Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:37]=[CH:36][C:10]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][C:17]([CH:21]=[C:22]4[S:26][C:25]([N:27]([CH3:34])[CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[N:24][C:23]4=[O:35])=[CH:18][CH:19]=3)[CH:14]=[N:13]2)=[C:9]([C:38]([F:41])([F:40])[F:39])[CH:8]=1.Br[CH2:43][CH2:44][O:45][CH3:46].C([O-])([O-])=O.[K+].[K+]>O>[Cl:6][C:7]1[CH:37]=[CH:36][C:10]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][C:17]([CH:21]=[C:22]4[S:26][C:25]([N:27]([CH:28]5[CH2:33][CH2:32][N:31]([CH2:43][CH2:44][O:45][CH3:46])[CH2:30][CH2:29]5)[CH3:34])=[N:24][C:23]4=[O:35])=[CH:18][CH:19]=3)[CH:14]=[N:13]2)=[C:9]([C:38]([F:41])([F:40])[F:39])[CH:8]=1
Reactant: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1)C1CCNCC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCN1CCC(N(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 50.7 %

Procedure:
To a DMF solution (1 mL) containing 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(methyl-piperidin-4-yl-amino)-thiazol-4-one (Example 16, 54 mg, 0.1 mmol) was added 1-bromo-2-methoxyethane (27.8 mg, 0.2 mmol) and K2CO3 (28 mg, 0.2 mmol). The mixture was stirred at 70° C. for 4 h, diluted with water and extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried (Na2SO4), and evaporated. The residue was purified by flash column chromatography on silica gel (EtOAc→10% MeOH/EtOAc) to afford the desired product (30 mg, 50%).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([CH3:7])[CH2:5][N:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.C(N(CC)CC)C.[C:22]([O:26][C:27](ON=C(C1C=CC=CC=1)C#N)=[O:28])([CH3:25])([CH3:24])[CH3:23]>O1CCOCC1>[NH3:1].[CH2:8]([N:4]1[CH2:5][C@@H:6]([CH3:7])[C@H:2]([NH:1][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:3]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)C[C@H]1N
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@@H]1CN(Cc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Product: N
Temperature: 25 °C
Yield: 171.7 %

Procedure:
To a solution of trans-3-amino-1-benzyl-4-methylpyrrolidine hydrocarbonate (4.0 g) and triethylamine (3.2 g) in 50% aqueous dioxane (50 ml) was added t-butoxycarbonyloxyimino-2-phenylacetonitrile (Boc-ON, 5.8 g) with stirring at room temperature. After stirring for 3 hours, the reaction mixture was poured into ice-water and extracted with ether. The organic layer was washed 1N aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica-gel column chromatography eluting with benzene to chloroform:methanol:concentrated aqueous ammonia (10:10:1) to give the title compound (5.24 g). Recrystallization from hexane gave colorless needles (5.04 g), mp 79°-80° C.
Reaction SMILES: CC1NC(C)=C(C(OCC[Cl:26])=O)C(C2C=CC=C([N+]([O-])=O)C=2)C=1C(OC)=O.[CH3:28][CH:29]([NH:44][CH3:45])[CH2:30][CH:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.C(OCC)C>[ClH:26].[CH3:28][CH:29]([NH:44][CH3:45])[CH2:30][CH:31]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCl)C1c1cccc([N+](=O)[O-])c1
Agent: CNC(C)CC(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cl
Reaction time: 25 h

