Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[CH:15].C(Cl)(Cl)Cl>CO>[CH2:8]([OH:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[CH:15]
Reactant: C#CCCCCCCOC1CCCCO1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C#CCCCCCCO
Yield: 88.9 %

Procedure:
A suspension of lithium acetylide ethylenediamine complex (Aldrich, 11.3 g, 122.5 mmol) and dimethyl sulfoxide (50 ml) was cooled to 5-10° C., and added dropwise with 1-bromo-6-tetrahydropyranyloxyhexane (Sigma, 25 g, 94.3 mmol) over two hours. Then, the reaction mixture was stirred at room temperature for two hours. The reaction mixture was added with water (10 ml), stirred for ten minutes, then poured into water (150 ml), and extracted with ether (300 ml). The ether layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to afford 18.1 g of 8-(tetrahydropyranyloxy)-1-octyne as oil (yield; 91.2%). Dowex 50WX8 (H+ type, 18 g) was added to a mixture of 8-(tetrahydropyranyloxy)-1-octyne (18 g, 85.6 mmol), chloroform (40 ml) and methanol (140 ml), and heated for 1 hour under reflux. After the resin was separated by filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; hexane-ethyl acetate mixed solvent) to afford 9.6 g of 7-octyn-1-ol (yield; 88.6%).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][CH2:2]1.C(N(CC)CC)C.[C:13]1([CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[C:13]1([CH2:19][CH2:20][CH2:21][C:22]([N:3]2[CH2:4][CH2:5][S:1][CH2:2]2)=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1CSCN1
Reactant: O=C(Cl)CCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCc1ccccc1)N1CCSC1
Temperature: 25 °C
Yield: 88 %

Procedure:
5.5 mmol of thiazolidine and 5.5 mmol of triethylamine were dissolved in 10 ml of methylene chloride. To the solution 5 mmol of 4-phenylbutanoyl chloride was added dropwise under ice-cooling with stirring. The mixture was left to raise to room temperature and further heated under refluxing for 2 hours. The resulting reaction mixture was washed with 1N hydrochloric acid, brine, and saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated by distillation and the residue was purified by column chromatography on silica gel to obtain 1.14 g of colorless crystals of N-(4-phenylbutanoyl)thiazolidine (yield: 88%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH3:22][C@@H:23]1OS(=O)(=O)[N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25][CH2:24]1.Cl>CN1C(=O)CCC1>[C:34]([O:33][C:31]([NH:26][CH2:25][CH2:24][C@H:23]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:22])=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Reactant: C[C@H]1CCN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n([C@H](C)CCNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.4 %

Procedure:
A stirred suspension of 60% NaH (840 mg, 21 mmol) in NMP (40 mL) is cooled in an ice bath, and a solution of diethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 5.8 g, 22 mmol) in NMP (20 mL) is added. The mixture is stirred for 20 min, then a solution of tert-butyl (6S)-6-methyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (5.0 g, 20 mmol) in NMP (20 mL) is added. The reaction mixture is stirred for 30 min at 0° C. and is warmed to room temperature and stirred for 48 h. The reaction is poured into ice water and the resultant solid is isolated by filtration. The filtrate is acidified to pH 3 with 1N aqueous HCl and extracted with EtOAc. The combined extracts are washed with water 4 times, then brine, dried (Na2SO4) and concentrated to afford the title compound (6.0 g, crude) as an oil which was used in the next step without purification.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[F:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[F:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([C@H:2]3[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[O:8])[CH2:3]3)[CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)C1
Reactant: Fc1cccc(N2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)[C@@H]1CC[C@H](N2CCN(c3cccc(F)c3)CC2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (R)-benzyl 3-oxocyclopentanecarboxylate (1.5 g, 6.87 mmol), 1-(3-fluorophenyl)piperazine (1.36 g, 7.56 mmol) in 1,2-dichloroethane (25 ml) were added 1-(3-fluorophenyl)piperazine (1.36 g, 7.56 mmol), glacial acetic acid (0.4 ml, 6.87 mmol) and Sodium triacetoxy borohydride (2.18 g, 10.31 mmol). The mixture was stirred at 25° C. for 24 h before removal of the solvent. The residue was treated with saturated sodium bicarbonate, extracted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude residue which was purified by column chromatography over silica gel using ethyl acetate in hexane as eluents to obtain the title compound as the major diastereomer (1.2 g, 45.7%).
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[F:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([F:28])[CH:27]=1>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=3)[CH2:34][CH2:33]2)=[O:20])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Product: COc1nc(C)c(C)cc1NC(=O)N1CCN(c2cc(F)cc(F)c2)CC1
Yield: 87 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Cl:7][C:8]1[N:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][N:9]=1.CC1(C)C(C)(C)OB([C:24]2[CH:29]=[CH:28][C:27]([C:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)O1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:36]([O:35][C:34]([NH:33][C:30]([C:27]1[CH:26]=[CH:25][C:24]([C:12]2[C:11]([Cl:15])=[CH:10][N:9]=[C:8]([Cl:7])[N:13]=2)=[CH:29][CH:28]=1)([CH3:32])[CH3:31])=[O:40])([CH3:37])([CH3:38])[CH3:39]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2nc(Cl)ncc2Cl)cc1
Yield: 81.7 %

