Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]([OH:15])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(C#N)(Cl)(Cl)Cl.[NH2:41][C@@:42]([C:57]1[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH2:65][CH2:66][C:67]([F:70])([F:69])[F:68])=[CH:59][CH:58]=1)([C:53]([F:56])([F:55])[F:54])[CH2:43][C:44]([C:46]1[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=1)=[O:45]>C(Cl)Cl.N1C=CC=CC=1>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][C:13]([NH:41][C@:42]([C:57]1[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH2:65][CH2:66][C:67]([F:68])([F:69])[F:70])=[CH:59][CH:58]=1)([CH2:43][C:44](=[O:45])[C:46]1[CH:47]=[CH:48][C:49]([CH3:52])=[CH:50][CH:51]=1)[C:53]([F:56])([F:55])[F:54])=[O:15]
Reactant: Cc1ccc(C(=O)C[C@](N)(c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: N#CC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)C[C@](NC(=O)CN2C(=O)c3ccccc3C2=O)(c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of 2-(1,3-dioxoisoindolin-2-yl)acetic acid (592 mg, 2.88 mmol) in dry DCM (10 mL) was added PPh3 (2269 mg, 8.65 mmol) fairy rapidly, and then CCl3CN (500 mg, 3.46 mmol) was added dropwise. The mixture was stirred at rt for 3 h and a solution of Intermediate 2F, isomer 2 (500 mg, 1.15 mmol) in dry DCM (3 mL), followed by pyridine (0.3 mL) were added. The mixture was stirred at rt overnight. The mixture was diluted with DCM (10 mL) and washed with sat'd NaHCO3 (2×8 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography to yield the desired product (620 mg, 87%). LCMS Anal. Calc'd for C31H26F6N2O5 620.17, found [M+H] 621.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:4]=1[C:5]([NH:7][C@H:8]1[C@H:11]([CH3:12])[N:10]([O:13]CC2C=CC=CC=2)[C:9]1=[O:21])=[O:6].C1CC=CCC=1>C(O)C.[Pd]>[CH3:27][O:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([NH:7][C@H:8]1[C@H:11]([CH3:12])[N:10]([OH:13])[C:9]1=[O:21])=[O:6]
Reactant: COc1cccc(OC)c1C(=O)N[C@@H]1C(=O)N(OCc2ccccc2)[C@H]1C
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: COc1cccc(OC)c1C(=O)N[C@@H]1C(=O)N(O)[C@H]1C

Procedure:
To a stirred solution of (3S-trans)-3-[(2,6-dimethoxybenzoyl)amino]-4-methyl-1-[(phenylmethyl)oxy]-2-azetidinone (0.848 g) in absolute ethanol (20 ml) under nitrogen is added 1,4-cyclohexadiene (8 ml) and freshly prepared palladium black (approximately 0.85 g). After one hour the reaction mixture is filtered and evaporated to a solid (0.605 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]2[N:9]([C:10]=1[S:11]([N:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([CH2:23][CH2:24][NH2:25])=[CH:15]1)(=[O:13])=[O:12])[CH:8]=[CH:7][S:6]2.C(N(CC)CC)C.[C:33](OC(=O)C)(=[O:35])[CH3:34].C([O-])(O)=O.[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:2][C:3]1[N:4]=[C:5]2[N:9]([C:10]=1[S:11]([N:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([CH2:23][CH2:24][NH:25][C:33](=[O:35])[CH3:34])=[CH:15]1)(=[O:12])=[O:13])[CH:8]=[CH:7][S:6]2
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1cn(S(=O)(=O)c2c(Cl)nc3sccn23)c2ccccc12
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1cn(S(=O)(=O)c2c(Cl)nc3sccn23)c2ccccc12
Reaction time: 16 h
Yield: 92 %

