Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([C:9]([CH3:17])([CH3:16])[CH2:10][C:11](=[O:15])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[CH3:8].S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[CH2:25]([O:13][C:12](=[O:14])[C:11](=[O:15])[CH2:10][C:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([Cl:1])[C:3]=1[O:18][CH3:19])([CH3:17])[CH3:16])[CH3:26]
Reactant: COc1c(C(C)(C)CC(=O)C(=O)O)ccc(C)c1Cl
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=O)CC(C)(C)c1ccc(C)c(Cl)c1OC
Yield: 81.6 %

Procedure:
5.37 g (18.86 mmol) of 4-(3-chloro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid is dissolved in 112 ml of ethanol, mixed with 2 ml of concentrated sulfuric acid and refluxed for five hours. The ethanol is drawn off in a rotary evaporator, and the residue is carefully mixed with saturated sodium bicarbonate solution after 50 ml of water is added. It is extracted twice with ethyl acetate. The combined organic extracts are washed with water and with brine. After drying, and after the desiccant is filtered off and the solvent is spun in, the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 4.81 g (81.6%) of the desired compound is isolated.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9][C:6]2=[N:7][CH:8]=1)#[N:2].[SH2:17]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9][C:6]2=[N:7][CH:8]=1)(=[S:17])[NH2:2]
Reactant: S
Reactant: CCOC(=O)c1cc2cc(C#N)cnc2o1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cc(C(N)=S)cnc2o1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Ethyl 5-cyanofuro[2,3-b]pyridine-2-carboxylate (773 mg, 4.14 mmol) was dissolved in a mixed solvent of pyridine (40 ml) and triethylamine (8 ml), and a hydrogen sulfide gas was blown in for 10 minutes. The mixture was stirred at room temperature for 14 hours. The solvent was distilled away from the reaction mixture under reduced pressure to give ethyl 5-thiocarbamoylfuro[2,3-b]pyridine-2-carboxylate as a yellow solid. Acetone (80 ml) and methyl iodide (8.0 ml) were added and the mixture was refluxed under heating for one hour. Low boiling matters were distilled away from the reaction mixture under reduced pressure to give ethyl 5-((1-methylthio)iminomethyl]furo[2,3-b]pyridine-2-carboxylate. Methanol (80 ml) and ammonium acetate (694 mg, 9.00 mmol) were added and the mixture was refluxed under heating for 3.5 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol 97/3-4/1) to give 2.05 g of ethyl 5-amidinofuro[2,3-b]pyridine-2-carboxylate hydrochloride as a yellow solid (69% in 3 steps).
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].Cl.[C:7]([C:9]1[CH:34]=[CH:33][C:12]([CH2:13][NH:14][C:15](=[O:32])[C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:31])[C@@H:22]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH2:23])=[CH:11][CH:10]=1)#[N:8].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:7]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH:14][C:15](=[O:32])[C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:31])[C@@H:22]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:23][S:2]([OH:5])(=[O:4])=[O:3])=[CH:33][CH:34]=1)#[N:8]
Reactant: N#Cc1ccc(CNC(=O)[C@@H]2CCCN2C(=O)[C@H](N)Cc2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(CNC(=O)[C@@H]2CCCN2C(=O)[C@@H](Cc2ccccc2)NS(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
0.58 g (0.33 ml, 5 mmol) of chlorosulfonic acid in 10 ml of DCM was slowly added dropwise at 20° C. with cooling to a solution of 1.8 g (4.36 mmol) of D-phenylalanylproline (p-cyanobenzyl)amide hydrochloride and 1.68 g (13.0 mmol) of diisopropylethylamine in 20 ml of DCM. After stirring at room temperature for 30 min, the mixture was diluted to 100 ml with DCM and extracted initially with 2M HCl and then twice with 10 ml of water, and the organic phase was dried over magnesium sulfate and evaporated in a rotary evaporator. 2.0 g of N-hydroxysulfonyl-D-phenylalanylproline (p-cyanobenzyl)amide were obtained as crude product which was used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][N:15]([CH2:28][C:29](O)=[O:30])[C:14]3=[O:32])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.CN(C(O[N:43]1N=N[C:45]2[CH:46]=CC=N[C:44]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)CC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=4)[CH2:16][N:15]([CH2:28][C:29]([NH:43][CH2:44][CH2:45][CH3:46])=[O:30])[C:14]3=[O:32])=[CH:9][CH:8]=2)=[CH:33][CH:34]=1
Reactant: O=C(O)CN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCCN
Product: CCCNC(=O)CN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)acetic acid (16.0 mg, 0.0326 mmol), HATU (18.6 mg, 0.0489 mmol) and iPr2NEt (17.0 μL, 0.0978 mmol) in DMF (0.5 mL) is added propylamine (5.36 μL, 0.0652 mmol). The reaction mixture is stirred at room temperature overnight before removal of the solvent. The residue is purified by preparative LC/MS to provide the title compound; HPLC-MS calculated for C27H25ClF3N3O3 (M+H+) 532.2, found 532.2.
