Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11](OS(C)(=O)=O)[CH2:10][C@@H:9]1[CH2:18][OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]([O-:23])(=[S:22])[CH3:21].[K+].C(OCC)(=O)C.Cl>CN(C)C=O>[C:20]([S:22][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@H:9]([CH2:18][OH:19])[CH2:10]1)(=[O:23])[CH3:21]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@@H]1CO
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Yield: 86 %

Procedure:
A solution of (2R,4S)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (i.e., a substrate) (11.8 g: 40 mmole) and potassium thioacetate (5.94 g: 52 mmole) in dimethylformamide (120 ml) is stirred at 65° C. for 3.75 hours. The reaction mixture is mixed with ethyl acetate (330 ml), ice water (100 ml), and 1N-hydrochloric acid (20 ml) to adjust the aqueous layer at pH 4. The organic layer is taken, successively washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel chromatography (toluene-ethyl acetate=2:1) to give (2S,4S)-4-acetylthio-1-t-butoxycarbonylpyrrolidine-2-methanol (9.48 g). Yield: 86%. Pale orange colored oil. NMR δ(CDCl3) ppm: 1.47(s, 9H), 2.34(s, 3H), 2.4 to 3.2(m, 2H), 3.58 to 4.1(m, 6H). IR ν (CHCl3) cm-1 : 3380, 1690.
Reaction SMILES: [Br-].[F:2][CH2:3][CH2:4][CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O.CCCCCC>O1CCCC1>[F:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH:36][C:35]1[CH:34]=[C:33]([F:32])[CH:40]=[CH:39][CH:38]=1
Reactant: FCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(F)c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: FCCCC=Cc1cccc(F)c1
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a mixture of 4-fluorobutyltriphenylphosphonium bromide 273 g (660 mmol) and tetrahydrofuran (abbreviated THF hereinafter) 1000 ml, potasium-tert-butoxide 88 g (684 mmol) was added under ice cooling and stirred for one hour. Then, under ice cooling, a solution of 3-fluorobenzaldehyde 74 g (596 mmol) in THF 200 ml was added dropwise, and the mixture was stirred for one hour at room temperature. The reaction mixture was poured into hexane 1000 ml, and the crystals deposited were filtered off. The filtrate was concentrated, and distilled (93° C./6 mmHg) to obtain 3-(5-fluoro-1-pentenyl)fluorobenzene 86 g. (Yield:79.6%).
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1.[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30])=[CH2:23].C(=O)([O-])O.[K+].ClN1C(=O)CCC1=O>C(OCC)(=O)C.O>[OH:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH:22]1[O:1][N:2]=[C:3]([C:4]2[N:5]=[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)[S:7][CH:8]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Reactant: C=Cc1ccccc1O
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4O)C3)cs2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-{4-[(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (3.46 g) and 2-vinylphenol (1.60 g) in ethyl acetate (50 ml) were added, at room temperature, potassium hydrogencarbonate (5.55 g) and N-chlorosuccinimide (1.78 g), and then one drop of water. After stirring at 60° C. overnight, the reaction mixture was admixed with ethyl acetate and water and extracted with ethyl acetate. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave tert-butyl 4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (1.70 g).
Reaction SMILES: [N:1]1[N:9]2[C:4]([CH2:5][S:6][CH2:7][CH2:8]2)=[CH:3][C:2]=1[CH2:10][OH:11]>O=[Mn]=O.C(Cl)(Cl)Cl>[N:1]1[N:9]2[C:4]([CH2:5][S:6][CH2:7][CH2:8]2)=[CH:3][C:2]=1[CH:10]=[O:11]
Reactant: OCc1cc2n(n1)CCSC2
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=Cc1cc2n(n1)CCSC2

