Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[NH:16]1[CH2:19][CH:18]([CH:20]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:17]1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:16]2[CH2:19][C:18](=[C:20]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=3)[C:21]([O:23][CH3:24])=[O:22])[CH2:17]2)=[CH:4][CH:5]=1
Reactant: COC(=O)C(c1cc(F)cc(F)c1)C1CNC1
Reactant: Clc1ccc(C(Br)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C(=C1CN(C(c2ccccc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1

Procedure:
A solution of 0.280 g (1 mmol) of 1-[bromo(phenyl)methyl]4-chlorobenzene, 0.120 g (0.5 mmol) of methyl azetidin-3-yl(3,5-difluorophenyl)acetate (Example 22, Step 1) and 0.12 mL (0.7 mmol) of diisopropylethylamine in 10 mL of acetonitrile was heated at 40° C. for 18 h. The solution was concentrated and the residue was dissolved in 20 mL of ethyl acetate. This solution was washed with 10 mL water and the aqueous layer was washed with a second aliquot of 20 mL ethyl acetate. The organic extracts were washed with brine, combined, and concentrated. The residue was dissolved in acetonitrile and purified by reverse phase chromatography (Waters Xterra C18, 19 mm×50 mm) using a gradient of acetonitrile-water-triethylamine (30:70:1 to 60:40:1) to afford the title compound; 1NMR (CDCl3) δ 3.74 (s, 3H), 3.88 (m, 2H), 4.24 (m, 2H), 4.55 (s, 1H), 6.70-6.86 (m, 3H), 7.21-7.43 (m, 911); Mass Spectrum: m/e=440 (M+1 35Cl) and 442 (M+1 37Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[S:13][CH2:14][CH3:15].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:21](=[O:22])[O:23][CH2:24][CH3:25])=[CH:8][C:7]=1[S:13][CH2:14][CH3:15]
Reactant: CCOC(=O)Cl
Reactant: CCSc1cc(N)ccc1Oc1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Oc2ccc(Cl)c(Cl)c2)c(SCC)c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
4-(3,4-Dichlorophenoxy)-3-(ethylthio)benzenamine, (0.1 mole) and pyridine (50 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer and are cooled to about 5° C. Ethyl chloroformate (0.125 mole) is added, with stirring, at about 5° C. Stirring is continued for a period of about 30 minutes at about 5° C., then for an additional 16 hours at room temperature. The mixture is then washed in 2 portions of water (50 ml), dried and the solvent is then removed to yield the desired product ethyl [4-(3,4-dichlorophenoxy)-3-(ethylthio)phenyl]carbamate.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH2:10])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:13]=1[C:14](Cl)=[O:15].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:5]1[S:9][C:8]([NH:10][C:14](=[O:15])[C:13]2[CH:17]=[C:18]([C:21]([F:22])([F:23])[F:24])[CH:19]=[CH:20][C:12]=2[F:11])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: CC(C)(C)c1nnc(N)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1nnc(NC(=O)c2cc(C(F)(F)F)ccc2F)s1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
To a solution of 5-tert-butyl-1,3,4-thiadiazol-2-amine (1.57 g, 10 mmol) and 2-fluoro-5-(trifluoromethyl)benzoyl chloride (2.27 g, 10 mmol) in CH2Cl2 (45 mL) at 0° C. was added triethylamine (1.7 mL, 12 mmol) dropwise and the reaction mixture was allowed to warm to ambient temperature for 12 hours. The mixture was then washed with water, brine, dried with MgSO4, filtered, and concentrated under reduced pressure to afford 3.2 g of the title compound. MS (DCI/NH3) m/z 348 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH2:11][CH2:10][C:9]=2[CH:13]=1)=[O:4].[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([CH2:36][C:37]([O:39][CH3:40])=[O:38])=C(C(C3N=CC4CCCCC=4C=3)=O)[NH:21]2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([CH2:36][C:37]([O:39][CH3:40])=[O:38])=[C:2]([C:3]([C:5]3[CH:6]=[CH:7][C:8]4[O:12][CH2:11][CH2:10][C:9]=4[CH:13]=3)=[O:4])[NH:21]2)=[CH:17][CH:16]=1
