Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=O.[OH-].[Na+].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1.[BH4-].[Na+]>C(O)C>[O:7]=[C:5]1[N:1]([CH2:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4]1
Reactant: N[C@H](CCC(=O)O)C(=O)O
Reactant: O=Cc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCC(=O)N1Cc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
D-glutamic acid (2.21 g, 15 mmol) was dissolved in 2N aqueous sodium hydroxide (15 ml, 30 mmol) at 0° C. and then treated with pyridine-3-carboxaldehyde (1.41 ml, 15 mmol) in ethanol (3 ml). The mixture was stirred at room temperature for 30 minutes and then cooled to 0° C. and treated portion-wise with sodium borohydride (0.189 g, 5 mmol). The mixture was allowed to warm to room temperature with stirring over 4 hrs then after washing with diethyl ether it was acidified to pH5-6 using concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with diethyl ether, and dried in vacuo. This material was then taken up in ethanol (50 ml) and refluxed overnight. Fine solids were removed by filtration and then concentration gave 5-oxo-1-(3-pyridinylmethyl)proline (2.04 g) as a white solid which was used without any further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.Cl.[CH3:24][NH:25][CH3:26].CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([N:25]([CH3:26])[CH3:24])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: CNC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
In an ice bath under N2-atmosphere, 3-nitro-5-trifluoromethyl-benzoic acid (Lancaster; 11.8 g, 50 mmol), CH2Cl2 (150 ml), 3 drops of DMF and oxalylchloride ( 7.0 ml, 81 mmol) are mixed and then stirred for 2.5 h at rt. The resulting solution is concentrated in vacuo. The residue is dissolved in CH2Cl2 (170 ml) and added dropwise to an ice cooled solution of dimethylamine hydrochloride (4.5 g, 55 mmol) and NEt3 (21 ml; 0.15 mol) in CH2Cl2 (100 ml). After stirring for 15 h at rt, the mixture is worked up as described in Stage 134.3, giving the title compound as an oil: MS: [M+1]+=263; 1H-NMR (CDCl3): 8.53 (s, 1H), 8.47 (s, 1H), 8.03 (s, 1H), 3.18 (s, 3H), 3.04 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:14])=[C:11]([N:26]2[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]2)[N:10]=[C:9]([S:33][CH3:34])[N:8]=1.ClC1C=CC=C(C(OO)=[O:48])C=1>C(Cl)Cl.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:14])=[C:11]([N:26]2[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]2)[N:10]=[C:9]([S:33]([CH3:34])=[O:48])[N:8]=1
Reactant: COc1ccc(CNc2nc(SC)nc(N3CCC(O)CC3)c2C(=O)OCCOCc2ccccc2)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CNc2nc(S(C)=O)nc(N3CCC(O)CC3)c2C(=O)OCCOCc2ccccc2)cc1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 4-(3-chloro-4-methoxybenzylamino)-5-(2-benzyloxyethoxycarbonyl)-6-(4-hydroxypiperidin-1-yl)-2-methylthiopyrimidine (prepared in the above (3)) 100 mg in methylene chloride 3 ml is added at room temperature a solution of m-chloroperbenzoic acid 79 mg in methylene chloride 2 ml, and the mixture is stirred for 30 minutes. The reaction mixture is diluted with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-(3-chloro-4-methoxybenzylamino)-5-(2-benzyloxyethoxycarbonyl)-6-(4-hydroxypiperidin-1-yl)-2-methylsulfinylpyrimidine.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[CH:11]1([C:14]2[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=2)[CH2:13][CH2:12]1.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:8][C:7]1[C:2]([NH:19][C:16]2[CH:15]=[C:14]([CH:11]3[CH2:13][CH2:12]3)[NH:18][N:17]=2)=[N:3][C:4]([Cl:10])=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Clc1cc(Cl)c(Nc2cc(C3CC3)[nH]n2)nc1Cl
Temperature: 25 °C
Yield: 12.8 %

