Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][C:15]2([CH2:21][CH:22]=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=[C:8]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:7]=1)(=[O:3])[CH3:2].[C:29]1([CH3:42])[CH:34]=[CH:33][C:32]([NH:35][CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][C:15]2([CH2:21][CH2:22][N:39]3[CH2:40][CH2:41][CH:36]([NH:35][C:32]4[CH:33]=[CH:34][C:29]([CH3:42])=[CH:30][CH:31]=4)[CH2:37][CH2:38]3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=[C:8]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc(COC(C)=O)cc(OCCC2(CC=O)CCCCC2)c1
Reactant: Cc1ccc(NC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(=O)OCc1cc(COC(C)=O)cc(OCCC2(CCN3CCC(Nc4ccc(C)cc4)CC3)CCCCC2)c1
Reaction time: 0.75 h
Yield: 107.4 %

Procedure:
1,3-Diacetoxymethyl-5-[2-[1-(formylmethyl)cyclohexyl]ethoxy]benzene (synthesized in Example 32) (215 mg) and 4-(p-toluidino)piperidine (synthesized in Preparation Example 4-5) (127 mg) were dissolved in 1,2-dichloroethane (5 mL). To this was added acetic acid (0.04 mL) at room temperature. The solution was stirred for 45 minutes. Sodium triacetoxyborohydride (294 mg) was added to the solution at room temperature. The solution was stirred for 3 hours. saturated aqueous sodium bicarbonate solution was added to the solution and it was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, chloroform-methanol (10:1)] to give the title compound (334 mg). This product was subjected to the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:24][CH2:25][C:26]([F:28])([F:27])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:16][NH:17][CH:18]=1)[CH2:9][CH2:8]3.C(=O)([O-])[O-].[K+].[K+].F[C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][N:37]=1.C(Cl)Cl>CN(C)C=O>[Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:24][CH2:25][C:26]([F:27])([F:28])[C:4]=2[CH:3]=1)[CH2:8][CH2:9][N:10]([CH2:13][C:14]1[C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:16][N:17]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][N:37]=2)[CH:18]=1)[CH2:11][CH2:12]3
Reactant: Fc1cccnc1F
Reactant: CCOC(=O)c1n[nH]cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(-c2ncccc2F)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Temperature: 60 °C
Yield: 65.6 %

Procedure:
To a solution of ethyl 4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-1H-pyrazole-3-carboxylate (22.5 g, 52.10 mmoles) in Dimethylformamide (225.00 mL) is added Potassium Carbonate (10.80 g, 78.14 mmoles) and 2,3-difluoropyridine (7.19 g, 62.52 mmoles) and the resulting suspension is stirred at 60° C. 15 h. Then, reaction mixture is poured over Ice/brine (30 mL) and CH2Cl2 (50 mL) is added to the resulting suspension. Solution is washed with H2O (2×50 mL). Organics are dried over sodium sulfate and concentrated to give a crude which is purified via SiO2 filtration eluting with 2-propanol/CH2Cl2 mixtures to give 18 g of the title compound. MS (m/z): 527 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)C(OC)=O.[OH-].[Li+]>CO.C1COCC1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1
Reactant: COC(=O)C(c1ccc([N+](=O)[O-])cc1)c1cccn1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cccc1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
Methyl 2-(1-methylpyrrol-2-yl)-2-(4-nitrophenyl)acetate (3.8 g, 14.0 mmol) [prepared as in Example 7, Step (a)] was dissolved in a 1:1 mixture of MeOH-THF (100 ml) and cooled in an ice bath under argon. A solution of 0.4 M lithium hydroxide (69 ml) was added and the reaction mixture was stirred at room temperature. After 2 h, the reaction mixture was poured into 1 M HCl/ice and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The solid residue was redissolved in DMF (40 ml) and heated at reflux. After 20 min the reaction mixture was poured into ice/water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated to dryness. Purification on a Florisil® column (hexane-ethyl acetate, 9:1) gave 4-(1-methylpyrrol-2-yl-methyl)nitrobenzene (2.53 g, 82%) as a solid. ##STR39##
