Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:21][NH2:22])([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25].N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)([CH2:21][NH:22][C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccc(I)cc2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)COC(=O)NCC1(c2ccc(I)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.5 %

Procedure:
To a stirred solution of 4-aminomethyl-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.10 g, 0.24 mmol) in CH2Cl2 (1.0 mL) at room temperature under Ar was added isobutyl chloroformate(0.033 mL, 0.26 mmol, 1.1 eq.) followed by pyridine (0.25 mL). The mixture was stirred at room temperature for 16 h, diluted with EtOAc (5 mL), washed with saturated aqueous NaHCO3 (5 mL) and saturated brine (5 mL) and dried over Na2SO4. Filtration and rotary evaporation gave the crude 4-(4-iodo-phenyl)-4-(isobutoxycarbonylamino-methyl)-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil (0.075 g, 0.15 mmol, ˜62%). 1H NMR (300 MHz, CDCl3): δ 7.81 (d, 2H), 7.15 (d, 2H), 4.42 (br.t, 1H), 3.88 (d, 2H), 3.79 (m, 2H), 3.42 (br.m, 2H), 3.25 (br.t, 2H), 2.13 (br.m, 3H), 1.88 (m, 3H), 1.54 (s, 9H), 0.99 (d, 6H). MS: 417 (M−Boc).
Reaction SMILES: COC(=O)C1C=CC=[C:6]([NH2:10])C=1.[S:12]1C=CC=C1C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:33][O:34][C:35](=[O:49])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][CH2:43][C:44]2[S:45][CH:46]=[CH:47][CH:48]=2)[CH:37]=1>>[CH3:33][O:34][C:35](=[O:49])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]([CH2:43][C:44]2[S:45][CH:46]=[CH:47][CH:48]=2)[C:6]([NH2:10])=[S:12])[CH:37]=1
Reactant: O=Cc1cccs1
Reactant: COC(=O)c1cccc(NCc2cccs2)c1
Reactant: COC(=O)c1cccc(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COC(=O)c1cccc(N(Cc2cccs2)C(N)=S)c1
Yield: 89.6 %

Procedure:
3-Amino-benzoic acid methyl ester (455 mg, 3.0 mmol), thiophene carboxaldehyde (290 μL, 3.15 mmol) and sodium triacetoxyborohydride (765 mg, 3.6 mmol) were combined according to general procedure D. 189 mg of the crude 3-[(thiophen-2-ylmethyl)-amino]-benzoic acid methyl ester (0.75 mmol) was treated with 1 eq. Fmoc-NCS to afford 206 mg 3-(1-thiophen-2-ylmethyl-thioureido)-benzoic acid methyl ester after purification.
Reaction SMILES: [ClH:1].[OH:2][C@@H:3]([CH2:19][N:20]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([O:35]CC)=[O:34])=[CH:27][CH:26]=1)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].Cl>C(O)C.C1COCC1>[ClH:1].[OH:2][C@@H:3]([CH2:19][N:20]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:29][CH:30]=1)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)COc1ccc(N(CC(C)C)C[C@H](O)COc2cccc3[nH]c4ccccc4c23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(OCC(=O)O)cc1
Reaction time: 1 h
Yield: 34.1 %

Procedure:
A solution of the free base (0.25 g, 0.47 mmol) from example 93 in ethanol/THF (50 mL/50 mL) was treated with 1N NaOH (14.1 mL, 14.1 mmol) and refluxed with stirring for 1 h, the reaction was neutralized with 1N HCl (13.6 mL, 13.6 mmol, 29 eq), and concentrated in vacuo. The resulting residue was slurried in ether (30 ml) and anhydrous HCl in ether (30 ml) was added. The resulting slurry was concentrated in vacuo. The residue was dissolved in EtOAc and filtered. The filtrate was concentrated in vacuo to provide 0.08 g (35%) of a tan solid. MS (FD+): m/z 463. Anal Calcd for C27H31N20O5Cl: C, 64.99; He 6.26; N, 5.61. Found: C, 65.29; H, 6.55; N, 5.35.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[S:6][C:7]([C:15]([O:17]C)=[O:16])=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[CH:3]=1.[OH-].[Na+].Cl>CO>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[S:6][C:7]([C:15]([OH:17])=[O:16])=[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:4]=2[CH:3]=1
Reactant: COC(=O)c1sc2ccc(Br)cc2c1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1sc2ccc(Br)cc2c1-c1ccccc1