Procedure:
2M aqueous Na2CO3 (4.7 ml, 9.4 mmol) was added to a solution of 2,4,5-trichloropyrimidine [Chesterfield, J.; McOmie, J. F. W.; Sayer, E. R.; J. Chem. Soc. (1955) 3478-3481] (1.18 g, 6.44 mmol), tert-butyl N-{1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]1-methylethyl}carbamate (1.55 g, 4.29 mmol) and tetrakis(triphenylphosphine)palladium (O) (150 mg, 0.13 mmol) in ethyleneglycol dimethylether (20 ml) under N2 and the mixture heated to reflux for 6 h. The reaction was diluted with H2O (30 ml) and extracted with ethyl acetate (3×50 ml), the combined ethyl acetate extracts were washed with brine (30 ml), dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 15% ethyl acetate in hexane) to give 4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2,5-dichloropyrimidine as a white solid (1.34 g). δH (d6DMSO) 8.62 (1H, s), 7.90 (2H, d, J 8.6 Hz), 7.54 (2H, dt, J 8.7, 2.1 Hz), 5.02 (1H, bs), 1.65 (6H, s) and 1.37 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11]([C:13]1(Br)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12].[Cl-].[Li+].CN(C)C=O>O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11]([C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1)=[O:12]
Reactant: COc1ccc(C(=O)C2(Br)CCCCC2)c(Cl)c1Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)C2=CCCCC2)c(Cl)c1Cl

Procedure:
1-Bromocyclohexyl (2,3-dichloro-4-methoxyphenyl) ketone (47.3 g., 0.13 mole), lithium chloride (16.5 g., 0.39 mole) and dimethylformamide (200 ml.) are heated at 90°C. for two hours, then poured into water (1 l.) to give 36.5 g. of 1-cyclohexenyl (2,3-dichloro-4 -methoxyphenyl) ketone which melts at 126°-129°C. after drying at 60°C. under vacuum for 16 hours.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[NH:17]1[CH2:22][CH:21]=[C:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][CH:24]=2)[CH2:19][CH2:18]1.C(=O)(O)[O-].[K+].O>CN(C)C(=O)C>[CH3:16][C:3]1([CH2:2][N:17]2[CH2:18][CH:19]=[C:20]([C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][CH:24]=3)[CH2:21][CH2:22]2)[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CC=C(c3c[nH]c4ccccc34)CC1)O2
Yield: 82.4 %

