Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])[OH:4].C(Cl)(Cl)Cl>[Cu].CO>[CH:3](=[N:1][C@H:2]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[OH:4])[C:5]1[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:11]
Reactant: COc1ccccc1C(O)(c1ccccc1OC)[C@H](N)Cc1ccccc1
Agent: [Cu]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccccc1C(O)(c1ccccc1OC)[C@@H](Cc1ccccc1)N=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.43 g. (1.4 millimols) of bis (salicylaldehydate) copper in 10 ml. methanol was added dropwise a solution of 1.1 g. (3.0 millimols) of (R)-2-amino-1,1-di(2-methoxyphenyl)-3-phenyl-1-propanol {[α]D +42.3° (c 1.1, chloroform)} in 10 ml. of methanol. The addition was carried out under thorough stirring at room temperature. The period of the addition was one hour and the reaction mixture was stirred for another one hour. The resulting solids were collected by filtration, washed with methanol and dried under reduced pressure to give a mononuclear complex of (R)-N-salicylidene-2-amino-1,1-di(2-methoxyphenyl)-3-phenyl-1-propanol as grayish blue crystals. Yield, 0.75 g. (58%), [α]546, +860° (c 0.065, benzene), melting point: 205° - 206° C. (decomposed).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]3[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[I-].[CH3:32][S+](C)C.CC(C)([O-])C.[K+]>O1CCCC1.CS(C)=O>[O:30]1[C:27]2([CH2:26][CH2:25][CH:24]([N:8]3[C:4]4[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=4[C:10]([C:11]4[CH:12]=[CH:13][C:14]([O:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:15][CH:16]=4)=[CH:9]3)[CH2:29][CH2:28]2)[CH2:32]1
Reactant: C[S+](C)C
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC2(CC1)CO2
Temperature: -5 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a mixture of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-cyclohexanone (2 g, 5 mmol) in tetrahydrofuran (17.5 mL) were added trimethyl-sulfonium iodide (1.53 g, 7.5 mmol) in dimethyl sulfoxide (25 mL) and potassium-t-butoxide (7.5 mL, 7.5 mmol, 1 M in tetrahydrofuran) under an atmosphere of nitrogen at −5° C. The mixture was stirred at −5° C. for 1 hour. The mixture was poured into ice water (50 mL). The water phase was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with saturated ammonium chloride solution (2×30 mL), water (1×30 mL), and brine (2×30 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to yield 7-(1-oxaspiro[2.5]oct-6-yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.9 g, 4.6 mmol, 2:1-mixture of trans and cis). The mixture was suspended in dichloromethane (3 mL). The solid was filtered and was washed with dichloromethane (1 mL) to yield 7-(1-oxaspiro[2.5]oct-6-yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.994 g, 2.4 mmol, 4:1-mixture of trans and cis).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9](#[N:13])[CH:10]([CH3:12])[CH3:11].[Cl:14][CH2:15][CH2:16][O:17][CH2:18]Cl.O>C1COCC1.CCOCC>[Cl:14][CH2:15][CH2:16][O:17][CH2:18][C:10]([CH3:12])([CH3:11])[C:9]#[N:13]
Reactant: CC(C)C#N
Reactant: ClCCOCCl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C#N)COCCCl
Reaction time: 0.33 h
Yield: 101.6 %

Procedure:
To a solution of LDA (0.14 mol) in 100 mL THF at −30 C under N2 was added drop-wise isobutyronitrile (9.7 g, 0.14 mol) in 40 mL THF over 20 min. After 20 min, a solution of 1-chloro-2-(chloromethoxy)ethane (18.1 g, 0.14 mol) in 50 mL THF was added drop-wise and the temperature was allowed to gradually rise to room temperature and stirred for 5 h. This was treated with 200 mL of water and Et2O and the layers separated. The aqueous layer was extracted further with Et2O. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to leave 23 g of crude product as a yellow oil. This was purified by silica chromatography using 9:1 hexanes/CH2Cl2 to 4:1 hexanes/CH2Cl2 as eluants. This yielded 7.4 g (32%) of the title compound as an oil. 1H NMR (300 MHz, CDCl3) δ: 1.33 (s, 6H), 3.43 (s, 2H), 3.61 (t, J=5.7 Hz, 2H), 3.77 (t, J=5.9 Hz, 2H). LC/MS (M+H): 162.
Reaction SMILES: [Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][NH:17][CH3:18])[CH:3]=1.[C:19](=[O:22])([O-])[OH:20].[Na+]>C(OCC)(=O)C>[C:4]([O:20][C:19](=[O:22])[N:17]([CH2:16][C:4]1[CH:3]=[C:2]([Br:1])[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=1)[CH3:18])([CH3:16])([CH3:5])[CH3:3]
Reactant: CNCc1cc(Br)n(S(=O)(=O)c2ccccc2)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN(Cc1cc(Br)n(S(=O)(=O)c2ccccc2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 73 %

