Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:9])[C:6]=1[CH2:7]O.[Br-:10].[C:11]1([PH+:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(#N)C>C(OCC)C>[Br-:10].[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:9])[C:6]=1[CH2:7][P+:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: Cc1csc(C)c1CO
Agent: [Br-]
Solvent: CC#N
Solvent: CCOCC
Product: Cc1csc(C)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
4.4 G. of 2,4-dimethyl-3-hydroxymethylthiophene and 10.7 g. of triphenylphosphonium bromide were dissolved in 40 ml. of acetonitrile and stirred at 40° C. for 1 hour. The resulting solution was cooled and 150 ml. of ethyl ether was added. The white precipitate which formed was filtered and washed with cold acetone to yield (2,4-dimethyl-3-thenyl)triphenylphosphonium bromide, m.p. 262°-265° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][CH2:21][CH2:22][C@H:23]([O:33][CH2:34][CH2:35][CH3:36])[C@H:24]([C@@H:30]([OH:32])[CH3:31])[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:10]([O:12]CC1C=CC=CC=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][CH2:21][CH2:22][C@H:23]([O:33][CH2:34][CH2:35][CH3:36])[C@H:24]([C@@H:30]([OH:32])[CH3:31])[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:10]([OH:12])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCO[C@@H](CCC[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1)[C@@H](CCC(C)C)[C@H](C)O
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCO[C@@H](CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)[C@@H](CCC(C)C)[C@H](C)O
Yield: 98.1 %

Procedure:
A solution of (2S,6S,7S)-benzyl 2-((tert-butoxycarbonyl)amino)-7-((S)-1-hydroxyethyl)-10-methyl-6-propoxyundecanoate (815 mg, 1.61 mmol) and 10% Pd/C (85 mg, 0.803 mmol) in THF (5.35 mL) was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 4 h. The hydrogen was removed using a stream of N2 and the reaction was filtered through a plug of Celite®. The plug was washed with DCM (2×5 mL) and the combined filtrate and washes were concentrated to dryness under reduced pressure to afford the title compound (660 mg, 1.58 mmol, 98%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 5.14 (d, J=8.2 Hz, 1H), 4.36-4.26 (m, 1H), 3.95-3.83 (m, 1H), 3.63-3.52 (m, 1H), 3.49-3.41 (m, 1H), 3.37-3.27 (m, 1H), 1.93-1.81 (m, 2H), 1.79-0.80 (m, 33H) (carboxylic acid peak is very broad (not listed) and alcohol proton is not visible); 13C NMR (101 MHz, CDCl3) δ 175.98, 155.52, 82.43, 79.93, 71.50, 69.42, 53.26, 45.32, 37.36, 32.61, 28.69, 28.31, 28.26, 25.17, 23.16, 22.66, 22.39, 21.82, 10.63; ESIMS m/z 416 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[CH:11](O)=O>>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][CH:11]=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(F)c(Br)cc1N
Reactant: O=CO
Product: Fc1cc2[nH]cnc2cc1Br

Procedure:
A mixture of 98 (600 mg, 2.93 mmol) in formic acid (5.0 mL) was heated to reflux overnight. The reaction mixture was concentrated in vacuo to afford a brown oil that was partitioned between EtOAc (300 mL) and a sat'd. aq. NaHCO3 (100 mL). The organic layer was separated, dried (MgSO4), filtered and evaporated in vacuo to afford 550 mg (87%) of 5-bromo-6-fluoro-1H-benzo[d]imidazole (100) as white solid (550 mg, 87%): MS (ESI) m/z=215 [M+1]+.
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[CH:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[CH:18][CH:17]=[CH:16]2)=[CH:11][CH:10]=1)([CH3:8])[CH3:7]>C(Cl)(Cl)Cl>[CH:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[CH:18][CH:17]=[C:16]2[S:2]([OH:5])(=[O:4])=[O:3])=[CH:11][CH:10]=1)([CH3:8])[CH3:7]
Reactant: CC(C)c1ccc(-n2cccc2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccc(-n2cccc2S(=O)(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
Chlorosulfonic acid (1.82 ml, 27.08 mmol) was slowly added to a solution of 1-(4′-isopropylphenyl)pyrrole (5.01 g, 27.08 mmol) in chloroform (100 ml) at 0° C. The resulting solution was stirred at 0° C. for 1 h and for an additional 1 h at room temperature. Chloroform was removed under reduced pressure. The resultant brown liquid was diluted with ethyl acetate (200 ml) and washed with 1 N sodium hydroxide. The aqueous layer was then acidified with concentrated hydrochloric acid (pH<1) and then extracted with chloroform (2×150 ml). The combined organic layers was dried over magnesium sulfate and was filtered. Removal of the solvent gave 1-(4′-isopropylphenyl)pyrrole-2-sulfonic acid as a brown syrup (3 g, 42% yield).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[O:28])[O:26][C:25]([CH3:30])([CH3:29])[O:24][C:23]=4[CH:31]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:34]([CH2:38][C:39](Cl)=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][N:18]([C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[O:28])[O:26][C:25]([CH3:29])([CH3:30])[O:24][C:23]=4[CH:31]=3)[C:39](=[O:40])[CH2:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1
Reactant: CC(C)(C)CC(=O)Cl
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CC(C)(C)C)c3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1

