Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH2:16][C:17]3[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]([F:25])[C:18]=3[F:26])[C:12]([O:27][CH3:28])=[CH:11][C:10]=2[Cl:29])[C:5]([C:30]([O:32]C)=[O:31])=[C:4]([CH3:34])[N:3]=1.ClC1N=C(Cl)C(C(OC)=O)=C(C)[N:37]=1.O.[N-]=[N+]=[N-].[Na+]>CN(C)C=O>[NH2:37][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH2:16][C:17]3[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]([F:25])[C:18]=3[F:26])[C:12]([O:27][CH3:28])=[CH:11][C:10]=2[Cl:29])[C:5]([C:30]([OH:32])=[O:31])=[C:4]([CH3:34])[N:3]=1
Reactant: COC(=O)c1c(C)nc(Cl)nc1Nc1cc(OCc2c(OC)ccc(F)c2F)c(OC)cc1Cl
Reactant: COC(=O)c1c(C)nc(Cl)nc1Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(Nc2nc(N)nc(C)c2C(=O)O)cc1OCc1c(OC)ccc(F)c1F
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a suspension of methyl 2-chloro-4-[2-chloro-5-(2,3-difluoro-6-methoxy-benzyloxy)-4-methoxyphenylamino]-6-methylpyrimidine-5-carboxylate (0.42 g), which was prepared in a similar manner to that described in Example 380 using methyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate instead of ethyl 4-chloro-6-methylpyrimidine-5-carboxylate, in N,N-dimethylformamide (12 mL) were added water (2 mL) and sodium azide (0.26 g), and the mixture was stirred at 60° C. for 2 hours. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the residue were added tetrahydrofuran (12 mL), methanol (12 mL) and 10% platinum-carbon powder (0.1 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. To the mixture were added tetrahydrofuran (12 mL) and 2 mol/L aqueous sodium hydroxide solution (12 mL), and the resulting mixture was stirred at 60° C. for 2 hours. The insoluble material was removed by filtration, and the filtrate was acidified by adding 1 mol/L hydrochloric acid. The precipitated crystals were collected by filtration. The crystals were washed with water, and dried under reduced pressure to give 2-amino-4-[2-chloro-5-(2,3-difluoro-6-methoxy-benzyloxy)-4-methoxyphenylamino]-6-methylpyrimidine-5-carboxylic acid (0.35 g). To this material were added 1,4-dioxane (30 mL), tetrahydrofuran (10 mL), triethylamine (3 mL) and diphenylphosphoryl azide (0.38 mL), and the reaction vessel was equipped with a reflux condenser, and the mixture was stirred at 100° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate−ethyl acetate/methanol=10/1) to give the title compound (0.2 g).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([Si:4]([CH3:20])([CH3:19])[O:5][CH2:6][CH:7]([OH:18])[CH2:8][CH2:9][O:10][Si:11]([CH3:17])([CH3:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:3].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:29][S:30]([O:18][CH:7]([CH2:8][CH2:9][O:10][Si:11]([CH3:17])([CH3:16])[C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:6][O:5][Si:4]([CH3:20])([CH3:19])[C:2]([CH3:21])([CH3:1])[CH3:3])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCC(O)CO[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCC(CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
To a solution of 2,2,3,3,10,10,11,11-octamethyl-4,9-dioxa-3,10-disiladodecan-6-ol (i.e. the product of Step A) (36.31 g, 0.109 mol) in dichloromethane (300 mL) cooled to about 0° C. under nitrogen, was added triethylamine (22.8 mL, 0.163 mol), followed by dropwise addition of a solution of methanesulfonyl chloride (10.14 mL, 0.13 mol) in dichloromethane (100 mL), maintaining the reaction mixture below 10° C. The reaction mixture was stirred for another 30 minutes, and then washed with citric acid (about 200 mL, 10%), water (about 200 mL) and sodium bicarbonate (about 200 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a yellow oil (42.16 g) which was used without further purification.
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].ON1C2C=CC=CC=2N=N1.[OH:60][CH2:61][C@@H:62]([C@@H:64]([C@@H:66]([CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[OH:67])[OH:65])[NH2:63].C(N=C=NC(C)C)(C)C>C(Cl)(Cl)Cl>[C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([NH:63][C@H:62]([C@@H:64]([C@@H:66]([CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[OH:67])[OH:65])[CH2:61][OH:60])=[O:49])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@@H](N)CO
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)[C@H](O)CCCCCCCCCCCCCC
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 52 %