Procedure:
To a solution of 1-[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (4.4 g) in ethyl acetate (60 mL) was added di-tert-butyl bicarbonate (2.8 mL), and the mixture was stirred at room temperature for 14 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1) to give the title compound as a colorless oil (yield 3.4 g, 73%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[CH3:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+].OC1C=CC=C2C=1N=CC=C2.N>CS(C)=O.[Cu]I.CCOC(C)=O.O>[CH3:13][C:14]1[N:15]=[CH:16][N:17]([C:2]2[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=2)[NH2:5])[CH:18]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: Cc1c[nH]cn1
Agent: [Cu]I
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Temperature: 120 °C
Reaction time: 16 h
Yield: 59.1 %

Procedure:
A suspension of 3-bromo-5-(trifluoromethyl)aniline (4.8 g, 20 mmol), 4-methylimidazole (1.97 g, 24 mmol), K2CO3 (3.04 g, 22 mmol), CuI (0.57 g, 3 mmol) and 8-hydroxyquinoline (0.44 g, 3 mmol) in 20 mL DMSO was stirred at 120° C. in a sealed tube under Ar2 for 16 hrs. The mixture was cooled down to 50° C. and 28% aq ammonia (10 mL) was added. The mixture was maintained at this temperature for 1 h. After cooling to rt, H2O and EtOAc were added. The aqueous layer was extracted with EtOAc (60 mL×3) and the organic layer was washed with brine, dried with Na2SO4, after filtration, the filtrate was concentrated under reduced pressure and purified by chromatography on silica gel (CH2Cl2/CH3OH 97:3) to give 2.85 g product as pale yellow solid (59.1%). 1H NMR (300 MHz, CDCl3) δ: 7.76 (1H, s), 7.01 (1H, s), 6.94 (1H, s), 6.84 (1H, s), 6.78 (1H, s), 4.11 (2H, brs), 2.29 (3H, s). LCMS: m/z [M+H]+ 242.0966.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH2:20])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH:21]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH:20][C:26]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:27])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: Cc1cc(C)cc(-c2nc(N)sc2-c2ccncc2)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)cc(-c2nc(NC(=O)C3CCCC3)sc2-c2ccncc2)c1
Temperature: 70 °C
Reaction time: 14 h
Yield: 60.3 %

Procedure:
To a solution of [4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.51 g, 1.8 mmol) and 4-dimethylaminopyridine (0.07 g, 0.56 mmol) in N,N-dimethylacetamide (10 mL) was added cyclopentanecarbonyl chloride (0.33 g, 2.47 mmol) and the mixture was stirred at 70° C. for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate solution and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.41 g, yield 59%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C@@H:14]2[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.Cl.CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)=[CH:38][CH:37]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:42]1([C:39]2[CH:40]=[CH:41][C:36]([C:2]3[N:11]=[C:10]([NH:12][CH2:13][C@@H:14]4[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]4)[C:9]4[C:4](=[N:5][CH:6]=[CH:7][N:8]=4)[CH:3]=3)=[CH:37][CH:38]=2)[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CNc2nc(Cl)cc3nccnc23)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](CNc2nc(-c3ccc(N4CCNCC4)cc3)cc3nccnc23)C1
Yield: 90 %

