Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([C:9]2[N:10]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([OH:20])=O)=[CH:13][CH:12]=3)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)([CH3:40])[CH3:39]>O1CCCC1>[CH:38]([N:41]1[CH2:46][CH2:45][N:44]([C:18]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([CH2:21][C:22]([F:23])([F:25])[F:24])[C:9]([C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:8])=[CH:17]3)=[O:20])[CH2:43][CH2:42]1)([CH3:40])[CH3:39]
Reactant: O=C(O)c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC(F)(F)F
Reactant: CC(C)N1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCOCC2)n3CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
A mixture of 2-(morpholine-4-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indole-5-carboxylic acid (100 mg, 0.28 mmol) and 1,1′-carbonyl-diimidazole (59 mg, 0.37 mmol) in tetrahydrofuran was stirred at room temperature overnight. 1-Isopropylpiperazine (72 mg, 0.56 mmol) was then added and the mixture was stirred for an additional 40 min. The volatiles were removed in vacuo and the residue was purified by flash chromatography on silica gel with dichloromethane:methanol:ammonia (95:5:0.25 v/v) as eluant, to give 90 mg (68%) of the desired compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: Clc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)C(=O)N(Cc2ccc(Cl)cc2)c2cc([N+](=O)[O-])c(N)cc21
Yield: 91.4 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1.2 g) is alkylated using 1-bromomethyl-4-chloro-benzene (0.98 g; 4.77 mmol) and K2CO3 (1.8 g; 13 mmol) at RT for 18 h. After aqueous work-up the crude material is de-acetylated using hydrochloric acid (60 ml; 6 N) at reflux. After aqueous work-up 5-amino-1-(4-chloro-benzyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (1.44 g) is obtained and used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[F:9][C:10]([F:36])([F:35])[C:11]([CH2:30][NH:31][CH2:32][CH2:33][CH3:34])([OH:29])[CH2:12][NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:32]([N:31]([CH2:30][C:11]([OH:29])([CH2:12][NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]([F:36])([F:35])[F:9])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH2:33][CH3:34]
Reactant: O=C(O)c1cccs1
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Product: CCCN(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1cccs1

Procedure:
Prepared similarly to Example 1 from 2-thiophenecarboxylic acid and 1,1,1-trifluoro-3-[(1-phenyl-1H-indazol-4-yl)amino]-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]2[O:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][NH:18][CH3:19]>C(O)C>[CH3:17][N:18]([CH3:19])[CH2:9][CH:8]([OH:10])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNC
Reactant: c1ccc(C(c2ccccc2)C2CO2)cc1
Solvent: CCO
Product: CN(C)CC(O)C(c1ccccc1)c1ccccc1
Yield: 90 %

Procedure:
1,1-Diphenyl-2,3-epoxy-propane prepared as described in Example 21, was further reacted with dimethylamine in ethanol by the procedure described in Example 8 to give 3-dimethylamino-1,1-diphenyl-propan-2-ol (90%) m.p. 72° - 73°
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]([CH3:15])[CH3:14])[C:5]([O:7]C)=O.[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:28][CH:27]=3)[S:23][C:22]=2[CH:40]=1>>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[C:25]([C:5]([C:4]3[CH:9]=[CH:10][C:11]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:2]([Br:1])[CH:3]=3)=[O:7])=[C:24]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:30][CH:31]=3)[S:23][C:22]=2[CH:40]=1
Reactant: COC(=O)c1ccc(CN(C)C)c(Br)c1
Reactant: COc1ccc2cc(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Product: COc1ccc2c(C(=O)c3ccc(CN(C)C)c(Br)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Yield: 66 %

Procedure:
By essentially following the procedure used to prepare Example 137, Part C, the title compound was prepared from methyl 3-bromo-4-[(dimethylamino)methyl]benzoate (Part A) and 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Example 1, Part B) in 66% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].C[O:12]C(OC)N(C)C.O.I([O-])(=O)(=O)=O.[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=[O:12])[C:5]#[N:6]
Reactant: Cc1ccc(C#N)cc1F
Reactant: COC(OC)N(C)C
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C=O)c(F)c1