Procedure:
MnO2 (activated) (11.46 g) was added to the CHCl3 (135 mL) solution of (6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazin-2-yl)methanol (2.31 g) and refluxed for 1 h under a nitrogen atmosphere. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated under a reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with n-hexane—AcOEt (1/1). The titled compound was obtained as pale yellow crystals (1.78 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH2:26][NH:27][CH2:28][CH2:29][CH:30]=1.O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:27]1[CH2:28][CH2:29][CH:30]=[C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[CH2:26]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: C1=C(c2ccccn2)CNCC1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: C[C@@H](N1CCC=C(c2ccccn2)C1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 61.9 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.83 g, 3.3 mmol) and 1′,2′,5′,6′-tetrahydro-2,3′-bipyridine (3.51 g, 21.9 mmol) were dissolved in acetonitrile (50 ml), and lithiumperchlorate trihydrate (1.50 g, 9.3 mmol) was added thereto and refluxed for 40 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 0.87 g of the intended substance (yield 61.9%).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH:22][C:23](=O)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:8]1[C:9]([NH:22][C:23](=[S:43])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(CC(=O)Nc2ncc(-c3ccc(OC)cc3)nc2Cc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CC(=S)Nc2ncc(-c3ccc(OC)cc3)nc2Cc2ccccc2)cc1
Temperature: 25 °C

Procedure:
Under an argon atmosphere, 3-benzyl-5-(4-methoxyphenyl)-2-[(4-methoxyphenyl)acetylamino]pyrazine (c-43) (prepared by the method described in Inouye, S. & Hosoya, T., Biochem. Biophys. Res. Commun., 386, 617-622 (2009)) (1.00 g, 2.28 mmol) was suspended in anhydrous toluene (30 mL) and to this was added Lawesson's reagent (552 mg, 1.37 mmol) while stirring at room temperature, and then heated to reflux for 17 h. After refluxing, it was cooled to room temperature, and concentrated under reduced pressure with a rotary evaporator. The residue was purified by silica gel column chromatography (100 g, dichloromethane/ethyl acetate=49/1) to give 3-benzyl-5-(4-methoxyphenyl)-2-[(4-methoxyphenyl)thioacetylamino]pyrazine (c-44) as a yellow oily substance (823 mg, 79.4%). Rf=0.43 (dichloromethane/ethyl acetate=19/1). 1H NMR (400 MHz, DMSO-d6) δ 2.84 (s, 3H), 3.82 (s, 3H), 3.92 (s, 2H), 4.07 (s, 2H), 6.90-6.96 (AA′BB′, 2H), 6.98-7.04 (AA′BB′, 2H), 7.05-7.11 (AA′BB′, 2H), 7.13-7.26 (m, 3H), 7.38-7.50 (m, 2H), 8.06-8.11 (AA′BB′, 2H), 8.99 (s, 1H), 12.12 (s, 1H). 13C NMR (67.8 MHz, DMSO-d6) δ 39.3, 50.8, 55.0, 55.3, 113.8 (2C), 114.5 (2C), 126.3, 127.6, 128.18 (2C), 128.21 (2C), 128.8, 128.9 (2C), 130.0 (2C), 137.8, 138.0, 145.0, 149.6, 152.1, 158.4, 160.8, 205.1. IR (KBr, cm−1) 704, 835, 1030, 1113, 1175, 1250, 1292, 1304, 1319, 1371, 1422, 1439, 1493, 1510, 1607, 2835, 2932, 2957, 3150. HRMS (ESI+) m/z 456.1747 ((M+H)+, C27H26N3O2S+ requires 456.1740).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].ClCCl.[OH:9][CH2:10][CH:11]([CH3:26])[CH2:12][CH2:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][C:21](=[O:25])[NH:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>O>[CH3:26][CH:11]([CH2:12][CH2:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][C:21](=[O:25])[NH:22]2)=[CH:17][CH:16]=1)[CH2:10][O:9][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CC(CO)CCOc1ccc2c(c1)NC(=O)CC2
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CCOc1ccc2c(c1)NC(=O)CC2)COS(C)(=O)=O

