Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:13][S:14][C:15](=[N:18][C:19]#[N:20])SC>C(O)C>[C:19]([NH:18][C:15](=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][N:7]=1)[S:14][CH3:13])#[N:20]
Reactant: NCCSCc1ncccc1O
Reactant: CSC(=NC#N)SC
Solvent: CCO
Product: CSC(=NCCSCc1ncccc1O)NC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
A solution of 2-((2-aminoethyl)thiomethyl)-3-hydroxypyridine (7.5 g) in ethanol was added slowly to a solution of dimethylcyanodithioimidocarbonate (6.0 g) in ethanol, with stirring at room temperature. The mixture was set aside overnight at room temperature. Filtration afforded N-cyano-N'-[2-((3-hydroxy-2-pyridyl)methylthio)-ethyl]-S-methylisothiourea (4.85 g), m.p. 192°-194°. Recrystallisation from aqueous ethanol gave fine needles, m.p. 196°-198°.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:40])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([NH:14][C:12]1[C:11]([C:19]([F:22])([F:20])[F:21])=[CH:10][C:9]2[NH:23][C:24](=[O:40])[CH2:25][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[CH:28]=3)=[N:7][C:8]=2[CH:13]=1)[CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CNc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccncc3)c1)=N2

Procedure:
The title compound was prepared from {5-isobutylamino-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M59) (0.56 g, 0.98 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (299 mg, 67%).
Reaction SMILES: [CH2:1]([O:4][NH:5][CH:6]1[CH2:11][NH:10][C@@H:9]([C:12]([NH2:14])=[O:13])[CH:8]=[C:7]1[CH:15]1[CH2:17][CH2:16]1)[CH:2]=[CH2:3].[CH2:18]([O:21]N1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O)C=C>>[CH2:1]([O:4][N:5]1[C:18](=[O:21])[N:10]2[CH2:11][C@H:6]1[C:7]([CH:15]1[CH2:16][CH2:17]1)=[CH:8][C@H:9]2[C:12]([NH2:14])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCONC1CN[C@@H](C(N)=O)C=C1C1CC1
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O
Product: C=CCON1C(=O)N2C[C@H]1C(C1CC1)=C[C@H]2C(N)=O

Procedure:
The title compound was prepared from (R)-5-(allyloxyamino)-4-cyclopropyl-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 270, 0.307 g, 1.29 mmol) following the procedure described for Intermediate 16. The desired product was obtained as a yellow oil (0.168 g, 49%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:12]=2)[NH:7][C:6]=1[CH2:20]C.C1(OC2C=C3C(=CC=2)NC(CC)=C3)CCCC1.C([Li])CCC.BrCC(OC)=O>CCCCCC.CCOCC.[Cl-].[Cl-].[Zn+2]>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:12]=2)[NH:7][C:6]=1[CH3:20]
Reactant: CCc1[nH]c2ccc(OC3CCCC3)cc2c1CC(=O)OC
Agent: CCc1cc2cc(OC3CCCC3)ccc2[nH]1
Agent: COC(=O)CBr
Agent: [Cl-]
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(=O)Cc1c(C)[nH]c2ccc(OC3CCCC3)cc12

Procedure:
5-Cyclopentoxy-2-ethyl-1H-indole-3-acetic acid methyl ester. As in Example 1, Part E, 2.33 g (0.0102 mol) of 5-cyclopentoxy-2-ethyl-1H-indole was treated with 6.4 mL (0.0102 mol) of a 1.6M solution of n-butyl lithum in hexane, 10.2 mL (0.0102 mol) of a 1M solution of ZnCl2 in ether, and 0.97 mL (0.0102 mol) of methyl 2-bromoacetate to give after chromatography on silica (5% EtOAc/toluene) 1.8 g (59%) of 5-cyclopentoxy-2-methyl-1H-indole-3-acetic acid methyl ester as an oil.
Reaction SMILES: [C:1]([OH:6])(=O)/[CH:2]=[CH:3]/[CH3:4].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:18][C:19]1[CH:20]=[C:21]([OH:26])[CH:22]=[CH:23][C:24]=1[CH3:25]>CN(C)C=O.CN(C)C(=O)C>[OH:26][C:21]1[CH:22]=[CH:23][C:24]([CH3:25])=[C:19]([NH:18][C:1](=[O:6])/[CH:2]=[CH:3]/[CH3:4])[CH:20]=1
Reactant: C/C=C/C(=O)O
Reactant: Cc1ccc(O)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: C/C=C/C(=O)Nc1cc(O)ccc1C
Yield: 59.8 %

