Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C@H:5]2[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(Cl)Cl>[CH:1]1([N:4]([C@H:5]2[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:7][CH2:6]2)[C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)C[C@H]1CC[C@H](NC2CC2)CC1
Reactant: COc1ccc(C(=O)O)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H]1CC[C@H](N(C(=O)c2ccc(OC)cc2)C2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(trans-4-(cyclopropylamino)cyclohexyl)acetate (0.150 g, 0.710 mmol) in CH2Cl2 (2.5 mL) were added diisopropylethylamine (0.173 ml, 0.994 mmol), 4-methoxybenzoic acid (0.130 g, 0.852 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.470 g, 1.85 mmol) sequentially. The mixture was stirred at room temperature overnight, diluted with CH2Cl2 (50 mL), and then washed with 10% Na2CO3 and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified through silica gel chromatography eluting with 18%-25% EtOAc-hexane. The desired amide product was obtained as a colorless oil (0.174 g). MS: 346 (M+1), C20H27NO4.
Reaction SMILES: [Na].C[O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][N:7]=1)=[O:5].Br[CH:14]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)[C:15]([O:17]C)=[O:16]>CO>[C:15]([CH:14]([S:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]([OH:3])=[O:5])=[N:7][CH:8]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=1)([OH:17])=[O:16]
Reactant: COC(=O)C(Br)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(S)cn1
Agent: [Na]
Solvent: CO
Product: O=C(O)c1ccc(SC(C(=O)O)c2cccc(C(F)(F)F)c2)cn1
Reaction time: 8 h

Procedure:
To the solution prepared from 80 ml of methanol and 0.89 g of sodium, 6.53 g of 5-mercaptopyridine-2-carboxylic acid methyl ester are added, followed by the solution of 12.6 g of methyl α-bromo-m-trifluoromethylphenylacetate in 50 ml of methanol while stirring under nitrogen. The mixture is warmed for 1/2 hour on the steam bath and allowed to stand at room temperature overnight. It is evaporated, the residue taken up in water-diethyl ether, the organic phase washed with water, dried and evaporated. The residue is dissolved in the minimum amount of methanolisopropanol (1:1), the solution mixed with 85 ml of N aqueous sodium hydroxide, warmed for 1/2 hour on the steam bath, and stored at room temperature overnight. The mixture is evaporated, the residue taken up in 2 N hydrochloric acid and the mixture extracted with diethyl ether-ethyl acetate (1:1). The extract is washed with water, dried and evaporated and the residue recrystalized from diethyl ether-ethyl acetate, to yield the 5-(α-carboxy-m-trifluoromethylbenzylmercapto)-pyridine-2-carboxylic acid melting at 190°-195°.
Reaction SMILES: C(OCCCC)CCC.[C:10]1([Li])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)C.[CH3:22][C:23]1[CH:28]=[N:27][CH:26]=[C:25]([CH3:29])[N:24]=1>O>[CH3:22][C:23]1[C:28]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:27][CH:26]=[C:25]([CH3:29])[N:24]=1
Reactant: [Li]c1ccccc1
Reactant: Cc1cncc(C)n1
Solvent: CCCCOCCCC
Solvent: CCOCC
Solvent: O
Product: Cc1cnc(-c2ccccc2)c(C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 16 %

