Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[C:15]3[N:22]=[C:21]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[S:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][C:10]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[Cl:35])C=C.C(O)(=O)C.C1([SiH3])C=CC=CC=1.O>C(Cl)Cl.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>[C:24]([NH:23][C:21]1[S:20][C:16]2[N:17]=[CH:18][N:19]=[C:14]([C:12]3[S:13][C:9]([C:5]4[NH:6][CH:7]=[CH:8][N:4]=4)=[C:10]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=4[Cl:35])[CH:11]=3)[C:15]=2[N:22]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: C=CCn1ccnc1-c1sc(-c2ncnc3sc(NC(C)(C)C)nc23)cc1-c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)Nc1nc2c(-c3cc(-c4ccc(Cl)cc4Cl)c(-c4ncc[nH]4)s3)ncnc2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
A solution of 7-[5-(1-allyl-1H-imidazol-2-yl)-4-(2,4-dichlorophenyl)-2-thienyl]-N-(tert-butyl)[1,3]thiazolo[5,4-d]pyrimidin-2-amine (100 mg, 0.185 mmol) and acetic acid (2 mL, 40 mmol) in DCM (6 mL) was degassed with vacuum and then the atmosphere was replaced with nitrogen. To the mixture, tetrakis(triphenylphosphine)palladium(0) (10.7 mg, 0.00923 mmol) and phenylsilane (0.136 mL, 1.11 mmol) were added. The resulting mixture was stirred at 40° C. for 30 min. The solution was allowed to cool to rt, followed by adding water and DCM. After being stirred for 10 min, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (46.0 mg, 50%) as a pale yellow solid. LCMS: (AA) ES+ 501, 503. 1H NMR (400 MHz, d6-DMSO) δ: 11.84 (bs, 1H), 8.69 (bs, 1H), 8.63 (s, 1H), 8.43 (s, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.46-7.43 (m, 1H), 7.34 (d, J=8.3 Hz, 1H), 7.14 (bs, 1H), 6.98 (bs, 1H), 1.47 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]([Cl:11])=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CN(C)C(=O)C>[Cl:11][C:8]1[C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:10][CH:9]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(Cl)ncc1Cl
Solvent: CC(=O)N(C)C
Product: O=C(O)c1cc(N2CCOCC2)ncc1Cl
Yield: 34 %

Procedure:
2,5-Dichloroisonicotinic acid, prepared by the method of E. Marzi, A. Bigi, M. Schlosser, Eur. J. Org. Chem. 2001, 1371-1376, (1.6 g, 0.0083 mol) and morpholine (10.9 g, 0.125 mol) in 4 mL of N,N-dimethylacetamide were heated at 80° C. for 4 days. The volatiles were removed under vacuum and the resulting yellow solid partitioned between water and Et2O. The aqueous layer was acidified to pH=1.5 using an aqueous solution of HCl and extracted once with Et2O (25 mL) and three times with CH2Cl2 (25 mL). The organic extracts were combined and the solvents removed under vacuum. The resulting yellow solid was crystallized from MeOH to afford the title compound 1.07 g (yield: 34%). 1H NMR (300 MHz, d6-DMSO): δ 3.45 (t, 4H, J=4.8 Hz), 3.67 (t, 4H, J=4.8 Hz), 7.06 (s, 1H), 8.21 (s, 1H), 13.79 (s (broad), 1H). 13C HMR (100 MHz, d6-DMSO): δ 45.6, 66.4, 107.3, 116.1, 141.3, 148.3, 158.5, 166.8. M+1=243.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]#[N:7])[CH3:2].[CH:16]([O:19][C:20](=[O:25])[CH2:21][C:22](=[NH:24])[NH2:23])([CH3:18])[CH3:17].CC[O-].[Na+]>C(O)C>[CH:16]([O:19][C:20]([C:21]1[CH:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])=[C:6]([NH2:7])[NH:24][C:22]=1[NH2:23])=[O:25])([CH3:18])[CH3:17]
Reactant: CCOC(=O)C(C#N)=Cc1ccccc1
Reactant: CC(C)OC(=O)CC(=N)N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OC(C)C)C1c1ccccc1
Yield: 54 %

