Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[C:30](Cl)[CH:29]=[CH:28]3)[C:20](=[O:36])[CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[K+].[OH-].[Na+]>C(Cl)Cl>[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[C:30]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:29]=[CH:28]3)[C:20](=[O:36])[CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1ccc2nc(Cl)ccc2c1
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1ccc2nc(Oc3ccccc3)ccc2c1
Temperature: 120 °C
Reaction time: 24 h
Yield: 91.9 %

Procedure:
A mixture of phenol (15.1 g, 160 mmol) and 4-(2-chloroquinolin-6-ylmethyl)-3-oxopiperazine-1-carboxylic acid benzyl ester (6.60 g, 16.1 mmol) is melted together at 70° C. until a homogeneous mixture is obtained. Potassium hydroxide (3.15 g, 56.1 mmol) is added and the resulting mixture is heated overnight at 120° C. After 24 hours, the brown/black residue is cooled to room temperature, diluted with CH2Cl2 and stirred with 1N NaOH (100 mL) for 30 minutes. The two layers are separated and the aqueous layer is extracted with CH2Cl2. The combined organic layers are washed with 1N NaOH, saturated NaCl, dried over Na2SO4, filtered and concentrated. The crude title compound (6.92 g, 14.8 mmol) is obtained as a beige foam and used in the subsequent step without further purification. 1H NMR (CDCl3, 300 MHz) δ8.07 (d, 1H), 7.76 (d, 1H), 7.63 (s, 1H), 7.50 (dd, 1H), 7.42 (m, 2H), 7.34 (m, 6H), 7.25 (m, 2), 7.09 (d, 1H), 5.14 (s, 2), 4.75 (s, 2H), 4.27 (s, 2H), 3.66 (m, 2H), 3.30 (bs, 2H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:14]=2[NH:13][C:12]([C:15](=[S:17])[NH2:16])=[CH:11]3)[CH2:3][CH2:2]1.Br[CH:27]([CH:30]=O)[CH:28]=[O:29].CN(C)C(=O)C>O>[CH:1]1([CH2:4][N:5]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:14]=2[NH:13][C:12]([C:15]2[S:17][C:27]([CH2:28][OH:29])=[CH:30][N:16]=2)=[CH:11]3)[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:20])[CH2:3][CH2:2]1
Reactant: NC(=S)c1cc2cccc(N(CC3CC3)S(=O)(=O)c3cccs3)c2[nH]1
Reactant: O=CC(Br)C=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=S(=O)(c1cccs1)N(CC1CC1)c1cccc2cc(-c3ncc(CO)s3)[nH]c12
Temperature: 90 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
A mixture of 7-[(cyclopropylmethyl)(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (225 mg), bromomalonaldehyde (182 mg) and N,N-dimethylacetamide (3 mL) was stirred at 90° C. for 1 hr. Water was added and the obtained precipitate was washed with water, and then with hexane. The solid was dissolved in a mixture of tetrahydrofuran (5 mL) and methanol (5 mL), and the mixture was cooled in an ice bath. Sodium borohydride (20 mg) was added and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated, and the residue was diluted with a mixture of tetrahydrofuran-ethyl acetate (1:1) and washed with saturated brine and aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtrated, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography and eluted with a mixture of ethyl acetate-hexane. The obtained solid was washed with a mixture of hexane-ether to give the title compound (100 mg, yield 50%) as crystals. melting point 174° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:65][S:66][C:67]1[CH:72]=[CH:71][C:70]([NH2:73])=[CH:69][CH:68]=1>C(Cl)Cl>[CH3:65][S:66][C:67]1[CH:72]=[CH:71][C:70]([NH:73][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:30])=[CH:69][CH:68]=1
Reactant: CSc1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (250 mg, 0.44 mmol) in methylene chloride (10 mL), HATU (Aldrich, 332 mg, 0.88 mmol) was added followed by the addition of DIPEA (0.230 mL, 1.31 mmol) and 4-amino-phenyl methyl sulfide (Aldrich, 122 mg, 0.88 mmol). The mixture was stirred at rt for 2 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (50 g column, eluent EtOAc/Hexanes, 5-10%) to give a white solid. 135 mg.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([S:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)=[O:17])=[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[S:13][C:12]=2[CH:31]=1.C(N(C(C)C)C(C)C)C>ClCCl>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([S:16]([C:15]2[C:11]3[CH:10]=[CH:9][C:8]([CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:31][C:12]=3[S:13][C:14]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:17])[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1sc2cc(CO)ccc2c1S(=O)c1cccc(OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1sc2cc(COS(C)(=O)=O)ccc2c1S(=O)c1cccc(OC)c1
Yield: 66.2 %

