Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)COB([C:8]2[C:17]([CH2:18][O:19][C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3[CH3:27])=[C:16]3[C:11]([NH:12][C:13]([CH3:31])([CH3:30])[C:14](=[O:29])[N:15]3[CH3:28])=[CH:10][CH:9]=2)OC1.[N+:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1I)([O-:35])=[O:34].C(=O)([O-])O.[Na+].CN(C)C=O>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.O.C(OCC)(=O)C>[F:26][C:24]1[CH:23]=[CH:22][C:21]([CH3:27])=[C:20]([CH:25]=1)[O:19][CH2:18][C:17]1[C:8]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N+:33]([O-:35])=[O:34])=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]([CH3:28])[C:14](=[O:29])[C:13]([CH3:31])([CH3:30])[NH:12]2
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: Cc1ccc(F)cc1OCc1c(B2OCC(C)(C)CO2)ccc2c1N(C)C(=O)C(C)(C)N2
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: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1OCc1c(-c2ccccc2[N+](=O)[O-])ccc2c1N(C)C(=O)C(C)(C)N2
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
A mixture of 7-(5,5-dimethyl[1,3,2]dioxaborinan-2-yl)-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 21, 68.2 mg, 0.155 mmol), 2-nitro-1-iodobenzene (79.0 mg, 0.317 mmol), sodium hydrogen carbonate (41.5 mg, 0.494 mmol) and tetrakis(triphenylphosphine)palladium (0) (19.0 mg, 0.0164 mmol) was suspended in mixed solvent of anhydrous N,N-dimethylformamide (0.5 ml) and water (0.5 mL), and stirred at 120° C. for 30 minutes by irradiated microwave. After cooling down, ethyl acetate (15 mL) and water (15 mL) were added and partitioned. The organic layer was washed with saturated brine (15 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (42.6 mg) as a yellow solid. (Yield 61%)
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]#[N:24])[CH:19]=[CH:20][CH:21]=1>>[C:23]([CH2:22][C:18]1[CH:17]=[C:16]([NH:15][C:12]([C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:14])[CH:21]=[CH:20][CH:19]=1)#[N:24]
Reactant: N#CCc1cccc(N)c1
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Product: N#CCc1cccc(NC(=O)c2ccc(-c3ccccc3)o2)c1

Procedure:
5-Phenyl-2-furoic acid (56) (223 mg, 1.2 mmol) was coupled to 3-aminophenyl acetonitrile (80) (157 mg, 1.19 mmol), using Method C. The crude residue was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([CH2:5][C:6](=[O:28])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1.OS(O)(=O)=O.[CH3:34]O>>[CH3:34][O:16][C:15](=[O:17])[CH2:14][CH2:13][C@H:12]([C@@H:11]1[C@:19]2([CH3:27])[C@H:8]([C@H:7]3[C@H:22]([CH2:21][CH2:20]2)[C@:23]2([CH3:26])[C@@H:4]([CH2:3][C@H:2]([OH:1])[CH2:25][CH2:24]2)[CH2:5][C:6]3=[O:28])[CH2:9][CH2:10]1)[CH3:18]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Step 1 is the reaction of 3α-hydroxy-7-keto-5β-cholan-24-oic acid (KLCA) with CH3OH and H2SO4 to form 3α-hydroxy-7-keto-5β-cholan-24-oic acid methyl ester (1). In one embodiment of step 1, the reaction mixture is heated for about 3 hours and the pH of the reaction mixture is adjusted with an aqueous basic solution to a pH-value of about 6.5 to about 8.0. In one embodiment, the isolation of 3α-hydroxy-7-keto-5β-cholan-24-oic acid methyl ester (1) further comprises treatment with activated carbon. In one embodiment, the isolation of 3α-hydroxy-7-keto-5β-cholan-24-oic acid methyl ester (1) does not further comprise treatment with activated carbon. In one embodiment, isolation of 3α-hydroxy-7-keto-5β-cholan-24-oic acid methyl ester (1) without the treatment with activated carbon affords a higher yield. In one embodiment, reacting 3α-hydroxy-7-keto-5β-cholan-24-oic acid (1) with CH3OH and H2SO4 is carried out in methanol. In one embodiment, the basic solution is an aqueous NaOH solution. In one embodiment, the pH-value is about 7.0 to about 7.5.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[C:6]([CH3:10])=[C:7]([Cl:9])[CH:8]=1.CS([N:18]1C2C(=CC=C(CC#N)C=2)C=[CH:19]1)(=O)=O.CS(N1C2C(=CC=C(CBr)C=2)C=C1)(=O)=O>>[Cl:9][C:7]1[CH:8]=[C:3]([CH2:2][C:19]#[N:18])[CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[C:6]=1[CH3:10]
Reactant: CS(=O)(=O)n1ccc2ccc(CC#N)cc21
Reactant: Cc1c(Cl)cc(CBr)cc1[N+](=O)[O-]
Agent: CS(=O)(=O)n1ccc2ccc(CBr)cc21
Product: Cc1c(Cl)cc(CC#N)cc1[N+](=O)[O-]

