Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:21])=[C:14]([C:19]#[N:20])[CH:15]=[N:16]2)=[CH:11][C:10]=1[O:22][CH3:23])C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[Cl:21][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:22][CH3:23])[CH:11]=2)[N:16]=[CH:15][C:14]=1[C:19]#[N:20]
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCc1ccccc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COc1cc2c(Cl)c(C#N)cnc2cc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 19.2 %

Procedure:
A stirred suspension of 0.54 g of 7-benzyloxy-4-chloro-6-methoxy-quinoline-3-carbonitrile in 10 ml of methylene chloride was cooled to 0° C. To this was added 10 ml of boron trichloride (1M in methylene chloride). The mixture darkened as it warmed to room temperature and a solid precipitated out. After stirring for 1 hour, no further reaction was observed. The solid (unreacted starting material) was filtered off, the remaining solution was cooled to 0° C. and quenched by the dropwise addition of methanol. Following evaporation of the solvent, the residue was dissolved in methylene chloride/methanol/acetone. Purification of this residue was carried out using silica gel chromatography, eluting with a solvent gradient of 1 to 5 percent methanol/methylene chloride, to provide 0.075 g of 4-chloro-7-hydroxy-6-methoxy-quinoline-3-carbonitrile as a yellow solid, dec >245° C.; mass spectrum (electrospray, m/e) M+H 235.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](F)=[C:8]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[CH:9]=1)([O-:3])=[O:2].[O-:26][CH2:27][CH3:28].[Na+]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:26][CH2:27][CH3:28])=[C:8]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Reactant: CC[O-]
Agent: [Na+]
Product: CCOc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 40a), from 2-(5-nitro-2-fluorophenyl)-5-phenylbenzoxazole (200 mg, 0.60 mmol) and sodium ethoxide (41 mg, 0.61 mmol) the subtitle compound was obtained (197 mg, 91%). 1H NMR (DMSO) δ 8.92(d, 1H), 8.51(dd, 1H), 8.18(s, 1H), 7.95(d, 1H), 7.83(d, 2H), 7.56(t, 3H), 7.47(t, 3H), 4.50(q, 2H), 1.57(t, 3H).
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][C@@H:4]([CH2:5][CH2:6][C@H:7]2[C:10]([NH:12][O:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:11])[N:3]1[O:24]S(O)(=O)=O.F[C:30](F)(F)[C:31](O)=O>C(Cl)Cl>[OH:24][N:3]1[C:2](=[O:1])[N:8]2[CH2:9][C@H:4]1[CH2:5][CH2:6][C@H:7]2[C:10]([NH:12][O:13][C@H:14]1[CH2:31][CH2:30][N:16]([C:17]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:23])[CH2:15]1)=[O:11]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate 44 (0.19 g, 0.45 mmol) in DCM (6.0 mL) was added trifluoroacetic acid (0.30 mL) at 0° C. The mixture was stirred at 0° C. for 1 h, concentrated and washed with ether. The white solid was collected by centrifugation. The crude product was purified by preparative HPLC to provide Compound 9 (Table 1) (44 mg) as a white solid.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]([CH3:21])([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=O)[C:7]([NH2:9])=[O:8])([CH3:5])[CH3:4]>>[CH:3]([C:6]1([CH3:21])[N:10]2[C:18](=[O:19])[C:17]3[C:12]([C:11]2=[N:9][C:7]1=[O:8])=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH3:5])[CH3:4]
Reactant: CC(C)C(C)(C(N)=O)N1C(=O)c2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)C1(C)C(=O)N=C2c3ccccc3C(=O)N21

Procedure:
Following the procedure described in Example 1 and sodium hydride as the base, but substituting (+)-α-isopropyl-α-methyl-1,3-dioxo-2-isoindoleacetamide for the racemic compound, the product (-)-3-isopropyl-3-methyl-5H-imidazo[2,1-a]isoindole-2(3H),5-dione is obtained, melting point 137.5°-139° C, [α]D25 -64.74° (THF, C 0.097).
Reaction SMILES: ClCCl.[Cl:4][C:5]1[CH:6]=[C:7]([CH:12]2[C:16]([OH:17])=[C:15]([C:18]([CH3:20])=[O:19])[CH:14]([CH3:21])[S:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11].S(Cl)(Cl)(=O)=O.O>CCCCCC.C(OCC)(=O)C>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[S:13][C:14]([CH3:21])=[C:15]([C:18]([CH3:20])=[O:19])[C:16]=2[OH:17])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: CC(=O)C1=C(O)C(c2ccc(Cl)c(Cl)c2)SC1C
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O=S(=O)(Cl)Cl
Product: CC(=O)c1c(C)sc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Yield: 31.2 %

