Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[N:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[C:19]([OH:21])=O.[NH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25].C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.C(OCC)(=O)C>[OH:25][CH2:24][C:23]([NH:22][C:19]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][N:13]=1)=[O:21])([CH3:27])[CH3:26]
Reactant: O=C(O)c1cnccn1
Reactant: CC(C)(N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1cnccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.3 %

Procedure:
WSC HCl (1.94 g, 10 mmol) was added to a mixture of 2-pyrazinecarboxylic acid (0.99 g, 8 mmol), 2-amino-2-methyl-1-propanol (0. 80 g, 9 mmol) and HOBt (1.36 g, 10 mmol) in methylene chloride (30 ml), and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine, successively, dried over Na2SO4 and concentrated under a reduced pressure. The residue was suspended in methanol (10 ml), added 2N aqueous NaOH to and stirred for 30 minutes. Methanol was evaporated under a reduced pressure, diluted with saturated aqueous NaHCO3 and extracted with chloroform. The extract was washed with with saturated aqueous NaHCO3 and brine, successively, dried over Na2SO4. After the solvent was evaporated, the obtained crystal was washed with hexane and dried to give the title compound (0.27 g; 18%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]#[C:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)C.O>[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:15]#[C:14][C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(C#Cc2cccs2)CC1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: C(#Cc1cccs1)C1=CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
A solution of 1-tert-butoxycarbonyl-4-(2-thienyl)ethynyl-1,2,3,6-tetrahydropyridine (530 mg, 1.8 mmol) (prepared in a manner analogous to Example 1) in diethyl ether (10 ml) at room temperature under a nitrogen atmosphere was treated with excess ethereal hydrogen chloride. Following a 3 hour stir at room temperature the dark mixture was diluted with water and extracted with diethyl ether (2×30 ml). The aqueous phase was made basic with potassium carbonate solution (sat.) and extracted with diethyl ether (3×50 ml). The extracts were dried (K2CO3) and evaporated in vacuo to give the title compound as a brown oil (267 mg, 77%); δH (CDCl3) 2.24-2.29 (2H, m, tetrahydropyridinyl CH2), 3.00 (2H, J 5.7 Hz, tetrahydropyridinyl CH2), 3.45-3.47 (2H, m, tetrahydropyridinyl CH2), 6.17-6.19 (1H, m, tetrahydropyridinyl CH), 6.94-6.97 (1H, m, ArH), 7.16-7.17 (1H, m, ArH) and 7.22-7.26 (1H, m, ArH).
Reaction SMILES: [CH2:1]([C@@:4]1([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:7][C@@H:6]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:5]1[OH:27])[CH:2]=C.I([O-])(=O)(=O)=[O:37].[Na+].C(O)(C)(C)C.[BH4-].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH2:29]([O:28][C@:4]1([CH2:1][CH2:2][OH:37])[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:7][C@@H:6]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:5]1[OH:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C=CC[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cn([C@@H]2O[C@H](COCc3ccccc3)[C@@](CCO)(OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of nucleoside 2 (1.00 g, 2.09 mmol) in THF (5.4 cm3) and water (5.4 cm3) was added sodium periodate (1.34 g, 6.27 mmol) and a 2.5% solution of osmium tetraoxide in tert-butanol (w/w, 0.265 cm3, 19 μmol). The solution was stirred at room temperature for 45 min. Water (25 cm3) was added and the solution was extracted with dichloromethane (2×50 cm3). The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×30 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was redissolved in THF (5.4 cm3) and water (5.4 cm3). The mixture was stirred at room temperature and sodium borohydride (79 mg, 2.08 mmol) was added. After stirring for 1.5 h, water (25 cm3) was added and the solution was extracted with dichloromethane (2×50 cm3). The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×30 