Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4](P(OCC)(OCC)=O)[CH2:5][CH3:6].[H-].[Na+].[C:18]([O:22][C:23]([C:25]1[S:26][C:27]([CH:30]=O)=[CH:28][CH:29]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1>[C:18]([O:22][C:23]([C:25]1[S:26][C:27](/[CH:30]=[C:4](/[C:3]([O:2][CH3:1])=[O:15])\[CH2:5][CH3:6])=[CH:28][CH:29]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)s1
Reactant: CCOP(=O)(OCC)C(CC)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC/C(=C\c1ccc(C(=O)OC(C)(C)C)s1)C(=O)OC
Reaction time: 0.5 h
Yield: 80 %

Procedure:
2-(Diethylphosphono)butyric acid methyl ester (46 g, 0.193 mol) was dissolved in tetrahydrofuran (300 mL), 60% sodium hydride (6.6 g, 0.165 mol) was added at 0° C., and the mixture was stirred for 30 minutes. To the reaction mixture was added a solution of 5-formyl-2-thiophenecarboxylic acid tert-butyl ester obtained in Example 1, step 2 (32.1 g, 0.15 mol) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was partitioned between ethyl acetate and 1N-hydrochloric acid solution, and washed successively with water and brine. After drying over anhydrous magnesium sulfate, the residue was purified by silica gel column chromatography to give the title compound (35.6 g, 0.12 mol, 80%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:32])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:31])(=[O:30])[NH2:29])=[CH:24][CH:23]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.CCN(C(C)C)C(C)C>>[NH:2]=[C:1]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:32])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:30])(=[O:31])[NH2:29])=[CH:24][CH:23]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)Nc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)Nc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCOCC1
Yield: 31.6 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylphenyl)benzenesulfonamide following procedure C and using 1 equivalent of morpholine as secondary amine and 0.5 equivalent of DIEA as base. The product was purified by preparative HPLC.
Reaction SMILES: [CH2:1]([C:8](=[CH2:13])[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][NH:15][CH3:16]>CO>[CH2:1]([CH:8]([CH2:13][N:15]([CH3:16])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: C=C(Cc1ccccc1)C(=O)OC
Solvent: CO
Product: COC(=O)C(Cc1ccccc1)CN(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 30.0 g of methyl α-benzylacrylate, prepared by the method of R. B. Miller and B. F. Smith, Synth. Commun. 3, 359 (1973) in methanol (50 ml) is added to a solution of dimethylamine (71.0 g) in methanol (210 ml), and the mixture is stirred at room temperature for 48 hours. The solvent is removed under reduced pressure to give methyl 2-benzyl-3-dimethylaminopropionate as a yellow oil, used without purification in the next synthetic step; NMR: δ7.14 (s, 5H), 3.52 (s, 3H), 2.82 (m, 3H), 2.17 (s, 6H), 2.63-2.17 (m, remaining H).
Reaction SMILES: [CH3:1][C:2]([S:18]([CH3:21])(=[O:20])=[O:19])([CH3:17])[CH2:3][C:4]1[N:8]([CH2:9][CH2:10][CH3:11])[N:7]=[C:6]([C:12](OCC)=[O:13])[CH:5]=1.[NH3:22]>CO>[CH3:1][C:2]([S:18]([CH3:21])(=[O:20])=[O:19])([CH3:17])[CH2:3][C:4]1[N:8]([CH2:9][CH2:10][CH3:11])[N:7]=[C:6]([C:12]([NH2:22])=[O:13])[CH:5]=1
Reactant: N
Reactant: CCCn1nc(C(=O)OCC)cc1CC(C)(C)S(C)(=O)=O
Solvent: CO
Product: CCCn1nc(C(N)=O)cc1CC(C)(C)S(C)(=O)=O
Temperature: 150 °C