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([S:20]([NH2:23])(=[O:22])=[O:21])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[O-]S(C(F)(F)F)(=O)=O.[C:32]([O:37][CH3:38])(=[O:36])[C@H:33]([CH3:35])O>O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([S:20]([NH:23][C@H:33]([CH3:35])[C:32]([O:37][CH3:38])=[O:36])(=[O:22])=[O:21])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: COC(=O)[C@H](C)O
Reactant: NS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H](C)NS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: -30 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
A solution of potassium tert-butoxide (0.87 ml, 1M in tetrahydrofuran) was added to a solution of [4-(4-chlorophenyl)piperazine-1-sulfonyl]amine (200 mg, 0.73 mmol), [prepared as described in Step 1 above], in tetrahydrofuran (10 ml) at -60° C. After 10 min., a solution of the triflate derivative of methyl (S)-lactate (604 mg, 2.56 mmol) in tetrahydrofuran (3 ml) was added and the reaction mixture was allowed to warm to -30° C. over 30 min. The reaction mixture was quenched with saturated ammonium chloride and the product was extracted into ethyl acetate. The solvent was removed in vacuo and the residue was chromatographed (SiO2, 30% ethyl acetate/hexane) to give methyl 2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]-amino}propionate as a colorless oil (66%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH2:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].O>C(O)C>[CH3:3][C:2]1[C:12]([CH3:11])=[N:1][C:2]2[C:12](=[CH:11][CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=2)[N:13]=1
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc2nc(C)c(C)nc2c1
Yield: 203.8 %

Procedure:
Ethyl 3,4-diaminobenzoate (500 mg, 2.77 mmol) and diacetyl (238 mg, 2.77 mmol) were dissolved in ethanol (20 ml), and the mixture was heated under reflux. One hour after, diacetyl (30 mg) was added thereto, and the mixture was heated under reflux. After the mixture was heated under reflux for 2.5 hours in total, the reaction solution was poured into water, and the precipitate was separated by filtration and washed with water. By through circulation drying for 15 hours, the title compound (650 mg, quantitative) as a light-brown powder was obtained.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
A mixture of hydroxylammonium chloride (1.50 g), sodium hydrogen carbonate (2.18 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(4-methoxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.46 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.42 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.88 g, 78%).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[N:13]([CH3:14])[N:12]=[CH:11][C:10]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl.O>CN(C=O)C>[CH3:14][N:13]1[CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[N:12]1
Reactant: CCOC(=O)c1cnn(C)c1N
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(C)c1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a solution of 90% t-butyl nitrite (50 mL, 0.37 mol) in 200 mL DMF was added in portions ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate (39 g, 0.23 mol), maintaining the temperature at around 30° C. After the addition, the resulting mixture was warmed to 50° C. and stirred at that temperature for 0.5 h. The mixture was poured into 100 mL conc HCl and 40 mL water and extracted with CH2Cl2. The organic solution was washed with water, brine, dried and concentrated. Vacuum distillation of the residue gave 32.4 g of ethyl 1-methyl-1H-pyrazole-4-carboxylate as a clear liquid. b.p. 65°-80° C. at 0.1 torr.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([OH:13])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:48][C:49]1[CH:50]=[C:51]([NH:56][C:57](=[O:69])[C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([C:67]#[N:68])([CH3:66])[CH3:65])[CH:59]=2)[CH:52]=[CH:53][C:54]=1[CH3:55]>CN(C=O)C>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([NH:48][C:49]1[CH:50]=[C:51]([NH:56][C:57](=[O:69])[C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([C:67]#[N:68])([CH3:65])[CH3:66])[CH:59]=2)[CH:52]=[CH:53][C:54]=1[CH3:55])=[O:13]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Reactant: Nc1c(C(=O)O)sc2nccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1sc2nccnc2c1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