Procedure:
A solution of 2,3,5,6-tetrachloropyridine (0.20 g, 0.9 mmol), 5-cyclopropyl-1H-pyrazol-3-amine (0.20 g, 1.8 mmol), and triethylamine (0.10 g, 1.4 mmol) in NMP (2 ml) was heated in a microwave at 200° C. for 30 min. The reaction was cooled to 25° C., quenched with water (10 ml), and extracted with MTBE (4×30 ml). The combined organic fractions were then dried, filtered, and concentrated. The resulting solid was purified by column chromatography (DCM-MeOH=50:1) to give the title compound (0.035 g, 12%). MS: Calcd.: 303. Found: [M+H]+ 303.
Reaction SMILES: [F:1][C@@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([O:33][CH2:34][CH2:35][O:36][CH3:37])[CH:30]=[C:29]([F:38])[C:28]=1[C:39]1[N:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[CH:41][C:40]=1[F:48]>>[NH2:9][C@H:8]1[C@@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:45](=[O:46])[C:43]2[CH:42]=[CH:41][C:40]([F:48])=[C:39]([C:28]3[C:29]([F:38])=[CH:30][C:31]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:32][C:27]=3[F:26])[N:44]=2)[CH2:6][CH2:7]1
Reactant: COCCOc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: COCCOc1cc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@@H](F)CO3)ccc2F)c(F)c1
Yield: 50 %

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3R,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 24), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 189 as a white solid (19 mg, 50%). 1H NMR (400 MHz, d6-DMSO) δ 10.45 (s, 1H), 8.26 (dd, J=8.6, 3.9 Hz, 1H), 8.19-8.09 (m, 1H), 7.95 (s, 1H), 7.03 (d, J=10.5 Hz, 2H), 4.95 (dd, J=8.3, 3.6 Hz, 1H), 4.69 (s, 1H), 4.57 (s, 1H), 4.24 (t, J=4.2 Hz, 2H), 3.98-3.78 (m, 2H), 3.73 (s, 3H), 3.70 (t, J=4.2 Hz, 2H), 3.30 (s, 3H), 3.15 (m, 1H), 2.20-2.11 (m, 1H), 1.89-1.72 (m, 2H), 1.72-1.62 (m, 1H), 1.59-1.50 (m, 1H). LCMS (ES+) m/z 538 (M+1).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.Cl.I[C:13]1[CH:14]=[C:15]([C:19]2([O:29][CH3:30])[CH2:23][CH2:22][N:21]([CH2:24][C:25]([F:28])([F:27])[F:26])[CH2:20]2)[CH:16]=[CH:17][CH:18]=1>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([S:1][C:13]2[CH:14]=[C:15]([C:19]3([O:29][CH3:30])[CH2:23][CH2:22][N:21]([CH2:24][C:25]([F:28])([F:27])[F:26])[CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: COC1(c2cccc(I)c2)CCN(CC(F)(F)F)C1
Reactant: CC(=O)c1ccc(S)cc1
Agent: Cl
Product: COC1(c2cccc(Sc3ccc(C(C)=O)cc3)c2)CCN(CC(F)(F)F)C1
Yield: 75 %

Procedure:
Using an analogous procedure to that described in Example 10, 4'-mercaptoacetophenone was reacted with 3-(3-iodophenyl)-3-methoxy-1-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride to give 3-[3-(4-acetylphenylthio)phenyl]-3-methoxy-1-(2,2,2-trifluoroethyl)pyrrolidine as a gum in 75% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([CH3:16])([CH3:15])[C:13]#[N:14])[C:6](=O)[C:5]12[O:22][CH2:21][CH2:20][CH2:19][O:18]1.N.C1COCC1>[Ni].CCO>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][N:14]=[C:6]3[C:5]3([O:18][CH2:19][CH2:20][CH2:21][O:22]3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)CN1C(=O)C2(OCCCO2)c2cc(Cl)ccc21
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CN=C2N(C1)c1ccc(Cl)cc1C21OCCCO1
Temperature: 135 °C