Procedure:
Heat 3 g. of methyl 5-bromo-3-phenyl-benzo[b]-thiophene-2-carboxylate in a mixture of 50 ml. of methanol and 30 ml. of 10% sodium hydroxide under reflux for one hour. Add concentrated hydrochloric acid to yield the title compound as a precipitate. Recrystallize it from benzene; m.p. 265°-266°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.CO[C:16]1[C:20](OC)=[N:19][S:18](=[O:23])[N:17]=1.[NH3:24]>CO>[NH2:24][C:16]1[C:20]([NH:12][CH2:11][CH2:10][CH2:9][NH:8][C:5]2[C:4]([CH3:13])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[N:19][S:18](=[O:23])[N:17]=1
Reactant: COC1=NS(=O)N=C1OC
Reactant: Cc1cc(Br)cnc1NCCCN
Reactant: N
Solvent: CO
Product: Cc1cc(Br)cnc1NCCCNC1=NS(=O)N=C1N
Reaction time: 4 h
Yield: 32 %

Procedure:
3-(5-Bromo-3-methylpyrid-2-ylamino)propylamine (0.713 g) was added dropwise to a stirred solution of 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (0.639 g) in methanol (25 ml) at room temperature. After 4 hours at room temperature, methanolic ammonia (25 ml) was added at 0°-5° C. with stirring, the mixture allowed to stand overnight, then evaporated in vacuo. The residue was chromatographed on silica in 10% CH3OH/CHCl3. The product was crystallised from ethanol to give 4-amino-3-[3-(5-bromo-3-methylpyrid-2-ylamino)propylamino]-1,2,5-thiadiazole-1-oxide (0.322 g, 32%) m.p. 204°-205° C.
Reaction SMILES: [C:1]1(=[O:28])[N:5]([O:6][CH2:7][C@H:8]2[O:12][C@@H:11]([N:13]3[CH:21]=[C:19]([CH3:20])[C:17](=[O:18])[NH:16][C:14]3=[O:15])[CH2:10][C@@H:9]2[OH:22])[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]12.[Si:29](Cl)([C:42]([CH3:45])([CH3:44])[CH3:43])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1C=CN=C1>CN(C=O)C>[Si:29]([O:22][C@@H:9]1[C@@H:8]([CH2:7][O:6][N:5]2[C:4](=[O:23])[C:3]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]3[C:1]2=[O:28])[O:12][C@@H:11]([N:13]2[CH:21]=[C:19]([CH3:20])[C:17](=[O:18])[NH:16][C:14]2=[O:15])[CH2:10]1)([C:42]([CH3:45])([CH3:44])[CH3:43])([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CON3C(=O)c4ccccc4C3=O)O2)c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](CON3C(=O)c4ccccc4C3=O)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
A mixture of 5'-O-phthalimidothymidine (8.54 g, 22 mmol), t-butyldiphenylsilylchloride (6.9 ml), 26.5 mmol), imidazole (3.9 g, 57.3 mmol) and dry DMF (130 ml) was stirred at room temperature for 16 h under argon. The reaction mixture was poured into ice-water (600 ml) and the solution was extracted with CH2Cl2 (2×400 ml). The organic layer was washed with water (2×250 ml) and dried (MgSO4). The CH2Cl2 layer was concentrated to furnish a gummy residue which on purification by silica gel chromatography (eluted with EtOAc:Hexanes; 1:1, v/v) furnished 12.65 g (92%) of 3'-O-(t-butyldiphenylsilyl)-5'-O-phthalimidothymidine as crystalline material (mp 172-173.5° C.). 1H NMR (DMSO-d6) δ 11.31 (s, 1, NH), 7.83 (m, 4, ArH), 7.59 (m, 4, TBDPhH), 7.51 (s, 1, C6H), 7.37-7.45 (m, 6, TBDPhH), 6.30 (dd, 1, H1', J1',2' =8.8 Hz, J1',2" =5.6 Hz), 4.55 (m, 1, H4'), 4.15 (m, 1, H3'), 3.94-4.04 (m, 2, H5',5"), 2.06-2.13 (m, 2, H2',2"), 1.97 (s, 3, CH3), 1.03 (s, 9, C(CH3)3). Anal. Calcd. for C34H35O7N3Si: C, 65.26; H, 5.64; N, 6.71. Found: C, 65.00; H, 5.60; N, 6.42.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.O[Li].O.[ClH:22].[Cl:23][CH2:24][C:25]1[C:26]([N:38]([CH3:40])[CH3:39])=[N:27][C:28]2[CH:29]=[C:30]3[O:37][CH2:36][O:35][C:31]3=[CH:32][C:33]=2[CH:34]=1.Cl.CO>C1(C)C=CC=CC=1>[ClH:23].[ClH:22].[CH3:40][N:38]([CH3:39])[C:26]1[C:25]([CH2:24][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=2[OH:18])=[CH:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][O:37][C:30]3=[CH:29][C:28]=2[N:27]=1
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: CN(C)c1nc2cc3c(cc2cc1CCl)OCO3
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCc1nc(O)c(Cc2cc3cc4c(cc3nc2N(C)C)OCO4)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 13 %