Procedure:
A solution of 3.94 g of methyl 2-chloroethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate and 4.78 g of l,N-dimethyl-3,3-diphenylpropylamine in 12 ml of toluene was refluxed under stirring for 25 hours. Upon completion of the reaction the mixture was diluted with diethyl ether and the l,N-dimethyl-3,3-diphenylpropylamine hydrochloride formed was collected by filtration. The filtrate was then evaporated, and the crude product thus obtained was purified by repeated chromatography on silica gel, using first chloroform, then chloroform: ethyl acetate (85:15 by volume) and lastly ethyl acetate as eluent. The purified product was dissolved in methanol and ethanolic hydrogen chloride was added. The solution was filtered and evaporated to dryness. Repeated washings with warm diethyl ether: acetone (98:2 by volume) afforded 2.98 g of the title compound, m.p. 113°-120° C.
Reaction SMILES: [O:1]1[CH2:14][CH:2]1[CH2:3][O:4][C:5]1[C:13]2[C:9](=[N:10][S:11][N:12]=2)[CH:8]=[CH:7][CH:6]=1.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>C(O)CCC>[C:15]([NH:19][CH2:14][CH:2]([OH:1])[CH2:3][O:4][C:5]1[C:13]2[C:9](=[N:10][S:11][N:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)N
Reactant: c1cc(OCC2CO2)c2nsnc2c1
Solvent: CCCCO
Product: CC(C)(C)NCC(O)COc1cccc2nsnc12
Yield: 57 %

Procedure:
12.5 g (60 mM) 4-(2,3-epoxypropyloxy)-2,1,3-benzthiadiazole were dissolved in 150 ml. n-butanol and, after the addition of 40 ml. tert.-butylamine, heated under reflux for 3 hours. When the reaction was finished, the reaction mixture was evaporated and the residue was chromatographed on a silica gel column in the manner described in Example 1. There were obtained 9.6 g (57% of theory) 4-(3-tert.-butylamino-2-hydroxy-propyloxy)-2,1,3-benzthiadiazole, which had a melting point of 89°-91° C.
Reaction SMILES: P([O-])(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)O>C1C=CC=CC=1>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: c1c[nH]cn1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1Cl
Agent: [O-]P(Oc1ccccc1)Oc1ccccc1
Solvent: c1ccccc1
Product: Clc1ccccc1C(c1ccccc1)(c1ccccc1)n1ccnc1
Yield: 78.9 %

Procedure:
A mixture of benzene (20 ml), diphenyl phosphite (5.62 g, 24 mmole), imidazole (2.45 g, 36 mmole) and o-chlorophenyldiphenylmethanol (2.95 g, 10 mmole) obtained in Example 1 (B) was refluxed for 8 hours. The reaction mixture was treated in the same manner as in Example 2 to give 2.72 g of 1-(o-chlorophenyldiphenylmethyl)imidazole. Yield, 79%. M.P., 143°-144° C.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1.[CH2:13]([O:15][C:16](=[O:29])[CH:17]=[C:18]1[CH2:21][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24](Br)[CH:23]=2)[CH2:19]1)[CH3:14].C(N(CC)CC)C>[Cu](I)I.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.ClCCl>[CH2:13]([O:15][C:16](=[O:29])[CH:17]=[C:18]1[CH2:21][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:11]#[C:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:12])[F:1])=[CH:5][CH:6]=3)[CH:23]=2)[CH2:19]1)[CH3:14]
Reactant: CCOC(=O)C=C1CC(c2cccc(Br)c2)C1
Reactant: C#Cc1ccc(OC(F)F)cc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C=C1CC(c2cccc(C#Cc3ccc(OC(F)F)cc3)c2)C1
Yield: 54.8 %