Procedure:
A dichloromethane (13 mL) solution of 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonyl-5-methyl-2,5-dihydrothiophene (806 mg, 2.66 mmol) was cooled to −72° C., and to this solution, a dichloromethane (2.7 mL) solution of sulfuryl chloride (0.11 mL, 0.5 equivalent amount) was dropwise added over a period of 3 minutes. After the temperature of the solution was raised to room temperature, the solution was mixed with water (16 mL) and a saturated sodium chloride aqueous solution (16 mL), and extracted with dichloromethane. The dichloromethane solution was dried over a drying agent and purified by silica gel column chromatography (eluent: hexane/ethyl acetate=85/15 and then 4/1 (v/v)) to give the desired product as a yellow solid (0.25 g, yield: 31%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([NH2:7])=[NH:6].[Cl:12][C:13]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:14]=1[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18]>>[NH2:20][CH2:19][C:16]1[C:17]([NH2:18])=[N:6][C:5]([C:4]2[CH:3]=[C:2]([F:1])[CH:10]=[C:9]([F:11])[CH:8]=2)=[N:7][C:15]=1[C:14]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:13]=1[Cl:12]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: N=C(N)c1cc(F)cc(F)c1
Product: NCc1c(N)nc(-c2cc(F)cc(F)c2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=380.9 (M+H+), was prepared from 3,5-difluorobenzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C:12]1([Si:18]2(CCCC)[CH2:23][CH2:22][CH:21]([CH:24]3[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)C=C[CH:15]=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][C@H:27]2[CH2:26][CH2:25][C@H:24]([CH:21]3[CH2:20][CH2:19][SiH:18]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:23][CH2:22]3)[CH2:29][CH2:28]2)=[O:8])=[CH:5][CH:4]=1
Reactant: CCCC[Si]1(c2ccccc2)CCC(C2CCC(O)CC2)CC1
Reactant: COc1ccc(C(=O)O)cc1
Product: CCCC[SiH]1CCC([C@H]2CC[C@H](OC(=O)c3ccc(OC)cc3)CC2)CC1

Procedure:
The general procedure of Example 31 was repeated using 4-methoxybenzoic acid and 4-(4-phenyl-4-n-butyl-4-silacyclohexyl)cyclohexanol, thereby obtaining the intended product.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:50]=[CH:49][C:39]([C:40]([NH:42][CH2:43][CH2:44][CH2:45][N:46]([CH3:48])[CH3:47])=[O:41])=[CH:38][CH:37]=1>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:50]=[CH:49][C:39]([C:40]([NH:42][CH2:43][CH2:44][CH2:45][N:46]([CH3:47])[CH3:48])=[O:41])=[CH:38][CH:37]=4)=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN(C)CCCNC(=O)c1ccc(N)cc1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: CN(C)CCCNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCCC2)CC(F)(F)C(=O)N3C)cc1
Yield: 69.5 %

