Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[C:11]([O:12][CH2:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[F:22])=[CH:10][C:9]([N:23]2[C:31](=[O:32])[NH:30][C:29]3[C:24]2=[N:25][C:26]([CH2:35][OH:36])=[N:27][C:28]=3[O:33][CH3:34])=[C:8]([Cl:37])[CH:7]=1)([OH:3])=O.CN.Cl.[CH2:41]([N:43]=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[Cl:37][C:8]1[C:9]([N:23]2[C:31](=[O:32])[NH:30][C:29]3[C:24]2=[N:25][C:26]([CH2:35][OH:36])=[N:27][C:28]=3[O:33][CH3:34])=[CH:10][C:11]([O:12][CH2:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[F:22])=[C:6]([CH:7]=1)[O:5][CH2:4][C:1]([NH:43][CH3:41])=[O:3]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cccc(F)c1COc1cc(-n2c(=O)[nH]c3c(OC)nc(CO)nc32)c(Cl)cc1OCC(=O)O
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CO)nc32)cc1OCc1c(F)cccc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
To a mixture of 9-[4-carboxymethoxy-2-chloro-5-(2-fluoro-6-methoxybenzyloxy)-phenyl]-2-hydroxymethyl-6-methoxy-7,9-dihydro-8H-purin-8-one (0.1 g), 40% aqueous methylamine solution (0.06 mL), 1-hydroxybenzo[r]azole monohydrate (34 mg) and triethylamine (0.1 mL) in N,N-dimethylformamide (2 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (72 mg), and the mixture was stirred at 60° C. overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate−ethyl acetate/methanol=9/1) to give the title compound (54 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([NH:14][C:15](=[O:28])[C:16]([CH3:27])([S:18]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)(=[O:20])=[O:19])[CH3:17])=[N:12][N:13]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:31]I>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:28])[C:16]([CH3:17])([S:18]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)(=[O:20])=[O:19])[CH3:27])[N:12]([CH3:31])[N:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nnc(NC(=O)C(C)(C)S(=O)(=O)C3CCOCC3)[nH]2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(NC(=O)C(C)(C)S(=O)(=O)C3CCOCC3)n(C)n2)cc1
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a solution of 238 mg (0.58 mmol) of N-[5-(4-methoxy-phenyl)-4H[1,2,4]triazol-3-yl]-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide (prepared according to Amide Method A) in anhydrous THF (2 mL) at room temperature are added 94 mg (2.32 mmol) of sodium hydride (60% dispersion in mineral oil). The reaction mixture is stirred for 1 h and then 145 μL (2.32 mmol) of methyl iodide are added. The reaction is stirred at room temperature for 1 h. The reaction mixture is quenched with saturated aqueous NH4Cl solution (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts are dried over Na2SO4, filtered and the filtrate is concentrated under reduced pressure. The residue is triturated with methanol and the resulting precipitate is purified by mass-directed preparative HPLC (neutral method) to afford 90 mg of N-[5-(4-methoxy-phenyl)-2-methyl-2H-[1,2,4]triazol-3-yl]-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide. Yield: 97%, ES-MS: m/z 423 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:17]=[C:5]2[NH:6][C:7]([CH3:16])=[C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:9](=O)[N:4]2[N:3]=1.O=P(Cl)(Cl)[Cl:20]>>[Br:1][C:2]1[CH:17]=[C:5]2[N:6]=[C:7]([CH3:16])[C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:9]([Cl:20])[N:4]2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)Cc1c(C)[nH]c2cc(Br)nn2c1=O
Product: COC(=O)Cc1c(C)nc2cc(Br)nn2c1Cl
Temperature: 0 °C
Yield: 82.7 %

