Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[N:15]=[CH:14][C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH:19]=O)[C:11]=2[N:21]=1.[NH2:22][C@@H:23]1[CH2:27][N:26]([C:28]2[CH:29]=[CH:30][C:31]3[O:32][CH2:33][C:34](=[O:38])[NH:35][C:36]=3[N:37]=2)[C:25](=[O:39])[CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[N:15]=[CH:14][C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH2:19][NH:22][C@@H:23]3[CH2:27][N:26]([C:28]4[CH:29]=[CH:30][C:31]5[O:32][CH2:33][C:34](=[O:38])[NH:35][C:36]=5[N:37]=4)[C:25](=[O:39])[CH2:24]3)[C:11]=2[N:21]=1
Reactant: N[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Reactant: COc1ccc2ncc(=O)n(CCC=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCCN[C@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2n1
Reaction time: 0.17 h
Yield: 11.4 %

Procedure:
Acetic acid (0.06 g, 1 mmol) was added dropwise to a mixture of 3-(6-methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)propanal (synthesized with reference to WO2008/9700; 0.2 g, 0.85 mmol), 6-[(4S)-4-amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Reference Example 22; 0.25 g, 1.0 mmol) and N,N-dimethylformamide (4 ml). Sodium triacetoxyborohydride (0.23 g, 1.1 mmol) was gradually added under cooling on ice to the obtained mixture, which was then stirred for 10 minutes. The mixture was further stirred at room temperature for 2 hours, cooled on ice, a saturated sodium hydrogen carbonate aqueous solution was added thereto, and the resultant was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane/methanol) to yield 45 mg (11%) of the title compound.
Reaction SMILES: [CH3:1][C@@:2]12[C:17]([CH3:19])([CH3:18])[C@@H:5]([C:6]3[C:7](=[O:16])[N:8]([CH2:11][C:12]([F:15])([F:14])[F:13])[NH:9][C:10]=31)[CH2:4][CH2:3]2.Br[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:1][C@@:2]12[C:17]([CH3:19])([CH3:18])[C@@H:5]([C:6]3[C:7](=[O:16])[N:8]([CH2:11][C:12]([F:13])([F:14])[F:15])[N:9]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:10]=31)[CH2:4][CH2:3]2
Reactant: BrCCc1ccccc1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(CC(F)(F)F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(CC(F)(F)F)n1CCc1ccccc1
Temperature: 100 °C
Yield: 11.5 %

Procedure:
A mixture of (4S,7R)-7,8,8-trimethyl-2-(2,2,2-trifluoro-ethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 47; 150 mg, 0.55 mmol), tetrabutylammonium iodide (220 mg, 0.60 mmol) and (2-bromoethyl)benzene (660 μL, 4.8 mmol) in dimethylformamide (2 mL) was heated in a pressure tube in an oil-bath at 100° C. for 24 h. Dichloromethane (75 mL) was added and the solution was washed with water (5×25 mL) and aqueous sodium thiosulfate (25 mL), dried (magnesium sulfate), filtered, evaporated and purified using an ISCO 40 g column, eluting with 20-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, co-evaporated with methanol, and dried under high vacuum at 90° C. for 3 h to give (4S,7R)-7,8,8-trimethyl-1-phenethyl-2-(2,2,2-trifluoro-ethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (24 mg, 12%) as a yellow gum. ES(+)-MS (M+H) 379.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]([C@H:17]([CH3:34])[C@:18]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])([OH:25])[CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH2:11]3)=[CH:4][CH:3]=1.[CH:37](N(C(C)C)CC)(C)[CH3:38].BrCC>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]([CH2:37][CH3:38])[C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]([C@H:17]([CH3:34])[C@:18]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])([OH:25])[CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH2:11]3)=[CH:4][CH:3]=1
Reactant: C[C@@H](N1Cc2cc(NCc3ccc(Cl)cc3)ccc2N1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCBr
Solvent: CCOC(C)=O
Product: CCN(Cc1ccc(Cl)cc1)c1ccc2c(c1)CN([C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F)N2
Reaction time: 0.5 h

