Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=N1.[Na].[NH:7]1[CH:11]=[N:10][C:9]([SH:12])=[N:8]1.Br[CH2:14][CH2:15][O:16][CH2:17][CH3:18]>C(O)C>[CH2:15]([O:16][CH2:17][CH2:18][S:12][C:9]1[N:10]=[CH:11][NH:7][N:8]=1)[CH3:14]
Reactant: CCOCCBr
Reactant: Sc1nc[nH]n1
Agent: [Na]
Agent: c1c[nH]nn1
Solvent: CCO
Product: CCOCCSc1nc[nH]n1

Procedure:
The novel intermediate triazole compounds used in the above preparation were prepared as follows. To a solution of 11.8 g. sodium in 350 ml. absolute ethanol was added 52.5 g. 1,2,4-triazole-3-thiol. To the resulting solution was added 84 g. 1-bromo-2-ethoxyethane and the resulting solution refluxed for 3 hours. The cooled reaction mixture was filtered, the filtrate was evaporated under reduced pressure to remove solvent, and the residue was dissolved in ether. The resulting solution was filtered, the filtrate was evaporated to remove solvent and the residue distilled under reduced pressure to give 3-(2-ethoxyethylthio)-1,2,4-triazole, b.p. 337°-345° C./0.3-0.5 mm. Elemental analysis satisfactory.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+].[CH2:22](O)[CH3:23]>>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]([CH3:18])[C:15]([O:17][CH2:22][CH3:23])=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: CC(C(=O)O)c1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)C(C)c1cccc(Oc2ccccc2)c1
Temperature: 0 °C

Procedure:
Two hundred grams of 2-(3-phenoxyphenyl)propionic acid, prepared according to Example 2, were dissolved in 1500 ml. of ethanol, and hydrogen chloride gas was passed into the ethanolic solution until it was saturated. The reaction mixture was then refluxed with stirring overnight after which a large portion of the ethanol was evaporated in vacuo, and the remaining reaction mixture was poured into ice water. The reaction mixture was basified with 10 percent sodium hydroxide, and extracted twice with ethyl ether. The combined ether extracts were washed twice with water and dried over sodium sulfate. The ethyl ether was evaporated, leaving crude ethyl 2-(3-phenoxyphenyl)propionate as an oily residue. The preparation was repeated with an additional 200 g. of 2-(3-phenoxyphenyl)propionic acid. The crude residues were combined and distilled through a 15 cm. Vigreux column to yield 339.9 g. of ethyl 2-(3-phenoxyphenyl)propionate, b.p., 128°-134° C./0.15 mm., nD25 = 1.5458.
Reaction SMILES: [O:1]=[S:2]1(=[O:46])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][CH2:16][C:17](=[O:33])[NH:18][C@@H:19]([C:26]([O:28]C(C)(C)C)=[O:27])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:5][C:4]([CH2:42][CH2:43][CH2:44][CH3:45])([CH2:40][CH3:41])[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:46]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][CH2:16][C:17](=[O:33])[NH:18][C@@H:19]([C:26]([OH:28])=[O:27])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:5][C:4]([CH2:42][CH2:43][CH2:44][CH3:45])([CH2:40][CH3:41])[CH2:3]1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OCCC(=O)N[C@@H](C(=O)OC(C)(C)C)c3ccccc3)cc2S(=O)(=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OCCC(=O)N[C@@H](C(=O)O)c3ccccc3)cc2S(=O)(=O)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84.5 %

