Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[CH:8]=[N:9][OH:10].ClN1C(=O)CCC1=O.[CH:20]1([C:24](=O)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:23][CH2:22][CH2:21]1.[O-]CC.[Na+]>CN(C)C=O.O1CCCC1.O>[CH:20]1([C:24]2[O:10][N:9]=[C:8]([C:7]3[C:6]([Cl:11])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])[C:25]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:22][CH2:23]1
Reactant: ON=Cc1c(Cl)cncc1Cl
Reactant: CCOC(=O)CC(=O)C1CCC1
Agent: CC[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(-c2c(Cl)cncc2Cl)noc1C1CCC1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 52.9 %

Procedure:
To a solution of 3,5-dichloro-4-pyridinecarbaldehyde oxime (3.15 g, 16.5 mmol) in N,N-dimethylformamide (13 mL) was added N-chlorosuccinimide (2.20 g, 16.5 mmol). The mixture was heated to 65° C. and all solids dissolved. The solution was stirred at 65° C. for approximately 1.5 hours, poured into water and extracted with ether. The ether layer containing the crude imidoyl chloride was washed with brine, dried over magnesium sulfate and concentrated. To a separate solution of ethyl 3-cyclobutyl-3-oxopropanoate (3.37 g, 19.8 mmol) in tetrahydrofuran (4 mL) at 0° C. was added sodium ethoxide (25 wt % in ethanol, 6.21 mL, 19.8 mmol) and the mixture was stirred for approximately 7 minutes. Then the above imidoyl chloride was added in tetrahydrofuran (13 mL) at a slow rate. A solid precipitated and the mixture was allowed to warm to ambient temperature and stir overnight. The mixture was concentrated and taken up with ethyl acetate and washed with water. The aqueous layer was back-extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate and purified by chromatography (silica gel, 0-10% ethyl acetate in hexanes gradient elution) to afford ethyl 5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolecarboxylate (2.98 g, 53%). 1H-NMR (400 MHz, DMSO-d6) δ 8.64 (s, 2H), 4.35-4.20 (m, 1H), 4.05 (q, J=7 Hz, 2H), 2.45-2.30 (m, 4H), 2.14-2.04 (m, 1H), 2.00-1.89 (m, 1H), 0.96 (t, J=7 Hz, 3H). LRMS (APCI) m/z 341 (M+H)+.
Reaction SMILES: FC1C=CC(S([N:11]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:30][CH2:29][C@@H:28](O)[C:27]3=[O:32])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=O)=O)=CC=1.CCN(C(C)C)C(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[F:57][C:58]([F:70])([F:69])[C:59]1[CH:68]=[C:67]2[C:62]([CH2:63][CH2:64][NH:65][CH2:66]2)=[CH:61][CH:60]=1.N1CCOCC1>C(Cl)Cl>[O:32]=[C:27]1[C@@H:28]([N:65]2[CH2:64][CH2:63][C:62]3[C:67](=[CH:68][C:59]([C:58]([F:57])([F:70])[F:69])=[CH:60][CH:61]=3)[CH2:66]2)[CH2:29][CH2:30][N:26]1[C:23]1[CH:24]=[CH:25][C:20]([S:17]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:19])=[O:18])=[CH:21][CH:22]=1
Reactant: FC(F)(F)c1ccc2c(c1)CNCC2
Reactant: O=C1[C@H](O)CCN1c1ccc(S(=O)(=O)N(c2nccs2)S(=O)(=O)c2ccc(F)cc2)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCN1
Product: O=C1[C@@H](N2CCc3ccc(C(F)(F)F)cc3C2)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: -25 °C
Reaction time: 1.5 h

