Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28]([CH:30]4[CH2:31][CH2:32]4)=[O:29])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CCCCCl)c1cccc(Cl)c1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: O=C(CCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1cccc(Cl)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(3-chlorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 439.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:15]([F:18])([F:17])[F:16])=[O:12])=[CH:8][C:7]=2[CH:29]=1.N1C=CC=CC=1.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl.C(OCC)(=O)C>[C:36]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=3)[C:15]([F:16])([F:17])[F:18])=[O:12])=[CH:8][C:7]=2[CH:29]=1)(=[O:38])[CH3:37]
Reactant: NCc1ccc2oc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)cc2c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)NCc1ccc2oc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)cc2c1
Temperature: 0 °C

Procedure:
A solution of 5-(aminomethyl)-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1-benzofuran-2-carboxamide (50 mg, 0.12 mmol) in dichloromethane (1 ml) was admixed with pyridine (0.01 ml) and cooled to 0° C. Then acetyl chloride (9 μl, 0.12 mmol) was added dropwise and the mixture was warmed up to room temperature overnight. The mixture was diluted with ethyl acetate and washed with hydrochloric acid (1 M). The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was chromatographed on a preparative HPLC with water/acetonitrile as the eluent (gradient=43 min from 10% acetonitrile in water to 100% acetonitrile).
Reaction SMILES: [Cl:1][C:2]1[C:17]([N+:18]([O-])=O)=[CH:16][C:5]2[C:6]([O:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[N:7][O:8][C:4]=2[CH:3]=1.Cl.[H][H]>[Pd].C(O)C>[ClH:1].[NH2:18][C:17]1[C:2]([Cl:1])=[CH:3][C:4]2[O:8][N:7]=[C:6]([O:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH:16]=1
Reactant: COC(=O)C(C)Oc1noc2cc(Cl)c([N+](=O)[O-])cc12
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COC(=O)C(C)Oc1noc2cc(Cl)c(N)cc12

Procedure:
A suspension of methyl 2-[(6-chloro-5-nitro-1,2-benzisoxazol-3-yl)oxy]propionate (2.0 g, 6.7 mmol), 5% palladium on activated carbon (0.1 g) and concentrated hydrochloric acid (0.6 mL) in ethanol is hydrogenated until 430 mL of hydrogen is taken up. The reaction mixture is then filtered through diatomaceous earth and concentrated in vacuo to give the title product as a brown gum which is identified by NMR spectral analyses.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[N:14]3[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30](O)=[O:31])[CH:25]=4)[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:33]1([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:18])[F:19])[N:14]3[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30]([N:36]5[CH2:35][CH2:34][N:33]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:37]5)=[O:31])[CH:25]=4)[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4ccnc(C(=O)O)c4)cc3N2)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4ccnc(C(=O)N5CCN(C(=O)OC(C)(C)C)CC5)c4)cc3N2)cc1OC
Yield: 42.9 %

Procedure:
Example ER-897034 was prepared in two steps from 4-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)picolinic acid (25 mg, 0.056 mmol) and commercially available tert-butyl piperazine-1-carboxylate (31 mg, 0.167 mmol) in a manner similar to that of example D-6 to afford intermediate tert-butyl 4-(4-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)picolinoyl)piperazine-1-carboxylate (15 mg, 0.024 mmol, 44% yield). Then, this intermediate (13 mg, 0.021 mmol) was treated with HCl in a manner similar to that of example ER-897560 to afford the desired product ER-897034 (12.2 mg, 98% yield).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][C@@:11]2([N:36]=1)[C:20]1([CH2:23][O:22][CH2:21]1)[C:19]([CH3:25])([CH3:24])[O:18][C:17]1[C:12]2=[CH:13][C:14]([NH:26][C:27]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)=[O:28])=[CH:15][CH:16]=1)(C)(C)C>C1(C)C=CC=CC=1>[NH2:7][C:8]1[O:9][CH2:10][C@@:11]2([N:36]=1)[C:20]1([CH2:21][O:22][CH2:23]1)[C:19]([CH3:24])([CH3:25])[O:18][C:17]1[C:12]2=[CH:13][C:14]([NH:26][C:27]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)=[O:28])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(CO1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1OC(C)(C)C21COC1
Solvent: Cc1ccccc1
Product: CC1(C)Oc2ccc(NC(=O)c3ccc(Cl)cn3)cc2[C@@]2(COC(N)=N2)C12COC2
Temperature: 120 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
A mixture of tert-butyl[(4S)-6′-{[(5-chloropyridin-2-yl)carbonyl]amino}-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]carbamate (1.02 g, 1.93 mmol), silica gel (neutral; 3.06 g) and toluene (20.4 mL) was stirred for 3 hours at 120° C. The reaction mixture was cooled down to ambient temperature and concentrated at reduced pressure. The residue was purified with column chromatography on silica gel (CHCl3-EtOH, a linear gradient of EtOH from 0 to 15%) and then with NH-silica gel (Hexane-EtOAc, a linear gradient of EtOAc from 50 to 100%). The purified product was recrystallized from EtOH/H2O (1:1), and the solid was collected by filtration and dried at reduced pressure to give a hydrate of N-[(4S)-2-amino-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-6′-yl]-5-chloropyridine-2-carboxamide (547 mg) as a crystal.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:26](=[O:27])[N:12]2[C:13]([C:23]([OH:25])=[O:24])=[C:14]([CH2:18]OC(=O)C)[C@H:15]([CH3:17])[S:16][C@H:11]12)=[O:8].C([O-])(O)=O.[Na+:32].[CH3:33][N:34]1[C:38]([SH:39])=[N:37][N:36]=[N:35]1>P(=O)(O)(O)O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:26](=[O:27])[N:12]2[C:13]([C:23]([O-:25])=[O:24])=[C:14]([CH2:18][S:39][C:38]3[N:34]([CH3:33])[N:35]=[N:36][N:37]=3)[C@H:15]([CH3:17])[S:16][C@H:11]12)=[O:8].[Na+:32]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S[C@H]1C
Reactant: Cn1nnnc1S
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [Na+]
Product: C[C@@H]1S[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C(C(=O)[O-])=C1CSc1nnnn1C
Temperature: 50 °C
Reaction time: 6 h
Yield: 30.3 %