Procedure:
To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-(2-{N-[(R)-α-(t-butoxycarbonyl)benzyl]carbamoyl}ethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 90; 77 mg, 0.108 mmol) in DCM (3 ml) was added at 0° C. TFA (0.75 ml). The reaction mixture was stirred at room temperature for 2 h and 45 min. The solvent was evaporated under reduced pressure and the crude product was purified by preparative HPLC using MeCN and ammonium acetate buffer (40:60 to 50:50) as eluent to give the title compound 60 mg (82%). NMR (500 MHz, CD3OD) 0.75–0.85 (m, 6H), 1.0–1.25 (m, 4H), 1.40–1.64 (m, 4H), 2.75–2.90 (m, 2H), 3.26 (s, 2H), 3.50–3.90 (m, 2H), 4.30–4.41 (m, 2H), 5.43 (s, 1H), 6.99 (t, 1H), 7.05–7.13 (m, 3H), 7.23–7.34 (m, 5H), 7.45 (d, 2H), 7.52 (s, 1H); m/z 658.
Reaction SMILES: [H-].[K+].N#N.[CH2:5]([N:12]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:26]I.[NH4+].[Cl-]>C1COCC1>[CH2:19]([N:12]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:13][CH2:14][C:15]([O:17][CH3:26])([CH3:18])[CH3:16])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CI
Reactant: CC(C)(O)CCN(Cc1ccccc1)Cc1ccccc1
Agent: N#N
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COC(C)(C)CCN(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
Add potassium hydride (30%, 2.6 g, 19.4 mmol) portion wise under N2 to a 0° C. solution of 4-(dibenzylamino)-2-methylbutan-2-ol (5 g, 17.6 mmol) in THF (50 mL). Stir the mixture at 0° C. for 0.5 h, treat drop-wise with methyl iodide [MeI] (2.76 g, 19.4 mmol), allow the mixture to warm to RT and stir for 3 h. Re-cool the mixture to 0° C., treat with saturated NH4Cl, and remove the organics under reduced pressure. Extract the residue with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate and purify via silica gel chromatography (Pet ether/EtOAc, 50:1) to afford the title compound (3.0 g, 57%). 1H NMR (400 MHz, DMSO-d6): δ 7.29 (m, 10H), 3.58 (s, 4H), 3.05 (s, 3H), 2.50 (m, 2H), 1.73 (m, 2H), 1.07 (s, 6H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16]CC)(=[O:15])[CH3:14].[CH3:19][C@H:20]([C@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])[C:21](Cl)=[O:22]>C1COCC1>[CH3:19][C@H:20]([C@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])[C:21](=[O:22])[CH2:14][C:13]([OH:16])=[O:15]
Reactant: CCC[C@@H](C)[C@@H](C)C(=O)Cl
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC[C@@H](C)[C@@H](C)C(=O)CC(=O)O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 89.2 %

Procedure:
To a solution containing 2.0 g (13.9 mmol) of (2R,3R)-2,3-dimethyl-hexanoic acid in 20 mL of dichloromethane was added 2.1 g (16.6 mmol) of chloromethylene dimethyl-ammonium chloride. After stirring the resulting solution under nitrogen for 1.5 hours, the solvent was evaporated to give (2R,3R)-2,3-dimethyl-hexanoyl chloride. Butyl lithium (32.7 ml, 52.4 mmol) was added to a solution of diisopropylamine (4.9 g, 48.5 mmol) in dry THF (20 mL) under nitrogen at 0° C. and stirred for 20 minutes. The solution was cooled to −78° C. and 4.3 g (48.5 mmol) of ethyl acetate was added. The solution was stirred at that temperature for 45 minutes. (2R,3R)-2,3-Dimethyl-hexanoyl chloride in dry THF (20 mL) was slowly added to the ethyl acetate enolate at −78° C. and the resulting reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 2.5 hours and was cooled to 0° C. The reaction was quenched with a saturated solution of ammonium chloride and extracted into ethyl acetate. The solution was washed with brine, dried over MgSO4 and concentrated. The resulting residue was filtered through a silica plug, eluting with 60/40 solution of hexane/ethyl acetate to afford 2.7 g (89.2% yield) of the titled compound as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=O)[CH2:11][CH2:10][C@H:9]1[C:14]([NH2:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>O1CCCC1>[CH2:1]([NH:8][CH2:12][CH:11]1[CH2:10][CH2:9][CH2:14][NH:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)[C@@H]1CCC(=O)N1Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc(CNCC2CCCN2)cc1
Yield: 122.7 %

