Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:8][CH:9]=1
Reactant: Cc1ccc(C(=O)C(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)c1ccc(CBr)cc1

Procedure:
To a suspension of 28.5 g. (1.17 g. atoms) magnesium turnings in 150 ml. tetrahydrofuran under a nitrogen atmosphere there is added 10 ml. of 4-bromo toluene (1.17 mole) in 650 ml. dry tetrahydrofuran; the reaction is started and the remainder of the bromo toluene solution is added dropwise at a rate that maintains a moderate reflux. After the addition is complete, the mixture is refluxed for an additional 11/2 hours. The resulting Grignard solution is added dropwise to a cold solution of 128.0 g. pivaloyl chloride (1.06 mole) in 500 ml. dry tetrahydrofuran at a rate that maintains the temperature at 0° to -5° C. The solution is stirred for an additional 11/2 hours at 0° C. and then at room temperature for 18 hours. The mixture is then cooled to 0° C. and hydrolyzed by the addition of 100 ml. 2N hydrochloric acid. The layers are separated and 200 ml. of ether is added to the organic phases which is then washed respectively with 100 ml. 2N hydrochloric acid, 100 ml. 10% sodium bicarbonate solution, and 100 ml. saturated sodium chloride. The resulting layer is dried over anhydrous sodium sulfate, filtered, and the solvent is removed in vacuo to give p-pivaloyl toluene (b.p. 80° to 84° C./0.7 mm, nC21 1.5108). A mixture of 156.3 g. (0.886 mole) of the resulting p-pivaloyl toluene is then added to 157.8 g. (0.886 mole) N-bromosuccinimide, 4.0 g. (0.016 mole) benzoyl peroxide and 150 ml. carbon tetrachloride and heated at reflux for 18 hours. The mixture is cooled and filtered and the resulting oil is distilled in vacuo to give α-bromo-p-pivaloyl toluene (b.p. 124°-132° C/0.7 mm, nD22 1.5546-V.P.C. 96% monobromo 4%-dibromo).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH2:32][CH:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:32][CH:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: CN1CCC(N)CC1
Product: CN1CCC(NC(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)cc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-amino-1-methylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z=543.96 (M+H+); retention time=0.51 minutes.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[C:8]2[C:20]3[N:19]4[CH:21]=[CH:22][N:23]=[C:18]4[C:17](=[O:24])[NH:16][C:15]=3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)=[CH:5][N:4]=[CH:3]1.Cl.[H][H]>[Pd].O>[CH3:1][N:2]1[C:6]([CH2:7][CH:8]2[C:20]3[N:19]4[CH:21]=[CH:22][N:23]=[C:18]4[C:17](=[O:24])[NH:16][C:15]=3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)=[CH:5][N:4]=[CH:3]1
Reactant: Cn1cncc1C=c1c2ccccc2c2[nH]c(=O)c3nccn3c12
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Product: Cn1cncc1CC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Yield: 65.2 %

