Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4](F)[C:3]=1[O:10][CH3:11].N(O)=O.[C:15](O)(=O)[CH:16]([CH3:18])[CH3:17].C[Si](C)(C)[N-:23][Si](C)(C)C.[K+].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([C:16]([CH3:18])([CH3:17])[C:15]#[N:23])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)C(=O)O
Reactant: COc1c(F)ccc(C)c1Cl
Agent: O=NO
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1c(C(C)(C)C#N)ccc(C)c1Cl
Temperature: 27 °C
Reaction time: 456 h
Yield: 53.4 %

Procedure:
17.6 g (100.8 mmol) of 2-chloro-6-fluoro-3-methylanisole is dissolved in 880 ml of toluene. After 27.8 g (403.2 mmol) of isobutyric acid nitrite is added, 302.4 ml (151.2 mmol) of a 0.5 molar solution of potassium hexamethyl disilazide in toluene is added in drops within 40 minutes (temperature increase to 27° C.). After 19 days of stirring at room temperature, the batch is mixed with 300 ml of water and 400 ml of ethyl acetate, and then acidified with 10% sulfuric acid until a pH of 4 is reached. The aqueous phase is shaken with 200 ml of ethyl acetate. The combined organic extracts are washed with water and twice with saturated NaCl solution ad then dried. After spinning-in and chromatography on silica gel (mobile solvent ethyl acetate/hexane), 12.01 g (53.4%) of the desired compound is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13]C(=O)N)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.C(#[N:28])C.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O>O>[NH2:28][CH2:13][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:17]([OH:19])=[O:18]
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC#N
Agent: O=Ic1ccccc1
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-(benzyloxycarbonyl)-L-asparagine (7.5 g) were added ethyl acetate (36 ml), acetonitrile (36 ml), water (18 ml) and iodosobenzene diacetate (10 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the obtained solid was washed with ethyl acetate to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].Br[C:12]#[N:13].[OH-].[Na+]>CO>[NH2:13][C:12]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=2[N:10]=1
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc2nc(N)[nH]c2c1
Temperature: 20 °C
Reaction time: 14 h
Yield: 65.5 %

Procedure:
To a suspension of 3,4-diaminobenzonitrile (400 mg) in CH3OH (4 ml) was added BrCN (477 mg), followed by stirring at 20° C. for 14 hours. To the reaction mixture was added a 1M aqueous NaOH solution (0.117 ml), followed by concentration. To the residue was added chloroform:CH3OH=10:1 (10 ml), and the resulting insolubles were removed by filtration. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography to obtain 2-amino-1H-benzimidazole-6-carbonitrile (311 mg) as pale orange color powders.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](/[CH:14]=[CH:15]/[C:16](O)=[O:17])=[C:12]([CH:19]([CH3:21])[CH3:20])[N:11]=[C:10]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH2:14]/[CH:15]=[CH:16]/[OH:17])=[C:12]([CH:19]([CH3:21])[CH3:20])[N:11]=[C:10]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1C/C=C/O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold mixture of 3-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl]-(2E)-acrylic acid (5 ml) in THF (50 ml) methylchloroformate (1.5 ml) was added dropwise at 0-5° C. Reaction mixture was stirred at this temperature for 30 min and sodium borohydride (0.5 g) was added at 0-5° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 30 h. After completion of the reaction, mixture was poured on a cold HCl (100 ml) and extracted with ethyl acetate (50 ml). Organic phase was washed with aqueous sodium bicarbonate (2×50 ml), dried and evaporated to give crude product which was purified by column chromatography using ethyl acetate and hexanes (1:9) to give pure 3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(2E)-propenol.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([OH:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.CCCCCC>[OH:6][CH2:1][CH2:2][CH2:3][C:4]([O:17][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:5]
Reactant: O=C1CCCO1
Reactant: CCCCCCCCCCO
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCCCCCOC(=O)CCCO
Temperature: 150 °C
Yield: 17.7 %

Procedure:
To a mixture of 10 ml of gamma-butyrolactone and 40 ml of 1-decanol was added a crystal of p-toluenesulfonic acid. The reaction mixture was heated at 150° C. for 72 hours with stirring, cooled to room temperature, and then treated with 10 mg of sodium acetate. Flash chromatography (silica; 4:1 hexane:ethyl acetate eluent) afforded 5.6 g (17.7%) of 4-hydroxybutanoic acid, n-decyl ester as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)[CH:9]=1)(C)(C)C.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>ClCCl>[NH2:7][C:8]1[CH:9]=[C:10]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[O:30])=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)[CH:11]=[CH:12][CH:13]=1.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4cccc(Br)c4)ccc3Sc3cccc(NC(=O)OC(C)(C)C)c3)ncnc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4cccc(Br)c4)ccc3Sc3cccc(N)c3)ncnc2n1
Reaction time: 0.5 h

Procedure:
To a slurry of the product of Example 95D (0.67 g, 0.98 mmol) in dichloromethane (10 mL) was added dropwise trifluoroacetic acid (5 mL). The solution was stirred for 30 minutes and concentrated under vacuum. The resultant residue was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (15 mg, 35%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (d, J=6.62 Hz, 6 H), 3.22-3.33 (m, 1 H), 6.31-6.64 (m, 3 H), 6.97 (t, J=7.91 Hz, 1 H), 7.23-7.41 (m, 3 H), 7.69-7.79 (m, 1 H), 7.83 (d, J=9.56 Hz, 1 H), 7.91 (d, J=11.03 Hz, 1 H Hz, 1 H), 7.99 (s, 1 H), 8.07 (s, 1 H), 8.79 (s, 1 H), 8.95 (d, J=7.35 Hz, 1 H), 10.41 (s, 1 H), 11.40 (s, 1 H).
