Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[C:15]3[Cl:20])C=CC=CC=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>CS(C)=O>[Cl:20][C:15]1[C:16]2[C:11](=[C:10]([NH:9][C:8]([NH:29][CH2:28][C:27]3[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:31][CH:30]=3)=[O:21])[CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:13][N:14]=1
Reactant: O=C(Nc1cccc2c(Cl)nccc12)Oc1ccccc1
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: CS(C)=O
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2c(Cl)nccc12
Yield: 62.1 %

Procedure:
(1-Chloro-isoquinolin-5-yl)-carbamic acid phenyl ester (150 mgs, 0.5 mmol), and 4-trifluoromethyl-benzylamine (88 mgs, 0.5 mmol) were combined and stirred overnight in DMSO (4 mL) at ambient temperature. The product was purified by directly injecting the crude reaction onto a reverse phase prep-HPLC (90–10% water:acetonitrile gradient). The appropriate fractions were lyophilized to yield 1-(1-Chloro-isoquinolin-5-yl)-3-(4-trifluoromethyl-benzyl)-urea (118 mgs, 61%) MS (MH+) 379.9; 1H NMR (DMSO-d6) δ 4.47 (d, 2H, J=5.8 Hz), 7.21 (m, 1H), 7.56 (d, 2H, J=8.1 Hz), 7.71–7.76 (m, 3H), 7.93 (d, 1H, J=8.5), 8.01 (d, 1H, J=6.0 Hz), 8.34–8.36 (m, 2H), 8.95 (s, 1H). HPLC Rt=4.57 min (90–10% water:acetonitrile gradient, 100% pure).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]([C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[S:13][CH:14]=1)[CH2:6][CH:7]([CH3:9])[CH3:8].[CH3:30][O:31][CH2:32][C:33](O)=[O:34]>>[CH3:30][O:31][CH2:32][C:33]([NH:4][C@H:5]([C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[S:13][CH:14]=1)[CH2:6][CH:7]([CH3:8])[CH3:9])=[O:34]
Reactant: COCC(=O)O
Reactant: COc1cc(Nc2nc([C@@H](N)CC(C)C)cs2)ccc1-n1cnc(C)c1
Agent: Cl
Product: COCC(=O)N[C@@H](CC(C)C)c1csc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1

Procedure:
The title compound was prepared in analogy to example 34 from 96 mg (0.2 mmol) [4-((S)-1-amino-3-methyl-butyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine trihydrochloride and 20 mg (0.22 mmol) methoxyacetic acid yielding 100 mg (100%) 2-methoxy-N—((S)-1-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-3-methyl-butyl)-acetamide as a viscous oil. MS ISP (m/e): 444.2 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.38 (s, 1H), 7.82 (d, 1H), 7.64 (s, 1H), 7.23 (d, 1H), 7.02 (s, 1H), 6.98 (d, 1H), 6.62 (s, 1H), 4.98 (q, 1H), 3.85 (s, 2H), 3.82 (s, 3H), 2.73 (s, 3H), 2.14 (s, 3H), 1.71 (t, 2H), 1.55 (m, 1H), 0.90 (t, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:24])=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][CH2:8][CH:9](O)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.S(=O)(=O)(O)O>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[C:4]([CH3:24])=[C:5]2[C:21]([CH:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=3)[CH2:8][NH:7][CH2:6]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(C(O)CNCc2cccc(OC)c2C)cc1OC
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CNCc3c2ccc(OC)c3C)cc1OC
Yield: 89.2 %

