Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:9])[N+:5]([O-:8])=[CH:6][CH:7]=1.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[OH:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[O:18][C:2]1[CH:3]=[C:4]([CH3:9])[N+:5]([O-:8])=[CH:6][CH:7]=1
Reactant: Oc1ccc(F)cc1F
Reactant: Cc1cc(Cl)cc[n+]1[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(Oc2ccc(F)cc2F)cc[n+]1[O-]
Temperature: 140 °C

Procedure:
4.3 g (30 mmol) of 4-chloro-2-picoline-N-oxide are added to a mixture of 4.6 g (35 mmol) of 2,4-difluorophenol in 25 ml of N,N-dimethylacetamide and 4.9 g (35 mmol) of finely powdered potassium carbonate and the mixture is warmed to 140° C. for 3 hours with stirring. After cooling, the reaction mixture is poured into 250 ml of water, extracted three times using dichloromethane, and the organic phases are dried over MgSO4 and concentrated. The residue is taken up in dichloromethane and extracted by shaking with saturated aqueous NaCl solution. After drying and freeing from solvent, the extract is brought to crystallization using diisopropyl ether and washed with ethyl acetate. Colorless crystals, m.p. 112°-124° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:29]=[O:30]>>[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH:29]=[O:30])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: O=C(OCc1ccccc1)c1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ccc(C(=O)OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1H-indole-5-carboxylic acid benzyl ester (3.5 g) in N,N-dimethylformamide (30 mL) was added phosphoryl chloride (2.6 g) under ice cooling and this mixture was stirred at room temperature for 2 hours. To this reaction mixture was added 2 mol/L aqueous sodium hydroxide solution until the pH became 6 and this mixture was stirred at 70° C. for 30 minutes. After cooling to ambient temperature, the precipitated solid was collected by filtration, and washed with water and methanol, dried to give the title compound (3.9 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.Cl>C(Cl)Cl.N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2/[CH:9]=[CH:10]/[C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(/C=C/c2cc(Cl)ccc2N)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(/C=C/c2cc(Cl)ccc2NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To methyl 4-[2-(2-amino-5-chlorophenyl)-(E)-vinyl]benzoate (130 mg; prepared in Reference Example 5.) in methylene chloride (3 ml), pyridine (0.073 μl) and p-chlorobenzenesulfonylchloride (114 mg) were added. The mixture was stirred overnight at room temperature. The reaction mixture was poured into diluted HCl and extracted with ethyl acetate. The organic layer was washed, dried over and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (AcOEt-hexane) to give the title compound (205 mg) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:26][CH3:27])=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH2:23]Cl)[CH2:9][CH2:8][C:7]=2[CH:25]=1.[NH2:28][C:29]1[C:34]([Cl:35])=[CH:33][C:32]([NH:36][CH2:37][CH2:38][NH2:39])=[CH:31][C:30]=1[Cl:40]>>[CH3:1][O:2][C:3]1[C:4]([O:26][CH3:27])=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH2:23][NH:39][CH2:38][CH2:37][NH:36][C:32]3[CH:31]=[C:30]([Cl:40])[C:29]([NH2:28])=[C:34]([Cl:35])[CH:33]=3)[CH2:9][CH2:8][C:7]=2[CH:25]=1
Reactant: COc1cc2c(cc1OC)N(Cc1ccccc1)C(=O)N(CCCCl)CC2
Reactant: NCCNc1cc(Cl)c(N)c(Cl)c1
Product: COc1cc2c(cc1OC)N(Cc1ccccc1)C(=O)N(CCCNCCNc1cc(Cl)c(N)c(Cl)c1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1-benzyl-1,3,4,5-tetrahydro-2H-1,3-benzdiazepin-2-on-3-yl)-1-chloropropane and 2-(4-amino-3,5-dichloro-phenylamino)-ethylamine analogously to Example 6.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH:17][S:19]([CH3:18])(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1cccc(-c2cnc3ccccc3n2)c1
Yield: 86.9 %

