Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[N:11]=2)(=O)=O)C=CC=CC=1.[C:25]1([Mg]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[C:25]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:17])=[O:18])[N:11]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=S(=O)(c1ccccc1)c1cccc(S(=O)(=O)c2ccccc2)n1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1cccc(-c2ccccc2)n1
Yield: 80 %

Procedure:
To a stirred solution of bis-(phenylsulfonyl)pyridine 4d (1.0 g, 2.78 mmol) in 10 mL THF at room temperature is charged 1.0 M PhMgBr (5.56 ml, 2.0 equiv) slowly over a period of 10 min. The progress of the reaction is monitored by LC-MS. Upon complete consumption of the starting material (about 2 h), the mixture is quenched with MeOH (2 mL). The crude mixture is then evaporated to dryness, and the product is isolated by flash column chromatography (silica gel, 15% ethyl acetate in hexanes) and dried to yield 656 mg of 3e as a white solid, 80% yield. 1H NMR (400 MHz, CDCl3) δ 8.14-8.08 (m, 3H), 7.95-7.91 (m, 3H), 7.83-7.86 (m, 1H), 7.62-7.51 (m, 3H), 7.46-7.40 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 158.7, 158.0, 138.9, 138.7, 137.1, 133.7, 130.0, 129.2, 128.9, 128.8, 127.0, 123.1, 119.8.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].N1C=CC=CC=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.O>C(Cl)Cl>[S:26]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27]
Reactant: OCCOCCOCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCO)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49 %

Procedure:
A cold (0°) solution of 23.3 g of tetraethylene glycol and 19 g of pyridine in 100 ml of methylene chloride, is treated portionwise while stirring vigorously with a total of 19 g of p-toluenesulphonyl chloride. After completion of the addition the mixture is stirred at room temperature for a further 5 hours. 200 ml of methylene chloride and 100 ml of water are then added thereto and the organic phase is separated. The organic phase is washed successively with 100 ml of 2N hydrochloric acid, 100 ml of 5% sodium hydrogen carbonate solution and 100 ml of water and dried over sodium sulphate. The solvent is removed in a vacuum and the residue is chromatographed over 400 g of silica gel with methylene chloride-ethyl acetate-methanol (5:4:1) as the eluent. In addition to small amounts of tetraethylene glycol ditosylate there are isolated 17 g of tetraethylene glycol monotosylate as a colourless liquid. RF (silica gel/methylene chloride-ethyl acetate-methanol 5:4:1): 0.6.
Reaction SMILES: [CH:1]([N:4]1[CH:12]=[C:11]2[C:6]([C:7](=[O:25])[NH:8][C:9]3([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH2:10]2)=[N:5]1)([CH3:3])[CH3:2].[ClH:26]>C(OCC)(=O)C.O1CCOCC1>[ClH:26].[CH:1]([N:4]1[CH:12]=[C:11]2[C:6]([C:7](=[O:25])[NH:8][C:9]3([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[CH2:10]2)=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cc2c(n1)C(=O)NC1(CCN(C(=O)OC(C)(C)C)CC1)C2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)n1cc2c(n1)C(=O)NC1(CCNCC1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 2′-isopropyl-7′-oxo-2′,4′,6′,7′-tetrahydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridine]-1-carboxylate (130 mg, 0.37 mmol) in ethyl acetate (5 mL) was added 4 M hydrochloric acid (2 mL) in 1,4-dioxane. The reaction mixture was stirred 3 hours at room temperature, the volatiles were removed under reduced pressure and the resultant residue was triturated with 10 mL heptane. The solid was dried under reduced pressure to yield 2′-isopropyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one hydrochloride (105 mg) as an off-white solid. +ESI (M+H) 249.1; 1H NMR (500 MHz, DMSO-d6, δ): 7.91 (s, 1H) 7.69 (s, 1H) 4.48-4.62 (m, 1H) 3.02-3.28 (m, 4H) 2.78 (s, 2H) 1.74-1.89 (m, 4H) 1.41 (d, J=6.59 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[N:11][CH:10]=[C:9]([OH:21])[C:8]=2[C:7]1=[O:22].C(OO)(=[O:29])C.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:21])[CH:10]=[N+:11]([O-:29])[C:12]=2[C:16]([N:18]([CH3:19])[CH3:20])=[O:17])[C:7]1=[O:22]
Reactant: CN(C)C(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: CC(=O)OO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)C(=O)c1c2c(c(O)c[n+]1[O-])C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 50 °C

