Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1.OO.C(C(C)=[O:22])C>O>[NH2:1][C:2]1[C:15]2[C:14](=[O:22])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C)=O
Reactant: Nc1cccc2c1Cc1ccccc1C2=O
Agent: OO
Solvent: O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The moist paste of 4-aminoanthrone is introduced into 300 ml of water and warmed to 60° C under nitrogen. The pH is checked every 1/4 of an hour and should lie in the range between 7.5 and 8.5. 75 ml of potassium waterglass (d = 1.25) are then added, whereupon a pH of 11 results. 375 ml of H2O2 solution are then added dropwise in the course of 2.5 hours, the solution being prepared by diluting 200 ml of 35% strength hydrogen peroxide (d = 1.135) to 1.0 liter. The mixture is warmed to 70° C and kept at this temperature for one hour. 500 ml of the azeotrope of methyl ethyl ketone (88%) and water (12%) which boils at 73.4° C, are then added and the mixture is heated to the boil for 10 hours (temperature 74° C). It is then cooled to 20° C, stirred for 1 hour at room temperature and then filtered. The residue is covered twice with 150 ml of water at a time, to remove the adhering methyl ethyl ketone. The azeotrope (boiling point 73° C) is recovered almost quantitatively from the combined filtrates by distillation. 4 g of a solid substance which contains about 50% of 1-aminoanthraquinone are isolated from the distillation residue. To remove adhering silica the moist paste of the 1-aminoanthraquinone, in 500 ml of water and 60 ml of concentrated sodium hydroxide solution (d = 1.48) must be subjected to incipient distillation for ~15 minutes. To avoid objectionable foaming during this operation, 5 drops of anti-foam agent are added. The product is filtered off hot, and the adhering sodium hydroxide solution is eluted with a little hot water. The paste weighs 140 g. It is dried at 70° C. 91 g are obtained.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Li+].[F:10][C:11]([F:16])([F:15])[C@@H:12]1[O:14][CH2:13]1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[CH2:17]([NH:24][CH2:13][C@@H:12]([OH:14])[C:11]([F:16])([F:15])[F:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: FC(F)(F)[C@H]1CO1
Reactant: NCc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: O[C@H](CNCc1ccccc1)C(F)(F)F
Temperature: 25 °C
Yield: 78.8 %

Procedure:
To a solution of lithium trifluoromethanesulfonate (1.43 g, 9.17 mmol) in CH3CN (30 ml) was added (R)-(+)-3,3,3-trifluoro-1,2-epoxypropane (10.77 g, 96 mmol) slowly at −10° C. After 5 minutes benzylamine (10 ml, 92 mmol) was added slowly. The mixture was allowed to warm as the bath warmed to rt overnight. The mixture was concentrated. The crude product was subjected to silica gel chromatography (330 g, 0-50% EtOAc/hexanes, 10 minute gradient) to afford (R)-3-(benzylamino)-1,1,1-trifluoropropan-2-ol (4-2, 15.9 g, 79%) as a white solid. LRMS m/z (M+H)+ 220.2 calc. 220.1 found.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:12](F)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.ClC1N=C(Cl)C=CN=1.OC1C=C(C=CC=1)N>>[OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Agent: Clc1ccnc(Cl)n1
Agent: Nc1cccc(O)c1
Product: Oc1cccc(Nc2ccnc(Nc3cccc(O)c3)n2)c1