Procedure:
A mixture of 27-linoleoyloxyheptacosanoic acid (5 g, 7.2 mmoles), chloroform (90 ml), dried 1-hydroxybenzotriazole (3.2 g, 27.3 mmoles), phytosphingosine (3.07 g, 9.7 mmoles) and N,N'-diisopropylcarbodiimide (2.2 ml, 14.1 mmoles) was stirred under nitrogen for 90 minutes at 45° C. and then overnight at room temperature. After washing with 50 ml of a 1N hydrochloric acid solution and brine and filtration the organic layer was concentrated. After addition of hot isopropanol (150 ml) the mixture was filtered while still hot. After cooling down the precipitate formed was filtered off, washed with isopropanol (30 ml), acetone (10 ml) and dried giving 3.7 g of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:34])[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[N:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[CH:22]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([CH3:15])=[CH:10][C:9]2[NH:16][C:17](=[O:34])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[N:31][CH:30]=[C:29]([CH3:33])[N:28]=4)[CH:22]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cncc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(Cl)cc3NC(=O)OC(C)(C)C)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cncc(-c2cccc(C3=Nc4cc(Cl)c(C)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (5-chloro-4-methyl-2-{3-[3-(6-methyl-pyrazin-2-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M119) (0.39 g, 0.79 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (260 mg, 88%).
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][C:7]=1[N+:17]([O-:19])=[O:18].[CH3:20]O>>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:20])=[O:15])=[CH:8][C:7]=1[N+:17]([O-:19])=[O:18]
Reactant: CO
Reactant: O=C(O)CCc1ccc(O)c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
With cooling at -30° C. or below, thionyl chloride (75 ml) was added dropwise to methanol (150 ml). At -30° C., 3-(4-hydroxy-3-nitrophenyl)propionic acid (26.20 g, 0.12 mol) was added to this solution. The reaction solution was stirred at room temperature for 1 hour and then at 40 to 50° C. for 3 hours. The reaction solution was concentrated under reduced pressure. Then, a procedure of adding toluene (100 ml) to the residue and concentrating the mixture under reduced pressure was repeated twice. Thereafter, the resulting residue was crystallized from ether-hexane to give methyl 3-(4-hydroxy-3-nitrophenyl)propionate (26.20 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:13])=[C:5]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:4]=1[CH3:20].Br[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([CH3:30])[CH:23]=1>>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([N:17]2[CH2:18][CH2:19][N:14]([C:5]3[C:4]([CH3:20])=[C:3]([O:2][CH3:1])[C:11]4[O:10][CH:9]([CH3:12])[CH2:8][C:7]=4[C:6]=3[CH3:13])[CH2:15][CH2:16]2)=[CH:23][C:24]=1[CH3:30]
Reactant: COc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Reactant: COc1ccc(Br)cc1C
Product: COc1ccc(N2CCN(c3c(C)c4c(c(OC)c3C)OC(C)C4)CC2)cc1C
Yield: 40.7 %