Procedure:
A stirred mixture of 2-{1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-1H-indol-3-yl}ethylamine hydrochloride, 417 mg, 1.00 mmol) in dichloromethane and triethylamine (0.40 mL, 3.0 mmol) is treated with catalytic 4-dimethylaminopyridine (DMAP) (˜5 mg) at room temperature under nitrogen. The heterogeneous mixture is treated with acetic anhydride (0.30 mL, 3.2 mmol) and the reaction becomes homogeneous. After 16 h, the reaction is treated with saturated aqueous NaHCO3 (8 mL) for 0.3 h and then extracted with dichloromethane. The extracts are combined, dried over MgSO4 and concentrated in vacuo to a foam. The foam is treated with 20:80 ethyl acetate:hexane and concentrated in vacuo to a solid. This is triturated with ether and filtered. The filtercake is dried to afford the title product as a white solid, 389 mg (92% yield), mp 150-152° C., characterized by CHN elemental analysis and 1H NMR.
Reaction SMILES: [Si:1]([O-:5])([O-:4])([O-:3])[O-:2].[Na+:6].[Na+].[Na+].[Na+].O.[Co:11]=O.[H][H]>>[Si:1]([O-:5])([O-:4])([O-:3])[O-:2].[Na+:6].[Na+:6].[Na+:6].[Na+:6].[Co:11]
Reactant: O=[Co]
Reactant: [H][H]
Agent: [Na+]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: O
Product: [Co]

Procedure:
The procedure of Example I is repeated using twice as much sodium silicate solution with the cobalt oxide hydrate. The resulting hydrogen-reduced catalyst has a bulk density of 72 lbs./cu. ft. and a crushing strength of 10 pounds.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:13])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:47][CH2:48][CH2:49][N:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1>CN(C=O)C>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([NH:47][CH2:48][CH2:49][N:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)=[O:8])=[C:4]([F:13])[CH:3]=1
Reactant: NCCN1CCCC1
Reactant: COc1cc(C(=O)O)c(F)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCN2CCCC2)c(F)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-amino-2-fluoro-5-methoxybenzoic acid (Intermediate 183; 0.75 g, 4.07 mmol), HATU (1.70 g, 4.48 mmol) and DIPEA (2.1 mL, 12.21 mmol) were stirred together in DMF (10 mL) for 25 mins. N-(2-aminoethyl)pyrrolidine (Aldrich; 0.51 g, 4.48 mmol) in DMF (2 mL) was added and the solution stirred at ambient temp for 2 hours.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[CH:11]([O:15][CH2:16][CH3:17])[C:12]([OH:14])=O.[NH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=1[Cl:28]>>[Cl:28][C:21]1[CH:22]=[C:23]([C:24]#[N:25])[CH:26]=[CH:27][C:20]=1[CH2:19][NH:18][C:12](=[O:14])[CH:11]([C:3]1[C:4]([F:10])=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[F:1])[O:15][CH2:16][CH3:17]
Reactant: N#Cc1ccc(CN)c(Cl)c1
Reactant: CCOC(C(=O)O)c1c(F)cc(OC)cc1F
Product: CCOC(C(=O)NCc1ccc(C#N)cc1Cl)c1c(F)cc(OC)cc1F

