Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][CH2:12][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]4[CH2:15][C:4]([C:5]=2[C:6]=34)=[CH:3][CH:2]=1.[Br:16]Br.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:16][C:2]1[CH:3]=[C:4]2[CH2:15][C:7]3[C:6]4[C:5]2=[C:14]([CH2:13][CH2:12][C:11]=4[CH:10]=[CH:9][CH:8]=3)[CH:1]=1
Reactant: c1cc2c3c(c1)Cc1cccc(c1-3)CC2
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1cc2c3c(c1)Cc1cccc(c1-3)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.1 %

Procedure:
8.5 g (44.2 mmol) of 8,9-dihydro-4H-cyclopenta[def]phenanthrene was dissolved in 80 ml of CCl4, and 7.1 g (44.2 mmol) of Br2 was then slowly added thereto at 0° C. The reaction solution was stirred at room temperature for 4 hours and a 10% Na2SO3 solution was added thereto to separate the organic layer. The obtained organic layer was dried with magnesium sulfate, the solvent was evaporated therefrom, and the resultant product was recrystallized with n-hexane. As a result, 9.6 g of the target material was obtained (yield: 80%). The obtained compound was confirmed by LC-MS.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=O)[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[S:19]([NH2:22])(=[O:21])=[O:20]>C(OCC)(=O)C>[Cl:1][C:2]1[C:3](=[O:13])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[N:22][S:19]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)(=[O:21])=[O:20])[CH:11]=1
Reactant: NS(=O)(=O)c1cccs1
Reactant: O=C1C=C(Cl)C(=O)c2ccccc21
Solvent: CCOC(C)=O
Product: O=C1C(Cl)=CC(=NS(=O)(=O)c2cccs2)c2ccccc21
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
385.2 mg 2-chloro-1,4-naphthoquinone (11) was mixed with 326.4 mg thiophene-2-sulfonamide in 15 ml dichloromethylene, to which at 0° C. was added 2 ml TiCl4 dichloromethylene solution followed by 613.3 μl. The mixture was heated at 60° C. with M.W. for 15 min and the black mixture was poured into 100 ml ethyl acetate. The insoluble was removed by filtrate through a pad of celite. The filtrate was concentrated and the residue was suspended in dichloromethylene. The brown insoluble stuff was removed by filtration and the filtrate was again concentrated to dryness. The residue was suspended in ethyl acteate/hexane (1:1) and the yellow solid was filtered. The solid was washed with ethyl acteate/hexane (1:1) and dried over vacuum affording title compound 377.7 mg (55.9%) as a yellow solid. When TiCl4.2THF and THF were used instead, the reaction afforded the title compound 522 mg (77.3%) as a yellow solid, m.p.: 167-169° C.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:23]#[N:24])=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2)(=[O:11])=[O:10].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]2[C:3]([S:9](=[O:10])(=[O:11])[NH:12][C:13]3[C:14]2=[CH:15][C:16]([C:23]#[N:24])=[C:17]2[C:22]=3[N:21]=[CH:20][CH:19]=[CH:18]2)=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(NS(=O)(=O)c2ccc(Cl)cc2N)c2ncccc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#Cc1cc2c(c3ncccc13)NS(=O)(=O)c1ccc(Cl)cc1-2
Yield: 43.3 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-4-chloro-N-(5-cyano-quinolin-8-yl)-benzenesulfonamide (Intermediate 286) (100 mg, 0.27 mmol), t-butyl nitrite (0.047 ml, 0.41 mmol) and AcOH: THF (2 ml: 1 ml) gave the title compound (40 mg, 42%) after purification by column chromatography with chloroform/MeOH (99.5:0.5) as the eluent.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:38])[C:21]([CH3:37])=[C:22]([C:24]3[N:29]=[CH:28][C:27]([C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:38])[C:21]([CH3:37])=[C:22]([C:24]3[N+:29]([O-:9])=[CH:28][C:27]([C:30]([NH:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NC(C)(C)C)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NC(C)(C)C)c[n+]1[O-]
