Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[N:9][C:10]([NH:13][C:14](=[O:24])[CH2:15][C:16]2[CH:17]=[N:18][C:19](Cl)=[C:20]([CH3:22])[CH:21]=2)=[CH:11][CH:12]=1.[CH3:25][C:26]1[CH:31]=[C:30]([Sn](CCCC)(CCCC)CCCC)[CH:29]=[CH:28][N:27]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[N:9][C:10]([NH:13][C:14](=[O:24])[CH2:15][C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([C:30]3[CH:29]=[CH:28][N:27]=[C:26]([CH3:25])[CH:31]=3)=[N:18][CH:17]=2)=[CH:11][CH:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C)c1
Reactant: Cc1cc(CC(=O)Nc2ccc(-c3ccccn3)cn2)cnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2ncc(CC(=O)Nc3ccc(-c4ccccn4)cn3)cc2C)ccn1
Temperature: 118 °C

Procedure:
To a reaction tube were added 5 N-(2,3′-bipyridin-6′-yl)-2-(6-chloro-5-methylpyridin-3-yl)acetamide 124-2 (52 mg, 0.15 mmol), 2-methyl-4-(tributylstannyl)pyridine (115 mg, 0.3 mmol), and Pd(PPh3)4 (35 mg, 0.03 mmol). The tube was subjected to vacuum and back filled with argon. DMF (1.0 ml) was added and the mixture was heated in 118° C. oil bath overnight. After cooled to room temperature, the mixture was filtered through celite, washed and diluted with ethyl acetate (30 ml) and extracted with 0.1 N HCl solution (30 ml). The acidic aqueous phase was treated with Na2CO3 to have pH around 9 and extracted with ethyl acetate (3×20 ml). The combined organic phase was dried over Na2SO4 and concentrated by evaporation. The residue was subjected to silica gel column chromatography with 5% MeOH in DCM as eluent to give N-(2,3′-bipyridin-6′-yl)-2-(2′,3-dimethyl-2,4′-bipyridin-5-yl)acetamide 124 as white solid. MS m/z 396.3 (M+1); 1H NMR 400 MHz (CDCl3) δ 8.93-8.89 (m, 1H), 8.72˜8.67 (m, 1 H), 8.59 (d, 1 H), 8.51 (d, 1 H), 8.37˜8.29 (m, 2 H), 8.23 (bs, 1 H), 7.76(m, 1H), 7.71 (m, 1 H), 7.65 (d, 1 H), 7.33 (bs, 1 H), 7.30˜7.24 (m, 1 H), 3.81 (s, 2H), 2.63 (s, 3H), 2.38 (s, 3 H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:21][O:22][CH2:23][CH2:24]Br.Cl>CN1C(=O)CCC1>[CH3:21][O:22][CH2:23][CH2:24][O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN1CCCC1=O
Product: COCCON1C(=O)c2ccccc2C1=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of N-hydroxyphthalimide (30.0 g, 184 mmol) and potassium carbonate (25.4 g, 138 mmol) in 300 mL NMP is heated to 50° C. Potassium iodide (0.15 g, 0.90 mmol) and 2-bromoethyl methyl ether (19.0 ml, 202 mmol) are added and the reaction mixture is stirred at 80° C. for 2 h. The reaction mixture is poured on 1 M aqueous HCl and extracted with ethyl acetate. The combined organic phases are dried over MgSO4 and concentrated in vacuo. The residue is triturated with water and subsequently crystallized from EtOH. Yield: 17.1 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[N:17]([CH2:33]OCC[Si](C)(C)C)[C:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:42]([O:46][C:47]([N:49]1[CH2:53][CH2:52][CH2:51][CH:50]1[C:54]1[N:55]([CH2:62][O:63][CH2:64][CH2:65][Si:66]([CH3:69])([CH3:68])[CH3:67])[CH:56]=[C:57]([C:59](O)=[O:60])[N:58]=1)=[O:48])([CH3:45])([CH3:44])[CH3:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[C:42]([O:46][C:47]([N:49]1[CH2:53][CH2:52][CH2:51][CH:50]1[C:54]1[N:55]([CH2:62][O:63][CH2:64][CH2:65][Si:66]([CH3:68])([CH3:67])[CH3:69])[CH:56]=[C:57]([C:59]([N:30]2[CH2:31][CH2:32][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:18]4[N:17]([CH3:33])[C:16]([CH:12]5[CH2:13][CH2:14][CH2:15][N:11]5[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:41])[CH:6]([CH3:7])[CH3:8])=[N:20][CH:19]=4)=[CH:26][CH:25]=3)[CH2:28][CH2:29]2)=[O:60])[N:58]=1)=[O:48])([CH3:44])([CH3:45])[CH3:43]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(N3CCNCC3)cc2)n1COCC[Si](C)(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc(C(=O)O)cn1COCC[Si](C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(N3CCN(C(=O)c4cn(COCC[Si](C)(C)C)c(C5CCCN5C(=O)OC(C)(C)C)n4)CC3)cc2)n1C)C(C)C
Reaction time: 18 h