Procedure:
In a manner analogous to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloropyrimidine with 3-hydroxyaniline gave N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine. LCMS: ret. time: 16.21 min.; purity: 100%; MS (m/e): 295 (MH+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:10]([C:12]1[C:13]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:14][N:15]([CH:17]([O:21][C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH:18]([CH3:20])[CH3:19])[N:16]=1)=[O:11]>>[CH3:37][O:36][C:35]1[C:7]([O:6][CH3:5])=[CH:8][C:9]([C:10]([C:12]2[C:13]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:14][N:15]([CH:17]([O:21][C:22]([O:24][CH:25]([CH3:26])[CH3:27])=[O:23])[CH:18]([CH3:20])[CH3:19])[N:16]=2)=[O:11])=[C:33]([N+:1]([O-:4])=[O:2])[CH:34]=1
Reactant: CCOC(=O)c1nn(C(OC(=O)OC(C)C)C(C)C)nc1C(=O)c1ccc(OC)c(OC)c1
Reactant: O=[N+]([O-])O
Product: CCOC(=O)c1nn(C(OC(=O)OC(C)C)C(C)C)nc1C(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
70% nitric acid (1 ml) was added to ethyl 5-(3,4-dimethoxybenzoyl)-2-(1-isopropoxycarbonyloxy-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate (86 mg, 0.19 mmol) as Intermediate 8 under ice cooling. The mixture was stirred at that temperature for 30 min. The reaction solution was poured into ice and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine solution in that order and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound as a single compound (49 mg, 52%). The Rf value of thin-layer chromatography on silica gel and 1H-NMR spectrum were the same as those of the title compound of Example 20 (a).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][N+:3]=1[O-].COS(OC)(=O)=O.[C-:20]#[N:21].[K+]>>[CH3:11][C:5]1[C:4]([C:20]#[N:21])=[N:3][C:2]([CH3:1])=[CH:7][C:6]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Reactant: [C-]#N
Agent: [K+]
Solvent: COS(=O)(=O)OC
Product: Cc1cc([N+](=O)[O-])c(C)c(C#N)n1

Procedure:
The title compound, was prepared by treatment of 2,5-Dimethyl-4-nitropyridine-N-oxide (CAS: [21816-42-2], J. Heterocyclic Chem. 34(3), 727(1997)) with Dimethylsulfate and Potassium cyanide in accordance with the general method of example 1, step 1 to yield the title compound as a brown solid.
Reaction SMILES: [Li].C[Si](C)(C)N[Si](C)(C)C.C1(P(C2CCCCC2)C2(N(C)C)CC=CC=C2C2C=CC=CC=2)CCCCC1.[C:39]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])(=[O:41])[CH3:40].[Br:47][C:48]1[CH:53]=[CH:52][C:51](I)=[C:50]([CH3:55])[CH:49]=1>C1(C)C=CC=CC=1.O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:43]([O:42][C:39](=[O:41])[CH2:40][C:51]1[CH:52]=[CH:53][C:48]([Br:47])=[CH:49][C:50]=1[CH3:55])([CH3:46])([CH3:45])[CH3:44]
Reactant: Cc1cc(Br)ccc1I
Reactant: CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)C1(P(C2CCCCC2)C2CCCCC2)CC=CC=C1c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(Br)ccc1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under an argon atmosphere 39.6 mL (39.6 mmol; 1M in hexane) of lithium-hexamethyldisilazane was added to a suspension of 145 mg (0.65 mmol) of palladium (II) acetate and 875 mg (2.22 mmol) of 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl in 40 mL of toluene and the reaction solution was stirred for 10 minutes at RT. Then the mixture was cooled to −10° C. and combined with 3.30 mL (24.5 mmol) of tert-butyl acetate (dried over basic Alox). 4.00 mL (22.2 mmol) of 4-bromo-1-iodo-2-methylbenzene were quickly added at −10° C. and the reaction solution was heated to RT. After the reaction was complete, the reaction solution was diluted with water and EtOAc. The organic phase was separated off, washed with aqueous ammonium chloride solution and water, and dried over magnesium sulfate. After the desiccant and solvent had been eliminated, the residue was purified by chromatography (silica gel, PE/EtOAc 9:1). Yield: 2.0 g (32% of theoretical; 45% content of product according to 1H-NMR); C13H17BrO2 (M=285.177).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccccc1CCl
Reactant: NC(=O)c1cc(-c2ccc(O)cc2)no1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccccc1COc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
3-(4-Hydroxy-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 2; 50 mg, 0.24 mmol), K2CO3 (37 mg, 0.27 mmol) and tetrabutylammonium iodide (9 mg, 0.024 mmol) were taken up in DMF (2.4 mL). 2-Methoxybenzyl chloride (42 mg, 0.27 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by high-throughput purification to give 3-[4-(2-methoxy-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (10.5 mg, 13%). LRMS (ESI+): m/z [M+H]+ 325.0.
Reaction SMILES: COC([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[CH2:7][CH2:6]1)=N.C(O)(=O)C>O>[NH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[CH2:9][CH2:10]1
Reactant: COC(=N)N1CCC(c2n[nH]c3ccccc23)CC1
Solvent: CC(=O)O
Solvent: O
Product: c1ccc2c(C3CCNCC3)n[nH]c2c1
Yield: 46.4 %

