Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:4].[CH3:19][S:20]([NH:23][C:24]1[CH:39]=[CH:38][C:27]2[NH:28][C:29]([CH2:34][C:35](O)=[O:36])=[N:30][S:31](=[O:33])(=[O:32])[C:26]=2[CH:25]=1)(=[O:22])=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[N:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:35](=[O:36])[CH2:34][C:29]1[NH:28][C:27]2[CH:38]=[CH:39][C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:25][C:26]=2[S:31](=[O:32])(=[O:33])[N:30]=1)=[O:4]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: COC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCC[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.4 %

Procedure:
(1R,2S)-2-(4-Fluoro-benzylamino)-cyclopentanecarboxylic acid methyl ester (106 mg, 0.42 mmol) and (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 140 mg, 0.42 mmol) were dissolved in a 1:1 mixture of dichloromethane and N,N′-dimethylformamide (6 mL). A 1.0 M solution of N,N′-dicyclohexylcarbodiimide in dichloromethane (0.46 mL, 0.46 mmol) was added. The reaction was stirred at 25° C. for 16 h. The mixture was concentrated in vacuo and purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 0-85% ethyl acetate in hexanes) to afford the desired product, (1R,2S)-2-{(4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid methyl ester (127 mg, 0.22 mmol, 52%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.80-2.22 (6H, m), 3.07 (3H, s), 3.24 (1H, dd, J1=18.8 Hz, J2=8.0 Hz), 3.32 (1H, dd, J1=15.6 Hz, J2=8.0 Hz), 3.69 (1H, s), 4.63 (2H, d, J=4.8 Hz), 4.67-4.74 (1H, m), 4.82-4.89 (1H, m), 6.99-7.14 (5H, m), 7.51-7.64 (2H, m). LC-MS (ESI) calcd for C24H27FN4O7S2 566.62, found 567.1 [M+H+].
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:15](=O)[CH2:16][N:17]([CH3:28])[C:18](=[O:27])/[CH:19]=[CH:20]/[C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].[NH2:30][OH:31].O>CCCCCC.C(OCC)(=O)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:15](=[N:30][OH:31])[CH2:16][N:17]([CH3:28])[C:18](=[O:27])/[CH:19]=[CH:20]/[C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: NO
Reactant: COc1ccc(C(=O)CN(C)C(=O)/C=C/c2cccnc2)cc1OC
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(CN(C)C(=O)/C=C/c2cccnc2)=NO)cc1OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 51.2 %

Procedure:
Acetic acid (3 ml) was added to (E)-N-[2-(3,4-dimethoxyphenyl)-2-oxoethyl]-N-methyl-3-(3-pyridyl)-2-propenoic acid amide (165 mg, 0.5 mmol) and allowed to stand at −20° C. After acetic acid was solidified, 50% aqueous hydroxylamine solution (0.62 ml, 10 mmol) was added under ice-cooling and reacted at the same temperature. After warming to room temperature and reacting for further 22 hours, water (10 ml) and ethyl acetate (10 ml) were added and extracted three times with ethyl acetate (10 ml). The organic layer was washed sequentially with water (40 ml) and aqueous saturated sodium chloride solution (40 ml) and dried over anhydrous magnesium sulfate (10 g). The drying agent was removed out and the filtrate was concentrated. The resulting dry product was purified by a column chromatography using silica gel (20 g) (elution with dichloromethane: methanol=100:3.5). After purification, the product was recrystallized in ethyl acetate (5 ml) and n-hexane (15 ml) to yield the titled compound (91 mg, yield 51%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)=O)=[CH:4][C:3]=1[F:17].[C:18]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[F:17]
Reactant: O=C1CCCCCC1
Reactant: O=C(c1cccc(O)c1)c1ccc(Br)c(F)c1
Product: Oc1cccc(C(=C2CCCCCC2)c2ccc(Br)c(F)c2)c1
Yield: 93 %

