Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:23])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:31])[CH:3]=1.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[Cl-].[CH3:45][S:46]([C:49]1[CH:50]=[C:51]([NH3+:55])[CH:52]=[CH:53][CH:54]=1)(=[O:48])=[O:47].CC(C)=O>C1COCC1>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:36]([NH:55][C:51]2[CH:52]=[CH:53][CH:54]=[C:49]([S:46]([CH3:45])(=[O:48])=[O:47])[CH:50]=2)=[O:42])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])=[CH:20][CH:21]=3)[S:15][C:8]=12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCCC5)cc4)sc23)c(F)c1
Reactant: CS(=O)(=O)c1cccc([NH3+])c1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CS(=O)(=O)c1cccc(NC(=O)Nc2ccc(Oc3ccnc4cc(-c5ccc(C(=O)N6CCCC6)cc5)sc34)c(F)c2)c1
Reaction time: 0.5 h
Yield: 11.5 %

Procedure:
To a solution of 126 (150 mg, 0.346 mmol) in THF (6 mL) was added TEA (175 mg, 1.730 mmol) and triphosgene (103 mg, 0.346 mmol) in THF (1 mL) and the mixture was stirred for 30 minutes. 3-(Methylsulfonyl)benzenaminium chloride (144 mg, 0.692 mmol) was added and the mixture was stirred at RT overnight. The mixture was then concentrated and the resultant solid was triturated with acetone, DCM and MeOH, followed by recrystallization from hot DMF. An additional trituration with acetone afforded 130 (25 mg, 11% yield) as a grey powder. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.32 (s, 1H), 9.24 (s, 1H), 8.52 (d, J=5.48 Hz, 1H), 8.16 (s, 1H), 8.13 (s, 1H), 7.94 (d, J=8.41 Hz, 2H), 7.75 (m, 1H), 7.66-7.62 (m, 3H), 7.56-7.53 (m, 2H), 7.45 (m, 1H), 7.31 (m, 1H), 6.64 (d, J=5.48 Hz, 1H), 3.48-3.37 (m, 4H), 3.19 (s, 3H), 1.86-1.81 (m, 4H). MS (m/z)=631.437 (M+H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([CH3:20])[CH:14]=1>>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:3](=[O:5])[CH2:2][C:1]([O:9][CH2:10][CH3:11])=[O:8])=[C:15]([CH3:20])[CH:14]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)CC(=O)Nc1ccc(Br)cc1C
Temperature: 160 °C
Yield: 62.5 %

Procedure:
Into a 500 milliliter four-necked round-bottom reaction flask equipped with a mechanical stirrer, Dean-Stark trap/condenser, thermometer and heating mantle was added 320 grams (2.0 mol) of diethyl malonate and 37.2 grams (0.2 mol) of 4-bromo-2-methylaniline. The resulting mixture was heated at a temperature of 160° C. for a period of four hours and then cooled to a temperature of about 0° C. to form a precipitate. After filtering on a fritted glass funnel, the wet-cake was washed with heptane and air dried to give 37.6 grams (0.125 mol) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate. Liquid chromatographic analysis indicated 97 percent purity by comparison with an authenic sample of pure material. NMR analysis of the product indicated the following: 'H NMR (CDCl3) δ9.52 (1H, bs), 8.02 (1H, d, J=9 Hz), 7.2-7.5 (2H, m), 4.30 (2H, q, J=7 Hz), 3.50 (2H, s), 2.30 (3H, s), 1.30 (3H, t, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:15]2[CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1)[CH3:10].C(OC([N:33]1[CH2:37][CH2:36][CH2:35][C@@H:34]1[C:38](O)=[O:39])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:15]2[CH:16]=[C:17]([N:20]3[CH2:21][CH2:22][N:23]([C:38]([C@H:34]4[CH2:35][CH2:36][CH2:37][NH:33]4)=[O:39])[CH2:24][CH2:25]3)[CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1)[CH3:10]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(N3CCNCC3)cc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(N3CCN(C(=O)[C@H]4CCCN4)CC3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
To a stirred solution of the crude (R)-1-(1-(2,4-dichlorophenyl)ethyl)-6-(piperazin-1-yl)-1H-benzo[d]imidazole (0.10 g, 0.27 mmol) and (R)-1-(t-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.064 g, 0.32 mmol) in dichloromethane (2 mL) was added HATU (0.12 g, 0.32 mmol) and triethylamine (Et3N, 0.2 mL, 1.4 mmol). The reaction mixture was stirred at room temperature for 2 h, and diluted with ethyl acetate. The mixture was washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 10% methanol in dichloromethane) to afford the desired product (0.11 g, 0.19 mmol, 71% for 2 steps).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])[C:10]=1F)[C:5]([OH:7])=[O:6].[CH3:20][O:21][CH2:22][CH2:23][NH2:24]>[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])[C:10]=1[NH:24][CH2:23][CH2:22][O:21][CH3:20])[C:5]([OH:7])=[O:6]
Reactant: COCCN
Reactant: O=C(O)c1cc(Br)c(F)c(S(=O)(=O)N2CCCC2)c1
Agent: [Na+]
Agent: [OH-]
Product: COCCNc1c(Br)cc(C(=O)O)cc1S(=O)(=O)N1CCCC1