Procedure:
To methyl 2-(2-bromo-5-methyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)acetate (180 mg, 0.600 mmol) was added POCl3 (1 mL, 10.73 mmol). The reaction mixture was heated at reflux for 1 h. After cooling, the reaction mixture was added drop-wise to ice-water. A brown solid precipitated. The solid was filtered and washed with water to give the title compound (158 mg, 83%). 1H NMR (500 MHz, DMSO-d6) δ 2.56 (3H, s), 3.69 (3H, s), 4.01 (2H, s), 6.99 (1H, s).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([OH:23])[C:16](=[CH:21][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:20][O:19][C:17](=[O:18])[C:16]1[CH:21]=[CH:22][C:13]([O:12][CH3:11])=[CH:14][C:15]=1[O:23][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)c1ccc(OC)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)cc1Oc1ccccc1[N+](=O)[O-]

Procedure:
A solution of 2-fluoronitrobenzene (3.978 g, 28.19 mmol), methyl 4-methoxysalicylate (5.131 g, 28.15 mmol), and potassium carbonate (7.800 g, 56.43 mmol) in DMF (30 mL) was warmed to 50° C. overnight. The solvent was removed in vacuo and the residue partitioned between dichloromethane and water. The water was extracted twice more with dichloromethane and the combined organic extracts washed with brine and dried (Na2SO4). The solvent was removed in vacuo to afford the title compound 1-1 as a pale yellow oil.
Reaction SMILES: [C:1]([C:4]1[NH:8][CH:7]=[C:6]([C:9]([OH:11])=[O:10])[C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)(=[O:3])[NH2:2].[H][H].[ClH:23]>CO.O1CCOCC1.[Pd]>[ClH:23].[C:1]([C:4]1[NH:8][CH:7]=[C:6]([C:9]([OH:11])=[O:10])[C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1[nH]cc(C(=O)O)c1-c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC(=O)c1[nH]cc(C(=O)O)c1-c1ccc(N)cc1

Procedure:
To a suspension of 0.135 g (0.126 mmol) of 10% palladium-on-charcoal in 20 cm3 of methanol is added, at a temperature in the region of 20° C., 0.15 g (0.545 mmol) of 5-carbamoyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylic acid. After hydrogenating for 3 hours in an autoclave under 3 bar of hydrogen, at a temperature in the region of 30° C., the reaction mixture is taken up in 5 cm3 of a 4N solution of hydrogen chloride in dioxane, and then filtered. The catalyst is rinsed with twice 2 cm3 of a 4N solution of hydrogen chloride in dioxane, and the filtrate is then concentrated to dryness under reduced pressure (2.7 kPa) to give 0.141 g of 5-carbamoyl-4-(4-aminophenyl)-1H-pyrrole-3-carboxylic acid hydrochloride in the form of a yellow solid; ES+: m/z=246: [M+H]+
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[CH:18][C:13]=3[C:12]([CH2:19][C:20]3[CH:21]=[N:22][C:23](S(C)(=O)=O)=[N:24][CH:25]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.CN1CCCC1=O.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][NH2:44].[OH-].[K+]>C(O)(=O)C>[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][NH:44][C:23]1[N:24]=[CH:25][C:20]([CH2:19][C:12]2[C:13]3[CH:18]=[N:17][CH:16]=[N:15][C:14]=3[NH:10][CH:11]=2)=[CH:21][N:22]=1
Reactant: NCc1ccccn1
Reactant: CS(=O)(=O)c1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncncc23)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: c1ccc(CNc2ncc(Cc3c[nH]c4ncncc34)cn2)nc1