Procedure:
To a solution of (3-quinoxalin-2-ylphenyl)amine (2.21 g, 0.01 mol) in pyridine (10 mL), methanesulfonyl chloride (0.77 mL, 0.01 mol) was added dropwise at 0-5° C. with stirring. The reaction mixture was stirred overnight at room temperature, and then diluted with water. The resulting solid was filtered and dried to afford N-[3-(quinoxalin-2-yl)phenyl]methanesulfonamide (2.6 g, 87% yield). LCMS calculated for C15H13N3O2S (M+H): 300.07. found 300. 1H-NMR (DMSO-d6, 250 Mhz) δH: 10.01 (1H, br. s), 9.50 (1H, s), 8.20-8.00 (4H, m), 7.95-7.70 (2H, m), 7.60-7.52 (1H, m), 7.48-7.40 (1H, m), 3.04 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:34]#[N:35])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C@H:25]3[CH2:30][CH2:29][C@@H:28]([O:31][CH3:32])[CH2:27][CH2:26]3)[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:33])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:34]#[N:35])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C@H:25]3[CH2:30][CH2:29][C@@H:28]([O:31][CH3:32])[CH2:27][CH2:26]3)[C:17]([OH:19])=[O:18])[C:10](=[O:33])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C[C@H]2CC[C@@H](OC)CC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cn(C(C[C@H]2CC[C@@H](OC)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
2.10 g (4.19 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(cis-4-methoxycyclohexyl)propanoate (racemate) in 6 ml of dichloromethane and 6.23 ml (83.8 mmol) of TFA were reacted according to General Method 6A. Yield: 2.10 g (quant.)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1.[CH:16](OCC)=[O:17].Cl>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH:16]=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1
Reactant: CCOC=O
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
Then, 4.19 g of sodium hydride (60% in oil) was suspended in 150 ml of tetrahydrofuran, to which a solution of 19.0 g of ethyl 4-chlorophenylacetate in 150 ml of tetrahydrofuran was added dropwise at 5° to 10° C. After stirring at room temperature for 1.5 hours, 8.42 g of ethyl formate was added, and the mixture was further stirred at room temperature for 4.5 hours. After completion of the reaction, the reaction mixture was cooled to ice temperature, neutralized by the addition of diluted hydrochloric acid, and concentrated. The residue was subjected to phase separation with ethyl acetatewater, and the organic layer was dried and then concentrated. The residue was subjected to silica gel chromatography, which afforded 17.0 g of ethyl 2-(4′-chlorophenyl)-2-formylacetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:20]2[CH:21]=[CH:22][NH:23][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[NH:23][CH:22]=[CH:21][C:20]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2[nH]ccc21
Product: CC1c2cc[nH]c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: [Br:1][C:2]1[C:12]2[C:13]3[C:5]([CH2:6][CH:7]([OH:14])[C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.Cl[Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CN=C1>C1COCC1.C(OCC)C>[Br:1][C:2]1[C:12]2[C:13]3[C:5]([CH2:6][CH:7]([O:14][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC1Cc2ccc(Br)c3cccc1c23
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC1Cc2ccc(Br)c3cccc1c23)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 5-bromo-1,2-dihydro-1-acenaphthylenol (0.25 g, 1 mmol) in dry THF (30 mL) was added chloro(tert-butyl)diphenylsilane (0.275 g, 1 mmol) and imidazole (0.34 g, 5 mmol), and the reaction stirred at room temperature under nitrogen for 18 h. The mixture was diluted with diethyl ether, filtered through a pad of silica, and evaporated in vacuo. Purification by flash chromatography on silica, eluting with ethyl acetate/hexane (1:9 to 1:1), yielded the title compound as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:46][S:47]([CH2:50][CH2:51][CH2:52][CH3:53])(=[O:49])=[O:48])[CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:35]2[CH:34]=[C:33]([NH:46][S:47]([CH2:50][CH2:51][CH2:52][CH3:53])(=[O:48])=[O:49])[CH:32]=[C:31]([O:30][CH3:29])[CH:36]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: CCCCS(=O)(=O)Nc1cc(OC)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCCS(=O)(=O)Nc1cc(OC)cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 79.9 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (120 mg, 0.27 mmol) were added N-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butane-1-sulfonamide (121 mg, 0.33 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (22 mg, 0.03 mmol) and 273 μl of a 2M aqueous solution of cesium carbonate in dioxane (5 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified using SP1® Purification System (0 to 80%, hexane-ethyl acetate) to give 130 mg (79% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:13])[CH2:6][C:7]2=[O:12])[CH3:2].[N+:14]([O-])([OH:16])=[O:15]>CCOCC>[CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:13])[CH:6]([N+:14]([O-:16])=[O:15])[C:7]2=[O:12])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCc1cccc2c1C(=O)CC2=O
Solvent: CCOCC
Product: CCc1cccc2c1C(=O)C([N+](=O)[O-])C2=O

