Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH:21][CH:22]([CH3:24])[CH3:23])[N:15]=3)=[CH:12][N:13]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[OH:26])[CH3:2].Cl[CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31]>CC(O)C.[OH-].[Na+].CCOC(C)=O>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH:21][CH:22]([CH3:23])[CH3:24])[N:15]=3)=[CH:12][N:13]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[O:26][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[CH3:2]
Reactant: OC[C@H](O)CCl
Reactant: CCc1cc(-c2ncc(-c3cc(C)nc(NC(C)C)n3)o2)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2ncc(-c3cc(C)nc(NC(C)C)n3)o2)cc(C)c1OCC(O)CO
Temperature: 25 °C
Reaction time: 15 h
Yield: 24.8 %

Procedure:
To a solution of 2-ethyl-4-[5-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-oxazol-2-yl]-6-methyl-phenol (30 mg, 85 μmol) in iPrOH (4 mL), 3M aq. NaOH (1 mL) followed by (S)-3-chloro-propane-1,2-diol (67 μL, 0.85 mmol) is added. The reaction mixture is stirred at rt for 15 h, and is then diluted with EtOAc and washed with 1M aq. NaOH followed by brine. The org. solution is dried over Na2SO4, filtered and evaporated to give 3-{2-ethyl-4-[5-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-oxazol-2-yl]-6-methyl-phenoxy}-propane-1,2-diol (9 mg) as a yellow solid; LC-MS: tR=0.79 min, [M+H]+=426.80.
Reaction SMILES: O.NN.O=C1C2C(=CC=CC=2)C(=O)[N:6]1[CH2:15][CH2:16][N:17]1[C@@H:22]([CH3:23])[CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C@H:18]1[CH3:31]>CO>[NH2:6][CH2:15][CH2:16][N:17]1[C@@H:22]([CH3:23])[CH2:21][N:20]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:19][C@H:18]1[CH3:31]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1CCN
Temperature: 50 °C
Reaction time: 18 h
Yield: 67.5 %

Procedure:
Hydrazine hydrate (0.11 ml) was added to a solution of tert-butyl (cis)-4-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3,5-dimethyl-1-piperazinecarboxylate (0.736 g) [see Preparation 6] in methanol (1.1 ml). The reaction mixture was then stirred at 50° C. for 18 hours, after which time the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and 10% citric acid. The aqueous layer was separated, basified with potassium carbonate, and the product extracted with tetrahydrofuran:ethyl acetate, 1:1, several times. The combined organic layers were dried over magnesium sulphate and the solvent removed under reduced pressure to afford tert-butyl (cis)-4-(2-aminoethyl)-3,5-dimethyl-1-piperazinecarboxylate (0.33 g) as a oil.
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]([S:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][C@@H:23]3[C:28]([NH:30][O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)=[O:29])(=[O:21])=[O:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:3]([O:2][C:1]([N:25]1[CH2:26][CH2:27][N:22]([S:19]([C:17]2[S:18][C:14]([C:11]3[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=3)=[CH:15][CH:16]=2)(=[O:21])=[O:20])[C@@H:23]([C:28]([NH:30][O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)=[O:29])[CH2:24]1)=[O:5])[CH3:4]
Reactant: CCOC(=O)Cl
Reactant: O=C(NOC1CCCCO1)[C@H]1CNCCN1S(=O)(=O)c1ccc(-c2ccc(F)cc2)s1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(S(=O)(=O)c2ccc(-c3ccc(F)cc3)s2)[C@@H](C(=O)NOC2CCCCO2)C1
Yield: 82.1 %

