Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](OC=C)(=O)[CH3:11]>>[C:1]([O:9][CH:10]=[CH2:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=COC(C)=O
Reactant: O=C(O)c1ccccc1
Product: C=COC(=O)c1ccccc1
Temperature: 65 °C

Procedure:
The catalyst is suspended once more in the mixture of benzoic acid and vinyl acetate and the batch is heated to 65° C., affording again about 7 g of vinyl benzoate after 30 hours.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[CH3:21][C@H:22]([C@H:26]([CH3:30])[CH2:27][CH2:28][CH3:29])C(Cl)=O>C(#N)C>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3](=[O:5])[C@H:22]([CH3:21])[C@H:26]([CH3:30])[CH2:27][CH2:28][CH3:29])[CH3:9]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CCC[C@@H](C)[C@@H](C)C(=O)Cl
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC[C@@H](C)[C@@H](C)C(=O)CC(=O)OCC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87.8 %

Procedure:
To a solution containing 1.0 g (6.9 mmol) of (2R,3R)-2,3-dimethyl-hexanoic acid in 10 mL of dichloromethane was added 1.1 g of chloromethylene dimethyl-ammonium chloride (8.3 mmol). The resulting solution was stirred under nitrogen for 1.5 hours. The solvent was subsequently evaporated to give (2R,3R)-2,3-dimethyl-hexanoyl chloride. To a solution containing 2.5 g (14.6 mmol) of potassium monoethyl malonate in 50 mL of acetonitrile was added 1.7 g (17.3 mmol) of magnesium chloride and 1.2 g (11.4 mmol) of triethylamine. The resulting mixture was stirred at room temperature for 2.5 hours. The reaction was cooled to 0° C. and a solution of the (2R,3R)-2,3-dimethyl-hexanoyl chloride in acetonitrile (20 mL) was slowly added followed by the addition of triethylamine (0.4 g, 0.4 mmol). The reaction was heated to 40° C. and stirred at that temperature for 6 hours. The reaction mixture was cooled to 25° C., quenched with a saturated solution of ammonium chloride and extracted into ethyl acetate. The solution was washed with brine, dried over MgSO4 and concentrated. The resulting residue was filtered through a silica plug, eluting with 60/40 solution of hexane/ethyl acetate to afford 1.3 g (87.8% yield) of the titled compound as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:16]([F:19])([F:18])[F:17])=[CH:4][C:5]([N+:13]([O-])=O)=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[CH:7]=1.O.O.Cl[Sn]Cl>C(O)C>[Br:1][C:2]1[C:3]([C:16]([F:19])([F:18])[F:17])=[CH:4][C:5]([NH2:13])=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[CH:7]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Br)cc1-n1ccnc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(C(F)(F)F)c(Br)cc1-n1ccnc1
Temperature: 25 °C
Yield: 90 %

Procedure:
1-[5-bromo-2-nitro-4-(trifluoromethyl)phenyl]-1H-imidazole (15.50 g, 0.0461 mol) is stirred with SnCl2.2H2O (51.77 g, 0.2274 mol) in ethanol (78 mL) at 80° C. for 2 hours. After cooling down to room temperature, the mixture is concentrated and partitioned between water (200 mL) and ethyl acetate (250 mL). Sodium hydrogencarbonate powder is added to adjust the pH to 8. The milky suspension is filtrated, the cake is washed with ethyl acetate and the combined organic phases are washed with water and dried over sodium sulfate. Concentration affords the title compound as a pale yellow solid (12.70 g, 90.0%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([S:15]([NH:18][C@H:19]([C:27]([N:29]1[CH:38]([C:39]([O:41]C)=[O:40])[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30]1)=[O:28])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:26])[NH2:25])(=[O:17])=[O:16])[CH:7]=[CH:6]2>CO.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([S:15]([NH:18][C@H:19]([C:27]([N:29]1[CH:38]([C:39]([OH:41])=[O:40])[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30]1)=[O:28])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:25])[NH2:26])(=[O:16])=[O:17])[CH:7]=[CH:6]2
Reactant: COC(=O)C1Cc2ccccc2CN1C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N3Cc4ccccc4CC3C(=O)O)cc2cc1OC
Reaction time: 15 h
Yield: 54.6 %

Procedure:
