Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C:12]1([PH:20]([NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:17][CH2:16][CH2:15][N:14]([NH2:18])[C:13]1=[O:19])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C:12]1([PH:20]([NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:17][CH2:16][CH2:15][N:14]([NH2:18])[C:13]1=[O:19]
Reactant: NN1CCCC(NC(=O)OCc2ccccc2)([PH](=O)NC(=O)c2ccccc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: NN1CCCC(N)([PH](=O)NC(=O)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Palladium black (12.1 mg) was added to a solution of (3S, P (RS))-3-benzyloxycarbonylamino-1-amino(benzoylamino)phosphinyl-2-piperidone (60.5 mg, 0.14 mmol) in ethanol (10 mL), and the resulting mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([CH2:20][C:21](=[O:31])[NH:22][C@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[CH2:16][C:17](O)=[O:18])=[CH:11][CH:10]=1.ClC(OCC(C)C)=O>O1CCCC1>[C:25]1([C@@H:23]([NH:22][C:21](=[O:31])[CH2:20][C@H:15]([C:12]2[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=2)[CH2:16][CH2:17][OH:18])[CH3:24])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C[C@H](NC(=O)C[C@@H](CC(=O)O)c1ccc(F)cc1)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)C[C@@H](CCO)c1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
3 mL of triethylamine was added to a solution of 5 g of compound 7a in 200 mL of tetrahydrofuran at room temperature. The solution was stirred for 60 min at room temperature and then was moved to a −78° C. dry ice acetone bath. To this solution was added dropwise 2.6 mL of iso-butyl chloroformate. The suspension was stirred from −78° C. to room temperature overnight. The mixture was filtered through a celite and silica gel pad, and washed with small amount tetrahydrofuran. To this solution in an ice bath was added 2.0 g of sodium borohydride, followed by dropwise addition of 10 mL of water. Carbon dioxide gas evolved violently. The reaction mixture was stirred for 2-4 hr, and was filtered through a celite pad. After the solvent evaporated, the aqueous layer was extracted several times with ethyl acetate. The organic layer was combined, washed with brine, dried over magnesium sulfate, and concentrated. The solid was recrystallized from ethyl acetate and hexanes to form the title compound as a colorless solid (80% yield, 95% de): mp 170.0-170.5° C.; [α]25D=−86.4 (c 1.0, CH3OH); 1H NMR (200 MHz, CDCl3) δ 7.40-7.10 (m, 7 H), 6.98 (t, J=8.7Hz, 2 H), 5.51 (br d, J=7.7 Hz, 1 H), 5.00 (quint, J=7.4 Hz, 1 H), 3.60-3.50 (m, 2 H), 3.33 (m, 1 H), 2.55 (dd, J=6.6, 14.2 Hz, 1 H), 2.38 (dd, J=8.6, 14.2 Hz, 1 H), 1.95-1.75 (m, 2 H), 1.27 (d, J=6.9 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 170.6, 161.6, 142.9, 139.6, 128.9, 128.6, 127.4, 126.1, 115.4, 60.1, 48.6, 44.0, 38.9, 38.4, 21.3. Anal. Calcd for C19H22FNO2: C, 72.36; H, 7.03; N, 4.44. Found: C, 72.35; H, 6.83; N, 4.33.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.[Cl:16][C:17]1[C:22]([CH3:23])=[C:21]([CH:24]([F:26])[CH3:25])[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C.Cl.C(OCC)C>CN1CCCC1=O.C(OCC)(=O)C>[ClH:16].[F:26][CH:24]([C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:12][CH2:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[NH:13][C:6]3=[N:7][CH:8]=2)[C:22]=1[CH3:23])[CH3:25]
Reactant: Cc1c(Cl)ncnc1C(C)F
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1c(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncnc1C(C)F
Temperature: 100 °C
Yield: 12.7 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 100 mg, 0.465 mmol), 4-chloro-6-(1-fluoroethyl)-5-methylpyrimidine (Intermediate 45, 153 mg, 0.874 mmol) and DIPEA (0.162 mL, 0.929 mmol) were added together in N-methyl-2-pyrrolidone (NMP) (3 mL) and the resulting mixture was heated at 100° C. for 2 hours and allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4, 25+M) eluting with a gradient of 0-100% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure. The residue (26 mg) was dissolved in methanol (2 mL), treated with 1M HCl in diethyl ether (0.1 mL, 0.100 mmol) and the resulting mixture was evaporated under reduced pressure. The resulting solid was dried under high vacuum at 40° C. for 18 hours to give the title compound as a white solid (23 mg);
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:16][CH:15]3[C:13]([CH2:17][O:18][C:19]4[C:20]([C:25]([O:27]CC)=[O:26])=[N:21][CH:22]=[CH:23][CH:24]=4)([CH2:14]3)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1.COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(OCC)=O)=NC=1>>[F:31][C:2]([F:1])([F:30])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:16][CH:15]3[C:13]([CH2:17][O:18][C:19]4[C:20]([C:25]([OH:27])=[O:26])=[N:21][CH:22]=[CH:23][CH:24]=4)([CH2:14]3)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1
Reactant: CCOC(=O)c1ncccc1OCC12CC1CN(C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1)C2
Agent: CCOC(=O)c1ncc(OC)cc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Product: O=C(O)c1ncccc1OCC12CC1CN(C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1)C2