Procedure:
To a solution of (2R,3R)-3-(5-(4-chlorobenzylamino)-1H-indazol-2-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (0.043 g, 0.08 mmol), prepared in Example 244, in N,N′-dimethylformamide (0.5 ml) was added diisopropylethylamine (0.015 ml, 0.08 mmol), followed by stirring for 30 min. The reaction solution was further stirred at 80° C. for 18 hours after the addition of bromoethane (0.019 ml, 0.17 mmol) thereto. The reaction product was diluted with ethyl acetate (10 ml) and washed with saturated ammonium chloride solution (10 ml), and then with brine (10 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated using vacuum evaporation. The crude product was purified by chromatography on silica gel to give the title compound.
Reaction SMILES: O=[C:2]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])(=O)C.[NH4+:17]>C(O)C>[NH2:17][C:2]([CH2:9][CH2:10][CH2:11][CH3:12])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCCCC(=O)CC(=O)OCC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCCCC(N)=CC(=O)OCC
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
Ethyl 3-oxoheptanoate (8.28 g, 48.13 mmol) and ammonium acetate (18.55 g, 240 mmol) were stirred in ethanol (80 ml) at room temperature for 96 hours. The solvent was evaporated and the residue stirred in dichloromethane (100 ml) for 30 minutes. The solid formed was filtered and the filtrate was washed with water (50 ml), saturated brine (50 ml) and dried over MgSO4 filtered and evaporated to give ethyl 3-aminohept-2-enoate (7.8 g, 94%) as a pale yellow oil.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccn3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccccn3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 31.2 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-pyridin-2-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (25 mg, 0.065 mmol), β-alanine (863 mg, 9.69 mmol) and NaOMe solution (15.5 mL, 7.75 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in water and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 1 M HCl, and the resulting precipitate was isolated by filtration to give 9 mg of the title compound. MS: (+) m/z 445.33 (M+1).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:34])[C:16]([NH:18][C:19]2[N:23](C(OC(C)(C)C)=O)[N:22]=[C:21]([CH:31]3[CH2:33][CH2:32]3)[CH:20]=2)=[O:17])=[CH:11][CH:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([CH3:34])[C:16]([NH:18][C:19]2[CH:20]=[C:21]([CH:31]3[CH2:33][CH2:32]3)[NH:22][N:23]=2)=[O:17])=[CH:13][CH:14]=1
Reactant: CC(C(=O)Nc1cc(C2CC2)nn1C(=O)OC(C)(C)C)c1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)Nc1cc(C2CC2)[nH]n1)c1ccc(N)cc1
Yield: 68.8 %

Procedure:
11.8 g (25.26 mmol) of tert-butyl 5-[(2-{4-[(tert-butoxycarbonyl)amino]phenyl}propanoyl)amino]-3-cyclopropyl-1H-pyrazole-1-carboxylate were dissolved in 200 ml of dichloromethane and 30 ml of trifluoroacetic acid were added. After 2.5 hours at room temperature the solvent was evaporated and the residue taken up with dichloromethane and washed with a saturated solution of sodium hydrogenocarbonate. The organic layer was then dried over sodium sulphate and evaporated to dryness, affording 4.7 g (70% yield) of the title compound.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:26][O-:27].[Na+]>C1(C)C=CC=CC=1>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([O:27][CH3:26])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: C[O-]
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 110 °C
Reaction time: 5.5 h

Procedure:
A heterogeneous mixture of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline (13.0 g, 30.0 mmol, Intermediate 4: step c), sodium methoxide (9.73 g, 180 mmol), and toluene (120 mL) was heated at 110° C. After 5.5 hours, the mixture was cooled to room temperature then filtered through Celite® rinsing with dichloromethane. The filtrate was concentrated to provide a crude yellow solid. The crude solid was purified by flash column chromatography (silica gel, 50% dichloromethane-hexanes initially, grading to 100% dichloromethane) to provide the title compound as a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[OH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+]>[Cu].CCOC(C)=O>[O:10]=[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: Oc1ccccn1
Reactant: COc1ccccc1I
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccccc1-n1ccccc1=O
Temperature: 200 °C

Procedure:
2-Iodoanisole (1.30 mL, 0.01 mol), 2-hydroxypyridine (0.95 g, 0.01 mol), anhydrous K2CO3 (2.76 g, 0.02 mol) and copper powder (0.0636 g, 0.001 mol) were combined and heated at 200° C. for 2 hr. The reaction mixture was cooled, EtOAc added, and filtered. The filtrate was washed with H2O, aqueous saturated NaHCO3 solution, brine, and dried (Na2SO4). Filtration and concentration gave the title compound after chromatography (silica gel, 2% CH3OH, CH2Cl2).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].[C-:11]#[N:12].[K+]>C(O)C.O>[O:8]=[C:7]([C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:1][C:3]1[CH:10]=[CH:9][C:6]([C:11]#[N:12])=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: N#Cc1ccc(C=O)cc1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(CC(=O)c2ccc(C#N)cc2)cc1

