Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][C:21]([S:27][CH2:28][CH:29]=O)=[CH:20]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:29][CH2:28][S:27][C:21]2[CH:22]=[N:23][C:24]3[C:19]([CH:20]=2)=[CH:18][C:17]([O:16][CH3:15])=[CH:26][CH:25]=3)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1ccc2ncc(SCC=O)cc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)OC(C)(C)C)CC3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.1 %

Procedure:
Piperidin-4-yl-carbamic acid tert-butyl ester (3.4 g, 17.15 mmol, 1.0 eq) is added at room temperature to a stirred solution of (6-methoxy-quinolin-3-ylsulfanyl)-acetaldehyde (4.0 g, 17.15 mmol, 1.0 eq) in 1,2-dichloroethane (200 mL), followed by sodium triacetoxyborohydride (2.06 g, 34.3 mmol, 2.0 eq). After 1 hour stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×50 mL) and a saturated sodium hydrogen carbonate aqueous solution (50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 20:1 to 10:1, v/v) to give a yellow solid that is further recrystallized with ethyl acetate:hexane (1:6, v/v) to afford {1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester as a yellow oil (724 mg, 10% yield).
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:29])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]O)[CH3:19])[CH2:12][CH2:11]1.[NH2:36][C:37]1[CH:49]=[CH:48][C:40]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[CH:39][CH:38]=1>>[C:1]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:19])[C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:36][C:37]2[CH:49]=[CH:48][C:40]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])=[CH:39][CH:38]=2)[CH2:12][CH2:11]1)=[O:29]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCCO
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCCNc1ccc(C(=O)OC(C)(C)C)cc1
Yield: 51.5 %

Procedure:
The compound (94 mg, 0.195 mmol) obtained in Example 39b was used to give a crude aldehyde compound according to the method described in Example 4g. The resulting crude aldehyde compound and tert-butyl 4-aminobenzoate (62 mg, 0.293 mmol) were used to give the title compound (66 mg; yield, 52%) as a white solid according to the method described in Example 18b.
Reaction SMILES: Cl.[NH2:2][C:3]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[C:4]([CH3:7])[C:5]#[N:6].C(N)(=[S:17])C>>[NH2:2][C:3]([C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)=[C:4]([CH3:7])[C:5]([NH2:6])=[S:17]
Reactant: CC(C#N)=C(N)c1ccc(Cl)cc1
Reactant: CC(N)=S
Agent: Cl
Product: CC(C(N)=S)=C(N)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 82.3 %

Procedure:
Add hydrogen chloride (4 M in 1,4-dioxane, 858 mL, 16.0 equiv; 3.43 mol) to an E-/Z-mixture of 3-amino-3-(4-chlorophenyl)-2-methylacrylonitrile (41.3 g, 1.00 equiv, 214.4 mmol) and thioacetamide (32.71 g, 2 equiv, 2.00 equiv; 428.8 mmol) in a 2 L round bottom flask RBF (fitted with rubber septum, nitrogen blanket, stir bar and cooling bath). Maintain a solution temperature below 30° C. with an ice bath until the addition is complete. Remove the ice bath, stir for 2 h, and slowly add the mixture to 1.5 L of 30% aqueous NH4OH in an ice bath with stirring. Extract the mixture 2 times with ethyl acetate. Wash the organic phase 2 times with brine, dry (K2CO3), filter, and concentrated to dryness. Crystallize the mixture from hexane and chloroform (10/90). Triturate the resulting solid from ethanol and water (10/90) to afford 3-amino-3-(4-chlorophenyl)-2-methyl-thioacrylamide (as an uncharacterized E-/Z-mixture). Yield: 82.3%. 1H NMR (CD3OD) δ 9.95 (s, 2H), 8.74 (s, 1H), 8.29 (d, J=6.0 Hz, 2H), 8.25 (s, 1H), 8.11 (d, J=6.0 Hz, 2H), 4.099 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:11][N:10]([S:12]([C:15]2[CH:36]=[CH:35][C:18]3[N:19]([CH2:26][CH:27]4[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]4)[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[N:21][C:17]=3[CH:16]=2)(=[O:14])=[O:13])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:22]([C:20]1[N:19]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30]([F:33])([F:34])[CH2:29][CH2:28]2)[C:18]2[CH:35]=[CH:36][C:15]([S:12]([N:10]3[CH2:9][CH:8]([NH2:7])[CH2:11]3)(=[O:14])=[O:13])=[CH:16][C:17]=2[N:21]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1CN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(N)C3)ccc2n1CC1CCC(F)(F)CC1