Procedure:
Benzyl-(-)-pyroglutamide (60 g.) was suspended in one liter of tetrahydrofuran (THF) and stirred under nitrogen. The mixture was cooled to below 10° C. in an ice bath and one liter of 1 M BH3THF complex was slowly added. The mixture was stirred for 20 hours at room temperature and then refluxed for 28 hours. The reaction mixture was then cooled and 200 milliliters of methanol was added dropwise. The solvent was then removed and the residue dissolved in 2 N HCl and warmed in a steam bath for one hour. The solution was then cooled and filtered through Cellite®, basified with 50 percent NaOH, extracted with diethyl ether and the extract was washed with brine. The solution was dried and the solvent was removed to afford 2-benzylaminomethylpyrrolidine (64.2 g.) as a viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([N:18]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:19](=[O:21])[CH3:20])[CH2:10][CH:9]2[CH3:29])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:40][CH2:41][N:42]=[C:43]=[O:44]>C(Cl)Cl>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([N:18]([C@H:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([N:1]4[CH2:40][CH2:41][NH:42][C:43]4=[O:44])=[CH:31][CH:30]=3)[C@@H:9]([CH3:29])[CH2:10]2)[C:19](=[O:21])[CH3:20])=[CH:27][CH:26]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)C1CC(C)N(C(=O)c2ccc(N)cc2)c2ccccc21
Reactant: O=C=NCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N3CCNC3=O)cc2)c2ccccc21
Temperature: 25 °C

Procedure:
N-[1-(4-Amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-(4-chloro-phenyl)-acetamide (156 mg, 0.373 mmol) was dissolved in methylene chloride (3 mL) and was added triethylamine (0.078 mL, 0.559 mmol) and 1-chloro-2-isocyanato-ethane 0.038 mL, 0.448 mmol). The reaction was stirred at room temperature over night, and the reaction was quenched with sat. aq. NaHCO3. The residue was partitioned between methylene chloride and water, then extracted three times with methylene chloride, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (ethyl acetate) to afford the product.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cu])=[CH:7][CH:6]=1.Br[CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH3:1][C:2]([CH3:12])=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(C)Br
Reactant: CC(C)=CCc1ccc([Cu])cc1
Product: CCOC(=O)C(C)c1ccc(CC=C(C)C)cc1
Yield: 6.7 %

Procedure:
In the same way as in Comparative Example 7, p-(3-methyl-2-butenyl)phenyl copper (I) was reacted with ethyl α-bromopropionate. Ethyl α-[p-(3-methyl-2-butenyl)phenyl]propionate was obtained in an amount of 1.64 g (yield 6.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([CH:18]=1)[CH2:7][C:8]1[C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=[CH:10][C:9]=1[OH:17].[OH:20]S(O)(=O)=O.O=S(=O)=O.C(=O)(O)[O-].[Na+]>>[Cl:1][C:2]1[C:18]2[C:14](=[O:16])[C:13]3[CH:12]=[N:11][CH:10]=[C:9]([OH:17])[C:8]=3[C:7](=[O:20])[C:6]=2[C:5]([F:19])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cncc(O)c1Cc1cc(Cl)ccc1F
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: O=S(=O)=O
Agent: [Na+]
Product: O=C1c2c(O)cncc2C(=O)c2c(Cl)ccc(F)c21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 4-(5'-chloro-2'-fluorobenzyl) -5-hydroxynicotinic acid of Preparative Example 27 (0.15 g) and 20% oleum (2 mL) is stirred for 45 minutes at 125°-130° C. (external bath temperature). The reaction mixture is then allowed to cool at room temperature and poured over 20 g of crushed ice and the resultant mixture neutralized with solid sodium bicarbonate to pH=7. The dione is extracted with dichloromethane (4×20 mL) and the combined organic phases are dried over MgSO4 and concentrated to dryness. The product is obtained as a yellow-tan solid (0.12 g) which darkens on standing in air.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[C:19]2[C:12]([NH:13][CH:14]=[C:15]2[CH2:16][CH2:17][NH2:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[BH4-].[Na+].C(O)(=O)C(O)=O>CO.O>[CH2:1]([O:8][C:9]1[CH:20]=[C:19]2[C:12](=[CH:11][CH:10]=1)[NH:13][CH:14]=[C:15]2[CH2:16][CH2:17][NH:18][CH2:31][C:30]1[CH:33]=[CH:34][CH:35]=[C:28]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: c1ccc(COc2ccc3[nH]cc(CCNCc4cccc(Oc5ccccc5)c4)c3c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 5-benzyloxy tryptamine (1.23 g, 4.6 mmol), 3-phenoxybenzaldehyde (97%, 1.09 g, 5.53 mmol) and molecular sieves 4 A (1.0 g) and stir in methanol (15 mL) for 4 h. Filter the molecular sieves and wash several times with MeOH. To this MeOH solution, add portionwise NaBH4 (174 mg, 4.60 mmol), stir the resulting mixture at room temperature for 1 h. Remove MeOH under vacuum, dilute the residue with CH2CL2/water, extract with CH2Cl2, combine organic layers, dry over Na2SO4 and concentrate the solvent in vacuo. Purification by silica gel chromatography(CH2Cl2/MeOH) to give the free base. Combine the free base with oxalic acid to form the salt: (300 MHz, DMSO-d6) 2.95–3.15 (m, 4H), 3.93 (s, 2H), 4.10 (br, 1H), 5.05 (s, 2H), 6.85–7.46 (m, 18H), 10.67 (br, 1H); ms (ELECTROSPRAY) m/e: 449.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[CH:4]=[N:5][C:6]([CH3:9])([CH3:8])[CH3:7].[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[CH2:4][NH:5][C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)N=Cc1ccc(F)cc1F
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)NCc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83 %