Procedure:
A pressure vessel containing ethyl 5-[2-methyl-2-(methylsulfonyl)propyl]-1-propyl-1H-pyrazole-3-carboxylate (9.4 g, 29.7 mmol) and ammonia (50 mL of a 7 N solution in methanol), and the vessel was sealed and heated at 150° C. for 41 hours and allowed to cool to room temperature. The volatiles were removed under reduced pressure to provide 8.5 g of 5-[2-methyl-2-(methylsulfonyl)propyl]-1-propyl-1H-pyrazole-3-carboxamide as a brown oil.
Reaction SMILES: [C:1](=[N:9][NH2:10])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[CH2:11]([N:14]=[C:15]=[S:16])[CH:12]=[CH2:13]>CO>[CH3:2]/[C:1](/[C:3]1[N:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[N:9]/[NH:10][C:15]([NH:14][CH2:11][CH:12]=[CH2:13])=[S:16]
Reactant: C=CCN=C=S
Reactant: CC(=NN)c1ccccn1
Solvent: CO
Product: C=CCNC(=S)N/N=C(/C)c1ccccn1
Yield: 53.3 %

Procedure:
A solution of 2.7 g (0.02 mol) of 2-acetylpyridine hydrazone in 5 ml of MeOH was treated with 3.1 g (0.03 mol) of allyl isothiocyanate and the solution was heated at reflux for 3 hours. The solution was cooled and the product which formed was collected. The crude material was recrystallized 3 times from MeOH, affording 2.5 g (49%) of white needles of 2-acetylpyridine 4-allyl-3-thiosemicarbazone, mp 107° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][CH:16]=2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[NH2:26][CH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1.[K+].C(#N)C.CO>C(OCC)(=O)C>[S:15]1[CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:26][CH:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][CH2:28]3)=[CH:7][CH:8]=2)[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]1=2
Reactant: BrCCCOc1ccc(-c2csc3ccccc23)cc1
Reactant: NC1CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)CCC2NCCCOc1ccc(-c2csc3ccccc23)cc1

Procedure:
The title compound is prepared from 3-[4-(3-bromo-propoxy)-phenyl]-benzo[b]thiophene, 1-aminoindan potassium carbonate and acetonitrile essentially as described above in Example 118 except that the column chromatography is performed with a graded solvent mixture from 100% ethyl acetate to 10% methanol in ethyl acetate. Purity by LC/MS=100%, [M+H]+=400.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.C=O.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:24][CH2:25][N:26]([CH3:31])[CH2:27][CH2:28]3)=[CH:21][CH:22]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(N2CCNCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1CCN(c2ccc(-c3oc(-c4c(F)cccc4F)nc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
To a stirred suspension of 2-(2,6-difluorophenyl)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide (0.025 g, 0.065 mmol) in DCE (2 mL) under an N2 atmosphere at room temperature was added formaldehyde 37% solution (10 uL, 0.12 mmol) followed by sodium triacetoxyborohydride (0.066 g, 0.31 mmol) and the resulting mixture stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM and washed with saturated sodium bicarbonate solution. The aqueous phase was extracted with DCM and the combined organic phases dried over MgSO4 and the solvent removed in vacuo to afford 2-(2,6-difluorophenyl)-5-(4-(4-methylpiperazin-1-yl)phenyl)oxazole-4-carboxamide (0.019 g, 0.048 mmol, 72%) as a white solid. 1H NMR (CDCl3) 2.36 (3H, s), 2.57 (4H, t), 3.34 (4H, t), 5.49 (1H, br. s), 6.97 (2H, d), 7.07 (2H, t), 7.19 (1H, br. s), 7.45 (1H, m), 8.31 (2H, d). LCMS (2) Rt: 2.75 min; m/z (ES+) 399.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[NH:11])OCC)=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:3]=1[C:20]#[N:21].Cl.Cl.N[CH:25]([CH2:30][NH2:31])[C:26]([O:28][CH3:29])=[O:27]>C(O)C>[Br:1][C:2]1[S:6][C:5]([C:7]2[NH:11][CH:25]([C:26]([O:28][CH3:29])=[O:27])[CH2:30][N:31]=2)=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:3]=1[C:20]#[N:21]
Reactant: CCOC(=N)c1sc(Br)c(C#N)c1-c1ccc(Cl)cc1Cl
Reactant: COC(=O)C(N)CN
Agent: Cl
Solvent: CCO
Product: COC(=O)C1CN=C(c2sc(Br)c(C#N)c2-c2ccc(Cl)cc2Cl)N1
Temperature: 80 °C
Reaction time: 4 h
Yield: 35.6 %

