Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([O:16]CC2C=CC=CC=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([OH:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(OCc2ccccc2)c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1cc2ccc(F)cc2c(O)c1C
Yield: 81.9 %

Procedure:
To a stirred solution of (4-benzyloxy-6-fluoro-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (15.8 g, 46.7 mmol) in MeOH (150 mL) was added 10% palladium on carbon (2.4 g). The resulting mixture was vigorously stirred under a balloon of hydrogen overnight. The reaction mixture was filtered through celite. The filtrate was concentrated to give the crude product, which was purified by silica gel chromatography (10% ethyl acetate in hexanes) to yield (6-fluoro-4-hydroxy-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (9.5 g, 82%) as a white solid. MS cald. for C1H13FO3 [(M+H)+] 249, obsd. 249.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1Br.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[C:38]([O:42][CH2:43][CH3:44])(=[O:41])[CH:39]=[CH2:40]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1/[CH:40]=[CH:39]/[C:38]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: C=CC(=O)OCC
Reactant: Nc1cnccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccncc1N
Temperature: 105 °C
Reaction time: 2 h
Yield: 28.9 %

Procedure:
3-Amino-4-bromopyridine (1.440 ml, 8.32 mmol), palladium (ii) acetate (0.195 g, 0.869 mmol), and tri(o-tolyl)phosphine (0.302 g, 0.992 mmol) were suspended in a mixture of triethylamine (5.0 ml, 35.9 mmol) and acetonitrile (5 mL) in a microwave vial under argon. Ethyl acrylate (1.1 ml, 10.12 mmol) was added and the cap sealed. It was heated in an oil bath to 105° C. After 2 hours the vial was opened and the reaction mixture partitioned between water (100 mL), saturated ammonium chloride (50 mL) and ethyl acetate (200 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (dichloromethane to ethyl acetate gradient) gave the desired (E)-ethyl 3-(3-aminopyridin-4-yl)acrylate (0.462 g, 2.404 mmol, 28.9% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=O)[CH3:13])=[CH:7][CH:6]=1.[OH:15][CH:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([F:27])[CH:20]=1)[CH2:17][NH2:18]>>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:18][CH2:17][CH:16]([OH:15])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([F:27])[CH:20]=2)[CH3:13])=[CH:7][CH:6]=1
Reactant: CC(=O)Cc1ccc(OCCO)cc1
Reactant: COc1ccc(C(O)CN)cc1F
Product: COc1ccc(C(O)CNC(C)Cc2ccc(OCCO)cc2)cc1F

Procedure:
The compound was prepared as in Example 7, from 1-[4-(2-hydroxyethoxy)phenyl]propan-2-one (3.9 g) and 2-hydroxy-2-(3-fluoro-4-methoxyphenyl)-ethanamine (3.75 g) and crystallised from ether-hexane, mp 112°-115° C. as a 82:18 mixture of diastereoisomers.
Reaction SMILES: [CH2:1]([PH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)(Cl)[Cl:11]>P(Cl)(Cl)Cl>[CH2:1]([P:5]([CH2:6][CH2:7][CH2:8][CH3:9])[Cl:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCPCCCC
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClP(Cl)Cl
Product: CCCCP(Cl)CCCC
Yield: 55.9 %

Procedure:
148 g (1 mol) di-n-butylphosphine was dropped at a maximum reaction temperature of 30° C. into a suspension of 232 g (1.1 mol) PCl5 in 500 ml toluene. HCl and PCl3 formed during the reaction were removed under a vacuum of 130 mbar and condensed in a cooling trap. After the reaction was complete, the reaction mixture was found to comprise two liquid phases. The upper phase contained PCl3 in toluene. The bulk quantity of chlorophosphine was in the lower phase (31P-NMR). It was worked up distillatively and 101 g product was obtained (55% of the theoretical). bp 92° C./16 mbar.
Reaction SMILES: [Na].CO.CN(C)[CH:6]=[O:7].[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14](Br)[CH:15]=1>O>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([O:7][CH3:6])[CH:15]=1
Reactant: CN(C)C=O
Reactant: Brc1cncc(Br)c1
Agent: [Na]
Solvent: O
Solvent: CO
Product: COc1cncc(Br)c1
Temperature: 0 °C
Yield: 57 %