Procedure:
Upon heating a solution of 10.1 g benzylidenecyanoacetic acid ethyl ester, 7.2 g amidinoacetic acid isopropyl ester and 0.6 g sodium ethylate in 150 ml ethanol for 4 hours, 2,6-diamino-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester 5-isopropyl ester of m.p. 170° is obtained.
Reaction SMILES: [NH:1]([C:22]([O:24]CC1C=CC=CC=1)=O)[CH2:2][C:3]([N:5]([CH3:21])[C@H:6]([C:14]([NH:16][NH:17][C:18]([NH2:20])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH:32]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@@H:33](C(O)=O)[CH2:34][C:35](=[O:37])[NH2:36].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>CO.CN(C=O)C>[NH:32]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@@H:33]([C:22]([NH:1][CH2:2][C:3]([N:5]([CH3:21])[C@H:6]([C:14]([NH:16][NH:17][C:18]([NH2:20])=[O:19])=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4])=[O:24])[CH2:34][C:35](=[O:37])[NH2:36]
Reactant: CN(C(=O)CNC(=O)OCc1ccccc1)[C@@H](Cc1ccccc1)C(=O)NNC(N)=O
Reactant: CC(C)(C)OC(=O)N[C@H](CC(N)=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C(=O)CNC(=O)[C@@H](CC(N)=O)NC(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NNC(N)=O
Reaction time: 15 h

Procedure:
0.85 g of Z-Gly-MePhe-NHNHCONH2 is subjected to catalytic reduction in methanol, dissolved in 10 ml of DMF, and after ice-cooling, 0.46 g of BOC-(D)-Asn-OH, 0.40 g of HONB and 0.45 g of DCC are added. The mixture is stirred for 15 hours. The precipitated DCU is filtered off, the solvent is distilled off and the residue is dissolved in n-butanol. The solution is washed with saturated aqueous sodium hydrogen carbonate and aqueous sodium chloride in that order and dried over anhydrous sodium sulfate. The solvent is distilled off, ether is added to the residue and the mixture is filtered to obtain a powder. Yield 0.78 g; m.p. 133°-136° C.; [α]D24 -36.5° (c=1.0, DMF); Rf1 0.09.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1.S(C1C=CC(CCl)=CC=1)(=O)(=O)N.[S:27]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)(=[O:30])(=[O:29])[NH2:28].S(Cl)(Cl)=O>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:11][C:35](=[O:36])[C:34]2[CH:38]=[CH:39][C:31]([S:27](=[O:30])(=[O:29])[NH2:28])=[CH:32][CH:33]=2)=[CH:8][CH:7]=1
Reactant: CN(C)CCOc1ccc(CN)cc1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: NS(=O)(=O)c1ccc(CCl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CN(C)CCOc1ccc(CNC(=O)c2ccc(S(N)(=O)=O)cc2)cc1
Yield: 40.8 %

Procedure:
To a cooled solution of 1.50 g of 4-[2-(dimethylamino)ethoxy]benzylamine and 0.87 g of triethylamine in 10 ml of chloroform was added 1.87 g of 4-sulfamoylbenzyl chloride, which was prepared from 1.71 g of 4-sulfamoylbenzoic acid with 16.3 g of thionyl chloride in the usual way, with stirring. The mixture was stirred at room temperature for 30 minutes and the solvent was evaporated. Hydrochloric acid (10%) was added to the residue and the aqueous solution was washed with ethyl acetate. The aqueous layer was made alkaline with potassium carbonate and was extracted with ethyl acetate. The extract was washed with water, dried, and evaporated. The residue was washed with ethyl acetate to give 1.19 g of pale yellow crystals, which were recrystallized from ethanol to give colorless crystals, m.p. 173.5°-174.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([Br:16])[CH:13]=[C:12]([Br:17])[C:3]=1[O:4][CH2:5][C:6]1([CH2:10]Cl)[CH2:9][O:8][CH2:7]1.[Br:18][C:19]1[C:24]([OH:25])=[C:23]([Br:26])[C:22]([Br:27])=[C:21]([Br:28])[C:20]=1[Br:29].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[Br:1][C:2]1[CH:15]=[C:14]([Br:16])[CH:13]=[C:12]([Br:17])[C:3]=1[O:4][CH2:5][C:6]1([CH2:10][O:25][C:24]2[C:23]([Br:26])=[C:22]([Br:27])[C:21]([Br:28])=[C:20]([Br:29])[C:19]=2[Br:18])[CH2:9][O:8][CH2:7]1
Reactant: ClCC1(COc2c(Br)cc(Br)cc2Br)COC1
Reactant: Oc1c(Br)c(Br)c(Br)c(Br)c1Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cc(Br)c(OCC2(COc3c(Br)c(Br)c(Br)c(Br)c3Br)COC2)c(Br)c1

