Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[NH2:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8](Cl)[N:7]=1>O1CCOCC1.C(OCC)(=O)C>[NH2:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([O:2][CH3:1])[N:7]=1
Reactant: CO
Reactant: Nc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cncc(N)n1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
To a stirred solution of methanol (89 μL; 2.2 mmol) in dioxane (1 mL) was added sodium hydride (53 mg; 2.2 mmol). After stirring for 30 minutes, 2-amino-6-chloropyrazine (258 mg; 2.0 mmol) was added and the reaction was heated to 90° C. After stirring for 12 hours, the reaction was cooled to room temperature, diluted with 30 mL of ethyl acetate and washed with aqueous 10% sodium carbonate (1×30 mL), and brine (30 mL), then dried (MgSO4) and filtered. The crude product was purified using the Biotage 12i cartridge eluting with hexane and ethyl acetate (3:1) to yield a white solid (11% yield).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][NH:13][CH2:14][CH2:15][OH:16].C(N([CH2:22][CH3:23])CC)C>ClCCl.COC(C)(C)C>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:16][CH2:15][CH2:14][N:13]([CH3:12])[S:7]([C:4]2[CH:5]=[CH:6][C:22]([CH3:23])=[CH:2][CH:3]=2)(=[O:9])=[O:8])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: CNCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: Cc1ccc(S(=O)(=O)OCCN(C)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
10.55 g of p-toluenesulphonyl chloride are added to a solution of 2.13 ml of 2-(methylamino)-ethanol and 8 ml of triethylamine in 25 ml of dichloromethane while cooling in ice, and the mixture is stirred at room temperature for 20 hours. The reaction mixture is diluted with 100 ml of tert-butyl methyl ether and washed with 0.1M HCl (50 ml), water (50 ml) and brine (50 ml). The organic phase is dried with sodium sulphate and evaporated, whereupon the title compound crystallizes as white solid. Rt=4.67.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11](F)=[N:12][CH:13]=1.[SH:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]>CN1CCCC1=O.C(OCC)C>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([S:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:12][CH:13]=1
Reactant: COC(=O)CS
Reactant: Fc1ccc(Br)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: COC(=O)CSc1ccc(Br)cn1
Temperature: 90 °C
Yield: 39 %

