Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH2:15])[CH:6]=1)[CH3:3].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:29]=[N:30][C:31]([CH3:35])=[C:32]([CH3:34])[CH:33]=2)=[CH:22][N:21]=1)([O-])=O>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:20]2[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([CH3:35])=[C:32]([CH3:34])[CH:33]=3)=[CH:22][N:21]=2)[CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccnc(CSCCN)c1
Reactant: Cc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cnc1C
Solvent: c1ccncc1
Product: Cc1cc(Cc2cnc(NCCSCc3cc(CN(C)C)ccn3)[nH]c2=O)cnc1C
Yield: 40.7 %

Procedure:
A mixture of 2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamine (1 g) and 2-nitroamino-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone (1.11 g) in pyridine (3 ml) was heated under reflux for 5 hours and evaporated to dryness in vacuo. The residue was purified by chromatography on silica gel eluted with 20% methanol/chloroform followed by recrystallisation from acetonitrile/water 1:1 to give 2-[2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamino]-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone (0.72 g) m.p. 72°-78°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:13][C:12](=[O:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[ClH:38].[N:39]12[CH2:46][CH2:45][CH:42]([CH2:43][CH2:44]1)[C@@H:41]([NH:47][C:48]([C:50]1[S:51][C:52]3[C:58](Br)=[CH:57][CH:56]=[CH:55][C:53]=3[CH:54]=1)=[O:49])[CH2:40]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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]>[ClH:38].[N:39]12[CH2:44][CH2:43][CH:42]([CH2:45][CH2:46]1)[C@@H:41]([NH:47][C:48]([C:50]1[S:51][C:52]3[C:58]([C:2]4[CH:7]=[CH:6][C:5]([CH:8]5[CH2:9][CH2:10][CH2:11][C:12](=[O:14])[NH:13]5)=[CH:4][CH:3]=4)=[CH:57][CH:56]=[CH:55][C:53]=3[CH:54]=1)=[O:49])[CH2:40]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Reactant: O=C1CCCC(c2ccc(Br)cc2)N1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C1CCCC(c2ccc(-c3cccc4cc(C(=O)N[C@H]5CN6CCC5CC6)sc34)cc2)N1

Procedure:
123.4 mg (0.49 mmol) of 6-(4-bromophenyl)-2-piperidinone, 142.2 mg (0.56 mmol) of bis(pinacolato)diboron, 146.6 mg (1.49 mmol) of potassium acetate, 13.7 mg (0.02 mmol) of PdCl2(dppf), 150 mg (0.37 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A), 0.93 ml of 2 M sodium carbonate solution and a further 13.7 mg (0.02 mmol) of PdCl2(dppf) in 2 ml of DMF are reacted by general method D. Drying under high vacuum results in 7.3 mg (4% of theory) of the title compound.
Reaction SMILES: [C:1]([C:6]1[C:7]([N:14]2[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]2)=[N:8][C:9](Cl)=[N:10][C:11]=1[CH3:12])([O:3][CH2:4][CH3:5])=[O:2].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.O>O1CCOCC1>[C:1]([C:6]1[C:7]([N:14]2[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]2)=[N:8][C:9]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:10][C:11]=1[CH3:12])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1c(C)nc(Cl)nc1N1CCS(=O)(=O)CC1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c(C)nc(N2CCNCC2)nc1N1CCS(=O)(=O)CC1