Procedure:
A solution of the obtained N-(2,4-difluorobenzylidene)-t-butylamine in methanol (5 ml) was cooled to 0° C. in ice-water bath. To the solution was added NaBH4 (138.3 mg, 3.65 mmol). The mixture was gradually warmed to room temperature and stirred for 2.5 hours. The mixture was added to sat. NaHCO3 aqueous solution, extracted three times with ethyl acetate and dried over MgSO4. The mixture was concentrated and purified by silica gel chromatography (hexane/ethyl acetate/triethylamine=100/5/1) to give the title compound (504.2 mg; 83%, 2 steps).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH:18]([CH2:20][C:21](Cl)=[O:22])=[CH2:19]>C(Cl)Cl>[CH:18]([CH2:20][C:21]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:22])=[CH2:19]
Reactant: C=CCC(=O)Cl
Reactant: NCCc1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC(=O)NCCc1ccc(O)cc1
Reaction time: 8 h
Yield: 80 %

Procedure:
A 1000-mL 3-neck, round bottom flask connected with a reflux condenser and a drying tube, is charged with 250 mL of methylene chloride, 5.48 grams (0.04 mole) 4-aminoethylphenol and 4.04 grams (0.04 mole) triethylamine. The contents are chilled with an ice bath. Through a dropping funnel, 4.18 g (0.04 mole) of vinylacetyl chloride is added into the flask over a period of 30 minutes. The ice bath is then removed and the contents are continuously stirred overnight. The mixture is then filtered and then condensed using a rotavapor. High performance liquid chromatography (HPLC) analysis indicates only one major product. The product is then passed through silica gel chromatography to give a final purified product with a yield of at least 80 percent. The product is identified by NMR and Mass Spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH:19]=O)(=[O:11])=[O:10].[NH2:25][NH:26][C:27]([NH2:29])=[S:28]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH:19]=[N:25][NH:26][C:27]([NH2:29])=[S:28])(=[O:11])=[O:10]
Reactant: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCC=O)c1
Reactant: NNC(N)=S
Solvent: CCO
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCC=NNC(N)=S)c1
Temperature: 25 °C