Procedure:
A suspension of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (0.85 g), 3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (1.1 g) and potassium bicarbonate (0.83 g) in N,N-dimethylactamide (6 mL) was refluxed for 7.5 hours under nitrogen atmosphere. To the mixture water was added and the product was extracted twice with ethyl acetate. The combined extract was washed with water followed by saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from acetone/diisopropyl ether to provide 0.99 g of the title compound. Yield 82%.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([N+:14]([O-:16])=[O:15])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.C(Cl)Cl>[F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([N+:14]([O-:16])=[O:15])[C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: Cc1c(F)c(F)c([N+](=O)[O-])c(C(=O)O)c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(F)c(F)c([N+](=O)[O-])c(C(=O)Cl)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension containing 27.0 g of 2,4,5-trifluoro-3-methyl-6-nitrobenzoic acid, 19.5 ml of oxalyl chloride, 270 ml of methylene chloride, and a few drops of N,N-dimethylformamide was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride. Separately, a few drops of carbon tetrachloride was added to a suspension of 3.08 g of magnesium in 6.4 ml of absolute ethanol, and then a solution of 19.2 ml of diethyl malonate in 12 ml of absolute ethanol was added dropwise to the suspension under heating at 50° C., and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and then, toluene was added to dissolve the residue and the solution was again concentrated. To a solution of the residue in 30 ml of toluene, a solution of 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride in 30 ml of toluene was added dropwise with stirring under ice cooling, and then stirring was continued for 2 hours at room temperature. The reaction mixture was added with 100 ml of 5% sulfuric acid, and was then extracted with diethyl ether. The extract was washed with brine, and then dried and concentrated to give 47.3 of brown oil.
Reaction SMILES: N[C:2]1[NH:7][C:6]2=[C:8]([C@@H:11]3[NH:19][C@H:16]([CH2:17][OH:18])[C@@H:14]([OH:15])[C@H:12]3O)[CH:9]=[N:10][C:5]2=[C:4]([OH:20])[N:3]=1.CC(OC(N(C)C)N(C)C)(C)C.C1(C)C=CC=CC=1>CN(C)C=O>[OH:20][C:4]1[N:3]=[CH:2][NH:7][C:6]2=[C:8]([C@@H:11]3[NH:19][C@H:16]([CH2:17][OH:18])[C@@H:14]([OH:15])[CH2:12]3)[CH:9]=[N:10][C:5]=12
Reactant: Nc1nc(O)c2ncc([C@@H]3N[C@H](CO)[C@@H](O)[C@H]3O)c-2[nH]1
Agent: CN(C)C(OC(C)(C)C)N(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: OC[C@H]1N[C@@H](c2cnc3c(O)nc[nH]c2-3)C[C@@H]1O
Temperature: 67.5 °C
Yield: 86.8 %

Procedure:
To a solution of the product from Example 1.2 (0.88 g) in N,N-dimethylformamide (5 ml) was added tert-butoxy bis(dimethylamine)methane (1.5 ml) and the solution was heated at 65-70° C. for 1 h. Toluene (20 ml) was added and the solution was washed (×3) with water, dried and concentrated to dryness. The residue was dissolved in tetrahydrofuran/acetic acid/water (1:1:1 v/v/v, 40 ml) at room temperature. After 1.5 h chloroform (50 ml) was added and the mixture was washed with water (×2), aqueous sodium bicarbonate, and then dried and evaporated to dryness. Chromatography of the residue gave (1S)-N-tert-butoxycarbonyl-5-O-tert-butyldimethylsilyl-1-C-(1-cyano-2-hydroxyethenyl)-1,4-dideoxy-1,4-imino-2,3-O-isopropylidene-D-ribitol (3) (0.68 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl.C(=O)(O)[O-].[Na+].[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1>>[Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][O:29]1)[CH:6]=2
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1cc(Br)cc2[nH]ncc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cc(Br)cc2nn(C3CCCCO3)cc12
Reaction time: 0.17 h

Procedure:
To 6-bromo-4-nitro-1H-indazole (10 g) in dihydropyran (100 ml) was added TFA (0.068 ml) and the reaction was heated for 1.5 h at reflux. After cooling, DCM (180 ml) and saturated sodium bicarbonate solution (50 ml) was added and stirred for 10 min. The DCM was separated from the aq which was re-washed with DCM (70 ml). The combined organic layers were passed through a hydrophobic frit and evaporated to dryness. The residual solid was triturated with ether then filtered. The solid material was dissolved in DCM and purified by chromatography on silica on the ISCO Companion, using an isocratic gradient of DCM. Purified fractions were combined and evaporated to dryness to afford the title compound, 7.78 g.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH2:13][C@H:14]4[CH2:27][C@H:15]4[C:16]=3[N:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[N:18]=2)=[O:10])[CH2:2]1.[C:28](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:28][N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH2:13][C@H:14]4[CH2:27][C@H:15]4[C:16]=3[N:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[N:18]=2)=[O:10])[CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCC1CNCCO1)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCOC(CNC(=O)c2nn(-c3ccc(F)cc3F)c3c2C[C@H]2C[C@@H]32)C1
Temperature: 23 °C
Reaction time: 18 h
Yield: 106.2 %