Procedure:
First, in a nitrogen atmosphere, 50 mL of a dibutylether solution containing phenyl lithium (produced by Wako Pure Chemical Industries, Ltd, 2.1 mol/L) and 250 mL of diethyl ether were mixed. Then, 10.33 g of 2,6-dimethylpyrazine was added into this solution while the solution was being cooled with ice, and stirred at a room temperature for 24 hours. Water was added into this mixture and an organic layer was extracted with diethylether. The obtained organic layer was washed with water and dried with magnesium sulfate. After the drying, the solution was filtrated. After the solvent of the filtrate was distilled off, the obtained residue was purified by silicagel column chromatography using dichloromethane as a developing solvent, thereby obtaining an objective pyrazine derivative Hmppr-Me (reddish brown liquid, yield: 16%). A synthesis scheme of Step 1 is shown by the following (a-2).
Reaction SMILES: C1(N2C(=O)C3=CNC4[CH:14]=[C:15]([N:19]5[CH2:24]CN[CH2:21][CH2:20]5)C=CC=4C3=N2)C=CC=CC=1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]2[C:32]3[C:33]([C:38](=[O:48])[N:39]([C:41]4[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=4)[N:40]=3)=[CH:34][NH:35][C:36]=2[CH:37]=1.CN1CCNCC1>>[Cl:47][C:44]1[CH:45]=[CH:46][C:41]([N:39]2[C:38](=[O:48])[C:33]3=[CH:34][NH:35][C:36]4[CH:37]=[C:28]([N:27]5[CH2:21][CH2:20][N:19]([CH3:24])[CH2:15][CH2:14]5)[CH:29]=[CH:30][C:31]=4[C:32]3=[N:40]2)=[CH:42][CH:43]=1
Reactant: Nc1ccc2c3nn(-c4ccc(Cl)cc4)c(=O)c-3c[nH]c2c1
Reactant: O=c1c2c[nH]c3cc(N4CCNCC4)ccc3c-2nn1-c1ccccc1
Agent: CN1CCNCC1
Product: CN1CCN(c2ccc3c4nn(-c5ccc(Cl)cc5)c(=O)c-4c[nH]c3c2)CC1

Procedure:
The title compound was prepared following the procedure for 14a using 13b and 1-methylpiperazine. 1H-NMR (CD3OD) δ (ppm): 2.39 (3H, s), 2.67 (4H, brm), 3.40 (4H, brm), 7.01 (1H, d, J=2.47 Hz), 7.34 (1H, dd, J=9.07, 2.47 Hz), 7.46 (2H, dd, J=6.87, 2.20 Hz), 8.09 (2H, dd, J=7.14, 1.92 Hz), 8.19 (1H, d, J=9.07 Hz), 8.51 (1H, s). m/z 394.9 (MH+).
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:16](O)=O)[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=O)(C)(C)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C@@H:27]([NH2:29])[CH3:28]>>[NH:13]1[CH:12]=[C:11]([CH2:10][C@@H:9]([NH2:8])[CH2:16][NH:29][C@H:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])[CH3:28])[N:15]=[CH:14]1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]cn1)C(=O)O
Reactant: COc1ccccc1[C@H](C)N
Product: COc1ccccc1[C@H](C)NC[C@H](N)Cc1c[nH]cn1
Yield: 24.2 %

Procedure:
By using N-t-butoxycarbonyl-(D)-histidine (405 mg), and (1S)-1-(2-methoxyphenyl)ethanamine compound (200 mg) obtained by the method described in the publication (Japanese Patent Unexamined Publication No. 54/154724) as starting materials, the title compound (88 mg) was obtained in the same manner as that of Reference Example 71.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:29])=[CH:6][C:7]([F:28])=[C:8]([N:10]2[C:19]3[C:14](=[C:15]([CH3:23])[C:16]([F:22])=[C:17](F)[C:18]=3[CH3:20])[C:13](=[O:24])[C:12]([C:25]([OH:27])=[O:26])=[CH:11]2)[CH:9]=1>N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:29])=[CH:6][C:7]([F:28])=[C:8]([N:10]2[C:19]3[C:14](=[C:15]([CH3:23])[C:16]([F:22])=[C:17]([NH:2][CH3:1])[C:18]=3[CH3:20])[C:13](=[O:24])[C:12]([C:25]([OH:27])=[O:26])=[CH:11]2)[CH:9]=1
Reactant: CN
Reactant: Cc1c(F)c(F)c(C)c2c1c(=O)c(C(=O)O)cn2-c1cc(N)c(F)cc1F
Solvent: c1ccncc1
Product: CNc1c(F)c(C)c2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1C
Temperature: 40 °C
Reaction time: 192 h

