant: Cc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reactant: CC(C)[N-]C(C)C
Agent: C#CCBr
Agent: [Li+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C#CCc1[nH]c(C)c2c1CN=C(c1ccccc1F)c1cc(Cl)ccc1-2
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
By means of a syringe 7 ml (4.2 mmole) of a 0.62 M tetrahydrofuran solution of lithium diisopropylamide was added dropwise to a solution of 1.3 g (4.0 mmole) of 8-chloro-6-(2-fluorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine in 30 ml of dry tetrahydrofuran which was cooled to -20° C. The solution was stirred at -20° C. for 5 minutes followed by the addition of 2.4 ml (25 mmole) of 80% propargyl bromide in toluene. The mixture was allowed to warm to room temperature and stirred for 2 hours. Water was added and the mixture was extracted with ether. The ether solution was washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give an amber foam. Purification by column chromatography (silica gel, 20 g; eluent 5% ether in methylene chloride) gave a foam. Crystallization from a mixture of ether and petroleum ether gave cream prisms, (mp 179-180).
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)C=1.[S:12]([O-:16])([O-])(=O)=[O:13].[Mg+2].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:27]2[C:31]([C:32]3[CH:37]=[CH:36][N:35]=[C:34](SC)[N:33]=3)=[CH:30][N:29]([CH2:40][C:41]#[N:42])[N:28]=2)[CH:23]=[C:24]([CH3:26])[CH:25]=1>ClCCl>[CH3:2][S:12]([C:34]1[N:33]=[C:32]([C:31]2[C:27]([C:22]3[CH:23]=[C:24]([CH3:26])[CH:25]=[C:20]([O:19][CH3:18])[CH:21]=3)=[N:28][N:29]([CH2:40][C:41]#[N:42])[CH:30]=2)[CH:37]=[CH:36][N:35]=1)(=[O:16])=[O:13]
Reactant: O=S(=O)([O-])[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(C)cc(-c2nn(CC#N)cc2-c2ccnc(SC)n2)c1
Agent: [Mg+2]
Solvent: ClCCl
Product: COc1cc(C)cc(-c2nn(CC#N)cc2-c2ccnc(S(C)(=O)=O)n2)c1
Yield: 70.5 %

Procedure:
m-Chloroperbenzoic acid (4.71 g, 27.3 mmol) and anhydrous magnesium sulfate (6.57 g, 54.6 mmol) in dichloromethane (100 mL) were dissolved at room temperature for 1 hour with stirring. To this solution was added [3-(3-methoxy-5-methylphenyl)-4-(2-methylthio-pyrimidin-4-yl)pyrazol-1-yl]acetonitrile (1.6 g, 4.55 mmol) which was subjected to oxidation to sulfone by stirring for an additional two hours. After completion of the reaction, the precipitate was filtered off and washed with dichloromethane. The filtrate was washed with brine and dichloromethane, and the organic layer was separated, dried over anhydrous magnesium sulfate and concentrated through vacuum distillation. The residue was purified by column chromatography to give the title compound (1.23 g, 70.4%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:16][NH2:17]>C1COCC1>[Br:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][C:5]([NH:16][NH2:17])=[N:6][CH:7]=1
Reactant: Clc1ccc(-c2cc(Cl)ncc2Br)cc1
Reactant: NN
Solvent: C1CCOC1
Product: NNc1cc(-c2ccc(Cl)cc2)c(Br)cn1
Temperature: 20 °C
Yield: 63.9 %

Procedure:
To a solution of 5-bromo-2-chloro-4-(4-chlorophenyl)pyridine (1.3 g, 4.3 mmol) in THF (10 mL) was added hydrazine (1.4 g, 43 mmol). The reaction mixture was refluxed under argon for 4 days, then allowed to cool to 20° C. and concentrated in vacuo. The residue was purified by using reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C18 30×100 mm; Eluted with 0% to 100% B, 10 min gradient, 100% B hold for 5 min, (A=90% H2O, 10% CH3CN, 0.1% trifluoroacetic acid and B=10% H2O, 90% CH3CN, 0.1% trifluoroacetic acid); Flow rate at 40 mL/min, UV detection at 220 nm), followed by basification with 1N aqueous NaOH to pH 12 and extraction with CHCl3 to afford 0.82 g (63%) of the title compound as an off-white solid. LC/MS (method B): retention time=1.47 min, [M+H]+=298.0.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH:33]([CH3:35])[CH3:34]>CN(C)C=O>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH:33]([CH3:35])[CH3:34])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:27])[CH3:28])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)C1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCC(N(C)C)C3)ccc21
Yield: 35 %

Procedure:
The title compound was synthesized in analogy to example 51, from (RS)-(4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 42, intermediate a)), sodium hydride and 2-bromopropane in N,N-dimethylformamide, to give the desired product as a colorless foam (35%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([C:16]([F:19])([F:18])[F:17])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][CH:21]([CH3:39])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[N:28]=[N:29][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:31][CH:32]=1)=[O:26]>>[CH3:20][CH:21]([CH3:39])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[N:28]=[N:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([C:13]([C:12]3[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[N:9]=[N:10][C:11]=3[C:16]([F:19])([F:18])[F:17])=[O:15])[CH2:35][CH2:34]2)=[CH:31][CH:32]=1)=[O:26]
Reactant: O=C(O)c1c(C(F)(F)F)nnn1Cc1ccccc1
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3c(C(F)(F)F)nnn3Cc3ccccc3)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 3-benzyl-5-trifluoromethyl-3H-[1,2,3]triazole-4-carboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white powder (37% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.04, 7.83, 7.36, 7.28, 6.99, 5.69, 3.94, 3.84, 3.70, 3.46, 1.75-1.61, 1.49, 0.91. MS (ES+) m/z 531.2 (M+1).