Procedure:
A mixture of 0.0562 g (0.18 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.0514 g (0.27 mmole) of toluenesulfonic acid monohydrate, 0.0398 g (0.18 mmole) of 4-amino-N-(3-dimethylamino-propyl)-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 16 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-methanol-triethylamine (80:20:2) to give 0.0645 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-benzamide (I-265).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C@@H:5]([NH:7][C@@H:8]([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:6].C[Mg]Br>C(OCC)C>[CH3:15][C@H:8]([N:7]1[C@@H:5]([CH3:6])[CH2:4][C:3]1=[O:2])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)C[C@H](C)N[C@@H](C)c1ccccc1
Agent: C[Mg]Br
Solvent: CCOCC
Product: C[C@H]1CC(=O)N1[C@@H](C)c1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution compound (35) from Example 21 (1.00 mmol) in anhydrous diethyl ether (5 ml) at 0° C. was added slowly, dropwise, 3.0 M methylmagnesium bromide (1.10 mmol). The resulting solution was stirred for 10 minutes and the reaction was then quenched by addition of pH7 buffer. Diethyl ether (20 ml) was added, whereafter the solution was washed with water (20 ml) and brine (20 ml), dried (magnesium sulphate) and filtered. The solvent was removed under reduced pressure to afford the title compound (41) as a clear oil which was subjected to flash chromatography on silica gel. [α]D21 -68.9 (c 1.61, CHCl3); νmax (CHCl3)/cm-1 1742 s (C=O), δH (300 MHz; CDCl3) 7.34-7.23(5H, m, Ph), 4.92 (1H, q, J=7.2, PhCHCH3), 3.51 (1H, m, CH3CHCH2); 2.97, 2.46 (2H, ABX system, JAB =14.4, JAX =5.1, JBX =2.4, CH2CO), 1.63 (3H, d, J=7.2, PhCHCH3), 1.25 (3H, d, J=6.1, CH3CHCH2); δC (50 MHz; CDCl3) 166.90 (C=O), 140.67 (Ph:Cipso), 128.85, 127,18 (Ph:Cortho,Cmeta), 127.77 (Ph: Cpara), 51.78, 47.18 (CHN), 43.45(CH2CO), 20.65, 19.25 (NCHCH3); m/z (CI) 190 (MH+, 100%), 174(5), 132 (10), 105 (8); (Found: C, 76.02; H, 7.98; 7.07. C12H15NO requires C, 76.16; H, 7.99; N, 7.40%).
Reaction SMILES: [CH2:1]([O:10][C:11](=[O:37])[CH:12]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])=[CH:23][CH:22]=1)[NH:13]C(OC(C)(C)C)=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[BrH:38].C(O)(=O)C>C(OCC)(=O)C>[BrH:38].[CH2:1]([O:10][C:11](=[O:37])[CH:12]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:30])=[CH:23][CH:22]=1)[NH2:13])[C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)OCC(=O)c1ccccc1)c1ccc(OCC(=O)c2ccccc2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NC(C(=O)OCC(=O)c1ccccc1)c1ccc(OCC(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of N-tert-butoxycarbonyl-2-(4-phenacyloxyphenyl)glycin phenacyl ester (1.0 g.) in ethyl acetate (10 ml.) was added a mixture of hydrobromic acid and acetic acid (2 ml., 4:1 v/v), and then the mixture was stirred for half an hour at ambient temperature. The precipitates were collected by filtration and washed with ethyl acetate to give 2-(4-phenacyloxyphenyl)glycine phenacyl ester hydrobromide (830 mg.), which was recrystallized from a mixture of ethanol, methanol and diethyl ether to give the pure crystals (550 mg.), mp 176° to 177° C.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:31])[C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])=[CH:18][CH:17]=1.O>CN(C)C(=O)C>[F:30][C:24]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=1[C:22]([C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:17][CH:18]=1)=[O:31]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(C(=O)c2cc(F)ccc2F)cc1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2cc(F)ccc2F)cc1)C(F)(F)F
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.95 g, 6.0 mmol) in N,N-dimethylacetamide (15 mL) was added thionyl chloride (0.72 g, 6.0 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 4'-Amino-2,5-difluoro benzophenone (1.00 g, 4.3 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured into water and the aqueous solution filtered to yield a brown solid. Recrystallization from methylene chloride/hexane yielded the title propanamide as a white solid (1.03 g, 69%); mp 145°-147° C. 1H-NMR (250 MHz, d6-DMSO): 1.59 (s, 3H, CH3) 7.44-7.47 (m, 3H, aromatic) 7.57 (s, 1H, OH) 7.77 (d, 2H, J=8.0 Hz, aromatic) 7.97 (d, 2H, J=8.0 Hz, aromatic) 10.40 (s, 1H, NH). MS (CI, CH4): 374 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[C:13]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:12]2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.C([O:42][C@@H:43]([CH3:47])[C:44](Cl)=[O:45])(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH2:3][NH:2][C:44](=[O:45])[C@@H:43]([OH:42])[CH3:47])[CH:9]=[CH:8][CH:7]=3)[N:12]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)[C@H](C)O)c1
Reaction time: 4 h