A solution of 3 g of methyl 2-[N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate in 15 ml of methanol and 5 ml of 2N NaOH solution was warmed to 50° C and held at that temperature for 15 hours. At the end of this period, the reaction mixture was concentrated and chromatographed on 200 ml of Daiaion® SK 102 ion exchange resin (200-300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with ethanol-water (1:4) and eluted with ethanol-water-NH4OH (10:9:1). The main fraction was evaporated to dryness and washed with ether to give 1.6 g of 2-[N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][N:6]([CH2:17][C:18]([O:20]CC)=[O:19])[C:7]1[CH:12]=[C:11]([C:13]([NH2:15])=[S:14])[CH:10]=[CH:9][C:8]=1[CH3:16])C.Cl[CH2:25][C:26](=O)[CH3:27]>C(O)C.CN(C)C=O>[CH3:16][C:8]1[CH:9]=[CH:10][C:11]([C:13]2[S:14][CH:25]=[C:26]([CH3:27])[N:15]=2)=[CH:12][C:7]=1[N:6]([CH2:5][C:4]([OH:3])=[O:23])[CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc(C(N)=S)ccc1C
Reactant: CC(=O)CCl
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1csc(-c2ccc(C)c(N(CC(=O)O)CC(=O)O)c2)n1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
The compound (0.70 g, 2.1 mmol) obtained in step A was dissolved in a ethanol (14 ml)-N,N-dimethylformamide (4 ml) mixed solvent. Then, chloroacetone (0.18 ml, 2.3 mmol) was added, and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the obtained oil was diluted with dichloromethane, washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give a crude oil of the title compound containing N,N-dimethylformamide. Using this oil and according to the method of Reference Example 62, step B, the title compound (0.56 g, yield 83%) was obtained as a pale-yellow oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:13]2[C:8](=[CH:9][C:10]([O:33][CH3:34])=[C:11]([O:31][CH3:32])[CH:12]=2)[N:7]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:19]([O:18][C:16]([C:15]1[C:6]([CH2:5][CH2:4][OH:3])=[N:7][C:8]2[C:13]([C:14]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)=[CH:12][C:11]([O:31][CH3:32])=[C:10]([O:33][CH3:34])[CH:9]=2)=[O:17])[CH3:20]
Reactant: CCOC(=O)Cc1nc2cc(OC)c(OC)cc2c(-c2ccc(OC)c(OC)c2)c1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CCO)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A solution of 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-3-ethoxycarbonylquinoline-2-acetic acid ethyl ester (5.8 g) in tetrahydrofuran (100 ml) was added drop by drop at 0° C. to a suspension of lithium aluminum hydride (0.455 g) in tetrahydrofuran (50 ml). After the reaction mixture was stirred at 0° C. for 1 hour, water (2.5 ml) was added drop by drop, followed by stirring for 30 more minutes. After the insoluble solid was filtered off, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform-ethyl acetate (1:1, v/v) to yield 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(2-hydroxyethyl)quinoline-3-carboxylic acid ethyl ester (1.75 g, 33%), which was then recrystallized from ethyl acetate-hexane to yield a colorless prismatic crystal having a melting point of 150° to 151° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](=[O:24])[C:5]2(O)[C:25]1[C:34]([OH:35])=[CH:33][C:28]2[O:29][CH2:30][CH2:31][O:32][C:27]=2[CH:26]=1.C1(C(C2C=CC=CC=2)N2C3C(=C(F)C=CC=3)C(O)(C3C(O)=CC4OCCOC=4C=3)C2=O)C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](=[O:24])[CH:5]2[C:25]1[C:34]([OH:35])=[CH:33][C:28]2[O:29][CH2:30][CH2:31][O:32][C:27]=2[CH:26]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccc(Br)cc2C1(O)c1cc2c(cc1O)OCCO2
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(F)c2C1(O)c1cc2c(cc1O)OCCO2
Product: O=C1C(c2cc3c(cc2O)OCCO3)c2cc(Br)ccc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 82C and making non-critical variations using 5-bromo-1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-4-fluoro-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one, 5-bromo-1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one was obtained (85%) as a colorless solid: MS (ES+) m/z 527.8 (M+1), 529.8 (M+1).
