Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[S:25][CH:26]=[CH:27][N:28]=1)CCC>C1(C)C=CC=CC=1.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>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Clc1ccc2c(cc(Br)n2Cc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc2c(cc(-c3nccs3)n2Cc2ccccc2)n1
Temperature: 110 °C

Procedure:
A mixture of 1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.10 g, 0.31 mmol, from Example 62, Step 2) and 2-(tributylstannyl)-1,3-thiazole (0.12 g, 0.31 mmol, Aldrich) in toluene (6.0 mL) was degassed by a stream of nitrogen through the solution. Tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.031 mmol) was added and the mixture was heated to 110° C. for 4 hours. Toluene was removed in vacuo and the residue was dissolved in MeCN, filtered, and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (33 mg, 32%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.C[C:12]([N:14](C)C)=O>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:2]([C:12]#[N:14])[C:3]=2[CH2:4][CH2:5]1
Reactant: Brc1cccc2c1CCN2
Reactant: CC(=O)N(C)C
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc2c1CCN2

Procedure:
Degas a solution of 4-bromo-2,3-dihydro-1H-indole (250 mg, 1.224 mmol) in dimethylacetamide (2 mL) under Ar. To this add zinc cyanide (147 mg, 1.224 mmol) followed by tetrakis-(triphenylphosphine) palladium(0) (143 mg, 0.123 mmol) and heat the reaction under argon in a sealed tube at 100° C. for 4 h. Quench the cooled reaction with sat. NH4Cl (50 mL) and extract with EtOAc (3×50 mL). Wash the organics with water (50 mL), dry (Na2SO4), then concentrate in vacuo to give a gum. Purify by silica gel chromatography eluting with 5% to 30% EtOAc/hexane. Pool and concentrate fractions containing product then dissolve the residue in Et2O (5 mL) and hexane (50 mL). Reconcentrate this to a solid. Suspend in hexane and filter washing with hexane to afford the product 2,3-dihydro-1H-indole-4-carbonitrile as a powder (131 mg, 0.863 mmol). MS, electrospray 145.2 (M+H), rt 1.02 min.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([O:11][CH3:12])[C:4]=1[O:13][CH3:14].P(Br)(Br)[Br:16]>CCOCC>[CH3:14][O:13][C:4]1[C:5]([O:11][CH3:12])=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[CH2:2][Br:16]
Reactant: COc1ccc(CO)c(OC)c1OC
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: COc1ccc(CBr)c(OC)c1OC
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A solution of 1-hydroxymethyl-2,3,4-trimethoxybenzene (1 g, 5 mmoles) in anhydrous ethered solution (10 ml) is injected into a three-necked flask supplied with a septum and equipped with a magnetic stirrer, which is swept with argon. Phosphorus tribromide at -20° C. (1.46 g, 5 mmoles) dissolved in ether (8 ml) is then added. The mixture is stirred at -10° C. for 2 hours and then washed with ice-cold water and finally with NaCl, and then dried over MgSO4. Evaporation at 0° C. under reduced pressure gives a colorless oil (1.24 g) which is homogeneous in TLC (Y=95%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31]>>[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:31]
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Reactant: O=C(Cl)c1cccs1
Product: O=C(Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1)c1cccs1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.061 mMol) 2-thiophenecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH:1]([O:4][P:5](/[CH:11]=[CH:12]/[CH2:13][CH2:14][O:15][N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[N:25]1C(=O)C2=CC=CC=C2C1=O)([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:3])[CH3:2].CNN>C(O)C>[CH:8]([O:7][P:5](/[CH:11]=[CH:12]/[CH2:13][CH2:14][O:15][N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH2:25])([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])([CH3:9])[CH3:10]
Reactant: CC(C)OP(=O)(/C=C/CCOn1cnc2c(N3C(=O)c4ccccc4C3=O)ncnc21)OC(C)C
Agent: CNN
Solvent: CCO
Product: CC(C)OP(=O)(/C=C/CCOn1cnc2c(N)ncnc21)OC(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.8 %

