Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[CH:3]=1.[OH-].[Na+:13].CCO>O>[C:1]([O-:11])(=[O:10])[C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[CH:3]=1.[Na+:13]
Reactant: O=C(O)c1cc(=O)[nH]c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C([O-])c1cc(=O)[nH]c(=O)[nH]1
Reaction time: 1 h

Procedure:
FIG. 2 illustrates the synthesis of Sodium Methotrexate Orotate. Orotic acid (1.74 g) was treated with sodium hydroxide (0.45 g) in water (100 mL). The mixture was warmed, stirred for 1 h and stored in the refrigerator overnight. Etanol (30 mL) was added to the solution and the precipitate was collected by filtration to give sodium orotate as a colorless solid which was dried in vacuum over night and used for the next step (1.51 g).
Reaction SMILES: [NH3:1].[CH2:2]([N:9]1[CH2:13][CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[CH2:2]([N:9]1[CH2:13][CH2:12][C@@H:11]([NH2:1])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N
Reactant: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1
Product: N[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 88 %

Procedure:
An autoclave was cooled with an acetone/dry ice bath, and an ammonia gas was blown to pool 477 cc of liquid ammonia (corresponding to 25 equivalent of (S)-1-benzyl-3-(methanesulfonyloxy)pyrrolidine). Thereto was added 180 g of (S)-1-benzyl-3-(methanesulfonyloxy)pyrrolidine (672.1 mmol, optical purity: 100% e.e.), which was heated to 100° C. whereby an internal pressure of 55 barr was observed. After allowing the reaction for 5 hrs, the reaction mixture was cooled to room temperature, and ammonia was removed by distillation under reduced pressure. As the residue, 306.7 g of a brown oily material was obtained (reaction yield: 88%, optical purity: 91.2% e.e.).
Reaction SMILES: [CH3:1][C:2]1([C:12]([OH:14])=[O:13])[S:9](=[O:11])(=[O:10])[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH2:3]1.S1(=O)(=O)C2SC=CC=2[CH2:17][CH:16]1C(O)=O.[H-].[Na+].C(I)CC>CN(C=O)C>[CH2:1]([C:2]1([C:12]([OH:14])=[O:13])[S:9](=[O:11])(=[O:10])[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH2:3]1)[CH2:16][CH3:17]
Reactant: O=C(O)C1Cc2ccsc2S1(=O)=O
Reactant: CC1(C(=O)O)Cc2ccsc2S1(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC1(C(=O)O)Cc2ccsc2S1(=O)=O
Yield: 90 %

Procedure:
The title compound was prepared in substantially the same way was 2,3-dihydro-2-methylthieno[2,3-b]thiophene-2-carboxylic acid-1,1-dioxide. Thus, 2,3-dihydrothieno[2,3-b]thiophene-2-carboxylic acid-1,1-dioxide (10.5 g, 0.048 mol) when reacted with NaH (5.76 g, 60% dispersion in oil) and n-propyl iodide (14 mL, 0.047 mol) in DMF (200 mL) gave the title compound as a gum (11.3 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][C:17]1[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=1>C(#N)C>[ClH:1].[CH3:16][C:17]1[CH:21]=[C:20]([CH3:22])[N:19]([C:2]2[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH3:15])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:18]=1
Reactant: CCCNc1nc(Cl)nc2ccccc12
Reactant: Cc1cc(C)[nH]n1
Solvent: CC#N
Product: CCCNc1nc(-n2nc(C)cc2C)nc2ccccc12
Product: Cl
Temperature: 170 °C
Yield: 44.9 %