Procedure:
2.0 gm (0.006 mol) of 5-carbethoxy-2-chloro-4-(1,1-dioxido-thiomorpholino)-6-methyl-pyrimidine were added in small portions to a boiling solution of 5.2 gm (0.06 mol) of piperazine in 70 ml of dioxane, and the mixture was refluxed for 20 minutes. The reaction mixture was then poured into 150 ml of water, and the aqueous mixture was extracted with chloroform. The organic extract was washed with water, dried with sodium sulfate, and the solvent was removed in vacuo. The residue was recrystallized from ethanol/petroleum ether. Yield: 1.7 gm (74% of theory); m.p. 154°-159°C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]1[CH2:11][C:10](=[O:12])[O:9][C:7]1=[O:8])=[O:4].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)C.C(OCC)(=O)C>[C:7]([CH:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:11][C:10]([C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)=[O:12])([OH:9])=[O:8]
Reactant: COC(=O)NC1CC(=O)OC1=O
Reactant: Clc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: COC(=O)NC(CC(=O)c1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To 17.58 g of 2-methoxycarbonylaminosuccinic anhydride and 33.77 g of 4-chlorobenzene suspended in 150 ml of dichloroethane was added 33.40 g of anhydrous aluminum chloride under ice cooling, and the mixture was stirred at room temperature for 1 hour. Under ice cooling, to the mixture were added 100 ml of 10% hydrochloric acid and then 500 ml of ethyl acetate. After the organic layer was collected by separation, washed with water and dried, the solvent was removed. The resulting crude crystals were recrystallized from ethyl acetate to obtain 24.2 g of 3-carboxy-3-methoxycarbonylamino-4'-chloropropiophenone.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH2:15]([O:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20])[CH3:16]>C(O)C>[CH2:15]([O:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1)[CH3:16]
Reactant: CCOc1ccccc1N
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2ccccc2OCC)[nH]c1=O
Reaction time: 48 h
Yield: 66.2 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (8 g) and 2-ethoxyaniline (6.1 g) are added to ethanol (60 ml), and the mixture is refluxed with stirring for 48 hours. After cooling, the precipitate is collected by filtration, washed with ethanol and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-2-(2-ethoxyanilino)-6-oxo-5-pyrimidinecarboxylate (7.5 g). M.p. 220°-221° C.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[CH2:12][C:13](=O)[CH3:14].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(=O)([O-])[O-].[K+].[K+].O>[F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:12]=[C:13]([CH3:14])[NH:9]2
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc2c(F)c(O)ccc2[nH]1
Reaction time: 1.5 h
Yield: 64.5 %

Procedure:
1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (1 g) was dissolved in a solution of potassium carbonate (1.3 g) in water (13 ml). A solution of sodium dithionite (5.24 g) in water (12.3 ml) was added dropwise. The mixture was stirred for 1.5 hours, then left to stand overnight. The solid was filtered and washed with water (6 ml). The solid was dried at 35° C. in a vacuum oven to give crude 4-fluoro-2-methyl-1H-indol-5-ol (0.5 g, 64.5%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([S:23][CH:24]5[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:33])=[N:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:35].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([S:23]([CH:24]5[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]5)=[O:35])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:33])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(SC4CCN(C(C)C)CC4)cc2OCC3)n(C(C)C)n1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2ccc(S(=O)C4CCN(C(C)C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-(1-isopropylpiperidin-4-ylsulfanyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 49 (102 mg, 0.219 mmol) in DCM (10 mL) was added TFA (84 μL, 1.09 mmol) followed by a solution of m-CPBA (42 mg, 0.241 mmol) in DCM (2 mL). The resulting mixture was stirred for 15 min at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 20-45% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH affording 242 as a colorless solid (92 mg, 87%). LCMS: RT 2.54 min [M+H]+ 483.1. 1H NMR (DMSO, 400 MHz): δ 8.58 (1H, d, J=8.39 Hz), 7.96 (1H, s), 7.36 (1H, dd, J=8.39, 1.75 Hz), 7.26 (1H, d, J=1.72 Hz), 5.86-5.73 (1H, m), 4.57 (4H, s), 2.90-2.59 (4H, m), 2.26 (3H, s), 2.17-2.02 (2H, m), 1.84 (1H, bd, J=12.25 Hz), 1.58-1.38 (9H, m), 0.92 (6H, dd, J=6.52, 1.72 Hz)
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][NH:8][CH2:9][CH:10](OC)OC)([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][C@H:27]([NH:31]C(OCC1C=CC=CC=1)=O)[C:28](O)=[O:29])=[O:22])([CH3:19])[CH3:18].Cl.C(N=C=NCCCN(C)C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+].[C:70]([OH:75])(=[O:74])[C:71]([OH:73])=[O:72]>CC(C)=O.C1(C)C=CC=CC=1.C(OCC)(=O)C.[Pd]>[C:70]([OH:75])(=[O:74])[C:71]([OH:73])=[O:72].[C:1]([O:5][C:6](=[O:15])[CH2:7][N:8]1[CH2:9][CH2:10][NH:31][C@@H:27]([CH2:26][CH2:25][CH2:24][NH:23][C:21]([O:20][C:17]([CH3:18])([CH3:16])[CH3:19])=[O:22])[C:28]1=[O:29])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(CNCC(=O)OC(C)(C)C)OC
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN1CCN[C@@H](CCCNC(=O)OC(C)(C)C)C1=O
Yield: 67 %

