Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[S:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14](=[O:18])[CH2:15][CH:16]=[CH2:17].C(N(CC)CC)C>C(O[Pd]OC(=O)C)(=O)C>[CH3:12][O:13][C:14](=[O:18])[CH2:15]/[CH:16]=[CH:17]/[C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[S:8][C:4]=2[CH:3]=1
Reactant: C=CCC(=O)OC
Reactant: Cc1nc2ccc(I)cc2s1
Agent: CC(=O)O[Pd]OC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C/C=C/c1ccc2nc(C)sc2c1
Temperature: 130 °C

Procedure:
A mixture of 6-iodo-2-methylbenzo[d]thiazole (275 mg, 1 mmol), but-3-enoic acid methyl ester (100 mg, 1.2 mmol), diacetoxypalladium (22 mg, 0.1 mmol) and triethylamine (304 mg, 3 mmol) MeCN (8 mL) is heated in a microwave apparatus at 130° C. for 30 minutes. The solvent is removed under reduce pressure and the residue is purified by flash chromatography (heptane:EtOAc, 2:1) to give (E)-4-(2-methyl-benzothiazol-6-yl)-but-3-enoic acid methyl ester. MS 248.3 (M+1).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O=S(Cl)[Cl:21]>>[CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:21])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Product: CCCCCCCCOc1ccc(C(=O)Cl)cc1

Procedure:
20 ml of SOCl2 was added to 4.0 g (1.6×10-2 mol) of 4-octyloxybenzoic acid, and the mixture was refluxed under heating for 4 hours. Excessive SOCl2 was distilled off to obtain 4-octyloxybenzoic acid chloride. 3.136 g (1.6×10-2 mol) of 4-(2'-methylbutyloxy)benzenethiol and 1.246 g of pyridine were dissolved in 12 ml of toluene, cooled with ice, and the 4-octyloxybenzoic acid chloride dissolved in 10 ml of toluene was added thereto. The mixture was left standing at 5° C. for 45 min, followed by stirring for 3.5 hours at room temperature.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][N:18](C)[CH2:19]CCN=C=NCC.Cl.CNC.C(Cl)Cl>CN(C)C1C=CN=CC=1.O>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:18]([CH3:19])[CH3:17])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)c1ccncc1
Agent: CNC
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
A mixture of 1-(tert-butoxycarbonyl)-L-proline (10.75 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.6 g), dimethylamine hydrochloride (5.33 g), 4-dimethylaminopyridine (6.1 g) and methylene chloride (200 ml) was stirred at ambient temperature for 4 hours. The mixture was poured into water. The organic layer was separated, washed in turn with a 1N aqueous potassium hydrogen sulphate solution, with a 5% aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and evaporated to give 1-(tert-butoxycarbonyl)-N,N-dimethyl-L-prolinamide (11.2 g); NMR Spectrum: (CDCl3) 1.4 and 1.5 (2 s, 9H), 1.8–1.9 (m, 2H), 1.95–2.2 (m, 2H), 3.0 and 3.1 (2 d, 6H), 3.35–3.6 (m, 2H), 4.55 and 4.7 (2 m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9](OCC)OCC)=[CH:4][C:3]=1[F:17].[OH-].[K+].C(=O)(O)O.[NH2:24][NH:25][C:26]([NH2:28])=[NH:27].Cl.C(=O)(O)[O-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:24]=[N:25][C:26]([NH2:28])=[N:27][CH:9]=2)=[CH:4][C:3]=1[F:17]
Reactant: CCOC(OCC)C(=O)c1ccc(Br)c(F)c1
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Agent: O=C([O-])O
Solvent: O
Solvent: CCO
Product: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
A 22 L flask was charged with 1-(4-bromo-3-fluorophenyl)-2,2-diethoxyethanone (6, 1240 g, 4.07 mol), ethanol (11 L), water (1.4 L), potassium hydroxide (KOH, 910 g, 16.3 mol, 4.0 equiv), and aminoguanidine bicarbonate (1105 g, 8.13 mol, 2.0 equiv) at room temperature. The resulting reaction mixture was then heated to 75° C. for 14 h. When HPLC showed the condensation reaction was deemed complete, the reaction mixture was cooled down to room temperature before being filtered. The filtrate was then concentrated under the reduced pressure to remove the most of the solvents. The residual aqueous solution was extracted with ethyl acetate (EtOAc, 3×6 L). The organic layers were combined and concentrated under the reduced pressure to give a dark brown solid. This solid was dissolved in ethanol (4 L) and the resulting solution was treated with a solution of 0.2 M aqueous hydrochloric acid solution (4 L). The resulting slurry was subsequently heated to 50° C. for 6 h before being allowed to cool down to room temperature. A solution of saturated aqueous sodium bicarbonate solution (NaHCO3, 2 L) was slowly added to the slurry and the resulting mixture was then concentrated under the reduced pressure to remove most of the solvents. The aqueous residue was then treated with ethyl acetate (20 L) to dissolve the solids. The two layers were separated and the aqueous layer was extracted with ethyl acetate (2×2 L). The combined organic layers were concentrated under the reduced pressure. The dark brown solids were treated with methyl tert-butyl ether (MTBE, 4 L) and the resulting slurry was heated to 30° C. and stirred at 30° C. for 30 min. The mixture was filtered and the solids (green to orange in color) were collected (save the filtrate) and washed with methyl tert-butyl ether (MTBE, 2 L) to give the first crop of the crude desired product (7). The filtrate was evaporated under the reduced pressure, and the resulting dark brown solids were treated with methyl tert-butyl ether (MTBE, 2 L). The resulting slurry was heated to 30° C. and stirred at 30° C. for 30 min. The mixture was filtered to give the second crop of the crude desired product (7) which was washed with MTBE (1 L). The combined solids were dried in vacuum at 40-45° C. to afford 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (7, 585 g, 1095.1 g theoretical, 53.4% yield) which was used in the subsequent reaction without further purification. For 7: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.86 (s, 1H), 7.97 (d, 1H, J=10.79 Hz), 7.81 (m, 2H), 7.52 (br s, 2H); C9H6BrFN4 (MW 269.07), LCMS (EI) m/e 269.0/271.1 (M++H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[C:15]([OH:16])=[N:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10]=2[CH:11]=1.[Br:19]Br.CCOC(C)=O.C([O-])(O)=O.[Na+]>CC(O)=O.ClCCl.[Zn]>[Br:19][C:12]1[C:8]2[NH:9][C:10]3[CH:11]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=[CH:5][C:6]=3[C:7]=2[C:15]([OH:16])=[N:14][CH:13]=1
Reactant: Oc1nccc2[nH]c3cc(C(F)(F)F)ccc3c12
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Oc1ncc(Br)c2[nH]c3cc(C(F)(F)F)ccc3c12
Reaction time: 0.17 h