Procedure:
By using 1-(7-methoxy-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (552 mg, 2.0 mmol) synthesized in Reference example 88 and 4-bromo-1-methoxy-2-methylbenzene (804 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 323 mg (yield 41%). Melting point was 94 to 96° C. (ethanol-water).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[S:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:34]=[CH:33][C:19]([CH2:20][N:21]4[CH:25]=[C:24]([CH:26]=O)[C:23]([C:28]5[S:29][CH:30]=[CH:31][CH:32]=5)=[N:22]4)=[CH:18][CH:17]=3)[N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OP([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])(OCC)=O)C.O>CN(C)C=O>[C:3]1([C:9]2[S:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:17]=[CH:18][C:19]([CH2:20][N:21]4[CH:25]=[C:24](/[CH:26]=[CH:43]/[C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:23]([C:28]5[S:29][CH:30]=[CH:31][CH:32]=5)=[N:22]4)=[CH:33][CH:34]=3)[N:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
Sodium hydride (60%, oily, 150 mg) was added to a solution of 1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (1.54 g) and ethyl diethylphosphonoacetate (0.82 g) in N,N-dimethylformamide (15 ml) at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl(E)-3-[1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]propenoate (1.65 g, yield: 93%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1: 2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 104˜105° C.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][N:7]([C:9]2[C:18]([F:19])=[C:17]3[C:12]([C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15][N:16]3[CH2:20][CH3:21])=[CH:11][C:10]=2[F:26])[CH2:6][CH2:5][O:4]1.[CH3:27][NH:28][CH3:29]>>[CH3:27][N:28]([CH2:2][CH:3]1[CH2:8][N:7]([C:9]2[C:18]([F:19])=[C:17]3[C:12]([C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15][N:16]3[CH2:20][CH3:21])=[CH:11][C:10]=2[F:26])[CH2:6][CH2:5][O:4]1)[CH3:29]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CCl)C3)c(F)c21
Reactant: CNC
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CN(C)C)C3)c(F)c21

Procedure:
By the use of 7-(2-chloromethylmorpholino)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and dimethylamine, the reaction is similarly carried out as Example 34 to give 7-[2-(dimethylaminomethyl)morpholino]-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, melting at 185°-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[OH:12].N12CCN(CC1)CC2.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[S:24]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[O:12][C:23](=[S:24])[N:22]([CH3:26])[CH3:21]
Reactant: CN(C)C(=S)Cl
Reactant: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=S)Oc1c(Cl)cc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.3 %

Procedure:
A solution of 2,6-dichloro-4-nitro-phenol (3.0 g, 14.4 mmol) in N,N-dimethylformamide (70 mL) at 25° C. was treated with 1,4-diazabicyclo[2.2.2]octane (3.16 mL, 28.8 mmol) and dimethylthiocarbamoyl chloride (2.85 g, 23.04 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was diluted with ethyl acetate (250 mL) and was then washed with a 1N aqueous hydrochloric acid solution (1×125 mL), water (1×125 mL), and a saturated aqueous sodium chloride solution (1×125 mL), dried with magnesium sulfate, filtered and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80:20 petroleum ether/ethyl acetate) afforded dimethyl-thiocarbamic acid O-(2,6-dichloro-4-nitro-phenyl)ester (79) (3.2 g, 75%) as a white solid; EL-LRMS for C9H8Cl2N2O3S (M−Cl)+ at m/z=259. Exact Mass=293.9633; Molecular weight=295.15
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:23])[CH2:16][CH:17]([OH:22])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:3].[Na+]>C(OCC)(=O)C>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]\[C@@H:15]([OH:23])[CH2:16][C@@H:17]([OH:22])[CH2:18][C:19]([OH:21])=[O:20])=[C:11]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:1]
Reactant: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)n1c(/C=C\[C@@H](O)C[C@@H](O)CC(=O)O)c(-c2ccc(F)cc2)c2ccccc21
Yield: 87.5 %

Procedure:
7.0 g (16 mmole) of fluvastatin sodium was dissolved in 300 mL ethyl acetate and washed with 300 mL 10% (w/v) aqueous sodium hydrogen sulfate solution (pH 3). The organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure to afford 5.76 g (14.0 mmole) of fluvastatin acid. This material was dissolved in 300 mL anhydrous toluene and stirred at room temperature for 7 days, at which time analytical thin-layer chromatography using 5:1 methylene chloride:acetone eluent indicated approximately 30% conversion of the starting acid to a less polar product. The toluene was removed under reduced pressure and the reaction mixture was fractionated on 400 cc of silica gel using 5:1 methylene chloride: acetone eluent to afford, after combining, concentrating and drying of the appropriate fractions, 2.02 g (5.14 mmol, 32% overall) of fluvastatin lactone as a white foam. The 400 MHz 1H nuclear magnetic resonance (NMR) spectrum and the electrospray mass spectrum (ES-MS) were consistent with the lactone product. 1H NMR (Me2SO-d6) δ 7.7 (d, 1H), 7.4 (br s, 3H), 7.3 (m, 2H), 7.2 (t, 1H), 7.1 (t, 1H) 6.8 (t, 1H), 5.7 (dd, 1H), 5.3 (s, 1H), 5.2 (m, 1H), 4.9 (m, 1H), 4.1 (br s, 1H), 2.7 (dd, 1H), 2.4 (d, 1H), 1.8 (d, 1H), 1.7 (t, 1H), 1.57 (d, 6H). ES-MS: obsvd. m/z 394 ([MH]+).
Reaction SMILES: C([SiH](CC)CC)C.[F:8][C:9]([F:32])([C:13]([F:31])([F:30])[C:14]([F:29])([F:28])[C:15]([F:27])([F:26])[C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[C:10](Cl)=[O:11]>[Pd].C([SiH](CC)CC)C>[C:9]([CH:10]=[O:11])([C:13]([C:14]([C:15]([C:16]([C:17]([C:18]([F:19])([F:20])[F:21])([F:22])[F:23])([F:25])[F:24])([F:27])[F:26])([F:29])[F:28])([F:31])[F:30])([F:32])[F:8]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Pd]
Agent: CC[SiH](CC)CC
Product: O=CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 112.9 %

