Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=3[O:22][CH3:23])[O:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[OH-].[K+].[Mn]([O-])(=O)(=O)=[O:27].[K+]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:7])[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:13]=2[O:22][CH3:23])=[C:9]([CH:10]=1)[C:8]([OH:27])=[O:11]
Reactant: COc1cc(C(F)(F)F)ccc1C1OC(=O)c2cc(Br)ccc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1cc(C(F)(F)F)ccc1C(=O)c1ccc(Br)cc1C(=O)O
Temperature: 100 °C
Reaction time: 4 h
Yield: 100.7 %

Procedure:
To a stirred mixture of 6-bromo-3-(2-methoxy-4-(trifluoromethyl)phenyl)isobenzofuran-1(3H)-one (2.06 g, 5.32 mmol) in KOH (21.3 mL, 5.32 mmol, 25% aqueous solution) and pyridine (10.6 mL) in a pressure tube was added powder potassium permanganate (1.26 g, 7.98 mmol). The reaction was heated at 100° C. After 4 h, the reaction was cooled to RT and the mixture was filtered, and the residue was washed with water. The filtrate was acidified with concentrated HCl until a pH of about 2. The white solid that precipitated out of the solution was filtered off with the aid of water and dried to afford 5-bromo-2-(2-methoxy-4-(trifluoromethyl)benzoyl)benzoic acid (2.16 g, 100% yield). This material was carried on to the next step. m/z (ESI) 405.0 (M+H)+.
Reaction SMILES: CS(OC[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:13]([C:16](=[O:36])[NH:17][C:18]3[CH:23]=[C:22]([C:24]4[N:28]=[C:27]([CH:29]5[CH2:32][C:31]([F:34])([F:33])[CH2:30]5)[O:26][N:25]=4)[CH:21]=[CH:20][C:19]=3[CH3:35])=[CH:14][N:15]=2)[CH:12]=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH2:43]([OH:46])[CH2:44][OH:45]>>[F:34][C:31]1([F:33])[CH2:30][CH:29]([C:27]2[O:26][N:25]=[C:24]([C:22]3[CH:21]=[CH:20][C:19]([CH3:35])=[C:18]([NH:17][C:16]([C:13]4[N:11]5[CH:12]=[C:7]([O:45][CH2:44][CH2:43][OH:46])[CH:8]=[CH:9][C:10]5=[N:15][CH:14]=4)=[O:36])[CH:23]=3)[N:28]=2)[CH2:32]1
Reactant: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(COS(C)(=O)=O)cn12
Reactant: OCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(OCCO)cn12
Temperature: 80 °C

Procedure:
N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxamide (F37) (0125 mg, 0.285 mmol) was dissolved in DCM (1 mL) and DIEA (0.854 mmol). MsCl (0.57 mmol) was added dropwise. After 15 minutes at room temperature the solvent was removed. MeOH (5 mL) and water (10 mL) were added to the residue. After sonication, most of the MeOH was removed from the mixture. Solid product was filtered and dried under vacuum to give the crude mesylate, which was used in the next step without purification. MS m/z 518.0 (M+1)+. A mixture of (3-((5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)carbamoyl)imidazo[1,2-a]pyridin-6-yl)methyl methanesulfonate (10.4 mg, 0.02 mmol) and K2CO3(8.3 mg, 0.06 mmol) in ethane-1,2-diol (0.5 mL) was heated at 80° C. for 20 minutes. The reaction mixture was purified by preparative HPLC to afford N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(2-hydroxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide (F38). 1H NMR (400 MHz, CDCl3) δ 9.56 (m, 1H), 8.60 (d, J=1.5 Hz, 1H), 8.21 (s, 1H), 7.89 (dd, J=1.7, 7.9 Hz, 1H), 7.77 (d, J=9.2 Hz, 1H), 7.60 (s, 1H), 7.50 (dd, J=1.7, 9.2 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 4.65 (s, 2H), 3.82 (s, 2H), 3.73-3.61 (m, 3H), 3.15 (m, 4H), 2.46 (s, 3H), 2.04 (s, 1H). MS m/z 484.2 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.C1C(=O)N([Cl:32])C(=O)C1>>[Cl:1][C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[C:18]=3[Cl:32])[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: COc1cc(Cn2nnc3c(Cl)nc(N)nc32)cc(OC)c1OC
Reactant: O=C1CCC(=O)N1Cl
Product: COc1cc(Cn2nnc3c(Cl)nc(N)nc32)c(Cl)c(OC)c1OC

