Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl.[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[C:16]([F:22])[CH:15]=1>C(Cl)Cl>[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C:1](=[O:3])[CH3:2])=[C:16]([F:22])[CH:15]=1
Reactant: CC(=O)Cl
Reactant: NCc1ccc(Br)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1ccc(Br)cc1F
Reaction time: 1.5 h
Yield: 73.4 %

Procedure:
Acetyl chloride (0.7 mL, 9.9 mmol) followed by triethylamine (2.8 mL, 19.9 mmol) were added to a suspension of 4-bromo-2-fluorobenzylamine hydrochloride (2 g, 8.3 mmol) in CH2Cl2 (20 mL). The mixture was stirred for 90 mins and then partitioned between 1 N HCl and EtOAc. The organic layers were brine, dried over Na2SO4 and concentrated. Purification by flash column chromatography (0% to 60% EtOAc in hexanes) gave the product as a clear oil (1.5 g, 74%). MS (ESI): 246.10, 248.10 (M+H)+
Reaction SMILES: [C:1]([C@@H:4]([N:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:31])[CH:29]=[CH2:30])=[CH:23][CH:22]=1)[S:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:3])[NH2:2].[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C1(C)C=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([S:10]([N:9]([C@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:1]([NH2:2])=[O:3])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:31])[CH2:29][CH2:30][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:23][CH:22]=2)(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: C=CC(=O)Nc1ccc(CN([C@@H](CC(C)C)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(C)C[C@H](C(N)=O)N(Cc1ccc(NC(=O)CCN2CCCCC2)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 86.9 %

Procedure:
To a solution of N-(4-{[N-((1S)-1-carbamoyl-3-methyl-butyl)-N-(4-chlorobenzenesulfonyl)amino]-methyl}-phenyl)-acrylamide (0.10 g, 0.22 mmol) in toluene (5 mL) was added piperidine (20 mg, 0.24 mmol). The mixture was heated at a gentle reflux for 1 h and then the solvent was removed in vacuo. Purification by flash chromatography (SiO2, 10% MeOH/CH2Cl2) afforded the title compound (105 mg) in 86% yield. MS (ESI), (M+H)+ 449.16, 1H NMR (CDCl3, 400 MHz) δ 7.69 (d, 2H, J=8.0), 7.63 (d, 2H, J=8.0), 7.38 (d, 2H, J=8.0), 7.23 (d, 2H, J=8.0), 6.25 (br s, 1H), 5.35 (br s, 1H), 4.75 (d, 1H, Jab=16), 4.38 (d, 1H, Jab=16), 3-25 (t, 1H, J=6.0), 2.65 (t, 2H, J=6.0), 2.56-2.44 (m, 6H), 1.95 (m, 1H), 1.68-1.45 (m, 8H), 0.98 (d, 3H, J=7.0), 0.94 (d, 3H, J=7.0)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:24][C:25]([F:28])([F:27])[F:26])(=O)=O.O>CN(C=O)C>[F:26][C:25]([F:28])([F:27])[CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(O)cn1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.4 %

