Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[CH3:25][CH:26]1[NH:31][CH2:30][CH2:29][NH:28][CH2:27]1>>[CH3:25][CH:26]1[NH:31][CH2:30][CH2:29][N:28]([CH2:22][C:17]2[CH:16]=[C:15]3[C:20]([CH:21]=[C:12]([C:10]4[N:11]=[C:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[S:8][CH:9]=4)[C:13](=[O:24])[NH:14]3)=[CH:19][CH:18]=2)[CH2:27]1
Reactant: CC1CNCCN1
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Product: CC1CN(Cc2ccc3cc(-c4csc(-c5ccncc5)n4)c(=O)[nH]c3c2)CCN1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and 3-methylpiperazine to give a yellow solid. MS m/z: 418.3 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:16])[C:11](=[CH:14][CH:15]=1)[CH:12]=[O:13].Br[CH2:18][C:19]([CH:21]([CH3:23])[CH3:22])=[CH2:20]>CN(C)C=O>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([O:16][CH2:20][C:19](=[CH2:18])[CH:21]([CH3:23])[CH3:22])[CH:9]=1
Reactant: O=Cc1ccc(Cl)cc1O
Reactant: C=C(CBr)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(COc1cc(Cl)ccc1C=O)C(C)C
Temperature: 70 °C
Yield: 91.6 %

Procedure:
To a solution of 8.8 g (0.064 mol) of potassium carbonate in 100 mL of dimethylformamide was added 10.0 g (0.064 mol) of 4-chlorosalicylaldehyde and 12.5 g (0.077 mol) of 2-(bromomethyl)-3-methyl-1-butene. The reaction mixture was heated at 70° C. for 2 hours, cooled to room temperature and poured into 600 mL ice/water. The crude mixture was extracted with ethyl acetate (3×100 mL). The ethyl acetate was washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford 14.0 g of a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Cl[C:16]1[N:21]=[C:20]([C:22]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=2[C:24]#[N:25])[C:19]([F:31])=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[K+]>CN(C)C(=O)C.CO.C(O)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:30][C:27]1[CH:28]=[CH:29][C:22]([C:20]2[C:19]([F:31])=[CH:18][CH:17]=[C:16]([C:12]3[N:4]4[CH:5]=[CH:6][C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:2]([F:1])[C:3]4=[N:14][CH:13]=3)[N:21]=2)=[C:23]([CH:26]=1)[C:24]#[N:25]
Reactant: N#Cc1cc(F)ccc1-c1nc(Cl)ccc1F
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(F)cc4C#N)n3)cnc2c1F
Temperature: 130 °C

Procedure:
To 2-(8-fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol (0.21 g, 1.10 mmol), 2-(6-chloro-3-fluoropyridin-2-yl)-5-fluorobenzonitrile (0.25 g, 1.00 mmol) and palladium acetate (0.011 g, 0.05 mmol) in N,N-dimethylacetamide (2 ml) was added triphenylphosphine (0.013 g, 0.05 mmol) followed by potassium acetate (0.14 g, 1.51 mmol) and the mixture heated at 130° C. for 2 h. The reaction was cooled to ambient temperature, diluted with methanol (8 ml) and 2 drops of acetic acid were added. The mixture was poured onto a strong cation exchange cartridge and eluted with several column lengths of methanol. Several column lengths of 2N ammonia in methanol were then eluted to recover the product. The pale yellow oil was chromatographed on silica, eluting with 3% methanol in dichloromethane, to give the title material as a white powdery solid. Recrystallised from ethyl acetate/ether to afford the title compound (215 mg): δH (400 MHz, CDCl3) 1.73 (6H, s), 2.07 (1H, s), 7.26 (1H, d, J 14.4), 7.45-7.49 (1H, m), 7.61 (1H, dd, J 2.6, 7.9), 7.67 (1H, t, J 9.0), 7.77-7.80 (1H, m), 7.88 (1H, dd, J 3.3, 8.9), 8.15 (1H, s), 9.59 (1H, d, J 7.3); m/z (ES+) 409.
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH2:23])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[F:24][C:25]([F:44])([F:43])[C:26]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:27]=1[C:28]([NH:30][CH2:31][C:32](O)=[O:33])=[O:29]>>[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH:23][C:32](=[O:33])[CH2:31][NH:30][C:28](=[O:29])[C:27]2[CH:35]=[C:36]([C:39]([F:42])([F:41])[F:40])[CH:37]=[CH:38][C:26]=2[C:25]([F:24])([F:43])[F:44])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(O)CNC(=O)c1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: CCN=C=NCCCN(C)C
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)c2cc(C(F)(F)F)ccc2C(F)(F)F)C1

