Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][N:4]2[N:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=[C:3]12.[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][N:16]=1>>[Cl:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([CH:7]2[CH2:6][CH2:5][N:4]3[N:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=[C:3]3[C:2]2=[O:1])=[O:20])=[CH:22][CH:23]=1
Reactant: O=C(O)c1cc2n(n1)CCCC2=O
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: O=C(O)c1cc2n(n1)CCC(C(=O)c1ccc(Cl)nc1)C2=O

Procedure:
A-07 is prepared using general procedure A2 starting from 4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridine-2-carboxylic acid (5.00 g, 27.8 mmol) and 6-chloro-nicotinoyl chloride (7.33 g, 41.6 mmol). Yield: 7.37 g. HPLC-MS: Rt=1.94 min, (M+H)+=320/322.
Reaction SMILES: S([C:5]1C=C[C:8](C)=[CH:7][CH:6]=1)([O-])(=O)=O.[F:12][C:13]1[CH:27]=[CH:26][C:16]2[C:17]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:18][O:19][C:15]=2[CH:14]=1.C(=O)([O-])[O-:29].[K+].[K+]>C(#N)C>[F:12][C:13]1[CH:27]=[CH:26][C:16]2[C:17]([CH:20]3[CH2:21][CH2:22][N:23]([CH2:5][CH2:6][CH:7]([OH:29])[CH3:8])[CH2:24][CH2:25]3)=[N:18][O:19][C:15]=2[CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [K+]
Solvent: CC#N
Product: CC(O)CCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C

Procedure:
Racemic 3-hydroxybutyl rosylate was prepared in a manner described by Ferreira et al., Tetrahedron, 46, pp. 6311-6318, (1990). To a solution of the racemic tosylate (9.2 g, 37.7 mmol) in acetonitrile (190 ml) was added 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (8.3 g, 37.7 mmol) followed by milled potassium carbonate (7.8 g, 56.6 mmol) at room temperature under nitrogen. The reaction mixture was warmed to reflux for 4.5 hours and allowed to cool to room temperature. The solids were removed via filtration through a pad of Celite and were washed with EtOAc. The combined filtrates were concentrated to give the crude product. Purification via preparative HPLC (silica gel, 10% MeOH/EtOAc) afforded 6.3 g (57%), m.p.=100°-102° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@@H:17]2[C@@:13]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH2:14][C:15](=[CH2:19])[CH2:16]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:30])=[N-]>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@@H:17]2[C@@:13]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH2:14][C:15]3([CH2:16]2)[CH2:30][CH2:19]3)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C1C[C@@H]2CN(C(=O)OCc3ccccc3)C[C@]2(NC(=O)OC(C)(C)C)C1
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@]12CN(C(=O)OCc3ccccc3)C[C@H]1CC1(CC1)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Palladium acetate (5.26 mg, 0.0234 mmol) was added to (1S,5R)-3-benzyloxycarbonyl-1-tert-butoxycarbonylamino-7-methylene-3-azabicyclo[3.3.0]octane (175 mg, 0.469 mmol) in diethyl ether (4.69 ml) in an open system under ice-cooling. The previously prepared solution of diazomethane in diethyl ether (20 ml) was slowly added to this solution under ice-cooling, and the mixture was stirred at room temperature for 16 hours. After filtration through Celite, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→88:12→87:13→86:14→85:15→83:17→80:20→75:25) to give 138 mg of the title compound as a transparent oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[N:13][O:14][CH2:15][CH2:16][OH:17])[CH3:12].O[C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26]([C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]2=[O:49])=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[N:13][O:14][CH2:15][CH2:16][O:17][C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26]([C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]2=[O:49])=[CH:21][CH:20]=1)[CH3:12]
Reactant: CC(=NOCCO)c1ccc2ccccc2n1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc2ccccc2n1