Procedure:
Chlorination of 7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine) (CF 2137) with NCS (1.5 equivalents) was done following the general procedure 3 to give the title compound: HPLC RT was 6.244 min. 1HNMR (CDCl3): δ 6.53 (s, 1H), 5.70 (s, 2H), 5.48 (s, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[N:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([C:39]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[O:40])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: O=C(Cl)N1CCOCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)N5CCOCC5)CC4)cn3)nc2n1C1CCCC1
Yield: 63.5 %

Procedure:
Following General Procedure G, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and morpholine-4-carbonyl chloride (38 mg, 0.690 mmol) gave 7-cyclopentyl-2-{5-[4-(morpholine-4-carbonyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (80 mg, 62%). MS (ESI) m/z 548.3 (M+H)+
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][C:7]1[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]2[O:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]=2[CH:17]=1>CCOCC>[C:18]([C:9]1[C:10]2[O:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]=2[CH:17]=[C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH:8]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1cc(N)cc2c1OCC2(C)C
Reactant: CCN=C=O
Solvent: CCOCC
Product: CCNC(=O)Nc1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Reaction time: 0.17 h
Yield: 50.6 %

Procedure:
Ethylisocyanate (0.18 mL, 2.28 mmol) is added dropwise to a solution of 5-amino-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofuran (500 mg, 2.28 mmol) in Et2O (5 mL). A solid forms after 10 min and the reaction is quenched with H2O (10 mL) after 40 min. The reaction is extracted with Et2O (3×10 mL) and the organic layers dried (MgSO4) and evaporated to a tan solid (657 mg). This solid is recrystallized from EtOAc to give the title compound as white prisms (335 mg, 51%), mp=197°-198° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O.O>[C:18]([N:2]([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][CH:5]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CNCc1ccc(SC)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CSc1ccc(CN(C)C(=O)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
N-Methyl-N-(4-methylthiobenzyl)amine (4.2 g) and potassium carbonate (5.2 g) are dissolved in a mixture of acetone (20 ml) and water (20 ml), and thereto is added dropwise benzoyl chloride (3.7 ml) gradually under ice cooling. After the mixture is stirred at the same temperature for 30 minutes, the reacting mixture is poured into water, and then extracted with dichloromethane. The extract is washed with aqueous sodium chloride solution, and dried over magnesium sulfate. Dichloromethane is distilled off to give N-benzoyl-N-methyl-N-(4-methylthiobenzyl)amine (6.8 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[Br:19][CH2:20][CH2:21][CH2:22]Br.CN(C)C=O>O>[Br:19][CH2:20][CH2:21][CH2:22][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: BrCCCBr
Reactant: O=C1CCc2cc(O)ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(OCCCBr)ccc2N1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 12.6 g (0.076 mol) of 6-hydroxy-1,2,3,4-tetrahydro-2-quinolinone, 15.8 g (0.115 mol) of potassium carbonate (anhydrous and powdered), 46.5 g (0.23 mol) of 1,3-dibromopropane and 40 ml of N,N-dimethylformamide is stirred at room temperature for 20 hours. 200 ml of water and 100 ml of petroleum ether are added and, after stirring for 1 hour, the precipitate which has formed is filtered off with suction, washed with petroleum ether and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[O:8])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13]
Reactant: Nc1ccc(C(=O)O)cc1OC(F)(F)F
Reactant: CN1CCC(N)CC1
Product: CN1CCC(NC(=O)c2ccc(N)c(OC(F)(F)F)c2)CC1