Procedure:
The titled compound was prepared following the procedure M using 7-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and tert-butyl acetyl chloride as an orange solid (71%). 1HNMR (CDCl3, 300 MHz) δ: 7.91 (d, J=8.3 Hz, 1H), 7.43 (m, 2H), 7.39 (m, 2H), 7.16 (m, 2H), 7.14 (m, 2H), 6.76 (m, 0.5H), 6.73 (m, 0.5H), 6.55 (m, 1H), 4.88 (s, 2H), 2.61 (t, J=7.7 Hz, 2H), 2.09 (s, 2H), 1.71 (s, 6H), 1.67-1.54 (m, 2H), 1.41-1.27 (m, 2H), 1.00 (s, 9H), 0.92 (t, J=7.4 Hz, 3H). HPLC, Rt: 6.02 min, (Purity: 98.9%).
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:28][C:29]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:30]=1[CH:31]=O>O1CCCC1>[CH:31]([C:30]1[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:29]=1[F:28])=[CH2:2]
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(F)c(C=O)c1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1cc(OC)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
39.4 g of methyltriphenylphosphonium iodide and 10.9 g of potassium t-butoxide were suspended in 150 ml of tetrahydrofuran. The resulting suspension was stirred at 0° C. under nitrogen stream for 30 minutes, followed by the dropwise addition thereto of a solution of 10 g of 2-fluoro-5-methoxybenzaldehyde in 20 ml of tetrahydrofuran. The resulting mixture was further stirred for one hour, quenched by the addition of water and extracted with ethyl acetate. The formed organic layer was washed with water and brine successively, dried over anhydrous magnesium sulfate, and evaporated. The resulting residue was subjected to silica gel column chromatography (developer: 5% ethyl acetate/n-hexane) to give 9.1 g of the title compound as a colorless oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C1CCN2C(=NCCC2)CC1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>C(#N)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:35])[NH:6][CH:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH3:2])=[O:14])=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)C(Cc1ccccc1)NC(=O)Nc1ccc(Cl)cc1
Yield: 98.9 %

Procedure:
To a solution of phenylalanine methyl ester hydrochloride (2.0 g) and DBU (1.4 ml) in acetonitrile (40 ml) was added 4-chlorophenyl isocyanate (1.4 g). The reaction mixture was mixed at room temperature for 1 hour, and then the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as colorless powder (3.0 g, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:16](O)[CH2:17][OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:9]1([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[O:18][CH2:17][CH2:16][O:15]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(C2(c3ccccc3)OCCO2)cc1

Procedure:
In 1300 milliliters of toluene in a flask equipped with a Dean-Stark tube are dissolved 100 grams of p-bromobenzophenone; and to this solution is added 150 grams of ethyleneglycol and 4.4 grams of p-toluenesulphonic acid. This mixture is refluxed until no further water collects in the Dean-Stark tube. After distilling off the toluene and recrystallization from methanol one obtains 2-phenyl-2-(p-bromophenyl)-1,3-dioxolane.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[CH3:11])=[O:2].[CH3:12][C:13]1([CH3:32])[O:17][CH:16]([CH2:18][O:19][C:20]2[C:29]([CH3:30])=[CH:28][C:23]([C:24]([NH:26]O)=[NH:25])=[CH:22][C:21]=2[CH3:31])[CH2:15][O:14]1>>[CH3:12][C:13]1([CH3:32])[O:17][CH:16]([CH2:18][O:19][C:20]2[C:21]([CH3:31])=[CH:22][C:23]([C:24]3[N:26]=[C:8]([C:6]4[S:7][C:3]([CH:1]=[O:2])=[C:4]([CH3:11])[CH:5]=4)[O:10][N:25]=3)=[CH:28][C:29]=2[CH3:30])[CH2:15][O:14]1
Reactant: Cc1cc(C(=O)O)sc1C=O
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Product: Cc1cc(-c2nc(-c3cc(C)c(OCC4COC(C)(C)O4)c(C)c3)no2)sc1C=O

