Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([OH:14])[CH2:10][CH2:11][CH:12]=[CH2:13])=[C:4]([Cl:15])[N:3]=1>[O-2].[O-2].[Mn+4].ClCCCl>[NH2:1][C:2]1[N:3]=[C:4]([Cl:15])[C:5]([C:9](=[O:14])[CH2:10][CH2:11][CH:12]=[CH2:13])=[C:6]([Cl:8])[N:7]=1
Reactant: C=CCCC(O)c1c(Cl)nc(N)nc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCCl
Product: C=CCCC(=O)c1c(Cl)nc(N)nc1Cl
Yield: 24.3 %

Procedure:
A mixture composed of the above crude 1-(2-amino-4,6-dichloropyrimidin-5-yl)pent-4-en-1-ol (5.06 g), 1,2-dichloroethane (300 mL) and manganese dioxide (20.15 g) was heated under reflux for 15 hours. After confirming that the raw material disappeared, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-chloroform) to obtain the title compound (1.22 g, 24.3%) as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]2[C:15]([S:25][CH3:26])=[N:16][N:17]3[C:22](Cl)=[CH:21][C:20]([CH3:24])=[N:19][C:18]=23)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:27]>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]2[C:15]([S:25][CH3:26])=[N:16][N:17]3[C:22]([NH2:27])=[CH:21][C:20]([CH3:24])=[N:19][C:18]=23)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: N
Solvent: CO
Product: CSc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
In an analogous manner to that described in Example 4, from 3-(4-tert-butyl-benzenesulphonyl)-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 3-(4-tert-butyl-benzenesulphonyl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p. >230°.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=CC=3)=NOC=2C(F)(F)F)=[N:34][CH:33]=1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:34][CH3:33])=[O:28])=[CH:5][N:6]=3)=[C:16]([C:17]([F:18])([F:20])[F:19])[O:15][N:14]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Product: CNC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Yield: 66 %

Procedure:
As described for example 129, 6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.25 mmol), instead of 6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, was converted to the title compound (66 mg, 66%) which was obtained as an off white solid. MS: m/e=396.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[C:6]([CH3:10])[N:5]=[C:4]([Cl:11])[CH:3]=1.[NH2:12][NH2:13]>CC(N(C)C)=O.CCOC(C)=O>[Cl:11][C:4]1[N:5]=[C:6]([CH3:10])[C:7]2[CH:8]=[N:12][NH:13][C:2]=2[CH:3]=1
Reactant: Cc1nc(Cl)cc(Cl)c1C=O
Reactant: NN
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1nc(Cl)cc2[nH]ncc12
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
A solution of 4,6-dichloro-2-methylnicotinaldehyde (5.25 g, 23.48 mmol) in DMA (50 mL) was treated with hydrazine (7.37 mL, 235 mmol) at 0° C. The reaction was stirred for 15 min and then warmed to 80° C. for 2 h. The reaction was cooled and diluted with EtOAc and washed with water. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (0-100% EtOAc/hexanes) to give 6-chloro-4-methyl-1H-pyrazolo[4,3-c]pyridine. MS ESI calc'd. for C7H6ClN3 [M+1]+ 168. found 168.
Reaction SMILES: [CH2:1]([OH:12])[C:2]([C@@H:4]([OH:11])[C@H:5]([OH:10])[C:6]([CH2:8][OH:9])=[O:7])=O.C([BH3-])#N.[Na+].[CH:17]([NH2:30])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C>CO>[CH:17]([N:30]1[C@:2]2([CH2:1][OH:12])[O:7][C@:6]1([C@H:5]([C@@H:4]2[OH:11])[OH:10])[CH2:8][OH:9])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=C(CO)[C@@H](O)[C@H](O)C(=O)CO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: OC[C@]12O[C@](CO)([C@@H](O)[C@@H]1O)N2C(c1ccccc1)c1ccccc1
Yield: 62.2 %