Procedure:
A suspension of N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see Intermediate 4) (100 mg, 0.2 mmol) in DCM (5 mL) and triethylamine (0.28 mL, 2 mmol) was treated with the (S)-2-acetoxypropionyl chloride (0.065 mL). After 4 h, the solvent was removed by evaporation and the residue was dissolved in methanol (10 mL) and then treated with solid potassium carbonate (277 mg, 2 mmol) and the mixture was stood at RT for 3 days. The mixture was concentrated under reduced pressure, and the residue was partitioned between 2M HCl and ethyl acetate. The organic solution was washed with more HCl, brine and dried (MgSO4). The filtrate was evaporated under reduced pressure to give a white solid (113 mg). The sample was dissolved in 1:1 MeOH-DMSO 2 mL and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier (Method A). The solvent was evaporated in vacuo to give the title compound (86 mg, 80%): LCMS (System A) RT=0.97 min, 100%, ES+ve m/z 535/537 (M+H)+; NMR δ (CD3OD) 7.27-7.15 (5H, m), 7.05 (1H, br d, J 7 Hz), 6.97 (1H, d, J 8 Hz), 6.89 (1H, d, J 4 Hz), 6.42 (1H, d, J 8 Hz), 5.47 (2H, s), 4.33 (2H, s), 4.12 (1H, q, J 7 Hz), 3.76 (3H, s), 1.30 (3H, d, J 7 Hz).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11](Cl)=[O:12].[CH2:14]([O:16][CH:17]([O:30][CH2:31][CH3:32])[CH2:18][CH2:19][CH2:20][NH:21]C(C1CCCCC1)=O)[CH3:15]>>[CH2:31]([O:30][CH:17]([O:16][CH2:14][CH3:15])[CH2:18][CH2:19][CH2:20][NH:21][C:11]([CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:12])[CH3:32]
Reactant: CCOC(CCCNC(=O)C1CCCCC1)OCC
Reactant: O=C(Cl)C1CCc2ccccc2C1
Product: CCOC(CCCNC(=O)C1CCc2ccccc2C1)OCC

Procedure:
1,2,3,4-Tetrahydro-naphthalene-2-carboxylic acid (4,4-diethoxy-butyl)-amide (23B) is prepared from 23A as described for 20A.
Reaction SMILES: Cl[CH2:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4]1.[F:14][C:15]([F:24])([F:23])[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:3]([CH2:2][C:18]([CH2:17][CH2:16][C:15]([F:14])([F:23])[F:24])([C:19]#[N:20])[C:21]#[N:22])[CH:4]=1)=[O:13]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: O=Cc1cn(CCl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(C=O)c2ccccc21
Yield: 53.8 %

Procedure:
3.02 g of 1-(chloromethyl)-3-formyl-1H-indole and 2.53 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 45 ml of N,N-dimethylformamide. 4.35 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 3 hours. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.68 g of [{3-formyl-1H-indole-1-yl}methyl](3,3,3-trifluoropropyl)malononitrile(referred to as the compound of the present invention (40), hereinafter) shown by below formula.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1.[Cl-:11].[Al+3].[Cl-:13].[Cl-]>C(Cl)Cl>[Cl:11][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([Cl:13])[C:2]=1[CH3:1])[C:8]([OH:10])=[O:9]
Reactant: [Cl-]
Reactant: Cc1ccc(C(=O)O)cc1
Agent: [Al+3]
Solvent: ClCCl
Product: Cc1c(Cl)cc(C(=O)O)cc1Cl
Reaction time: 4 h

Procedure:
To a solution of p-toluic acid (95.0 g,0.698 mole) in methylene chloride (1 liter), was added aluminum chloride (260.0 g,1.948 mole), portionwise, while keeping the reaction temperature below 10° C. When the addition was completed, chlorine gas was bubbled in at such a rate as to keep the temperature below 10° C. The reaction was followed by GLC. After about 4 hours most of the starting material had been converted to the expected compound. The resulting mixture was poured into ice and concentrated hydrochloric acid, and then extracted with ethyl acetate several times. The combined organic layers were washed with water and then dried over anhydrous sodium sulfate. Removing the solvent in the rotavap yielded the crude product as a white solid. Recrystalization from acetone/water yielded 3,5-dichloro-4-methylbenzoic acid with minor impurities 115.4 g (81% yield of product).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:30][CH2:31][CH2:32][OH:33])=[N:12][N:13]([CH3:29])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[C:35]1[N:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][N:36]=1>O1CCCC1.CC(N(C)C)=O.[H-].[Na+]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:30][CH2:31][CH2:32][O:33][C:35]4[N:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][N:36]=4)=[N:12][N:13]([CH3:29])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:26])[CH3:27])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CS(=O)(=O)c1cnc(Cl)nc1
Reactant: Cn1nc(OCCO)c(-c2ccc3c(c2)OCO3)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cn1nc(OCCOc2ncc(S(C)(=O)=O)cn2)c(-c2ccc3c(c2)OCO3)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 16.4 %