Procedure:
To 31.5 g. (0.07 moles) of 3-[2,4,6-tribromophenoxymethyl]-3-[chloromethyl]oxetane was added pentabromophenol (36 g., 0.074 moles), potassium carbonate (10 g., 0.077 moles), potassium iodide (0.5 g.) and dimethyl formamide (75 ml.). The reactants were stirred in a nitrogen atmosphere and heated to 140°-148° C. for 21/2 hours. The cooled reaction mixture was diluted with 500 ml. of water. The resulting solid 3-[2,4,6-tribromophenoxymethyl]-3-[pentabromophenoxymethyl]oxetane was collected by filtration and washed on the funnel with water and with ethanol. The yield was 48 g. (76%). A small sample recrystallized from dioxane (6 ml./g.) melted at 202°-204° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f9) and commercially methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])(=[O:10])=[O:9])=[CH:4][N:3]=1.[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC>O1CCCC1.C(OCC)(=O)C>[CH:18]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])(=[O:10])=[O:9])=[CH:4][N:3]=1)=[CH2:19]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(c1ccc(Cl)nc1)c1ccccc1F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=Cc1ccc(S(=O)(=O)c2ccccc2F)cn1
Temperature: 150 °C
Yield: 66.2 %

Procedure:
2-Chloro-5-[(2-fluorophenyl)sulfonyl]pyridine (Example 1 Steps 1 and 2, 410 mg, 1.52 mmol), tributyl(vinyl)tin (535 mg, 1.69 mmol) and tetrakis-(triphenylphosphine)palladium(0) (87 mg) were combined in tetrahydrofuran (10 mL) in three batches in 5 mL microwave vials. The vials were heated to 150° C. for 10 minutes in a Smith synthesiser microwave reactor. The combined reactions were diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution. The organic layers were dried over MgSO4 and concentrated in vacuo while loading onto silica. Dry flash column chromatography using 10–20% ethyl acetate/isohexane gave 2-vinyl-5-[(2-fluorophenyl)sulfonyl]pyridine as a colourless solid (265 mg, 66%). δH (500 MHz, d6 DMSO): 9.03 (1H, s), 8.30 (1H, dd, J=1.4, 8.3 Hz), 7.51 (1H, td, J=7.9, 0.85 Hz), 7.43 (1H, dd, J=9.1, 10.6 Hz), 6.92 (1H, dd, J=10.7, 17.4 Hz), 6.43 (1H, dd, J=1.2, 17.4 Hz), 5.70 (1H, dd, J=1.2, 10.7 Hz); m/z (ES+) 364 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.Cl.[OH:23][C:24]1[C:33]([N:34]([CH3:36])[CH3:35])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:18]=[C:17]([C:19]([N:28]2[CH2:27][CH2:26][C:25]3[C:30](=[CH:31][CH:32]=[C:33]([N:34]([CH3:36])[CH3:35])[C:24]=3[OH:23])[CH2:29]2)=[O:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2ccc(F)cc2F)nc2ccccc12
Agent: Cl
Product: CN(C)c1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(F)cc3F)nc3ccccc13)C2
Yield: 8 %

Procedure:
Reaction of 2-(2,4-difluorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 60 (8% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 2.64 and 2.70 (2s, 6H), 2.85 and 3.08 (2t, 2H), 3.62 and 4.19 (2t, 2H), 4.53 and 5.07 (2s, 2H), 6.38 and 6.81 (2d, 1H), 6.96-7.15 (m, 3H), 7.63-7.70 (m, 1H), 7.96-8.09 (m, 2H), 8.14-8.26 (m, 2H); MS (ESI) m/z 461 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([C:12]([OH:14])=O)=[CH:7][CH:8]=2)[N:3]=1.[CH:16]([NH2:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>CC#N.O>[CH:16]([NH:19][C:12]([C:6]1[C:5]([CH3:15])=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1)=[O:14])([CH3:18])[CH3:17]
Reactant: Cc1ccc2ccc(C(=O)O)c(C)c2n1
Reactant: CC(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: Cc1ccc2ccc(C(=O)NC(C)C)c(C)c2n1
Temperature: 0 °C
Reaction time: 18 h
Yield: 92.6 %