Reaction SMILES: [NH2-].[Na+].[C:3]1([C:9]#[CH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N.[C:12]1(=[O:19])[CH:17]=[CH:16][C:15](=[O:18])[CH:14]=[CH:13]1>C1COCC1>[OH:18][C:15]1([C:10]#[C:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:16]=[CH:17][C:12](=[O:19])[CH:13]=[CH:14]1
Reactant: C#Cc1ccccc1
Reactant: O=C1C=CC(=O)C=C1
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C=CC(O)(C#Cc2ccccc2)C=C1
Temperature: -78 °C

Procedure:
Sodium amide (0.35 g, 0.009 mole), dry THF (25 mL), and phenylacetylene (0.92 g, 0.009 mole) were placed in a 100 mL, three-necked round-bottomed flask under nitrogen. The reaction was heated at reflux while nitrogen was blown through the flask until ammonia evolution ceased. The reaction slurry was cooled to -78° C., then added to a mixture of benzoquinone (0.97 g, 0.009 mole) in THF (50 mL) at about -108° C. The reaction mixture was allowed to warm to -30° C., then quenched into a saturated solution of ammonium chloride and extracted with ether. The ether extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed as in Example 3 to yield 0.05 g (2.6%) of the title carbinol.
Reaction SMILES: [F:1][C:2]1[CH:47]=[CH:46][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[O:44][CH3:45])[S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4C(=O)C5=CC=CC=C5C4=O)=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.O.NN.C(=O)(O)[O-].[Na+]>CO.C1COCC1.C(OCC)(=O)C>[NH2:27][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:47][CH:46]=3)[CH2:9][CH2:10]2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[O:44][CH3:45])(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)S(=O)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)S(=O)(=O)c1ccc(CN)cc1
Reaction time: 0.25 h
Yield: 76.4 %

Procedure:
N-{2-[4-(4-Fluorobenzoyl)piperidino]ethyl}-N-(2-methoxyphenyl)-4-phthalimidomethylbenzenesulfonamide (77 mg, 0.117 mmol) was dissolved in a methanol-THF (3:2) mixture solution (2.5 ml) to which was subsequently added hydrazine hydrate (1 ml) while cooling in an ice bath. After 15 minutes of stirring at the same temperature, the organic solvent was removed by evaporation, and the resulting residue was extracted with methylene chloride. The resulting organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine, and dried on anhydrous sodium carbonate, followed by the removal of the solvent by evaporation. To the resulting residue was added an acetic acid-THF-water (3:1:1) mixture solution (3 ml). After 2 hours of stirring at room temperature, the solvent was removed by evaporation, and the resulting reaction solution was diluted with ethyl acetate (15 ml), mixed with saturated sodium bicarbonate aqueous solution (5 ml) and then extracted with ethyl acetate. After drying the extract on anhydrous sodium carbonate, the solvent was removed by evaporation, and the resulting light yellow oily residue was purified by a silica gel column chromatography (methylene chloride:methanol=20:1 to 9:1) to obtain 47 mg (76.4%) of the title compound in a colorless oily form.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:10]([O:17][C:18]1[CH:19]=[C:20](/[C:24](=[N:26]/[S@@:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])/[CH3:25])[CH:21]=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)C>O1CCCC1.[Zn]>[CH2:6]([O:5][C:3](=[O:4])[C:2]([F:9])([F:8])[C@@:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:19]=1)([NH:26][S@@:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])[CH3:25])[CH3:7]