Procedure:
Following the same procedure in Example 37, Step A, using tert-butyl[1-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)azetidin-3-yl]carbamate (0.34 g, 0.63 mmol) and TFA (5 mL) in CH2Cl2 (10 mL). Yield: 0.26 g (93%). 1H NMR (400 MHz, METHANOL-D4) δ 1.47-1.57 (m, 2 H), 1.61 (s, 9 H), 1.63-1.84 (m, 4 H), 1.98-2.13 (m, 2 H), 2.16-2.32 (m, 1 H), 3.79-3.90 (m, 3 H), 3.97-4.08 (m, 2 H), 4.45 (d, J=7.42 Hz, 2 H), 7.75-7.84 (m, 1 H), 7.86-7.92 (m, 1 H), 8.14 (d, J=1.37 Hz, 1 H); MS (ESI) (M+H)+=441.3; Anal. Calcd for C21H30F2N4O2S+2.10 TFA (680.01): C, 44.51; H, 4.76; N, 8.24. Found: C, 44.48; H, 4.65; N, 8.43.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)=[O:15]>C(OCC)C>[CH2:22]([CH:19]1[CH2:18][CH2:17][N:16]([C:14](=[O:15])[CH2:13][NH:1][C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)[CH2:21][CH2:20]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Reactant: O=C(CCl)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Product: O=C(CNc1ccc2[nH]c(=O)oc2c1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 6-amino-3H-benzoxazol-2-one and 2-chloro-1-(4-benzyl-piperidin-1-yl)-ethanone (Example 200a) according to the method described in Example 142b. Melting Point: 204-206° C. (diethylether)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([O:18][CH3:19])=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>C1(C)C=CC=CC=1>[C:21]([O:20][CH:15]([C:8]1[N:9]([CH3:14])[C:10](=[O:13])[C:11]2[C:6]([C:7]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=1)=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][C:36]([NH:35][CH2:33][CH3:34])=[O:37])[CH:12]=2)[C:16]([O:18][CH3:19])=[O:17])([CH3:22])([CH3:23])[CH3:24]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CN)cc2c(=O)n1C
Reactant: CCN=C=O
Solvent: Cc1ccccc1
Product: CCNC(=O)NCc1ccc2c(-c3ccc(C)c(C)c3)c(C(OC(C)(C)C)C(=O)OC)n(C)c(=O)c2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A solution of methyl 2-(7-(aminomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-(tert-butoxy)acetate (17 mg, 0.039 mmol) in Toluene (750 μl) was treated with ethyl isocyanate (9.25 μl, 0.117 mmol) and stirred at 70° C. for 2 hours. The reaction was cooled to rt, concentrated, and purified with column chromatography (0-10% MeOH/DCM) to afford methyl 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-7-((3-ethylureido)methyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (11.8 mg, 0.023 mmol, 59.7% yield). The methyl ester was then hydrolyzed in a manner similar to that described in Example 165 Step C and purified by reverse phase HPLC to afford 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-7-((3-ethylureido)methyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetic acid (9.1 mg, 0.018 mmol, 86% yield) as a white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.35 (s, 1 H), 7.56-7.42 (m, 1 H), 7.37-7.28 (m, 1 H), 7.25-7.20 (m, 1 H), 7.12 (dd, J=8.5, 11.0 Hz, 1 H), 7.08-6.97 (m, 1 H), 5.32 (d, J=3.1 Hz, 1 H), 4.46 (s, 2 H), 3.69 (s, 3 H), 3.18 (q, J=7.1 Hz, 2 H), 2.36 (s, 3 H), 2.30 (d, J=9.4 Hz, 3 H), 1.13 (t, J=7.2 Hz, 3 H), 1.04 (d, J=5.1 Hz, 9 H); LCMS (m/z) ES+=494 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:30][CH2:31]O)[CH:11]=[C:12]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.S([O-])(O)(=O)=O.[K+]>O1CCCC1>[CH2:16]([O:15][C:14]1[C:13](=[O:23])[C:12]([C:24](=[O:29])[C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:11][N:10]2[CH2:30][CH2:31][N:6]([CH2:5][C:4]3[CH:33]=[CH:34][CH:35]=[C:2]([Cl:1])[CH:3]=3)[C:7](=[O:8])[C:9]=12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)C(=O)c1cn(CCO)c(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Agent: CS(=O)(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N(Cc1cccc(Cl)c1)CC2
Yield: 50.2 %

Procedure:
To a solution of 3-benzyloxy-5-(2,2-dimethylpropionyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (91 mg) in tetrahydrofuran (3 ml) was added N,N-diisopropylethylamine (0.187 ml) and the mixture was ice-cooled. Methanesulfonyl chloride (0.07 ml) was added at the same temperature over 30 min with stirring. After confirmation of the completion of the reaction by thin layer chromatography, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with brine, aqueous sodium hydrogen carbonate solution and brine, dried and concentrated. The obtained residue was dissolved in dimethylformamide (2 ml) and 60% sodium hydride (50 mg) was added by small portions with stirring at room temperature. After stirring for 30 min, the reaction mixture was ice-cooled and 5% aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried and concentrated. The obtained residue was purified by silica gel thin layer chromatography (ethyl acetate) to give 9-benzyloxy-2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (44 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]([OH:15])=O)=[N:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.Cl.Cl.[F:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[F:29])[N:25]=[C:24]([NH:30][CH2:31][CH2:32][NH:33][CH3:34])[CH:23]=[N:22]2>>[F:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[F:29])[N:25]=[C:24]([NH:30][CH2:31][CH2:32][N:33]([CH3:34])[C:13]([C:9]1[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:12][NH:11][N:10]=1)=[O:15])[CH:23]=[N:22]2
Reactant: O=C(O)c1n[nH]cc1-c1ccc(F)cc1
Reactant: CNCCNc1cnc2cc(F)c(F)cc2n1
Agent: Cl
Product: CN(CCNc1cnc2cc(F)c(F)cc2n1)C(=O)c1n[nH]cc1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 4-(4-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid (43 mg, 0.21 mmol) and N-(6,7-difluoro-quinoxalin-2-yl)-N′-methyl-ethane-1,2-diamine.dihydrochloride, D2 (65 mg, 0.21 mmol) according to the procedure described for Example 1, as a yellow solid (65 mg, 71%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[OH-].[Na+].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2]
Reactant: BrCCCCBr
Reactant: CCc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccccc1OCCCCBr

Procedure:
The solution of 19.04 ml of 2-ethylphenol in 24 ml of 1,4-dibromobutane is heated to 100° C. with stirring and admixed slowly with 99.2 ml of 1.6M NaOH. The emulsion is stirred at 100° C. over 20 h. The reaction mixture is cooled and extracted with tertbutyl methyl ether (2×150 ml). The organic phases are washed successively with 2M NaOH (1×150 ml), water (1×150 ml) and brine (1×150 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of distillation. b.p. 132° C. (1.1 mbar); Rt=5.75.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.[F:14][C:15]([F:20])([F:19])[CH:16]1[O:18][CH2:17]1>>[F:1][C:2]([F:12])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][NH:11][C:16]([OH:18])([CH3:17])[C:15]([F:20])([F:19])[F:14])[CH:7]=[CH:8][CH:9]=1
Reactant: FC(F)(F)C1CO1
Reactant: NCc1cccc(OC(F)(F)F)c1
Product: CC(O)(NCc1cccc(OC(F)(F)F)c1)C(F)(F)F
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Ex-632A) 3-Trifluoromethoxybenzenemethanamine (1.15 g, 6 mmol) and 1,1,1-trifluoro-2,3-epoxypropane (0.67 g, 6 mmol) were combined and stirred at 80° C. for 1.5 h. The mixture was cooled to room temperature, and the resulting solid was recrystallized from hot hexanes. The white solid was isolated by vacuum filtration and washed with cold hexanes to give 0.67 g (37%) of pure 3-[[[3-(trifluoromethoxy)-phenyl]methyl]amino-1,1,1-trifluoro-2-propanol. 1H NMR (CDCl3) δ7.37 (t, 1H), 7.24 (d, 1H), 7.15 (m, 2H), 3.99 (m, 1H), 3.85 (d, 2H), 2.98 (dd, 1H), 2.88 (dd, 1H), 2.79 (s, 1H). 19F NMR (CDCl3) δ−58.19 (s, 3F), −78.88 (s, 3F). HRMS calcd. for C11H11F6NO2: 304.0772 [M+H]+, found: 304.0794.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([OH:21])=O)=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23].[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:21])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc3c(C(=O)O)cnn23)c1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Yield: 43.1 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,5-dimethylphenylamino)-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.065 g, 0.13 mmol) obtained in step 2 and ethanesulfonamide (0.068 g, 0.65 mmol), the title compound (0.033 g, 43%) was obtained.