Procedure:
A solution of ethyl chlorocarbonate (42 mg) in CHCl3 (1 ml) was added dropwise to a solution of (2R)-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (150 mg) and triethylamine (39 mg) in CHCl3 (2 ml) with cooling on an ice bath. The reaction mixture was stirred at said temperature for 30 minutes and the reaction was quenched by adding 3-(N,N-dimethylamino)propylamine (0.5 ml). The mixture was concentrated in vacuo, and the residue was partitioned between AcOEt and 5% aqueous citric acid. The organic layer was washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried over MgSO4, and concentrated in vacuo. The residue was purified by SiO2 column chromatography eluted with AcOEt in hexane gradually from 40% to 60%, to give 142 mg of (2R)-4-ethoxycarbonyl-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide.
Reaction SMILES: O[CH2:2][CH:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:4]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]1(=[O:50])[NH:44][C:43](=[O:45])[C:42]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]12.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CO>[O:45]=[C:43]1[C:42]2[C:41](=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:40](=[O:50])[N:44]1[CH2:2][CH:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:4]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5]
Reactant: CC(C)(C)OC(=O)NC(CO)C(C)(C)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CN1C(=O)c2ccccc2C1=O)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
To a solution of 1,1-dimethylethyl [1-(hydroxymethyl)-2-methyl-2-phenylpropyl]carbamate (775 mg, 2.8 mmol), triphenylphosphine (915 mg, 3.5 mmol) and phthalimide (499 mg, 3.4 mmol) in THF (15 mL) at 25° C. was added diethyl azodicarboxylate (0.54 mL, 3.4 mmol). After stirring at RT for 1 h, MeOH was added (5 mL) and the reaction solution was adsorbed onto silica then purified via column chromatography(1% MeOH in DCM) affording the title compound (723 mg, 64%) as a white solid: LCMS (ES) m/z 409 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([C:19]2[C:20]3[C:21]4[CH:35]=[CH:34][S:33][C:22]=4[C:23](=[O:32])[NH:24][C:25]=3[C:26]([CH3:31])=[CH:27][C:28]=2[O:29]C)[CH:16]=[CH:15][C:3]=1[CH2:4][CH2:5][N:6](C)[C:7](=O)OC(C)(C)C.B(Br)(Br)Br.C(Cl)[Cl:41]>>[ClH:41].[F:1][C:2]1[CH:18]=[C:17]([C:19]2[C:20]3[C:21]4[CH:35]=[CH:34][S:33][C:22]=4[C:23](=[O:32])[NH:24][C:25]=3[C:26]([CH3:31])=[CH:27][C:28]=2[OH:29])[CH:16]=[CH:15][C:3]=1[CH2:4][CH2:5][NH:6][CH3:7]
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCN(C)C(=O)OC(C)(C)C)c(F)c1
Reactant: ClCCl
Agent: BrB(Br)Br
Product: CNCCc1ccc(-c2c(O)cc(C)c3[nH]c(=O)c4sccc4c23)cc1F
Product: Cl
Temperature: 25 °C
Yield: 67 %

Procedure:
Following General Procedure F, tert-butyl 2-fluoro-4-(8-methoxy-6-methyl-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenethyl(methyl)carbamate (60 mg, 0.12 mmol) in CH2Cl2 at 0° C. was added BBr3 (1.0 M in CH2Cl2, 6 mL, 6 mmol) and the reaction was warmed to room temperature for 4 h. The reaction was quenched by pouring onto water or ice-water and the resulting mixture was concentrated and purified by preparatory HPLC (C18 silica, acetonitrile/water (with 0.05% TFA) gradient). The desired product was dissolved in aqueous HCl, concentrated and dried under high vacuum to afford the desired product as a off-white solid (31 mg, 67%): 1H NMR (500 MHz, (CD3OD) 7.63 (d, J=5.4 Hz, 1H), 7.51 (t, J=7.9 Hz, 1H), 7.15-7.06 (m, 3H), 6.20 (d, J=5.4 Hz, 1H), 3.42-3.35 (m, 2H), 3.30-3.10 (m, 2H), 2.80 (s, 3H), 2.57 (s, 3H); ESI MS m/z 383 [C21H11FN2O2S+H]+, HPLC >99% (AUC), tR=8.65 min.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[OH:10].C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].O>ClCCl>[CH2:22]([O:21][C:19]([O:10][C:3]1[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=1[F:1])=[O:20])[CH3:23]
Reactant: Oc1ccc(F)c(F)c1F
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1ccc(F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.3 %

