Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4](C(Cl)=O)=[CH:3][CH:2]=1.C(O)CCCCCCCCC[OH:28].C(N(CC)CC)C>O1CCCC1>[C:1]1(=[O:28])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: O=C(Cl)c1cccc2c1-c1ccccc1C2=O
Reactant: OCCCCCCCCCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1C=CC=C2C1=Cc1ccccc12
Reaction time: 0.5 h

Procedure:
A 4.85 g quantity of 9-fluorenone-4-carbonyl chloride (0.02 mole, obtained from Aldrich Chemicals Co, Milwaukee, Wis. 53201, USA) and 100 ml of tetrahydrofuran (obtained from Aldrich) were added to a 250 ml, 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The solution was stirred for about ½ hour, and then 1.74 g of 1,10-decanediol (0.01 mole, obtained from Aldrich) in 50 ml of tetrahydrofuran were added, followed by the addition of 2 g of triethylamine (0.02 mole, obtained from Aldrich). The solution was refluxed for 6 hours and filtered hot to remove triethylamine hydrochloride salt by-product, and the filtrate was evaporated to dryness. A liquid product was obtained, which solidified upon standing at room temperature for a couple of hours. The crude product was recrystallized from ethyl acetate with activated charcoal. The product was dried at 60° C. in a vacuum oven for 6 hours to yield a second dimeric fluorenone derivative, which was a yellow solid (2.5 g, 43% yield). The product had a melting point of 101–102° C. A 1H-NMR spectrum (300 MHz) in CDCl3 yielded chemical shifts (ppm) as follows: 1.15–1.61 (m, 12H); 1.71–1.92 (q, 4H); 4.34–4.47 (t, 4H); 7.32–7.37 (m, 4H); 7.50 (td, 2H); 7.70 (d, 2H); 7.82 (dd, 2H); 7.93 (dd, 2H); 8.28 (d, 2H).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:11][CH:12](OCC)OCC.[OH-].[Na+]>C1COCC1.O>[C:2]1([C:1]2[S:8][CH:11]=[CH:12][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccccc1
Reactant: CCOC(CBr)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(-c2nccs2)cc1
Temperature: 25 °C
Yield: 34 %

Procedure:
To a solution of thiobenzamide (1 g, 7.3 mmol) in THF (10 ml) was added a solution of 2-bromo-1,1-diethoxy-ethane (1.4 g, 7.3 mmol) in THF (5 ml) and the reaction was heated at reflux overnight. The reaction mixture was cooled to room temperature and diluted with water (50 ml). The solution was basified with dilute sodium hydroxide and extracted with ethyl acetate: pet ether (1:4). The organic layer was then washed with water, brine and dried. Evaporation gave a residue which was purified by column chromatography over silica gel using EtOAc/pet ether as eluent to give 2-phenyl thiazole (400 mg, 34%) as solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[F:18][C:14]1[C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=2)=[O:11])[CH:17]=[CH:16][CH:15]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-c2ncccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-c2ncccn2)[C@@H]1CNc1ncc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 441 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([OH:18])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].[CH3:19][C:20]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([N:23]3[CH2:24][CH2:25][C:20]([CH3:19])([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:22]3)=[O:18])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CC1(c2ccccc2)CCNCC1
Reactant: CCOC(=O)c1cnn2c(O)c(C(=O)O)cnc12
Product: CCOC(=O)c1cnn2c(O)c(C(=O)N3CCC(C)(c4ccccc4)CC3)cnc12
Yield: 68.6 %

