Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCCC(OC(=O)C)CCCCC.ClCCCC(OC(=O)C)CCCC=C.C([O:32][CH:33]([CH2:53][CH2:54][CH2:55][CH:56]=[CH2:57])[CH2:34][CH2:35][CH2:36][N:37]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:50]CC)=[O:49])[S:38]([CH3:41])(=[O:40])=[O:39])(=O)C>>[OH:32][C@H:33]([CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:34]#[C:35][CH2:36][N:37]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49])[S:38]([CH3:41])(=[O:39])=[O:40]
Reactant: C=CCCCC(CCCN(CCCCCCC(=O)OCC)S(C)(=O)=O)OC(C)=O
Agent: C=CCCCC(CCCCl)OC(C)=O
Agent: CCCCCC(CCCCl)OC(C)=O
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)S(C)(=O)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-chloro-4-acetoxy-8-nonene. The product of Step A is thus ethyl 7-[N-(4-acetoxy-8-nonenyl)methanesulfonamido]heptanoate. The subsequent step yields 7-[N-(4-hydroxy-8-nonenyl)methanesulfonamido]heptanoic acid (B).
Reaction SMILES: C[O:2][C:3]1[C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[C:11]([CH:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)(O)[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4]=1.FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]2[C:11](=[C:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:5]3[CH2:4][C:3](=[O:2])[C:13]=2[CH:14]=1
Reactant: COC1=Cc2cccnc2C(O)(C2CCN(C)CC2)c2ccc(Cl)cc21
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CN1CCC(=C2c3ccc(Cl)cc3C(=O)Cc3cccnc32)CC1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A mixture of 2.00 g (5.39 mmol) of 6-methoxy-8-chloro-11-(1-methyl-4-piperidinyl)-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol in 87% aqueous sulfuric acid was stirred at room temperature and under an argon atmosphere. After 30 min 30 mL of trifluoromethanesulfonic acid was added and the mixture was heated to 115° C. One hour later the mixture was cooled to room temperature, poured onto ice, basified with 5% aqueous sodium hydroxide and extracted with methylene chloride (2×). The combined organic portions were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 1.41 g of 8-chloro-5,11-dihydro-11-(1-methyl-4-piperidinylidene)-6H-benzo[5,6]cyclohepta-[1,2-b]pyridin-6-one. The material was recrystallized from ethyl acetate/isopropyl ether to give 1.12 g (61%) of the ketone as a granular solid: mp 181°-183° C.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=3[N+:19]([O-:21])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[OH-].[Na+].[CH2:29](O)[CH3:30]>>[CH2:29]([O:17][C:16]([C:12]1[CH:13]=[C:14]2[C:9](=[C:10]([N+:19]([O-:21])=[O:20])[CH:11]=1)[NH:8][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:15]2)=[O:18])[CH3:30]
Reactant: O=C(O)c1cc([N+](=O)[O-])c2[nH]c(-c3ccccc3)cc2c1
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cc([N+](=O)[O-])c2[nH]c(-c3ccccc3)cc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
2-Phenyl-7-nitro-1H-indole-5-carboxylic acid (14.1 g, 50 mmol) prepared in Preparation 30 was dissolved in ethanol (40 mL). Conc. sulfuric acid (10 mL) was added thereto, and the mixture was stirred for 2 h at 50° C. After completion of the reaction, 1N NaOH was added to the reaction mixture, which was then extracted with EtOAc, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was recrystallized from EtOAc and hexane to give the title compound (14.1 g, Yield 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[N+:21]([C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[S:34](Cl)(=[O:36])=[O:35])([O-:23])=[O:22]>>[Cl:19][C:6]1[CH:5]=[C:4]([NH:20][S:34]([C:25]2[CH:26]=[CH:27][C:28]([C:30]([F:32])([F:33])[F:31])=[CH:29][C:24]=2[N+:21]([O-:23])=[O:22])(=[O:35])=[O:36])[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1