Procedure:
A solution of 3-Bromo-4-fluoro-5-(pyrrolidine-1-sulfonyl)-benzoic acid (500 mg) in 2-methoxy-ethylamine was heated at 80° C. for 3 h. The mixture was dissolved in 2 M aq. NaOH and washed with EtOAc. The aqueous layer was acidified with 2 M HCl and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated in vacuo. Yield: 543 mg.
Reaction SMILES: [C:1]([N:5]([C:7]([C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1)=[O:8])[NH2:6])([CH3:4])([CH3:3])[CH3:2].[C:16]1([CH:22]([CH:26]([CH3:29])[CH2:27][CH3:28])[C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.[OH-].[Na+]>[C:1]([N:5]([C:7]([C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1)=[O:8])[NH:6][C:23](=[O:24])[CH:22]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:26]([CH3:29])[CH2:27][CH3:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(C(=O)N(N)C(C)(C)C)c1
Reactant: CCC(C)C(C(=O)Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCC(C)C(C(=O)NN(C(=O)c1cccc(C)c1)C(C)(C)C)c1ccccc1
Reaction time: 8 h

Procedure:
To a stirred suspension of N'-t-butyl-N'-(3toluoyl)hydrazine (0.7 g) in toluene (10 ml) and aqueous sodium hydroxide (12 drops of 50% aqueous sodium hydroxide) was added dropwise 2-phenyl-3-methyl-pentanoyl chloride (1.0 g). The reaction mixture was stirred overnight, diluted with hexanes and the solids filtered. The solids were washed with hexane and air dried.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:33]([OH:35])[CH3:34])[C@@H:3]1[O:5][C@H:4]1[CH2:6][C@@H:7]1[C@@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:19])[O:9][CH2:8]1.[Ca:36].C(C(CCCC)C([O-])=[O:41])C>C(OC)(C)(C)C.O>[CH3:1][C@H:2]([C@H:3]1[C@H:4]([CH2:6][C@H:7]2[CH2:8][O:9][C@@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[O:19])[C@H:11]([OH:14])[C@@H:12]2[OH:13])[O:5]1)[C@H:33]([CH3:34])[OH:35].[CH3:1][C@H:2]([C@H:3]1[C@H:4]([CH2:6][C@H:7]2[CH2:8][O:9][C@@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[O:19])[C@H:11]([OH:14])[C@@H:12]2[OH:13])[O:5]1)[C@H:33]([CH3:34])[OH:35].[OH2:41].[OH2:5].[Ca+2:36]
Reactant: [Ca]
Reactant: C/C(=C\C(=O)OCCCCCCCCC(=O)O)C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Reactant: CCCCC(CC)C(=O)[O-]
Solvent: COC(C)(C)C
Solvent: O
Product: C/C(=C\C(=O)OCCCCCCCCC(=O)[O-])C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Product: [Ca+2]
Temperature: 5 °C
Reaction time: 24 h