Procedure:
Methanesulfonyl chloride (0.043 ml, 0.55 mmol) was added to a stirred solution of ethyl 6-(hydroxymethyl)-3-[(3-methoxyphenyl)sulfinyl]benzo[b]thiophene-2-carboxylate (Preparation 17, 195 mg, 0.5 mmol) and N-ethyl-N,N-diisopropylamine (0.1 ml, 0.55 mmol) in dichloromethane (3 ml) at 0° C. After 3 hours the solution was washed twice with water, dried (magnesium sulfate), and the solvent removed under reduced pressure. The residue was crystallised from diethyl ether to give the title compound as a colourless solid (155 mg).
Reaction SMILES: C([O:8][C:9]1[CH:30]=[C:29]([Cl:31])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:27][CH2:26][C:25]4[C:21](=[CH:22][NH:23][N:24]=4)[CH2:20]3)[C:15]2=[O:28])=[C:11]([Cl:32])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:30]=[C:29]([Cl:31])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:27][CH2:26][C:25]4[C:21](=[CH:22][NH:23][N:24]=4)[CH2:20]3)[C:15]2=[O:28])=[C:11]([Cl:32])[CH:10]=1
Reactant: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1[C@H]1CCc2n[nH]cc2C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C1[C@H](Cc2c(Cl)cc(O)cc2Cl)CCN1[C@H]1CCc2n[nH]cc2C1
Reaction time: 6 h

Procedure:
Dissolve (3R,5S)-3-(4-Benzyloxy-2,6-dichloro-benzyl)-1-(4,5,6,7-tetrahydro-2H-indazol-5-yl)-pyrrolidin-2-one (Example 35) (8.79 g, 18.7 mmol) in absolute ethanol (60 mL), treat with 20% Pd(OH)2 (6.0 g) and stir at 30 psi hydrogen pressure. After 6 h, ESMS shows starting material consumed and product formed. Remove the catalyst by filtration, rinse with ethanol and evaporate to a dark foam. Filtration through 50 g SCX mega-bond elut using 95:5 CH2Cl2/MeOH followed by 95:5 CH2Cl2/7.0 M NH3/MeOH yields 5.6 g (79%) as an amorphous solid MS (m/z): 380 (M+1)
Reaction SMILES: OC(C(F)(F)F)=O.[OH:8][CH:9]1[CH2:13][NH:12][CH2:11][CH:10]1[NH:14][C:15]([CH:17]([NH:29][C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:31])[CH2:18][S:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:21])=[O:20])=[O:16].C([O-])(O)=O.[Na+].[C:43](Cl)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCOCC1>[C:43]([N:12]1[CH2:13][CH:9]([OH:8])[CH:10]([NH:14][C:15]([CH:17]([NH:29][C:30]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)=[O:31])[CH2:18][S:19]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)(=[O:21])=[O:20])=[O:16])[CH2:11]1)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(NC1CNCC1O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: O=C(NC1CN(C(=O)c2ccccc2)CC1O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
Morpholine-4-carboxylic acid [1-(4-hydroxy-pyrrolidin-3-ylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide TFA salt (215 mg, 0.39 mmol) was dissolved in 1,4-dioxane (20 mL). Saturated aqueous NaHCO3 solution (10 mL) was added followed by benzoyl chloride (0.2 mL, 1.72 mmol). The mixture was stirred at ambient temperature for 1 hour and then extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried with MgSO4 and evaporated under vacuum. The residue was purified by flash chromatography on silica gel (Eluent: 5% methanol in ethyl acetate to 20% methanol in ethyl acetate) to yield morpholine-4-carboxylic acid [1-(1-benzoyl-4-hydroxy-pyrrolidin-3-ylcarbamoyl)-2-phenylmethane-sulfonyl-ethyl]-amide (92mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[C:11]2[N:13]=[C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:15]=[CH:16][C:10]2=[N:9][CH:8]=1)(=O)=O.[Br-:29]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:29][C:7]1[N:12]=[C:11]2[N:13]=[C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:15]=[CH:16][C:10]2=[N:9][CH:8]=1
Reactant: COc1ccc(COc2ccc3ncc(OS(=O)(=O)C(F)(F)F)nc3n2)cc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(COc2ccc3ncc(Br)nc3n2)cc1
Temperature: 85 °C
Yield: 102.6 %

