Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:4][CH2:3]1.[C:22]1([CH:28]([N:35]=[C:36]=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[CH:28]([NH:35][C:36]([N:19]1[CH2:18][CH2:17][N:16]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH3:9])[CH2:21][CH2:20]1)=[O:37])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN1CCC(C(C)(c2ccccc2)N2CCNCC2)CC1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CN1CCC(C(C)(c2ccccc2)N2CCN(C(=O)NC(c3ccccc3)c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a solution of 1-[1-(1-methylpiperidin-4-yl)-1-phenylethyl]piperazine 0.1 g (0.348 mmol) dissolved in methylene chloride (20 ml) was added diphenylmethyl isocyanate 0.073 g (0.348 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated. The residue was applied to flash column chromatography using methylene chloride and methanol (100:10) as eluents to give 0.15 g of desired product in 87% yield.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1.O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:41]([C:38]4[CH:39]=[CH:40][C:35]([CH3:34])=[CH:36][CH:37]=4)(=[O:43])=[O:42])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2c(=O)n(-c3ccc(C(C)(C)C#N)cc3)c3c4cc(Br)ccc4ncc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg, 0.36 mmol) in dichloromethane (6 ml) was added 4-methylbenzene-1-sulfonyl chloride (35.02 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 17 mg (25.37%); 1H NMR (CDCl3, 300 MHz): δ 9.59 (s, 1H), 8.085-8.113 (d, 2H, J=8.4 Hz), 7.97-8.001 (d, 1H, J=9 Hz), 7.707-7.735 (d, 2H, J=8.4 Hz), 7.621-7.659 (dd, 1H, J=9.3, 2.1 Hz), 7.422-7.450 (d, 2H, J=8.4 Hz), 7.351-7.378 (d, 2H, J=8.1 Hz), 6.989-6.996 (d, 1H, J=2.1 Hz), 2.43 (s, 3H), 1.81 (s, 6H); MS: ink 561 (M+).
Reaction SMILES: [OH:1][C:2]1([CH2:13][N+:14]([O-])=O)[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.CO.[H][H]>[Pd].C(O)(=O)C>[NH2:14][CH2:13][C:2]1([OH:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CCOC(=O)N1CCC(O)(C[N+](=O)[O-])CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)N1CCC(O)(CN)CC1

Procedure:
A mixture of 73 parts of ethyl 4-hydroxy-4-(nitromethyl)-1-piperidinecarboxylate, 400 parts of methanol and 150 parts of acetic acid was hydrogenated in the Parr-apparatus with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. To the residue was added crushed ice and the whole was alkalized with potassium hydroxide. The aqueous phase was salted out with potassium carbonate and the product was extracted with benzene. The extract was dried, filtered and evaporated, yielding 63.5 parts of ethyl 4-(aminomethyl)-4-hydroxy-1-piperidinecarboxylate; mp. ±82° C. (intermediate 6).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[C:5]([CH3:12])[C:4]=1[CH3:13].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[C:5]([CH3:12])[C:4]=1[CH3:13]
Reactant: COc1ccc(CC#N)c(C)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccc(CCN)c(C)c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.5 %

Procedure:
A solution of (4-methoxy-2,3-dimethylphenyl)acetonitrile (0.20 g) in 15 mL diethyl ether was cooled to 0° C. Lithium aluminum hydride (0.20 g) was added in portions to the stirring nitrile solution. The resulting slurry was allowed to warm to rt and stirred for 20 h. The mixture was cooled to 0° C. and carefully quenched by the sequential addition of 0.2 mL of water, followed by 0.2 mL of 3 N sodium hydroxide and 0.6 mL of water. The mixture was stirred for 15 min and filtered to remove the aluminum salts. The filtrate was collected and the volatile material was removed by a rotary evaporator to give 130 mg of 2-(4-methoxy-2,3-dimethylphenyl)ethylamine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([Cl:9])[CH:3]=1.[Li]CCCC.[CH3:15][C:16]([CH3:18])=[O:17]>C1COCC1>[Cl:9][C:4]1[CH:3]=[C:2]([C:16]([OH:17])([CH3:18])[CH3:15])[CH:7]=[CH:6][C:5]=1[CH3:8]
Reactant: CC(C)=O
Reactant: Cc1ccc(Br)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(C)O)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 4-bromo-2-chlorotoluene (10 g, 48.7 mmol) in THF was added n-BuLi at −78° C. After the reaction mixture was stirred at −78° C. for 30 minutes, dry acetone was slowly added. The resulting content was maintained at −78° C. for 3 hours and slowly warmed up to RT overnight. The reaction mixture was then partitioned between ethyl acetate and water. The ethyl acetate layer was then washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude oil. The crude solid was purified via flash chromatography (30% EtOAc in n-hexane) yielded the title compound as an oil (7.2 g, 80%)
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]([OH:55])[CH3:54])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]>CC(C)=O.O.Cl>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:29][N:30]=[N:31][N:32]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]([OH:55])[CH3:54])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C(C)O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCCCc1nc2ccc(C(C)O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 68818.6 %

