Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH:7]([NH:23][C:24](=[O:31])[CH:25]([NH2:30])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH:33]([C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1)([CH3:35])[CH3:34]>>[C:1]([O:5][C:6](=[O:32])[C@@H:7]([NH:23][C:24](=[O:31])[C@@H:25]([NH:30][S:42]([C:39]1[CH:40]=[CH:41][C:36]([CH:33]([CH3:35])[CH3:34])=[CH:37][CH:38]=1)(=[O:44])=[O:43])[CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)CC(N)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)C[C@H](NS(=O)(=O)c1ccc(C(C)C)cc1)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Yield: 71 %

Procedure:
Using a procedure similar to that described in Example 36, the product from Example AI ([S-(R*,R*)]-2-{2-amino-4-methyl-pentanoylamino}-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (0.20 g, 0.45 mmol) and 4-isopropylphenylsulfonyl chloride (0.10 g, 0.45 mmol) were coupled to give the title compound as a white solid (0.20 g, 71%), mp=147-148° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH:14]1[CH2:22][CH:21]2[CH:17]([CH2:18][N:19]([C:23](=[O:34])[C@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])[CH3:25])[CH2:20]2)[C:16]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:42][CH3:43])([OH:35])[CH2:15]1.C(N(CC)CC)C>ClCCl>[CH3:43][O:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C@:16]1([OH:35])[CH2:15][C@H:14]([CH2:13][O:12][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:22][C@@H:21]2[C@H:17]1[CH2:18][N:19]([C:23](=[O:34])[C@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33])[CH3:25])[CH2:20]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1[C@H](C)C(=O)N1CC2CC(CO)CC(O)(c3ccccc3OC)C2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@@H](COS(=O)(=O)c3ccc(C)cc3)C[C@@](O)(c3ccccc3OC)[C@@H]2C1
Temperature: 20 °C
Reaction time: 48 h
Yield: 20.7 %

Procedure:
20.1 g of p-toluenesulphonyl chloride are added to a solution of 23.2 g of 6-hydroxymethyl-4-(2-methoxyphenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol (mixture of the 2 diastereoisomers, 3aR,4R,6S,7aS,S and 3aS,4S,6R,7aR,S) and 14.9 cm3 of triethylamine in 300 cm3 of dichloromethane. After stirring at 20° C. for 48 hours, the reaction mixture is washed with 150 cm3 of water, then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.06-0.20 mm, diameter 8.0 cm, height 45 cm), eluting under a pressure of 0.8 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50:50 by volume) and collecting fractions of 500 cm3. Fractions 14 to 17 are concentrated to dryness under reduced pressure. The residue obtained is subsequently chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 7.5 cm, height 60 cm), eluting under a pressure of 0.8 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (60:40 then 50:50 by volume) and collecting fractions of 500 cm3. Evaporation to dryness of fractions 22 to 26 gives 6.5 g of the (3aS,4S,6R,7aR)-4-(2-methoxyphenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]-6-tosyloxymethyl perhydroisoindol-4-ol diastereoisomer in the form of a thick white foam.
Reaction SMILES: [CH2:1]1[O:19][C:18]2[C:3](=[CH:4][C:5]3[C:11](=[O:12])[CH2:10][S:9][CH:8]([C:13]([O:15]C)=[O:14])[CH2:7][C:6]=3[CH:17]=2)[O:2]1.[OH-].[K+].O>CO>[CH2:1]1[O:19][C:18]2[C:3](=[CH:4][C:5]3[C:11](=[O:12])[CH2:10][S:9][CH:8]([C:13]([OH:15])=[O:14])[CH2:7][C:6]=3[CH:17]=2)[O:2]1
Reactant: COC(=O)C1Cc2cc3c(cc2C(=O)CS1)OCO3
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1CSC(C(=O)O)Cc2cc3c(cc21)OCO3
Temperature: 25 °C
Yield: 86.1 %