Procedure:
In a CEM snap top microwave vial were combined 1-Difluoromethoxy-4-ethynyl-benzene (1.48 g, 8.80 mmol), [3-(3-Bromo-phenyl)-cyclobutylidene]-acetic acid ethyl ester (2.00 g, 6.78 mmol), Copper iodide (232 mg, 0.131 mmol), Tetrakis(triphenylphosphine)palladium (470 mg, 1155.56 g/mol, 0.046 mmol), and triethylamine (20 g, 198 mmol). The capped vial was placed in a CEM Explorer microwave instrument and irradiated for 30 minutes at 80° C. The crude reaction mixture and dichloromethane washings were poured directly onto silica gel. Purification by column chromatography (isocratic; 5% EtOAc in hexanes) afforded an oil 1.42 g (55%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (t, J=7.2 Hz, 3H) 2.94-3.03 (m, 1H) 3.06-3.16 (m, 1H) 3.19-3.28 (m, 1H) 3.49-3.60 (m, 1H) 3.62-3.72 (m, 1H) 4.08 (q, J=7.2 Hz, 2H) 5.68-5.78 (m, 1H) 7.06-7.32 (m, 3H) 7.39 (dd, J=8.8, 3.7 Hz, 3H) 7.46-7.52 (m, 1H) 7.62 (d, J=8.8 Hz, 2H); MS (ES) m/z 383.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[C:17]([F:25])[C:18]([F:24])=[C:19]([F:23])[C:20]=3[F:22])[C:15](=[O:26])[N:14]2[CH3:27])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:28]=[C:29]1[NH:34][CH2:33][CH2:32][CH2:31][N:30]1[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[C:17]([F:25])[C:18]([F:24])=[C:19]([F:23])[C:20]=3[F:22])[C:15](=[O:26])[N:14]2[CH3:27])[CH2:10][CH2:11][N:38]2[CH2:39][CH2:40][CH:35]([N:30]3[CH2:31][CH2:32][CH2:33][NH:34][C:29]3=[O:28])[CH2:36][CH2:37]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: CN1C(=O)c2c(F)c(F)c(F)c(F)c2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Product: CN1C(=O)c2c(F)c(F)c(F)c(F)c2C1C(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 145.7 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(4,5,6,7-tetrafluoro-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.43 g) was coupled to 4-(2-oxoperhydropyrimidine-1-yl)piperidine (0.183 g) by a method similar to that described in Example 8. The reaction product was not purified by chromatography but converted to the corresponding hydrochloride salt as described in the Example 8 to afford the desired 3-[1-(3,4-Dichlorophenyl)-3-(4-(2-oxoperhydropyrimidine-1-yl)piperidino)propyl]-2-methyl-2,3-dihydro-4,5,6,7-terafluoro-isoindol-1-one hydrochloride (0.465 g); mp 220° C. (d); MS: m/z=587(M+1); NMR: 1.18 (m,4), 2.67 (m,4), 3.36 (s,3), 4.58 (m,1), 4.90 (s,1), 6.87-7.37 (m,3). Analysis for C27H28Cl2N4O2F4.1.5.HCl.2H2O: Calculated: C, 47.82; H, 4.98, N, 8.26; Found: C, 48.15; H, 4.73; N, 7.99.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[CH2:8])([O-:3])=[O:2].CC1(C)O[C@H]2[C@@H]3OC(C)(C)O[C@]3(C(O)=O)O[C@H]2C[O:14]1.O.OO.NC(N)=O>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]2[CH2:8][O:14]2)[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: C=Cc1cccc([N+](=O)[O-])c1
Reactant: CC1(C)OC[C@@H]2O[C@@]3(C(=O)O)OC(C)(C)O[C@H]3[C@@H]2O1
Agent: NC(N)=O
Agent: OO
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cccc(C2CO2)c1
Temperature: 25 °C
Yield: 75 %

