Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][SH:3].[CH2:4](Br)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-:21].[K+]>CCO.O>[CH2:4]([S:3][CH2:2][CH2:1][OH:21])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: [OH-]
Reactant: CCS
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCSCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thioethanol (5.0 g, 64 mmol), hexadecyl bromide (25.0 g, 82 mmol), and KOH (4.5 g, 80 mmol) were combined in 95% EtOH (150 mL). The reaction mixture was stirred at room temperature overnight and then diluted with H2O. The precipitate was collected and recrystallized from MeOH to provide the thioether: 19.0 g, 96%; mp 50° C.; NMR (300 MHz, CDCl3) δ 0.89 (t, 3 H, CH3), 1,30 (m, 26 H, (CH2)13), 1.60 (m, 2 H, CH2CH2S), 2.52 (t, 2 H, SCH2), 2.72 (m, 2 H, CH2S), 3.72 (m, 2 H, CH2OH).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH:16]([NH:20][C:21]([NH:23][CH:24]([CH2:26][CH3:27])[CH3:25])=[S:22])([CH2:18][CH3:19])[CH3:17].C(OCC)C>C(OCC)(=O)C>[ClH:1].[CH:24]([N:23]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=2)([OH:4])[CH2:2][S:22][C:21]1=[N:20][CH:16]([CH2:18][CH3:19])[CH3:17])([CH2:26][CH3:27])[CH3:25]
Reactant: NS(=O)(=O)c1cc(C(=O)CCl)ccc1Cl
Reactant: CCC(C)NC(=S)NC(C)CC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCC(C)N=C1SCC(O)(c2ccc(Cl)c(S(N)(=O)=O)c2)N1C(C)CC
Product: Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5.3 g of 2,4'-dichloro-3'-sulfamoylacetophenone and 3.8 g of 1,3-di-sec.-butylthiourea was reacted in the manner described in Example 16, the reaction mixture was introduced into a solution of 40 ml of diethyl ether and 120 ml of ethyl acetate and the colorless, crystalline end product was filtered off after stirring for 4 hours at room temperature. Melting point: 186° C. (decomposition).
Reaction SMILES: COCC1CCCCN1C1N=CN=C(NC2C=C(CS(N)(=O)=O)C=CC=2)N=1.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]2[CH:37]=[C:38]([CH2:42][S:43]([NH2:46])(=[O:45])=[O:44])[CH:39]=[CH:40][CH:41]=2)[N:30]=1.[CH2:47]([CH:54]1[CH2:58][CH2:57][CH2:56][NH:55]1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[CH2:47]([CH:54]1[CH2:58][CH2:57][CH2:56][N:55]1[C:29]1[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]2[CH:37]=[C:38]([CH2:42][S:43]([NH2:46])(=[O:45])=[O:44])[CH:39]=[CH:40][CH:41]=2)[N:30]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: c1ccc(CC2CCCN2)cc1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCCC3Cc3ccccc3)n2)c1

Procedure:
B26 was prepared following the procedure reported for B4 using A1 and rac-2-benzylpyrrolidine. It was obtained as a white crystalline solid; yield: 160 mg (42%). 1H NMR (300 MHz, d6-DMSO, 300K) δ 1.67-1.92 (m, 4H), 2.57-2.77 (m, 1H), 3.03-3.21 (m, 1H), 3.42-3.62 (m, 2H), 4.20 (2 s, 2H), 4.28-4.48 (m, 1H), 6.88 (bs, 2H), 6.93-7.08 (m, 1H), 7.12-7.38 (m, 6H), 7.58 and 7.71 (2 m, 1H), 7.82-8.01 (m, 1H), 8.23 and 8.30 (2 s, 1H), 9.66 (bs, 1H). MS (ES) C21H24N6O2S requires: 424. found: 425 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([N:13]=CN(C)C)[N:5]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][C:19]=2[Cl:29])[N:4]=1)#[N:2].[H-].[Na+].ClC(Cl)(Cl)S(O[CH2:38][C:39]([F:42])([F:41])[F:40])(=O)=O.ClCCl>CN1CCCC1=O>[NH2:13][C:6]1[N:5]([C:18]2[C:19]([Cl:29])=[CH:20][C:21]([C:25]([F:26])([F:27])[F:28])=[CH:22][C:23]=2[Cl:24])[N:4]=[C:3]([C:1]#[N:2])[C:7]=1[N:8]([CH2:38][C:39]([F:42])([F:41])[F:40])[S:9]([CH3:12])(=[O:10])=[O:11]
Reactant: CN(C)C=Nc1c(NS(C)(=O)=O)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CS(=O)(=O)N(CC(F)(F)F)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.3 %