Procedure:
Methanesulfonyl chloride (1.0 ml) was added to a dichloromethane (80 ml) solution of 2.8 g of 7-(4-hydroxy-3-methyl butoxy)-3,4-dihydro-1H-quinolin-2-one and 2.4 ml of triethylamine while being stirred under ice-cooling and stirred at room temperature overnight. Water was added to the reaction solution, which was then extracted with dichloromethane and, after washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1), and methanesulfonic acid 2-methyl-4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)butyl ester (2.8 g) was obtained in the form of a green powder.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([CH2:19][N:20]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:17][CH:18]=3)[CH:12]=[C:6]2[C:5]=1[NH:31][C@H:32]1[C@@H:36]([CH2:37][CH3:38])[CH2:35][N:34]([C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[CH2:33]1)(=[O:3])[NH2:2].O.NN.C1COCC1>CCO>[NH2:20][CH2:19][C:16]1[N:15]=[CH:14][C:13]([C:11]2[CH:12]=[C:6]3[C:5]([NH:31][C@H:32]4[C@@H:36]([CH2:37][CH3:38])[CH2:35][N:34]([C:39]([O:41][CH2:42][C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)=[O:40])[CH2:33]4)=[C:4]([C:1](=[O:3])[NH2:2])[CH:9]=[N:8][N:7]3[CH:10]=2)=[CH:18][CH:17]=1
Reactant: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CN4C(=O)c5ccccc5C4=O)nc3)cc12
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CN)nc3)cc12
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 65.2 %

Procedure:
A mixture of (3S,4S)-benzyl 3-((3-carbamoyl-6-(6-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (57 mg, 0.089 mmol) and hydrazine, hydrate (8.29 μl, 0.266 mmol) in EtOH (2 mL) was heated to 70° C. for 10 minutes. THF (0.5 ml) was added to obtain homogeneity and heating was continued for 1.5 hr. Additional hydrazine, hydrate (8.29 μl, 0.266 mmol) (times 4; total of 12 equivalents) was added and heating was continued for 1.5 hr. A precipitation was observed. After cooling to rt, the reaction mixture was filtered and the filtrate was concentrated to a residue that was triturated with EtOAc. Filtration and drying afforded (3S,4S)-benzyl 3-((6-(6-(aminomethyl)pyridin-3-yl)-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (30 mg, 0.058 mmol, 66.0% yield) as a tan solid. The material is contaminated with the hydrazide by-product and will be used as is in the next step. MS (ES+) m/z: 514.4 (M+H); LC retention time: 2.303 min (analytical HPLC Method O).
Reaction SMILES: Br[C:2]1[S:3][C:4](Br)=[C:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C([Sn](CCCC)(CCCC)[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)CCC>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:2]1[S:3][C:4]([C:31]2[S:30][CH:29]=[CH:33][CH:32]=2)=[C:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCc1c(Br)sc(Br)c1CCCCCCCC
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCc1c(-c2cccs2)sc(-c2cccs2)c1CCCCCCCC
Yield: 145.7 %

Procedure:
In a dry box under an inert atmosphere, Pd(PPh3)2Cl2 (0.15 gram, 0.2 mmol) was added to a mixture of 2,5dibromo-3,4-dioctylthiophene (4.2 grams, 9.0 mmol) and 2-(tributylstannyl)-thiophene (7.4 grams, 19.8 mmol) in anhydrous tetrahydrofuran (50 milliliters) in a 250 milliliter round-bottomed flask. The mixture was then refluxed for 12 hours and the solvent was removed by evaporation. The crude product thus obtained was purified by flash chromatography on silica gel using hexane as eluent to give 3.1 grams of 2,5-bis(2thienyl)-3,4-dioctylthiophene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([N:16]([CH3:18])[CH3:17])[N:13]=[C:12]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.Cl[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[CH:37]=1>O1CCOCC1>[CH3:43][O:42][C:38]1[CH:37]=[C:36]([CH:41]=[CH:40][CH:39]=1)[CH2:35][N:22]1[CH2:23][CH2:24][N:19]([C:12]2[N:11]=[C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:15]=[C:14]([N:16]([CH3:18])[CH3:17])[N:13]=2)[CH2:20][CH2:21]1
Reactant: COc1cccc(CCl)c1
Reactant: COc1cccc(Nc2cc(N(C)C)nc(N3CCNCC3)n2)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CN2CCN(c3nc(Nc4cccc(OC)c4)cc(N(C)C)n3)CC2)c1
Yield: 71.3 %