Procedure:
The title compound was prepared according to the method described for Preparation 25 using 4-amino-3-(trifluoromethoxy)benzoic acid and 4-amino-1-methylpiperidine.
Reaction SMILES: C[Sn](C)(C)[C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([O:12][CH3:13])=[C:5]([O:14][CH3:15])[CH:4]=1.[C:18]([O:21][CH2:22][CH3:23])(=O)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:12][C:6]1[C:5]([O:14][CH3:15])=[CH:4][C:3]([C:3]2[CH:4]=[C:5]3[C:6](=[CH:7][CH:8]=2)[CH:23]=[C:22]([O:21][CH3:18])[C:22]([O:21][CH3:18])=[CH:23]3)=[C:8]([N+:9]([O-:11])=[O:10])[CH:7]=1
Reactant: COc1cc([N+](=O)[O-])c([Sn](C)(C)C)cc1OC
Reactant: CCOC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(-c2ccc3cc(OC)c(OC)cc3c2)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (80 mg) and cuprous bromide (16 mg) were added to a solution of 6,7-dimethoxy-2-naphthalenetriflate (10, 220 mg, 0.655 mmol) and trimethyl(3,4-dimethoxy-6-nitrophenyl)stannane (16, 220 mg, 0.64 mmol) in THF (25 mL). The mixture was stirred at room temperature for 0.5 h., and then refluxed under nitrogen for 32 hr. After Cooling, THF was rotaevaporated and ethyl acetate (50 ml) was added to the residue the solution was washed with water (30 mL). The organic layer was separated and passed through a celite bed to remove suspended particles. The organic layer was then washed with brine, dried (anhydrous Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel using 60:40 hexanes:ethyl acetate to give compound 17; 1H NMR (CDCl3) d 3.95(3H, s), 3.99(6H, s), 4.01(3H, s), 6.86(1H, s), 7.12(1H, s), 7.14(1H, s), 7.23(1H, dd, J=8.4, J=1.8), 7.56(1H, s), 7.61(1H, d, J=1.7), 7.70(1H, d, J=8.4); 13C NMR d 56.4, 56.9, 106.7, 107.0, 108.3, 114.4, 124.9, 125.7, 127.0, 129.0, 129.5, 132.2, 134.6, 141.6, 148.4, 150.4, 152.7.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10]>>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:11]([CH2:12][CH3:13])[CH2:9][CH3:10])(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCNCC
Product: CCN(CC)S(=O)(=O)CCCCl

Procedure:
The procedure used for the preparation of Intermediate D was used to prepare the title compound from 3-chloropropanesulfonyl chloride and diethylamine. High vacuum drying gave the title compound (570 mg, 95%) which was used without characterization in the next step.
Reaction SMILES: CO[C:3](=[O:39])[N:4]=[C:5](SC)[C:6](=[N:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:21]=1)[C:7]1[CH:8]=[C:9]([O:17][CH3:18])[C:10]2[O:15][CH2:14][O:13][CH2:12][C:11]=2[CH:16]=1.C1COCC1.[CH3:45][O:46][C:47]([C:49]1[S:50][CH:51]=[CH:52][C:53]=1[NH:54][NH2:55])=[O:48]>C(N(CC)CC)C>[CH3:45][O:46][C:47]([C:49]1[S:50][CH:51]=[CH:52][C:53]=1[N:54]1[C:3](=[O:39])[NH:4][C:5]([CH:6]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:21]=2)[C:7]2[CH:8]=[C:9]([O:17][CH3:18])[C:10]3[O:15][CH2:14][O:13][CH2:12][C:11]=3[CH:16]=2)=[N:55]1)=[O:48]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)c(CNC(=O)OC(C)(C)C)c1)c1cc2c(c(OC)c1)OCOC2
Reactant: COC(=O)c1sccc1NN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1sccc1-n1nc(C(Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)c2cc3c(c(OC)c2)OCOC3)[nH]c1=O
Temperature: 65 °C
Reaction time: 15 h
Yield: 87.2 %