Procedure:
In the same manner as in Example 1, step 2 and using 3-ethoxycarbonyl-7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylic acid (583 mg, 2.32 mmol) obtained in Example 19, step 2 and 4-methyl-4-phenylpiperidine (Journal of Medicinal Chemistry, vol. 41, page 5320, 590 mg, 2.79 mmol), the title compound (650 mg, 69%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[Cl-].[Al+3].[Cl-].[Cl-].C[Si]([C:24]#[N:25])(C)C>C1C=CC=CC=1>[C:24]([CH2:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]=[CH:8]2)#[N:25]
Reactant: COc1ccc2c(c1OC)CCCC2=O
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: COc1ccc2c(c1OCC#N)CCC=C2
Temperature: 70 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
5,6-dimethoxytetralone (20 g) was dissolved in benzene (20 ml) and trimethylsilyl cyanide (16 ml). A catalytic amount of aluminum chloride was added and the reaction heated at 70° C. under nitrogen for 30 minutes. The volatiles were removed in vacuo and methanol (20 ml) added. Gaseous hydrochloric acid was bubbled through the methanol solution for 30 minutes resulting in precipitation of a solid. Stirring was continued for 1 hour, then the mixture was filtered and dried affording 19.9 g. of product (96% yield); m.p. 138°-9° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([SH:11])[CH:3]=1.S(=O)(=O)(O)O.[CH3:17]O>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([SH:11])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(F)cc1S
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(F)cc1S
Yield: 70 %

Procedure:
A mixture of 4-fluoro-2-sulfanylbenzoic acid (6.0 g, 34.9 mmol), concentrated sulfuric acid (6 mL) in methanol (200 mL) was refluxed for 18 hours under argon atmosphere. The resulting mixture was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with water, basified with a saturated aqueous solution of sodium bicarbonate to about pH 8. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 4.54 g of the crude product as a brown oil (yield was 70%), which was used directly for the next step without further purification. MS obsd. (ESI−) [(M−H)−] 185.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:23])=[CH:4][C:5]2[O:9][C:8]([CH:10]=[CH:11][C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=3)=[N:7][C:6]=2[CH:22]=1.C(O)(=O)C.S(=O)(=O)(O)O>O>[CH3:1][C:2]1[C:3]([CH3:23])=[CH:4][C:5]2[O:9][C:8]([CH:10]=[CH:11][C:12]3[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=3)=[N:7][C:6]=2[CH:22]=1
Reactant: COC(=O)c1ccc(C=Cc2nc3cc(C)c(C)cc3o2)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2nc(C=Cc3ccc(C(=O)O)cc3)oc2cc1C
Yield: 89.8 %

Procedure:
A mixture of 3.0 g methyl 4-[(5,6-dimethyl-2-benzoxazolyl)vinyl]benzoate, 25 mL of acetic acid, 9.0 mL of concentrated sulfuric acid, and 7 mL of water is stirred and refluxed for three hours. The mixture is cooled and added to water. The product is collected by filtration, washed with water and air dried. The crude product is recrystallized from N,N-dimethylformamide to give 2.57 g of 4-[2-(5,6-dimethyl-2-benzoxazolyl)vinyl]benzoic acid, which melts at >300° C.
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([C:5]([OH:7])=[O:6])[NH2:4].[CH2:8]([O:15][C:16](Cl)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>>[CH2:8]([O:15][C:16]([NH:4][C@H:3]([C:5]([OH:7])=[O:6])[CH2:2][Cl:1])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N[C@@H](CCl)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@@H](CCl)C(=O)O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
To 86.19 g of an aqueous solution containing 7.47 g of β-chloroalanine was added 11.35 g of benzyloxycarbonyl chloride (1.1 moles per mole of β-chloroalanine) dropwise over 1 hour under constant stirring at about 5° C., with the reaction system being maintained at pH 9.7 with a 30% aqueous solution of sodium hydroxide. The reaction was further continued for 3 hours, at the end of which time the reaction mixture was washed with 50 ml of toluene. This washed reaction mixture, 89.53 g, contained 15.52 g (yield 100%) of N-benzyloxycarbonyl-β-chloroalanine.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[C:4]#[N:5].[S:11](Cl)(=[O:14])(=[O:13])[NH2:12]>>[C:4]([C:3]1[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:2]=1[NH:1][S:11]([NH2:12])(=[O:14])=[O:13])#[N:5]
Reactant: NS(=O)(=O)Cl
Reactant: Cc1ccc(N)c(C#N)c1
Product: Cc1ccc(NS(N)(=O)=O)c(C#N)c1