Procedure:
A suspension of 5-keto-D-fructose (Formula X, 50 g, 0.28 mol; obtained from Chemical Dynamics) in 400 mL of MeOH was treated with sodium cyanoborohydride (40 g, 0.476 mol). A slurry of benzhydrylamine (42.0 mL, 0.234 mol) in 120-mL of MEOH was treated with sufficient acetic acid to bring the pH to 6-7 and then added over a 0.5 h period to the 5-keto-D-fructose (Formula X) and sodium cyanoborohydride suspension. An additional portion of sodium cyanoborohydride (20 g. 0.235 mol) was added and the mixture was stirred at reflux for 6 h. The solvent was then removed, and the residue treated with 10% sodium carbonate (ca. 100 mi), and the product was extracted into chloroform. The chloroform layers were dried (MgSO4), filtered and concentrated to give a tacky yellow solid. This was purified on two Waters Prep 500 columns (CHCl3 /MeOH/NH4OH, 88:11:1) to give ca. 50 g of the target compound. Recrystallization from ethyl acetate gave 21.3 g (28%) of white needles, 152.5°-154.5° C. (corrected). Both 1H and 13C NMR in CDCl3 supported the assigned structure.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:17]([CH2:18][OH:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH2:28][CH3:29])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[S:14]2)[C@@H:10]1[F:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:31](Cl)Cl>C1COCC1>[Si:1]([O:8][C@@H:9]1[C@@H:17]([C@@H:18]([OH:19])[CH3:31])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH2:28][CH3:29])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[S:14]2)[C@@H:10]1[F:30])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: ClCCl
Reactant: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@H](F)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O[C@@H]2S1
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@H](F)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]([C@H](C)O)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (3aR,5R,6R,7S,7aR)-6-(tert-butyldimethylsilyloxy)-7-fluoro-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(ethyl)carbamate (600 mg, 1.3 mmol) in DCM (30 mL) was added DMP (806 mg, 1.9 mmol) at 0° C. After stirring at room temperature for 2 h, the reaction was quenched with mixed saturated aqueous NaHCO3 (20 mL) and Na2S2O3 (20 mL). The resulting solution was extracted with DCM (3×30 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude aldehyde. The aldehyde was dissolved in THF (30 mL), treated with MeMgC1 (3 M in THF, 1.1 mL, 3.3 mmol) at 0° C.˜25° C. for 3 h. The reaction was then quenched with H2O (50 mL) and extracted with EtOAc (3×40 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by a silica gel column, eluted with 3%-30% EtOAc in petroleum ether to give tert-butyl (3aR,5R,6R,7S,7aR)-6-(tert-butyldimethylsilyloxy)-7-fluoro-5-((S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(ethyl)carbamate as a yellow oil (355 mg, 57% of 2 steps). (ES, m/z) [M+H]+ 479.0; 1H NMR (300 MHz, CDCl3) δ 6.20-6.14 (m, 1H), 4.95-4.65 (m, 1H), 4.44-4.25 (m, 2H), 4.08-3.79 (m, 4H), 1.51 (s, 9H), 1.25-1.14 (m, 6H), 0.87 (s, 9H), 0.12-0.06 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[NH:21][C:22](=[O:49])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[CH:25][C:24]=2[N:36]([CH:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)C(=O)C(F)(F)F)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C>CO>[F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[NH:21][C:22](=[O:49])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)=[CH:25][C:24]=2[NH:36][CH:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)(=[O:10])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(S(=O)(=O)c5cc(F)cc(F)c5)cc34)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(S(=O)(=O)c5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
A mixture of N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzamide (1.41 g, 2.0 mmol), triethylamine (5.6 mL) and methanol (30 mL) was stirred at room temperature overnight. The solvents were removed under reduced pressure and the residue treated with methanol (10 mL), stirred at 45° C. for 30 minutes, filtered and dried in oven affording 1.0 g of the title compound as a white solid (81% yield).
Reaction SMILES: [S:1]1[C:6]2=[CH:7][CH:8]=[CH:9][C:10]3[C:11](=[O:14])[C:12](=[O:13])[N:4]([C:5]=32)[CH2:3][CH2:2]1.[Br:15]Br>C(O)(=O)C>[Br:15][C:8]1[CH:7]=[C:6]2[S:1][CH2:2][CH2:3][N:4]3[C:12](=[O:13])[C:11](=[O:14])[C:10]([CH:9]=1)=[C:5]23
Reactant: BrBr
Reactant: O=C1C(=O)N2CCSc3cccc1c32
Solvent: CC(=O)O
Product: O=C1C(=O)N2CCSc3cc(Br)cc1c32
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
To a solution of 2,3-dihydropyrrolo[1,2,3-de]-1,4-benzothiazine-5,6-dione (2.05 g) in acetic acid (40 ml) was added bromine (0.5 ml) in acetic acid (10 ml) dropwise. The mixture was stirred for 5 hours at room temperature and poured into ice water (200 ml) and the resultant precipitate was collected by filtration, washed with water and dried to yield the title compound (2.10 g, 73.9%). The compound was recrystallized from acetonitrile to give dark red needles, mp 196° C.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:35][N:36]([CH3:42])[CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][CH:37]([N:36]([CH3:42])[CH3:35])[CH2:38]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1
Reactant: CN(C)C1CCNC1
Reactant: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(c2ccc3c(C(=O)NCC4(O)CCCC(F)(F)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-1-hydroxy-cyclohexylmethyl)-amide, DIPEA and 3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (m, 1H), 7.85 (1H), 7.48 (m, 2H), 6.69 (1H), 4.66 (s, 1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.45 (m, 1H), 3.26 (m, 2H), 2.85 (m, 1H), 2.54 (m, 4H), 2.22 (s, 6H), 2.15 (m, 1H), 2.06 (m, 2H), 1.85 (m, 3H), 1.74-1.76 (m, 5H). m/z: 467 [M+H]
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:32])([F:33])[F:19])=[CH:26][CH:25]=3)=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 05: tR=0.86 min; [M+H]+=420.88.
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][C:8]([C:10]3[O:11][C:12]4[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([O:20][CH2:21][C:22]5[N:23]=[C:24]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=6)[S:25][CH:26]=5)[C:13]=4[CH:14]=3)=[CH:9][N:4]2[N:3]=1.[CH3:33][OH:34].C[O-].[Na+]>ClCCl>[F:19][C:17]1[CH:16]=[C:15]([O:20][CH2:21][C:22]2[N:23]=[C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[S:25][CH:26]=2)[C:13]2[CH:14]=[C:10]([C:8]3[N:7]=[C:5]4[N:4]([CH:9]=3)[N:3]=[C:2]([O:34][CH3:33])[S:6]4)[O:11][C:12]=2[CH:18]=1
Reactant: CO
Reactant: Fc1cc(OCc2csc(-c3ccccc3)n2)c2cc(-c3cn4nc(Br)sc4n3)oc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1nn2cc(-c3cc4c(OCc5csc(-c6ccccc6)n5)cc(F)cc4o3)nc2s1
Reaction time: 0.42 h
Yield: 64 %