Procedure:
510 mg of α-[[(3-methoxy-2-methylbenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol was dissolved in 3.8 ml of trifluoroacetic acid, 0.12 ml of conc. sulfuric acid was added dropwise under ice cooling, and the mixture was allowed to react for 30 minutes. The reaction solution was concentrated, and subjected to azeotropic distillation with toluene 2 times. The residue was dissolved in chloroform, and basified by addition of 28% aqueous ammonia. The chloroform layter was collected, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-n-hexane, giving 430 mg of 7-methoxy-4-(3,4-dimethoxyphenyl)-8-methyl-1,2,3,4-tetrahydroisoquinoline, m.p. 128°-129° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][NH:15]C2N=C(N(C)C)C3C(=CC=CC=3)N=2)[CH2:10][CH2:9]1)(C)(C)C.Cl.[CH3:31][CH2:32][O:33][C:34](C)=[O:35]>>[CH2:32]([O:33][C:34](=[O:35])[NH:15][CH2:14][C@H:11]1[CH2:12][CH2:13][C@@H:8]([NH2:7])[CH2:9][CH2:10]1)[C:31]1[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(C)=O
Reactant: CN(C)c1nc(NC[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)nc2ccccc12
Agent: Cl
Product: N[C@H]1CC[C@@H](CNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of cis-[4-(benzyloxycarbonylamino-methyl)-cyclohexyl]-carbamic acid tert-butyl ester obtained in step C of example 23 (12.9 g, 35.6 mmol) in EtOAc (129 mL) was added 4 M hydrogen chloride in EtOAc (129 mL). The reaction mixture was stirred at ambient temperature for 3 hr, filtered, washed with EtOAc, and dried under reduced pressure. The solid was dissolved in saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 (five times), dried over MgSO4, filtered and concentrated, and dried under reduced pressure to give cis-(4-amino-cyclohexylmethyl)-carbamic acid benzyl ester (8.88 g, 95%) as a colorless oil.
Reaction SMILES: CCCCCC.C([Li])CCC.C([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)C1C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH:32]=O.[Cl-].[NH4+].Cl>C1COCC1.CO.[OH-].[Pd+2].[OH-]>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH2:32][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[OH:19]
Reactant: COc1ccc(C=O)cc1OC
Reactant: Brc1ccccc1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [Cl-]
Solvent: CCCCCC
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cc2ccccc2O)cc1OC
Reaction time: 1 h
Yield: 44.4 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.59 M, 4.4 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (1.74 g, 6.61 mmol) in THF (30 mL) at −78° C. and the mixture solution was stirred at the same temperature for one hour. To this solution, a solution of 3,4-dimethoxybenzaldehyde (1.00 g, 6.02 mmol) in THF (8 mL) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for 1.5 hours, and then a saturated ammonium chloride aqueous solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure to obtain a crude product (2.38 g). The obtained crude product was dissolved in methanol (20 mL) and a 20% palladium hydroxide catalyst (196 mg) was added and furthermore 2N—HCl (30 μL) was added thereto. The mixture solution was stirred under a hydrogen atmosphere for 23 hours, and then the catalyst was filtered off. The solvent was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (653 mg, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:14]([CH3:16])[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.[OH-].[Na+].O>ClCCl.II>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:25][C:14]2([CH3:15])[CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=C(C)C)c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: II
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1(c2ccc(Cl)cc2)OC1(C)C
Reaction time: 48 h
Yield: 70.3 %

Procedure:
A solution of ethyl 2-(4-chlorophenyl)-3-methylbut-2-enoate (11.4 g, 0.048 mol), prepared in Example 1c, m-chloroperbenzoic acid (15.7 g, 0.050 mol) and iodine (0.1 g) in dichloromethane (400 ml) was stirred for 48 hours at 50°-55° c. During this period, the course of the reaction was monitored by analytical thin layer chromatography and three further portions (2.0 g) of m-chloroperbenzoic acid and two further portions (0.1 g) of iodine were added to the mixture. The precipitate which formed during this time was dissolved by the addition of 2N sodium hydroxide solution (40 ml) and iced water (200 ml). The organic phase was then separated and washed with dilute sodium hydroxide solution (100 ml) and then with water (3×200 ml). The solution was dried (sodium sulphate), evaporated in vacuo, and the crude product purified by flash silica column chromatography, eluting with 1,2-dichloroethane, to give the title compound (8.6 g, 71%) as an oil.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][P:18]([O:22][CH3:23])([O:20][CH3:21])=[O:19])[CH2:13][C@@H:12]1[C:24]([OH:26])=[O:25])=O)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:21][O:20][P:18]([CH2:17][C@H:14]1[CH2:15][CH2:16][NH:11][C@@H:12]([C:24]([OH:26])=[O:25])[CH2:13]1)([O:22][CH3:23])=[O:19]
Reactant: COP(=O)(C[C@H]1CCN(C(=O)OCc2ccccc2)[C@@H](C(=O)O)C1)OC
Agent: [Pd]
Solvent: CCO
Product: COP(=O)(C[C@H]1CCN[C@@H](C(=O)O)C1)OC