Procedure:
Prepared as in Example 77a from 2-amino-5-methylbenzonitrile (Example 14b) and sulfamoyl chloride.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][CH:15]=O)[C:6](=[O:17])[CH2:5]1)(=[O:3])[CH3:2].[C:18]([O:22][C:23](=[O:42])[N:24]([CH2:31][C:32]1[CH:41]=[CH:40][C:35]2[O:36][CH2:37][CH2:38][O:39][C:34]=2[CH:33]=1)[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:18]([O:22][C:23](=[O:42])[N:24]([CH2:31][C:32]1[CH:41]=[CH:40][C:35]2[O:36][CH2:37][CH2:38][O:39][C:34]=2[CH:33]=1)[CH:25]1[CH2:30][CH2:29][N:28]([CH2:15][CH2:14][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:4]([C:1](=[O:3])[CH3:2])[CH2:5][C:6]2=[O:17])[CH2:27][CH2:26]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: CC(=O)N1CC(=O)N(CC=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)N1CC(=O)N(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To 15 mL of a chloroform solution containing 337 mg of (4-acetyl-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl)acetaldehyde and 504 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 83 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 477 mg of sodium triacetoxyborohydride was added, and stirred for 1.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=20:1] to give 691 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-acetyl-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:28](Cl)(=[O:30])[CH3:29]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:28](=[O:30])[CH3:29])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(C)=O

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:53])[NH:10][CH2:11][C:12]1([C:15]([NH:17][C@@H:18]([CH2:41][C:42]2[CH:47]=[CH:46]C(OC(C)(C)C)=[CH:44][CH:43]=2)[C:19]([N:21]([CH2:33][CH:34](OCC)OCC)[CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)=[O:20])=[O:16])[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:54]([OH:56])=O.O>>[CH2:1]([NH:8][C:9]([N:10]1[CH2:11][C:12]2([CH2:14][CH2:13]2)[C:15](=[O:16])[N:17]2[CH:18]([CH2:41][C:42]3[CH:43]=[CH:44][C:54]([OH:56])=[CH:46][CH:47]=3)[C:19](=[O:20])[N:21]([CH2:22][C:23]3[C:32]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:26]=[CH:25][CH:24]=3)[CH2:33][CH:34]12)=[O:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)C1(CNC(=O)NCc2ccccc2)CC1)OCC
Reactant: O=CO
Solvent: O
Product: O=C1C(Cc2ccc(O)cc2)N2C(=O)C3(CC3)CN(C(=O)NCc3ccccc3)C2CN1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
To (S)-1-((3-benzylureido)methyl)-N-(3-(4-tert-butoxyphenyl)-1-((2,2-diethoxyethyl)(naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)cyclopropanecarboxamide (Compound II-1) (188 mg, 0.26 mmol) was added 10%-HCOOH/water (2.0 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol=100:0 to 90:10) to obtain the title compound (47 mg, 29%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[O:12]=[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=2)[CH:16]=[CH:15][NH:14]1>>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][N:14]2[CH:15]=[CH:16][C:17]3[C:22](=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=3)[C:13]2=[O:12])=[CH:6][CH:7]=1
Reactant: Clc1ccc(CCCBr)cc1
Reactant: COC(=O)c1ccc2cc[nH]c(=O)c2c1
Product: COC(=O)c1ccc2ccn(CCCc3ccc(Cl)cc3)c(=O)c2c1