Procedure:
A suspension of 4-ethyl indane-1,3-dione (0.52 g; 0.003 mole) in dry ether (5 ml) was treated dropwise at 10°C with fuming nitric acid (1.0 ml) and the precipitated product filtered after 40 mins. at room temperature; m.p. (water, hydrochloric acid) 98°-100°C; (Found; C, 59.98; H, 4.18; N, 6.34; C11H9NO4 requires: C, 60.28; H, 4.14; N, 6.39%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[C:7]([CH3:15])=[CH:6]1)(=[O:4])=[O:3].[ClH:16].CS(N1C2C(=CC=C(N=[C:31]3[NH:35][CH2:34][CH2:33][NH:32]3)C=2)C=C1)(=O)=O>>[ClH:16].[NH:32]1[CH2:33][CH2:34][NH:35][C:31]1=[N:14][C:11]1[CH:12]=[C:13]2[C:8]([C:7]([CH3:15])=[CH:6][N:5]2[S:2]([CH3:1])(=[O:4])=[O:3])=[CH:9][CH:10]=1
Reactant: CS(=O)(=O)n1ccc2ccc(N=C3NCCN3)cc21
Reactant: Cc1cn(S(C)(=O)=O)c2cc(N)ccc12
Agent: Cl
Product: Cc1cn(S(C)(=O)=O)c2cc(N=C3NCCN3)ccc12

Procedure:
Imidazolidin-2-ylidene-(1-methanesulfonyl-3-methyl-1H-indol-6-yl)-amine hydrochloride (mp 236.4-236.7° C.) was prepared from 1-methanesulfonyl-3-methyl-6-amino-1H-indole by a procedure which was similar to that for the preparation of N-methanesulfonyl-6-(imidazolidin-2-ylideneamino)indole hydrochloride.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:38])[CH2:18][C:19]3[CH:24]=[CH:23][C:22](B4OC(C)(C)C(C)(C)O4)=[C:21]([C:34]([F:37])([F:36])[F:35])[CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl[C:40]1[CH:45]=[CH:44][N:43]=[C:42]([CH3:46])[N:41]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:38])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:40]4[CH:45]=[CH:44][N:43]=[C:42]([CH3:46])[N:41]=4)=[C:21]([C:34]([F:36])([F:35])[F:37])[CH:20]=3)=[N:14][CH:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(B4OC(C)(C)C(C)(C)O4)c(C(F)(F)F)c3)nc2)CC1
Reactant: Cc1nccc(Cl)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(C)n4)c(C(F)(F)F)c3)nc2)CC1
Temperature: 100 °C