Procedure:
(2-Chloro-quinazolin-4-yl)-propylamine (450 mg, 2.03 mmol) was dissolved in acetonitrile (7.5 mL) and 3,5-dimethylpyrazole (215 mg, 2.23 mmol) was added. The mixture was heated in a microwave oven at 170° C. for 20 minutes. Filtration gave [2-(3,5-dimethylpyrazol-1-yl)-quinazolin-4-yl]-propylamine, hydrochloride (290 mg, 51%) as a pale red crystalline compound. Mp. 208° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[C:5](=[C:6]([C:22](=[O:24])[CH3:23])[N:7](COCC[Si](C)(C)C)[N:8]=2)[CH:4]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][N:7]=[C:6]2[C:22](=[O:24])[CH3:23]
Reactant: COc1cc2nn(COCC[Si](C)(C)C)c(C(C)=O)c2cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2[nH]nc(C(C)=O)c2cc1OC

Procedure:
The title compound was prepared in a similar manner as described by G. Luo et al., J. Org. Chem. 2006, 71, 5392-5395: To a solution of 1-(5,6-dimethoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-3-yl]ethanone (200 mg, 0.57 mmol) in THF (6 mL) was added a 1M solution in THF of TBAF (2.85 mL, 2.85 mmol), and the mixture was heated to reflux for 16 h. The reaction mixture was then diluted with EtOAc and successively washed with water and brine, then dried (Phase separator) and evaporated. The crude product was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to give after lyophilization of the purified fractions the title compound. MS (LC-MS): 221 [M+H]+; tR (HPLC conditions k): 2.61 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:11]2[NH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[I:8].[CH3:30][Si:31]([CH3:38])([CH3:37])[CH2:32][CH2:33][O:34][CH2:35]Cl.C(N(CC)C(C)C)(C)C.C(Cl)Cl>O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[C:11]2[N:12]([CH2:35][O:34][CH2:33][CH2:32][Si:31]([CH3:38])([CH3:37])[CH3:30])[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)c(Br)c1)c1ncc(-c2ccccc2)[nH]1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)c(Br)c1)c1ncc(-c2ccccc2)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A solution of tert-butyl [(1S)-2-(3-bromo-4-iodophenyl)-1-(5-phenyl-1H-imidazol-2-yl)ethyl]carbamate (950 mg, 836 μmol), [β-(trimethylsilyl)ethoxy]methyl chloride (163 μL, 919 μmol), N,N-diisopropylethylamine (582 μL) and methylene chloride (8.91 mL) was stirred at 0° C. for 60 min and stirred at 25° C. for 2 h. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (432 mg, 59%). MF=C28H37BrIN3O3Si; LCMS found for C28H38BrIN3O3Si (M+H)+: m/z=698.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]2[S:14][C:15]([C:24]([O-])=[O:25])=[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:5]=2[CH:4]=[CH:3]1.[NH4+].C(N1C=CN=C1)([N:30]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[O:1]=[C:2]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:6]2[S:14][C:15]([C:24]([NH2:30])=[O:25])=[C:16]([NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:5]=2[CH:4]=[CH:3]1
Reactant: O=C([O-])c1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.4 %

Procedure:
To a suspension of the compound of Example 14 (370 mg, 1.02 mmol) in anhydrous DMF (5 mL) was added 1,1′-carbonyldiimidazole (182 mg, 1.12 mmol) and the reaction stirred at r.t. under nitrogen for 20 mins. Ammonium hydroxide (2 mL of 28% NH3 in water) was added and the reaction stirred for 72 h. Solvents were removed in vacuo and the crude residue purified by chromatography on silica (0-15% THF in DCM) to give the title compound as a white solid (123 mg). δH (DMSO-d6) 8.74 (1H, s), 7.67-7.34 (3H, m), 7.33-7.27 (2H, m), 7.22-7.00 (5H, m), 6.82-6.71 (3H, m), 6.21 (1H, d, J 9.7 Hz). LCMS (ES+) RT 3.04 minutes, 362 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(=O)CC1)=O)(C)(C)C.C(N)C1C=CC=CC=1.[N+](C1C=CC(C=C[N+]([O-])=O)=CC=1)([O-])=O>C1(C)C=CC=CC=1>[CH2:26]([N:14]1[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=2[C:16]([C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)=[CH:15]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc([N+](=O)[O-])cc3)cn2Cc2ccccc2)C1
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=[N+]([O-])C=Cc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: NCc1ccccc1
Product: O=[N+]([O-])c1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1
Reaction time: 0.17 h