Procedure:
Pyridine (300 mg) and a 40% aqueous solution (150 mg) of methylamine were added to 1-(5-amino-2,4-difluorophenyl)-6,7-difluoro-5,8-dimethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (110 mg), and the mixture was heated and stirred at 40° C. for 8 days. The solvent and the like were distilled off under reduced pressure, and ethanol (0.5 ml) was added to the residue. The mixture was left to stand for 3 days, and solids deposited were collected by filtration and washed with ethanol and diethyl ether to obtain the title compound (20 mg) as a pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CI.[C:17]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([CH3:17])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN1CCC(O)(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A reaction mixture of 4-(4-bromophenyl)piperidin-4-ol (1.5 g, 5.9 mmol), methyl iodide (0.4 mL, 6.4 mmol), and K2CO3 (1.2 g, 8.8 mmol) in acetone was stirred at rt for 90 min
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C@@:14]4([CH3:19])[C:16]([CH3:18])([CH3:17])[C@H:11]([CH2:12][CH2:13]4)[C:10]=3[C:9](=[O:20])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1>ClCCl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:19][C@@:14]12[C:16]([CH3:17])([CH3:18])[C@@H:11]([C:10]3[C:9](=[O:20])[N:8]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:15]=31)[CH2:12][CH2:13]2
Reactant: OB(O)c1ccccc1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)[nH]n1-c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccccc2)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 44.7 %

Procedure:
A mixture of (4S,7R)-1-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 8; 1.00 g, 3.7 mmol), phenyl-boronic acid (0.94 g, 7.5 mmol), and copper(II) acetate (1.03 g, 5.6 mmol) in dichloromethane (10 mL) and pyridine (0.6 mL, 7.5 mmol) was stirred at room temperature for 2 days and then heated at reflux for 2 h. The reaction mixture was diluted with water and dichloromethane. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were washed with water, 10% copper(II) sulfate solution, water, and brine. The solution was then dried (magnesium sulfate), filtered, evaporated and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an Analytical Sales Aspire 90 g column, eluting with 10-50% ethyl acetate/hexanes to give (4S,7R)-7,8,8-trimethyl-1,2-diphenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (0.57 g, 44%) as a light brown solid. ES(+)-MS (M+H) 345.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[CH3:32][N:33]([CH3:39])[C@@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1.[Li+].[Cl:41][C:42]1[CH:47]=[CH:46][N:45]=[C:44]2[CH:48]=[C:49]([C:51]([O-])=[O:52])[S:50][C:43]=12>CN(C=O)C>[Cl:41][C:42]1[CH:47]=[CH:46][N:45]=[C:44]2[CH:48]=[C:49]([C:51]([N:36]3[CH2:37][CH2:38][C@@H:34]([N:33]([CH3:39])[CH3:32])[CH2:35]3)=[O:52])[S:50][C:43]=12
Reactant: CN(C)[C@@H]1CCNC1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 32.1 %

Procedure:
HATU (4.99 g, 26.25 mmol) and Et3N (7.23 mL, 52.50 mmol) was added to a solution of (3R)-N,N-dimethylpyrrolidin-3-amine (1.0 g, 17.5 mmol) and 7-chlorothieno[3,2-b]pyridine-2-carboxylic acid lithium salt (3.85 g, 17.5 mmol) in 30 mL DMF at 0° C. The reaction mixture was stirred at 0° C. for 15 min and solvent was concentrated. The residue was partition between H2O and 10% CH3OH in EtOAC. The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (5-7% CH3OH in CH2Cl2) to give a white solid (1.74 g, 32%). 1H NMR (CD3OD) δ 8.57 (1H, d, J=5.2 Hz), 7.90 (1H, d, J=7.9 Hz), 7.48 (1H, d, J=5.2 Hz), 4.11-3.97 (1H, m), 3.90-3.36 (3H, m), 2.99-2.90 (1H, m), 2.30 (3H, s), 2.26 (3H, s), 1.97-1.72 (2H, m). ESIMS (MH+): 310.10.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:6]=2[CH:22]=1.[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[CH:24]=[CH2:25]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([CH2:25][CH2:24][C:23]([O:27][CH2:28][CH3:29])=[O:26])[CH2:18][CH2:17]3)[C:6]=2[CH:22]=1
Reactant: C=CC(=O)OCC
Reactant: Clc1ccc2c(c1)C(N1CCNCC1)=Nc1ccccc1O2
Solvent: CCO
Product: CCOC(=O)CCN1CCN(C2=Nc3ccccc3Oc3ccc(Cl)cc32)CC1
Yield: 88.8 %