Procedure:
A mixture of 3-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy-]-propionaldehyde (472.5 mg, 1.35 mmol, as prepared in step d of example 8), thiosemicarbazide (124.5 mg, 1.37 mmol) and ethanol (4.5 mL) was refluxed for 2 hours. The solution was cooled to room temperature and approximately 3 mL ethanol was removed by rotary evaporation. The residual oil in ethanol was heated to 50° C. and the product crystallized. The title compound was isolated by filtration as a white solid (493 mg, 86%). 1H-NMR (300 MHz, DMSO-d6) δ 7.76 (ddd, 1H, J=1.8, 7.4, 8.4 Hz), 7.69 (dd, 1H, J=1.7, 7.9 Hz), 7.43 (t, 1H, J=4.8 Hz), 7.36 (d, 1H, J=8.4 Hz), 7.09 (ddd, 1H, J=0.9, 7.4, 7.8 Hz), 6.72 (br s, 1H), 6.48 (br s, 1H), 6.37 (t, 1H, J=2.3 Hz), 4.08 (t, 2H, J=6.5 Hz), 3.99 (s, 3H), 2.58 (q, 2H, J=6.4 Hz), 2.21 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C18H21N3O5S2 : 424.1 (M+H), 446.1 (M+Na). Found: 423.9, 445.9.
Reaction SMILES: [C:1]([NH:8][C:9]1([CH2:12][OH:13])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:22]>C(N(CC)CC)C>[S:15]([OH:17])(=[O:22])(=[O:16])[CH3:14].[C:1]([NH:8][C:9]1([CH2:12][OH:13])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CS(=O)(=O)Cl
Agent: CC(C)(C)OC(=O)NC1(CO)CC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Boc-1-amino-1-hydroxymethylcyclopropane is dissolved in triethylamine under argon at 0° C. Methanesulfonyl chloride is added with a syringe and the contents stirred at room temperature overnight. The solution is poured into 10% aqueous citric acid and extracted with ethyl acetate. The organic layer is dried over MgSO4 filtered and evaporated to give N-Boc-1-amino-1-hydroxymethylcyclopropane mesylate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH:16]([OH:27])[C:17]3[N:21]([CH3:22])[C:20]4[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=4[N:18]=3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[C:3]=1[C:32]#[N:33].CN(C=O)C.[SH:39][CH2:40][C:41]([NH2:43])=[O:42].C[O-].[Na+]>CO>[NH2:33][C:32]1[C:3]2[C:2](=[N:7][C:6]([N:8]3[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH:16]([OH:27])[C:17]4[N:21]([CH3:22])[C:20]5[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=5[N:18]=4)[CH2:10][CH2:9]3)=[CH:5][C:4]=2[C:28]([F:31])([F:30])[F:29])[S:39][C:40]=1[C:41]([NH2:43])=[O:42]
Reactant: NC(=O)CS
Reactant: Cn1c(C(O)CNC2CCN(c3cc(C(F)(F)F)c(C#N)c(Cl)n3)CC2)nc2ccccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1c(C(O)CNC2CCN(c3cc(C(F)(F)F)c4c(N)c(C(N)=O)sc4n3)CC2)nc2ccccc21
Temperature: 60 °C

Procedure:
6′-Chloro-4-[2-hydroxy-2-(1-methyl-1H-benzoimidazol-2-yl)-ethylamino]-4′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile (344.0 mg, 0.718) mmol was dissolved into 2 mL of dry DMF. To this was added a 1.09 M MeOHic solution of mercaptoacetamide (1.00 mL, 1.09 mmol) and a 1 M solution of MeOHic NaOMe (2.87 mL, 2.87 mmol). The reaction mixture was heated at 60° C. for 2 h. LC-MS indicated complete conversion to the mercaptoacetamide adduct. The reaction was then heated at 80° C. overnight. The reaction mixture was concentrated on a rotary evaporator with heating to 70° C. to give a dark orange oil. The oil was dissolved into a minimal amount of MeOH, applied to a SIO2 column and eluted with 0–10% MeOH/CH2Cl2 and 0–10% MeOH/CH2Cl2-1% NH3) to give 213.7 mg, 55.8%, of the title compound. ES+ 534.3 m/z (MH+)
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[CH3:25][N:26]1[C:34]2[CH2:33][C:32]([CH3:36])([CH3:35])[CH2:31][CH2:30][C:29]=2[C:28]([Sn](CCCC)(CCCC)CCCC)=[N:27]1>CN(C=O)C.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.[Cu]I>[CH:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:28]3[C:29]4[CH2:30][CH2:31][C:32]([CH3:35])([CH3:36])[CH2:33][C:34]=4[N:26]([CH3:25])[N:27]=3)[N:3]=2)[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=1)=[O:12])([CH3:16])[CH3:15]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2c1CCC(C)(C)C2
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4c3CCC(C)(C)C4)nc12
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 69.9 %