Procedure:
(3-Chloro-4-methyl-5-nitrophenyl) acetonitrile was prepared from 5-bromomethyl-1-chloro-2-methyl-3-nitrobenzene in a manner similar to that described in Example 10 for the preparation of N-methanesulfonyl-6-cyanomethyl indole from N-methanesulfonyl-6-bromomethyl indole.
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[O:11])=[CH:2]1.CC([OH:16])(C)C.CC(=CC)C.[O-]Cl=O.[Na+]>O>[O:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([OH:16])=[O:11])=[CH:2]1
Reactant: O=Cc1coc2ncccc12
Reactant: CC(C)(C)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Product: O=C(O)c1coc2ncccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of furo[2,3-b]pyridine-3-carboxaldehyde (67 mmol) [J. Heterocyclic Chem., 23, 1465 (1986)] in 52 mL H2O were added NaH2PO4 (67 mmol), 260 mL t-BuOH, 71 mL 2-methyl-2-butene followed by portionwise addition of NaClO2 (100 mmol) at 0° C. After 15 min, the cooling bath was removed and the reaction was stirred at RT for 24 h. A solution of sat. aq. NaHCO3 was added and the mixture was extracted with EtOAc. The water phase was acidified with 1N HCl solution and it was then extracted 3 times with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to obtain the desired compound as beige solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8]CCO.[CH2:12]([O:19][C:20]([C@H:22]1[NH:25][C:24](=[O:26])[CH2:23]1)=[O:21])[C:13]1C=CC=CC=1>[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4]>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:13][CH2:12][O:19][C:20]([C@H:22]1[NH:25][C:24](=[O:26])[CH2:23]1)=[O:21]
Reactant: COCCOCCOCCO
Reactant: O=C1C[C@@H](C(=O)OCc2ccccc2)N1
Agent: [Ti+4]
Agent: CCCC[O-]
Product: COCCOCCOCCOC(=O)[C@@H]1CC(=O)N1
Temperature: 90 °C

