Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:24][NH2:25].C(N(CC)CC)C>C(O)C(C)C>[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:24][NH:25][C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1
Reactant: OC[C@H]1O[C@@H](n2c(Cl)nc3ccccc32)[C@H](O)[C@@H]1O
Reactant: NCc1ccc(-c2ccccc2)c(O)c1
Solvent: CCN(CC)CC
Solvent: CC(C)CO
Product: OC[C@H]1O[C@@H](n2c(NCc3ccc(-c4ccccc4)c(O)c3)nc3ccccc32)[C@H](O)[C@@H]1O
Yield: 30.3 %

Procedure:
2-Chloro-1-(β-D-ribofuranosyl)-1H-benzimidazole (0.21 g) and 3-hydroxy-4-phenylbenzylamine (0.19 g) were suspended in isobutanol (5 mL). To the mixture was added triethylamine (0.36 mL), and the mixture was stirred for reflux for 16 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: methanol/ethyl acetate=1/20) to give the title compound (0.1 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][NH:12][CH3:13].CN[C:16](C1N(C)C2C(C=1)=CC=CC=2)=[O:17]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:17][CH3:16])[CH:9]=2)[CH:4]=[C:3]1[CH2:11][NH:12][CH3:13]
Reactant: CNC(=O)c1cc2ccccc2n1C
Reactant: CNCc1cc2ccccc2n1C
Product: CNCc1cc2ccc(OC)cc2n1C
Yield: 76 %

Procedure:
According to the procedure of Preparation 1 (c), except substituting N,1-dimethyl-6-methoxy-1H-indole-2-carboxamide for N,1-dimethyl-1H-indole-2-carboxamide, the title compound (76%) was prepared as a light gray solid: MS (ES) m/e 205.2 (M+H)+, 409.4 (2M+H)+.
Reaction SMILES: [CH2:1]([C@:8]1([NH:19]C(=O)OC(C)(C)C)[C:15](=[O:16])[N:14]2[C@@H:10]([S:11][CH2:12][C@H:13]2[C:17]#[N:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(SC)C=CC=CC=1.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[NH2:19][C@@:8]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:15](=[O:16])[N:14]2[C@@H:10]([S:11][CH2:12][C@H:13]2[C:17]#[N:18])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@]1(Cc2ccccc2)C[C@@H]2SC[C@@H](C#N)N2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: N#C[C@@H]1CS[C@H]2C[C@](N)(Cc3ccccc3)C(=O)N12
Reaction time: 0.25 h

Procedure:
A mixture consisting of 50 mg of tert-butyl (3R,6R,7aS)-(6-benzyl-3-cyano-5-oxohexahydropyrrolo[2,1-b]thiazol-6-yl)-carbamate, 0.1 ml of thioanisole and 1 ml of trifluoroacetic acid is stirred in an ice bath for 15 minutes. After room temperature was reached, the mixture was concentrated in vacuo at 40° C., and the residue was stirred with diisopropyl ether and the solid product was filtered off with suction.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](O)[CH:5]=[CH:4][N:3]=1.P(Br)(Br)([Br:14])=O.ClCCl>C(Cl)(Cl)Cl>[Br:14][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=P(Br)(Br)Br
Reactant: Cc1nccc(O)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1nccc(Br)c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 49.7 %