Procedure:
A solution of 1.0 g of cis-1-benzyloxycarbonyl-4-dimethylphosphonomethyl-2-piperidinecarboxylic acid in 30 ml of ethanol is hydrogenated at 3 atmospheres pressure over 500 mg of 10% palladium on carbon catalyst in 30 ml of ethanol. Filtration and removal of solvent affords cis-4-dimethylphosphonomethyl-2-piperidine-carboxylic acid as an amorphous solid.
Reaction SMILES: C(OC(=O)[N:7]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:39][CH2:40][CH3:41])[CH2:36][CH2:37][CH3:38])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:25][C:26]2[NH:27][CH:28]=[CH:29][N:30]=2)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)=[CH:11][CH:10]=1)(C)(C)C.Cl.C(OCC)C>CO>[NH:27]1[CH:28]=[CH:29][N:30]=[C:26]1[CH2:25][N:16]([CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH:7][CH2:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:36][CH2:37][CH3:38])[CH2:39][CH2:40][CH3:41])=[CH:10][CH:11]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=1
Reactant: CCCN(CCC)CCCCN(Cc1ccc(CN(Cc2ccc(C)cn2)Cc2ncc[nH]2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CCCN(CCC)CCCCNCc1ccc(CN(Cc2ccc(C)cn2)Cc2ncc[nH]2)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
The compound (35.5 mg) obtained in Example 75-2 was dissolved in methanol (1.0 ml) and then added with a 1 mol/l hydrogen chloride/diethyl ether solution (2 ml), followed by stirring at 40° C. for 1 hour. The solvent was distilled off, thereby obtaining hydrochloride (36.9 mg) of the subject compound as a yellow solid.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]([CH3:22])[CH2:19][CH2:20][OH:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].CCN(CC)CC>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]([CH2:19][CH:20]=[O:21])[CH3:22])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC=O)C(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 74.9 %

Procedure:
To a stirring solution of DMSO (1.34 g) in CH2Cl2 (10 ml) was added dropwise a solution of oxalyl chloride (1.45 g) in CH2Cl2 (5 ml) at -60° C. under nitrogen atmosphere. After five minutes, a solution of N-(tert-butoxycarbonyl)-N-methylethanolamine (1.00 g) in CH2Cl2 (5 ml) was added dropwise to the solution and the mixture was stirred at the same temperature for five minutes. To this solution was added Et3N (2.89 g) and the temperature was allowed to rise to 0° C. and the mixture was stirred at the same temperature for thirty minutes. After evaporation of the solvent, the residue was dissolved in EtOAc (50 ml) and washed with 1N aq. HCl (50 ml), water (50 ml), saturated sodium bicarbonate solution (50 ml) and brine (50 ml), successively. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo to give N-(tert-butoxycarbonyl)-N-methylaminoacetaldehyde (0.74 g) as an oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].Br[C:54]1[CH:59]=[CH:58][C:57]([S:60][C:61]([F:64])([F:63])[F:62])=[CH:56][CH:55]=1.[C:65]([O:69][C:70]([N:72]1[CH2:77][CH2:76][CH:75]([NH2:78])[CH2:74][CH2:73]1)=[O:71])([CH3:68])([CH3:67])[CH3:66]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:65]([O:69][C:70]([N:72]1[CH2:77][CH2:76][CH:75]([NH:78][C:54]2[CH:59]=[CH:58][C:57]([S:60][C:61]([F:64])([F:63])[F:62])=[CH:56][CH:55]=2)[CH2:74][CH2:73]1)=[O:71])([CH3:68])([CH3:66])[CH3:67]
Reactant: FC(F)(F)Sc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(SC(F)(F)F)cc2)CC1
Temperature: 25 °C
Yield: 48.4 %