A solution of 7-aminothieno[2,3-b]pyrazine-6-carboxylic acid (8) (1.6 g, 8.20 mmol), HATU (3.43 g, 9.02 mmol) and DIPEA (4.06 mL, 24.59 mmol) in DMF (20 mL) was stirred at rt for 20 min. N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide hydrochloride 6 (2.70 g, 8.20 mmol) was added and stirred overnight at 80° C. Quenched in cold citric acid solution and the resulting precipitate was collected and dried to give crude compound 9 (3.55 g). Triturating with acetonitrile, stirred in water at 90° C. for 30 min, filtrated and dried to yield the title compound 7-amino-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 9 (2.12 g, 55.0%). 1H-NMR (400 MHz, DMSO-d6) 1.77 (s, 6H), 2.23 (s, 3H), 7.06 (br s, 2H), 7.27 (d, J=8.6 Hz, 1H), 7.60 (t, J=7.8 Hz, 2H), 7.75 (m, 1H), 7.82 (br s, 1H), 7.95 (d, J=7.8 Hz, 1H), 8.05 (m, 1H), 8.78 (q, J=2.7 and 2.3 Hz, 2H), 9.47 (br s, 1H), 10.32 (br s, 1H). (m/z)=471 (M+H)+.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1O[C@H:6]([O:8][C@:9]2(CO)O[C@H:12]([CH2:14]O)[C@@H:11](O)[C@@H:10]2O)[C@H:5]([OH:20])[C@@H:4](O)[C@@H:3]1[OH:22].O.[CH3:25][C:26]1([CH3:44])OC(=O)C=C(CC(=O)CCC2C=CC=CC=2)[O:27]1.[C:45](OCC)(=O)[CH3:46]>>[CH3:25][C:26]1([CH3:44])[O:27][C:1](=[O:23])[CH:2]=[C:3]([CH2:4][CH:5]([OH:20])[CH2:6][O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:14]=[CH:46][CH:45]=2)[O:22]1
Reactant: CC1(C)OC(=O)C=C(CC(=O)CCc2ccccc2)O1
Reactant: CCOC(C)=O
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: O
Product: CC1(C)OC(=O)C=C(CC(O)COCc2ccccc2)O1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
30 g of baker's yeast (made by Oriental Yeast Co., Ltd.) and 15 g of saccharose were added in 30 ml of tap water at 32° C., and the solution was then stirred for 30 minutes. Afterward, 300 mg of 2,2-dimethyl-6-(3-benzyl-2-oxopropyl)-1,3-dioxin-4-one were added thereto, and the solution was then stirred overnight at the same temperature. 7.5 g of saccharose were further added thereto, followed by stirring overnight. Water of the reaction solution was then distilled off under reduced pressure, and the residue was extracted with dichloromethane and then dried over anhydrous sodium sulfate. Afterward, the solvent was distilled off, and the residue was then subjected to column chromatography (an eluent of hexane:ethyl acetate=4:1), thereby obtaining 168 mg (yield 56%) of (-)-2,2-dimethyl-6-(3-benzyloxy-2-hydroxypropyl)-1,3-dioxin-4-one [a compound having the formula (1) in which n is 1, X is a benzyloxy group, Y is the hydrogen atom, and a substituent is present at the 6-position].
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([F:13])[C:3]=1[NH2:4].OS(O)(=O)=O.OS(O)(=O)=O.[N:24]([O-])=O.[Na+].[C:28]([CH2:30][C:31]([C:34]#[N:35])=CO)#[N:29].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[NH2:29][C:28]1[N:4]([C:3]2[C:5]([F:13])=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:2]=2[Cl:1])[N:24]=[C:31]([C:34]#[N:35])[CH:30]=1
Reactant: N#CCC(C#N)=CO
Reactant: Nc1c(F)cc(C(F)(F)F)cc1Cl
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cc(N)n(-c2c(F)cc(C(F)(F)F)cc2Cl)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of 2-chloro-6-fluoro-4-trifluoromethylaniline (210 g, 985.9 mmol) in acetic acid (1.05 L) was added concentrated H2SO4 (44.45 mL) at rt. Then the solution was added dropwise to the above H2SO4—NaNO2 mixture at 0° C. Then the mixture was heated to 50° C. After stirring for 1 hour, this reaction mixture was added to a suspension of 1,2-dicyano-3-hydroxyprop-2-ene (224 g, 1.48 mol, 1.5 eq.) and anhydrous sodium acetate (1.68 kg, 20.4 mol, 13.78 eq.) in H2O (1.05 L) at 5-10° C. After stirring for 1 hour, this reaction mixture was diluted with water and extracted with dichloromethane (DCM). The organic layers were stirred vigorously with 30% ammonium hydroxide solution overnight. The organic phase separated, dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give yellow solid. The solid was recrystallized from ethyl acetate (EA) to afford 5-amino-1-(2-chloro-6-fluoro-4-(trifluoromethyl)-phenyl)-1H-pyrazole-3-carbonitrile as yellow solid (220 g, 73%).
