Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:20]=[CH:19][C:8]([CH:9]=[CH:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[CH2:4].[Br-].[C:22]([C:26]1[CH:51]=[CH:50][C:29]([CH2:30][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:27]=[CH:28][C:29]([CH:30]=[CH:15][C:14]2[CH:17]=[CH:18][C:11]([CH:10]=[CH:9][C:8]3[CH:7]=[CH:6][C:5]([CH:3]=[CH2:4])=[CH:20][CH:19]=3)=[CH:12][CH:13]=2)=[CH:50][CH:51]=1)([CH3:23])([CH3:24])[CH3:25]
Reactant: C=Cc1ccc(C=Cc2ccc(C=O)cc2)cc1
Reactant: CC(C)(C)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Product: C=Cc1ccc(C=Cc2ccc(C=Cc3ccc(C(C)(C)C)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Solid NaH (396 mg, 16.5 mmol) was added in small portions into a suspension of 4-(4′vinylstyryl)benzaldehyde (703 g, 3.0 mmol) and 4-tert-butylbenzyltriphenylphosphonium bromide (1.61 g, 3.3 mmol). The reaction mixture was stirred under nitrogen at room temperature for 24 hours. The reaction was quenched slowly with water, extracted with CHCl3, washed with brine, and the solvent was evaporated under reduced pressure to dryness. To the residue, 100 mL of dry toluene was added and evaporated to dryness. The light yellow solid was triturated with ethanol, filtered to give light yellow solid (which is the all-trans isomer by NMR). The filtrate was concentrated and purified with silica gel chromatography (10-20% CHCl3/hexanes) to give another portion of product (a mixture of cis and trans isomers). Yield: 1.1 g (>99%). 1H NMR (CDCl3) of the all-trans isomer: δ 7.51 (s, 4H), 7.49, 7.47 (d, J=8.46 Hz, 4H), 7.41, 7.39 (d, J=8.45 Hz, 4H), 7.13, 7.07 (d, J=16.28 Hz, 2H), 7.11 (s, 2H), 6.72 (dd, J1=10.85 Hz, J2=17.55 Hz, 1H), 5.78 (d, J=17.55 Hz, 1H), 5.26 (d, J=10.85 Hz, 1H), 1.34 (s, 9H). The compound is too insoluble for 13C NMR spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:23]([Cl:38])=[CH:22][N:21]=1>>[Cl:38][C:23]1[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[N:25][C:20]([NH:1][C:2]2[CH:18]=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:15])[CH3:16])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:21][CH:22]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CN(C)C(=O)CN1CCc2ccc(N)cc2CC1
Product: CN(C)C(=O)CN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc2CC1