Procedure:
In the same manner as in Example 259 and using (2E)-but-2-enoic acid (1680 mg, 19 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (1670 μL, 19 mmol), 3-amino-4-methylphenol (2000 mg, 16 mmol) and N,N-dimethylacetamide (35 mL) as starting materials, the title compound (1830 mg, 59%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:29]=[CH:28][C:23]3[N:24]=[C:25]([CH3:27])[S:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C[C:32]([N:34](C)C)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.[Zn]>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:32]#[N:34])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:29]=[CH:28][C:23]3[N:24]=[C:25]([CH3:27])[S:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)N(C)C
Reactant: CCCCOC(=O)c1nc(Cl)c2ccc(Oc3ccc4nc(C)sc4c3)cc2c1O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc4nc(C)sc4c3)cc2c1O
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 1-chloro-4-hydroxy-6-(2-methyl-benzothiazol-6-yloxy)-isoquinoline-3-carboxylic acid butyl ester (369 mg, 0.84 mmol), tris(dibenzylideneacetone)dipalladium(0) (38 mg, 0.04 mmol), 1,1′-bis(diphenylphosphino)ferrocene (46 mg, 0.08 mmol), zinc cyanide (59 mg, 0.50 mmol), zinc (6 mg, 0.10 mmol) and dimethylacetamide (2 mL) was stirred at 120° C. for two hours and twenty minutes before it was cooled to room temperature, partitioned between ethyl acetate and water, and filtered. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (245 mg): MS: (+) m/z 434.30 (M+1).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Cl.C(O[C:13](=N)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])C>CCO>[N:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:13]=1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=N)CC(=O)OCC
Reactant: Nc1ccccc1N
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1nc2ccccc2[nH]1
Temperature: 25 °C

Procedure:
A solution of 1,2-phenylenediamine (1.0 eq) and ethyl 3-ethoxy-3-iminopropanoate hydrochloride (1.3 eq) in EtOH was stirred at 90° C. overnight. The reaction was cooled to room temperature and the solvent removed in vacuo. Water and CH2Cl2 were added to the residue. The organic layer was separated, dried over Na2SO4 and the solvent removed. The solid recovered was used without purification. LC/MS m/z 205.2 (MH+), Rt 1.44 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[C:4]([CH3:13])[CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]3[C:30]4[C:35]([CH:36]=[CH:37][C:22]2=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:16]=1.ClC1C=CC(OCC(Cl)=O)=C(C)C=1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]4[C:30]5[C:35]([CH:36]=[CH:37][C:22]3=4)=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:17][CH:16]=2)=[O:10])=[C:4]([CH3:13])[CH:3]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: Cc1cc(Cl)ccc1OCC(=O)O
Agent: Cc1cc(Cl)ccc1OCC(=O)Cl
Product: Cc1cc(Cl)ccc1OCC(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 99 %