Procedure:
A mixture of 3.2 g of 10-[(1-methylimidazol-5-yl)methylene]-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one, 60 ml of 1N hydrochloric acid and 30 ml of water is hydrogenated, at a temperature in the region of 20° C. and at a pressure of 1.7 bar of hydrogen, for 6 hours in the presence of 10% palladium-on-charcoal. The catalyst is removed by filtration under an inert atmosphere and the filtrate is brought to pH=6 with concentrated sodium hydroxide. The white precipitate formed is filtered off, washed with distilled water and dried at 35° C. under vacuum (1 mmHg; 0.13 kPa). 2.1 g of 10-[(1-methylimidazol-5-yl)methyl]-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are obtained in the form of a white solid melting above 260° C. (Analysis, % calculated C: 68.13, H: 4.76, N: 22.07, O: 5.04, % found C: 67.8, H: 4.9, N: 22.5).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[N:3]=1.[CH2:24]([NH2:28])[CH:25]([CH3:27])[CH3:26]>C1COCC1.CCOC(C)=O>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:4]1[N:3]=[C:2]([NH:28][CH2:24][CH:25]([CH3:27])[CH3:26])[C:7]([C:8]#[N:9])=[CH:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1Cl
Reactant: CC(C)CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)CNc1nc(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the product of Step C EXAMPLE 26 (300 mg) in THF (3.3 mL) was added isobutylamine (0.83 mL). The reaction stirred at room temperature overnight at which point LC/MS indicated incomplete reaction. The temperature was elevated to 50° C. for 6 hours at which point the reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution. The solution was concentrated and purified via flash chromatography on silica gel with a gradient elution of 0% to 15% EtOAc in hexane affording the title compound. HPLC/MS: 396.1 (M+1), 398.1 (M+3); Rt=4.77 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5]
Reactant: Oc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccccc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
Part A: To a cooled (ice bath) solution of 2,4-dichlorobenzoyl chloride (5 mL, 35.66 mmol) in 50 mL CH2Cl2 was added phenol (3.13 mL, 35.66 mmol), followed by triethylamine (4.97 mL, 35.66 mmol). The resulting reaction mixture was stirred at room temperature for 5 h. The mixture was then partitioned between CH2Cl2 and water. The organic layer was dried (Na2SO4), filtered, and evaporated in vacuo to yield 9.5 g of phenyl 2,4-dichlorobenzoate. MS (NH3-CI) 284 (M+NH4)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH2:8][CH:9](O)[CH2:10][S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:22][N:21]=2)[CH2:16][CH2:15]1)(=[O:13])=[O:12].CS(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[F:30][C:28]([F:29])([F:31])[CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([N:17]2[CH2:16][CH2:15][N:14]([S:11](/[CH:10]=[CH:9]/[CH2:8][CH2:7][C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)(=[O:13])=[O:12])[CH2:19][CH2:18]2)=[N:21][CH:22]=1
Reactant: O=S(=O)(CC(O)CCc1ncccn1)N1CCN(c2ccc(OCC(F)(F)F)cn2)CC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(/C=C/CCc1ncccn1)N1CCN(c2ccc(OCC(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
To a stirred solution of the 4-pyrimidin-2-yl-1-({4-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]piperazin-1-yl}sulfonyl)butan-2-ol (13.7 g, 28.8 mmol) in DCM (250 mL) at 0° C. was added methanesulfonyl chloride (2.68 mL, 34.6 mmol). The reaction was stirred at 0° C. for 20 minutes before dropwise addition of triethylamine (18.1 mL, 129 mmol). Warmed to room temperature and stirred for 16 hours. The reaction mixture was then diluted with DCM (1 L), washed with water (150 mL) and dried (brine, MgSO4), filtered and concentrated in vacuo. The residue was then purified by flash chromatography (silica, 0-5% MeOH in DCM) to give 2-[(3E)-4-({4-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]piperazin-1-yl}sulfonyl)but-3-en-1-yl]pyrimidine as a yellow solid (11.9 g, 18.6 mmol, 90%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([OH:11])[CH2:8][C@H:7]1[C:12](=[O:19])[NH:13][C:14]1([C:17]#[N:18])[CH2:16][CH2:15]1)=[O:5])[CH3:2].[S:20]([O-])(=[O:23])(=[O:22])[CH3:21]>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][S:20]([CH3:21])(=[O:23])=[O:22])[CH2:8][C@H:7]1[C:12](=[O:19])[NH:13][C:14]1([C:17]#[N:18])[CH2:16][CH2:15]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(O)C[C@H]1C(=O)NC1(C#N)CC1
Reactant: CS(=O)(=O)[O-]
Product: CCOC(=O)[C@@H]1CC(OS(C)(=O)=O)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
The mixture of (1R,2R,4R) and (1R,2R,4S)-2-(1-cyano-cyclopropylcarbamoyl)-4-hydroxy-cyclopentanecarboxylic acid ethyl ester from step 2 was converted to the corresponding mesylate according to the procedure from example 1, step 4 to give (1R,2R)-2-(1-cyano-cyclopropylcarbamoyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester as a 2:1 mixture of epimers as a colorless solid. MS: 345.0 (M+H)+.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].C1COCC1.[NH2:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=1.[O-]S([O-])(=O)=O.[Na+].[Na+]>CCOC(C)=O>[CH3:29][N:24]1[C:23]([C:21]([NH:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3](=[CH:2][NH:36][C:37]4[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=4)[C:4](=[O:30])[NH:5]3)=[CH:10][CH:9]=2)=[O:13])=[O:22])=[CH:27][C:26]([CH3:28])=[N:25]1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(C(=O)O)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2 mL). To the resulting solution was added 4-Amino-benzoic acid (37.5 mg, 0.274 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. The yellow solid was dissolved into a solution of 98% EtOAc/2% i-prOH (3 mL) and washed with water (3×2 mL). The organic layers were combined and dried over anhydrous Na2SO4 affording 47.8% (0.062 g, 0.119 mmol) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:8]=2[C:26]([O:28]C(C)(C)C)=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(Cl)(Cl)C(O)=O.O>C(Cl)Cl>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)(=[O:18])=[O:17])[C:8]=2[C:26]([OH:28])=[O:27])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(C(=O)OC(C)(C)C)c(-c3ccccc3)c3ccccc32)cc1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(C(=O)O)c(-c3ccccc3)c3ccccc32)cc1
Reaction time: 16 h
Yield: 94.2 %

