Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][C:12]([CH3:15])([OH:14])[C:11]([CH2:16][CH3:17])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:27][O:28][CH2:29]Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)(Cl)Cl>[Si:1]([O:8][CH:9]1[CH2:13][C:12]([CH3:15])([O:14][CH2:27][O:28][CH3:29])[C:11]([CH2:16][CH3:17])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COCCl
Reactant: CCC1=CC(O[Si](C)(C)C(C)(C)C)CC1(C)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCC1=CC(O[Si](C)(C)C(C)(C)C)CC1(C)OCOC
Yield: 95 %

Procedure:
To a solution mixture of 2.1 g of (1RS,4RS)-3-ethyl-4-methyl-4-hydroxy-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether, 2.7 g of N,N-diisopropylethylamine and 30 ml of chloroform was added under ice-cooling 1.24 ml of chloromethyl methyl ether, and the resulting mixture was allowed to react at room temperature for 8 hours. Then the reaction liquid was poured into ice-cooled 5% aqueous solution of citric acid and extracted two times with diethyl ether. The combined ether layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography to obtain 2.35 g of (1RS,4RS)-3-ethyl-4-methyl-4-methoxymethoxy-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether. Yield 95%
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13]([O:17][CH2:18][CH:19]=[O:20])[CH2:14]2)[N:11]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:9])#[N:2].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13]([O:17][CH2:18][CH2:19][OH:20])[CH2:14]2)[N:11]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2OCC=O)[C@H]1C(=O)N1CCC[C@H]1C#N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2OCCO)[C@H]1C(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.9 %

Procedure:
To a solution of tert-butyl (1R,3S,4S,6R)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-6-(2-oxoethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 25-1 (238 mg) in methanol (6 mL), was added sodium borohydride (26.2 mg). The mixture was stirred at room temperature for 20 minutes. To the resulting mixture, was added citric acid solution. The mixture evaporated in vacuo. The residue was diluted with ethyl acetate, and washed with water and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo to give the target compound (220 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1.Br[CH2:26][C:27](=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29].C([O-])(O)=O.[Na+]>COCCOC>[CH2:31]([O:30][C:28]([C:27]1[N:23]=[C:20]2[CH:19]=[CH:18][C:17]([CH2:16][C:10]3[C:9]([F:24])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:13]([O:14][CH3:15])=[CH:12][CH:11]=3)=[CH:22][N:21]2[CH:26]=1)=[O:29])[CH3:32]
Reactant: CCOC(=O)C(=O)CBr
Reactant: COc1ccc(Cc2ccc(N)nc2)c(F)c1-c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1cn2cc(Cc3ccc(OC)c(-c4cccc(Cl)c4)c3F)ccc2n1
Yield: 27.3 %

Procedure:
Into a 20 mL vial with stir bar was added 5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylamine (P-252, 565 mg, 1.65 mmol), ethyl bromopyruvate (0.52 mL, 4.12 mmol), and 5 mL of DME. The reaction was stirred at room temperature for 18 hours, then basified with NaHCO3 (aq. sat). The product was extracted with ethyl acetate and concentrated. Purification by flash column chromatography (5% acetone/dichloromethane) provided a tan solid which was triturated with ether to obtain 6-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (I-37) (198 mg, 27%) as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]2[O:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:19]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+].Cl>CN(C)C=O.O>[OH:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]2[O:10][CH:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][S:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:29])=[O:28])=[CH:15][CH:16]=3)[C:7](=[O:18])[C:6]=2[CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(-c2coc3cc(O)c(O)cc3c2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)coc2cc(O)c(O)cc12