Procedure:
Tris(dibenzylideneacetone)dipalladium (23 mg; 0.03 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (46 mg; 0.07 mmol), sodium tert-butoxide (176 mg; 1.83 mmol), 1-bromo-4-trifluoromethylsulfanyl-benzene (314 mg; 1.22 mmol) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (302 mg; 1.51 mmol) are suspended in dry toluene (5 mL) and the mixture is irradiated in a mono-mode microwave oven for 20 minutes at 120° C. The mixture is then cooled down to room temperature, is diluted with ethyl acetate (15 mL), filtered and concentrated under reduced pressure. The crude residue is then diluted in dichloromethane (15 mL) and filtered over a short silica gel pad. The desired product is eluted from the silica gel pad with dichloromethane and the fractions of interest are concentred under reduced pressure to afford the desired product (220 mg; 0.59 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[N:9])[N:3]=1.[K].C(=O)([O-])[O-].[OH:15][C:16]1[CH:17]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:20][CH:21]=1.O>CN(C=O)C>[F:23][C:22]([F:24])([F:25])[C:18]1[CH:17]=[C:16]([O:15][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[N:9])[N:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: N#Cc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(Oc2cccc(C(F)(F)F)c2)n1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
4.00 g (28.9 mmol) of 2-chloro-6-cyanopyridine were introduced together with 9.57 g (69.3 mmol) of potassium /carbonate in 20 ml of anhydrous DMF, and 5.62 g (34.6 mmol) of 3-hydroxybenzotrifluoride were added. After 10 h of stirring at 90° C., H2O was added and the mixture was subjected to repeated extraction with ethyl acetate. The organic phase was then washed twice with water, dried over MgSO4 and concentrated.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([F:14])=[C:12](F)[C:11]([N+:16]([O-:18])=[O:17])=[C:10]([F:19])[C:9]=2[F:20])[CH2:4][CH2:3]1.[CH:21]1([NH2:24])[CH2:23][CH2:22]1>C(N(CC)CC)C>[CH:21]1([NH:24][C:12]2[C:11]([N+:16]([O-:18])=[O:17])=[C:10]([F:19])[C:9]([F:20])=[C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[C:13]=2[F:14])[CH2:23][CH2:22]1
Reactant: CN1CCN(c2c(F)c(F)c([N+](=O)[O-])c(F)c2F)CC1
Reactant: NC1CC1
Solvent: CCN(CC)CC
Product: CN1CCN(c2c(F)c(F)c([N+](=O)[O-])c(NC3CC3)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
1-Methyl-4-(2,3,5,6-tetrafluoro-4-nitrophenyl)piperazine(9.4 g,34.15 mmol) is suspended in triethylamine (20 ml) and treated dropwise with cyclopropylamine (2.9 ml, 41 mmol). During the addition, the temperature is maintained below +10° C. The reaction mixture is stirred at room temperature overnight, then evaporated, suspended in ether (200 ml) and sequentially washed with 1N aqueous sodium hydroxide solution (45 ml), saturated aqueous sodium chloride solution, then dried (magnesium sulfate) and evaporated. Recrystallization from n-hexane yields 9.7 g of N-cyclopropyl-2,4,5-trifluoro-3-(4-methyl-1-piperazinyl)-6-nitroaniline as orange crystals (86%): mp:75° C.; NMR (CDCl3): 0.55 (m,2H),0.75(m,2H),2.35(s,3H),2.53(m,4H),2.92(m,1H),3.40(m,4H), 6.65(s,1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:3]1([CH3:8])[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[SH:15]
Reactant: Sc1ccccc1
Reactant: Cc1ccccc1I
Product: Cc1ccccc1-c1ccccc1S

Procedure:
The general procedure was used to convert 2-iodotoluene and thiophenol to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (386 mg, 96% yield). 1H NMR (300 MHz, CDCl3) δ 7.20–7.00 (m, 9H; Ha, Hb, Hc, Hd, He, He′, Hf, Hf′, Hg), 2.26 (s, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 139.88 (C8), 136.08 (C6), 133.69 (C1), 132.93 (C2), 130.54 (C5), 129.55 (C9, C13), 129.07, (C10, C12), 127.84 (C3), 126.66 (C11), 126.27 (C4), 20.55 (C7). Anal. Calcd. for C13H12S: C, 77.95; H, 6.04; S, 16.01; Found C, 77.87; H, 6.06; S, 15.81.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]=[CH:6][C:7]1[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)C.[Li+].[OH-]>C1COCC1.O>[C:17]1([C:8]2[C:7]([CH:6]=[CH:5][C:4]([OH:23])=[O:3])=[CH:12][CH:11]=[C:10]([C:13]([F:16])([F:14])[F:15])[N:9]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C=Cc1ccc(C(F)(F)F)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.5 %

Procedure:
To a suspension of 3-(2-phenyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid ethyl ester (20 mg, 0.062 mmol) in THF (1 ml) was added an aqueous solution of 0.5 N-LiOH (0.3 ml), and the mixture was stirred for 3 hours at room temperature. The resulting residue was dissolved in H2O and then washed three times with EtOAc, acidified with 1N HCl to pH 1˜2. The solution was extracted three times with methylene chloride and then dried over anhyd. Na2SO4 and concentrated in vacuo to give 3-(2-phenyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (19 mg, 96%). To a suspension of N-(4-aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (21 mg, 0.074 mmol) in THF (3 mL) was added N-methylmorpholine (0.015 ml, 0.148 mmol). The mixture was stirred for 5 minutes, to which were added 3-(2-phenyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (19 mg, 0.065 mmol) and 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM, 19 mg, 0.068 mmol). The mixture was stirred overnight at room temperature and was concentrated under reduced pressure. The residue was diluted with EtOAc and water. The organic layer was washed with saturated sodium bicarbonate, 1N HCl and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by recrystallization from Et2O to give N-(3-ethynyl-5-fluoro-4-methane sulfonylamino-benzyl)-3-(2-phenyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (18 mg, 56%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:2]1.[NH2:19][C@@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22]>>[C:21]([C@@H:20]([NH:19][C:12]([C:10]1[CH:9]=[CH:8][C:7]([C:15]([F:18])([F:17])[F:16])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:22])[NH2:23]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CC2)n1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113 d) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=374.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:30](=O)[CH3:31]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])/[C:11](=[CH:30]/[CH3:31])/[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: CC=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C/C=C1\C[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc2C1=O
Temperature: 0 °C
Yield: 88.8 %