Procedure:
3 was prepared by transesterification of 1 with triethyleneglycol monomethyl ether following the procedure reported by Muñoz-Guerra et al.21 A vigorously stirred solution of 1 (2.05 g, 10 mmol) and titanium(IV) tetrabutoxide (0.1 g, 0.3 mmol) in dry tri(ethylene glycol) monomethyl ether (20 mL) was heated at 90° C. for 12 h. The course of transesterification was followed by TLC. The reaction was assumed to be complete when no trace of UV absorption indicative of 1 was detectable. The unreacted tri(ethylene glycol) monomethyl ether was distilled off under vacuum and can be reused. The remaining brown residue was purified by passage through a silica gel column (ethyl acetate and hexane, 1:1). The eluent fractions containing product were combined and the solvent was evaporated under vacuum to afford a light yellow oil. Pure compound 3 was obtained by vacuum distillation of this oil (1.21 g, 46%). FTIR (THF): 1779 cm−1 (νCO, lactam, s), 1745 cm−1 (νCO, ester, s). 1H NMR (CDCl3, 500 MHz) δ 6.73 (br, 1H, CH—2C(O)NHCH(CO2CH2CH2OCH2CH2OCH2CH2OCH3)), 4.36 (m, 2H, CH—2C(O)NHCH(CO2CH2CH2OCH2CH2OCH2CH2OCH3)), 4.19 (dd, 1H, CH—2C(O)NHCH(CO2CH2CH2OCH2CH2OCH2CH2OCH3)), 3.71 (m, 2H, CH—2C(O)NHCH(CO2CH2CH2OCH2CH2OCH2CH2OCH3)), 3.63 (m, 6H, CH—2C(O)NHCH(CO2CH2CH2OCH2CH2OCH2CH2OCH3)), 3.54 (m, 2H, CH—2C(O)NHCH(CO2CH2CH2OCH2CH2OCH2CH2OCH3)), 3.37 (s, 3H, CH—2C(O)NHCH(CO2CH2CH2OCH2CH2OCH2CH2OCH3)), 3.26 (ddd, 1H, CH—2C(O)NHCH(CO2CH2CH2OCH2CH2OCH2CH2OCH3)), 3.08 (ddd, 1H, CH—2C(O)NHCH(CO2CH2CH2OCH2CH2OCH2CH2OCH3)). 13C NMR (CDCl3, 200 MHz) δ 171.4, 166.4, 72.2, 71.0, 70.9, 70.8, 69.1, 64.9, 59.3, 47.6, 43.9. [α]25D: −15.1 (C 0.52 in THF) MS calcd: 261.28; found: 262.33 (MH+).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][O:11][C:10]2=[O:15])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([Sn](CCCC)(CCCC)CCCC)[S:25][C:18]=12>C1(C)C=CC=CC=1.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:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([C:2]3[N:7]=[CH:6][C:5]([CH2:8][N:9]4[CH2:14][CH2:13][CH2:12][O:11][C:10]4=[O:15])=[CH:4][CH:3]=3)[S:25][C:18]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Reactant: O=C1OCCCN1Cc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C1OCCCN1Cc1ccc(-c2cc3nccc(Cl)c3s2)nc1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
To a solution of 197 (373 mg, 1.376 mmol) in toluene (10 mL) was added the 7-chloro-2-(tributylstannyl)thieno[3,2-b]pyridine 198 (631 mg, 1.376 mmol) and Pd(PPh3)4 (159 mg, 0.138 mmol). The reaction mixture was heated to reflux for 24 hours. The reaction mixture was then cooled to RT and concentrated. The residue was triturated with Et2O to afford the title compound 199 (363 mg, 73% yield) as beige solid. MS: 360 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:20]2[CH:24]=[CH:23][O:22][CH:21]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([S:13]CC[Si](C)(C)C)=[CH:8][CH:7]=2)#[N:2].[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>CN(C=O)C.C1COCC1.Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:20]2[CH:24]=[CH:23][O:22][CH:21]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([SH:13])=[CH:8][CH:7]=2)#[N:2]
Reactant: C[Si](C)(C)CCSc1ccc2c(-c3ccoc3)cc(C#N)cc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1cc(-c2ccoc2)c2ccc(S)cc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.4 %