Procedure:
To a solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (250 mg, 1.0 mmol) in toluene in a 20 mL microwave vial was added LiOH.H2O (84 mg, 2.0 mmol) and 7-(chloromethyl)-N,N-dimethyl-[1,3]dioxolo[4,5-g]quinolin-6-amine hydrochloride RBO 35172 (301 mg, 1.0 mmol). The mixture was stirred at 150° C. for 1.5 h under microwave irradiation then cooled to RT. The volatiles were removed under vacuum and the residue was taken back in dichloromethane (30 mL), washed with water (3×10 mL), brine (10 mL), dried over Na2SO4, filtered and evaporated to give an orange solid. This solid was purified by column chromatography (SiO2, eluent CH2Cl2:7 N NH3 solution in MeOH=100:0 to 95:5) to give after evaporation and drying 4-((6-(dimethylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol (142 mg). This free base was dissolved in MeOH (5 mL) and a HCl 0.19 N solution in MeOH (1.35 mL, 0.26 mmol) was slowly added. The reaction mixture was stirred at 4° C. for 15 min. After evaporation and drying under vacuum pump under P2O5, 4-((6-(dimethylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 63 was obtained as a yellow solid (148 mg, 55% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH3:39])(=[O:38])=[O:37])(=[O:29])=[O:28])[CH:5]=[C:6]([CH:25]=1)[O:7][CH2:8][C:9]1([CH2:12][O:13][N:14]2C(=O)C3=CC=CC=C3C2=O)[CH2:11][CH2:10]1.O1CCCC1.[BH4-].[Na+].Cl>C(O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([O:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH3:39])(=[O:38])=[O:37])(=[O:29])=[O:28])[CH:5]=[C:6]([CH:25]=1)[O:7][CH2:8][C:9]1([CH2:12][O:13][NH2:14])[CH2:11][CH2:10]1
Reactant: Cc1cc(OCC2(CON3C(=O)c4ccccc4C3=O)CC2)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCC2(CON)CC2)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a solution of N-{1-[[5-methyl-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]methyl]cyclopropylmethoxy}phthalimide (5.4 g, 9.5 mmol), as prepared in the preceding step, in ethanol (100 mL)/tetrahydrofuran (100 mL)/water (50 mL) was added sodium borohydride (1.15 g, 30.0 mmol). The reaction mixture was stirred at ambient temperature overnight. 2N HCl was added to adjust the pH to 1-2, the mixture was heated to 50° C. for 2 hours. The reaction mixture was concentrated to about 100 mL, water (50 mL) was added and the mixture was neutralized to pH 8-9 with 2N NaOH. The mixture was extracted into ethyl acetate (3×100 mL) and the organic phase was washed with brine (2×100 mL) and then dried over Na2SO4. After removing the solvent, the residue was purified by flash column chromatography (4:1 ethyl acetate/hexane) to give the title compound as a white solid (3.6 g, 86%). 1H-NMR (300 MHz, CDCl3) δ8.45 (d, J=7.8 Hz, 1H), 8.13 (d, J=7.8 Hz, 1H), 7.88 (t, J=7.7 Hz, 1H), 7.74 (t, J=7.7 Hz, 1H), 6.61 (s, 1H), 6.58 (s, 2H), 5.44 (br s, 2H),3.76 (s, 2H), 3,63 (s 2H), 3.45 (s, 3H), 2.23 (s, 3H), 0.57-0.65 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[NH:5][C:4](=[O:11])[C:3]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[N:37]=[C:36](C(Cl)(Cl)Cl)[O:35][N:34]=2)=[CH:23][CH:22]=1.C(=O)([O-])[O-:43].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:37][C:36](=[O:43])[O:35][N:34]=3)=[CH:23][CH:22]=2)[C:4](=[O:11])[C:3]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: CCCc1nc(C)c(Cc2ccccn2)c(=O)[nH]1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(Cc2ccccn2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 12 h
Yield: 4.2 %