Procedure:
To a suspension of 2.00 g of 2-butyl-6-(1-hydroxyethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone in 70 ml of 3:1 acetone-water is added one drop of 5% aqueous hydrochloric acid solution. The mixture is then heated at reflux for 16 hours. After cooling, the reaction mixture is concentrated in vacuo and the residue purified by flash chromatography on silica gel by elution with 9:1 chloroform-methanol to afford 0,915 g of the desired product as a white solid, m.p. 146°-147° C.
Reaction SMILES: [CH2:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][C:3](=[O:11])[O:2]1.[H-].[Al+3].[H-].[H-].CCOCC.Cl>ClCCl>[CH2:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH:3]([OH:11])[O:2]1
Reactant: O=C1Cc2ccccc2CO1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: ClCCl
Product: OC1Cc2ccccc2CO1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.2 %

Procedure:
To a solution of 3.00 g (0.020 mol) of 1,4-dihydro-3H-2-benzopyran-3-one in 100 mL of dry dichloromethane, cooled to -78° C., was added dropwise, over 1 hour, 24 mL (0.022 mol) of a 1M solution of disobutyl aluminum hydride in dichloromethane. After stirring at -78° C. for 2 hours and at 0° C. for 15 minutes, 100 mL of ether was added, followed by dropwise addition of 1.2N HCl until a pH of 1-2 was reached. Separation of the organic phase, extraction of the aqueous phase with ether and concentration of the combined dried (MgSO4) extracts provided 2.8 g (91%) of 3,4-dihydro-1H-2-benzopyran-3-ol. This product decomposes on standing or on chromatography on silica gel and consequently was used directly for the next reaction step. TLC Rf 0.13 (SiO2, CH2Cl2, brown-orange CAS and heat).
Reaction SMILES: C[C:2]([CH3:10])([C:7]([O-:9])=[O:8])[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[CH2:13](C(N)CC)C>CS(C)=O>[CH3:6][O:5][C:3](=[O:4])[CH:2]([CH3:10])[C:7]([O:9][CH3:13])=[O:8]
Reactant: COC(=O)C(C)(C)C(=O)[O-]
Reactant: CCC(N)CC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of methyl dimethylmalonate (260 mg) and 60% sodium hydride in oil (70 mg) in 4 ml of DMSO was stirred at room temperature for 10 min. A solution of 3-chloromethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-amine (200 mg) in 2 ml of DMSO was added. The mixture was stirred at room temperature for 3 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give the crude material which was purified through silica gel using hexane to 10% ethyl acetate in hexane as eluent to give 137 mg of 2-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]methyl]-2-methyl-malonic acid dimethyl ester as a white solid. 1H NMR (CDCl3) δ 6.83(s,2H), 6.01(s,1H), 5.00(m,1H), 3.70(s,6H), 3.40(s,2H), 3.25(m,1H), 2.27(s,3H), 2.12(s,3H), 2.05(s,6H), 1.5-1.7(m,4H), 1.48(s,3H), 0.94(t,6H)ppm.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])(=[O:3])[CH3:2].[CH3:26]I.[H-].[Na+]>CN(C=O)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][C@H:8]([N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:26])[CH2:9][O:10][Si:11]([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:12])[CH3:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCC[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 105.6 %