Procedure:
A solution of (R)-4-fluoro-N-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)phenylsulfonyl)-N-(thiazol-2-yl)benzenesulfonamide (12.4 g, 24.9 mmol) in DCM (80 mL) was stirred under nitrogen at −25° C. To the reaction mixture was added DIEA (9.6 g, 13 mL, 74.6 mmol) followed by dropwise addition of triflic anhydride (10.5 g, 6.30 mL, 37.3 mmol). The reaction mixture was stirred at −25° C. for 90 minutes. A solution of 7-trifluoromethyl-tetrahydroisoquinoline (5.0 g, 24.9 mmol) in DCM (10 mL) was added to the reaction mixture and stirring was continued under nitrogen at −25° C. for 1 h. Morpholine (4.33 g, 4.3 mL, 49.7 mmol) was added and the cooling bath was removed. The reaction mixture was stirred at room temperature for 30 minutes, concentrated under reduced pressure and purified by silica gel column chromatography (0.5-10% MeOH in DCM). The product obtained was taken up in DCM and precipitated by addition of Et2O providing a white solid (5.25 g, 40%), which was collected by filtration. 1H NMR (400 MHz, DMSO-d6) δ: 12.0 (s, 1H), 7.84 (dd, J=9.0, 22.8 Hz, 4H), 7.46 (bs, 2H), 7.32-7.30 (m, 1H), 7.26 (d, J=4.6 Hz, 1H), 6.83 (d, J=4.6 Hz, 1H), 4.12 (d, J=15.3 Hz, 1H), 3.92-3.78 (m, 4H), 3.15-3.10 (m, 1H), 2.90-2.83 (m, 3H), 2.34-2.27 (m, 1H) and 2.19-2.10 (m, 1H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=523.3; tR=1.18 minMS (ESI) m/e (M+H+) 523.3, retention time: 1.18 min (10-99% CH3CN in H2O).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)=[CH2:6])[CH3:3].[CH3:14][N:15]=[C:16]=[O:17].C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>C(OCC)C>[CH3:1][N:2]([CH2:4][C:5]([C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:16](=[O:17])[NH:15][CH3:14])=[CH:9][CH:8]=1)=[CH2:6])[CH3:3]
Reactant: C=C(CN(C)C)c1ccc(N)cc1
Reactant: CN=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCOCC
Product: C=C(CN(C)C)c1ccc(NC(=O)NC)cc1
Temperature: 25 °C

Procedure:
To 9.3 g (0.053 Mol) 4(1-dimethylaminomethyl-ethenyl)-aniline in 220 ml absolute diethylether are added 5 ml (0.085 Mol) methylisocyanate and the reaction solution, after addition of 0.3 ml dibutyl tin diacetate, stirred over night, at room temperature. The crystals that precipitated after 18 hours are filtered off and washed with petrol ether to give the analytically pure title compound, m.p. 123°-124°.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([O:15][CH3:16])[CH:6]=1)=O.[NH2:17][C:18]([NH2:20])=[S:19].C([O-])(=O)C.[Na+]>C(O)C>[NH2:20][C:18]1[S:19][CH:2]=[C:3]([C:5]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([O:15][CH3:16])[CH:6]=2)[N:17]=1
Reactant: COc1cc(C(=O)CBr)cc([N+](=O)[O-])c1O
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(-c2csc(N)n2)cc([N+](=O)[O-])c1O
Reaction time: 6 h

Procedure:
aaa) A suspension of 2.9 g of 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and 761.2 mg of thiourea in 170 ml of ethanol is treated at 60° with 820.3 mg of sodium acetate and stirred for 6 hours. The reaction mixture is then evaporated, the residue is treated with 170 ml of water and heated to 60° for 30 minutes. After cooling the product is filtered under suction and washed with water. There is obtained 4-(2-amino-4-thiazolyl)-2-methoxy-6-nitrophenol of m.p. 248°-250° (from ethanol).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19](OC(C)(C)C)=[O:20])[CH:13]([CH3:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH:18]=[C:19]=[O:20])[CH:13]([CH3:26])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(C(=O)OCc2ccccc2)CCC1OCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(C(=O)OCc2ccccc2)CCC1OC=C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.59 g of N-benzyloxycarbonyl-4-tert-butoxycarbonylmethyloxy-3-methylpiperidine was dissolved in 20 ml of methylene chloride, and 5 ml of trifluoroacetic acid was added to the solution. The solution was stirred overnight at room temperature, and the resulting solution was concentrated under reduced pressure to obtain N-benzyloxycarbonyl-4-carbonylmethyloxy-3-methylpiperidine, which was an oily product with no color. The concentrate was dissolved in 40 ml of DMF, and 1.93 g of BOP reagent, 1.09 g of 7-amino-2-(2-(ethoxycarbonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline obtained in Example 2, and 1.33 g of triethylamine were added to this solution in an ice bath. The solution was stirred overnight at room temperature, and the resulting solution was extracted with ethyl acetate, washed with water, saturated aqueous solution of sodium bicarbonate, and saturated aqueous solution of sodium chloride, and dried with anhydrous sodium sulfate. After separating the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, and from the fractions eluted with chloroform-methanol (100:3 v/v) was obtained 1.14 g of 7-[1-(benzyloxycarbonyl)-2-methylpiperidine-4-yloxyacetylamino]-2-[2-(ethoxycarbonyl)ethyl]-1,2,3,4-tetrahydroisoquinoline, which was an oily product (yield: 49%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N:17](Cl)[C:18](=[O:23])C(Cl)(Cl)Cl)=[CH:13][CH:12]=2)[CH:7]=[CH:6][N:5]=1.N12CCCN=C1CCCCC2.[F:37][C:38]([F:48])([F:47])[C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][C:45]=1[Cl:46])[NH2:42]>CN(C)C=O.C(OCC)(=O)C>[Cl:46][C:45]1[CH:44]=[CH:43][C:41]([NH:42][C:18](=[O:23])[NH:17][C:14]2[CH:13]=[CH:12][C:11]([O:10][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([C:3]([NH:2][CH3:1])=[O:25])[CH:9]=3)=[CH:16][CH:15]=2)=[CH:40][C:39]=1[C:38]([F:37])([F:47])[F:48]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNC(=O)c1cc(Oc2ccc(N(Cl)C(=O)C(Cl)(Cl)Cl)cc2)ccn1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 110 °C
Yield: 66.8 %