Procedure:
To a suspension of 7-(trifluoromethyl)-5H-pyrido[4,3-b]indol-1-ol in AcOH (0.3 M) in a cold water bath was added a solution (0.3 M) of Br2 (1 equiv) in dichloromethane to provide a homogeneous mixture. After standing at room temperature a precipitate formed, and Zn powder (excess) was added at 0° C. After a period of 10 min, the reaction mixture was poured over EtOAc and saturated NaHCO3. The organic phase was separated, dried over Na2SO4 and evaporated. The resulting solid was suspended in ether and hexanes, and was then collected by filtration.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].[I:19]Cl.O>C(O)(=O)C>[I:19][C:10]1[C:11]([NH2:13])=[CH:12][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[N:8][CH:9]=1
Reactant: Nc1ccnc(N2CCOCC2)c1
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(N2CCOCC2)ncc1I
Temperature: 15 °C
Reaction time: 0.33 h
Yield: 17.8 %

Procedure:
To a stirred solution of 92.8 g (311 mmol, 60 wt % purity) 2-morpholin-4-yl-pyridin-4-ylamine in 1000 ml glacial acetic acid was added 76.5 g (932 mmol) sodium acetate and the mixture was then cooled to 15° C. in an ice-bath. A solution of 50.4 g (311 mmol) iodine monochloride in 200 ml glacial acetic acid was then added dropwise at a rate such that the reaction temperature remained at 10-15° C. After 40 min the addition was complete. The reaction mixture was then stirred for a further 20 min before being poured onto 1000 ml water. The mixture was concentrated in vacuo and the residue partitioned between THF/ethyl acetate (1:1) and saturated brine. 5 N aqueous sodium hydroxide solution was added until the aqueous phase was pH 14, whereupon some product precipitated. The crystals were collected by filtration to afford 16.9 g (18%) 5-iodo-2-morpholin-4-yl-pyridin-4-ylamine as a yellow crystalline solid. The mother liquid phases were separated and the organic phase dried over sodium sulfate and concentrated in vacuo. The residue was triturated in ether and the resulting crystals collected by filtration to afford a further 47.2 g (50%) of 5-iodo-2-morpholin-4-yl-pyridin-4-ylamine as a yellow crystalline solid. The mother liquor was concentrated in vacuo and the residue was purified by flash chromatography (1/1-1/2 heptane/ethyl acetate) to afford a further 9.4 g (10%) 5-iodo-2-morpholin-4-yl-pyridin-4-ylamine as a yellow crystalline solid. Meanwhile, the aqueous phase from the initial aqueous extraction was left to stand for 2 days whereupon crystals deposited. These crystals were collected by filtration to afford a further 5.2 g (5%) 5-iodo-2-morpholin-4-yl-pyridin-4-ylamine as a yellow crystalline solid. ES-MS m/e (%): 306 (M+H+, 100).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7](=[O:19])(=[O:18])[C:6]=2[CH:5]=1)([OH:3])=[O:2].[C:20](Cl)(Cl)(Cl)Cl>S(Cl)(Cl)=O>[CH3:20][O:2][C:1]([C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7](=[O:19])(=[O:18])[C:6]=2[CH:5]=1)=[O:3]
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1O2
Reactant: ClC(Cl)(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1O2

Procedure:
2-carboxyphenoxathiin-10,10-dioxide (0.50g.) in carbon tetrachloride (25ml.) and thionyl chloride (2.0 ml.) was boiled under reflux for 2 hr. The solvent was evaporated and methanol (20. ml.) added. The mixture was boiled under reflux for 20 min., and cooled, whereupon 2-methoxycarbonylphenoxathiin-10,10-dioxide crystallised out and was filtered off and dried, m.pt. 160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:19]([F:18])[CH:20]=2)[CH:5]=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: O=Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1Cl