Procedure:
(2-Methyl-1-{2-[5-(4-piperazin-1-yl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (28 mg, 0.047 mmol) and 2-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylic acid (20 mg, 0.047 mmol) in DMF (1 mL) were treated with HATU (20 mg, 0.052 mmol) and N-methyl morpholine (0.26 mL, 0.23 mmol). The mixture was stirred for 18 hours then diluted with EtOAc (25 mL), and washed with saturated NaHCO3 (3 10 mL), H2O (10 mL), and brine (10 mL). The solution was dried over MgSO4 to afford crude 2-[4-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3-methyl-3H-imidazol-4-yl}-phenyl)-piperazine-1-carbonyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester, which was used without further purification: MS (ESI) m/z 978 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[C:10]=2[NH:20][C:21]([NH:23][C:24]2[CH:29]=[C:28]([CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:27]=[CH:26][C:25]=2[C:37]([CH3:40])([CH3:39])[CH3:38])=[O:22])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].I[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>CN(C=O)C.O>[CH2:50]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][N:14]=2)[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[C:10]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[C:28]([CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:27]=[CH:26][C:25]=2[C:37]([CH3:40])([CH3:39])[CH3:38])=[O:22])[C:11]1=[O:19])[CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCI
Reactant: COc1cccc(-c2c(NC(=O)Nc3cc(CN4CCOCC4)ccc3C(C)(C)C)c(=O)[nH]c3ncccc23)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCn1c(=O)c(NC(=O)Nc2cc(CN3CCOCC3)ccc2C(C)(C)C)c(-c2cccc(OC)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a solution of N-[4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-[2-tert-butyl-5-(morpholinomethyl)phenyl]urea (300 mg, 0.55 mmol) in DMF (10 ml) are added successively potassium carbonate (91.8 mg, 0.66 mmol), potassium iodide (18.4 mg, 0.11 mmol) and 1-iodohexane (117 mg, 0.55 mmol), and the mixture is stirred at room temperature for one hour, and stirred at 40-50° C. for 4 hours. The reaction solution is poured into water, and the mixture is extracted with ethyl acetate. The extract is washed with water and a saturated brine, and dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (chloroform→3% methanol/chloroform) to give the title compound (290 mg, 0.47 mmol) as colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH:10][C:11]([NH:13][CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[CH2:18]2)=[O:12])#[N:2].Cl.[H][H]>C(O)(C)C.C(O)(=O)C.[Pt]=O>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH:10][C:11]([NH:13][CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[CH2:18]2)=[O:12]
Reactant: Cc1ccc(C#N)c(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)c1
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CC(C)O
Solvent: CC(=O)O
Product: Cc1ccc(CN)c(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)c1

