Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[C:12](Cl)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([C:12]2[O:11][C:5]3[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:4]=3[C:2](=[O:3])[CH:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)c1c(O)cccc1F
Reactant: O=C(Cl)c1ccccc1
Product: O=c1cc(-c2ccccc2)oc2cccc(F)c12

Procedure:
4 is prepared from 2-fluoro-6-hydroxyacetophenone (see Example 6) and benzoyl chloride by the procedure of Example 1. The material is purified by flash chromatography (eluting with 25% ethyl acetate in hexane), yielding 4 with a melting point of 144°-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH2:14][C:15]([OH:17])=[O:16])[CH:3]=1.S(=O)(=O)(O)O.[CH2:23](O)[CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH2:14][C:15]([O:17][CH2:23][CH3:24])=[O:16])[CH:3]=1
Reactant: CCO
Reactant: O=C(O)Cc1cc(Cl)ccc1-c1ccccc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(Cl)ccc1-c1ccccc1

Procedure:
A mixture composed of 900 mg (3.65 mmol) of (4-chlorobiphenyl-2-yl)acetic acid (J. Am. Chem. Soc. (1955), 77, 2325), 25 ml of absolute ethanol and 50 μl of concentrated sulfuric acid is refluxed for 8 hours. After cooling and concentrating under vacuum, the reaction medium is taken up in ether, washed with saturated NaHCO3 solution and then with water, and then dried over Na2SO4. After concentrating under vacuum, 1 g of a yellow oil is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:6]=[CH:5][C:4]=2[C:3]=1[NH2:21].C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C>[Br:29][C:9]1[C:8]2[N:7]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:6]=[CH:5][C:4]=2[C:3]([NH2:21])=[C:2]([CH3:1])[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N)c(C)ccc32)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N)c(C)cc(Br)c32)cc1
Temperature: 0 °C

Procedure:
To a solution of 5-methyl-1-tosyl-1H-indol-4-amine (Example 110-F) (1.06 g, 3.53 mmol) in DMF (35.3 mL) at 0° C. was added NBS (0.628 g, 3.53 mmol), and the mixture was stirred at 0° C. After 5 minutes the reaction was quenched with sat. aq. NaHCO3, then with sat. aq. sodium thiosulfate, extracted with EtOAc (2×), dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-80% EtOAc in heptanes) to provide the title compound, which was used in the next reaction without any further purification. MS (ESI+) m/z 379.0, 380.9 (M+H).
Reaction SMILES: O.O.[C:3]([OH:8])(=[O:7])[C:4]([OH:6])=[O:5].[Ti:9](Cl)(Cl)(Cl)Cl.[C:14]([OH:19])(=[O:18])[C:15]([OH:17])=[O:16].[OH-].[NH4+:21]>O>[C:3]([O-:8])(=[O:7])[C:4]([O-:6])=[O:5].[NH2:21][Ti+3:9].[C:14]([O-:19])(=[O:18])[C:15]([O-:17])=[O:16].[C:3]([O-:8])(=[O:7])[C:4]([O-:6])=[O:5].[NH2:21][Ti+3:9]
Reactant: Cl[Ti](Cl)(Cl)Cl
Reactant: [NH4+]
Reactant: O=C(O)C(=O)O
Agent: [OH-]
Solvent: O
Product: N[Ti+3]
Product: O=C([O-])C(=O)[O-]
Temperature: 7.5 °C
Reaction time: 0.5 h

Procedure:
Approximately 1,000 g of deionized water and oxalic acid dihydrate (381.9 g, 99% 3.0 moles), were charged to a 5-liter flask that was maintained under a nitrogen atmosphere. The resultant slurry was cooled to about 5 to 10 degrees C. and approximately 569.1 g (3.0 moles) of titanium tetrachloride were added dropwise over about 2 hours to the aqueous slurry containing oxalic acid. Deionized water, 1,082 g, was added rapidly over about 3 minutes to the slurry at temperatures from about 9 to 24 degrees C. The slurry was warmed to a temperature of about 30 degrees C. for about 10 minutes to provide a clear solution. Concentrated ammonium hydroxide solution was added dropwise over about 2 hours at a temperature from about 25 to 30 degrees C. to provide a white slurry with a pH of about 9.0. The slurry was stirred for about 30 minutes while the pH was maintained at about 9.0 by the addition of small amounts of ammonium hydroxide. The total amount of concentrated ammonium hydroxide (about 29.5% NH3) consumed was approximately 1,336 g (about 22.7 moles). The white slurry was filtered and the wet cake washed with six 645 ml displacement washes of 2% ammonium hydroxide solution. The wet cake, which weighed about 1,327.6 g, was dried in a vacuum oven at about 120 degrees C. to provide about 550.5 g of amino titanium oxalate. The dry amino titanium oxalate was shown by ignition at 750 degrees C. for 3 hours to remove the volatiles to have a titanium dioxide content of about 43.27%. This represents a 99% by wt. yield.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:6][C:7]=1[CH:8]=[O:9])[CH3:2].[CH:20]1([Mg]Br)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O1CCCC1>>[CH:20]1([CH:8]([C:7]2[CH:6]=[C:5]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][CH:11]=3)[O:4][C:3]=2[CH2:1][CH3:2])[OH:9])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Br[Mg]C1CCCCC1
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C=O
Solvent: C1CCOC1
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Yield: 76 %