Procedure:
To a solution of N-(3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazol-4-yl)methanesulfonamide (250 mg, 0.53 mmol) in 1-methyl-2-pyrrolidinone (anhydrous, 5 ml) was added sodium hydride (60% in oil, 16.6 mg, 0.69 mmol) and 2,2,2-trifluoroethyl trichloromethanesulphonate (195 mg, 0.69 mmol). The reaction mixture was then stirred at room temperature for 3 h. To the reaction mixture was added dichloromethane (20 ml) and the resulting mixture was extracted with water (20 ml). The organic phase was washed with water (2×20 ml) and brine (2×20 ml), dried (Na2SO4) and concentrated in vacuo. To the residue was added methanol (5 ml) and hydrochloric acid (4M, 3 ml) and the mixture was heated at reflux for 60 h. The reaction mixture was concentrated in vacuo and to the residue was added ethyl acetate (20 ml) and water (20 ml). The organic phase was separated, washed with water (2×20 ml) and brine (2×20 ml), dried (Na2SO4) and concentrated in vacuo. The crude product was dissolved in acetonitrile/dimethyl sulphoxide/water (1:4:1, 6 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm×30 mm Phenomonex LUNA C18(2) 10 μm column) using an acetonitrile:water gradient [52.5:47.5 to 95:5]. The appropriate fractions were concentrated in vacuo to give the titled compound (135 mg).
Reaction SMILES: [Cl:1][C:2]1([F:24])[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]1=[C:4]([CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH:5]([C:12]([O:14]CC)=[O:13])[NH:6]2.O.O.O.[OH-].[Li+]>O1CCCC1.O>[C:19]([CH2:18][CH2:17][C:4]1[CH:5]([C:12]([OH:14])=[O:13])[NH:6][C:7]2[C:3]=1[C:2]([Cl:1])([F:24])[CH:10]=[C:9]([Cl:11])[CH:8]=2)([OH:21])=[O:20]
Reactant: CCOC(=O)CCC1=C2C(=CC(Cl)=CC2(F)Cl)NC1C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCC1=C2C(=CC(Cl)=CC2(F)Cl)NC1C(=O)O
Temperature: 25 °C
Yield: 95 %

Procedure:
Ethyl 4,6-dichloro-4-fluoro-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate (1.13 g, 3 mmol) was dissolved in 15 ml tetrahydrofurane (THF) with stirring at rt. Then a solution of 0.38 g of lithium hydroxide trihydrate (3 equiv.) in 15 ml water was added and the resulting mixture was let to stir at rt for 24 h. After completion of the reaction THF was removed under reduced pressure and the pH was adjusted to 4-5, and the product was extracted with diethyl ether (3×15 ml). The organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness to yield a light-beige-colored solid in 95-100% yield. mp. 292-294° C. 1H-NMR (DMSO-d6) δ 2.48 (m, 2H, 2′-H); 3.48 (m, 2H, 1′-H); 7.49 (dd, 1H, 2J=6 Hz, 7-H); 11.98 (s, 1H, NH); 12.72 (b, 2H, 2CO2H). 13C-NMR (DMSO-d6) δ 20.1 (C-2′); 36.1 (C-1′); 112.5 (C-7); 113.0, 113.2, 117.6, 117.7, 121.3, 121.4 (C-5); 122.3 (C-4); 127.7 (C-6); 132.5 (C-3); 147.2 (C-3a); 149.0 (C-2); 162.5 (2′-CO2H), 173.6 (2-CO2H). LC-MS (m/z): 337 [M-NH4+]+, 320 [M]+, 318 [M]−. Purity (LC-MS): 98.6%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([CH:39]=[C:40]([OH:42])[CH:41]=1)[C:34]([N:36]([CH3:38])[CH3:37])=[O:35].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CC(C)=O.O.Cl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:42][C:40]2[CH:39]=[C:33]([C:34](=[O:35])[N:36]([CH3:38])[CH3:37])[CH:32]=[C:31]([Br:30])[CH:41]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: CN(C)C(=O)c1cc(O)cc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N(C)C)c2)c1CCC(=O)OCC
Temperature: 70 °C
Yield: 79.2 %