Procedure:
To a solution of N-[4-(1,3-benzodioxol-5-yl)-3-(2-hydroxyethoxy)-1-methyl-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide (Example 17) (300 mg, 0.63 mmol) in anhydrous tetrahydrofuran (12 ml) and dimethyl acetamide, sodium hydride 60% dispersion in oil (55 mg, 1.39 mmol) was added under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 20 minutes. 2-chloro-5-(methylsulfonyl)pyrimidine (0.69 mmol) was added, in one portion, to the reaction mixture which was then stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue poured onto water (150 ml). The aqueous was extracted with ethyl acetate (4×50 ml). The organic fractions were washed with brine (4×100 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to yield the title compound (65 mg) as a yellow crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:10])[CH:3]=1.[Na].[OH-].[Na+].[CH2:14](Br)[C:15]#[CH:16].C1(C)C=CC=CC=1>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH2:16][C:15]#[CH:14])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1O
Reactant: C#CCBr
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: C#CCOc1cc(Br)ccc1C=O

Procedure:
Conversion of 4-bromo-2-hydroxybenzaldehyde to its sodium salt was carried out as follows: A solution of 4-bromo-2-hydroxybenzaldehyde (3.0 g, 24.9 mmol) in MeOH (˜150 mL) was treated with 1N aq. NaOH (15.7 mL, 1.05 equiv). The resulting pale yellow solution was concentrated under reduced pressure. EtOH (30 mL) was added to the residue and the solution was concentrated under reduced pressure. This was repeated with EtOH (30 mL) and then with heptane (50 mL). The resulting yellow, powdery sodium salt was dissolved in DMF (60 mL) with stirring and to it was added propargyl bromide in toluene (80 wt %, 2.33 mL, 1.4 equiv). The reaction mixture was stirred at ambient temperature for 22 h, after which time the volatiles were concentrated under reduced pressure. The residue was partitioned between EtOAc (70 mL) and water (40 mL). The organic layer was separated and treated with charcoal (˜1 g) then dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained was crystallized from EtOAc and hexane (3:7). Crop I afforded 4-bromo-2-(prop-2-ynyloxy)benzaldehyde (893 mg) as colorless needles. The mother liquor was concentrated under reduced pressure and crystallized again from EtOAc and hexane (7:93) to obtain a further Crop II of 4-bromo-2-(prop-2-ynyloxy)benzaldehyde (1.902 g). The mother liquor was concentrated again and subjected to one more crystallization as described before. Crop III yielded additional 4-bromo-2-(prop-2-ynyloxy)benzaldehyde (344 mg). All the three crops were combined to give a total of 3.14 g (87% yield) of 4-bromo-2-(prop-2-ynyloxy)benzaldehyde as colorless needles. 1H NMR (500 MHz, CDCl3) δ 10.43 (s, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.31 (d, J=1.5 Hz, 1H), 7.24-7.28 (m, 1H), 4.85 (d, J=2.4 Hz, 2H), 2.64 (t, J=2.4 Hz, 1H); LCMS (Method A) (ESI) m/e 239.0, 241.0 Br pattern [(M+H)+, calcd for C10H7BrO2 239.0]; SiO2 TLC (EtOAc:Hexane=1:9) indicated Rf of 0.32 compared with an Rf of 0.43 for starting material aldehyde.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1.C([Li])CCC.CN([CH:18]=[O:19])C>C1COCC1.C(OCC)C>[CH2:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:18]=[O:19])[CH3:9]
Reactant: CN(C)C=O
Reactant: CCc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1cccc(C=O)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 109.6 %

Procedure:
To a solution of 1-bromo-3-ethylbenzene (5 g, 27.2 mmol) in THF (135 mL) at −78° C. was added butyl lithium (1.6 M in hexanes, 18 mL, 28.8 mmol) dropwise. The mixture was stirred at −78° C. for 5 min. DMF (2.1 mL, 27.2 mmol) was added and the mixture was warmed to ambient temperature over 2 h. The mixture was diluted with diethyl ether (500 mL), washed with sat. NaHCO3 and brine, dried (Na2SO4) and concentrated to yield 4 g of Intermediate 370.1 as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.27 (t, J=7.58 Hz, 3H) 2.73 (q, J=7.58 Hz, 2H) 7.39-7.51 (m, 2H) 7.64-7.76 (m, 2H) 9.99 (s, 1H).