Procedure:
A mixture of 2,8-dimethylquinoline-7-carboxylic acid (0.20 g, 0.994 mmol), isopropylamine (0.102 mL, 1.19 mmol) and HATU (0.491 g, 1.29 mmol) in anhydrous MeCN (5 mL) under a nitrogen atmosphere was cooled to 0° C. in an ice bath. To the cooled mixture was added dropwise DIEA (0.69 mL, 3.98 mmol) and the resulting mixture stirred at ambient temperature for 18 hours. The mixture was diluted with water, neutralized with aqueous 1N HCl and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Biotage SP4, 25M C-18, 5-60% MeCN—H2O) to afford N-isopropyl-2,8-dimethylquinoline-7-carboxamide (0.223 g, 93%).
Reaction SMILES: [I:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[C:3]=1[C@@H:21]([CH2:23][C:24]([O:26]C)=[O:25])[CH3:22].O.[OH-].[Li+].Cl>O1CCCC1.O>[C:17]([O:16][C:14]([N:11]1[CH2:10][CH2:9][N:8]([C:4]2[C:3]([C@H:21]([CH3:22])[CH2:23][C:24]([OH:26])=[O:25])=[C:2]([I:1])[N:7]=[CH:6][N:5]=2)[CH2:13][CH2:12]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)C[C@@H](C)c1c(I)ncnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CC(=O)O)c1c(I)ncnc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.1 %

Procedure:
Into a solution of (R)-tert-butyl 4-(6-iodo-5-(4-methoxy-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate (219 g, 0.447 mol) in tetrahydrofuran (657 mL) was added a solution of lithium hydroxide monohydrate (56.2 g, 1.34 mol) in 329 mL of water at 25° C. The mixture was stirred at 25° C. for 5 h. The bottom aqueous layer was discarded. The mixture was acidified with 1 N hydrochloric acid at 5° C. to give a final pH value of between about 1 to 2. The layers were separated. The top layer was then extracted with isopropyl acetate (440 mL×3), combined with the bottom layer, and washed with water (220 mL×2). The solvents was distilled off at reduced pressure below 50° C. The residual isopropyl acetate was azeotroped off with heptane under reduced pressure below 50° C. Product gradually precipitated out and was filtered to give an off-white to light yellow powder (196 g, 84% yield). 1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 3.80-3.68 (m, 1H), 3.59-3.56 (m, 4H), 3.23-3.14 (m, 5H), 2.86 (dd, J=16.5, 5.4 Hz, 1H), 1.50 (d, J=7.2 Hz, 3H), 1.48 (s, 9H). HRMS calcd. For C17H26IN4O4 [M+H]+: 477.0993. found 477.0995.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][NH:6][CH:7]([CH3:14])[CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1.Cl.O1CCO[CH2:21]1>>[ClH:2].[Cl:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH:7]([CH3:14])[CH2:8][C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH2:21]1
Reactant: CC(Cc1cccs1)NCc1ccccc1Cl
Reactant: C1COCO1
Agent: Cl
Product: CC1Cc2sccc2CN1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 63 %

Procedure:
N-2-chlorobenzyl-1-methyl-2-(2-thienyl)ethylamine HCl (16.4 g) is suspended in 50 ml of 1,3-dioxolane. Hydrochloric acid (37% concentration) (0.2 ml) is added and the temperature of the reaction mixture is brought to 80° C. for 6 hours. When the reaction is complete, the mixture is cooled to room temperature, and the precipitation of the product is completed by adding 50 ml of ethyl acetate. The crystalline product is filtered, washed with ethyl acetate and dried under vacuum at 60° C. 5-(2-chlorobenzyl)-6-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine HCl (10.7 g, 63% yield) is obtained having a m.p. 179-180° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[CH:11][C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:27][CH2:28][CH:29]1[CH2:31][O:30]1.Cl.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C(N(CC)CC)C>>[ClH:27].[CH3:20][C:10]1[CH:11]=[C:12]([O:19][CH2:28][CH:29]([OH:30])[CH2:31][N:43]2[CH2:42][CH2:41][N:40]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[F:33])[CH2:45][CH2:44]2)[C:13]2[C:18]([C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: Cc1cc(O)c2ccccc2c1OCc1ccccc1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: ClCC1CO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: Cc1cc(OCC(O)CN2CCN(c3ccccc3F)CC2)c2ccccc2c1OCc1ccccc1
Yield: 57.7 %