Procedure:
1-Benzyl-3-(4-nitro-phenyl)-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester. To a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.69 g) in toluene (5 mL) was added 378 μL of benzylamine. The mixture was stirred for 10 min and then 0.70 g of silica gel (SiO2) was added. After stirring at RT for 8 h, 0.77 g of 1-nitro-4-(2-nitro-vinyl)-benzene in toluene (5 mL) was added and the mixture was stirred for 14 h at RT. The mixture was then filtered through diatomaceous earth and the filtrate was concentrated in vacuo. Chromatography on SiO2 (8 to 20% EtOAc/hexanes) afforded 0.48 g of the desired compound. MS (ESI): exact mass calculated for C25H27N3O4, 433.20; found, m/z 434.2 [M+H]+, 456.2 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][CH:19]([C:24]2([CH3:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][C:21]([OH:23])=[O:22])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1.[CH:31](O)=O.[C:34](#N)[CH3:35]>>[C:24]12([CH:19]([NH:18][C:3]3[C:2]([F:1])=[CH:7][N:6]=[C:5]([C:8]4[C:16]5[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=5)[NH:10][CH:9]=4)[N:4]=3)[CH2:20][C:21]([OH:23])=[O:22])[CH2:30][CH:34]3[CH2:35][CH:28]([CH2:27][CH:26]([CH2:31]3)[CH2:25]1)[CH2:29]2
Reactant: CC1(C(CC(=O)O)Nc2nc(-c3c[nH]c4ncc(F)cc34)ncc2F)CCCCC1
Reactant: O=CO
Reactant: CC#N
Product: O=C(O)CC(Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F)C12CC3CC(CC(C3)C1)C2

Procedure:
Compound 86 was synthesized in a manner similar to 3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3-(1-methylcyclohexyl)propanoic acid, 78, using adamantine-1-carbaldehyde as the starting material: 1H NMR (400 MHz, CD3OD) δ 8.75 (dd, J=9.7, 2.7 Hz, 1H), 8.18 (s, 2H), 8.00 (d, J=4.2 Hz, 1H), 2.81 (dd, J=15.2, 3.1 Hz, 1H), 2.55 (dd, J=15.2, 10.8 Hz, 1H), 2.00 (m, 3H), 1.82-1.49 (m, 12H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.40 minutes (M+H) 454.34.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH2:7]([O:9][C:10]([C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](O)=[O:16])=[O:11])[CH3:8].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl.C(OCC)C>[CH2:7]([O:9][C:10]([C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][C@H:14]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:15]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:16])=[O:11])[CH3:8]
Reactant: NCCC(=O)O
Reactant: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCC(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 0.01 mole of 3-aminopropionic acid and 0.01 mole of (R*,R*)-4-ethoxycarbonyl-2,4-dibenzylbutyric acid in 40 ml of methylene chloride are added 0.01 mole of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.01 mole of triethylamine. The reaction mixture is stirred at room temperature for 3 days. Diethyl ether (250 ml) is added and the mixture is washed with 25 ml of water, 25 ml of 2N aqueous hydrochloric acid and 25 ml of saturated aqueous sodium bicarbonate solution. The organic layer is dried over magnesium sulfate and evaporated to give N-[4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl]-3-aminopropionic acid, the compound of example 5(a).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].FC(F)(F)C(O[Si](C)(C)C)=O.[CH:22](OCC)(OCC)OCC.[N:32]([Si](C)(C)C)=[N+:33]=[N-:34]>CC(O)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:22]=[N:32][N:33]=[N:34]2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Agent: C[Si](C)(C)OC(=O)C(F)(F)F
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(-n2cnnn2)nc1
Reaction time: 0.08 h

