Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>>[Cl:32][C:33]1[CH:38]=[C:37]([C:12]2[N:13]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)[CH:36]=[CH:35][CH:34]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Clc1cccc(-c2c3c(nn2C2CCCCC2)CCNCC3)c1
Yield: 10.2 %

Procedure:
The title compound (14.4 mg) was prepared as in Example 177, Steps C and D, using 199.3 mg of 2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 177, Step B) and 216.2 mg of 3-chlorophenylboronic acid. MS (ESI): exact mass calculated for C19H24ClN3, 329.87; found, m/z 330.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.57-7.54 (m, 2H), 7.35 (s, 1H), 7.28-7.25 (m, 1H), 3.91-3.84 (m, 1H), 3.43-3.38 (m, 2H), 3.19-3.14 (m, 2H), 2.79-2.74 (m, 2H), 1.97-1.80 (m, 6H), 1.71-1.64 (m, 1H), 1.28-1.19 (m, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH2:18].[CH3:19][C:20]([CH3:25])([CH3:24])[C:21](Cl)=[O:22]>ClCCl>[CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH:18][C:21](=[O:22])[C:20]([CH3:25])([CH3:24])[CH3:19]
Reactant: Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Yield: 67.8 %

Procedure:
Following the procedure of Example 1, Step 4, 5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-amine (0.12 g, 0.50 mmol), trimethylacetyl chloride (0.065 mL, 0.52 mmol) and poly-(4-vinylpyridine) (700 mg) in dichloromethane (10 mL) provided 0.11 g of N-5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-yl-2,2-dimethylpropanamide. MS (ESI) m/z 325; HPLC purity major: no impurities detected at 210-370 nm window; 99.5% at 246 nm (max. abs), RT=10.7 (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C21H28N2O+H+, 325.22744; found (ESI, [M+H]+), 325.2271.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[S:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10]Br)[C:3]1=[O:12].[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[Br-]>C(OCC)(=O)C.CO.CCOC(C)=O.C(#N)C>[CH3:1][C:2]1([CH3:13])[S:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][N:27]2[CH2:28][CH2:29][N:24]([C:15]3[CH:16]=[CH:17][C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:14]=3)[CH2:25][CH2:26]2)[C:3]1=[O:12]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: CC1(C)SCN(CCCCBr)C1=O
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [I-]
Solvent: CC#N
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C)SCN(CCCCN2CCN(c3ccc4ccccc4n3)CC2)C1=O
Temperature: 95 °C
Reaction time: 44 h
Yield: 67.1 %

Procedure:
A mixture of 5,5-dimethyl-3-(4-bromobutyl)-4-thiazolidinone (4.20 g), 1-(2-quinolinyl)piperazine (3.70 g), K2CO3 (6.55 g), NaI (200 mg) and acetonitrile (150 mL) was heated at reflux (bath temperature 95° C.) under N2 for 20 h. TLC analysis (silica gel, 10% MeOH/EtOAc) showed the absence of starting bromide and the formation of a major product, Rf =0.31. The reaction mixture was cooled to room temperature and left standing for 44 h. To this was added ethyl acetate (100 ml) and the resultant mixture was filtered. The filtrate was concentrated in vacuo to an oily solid which was redissolved in ethyl acetate (200 mL) causing a white solid to precipitate. The mixture was gravity filtered and the filtrate concentrated to an off-white solid (6.86 g). Chromatography of the crude product (Waters Prep 500, 1 silica gel column, 10% MeOH/EtOAc) yielded 4.22 g of a white solid (Rf =0.26), mp 107°-111° C. It was recrystallized from ethyl acetate/hexane (1:2) to yield 2.83 g of white crystals, mp 110.5°-111.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5].NC1C=C(C(N2CCOCC2)=[O:42])C=CC=1N>>[Cl:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([C:21]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[O:42])=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1N
Product: O=C(Nc1c[nH]nc1-c1nc2cc(C(=O)N3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl

Procedure:
The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (Example 94E), but using (3,4-diamino-phenyl)-morpholin-4-yl-methanone (Example 94B) to give 2,6-dichloro-N-{3-[5-(morpholine-4-carbonyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}-benzamide (17 mg) as a beige solid. (LC/MS: Rt 2.98, [M+H]+ 485.13).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([OH:35])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.[ClH:36]>C(Cl)Cl.O1CCOCC1>[ClH:36].[ClH:36].[ClH:36].[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([OH:35])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ncccc24)C3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1/C(=C/c2c[nH]c3ncccc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0788 g, 0.165 mmol) in methylene chloride (2 mL) was added with a 4 M solution of hydrochloric acid in dioxane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the resulting solid was washed with acetonitrile to obtain the objective (Z)-2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one trihydrochloride (0.0518 g, 64%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([C:18]#[N:19])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1.[Br:20]Br.Cl>ClCC(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:20][C:11]1[CH:10]=[C:9]([C:12]2[C:13]([C:18]#[N:19])=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:8]=[CH:7][C:6]=1[CH3:5]
Reactant: BrBr
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: ClCC(Cl)(Cl)Cl
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2C#N)cc1Br
Reaction time: 24 h

Procedure:
A suspension of 21.0 g (0.157 mol) of anhydrous aluminium chloride in 800 ml of tetrachloroethane is treated with 25.0 g (0.129 mol) of 4'-methyl-1,1'-biphenyl-2-carbonitrile and brought to an internal temperature of 60° with stirning. As soon as the aluminium chloride has gone into solution, a solution of 20.7 g (0.129 mol) of bromine in 100 ml of tetrachloroethane is added dropwise at an internal temperature of 60°. The reaction mixture is stirred at 60° for 24 hours. After addition of a further 6.2 g of aluminium chloride and warming to 60-70°, starting material can no longer be detected in the TLC (toluene). The reaction mixture is then decomposed with 20 ml of conc. hydrochloric acid with ice-cooling, and the organic phase is separated off and evaporated in vacuo. The dark residue is dissolved in ethyl acetate, washed with water and sodium carbonate solution, dried (MgSO4) and evaporated. The crude product is purified by flash chromatography, as a result of which 22.0 g (62% of theory) of the title compound are obtained, m.p. 104-106° (from cyclohexane).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][O:20]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCOCC1>CO>[NH2:26][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][O:20]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCCO3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CCCCC3CCCO3)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
To a solution of N2-butyl-8-(methyloxy)-9-[4-(tetrahydro-2-furanyl)butyl]-9H-purine-2,6-diamine (75 mg, 0.207 mmol) in methanol (10 ml) at room temperature was added 4M HCl in 1,4-dioxane (1.324 ml, 5.30 mmol) to give a pale straw coloured solution. The reaction mixture was stirred at ambient temperature overnight (16 hours) when LCMS showed the reaction had not proceeded to completion. The solvent was removed overnight (16 hours) using a nitrogen blowdown unit when LCMS confirmed the presence of the desired product. This crude product was loaded in methanol onto a 5 g aminopropyl SPE cartridge and eluted with methanol over 20 mins. The appropriate fractions were combined and evaporated under a stream of nitrogen to give the title compound as a white powder (49 mg).
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[N:24][C:23]([C:26](=[O:29])[CH2:27][OH:28])=[CH:22][N:21]=3)[C@H:16]([CH3:30])[CH2:15]2)=[C:10]([CH3:31])[C:9]=1[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CCO>[CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[N:24][C:23]([CH:26]([OH:29])[CH2:27][OH:28])=[CH:22][N:21]=3)[C@H:16]([CH3:30])[CH2:15]2)=[C:10]([CH3:31])[C:9]=1[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCN(c3cnc(C(=O)CO)cn3)[C@H](C)C2)c1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(Cc2ccccc2)nnc(N2CCN(c3cnc(C(O)CO)cn3)[C@H](C)C2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
To a solution of 1-[(R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl)-2-hydroxy-ethanone (example 114, 110 mg, 0.25 mmol) and EtOH (20 ml) is added NaBH4 (14 mg, 0.38 mmol) at 0° C. The mixture is warmed up to room temperature and stirred for 3 h. The reaction solution is acidified with 3N HCl to pH˜7 and the organic solvent is removed. The residue is dissolved in saturated NaHCO3 solution and extracted with DCM. The organic layer is concentrated to afford the title compound (96 mg, 91%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18]([S:23]([CH3:25])=[O:24])=[N:19][CH:20]=2)[N:15]([CH2:26][CH3:27])[C:14]1=[O:28].[NH2:29][CH2:30][CH2:31][CH2:32][N:33]([CH2:37][CH2:38][OH:39])[CH2:34][CH2:35][OH:36]>>[F:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18]([S:23]([CH3:25])=[O:24])=[N:19][CH:20]=2)[N:15]([CH2:26][CH3:27])[C:14]1=[O:28].[OH:39][CH2:38][CH2:37][N:33]([CH2:34][CH2:35][OH:36])[CH2:32][CH2:31][CH2:30][NH:29][C:18]1[N:17]=[C:16]2[N:15]([CH2:26][CH3:27])[C:14](=[O:28])[N:13]([C:3]3[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=3[F:12])[CH2:22][C:21]2=[CH:20][N:19]=1
Reactant: NCCCN(CCO)CCO
Agent: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(S(C)=O)nc21
Product: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(NCCCN(CCO)CCO)nc21
Yield: 139.2 %