Procedure:
The general McMurry protocol, described for 14 was followed. Reaction of (4-bromo-3-fluorophenyl)(3-hydroxyphenyl)methanone (196 (0.860 g, 2.3 mmol) and cycloheptanone (0.814 mL, 6.87 mmol) afforded 0.80 g, (93%) of the title compound 197 as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.89 (app t, J=7.5 Hz, 1H), 7.17 (app t, J=7.8 Hz, 1H), 6.96 and 6.92 (dd, J1=9.6 Hz, J2=1.8 Hz, 1H), 6.86 and 6.84 (dd, J1=8.1 Hz, J2=1.8 Hz, 1H), 6.73 (app br d, J=8.1 Hz, 1H), 6.70 and 6.68 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 6.61 (app t, J=1.8 Hz, 1H), 4.86 (s, 1H), 2.31 (br s, 4H), 1.59 (br s, 8H).
Reaction SMILES: [CH3:1][NH:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([F:14])[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4]1.[CH2:22]=[O:23]>O>[OH:23][CH2:22][N:2]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([F:14])[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4]1)[CH3:1]
Reactant: C=O
Reactant: CCOC(=O)c1cn(NC)c2c(F)c(F)c(F)cc2c1=O
Solvent: O
Product: CCOC(=O)c1cn(N(C)CO)c2c(F)c(F)c(F)cc2c1=O
Temperature: 100 °C

Procedure:
A suspension of ethyl 1-methylamino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (10 g) in water (100 ml) and 37% aqueous formaldehyde (100 ml) was heated to 100° C. for 1 hour. The mixture was cooled and the solid removed by filtration and washed with water. The resulting yellow colored solid was dried to constant weight in vacuo over phosphorus pentaoxide to yield ethyl 1-[N-(hydroxymethyl)-N-methylamino]-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (10.25 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:24]=[C:25]([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH:26]=1)[NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:36][C:37]([S:44][S:45][CH3:46])([CH3:43])[CH2:38][CH2:39][C:40](O)=[O:41].C(Cl)CCl>ClCCl.CN(C1C=CN=CC=1)C.O>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:13]([CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[C:40](=[O:41])[CH2:39][CH2:38][C:37]([CH3:43])([S:44][S:45][CH3:46])[CH3:36])[CH:24]=[C:25]([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])[CH:26]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: COCCOCCOCCNc1cc(CO[Si](C)(C)C(C)(C)C)cc(CO[Si](C)(C)C(C)(C)C)c1
Reactant: CSSC(C)(C)CCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: COCCOCCOCCN(C(=O)CCC(C)(C)SSC)c1cc(CO[Si](C)(C)C(C)(C)C)cc(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 47.8 %

Procedure:
To a mixture of 3,5-bis((tert-butyldimethylsilyloxy)methyl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)aniline (267a) (525 mg, 0.995 mmol) and 4-methyl-4-(methyldisulfanyl)pentanoic acid (232 mg, 1.193 mmol) in anhydrous dichloromethane (9.0 mL) was added EDC (229 mg, 1.193 mmol) and DMAP (12.15 mg, 0.099 mmol). The reaction was stirred at room temperature for five hours. The mixture was diluted with dichloromethane and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (30% Ethyl acetate/Hexanes) gave N-(3,5-bis((tert-butyldimethylsilyloxy)methyl)phenyl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-4-methyl-4-(methyldisulfanyl)pentanamide (267b) (335 mg, 48%).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([CH2:12][O:13]S(C)(=O)=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:18]([C:21]1[CH:22]=[C:23](O)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)([O-:20])=[O:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C([O-])(O)=O.[Na+].CCOC(C)=O>[C:1]([N:8]1[CH2:11][CH:10]([CH2:12][O:13][C:23]2[CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(COc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-Boc-3-methylsulfonyloxymethyl-azetidine (1.47 g), 3-nitro-5-trifluoromethyl-phenol (1.15 g) and K2CO3 (1.15 g) in DMF (20 ml) at 80° C. was stirred overnight. The reaction was cooled to RT and diluted with 25 mL of sat. NaHCO3 and 50 mL of EtOAc. The organic phase was separated and washed with brine (25 mL), dried over Na2SO4 and concentrated in vacuo. The crude compound was purified by column chromatography (50% EtOAc/hex).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:19][CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[N:23]([O:28][CH3:29])[C:22]([CH3:31])([CH3:30])[CH2:21]1.N1C=CC=CC=1.CO>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([O:19][CH:20]1[CH2:25][C:24]([CH3:26])([CH3:27])[N:23]([O:28][CH3:29])[C:22]([CH3:31])([CH3:30])[CH2:21]1)=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CON1C(C)(C)CC(O)CC1(C)C
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Solvent: CO
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CON1C(C)(C)CC(OC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CC1(C)C
Reaction time: 1 h
Yield: 61 %