Procedure:
(RS)-(2,6-Difluoro-4-methoxy-phenyl)-ethoxy-acetic acid was coupled with 4-aminomethyl-3-chlorobenzonitrile (CAS 202521-97-9) according to general procedure C to give (RS)-N-(2-chloro-4-cyano-benzyl)-2-(2,6-difluoro-4-methoxy-phenyl)-2-ethoxy-acetamide. Colorless oil. MS 395.0 ([M+H]+)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:7][N:6]=[N:5]1.C(N(CC)CC)C.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCCC1>[C:28]([CH2:27][NH:1][CH2:2][CH2:3][N:4]1[C:8]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:7][N:6]=[N:5]1)([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(CSc2nnnn2CCN)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNCCn1nnnc1SCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
To a solution of 15.0 g. (56 mmol) of 1-(2-aminoethyl)-5-[(4-methoxybenzyl)thio]-1H-tetrazole in 70 ml. of dry tetrahydrofuran was added 7.7 ml. (56 mmol) of triethylamine, and 6.2 ml. (56 mmol) of ethyl bromoacetate. After stirring at room temperature for 15 hours, the mixture was filtered, and the filtrate was evaporated in vacuo to dryness. The residue was dissolved in 70 ml. of chloroform and decolorized with charcoal. The filtrate was chromatographed on silica gel, eluting with a gradient of 0-15% ethyl acetate in chloroform. Fractions containing product by thin layer chromatography were pooled and evaporated to dryness to give 12.5 g. (62% yield) of 1-[2-[[(carbethoxy)methyl]amino]ethyl]-5-[(4-methoxybenzyl)thio]-1H-tetrazole as a brown oil.
Reaction SMILES: [OH-].[Na+].[CH:3]1([N:6]2[C:14]3[N:13]=[CH:12][NH:11][C:10]=3[C:9](=[O:15])[NH:8][C:7]2=[O:16])[CH2:5][CH2:4]1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CO>[CH2:17]([N:11]1[C:10]2[C:9](=[O:15])[NH:8][C:7](=[O:16])[N:6]([CH:3]3[CH2:5][CH2:4]3)[C:14]=2[N:13]=[CH:12]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=c1[nH]c(=O)n(C2CC2)c2nc[nH]c12
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1[nH]c(=O)n(C2CC2)c2ncn(Cc3ccccc3)c12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
10.4 g (0.26 mol) of sodium hydroxide dissolved in 110 ml of water were added to a suspension of 50 g (0.26 mol) of 3-cyclopropylxanthine in 300 ml of methanol and the reaction mixture was stirred for one hour at 70° C., then treated dropwise at the same temperature with 44.5 g (0.26 mol) of benzyl bromide and kept between 70° and 80° C. for 4 hours. 1.04 g (0.026 mol) of sodium hydroxide and 4.45 g (0.026 mol) of benzyl bromide were then added. After a further hour, the mixture was cooled and filtered cold on a suction filter and the product was washed with water on the suction filter. The crude product thus obtained could be employed without further purification.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.O1CCCC1>[C:1]1([C:7]2[N:8]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cn2c(-c3ccccc3)cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.8 %

Procedure:
A solution of 2-phenylindole (4.2 g, 21.7 mmol) and sodium hydride (60% in oil, 0.96 g, 24 mmol) in a mixed solvent of tetrahydrofuran (90 mL) and N,N-dimethylformamide (10 mL) was stirred under ice-cooling for 20 min. Methyl 4-(bromomethyl)benzoate (5.0 g, 21.8 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 18 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography (ethyl acetate:hexane=1:10-1:5-1:2) to give the title compound (2.8 g, yield 38%) as a pale-yellow oil.
Reaction SMILES: I.CS[C:4](=[N:18][CH2:19][CH3:20])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:21][NH2:22]>C(O)C>[CH2:19]([NH:18][C:4]([NH:22][CH3:21])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH3:20]
Reactant: CN
Reactant: CCN=C(Nc1ccccc1N1CCOCC1)SC
Agent: I
Solvent: CCO
Product: CCNC(=Nc1ccccc1N1CCOCC1)NC
Temperature: 45 °C
Reaction time: 336 h

Procedure:
A mixture of 2-methyl-3-ethyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (6 g) and 33% methylamine in absolute ethanol solution (250 ml) was heated initially for 24 hours at 45° C. and then left at room temperature for 14 days to yield 1-ethyl-2-(2-morpholinophenyl)-3-methylguanidine as a colourless solid (m.p. 118°-119° C.) which was recrystallised from hexane.
Reaction SMILES: F[C:2]1[C:3]([CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH:18]([CH3:21])[CH2:17][NH:16][C:15](=[O:22])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:24][C:25]([NH2:28])([CH3:27])[CH3:26].CO.C(Cl)Cl>CS(C)=O>[C:25]([NH:28][C:2]1[C:3]([CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH:18]([CH3:21])[CH2:17][NH:16][C:15](=[O:22])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:27])([CH3:26])[CH3:24]
Reactant: CC(C)(C)N
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)C(C)CNC4=O)c2nc1F
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CO
Product: Cc1nc2cccc(-c3cc4c([nH]3)C(C)CNC4=O)c2nc1NC(C)(C)C
Temperature: 100 °C
Yield: 53.6 %