Procedure:
To a solution of 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (3.48 g, 7.4 mmol), 3-bromo-5-hydroxy-N,N-dimethyl-benzamide (1.5 g, 6.17 mmol) in N,N-dimethylformamide (30 mL) and acetone (60 mL) was added potassium carbonate (8.51 g, 61.7 mmol). The resulting suspension was heated to 70° C. for 24 h. Then the reaction mixture was cooled to room temperature and diluted with water and 10% aq. HCl. The organic compound was extracted into ethyl acetate and the combined organic extracts were washed with water and brine solution. The organic extracts were dried over anhydrous sodium sulfate and removal of the solvent under reduced pressure gave the crude product which was purified on ISCO™ column (120 g) using 50% ethyl acetate in hexanes as eluting solvent to give the title compound (3.1 g, 80%) as colorless oil.
Reaction SMILES: C(OC([NH:8][C:9]1[CH2:10][C:11]([C:36](=[O:52])[N:37]([CH2:41][CH2:42][CH2:43][O:44][Si](C(C)(C)C)(C)C)[CH2:38][CH2:39][CH3:40])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH2:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])=[O:28])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[CH2:10][C:11]([C:36](=[O:52])[N:37]([CH2:41][CH2:42][CH2:43][OH:44])[CH2:38][CH2:39][CH3:40])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH2:30][CH2:31][CH2:32][N:33]([CH3:34])[CH3:35])=[O:28])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCCCN(C)C)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCCO)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCCCN(C)C)cc3)cc2N=C(N)C1
Reaction time: 1 h

Procedure:
3-(dimethylamino)propyl 2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate was dissolved in 2 mls of dichloromethane and 0.5 ml of TFA. After about one hour, the mixture was concentrated under reduced pressure and the resulting residue was then re-dissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2×), extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 10% MeOH/DCM/0.5% NH4OH) afforded 3-(dimethylamino)propyl 2-(4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate. 1H NMR (400 MHz, CDCl3) δ 7.57-7.65 (m, 2H), 7.46-7.51 (m, 1H), 7.28-7.40 (m, 4H), 6.87 (s, 2H), 4.07-4.21 (m, 2H), 3.56-3.71 (m, 6H), 3.40-3.54 (m, 2H), 2.82 (s, 2H), 2.26-2.36 (m, 2H), 2.20 (s, 6H), 1.59-1.87 (m, 6H), 0.86-0.99 (m, 3H); m/z (APCI-pos) M+1=521.3.
Reaction SMILES: [C:1]([CH:3]([CH:9]1[CH2:11][CH2:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[ClH:12].[NH3:13]>C(O)C>[ClH:12].[CH:9]1([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:1]([NH2:13])=[NH:2])[CH2:10][CH2:11]1
Reactant: CCOC(=O)C(C#N)C1CC1
Reactant: N
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(C(=N)N)C1CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Into a stirred solution of 38.72 g (0.253 mol) of ethyl 2-cyano-2-cyclopropylacetate (preparation described by R. W. J. Carney and J. Wojtkunski, Org. Prep. Proced. Int., 5, 25 (1973)) in 17.7 mL (0.303 mol) of anhydrous ethanol under a dry N2 atmosphere was introduced 10.0 g (0.274 mol) of gaseous hydrogen chloride with ice cooling. The mixture was allowed to warm to room temperature and stand for 72 hours. The reaction was diluted with 100 mL of anhydrous ethanol, 70 mL of ammonia in ethanol (4.17M) was added slowly at room temperature and the reaction was stirred for 3 hours. The reaction mixture was filtered to remove the ammonium chloride, and the solvent was removed to afford the title compound as a viscous off-white oil, which was taken directly to the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[CH2:6][C:7]1[C:8](Cl)=[N:9][C:10](Cl)=[N:11][CH:12]=1)[CH3:2].[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:1]([O:3][C:4](=[O:25])[CH:5]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[CH2:6][C:7]1[C:8]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:9][C:10]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:11][CH:12]=1)[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(Cc1cnc(Cl)nc1Cl)c1ccc(OC)c(OC)c1
Product: CCOC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1ccc(OC)c(OC)c1
Temperature: 110 °C