Procedure:
2-{7-[5-Chloro-4-((1R,2R)-2-methanesulfonylamino-cyclohexylamino)-pyrimidin-2-ylamino]-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl}-N,N-dimethyl-acetamide was prepared from 2-(7-amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 308c. Product isolated as a yellow foam (88 mg, 39%). LCMS (m/e) 550 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.93 (s, 1H), 7.30-7.22 (m, 2H), 7.05 (d, 1H, J=8.0 Hz), 6.85 (s, 1H), 5.56-5.35 (m, 2H), 3.93-3.82 (m, 1H), 3.31 (s, 2H), 3.31-3.20 (m, 1H), 3.15 (s, 3H), 3.09 (s, 3H), 2.97-2.87 (m, 4H), 2.81 (s, 3H), 2.77-2.67 (m, 4H), 2.27-2.17 (m, 2H), 1.89-1.79 (m, 2H), 1.45-1.32 (m, 4H).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:27])[CH3:28])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1ccnc(OCc2cnc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ncc(COc3cc(C(CC(=O)O)C4CC4)ccn3)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(2-((6-(2-fluoro-5-methoxyphenyl)-5-neopentylpyridin-3-yl)methoxy)pyridin-4-yl)propanoate (28 mg) in THF (1.0 mL) and methanol (0.50 ml) was added 1N aqueous sodium hydroxide solution (1.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent in the reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (21 mg) as a yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:4][CH:3]=1.Cl.[CH3:25][NH:26][O:27][CH3:28].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C1COCC1.C(OCC)(=O)C>[CH3:28][O:27][N:26]([CH3:25])[C:13]([C:11]1[N:10]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:12]=1)=[O:15]
Reactant: O=C(O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: CNOC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1H-imidazole-4-carboxylic acid I-7d (1.31 g, 3.57 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.42 g, 1.2 equiv) in THF (14 ml) were added TEA (4.97 ml, 10 equiv) and 1-propane phosphonic acid cyclic anhydride (3.21 ml, 1.5 equiv). The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate and washed with water, 10% citric acid, and saturated aqueous sodium chloride. The organic phase was dried over anhydrous magnesium sulfate and concentrated to a foam which was purified by flash column chromatography (silica, 70:30 ethyl acetate/hexane grading to ethyl acetate) to give 1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1H-imidazole-4-carboxylic acid methoxy-methyl-amide I-7e (485 mg, 33%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32](Br)=[O:33])=[CH:30][CH:29]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:12]1[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][C:28]([C:27]([F:26])([F:37])[F:38])=[CH:29][CH:30]=4)=[CH:3][CH:4]=3)[CH:9]=2)[C:13]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: O=C(Br)c1ccc(C(F)(F)F)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 308 was prepared analogous to compound of example 304 by reaction of compound of example 223 with 4-trifluoromethyl benzoyl bromide. The compound of example 308 was used directly without isolation, for the preparation of compound of example 309.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)=[CH:19][CH:18]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[K+].[Br-]>>[Cl:32][C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([Cl:31])[CH:28]=1)[CH2:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][S:15][C:12]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])=[C:7]3[C:11]=2[CH2:10][CH2:9][CH2:8]3)=[CH:22][CH:21]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3cc(Cl)cc(Cl)c3)cc2)c2c1CCC2
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1ccc(SCc2ccc(OCc3cc(Cl)cc(Cl)c3)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 77A. mp 134-135° C.; IR (KBr) cm−1: 3070, 1747, 1708, 1572, 1432, 1244; 400 MHz 1H NMR (DMSO-d6): δ 12.95 (br(s), 1H), 7.51-7.53 (m, 1H), 7.42-7.45 (m, 2H), 7.07-7.13 (m, 2H), 7.04 (d, 1H, J=8.6 Hz), 6.83-6.90 (m, 2H), 6.56 (d, 1H, J=8.6 Hz), 5.05 (s, 2H), 4.61 (s, 2H), 3.93 (s, 2H), 2.75 (t, 2H, J=7.5 Hz), 2.66 (t, 2H, 7.5 Hz), 1.88 (pentet, 2H); MS m/z 487 (M−1). Anal. Calc'd for C25H22Cl2O4S: C, 61.35; H, 4.53. found: C, 61.01; H, 436.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([O:21][CH3:22])=[CH:14][C:13]=1[CH:23]=[CH2:24].C1(C=CC(O)=CC=1)O>C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:24][CH2:23][C:13]2[CH:14]=[C:15]([O:21][CH3:22])[C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=2[Cl:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: C=Cc1cc(OC)c([N+](=O)[O-])cc1Cl
Agent: Oc1ccc(O)cc1
Solvent: CCCCO
Product: COc1cc(CCN[C@@H](C)c2ccc(Br)cc2)c(Cl)cc1[N+](=O)[O-]
Yield: 56.8 %