Procedure:
The title compounds were prepared as white solids from EDCI coupling between 3-amino-azetidine-1-carboxylic acid tert-butyl ester and (2,5-bistrifluoromethyl-benzoylamino)-acetic acid (prepared by the method similar to Ingersoll, A. W. et. al., Organic Syntheses 1932, XII, 40-2) using the procedure described in Step C of Example 1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=CC=[CH:16][C:15]=2F)=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.[C:39](O)([C:41]([F:44])(F)F)=O>C(Cl)Cl>[F:44][C:41]1[CH:39]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([N:31]5[CH:35]=[CH:34][N:33]=[N:32]5)[CH:26]=4)[CH2:23][C:22](=[O:37])[NH:21][C:9]=3[CH:10]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnn3)c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1

Procedure:
Prepared from {2′-fluoro-3-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K81) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (29 mg).
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([CH2:8][C:9]([F:12])([F:11])[F:10])[C:6](=[O:13])[C@@H:5]([NH:14]C(=O)OC(C)(C)C)[CH2:4][C@H:3]1[C:22]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=1[F:30].[ClH:31]>CCOC(C)=O>[ClH:31].[NH2:14][C@H:5]1[CH2:4][C@@H:3]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=2[F:30])[C@@H:2]([CH3:1])[N:7]([CH2:8][C:9]([F:12])([F:11])[F:10])[C:6]1=[O:13]
Reactant: C[C@@H]1[C@H](c2c(F)ccc(F)c2F)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@H](c2c(F)ccc(F)c2F)C[C@H](N)C(=O)N1CC(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl [(3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]carbamate (122 mg, 0.277 mmol) in EtOAc (10 mL) was saturated with HCl(g) and aged for 30 min. The resulting mixture was concentrated in vacuo to give the title compound. MS: m/z=341.1 (M+1); 1H NMR (500 MHz, CD3OD) δ 7.33 (qd, 1H, J=9.3, 4.9 Hz), 7.05 (tdd, 1H, J=9.8, 3.7, 2.2 Hz), 4.78 (dq, 1H, J=15.4, 9.3 Hz), 4.22 (dd, 1H, J=12.2, 6.6 Hz), 4.06 (ddd, 1H, J=13.3, 4.5, 2.7 Hz), 3.97 (m, 1H), 3.73 (dq, 1H, J=15.4, 8.8 Hz), 2.91 (qt, 1H, J=12.7, 3.1 Hz), 2.36 (ddd, 1H, J=12.7, 6.4, 2.0 Hz), 1.22 (d, 3H, J=6.6 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][CH:19]=[C:18]2[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cccc(C(=O)c2ccc(O)cc2)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COc1cc2nccc(Oc3ccc(C(=O)c4cccc(C)c4)cc3)c2cc1OC
Yield: 45.3 %

Procedure:
(4-Hydroxyphenyl)(3-methylphenyl)methanone (307 mg) was dissolved in xylene to prepare a solution. 4-Dimethylaminopyridine (194 mg) and 4-chloro-6,7-dimethoxyquinoline (342 mg) were added to the solution, and the mixture was heated under reflux for 23 hr. A saturated aqueous sodium hydrogencarbonate solution was added thereto, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and was then concentrated. The residue was subjected to separation and purification by column chromatography on silica gel using hexane-ethyl acetate, chloroform, and hexane-acetone as solvents to give the title compound (262 mg, yield 45%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-])=O)=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2>[Pd].C(O)C>[NH2:11][C:3]1[C:2]([CH3:1])=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: Cc1c([N+](=O)[O-])ccc2cc[nH]c12
Agent: [Pd]
Solvent: CCO
Product: Cc1c(N)ccc2cc[nH]c12
Reaction time: 7 h
Yield: 76.5 %

