Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:26]C)[C:10](=[O:25])[N:11]3[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][N:17]([CH3:23])[C:16](=[O:24])[C:12]3=2)[C:7]1=[O:28].Br>C(O)(=O)C.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:26])[C:10](=[O:25])[N:11]3[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][N:17]([CH3:23])[C:16](=[O:24])[C:12]3=2)[C:7]1=[O:28]
Reactant: COc1c2c(c3n(c1=O)CCC(=O)CN(C)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: Br
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CN1CC(=O)CCn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-methyl-5,6,12,13-tetrahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,4,8,10(3H, 11H)-tetrone (25 mg, 0.05 mmol) and 33% hydrogen bromide in acetic acid (0.5 mL) in dioxane (1 mL) was stirred at room temperature for 1.5 hour. The product mixture was concentrated under vacuum. The residue was dissolved in DMSO and subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and lyophilization of appropriate fractions afforded the title compound.
Reaction SMILES: CC(=C[N:5]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1[CH:11]=CC=C[CH:7]=1)C.[C:19]1([CH3:26])[CH:24]=[CH:23][CH:22]=[C:21](C)[CH:20]=1>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:7][C:6]1([CH3:11])[CH2:26][C:19]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Cc1cccc(C)c1
Reactant: CCCCCCCN(C=C(C)C)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CCCCCCCN1c2ccccc2CC1(C)C
Yield: 95.8 %

Procedure:
N-(2-methylprop-2-en-3-yl)N-n-heptyl aniline (0.38 mole), zinc chloride (0.4 mole) and m-xylene (200 cm3) were refluxed for 17 hours before cooling and dissolving in dichloromethane. The dichloromethane was filtered and washed with water, separated, dried over magnesium sulphate, filtered and evaporated to leave an oil. The oil was eluted from silica using 50:50 dichloromethane/hexane as eluent evaporated of the solvent gave 2,2-dimethyl-N-n-heptylindoline (122 g, 95.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)=[CH:4][CH:3]=1.Br[CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:28])[F:29])[CH:21]=2)=[CH:31][CH:32]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCC(=O)OC(C)(C)C)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 100 °C
Yield: 40.8 %