Procedure:
Methyl 7,8-methylenedioxy-5-oxo-1,2,4,5-tetrahydro-3-benzothiepine-2-carboxylate (16.5 g) was suspended in methanol (100 ml), to which 2N--KOH (100 ml) was added. After stirring for an hour at room temperature, the mixture was poured into water, acidified and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated to afford 7,8-methylenedioxy-5-oxo-1,2,4,5-tetrahydro-3-benzothiepine-2-carboxylic acid (13.5 g, 86%). Recrystallization from ethyl acetate gave colorless prisms.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[C:12]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:12]([CH:13]([C@@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19])[CH3:22]
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)[C@H](C[N+](=O)[O-])c1ccccc1
Reaction time: 24 h

Procedure:
To a solution (0.40 ml) of trans-β-nitrostyrene (29.8 mg, 0.20 mmol) and diethyl malonate (0.061 ml, 0.40 mmol) in toluene was added, as an asymmetric catalyst, (R,R)-trans-1-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(N,N-dimethylamino)cyclohexyl]thiourea (8.2 mg, 0.02 mmol) obtained in Example 1A at room temperature under an argon atmosphere. After 24 hr, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (elution solvent: n-hexane/diethyl ether) to give the title compound as colorless needle crystals (53.3 mg, yield 86%). The yield and optical purity are shown in Tables 1-3. melting point: 45-47° C. (n-hexane/diethyl ether)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.Cl.[C:20](Cl)(Cl)=[O:21]>ClC1C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([N:14]=[C:20]=[O:21])=[CH:15][CH:16]=2)=[N:7][CH:8]=1
Reactant: Nc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Clc1ccccc1
Product: O=C=Nc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
20.3 g (0.08 mol) of 4-(5-trifluoromethylpyrid-2-yloxy)aniline are dissolved in 200 ml of dry chlorobenzene. This solution is cooled to -20° C. and rapidly added a solution of 3.7 g of gaseous HCl in 80 ml of dry chlorobenzene. The resultant crystalline slurry is cooled to -30° C. and a strong flow of about 40 g of phosgene is introduced over 1 hour. The addition of phosgene is then discontinued and the reaction mixture is stirred for 1 hour at 20° C. and subsequently for 1 hour in an oil bath at 110° C. A clear solution forms which is then cooled in a stream of nitrogen and, with stirring, excess phosgene is expelled with nitrogen. First the chlorobenzene is distilled off under normal pressure and then the isocyanate is distilled off under a high vaccum. Boiling point 105°-107° C./0.03 mbar; yield>90%.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([CH3:47])([CH3:46])[O:39]C3CCCCO3)=[CH:29][CH:28]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C>S(=O)(=O)(O)O.C1COCC1.O>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([CH3:47])([OH:39])[CH3:46])=[CH:31][CH:32]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][OH:17]
Reactant: CC(C)(CCCCCc1ccc(C=Cc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)cc1)OC1CCCCO1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)CCCCCc1ccc(C=Cc2ccc(CO)c(CO)c2)cc1

Procedure:
In a manner similar to Example 25(d), by reacting 5 drops of concentrated sulphuric acid with 335 mg (0.49 mmol) of 2-[6-(4-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl]vinyl}phenyl)-1,1-dimethylhexyloxy]tetrahydropyran in 5 ml of THF and 5 ml of water, white crystals (m=94 mg; Y=52%) are obtained. m.p. 112-4° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][N:15](C(OC=C)=O)[CH2:14][C:13]=3[NH:12][C:11]3[CH2:25][O:26][CH2:27][C:28](=[O:29])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].[ClH:30]>C(O)C>[ClH:30].[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][NH:15][CH2:14][C:13]=3[NH:12][C:11]3[CH2:25][O:26][CH2:27][C:28](=[O:29])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C=COC(=O)N1CC(=O)C2=C(C1)NC1=C(C(=O)COC1)C2c1ccc(F)c(Br)c1
Agent: Cl
Solvent: CCO
Product: O=C1CNCC2=C1C(c1ccc(F)c(Br)c1)C1=C(COCC1=O)N2