Procedure:
A sample of triethylsilane (4.24 g, 36.5 retool) was cooled to 0° C. and treated with 10% Pd/C(0.35 g). After the exotherm subsided, perfluorooctanoyl chloride (15.8 g, 36.5 mmol) was added dropwise, controlling the temperature below ca. 6°-8° C. The mixture was stirred for 1.0 hr at 0° C. Another 0.59 g triethylsilane was added, and the mixture was stirred for 1.5 hr. An additional 0.13 g of triethylsilane was added. After 1.0 hr, vacuum transfer gave 16.4 g of liquid which was cooled at -25° C. for several hours. The top liquid layer was removed from the solid to provide ca. 10.5 g of the titled product. 19F NMR: -81.3 (t of t's, J=9.8, 2.3), -121.8 (m), -122.3 (m), -123.0 (m), -123.7 (m), -125.4 (t of m's, with JFCCH =3 Hz), -126.5 (m).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([NH:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2)=[O:15].C([Sn](CCCC)(CCCC)[C:31]1[S:32][CH:33]=[CH:34][N:35]=1)CCC>>[NH:22]1[C:23]2[C:19](=[CH:18][C:17]([NH:16][C:14](=[O:15])/[CH:13]=[CH:12]/[C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=3[C:31]3[S:32][CH:33]=[CH:34][N:35]=3)=[CH:25][CH:24]=2)[CH:20]=[CH:21]1
Reactant: O=C(/C=C/c1ccc(C(F)(F)F)cc1Br)Nc1ccc2[nH]ccc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Product: O=C(/C=C/c1ccc(C(F)(F)F)cc1-c1nccs1)Nc1ccc2[nH]ccc2c1

Procedure:
Analogous to the procedure used to prepare Example 100, (2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide, Example 97, (100 mg, 0.24 mmol) and 2-tributylstannylthiazole (155 mg, 0.42 mmol, Frontier Scientific) provided, after purification by silica gel chromatography (gradient: 0-35%EtOAc in hexane), the title product as an orange solid. MP 203-204° C. MS (ESI, pos. ion) m/z: 414 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13]I)[CH2:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:22]([NH2:24])[CH3:23]>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][NH:24][CH2:22][CH3:23])[CH2:7][CH2:6][CH2:5]2
Reactant: CCN
Reactant: Brc1ccc2c(c1)CCCN2CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCNCCN1CCCc2cc(Br)ccc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
A solution of 6-bromo-1-(2-iodoethyl)-1,2,3,4-tetrahydroquinoline (compound 3, 100 mg, 0.273 mmol) in acetonitrile (4.75 mL) and water (0.25 mL) in a 20 mL pressure vessel fitted with a stir-bar is treated with potassium carbonate (0.378 g, 2.73 mmol) and ethylamine hydrochloride (0.223 g, 2.73 mmol) and the sealed vessel stirred at 70° C. overnight. After 18 hours the mixture was partitioned between CH2Cl2 (50 mL) and water (10 mL) and transferred to a separatory funnel. The organic layer was separated and the aqueous layer extracted further with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give a yellow residue. The residue was purified on silica gel eluting with 7.5% 2M NH3 in methanol/92.5% dichloromethane to yield a yellow oil/residue, 4 (55 mg, 71.1%). 1H-NMR (CDCl3) δ 7.09 (dd, 1H, J=8.7, 2.4 Hz), 7.06-7.01 (m, 1H), 6.51 (d, 1H, J=8.7), 3.36 (t, 2H, J=6.8 Hz), 3.29 (t, 2H, J=5.5 Hz), 2.82 (t, 2H, J=6.8 Hz), 2.80-2.65 (2×m, 4H), 1.96-1.88 (m, 2H), 1.11 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:13])=[CH:8][CH2:7][CH2:6]2.CN(C)[CH:16]=[O:17].P(Cl)(Cl)(Cl)=O.C([O-])(=O)C.[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:13])=[C:8]([CH:16]=[O:17])[CH2:7][CH2:6]2
Reactant: CN(C)C=O
Reactant: COc1ccc2c(c1)CCC=C2C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)CCC(C=O)=C2C
Temperature: 72.5 °C
Reaction time: 3 h
Yield: 43.5 %