Procedure:
3-Nitrostyrene (1 g, 6.71 mmol) was taken with 100 mg Immobilized lipase and 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid monohydrate (0.3 g, 1.03 mmol) in dry dichloromethane (15 mL) and stirred at 25° C. and added urea hydrogen peroxide (3 g, 32 mmol) portion-wise at a pH 5 for 20 hours. The reaction was monitored occasionally on TLC. The mixture was filtered and washed the residue with dichloromethane and the filtrate was reduced its volume under reduced pressure using vacuum flash evaporator. The product was purified by preparative TLC with 25% EtOAc/hexane. 75% Yield; Yellow oil (Found: C, 58.22; H, 4.28; N, 8.50. C8H7NO3 requires C, 58.18; H, 4.27; N, 8.48%); Rf (25% EtOAc/hexane) 0.50; [α]D20−1.51 (c 2.0, CHCl3); {lit., [α]D18+2.5 (c 2.8, CHCl3, S}; HPLC analysis using a Chiralpak AD column showed it to be 60% ee [hexane: 2-propanol=9:1, flow rate 0.8 cm3 min−1]; νmax (neat/cm−1) 3113, 2995, 1517, 1343, 1301, 1042, 983, 888, 788, 740; δH (300 MHz; CDCl3) 2.80 (1H, dd, J 2.5 and 4.8, HCOCHH), 3.21 (1H, dd, J 3.9 and 4.8, HCOCHH), 3.97 (1H, dd, J 2.5 and 3.9, PhCHOCH2), 7.40-7.75 (2H, m, 2×CH, arom.) and 8.01-8.24 (2H, m, 2×CH, arom.); δC (300 MHz; CDCl3) 51.7 (CH2), 51.9 (CH), 126.0, 126.4, 145.4 and 148.6 (6×C-Ph); MS m/z (rel. intensity %): 165 (M+, 18), 150(32), 136(68), 120(25), 105(17), 90(100), 77(22), 74(12), 65(52), 63 (59).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:14]([NH2:17])[CH:15]=[CH2:16].S(Cl)(Cl)=O.Cl>O1CCCC1.C(OCC)(=O)C>[CH2:14]([NH:17][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[Br:1])[CH:15]=[CH2:16]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Br
Reactant: C=CCN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: C=CCNC(=O)c1ccc([N+](=O)[O-])cc1Br
Reaction time: 20 h

Procedure:
5 g of 2-bromo-4-nitrobenzoic acid is converted into acid chloride, which is dissolved in 50 ml of tetrahydrofuran and added in drops to 3 ml of allylamine in 20 ml of tetrahydro-furan, by 2 hours of boiling with 30 ml of thionyl chloride and distilling-off of excess thionyl chloride. After 20 hours at room temperature, it is dispersed between 1N hydrochloric acid and ethyl acetate, the ethyl acetate phase is washed with water, dried (Na2SO4) and concentrated by evaporation. The residue is crystallized with hexane. 5.6 g of 2-bromo-4-nitrobenzoic acid-allylamide, melting point 98-100° C., is obtained.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:7][CH:8]=1.[Br:15][C:16]1[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][C:17]=1[CH:18]=O.[C:26]([O:32][CH3:33])(=[O:31])[CH2:27][C:28]([CH3:30])=O.C[Si](OP([O-])([O-])=O)(C)C.Cl>C1COCC1>[CH3:33][O:32][C:26]([C:27]1[CH:18]([C:17]2[CH:20]=[CH:21][C:22]([C:24]#[N:25])=[CH:23][C:16]=2[Br:15])[NH:12][C:10](=[S:11])[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=2)[C:28]=1[CH3:30])=[O:31]
Reactant: N#Cc1ccc(C=O)c(Br)c1
Reactant: NC(=S)Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)CC(C)=O
Agent: C[Si](C)(C)OP(=O)([O-])[O-]
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1Br
Temperature: 75 °C
Reaction time: 17 h
Yield: 50 %

Procedure:
3-Trifluoromethylphenylthiourea (12.8 g, 87 mmol), 2-bromo-4-cyanobenzaldehyde (18.3 g, 87 mmol), and methyl acetoacetate (10.4 mL, 96 mmol) were dissolved in THF (300 mL) under an atmosphere of N2 and then trimethylsilylphosphate (18 g) in THF (50 mL) was added, and the mixture heated at 75° C. After 17 hours the reaction mixture was allowed to cool, poured onto 0.5 M HCl (600 mL) and stirred for 30 minutes. The mixture was extracted into EtOAc. The organic phase was washed with water, then brine and dried (Na2SO4) before being concentrated in vacuo. The resulting solid was triturated with Et2O (50 mL), filtered and the solid collected to yield the title compound as a white solid (22.2 g).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13](#[N:17])[CH2:14][C:15]#[N:16].[CH3:18][C:19]1[CH:32]=[CH:31][C:22]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)=[CH:21][CH:20]=1>O1CCCC1.C(OCC)(=O)C>[CH3:18][C:19]1[CH:32]=[CH:31][C:22]([C:23](=[C:14]([C:13]#[N:17])[C:15]#[N:16])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1
Reactant: N#CCC#N
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=C(C#N)C#N)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 104.3 %