Procedure:
N-methyl-4-(4-(2,2,2-trichlorochloroacetamido)phenoxy)picolinamide (25 g, 0.0644 mol) was dissolved in N,N-dimethyl formamide (75 ml). 1,8-Diazabicyclo[5.4.0]undec-7-ene (11.35 ml, 0.0805 mol) and 3-trifluoromethyl-4-chloroaniline (12.60 g, 0.0644 mol) were added in one lot. The reaction mass was then heated to 110° C. for 8-9 hours, cooled to room temperature and quenched in water (250 ml). The quenched mass was extracted repeatedly with ethyl acetate and the combined ethyl acetate layer was back washed with water to remove DMF traces. It was dried over sodium sulfate and evaporated under vacuum to obtain solid. The obtained solid was slurried in ethyl acetate (350 ml) at ambient temperature and filtered to give 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide (sorafenib base) (20 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:18]2[O:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:18]2[O:17][CH2:16][CH2:15][NH:14][CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccccc2Cl)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: Clc1ccccc1-c1cccc2c1OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 148.6 %

Procedure:
A mixture of tert-Butyl 9-(2-chlorophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (180 mg, 0.500 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (110 mg, 74.3%) as a solid.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:9][C:10]1[S:14][C:13](B(O)O)=[CH:12][CH:11]=1)[CH2:2][CH3:3].Br[C:19]1[CH:20]=[C:21]2[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=1)[NH:24][CH:23]=[C:22]2[CH:31]1[CH2:36][CH2:35][N:34]([S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])[CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>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>[CH2:40]([S:37]([N:34]1[CH2:33][CH2:32][CH:31]([C:22]2[C:21]3[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=[C:19]([C:13]4[S:14][C:10]([CH2:9][NH:8][CH2:7][CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH3:3])=[CH:11][CH:12]=4)[CH:20]=3)[NH:24][CH:23]=2)[CH2:36][CH2:35]1)(=[O:39])=[O:38])[CH3:41]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CCCOCCCNCc1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCOCCCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Yield: 2 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [3-(propyloxy)propyl]amine (38 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[3-(propyloxy)propyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[3-(propyloxy)propyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The crude product was purified twice on an Agilent MDAP using the procedure shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide. The purified product was washed with a 20:4:1 mixture of hexanes/EtOAc/MeOH (2.5 mL), taken up in EtOAc (2 mL) and washed with saturated K2CO3 (1 mL). The organic layer was concentrated to give to give 1.4 mg of the title compound (2%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1)#[CH:2].[Br:11][C:12]1[CH:17]=[C:16](I)[CH:15]=[CH:14][C:13]=1[F:19].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:11][C:12]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=2)[CH:15]=[CH:14][C:13]=1[F:19]
Reactant: C#Cc1cncc(OC)c1
Reactant: Fc1ccc(I)cc1Br
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cncc(C#Cc2ccc(F)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.2 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (93 mg, 0.13 mmol), copper (I) iodide (50 mg, 0.26 mmol), and 3-ethynyl-5-methoxypyridine, (prepared as described in PREPARATION 10), (350 mg, 2.6 mmol) to a solution of 2-bromo-1-fluoro-4-iodobenzene, (prepared as described in PREPARATION 43), (1.03 g, 3.4 mmol) in triethylamine (4.0 mL, 39.5 mmol). Stir at room temperature for 20 h then concentrate. Purify by silica gel chromatography, eluting with 100:0 to 80:20 dichloromethane:ethyl acetate, followed by a second silica gel chromatography, eluting with 75:25 to 60:40 hexanes:ethyl acetate, to give the title compound as a white solid (750 mg, 93%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2([CH2:15][NH2:16])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(N(CC)CC)C.[CH3:24][C:25]1[C:26]([C:31](Cl)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1.O>ClCCl>[Cl:1][C:2]1[C:3]([C:12]2([CH2:15][NH:16][C:31]([C:26]3[C:25]([CH3:24])=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:32])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: Cc1cccnc1C(=O)Cl
