Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C@H:10]([C:24]2[NH:28][C:27]3[CH:29]=[CH:30][C:31]([C:33]#[CH:34])=[CH:32][C:26]=3[N:25]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]1[C:51]1[NH:55][C:54]2[CH:56]=[CH:57][C:58](I)=[CH:59][C:53]=2[N:52]=1)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C.CCOC(C)=O.O.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C@H:10]([C:24]2[NH:28][C:27]3[CH:29]=[CH:30][C:31]([C:33]#[C:34][C:57]4[CH:58]=[CH:59][C:53]5[NH:52][C:51]([C@@H:46]6[CH2:47][CH2:48][CH2:49][CH2:50][N:45]6[C:43]([O:42][CH2:35][C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)=[O:44])=[N:55][C:54]=5[CH:56]=4)=[CH:32][C:26]=3[N:25]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc2[nH]c([C@@H]3CN(C(=O)OC(C)(C)C)CCN3C(=O)OCc3ccccc3)nc2c1
Reactant: O=C(OCc1ccccc1)N1CCCC[C@H]1c1nc2cc(I)ccc2[nH]1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)[C@H](c2nc3cc(C#Cc4ccc5[nH]c([C@@H]6CCCCN6C(=O)OCc6ccccc6)nc5c4)ccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7893.4 %

Procedure:
To a stirring solution of (S)-2-(5-ethynyl-1H-benzoimidazol-2-yl)-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester (77 mg, 0.16 mmol), (S)-2-(5-iodo-1H-benzoimidazol-2-yl)-piperidine-1-carboxylic acid benzyl ester (70 mg, 0.15 mmol), CuI (3 mg, 0.015 mmol) and bis(triphenylphosphine)palladium (II) dichloride (10.6 mg, 0.015 mmol) in DMF (2 mL) is added TEA (0.1 mL, 0.76 mmol). The reaction mixture is stirred at room temperature for 2 hours, diluted with EtOAc and water. The mixture is filtered to remove insoluble material and the layers of the filtrate are separated. The organic layer is dried over sodium sulfate and concentrated in vacuum to dryness. The residue is purified by flash column chromatography on silica gel (MeOH/DCM 0% to 20%) and repurified by reverse phase HPLC using a gradient of CH3CN/water to give the title compound (9.4 g, 7%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[CH:8]=2)[N:3]=1.[NH:24]1[CH2:34][CH2:33][CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:25]1.CN1CCCC1=O>O>[CH2:31]([O:30][C:28]([CH:27]1[CH2:33][CH2:34][N:24]([C:2]2[CH:11]=[C:10]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[CH:8]=3)[N:3]=2)[CH2:25][CH2:26]1)=[O:29])[CH3:32]
Reactant: Clc1ccc2nc(Cl)cc(NCc3ccc4c(c3)OCO4)c2c1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)C1CCN(c2cc(NCc3ccc4c(c3)OCO4)c3cc(Cl)ccc3n2)CC1
Reaction time: 3 h

Procedure:
A reaction of a mixture comprising 130 mg of 2,6-dichloro-4-(3,4-methylenedioxybenzyl)aminoquinoline, 500 μl of ethyl isonipecotate and 1 ml of N-methyl-2-pyrrolidone was conducted on an oil bath at 150° C. for 3 hours. The reaction mixture was cooled, followed by the addition of water. The resulting mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography with 20 to 50% ethyl acetate/hexane to give 150 mg of the title compound.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=1)#[N:2].[NH2:15]N>>[NH:8]1[CH:3]=[CH:1][N:2]=[N:15]1.[N:8]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: N#Cc1cccc(-c2ccccn2)n1
Reactant: NN
Product: c1c[nH]nn1
Product: c1ccc(-c2ccccn2)nc1

Procedure:
enabling the 6-cyano-bipyridine derivative to react with hydrazine and a carboxylic acid derivative for cyclization, thus obtaining a bipyridine triazole type compound; and
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[N:4]([CH2:12][CH2:13][CH2:14][CH2:15][P:16](=[O:23])([O:20]CC)[O:17]CC)[C:3]1=[O:24].Cl>>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[N:4]([CH2:12][CH2:13][CH2:14][CH2:15][P:16](=[O:17])([O-:20])[O-:23])[C:3]1=[O:24].[NH4+:2].[NH4+:2]
Reactant: CCOP(=O)(CCCCn1c(=O)c2[nH]cnc2n(C)c1=O)OCC
Agent: Cl
Product: Cn1c(=O)n(CCCCP(=O)([O-])[O-])c(=O)c2[nH]cnc21
Product: [NH4+]