Procedure:
To a stirred solution of 2.55 g of compound J in 10 cc of methylene chloride was added 2.20 g of trichloroacetic acid under ice-cooling and the mixture was stirred for 16 hours. Water was added to the reaction mixture, the desired compound was extracted with ethyl acetate. The extract was dried over magnesium sulfate and distilled to remove the solvent. The crude product thus obtained was purified by a silica gel column chromatography (eluent: ethyl acetate/hexane=3/7) to obtain 2.10 g of 3-phenyl-1-(p-toluenesulfonyl)indole-2-carboxylic acid. Yield: 94.1%.
Reaction SMILES: [C:1]1([O:7][CH2:8][CH2:9][CH2:10]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC(N)=[S:14].[OH-].[K+].Cl>C(O)C.CO>[O:7]([CH2:8][CH2:9][CH2:10][SH:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(N)=S
Reactant: BrCCCOc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: SCCCOc1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
160 g of 3-bromopropyl phenyl ether and 63 g of thiourea were dissolved in 300 ml of ethanol and the solution was refluxed with heating for 3 hours. A methanol solution containing 194 g of potassium hydroxide was added to the reaction solution and the mixture was stirred at 50° C. for 2 hours. The mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate followed by distillation under reduced pressure to obtain 76.5 g of 3-phenoxypropanethiol. A boiling point was 135° to 138° C. at 17 mm Hg.
Reaction SMILES: CS(O[CH:6]([CH:18]1[CH2:20][CH2:19]1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=O)=O.C([O-])(C)(C)C.[K+].O>CN(C)C=O>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:8]1[CH2:7][CH:6]1[CH:18]1[CH2:20][CH2:19]1)([O-:17])=[O:16]
Reactant: CS(=O)(=O)OC(CCc1ccccc1[N+](=O)[O-])C1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1C1CC1C1CC1
Reaction time: 1 h
Yield: 84.9 %

Procedure:
1.18 g of 1-cyclopropyl-3-(2-nitrophenyl)-propyl methanesulfonate (3.94 mmol) is dissolved in 40 ml of dimethylformamide, 0.91 g of potassium tert-butanolate (97%, 7.88 mmol) are added and stirring is carried out for 1 hour at ambient temperature under a nitrogen atmosphere. Water is added to the reaction mixture. Extraction is carried out with ethyl acetate, and the organic phase is dried over sodium sulfate and concentrated by evaporation. Chromatography on silica gel is carried out in order to remove by-products (eluant: ethyl acetate/hexane 1:2). After removal of the eluant, 0.68 g of 2-(2-nitrophenyl)-bicyclopropane (85% of theory) is obtained in the form of an orange-coloured liquid (trans:cis ratio: 6.5:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([CH:7]=O)=[C:5]([OH:13])[CH:4]=1.[OH-].[K+].[CH3:16][O:17][C:18](=[O:25])[CH2:19][CH2:20][C:21](=[O:24])[CH2:22]Br>C(O)C.O>[CH3:16][O:17][C:18](=[O:25])[CH2:19][CH2:20][C:21]([C:22]1[O:13][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[CH:9][C:6]=2[CH:7]=1)=[O:24]
Reactant: COc1cc(O)c(C=O)cc1OC
Reactant: COC(=O)CCC(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(=O)CCC(=O)c1cc2cc(OC)c(OC)cc2o1
Reaction time: 0.33 h
Yield: 32.1 %