Procedure:
N-[3,5-Dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenyl]-2-nitro-4-trifluoromethyl-benzenesulfonamide was synthesized (48%) from 3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (420) and 2-nitro-4-trifluoromethylbenzenesulfonyl chloride (Aldrich) in a similar manner as described in Examples 70-91.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[CH:10]([CH3:16])[C:11]([O:13]CC)=[O:12]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[CH:10]([CH3:16])[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)C(C)C(=O)Nc1ccccc1Br
Solvent: C1CCOC1
Product: CC(C(=O)O)C(=O)Nc1ccccc1Br

Procedure:
The acid was prepared according to Procedure B using ethyl 3-(2-bromophenylamino)-2-methyl-3-oxopropanoate (2.7 g, 9.00 mmol) in THF (9.00 mL) to give 3-(2-bromophenylamino)-2-methyl-3-oxopropanoic acid. Mass Spectrum (ESI) m/e=272.0 (M+1).
Reaction SMILES: [OH:1]O.[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH:4]=1>C(O)(=O)C>[O-:1][N+:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH:4]=1
Reactant: OO
Reactant: COC(=O)c1ccc(-c2cccnc2)cc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2ccc[n+]([O-])c2)cc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
Acetic acid (10 mL) and aqueous 30% hydrogen peroxide (452 μL) were added to methyl 4-pyridin-3-ylbenzoate (708 mg), followed by stirring at 70° C. for 18 hours. The reaction mixture was concentrated under reduced pressure, an aqueous saturated sodium hydrogencarbonate solution was added, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol/chloroform=0% to 10%) to obtain methyl 4-(1-oxidopyridin-3-yl)benzoate (720 mg) as a white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[Cl-].Cl[CH2:17][C:18]1[S:19][CH:20]=[CH:21][NH+:22]=1>CN(C=O)C.CCN(C(C)C)C(C)C.O>[S:19]1[CH:20]=[CH:21][N:22]=[C:18]1[CH2:17][O:12][CH:10]1[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: ClCc1[nH+]ccs1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(OCc2nccs2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
To a solution of N-Boc-azetidin-3-ol (260 mg, 1.5 mmol) in DMF (3.5 mL) at 0° C. under nitrogen was added NaH (60% in oil, 126 mg, 3.15 mmol). The suspension was stirred for 0.5 h at 0° C. then treated with 2-(chloromethyl)-1,3-thiazol-3-ium chloride (510 mg, 3.0 mmol; which may be prepared as described in Step 1) dissolved in DMF (1 mL) and DIPEA (1.05 mL). The mixture was allowed to warm to room temperature then heated to 80° C. overnight. The reaction mixture was cooled, water (20 drops) was added and the mixture concentrated under reduced pressure. The crude material was purified on column chromatography (eluent: Pentane/EtOAc, 90/10 to 50/50) to give the product (193 mg, 48%) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[C:11]2[C:5]([C:6](=[O:13])[NH:7][S:8]2(=[O:10])=[O:9])=[N:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:19][OH:20]>>[CH3:19][O:20][C:6]([C:5]1[C:11]([S:8]([NH2:7])(=[O:10])=[O:9])=[CH:12][C:2]([CH3:1])=[CH:3][N:4]=1)=[O:13]
Reactant: Cc1cnc2c(c1)S(=O)(=O)NC2=O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ncc(C)cc1S(N)(=O)=O

Procedure:
1 mol of 6-methyl-4-azasaccharine is suspended in 10 times the volume of methanol and heated at 100° C. with 1/10 molar equivalent of concentrated sulfuric acid in a bomb tube. After 18 hours the batch is concentrated by evaporation and the residue is washed with CHCl3 /NaHCO3 to give 3-(aminosulfonyl)-5-methylpyridine-2-carboxylic acid methyl ester in the form of a beige powder having a melting point of 86°-88° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:28]=[C:29]([N:34]=[C:35]=[O:36])[CH:30]=[C:31]([F:33])[CH:32]=1>>[CH3:22][O:21][C:19](=[O:20])[C@@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:35]([NH:34][C:29]4[CH:30]=[C:31]([F:33])[CH:32]=[C:27]([F:26])[CH:28]=4)=[O:36])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[CH:23]([CH3:25])[CH3:24]
Reactant: O=C=Nc1cc(F)cc(F)c1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cc(F)cc(F)c4)cc3)cc2C1=O