Procedure:
A solution of 7.6 g (28.3 mmol) of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in toluene (35 ml) is added dropwise over 20 minutes to a solution of 5.3 g (28.3 mmol) of 4-hydroxy-1-methoxy-2,2,6,6-tetramethylpiperidine and 2.46 g (31.1 mmol) of pyridine in toluene (30 ml). The reaction temperature is kept below 60° C. during the addition and the reaction mixture is stirred for one hour at 55°-60° C. after the addition and then filtered. The filtrate is washed with 1N HCl (2×50 ml), water (100 ml), saturated NaHCO3 (100 ml), dried (magnesium sulfate), and concentrated. The crude oil is chromatographed on silica gel (9:1 hexane:ethyl acetate) to obtain 7.3 g (61% yield of a white crystalline solid, m.p. 126°-8° C. (methanol).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[Br:11]N1C(=O)CCC1=O.O.BrC1C=CC(C(C)C)=CC=1O>C(=S)=S>[Br:11][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[OH:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1cccc(O)c1
Agent: CC(C)c1ccc(Br)c(O)c1
Solvent: S=C=S
Solvent: O
Product: CC(C)c1cccc(O)c1Br
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a solution of 3-isopropylphenol (10.0 g, 73.4 mmol) in carbon disulfide (200 mL) was slowly added N-bromosuccinimide (13.1 g, 73.4 mmol) with ice-cooling, and the mixture was stirred for 1 hour. The reaction solution was stirred at room temperature for 1 hour, and then water was added thereto, which was extracted with ethyl acetate. The combined organic layer was washed with water and a saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=15:85) to obtain a mixture of 2-bromo-5-isopropylphenol and 2-bromo-3-isopropylphenol (3:1) 11.0 g (yield 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:25])[C:7]3[C:14](=[O:15])[N:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)[C:12](=[O:24])[C:8]=3[NH:9][C:10]=2[CH:11]=1.CS(O)(=O)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:25])[C:7]3[C:14]([OH:15])=[N:13][N:16]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)[C:12](=[O:24])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: O=C1c2[nH]c3cc(Cl)ccc3c(=O)c2C(=O)N1Nc1ccc(F)cc1
Agent: CS(=O)(=O)O
Solvent: CO
Product: O=c1c2ccc(Cl)cc2[nH]c2c(=O)n(-c3ccc(F)cc3)nc(O)c12
Temperature: 25 °C
Yield: 26.7 %