Procedure:
6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide (24 g, 63.5 mmol) was dissolved in 1000 mL glacial acetic acid and per-acetic acid (32% by weight in acetic acid, 151 mL, 635 mmol) and sodium acetate (2.6 g, 31.7 mmol) was added. The reaction was warmed to 50° C. and aged overnight at which time LCMS showed the reaction done. The solution reduced in volume to ⅓ on the rotoevaporator, cooled in an ice bath and quenched slowly with 10% Na2SO3 solution until no peroxide was detected by a starch paper test. The reaction was transferred to a separatory funnel and water (500 mL) and chloroform was added. The layers were separated and the water extracted with CHCl3 several times. The combined organic layers were washed with slightly acidic water, brine and dried over Na2SO4, filtered and evaporated to give the product as an oil. The initial NMR shows an excessive number of methyl group peaks, perhaps as a result of oxalyl chloride reacting with dimethylamine in the second step and this impurity being carried through. A small sample was purified by reverse phase chromatography eluting with 95:5-5:95 water/acetonitrile 0.1% TFA to give clean material for NMR.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[F:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][N:10]=1>>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[CH3:7])=[CH:11][N:10]=1
Reactant: Cc1ccsc1Br
Reactant: OB(O)c1ccc(F)nc1
Product: Cc1ccsc1-c1ccc(F)nc1
Yield: 75.9 %

Procedure:
This compound was prepared in analogy to Example 52, starting from 2-bromo-3-methylthiophene (2.6 g, 15 mmol) and 2-fluoro-5-pyridine-boronic acid (2.3 g, 16.5 mmol, 1.1 equiv.) to obtain 2.2 g of the desired compound as a light yellow oil. MS (ES): m/e 194.2 (M+H)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]([OH:14])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl:15]CCl>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]([Cl:15])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Reactant: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1ccc2c(c1)OCO2
Temperature: 40 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
(Method G2) To a suspension of 3-benzo[1,3]dioxol-5-yl-acrylic acid (1a) (0.38 g, 1.98 mmol) in dichloromethane (8.0 ml) oxalyl chloride (0.62 ml, 7.08 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.41 g, 98%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C([N:14]1[CH2:20][CH2:19][C:18]([CH:21]=[O:22])=[C:17]([Cl:23])[CH2:16][CH2:15]1)C1C=CC=CC=1>C(Cl)Cl>[CH2:5]([O:4][C:2]([N:14]1[CH2:20][CH2:19][C:18]([CH:21]=[O:22])=[C:17]([Cl:23])[CH2:16][CH2:15]1)=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: O=CC1=C(Cl)CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Product: CCOC(=O)N1CCC(Cl)=C(C=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3.6 gm (0.033 mol) of ethyl chloroformate in 15 ml of dry methylene chloride was added dropwise at room temperature, while stirring, within 30 minutes to a solution of 7.5 gm (0.03 mol) of 1-benzyl-4-chloro-5-formyl-2,3,6,7-tetrahydro-1H-azepine in 50 ml of dry methylene chloride, whereupon the temperature of the reaction mixture increased from 22° C. to 27° C. After the addition was complete, the mixture was stirred at room temperature for another 3 hours. Then, the methylene chloride was distilled off in a rotary evaporator, and the residue was distilled in a high vacuum.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([N:9]=[C:10]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:11]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[C:12]2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[N:7]1)C.Cl>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[C:13]3[C:8](=[N:7][N:6]([CH2:5][CH:4]=[O:3])[CH:14]=3)[N:9]=[C:10]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:11]=2[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:16][CH:17]=1
Reactant: CCOC(Cn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1)OCC
Agent: Cl
Product: O=CCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Temperature: 100 °C
Yield: 64.9 %