Procedure:
To a stirred suspension of 4,5-dimethoxy-2-hydroxy-benzaldehyde (9.3 g) in dry ethanol (90 ml) under nitrogen was added slowly a solution of potassium hydroxide (3.14 g) in dry ethanol (60 ml). The resulting solution was stirred for 20 minutes, then 5-bromo-4-oxo-pentanoic acid methyl ester (10.65 g) was added slowly. The mixture was stirred for 24 hours, then diluted slowly with water (900 ml). The precipitated solid was filtered off, washed with water, dried under vacuum and crystallized from acetone-ether to give 4-(5,6-dimethoxy-benzo[b]furan-2-yl)-4-oxo-butanoic acid methyl ester (4.78 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].C(N(CC)CC)C.[NH2:18][CH2:19][C:20]1[CH:36]=[CH:35][C:23]([C:24]([N:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH3:27])=[O:25])=[CH:22][C:21]=1[CH3:37]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:18][CH2:19][C:20]1[CH:36]=[CH:35][C:23]([C:24]([N:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH3:27])=[O:25])=[CH:22][C:21]=1[CH3:37])=[O:6]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Cc1cc(C(=O)N(C)c2ccc(Cl)cc2)ccc1CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)N(C)c2ccc(Cl)cc2)ccc1CNC(=O)c1cccc(Cl)c1
Reaction time: 1 h
Yield: 69 %

Procedure:
3-Chlorobenzoyl chloride (61 mg, 0.35 mmol) and triethyl-amine (to pH9) were added to a solution of 4-aminomethyl-N-(4-chloro-phenyl)-3,N-dimethyl-benzamide from Example E115.2 (100 mg, 0.35 mmol) in dichloro-methane (5 ml) at room temperature. The mixture was stirred for 1 h then concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as the title compound (101 mg, 69%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]([OH:17])=O)=[N:8][C:7]=3[C:6]=2[CH:18]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C.[CH:33]([NH:36][CH2:37][CH2:38][OH:39])([CH3:35])[CH3:34]>>[OH:39][CH2:38][CH2:37][N:36]([CH:33]([CH3:35])[CH3:34])[C:15]([C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:18][C:6]=3[C:7]=2[N:8]=1)=[O:17]
Reactant: O=C(O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: CC(C)NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reaction time: 2 h
Yield: 67.4 %

Procedure:
9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2.4 g, 7.4 mmol) was dissolved in N,N-Dimethylformamide (DMF, 50 mL, 600 mmol). Added N,N,N′N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uranium Hexafluorophosphate (3.1 g, 8.1 mmol) and N,N-Diisopropylethylamine (6.4 mL, 37 mmol) and let stir for 10 minutes. Added 2-(isopropylamino)ethanol (1.5 g, 15 mmol) and let the reaction stir for 2 hours. More N,N,N′N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uranium Hexafluorophosphate was added to the reaction (2.8 g, 7.4 mmol) and let the reaction stir for another 3 hours. Reaction was complete by LCMS. Concentrated in vacuo and flash purified on the ISCO 0 to 50% ethyl acetate in hexanes two times to give 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide (2.05 g, 68% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([CH:25]([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][C:22]([CH:25]([F:27])[F:26])=[CH:23][CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: NCC(CC1CC1)c1ccc(C(F)F)nc1
Reactant: O=C(O)c1c(Cl)cccc1Cl
Product: O=C(NCC(CC1CC1)c1ccc(C(F)F)nc1)c1c(Cl)cccc1Cl

