Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1.[Br:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[Br:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: CC(C)CN
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CNS(=O)(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.5 %

Procedure:
A solution of isobutylamine (1.10 mL, 11.14 mmol) and pyridine (600 μL, 7.42 mmol) in DCM (60 mL) was treated with 4-(bromomethyl)benzene sulfonyl chloride (2.00 g, 7.42 mmol) and stirred at room temperature for 1.5 hours. The mixture was diluted with DCM, washed with 1 N aqueous HCl, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-50% EtOAc in cyclohexane) gave 4-bromomethyl-N-isobutyl-benzenesulfonamide (1.08 g, 48%). 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 4.50 (s, 2H), 4.43 (t, J=6.4 Hz, 1H), 2.78 (t, J=6.6 Hz, 2H), 1.81-1.65 (m, 1H), 0.88 (d, J=6.7 Hz, 6H). LCMS (m/z, Method A) ES+ 308.0 [M+Na]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:38]=[CH:37][C:27]([CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[C:26]([F:39])[C:25]=1[O:40][CH3:41]>>[F:39][C:26]1[C:25]([O:40][CH3:41])=[C:24]([NH:23][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11](=[O:12])[NH:13][CH3:14])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=2)[CH:38]=[CH:37][C:27]=1[CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Reactant: CCOP(=O)(Cc1ccc(N)c(OC)c1F)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)c(OC)c1F)OCC

Procedure:
The title compound was prepared according to the procedure from Example 102 using 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 104A) and Diethyl (4-amino-2-fluoro-3-methoxybenzyl)phosphonate (Compound 147A). 1H NMR (CD3OD, 400 MHz): δ=1.26-1.36 (m, 6H), 1.44 (t, J=6.95 Hz, 3H), 3.32-3.39 (m, 2H), 4.04-4.15 (m, 4H), 4.22 (q, J=7.07 Hz, 2H), 7.00 (dd, J=8.34, 1.77 Hz, 1H), 7.21 (d, J=1.77 Hz, 1H), 7.75 (d, J=8.34 Hz, 1H). MS (ES+): m/z 586.14 [MH+] (TOF, polar).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[N:13]/[OH:14])/[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8].[CH:15]([O:28][C:29]1[C:30](=[O:37])[CH:31]=[C:32]([CH2:35]O)[O:33][CH:34]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[N:13]/[O:14][CH2:35][C:32]1[O:33][CH:34]=[C:29]([O:28][CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:30](=[O:37])[CH:31]=1)/[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8]
Reactant: O=c1cc(CO)occ1OC(c1ccccc1)c1ccccc1
Reactant: C=CCOC(=O)/C(=N\O)c1cccs1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOC(=O)/C(=N\OCc1cc(=O)c(OC(c2ccccc2)c2ccccc2)co1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 207.6 %

Procedure:
To an ice cooled solution of allyl (E)-2-(2-thienyl)-2-(hydroxyimino)acetate (1.0 gm, 4.734 mmol), 5-benzhydryloxy-2-(hydroxymethyl) pyran-4-one (1.46 gm, 4.734 mmol) and triphenylphosphine (1.24 gm, 4.734 mmol) in dry THF (30 ml) under nitrogen was added dropwise diethyl azodicarboxylate (820 μl, 5.208 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure to afford the crude as yellow gum (4.93 gm). The product was purified by silica gel column chromatography using hexane-ethyl acetate (2:1) as eluant to provide the title compound as a gummy foam in 47% yield (1.11 gm).
Reaction SMILES: OC[C:3]([CH3:7])([CH2:5][OH:6])[CH3:4].[Cl:8][CH2:9][C:10]([CH2:12][Cl:13])=[O:11].C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[Cl:8][CH2:9][C:10]1([CH2:12][Cl:13])[O:6][CH2:5][C:3]([CH3:4])([CH3:7])[O:11]1
Reactant: O=C(CCl)CCl
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)COC(CCl)(CCl)O1
Reaction time: 8 h
Yield: 34.6 %

Procedure:
This compound was synthesized by substantially following the procedure of the above-mentioned article by Isaka, Ejiri, and Nakamura. 69 grams of neopentyl glycol, 76 grams of 1,3-dichloroacetone, 50 ml of benzene, and 2.3 g of p-toluenesulfonic acid were refluxed through a Dean-Stark water separator for 8 hours whereon the reaction was diluted with hexanes and neutralized with aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo yielding 41.2 g of 2,2-bis-chloromethyl-5,5-dimethyl-1,3-dioxolane, a pale yellow liquid.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([CH3:35])[CH:3]=1.[O:36]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>Cl.CCOC(C)=O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:41][C:38]4[CH:39]=[CH:40][O:36][N:37]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([CH3:35])[CH:3]=1
Reactant: Cc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ccon1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.5 %