Procedure:
To a solution of methyl 5-hydroxypyridine-2-carboxylate (10.1 g, 65.95 mmol) and cesium carbonate (42.9 g, 131.9 mmol) in DMF (1 L) is added a solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate (22.96 g, 98.93 mmol) in 20 ml of DMF over 2 hours. The reaction is stirred 4 hours at room temperature and then poured over water (1 L) and stirred for additional 1 hour. A brown solid is collected by filtration and washed with additional water. The solid is dried to a constant weight to give the intermediate compound (10.3 g 66%) of methyl 5-(2,2,2-trifluoroethoxy)pyridine-2-carboxylate which is used without further purification. To a solution of methyl 5-(2,2,2-trifluoroethoxy)pyridine-2-carboxylate (4.5 g, 19.1 mmol) in methanol (45 mL) is added sodium hydroxide 1 M solution (38.2 ml, 38.2 mmol) and the reaction is stirred for 2 hours at room temperature. The pH of the reaction mixture is adjusted with HCl 35% w/w to adjust pH=1 and then the resulting solid is isolated by filtration. The solid is washed with water and then dried under vacuum to give the title compound (3 g, 70%). ES/MS (m/z): 222.1 (M+1).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].C(N(CC)CC)C.[C:16](Cl)(=[O:18])[O-:17]>ClCCl>[C:16](=[O:18])([OH:1])[OH:17].[OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8]
Reactant: O=C([O-])Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.2 g of N-hydroxysuccinimide and 1.0 g of triethylamine were dissolved in 20 ml of dichloromethane, and 3.92 g of the chlorocarbonate of Lutensol T03 in 10 ml of dichloromethane were added dropwise over the course of 5 min. The mixture was left to stir at room temperature for 2 h, the solvent was removed under reduced pressure, and the residue was taken up in ethyl acetate. The remaining solid was separated off, and the solvent was removed from the filtrate under reduced pressure to afford 4.3 g of the N-hydroxysuccinimide carbonate of Lutensol T03.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1.[NH4+:22].[OH-]>>[NH2:22][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: O=C(O)c1cccc2cc(Oc3ccnc(F)n3)ccc12
Agent: [OH-]
Product: Nc1nccc(Oc2ccc3c(C(=O)O)cccc3c2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-(2-Fluoropyrimidin-4-yloxy)-1-naphthoic acid (1.2 g, 4.2 mmol) was dissolved in NH4OH (37% water, 20 mL) and stirred at RT for 3h. Solvent was evaporated. A little bit of MeOH was added to the slurry followed by ether until the compound crashed out. Solid was filtered.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([N+:14]([O-])=O)=[C:9]([O:12][CH3:13])[CH:10]=2)[NH:5][C:4](=[O:17])[CH2:3]1.CO.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH3:1])([CH3:18])[CH2:3][C:4](=[O:17])[NH:5]2)=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: [H][H]
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CC2(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2c(cc1N)NC(=O)CC2(C)C
Yield: 92 %

Procedure:
4,4-dimethyl-6-(methyloxy)-7-nitro-3,4-dihydro-2(1H)-quinolinone (250 mg, 1.00 mmol) was dissolved in ethyl acetate (10 mL) and transferred to a Fischer Porter apparatus. 10% Palladium on carbon (250 mg, Aldrich) was added followed by methanol (20 mL) and the mixture stirred under 60 psi hydrogen pressure for 16 h. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite and the filtrate was concentrated to provide 7-amino-4,4-dimethyl-6-(methyloxy)-3,4-dihydro-2(1H)-quinolinone (213 mg, 0.92 mmol, 92%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (s, 6 H), 2.22 (s, 2 H), 3.72 (s, 3 H), 4.66 (s, 2 H), 6.20 (s, 1 H), 6.67 (s, 1 H), 9.76 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].C([Li])CCC.[CH3:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](=[O:42])[CH:29]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[CH2:30][S:31]2)=[CH:26][CH:25]=1.O>O1CCCC1>[Si:7]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([C:28]2([OH:42])[C:27]3[C:32](=[CH:33][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[S:31][CH2:30][CH:29]2[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH:16]=[CH:15][CH:14]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1
Reactant: COc1ccc(C2CSc3cc(OC)ccc3C2=O)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2CSc3cc(OC)ccc3C2(O)c2cccc(CO[Si](C)(C)C(C)(C)C)c2)cc1
Reaction time: 0.83 h
Yield: 28.1 %