Procedure:
The title compound was prepared according to the procedure described in Step 4 of EXAMPLE 31 using ethyl 3-((3-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)methoxy)picolinate (EXAMPLE 88 Step 3) in stead of ethyl 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CN(C)C(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: C1CNCCN1
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(N2CCNCC2)cc1Cl
Temperature: 85 °C

Procedure:
A mixture of 7.0 mmol 2-chloro-4-fluorobenzonitrile (commercial), 10.5 mmol piperazine in 4 ml N,N-dimethylacetamide was heated for 1 h at 85° C. After cooling to RT and evaporation in vacuo, the mixture was diluted with dichloromethane and purified on silica, eluting with a gradient of dichloromethane/MeOH to yield after evaporation the title compound. MS (m/e): 222.1 (MH+, 100%)
Reaction SMILES: [C:1]([C:4]1[C:5]([N:16]([CH3:18])[CH3:17])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Cl>C(O)(C)C>[C:1]([C:4]1[C:5]([N:16]([CH3:18])[CH3:17])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[Cl:19])[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: ClCc1ccccc1Cl
Reactant: CC(=O)c1c(C)[nH]c(-c2ccccc2)c1N(C)C
Solvent: CC(C)O
Product: CC(=O)c1c(N(C)C)c(-c2ccccc2)n(Cc2ccccc2Cl)c1C
Yield: 67 %

Procedure:
The title compound is prepared in a 67% yield by starting from the compound of Example 43 and o-chlorobenzyl chloride, using procedure (a) of Example 49; m.p. 103°-105° C. (from isopropanol).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH:10]([OH:28])[CH2:11][N:12]2[CH2:19][CH:18]3[CH2:20][CH:14]([CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17]3)[CH2:13]2)=[CH:6][CH:5]=1)#[N:3]>CCOC(C)=O>[CH:14]12[CH2:20][CH:18]([CH2:17][NH:16][CH2:15]1)[CH2:19][N:12]([CH2:11][CH:10]([OH:28])[CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:30][CH:29]=1)[CH2:13]2
Reactant: CC(C)(C)OC(=O)N1CC2CC(CN(CC(O)COc3ccc(C#N)cc3)C2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(OCC(O)CN2CC3CNCC(C3)C2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
HCl-saturated EtOAc (600 mL) was added to a solution of tert-butyl 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (62 g; see Example 2 below) in EtOAc (600 mL) and the mixture was stirred at rt. for 4 h. The solvent was removed under reduced pressure, the residue was dissolved in MeCN (1.3 L) and K2CO3 (100 g) was added. The suspension was stirred for 12 h and filtered. Concentration of the filtrate gave the title compound in a 90% yield.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]1[C@H:8]([OH:9])[C@H:7]([C@H:10]([OH:13])[CH:11]=[CH2:12])[O:6][C:5]1=[O:14])[CH3:2].C([CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=C>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.C(Cl)Cl>[CH:17]1(/[CH:12]=[CH:11]/[C@H:10]([C@@H:7]2[O:6][C:5](=[O:14])[C@H:4]([O:3][CH2:1][CH3:2])[C@@H:8]2[OH:9])[OH:13])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C=CC1CCCC1
Reactant: C=C[C@@H](O)[C@@H]1OC(=O)[C@H](OCC)[C@@H]1O
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: CCO[C@H]1C(=O)O[C@@H]([C@H](O)/C=C/C2CCCC2)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 12.7 %