Procedure:
The title compound was prepared from 1-(3-bromopropyl)-4-chlorobenzene (0.35 g, 1.48 mmol) and methyl 1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.20 g, 0.98 mmol) following the procedure outlined in Example 3, step 1 (0.16 g, 44%). LC-MS: (FA) ES+ 356.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[NH:10][N:9]=1.Br[CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1.O>CN(C=O)C>[CH3:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH2:20][CH2:21][O:22][C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=2)[N:9]=1
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: Cc1n[nH]c(=O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(CCOc2ccc(C=O)cc2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
##STR30## To a stirred suspension of K2CO3 (11.3 g, 82.5 mmol) in dry DMF (50 mL) at 25-30° C. was added a solution of 4-methyl-1(2H)-phthalazinone (6.6 g, 41.25 mmol) (Ref: Chemistry of Heterocyclic Compounds; Condensed Pyridazines including Cinnolines and Phthalazines, edited by R. N. Castle; John Wiley and Sons, 27, (1973) 375-441) in dry DMF (100 mL). The reaction mixture was stirred for 30 min at 25° C. and 4-(2-bromoethoxy)benzaldehyde (9.4 g, 41.25 mmol) was added. The reaction mixture was immersed in a pre-heated oil bath at 70° C. and stirred at 65-70° C. for 24 h. The reaction mixture was cooled to room temperature and water (50 mL) was added. The reaction mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude compound was recrystallised from methanol to obtain the title compound (9.7 g, 77%). mp: 90° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])=[CH:11][CH:12]=2)[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH3:24])[CH2:6][C:5]1([CH3:32])[CH3:31])(=[O:3])[CH3:2].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:11][CH:12]=2)[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH3:24])[CH2:6][C:5]1([CH3:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N1c2ccc(NC(=O)c3ccccc3O)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc(NC(=O)c3ccccc3OS(C)(=O)=O)cc2C(C)(c2ccccc2)CC1(C)C
Reaction time: 16 h

Procedure:
Sulfonylation of 1-acetyl-6-(2-hydroxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (12 mg) with methylsulfonyl chloride (6.5 μl) was performed in pyridine (1 ml). TLC analysis after stirring for 16 h showed conversion to a higher-running product. The mixture was concentrated, the residue was dissolved in dichloromethane and washed with water. The organic layer was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel column chromatography. Eluent: heptane/ethyl acetate=8/2 (v/v).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)=O>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[N:20]=2)=[CH:6][CH:7]=1
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2cc(-c3ccc(F)cc3)nc2-c2ccc(Cl)cc2)cc1
Yield: 36.3 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (400 mg, 1.29 mmol) and sodium bicarbonate (216 mg, 2.59 mmol) in isopropanol (25 mL), 2-chloro-4'-fluoroacetophenone (670 mg, 3.87 mmol) was added. After heating the reaction mixture at 80°-85° C. for 48 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (800 mg) was chromatographed (silica gel, hexane/ethyl acetate, 1/1) to give 2-(4-chlorophenyl) -4-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (200 mg, 36%) as a pale yellow solid: mp (DSC) 180° C. Anal. Calc'd. for C22H16N2SO2FCl: C, 61.90, H, 3.78, N, 6.56, S, 7.51. Found: C, 61.92, H, 3.74, N, 6.43, S, 7.62.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH2:19]S(C(F)(F)F)(=O)=O)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH:30]([C:32]1[CH:37]=[N:36][CH:35]=[CH:34][N:33]=1)=C>>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH:19]=[CH:30][C:32]3[CH:37]=[N:36][CH:35]=[CH:34][N:33]=3)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1cnccn1
Reactant: CC(C)(Cc1c[nH]c2c(CS(=O)(=O)C(F)(F)F)cccc12)NC(=O)OC(C)(C)C
Product: CC(C)(Cc1c[nH]c2c(C=Cc3cnccn3)cccc12)NC(=O)OC(C)(C)C

Procedure:
{1,1-Dimethyl-2-[7-(2-pyrazin-2-yl-vinyl)-1H-indol-3-yl]-ethyl}-carbamic acid tert-butyl ester is prepared from [1,1-dimethyl-2-(7-trifluoromethanesulfonylmethyl-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester and 2-vinylpyrazine as described for the preparation of Amine 23 (99%). FDMS m/e=393.2 (M++1)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1>>[B:8]([C:5]1[CH:4]=[N:3][C:2]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]2)=[N:7][CH:6]=1)([OH:10])[OH:9]
Reactant: O=C(O)[C@H]1CCCNC1
Reactant: OB(O)c1cnc(Cl)nc1
Product: O=C(O)[C@H]1CCCN(c2ncc(B(O)O)cn2)C1