Procedure:
5.2 g (0.0125 mol) of diethyl [4-(3-methylxanthin-1-yl)butyl]phosphonate were heated under reflux with 30 ml of 20% strength hydrochloric acid for 4 hours. The hydrochloric acid was evaporated and the oily residue was dried over potassium hydroxide in a desiccator. The phosphonic acid formed was then treated with a methanolic ammonia solution, the solvent was evaporated and the residue was crystallized from a methanol/diisopropyl ether mixture.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:12]1([N+:18]#[C-:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>Cl(O)(=O)(=O)=O>[CH:12]1([NH:18][C:19]2[N:3]3[C:4]4[C:9]([CH:10]=[CH:11][C:2]3=[N:1][C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1ccc2ccccc2n1
Reactant: [C-]#[N+]C1CCCCC1
Reactant: O=Cc1ccccc1
Agent: [O-][Cl+3]([O-])([O-])O
Product: c1ccc(-c2nc3ccc4ccccc4n3c2NC2CCCCC2)cc1

Procedure:
Compound (15) was prepared according to the general synthesis instructions from 1.0 ml of 2-aminoquinoline solution (0.1 M, DCM), 0.575 ml of cyclohexyl isocyanide solution (0.2 M, DCM), 0.500 ml of benzaldehyde solution (0.3 M, DCM), and 10 μl of perchloric acid (w=20%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][N:4]=[C:5]([NH2:27])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH2:26])=S)[N:11]=1.C(N(CC)CC)C>CN(C)C=O.[N+]([O-])([O-])=O.[Ag+]>[F:1][C:2]([F:29])([F:28])[CH2:3][N:4]=[C:5]([NH2:27])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]2[NH:26][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=2)[N:11]=1
Reactant: NC(=NCC(F)(F)F)Nc1nc(CCCCNC(=S)Nc2ccccc2N)cs1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=NCC(F)(F)F)Nc1nc(CCCCNc2nc3ccccc3[nH]2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(3-[2-aminophenyl]thioureido)butyl]thiazole (0.45 g.), silver nitrate (0.34 g.) and triethylamine (0.28 ml.) in dimethylformamide (3 ml.) was stirred vigorously at ambient temperature overnight. Hydrogen sulphide gas was then bubbled through the reaction mixture until no more solid precipitated. The reaction mixture was filtered through a pad of diatomaceous earth and the filtrate evaporated to dryness in vacuo. The residue was purified by low pressure liquid chromatography using chloroform/methanol/ammonia, 9:1:0.1 v/v/v as eluant to give 2-[4-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)butylamino]benzimidazole which was converted to the hydrogen maleate salt (0.25 g.), m.p. 183°-186°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([F:30])[CH:21]=2)([NH:13]C(=O)C(C)(C)C)[CH2:9][C:10]([OH:12])=O)=[N:6][CH:7]=1.Cl.[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CO.C(#N)C.CO.O>[NH2:13][C@:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)([C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:23]=[C:22]([F:30])[CH:21]=1)[CH2:9][C:10]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:12]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)C(=O)N[C@@](CC(=O)O)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: O
Solvent: CC#N
Product: N[C@@](CC(=O)Nc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
(S)-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-3-pivalamidopropanoic acid (0.10 g, 0.21 mmol) was dissolved in MeOH (2 mL) and 4M HCl in dioxanes added (2 mL). The resulting solution was stirred at RT for 30 mins then the solvents were removed under reduced pressure yielding a pale yellow oil (crude quantative) LCMS: 1.31 min [M+1] 363.2 (2 min gradient, MeOH/H2O 0.1% TFA). The residue was dissolved in acetonitrile (5 mL) and TEA, (0.3 mL, excess), aniline (0.030 g, 0.32 mmol) and PyBrOP (0.11 g, 0.24 mmol) added at RT. The RM was stirred for 14 h, concentrated to 1.5 mL, filtered and purified by prep HPLC: YMC ODSA30×100 mm, 40ml/min, 20-100% MeOH (0.1% TFA) over 10 min. The product (S)-3-amino-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-N-phenylpropanamide with a retention time of 7.52 min was isolated as a pale yellow oil, (0.054 g, 58% yield). LCMS: 1.48 min [M+1] 438.2 (2 min gradient, MeOH/H2O 0.1% TFA).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=O)[C:13]([CH3:15])=C)C(C(O)=O)C2.[C:20](SCC(C)C(N1C2C(=CC(Cl)=CC=2)CC1C(O)=O)=O)(=O)[C:21]1C=CC=C[CH:22]=1>>[CH:12]1([NH:8][CH:9]2[CH2:10][CH2:11][CH2:3][CH2:4][CH2:5]2)[CH2:13][CH2:15][CH2:22][CH2:21][CH2:20]1
Reactant: C=C(C)C(=O)N1c2ccc(OC)cc2CC1C(=O)O
Reactant: CC(CSC(=O)c1ccccc1)C(=O)N1c2ccc(Cl)cc2CC1C(=O)O
Product: C1CCC(NC2CCCCC2)CC1