Procedure:
550 mg of 51 (2.47 mmol), 0.987 g of vinylcyclopentane (10.26 mmol), 18 mL of CH2Cl2 and 63 mg of 2nd generation Grubb's catalyst (C46H65Cl2N2PRu, MW 848.98, 0.030 mmol) are added to a 50 mL round-bottomed flask. The medium is stirred for 24 h at RT and then the insoluble material is filtered and the solvent is evaporated. The crude product is chromatographed on a silica cartridge (40 g, eluent AcOEt/heptane—in an AcOEt gradient: 50 to 100%). 85 mg of expected product 52 are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH2:20](O)[CH2:21][OH:22].CC1C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>O.C1C=CC=CC=1>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2([C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:17]([O-:19])=[O:18])[CH:4]=3)[O:22][CH2:21][CH2:20][O:9]2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(C(=O)c2ccc(F)cc2)cc1[N+](=O)[O-]
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: O
Solvent: c1ccccc1
Product: Nc1ccc(C2(c3ccc(F)cc3)OCCO2)cc1[N+](=O)[O-]
Reaction time: 72 h
Yield: 33.2 %

Procedure:
A mixture of 26 parts of (4-amino-3-nitrophenyl)(4-fluorophenyl)methanone, 12 parts of 1,2-ethanediol, 10 parts of 4-methylbenzenesulfonic acid, 32 parts of butanol and 360 parts of benzene is stirred and refluxed for 96 hours with water-separator. Another 5 parts of 4-methylbenzenesulfonic acid are added and stirring at reflux is continued for 72 hours. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified twice by column-chromatography over silica gel using first a mixture of trichloromethane and 2% of methanol and then trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated, yielding 10.1 parts (33.2%) of 4-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-2-nitrobenzenamine; mp. 105° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][CH:13]3[N:15](C)[CH:10]([CH2:11][CH2:12]3)[CH:9]=2)=[CH:4][CH:3]=1.ClC(OC(Cl)C)=O.[C:24]([OH:30])(=[O:29])[CH2:25][C:26]([OH:28])=[O:27]>C(O)(C)C>[C:24]([OH:30])(=[O:29])[CH2:25][C:26]([OH:28])=[O:27].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH:10]3[NH:15][CH:13]([CH2:12][CH2:11]3)[CH:14]=2)=[CH:6][CH:7]=1
Reactant: CN1C2C=C(c3ccc(F)cc3)CC1CC2
Agent: CC(Cl)OC(=O)Cl
Agent: O=C(O)CC(=O)O
Solvent: CC(C)O
Product: Fc1ccc(C2=CC3CCC(C2)N3)cc1

Procedure:
The title compound was prepared from (±)-3-(4-fluorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (1.6 g, 7.37 mmol) and 1-chloroethyl chloroformate (1.2 mL, 1.6g, 11 mmol). The free base of the title compound was dissolved in isopropanol and added malonic acid (0.43 g, 4.1 mmol), the title compound precipitated from this solution and was isolated by filtration. Yield 1.14 g (50%) m.p. 132.2-132.6° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([N:18]1[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]2[C:34]([F:35])=[CH:33][C:27]([C:28](OCC)=[O:29])=[CH:26][N:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+].[O-]S([O-])(=O)=O.[Na+].[Na+]>CCCCCC.C1COCC1>[CH2:11]([N:18]1[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]2[C:34]([F:35])=[CH:33][C:27]([CH:28]=[O:29])=[CH:26][N:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)c(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)c(F)c1
Yield: 97.5 %

Procedure:
0.94 M solution of diisobutylaluminium hydride in hexane (2.73 ml) was added dropwise to a solution of ethyl 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-fluoronicotinate (294 mg) in THF (10 ml) with stirred below 5° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at the same temperature for 1.5 hrs. To the reaction mixture was added saturated aqueous ammonium chloride (0.727 ml) below 5° C., then the mixture was stirred at 25° C. for 30 minutes. Na2SO4 (2.87 g) was added to the solution, and the mixture was stirred at 25° C. for 15 minutes. The reaction mixture was filtrated, the filtrate was evaporated in vacuo. Toluene (15 ml) was added to the residue, and the mixture was evaporated in vacuo. The resulting residue and activated MnO2 (744 mg) in ethyl, acetate (20 ml) were stirred at 75° C. for 1 hour. After removal of the insoluble material by filtration, the filtrate was evaporated in vacuo to give 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-fluoronicotinaldehyde (250 mg, 98%) as syrup. The compound was used in the next step reaction without purification.
Reaction SMILES: [OH-].[Na+].C[CH:4]([CH2:8][CH2:9][CH2:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6]>CO>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([CH2:10][CH2:9][CH2:8][CH2:4][C:5]([OH:7])=[O:6])=[O:19])=[CH:13][CH:14]=1
Reactant: Cc1ccc(C(=O)CCCC(C)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C(=O)CCCCC(=O)O)cc1
Yield: 33.4 %