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (98:2, v/v) as eluent to give nucleoside 9 as a white solid material (488 mg, 48%). δH (CDCl3) 9.14 (1 H, br s, NH), 7.60 (1 H, d, J 1.1, 6-H), 7.40-7.22 (10 H, m, Bn), 6.25 (1 H, d, J 7.7, 1′-H), 4.59 (1 H, d, J 7.1 Bn), 4.49 (1 H, d, J 7.1 Bn), 4.39-3.30 (m, 8H, 4′-H, 2′-H, Bn, 5′-Ha, 5-′Hb, 2″-Ha, 2″-Hb), 2.23-2.00 (2 H, m, 1″-Ha, 1″-Hb), 1.49 (3 H, d, J 0.7 CH3). δC (CDCl3) 163.5 (C-4), 151.2 (C-2), 137.1, 136.5 (Bn), 135.7 (C-6), 128.7, 128.5, 128.2, 127.8, 127.6, 127.2 (Bn), 111.3 (C-5), 87.0, 82.7, 81.1, 78.3 (C-1′, C-2′, C-3′, C-4′), 73.7, 69.6 (Bn), 64.4 (C-5′), 57.0 (C-2″), 32.4 (C-1″), 11.8 (CH3) (Found: C, 63.9; H, 6.3; N, 5.4. C26H30N2O7,0.25H 2O requires C, 64.1; H 6.3; N, 5.75%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=[CH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([C:32]([OH:34])=[O:33])[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[O:4][N:3]=1>CCOC(C)=O.CO.[Pd]>[CH3:1][C:2]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:5]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([C:32]([OH:34])=[O:33])[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1C=CCCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCCCc1ccccc1
Reaction time: 8 h

Procedure:
1-{4′-[3-Methyl-4-(4-phenyl-but-1-enyl)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (0.030 g, 0.07 mmol) was dissolved in EtOAc and MeOH. 10% Palladium on carbon (spatula tip) was added, and the reaction was stirred under a balloon of H2 overnight. The mixture was filtered and concentrated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]([NH2:11])=[O:10])=[C:4]([F:13])[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.Cl.[CH:27]1([N:30]2[CH2:35][C:34]3([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[O:33][CH2:32][C:31]2=[O:41])[CH2:29][CH2:28]1>C(#N)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:38]2[CH2:39][CH2:40][C:34]3([O:33][CH2:32][C:31](=[O:41])[N:30]([CH:27]4[CH2:28][CH2:29]4)[CH2:35]3)[CH2:36][CH2:37]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:13])[CH:3]=1
Reactant: NC(=O)C(O)c1ccc(Br)cc1F
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: NC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.9 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)-2-hydroxyacetamide (14.35 mmol) and triethylamine (43.1 mmol) in anhydrous acetonitrile (50.0 ml) was added neat methanesulfonyl chloride (20.81 mmol). The reaction stirred at room temperature for 18 hours then additional triethylamine (43.1 mmol) was added followed by solid 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (15.79 mmol) in one portion. The reaction was heated at 90° C. for 3 hours then cooled to room temperature, diluted with water (150 mL) and stirred for 1 hour. The solids were collected by filtration, rinsed with water, and then dried by air suction and then vacuum to afford the title compound (3.53 g, 55% yield) as a white solid. MS(ES)+ m/e 440.1, 442.3 [M+H]+.
Reaction SMILES: Cl.[C:2](=[NH:7])([O:4][CH2:5][CH3:6])[CH3:3].C(N(CC)CC)C.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:5]([O:4][C:2](=[N:7][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:3])[CH3:6]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(C)=NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
First, 15.5 g of ethyl acetimidate hydrochloride, 150 mL of toluene, and 31.9 g of triethylamine (Et3N) were put into a 500-mL three-neck flask and the mixture was stirred at room temperature for 10 minutes. With a 50-mL dropping funnel, a mixed solution of 17.7 g of benzoyl chloride and 30 mL of toluene was added dropwise to this mixture, and the mixture was stirred at room temperature for 24 hours. After a predetermined time elapsed, the reaction mixture was suction-filtered, and the solid was washed with toluene. The obtained filtrate was concentrated to give N-(1-ethoxyethylidene)benzamide (a red oily substance, 82% yield). A synthesis scheme of Step 1 is shown in (a-1) below.