Reactant: C/C(=N\[S@](=O)C(C)(C)C)c1cccc(OCc2ccccc2)c1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Zinc (5.07 g, 77.5 mmol) and cuprous chloride (2.64 g, 25.8 mmol) were stirred in a dried apparatus and heated for 1 minute with a heat gun under a flow of argon. After cooling to room temperature, tetrahydrofuran (85.1 ml) was added. The reaction mixture was stirred in a 70° C. oil bath for 30 minutes, then cooled to room temperature. A solution of ethyl bromodifluoroacetate (13.5 g, 8.54 ml, 64.6 mmol) in tetrahydrofuran (25.5 ml) was added dropwise while maintaining the temperature between 26 and 29° C. After stirring for 10 minutes at 23° C., a solution of (R,E)-N-(1-(3-(benzyloxy)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (intermediate A2.6) (8.51 g, 25.8 mmol) in tetrahydrofuran (25.5 ml) was added dropwise and stirring continued for 24 hours at room temperature. For the workup, the reaction mixture was cooled to 0° C. and ethanol (3 ml) was added dropwise. The mixture was filtered through a pad of Dicalite® and washed with ethyl acetate. The filtrate was concentrated at reduced pressure. The residue was taken in ethyl acetate (40 ml) and water was added. The emulsion was filtered again through a pad of Dicalite®. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated at reduced pressure. The crude product (13.7 g, yellow oil) was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 50:50 as the eluent. The (R)-3-(3-benzyloxy-phenyl)-2,2-difluoro-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester (7.72 g, 66% yield) was obtained as a yellow oil. MS (ISP): m/z=454.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[Br:17]N1C(=O)CCC1=O>COCCOCCOC>[CH2:13]([O:12][C:10](=[O:11])[CH:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[Br:17])[CH3:14]
Reactant: CCOC(=O)Cc1ccc(C#N)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: CCOC(=O)C(Br)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1,9 g of ethyl p-cyanophenylacetate in 50 ml of diglyme is added to a slurry of 0.48 g of sodium hydride (50% oil dispersion) in 10 ml of diglyme. The reaction mixture is stirred at room temperature for 2 h, cooled to 0° and 1.75 g of N-bromosuccinimide is added portionwise. The solvent is evaporated under high vacuum and the residue is chromatographed on 50 g of silica with ether to yield ethyl-α-bromo-p-cyanophenylacetate.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([Sn](CCCC)(CCCC)CCCC)[CH:21]=[CH2:22]>CN(C)C=O.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>[CH2:22]([C:17]1[CH:18]=[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=1)[CH:21]=[CH2:20]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Br)cnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 59.8 %

Procedure:
To a solution of 1-benzenesulfonyl-5-bromo-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 7) (10 g, 29.7 mmol) in N,N-dimethylformamide (20 mL) was added allyltributylstannane (14 mL, 44.51 mmol), and tetrakis(triphenylphosphine)palladium(0) (1.72 g, 1.49 mmol) at room temperature and then stirred at 80° C. for 12 h. The mixture was cooled to room temperature and extracted with ethyl acetate (2×250 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 33% ethyl acetate/hexanes) afforded 5-allyl-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine as a white solid (5.3 g, 60%): LC/MS m/e calcd for C16H14N2O2S [M+H]+ 299.37, observed 299.1.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11](=O)[CH2:12][N:13]2[CH2:30][CH2:29][C:16]3([C:20](=[O:21])[N:19]([C:22]4[CH2:23][O:24][C:25](=[O:28])[C:26]=4[CH3:27])[CH2:18][CH2:17]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:32].[CH:33]1([NH2:36])[CH2:35][CH2:34]1.[BH3-]C#N.[Na+]>CC(O)=O.C1COCC1>[CH:33]1([NH:36][CH:11]([C:10]2[C:2]([CH3:1])=[C:3]3[C:7](=[CH:8][CH:9]=2)[C:6](=[O:32])[O:5][CH2:4]3)[CH2:12][N:13]2[CH2:30][CH2:29][C:16]3([C:20](=[O:21])[N:19]([C:22]4[CH2:23][O:24][C:25](=[O:28])[C:26]=4[CH3:27])[CH2:18][CH2:17]3)[CH2:15][CH2:14]2)[CH2:35][CH2:34]1
Reactant: NC1CC1