Procedure:
Potassium tert-butoxide (740.0 mg, 6.60 mmol) was added portionwise at room temperature to a solution of 5-bromo-2-fluoropyridine A-5 (0.31 mL, 3.00 mmol) and methyl 2-mercaptoacetate (0.55 mL, 6.00 mmol) in anhydrous 1-methylpyrrolidin-2-one (12.0 mL) under an argon atmosphere, in a 20 mL microwave reactor vial. The reaction mixture was sealed and heated at 90° C. for 3 mins under microwave irradiation, then successively cooled to room temperature, diluted with diethyl ether (150 mL), quenched with water (80 mL) and decanted. The aqueous layer was extracted with diethyl ether (2×150 mL); the combined extracts were sequentially washed with water (2×150 mL), brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give methyl 2-(5-bromopyridin-2-ylthio)acetate A-13 (300.0 mg, Yield=39%). MS (ESI), [M+1]+ 262, 264.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C1COCC1.O.C(OC)(C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:15]([CH3:14])(=[O:17])=[O:16])=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Brc1ccc(Br)nc1
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CS(=O)(=O)c1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2,5-dibromopyridine (5 g, 21.1 mmol) in THF (20 mL) at 0° C. was slowly added 2M isopropylmagnesium chloride in THF (14.4 ml). The mixture was stirred at 0° C. for 1 hour, cooled to −15° C. followed by the dropwise addition of methane sulfonyl chloride in 5 mL THF. The mixture was slowly warmed up to room temperature, diluted with water (5 mL) and t-butylmethyl ether (3×50 mL). The layers were separated and the aqueous layer extracted with t-butylmethyl ether (2×). The combined organic layers were washed with brine, dried MgSO4, filtered and concentrated under reduced pressure and purified by chromatography (silica gel, eluting with 30% hexane-70% ethyl acetate) to provide the titled compound. MS (CI) m/z 237 (M+1)+, 254 (M+NH4)+ 1H NMR (300 MHz, CDCl3) δ ppm: 8.92 (d, 1H), 8.06 (dd, 1H), 7.73 (d, 1H), 3.12 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[N:30]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].Cl.Cl[CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[N:30]([CH2:47][C:48]4[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=4)[C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: ClCc1cccnc1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4cccnc4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-[2-[4-[1H-benzoimidazole-2-carbonyl]-piperidin-1-yl]-ethyl]-3-phenyl-pyrrolidine (710 mg, 1.19 mmol), 3-(chloromethyl)pyridine hydrochloride (794 mg, 4.84 mmol), potassium carbonate (1.337 g, 9.67 mmol) in acetone (21 mL) and water (7 mL). Stir and heat at reflux for 24 h. Allow reaction mixture to cool to room temperature, and remove the acetone under vacuum. Add ethyl acetate to the reaction mixture and separate the organic layer. Extract the organic layer with saturated aqueous NaCl solution, dry over anhydrous Na2SO4, filter and concentrate in vacuo. Chromatograph the residue on silica gel eluting with 30% methanol/ethyl acetate to give the title compound: Rf=0.16 (silica gel, 20% methanol/ethyl acetate)]. Elemental Analysis calculated for C41H44N5O5: C 71.59; H 6.59; N 10.18; Found: C 69.84; H 6.75; N 9.82.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=2)[C:12]=1[CH3:13])=[O:7])[CH3:4].[CH3:22]I.O>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][O:21][CH3:22])=[CH:18][CH:19]=2)[C:12]=1[CH3:13])=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cnn(-c2ccc(CO)cc2)c1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2ccc(COC)cc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (129 mg) was added to a solution of 1-[4-(hydroxymethyl)phenyl]-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (700 mg) in N,N-dimethylformamide (13 ml) at room temperature and stirred at the same temperature for 0.5 hour. Methyl iodide (0.3 ml) was added therein and stirred at 80° C. for two hours. Methyl iodide (0.2 ml) was further added and stirred at the same temperature for an hour. After completion of the reaction, the reaction solution was cooled to room temperature, water was added therein and extracted with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-[4-(methoxymethyl)phenyl]-5-methyl-1H-pyrazol-4-carboxylic acid ethyl ester (401 mg) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]([CH3:33])[C@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>>[CH3:26][N:27]([CH3:33])[C@H:28]1[CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[CH2:29]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CC[C@H](N(C)C)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)—N,N-dimethylpyrrolidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.09-2.30 (m, 1H) 2.33 (d, J=2.27 Hz, 4H) 2.76-2.93 (m, 6H) 3.52-3.78 (m, 3H) 3.83-4.00 (m, 2H) 7.63 (d, J=7.83 Hz, 1H) 7.74 (t, J=7.58 Hz, 1H) 8.21 (d, J=7.58 Hz, 3H) 8.67 (s, 1H).). ESI-MS m/z [M+H]+ 435.3.
Reaction SMILES: [C:1]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])(OCC)=O.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26]CN)=[CH:18]1>>[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][CH2:1][N:6]2[C:7](=[O:16])[C:8]3[C:9](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:11])=[CH:18]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Product: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccccc12
Temperature: 25 °C
Yield: 85.5 %

Procedure:
To a stirred suspension of 2-(1H-indol-3-yl)ethylamine (2.0 g in 20 mL of dry tetrahydrofuran) was added N-carbethoxyphthalimide (2.85 g) and the mixture heated to reflux on an oil bath. After 48 hours the reaction was cooled to room temperature, filtered and the filtrate concentrated in vacuo. The resulting solid was suspended in a mixture of hexane/methylene chloride (2.5:1) and filtered. Purification of the collected solids by flash chromatography on silica gel (methylene chloride:methanol, 97:3) gave the title compound (3.1 g).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH3:6])([O-:3])=[O:2].CO[CH:9]([O:15]C)[CH2:10][CH2:11][CH2:12][CH:13]=O>CCOC(C)=O.CCCCCC>[N+:1](/[C:4](/[CH2:5][CH3:6])=[CH:13]/[CH2:12][CH2:11][CH2:10][CH:9]=[O:15])([O-:3])=[O:2]
Reactant: COC(CCCC=O)OC
Reactant: CCC[N+](=O)[O-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC/C(=C\CCCC=O)[N+](=O)[O-]
Yield: 55.1 %

Procedure:
Prepared according to the general procedure A from 1-nitropropane 112c (80 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (1.51 g, 55% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([CH2:9][O:10][CH2:11][C@@H:12]1[CH2:16][C@@H:15]([OH:17])[CH2:14][N:13]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:19])([OH:8])=[O:7].C(N(CC)CC)C.Cl>ClCCl.O>[C:6]([CH2:9][O:10][CH2:11][C@@H:12]1[CH2:16][C@@H:15]([O:17][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:14][N:13]1[C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=1)=[O:19])([OH:8])=[O:7]
Reactant: O=C(O)COC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h