Procedure:
2-Bromo-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (107 mg, 259 μmol) and 1,6,6-trimethyl-3-(tributylstannyl)-4,5,6,7-tetrahydro-1H-indazole (see Example 70, 188 mg, 414 μmol.6) were dissolved in DMF (2.5 mL) under argon, tetrakis(triphenylphosphine)palladium (0) (15.0 mg, 12.9 μmol) and CuI (4.64 mg, 51.8 μmol, Eq: 0.20) were added and the mixture sonicated for 5 min with bubbling argon. The reaction mixture was stirred at 90° C. (oil bath temperature) for 2.5 h. The reaction mixture was concentrated under high vacuum and the residue was purified by chromatography (silica, 40 g column, 50 μm from Analogix, 0-50% EtOAc in hexanes over 15 min) to give N-isopropyl-2-(1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (90 mg, 181 μmol, 70.0%) as a light yellow solid and of approximately 75% purity. MS (M+H)+=497.1; 1H NMR (CDCl3) δ: 9.10 (s, 1H), 8.26 (s, 1H), 8.18 (d, J=7.9 Hz, 1H), 5.68 (s, 2H), 4.34-4.60 (m, 1H), 3.82 (s, 3H), 3.48-3.61 (m, 2H), 3.03 (t, J=6.2 Hz, 2H), 2.41 (s, 2H), 1.61 (t, J=6.4 Hz, 2H), 1.33 (d, J=6.8 Hz, 6H), 1.09 (s, 6H), 0.83-0.97 (m, 2H), −0.06 (s, 9H). NMR and LCMS showed an impurity that was identified as the dimer of the tetrahydroindazole (MW 326.49) linked at the 3-position.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][O:23][CH3:24]>CC(C)=O>[Cl:1][C:2]1[C:3]([O:13][CH2:21][CH2:22][O:23][CH3:24])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2
Reactant: Cc1ccc2ccc(O)c(Cl)c2n1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1ccc2ccc(C)nc2c1Cl

Procedure:
8-chloro-2-methylquinolin-7-ol (80 mg, 0.41 mmol), potassium carbonate (171 mg, 1.2 mmol) and 1-bromo-2-methoxyethane (115 mg, 0.83 mmol) in acetone (10 mL) were stirred at 70° C. in a sealed tube for 20 hours. After dilution with water (50 mL) the reaction was extracted with DCM. The DCM phases were concentrated under reduced pressure and the residue purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 8-chloro-7-(2-methoxyethoxy)-2-methylquinoline as a solid.
Reaction SMILES: [OH-].[Na+:2].[Cl:3][C:4]1[C:13]2[C:8](=[C:9]([CH2:24][CH:25]=[CH2:26])[C:10]3[O:17][C:16]([C:18]([O:20]CC)=[O:19])=[CH:15][C:14](=[O:23])[C:11]=3[CH:12]=2)[N:7]=[C:6]([C:27]([O:29]C)=[O:28])[CH:5]=1>CO>[Cl:3][C:4]1[C:13]2[C:8](=[C:9]([CH2:24][CH:25]=[CH2:26])[C:10]3[O:17][C:16]([C:18]([O-:20])=[O:19])=[CH:15][C:14](=[O:23])[C:11]=3[CH:12]=2)[N:7]=[C:6]([C:27]([O-:29])=[O:28])[CH:5]=1.[Na+:2].[Na+:2]
Reactant: C=CCc1c2nc(C(=O)OC)cc(Cl)c2cc2c(=O)cc(C(=O)OCC)oc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCc1c2nc(C(=O)[O-])cc(Cl)c2cc2c(=O)cc(C(=O)[O-])oc12

Procedure:
0.1 m sodium hydroxide solution (24.9 ml) was added dropwise to the product of step (d) (0.5 grams) in refluxing pure methanol (100 ml), with stirring. The whole was refluxed for a further 10 minutes after addition, the methanol was removed under reduced pressure and the title compound obtained by precipitation by the addition of acetone. The product was collected by filtration and dried in vacuo at 60° C. to give 0.37 grams of dark yellow solid.