Procedure:
(4-Chloro-2-methylphenoxy)acetic acid (38 mg, 0.189 mmol) was made into acid chloride in a conventional manner. By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, and (4-chloro-2-methylphenoxy)acetic acid chloride mentioned above, the title compound (47 mg, yield 99%) was obtained in the same manner as that of Example 1.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH:8](Br)[C:9]([C:11]([F:14])([F:13])[F:12])=O.[NH2:16][CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[F:28])[C:18]([NH2:20])=[O:19].Cl>O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:17]2[C:18](=[O:19])[NH:20][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][N:16]=2)=[C:22]([F:28])[CH:23]=1
Reactant: NC(=O)C(N)c1ccc(Cl)cc1F
Reactant: O=C(C(Br)Br)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c(C(F)(F)F)cnc1-c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of 35.5 g of sodium carbonate and 120 ml of water was added dropwise 22.7 g of 1,1-dibromo-3,3,3-trifluoroacetone at such a rate that the temperature of the reaction mixture became not higher than 55° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes, followed by adding 150 ml of water and then 12.8 g of 2-amino-2-(4-chloro-2-fluorophenyl)acetamide, and the reaction was allowed to proceed at 60° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to 10° C. or lower, made acidic by adding 20 ml of concentrated hydrochloric acid at the same temperature, and extracted with ethyl acetate. The organic layer was washed with water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=4:1), which afforded 5.83 g (yield, 32%) of the desired compound, 3-(4-chloro-2-fluorophenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (compound 1-1005; m.p., 83.2° C.). The continued elution with the above solvent system gave 4.32 g of the configurational isomer, 3-(4-chloro-2-fluorophenyl)-5-trifluoromethyl-2-oxo-1,2-dihydropyrazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].S(=O)(=O)(O)O.[N+:24]([O-])([OH:26])=[O:25]>O>[Cl:1][C:2]1[C:14]([C:15]([F:16])([F:17])[F:18])=[CH:13][C:12]([N+:24]([O-:26])=[O:25])=[C:4]([CH:3]=1)[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C=Cc1ccc(C(F)(F)F)c(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C=Cc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
To a solution of 100 mg of ethyl 3-chloro-4-trifluoromethylcinnamate and 1.8 ml of concentrated sulfuric acid was added 42 ml of 60% nitric acid at -15° C. After stirring at the same temperature for a few minutes, the reaction mixture was poured into a cold water, and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated. The residue was purified by a silica gel column chromatography to give 102 mg of ethyl 5-chloro-2-nitro-4-trifluoromethylcinnamate.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C@@H:37]5[CH2:41]CCO5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].O1CC[CH2:48][C@H:47]1CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C@@H:37]([CH3:41])[CH2:47][CH3:48])[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:12])=[O:11])[CH3:9]
Reactant: NC[C@@H]1CCCO1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)CNCc1cc(F)cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Yield: 41.7 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting (2S)-2-methyl-1-butanamine (45 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 23.3 mg of the title compound (41.7%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.Cl.[CH3:42][N:43]([CH3:50])[CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:47]1[CH2:48][CH2:49][CH:44]([N:43]([CH3:50])[CH3:42])[CH2:45][CH2:46]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Reactant: CN(C)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)N3CCC(N(C)C)CC3)ccc2[nH]1
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-dimethylamino-piperidine dihydrochloride (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light yellow foam (67%).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[O-:2].[C:6]1([C:12]2[CH:17]=[C:16](C3C=CC=CC=3)C=C(C3C=CC=CC=3)[O+]=2)[CH:11]=C[CH:9]=[CH:8][CH:7]=1.C(O)C.[CH2:33]([C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].NC1C=CC=CC=1>C(#N)C>[S:1](=[O:3])(=[O:2])([OH:5])[O-:4].[CH2:33]([C:43]1[CH:44]=[CH:45][C:46]([N+:47]2[C:17]([CH3:16])=[CH:12][C:6]([CH3:11])=[CH:7][C:8]=2[CH3:9])=[CH:48][CH:49]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: c1ccc(-c2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cc1
Reactant: CCCCCCCCCCc1ccc(N)cc1
Agent: O=S(=O)([O-])O
Solvent: CC#N
Solvent: CCO
Solvent: Nc1ccccc1
Product: CCCCCCCCCCc1ccc(-[n+]2c(C)cc(C)cc2C)cc1

Procedure:
In a 500-ml round-bottom flask is placed 2.03 g (0.005 mole) of 2,4,6-triphenylpyrylium bisulfate. To this is added 150 ml of ethanol followed by 2.34 g (0.01 mole) of p-decylaniline. This mixture is refluxed for about 8 hours and allowed to cool. A quantity of the starting aniline precipitates and is removed by filtration. The ethanol is then removed to give a yellow waxy material which is washed with ether to give a white powder. This material is then dissolved in acetonitrile to cause the remaining aniline to precipitate. The acetonitrile is removed to give the desired product which is then rinsed with ether to remove any residual acetonitrile. The yield is 1.77 g (0.0028 mole) of 2,4,6-triphenylpyridinium bisulfate as confirmed by nuclear magnetic resonance (1H) and elemental analysis.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([CH3:9])([OH:8])[CH2:4][N+:5]([O-])=O.[H][H].[ClH:14]>C(O)C.CO.[Pd]>[ClH:14].[NH2:5][CH2:4][C:3]([CH3:9])([OH:8])[C:2]([F:11])([F:10])[F:1]
Reactant: [H][H]
Reactant: CC(O)(C[N+](=O)[O-])C(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CC(O)(CN)C(F)(F)F
Reaction time: 48 h