Procedure:
2-(3-(tert-Butylamino)-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one enantiomers were prepared similar to that described in Example 131 using rac-2-(3-fluoro-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 156; 69.4 mg, 0.224 mmol) and 2-methylpropan-2-amine (TCI America, Portland, Oreg.; 0.071 mL, 0.671 mmol) in DMSO (1.0 mL), heating 100° C. for 1.5 h. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished rac-2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (43.6 mg, 0.120 mmol, 54% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.60 (1H, br. s.), 7.79 (1H, d, J=7.4 Hz), 7.59 (1H, d, J=8.2 Hz), 7.33 (1H, t, J=7.8 Hz), 6.95 (1H, s), 6.92 (1H, br. s.), 5.97 (1H, s), 3.45-3.55 (1H, m), 3.01-3.14 (2H, m), 2.55 (3H, s), 1.54 (9H, s), 1.27 (3H, d, J=6.3 Hz). m/z (ESI, +ve) 364.2 (M+H)+. Separation of this material by supercritical-fluid chromatography (Chiralpak AS-H (250×21 mm, 5 μm), 70% liquid CO2/30% MeOH (+20 mM NH3), 70 mL/min) separately afforded: 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one, first-eluting enantiomer (162; 17.4 mg, 0.048 mmol) as a yellow solid; and 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one, second-eluting enantiomer (163; 16.4 mg, 0.045 mmol) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C@@H:5]2[CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][C@H:4]2[NH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:3]1[C:2](=[O:1])[CH2:7][O:6][C@@H:5]2[CH2:8][NH:9][CH2:10][CH2:11][C@@H:4]12
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2NC(=O)CO[C@@H]2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CO[C@@H]2CNCC[C@H]2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 249C (70.0 mg, 0.0.27 mmol) in 1 mL of CH2Cl2 at room temperature was added TFA (2.00 mL, 25.9 mmol). The mixture was stirred at room temperature for 1 hr and concentrated in vacuo to give crude 249D. This material was mixed with DMA to make a 2 mL stock solution and was used as is in next step reaction.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11](Cl)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:15][CH2:16][CH:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]([N:22]2[CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:18][CH:17]2[CH2:16][OH:15])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncc(Cc2ccccc2)cn1
Reactant: CC(C)(C)OC(=O)N1CCNC(CO)C1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Cc3ccccc3)cn2)C(CO)C1
Temperature: 25 °C
Yield: 22.5 %

Procedure:
A solution of 5-benzyl-2-chloropyrimidine (944 mg, 4.626 mmol), tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1.0 g, 6.939 mmol) and diisopropylethylamine (1.8 g, 13.878 mmol) in dioxane (100 mL) was stirred at 110° C. for two days. The reaction mixture was cooled to room temperature, concentrated and directly purified by silica gel chromatography eluting with petroleum ether:ethyl acetate=1:1, to afford tert-butyl 4-(5-benzylpyrimidin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (400 mg, 15%) as a white solid. MS (ES+) C21H28N4O3 requires: 384, found: 385 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:15][C:16](=[O:25])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.[OH-].[K+].Cl>O1CCCC1>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:16]([CH2:15][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:4]([OH:5])=[O:3])=[O:25])=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cc2ccccc2n1CC(=O)Nc1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Cn1c(C(=O)O)cc2ccccc21)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.45 g 1-[(4-chloro-phenylcarbamoyl)-methyl]-1H-indole-2-carboxylic acid ethyl ester in 100 ml tetrahydrofuran 30 ml water and 0.59 g potassium hydroxide were added. After stirring for 2 hours at room temperature the reaction mixture was acidified with 6 N hydrochloric acid. The precipitate was collected by filtration and was washed with 20 ml water. The product was obtained as a white solid which was dried under reduced pressure.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][CH:10]=1)([O-:8])=[O:7]>C(Cl)Cl>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][NH:17][C:3](=[O:4])[CH2:2][Br:1])=[CH:13][CH:14]=1)([O-:8])=[O:7]
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Product: O=C(CBr)NCCc1ccc([N+](=O)[O-])cc1