Reaction SMILES: [OH-].[Na+].Cl.[CH3:4][O:5][C:6]1[CH:26]=[CH:25][C:9]2[NH:10][C:11]([S:13][CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)=[N:12][C:8]=2[CH:7]=1.C1(=O)OC(=[O:31])C2=CC=CC=C12.C(=O)([O-])[O-].[Na+].[Na+].OO>ClCCl.O>[CH3:24][C:18]1[CH:17]=[N:16][C:15]([CH2:14][S+:13]([O-:31])[C:11]2[NH:10][C:9]3[CH:25]=[CH:26][C:6]([O:5][CH3:4])=[CH:7][C:8]=3[N:12]=2)=[C:20]([CH3:21])[C:19]=1[O:22][CH3:23]
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: OO
Solvent: ClCCl
Solvent: O
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Reaction time: 0.17 h
Yield: 85.3 %

Procedure:
Sodium hydroxide solution (5%, 100 ml) was added to a suspension of 36.50 gm of 5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridinyl)methylthio]-1H-benzimidazole hydrochloride (X) in DCM (200 ml) and stirred for 10 mins. The DCM (dichloromethane) layer was separated and to it was added phthalic anhydride (20 gm, 0.135 mole). The reaction mixture was cooled and to it was added sodium carbonate (18 gm) and water 20 ml. Hydrogen peroxide (45%, 12 ml) was added dropwise at −5 to 0° C. when the reaction was complete it was worked-up as in Example-9 to yield 29.4 gm of Omeprazole. Yield 85.90%.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)([CH3:9])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].[F:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:43][CH2:44][C:45]1[N:50]([CH2:51][C:52](O)=[O:53])[C:49]2[N:55]=[CH:56][CH:57]=[CH:58][C:48]=2[C:47](=[O:59])[N:46]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:43][CH2:44][C:45]1[N:50]([CH2:51][C:52]([N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][C:31]([F:33])([F:32])[F:34])=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[CH:13]2[CH2:14][CH2:15][N:10]([C:2]([CH3:1])([CH3:9])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4])[CH2:11][CH2:12]2)=[O:53])[C:49]2[N:55]=[CH:56][CH:57]=[CH:58][C:48]=2[C:47](=[O:59])[N:46]=1
Reactant: CC(C)OC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2cccnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)OC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3cccnc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.6 %

Procedure:
A mixture of 1-methylethyl 2-methyl-2-{4-[({4′-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)amino]-1-piperidinyl}propanoate (Int. B5) (80 mg, 1 equiv), [2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetic acid (Int. D1) (67 mg, 1 equiv), HATU (400 mg, 5 equiv), DIPEA (0.22 ml, 1.5 equiv) and DMF (2.0 ml) was stirred at room temperature for 30 min. The crude reaction mixture was applied directly to reverse-phase HPLC (Preparative Method A) to obtain 1-methylethyl 2-{4-[{[2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetyl}({4′-[(trifluoromethyl)oxy]-4-biphenylyl} methyl)amino]-1-piperidinyl}-2-methylpropanoate (25 mg).