Procedure:
A mixture of 3-(5′-chloro-2′-oxospiro[1,3-dioxane-2,3′-indol]-1′(2′H)-yl)-2,2-dimethylpropanenitrile (0.81 g, 2.53 mmol ), and wet Raney Nickel (0.88 g), in 2M EtOH.NH3 (60 mL) and THF (10 mL) was hydrogenated in a Parr Hydrogenation Bottle (500 mL) at 56 lb/in2 H2 for 17 hr. The Raney Nickel was removed by filtration through Sulka Floc and the filtrate was poured into a steel pressure vessel and heated at 135° C. for 22 hr. The reaction mixture was cooled to room temperature and concentrated. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/CH3OH/NH4OH, (97/2/1) to give the title compound as an off white solid (0.68 g, 88% yield). Anal. Calc'd for C16H19ClN2O2: C, 62.64; H, 6.24; N, 9.13. Found: C, 62.59; H, 6.19; N, 9.04. NMR (300 Mz, DMSO-d6): consistent; IR: consistent MS: (ES+) m/z 307 [M+H], one Cl pattern observed; m.p.: 121-122° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@@H:5]([CH2:7][CH2:8]OS(C)(=O)=O)[CH2:4][O:3]1.[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C)C=O>[N:15]([CH2:8][CH2:7][C@H:5]1[CH2:4][O:3][C:2]([CH3:14])([CH3:1])[O:6]1)=[N+:16]=[N-:17]
Reactant: CC1(C)OC[C@H](CCOS(C)(=O)=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](CCN=[N+]=[N-])O1
Temperature: 25 °C
Reaction time: 70 h
Yield: 88.9 %

Procedure:
Step B To a solution of methanesulfonic acid 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl ester (31.7 g, 0.14 mol) in N,N-dimethylformamide (200 mL) was added NaN3 (46 g, 0.71 mol). The reaction mixture was stirred at room temperature for 70 h. Then the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine several times, dried over MgSO4, concentrated to give (S)-4-(2-azido-ethyl)-2,2-dimethyl-[1,3]dioxolane as a yellow oil (21.3 g, 88%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=[O:17])=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[CH2:34](O)[CH3:35]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([O:18][CH2:34][CH3:35])=[O:17])=[O:7])=[CH:32][CH:33]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCO
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)[C@@H]1CC(=NOC)CN1C(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method as outlined in Example 11, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and ethanol, the title compound was isolated as a mixture of two isomers in 87.2% purity by HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[C:17]=1[N+:24]([O-])=O)[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[C:17]=1[NH2:24])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(Oc3cc(F)cc(F)c3[N+](=O)[O-])cccc2[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(Oc3cc(F)cc(F)c3N)cccc2[nH]1
Reaction time: 2 h

Procedure:
154 (1.8 g, 4.87 mmol) is dissolved in 150 ml of ethyl acetate and, after addition of Pd—C (500 mg), the mixture is hydrogenated at room temperature for 2 hours. The mixture is filtrated over celite to remove the catalyst and evaporated.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH2:13][CH:12]3[CH:10]([CH2:11]3)[CH:9]2[C:14](O)=[O:15])=[CH:5][CH:4]=1.Cl.[NH2:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24].CCN=C=NCCCN(C)C.Cl>>[F:19][C:2]([F:1])([F:20])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH2:13][CH:12]3[CH:10]([CH2:11]3)[CH:9]2[C:14]([NH:22][C@H:23]([C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)[CH3:24])=[O:15])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)C1C2CC2CN1Cc1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)C2C3CC3CN2Cc2ccc(C(F)(F)F)cc2)cc1
Yield: 98.7 %

Procedure:
The title compound (D153) (85 mg) was prepared according to the general procedure for amides preparation (Method A) starting from 3-(4-(trifluoromethyl)benzyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (D110) (55 mg) and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (43.3 mg). (EDC.HCl: 1.05 eq; reaction time: 18 hrs; RT)
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=O)[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1(C)C=CC=CC=1.O>[C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[S:30])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: S=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Temperature: 25 °C
Yield: 68.7 %

