Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[Cl:8][C:9]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12].[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20]>O1CCOCC1>[Cl:8][C:9]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[C:11]([CH:7]1[CH2:6][CH2:17][CH2:9][CH:10]([CH2:20][C:19]([O:22][CH2:23][CH3:24])=[O:21])[C:11]1=[O:12])=[O:12]
Reactant: CCOC(C)=O
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)CC1CCCC(C(=O)c2ccc(Cl)cc2Cl)C1=O

Procedure:
Intermediate 2 (2 g, 8.44 mmol) was dissolved in dioxane (50 ml) and triethylamine (1.18 ml, 8.44 mmol) and 2,4-dichlorobenzoyl chloride (1.76 g, 844 mmol) added. The reaction mixture was stirred at reflux for 16 h. The mixture was then allowed to cool and diluted with ethyl acetate and washed with saturated sodium bicarbonate and then brine. The organics were dried over sodium sulfate and purified by column chromatography to give the desired ethyl [3-(2,4-dichlorobenzoyl)-2-oxocyclohexyl]acetate (220 mg) as a colourless oil. 1H NMR δ (ppm)(CDCl3): 7.36 (1H, d, J=2.0 Hz), 7.23, (1 H, dd, J=8.3, 2.0 Hz), 7.12 (1 H, d, J=8.3 Hz), 4.13-4.07 (2 H, m), 2.93-2.84 (1 H, m), 2.78 (1 H, dd, J=16.1, 5.9 Hz), 2.45 (1 H, dd, J=16.1, 8.3 Hz), 2.11-1.84 (4 H, m), 1.70-1.62 (1 H, m), 1.51-1.40 (2 H, m), 1.20 (3 H, t, J=7.0 Hz).
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-:8].[Na+].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](C)=[C:18]([C:22]#[N:23])[C:19]([NH2:21])=S)=[CH:13][CH:12]=1>C(O)C>[NH2:23][C:22]1[N:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[N:7]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:18]=1[C:19]([NH2:21])=[O:8]
Reactant: CC(C)(C)NN
Reactant: [OH-]
Reactant: CC(=C(C#N)C(N)=S)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)n1nc(-c2ccc(Cl)cc2)c(C(N)=O)c1N
Yield: 76.1 %

Procedure:
To a solution of tert-butyl hydrazine hydrochloride (523 mg, 3.50 mmol) in ethyl alcohol (20 ml) was added powdered sodium hydroxide (168 mg, 4.20 mmol), followed by 3-(4-chlorophenyl)-2-cyano-3-methylthioacrylamide (884 mg, 3.50 mmol) and the mixture was heated at reflux for 4 h. On cooling, the solvent was removed under reduced pressure and the residue partitioned between water (80 ml) and ethyl acetate (80 ml). The aqueous layer was further extracted with ethyl acetate (2×80 ml) and the combined organic layers were washed with brine (1×100 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to column chromatography (SiO2, 45-75% ethyl acetate-hexane) to afford the title compound (780 mg) after recrystallisation from methanol as a colorless solid m.p. 156°. δH (d6DMSO) 1.66 (9H, s), 5.16 (2H, br s), 5.68 (2H, br s), 7.42 (2H, dt, J 8.6, 2.1 Hz), and 7.51 (2H, dt, J 8.7, 2.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][N:28]([C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[F:1])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1ccccc1F
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3ccccc3F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2-fluorobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (20.3% yield). 1H NMR (300 MHz, CDCl3) δ8.04, 7.98, 7.47-7.40, 7.26-7.21, 7.15-7.09, 6.99, 3.95-3.78, 3.58-3.5, 1.54-1.47, 0.78-0.69, 0.48-0.42, 0.11-0.05.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:29])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.I[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:29])[CH:16]([C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:21][CH:22]=1)[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1ccc(N2CCOCC2)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(CC1CCCC1)c1ccc(N2CCOCC2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 51.3 %