Yield: 87.4 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 461 mg of 2-[1-(2-quinolyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 14), 716 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 525 mg of triphenylphosphine and 348 mg of diethyl azodicarboxylate, 911 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@@H:3]1[N:8]1[C:17]2[C:12](=[CH:13][N:14]=[C:15]3[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:18][C:16]3=2)[C:11](=[O:29])[CH:10]=[CH:9]1.C(N(CC)C(C)C)(C)C.[CH3:39][CH:40]([CH3:46])[CH2:41][S:42](Cl)(=[O:44])=[O:43].O>ClCCl>[CH2:41]([S:42]([N:5]1[CH2:6][CH2:7][C@@H:2]([CH3:1])[C@@H:3]([N:8]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]4[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:18][C:16]4=3)[C:11](=[O:29])[CH:10]=[CH:9]2)[CH2:4]1)(=[O:44])=[O:43])[CH:40]([CH3:46])[CH3:39]
Reactant: C[C@@H]1CCNC[C@@H]1n1ccc(=O)c2cnc3c(ccn3COCC[Si](C)(C)C)c21
Reactant: CC(C)CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CS(=O)(=O)N1CC[C@@H](C)[C@@H](n2ccc(=O)c3cnc4c(ccn4COCC[Si](C)(C)C)c32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
rac-1-[(3R,4R)-4-Methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one (23 mg, 0.056 mmol) in dichloromethane (2 mL) was mixed with N,N-diisopropylethylamine (30 μL, 0.17 mmol) and 2-methylpropane-1-sulfonyl chloride (12 μL, 0.092 mmol) under cooling with ice and stirred at room temperature for 2 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol=1/1/0→0/10/1 (v/v/v)) to give the title compound as a pale pink solid (18.3 mg, yield 62%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[NH2:16][C:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[NH:19][N:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:13]([NH:16][C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:19][N:18]=2)=[O:15])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:9])([F:10])[F:11])[N:7]=1
Reactant: Nc1n[nH]c2ncccc12
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1n[nH]c2ncccc12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture comprising 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate 2) (0.320 g, 1.118 mmol), 3-aminopyrazolo[3,4-b]pyridine (0.150 g, 1.118 mmol) and HATU (0.425 g, 1.118 mmol) in DMF (5 ml) was treated with N-methylmorpholine (0.111 ml, 1.118 mmol) and stirred at 80° C. overnight. After cooling to RT, the mixture was diluted with water (25 ml) and the resulting yellow precipitate was filtered under vacuum and washed with water. The crude material was purified by chromatography on silica eluting with iso-hexane:EtOAc (gradient of 0 to 100 EtOAc) to give the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.C(OCC)(=O)C>CN(C=O)C>[C:14]1([S:20]([N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[O:2][CH3:1])[CH:8]=[CH:9]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc2ccn(S(=O)(=O)c3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-methoxyindole (1 eq) in DMF cooled in an ice bath was added NaH (60% dispersion in oil, 1.2 eq). The reaction was stirred for 1 hr at room temperature then recooled in an ice bath. Benzenesulfonyl chloride (1.1 eq) was added then the reaction was stirred for 2 hrs at room temperature. Water/ethyl acetate were added and the ethyl acetate layer was washed repeatedly (3×) with water. The ethyl acetate layer was concentrated and evaporated to dryness.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.CN1C(=O)CCC1.Cl.Cl.[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:38]=[C:39]([CH:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)[N:40]([CH2:42][CH2:43][N:44]([CH3:46])[CH3:45])[CH:41]=2)=[CH:33][C:32]=1[C:53]([F:56])([F:55])[F:54].CCN(C(C)C)C(C)C.OP(O)(O)=O>>[CH3:45][N:44]([CH3:46])[CH2:43][CH2:42][N:40]1[CH:41]=[C:37]([C:34]2[CH:35]=[CH:36][C:31]([F:30])=[C:32]([C:53]([F:55])([F:54])[F:56])[CH:33]=2)[N:38]=[C:39]1[CH:47]1[CH2:48][CH2:49][N:50]([C:2]2[C:3]3[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:51][CH2:52]1
Reactant: COc1ccc(CN2C(=O)Cc3c(Cl)ncnc32)cc1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Agent: Cl