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13](Br)=[CH:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH3:29])[C:20]3[C:25]([S:26][C:27]=2[CH:28]=1)=[CH:24][CH:23]=[CH:22][CH:21]=3.[N:31]12[CH2:38][CH2:37][CH:34]([CH2:35][CH2:36]1)[C:33](=[O:39])[CH2:32]2>O.C1COCC1>[OH:39][C:33]1([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([CH3:29])[C:20]4[C:25]([S:26][C:27]=3[CH:28]=2)=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:34]2[CH2:37][CH2:38][N:31]([CH2:36][CH2:35]2)[CH2:32]1
Reactant: O=C1CN2CCC1CC2
Reactant: CN1c2ccccc2Sc2cc(C=C(Br)Br)ccc21
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN1c2ccccc2Sc2cc(CCC3(O)CN4CCC3CC4)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
In an atmosphere of argon, a hexane solution of n-butyl lithium (1.65M, 10.1 ml, 16.7 mmol) was added at -78° C. to a THF (25 ml) solution of 3-(2,2-dibromovinyl)-10-methylphenothiazine (3.13 g, 7.94 mmol), and the mixture was stirred for 1 hour and then at room temperature for 1 hour. The reaction mixture was again cooled at -78° C., and a THF (8 ml) solution of 3-quinuclidinone (1.09 g, 8.70 mmol) was added dropwise. The mixture was stirred at -78° C. for 1 hour and then with ice-cooling for 30 minutes. Water (5 ml) was added to the reaction mixture and the mixture was concentrated under a reduced pressure. A potassium carbonate aqueous solution was added and the reaction product was extracted with chloroform which was heated at about 50° C. The extract was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The resulting residue was recrystallized from ethanol-chloroform to give the title compound (1.75 g, 4.83 mmol, 61%) as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[N:13][O:14][CH2:15][C:16]([OH:18])=O)[CH2:7][CH:6]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:5][C:4]=2[N:3]=1.S(Cl)(Cl)=O.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(N(CC)CC)C>C(Cl)Cl>[N:35]1([C:16](=[O:18])[CH2:15][O:14][N:13]=[C:8]2[CH2:7][CH:6]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:5][C:4]3[N:3]=[C:2]([NH2:1])[N:11]=[C:10]([CH3:12])[C:9]2=3)[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: Cc1nc(N)nc2c1C(=NOCC(=O)O)CC(c1ccccc1-c1ccccc1)C2
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1nc(N)nc2c1C(=NOCC(=O)N1CCOCC1)CC(c1ccccc1-c1ccccc1)C2

Procedure:
The title compound was prepared from (2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-ylideneaminooxy)-acetic acid (compound 69) by treating with thionyl chloride followed by amidation using morpholine and triethylamine in DCM.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11][NH2:12])=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23](=[O:27])[CH2:24][CH2:25]Br)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:20]([O:22][C:23](=[O:27])[CH2:24][CH2:25][NH:12][CH2:11][CH2:10][CH2:9][CH:8]([C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:21]
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCNCCCC(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
26.1 g (0.1 mol) of 4,4-di(p-fluorophenyl)butylamine and 18.1 g of 3-bromopropionic acid ethyl ester are refluxed with 21.0 g of potassium carbonate in 200 ml of 2-butanone for 24 hours while stirring. The reaction mixture is filtered and the filtrate is concentrated by evaporation under reduced pressure, yielding crude 3-[4,4-di(p-fluorophenyl)-butylamino]-propionic acid ethyl ester in the form of an oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[N+:7]=1[O-].[N+]([O-])=O.O.N>S(=O)(=O)(O)O>[Cl:5][C:6]1[CH:11]=[C:10]([N+:1]([O-:4])=[O:2])[CH:9]=[C:8]([Cl:12])[N:7]=1
Reactant: O=[N+]([O-])O
Reactant: [O-][n+]1c(Cl)cccc1Cl
Agent: N
Agent: O=S(=O)(O)O