Procedure:
The compound of example 29 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 3,5-difluorophenyl isocyanate. The compound of example 29 was used directly without isolation for the preparation of compound of example 30.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[O:11][C:12]3[N:13]=[C:14]([S:23][CH3:24])[N:15]=[C:16]([O:19][CH2:20][CH2:21][CH3:22])[C:17]=3[N:18]=2)=[CH:5][C:4]=1[CH3:25].B(Br)(Br)Br>ClCCl>[CH3:9][C:8]1[CH:7]=[C:6]([C:10]2[O:11][C:12]3[N:13]=[C:14]([S:23][CH3:24])[N:15]=[C:16]([O:19][CH2:20][CH2:21][CH3:22])[C:17]=3[N:18]=2)[CH:5]=[C:4]([CH3:25])[C:3]=1[OH:2]
Reactant: CCCOc1nc(SC)nc2oc(-c3cc(C)c(OC)c(C)c3)nc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCOc1nc(SC)nc2oc(-c3cc(C)c(O)c(C)c3)nc12
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a solution of 2.5 g of 2-(4-methoxy-3,5-dimethyl-phenyl)-5-methylsulfanyl-7-propoxy-oxazolo[5,4-d]pyrimidine in 50 ml of dichloromethane 0.70 ml of boron tribromide were added slowly at −20° C. After 1 h at −20° C. and 2 h at room temperature, the mixture was quenched by addition of a saturated aqueous sodium hydrogencarbonate solution while maintaining a temperature below 5° C. The phases were separated, and then the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried and concentrated in vacuo. 2.0 g of the title compound were obtained.
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+].Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[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][CH:33]=[CH:32][CH:31]=3)[N:20]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2cc(-c3ccccc3)nc2-c2ccc(Cl)cc2)cc1
Temperature: 55 °C
Yield: 56.9 %