Reactant: O=C(CBr)c1ccc2c(c1)CCO2
Reactant: COC(=O)Cc1c(C(=O)c2cc3c(cn2)CCCC3)[nH]c2cc(Cl)ccc12
Product: COC(=O)Cc1c(C(=O)c2ccc3c(c2)CCO3)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 5-bromoacetyl-2,3-dihydro-1-benzofuran* and methyl trans-4-chloro-2-[(Phenylsulfonyl)amino]cinnamate (Example 1, step 1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:32][C@:31]2([C:33](=[O:36])CO)[C@@H:10]([CH2:11][C@H:12]3[C@H:25]4[C@@:16]([F:29])([C@:17]5([CH3:28])[C:22]([C@@H:23]([F:26])[CH2:24]4)=[CH:21][C:20](=[O:27])[CH:19]=[CH:18]5)[C@@H:15]([OH:30])[CH2:14][C@@:13]32[CH3:37])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:38].[Na+]>C1COCC1.O>[CH2:1]([N:8]1[CH2:32][C@:31]2([C:33]([OH:36])=[O:38])[C@@H:10]([CH2:11][C@H:12]3[CH:25]4[C@@:16]([F:29])([C@:17]5([CH3:28])[C:22]([C@@H:23]([F:26])[CH2:24]4)=[CH:21][C:20](=[O:27])[CH:19]=[CH:18]5)[C@@H:15]([OH:30])[CH2:14][C@@:13]32[CH3:37])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@H]1[C@@H]3C[C@H]4CN(Cc5ccccc5)C[C@@]4(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12C=CC(=O)C=C1[C@@H](F)CC1[C@@H]3C[C@H]4CN(Cc5ccccc5)C[C@@]4(C(=O)O)[C@@]3(C)C[C@H](O)[C@@]12F
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.5 %

Procedure:
A mixture of compound 8 (460 mg, 0.899 mmol) and NaOH 6N (1350 μl, 11.10 mmol) in THF (20 ml) and water (10 ml) is stirred at RT for 3 days. Water is added and the organic solvent is evaporated. The basic aqueous solution (pH 12) is washed with AcOEt. The aqueous phase is then treated with HCl 6N until pH 6 when a solid precipitated. The solid is recovered by filtration and the aqueous phase is extracted with AcOEt, washed with brine, dried over Na2SO4 and then evaporated. The two fractions of obtained solid are combined and triturated with AcOEt (containing 2% MeOH) to give the title compound (150 mg, 0.301 mmol, 33.5% yield).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[O:12])[CH2:16][CH2:15]1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2ccc3[nH]cnc3c2)CC1
Yield: 62.2 %

Procedure:
In a procedure analogous to example 20, reaction of benzimidazole-5-carboxylic acid (400 mg, 2.50 mmol) and N-methylpiperazine (550 mg, 5.0 mmol) furnished the product (380 mg, 63%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].CN(CCN(C)C)C.[Li]CCCC.[I:27]I>C1COCC1>[I:27][C:3]1[C:2]([NH:7][C:8](=[O:13])[C:9]([CH3:10])([CH3:12])[CH3:11])=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ncccc1I
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