Procedure:
A mixture of (E)-9-[4-(Diisopropoxyphosphoryl)but-3-enyloxy]-6-phthalimidopurine (186 mg, 370 μmol) and methylhydrazine (18 mg, 390 μmol) in ethanol (4 ml) was stirred at room temperature for 1.5 hr. The solvent was removed and the residue purified by column chromatography on silica gel eluting with dichloromethane-methanol (4:1) to afford (E)-9-[4-(diisopropoxyphosphoryl)but-3-enyloxy]-adenine as a gum (120 mg, 88%); λmax (EtOH) 260 (12,860)nm; υmax (film) 3310, 3170, 2970, 1640, 1590, 1290, 1230 and 980 cm-1 ; δH [(CD3)2SO] 1.26 (12H, pseudo t, J 6 Hz, CH(CH3)2), 2.67 (2H, m, CH2), 4.50 (4H, m, CH2O and CH(CH3)2), 6.05 (1H, dd, J 17 Hz and 22 Hz, PCH=CH), 6.70 (1H, ddt, J 6 Hz, 17 Hz and 22 Hz, PCH=CH), 7.38 (2H, br.s, NH2), 8.14 (1H, s, H-2/H-8), 8.36 (1H, s, H-2/H-8) (Found: M+ 369.1568. C15H24N5O4P requires M+ 369 1566).
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C)=[CH:16]2)=[CH:11][C:10]=1[C:31]1[N:32]=[N:33][C:34]([N:37]([CH3:48])[CH:38]2[CH2:43][C:42]([CH3:45])([CH3:44])[NH:41][C:40]([CH3:47])([CH3:46])[CH2:39]2)=[CH:35][CH:36]=1>C(Cl)Cl.CO>[NH2:23][CH2:22][CH2:21][CH2:20][O:19][C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[C:10]([C:31]3[N:32]=[N:33][C:34]([N:37]([CH3:48])[CH:38]4[CH2:43][C:42]([CH3:44])([CH3:45])[NH:41][C:40]([CH3:47])([CH3:46])[CH2:39]4)=[CH:35][CH:36]=3)[C:9]([OH:8])=[CH:18]2)=[CH:13][CH:14]=1
Reactant: CN(c1ccc(-c2cc3ccc(OCCCNC(=O)OC(C)(C)C)cc3cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CN(c1ccc(-c2cc3ccc(OCCCN)cc3cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
TFA (1.5 ml, 19.47 mmol) was added to a solution of Example 20-4 (289.4 mg, 0.513 mmol) in DCM (6 ml) at RT. The reaction mixture was stirred at RT for 30 min, diluted with MeOH then adsorbed onto a MeOH conditioned SCX column (10 g). The column was washed several times with MeOH then eluted with 3 N NH3 in MeOH. Evaporation of the solvent afforded the title compound as a beige solid (178 mg, 75% yield). LCMS Rt=0.44 min (LCMS method Q); MS (M+1)=464.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.35 (s, 1H), 8.28 (d, J=9.60 Hz, 1H), 7.77 (d, J=9.09 Hz, 1H), 7.36 (d, J=9.60 Hz, 1H), 7.16-7.18 (m, 1H), 7.11 (d, J=2.53 Hz, 1H), 6.96 (dd, J=8.84, 2.27 Hz, 1H), 4.91-5.04 (m, 1H), 4.56 (s, 1H), 4.17 (t, J=6.32 Hz, 2H), 2.98 (s, 3H), 2.88 (d, J=7.07 Hz, 2H), 1.90-2.05 (m, 2H), 1.46-1.62 (m, 4H), 1.30 (s, 6H), 1.14 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH2:24][OH:25])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([CH:24]=[O:25])=[C:5]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CS(=O)(=O)c1ccc(Cn2c(CO)c(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Solvent: CO
Product: CS(=O)(=O)c1ccc(Cn2c(C=O)c(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1

Procedure:
In the same manner as in Example 311, the title compound was synthesized using 6-chloro-3-hydroxymethyl-2-(4-methanesulfonylbenzyl)-4-phenyl-2H-isoquinolin-1-one. Crystals (methanol).
Reaction SMILES: [NH2:1][CH:2]1[CH:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([F:31])=[C:7]([O:18][CH2:19][CH2:20][NH:21][S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:24])=[O:23])[CH:8]=2)[CH2:3]1.Br[CH2:33][CH:34]([CH3:37])[CH2:35]Cl.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O.ClCCl>[CH2:11]([CH:10]1[C:9]2[C:4](=[CH:5][C:6]([F:31])=[C:7]([O:18][CH2:19][CH2:20][NH:21][S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:24])=[O:23])[CH:8]=2)[CH2:3][CH:2]1[N:1]1[CH2:35][CH:34]([CH3:37])[CH2:33]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cn1cnc(S(=O)(=O)NCCOc2cc3c(cc2F)CC(N)C3Cc2ccccc2)c1
Reactant: CC(CCl)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CC1CN(C2Cc3cc(F)c(OCCNS(=O)(=O)c4cn(C)cn4)cc3C2Cc2ccccc2)C1