Procedure:
A degassed suspension of 7-methyl-6-nitroindole (1.5 g, 8.5 mmol) and catalytic 10% palladium on carbon in ethanol (75 mL) is placed under an atmosphere of hydrogen at 50 p.s.i. for 7 hours. The reaction mixture is filtered through Celite and the mixture concentrated by rotary evaporation. The crude residue is purified via silica gel column chromatography using 20% isopropanol/hexanes as the eluting solvent. The product containing fractions are combined and the solvents removed by rotary evaporation to yield 0.95 g of 6-amino-7-methylindole as a light brown solid (76% yield).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.O[C:21]1C=CC(C(OC)=O)=CC=1.C1(CO)CCCC1>>[CH:4]1([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:18][CH:19]=2)[CH2:1][CH2:3][CH2:2][CH2:21]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Agent: OCC1CCCC1
Product: O=C(O)CNC(=O)c1ccc(OCC2CCCC2)cc1
Yield: 35 %

Procedure:
Reactions similar to those described in Example 1 (1a) and (1b) were conducted using methyl 4-hydroxybenzoate (22.8 g, 150 mmol) and cyclopentylmethanol (10.0 g, 100 mmol) to give 9.3 g of the title compound (colorless crystal, yield: 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH:39]([F:41])[F:40])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH:26]=[C:27]3[CH2:32][CH2:31][CH:30]([NH:33][CH2:34][CH2:35][C:36]#[N:37])[CH2:29][CH2:28]3)[N:9]=2)[CH:7]=1.C=O.[BH3-][C:45]#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH:39]([F:41])[F:40])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH:26]=[C:27]3[CH2:32][CH2:31][CH:30]([N:33]([CH2:34][CH2:35][C:36]#[N:37])[CH3:45])[CH2:29][CH2:28]3)[N:9]=2)[CH:7]=1
Reactant: N#CCCNC1CCC(=CCn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN(CCC#N)C1CCC(=CCn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(2-cyanoethyl)amino]cyclohexylidene]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (140.0 mg, 0.241 mmol) in methanol (20 mL) was added 40% HCHO aqueous solution (75 mg, 0.96 mmol). The resulting solution was stirred at room temperature overnight. Then NaBH3CN (15.14 mg, 0.241 mmol) was added. The resulting solution was stirred at room temperature for 4 h and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/MeOH (10/1). This resulted in 34.7 mg (24%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(2-cyano ethyl)(methyl)amino]cyclohexylidene]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 33) [M+H]+=595.4, RT=1.43 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.73 (s, 1H), 9.33 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.66 (m, 2H), 8.28 (s, 1H), 7.64-7.60 (m, 2H), 7.43 (d, 1H, J=8.4 Hz), 7.27 (dd, 1H, J=4.5, 7.5 Hz), 7.00 (t, 1H, J=73.5 Hz), 5.43 (t, 1H, J=7.2 Hz), 4.81 (d, 2H, J=6.9 Hz), 2.88-2.82 (m, 1H), 2.66-2.59 (m, 5H), 2.33-2.29 (m, 1H), 2.22 (s, 3H), 2.10-2.05 (m, 1H), 1.93-1.80 (m, 3H), 1.37-1.25 (m, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][C:22]1[CH:23]=[C:24]([CH3:41])[CH:25]=[C:26]2[C:31]=1[O:30][CH:29]([C:32]([F:35])([F:34])[F:33])[C:28]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:27]2.[C:42]1([SH:48])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:41][C:24]1[CH:25]=[C:26]2[C:31](=[C:22]([CH2:21][S:48][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:23]=1)[O:30][CH:29]([C:32]([F:34])([F:35])[F:33])[C:28]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:27]2
Reactant: Sc1ccccc1
Reactant: CCOC(=O)C1=Cc2cc(C)cc(CO)c2OC1C(F)(F)F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2cc(C)cc(CSc3ccccc3)c2OC1C(F)(F)F
Reaction time: 0.25 h
Yield: 98 %