Procedure:
The product from Step 1 (1.8 g) was dissolved in DMF (40 mL) and there was added n-Bu4NF (1M) in THF (15 mL). The resulting mixture was stirred at r.t. for 1.5 h, diluted with 1N aqueous HCl (40 mL) then H2O (300 mL) and filtered to afford the title thiol (1.06 g) as a light orange solid m.p.: 144°-146° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([NH:11][C:12]1[CH:13]=[C:14]([C:21]([OH:23])=O)[C:15]2[O:19][CH2:18][CH2:17][C:16]=2[CH:20]=1)=[O:10].Cl.C(C(NCCCN(C)C)=N)C.ON1C2C=CC=CC=2N=N1.[F:48][C:49]([F:59])([F:58])[C:50]1[CH:57]=[CH:56][CH:55]=[CH:54][C:51]=1[CH2:52][NH2:53]>CN(C=O)C.C(N(CC)CC)C>[F:48][C:49]([F:58])([F:59])[C:50]1[CH:57]=[CH:56][CH:55]=[CH:54][C:51]=1[CH2:52][NH:53][C:21]([C:14]1[C:15]2[O:19][CH2:18][CH2:17][C:16]=2[CH:20]=[C:12]([NH:11][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:25])([F:24])[F:1])=[O:10])[CH:13]=1)=[O:23]
Reactant: NCc1ccccc1C(F)(F)F
Reactant: O=C(Nc1cc2c(c(C(=O)O)c1)OCC2)c1ccccc1C(F)(F)F
Agent: CCC(=N)NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc2c(c(C(=O)NCc3ccccc3C(F)(F)F)c1)OCC2)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-2,3-dihydro-1-benzofuran-7-carboxylic acid (35 mg) in DMF (2 mL), N′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine hydrochloride (23 mg), 1-hydroxybenzotriazol (23 mg) and triethylamine (17 μL) were added. Under ice-cooling, to the mixture was added 2-(trifluoromethyl)benzylamine (15 μL), and it was stirred at room temperature overnight. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was washed with n-hexane/ethyl acetate (1:1) and collected by filtration to obtain the titled compound (43 mg) as colorless powder. MS (ESI+) m/z 509 (M+H)+, Rt=2.31 minutes (method A)
Reaction SMILES: Br[CH:2]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[SH:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([S:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[CH3:7]
Reactant: Oc1ccc(S)cc1
Reactant: CCOC(=O)C(Br)c1cccc2ccccc12
Product: CCOC(=O)C(Sc1ccc(O)cc1)c1cccc2ccccc12
Yield: 63.3 %

Procedure:
Ethyl[(4-hydroxyphenyl)sulfanyl](1-napthyl)acetate was prepared according to the general method as outlined in Example 1 (Step 1). Starting from ethyl bromo(1-napthyl)acetate (11.0 g, 38 mmol) and 4-mercaptophenol (4.8 g, 38 mmol), 8.14 g of ethyl[(4-hydroxyphenyl)sulfanyl](1-napthyl)acetate was isolated. Yield (64%); amber oil; MS 337.1 (M−H)−
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:7][CH:8]([OH:29])[CH2:9][NH:10][C:11]([C:13]1[N:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:5][CH3:6])[CH3:3].C(N(CC)CC)C.[C:37]([Cl:43])(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>C(Cl)Cl>[ClH:43].[CH2:2]([N:4]([CH2:7][CH:8]([OH:29])[CH2:9][NH:10][C:11]([C:13]1[N:14]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:15]2[C:20]([C:21]=1[O:22][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:5][CH3:6])[CH3:3]
Reactant: CCN(CC)CC(O)CNC(=O)c1c(O)c2ccccc2n1-c1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)CC(O)CNC(=O)c1c(OC(=O)C(C)(C)C)c2ccccc2n1-c1ccccc1
Reaction time: 3 h