N-(pyridin-2-yl)pivalamide (14.25 g, 80 mmole) and TMEDA (29.80 ml, 200 mmole) were dissolved in THF (400 ml) under nitrogen and n-BuLi (125 ml, 200 mmole; 1.6 M solution in n-hexane) was added dropwise at −75° C. The mixture was stirred for 15 minutes at −75° C. and then for 2 hours at −10° C. After renewed cooling to −75° C. a solution of iodine (50.76 g, 200 mmole) in THF (200 ml) was added dropwise and the reaction mixture was stirred for 2 hours. The mixture was heated to 0° C. and quenched with saturated aqueous sodium thiosulfate solution. The aqueous phase was extracted with DCM (2×150 ml) and the combined organic phases were dried over MgSO4. After filtering off the drying agent and removing the solvent on a rotary evaporator, the residue was purified by column chromatography (ether: cyclohexane=3:1) and N-(3-iodopyridin-2-yl)pivalamide (14.80 g, 61%) was thereby obtained.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[CH:10]([O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)([CH3:12])[CH3:11]>>[CH:10]1([O:13][C:14]2[CH:15]=[C:16]([C:2]3[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:11]1
Reactant: CC(C)Oc1cccc(B(O)O)c1
Reactant: Nc1ccc(Br)cc1F
Product: Nc1ccc(-c2cccc(OC3CC3)c2)cc1F
Yield: 18 %

Procedure:
The title compound (230 mg) was prepared from 4-bromo-2-fluoroaniline (1 g, 5.26 mmol) and 3-isopropoxyphenylboronic acid (1.8 g, 6.84 mmol) as a yellow liquid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21].C([O-])([O-])=O.[K+].[K+].[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=[CH2:31]>CC(C)=O.O>[CH3:34][O:33][C:29](=[O:32])[CH2:30][CH2:31][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21]
Reactant: C=CC(=O)OC
Reactant: Cc1c(CC(N)=O)c2cc(O)ccc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)CCOc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccccc1
Yield: 55 %

Procedure:
5-Hydrox-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide (550 mg, 1.3 mmol), 550 mg (4 mmol) of K2CO3 and 0.2 mL of methyl acrylate in 40 mL of acetone was heated to maintain reflux for 100 hours (additional methyl acrylate was added at various times). After cooling, the mixture was diluted with water, extracted with EtOAc, the EtOAc solution washed with saturated NaCl solution and dried (Na2SO4). After concentrating, the residue was chromatographed on silica (eluted with CH2Cl2→1% MeOH/CH2Cl2) and crystallized from CH2Cl2/ether to give 375 mg (55% yield) of 3-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]-propanic acid methyl ester, mp, 113-115° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:19][C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]=1.[CH3:20][O:21]C(Cl)Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[N:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[NH:19][C:11]=1[C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([O:9][CH3:10])=[C:6]([CH:5]=1)[CH:20]=[O:21]
Reactant: COc1ccc(-c2nc3cccnc3[nH]2)c(OC)c1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(OC)c(-c2nc3cccnc3[nH]2)cc1C=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
Ex-76B: To a suspension of 2-(2,4-dimethoxy-phenyl)-3H-imidazo[4,5-b]pyridine (0.44 g, 1.7 mmol) in 20 ml of CH2Cl2, 1,1-dichlorodimethyl ether (0.55 g, 4.8 mmol) was added. The mixture was cooled to 0° C. with a water-ice bath, and 7 ml (7 mmol) of TiCl4 (1.0 m in CH2Cl2) was added dropwise. The mixture was stirred at 0° C. for 2 hrs, then room temperature for overnight. The reaction mixture was poured into ice-water and the precipitate was filtered to give 0.31 g (63%) of 5-(3H-imidazo[4,5-b]pyridin-2-yl)-2,4-dimethoxy-benzaldehyde as a white solid. 1H-NMR (DMSO-d6) δ 10.22 (s, 1H), 8.67 (s, 1H), 8.56 (d, J=5 Hz, 1H), 8.44 (d, J=8 Hz, 1H), 7.57–7.61 (m, 1H), 6.97 (s, 1H), 4.19 (s, 3H), 4.06 (s, 3H). HMRS (EI) calc. for C15H13N3O3: 283.0957; found: 283.0952.