Reaction SMILES: C(OC(=O)[N:7]([CH2:25][C:26]#[N:27])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:21]([F:24])([F:23])[F:22])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:24][C:21]([F:22])([F:23])[O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[NH:7][CH2:25][C:26]#[N:27]
Reactant: CC(C)(C)OC(=O)N(CC#N)c1cnccc1-c1ccccc1OC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCNc1cnccc1-c1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of cyanomethyl-[4-(2-trifluoromethoxy-phenyl)-pyridin-3-yl]-carbamic acid tert-butyl ester (185 mg, 0.47 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (1 mL) at 0° C. The reaction mixture was stirred at 25° C. for 2 hours and then concentrated under vacuum. The residue was dissolved in 10 mL aqueous sodium bicarbonate solution and 20 mL CH2Cl2 and the layers were separated. The aqueous layer was extracted again with 10 mL CH2Cl2. The combined organic layer was washed with 20 mL brine, dried over Na2SO4, filtered and concentrated under vacuum. The resulting light yellow solid was pure enough to be used in the next step without further purification (115 mg, 83%). LC-MS (ESI): m/z=294.0 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:1][CH2:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C1=COCCC1
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a 1-L round-bottom flask equipped with a magnetic stir-bar and a N2inlet was added Ethyl 4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate (42g, 0.127moles, 1eq) and dry CH2Cl2(300ml) at room temperature. This was followed by the addition of 3,4-dihydro-2H-pyran (14ml, 0.152moles, 1.2eq) as a neat liquid and pyridinium p-toluenesulfonate (6.4g, 25.4mmoles, 20mol %). The reaction mixture was stirred at room temperature overnight (10hrs). The volatiles were then removed in vacuo and the residue was purified by flash silica gel chromatography (10% EtOAc/Hexanes to 30% EtOAc/Hexanes) to yield 34g (64%) of pure title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[C:4]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[N:14]3)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]=[C:30]=[O:31])[CH:24]=1>C(Cl)Cl>[F:21][C:3]1[C:4]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[N:14]3)=[O:10])=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:1][C:30]([NH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=1)=[O:31]
Reactant: Nc1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1F
Reactant: O=C=Nc1cccc(F)c1
Solvent: ClCCl
Product: O=C(Nc1cccc(F)c1)Nc1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
To a solution of (3-amino-2,6-difluorophenyl)(quinoxalin-6-yl)methanone (40 mg, 0.15 mmol, 1.0 eq.) in DCM (5 mL) were added TEA (42.4 mg, 0.42 mmol, 3.0 eq.) and 1-fluoro-3-isocyanatobenzene (23.3 mg, 0.17 mmol, 1.2 eq.). The resulting mixture was stirred at rt for 1 h, then concentrated. The resulting residue was purified via flash column chromatography (PE/EA=1/1, v/v) to afford 1-(2,4-difluoro-3-(quinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea (10.5 mg, 16.7%). LRMS (M−H+) m/z caculated 423.1. found 423.1. 1H NMR (DMSO-d6, 400 MHz) δ 9.31 (s, 1H), 9.11-9.13 (d, 2H), 8.76 (s, 1H), 8.46 (s, 1H), 8.33-8.34 (m, 3H), 7.49-7.52 (d, 1H), 7.32-7.35 (m, 2H), 7.10-7.12 (d, 1H), 6.82 (t, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([S:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])=[O:32])[CH:25]=[CH:24]2>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][C:16]([N:37]2[CH2:36][CH2:35][N:34]([S:31]([C:26]3[CH:25]=[CH:24][C:23]4[C:28](=[CH:29][CH:30]=[C:21]([Cl:20])[CH:22]=4)[CH:27]=3)(=[O:33])=[O:32])[CH2:39][CH2:38]2)=[O:18])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1