Procedure:
2-Bromo-6-(6-fluoro-4-((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (17 mgs, 0.032 mmol) was dissolved in dichloromethane (1.3 mL) (some heat and sonication were required). Methanol was then added (0.3 mL) followed by sodium methoxide (14.74 μL, 0.064 mmol) in one shot. The reaction was stirred at r.t for 25 min., then quenched with HCl 1.0 N and stirred until the reaction color changes to yellow. Sat. NaHCO3 was then added and this was extracted with dichloromethane (4×). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography (BIOTAGE® 12 g column using 100% dichloromethane to 5% ethyl acetate in dichloromethane (increment of 1%) to give the title material (10 mgs, 64%) as a yellowish solid. LC (Method A): 2.488 min. HRMS (ESI) calcd for C23H15FN4O3S2 [M+H]+ m/z 479.0570, found 479.0661. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.94-8.03 (m, 2H), 7.89 (s, 1H), 7.43-7.53 (m, 3H), 7.39 (s, 1H), 7.19 (s, 1H), 6.85-6.94 (m, 1H), 6.59-6.68 (m, 1H), 5.40 (s, 2H), 4.23 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([CH3:12])[CH:6]=1.C([O-])(O)=O.[Na+].Br[C:32]1[CH:37]=[CH:36][N:35]([CH2:38][CH2:39][CH2:40][CH3:41])[C:34](=[O:42])[C:33]=1[C:43]#[N:44]>O1CCOCC1.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>[CH2:38]([N:35]1[CH:36]=[CH:37][C:32]([C:15]2[CH:14]=[CH:13][C:3]([O:4][C:5]3[CH:6]=[C:7]([CH3:12])[N:8]=[C:9]([CH3:11])[CH:10]=3)=[C:2]([F:1])[CH:16]=2)=[C:33]([C:43]#[N:44])[C:34]1=[O:42])[CH2:39][CH2:40][CH3:41]
Reactant: CCCCn1ccc(Br)c(C#N)c1=O
Reactant: Cc1cc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)cc(C)n1
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: C1COCCO1
Product: CCCCn1ccc(-c2ccc(Oc3cc(C)nc(C)c3)c(F)c2)c(C#N)c1=O