Procedure:
A mixture of 2-methyl-3-nitropyridin-4-ol (2 g, 12.98 mmol) and phosphorus oxybromide (24.93 g, 87 mmol) was melted at 140° C. in a pressure vessel over 3 hours. The reaction mixture was cooled, poured into chloroform (100 mL) and ice water (100 mL). The layers were separated and the organic layer was washed with water (2×25 mL), saturated sodium bicarbonate (2×75 mL), dried over magnesium sulfate, filtered, and concentrated to give an oil. The oil was treated with a mixture of dichloromethane and chloroform (50 mL, 3:1) to give a solid which was filtered and dried under vacuum. The filtrate was reduced in volume by 50% under vacuum, loaded on a silica column and eluted with 2% methanol in dichloromethane to give additional product which was concentrated and combined with the initial batch to give 4-bromo-2-methyl-3-nitropyridine (1.4 g, 6.45 mmol, 49.7% yield); MS [M+H] found 217.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.53 (s, 3H) 7.88 (dd, J=5.31, 0.51 Hz, 1H) 8.52-8.59 (m, 1H).
Reaction SMILES: [Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)[C:4]1C=CC=C[CH:5]=1.[NH2-].[Na+].C1COCC1.[CH3:29][O:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][C:32]=1[O:41][CH:42]([CH3:47])[C:43](=O)[CH2:44]C>C1(C)C=CC=CC=1>[CH2:4]([C:42]1([CH2:43][CH3:44])[CH2:47][C:33]2=[C:34]([C:35]([O:37][CH3:38])=[O:36])[CH:39]=[CH:40][C:31]([O:30][CH3:29])=[C:32]2[O:41]1)[CH3:5]
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC(=O)C(C)Oc1cc(C(=O)OC)ccc1OC
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC1(CC)Cc2c(C(=O)OC)ccc(OC)c2O1
Reaction time: 0.5 h

Procedure:
10 of methyltriphenylphosphonium bromide-sodium amide mixture (FLUKA 69500) are added to 100 ml of abs. THF at about 10° C. under protective gas (nitrogen), and the mixture is warmed to RT and stirred for about 30 min. A solution of 5.3 g of methyl 4-methoxy-3-(1-methyl-2-oxobutoxy)benzoate is then added dropwise. The mixture is stirred at RT for 1 h, then poured onto water and extracted 3 times with about 50 ml of ethyl acetate. The combined extracts are dried over sodium sulfate and concentrated, and the oily residue is dried in a high vacuum. The oil obtained (3.8 g) is stirred at 190-200° C. for 1 h, cooled and dissolved in 100 ml of toluene. The solution is treated with 5 g of Amberlyst 15 and vigorously stirred at 80° C. overnight. The Amberlyst is then filtered off, the solution is concentrated and the residue is chromatographed on a silica gel column using ethyl acetate/petroleum ether 4:6. The chromatographically pure fractions are combined and concentrated, and the residue is dried in a high vacuum. 1.5 g of the title compound are obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([F:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17](F)[C:18]=3[Cl:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1>N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([F:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17]([NH:2][CH3:1])[C:18]=3[Cl:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CN
