Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13].B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13]
Reactant: COc1cccc2c1CCCC2=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C1CCCc2c(O)cccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1 mol of 5-methoxy-1-tetralone are dissolved in 5 l of methylene chloride and the solution is cooled to -78° C. 500 ml of boron tribromide in 2.3 l of methylene chloride are added dropwise to this solution. The mixture is stirred at -78° C. for 30 minutes and then at 0° C. for 2.5 hours and cooled again to -78° C., and 3 l of methanol are slowly added dropwise. The mixture is evaporated, the residue is taken up in methylene chloride and the mixture is extracted 3 times with 10% strength sodium hydroxide solution. The combined sodium hydroxide solutions are acidified with concentrated hydrochloric acid and extracted 3 times by shaking with methylene chloride. After drying over sodium sulphate, the extract is evaporated. The residue is pure product and does not need to be recrystallized. The melting point is 210°-215° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].[Cl:32][C:33]1[CH:40]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:38]=[CH:37][C:34]=1[CH2:35]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:41]([C:39]1[CH:38]=[CH:37][C:34]([CH2:35][O:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2/[CH:24]=[CH:23]/[CH:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[C:33]([Cl:32])[CH:40]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)c1ccc(CBr)c(Cl)c1
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2Cl)CCc2ccc(C#N)cc2)cc1

Procedure:
A solution of 450 mg (1.09 mmol) of methyl 4-[(3E)-2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-en-1-yl)benzoate in 10 ml of dry acetonitrile is mixed with 825.2 mg (1.64 mmol) of 2-chloro-4-(tert-butyl)benzyl bromide and 453.4 mg (3.28 mmol) of anhydrous potassium carbonate and heated under reflux for 12 h. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The resulting crude product is purified by preparative HPLC. 518 mg (0.87 mmol, 73.9% of theory) of a colorless foam are obtained.
Reaction SMILES: [CH:1]1([CH:4]([NH:7][C:8]2[C:13]([N+:14]([O-])=O)=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[CH3:25])[CH:11]=[CH:10][N:9]=2)[CH2:5][CH3:6])[CH2:3][CH2:2]1.[NH4+].[OH-].[O-]S(S([O-])=O)=O.[Na+].[Na+]>O1CCOCC1.O>[CH:1]1([CH:4]([NH:7][C:8]2[C:13]([NH2:14])=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[CH3:25])[CH:11]=[CH:10][N:9]=2)[CH2:5][CH3:6])[CH2:3][CH2:2]1
Reactant: CCC(Nc1nccc(-c2ccc(OC)cc2C)c1[N+](=O)[O-])C1CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCC(Nc1nccc(-c2ccc(OC)cc2C)c1N)C1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(1-Cyclopropyl-propyl)-[4-(4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-amine (0.220, 0.64 mmol) was dissolved in dioxane (10 mL) and H2O (10 mL), followed by conc. NH4OH (0.4 mL) and Na2S2O4 (0.906 g, 5.2 mmol) and stirred at room temperature for 4 h. The solution was extracted with EtOAc, washed with H2O, brine, dried Na2SO4, filtered, and concentrated in vacuo to produce the crude intermediate N2-(1-cyclopropyl-propyl)-4-(4-methoxy-2-methyl-phenyl)-pyridine-2,3-diamine; MS(AP) m/z 312.2 [(M+H)+, 100]. The crude intermediate was used in the following step.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=3[Br:28])=[N:14][CH:15]=[N:16]2)=[C:11]([O:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>>[Br:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[NH:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][C:11]=2[O:29][CH:30]2[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]2)[N:16]=[CH:15][N:14]=1
Reactant: COc1ccc(Br)c(Nc2ncnc3cc(OCc4ccccc4)cc(OC4CCNCC4)c23)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Br)c(Nc2ncnc3cc(O)cc(OC4CCNCC4)c23)c1
Temperature: 80 °C

Procedure:
A mixture of 7-benzyloxy-4-(2-bromo-5-methoxyanilino)-5-piperidin-4-yloxyquinazoline (0.35 g) and trifluoroacetic acid (6 ml) was stirred and heated to 80° C. for 5 hours. The mixture was evaporated and the residue was dissolved in water (12 ml). The solution was basified to pH8 by the addition of sodium bicarbonate. The resultant precipitate was isolated, washed with water and with ethyl acetate and dried under vacuum. There was thus obtained the title compound (0.26 g); NMR Spectrum: (DMSOd6) 1.95-2.15 (m, 2H), 2.32 (d, 2H), 3.05 (t, 2H), 3.3-3.4 (m, 2H), 3.8 (s, 3H), 5.0 (m, 1H), 6.75 (m, 2H), 6.85 (s, 1H), 7.6 (d, 1H), 7.98 (s, 1H), 8.4 (s, 1H), 9.58 (s, 1H); Mass Spectrum: M+H+ 445 and 447.