Procedure:
7-(4-Chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)-1H-purine-2,6(3H,7H)-dione (0.50 g, 1.07 mmol, intermediate 9), tert-butyl 3-bromopropanoate (0.22 mL, 1.29 mmol) and potassium carbonate (0.22 g, 1.61 mmol) were combined in DMF (5 mL) and heated at 100° C. for 24 h. The reaction was cooled, diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were washed with 1N lithium chloride (2×50 mL), dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to leave a white solid. This solid was purified using a 25 g silica gel flash column eluted with 10% ethyl acetate/hexanes to give tert-butyl 3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propanoate (0.26 g, 41% yield) as a white solid. LCMS retention time=4.841 min and 99% purity, LCMS MH+=595. 1H NMR (CDCl3) δ 7.12-7.46 (m, 8H), 5.41 (s, 2H), 4.29 (t, 2H, J=8 Hz), 3.53 (s, 3H), 2.61 (t, 2H, J=8 Hz), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].CS(C)(=O)=O.O1[CH2:49][CH2:48]OCC1>>[CH2:10]([N:5]1[CH2:49][CH2:48][N:11]([C:14]2[N:13]=[C:12]([NH:11][C@H:7]3[CH2:8][CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6]3)[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=2)[CH2:7][CH2:6]1)[CH3:9]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Reactant: C1COCCO1
Agent: CS(C)(=O)=O
Product: CCN1CCN(c2ncc(-c3cnc4[nH]ccc4n3)c(N[C@H]3CCCN(S(C)(=O)=O)C3)n2)CC1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1,1-ethyl-piperazine was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give [2-(4-ethyl-piperazin-1-yl)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-4-yl]-((S)-1-methanesulfonyl-piperidin-3-yl)-amine. MS (ES+): 486.
Reaction SMILES: I[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.CN(C1CCCCC1)C1CCCCC1.[O:39]1[CH2:43][CH:42]=[CH:41][CH2:40]1>O1CCOCC1.CO.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[O:39]1[CH:40]=[CH:41][CH2:42][CH:43]1[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=CCOC1
Reactant: Ic1cccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: CO
Solvent: C1COCCO1
Product: C1=COC(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of N-(4-(3-iodopyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (0.403 g, 0.905 mmol), N-methyldicyclohexylamine (0.400 mL, 1.886 mmol, Aldrich), bis(tri-tert-butylphosphine)palladium (0) (0.045 g, 0.088 mmol, Strem) and 2,5-dihydrofuran (0.500 mL, 6.78 mmol, Aldrich) in 5 mL of dioxane was capped under an atmosphere of argon and stirred at rt for 3 h and then heated at 45° C. overnight. The reaction mixture was diluted with MeOH, evaporated onto silica gel and purified by flash chromatography (Isco, (40 gram)) eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→3:97) to give a white amorphous solid. MS (ESI, pos. ion) m/z: 386.0 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:33][C@H:34]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[CH:46][CH:45]=1)[CH2:35][C@:36]([CH2:41][OH:42])([CH3:40])[C:37]([OH:39])=[O:38]>CCN(C(C)C)C(C)C.CN(C=O)C>[C:47]1([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:46]=[CH:45][C:44]([CH2:43][C@@H:34]([NH:33][C:6]([C:4]2[NH:3][N:2]=[N:1][CH:5]=2)=[O:8])[CH2:35][C@:36]([CH2:41][OH:42])([CH3:40])[C:37]([OH:39])=[O:38])=[CH:49][CH:48]=1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)O
Reactant: O=C(O)c1c[nH]nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)O
Reaction time: 0.25 h
Yield: 30.7 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (130 mg, 1.2 mmol, 1.2 eq.) and HATU (400 mg, 1.1 mmol, 1.1 eq.) were dissolved in DIPEA (167 μL) and the resulting mixture was stirred for 5 minutes at room temperature in DMF (0.2 mL). DIPEA (3 eq.) and (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid (300 mg, 957 μmol, 1.0 eq.) dissolved in DMF (0.2 mL) was added, and the resulting mixture was stirred for 15 minutes. The reaction was quenched with AcOH and the product was purified by preparative HPLC then lyophilized to yield the title compound (120 mg, 95% purity). MS m/z [M+H]+ calc'd for C22H24N4O4, 409.18. found 409.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:21]1[CH2:25][CH2:24][CH:23]([CH2:26]O)[CH2:22]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:26][CH:23]2[CH2:24][CH2:25][O:21][CH2:22]2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Reactant: OCC1CCOC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2OCC2CCOC2)C1
Temperature: 120 °C
Yield: 62.5 %

Procedure:
A mixture of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.5 mmol), tetrahydro-furan-3-yl-methanol (0.5 mmol), and cyanomethylenetri-n-butylphosphorane (0.5 mmol) in toluene (3 mL) was heated at 120° C. in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing 3-[5-chloro-2-(tetrahydro-furan-3-ylmethoxy)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester (120 mg). To this compound was added CH2Cl2 (20 mL) and TFA (3 mL). After 4 h at rt the mixture was concentrated to give the title compound (161 mg). MS (ESI): mass calcd. for C14H18ClNO3, 283.1; m/z found, 284.0 [M+H]+. 1H NMR (MeOD): 7.05-6.96 (m, 2H), 6.88 (d, J=1.9 Hz, 1H), 5.15-5.05 (m, 1H), 4.57-4.48 (m, 2H), 4.28-4.19 (m, 2H), 4.04-3.88 (m 4H), 3.82-3.70 (m 2H), 2.82-2.70 (m, 1H), 2.20-2.09 (m, 1H), 1.84-1.73 (m, 1H).
Reaction SMILES: O=[C:2]([CH2:10][CH2:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:23][CH2:22][O:21][C:20]2=[O:24])=[CH:15][CH:14]=1)[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][C:28]=1[CH3:36]>CCO.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Zn+2]>[C:31]([C:30]1[CH:34]=[CH:35][C:27]([N:26]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][CH2:22][O:21][C:20]4=[O:24])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:2]2[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:28]([CH3:36])[CH:29]=1)(=[O:32])[NH2:33]
Reactant: CCOC(=O)CCC(=O)CCC(=O)c1ccc(N2CCOC2=O)cc1
Reactant: Cc1cc(C(N)=O)ccc1N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(-c2ccc(N3CCOC3=O)cc2)n1-c1ccc(C(N)=O)cc1C
Temperature: 120 °C
Yield: 38.8 %