Procedure:
A mixture of 1-(2-cyano-5-methylphenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea (0.54 g, 1.0 mmol), platinum oxide (0.1 g), and 5-6M HCl in isopropanol (2 mL) in acetic acid (15 mL) is hydrogenated under 50 psi hydrogen for 48 hrs. The mixture is filtered through Celite, the filtrate is evaporated under vacuum, and the residue is purified by preparative HPLC to provide the product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[S:14][CH2:13][C:12]1([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH3:23].[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C.O>ClCCl.C(OCC)(=O)C.CCCCCC>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:12]2([CH3:23])[CH:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:32]([CH3:31])(=[O:34])=[O:33])[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[S:14][CH2:13]2)=[CH:29][CH:28]=1
Reactant: COc1ccc2c(c1)SCC(C)(c1ccc(F)cc1)C2CCCCCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COc1ccc2c(c1)SCC(C)(c1ccc(F)cc1)C2CCCCCCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
4-(9-Hydroxynonyl)-3-(4-fluorophenyl)-7-methoxy-3-methylthiochroman (0.41 g, 0.95 mmol) was dissolved in dichloromethane (50 ml), methanesulfonyl chloride (0.44 g) and triethylamine (0.41 g) were added thereto, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, water was poured thereto, and the mixture was extracted with chloroform (50 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product. This crude product thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give 3-(4-fluorophenyl)-4-(9-methanesulfonyloxynonyl)-7-methoxy-3-methylthiochroman (a mixture of (3RS,4RS) and (3RS, 4SR), (3RS,4RS)/(3RS,4SR)=about 6/1) (480 mg, yield 99%).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:14]1[N:15]=[CH:16][C:17]2[C:23](=[O:24])[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][N:20]([CH2:30][CH3:31])[C:18]=2[N:19]=1.Cl.C1(N2CCNCC2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:14]3[N:15]=[CH:16][C:17]4[C:23](=[O:24])[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][N:20]([CH2:30][CH3:31])[C:18]=4[N:19]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)ncc2c1=O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(c4ccccc4)CC3)ncc2c1=O
Yield: 83 %

Procedure:
A solution of 3.2 g (0.02 mol) of N-phenyl-piperazine in 30 cm3 of toluene is added to 2.8 g (0.01 mol) of 2-chloro-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)-pyrimidine dissolved in 30 cm3 of toluene. Reaction takes place practically instantaneously with evolution of heat and the mixture sets solid due to formation of phenylpiperazine hydrochloride. The mixture is diluted with 100 cm3 of ethyl acetate, the solution is filtered, washed with water and dried (MgSO4) and the solvent is evaporated. The residue is recrystallised from 110 cm3 of isopropanol and yields 3.38 g (84%) of 2-(4'-phenyl-piperazino)-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine; melting point 186°C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.N1C=CN=C1.[Si:20](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[Si:20]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
10.0 g (49.7 mmol) of tert-butyl 4-hydroxypiperidine-1-carboxylate and 4.06 g (59.7 mmol) of imidazole were initially charged in 100 ml of anhydrous DMF, and 15.02 g (54.7 mmol) of tert-butyl(diphenyl)silyl chloride were added at 0° C. After the reaction mixture had been stirred at RT for 48 h, it was poured into 1.6 liters of water and then extracted three times with approx. 500 ml each time of diethyl ether. The combined organic extracts were washed successively with saturated sodium hydrogencarbonate solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate, the mixture was filtered and the solvent was removed on a rotary evaporator. The remaining residue was roughly purified by means of suction filtration (approx. 300 g of silica gel, eluent: cyclohexane→2:1 cyclohexane/ethyl acetate). 22.21 g (91% of theory, approx. 90% purity) of the title compound were obtained.
Reaction SMILES: C(OC(=O)CC1C=CC=CC=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:29])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-:37].[Na+]>C1COCC1.O>[C:16]1([CH:19]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH3:29])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH2:20][OH:37])[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: [OH-]
Reactant: CCOC(=O)Cc1ccccc1Oc1ccc(C2CCN(C)c3ccccc32)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(c2ccc(OC(CO)c3ccccc3)cc2)c2ccccc21
Reaction time: 3 h

Procedure:
A solution of 10 g. of 2-[4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxy]-phenylacetic acid ethyl ester in 25 ml. of the THF is added dropwise, over the course of 30 minutes, to a solution of 1.1 g. of LiAlH4 in 25 ml. of THF. The mixture is boiled for 3 hours, cooled, a mixture of 10 ml. of water and 40 ml. of THF and then 10 ml. of concentrated sodium hydroxide solution are added dropwise, the phases are separated and the organic phase is evaporated to give 2-phenyl-2-[4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)phenoxy)-ethanol; nD20 1.6085. Hydrochloride, softens above 75° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[S-:12][C:13]#[N:14].[Na+].O>C(O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14])=[CH:6][CH:7]=1
Reactant: N#C[S-]
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CSCC(=O)c1ccc(F)cc1