Procedure:
A stirred suspension of 6-chloro-2-(4-fluoroanilino)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (1.40 g, 3.90 mM) in a solution of methanol (0.73 L) and methanesulfonic acid (73 mL) was refluxed for 16 hour s and cooled to room temperature. The resulting orange suspension was filtered (the filtrate was saved for use in Example 26) and the collected solids were washed successively with methanol and ether to give the title compound (0.374 g, 27%) as a light orange powder, mp>400° C.; MS(CI): 358 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:13][C:12]([F:15])([F:14])[CH2:11][NH:10][C@@H:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:20][C:21]1[CH:28]=[C:27]([C:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH:34]=2)[CH:26]=[C:25]([CH3:35])[C:22]=1[C:23]#[N:24].CN(C)C=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[C:23]([C:22]1[C:25]([CH3:35])=[CH:26][C:27]([C:29]2[CH2:34][CH2:33][N:32]([C:16]([C@@H:9]3[C@@H:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][C:12]([F:14])([F:15])[CH2:11][NH:10]3)=[O:18])[CH2:31][CH:30]=2)=[CH:28][C:21]=1[CH3:20])#[N:24]
Reactant: CC(C)(C)OC(=O)[C@H]1CC(F)(F)CN[C@@H]1C(=O)O
Reactant: Cc1cc(C2=CCNCC2)cc(C)c1C#N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C2=CCN(C(=O)[C@H]3NCC(F)(F)C[C@@H]3C(=O)OC(C)(C)C)CC2)cc(C)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2S,3S)-3-(tert-butoxycarbonyl)-5,5-difluoropiperidine-2-carboxylic acid (48 mg, 0.00018 mol) and 2,6-dimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile hydrochloride (84.7 mg, 0.000217 mol) TFA salt in N,N-dimethylformamide (0.406 mL, 0.00524 mol) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (96.0 mg, 0.000217 mol), followed by N,N-diisopropylethylamine (0.0756 mL, 0.000434 mol). The mixture was stirred at rt overnight, then quenched with aq. sodium bicarbonate. The mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried, and evaporated to dry. The residue was used directly in next step without further purification. LCMS (M+H) 460.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.C(N(CC)CC)C.[C:18](Cl)(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>ClCCl>[C:18]([CH:6]1[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:5])(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Meldrum's acid (7.20 g, 50 mmol) and triethyl amine (5.56 g, 55 mmol) were dissolved in dichloromethane (50 mL), and decanoic acid chloride (10.48 g, 55 mmol) was added to the resulting mixture dropwise while cooling with ice. The reaction mixture was stirred at room temperature for about 12 hours, and then concentrated under reduced pressure. The ethyl acetate layer thus obtained was washed with diluted hydrochloric acid and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified using silica gel chromatography (developing solvent: n-hexane/ethyl acetate=3/7) to obtain 5-decanoyl-2,2-dimethyl-1,3-dioxane-4,6-dione.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[CH2:16][C:15](=[O:19])[NH:14][C:13]2[C:20]3[C:25]([CH:26]=[CH:27][C:12]1=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].[I:40][C:41]1[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=1C(Cl)=O>ClCCl>[I:40][C:41]1[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=1[C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[CH2:16][C:15](=[O:19])[NH:14][C:13]2[C:20]3[C:25]([CH:26]=[CH:27][C:12]1=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:7]
Reactant: CC(C)(C)OC(=O)NCCN1C(=O)CC(=O)Nc2c1ccc1ccccc21
Reactant: O=C(Cl)c1ccccc1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(=O)N(CCNC(=O)c2ccccc2I)c2ccc3ccccc3c2N1
Temperature: 25 °C
Reaction time: 19 h
Yield: 41.9 %

Procedure:
5-[2-(tert-Butoxycarbonyl)aminoethyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (16 mg, 0.043 mmol) was dissolved in dichloromethane (4 mL), the solution was added with trifluoroacetic acid (0.1 mL), and the mixture was stirred at room temperature for 19 hours. This reaction mixture was added with saturated aqueous sodium hydrogencarbonate (8 mL) with stirring under ice cooling, and the mixture was stirred for 5 minutes. Further, the mixture was added with 2-iodobenzoyl chloride (0.22 mmol) dissolved in dichloromethane (4 mL) with stirring under ice cooling. This reaction mixture was stirred under ice cooling for 30 minutes, and then at room temperature for 30 minutes. The dichloromethane layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (methanol/chloroform=1/50), and then recrystallized from ethyl acetate/hexane to give the title compound (9 mg, yield 42%) as white crystals. The structure was confirmed by NMR and MS.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C([O-])(=O)C.[Na+].Cl.Cl[CH:12]([C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[O:21])[C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>O1CCCC1.O>[NH2:1][C:2]1[S:3][C:12]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[O:21])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:4]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=O)C(Cl)C(=O)c1ccccn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N)sc1C(=O)c1ccccn1
Reaction time: 2 h
Yield: 20.7 %