Procedure:
In a volumetric flask, 2-(2,2-diethoxyethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (0.31 g, 0.6 mmol, obtained in example 73) and 1 N HCl (2.6 mL) were introduced. The mixture was heated to 100° C. for 1 hour. It was allowed to cool, adjusted to pH=7 and extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity eluent, to afford 166 mg of the title compound (yield: 65%).
Reaction SMILES: CC1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:41])[CH2:13][N:14]([C@@H](C3C=CC=CC=3)CO)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:11][C:5]=2[CH2:4][O:3]1.O>C(O)C.[OH-].[OH-].[Pd+2]>[OH:3][CH2:4][C:5]1[CH:11]=[C:10]([C@@H:12]([OH:41])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:9]=[CH:8][C:6]=1[OH:7]
Reactant: CC1(C)OCc2cc([C@@H](O)CN(CCCCCCOCCCCc3ccccc3)[C@H](CO)c3ccccc3)ccc2O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCc1cc([C@@H](O)CNCCCCCCOCCCCc2ccccc2)ccc1O
Yield: 86.9 %

Procedure:
A solution of (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[(1S)-2-hydroxy-1-phenylethyl][6-(4-phenylbutoxy)hexyl]amino}ethanol (110 mg), in ethanol (75 ml), was hydrogenated over Pearlman's catalyst [Pd(OH)2, 60% H2O, 55 mg) for 18 h. The catalyst was removed by filtration and the residue was washed with methanol. The combined filtrate and washings were concentrated and then applied to a 10 g SCX ion exchange cartridge. The cartridge was eluted with methanol (4 column volumes) and then with 10% aqueous 880 NH3 in methanol (3 column volumes). The ammoniacal eluent was concentrated under reduced pressure to give the title compound (69 mg) as a colourless oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[NH2:9])[CH3:2].Cl.[C:11](Cl)(Cl)=[O:12]>CO>[CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[N:9]=[C:11]=[O:12])[CH3:2]
Reactant: CCC1CCCCC1N
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: CO
Product: CCC1CCCCC1N=C=O
Temperature: 110 °C

Procedure:
To a solution of 2-ethylcyclohexylamine (0.61 mmol) in methanol was added HCl (4.0 M in dioxane, 0.152 mL), and concentrated to give a residue. Phosgene solution (20% in toluene, 6.0 mL) was added, and the reaction was heated at 110° C. overnight. Toluene and excess of phosgene were removed in vacuo to give a residue.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:6]([NH:13][C:14](=[O:36])[N:15]([C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][C:24]=2[OH:35])[CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:2]([O:35][C:24]1[CH:25]=[C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][C:23]=1[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([N:15]([CH3:16])[C:14]([NH:13][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:36])[CH:18]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCI
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCC)c1

Procedure:
In a manner similar to that of Example (25a), by reaction of 114 μL (1.0 mmol, 1.5 eq) of 1-iodobutane and 285 mg (0.67 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 6 ml of methyl ethyl ketone in the presence of 200 mg of potassium carbonate, methyl 3-[2-butoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate is obtained in oil form and is used in the following reaction without further purification.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.Cl.Cl[CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.C(O)(=O)C>C(O)C>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH2:17][O:3][C:4]2[CH:5]=[CH:6][C:7](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=2)[CH:19]=1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)/C=C/c1ccc(OCc2cccnc2)cc1
Reaction time: 0.17 h
Yield: 61.1 %