Procedure:
A solution of 4.7 g of 4-(1H-indazol-3-yl)piperidine-1-carboximidic acid methyl ester and 80% of acetic acid was heated under reflux for 48 hrs. The reaction mixture was cooled and poured into water The aqueous phase was extracted with ether and then made basic by the slow addition of a 50% aqueous sodium hydroxide solution. A solid separated from the solution. The solid was collected and dried. Recrystallization from ethanol yielded 1.7 g (46%) of product. Concentration of the mother liquors from this and another experiment gave additional product mp 213°-215° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8]1)=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:21]([CH3:25])[C:22](=[O:24])[CH3:23])C=CC=CC=1>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH:9]([CH:12]=[C:21]([CH3:25])[C:22](=[O:24])[CH3:23])[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CCC(C=O)C1
Reactant: CC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: C=CCOC(=O)N1CCC(C=C(C)C(C)=O)C1
Yield: 94.8 %

Procedure:
A solution of 1-allyloxycarbonyl-3-formylpyrrolidine (13.45 g) and 3-triphenylphosphoranylidenebutan-2-one (25.60 g) in dichloromethane (15 ml) was refluxed for 20 hours. The mixture was concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (200 g) and eluted with a mixture of ethyl acetate and hexane (4:6 V/V) to give 1-allyloxycarbonyl-3-(2-methyl-3-oxo-1-butenyl)pyrrolidine (16.52 g).
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=[O:4].[C:7](=[O:17])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:8]>CCOCC>[CH2:10]([O:9][C:7]([NH:8][CH:3]([OH:4])[C:2]([OH:6])=[O:5])=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CC(=O)O
Reactant: NC(=O)OCc1ccccc1
Solvent: O
Solvent: CCOCC
Product: O=C(NC(O)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
Glyoxylic acid monohydrate (20.3 g, 221 mmol) and benzyl carbamate (30.6 g, 202 mmol) are added to ether (200 mL). The solution is allowed to stir for 24 h at rt. The resulting thick precipitate is filtered, and the residue is washed with ether, affording ([(benzyloxy)carbonyl]amino)(hydroxy)acetic acid (C150) as a white solid (47% yield). MS (CI) for C10H11NO5+H m/z: 226 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([F:17])([F:16])[S:11][CH2:12][CH2:13][O:14]C.F[C:26]1C=C(F)C=C[C:27]=1C(O)(CN1C=NC=N1)C(F)(F)SCCO.CI.C(I)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:24][CH2:26][CH3:27])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([S:11][CH2:12][CH2:13][OH:14])([F:17])[F:16]
Reactant: OCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: COCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CI
Solvent: CCI
Product: CCOC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)SCCO