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 15 mg) was added to a solution of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1,1-dimethylethyl)-3-pyridinecarboxamide (Intermediate 9, 20 mg) in chloroform (3 ml) at 60° C. and the reaction maintained at 60° C. for 7 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (2 g) and an SCX SPE (1.0 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1,1-dimethylethyl)-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:27]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCSc3ccc(Cl)c(Cl)c3)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[3-(3,4-dichloro-phenylmercapto)-propoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:21]/[N:22]=[C:23](/[C:27]2[N:28]=[C:29]([NH:32][C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[S:30][CH:31]=2)\[C:24](O)=[O:25])[CH2:20][CH2:19][CH2:18]1)=[O:16])([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.[NH2:52][CH:53]1[C:78](=[O:79])[N:55]2[C:56]([C:62]([O:64][CH:65]([C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)[C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)=[O:63])=[C:57]([CH2:60][Cl:61])[CH2:58][S:59][C@H:54]12.CN(C)C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(Cl)Cl.O.C(Cl)(Cl)Cl>[CH:1]([O:14][C:15]([C:17]1([O:21]/[N:22]=[C:23](/[C:27]2[N:28]=[C:29]([NH:32][C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[S:30][CH:31]=2)\[C:24]([NH:52][CH:53]2[C:78](=[O:79])[N:55]3[C:56]([C:62]([O:64][CH:65]([C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)[C:72]4[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=4)=[O:63])=[C:57]([CH2:60][Cl:61])[CH2:58][S:59][C@H:54]23)=[O:25])[CH2:20][CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: O=C(O)/C(=N\OC1(C(=O)OC(c2ccccc2)c2ccccc2)CCC1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS[C@@H]2C(NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CCC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Reaction time: 4 h

Procedure:
1.82 g (2.62 mmol) of [(Z)-2-(1-benzhydryloxycarbonyl-1-cyclobutoxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid and 1.09 g (2.62 mmol) of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate were dissolved in 40 ml of methylene chloride, and then 1.06 ml (8.39 mmol) of N,N-dimethylaniline and 0.26 ml (2.75 mmol) of phosphorus oxychloride were dropwise added thereto under cooling with ice. The mixture was stirred at the same temperature for 4 hours. To the reaction solution, 30 ml of chloroform and 30 ml of water were added. The organic layer was washed with water and with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated to obtain a residue of the above-identified compound. The residue of the compound thus obtained was employed for the next reaction without purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:13]=[C:14]([CH3:26])[CH2:15][P:16]([O:22][CH:23]([CH3:25])[CH3:24])([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=[CH:29][CH:28]=1>ClCCl.C(O)C>[CH2:28]([O:11][C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:13]=[C:14]([CH3:26])[CH2:15][P:16]([O:22][CH:23]([CH3:25])[CH3:24])([O:18][CH:19]([CH3:20])[CH3:21])=[O:17])[CH3:29]
Reactant: CC(=C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)CP(=O)(OC(C)C)OC(C)C
Reactant: c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)[C@@H](C=C(C)CP(=O)(OC(C)C)OC(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
0.09 g of 1-amino-1-chloro-N,N,2-trimethylpropene is added at 0°-5° to a solution of 0.2 g of acid 3 according to c) in 15ml of dry dichloromethane. After stirring for 30 minutes at 0°, 0.4 g of pyridine in 5 ml of ethanol is added. The mixture is stirred further at 0° for 90 minutes and at room temperature for 15 hours, and is then diluted with 20 ml of dichloromethane and washed twice with 20 ml of water each time. The organic phase is dried using sodium sulphate, concentrated by evaporation and chromatographed on 25 g of silica gel. Elution with ethyl acetate/ methanol 10:1 yields 0.12 g of 4. 1H-NMR(300 MHz, CDCl3): 1.2-1.4 (m, 2 (CH3)2CHO, CH3CH2O); 1.45 (s, (CH3)3CO); 1.98 (d, J=3, CH3 --C(4)); 2.55 (d, J=23, 2H--C(5)); 4.2 (m, CH3CH2O); 4.69 (m, 2 (CH3)2CHO); 5.0 (m, H--C(2)); 5.16 (m, H--C(3), NH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[CH2:20]([C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29]([F:33])=[C:30](F)[F:31])[CH2:25][CH2:24]1)[CH2:21][CH3:22].Cl>C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:30](/[F:31])=[C:29](/[C@H:26]2[CH2:27][CH2:28][C@H:23]([CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25]2)\[F:33])=[CH:4][CH:3]=1