Procedure:
A solution of (S)-tert-butyl 2-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)morpholine-4-carboxylate (3.96 g, 10.43 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine hydrochloride (4.4 g, 13.55 mmol), Pd(PPh3)4 (2.41 g, 2.09 mmol) and Cs2CO3 (10.19 g, 31.29 mmol) in 150 mL of dioxane and 3 mL of water, under N2, was stirred at 110° C. overnight. The volatiles were removed in vacuo, and the residues was purified by chromatography with MeOH/H2O (1:20-5:1) to give 4.747 g of title compound. MS (m/z)=506 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B1OC(C)(C)C(C)(C)O1.[Br:20][C:21]1[CH:22]=[C:23]2[C:29](I)=[N:28][N:27]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:24]2=[N:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>C1COCC1>[Br:20][C:21]1[CH:22]=[C:23]2[C:29]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][CH:2]([F:1])[F:19])=[N:28][N:27]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:24]2=[N:25][CH:26]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(Br)cnc21
Reactant: CC1(C)OB(c2ccccc2OC(F)F)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(-c2ccccc2OC(F)F)c2cc(Br)cnc21
Temperature: 60 °C
Reaction time: 12 h
Yield: 97.4 %

Procedure:
2-(2-difluoromethoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (208 mg, 0.77 mmol), 5-bromo-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (350 mg, 0.77 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (28 mg, 0.035 mmol) and aqueous solution of sodium carbonate (2 M, 0.77 mL) were suspended in anhydrous THF (7 mL) and acetonitrile (7 mL) under an atmosphere of nitrogen. The mixture was stirred at 60° C. for 12 h. The cooled mixture was applied to a Varian Chemelut cartridge and eluted with ethyl acetate. Purification by flash silica gel chromatography using a gradient of ethyl acetate and hexanes afforded 355 mg (0.75 mmol, 95%) of 5-bromo-3-(2-difluoromethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine as a white solid. MS: m/z 471 [MH+] which was directly used in the next step.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[H-].[Na+].CS([C:15]1[N:20]=[C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([Cl:31])[CH:24]=2)[C:18]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:17][N:16]=1)(=O)=O>O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:1][C:15]1[N:20]=[C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([Cl:31])[CH:24]=2)[C:18]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:17][N:16]=1
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1NCc1ccc(OC)c(Cl)c1
Reactant: OCc1ccccn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(OCc2ccccn2)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2-hydroxymethylpyridine 32 mg and sodium hydride (suspension in 60% oil) 11.8 mg in tetrahydrofuran 2.5 ml is stirred at room temperature for 5 minutes. To the mixture is added at room temperature a solution of 2-methylsulfonyl-5-ethoxycarbonyl-4-(3-chloro-4-methoxybenzylamino)pyrimidine (prepared in the above (2)) 118 mg in tetrahydrofuran 2.5 ml, and the mixture is stirred for 30 minutes at room temperature. The reaction mixture is diluted with an aqueous 10% citric acid solution and extracted twice with ethyl acetate. The combined organic layer is washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel chromatography (solvent; chloroform:ethyl acetate=4:1→1:2) and concentrated in vacuo to give 2-(2-pyridylmethoxy)-5-ethoxycarbonyl-4-(3-chloro-4-methoxybenzylamino)pyrimidine as a colorless caramel, 106 mg.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[C:6](Cl)[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1.[CH3:24][C:25]1([CH3:32])[O:29][CH:28]([CH2:30][NH2:31])[CH2:27][O:26]1>C(O)C>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:7]1[C:6]([NH:31][CH2:30][CH:28]2[CH2:27][O:26][C:25]([CH3:32])([CH3:24])[O:29]2)=[N:5][C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:3][C:2]=1[Cl:1]
Reactant: Clc1nc(N2CCOCC2)nc(Cl)c1-c1nc2ccccc2s1
Reactant: CC1(C)OCC(CN)O1
Solvent: CCO
Product: CC1(C)OCC(CNc2nc(N3CCOCC3)nc(Cl)c2-c2nc3ccccc3s2)O1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
Into a solution of 2-[4,6-dichloro-2-(morpholin-4-yl)pyrimidin-5-yl]-1,3-benzothiazole (200 mg, 0.54 mmol, 1.00 equiv) in ethanol (3 mL) was added (2,2-dimethyl-1,3-dioxolan-4-yl)methylamine (142.9 mg, 1.09 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 85° C. Removal of the solvent under reducing pressure gave 0.35 g (crude) of the title compound as a yellow solid, which was used for next step without further purification. MS m/z [M+H]+ (ESI): 462.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.C(#N)C.CS(Cl)(=O)=O.[NH2:25][C:26]1[C:34]([CH3:35])=[CH:33][C:32]([Cl:36])=[CH:31][C:27]=1[C:28](O)=[O:29]>C(N(CC)CC)C>[Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:9][C:28](=[O:29])[C:27]3[CH:31]=[C:32]([Cl:36])[CH:33]=[C:34]([CH3:35])[C:26]=3[N:25]=2)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.9 %