Procedure:
To a solution of 25 g of p-cyanobenzaldehyde in 50 ml of ethanol was added 5 g of potassium cyanide in 10 ml of water. The mixture was heated at reflux for 1 hr, cooled, and the crystalline product was filtered and washed with cold ethanol. Recrystallization from acetic acid afforded 4.7 g of the part (a) title compound, mp. 209°-215° C.
Reaction SMILES: C([O:4][C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=O)C.O1CCCC1.BrNC(=O)C>O>[C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:6]1[C:5](=[O:4])[CH2:9][CH2:8][CH:7]=1)([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CCCCCCC1=C(OC(C)=O)CCC1
Agent: CC(=O)NBr
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCCCCCC1=CCCC1=O
Temperature: 90 °C
Reaction time: 1 h

Procedure:
This preparation illustrates methods of preparing 2-(carboalkoxy-alkyl)-1-oxo-cyclopent-2-ene. In this example 20.1 g. of crude 1-acetoxy-2-(6-carbomethoxy-hexyl)-cyclopent-1-ene, prepared according to Preparation 4, is dissolved in 180 ml. of tetrahydrofuran and 20 ml. of water and then cooled to 0° C. under nitrogen. Eleven grams of N-bromoacetamide is added. The resulting reaction solution is monitored by thin-layer chromatography and allowed to stand until complete reaction is indicated. The reaction mixture is then poured into water and extracted with methylene chloride. 150 Milliliters of pyridine and 3 g. of lithium carbonate are added to the methylene chloride extract and the resulting mixture then concentrated by evaporation under reduced pressure to remove most of the methylene chloride. The concentrate is stirred at 90° C. under nitrogen, for 1 hour and then examined by thin-layer chromatography to ensure complete reaction. The reaction solution is then cooled to room temperature and poured into water and extracted with methylene chloride. The methylene chloride extract is washed with water, washed with saturated aqueous sodium chloride, then dried over sodium sulfate, and evaported to dryness affording a crude residue of 2-(6-carbomethoxy-hexyl)-1-oxo-cyclopent-2-ene, which is further purified by high vacuum distillation. This product is then dissolved in 350 ml. of methanol, and a solution containing 4.6 g. of semicarbazone hydrochloride and 5 g. of pyridine in 40 ml. of water is then added. The resulting mixture is stirred at room temperature for two hours and then poured into water. The water mixture is filtered, and the collected precipitate is washed with hexane. The filtrate and washings are combined and extracted four times with hexane. The extracts are combined and washed with water, washed with saturated aqueous sodium chloride solution, and then dried over sodium sulfate and evaporated to dryness affording pure 2-(6-carbomethoxy-hexyl)-1-oxo-cyclopent2-ene.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19]3[C:14](=[C:15]([O:20][CH:21]([F:23])[F:22])[CH:16]=[CH:17][CH:18]=3)[C:13](=[O:24])[C:12]([C:25]([O:27]CC)=[O:26])=[N:11]2)=[CH:6][CH:5]=1.[OH-].[Na+].C(O)C>O>[F:31][C:2]([F:1])([F:30])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:19]3[C:14](=[C:15]([O:20][CH:21]([F:23])[F:22])[CH:16]=[CH:17][CH:18]=3)[C:13](=[O:24])[C:12]([C:25]([OH:27])=[O:26])=[N:11]2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)c2cccc(OC(F)F)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1nn(-c2ccc(OC(F)(F)F)cc2)c2cccc(OC(F)F)c2c1=O
Temperature: 25 °C
Yield: 64 %

