Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:18])[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[O:25]1[CH2:30][CH2:29][O:28][C:27]2[C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=[CH:34][C:26]1=2>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:18][C:35]([C:31]2[C:27]3[O:28][CH2:29][CH2:30][O:25][C:26]=3[CH:34]=[CH:33][CH:32]=2)=[O:36])[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)C(C)C)c2c1N
Reactant: O=C(O)c1cccc2c1OCCO2
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](NC(=O)c3cccc4c3OCCO4)C(C)C)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate (Example 95b) and 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid as brown solid (36%). MS 494 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]1([C@@H:28]2[CH2:30][C@H:29]2[C:31](O)=[O:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C.C(OCC)C.CCCCCC.C(OCC)(=O)C>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:31]([C@H:29]3[CH2:30][C@@H:28]3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:32])[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1NN=Cc2c(-c3ccccc3)[nH]c3cc(NC(=O)[C@H]4C[C@@H]4c4ccccc4)cc1c23
Yield: 13.6 %

Procedure:
Preparation of example 45 from the title compound of Example 7 (30 mg, 0.11 mmol), ±trans-2-phenyl-1-cyclopropanecarboxylic acid (26 mg, 0.16 mmol), triethylamine (0.076 mL, 0.55 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (62 mg, 0.16 mmol) in N,N-dimethylformamide (1.0 mL) was carried out analogously to Example 11. Silica gel chromatography (1:1 ethyl acetate:hexane), also in an analogous manner, followed by trituration with ethyl acetate/diethyl ether afforded the title compound (6.5 mg, 0.015 mmol) (mixture of trans diastereomers) as a yellow powder in 14% yield.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:25])([F:24])[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[C:10]=1[C:11](O)=[O:12].[NH2:26][NH2:27]>CN(C)C=O.C(O)C>[F:5][C:6]([F:25])([F:24])[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[C:10]=1[C:11]([NH:26][NH2:27])=[O:12]
Reactant: NN
Reactant: O=C(O)c1c(OCC(F)(F)F)cccc1OCC(F)(F)F
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: NNC(=O)c1c(OCC(F)(F)F)cccc1OCC(F)(F)F
Reaction time: 8 h

Procedure:
Thionyl cloride (11.9 g., 100 mmole), 2,6-di(2,2,2-trifluoroethoxy)benzoic acid (2.0 g., 6.3 mmole) and two drops of dimethyl formamide are heated to reflux temperature and maintained at reflux for 4 hours. Unreacted thionyl chloride is removed by distillation on a steam bath at water aspirator pressure. The residue is dissolved in dry tetrahydrofuran and added dropwise to a solution of 95 per cent hydrazine (3.2 g., 100 mmole) in ethanol (15 ml.). The mixture is allowed to sit overnight and evaporate to dryness. The residue is diluted with water and a white solid collected and purified by sublimation (138°-140°/0.2 to 0.5 mm. Hg.) followed by recrystallization from benzene to give 2,6-di-(2,2,2-trifluoroethoxy)benzoic acid hydrazide, m.p. 153°-154° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:3]=1.Cl.[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[CH:23][CH:22]=[C:21]([NH:27][CH:28]2[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]2)[N:20]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[CH:23][CH:22]=[C:21]([NH:27][CH:28]2[CH2:33][CH2:32][CH2:31][N:30]([C:2]3[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=4)[N:3]=3)[CH2:29]2)[N:20]=1
Reactant: N#Cc1ccc(NC2CCCNC2)nc1N
Reactant: N#Cc1ccc(-c2ccc(F)cc2)nc1Cl
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NC2CCCN(c3nc(-c4ccc(F)cc4)ccc3C#N)C2)nc1N
Temperature: 120 °C