Procedure:
To a solution of thiourea (4.5 g) and sodium acetate (5 g) in a mixture of tetrahydrofuran (50 ml) and water (15 ml) was added ethyl 3-chloro-4-(2-pyridyl)-2,4-dioxo-butyrate hydrochloride (5.6 g). After the mixture was stirred at 45° C. to 50° C. for 2 hours, water (50 ml) was added thereto. The resulting mixture was acidified to pH 1.0 with 10% hydrochloric acid. The precipitate was collected by filtration. The precipitate was added to a mixture of water and ethyl acetate, and adjusted to pH 6.0 with 10% potassium carbonate. The separated ethyl acetate layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give ethyl 2-amino-5-(2-pyridinecarbonyl)-4-thiazolecarboxylate (1.1 g).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:20](=[O:22])[CH3:21])[C:10]([O:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:11][CH:12]=2)[O:7][C:6](=[O:23])[CH:5]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35])[CH:29]=O>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:20](=[O:22])[CH:21]=[CH:29][C:28]3[CH:31]=[C:32]([O:36][CH3:37])[C:33]([O:34][CH3:35])=[C:26]([O:25][CH3:24])[CH:27]=3)[C:10]([O:14][CH2:15][CH:16]=[C:17]([CH3:18])[CH3:19])=[CH:11][CH:12]=2)[O:7][C:6](=[O:23])[CH:5]=1
Reactant: CC(=O)c1c(OCC=C(C)C)ccc2c(C)cc(=O)oc12
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(C=CC(=O)c2c(OCC=C(C)C)ccc3c(C)cc(=O)oc23)cc(OC)c1OC
Temperature: 25 °C
Yield: 37.3 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-(3-methylbut-2-enyloxy)-8-acetylcoumarin (2.14 g, 0.0075 mol) and 3,4,5-trimethoxy-benzaldehyde (1.47 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified. The precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 1.3 g of product m.p. 148-150° C., 1H-NMR (CDCl3) δ: 1.69 (s, 3H,); 1.72 (s, 3H); 2.44 (d, 3H, J=1.2 Hz); 3.74-3.88 (m, 9H); 4.65 (d, 2H, J=6.5 Hz); 5.34-5.38 (m, 1H); 6.16 (s, 1H); 6.93 (d, 1H, J=16 Hz); 6.95 (d, 1H, J=8.9 Hz); 7.25 (d, 1H, J=16 Hz); 7.63 (d, 1H, J=8.9 Hz).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9](O)[CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].S(Cl)([Cl:23])=O.O>C(Cl)(Cl)Cl>[Cl:23][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=1)[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCc1ccc(C(Cl)COc2ccc(C=O)cc2)nc1
Yield: 76.7 %

Procedure:
To a stirred solution of 5 g (0.018 mol) 4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde dissolved in chloroform was added 2.63 g (0.022 mol) thionyl chloride at 55-60° C. Reaction mixture was refluxed for 1 hr. Progress of the reaction was monitored by TLC and after completion of reaction, subsequent work-up in alkaline water yielded 4 g (75%) of the desired product.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:9]=1)=[O:7])(C)(C)C.O1CCCC1.O.C(OCC)(=O)C>CCCCCC>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=3)[CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:11][C:12]=1[OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 99.8 %

Procedure:
To a stirred solution 5-benzyloxy-6-hydroxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-pyrimidine-4-carboxylic acid tert-butyl ester (243) (250 mg, 0.53 mmol) in the mixture of tetrahydrofuran-water (2:1, 10 mL) was added lithium-hydroxide monohydrate (477 mg, 11.36 mmol) and the reaction mixture was refluxed for 20 h. Very small amounts of the starting ester remained. Silica thin layer chromatography was performed (50% ethyl acetate in hexane, Rf=0.1). Volatiles were evaporated, water added (10 mL) and the aqueous part was extracted with ethyl acetate (2×3 0 mL). The ethyl acetate part was thereafter discarded and the aqueous part was acidified with 1N HCl to a pH of about 5-6. The acidified aqueous part was extracted with ethyl acetate (3×30 mL), dried and concentrated to get 5-benzyloxy-6-hydroxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-pyrimidine-4-carboxylic acid (244) (250 mg, 93.13%) as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[O:10][C:11]=1[CH3:12].[C:18](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:17][N:5]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[O:10][C:11]=2[CH3:12])=[C:2]([CH3:18])[CH:3]=[N:4]1
Reactant: COC(=O)c1cc(-c2c(Br)cnn2C)c(C)o1
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2c(C)cnn2C)c(C)o1
Yield: 60.5 %

Procedure:
A solution of methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate (130 mg, 0.43 mmol), potassium carbonate (300 mg, 2.17 mmol), PdCl2(dppf) (15.9 mg, 0.02 mmol) and trimethylboroxine (0.12 ml, 0.87 mmol) in N,N-Dimethylformamide (3.5 ml) was stirred at 110° C. in a sealed tube for 2 h. The reaction mixture was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate (60 mg, 0.26 mmol, 59% yield) as a yellow oil: LCMS (ES) m/z=235 (M+H)+.