Procedure:
Ethyl 1-(4-trifluoromethoxyphenyl)-1,4-dihydro-4-oxo-5-difluoromethoxycinnoline-3-carboxylate (200 mg) and a 1N aqueous solution of sodium hydroxide (0.93 ml) were added to a mixed solvent of ethanol (5.5 ml) and water (1.5 ml), and the resultant mixture was stirred at 70° to 80° C. for 3 hours. After being allowed to cool to room temperature, the mixture was diluted with water (50 ml), and washed with ethyl acetate (20 ml). The pH of the water layer was adjusted to pH 2 with concentrated hydrochloric acid to precipitate crystals. The precipitated crystals were collected by filtration, washed with water (5 ml) two times, and dried under reduced pressure to give 120 mg of desired 1-(4-trifluoromethoxyphenyl)-1,4-dihydro-4-oxo-5-difluoromethoxycinnoline-3-carboxylic acid (yield: 64.2%). m.p., 236.5° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16](Cl)=[N:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:31][CH2:30][CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:22]1.C(OC(C1CCN(C2C=CC(C(=O)NC3C=CC(C)=C(I)C=3)=CN=2)CC1)=O)C>CCOC(C)=O>[CH2:28]([O:27][C:25]([CH:24]1[CH2:30][CH2:31][N:21]([C:16]2[CH:17]=[CH:18][C:13]([C:12](=[O:20])[NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)=[CH:14][N:15]=2)[CH2:22][CH2:23]1)=[O:26])[CH3:29]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Reactant: CCOC(=O)C1CCNCC1
Agent: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C(C)(C)C)cc3)cn2)CC1

Procedure:
5′-(4-tert-Butyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester was prepared from N-(4-tert-butyl-phenyl)-6-chloro-nicotinamide and ethyl isonipecotate following a procedure similar to the one described in the synthesis of 5′-(3-iodo-4-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester above. The product was isolated by silica gel column purification with 20-30% EtOAc in hexanes gradient. HRMS m/z calcd for C24H31N3O3 [M+H]: 410.2438. Found: 410.2439.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH2:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12]([NH:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1C
Reactant: NC1CCOCC1
Product: Cc1cc(F)ccc1-c1nc(NC2CCOCC2)nc2c1ccc(=O)n2-c1ccccc1C
Yield: 90 %

Procedure:
Following the general procedure outlined in Example 126, the product of Example 121 (150 mg, 0.35 mmol), and 4-aminotetrahydropyran (179 mg, 1.77 mmol) were reacted to give the crude material, which was purified as described in Example 198 to give the desired product 140 mg (90%). LC-MS: 445.4 (MH+, m/z), 2.27 (Rt, min).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[C:22]([C:27]([F:30])([F:28])[F:29])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2ccnc3c(C(F)(F)F)cccc23)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2ccnc3c(C(F)(F)F)cccc23)c2ccccc12

Procedure:
0.32 g (7.62 mmol) of lithium hydroxide monohydrate and 8 cm3 of water are added to 0.94 g (2.54 mmol) of 3-methoxycarbonyl-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole dissolved in 8 cm3 of tetrahydrofuran. After stirring at reflux for 15 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 20 cm3 of water (pH=10). The resulting aqueous solution is washed with 30 cm3 of ethyl acetate, adjusted to pH 6 with N hydrochloric acid and extracted with 50 cm3 of ethyl acetate. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is triturated in 20 cm3 of isopropyl ether and filtered off, resulting in 0.50 g of 3-carboxy-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole in the form of a white powder. Mass spectrum (EI): m/e 356 (M+•).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7]2[C:8]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:9]([C:13]([CH:15]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH3:25])=[C:19]([CH3:26])[CH:18]=3)[OH:16])=[O:14])[CH:10]=[CH:11][CH:12]=2)[S:5][CH:6]=1.[Bi]=O>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:7]2[C:8]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[C:9]([C:13]([C:15]([C:17]3[CH:18]=[C:19]([CH3:26])[C:20]([O:24][CH3:25])=[C:21]([CH3:23])[CH:22]=3)=[O:16])=[O:14])[CH:10]=[CH:11][CH:12]=2)[S:5][CH:6]=1
Reactant: COc1c(C)cc(C(O)C(=O)c2cccc(-c3cc(C)cs3)c2-c2ccccc2)cc1C
Agent: O=[Bi]
Solvent: CC(=O)O
Product: COc1c(C)cc(C(=O)C(=O)c2cccc(-c3cc(C)cs3)c2-c2ccccc2)cc1C
Yield: 68.1 %