Procedure:
In a similar manner to Referential Example 12 except for the use of 3-(1-tert-butoxycarbonylpiperidin-4-yl)propionic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][C:24]([NH2:28])([C:26]#[CH:27])[CH3:25]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:28][C:24]([CH3:25])([CH3:23])[C:26]#[CH:27])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: C#CC(C)(C)N
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: C#CC(C)(C)NCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 6, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and 1,1-dimethylpropargylamine were converted to yield {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-(1,1-dimethyl-prop-2-ynyl)-amine as colorless oil, MS: 443(MH+, 1Br).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[C:19]=3[C:20]([NH2:22])=[O:21])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:30]1CCOC[CH2:31]1>>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[C:18]4[C:19](=[C:23]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:25][CH:26]=4)[C:20](=[O:21])[NH:22][C:31]3=[O:30])[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1COCCO1
Reactant: NC(=O)c1c(NCCCCN2CC=C(c3ccccc3)CC2)cccc1[N+](=O)[O-]
Product: O=c1[nH]c(=O)n(CCCCN2CC=C(c3ccccc3)CC2)c2cccc([N+](=O)[O-])c12
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A mixture of 2-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butylamino]-6-nitrobenzamide (300 mg) and N,N'-carbonyldiimidazole (554 mg) in dioxane (3 ml) was stirred for 2 hours at 150° C. The solvent was removed during the reaction. The residue was crystallized from a mixture of ethanol and ether. The crude crystalline materials were collected, washed with methylene chloride, and recrystallized from ethanol to afford 1-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-5-nitro-2,4(1H,3H)-quinazolinedione (265 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[S:12][C:13]([CH2:15]O)=[CH:14][C:10]=2[CH:9]=1)([O-:7])=[O:6]>N1C=CC=CC=1.ClCCl>[Cl:3][CH2:15][C:13]1[S:12][C:11]2[CH:17]=[CH:18][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][C:10]=2[CH:14]=1
Reactant: O=[N+]([O-])c1ccc2sc(CO)cc2c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2sc(CCl)cc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Thionyl chloride (1.0.ml) was added dropwise to a stirred mixture of 5-nitrobenzo[b]thiophene-2-methanol (1.0 g) and pyridine (2 drops) in dichloromethane (10 ml). The solution was stirred at room temperature for 4 hours and then washed with water followed by aqueous sodium bicarbonate solution, and then dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane gave a solid which was crystallised from ethyl acetate to give the title compound (0.73 g), m.p. 110°-112°, used directly in the next stage.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([CH2:19][OH:20])=[CH:14][CH:13]=2.O>CS(C)=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([CH:19]=[O:20])=[CH:14][CH:13]=2
Reactant: OCc1ccc2[nH]c(CCOC3CCCCO3)cc2c1
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc2[nH]c(CCOC3CCCCO3)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{2-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-1H-indol-5-yl}-methanol (11.5 g 41.7 mmol) in anhydrous DMSO (45 mL) was added IBX (12.3 g, 43.8 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (300 mL), the organic phase was washed with water, then brine, and was purified by column chromatography on silica gel, eluting with dichloromethane, to give 2-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-indole-5-carbaldehyde as a white solid. Yield: 8.50 g (75%).