Procedure:
6,7-Dihydroxy-3-(4-aminophenyl)-4H-1-benzopyran-4-one [see Example 51a] (538 mg) is dissolved in a mixture of dimethylformamide and water 15:85 (5 ml) and the solution is heated to 90° in the presence of benzenesulfonyl chloride (210 mg). After 15 minutes the pH has dropped to 3 and it is adjusted to 9 by addition of a 25% sodium hydroxide solution. Benzenesulfonyl chloride (additional 143 mg) and 25% sodium hydroxide solution (total amount used: 1 ml) are added in the same way until the pH does not vary any more. Aqueous hydrochloric acid is then added to lower the pH to 3 and the solution is cooled until precipitation occurs. The precipitate is filtered, washed with water and dried to give 6,7-dihydroxy-3-(4-phenylsulfonylaminophenyl)-4H-1-benzopyran-4-one, m.p. 285°-286°.
Reaction SMILES: C(N(CC)CC)C.[C:8]([SiH:12]([CH3:14])[CH3:13])([CH3:11])([CH3:10])[CH3:9].C[O:16][C:17](=[O:29])[CH2:18][NH:19][CH2:20][CH:21]=[CH:22][C:23]([O:25]CC=C)=[O:24].[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl>[Si:12]([O:25][C:23]([CH:22]=[CH:21][CH2:20][NH:19][CH2:18][C:17]([OH:29])=[O:16])=[O:24])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:14])[CH3:13]
Reactant: C=CCOC(=O)C=CCNCC(=O)OC
Reactant: C[SiH](C)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC(=O)C=CCNCC(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a dichloromethane solution (1.0 ml) of palladium (II) acetate (8.0 mg, 0.04 mmol) and triethylamine (16 μl, 0.12 mmol), t-butyldimethylsilane (187 μl, 1.1 mmol) was added and the mixture was stirred for 15 minutes at room temperature in an argon atmosphere. To the resulting black suspension, a dichloromethane solution (1.0 ml) of N-allyloxycarbonylallylglycine methyl ester (150 mg, 0.75 mmol) was added and the mixture was stirred for an additional 20 hours. After a saturated aqueous solution of ammonium chloride was added to quench the reaction, extraction with ether was conducted and the ether layer was dried over anhydrous magnesium sulfate and filtered. By distilling off the solvent, N-t-butyldimethylsilyloxycarbonylallylglycine was obtained in an amount of 184 mg (yield, 90%). The physical data for this compound were in agreement with those reported in Examples 3 and 11.
Reaction SMILES: C(OC([N:7]1[C@H:11](/[CH:12]=[CH:13]\[C:14]2[N:15]3[CH:21]=[N:20][CH:19]=[C:16]3[S:17][CH:18]=2)[CH2:10][C@H:9]([S:22][C:23]2[C@H:24]([CH3:40])[C@@H:25]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:26]3[C:27]=2[C:28]([O:30]CC=C)=[O:29])[CH2:8]1)=O)C=C.CNC1C=CC=CC=1>ClCCl.CN(C=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>[OH:38][C@@H:36]([C@H:35]1[C:34](=[O:39])[N:26]2[C:27]([C:28]([OH:30])=[O:29])=[C:23]([S:22][C@H:9]3[CH2:10][C@@H:11](/[CH:12]=[CH:13]\[C:14]4[N:15]5[CH:21]=[N:20][CH:19]=[C:16]5[S:17][CH:18]=4)[NH:7][CH2:8]3)[C@H:24]([CH3:40])[C@H:25]12)[CH3:37]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](/C=C\c3csc4cncn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CNc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](/C=C\c4csc5cncn45)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.9 %

Procedure:
Allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[2 (Z)-(imidazo[5,1-b]thiazol-3-yl)ethenyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate (80 mg) is dissolved in 1 ml of dichloromethane and 1 ml of DMF. N-Methylaniline (0.060 ml) and 40 mg of tetrakis(triphenylphosphine)palladium(0) are added thereto, and the mixture is stirred in an argon atmosphere at room temperature for 30 min. The reaction mixture is concentrated under reduced pressure. Ethyl acetate is added to the concentrate, and the resultant precipitate is collected by filtration and then purified by column chromatography on Cosmosil 40C18-PREP and Amberlyst A-26 (Cl− form) to give 11.9 mg of the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:12]2[C:13]([C:17](Cl)=[O:18])=[C:14]([CH3:16])[O:15][C:11]=2[CH:10]=[CH:9][C:8]=1[O:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1)=[O:6])[CH:2]=[CH2:3].[CH3:31][NH:32][CH3:33].O>ClCCl>[CH3:30][O:29][C:23]1[CH:24]=[C:25]([O:27][CH3:28])[N:26]=[C:21]([O:20][C:8]2[C:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[C:12]3[C:13]([C:17](=[O:18])[N:32]([CH3:33])[CH3:31])=[C:14]([CH3:16])[O:15][C:11]3=[CH:10][CH:9]=2)[N:22]=1
Reactant: C=CCOC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc2oc(C)c(C(=O)Cl)c12
Reactant: CNC
Solvent: O
Solvent: ClCCl
Product: C=CCOC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc2oc(C)c(C(=O)N(C)C)c12
Reaction time: 0.5 h
Yield: 60 %