Procedure:
A mixture of 3.14 g of 2-chloro-11-(1-piperazinyl)dibenz[b,f][1,4]oxazepine and 1.20 g of ethyl acrylate in 16 ml of ethanol was refluxed for 2 hrs. The reaction mixture was concentrated and the residue was chromatographed on silica gel using a mixture of n-hexane and ethyl acetate (2:1 and 1:1) as eluents to give 3.68 g of yellow crystals, which were recrystallized from a mixture of isopropyl ether and n-pentane to give yellow prisms, mp 73°-75° C.
Reaction SMILES: [C:1]([O:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]1)(=[O:21])[C:2]1[CH:20]=[CH:19][CH:18]=[C:4]([C:5]([O:7][CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]2)=[O:6])[CH:3]=1.[C:33]([O:37]O)([CH3:36])([CH3:35])C>[Mo](=O)(=O)=O.C1CCCCC1>[C:5]([O:7][CH:8]1[CH2:9][C:10]([CH3:17])([CH3:16])[N:11]([O:37][CH:33]2[CH2:36][CH2:18][CH2:4][CH2:5][CH2:35]2)[C:12]([CH3:14])([CH3:15])[CH2:13]1)(=[O:6])[C:4]1[CH:18]=[CH:19][CH:20]=[C:2]([C:1]([O:22][CH:23]2[CH2:24][C:25]([CH3:32])([CH3:31])[N:26]([O:37][CH:33]3[CH2:36][CH2:3][CH2:2][CH2:1][CH2:35]3)[C:27]([CH3:30])([CH3:29])[CH2:28]2)=[O:21])[CH:3]=1
Reactant: CC(C)(C)OO
Reactant: CC1(C)CC(OC(=O)c2cccc(C(=O)OC3CC(C)(C)NC(C)(C)C3)c2)CC(C)(C)N1
Agent: O=[Mo](=O)=O
Solvent: C1CCCCC1
Product: CC1(C)CC(OC(=O)c2cccc(C(=O)OC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)c2)CC(C)(C)N1OC1CCCCC1
Temperature: 140 °C
Yield: 143.5 %