Procedure:
In a microwave vial, 7-benzenesulfonyl-5-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (58, 12 mg, 0.028 mmol) was mixed with 600 μL of N-methylpyrrolidone and C-pyridin-2-yl-methylamine (59, 19.5 mg, 0.18 mmol). The reaction was irradiated at 160° C. for 40 minutes in microwave, then potassium hydroxide (500 μL, 4.00 M in water) was added and the reaction irradiated at 90° C. for 10 minutes in microwave. The reaction was neutralized with the addition of 120 μL of acetic acid, solvents were removed under vacuum, and the resulting material was dissolved in 400 μL at of dimethylsulfoxide for purification by HPLC. Samples were purified on Phenomenex C18 column (50 mm×10 mm ID) with mobile phase A of 0.1% trifluoroacetic acid in water, mobile phase B of 0.1% trifluoroacetic acid in acetonitrile, 20-100% B over 16 minutes at a flow rate of 6 mL/min. Appropriate fractions were collected and solvents removed under vacuum to provide the desired compound. MS (ESI) [M+H+]+=317.9.
Reaction SMILES: CN(C=O)C.[C:6]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[CH3:7].[H-].[Na+].[C:18]1([N:24]=[C:25]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:26]=[CH:27]S(C2C=CC=CC=2)(=O)=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C>[C:18]1([N:24]=[C:25]([O:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:26]=[CH:27][N:9]([C:6](=[O:8])[CH3:7])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(C=CC(=Nc1ccccc1)Oc1ccccc1)c1ccccc1
Reactant: CC(=O)Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N(C=CC(=Nc1ccccc1)Oc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
To DMF (3 ml) solution of acetanilide (0.14 g) was added sodium hydride (60% in oil: 0.043 g) under ice-cooling, and DMF (2 ml) solution of phenyl N-phenyl-3-(phenylsulfonyl)acrylimidate (0.30 g) was added dropwise. It was stirred for two hours under ice-cooling and for one hour at room temperature. Ethyl acetate (100 ml) was added to the reaction mixture and was successively washed with water and aqueous saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain phenyl N-phenyl-3-(N′-acetyl-N′-phenylamino)acrylimidate (0.050 g) as yellow crystal.
Reaction SMILES: ClC(Cl)C.[Br:5][C:6]1[CH:15]=[N:14][C:13]2[NH:12][C:11](=O)[C:10]([CH3:18])([CH3:17])[O:9][C:8]=2[CH:7]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:25][NH2:26]>C(Cl)Cl>[Br:5][C:6]1[CH:15]=[N:14][C:13]2[NH:12]/[C:11](=[N:26]/[CH3:25])/[C:10]([CH3:18])([CH3:17])[O:9][C:8]=2[CH:7]=1
Reactant: CN
Reactant: CC1(C)Oc2cc(Br)cnc2NC1=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: C/N=C1/Nc2ncc(Br)cc2OC1(C)C
Temperature: -78 °C
Yield: 89 %

Procedure:
A dichloroethane (5 mL) solution of 7-bromo-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (520 mg, 2 mmol) and phosphorus pentachloride (840 mg, 4 mmol) was irradiated in a microwave oven for 10 min at 160° C. The solution was cooled to −78° C. and methylamine (2M in THF) was added it slowly until it became permanently basic. The mixture was diluted with CH2Cl2, washed with dilute solution of NaOH, dried and evaporated. Crystallization from CH2Cl2/hexane afforded 480 mg (89%) of the title compound. 1H NMR (300 MHz, CDCl3, 8) 8.07 (d, J=2.1 Hz, 1H), 7.21 (d, J=2.1 Hz, 1H), 4.9 (s, br, 1H), 3.06 (d, J=4.5 Hz, 3H), 1.46 (s, 6H). MS (ESI) m/e 270 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]2[C:21]([O:23][CH3:24])=[O:22])[CH2:4][CH2:3]1.[O:25]1[C:34]2[CH:33]=[C:32]([CH:35]=O)[N:31]=[CH:30][C:29]=2[O:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[O:25]1[C:34]2[CH:33]=[C:32]([CH2:35][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:18]5[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=5)[CH:12]=[C:11]4[C:21]([O:23][CH3:24])=[O:22])[CH2:6][CH2:7]3)[N:31]=[CH:30][C:29]=2[O:28][CH2:27][CH2:26]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: COC(=O)c1cc2ccc(OC)cc2n1CCN1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc2ccc(OC)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of methyl 1-[2-(4-aminopiperidin-1-yl)ethyl]-6-methoxy-1H-indole-2-carboxylate (Intermediate 12, 200 mg, 0.60 mmol) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (100 mg, 0.60 mmol) in dry chloroform/methanol (10 mL, 1:1) was heated over 3 Å molecular sieves at 70° C. for 3 hours. The reaction mixture was cooled to 0° C., sodium triacetoxy borohydride (384 mg, 1.8 mmol) was added and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through a 0.45 μm membrane and concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (150 mL) and saturated aqueous sodium hydrogen carbonate solution (30 mL), the aqueous phase back extracted once with dichloromethane (70 mL) and the combined organic phases were dried over sodium sulfate. Chromatography on silica gel with dichloromethane/methanol (5:1), containing 0.125% ammonium hydroxide, gave the free base of the title compound, 239 mg (82% yield), as a colorless solid, mp 130° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C1CCCNC1
Reaction time: 0.01 h