Procedure:
A mixture of 3-(2,4-dichloro-pyrimidin-5-yl)-2-(3,4-dimethoxy-phenyl)-propionic acid ethyl ester (440 mg, 1.1 mmol) (from Example 11a supra) and aniline (2.0 mL) (Aldrich) was heated at 110° C. for 2 hours. The reaction mixture was washed with hexanes (50 mL×3) and the supernatant was decanted off after each time. The residue was then dissolved in ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (30 mL), water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was then purified by flash column chromatography to give the crude 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-(3,4-dimethoxy-phenyl)-propionic acid ethyl ester as an off-white solid. (Yield 470 mg, 86%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([C:16]2[CH:25]=[C:24]([CH3:26])[C:19]3[NH:20][C:21](=[O:23])[O:22][C:18]=3[CH:17]=2)=[O:15])[CH:11]=[CH:10][N:9]=1.CI>C1COCC1.CCOC(C)=O>[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([C:16]2[CH:25]=[C:24]([CH3:26])[C:19]3[N:20]([CH3:1])[C:21](=[O:23])[O:22][C:18]=3[CH:17]=2)=[O:15])[CH:11]=[CH:10][N:9]=1
Reactant: CC(C)(C)[O-]
Reactant: Cc1cc(C(=O)c2ccnc(Cl)c2)cc2oc(=O)[nH]c12
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)c2ccnc(Cl)c2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
220 mg (1.94 mmol) potassium-tert-butoxide were added to 500 mg (1.73 mmol) 6-(2-chloro-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in 10.0 mL THF and the mixture was stirred for 30 min at RT. Then 0.220 mL (3.46 mmol) methyl iodide were added and the mixture was stirred overnight at RT. The reaction mixture was diluted with EtOAc and washed several times with saturated sodium chloride solution. The organic phase was dried on magnesium sulphate, filtered and evaporated down i. vac. The residue was triturated with DIPE and suction filtered.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[S:21][C:20]([C:22]3([NH2:26])[CH2:25][CH2:24][CH2:23]3)=[N:19][CH:18]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28]>O1CCCC1.O.[Cl-].[Na+].O>[Cl:1][C:2]1[C:3]([C:17]2[S:21][C:20]([C:22]3([NH:26][C:30]([NH:29][CH2:27][CH3:28])=[O:31])[CH2:25][CH2:24][CH2:23]3)=[N:19][CH:18]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCN=C=O
Reactant: Cn1cc(-c2cc3c(-c4cnc(C5(N)CCC5)s4)c(Cl)cnc3[nH]2)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)NC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5cnn(C)c5)cc34)s2)CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1-(5-(5-chloro-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanamine (30 mg, 0.078 mmol) (Example 121B) in anhydrous tetrahydrofuran (1 mL) was treated with ethyl isocyanate (6.79 μL, 0.086 mmol), and the reaction mixture was stirred at ambient temperature for about 4 hours. The reaction was diluted with water and brine, and extracted with dichloromethane. The extracts were combined and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 2% to 8% methanol in dichloromethane, to provide the title compound. MS ESI(+) m/z 456.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6) ppm 12.34 (s, 1H) 8.26 (s, 1H) 8.22 (s, 1H) 8.16 (s, 1H) 8.03 (s, 1H) 7.06 (s, 1H) 6.75 (s, 1H) 5.93 (t, 1H) 3.89 (s, 3H) 3.01 (dd, 2H) 2.70 (m, 2H) 2.40 (m, 2H) 2.05 (m, 2H) 0.99 (t, 3H).
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[CH:11][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[CH:17][CH:16]=3)[CH:13]=[C:9]2[C:8](=[O:27])[N:7]([CH3:28])[C:6]1=[O:29])[CH:2]([CH3:4])[CH3:3].Cl[N:31]1[C:35](=[O:36])[CH2:34][CH2:33][C:32]1=[O:37]>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[O:37]=[C:32]1[CH2:33][CH2:34][C:35](=[O:36])[N:31]1[C:11]1[N:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:13]=[C:9]2[C:8](=[O:27])[N:7]([CH3:28])[C:6](=[O:29])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:10]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3ccc(-c4ccccn4)cc3)cc21
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3ccc(-c4ccccn4)cc3)c(N3C(=O)CCC3=O)c21
Temperature: 100 °C
Yield: 17.2 %

Procedure:
1-isobutyl-3-methyl-6-(4-(pyridin-2-yl)benzyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (186 mg, 0.48 mmol) is dissolved in a mixture of CCl4 and DMF (3/1, v/v), and then N-chlorosuccinimide (67 mg, 0.51 mmol) is added. The reaction mixture is heated in a Biotage microwave at 100° C. for 30 min. Solvents are removed under vacuum, and the residue is purified by a semi-preparative HPLC to give pure product as white solids (40 mg, yield 20%). MS (ESI) m/z 486.2 [M+H]+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:19][C:20]1[CH:29]=[CH:28][C:27]2[NH:26][C:25](=[O:30])[C:24]3[NH:31][CH:32]=[CH:33][C:23]=3[C:22]=2[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:34]([C:36]([O-:38])=[O:37])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>ClCCl.O1CCOCC1>[O:30]=[C:25]1[C:24]2[NH:31][CH:32]=[CH:33][C:23]=2[C:22]2[CH:21]=[C:20]([S:19]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:9])[CH:29]=[CH:28][C:27]=2[NH:26]1.[CH2:34]([C:36]([O-:38])=[O:37])[CH3:35]
Reactant: O=c1[nH]c2ccc(SCc3ccccc3)cc2c2cc[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CCC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(S(=O)Cc3ccccc3)cc2c2cc[nH]c12
Temperature: 2.5 °C
Reaction time: 6 h
Yield: 42.1 %