Agent: O=P(O)(O)O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2C(=O)Cc3c(N4CCC(c5nc(-c6ccc(F)c(C(F)(F)F)c6)cn5CCN(C)C)CC4)ncnc32)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
Add a solution of 4-chloro-7-(4-methoxybenzyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (18.11 g; 1.05 equiv; 62.52 mmol) in NMP (156.50 mL; 1.62 mol) at RT to 2-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)-N,N-dimethylethanamine dihydrochloride (31.30 g; 1.00 equiv; 59.54 mmol) and DIPEA (51.92 mL; 297.71 mmol) and stir overnight at 50° C. Quench the reaction with water (900 mL) and EA (200 mL) and adjust the pH of the mixture to 1-2 with H3PO4 [85% aqueous (aq.)]. Stir for 15 min and separate the phases. Extract the organic phase with a H3PO4 solution (15% aq. 3×100 mL). Wash the combined aqueous phases with EA/tert-butylmethyl ether (tBuOMe) (4/1) (3×150 mL). Adjust the pH of the aqueous phase to 9 with solid K2CO3 and extract with EA (3×15 mL). Wash the combined organic phases with brine, decolor with charcoal, and filter over Celite®. Combine the filtrates and evaporate. Crystallize the residue from EA/tBuOMe to obtain the title compound (17.00 g; 26.66 mmol; 44.77% yield) as pale rose solid. 1H NMR (300 MHz, CDCl3): 8.36 (s, 1H), 7.91-7.83 (m, 2H), 7.43-7.40 (m, 2H), 7.17-7.11 (m, 2H), 6.86-6.81 (m, 2H), 4.87 (s, 2H), 4.56 (d, J=13.4 Hz, 2H), 4.13-4.07 (m, 2H), 3.77 (s, 3H), 3.63 (s, 2H), 3.40-3.36 (m, 2H), 3.21-3.05 (m, 3H), 2.74 (t, J=6.6 Hz, 2H), 2.40-2.35 (m, 6H), 2.09-1.99 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C@H:6]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[O:12])[CH2:7]2)[CH2:2]1.[I-].[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH2:26][N:25]([C:30](N1C=C[N+](C)=C1)=[O:31])[CH2:24][CH2:23]2.CCN(CC)CC.O>C(Cl)Cl>[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH2:26][N:25]([C:30]([N:1]1[CH2:2][CH:3]([NH:5][C@H:6]3[CH2:10][CH2:9][N:8]([C:11]([C:13]4[S:14][CH:15]=[CH:16][N:17]=4)=[O:12])[CH2:7]3)[CH2:4]1)=[O:31])[CH2:24][CH2:23]2
Reactant: O=C(c1nccs1)N1CC[C@H](NC2CNC2)C1
Reactant: C[n+]1ccn(C(=O)N2CCc3cc(Br)ccc3C2)c1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(c1nccs1)N1CC[C@H](NC2CN(C(=O)N3CCc4cc(Br)ccc4C3)C2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of compound 1g (di-HCl salt, 105 mg, 0.327 mmol) and compound 1j (162 mg, 0.36 mmol) in CH2Cl2 (2 mL) was added Et3N (0.09 mL, 0.65 mmol). The reaction was stirred room temperature overnight. To the reaction mixture was added water, and the resultant mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 5% MeOH/EtOAc+0.5% TEA) gave compound 10 (136 m g). MS m/z (M+H+) 490, 492. 1H NMR (300 MHz, CDCl3): δ 7.90 (m, 1H), 7.54 (m, 1H), 7.31-7.28 (m, 2H), 6.96 (m, 1H), 4.42 (d, J=3 Hz, 2H), 4.31-4.16 (m, 3H), 3.96-3.68 (m, 4H), 3.53-3.40 (m, 3H), 2.83 (m, 2H), 2.12 (m, 1H), 1.84 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH2:23](Br)[CH:24]=[CH2:25]>C(#N)C>[CH2:25]([N:9]1[CH2:10][CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:13]([O:14][CH3:15])=[CH:12][C:6]=2[CH2:7][CH2:8]1)[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: COc1cc2c(cc1OC)CCNCC2
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCN1CCc2cc(OC)c(OC)cc2CC1

Procedure:
To a mixture of 7 g. (0.0337 mole) of 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine dissolved in 170 ml. of acetonitrile and 5 ml. of triethylamine, cooled in an ice bath, was added 4.25 g. (0.035 mole) of allyl bromide in 30 ml. of acetonitrile, dropwise with stirring. The mixture was brought to room temperature and refluxed for 11/2 hours. The reaction mixture was evaporated to dryness, partitioned between ethyl acetate and 5% sodium bicarbonate solution, and the separated ethyl acetate dried and evaporated to give 3-allyl-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[NH:6]1[CH:10]=[CH:9][N:8]=[CH:7]1>C(#N)C>[OH:5][CH:3]([CH3:4])[CH2:2][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: c1c[nH]cn1