Procedure:
The reaction was carried out under argon. 3-Fluoro-4-methylbenzonitrile (121 g, 895 mmol) and N,N-dimethylformamide dimethyl acetal (245 g, 2.06 mol) were dissolved in DMF (1.8 liters) and stirred under reflux overnight. The contents of the flask was then poured into water (2 liters), the mixture was extracted twice with ethyl acetate and the combined organic phases were washed with saturated sodium chloride solution. The organic phase was concentrated, and the residue was dissolved again in THF/water (1:1, 2.7 liters). Sodium periodate (503 g, 2.35 mol) was added, and the mixture was stirred at room temperature for one hour. The precipitate was then separated off, and the filtrate was recovered and extracted repeatedly with ethyl acetate. The combined organic phases were washed once with saturated sodium bicarbonate solution and once with saturated sodium chloride solution, dried and concentrated to give an oil. This was purified by column chromatography on silica gel (mobile phase: petroleum ether/dichloromethane 6:4, then 4:6, finally pure dichloromethane). The product fractions were concentrated. This gave 28.0 g (20% of theory) of the target compound as a white crystalline solid.
Reaction SMILES: [CH2:1]([S:6][C:7]1[N:11]=[CH:10][N:9](COCC[Si](C)(C)C)[C:8]=1[C:20]1[CH2:21][N:22]([CH3:26])[CH2:23][CH2:24][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH3:5].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([S:6][C:7]1[N:11]=[CH:10][NH:9][C:8]=1[C:20]1[CH2:21][N:22]([CH3:26])[CH2:23][CH2:24][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCSc1ncn(COCC[Si](C)(C)C)c1C1=CCCN(C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCCSc1nc[nH]c1C1=CCCN(C)C1

Procedure:
To a solution of anhydrous THF (20 ml) containing 75A (0.42 g, 1.06 mmol) were added 3.18 ml (3 eq) of TBAF (1.0 M in THF) under N2. After the addition, the resulting solution was refluxed for 18 hours and subsequently concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with a concentrated NaHCO3 solution, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (MeOH), followed by a further purification on (25 g) SCX-2 (MeOH followed by 1 N NH3/MeOH) to afford the title compound 76A. (oil, 0.2 g, 73%). LCMS (Method A): Rt: 1.0 min, ([M+H]+=266). 1H-NMR (400 MHz, CDCl3): δ 7.54 (s, 1H), 6.36-6.31 (m, 1H), 3.49-3.46 (m, 2H), 2.75 (t, J=7 Hz, 2H), 2.64 (t, J=6 Hz, 2H), 2.47 (s, 3H), 2.43-2.38 (m, 2H), 1.55-1.49 (m, 2H), 1.35-1.23 (m, 4H), 0.85 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O-:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C([N:18]2C=CC(C(F)(F)F)=N2)C=CC=1C(F)(F)CNC(C1C(C(F)(F)F)=CC=CN=1)=O.N>CO>[C:1]1([CH2:7][C:8]([NH2:18])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])Cc1ccccc1
Reactant: O=C(NCC(F)(F)c1ccc(-n2ccc(C(F)(F)F)n2)cc1Cl)c1ncccc1C(F)(F)F
Agent: N
Solvent: CO
Product: NC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 2-chloro-α,α-difluoro-4-[3-trifluoromethyl)-1H-pyrazol-1-yl]benzeneacetate (i.e. the product of Step B; 500 mg, 1.35 mmol in methanol was added dropwise ammonia in methanol (2 M, 3.37 mL, 6.75 mmol), and the resulting mixture was stirred for 24 h at room temperature. The solvent was removed under reduced pressure to afford crude 2-chloro-α,α-difluoro-4-[3-trifluoromethyl)-1H-pyrazol-1-yl]benzeneacetamide, which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)=[CH:3][C:2]=1[C:31]1[C:26]([F:25])=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: OB(O)c1cccnc1F
Reactant: NC1=NC(c2ccncc2)(c2ccc(F)c(Br)c2)c2ccccc21
Product: NC1=NC(c2ccncc2)(c2ccc(F)c(-c3cccnc3F)c2)c2ccccc21