Procedure:
55 mg (0.24 mmol) of 2-chloro-6-(4-fluorophenyl)pyridine-3-carbonitrile, 74 mg (0.28 mmol) of 2-amino-6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 11A) and 0.206 ml (1.18 mmol) of N,N-diisopropylethylamine were initially charged in 2 ml of DMSO. The mixture was heated at 120° C. in a microwave for 30 min. The crude product was purified by means of preparative HPLC (method 13). 47 mg (48% of theory) of the product were obtained in solid form.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C1CCN(Cc2ccccc2)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#CC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
5 ml N,N-dimethylformamide was added to a mixture of 12.7 g 1-benzyl-4-piperidine carboxamide and 60 ml phosphorus oxychloride under ice-cooling, and it was stirred at room temperature for 1.5 hr. It was evaporated, and the resulting residue was dissolved in ethyl acetate and washed with aqueous sodium hydroxide and brine. After drying over anhydrous sodium sulfate, it was evaporated, and the resulting residue was purified by silica gel column chromatography to give 11.0 g of 1-benzyl-4-piperidine carbonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].NC1C=CC=CC=1.N>C(Cl)Cl.O.C1COCC1.CO>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 4-bromoaniline (1.0 g, 5.81 mmol) and triethylamine (2.43 mL, 17.4 mmol) in DCM (10 mL) at 0° C. is treated with methanesulfonyl chloride (0.47 mL, 6.10 mmol) over 5 minutes via syringe. The reaction is then warmed to RT and stirred 1 h. Analysis by LC/MS at this juncture indicated the reaction mixture contained unreacted starting material, the desired mono-sulfonamide and undesired bis-sulfonamide in a 1:1:1 ratio. Thus more triethylamine (5.0 mL, 35.9 mmol) and methanesulfonyl chloride (1.0 mL, 12.9 mmol) is added and the reaction stirred at RT a further 2 h. On confirmation by LC/MS that all the starting aniline had been converted to the mono- or bis-sulfonamide, the reaction is diluted with water (15 mL) and extracted into EtOAc (3×25 mL). The combined EtOAc phases are then dried (Na2SO4) and reduced in vacuo. The residue thus obtained is dissolved in THF (50 mL) and MeOH (50 mL) then treated with conc. ammonia solution (75 mL) at RT and stirred 16 h. The reaction mixture is then concentrated in vacuo, diluted with water (50 mL) and extracted into EtOAc (3×25 mL). The combined EtOAc phases are dried (MgSO4) and reduced in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13](Cl)[N:12]=1)=[O:4].[NH2:19][C:20]1[C:36]([O:37][CH3:38])=[CH:35][C:23]2[CH2:24][CH2:25][N:26]([CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH2:27][CH2:28][C:22]=2[CH:21]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[CH3:1][NH:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:19][C:20]2[C:36]([O:37][CH3:38])=[CH:35][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][C:30](=[O:31])[N:32]([CH3:33])[CH3:34])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:12]=1)=[O:4]
Reactant: CNC(=O)[C@@H]1CCC[C@@H]1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)[C@@H]1CCC[C@@H]1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(=O)N(C)C)CC3)ncc1Cl
Temperature: 120 °C
Yield: 50.7 %

Procedure:
cis-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclopentanecarboxylic acid methylamide (46 mg, 0.160 mmol), 2-(7-amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide (44 mg, 0.160 mmol) and camphorsulfonic acid (56 mg, 0.240 mmol) were combined in 3 mL isopropanol and heated at 120° C. in microwave for a total of 90 min. The reaction was concentrated to be taken up in dichloromethane and washed with saturated sodium bicarbonate solution (2×30 mL). The organic layer was dried over MgSO4 and filtered. The filtrate was chromatographed on a 4 g amine capped ISCO flash column from 0-100% ethyl acetate in hexanes. The product was collected as a foam after concentrating to afford 43 mg (51%) of a white foam. Compound 5: mp 240° C.; MS (ES+ calculated—529; found—530 M+H). 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.89 (s, 1H), 7.40 (s, 1H), 6.65 (s, 1H), 6.14 (d, J=7 Hz, 1H), 5.57 (br s, 1H), 4.61 (t, J=7 Hz, 1H), 3.88 (s, 3H), 3.29 (s, 2H), 3.15 (s, 3H), 2.99 (s, 3H), 2.89 (s, 4H), 2.71 (d, J=4 Hz, 6H), 2.17 (m, 1H), 2.08 (m, 1H), 1.98 (br s, 2H), 1.65 (m, 1H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](=[CH:7][CH:8]=1)[OH:6].Br[CH2:11]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:11]1[O:6][C:5]2[CH:7]=[CH:8][C:2]([CH3:1])=[CH:3][C:4]=2[O:9]1
Reactant: Cc1ccc(O)c(O)c1
Reactant: BrCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Product: Cc1ccc2c(c1)OCO2
Yield: 89 %