Procedure:
7.40 g (50.0 mmol) of 2,3,4-trifluorophenol was dissolved in 50 mL of dichloromethane, 8.30 mL (60.0 mmol) of triethylamine and 5.74 mL (60.0 mmol) of ethyl chloroformate were added under ice-cooling and the mixture was stirred at room temperature for 20 minutes. Water was added to the reaction solution and the mixture was extracted once with chloroform. The organic layer was washed once with an aqueous saturated solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 9.83 g of O-ethoxycarbonyl-2,3,4-trifluorophenol (yield: 89%).
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH:6]([CH3:13])[CH2:7][CH2:8][C:9]([CH2:11][F:12])=[O:10])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.[BH4-].[Na+].Cl>O1CCCC1.CO>[F:12][CH2:11][CH:9]([OH:10])[CH2:8][CH2:7][CH:6]([N:5]1[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]2[C:1]1=[O:19])[CH3:13]
Reactant: CC(CCC(=O)CF)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(CCC(O)CF)N1C(=O)c2ccccc2C1=O
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
To a solution of 550 mg (2.2 mmole) of fluoromethyl 3-phthalimido-3-methylpropyl ketone in a mixture of 5 ml of tetrahydrofuran and 5 ml of methanol cooled to -20° C. is added a solution of 0.8 mmole of sodium borohydride in a mixture of 5 ml of tetrahydrofuran and 5 ml of methanol precooled to -20° C. The reaction mixture is stirred for 15 minutes at -20° C. and then neutralized with 2 M HCl to a pH of 1. The solvents are evaporated under reduced pressure and the residue is partitioned between water and chloroform. The organic phase is washed and brine, dried over magnesium sulfate and concentrated to give a residue which is recrystallized from tetrahydrofuran-diethylether to afford 1-fluoro-5-phthalimido-5-methyl-2-pentanol. A mixture of 264 mg (1.05 mmole) of 1-fluoro-5-phthalimido-5-methylpentanol, 170 mg (1.05 mmole) of the phthalimide, 302 mg (1.05 mmole) of triphenylphosphine and 201 mg (1.15 mmole) of diethylazodicarboxylate in 8 ml of tetrahydrofuran is stirred under nitrogen for 2 hours at 25° C. The solvent is evaporated under reduced pressure and the residue taken up in benzene. The insoluble material is discarded and the residue obtained after concentration of the filtrate is recrystallized from tetrahydrofuran-diethylether to give 1-fluoromethyl-4-methyl-1,4-butanediyl-bis-phthalimide. A suspension of 3.1 g of 1-fluoromethyl-4-methyl-1,4-butanediyl-bis-phthalimide in 140 ml of concentrated HCl is heated at reflux temperature for 3 days. The phthalic acid which precipitates on cooling to 4° C. is filtered off. The filtrate is concentrated to about 20 ml and cooled to 4° C. The remaining phthalic acid which separates is filtered off and the filtrate is concentrated under reduced pressure. The residue is treated with 40 ml of boiling isopropyl alcohol 3 times and then recrystallized from absolute ethanol to give 1-fluoromethyl-4-methyl-1,4-butanediamine dihydrochloride.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH3:11]>C(O)(=O)C>[Br:1][CH2:11][C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[Cl:3])=[O:12]
Reactant: CC(=O)c1ccccc1Cl
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bromine (3.8 mL, 65 mmol) was added dropwise to a solution of 1-(2-chloro-phenyl)-ethanone (10 g. 65 mmol) in acetic acid (75 mL) at 0° C. The mixture was then warmed to room temperature and stirred overnight. The mixture was evaporated to dryness and used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:10]#[N:11])[C:4]=2[CH:3]=[CH:2]1.[CH3:12][CH2:13][O:14]C(C)=O.[CH3:18][C:19](OC(C)=O)=[O:20]>[Pd].CCN(CC)CC>[C:13]([N:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:19](=[O:20])[CH3:18])=[C:4]2[CH:3]=[CH:2]1)(=[O:14])[CH3:12]
Reactant: N#Cc1ccnc2[nH]ccc12
Reactant: CCOC(C)=O
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccnc2c1ccn2C(C)=O
Temperature: 25 °C
Reaction time: 10 h