Procedure:
In 54.6 cc of acetone was dissolved (2,2-dimethoxyethyl)aminoacetic acid t-butyl ester (6.0 g, 27.7 mmol) and N--Z--Orn(Boc)--OH (10.0 g, 27.7 mmol). To the solution was added, at 15° C. under stirring, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (5.6 g, 29.2 mmol). The mixture was stirred for one hour at room temperature, and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate, and washed with a 5% aqueous solution of potassium hydrogen sulfate and a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was concentrated under reduced pressure to give a pale yellow oily substance. This oily substance and p-toluenesulfonic acid 1.0 hydrate (1.04 g, 5.46 mmol) were dissolved in 137 cc of toluene, and the solution was stirred for two hours at 70° C. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and purified by means of silica gel column chromatography (hexane/ethyl acetate=3/2) to give 8.3 g of a pale yellow oily substance. This oily substance (8.3 g, 16.5 mmol) was dissolved in 166 cc of ethyl acetate, to which was added 1.7 g of 10% Pd-C, and then the mixture was stirred for two hours under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was dissolved in 16.6 cc of methanol. To the solution was added oxalic acid 2.0 hydrate (2.1 g, 16.5 mmol), and the mixture was concentrated under reduced pressure. The resulting crystalline product was washed with ethyl acetate to afford 5.1 g (66.8%) of the title compound as white crystals.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][NH:4][C:5]1[C:13]2[N:12]=[CH:11][N:10]([C:14]3C=CC(C#N)=CC=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].[C:25](O)(=O)[CH2:26][C:27]([CH2:32][C:33](O)=O)([C:29]([OH:31])=[O:30])O>C(O)C>[CH3:1][CH:2]([CH3:22])[CH2:3][NH:4][C:5]1[C:13]2[N:12]=[CH:11][N:10]([C:14]3[CH:33]=[CH:32][C:27]([C:29]([OH:31])=[O:30])=[CH:26][CH:25]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)CNc1cccc2c1ncn2-c1ccc(C#N)cc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CNc1cccc2c1ncn2-c1ccc(C(=O)O)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 91.7 %

Procedure:
To a stirred solution of 4-{4-[(2-methylpropyl)amino]-1H-benzimidazol-1-yl}benzonitrile (220 mg, 0.758 mmol) in ethanol (14 m L) at rt was added sodium hydroxide (7 N aqueous solution, 14 mL) in one portion. After stirring at 90° C. for 24 h, the mixture is cooled to rt and acidified with citric acid (10% aqueous solution). The precipitate was filtered, and the remaining solid was washed and dried to yield 4-{4-[(2-methylpropyl)amino]-1H-benzimidazol-1-yl}benzoic acid as a white solid (215 mg, 91.7%).
Reaction SMILES: C([NH:4][CH2:5][C:6]1[S:7][C:8]([C:11]2[N:12]=[C:13]([N:16]=[C:17]([NH2:19])[NH2:18])[S:14][CH:15]=2)=[CH:9][N:10]=1)(=O)C.Cl>C(O)C>[NH2:4][CH2:5][C:6]1[S:7][C:8]([C:11]2[N:12]=[C:13]([N:16]=[C:17]([NH2:19])[NH2:18])[S:14][CH:15]=2)=[CH:9][N:10]=1
Reactant: CC(=O)NCc1ncc(-c2csc(N=C(N)N)n2)s1
Agent: Cl
Solvent: CCO
Product: NCc1ncc(-c2csc(N=C(N)N)n2)s1

Procedure:
A solution of 4-(2-acetylaminomethylthiazol-5-yl)-2-(diaminomethyleneamino)thiazole (1.46 g) and concentrated hydrochloric acid (2.18 ml) in ethanol (15 ml) was refluxed for 5 hours with stirring. The solvent was evaporated in vacuo. The residue was made basic to pH 10 with 20% aqueous potassium carbonate and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was dried over magnesium sulfate and evaporated in vacuo to give 4-(2-aminomethylthiazol-5-yl)-2-(diaminomethyleneamino)thiazole. 1N-hydrochloric acid (4 ml) and then potassium cyanate (360 mg) was added to the suspension of the above residue in water (10 ml) and the mixture was stirred for two hours at ambient temperature. The reaction mixture was alkalized to pH 10 with 20% aqueous potassium carbonate and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was dried over magnesium sulfate and evaporated in vacuo. The obtained free base was converted to the dihydrochloride in an usual manner, and which was recrystallized from a mixture of methanol, water and tetrahydrofuran to give 2-(diaminomethyleneamino)-4-(2-ureidomethylthiazol-5-yl)thiazole dihydrochloride (0.65 g).
Reaction SMILES: [Cl:1][C:2]1[C:27]([C:28]2([C:31]#[N:32])[CH2:30][CH2:29]2)=[CH:26][CH:25]=[CH:24][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[F:23])=[O:5].[Cl-].[Ca+2].[Cl-].[OH-].[Na+]>C(OCC)(=O)C.O.C(O)C>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:11]2[CH:10]=[CH:9][C:8]([F:23])=[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:24]=[CH:25][CH:26]=[C:27]([C:28]4([C:31]#[N:32])[CH2:29][CH2:30]4)[C:2]=3[Cl:1])[CH:12]=2)=[N:15][CH:16]=1
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc([N+](=O)[O-])cn4)ccc3F)c2Cl)CC1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc(N)cn4)ccc3F)c2Cl)CC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 68.5 %