Procedure:
An operation similar to that in Example 3 (2) was performed using 2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furaldehyde (1.21 g) and 1N cyclohexylmagnesium bromide-tetrahydrofuran solution (6.8 mL) to give the title compound (1.21 g, 76%) as a yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][NH2:20])=O)[N:12]=2)=[O:9])[CH:3]=1.[CH:21]1([NH2:24])[CH2:23][CH2:22]1.[C:25](O)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[N:24]([CH:21]4[CH2:23][CH2:22]4)[CH:25]=[N:20][N:19]=3)[N:12]=2)=[O:9])[CH:3]=1
Reactant: NC1CC1
Reactant: CC(=O)O
Reactant: NNC(=O)c1cccc(NC(=O)c2cc(Cl)ccn2)n1
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(-c2nncn2C2CC2)n1)c1cc(Cl)ccn1
Temperature: 150 °C
Yield: 72 %

Procedure:
To a suspension of 4-chloro-N-(6-(hydrazinecarbonyl)pyridin-2-yl)picolinamide (1.00 g, 3.43 mmol) in toluene (0.20 M) was added a mixture of N,N-dimethylformamide•N-dimethylacetamide (1.14 mL, 8.56 mmol), cyclopropylamine (873 μL, 13.7 mmol), and acetic acid (194 μL, 3.43 mmol). The reaction mixture was heated to 150° C. for 30 minutes in a microwave reactor. The reaction product was concentrated under reduced pressure, and the residue was suspended in acetonitrile/diethylether (1.5 mL, 1:1 ratio), filtered, and the solid washed with acetonitrile/diethylether (2×10 mL). The filtrate was concentrated and the solid thus obtained was purified as above. The combined solids were dried under reduced pressure to afford 842 mg (72% yield) of 4-chloro-N-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)picolinamide as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[N:8]=[O:9].C1N2CN3CN(C2)CN1C3.Cl.FC(F)(F)[C:24](O)=[O:25]>>[OH:10][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([N:8]=[O:9])=[CH:6][C:5]=1[CH:24]=[O:25]
Reactant: Cc1cc(O)ccc1N=O
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: Cc1cc(O)c(C=O)cc1N=O
Reaction time: 0.25 h

