Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].C1CCNCC1.[N+:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24]>O1CCCC1>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])=[O:31])=[CH:33][CH:34]=1)([O-:25])=[O:24]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc([N+](=O)[O-])cc3)c2)CC1
Yield: 110.5 %

Procedure:
To a mixture of 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and (piperidinomethyl)-polystyrene (176 mg, 0.458 mmol) in tetrahydrofuran (1 mL) was added 4-nitrobenzoyl chloride (85 mg, 0.458 mmol) in tetrahydrofuran (1 mL). The reaction mixture was mixed for 18 h at ambient temperature. The reaction mixture was filtered and the filter cake was rinsed with methanol. The filtrate solution was diluted with 10% acetic acid in methanol and poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed with methanol to remove impurities, then treated with a 7M ammonia in methanol to elute the product from the column. The solvent was evaporated to give 93 mg (>100%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[C:3]=1[N+:11]([O-])=O.O.O.[C:16](O)(=[O:20])[C:17](O)=[O:18]>C(O)C>[OH:18][C:17]1[C:16]([OH:20])=[N:1][C:2]2[CH:10]=[CH:9][C:5]3[S:6][CH:7]=[CH:8][C:4]=3[C:3]=2[N:11]=1
Reactant: Nc1ccc2sccc2c1[N+](=O)[O-]
Reactant: O=C(O)C(=O)O
Solvent: O
Solvent: CCO
Product: Oc1nc2ccc3sccc3c2nc1O
Yield: 100.8 %

Procedure:
A solution of 5-amino-4-nitrobenzo[b]thiophene (0.50 g, 2.6 mmol) in 50 ml of 96% ethanol was hydrogenated at room temperature and atm. pressure in the presence of 5% palladium-on-carbon until the theoretical amount of hydrogen was absorbed. The catalyst was filtered off, and the filtrate was acidified with 1 N hydrochloric acid and evaporated to dryness. The residue was refluxed with oxalic acid dihydrate (0.40 g, S.1 mmol) in 25 ml of 4M hydrochlorio acid for 2 h. The mixture was cooled, and the precipitated solid was isolated by filtration, washed with water, ethanol and ether, and dried. The crude product was dissolved in a minimum amount of 2N sodium hydroxide, treated with decolourising charcoal, and filtered. The filtrate was acidified with 4M hydrochloric acid and the resulting precipitate was collected by filtration, washed with water, ethanol and ether to give 0.22 g (39%) of the thienoquinoxaline; m.p. 186.6° C.; IR (KBr): 1680 cm-1 ; H-NMR (DMSO-d 6): 7.13 (d,J=9 Hz, IH, ArH), 7.62 (D,J=9 Hz, IH, ArH), 7.72 (d,J=5 Hz, IH, ArH),
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]1[N:13]=[C:14]([NH2:17])[S:15][CH:16]=1.[C:18]1([C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]1[N:13]=[C:14]([NH:17][S:30]([C:27]2[CH:26]=[CH:25][C:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:29][CH:28]=2)(=[O:32])=[O:31])[S:15][CH:16]=1
Reactant: Nc1nc(-c2cc([N+](=O)[O-])ccc2Cl)cs1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Agent: Br
Product: O=[N+]([O-])c1ccc(Cl)c(-c2csc(NS(=O)(=O)c3ccc(-c4ccccc4)cc3)n2)c1

Procedure:
The title compound was prepared from 4-(2-chloro-5-nitrophenyl)-1,3-thiazol-2-amine hydrobromide and 4-phenylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (11.9 mg) with purity >90%. MS (pos) m/z 472.1.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([C:17]([NH:19][C:20]3[CH:51]=[CH:50][C:23]([C:24]([N:26]([CH3:49])[C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=4[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]4)=[O:41])=[O:25])=[CH:22][C:21]=3[O:52][CH3:53])=[O:18])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:54][N:55]1C(=O)C2=CC=CC=C2C1=O)=O)(C)(C)C>C(O)C.[OH-].[Na+].O>[NH2:55][CH2:54][C:9]1[NH:8][C:16]2[C:11]([CH:10]=1)=[C:12]([C:17]([NH:19][C:20]1[CH:51]=[CH:50][C:23]([C:24]([N:26]([CH3:49])[C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=3[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)=[O:41])=[O:25])=[CH:22][C:21]=1[O:52][CH3:53])=[O:18])[CH:13]=[CH:14][CH:15]=2
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2c1cc(CN1C(=O)c3ccccc3C1=O)n2C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(CN)cc12
Yield: 98.8 %