Procedure:
A solution of N4-(3-methoxyphenyl)-N6,N6-dimethyl-2-(1-piperazinyl)-4,6-pyrimidinediamine (36 mg, 0.1 mmol), DIPEA (52 mg, 0.4 mmol), and 1-(chloromethyl)-3-methoxybenzene (20 mg, 0.13 mmol) in 5 mL of dioxane was stirred at 100° C. for 16 h. The crude product was concentrated in vacuo and treated with saturated NaHCO3 (50 mL) and extracted with CH2Cl2 (3×50 mL). The organic layer was washed with brine (2×100 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (32 mg, 70%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:13]([SH:16])[CH2:14][SH:15].B(F)(F)F.CCOCC>C(Cl)Cl>[S:15]1[C:2]2([CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[S:16][CH2:13][CH2:14]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: SCCS
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C1CCC2(CC1)SCCS2
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a stirred solution of ethyl 4-oxocyclohexane carboxylate (5 g, 29.41 mmol) and ethane-1,2-dithiol (4.14 g, 44.11 mmol) in DCM (25 mL) was added BF3.Et2O (4.17 g, 29.41 mmol) at 0° C. and the reaction mixture was allowed to stir at 20-35° C. for 2 h. Then the reaction mixture was rotary evaporated under vacuum to get residue which was purified by column chromatography using mixture of 5% ethyl acetate/hexane as an eluent to get the desired compound as a yellow liquid (5.4 g, 75%); 1H NMR (400 MHz, DMSO-d6) δ 4.05 (q, J=7.4 Hz, 2H), 3.34-3.26 (m, 4H), 2.42-2.34 (m, 1H), 2.10-2.02 (m, 2H), 1.96-1.84 (m, 4H), 1.66-1.54 (m, 2H), 1.17 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:15])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH3:16][C:17]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].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>>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([CH3:26])[C:17]=2[CH3:16])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2C)Cc2ccccc2C1
Yield: 86.4 %