Procedure:
In a similar manner to Example 1 except that 2-(2,4-difluorophenyl)-1,1-difluoro-1-[(2-methoxyethyl)thio]-3-(1H-1,2,4-triazol-1-yl)-2-propanol was replaced with 2-(2,4-difluorophenyl)-1,1-difluoro-1-[(2-hydroxyethyl)thio]-3-(1H-1,2,4-triazol-1-yl)-2-propanol and methyl iodide was replaced with ethyl iodide, the experiment was carried out, whereby 2-{[2-(2,4-difluorophenyl)-2-ethoxy-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)propyl]thio}-1-ethanol was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:28][CH2:27][C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([NH2:29])[CH2:25][CH2:24]3)=[O:22])[C:9]=2[CH3:36])=[CH:4][CH:3]=1.[C:37]([N:41]=[C:42]=[O:43])([CH3:40])([CH3:39])[CH3:38].C(N(CC)CC)C.O1CCCC1>ClCCl>[C:37]([NH:41][C:42](=[O:43])[NH:29][C:26]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:25][CH2:24][N:23]([C:21]([C:10]2[C:9]([CH3:36])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=2)=[O:22])[CH2:28][CH2:27]1)([CH3:40])([CH3:39])[CH3:38]
Reactant: Cc1c(C(=O)N2CCC(N)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CC(C)(C)N=C=O
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)N2CCC(NC(=O)NC(C)(C)C)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
1-{[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-amine (1 eq, 39.3 mg, 0.073 mmol), tert-butyl isocyanate (1.5 eq, 0.013 mL, 0.109 mmol), and triethylamine (3.0 eq, 0.03 mL, 0.218 mmol) was stirred in dichloromethane (5 mL) for 16 h. Next, tetrahydrofuran (5 mL) and an additional 0.02 mL of tert-butyl isocyanate were added and the reaction was stirred for 16 h Finally, the reaction was heated to 40° C. for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure 3-tert-butyl-1-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-yl)urea (21 mg, 45%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.15 (s, 9H) 1.93-2.17 (m, 4H) 2.20 (s, 3H) 2.42 (br. s., 1H) 3.13-3.35 (m, 1H) 3.58 (br. s., 1H) 4.25 (br. s., 1H) 4.44 (s, 1H) 4.52-4.69 (m, 1H) 5.13 (s, 1H) 7.03-7.10 (m, 2H) 7.13-7.37 (m, 7H) 7.38-7.46 (m, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH2:31][S:30][CH2:29][C:16]=3[N:17]=[C:18]([C:20]3[CH:25]=[C:24]([F:26])[C:23]([Cl:27])=[CH:22][C:21]=3[F:28])[N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32].O1CCOCC1.[OH-].[Na+].C(OCC)C>CO>[ClH:27].[ClH:32].[Cl:27][C:23]1[C:24]([F:26])=[CH:25][C:20]([C:18]2[N:19]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:15]3[CH2:31][S:30][CH2:29][C:16]=3[N:17]=2)=[C:21]([F:28])[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3c2CSC3)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOCC
Product: Fc1cc(-c2nc3c(c(N4CCNCC4)n2)CSC3)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 503 mg of 1-tert-butoxycarbonyl-4-[2-(4-chloro-2,5-difluorophenyl)-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperazine, 2 ml of MeOH, and 6 ml of 4M HCl-dioxane solution was stirred at ambient temperature for 1 hour. To the reaction mixture were added 15 ml of 1M aqueous sodium hydroxide and 2 ml of diethyl ether, and the precipitate was collected by filtration, washed with water and then diethyl ether, and dried under reduced pressure. The solid obtained was dissolved in 5 ml of MeOH, here was added 2 ml of 4M HCl-dioxane solution, and the solvent was then distilled off under reduced pressure. The residue obtained was washed with EtOH-EtOAc and dried under reduced pressure to yield 423 mg of 2-(4-chloro-2,5-difluorophenyl)-4-piperazin-1-yl-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25](O)=[O:26])=[CH:17]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:25]([C:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:16][CH:17]=3)=[O:26])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Oc2ccc(N)cn2)cn1
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(NC(=O)c3c[nH]c4ccccc34)cn2)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
The 6-(6-methylpyridine-3-yloxy)-pyridine-3-amine (300 mg, 1.49 mmol) and indole-3-carboxylic acid (240 mg, 1.49 mmol) were dissolved in DMF (10 ml), DCC (280 mg, 1.49 mmol) was added to the solution, and then the mixture was stirred at 80° C. for 3 hours. After the reaction was completed, the product was washed and filtered to yield a target compound as a grey solid (340 mg, 66%) by chromatography (methanol:dichloromethane=1:30).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13]1[C:14](=O)[C:15](=[O:20])[C:16]=1[O:17]CC)[CH3:11]>C(O)C>[O:17]=[C:16]1[C:15](=[O:20])[C:14]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[C:13]1[O:12][CH2:10][CH3:11]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: N#Cc1ccc(N)cc1
Solvent: CCO
Product: CCOc1c(Nc2ccc(C#N)cc2)c(=O)c1=O

Procedure:
4-Aminobenzonitrile (17.58 g, 149 mmol) was added to a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (25.31 g, 149 mmol) in absolute ethanol (450 mL). The mixture was heated at reflux overnight and the resulting suspension filtered hot to remove a small amount of a dirty yellow solid (discarded). The filtrate was gradually concentrated to afford several crops of 4-(3,4-dioxo-2-ethoxy-cyclobut-1-enylamino)benzonitrile, as a bright yellow solid, which were collected by filtration and combined. Yield: 29.11 g (81%): 1H NMR (DMSO-d6): δ11.07 (s, 1H), 7.81 (d, 2H), 7.56 (d, 2H), 4.79 (q, 2H), 1.46 (t, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.Br[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:22]1([CH2:21][CH2:20][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCCc1ccccc1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCN(CCc2ccccc2)C1)C12CC3CC(CC(C3)C1)C2
Temperature: 70 °C
Yield: 77.8 %