Reactant: CCC[C@H]1CC[C@H](C(F)=C(F)F)CC1
Reactant: Fc1ccc(I)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCC[C@H]1CC[C@H](/C(F)=C(\F)c2ccc(F)cc2)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Into a 300 cc four-necked flask, 5.59 g (25.2 mmol) of 4-fluroiodobenzene and 30 cc of dry ethyl ether were charged and cooled to -78° C. Then, 17 cc (27.8 mmol) of a n-hexane solution of n--C4H9Li (1.63 mol/l) was dropwise added thereto over a period of 15 minutes. Further, the mixture was stirred at -78° C. for one hour. Then, 3.8 cc (25.5 mmol) of N,N,N',N'-tetramethylene ethylenediamine was added thereto. Further, a dry diethyl ether (10 cc) solution containing 1.3 g (6.31 mmol) of 2-(trans-4-n-propylcyclohexyl)-1,1,2-trifluoroethylene obtained in Example 1, was dropwise added thereto over a period of 30 minutes. Further, the mixture was reacted at the same temperature for one hour, and then stirred at room temperature for one hour. Then, 50 cc of 1N hydrochloric acid was added thereto. The organic layer was separated. The aqueous layer was extracted with n-hexane, and the extract was combined with the organic layer. The combined organic layer was washed with water and dried. Further, the solvent was distilled off. The obtained crude solution was purified by silica gel column chromatography to obtain a solid. This solid was recrystallized from methanol to obtain 0.71 g (yield: 40%) of (E)-1-(4-fluorophenyl)-2-(trans-4-n-propylcyclohexyl)-1,2-difluoroethylene.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Li]CCCC.[CH3:17][S:18]SC.O>C1COCC1>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([S:18][CH3:17])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CSSC
Reactant: COc1cccc2scnc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2sc(SC)nc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of 4-methoxybenzothiazole (495 mg, 3.0 mmol) in anhydrous THF (12 mL) at −78° C. was added BuLi (2.5 mL, 1.6M in hexanes, 4.0 mmol) dropwise. The resulting red solution was stirred at −78° C. for 2 h under N2. Methyl disulfide (0.55 mL, 6.0 mmol) was added dropwise at −78° C. and the mixture was allowed to warm to ambient temperature overnight. The reaction mixture was combined with water and then extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a yellow oil (632 mg, 100%), which solidified upon standing and was used without purification. 1H-NMR (CDCl3): δ 7.35 (1H, d), 7.24 (1H, q), 6.86 (1H, d), 4.06 (3H, s), 2.79 (3H, s).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:32])[CH2:23][NH:24]C(=O)OC(C)(C)C)[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[ClH:33].O1CCOCC1>O1CCOCC1>[ClH:33].[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6](=[C:16]3[CH2:17][CH2:18][N:19]([C:22](=[O:32])[CH2:23][NH2:24])[CH2:20][CH2:21]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reaction time: 8 h

Procedure:
1.40 g (3.25 mmol) of t-butyl 2-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-2-oxoethylcarbamate was dissolved in 20 ml of 1,4-dioxane. 12 ml of 4 N hydrochloric acid/1,4-dioxane solution was added to the obtained solution, and they were stirred overnight. After the neutralization with 4 N aqueous sodium hydroxide solution, the solvent was evaporated under reduced pressure. Saturated aqueous sodium chloride solution was added to the reaction mixture. After the extraction with ethyl acetate 3 times, the extract was dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. 10 ml of a solution of ethyl acetate:hexane (1:2) and then 2 ml of 4 N hydrochloric acid/1,4-dioxane solution were added to the residue. The resultant precipitates were taken by the filtration, washed with a solution of ethyl acetate:hexane (1:2) and air-dried. After further drying under reduced pressure, the title compound was obtained.