Procedure:
A mixture of N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl)acetamide 192-3 (53 mg, 0.1 mmol), 4-chloro-2-methylpyrimidine 192-4 (18 mg, 0.14 mmol) Pd(PPh3)4 (11 mg, 0.01 mmol) and K3PO4 (42 mg, 0.2 mmol) in dioaxane (1.0 mL) was flushed with nitrogen and heated to 100° C. for 2 hours. The salt was removed by filtration and the filtrate was taken to dryness by rotary evaporation. The residue was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(2-methylpyrimidin-4-yl)-3-(trifluoromethyl)phenyl)acetamide 192. MS m/z 499.2 (M+1). 1H NMR 400 MHz (DMSO-d6) δ10.58 (s, 1H), 8.77 (d, 1H), 8.02 (s, 1H), 7.89 (m, 2H), 7.73 (d, 1H), 7.54 (d, 1H), 7.42 (m, 2H), 3.76 (s, 2H), 3.66 (b, 4H), 3.14 (b, 2H), 3.07 (b, 2H), 2.64 (s, 3H), 2.03 (s, 3H).
Reaction SMILES: [H-].[Na+].C(O[C:12]1[CH:19]=[C:18]([CH:20]=[CH:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]=[CH2:29])=[CH:24][CH:23]=2)[C:17]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:16][C:13]=1[CH:14]=O)CCCCCCC.[Br-].[CH2:40]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH2:31]([O:30][C:17]1[C:16]([O:30][CH2:17][CH2:16][CH2:13][CH2:12][CH2:19][CH2:18][CH2:20][CH3:21])=[C:13]([CH:14]=[CH:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:12]=[CH:19][C:18]=1[CH:20]=[CH:21][C:22]1[CH:23]=[CH:24][C:25]([CH:28]=[CH2:29])=[CH:26][CH:27]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: C=Cc1ccc(C=Cc2cc(OCCCCCCCC)c(C=O)cc2OCCCCCCCC)cc1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Product: C=Cc1ccc(C=Cc2ccc(C=Cc3ccccc3)c(OCCCCCCCC)c2OCCCCCCCC)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Solid NaH (300 mg, 12.4 mmol) was added in small portions into a suspension of 2,5-dioctoxy-4-(4′-vinylstyryl)benzaldehyde (1.27 g, 2.59 mmol) and benzyltriphenylphosphonium bromide (1.35 g, 3.11 mmol). The reaction mixture was stirred under nitrogen at room temperature for 24 hours. The reaction was quenched slowly with water, extracted with CH2Cl2, washed with brine, dried over MgSO4 and the solvent was evaporated under reduced pressure. The crude product was purified on a silica gel column (25-40% CHCl3/hexanes) to give a greasy yellow solid which is a mixture of cis and trans isomers. Yield 1.2 g (82%). 1H NMR (CDCl3): δ 7.51 (d, J=9.26 Hz, 2H), 7.47 (d, J=9.25 Hz, 1H), 7.42 (s, 2H), 7.29 (d, J=7.36 Hz, 2H), 7.25 (dd, J1=6.38 Hz, J2=7.36 Hz, 2H), 7.18 (t, J=7.34 Hz, 1H), 7.14 (s, 1H), 6.76 (d, J=11.97 Hz, 1H), 6.72 (dd, J1=17.72 Hz, J2=10.85 Hz, 1H), 6.34 (d, J=12.00 Hz, 1H), 5.78 (d, J=17.72 Hz, 1H), 5.25 (d, J=10.85 Hz, 1H), 4.02 (t, J=6.54 Hz, 2H), 3.55 (t, J=6.87 Hz, 2H), 1.78 (m, 4H), 1.64 (m, 4 H), 1.23-1.42 (m, 16H), 0.90 (m, 6H). 13C NMR (CDCl3): δ 151.34, 150.35, 137.89, 137.79, 136.81, 136.72, 130.24, 129.12, 128.49, 128.36, 127.14, 126.84, 126.73, 126.70, 125.62, 123.74, 114.81, 113.71, 110.37, 69.56, 69.16, 32.06, 29.61, 29.51, 26.33, 22.90, 14.35. FABMS: m/z 564 (M+).
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]([CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.Cl>CO>[CH2:24]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1)=[O:10])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N(Cc2ccccc2)Cc2ccccc2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(C1CCNCC1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 6 h
Yield: 97.3 %

Procedure:
To a stirred solution of tert-butyl 4-[(dibenzylamino)carbonyl]piperidine-1-carboxylate (EXAMPLE 4, Step 1, 4.0 g, 10.0 mmol) in methanol (550 mL) was added 4N HCl dioxane solution (80 mL, 320 mmol) at 0° C. The mixture was stirred for 6 h and evaporated. The resulting amorphous was dissolved in aqueous ammonia and the mixture was extracted with dichloromethane. The combined extract was dried over magnesium sulfate, and concentrated to afford 3.0 g (99%) of the title compound as a colorless amorphous powder.
Reaction SMILES: [CH2:1]([C:11]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl-:37].[Ca+2].[Cl-].Cl>C(Cl)Cl>[CH2:1]([C:11]([Cl:37])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCCCCCC(O)(CCCCCCCCCC)CCCCCCCCCC
Reactant: [Cl-]
Agent: Cl
Agent: [Ca+2]
Solvent: ClCCl
Product: CCCCCCCCCCCCCCC(Cl)(CCCCCCCCCC)CCCCCCCCCC