Procedure:
To a mixture of {2-[3-(t-butoxycarbonylaminomethyl)-4-cyanophenylimino]-2-(8-methoxy-4H-benzo[1,3]-dioxin-6-yl)-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (2c))(101 mg) and THF (2.0 mL) there were added 3-hydrazinothiophene-2-carboxylic acid methyl ester (33.1 mg) and triethylamine (27.9 μL), and the mixture was stirred at 65° C. for 15 hours under a nitrogen atmosphere. The solvent in the mixture was distilled off. DMF (2.0 mL) was added to the residue, and the mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The solvent in the mixture was distilled off, and methanol (5 mL) and acetic acid (52.1 μL) were added to the residue. Sodium cyanotrihydroborate (114 mg) was then added to the mixture and the mixture was stirred overnight at room temperature. Water (25 mL) and ethyl acetate (50 mL) were added to the mixture, and after sufficiently shaking the mixture, the organic layer was separated off. The organic layer was washed twice with water (25 mL) and once with saturated aqueous sodium chloride (25 mL) in that order, and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate mixture) to obtain the target compound (103 mg) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=[O:5].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl.O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=[O:5]
Reactant: C1=COCCC1
Reactant: Cc1cc(O)cc(O)c1C=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(OC2CCCCO2)cc(O)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
A light yellow suspension of 2,4-dihydroxy-6-methyl-benzaldehyde (4.90 g, 24.98 mmol) in DCM (400 mL) was treated with 3,4-dihydro-2H-pyran (3.5 mL, 38.61 mmol) followed by pyridinium-p-toluenesulfonate (0.20 g, 0.80 mmol). The suspension slowly cleared to a yellow solution. The solution was stirred at rt overnight then diluted with water and washed with saturated NaHCO3. The organic layer was dried (Na2SO4), filtered and concentrated to a yellow oil. The residue was purified by column chromatography (SiO2, EtOAc/hexanes; 1:9) to afford 2-hydroxy-6-methyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (4.60 g, 70%), as a light yellow liquid. 1H NMR (400 MHz, CDCl3) δ 12.33 (s, 1H), 10.09 (s, 1H), 6.45 (d, J=2 Hz, 1H), 6.08 (d, J=2 Hz, 1H), 5.49-5.40 (m, 1H), 3.90-3.80 (m, 1H), 3.65-3.60 (m, 1H), 2.52 (s, 3H), 2.10-1.40 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH:25]=O)[CH:7]=1)[CH3:2].[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C@@H:30]([NH2:37])[C@H:29]1[OH:38]>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][C:16]=2[CH2:25][NH:37][C@@H:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:28][C@@H:29]2[OH:38])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2C=O)c1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CN[C@@H]2c3ccccc3C[C@@H]2O)c1

Procedure:
Prepared according to the procedure described in Example 45, Step 3, using the following starting materials: [3-(2-Formyl-4-trifluoromethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and (1R,2S)-(+)-cis-1-amino-2-indanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:24]([F:27])([F:26])[F:25])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:28]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])(=[O:30])[NH2:29]>>[F:25][C:24]([F:27])([F:26])[C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([S:28]([NH2:29])(=[O:31])=[O:30])[CH:37]=3)[CH:7]=[CH:6][CH:5]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1ccc(-c2cc(-c3cccc(Br)c3)nc(C(F)(F)F)c2)cc1
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.81) (0.200 g, 0.448 mmol) and 3-sulfamoyl-benzeneboronic acid (example F.2) (0.100 g, 0.488 mmol) according to the general procedure VI. Obtained as a white solid (0.040 g, 15%). MS (ISP) 523.3 [(M+H)+]; mp 187° C.
Reaction SMILES: [OH-:1].[Li+].[CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8][C:7]=2[CH:6]=[CH:5][C:4]=1[O:16][CH:17]1[CH2:21][CH:20]([C:22]([O:24]C)=[O:23])[NH:19][C:18]1=[O:26].Cl>O.O1CCCC1>[CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8][C:7]=2[CH:6]=[CH:5][C:4]=1[O:16][CH:17]([C:18]([OH:1])=[O:26])[CH2:21][C@@H:20]([C:22]([OH:24])=[O:23])[NH2:19]
Reactant: [OH-]
Reactant: COC(=O)C1CC(Oc2ccc3oc4ccccc4c3c2)C(=O)N1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](CC(Oc1ccc2oc3ccccc3c2c1)C(=O)O)C(=O)O
Temperature: 61 °C
Reaction time: 2.4 h