Procedure:
To a solution of intermediate 20 (1.078 mmol) in 1,4-dioxane (6 ml) and a saturated solution of NaHCO3 (5 ml) was added intermediate 6 (0.25 g, 0.979 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.113 mg, 0.098 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was filtered through a pad of diatomaceous earth and the pad of diatomaceous earth was washed with EtOAc. The combined filtrates were washed with water and the organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/MeOH up to 2% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 7 that was precipitated from diethylether (0.225 g, 59%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[CH:13][C:14](Cl)=[N:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH4+:18].[OH-]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:18])=[N:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Br)cc1)c1ccc(Cl)nc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)c2ccc(Br)cc2)cn1
Temperature: 120 °C

Procedure:
5-((4-Bromophenyl)sulfonyl)-2-chloropyridine (98 mg, 0.29 mmol), concentrated NH4OH (3 mL), and EtOH (3 mL) were added to a high-pressure reaction vessel. The vessel was sealed and heated at 120° C. for 18 h. After cooling to room temperature, the solvent was partially removed under vacuum. The white precipitate obtained was filtered, washed with ether, and dried under vacuum to provide 5-((4-bromophenyl)sulfonyl)-2-pyridinamine (75 mg) as a white solid.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][C:4](=[O:7])[C:3]2=[CH:8][S:9][CH:10]=[C:2]12.[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C>[N+:11]([C:5]1[C:4](=[O:7])[C:3]2[C:2](=[CH:10][S:9][CH:8]=2)[NH:1][CH:6]=1)([O-:13])=[O:12]
Reactant: O=c1cc[nH]c2cscc12
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=c1c([N+](=O)[O-])c[nH]c2cscc12
Temperature: 70 °C
Reaction time: 0.05 h
Yield: 48.4 %

Procedure:
To a suspension of 4.00 g of thieno[3,4-b]pyridin-4(1H)-one 9 in 120 ml of acetic acid is added 3.00 g of nitric acid (d=1.38). The reaction mixture is stirred at 70° C. for 3 minutes and cooled to room temperature. The resulting crystals are collected by filtration, and then washed with water and methanol-ether, affording 2.51 g (48%) of Compound 10. An analytical sample is recrystallized from dimethylsulfoxide-methanol to give yellow crystals melting at 329°-332° C.
Reaction SMILES: [Cl:1]CCl.[OH:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17].S(Cl)(Cl)=O.Cl>CN(C)C=O>[OH:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9]([Cl:1])=[O:10])=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17]
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Reactant: ClCCl
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1O
Temperature: 40 °C

Procedure:
In a reactor 68 kg dichloromethane, 20 kg 5-nitro-vanillic acid of example 1b, 76 gram of N,N-dimethylformamide and 13.4 kg (8 L) thionyl chloride, was charged at 20.2° C. The mixture was heated to 40° C. until all the starting material dissolved and the evolution of HCl and SO2 stopped. When all the starting material was consumed 5-10 L dichloromethane was distilled off at normal pressure at 40° C. then the mixture was cooled to 20-25° C. and the distillation was continued until dry under vacuum at 40° C. The evaporation residue was dissolved in 36 kg dry THF. The THF solution was used in Example 4d.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH2:13][N:14]3[C:18]4[CH:19]=[CH:20][C:21]([C:23]([O:25]C)=[O:24])=[CH:22][C:17]=4[NH:16][C:15]3=[O:27])=[CH:10]2)=[CH:5][CH:4]=1)#[N:2].[Li+].[OH-].Cl>CC#N.CO>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH2:13][N:14]3[C:18]4[CH:19]=[CH:20][C:21]([C:23]([OH:25])=[O:24])=[CH:22][C:17]=4[NH:16][C:15]3=[O:27])=[CH:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)n2Cc1ccc2ccc(C#N)cc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: N#Cc1ccc2ccc(Cn3c(=O)[nH]c4cc(C(=O)O)ccc43)cc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.2 %