Procedure:
A solution of (S)-1-(4-bromophenyl)ethylamine (0.94 g, 4.69 mmol), 1-chloro-4-methoxy-5-nitro-2-vinylbenzene (Example 50C) (0.5 g, 2.34 mmol) and quinol (0.1 g, 0.94 mmol) in n-butanol (6 mL) was heated to reflux for 18 hours. The reaction mixture was concentrated under reduced pressure then the residue partitioned between EtOAc (40 mL) and water (30 mL). The separated aqueous phase was extracted with EtOAc (3×40 mL), and then the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using 0-1% MeOH in DCM to give the title compound (0.55 g, 57%).
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].CC(NS(C1C=CC2CCCCC=2C=1)(=O)=[O:25])(C)C.C([Li])CCC>O1CCCC1>[CH3:4][C:2]([NH:5][S:6]([C:9]1[C:18]2[CH:17]([OH:25])[CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc2c(c1)CCCC2
Reactant: CC(C)(C)NS(=O)(=O)c1cccc2c1CCCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cccc2c1C(O)CCC2
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 25.2 g (93.5 mmol) of a 1:1 mixture of N-(1,1-dimethylethyl)-5,6,7,8-tetrahydro-1-naphthalenesulfonamide and N-(1,1-dimethylethyl)-5,6,7,8-tetrahydro-2-naphthalenesulfonamide in 450 mL of tetrahydrofuran at -10° C., was added dropwise 75 mL (187 mmol) of a 2.5M solution of n-butyllithium in hexanes. After 90 minutes at this temperature the reaction mixture had turned red. The reaction mixture was cooled to -78° C. and oxygen was bubbled through for 15 minutes until the red color disappeared. After an additional 15 minutes, 200 mL of 5% NaHSO3 was added. The reaction mixture was extracted with ethyl acetate, dried (Na2SO4) and the solvent was removed with a rotary evaporator. The residue was purified by flash chromatography to give 6.0 g of the title compound as a sticky solid; m.p. 100°-111° C.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][CH2:9][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][CH2:26][CH3:27])(=O)=O.[CH2:28]([OH:40])[CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38]O.C(O[K])(C)(C)C>C(OCC)(=O)C>[CH2:6]([O:5][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][OH:40])[CH2:7][CH2:8][CH2:9][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][CH2:26][CH3:27]
Reactant: OCCOCCOCCOCCO
Reactant: CCCCCCCCCCCCCCCCCCCCCCOS(C)(=O)=O
Agent: CC(C)(C)O[K]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCCCCCOCCOCCOCCOCCO
Temperature: 110 °C
Reaction time: 3 h

Procedure:
80.4 g of 1-docosanyl methanesulfonate was added to 207 mL of tetraethylene glycol, and the mixture was heated at 110° C. 40.0 g of t-butoxypotassium was gradually added over 2 hours. The mixture was further stirred for 3 hours, and after cooling, the reaction mixture was poured into 3 L of ice water, to which was then added 2 L of ethyl acetate, the mixture was stirred, and 22.2 g of an insoluble matter was filtered. An ethyl acetate phase was extracted and separated from the filtrate, after concentration under reduced pressure, 0.5 L of acetonitrile was added, and the mixture was stirred under ice cooling for one hour. The reaction mixture was filtered under reduced pressure and washed with 0.2 L of cold acetonitrile to obtain 81.6 g of a white crystal.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=O)[CH2:10]2)(=[O:3])[CH3:2].[ClH:16].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][CH2:23][NH2:24].C([BH3-])#N.[Na+].Cl>CO.O>[ClH:16].[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([NH:24][CH2:23][CH2:22][C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)[CH2:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1CCC(=O)C2
Reactant: NCCc1cccs1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)Nc1cccc2c1CCC(NCCc1cccs1)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.03 g of (0.01 mol) of 5-acetylamino-2-tetralone, 3.2 g (0.02 mol) of 2-(2-thienyl)-ethyl-aminehydrochloride and 0.75 g (0.012 mol) of sodium cyanoborohydride are dissolved in 30 ml of methanol and stirred for 24 hours at ambient temperature. The mixture is then acidified by the dropwise addition of conc. hydrochloric acid with stirring and cooling with ice. After 10 minutes, 100 ml of water is added whilst stirring continues and then a total of 4.0 g of anhydrous soda is added in batches. Then extraction is carried out with 50 ml of methylene chloride and twice with 25 ml of methylene chloride. The combined extracts are washed with 20 ml of water, dried with sodium sulphate and after separation of the drying agent, concentrated by evaporation in a rotary evaporator, finally at 90° C. and under a complete water-jet vacuum. The residue is dissolved with 5 ml of methanol and 4.0 ml of 2.5 N ethanolic hydrochloric acid and the solution is mixed with diethylether until turbidity is just beginning. After standing for a period of about 12 hours at 5° C. the title compound is suction filtered, washed with ethanol/ether and dried at 80° C. until the weight remains constant. Yield: 3.1 g (88.3% of theory), melting point 276° C. (unchanged after recrystallisation from methanol/ether).
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[C:5]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH:4]=1)#N.C(O)=[O:24]>[Ni]>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[O:14][C:5]1[CH:4]=[C:3]([CH:1]=[O:24])[CH:13]=[CH:12][C:6]=1[NH:7][S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: O=CO
Reactant: CS(=O)(=O)Nc1ccc(C#N)cc1Oc1ccc(F)cc1F
Agent: [Ni]
Product: CS(=O)(=O)Nc1ccc(C=O)cc1Oc1ccc(F)cc1F