Procedure:
A mixture of lithium hydroxide (0.0943 g) in water (1.4 ml) and tetrahydrofuran (4.3 ml) was treated with methyl 3-(2-dibenzofuranoxy)-2-pyrrolidone-5-carboxylate (0.427 g), and heated to 61° C. After about 2.4 hours, the reaction mixture was allowed to cool to room temperature. The reaction mixture was treated with 5N HCl (787 ml). The reaction mixture was then treated with water (3 ml). The insolubles were collected by filtration, washed with 1:1 tetrahydrofuran:water (2 ml), tetrahydrofuran (5 ml). The insolubles were dried overnight in at vacuum oven at 70° C. to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([CH2:20][O:21][CH3:22])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=O.C(OC(Cl)=O)C(C)C.CN1CCOCC1.[CH:39]1([NH2:43])[CH2:42][CH2:41][CH2:40]1>O1CCCC1.Cl>[CH:39]1([NH:43][C:10](=[O:12])[C:9]2[CH:13]=[C:5]([O:4][C:3]3[C:2]([Cl:1])=[CH:19][C:18]([CH2:20][O:21][CH3:22])=[CH:17][C:16]=3[Cl:23])[CH:6]=[CH:7][C:8]=2[O:14][CH3:15])[CH2:42][CH2:41][CH2:40]1
Reactant: NC1CCC1
Reactant: COCc1cc(Cl)c(Oc2ccc(OC)c(C(=O)O)c2)c(Cl)c1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COCc1cc(Cl)c(Oc2ccc(OC)c(C(=O)NC3CCC3)c2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
To a solution of the title compound of Step D (238 mg, 0.67 mmol) in tetrahydrofuran (7 ml) at 0° C. under nitrogen was added isobutylchloroformate (0.13 mL, 1 mmol) and N-methylmorpholine (0.15 ml, 1.3 mmol). After stirring for about 30 minutes at 0° C., cyclobutylamine (0.11 ml, 1.3 mmol) was added. The reaction mixture was warmed to room temperature and stirred for about 19 hours. The reaction solution was diluted with 1N HCl (30 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with 1N HCl (2×50 ml), brine (50 ml), dried, filtered, and concentrated. The crude product was purified by preparative TLC (50% ethyl acetate in hexanes) to afford the title compound (170 mg) as a viscous oil. MS (APCl+) Calc: 409.1, found: 409.7 (M+1)
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[N:29]([CH3:36])[CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:11][C:10]([F:13])([F:12])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:33]2[CH2:34][CH2:35][CH:30]([N:29]([C:21]3[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:20]=3[F:19])[CH3:36])[CH2:31][CH2:32]2)=[CH:4][CH:5]=1)([OH:18])[C:14]([F:17])([F:16])[F:15]
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: CN(c1ccc([N+](=O)[O-])cc1F)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(c1ccc([N+](=O)[O-])cc1F)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Yield: 124.3 %

Procedure:
2-(4-(Bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (2.369 mmol, 1.141 mL, 798 mg), N-(2-fluoro-4-nitrophenyl)-N-methylpiperidin-4-amine (2.369 mmol, 600 mg) and potassium carbonate (7.11 mmol, 982 mg) were combined and stirred at 70° C. overnight in acetonitrile (50 mL). The reaction mixture was filtered and concentrated under vacuum. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate and concentrated under vacuum to give the intermediate 1,1,1,3,3,3-hexafluoro-2-(4-((4-((2-fluoro-4-nitrophenyl)(methyl)amino)piperidin-1-yl)methyl)phenyl)propan-2-ol (1.5 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8](Br)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[C:14]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)#[CH:15]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([C:15]#[C:14][C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: C#Cc1ccc(N)cc1
Reactant: CCOC(=O)c1c(C)nc(Br)n1C
Product: CCOC(=O)c1c(C)nc(C#Cc2ccc(N)cc2)n1C

Procedure:
The title compound, MS: m/e=284.4 (M+H+) was prepared in accordance with the general method of example 1b from 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and 4-ethynylaniline.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH2:14][CH3:15])[C:8]([OH:10])=[O:9])[N:6]=1.[C:16](OC(=O)C)(=[O:18])C>C(O)=O>[CH:16]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH2:14][CH3:15])[C:8]([OH:10])=[O:9])[N:6]=1)=[O:18]
Reactant: CCCON=C(C(=O)O)c1csc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CCCON=C(C(=O)O)c1csc(NC=O)n1
Yield: 78.5 %

Procedure:
2-(2-Aminothiazol-4-yl)-2-n-propoxyiminoacetic acid (syn isomer, 21.8 g.), acetic anhydride (38.8 g.) and formic acid (17.5 g.) were treated in a similar manner to that of Example F-(5), and then the obtained oil was triturated with diisopropyl ether to give 2-(2-formamidothiazol-4-yl)-2-n-propoxyiminoacetic acid (syn isomer, 19.2 g.), mp. 164° C. (dec.).