Procedure:
To a solution of 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (500 mg, 2.18 mmol) in CH2Cl2 (10 mL) was added TFA (5 ml). The reaction mixture was stirred for an hour. Excess TFA was removed under reduced pressure, and the piperidine-3-carboxylic acid was used without neutralization for the next step. LC/MS: m/z 1303 (M+H)+ at 0.35 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([C:3]1([OH:10])[CH2:5][CH:4]1[Si:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].C(N(CC)CC)C.[CH2:18]([S:20](Cl)(=[O:22])=[O:21])[CH3:19].C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([C:3]1([O:10][S:20]([CH2:18][CH3:19])(=[O:22])=[O:21])[CH2:5][CH:4]1[Si:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2]
Reactant: CCC1(O)CC1[Si](C)(C)C
Reactant: CCS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1(OS(=O)(=O)CC)CC1[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
2.5 g of 1-ethyl-1-hydroxy-2-(trimethylsilyl)cyclopropane prepared in Section (1) was dissolved in 15 mL of dichloromethane, and 2.3 g of triethylamine was added to the resulting solution. The reaction solution thus prepared was cooled to 0° C., 1.8 g of ethanesulfonylchloride was gradually added thereto and the mixture was vigorously stirred for 1 hour. 5 mL of a saturated NaHCO3 solution was added to the reaction solution, thereby terminating the reaction. An organic layer was separated from the reaction solution, dried over anhydrous magnesium sulfate (MgSO4), and concentrated by solvent distillation at a low temperature of less than 30° C. Although it may be used directly without any further treatment, the resulting concentrate was purified by silica gel chromatography using hexane and ethyl acetate to obtain 1.62 g of 1-ethyl-1-(ethanesulfonyloxy)-2-(trimethylsilyl)cyclopropane as a pure trans isomer. Results of 1H-NMR and 13C-NMR for the trans isomer are given below.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C([O-])(=O)C.[Na+].[H][H]>C(OCC)(=O)C.O.[Pd]>[NH2:13][C:4]1[C:5]([OH:12])=[C:6]([CH:11]=[CH:2][CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: [H][H]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(N)c1O
Yield: 58.4 %

Procedure:
A suspension of methyl 5-bromo-2-hydroxy-3-nitrobenzoate (38.4 g, 0.14 mol), sodium acetate (19.63 g, 0.24 mol) and 10% Pd/C (3.84 g) in ethyl acetate (500 mL) and water (30 mL) was stirred at 25° C. under 1 atm of hydrogen for 16 hr. The mixture was filtered and the filtrate was washed with water (500 mL×2), brine (300 mL), dried over anhydrous sodium sulfate and concentrated to give crude product. The crude product was washed with methanol at 0° C. to give methyl 3-amino-2-hydroxybenzoate (13.67 g, yield 59%) as a light yellow solid. 1H-NMR (400 MHz, CDCl3-d) δ 3.88-3.94 (s, br, 2H), 3.91 (s, 3H), 6.70-6.74 (t, J=7.8 Hz, 1H), 6.88-6.90 (m, 1H), 7.24-7.26 (m, 1H), 10.91 (s, 1H); LC-MS (ESI) m/z 168 [M+1]−.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H]>C(O)C>[Cl:1][CH2:2][CH:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: [H][H]
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Product: CCOC(=O)CC(O)CCl
Temperature: 100 °C
Yield: 96.9 %