Procedure:
To a solution of (S)-4-(tert-butoxycarbonylamino)-5-(tert-butyldimethylsilyloxy)pentyl acetate (48.2 g, 0.124 mol) and MeI (23.2 mL, 0.372 mol) in DMF (500 mL) was added sodium hydride (60%, 9.9 g, 0.248 mol) at 0° C. The resulting mixture was stirred at 0° C. for 2½ h and LC-MS indicated the reaction was completed. The reaction was quenched with saturated NH4Cl solution and diluted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated to give (S)-4-(tert-butoxycarbonyl(methyl)amino)-5-(tert-butyldimethylsilyloxy)pentyl acetate (51 g, crude). LRMS (M+H+-Boc) m/z 290.2.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[F:22][C:23]([F:32])([F:31])[C:24]1[N:25]=[C:26]([CH2:29]O)[S:27][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1.O>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:29][C:26]5[S:27][CH:28]=[C:24]([C:23]([F:32])([F:31])[F:22])[N:25]=5)=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1
Reactant: OCc1nc(C(F)(F)F)cs1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4nc(C(F)(F)F)cs4)cc3=O)cn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.6 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (49 mg), (4-(trifluoromethyl)-1,3-thiazol-2-yl)methanol (68.3 mg) and triphenylphosphine (137 mg) in THF (5 ml) was added bis(2-methoxyethyl) azodicarboxylate (122 mg), and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-hexane to give the title compound (21.5 mg) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:19][C:20](OC(C)=O)=[O:21].O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:18])[CH:9]=2)=[CH:6][CH:7]=1)(=[O:21])[CH3:19]
Reactant: O=c1cc(-c2ccc(O)cc2)oc2ncccc12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1ccc(-c2cc(=O)c3cccnc3o2)cc1
Yield: 52.7 %

Procedure:
In a 50 mL round-bottomed flask fitted with condenser and magnetic stirrer were placed 2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one (1.5 g, 6.27 mmol), Ac2O (700 mg, 6.89 mmol) and a catalytic amount of DMAP (50 mg) in pyridine (10 mL) and the reaction mixture was stirred for 16 h at rt. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer washed with water, dried and concentrated to give a 2-(4-acetoxyphenyl)-pyrano[2,3-b]pyridin-4-one (930 mg, 53%). To a stirred solution of the 4-acetoxy compound (930 mg, 3.30 mmol) in CH2Cl2 (50 mL), mCPBA(1.9 g, 11.3 mmol) was added and the reaction mixture was stirred at rt for 5 days. The reaction mixture was diluted with CH2Cl2 and washed with NaHCO3 solution. The organic layer was separated, washed with water, brine, dried and concentrated to give crude product, which was purified by column chromatography, using 5% methanol in CH2Cl2 to give 168 mg of N-oxide product in 17% yield. To a solution of the acetoxy N-oxide (168 mg, 0.565 mmol) in methanol: THF (10 mL: 10 mL), K2CO3 (156 mg, 1.13 mmol) was added and the mixture was stirred for 2 h at rt. The reaction mixture was neutralized by dilute HCl. The solid was isolated by filtration, washed with water and dried to give 2-(4-hydroxyphenyl)-4-oxo-4H-pyrano[2,3-b]pyridine 8-oxide (150 mg, 100%). MS (ES) m/z: 255.90 (M); Mp. 314-315° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([CH2:13][C:14]([O:16]CC)=[O:15])=[N:9]2)=[CH:5][CH:4]=1.[OH-].[Li+]>O1CCCC1.CO.O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[N:9]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)Cc1nnn(Cc2ccc(OC)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(Cn2nnc(CC(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
The ethyl 2-[2-(4-methoxybenzyl)-2H-1,2,3,4-tetrazol-5-yl]acetate (2.15 g, 7.78 mmol) obtained in (A) was dissolved in tetrahydrofuran/methanol (3:1, v/v, 60 ml), added dropwise with a solution of lithium hydroxide (359.2 mg, 8.56 mmol) in water (15 ml) under ice cooling and then stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was added with 1 N aqueous hydrochloric acid to obtain pH of about 1. The solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Then, the solvent was evaporated to obtain the title compound (1.91 g, 98.8%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:10]2([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:28]=[N:29][CH:30]=[N:31][CH:32]=4)[CH:22]=3)[C:18]3[C:13](=[C:14]([F:19])[CH:15]=[CH:16][CH:17]=3)[C:12]([NH2:20])=[N:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[CH3:62][N:63](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[NH2:20][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([CH:3]=2)[C:62]#[N:63])([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)[CH:22]=2)[N:11]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc1Cl
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: COc1ccc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc1C#N
Temperature: 160 °C
Yield: 45 %