Agent: O=[N+][O-]
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
To a solution of 95% concentrated nitric acid (21 mL) and 98% concentrated sulfuric acid (50 mL) was added 2,6-dichloropyridine-N-oxide (12.8 g, 78 mmol). After the reaction was performed at 148° C. by stirring for 1 h, it was continued when the temperature was increased to 156° C. until no nitrogen dioxide was released. The reaction solution was cooled to room temperature, poured into 150 g ice water, and adjusted to pH=6 with ammonia water to precipitate a solid product. It was subjected to suction filtration. The resultant crude product was recrystallized with petroleum ether to afford 10 g yellow solid with a yield of 66.4%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][NH:8][NH2:9].F[C:11](F)(F)[CH2:12]NN>>[CH3:7][N:8]1[C:12]([CH:4]2[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]2)=[C:11]2[C:2]([CH2:3][CH2:4][CH2:5][CH2:6]2)=[N:9]1
Reactant: CNN
Reactant: NNCC(F)(F)F
Reactant: C1CCNCC1
Product: Cn1nc2c(c1C1CCNCC1)CCCC2

Procedure:
The title compound was prepared using procedures analogous to that described for Piperidine 11, except methylhydrazine was substutited for (2,2,2-trifluoroethyl)hydrazine. 1H-NMR (500 MHz) δ 1.69–1.89 (m, 8H), 2.33 (br m, 1H), 2.57–2.78 (m, 7H), 3.18–3.21 (m, 2H), 3.77 (s, 3H).
Reaction SMILES: [CH:1](N(C(C)C)CC)(C)C.N[C:11]1[N:16]=[CH:15][N:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24]C(NC(=O)CC3C=CC(F)=CC=3)=S)=[CH:20][C:19]=2[F:38])[CH:12]=1.[F:39][C:40]1[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][C:41]=1[C:42]([OH:44])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:14][C:15]1[CH:1]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:42](=[O:44])[C:41]3[CH:45]=[C:46]([CH3:49])[CH:47]=[CH:48][C:40]=3[F:39])=[CH:20][C:19]=2[F:38])[CH:12]=[CH:11][N:16]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1cc(Oc2ccc(NC(=S)NC(=O)Cc3ccc(F)cc3)cc2F)ncn1
Reactant: Cc1ccc(F)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(C(=O)Nc2ccc(Oc3ccnc(N)c3)c(F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
Diisopropylethylamine (0.035 mL, 0.200 mmol, 2.0 eq) was added to a solution of 4-(4-amino-2-fluorophenoxy)pyridin-2-amine (Compound B of Example 24, 0.022 g, 0.100 mmol, 1.0 eq), 2-fluoro-5-methyl benzoic acid (Aldrich, 0.015 g, 0.100 mmol, 1.0 eq), EDCI (0.021 g, 0.11 mmol, 1.1 eq) and HOBT (0.014 g, 0.100 mmol, 1.0 eq) in DMF (0.700 mL) at room temperature. The reaction mixture was stirred at room temperature for 8 h, quenched with saturated aqueous NaHCO3 solution and extracted with CHCl3 (3×10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC (YMC ODS-A S10 30×500 mm, 30-90% aqueous MeOH with 0.1% TFA, 30 minute gradient) and the appropriate fractions were concentrated in vacuo. The concentrate was neutralized with saturated aqueous NaHCO3 solution and the mixture extracted with CHCl3 (3×30 mL). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (0.014 g, 40%) as a solid. 1H NMR (CD3OD) δ 7.67-7.80 (m, 2H), 7.36-7.45 (m, 3H), 7.03-7.14 (m, 2H), 6.14-6.16 (m, 1H), 5.89-5.90 (m, 1H), 2.29 (s, 3H); MS(ESI+) m/z 356 (M+H)+; HRMS(ESI+) calcd.: 356.1211, found: 356.1203.