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 40% aqueous solution (100 mg) of methylamine and 1-(5-amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg) were added to pyridine (2 ml), and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, ethanol was added to the residue, and the mixture was left to stand overnight. Solids deposited were collected by filtration to obtain the title compound (40 mg) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH2:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCCc2ccccc2)c2sc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 52 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41 and potassium carbonate (152 mg) are suspended in DMF (10 mL) and to the mixture is added 1-bromo-3-phenylpropane (167 μL). The reaction mixture is allowed to stir at room temperature for 72 h. The reaction mixture is poured into water (25 mL) and extracted with EtOAc (2×25 mL). The organic layer is dried (Na2SO4) and concentrated. The resulting crude solid is purified by recrystallization from ethanol to afford 277 mg (52%) of the title compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3](=O)[CH3:4].[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][NH2:13].C(O)(=O)C>N1C=CC=CC=1.CO>[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12]/[N:13]=[C:3](\[CH3:4])/[CH2:2][OH:1]
Reactant: NOC1CCCCO1
Reactant: CC(=O)CO
Solvent: CO
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: C/C(CO)=N\OC1CCCCO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
To a solution of 1-hydroxypropan-2-one (1 g, 13.5 mmol) and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (1.9 g, 16.2 mmol) in pyridine (7 mL) and methanol (20 mL) was added acetic acid (0.23 mL, 4 mmol) and the resulting mixture was stirred at room temperature for 12 hours. The mixture was then concentrated under reduced pressure and the residue was treated with a saturated solution of NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography (EtOAc-Hexanes 2:1) to afford 1.8 g of the title compound. MS (DCI/NH3) m/z 174 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH2:6].C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH:6][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@@H](NC(=O)c1ccccc1)[C@@H](C)O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
3.00 g (17.7 mmol/1 eq) of L-threonine methyl ester hydrochloride are suspended in 50 ml of methanol, and 7.4 ml (53 mmol/3 eq) of triethylamine are added thereto. After 10 minutes, the mixture is cooled to 0° C. and the benzoyl chloride (2.74 g/190.5 mmol/1.1 eq) is added. Stirring is carried out at 0° C. for a further two hours. The solvent is then removed using a rotary evaporator. The solid that remains behind is taken up with ethyl acetate/H2O (50/20 ml). The aqueous phase is separated off and extracted by shaking twice more with ethyl acetate (30 ml each time). The combined organic phases are washed with 15 ml each of H2O and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. 4.07 g (97% of theory) of a white solid are obtained.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:43])[NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:22]([CH3:39])[C:23]([CH2:26][N:27]([CH2:35][CH2:36][O:37][CH3:38])C(=O)OC(C)(C)C)=[CH:24][N:25]=5)[S:20][C:13]=34)=[C:9]([F:42])[CH:8]=2)[CH2:3][CH2:2]1.Cl.O1CCOCC1>C(Cl)Cl.O.C([O-])(O)=O.[Na+]>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:22]([CH3:39])[C:23]([CH2:26][NH:27][CH2:35][CH2:36][O:37][CH3:38])=[CH:24][N:25]=5)[S:20][C:13]=34)=[C:9]([F:42])[CH:8]=2)=[O:43])[CH2:3][CH2:2]1
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COCCNCc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.2 %