Procedure:
To a mixture of 0.44 g of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid, 6 ml of acetonitrile and 0.20 g of triethylamine was added 0.125 ml of methanesulfonyl chloride. After the resulting mixture was stirred at room temperature for 15 minutes, 0.27 g of 2-amino-5-chloro-3-methylbenzoic acid was added and the mixture was stirred at room temperature for 20 minutes. To the mixture, 0.40 ml of triethylamine was added. After the mixture was stirred at room temperature for 20 minutes, 0.13 ml of methanesulfonyl chloride was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filter cake was washed with methyl tert-butyl ether. The resulting filter cake was dissolved in ethyl acetate, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.098 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-one. In addition, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 0.093 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[C:10](/[CH2:17][CH3:18])=[CH:11]/[C:12](OCC)=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].C([Al+]CC(C)C)C(C)C.O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6](/[C:10](/[CH2:17][CH3:18])=[CH:11]/[CH2:12][OH:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)/C=C(\CC)c1cccc([N+](=O)[O-])c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])O
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC/C(=C\CO)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a solution of ethyl (E)-3-(3-nitrophenyl)-2-pentenoate (Preparation 13, 105 g, 0.43 mol) in toluene (1400 ml) at −10° C. under nitrogen was added dropwise over 3 h diisobutylaluminium hydride (1.0 M in toluene, 1 l, 1.0 mol), then the mixture was stirred at 0° C. for 1 hour. Water (400 ml) was carefully added, followed by sodium hydrogen carbonate (700 g). The resulting slurry was vigorously stirred for 10 minutes, then ethyl acetate (2 l) was added, and the mixture stirred for 1 h. The mixture was dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a pale brown oil (80 g, 90%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.Cl>CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:6][CH:5]=1
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CO
Product: Nc1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 4-nitrobenzenesulfonamide obtained (5.9 g) was dissolved in methanol (100 ml), and after an addition of conc. hydrochloric acid, reduced iron (4.2 g) was added and the mixture stirred at room temperature for 2 hours. After filtration, methanol was evaporated under a reduced pressure, the residue was made basic with an addition of 4 N sodium hydroxide, and the mixture of the desired product and iron oxide precipitated was collected by filtration. The mixture was dissolved in acetone (200 ml), filtered to remove iron oxide, and the solvent was evaporated under a reduced pressure to obtain 4-aminobenzenesulfonamide (3.7 g) (m.p. 164° C.-165.5° C.).
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:8][C:9]1([F:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=O)=O.[CH3:24][NH2:25]>C(O)C>[F:15][C:9]1([CH2:8][C@H:7]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:6][NH:25][CH3:24])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CN
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1(F)CCCCC1
Solvent: CCO
Product: CNC[C@H](CC1(F)CCCCC1)NC(=O)OC(C)(C)C
Temperature: 50 °C