Procedure:
Then, 1N sodium hydroxide (30 ml) is added to a solution of methyl 5-(4-methylbenzoyl)pentanoic acid (3.5 g) in methanol (100 ml) and the mixture heated under reflux for 5 hours. The methanol is removed in vacuo and water added to the residue. The resulting mixture is filtered and the filtrate acidified with 3N hydrochloric acid. The precipitate is collected by filtration and washed with water to provide 5-(4-methylbenzoyl)pentanoic acid (1.1 g) as colorless crystals, m.p. 147°-148° C. The structure is confirmed by NMR and 1R spectroscopy.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Br[CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27].C(=O)([O-])O.[Na+]>CN(C)C=O>[F:27][C:26]([F:29])([F:28])[CH2:25][CH2:24][N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: FC(F)(F)CCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCC(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(tert-butoxycarbonyl)piperazine (5.00 g) and N,N-diisopropylethylamine (4.68 ml) in N,N-dimethylformamide (13 ml) was added 1-bromo-3,3,3-trifluoropropane (5.00 ml) at 60° C. The mixture was stirred at 60° C. for 4 hours. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with hexane. The organic layer was washed successively with saturated aqueous ammonium chloride solution, aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated to give the title compound (5.38 g) as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:26]=2)=[O:23])[C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:58][CH2:59][CH2:60][S:61]([OH:64])(=[O:63])=[O:62].C(N(C(C)C)CC)(C)C.S([O-])(O)(=O)=O.[Na+]>CN(C=O)C.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([S:32]([CH3:35])(=[O:33])=[O:34])[CH:26]=2)=[O:23])[C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:58][CH2:59][CH2:60][S:61]([OH:64])(=[O:63])=[O:62])=[O:17])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCS(=O)(=O)O
Reactant: Cc1ccc(NC(=O)NC(c2ccc(C(=O)O)cc2)c2ccc(C(C)(C)C)cc2)cc1S(C)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)NC(c2ccc(C(=O)NCCS(=O)(=O)O)cc2)c2ccc(C(C)(C)C)cc2)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
4-[1-(4-tert-Butylphenyl)-3-(3-methylsulfonyl-4-methylphenyl)ureidomethyl]benzoic acid (300 mg, 0.6 mmol) was dissolved in DMF (10 ml). Hydroxybenzotriazole (100 mg, 0.7 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (130 mg, 0.7 mmol) were added and the mixture was stirred for 30 minutes at room temperature followed by addition of 2-aminoethanesulfonic acid (110 mg, 0.9 mmol) and diisopropylethylamine (120 mg, 160 μl, 1.0 mmol). After 16 hours the reaction mixture was poured into water (40 mL), pH was adjusted to acidic reaction with sodium hydrogen sulphate and the solution was concentrated in vacuo. The residue was purified by flash chromatography (20 g Silica Gel) using methanol and dichloromethane (10:90) as eluent to give 0.2 g of the title compound.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH:14]([CH3:16])[CH3:15])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH:17](C1C=CC(C(O)=O)=CC=1)(C)C.C([O-])(O)=O.[Na+].[O-]S([O-])=O.[Na+].[Na+].BrCC(O)=O.[OH-].[Na+]>O>[CH3:17][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH:14]([CH3:16])[CH3:15])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3]
Reactant: CC(C)c1ccc(C(=O)O)cc1S(=O)(=O)Cl
Reactant: CC(C)c1ccc(C(=O)O)cc1
Agent: O=C(O)CBr
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: O
Product: CC(C)c1ccc(C(=O)O)cc1S(C)(=O)=O
Temperature: 105 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
3-Chlorosulfonyl-4-iso-propylbenzoic acid (2.62 g, 10 mmol) [made from 4-iso-propyl benzoic acid in a manner similar to that described in Procedures 7 and 8] was added slowly to a slurry of NaHCO3 (2.52 g, 30 mmol) and Na2SO3 (1.26 g 10 mmol) in water (9 ml) at 75° C. The mixture was stirred for 1 h and then treated with bromoacetic acid (2.08 g, 15 mmol) and NaOH (0.60 g, 15 mmol). The temperature was raised to 105° C. and the mixture heated at reflux for 24 h. The mixture was cooled, acidified to pH 1 and the resultant precipitate collected, washed and dried to give the title compound (1.43 g, 59%).
Reaction SMILES: [CH2:1]([C:3]1([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([S:17][CH3:18])[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:2].[OH:19]O.[OH-].[Na+]>CS(C)=O.O>[CH2:1]([C:3]1([NH:8][C:9]2[C:14]([C:15]([NH2:16])=[O:19])=[CH:13][N:12]=[C:11]([S:17][CH3:18])[N:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7]1)[CH3:2]
Reactant: OO
Reactant: CCC1(Nc2nc(SC)ncc2C#N)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCC1(Nc2nc(SC)ncc2C(N)=O)CCCC1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
To a stirred solution of 4-(1-ethylcyclopentylamino)-2-(methylthio)-pyrimidine-5-carbonitrile (830 mg, 3.2 mmol) in DMSO (10 mL) was added aqueous hydrogen peroxide (1.8 g, 30%, 16 mmol), and aqueous sodium hydroxide solution (2.7 mL, 6 mol/L, 16 mmol) at 0° C. The mixture was stirred at 50° C. for 15 min and diluted with water. The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave the crude product, which was purified by silica gel column chromatography (5% methanol in DCM) to afford the desired product as a white solid (800 mg, 2.9 mmol, 90% yield). MS (ESI) m/z=281.2 [M+1]
Reaction SMILES: [OH:1][C@H:2]1[CH2:5][C@H:4]([C:6]2[N:10](C(OC(C)(C)C)=O)[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[N:7]=2)[CH2:3]1>ClCCl.C(O)(C(F)(F)F)=O>[NH:7]1[C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=2[N:10]=[C:6]1[C@H:4]1[CH2:3][C@H:2]([OH:1])[CH2:5]1
Reactant: CC(C)(C)OC(=O)n1c2ccccc2nc1[C@H]1C[C@H](O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O[C@H]1C[C@H](c2nc3ccccc3[nH]2)C1
Yield: 53.2 %