Procedure:
In 20 ml of 1/15M phosphoric acid buffer solution (pH 6.4) were dissolved 410 mg of 7-(2-thienylacetamido)-2β-methyl-3-acetoxymethylceph-3-em-4-carboxylic acid and 84 mg of NaHCO3, and 139 mg of 1-methyl-5-mercaptotetrazole was then added to the solution. The reaction solution was stirred at 50° C. for 6 hours, while maintaining it at pH 6.4 by pouring 5% aqueous NaHCO3, and then added on a column of Amberlite XAD-II (produced by Rohm & Haas), followed by washing with water and eluting by the gradient method with 0 to 70% aqueous methanol. The eluted fractions were collected, concentrated under reduced pressure and freeze-dried, thus yielding 148 mg (30%) of sodium 7-(2-thienylacetamido)-2β-methyl-3-(1-methyl-1H-tetrazol-5-yl)thiomethylceph-3-em-4-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@@H:8]([CH2:11][CH3:12])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>CCOCC>[CH3:21][S:22]([O:10][CH2:9][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13])[CH2:11][CH3:12])(=[O:24])=[O:23]
Reactant: CC[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To an ice cold solution of (S)-tert-butyl(1-hydroxybutan-2-yl)carbamate (9.5 g, 50 mmol) and triethylamine (10.5 mL, 75 mmol) in ether (200 mL) was added methanesulfonyl chloride (4.0 mL, 50 mmol). After 1 h, water was added, and the resulting mixture was extracted with DCM, dried (Na2SO4), filtered, and concentrated to give an oil (13.4 g, 100%) which was used directly without further purification.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([C@@H:8]2[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:5]=2[N:4]=1.[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][C@H:24]([CH:29]=O)[CH2:23]2>>[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][C@H:24]([CH2:29][NH:13][C@H:10]1[CH2:11][CH2:12][C@@H:8]([N:7]3[C:6]4[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:5]=4[N:4]=[C:3]3[CH3:2])[CH2:9]1)[CH2:23]2
Reactant: Cc1ccc2c(c1)nc(C)n2[C@@H]1CC[C@H](N)C1
Reactant: O=C[C@H]1Cc2ccc(Br)cc2C1
Agent: Cl
Product: Cc1ccc2c(c1)nc(C)n2[C@@H]1CC[C@H](NC[C@H]2Cc3ccc(Br)cc3C2)C1

Procedure:
This compound was prepared from cis-3-(2,5-dimethyl-benzoimidazol-1-yl)-cyclopentylamine hydrochloride and (S)-5-bromo-indan-2-carbaldehyde using the same reductive amination method described in previous example. 1H-NMR is consistent with the assigned structure. LC-MS showed a single peak, C24H28BrN3 (m/e) calcd 437.1467, obsd 438.1 (M+H).
Reaction SMILES: C([O:3][C:4]([CH2:6][C@H:7]1[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:10]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:9][CH2:8]1)=O)C.[BH4-].[Li+].C(=O)(O)[O-].[K+]>C(OCC)C>[OH:3][CH2:4][CH2:6][C@H:7]1[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[C@H:10]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:9][CH2:8]1
Reactant: CCOC(=O)C[C@@H]1CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [K+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](CCO)N1C(=O)OC(C)(C)C
Reaction time: 6 h

