Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[NH2:14])#[C:2]CC.FC(F)(F)C(O[C:20](=O)[C:21](F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].[I:34]I>C1COCC1.O.C(OCC)(=O)C>[CH2:20]([N:14]1[C:6]2[C:5](=[CH:10][CH:9]=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=2)[C:1]([I:34])=[CH:2]1)[CH3:21]
Reactant: II
Reactant: CCC#Cc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCn1cc(I)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.5 %

Procedure:
Add to a solution of 2-but-ynyl-5-nitro-phenylamine (2.98 g, 15.68 mmol) in anhydrous THF (100 mL) 2,6-di-t-butyl-4-methylpyridine followed by trifluoroacetic anhydride (2.7 mL, 19.61 mmol) and stir at room temperature for 18 hours. Quench the reaction with 1N HCl and add ethyl acetate. Extract the organic layer 2×1N HCl, 1× brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and redissolve in anhydrous acetonitrile (150 mL). Add to the solution potassium carbonate (6.49 g, 47.04 mmol) and cool to 0° C. Add iodine (11.94 g, 47.04 mmol) and stir at 0° C. for 30 min. Quench the reaction with 1M sodium thiosulfate (100 mL) and add water (250 mL). Stir the mixture 30 min., then filter and rinse with water to afford 3.94 g (80%) of the title compound.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][C:36]5[CH:41]=[CH:40][C:39]([C:42](=O)[CH3:43])=[CH:38][CH:37]=5)=[CH:31][CH:30]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:45][O:46][C:47](=[O:49])[CH3:48])[CH2:7][O:8]2)(=[O:3])[CH3:2].N1C=CC=CC=1.Cl.[CH2:57]([O:59][NH2:60])[CH3:58]>C(O)C.C(OCC)(=O)C>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][C:36]5[CH:41]=[CH:40][C:39]([C:42](=[N:60][O:59][CH2:57][CH3:58])[CH3:43])=[CH:38][CH:37]=5)=[CH:31][CH:30]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:45][O:46][C:47](=[O:49])[CH3:48])[CH2:7][O:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(Oc5ccc(C(C)=O)cc5)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Reactant: CCON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCON=C(C)c1ccc(Oc2ccc(Cc3cc([C@]45OC[C@](COC(C)=O)(O4)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]5OC(C)=O)ccc3Cl)cc2)cc1
Temperature: 80 °C
Yield: 72.5 %

Procedure:
To a solution of (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(3-(4-(4-acetylphenoxy)benzyl)-4-chlorophenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (300.0 mg, 0.43 mmol) in ethanol (5 mL) under nitrogen atmosphere, was added pyridine (0.17 mL, 2.15 mmol) and O-ethylhydroxylamine hydrochloride (84.0 mg, 0.86 mmol). The reaction mixture was heated at 80° C. for 4 h. After completion of the reaction as confirmed by TLC, the crude compound was diluted with ethyl acetate (2×20 mL). The organic layer was separated, washed with 5% HCl (10 mL), water (10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1:4 EtOAc:Pet Ether) to afford the title compound (230.0 mg, 72%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@@H:8]([CH2:11][CH3:12])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>CCOCC>[CH3:21][S:22]([O:10][CH2:9][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13])[CH2:11][CH3:12])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: CC[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To an ice cold solution of (S)-tert-butyl(1-hydroxybutan-2-yl)carbamate (9.5 g, 50 mmol) and triethylamine (10.5 mL, 75 mmol) in ether (200 mL) was added methanesulfonyl chloride (4.0 mL, 50 mmol). After 1 h, water was added, and the resulting mixture was extracted with DCM, dried (Na2SO4), filtered, and concentrated to give an oil (13.4 g, 100%) which was used directly without further purification.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10]([C:12]1[O:20][C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:13]=1[OH:21])=[O:11])[CH3:8].[CH:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][CH:23]=1.O>CN(C=O)C>[CH2:7]([O:9][C:10]([C:12]1[O:20][C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:13]=1[O:21][CH2:28][C:25]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1)=[O:11])[CH3:8]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1oc2ccncc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1oc2ccncc2c1OCc1ccccc1
Reaction time: 0.08 h

Procedure:
K2CO3 (2.34 g, 17.0 mmol) was added to a stirred solution of 3-hydroxyfuro[3,2-c]pyridine-2-carboxylic acid ethyl ester (1.76 g, 8.5 mmol) in DMF (40 mL). After 5 min, BnBr (1.25 mL, 10.6 mmol) was added, then the mixture was stirred for 16 h, before being poured into H2O and extracted with EtOAc (3×). The combined organic extracts were washed with brine, before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (EtOAc) yielded the title compound: m/z (ES+)=298.0 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([C:14]([OH:16])=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH3:23]>C1(C)C=CC=CC=1.CCOCC>[CH:1]1[C:13]2[CH:12]([C:14]([NH2:23])=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1c2ccccc2-c2ccccc21
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: NC(=O)C1c2ccccc2-c2ccccc21

Procedure:
The compound was prepared substantially in accordance with the procedure detailed in Example 21A, using 9-fluorenecarboxylic acid (6.00 g, 28.5 mmol) and oxalyl chloride (3.5 ml, 39.9 mmol) in 30 ml of toluene to provide a clear oil that was dissolved in Et2O and treated with ammonia.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:5][CH:4]=1.[OH-].[Na+].Cl>CO.O1CCCC1>[CH3:1][N:2]([CH3:22])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1cccc2cc(-c3ccc(N(C)C)cc3)oc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)c1ccc(-c2cc3cccc(C(=O)O)c3o2)cc1
Temperature: 50 °C
Yield: 99.3 %

Procedure:
920 mg of methyl 2-(4-dimethylaminophenyl)benzofuran-7-carboxylate are dissolved in a mixture of 20 ml of methanol and 20 ml of tetrahydrofuran. 10 ml of an aqueous 1N sodium hydroxide solution are added to the solution and the mixture is heated at 50° C. for 40 minutes. After cooling, the reaction mixture is neutralized with 10% hydrocloric acid and extracted with ethyl acetate. The extract is dried and evaporated to remove solvent to give 870 mg of 2-(4-dimethylaminophenyl)benzofuran-7-carboxylic acid as yellow powder.
Reaction SMILES: Cl[C:2]1[N:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:8]=1)=[O:5].[NH2:30][C:31]1[CH:39]=[C:38]2[C:34]([CH:35]=[N:36][NH:37]2)=[CH:33][CH:32]=1.C(O)(C(F)(F)F)=O>Cl>[NH:37]1[C:38]2[C:34](=[CH:33][CH:32]=[C:31]([NH:30][C:2]3[N:29]=[CH:28][CH:27]=[CH:26][C:3]=3[C:4]([NH:6][C:7]3[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([CH2:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:8]=3)=[O:5])[CH:39]=2)[CH:35]=[N:36]1
Reactant: O=C(Nc1cc(CCCN2CCOCC2)cc(C(F)(F)F)c1)c1cccnc1Cl
Reactant: Nc1ccc2cn[nH]c2c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(CCCN2CCOCC2)cc(C(F)(F)F)c1)c1cccnc1Nc1ccc2cn[nH]c2c1
Temperature: 155 °C

Procedure:
2-Chloro-N-[3-(3-morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-nicotinamide (2.95 g) was dissolved in a small volume of IpOH. 6-amino indazole (2.75 g) and 0.53 mL of TFA were added. The reaction mixture was heated to 155° C. in an open flask for 3.5 h. After cooling to RT the residue was dissolved in 2 N HCl. The aqueous solution was extracted 2 times with CH2Cl2, basified to pH 12 by the addition of Na2CO3 and 1 N NaOH. The solution was extracted 6 times with CH2Cl2 to isolate the product. The combined 5 extractions were dried over Na2SO4, filtered and stripped. The crude product was purified by silica gel chromatography eluting with a step gradient of 3-5% MeOH:CH2Cl2 to yield the titled compound. MS: 525 (M+1) Calc'd for C27H27F3N6O2—524.5.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH3:21][C:22]1([CH3:28])[CH2:27][O:26][CH2:25][CH2:24][NH:23]1.Cl.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:23]3[CH2:24][CH2:25][O:26][CH2:27][C:22]3([CH3:28])[CH3:21])[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: CC1(C)COCCN1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cn1c(CCN2CCOCC2(C)C)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 28 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (119 mg, 0.40 mmol) in DCE (10 mL) was added 3,3-dimethylmorpholine.HCl (61 mg, 0.40mmol), triethylamine (0.06 mL, 0.40 mmol) and powdered 4 Å molecular sieves. After stirring at room temperature for 4 h, sodium triacetoxyborohydride (171 mg, 0.80 mmol) was added and the resulting mixture stirred for a further 16 h. The reaction mixture was filtered through Celite®, loaded onto an Isolute® SCX-2 cartridge, the cartridge was washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by column chromatography (Si—PCC, 0-7% MeOH in DCM) to give the title compound as a pale yellow oil (44 mg, 28%). LCMS (Method H): RT=2.45 min, [M+H]+ 395.5
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]([OH:19])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]=1[CH3:20].[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22]>CCOCC>[CH2:21]([NH:23][C:24]([N:2]([CH3:1])[C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]([OH:19])([C:11]([F:12])([F:13])[F:14])[C:15]([F:16])([F:17])[F:18])=[CH:5][C:4]=1[CH3:20])=[O:25])[CH3:22]
Reactant: CNc1c(C)cc(C(O)(C(F)(F)F)C(F)(F)F)cc1C
Reactant: CCN=C=O
Solvent: CCOCC
Product: CCNC(=O)N(C)c1c(C)cc(C(O)(C(F)(F)F)C(F)(F)F)cc1C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
Heat at reflux for three hours 13.5 g of N,2,6-trimethylaniline (0.100 mole) and 40 g of hexafluoroacetone sesquihydrate (0.21 mole). Allow to cool, pour onto water. Collect the solid, dry and recrystallize from ether-hexane to give 27.9 g white solid; m.p. 143°-144° C. Dissolve 6 g of the product, N,2,6-trimethyl-4-(hexafluoro-2-hydroxy-2-propyl)aniline (20 mmole) and 5.4 g of ethyl isocyanate (80 mmole) in Et2O. After 16 hours, concentrate and recrystallize the residual solid from etherhexane to give 6.2 g of a white solid; m.p. 178°-179° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.Cl>C(OCC)C>[CH3:32][O:31][C:25]1[CH:24]=[C:23]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:22]3)[CH:28]=[CH:27][C:26]=1[O:29][CH3:30]
Reactant: COc1ccc(-c2ccc3[nH]c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3c2)cc1OC
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(-c2ccc3[nH]c(C4CCNCC4)cc3c2)cc1OC
Reaction time: 2 h

Procedure:
A 50 mL round bottom flask was charged with 4-[5-(3,4-dimethoxy-phenyl)-1H-indol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.15 mmol), dichloromethane (5.8 mL), and 1M hydrochloric acid in diethyl ether (5.8 mL) and the resulting mixture stirred for 2 h. The resulting mixture was then concentrated in vacuo, the residue triturated with diethyl ether, and then placed under high vacuum to yield 5-(3,4-dimethoxyphenyl)-2-(piperidin-4-yl)-1H-indole. 1H NMR (300 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.29-7.37 (m, 2H), 7.09-7.22 (m, 2H), 6.99 (d, J=8.2 Hz, 1H), 6.22 (s, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.67-3.74 (m, 1H), 3.02-3.15 (m, 4H), 2.50-2.61 (m, 2H), and 1.81-2.01 (m, 2H); MS (ES+) 337 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.Cl[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl>C1(C)C(C)=CC=CC=1>[N:1]1([C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: ClCCNCCCl
Agent: Cl
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cccc(N2CCNCC2)c1
Reaction time: 48 h
Yield: 68.4 %

Procedure:
Ethyl 3-aminobenzoate (1.65 g) was dissolved in xylene (20 ml), and bischloroethylamine hydrochloride (1.79 g) was added to the solution. The mixture was heated under reflux with stirring for two days. The solvent was removed from the reaction solution by distillation under the reduced pressure. Water and a saturated aqueous sodium hydrogencarbonate solution were added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=9:1-5:1) to give 1.60 g (70.0%) of ethyl 3-piperazin-1-yl-benzoate.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]2[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Br:22])=[N:11][CH2:12][C:13](=S)[NH:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].[C:23]([NH:27][NH2:28])(=O)[CH2:24][CH3:25]>C(O)C>[CH2:1]([S:3][C:4]1[C:9]2[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Br:22])=[N:11][CH2:12][C:13]3[N:14]([C:23]([CH2:24][CH3:25])=[N:27][N:28]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCSc1cccc2c1C(c1ccccc1Br)=NCC(=S)N2
Reactant: CCC(=O)NN
Solvent: CCO
Product: CCSc1cccc2c1C(c1ccccc1Br)=NCc1nnc(CC)n1-2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 6-ethylthio-1,3-dihydro-5-(o-bromophenyl)-2H-1,4-benzodiazepine-2-thione is heated in ethanol with propionic acid hydrazide and the resulting product heated to 250° C. to give 7-ethylthio-1-ethyl-6-(o-bromophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[N+:19]([O-])=O)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:33])[N:6]2[C@H:22]1[C:31]2[C:26](=[C:27]([F:32])[CH:28]=[CH:29][CH:30]=2)[O:25][CH2:24][CH2:23]1.C(O)(=O)C.O.[OH-].[NH4+]>[Fe].C(O)C>[NH2:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[NH:11][C:9]1[N:8]=[C:7]2[C:3]([NH:4][C:5](=[O:33])[N:6]2[C@H:22]2[C:31]3[C:26](=[C:27]([F:32])[CH:28]=[CH:29][CH:30]=3)[O:25][CH2:24][CH2:23]2)=[C:2]([Cl:1])[N:10]=1
Reactant: O=c1[nH]c2c(Cl)nc(Nc3cc(F)ccc3[N+](=O)[O-])nc2n1[C@@H]1CCOc2c(F)cccc21
Agent: [Fe]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(F)cc1Nc1nc(Cl)c2[nH]c(=O)n([C@@H]3CCOc4c(F)cccc43)c2n1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To a round bottom flask containing (R)-6-chloro-2-(5-fluoro-2-nitrophenylamino)-9-(8-fluorochroman-4-yl)-7H-purin-8(9H)-one (310 mg, 0.65 mmol) was added glacial acetic acid (15 mL), water (37.5 mL) and ethanol (75 mL), followed by iron powder (370 mg, 6.5 mmol, 10 equiv.) and the resulting mixture heated at 90° C. for 15 min (HPLC monitoring). The reaction mixture was left to cool down to room temperature, concentrated ammonium hydroxide solution (32 mL) was added to bring the pH to basic, and the mixture was stirred for 10 min. The aqueous layer was extracted with ethyl acetate (5×100 mL), the combined organic layers were washed with brine, dried (anhydrous Na2SO4), and the solvent removed in vacuo to give the desired product as a pink solid (yield quantitative). This material was used in the next step without further purification. MS (EI) m/z 445.2 (MH)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH:25]([NH:28][C:29](=[O:32])[CH2:30]Cl)([CH3:27])[CH3:26].[H-].[Na+]>>[CH:25]([NH:28][C:29](=[O:32])[CH2:30][N:22]1[CH2:21][CH2:20][N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24])([CH3:27])[CH3:26]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: CC(C)NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Product: CC(C)NC(=O)CN1CCn2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O
Yield: 79 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), N-isopropyl chloroacetamide and sodium hydride, to give the desired product as a white solid (79%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[C:35]([N:38]1[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40][CH2:39]1)(=[O:37])[CH3:36]>C1COCC1>[C:35]([N:38]1[CH2:43][CH2:42][CH:41]([NH:44][C:2]2[N:7]=[C:6]([C:8]3[S:12][C:11]([CH:13]([CH3:14])[CH3:15])=[N:10][C:9]=3[C:16]3[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]4[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=4[F:33])(=[O:24])=[O:25])[CH:21]=3)[CH:5]=[CH:4][N:3]=2)[CH2:40][CH2:39]1)(=[O:37])[CH3:36]
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cc(F)ccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CC(=O)N1CCC(N)CC1
Solvent: C1CCOC1
Product: CC(=O)N1CCC(Nc2nccc(-c3sc(C(C)C)nc3-c3ccc(F)c(NS(=O)(=O)c4cc(F)ccc4F)c3)n2)CC1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.10 g, 0.19 mmol) and 1-acetyl-4-piperidinamine (0.27 g, 1.9 mmol) in THF (1 mL) the title compound was obtained as an off-white solid (0.075 g, 0.12 mmol, 62% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.82 (s, 1H), 8.12 (d, J=5.0 Hz, 1H), 7.68-7.43 (m, 3H), 7.44-7.17 (m, 5H), 4.33-4.18 (m, 1H), 3.83-3.73 (m, 1H), 3.44-3.20 (m, 2H), 2.66-2.32 (m, 4H), 1.99 (s, 3H), 1.36 (d, J=6.8 Hz, 6H), 1.35-1.10 (m, 2H). MS (ESI): 631 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C@:10]3([C@@H:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=4[F:22])[C@H:13]([C:23]([NH:25][C:26]4[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([O:35][CH3:36])[CH:27]=4)=[O:24])[NH:12][C@H:11]3[CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:5]2=[CH:4][CH:3]=1.CC[N:45]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-].C(N(CC)CC)C>CN(C)C=O.O>[C:30]([C:29]1[CH:33]=[CH:34][C:26]([NH:25][C:23]([CH:13]2[NH:12][CH:11]([CH2:37][C:38]([CH3:40])([CH3:41])[CH3:39])[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:42])[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])=[O:24])=[CH:27][C:28]=1[O:35][CH3:36])(=[O:31])[NH2:45]
Reactant: COc1cc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)ccc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)C2NC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)ccc1C(N)=O
Temperature: 80 °C

Procedure:
To a solution of rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-2-methoxy-benzoic acid prepared in Example 16 (55 mg, 0.09 mmol) in N,N-dimethylformamide (2 mL) was added EDCI (34 mg, 0.18 mmol), HOBt (24 mg, 0.18 mmol), NH4Cl (48 mg, 0.9 mmol), and triethylamine (18 mg, 0.18 mmol) sequentially. The reaction mixture was heated at 80° C. for 1 h. The mixture was poured into water, then extracted with ethyl acetate three times. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (25% to 100% EtOAc in hexanes) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-3-methoxy-phenyl)-amide as a off white solid (Yield, 35 mg, 64%)
Reaction SMILES: O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH3:34])[CH2:29][C@@H:28]1[C:35]([OH:37])=O)=[O:26])([CH3:23])([CH3:22])[CH3:21].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>ClCCl>[CH2:33]([N:30]1[CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:26])[C@@H:28]([C:35]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[O:37])[CH2:29]1)[CH3:34]
Reactant: CCN1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Reactant: C1CNCCN1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCN1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)N2CCNCC2)C1
Reaction time: 18 h
Yield: 50.4 %

Procedure:
4-(4,6-Dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (253 mg, Acros chemicals) was added to a solution of (2R)-1-(tert-butoxycarbonyl)-4-ethylpiperazine-2-carboxylic acid (212 mg) in dry dichloromethane (6 ml) followed by addition on N-methyl morpholine (0.28 ml) and stirring under argon for 1 h. piperazine (234 mg) was then added and stirring was continued for 18 h. Dichloromethane (30 ml) was added and extracted with 1M NaOH (2×10 mL). The organic layer was dried (MgSO4), filtered and evaporated. Purification by chromatography (5-50% MeOH:DCM) afforded the title compound (135 mg) as a foam.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[C:8](O)(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([C:8]2[S:4][CH2:3][CH:2]([C:5]([OH:7])=[O:6])[N:1]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N[C@H](CS)C(=O)O
Reactant: O=C(O)c1ccccc1
Product: O=C(O)C1CSC(c2ccccc2)=N1

Procedure:
(S)-Cysteine is reacted with benzoic acid to form 2-phenylthiazoline-4-carboxylic acid. 2-Phenylthiazoline-4-carboxylic acid is amidated with 4-benzyloxazolidone. The amidated 2-phenylthiazoline-4-carboxylic acid is alkylated with methyl iodide in the presence of TiCl4 and lithium diisopropylamide. The alkylated species is hydrolyzed by lithium hydroxide in methanol to obtain (S)-2-methylcysteine methyl ester.