Procedure:
A solution of diisopropylamine (344 μL, 2.45 mmol) in dry tetrahydrofuran (2.9 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (981 μL, 2.45 mmol). The reaction mixture was stirred at −78° C. for 15 min and then treated dropwise with a solution of (4-morpholin-4-yl-phenyl)-acetic acid methyl ester (549.9 mg, 2.34 mmol) in dry tetrahydrofuran (2 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The resulting reaction mixture was allowed to stir at −78° C. for 30 min, at which time, a solution of iodomethylcyclopentane (540.0 mg, 2.57 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was then allowed to warm to 25° C. where it was stirred for 67 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was diluted with ethyl acetate (200 mL). The organic phase was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-morpholin-4-yl-phenyl)-propionic acid methyl ester (381.4 mg, 51%) as a white solid: mp 68-70° C.; EI-HRMS m/e calcd for C19H27NO3 (M+) 317.1991, found 317.2001.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].C(Cl)(Cl)Cl.[CH3:40][CH:41]1[CH2:46][CH2:45][N:44]([CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:43][CH2:42]1.C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:50]3[CH2:51][CH2:52][CH:47]([N:44]4[CH2:45][CH2:46][CH:41]([CH3:40])[CH2:42][CH2:43]4)[CH2:48][CH2:49]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CC1CCN(C2CCNCC2)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 69.7 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (36 mg, 0.072 mmol) in THF (2 mL)/CHCl3 (2 mL) were added 4-methyl-1,4′-bipiperidine (40 mg, 0.22 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.5 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM [90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (31 mg, 70%). LC-MS m/z 618 (M+H)+; 1H-NMR (MeOD) δ 1.00 (d, 3H), 1.22 (m, 2H), 1.27 (d, 6H), 1.38 (m, 3H), 1.68 (d, 2H), 1.81 (d, 2H), 2.19 (t, 2H), 2.30 (s, 3H), 2.50 (t, 1H), 2.71 (t, 2H), 2.93 (d, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 4.45 (m, 2H), 7.16 (t, 2H), 7.46 (d, 1H), 7.50 (m, 1H), 7.68 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][NH:11]2)=[C:7]([CH3:14])[CH:6]=1)=[O:4].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:26][CH3:27])=[C:20]([S:22](Cl)(=[O:24])=[O:23])[CH:21]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][N:11]2[S:22]([C:20]2[CH:21]=[C:16]([Cl:15])[CH:17]=[CH:18][C:19]=2[O:26][CH3:27])(=[O:23])=[O:24])=[C:7]([CH3:14])[CH:6]=1)=[O:4]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: COC(=O)c1cc(C)c2c(c1)NCC2
Product: COC(=O)c1cc(C)c2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CC2

Procedure:
4-Methyl-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester was reacted with 5-chloro-2-methoxybenzenesulfonyl chloride in analogy to example 34, step 2, yielding 1-(5-chloro-2-methoxy-benzenesulfonyl)-4-methyl-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester. Pink solid, MS (ISP): m/e 396.1 (M+H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])=[C:13]([CH:15]=1)[NH2:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:27](Cl)(Cl)=[O:28].[N:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][CH:40]([CH2:43][OH:44])[CH2:39][CH2:38]2)=[CH:33][CH:32]=1>C1(C)C=CC=CC=1.C(Cl)Cl.CCCCCC>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:16]2[C:17](=[O:26])[C:18]3=[CH:25][CH:24]=[CH:23][CH:22]=[C:19]3[C:20]2=[O:21])=[C:13]([CH:15]=1)[NH:14][C:27]([O:44][CH2:43][CH:40]1[CH2:39][CH2:38][N:37]([C:34]2[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=2)[CH2:42][CH2:41]1)=[O:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OCC1CCN(c2ccncc2)CC1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N2C(=O)c3ccccc3C2=O)c(N)c1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N2C(=O)c3ccccc3C2=O)c(NC(=O)OCC2CCN(c3ccncc3)CC2)c1
Reaction time: 1.5 h
Yield: 90 %

Procedure:
A solution of 5-(tert-butyldimethylsilyloxy)-2-phthalimidoaniline (1.02 g, 2.77 mmol) in toluene (15 mL) was treated with a solution of 20% phosgene in toluene (2 mL) at reflux for 20 min. The volatile materials were removed in vacuo to give a tan solid, which was dissolved in dry methylene chloride (20 mL) and treated with 1-(4-pyridyl)piperidine-4-methanol (0.53 g, 2.77 mmol). The resulting suspension was stirred for 90 min then diluted with hexane. The mixture was allowed to stand overnight and the resulting precipitate collected by vacuum filtration and dried to yield 1.46g (90%) of the title compound as a tan powder.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:12]1([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=2)[NH2:7])[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: c1nc[nH]n1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(-n2cncn2)ccc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 5 h