Procedure:
43 g of the product from 1d were dissolved in 300 ml of diethyl ether. A solution of 3.1 g of lithium borohydride in 300 ml of diethyl ether was added dropwise thereto. The mixture was stirred for 6 h and the reaction was stopped by cautious addition of 300 ml of a saturated potassium bicarbonate solution. The phases were separated and the organic phase was washed with 250 ml of a saturated sodium chloride solution. The organic phase was dried with sodium sulfate, and the solvent was removed in vacuo. The residue was chromatographed on silica gel.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])(=O)=O.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C1COCC1>[N:21]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:12])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CS(=O)(=O)OCCCCNC(=O)OCc1ccccc1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: O=C(NCCCCN1CCCC1)OCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a pressure vessel was added 4-(benzyloxycarbonylamino)butyl methanesulfonate (330 mg, 1.10 mmol) and pyrrolidine (234 mg, 3.3 mmol) in THF. The reaction was heated to 100° C., stirred overnight, cooled to 20-25° C., and concentrated. The crude concentrate was purified by Biotage column chromatography to give benzyl 4-(pyrrolidin-1-yl)butylcarbamate (200 mg).
Reaction SMILES: [O:1]=[C:2]1[C@H:6]([NH:7][C:8]([C:10]2[C:14]([CH3:15])=[C:13](/[CH:16]=[C:17]3\[C:18](=[O:27])[NH:19][C:20]4[C:25]\3=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[NH:12][C:11]=2[CH3:28])=[O:9])[CH2:5][O:4][NH:3]1.[Na+].[I-].CCN(C(C)C)C(C)C.[H-].[Na+].[Cl-].Cl[CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>CN(C=O)C>[N:46]1([CH2:45][CH2:44][N:3]2[C:2](=[O:1])[C@H:6]([NH:7][C:8]([C:10]3[C:14]([CH3:15])=[C:13](/[CH:16]=[C:17]4\[C:18](=[O:27])[NH:19][C:20]5[C:25]\4=[CH:24][C:23]([F:26])=[CH:22][CH:21]=5)[NH:12][C:11]=3[CH3:28])=[O:9])[CH2:5][O:4]2)[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)N[C@@H]1CONC1=O
Reactant: ClCCN1CCOCC1
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)N[C@@H]1CON(CCN2CCOCC2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
To a solution of 42b (200 mg, 0.52 mmol), NaI (78 mg, 0.52 mmol) and DIEA (134 mg, 1.04 mmol) in DMF (25 mL) was added 60% NaH (125 mg, 3.13 mmol) at 0° C. After stirring at room temperature for 1 h, the mixture was added 4-(2-Chloro-ethyl)-morpholine chloride (194 mg, 1.05 mmol). The obtained mixture was stirred 48 h at room temperature. LC-MS was used to detect completion of the reaction. The mixture was evaporated under reduced pressure and the residue was triturated with 5% diethylamine/methanol (25 mL). The solid was collected by filtration which was purified again by column chromatography (CH2Cl2:MeOH=20:1) to provide the title compound (60 mg, 23%) as orange solid. 1H NMR (300 MHz, DMSO-d6): δ=13.59 (s, 1H), 11.53 (s, 1H), 7.79-8.13 (m, 3H), 7.04-7.12 (m, 2H), 5.00-5.06 (q, 1H), 4.57-4.62 (t, 1H), 3.97-4.10 (m, 3H), 3.44-3.58 (m, 4H), 2.78-2.94 (m, 1H), 2.47-2.50 (ds, 6H). LC/MS: 498.2 [M+H]+.
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].[CH3:7][O:8][C:9](=[O:21])[N:10]=[CH:11][CH2:12][C:13](OCCOCC)=[O:14]>CO>[NH2:5][C:4]1[NH:6][C:13](=[O:14])[CH:12]=[C:11]([NH:10][C:9]([O:8][CH3:7])=[O:21])[N:3]=1
Reactant: CCOCCOC(=O)CC=NC(=O)OC
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COC(=O)Nc1cc(=O)[nH]c(N)n1