Procedure:
In a 500 mL recovery flask, 5.0 g (36.5 mmol) of 3-methyl-4-nitrosophenol (manufacture by Aldrich Inc.) and 7.63 g (54.7 mmol, 1.5 eq) of hexamethylenetetramine (manufactured by Tokyo Chemical Industry Co., Ltd.) were dissolved in 100 ml of trifluoroacetic acid (manufactured by Kanto Chemical Co., Inc.) and reacted at 95° C. for 10 hours. After the reaction was completed, in an ice bath, 200 ml of 1 N hydrochloric acid was added thereto and the resultant was stirred for 15 minutes. After the stirring, the resultant was extracted with chloroform to obtain an extract. The extract was washed with hydrochloric acid and unsaturated saline, thereby obtaining 1.51 g (9.13 mmol) of 2-hydroxy-4-methyl-5-nitroso-benzaldehyde.
Reaction SMILES: O=[O+][O-].[CH3:4][C@@H:5]([C@@H:13]1[C@@:17]2([CH3:32])[CH2:18][CH2:19][CH2:20]/[C:21](=[CH:22]\[CH:23]=[C:24]3\[CH2:25][C@@H:26]([OH:31])[CH2:27][CH2:28][C:29]\3=C)/[C@@H:16]2[CH2:15][CH2:14]1)/[CH:6]=[CH:7]/[C@@H](C(C)C)C.N1C=CC=CC=1.[BH4-].[Na+].[CH3:41][OH:42]>>[CH3:7][CH2:6][C@@H:5]([C@@H:13]1[C@@:17]2([CH3:32])[CH2:18][CH2:19][CH2:20]/[C:21](=[CH:22]\[CH:23]=[C:24]3[CH2:29][C@@H:41]([OH:42])[C:27](=[CH2:28])[C@H:26]([OH:31])[CH2:25]3)/[C@@H:16]2[CH2:15][CH2:14]1)[CH3:4]
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)/C=C/[C@H](C)C(C)C)CC[C@@H]12
Reactant: CO
Agent: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: C=C1[C@H](O)CC(=C/C=C2\CCC[C@]3(C)[C@@H]([C@@H](C)CC)CC[C@@H]23)C[C@H]1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
Ozone was passed through a solution of vitamin D2 (3 g, 7.6 mmol) in methanol (250 mL) and pyridine (2.44 g, 2.5 mL, 31 mmol) for 50 minutes at −78° C. The reaction mixture was then flushed with oxygen for 15 min to remove the residual ozone, and the solution was treated with NaBH4 (0.75 g, 20 mmol). After 20 minutes, the second portion of NaBH4 (0.75 g, 20 mmol) was added, and the mixture was allowed to warm to room temperature. The third portion of NaBH4 (0.75 g, 20 mmol) was then added and the reaction mixture was stirred for 18 hours. The reaction was quenched with water (40 mL), and the solution was concentrated under reduced pressure. The residue was extracted with ethyl acetate (3×80 mL), and the combined organic phases were washed with 1M aq. HCl, saturated aq. NaHCO3, dried (Na2SO4) and concentrated under reduced pressure. The residue was chromatographed on silica gel with hexane/ethyl acetate (75:25) to give (20S)-de-A,B-20-(hydroxymethyl)pregnan-8β-ol 1 (1.21 g, 75% yield) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:14])[C:7]=2[CH:6]=[CH:5][C:4]=1[O:15][CH3:16].C[O-:18].[Na+].C[O:21][CH3:22].[Na]>CO>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH:12]([C:22]([OH:21])=[O:18])[C:13](=[O:14])[C:7]=2[CH:6]=[CH:5][C:4]=1[O:15][CH3:16]
Reactant: COc1ccc2c(c1OC)CCCCC2=O
Reactant: COC
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1ccc2c(c1OC)CCCC(C(=O)O)C2=O

Procedure:
A mixture of 1,2-dimethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one [Itoh et al., Chem. Pharm. Bull., 26, 504 (1978)] (2.2 g), powdery sodium methoxide [prepared by subjecting a 28% methanol solution of sodium methyoxide (8.5 g) to evaporation to dryness under reduced pressure] and dimethyl carbonate (40 ml) is heated for 9 hours under reflux in a stream of nitrogen. After cooling and subsequent addition of water (100 ml) and ethyl acetate (200 ml), the mixture is made acid with hydrochloric acid and shaken thoroughly. The organic layer is separated and evaporated under reduced pressure to give methyl ester of 1,2-dimethoxy-5-oxo-6,7,8,9,-tetrahydro-5H-benzocycloheptene-6-carboxylic acid. This product is dissolved in a mixture of methylene chloride (50 ml) and methanol (50 ml). To the solution is added sodium borohydride (0.5 g), and the mixture is stirred for 30 minutes. After addition of water (200 ml), the reaction mixture is extracted with methylene chloride (100 ml). The organic layer is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give methyl ester of 1,2-dimethoxy-5-hydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylic acid (1.6 g) as a pale yellow oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1B(O)O.Br[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]2([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:24]1[CH:23]=[C:22]2[C:17](=[CH:16][CH:15]=1)[C:18]([CH3:28])([CH3:27])[CH2:19][CH2:20][C:21]2([CH3:26])[CH3:25]
Reactant: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Reactant: COc1cccc(OC)c1B(O)O
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: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COc1cccc(OC)c1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 103.5 %