Procedure:
A mixture of 2-chloro-3-(1-cyanocyclopropyl)-N-{2-fluoro-5-[(5-nitropyridin-2-yl)oxy]phenyl}benzamide (6.60 g, 14.6 mmol), reduced iron (1.68 g, 30.0 mmol), calcium chloride (3.33 g, 30.0 mmol), water (80 mL) and ethanol (20 mL) was stirred at 80° C. for 18 hr. The mixture was cooled to room temperature, water (250 mL), 1N aqueous sodium hydroxide solution (250 mL), ethyl acetate (300 mL) and celite (50 g) were added, and the mixture was stirred. The mixture was filtered through celite, and the insoluble material was washed with ethyl acetate (100 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was crystallized from diethyl ether to give the title compound (4.23 g, 69%) as a pale-yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=[O:6].[C:18](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([O:7][CH3:18])=[O:6]
Reactant: O=C(O)c1ccc(C(=O)N2CCCC2)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(C(=O)N2CCCC2)c(Br)c1

Procedure:
20 g (67.1 mmol) of 3-bromo-4-(pyrrolidin-1-ylcarbonyl)benzoic acid is dissolved in 400 mL of N,N-dimethylformamide and combined with 21.9 g (67.1 mmol) cesium carbonate with stirring. Then 4.21 mL (67.1 mmol) of iodomethane is slowly added dropwise at ambient temperature and the mixture is stirred for 16 hours at ambient temperature. After the solid constituents have been removed by filtration with suction, volatile constituents are removed in vacuo. Yield: 20.94 g (75%); Rf value: 0.42 (silica gel; dichloromethane/ethanol=98:2); C13H14BrNO3 (312.17); mass spectrum: (M+H)+=312/314 (bromine isotope).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]#[N:10])[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)(=[S:23])C>C(O)(=O)C>[N:1]1([C:6]2[CH:7]=[C:8]([C:9](=[S:23])[NH2:10])[CH:11]=[CH:12][C:13]=2[O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(O)=S
Reactant: N#Cc1ccc(Oc2ccccc2)c(-n2ccnc2)c1
Solvent: CC(=O)O
Product: NC(=S)c1ccc(Oc2ccccc2)c(-n2ccnc2)c1
Temperature: 50 °C

Procedure:
A reaction mixture prepared by suspending 65.2 mg of 3-(1H-imidazol-1-yl)-4-phenoxybenzonitrile in a mixture of 0.3 mL of acetic acid and 1.0 mL of thioacetic acid was heated at 50° C. for 14 hours under a nitrogen atmosphere. A crude product of 3-(1H-imidazol-1-yl)-4-phenoxybenzene-1-carbothioamide was obtained by concentrating under reduced pressure.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:20])[CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.[CH2:38]([O:45][C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=1)[CH:49]=[O:50])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.P([O-])([O-])(O)=O.[Na+].[Na+].OO>C1(C)C=CC=CC=1.ClCCl.CO.C(N(CC)CC)C>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:20])[C@@H:15]([O:16][CH:17]([CH3:18])[CH3:19])[CH:49]([C:48]1[CH:51]=[CH:52][CH:53]=[C:46]([O:45][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:47]=1)[OH:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Agent: CCCC[B+]CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])([O-])O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)O[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(O)c1cccc(OCc2ccccc2)c1
Temperature: -75 °C
Reaction time: 0.83 h
Yield: 109.2 %