Procedure:
Pd/C was added (1 g) to a 200 ml glass vessel. Ethanol (50 ml, dry) was added cautiously under an atmosphere of CO2. 1,1,1-Trifluoro-2-methyl-3-nitropropan-2-ol (10 g, 57.8 mmol) was dissolved in ethanol (50 ml, dry) and added to the glass vessel. The reaction mixture was put under a positive pressure of hydrogen (5 bar) at room temperature and hydrogenated for 2 days. The reaction mixture was filtered through Celite® (filter material) and washed with excess ethanol. The solvent was removed in vacuo to yield a colourless oil. The oil was dissolved in MeOH (50 ml) and treated dropwise with HCl (1M) in MeOH (30 ml). The solution was left to stir for 30 minutes and concentrated in vacuo azeotroping with MeCN to afford the title compound as a waxy white solid; 1H NMR (DMSO-d6, 400 MHz) δ 8.3 (3H, broad s), 6.9 (1H, broad), 3.0 (2H, q), 1.4 (3H, s).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>>[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5])=[O:17]
Reactant: N#Cc1c(F)cc(Cl)cc1Br
Reactant: O=C(Cl)c1cccc(Br)c1
Product: N#Cc1c(F)cc(Cl)cc1C(=O)c1cccc(Br)c1
Yield: 55 %

Procedure:
The title compound was synthesized as described for Example 64i in 55% yield starting from 2-bromo-4-chloro-6-fluorobenzonitrile (6.35 g, 27.08 mmol) and 3-bromobenzoyl chloride (3.58 mL, 27.08 mmol).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C([Mg]Cl)(C)C.CON(C)[C:18](=[O:20])[CH3:19].[NH4+].[Cl-]>C1COCC1>[N:4]1([CH2:1][C:2]#[C:3][C:18](=[O:20])[CH3:19])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: C#CCN1CCOCC1
Reactant: CON(C)C(C)=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)C#CCN1CCOCC1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
4-Prop-2-ynyl-morpholine (22 g, 176 mmol) was dissolved under nitrogen in THF (40 mL) and cooled to −40° C. Then a 2 M solution of isopropyl magnesium chloride in THF (97 mL, 193 mmol) was added while keeping the temperature below −20° C. Stirring at −40° C. to −30° C. was continued for 30 min. In a separate flask, N-methoxy-N-methylacetamide (20 g, 193 mmol) was dissolved under nitrogen in THF (40 mL) and cooled to −10° C. in ice/MeOH. The Grignard solution prepared above was transferred to the Weinreb amide solution at −10° C. via teflon tubing under slightly positive nitrogen pressure in vessel 1. There was no exotherm. Stirring at −10° C. to 0° C. was continued for 2 h. Ther resulting white suspension was poured on a 1:1-mixture of ice and saturated NH4Cl solution (400 mL). Extraction: 2×AcOEt, 1× saturated NaCl solution. One obtained a yellow oil (26.1 g, 89%). Chromatography on silica gel in heptane/ethyl acetate 1:2 gave 19.4 g (66%) of a brown oil which was distilled in the Kugelrohr at 130° C./0.2 mbar. One obtained 15.8 g (53%) of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:23][S:24]([Cl:27])(=[O:26])=[O:25].[ClH:28]>>[ClH:27].[ClH:28].[CH2:16]([N:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:7][CH:6]=2)[CH2:13][CH2:12]1)[CH3:15])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(Cc1ccccc1)C1CCN(c2ccc(N)cc2)CC1
Agent: Cl
Product: CN(Cc1ccccc1)C1CCN(c2ccc(NS(C)(=O)=O)cc2)CC1