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](=[O:6])[CH2:4][OH:5].CC(C)([O-])C.[K+].[F:19][C:20]([F:34])([F:33])[C:21]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24](Cl)[O:23][N:22]=1.C(Cl)Cl>C1COCC1>[CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](=[O:6])[CH2:4][O:5][C:24]1[O:23][N:22]=[C:21]([C:20]([F:34])([F:33])[F:19])[C:25]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: FC(F)(F)c1noc(Cl)c1-c1ccccc1
Reactant: CN(C(=O)CO)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C(=O)COc1onc(C(F)(F)F)c1-c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
0.99 g (6.0 mmole) of N-methyl-N-phenyl-2-hydroxyacetamide was dissolved in THF (6 ml) and the solution was mixed with 0.75 g (6.0 mmole) of 90% potassium t-butoxide with ice cooling. The mixture was stirred for 30 minutes and then 1.24 g (5.0 mmole) of 3-trifluoromethyl-4-phenyl-5-chloroisoxazole was added dropwise to the mixture. After being stirred for 30 minutes, the mixture was refluxed for 24 hours. After cooling the reaction mixture, 60 ml of methylene chloride was added and the mixture was washed with a 5% solution of HCl and water. The methylene chloride phase was evaporated under reduced pressure and the residue was purified by chromatography on silica gel to give 1.15 g of colorless crystals. These were recrystallized from n-hexane to give 950 mg of the titled compound, yield 50.5%, m.p. 93.0°-94.0° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]2)=[CH:4][CH:3]=1.O.[H][H]>C(O)C.[Ru]>[OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[CH2:9][C:10]([CH3:17])([CH3:16])[NH:11][C:12]([CH3:15])([CH3:14])[CH2:13]2)[CH2:4][CH2:3]1
Reactant: CC1(C)CC(c2ccc(O)cc2)CC(C)(C)N1
Reactant: [H][H]
Agent: [Ru]
Solvent: CCO
Solvent: O
Product: CC1(C)CC(C2CCC(O)CC2)CC(C)(C)N1

Procedure:
10 parts of 4-(4'-hydroxyphenyl)-2,2,6,6-tetramethylpiperidine were dissolved in 150 parts of ethanol and treated with 30 parts of water, the mixture being warmed to maintain solution. The solution was then hydrogenated using 3 parts of ruthenium on carbon (5%) catalyst at 125° C and 100 atmospheres of hydrogen. The catalyst was separated and the solvent evaporated under reduced pressure. The residue was dissolved in chloroform, dried with magnesium sulphate and evaporated under reduced pressure. The residue was crystallised from petroleum (b.p. 80°-100° C) to yield the desired product melting at 145°-150° C and having the following elemental analysis.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[CH3:18].Br[CH2:20][CH2:21][CH3:22].[H-].[Na+]>>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([CH2:20][CH2:21][CH3:22])[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[CH3:18]
Reactant: Cc1cc2ccccc2n1Nc1ccncc1F
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCN(c1ccncc1F)n1c(C)cc2ccccc21

Procedure:
The title compound was prepared from N-(3-fluoro-4-pyridinyl)-2-methyl-1H-indol-1-amine and 1-bromo-propane with the aid of sodium hydride in substantially the same manner as in Example 20, m.p. 5° C.
