Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([Sn](CCCC)(CCCC)CCCC)[N:3]=1.[Cl:23][C:24]1[C:33](Cl)=[N:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1>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>[Cl:23][C:24]1[C:33]([C:4]2[CH:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([CH3:1])[N:3]=2)=[N:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(SC)nc(C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CSc1cc(-c2nc3ccccc3nc2Cl)nc(C)n1
Temperature: 120 °C
Yield: 70.8 %

Procedure:
A glass microwave reaction vessel was charged with 2-methyl-4-(methylthio)-6-(tributylstannyl)pyrimidine (1.6 g, 3.73 mmol), 2,3-dichloroquinoxaline (1.484 g, 7.45 mmol, Aldrich) and tetrakis(triphenylphosphine)palladium (0.431 g, 0.373 mmol, Strem Chemicals) in toluene (5 mL). Argon was bubbled through for 2 min. The reaction mixture was stirred and heated at 120° C. for 36 h. The mixture was cooled to room temperature, filtered through Celite® (diatomaceous earth) washing with 10% methanol-DCM, and the filtrate was concentrated. The crude product was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0-100% DCM-hexane to give 2-chloro-3-(2-methyl-6-(methylthio)pyrimidin-4-yl)quinoxaline (0.8 g, 2.64 mmol, 70.9% yield) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 8.23 (dd, J=8.02, 1.56 Hz, 1H); 8.13-8.19 (m, 1H); 7.96-8.05 (m, 2H); 7.73 (s, 1H); 2.67 (s, 3H); 2.61 (s, 3H). m/z (ESI, +ve ion) 303 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[N:25]([CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)[CH:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1>O1CCCC1.Cl>[ClH:1].[ClH:1].[ClH:1].[NH2:28][CH2:27][CH2:26][N:25]1[C:18]2[C:17]([NH:16][C:4]3[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=4)=[C:2]([Cl:1])[CH:3]=3)=[N:22][CH:21]=[N:20][C:19]=2[CH:23]=[CH:24]1
Reactant: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c21
Agent: Cl
Solvent: C1CCOC1
Product: NCCn1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c21
Temperature: 60 °C
Reaction time: 16 h
Yield: 410.5 %

Procedure:
tert-Butyl [2-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (790 mg) was dissolved in tetrahydrofuran (24 mL)/2N hydrochloric acid (12 mL), and the mixture was stirred at 60° C. for 16 hrs. The reaction mixture was concentrated under reduced pressure, ethanol (30 mL) was added to the residue and the mixture was concentrated again under reduced pressure. Ethyl acetate was added to the residue and the solid was collected by filtration and dried under reduced pressure to give the title compound (826 mg) as a solid powder.
Reaction SMILES: [CH3:1]CCCC.C([Li])(C)(C)C.[CH2:11]([CH:13]1[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[S:23][C:24]([CH:26]=O)=[CH:25][C:15]=2[N:14]1[S:28]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:11]([CH:13]1[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[S:23][C:24]([CH:26]=[CH2:1])=[CH:25][C:15]=2[N:14]1[S:28]([C:31]1[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=1)(=[O:29])=[O:30])[CH3:12]
Reactant: CCC1c2ccccc2-c2sc(C=O)cc2N1S(=O)(=O)c1ccc(OC)cc1
Reactant: CCCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C=Cc1cc2c(s1)-c1ccccc1C(CC)N2S(=O)(=O)c1ccc(OC)cc1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A suspension of methyltriphenylphosphonium bromide (2.30 g, 6.44 mmol) in dry tetrahydrofuran (16 mL) was treated dropwise with a pentane solution of t-butyllithium (1.0 M, 3.9 mL, 3.9 mmol) at 0° C. during several min. After the addition was complete, the suspension was warmed to 23° C. and after a further 10 min, a solution of 5-ethyl-4-[(4-methoxyphenyl)sulfonyl]-4,5-dihydrothieno[3,2-c]isoquinoline-2-carbaldehyde (1.33 g, 3.22 mmol) in dry tetrahydrofuran (16 mL+8 mL wash) was added. After a further 15 min, the reaction was quenched with water (160 mL) and extracted with ethyl acetate (160 mL). The extract was washed with brine (160 mL), dried (Na2SO4), and concentrated in vacuo to give the crude product as an orange solid (2.46 g). Flash chromatography on silica gel (24 g) eluting 25-, and then 50% methylene chloride-hexane gave the title compound (1.20 g, 90%, m.p. 131-33° C.) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>C(Cl)Cl>[C:18]([Si:15]([O:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])([CH3:17])[CH3:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cccc(F)c1O
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(F)c1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-fluoro-6-methylphenol (176 mg, 1.40 mmol) in DCM (6.3 mL), cooled to 0° Celsius, were added imidazole (142 mg, 2.09 mmol) followed by tert-butyldimethylsilyl chloride (231 mg, 1.54 mmol). The flask was warmed to rt and stirred for 2 hours The reaction mixture was then poured in to water (50 mL) and extracted with DCM (3×50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to dryness to provide the title compound that was used without further purification. 1H NMR (500 MHz, CDCl3) δ 6.91-6.85 (m, 2H), 6.80-6.73 (m, 1H), 2.24 (t, J=0.7, 3H), 1.02 (s, 9H), 0.20 (d, J=2.5, 6H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([OH:11])=[CH:9][C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[N:6]=1)=O.C(O)(=O)C.[NH3:27]>CO>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([N:7]2[C:8](=[O:12])[CH:9]=[C:10]([OH:11])[C:5]([C:3]([NH2:27])=[O:2])=[N:6]2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COC(=O)c1nn(-c2ccc(OC)c(OC)c2)c(=O)cc1O
Reactant: N
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(-n2nc(C(N)=O)c(O)cc2=O)cc1OC