Procedure:
The title compound was synthesized from 1-(3-bromo-4-fluorophenyl)-1-pyridin-4-yl-1H-isoindol-3-amine (Scheme #11, G) as described in Example 67 Scheme #10, D using 2-fluoropyridine-3-boronic acid. 1H NMR (DMSO-d6) δ 8.49-8.41 (m, 2 H), 8.32-8.27 (m, 1 H), 8.04-7.95 (m, 1 H), 7.88-7.79 (m, 2 H), 7.55-7.40 (m, 5 H), 7.35-7.25 (m, 3 H), 6.92 (br s, 2 H); MS (ESI) m/z 399 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH2:9][CH:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:7][C:6]2=1.[H-].[Na+].[CH3:24][N:25]([CH2:27][CH2:28][CH2:29]Cl)[CH3:26].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:29][CH2:28][CH2:27][N:25]([CH3:26])[CH3:24])[C:11]1[CH2:10][CH2:9][CH:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:7][C:6]2=1
Reactant: COc1ccc2[nH]c3c(c2c1)CC(c1ccccc1)CC3
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c1c(n2CCCN(C)C)CCC(c2ccccc2)C1
Temperature: 100 °C

Procedure:
A mixture containing 6-methoxy-3-phenyl-1,2,3,4-tetrahydrocarbazole (5.5 g), 50% sodium hydride (1.0 g) in dimethylformamide (30 ml) is heated at 100° C. for 11/2 hours, and then dimethylamino propyl chloride is added. The mixture is heated at 80° C. for 2 hours, then cooled and water (40 ml) is added. The solid which precipitates is recrystallized with methylene chloride:ether (1:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:9][CH2:10][C:11](=O)[CH2:12]Cl>CCO>[Cl:9][CH2:10][C:11]1[N:8]=[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]2[CH:12]=1
Reactant: Nc1ccc(F)cn1
Reactant: O=C(CCl)CCl
Solvent: CCO
Product: Fc1ccc2nc(CCl)cn2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
According to the general protocol described in J. Heterocyclic. Chem., 1988, 25, 129-137, to solution of 5-fluoropyridin-2-amine (1.80 g, 16 mmol) in EtOH (24 mL) was added 1,3-dichloropropan-2-one (2.03 g, 16 mmol) and the resulting mixture was stirred overnight at 80° C. The solvent was evaporated, and the residue was dissolved in a minimum volume of water. The solution was neutralized (pH=8) with saturated NaHCO3. The aqueous layer was extracted with AcOEt and the organic layer was washed with saturated NaCl. The solvent was evaporated and the crude product was purified by chromatography (prepacked 25 g silicagel column, DCM as eluent) to afford 1.7 g of 2-(chloromethyl)-6-fluoro-imidazo[1,2-a]pyridine (Yield: 57%) as a beige solid.
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH:13]1([CH2:16]Br)[CH2:15][CH2:14]1.CI>>[CH:13]1([CH2:16][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:11]=3)[CH2:6][CH2:7][C:8]2=[O:12])[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: O=C1CCc2ccc(I)cc2N1
Solvent: CI
Product: O=C1CCc2ccc(I)cc2N1CC1CC1