Procedure:
The title compound was synthesised from (2-chloropyrimidin-5-yl)boronic acid and (3S)-piperidine-3-carboxylic acid in accordance with General Method C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:14][C:15]([F:18])([F:17])[F:16])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].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.[NH2:58][CH2:59][C:60]1[C:61](=[O:68])[NH:62][C:63]([CH3:67])=[CH:64][C:65]=1[CH3:66]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[CH2:14][C:15]([F:16])([F:17])[F:18])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([NH:58][CH2:59][C:60]1[C:61](=[O:68])[NH:62][C:63]([CH3:67])=[CH:64][C:65]=1[CH3:66])=[O:8]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: COC(=O)c1cc(Br)cc(N(CC(F)(F)F)C2CCOCC2)c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(CC(F)(F)F)C3CCOCC3)c2C)c(=O)[nH]1
Reaction time: 0.08 h
Yield: 74.5 %

Procedure:
A stirred solution of methyl 5-bromo-2-methyl-3-[(oxan-4-yl)(2,2,2-trifluoroethyl)amino]benzoate (250 mg, 0.63 mmol) in dry DMF (3.0 ml) at 0° C. under a balloon of nitrogen, was treated with HATU (288 mg, 0.76 mmol) and DIPEA (220 μl, 1.3 mmol) dropwise. The resulting solution was stirred for 5 minutes and then treated with 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 119 mg, 0.69 mmol). The resulting suspension was stirred at 0° C. for 20 minutes and then stirred at room temperature for 16.5 hours. The reaction mixture was treated with 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (30 mg). Stirring was continued for further 23 hours and the reaction mixture was then partitioned between water (30 ml) and CH2Cl2 (20 ml). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×20 ml). The combined organics were washed with a saturated solution of NaHCO3 (aq) (50 ml), water (60 ml), brine (2×40 ml), dried over MgSO4, filtered and concentrated in-vacuo. The crude residue was purified by flash column chromatography (10 g SNAP cartridge, Isolera, 0-10% MeOH/CH2Cl2) and triturated from ether (10 ml) with sonication. The resulting precipitate was collected by filtration and dried in-vacuo to give the title compound (249 mg, 74%) as a white solid. LC-MS100%, 4.08 min (7 minute LC-MS method), m/z=530.0, 531.0, 532.0, 533.0; 1H NMR (500 MHz, Acetone) δ 10.67 (s, 1H), 7.55 (d, J=1.8 Hz, 2H), 7.27 (d, J=1.9 Hz, 1H), 5.90 (s, 1H), 4.40 (d, J=5.5 Hz, 2H), 3.90 (dd, J=11.2, 4.6 Hz, 4H), 3.28 (t, J=11.6 Hz, 2H), 3.07-2.97 (m, 1H), 2.32 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H), 1.76 (dd, J=12.3, 1.6 Hz, 2H), 1.61 (qd, J=12.0, 4.5 Hz, 2H).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([N:12]1[C:16]2[CH:17]=[C:18]([F:22])[C:19]([F:21])=[CH:20][C:15]=2[N:14]=[C:13]1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)C.O.[OH-].[Li+]>O1CCOCC1.O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:13]2[N:12]([CH:5]([CH:6]3[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]3)[C:4]([OH:30])=[O:3])[C:16]3[CH:17]=[C:18]([F:22])[C:19]([F:21])=[CH:20][C:15]=3[N:14]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To the solution of 24 g (0.055 mol) [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid ethyl ester in 240 ml dioxan, 240 ml water and 7.0 g (0.166 mol) lithium hydroxide monohydrate were added. The solution was stirred for 2 h at 100° C. After cooling to room temperature the organic solvent was evaporated. Under stirring 162 ml 1M hydrochloric acid were added. The resulting suspension was filtered, the filter cake washed with water and dried under high vacuum to give 21.7 g (95%) of the desired compound as a white solid.