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][S@@](C(C)(C)C)=O)[CH3:10])=[C:5]([F:18])[CH:4]=1.Cl.C(OCC)C>O1CCOCC1>[F:19][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH2:11])[CH3:10])=[C:5]([F:18])[CH:4]=1
Reactant: C[C@H](N[S@](=O)C(C)(C)C)c1ccc(C(F)F)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: C[C@H](N)c1ccc(C(F)F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To (R)—N—((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (160 mg, 0.545 mmol) was added 4M HCl in dioxane (409 μL) to give a yellow solution. The resulting mixture was stirred at room temperature for ˜1 hour. To the mixture was added slowly diethylether (˜20 mL). The solids were filtered off, suspended in diethylether, filtered off and rinsed with diethylether, dried under reduced pressure providing (S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethanamine (103 mg) as an off-white solid, which was used without further purification. LCMS m/z 190.1 (M+H)+, Rt 0.42 min.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.S(=O)(=O)(O)O.[CH3:21]O>>[OH:1][C:2]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:21])=[O:5]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1O
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C(F)(F)F)cc1O
Temperature: 80 °C
Yield: 73 %

Procedure:
2-Hydroxy-4-(trifluoromethyl)benzoic acid (5.0 g, 24.26 mmol), hydrochloric acid (0.2 mL, 2.40 mmol), sulfuric acid (1.5 mL, 28.1 mmol) and methanol (40 mL) were mixed together and the reaction mixture was stirred at 80° C. over night. The mixture was concentrated and reloaded, stirred at 100° C. overnight. More H2SO4 was added (heated to 100° C. overnight). The mixture was concentrated and ether was added. The organic layer was washed with water twice, saturated solution of bicarbonate then brine, dried over Na2SO4, filtered and concentrated. The residue was dissolved in 20 ml Et2O and filtered (to remove starting material) and the filtrate was evaporated to afford title compound 58 (3.9 g, 73%) as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]1[C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[NH:20][S:21]([CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)(=[O:23])=[O:22])[N:13]([CH:37]([CH3:39])[CH3:38])[CH:12]=1)[N:7]([CH3:40])[CH2:6][CH2:5]2.[ClH:41].O1CCOCC1>C(Cl)Cl>[ClH:41].[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]1[C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[NH:20][S:21]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)(=[O:23])=[O:22])[N:13]([CH:37]([CH3:38])[CH3:39])[CH:12]=1)[N:7]([CH3:40])[CH2:6][CH2:5]2
Reactant: CC(C)n1cc(-c2cc3c(cc2F)CCN3C)c2c(NS(=O)(=O)C3CCN(C(=O)OC(C)(C)C)CC3)ccnc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)n1cc(-c2cc3c(cc2F)CCN3C)c2c(NS(=O)(=O)C3CCNCC3)ccnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of tert-butyl 4-(N-(3-(5-fluoro-1-methylindolin-6-yl)-1-isopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfamoyl)piperidine-1-carboxylate (D38) (442 mg, 0.773 mmol) in DCM (5 mL) at RT was added 4M HCl in 1,4-dioxane (1.933 mL, 7.73 mmol). The reaction mixture stirred at RT overnight. The reaction mixture was concentrated in vacuo to afford the title compound (500 mg). The material was used in next step without further purification. LCMS (A): m/z [(M−HCl)+H]+ 472, C24H30FN5O2S.HCl requires 507 (acidic).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]([NH:19][C:20](=[O:26])OC(C)(C)C)[C:13]2=[O:27])[CH2:10][CH2:9]1.C(N(C(C)C)CC)(C)C.[O:37]=[C:38]1[N:47]([CH:48]2[CH2:53][CH2:52][N:51](C(Cl)=O)[CH2:50][CH2:49]2)[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39]1>ClCCl.ClCCCl>[CH:8]1([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]([NH:19][C:20]([N:51]3[CH2:50][CH2:49][CH:48]([N:47]4[CH2:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[NH:39][C:38]4=[O:37])[CH2:53][CH2:52]3)=[O:26])[C:13]2=[O:27])[CH2:9][CH2:10]1
Reactant: O=C(Cl)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCN(CC2CC2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CCCCN(CC2CC2)C1=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl (3R)-1-(cyclopropylmethyl)-2-oxoazepan-3-ylcarbamate (257 mg, 0.91 mmol) in dichloromethane (10 mL). After 1 h, the mixture was concentrated and azeotroped with dichloromethane (3×) to give the crude amine. Diisopropylethylamine (0.070 mL, 0.40 mmol) was added to a solution of the crude amine (39 mg, 0.13 mmol) and 4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonyl chloride (39 mg, 0.13 mmol) in 1,2-dichloroethane (2 mL) and the mixture was heated to reflux. After 1 h, the reaction was allowed to cool to ambient temperature. Purification by silica gel chromatography (1% methanol/dichloromethane→5% methanol/dichloromethane) gave the title compound (32 mg). MS 440 (M+1).