Procedure:
According to the Step 8-1 in synthetic method for EXAMPLE aa8, 3,4-dihydro-7-iodo-2(1H)-quinolinone (1.50 g) and cyclopropylmethyl bromide (0.80 mL) were used instead of a7-1 and MeI to obtain compound aa20-1 (1.23 g) as a pale red amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13](=[S:15])[NH2:14])=[CH:9]2)[CH3:2].[C:27]([O:32][CH2:33][CH3:34])(=[O:31])[C:28]#[C:29][CH3:30].O1CCCC1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:15][CH:29]([CH2:28][C:27]([O:32][CH2:33][CH3:34])=[O:31])[CH2:30][N:14]=1)=[CH:9]2)[CH3:2]
Reactant: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OCC)c3[nH]2)S1
Temperature: 40 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a stirred solution of 7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carbothioamide (0.41 g), ethyl 2-butynoate (0.25 mL), tetrahydrofuran (10 mL) and toluene (15 mL) was added tributylphosphine (0.31 mL) at room temperature under argon atmosphere. After stirring at 40° C. for 3 h, the reaction mixture was concentrated to give a light brown oil, which was purified by silica gel chromatography (ethyl acetate:hexane=30:70 to 50:50, volume ratio) to give the title compound (350 mg, 66%) as a light yellow oil. MS 504 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][C:30]=1[N+:39]([O-:41])=[O:40]>C1COCC1>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:11][N:10]=[CH:9][N:8]=1)[S:35]([C:32]1[CH:33]=[CH:34][C:29]([F:28])=[C:30]([N+:39]([O-:41])=[O:40])[CH:31]=1)(=[O:36])=[O:37]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1F
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c([N+](=O)[O-])c2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 100-mL round-bottom flask was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (INTERMEDIATE A, 1.478 g, 5.88 mmol) and THF (10 mL) to give a clear, light-yellow solution. The flask was cooled in a dry ice-acetone bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (5.88 mL, 5.88 mmol) was added dropwise over 2 min. The cooling bath was removed for 5 minutes, then re-cooled for 5 min. A solution of 4-fluoro-3-nitrobenzene-1-sulfonyl chloride (1.281 g, 5.35 mmol) in THF (3 mL with a 1 mL flask/syringe wash) was added dropwise over 2 minutes. The cooling bath was removed and the reaction was warmed to room temperature. The mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was concentrated from EtOAc (2×), then taken up in EtOAc, sonicated for 1 min, and filtered through a membrane filter. The resulting solid was transferred to a sonication vial, then put under high vacuum at 60° C. for 10 min to give N-(2,4-dimethoxybenzyl)-4-fluoro-3-nitro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (INTERMEDIATE S) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=8.24 (s, 1 H), 8.18 (dd, J=2.4, 6.7 Hz, 1 H), 7.99 (ddd, J=2.4, 3.9, 8.8 Hz, 1H), 7.33-7.28 (m, 1 H), 7.09 (d, J=8.4 Hz, 1 H), 6.32 (dd, J=2.3, 8.4 Hz, 1 H), 6.21 (d, J=2.4 Hz, 1 H), 5.37 (s, 2 H), 3.76 (s, 3 H), 3.63 (s, 3 H). m/z (ESI) 477.0 (M+Na)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7](Br)[S:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[Na].[CH3:13][OH:14]>>[C:1]([NH:4][C:5]1[N:6]=[C:7]([O:14][CH3:13])[S:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)Nc1nc(Br)sc1C
Agent: [Na]
Product: COc1nc(NC(C)=O)c(C)s1

Procedure:
4-Acetamido-2-bromo-5-methylthiazole (prepared by acylating 4-amino-2-bromo-5-methylthiazole with acetic anhydride) is treated with sodium in absolute methanol as described in Example 1 to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11]12([C:21](Cl)=[O:22])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:21]([C:11]23[CH2:20][CH:15]4[CH2:14][CH:13]([CH2:19][CH:17]([CH2:16]4)[CH2:18]2)[CH2:12]3)=[O:22])=[CH:5][CH:4]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(CN)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CNC(=O)C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
Subject 4.0 g. (29.0 mmoles) of p-methoxy-benzylamine, 5.7 g. (29.0 mmoles) of adamantane carboxylic acid chloride and 10 ml. of triethylamine to the process of Example 11. Crystallize the residue obtained thereby from chloroform to obtain the product of this Example, m.p. 91°-94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:34])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:29]=[CH:28][C:17]([C:18]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[O:19])=[C:16](F)[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:35][S:36](C)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:34])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:29]=[CH:28][C:17]([C:18]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[O:19])=[C:16]([S:36][CH3:35])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CS(C)=O
Reactant: O=C(NCc1ccccn1)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1F
Solvent: O
Product: CSc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccccn1
Temperature: 25 °C