Reactant: COc1ccc(B(O)O)cc1F
Product: COc1ccc(-c2ccc(C=O)c(Cl)c2)cc1F

Procedure:
The title compound was prepared by reacting trifluoro-methanesulfonic acid 3-chloro-4-formyl-phenyl ester (2.8 g, 9.62 mmol) with 3-fluoro-4-methoxyphenylboronic acid (1.8 g, 10.6 mmol) according to Method B to yield 1.87 g (74%, over two steps) of white solid: mp 116-118° C.; 1H NMR (DMSO-d6): δ 3.91 (3H, s), 7.30 (1H, t, J=8.79 Hz), 7.66-7.68 (1H, m), 7.79 (1H, dd, J=12.91 Hz, J=2.47 Hz), 7.85-7.87 (1H, m), 7.91 (1H, d, J=8.24 Hz), 7.96 (1H, d, J=1.65 Hz), 10.34 (1H, s); IR 1688 cm−1; MS (ESI) m/z 265/267 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19](=[O:26])[C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22][OH:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.O>[CH2:11]([O:18][C:19](=[O:26])[C:20]([CH3:24])([CH3:25])[CH2:21][CH:22]=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(CCO)C(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(CC=O)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 65.8 %

Procedure:
Step C To a solution of oxalyl chloride (2.8 mL, 22 mmol) (Aldrich) in dichloromethane (40 mL) at −78° C. was added the solution of dimethyl sulfoxide (3.1 mL, 44 mmol) in dichloromethane (5 mL) dropwise. After 5 mins, the solution of 4-hydroxy-2,2-dimethyl-butyric acid benzyl ester (4.5 g, 20 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 15 min. Triethylamine (10 mL, 72 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 2,2-dimethyl-4-oxo-butyric acid benzyl ester as a colorless oil (Yield: 2.9 g, 66%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH3:22])[C:15]([CH3:24])([CH3:23])[CH2:14]2)[N:5]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[N:33]([O:38][CH3:39])[C:32]([CH3:41])([CH3:40])[CH2:31]2)[N:3]=1.[NH2:42][CH2:43][C:44]([OH:46])=[O:45]>>[CH3:22][O:21][N:16]1[C:15]([CH3:23])([CH3:24])[CH2:14][CH:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]2[N:5]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]3[CH2:35][C:34]([CH3:36])([CH3:37])[N:33]([O:38][CH3:39])[C:32]([CH3:40])([CH3:41])[CH2:31]3)[N:3]=[C:2]([NH:42][CH2:43][C:44]([OH:46])=[O:45])[N:7]=2)[CH2:18][C:17]1([CH3:20])[CH3:19]
Reactant: NCC(=O)O
Reactant: CON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C
Product: CON1C(C)(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)nc(NCC(=O)O)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[N-(1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine and glycine according to the procedure of Example 15.
Reaction SMILES: S(=O)(=O)(O)O.[O-]S(OOS([O-])(=O)=O)(=O)=O.[K+].[K+].[Br:18][C:19]1[CH2:23][CH:22]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:25])[N:21]([C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][N:33]=2)[N:20]=1.C(#N)C>O>[Br:18][C:19]1[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:25])[N:21]([C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][N:33]=2)[N:20]=1
Reactant: CCCCCOC(=O)C1CC(Br)=NN1c1ncccc1Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCCOC(=O)c1cc(Br)nn1-c1ncccc1Cl
Reaction time: 0.25 h
Yield: 47.3 %