Procedure:
To N-(2-(2-amino-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide (20.7 mg, 0.047 mmol), 10 equivalents 1-bromo-3-chloro-2-methylpropane and potassium carbonate(70.8 mg) in water (1 mL) +1 drop acetonitrile were added. Microwave at 120° C. Evaporated acetonitrile, re-dissolved in dichloromethane and extracted with water and brine, dried over sodium bicarbonate, filtered and evaporated to obtain the crude product and was purified by flash silica gel chromatography on 4 g SiO2-cartridge using 10% methanol in dichloromethane to afford N-(2-(3-benzyl-6-fluoro-2-(3-methylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide as a clear glass m=2.0 mg (8.6%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[C:4]=1[C:14]([F:17])([F:16])[F:15].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:13][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[C:4]2[C:14]([F:16])([F:15])[F:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(C)cccc2c1C(F)(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(CBr)cccc2c1C(F)(F)F
Yield: 106.5 %

Procedure:
A suspension of 2-methoxy-5-methyl-1-(trifluoromethyl)naphthalene (1.2 g, 5.0 mmol), N-bromosuccinimide (1.07 g, 6.0 mmol) and benzoyl peroxide (20-30 mg) in carbon tetrachloride (10 mL) was heated at reflux for 1.5 hr. The residual solid in the reaction mixture was removed by filtration, and the collected solid on the filter was washed with methylene chloride. The combined filtrates were washed with water, dried (MgSO4) and evaporated to give 1.7 g of 5-(bromomethyl)-1-(trifluoromethyl)-2-methoxynaphthalene (IX, R=CH3 and R1 =CH2Br) which was used in the next step without purification. Crystallization of a sample from hexane furnished pure 5-(bromomethyl)-1-trifluoromethyl-2-methoxynaphthalene having mp 97°-99° C.; nmr (CDCl3) δ 3.95 (s, 3H), 4.85 (s, 2H), 7.7 (m, 5H); ir (CHCl3) 1265, 1125 cm-1 ; uvλmax (MeOH) 339 nm (ε3,510), 326 (3,280), 300 (7,230), 288 (7,150), 229 (44,150); anal Calcd for C13H10BrF3O: C, 48.93% H, 3.16%; Found: C, 48.88% H, 3.14%.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([OH:8])[CH2:7][O:6][CH2:5]1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16](=O)[O:17]C1C=CC=CN=1>C1COCC1.CCOC(C)=O>[C:16](=[O:17])([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=1)[O:8][C:4]1([CH3:3])[CH2:7][O:6][CH2:5]1
Reactant: CC1(O)COC1
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(OC(=O)Oc2ccccn2)COC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
To a suspension of sodium hydride, 60% in mineral oil (0.817 g, 20.43 mmol) in THF (55 mL) was added 3-methyloxetan-3-ol (1.5 g, 17.03 mmol) at 0° C. After stirring 30 min, the solution was transferred to a solution of di(pyridin-2-yl)carbonate (3.68 g, 17.03 mmol) in THF (55 mL) through a cannula. The formed slurry was stirred at 0° C. for 30 min. The slurry was warmed to rt and stirred for 2 h. The reaction was diluted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated to give a residue that was purified by Biotage (5-40% EtOAc:Hex) to afford the desired product 3-methyloxetan-3-yl pyridin-2-yl carbonate (1.00 g, 28.1% yield) as an oil. 1H NMR (400 MHz, CHLOROFORM-d) d 8.52-8.35 (m, 1H), 7.84 (ddd, J=8.1, 7.3, 2.1 Hz, 1H), 7.31-7.27 (m, 1H), 7.15 (dt, J=8.1, 0.8 Hz, 1H), 4.97-4.85 (m, 2H), 4.54 (d, J=8.0 Hz, 2H), 1.86 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([OH:14])[CH:10]([NH2:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](Cl)(=[O:26])[CH2:24][CH3:25].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([OH:14])[CH:10]([NH:22][C:23](=[O:26])[CH2:24][CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(N)C1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NC1CN(C(=O)OC(C)(C)C)CCC1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.2 %