Reaction SMILES: [OH:1][CH:2]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[CH3:26])[C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][C:4]=1[CH3:14].[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][C@@H:38]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:39](Cl)=[O:40])(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClC(Cl)C.N1C=CC=CC=1>[N:9]1([C:7]2[CH:6]=[CH:5][C:4]([CH3:14])=[C:3]([CH:8]=2)[CH:2]([C:15]2[C:16]([CH3:26])=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][C:24]=2[CH3:25])[O:1][C:39](=[O:40])[C@@H:38]([NH:37][S:34]([C:31]2[CH:30]=[CH:29][C:28]([CH3:27])=[CH:33][CH:32]=2)(=[O:36])=[O:35])[CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: COC(=O)c1cc(C)c(C(O)c2cc(-n3ccnc3)ccc2C)c(C)c1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: COC(=O)c1cc(C)c(C(OC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2ccc(C)cc2)c2cc(-n3ccnc3)ccc2C)c(C)c1
Yield: 100.5 %

Procedure:
Methyl (±)-4-[α-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoate (46 g) was suspended in dichloroethane (550 ml) and pyridine (15.8 ml), and a solution of (S)-2-(4-methylbenzenesulfonylamino)-3-phenylpropionyl chloride (53.2 g) in dichloroethane (125 ml) was added dropwise to the suspension over 10 minutes with stirring under ice-cooling. The mixture was stirred at room temperature for 4 hours, and the reaction mixture was washed successively with water, 5% citric acid, 5% potassium carbonate and water. The organic layer was separated and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 86 g of methyl (±)-4-[5-(1-imidazolyl)-2-methyl-α-{(S)-2-(4-methylbenzenesulfonylamino)-3-phenylpropionyloxy}-benzyl]-3,5-dimethylbenzoate as a pale-yellow oil. This was crystallized from ethyl acetate (150 mil) and isopropyl ether (600 ml) and the obtained crystals were recrystallized from ethyl acetate (75 ml) and isopropyl ether (150 ml) to give 29.8 g of methyl (S)-4-[5-(1-imidazolyl)-2-methyl-α-{(S)-2-(4-methylbenzenesulfonylamino)-3-phenylpropionyloxy}benzyl]-3,5-dimethylbenzoate as white crystals, melting point 111-112° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:23]=[CH:22][C:13]([O:14][CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=1.OO.S(=O)(O)[O-:29].[Na+]>S(=O)(=O)(O)O.C(O)(=O)C>[F:25][C:2]([F:24])([F:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C:10]1[CH:23]=[CH:22][C:13]([O:14][CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=1)=[O:29]
Reactant: O=S([O-])O
Reactant: CCOC(=O)C(C)Oc1ccc(Sc2ccccc2C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(C)Oc1ccc(S(=O)c2ccccc2C(F)(F)F)cc1

Procedure:
To a stirred solution containing 7.4 g. (0.020 mole) of ethyl 2-[4-(2-trifluoromethylphenylthio)phenoxy]propionate and a catalytic amount of sulfuric acid (3 drops) in 50 ml of glacial acetic acid is added a solution containing 2.23 g. (0.021 mole) of 32% hydrogen peroxide in 10 ml. of glacial acetic acid over a period of several minutes at 25°. The resultant solution is stirred for 24 hours under ambient conditions, at which time the reaction is essentially complete. After the reaction mixture is treated with sodium bisulfite to destroy any excess peroxide the solvent is removed in vacuo at 40° and the residue taken-up in ether. The ethereal solution is washed with a 5% potassium carbonate solution until basic, water until neutral, a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo to give 6.85 g. of material. The last traces of solvent are removed by exposure to high vacuum (0.1 mm) at 70° to afford ethyl 2-[4-(2-trifluoromethylphenylsulfinyl)phenoxy]propionate.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[N-:8]=[N+:9]=[N-:10].[Na+]>C(O)(=O)C.O>[N:8]([C:2]([CH3:7])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])=[N+:9]=[N-:10]