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:36][Si:37]([CH3:44])([CH3:43])[CH2:38][CH2:39][O:40][CH2:41]Cl>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH2:16][CH2:15][C:14](=[O:17])[CH:13]([CH2:41][O:40][CH2:39][CH2:38][Si:37]([CH3:44])([CH3:43])[CH3:36])[CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reactant: C[Si](C)(C)CCOCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCC1CC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexanone (WO 02/081435) (2.0 g, 5.2 mmol) in dry tetrahydrofuran (10 mL) was added dropwise to a cooled solution of 0.5 M lithium hexamethyldisilazide in tetrahydrofuran (11.4 mL) at −78° C. The mixture was stirred at this temperature for 2 hours before adding 2-(trimethylsilyl)ethoxymethyl chloride (1.4 mL, 7.8 mmol) and the solution allowed to warm to rt. over 16 hours. The reaction mixture was diluted with ethyl acetate (10 mL), washed with water (10 mL), and the organic phase separated, dried (MgSO4) and evaporated to dryness. The product was purified on silica eluting with [9:1] hexane-ethyl acetate to yield 1.2 g of the title compound. 1H NMR CDCl3 7.38 (4H, s), 7.24-7.16 (1H, m), 7.12-7.06 (1H, m), 6.97-6.87 (1H, m), 3.66 (1H, dd, J=9.7 and 3.0 Hz), 3.51-3.45 (3H, m), 3.17-3.15 (1H, m), 3.05-2.98 (1H, m), 2.56-2.49 (2H, m), 241-2.35 (2H, m), 2.23-2.17 (1H, m), 0.91-0.87 (2H, m) and 0.03 (9H, s).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@@H:22]3[C@@H:18]([CH2:19][NH:20][CH2:21]3)[C@@H:17]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C=O.[C:36]([O-])(=O)C.[Na+].[BH4-].[Na+]>CO.O>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@@H:22]3[C@@H:18]([CH2:19][N:20]([CH3:36])[CH2:21]3)[C@@H:17]2[C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CC[C@H]2CNC[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@@H](O[C@H]1CC[C@H]2CN(C)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 30 mg (0.063 mmol) of (3aR,4R,5S,7aR)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindole (Example 2) in ˜2 mL methanol was added ˜20 mg (excess) aq. formaldehyde and 40 mg sodium acetate. The resulting mixture was stirred at RT for 10 min then 20 mg of NaBH4 was added. The resulting mixture was stirred at RT for 1 hr then water was added. The methanol was evaporated under vacuum and residue extracted with ether (2×25 mL). The combined extracts were dried over drying agent, filtered and the solvent was evaporated under vacuum. The residue was purified by prep TLC eluting with EtOAc/MeOH (9/1) to give the title compound. 1H-NMR (CDCl3): δ: ppm. 7.68 (1H, s), 7.23 (2H, s), 7.02 (2H, m), 6.87 (2H, m), 4.45 (1H, m), 3.27 (1H, ), 2.78-2.65 (2H, m), 2.57 (2H, m), 2.45-2.30 (3H, m), 2.23-2.12 (2H, m), 1.98 (1H, m), 1.83-1.68 (2H, m), 1.30 (3H, 6.2) MS: (MH)+489.9.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][Cl:23].O>CN(C)C=O>[Cl:23][CH2:22][CH2:21][CH2:20][CH2:19][N:3]1[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:9])[F:10])=[N:7][C:2]1=[O:1]
Reactant: ClCCCCBr
Reactant: Oc1nccc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1nc(C(F)(F)F)ccn1CCCCCl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4.6 g (28.3 mmol) of 2-hydroxy-4-trifluoromethylpyrimidine were stirred in 60 ml of N,N-dimethylformamide (DMF) and 3.9 g (28.3 mmol) of K2CO3 at room temperature for 1 hour. Then 4.9 g (28.3 mmol) of 1-bromo-4-chlorobutane were added dropwise, and the reaction mixture was stirred at room temperature for 6 hours. Water was then added to the reaction mixture, and the aqueous mixture was extracted with diethyl ether. The aqueous phase was made alkaline by adding NaOH, and the aqueous phase was extracted with methylene chloride. The organic phase was then dried, the desiccant was removed by filtration, and the solvent was evaporated to dryness in vacuo; yield: 1.7 g.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:6][N:5]=[C:4]([S:16][CH3:17])[N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1>C(Cl)(Cl)Cl>[CH3:13][C:12]([NH:11][S:8]([C:7]1[C:2]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)=[N:3][C:4]([S:16][CH3:17])=[N:5][CH:6]=1)(=[O:10])=[O:9])([CH3:15])[CH3:14]
Reactant: CSc1ncc(S(=O)(=O)NC(C)(C)C)c(Cl)n1