Procedure:
Compound 12 (48.6 mg, 0.18 mmol) in toluene (2 mL) was treated with Lawesson's reagent (75 mg, 0.18 mmol) at room temperature. The solution was heated at reflux for 2 h, then allowed to cool to room temperature and diluted with water. The mixture was extracted with EtOAc (3×5 mL). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The crude product was crystallized (CH2Cl2/hexanes) to give the thioamide 34.4 mg (68%) as a yellow solid. mp 223-226° C. (dec.); 1H NMR (300 MHz, d6-DMSO) δ 3.10 (m, 2H), 3.50 (m, 2H), 7.23 (app t, 1H, J=7.8 Hz), 7.57 (m, 1H), 7.61 (m, 3H), 7.69 (m, 2H), 8.19 (d, 1H, J=7.6 Hz), 10.56 (br t, 1H), 11.68 (br s, 1H); HRMS (FAB, MH+) Calcd for C17H15N2S: 279.0956, Found: 279.0952; Anal. (C17H14N2S.0.25 H2O) C, H, N, S.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH:29]([OH:31])[CH3:30])[CH:26]=[CH:25][C:24]=1[O:32][CH3:33])[C:8](=[O:11])[O:9][CH3:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)C>[C:29]([C:27]1[CH:26]=[CH:25][C:24]([O:32][CH3:33])=[C:23]([C:14]2[CH:15]=[CH:16][C:17]([C:19]([F:21])([F:22])[F:20])=[CH:18][C:13]=2[CH2:12][N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:36]=[C:35]([C:37]([F:38])([F:40])[F:39])[CH:34]=2)[C:8](=[O:11])[O:9][CH3:10])[CH:28]=1)(=[O:31])[CH3:30]
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)O)ccc1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)=O)ccc1OC

Procedure:
Methyl [3,5-bis(trifluoromethyl)benzyl]{[5′-(1-hydroxyethyl)-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (Example 140, 29 mg, 0.048 mmol) was dissolved in methylene chloride, and Dess-Martin periodinane (31 mg, 0.072 mmol) was added. Once the reaction was complete, the solution was diluted in diethyl ether and washed sequentially with saturated sodium thiosulfate, saturated sodium bicarbonate and water. The aqueous extracts were combined and back extracted with diethyl ether then recombined with the previous organic layers. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The title compound was obtained by preparative thin layer chromatography using 2:3 EtOAc:hexane. 1HNMR (CDCl3, 600 MHz) δ 8.02 (d, J=7.8 Hz, 1H), 7.76 (d, J=2.4 Hz, 1H), 7.73 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.32-7.55 (m, 4H), 6.99 (m, 1H), 4.18-4.58 (m, 4H), 3.79 (s, 3H), 3.69-3.76 (m, 3H), 2.57 (s, 3H). LC-MS (M+1) 608.3 (4.19 min).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]2[CH2:25][C:24]([CH3:27])([CH3:26])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:28](O)=[O:29])[CH:22]=3)[NH:17]2)[CH:13]=[CH:14][CH:15]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]2[CH2:25][C:24]([CH3:27])([CH3:26])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:28]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:29])[CH:22]=3)[NH:17]2)[CH:13]=[CH:14][CH:15]=1
Reactant: COc1cccc(C2CC(C)(C)c3cc(C(=O)O)ccc3N2)c1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(C2CC(C)(C)c3cc(C(=O)NS(C)(=O)=O)ccc3N2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
To a suspension of methanesulfonamide (480 mg, 5.0 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (200 mg, 5.0 mmol). The resulting mixture was stirred at 25° C. for 1 h to afford Solution A36. A solution of 2-(3-methoxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (310 mg, 1.0 mmol) and 1,1′-carbonyldiimidazole (320 mg, 2.0 mmol) in N,N-dimethylformamide (5 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B36. Solution B36 was added to Solution A36 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[2-(3-methoxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (116 mg, 30%) as a white solid: MS (ESI) M+1=389.3.
Reaction SMILES: [OH:1][CH:2]([CH2:15][OH:16])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=1.[C:17](Cl)(=O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>ClCCl.N1C=CC=CC=1>[CH2:17]([O:1][CH:2]([CH2:15][O:16][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: OCC(O)C#Cc1ccc(-c2cccs2)s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCC(C#Cc1ccc(-c2cccs2)s1)OCCCCCCCCCCCCCCCCCC
Reaction time: 48 h