Procedure:
3.0 g of 4-allyloxycarbonyl-5-(4,6-dimethoxypyrimidin-2-yl)oxy-2-methylbenzofuran-3-carbonyl chloride was dissolved in 13 ml of dichloromethane, and 1.5 g of a 50% dimethylamine aqueous solution was dropwise added thereto under cooling with ice. After stirring for 30 minutes, the reaction solution was poured into water and extracted with dichloromethane. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The oily substance obtained by concentration under reduced pressure, was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to obtain 1.84 g (yield: 60%) of the desired compound.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8](O)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:11]1([CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:16][CH2:15]CCC1>>[CH:1]1([CH2:6][CH2:7][CH2:8][C:19]([CH:18]2[CH2:15][CH2:16][CH2:11][CH2:17]2)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CCC1CCCC1
Reactant: O=C(O)CCC1CCCCC1
Product: O=C(CCCC1CCCC1)C1CCCC1

Procedure:
The title compound was prepared analogously to Example A(44), where 3-cyclopentyl propionic acid was substituted in place of 3-cyclohexylpropionic acid in Step 1 of that example.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1.[F:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[CH:22][C:20]=1[NH2:21]>CC(O)CCC>[ClH:2].[F:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[CH:22][C:20]=1[NH:21][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COCCOc1ccc2c(Cl)ncnc2c1
Agent: Cl
Solvent: CCCC(C)O
Product: COCCOc1ccc2c(Nc3cc(O)c(C)cc3F)ncnc2c1
Yield: 77.7 %

Procedure:
A solution of 4-chloro-7-(2-methoxyethoxy)quinazoline hydrochloride (275 mg, 1 mmol) and 2-fluoro-5-hydroxy4-methylaniline (170 mg, 1.2 mmol), (prepared as described for the starting material in Example 8), in 2-pentanol (5 ml) was heated at reflux for 2 hours. The mixture was allowed to cool and the precipitate was collected by filtration, washed with isopropanol and ether, and dried under vacuum at 70° C. to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-methoxyethoxy)quinazoline hydrochloride(295 mg, 78%) as a cream solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH:8]1([C@H:11]([NH2:33])[C:12]([N:14]2[CH2:18][C:17]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[F:26])=[CH:16][C@H:15]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:13])[CH2:10][CH2:9]1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:1][CH2:2][CH2:3][S:4]([NH:33][C@@H:11]([CH:8]1[CH2:10][CH2:9]1)[C:12]([N:14]1[CH2:18][C:17]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])=[CH:16][C@H:15]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:13])(=[O:6])=[O:5]
Reactant: N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C([C@@H](NS(=O)(=O)CCCl)C1CC1)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
2-chloroethanesulfonyl chloride (81 μL, 0.78 mmol, 1.1 equiv) was added to a solution of (1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethanamine (16-7, 250 mg, 0.705 mmol, 1 equiv) and N,N-diisopropylethylamine (160 μL, 0.917 mmol, 1.30 equiv) in dichloromethane (5 mL) at 0° C., and the resulting mixture was stirred for 15 minutes, then warmed to 23° C. and stirred for an additional 15 minutes. Additional 2-chloroethanesulfonyl chloride (1.2 equiv) and N,N-diisopropylethylamine (1.3 equiv) were added and the mixture was stirred for 30 minutes, then partitioned between water (75 mL) and dichloromethane (2×60 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 2-chloro-N-{(1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}ethanesulfonamide (27-1) as a colorless oil. LRMS m/z (M+H—Cl) 445.4 found, 445.1 required.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.[Cl:18][C:19]1[CH:24]=[C:23]([C@H:25](O)[CH3:26])[CH:22]=[CH:21][N:20]=1.C1CCN2C(=NCCC2)CC1.O>C1(C)C=CC=CC=1.CCOCC>[N:15]([C@H:25]([C:23]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:18])[CH:24]=1)[CH3:26])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](O)c1ccnc(Cl)c1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: C[C@H](N=[N+]=[N-])c1ccnc(Cl)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Diphenylphosphoryl azide (6.57 mL) was added to a solution of (R)-1-(2-chloropyridin-4-yl)ethanol in toluene (50 mL) in a nitrogen atmosphere, and the reaction solution was cooled to 0° C. DBU (4.52 mL) was added to the reaction solution, which was then heated to room temperature and stirred overnight. Water and an ether were added to the reaction solution, and the organic layer was separated. The organic layer was dried over magnesium sulfate, and the residue was purified by silica gel chromatography (carrier: Chromatorex; elution solvent: hexane-ethyl acetate) to obtain the title compound (4.44 g) The property values of the compound are as follows.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][C:9]1[S:13][CH:12]=[C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=2)[NH:19][CH:18]=[C:17]3[CH:26]2[CH2:31][CH2:30][N:29]([S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[CH2:28][CH2:27]2)[CH:10]=1.N1CCC[C@@H:39]1CO>>[CH:5]1([N:4]([CH2:8][C:9]2[S:13][CH:12]=[C:11]([C:14]3[CH:15]=[C:16]4[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=3)[NH:19][CH:18]=[C:17]4[CH:26]3[CH2:27][CH2:28][N:29]([S:32]([CH:35]([CH3:36])[CH3:37])(=[O:34])=[O:33])[CH2:30][CH2:31]3)[CH:10]=2)[CH3:39])[CH2:2][CH2:3][CH2:7][CH2:6]1
Reactant: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCC[C@@H]5CO)c4)cc23)CC1
Reactant: OC[C@H]1CCCN1
Product: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)C5CCCC5)c4)cc23)CC1
Yield: 54.3 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide, substituting N-methylcyclopentanamine (90.13 mg, 1.20 mmol) for (2R)-2-pyrrolidinylmethanol to afford 10 mg of the title compound (54.3%)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](/[N:8]=[CH:13]/[N:14]([CH3:16])[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Br)cc1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=N/C(=O)c1ccc(Br)cc1
Reaction time: 1.5 h
Yield: 77.4 %