Procedure:
One mole of di-n-decyl-n-tetradecylcarbinol is added to 0.2 liters of methylene chloride and 0.32 moles calcium chloride. Approximately 1.5 moles of HCl gas is slowly bubbled through the solution. The product mixture is then washed with 1 liter of a 10% sodium carbonate solution. The organic layer is dried with magnesium sulfate and the methylene chloride is evaporated off to give di-n-decyl-n-tetradecyl-methylchloride.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Cl[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][N:3]=1
Reactant: ClC1CCCC1
Reactant: Oc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncc(OC2CCCC2)cn1
Temperature: 65 °C
Yield: 54.6 %

Procedure:
A mixture of 2-chloropyrimidin-5-ol (1 g, 7.66 mmol), chlorocyclopentane (2.39 mL, 22.98 mmol) and potassium carbonate (3.18 g, 22.98 mmol) in N,N-dimethylformamide were heated at 65° C. for 16 h at ambient temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (0-25% ethyl acetate/hexanes) to afford 2-chloro-5-(cyclopentyloxy)pyrimidine (831 mg, 4.18 mmol, 54.6% yield) as a white solid. MS (LC/MS) R.T.=2.32; [M+H]+=199.23.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:39][N:40]1[CH2:45][CH2:44][CH2:43][C:42]([CH2:55][OH:56])([O:46][C:47]2[CH:52]=[C:51]([F:53])[CH:50]=[CH:49][C:48]=2[F:54])[CH2:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:54][C:48]1[CH:49]=[CH:50][C:51]([F:53])=[CH:52][C:47]=1[O:46][C:42]1([CH2:55][OH:56])[CH2:43][CH2:44][CH2:45][N:40]([NH:39][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:18])[CH2:41]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Reactant: NN1CCCC(CO)(Oc2cc(F)ccc2F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NN4CCCC(CO)(Oc5cc(F)ccc5F)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.3 mmol, 150 mg), (1-amino-3-(2,5-difluorophenoxy)piperidin-3-yl)methanol (0.28 mmol, 81 mg), HATU (0.3 mmol, 115 mg) and DIEA in DMA was stirred at room temperature for overnight. The product, N-(3-(2,5-difluorophenoxy)-3-(hydroxymethyl)piperidin-1-yl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, was obtained after rotary evaporation of solvent.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:24][C:25]2[CH:33]=[CH:32][C:28]3[NH:29][CH:30]=[N:31][C:27]=3[CH:26]=2)[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([NH:22][CH3:23])[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:34].C(Cl)(=O)C.[O:39]1[CH2:44][CH2:43]OCC1>C(N(CC)CC)C>[NH2:1][C:2]1[C:3]([Cl:34])=[CH:4][C:5]([S:9]([NH:12][CH:13]([CH2:24][C:25]2[CH:33]=[CH:32][C:28]3[NH:29][CH:30]=[N:31][C:27]=3[CH:26]=2)[C:14]([N:16]2[CH2:17][CH2:18][CH:19]([N:22]([CH3:23])[C:44](=[O:39])[CH3:43])[CH2:20][CH2:21]2)=[O:15])(=[O:10])=[O:11])=[CH:6][C:7]=1[Cl:8]
Reactant: C1COCCO1
Reactant: CNC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N(C)C1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1

Procedure:
Prepared from 4-amino-N-[1-(1H-benzimidazol-5-yl-methyl)-2-(4-methylamino-piperidin-1-yl)-2-oxo-ethyl]-3,5-dichloro-benzenesulphonamide and acetylchloride in dioxane and triethylamine analogously to Example 2.