Procedure:
A solution of methanesulfonyl chloride (0.62 ml) in dichloromethane (2 ml) was dropwise added to a solution of (2S,4R)-2-(carboxymethyloxymethyl)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.42 g) and triethylamine (1.4 ml) in dichloromethane (14 ml) at 0°-5° C. and the mixture was stirred at the same temperature for 1 hour. The mixture was poured into water (50 ml), adjusted to pH 2.5 with 6N hydrochloric acid and extracted with dichloromethane (50 ml×2). The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (1:99 V/V) to give (2S,4R)-2-(carboxymethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.30 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][OH:10])=[CH:4][CH:3]=1.[NH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH2:13]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:13][NH:12][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: O=C(CO)c1ccc(Cl)cc1
Reactant: CCOC(=O)NN
Solvent: CCO
Product: CCOC(=O)NN=C(CO)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A mixture of the compound obtained in Step A (195 mmoles) and ethyl hydrazinecarboxylate (224 mmoles) in ethanol is stirred at reflux for 18 hours. The reaction mixture is cooled to 0° C. and the precipitate formed is filtered off, washed with ethyl ether and dried, in vacuo to yield the title product, which is used directly in the next Step.
Reaction SMILES: [CH:1]1[C:10]2[N:9]3[CH:11]=[CH:12][CH:13]=[C:8]3[C:7]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[O:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[F:26][C:27]([F:42])([F:41])[S+]1C2C=CC=CC=2C2C=CC=CC1=2.O>CN(C=O)C>[F:26][C:27]([F:42])([F:41])[C:11]1[N:9]2[C:10]3[CH:1]=[CH:2][CH:3]=[N:4][C:5]=3[O:6][C:7]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:8]2=[CH:13][CH:12]=1
Reactant: FC(F)(F)[s+]1c2ccccc2c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ncccc1-n1cccc12
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ncccc1-n1c(C(F)(F)F)ccc12
Yield: 51.6 %

Procedure:
A solution of tert-butyl spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate (134 mg, 0.393 mmol) and 5-(trifluoromethyl)dibenzothiophen-5-ium (99.4 mg, 0.393 mmol) in DMF (2 mL) was stirred at 80° C. for 1.5 hours. The mixture was poured into water and was extracted with EtOAc (3×). The organics were combined, washed with water and brine, dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography (1-30% EtOAc/hexanes) to give tert-butyl 9′-(trifluoromethyl)spiro-[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate (83 mg, 56%). ESI-MS m/z calc. 409.2, found 410.5 (M+1)+; Retention time: 1.92 minutes (3 min run).
Reaction SMILES: [C:1]([C:5]1[C:13]2[C:12]([Cl:14])=[N:11][C:10]([NH2:15])=[N:9][C:8]=2[N:7]([CH2:16][C:17]2[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=2)[CH:6]=1)#CC=C.CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:48]C)C=C4)N(CC2)C1.C[C:86]([OH:89])([CH3:88])[CH3:87].C1COCC1.O>>[NH2:15][C:10]1[N:11]=[C:12]([Cl:14])[C:13]2[C:5]([C:1]#[C:87][C@H:86]([OH:89])[CH2:88][OH:48])=[CH:6][N:7]([CH2:16][C:17]3[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=3)[C:8]=2[N:9]=1
Reactant: C=CC#Cc1cn(Cc2ncc(C)c(OC)c2C)c2nc(N)nc(Cl)c12
Reactant: CC(C)(C)O
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)cnc(Cn2cc(C#C[C@H](O)CO)c3c(Cl)nc(N)nc32)c1C

Procedure:
Treatment of 5-(but-3-en-1-ynyl)-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo [2,3-d]pyrimidin-2-amine (see example 46) (35 mg) with AD-mix-α (Aldrich, 540 mg) in t-BuOH:THF:water 1:1:1 (6 mL) at rt overnight, followed by work-up and reverse-phase preparative HPLC gave the title compound (10 mg), as a solid. HPLC Rt=4.13 min
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].N1C=CC=CC=1.[CH3:41][S:42](Cl)(=[O:44])=[O:43].O>ClCCl>[CH3:41][S:42]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(N)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(NS(C)(=O)=O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reaction time: 1.5 h
Yield: 44.1 %