Procedure:
A suspension of 4-bromobenzamide (9.50 g, 47.5 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (17.2 mL, 47.5 mmol) in a round bottom flask topped with a short path distillation head was placed in a preheated sand bath at 122° C. The reaction mixture was allowed to stir at this temperature for 1.5 hours, during which time the MeOH that was formed was collected from the distillation condenser. Upon cooling solids were formed and collected by vacuum filtration affording (E)-4-bromo-N-((dimethylamino)methylene)benzamide as a pale yellow solid (9.38 g, 77%) which was used directly in the next step without further purification. LCMS (APCI+) m/z 255, 257 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])[CH3:3].C(=O)(O)[O-].[K+].CN(C)C=O.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(OCC)(=O)C>[C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH2:11][OH:12])[C:13]([O:15][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:14])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-t-Boc-L-homoserine (5.14 g, 23.45 mmol) and potassium bicarbonate (2.46 g, 24.6 mmol) was weighed out in a round bottom flask and to it was added anhydrous N,N-dimethylformamide (100 mL) and benzyl bromide (4.2 g, 24.6 mmol). The mixture was stirred at room temperature for 18 hours. The crude mixture was then diluted with ethyl acetate and washed, respectively, with brine, saturated NaHCO3 and brine, and dried over Na2SO4. The organic layer was then concentrated down on rotovap and purified on normal phase column chromatography. Yield=7.27 g (100%).
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[CH3:11][CH:12]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:26])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[C:13](=[O:15])[CH3:14]>CCOCC>[CH3:11][CH:12]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:26])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[C:13](=[O:15])[CH2:14][C:3]([O:7][CH2:8][CH3:9])=[O:10]
Reactant: CC(=O)C(C)CCC=C(C)CCC=C(C)C
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)CC(=O)C(C)CCC=C(C)CCC=C(C)C
Temperature: 0 °C
Yield: 69.5 %