Reaction SMILES: C(O[C:4](=[O:21])[C:5](=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[N:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:21])[C:18]2[C:13](=[N:14][C:15]([CH2:19][CH3:20])=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1cccc(CC)n1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2nc(CC)ccc2c1=O
Yield: 80 %

Procedure:
The product of Example 8c (7.16 g, 0.024 mol) was heated in diphenyl ether following the procedure in Example 7b giving the title compound (4.73 g, 79%) as a tan solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:33]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>CCOC(C)=O.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.O>[CH3:30][O:31][C:32]1[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:35]=[CH:34][C:33]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Br)cncc3c2)cc1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(C(F)(F)F)ccc1-c1cncc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A microwave vial charged with 4-bromo-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-7-sulfonamide (Intermediate PPPP) (0.066 g, 0.135 mmol), 2-methoxy-4-(trifluoromethyl)phenylboronic acid (Combi-Blocks, San Diego, Calif.) (0.044 g, 0.202 mmol), potassium carbonate (0.093 g, 0.673 mmol), dioxane (0.673 ml) and water (0.224 ml) was purged with argon prior to the addition of Pd(PPh3)4 (0.016 g, 0.013 mmol). The vessel was sealed and irradiated at 100° C. for 30 min. The resulting mixture was diluted with EtOAc and extracted with water, the aqueous phase was extracted with EtOAc and the combined organics were dried under reduced pressure. To the crude brown oil was added DCM (3 ml) and TFA (1 ml) and the resulting solution stirred overnight at RT affording conversion to desired product. The mixture was dried under reduced pressure and purified with a 25 g HP spherical silica gel (Interchim, Mouintlucon, France, 15 μm) ramping EtOAc in heptane (0 to 50%, 10% DCM isocratic throughout) providing product as a film which was lyophilized from MeOH/H2O to provide 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-7-sulfonamide (38 mg, 0.082 mmol, 60.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.87 (d, J=4.60 Hz, 1H) 7.28 (d, J=4.60 Hz, 1H) 7.46-7.53 (m, 2H) 7.54-7.59 (m, 1H) 7.61 (d, J=8.90 Hz, 1H) 8.02 (dd, J=8.85, 1.91 Hz, 1H) 8.53 (s, 1H) 8.75 (d, J=1.56 Hz, 1H) 9.55-9.66 (m, 1H) 12.88 (br. s., 1H). m/z (ESI) 466.2 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@:10]([C:13]1[N:14]=[N:15][N:16]([CH:18]([F:20])[F:19])[N:17]=1)([NH2:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.ClCCCl.Cl.[F:33][C:34]1[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:35]=1[CH2:36][O:37][C:38]1[C:39]2[N:40]([C:44]([C:48](Cl)=[O:49])=[C:45]([CH3:47])[N:46]=2)[CH:41]=[CH:42][CH:43]=1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C.O>[C:4]([Si:1]([CH3:2])([CH3:3])[O:8][CH2:9][C@:10]([NH:12][C:48]([C:44]1[N:40]2[CH:41]=[CH:42][CH:43]=[C:38]([O:37][CH2:36][C:35]3[C:34]([F:33])=[CH:54][CH:53]=[CH:52][C:51]=3[F:55])[C:39]2=[N:46][C:45]=1[CH3:47])=[O:49])([C:13]1[N:14]=[N:15][N:16]([CH:18]([F:20])[F:19])[N:17]=1)[CH3:11])([CH3:5])([CH3:6])[CH3:7]
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OC[C@](C)(N)c1nnn(C(F)F)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)N[C@@](C)(CO[Si](C)(C)C(C)(C)C)c1nnn(C(F)F)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