Procedure:
0.5 ml of concentrated sulfuric acid and 1.4 g of potassium peroxodisulfate were added to a mixed solution comprising 1.0 g of pentyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate and 20 ml of acetonitrile, followed by reflux with heating for 3 hours and 20 minutes. After the reaction liquid was stood to cool, the reaction liquid was slowly added to water, followed by stirring for 15 minutes. The mixed liquid was subjected to extraction with ethyl acetate, and the organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=8.5/1.5 to 8/2) to obtain 0.47 g of the oily desired product.
Reaction SMILES: O[CH:2]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][C:4]2[CH:19]=[CH:20][C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][C:3]1=2.O=S(Cl)Cl.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[C:13]1([C:10]2[CH:11]=[C:12]3[CH:2]([N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[C:3]4[CH:22]=[C:21]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])[CH:20]=[CH:19][C:4]=4[CH:5]=[CH:6][C:7]3=[N:8][CH:9]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(O)c1cc(-c3ccccc3)cnc1C=C2
Reactant: C1CCNC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CS(=O)(=O)Nc1ccc2c(c1)C(N1CCCC1)c1cc(-c3ccccc3)cnc1C=C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-(5-hydroxy-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide (40 mg, 0.11 mmol) in CH2Cl2 (2 mL) was added SOCl2 (30 uL, 0.41 mmol) at 0° C. The mixture was left to stir at 0° C. for 1 h and concentrated in vacuo. To the residue were added CH2Cl2 (2 mL) and pyrroldine (0.10 mL, 1.2 mmol) at 0° C. The mixture was allowed to warm to room temperature as the bath did, and left to stir overnight. The mixture was concentrated and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CD3OD) δ 8.83 (s, 1EI); 7.91 (s, 1H); 7.15-7.64 (m, 10H); 4.31 (br s, 1H); 3.02 (s, 3H); 2.09 (br s, 4H); 1.61 (br s, 4H). LRMS (APCI) calc'd for (C25H26N3O2S) [M+H]+, 432.2; found 432.1.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[CH:14]([CH2:20][CH:21]=O)[CH2:13][CH2:12]2>C(Cl)Cl>[Cl:8][C:9]1[CH:18]=[CH:17][C:16]2[C:15]3[N:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:21]=[CH:20][C:14]=3[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: CC(=O)NCCN
Reactant: O=CCC1CCc2cc(Cl)ccc2C1=O
Solvent: ClCCl
Product: CC(=O)NCCn1ccc2c1-c1ccc(Cl)cc1CC2
Yield: 67.5 %