Procedure:
A mixture of 4'-cyano-2'-(2,4-difluorophenoxy)methanesulfonanilide (1.5 g) and Raney's Nickel (1.5 g) in 75% formic acid (40 ml) was refluxed for 2 hours. The mixture was filtered and the filtrate was concentrated to dryness. The residue was recrystallized from ethanol to give pale yellow needles of 2'-(2,4-difluorophenoxy)-4'-formylmethanesulfonanilide (1.4 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9].[K].[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12>>[CH:21]1([S:20][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:32]2[C:28](=[O:38])[C:29]3[C:30](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:31]2=[O:33])[C:8]#[N:9])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc(C(C#N)(CCCCCCl)SC2CCCCC2)cc1OC
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: COc1ccc(C(C#N)(CCCCCN2C(=O)c3ccccc3C2=O)SC2CCCCC2)cc1OC

Procedure:
The procedure of Example 24 is repeated using 2.1 g of α-(5-chloropentyl)-α-(cyclohexylthio)-3,4-dimethoxybenzeneacetonitrile and 0,954 g of the potassium salt of phthalimide. This affords 2.13 g of the desired product as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]([CH3:14])[CH3:13])=[CH:9][CH:10]=2)[C:5]([O:15][CH3:16])=[CH:4][N:3]=1.[F-:17].C[N+](C)(C)C>CS(C)=O.C(OC(=O)C)C>[F:17][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]([CH3:14])[CH3:13])=[CH:9][CH:10]=2)[C:5]([O:15][CH3:16])=[CH:4][N:3]=1
Reactant: [F-]
Reactant: COc1cnc(Cl)c2ccc(N(C)C)cc12
Agent: C[N+](C)(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cnc(F)c2ccc(N(C)C)cc12
Temperature: 110 °C
Yield: 55.9 %

Procedure:
To a solution of 1-chloro-4-methoxy-N,N-dimethylisoquinolin-6-amine (250 mg, 1.056 mmol) in DMSO (5 mL) was added tetramethylammonium fluoride (295 mg, 3.17 mmol) and the solution was heated to 110° C. for 1 h. The reaction was diluted with Ethylacteate and washed with water, and brine. The organic phase was collected, dried over sodium sulfate, and concentrated under vacuum to give the crude product which was purified by silica gel chromatography using 80% DCM/hexanes. The product fractions were collected and the solvent removed under vacuum to give 1-fluoro-4-methoxy-N,N-dimethylisoquinolin-6-amine (130 mg, 56% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.00 (d, J=9.3 Hz, 1H), 7.37 (d, J=1.3 Hz, 1H), 7.28-7.24 (m, 1H), 7.17 (s, 1H), 4.04 (s, 3H), 3.20 (s, 6H); MS m/z 221.0 (M++1).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[CH2:29]([O:31][CH2:32][CH2:33][C:34](=[NH:37])[NH:35]O)[CH3:30]>>[CH2:29]([O:31][CH2:32][CH2:33][C:34]1[N:37]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:27][N:35]=1)[CH3:30]
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: CCOCCC(=N)NO
Product: CCOCCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 6A, 600 mg (1.434 mmol) of the compound from Example 25A and 307 mg (approx. 1.864 mmol) of 3-ethoxy-N-hydroxypropanimidamide were reacted Yield: 403 mg (55% of theory)
Reaction SMILES: [OH:1][C:2]1[N:7]([C:8]#[C:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[CH:6]=[N:5][C:4]2=[N:20][C:21]([CH3:31])=[C:22](COC(=O)C(C)(C)C)[C:3]=12>CO.[Cl-].[Pd]>[OH:1][C:2]1[N:7]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[CH:6]=[N:5][C:4]2=[N:20][C:21]([CH3:31])=[CH:22][C:3]=12
Reactant: COC(=O)c1ccc(C#Cn2cnc3nc(C)c(COC(=O)C(C)(C)C)c-3c2O)cc1
Agent: [Pd]
Agent: [Cl-]
Solvent: CO
Product: COC(=O)c1ccc(CCn2cnc3nc(C)cc-3c2O)cc1