Procedure:
Bromoacetyl bromide (806 mg, 4.0 mmol) was added dropwise to a solution of p-nitrophenylethylamine (665 mg, 4.0 mmol, freshly prepared from the hydrochloride salt) in 30 mL CH2Cl2 over 6 min at 0° C. with stirring. Then, the reaction mixture was stirred at 0° C. for 1 h. The resulting precipitate was filtered off and washed twice with 10 mL CH2Cl2, which was combined with tiltrate and rotoevaporated to dryness. Chromatography over 20 g silica gel and elution with 5:3 ethyl acetate:hexane gave crystalline N-(4-nitrophenylethyl)bromoacetamide (compound 74). Recrystallization from ethyl acetate-hexane gave 290 mg (58% yield) of compound 74 as yellow needles: mp 123°-124° C. IR (nujol) 3276, 1659, 1515, 1343 cm-1 ; NMR δ 2.99 (t, 2H), 3.60 (q, 2H), 3.88 (s, 2H), 6.54 (m, 1H), 7.38-8.20 (AA'BB', 4H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][SH:14].[Na]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:13]([S:14][CH:13](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: SCc1ccccc1Cl
Agent: [Na]
Product: Cc1ccc(/C=C\C(SC(/C=C\c2ccc(C)cc2)c2ccccc2Cl)c2ccccc2Cl)cc1

Procedure:
A solution of 4-methylphenylacetylene (0.02 mol) and 2-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-methylstyryl 2-chlorobenzylsulfide. The title compound was obtained in 76% yield following oxidation. 1HNMR (CDCl3) δ 2.50 (3H, s), 4.58 (2H, s), 6.80(1H, d, JH,H=11.88), 7.20-7.63 (9H aromatic+1H ethylenic).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13](I)[C:12]([NH2:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2].[CH2:20](C([Sn])=C(CCCC)CCCC)[CH2:21]CC>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:20]=[CH2:21])[C:12]([NH2:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(N)c(I)cc1CNC(=O)OC(C)(C)C
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(CNC(=O)OC(C)(C)C)c(OC)cc1N
Yield: 42.7 %

Procedure:
To a solution of (4-amino-5-iodo-2-methoxy-benzyl)-carbamic acid tert-butyl ester (700 mg, 1.85 mmol) and tributylvinyltin (783 mg, 2.68 mmol) in toluene was added Pd(PPh3)4 (214 mg, 0.19 mmol) under argon. The resulting mixture was heated with reflux for 8 hrs, filtered through celite, and then concentrated under reduced pressure. The crude residue was column-chromatographed (hexane/ethylacetate=2/1 to 1/1) to yield (4-amino-2-methoxy-5-vinyl-benzyl)-carbamic acid tert-butyl ester (220 mg, 43%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:19]CC3C=CC(OC)=CC=3)[N:13]=[C:12]2[CH3:29])[CH:5]=1.Cl[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[N:34]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:19][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[N:34]=3)[N:13]=[C:12]2[CH3:29])[CH:5]=1
Reactant: Fc1cccc(CCl)n1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(OC)cc3)c(Cl)c2=O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(F)n3)c(Cl)c2=O)c1
Temperature: 45 °C
Yield: 53 %

Procedure:
To a solution of Intermediate 3 (250 mg, 0.81 mmol) in N,N-dimethylformamide (3 mL) was added 2-chloromethyl-6-fluoro-pyridine from Step A (118 mg, 0.81 mmol), potassium carbonate (224 mg, 1.62 mmol) and 18-crown-6 (40 mg). The slurry was heated at 45° C. for eighteen hours. After cooling the reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the alkylated product as a white solid. (180 mg, 53% yield). MS (M+H): 418
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:6][CH:5]=1.NN.O.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(OCCCCCN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(OCCCCCN)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A suspension of 4-[5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pentyloxy]-benzoic acid methyl ester (1 g, 2.72 mmol, Example 283: step a) and hydrazine (98.4 μL, 3.13 mmol) in MeOH:H2O (10 mL, 4:1) was heated to 65° C. for 2 hrs. Additional hydrazine was added (171 μL, 5.44 mmol) to the reaction mixture at rt. The reaction mixture was heated to 70° C. for 2 hrs then stirred overnight at rt. Potassium carbonate (30 mL, 1N aqueous) and methylene chloride (200 mL) were added to the reaction. The organic layer was dried over magnesium sulfate. The solvents were removed in vacuo to afford the title compound as a white solid (500 mg, 77%). 1H-NMR (CDCl3): δ 7.95–8.00 (m, 2H), 6.88–6.92 (m, 2H), 4.02 (t, 2H, J=6.43 Hz), 3.88 (s, 3H), 2.71–2.76 (m, 2H), 1.79–1.86 (m, 2H), 1.49–1.56 (m, 4H).