Procedure:
To a solution of ethyl 5-bromo-4-cyano-3-(2,4-dichlorophenyl)thiophene-2-carboximidoate (0.548 g, 1.36 mmol) in ethanol (26 mL) was added methyl 2,3-diaminopropanoate dihydrochloride (0.313 g, 1.64 mmol). The solution was stirred at 80° C. for 4 hours. The solvent was evaporated, and column chromatography was performed to yield the title compound (0.222 g, 36%). LCMS: (FA) ES+ 460. 1H NMR (400 MHz, d4-methanol) 7.70 (s, 1H), 7.55-7.43 (m, 2H), 3.76-3.66 (m, 4H), 1.36-1.26 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1)CCC>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1)[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: O=Cc1cc2cccc(Cl)c2nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=Cc1cc2cccc(Cl)c2nc1-c1cnccn1
Temperature: 110 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A mixture of 2,8-dichloroquinoline-3-carbaldehyde (2.3 g, 10.18 mmol), 2-(tributylstannanyl)pyrazine (4.5 g, 12.2 mmol) and tetrakis(triphenylphosphine)-palladium(0) (0.4 g, 0.35 mmol) in 1,4-dioxane (25 mL) was degassed and the mixture was heated under nitrogen at 110° C. for 5 h. The mixture was allowed to cool to room temperature overnight and the solidified product was collected by filtration and washed repeatedly with ether. The filtrate was concentrated and left in a refrigerator for 2 h to give a second crop, which was filtered, washed with ether and combined with the bulk material to give the title compound (2.74 g, 99%) as a yellow crystalline solid. LCMS (ES+) 270 (M+H)+, RT 1.41 minutes.
Reaction SMILES: [CH2:1]([N:13]1[CH2:17][C@H:16]([OH:18])[CH2:15][C@H:14]1[C:19]([O:21][CH3:22])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[I:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1.C(N(CCOC1C=CC(CCC(OC)=O)=CC=1)C)CCCCCCCCCCC>>[CH2:1]([N:13]1[CH2:17][C@@H:16]([O:18][C:27]2[CH:28]=[CH:29][C:24]([I:23])=[CH:25][CH:26]=2)[CH2:15][C@H:14]1[C:19]([O:21][CH3:22])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN1C[C@H](O)C[C@H]1C(=O)OC
Reactant: Oc1ccc(I)cc1
Agent: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)OC)cc1
Product: CCCCCCCCCCCCN1C[C@@H](Oc2ccc(I)cc2)C[C@H]1C(=O)OC
Yield: 86.8 %

Procedure:
(2S, 4R)-1-N-Dodecyl-4-hydroxypyrrolidine-2-carboxylic acid, methyl ester (1.75 g, 7.94 mmol) and 4-iodophenol (2.26 g, 7.22 mmol) were reacted under Mitsunobu conditions as described in the preparation of 3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]phenyl]propanoic acid, methyl ester. The residue was chromatographed on silica gel (hexane/ethyl acetate 15:1 to 10:1) to afford the title compound (3.23 g, 79%) as a white solid. [a]D=−30.8° (c 1.0, CHCl3)
Reaction SMILES: C1(C(C2C=CC=CC=2)([C@H]2CCCN2)O)C=CC=CC=1.[Br:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:26]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:25]=1)=[O:23].S(C)C.C1COCC1.Br>C1(C)C=CC=CC=1.CB1OB(C)OB(C)O1.C1COCC1>[Br:20][CH2:21][C@@H:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:26]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:25]=1)[OH:23]
Reactant: CS(=O)(=O)Nc1cc(C(=O)CBr)ccc1OCc1ccccc1
Agent: Br
Agent: CB1OB(C)OB(C)O1
Agent: OC(c1ccccc1)(c1ccccc1)[C@H]1CCCN1
Solvent: CSC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Yield: 89.1 %