Reaction SMILES: [S:1]([C:5]1[CH:21]=[CH:20][C:8]([NH:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].Cl[C:23](OC)=[O:24]>>[S:1]([C:5]1[CH:6]=[CH:7][C:8]([N:9]2[CH2:10][C:11](=[O:12])[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:23]2=[O:24])=[CH:20][CH:21]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: COC(=O)Cl
Reactant: NS(=O)(=O)c1ccc(NCC(=O)Nc2ccccc2)cc1
Product: NS(=O)(=O)c1ccc(N2CC(=O)N(c3ccccc3)C2=O)cc1

Procedure:
2-(4-Sulphamoylanilino)-N-phenylacetamide (1.5 g) and methyl chloroformate (15.0 ml) were heated together for 3 hours in an autoclave at 130°C. The product was filtered off as crystals; yield 500 mg, m.p. 255° - 257°C (acetone).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[C:30]([Cl:31])=[CH:29][C:14]([C:15]([NH:17][C@H:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][NH2:26])[CH2:20][C@H:19]2[O:27][CH3:28])=[O:16])=[C:13]([O:32][CH3:33])[CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>ClCCl>[NH2:10][C:11]1[C:30]([Cl:31])=[CH:29][C:14]([C:15]([NH:17][C@H:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][NH:26][C:2]3[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:20][C@H:19]2[O:27][CH3:28])=[O:16])=[C:13]([O:32][CH3:33])[CH:12]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCN)C[C@H]1OC
Reactant: N#Cc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCNc2ncccc2C#N)C[C@H]1OC
Temperature: 70 °C
Reaction time: 20 h
Yield: 21.6 %

Procedure:
A mixture of 1.66 parts of 2-chloro-3-pyridinecarbonitrile, 4.28 parts of cis-4-amino-N-[1-(2-aminoethyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide, 1.3 parts of sodium carbonate and 22.5 parts of N.N-dimethylacetamide was stirred for 20 hours at 70° C. The reaction mixture was taken up in dichloromethane. The organic layer was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.19 parts (21.6%) of cis-4-amino-5-chloro-N-[1-[2-[(3-cyano-2-pyridinyl)amino]ethyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 134.0° C. (compound 32).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:16]([C:18]1[C:30]([O:31][CH3:32])=[CH:29][C:21]([O:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25])=[C:20]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)[CH:19]=1)=O.C[O-].[Li+]>CN(C=O)C.CO.O>[CH3:14][S:11]([N:10]([CH3:15])[C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])/[CH:2]=[CH:16]/[C:18]2[C:30]([O:31][CH3:32])=[CH:29][C:21]([O:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25])=[C:20]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)[CH:19]=2)=[CH:9][CH:8]=1)(=[O:12])=[O:13]
Reactant: COc1cc(OC(C)(C)C(=O)O)c(-c2cccs2)cc1C=O
Reactant: CC(=O)c1ccc(N(C)S(C)(=O)=O)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(OC(C)(C)C(=O)O)c(-c2cccs2)cc1/C=C/C(=O)c1ccc(N(C)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of N-(4-acetyl-phenyl)-N-methyl-methanesulfonamide (Ex-101A, 298 mg, 1.31 mmol) and 2-(4-formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propionic acid (Ex-47D, 400 mg, 1.20 mmol) in DMF (5.25 mL) and MeOH (2.25 mL) was treated with lithium methoxide (182 mg, 4.8 mmol) and stirred for 6 hours at room temperature under nitrogen atmosphere. The reaction mixture was diluted with water (25 mL) which was then extracted with isopropyl acetate (2×50 mL). The aqueous portion was collected and acidified to a pH of 3 with 3N HCl. The aqueous solution was then extracted with isopropyl acetate (2×50 mL).