Procedure:
To a solution of (3-bromobenzyloxy)-t-butyldimethylsilane (2.207 g, 7.326 mmol) in dry tetrahydrofuran (20 ml) was added n-butyl lithium (4.18 ml, 6.66 mmol, 1.59M tetrahydrofuran solution) at −78° C. over 25 minutes and stirred for 50 minutes. Then to the reaction mixture was added 7-methoxy-3-(4-methoxyphenyl)thiochroman-4-one (1 g, 3.33 mmol) dissolved in tetrahydrofuran at the same temperature over 10 minutes. The reaction mixture was stirred for 20 minutes at −78° C., followed at −15° C. for 12 h and at 0° C. for 8 h. When the reaction was completed, water was added to the reaction solution which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (n-hexane:ethyl acetate=8:2) to give 0.49 g (yield: 28%) of the title compound as a colorless oil. In this reaction 0.55 g (55%) of the unreacted starting compound was recovered.
Reaction SMILES: C(O[C:6](=[O:18])[CH2:7][C:8]([CH2:12][O:13]C(C)(C)C)([OH:11])[CH2:9][F:10])(C)(C)C>FC(F)(F)C(O)=O>[F:10][CH2:9][C:8]1([OH:11])[CH2:12][O:13][C:6](=[O:18])[CH2:7]1
Reactant: CC(C)(C)OCC(O)(CF)CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(O)(CF)CO1
Yield: 96.6 %

Procedure:
A solution of 17.47 g crude 3-tert-butoxymethyl-4-fluoro-3-hydroxybutyric acid tert-butyl ester (from 64.85 mmol 1-tert-butoxy-3-fluoro-propan-2-one) in 20 mL trifluoroacetic acid was stirred at 40° C. for 30 min. The resulting brown solution was evaporated and the residue subjected to bulb-to-bulb distillation at 150-160° C./0.4 mbar to provide 8.40 g (96.6% from 1-tert-butoxy-3-fluoro-propan-2-one) 4-fluoromethyl-4-hydroxy-dihydro-furan-2-one as yellow oil. 1H-NMR (CDCl3, 300 MHz): 4.46 (d, J=47, CH2F); 4.33 (AB with fine structure, J=10 and 2, —CH2—O); 3.33 (s br, OH); 2.70 (AB with fine structure, J=18, —CH2—C(O)).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1
Reactant: COC(=O)c1ccc2occ(Br)c2c1
Reactant: OB(O)c1ccccc1Cl
Product: COC(=O)c1ccc2occ(-c3ccccc3Cl)c2c1
Yield: 92 %

Procedure:
In the same manner as in Reference Example 19 and using methyl 3-bromo-1-benzofuran-5-carboxylate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and (2-chlorophenyl)boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 92%) was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Br)C.[CH3:30][C:31]1([CH3:39])[C:33]([CH3:35])([CH3:34])[CH:32]1[C:36](Cl)=[O:37]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:14][CH:13]=[C:12]2[C:36]([CH:32]1[C:33]([CH3:35])([CH3:34])[C:31]1([CH3:39])[CH3:30])=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: c1ccc(COc2cc3cc[nH]c3cc2OCc2ccccc2)cc1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3cc(OCc4ccccc4)c(OCc4ccccc4)cc23)C1(C)C
Yield: 55 %

Procedure:
The 5,6-dibenzyloxyindole (Sigma, 0.60 g, 1.8 mmol), ethylmagnesium bromide (1.0 M solution in THF, 2.2 mL, 2.2 mmol), zinc chloride (1.0 M solution in Et2O, 2.2 mL, 2.2 mmol) and the product of Example 1A (2.7 mmol) in 20 mL of dichloromethane were processed as described in Example 1B to provide the title compound (0.45 g, 0.99 mmol, 55% yield). MS (DCI/NH3) m/z 454 (M+H)+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([OH:11])=[O:10].[C:12](=O)(O)[O-].[Na+].C[Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[NH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C([O-])O
Reactant: O=C(O)C1CNCCN1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CNCCN1
Reaction time: 4 h
Yield: 28119.6 %