Procedure:
Crude (S)-2-(tert-butoxycarbonylamino)-3-(1-fluorocyclohexyl)propyl methanesulfonate and (n-Bu)4N+T (249 mg, 1.0 mmol) were dissolved in 33% methylamine in ethanol (50 mL). The mixture was heated to 50° C. for 17 h. The solution was cooled to rt and the volatile materials were removed in vacuo. The residue was dissolved in ether, washed with brine, dried over Na2SO4, filtered and evaporated. To afford crude (S)-tert-butyl 1-(1-fluorocyclohexyl)-3-(methylamino)propan-2-ylcarbamate.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[Cl:12][C:13]1[C:14]([C:19](O)=[O:20])=[N:15][CH:16]=[CH:17][CH:18]=1.CCN=C=NCCCN(C)C.Cl.C(=O)(O)[O-].[Na+]>C1C=CC2N(O)N=NC=2C=1.N1C=CC=CC=1>[Cl:12][C:13]1[C:14]([C:19]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=2)=[O:20])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ncccc1Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ncccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 0.80 g of 4-trifluoromethylaniline, 0.78 g of 3-chloropicolinic acid, 1.15 g of EDCI hydrochloride, 0.06 g of HOBt and 10 mL of pyridine was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting solid was washed with hexane and dried to obtain 1.34 g of 3-chloro-N-(4-trifluoromethylphenyl)picolinamide.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([C:19]([O:21]CC)=[O:20])[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:24]=[CH:25][CH:26]=[CH:27][C:9]2=3)[CH2:4][CH2:3]1.[OH-].[K+]>CO>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:24]=[CH:25][CH:26]=[CH:27][C:9]2=3)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc2c(c1)C(=C1CCN(C)CC1)c1ccccc1C=C2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CCC(=C2c3ccccc3C=Cc3ccc(C(=O)O)cc32)CC1
Yield: 94.5 %

Procedure:
A solution of 1.24 g of (-)-ethyl 5-(1-methyl-4-piperidylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylate and 4.12 ml of 2 N potassium hydroxide in 55 ml of methanol was stirred at room temperature for seven days. The methanol was removed by evaporation at 25°. The residue was dissolved in water and extracted with 50 ml of ether. The clear, colorless aqueous phase was acidified with glacial acetic acid. The white precipitate that formed was removed by filtration, and washed thoroughly with water. After drying at 100° in vacuo, 1.08 g of (-)-5-(1-methyl-4-piperidylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylic acid was obtained, m.p. 300°-305°; [α]58925 -180°; [α]57825 -194°; [α]54625 -239°; [α]43625 -675°; (c=0.004968 g/ml 0.10 NHCl). Rf : 0.70 (fluorescent silica gel, n-butanol/acetic acid/water (5:2:3).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([CH3:21])[S:20][C:13]=34)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:22](Cl)=[O:23].[N:25]1([CH2:31][CH2:32][NH2:33])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([CH2:31][CH2:32][NH:33][C:22]([C:3]2[C:4]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:17]=[CH:16][N:15]=[C:14]5[CH:18]=[C:19]([CH3:21])[S:20][C:13]=45)=[CH:7][C:5]=3[S:6][C:2]=2[CH3:1])=[O:23])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: Cc1cc2nccc(Oc3ccc4c(C(=O)Cl)c(C)sc4c3)c2s1
Reactant: NCCN1CCOCC1
Product: Cc1cc2nccc(Oc3ccc4c(C(=O)NCCN5CCOCC5)c(C)sc4c3)c2s1
Yield: 74.8 %

Procedure:
This material was prepared from 2-methyl-6-(2-methylthieno[3,2-b]pyridin-7-yloxy)benzo[b]thiophene-3-carbonyl chloride 139d (112 mg, 0.3 mmole) and 2-(morpholin-4-yl)ethylamine (157 mg, 1.2 mmole) in a similar manner as that described for example 108 to give a yellow solid (105 mg, 75%). 1H NMR (DMSO-d6) δ8.44 (1H, d, J=5.5 Hz),8.29 (1H, t, J=4.8 Hz), 7.94 (1H, d, J=8.7 Hz), 7.92 (1H, d, J=2.3 Hz), 7.31 (1H, s), 7.30 (1H, dd, J=2.3, 8.7 Hz), 6.60 (1H, d, J=5.5 Hz), 3.60 (4H, t, J=4.2 Hz), 3.45 (2H, dt, J=4.8, 6.2 Hz), 2.64 (3H, s), 2.62 (3H, s), 2.55-2.41 (6H, m).