Procedure:
To a solution of 6-methyl-2-propyl-5-(pyridin-2-ylmethyl)pyrimidin-4(3H)-one (0.51 g) and 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (1.0 g) in acetonitrile (20 mL) was added potassium carbonate (0.58 g), and the mixture was stirred for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran-ethanol (1:1, 4 mL), 1 M sodium hydroxide (2 mL) was added and the mixture was stirred for 30 min. The reaction mixture was weakly acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.043 g, 4%) as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.Cl.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]2[CH2:35][CH2:34][N:33]([C:2]3[C:3]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:4][C:5]4[C:10]([N:11]=3)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=4)[CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1
Reactant: Clc1cccc(C2CCNCC2)c1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4cccc(Cl)c4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
A solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 4-(3-chlorophenyl)piperidine hydrochloride (204.2 mg, 0.88 mmol, 2.00 equiv), and DIEA (194.8 mg, 1.51 mmol, 5.00 equiv) in DMF (4 mL) was placed in an 8-mL sealed tube and stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of water, then concentrated under vacuum. Purification via silica gel column (ethyl acetate/petroleum ether (1:100)) yielded 143.5 mg (64%) of methyl 3-(4-(3-chlorophenyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.[CH3:15][O-:16].[Na+].O>COCCOC>[NH2:1][C:2]1[CH:7]=[C:6]([O:16][CH3:15])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1
Reactant: C[O-]
Reactant: Nc1cc(Cl)nc(N2CCOCC2)n1
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(N)nc(N2CCOCC2)n1
Temperature: 20 °C
Reaction time: 22 h
Yield: 66 %

Procedure:
60.46 g of 4-amino-6-chloro-2-morpholinopyrimidine (described in Chem. Pharm. Bull. 13, 557) are suspended in 190 ml of 1,2-dimethoxyethane and to this suspension are added 35.4 g of sodium methylate. The suspension is subsequently stirred for 22 hours under reflux and then cooled to 20° C. After addition of 180 ml of water the precipitated product is collected by suction and dried in vacuo at 80° C., affording 39.1 g (66% of theory) of 4-amino-6-methoxy-2-morpholinopyrimidine with a melting point of 162° C.-164° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH3:20])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].F[C:22]1[N:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C>>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:22]3[N:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=3)[CH2:15][C@H:14]2[O:19][CH3:20])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: COC(=O)c1ccc(F)nc1
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCNC[C@H]2OC)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ccc(C(=O)OC)cn3)C[C@H]2OC)nc1Cl
Yield: 96.3 %