Procedure:
A solution of Example 24B in ethanol (10 mL) was treated with 6N HCl (5 mL), refluxed for 3 hours and concentrated. Purification by flash chromatography over silica gel (10% methanol/ammonia saturated methylene chloride) provided the title compound (0.080 g) which was converted to the hydrochloride salt.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:29])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:18][N:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.C1(N[C:34](=[O:58])[C:35]2C=CC(C)=C(C3C=C4C(=CC=3)C(C3CCNCC3)=NN=C4)C=2)CC1>C(O)C>[C:34]([N:26]1[CH2:27][CH2:28][CH:23]([C:19]2[C:20]3[C:15](=[CH:14][C:13]([C:8]4[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=4[CH3:12])[C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:29])=[CH:22][CH:21]=3)[CH:16]=[N:17][N:18]=2)[CH2:24][CH2:25]1)(=[O:58])[CH3:35]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C3CCNCC3)nncc2c1
Solvent: CCO
Product: CC(=O)N1CCC(c2nncc3cc(-c4cc(C(=O)NC5CC5)ccc4C)ccc23)CC1
Temperature: 25 °C

Procedure:
A mixture of N-cyclopropyl-4-methyl-3-(1-(piperidin-4-yl)phthalazin-6-yl)benzamide N-cyclopropyl-4-methyl-3-(1-(piperidin-4-yl)phthalazin-6-yl)benzamide (29 μmol) in 2 mL ethanol was stirred at RT and treated with 2-trifluoromethylamine diacetate (142 μmol). The mixture was stirred at RT for 4 h, then purified directly by silica gel chromatography, eluting with 5% 2 M ammonia methanol/dichloromethane to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=2)[O:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH2:30][CH2:31][CH2:32]I>C1COCC1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:18])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:16]#[N:17])[CH2:32][CH2:31][CH2:30]3)=[CH:11][CH:10]=2)[O:5]1
Reactant: ICCCI
Reactant: CC1(C)OB(c2ccc(CC#N)cc2)OC1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(C3(C#N)CCC3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
To a solution of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (7.0 g, 29 mmol) in THF at 0° C. was added NaHMDS (1.0 M, 120 mL, 120 mmol). After stirring for 20 min 1,3-diiodopropane (26 g, 86 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0° C., quenched with MeOH (5.0 mL) and the residue was purified by column chromatography (silica, ethyl acetate/hexanes gradient) to afford the desired product (4.0 g, 47%) as a yellow oil: ESI MS m/z 286 [C17H22BNO2+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=O.[C:12]([O:16][C:17](=[O:40])[NH:18][C:19]1[N:28]([CH2:29][CH2:30][CH3:31])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=3)[CH:25]=2)[N:20]=1)([CH3:15])([CH3:14])[CH3:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CO>ClCCCl>[C:12]([O:16][C:17](=[O:40])[NH:18][C:19]1[N:28]([CH2:29][CH2:30][CH3:31])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][CH2:4][C:3]4[C:2]([CH3:1])=[CH:9][C:8]([CH3:10])=[CH:7][C:6]=4[CH3:11])[CH:34]=3)[CH:25]=2)[N:20]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: Cc1cc(C)c(C=O)c(C)c1
Reactant: CCCN1Cc2cc(Oc3cccc(N)c3)ccc2N=C1NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: CCCN1Cc2cc(Oc3cccc(NCc4c(C)cc(C)cc4C)c3)ccc2N=C1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2,4,6-Trimethyl-benzaldehyde (0.0005 mol) was added to a mixture of [6-(3-amino-phenoxy)-3-propyl-3,4-dihydro-quinazolin-2-yl]-carbamic acid tert-butyl ester (0.0005 mol) in DCE (3 mL) and the mixture was stirred for 5 min. at room temperature, and then NaBH(OAc)3 (0.0006 mol) was added and the reaction mixture was stirred overnight at room temperature. The excess NaBH(OAc)3 was decomposed with CH3OH, and the solvent was evaporated. The obtained residue was purified by Biotage column chromatography (eluent: 100% CH2Cl2). The purest product fractions were collected and then the solvent was evaporated and co-evaporated with toluene to yield the title compound as a residue.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11](I)=[CH:10][C:9]=1[N+:21]([O-:23])=[O:22])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[C:9]([N+:21]([O-:23])=[O:22])=[CH:10][C:11]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[F:25])=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1F
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(I)cc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from [4-iodo-2-nitro-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert.-butyl ester (Example B4) and 2-fluorophenylboronic acid according to the general procedure D. Obtained as a yellow solid (1.39 g).
Reaction SMILES: C([O-])(=O)C.[NH4+].[C:6]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH:13]([CH2:18][CH3:19])[CH2:12]1)([O:8][CH2:9][CH3:10])=[O:7].C([BH3-])#[N:21].[Na+]>CO>[NH2:21][CH:14]1[CH2:15][CH2:16][N:11]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:12][CH:13]1[CH2:18][CH3:19]
Reactant: CCOC(=O)N1CCC(=O)C(CC)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(N)C(CC)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ammonium acetate (33 g) was added to the stirred solution of 1-carbethoxy-3-ethyl-4-piperidinone (8.2 g, 41 mmol) in methanol (125 ml) and stirring was continued for 3 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (2.5 g, 39 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 6 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish crude 4-amino-1-carbethoxy-3-ethylpiperidine, which was used as such in the next step. 4-Amino-1-carbethoxy-3-ethylpiperidine was suspended in 5 M NaOH solution (36 ml), stirred at 120° C. for 120 hr, cooled, extracted with ethyl acetate, dried (Na2SO4) and concentrated to dryness to afford 4-amino-3-ethylpiperidine. Yield 3.1 g (59.6%), C7H16N2, m/z 129 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1C1CCN(C(=O)c2cnc3c(C(=O)O)cnn3c2NCc2ccccc2)CC1
Reactant: CS(N)(=O)=O
Product: COc1ccccc1C1CCN(C(=O)c2cnc3c(C(=O)NS(C)(=O)=O)cnn3c2NCc2ccccc2)CC1
Yield: 55.5 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(2-methoxyphenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.153 g, 0.317 mmol) obtained in step 5 and methanesulfonamide (0.175 g, 1.85 mmol), the title compound (0.099 g, 56%) was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>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>[C:10]1([C:2]2[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1cccnc1Cl
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: Cc1ccccc1
Product: N#Cc1cccnc1-c1ccccc1
Yield: 94.7 %