Procedure:
Add sodium (0.583 g, 25 mmol) to methanol (10 mL) at 0° C. Stir the mixture at 0° C. until obtain a solution and concentrate. Add N,N-dimethylformamide (25 mL) and add 3,5-dibromopyridine (3.0 g, 12.66 mmol). Stir at 70° C. for 4 h. Cool to room temperature and add water. Extract twice with diethyl ether. Combine the organic phases, wash once with water, dry over sodium sulfate and concentrate. Purify the residue by silica gel chromatography, eluting with a gradient of 100:0 to 50:50 hexanes:ethyl acetate, to give the title compound as a solid (1.37 g, 57%).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:21])[N:8]([C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:20])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:22]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=1)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[CH2:1]([C:5]1[N:6]([CH2:42][C:39]2[CH:40]=[CH:41][C:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[S:27](=[O:29])(=[O:28])[NH:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[CH:37][CH:38]=2)[C:7](=[O:21])[N:8]([C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:20])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nn(-c2cc(C(=O)OC)ccc2Cl)c(=O)[nH]1
Product: CCCCc1nn(-c2cc(C(=O)OC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Yield: 85 %

Procedure:
By the procedure of Example 13, Step A, 5-n-butyl-2-[5-(carbomethoxy)-2-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step A) was alkylated with [2'-(N-t-butylsulfamoyl)biphenyl- 4-yl]methyl bromide (from Example 12, Step D). Flash chromatography of the crude product on silica gel (gradient elution with 0.5-5.0% MeOH in CH2Cl2) gave an 85% yield of the title compound as a white solid, mp 65°-67° C., homogeneous by TLC (98:2 CH2Cl2 --MeOH), mass spectrum (FAB) m/e 555 [M-(t-Bu)]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.BrN1C(=[O:18])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[OH-].[Na+]>ClC1C=CC=CC=1.O>[OH:18][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nccnc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: O
Product: OCc1ccc2nccnc2c1
Temperature: 85 °C