Procedure:
The title compound is prepared according to Method A starting from 5-formyl-4-methyl-thiophene-2-carboxylic acid and rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine; LC-MS: tR=1.16 min; [M+1]+=429.16; 1H NMR (D6-DMSO): δ1.34 (s, 3H), 1.38 (s, 3H), 2.34 (s, 6H), 2.65 (s, 3H), 3.79-3.93 (m, 3H), 4.10-4.15 (m, 1H), 4.42-4.49 (m, 1H), 7.75 (s, 2H), 8.07 (s, 1H), 10.17 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[N:3]=1.C(N(C(C)C)CC)(C)C.[NH2:28][CH:29]1[CH2:35][CH2:34][CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]1>CC(N(C)C)=O>[NH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH:29]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:3]=2)[CH2:30]1
Reactant: Oc1ccccc1-c1nc(Cl)c2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCCCC(N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Oc1ccccc1-c1nc(NC2CCCCNC2)c2ccccc2n1
Temperature: 60 °C
Reaction time: 18 h
Yield: 5.8 %

Procedure:
2-(4-Chloroquinazolin-2-yl)phenol (0.093 g, 0.362 mmol) was dissolved in DMA (3.6 mL) and then treated with diisopropylethylamine (0.189 mL, 1.087 mmol) followed by tert-butyl 3-aminoazepane-1-carboxylate (0.078 g, 0.362 mmol) and the solution was heated at 60° C. After 18 hours, the reaction mixture was concentrated in vacuo to remove the excess amine and purified by ion exchange chromatography on SCX-2 Isolute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. The solvent was removed in vacuo and the residue was dissolved in methanol (0.22 mL) and treated with 4 M HCl in dioxane (0.22 mL). After 18 hours, the reaction mixture was concentrated in vacuo and purified by ion exchange chromatography on SCX-2 Isolute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. Further purification by silica column chromatography, eluting with a gradient of 3% to 30% methanol in dichloromethane, gave the title compound as a yellow solid (0.007 g, 6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17]C(=O)[CH2:15][CH2:14]1)(=[O:12])=[O:11].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CO[CH:44]([O:47][CH3:48])[O:45][CH3:46].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:44]([O:45][CH3:46])([O:47][CH3:48])[CH2:15][CH2:14]1)(=[O:11])=[O:12]
Reactant: CCOC(=O)C1=CC(=O)CCC1S(=O)(=O)Nc1ccc(F)cc1Cl
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: CCOC(=O)C1=CC(OC)(OC)CCC1S(=O)(=O)Nc1ccc(F)cc1Cl
Yield: 87.8 %