Procedure:
10 g of sodium are dissolved in 200 ml of absolute methanol, whereupon the solution is treated with 30 g of guanidine hydrochloride. While stirring there is added thereto a solution of 50 g of methyl[(1-ethoxy-2-ethoxycarbonyl)ethylidene]carbamate in 150 ml of absolute methanol. The resulting suspension is stirred overnight and thereafter concentrated at 40° in a water-jet vacuum. 600 ml of water are added to the residue and the resulting suspension is adjusted to pH 5 with glacial acetic acid while stirring. The resulting precipitate is filtered off under suction, washed with 250 ml of water and dried at 50° in vacuo. There is obtained methyl 2-amino-1,6-dihydro-6-oxo-4-pyrimidinecarbamate which is uniform according to thin-layer chromatography.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.[O:10]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.ClCCl.O.C(#N)C>[CH3:8][C:7]1[C:2]([C:20]2[CH:21]=[CH:22][C:17]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:18][CH:19]=2)=[N:3][CH:4]=[C:5]([CH3:9])[N:6]=1
Reactant: Cc1cnc(Cl)c(C)n1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cnc(-c2ccc(Oc3ccccc3)cc2)c(C)n1
Yield: 89 %

Procedure:
First, into a recovery flask equipped with a reflux pipe were placed 1.35 g of 2-chloro-3,5-dimethylpyrazine, 2.02 g of 4-phenoxyphenylboronic acid, 1.00 g of sodium carbonate, 0.043 g of bis(triphenylphosphine)palladium(II)dichloride (abbreviation: Pd(PPh3)2Cl2), 15 mL of water, and 15 mL of acetonitrile, and the air inside the flask was replaced with argon. Heating was performed by microwave irradiation (2.45 GHz, 100 W) of this reaction container for 10 minutes, so that reaction occurred. After that, water was added to this reaction solution, and extraction with dichloromethane was carried out. A solution of the obtained extract was washed with water and dried over magnesium sulfate. After the drying, the solution was filtered. After the solvent of this solution was distilled, the obtained residue was washed with methanol, so that the pyrazine derivative which was the object of the synthesis, Hdmpoppr, was obtained (a white powder in a yield of 89%). Note that a microwave synthesis system (Discover, produced by CEM Corporation) was used for the microwave irradiation. The synthesis scheme of Step 1 is illustrated in the following formulae (e).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[NH2:28][C:29]1[S:30][CH:31]=[C:32]([CH3:37])[C:33]=1[C:34]([NH2:36])=[O:35].CCN=C=NCCCN(C)C>CN(C=O)C.C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:37][C:32]1[C:33]([C:34]([NH2:36])=[O:35])=[C:29]([NH:28][C:18](=[O:20])[CH2:17][C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:16][CH:15]=2)[S:30][CH:31]=1
Reactant: Cc1csc(N)c1C(N)=O
Reactant: O=C(O)Cc1ccc(OCCCN2CCCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1csc(NC(=O)Cc2ccc(OCCCN3CCCCC3)cc2)c1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring mixture of 2-(4-(3-(piperidin-1-yl)propoxy)phenyl)acetic acid (800 mg) in DMF/DCM (6 mL, 1:1) was added triethylamine (1.2 mL), DMAP (180 mg), 2-amino-4-methylthiophene-3-carboxamide (440 mg), and EDCI (1.1 g). The reaction mixture was stirred at rt overnight, quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified via preparative HPLC to give 4-methyl-2-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)acetamido)thiophene-3-carboxamide. Method[7], MS (ESI) 416.2 [M+H], Retention time=2.254 min.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]1([CH3:32])[CH:13]=[CH:12][C:11]([S:14]([O:17][CH2:18][C@H:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:20]C(OC)(C)C)(=[O:16])=[O:15])=[CH:10][CH:9]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:8]1([CH3:32])[CH:9]=[CH:10][C:11]([S:14]([O:17][CH2:18][C@H:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[OH:20])(=[O:16])=[O:15])=[CH:12][CH:13]=1
Reactant: COC(C)(C)O[C@H](COS(=O)(=O)c1ccc(C)cc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Into toluene (10 ml) were added (S)-2-phenyl-2-(1-methoxy-1-methylethyloxy)ethyl p-toluenesulfonate (3.0 g), p-toluenesulfonic acid monohydrate (1.7 g) and methanol (0.5 g), and the resulting mixture was stirred at 50° C. for 1 hour. The reaction mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, then with a saturated aqueous sodium chloride solution, and dried with anhydrous magnesium sulfate. The desiccant was filtered off and then the solvent was distilled off under reduced pressure to obtain a colorless oily compound mentioned above (2.1 g, 88.0%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].C(C1C=CC(C2CCCN(C(OC(C)(C)C)=O)CC=2)=CC=1)#N>[Pd].C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC=C(c2ccc(C#N)cc2)CC1
Agent: [Pd]
Agent: CC(C)(C)OC(=O)N1CC=C(c2ccc(C#N)cc2)CCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C