Procedure:
To a solution of ethyl 4,7-dioxo-7-(4-(2-oxooxazolidin-3-yl)phenyl)heptanoate (158 mg, 0.43 mmol) and 4-amino-3-methylbenzamide (130 mg, 0.68 mmol) in EtOH (1 mL) was added Zn(OTf)2 (313 mg, 0.86 mmoL). The mixture was heated to 120° C. under microwave for 2 h. After evaporation under reduced pressure, the crude product was purified by silica gel column chromatography (DCM:MeOH=20:1) to afford the titled compound as a yellow solid (77 mg, yield 39%).
Reaction SMILES: C(N[C:9]1[CH:10]=[C:11]2[C:16](=[N:17][CH:18]=1)[NH:15][C:14](=[O:19])[C:13]1[CH:20]=[CH:21][CH:22]=[CH:23][C:12]2=1)C1C=CC=CC=1.C([O-])=O.[NH4+:27]>CO.[Pd]>[CH2:11]([NH:27][C:21]1[CH:22]=[CH:23][C:12]2[C:11]3[C:16](=[N:17][CH:18]=[CH:9][CH:10]=3)[NH:15][C:14](=[O:19])[C:13]=2[CH:20]=1)[C:12]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:13]=1
Reactant: [NH4+]
Reactant: O=c1[nH]c2ncc(NCc3ccccc3)cc2c2ccccc12
Agent: [Pd]
Agent: O=C[O-]
Solvent: CO
Product: O=c1[nH]c2ncccc2c2ccc(NCc3ccccc3)cc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
2-Benzylamino-5H-benzo[c][1,8]naphthyridin-6-one (100 mg, 0.33 mmol), ammonium formate (209 mg, 3.30 mmol), and palladium/carbon (200 mg, 10% weight) were suspended in MeOH (6 mL) and stirred overnight at 60° C. The reaction mixture was filtered through celite, and the celite was washed with methanol. The filtrate was concentrated, and the crude product was purified via prep-LC-MS to provide 19 (10 mg, 14% yield) as a yellow solid. LC-MS (M+H=212, obsd.=212). 1H NMR (400 MHz, d6-DMSO): δ 11.63 (s, 1H), 8.31 (d, 1H), 8.28 (d, 1H), 7.96 (d, 1H), 7.85 (m, 2H), 7.64 (t, 1H), 7.31 (m, 1H), 7.24 (m, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([S:11](=[O:30])(=[O:29])[N:12]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[O:27][CH3:28])[C:13]3[S:17][N:16]=[CH:15][N:14]=3)=[CH:8][CH:9]=2)[N:4]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:3]=1.[CH3:38][N:39]1[C:43]([C:44]2[CH:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:47]=[CH:46][C:45]=2B(O)O)=[CH:42][CH:41]=[N:40]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH3:28][O:27][C:20]1[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=1[CH2:18][N:12]([C:13]1[S:17][N:16]=[CH:15][N:14]=1)[S:11]([C:7]1[N:6]=[C:5]2[N:4]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH:3]=[C:2]([C:45]3[CH:46]=[CH:47][C:48]([C:50]([F:53])([F:51])[F:52])=[CH:49][C:44]=3[C:43]3[N:39]([CH3:38])[N:40]=[CH:41][CH:42]=3)[C:10]2=[CH:9][CH:8]=1)(=[O:29])=[O:30]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C(=O)OC(C)(C)C)c3n2)c(OC)c1
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccnn4C)cn(C(=O)OC(C)(C)C)c3n2)c(OC)c1
Temperature: 90 °C
Yield: 71.3 %

Procedure:
A vial was charged with tert-butyl 3-bromo-6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (531.8 mg, 0.871 mmol), (2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid (306 mg, 1.132 mmol), potassium phosphate (555 mg, 2.61 mmol), and Pd(AmPhos)2Cl2 (30.8 mg, 0.044 mmol). 1,4-Dioxane (2178 μl) and water (726 μl) were added in sequence. The vial was sealed and heated in a microwave reactor for 30 min at 90° C. The organic layer was removed via pipette, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were concentrated in vacuo. The crude product was purified by chromatography on silica gel (0 to 50% EtOAc/Heptane) to give tert-butyl 6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (469 mg, 0.621 mmol, 71.2% yield) as a white solid. m/z (ESI) 756.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)=[O:12])[CH:6]=[CH:5]2.OC1C=C2C(=CC=1)N(C(NC1C=CC=C(C(F)(F)F)C=1)=O)CC2.[OH-].[Na+].[Cl:49][C:50]1[N:55]=[C:54](Cl)[CH:53]=[CH:52][N:51]=1>CC(C)=O.O>[Cl:49][C:50]1[N:55]=[C:54]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)=[O:12])[CH:6]=[CH:5]3)[CH:53]=[CH:52][N:51]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(O)ccc21
Agent: O=C(Nc1cccc(C(F)(F)F)c1)N1CCc2cc(O)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3ccnc(Cl)n3)ccc21
Reaction time: 1.5 h

