Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:9][O:10][CH2:11][C:12](OC)=[O:13]>C[O-].[Na+].C1(C)C=CC=CC=1>[CH3:9][O:10][CH2:11][C:12]([O:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:13]
Reactant: COCC(=O)OC
Reactant: OCCn1ccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCC(=O)OCCn1ccnc1
Yield: 90.2 %

Procedure:
In a nitrogen atmosphere, a mixture of 112 g of 2-(1H-imidazol-1-yl)ethanol, synthesized in Synthesis Example 1, 156 g of methyl methoxyacetate, 3.0 g of sodium methoxide, and 200 g of toluene was heated under reflux for 20 hours while distilling off the methanol formed during the reaction. The solvent was distilled off in vacuo. Purification by vacuum distillation gave 166 g of 2-(1H-imidazol-1-yl)ethyl methoxyacetate (boiling point 126° C./27 Pa, yield 90%).
Reaction SMILES: FC(F)(F)C([NH:5][C@H:6]1[CH2:10][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:7]1=[O:21])=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:5][C@H:6]1[CH2:10][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:17][CH:18]([CH3:19])[CH3:20])[C:7]1=[O:21]
Reactant: CC(C)CN1C(=O)[C@@H](NC(=O)C(F)(F)F)C[C@@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)CN1C(=O)[C@@H](N)C[C@@H]1c1ccccc1
Reaction time: 27 h
Yield: 100.2 %

Procedure:
To a solution of trans-2,2,2-trifluoro-N-(1-isobutyl-2-oxo-5-phenylpyrrolidin-3-yl)acetamide (63.2 mg, 0.192 mmol) in methanol (3 mL) and water (1 mL) was added potassium carbonate (79.8 mg, 0.578 mmol). After 27 hours, the reaction solution was concentrated and worked up with methylene chloride and water. The organic extracts were dried over sodium sulfate, filtered and concentrated to produce the title compound (44.7 mg). MS 233 (M+1).
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]([CH3:28])([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19]1)=[O:10].IC>CN(C=O)C>[CH3:7][C:8]([CH3:28])([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[CH3:1])=[O:10]
Reactant: CC(C)(C)C(=O)Nc1ccccc1C1Cc2ccccc2N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1c2ccccc2CC1c1ccccc1NC(=O)C(C)(C)C
Temperature: 25 °C
Yield: 46.2 %

Procedure:
To a mixture of 9.40 g K2CO3 and 10.05 g 2,2-dimethyl-N-[2-(2,3-dihydro-1H-indol-2-yl)phenyl]propanamide in 125 ml DMF at 0° C., was added 3.64 ml iodomethane. The resulting mixture was stirred twenty-eight hours at room temperature. Upon dilution with water, a solid precipitated, which was collected and washed with water. Recrystallization from EtOH/water yielded 4.86 g solid, m.p. 133°-135° C.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][C:9]#[CH:10])[CH3:7].[CH2:11]([Sn:15](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>C(OCC)C>[CH2:20]([Sn:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH3:19])[C:10]#[C:9][O:8][CH2:6][CH3:7])[CH2:21][CH2:22][CH3:23]
Reactant: C#COCC
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](C#COCC)(CCCC)CCCC
Temperature: -35 °C
Reaction time: 2 h

Procedure:
A solution of n-butyllithium (18.7 mL-1.6 M in hexanes, 30.0 mmole) was added to anhydrous ethyl ether (20 mL) and the resulting mixture was then cooled to −30 to −40 ° C. A solution of ethoxy acetylene (5.00 g-40% in hexanes, 28.5 mmole) in ethyl ether (10 mL) was then added dropwise over 10 minutes. The resulting suspension was allowed to warm to room temperature, tributyltin chloride (9.29 g, 28.5 mmole) was added dropwise over 10 minutes and the mixture was stirred for 2 hrs. The mixture was filtered through a celite pad, washed with ethyl ether and concentrated in vacuo to give an assumed quantitative yield of the crude product as a red oil: 1H NMR (dmso-d6/300 MHz) 4.04 (q, 2H, J=7.05 Hz), 1.54-1.44 (m, 6H), 1.34-1.21 (m, 12H), 0.96-0.78 (m, 15H).
Reaction SMILES: C(OP([CH2:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Br:18][C:19]1[C:28]2[C:27]([CH3:30])([CH3:29])[CH2:26][CH:25]=[C:24]([CH:31]([CH3:33])[CH3:32])[C:23]=2[CH:22]=[C:21](/[C:34](/[CH3:39])=[C:35](/[F:38])\[CH:36]=O)[C:20]=1[O:40][CH:41]([CH3:43])[CH3:42]>>[Br:18][C:19]1[C:28]2[C:27]([CH3:30])([CH3:29])[CH2:26][CH:25]=[C:24]([CH:31]([CH3:33])[CH3:32])[C:23]=2[CH:22]=[C:21](/[C:34](/[CH3:39])=[C:35](/[F:38])\[CH:36]=[CH:9]\[C:10](\[CH3:17])=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:20]=1[O:40][CH:41]([CH3:43])[CH3:42]
Reactant: C/C(=C(\F)C=O)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)C
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Product: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)C