Procedure:
A 10.0 g portion of 5-chloro-2-nitroaniline, 8.0 g of 1,2,4-triazole and 16.0 g of potassium carbonate were suspended in 50 ml of DMF and stirred for 5hours while heating at 130° C. The reaction solution was poured into ice water, and the thus precipitated crystals were collected by filtration and washed with purified water. By washing the crystals with methanol, 10.0 g (84% in yield) of the title compound was obtained. Its physical property values are shown below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([O:10][CH3:11])[CH:4]=1.[CH3:12][CH:13]([CH3:17])[C:14](Cl)=[O:15]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=1[C:14](=[O:15])[CH:13]([CH3:17])[CH3:12]
Reactant: CC(C)C(=O)Cl
Reactant: COc1cc(F)cc(OC)c1
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1cc(F)cc(OC)c1C(=O)C(C)C
Temperature: 5 °C

Procedure:
Into a 1-liter, three-necked round-bottom flask was placed 20.0 g (0.13 mole) of 1,3-dimethoxy-5-fluorobenzene, 13.6 g (0.0.13 mole) of 2-methylpropanoyl chloride, and 100 ml of nitrobenzene. The mixture was flushed with argon and an equal molar amount of AlCl3 (17.2 g) was added to the reaction mixture while stirring at 5° C. The mixture was stirred at a temperature of 5° C. for about 1 hour after the addition of the AlCl3. The reaction mixture was then mixed with about 100 ml of distilled water and extracted with dichloromethane. The organic layer was washed with NaHCO3 solution, salt water, and then dried. The solvent was removed by vacuum to yield the final product, 1-(2,6-dimethoxy-4-fluorophenyl)-2-methylpropan-1-one. The yield of the reaction was 22.8 g of product (77%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6][CH2:5]2.[B-](F)(F)(F)[CH:14]=[CH2:15].[K+].ClCCl.C(N(CC)CC)C>C(O)C>[CH:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6][CH2:5]2)=[CH2:15]
Reactant: O=C1OCCc2cc(Br)ccc21
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=Cc1ccc2c(c1)CCOC2=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 100 mL round bottom flask was added 6-bromo-3,4-dihydro-1H-isochromen-1-one (20 g, 88 mmol, 1.0 eq), potassium trifluoro(vinyl)borate (23.6 g, 176 mmol, 2.0 eq), [1,1′-bis(diphenylposphino)-ferrocene]dichloropalladium(II) complex with dichloromethane(1:1) (7.2 g, 8.8 mmol, 0.1 eq) and triethylamine (24.5 mL, 2.0 eq). To above mixture was added ethanol (400 mL). The flask was degassed and filled with nitrogen. The reaction was heated to reflux under N2 for 10 hr, then cooled and stirred at r.t. for 5 hr. The mixture was then diluted with EtOAc, filtered through a pad of Celite® and washed with brine. The organic phase was dried over Na2SO4, filtered and purified by flash column chromatography using Biotage and the solvent systems (0-50% EtOAc/Hexane). The fractions containing desired product were collected and concentrated to give 6-vinyl-3,4-dihydro-1H-isochromen-1-one.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][N:10](C)[C:11](OC(C)(C)C)=O)=[O:8])=[CH:5][CH:4]=1)#[N:2].C1(OC)C=CC=CC=1.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>ClCCl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][NH:10][CH3:11])=[O:8])=[CH:19][CH:20]=1)#[N:2]
Reactant: CN(NC(=O)c1ccc(C#N)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CNNC(=O)c1ccc(C#N)cc1

Procedure:
In a similar manner to Example 14, starting material step (b), the product of step (a) (2.2 g), anisole (2 ml), dichloromethane (20 ml) and TFA (27 ml) were reacted to give N-(4-cyanobenzoyl)-N'-methylhydrazine, trifluoroacetate salt (2.3 g), as a white solid: m.p. 131°-134° C.; NMR Spectrum (DMSO-d6) 2.76 (3H, s), 8.00 (4H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:17])=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]3)=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([NH:35][CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[C:7]([CH3:17])=[CH:8][C:9]4=[O:16])[CH2:31][CH2:30]3)=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1
Reactant: COc1ccc2c(C)cc(=O)n(CC=O)c2c1
Reactant: NC1CCN(Cc2ccc3c(c2)OCCO3)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(C)cc(=O)n(CCNC3CCN(Cc4ccc5c(c4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To 10 mL of a chloroform solution containing 120 mg of (7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde and 165 mg of 1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperidin-4-ylamine, 30 μL of acetic acid was added and stirred at room temperature for 1 hour. To the reaction mixture, 176 mg of sodium triacetoxyborohydride was added and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=5:1], to give 150 mg of 1-(2-(1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperidin-4-ylamino)ethyl)-7-methoxy-4-methylquinolin-2(1H)-one.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=O)[CH2:4][CH2:3]1.P(Cl)(Cl)([Cl:10])=O.[CH:13]1[C:26]2[NH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[S:18][C:17]=2[CH:16]=[CH:15][CH:14]=1.[OH-].[K+]>ClCCCl>[ClH:10].[CH3:1][CH:2]1[N:6]([C:5]2[CH2:4][CH2:3][CH:2]([CH3:1])[N:6]=2)[C:5]([N:25]2[C:26]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[S:18][C:19]3[C:24]2=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:4][CH2:3]1
Reactant: CC1CCC(=O)N1
Reactant: O=P(Cl)(Cl)Cl
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: [K+]
Agent: [OH-]
Solvent: ClCCCl
Product: CC1CCC(N2C(N3c4ccccc4Sc4ccccc43)=CCC2C)=N1
Product: Cl
Yield: 17 %

Procedure:
A mixture of 5-methyl-2-pyrrolidinone (6.0 g., 0.06 mole), phosphorus oxychloride (9.2 g., 0.06 mole) in 60 ml. of 1,2-dichloroethane is refluxed for 10 min. A solution off phenothiazine (6.0 g., 0.03 mole) in 20 ml. of 1,2-dichloroethane is added at the end of the reflux period and the reaction mixture stirred and refluxed for 20 hr., and then poured onto 20 ml. of 5N potassium hydroxide and 20 g. of crushed ice. The 1,2-dichloroethane layer is separated and extracted with 30 ml. of 1.5N hydrochloric acid and 30 ml. of water removing water soluble by-product 10-[2-(5-methyl-1-pyrrolinyl)]phenothiazine hydrochloride. After drying the 1,2-dichloroethane solution over magnesium sulfate, the 1,2-dichloroethane solution is concentrated and the solid thus obtained stirred with 40 ml. of acetone and filtered. Crystallization of the filtercake from ethanol-ether provides analytically pure 10-[5-METHYL-1-(5-METHYL-1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOTHIAZINE HYDROCHLORIDE in a yield of 17%, m.p. 257°-264° C. (corr.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[C:20]1([O:26][CH2:27][CH3:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([Cl:11])=[C:6]([C:7]([C:23]2[CH:24]=[CH:25][C:20]([O:26][CH2:27][CH3:28])=[CH:21][CH:22]=2)=[O:9])[CH:10]=1
Reactant: COc1cc(Br)cc(C(=O)O)c1Cl
Reactant: CCOc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)c2cc(Br)cc(OC)c2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of acid 56 (4.9 g, 18.57 mmol) in CH2Cl2 (62 mL) were added oxalyl chloride (2.1 mL, 24.14 mmol) and catalytic amounts of DMF at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was evaporated in vacuo and dried under high vacuum. The crude acid chloride was dissolved with CH2Cl2 (93 mL) and cooled to 0° C. To the mixture was added phenetole (2.4 mL, 18.57 mmol) at 0° C. and stirred at 0° C. for 5 min. To the reaction mixture was added AlCl3 (2.7 g, 20.43 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 30 min, warmed up to room temperature and stirred at room temperature for 15 hours. The mixture was poured into ice-water and extracted with CH2Cl2 (100 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product 73 was dried under high vacuum and used without further purification (7.0 g).
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[CH3:13][C:14]1([CH2:22][C:23]([CH3:25])=[CH2:24])[CH2:19][CH2:18][CH2:17][CH:16]([CH3:20])[C:15]1=[O:21]>C1(C)C=CC=CC=1>[CH3:24][C:23]1([CH3:25])[CH2:22][C:14]2([CH3:13])[CH2:19][CH2:18][CH2:17][CH:16]([CH3:20])[CH:15]2[O:21]1
Reactant: C=C(C)CC1(C)CCCC(C)C1=O
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1CCCC2(C)CC(C)(C)OC12
Temperature: 100 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
A 3 L reaction flask was charged with Vitride® (325 g, 0.9 mol) and toluene (500 mL), heated to 100° C., fed with 2,6-dimethyl-2-(2-methyl-allyl)-cyclohexanone (200 g, 1.1 mol, obtained in EXAMPLE I) for over 2 hours, and aged for another 2 hours. After the reaction completed, the reaction mixture was cooled to room temperature, quenched with IPA (100 mL). NaOH (50%, 300 g) and water (200 mL) were then added, heated to 80° C., and aged for another hour. The reaction mixture was cooled to room temperature and more water (200 mL) was added. Layers were split to dispose the aqueous waste. The organic layer was charged back to the flask. Toluene (300 mL) was added and water was removed with a Dean-Stark trap through azeotrope. The resuling mixture was cooled to 50° C. MSA (28 g, 0.3 mol) was added and the reaction mixture was heated to reflux. The consumption of the starting material was indicated after 3 hours. The resulting mixture was then cooled to room temperature and washed with saturated sodium carbonate solution (1 L) followed by brine (1 L). Distillation and fractionation provided the product 2,2,3a,7-tetramethyl-octahydro-benzofuran (125 g) in 63% yield.
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:11]#[C:12][Br:13]>C(O)C>[BrH:13].[C:1]1([N:7]2[CH2:8][CH2:9][N:10]=[C:12]2[NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCNc1ccccc1
Reactant: N#CBr
Solvent: CCO
Product: Br
Product: NC1=NCCN1c1ccccc1
Yield: 67.5 %