Procedure:
6.1 g (16.2 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7 was dissolved in 120 ml of methanol and 4.1 g (16.2 mmol) of pyridinium p-toluenesulfonate and 8.86 ml (81.0 mmol) of trimethoxymethane were sequentially added thereto with stirring under ice-cooling, followed by stirring overnight at room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=2:1) to give 6.0 g of the title compound as a white powder (yield: 88%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([O:13]CC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CCO>O>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
To a suspension of 73 (4.0 g, 15.6 mmol) in H2O (150 ml) were added NaOH (3.1 g, 78.0 mmol) and EtOH (5 ml). The mixture was reflux for 12 h, and cooled to 25° C. The solid was filtered out and the filtrate was acidified with 2N HCl. The precipitate was collected and washed with H2O. The crude product was recrystallized from to give 78 as white solid. (3.0 g, 13.2 mmol). Yield: 84.6%; mp 73-75° C.; MS (EI, 70 eV): m/z 228.3 (M+); 1H-NMR (CDCl3, 200 MHz): δ 5.27 (s, 2H), 7.08-7.54 (m, 8H), 6.93 (dd, J=8.0, 1.8 Hz, 1H); 13C-NMR (CDCl3, 50 MHz) δ: 165.43, 157.40, 135.02, 134.34, 133.88, 129.16, 127.92, 122.44, 118.09, 113.11, 72.23; Anal. Calcd for C14H12O3: C, 73.67; H, 5.30.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]([CH:29]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[CH2:30][O:31][C:32]3[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][C:33]=3[F:40])=[C:27]3[C:22]([CH:23]=[CH:24][CH:25]=[CH:26]3)=[N:21]2)=[CH:16][CH:15]=1>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]([CH:29]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[CH2:30][O:31][C:32]3[CH:39]=[CH:38][C:35]([C:36]4[N:1]=[N:2][NH:3][N:37]=4)=[CH:34][C:33]=3[F:40])=[C:27]3[C:22]([CH:23]=[CH:24][CH:25]=[CH:26]3)=[N:21]2)=[CH:16][CH:15]=1
Reactant: N#Cc1ccc(OCC(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Fc1cc(-c2nn[nH]n2)ccc1OCC(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Temperature: 120 °C
Reaction time: 14 h
Yield: 37.2 %

Procedure:
Sodium azide (14 mg, 215 umol) and triethylamine hydrochloride (29 mg, 215 umol) were added to a solution of [rac]-4-{2-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-2-cyclohexyl-ethoxy}-3-fluoro-benzonitrile (20 mg, 43 umol; example 30) in DMF (0.4 ml). The solution was stirred at 120° C. for 14 h, poured onto ice water/1 N aqueous HCl solution 1/1 and extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give a solid which was crystallized from acetonitrile to obtain the title compound (8 mg, 16 umol; 37%) as off-white solid. MS: m/e=518.0 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:8]([CH2:9][OH:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ncccc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
To a solution of 2-methoxy-pyridine-3-carbaldehyde (2.05 g, 14.9 mmol) in MeOH (70 mL) cooled to 0° C. was added sodium borohydride (670 mg, 17.7 mmol, 1.18 equiv.) as a solid in one portion. The reaction was allowed to slowly warm to room temperature and stirred for 2 h. Excess hydride was consumed by the addition of H2O and the reaction mixture was concentrated under reduced pressure. The residue was taken back up in EtOAc and washed with H2O. The aqueous phase was back extracted with EtOAc and the combine organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash silica gel chromatography using a 5% MeOH/DCM to provide, after concentration of the eluent, to give (2-methoxy-pyridin-3-yl)-methanol (1.65 g, 11.9 mmol, 81.3 %) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](O)=O)=[CH:10][C:9]=1[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19].[NH2:22][C:23](=[N:35][OH:36])[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([Cl:34])[CH:25]=1>>[Cl:34][C:26]1[CH:25]=[C:24]([C:23]2[N:22]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])=[C:9]([CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:10]=3)[O:36][N:35]=2)[CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1CS(C)(=O)=O
Reactant: COC(=O)c1ccc(C(N)=NO)cc1Cl
Product: COC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(CS(C)(=O)=O)c3)n2)cc1Cl

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 40 (182.62 mg; 0.60 mmol) and Intermediate 34 (114.32 mg; 0.50 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/EtOAc: 1/1), affording the title compound. 1H NMR (CDCl3) δ 8.58 (d, J=1.7 Hz, 1H), 8.32 (d, J=1.5 Hz, 1H), 8.28 (dd, J=8.0, 1.8 Hz, 1H), 8.15 (dd, J=8.1, 1.6 Hz, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.41-7.29 (m, 3H), 7.20 (d, J=7.3 Hz, 1H), 4.33 (d, J=13.9 Hz, 1H), 4.19 (d, J=14.0 Hz, 1H), 3.98 (s, 3H), 2.64 (s, 3H), 2.09 (s, 3H). LC/MS (Method B): 495.2 (M−H)−, 497.1 (M+H)+. HPLC (Method A) Rt 5.51 min (Purity: 99.6%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B(O)O)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Br[C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]([Cl:22])[N:16]=1.O.C(=O)([O-])[O-].[K+].[K+]>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>[Cl:22][C:17]1[N:16]=[C:15]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[N:3]=[CH:4]3)[C:20]([CH3:21])=[CH:19][CH:18]=1
Reactant: Cc1ccc(Cl)nc1Br
Reactant: Cn1ncc2cc(B(O)O)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(Cl)nc1-c1ccc2c(cnn2C)c1
Temperature: 110 °C