Procedure:
By substituting 5-chloro-2,3-dihydro-1-(2-methyl-1-oxo-2-propenyl)-1H-indole-2-carboxylic acid from Example 34 for 2,3-dihydro-5-methoxy-1-(2-methyl-1-oxo-2-propenyl)-1H-indole-2-carboxylic acid in the procedure of Example 25, 1-[3-(benzoylthio)-2-methyl-1-oxopropyl]-5-chloro-2,3-dihydro-1H-indole-2-carboxylic acid, dicyclohexylamine was obtained. The latter salt was then treated with 5% aqueous potassium hydrogen sulfate as in Example 15 to give the titled compound.
Reaction SMILES: [Br:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[O:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>C(Cl)Cl>[Br:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17]([CH3:18])=[O:32])[O:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CSc1nc2ccc(Cn3cnc4cc(Br)c(Cl)cc43)cc2o1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)c(Cl)cc43)cc2o1
Yield: 66.7 %

Procedure:
A solution of 6-((5-bromo-6-chloro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazole (554 mg, 1.80 mmol) and m-CPBA (403 mg, 2.34 mmol) in DCM (18 mL) was stirred at 0° C. for 3 h. The reaction mixture was washed with aqueous Na2S2O3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:5 petroleum ether/ethyl acetate to give 6-((5-bromo-6-chloro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (510 mg, 87.5%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.08 (s, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.50 (d, J=9.3 Hz, 1H), 5.69 (s, 2H), 3.18 (s, 3H). LCMS (ESI) m/z 424 (M+H)+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[OH:22][C:23]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[OH-].[K+]>O.C(O)C>[OH:22][C:23]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:28][CH2:27][N:26]([CH2:3][C:4]2[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=2)[O:7][CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:25][CH2:24]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OC1(c2ccccc2)CCN(Cc2cccc(OCc3ccc4ccccc4n3)c2)CC1
Yield: 47.1 %

Procedure:
A mixture of 3.2 g (0.01 mol) 2-(3-chloromethyl-phenoxymethyl)quinoline hydrochloride, 1.7 g (0.01 mol) 4-hydroxy-4-phenylpiperidine and 1.2 g (0.02 mol) KOH in 5 ml of H2O and 50 ml ethanol was heated over steam bath for a period of 3 hours. Reaction mixture was concentrated to dryness and slurried into water, and extracted with methylene chloride. The methylene chloride extract dried over MgSO4 and concentrated to dryness under reduced pressure to obtain solid. Repeated recrystallization from isopropanol and acetronitrite gave desired product 2 g, m.p. 123°-225° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[CH3:11]OC(OC)OC.[NH2:18][C:19]1[CH:20]=[C:21]([O:25][CH3:26])[CH:22]=[N:23][CH:24]=1>CCCCCC>[CH3:26][O:25][C:21]1[CH:20]=[C:19]([NH:18][CH:11]=[C:6]2[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:5])[CH:24]=[N:23][CH:22]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COC(OC)OC
Reactant: COc1cncc(N)c1
Solvent: CCCCCC
Product: COc1cncc(NC=C2C(=O)OC(C)(C)OC2=O)c1
Temperature: 102.5 °C
Reaction time: 4 h

Procedure:
A two-necked round bottomed flask equipped with a reflux condenser was charged with Meldrum's acid (14.4 g, 100 mmol) and trimethylorthoformate (100 mL). The reaction mixture was heated at 100-105° C. for 2 h. 5-amino-3-methoxy pyridine (12.5 g, 100 mmol) was added to the reaction mixture and heating was continued for an additional 4 h at the same temperature. The reaction mixture was allowed to cool to RT, diluted with hexane and filtered to obtain the product as light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1.Br[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[N:21][CH:22]=1>>[CH3:23][C:20]1[N:21]=[CH:22][C:17]([CH2:16][O:1][C:2]2[CH:7]=[N:6][N:5]([CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][O:9]3)[C:4](=[O:14])[CH:3]=2)=[CH:18][CH:19]=1
Reactant: O=c1cc(O)cnn1C1CCCCO1
Reactant: Cc1ccc(CBr)cn1
Product: Cc1ccc(COc2cnn(C3CCCCO3)c(=O)c2)cn1
Yield: 43.6 %