Procedure:
A 25 mL round bottom flask with magnetic stirbar and toluene-filled Dean-Stark trap with reflux condenser and gas bubbler, was charged with (R)-α,α-diphenyl-2-pyrrolidinemethanol (1.13 g, 4.46 mmol) and trimethylboroxine (418 μL, 2.99 mmol) in toluene (11 mL) under N2. The reaction was stirred at ambient for ~30 minutes and then heated to reflux for 2.75 hours. Upon cooling, this solution was added to a stirred ~13° C. THF (185 mL) solution under N2 containing 2-bromo-1-[4-phenylmethoxy-3-[(methylsulfonyl)amino]phenyl]ethanone (14.25 g, 36 mmol) prepared as described in step F of Example 1. To this was added 5.2 mL of 10.1M BH3 -Me2S/THF (52 mmol) over ~5 minutes, keeping T≤-11.6° C. Upon completion of the reaction, HBr was bubbled through the solution until the pH was ~1 whereupon a solution of 50 mL MeOH in 100 mL methyl tert-butyl ether was carefully added. The mixture was washed with H2O (4×100 mL=400 mL) (until final wash had pH~4-5), diluted with EtOAc (50 mL), dried over Na2SO4. After solvent removal in vacuo, 12.84 g (90%) of crude title compound was obtained in 86% purity with an ee of 96.9%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:36]([O:38]C(C)(C)C)=[O:37])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(C(O)=O)=NC(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)=NC=1O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:10]([C:36]([OH:38])=[O:37])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[C:24]([C:32]([F:33])([F:34])[F:35])[CH:25]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:27]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCCC2)nc(O)c1OCc1ccccc1
Agent: O=C(O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Product: O=C(O)c1nc(CC2(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
5-(benzyloxy)-2-((1-(3,5-bis(trifluoromethyl)phenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-carboxylic acid (462) was synthesized as a white solid from tert-butyl 5-(benzyloxy)-2-((1-(3,5-bis(trifluoromethyl)phenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-carboxylate (461) following the procedure described for 5-benzyloxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (244).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([OH:22])[C:3]=1[O:23][CH3:24].[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[C:35](Cl)=[O:36].C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([O:22][C:35]([C:26]2[CH:27]=[CH:28][C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:25]=2)=[O:36])[C:3]=1[O:23][CH3:24]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1OC(=O)c1ccc2ccccc2c1
Reaction time: 2 h

Procedure:
3-(4-chloro-6-fluoro-2-hydroxy-3-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.10 g, 0.27 mmol) was dissolved in dioxane (10 ml) and the solution added with 2-naphthoyl chloride (0.062 g, 0.33 mmol), triethylamine (0.033 g, 0.33 mmol). After stirred for 2 hr, solvent was evaporated and the residue purified by column chromatography (silica gel, hexane/ether=4/1). Yield: 0.12 g, 0.23 mmol.
Reaction SMILES: [CH2:1]1[NH:6][C:4](=[O:5])[NH:3][CH2:2]1.[CH2:7]([N:9]([CH2:14][CH3:15])[S:10](Cl)(=[O:12])=[O:11])[CH3:8]>>[CH2:7]([N:9]([CH2:14][CH3:15])[S:10]([N:3]1[CH2:2][CH2:1][NH:6][C:4]1=[O:5])(=[O:12])=[O:11])[CH3:8]
Reactant: CCN(CC)S(=O)(=O)Cl
Reactant: O=C1NCCN1
Product: CCN(CC)S(=O)(=O)N1CCNC1=O