Procedure:
To a suspension of methyl 1-[(7-cyano-2-naphthyl)methyl]-2-oxo-(3H)—benzimidazole-5-carboxylate (82 mg, 0.23 mmol) in CH3CN (2.5 mL) and methanol (2 mL) was added 1N LiOH (2.3 mL, 10 eq.). The reaction mixture was stirred at room temperature for 3 days, acidified with 1N HCl (2.4 mL), filtered and dried to yield 1-[(7-cyano-2-naphthyl)methyl]-2-oxo-(3H)—benzimidazole-5-carboxylic acid (72 mg, 91%) as a white solid. 1H NMR(CDCl3) δ: 5.16 (s, 2H); 6.77-6.79 (d, 1H); 7.50-7.54 (t, 2H); 7.62-7.64 (dd, 1H); 7.68 (s, 1H); 7.72 (s, 1H); 7.78-7.84 (dd, 2H); 8.11 (s, 1H); 10.8 (s, 1H). ES-MS (M+H)+=344.1.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[C:5](I)[CH:4]=1)#[N:2].[CH2:19]([S:21][CH2:22][C:23]([CH3:27])([OH:26])[C:24]#[CH:25])[CH3:20]>>[CH2:19]([S:21][CH2:22][C:23]([C:24]1[N:13]([S:14]([CH3:17])(=[O:16])=[O:15])[C:6]2[C:5]([CH:25]=1)=[CH:4][C:3]([C:1]#[N:2])=[C:8]([C:9]([F:12])([F:11])[F:10])[CH:7]=2)([OH:26])[CH3:27])[CH3:20]
Reactant: C#CC(C)(O)CSCC
Reactant: CS(=O)(=O)Nc1cc(C(F)(F)F)c(C#N)cc1I
Product: CCSCC(C)(O)c1cc2cc(C#N)c(C(F)(F)F)cc2n1S(C)(=O)=O

Procedure:
This compound was prepared using the general Sonagashira procedure as describe in General Procedures Example C, reacting N-(4-cyano-2-iodo-5-trifluoromethyl-phenyl)-methanesulfonamide (1.0 g, 2.56 mmol) and 1-ethylsulfanyl-2-methyl-but-3-yn-2-ol (0.37 g, 2.56 mmol) to yield the title compound as a yellow sticky oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[C:11][Si](C)(C)C)[C:3]=1[CH:4]=O.[NH3:16]>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:3]=1[CH:4]=[N:16][CH:11]=[CH:10]2
Reactant: C[Si](C)(C)C#Cc1cccc(F)c1C=O
Reactant: N
Product: Fc1cccc2ccncc12
Temperature: 80 °C

Procedure:
2-Fluoro-6-(2-(trimethylsilyl)ethynyl)benzaldehyde (2.3 g, 10.5 mmol) was dissolved in ammonia (2M in methanol, 15 mL, 30 mmol) and the resulting mixture was heated at 80° C. in a sealed tube for 2.5 h. The solvent was removed under high vacuum and the resulting crude product purified by silica gel chromatography (20-30% EtOAc in hexanes) to give 8-fluoroisoquinoline as a pale yellow solid. MS (ESI, pos. ion) m/z: 148 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:26][CH2:27][C:28]#[N:29].CC([O-])(C)C.[K+].[CH:36]1[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=1>C1COCC1>[CH2:42]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:12]1[C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([Br:1])=[C:3]([O:26][CH2:27][C:28]#[N:29])[CH:4]=[CH:5]2)[C:39]1[CH:40]=[CH:41][CH:36]=[CH:37][CH:38]=1
Reactant: CCCCCc1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)[nH]c2ccccc12
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCc1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)n(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
To a stirred solution of {[1-bromo-6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile (0.135 g, 0.257 mmol) in THF (5 mL) at 0° C. was added KOt-Bu (0.032 g, 0.283 mmol) followed by BnBr (0.019 mL, 0.308 mmol). The reaction was warmed to rt and let stir for 24 h. After this time, the reaction mixture was quenched with 1 N HCl (˜2 mL). The resulting solution was diluted with EtOAc (100 mL). The organic layer was washed with 1 N HCl (10 mL), sat. aq. NaHCO3 (10 mL), and brine (10 mL) and then dried (MgSO4). After concentration, the residue was purified by preparatory plate chromatography (20% EtOAc:petroleum ether) to afford the product (0.105 g, 56%) as a solid; 1H NMR (DMSO-d6) δ 0.73 (t, J=7.4 Hz, 3H), 1.09-1.23 (m, 4H), 1.47-1.63 (m, 2H), 2.70 (t, J=7.7 Hz, 2H), 5.34 (s, 2H), 5.46 (s, 2H), 6.81 (d, J=7.4 Hz, 2H), 7.04-7.23 (m, 5H), 7.41 (d, J=8.1 Hz, 1H), 7.62-7.73 (m, 3H), 8.02 (s, 1H), 8.12 (d, J=9.2 Hz, 1H), 8.20 (d, J=9.2 Hz, 1H); mass spectrum [(+) ESI], m/z 537/539 (M+H)+.