Procedure:
In a 200 ml-volume stainless steel-made autoclave whose atmosphere had been replaced with nitrogen were charged 8.23 g (50 mmoles) of ethyl 4-chloroacetoacetate and 20 ml of ethanol. To the mixture was added 84 mg (0.05 mmole) of Ru2Cl4 ((-)-BINAP)2 (C2H5)3N, and the mixture was heated to 100° C. When the temperature reached 100° C., 100 kg/cm2 of hydrogen was introduced into the autoclave, and the mixture was stirred under heating. After cooling to room temperature, the reaction mixture was taken out, and the ethanol was removed by distillation. Distillation of the residue gave 8.07 g (97) of ethyl 4-chloro-3-hydroxybutyrate having a boiling point of 74°-75° C./l mmHg).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([OH:9])([CH3:8])[CH2:4][C:5]([OH:7])=O.[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1>>[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:5](=[O:7])[CH2:4][C:3]([OH:9])([CH3:8])[C:2]([F:1])([F:11])[F:10])[CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: CC(O)(CC(=O)O)C(F)(F)F
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: CC(O)(CC(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1)C(F)(F)F

Procedure:
Following the procedure of Example 9, making variations only as required to use 4,4,4-trifluoro-3-hydroxy-3-methylbutyric acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (50.1% yield). 1H NMR (300 MHz, CDCl3) δ 8.07, 7.96, 6.98, 6.23, 4.05-3.52, 2.90, 2.47, 1.53-1.43, 0.76, 0.46, 0.09. MS (ES+) m/z 430 (M+1).
Reaction SMILES: C(Cl)CCl.[CH3:5][C:6]1[O:7][C:8]([CH3:14])=[C:9]([C:11]([OH:13])=O)[N:10]=1.C[O:16][C:17](=[O:67])[C@@H:18]([NH:34][C:35]([C@@H:37]1[CH2:46][C:45]2[CH:44]=[C:43]3[O:47][CH2:48][C@H:49]([C:51]4[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]5[CH:64]=[CH:63][C:62]([Cl:65])=[C:61]([Cl:66])[CH:60]=5)=[CH:53][CH:52]=4)[O:50][C:42]3=[CH:41][C:40]=2[CH2:39][NH:38]1)=[O:36])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>C(Cl)Cl>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([C:23]2[CH:22]=[CH:21][C:20]([CH2:19][C@H:18]([NH:34][C:35]([C@@H:37]3[CH2:46][C:45]4[CH:44]=[C:43]5[O:47][CH2:48][C@H:49]([C:51]6[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]7[CH:64]=[CH:63][C:62]([Cl:65])=[C:61]([Cl:66])[CH:60]=7)=[CH:53][CH:52]=6)[O:50][C:42]5=[CH:41][C:40]=4[CH2:39][N:38]3[C:11]([C:9]3[N:10]=[C:6]([CH3:5])[O:7][C:8]=3[CH3:14])=[O:13])=[O:36])[C:17]([OH:67])=[O:16])=[CH:25][CH:24]=2)=[CH:27][CH:28]=1)#[N:33]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: Cc1nc(C(=O)O)c(C)o1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1nc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccc(C#N)cc3)cc2)C(=O)O)OC[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)c(C)o1
Reaction time: 0.67 h

Procedure:
EDC (3 eq.) and 2,5-dimethyl-oxazole-4-carboxylic acid (6 eq.) were dissolved in DCM and stirred 40 minutes. To this solution was added (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (20 mg) and stirred for 12 hours. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (22 mg). LCMS (m/z): 860.
Reaction SMILES: [CH:1]#[C:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C([Mg]Br)C.[I:19]I>CCOCC>[I:19][C:1]#[C:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C#CCOCCCCCCCCCC
Reactant: II
Agent: CC[Mg]Br
Solvent: CCOCC
Product: CCCCCCCCCCOCC#CI
Yield: 71 %