Procedure:
2-Amino-indane-2-carboxylic acid ethyl ester (250 mg, 1.2 mmol), 2,3-dimethyl-benzoic acid (183 mg, 1.2 mmol) and HATU (555 mg, 1.46 mmol) are taken in a vial, evacuated and refilled with nitrogen. Anhydrous DMF (2 mL) is added and stirring is initiated. After a few min, DIPEA (0.302 mL, 1.82 mmol) is added and stirred at RT overnight. Analysis by tlc of the reaction mixture (silica, 50% EtOAc/heptanes) indicates complete consumption of the starting amine. Water (10 mL) is added, extracted with EtOAc (3×5 mL), dried over Na2SO4, concentrated and the crude product is chromatographed on a 25 g silica gel column using 20-50% EtOAc in heptane as a gradient to afford 2-(2,3-dimethyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (350 mg, 87%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.O.CN(C)[CH:21]=[O:22]>>[CH:15]1[CH:14]=[CH:13][C:12]([CH2:11][O:10][C:4]2[C:5]3[NH:9][C:21]([NH:8][C:6]=3[N:7]=[C:2]([NH2:1])[N:3]=2)=[O:22])=[CH:17][CH:16]=1
Reactant: Nc1nc(N)c(N)c(OCc2ccccc2)n1
Reactant: CN(C)C=O
Solvent: O
Product: Nc1nc(OCc2ccccc2)c2[nH]c(=O)[nH]c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4,5-Triamino-6-benzyloxypyrimidine (Pfleiderer et al., Chem. Ber., 94, 12-18 (1961)) (1.85 g, 8 mmol) and 1,11-carbonyldiimidazole (1.30 g, 8 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL) under argon. The solution was stirred at room temperature overnight and was mixed with water (200 mL) to precipitate a white solid. The solid was collected by filtration, and dissolved in 250 mL of aqueous 2 N NaOH solution. Undissolved material was removed by filtration, and the filtrate was neutralized with glacial acetic acid to precipitate a white solid. The solid was collected by filtration, was washed with water, and was recrystallized from 50% aqueous ethanol to afford analytically pure 1c: yield, 1.63 g (79%); mp 256-257° C. dec.; UV (pH 1) 1max 243 nm (e=0.717×104), 306 (1.499×104); (pH 6.9) 243 (0.915×104), 290 (1.108×104); (pH 13) 249 (sh) (0.443×104), 293 (1.368×104); 1H NMR d 5.41 (s, 2 H, ArCH2), 6.13 (s, 2 H, NH2, exchange with D2O), 7.33-7.51 (m, 5 H, ArH), 10.46 (s, 1 H, exchanges with D2O), 11.04 (s, 1 H, exchanges with D2O); MS (EI) Calcd. m/z for C12H11N5O2 : 257.0912. Found: 257.0914. Anal. (C12H11N5O2. 1/2 H2O) C, N, H.
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:5]([C:17]#[N:18])=[C:4]([O:19][CH3:20])[N:3]=1.N(OCCC(C)C)=O.[ClH:29]>C(#N)C.[Cu](Cl)Cl>[Cl:29][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:5]([C:17]#[N:18])=[C:4]([O:19][CH3:20])[N:3]=1
Reactant: Cl
Reactant: COc1nc(N)c(C#N)c(-c2ccc(O)cc2)c1C#N
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COc1nc(Cl)c(C#N)c(-c2ccc(O)cc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.98 g (15.285 mmol) of 2-amino-4-(4-hydroxyphenyl)-6-methoxypyridine-3,5-dicarbonitrile are initially charged in 120 ml of acetonitrile, 6.175 ml (45.855 mmol) of isoamyl nitrite and 6.165 g (45.855 mmol) of copper(II) chloride are added and the mixture is stirred at room temperature overnight. 1N hydrochloric acid is added, and the reaction mixture is extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium bicarbonate solution and with water, dried over sodium sulphate and concentrated. The residue is purified on a silica gel column (mobile phase: toluene/ethyl acetate 2:1). This gives 1.3 g (23% of theory) of the target compound.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20])[C:11](Cl)=[O:12].[CH:21]1([CH2:26][NH2:27])[CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(OCC)(=O)C>[CH:21]1([CH2:26][NH:27][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]#[CH:20])=[C:8]([O:7][CH3:6])[CH:9]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C#CCOc1ccc(C(=O)Cl)cc1OC
Reactant: NCC1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCOc1ccc(C(=O)NCC2CCCC2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
To a mixture of 10 ml of THF and 0.3 g of 3-methoxy-4-(2-propynyloxy)benzoyl chloride were added dropwise 0.15 g of cyclopentylmethylamine and 0.16 g of triethylamine in order under ice cooling. The mixture obtained was stirred at room temperature for 4 hours. Then, ethyl acetate was added to the reaction mixture and it was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.31 g of N-cyclopentylmethyl-4-(2-propynyloxy)-3-methoxybenzamide (hereinafter, described as the compound 11 of the present invention) represented by the formula:
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[CH:8]3[CH2:17][CH2:16][CH2:15][CH:9]3[C:10](=[O:14])[NH:11][C:12]=2[CH:13]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[Cl:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[CH2:44][NH2:45].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl.C(OCC)(=O)C>[Cl:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[CH2:44][NH:45][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[CH:8]3[CH2:17][CH2:16][CH2:15][CH:9]3[C:10](=[O:14])[NH:11][C:12]=2[CH:13]=1
Reactant: NCc1cccc(Cl)c1
Reactant: O=C1Nc2cc(CCO)ccc2C2CCCC12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1Nc2cc(CCNCc3cccc(Cl)c3)ccc2C2CCCC12
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 23.7 %

Procedure:
A solution of 0.19 g (0.82 mmol) of 7-hydroxyethyl-1,2,3,3a,5,9b-hexahydro-cyclopenta[c]quinolin-4-one in 20 ml of dichloromethane is mixed at 0° C. with 0.38 g (0.90 mmol) of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277). The batch is stirred for 10 minutes at 0° C. and for 40 minutes at room temperature, diluted with dichloromethane (100 ml), washed with saturated NaHCO3 (30 ml), dried (Na2SO4) and concentrated by evaporation in a vacuum. The residue is dissolved in 1,2-dichloroethane (20 ml) and mixed with 0.11 ml (0.90 mmol) of 3-chlorobenzylamine, 0.30 g (1.40 mmol) of sodium (triacetoxy)borohydride and 0.05 ml (0.85 mmol) of acetic acid. After 20 hours at room temperature, the batch is diluted with ethyl acetate (150 ml), washed with water (2×50 ml), dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with dichloromethane-ethanol yields 69 mg of product.