Procedure:
12.6 g of 2-[3-(N,N-diethylamino)-2-hydroxypropylaminocarbonyl]-3-hydroxy-1-phenylindole hydrochloride (0.03 mole) are mixed with 150 ml of methylene chloride, 4.2 ml of triethylamine (0.03 mole) and 3.9 ml of pivaloyl chloride (0.03 mole) and the reaction mixture allowed to stand for 3 h at room temperature. The mixture is subsequently washed with a saturated sodium chloride solution, dried over sodium sulfate and filtered. The solution is then evaporated, the residue dissolved in methylene chloride and purified by means of low pressure chromatography over silica gel acid. As the elution agent, first methylene chloride and subsequently methylene chloride containing 10% methanol are used. The 2-[3-(N,N-diethylamino)-2-hydroxypropylaminocarbonyl]-3-pivaloyloxy-1-phenylindole hydrochloride obtained as the residue after the evaporation of the eluate is then recrystallized from isopropanol. Melting point: 157°-159°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([NH2:19])[CH:13]=2.[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH:19][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:10]([C:3]3[C:4]([O:8][CH3:9])=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[NH:11]2)=[CH:16][CH:15]=1)=[O:25]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: COc1nccc(Cl)c1-c1cc2ccc(N)cc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1nccc(Cl)c1-c1cc2ccc(NC(=O)c3cccc(Cl)c3)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
To a solution of 2-(4-chloro-2-methoxy-pyridin-3-yl)-1H-indol-6-ylamine (30 mg, 0.11 mmol) in CH2Cl2 (5 mL) was added 3-chlorobenzoic acid (17 mg, 0.11 mmol) and HATU (42 mg, 0.11 mol). The solution was stirred at 25° C. for 1 h and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded 3-chloro-N-[2-(4-chloro-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-benzamide (35 mg, 78%) as a white solid. MH+ 411.9.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][NH:8][C:6]=2[N:7]=1.P(Br)(Br)([Br:18])=O>C(#N)C>[Br:18][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][NH:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)c1cc(O)nc2[nH]ncc12
Reactant: O=P(Br)(Br)Br
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)nc2[nH]ncc12
Yield: 77.1 %

Procedure:
Ethyl 6-hydroxy-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (25 g, 120 mmol) was suspended in acetonitrile (250 mL) and POBr3 (69.56 g, 241.54 mmol) was added to it. The reaction mixture was refluxed for 6 h. On completion of reaction, acetonitrile was removed under reduced pressure and residue neutralized with saturated NaHCO3 solution was added to it. Extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to provide the desired intermediate (25 g, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]([O:12][CH3:13])([CH2:9][CH2:10][CH3:11])[C:4](=[N:7][OH:8])[CH2:5][CH3:6].[ClH:14].ClCl>C(Cl)Cl>[Cl:14][CH:9]([CH2:10][CH3:11])[C:3]([O:2][CH3:1])([O:12][CH3:13])[C:4](=[N:7][OH:8])[CH2:5][CH3:6]
Reactant: CCCC(OC)(OC)C(CC)=NO
Reactant: Cl
Agent: ClCl
Solvent: ClCCl
Product: CCC(=NO)C(OC)(OC)C(Cl)CC

Procedure:
Following the general procedure of Example 1, to a solution of 4.73 parts of 4,4-dimethoxy-3-oximinoheptane and 0.2 parts anhydrous hydrogen chloride dissolved in 20 parts dry methylene chloride, at 30 to 35° C., under a dry nitrogen atmosphere, was added 1.8 parts of elemental chlorine over a 1/2-hour period. After the addition, the contents were stirred for 1/2-hour and then treated according to the procedure in Example 1 to yield 3.5 parts of 5-chloro-4,4-dimethoxy-3-oximinoheptane as determined by nuclear magnetic resonance spectroscopy.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9](=O)[CH3:10].[OH-:12].[K+].O.NN>C(O)CO>[OH:12][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH2:9][CH3:10]
Reactant: CC(=O)c1cccn1CCBr
Reactant: [OH-]
Agent: NN
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: CCc1cccn1CCO
Temperature: 200 °C
Reaction time: 1.5 h