Procedure:
3-(2,6-Difluoro-3,5-dimethoxy-phenyl)-1-ethyl-7-methylsulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared using 0.50 g (1.21 mmol) of 3-(2,6-difluoro-3,5-dimethoxy-phenyl)-1-ethyl-7-methylsulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.59 g (3.64 mmol) of N-(3-amino-propyl)diethanolamine. The crude product was purified using medium-pressure chromatography eluting with a gradient of 9:1 ethyl acetate/methanol to 9:1:0.25 to 9:1:0.5 ethyl acetate/methanol/triethylamine to give 0.43 g (69%) of the title compound: mp 128° C.–129° C. MS (APCI) (m+1)/z 511.2.
Reaction SMILES: CO[C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].[O:24]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25]1.N12CCCNC1=NCCC2>C1(C)C=CC=CC=1>[O:24]1[CH2:28][CH2:27][CH:26]([NH:29][C:3]([C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:6]=2)=[O:4])[CH2:25]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)no1
Reactant: NC1CCOC1
Agent: C1CN=C2NCCCN2C1
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NC2CCOC2)on1
Temperature: 50 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To a solution of 3-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (298 mg, 0.95 mmol) and tetrahydrofuran-3-ylamine (99 mg, 1.14 mmol) in toluene (1.5 mL) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (40 mg, 0.28 mmol) and the reaction stirred under argon overnight at 50° C. Then the mixture was evaporated and the residue purified by chromatography (silica, heptane:ethyl acetate=4:1 to 1:1) to afford the title compound (87 mg, 25%) which was obtained as a colourless gum. MS: m/e=370.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[C:5]([C:12]([OH:14])=O)=[CH:6][NH:7]2.[CH:16]12[N:22]([C:23]3[N:28]=[CH:27][C:26]([NH2:29])=[C:25]([CH3:30])[CH:24]=3)[CH:19]([CH2:20][CH2:21]1)[CH2:18][CH2:17]2.N1C=CC=CC=1>CC1CCCO1.C(OCC)(=O)C>[CH:16]12[N:22]([C:23]3[N:28]=[CH:27][C:26]([NH:29][C:12]([C:5]4[C:4](=[O:15])[C:3]5[C:8](=[CH:9][CH:10]=[CH:11][C:2]=5[CH3:1])[NH:7][CH:6]=4)=[O:14])=[C:25]([CH3:30])[CH:24]=3)[CH:19]([CH2:20][CH2:21]1)[CH2:18][CH2:17]2
Reactant: Cc1cccc2[nH]cc(C(=O)O)c(=O)c12
Reactant: Cc1cc(N2C3CCC2CC3)ncc1N
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1cc(N2C3CCC2CC3)ncc1NC(=O)c1c[nH]c2cccc(C)c2c1=O
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
To a solution of 5-methyl-4-oxo-1H-quinoline-3-carboxylic acid (60 mg, 0.2953 mmol) and 6-(7-azabicyclo[2.2.1]heptan-7-yl)-4-methyl-pyridin-3-amine (60.03 mg, 0.2953 mmol) in 2-methyltetrahydrofuran (1 mL) was added propyl phosphonic acid cyclic anhydride (375.8 μL of 50% w/v, 0.5906 mmol) followed by pyridine (46.72 mg, 47.77 μL, 0.5906 mmol). The mixture was irradiated under microwave conditions for 1 h at 100° C. The crude reaction mixture was diluted with ethyl acetate (2 mL) and quenched with 10% NaHCO3 solution (3 mL). The resulting precipitate was filtered and washed with ethyl acetate (5 mL). The solid was resuspended in 20% aqueous Na2CO3 (5 mL)/methanol (2 mL) and stirred for 30 min. The solid was filtered, rinsed with water and air dried to provide N-(6-(7-azabicyclo[2.2.1]heptan-7-yl)-4-methylpyridin-3-yl)-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (30 mg, 26% yield). LC/MS m/z 389.4 [M+H]+, retention time 1.33 min (RP-C18, 10-99% CH3CN/0.05% TFA over 3 min).
Reaction SMILES: [Cl:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]([CH2:11][CH3:12])[C:4](=[O:13])[C:3]=1[CH:14]=[N:15]O.P(Cl)(Cl)(Cl)=O>O1CCCC1>[Cl:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]([CH2:11][CH3:12])[C:4](=[O:13])[C:3]=1[C:14]#[N:15]
Reactant: CCn1c(Cl)c(C=NO)c(=O)n(CC)c1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCn1c(Cl)c(C#N)c(=O)n(CC)c1=O