Procedure:
After cooling a solution containing 8.1 g of (4S)-4-benzyl-3-(2-isopropoxyacetyl)-1,3-oxazolidin-2-one in toluene (120 ml) was cooled to −75° C., 5.0 ml of triethylamine was added. 30.5 ml of dibutylboron triflate (1M solution in dichloromethane) was added dropwise at such a rate that the inside temperature did not exceed −70° C. After the dropwise addition, the mixture was stirred for 50 minutes. Then, the inside temperature was raised to 0° C. and the mixture was stirred for another 50 minutes, and again cooled to −75° C. To the reaction solution was added a solution containing 5.2 g of 3-benzyloxybenzaldehyde in dichloromethane (25 ml) by means of cannula, and stirring was continued at −75° C. for 30 minutes. Then, the inside temperature was raised to 0° C. over about 1 hour by 10° C. per 10 minutes. Again after cooling to −75° C., a solution containing 2.0 g of 3-benzyloxybenzaldehyde in dichloromethane (10 ml) was added. The temperature was gradually raised to room temperature and stirred for 3 days at room temperature. The reaction solution was poured into a mixed solution of 150 ml of methanol, 100 ml of pH 7 buffer (disodium hydrogen phosphate-citric acid) and 30 ml of hydrogen peroxide (30% aqueous solution), and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 13.1 g of 4 (S)-benzyl-3-[3-(3-benzyloxyphenyl)-3-hydroxy-2 (S)-isopropoxypropionyl]oxazolidin-2-one as a colorless oil in the 2:1→3:2 hexane-ethyl acetate fraction.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:4]([CH3:8])[CH:5]=[CH:6][N:7]=1.C[O-].[Na+].[CH:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>C(O)C>[ClH:1].[CH3:8][N:4]1[CH:5]=[CH:6][N:7]=[C:3]1[N:2]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cn1ccnc1N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C=Nc2nccn2C)cc1
Yield: 30.1 %

Procedure:
2-Amino-1-methylimidazole hydrochloride (0.3 g) was dissolved in ethanol (4 ml), and sodium methoxide (28% methanol solution: 0.5 ml) and p-anisaldehyde (0.34 g) were added. The mixture was heated at reflux overnight. The solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: methanol-chloroform=5:95), and the solvent in the desired fraction was evaporated. The precipitated pale yellow prisms were separated by filtration using hexane. The resulting crystals were dissolved in chloroform, and 4N hydrochloric acid--ethyl acetate (0.22 ml) was added. The solvent was evaporated, and the precipitated pale yellow was separated by filtration using diethyl ether to give the title compound (0.17 g, 26.9%).
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1.[NH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]1[N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>CN(C=O)C>[Cl:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C@@H:2]([NH:1][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11](=[O:13])[N:53]2[CH2:54][CH2:55][N:50]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][N:44]=3)[CH2:51][CH2:52]2)=[CH:9][CH:8]=1
Reactant: C1CCC(N2CCNCC2)NC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccn2)CC1

Procedure:
N-{(1R)-1-[(4-Chlorophenyl)methyl]-2-oxo-2-(4-(2-pyridyl)piperazinyl)ethyl}(tert-butoxy)carboxamide was prepared according to the procedure for Preparation XIX using Boc-p-Cl-D-Phe-OH (550 mg, 1.8 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (1.1 g, 3.80 mmol), HOAT (260 mg, 1.9 mmol), DMF (15 mL), and 1-(2-piperidyl)piperazine (280 μl, 1.8 mmol) (Aldrich). The crude material was concentrated in vacuo to yield 810 mg. MS (ESI, pos. ion) m/z: 445 (M+H), (ESI, neg. ion) m/z: 443 (M−H). Calc'd for C23H29ClN4O3: 444.95.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([N:18]1[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]2[C:34]([Cl:35])=[CH:33][C:27]([C:28](OCC)=[O:29])=[CH:26][N:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1.CO>[CH2:11]([N:18]1[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]2[N:25]=[CH:26][C:27]([CH2:28][OH:29])=[CH:33][C:34]=2[Cl:35])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Solvent: Cc1ccccc1
Product: OCc1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)c(Cl)c1
Yield: 45 %

Procedure:
A diisobutylaluminium hydride in toluene solution (15.7 ml) was dropwise added to a solution of ethyl 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloronicotinate (4.7 g) in toluene (50 ml) with stirring at −30˜−50° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at −20˜−40° C. for 2 hours. A MeOH (5 ml) was added to a reaction mixture at −40° C. and saturated sodium potassium tartrate aqueous solution (10 ml) and MgSO4 (10 g) and the resultant mixture was stirred at ambient temperature for 20 minutes. The reaction mixture was filtrated and the filtrate was dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give (6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridyl)methanol (1.87 g).