Procedure:
1H-Pyrrolo[2,3-b]pyridine-4-carbonitrile (11.2 g, 83.8 mmol) was dissolved into 400 mL EtOAc, 100 mL of Et3N. Pd/C (2.8 g) was added followed by 20 mL of Ac2O. H2 was introduced via balloon and the mixture was stirred at RT under balloon pressure of H2 for 8-12 h. After most of the starting material was consumed, catalyst was removed by filtration through a pad of Celite®. The pad was washed by EtOAc, CH2Cl2, and MeOH. The solvent was evaporated. The residue was taken into CH2Cl2 and the solid was collected by filtration to afford 471 g of N-((1-acetyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)acetamide. The filtrate was concentrated and purified on a column (0-10% MeOH/CH2Cl2+NH4OH) to obtain (N-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-acetamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:8][CH2:9][NH:10][C:11]1[N:16]2[N:17]=[C:18]([CH3:21])[C:19](I)=[C:15]2[N:14]=[C:13]([CH3:22])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>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:28])[N:7]([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:8][CH2:9][NH:10][C:11]1[N:16]2[N:17]=[C:18]([CH3:21])[C:19]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:29])[C:35]=3[Cl:36])=[C:15]2[N:14]=[C:13]([CH3:22])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(NCCN(C(=O)OC(C)(C)C)C2CCCC2)n2nc(C)c(I)c2n1
Reactant: OB(O)c1cccc(Cl)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(NCCN(C(=O)OC(C)(C)C)C2CCCC2)n2nc(C)c(-c3cccc(Cl)c3Cl)c2n1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 60 %

Procedure:
A suspension of cyclopentyl-[2-(3-iodo-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino)-ethyl]-carbamic acid tert-butyl ester (38 mg, 0.076 mmol) and 2,3-dichlorobenzeneboronic acid in toluene (0.5 mL)/ethanol (0.5 mL)/2 M aqueous sodium carbonate (0.22 mL) was degassed (3×) by alternately pulling a vacuum followed by repressurization with nitrogen. Tetrakis(triphenylphosphine)palladium (10 mg, 0.009 mmol) was added, and the mixture was degassed (3×) again. The mixture was stirred for 2.5 hours at 100° C., concentrated under reduced pressure, and then chromatographed (4:1 hexanes/ethyl acetate) to give the product as colorless oil (24 mg, 60%): +APcI MS (M+1)+ 518; 1H NMR (CDCl3) δ7.42 (dd, 1 H), 7.30 (dd, 1H), 7.22 (t, 1H), 5.84 (s, 1H ), 4.25-4.10 (br s, 1H), 3.49 (s, 4H), 2.44 (s, 3H), 2.32 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[Br:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33]([CH2:35]Cl)[CH:34]=1.O>C(#N)C>[Br:28][C:29]1[CH:34]=[C:33]([CH2:35][N:11]2[C:10](=[O:13])[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:12]2)[CH:32]=[N:31][CH:30]=1
Reactant: ClCc1cncc(Br)c1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: O=c1n(Cc2cncc(Br)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 65 °C
Reaction time: 5 h

Procedure:
171 mg (0.56 mmol) of the compound from Example 5A and 543 mg (1.67 mmol) of cesium carbonate were dissolved in 11 ml of acetonitrile, and 135 mg (0.56 mmol) of 3-bromo-5-(chloromethyl)pyridine hydrochloride were added. The mixture was stirred at 65° C. for 5 h. After cooling to RT, 10 ml of water were added and the mixture was extracted three times with in each case 10 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC [Method 19]. This gave 102 mg (38% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[CH2:5]([N:8]1[C:12](=[O:13])[CH2:11][NH:10][C:9]1=[S:14])[CH:6]=[CH2:7].N1CCOCC1>C(OCC)(=O)C>[CH2:5]([N:8]1[C:12](=[O:13])[C:11](=[C:2]([CH3:4])[CH3:1])[NH:10][C:9]1=[S:14])[CH:6]=[CH2:7]
Reactant: C=CCN1C(=O)CNC1=S
Reactant: CC(C)=O
Solvent: CCOC(C)=O
Solvent: C1COCCN1
Product: C=CCN1C(=O)C(=C(C)C)NC1=S

Procedure:
A flask equipped with a reflux condenser and nitrogen atmosphere was charged with acetone (20 mL), 3-allylthiohydantoin (2.0 g, 0.013 mol), and morpholine (1.1 g, 0.013 mol). The mixture was heated at reflux for 80 min and, after cooling, was diluted with 40 mL of ethyl acetate. The resulting solution was washed with 2×20 mL 1.2 M HCl, 20 mL of water, and 20 mL of saturated aqueous NaCl. The solution was then filtered through 1 PS paper and concentrated to dryness at aspirator pressure and then high vacuum. The off-white crystalline residue weighed 2.3 g (92%). No other components were detectable by HPLC at 215 nm. NMR (CDCl3) δ 9.9 (bs, 1H), 5.1-6.1 (m, 3H), 4.6 (d, 2H), 2.3 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([N:14]3C[CH2:17][CH2:16][C@H:15]3[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[C:4](=[O:27])[C:3]1=[O:28].O(C[C@@H]1CCN1S(C1C=C2C(=CC=1)NC(=O)C2=O)(=O)=O)C1C=CC=CC=1.[CH3:55][S:56][C:57]1[CH:64]=[CH:63][C:60](CBr)=[CH:59][CH:58]=1>>[CH3:55][S:56][C:57]1[CH:64]=[CH:63][C:60]([CH2:1][N:2]2[C:10]3[C:5](=[CH:6][C:7]([S:11]([N:14]4[CH2:17][CH2:16][C@H:15]4[CH2:19][O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:13])=[O:12])=[CH:8][CH:9]=3)[C:4](=[O:27])[C:3]2=[O:28])=[CH:59][CH:58]=1
Reactant: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Reactant: CSc1ccc(CBr)cc1
Agent: O=C1Nc2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc2C1=O
Product: CSc1ccc(CN2C(=O)C(=O)c3cc(S(=O)(=O)N4CC[C@H]4COc4ccccc4)ccc32)cc1
Yield: 45 %

Procedure:
(S)-1-(4-Methylthiobenzyl)-5-(2-phenoxymethyl-azetidine-1-sulfonyl)-1H-indole-2,3-dione (18d) was prepared according to the same procedure for compound 11a, except using compound 17 and 4-methylthiobenzyl bromide, and purified with hexanes-ether (1:2) to afford 57 mg (45%) of 18d as an orange solid, mp 167.6-169.2° C. 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=1.5 Hz, 1H), 7.96 (dd, J=8.4 Hz, J=1.8 Hz, 1H), 7.25 (m, 6H), 6.95 (t, J=7.2 Hz, 1H), 6.86-6.78 (m, 3H), 4.89 (s, 2H), 4.46 (m, 1H), 4.11 (m, 2H), 3.82 (m, 2H), 2.49 (s, 3H), 2.39-2.25 (m, 2H). Anal. Calcd for C26H24N2O5S2: C, 61.40, H, 4.76; N, 5.51. Found: C, 60.99, H, 4.71; N, 5.36.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][C:3]=1[CH3:10].[Li]CCCC.CN([CH:19]=[O:20])C>C1COCC1.[Cl-].[NH4+]>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([CH:19]=[O:20])=[C:3]([CH3:10])[CH:4]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)c(C)cc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C=O)c(C)cc1Br
Temperature: -78 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
4 g (15 mmol, 1 eq.) of 1,4-dibromo-2,5-dimethylbenzene are solubilized in 50 mL of distilled THF, in a Schlenk tube under argon. The medium is then cooled to −78° C., then 6.6 mL (16.6 mmol, 1.1 eq.) of BuLi (2.5M in hexane) are added dropwise. After stirring at this temperature for 1 hour, 5.3 mL (68 mmol, 4.5 eq.) of freshly distilled DMF are added. The reaction medium is again stirred at this temperature for 1 hour, and then the temperature returns to ambient temperature overnight. Next, the medium is diluted with a solution of ammonium chloride and then extracted three times with ethyl acetate. The organic phases are combined, dried over magnesium sulphate, and concentrated under reduced pressure. The residue is purified by silica column chromatography (eluent: ethyl acetate/petroleum ether: 80/20), so as to give a white solid (m: 1.3 g, yield: 40%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[C:13](OC(=O)C)(=[O:15])[CH3:14]>O>[C:13]([NH:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:15])[CH3:14]
Reactant: COC(=O)c1ccc(N)cc1O
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: COC(=O)c1ccc(NC(C)=O)cc1O
Temperature: 25 °C
Yield: 57.4 %

Procedure:
To a suspension of 4.17 g (0.025 mole) methyl 4-aminosalicylate (9) in 20 mL water, was added 3 mL (0.032 mole) acetic anhydride (Aldrich 11,004-3) while stirring. The mixture was heated at 800 for 30 minutes and cooled to room temperature. The precipitate was collected and added into 100 ml of 10% hydrochloric acid. This suspension was stirred at room temperature for 10 minutes, filtered and dried to give 4.3 g (82%) of a crude solid, which was recrystallized from H2O/CH3OH, yielding 3 g (70%) of 10 as white crystals, mp 153-154 . Infrared (IR) and NMR analysis gave the following results: IR (potassium bromide): 3319(NH), 1680 (C=O),1604, 1157 cm−1. 1H nmr (90 MHz, CDCI3 +DMSO-d6):δ 10.80 (1H, S, OH), 9.74 (1H, br s, NH), 7.73 (1H; d, 3JH5-H6=9 Hz; H-6), 7.37 (1H; d, 4JH5-H3=1.8 Hz; H-3),7.11 (1H; dd, 3JH6-H5=9HZ, 4JH3-H5=1.8 Hz; H-5), 3.91 (3H; s; OCH3), 2.15 (3H, s, CH3).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C@H:24]([CH3:25])[CH2:23][CH2:22][C@H:21]3[CH3:26])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH3:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:26][C@@H:21]1[CH2:22][CH2:23][C@@H:24]([CH3:25])[N:20]1[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:31]3[CH2:32][CH2:33][CH:28]([CH3:27])[CH2:29][CH2:30]3)=[CH:7][CH:8]=2)=[CH:13][CH:14]=1)=[O:19]
Reactant: CC1CCNCC1
Reactant: C[C@@H]1CC[C@@H](C)N1C(=O)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Product: CC1CCN(CCCOc2ccc(-c3ccc(C(=O)N4[C@H](C)CC[C@H]4C)cc3)cc2)CC1

Procedure:
The product from Example 4A and 4-methylpiperidine were processed as described in Example 10F to provide the title compound.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N:29]=[CH:28][C:27]([C:30]([NH:32][C@H:33]([CH3:37])[CH:34]([CH3:36])[CH3:35])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N+:29]([O-:9])=[CH:28][C:27]([C:30]([NH:32][C@H:33]([CH3:37])[CH:34]([CH3:35])[CH3:36])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@H](C)C(C)C)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@H](C)C(C)C)c[n+]1[O-]
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 10 mg) dissolved in chloroform (0.1 ml) was added to a solution of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1R)-1,2-dimethylpropyl]-3-pyridinecarboxamide (Intermediate 17, 10 mg) in chloroform (2 ml) at 60° C. and the reaction maintained at 60° C. for 5 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (1 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1R)-1,2-dimethylpropyl]-3-pyridinecarboxamide 1-oxide as a white solid.