Procedure:
The pyridazine (29) (295 mg) was dissolved in 3 ml of 7N NH3 in methanol and heated to reflux in a sealed tube for 4 hours. The reaction was allowed to cool, neutralized with acetic acid, and concentrated to dryness to give 266 mg of desired amide (30) as a solid. MS+: m/e=292.0 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1>>[N+:11]([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(CCO)cc1
Product: O=[N+]([O-])c1ccc(Nc2ccc(CCO)cc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2-chloro-1,5-dinitrobenzene and 4-aminophenylethyl alcohol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.[Br:11][CH2:12][CH2:13]Br>>[Br:11][CH2:12][CH2:13][O:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[Cl:10]
Reactant: BrCCBr
Reactant: Cc1cc(Cl)c(O)c(Cl)c1
Product: Cc1cc(Cl)c(OCCBr)c(Cl)c1
Yield: 61 %

Procedure:
4-Methyl-2,6-dichlorophenol was reacted with 1,2-dibromoethane according to the procedure described in Step 2A to yield the titled compound (4.66 g, 61%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.29 (s, 3H) 3.70 (d, J=7.20 Hz, 2H) 4.29 (d, J=7.20 Hz, 2H) 7.11 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[NH:6]2.ClS([N:20]=[C:21]=[O:22])(=O)=O>C(#N)C>[C:21]([C:4]1[C:3]2[C:7](=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[CH3:1])[NH:6][C:5]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:22])[NH2:20]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COC(=O)c1cc2c(C)ccc(C)c2[nH]1
Solvent: CC#N
Product: COC(=O)c1[nH]c2c(C)ccc(C)c2c1C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
A solution of 2.0 g (9.9 mmol) of methyl 4,7-dimethylindole-2-carboxylate in 200 ml of anhydrous acetonitrile was cooled to 0° C. A solution of 3 ml (9.9 mmol) of chlorosulfonylisocyanate in 50 ml of anhydrous acetonitrile was added dropwise over a period of 15 minutes and the reaction mixture was stirred at room temperature for 30 minutes. After distilling off acetonitrile under reduced pressure, the residue was dissolved in 15 ml of acetonitrile-water (4:1). The pH of the solution was adjusted to 8 by gradually adding 10% potassium hydroxide aqueous solution dropwise. The white crystals precipitated were separated by filtration and air-dried and then dried under reduced pressure to provide 1.0 g of white crystals.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:13]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C.O>[Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:23]([C:20]3[CH:21]=[CH:22][C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1cnc2[nH]ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(S(=O)(=O)n2ccc3nc(Br)cnc32)cc1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
A solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (5.00 g, 25.2 mmol, Ark Pharm) in DMF (150 mL) was cooled in an ice bath to about 0° C. and then NaH (60% dispersion in mineral oil, 1.21 g, 30.3 mmol) was added. After about 15 min, 4-tert-butylbenzene-1-sulfonyl chloride (6.46 g, 27.8 mmol) was added. The reaction was maintained between about 0-10° C. for about 2 h. Then, the reaction was diluted with water (200 mL) to give a yellow suspension. The solid was collected by vacuum filtration, while washing with additional water (100 mL), and dried in a vacuum oven at about 70° C. to give 2-bromo-5-(4-tert-butylphenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (9.05 g, 91%): LC/MS (Table 2, Method a) Rt=3.05 min; MS m/z: 394/396 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([CH3:10])[N:3]=1.S(Cl)([Cl:13])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][Cl:13])[CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1cc(CO)cc(Cl)n1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(CCl)cc(Cl)n1