Procedure:
A mixture of 51.6 g of ethylene urea and 90 g of N,N-diethyl-sulphamoyl-chloride is heated at 110° for 3 hours. The reaction mixture is cooled and triturated with 300 ml of methanol, filtered and the filtrate evaporated off to dryness and the residue dissolved in 5% methanol in chloroform and chromatographed on a column of silica gel. That fraction which elutes with 5% methanol in chloroform is recrystallized from a mixture of methylenechlorid and hexane to give 1-(N,N-diethylsulphamoyl)-2-oxo-tetrahydroimidazole which melts at 80°-82°.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:19][O:20][C:21]1[CH:44]=[CH:43][C:24]([CH2:25][N:26]2[CH:30]=[C:29]([CH2:31][CH2:32][C:33](OC)=[O:34])[C:28]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[N:27]2)=[CH:23][CH:22]=1.O.Cl>C(OCC)C>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[CH2:19][O:20][C:21]1[CH:44]=[CH:43][C:24]([CH2:25][N:26]2[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][OH:34])[C:28]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[N:27]2)=[CH:23][CH:22]=1
Reactant: COC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCCO)c(-c3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
Lithium aluminium hydride (262 mg) was added to a solution of methyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (3.50 g) in diethyl ether (50 ml) at 0° C., and the mixture was stirred at 0° C. for one hour. After adding water, the reaction mixture was acidified with diluted hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propan-1-ol (3.04 g, yield: 92%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (3:2, volume ratio).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:10]([O:14][C:15](=[O:25])[NH:16][C:17]1[C:18]([CH:23]=O)=[N:19][CH:20]=[CH:21][CH:22]=1)([CH3:13])([CH3:12])[CH3:11].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:10]([O:14][C:15](=[O:25])[NH:16][C:17]1[C:18]([CH2:23][NH:9][CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:19][CH:20]=[CH:21][CH:22]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1C=O
Reactant: Cc1cccnc1CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CNCc1ncccc1NC(=O)OC(C)(C)C

Procedure:
Using General Procedure B: Reaction of C-(3-methyl-pyridin-2-yl)-methylamine and (2-formyl-pyridin-3-yl)-carbamic acid tert-butyl ester with NaBH(OAc)3 in CH2Cl2 gave (2-{[(3-Methyl-pyridin-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-carbamic acid tert-butyl ester as a yellow oil.
Reaction SMILES: [Si]([O:8][CH2:9]/[CH:10]=[CH:11]\[Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])(C(C)(C)C)(C)C>CO>[Si:12](/[CH:11]=[CH:10]\[CH2:9][OH:8])([C:15]([CH3:17])([CH3:18])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)/C=C\CO[Si](C)(C)C(C)(C)C
Solvent: CO
Product: CC(C)(C)[Si](C)(C)/C=C\CO

Procedure:
A mixture of 1.2 g, 4.2 mmol) of (Z)-O-(t-butyldimethylsilyl)-3-(t-butyldimethylsilyl)-2-propen-1-ol and 0.04 g of diisocyanate tetrabutylstannoxane [Otera, Nozaki, Tetrahedron Lett., 27, 5743 (1986)] in 140 ml of methanol is refluxed for 9 hours. Most of solvent is removed under reduced pressure and the residue is dissolved in a ether-water mixture. Etheral phase is washed with water and brine, dried with sodium sulfate, filtered and concentrated under reduced pressure to afford 0.7 g (quantitatif crude yield) of (Z)-3-(t-butyldimethylsilyl)-2-propen-1-ol as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:26])[CH:13]([CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14](=O)[CH3:15])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)(Cl)Cl>[CH2:9]([O:11][C:12]([C:13]1[CH:17]=[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=2)[C:14]=1[CH3:15])=[O:26])[CH3:10]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Reactant: Nc1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(F)c2)c1C