Procedure:
The solution of 4-[(1-tert-butoxycarbonyl-2-phthalimidomethylindol-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (312 mg) in ethanol (5.0 ml) and 1N sodium hydroxide aqueous solution (1.76 ml) was stirred at ambient temperature for 6 hours. The resulting solution was diluted with water and extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford 4-[(2-aminomethylindol-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (228 mg).
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOc1ccc(F)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To the crude product (700 mg) of t-butyl 2-bromoethylcarbamate obtained in Step 1 were added 4-fluorophenol (875 mg), potassium carbonate (1.08 g) and DMF (7 ml), and the mixture was stirred overnight at 90° C. The solvent was evaporated, and the mixture was diluted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained crude product was purified by silica gel chromatography (ethyl acetate-hexane) to give t-butyl 2-(4-fluorophenoxy)ethylcarbamate (390 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([OH:16])=O)[O:10][C:11]=1[CH2:12][CH3:13].[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40])[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:40])[F:41])[CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[O:16])[O:10][C:11]=1[CH2:12][CH3:13]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: CCc1oc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1oc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxylic acid (145 mg, 0.57 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (219 mg, 0.57 mmol)[prepared according to Preparation 6] and N,N-diisopropylethylamine (0.50 ml, 2.85 mmol) in dichloromethane (4.6 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (292 mg, 0.63 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-furancarboxamide (250 mg, 0.41 mmol, 71% yield) as a white solid: LCMS (ES) m/e 585, 587 (M, M+2)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:4][CH:3]1[C:5]([NH:7][C:8](=[CH:16][CH2:17][CH2:18][CH3:19])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:6].[ClH:21].C[CH2:23][O:24]CC>>[CH3:1][C:2]1([CH3:20])[CH2:4][CH:3]1[C:5]([NH:7][C:8]([O:24][CH3:23])([CH:16]=[CH:17][CH2:18][CH3:19])[C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[O:6].[ClH:21]
Reactant: CCOCC
Reactant: CCCC=C(NC(=O)C1CC1(C)C)C(=O)OC(C)(C)C
Agent: Cl
Product: CCC=CC(NC(=O)C1CC1(C)C)(OC)C(=O)OC(C)(C)C
Reaction time: 17 h

Procedure:
A solution of 0.84 g (3.0 mmole) of t-butyl 2-(2,2-dimethylcyclopropanecarboxamido)-2-hexenoate in 10 ml of Et2O saturated with anhydrous HCl was allowed to stand at room temperature under a drying tube. After 17 hrs, the solution was evaporated, and the residual gum was dissolved in 10 ml of saturated NaHCO3. This solution was washed with an additional 15 ml of 0.5 N HCl, then dried (MgSO4), filtered, and concentrated to give a viscous oil. The oil was crystallized from toluene. Yield of white crystals =0.32 g (47%), m.p. 119°-122°. TLC (4:1 toluene-AcOH) showed a single spot. NMR indicated essentially pure Z-isomer. (Note: Treatment of the methanol adduct, t-butyl 2-(2,2-dimethylcyclopropanecarboxamido)-2-methoxyhexenoate, with anhydrous HCl in Et2O under similar conditions gave the same product.)
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH2:7])[CH3:6])[CH3:2].[C:11]1([CH:21]=O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH:7][CH2:21][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:6])[CH3:2]
Reactant: CCOC(OCC)[C@H](C)N
Reactant: O=Cc1cccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(OCC)[C@H](C)NCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To the solution of (S)-1,1-diethoxypropan-2-amine (Compound XIX-1) 682 mg (3.55 mmol) in tetrahydrofuran 2 ml, 1-naphthaldehyde 554 mg (3.55 mmol) was added and stirred at room temperature for 0.5 hour. The reaction mixture was diluted with tetrahydrofuran 3 ml and sodium triacetoxyborohydride 829 mg (3.91 mmol) was added and stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate 50 ml and washed with saturated sodium bicarbonate aq. 50 ml twice, water 50 ml twice and brine 50 ml twice. The organic phase was dried with magnesium sulfate and filtered and the mother solution was concentrated in vacuo to obtain the title compound 685 mg (67.1%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH:11][C:12]3[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14](O)=O)=[CH:9][CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH4+].[OH-].O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:14]1[C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=[C:10]2[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=[CH:8][C:9]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1ccccc1Nc1ccnn1C1CCCC1
Agent: [NH4+]
Agent: [OH-]
Product: Clc1c2ccccc2nc2c1cnn2C1CCCC1