Procedure:
Using 5.3 g (0.02 mol) of 4-benzyloxy-3-methylnaphthol, 2.8 g (0.02 mol) of anhydrous potassium carbonate, 9.3 g (0.10 mol) of chloromethyloxirane, 4.3 g (0.02 mol) of 1-(2-fluorophenyl)piperazine hydrochloride and 2.0 g (0.02 mol) of triethylamine, reaction was carried out as in Example 1-A to give 6.2 g of white crystals, m.p. 218-220° C. (decomp.).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30].[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:27](=[O:28])[NH:26][C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:30])([F:31])[F:32])[CH:22]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Oc1ccc2c(c1)CCCN2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Temperature: 35 °C
Reaction time: 14 h

Procedure:
A mixture of 1-benzyl-1, 2, 3, 4-tetrahydro-quinolin-6-ol (0.24 g., 1 mmol), 4-chloro-3-trifluoromethyl-phenyl isocyanate (0.265 g., 1 mmol), pulverized sodium hydroxide (0.044 g., 1 mmol) in dry tetrahydrofuran (20 ml) was stirred for 14 hours at room temperature (35° C.). The reaction mixture was concentrated under vaccum, diluted with water, extracted with chloroform and concentrated under vaccum. The residue was then chromatographed on silica gel using chloroform-hexane (30.70) as eluant to give 2k; yield: 0.20 g. (43.4%).
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]([C:18](=[O:31])CC(NCC(OC(C)(C)C)=O)=O)[C:9]2(C(OC)=O)[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1.[C:38](=[O:41])([O-])[O-:39].[Cs+].[Cs+].[CH2:44]([OH:46])[CH3:45]>>[C:1]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:9]3([CH2:10][CH2:11][CH2:12][CH2:13]3)[C:44]([OH:46])=[C:45]([C:18]([NH:8][CH2:7][C:38]([OH:39])=[O:41])=[O:31])[C:18]2=[O:31])=[CH:5][CH:6]=1
Reactant: CCO
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C1(N(Cc2ccc(-c3ccccc3)cc2)C(=O)CC(=O)NCC(=O)OC(C)(C)C)CCCC1
Agent: [Cs+]
Product: O=C(O)CNC(=O)C1=C(O)C2(CCCC2)N(Cc2ccc(-c3ccccc3)cc2)C1=O
Temperature: 25 °C

Procedure:
To a solution in ethanol (5.31 mL) of the compound (270 mg) obtained in step (1) above, cesium carbonate (346 mg) was added and the mixture was stirred at room temperature for an hour. The reaction mixture was concentrated under reduced pressure and 1 mol/L hydrochloric acid was added to the resulting residue. Extraction was conducted with ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. To a solution of the resulting concentrate (253 mg) in chloroform (4.88 mL), trifluoroacetic acid (2.44 mL) was added and the mixture was stirred at room temperature for 15 hours. After concentrating under reduced pressure, the residue was recrystallized with a liquid mixture of n-hexane and ethyl acetate and the precipitate was recovered by filtration to give the titled compound as a colorless solid (335 g).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13].[NH2:18][C:19]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:18][C:19]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[O:13]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1cccc(Br)c1
Reaction time: 1 h

Procedure:
0.056 mL of triethylamine and 0.029 mL of 3-bromobenzoyl chloride were added to 3.0 mL of methylene chloride solution containing 57 mg of tert-butyl 2-amino-4-phenoxybenzoate at room temperature sequentially and stirred at the same temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture. The organic layer was separated and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(3-bromobenzamido)-4-phenoxybenzoate.
Reaction SMILES: [I:1][CH3:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH2:20])=[S:19])[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[N:14][C:13]([CH3:16])=[N:12]1>C(O)C>[IH:1].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([NH:17][C:18]([S:19][CH3:2])=[NH:20])[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[N:14][C:13]([CH3:16])=[N:12]1
Reactant: CI
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)n1
Solvent: CCO
Product: COc1cc(NC(=N)SC)ccc1-n1cnc(C)n1
Product: I
Temperature: 70 °C
Yield: 101.4 %

Procedure:
Step F (5): Iodomethane (1.04 mL, 16.67 mmol) was added to a solution of 1-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)thiourea (4.18 g, 15.87 mmol) in absolute ethanol (100 mL). The resulting mixture was heated at 70° C. for 3 h. After cooling to rt, the reaction was concentrated in vacuo. The residual volatiles were removed in high vacuo to afford methyl 3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydroiodide (6.52 g, 16.09 mmol, 101% yield) as a white solid. LC-MS (M+H)+ 278.1.