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-bromoacetophenone (780 mg, 3.87 mmol) was added. After heating the reaction mixture at 55° C. for 20 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 (1.2 g) was purified by chromatography on silica gel with toluene/ethyl acetate (75/25) to give pure 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-phenyl-1H-imidazole (300 mg, 57%) as a white solid: mp (DSC) 202° C. Anal. Calc'd. for C22H17N2SO2Cl: C, 63.78, H, 4.28, N, 6.76, S, 7.74. Found: C, 63.69, H, 4.11, N, 6.68, S, 7.65.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]([NH2:33])=[N:31][OH:32])[CH2:26][CH2:25]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[C@@H:14]([CH3:15])[CH2:13][CH2:12][CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10]1(=[O:23])=[O:22].[CH:34](OCC)(OCC)OCC>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]3[N:33]=[CH:34][O:32][N:31]=3)[CH2:26][CH2:25]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[C@@H:14]([CH3:15])[CH2:13][CH2:12][CH:11]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[S:10]1(=[O:22])=[O:23]
Reactant: C[C@H]1CCC(c2ccccc2)S(=O)(=O)N1Cc1ccc(N2CCC(C(N)=NO)CC2)cc1F
Reactant: CCOC(OCC)OCC
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CCC(c2ccccc2)S(=O)(=O)N1Cc1ccc(N2CCC(c3ncon3)CC2)cc1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
A solution of 1-[3-fluoro-4-[[(3S)-3-methyl-1,1-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]-N′-hydroxy-piperidine-4-carboxamidine Stereoisomer A (150 mg, 0.32 mmol) in triethyl orthoformate (2 mL) was heated to 100° C. for 1 hour. 2 drops of trifluoroacetic acid were then added and the reaction was stirred at 100° C. for 1 hour. The solution was then concentrated and purified by preparative HPLC to give (3S)-2-[[2-fluoro-4-[4-(1,2,4-oxadiazol-3-yl)-1-piperidyl]phenyl]methyl]-3-methyl-6-phenyl-thiazinane 1,1-dioxide Stereoisomer A (31.8 mg, 21% yield). 1H NMR (400 MHz, DMSO) δ 9.53-9.49 (s, 1H), 7.49-7.43 (m, 2H), 7.43-7.35 (m, 3H), 7.35-7.29 (m, 1H), 6.85-6.79 (m, 1H), 6.77-6.69 (m, 1H), 4.50-4.36 (m, 2H), 4.32-4.23 (m, 1H), 4.15-4.02 (m, 1H), 3.81-3.69 (m, 2H), 3.13-3.01 (m, 1H), 2.97-2.83 (m, 2H), 2.46-2.37 (m, 1H), 2.14-1.97 (m, 3H), 1.89-1.70 (m, 3H), 1.70-1.59 (m, 1H), 1.13-1.05 (d, J=6.8 Hz, 3H); LCMS [M+1]+=485.2.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[N:20]=[C:19]([C:21](OCC)=[O:22])[CH:18]=[CH:17][C:16]=3[CH3:26])=[CH:14][C:9]=2[N:8]([CH3:27])[S:7]1(=[O:29])=[O:28].CC(C[AlH]CC(C)C)C>C1COCC1>[F:30][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[N:20]=[C:19]([CH2:21][OH:22])[CH:18]=[CH:17][C:16]=3[CH3:26])=[CH:14][C:9]=2[N:8]([CH3:27])[S:7]1(=[O:28])=[O:29]
Reactant: CCOC(=O)c1ccc(C)c(-c2ccc3c(c2)N(C)S(=O)(=O)N3CC2CC2(F)F)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Cc1ccc(CO)nc1-c1ccc2c(c1)N(C)S(=O)(=O)N2CC1CC1(F)F
Temperature: -78 °C

Procedure:
Ethyl 6-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}-5-methylpyridine-2-carboxylate (26-5) (85 mg, 0.19 mmol, 1 eq) was dissolved in THF (1 mL) and cooled to −78° C. DIBAL-H (0.97 mL, 0.97 mmol, 5.0 eq, 1.0 M in heptane) was added and the mixture was stirred at the same temperature. After 20 minutes the reaction was quenched by an addition of Rochelle's Salt (1 mL) and stirred for 2 hours warming to ambient temperature. The mixture was extracted with EtOAc (10 mL), washed with water (1 mL) and brine (1 mL), dried over MgSO4, filtered and concentrated to afford (6-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}-5-methylpyridin-2-yl)methanol (26-6). HRMS m/z (M+H) 396.1186 found, 396.1188 required.
Reaction SMILES: [N:1]1[CH:5]=[C:4]([CH2:6][CH2:7][N:8]2[CH:13]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:12][CH2:11][CH2:10][CH:9]2[C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[NH:3][CH:2]=1.[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH2:30]([N:1]1[CH:5]=[C:4]([CH2:6][CH2:7][N:8]2[CH:9]([C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:10][CH2:11][CH2:12][CH:13]2[C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=[CH:2]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1CCc1cnc[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1CCc1cn(Cc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of 1′-[2-(3H-imidazol-4-yl)-ethyl]-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (191 mg, 0.53 mmol) in THF (5 mL) at 0° C. was added NaH (60%, 8 mg, 0.20 mmol). After stirring at 0° C. for 30 min, benzyl bromide (21 μL, 0.18 mmol) was added and the resulting mixture was stirred overnight at room temperature. The next morning the mixture was concentrated under reduced pressure to afford a brown residue. Purification by radial chromatography on silica gel (1 mm plate; using CH2Cl2/MeOH/NH4OH; 50:1:1→10:1:1) afforded the product as a yellow oil (39 mg, 48%). 1H NMR (CDCl3) δ 1.57-1.70 (m, 3H), 1.93-2.16 (m, 5H), 2.46 (br s, 8H), 4.12 (d, 2H, J=9.0 Hz), 4.36 (s, 2H, 4.83 (s, 2H), 5.94(s, 1H), 6.99 (br s, 4H), 7.17 (s, 1H), 7.28 (s, 3H), 7.36 (d, 2H, J=9.0 Hz), 8.42 (s, 2H). 13C NMR (CDCl3) δ 19.23, 23.41, 25.39, 32.47, 50.23, 50.97, 62.04, 115.12, 122.07, 127.64, 128.49, 129.23, 136.52, 138.84, 147.33, 160.82. ES-MS m/z 452 [M+H]+. Anal. Calcd. for C29H33N5.0.5CH2Cl2: C, 71.71; H, 6.94; N, 14,17. Found: C, 71.78; H, 7.23; N, 14.10.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].CO.[Si](C=[N+]=[N-])(C)(C)[CH3:19].CCOC(C)=O.CCCCCC>C1COCC1>[CH3:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[C:3]([O:11][C:12]([F:13])([F:14])[F:15])[CH:4]=1
Reactant: Nc1ccc(C(=O)O)cc1OC(F)(F)F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(N)c(OC(F)(F)F)c1