Reaction SMILES: [CH:1]([C:4]1[C:12]([CH:13]([O:17][CH2:18][CH:19]2[O:21][CH2:20]2)[CH:14]([CH3:16])[CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].O>O1CCCC1.CCOCC>[CH:1]([C:4]1[C:12]([CH:13]([O:17][CH2:18][CH:19]([OH:21])[CH3:20])[CH:14]([CH3:15])[CH3:16])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1nn2ccccc2c1C(OCC1CO1)C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(O)COC(c1c(C(C)C)nn2ccccc12)C(C)C
Reaction time: 0.67 h
Yield: 83.4 %

Procedure:
A solution of 1 g of 2-isopropyl-3-[1-(2,3-epoxypropoxy)-2-methylpropyl]pyrazolo[1,5-a]pyridine (Example 34) in 10 ml of tetrahydrofuran was added to a suspension of 330 mg of lithium aluminum hydride in 10 ml of dry tetrahydrofuran under cooling. The mixture was stirred for 40 minutes, followed by addition of 1 ml of aqueous 15% sodium hydroxide solution with cooling, 3 ml of water and an adequate amount of ether successively. The resulting precipitates were filtered off and the filtrate was extracted with ether. The ether layer was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was recrystallized from hexane to give 840 mg (83%) of the desired product as colorless crystals, mp 112° C.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:16][CH2:17]O)[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O.[OH-].[Na+]>O>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:26]2[CH2:2][CH2:3][N:4]([C:5]3[CH:6]=[C:7]4[C:12](=[CH:13][CH:14]=3)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]4)[CH2:16][CH2:17]2)=[CH:23][CH:22]=1
Reactant: O=C1CCc2cc(N(CCO)CCO)ccc2N1
Reactant: COc1ccc(CN)cc1
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: O
Product: COc1ccc(CN2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1
Yield: 76.2 %

Procedure:
A mixture of 9 g of 6-[bis(2-hydroxyethyl)amino]-3,4-dihydrocarbostyril, 4.1 g of 4-methoxybenzylamine and 7.6 g of polyphosphoric acid prepared from 3.8 g of phosphorus pentoxide and 3.8 g of phosphoric acid was reacted at 160° to 170° C. for about 6 hours. After allowing to cool, to the reaction mixture was added dropwise about 500 ml of water to dissolve. The solution was neutralized with an aqueous 48% sodium hydroxide solution and extracted with chloroform. After drying the extract over potassium carbonate, chloroform was distilled off. Recrystallization of the residue from ethanol gave 8 g of 6-[4-(4-methoxybenzyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 196°-198° C., colorless needles.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[S:26][CH:27]=[N:28][N:29]=4)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][N:12]=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1Cl.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[S:26][CH:27]=[N:28][N:29]=4)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][N:12]=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([F:30])[CH:36]=1
Reactant: COc1nc(Cl)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1nc(-c2cccc(F)c2)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12

Procedure:
A microwave vial was charged with 1-(5,6-dichloro-2-methoxypyridin-3-yl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (0.032 g, 0.068 mmol), (3-fluorophenyl)boronic acid (0.014 g, 0.102 mmol), potassium carbonate (0.028 g, 0.205 mmol), and Pd(Ph3P)4 (7.90 mg, 6.83 μmol). The vial was flushed with Ar (g), then Dioxane (0.512 ml) and Water (0.171 ml) were added. The reaction was microwaved at 90° C. for one hour. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 12 g, gradient elution 0-10% MeOH:DCM) to afford 1-(5-chloro-6-(3-fluorophenyl)-2-methoxypyridin-3-yl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ=8.80 (s, 1H), 8.74 (d, J=5.7 Hz, 1H), 8.60 (s, 1H), 8.19 (d, J=5.9 Hz, 1H), 8.12 (s, 1H), 7.91 (s, 2H), 7.74 (d, J=8.0 Hz, 1H), 7.72-7.67 (m, J=2.2, 9.7 Hz, 1H), 7.61 (dt, J=6.1, 7.9 Hz, 1H), 7.37 (dt, J=2.2, 8.5 Hz, 1H), 3.82 (s, 3H). m/z (ESI) 528.2 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:22]([C:31](OC)=[O:32])=[CH:21]2)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].CCCCCC>O1CCCC1>[CH2:7]([O:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:22]([CH2:31][OH:32])=[CH:21]2)=[CH:17][CH:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1cn(Cc2ccc(OCc3ccccc3)cc2)cc1-c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCc1cn(Cc2ccc(OCc3ccccc3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