Procedure:
3-Amino-4-(4-chloro-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.116 g, 0.35 mmol) was dissolved in CH2Cl2. Propionyl chloride (0.034 mL, 0.39 mmol) and triethylamine (0.109 mL, 0.78 mmol) were added and the solution was stirred for 24 h at room temperature. The reaction was concentrated in vacuo, then purified by Biotage flash chromatography (30% ethyl acetate/70% hexane to 50% ethyl acetate/50% hexane) to yield the title compound (0.133 g, 97%). 1H-NMR (CDCl3): δ 0.87 (t, 3H), 1.44 (s, 9H), 1.78-1.95 (m, 3H), 2.20 (dt, 1H), 3.24 (t, 1H), 3.50 (d, 1H), 3.90 (t, 1H), 4.08 (q, 2H), 4.28 (d, 1H), 5.48 (bd, 1H), 7.26 (d, 2H), 7.37 (d, 2H). ESI-MS m/z: 383 (M+1), retention time 2.21.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH2:16][CH3:17])[N:7]=1)C.[Li+].[OH-].Cl>C1COCC1>[CH2:16]([O:15][C:8]1[CH:9]=[C:10]([O:12][CH2:13][CH3:14])[N:11]=[C:6]([CH2:5][C:4]([OH:18])=[O:3])[N:7]=1)[CH3:17]
Reactant: CCOC(=O)Cc1nc(OCC)cc(OCC)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(OCC)nc(CC(=O)O)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To (4,6-diethoxy-pyrimidin-2-yl)-acetic acid ethyl ester (0.218 g, 0.86 mmol) in THF (3 mL) was added 1N aqueous LiOH (2.58 mL, 2.58 mmol), and the reaction was stirred at 50° C. for 1 hour, and then at room temperature overnight. The mixture was acidified with 1N aqueous HCl and extracted three times with EtOAc. The combined organic layers were dried, filtered, and concentrated to give (4,6-diethoxy-pyrimidin-2-yl)-acetic acid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[CH2:6][P:7](=[O:14])([O:11]CC)[O:8]CC>Cl.C(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:17]=1)[CH2:6][P:7](=[O:8])([OH:11])[OH:14]
Reactant: CCOP(=O)(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)OCC
Agent: Cl
Solvent: CCO
Product: O=P(O)(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 49.3 %

Procedure:
Diethyl 3,5-bis(trifluoromethyl)benzylphosphonate (1.0 g, 2.7 mmol) in 15 mL of conc hydrochloric acid and 0.5 mL of ethanol was heated at reflux for 72 hours. The mixture was evaporated to an oily residue which crystallized upon standing to give 0.41 g of the product (49% yield) the as a white solid: mp. 206°-208° C.; D.C.I.M.S. [MH+, 309].
Reaction SMILES: [ClH:1].C[O:3][C:4]([C:6]1[CH2:7][N:8]([CH2:12][CH2:13][O:14][CH:15]=[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:9][CH2:10][CH:11]=1)=[O:5].[OH-].[Na+]>C(O)C>[ClH:1].[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:15][O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH:11]=[C:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: COC(=O)C1=CCCN(CCOC=C(c2ccccc2C)c2ccccc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1C(=COCCN1CCC=C(C(=O)O)C1)c1ccccc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91 %

Procedure:
1-(2-((2-(2-Fluorophenyl)-2-(2-methylphenyl)ethenyl)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid methyl ester hydrochloride (2.18 g, 0.0049 mol, prepared similarly to the method described in Example 70) was dissolved in ethanol (24 ml) and 12 N sodium hydroxide solution (1.83 ml) was introduced at 5° C. The solution was stirred at room temperature for 2.5 h and stored at −10° C. for 18 h. The reaction mixture was evaporated to a residue after pH had been adjusted to 6.5 with 4 N hydrochloric acid solution. Water (20 ml) and ethyl acetate (50 ml) were added, the aqueous layer was separated and extracted again with ethyl acetate (25 ml). The combined ethyl acetate extracts was washed with saturated brine (40 ml), dried (MgSO4) and evaporated to a residue, which was co-evaporated with dichloromethane (3×40 ml). The residue (1.9 g) was dissolved in toluene (15 ml) and methanol (0.2 ml) was introduced followed by chlorotrimethylsilane (0.62 ml). The mixture was stirred for 18 h at room temperature and cooled to 0° C. for 2 h. The title compound (1.9 g, 91%) was obtained as white crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1>CN(C)C=O>[CH3:3][C:4]1[N:5]=[CH:6][N:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)[CH:8]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(C=O)cc2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.4 %