Procedure:
6-({[4-(Methyloxy)phenyl]methyl}oxy)pyrido[2,3-b]pyrazin-3-yl trifluoromethanesulfonate (1.39 g, 3.35 mmol) was dissolved in dry toluene (100 mL) under argon and tetrabutylammonium bromide (2.16 g, 6.7 mmol) was added. The reaction was heated at 85° C. for 4 h; 1.08 g of tetrabutylammonium bromide were added and the reaction was heated at 90° C. for another 6 h; 0.54 g of bromide were added and the reaction was heated for 3 h. The reaction was cooled to rt, the toluene was evaporated, the residue was partitioned between water (200 mL) and diethyl ether (400 mL). The layers were separated and the aqueous was extracted with diethyl ether (2×300 mL). The organic phases were combined and washed with water (300 mL) then dried and evaporated to afford the title compound (1.19 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N+:3]=1[O-:10].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][N+:3]=1[O-:10]
Reactant: C1CCNC1
Reactant: [O-][n+]1cc(CCl)ccc1Cl
Solvent: CC#N
Product: [O-][n+]1cc(CN2CCCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine 1-oxide (477 mg, 2.68 mmol; described in: Tilley, J. W. et al, J. Heterocyclic Chem. 1979, 16, 333) in acetonitrile (10 mL) was added pyrrolidine (381 mg, 5.36 mmol), and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in 2 M HCl(aq) and washed with ethyl acetate. The aqueous layer was alkalized to pH 8 with NaHCO3 (s), and the mixture was extracted four times with ethyl acetate. The combined organic layers were dried (Na2SO4), and the solvent was evaporated to give 0.43 g (75% yield) of the title compound as a red oil: 1H NMR (CDCl3, 400 MHz) δ 8.37 (d, J=1 Hz, 1 H), 7.44 (d, J=8 Hz, 1 H), 7.23 (dd, J=8, 2 Hz, 1 H), 3.57 (s, 2 H), 2.51 (m, 4 H), 1.80 (m, 4 H); 13C NMR (CDCl3, 100 MHz) δ 140.1, 139.9, 137.2, 126.4, 126.4, 56.4, 54.0, 23.5; MS (ES) m/z 213 (M++1).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)[CH:20]=1)=O)(C)(C)C.[ClH:30].CCOCC>CO>[ClH:30].[N:21]1([C:19]2[CH:18]=[N:17][CH:16]=[C:15]([O:14][CH2:13][C@@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)[CH:20]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CCc3ccccc32)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: c1ccc2c(c1)CCN2c1cncc(OC[C@@H]2CCCN2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[[N-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-(1-indolinyl)pyridine (71 mg, 0.18 mmol) in MeOH (0.2 mL) was added 2N anhydrous HCl/ether (1 mL) under Ar at room temperature. The mixture was stirred at room temperature overnight. After the solvent was evaporated, the residue was dissolved in deionized water. The aqueous solution was washed twice with EtOAc, then filtered over a cotton plug. The water was removed under reduced pressure at 35° C. After lyophilization from water, the hydrochloride (71 mg) was obtained as yellow solid. [α]20D+7.0 (c 1.0 g/L, MeOH). 1H NMR (D2O, 400 MHz) δ 7.97 (s, 1H), 7.83 (s, 1H), 7.41 (s, 1H), 7.12 (d, 1H, J=7.2 Hz), 7.05 (m, 2H), 6.82 (t, 1H, J=7.2 Hz), 4.45 (dd, 1H, J=3.2 Hz, J=10.4 Hz), 4.31 (dd, 1H, J=7.6 Hz, J=10.4 Hz), 4.15 (m, 1H), 3.78 (t, 2H, J=8.4 Hz), 3.45 (t, 2H, J=7.2 Hz), 3.01 (t, 2H, J=8.4 Hz), 2.32 (m, 1H), 2.14 (m, 2H), 1.97 (m, 1H). 13C NMR (D2O, 100 MHz) δ 156.2, 142.5, 141.9, 132.2, 126.7, 125.3, 121.9, 121.5, 118.2, 114.2, 109.6, 67.3, 58.1, 51.0, 45.6, 26.6, 25.5, 23.0. HRMS (ESI) calcd for C18H22N3O (M+H+) m/z 296.1763, found 296.1758. Anal. Calcd. for C18H21N3O.3.0HCl.0.1H2O: C, 53.18; H, 6.00; N, 10.34; Cl, 26.16. Found: C, 53.27; H, 6.18; N, 10.26; Cl, 26.03.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:15]2[CH2:17][CH2:16]2)[C@H:10]([CH2:18][N:19]([C:23](=[O:37])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[CH:25]=2)[CH:20]([CH3:22])[CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].C(N([CH2:44][CH3:45])CC)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:18][N:19]([C:23](=[O:37])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[CH:25]=2)[CH:20]([CH3:22])[CH3:21])[C@H:11]([CH2:13][N:14]([CH:15]2[CH2:16][CH2:17]2)[C:1](=[O:5])[CH2:2][C:45]2[CH:44]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC)CC
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C(C)C)ccc1C
Agent: [Cl-]
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)Cc2ccccc2)C2CC2)C(C)C)ccc1C