Reaction SMILES: [S:1]1C2=CN=CC=C2C(C2OC3=CN=CC=C3C=2)=C1.[I:19][C:20]1[CH:25]=[N:24][C:23]([NH2:26])=[C:22]2[O:27][C:28]([C:30]3[CH:39]=CC=[C:36]4[C:31]=3[CH:32]=[CH:33][N:34]=[CH:35]4)=[CH:29][C:21]=12>>[I:19][C:20]1[CH:25]=[N:24][C:23]([NH2:26])=[C:22]2[O:27][C:28]([C:30]3[C:31]4[C:36](=[CH:35][N:34]=[CH:33][CH:32]=4)[S:1][CH:39]=3)=[CH:29][C:21]=12
Reactant: c1cc2cc(-c3csc4cnccc34)oc2cn1
Reactant: Nc1ncc(I)c2cc(-c3cccc4cnccc34)oc12
Product: Nc1ncc(I)c2cc(-c3csc4cnccc34)oc12
Yield: 77 %

Procedure:
The title compound was prepared in 77% yield from 2-thieno[2,3-c]pyridin-3-yl-furo[2,3-c]pyridin]-7-ylamine by a procedure analogous to Intermediate 10, Step B. 1H NMR (300 MHz, CDCl3+CD3OD): δ 6.83 (s, 1H), 7.82 (s, 1H), 8.11 (d, J=5.6 Hz, 1H), 8.26 (s, 1H), 8.44 (d, J=5.8 Hz, 1H), 9.02 (s, 1H).
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1[C:5]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:6]=2[S:7][C:8]=1[CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.[OH-].[Na+].O>C(O)C>[CH3:3][C:4]1[C:5]2[CH:19]=[C:18]([C:20]([NH2:21])=[O:1])[CH:17]=[CH:16][C:6]=2[S:7][C:8]=1[CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1c(Cc2cccnc2)sc2ccc(C#N)cc12
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(Cc2cccnc2)sc2ccc(C(N)=O)cc12
Reaction time: 2 h

Procedure:
Hydrogen peroxide (1.6 ml of 30% w/v solution) was added to a stirred solution of 3-methyl-2-(3-pyridylmethyl)benzo[b]thiophene-5-carbonitrile (the product of Example 12(ii)) (0.30 g) in ethanol (3.5 ml) followed by 6N sodium hydroxide solution (1.6 ml). The resulting micture was heated at 50°-55° C. with stirring for 2 hours and then cooled and poured into water. The solid was filtered off, washed with water and crystallised from ethanol/water to give 3-methyl-2-(3-pyridylmethyl)benzo[b]thiophene-5-carboxamide (0.21 g), m.p. 194°-195°.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[C:16]([CH:23]=[CH:24][C:25]=3[CH3:26])[C:17]([NH:19][CH:20]3[CH2:22][CH2:21]3)=[O:18])=[CH:11][CH:12]=2)[CH:7]([CH3:27])[NH:6][N:5]=1)(=[O:3])[CH3:2].[Mn]([O-])(=O)(=O)=O.[K+]>CCO.O>[C:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[C:16]([CH:23]=[CH:24][C:25]=3[CH3:26])[C:17]([NH:19][CH:20]3[CH2:22][CH2:21]3)=[O:18])=[CH:11][CH:12]=2)[C:7]([CH3:27])=[N:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)C1=NNC(C)c2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc21
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(=O)c1nnc(C)c2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
3-(1-Acetyl-4-methyl-3,4-dihydrophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (24 mg, 66 μmol) was dissolved in EtOH/water (2:1) (664 μl) and potassium permanganate (10 mg, 66 μmol) was added. The mixture was stirred at RT for 40 min, quenched with saturated, aqueous sodium thiosulfate and diluted with 50 mL of chloroform. In a separatory funnel, the mixture was washed 2×20 mL with sodium thiosulfate and the organics were separated, dried over sodium sulfate, concentrated in