Procedure:
Following the procedure described in Vaughn, T. H., J. Am. Chemical Soc'y 55 3456 (1933), 4-oxatetradecyne (13 g, 66.2 mmol) was reacted with ethylmagnesium bromide (73 mmol) in dry ether. The resulting alkynyl magnesiumbromide was reacted with iodine and provided 15 g of 1-iodo-4-oxa-tetradecyne as viscous liquid (71% yield). The sample was analyzed with 1H-NMR in CDCl3, and the observed chemical shift peaks were at δ=0.88 (t, 3H, --CH3), 1.23-1.4 (br singlet, 14H, --CH2 --), 1.57 (pentate center, 2H, --CH2 --), 3.51 (t, J=7.0 Hz, 2H, --CH2 --O), and 4.28 (s, 2H, O--CH2 --C≡C). Observed IR (KBr) peak was at 2120 (--C≡C--) cm-1 ; no peak was observed at 3298 (--C≡CH) cm-1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:13])([CH3:12])[CH3:11])[CH:3]=[N:2]1.[I:14]I.[OH-].[K+]>CN(C=O)C>[I:14][C:3]1[C:4]2[C:9](=[C:8]([C:10]([OH:13])([CH3:11])[CH3:12])[CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: II
Reactant: CC(C)(O)c1cccc2cn[nH]c12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(O)c1cccc2c(I)n[nH]c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a round-bottomed flask, 2-(1H-indazol-7-yl)-propan-2-ol (204 mg, 1.16 mmol) was dissolved in DMF (3 ml) and iodine (588 mg, 2.32 mmol) and potassium hydroxide (251 mg, 4.48 mmol) were added. The dark brown suspension was stirred at room temperature for 5 h then quenched with 10% aqueous NaHSO3 and extracted with a mixture of diethyl ether and EtOAc (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to afford 2-(3-iodo-1H-indazol-7-yl)-propan-2-ol as a light yellow oil which was used without further purification.
Reaction SMILES: [O-]CC.[Na+].[SH:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:12]([Si:16]([CH3:49])([CH3:48])[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:29]2[S:33][C:32]([CH2:34]OS(C3C=CC(C)=CC=3)(=O)=O)=[C:31]([CH3:46])[CH:30]=2)([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:20][C:19]=1[CH3:47])([CH3:15])([CH3:14])[CH3:13]>CCO>[CH2:10]([O:9][C:7](=[O:8])[CH2:6][S:5][CH2:34][C:32]1[S:33][C:29]([C:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][Si:16]([C:12]([CH3:13])([CH3:15])[CH3:14])([CH3:49])[CH3:48])=[C:19]([CH3:47])[CH:20]=2)([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:30][C:31]=1[CH3:46])[CH3:11]
Reactant: CCC(CC)(c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1)c1cc(C)c(COS(=O)(=O)c2ccc(C)cc2)s1
Reactant: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSCc1sc(C(CC)(CC)c2ccc(O[Si](C)(C)C(C)(C)C)c(C)c2)cc1C
Temperature: 25 °C
Yield: 26.8 %

Procedure:
To a solution of 2.68 M sodium ethoxide (507 μl, 1.36 mmol) in EtOH (2 ml) is added ethyl 2-mercaptoacetate (149 μl, 1.36 mmol) and stirred at RT for 30 m. The mixture is added a solution of toluene-4-sulfonic acid 5-{1-[4-(tert-butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophen-2-ylmethyl ester (740 mg, 1.29 mmol) in EtOH (2 ml) is added and refluxed for 15 m. The reaction is concentrated and partitioned between EtOAc (100 ml) and 0.2N HCl (50 ml). The organic layer is washed with water (50 ml), dried (MgSO4), concentrated, and chromatographed (12 g SiO2, 5% EtOAc/Hex) to yield the title compound (180 mg, 27%). 1NMR (400 MHz, CDCl3) δ 7.00 (d, 1H, J=2.2 Hz), 6.92 (dd, 1H, J=8.4, 2.2 Hz), 6.64 (d, 1H, J=8.4 Hz), 6.46 (s, 1H), 4.17 (q, 2H, J=7.2 Hz), 3.92 (s, 2H), 3.14 (s, 2H), 2.16 (s, 3H), 2.12 (s, 3H), 2.07-1.98 (m, 4H), 1.28 (t, 3H, J=7.0 Hz), 1.00 (s, 9H), 0.68 (t, 6H, J=7.3 Hz), 0.20 (s, 6H).