Procedure:
piperazine-2-carboxylic acid dihydrochloride (750 mg, 3.7 mmol) was suspended in MeOH (15 mL) and sodium bicarbonate (620 mg, 7.4 mmol) was added and stirred for 4 h. The reaction mixture was diluted with CH2Cl2 (15 mL) and cooled to 0° C. (Trimethylsilyl)diazomethane (15 mL, 2M in hexane) was added dropwise until the yellow color persisted. The solution was stirred at room temperature for 3 h and concentrated under reduced pressure. The crude product was purified by column chromatography (neutral alumina, eluent 5-6% MeOH in CHCl3) to get methyl piperazine-2-carboxylate (150 g, yield 28%). 1H NMR (300 MHz, CDCl3) δ 3.74 (s, 3H), 3.51-3.47 (dd, J=8.0 Hz, 3.4 Hz, 1H), 3.24-3.19 (dd, J=12.1 Hz, 3.3 Hz, 1H), 3.04-2.99 (m, 1H), 2.96-2.86 (m, 3H), 2.83-2.77 (m, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[CH:13]=[C:12]([O:14][CH:15]([F:17])[F:16])[N:11]([CH3:18])[N:10]=2)=[CH:4][C:3]=1[N+:19]([O-])=O.[H][H]>O1CCCC1.CO.[Ni]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[CH:13]=[C:12]([O:14][CH:15]([F:17])[F:16])[N:11]([CH3:18])[N:10]=2)=[CH:4][C:3]=1[NH2:19]
Reactant: Cn1nc(-c2cc([N+](=O)[O-])c(Cl)cc2Cl)cc1OC(F)F
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nc(-c2cc(N)c(Cl)cc2Cl)cc1OC(F)F

Procedure:
1.5 g (4.2 mmol) of 2,4-dichloro-5-(5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)nitrobenzene were dissolved in a mixture of 50 ml of tetrahydrofuran and 50 ml of methanol and admixed with 4 g of Raney nickel. The mixture was stirred at room temperature under a gage pressure of 0.3 bar of hydrogen for 4 h and then filtered through kieselguhr. The filtrate was dried using magnesium sulfate and then evaporated to dryness. This gave 1.3 g of the aniline.
Reaction SMILES: [ClH:1].Cl.[OH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[C:5]=1[C:6]([NH2:8])=[NH:7].O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]1>>[ClH:1].[NH2:7][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[OH:3])[NH:13][C:15]2([CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)[N:8]=1
Reactant: N=C(N)c1c(N)cccc1O
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: Cl
Product: CCOC(=O)N1CCC2(CC1)N=C(N)c1c(O)cccc1N2

Procedure:
This was prepared by the method of Example 173 using 2-hydroxy-6-aminobenzamidine dihydrochloride (Example D) and ethyl 4-oxopiperidine-1-carboxylate to give the title compound as a yellow solid, MS (+CI) 305 ([M+H]+), 1H NMR (d6 -DMSO) 11.80 (1H, s), 9.96 (1H, s), 8.64 (1H, s), 8.54 (1H, s), 7.49 (1H, s), 7.23 (1H, t), 6.31 (1H, d), 6.27 (1H, d), 4.02-4.08 (2H, m), 3.5-3.7 (2H, m), 3.3-3.5 (2H, m), 1.6-1.8 (2H, m), 1.19 (3H, t).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[C:13]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)C(C)C)C>>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:22]2[CH2:23][CH2:24][CH:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:21]2)[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(Cl)c(C#N)c(N2CCC(c3ccccc3)CC2)n1