Procedure:
To a 25 mL round bottom flask containing a mixture of tert-butyl 4-(4-cyanophenyl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate and tert-butyl 5-(4-cyanophenyl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (compound 40.2, 167 mg, 0.56 mmol) was added 10% palladium on carbon (40 mg) and ethyl acetate (6 mL). The system was purged with nitrogen then charged with hydrogen and stirred at room temperature. After purging the system with nitrogen, the mixture was filtered through celite and the filtrate was concentrated. The residue was purified by preparative TLC to obtain a colorless wax (77 mg, 45%). m/z (ES+) 245 (M minus t-butyl+H)+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([S:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=1.[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25]([SH:27])=[N:26][C:22]=2[CH:21]=1.[OH-].[Na+]>C(O)C>[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25]([S:27][CH2:3][C:4]3[C:9]([CH3:10])=[C:8]([S:11][CH2:12][C:13]4[O:14][CH:15]=[CH:16][CH:17]=4)[CH:7]=[CH:6][N:5]=3)=[N:26][C:22]=2[CH:21]=1
Reactant: COc1ccc2[nH]c(S)nc2c1
Reactant: Cc1c(SCc2ccco2)ccnc1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2[nH]c(SCc3nccc(SCc4ccco4)c3C)nc2c1
Yield: 81 %

Procedure:
2-Chloromethyl-4-(2-furylmethylthio)-3-methylpyridine hydrochloride, 5-methoxy-2-mercapto-1H-benzimidazole and sodium hydroxide are reacted in ethanol at 60° C. for 4 h. This gives the title compound as a colorless solid. Yield: 81%, m.p. 106-108° C.
Reaction SMILES: [Cl-].C([Al+]CC)C.[N-:7]=[N+:8]=[N-:9].[Na+].[OH:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15].[Na+].[Cl-]>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[OH:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]1[NH:15][N:9]=[N:8][N:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1O
Agent: CC[Al+]CC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccccc1-c1nnn[nH]1
Temperature: 0 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
Into the flask, 100 mL of anhydrous toluene and diethyl aluminum chloride (40 mmol, 1.8 M toluene solution) were put and cooled to 0° C. Sodium azide (2.6 g, 40 mmol) was put into the mixture, and the mixture was agitated at room temperature for 4 hours. After the agitated solution was cooled to 0° C. again, 2-hydroxybenzonitrile (20 mmol, 2.38 g) was added thereto. The reaction mixture was refluxed at 80 for 1 day. After the reaction was finished, the mixture was cooled to 0° C., 70 mL of 6 M HCL, 50 mL of distilled water, 100 mL of ethyl acetate, and 80 mL of saturated NaCl were dropped thereon, treated, and extracted. The organic phase was reextracted by using 200 mL of water twice. The combined water layers were extracted with 200 mL of ethyl acetate twice. The combined organic layers were dried through Na2SO4. The solvent was removed to obtain the product. The product was recrystallized from ethyl acetate to obtain a pure product (yield 80%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:13][C:14]1[CH:15]=[C:16]([NH:27][C:28]2[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=2)[CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=2)[CH:19]=1>C(Cl)Cl>[CH3:13][C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][S:2]([CH3:1])(=[O:4])=[O:3])[CH:21]=2)[CH:17]=[C:16]([NH:27][C:28]2[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=2)[CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cccc(N)c2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cccc(NS(C)(=O)=O)c2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Methanesulfonyl chloride (0.017 g, 0.150 mmol) and triethylamine (0.028 ml, 0.200 mmol) were added to a solution of 5-methyl-N3-[4-(trifluoromethyl)pyrimidin-2-yl]biphenyl-3,3′-diamine (0.034 g, 0.100 mmol) in DCM (1.00 ml) and stirred for 14 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DMSO (1 mL), then purified by mass triggered reverse phase HPLC to give N-(3′-methyl-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)methanesulfonamide. MS ESI calcd. for C19H18F3N4O2S [M+H]+ 423, found 423. 1H NMR (600 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.78 (d, J=4.9 Hz, 1H), 7.83 (s, 1H), 7.52 (s, 1H), 7.40 (dt, J=15.7, 4.8 Hz, 2H), 7.30 (d, J=7.7 Hz, 1H), 7.23 (d, J=4.9 Hz, 1H), 7.17 (dd, J=8.0, 1.3 Hz, 1H), 7.04 (s, 1H), 2.99 (s, 3H), 2.32 (s, 3H).