Procedure:
To a solution of Compound B (0.44 g, 2.5 mmole) in dry dimethylformamide (1.3 ml, 16.8 mmole) at ice cooling and stirring under argon atmosphere, phosphorus oxychloride (0.62 ml, 6.65 mmole) was added drop-by-drop in 2 minutes. The reaction mixture was stirred in an oil bath of 70-75° C. for 3 hours. After cooling in an ice bath, ice (6 g) was added, then sodium acetate (anhydrous, 3.7 g) was added, and the mixture (pH ˜6) was warmed in an oil bath at 70-75° C. for 15 minutes. After cooling, it was extracted with ether (1×10 ml and 3×5 ml), the combined organic solutions were washed with water (3×3 ml), dried (magnesium sulfate), decolorized (with activated carbon), and evaporated. The residue (0.33 g) was recrystallized from cyclohexane (2 ml) and dried over potassium hydroxide in a vacuum giving the pure product 6-Methoxy-1-methyl-3,4-dihydro-2-naphthaldehyde (Compound C, 0.22 g, 44%) as light brown crystals, mp. 70-72° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:28]Cl.C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:28][C:27]3[CH:30]=[CH:31][C:32]([Cl:33])=[C:25]([Cl:24])[CH:26]=3)[C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)N1CC(=O)N(Cc2ccc(Cl)c(Cl)c2)c2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 mg (0.067 mmol) of 4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 5 ml of DMF. 3 mg (0.08 mmol) of sodium hydride was added to the obtained solution, and they were stirred at room temperature for 30 minutes. 16 mg (0.08 mmol) of 3,4-dichlorobenzyl chloride was added to the obtained mixture and they were stirred at 60° C. overnight. The reaction mixture was treated with ethyl acetate as the extracting solvent by an ordinary method to obtain the crude product. After the purification by the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.Cl.[CH3:14][NH:15][O:16][CH3:17].CN(C)CCCN=C=NCC.N1C=CC=CC=1>O1CCCC1>[CH3:17][O:16][N:15]([CH3:14])[C:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:12]
Reactant: CNOC
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 107.3 %

Procedure:
In a round-bottomed flask, 5.0 g of indole-6-carboxylic acid, 3.3 g of N,O-dimethylhydroxylamine hydrochloride, 11.9 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 10 ml of pyridine are placed in 150 ml of tetrahydrofuran. The mixture is stirred at ambient temperature for 40 h. The mixture is concentrated, and the residue is taken up in 150 ml of ethyl acetate and 50 ml of water. The organic phase is washed with 50 ml of a 1N solution of sodium hydroxide and 50 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. 6.8 g of compound are obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](Cl)=[O:35])=[CH:29][CH:28]=1>CO>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:34](=[O:35])[CH2:33][C:30]4[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Solvent: CO
Product: COc1ccc(CC(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 74 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-methoxyphenylacetyl chloride, the title compound was synthesized according to Example 1b. Yield: 74%. Melting point: 171-173° C. (Methanol)