Under a nitrogen atmosphere, to a mixture of 5.55 g of (2R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-[2-(difluoromethyl)-2H-tetrazol-5-yl]propan-2-amine, 7.5 ml of triethylamine, 220 mg of 4-dimethylaminopyridine, and 110 ml of 1,2-dichloroethane was added 8.88 g of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carbonyl chloride hydrochloride, followed by stirring at 70° C. for 2 hours. The reaction mixture was left to be cooled to room temperature, and was added to the mixture of water and ethyl acetate. The insoluble materials were separated by filtration and washed with ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The organic layer was combined, washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 8.70 g of N-{(2R)-1-{[tert-butyl (dimethyl)silyl]oxy}-2-[2-(difluoromethyl)-2H-tetrazol-5-yl]propan-2-yl}-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH2:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C1CCN2C(=NCCC2)CC1.F[C:32]1[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1.O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:32]3[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CS(=O)(=O)c1ccc(NCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanamine (30 mg, 0.11 mmol) from Example 5 step 3 was dissolved in NMP (0.21 mL), DBU (24.4 mg, 0.16 mmol) was added, stirred at room temperature for 5 minutes. 1-fluoro-4-(methylsulfonyl)benzene (22.3 mg, 0.13 mmol) was added. Reaction was heated to 110° C. for 17 hours. The reaction was cooled down to room temperature, water (10 mL) was added, extracted with EtOAc (10 mL×2), second wash with Brine (10 mL). The organic phase was dried by magnesium sulfate, filter, concentrated and purified by purified by column chromatography through a 12 gram RediSep Rf™ silica gel cartridge eluting with 30% acetone/hexanes to give the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:15][CH2:16][CH3:17])=[C:4]([CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:18][O:1][C:2]1[C:3]([CH2:15][CH2:16][CH3:17])=[C:4]([CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9]=1[O:10][CH3:11])[CH:5]=[O:6]
Reactant: CCCc1c(C=O)cc([N+](=O)[O-])c(OC)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCc1c(C=O)cc([N+](=O)[O-])c(OC)c1OC
Yield: 64.4 %

Procedure:
A solution of the product from step (c) (40.2 g), potassium carbonate (46.5 g) and methyl iodide (20.9 ml) in dry dimethylformamide (150 ml) was stirred at 20° C. for 16 hours. The solvent was evaporated and the residue quenched with water. The aqueous phase was extracted with ethyl acetate which was washed with brine, dried, filtered and evaporated to leave a yellow oil (27.4 g), MS; m/e 283.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:16][CH:15]([CH2:17][OH:18])[CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25]>O1CCCC1>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:14][CH:15]([CH2:17][O:18][CH2:20][C:21]4[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=4)[C:24]#[N:25])[CH2:16]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1cccc(CBr)c1
Reactant: OCC1CC(c2ccc(CN3CCCC3)cc2)C1
Solvent: C1CCOC1
Product: N#Cc1cccc(COCC2CC(c3ccc(CN4CCCC4)cc3)C2)c1
Temperature: 40 °C
Yield: 40.2 %

Procedure:
To a stirring solution of [3-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutyl]-methanol (50.0 mg, 0.20 mmol) prepared above (Step F) in 3 mL of tetrahydrofuran was added a solution of KotBu (0.42 mL, 0.41 mmol, 1M THF). After 30 minutes 3-(bromomethyl)-benzonitrile (42.0 mg, 0.21 mmol), in 1 mL of THF was added and then the reaction was heated to 40° C. (oil bath). After 3 hours the reaction was quenched with water and diluted with EtOAc. The layers were separated and the organic layer was dried over MgSO4, filtered through a fitted funnel and concentrated under reduced pressure. This material was purified by flash chromatography using a 4 g ISCO column, eluting with a gradient of 2%, 4%, 8% MeOH/CH2Cl2 w/0.1% NH4OH. The product containing fractions were collected and concentrated to give the title compound (29.0 mg, 39% yield) as a colorless oil and a mixture of cis:trans isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[S:11][C:12]2[C:18]([CH3:20])([CH3:19])[O:17][CH2:16][CH2:15][C:13]=2[N:14]=1)=[O:8].[CH3:24][C:25]([CH3:28])([O-])[CH3:26].[K+].BrCC(C)C>CN(C=O)C.C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:21]=1)[C:7](/[N:9]=[C:10]1\[S:11][C:12]2[C:18]([CH3:19])([CH3:20])[O:17][CH2:16][CH2:15][C:13]=2[N:14]\1[CH2:24][CH:25]([CH3:28])[CH3:26])=[O:8]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1nc2c(s1)C(C)(C)OCC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)CBr
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc2c(n1CC(C)C)CCOC2(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 7.9 %

Procedure:
To a solution of Example 89F (1.0 g, 2.8 mmol) in DMF/THF (1:4, 20 mL) were added potassium tert-butoxide (0.35 g, 3.1 mmol, Aldrich), 1-bromo-2-methylpropane (0.43 g, 3.1 mmol, Aldrich) and tetrabutylammonium iodide (0.1 g, 0.3 mmol, Aldrich). The reaction mixture was stirred at 80° C. for 16 h, cooled to room temperature, quenched with saturated aqueous NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-1% methanol in dichloromethane) to afford 90 mg (29%) of the title compound. MS (ESI+) m/z 409 (M+H)+
Reaction SMILES: CN(C)C=O.P(Cl)(Cl)(Cl)=O.[CH3:11][S:12]([O:15][C@H:16]1[CH2:20][N:19]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[C@H:18]([C:34](O)=[O:35])[CH2:17]1)(=[O:14])=[O:13].[N:37]1[N:41]2[CH2:42][CH2:43][CH2:44][NH:45][C:40]2=[CH:39][CH:38]=1>O1CCCC1.O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:11][S:12]([O:15][C@H:16]1[CH2:20][N:19]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[C@H:18]([C:34]([N:45]2[CH2:44][CH2:43][CH2:42][N:41]3[N:37]=[CH:38][CH:39]=[C:40]23)=[O:35])[CH2:17]1)(=[O:14])=[O:13]
Reactant: c1cc2n(n1)CCCN2
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCCn3nccc32)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 75.5 %

Procedure:
To a mixture of N,N-dimethylformamide (1.20 ml) and tetrahydrofuran (2.4 ml) was added dropwise phosphorus oxychloride (1.25 ml) at -20° C. and the mixture was stirred at 5° C. for 5 minutes. To the mixture was added a solution of (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)proline (4.0 g) in tetrahydrofuran (10 ml) under ice-cooling. The mixture was stirred at the same temperature for 30 minutes. To a solution of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (1.40 g) in tetrahydrofuran (20 ml) and water (10 ml) was added dropwise the solution obtained above with stirring under ice-cooling, keeping the pH to 8-10 with triethylamine. The mixture was stirred at the same condition for 1 hour. To the reaction mixture was added ethyl acetate (100 ml) and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride successively, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-{4,5,6,7-tetrahydropyrazolo [1,5-a]pyrimidin-4-yl)carbonylpyrrolidine (3.84 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=4[NH2:28])[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:29]1([CH:35]=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C([O-])(O)=O.[Na+].O>[CH:29]1([CH2:35][NH:28][C:19]2[CH:20]=[C:21]([C:24]([F:25])([F:27])[F:26])[CH:22]=[CH:23][C:18]=2[C:14]2[CH:13]=[C:12]([O:11][C:8]3[CH:9]=[C:10]4[C:5]([CH:4]=[CH:3][CH:2]=[N:1]4)=[CH:6][CH:7]=3)[N:17]=[CH:16][N:15]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=CC1CCCCC1