Procedure:
In a 100 ml flask, 6-methyl-quinoxaline (1.25 g, 8.68 mmol) was dissolved with N-bromosuccinimide (2.32, 13.0 mmol) and benzoyl peroxide (0.15 g, 0.62 mml) in 31 g of chlorobenzene. The mixture was heated up to 85° C. to give a pale yellow solution that turned reddish with time. The solution was maintained at 85° C. for two hours and it was then cooled to −10° C. and filtered. The solution was vacuum dried to give an orange solid residue. The orange solid was then mixed with an alkaline solution prepared by dissolving 2.6 g of sodium hydroxide pellets in 50 ml of water. The mixture was gently heated to 85-95° C. to give a solution of 6-hydroxymethyl-quinoxaline that was mixed with the catalyst (5% Pt/C, 0.2 g) and maintained at that temperature with air sparging. The reaction was monitored by GCMS showing the consumption of 6-hydroxymethyl-quinoxaline and the formation of 6-quinoxalinecarboxaldehyde. After 10 hours, both compounds were completely consumed indicating the end of the reaction. The aqueous solution was cooled to room temperature and filtered. The yellow solution obtained was neutralized with 3.18 g of 96% sulfuric acid dissolved in 5 ml of water. A yellow precipitated was formed during the addition of acid. The yellow solid was filtered and air dried to give 0.67 g of dry product (45% yield). The lower yield in this experiment is attributed to a loss of bromomethyl-quinoxaline that was not recovered with from the succinimides precipitate by washings with pentane as explained in Examples 1 and 2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH:9]1[CH2:11][C:10]1([C:20](=[O:22])[CH3:21])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[K+]>CO>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH:9]1[CH2:11][C:10]1([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH:20]([OH:22])[CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CC1CNC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: CC(O)C1(c2ccc(Cl)c(Cl)c2)CC1CNC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
(±)-[2-Acetyl-2-(3,4-dichlorophenyl)-cyclopropylmethyl]-carbamic acid tert-butyl ester was added to methanol and stirred at ambient temperature under Ar (g) in a 50 mL round-bottomed flask. Potassium borohydride was added portion wise and the suspension stirred overnight. The resulting suspension partitioned between EtOAc (10 mL) and water (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL), and the combined layers washed with brine (10 mL). The organic layer was dried over sodium sulfate for 2 hours and filtered, concentrated under reduced pressure, and dried for 1 hour to afford 0.523 g of a white sticky solid. The solid was purified on a filter pad of silica eluting with 4/1 hexanes/EtOAc (v/v), switching to 6/4 hexanes/EtOAc (v/v) upon collection of the major spot. The second (other)diastereomer was collected. The desired compound is pale oil; Yield: 0.328 g 49%; The undesired diastereomer is a white solid; Yield: 0.120 g 18%; 1H NMR: Desired diastereomer: (300 MHz, DMSO-d6) δ□ 7.50-53 (m, 2H, J=2.1 Hz, ArH), 7.22-25 (dd, 1H, J=9.0 Hz, dr=1.8 Hz, ArH), 6.91 (bs, 1H, OH), 4.26 (m, 1H, NH), 3.50 (m, 1H, CH2N), 3.32 (m, 1H, CH2N), 3.26 (m, 3H, CH3), 1.40 (s, 9H, tert-Bu), 1.02 (m, 2H, ArCCH2), 0.55 (m, 1H, CHCH2N); Undesired diastereomer (not shown): (300 MHz, CDCl3) δ□ 7.57 (m, 1H, ArH), 7.50 (d, 1H, J=8.1 Hz, ArH), 7.31 (dd, 1H, J=8.4 Hz, J=1.8 Hz, ArH), 7.11 (bs, 1H, OH), 4.63 (d, 1H, J=3.3 Hz, NH), 3.46 (m, 1H), 3.33 (s, 3H), 3.12 (m, 2H), 1.38 (s, 9H, tert-Bu), 1.30 (m, 1H), 0.85 (d, 2H, J=6.0 Hz, ArCCH2), 0.78 (m, 1H, CHCH2N)
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[N:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][C:17]=4[CH3:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1.[OH-:30].[K+].O>C(O)(C)(C)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[N:21]=[CH:20][C:19]([C:22]([NH2:23])=[O:30])=[CH:18][C:17]=4[CH3:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(C#N)cc1C
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(C(N)=O)cc1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A mixture of 6-[10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-1-yl]-5-methylpyridine-3-carbonitrile (100 mg, 0.245 mmol) and potassium hydroxide (41 mg, 0.735 mmol) in tert-butanol (2 mL) was stirred at 80° C. for 2 hr. After cooling, water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was recrystallized from ethyl acetate/isopropyl ether to afford the title compound (70 mg, 67%) as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[N:21]([S:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)(=[O:36])=[O:35])[C:22]([C:24]5[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][CH:25]=5)=[CH:23][C:16]=34)=[CH:13][N:12]([CH2:43][CH3:44])[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[OH-].[Pd+2].[OH-]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[N:21]([S:34]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)(=[O:35])=[O:36])[C:22]([C:24]5[CH:25]=[CH:26][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:28][CH:29]=5)=[CH:23][C:16]=34)=[CH:13][N:12]([CH2:43][CH3:44])[N:11]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CCn1cc(-c2ccnc3c2cc(-c2ccc(NC(C)=O)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd+2]
Agent: [OH-]
Product: CCn1cc(-c2ccnc3c2cc(-c2ccc(NC(C)=O)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(N)cc2)n1
Yield: 52 %

Procedure:
A stirred solution of 4-[3-(4-nitrophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-(4-acetamidophenyl)-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine (0.8 mmol) and 20% palladium(II)hydroxide on carbon (0.1 g) was hydrogenated with a balloon of hydrogen for 3 days at room temperature. The reaction was filtered through a pad of Celite, rinsed with ethyl acetate and concentrated under vacuum to give the title product as an off-white solid (52%). ESMS [M+H]+: 577.4
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:9][CH:8]=[CH:7]2)([O-])=O.[H][H]>CO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[N:9][CH:8]=[CH:7]2
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc([N+](=O)[O-])ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Yield: 94.7 %