Procedure:
An aqueous solution of 2M NaOH (165 ml) was added to a solution of (E)-3-[4-hydroxyphenyl]-2-propenoic acid (16.4 g, 100 mmol) in ethanol (100 ml). The mixture was stirred for 10 minutes, and then 3-(chloromethyl)-pyridine hydrochloride (19.7 g, 120 mmol) was added in portions. The mixture was stirred for 20 hours, and the solvents were evaporated under reduced pressure. Water was added and the suspension heated to give a solution. To this solution was added acetic acid, and the resultant precipitate was filtered and recrystallised from methanol to give the title compound as a colourless solid (15.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][N:11]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:6]2=[CH:5][C:4]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+].FC(F)(F)S(O[C:39]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH:40]=1)(=O)=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.O.O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][N:11]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:6]2=[CH:5][C:4]=1[C:39]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH:40]=1
Reactant: COc1nc2ccn([Si](C(C)C)(C(C)C)C(C)C)c2cc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)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: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: COc1nc2ccn([Si](C(C)C)(C(C)C)C(C)C)c2cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To 5-methoxy-1-(triisopropylsilyl)-1H-pyrrolo[3,2-b]pyridin-6-ylboronic acid (900 mg, 2.58 mmol) was added sodium carbonate (548 mg, 5.17 mmol), lithium chloride (219 mg, 5.17 mmol), tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (856 mg, 2.58 mmol) and deairared 1,4-dioxane (15 mL) at rt temperature, followed by tetrakis(triphenylphosphine)palladium(0) (149 mg, 0.1297 mol), and H2O (1 mL). The resulting light brown mixture was stirred at 80° C. for 2 hr, and the conversion was completed as determined by LC/MS. After cooling down to rt, the mixture was partitioned between H2O/EtOAc (50 mL/100 mL). After separation, the organic phase was washed with brine, dried (Na2SO4), concentrated on rotary vacuo, and purified on Biotage Flash Collector eluting with 30-80% EtOAc/Hexanes (1200 mL) to afford the expected product, tert-butyl 4-(5-methoxy-1-(triisopropylsilyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (998 mg, 80%) as a white solid. 1H-NMR (400 MHz, MeOD) δ ppm 1.12 (s, 18 H) 1.49 (s, 9 H) 2.52 (s, 2 H) 3.47 (s, 3 H) 3.62 (s, 2 H) 4.00 (s, 3 H) 4.09 (s, 2 H) 5.78 (s, 1 H) 6.65 (s, 1 H) 7.33(s, 1 H) 7.51 (s, 1 H). Mass spec 486.28 (MH+) Calc for C27H43N3O3Si 485.31.
Reaction SMILES: [CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29]O)=[N:27][CH:28]=1.CP(C)C>O1CCCC1.C(OCC)(=O)C>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:9]3[CH:8]=[CH:7][C:6]4[C:11](=[C:12]([CH3:13])[N:4]([CH:1]5[CH2:2][CH2:3]5)[N:5]=4)[CH:10]=3)[C:15](=[O:21])[CH:16]=2)=[N:27][CH:28]=1
Reactant: OCc1ccc(Cl)cn1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C1CC1
Agent: CP(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c2cc(-n3ccc(OCc4ccc(Cl)cn4)cc3=O)ccc2nn1C1CC1
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (30 mg) in tetrahydrofuran (2 ml) were added (5-chloropyridin-2-yl)methanol (31 mg), bis(2-methoxyethyl)azodicarboxylate (55 mg) and trimethylphosphine (1 M tetrahydrofuran solution, 235 μl) at room temperature, and the mixture was stirred at the same temperature for 2 hr. The mixture was diluted with ethyl acetate, and washed with water, 1 M aqueous sodium hydroxide solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) and recrystallized from ethyl acetate to give the title compound (22 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].C1([Li])C=CC=CC=1.[CH:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CCOCC.C1C=CC=CC=1>[OH:22][CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: Cc1ccccn1
Reactant: O=Cc1ccccc1
Agent: [Li]c1ccccc1