Procedure:
Following General Procedure I-1, ethyl 4-(diethoxyphosphoryl)-3-methyl-but-2E-enoate (417 mg, 1.58 mmol) and (2E)-3-(4-bromo-3-isopropoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-but-2-enal (Compound A-150, 167 mg, 0.39 mmol) were reacted to give the title compound as a colorless oil after purification by column chromatography (silica gel, 2% ethyl acetate in hexane).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH2:35][C:36]([NH2:38])=[O:37])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([CH2:35][C:36]([NH2:38])=[O:37])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CN(C)C(=O)[C@@H](N)CC(N)=O
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@@H](CC(N)=O)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.08 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 67-2 (15.5 mmol, crude form) as starting materials, 576 mg of the title compound (colorless amorphous) was obtained by a similar method to Step 4-2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][NH2:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[CH2:13][NH2:14].[C:15]1(=[O:25])O[C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12>CN1CCCC1=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]3[C:15]2=[O:25])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[CH2:13][N:14]1[C:15](=[O:25])[C:16]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:17]2[C:18]1=[O:19]
Reactant: NCc1c(Cl)c(Cl)c(CN)c(Cl)c1Cl
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CN1CCCC1=O
Product: O=C1c2ccccc2C(=O)N1Cc1c(Cl)c(Cl)c(CN2C(=O)c3ccccc3C2=O)c(Cl)c1Cl

Procedure:
In a 3 liter, round-bottom flask equipped with a heating mantle, mechanical stirrer, thermometer, nitrogen inlet and condenser, 137 gms (0.5 mole) of 2,3,5,6-tetrachloro-p-xylylenediamine was dissolved at room temperature in 1 liter N-methyl-2-pyrrolidone (NMP). While stirring, 150 gms (1.0 mole) solid phthalic anhydride was added, the temperature rising to 47° C. The resulting greenish solution was heated to 180°-185° C. for 30 minutes, after which period crystallization took place. The hot mixture was poured into a 2 liter beaker when mass crystallization occurred.
Reaction SMILES: [NH:1]1[C:5]([NH:6][C:7]([C:9]2[C:17](=[O:18])[N:16]3[C:12]([S:13][C:14]4[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:15]=43)=[N:11][CH:10]=2)=[O:8])=[N:4][N:3]=[N:2]1.O.[OH-].[Na+].[H][H]>[Pt]=O.CN(C)C=O>[NH:1]1[C:5]([NH:6][C:7]([C:9]2[C:17](=[O:18])[N:16]3[C:12]([S:13][C:14]4[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:15]=43)=[N:11][CH:10]=2)=[O:8])=[N:4][N:3]=[N:2]1
Reactant: O=C(Nc1nnn[nH]1)c1cnc2sc3ccc([N+](=O)[O-])cc3n2c1=O
Reactant: [H][H]
Agent: O=[Pt]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc2sc3ncc(C(=O)Nc4nnn[nH]4)c(=O)n3c2c1