Reactant: NCC1(c2ncc(C(F)(F)F)cc2Cl)CC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccnc1C(=O)NCC1(c2ncc(C(F)(F)F)cc2Cl)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
180 mg of C-[1-(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-cyclopropyl]-methylamine (step 1) was dissolved in 5 ml of dichloromethane and cooled to 0° C. Then 145 mg of triethylamine was added, followed by dropwise addition of a solution of 112 mg of 3-methyl-pyridine-2-carbonyl chloride in 1 ml of dichloromethane. The reaction mixture was stirred at ambient temperature for 2 hours. Then 6 ml of water were added, the resulting phases were separated and the organic phase was washed with aqueous 2N sodium hydroxide solution, then with 1N aqueous hydrochloric acid and brine, dried over sodium sulfate, filtered and concentrated. Thus, 282 mg of crude material was obtained as a brown sticky solid. This residue was purified by chromatography on silica gel, with cyclohexane/ethyl acetate (1:1) as a eluent. Thus, 104 mg of 3-methyl-pyridine-2-carboxylic acid [1-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-cyclopropylmethyl]-amide was obtained as a sticky oil. 1H-NMR (CDCl3): 8.64 ppm (s, 1H), 8.35 ppm (m, 2H), 7.90 ppm (s, 1H), 7.53 ppm (m, 1H), 7.27 ppm (m, 1H), 3.74 (d, 2H), 2.60 ppm (s, 3H), 1.16 ppm (m, 2H), 1.12 ppm (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:11].F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(-c2cccnn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2cccnn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyridazin-3-yl)phenyl)methanone and 2-fluoro-5-trifluoromethylpyridine. ESI-MS (m/z): 470 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][C:23]([CH3:27])([C:24](O)=[O:25])[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1.Cl.[Cl:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][C:39]=1[Cl:40])[C:33]([NH:35][NH2:36])=O.C(N(CC)CC)C.O>CN(C=O)C>[Cl:29][C:30]1[CH:31]=[C:32]([C:33]2[O:25][C:24]([C:23]3([CH3:27])[CH2:22][CH2:21][CH2:20][N:19]4[C:15]([C:5]5[CH:6]=[CH:7][C:8]([C:9]6[O:13][C:12]([CH3:14])=[N:11][CH:10]=6)=[C:3]([O:2][CH3:1])[CH:4]=5)=[N:16][N:17]=[C:18]34)=[N:36][N:35]=2)[CH:37]=[CH:38][C:39]=1[Cl:40]
Reactant: COc1cc(-c2nnc3n2CCCC3(C)C(=O)O)ccc1-c1cnc(C)o1
Reactant: NNC(=O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2nnc3n2CCCC3(C)c2nnc(-c3ccc(Cl)c(Cl)c3)o2)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 26.6 %

Procedure:
A mixture of 3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-8-methyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid (100 mg), 3,4-dichlorobenzohydrazide hydrochloride (79 mg) and triethylamine (114 μL) in DMF (1.5 ml) was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in acetonitrile (1.5 ml), trichloroacetonitrile (114 μL) and triphenylphosphine (286 mg) were added, and the mixture was stirred at 70° C. for 2 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (38.8 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].OS(O)(=O)=O.[CH3:23]O>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:9]([O:11][CH3:23])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CO
Reactant: CCCCOc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: CCCCOc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 3-butoxy-4-nitrobenzoic acid (City Chemicals) (2.5 g, 10.5 mmol) in methanol (10 mL) were added concentrated H2SO4 (1 g, 10.5 mmol). The reaction mixture was heated at reluxing for 2 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with water, aqueous saturated NaHCO3 solution, brine, dried over MgSO4, and concentrated to give methyl 3-butoxy-4-nitrobenzoate as a brown oil (2.5 g, 95%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH2:19][CH2:18]2)=[CH:5][N:4](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]=1.[ClH:52]>>[ClH:52].[ClH:52].[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH2:18][CH2:19][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)[CH2:21][CH2:22]2)=[CH:5][NH:4][N:3]=1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(c4cccc(C(F)(F)F)c4)CC3)c2c1
Agent: Cl
Product: Cc1n[nH]cc1-c1ccc2nccc(N3CCN(c4cccc(C(F)(F)F)c4)CC3)c2c1