Procedure:
To a solution of 2-chloro-3-cyanopyridine (4.06 g, 29.3 mmol) in toluene (60 mL) was added phenylboronic acid (5.4 g, 43.9 mmol), potassium carbonate (6.1 g, 44.1 mmol) and tetrakis(triphenylphosphine)palladium (1.7 g, 1.5 mmol). The mixture was refluxed under nitrogen for 24 hours, then the solvent was removed under reduced pressure. The residue was purified on a silica gel column using 100% CH2Cl2 then 99:1 CH2Cl2:MeOH as mobile phase. Pure fractions were combined and dried in vacuo to yield the solid 2-phenyl-3 cyanopyridine (5.0 g, HPLC RT=2.98 min, method A; LC-MS m/z=181).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH2:25][CH2:26][CH2:27][CH3:28])[CH:5]=[CH:4][C:3]=1[C:29]1[NH:33][C:32](=[O:34])[O:31][N:30]=1.[Cu](C#N)[C:36]#[N:37]>N1C=CC=CC=1>[CH2:25]([C:11]1[N:12]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)[S:14][C:10]=1[CH2:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([C:29]2[NH:33][C:32](=[O:34])[O:31][N:30]=2)=[C:2]([CH:7]=1)[C:36]#[N:37])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2noc(=O)[nH]2)c(Br)c1
Reactant: N#C[Cu]C#N
Solvent: c1ccncc1
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2noc(=O)[nH]2)c(C#N)c1
Temperature: 21 °C
Yield: 10.5 %