Procedure:
Under a nitrogen atmosphere, a solution of perfluorophenyl 1-(4-bromo-5-fluoro-2-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (1.50 g, 2.59 mmol), isoxazol-3-amine (0.268 ml, 3.63 mmol) and THF (25.9 ml) was cooled in an ice-bath for 15 min, then lithium bis(trimethylsilyl)amide (1M in THF) (6.48 ml, 6.48 mmol) was added dropwise. After 10 min, the whole was warmed to rt and stirred for 30 min. 6.48 mL of additional LHMDS was added and the reaction was stirred for 1 h. The mixture was diluted with 1N aq. HCl and EtOAc. The layers were separated, and the organic layer was washed with 1N aq. HCl. The aq. layers were combined and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 70% EtOAc in heptane, to provide 1-(4-bromo-5-fluoro-2-methylphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (873 mg, 70.4% yield) as brown solid. m/z (ESI) [M+H]+=477.9. NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=7.15 Hz, 1 H) 1.86 (s, 2 H) 1.99 (s, 1 H) 5.55 (br. s., 1 H) 5.88 (d, J=1.76 Hz, 1 H) 6.44 (d, J=1.87 Hz, 1 H) 6.78 (d, J=9.02 Hz, 1H) 6.83 (d, J=9.64 Hz, 1 H) 7.55 (d, J=9.12 Hz, 1 H) 7.84 (dd, J=8.91, 2.28 Hz, 1 H) 7.92 (dd, J=7.57, 0.52 Hz, 1 H) 8.27 (d, J=9.54 Hz, 1 H) 8.32 (d, J=1.76 Hz, 1 H) 8.40 (d, J=2.28 Hz, 1 H) 8.72 (d, J=1.76 Hz, 1 H) 11.67 (s, 1 H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=2)[C:4]=1[C:19]([O:21][CH3:22])=[O:20])=[CH2:2].[C:23]([OH:26])(=[S:25])[CH3:24].CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[C:23]([S:25][CH2:2][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=2)[C:4]=1[C:19]([O:21][CH3:22])=[O:20])(=[O:26])[CH3:24]
Reactant: CC(O)=S
Reactant: C=Cc1cccc(-c2cccc(C(=O)OC)c2)c1C(=O)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COC(=O)c1cccc(-c2cccc(CCSC(C)=O)c2C(=O)OC)c1
Yield: 47.2 %

Procedure:
To a solution of 3-ethenyl-[1,1′-biphenyl]-2,3′-dicarboxylic acid, dimethyl ester (0.85 g, 2.9 mmol) in benzene (10 mL) was added thioacetic acid (2.1 mL, 29.4 mmol) followed by AIBN (0.053 g, 0.32 mmol). The solution was deoxygenated for 30 min by bubbling nitrogen through the solution and then heated at reflux for 4 h. Saturated aqueous NaHCO3 (20 mL) was added to the solution and the mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (1:12 EtOAc/hexanes) to give 3-[2-(acetylthio)ethyl]-[1,1′-biphenyl]-2,3′-dicarboxylic acid, dimethyl ester (0.51 g, 48%) as an off white solid: 1H NMR (CDCl3) δ2.35 (s, 3H), 2.93 (m, 2H), 3.14 (m, 2H), 3.62 (s, 3H), 3.93 (s, 3H), 7.29 (dd, J=7.6, 0.9 Hz, 1H), 7,35 (dd, J=7.5, 0.8 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.5 Hz, 1), 7.55 (dt, J=8.0, 1.5 Hz, 1H), 8.03 (dt, J=7.9, 1.5 Hz, 1H), 8.07 (t, J=1.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[CH3:11][C:12]([C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[O:22][CH3:23])=[O:13].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[CH:11][C:12]([C:14]1[C:15]([O:22][CH3:23])=[CH:16][CH:17]=[CH:18][C:19]=1[O:20][CH3:21])=[O:13]
Reactant: COc1cccc(OC)c1C(C)=O
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(OC)c1C(=O)C=Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.5 %

Procedure:
(40) To a solution of 2,6-dichlorobenzaldehyde (485 mg, 2.77 mmol) and 2,6-dimethoxyacetophenone (500 mg, 2.77 mmol) in 4.1 ml of methanol was added 1.0 ml of 40% sodium hydroxide in water at 10° C. After stirring for 1.5 hours at room temperature, a solid appeared and was filtered. The precipitate was recrystallized from methanol to afford 481 mg (51.5%) of faint-yellow needles: mp 126.8-127.8° C. 1H NMR (250 MHz) δ 7.48-7.42 (d, 1H), 7.37-7.31 (m, 3H), 7.11-6.63-6.60 (d, 2H), 3.81 (s, 6H); 13C NMR (62.7 MHz) 195.1, 158.0, 138.4, 136.5, 135.2, 132.6, 131.4, 130.0, 129.0, 117.9, 104.2, 56.1 ppm. Elemental Analysis. Calculated for C17H14Cl2O3: C, 60.55; H, 4.19. Found: C, 60.60; H, 4.18.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]([C:16]([O:18][CH3:19])=[O:17])[C:9](=[N:12][N+:13]([O-:15])=[O:14])SC)=[CH:5][N:6]=1.[CH3:20][NH2:21].CO>CO>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]([C:16]([O:18][CH3:19])=[O:17])[C:9]([NH:21][CH3:20])=[N:12][N+:13]([O-:15])=[O:14])=[CH:5][N:6]=1
Reactant: CN
Reactant: COC(=O)N(Cc1cnc(Cl)s1)C(=N[N+](=O)[O-])SC
Solvent: CO
Product: CNC(=N[N+](=O)[O-])N(Cc1cnc(Cl)s1)C(=O)OC
Yield: 48.5 %

Procedure:
To a solution of N-(2-chloro-5-thiazolylmethyl)-N-methoxycarbonyl-S-methyl-N'-nitroisothiourea (500 mg) in MeOH (5 ml) was added 40% methylamine-methanol solution (120 mg) dropwise below -10° C. and the mixture was stirred at the same temperature. Precipitated crystals were collected by filtration and dried to afford 230 mg of 1-(2-chloro-5-thiazolylmethyl)-1-methoxycarbonyl-3-methyl-2-nitroguanidine (Compound No. 19) as a white crystal. The filtrate was concentrated to leave the residue to which MeOH (3 ml) was added. The product (Compound No. 19, 140 mg) was obtained after drying. The properties, i.e. m.p., NMR and IR, of the product are identical with those of the compound prepared according to Example 3.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]1[CH:33]=[CH:32][C:14]2[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:42]([O:44][CH2:45][CH3:46])=[O:43]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]1[CH:33]=[CH:32][C:14]2[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccn1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OCC)cc1OC)n2C)c1ccccn1
Yield: 43 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidino-2-methoxyphenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and ethyl chloroformate. Yield: 43% of theory, C31H35N7O6 (601.7); Rf value: 0.44 (silica gel; dichloromethane/ethanol=9:1); EKA mass spectrum: (M+H)+=602; (M+H+Na)++=312.8.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[Cl:23])=[C:13]([Cl:24])[C:8]2[N:9]=[CH:10][N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4].C1COCC1.O.[OH-].[Na+].Cl>O>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]3[N:11]([CH3:12])[CH:10]=[N:9][C:8]=3[C:13]=2[Cl:24])=[C:17]([Cl:23])[CH:18]=1
Reactant: COC(=O)c1cc2c(ncn2C)c(Cl)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cnc2c(Cl)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cc21
Reaction time: 4 h

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester 10ee (21 mg, 0.048 mmol) is dissolved into 2:1 THF/water (1.2 mL) and NaOH (0.190 mL, 1.0 M aqueous solution, 0.190 mmol) is added. After stirring for 4 hours the reaction is diluted with water and acidified to pH 2 by addition of 1.0 M HCl. The mixture is then extracted with 3:1 EtOAc/THF (3×), dried (Na2SO4) and concentrated to give quantitative yield of desired product as a white solid. MS APCI (+) m/z 414, 416 (M+, Br pattern) detected.
Reaction SMILES: [NH3:1].[C:2]1([CH:8](Br)[CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>>[C:2]1([CH:8]([NH2:1])[CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(CCOc1ccccc1)c1ccccc1
Reactant: N
Product: NC(CCOc1ccccc1)c1ccccc1

Procedure:
1-Phenyl-3-phenoxypropylamine was prepared by the reaction of anhydrous ammonia and 1-phenyl-3-phenoxypropylbromide in a sealed vessel by the above procedure. The compound distilled at 137°-139° C. at 0.03 torr. The corresponding hydrochloride salt melted at 159°-161° C. after recrystallization from an ethyl acetate-acetone solvent mixture
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH:22]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[C:21](=O)[C:20]3[C:19]([C:31](OCC)=[O:32])=[CH:18][CH:17]=[CH:16][C:15]=3[NH:14]2)=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].O.[NH2:37][NH2:38]>CO>[CH2:4]([N:3]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[NH:14][C:15]3[C:20]4[C:21](=[N:37][NH:38][C:31](=[O:32])[C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH:22]2[C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)=[CH:9][CH:8]=1)[CH2:1][CH3:2])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C)cc1)C(c1ccc(CN(CC)CC)cc1)N2
Solvent: CO
Solvent: O
Product: CCN(CC)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C)cc2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
A mixture of ethyl 2-(4-((diethylamino)methyl)phenyl)-4-oxo-3-p-tolyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (320 mg) in hydrazine monohydrate (2 mL, 85%) and methanol (10 mL) was stirred at 30° C. for overnight. Methanol was removed under reduced pressure. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=1:1) to give the title compound (85 mg, yield 29%). LC-MS (ESI) m/z: 439 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.93 (t, 6H), 2.20 (s, 3H), 2.39 (q, 4H), 3.42 (d, 2H), 4.27 (d, J=8.0 Hz, 1H), 4.73 (d, J=8.0 Hz, 1H), 6.98-7.00 (m, 4H), 7.15-7.17 (m, 3H), 7.22-7.24 (m, 2H), 7.35-7.38 (m, 2H), 7.54-7.56 (m, 1H), 12.12 (s, 1H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].BrCN1C(=O)C(C)(C)N(C)C1=O.[C:23]([O:27][C:28]([C@H:30]([C@@H:42]([CH2:51][CH:52]1[CH2:56][CH2:55][CH2:54][CH2:53]1)[C:43]([N:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)=[O:44])[CH2:31][N:32]1[C:36](=[O:37])[C:35]([CH3:39])([CH3:38])[N:34]([CH3:40])[C:33]1=[O:41])=[O:29])([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[C:23]([O:27][C:28]([C@@H:30]([C@@H:42]([CH2:51][CH:52]1[CH2:53][CH2:54][CH2:55][CH2:56]1)[C:43]([N:45]1[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]1)=[O:44])[CH2:31][N:32]1[C:36](=[O:37])[C:35]([CH3:38])([CH3:39])[N:34]([CH3:40])[C:33]1=[O:41])=[O:29])([CH3:24])([CH3:25])[CH3:26]
Reactant: CN1C(=O)N(C[C@H](C(=O)OC(C)(C)C)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Agent: CN1C(=O)N(CBr)C(=O)C1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CN1C(=O)N(C[C@@H](C(=O)OC(C)(C)C)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of 10.7 g of the ester from Example 3 in 50 ml of tetrahydrofuran was added dropwise at −60° to a solution of 8.76 g of potassium bis-trimethylsilylamide in 80 ml of tetrahydrofuran and the mixture was stirred at −60° for 30 min. Subsequently, a solution of 7.76 g of 3-bromomethyl-1,5,5-trimethylhydantoin in 40 ml of tetrahydrofuran was added at −60° and the mixture was stirred at −60° for 30 min. The reaction mixture was washed with semi-saturated sodium chloride solution and with dilute hydrochloric acid, dried, filtered and concentrated, there being obtained 15.11 g of a 9:1 mixture of 1-[2(R)-[1(R)-(tert-butoxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentyl-propionyl]piperidine and 1-[2(R)-[1(S)-(tert-butoxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1imidazolidinyl)ethyl]-3-cyclopentylpropionyl]piperidine (78% yield of pure anti-compound), which was used in the next step without further purification. The mixture can be separated by chromatography on silica gel with hexane/ethyl acetate (1:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:36][CH3:37])=[CH:5][C:6]2[S:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:35]=1.I([O-])(=O)(=O)=[O:39].[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4]([O:36][CH3:37])=[CH:5][C:6]2[S:12](=[O:39])[CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:35]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COc1cc2c(cc1OC)SCCC(C(=O)N1CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC1)=C2
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1OC)S(=O)CCC(C(=O)N1CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC1)=C2
Reaction time: 48 h
Yield: 78.9 %

Procedure:
In methanol (10 ml) is dissolved 1-(7,8-dimethoxy-2,3-dihydro-1-benzothiepin-4-carbonyl)-4-(3,4,5-trimethoxybenzoyl)piperazine (1.6 g) obtained in Working Example 24. To the solution is added dropwise, while stirring under ice-cooling, a solution of sodium periodate (960 mg) in water (1 ml). The mixture is stirred for one hour under ice-cooling, and left standing for 48 hours at -5° C. Resultant precipitates are filtered off. To the filtrate is added water, followed by extraction with methylene chloride. The organic layer is washed with an aqueous solution of sodium hydrogencarbonate, dried, and concentrated under reduced pressure. The residue is recrystallized from ethanol-ether to give 1-(7,8-dimethoxy-1-oxo-2,3-dihydro1-benzothiepin-4-carbonyl)-4-(3,4,5-trimethoxybenzoyl)piperazine as colorless prisms (1.3 g), m.p. 138° C.
Reaction SMILES: [OH:1][C:2]([P:15](=[O:18])([OH:17])[OH:16])([P:11](=[O:14])([OH:13])[OH:12])[CH2:3][CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.I[CH3:20]>[OH-].[Na+].O.C(O)C>[OH-:1].[OH:1][C:2]([P:15]([OH:16])([OH:17])=[O:18])([P:11]([OH:12])([OH:13])=[O:14])[CH2:3][CH2:4][C:5]1[CH:6]=[N+:7]([CH3:20])[CH:8]=[CH:9][CH:10]=1
Reactant: CI
Reactant: O=P(O)(O)C(O)(CCc1cccnc1)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[n+]1cccc(CCC(O)(P(=O)(O)O)P(=O)(O)O)c1
Temperature: 80 °C
Yield: 90.1 %

Procedure:
[1-Hydroxy-3-(3-pyridinyl)propylidene]bis[phosphonic acid](3.37 mmol, 1.0 g) is dissolved in 8.4 ml of 1N NaOH solution with 29 ml of distilled water. Iodomethane (16.83 mmol, 1.05 ml) is added in 19 ml of ethanol. This reaction mixture is heated at 80° C. overnight. The solvent is evaporated in vacuo and the residue is triturated with acetone then recrystallized from ethanol and water to yield 0.5 g of 3-(3-hydroxy-3,3-diphosphono-propyl)-1-methyl pyridinium hydroxide, inner salt.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([NH:9][C:10]1[C:11](Cl)=[C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]2=[C:14]([CH:29]=1)[C:15](=[O:28])[N:16]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:17]3=[O:22])(=[O:8])[CH3:7]>O>[C:6]([NH:9][C:10]1[C:11]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]2=[C:14]([CH:29]=1)[C:15](=[O:28])[N:16]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:17]3=[O:22])(=[O:8])[CH3:7]
Reactant: CC(=O)Nc1cc2c3c(cccc3c1Cl)C(=O)N(OC(C)(C)C)C2=O
Reactant: C1CCNC1
Solvent: O
Product: CC(=O)Nc1cc2c3c(cccc3c1N1CCCC1)C(=O)N(OC(C)(C)C)C2=O
Temperature: 100 °C
Yield: 94.8 %

Procedure:
Pyrrolidine (0.85 g, 12.0 mmol) was added to 5-acetamido-2-tert-butyloxy-6-chloro benzo[de]isoquinoline-1,3-dione (0.30 g, 0.8 mmol, from Example P2). The solution was heated at 100° C. overnight followed by addition of water (10 mL). The precipitate was filtered to give 0.30 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]([CH3:26])[N:24]=[CH:23][C:22]=2/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:17][CH:16]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:25]([CH3:26])[N:24]=[CH:23][C:22]=2/[CH:27]=[CH:28]/[C:29]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=2)=[O:30])=[CH:19][CH:20]=1
Reactant: Cn1ncc(/C=C/C(=O)O)c1-c1ccc(F)cc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
A mixture of ethyl (4-aminophenyl)acetate (0.88 g), (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylic acid (1.0 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.81 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.02 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give ethyl [4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)phenyl]acetate as colorless crystals (1.49 g, yield 89%). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 177-178° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14](Cl)=[O:15])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([CH2:26][CH:27]3[NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH2:28]3)=[CH:23][C:22]=2[CH:34]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([CH2:26][CH:27]3[CH2:28][N:29]([CH3:33])[CH2:30][CH2:31][N:32]3[C:14]([C:9]3[N:10]=[C:11]([CH3:13])[S:12][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:15])=[CH:23][C:22]=2[CH:34]=1
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Reactant: CN1CCNC(Cc2cc3cc(Cl)ccc3o2)C1
Product: Cc1nc(C(=O)N2CCN(C)CC2Cc2cc3cc(Cl)ccc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound (135 mg) was prepared from 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (211 mg) and 3-(5-Chloro-benzofuran-2-ylmethyl)-1-methyl-piperazine, D63 (200 mg) by a procedure similar to that described for Example 1.