Procedure:
5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (2.62 g, 13.4 mmol) and 5-(bromomethyl)-2-methylpyridine (7.47 g, 40.2 mmol) were reacted following the procedure for Example 17 (step a) to provide the title compound (1.76 g, 43%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.47 (s, 1H), 7.67 (d, J=6.2 Hz, 1H), 7.62-7.59 (dd, J=7.9, 2.3 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 6.19 (d, J=2.8 Hz, 1H), 6.03-5.99 (dd, J=10.5, 2.0 Hz, 1H), 4.97 (s, 2H), 4.15-4.08 (m, 1H), 3.78-3.69 (td, J=11.6, 2.6 Hz, 1H), 2.59 (s, 3H), 2.16-2.00 (m, 2H), 1.74-1.54 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[C:37]([NH:36][S:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=1)(=[O:35])=[O:34])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(C)NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1)(355 mg, 1.0 mmol) and 3-Bromo-N-tert-butyl-benzenesulfonamide (example B.9) (321 mg, 1.1 mmol) according to general procedure II. Obtained as a light-brown solid (110 mg, 20%). MS (ISP) 567.2 [(M+H)+]; mp 192-200° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:12]([CH3:25])=[N:13][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)[C:15]=3[CH3:16])=[CH:9][N:8]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.[CH2:36]([O:43][CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][C:50](B2OC(C)(C)C(C)(C)O2)=[CH:49][C:48]=1[NH:62][S:63]([CH3:66])(=[O:65])=[O:64])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[CH2:36]([O:43][CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[C:12]([CH3:25])=[N:13][N:14]([CH2:17][C:18]5[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=5)[C:15]=4[CH3:16])=[CH:9][N:8]([S:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=4)(=[O:27])=[O:28])[C:5]3=[N:6][CH:7]=2)=[CH:49][C:48]=1[NH:62][S:63]([CH3:66])(=[O:64])=[O:65])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC1(C)OB(c2ccc(OCCOCc3ccccc3)c(NS(C)(=O)=O)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(Br)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(OCCOCc5ccccc5)c(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 55.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of step-i of example-14) (150 mg, 0.271 mmol) was coupled with N-(2-(2-(benzyloxy)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (intermediate 28) (242 mg, 0.542 mmol) in sodium carbonate (86 mg, 0.813 mmol) Pd(PPh3)2Cl2 (10 mg, 0.0135 mmol), Toluene/ethanol/water (5/2.5/1 ml) to afford 120 mg (55.8% yield) of the titled compound after purification by column (SiO2-eluted by 30% EA in hexanes). MS: m/z=794.1 (M+1).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:11][C:12]1[N:17]=[CH:16][C:15]2[CH:18]=[C:19]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[NH:20][C:14]=2[CH:13]=1.Br[CH2:28][CH:29]1[CH2:31][CH2:30]1>CN(C=O)C.O.CCOC(C)=O>[Br:11][C:12]1[N:17]=[CH:16][C:15]2[CH:18]=[C:19]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[N:20]([CH2:28][CH:29]3[CH2:31][CH2:30]3)[C:14]=2[CH:13]=1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Reactant: BrCC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc3cnc(Br)cc3n2CC2CC2)cn1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
NaHMDS (173 mL, 0.173 mmol) was added to a solution of 6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 40 mg, 0.144 mmol) in DMF (630 mL). The reaction mixture was stirred for 15 minutes at 60° C. before the addition of (bromomethyl)cyclopropane (21 mL, 0.217 mmol). The reaction was then stirred for 24 hours at 60° C. before being diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude was purified via Biotage silica gel column chromatography eluting with DCM/EtOAc (99/1 to 80/20) to afford a colourless oil as the title compound. (29 mg, 61%). 1H NMR (500 MHz, CDCl3) d 0.21-0.24 (m, 2H), 0.52-0.56 (m, 2H), 1.08-1.15 (m, 1H), 4.02 (s, 3H), 4.06 (d, J=6.3 Hz, 2H), 6.54 (d, J=0.9 Hz, 1H), 7.45 (t, J=0.9 Hz, 1H), 7.61 (d, J=0.8 Hz, 1H), 7.70 (d, J=0.8 Hz, 1H), 8.60 (d, J=0.9 Hz, 1H). LC (Method B)-MS (ESI, m/z) tR 2.64 min, 331 [(M+H+), 100%].
Reaction SMILES: [NH2:1][C@H:2]1[C@:12]2([CH3:14])[O:13][C@@:4]3([C@H:15]4[C@H:8]([N:9]([C:17]5[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=5)[C:10](=[O:16])[C@@H:11]24)[O:7][CH2:6][CH2:5]3)[CH2:3]1.[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30].[CH3:41][OH:42].C[O-].[Na+]>C1COCC1>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([N:9]2[C@H:8]3[C@H:15]4[C@H:11]([C@@:12]5([CH3:14])[O:13][C@:4]4([CH2:5][CH2:6][O:7]3)[CH2:3][C@H:2]5[NH:1][C:29](=[O:30])[O:42][CH3:41])[C:10]2=[O:16])=[CH:18][C:19]=1[C:25]([F:26])([F:27])[F:28])#[N:22]
Reactant: CO
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@@]12O[C@]3(CCO[C@@H]4[C@H]3[C@H]1C(=O)N4c1ccc(C#N)c(C(F)(F)F)c1)C[C@H]2N
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N[C@@H]1C[C@]23CCO[C@@H]4[C@H]2[C@@H](C(=O)N4c2ccc(C#N)c(C(F)(F)F)c2)[C@@]1(C)O3
Reaction time: 0.5 h