Procedure:
A mixture of 35.0 g (78.7 mmol) of di-(2,2,6,6-tetramethyl-piperidin-4-yl) isophthalate, 47.3 g (472 mmol) of 90% aqueous t-butyl hydroperoxide, 2.0 g of molybdenum trioxide, and 300 ml of cyclohexane is heated two hours at 140° C. in a Fischer-Porter bottle. The red reaction mixture is treated with an additional 20.0 g (90%, 200 mmol) of t-butyl hydroperoxide and heated at 140° C. for 120 minutes to discharge the red color. The reaction mixture is cooled, filtered, and the filtrate is evaporated to an oil which is crystallized from ethanol to afford 36.2 g (72% yield) of a white solid, m.p. 135°-141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](O)([C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[C:9](=[O:21])[N:8]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[O:33][C:34]([F:37])([F:36])[F:35])(=[O:24])=[O:23])[C:5]2=[N:6][CH:7]=1.CS(OS(C)(=O)=O)(=O)=O.CCN(CC)CC.FC(F)(F)C(O)=O.[OH:61][C@H:62]1[CH2:66][NH:65][C@H:64]([C:67]([N:69]([CH3:71])[CH3:70])=[O:68])[CH2:63]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([N:65]3[CH2:66][C@H:62]([OH:61])[CH2:63][C@H:64]3[C:67]([N:69]([CH3:71])[CH3:70])=[O:68])([C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[C:9](=[O:21])[N:8]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[O:33][C:34]([F:35])([F:36])[F:37])(=[O:24])=[O:23])[C:5]2=[N:6][CH:7]=1
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(O)(c3cc(C)ccc3OC)c3cc(Cl)cnc32)c(OC(F)(F)F)c1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)cnc32)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, to a solution of 280 mg of the compound obtained in Step 118-6 in CHCl3 (2.8 ml) was added sequentially 107 mg of methanesulfonic acid anhydride and Et3N (104 mg), then, the reaction mixture was stirred for 30 minutes under the same condition. Under nitrogen atmosphere, to a suspension of (4R)-4-hydroxy-N,N-dimethyl-L-prolinamide trifluoroacetate (2.57 mmol) in CHCl3 (5 ml) was added Et3N (520 mg) under dry ice-acetone cooling. To the reaction solution was added dropwise over 30 seconds the reaction solution of the mesyl form prepared above, then the reaction mixture was warmed to room temperature over two hours. To the reaction solution was added water and CHCl3, liquid separation was performed, and the aqueous layer was extracted with CHCl3. The combined organic layer was washed with saturated brine, dried over MgSO4, then, the drying agent was separated by filtration and the filtrate was concentrated. The obtained residue was separated and purified by column chromatography (silicagel 60; mobile phase: CHCl3/MeOH/NH4OH=95/5/0.5; v/v/v) to obtain respectively 33 mg (Isomer A: brown amorphous) and 24 mg (Isomer B: pale brown amorphous) of two species of diastereoisomers of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15]OCC2)=[C:6]([NH:8][C:9]#[N:10])[CH:7]=1.[CH3:17][NH:18][CH3:19].[CH2:20]([OH:22])[CH3:21]>>[CH3:17][N:18]([CH3:19])[C:9]([NH2:10])=[N:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N:11]1[CH2:16][CH2:15][O:22][CH2:20][CH2:21]1
Reactant: N#CNc1cc(F)ccc1N1CCOCC1
Reactant: CCO
Reactant: CNC
Product: CN(C)C(N)=Nc1cc(F)ccc1N1CCOCC1

Procedure:
In a similar manner to that described in Example 286, N-(5-fluoro-2-morpholinophenyl)cyanamide (2.2 g) in ethanol (10 ml) and a 33% ethanolic solution of dimethylamine (6 ml) was heated under reflux for 20 minutes to give 1,1-dimethyl-2-(5-fluoro-2-morpholinophenyl)guanidine (m.p. 137°-138° C.) which was recrystallised from hexane and converted into its fumarate salt (m.p. 222°-224° C.) which was recrystallised from methanol.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[N:15]1([C:22]2[C:31]3[C:26](=[CH:27][C:28]([CH2:33][OH:34])=[C:29]([CH3:32])[CH:30]=3)[N:25]=[C:24]([Cl:35])[CH:23]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[F:36][C:37]([F:46])([F:45])[C:38]1[CH:39]=[C:40](O)[CH:41]=[CH:42][CH:43]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C(OCC)(=O)C>[N:15]1([C:22]2[C:31]3[C:26](=[CH:27][C:28]([CH2:33][O:34][C:42]4[CH:41]=[CH:40][CH:39]=[C:38]([C:37]([F:46])([F:45])[F:36])[CH:43]=4)=[C:29]([CH3:32])[CH:30]=3)[N:25]=[C:24]([Cl:35])[CH:23]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: Cc1cc2c(N3CCCCCC3)cc(Cl)nc2cc1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc2c(N3CCCCCC3)cc(Cl)nc2cc1COc1cccc(C(F)(F)F)c1
Yield: 79.7 %