Procedure:
A mixture containing 2-bromoethyl-2-acetyl-1H-pyrrole (8.2 g), ethylene glycol (45 mL), 85% potassium hydroxide pellets (8.91 g) and 80% hydrazine hydrate (6.76 mL) was stirred at 200° C. for about 1.5 hr along with simultaneous distillation of volatile materials. The product obtained was extracted with ethyl acetate (2×100 mL). The ethyl acetate layer was washed with water (100 mL), dried over sodium sulfate, filtered and evaporated. The crude product obtained was purified by column chromatography (silica gel 100-200), using ethyl acetate:pet. ether (8:2) as an eluent to obtain 2.2 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[C:15](=[O:20])[N:14]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23](Br)[CH:22]=1)[CH:13]=[CH:12]2)[CH3:8])([CH3:4])([CH3:3])[CH3:2].Br[C:33]1[CH:38]=[C:37](F)C=C[C:34]=1[N+:40]([O-])=O.[Si](C#C)(C)(C)C.C(N)CCC>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.[Cu]I.CN(C=O)C>[C:1]([O:5][C:6](=[O:31])[N:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[C:15](=[O:20])[N:14]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([NH:40][CH2:34][CH2:33][CH2:38][CH3:37])[CH:22]=1)[CH:13]=[CH:12]2)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Reactant: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc([N+](=O)[O-])c(Br)c3)c(=O)c2cc1F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#C[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: CCCCN
Product: CCCCNc1cc(-n2ccc3cc(N(C)C(=O)OC(C)(C)C)c(F)cc3c2=O)ccc1[N+](=O)[O-]

Procedure:
[2-(3-Bromo-4-nitro-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester was generated by Method A (Example 46) using 2-bromo-4-fluoro-1-nitro-benzene. A mixture of [2-(3-Bromo-4-nitro-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (21 mg, 0.0427 mmol), tetrakis(triphenylphosphine)palladium(0) (2.5 mg, 0.002 mmol), copper (I) iodide (2 mg, 0.008 mmol), TMS acetylene (10 ul, 0.07 mmol), n-butylamine (1.5 ml) and 1 mL DMF was purged with argon for 2 minutes. The mixture was then subjected to microwave irradiation (120° C.) for 5 minutes, then diluted with ethyl acetate and washed with brine. The organic layers were combined and concentrated in vacuo to give a crude residue, which was purified by column chromatography (silica 5-25% EtOAc/hexane) to give [2-(3-butylamino-4-nitro-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH2:19])(C)(C)C.CC1(C)O[C:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]#[N:32])=[CH:25][C:24](=[O:36])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:36]=[C:24]1[CH2:25][C:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]#[N:32])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[CH:10][C:9]=2[NH:19]1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(-c4cccs4)cc3NC(=O)C2)c1

Procedure:
Prepared from (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert.-butyl ester (Example G18) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (108 mg).
Reaction SMILES: O.[C:2](Cl)(Cl)=[S:3].[NH2:6][C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]>C(Cl)Cl>[C:9]([C:8]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:7]=1[N:6]=[C:2]=[S:3])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccccc1)c1cc(Cl)ccc1N=C=S

Procedure:
A 5 liter, 3-necked, round-bottom flask equipped with a condenser plus scrubber, mechanical stirrer, and dropping funnel was used as the reaction vessel. The reaction vessel was cooled in an ice bath after charging with 1.2 liters of water. After the water had cooled, 126 ml (1.65 moles) of thiophosgene was added. The mixture was stirred vigorously while a solution containing 352 grams (1.52 moles) of 2-amino-5-chlorobenzophenone in about 1 liter of methylene chloride was added over a period of 20 to 25 minutes. After addition was complete the funnel was rinsed with about 150 ml of methylene chloride and the reaction mixture was stirred for about 1 hour with the ice bath in place. Then the ice bath was removed and the reaction mixture was stirred for 1 additional hour. The organic phase was separated, dried with magnesium sulfate, and concentrated in vacuo. The 2-benzoyl-4-chlorophenylisothiocyanate remained behind as a brown oil which solidified on cooling. The product was recrystallized from hexane to yield tan crystals.