Procedure:
Alternatively, a solution composed of 0.7 mol of the compound (V) obtained by the above process, 1.75 mols of sodium hydroxide, and a 2.8-fold amount by weight, based on (V), of water was added dropwise to a solution composed of a 1.6-fold amount by weight, based on (V), of water, 2.0 mols of dibromomethane, and 0.007 mol of tetra-n-butylammonium bromide over 5 hours under reflux condition. After completion of the dropwise addition, the mixture was maintained at the same temperature for 2 hours while stirring. After completion of the reaction, the reaction mixture was extracted with toluene and, after liquid separation, the toluene was distilled off from the resulting organic layer. Distillation of the residue gave 3,4-methylenedioxytoluene (VI-1) in 89% yield.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:4]=[C:5]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:6]2=[N:7][CH:8]=1.FC(F)(F)S(O[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[O:29][CH:28]=1)(=O)=O>>[O:29]1[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:35]2[C:27]([C:3]2[CH:4]=[C:5]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:6]3=[N:7][CH:8]=2)=[CH:28]1
Reactant: C[Sn](C)(C)c1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Reactant: O=S(=O)(Oc1coc2ncccc12)C(F)(F)F
Product: c1cnc2occ(-c3cnc4c(c3)C[C@@]3(CN5CCC3CC5)O4)c2c1

Procedure:
Prepared by a method analogous to that described for the preparation of Example 1 from (2′R)-5′-trimethylstannyl-spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] and furo[2,3-b]pyridin-3-yl trifluoromethanesulfonate. The title compound was obtained as a colourless solid; m/e 334 (MH+).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=O)=[CH:10][N:9]=1.[CH3:19][C:20]1[C:21]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:22][C:23]([CH3:27])=[C:24]([CH3:26])[CH:25]=1>>[O:18]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[N:9]=[CH:10][C:11]([C:12]([N:31]2[CH2:32][CH2:33][N:28]([C:21]3[C:20]([CH3:19])=[CH:25][C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=3)[CH2:29][CH2:30]2)=[O:14])=[CH:16][CH:17]=1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Reactant: COC(=O)c1ccc(CN2CCCS2(=O)=O)nc1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(CN4CCCS4(=O)=O)nc3)CC2)nc1C
Yield: 67.4 %

Procedure:
Using methyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)nicotinate (107 mg) described in Preparation Example 45 and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (81 mg) described in Preparation Example 92 and by the reaction and treatment in the same manner as in Example 109, the title compound (118 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]=2)=[C:6]([C:23]([F:26])([F:25])[F:24])[CH:5]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)=[C:6]([C:23]([F:26])([F:24])[F:25])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2C(F)(F)F)CC1
Yield: 56.5 %

Procedure:
Stir the mixture of tert-butyl 4-(4-nitro-2-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (289 mg, 0.776 mmol), methanol (50 mL) and Pd/C (10%, 25 mg) under hydrogen atmosphere for 30 hrs. Remove H2, filter the mixture and concentrate the filtrate under reduced pressure. Purify the residue with flash chromatography (silica gel, PE:EtOAc=5:1) to afford the desired product (151 mg, 84%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=3)[CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[CH3:35][O:36][C:37](=[O:47])[C:38]1[CH:43]=[CH:42][C:41]([C:44](Cl)=[O:45])=[CH:40][CH:39]=1>C1COCC1>[CH3:35][O:36][C:37](=[O:47])[C:38]1[CH:43]=[CH:42][C:41]([C:44]([N:8]2[C:9]3[C:14](=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=3)[CH:15]=[C:7]2[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:45])=[CH:40][CH:39]=1
Reactant: N#Cc1ccc2[nH]c(-c3cccnc3)cc2c1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)n2c(-c3cccnc3)cc3cc(C#N)ccc32)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 8, 240 mg, 1.09 mmol) in THF (10 mL) at room temperature is added 0.5 M KHMDS in toluene (4.0 mL, 2.0 mmol). After 30 min, 4-chlorocarbonyl-benzoic acid methyl ester (400 mg, 2.0 mmol) is added. The mixture is stirred under N2 for 1 h. The reaction is quenched with aqueous sodium bicarbonate and the volatiles are removed in vacuo. Purification by silica gel flash chromatography using a heptane-ethyl acetate gradient affords 4-(5-cyano-2-pyridin-3-yl-indole-1-carbonyl)-benzoic acid methyl ester. 1H NMR (400 MHz, MeOD) δ ppm 3.90 (s, 3H), 7.12 (s, 1H), 7.26 (dd, J=8.0, 4.9 Hz, 1H), 7.63-7.72 (m, 3H), 7.77-7.81 (m, 1H), 7.91-7.96 (m, 3H), 8.17 (d, J=1.5 Hz, 1H), 8.32 (dd, J=4.8, 1.5 Hz, 1H), 8.56 (d, J=2.3 Hz, 1H). HRMS (ESI) m/z 382.1186 [(M+H)+ Calcd for C23H16N3O3: 382.1192].
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[Cl:5][C:6]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:7]=1[O:8][C:9]1[CH:10]=[C:11]([C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)[CH2:12][OH:13].S(=O)(=O)(O)O>ClCCCl>[C:2]([O:13][CH2:12][C:11]1[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=[C:9]([O:8][C:7]2[CH:20]=[CH:21][C:22]([C:24]([F:25])([F:26])[F:27])=[CH:23][C:6]=2[Cl:5])[CH:10]=1)([CH3:3])([CH3:1])[CH3:4]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1CO
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: CC(C)(C)OCc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 89 %