Procedure:
2.2 1.14 g of (2-chloro-6-methylpyridin-4-yl)methanol are initially introduced in 50 ml of toluene, and 1.05 ml of thionyl chloride are slowly added dropwise with ice cooling. The mixture is boiled under reflux overnight. After cooling, the solvent is removed, giving 2-chloro-4-chloromethyl-6-methylpyridine as brown oil (1.1 g).
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]=1[CH2:7]Br.C([O-])(O)=[O:14].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[O:3][C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]=1[CH2:7][OH:14]
Reactant: BrCc1c(Br)oc2ccccc12
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: OCc1c(Br)oc2ccccc12
Temperature: 25 °C

Procedure:
2-bromo-3-bromomethyl benzofuran prepared from Step A (7.67 g, 26.45 mmol) was immediately dissolved in dioxane (30 mL), followed by a solution of NaHCO3 (2.67 g, 1.2 eq.) in water (30 mL). The mixture was refluxed for 1 h with vigorous stirring, cooled to room temperature, diluted with water (150 mL) and extracted with dichloromethane (5×100 mL). The extract was washed with brine, dried over sodium sulfate, and the solvent removed under reduced pressure. The resulting orange oil was dissolved in chloroform (12 mL) and left to stand at −20° C. The resulting yellow prisms were filtered at −40° C., washed with chloroform, and filtered cold. Yield: 3.72 g (62%). MS (m/e): 228, 226 (M+), 211, 209, 183, 181, 171, 169, 147, 118, 102, 91. 1H-NMR (acetone-D6): 4.29 (t, 1H, J=6 Hz) 4.73 (d, 2H, J=6 Hz) 7.32 (m, 2H) 7.51 (d, 1H, J=8 Hz) 7.78 (dd, 1H, J=8 Hz, 2 Hz). 13C-NMR (acetone-D6): 54.74, 110.64, 119.96, 123.28, 124.57, 126.51, 128.12, 155.37.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:9])([CH3:8])[C:5]([OH:7])=O.[CH3:10][O:11][NH:12][CH3:13].Cl.C([O-])([O-])=O.[K+].[K+]>S(Cl)(Cl)=O>[CH3:1][O:2][CH2:3][C:4]([CH3:9])([CH3:8])[C:5]([N:12]([O:11][CH3:10])[CH3:13])=[O:7]
Reactant: CNOC
Reactant: COCC(C)(C)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Product: COCC(C)(C)C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.5 %