Procedure:
10 g (46 mmol) of 2-bromo-1-(4-fluorophenyl)ethanone and 3.74 g (46 mmol) of sodium thiocyanate were stirred in 80 ml ethanol at 50° C. for 2 h. After addition of water the separated solid was isolated by filtration, washed and dried. Yield: 8.96 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[C:4]([C:11](OCC)=[O:12])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].[NH2:17][C:18]1[N:22]=[CH:21][NH:20][N:19]=1.BrC1C=CC=CC=1>CCCCCC>[Cl:1][C:2]1[C:3]([OH:16])=[C:4]([C:11]([NH:17][C:18]2[N:22]=[CH:21][NH:20][N:19]=2)=[O:12])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: Nc1nc[nH]n1
Reactant: CCOC(=O)c1c(O)c(Cl)c(C)n(C)c1=O
Solvent: CCCCCC
Solvent: Brc1ccccc1
Product: Cc1c(Cl)c(O)c(C(=O)Nc2nc[nH]n2)c(=O)n1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
161 mg of ethyl 5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 51 mg of 3-amino-1,2,4-triazole were added to 1.5 ml of bromobenzene, then, the mixture was stirred for 5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature, then, hexane was added to this and the resultant mixture was allowed to stand still. The resulting solid was collected by filtration, and washed with a mixture of t-butyl methyl ether and n-hexane and dried to obtain 153 mg of 5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-N-(1,2,4-triazol-3-yl)-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 29) represented by the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]=[C:11]=[S:12])=[O:9].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[C:29]=1[CH3:36].C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH:10][C:11]([NH:32][C:31]1[CH:33]=[CH:34][C:28]([O:27][C:18]2[C:17]3[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=3)[N:21]=[CH:20][CH:19]=2)=[C:29]([CH3:36])[C:30]=1[CH3:35])=[S:12])=[O:9]
Reactant: O=C(N=C=S)c1ccccc1Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Cl)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Commercially available 2-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (68 mg, yield 85%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[H-].[Na+].CS(O[CH2:21][CH2:22][N:23]1[CH2:28][CH:27]2[CH:25]([CH:26]2[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24]1)(=O)=O.COC1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>ClCCl.CO>[C:12]([C:9]1[CH:10]=[CH:11][C:5]2[O:4][CH2:3][C:2](=[O:1])[N:7]([CH2:21][CH2:22][N:23]3[CH2:24][CH:25]4[CH:27]([CH:26]4[NH:29][C:30](=[O:31])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:28]3)[C:6]=2[CH:8]=1)#[N:13]
Reactant: CC(C)(C)OC(=O)NC1C2CN(CCOS(C)(=O)=O)CC21
Reactant: N#Cc1ccc2c(c1)NC(=O)CO2
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1C2CN(CCN3C(=O)COc4ccc(C#N)cc43)CC21
Yield: 74 %