Procedure:
The benzil was synthesized according to the procedure of Example 41, Step 3 using the benzoin of Step 4 (1.6 g, 5 mmol) and bismuth oxide (2.9 g, 6 mmol) in acetic acid (16 ml). There was obtained 1.5 g (95%) of the desired benzil as a crystalline solid: mp 132-134° C. Anal. Calc'd. for C18H18O3S (MW 314.40): C, 68.76; H, 5.77; S, 10.20. Found: C, 68.70; H, 5.81; S, 10.25.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH2:12][CH2:11][C@@H:10]([C:13]([CH3:15])=[CH2:14])[CH2:9][CH:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.CCOCC>[Cl:26][C:4]1[O:5][C:6]([C:7]2[CH2:12][CH2:11][C@@H:10]([C:13]([CH3:15])=[CH2:14])[CH2:9][CH:8]=2)=[C:2]([CH3:1])[N:3]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: C=C(C)[C@H]1CC=C(c2ocnc2C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(C)[C@H]1CC=C(c2oc(Cl)nc2C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a solution of Example 32A (0.55 g, 2.7 mmol) in THF (20 mL) at −78° C. was added LiHMDS (1 M in THF, 3.25 mL, 3.25 mmol) dropwise over a period of 6-8 min. After 30 min hexachloroethane (1.28 g, 5.41 mmol) was added at once as a solid and the mixture was left to stir overnight warming to ambient temperature. The mixture was diluted with Et2O and washed with aqueous NH4Cl solution and water. The organic layer was separated and concentrated in vacuo, and the residue chromatographed on silica gel with EtOAc/hexanes (0%-20%) to yield 0.47 g (73%) of the title compound as an oil. 1H NMR (300 MHz, DMSO-d6) δ 6.11 (m, 1H), 4.74 (m, 2H), 2.48-2.24 (m, 3H), 2.23-2.00 (m, 5H), 1.92-1.82 (m, 1H), 1.73 (s, 3H), 1.57-1.41 (m, 1H). MS (ESI+) m/z 238 (M+H).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][P:18]([O:26][CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])=[CH:14][CH:15]=2)[C:10]([C:28]2[N:29](C(OC(C)(C)C)=O)[CH:30]=[CH:31][CH:32]=2)=[N:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:29]1[CH:30]=[CH:31][CH:32]=[C:28]1[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][P:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)(=[O:19])[O:26][CH3:27])[CH:12]=2)[NH:8][N:9]=1
Reactant: COP(=O)(Oc1ccc2c(c1)c(-c1cccn1C(=O)OC(C)(C)C)nn2C(=O)OC(C)(C)C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COP(=O)(Oc1ccc2[nH]nc(-c3ccc[nH]3)c2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
39 mg of 3-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-5-(methoxyphenyl-phosphinoyloxy)indazole-1-carboxylic acid tert-butyl ester are dissolved in 0.5 ml of dichloromethane and then 0.5 ml of trifluoroacetic acid is added. The solution is stirred at ambient temperature for approximately two hours. The solvent is evaporated off under reduced pressure in a rotary evaporator. The reaction crude is purified by preparative LC/MS to obtain 19 mg of phenylphosphonic acid methyl ester 3-(1H-pyrrol-2-yl)-1H-indazol-5-yl ester as a trifluoroacetate salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([CH2:28]O)[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]1)=[N:9][C:8]([O:30]C)=[CH:7][CH:6]=2.CO.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O>ClCCl>[F:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][C:8](=[O:30])[N:9]3[CH2:28][CH:12]([CH2:13][N:14]4[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:16][CH2:15]4)[C:11]=1[C:10]=23
Reactant: COc1ccc2ncc(F)c(C(CO)CN3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)CC1
Temperature: 55 °C

Procedure:
A solution of 1,1-dimethylethyl (1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-3-hydroxypropyl}-4-piperidinyl)carbamate (18.28 g, containing some non-alcohol impurity and a little MeOH, judged to contain 40 mmol alcohol-containing compounds) in dichloromethane (180 ml) was stirred under argon, ice-cooled and treated with triethylamine (11.1 ml, 80 mmol) and methanesulfonic anhydride (8.7 g, 50 mmol). After 1 hour the solution was heated to reflux for 2 days, evaporated and redissolved in chloroform (180 ml). This solution was heated under argon at 55° C. for 3 days, cooled, washed with aqueous sodium bicarbonate and the aqueous twice re-extracted with chloroform. The combined organic phases were dried and evaporated. Chromatography of the residue (methanol/dichloromethane gradient) and rechromatography of some impure fractions gave the product (13.35 g, containing 12.5% dichloromethane by weight).