Reactant: Cc1cccc(N)c1
Solvent: ClC(Cl)Cl
Product: CSc1ncc(S(=O)(=O)NC(C)(C)C)c(Nc2cccc(C)c2)n1
Temperature: 25 °C
Yield: 96.7 %

Procedure:
4-Chloro-N-(1,1-dimethylethyl)-2-(methylthio)-5-pyrimidinesulfonamide (1.45 g, 4.91 mmol) was dissolved in chloroform (15 mL). m-Toluidine (1.08 mL, 10.07 mmol, 2.05x) was added, and the mixture was refluxed for 90 minutes. The reaction was cooled to ambient temperature, the chloroform removed under reduced pressure, and the residue crystallized from ethanol and water to yield 1.74 g (4.75 mmoles, 97%) of pale yellow needles, m.p. 177.5°-178° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([O:10][CH3:11])[CH:3]=1.ClCCl.[CH2:15](N(CC)CC)[CH3:16]>C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.CCO>[CH:15]([C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([O:10][CH3:11])[CH:3]=1)=[CH2:16]
Reactant: COc1cc(Cl)ncc1C#N
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCO
Solvent: ClCCl
Product: C=Cc1cc(OC)c(C#N)cn1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A 20 mL microwave tube was charged with 6-chloro-4-methoxypyridine-3-carbonitrile (200.0 mg, 1.2 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (97.0 mg, 0.12 mmol), potassium vinyl trifluoroborate (318.0 mg, 2.37 mmol), and triethylamine (0.33 mL, 2.37 mmol), and EtOH (6 mL). The microwave tube was evacuated and filled with nitrogen (two times) and heated to 140° C. After 1 hour, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. The extracts were concentrated and chromatographed over a column of SiO2 (0-30% EtOAc/hexanes as eluent). Evaporation of the solvent yielded the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.CN(C=O)C.[Br:17][CH2:18][C:19](Br)=[O:20].[Cl-]>O1CCOCC1>[Br:17][CH2:18][C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)=[O:20]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=C(Br)CBr
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(NC(=O)CBr)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 4-aminophenylacetic acid (3.0 g, 19.8 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (4.00 g, 1.74 mL, 19.8 mmol) was added dropwise, keeping the internal temperature between 0° and 5° C. over a 1/2 h period. After the addition of the chloride was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water. The resulting precipitate was filtered, washed with water, add then dried in a vacuum dessicator overnight to afford 2.75 (51%) of the title compound as a pale yellow crystals, mp 168°-171° C.: 1H NMR (DMSO-d6) δ12.28 (bs, 1H), 10.36 (s, 1H), 7.50 (d, J=8.8, 2H), 7.20 (d, J=8.4, 2H), 4.02 (s, 2H), 3.51(s, 2H); 13C NMR (DMSO-d6) δ172.70, 164.65, 137.12, 130.45, 129.76, 119.12, 40.12, 30.40; MS (EI, m/z) 271 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])N.[OH:11]S(O)(=O)=O.NC(N)=O>O.[O-]S([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([OH:11])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(N)c(C)c1Cl
Agent: [Cu+2]
Agent: NC(N)=O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: Cc1ccc(O)c(C)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-chloro-2,4-dimethyl-aniline (0.47 g, 3.0 mmol), in a mixture of water (3 mL) and conc. H2SO4 (2 ml), a solution of Na2NO2 (0.22 g) in H2O (5 ml) was added dropwise at 0° C. The mixture was stirred 1 h at 0° C., than treated with urea (0.2 g), stirred for 10 min at 0° C. A solution of CuSO4 (1.0 g) in water (6 mL) was added and the mixture was stirred for 60 h at RT. The reaction mixture was extracted with CH2Cl2 (2×20 ml), extracts were dried over Na2SO4 and evaporated. The residue was separated on SiO2 (4.0 g) column, hexane-EtOAc (0 to 10%). Brown crystals, 45 mg (0.29 mmol, 10%).