Procedure:
From (3R,4R)-3-({[4-methyl-3-(3-methoxy-propoxy)-benzoyl]-isopropyl-amino}-methyl)-4-cyclopropylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.3 g, 0.579 mmol), phenylacethyl chloride (0.092 mL, 0.695 mmol) and triethylamine (0.12 mL, 0.869 mmol) and purification by flash chromatography (c-hexane/AcOEt 1:1 to 0:1) to give the title compound as colorless oil. TLC, Rf (AcOEt/c-hexane 4:1)=0.15. MS (LC-MS): 610.3 [M+H]+; (LC-MS Waters Symmetry C18, 2.1×30 mm, 20-100% CH3CN/5 min): 4.63 min.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[OH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1.C1(C)C=CC(S(O[CH2:31][CH2:32][F:33])(=O)=O)=CC=1>C(OCC)(=O)C>[F:33][CH2:32][CH2:31][O:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCCF)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
Sodium hydride (55% oiliness, 140 mg, 3.2 mmols) was added to DMF (5 mL) solution of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (501.2 mg, 2.7 mmols) and stirred at room temperature for 30 minutes, followed by addition of 2-fluoroethyl p-toluenesulfonate (1.17 g, 5.4 mmols) and further 24 hours' stirring at the same temperature. Ethyl acetate was added to the reaction liquid which then was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was purified on silica gel column chromatography (KP-Sil Sil FLASH 25+M, ethyl acetate:hexane=1:10→2:8) to provide the title compound (253 mg, 41%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]=[CH:13][CH2:14]O.N1C(C)=CC(C)=CC=1C.[Cl-].[Li+].CS([Cl:31])(=O)=O.[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]=[CH:13][CH2:14][Cl:31]
Reactant: CS(=O)(=O)Cl
Reactant: OCC=Cc1ccc2ccccc2c1Br
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: ClCC=Cc1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.4 %