Procedure:
The same operation as in Example (158a) was performed using cis(±)-4-chloro-5-ethyl-N-(3-methoxypiperidin-4-yl)-1H-imidazole-2-carboxamide hydrochloride obtained in Example (159a) (104 mg, 0.32 mmol), methyl 6-fluoropyridine-3-carboxylate (50 mg, 0.32 mmol) and diisopropylethylamine (125 mg, 0.97 mmol), to obtain 130 mg of the title compound as a yellow brown oily substance (96%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:21])[C:12]3[S:18][C:17]([CH2:19][OH:20])=[CH:16][C:13]=3[NH:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:31][C:32]([N:34]([O:36][CH3:37])[CH3:35])=[O:33]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:21])[C:12]3[S:18][C:17]([CH2:19][OH:20])=[CH:16][C:13]=3[N:14]([CH2:31][C:32]([N:34]([O:36][CH3:37])[CH3:35])=[O:33])[CH:15]=2)=[O:9])=[CH:22][CH:23]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1c[nH]c2cc(CO)sc2c1=O
Reactant: CON(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CO)cc21
Reaction time: 48 h
Yield: 69.5 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(hydroxymethyl)-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.288 mmol), potassium carbonate (60 mg, 0.43 mmol) and 2-chloro-N-methoxy-N-methylacetamide (200 mg) in DMF (1.5 mL) was shaken at room temp. for 48 hrs. The mixture was diluted with water (5 mL), and the resulting solid was collected by filtration. The crude solid was recrystallized from aq. ethanol to afford title compound (90 mg). The title compound is also a compound of formula I.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.CCN=C=NCCCN(C)C.Cl.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCOCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butoxycarbonylaminophenylacetic acid (4.0 mmol) in CH2Cl2 (8.0 mL) is added morpholine (4.0 mmol), EDCl—H2O (4.8 mmol) and DMAP (0.40 mmol) at room temperature. After stirring at room temperature for 24 h, the reaction is quenched by the addition of water. The mixture is extracted with AcOEt. The combined organic extracts are washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting solid is triturated with ether-n-hexane to give the title compound; 1H NMR (CDCl3) δ 1.41 (s, 9H), 3.08-3.12 (m, 1H), 3.20-3.28 (m, 1H), 3.39-3.45 (m, 1H), 3.49-3.60 (m, 3H), 3.66-3.76 (m, 2H), 5.54 (d, 1H), 6.01 (d, 1H), 7.29-7.36 (m, 5H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:6]([O:21][CH2:22][CH2:23][CH3:24])[CH2:5]1)(=[O:3])[NH2:2].Br[CH:26]([CH3:36])[C:27](=O)[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:13]([O:12][C:11]([NH:10][C@H:7]1[CH2:8][CH2:9][N:4]([C:1]2[O:3][C:26]([CH3:36])=[C:27]([C:28]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29])[N:2]=2)[CH2:5][C@H:6]1[O:21][CH2:22][CH2:23][CH3:24])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCCOC(=O)C(=O)C(C)Br
Reactant: CCCO[C@@H]1CN(C(N)=O)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OCCC)C2)oc1C
Yield: 86.6 %

Procedure:
The same operation as in Example (103c) was performed using cis(±)-benzyl (1-carbamoyl-3-propoxypiperidin-4-yl)carbamate obtained in Example (113f) (0.80 g, 2.39 mmol), butyl 3-bromo-2-oxobutanoate obtained in Example (106a) (4 g, 16.9 mmol), sodium bicarbonate (0.7 g, 8.33 mmol) and THF (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/10, 1/2, 1/1, 2/1, 4/1) to obtain 0.98 g of the title compound as a light brown oily substance (98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:51][C:52]1[CH:60]=[CH:59][CH:58]=[CH:57][C:53]=1[CH:54]([OH:56])[CH3:55]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:56][CH:54]([C:53]2[CH:57]=[CH:58][CH:59]=[CH:60][C:52]=2[Br:51])[CH3:55])=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)c1ccccc1Br
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OC(C)c4ccccc4Br)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 48.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (85 mg) was added to toluene/triethylamine=10/1 (9 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (148 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-bromo-α-methylbenzyl alcohol (90 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (70 mg, yield 45%).
Reaction SMILES: O=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH:13]1([CH2:16][NH2:17])[CH2:15][CH2:14]1.[Cl:18][CH2:19][CH2:20][N:21]=[C:22]=[O:23]>>[Cl:18][CH2:19][CH2:20][NH:21][C:22]([N:17]([CH2:16][CH:13]1[CH2:15][CH2:14]1)[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@@H:3]1[OH:4])=[O:23]
Reactant: NCC1CC1
Reactant: O=C=NCCCl
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C(NCCCl)N(CC1CC1)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Yield: 63.5 %

Procedure:
3.6 g of D-mannose, 2.2 g of cyclopropylmethylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 31-(1). 4.3 g of 1-(2-chloroethyl)-3-cyclopropylmethyl-3-(D-mannopyranosyl)urea are thereby obtained as colorless caramel.