Procedure:
To a solution of the 347 (426 mg, 0.698 mmol) in DCM (10 ml) was added HCl in dioxane (0.7 ml, 4.01 eq, 2.80 mmol, 4M in dioxane) and the reaction mixture was stirred at RT for 3 hours. The mixture wad diluted with water and solid NaHCO3 was added. The reaction mixture was extracted well with EtOAc then the organic phase was collected, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (eluent 25% MeOH in EtOAc to 50% MeOH in EtOAc) to afford the desired compound 348 as a yellow powder (211 mg, 59% yield). MS (m/z)=511.4 (M+H).
Reaction SMILES: [S:1]([C:8]1[CH:28]=[CH:27][C:11]([N:12](CC2C=CC=CC=2)CC2C=CC=CC=2)=[CH:10][CH:9]=1)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2]>C(O)=O.CO.[Pd]>[S:1]([C:8]1[CH:28]=[CH:27][C:11]([NH2:12])=[CH:10][CH:9]=1)([C:4]([F:5])([F:6])[F:7])(=[O:3])=[O:2]
Reactant: O=S(=O)(c1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1

Procedure:
To a stirred solution of 0.1 g of palladium black in 4.4% formic acid-methanol is added 37.3 g (0.1 mole) of 4-triflyl-N,N-dibenzylaniline in 4.4% formic acid-methanol. The reaction is stirred under an argon atmosphere until complete as indicated by thin layer chromatographic analysis. The catalyst is removed by filtration and washed with additional portions of methanol followed by water. The combined methanol and water washes are evaporated, and compound B is purified by distillation.
Reaction SMILES: C([Li])CCC.I[C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1.[CH3:14][CH:15]([CH3:19])[C:16](=[O:18])[CH3:17]>C1COCC1>[I:13][C:10]1[CH:11]=[CH:12][C:7]([C:16]([OH:18])([CH:15]([CH3:19])[CH3:14])[CH3:17])=[CH:8][CH:9]=1
Reactant: CC(=O)C(C)C
Reactant: Ic1ccc(I)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)C(C)(O)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (139 mL of a 2M solution in hexanes, 277 mmol) was added via canula to a stirred solution 1,4-diiodobenzene (89.0 g, 277 mmol) in THF (500 mL) at −78° C. such that the internal temperature was maintained below −65° C. during the addition process. After 0.5 h, 3-methyl-2 butanone (24.0 g, 280 mmole) was added via syringe, again maintaining the internal temperature below −65° C. After 0.5 h, the reaction mixture was warmed to 0° C. and quenched with saturated aqueous ammonium chloride. The resulting mixture was dried (MgSO4), concentrated in vacuo, and the crude residue purified by flash chromatography on silica gel (gradient elution; 10-25% EtOAc/hexanes) to afford the title compound 5a. 1H NMR (500 MHz, CDCl3) δ 7.67 (d, 2H, J=7.5 Hz), 7.20 (d, 2H, J=7.5 Hz), 3.79 (s, 1H), 2.00 (m, 1H, J=7.0 Hz), 1.52 (s, 3H), 0.92 (d, 3H, J=7.0 Hz), 0.81 (d, 3H, J=7.0 Hz).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[CH3:18][C:19]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[CH3:18][C:19]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Cc1ccc(CBr)c(C)c1
Product: Cc1ccc(CN2N(C3C4CC5CC(C4)CC3C5)C(=O)C2(C)C)c(C)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,4-dimethylbenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].N[C@H](C(O)=O)CC(=O)O.N[C@@H](C(O)=O)CC(=O)O.N[C@H](C(O)=O)CCC(=O)O.N[C@H](C(O)=O)CCC(=O)N.N[C@@H](C(O)=O)CCC(=O)N>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: NC(=O)C[C@@H](N)C(=O)O
Agent: NC(=O)CC[C@@H](N)C(=O)O
Agent: NC(=O)CC[C@H](N)C(=O)O
Agent: N[C@@H](CC(=O)O)C(=O)O
Product: NC(=O)C[C@H](N)C(=O)O

Procedure:
D-Asn, Asp, D-Asp, Glu 1 D-Glu, Gln, D-Gln
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:14]=1[NH2:15]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:15][C:14]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:13]=1[Cl:12])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1cc(Cl)ccc1Cl
Product: O=C(Nc1cc(Cl)ccc1Cl)c1cc(Cl)ccc1O
Yield: 10.8 %

Procedure:
Using 5-chlorosalicylic acid and 2,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:18]Br>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([Br:18])=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: COC(=O)c1cccc(N)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1nc(N)ccc1Br
Temperature: 25 °C
Reaction time: 7 h
Yield: 29.3 %

Procedure:
To a suspension of methyl 6-aminopyridine-2-carboxylate (5.98 g, 39.5 mmol) and sodium carbonate (2.64 g, 24.9 mmol) in acetic acid (150 mL) was added bromine (7.89 g, 49.4 mmol), and the mixture was stirred at room temperature for 7 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. This was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→80/20) to give the title compound (2.67 g, yield 29%).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([CH3:25])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:14]=2)[C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Li].[H-]>O1CCCC1>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([CH3:25])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:14]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2ccccn2)c1
Agent: [H-]
Agent: [Li]
Solvent: C1CCOC1
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.2 %