Procedure:
4-Amino-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0820 g, 0.178 mmol) was dissolved in dichloromethane (4.0 mL), and the solution was added with pyridine (0.0430 mL, 0.534 mmol) and methanesulfonyl chloride (0.0210 mL, 0.267 mmol), followed by stirring for 1.5 hours under ice-cooling. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (chloroform/methanol=4/1) to obtain 4-methanesulfonylamino-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0423 g, yield 44%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][N:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][C:8]=2[CH3:17])[C:4](=[O:18])[NH:3]1.[OH-].[K+]>CO.O>[CH3:1][C:2]1([CH3:19])[CH2:6][N:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[CH3:17])[C:4](=[O:18])[NH:3]1
Reactant: COC(=O)c1ccc(N2CC(C)(C)NC2=O)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)O)ccc1N1CC(C)(C)NC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.70 g (10.3 mmol) methyl 4-(4,4-dimethyl-2-oxo-imidazolidin-1-yl)-3-methyl-benzoate are suspended in 75 ml of methanol and combined with a solution of 1.68 g (30.0 mmol) potassium hydroxide in 10 ml of water. It is stirred for 3 hours at ambient temperature and then evaporated down i. vac. The aqueous residue is diluted with water, acidified with 1-molar hydrochloric acid and the precipitate obtained is suction filtered, washed with water and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].[C:13]1([Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CO.C(O)(C(F)(F)F)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([OH:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1Nc2c(F)cccc2C1=O
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C1Nc2c(F)cccc2C1(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirring solution of 7-fluoroindoline-2,3-dione (12.22 g, 74 mmol) in THF (40 mL) at 0° C. was added phenylmagnesium bromide (148 mL, 148 mmol) dropwise. The reaction mixture was allowed to stir at room temperature for 15 min after the addition was completed. The reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel chromatography (EtOAc/hexane) to afford Intermediate A-7A (18.84 g, 88%) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.37-7.25 (m, 5H), 7.19 (ddd, J=10.4, 8.1, 1.3 Hz, 1H), 7.04-6.92 (m, 2H); HPLC: RT=1.810 min (CHROMOLITH® SpeedROD column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm); MS(ES): m/z=599 [M+H−H2O]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].[CH:31]1[C:43]2[CH:42]([CH2:44][O:45][C:46]([NH:48][C@H:49]([C:54]3[CH:59]=[CH:58][C:57](O)=[CH:56][CH:55]=3)[C:50]([O:52][CH3:53])=[O:51])=[O:47])[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]=2[CH:34]=[CH:33][CH:32]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:26]([O:25][C:24]([NH:23][CH2:22][CH2:21][O:20][C:57]1[CH:58]=[CH:59][C:54]([C@@H:49]([NH:48][C:46]([O:45][CH2:44][CH:42]2[C:43]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=3[C:36]3[C:41]2=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:47])[C:50]([O:52][CH3:53])=[O:51])=[CH:55][CH:56]=1)=[O:30])([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COC(=O)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccc(OCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
To a solution of 0.465 g (1.77 mmol) of triphenylphosphine in 10 mL of THF was added 0.286 g (1.77 mmol) of tert-butyl N-(2-hydroxyethyl)-carbamate followed by 0.476 g (1.18 mmol) of methyl(2R)-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}(4-hydroxyphenyl)ethanoate and 0.279 mL (1.77 mmol) of diethyl azodicarboxylate. The reaction was stirred overnight at room temperature and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:3) to give 0.383 g of methyl (2R)-(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl){[(9H-fluoren-9-ylmethoxy)carbonyl]amino}ethanoate as a white solid. Electrospray Mass Spec 547.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:10]2=[C:13]3[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]3[CH2:8][C:9]2=[O:14].[H-].[Na+].[CH2:17](I)[CH2:18][CH3:19].[CH2:21]1[CH2:25]OC[CH2:22]1>>[CH2:17]([C:8]1([CH2:22][CH2:21][CH3:25])[C:7]2[C:13]3[C:3]([CH:4]=[CH:5][CH:6]=2)=[C:2]([Br:1])[CH:12]=[CH:11][C:10]=3[C:9]1=[O:14])[CH2:18][CH3:19]
Reactant: O=C1Cc2cccc3c(Br)ccc1c23
Reactant: CCCI
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCCC1(CCC)C(=O)c2ccc(Br)c3cccc1c23
Reaction time: 1 h
Yield: 80 %

Procedure:
To a heat dried 8 ml vial loaded with 6-bromo-1,2-dihydroacenaphthylen-1-one (100 mg, 0.41 mmol) and sodium hydride (49 mg, 0.4 mmol) was added 1 ml THF. Propyl iodide (230 μl, 0.4 mmol) was then added to the above purple solution and the mixture was stirred for 1 hour. The reaction was then quenched with 300 ml acetic acid followed by the addition of DCM. The precipitate formed was filtered off and the filtrate concentrated to dryness to give 2.5 grams (80%) of product. NMR and MS confirmed the product.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[C:12]1([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Brc1ccccc1
Reactant: CC(C)(C)N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)Nc1ccccc1
Reaction time: 0.5 h
Yield: 50 %

Procedure:
t-Butylamine (2.0 eq.) was stirred in dry THF at r.t. and n-butyllithium (1.2 eq.) was added slowly. The resulting mixture was stirred for 30 min. and then bromobenzene (1.0 eq.) added, refluxed for 4 hr. After work-up, it was purified and separated by a column(silica) to elute with hexane and ethyl acetate (9:1). Yield 50%.