Procedure:
A mixture of N-(1-cyclopentylpyrazol-5-yl) anthranilic acid (21 g, 0.0775 mol) and POCl3 (100 ml) is refluxed for 8 hours. The reaction mixture is poured into ice waterl and neutralized with NH4OH. A gum forms which is extracted with CH2Cl2. The CH2Cl2 layer is then washed with water, dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography on silica gel eluting with 40% to 70% CH2Cl2 /hexane to afford 7.5 g of 4-chloro-1-cyclopentyl-1H-pyrazolo[3,4-b]quinoline, m.p. 97°-98° C.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[NH2:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.N1C=CC=CC=1>C(Cl)Cl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([NH:14][C@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)=[O:3])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.5 h

Procedure:
To a stirred solution 4-nitrophenyl chloroformate (26.0 mg, 0.13 mmol) in anhydrous CH2Cl2 was added a solution of (S)-tert-butyl 3-aminopiperidine-1-carboxylate (27.0 mg, 0.13 mmol) and pyridine (7 μL) in CH2Cl2 (0.5 mL). The mixture was stirred for 30 min. LC-MS showed complete conversion. This intermediate was used as a solution for the next step.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:20][CH2:21][O:22][CH3:23])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[NH2:19].[CH3:24][S:25]([NH2:28])(=[O:27])=[O:26].[H-].[Na+].[I-].[Na+]>>[NH2:19][C:10]1[C:9]2=[N:8][N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:28][S:25]([CH3:24])(=[O:27])=[O:26])=[C:18]2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CS(N)(=O)=O
Reactant: COCCn1nc2c(N)nc3ccccc3c2c1CCCCCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: COCCn1nc2c(N)nc3ccccc3c2c1CCCCNS(C)(=O)=O

Procedure:
The method described in Example 1254 was used to treat 1-(4-chlorobutyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (1.1 g, 3.3 mmol) with methanesulfonamide pretreated with sodium hydride in the presence of sodium iodide. The crude was purified by chromatography using a HORIZON HPFC system (40+M cartridge, eluting with 0-30% CMA in chloroform) followed by recrystallization from acetonitrile to provide 600 mg of N-{4-[4-amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]butyl}methanesulfonamide as white crystals, mp 159-161° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1.[F:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([CH:28]=[C:29]([C:31](O)=[O:32])[N:30]=2)[CH:27]=1>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C@H:3]([OH:20])[CH2:2][NH:1][C:31]([C:29]2[N:30]=[C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][N:26]3[CH:28]=2)=[O:32])[CH2:6][CH2:7]1
Reactant: O=C(O)c1cn2cc(F)ccc2n1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Product: O=C(NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)c1cn2cc(F)ccc2n1

Procedure:
Prepared as described in Example 1 from (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1 g) and 6-fluoroimidazo[1,2-a]pyridine-2-carboxylic acid (0.056 g). Title compound obtained as white solid (0.076 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[C-:27]#[N:28].[Na+]>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([C:27]#[N:28])=[CH:22][CH:21]=2)(=[O:18])=[O:19])=[CH:15][CH:16]=1
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(CCc2ccc(F)cc2F)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1ccc(S(=O)(=O)c2ccc(CCc3ccc(F)cc3F)cc2)cc1
Temperature: 100 °C
Yield: 34.4 %