Procedure:
N-Acetylethylenediamine (2.4 g) was dissolved in 40 ml of methylene chloride under argon, treated in succession with 40 g of molecular sieve 4 Å and a solution of 4.8 g of 6-chloro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetaldehyde in 20 ml of methylene chloride and refluxed for 40 hours while stirring. The reaction mixture was cooled, filtered over a Celite® pad and the filtrate was freed from solvent. The crude product, 5.6 g of brown solid, was dissolved in a 6-fold amount of hot ethyl acetate and, after the addition of an 8-fold amount of hexane, boiled briefly. There were obtained 4.2 g (67%) of N-[2-(7-chloro-4,5-dihydro-1H-benz[g]indol-1-yl)ethyl]acetamide; m.pt.: 144°-145° C.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][CH2:5][S:6]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[C:23]3[C:18](=[C:19]([C:32]([NH2:34])=[O:33])[CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][OH:31])[CH:25]=4)[CH:22]=3)[NH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])=[O:7]>C1COCC1.O=[Mn]=O>[CH3:35][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][S:6]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[C:23]3[C:18](=[C:19]([C:32]([NH2:34])=[O:33])[CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=[O:31])[CH:25]=4)[CH:22]=3)[NH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])=[O:7]
Reactant: CN(C)CCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CO)c4)cc23)CC1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CN(C)CCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
To a solution of 3-(1-{[3-(dimethylamino)propyl]sulfonyl}-4-piperidinyl)-5-[3-(hydroxymethyl)phenyl]-1H-indole-7-carboxamide (230 mg, 0.47 mmol) in THF (60 mL) was added MnO2 (1.3 g, 14.05 mmol). The reaction mixture was stirred at room temperature overnight and filtered through a pad of celite after that. The filtrate was collected and concentrated at reduced pressure to give the crude product (150 mg, 65%), which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.O.[C:32]1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(OCC)OCC.O(C(C)(C)C)[K].[NH4+].[Cl-].C([O-])(O)=O.[Na+]>ClCCCl.C1COCC1.CCOC(C)=O.O>[CH2:14]([N:11]1[CH2:10][CH2:9][N:8]([C:5]2[N:4]=[C:3]3[C:21]([S:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)(=[O:24])=[O:23])=[CH:32][NH:1][C:2]3=[CH:7][CH:6]=2)[CH2:13][CH2:12]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc(N2CCN(Cc3ccccc3)CC2)nc1CS(=O)(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(C)(C)O[K]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CCOC(OCC)OCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1c[nH]c2ccc(N3CCN(Cc4ccccc4)CC3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
A stirred solution of 3-amino-6-(4-benzylpiperazin-1-yl)-2-[(phenylsulfonyl)-methyl]pyridine (1.41 g, 3.34 mmol), p-toluenesulfonic acid monohydrate (63 mg, 0.33 mmol), triethyl orthoformate (2.78 mL, 16.7 mmol) in 1,2-dichloroethane is heated at reflux temperature under nitrogen for 7.5 h, stirred at room temperature for 16 h and in vacuo to afford an oil residue. The residue is stirred in dry THF, treated with 1.0M KO-t-Bu in THF (4.35 mL, 4.35 mmol) for 2 h, treated sequentially with saturated aqueous NH4Cl, saturated aqueous NaHCO3 and water and extracted with CH2Cl2. The combined extracts are dried over MgSO4 and concentrated in vacuo to give a yellow solid residue. This residue is chromatograped (silica gel, EtOAc as eluent to afford the title compound as a pale yellow solid, 1.18 g (79% yield), mp 238-239° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[NH:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][CH:44]1[CH2:46][CH2:45]1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[CH:44]1([CH2:43][N:3]2[C:2](=[O:1])[CH2:7][O:6][C:5]3[N:8]=[C:9]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:25][CH2:26][CH2:27]5)=[CH:20][CH:19]=4)[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][C:4]2=3)[CH2:46][CH2:45]1
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CC3CC3)C(=O)CO4)cc2)CCC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
In a 15 mL reaction tube was added tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (50 mg, 0.106 mmol), potassium carbonate (44 mg, 0.318 mmol) and (bromomethyl)cyclopropane (0.031 mL, 0.318 mmol) in anhydrous N,N-dimethylformamide (1 mL) to give an orange suspension. The reaction mixture was stirred at 80° C. for one hour. The reaction mixture was allowed to cool to room temperature, diluted with saturated sodium bicarbonate solution (5 mL) and extracted into dichloromethane (3×3 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give a yellow oil. This was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 90:10 to 20:80) to give the desired product as an off-white solid (40 mg, 72% yield). 1H-NMR (500 MHz, CDCl3) δ 7.32 (1H, s), 7.10-7.28 (9H, m), 4.98 (1H, br s), 4.82 (2H, s), 3.79 (2H, d), 2.05-2.60 (4H, m), 1.90-2.05 (1H, m), 1.65-1.79 (1H, m), 1.00-1.45 (10H, br m), 0.45-0.57 (2H, m), 0.35-0.45 (2H, m). LCMS (Method A) RT=7.79 min, M+H+=526.18.