Reactant: CC1=C(N2CCC3(CCN(CC(=O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1=C(N2CCC3(CCN(CC(NC4CC4)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 8-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxoethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (25 mg, 0.057 mmol) and cyclopropanamine (6.5 mg, 0.114 mmol) in anhydrous 5% HOAc/THF (1 mL) was added NaCNBH3 (18 mg, 0.28 mmol). The reaction was sealed and shaken at ambient temperature for 16 h. LCMS showed that the product was formed. The reaction was quenched with water (0.5 mL) and the solvent was evaporated under reduced pressure. The residue was dissolved in DMSO (1.5 mL) and filtered. The crude product was purified by using reversed-phase HPLC (Acetonitrile with 0.1% TFA: water with 0.1% TFA from 10% to 60%) to give the title compound. LC-MS (IE, m/z): 480 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)=[O:4].C(Cl)(=O)C(Cl)=O.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>ClCCl.CN(C)C=O>[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:10](=[O:12])[C:9]2[CH:13]=[C:5]([CH:6]=[CH:7][C:8]=2[N+:14]([O-:16])=[O:15])[C:3]([O:2][CH3:1])=[O:4])=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: Nc1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(C(=O)Nc2ccc(Cl)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
5-(Methoxycarbonyl)-2-nitrobenzoic acid (CAS registry number: 76143-33-4) (1.50 g) and 0.05 mL of N,N-dimethylformamide were dissolved in 150 mL of dichloromethane, and the solution was cooled to 0° C. To this solution, 0.87 mL of oxalyl chloride was added little by little, and the mixture was stirred for 30 minutes at 0° C., followed by stirring the mixture for 13 hours at room temperature. The reaction mixture was distilled under reduced pressure, and dried to obtain a light yellow solid, which was dissolved in 150 mL of dichloromethane. To this solution, a solution of 0.94 g of 4-chloroaniline and 3.57 mL of N,N-diisopropylethylamine dissolved in 25 mL of dichloromethane was added little by little. The mixture was stirred for 2 hours and a half at room temperature, whereafter 100 mL of a saturated aqueous solution of ammonium chloride was added to separate the organic layer. The aqueous layer was extracted twice with 50 mL of dichloromethane. The respective organic layers were combined, whereafter the combined organic layer was washed with 50 mL of a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and washed with dichloromethane. The filtrate and the washings were combined, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography. The resulting solid was dried under reduced pressure to obtain 1.82 g (81%) of methyl N-(4-chlorophenyl)-4-nitroisophthalamate.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([C:18]2[CH:27]=[C:26]3[C:21]([C:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25]3)=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1.[OH-].[K+].C1COCC1.Cl>C(O)C.O>[CH3:28][C:22]1([CH3:29])[C:21]2[C:26](=[CH:27][C:18]([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][O:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:30])=[O:2])=[CH:9][CH:8]=3)=[CH:19][CH:20]=2)[O:25][CH2:24][CH2:23]1
Reactant: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)OCCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(COc1ccc(C(=O)O)cc1)c1ccc2c(c1)OCCC2(C)C
Temperature: 45 °C
Yield: 79.4 %

Procedure:
A solution of 4-[2-(4,4-dimethyl-chroman-7-yl)-heptyloxy]-benzoic acid methyl ester (0.474 g, 1.15 mmole) in 8 mL of ethanol was treated with a solution of potassium hydroxide (1.3 g) in 5 mL of water. THF (4 mL) was added and the mixture was heated at 45° C. for two hours, diluted with 20 mL of water and the pH was adjusted to 2 with concentrated HCl. The mixture was then extracted with three 20 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a pale yellow foam. The product was purified by recrystallization from acetonitrile/water to yield 0.362 g of 4-[2-(4,4-dimethyl-chroman-7-yl)-heptyloxy]-benzoic acid (1) as a white solid. M.p.: 91.5-93.3° C.