Procedure:
From 2,6-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine. LCMS (MH+): m/z=399.1, tR (minutes, Method F)=3.06
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH:12]=O)[CH2:3][CH2:2]1.[C:14]([NH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)(=[O:16])[CH3:15].CC(O)=O>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH2:12][N:21]2[CH2:22][CH2:23][CH:18]([NH:17][C:14](=[O:16])[CH3:15])[CH2:19][CH2:20]2)[CH2:3][CH2:2]1
Reactant: CC(=O)NC1CCNCC1
Reactant: O=CCC1CCOc2ccccc21
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)NC1CCN(CCC2CCOc3ccccc32)CC1
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a stirred solution of 2-(3,4-dihydro-2H-1-benzopyran-4-yl]ethanal (2.50 g, 14.28 mmol) and 4-acetamidopiperidine AcOH (2.88 g, 14.28 mmol) (preparation described in U.S. Pat. No. 5,028,616) in ethanol (80 ml) under a nitrogen atmosphere, borane/pyridine complex (1.5 ml, 15 mmol) was added. The reaction mixture was stirred overnight (ca 15 h) and evaporated to an oily gum which was neutralized by careful addition of 10% hydrochloric acid. The acidic solution was extracted with diethyl ether and the diethyl ether extracts were discarded. The acidic aqueous layer was basified by dropwise addition of a 50% sodium hydroxide solution. The basic solution (>pH 12) was extracted with ethyl acetate. The ethyl acetate layer was washed with distilled water, dried (Na2SO4), filtered and evaporated to afford an oily gum (3.56 g). The resulting gum was purified by chromatography on silica (eluant: chloroform/ethanol/ammonium hydroxide; 85/14/1) to afford an oil (2.56 g) which was crystallized from diethyl ether to afford the title compound (2.40 g, 56%) mp=126-8°. Anal: C18H26N2O2Calc.: C 71.49; H 8.67; N 9.26; Found C 71.46; H 8.84; N 9.26.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:7]([CH2:11][C:12]3[CH:13]=[C:14]([C:18]4[CH:22]=[C:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:20][C:19]=4[S:27]([NH:30]C(C)(C)C)(=[O:29])=[O:28])[CH:15]=[CH:16][CH:17]=3)[CH:8]=[CH:9][N:10]=2)=[CH:2]1.B(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].Cl[C:46]([O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:47]>C(Cl)Cl.O>[CH2:49]([O:48][C:46]([NH:30][S:27]([C:19]1[S:20][C:21]([CH2:23][CH:24]([CH3:25])[CH3:26])=[CH:22][C:18]=1[C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH:13]=1)(=[O:29])=[O:28])=[O:47])[CH2:50][CH2:51][CH3:52]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)Cc1cc(-c2cccc(Cn3ccnc3-c3ccsc3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2ccnc2-c2ccsc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of 3-[3-(2-thiophen-3-yl-imidazol-1-ylmethyl)-phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (38.2 mg, 0.0744 mmol; see step (a)) in CH2Cl2 (1 mL) was added BCl3 (0.2 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in CH2Cl2 (5 mL) was added Na2CO3 (35.5 mg, 0.335 mmol), water (2 mL) and butyl chloroformate (11.4 μL, 0.0893 mmol) and the reaction mixture was stirred for 5 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 (30 mL) and washed with citric acid (10% aq), brine and water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (5:95) as eluent to give the title compound as a white solid in 67% yield, over two steps, (28 mg, 0.050 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:25]1([NH:31][C:32](=[O:49])[CH2:33][C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[C:25]1([NH:31][C:32](=[O:49])[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:10]3[C:3]4[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=4[N:8]([CH:12]4[CH2:17][CH2:16][CH:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[CH2:14][CH2:13]4)[CH:9]=3)=[CH:36][CH:35]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC1(C)OB(c2ccc(CC(=O)Nc3ccccc3)cc2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3cc(I)c4c(Cl)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN(C2CCC(n3cc(-c4ccc(CC(=O)Nc5ccccc5)cc4)c4c(Cl)ncnc43)CC2)CC1
Temperature: 85 °C
Yield: 62.5 %

Procedure:
A mixture of cis-4-chloro-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 2.18 mmol), N1-phenyl -2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide (0.81 g, 2.40 mmol), tetrakis(triphenyl-phosphine)palladium (70 mg, 0.131 mmol) and sodium carbonate monohydrate (0.65 g, 2.40 mmol) in ethylene glycol dimethyl ether (16 mL) and water (8 mL) was heated at 85° C. under an atmosphere of nitrogen for 18 hours. The mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica using dichloromethane/methanol (9:1) as an eluent to give N1-phenyl-2-(4-{4-chloro-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine-5-yl}phenyl)acetamide (0.74 g, 62%): 1H NMR (DMSO-d6, 400 MHz) 10.20(s, 1H), 8.66(s, 1H), 7.81(s, 1H), 7.62(d, 2H), 7.52(d, 2H), 7.41(d, 2H), 7.31(t, 2H), 7.04(t, 1H), 4.83(m, 1H), 3.70(s, 2H)<2.05-2.5(m, 13H), 2.17(s, 3H), 1.59-1.77(m, 4H); RP-HPLC (Hypersil HS C18, 5 m, 100 A, 250×4.6 mm; 25%-100% acetontrile over 10 min, 1 mL/min) tr 8.23 min.; MS:MH+ 543.2.