Procedure:
To a suspension of 4.5 g. of N-(5-tetrazolyl)-7-nitro-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide in 50 ml. of water and 25 ml. of dimethylformamide is added sufficient 1N aqueous sodium hydroxide to effect a solution. Platinum oxide (300 mg.) is added and the suspension shaken in a hydrogen atmosphere at an initial pressure of 30 p.s.i. When the theoretical amount of hydrogen is absorbed the spent catalyst is filtered and the filtrate treated with sufficient 6N hydrochloric acid to register acid to Congo red paper. The acidified filtrate is further diluted with 25 ml. of water and cooled in an ice bath. The desired product is filtered and recrystallized from dimethylformamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:14])=[C:12]([CH:15]=[O:16])[CH:11]=[N:10]2)=[CH:5][CH:4]=1.[CH2:17](O)[CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:16]1[CH2:17][CH2:18][O:19][CH:15]1[C:12]1[CH:11]=[N:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:13]=1[CH3:14]
Reactant: COc1ccc(-n2ncc(C=O)c2C)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-n2ncc(C3OCCO3)c2C)cc1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A mixture of 1-(4-methoxy-phenyl)-5-methyl-1H-pyrazole-4-carbaldehyde (0.5 g, 2.3 mmol), ethylene glycol (1.44 g, 23.1 mmol) and p-toluenesulfonic acid (0.2 g, 1.2 mmol) in toluene (10 mL) was refluxed for 18 h (Dean Stock to remove water formed). After it was allowed to cool to room temperature, the reaction mixture was diluted with ethyl acetate, washed with sat. NaHCO3 (aq) and brine, and dried over Na2SO4. After concentrated, the residue was purified by a column chromatography on silica gel to yield the title compound (0.35 g, 58%); MS (APCI) m/z: 261 (M+1, 80).
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)=O.[I:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[I:15][C:16]1[CH:22]=[CH:21][C:19](/[N:20]=[CH:1]/[C:3]2[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)COc1ccc(C=O)cc1
Reactant: Nc1ccc(I)cc1
Solvent: Cc1ccccc1
Product: COC(=O)COc1ccc(/C=N/c2ccc(I)cc2)cc1

Procedure:
Methyl (4-formylphenoxy)acetate (8.0 g, 40 mmol) was dissolved in 100 ml toluene and p-iodoaniline (9.1 g, 40 mmol) was added. The mixture was refluxed over night using a Dean-Stark apparatus. The reaction mixture was partly evaporated under reduced pressure. Methanol was added to the suspension and the mixture was stirred for a few minutes. The precipitate was filtered off, washed with methanol and dried under reduced pressure over night to yield the title compound. 1H-NMR (400 MHz, CDCl3) δ: 3.83 (s, 3H), 4.72 (s, 2H), 6.95 (d, 2H), 7.00 (d, 2H), 7.69 (d, 2H), 7.86 (d, 2H), 8.35 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](B(O)O)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:36])[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[NH:10][CH:9]=[C:8]4[CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:22][CH:23]=2)=[O:36])=[CH:30][CH:31]=1
Reactant: CN1CCC(c2c[nH]c3ccc(B(O)O)cc23)CC1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCC(c2c[nH]c3ccc(-c4ccc(NC(=O)c5ccc(F)cc5)cc4)cc23)CC1
Yield: 29.4 %

Procedure:
The title compound was prepared by the procedure of Example 10, beginning with 3-(1-methylpiperidin-4-yl)-1H-indole-5-boronic acid (0.200 g, 0.77 mmol), 1-bromo-4-(4-fluorobenzamido)benzene (0.217 g, 0.74 mmol), tetrakis(triphenylphosphine)palladium(0) (0.045 g, 0.039 mol), and 2M aqueous sodium carbonate solution (2 mL) in 15 mL of tetrahydrofuran:methanol (1:1) to give the title compound (0.093 g, 29%) as an amorphous solid. FDMS m/e=427 (M+). EA calculated for C27H26N3OF: C, 75.85; H, 6.13; N, 9.83. Found: C, 75.55; H, 6.18; N, 9.73.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([OH:33])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH2:48][CH:47]([CH2:51][CH2:52]Br)[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:52][CH2:51][CH:47]4[CH2:48][CH2:49][CH2:50][N:45]([C:43]([O:42][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:44])[CH2:46]4)[C:10]=3[N:9]=2)=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCBr)C1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(O)cccc32)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCCC4CCCN(C(=O)OC(C)(C)C)C4)cccc32)C1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of (RS) 2-(4-chlorophenoxymethyl)-4-hydroxy-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]benzimidazole (75 mg, 0.15 mmol, 1.0 eq) in dry N,N-dimethylformamide (1.0 ml) was treated with sodium hydride (60% in oil, 7.5 mg, 0.18 mmol, 1.20 eq). The resulting mixture was stirred at room temperature for thirty minutes, after which time 2-[1-(t-butoxycarbonyl)piperidin-3-yl]ethyl bromide (0.18 mmol, 1.2 eq) was added. The resulting mixture was stirred for three hours at 70° C. The reaction was quenched by the addition of water (10 ml). The aqueous fraction was extracted with diethyl ether (3×10 ml). The organic fractions were combined, washed with water (2×10 ml), then brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to give a crude product. The title product was further purified by flash chromatography to provide a crystalline product. Yield: 92%
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([C:5]1[N:9]([CH3:10])[N:8]=[C:7]([CH3:11])[C:6]=1[N+:12]([O-])=O)=[O:4].[H][H]>CO.[Pd]>[NH2:12][C:6]1[C:7]([CH3:11])=[N:8][N:9]([CH3:10])[C:5]=1[C:3]([N:2]([CH3:1])[CH3:15])=[O:4]
Reactant: Cc1nn(C)c(C(=O)N(C)C)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1nn(C)c(C(=O)N(C)C)c1N
Yield: 98.7 %