Procedure:
A mixture of 2,6-dimethoxy-phenylboronic acid (1.0 g, 5.48 mmol), 6-bromo-1,1,4,4 tetramethy 1,2,3,4-tetrahydronaphthalene (0.73 g, 2.74 mmol) and potassium carbonate (1.50 g, 10.96 mmol) in 1,2-dimethoxyethane (20 mL) and water (1.0 mL) was degassed with argon for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.60 g, 0.54 mmol) was added and the mixture heated at reflux under argon for 5 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (eluent: ethyl acetate/hexane, 1:9) to give 0.92 g of 6-(2,6-Dimethoxyphenyl)-1,1,4,4-tetramethy-1,2,3,4-tetrahydronaphthlene.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:20][CH:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)[C:17]([OH:19])=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.[N+](=[CH:30][Si](C)(C)C)=[N-].CO>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:20][CH:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)[C:17]([O:19][CH3:30])=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:14][CH2:15]2)(=[O:12])=[O:11])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C1CCC(C[C@@H](C(=O)O)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)CC1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)[C@H](CC1CCC(=O)CC1)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-(4-oxocyclohexy)propanoic acid (45 mg), diazomethyltrimethylsilane (2.0 M diethyl ether solution, 0.1 mL), methanol (0.2 mL), and toluene (0.8 mL) was stirred at room temperature for 10 minutes. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50) to obtain methyl (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-(4-oxocyclohexyl)propanoate (29 mg) as a colorless oil.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[N:17]=[C:18]([N:31]2[CH2:36][CH2:35][CH:34]([CH:37]=O)[CH2:33][CH2:32]2)[C:19]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:23][S:22][C:20]=2[N:21]=1.[CH3:39][NH:40][CH:41]1[CH2:45][N:44]([CH3:46])[CH2:43][CH2:42]1.C(O)(=O)C>ClCCl.O>[Cl:15][C:16]1[N:17]=[C:18]([N:31]2[CH2:36][CH2:35][CH:34]([CH2:37][N:40]([CH3:39])[CH:41]3[CH2:42][CH2:43][N:44]([CH3:46])[CH2:45]3)[CH2:33][CH2:32]2)[C:19]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:23][S:22][C:20]=2[N:21]=1
Reactant: CNC1CCN(C)C1
Reactant: O=CC1CCN(c2nc(Cl)nc3scc(-c4ccccc4)c23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CN1CCC(N(C)CC2CCN(c3nc(Cl)nc4scc(-c5ccccc5)c34)CC2)C1
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (1.54 g, 7.28 mmol) was added to a stirred solution of 1-(2-chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)piperidine-4-carbaldehyde (1.3 g, 3.64 mmol), N,N′-dimethyl-3-aminopyrrolidine (519 ul, 4.00 mmol) and acetic acid (240 ul, 4.00 mmol) in dry dichloromethane (20 ml) at room temperature. The solution was stirred for ˜2 h, after which time the reaction had reached completion. Water (20 ml) was added and the organic layer separated, the aqueous phase was extracted with dichloromethane (×3) and the combined organics washed with brine, then dried (MgSO4) and evaporated. The crude residue was purified by flash column chromatography (0 to 5% 7.0M NH3/MeOH in dichloromethane). N—[[1-(2-chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-4-piperidyl]methyl]-N,1-dimethyl-pyrrolidin-3-amine was isolated as a pale yellow oil (1.25 g, 76%). LCMS: (M+H)+ 456.2, RT=2.99.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[N:19][N:18]=[C:17]2[CH2:21][N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[Cl:33]NC(=O)CCCCC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:17]([CH2:21][N:22]3[C:26](=[O:27])[C:25]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]4[C:23]3=[O:32])=[N:18][N:19]=[C:20]2[Cl:33])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CCCCCC(=O)NCl
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O
Product: O=C(c1ccccc1)c1cc(Cl)ccc1-n1c(Cl)nnc1CN1C(=O)c2ccccc2C1=O

Procedure:
Following the procedure of Example 1, 5-chloro-2-(3-phthalimidomethyl-4H-1,2,4-triazol-4-yl)benzophenone is reacted with N-chlorohexanoamide to form 5-chloro-2-(3-chloro-5-phthalimidomethyl-4H-1,2,4-triazol-4-yl)benzophenone.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=O)(C)(C)C.[CH2:20]([N:22]1[C:34]2[CH:33]=[CH:32][C:31]([NH2:35])=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH3:21]>>[CH2:15]([O:14][N:13]=[C:11]1[CH2:12][NH:8][C@H:9]([C:17]([NH:35][C:31]2[CH:32]=[CH:33][C:34]3[N:22]([CH2:20][CH3:21])[C:23]4[C:28]([C:29]=3[CH:30]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:19])[CH2:10]1)[CH3:16]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CCON=C1CN[C@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 91% purity by LC/MS. MS(ESI+): m/z=365.2.
Reaction SMILES: [SH:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][SH:8])=[O:4].[C:14](O)(=O)C>CCOCC.[N+](=C)=[N-]>[CH3:14][O:10][C:9](=[O:11])[C@H:6]([CH2:7][SH:8])[NH:5][C:3](=[O:4])[C:2]([SH:1])([CH3:13])[CH3:12]
Reactant: CC(=O)O
Reactant: CC(C)(S)C(=O)N[C@@H](CS)C(=O)O
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)[C@H](CS)NC(=O)C(C)(C)S
Yield: 94 %