Procedure:
Into ether (800 ml), 52% paraffin solution of sodium hydride (22.8 g) is suspended, and diethyl carbonate (89.4 g) is portionwise added thereto while cooling with ice in nitrogen stream. Then, 3,7,11-trimethyl-6,10-dodecadien-2-one (88 g) is dropwise added thereto. After refluxing for 15 hours, the reaction mixture is poured into ice water. The ether layer is separated, washed with water, dried and evaporated. The residue is distilled under reduced pressure to give ethyl 3,7,11-trimethyl-6,10-dodecadien-2-one-1-carboxylate (81 g). B.P. 130° to 135°C/0.05 mmHg. IR: 1640, 1675, 1710, 1740 cm-1. NMR (carbon tetrachloride): 1.10 (d), 1.29 (t), 1.60 (s), 1.68 (s), 1.98 (s), 2.00-2.80 (broad), 3.33 (s), 4.15 (q), 4.8-5.3 (broad).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]([O:19]C)=[O:18])[C:9]2=[O:21])(=[O:4])=[O:3].Cl>O1CCOCC1.O>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]([OH:19])=[O:18])[C:9]2=[O:21])(=[O:3])=[O:4]
Reactant: COC(=O)CN1C(=O)c2ccc(NS(C)(=O)=O)cc2C1=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.6 %

Procedure:
To a solution of methyl 2-(5-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (obtained as described in Example 30, Step 3, theoretical amount 1.622 mmol) in dioxane (10 ml), a 36% solution of HCl in water (10 ml) was added, and the mixture was stirred for 3 hours at room temperature. The volatiles were evaporated and the resulting crude was purified by flash chromatography on silica gel (eluent: DCM/MeOH 95:5). The title compound was obtained as a pale yellow solid (230 mg, 0.772 mmol, 47.6% yield over 2 steps, MS/ESI+ 299.1 [MH]+).
Reaction SMILES: [NH2:1][C:2]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH:7]([CH3:9])[CH3:8])=[O:5].C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24].CN(C1C=CC=CN=1)C>ClCCl.Cl>[CH3:14][C:13]1[C:2]([NH:1][C:22](=[O:25])[CH:23]=[CH2:24])=[C:3]([CH:10]=[CH:11][CH:12]=1)[C:4]([NH:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: C=CC(=O)Cl
Reactant: Cc1cccc(C(=O)NC(C)C)c1N
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1c(C)cccc1C(=O)NC(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To a solution of the title compound of Step B (0.93 g, 4.8 mmol) in dichloromethane (10 mL) was added triethylamine (0.876 mL, 6.2 mmol) and the mixture was cooled to 0° C. Acryloyl chloride (0.433 mL, 5.3 mmol) was then added and the mixture was warmed to ambient temperature and stirred overnight. Dimethylaminopyridine (1.0 g, 7.7 mmol) was then added followed by acryloyl chloride (0.475 mL, 5.8 mmol). The mixture was stirred at ambient temperature for 0.5 h before being diluted with 1N HCl and extracted twice with dichloromethane. The organic extracts were dried (MgSO4) and concentrated to give the product of Step C (0.62 g) as a white solid.
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][O:9][CH3:10])=[CH:6][C:5]([O:11][CH2:12][O:13][CH3:14])=[CH:4][C:3]=1[O:15][CH2:16][O:17][CH3:18].[Li]CCCC.CN([CH:27]=[O:28])C>CCOCC>[CH3:18][O:17][CH2:16][O:15][C:3]1[CH:4]=[C:5]([O:11][CH2:12][O:13][CH3:14])[CH:6]=[C:7]([CH2:8][O:9][CH3:10])[C:2]=1[CH:27]=[O:28]
Reactant: CN(C)C=O
Reactant: COCOc1cc(COC)c(Br)c(OCOC)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COCOc1cc(COC)c(C=O)c(OCOC)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a solution of 2-bromo-1,5-bis-methoxymethoxy-3-methoxymethyl-benzene (5.66 g, 17.59 mmol) in Et2O (60 mL) was added n-BuLi (15.47 mL, 2.5 M in Hexane) at −78° C. After stirring for 1 hour at −78° C., DMF (13.6 mL, 175.8 mmol) was the added and reaction mixture was allowed to warm to room temperature over 3 hours. The reaction was quenched with saturated NH4Cl and extracted with Et2O. The organic extracts were dried and concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give 2,4-bis-methoxymethoxy-6-methoxymethyl-benzaldehyde (3.93 g, 82%). 1H NMR (400 MHz, CDCl3δ 10.50 (s, 1H), 7.03 (s, 1H), 6.77 (s, 1H), 5.30 (s, 2H), 5.27 (s, 2H), 4.80 (s, 3H), 3.50 (s, 3H), 4.49 (s, 3H).