Procedure:
The product from Example 8 was reacted in a similar manner to Example 4 with methanesulfonyl chloride and then converted into the hydrochloride. 4-(N-Benzyl-N-methylamino)-1-(4-methanesulfonylaminophenyl)piperidine dihydrochloride was obtained. Melting point 221° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9](Cl)=[C:8]2[C:3]=1[C:4](=[O:18])[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:7]2.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCCC1>[CH2:16]([O:15][C:13]([C:6]1[O:7][C:8]2[C:3]([C:4](=[O:18])[CH:5]=1)=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=2[N:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1)=[O:14])[CH3:17]
Reactant: CCOC(=O)c1cc(=O)c2c(C)ccc(Cl)c2o1
Reactant: CN1CCNCC1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCC1)C1CCCC1
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(=O)c2c(C)ccc(N3CCN(C)CC3)c2o1
Temperature: 80 °C
Reaction time: 96 h

Procedure:
Ethyl 5-methyl-8-chloro-4-oxo-4H-chromene-2-carboxylate (1.0 g, 3.6 mmol) as prepared in Reference Example 6c above, was azeotroped with anhydrous toluene then the white solid was dissolved in 100 ml anhydrous toluene in a 250 mL single-neck round bottom flask. The mixture was degassed by alternating argon sparge and vacuum (3×), and the following were added in order: N-methylpiperazine (0.6 ml, 5.37 mmol), (2′-dicyclohexylphosphanyl-biphenyl-2-yl)dimethyl-amine (JACS 1998, 120, p 9722) (40 mg, 0.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (66 mg, 0.072 mmol) then cesium carbonate (1.6 g, 5.37 mmol). The mixture was again degassed via alternating argon sparge and vacuum and was heated at 80° C. for 17 h. Additional tris(dibenzylideneacetone)dipalladium(0) (66 mg, 0.072 mmol) and (2′-dicyclopentylphosphanyl-biphenyl-2-yl)-dimethyl-amine (40 g, 0.1 mmol) were added and the reaction was stirred at 80° C. for another four days at which time the conversion was still only about 50% complete by HPLC. Tetrahydrofuran (100 mL) was added, and the combined mixture was filtered, concentrated under vacuum and purified by chromatography on silica eluted with 2.5% methanol in chloroform. The desired fractions were concentrated under vacuum to yield a yellow powder (250 mg=21%).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Cl:9][C:10]1[N:19]=[CH:18][C:17]2[C:12](=[C:13]([OH:20])[CH:14]=[CH:15][CH:16]=2)[N:11]=1.C(NC(C)C)(C)C>C(Cl)(Cl)Cl>[Br:8][C:14]1[C:13]([OH:20])=[C:12]2[C:17]([CH:18]=[N:19][C:10]([Cl:9])=[N:11]2)=[CH:16][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1cccc2cnc(Cl)nc12
Solvent: ClC(Cl)Cl
Solvent: CC(C)NC(C)C
Product: Oc1c(Br)ccc2cnc(Cl)nc12
Temperature: -2.5 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
Solid NBS (1.09 g, 6.11 mmole) was added to a stirred solution of 2-chloroquinazolin-8-ol (1.10 g, 6.11 mmole) and diisopropyl amine (2.2 mL, 15.30 mmole) in CHCl3 (60 mL) at −5° C. under argon. After stirring at −5 to 0° C. for 1 hour, LCMS showed that the reaction was complete. The reaction was evaporated to a residue which was dissolved in DMSO (5 mL) and purified by prep. HPLC. The pure product was obtained as a white solid in 51% yield (800 mg, 3.08 mmole).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=O)[C:8]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].O.NN.O.[CH2:24](O)CO>>[CH3:24][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8](=[O:17])[CH2:9]2
Reactant: O=C1C(=O)N(c2ccccc2)c2ccccc21
Reactant: OCCO
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(c1)CC(=O)N2c1ccccc1

Procedure:
A suspension of 1-phenyl-1H-indole-2,3-dione (1.908 g, 11.83 mmol) in ethylene glycol (30 mL) is treated with powdered potassium hydroxide (1.92 g, 112 mmol), hydrazine hydrate (16.35 mL) and water (4 mL) as described hereinabove. The crude product is purified by flash chromatography eluting with dichloromethane. Product containing fractions are combined, concentrated and the residue is triturated with pentane to afford 5-methyl-1-phenyl-1H-indol-2-one as an off-white solid. MS 224 (M+1)