Procedure:
To a stirred solution of the oxime (16 g) in tetrahydrofuran (320 ml)was added dropwise phosphorus oxychloride (30 g) with stirring. The reaction mixture was concentrated under reduced pressure. To the concentrate was added diisopropylether(200 ml), whereupon 6-chloro-5-cyano-1,3-diethylpyrimidine-2,4(1H,3H)-dione precipitated out as pale yellow prisms(12.4 g), m.p. 92°-94° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([N-]C(C)C)(C)C.[Li+].[Li]CCCC.C(NC(C)C)(C)C.IC>C1COCC1.O>[CH3:14][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=[O:13]
Reactant: O=C1CCCCC1c1ccccc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: CC1(c2ccccc2)CCCCC1=O
Temperature: 25 °C

Procedure:
2-Methyl-2-phenyl-cyclohexanone was prepared according to the procedure described by Paquette et al., J. Org. Chem., 54, 5044 (1989). A solution of 2-phenylcyclohexanone (10 g, 57 mmol) in 40 mL of THF was slowly added to a −50° C. solution of lithium diisopropylamide (prepared by addition of 22 mL of 2.5 M n-BuLi (55 mmol) to a solution of 8.4 mL (60 mmol) of diisopropylamine in 75 mL of THF). The resulting solution was stirred with warming to room temperature over 2 hours and was then cooled to −60° C. Iodomethane (4.7 mL, 75 mmol) was added and the mixture was allowed to warm to room temperature over 12 hours. Water was added and the mixture was extracted twice with ether. The combined ether extract was washed with aqueous sodium sulfite solution and brine, dried (sodium sulfate) and evaporated to an oil which was purified by flash chromatography (5% ethyl acetate-hexane) to afford 7 g of 2-methyl-2-phenyl-cyclohexanone as an oil.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])[N:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:4]2[C:5]3[C:10](=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=3)[C:2]([C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)=[N:3]2)=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:16]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=Cc1ccc2c(c1)c(Br)nn2Cc1ccc(Cl)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1ccc2c(c1)c(-c1ccc(F)cc1)nn2Cc1ccc(Cl)cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 3-bromo-1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazole-5-carbaldehyde (0.311 mmol from Example 407), 4-fluorophenylboronic acid (0.498 mmol), Pd(dppf)Cl2 dichloromethane complex (0.0311 mmol) and sodium carbonate (0.933 mmol) in DME/H2O (4 mL; 4:1) under argon was stirred at 100° C. for 6 h, then concentrated. The residue was purified by chromatography (silica gel, hexanes to hexanes:EtOAc, 1:1) to afford 1-(4-chloro-2-trifluoromethylbenzyl)-3-(4-fluorophenyl)-1H-indazole-5-carbaldehyde as white solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:36]([CH3:37])=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][C:5]=1[CH3:38].[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]=[C:47]=[S:48])=[CH:42][CH:41]=1.C(N(CC)CC)C>O1CCCC1>[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47]([NH:3][C:4]2[C:5]([CH3:38])=[CH:6][C:7]([O:8][C:9]3[CH:10]=[CH:11][C:12]4[N:16]=[C:15]([CH2:17][O:18][C:19]5[CH:20]=[CH:21][C:22]([CH2:23][CH:24]6[S:28][C:27](=[O:29])[NH:26][C:25]6=[O:30])=[CH:31][CH:32]=5)[N:14]([CH3:33])[C:13]=4[CH:34]=3)=[CH:35][C:36]=2[CH3:37])=[S:48])=[CH:42][CH:41]=1