Procedure:
A mixture of 5-hydroxy-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide and 5-hydroxy-N-(3-(trifluoromethyl)phenyl)indoline-1-carboxamide (6:4) (3 g) is mixed with sodium hydroxide (0.45 g, 11.2 mmol) and 2,4-dichloropyrimidine (1.68 g, 11.2 mmol) in 50 mL of acetone and 50 mL of water at 0° C. and stirred for 1.5 h. Additional sodium hydroxide (0.075 g, 1.88 mmol) and (0.279 g, 1.88 mmol) are added. After additional 30 min stirring the reaction is concentrated, diluted with EtOAc, washed with water and brine before the organic layer is dried over sodium sulfate and concentrated. The residue is separated via FCC (5-50% EtOAc in heptane) to give 5-(2-chloropyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide. 1H NMR (400 MHz, CDCl3) δ ppm 8.45 (d, J=5.7 Hz, 1 H), 8.24 (d, J=9.0 Hz, 1 H), 7.86 (s, 1 H), 7.78 (d, J=8.2 Hz, 1H), 7.60 (d, J=3.7 Hz, 1 H), 7.55 (t, J=8.0 Hz, 1 H), 7.45-7.50 (m, 2 H), 7.42 (d, J=2.1 Hz, 1 H), 7.15 (dd, J=8.9, 2.3 Hz, 1 H), 6.82 (d, J=5.7 Hz, 1 H), 6.73 (dd, J=3.7, 0.6 Hz, 1 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7](=[S:9])=[S:8]>C(Cl)Cl.[O-]Cl.[Na+]>[CH2:6]1[N:1]([C:7]([S:9][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[S:8])[CH2:2][CH2:3][O:4][CH2:5]1
Reactant: C1COCCN1
Reactant: S=C=S
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: S=C(SN1CCOCC1)N1CCOCC1
Reaction time: 1 h

Procedure:
In this example, a methylene chloride solution of N-oxydiethylenethiocarbamyl-N'-oxydiethylenesulfenamide was prepared by reacting morpholine, dissolved in methylene chloride, sequentially with a NaOCl bleach solution and carbon disulfide in the manner described in U.S. Pat. No. 3,985,743. At the end of the reaction the methylene chloride organic phase was separated from the water phase. The methylene chloride solution was diluted with methylene chloride to a total solids content of 12 percent. 100 volumes of this organic solution containing the N-oxydiethylenethiocarbamyl-N'-oxydiethylenesulfenamide was stirred with 100 volumes of hydrochloric acid having a normality of 0.06 N, the HCl being used in amount of 5.8 milliequivalents of acid based on 15.7 grams of solids. The aqueous acid and organic solutions were stirred together for about 15 minutes to a pH of the mixture of 2.7. The acid phase was separated from the organic solution by transferring the mixture to a separating vessel settling the layers, and decanting. The organic solution was then washed twice with 100 volumes of distilled water and separated from the water. The methylene chloride was then flashed off and the dried N-oxydiethylenecarbamyl-N'-oxydiethylenesulfenamide collected. The melting point of the N-oxydiethylenecarbamyl-N'-oxydiethylenesulfenamide was found to be 134.8° C. A sample of N-oxydiethylenecarbamyl-N'-oxydiethylenesulfenamide was aged in an air over at 100° C. for 60 minutes to test for stability. The melting point after aging was determined and found to be 133.0° C., for a ΔT of 1.8, this sample being very stable. When a control run was made without the acid wash, using only water washes, the unaged melting point was found to be 134.4° C. and the aged melting point was found to be 128.4° , for a ΔT of 6.0, which represents a very unstable product with unsatisfactory storage stability and product activity.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[OH:13].[CH3:15][S:16](Cl)(=[O:18])=[O:17].CCOC(C)=O>C1COCC1>[CH3:3][O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[O:13][S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: COC(=O)c1cc(C)ccc1O
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)ccc1OS(C)(=O)=O
Temperature: 0 °C