Procedure:
tert-Butyl 2-(trans-3-hydroxycyclobutyl)-1H-benzo[d]imidazole-1-carboxylate (0.31 g, 1.09 mmol) was stirred in a mixture of dichloromethane (5 mL) and TFA (5 mL) at RT for 4 h, then the mixture was concentrated in vacuo. The residue was partitioned between saturated aqueous sodium bicarbonate solution and 10:1 DCM/MeOH the layers were separated and the aqueous layer was extracted with 10:1 DCM/MeOH (3×). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give trans-3-(1H-benzo[d]imidazol-2-yl)cyclobutanol (0.11 g, 0.58 mmol, 54% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:18]([F:19])([F:20])[F:21]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(F)c(C(F)(F)F)c2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Oc2ccc(F)c(C(F)(F)F)c2)cc1
Yield: 95 %

Procedure:
The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (50 mg) until completion as indicated by TLC or LC-MS, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline, which was used directly for further transformation without purification (overall yield: 95%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([CH3:11])=[CH:9][C:8](Cl)=[N:7][C:6]=1[CH3:13])[CH3:2].CC1(C)C(C)(C)OB([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=2)O1>>[CH2:1]([O:3][C:4]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=2)=[N:7][C:6]=1[CH3:13])=[O:14])[CH3:2]
Reactant: CC1(C)OB(c2cncc(C(F)(F)F)c2)OC1(C)C
Reactant: CCOC(=O)c1c(C)cc(Cl)nc1C
Product: CCOC(=O)c1c(C)cc(-c2cncc(C(F)(F)F)c2)nc1C

Procedure:
In analogy to the procedures described for example 1, for intermediate 5B and for intermediate 1, the title compound has been prepared by the following reaction sequence: i) 6-chloro-2,4-dimethyl-nicotinic acid ethyl ester [Zhou, Y.; Bridger, G. J.; Skerlj, R. T.; Bogucki, D.; Yang, W.; Bourque, E.; Langille, J.; Li, T.-S.; Metz, M. U.S. Pat. Appl. Publ. (2005), US 2005277668 A1] was reacted with 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-pyridine (intermediate 6) to give 4,6-dimethyl-5′-trifluoromethyl-[2,3′]bipyridinyl-5-carboxylic acid ethyl ester; ii) 4,6-dimethyl-5′-trifluoromethyl-[2,3′]bipyridinyl-5-carboxylic acid ethyl ester has been saponified to give 4,6-dimethyl-5′-trifluoromethyl-[2,3′]bipyridinyl-5-carboxylic acid; iii) 4,6-dimethyl-5′-trifluoromethyl-[2,3′]bipyridinyl-5-carboxylic acid was converted into its acid chloride and reacted with 4-pyrrolidin-1-yl-piperidine to give the title compound as colorless amorphous solid. MS: 433.3 (MH+).