Procedure:
m-Fluoroaniline (5 mmol, 0.6 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid were combined in ethanol, then heated under reflux. The resulting solid was resuspended in chloroform, then washed with water, 5% sodium bicarbonate, and brine. The organic layer was dried over NaSO4, then the solids were separated and the solvents removed under vacuum. The named product was recrystallized from ethanol (m.p. 96.3° C.-98.0° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[F:15])[N:11]=[CH:10][CH:9]=[CH:8]2.N1C=CC=CC=1.[Br:23]Br>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[F:15])[N:11]=[CH:10][C:9]([Br:23])=[CH:8]2
Reactant: COC(=O)Cc1cc2cccnc2cc1F
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)Cc1cc2cc(Br)cnc2cc1F
Temperature: 25 °C
Yield: 73 %

Procedure:
To a mixture of (7-fluoro-quinolin-6-yl)-acetic acid methyl ester (14.0 g, 63.9 mmol) and pyridine (10.4 mL, 127.8 mmol) in 200 mL of carbon tetrachloride was added bromine (6.6 mL, 127.8 mmol) in a dropwise fashion. The mixture was heated to reflux for 2 hrs before being cooled to ambient temperature. The liquid in the flask was decanted and washed with NaHCO3 and water. The dark solid on the bottom of the flask was treated with NaHCO3 and dichloromethane. The combined organic layers were washed with water, dried (Na2SO4) and evaporated to dryness. The crude product was purified via flash column chromatography eluting with petroleum ether/ethyl acetate (40/1˜3/1) to return 13.9 g (75% yield) of the title compound as white crystalline solid. 1H NMR (DMSO-d6): δ 8.89 (s, 1H), 8.27 (m, 1H), 7.66˜7.74 (m, 2H), 3.87 (s, 2H), 3.74 (s, 3H).
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(N(CC)C(C)C)(C)C.[O:37]=[C:38]1[N:47]([CH2:48][CH2:49][CH3:50])[C:46](=[O:51])[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([C:52]([C:54]3[N:58]4[CH:59]=[CH:60][CH:61]=[CH:62][C:57]4=[C:56]([C:63]4[CH:64]=[C:65]([CH:69]=[CH:70][CH:71]=4)[C:66](O)=[O:67])[N:55]=3)=[O:53])[CH:44]=2)[NH:39]1>CN(C=O)C>[C:1]([NH:4][NH:5][C:66](=[O:67])[C:65]1[CH:69]=[CH:70][CH:71]=[C:63]([C:56]2[N:55]=[C:54]([C:52]([C:43]3[CH:44]=[C:45]4[C:40](=[CH:41][CH:42]=3)[NH:39][C:38](=[O:37])[N:47]([CH2:48][CH2:49][CH3:50])[C:46]4=[O:51])=[O:53])[N:58]3[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=23)[CH:64]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NN
Reactant: CCCn1c(=O)[nH]c2ccc(C(=O)c3nc(-c4cccc(C(=O)O)c4)c4ccccn34)cc2c1=O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCn1c(=O)[nH]c2ccc(C(=O)c3nc(-c4cccc(C(=O)NNC(C)=O)c4)c4ccccn34)cc2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
29.6 mg (0.4 mmol) of acetohydrazide, 98.4 mg (0.3 mmol) of TOTU and 0.104 ml (0.6 mmol) of N,N-diisopropylethylamine are added, under an inert atmosphere, at 0° C., to 93.7 mg (0.2 mmol) of 3-{3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoic acid in 6 ml of DMF. The reaction medium is stirred for 1 hour at 0° C. and then for 6 hours at 50° C. and then concentrated under reduced pressure. The residue is taken up in 10 ml of methanol. The precipitate obtained is filtered off, washed with dyethyl ether and with pentane, and then dried under reduced pressure at 40° C. overnight. 45 mg of a yellow solid are obtained.