Procedure:
Pseudomonic acid (10.00 g, 20 mmole) was dissolved in methyl tertbutyl ether (180 ml) at 40° C. Calcium-2-ethyl-hexanoate (3.32 g, 10 mmole) was suspended in water (50 ml). (It is possible to obtain a solution by using a larger amount of water or an alcohol/water mixture). The solution of pseudomonic acid was added to the calcium-2-ethyl-hexanoate suspension, and the two phase system was stirred for 24 hours. The two phases were separated, 50 ml methyl tertbutyl ether was added to the aqueous phase and stirred for 10 minutes. The two resulting phases were separated, and the methyl tertbutyl ether was evaporated from the aqueous phase. The aqueous mupirocin calcium suspension was cooled in the refrigerator at 5° C. The solid mupirocin calcium dihydrate was filtered, washed with water (20 ml) and dried under vacuum at 35° C. for 14 hours. The mass of product was 8.65 grams. Assay: 95.68%, water: 3.48%
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:9]=[C:10]([S:15]([N:18]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]2)(=[O:17])=[O:16])[CH:11]=[CH:12][C:13]=1[F:14].O.CC1C=CC(S(O)(=O)=O)=CC=1.ClCCl>O>[Br:7][C:8]1[CH:9]=[C:10]([S:15]([N:18]2[CH2:19][CH2:20][CH:21]([O:24][CH:6]3[CH2:5][CH2:4][CH2:3][CH2:2][O:1]3)[CH2:22][CH2:23]2)(=[O:17])=[O:16])[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: C1=COCCC1
Reactant: O=S(=O)(c1ccc(F)c(Br)c1)N1CCC(O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(c1ccc(F)c(Br)c1)N1CCC(OC2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.3 %

Procedure:
3,4-Dihydro-2H-pyran (0.28 mL, 3.1 mmol) was added dropwise to a 0° C. solution of Example 354a (0.51 g, 1.5 mmol), 4-methylbenzenesulfonic acid hydrate (0.59 g, 3.1 mmol), and dichloromethane (28 mL). The reaction mixture was stirred at ambient temperature for 5 hours. Water was added and the mixture was extracted with dichloromethane. The organic layer was washed with water, saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, dichloromethane/gradient with methanol) to afford the title compound (420 mg, 65.9% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:5]=2[N:4]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:8][N:7]1[C:6]2[CH:9]=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:5]=2[N:4]=[C:3]1[CH2:2][N:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3]2[N:7]([CH3:8])[C:6]3[CH:9]=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:5]=3[N:4]=2)[CH2:21][CH2:20]1
Reactant: COc1cc2c(nc(CCl)n2C)c(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc2c(nc(CN3CCN(Cc4nc5c(OC)c(OC)c(OC)cc5n4C)CC3)n2C)c(OC)c1OC

Procedure:
2-Chloromethyl-1-methyl-4,5,6-trimethoxy-benzimidazole (75 mg) and piperazine (10 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][C:5]([OH:7])=O.[CH:8]([N:11]=[C:12]=[O:13])([CH3:10])[CH3:9].Cl>O>[CH:8]([N:11]1[C:5](=[O:7])[CH2:4][NH:3][C:12]1=[O:13])([CH3:10])[CH3:9]
Reactant: CC(C)N=C=O
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)N1C(=O)CNC1=O
Temperature: 5 °C

Procedure:
To a solution of 3.6 g of sodium hydroxide in 75 ml of water was added 7.5 g of glycine. The solution was cooled to 5° C. and treated with 9.8 ml of isopropylisocyanate. After 5 h the reaction mixture was neutralised with 50 ml concentrated hydrochloric acid added dropwise to the slurry. This mixture was refluxed for 2 h then cooled to rt. The product was extracted with ethyl acetate to give 10.9 g of a colourless oil. 1H NMR (400 MHz, deuteriochloroform): δ=1.45 (6H, d, J=7 Hz), 3.92 (2H, s), 4.35 (1H, septet, J=7 Hz), 6.39 (1H, br s).
Reaction SMILES: Cl.[NH2:2][C:3](OCC)=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].CN1CC[O:17][CH2:16][CH2:15]1.Cl[C:21]([O:23][CH3:24])=[O:22]>C(Cl)Cl>[CH3:24][O:23][C:21](=[O:22])[N:2]=[CH:3][CH2:4][C:5]([O:7][CH2:8][CH2:9][O:17][CH2:16][CH3:15])=[O:6]
Reactant: CCOC(=O)C=C(N)OCC
Reactant: COC(=O)Cl
Reactant: CN1CCOCC1
Agent: Cl
Solvent: ClCCl
Product: CCOCCOC(=O)CC=NC(=O)OC