Procedure:
To a ice cooled suspension of sodium hydride (60%, 1.3 g, 78.3 mmol) in THF (100 mL) is added a solution of 2-hydroxy-5-methylbenzoic acid methyl ester (10 g, 60 mmol) in THF (20 mL) and it is stirred at 0° C. Then a solution of methanesulfonyl chloride (8.2 g, 72 mmol) in THF (20 mL) is added dropwise. The reaction mixture is stirred at RT for 18 h. Then the reaction mixture is cooled in an ice bath and slowly ice is added to quench the reaction. EtOAc is used to extract. Brine is added to the aqueous phase and re-extracted with EtOAc. The combined organic phase is washed with water, brine, dried over NaSO4 and MgSO4, and concentrated to give the title compound as an oil. It is used directly in the next step.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([O-:16])=O)[S:13][C:6]=12.[Li+]>>[CH3:1][N:2]([CH3:3])[C:14]([C:12]1[S:13][C:6]2[C:7](=[N:8][CH:9]=[CH:10][C:5]=2[Cl:4])[CH:11]=1)=[O:16]
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: CNC
Agent: [Li+]
Product: CN(C)C(=O)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from dimethyl amine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 239/241 (MH+); HPLC Rf: n.d.; HPLC purity: n.d.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:17][NH2:18]>CO>[CH3:17][NH:18][C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1N1CCCCC1
Reactant: CN
Solvent: CO
Product: CNc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Yield: 100 %

Procedure:
A solution of 1-(5-fluoro-2-nitro-phenyl)-piperidine (200 mg, 0.890 mmol) in 4 mL of 2M methylamine in MeOH was heated in a sealed tube for 12 h at 80° C. Removal of the solvent under vacuum afforded methyl-(4-nitro-3-piperidin-1-yl-phenyl)-amine (209 mg, 100%). Mass spectrum (ESI, m/z): Calcd. for C12H17N3O2, 236.1 (M+H), found 236.1.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[C:21](F)=[CH:22][C:23]([F:33])=[C:24]([CH:32]=1)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CC(C)([O-])C.[K+]>CS(C)=O>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][C:21]2[C:20]([Cl:19])=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[C:23]([F:33])[CH:22]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Temperature: 20 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
A mixture of 1-benzhydrylazetidin-3-ol (500 mg, 2.08 mmol), tert-butyl 5-chloro-2,4-difluorobenzoate (568 mg, 2.29 mmol) and potassium tert-butoxide (349 mg, 3.12 mmol) in DMSO (30 mL) was stirred at 20° C. for 1 h. The mixture was quenched with water and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to get the target compound (700 mg, 72%) which was used in the next step without further purification. LCMS (ESI) m/z: 468.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40].C([O-])([O-])=O.[Na+].[Na+].O>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][NH:17][C:15](=[O:16])[C:14]1[CH:19]=[CH:20][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:35]4[CH:36]=[C:37]([O:41][CH3:42])[C:38]([O:39][CH3:40])=[C:33]([O:32][CH3:31])[CH:34]=4)[CH:3]=3)[NH:8][CH:9]=2)=[CH:12][CH:13]=1
Reactant: CNC(=O)c1ccc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(Br)cc23)cc1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1ccc(-c2c[nH]c3ncc(-c4cc(OC)c(OC)c(OC)c4)cc23)cc1
Yield: 46.5 %

Procedure:
4-[5-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-N-methyl-benzamide (Intermediate CE, 100 mg, 0.206 mmol), 3,4,5-trimethoxyphenylboronic acid (53 mg, 0.248 mmol) and dichlorobis(triphenylphosphine)palladium (II) (9 mg, 0.012 mmol) were combined in CH3CN (2 ml) and 1 M Na2CO3 (2 ml) and reacted in a microwave reactor for 20 min at 150° C. Water was added, the aqueous phase was extracted with DCM and the organic phase was dried and evaporated. Purification by silica gel chromatography using 0-8% MeOH:DCM yielded 40 mg (47%) of the title compound. 1H NMR (CDCl3, 300 MHz): δ 12.09 (s, 1H), 8.59 (d, J=1.2 Hz, 1H), 8.48 (d, J=1.2 Hz, 1H), 8.43 (q, J=2.7 Hz, 1H), 8.04 (s, 1H), 7.94 (d, J=4.0, 2H), 7.91 (d, J=4.0 Hz, 2H), 7.00 (s, 2H), 3.89 (s, 6H), 3.70 (s, 3H), 2.80, (d, J=4.5 Hz, 3H).