Procedure:
To 5-nitropyridin-2-amine (1.00 g, 7.19 mmol) in AcOH was added trimethylsilyl trifluoroacetate (2.111 mL, 12.22 mmol). After stirring for 5 min, triethyl orthoformate (2.155 ml, 12.94 mmol) was added. Azidotrimethylsilane (1.513 mL, 11.50 mmol) was added after stirring for another 5 min. The reaction mixture was stirred at RT overnight, and was concentrated to give the crude solid. The solid was washed with DCM, and dried under vacuum to give title compound. LC/MS: [(M+1)]+=193.19, [(M+1-28)]+=165.19
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11](O)=[O:12])[CH:8]=[C:7]([Cl:14])[C:3]=1[C:4]([OH:6])=[O:5].C1N=[CH:18][N:17](C(N2C=NC=C2)=O)[CH:16]=1.CNC>ClC1CC(C(C)C)CCC1(Cl)C>[Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[O:12])[N:17]([CH3:18])[CH3:16])[CH:8]=[C:7]([Cl:14])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Agent: CC(C)C1CCC(C)(Cl)C(Cl)C1
Agent: CNC
Product: CN(C)C(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2,6-dichloroterephthalic acid (100 mg, 0.46 mmol) in dichloromenthane was added CDI (62 mg, 0.46 mmol) in one portion. The reaction mixture was stirred at room temperature for 1.5 hours and then dimethyl amine (1.0 M in THF, 2 mL, 2.0 mmol) was added. The reaction was concentrated under reduced pressure to give the crude 2,6-dichloro-4-(dimethylcarbamoyl)benzoic acid, which was used in the next step without further purification. 1H NMR (500 MHz, DMSO-d6): δ 14.35 (s, 1H), 7.56 (s, 2H), 2.97 (s, 3H), 2.89 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.I[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[O:44][CH3:45]>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[O:44][CH3:45])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: COc1ccccc1I
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: COc1ccccc1-c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1), bis(pinacolato)diboron and 2-iodoanisole according to the general procedure C. Obtained as a yellow solid (735 mg).
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].Cl.[CH3:24][NH:25][CH3:26].C[Si](Cl)(C)C.O>ClCCl>[CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:25]([CH3:26])[CH3:24])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)CCCOc1ccc(C(=O)Cl)cc1
Reactant: CNC
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)N(C)C)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
6.5 g of 4-(3-dibutylaminopropoxyl)benzoyl chloride (V) (0.02 mol) is dissolved in 60 mL of dichloromethane. 1.63 g of dimethylamine HCl (0.02 mol, 1 eq) is added and the reaction mixture is cooled to 0° C. 0.43 g TMSCl (0.004 mol, 0.2 eq) is added in 5 min. The reaction mixture is heated to room temperature and stirred for 5 hours. 50 mL of water is added to the mixture, it is stirred for 15 min and the phases are separated. The organic phase is washed with 30 mL of water then it is concentrated. The residue is purified by column chromatography (spheric silica; eluent: toluene:MTBE:methanol=5:4:1) to give 4.68 g of the title compound (VIb) (70%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:31](Cl)([CH3:34])(=[O:33])=[O:32]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([N:17]2[CH2:18][CH2:19][CH:20]([O:23][S:31]([CH3:34])(=[O:33])=[O:32])[CH2:21][CH2:22]2)=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)N2CCC(O)CC2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)N2CCC(OS(C)(=O)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
To 16.3 g (0.05 mol) of 1-(1-tert-butoxycarbonyl-4-piperidylacetyl)-4-hydroxypiperidine [5], 147.1 g of toluene and 6.58 g (0.065 mol) of triethylamine were added. 6.30 g (0.055 mol) of mesyl chloride was added dropwise to the mixture at a temperature in the range of 0 to 5° C. and the reaction was allowed to proceed for 2 hours at the temperature in the range. Toluene was added to the reaction mixture. Thereafter, the reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate and an aqueous solution of sodium chloride, and concentrated under a reduced pressure. 70.8 g of toluene was added to the concentrated residue, and the temperature of the mixture was increased. After the residue was dissolved in toluene, filtration was carried out. Thereafter, the filtrate was cooled to room temperature and the crystals which precipitated at room temperature were collected by filtration. The resultant wet crystals were dried under a reduced pressure, whereby 17.2 g of the title compound in the state of white crystalline powder was obtained (the yield was 84.8%). The values obtained by the analysis of 1HNMR, 13CNMR and mass spectroscopy were substantially the same as those obtained in Step 5a of Example 2.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH2:22][N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:21][C:16]=2[O:15][CH2:14]1.[NH2:29][C:30]1[CH:35]=[C:34]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)[CH:33]=[CH:32][C:31]=1[NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45]>C(Cl)Cl.N1C=CC=CC=1>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH2:22][N:23]3[CH2:24][CH2:25][N:26]([C:2]([NH:29][C:30]4[CH:35]=[C:34]([C:36]5[S:37][CH:38]=[CH:39][CH:40]=5)[CH:33]=[CH:32][C:31]=4[NH:41][C:42](=[O:48])[O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:4])[CH2:27][CH2:28]3)=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 16.8 %