Procedure:
The polymer bound triphenylphosphine (1.2 g, 3.6 mmole) was suspended in anhydrous THF (10 mL) and the mixture was allowed to stir for 15 minutes. The ethyl 8-(hydroxymethyl)-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 605b, Step 1 (0.38 g, 1.20 mmole), benzenethiol (0.20 g, 1.80 mmole) and DEAD (0.31 g, 1.80 mmole) were added to above mixture, which was allowed to stir for 18 hours. The resulting mixture was filtered through a plug of celite and condensed in vacuo to give a yellow oil (0.49 g, 98%). No further purification was performed. GCMS m/z 408.0 (M+).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1>CN(C=O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: OCC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1
Reaction time: 2 h
Yield: 90.3 %

Procedure:
2,2,2-Trifluoro-ethanol (7.09 g, 70.09 mmol) and stirred for 30 min. A solution of 1-Fluoro-4-nitro-benzene (10 g, 70.09 mmol) in DMF (25 mL) was added at 5-15° C., allowed to rt, stirred for 2 h, quenched with ice-water, filtered, washed with water and dried under high vacuum to obtain 14 g (89%) 1-Nitro-4-(2,2,2-trifluoro-ethoxy)-benzene as yellow solid. Subsequently, a solution of 1-Nitro-4-(2,2,2-trifluoro-ethoxy)-benzene (50 g, 226.2 mmol) in methanol (400 mL) was purged with nitrogen and 10% Pd—C (4.6 g) was added under nitrogen. This was stirred at rt under hydrogen atmosphere (balloon pressure) for 24 h. The reaction mixture was filtered through a celite bed and washed with methanol and the filtrate was removed under reduced pressure and washed with hexane to get 37 g (87%) 4-(2,2,2-Trifluoro-ethoxy)-phenylamine as a brown liquid. LC-MS: 192.4 [M+1]+. To a solution of 4-(2,2,2-Trifluoro-ethoxy)-phenylamine (12 g, 62.82 mmol) in DCM (1000 mL) was added solid NaHCO3 (52.77 g, 628.2 mmol). After 10 min, triphosgene (27.96 g, 94.24 mmol) dissolved in toluene (30 mL) was added to the reaction mixture under cooling at 10° C. and stirred for 10 min. The reaction mixture was filtered and the filtrate was concentrated, azeotroped twice with dry toluene to give 10 g 1-Isocyanato-4-(2,2,2-trifluoro-ethoxy)-benzene as yellow oily liquid which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)O)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[BrH:19]>O>[Br:19][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:16]([O-:18])=[O:17])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(C(O)c2ccccc2)ccc1Cl
Reactant: Br
Solvent: O
Product: O=[N+]([O-])c1cc(C(Br)c2ccccc2)ccc1Cl
Reaction time: 0.75 h
Yield: 99.3 %

Procedure:
A mixture of 58 parts of 4-chloro-3-nitro-α-phenylbenzenemethanol and 450 parts of a hydrobromic acid solution 48% in water was stirred for 45 minutes at reflux temperature. After cooling, the product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 71.4 parts (99.3%) of 4-(bromophenylmethyl)-1-chloro-2-nitrobenzene as a residue (int. 132).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][C:25]([CH3:27])=[CH:24][N:19]3[C:20](=[O:23])[C:21]=2I)[CH2:3][CH2:2]1.[F:28][C:29]([F:41])([F:40])[O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][C:25]([CH3:27])=[CH:24][N:19]3[C:20](=[O:23])[C:21]=2[C:34]2[CH:33]=[CH:32][C:31]([O:30][C:29]([F:28])([F:40])[F:41])=[CH:36][CH:35]=2)[CH2:3][CH2:2]1
Reactant: COc1cccc(/C=C/c2nc3sc(C)cn3c(=O)c2I)c1OCC1CC1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cccc(/C=C/c2nc3sc(C)cn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)c1OCC1CC1
Yield: 56.2 %