Procedure:
In analogy to the procedure described in example 57a, the 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbonitrile (J. Heterocycl. Chem. 1971, 8, 445-453) was treated with 4-phenyl-piperidine in the presence of N-ethyl-diisopropylamine at room temperature during 18 hours to yield the 4-chloro-2-methylsulfanyl-6-(4-phenyl-piperidin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=345.
Reaction SMILES: Cl[C:2]1[C:10]2[C:9]3[CH:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:8]=3[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[N:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]1>CN(C)C(=O)C.C(OCC)(=O)C>[C:15]([C:12]1[N:13]=[CH:14][C:8]2[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]3[N:5]=[CH:4][CH:3]=[C:2]([N:25]4[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:26]4)[C:10]=3[C:9]=2[CH:11]=1)#[N:16]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(Cl)ccnc21
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (100 mg, 0.3 mmol) and (S)-tert-butyl piperidin-3-ylcarbamate (167 mg, 0.9 mmol) in N,N-dimethylacetamide (1.3 mL) was heated at 100° C. for 2 hours. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 4 g, ISCO, 0-60% ethyl acetate in heptane) to afford the title compound as a white solid, which was used in the next step without any further purification (130 mg, 90%).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)=[O:5])C>C(O)C.O1CCCC1.[OH-].[Na+]>[CH3:12][O:11][C:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[S:7][CH:8]=1
Reactant: CCOC(=O)c1cc(OC)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1csc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Methoxythiophene (4.0 ml) was dissolved in tetrahydrofuran (50 ml), and the mixture was cooled to -78° C. n-Butyllithium (1.6M in hexane, 19.5 ml) was slowly added dropwise, and the mixture was stirred at the same temperature for 1 hour. The mixture was poured into a mixture of dry ice and diethyl ether, and warmed to room temperature with stirring. The solvent was distilled off, and the residue was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a mixture of 3-methoxy-2-thiophenecarboxylic acid and 4-methoxy-2-thiophenecarboxylic acid (6.0 g). This mixture was dissolved in N,N-dimethylformamide (50 ml), and iodothane (3.0 ml) and potassium carbonate (5.25 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 4-methoxy-2-thiophenecarboxylic acid ethyl ester (2.69 g) and 3-methoxy-2-thiophenecarboxylic acid ethyl ester (3.98 g). 4-Methoxy-2-thiophenecarboxylic acid ethyl ester (2.69 g) was dissolved in a mixture of ethanol (25 ml) and tetrahydrofuran (25 ml), and 1N aqueous sodium hydroxide (22 ml) was added. The mixture was stirred at room temperature for 3 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-methoxy-2-thiophenecarboxylaic acid (2.11 g) as crystals.
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: ClCCCl
Solvent: CC(=O)O
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: [CH2:1]([NH:3][C:4]1[CH:24]=[CH:23][C:7]([CH2:8][C:9]2[NH:10][C:11](=[O:22])[C:12]3[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:13]=3[N:14]=2)=[CH:6][CH:5]=1)[CH3:2].[C:25](OCC)(=[O:27])[CH3:26]>>[CH2:1]([N:3]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][C:9]2[NH:10][C:11](=[O:22])[C:12]3[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:13]=3[N:14]=2)=[CH:6][CH:5]=1)[C:25](=[O:27])[CH3:26])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(NCC)cc3)nc12
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(N(CC)C(C)=O)cc3)nc12

Procedure:
The title compound was prepared from 5-[4-(ethylamino)benzyl]-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one following the procedure described in Example 47 and was obtained, after trituration with ethyl acetate as a solid (59%), m.p.149-151° C.
Reaction SMILES: [CH2:1]([N:13]1[N:17]=[N:16][C:15]([C:18](O)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(S(F)(F)([F:37])(CC)N)C>C(Cl)Cl>[CH2:1]([N:13]1[N:17]=[N:16][C:15]([C:18]([F:37])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCn1nnc(C(O)(C(=O)OCC)c2ccccc2)n1
Reactant: CCS(N)(F)(F)(F)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCn1nnc(C(F)(C(=O)OCC)c2ccccc2)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
A solution of 2-dodecyl-α-hydroxy-α-phenyl-2H-tetrazole-5-acetic acid, ethyl ester (0.45 g, 1.08 mole) in CH2Cl2 (2 mL) was added dropwise to a -78° C. solution of diethyl amino sulfur trifluoride (DAST, J. Org. Chem. 1975;(40):574:578, 0.15 mL, 1.1 mole) in CH2Cl2 (1 mL) under dry nitrogen. The mixture was stirred for 60 minutes at -78° C. before the cooling bath was removed and the solution allowed to warm to room temperature, where it was stirred an additional 3 hours. The mixture was poured into ice water and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate extracts were washed with brine (50 mL) and dried. Filtration and concentration produced an oil which was flash chromatographed (silica gel, 7:1 hexane-ethyl acetate) to afford 0.3 g (66%) of the title compound as an oil.