Procedure:
In a solution of 0.92 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-fluoro-N-(2-pyridylmethyl) benzoic acid amide (Compound of the present invention No. 5-041) synthesized similarly to Synthetic Example 4 in 12 ml of dimethylsulfoxide, 0.12 g of sodium methane thiolate was added with stirring at room temperature, and stirred at 100° C. for 90 minutes. After the completion of the reaction, the reaction mixture was poured in 30 ml of water, and extracted with ethyl acetate (20 ml×3). The organic phase was washed with 30 ml of water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with chloroform, and 0.89 g of the aimed product was obtained as colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([C:18]3[N:22]([CH3:23])[CH:21]=[N:20][N:19]=3)[CH:17]=2)[C:11]([O:13]C)=[O:12])=[N:6][CH:7]=1.[OH-].[Li+].Cl>C1COCC1.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([C:18]3[N:22]([CH3:23])[CH:21]=[N:20][N:19]=3)[CH:17]=2)[C:11]([OH:13])=[O:12])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)cc(-c2nncn2C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)O)cc(-c3nncn3C)c2)nc1
Reaction time: 16 h
Yield: 121.8 %

Procedure:
To a solution of methyl 3-(5-methylpyridin-2-yl)-5-(4-methyl-4H-1,2,4-triazol-3-yl)benzoate (0.37 g, 1.20 mmol) in THF (5 mL) was added lithium hydroxide (86 mg, 3.60 mmol) in 5 mL of water. After 16 h, the reaction was acidified to pH 1 by 1 M HCl. The solution was concentrated and dried under vacuum to give the hydrochloride salt of the title compound (0.43 g). MS 295.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:16][Br:17])[CH2:12][CH2:11][CH:10]([CH2:13]CC)[O:9]2)=[CH:4][CH:3]=1.Cl[C:19]1C=CC(C(CCC(O)(C)C)=C)=CC=1.BrBr.N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:16][Br:17])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:19])[O:9]2)=[CH:6][CH:7]=1
Reactant: C=C(CCC(C)(C)O)c1ccc(Cl)cc1
Reactant: CCCC1CCC(CBr)(c2ccc(Cl)cc2)O1
Agent: BrBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CCC(CBr)(c2ccc(Cl)cc2)O1

Procedure:
By the cyclisation procedure described for the preparation of 2-(4-chlorophenyl)-2-bromomethyl-5-prop-1-yltetrahydrofuran (see Example 1), 2-(4-chlorophenyl)-5-hydroxy-5-methylhex-1-ene (5.3 g), bromine (3.8 g), and pyridine (1.9 g), in dichloromethane (60 ml), gave 2-(4-chlorophenyl)-2-bromomethyl-5,5-dimethyltetrahydrofuran (7.6 g) as a red oil, 1H nmr (CDCl3): δ1.2 (3H, singlet) and 1.4 (3H, singlet), 2×CH3, 3.5 (2H, singlet, CH2Br).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)N)=[CH:14][CH:13]=1.Cl>C(O)C>[CH3:1][N:2]([CH3:10])[CH:3]1[CH2:8][C:7]2[C:21]3[C:20](=[CH:25][CH:24]=[C:23]([F:26])[CH:22]=3)[N:18]([C:15]3[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CN(C)C1CCC(=O)CC1
Reactant: NN(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: CN(C)C1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1

Procedure:
A solution of 7.8 g. of 4-dimethylaminocyclohexanone and 11 g. of 1,1-bis(4-fluorophenyl)hydrazine in 350 ml. of absolute ethyl alcohol and 90 ml. of 5-N hydrogen chloride in absolute ethyl alcohol was heated under reflux for five hours, cooled, and filtered. The solids were suspended in ether and treated with dilute sodium hydroxide solution and the ether extract was separated, dried and evaporated to dryness. The resulting oil was dissolved in ethyl alcohol, treated with hydrogen chloride in ethyl alcohol and the solution was concentrated and cooled. The resulting solids were collected by filtration to give, after recrystallization from ethyl alcohol, 5.6 g. of 3-(dimethylamino)-6-fluoro-9-(4-fluorophenyl)-1,2,3,4-tetrahydrocarbazole hydrochloride, m.p. 283°-285°C.