Reactant: CC(=O)CCl
Solvent: CC#N
Product: CC(O)Cn1ccnc1
Reaction time: 24 h

Procedure:
Chloroacetone (9.25 g.) in dry acetonitrile was added dropwise with stirring and ice cooling to a slurry of imidazole (13.6 g.) in acetonitrile (100 ml.). The mixture was stirred for 4 hours with ice cooling and then for 24 hours at room temperature. The solvent was removed and the product isolated by chromatography on silica gel, eluting with 10% methanol/dichloromethane. This material in 100 ml. of methanol was treated with excess sodium borohydride at 0° C. for 1 hours and acidified with methanolic hydrogen chloride. The solvent was removed, ethyl acetate added and the stirred mixture treated dropwise with saturated potassium carbonate solution until basic. The ethyl acetate was then decanted, dried, evaporated and the residue chromatographed on silica gel eluting with 10% methanol/dichloromethane to give pure 1-(2-hydroxypropyl)imidazole.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][CH:18]=2)[C:6](=[O:16])[C:7]2[CH:13]=[CH:12][C:11]([O:14]C)=[N:10][C:8]=2[N:9]=1)[CH3:2].Cl.N1C=CC=CC=1.Cl>CN(C)C=O>[CH2:1]([S:3][C:4]1[N:5]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:27])([F:28])[F:26])=[CH:19][CH:18]=2)[C:6](=[O:16])[C:7]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1)[CH3:2]
Reactant: CCSc1nc2nc(OC)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCSc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 94.6 %

Procedure:
A mixture of 2-(ethylsulfanyl)-7-methoxy-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidin-4(3H)-one (150 mg), pyridine hydrochloride (1156 mg) and N,N-dimethylformamide (1 ml) was stirred at 120° C. for 15 min. The reaction mixture was poured into 0.2M hydrochloric acid (10 ml), and the precipitated white solid was collected by filtration, and washed with water. The obtained solid was dissolved in tetrahydrofuran (5 ml), and the solution was diluted with ethyl acetate (70 ml), washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (137 mg) as a white solid.
Reaction SMILES: [C:1]1([CH:7]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][C:9](O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:21])=O.C([O-])(=O)C.[Na+].CN(C)[CH:31]=[O:32]>>[Cl:21][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[S:12][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]=1[CH:31]=[O:32]
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)CC(Sc1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=CC1=C(Cl)c2ccccc2SC1c1ccccc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 1.3 g 3-phenyl-3-phenylmercapto-propionic acid and 4ml phosphorous oxychloride is stirred under nitrogen at 70° C. for four hours. The reaction mixture is then cooled to 4° C. with an ice bath and 4 ml dimethylformamide is added. Stirring is maintained at room temperature for five hours. After cooling with an ice bath, 30 ml of a cooled saturated sodium acetate aqueous solution is added. After a few minutes stirring, the reaction mixture is extracted with methylene chloride, the organic layer washed with a saturated sodium bicarbonate aqueous solution then with water, dried over magnesium sulfate, filtered and evaporated to dryness. The residual oil is purified by column chromatography and pure yellow 4-chloro-3-formyl-thioflav-3-ene is obtained which crystallised after a few days; m.p. 63°-65° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]([OH:16])=O)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[CH3:28][NH2:29]>>[CH:1]1([C:4]2[C:5]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:14](=[O:16])[NH:29][CH3:28])[C:17]([CH3:19])([CH3:20])[CH3:18])=[O:11])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(=O)O
Reactant: CN
Agent: Cl
Product: CNC(=O)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoic acid (Example 194b) and methanamine hydrochloride as starting materials and isolated (114 mg, 96%) as a racemate; MS (ESI, m/z): 388.6 (M+H+).