Procedure:
Isobutylene gas was passed into a solution of 17.4 parts by weight of 3-(2'-chloro-4'-trifluoromethylphenoxy)-6-nitrobenzyl alcohol in 100 parts by volume of 1,2-dichloroethane and 0.5 parts by weight of sulfuric acid at 40° C. for two hours. The reaction mixture was then washed with dilute aqueous sodium bicarbonate solution and twice with water, and the organic phase was dried with magnesium sulfate, filtered and concentrated. 18 parts by weight (89% of theory) of 3-(2'-chloro-4'-trifluoromethylphenoxy)-6-nitrobenzyl tert.-butyl ether (compound No. 16) of melting point 75°-78° C. were obtained.
Reaction SMILES: [F:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:10][C:9]2[N:8]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:7](=[O:23])[C:6]3[CH2:24][N:25](C4CCCCO4)[NH:26][C:5]=3[C:4]=2[CH:3]=1.[ClH:33]>O1CCOCC1>[ClH:33].[F:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:10][C:9]2[N:8]([CH2:18][C:19]([F:21])([F:22])[F:20])[C:7](=[O:23])[C:6]3[CH:24]=[N:25][NH:26][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=c1c2c(c3cc(F)c(-c4ccccn4)cc3n1CC(F)(F)F)NN(C1CCCCO1)C2
Agent: Cl
Solvent: C1COCCO1
Product: O=c1c2cn[nH]c2c2cc(F)c(-c3ccccn3)cc2n1CC(F)(F)F
Yield: 75 %

Procedure:
The product is obtained according to the procedure described in Step 1.7. by treating 8-fluoro-7-(pyrid-2-yl)-2-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one with HCl in dioxane (4M). It is in the form of a white powder (hydrochloride; yield 75%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH:11]([CH:28]=O)[CH2:10]1)(=[O:8])=[O:7].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[F:25][C:22]([F:23])([F:24])[C:21]([C:18]1[CH:17]=[CH:16][C:15]([N:12]2[CH2:13][CH2:14][N:9]([S:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)(=[O:7])=[O:8])[CH2:10][CH:11]2[CH2:28][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:20][CH:19]=1)([OH:27])[CH3:26]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2C=O)cc1)C(F)(F)F
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2CN2CCOCC2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.6 %

Procedure:
To a solution of 4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinecarbaldehyde (45 mg, 0.100 mmol) and morpholine (26.2 mg, 0.301 mmol, Aldrich, St. Louis, Mo.) in 1,2-dichloroethane (2.0 mL) was added sodium triacetoxyborohydride (106 mg, 0.502 mmol) and acetic acid (5.74 μL, 0.100 mmol). The reaction was stirred at room temperature for 1 h then quenched with methanol (5 mL) and concentrated. The crude material was dissolved in methanol, filtered and purified using prep HPLC (Phenomenex C18 column (150×30 mm) eluting with TFA in CH3CN/H2O (10% to 90% gradient over 25 min) at a 30 mL/min flow rate) to yield 1,1,1-trifluoro-2-(4-(2-(4-morpholinylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (5 mg) as a mixture of four isomers.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][C:27]=3[S:26][C:25]2=[O:41])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11].C(N(CC)CC)C.[C:49](Cl)(=[O:53])[CH2:50][CH2:51][CH3:52]>C(OCC)(=O)C>[C:33]([C:31]1[CH:30]=[CH:29][C:28]2[N:24]([CH2:23][CH2:22][O:21][C:18]3[CH:17]=[CH:16][C:15]([CH2:14][CH:9]([NH:8][C:49](=[O:53])[CH2:50][CH2:51][CH3:52])[C:10]([O:12][CH3:13])=[O:11])=[CH:20][CH:19]=3)[C:25](=[O:41])[S:26][C:27]=2[CH:32]=1)(=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCCC(=O)Cl
Reactant: COC(=O)C(N)Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCCC(=O)NC(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)C(=O)OC
Reaction time: 8 h