Procedure:
To a stirred solution of 4-amino-3-trifluoromethoxy-benzoic acid (1.2 g, 5.4 mmol) in 16 mL of 4:1 THF:MeOH at 0° C. was added TMS-diazomethane (2M solution in hexane, 6 mL, 12 mmol) dropwise and conversion was monitored by TLC in 2/3 EtOAc/hexane. When complete, the reaction was concentrated to a white solid corresponding to the methyl ester (1.27 g, quantitative).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:51])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:27]5[C:32]([O:33][C@H:34]([CH2:36]C=C)[CH3:35])=[CH:31][CH:30]=[CH:29][C:28]=5[Cl:39])[C:23]([F:26])=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:40])[C:12]=2[C@H:41]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:42]([O:44][CH3:45])=[O:43])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[Cl:39][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:27]=1[C:22]1[CH:21]=[C:20]([C:18]3[CH:19]=[C:15]4[N:14]=[C:13]([CH3:40])[C:12]([C@H:41]([O:46][C:47]([CH3:49])([CH3:50])[CH3:48])[C:42]([O:44][CH3:45])=[O:43])=[C:11]([N:8]5[CH2:9][CH2:10][C:5]([CH3:51])([O:4][CH2:1][CH:2]=[CH:3][CH2:36][C@H:34]([CH3:35])[O:33]2)[CH2:6][CH2:7]5)[N:16]4[N:17]=3)[CH:25]=[CH:24][C:23]=1[F:26]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4ccc(F)c(-c5c(Cl)cccc5O[C@@H](C)CC=C)c4)nn23)CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cccc(Cl)c1-c1cc-3ccc1F
Temperature: 95 °C
Reaction time: 2 h

Procedure:
To a solution of (2S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(2′-chloro-6-fluoro-6′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (120 mg, 0.167 mmol, 1.0 equiv) in DCE (83 mL) was added Hoveyda-Grubbs Catalyst 2nd Generation (10.45 mg, 0.017 mmol, 0.1 equiv) and stirred for 2 h at 95° C. The solvent was evaporated and the residue was used as is. LCMS (M+1)=687.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])[C:5]([Cl:25])=[CH:4][N:3]=1.[NH2:26][CH2:27][CH2:28][OH:29]>O1CCOCC1>[Cl:25][C:5]1[C:6]([CH:8]([S:17][C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])=[CH:7][C:2]([NH:26][CH2:27][CH2:28][OH:29])=[N:3][CH:4]=1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Reactant: NCCO
Solvent: C1COCCO1
Product: OCCNc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Temperature: 25 °C
Yield: 56 %