Solvent: O
Solvent: c1ccccc1
Solvent: CCOCC
Product: OC(Cc1ccccn1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4.65 grams (0.05 mole) of 2-picoline in 40 milliliters of ether was added, with stirring, to a solution of phenyllithium (0.05 mole) in 30 milliliters of benzene diluted with 50 milliliters of ether. The solution was refluxed for 1 hour and then cooled to 0° C.; a solution of 5.3 grams (0.05 mole) of benzaldehyde in 30 milliliters of ether was added slowly at 0° C. The reaction mixture was stirred at room temperature for 30 minutes. Water was added, and the organic layer was separated and washed with water. Methylene chloride (100 milliliters) was added; the solution was dried over magnesium sulfate and evaporated under reduced pressure to give a solid. The solid was stirred with 50 milliliters of ether, filtered, and washed with 20 milliliters of ether to give 4.1 grams (40%) of virtually pure product. Recrystallization from 1:1 hexane-acetone gave plates, m.p. 105°-107° C. (Lit. m.p., 110° C., Beyerman, H. C., W. Eveleens, and Y. M. F. Muller, Rec. Trav. Chim., 75, 1956, p. 63).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1.C(N(CC)CC)C.Cl>C(Cl)Cl.CN(C)C=O.O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[C:14]([NH:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=2)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Reactant: Nc1ccc2ccccc2n1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc3ccccc3n2)cc1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
A solution of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 26, 125 mg, 0.389 mmol) in methylene chloride (3 mL) was treated with N,N-dimethylformamide (1 drop) and then cooled to 0° C. The reaction mixture was then treated with oxalyl chloride (0.051 mL, 0.583 mmol). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred for 1 h. The reaction mixture was then concentrated in vacuo. The resulting yellow gel was diluted with methylene chloride (2 mL) and then slowly added to a solution of 2-aminoquinoline (84 mg, 0.583 mmol) and triethylamine (0.108 mL, 0.778 mmol) in N,N-dimethylformamide (2 mL). The resulting reaction mixture was stirred at 25° C. for 20 h. The reaction mixture was then diluted with water (25 mL), a 1N aqueous hydrochloric acid solution (5 mL), and ethyl acetate (25 mL). The layers were separated, and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-quinolin-2-yl-propionamide (50.6 mg, 30%) as an off-white foam: mp 95-99° C. (foam to gel); EI-HRMS m/e calcd for C25H25N3O3S (M+) 447.1617, found 447.1616.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=2[F:31])[CH2:17][O:16][C@H:15]([C:18]([F:21])([F:20])[F:19])[C@H:14]1[CH2:22][OH:23].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:31][C:25]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:24]=1[C@@:13]1([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])[C@H:14]([CH2:22][OH:23])[C@@H:15]([C:18]([F:21])([F:19])[F:20])[O:16][CH2:17]1
Reactant: N[C@@]1(c2cccc(F)c2F)CO[C@H](C(F)(F)F)[C@H]1CO
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2cccc(F)c2F)CO[C@H](C(F)(F)F)[C@H]1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzoyl isothiocyanate (2.0 mL) was added to a solution containing ((2S,3R,4S)-4-amino-4-(2,3-difluorophenyl)-2-(trifluoromethyl)tetrahydrofuran-3-yl)methanol (3.12 g) in DCM (20 mL), and the mixture was stirred at RT for 18 h. Sodium bicarbonate (sat., aq., 50 mL) was then added, the mixture extracted with EtOAc (3×75 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% to 40% EtOAc in hexanes) to obtain the title compound (4.18 g). 1H NMR (400 MHz, CDCl3) δ ppm 3.12 (dd, J=7.6, 4.3 Hz, 1 H), 3.18-3.29 (m, 1 H), 4.03 (ddd, J=12.3, 7.2, 4.5 Hz, 1 H), 4.35-4.49 (m, 1 H), 4.59 (d, J=9.9 Hz, 1 H), 4.81 (d, J=9.6 Hz, 1 H), 7.07-7.23 (m, 2 H), 7.49 (t, J=7.2 Hz, 1 H), 7.56 (t, J=7.7 Hz, 2 H), 7.67 (t, J=7.5 Hz, 1 H), 7.88 (d, J=7.1 Hz, 2 H), 8.92 (s, 1 H), 11.89 (s, 1H)