Procedure:
To a mixture of (1aR,5aR)-2-(2,4-Difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (morpholin-2-ylmethyl)-amide (40 mg, 0.097 mmol) and potassium carbonate (26.9 mg, 0.195 mmol) in DMF (0.5 mL) was added iodomethane (6.06 μL, 0.097 mmol). The reaction was stirred at 23° C. for 18 h. The mixture was filtered then purified by HPLC to provide the title compound (TFA salt, 40 mg) as a hygroscopic white solid. LCMS m/z=389.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.37-0.41 (m, 1H), 1.14-1.20 (m, 1H), 2.11-2.21 (m, 1H), 2.25-2.32 (m, 1H), 2.74-3.47 (m, 11H), 3.61-3.69 (m, 1H), 3.77-3.83 (m, 1H), 3.94-4.05 (m, 1H), 7.30-7.35 (m, 1H), 7.59-7.64 (m, 1H), 7.74-7.80 (m, 1H), 8.15-8.21 (m, 1H).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Cl:28][C:29]1[C:30]([Cl:44])=[CH:31][C:32]2[O:37][CH2:36][C:35](=[O:38])[N:34]([CH2:39][C:40]([OH:42])=O)[C:33]=2[CH:43]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:28][C:29]1[C:30]([Cl:44])=[CH:31][C:32]2[O:37][CH2:36][C:35](=[O:38])[N:34]([CH2:39][C:40]([N:2]([CH3:1])[C@H:3]([C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)[CH2:4][N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)=[O:42])[C:33]=2[CH:43]=1
Reactant: CCOC(=O)c1ccc(-c2ccc([C@H](CN3CCOCC3)NC)cc2)cc1
Reactant: O=C(O)CN1C(=O)COc2cc(Cl)c(Cl)cc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc([C@H](CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)cc1
Temperature: 0 °C
Yield: 69.5 %

Procedure:
Ethyl 4′-[(1R)-1-(methylamino)-2-(4-morpholinyl)ethyl]-4-biphenylcarboxylate (crude, 26.5 g) was dissolved in 500 mL of DMF at room temperature with magnetic stirring. The resulting solution was treated with (6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetic acid (28.8 g, 80.4 mmol, with 23 wt % LiCl) and cooled to 0° C. To this solution was added triethylamine (20.5 mL, 147.4 mmol) and BOP (35.5 g, 80.4 mmol). The reaction mixture was maintained at room temperature overnight. The reaction mixture was filtered. The filtrate was slowly added to 2500 mL of H2O with vigorous stirring. The resulting precipitate was collected by filtration and partitioned between 300 mL of brine solution and 1000 mL of DCM. The organic layer was dried over MgSO4, filtered, and concentrated. The brown residue was purified by column chromatography (250 g silica gel 60, 230-400 mesh, 2% MeOH and 0.5% NEt3 in CH2Cl2 as eluent) to give the title compound as a brown solid (31.3 g, 75% yield). MS (ES) m/e 626 [M+H]+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][CH2:12][OH:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([O:18][C:19](=[O:35])[NH:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30](O)[CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:17])([CH3:16])[CH3:15].O1CCOC1CC1C=CC(CO)=CC=1.OC1C=C(C=CC=1)C(C1C=CC=CC=1)=O>>[C:1]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:21]([NH:20][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:35])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:27]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(O)c1
Reactant: O=C(OCCCO)c1ccccc1
Agent: O=C(c1ccccc1)c1cccc(O)c1
Agent: OCc1ccc(CC2OCCO2)cc1
Product: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCCCOC(=O)c2ccccc2)c1