Procedure:
170 mg (0.68 mmole) of 5-(3,4-dihydroxy-1-butynyl)-2,2-bithiophene was dissolved in a mixture of 10 ml of dichloromethane and 0.2 ml of pyridine. 0.7 g of stearoyl chloride dissolved in 10 ml of dichloromethane was then dropped into the reaction mixture in ice bath. This reaction solution was stirred for 2 days. It was monitored by thin layer chromatography to determine if there were 3 products obtained, i.e. a mixture of 1 diester and 2 monoesters.
Reaction SMILES: [B:1](OCCCC)(OCCCC)[O:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:17]([C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:22]=1[OH:32])([CH3:20])([CH3:19])[CH3:18].[CH3:33][CH:34]1[CH:39]([CH3:40])[CH2:38][CH2:37][CH:36]([OH:41])[CH2:35]1>C(O)CCC>[B:1]([O:32][C:22]1[C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:26][C:25]([CH3:27])=[CH:24][C:23]=1[C:28]([CH3:31])([CH3:30])[CH3:29])([O:41][CH:36]1[CH2:37][CH2:38][CH:39]([CH3:40])[CH:34]([CH3:33])[CH2:35]1)[O:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC1CCC(O)CC1C
Solvent: CCCCO
Product: CCCCOB(Oc1c(C(C)(C)C)cc(C)cc1C(C)(C)C)OC1CCC(C)C(C)C1
Temperature: 280 °C

Procedure:
n-butyl 3,4-dimethylcyclohexyl 2,6-di-t-butyl-4-methylphenyl borate was prepared by successively transesterifying tri-n-butyl borate with 2,6-di-t-butyl-4-methylphenol and 3,4-dimethylcyclohexanol. Tri-n-butyl borate (1 mole) and 2,6-di-t-butyl-4-methylphenol (1 mole) were heated, with stirring, to a temperature of 280° C. and n-butanol collected as a distillate. After seven hours 0.81 moles had been collected and a total of 0.82 moles collected after ten hours. After cooling the reaction vessel and adding 1 mole of 3,4-dimethylcyclohexanol, the reaction mixture was again heated to 280° C. for six hours, after which time a further 0.9 moles of n-butanol had been collected. Volatile components were then removed under reduced pressure (90° C./0.1 mm) to leave a viscous golden yellow liquid as product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[S:17][C:18]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](S(C)=O)[N:22]=3)=[CH:19][CH:20]=2)(=[O:15])=[O:14])[C:8]1=[O:30])#[N:2].C(C1C=C(C=CC=1)CN1CC[C@H](NS(C2SC(C3C=CN=C(S(C)(=O)=O)N=3)=CC=2)(=O)=O)C1=O)#[N:35]>CCO>[C:1]([C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[S:17][C:18]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH2:35])[N:22]=3)=[CH:19][CH:20]=2)(=[O:15])=[O:14])[C:8]1=[O:30])#[N:2]
Reactant: CS(=O)(=O)c1nccc(-c2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)s2)n1
Reactant: CS(=O)c1nccc(-c2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)s2)n1
Solvent: CCO
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc(-c4ccnc(N)n4)s3)C2=O)c1
Temperature: 90 °C

Procedure:
A mixture of [5-(2-methylsulfinyl-pyrimidin-4-yl)-thiophene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide and [5-(2-methylsulfonyl-pyrimidin-4-yl)-thiophene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide (0.20 g, 0.39 mmol) is dissolved in 10 mL of EtOH and NH3 gas is bubbled through the solution for 5 minutes. The resulting mixture is heated at 90° C. for 3 hours in a stainless steel Parr high pressure reaction vessel. After this time, the solution is allowed to cool to room temperature and is concentrated in vacuo to give [5-(2-amino-pyrimidin-4-yl)-thiophene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide (0.20 g) as a crude product. FAB MS, [M+H]+ =455. The crude [5-(2-amino-pyrimidin-4-yl)-thiophene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide is converted to the title compound as described in EXAMPLE 1, Part F. The crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 60% CH3CN/H2O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.