Procedure:
A solution of Example 3C (0.85 g, 3.24 mmol), collidine (0.94 mL, 7.13 mmol) and lithium chloride (0.21 g, 4.97 mmol) in DMF (10 mL) at 0° C. was treated with methanesulfonyl chloride (0.38 mL, 4.87 mmol), stirred 16 hours at room temperature, poured into aqueous ammonium chloride, and extracted with ethyl acetate. The ethyl acetate was washed with water, brine, dried (MgSO4), filtered, concentrated, and purified on silica gel with 3% ethyl acetate/hexanes to provide 0.35 g (38%) of the desired compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][CH2:4][Si:5]([Cl:8])([Cl:7])Cl.[CH3:15][CH:16]([CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:17][CH2:18][Mg]Br>O1CCCC1>[CH3:15][CH:16]([CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:17][CH2:18][Si:5]([CH2:4][CH2:3][CH:2]([CH3:1])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])([Cl:7])[Cl:8]
Reactant: CC(C)CCCC(C)CC[Si](Cl)(Cl)Cl
Reactant: CC(C)CCCC(C)CC[Mg]Br
Solvent: C1CCOC1
Product: CC(C)CCCC(C)CC[Si](Cl)(Cl)CCC(C)CCCC(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
Tetrahydrofuran (50 mL) and 3,7-dimethyloctyl trichlorosilane (11.27 g, 40.9 mmol) were placed in a 200 mL four-necked flask in a nitrogen atmosphere, and cooled to −20° C. 3,7-dimethyloctyl magnesium bromide (Sigma-Aldrich Co. LLC., 1.0 M, 42.9 ml) was added dropwise, and the mixture was agitated for 1 hour at 10° C. or less. The temperature was raised gradually to room temperature over the course of about 1 hour, and the mixture was left standing overnight. The precipitated salt was filtered out, the tetrahydrofuran was removed by concentration under reduced pressure, and the mixture was distilled under reduced pressure to obtain the target bis(3,7-dimethyloctyl)dichlorosilane (Compound E27) (150-152° C./0.6 Torr, 11.3 g, yield 73%).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:3])=[O:2].C(=O)(O)[O-].[Na+].I[CH2:18][CH3:19]>CN(C)C=O.O>[CH:6]([C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[C:1]([O:3][CH2:18][CH3:19])=[O:2])=[O:7]
Reactant: CCI
Reactant: O=Cc1ccccc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccccc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
2-Carboxybenzaldehyde (2.018g, 13.4 mmol, 1.0 eq.) was combined with sodium bicarbonate (2.258 g, 26.9 mmol, 2.0 eq.) and iodoethane (2.15 ml, 26.9 mmol, 2.0 eq.) in dimethylformamide (13.4 ml, 1M) and stirred at room temperature for 16 hours. The reaction was diluted with water (25 ml) and extracted with ether: hexane (1:1, 3X20 ml). The combined organic extracts were washed with aqueous 10% sodium bisulfite (1X25 ml), water (1X25 ml) and aqueous saturated sodium chloride (1X25 ml), dried over sodium sulfate, filtered through magnesium sulfate and concentrated. The residue was chromatographed on Merck silica gel (20 g) eluting with hexane: ether (14:1) to provide the title A compound (1.485 g).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:18][C:19](=[O:31])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([OH:29])=[C:24]([F:30])[CH:23]=1)C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:29][C:25]3[C:24]([F:30])=[CH:23][C:22]([CH2:21][CH2:20][C:19]([OH:31])=[O:18])=[CH:27][C:26]=3[F:28])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccnc1SC1CCCCC1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: O=C(O)CCc1cc(F)c(OCc2cccnc2SC2CCCCC2)c(F)c1
Yield: 76.3 %

Procedure:
3-Chloromethyl-2-cyclohexylsulfanyl-pyridine (0.074 mmol) obtained in Step C of Preparation Example 22 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (17.5 mg, 0.074 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (23 mg, 74%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])[CH2:8][CH:9]1[CH2:11]O1)([CH3:4])([CH3:3])[CH3:2].NC(N)=[S:22].O>CO>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])[CH2:8][CH:9]1[CH2:11][S:22]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(CC2CO2)cc(C(C)(C)C)c1O
Reactant: NC(N)=S
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(CC2CS2)cc(C(C)(C)C)c1O

Procedure:
A solution of 26.2 g [0.10 mol] of 3,5-di-tert.-butyl-4-hydroxybenzyl-oxirane [Example 1] and 8.4 g [0.11 mol] of thiourea in 100 ml of methanol is stirred for 12 hours at room temperature and subsequently poured into water. Extraction of the aqueous phase with chloroform, drying over sodium sulphate and evaporation of the solvent yields crude 3,5-di-tert.-butyl-4-hydroxybenzyl-thiirane, which after recrystallization from petroleum ether melts at 62°-63° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:28])[C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](OC)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([NH:35][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([CH3:29])=[CH:31][CH:32]=3)=[O:24])[N:17]=[CH:16]4)[C:10]([CH3:27])=[C:9]([F:28])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(CN)cc1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc21
Product: Cc1ccc(CNC(=O)Cn2ncc3cc(-c4cc(C(=O)NC5CC5)cc(F)c4C)ccc32)cc1

Procedure:
Example 133 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 123) and 4-methylbenzylamine to give the title compound (0.011 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1)[CH3:2].[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][CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc(-c2nc3ccccc3o2)cc1

Procedure:
To a solution of 7.1 gm. of 2-(4-ethylphenyl) benzoxazole in 125 cc. of carbon tetrachloride is added 6.2 gm. of N-bromosuccinimide and 50 mg. of benzoyl peroxide. The mixture is refluxed for about one half hour at which time the N-bromosuccinimide was consumed. Filtration followed by concentration of the filtrate gives 2-(4-[1-bromoethyl]phenyl)benzoxazole, m.p. 128°-131°C.