Procedure:
A solution consisting of 96 g of ethyl β-amino-β-ethoxyacrylate hydrochloride, 800 ml of methylene chloride and 120 ml of N-methylmorpholine is warmed to 40°. While stirring there is added dropwise within 2 hours a solution of 65 ml of methyl chloroformate in 350 ml of methylene chloride. After completion of the addition, the mixture is stirred at 40° for a further 2 hours. Thereupon, the resulting salt is filtered off under suction and washed with about 50 ml of methylene chloride. The filtrate is evaporated at 40° in a water-jet vacuum. There is obtained crude methyl[(1-ethoxy-2-ethoxycarbonyl)-ethylidene]carbamate in the form of a pale yellow oil which is used immediately in the next step.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]([CH3:53])[CH2:46][CH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]([CH3:53])[CH2:46][CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(CC1CCOCC1)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)CC2CCOCC2)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 21.1 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N-(tetrahydropyran-4-ylmethyl)acetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (3.5 mg) was obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C@H:9]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)/[CH:10]=[CH:11]/[C@@H:12]2[C@@H:24]3[C@@H:15]([O:16][C:17](=[O:25])[CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH2:23]3)[CH2:14][C@H:13]2[O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:40]([NH2:42])[CH3:41].Cl>O1CCCC1.O>[CH2:40]([NH:42][C:17](=[O:25])[CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][C@H:24]1[C@@H:15]([OH:16])[CH2:14][C@@H:13]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C@@H:12]1/[CH:11]=[CH:10]/[C@@H:9]([O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:41]
Reactant: CCN
Reactant: O=C1CCCC=CC[C@@H]2[C@@H](/C=C/[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: Cl
Agent: O=C1CCC/C=C\C[C@@H]2[C@@H](/C=C/[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@H](CCc2ccccc2)OC2CCCCO2)[C@H](OC2CCCCO2)C[C@@H]1O
Temperature: 40 °C
Yield: 73.8 %

Procedure:
A solution of (6Z,8aR,9R,10R,11aS)-4,5,8,8a,9,10,11,11a-octahydro-9-((S,E)-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pent-1-enyl)-10-(tetrahydro-2H-pyran-2-yloxy)cyclopenta[b]oxecin-2(3H)-one (3.0 g, 5.57 mmol) in 15 mL tetrahydrofuran (THF) was treated with 2 M ethylamine (31 ml) in THF. This mixture was stirred and heated at 40° C. over 18 hours under an atmosphere of nitrogen. The mixture was diluted with 50 mL water and the pH was adjusted to 6 with 1N HCl. The layers were separated and the aqueous layer was extracted with 20 mL ethyl acetate twice. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. Then, the crude product was purified by column chromatography providing 2.4 g of the title compound (73.8% yield).
Reaction SMILES: [O:1]1[CH2:5][CH2:4]OC1.[CH:6]12[C:12]([CH3:14])([CH3:13])[CH:11]1[CH2:10][CH2:9]C(C)=[CH:7]2.N1C=CC=CC=1.[OH:22]O>C[Re](=O)(=O)=O>[C:5]1([OH:1])([CH3:4])[CH2:9][CH2:10][CH:11]([C:12]([OH:22])([CH3:14])[CH3:13])[CH:6]=[CH:7]1
Reactant: C1COCO1
Reactant: OO
Reactant: CC1=CC2C(CC1)C2(C)C
Agent: C[Re](=O)(=O)=O
Solvent: c1ccncc1
Product: CC1(O)C=CC(C(C)(C)O)CC1
Temperature: 0 °C
Yield: 69.8 %

Procedure:
131 mg methyl trioxorhenium was dissolved in 30% aqueous hydrogen peroxide (23.6 ml) and cooled to 0° C. internal in a 21, 3-necked flask. A solution was separately prepared from 1,3-dioxolane (100 ml), (+)-2-carene (13.6 g, 0.1 mol), and pyridine (12 ml). This was also cooled to 0° C. internal. While stirring the cold aqueous solution vigorously, the cold dioxolane solution was added over 70 minutes, keeping the exothermic reaction at 0-5° C. After three hours (when TLC indicated disappearance of (+)-2-carene), the mixture was poured in to a separating funnel and the layers were separated. Saturated NaCl solution (20 ml) was added to the aqueous layer and more separation occurred. The layers were separated again. The aqueous layer was extracted once more with dioxolane (10 ml). The organics were combined. Aqueous pH 5.8 buffer solution (304 ml) was added and stirred vigorously at room temperature until (+)-2-carene epoxide had disappeared by TLC and HPLC (4 hours). The reaction was transferred to a separating funnel and washed once with heptane (75 ml). NaCl (45 g) was added to the aqueous layer and this was extracted with ethyl acetate (3×125 ml, 1×100 ml). The ethyl acetate extracts were combined, dried over Na2SO4, and concentrated in vacuo to ˜150 ml. 200 ml heptane was added and the solution was concentrated to ˜150 ml. 5-10 ml of EtOAc was added to dissolve the solid. It was allowed to cool with stirring and then cooled to 0° C. The solid was collected by vacuum filtration and washed twice with cold 5% EtOAc/heptane. After drying under vacuum, 11.857 g of (+)-p-menth-2-ene-1,8-diol (69.8% yield from (+)-2-carene) was obtained. NMR showed some residual heptane. Elemental Analysis: 70.6% C, 10.6% H.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:18]2[C:13](=[C:14]([F:23])[CH:15]=[CH:16][C:17]=2[O:19][CH2:20][CH2:21][CH3:22])[C:12](=[O:24])[C:11]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:10]1)=[O:4].[CH3:33][O:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(N(CC)CC)C>C(#N)C>[ClH:1].[F:23][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH2:21][CH3:22])=[C:18]2[C:13]=1[C:12](=[O:24])[C:11]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)=[CH:10][N:9]2[CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:40]1[CH2:41][CH2:42][N:37]([CH2:36][CH2:35][O:34][CH3:33])[CH2:38][CH2:39]1
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCCNC(=O)CCl)c12
Reactant: COCCN1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCCNC(=O)CN3CCN(CCOC)CC3)c12
Product: Cl
Temperature: 75 °C
Reaction time: 6 h
Yield: 41.3 %