Reactant: Cc1cc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc(C)c1N
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc(C)c1NC(=S)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 63.9 %

Procedure:
A mixture of 5-[4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (288 mg), 4-chlorophenyl isothiocyanate (102 mg), triethylamine (121 mg) and anhydrous tetrahydrofuran (10 ml) was stirred at room temperature for 23 hours. The reaction mixture was concentrated and diluted with water. The precipitate was isolated by filtration and then chromatographed on a silica gel column using ethyl acetate:n-hexane=3:1 as the eluant to afford the title compound (215 mg, mp 160-162° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:40])[C:31]1[C:36]([CH3:37])=[CH:35][C:34](O)=[CH:33][C:32]=1[CH3:39].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:28][O:29][C:30](=[O:40])[C:31]1[C:32]([CH3:39])=[CH:33][C:34]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:35][C:36]=1[CH3:37]
Reactant: COC(=O)c1c(C)cc(O)cc1C
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1c(C)cc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1C
Yield: 12 %

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 4-hydroxy-2,6-dimethyl-benzoic acid methyl ester (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. The resulting solid was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane and ethyl acetate (100:0 to 60:40) to give the desired compound as a light yellow solid (12%). MS (Turbo Spray): m/z=553.3 [M+H].
Reaction SMILES: O1CCCC1.[Cl:6][CH2:7][CH2:8][CH2:9][S:10]([N:13]([C:21]1[CH:26]=[C:25]([CH:27]([S:36]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)(=[O:38])=[O:37])[C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])[C:24]([Cl:46])=[CH:23][N:22]=1)S(CCCCl)(=O)=O)(=[O:12])=[O:11].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>CCCCCC>[Cl:6][CH2:7][CH2:8][CH2:9][S:10]([NH:13][C:21]1[CH:26]=[C:25]([CH:27]([S:36]([C:39]2[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=2)(=[O:37])=[O:38])[C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])[C:24]([Cl:46])=[CH:23][N:22]=1)(=[O:11])=[O:12]
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)c1cc(N(S(=O)(=O)CCCCl)S(=O)(=O)CCCCl)ncc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=S(=O)(CCCCl)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a tetrahydrofuran (5 ml) solution of 3-chloro-N-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]-N-(3-chloropropylsulfonyl)propane-1-sulfonamide (193 mg, 0.272 mmol) was added to a tetrahydrofuran solution (11.0M, 0.28 ml, 0.28 mmol) of tetrabutylammonium fluoride. The resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate (=4:1) eluate was concentrated under reduced pressure to give the title compound (108 mg, 0.190 mmol, 70%) as a white solid.