Procedure:
A mixture of 1.0 g of methyl 4-(4-hydroxy-5-pivaloyloxymethyl-6-methylpyrrolo[2,3-d]pyrimidin-3-ylethynyl)benzoate in 250 mL of 50% methanol in methylyne chloride and 0.8 g of 3% palladium-on-carbon is hydrogenated under reduced pressure. The solid is collected and there is obtained methyl 4-[2-(4-hydroxy-6-methylpyrrolo[2,3-d]pyrimidin-3-yl)ethyl]benzoate.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:14][C:11]([F:12])([F:13])[C:10]1[O:15][C:2]2[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=2[N:9]=1
Reactant: O=C(Nc1ccc(O)cc1O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1ccc2nc(C(F)(F)F)oc2c1
Yield: 40.8 %

Procedure:
A stirred solution of 0.8 gram (0.0036) of N-(2,4-dihydroxyphenyl)-2,2,2-trifluoroacetamide and a catalytic amount of p-toluenesulfonic acid in 50 mL of toluene was heated at reflux during an 18 hour period while the theoretical amount of water by-product was collected in a Dean-Stark trap. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using methylene chloride as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.3 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.Br[CH:3]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N-]=[N+]=[N-].[Na+].[OH2:19]>CN(C)C=O>[OH2:5].[N:12]1[CH:13]=[CH:14][C:9]([C:3](=[O:19])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(Br)c1ccncc1
Agent: Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1ccncc1
Reaction time: 0.5 h

Procedure:
Ethyl bromo(pyridin-4-yl)acetate hydrochloride (2.05 g) was dissolved in N,N-dimethylformamide (10 ml) at room temperature, followed by the addition of sodium azide (1.43 g). The resulting mixture was stirred for 30 minutes. After the addition of water and stirring, the insoluble matter was filtered off and the filtrate was concentrated. The residue was extracted with diethyl ether and saturated aqueous NaCl solution. The organic layer thus obtained was dried over anhydrous magnesium sulfate. The filtrate was concentrated and the residue was crystallized from methylene chloride, whereby the title compound (yellow powder, 300 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.O=[CH:20][C:21]([Cl:24])([Cl:23])[Cl:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([C:12]3[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[CH:20]2[C:21]([Cl:24])([Cl:23])[Cl:22])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(NCCNc2cccc(Cl)c2)cc1
Reactant: O=CC(Cl)(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(N2CCN(c3cccc(Cl)c3)C2C(Cl)(Cl)Cl)cc1
Yield: 35.6 %

Procedure:
A mixture consisting of 12.2 gm of N-(3-chlorophenyl)-N'-(4-methyl-phenyl)-ethylenediamine, 9 gm of chloral, 100 ml of toluene and 1.2 gm of p-toluenesulfonic acid was heated at its boiling point for 45 minutes in a vessel equipped with a water trap. Thereafter, the reaction mixture was filtered while still hot, and the filtrate was evaporated in vacuo. The oily residue was allowed to cool and was then triturated with a little glacial acetic acid, whereupon crystallization occurred. The crystals were collected by suction filtration, washed with cold methanol, and recrystallized from ethanol, yielding 6.5 gm of the compound of the formula ##STR14## which had a melting point of 34°-36° C.
Reaction SMILES: [CH3:1][CH:2]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[C:3]([O:5]CC)=O.[CH3:14][C@H:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([CH3:21])[N:16]1[CH2:22][CH2:23][CH2:24][NH2:25]>>[CH3:14][C@H:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([CH3:21])[N:16]1[CH2:22][CH2:23][CH2:24][NH:25][C:3](=[O:5])[CH:2]([CH3:1])[N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13]
Reactant: CCOC(=O)C(C)N1CCCC1=O
Reactant: C[C@@H]1CCC[C@H](C)N1CCCN
Product: CC(C(=O)NCCCN1[C@H](C)CCC[C@@H]1C)N1CCCC1=O

Procedure:
From 9.25 g. of ethyl α-methyl-2-oxo-1-pyrrolidineacetate and 10.5 g. of cis-3-(2,6-dimethyl-1-piperidinyl)propylamine, following the procedure of Example 21, there is obtained cis-(±)-N-[3-(2,6-dimethyl-1-piperidinyl)propyl]-α-methyl-2-oxo-1-pyrrolidineacetamide; b.p. 165°-170° C./0.1 mm.