Procedure:
A solution of 3-methoxy-2,2-dimethyl-propionic acid (1.0 g, 7.6 mmol) in thionyl chloride (5 ml) was heated to 50° C. for 16 hours. The reaction mixture was concentrated to a yellow residue and then dissolved in DCM (15 ml). O,N-Dimethyl-hydroxylamine-hydrogen chloride (886 mg, 9.1 mmol) and powdered K2CO3 (2.2 g, 16 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through a filter funnel, and the filtrate was collected and concentrated giving a white semisolid. The crude product was purified by silica gel chromatography using 20-50% EtOAc in hexanes as eluant providing 260 mg (20%) of 3,N-dimethoxy-2,2,N-trimethyl-propionamide as a colorless oil.
Reaction SMILES: [CH2:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:3](=[O:4])[CH2:2]1.O.[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[N+:13]([C:8]1[CH:7]=[C:1]2[C:11](=[CH:10][CH:9]=1)[CH2:6][NH:5][C:3](=[O:4])[CH2:2]2)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCc2ccccc2N1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1Cc2cc([N+](=O)[O-])ccc2CN1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To a solution of hydrocarbostyril (9.00 g, 61.2 mmol) in conc. H2SO4 (180 mL) cooled to −10° C. was slowly added H2O (45 mL), followed by HNO3 (65%, 4.5 mL). The yellow solution was stirred at −10° C. for 10 min and then carefully quenched at −10° C. with H2O (500 mL). The precipitated yellow solid was filtered off, washed with H2O and dried in vacuo to yield 1,2-dihydro-6-nitroisoquinolin-3(4H)-one (10.3 g, 88% yield). 1H NMR (400 MHz, CDCl3): δ 9.35 (brs, 1H), 8.12-8.09 (m, 2H), 6.95-6.92 (m, 1H), 3.10 (t, J=7.6 Hz, 2H), 2.73 (t, J=7.8 Hz, 2H); MS (ESI) m/z: 193.0 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:14]([CH2:20][CH2:21][OH:22])[O:13][C:12]1([CH3:24])[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:18])[CH3:19])[C@H:14]([CH2:20][CH2:21][O:22][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[O:13][C:12]1([CH3:24])[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)C[C@H]1[C@H](CCO)OC(C)(C)N1C(=O)OCc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC[C@@H]2OC(C)(C)N(C(=O)OCc3ccccc3)[C@H]2CC(C)C)cc1
Yield: 78.7 %

Procedure:
3.89 g of (4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-5-(2-hydroxyethyl)-4-isobutyloxazolidine was dissolved in 15 ml of pyridine, and 2.65 g of p-toluenesulfonyl chloride was added and dissolved therein. The mixture was then reacted at room temperature overnight. The reaction solution thus obtained was concentrated, and precipitated insolubles were filtered off. The filtrate thus obtained was purified by silica gel column chromatography (developer: benzene/ethyl acetate (30/1)) to obtain 4.47 g of (4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-5-(2-p-toluenesulfonyloxyethyl)-4-isobutyloxazolidine as a syrup.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:52])([CH3:51])[CH2:35][CH:36]([Sn:38]([CH2:47][CH2:48][CH2:49][CH3:50])([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41][CH3:42])O)=[CH:30][CH:29]=1>C(Cl)Cl.C(#N)C>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:52])([CH3:51])[CH2:35][CH:36]([I:25])[Sn:38]([CH2:47][CH2:48][CH2:49][CH3:50])([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41][CH3:42])=[CH:30][CH:29]=1
Reactant: II
Reactant: CCCC[Sn](CCCC)(CCCC)C(O)CC(C)(C)c1ccc(F)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)C(I)CC(C)(C)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 39.8 %

Procedure:
A solution of 30.4 grams (0.116 mole) of triphenylphosphine in about 116 mL of methylene chloride is stirred, and 7.9 grams (0.116 mole) of imidazole is added. Upon completion of addition, the reaction mixture is stirred about one hour until the imidazole dissolves, then 29.4 grams (0.116 mole) iodine is added portionwise. After the iodine dissolves, the reaction mixture is cooled to 0° C., and a solution of 36.3 grams (0.077 mole) of 3-(4-fluorophenyl)-3-methyl-1-tributylstannylbutanol in about 77 mL of methylene chloride is added dropwise, while maintaining the reaction mixture temperature below 0° C. Upon completion of addition, the reaction mixture is allowed to warm to ambient temperature where it is stirred for about 18 hours. The reaction mixture is then taken up in about 500 mL of acetonitrile and extracted with three 300 mL portions of hexane. The combined extracts are concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel, using petroleum ether as the eluant. The product-containing fractions are combined and concentrated under reduced pressure, yielding 17.8 grams of 3-(4-fluorophenyl)-3-methyl-1-iodo-1-tributylstannylbutane. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: CN1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][CH2:4][C:3]1=[O:19].[CH2:20]([O:22]C(=O)OCC)[CH3:21]>>[CH2:20]([O:22][C:3]([C:4]1[NH:5][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=[O:19])[CH3:21]
Reactant: CN1C(=O)CN=C(c2ccccc2)c2ccccc21
Reactant: CCOC(=O)OCC
Product: CCOC(=O)c1[nH]c(-c2ccccc2)c2ccccc12