Procedure:
To a solution of 0.85 mL (6 mmol) of diisopropylamine in 11.3 mL of dry tetrahydrofuran, cooled to -78° C., was added 3.5 mL (5.6 mmol) of BuLi and the resulting mixture was stirred for 10 min. Next, 0.34 g (5.1 mmol) of malononitrile dissolved in 1.7 mL of tetrahydrofuran was carefully added and the resulting mixture was stirred for 30 min more. Finally, 1 g (5.1 mmol) of 4-methylbenzophenone in 1.7 mL of tetrahydrofuran was added. The mixture was allowed to warm up to room temperature and then it was heated at reflux for 2 days. Ethyl acetate was added and the resulting solution was washed with water. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried and the solvent was removed to yield 1.3 g of the desired product as a reddish oil (yield: quantitative).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.[NH2:37][C:38]1[CH:39]=[CH:40][C:41]([Cl:48])=[C:42]([CH:47]=1)[C:43]([O:45][CH3:46])=[O:44]>CN(C)C=O.O>[CH3:46][O:45][C:43](=[O:44])[C:42]1[CH:47]=[C:38]([NH:37][C:4]([C:3]2[C:2]([CH3:1])=[N:10][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=2)=[O:6])[CH:39]=[CH:40][C:41]=1[Cl:48]
Reactant: COC(=O)c1cc(N)ccc1Cl
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(NC(=O)c2ccc(C(F)(F)F)nc2C)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of 2-methyl-6-trifluoromethynicotinic acid (4.77 g; 23 mmol) in dimethyl formamide (100 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.46 g; 23 mmol) and 1-hydroxy-7-azabenzotriazole (3.17 g; 23 mmol) and the resulting solution was stirred at room temperature for 30 minutes. To this was added a solution of methyl 5-amino-2-chlorobenzoate (3.6 g; 19 mmol) in dimethyl formamide (25 ml) and the resulting solution stirred at room temperature for 18 hours. Water (200 ml) was added to the reaction mixture and this was extracted with ethyl acetate (3×200 ml). The combined organic layers were washed with saturated sodium bicarbonate solution (2×300 ml). The organic layer was dried (magnesium sulphate), filtered and evaporated to give 2-chloro-5-[(2-methyl-6-trifluoromethyl-pyridine-3-carbonyl)-amino]-benzoic acid methyl ester (6.6 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=2)=[N:9][C:10]2[S:11][C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=2)=[N:6][CH:7]=1.[Si]([C:32]#[N:33])(C)(C)C>CO.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:9][C:10]2[S:11][C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=2)([C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[C:19]([F:27])[CH:18]=2)[C:32]#[N:33])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)C#N
Reactant: Cc1nc(N=C(c2cc(F)cc(C(F)(F)F)c2)c2ccc(Cl)cn2)sc1C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CO
Product: Cc1nc(NC(C#N)(c2cc(F)cc(C(F)(F)F)c2)c2ccc(Cl)cn2)sc1C
Temperature: 25 °C