Procedure:
1-(3-Chloro-4-methoxyphenyl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine (190 mg, 0.43 mmol), zinc cyanide (0.024 mL, 0.38 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (52.6 mg, 0.13 mmol), tris(dibenzylideneacetone)dipalladium(0) (58.7 mg, 0.06 mmol), DMF (5 mL) and a drop of water were added into a vial and heated in a microwave reactor for 1 h at 160° C. The mixture was filtered, diluted with MeOH and purified by preparative HPLC. The fractions containing the desired product were pooled and the MeCN removed in vacuo. The resulting aqueous residue was diluted with saturated aqueous NaHCO3 and extracted with DCM. The combined organics were passed through a phase separator (Sorbent), concentrated and dried in vacuum oven at 40° C. over night, to afford 85 mg (45%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[CH:8]=[C:9]([O:13][CH2:14][CH2:15][NH2:16])[CH:10]=[N:11][CH:12]=1.[C:17]1(=[S:22])[O:21][CH2:20][CH2:19][CH2:18]1.CO>O>[SH:22][CH2:17][CH2:18][CH2:19][C:20]([NH:16][CH2:15][CH2:14][O:13][C:9]1[CH:10]=[N:11][CH:12]=[C:7]([C@@H:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])[CH:8]=1)=[O:21]
Reactant: CN1CCC[C@H]1c1cncc(OCCN)c1
Reactant: S=C1CCCO1
Solvent: CO
Solvent: O
Product: CN1CCC[C@H]1c1cncc(OCCNC(=O)CCCS)c1
Temperature: 60 °C
Yield: 43 %

Procedure:
A solution of 2-({5-[(2S)-1-methylpyrrolidin-2-yl]pyridin-3-yl}oxy)ethanamine (preparation 12) (1100 mg, 4.971 mmol), in water (10 ml), was treated with γ-thiobutyrolactone (861 ul, 9.94 mmol) and the reaction mixture was heated to 60° C. overnight. It was then evaporated in vacuo to leave a colourless gum, which was pre-adsorbed onto silica from MeOH. This was then chromatographed on a 40 g ISCO column, eluting with EtOAc to EtOAc:MeOH:NH3 80:20:1. The appropriate fractions were evaporated in vacuo to give the title compound as a colourless gum, 690 mg. Yield=43%.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([CH2:13][N:14]3C(=O)C4=CC=CC=C4C3=O)[CH2:8]2)=[CH:4][CH:3]=1.O.NN.O1CCOCC1>C(O)C>[NH2:14][CH2:13][CH:9]1[O:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:8]1
Reactant: O=C1c2ccccc2C(=O)N1CC1CN(Cc2ccc(Cl)cc2)CCO1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: NCC1CN(Cc2ccc(Cl)cc2)CCO1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
To a solution of 4-(p-chlorobenzyl)-2-phthalimidomethylmorpholine (20.28 g, 54.7 mmol) in ethanol (110 ml) was added hydrazine monohydrate (5.71 g, 0.114 mol) and the mixture was stirred at room temperature. 50 ml of dioxane was further added and the mixture was stirred at room temperature overnight. The crystal thus separated was filtered off and the filtrate was concentrated. The residue was dissolved in chloroform and the insolubles were filtered off. The filtrate was distilled off to give 9.31 g of the title compound as an oily substance. Yield=71%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH:12]([CH2:18][NH2:19])[CH2:11]2)=[CH:4][CH:3]=1.C1([O:26][C:27](=O)[NH:28][C:29]2[CH:34]=[C:33]([C:35]3[N:39]([CH3:40])[N:38]=[N:37][N:36]=3)[CH:32]=[C:31]([CH2:41][CH3:42])[CH:30]=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH2:41]([C:31]1[CH:30]=[C:29]([NH:28][C:27]([NH:19][CH2:18][CH:12]2[C:13]([CH3:17])([CH3:16])[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:11]2)=[O:26])[CH:34]=[C:33]([C:35]2[N:39]([CH3:40])[N:38]=[N:37][N:36]=2)[CH:32]=1)[CH3:42]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2nnnn2C)c1
Reactant: CC1(C)CCN(CCc2ccc(F)cc2)CC1CN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(NC(=O)NCC2CN(CCc3ccc(F)cc3)CCC2(C)C)cc(-c2nnnn2C)c1
Reaction time: 18 h
Yield: 50.9 %