Procedure:
Diisopropylazodicarboxylate (66 mg, 0.33 mmol) was added dropwise at r.t. to a solution of (4-Azepan-1-yl-2-chloro-6-methyl-quinolin-7-yl)-methanol (example 82, 100 mg, 0.33 mmol), 3-trifluoromethylphenol (53 mg, 0.33 mmol), and triphenylphosphine (86 mg, 0.33 mmol) in dichloromethane (2 mL), then after 2 h ethyl acetate was added and the solution was washed with 1 M aq. sodium hydroxide solution and brine, dried (MgSO4), and evaporated. Flash chromatography (SiO2, hexane/ethyl acetate gradient) yielded the title compound (118 mg, 80%). White solid, ISP-MS: m/e=449.4 ([M+H]+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.N1C(C)=CC=CC=1C.[Br:45][C:46]1[N:47]([C:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[C:59]([CH:66]3[CH2:68][CH2:67]3)=[CH:58][CH:57]=2)[C:48]([S:51][CH2:52][C:53](O)=[O:54])=[N:49][N:50]=1>ClCCl>[Br:45][C:46]1[N:47]([C:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[C:59]([CH:66]3[CH2:68][CH2:67]3)=[CH:58][CH:57]=2)[C:48]([S:51][CH2:52][C:53]([NH:6][CH:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH3:2])=[O:14])=[O:54])=[N:49][N:50]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)C(Cc1ccccc1)NC(=O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Phenylalanine methyl ester hydrochloride (1.48 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.86 mmol), 1-hydroxy-7-azabenzotriazole (1.86 mmol) and 2,6-lutidine (0.43 mL, 3.71 mmol) are added to a solution of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (0.5 g, 1.24 mmol) in dichloromethane (6.18 mL). The mixture is stirred at room temperature for 18 hours and then purified by SGC (0-100% EtOAc/Hexanes).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH2:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1COCC1.[N+](=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N-]>C1(C)C=CC=CC=1.[Cu]Cl>[C:11]([NH:10][C:3]1[CH:4]=[CH:5][C:6]([C@@H:8]2[CH2:9][C@H:26]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:7][C:2]=1[CH3:1])(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1ccc(NC(=O)c2ccccc2)c(C)c1
Agent: Cl[Cu]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(NC(=O)c2ccccc2)c(C)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of N-(4-bromo-2-methylphenyl)benzamide(4.35 g) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.54 g) in THF (64.3 mL)/water (10.7 mL) were added 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (0.367 g) and triethylamine (4.18 mL). The reaction mixture was stirred at 60° C. overnight, and poured into saturated aqueous ammonium chloride solution. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give a mixture (4.42 g) containing N-(2-methyl-4-vinylphenyl)benzamide. To a solution of the mixture (4.42 g) and copper(I) chloride (0.233 g) in toluene (36 mL)/THF (5 mL) was added dropwise a solution of ethyl diazoacetate (9.79 mL) in toluene (25 mL) at 80° C. over 1 hr or longer. The mixture was stirred at 80° C. overnight, cooled to room temperature, and filtered through celite. The mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.29 g).
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH3:15])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19](F)[CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[C:23]([CH:24]=1)[O:1][CH:2]([CH2:14][CH3:15])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:11])[CH3:9]
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: CCC(O)CCN(C)C(=O)OC(C)(C)C
Product: CCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)ccc1C#N

Procedure:
The title compound was prepared according to the method of Example 3 step (b) but using (3-hydroxypentyl)methylcarbamic acid, 1,1-dimethylethyl ester and 4-chloro-2-fluorobenzonitrile.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[CH:4]=1.Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>C1COCC1>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:4]=1
Reactant: COC(=O)CBr
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COc1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
Sodium hydride (3.78 g, 80% suspension in oil) was added to a solution of 3-pyridinol (10 g) in THF (150 ml) at 0°. The mixture was stirred under nitrogen for 30 min, treated dropwise with methyl bromoacetate (19.3 g), heated under reflux for 24 h, poured into ice-water (200 ml) and extracted with ethyl acetate (2×100 ml). The combined organic extracts were dried and concentrated to give an oil which was purified by FCC, eluting with System G (98:2:1) to give the title compound (4 g), as an oil. T.l.c. (System E 80:20:1) Rf 0.46
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccccc1
Reactant: O=CC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: CC(C)(C)c1ccc(C(O)C(=O)c2ccccc2)cc1

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and tert-butylbenzene (0.62 ml, 4 mM) were dissolved in dichloroethane (2 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 2.5 hours. Using the same procedure as in Example 1, 4'-tert-butylbenzoin was obtained as crystal (216.9 mg, 40.5% yield).