Procedure:
The title compound was prepared as described in Example 22 Step 3 with 3-hydroxypropyl benzoate (prepared as outlined in Organic & Biomolecular Chemistry, 8(24), 5505-5510; 2010, which is incorporated herein by reference in its entirety) and tert-butyl((3-hydroxyphenyl)(phenyl)methyl)carbamate (derived from the second eluting isomer Chiral Example 1 Step 4) replacing (4-((1,3-dioxolan-2-yl)methyl)phenyl)methanol and 3-hydroxybenzophenone respectively.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[C:9]([NH:11][C:12]([NH2:14])=[NH:13])#[N:10]>C(O)CCC>[ClH:1].[CH3:8][C:6]1[O:5][N:4]=[C:3]([NH:2][C:9]([NH:11][C:12]([NH2:14])=[NH:13])=[NH:10])[CH:7]=1
Reactant: Cc1cc(N)no1
Reactant: N#CNC(=N)N
Agent: Cl
Solvent: CCCCO
Product: Cc1cc(NC(=N)NC(=N)N)no1
Yield: 41.6 %

Procedure:
In a 2 liter three-necked flask are added 370 g of 3-amino-5-methyl-isoxazole hydrochloride, 231 g of 1-cyanoguanidine and 500 ml of butanol. The temperature is gradually raised to the refluxing temperature of the solvent, at which level it is then maintained during 10 minutes. The reaction mixture is allowed to cool and, after incipient crystallization, is poured over 2 liters of butanol. After complete crystallization, the resulting material is filtered, the solid is washed with 300 ml of isopropanol. The solid is recrystallized from 1 liter 90% ethanol, to give 250 g of (5-methyl-isoxazol-3-yl)biguanide hydrochloride. M.p. (Kofler) = 210°-212° C. M.p. (cap.) = 195°-196° C. with introduction at 185° C. and heating at a rate of 2° C./minute.
Reaction SMILES: [C:1]([C:4]1[O:8][N:7]=[C:6]([C:9]([OH:11])=O)[CH:5]=1)(=[O:3])[CH3:2].[NH2:12][CH2:13][C@H:14]([N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1)[CH3:15]>>[C:1]([C:4]1[O:8][N:7]=[C:6]([C:9]([NH:12][CH2:13][C@H:14]([N:16]2[CH:20]=[CH:19][C:18]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=3)=[N:17]2)[CH3:15])=[O:11])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(=O)O)no1
Reactant: C[C@H](CN)n1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CC(=O)c1cc(C(=O)NC[C@@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1
Yield: 19.16 %

Procedure:
(R)-5-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)-isoxazole-3-carboxamide was prepared using the method of Example 34(d) starting from 5-acetylisoxazole-3-carboxylic acid (0.314 g, 2.025 mmol) and (R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.44 g, 1.688 mmol). The product was purified by Flash-chromatography. Yield 19.16%. 1H-NMR (400 MHz; CDCl3): δ 1.63 (d, 3H), 2.63 (s, 3H), 3.79-3.87 (m, 1H), 3.92-3.99 (m, 1H), 4.60-4.66 (m, 1H), 6.63 (d, 1H), 7.29 (s, 1H), 7.50 (d, 1H), 7.69-7.74 (m, 2H), 7.82 (dd, 1H), 8.05 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[CH:7]=1.[C:22]([C:24]([CH3:36])([O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])[CH3:25])#[N:23].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.O>N1C=CC=CC=1>[C:14]([NH:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([O:26][C:24]([C:22]#[N:23])([CH3:25])[CH3:36])[CH:28]=4)[CH:21]=[CH:20][CH:19]=3)[CH:18]=[CH:17][C:9]=2[N:10]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)cc2s1
Reactant: CC(C)(C#N)Oc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(OC(C)(C)C#N)c4)c3)cc2s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.3 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)-1,3-benzothiazol-2-yl]acetamide (160 mg, 0.534 mmol) produced in Example A40(x) and 3-(1-cyano-1-methylethoxy)benzoic acid (219 mg, 1.07 mmol) in pyridine (5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (407 mg, 1.07 mmol) under ice-cooling, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was poured into water (100 mL), and extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined and dried over anhydrous sodium sulfate, and the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→0/100), and crystallized from ethyl acetate to give the title compound (141 mg, 54%) as colorless crystals.