vacuo, and purified by HPLC to give the title compound. MS (ES+): 360 (M+H)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[Cl:26][C:27]1[S:31][C:30]([Mg]Br)=[CH:29][CH:28]=1>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:30]3[S:31][C:27]([Cl:26])=[CH:28][CH:29]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: Clc1ccc([Mg]Br)s1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)s1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 0.5 mL THF and 2.0 mL 0.25M 5-chloro-2-thienylmagnesium bromide. Yield: 56 mg of a white solid. LC-MSD, m/z for C20H12BrClN2O2S [M+H]+=458.9, 460.9, 462.9; HPLC retention time: 2.5 min.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([C:20](O)=[O:21])[C:18]=3[N:19]=2)[CH:7]=[CH:8][CH:9]=1.[NH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[S:27]1[CH:28]=[CH:29][N:30]=[C:26]1[NH:25][C:20]([C:17]1[C:18]2[N:19]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:1])([F:23])[F:24])[CH:5]=3)[CH:11]=[N:12][C:13]=2[CH:14]=[CH:15][CH:16]=1)=[O:21]
Reactant: O=C(O)c1cccc2ncc(-c3cccc(OC(F)(F)F)c3)nc12
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nccs1)c1cccc2ncc(-c3cccc(OC(F)(F)F)c3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A mixture of 3-(3-(trifluoromethoxy)phenyl)quinoxaline-5-carboxylic acid (100 mg, 0.30 mmol), 2-aminothiazole (30 mg, 0.30 mmol), HATU (171 mg, 0.45 mmol) and DIEA (116 mg, 0.9 mmol) in DMF (10 mL) was stirred at room temperature for 2 h. Water (20 mL) was added, and the resulting precipitate was collected by filtration and dried under vacuum to give N-(thiazol-2-yl)-3-(3-(trifluoromethoxy)phenyl)quinoxaline-5-carboxamide as a solid (115.5 mg, 92% yield). MS (ESI) calcd for C19H11F3N4O2S (m/z): 416.06. found: 417 [M+1].
Reaction SMILES: N[C:2]1[C:6]2[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.[OH-:15].[Na+]>O>[CH3:12][O:11][C:7]1[C:6]2[C:2](=[O:15])[NH:3][S:4](=[O:14])(=[O:13])[C:5]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc2c1C(N)=NS2(=O)=O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: COc1cccc2c1C(=O)NS2(=O)=O
Yield: 79.7 %

Procedure:
2.5 gm (11.8 mmols) of 3-amino-4-methoxy-1,2-benzoisothiazole-1,1-dioxide were refluxed for 3 hours in a solution of 0.47 gm (11.8 mmols) of sodium hydroxide in 300 ml of water. The reaction mixture was filtered while still hot and acidified with hydrochloric acid. The resulting precipitate was filtered off, dried and recrystallized from benzene/ethyl acetate. 2.0 gm (9.4 mmols) of 4-methoxy-1,2-benzoisothiazol-3(2H)-one-1,1-dioxide (m.p.: 224° C.) were obtained, which were dissolved in 500 ml of ethylene chloride, and the solution was admixed with 10 gm (40 mmols) of boron tribromide. The reaction mixture was slowly heated and refluxed for 1 hour. The reaction mixture was evaporated in vacuo and then repeatedly evaporated in vacuo after addition of ethanol. The obtained product was recrystallized from water, yielding 1.6 gm (68% of theory) of 4-hydroxy-1,2-benzoisothiazol-3(2H)-one-1,1-dioxide.