Procedure:
Example 13 (1.18 g, 3.0 mmol) in THF (10 mL) was added drop wise over 10 min to a solution of carbonyldiimidazole (1.5 g, 9.25 mmol) in THF (10 mL). The mixture was stirred for 30 min. Next, MeOH (20 mL) was added followed by the addition of NaOMe (0.162 g, 3 mmol). The reaction mixture was stirred for 5 min and then concentrated in vacuo. To the residue was added EtOAc and washed twice with 1M HCl and once with sat. NaHCO3 aq. The organic layer was dried over MgSO4, filtered, and then concentrated in vacuo. The residue was purified by silica gel chromatography on a 120 g ISCO column eluting with a gradient from 100% CH2Cl2 up to 6% MeOH/CH2Cl2. The product was collected, concentrated in vacuo, and dried to give 1.2 g of Example 14.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:17]=[CH:18][C:19](Cl)=[O:20]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:17]=[CH:18][C:19]([NH:11][C:5]1[C:6](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:7]([OH:9])=[O:8])=[O:20]
Reactant: COc1ccc(C=CC(=O)Cl)cc1OC
Reactant: Nc1ccc(Cl)cc1C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C=CC(=O)Nc2ccc(Cl)cc2C(=O)O)cc1OC
Yield: 43.2 %

Procedure:
In a mixture of 30 ml of chloroform and 3 ml of triethylamine is dissolved 3.4 g of 5-chloroanthranilic acid. To this solution is added a solution of 4.5 g of 3,4-dimethoxycinnamoylchloride in chloroform, and the mixture is heated under reflux for 2 hours. The reaction mixture is concentrated under a reduced pressure, and to the residue is added water and hydrochloric acid then added to make the mixture weakly acidic. The precipitated crystals are collected by filtration and recrystallized from ethanol to obtain 3.1 g of N-(3,4-dimethoxycinnamoyl)-5-chloroanthranilic acid as pale yellow needles.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[C:7]([CH3:13])[C:6]=1[CH3:14])(=[O:3])[CH3:2].[CH3:15][C:16]([CH2:18][CH2:19][CH2:20][CH:21]([CH3:33])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[CH2:17].C=O.[CH2:36](NCCCC)CCC.C(O)(=O)C>>[CH3:36][C:9]1[C:10]([CH3:11])=[C:5]([O:4][C:1]([CH3:2])=[O:3])[C:6]([CH3:14])=[C:7]2[CH2:13][CH2:17][C@:16]([CH2:18][CH2:19][CH2:20][C@@H:21]([CH2:22][CH2:23][CH2:24][C@@H:25]([CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:32])[CH3:33])([CH3:15])[O:12][C:8]=12
Reactant: CCCCNCCCC
Reactant: C=C(C)CCCC(C)CCCC(C)CCCC(C)C
Reactant: CC(=O)Oc1c(C)cc(O)c(C)c1C
Agent: C=O
Solvent: CC(=O)O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Temperature: 170 °C
Reaction time: 4 h

Procedure:
A pressure-proof reaction vessel equipped with a stirrer was charged with 7.0 g (0.036 mole) of 4-acetoxy-2,3,5-trimethylphenol, 50.0 g (0.18 mole) of 2,6,10,14-tetramethyl-1-pentadecene, 1.4 g (0.045 mole) of 80% paraformaldehyde, 0.5 g (0.0036 mole) of dibutylamine and 1.1 g (0.018 mole) of acetic acid, and the mixture was reacted, with stirring, at 170° C. for 4 hours.