Procedure:
The starting material can be prepared from 1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and diethylcarbonate in a manner analogous to that described in Example 1. After recrystallization from ethanol, there is obtained 3-phenylisoindole-1-carboxylic acid ethyl ester; m.p. 144°-147° C (decomposition).
Reaction SMILES: CCN(C(C)C)C(C)C.Br[CH2:11][CH2:12][F:13].[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]2[N:22]([C:37]3[C:38]4[C@H:45]([CH3:46])[CH2:44][CH2:43][C:39]=4[N:40]=[CH:41][N:42]=3)[CH2:23][C:24]3([CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)[C:17]=12>CN(C=O)C>[F:13][CH2:12][CH2:11][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]2[N:22]([C:37]3[C:38]4[C@H:45]([CH3:46])[CH2:44][CH2:43][C:39]=4[N:40]=[CH:41][N:42]=3)[CH2:23][C:24]3([CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:26][CH2:25]3)[C:17]=12
Reactant: FCCBr
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c(CN)cccc43)c21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c(CNCCF)cccc43)c21
Temperature: 80 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
DIEA (0.015 mL, 0.093 mmol) and 1-bromo-2-fluoroethane (0.0067 mL, 0.075 mmol) was added to a stirred solution of (R)-tert-butyl 4-(aminomethyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (28 mg, 0.062 mmol) in DMF (0.6 mL) The reaction mixture was stirred at 80° C. overnight. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (DCM:MeOH, 60:1) to give (R)-tert-butyl 4-((2-fluoroethylamino)methyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (12 mg, 39%) as an oil. LCMS (APCI+) m/z 496 [M+H]+; Rt=3.03 min.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:2].Cl.C(OCC)(=O)C>[Pd].C(O)C>[NH2:2][CH2:1][CH2:3][N:4]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cc2c(n1CC#N)CCCC2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(n1CCN)CCCC2
Reaction time: 6 h
Yield: 56.1 %

Procedure:
A 200-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 1.28 g dry weight), 115i (3.00 g, 12.9 mmol), 12% hydrochloric acid (6.5 mL, 25 mmol), ethyl acetate (60 mL) and ethanol (40 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 6 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (4.0 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×20 mL), and the combined filtrates were concentrated to dryness under reduced pressure. The residue was partitioned between ethyl acetate (150 mL) and 10% aqueous potassium carbonate (100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×75 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with ethanol (5 mL) to afford a 71% yield (1.71 g) of 115j as a white solid: mp 102-104° C.; 1H NMR (500 MHz, DMSO-d6) δ 6.61 (s, 1H), 6.22 (br, 2H), 4.15 (m, 4H), 2.77 (m, 2H), 2.59 (t, 2H, J=6.5 Hz), 2.42 (t, 2H, J=6.5 Hz), 1.70 (m, 2H), 1.62 (m, 2H), 1.23 (t, 3H, J=7.0 Hz); MS (APCI+) m/z 237.2 (M+H)
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].C(=O)([O-])O.[NH4+].O>C(#N)C>[C:1]([NH:4][C@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc([N+](=O)[O-])c1)NC(C)=O
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)[C@@H](Cc1cccc([N+](=O)[O-])c1)NC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
A mixture of 2.8 g of ethyl 2-(acetylamino)-3-(3-nitrophenyl)propanoate in 17 cm3 of acetonitrile [lacuna] to which is added 3.95 g of ammonium hydrogen carbonate and 35 cm3 of water at a pH in the region of 8. 0.017 g of type-II α-chymotrypsin is then introduced and the mixture is left stirring at room temperature for 1 hour 15 min, while measuring the pH regularly. After this reaction time, the pH is less than 8, a further 0.017 g of type-II α-chymotrypsin is added and stirring of the reaction medium is continued for 2 hours 45 min. The aqueous phase is extracted with 3 times 50 cm3 of ethyl acetate; the combined organic phases are then dried over sodium sulfate, filtered and evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.4 g of ethyl (2R)-2-(acetylamino)-3-(3-nitrophenyl)propanoate are obtained in the form of white crystals melting at 110° C.