Procedure:
At 0° C. to a solution of N-((5-chloropyridin-2-yl)(3-fluoro-5-(trifluoromethyl)phenyl)methylene)-4,5-dimethylthiazol-2-amine (848 mg, 2.05 mmol) in MeOH (10 mL) was added ZnCl2 (214 mg, 1.43 mmol), followed by the addition of TMSCN (830 μL, 6.19 mmol). The reaction was allowed to slowly warm up to room temperature and heated at 65° C. for 18 h. The reaction mixture was cooled down to room temperature and concentrated. The residue was diluted by addition of DCM. The solid was removed by filtration and the filtrate was concentrated. A portion of the residue was purified by ISCO chromatography (12 g column) using hexanes/EtOAc (0-300%) over 22 min. Methyl 2-(5-chloropyridin-2-yl)-2-(4,5-dimethylthiazol-2-ylamino)-2-(3-fluoro-5-(trifluoromethyl)phenyl)acetate eluted at a retention time of 7-8 min. LCMS RT=3.25 min [M+H] 473.84 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). NMR: 400 MHz 1H (CDCl3) 7.74 ppm, 1H, s; 7.67 ppm, 1H, dd, J=8.57, 2.42 Hz; 7.56 ppm, 1H, m; 7.30 ppm, 2H, m; 3.76 ppm, 3H, m; 2.09 ppm, 6H, m.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.ClC(Cl)(O[C:30](=[O:36])OC(Cl)(Cl)Cl)Cl.[F:38][C:39]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:40]=1[NH2:41].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[F:38][C:39]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:40]=1[NH:41][C:30]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[N+:23]([O-:25])=[O:24])=[O:36]
Reactant: Nc1ccc(F)cc1F
Reactant: COc1cc2nccc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c([N+](=O)[O-])c3)c2cc1OC
Yield: 55.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-nitroaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml), and a solution of triphosgene (96 mg) in chloroform was then added to the solution. The mixture was heated under reflux for 5 min. Next, 2,4-difluoroaniline (45 mg) was added to the reaction solution, and the mixture was further heated under reflux overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was supported on diatomaceous earth, followed by extraction with chloroform. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography on silica gel by development with chloroform/acetone (3/1) to give 81 mg (yield 56%) of the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:20]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[OH:4].[F:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([C:43](O)=[O:44])=[CH:35][CH:34]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([C:43]([NH:1][CH:2]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:30])([F:31])[CH:27]([F:28])[F:29])[CH:20]=2)[CH:3]([OH:4])[C:5]2[CH:6]=[CH:7][C:8]([O:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:9][CH:10]=2)=[O:44])=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccc2)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-phenoxyphenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol (300 mg, 0.69 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (131 mg, 0.69 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198 mg, 1.03 mmol) and 1-hydroxybenzotriazole hydrate (105 mg, 0.69 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted-with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-ethyl acetate). Recrystallization from ethyl-acetate-hexane gave the objective substance (286 mg, 68%).
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([O:8]S(C)(=O)=O)[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3]1.[F:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([C:27]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[C:33](O)[CH:34]=[CH:35][CH:36]=4)[N:31]=3)=[N:28][N:29]=2)[CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC(N(C)C)=O>CCOC(C)=O.O>[F:1][C@H:2]1[C@@H:7]([O:8][C:33]2[CH:34]=[CH:35][CH:36]=[C:37]3[C:32]=2[N:31]=[C:30]([C:27]2[N:25]4[CH:26]=[C:21]([F:20])[CH:22]=[CH:23][C:24]4=[N:29][N:28]=2)[CH:39]=[CH:38]3)[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)[C@H](F)C1
Reactant: Oc1cccc2ccc(-c3nnc4ccc(F)cn34)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc3ccc(-c4nnc5ccc(F)cn45)nc23)[C@H](F)C1
Temperature: 90 °C
Yield: 81 %

Procedure:
A mixture of (trans)-tert-butyl 3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate (24 mg, 0.0807 mmol), 2-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol (23.8 mg, 0.0850 mmol) and Cs2CO3 (55.4 mg, 0.170 mmol) in DMA (425 μl, 0.0850 mmol) was heated to 90° C. for 16 hours. The mixture was transferred to a separatory funnel and diluted with EtOAc and water. The mixture was then extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to a residue under reduced pressure to give the product without further purification (33 mg, 81% yield). MS APCI (+) m/z 481.9 (M+1) detected.