Procedure:
To a solution of (S)-4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1 (2H)-one 1 (3.0 g, 10.3 mmol) in THF (50 mL) at −78 ° C was added LiHMDS (1.0 M, 12.4 mL, 12.4 mmol). The reaction mixture was stirred for 20 min before acetaldehyde (0.55 g, 0.70 mL, 12.41 mmol) was added. The reaction mixture was stirred and warmed to 0° C. over 2 h before being quenched with a saturated solution of NH4Cl (10 mL). The product was extracted with ethyl acetate, dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:7 to 1:5) to give (S,E)-4-(3,4-dichlorophenyl)-2-ethylidene-3,4-dihydronaphthalen-1(2H)-one 42 (2.9 g, 88%).
Reaction SMILES: [C:1]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:12](=[O:16])[CH2:13][CH2:14][CH:15]=1)([OH:3])=[O:2].[C:17]1(C)C=CC(S(O)(=O)=O)=C[CH:18]=1>C(O)C>[C:1]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:12](=[O:16])[CH2:13][CH2:14][CH:15]=1)([O:3][CH2:17][CH3:18])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CSCCCCCC1=CCCC1=O
Solvent: CCO
Product: CCOC(=O)CSCCCCCC1=CCCC1=O

Procedure:
A mixture of 74 g. (0.306 mols) of 2-(7-carboxy-6-thiaheptyl)-2-cyclopentenone, 1200 ml. of ethanol and 1 g. p-toluenesulfonic acid is stirred and refluxed for 18 hours. The resulting solution is concentrated and the residue is dissolved in ether. The organic phase is washed with water, sodium bicarbonate solution and saline, dried (MgSO4) and evaporated. The residue is distilled to give a light yellow oil, o.p. 147°-150° C. (0.07 Torr).
Reaction SMILES: [CH2:1]([NH:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14])[CH2:2][CH3:3].C1(O)C=CC=CC=1.Cl.Br[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[OH-].[Na+]>>[CH2:1]([N:4]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14])[CH2:2][CH3:3]
Reactant: Brc1ccncc1
Reactant: CCCNN1C(=O)Cc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Product: CCCN(c1ccncc1)N1C(=O)Cc2ccccc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 14.4 %

Procedure:
To a stirred solution of 1,3-dihydro-1-(propylamino)-2H-indol-2-one (10.4 g) and phenol (30.8 g), preheated to 150° C. under nitrogen, was added 4-bromopyridine hydrochloride (11.04 g) over 5 min. Heating was continued for 7 hours at which time the reaction mixture was cooled to room temperature and made basic by slow addition of dilute aqueous sodium hydroxide. The product was extracted four times with ethyl acetate and the combined organic layers back-extracted with dilute aqueous sodium hydroxide, washed with brine, and dried (K2CO3). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, EtOAc), preparative high performance liquid chromatography (HPLC) (silica gel, EtOAc-.2% Et3N/0-7% MeOH/EtOAc), and a third column (alumina, EtOAc) followed. Recrystallization from ethyl acetate-pentane afforded 2.10 g (14%) of 1,3-dihydro-1-(propyl-4-pyridinylamino)-2H-indol-2-one, as a solid, m.p. 140°-143° C.
Reaction SMILES: CO[N:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li].C(N)CN.C(O)(C)(C)C>C(N)CC>[CH2:4]([NH2:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCC=NOC
Agent: [Li]
Solvent: CC(C)(C)O
Solvent: NCCN
Solvent: CCCN
Product: CCCCCCCCCN
Temperature: 0 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
Reduction of n-nonanal O-methyloxime. Lithium (1.6 g, 0.228 mol) was added in one portion to a solution of n-nonanal O-methyloxime (5.13 g, 0.030 mol) in n-propylamine (50 mL), ethylenediamine (9 g, 0.15 mol) and t-butanol (11 g, 0.15 mol). After 3 hr, an aliquot was analyzed by glpc and no oxime was present. The reaction mixture was poured into ice-water (150 mL) and the mixture was extracted with ether (3×100 mL). The combined ether extracts were washed with brine (4×100 mL), dried over magnesium sulfate and concentrated under reduced pressure. Distillation of the residue afforded n-nonylamine (3.0 g, 70%), bp 98-100° (20 mm). The nmr spectrum was identical with that of an authentic sample.