Procedure:
2,4-Difluoro-1-(2-{4-[(4-fluorophenyl)sulfonyl]phenyl }ethyl)benzene (Example 122, 20 mg, 0.053 mmol) was dissolved in dimethylsulfoxide (0.1 mL) and sodium cyanide (5.2 mg, 0.106 mmol) was added. The reaction was heated to 100° C. overnight. The cooled reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 25% ethyl acetate/isohexane, to yield the title compound as a white solid (7 mg, 36%). δH (400 MHz, d6 DMSO): 8.10–8.07 (4H, m), 7.89 (2H, d, J=8.4 Hz), 7.46 (2H, d, J=8.4 Hz), 7.29 (1H, q, J=7.6 Hz), 7.14–7.10 (1H, m), 6.98–6.94 (1H, m), 2.94–2.86 (4H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8]C)=[N:6][CH:7]=1.IC.[CH3:12]C(O[K])=O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH3:12])[CH:7]=1
Reactant: COc1ccc(Br)cn1
Reactant: CC(=O)O[K]
Solvent: CC#N
Solvent: CI
Product: Cn1cc(Br)ccc1=O
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-2-methoxypyridine (1) (500 mg, 2.66 mmol), iodomethane (755 mg, 5.32 mmol) and CH3COOK (782 mg, 7.98 mmol) in acetonitrile (5 mL) was heated at reflux for 18 h. After cooled to rt, the mixture was filtered. The filtrate was concentrated and purified by reverse phase silica gel (MeOH in 0.05% NH3.H2O/H2O 10-95% v/v as mobile phase) to afford 2 as a white solid. ESI-MS: 189.0 (M+1)+.
Reaction SMILES: [Na+].[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(OC)(C)(C)C.Cl>O>[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1ccc(S(=O)O)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of p-toluenesulfinic acid sodium salt (30 g) in H2O (100 mL) was added methyl t-butyl ether (50 mL) followed by dropwise addition of conc HCl (15 mL). After stirring 5 min, the organic phase was removed and the aqueous phase was extracted with methyl t-butyl ether. The organic phase was dried (Na2SO4) and concentrated to near dryness. Hexane was added and the resulting precipitate collected to afford p-toluenesulfinic acid; yield 22 g. p-Toluenesulfinic acid (22 g, 140.6 mmol), p-fluorobenzaldehyde (22 mL, 206 mmol), formamide (20 mL, 503 mmol) and camphor sulphonic acid (4 g, 17.3 mmol) were combined and stirred at 60° C. 18 h. The resulting solid was broken up and stirred with a mixture of MeOH (35 mL) and hexane (82 mL) then filtered. The solid was resuspended in MeOH/hexanes (1:3, 200 mL) and stirred vigorously to break up the remaining chunks. Filtration afforded the title compound (27 g, 62% yield): 1H NMR (400 MHz, CDCl3) d 8.13 (s, 1H), 7.71 (d, 2H), 7.43 (dd, 2H), 7.32 (d, 2H), 7.08 (t, 2H), 6.34 (d, 1H), 2.45 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[I-].C[N+]1C=CN([C:20](=[O:29])[N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)C=1.C(N(CC)CC)C>C(#N)C>[CH3:12][C:11]1[C:2]([O:1][C:20](=[O:29])[N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: Cc1nc2ccccc2nc1O
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2nc1OC(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
A mixture of 2-hydroxy-3-methylquinoxaline (0.48 g, 3.00 mmol)), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours followed by heating at 50° C. for 3 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (50:50)) yielding the title compound (0.59 g, 67% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C([Li])(C)(C)C.CCCCC.[B:28](OC)([O:31]C)[O:29]C>O1CCCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([B:28]([OH:31])[OH:29])[CH:3]=[C:4]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]=2[O:9][CH2:8]1
Reactant: COB(OC)OC
Reactant: CC(C)(C)Cc1cc(Br)cc2c1OCC2(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)Cc1cc(B(O)O)cc2c1OCC2(C)C

Procedure:
Following General Procedure A and using 5-bromo-3,3-dimethyl-7-(2,2-dimethyl-propyl)-2,3-dihydro-benzofuran (Intermediate 32, 0.7 g, 2.37 mmol), 15 mL of anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane (3.53 mL, 6 mmol) and trimethyl borate (0.75 mL, 6 mmol) the title compound was obtained as a foam that was used as such for the next step without purification and characterization.
Reaction SMILES: Br[C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)C(C)C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:73]([SH:80])[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:73]([S:80][C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cc(SCc2ccccc2)c(F)c(F)c1Nc1ccccc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a solution of methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (12.85 g, 35.80 mmol) in anhydrous 1,4-dioxane (30 mL) was added N,N-diisopropylethylamine (9.21 g, 71.60 mmol). Then Pd2(dba)3 (1.63 g, 1.78 mmol) followed by Xantphos (2.06 g, 3.56 mmol) and BnSH (4.44 g, 35.80 mmol) was added under nitrogen atmosphere. The mixture was stirred overnight at 100° C. under N2 atmosphere. Then the reaction was allowed to warm to ambient temperature and quenched with water (150 mL). The aqueous layer was extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with water (200 mL×3) and brine (200 mL) sequentially, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v) to give the desired product (white solid, 12.64 g, 88% yield). 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 7.68 (dd, J=7.5, 2.1 Hz, 1H), 7.21-7.14 (m, 5H), 7.05-6.89 (m, 4H), 3.97 (s, 2H), 3.80 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6](O)=[O:7].C(Cl)(=O)C([Cl:16])=O.CN(C)C=O>C(Cl)Cl>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([Cl:16])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccccc1CCC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1CCC(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-methylhydrocinnamic acid (3.0 g, 18.3 mmole), oxalyl chloride (3.19 ml, 36.6 mmole) and methylene chloride (30 ml) was cooled in an ice bath and N,N-dimethylformamide (0.14 ml, 1.81 mmole) was added dropwise. The mixture was stirred at room temperature overnight. Concentration in vacuo gave 3-(2-methylphenyl)propanoyl chloride which was taken up in methylene chloride and used in the next step as a crude.