Procedure:
2-Chloro-N-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propyl}acetamide (370 mg, 0.8 mmol) was suspended in acetonitrile (12 ml). 1-(2-Methoxyethyl)piperazine (138 mg, 0.96 mmol), triethylamine (162 mg, 1.6 mmol) and acetonitrile (2 ml) were added to the suspension, and stirred at 70 to 80° C. for 6 hours. The resulting mixture was concentrated under reduced pressure, and the residue was subjected to extraction using ethyl acetate. The extract was then sequentially washed with water, an aqueous saturated sodium chloride solution, and an aqueous saturated sodium bicarbonate solution. The washed product was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (dichloromethane:methanol=30:1→10:1). The purified product was concentrated under reduced pressure, and the residue was then dissolved in ethyl acetate (5 ml). A 4N hydrogen chloride ethyl acetate solution (0.19 ml) was added thereto and stirred, and then the mixture was concentrated to dryness under reduced pressure, giving a pale yellow amorphous solid of N-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propyl}-2-[4-(2-methoxyethyl)piperazin-1-yl]acetamide hydrochloride (200 mg).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[N+]=[N-].[H][H]>CCO.[OH-].[OH-].[Pd+2]>[NH2:1][CH2:4][CH2:5][CH2:6][P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13]
Reactant: [H][H]
Reactant: CCOP(=O)(CCCN=[N+]=[N-])OCC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOP(=O)(CCCN)OCC
Reaction time: 3 h

Procedure:
Diethyl 3-azidopropylphosphonate (1 eq) was dissolved in EtOH (0.1 M). Pd(OH)2 (0.02 eq) was added to the reaction. Hydrogen gas was introduced via a balloon and the reaction was stirred for 3 hours. The reaction was stirred for for a further 2 hours at room temperature and filtered through Celite and washed with methanol. The solvent was removed en vaccuo and the crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% MeOH in DCM with 0.5% NH3 in MeOH to give the product as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][C@H:10]2[O:18][CH3:19])=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1.C(N(CC)CC)C.Cl[C:33]1[N:38]=[CH:37][CH:36]=[CH:35][N:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)Cl>[OH2:7].[NH2:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[CH2:11][C@H:10]2[O:18][CH3:19])=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCN)C[C@H]1OC
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCNc2ncccn2)C[C@H]1OC
Product: O
Yield: 29.2 %

Procedure:
To a stirred mixture of 4.28 parts of cis-4-amino-N-[1-(2-aminoethyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide, 1.21 parts of N,N-diethylethanamine and 150 parts of trichloromethane was added a solution of 1.5 parts of 2-chloropyrimidine in 75 parts of trichloromethane. The whole was stirred and refluxed for 80 hours. After cooling, the reaction mxiture was poured into a saturated sodium carbonate solution. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.52 parts (29.2%) of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[2-(2-pyrimidinylamino)ethyl]-4-piperidinyl]benzamide monohydrate; mp. 123.5° C. (compound 46).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4]Br.[CH3:12][C@H:13]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:16][C:15](=[O:24])[NH:14]1>>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:14]1[C@@H:13]([CH3:12])[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:16][C:15]1=[O:24]
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Reactant: COc1ccc(Br)c(CBr)c1
Product: COc1ccc(Br)c(CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 3, using the following starting materials: 2-bromo-5-methoxybenzyl bromide and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone.