Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.C[O:14][C:15](=[O:36])[C@H:16]([CH2:25][CH2:26][CH2:27][N:28]=CC1C=CC=CC=1)[N:17]=CC1C=CC=CC=1.Cl[CH:38]([F:40])[F:39].Cl>CCCCCC.O1CCCC1>[F:39][CH:38]([F:40])[C:16]([NH2:17])([CH2:25][CH2:26][CH2:27][NH2:28])[C:15]([OH:14])=[O:36]
Reactant: COC(=O)[C@H](CCCN=Cc1ccccc1)N=Cc1ccccc1
Reactant: FC(F)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: NCCCC(N)(C(=O)O)C(F)F
Temperature: 40 °C

Procedure:
Under nitrogen, a solution (500 ml) of 2 M butyllithium in hexane is added to a stirred solution of diisopropylamine (143.1 ml) in tetrahydrofuran (1.5 l) at -78° C. after which dibenzylidene ornithine methyl ester (261 g, 0.81 mole) in tetrahydrofuran (1.5 l) is added. Upon completion of the addition, the reaction temperature is raised to 40° C. and maintained between 40° and 50° C. for 3 hours during which time chlorodifluoromethane gas is bubbled through the mixture with stirring. The reaction mixture is then treated with a saturated solution of sodium chloride. The organic material is extracted with ether, and the ether extract washed several times with sodium chloride solution, dried over magnesium sulfate and evaporated to give a viscous oil. The oil is stirred with 1 N HCl (1.5 l) for 3 hours, the mixture extracted several times with chloroform and the aqueous solution evaporated to dryness. The oily residue is refluxed with 12 N hydrochloric acid (1.5 l) for 16 hours, the cooled solution clarified by chloroform extraction before concentration, decolorization (charcoal), and further concentration to about 750 ml. The pH of the solution is adjusted to 3.5 by the addition of triethylamine, the solution treated again with charcoal before concentration to about 500 ml and dilution with acetone (7-8 l). The precipitated product is filtered off and washed with ethanol. The crude product is recrystallized by dissolving in hot water (about 150 ml) and treatment of the solution with hot ethanol (450 ml). On cooling crystals of 2-difluoromethyl-2,5-diaminopentanoic acid as the hydrochloride monohydrate separate (71 g): m.p. 183° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[N:21]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:8][CH:7]=1)=O)C.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O-]S([O-])(=O)=O.[Na+].[Na+]>ClCCl>[OH:3][CH2:4][C:6]1[O:10][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[N:21]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)o1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCc1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)o1
Temperature: 0 °C

Procedure:
Combine 2-chloro-1-(5-ethyoxycarbonylfur-2-ylmethyl)-1H-benzimidazole (9.50 g, 31.2 mmol) and [1,4]diazepane (6.24 g, 62.3 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (5.6 mL, 37.4 mmol), and pyridine (90 mL). Heat to reflux. After 18 hours, cool to ambient temperature and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with methanol and then 2% concentrated aqueous ammonia/methanol to give 4-(1-(5-ethyoxycarbonylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane. Combine 4-(1-(5-ethyoxycarbonylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.0 g, 2.7 mmol) and tetrahydrofuran (10 mL). Add a solution of lithium aluminum hydride (2.7 mL, 1.0 M in tetrahydrofuran, 2.7 mmol). After 18 hours pour the reaction mixture into a beaker, dilute with dichloromethane, and cool to 0° C. With stirring add portionwise, Glauber's salt (Na2SO4.10H2O) until the evolution of gas ceases. Add dichloromethane to about double the volume, add celite, stir to form a thick slurry, and filter. Evaporate the filtrate in vacuo to give the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)C1C=CC=CC=1.[CH3:24][O:25][C:26]1[CH:35]=[CH:34][C:29]2[C:30](=O)[CH2:31][O:32][C:28]=2[CH:27]=1>>[OH:8][C:9]1[CH:14]=[C:13]([C:30]2[C:29]3[CH:34]=[CH:35][C:26]([O:25][CH3:24])=[CH:27][C:28]=3[O:32][CH:31]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:21])(=[O:22])[NH:19][C:18](=[O:23])[CH2:17]1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: COc1ccc2c(c1)OCC2=O
Product: COc1ccc2c(-c3ccc(N4CC(=O)NS4(=O)=O)c(O)c3)coc2c1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one and 6-methoxybenzofuran-3-one analogous to Example 274: (M−1)−=373; HPLC retention time=1.09 min. (Method A).
Reaction SMILES: [NH2:1][C:2]1[C:3](C(OCC)=O)=[N:4][C:5]2[CH2:11][CH2:10][N:9](C(OCC)=O)[CH2:8][CH2:7][C:6]=2[N:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[N:17]=1
Reactant: CCOC(=O)c1nc2c(nc1N)CCN(C(=O)OCC)CC2
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Nc1cnc2c(n1)CCNCC2
Temperature: 180 °C

Procedure:
A mixture of 1.6 gm (5.2 mmols) of diethyl 2-amino-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine-3,7-dicarboxylate and 20 ml of 80% sulfuric acid was heated for 30 minutes at 180° C. Thereafter, the mixture was cooled, made alkaline with an aqueous sodium carbonate solution, and extracted with chloroform for 24 hours with a perforator. The chloroform extract was chromatographed in silicagel with chloroform/methanol/concentrated ammonia (24:12:1) as the mobile phase.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]([OH:7])=[O:6].[CH3:8][NH:9][CH3:10].C(Cl)CCl>C1COCC1.CN(C=O)C>[CH3:8][N:9]([CH3:10])[CH2:2][CH:3]=[CH:4][C:5]([OH:7])=[O:6]
Reactant: O=C(O)C=CCBr
Reactant: CNC
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)CC=CC(=O)O
Temperature: 25 °C
Yield: 40 %

Procedure:
100 mg of 4-dimethylamino-2-butenoic acid (0.63 mmol) which was prepared by reaction between 4-bromo-2-butenoic acid and dimethylamine in THF, was added in 2 ml DMF and 185 mg of 4 (0.53 mmol) was added followed by 0.6 mmol EDC. The mixture was stirred over night at room temperature and the final product was purified by preparative HPLC to give 120 mg product as light yellow solid, yield 40%. HPLC-MS: m/z: 496 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:34][O:35][C:36]([C:38]1[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][CH:39]=1)=[O:37].C1C=CC2N(O)N=NC=2C=1.N=C=N.C(=O)([O-])[O-].[N-]=C=O>CN(C=O)C>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:42]([C:41]2[CH:45]=[CH:46][C:38]([C:36]([O:35][CH3:34])=[O:37])=[CH:39][CH:40]=2)=[O:43])[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: N=C=N
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)cc1
Reaction time: 8 h

Procedure:
To a mixture of 13.3 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate, 6.3 mg of 4-methoxycarbonyl benzoic acid, 4.7 mg of HOBt, and 1 mL of DMF was added 100 mg of PS-Carbodiimide (Argonaut Technologies, USA) at room temperature, followed by stirring overnight. To the reaction mixture was added 50 mg of MP-Carbonate (Argonaut Technologies, USA), 50 mg of PS-Isocyanate (Argonaut Technologies, USA), and 0.5 mL of DMF at room temperature, followed by stirring for 4 hours, and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain methyl 4-{[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}benzoate as a crude product. To 0.5 mL of a 1,4-dioxane solution of the obtained crude product were added 0.5 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring for 6 hours. The reaction mixture was concentrated under reduced pressure to obtain methyl 4-{[4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}benzoate as a crude product. To 0.5 mL of a THF solution of the obtained crude product was added 0.5 mL of methanol and 0.5 mL of a 1 M aqueous sodium hydroxide solution at room temperature, followed by stirring overnight. To the reaction mixture was added 0.5 mL of 1 M hydrochloric acid, followed by concentration under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography (column: registered trademark SunFire, Waters, particle diameter of 5 μm, inner diameter of 19 mm, and length of 100 mm), flow rate: 25 ml/min., column temperature: 20° C., methanol—a 0.1% aqueous formic acid solution) to obtain 7.7 mg of 4-{[4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}benzoic acid.
Reaction SMILES: C(OC([N:8]([CH2:30][C@@H:31]([C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([N:46](C(OC(C)(C)C)=O)[S:47]([CH3:50])(=[O:49])=[O:48])[CH:41]=1)[O:32][Si](CC)(CC)CC)[CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH2:28][CH3:29])=[N:17][N:18]2C(OC(C)(C)C)=O)=[CH:14][CH:13]=1)=O)(C)(C)C.C(OCC)(=O)C.[ClH:64]>>[OH:32][C@H:31]([C:40]1[CH:41]=[C:42]([NH:46][S:47]([CH3:50])(=[O:48])=[O:49])[CH:43]=[CH:44][CH:45]=1)[CH2:30][NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH2:28][CH3:29])=[N:17][NH:18]2)=[CH:14][CH:13]=1.[ClH:64]
Reactant: CCc1nn(C(=O)OC(C)(C)C)c2cc(OCCN(C[C@H](O[Si](CC)(CC)CC)c3cccc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)c3)C(=O)OC(C)(C)C)ccc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCc1n[nH]c2cc(OCCNC[C@H](O)c3cccc(NS(C)(=O)=O)c3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 4 mol/L hydrogen chloride-ethyl acetate solution (70 mL; manufactured by Kokusan Chemical Co., Ltd.) was added to (R)-tert-butyl 6-(2-(tert-butoxycarbonyl-(2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)phenyl)-2-(triethylsilyloxy)ethyl)amino)ethoxy)-3-ethylindazole-1-carboxylate (3.56 g) that can be produced by the method described in Reference Example 15 or the like, and the mixture was stirred overnight at room temperature. Precipitates were filtered, and the Solids were washed five times with ethyl acetate (3 mL) and once with diethyl ether (1 mL). Thus, the title compound was obtained in the form of hydrochloride (2.056 g).
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=3)[CH2:9]2)=CC=1.[ClH:23]>CO.[OH-].[OH-].[Pd+2]>[ClH:23].[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: COC(=O)c1ccc2c(c1)CN(Cc1ccc(OC)cc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CNC2
Reaction time: 48 h
Yield: 2242.3 %

Procedure:
To a mixture of methyl 2-(4-methoxybenzyl)isoindoline-5-carboxylate (0.82 g, 2.76 mmol) and 20% palladium hydroxide on carbon (0.194 g, 0.276 mmol) in methanol (25 mL) was added concentrated HCl (0.41 mL, 0.11 mmol). The mixture was degassed and stirred under a balloon atmosphere of H2 for two days. Additional 20% palladium hydroxide on carbon (0.08 g, 0.11 mmol) was then added and the reaction was continued for an additional day. The insolubles were removed via filtration through Clite and the solution was concentrated. Further drying under vacuum afforded a white powder (0.527 g, 91%). LCMS: (FA) ES+ 179. 1H NMR (d6-DMSO, 400 MHz) δ 9.71 (br s, 2H), 8.01 (s, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.55 (d, J=7.7 Hz 2H), 4.56 (d, J=6.0 Hz, 4H), 3.87 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=[S:30]>O1CCCC1>[CH2:22]([N:19]1[CH2:18][CH2:17][CH:16]([N:15]2[CH:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[NH:1][C:29]2=[S:30])[CH2:21][CH2:20]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccccc1C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1
Solvent: C1CCOC1
Product: S=C1Nc2ccccc2C(c2ccccc2)N1C1CCN(Cc2ccccc2)CC1
Yield: 96.3 %

Procedure:
To a solution of 503 mg (1.35 mmol) of α-(2-aminophenyl)-N-(1-benzylpiperidin-4-yl)benzylamine in 10 mL of tetrahydrofuran was added 300 mg (1.68 mmol) of 1,1'-thiocarbonyldiimidazole, and the mixture was heated under reflux for 3 hours. After being cooled, the reaction mixture was concentrated in vacuo, and the residue was purified by means of column chromatography (silica gel, 1:4 ethyl acetate:chloroform) to give 540 mg (1.30 mmol) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C([O-])([O-])=O.[Cs+].[Cs+].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.N#N>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[N:18]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: C1COCCN1
Agent: [Pd]
Agent: N#N
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: O=C1CCc2cc(N3CCOCC3)ccc21
Yield: 51.1 %

Procedure:
A mixture of 5-bromo-1-indanone (0.76 g, 3.60 mmol), Cs2CO3 (1.64 g, 5.04 mmol), Pd2(dba)3 (82 mg, 0.09 mmol), BINAP (112 mg, 0.18 mmol), morpholine (0.94 mL, 10.8 mmol) and THF (15 ml) was pumped with N2 for 0.5 hour and then heated to reflux overnight. The reaction mixture was concentrated, and purified by flash chromatography to give the above intermediate (0.40 g, 51.1%). MS (ESI) m/z 218 (M+H)+; 1H NMR (300 MHz, CD3OD) δ ppm 2.59-2.65 (m, 2H) 3.03-3.10 (m, 2H) 3.34-3.40 (m, 4H) 3.79-3.85 (m, 4H) 6.95 (s, 1H) 6.99 (m, 1H) 7.57 (d, J=8.48 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[NH:17][C:18]4[C:24]([NH:25][C:26](=O)[C:27]5[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=5)=[CH:23][C:22]([C:37]([F:40])([F:39])[F:38])=[CH:21][C:19]=4[N:20]=3)[C@H:12]([CH3:41])[CH2:11]2)=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1>C1COCC1.CO.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[N:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[NH:17][C:18]3[C:24]([NH:25][CH2:26][C:27]4[CH:28]=[C:29]([F:35])[C:30]([F:34])=[C:31]([F:33])[CH:32]=4)=[CH:23][C:22]([C:37]([F:39])([F:38])[F:40])=[CH:21][C:19]=3[N:20]=2)[C@H:12]([CH3:41])[CH2:11]1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(NC(=O)c3cc(F)c(F)c(F)c3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(NCc3cc(F)c(F)c(F)c3)c2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-{2-[(2R)-4-(3-chloro-5-hydroxymethyl-pyridin-2-yl)-2-methyl-piperazin-1-yl]-6-trifluoromethyl-3H-benzoimidazol-4-yl}-3,4,5-trifluoro-benzamide (120 mg, 0.2 mmol, Example 170c) in THF (1 mL) was added BH3. THF (0.6 mL, 0.6 mmol, Aldrich) dropwise with stirring at 0° C. The mixture was heated at reflux for 5 h, cooled to room temperature and diluted with 1:1 mixture of MeOH and 1N NaOH (2 mL). The mixture was stirred at room temperature for 30 min and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with 5% MeOH/CH2Cl2 to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 586 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH:9][C:10](=[S:12])[S-:11])[CH:6]=[CH:5][CH:4]=1)[CH3:2].C([NH+](CC)CC)C.Cl[CH2:21][C:22](=[O:25])[CH2:23][CH3:24]>C(#N)C>[CH2:23]([C:22]1([OH:25])[CH2:21][S:12][C:10](=[S:11])[N:9]1[C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:1][CH3:2])[N:8]=1)[CH3:24]
Reactant: CCc1cccc(NC(=S)[S-])n1
Reactant: CCC(=O)CCl
Agent: CC[NH+](CC)CC
Solvent: CC#N
Product: CCc1cccc(N2C(=S)SCC2(O)CC)n1
Reaction time: 4 h
Yield: 57.9 %

Procedure:
The procedure of Example 4 is followed but starting with triethylammonium (6-ethylpyrid-2-yl)dithiocarbamate (72.0 g) and 1-chlorobutan-2-one (25.5 g) in anhydrous acetonitrile (400 cc) at a maximum temperature of 25° C. The reaction is continued for 4 hours at 20°-25° C. The product is purified by chromatography over silica (470 g; 0.063-0.200 mm) contained in a column 3.8 cm in diameter, eluting with chloroform (5 liters). The chromatographed product (43.0 g) is recrystallised from ethanol (120 cc) to give 4-ethyl-3-(6-ethylpyrid-2-yl)-4-hydroxythiazolidine-2-thione (37.2 g) melting at 84° C.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)[NH2:2].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20](=[CH:26]N(C)C)[C:21](OCC)=[O:22])=[CH:16][CH:15]=1)#[N:13].Cl.CCN(C(C)C)C(C)C>CC(O)C>[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:26]=[N:2][N:1]([C:3]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=3)[C:21]=2[OH:22])=[CH:16][CH:15]=1)#[N:13]
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1
Reactant: NNc1ccc(C(=O)O)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
Combined 6-hydrazinylnicotinic acid (6.00 g, 39.2 mmol) and ethyl 2-(4-cyanophenyl)-3-(dimethylamino)acrylate (10.05 g, 41.1 mmol) and 2-propanol (80 mL) and treated with 1.85% hydrochloric acid (77 mL, 39.2 mmol). The reaction was stirred at room temperature for 16 h, then Hunig's base (34.1 mL, 196 mmol) was add to the suspension which became homogeneous. The mixture was stirred for 3 h. The reaction mixture was washed with isopropyl acetate (2×150 mL). The combined organic layers were extracted with water (40 mL) and the combined aqueous layers were concentrated in vacuo to give a solid. The solid was triturated with 1N HCl (300 mL), filtered and washed with water (20 mL), then slurried in ethanol (350 mL) and granulated overnight. The solid was collected by filtration and dried in vacuum to give the title compound (9.20 g, 77% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.79 (d, J=8.34 Hz, 2H) 8.14 (br. s., 2H) 8.47 (d, J=7.07 Hz, 1H) 8.71 (br. s., 2H) 8.97 (s, 1H) 13.44 (br. s., 1H) 13.60 (br. s., 1H). MS [M+H]307.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-:8].O[CH2:10][P+:11]([CH2:16]O)([CH2:14]O)[CH2:12]O>CC(C)=O>[Cl-:8].[NH:1]([CH2:10][P+:11]([CH2:16][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH2:14][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[P+](CO)(CO)CO
Reactant: Nc1ccccc1
Agent: [Cl-]
Solvent: CC(C)=O
Product: c1ccc(NC[P+](CNc2ccccc2)(CNc2ccccc2)CNc2ccccc2)cc1
Reaction time: 2 h
Yield: 66.5 %

Procedure:
Aniline (9.30 g) was added all at once to a slurry of 4.76 g of tetrakis(hydroxymethyl)phosphonium chloride (THPC) in 50 ml of acetone. The THPC dissolved within 1 minute, with slight warming, giving a clear solution that deposited solids on standing. After 2 hr, the mixture was filtered, giving 8.15 g (66.0 percent yield) of tetrakis(anilinomethyl)phosphonium chloride, m.p. 120°-121°. The filtrate, concentrated on a rotary evaporator, left 16.45 g of a neutral, dark yellow liquid. Beilstein tests on these products were strongly positive on the solid fraction and faintly positive on the liquid fraction, showing that most of the chlorine went into the solid fraction.
Reaction SMILES: COC1C(OC)=NS(=O)(=O)N=1.[CH3:12][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])=[CH:18][C:17]=1[CH3:26])[CH3:14].CN(CC1OC(CSC[CH2:39][NH:40][C:41]2[C:45](OC)=[N:44][S:43](=[O:49])(=[O:48])[N:42]=2)=CC=1C)C.CN>CO>[CH3:14][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][S:22][CH2:23][CH2:24][NH:25][C:45]2[C:41]([NH:40][CH3:39])=[N:42][S:43](=[O:49])(=[O:48])[N:44]=2)=[CH:18][C:17]=1[CH3:26])[CH3:12]
Reactant: Cc1cc(CSCCN)oc1CN(C)C
Reactant: COC1=NS(=O)(=O)N=C1NCCSCc1cc(C)c(CN(C)C)o1
Agent: CN
Agent: COC1=NS(=O)(=O)N=C1OC
Solvent: CO
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1cc(C)c(CN(C)C)o1

Procedure:
When a methanol suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is reacted with an equimolar amount of 2-[(5-dimethylaminomethyl-4-methyl-2-furyl)methylthio]ethylamine [prepared in Step C] and the resultant 3-{2-[(5-dimethylaminomethyl-4-methyl-2-furyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide is treated with an excess of methylamine, the title compound is produced.
Reaction SMILES: [F:1][C:2]([F:23])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][NH:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[F:24][C:25]([F:30])([F:29])[CH:26]1[O:28][CH2:27]1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C>[F:1][C:2]([F:23])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([CH2:27][CH:26]([OH:28])[C:25]([F:30])([F:29])[F:24])[C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: N#Cc1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Reactant: FC(F)(F)C1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: N#Cc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Temperature: 50 °C
Yield: 75.6 %

Procedure:
The benzonitrile (1.58 g, 4.88 mmol) from EX-576A and 1,1,1-trifluoro-2,3-epoxy-propane (546 mL, 6.34 mmol) were dissolved in 4 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (304 mg, 0.49 mmol) was added, and the stirred solution was warmed to 50° C. overnight. The reaction was quenched with water and extracted with ether. The ether layer was washed with brine, dried over MgSO4 and evaporated. The crude product was purified by MPLC on silica gel eluting with dichloromethane to give 1.61 g (76%) of the desired 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-(3,3,3-trifluoro-2-hydroxypropyl)amino]benzonitrile product as a clear oil, greater than 98% by reverse phase HPLC. HRMS calcd. for C19H15F7N2O2: 437.1100 [M+H]+, found: 437.1097. 1H NMR (CDCl3) δ3.60-3.69 (m, 1H), 3.86 (d, 1H), 4.32 (bs. 1H), 4.69 (q, 2H), 5.86 (dt, 1H), 6.85-6.95 (m, 2H), 6.97-7.01 (m, 2H), 7.04-7.12 (m, 2H), 7.23-7.37 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH3:32])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:15](=[O:17])(=[O:16])[CH2:14][CH2:13][C:12]([C:18]([O:20]C)=[O:19])=[CH:11][C:10]=2[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl>O1CCCC1.CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH3:32])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:15](=[O:16])(=[O:17])[CH2:14][CH2:13][C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=2[CH:22]=1
Reactant: CCCOCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCOCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1C
Temperature: 65 °C
Yield: 82.3 %

Procedure:
Into a mixed solution of methyl 7-[3-methyl-4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (470 mg) in tetrahydrofuran (10 ml) and methanol (5 ml) was added a 1 N aqueous solution of potassium carbonate (2.9 ml), and the resulting mixture was heated at 65° C. for one day. After cooling, the reaction mixture was mixed with water, was acidified (pH=4) with 1N hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 7-[3-methyl-4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (375 mg) as a brown oily substance.