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:16]1(/[CH:19]=[N:20]/[S:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH2:18][CH2:17]1>C1COCC1>[C:1]([C:2]([CH3:4])([CH3:3])[CH:19]([NH:20][S:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH:16]1[CH2:17][CH2:18]1)#[N:5]
Reactant: CC(C)C#N
Reactant: CC(C)(C)S(=O)/N=C/C1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C#N)C(NS(=O)C(C)(C)C)C1CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
To a solution of isobutyronitrile (0.30 g, 4.35 mmol) in THF (8 mL) at −78° C. was added LiHMDS (1.0M in THF, 4.8 mL, 4.8 mmol). The pale yellow reaction mixture was stirred at −78° C. for 30 min then a solution of 2-methyl-propane-2-sulfinic acid 1-cyclopropyl-meth-(E)-ylideneamide (0.50 g, 2.90 mmol) [prepared according to WO2008/147800] in THF (2 mL) was slowly added. The reaction mixture was stirred at −78° C. for 2 h then quenched with saturated aqueous NH4Cl and warmed to room temperature. The mixture was diluted with water and extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated to afford 0.70 g of 2-methylpropane-2-sulfinic acid (2-cyano-1-cyclopropyl-2,2-dimethyl-ethyl)-amide as a viscous colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([NH:23]S(C(C)(C)C)=O)[CH2:17][CH2:18][O:19][CH2:20][C:21]#[N:22].Cl.C1(C)C=CC=CC=1.C[Al](C)C>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]3([CH2:17][CH2:18][O:19][CH2:20][C:21]([NH2:22])=[N:23]3)[C:6]3[CH:11]=[C:10]([Cl:12])[N:9]=[CH:8][C:7]=3[O:13][C:14]2=[CH:15][CH:16]=1
Reactant: CC(C)(C)S(=O)NC1(CCOCC#N)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Agent: C[Al](C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: NC1=NC2(CCOC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a vial was added N-(7-bromo-3-chloro-5-(2-(cyanomethoxy)ethyl)-5H-chromeno[2,3-c]pyridin-5-yl)-2-methylpropane-2-sulfinamide (242 mg, 0.485 mmol) and HCl (4.0M solution in 1,4-dioxane, 0.970 mL, 3.88 mmol) in dioxane (4 mL). The mixture was stirred at RT for 20 mins, then quenched with 5 mL of a saturated aqueous solution of Na2CO3 and extracted into EtOAc. The organic extract was washed with saturated NaCl aqueous solution, dried over MgSO4, filtered and concentrated to give the crude product as orange oil. The crude product was dissolved with 4 mL of toluene and trimethylaluminum solution (2M in toluene, 0.728 mL, 1.455 mmol) was added to the mixture (exothermic after addition). The mixture was heated to 90° C. in oil bath for 10 min, then quenched with Rochelle's salt (12 mL) at 0° C. and stirred overnight at RT. The reaction mixture was diluted with water and extracted with EtOAc (10 mL×2). The organic extract was washed with saturated NaCl aqueous solution, dried over MgSO4, filtered and concentrated to give the crude material as orange oil. It was absorbed onto a plug of silica gel and purified by chromatography through a gold Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 30% to 50% to 80% DCM/MeOH/NH4OH (90/10/1) in 40% EtOAc in Heptane to provide (E)-7-bromo-3-chloro-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03-2.22 (m, 4 H) 4.42 (s, 2 H) 6.18 (br. s., 2 H) 7.21 (d, J=8.51 Hz, 1 H) 7.39 (s, 1 H) 7.45-7.62 (m, 2 H) 8.36 (s, 1 H). The other stereoisomer is Example 3B in Table 1.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[N:16]=[C:15]2[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[N:16]=[C:15]2[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[CH2:10][CH2:9]1
Reactant: Fc1ccc2c(c1)nc(C(F)(F)C(F)(F)F)n2C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: Fc1ccc2c(c1)nc(C(F)(F)C(F)(F)F)n2C1CCNCC1
Reaction time: 2 h
Yield: 86.7 %

Procedure:
5.7 g 1-(1-Benzyl-piperidin-4-yl)-5-fluoro-2-pentafluoroethyl-1H-benzoimidazole were dissolved in 100 ml methanol and hydrogenated with 2 g Pd/C (10%) at 50° C. and 60 psi for 2 h. The catalyst was removed and the filtrate was evaporated. The residue was crystallized with diisopropyl ether and petrol ether 1:1 to yield 3.9 g beige crystals (mp. 177–178° C.).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:25])=[C:5]([C:21]([O:23]C)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[OH-].[Na+]>CO>[CH3:11][O:10][C:8]([C:7]1[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:5]([C:21]([OH:23])=[O:22])=[C:4]([CH3:25])[NH:3][C:2]=1[CH3:1])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Yield: 57.2 %

Procedure:
3.5 g dimethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (0.01 mol) and 150 mL methanol were mixed. To the mixture was added a saturated aqueous NaOH solution (9 g, 0.225 mol) under stirring. The reaction was conducted at 70° C. under violent stirring for 6 hours, and evaporated under reduced pressure to remove 80 mL methanol. To the residue was added 200 mL water. The unreacted starting materials are removed by filtration. The filtrate was adjusted to a pH of about 2.5 with 1 mol/L hydrochloric acid to separate a yellow solid, which was filtered and dried to produce a khaki powder. The resulting powder was treated with methanol to produce the title product as a yellow solid (1.9 g) in a yield of 57.2%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=O)[CH3:13])=[CH:7][C:6]=1[C:15]([F:18])([F:17])[F:16])(=[O:4])=[O:3].BrBr.[N:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[NH:27][C:28]([NH2:30])=[S:29]>O1CCOCC1.C(O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:29][C:28]([NH:27][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][N:21]=3)=[N:30][C:12]=2[CH3:13])=[CH:7][C:6]=1[C:15]([F:18])([F:17])[F:16])(=[O:4])=[O:3]
Reactant: CC(=O)Cc1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Reactant: NC(=S)Nc1cnccn1
Agent: BrBr
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1nc(Nc2cnccn2)sc1-c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
1-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-propan-2-one (Example 59c) (0.60 g, 2.14 mmol) is dissolved in dioxan (50 ml) and the solution is cooled to 10° C. at which point the mixture is semi frozen. Bromine (0.088 ml, 1.7 mmol) is added slowly and the mixture is stirred for an additional 30 min in a semi frozen state. The mixture is then allowed to warm to room temperature and the solvent is removed to give a brown oil. This material is dissolved in ethanol and pyrazin-2-yl-thiourea (1a) is added in one portion. The mixture is stirred at 60° C. for 30 minutes then allowed to cool whereupon the titled product precipitates and is removed by filtration.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17](=O)[CH3:18])=[CH:10][CH:9]=1>C(#N)C>[CH3:6][O:7][C:8]1[CH:13]=[C:12]2[C:11]([CH2:14][CH2:15][N:16]=[C:17]2[CH3:18])=[CH:10][CH:9]=1
Reactant: COc1ccc(CCNC(C)=O)cc1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)C(C)=NCC2
Temperature: 120 °C
Yield: 45.3 %

Procedure:
Phosphorus oxychloride (22.5 mL) was added to a solution of N-[2-(4-methoxy-phenyl)-ethyl]-acetamide (6.5 g) in acetonitrile (200 mL). The mixture was heated at 120° C. in a sealed tube for 16 h. The solvent was evaporated. The residue was dissolved in dichloromethane (200 mL) and washed with aqueous sodium bicarbonate (saturated, 100 mL) and brine (100 mL). The dichloromethane layer was dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography (5% methanol in dichloromethane) to afford 7-methoxy-1-methyl-3,4-dihydro-isoquinoline (2.67 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[NH2:13][C:14]1[N:19]=[N:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([NH:13][C:14]2[N:19]=[N:18][C:17]([N:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:27])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[CH2:24][CH2:25]3)=[CH:16][CH:15]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C(O)CCc1ccc(F)cc1
Product: O=C(CCc1ccc(F)cc1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 2, making variations only as required to use 3-(4-fluorophenyl)propionic acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (58.5% yield). 1H NMR (300 MHz, CDCl3) δ 10.33, 8.40, 7.78, 7.67, 7.60, 7.36, 7.14, 7.08, 6.85, 3.90, 3.51, 3.20, 3.02, 2.92. MS (ES+) m/z 502.7 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH2:24][CH2:25][NH2:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[Br:15][C:16]1[CH:17]=[C:18]([CH2:24][CH2:25][NH:26][C:12]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10][CH2:11]2)=[O:14])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(CCN)cc1Br
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Product: COc1ccc(CCNC(=O)C2(c3ccc(Cl)cc3)CCC2)cc1Br

Procedure:
Prepared from 1-(4-chlorophenyl)cyclobutanecarboxylic acid and 2-(3-bromo-4-methoxyphenyl)ethanamine following the procedure described in example 85, step 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1/[N:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Li][C:18]([CH3:21])([CH3:20])[CH3:19].O>C1COCC1.CCCCC>[CH3:19][C:18]([CH3:21])([CH3:20])[CH:6]([NH:5][C:4]1[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=1[O:2][CH3:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1ccccc1/N=C/c1ccccc1
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCC
Product: COc1ccccc1NC(c1ccccc1)C(C)(C)C
Temperature: -80 °C
Yield: 92.8 %

Procedure:
To a solution of 1.27 g (6.00 mmol) of 9 in 40 mL of THF, 4.20 mL (6.30 mmol) of 1.5 M tBuLi in pentane was added with vigorous stirring at −80° C. The mixture was slowly warmed to room temperature, and then 2 mL of water was added. The resulting mixture was evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um, eluent: from hexanes to hexanes-diethyl ether=40:1, vol.) to yield 1.50 g (93%) of B1.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[N:34]=[C:35]=[O:36].C(N(CC)CC)C.Cl>C(#N)C>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[NH:34][C:35]([NH:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2)=[O:36]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc(Cl)cc4Cl)ccc3C2=O)C(=O)N1
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.37 g, 1.0 mmol) and 2,4-dichlorophenylisocyanate (0.19 g, 1.0 mmol) in acetonitrile (10 mL), was added triethylamine (0.28 mL, 2.0 mmol) at room temperature under nitrogen. After 2 h, 1 N aq. HCl (15 mL) was added and the solids were isolated by filtration, washed with water (3×20 mL) and dried in vacuo to give 1-(2,4-dichloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.44 g, 96% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 8.99 min (96.51%); mp: 265-267° C.; 1H NMR (DMSO-d6) δ 1.89-2.06 (m, 1H, CHH), 2.29-2.47 (m, 1H, CHH), 2.54-2.70 (m, 1H, CHH), 2.78-3.06 (m, 1H, CHH), 4.32 (d, J=17.4 Hz, 1H, CHH), 4.38-4.53 (m, 3H, CHH, CH2), 5.11 (dd, J=5.0, 13.3 Hz, 1H, CH), 7.33 (dd, J=2.5, 9.1 Hz, 1H, Ar), 7.46 (d, J=7.7 Hz, 1H, Ar), 7.53 (s, 1H, Ar), 7.57 (d, J=2.5 Hz, 1H, Ar), 7.62 (t, J=5.8 Hz, 1H, NH), 7.71 (d, J=7.7 Hz, 1H, Ar), 8.20 (d, J=8.9 Hz, 1H, Ar), 8.26 (s, 1H, NH), 10.99 (br. s., 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.82, 47.13, 51.58, 121.63, 121.92, 122.02, 123.04, 125.33, 126.99, 127.50, 128.39, 130.45, 135.81, 142.48, 144.12, 154.67, 167.90, 170.99, 172.86; LCMS: MH=461/463/465; Anal Calcd for C21H18N4O4Cl2: C, 54.68; H, 3.93; N, 12.15; Cl, 15.37. Found: C, 54.37; H, 3.84; N, 12.15; Cl, 15.50.