Reaction SMILES: [CH:1]1([Li])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH3:15])=[CH:10][CH:9]=1>C(OCC)C>[CH3:15][C:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=1)=[C:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: [Li]C1C=CC=C1
Reactant: CC(=O)c1ccc(C)cc1
Solvent: CCOCC
Product: CC(=C1C=CC=C1)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.2 %

Procedure:
Under a nitrogen atmosphere, a solution of a cyclopentadienyllithium salt (5.9 g, 81.9 mmol) in dry diethyl ether (100 mL) was cooled in an ice bath, and 4′-methylacetophenone (10.0 g, 74.5 mmol) was dropped thereinto. Then, the product was stirred at room temperature for 20 hours to induce a reaction. After the reaction was terminated, dilute aqueous hydrochloric acid was added thereto, the product was subjected to extraction with hexane, the organic layer was subsequently washed with water and then dehydrated with anhydrous magnesium sulfate, and then the solvent was distilled off to produce a red liquid. The red liquid was purified by column chromatography (silica gel, solvent: hexane) to produce 9.8 g of 6-methyl-6-(p-tolyl)fulvene. The analytical values were as follows.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:17]1[C:22]([O:23][CH2:24][CH3:25])=[CH:21][C:20](=[O:26])[N:19]([CH3:27])[CH:18]=1.[C:33]([O-:36])([O-])=O.[K+].[K+]>>[F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:2][C@H:3]2[CH2:33][O:36][CH2:6][CH2:5][O:4]2)[S:12]([CH2:15][CH3:16])(=[O:13])=[O:14])=[CH:7][C:6]=1[C:17]1[C:22]([O:23][CH2:24][CH3:25])=[CH:21][C:20](=[O:26])[N:19]([CH3:27])[CH:18]=1
Reactant: O=C([O-])[O-]
Reactant: CCOc1cc(=O)n(C)cc1-c1cc(NS(=O)(=O)CC)ccc1Oc1ccc(F)cc1F
Agent: [K+]
Product: CCOc1cc(=O)n(C)cc1-c1cc(N(C[C@H]2COCCO2)S(=O)(=O)CC)ccc1Oc1ccc(F)cc1F
Yield: 75.5 %

Procedure:
A stock solution of Example 72A (0.16 M in DMF, 200 μL, 0.03 mmol Example 72A (1.0 equivalent)), K2CO3 (13.4 mg, 0.096 mmol, 3.2 equivalents) and (25)-4-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (0.04 M in DMA, 89 μL, 0.036 mmol, 1.2 equivalents), were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL min−1 (10 minute residence time). Upon exiting the reactor, the reaction was loaded directly into an injection loop and purified by preparative HPLC on a Phenomenex Luna C8(2) 5 μm 100 Å AXIA column (50 mm×21.2 mm). A gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) was used, at a flow rate of 30 mL/min (0-0.5 min 5% A, 0.5-6 5 min linear gradient 5-60% A, 6.5-7.0 min linear gradient 60-100% A, 7.0-8.9 min 100% A, 8.9-9.0 min linear gradient 100-5% A, 9.0-10 min 5% A) to yield the title compound (6.39 mg, 32% yield). 1H NMR (400 MHz, DMSO-d6/D2O) δ 7.56 (m, 1H), 7.44-7.38 (m, 2H), 7.29 (m, 1H), 7.15-7.03 (m, 2H), 6.96 (m, 1H), 5.87 (s, 1H), 4.02 (q, J=7.0 Hz, 2H), 3.80 (m, 1H),3.77-3.72 (m, 2H), 3.70-3.62 (m, 2H), 3.61-3.49 (m, 4H), 3.44 (s, 3H), 3.20 (m, 2H), 1.31 (t, J=7.4 Hz, 3H), 1.24 (t, J=7.0 Hz, 3H). MS (ESI+) m/z 565.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:5]2[CH3:27].C1CCCCC=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)(=[O:18])=[O:17])[CH:5]2[CH3:27]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3C2C)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A stirred suspension of 8-fluoro-5-(4-methoxyphenylsulfonyl)-6-methyl-5,6-dihydrophenanthridine (1.26 g, 3.29 mmol) and cyclohexene (6.0 mL, 59 mmol) was treated drop-wise with a solution of 1 M boron tribromide (20 mL, 20 mmol) in dichloromethane at room temperature under nitrogen. After stirring for 20 hours at room temperature, a saturated, aqueous, sodium bicarbonate solution (300 mL) was added drop-wise, and the resulting mixture extracted with dichloromethane (6×20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:19 to 1:4 gradient), followed by re-crystallization from a mixture of dichloromethane-hexane to yield the title compound as a homogeneous, white, crystalline, solid (1.1 g, 90%). The melting point, mass spectum, and NMR spectrum of this product were identical to the authentic material prepared in Example 32, Method A, Step e.