Reactant: CC(C)=CC(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(CC(=O)O)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3,3-dimethylacrylic acid (20 g, 0.2 mol) in glacial acetic acid (50 mL) was added a solution of sodium azide (52 g, 0.8 mol) in water (100 mL) in one portion. The clear yellow solution was stirred for 1 hour at room temperature and then heated in an oil bath at 95° C. for 2 days. Water (50 mL) was added to the cooled orange solution. This solution was poured into a separatory funnel and extracted with ether (5×200 mL). The combined organic extracts were dried over anhydrous MgSO4 and concentrated to an orange oil. This oil was used without further purification. 1H NMR (CDCl3, 400 MHz): δ 1.44 (s, 6H), 2.55 (s, 2H), 11.80 (bs, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][C:8](=[O:23])[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:10]=1)[CH3:2].[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][C:8](=[O:23])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][Br:25])=[C:11]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)CCCC(=O)c1ccc(O)c(CCC(=O)OCC)c1
Reactant: BrCCCCCBr
Product: CCOC(=O)CCCC(=O)c1ccc(OCCCCCBr)c(CCC(=O)OCC)c1
Yield: 85.7 %

Procedure:
Starting with 0.332 g (0.99 mmol) of 3-(3-ethoxy-3-oxopropyl)-4-hydroxy-δ-oxobenzenepentanoic acid ethyl ester, and 1.16 g (5.04 mmol) of 1,5-dibromopentane, the title compound was obtained in 85.7% yield as a white solid, mp 48°-49° C., using the procedure of example 21.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([N:13]([CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[C:14]([C@@H:16]2[CH2:20][CH2:19][CH2:18][O:17]2)=[O:15])[CH2:10][C@H:9]1[C:29]([NH:31][CH2:32][CH3:33])=[O:30])(OC(C)(C)C)=O>C(Cl)Cl>[CH3:28][C:24]1([CH3:27])[CH2:25][CH2:26][CH:21]([N:13]([C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][O:17]2)=[O:15])[C@@H:11]2[CH2:12][NH:8][C@H:9]([C:29]([NH:31][CH2:32][CH3:33])=[O:30])[CH2:10]2)[CH2:22][CH2:23]1
Reactant: CCNC(=O)[C@@H]1C[C@H](N(C(=O)[C@@H]2CCCO2)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CCNC(=O)[C@@H]1C[C@H](N(C(=O)C2CCCO2)C2CCC(C)(C)CC2)CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 1-BOC-(2S,4S)-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-2-[(ethylamino)carbonyl)pyrrolidine (0.95 g, 2.0 mmol) prepared in Step A in DCM (1□) was added dropwise 4M HCl (1□). The reaction mixture was stirred at rt for 1 h, and concentrated in vacuo. The residue was concentrated in vacuo to give the title compound (730 mg, 99.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[N:6][CH:7]=1.Cl.[NH2:15][C@@H:16]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:17]([N:19]1[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20]1)=[O:18].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][C@H:16]([NH:15][C:11]([C:9]2[NH:8][C:5]3=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])[C:17]([N:19]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]2)=[O:18])=[CH:27][CH:28]=1
Reactant: O=C(O)c1cc2cc(Cl)cnc2[nH]1
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)N1CC[C@H](O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)C1)c1cc2cc(Cl)cnc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Preparation 57, 34 mg, 0.17 mmol) in DMF (5 mL) was added 2-(S)-amino-3-(4-fluorophenyl)-1-(3-(S)-hydroxypyrrolidin-1-yl)propan-1-one hydrochloride (Preparation 103, 50 mg, 0.17 mmol), HOBt (23 mg, 0.17 mmol) and DIPEA (94 μL, 0.54 mmol). After 5 min, EDCI (43 mg, 0.23 mmol) was added and the reaction stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (25 mL) and ethyl acetate (3×20 mL). The combined organic layer was washed with 2N sodium hydroxide solution (2×10 mL), brine (10 mL), dried (MgSO4) and concentrated in vacuo. Purification via chromatography on silica gel eluting with methanol:dichloromethane (7:93) gave the title compound. m/z (ES+)=431 [M+H]+; RT=3.49 min.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)#[CH:12].N>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:12]=2)=[CH:14][CH:15]=1
Reactant: ON=C(Cl)c1cccnc1
Reactant: C#Cc1ccc(F)cc1
Agent: N
Product: Fc1ccc(-c2cc(-c3cccnc3)no2)cc1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-ethynyl-4-fluorobenzene (Aldrich, 60 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.40-7.52 (m, 2H), 7.70-7.81 (m, 2H), 7.92-8.08 (m, 2H), 8.44 (dt, J=8.0, 1.9 Hz, 1H), 8.80 (d, J=4.4 Hz, 1H), 9.18 (s, 1H) ppm; MS (DCI/NH3) m/z 241 (M+H)+.