Procedure:
To a solution of N-(2-mercapto-2-methylpropionyl)-L-cysteine (1.0 g) in ether(3 ml), diazomethane dissolved in ether(12 ml) was added dropwise under ice-cooling. After the addition, acetic acid was added to the reaction mixture. The reaction mixture was washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 1.0 g(94%) of the titled compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33]>C(O)C.O.Cl>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Yield: 64.3 %

Procedure:
A mixture of 1.0 g (0.0032 mole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-100) and 0.63 g (0.0038 mole) of 4-amino-3-methoxy-benzoic acid in 76 mL of ethanol-water-hydrochloric acid (20:80:1) was heated at reflux for 18 hours, then cooled and partially concentrated under reduced pressure. The resulting solid was collected by filtration, washed with water and dried to give 0.92 g of crude 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-100) which was used without further purification in subsequent steps.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:22]=[CH:21][C:20]([CH:23]([OH:27])[CH2:24][CH2:25][CH3:26])=[CH:19][C:16]=1[C:17]#[N:18].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[OH:27][CH:23]([C:20]1[CH:19]=[C:16]([C:17]#[N:18])[C:15]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[CH:22][CH:21]=1)[CH2:24][CH2:25][CH3:26]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCCC(O)c1ccc(Br)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCCC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(C#N)c1
Temperature: 140 °C
Yield: 83.2 %

Procedure:
A sealed flask was charged with the (4-(trifluoromethyl)phenyl)boronic acid (1.09 g, 5.76 mmol), 2-bromo-5-(1-hydroxybutyl)benzonitrile (1.33 g, 5.23 mmol) and acetonitrile (17 mL). Once everything get into solution, 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (115 mg, 157 μmol) was added followed by the sodium carbonate 2M aq. (6.54 mL, 13.1 mmol). Flask sealed and heated at 140° C. for 1 hour. Organic solvent removed under reduced pressure and ethyl acetate added. Organics washed with water (1×), with brine (1×), dried over sodium sulfate, filtered and concentrated to provide the crude material. Purification by silica gel flash chromatography (Ethyl Acetate/Heptane) provide the title compound as a colorless oil (1.39 g, 83.2%). 1H NMR (400 MHz, DMSO-d6) δ 0.87-0.93 (m, 3 H) 1.25-1.45 (m, 2 H) 1.57-1.67 (m, 2 H) 4.64-4.70 (m, 1 H) 5.41 (d, J=4.68 Hz, 1 H) 7.64 (d, J=8.00 Hz, 1 H) 7.75-7.79 (m, 1 H) 7.82 (d, J=8.00 Hz, 2 H) 7.88-7.94 (m, 3 H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[Br:12]Br.CCOC(C)=O.[O-]S([O-])=O.[Na+].[Na+]>O1CCOCC1>[Br:12][C:10]1[C:5]2[C:4]([Cl:11])=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[NH:8][CH:9]=1
Reactant: BrBr
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Clc1nc(Cl)c2c(Br)c[nH]c2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 935 mg 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (3a) (5.0 mmol) in 100 mL of 1,4-dioxane was slowly added 256 μL of Br2 (5.0 mmol) at 0° C. over a period of 10 minutes. After stirring for 30 minutes at 0° C., the reaction mixture was poured into a mixture of 150 mL of EtOAc and 150 mL of saturated aqueous Na2SO3 then filtered through celite. The aqueous phase was extracted with EtOAc (3×100 mL) and combined organic layers were washed with brine, concentrated and purified by flash column chromatography to give the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].[NH:13]1[CH2:17][CH2:16][NH:15][C:14]1=[S:18].[I:19]I.[I-].[K+]>CO.O>[IH:19].[NH:15]1[CH2:16][CH2:17][N:13]=[C:14]1[S:18][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: S=C1NCCN1
Reactant: II
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: I
Product: O=C(O)c1[nH]c2ccccc2c1SC1=NCCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3.2 g indole-2-carboxylic acid in 50 ml methanol and 2 g 2-imidazolidinethione in 100 ml methanol is added to a well-stirred solution of 3 g iodine and 25 g potassium iodide in 50 ml water. After being stirred for 2 hours at room temperature, the mixture is filtered to remove the product. The filtrate is concentrated and cooled to give further yield. The combined product is recrystallised from alcohol-ether to give 3-(2-imidazolin-2-ylthio)-indole-2-carboxylic acid hydriodide melting above 310°.