Lithium aluminium hydride (2.53 g) was added to a solution of methyl 1-(4-benzyloxybenzyl)-4-phenylpyrrole-3-carboxylate (21.52 g) in tetrahydrofuran (100 ml) at 0° C., and the mixture was stirred at room temperature for one hour. Sodium sulfate decahydrate (30.00 g) and hexane (100 ml) were added to the reaction mixture and the mixture was stirred at room temperature for one hour. After the precipitate was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and [1-(4-benzyloxybenzyl)-4-phenyl-3-pyrrolyl]methanol (19.68 g, yield: 98%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 122–123° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[O:9])[CH:3]=1.[CH2:10]1COCC1.C[Mg]Br>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([OH:9])[CH3:10])[CH:3]=1
Reactant: O=Cc1cc(Br)ccn1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1cc(Br)ccn1
Temperature: -78 °C

Procedure:
An oven-dried flask was cooled under argon, and to it was added 4-bromopicolinaldehyde (2.98 g, 16 mmol) and anhydrous THF (50 mL). The mixture was cooled to −78° C., and 3M methylmagnesium bromide in Et2O (6.4 mL) was added dropwise. The mixture was then allowed to warm slowly to room temperature, whereupon it was quenched with saturated NH4Cl solution. The aqueous layer was extracted with EtOAc, dried over Na2SO4, concentrated, and purified by column chromatography (gradient 0 to 60% EtOAc in hexanes) to give the product. 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J=5.3 Hz, 1H), 7.57-7.48 (m, 1H), 7.38 (dd, J=5.3, 1.4 Hz, 1H), 4.88 (q, J=6.6 Hz, 1H), 3.84 (br s, 1H), 1.51 (d, J=6.6 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]([NH:8][CH2:9][C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].I[CH3:17].[H-].[Na+]>CN(C=O)C>[O:1]=[C:2]([N:8]([CH3:17])[CH2:9][C:10]1[N:11]=[CH:12][CH:13]=[CH:14][N:15]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CI
Reactant: CCOC(=O)C(=O)NCc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)N(C)Cc1ncccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution ethyl 2-oxo-2-[(pyrimidin-2-yl)methylamino]acetate from the previous step (1.0 g, 4.8 mmol) and iodomethane (0.5 mL, 8 mmol) in DMF (15 mL) was cooled to 0° C. and NaH (0.23 g of a 60% dispersion in mineral oil, 5.7 mmol) was added. The cooling bath was removed and the mixture was stirred at ambient temperature for 18 hours. Ethanol was added to quench the reaction and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient of 80-100% EtOAc in hexanes. The solvent was removed under reduced pressure from the fractions containing product to give the title compound as an oil. 1H NMR (400 MHz, DMSO-d6) δ 8.81 (m, 2H), 7.45 (m, 1H), 4.74 (m, 2H), 4.32, 4.13 (two q, rotamers, J=7 Hz, 2H), 3.08, 3.00 (two s, rotamers, 3H), 1.30, 1.08 (two t, rotamers, 3H); ES MS M+1=224.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Br:12]Br.C(=O)([O-])[O-].[Na+].[Na+]>[N+](C1C=CC=CC=1)([O-])=O>[Br:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][C:2]=1[CH3:1]
Reactant: Cc1cc2ccccc2cn1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ncc2ccccc2c1Br
Temperature: 180 °C
Yield: 72.3 %

Procedure:
To 3-methylisoquinoline (0.500 g, 3.49 mmol) in 1 ml nitrobenzene, bromine (0.196 ml, 3.84 mmol) was added and the contents heated in a sealed tube at 180° C. for 4 hours. The solution was cooled to room temperature, neutralized with solid sodium carbonate (pH=8) and extracted with ethyl acetate (2×20 ml). The organic layer was dried over sodium sulfate, filtered, concentrated and column purified (hexane:EtOAc; 4.5:0.5) to give 0.560 g (72%) of the product as syrup.