Procedure:
115 mg 6-(3-methyl-1-trityl-1H-4-pyrazolyl)-4-[4-(3-trifluoromethylphenyl)piperazin-1-yl]quinoline obtained in Example 176 and 1.3 mL of 5 N hydrochloric acid were reacted in the same manner as in Example 163, to give 68 mg of the title compound as yellowish orange crystals.
Reaction SMILES: [O:1]=[S:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[NH:14][C:15](=O)[C:16]3[S:21][C:20]([CH3:22])=[CH:19][C:17]=3[N:18]=2)[CH2:4][CH2:3]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1.[NH2:73][CH2:74][C:75]1([NH2:79])[CH2:78][O:77][CH2:76]1>CN(C)C=O.O>[NH2:79][C:75]1([CH2:74][NH:73][C:15]2[C:16]3[S:21][C:20]([CH3:22])=[CH:19][C:17]=3[N:18]=[C:13]([N:5]3[CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[S:2](=[O:1])[CH2:3][CH2:4]3)[N:14]=2)[CH2:78][O:77][CH2:76]1
Reactant: NCC1(N)COC1
Reactant: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)[nH]c(=O)c2s1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)nc(NCC3(N)COC3)c2s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A suspension of 2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylthieno[3,2-d]pyrimidin-4(3H)-one (250 mg, 0.72 mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (415 mg, 0.94 mmol) and 1,8-diazabicycloundec-7-ene (165 mg, 1.08 mmol) in anhydrous N,N-dimethylformamide (10 mL) was stirred at r.t. for 10 min, then a solution of 3-aminomethyl-oxetan-3-ylamine (150 mg, 1.44 mmol) in N,N-dimethylformamide (5 mL) was added dropwise. After the addition was complete, the mixture was heated at 60° C. overnight, then it was diluted with water (50 mL), extracted by dichloromethane, washed by brine, dried with anhydrous sodium sulfate. The solvent was removed and the residue was purified by preparative HPLC to afford N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)thieno[3,2-d]pyrimidin-4-amine as a white solid. MS obsd. (ESI+) [(M+H)+] 430, 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.67-7.80 (m, 2H), 7.45 (t, J=5.8 Hz, 2H), 6.82 (s, 1H), 5.21 (d, J=15.4 Hz, 1H), 4.71 (br. s., 1H), 4.63 (d, J=6.3 Hz, 2H), 4.46-4.56 (m, 2H), 4.01 (s, 2H), 3.30-3.49 (m, 4H), 2.55 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:22])[C:6]([NH:9][CH2:10][C:11]2[CH:21]=[CH:20][C:14]3[N:15]=[C:16]([S:18][CH3:19])[O:17][C:13]=3[CH:12]=2)=[CH:7][CH:8]=1.[CH2:23](OC(OCC)OCC)C>C(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]([CH2:10][C:11]3[CH:21]=[CH:20][C:14]4[N:15]=[C:16]([S:18][CH3:19])[O:17][C:13]=4[CH:12]=3)[CH:23]=[N:22][C:5]=2[CH:4]=1
Reactant: COc1ccc(NCc2ccc3nc(SC)oc3c2)c(N)c1
Reactant: CCOC(OCC)OCC
Solvent: O=CO
Product: COc1ccc2c(c1)ncn2Cc1ccc2nc(SC)oc2c1
Yield: 87.6 %

Procedure:
A solution of 4-methoxy-N1-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)benzene-1,2-diamine (755 mg, 2.40 mmol) in triethoxymethane (8 mL) and HCOOH (0.2 mL) was stirred at 90° C. for 40 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:2 petroleum ether/ethyl acetate to give 6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazole as a light brown solid (683 mg, 87.6%). 1H NMR (300 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.66 (s, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.43 (d, J=9.0 Hz, 1H), 7.30 (d, J=6.6 Hz, 1H), 7.16 (s, 1H), 6.82 (d, J=6.6 Hz, 1H), 5.54 (s, 2H), 3.75 (s, 3H), 2.73 (s, 3H). LCMS (ESI) m/z 326 (M+H)+.