Procedure:
3-Oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 60) (231 mg, 1.5 mmol) was deprotonated with sodium hydride and alkylated with 2-{6-[(tert-butoxycarbonyl)amino]-3-azabicyclo[3.1.0]hex-3-yl}ethyl methanesulfonate (Intermediate 95) (1.55 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (20:1) gave 442 mg (94%) product as a yellow gum.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[N:18]=[CH:19][N:20]([CH3:22])[CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>CO.ClCCl.C(OCC)C>[ClH:23].[CH3:22][N:20]1[CH:21]=[C:17]([S:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)(=[O:15])=[O:16])[N:18]=[CH:19]1
Reactant: Cn1cnc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: Cn1cnc(S(=O)(=O)N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(1-Methylimidazole-4-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (730 mg) was dissolved in methanol (10 ml) and dichloromethane (5 ml), 2M HCl in diethyl ether (11 ml) was added and the reaction mixture was stirred at room temperature overnight. Volatiles were removed in vacuo to yield 4-(1-methylimidazole-4-sulfonyl)-piperazine hydrochloride salt (704 mg).
Reaction SMILES: C(N(CC)CC)C.[O:8]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=O)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[C:26]1([C:32]2[CH:33]3[C:46](=O)[CH:37]([CH:38]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH:39]=2)[CH2:36][CH2:35][CH2:34]3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.CCCCCC.[Zn]>[O:8]([C:16]1[CH:17]=[C:18]([CH2:19][O:21][CH:22]=[C:36]2[CH2:35][CH2:34][CH:33]3[CH2:46][CH:37]2[CH:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:39]=[C:32]3[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: O=C1C2CCCC1C(c1ccccc1)C=C2c1ccccc1
Reactant: COC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(COC=C2CCC3CC2C(c2ccccc2)C=C3c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Into a 1000 mL three-neck flask equipped with magnetic stirrer, pressure-equalizing addition funnel and nitrogen line was charged with 200 mL of anhydrous THF. Ttitanium tetrachloride (17 mL) was added dropwise over a period of 30 minutes. The suspension was stirred for 20 minutes and 25.5 parts of zinc was added in small portions . The reaction mixture was heated under reflux for 2 hours and 42.5 mL of triethylamine was added dropwise. After refluxing one hour, 9 parts of a solution of methyl 3-tert-butyldimethylsiloxybenzoate and 4 parts of ketone (77) in 100 mL of dry THF was added over a period of 60 minutes and the reaction mixture was heated for one hour. The mixture on TLC silica gel plate showed the presence of the starting ester. An additional 1 part of starting ketone (77) in 35 mL of dry THF was added dropwise over 45 minutes and refluxed for two hours. The mixture was cooled to room temperature, diluted with 600 mL of hexane and decanted. The residue was washed with 3×250 mL of hexane. The combined hexane layer was filtered and evaporated under reduced pressure to give an oily material which was purified by chromatography on silica gel column using 5% ethyl acetate/hexane as an eluant. The fractions were checked by TLC on silica gel plate and the desired fractions were combined. The solvent was evaporated under reduced pressure to give an oil, yield 9.6 parts.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].[C:9](Cl)(=[O:11])[CH3:10]>>[C:9]([O:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5])(=[O:11])[CH3:10]
Reactant: CC(C)(CO)C(=O)O
Reactant: CC(=O)Cl
Product: CC(=O)OCC(C)(C)C(=O)O
Yield: 81 %

Procedure:
A solution of 3-hydroxy-2,2-dimethyl-propionic acid (1.5 g, 12.69 mmol) in 5 ml of acetyl chloride was heated at 80° C. under nitrogen for 2 hours. The excess of acetyl chloride was evaporated under reduced pressure. The resulting residue was dissolved in dichloromethane and washed with water. The organic layer was separated, dried and evaporated to get the desired 3-acetoxy-2,2-dimethyl-propionic acid (1.65 g, 81% yield) as a colorless liquid.
Reaction SMILES: O=[C:2]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[C:31]([CH3:32])=[CH:30][C:29]([O:33][CH3:34])=[C:28]([O:35][CH3:36])[C:27]=1[OH:37])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.CN(C)C=O.S1(CCCC1)(=O)=O>C1CCCCC1>[OH:37][C:27]1[C:28]([O:35][CH3:36])=[C:29]([O:33][CH3:34])[CH:30]=[C:31]([CH3:32])[C:26]=1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: COc1cc(C)c(CCCCCCCCCC(=O)CCCCCCCCCCCC(=O)O)c(O)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Solvent: O=S1(=O)CCCC1
Product: COc1cc(C)c(CCCCCCCCCCCCCCCCCCCCCC(=O)O)c(O)c1OC
Yield: 58.6 %

Procedure:
13-oxo-22-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)docosanoic acid (5.21 g) is reduced in the presence of p-toluenesulfonic acid (250 mg) and p-toluenesulfonyl hydrazide (2.33 g) in a solvent mixture of dimethylformamide (25 ml)-sulfolane (25 ml)-cyclohexane (25 ml) as in the corresponding step of Reference Example 5. The resultant crude product is recrystallized from methanol to obtain 2.97 g of 22-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)docosanoic acid, m.p. 67° C.-68° C. The physico-chemical constants of this product are all in agreement with those of the crystals obtained in Reference Example 4.