Reaction SMILES: [CH:1]#[C:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH:10]([O:12][CH2:13][CH3:14])=[CH2:11].O>O1CCOCC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:10]([O:12][CH:13]([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1)[CH3:14])[CH3:11].[OH:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1
Reactant: C#Cc1ccc(O)cc1
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OC(C)OCC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.5 %

Procedure:
A solution of poly(p-hydroxystyrene) (8.0 g) [MARUKA LYNCUR-M, manufactured by Maruzene Petrochemical Co., Ltd., having Mw 10000 and Mn 5000], ethyl vinyl ether (3.0 g) and pyridinium p-toluenesulfonate (0.5 g) in dioxane (70 ml) was reacted with stirring at room temperature for 24 hours. After reaction, the mixture was poured into H2O, was precipitated with stirring, and the precipitate was filtered, washed with H2O and then dried in vacuo. There was obtained 10.0 g of the desired product as a white powder having Mw 11000 (GPC with polystyrene calibration). The polymer was found to have p-(1-ethoxyethoxy)styrene unit and p-hydroxystyrene unit in a molar ratio of ca. 1:1 based on 1HNMR.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]2([CH2:15][CH2:14][C:13](=[O:16])[C:12]3[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=3[NH:10]2)[CH2:6][CH2:5]1)(=O)C>Cl.[OH-].[Na+]>[NH:4]1[CH2:9][CH2:8][C:7]2([CH2:15][CH2:14][C:13](=[O:16])[C:12]3[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=3[NH:10]2)[CH2:6][CH2:5]1
Reactant: CC(=O)N1CCC2(CCC(=O)c3ccccc3N2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCC2(CCNCC2)Nc2ccccc21
Temperature: 85 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
Acetate 10 (20 mg, 0.072 mmoles) was dissolved in 2 N HCl (0.31 mL) and heated to 85° C. After 3 h, the reaction mixture was diluted with 5 N NaOH to a pH˜11 and extracted with CH2Cl2 (3×3 mL). The combined organic layers were dried over Na2SO4 and concentrated to afford 11 (16.2 mg, 0.071 mmoles, 96%) as a colorless oil. 1H NMR (CDCl3) δ 7.83 (1H, dd, J=1.7, 7.6 Hz), 7.32 (1H, ddd, J=2.2, 8.1, 9.1 Hz), 6.93 (1H, m), 6.77 (1H, d, J=7.9 Hz), 3.76 (1H, d, J=7.9 Hz), 3.98 (1H, s), 2.83 (6H, m), 1.31 (2H, m), 1.64 (5H, m); IR (thin film, NaCl) 3290, 2964, 1716, 1664, 1422 cm−1; LRMS: M+=230.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[S:6][CH:7]=1>CS(C)=O.C(N(CC)CC)C.C(OCC)(=O)C>[CH3:19][O:18][C:10]1[CH:9]=[C:8]([C:5]2[S:6][CH:7]=[C:3]([CH:2]=[O:1])[N:4]=2)[CH:13]=[C:12]([O:14][CH3:15])[C:11]=1[O:16][CH3:17]
Reactant: COc1cc(-c2nc(CO)cs2)cc(OC)c1OC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2nc(C=O)cs2)cc(OC)c1OC
Reaction time: 1 h

Procedure:
4-Hydroxymethyl-2-(3,4,5-trimethoxyphenyl)thiazole (1.53 g) was dissolved in a mixed solvent of DMSO (5 mL) and triethylamine (2.3 mL), and sulfur trioxide pyridine complex (98%, 3.09 g) was added portionwise to the solution at room temperature. After 1 hour, the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine and dried over anhydrous sodium sulfate. After concentrating the reaction mixture under reduced pressure, the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1 to 1:2) to obtain the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[CH:21][O:22][C:15]=3[CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][NH:24][CH3:25].[CH2:26]=O>C(O)(=O)C>[CH3:23][N:24]([CH2:26][C:21]1[O:22][C:15]2[CH2:14][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:19][CH2:18][CH2:17][C:16]=2[CH:20]=1)[CH3:25]
Reactant: C=O
Reactant: c1ccc(CCCCCCN2CCCc3ccoc3C2)cc1
Reactant: CNC
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(CCCCCCc1ccccc1)CCC2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.945 g (3.18 mmol) of 7-(6-phenylhexyl)-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepine in 20 ml of acetic acid, 0.34 g (3.8 mmol) of 50% aqueous dimethylamine and 0.31 g (3.8 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 30 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.