Procedure:
19.0 g of N,N,1,3-tetramethyl-4-nitropyrazole-5-carboxamide in 400 ml of methanol are hydrogenated in the presence of 2.0 g of 10% strength palladium-on-charcoal in an autoclave at a hydrogen pressure of from 80 to 110 bars (8,000 to 11,000 kPa) for 8 hours at room temperature. The mixture is filtered, and the solvent is removed by distillation in vacuo to yield 16.1 g of crystalline 4-amino-N,N,1,3-tetramethylpyrazole-5-carboxamide, mp 116° to 118° C. (from ethyl acetate).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[C:17]1([C:14]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH2:8][NH:7][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])[CH2:16][CH2:15]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)NCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reaction time: 48 h
Yield: 78.2 %

Procedure:
Diketene (0.44 mL, 5.68 mmol, 1.3 equiv, Aldrich) was added at room temperature to a stirred solution of 1-(3-aminopropyl) -4-,4-diphenylpiperidine (1.288 g, 4.37 mmol, 1.0 equiv) in anhydrous toluene (15 mL) under argon, and stirring was continued for 48 hours. The mixture was concentrated to give 1.294 g (78%) of white solid, which was used for the next reaction without purification: 1H NMR (300 MHz, CDCl3) δ 1.70 (tt, J=6.4, 6.4 Hz, 2H), 2.23 (s, 3H), 2.44 (br t, J=6.5 Hz), 2.49-2.67 (m, 8H), 3.32 (br t, J=5.8 Hz), 3.36 (s, 2H), 7.16 (m, 2H), 7.27 (m, 8H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:10][CH:9]([CH2:22]Br)[S:8]1)=[O:5])[CH3:2].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[CH2:10][C:9](=[CH2:22])[S:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N=C1SC(CBr)CN1c1cccc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: C=C1CN(c2cccc(C(F)(F)F)c2)C(=NC(=O)OCC)S1
Yield: 44.5 %

Procedure:
A solution of 2-ethoxycarbonylimino-3-(3-trifluoromethylphenyl)-5-bromomethylthiazolidine (0.7 g) and potassium t-butoxide (0.25 g) in t-butanol (30 ml) was refluxed for 5 hours, and the solvent was distilled off under reduced pressure. The residue was extracted with chloroform (100 ml), washed with water and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was subjected to column chromatography to give 0.25 g of 2-ethoxycarbonylimino-3-(3-trifluoromethylphenyl)-5-methylenethiazolidine (Compound (i)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:36])([CH2:30][N:31]1[CH:35]=[N:34][CH:33]=[N:32]1)[CH:10]([N:12]1[C:17](=[O:18])[C:16]2[S:19][C:20]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)=[CH:21][C:15]=2[N:14]=[CH:13]1)[CH3:11].[CH3:37][OH:38]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:36])([CH2:30][N:31]1[CH:35]=[N:34][CH:33]=[N:32]1)[C@H:10]([N:12]1[C:17](=[O:18])[C:16]2[S:19][C:20]([C:22]3[CH:29]=[CH:28][C:25]([C:26](=[NH:27])[O:38][CH3:37])=[CH:24][CH:23]=3)=[CH:21][C:15]=2[N:14]=[CH:13]1)[CH3:11]
Reactant: CO
Reactant: CC(n1cnc2cc(-c3ccc(C#N)cc3)sc2c1=O)C(O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: ClC(Cl)Cl
Product: COC(=N)c1ccc(-c2cc3ncn([C@H](C)[C@](O)(Cn4cncn4)c4ccc(F)cc4F)c(=O)c3s2)cc1
Reaction time: 8 h
Yield: 94 %