Procedure:
To a solution of 100 mg of 3-{2-bromo-4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one in 4 ml of pyridine was added 29 mg of copper cyanide. The resulting mixture was stirred under microwave heating at 21° C. for 10 minutes, then concentrated under reduced pressure. The residue was taken into ethyl acetate, washed with a pH 9 aqueous solution of ammonia, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography on silica gel (dichloromethane 95/methanol 5) and precipitated from ethyl acetate/diisopropyl ether/pentane to give 9.5 mg of 5-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzonitrile
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1.C([Li])CCC.CCCCCC.CN([CH:31]=[O:32])C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[CH:10]=[C:9]([CH:31]=[O:32])[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2ccsc2n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-chloro-4-morpholinothieno[2,3-d]pyrimidine (1.75 g, 6.85 mmol) in dry THF (40 mL) at −78° C. was added a 2.5M solution of n-butyllithium (nBuLi) in hexane (3.3 mL, 1.2 eq.). After stirring for 1 h, dry DMF (796 μL, 1.5 eq.) was added. The reaction mixture was stirred for 1 h at −78° C. and then warmed slowly to room temperature. After a further 2 h at room temperature the reaction mixture was poured onto ice/water yielding a yellow precipitate. This was collected by filtration and air-dried to yield 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde (1.50 g) MS (Q1) 284 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:36][CH2:35][CH2:34][N:33]2C(OC(C)(C)C)=O)=[CH:28][CH:27]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[CH:15]=[N:14][C:13]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([CH:32]4[CH2:36][CH2:35][CH2:34][NH:33]4)=[CH:30][CH:31]=3)=[N:12][C:11]=2[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(N)cc1
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=c1c2cnc(Nc3ccc(C4CCCN4)cc3)nc2n2ccnc2n1-c1ccccc1Cl
Temperature: 35 °C
Reaction time: 8 h

Procedure:
A mixture of Example 1E (0.048 g, 0.133 mmol) and tert-butyl 2-(4-aminophenyl)pyrrolidine-1-carboxylate (0.056 g, 0.213 mmol) was heated in a capped vial at 130° C. for 30 minutes. The reaction mixture was treated with ethyl acetate and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was dissolved in CH2Cl2 (2 mL) and treated with trifluoroacetic acid (0.103 ml, 1.334 mmol). The mixture was stirred at 35° C. overnight, concentrated, and purified by HPLC (see protocol in Example 1F) to provide the title compound as a trifluoroacetic acid salt. 1H NMR (500 MHz, CD3OD) δ 2.36-2.19 (m, 3H), 2.57-2.47 (m, 1H), 3.53-3.41 (m, 2H), 4.69-4.62 (m, 1H), 7.08 (d, J=1.9 Hz, 1H), 7.62-7.51 (m, 5H), 7.72-7.66 (m, 1H), 7.88 (d, J=1.9 Hz, 1H), 7.97-7.92 (m, 2H), 9.19 (s, 1H). MS (ESI+) m/z 458.2 (M+H)+.
Reaction SMILES: [CH2:1]([C@:4]1([CH2:37][CH2:38][OH:39])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][N:26]([CH3:33])[S:27]([CH:30]2[CH2:32][CH2:31]2)(=[O:29])=[O:28])[C:5]1=[O:36])[CH:2]=[CH2:3].N1C=CN=C1.[CH3:45][CH:46]([Si:48](Cl)([CH:52]([CH3:54])[CH3:53])[CH:49]([CH3:51])[CH3:50])[CH3:47]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([C@:4]1([CH2:37][CH2:38][O:39][Si:48]([CH:52]([CH3:54])[CH3:53])([CH:49]([CH3:51])[CH3:50])[CH:46]([CH3:47])[CH3:45])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][N:26]([CH3:33])[S:27]([CH:30]2[CH2:32][CH2:31]2)(=[O:28])=[O:29])[C:5]1=[O:36])[CH:2]=[CH2:3]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: C=CC[C@]1(CCO)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=CC[C@]1(CCO[Si](C(C)C)(C(C)C)C(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O
Temperature: 25 °C

Procedure:
To a solution of 2.52 g (4.25 mmol) N—((S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-hydroxyethyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide (Example 408, Step D), DMAP (0.026 g, 0.212 mmol), and imidazole (0.723 g, 10.61 mmol) in DCM (16.98 mL) at 0° C. was added slowly by syringe TIPS-Cl (1.17 mL, 5.52 mmol). The reaction was stirred at ambient temperature, with addition of reagents until reaction was judged complete by LCMS and TLC. The reaction mixture was quenched by addition of 6 mL of MeOH, then extracted with DCM (70 mls×2). The combined organics were washed with water (30 mL), satd. aq.NH4Cl solution (20 mL), dried over Na2SO4, filtered and the filtrate was concentrated. Purification by chromatography on silica gel (eluent: 0 to 40% EtOAc/DCM, gradient elution) provided the title compound as a clear, colorless oil. Mass Spectrum (ESI) m/z=749.4 (M+1).