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (3.9 g) and 2-bromoethylbenzene (2.9 g) were dissolved in DMF, and potassium carbonate was added. The mixture was stirred under heating at 70° C. for 5 hours, and after the completion of the reaction, the solvent was evaporated under reduced pressure. Ethyl acetate was added to the obtained residue and the mixture was washed with saturated brine. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform:methanol=30:1). The obtained eluate was concentrated and IPE was added. The precipitated crystals were collected by filtration to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide (4.3 g), melting point 119-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.Cl[C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13]>>[CH3:15][O:14][C:12](=[O:13])[C:11]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)[CH3:9])=[O:16]
Reactant: CNc1ccc(Cl)cn1
Reactant: COC(=O)C(=O)Cl
Product: COC(=O)C(=O)N(C)c1ccc(Cl)cn1

Procedure:
The method described in Referential Example 242 was performed by use of 5-chloro-N-methyl-2-pyridinamine and methyl chlorooxoacetate, whereby the title compound was obtained. 1H-NMR(CDCl3)δ: 3.43(3H, s), 3.81(3H, s), 7.08(1H, br.s), 7.68-7.78(1H, m), 8.27(1H, br.s).
Reaction SMILES: CC([N:5]([C@H:9]([CH3:29])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([O:27][CH3:28])[CH:21]=2)=[CH:15][CH:14]=1)=[O:11])C(=O)[O-])(C)C.ClCCl>>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:29])[NH2:5])=[CH:14][CH:15]=2)=[CH:21][C:22]=1[O:27][CH3:28]
Reactant: COc1cc(Oc2ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cc2)ccc1C
Solvent: ClCCl
Product: COc1cc(Oc2ccc(NC(=O)[C@@H](C)N)cc2)ccc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.1 %

Procedure:
To a solution of 1,1-dimethylethyl{(1R)-1-methyl-2-[(4-{[4-methyl-3-(methyloxy)phenyl]oxy}phenyl)amino]-2-oxoethyl}carbamate (Intermediate 21, 300 mg) in dry dichloromethane (7.5 mL) TFA (2.5 mL, 32.4 mmol) was slowly added and the reaction mixture was stirred for 1.5 hours at room temperature. The solvent and the excess of TFA were evaporated and the residue was purified by SCX cartridge (10 g) to afford the title compound as an orange oil (219 mg).
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:30])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[CH3:31][C:32]([CH3:43])([NH2:42])[CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>O1CCCC1>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:42][C:32]([CH3:43])([CH3:31])[CH2:33][CH2:34][CH2:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: O=C(/C=C/C=C(c1ccc(F)cc1)c1ccc(F)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(N)CCCc1cccnc1
Solvent: C1CCOC1
Product: CC(C)(CCCc1cccnc1)NC(=O)/C=C/C=C(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
As in Example 134, a solution of (E)-5,5-bis(4-fluorophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (1.63 g) and alpha,alpha-dimethyl-3-pyridinebutanamine (0.9 mL) in tetrahydrofuran (20 mL) was stirred at reflux for 24 hours. The crude product, isolated in the usual manner, was crystallized from ethyl acetate to yield 1.6 g of (E)-5,5-bis(4-fluorophenyl)-N-[1,1-dimethyl-4-(3-pyridinyl)butyl]-2,4-pentadienamide, mp 163.5°-164.5° C.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH:3]2[CH2:7][CH:8]3[C:13]([CH:2]12)=[CH:12][CH2:11][CH2:10][CH2:9]3.OS(C(F)(F)F)(=O)=O>>[NH:1]1[C:5](=[O:6])[CH2:4][CH:3]2[CH2:7][C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[CH:2]12
Reactant: O=C1CC2CC3CCCC=C3C2N1
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C1CC2CC3=C(CCCC3)C2N1
Temperature: 40 °C
Reaction time: 4 h
Yield: 53.7 %

Procedure:
To a solution of 3,3a,4,4a,5,6,7,8b-octahydro-1H-indeno[1,2-b]pyrrol-2-one (600 mg, 3.38 mmol) in chloroform-d-3 (4 mL) under argon was added triflic acid (0.152 mL) and the solution was stirred 4 h at 40° C. The solution was cooled down and passed through celite, washed with dichloromethane and evaporated. Purification by flash chromatography (ethyl acetate) gave 3,3a,4,5,6,7,8,8b-octahydro-1H-indeno[1,2-b]pyrrol-2-one (322 mg, 53%) as an orange oil. LCMS (Method B): 0.76 min; ES+ 178 (M+H+).