Procedure:
To a cooled (0° C.) solution of (1R,2R)-(4-[3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-6-yl]benzonitrile (1.03 g, 2.04 mmol) (obtained in example 32) in MeOH (25 mL) and CHCl3 (5 mL) was bubbled HCl gas until saturation. The reaction mixture was allowed to stand at 0° C. overnight, and was then concentrated and poured to aqueous K2CO3 solution. CHCl3 was added, the organic phase was separated and the aqueous phase was reextracted with CHCl3. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and concentrated to give the title compound as a white solid (1.03 g, 94%): mp 194°-201° C.; 1H NMR (300 MHz, CDCl3) δ (TMS) 8.60 (s, 1H, N=CH--N), 7.78 (s, 1H, triazole), 7.77 (s, 4H, arom), 7.74 (s, 1H, triazole), 7.60 (s, 1H, thiophene), 7.49 (dt, Jd =6.4, Jt =8.8, 1H, arom), 6.9-6.7 (m, 2H, arom), 5.98 (q, J=7.3, 1H, MeCH), 5.56 (broad s, 1H, OH), 5.20 (d, J=14.2, 1H, CH(H)), 4.02 (d, J=14.2, 1H, CH(H)), 3.97 (s, 3H, OCH3),1.32 (d, J=7.3, 3H, CHMe).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])=[C:5]([CH3:16])[C:4]([C:17]([O:19]CC)=[O:18])=[C:3]1[CH2:22][C:23]([O:25]CC)=[O:24].[OH-].[Na+]>>[C:17]([C:4]1[C:5]([CH3:16])=[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])[N:2]([CH3:1])[C:3]=1[CH2:22][C:23]([OH:25])=[O:24])([OH:19])=[O:18]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(C)c(C(=O)c2ccc(C)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C(=O)c2c(C)c(C(=O)O)c(CC(=O)O)n2C)cc1

Procedure:
A suspension of 54 g. (0.145 mole) of ethyl 1,4-dimethyl-3-ethoxycarbonyl-5-(p-toluoyl)-pyrrole-2-acetate in 500 g. of 25% sodium hydroxide is heated at just below reflux for 3 hours. The yellow suspension is then poured into ice-hydrochloric acid, and the precipitated solid is collected, air dried and recrystallized from acetone-water to give 3-carboxy-1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetic acid as a white solid, m.p. 229-230° C. Anal. Calcd. for C17H17NO5: C, 64.75; H, 5.43; N, 4.44%. Found: C, 64.86; H, 5.53; N, 4.47%.
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[N:29]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=5)[C:28]([CH3:39])=[N:27][N:26]=4)[CH:22]=[CH:21][C:20]=3[CH3:40])[C:9]=2[C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH3:3]>CC(O)C>[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[N:29]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=5)[C:28]([CH3:39])=[N:27][N:26]=4)[CH:22]=[CH:21][C:20]=3[CH3:40])[C:9]=2[C:10]([NH2:1])=[N:11][CH:12]=1)=[O:6])[CH3:3]
Reactant: N
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4nnc(C)n4Cc4ccc(OC)cc4)ccc3C)csc12
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4nnc(C)n4Cc4ccc(OC)cc4)ccc3C)csc12
Temperature: 140 °C

Procedure:
Ammonia gas was bubbled into a suspension of 4-chloro-3-{5-[4-(4-methoxy-benzyl)-5-methyl-4H-[1,2,4]triazol-3-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.330 g; 0.59 mmol) (from Example 58 supra) in 2-propanol (20 mL) for 15-20 minutes. The mixture was then heated in a microwave reactor at 140° C. for 90 minutes. The reaction mixture was concentrated and the residue was purified by flash chromatography (120 g column; 4% methanol in dichloromethane followed by a gradient to 40% methanol) to give 4-amino-3-{5-[4-(4-methoxy-benzyl)-5-methyl-4H-[1,2,4]triazol-3-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.263 g; 96% pure; 78.72%).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2>CC(O)=O>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([N:12]=[C:4]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:1][C:2]3=[O:3])=[CH:21][CH:20]=2)[CH:16]=[N:17]1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2C1=Nc1ccc2[nH]ncc2c1
Yield: 62.9 %

Procedure:
The title compound (165 mg, 63%) was synthesized as a yellow solid according to the method described for Example A74 using isatin (147 mg, 1 mmol), 5-aminoindazole (133 mg, 1 mmol) and 2 drops of HOAc. 1H NMR indicated a 5:1 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H, NH), 11.00 (s, 1H, NH), 8.07 (s, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.35 (s, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.07 (dd, J=9.2 Hz, 1.6 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H), 6.67 (t, J=8.0 Hz, 1H), 6.45 (d, J=7.6 Hz, 1H); MS ESI 263.0 [M+H]+, calcd for [C15H10N4O+H]+ 263.1.