Procedure:
A solution of triphosgene (544 mg, 1.83 mmol, 1.05 eq.) in DCM (5 mL) stirred at 0° C. under nitrogen was treated with a solution of 1-(benzo[d][1,3]dioxol-5-ylmethyl)piperazine (314, 1.16 g, 5.24 mmol) in anhydrous pyridine (7 mL), added dropwise over 5 min. The resulting mixture was stirred at 0° C. for 3 h and then at room temperature for 30 min, transferred with a syringe into a flask containing solid amine 4 (832 mg, 2.87 mmol), stirred at room temperature for 21 h, diluted with DCM, washed (saturated NaHCO3 then water), dried over MgSO4, filtered and concentrated. Purification by flash column chromatography (elution with 5% isopropyl alcohol in DCM) gave title compound 315 (165 mg, 11% yield) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[N:10][C:9]2[NH:8][C:7](=[O:12])[CH2:6][O:5][C:4]=2[CH:3]=1.[Li]N([Si](C)(C)C)[Si](C)(C)[CH3:16].COS(OC)(=O)=O>C1COCC1>[CH3:16][N:8]1[C:7](=[O:12])[CH2:6][O:5][C:4]2[CH:3]=[C:2]([Br:1])[CH:11]=[N:10][C:9]1=2
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Reactant: O=C1COc2cc(Br)cnc2N1
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: CN1C(=O)COc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 5 g of 7-bromo-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (0.022 mole) in 90 ml of THF is added 24 ml of LiN(TMS)2 (0.024 mole) in THF. The homogenous solution is maintained under nitrogen at room temperature for 20 min., 3.03 g (0.024 mole) of dimethylsulfate is added and the reaction mixture allowed to stir overnight. The reaction mixture is then quenched with 20 ml of sat. ammonium chloride and extracted with 3×80 ml ethyl acetate. The ethyl acetate is then washed with 3×30 ml sat. ammonium chloride, dried over sodium sulfate and concentrated to obtain off white product which is used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5]2[O:7][C@H:8]([C@H:10]([OH:13])[CH2:11][OH:12])[CH2:9][C@H:4]2[O:3]1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:12][CH2:11][C@H:10]([C@H:8]2[O:7][C@@H:5]3[O:6][C:2]([CH3:14])([CH3:1])[O:3][C@@H:4]3[CH2:9]2)[OH:13])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CC1(C)O[C@H]2O[C@H]([C@H](O)CO)C[C@H]2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@@H]2C[C@H]3OC(C)(C)O[C@H]3O2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74 %

Procedure:
To a solution of (1R)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]ethane-1,2-diol (100 g, 490 mmol) in dry pyridine (1000 mL) was added p-toluenesulfonyl chloride (139 g, 735 mmol) at 0° C. After being stirred at room temperature for 12 hours, the resulted solution was quenched by water (100 mL) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:10 to 1:3 EtOAc in petroleum ether) to afford 130 g of [(2R)-2-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-2-hydroxy-ethyl] 4-methylbenzenesulfonate (compound 6a) as a slight yellow oil.