Procedure:
A solution of 1-[2-(4-fluorophenyl)ethyl]-4,4-dimethyl-piperidin-3-ylmethylamine (53 mg, 199 μmol) and [3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-carbamic acid phenyl ester (50 mg, 199 μmol) in N,N-dimethylformamide (1.0 mL) was treated with triethylamine (55 μL, 398 μmol). After 18 hours, the mixture was concentrated under vacuum. The residue was purified by flash chromatography, eluting with 5% methanol in dichloromethane containing 0.5% aqueous ammonium hydroxide, providing an amorphous solid (50 mg, 50%). 1H NMR (300 MHz, CDCl3) δ8.45 (s, 1H), 7.66 (s, 1H), 7.62 (s, 1H), 7.09 (m, 2H), 7.07 (s, 1H), 6.91 (t, J=9 Hz, 2H), 6.23 (m, 1H), 4.13 (s, 3H), 3.38 (m, 1H), 3.10 (m, 2H), 2.85 (m, 3H), 2.74 (m, 2H), 2.62 (q, J=7 Hz, 2H), 2.45 (m, 1H), 2.32 (m, 1H), 1.8-1.6 (m, 2H), 1.46 (m, 1H), 1.21 (t, J=7 Hz, 3H), 1.02 (s, 3H), 0.88 (s, 3H). Mass spec (ES+) m/z 494.3 (M+H+, 100%).
Reaction SMILES: [Br:1][C:2]1[C:3]([Br:15])=[C:4]([Br:14])[C:5]([Br:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]=12.[CH2:16]([CH2:18][NH2:19])[OH:17].O>C1(C)C(C)=CC=CC=1>[OH:17][CH2:16][CH2:18][N:19]1[C:8](=[O:10])[C:7]2=[C:2]([Br:1])[C:3]([Br:15])=[C:4]([Br:14])[C:5]([Br:13])=[C:6]2[C:11]1=[O:12]
Reactant: NCCO
Reactant: O=C1OC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1c2c(Br)c(Br)c(Br)c(Br)c2C(=O)N1CCO

Procedure:
To a suspension of 464 gm (1 mole) of tetrabromophthalic anhydride in 1.2 liters of xylene was added 61 gm (1 mole) of ethanolamine. The solution was heated and refluxed with a Dean-Stark water separator until the theoretical amount of water separated. The mixture was cooled, diluted with hexane, and filtered. The resulting 413 gm of an off-white solid was washed with hexane and dried at 100° C. This material is used as is for subsequent reactions without further purification.
Reaction SMILES: C[C:2]1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.N1C=CC=CC=1.[Br:17][CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])C(Cl)=O>ClCCCl>[Br:17][CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:4](=[O:5])[CH2:6][C:7]([O:9][CH3:2])=[O:8]
Reactant: CCCCCCCCCCCCCCC(Br)C(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCC(Br)C(=O)CC(=O)OC

Procedure:
1.8 mol of Meldrum's acid were mixed with 3.96 mol of pyridine in a round-bottomed flask containing 1,2-dichloroethane, placed at 0° C. under argon and with stirring. 1.98 mol of 2-bromohexadecanoyl chloride were then introduced slowly and the mixture was left stirring for 2 hours at 0° C.