Procedure:
The title compound was prepared from Intermediate 16 (100 mg, 0.202 mmol) and 4-trifluoromethoxyphenylboronic acid (58 mg, 0.283 mmol) using Pd[(C6H5)3P]4 (90 mg, 0.008 mmol) and sodium carbonate (128 mg, 1.213 mmol) in toluene (10 ml) and ethanol (5 ml) and water (4 ml) according to the procedure outlined in Example 1 to afford crude residue which was purified by column chromatography to afford 60 mg of the desired product; 1H NMR (300 MHz, DMSO-d6) δ 0.22-0.27 (m, 2H), 0.46-0.52 (m, 3H), 0.98-1.01 (m, 1H), 2.44 (s, 3H), 3.67 (d, J=6.9 Hz, 2H), 3.76 (s, 3H), 6.86-6.92 (m, 2H), 6.99-7.00 (m, 2H), 7.45 (m, 1H), 7.84 (s, 1H), 8.12 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 529.23 (M+H)+.
Reaction SMILES: C(SCC1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](C3C=CC=CC=3OC)[CH:18]=2)[NH:13]C(C)(C)C=1)C1C=CC=CC=1.Br[CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[O:48][CH3:49])[CH:40]=2)[NH:35][C:34]([CH3:51])([CH3:50])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+].C(S)C1C=CC=CC=1>>[CH3:49][O:48][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[C:39]1[CH:40]=[C:41]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([CH3:51])([CH3:50])[CH:33]=[C:32]2[CH2:31][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CSCc1ccccc1)=CC(C)(C)N2
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: SCc1ccccc1
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
4-Benzylsulfanylmethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline 80 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 69 mg of potassium carbonate, and 52 μL of benzyl mercaptan reacted to give 12 mg of the title compound as an oil.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([CH2:16][CH2:17]O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:1]([O:9][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCc1ccccc1
Reactant: O=C(O)c1ccccc1
Product: O=C(OCCc1ccccc1)c1ccccc1
Temperature: 180 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
A 2-L, 4-neck round bottom flask, fitted with a thermometer, mechanical stirrer, nitrogen inlet tube and Liebig condenser/receiving flask, was charged with 671.7 g (5.50 mol, 1.00 equiv) of benzoic acid, 806.3 g (6.60 mol, 1.20 equiv) of 2-phenylethyl alcohol, and 1.25 g (0.1% w/w) of Fascat 2001®. The system was heated gently with slow stirring (<50 rpm) until the benzoic acid dissolved. The air was removed with three cycles of evacuation/nitrogen fill using a mechanical vacuum pump (50-100 torr). The rate of stirring was increased to ca. 200 rpm, the nitrogen sparge was set at 0.2 scfh, and the reaction mixture was heated to 180° C. After a 1-h hold, the temperature was increased to 190° C. for 1 h and then to 200° C. for 1 h. The temperature was increased to 210° C. and the nitrogen sparge was increased to 0.5 scfh. After a 1-h hold, the temperature was further increased to 220° C. for 1 h. The total amount of distillate was 159.2 g, from which 94.4 g of water (theor. 99.1 g) was separated as the top layer. The reaction mixture was cooled to room temperature and sampled for analysis. The acid number was 1.10 mg KOH/g (99.7% conversion) and the APHA color was 115. The excess 2-phenylethyl alcohol (5.5% by GLC) was removed by vacuum distillation. Thus, after 1 h at 180-190° C. and 20 torr (0.5 scfh nitrogen sweep), the residual 2-phenylethyl alcohol was <0.05% by GLC and the APHA color was 222. Activated carbon (37.3 g, 3% w/w) was added, and the mixture was heated at 75-80° C. under vacuum (50-70 torr) for 1 h. After cooling to room temperature, filtration through Celite® gave 1100 g (90%) of 2-phenylethyl benzoate. The APHA color was 20, the acid number was 0.14 mg KOH/g, the saponification number was 246 mg KOH/g (theor. 248), and the residual tin was <10 ppm.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[C:19]1([CH:29]=O)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:29][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: O=Cc1cccc2ccccc12
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc2ccccc12

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available 1-naphthaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.87 min.; [M+H]+: 362.17 g/mol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH:54]2[CH2:56][O:55]2)=[CH:48][CH:47]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[OH:55][C@H:54]([CH2:53][O:52][C:49]1[CH:50]=[CH:51][C:46]([OH:45])=[CH:47][CH:48]=1)[CH2:56][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(NC2CCN(C(=O)c3n[nH]c4ccccc34)CC2)cc1
Product: O=C(c1n[nH]c2ccccc12)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 32 %

Procedure:
{4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}(1H-indazol-3-yl)methanone (0.20 g, 0.55 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.222 g, 0.55 mmol) according to Procedure G to give the title compound (0.093 g, 0.176 mmol).