Procedure:
3-Hexyl-6-methyl-6-[3-(2-pyridinyl)phenyl]-3-azabicyclo[3.1.0]hexan-2-one (Preparation 68, 33 mg, 0.09 mmol) was dissolved in tetrahydrofuran (10 ml) at 0° C. Lithium alumninium hydride (1M in tetrahydrofuran, 0.2 ml, 0.2 mmol) was added under nitrogen and then the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by adding aqueous sodium hydroxide solution (2N, 0.4 ml), followed by solid sodium hydrogen carbonate and ethyl acetate. The reaction mixture was stirred vigorously and then filtered through Celite®. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate to give the product as a colourless oil (13 mg, 41%).
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[N:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]([O:13][CH3:14])[CH:6]=1)[OH:4].C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:14][O:13][C:7]1[CH:6]=[C:5]([CH:3]2[CH2:2][O:4]2)[N:10]=[CH:9][C:8]=1[C:11]#[N:12]
Reactant: COc1cc(C(O)CBr)ncc1C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C2CO2)ncc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-(2-bromo-1-hydroxyethyl)-4-methoxypyridine-3-carbonitrile (74.0 mg, 0.288 mmol) in anhydrous methanol (7 mL) was treated with sodium carbonate (61.0 mg, 0.576 mmol, 2.0 equiv), and allowed to stir at room temperature overnight. The solvent was evaporated. The residue was taken up in EtOAc (30 mL) and washed with water and brine. After drying over Na2SO4, the organic layer was removed and the residue was purified over SiO2 (10-45% EtOAc/hexanes as eluent) to yield 4-methoxy-6-(oxiran-2-yl)pyridine-3-carbonitrile.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:8]=[C:9]([N:13]2[C:17]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[O:19])=[CH:16][C:15]([C:30]([F:33])([F:32])[F:31])=[N:14]2)[CH:10]=[CH:11][CH:12]=1>CC(O)=O.O>[CH:2]([C:7]1[CH:8]=[C:9]([N:13]2[C:17]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[O:19])=[CH:16][C:15]([C:30]([F:32])([F:33])[F:31])=[N:14]2)[CH:10]=[CH:11][CH:12]=1)=[O:1]
Reactant: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(C2OCCCO2)c1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(C=O)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A stirred solution of 148 (105 mg, 0.228 mmol) in AcOH (1.8 mL) and water (0.5 mL) was allowed to stir at 90° C. for 2 h. After cooling to room temperature, water was added and the mixture was extracted with EtOAc and the extractis were dried over Na2SO4 and concentrated to give crude 149 (92 mg, 0.228 mmol, 100% yield) as a pale yellow solid. The material was used as is for the next step.
Reaction SMILES: [OH:1][C@@H:2]([CH3:26])[C@@H:3]([N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=O)[N:18]=[CH:17]1)[CH2:4][S:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[OH-].[NH4+:28]>COCCOC>[C:6]1([S:5][CH2:4][C@H:3]([N:16]2[CH:20]=[C:19]([C:21]([NH2:28])=[O:23])[N:18]=[CH:17]2)[C@@H:2]([OH:1])[CH3:26])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cn([C@@H](CSc2cccc3ccccc23)[C@H](C)O)cn1
Reactant: [NH4+]
Agent: [OH-]
Solvent: COCCOC
Product: C[C@H](O)[C@H](CSc1cccc2ccccc12)n1cnc(C(N)=O)c1

Procedure:
A mixture of ethyl 1-{(1R,2S)-2-hydroxy-1-[(1-naphthylthio)methyl]propyl}-1H-imidazole-4-carboxylate (0.18 g), 28% ammonium hydroxide (5 mL) and 1,2-dimethoxyethane (10 mL) was heated at 100° C. in the stainless steel bottle for 24 hours. After cooling, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (gradient elution; 15:1 to 10:1 chloroform-methanol) to give 1-[(2R,3S)-1-(1-naphthylthio)-3-hydroxy-2-butyl]imidazol-4-carboxamide. The product was dissolved in MeOH (5 mL) and treated with a solution of 4 N hydrogen chloride in ethyl acetate (1 mL). The mixture was concentrated in vacuo and the residue was recrystallized from 5:1 ethyl acetate-methanol (6 mL) to give 1-{(1R,2S)-2-hydroxy-1-[(1-naphthylthio)methyl]propyl}-1H-imidazole-4-carboxamide hydrochloride (103) (0.11 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH3:12])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
5-Fluoro-2-nitrophenol (10.3 g), potassium carbonate (27.1 g), methyl iodide (11.1 g) and acetone (100 mL) was heated at reflux until the starting materials were consumed. After cooling down to room temperature, the reaction mixture was diluted with ethylacetate, washed with hydrogen chloride (1 N) and brine. After puridication on column (silica gel, ethyl acetate/petrolium ether, 1:9), 10.8 g (96%) of of 5-fluoro-2-nitroanisole was obtained.