Procedure:
A 1,4-dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (180 mg, 0.43 mmol) obtained in Example 54 and 2-aminoethanol (300 μl) was stirred at 120° C. for 64 hours under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (106 mg, 56%) as an oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([OH:19])[CH:12]=2)=[CH:5][N:4]=1.Br[CH2:21][CH2:22][NH:23][S:24](=[O:36])([C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:35])[CH3:34])=[CH:28][CH:27]=1)=[O:25].[OH-].[K+]>CO>[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:21][CH2:22][NH:23][S:24](=[O:36])([C:26]3[CH:27]=[CH:28][C:29]([NH:32][C:33](=[O:35])[CH3:34])=[CH:30][CH:31]=3)=[O:25])[CH:12]=2)=[CH:5][N:4]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)NCCBr)cc1
Reactant: COc1ccc(Cc2cnc(N)nc2N)cc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Cc2cnc(N)nc2N)cc1OCCNS(=O)(=O)c1ccc(NC(C)=O)cc1

Procedure:
A mixture of 1.41 g (0.005 mole) of 2,4-diamino-5-(3'-hydroxy-4'-methoxybenzyl)pyrimidine hydrochloride, 2.0 g (0.00625 mole) of N1 -(2-bromoethyl)-N4 -acetylsulfanilamide, 25 ml of methanol, and 6.0 ml of an aqueous solution containing 0.013 mole of potassium hydroxide is heated at reflux for 1.5 hr.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=2)[CH:20]=[CH:19][N:18]=1)[CH2:12][C:13]([O:15]C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]([N:11]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:29])([F:30])[F:28])[CH:25]=2)[CH:20]=[CH:19][N:18]=1)[CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CN(C(=O)OCc1ccccc1)c1nccc2ccc(C(F)(F)F)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN(C(=O)OCc1ccccc1)c1nccc2ccc(C(F)(F)F)cc12

Procedure:
A methanolic solution of methyl 2-(((benzyloxy)carbonyl)(7-(trifluoromethyl)isoquinolin-1-yl)amino)acetate (241 mg, 0.58 mmol) from above step G was cooled in an ice bath and treated with a solution of 1N NaOH (2.88 ml, 2.88 mmol). The solution was stirred for 4 h (monitored with TLC for completion), MeOH evaporated under vacuum (no heat), and the residue treated with 1N HCl and extracted with EtOAc. The EtOAc layer was washed with saturated NaCl, dry over Na2SO4 and evaporated to give the title compound.
Reaction SMILES: C(OC(=O)[N:7]([CH2:11][CH2:12][NH:13][C:14]([C:16]1[CH:36]=[CH:35][C:19]2[N:20]([CH3:34])[C:21]([NH:23][C:24]3[S:25][C:26]4[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:27]=4[N:28]=3)=[N:22][C:18]=2[CH:17]=1)=[O:15])[CH2:8][CH2:9][F:10])(C)(C)C>Cl.O1CCOCC1>[ClH:33].[ClH:33].[F:10][CH2:9][CH2:8][NH:7][CH2:11][CH2:12][NH:13][C:14]([C:16]1[CH:36]=[CH:35][C:19]2[N:20]([CH3:34])[C:21]([NH:23][C:24]3[S:25][C:26]4[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:27]=4[N:28]=3)=[N:22][C:18]=2[CH:17]=1)=[O:15]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCN(CCF)C(=O)OC(C)(C)C)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCNCCF)ccc21
Yield: 293.1 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2-(2-fluoro-ethylamino)-ethyl]-amide dihydrochloride (65 mg) was prepared by following General Procedure L starting from (2-{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-ethyl)-(2-fluoro-ethyl)-carbamic acid tert-butyl ester (70 mg) in 4M HCl in dioxane (1 mL). LC/MS: m/z 446.6.