Procedure:
Reaction of N-phenylethylenediamine (9.80 g, 0.072 mol) with cyanogen bromide (7.62 g, 0.072 mol) as described in the preparation of intermediate 6 gave 11.76 g (67% yield) of the title product as white crystals from ethanol. 1HNMR 400 MHz (DMSO-d,) δ (ppm): 3.68 (2H, t, J=8.7 Hz, CH2), 4.08 (2H, t, J=8.7 Hz, CH2), 7.40-7.54 (5H, m, aromatics), 8.08 (broad s, NH). MS (ESI+) m/e 162 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([F:11])=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[NH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26]([OH:28])=[O:27].Cl>CC(O)C.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=2[C:26]([OH:28])=[O:27])[C:5]2[C:10]([F:11])=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(F)c3c(Cl)nc(Cl)nc32)cc1
Reactant: Nc1cccc(F)c1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)n2cc(F)c3c(Nc4cccc(F)c4C(=O)O)nc(Cl)nc32)cc1
Temperature: 25 °C
Yield: 41.5 %

Procedure:
A slurry of 2,4-dichloro-5-fluoro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (1.250 g, 3.47 mmol) DIPEA (3.03 mL, 17.35 mmol) and 2-amino-6-fluorobenzoic acid (0.646 g, 4.16 mmol) in iPrOH (30 mL) was heated at 90° C. for 3 h. The resulting mixture was allowed to cool to rt and diluted with EtOAc (100 mL) and a 1N HCl solution (100 mL). The organic layer was washed with a saturated NaHCO3 solution (100 mL) and a saturated NaCl solution (100 mL). The organic layer was diluted with Et2O and the resulting slurry filtered. The solids were washed with Et2O and dried in vacuum to afford 2-({2-chloro-5-fluoro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzoic acid (0.69 g, 41%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.38 (s, 3H), 6.71-6.87 (m, 1H), 7.21-7.36 (m, 1H), 7.48 (d, J=8.06 Hz, 2H), 7.76 (s, 1H), 7.96 (d, J=8.42 Hz, 2H), 8.26 (d, J=8.61 Hz, 1H).