Reactant: Nc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cccnc4c3)ncn2)c(NCC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenylamine, (Example 163), (0.40 g, 1.1 mmol) in 1,2-dichloroethane (11 mL) was added cyclohexanecarboxaldehyde (0.32 mL, 2.6 mmol, Aldrich) and the mixture was stirred at room temperature for 18 h. NaBH(OAc)3 (0.55 g, 2.6 mmol) was added and stirring was continued for 8 h at 40° C. The reaction was diluted with satd NaHCO3 and H2O, and extracted with EtOAc (2×75 mL). The combined extracts were washed with H2O (75 mL) and brine (75 mL), dried over Na2SO4, filtered and concentrated onto silica gel. Purification by silica gel chromatography (gradient, 10 to 40% EtOAc/hexanes) afforded the title compound as a yellow solid. Mp: 137–138° C. MS (ESI, pos. ion) m/z: 479.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:3]=1.[F:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([F:33])[CH:32]=1)[NH2:29].C(OCC)(=O)C.O>CN1CCCC1=O.CCCCCC>[F:25][C:26]1[CH:27]=[C:28]([NH:29][C:2]2[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:17])=[CH:11][CH:10]=3)[CH:3]=2)[CH:30]=[C:31]([F:33])[CH:32]=1
Reactant: O=C(Nc1ccccc1)Nc1ccc(Oc2cc(Cl)ncn2)cc1
Reactant: Nc1cc(F)cc(F)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(Nc1ccccc1)Nc1ccc(Oc2cc(Nc3cc(F)cc(F)c3)ncn2)cc1
Yield: 20 %

Procedure:
N-(4-(6-Chloropyrimidin-4-yloxy)phenyl)-N′-phenylurea (68.0 mg, 0.200 mmol) and 3,5-difluoroaniline (129 mg, 1.00 mmol) were heated and stirred in 1-methylpyrrolidone (1 ml) at 170° C. for 3 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent-ethyl acetate:hexane=1:1), the fraction containing the target substance was concentrated and suspended in ethyl acetate, the suspension was diluted with hexane and the crystals were filtered out, washed with hexane and blow-dried to obtain the title compound (17.5 mg, 0.040 mmol, 20%) as colorless crystals.
Reaction SMILES: [CH2:1]([C:5]1[NH:9][C:8]2=[CH:10][S:11][CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:15]([O:19][C:20]([C:22]1[C:23]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C.[Cl-].[Na+].O>[C:15]([O:19][C:20]([C:22]1[C:23]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][N:9]3[C:8]4=[CH:10][S:11][CH:12]=[C:7]4[N:6]=[C:5]3[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:30][CH:29]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc2cscc2[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc2cscc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
To a stirred solution of 2-butyl-1H-thieno-[3,4-d]imidazole (38 mg, 0.211 mmol) in DMF (1.6 mL) at room temperature was added NaH (316 mmol). After 30 minutes, tert-butyl-4'-bromomethylbiphenyl-2-carboxylate (80.5 mg, 0.232 mmol) was added in one portion. The reaction mixture was stirred for 2 hours and brine (5 mL) was added. Extractive workup (EtOAc) and purification by flash chromatography (SiO2, 40% EtOAc/hexane) gave 64 mg (68%) of 4'-[(2-butyl-1H-thieno[3,4-d]imidazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid t-butyl ester as a thick oil: 1H NMR (300 MHz, CDCl3) δ 7.78 (dd, 1H, J=7.5 and 1 Hz), 7.48 (td, 1H J=7.5 and 1 Hz), 7.40 (td, 1H, J=7.5 and 1 Hz) 7.32-7.26 (m, 3H), 7.19 (d, 2H, J=8 Hz), 6.99 (d, 1H, J=2.5 Hz), 6.28 (d, 1H, J=2.5 Hz), 5.17 (s, 2H), 2.78 (t, 2H, J=8 Hz), 1.91-1.81 (m, 2H), 1.54-1.41 (m, 2H), 1.23 (s, 9H), 0.96 (t, 3H, J=7 Hz).