Procedure:
41 mg (0.24 mmol) of metachloroperbenzoic acid is added at 0° C. to a solution of 90 mg (0.24 mmol) of 8-benzylsulfanyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate suspended in dichloromethane (8 mL) and dioxan (8 mL). The reaction mixture is stirred for 6 hours at 0-5° C. then an aqueous solution of potassium carbonate is added and the product is extracted with ethyl acetate. The organic phase is washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated. The residue is purified by preparative LCMS to give 40 mg (42%) of 4-oxo-8-phenylmethanesulfinyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2([CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([O:21][CH:22]([CH3:24])[CH3:23])[CH:13]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4]1)[CH3:2].O.NN>C(O)C.[Pd]>[CH2:1]([N:3]1[C:7]2([CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([O:21][CH:22]([CH3:23])[CH3:24])[CH:13]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCCC12CCN(c1ccc([N+](=O)[O-])c(OC(C)C)c1)C2
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CCN1CCCC12CCN(c1ccc(N)c(OC(C)C)c1)C2
Temperature: 80 °C
Yield: 101.1 %

Procedure:
A mixture of 250 mg of 1-ethyl-7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane, 450 mg of hydrazine hydrate and 40 mg of 10% palladium-on-carbon in 10 ml of ethanol is heated at 80° C. (bath) for 4 h 30 min. 450 mg of hydrazine hydrate are then added and the reflux is maintained for 1 h. The mixture is filtered and the filtrate is concentrated under vacuum, so as to obtain 230 mg of 4-(1-ethyl-1,7-diazaspiro[4.4]non-7-yl)-2-(propan-2-yloxy)aniline in the form of a brown oil.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:25](O)=[O:26])#[N:2].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1.C(N(C(C)C)CC)(C)C>CN(C)C=O.ClCCl>[Cl:23][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:24])[C:17]=1[CH2:16][O:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:5][CH2:4][CH2:3][C:1]#[N:2])[C:7]([C:25]([N:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1)=[O:26])=[CH:8]2
Reactant: C1COCCN1
Reactant: N#CCCCn1c(C(=O)O)cc2cc(OCc3c(Cl)cccc3Cl)ccc21
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CCCCn1c(C(=O)N2CCOCC2)cc2cc(OCc3c(Cl)cccc3Cl)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.1 %

Procedure:
1-(3-Cyanopropyl)-5-(2,6-dichlorobenzyloxy)-1H-indole-2-carboxylic acid (0.10 g, 0.25 mmol) was dissolved in dimethylformamide (15 mL). PyBroP (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate) (0.13 g, 0.27 mmol) was added followed by morpholine (0.065 g, 0.74 mmol), diisopropylethylamine (0.13 g, 0.99 mmol), and a catalytic amount of N,N-dimethylaminopyridine. The reaction mixture was stirred for 18 h under argon at ambient temperature. The solution was diluted with dichloromethane and washed with water (3×) and brine. The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification by flash chromatography (silica gel, 25% acetone/chloroform) yielded an off-white solid (0.11 g, 95%). MS(ES) m/e 472.2 [M +H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][CH:5]=1.[B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:29]>C(Cl)Cl.FC(F)(F)S(O)(=O)=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([I:29])[C:7]([NH2:10])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: [IH2+]
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cnc(N)c(I)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 5 g 6-Amino-nicotinic acid methyl ester and 16.2 g Bis(pyridine)iodonium(I) tetrafluoroborate in 250 mL DCM, 7.6 mL Trifluoromethanesulfonic acid were added dropwise at 0° C. The mixture was stirred for 24 h at RT. Then additional 3.2 g Bis(pyridine)iodoniun(I) tetrafluoroborate and 1.5 mL Trifluoromethanesulfonic acid were added. After stirring for 2 h at RT the reaction mixture was concentrated under reduced pressure and then taken-up with concentrated aqueous Na2SO3 solution and brought to pH 8 with concentrated aqueous ammonia. The mixture was extracted with ethyl acetate (2×150 ml). The combined organic layers were washed with brine and then dried over MgSO4. After filtration the solvent was removed under reduced pressure and the residue was codestilled with 100 mL toluene. Yield: 9.6 g.