Procedure:
di-tert-butyl (6-nitroisoquinolin-1-yl)imidodicarbonate (75.00 g, 0.193 mol) in methanol/THF (500 ml/500 ml) was hydrogenated with a hydrogen balloon in the presence of Pd/C (5%, 5 g) for 2.0 h. Filtration of the Pd/C and concentration gave a solid, which was recrystallized from methanol to give 65.72 g (94.97%) of di-tert-butyl (6-aminoisoquinolin-1-yl)imidodicarbonate as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.33 (m, 18 H) 4.18 (s, 2 H) 6.89 (d, J=2.20 Hz, 1 H) 6.99 (dd, J=9.01, 2.42 Hz, 1 H) 7.35 (d, J=6.59 Hz, 1 H) 7.75 (d, J=8.79 Hz, 1 H) 8.22 (d, J=5.71 Hz, 1 H). LC-MS: 741 (2M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[C:4]([Cl:17])[CH:3]=1.C(N(CC)CC)C.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>O1CCCC1>[Cl:17][C:4]1[CH:3]=[C:2]([NH:1][C:28]([CH:25]2[CH2:27][CH2:26]2)=[O:29])[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[CH2:11][O:10]1
Reactant: O=C(Cl)C1CC1
Reactant: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CON(Cc2ccc(NC(=O)C3CC3)cc2Cl)C1=O
Reaction time: 16 h
Yield: 64.5 %

Procedure:
To a stirred solution of 3.0 grams (0.012 mole) of 2-(4-amino-2-chlorophenyl)methyl-4,4-dimethyl-3-isoxazolidinone and 1.2 grams (0.012 mole) of triethylamine in 30 ml of tetrahydrofuran was added dropwise 1.4 grams (0.013 mole) of cyclopropanecarboxylic acid chloride in 20 ml of tetrahydrofuran. During the addition the reaction mixture was cooled in an ice-water bath. Upon completion of addition the reaction mixture stirred for 16 hours; then was concentrated under reduced pressure to a residual solid. The solid was dissolved in 250 ml of methylene chloride. The solid was washed with water, which caused the precipitation of a solid that was insoluble in the liquid phases. The solid was removed by filtration. The organic phase was separated and washed with three 100 ml portions of water. The organic phase was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual solid. Both solids collected were subjected to thin layer chromatography and were determined to be the same material. The solids were combined and recrystallized from ethyl acetate/acetonitrile to give 2.5 grams of 2-[2-chloro-4-(cyclopropylcarbonylamino)phenyl]methyl-4,4-dimethyl-3-isoxazolidinone; m.p. 191°-193° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.Cl[C:19]([O:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:20]>>[CH:22]1([O:21][C:19]([NH:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:6][CH2:7]2)=[O:20])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(Cl)OC1CCCC1
Product: O=C(NC1CCN(C(=O)OCc2ccccc2)CC1)OC1CCCC1

Procedure:
The title compound is prepared from benzyl 4-aminopiperidine-1-carboxylate and cyclopentyl chloroformate following a procedure analogous to that described for Intermediate 26 Step 1. LC (method 1): tR=1.06 min; Mass spectrum (ESI+): m/z=347 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.C1CCN2C(=NCCC2)CC1.N1([C:28](=[O:33])[CH2:29][CH2:30][O:31][CH3:32])C=CN=C1>C(#N)C>[CH3:32][O:31][CH2:30][CH2:29][C:28]([NH:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1)=[O:33]
Reactant: COCCC(=O)n1ccnc1
Reactant: Nc1nc2c(s1)C(=O)CCC2
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COCCC(=O)Nc1nc2c(s1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 2-amino-5,6-dihydro-4H-benzothiazol-7-one (3.0 g, 18 mmol) and DBU (5.3 mL, 36 mmol) in 100 mL acetonitrile is added a solution of 1-imidazol-1-yl-3-methoxy-propan-1-one (6.9 g, 45 mmol) in acetonitrile. The reaction mixture is stirred for 15 min at RT and then concentrated under reduced pressure. The residue is poured in water, acidified to pH 5 with 6 M aqueous HCl and the product is extracted with ethyl acetate. The combined organic phases are dried over MgSO4 and concentrated under reduced pressure. Yield: 3.8 g. The product is used in the next step without purification. A-36 is synthesized according to general procedure A1 starting from 3.8 g (15 mmol) A-36c and 6.8 g (24 mmol) A-36b. Yield: 1.23 g.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[C:5]1(=[O:15])[NH:9][C:8](=[O:10])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[K]>CN(C=O)C.C(OCC)C>[CH2:1]([N:9]1[C:8](=[O:10])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]2[C:5]1=[O:15])[C:2]#[CH:3]
Reactant: C#CCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C#CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
Propargyl bromide (1.3 mL, 17.4 mmol) is dissolved in DMF (30 mL) and potassium phtalimide (3.4 g; 18.4 mmol) is added. The mixture is refluxed for 5 h. After cooling at room temperature the mixture is diluted with diethyl ether, washed with water (3×50 mL), dried over Na2SO4 and evaporated under vacuum to give N-propargyl phtalimide as white solid (3.15 g; 17 mmol).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:10](Cl)=[O:11].[OH:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18]C(=O)C1C=CC=CC=1>>[OH:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:10]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)=[O:11]
Reactant: O=C(NCCCCO)c1ccccc1
Reactant: O=C(Cl)N1Cc2ccccc2C1
Product: O=C(NCCCCO)N1Cc2ccccc2C1
Yield: 97 %