Procedure:
500 mg of the compound obtained in Step A of Example 12 are dissolved in 10 ml of ethyl acetate; 0.353 ml of triethylamine is then added and the temperature is lowered to 0° C. 0.177 ml of butyryl chloride is added and the mixture is allowed to return to ambient temperature and is stirred overnight.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11](=[O:12])[C:10]3=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]3[C:8]2=[O:17])[CH2:3]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:28][CH2:29]Cl)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:28][CH2:29][N:2]2[CH2:6][CH2:5][CH:4]([N:7]3[C:11](=[O:12])[C:10]4=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]4[C:8]3=[O:17])[CH2:3]2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(CCCl)cc1OC
Reactant: O=C1c2ccccc2C(=O)N1C1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CCN2CCC(N3C(=O)c4ccccc4C3=O)C2)cc1OC
Yield: 11.3 %

Procedure:
6.03 g of the hydrochloride was suspended into 100 ml of acetonitrile, to which 4.79 g of 2-(3,4-dimethoxyphenyl) ethyl chloride, 8.24 g of anhydrous potassium carbonate and n-tetrabutyl ammonium iodide (catalytic amount) were added and refluxed under heating for 20 hours. After allowing them to cool, the inorganic salts were filtered out and the solvent was distilled off. After adding ethyl acetate and washed with water, they were dried with anhydrous magnesium sulfate. The solvent was concentrated and purified on silica gel chromatography to obtain 1.03 g of the above-captioned compound (total yield: 6.5%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH2:31][CH2:32][O:33][CH3:34])[N:21]=[CH:20][N:19]=[C:18]2[CH:7]1[C:6]2[C:10](=[CH:11][C:3]([C:2]([F:1])([F:13])[F:14])=[CH:4][CH:5]=2)[NH:9][C:8]1=[O:12]
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: O=C1Cc2ccc(C(F)(F)F)cc2N1
Agent: [H-]
Agent: [Na+]
Product: COCCOc1cc2ncnc(C3C(=O)Nc4cc(C(F)(F)F)ccc43)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
6-Trifluoromethyloxindole (270 mg, 1.3 mmol) was dissolved in dry, degassed DMF (5 ml) under argon. Sodium hydride (63 mg, 1.6 mmol) was added and the suspension stirred for 30 minutes at ambient temperature. A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (111 mg, 0.332 mmol), (prepared as described for the starting material in Example 2), in dry, degassed DMF (5 ml) was added dropwise and the mixture heated at 100° C. for 2 hours. The mixture was allowed to cool and the DMF was removed by evaporation. The residue was purified by flash column chromatography eluting with methylene chloride/methanol (100/0 and then 15/1). The purified orange solid was triturated with ether, collected by filtration and dried under vacuum at 40° C. to give 6-methoxy-7-(2-methoxyethoxy)-4-(6-trifluoromethyloxindol-3-yl)quinazoline (100 mg, 52%).
Reaction SMILES: B.C1COCC1.[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:17][CH2:16][CH:15]([C:18](O)=[O:19])[CH2:14][C:13]=2[CH:21]=1>C1COCC1>[OH:19][CH2:18][CH:15]1[CH2:14][C:13]2[CH:21]=[C:9]([O:8][CH3:7])[CH:10]=[CH:11][C:12]=2[S:17][CH2:16]1
Reactant: COc1ccc2c(c1)CC(C(=O)O)CS2
Agent: B
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC(CO)CS2
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: Borane-THF complex (1M in THF, 55.4 ml, 55.4 mmol) is cooled to 0° C. To this mixture is added 6-methoxy-3,4-dihydro-2H-1-benzothiopyran-3-carboxylic acid (6.1 g, 25 mmol) in 30 ml of THF dropwise. The cooling bath is then removed and the mixture is stirred overnight. This is quenched by addition of 50% aqueous acetic acid (8 ml), and concentrated in vacuo at 50° C. The residue is purified by flash chromatography (silica gel, 40% EtOAc/hexane) to give 3-hydroxymethyl-6-methoxy-3,4-dihydro-2H-1-benzothiopyran as an oil which crystallizes on standing.