Procedure:
4.20 g of sodium hydride (a 60% suspension thereof in a mineral oil) was suspended in 150 ml of dimethylformamide to obtain a suspension. 8.62 g of 4-methylimidazol was added to the suspension at a room temperature under stirring in portions. After one hour, 12.4 g of 4-fluorobenzaldehyde was added to the obtained mixture. The obtained mixture was stirred for 4 hours and poured into ice-water. The obtained mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and distilled under a reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography (solvent: chloroform/methanol (50:1)) to obtain a solid product. This solid product was washed with ether to obtain 2.67 g of the title compound as a pale yellow powder (yield: 14%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[H-].[Na+].C(OCC1C=CC(C(O)=O)=CC=1)CC=C.[CH:29]([OH:32])([CH3:31])[CH3:30]>>[CH:29]([O:32][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])([CH3:31])[CH3:30]
Reactant: O=C(O)c1cccc(CCl)c1
Reactant: CC(C)O
Agent: C=CCCOCc1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)OCc1cccc(C(=O)O)c1

Procedure:
The reaction of isopropanol and 3-Chloromethyl-benzoic acid in the presence of sodium hydride was performed as described for Compound 33 to give 3-isopropoxymethyl-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 7.89 (m, 1 arom.H); 7.84 (m, 1 arom.H); 7.54 (m, 1 arom.H); 7.46 (m, 1 arom.H); 4.49 (s, OCH2C6H4—); 3.653 (m, CH(CH3)2); 1.14 (d, CH(CH3)2). 13C-NMR (100 MHz, d6-DMSO): 167.24 (—C═O); 139.79; 131.56; 130.68; 128.43; 128.08; 127.92; 70.54; 68.50; 22.02 (2 C).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-:28])=[O:27])(=[O:19])=[O:18])=[CH:12][C:11]=1[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31].[CH:34]1([CH:37]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50]O)[CH:45]=2)[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:36][CH2:35]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH:34]1([CH:37]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][N:16]([C:13]3[CH:14]=[CH:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:12]=3)[S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:26]([O-:28])=[O:27])(=[O:18])=[O:19])[CH:45]=2)[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:36][CH2:35]1
Reactant: COc1ccc(F)c(-c2ccc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])cc2CC(C)(C)C)c1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cccc(CN(c2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a solution of N-(2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)-2-nitrobenzenesulfonamide (892 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (445 mg) and triphenylphosphine (990 mg) in THF (19 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (1.49 mL) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.22 g) as a colorless gummy substance.
Reaction SMILES: [CH2:1]([C:8]1([CH3:21])[CH2:16][C:15]2[C:10](=[C:11]([Cl:19])[C:12]([Cl:18])=[C:13]([OH:17])[CH:14]=2)[C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>O1CCCC1>[CH2:1]([C:8]1([CH3:21])[CH2:16][C:15]2[C:10](=[C:11]([Cl:19])[C:12]([Cl:18])=[C:13]([OH:17])[CH:14]=2)[CH:9]1[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(Cc2ccccc2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(Cc2ccccc2)Cc2cc(O)c(Cl)c(Cl)c2C1O

Procedure:
2-Benzyl-2-methyl-6,7-dichloro-1,5-indandiol is prepared following substantially the same procedure described in Example 4, Step E, using the following substances: 2-benzyl-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (4.8 g., 0.015 mole); sodium bis-(2-methoxyethoxy)-aluminum hydride (70% in benzene [5 ml.]); and tetrahydrofuran (50 ml.).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH3:20])[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>C(OCC)(=O)C.CO>[CH3:23][N:24]([CH3:26])[CH:25]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH3:20])[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cccc(N(C)S(=O)(=O)c2ccccc2)c1
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)C=CC(=O)c1cccc(N(C)S(=O)(=O)c2ccccc2)c1
Yield: 84 %

Procedure:
1.25 g (4.32 mmol) of N-(3-acetyl-phenyl)-N-methyl-benzenesulfonamide were dissolved in 10 ml of N,N-dimethylformamide dimethylacetal and the resultant solution was refluxed for 18 hours. The excess of volatile reagent was removed by reduced pressure distillation to yield a crude which was chromatographied over silica gel using a gradient of ethyl acetate/methanol as eluent. 1.25 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methyl-benzenesulfonamide as a yellowish-white solid were obtained (yield 84%).