Procedure:
1,3-Dihydro-isoindole-2-carboxylic acid-(4-hydroxybutyl)amide (27B) is prepared from 27A as described for 1D.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+].O>S1(CCCC1)(=O)=O>[CH:12]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][N:16]=2)=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)=[O:13]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=Cc1ccc(O)c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: N#Cc1ccc(Oc2ccc(C=O)c3cccnc23)nc1
Temperature: 90 °C

Procedure:
To a solution of 8-hydroxyquinoline-5-carbaldehyde (692 mg, 4 mmol) in sulfolane (8 mL) was added 2-chloro-5-cyanopyridine (552 mg, 4 mmol) and K2CO3 (1.7 g, 12 mmol). The reaction was heated at 90° C. for 2 h in a microwave. The reaction was cooled to rt and poured into water (100 mL). The resulting solid was filtered, washed with water, ether and air dried to give the title compound: RT=3.02 min; m/z (ES+)=276.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18]([OH:20])=[O:19])=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:27])[CH:14]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CN(C=O)C>O>[CH2:35]([O:19][C:18]([C:17]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:28])[C:10]2[C:15]([C:16]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[CH:14][C:13]([Br:27])=[CH:12][CH:11]=2)=[O:20])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
A mixture of 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (150 mg), potassium carbonate (95 mg), benzylbromide (81 μl) and DMF (5 ml) was stirred at room temperature for 3 hrs. After diluting with water, the mixture was extracted with ether. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and ethyl acetate and n-hexane was added to the residue. The mixture was crystallized to give the title compound (152 mg, 84%).
Reaction SMILES: C([BH3-])#N.[Na+].[F:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2>C(O)(=O)C>[F:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][NH:10]2
Reactant: Fc1cccc2[nH]ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Fc1cccc2c1CCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
Sodium cyanoborohydride (1.86 g, 29.62 mmol) was added portion wise to a solution of 4-fluoro-1H-indole (2 g, 14.81 mmol) in acetic acid (20 mL) at 0° C. and stirred at ambient temperature for 2 h. The resulting mixture was concentrated in vacuo and partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (5×30 mL). The combined organic layers were then washed with water (5×20 mL), sodium bicarbonate solution (3×30 mL), brine (3×20 mL), dried over anhydrous sodium sulphate and concentrated in vacuo to give the crude product. Purification by column chromatography over neutral alumina using 5% ethyl acetate in hexane as eluent to afforded 4-fluoroindoline (1 g, 45%) as a brown liquid.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.[H-].[Na+].Cl[CH2:15][C:16]#[N:17].O>CN(C=O)C>[O:11]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[N:2]1[CH2:15][C:16]#[N:17]
Reactant: N#CCCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCN1C(=O)c2ccccc2C1=O
Yield: 89.4 %

Procedure:
32 g (0.217 mol) of isoindole-1,3-dione in 160 mL of DMF were treated with 11.75 g (0.294 mol, 1.35 eq) of NaH (60% in oil) over 45 min at 0° C. 22.17 g (0.294 mol, 1.35 eq) of chloro-acetonitrile were added, and the reaction was stirred over night. The reaction mixture was poured into 1.5 L of water, and the precipitate was collected by filtration, washed with Et2O and dried under high vacuum to afford 36.1 g (89%) of (1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetonitrile as a white solid, MS: 187 (MH+).