Procedure:
In a 10 mL reaction vial, the 1-methyl-1H-indazol-5-ylboronic acid (500 mg, 2.84 mmol) and the 2-bromo-6-chloro-3-methylpyridine (585 mg, 2.84 mmol) were dissolved in dioxane (7 mL) and water (1.7 mL) under argon atmosphere. The mixture was bubbled with argon for 5 min. Then potassium carbonate (979 mg, 7.1 mmol) and Pd(PPh3)4 (49 3 mg, 0.428 mmol) were added sequentially. The resulting reaction mixture was then sealed and heated in oil bath at 110° C. for 2.5 h. Reaction was then partitioned between EtOAc (30 mL) and water (30 mL).The organic phase was washed with water (3×20 mL) and was concentrated. Residue was purified on silica gel column with 0-50% EtOAc/Hex to afford the title compound. LCMS-ESI+: calc'd for: C14H12ClN3: 258.1 and 260.1 (M+H+); found: 258.0 and 260.0 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:14][CH2:15][C:16](=O)[CH2:17][CH3:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:15]([C:16]1([CH2:17][CH3:18])[NH:6][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=2[O:1]1)[CH3:14]
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1O
Reactant: CCC(=O)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(CC)NC(=O)c2ccc([N+](=O)[O-])cc2O1

Procedure:
A suspension of the compound obtained in (1) described above (5 g), 3-pentanone (6.6 g) and p-toluenesulfonic acid monohydrate (1.6 g) in toluene (70 mL) was heated under reflux overnight. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (100 mL) and the mixture was extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was recrystallized from ethyl acetate/dichloromethane (1:1) to give the titled compound (5 g) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([CH2:15]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:6][C:5]2=1.[C-:27]#[N:28].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([CH2:15][C:27]#[N:28])[CH2:6][C:5]2=1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3[nH]c4ccc(F)cc4c3C2)cc1
Agent: [Na+]
Solvent: CCO
Product: N#CCC1CCc2[nH]c3ccc(F)cc3c2C1
Reaction time: 2 h

Procedure:
To a suspension of the crude toluene-4-sulfonic acid 6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl-methyl ester (9.827 g, 0.0263 mol) in ethanol (70 mL) was added solid sodium cyanide (49.01 g, 0.0447 mol). The mixture was stirred at gentle reflux for 16 hours. Following TLC, a small amount of additional sodium cyanide was added and heating resumed for 2 hours. Most of the solvent was removed under reduced pressure (ca 55 mL). The residue was slurried in water (70 mL) and extracted with diethyl ether (3×). The extracts were washed with water and brine, and dried over anhydrous magnesium sulfate. Removal of the solvent provided a mustard colored solid which was purified by flash chromatography on silica gel Merck-60 using a gradient from 8:2 to 1:1 of ethyl acetate in hexane. The desired title compound was obtained as a yellow oil that solidifies in vacuo to yield light yellow crystals (5.2 g), m.p. 136-138° C. MS (ES): [M−H]− @m/z 227.1.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[CH:9][S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[NH:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].C(N(CC)CC)C>CC(C)=O>[N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[CH:9][S:10]([NH:25][C:23](=[NH:24])[C:22]2[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:27][CH:26]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N=C(N)c1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(C=CS(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: N=C(NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
4-Nitrostyrylsulfonyl chloride (2.5 g., 0.01 mole) is added portion-wise to a solution of 4-nitrobenzamidine (1.65 g., 0.01 mole), prepared according to the procedure of L. Weintraub, et al., J. Org. Chem., 33, 1679 (1968), and triethylamine (1.01 g., 0.01 mole) in 50 ml. of acetone at 10° C. After stirring for a period of 1 hr. at 25° C., the mixture is concentrated under reduced pressure and the residual material stirred with water and collected. Triturating the filter cake with acetone provides N-(4-NITROSTYRYLSULFONYL)-4-NITROBENZAMIDINE, m.p. 173°-177° C.