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:19])([F:18])[C:8]([C:14]([F:17])([F:16])[F:15])([OH:13])[CH2:9][CH2:10][CH2:11][OH:12].[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22]>C1COCC1.C(OCC)C>[C:20]([O:12][CH2:11][CH2:10][CH2:9][C:8]([C:14]([F:15])([F:16])[F:17])([OH:13])[C:7]([F:18])([F:19])[F:6])(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: OCCCC(O)(C(F)(F)F)C(F)(F)F
Reactant: C=C(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(C)C(=O)OCCCC(O)(C(F)(F)F)C(F)(F)F
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a 3-necked, 2-L round-bottomed flask equipped with an overhead stirrer, digital thermometer and a 1-L constant-pressure addition funnel with a nitrogen inlet was added 590 mL (0.944 mol) of n-butyllithium (1.6M in hexane). The addition funnel was charged with a solution of 107 g (0.47 mol) of 1,1,1-trifluoro-2-trifluoromethyl-2,5-pentanediol in 300 mL of anhydrous THF. The flask was cooled and the diol was added dropwise with stirring while maintaining a temperature below 15° C. The resulting yellow-orange solution was stirred for an additional 2 hours at which time a solution of 54.5 g (0.52 mol) of methacryloyl chloride in 200 mL of anhydrous THF was added dropwise over 1 h at 10° C. The reaction mixture was allowed to reach room temperature overnight after which it was diluted with 500 mL of diethylether and washed with 2×500 mL of saturated ammonium chloride and brine, dried over MgSO4, evaporated and distilled at 74° C. at 1.0 mm Hg (0.5 g of phenothiazine was added to the pot prior to distillation) to yield 109 g (79%) of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:15].[O:16]=[C:17]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH2:18][CH2:19][C:20](O)=[O:21].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[O:16]=[C:17]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH2:18][CH2:19][C:20]([NH:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[NH:7][C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[CH:14]2)=[O:21]
Reactant: Nc1cccc2cc(-c3nccs3)[nH]c12
Reactant: O=C(O)CCC(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCC(=O)c1cccs1)Nc1cccc2cc(-c3nccs3)[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 220.3 %

Procedure:
To a mixture of 2-(1,3-thiazol-2-yl)-1H-indole-7-amine (0.31 g), 4-oxo-4-(2-thienyl)butanoic acid (0.89 g), 1H-1,2,3-benzotriazol-1-ol (0.75 g) and N,N-dimethylformamide (20 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.06 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (1.21 g, yield. 69%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (3:1, volume ratio). melting point 140-141° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C:13]1[NH:14][C:15](=[O:25])[C:16]([OH:24])=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=1)([O:9][CH2:10][CH2:11]O)[CH2:7][Cl:8])(=[O:3])[CH3:2].[CH3:26][S:27](Cl)(=[O:29])=[O:28].CCN(CC)CC>O1CCCC1>[C:1]([O:4][CH2:5][C:6]1([CH2:7][Cl:8])[C:13]2=[N:18][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]([O:24][S:27]([CH3:26])(=[O:29])=[O:28])[C:15](=[O:25])[N:14]2[CH2:11][CH2:10][O:9]1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1nc(C(CCl)(COC(C)=O)OCCO)[nH]c(=O)c1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc2n(c(=O)c1OS(C)(=O)=O)CCOC2(CCl)COC(C)=O
Temperature: 60 °C

Procedure:
A solution of ethyl 2-(3-acetoxy-1-chloro-2-(2-hydroxyethoxy)propan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (2.322 g, 6.13 mmol) in tetrahydrofuran (100 mL) was treated with methane sulfonylchloride (2.11 g, 18.4 mmol) and Et3N (2.25 g, 22 mmol) and then heated (60° C., oil bath) for 3 hrs. Solvent was removed in-vacuo and the crude product was dissolved in ethyl acetate (100 mL), then washed with water (2×50 mL). The organic solution was dried (Na2SO4), filtered and concentrated in-vacuo to give the title compound as a viscous amber oil which was used immediately in the following reaction.