Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[CH:13][C:5]2[NH:6][C:7]([NH:9][CH:10]([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(O[CH:44]1[O:56][C@H:55]([CH3:57])[C@@H:50]([O:51][C:52](=[O:54])[CH3:53])[C@H:45]1[O:46][C:47](=[O:49])[CH3:48])(=O)C.C(=O)(O)[O-].[Na+]>C(#N)C>[F:15][C:14]1[C:2]([F:1])=[CH:3][C:4]2[N:8]([C@@H:44]3[O:56][C@H:55]([CH3:57])[C@@H:50]([O:51][C:52](=[O:54])[CH3:53])[C@H:45]3[O:46][C:47](=[O:49])[CH3:48])[C:7]([NH:9][CH:10]([CH3:11])[CH3:12])=[N:6][C:5]=2[CH:13]=1
Reactant: CC(=O)OC1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(C)Nc1nc2cc(F)c(F)cc2[nH]1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(NC(C)C)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.7 %

Procedure:
5,6-Difluoro-N-(1-methylethyl)1H-benzimidazol-2-amine (0.24 g, 1.1 mmol), N,O-bis(trimethylsilyl) acetamide (Aldrich, 0.30 mL, 1.2 mmol), and acetonitrile (Aldrich Sure Seal, 40 mL) were combined and refluxed under nitrogen for 15 min. The solution was cooled to room temperature and trimethylsilyl triflate (Aldrich, 0.13 mL, 0.7 mmol) was added. After 10 min, 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose (0.38 g, 1.5 mmol) dissolved in acetonitrile (Aldrich Sure Seal, 15 mL) was added. The solution was stirred under nitrogen at rt for 4.5 h and then heated in an 80° C. oil bath for 2 h. The solution was then poured into 5% aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were dried with magnesium sulfate (anhyd), filtered, and evaporated. The crude residue was purified on a silica gel column (2.5×20 cm, 230-400 mesh) with 95:5 dichloromethane-methanol to give the title compound (0.32 g, 0.8 mmol, 71%); 1H NMR (DMSO-d6) δ7.40-7.46 (m 1H, Ar—H), 7.21-7.28 (m, 1H, Ar—H), 6.74 (d, 1H, NH, J=7.5 Hz), 6.05 (d, 1H, H-1′, J=6.6 Hz), 5.55-5.59 (m, 1H, CH), 5.21-5.25 (m, 1H, CH), 4.00-4.24 (m, 2H, CH), 2.14 (s, 3H, OAc), 2.01 (s, 3H, OAc), 1.49 (d, 3H, 5′-CH3, J=6.3 Hz), 1.20-1.24 (m, 6H, CH3).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[CH:3]=1.[C:21]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)(=O)C.O>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=1
Reactant: O=C1CCCCC1
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1=CCCCC1
Temperature: 120 °C

Procedure:
A solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl) pyrazole (1 g, the compound of Reference Example 1 from EP 295,117) and cyclohexanone (1.6 ml) in acetic acid (5 ml) was stirred and heated at 120° C. overnight under an atmosphere of nitrogen. The cooled reaction mixture was diluted with water and extracted with ethyl acetate and then ether. The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution, then water. After drying (MgSO4), evaporation gave the crude product which was purified by column chromatography on silica gel (50 g) eluted with dichloromethane:hexane (1:2), then dichloromethane:hexane (1:1). Combination and evaporation of appropriate fractions provided the title compound as a white solid m.p. 175-7° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:32])([F:31])[C:14]1([CH2:17][CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:16][CH2:15]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=1)[CH2:17][C:14]1([C:13]([F:12])([F:31])[F:32])[CH2:16][CH2:15]1)=[O:6]
Reactant: NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)(F)F)nc1)c1cccc(F)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3-fluorobenzoic acid and 3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=470.0, tR (minutes, Method F)=3.07. [α]D20=28.85 (c=3.05 mg/mL,CHCl3)
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH3:29][S:30]([O-:32])=[O:31].[Na+].CN(C)CCN>>[CH3:29][S:30]([C:2]1[CH:28]=[CH:27][C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1)(=[O:32])=[O:31]
Reactant: CS(=O)[O-]
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2s1
Agent: CN(C)CCN
Agent: [Na+]
Product: CS(=O)(=O)c1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 125 °C
Yield: 29.9 %

Procedure:
A stirred suspension of (1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (100 mg, 0.22 mmol) (prepared as described in Example 108, steps 1 through 6), sodium methane sulfinate (89 mg, 0.9 mmol) and N,N-dimethylethylenediamine (9.6 μL, 0.9 mmol) was degassed under a stream of argon for 5 min. Copper (I) trifluoromethane-sulfonate benzene complex (22 mg, 0.04 mmol) was added and the mixture was sealed and heated at 125° C. for 7 h. The mixture was cooled to rt, filtered, and the filtrate subjected to purification by reverse-phase preparative HPLC eluting with a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and a Varian diphenyl column as the stationary phase, to afford (1R,2R)-2-((6-((5-(methylsulfonyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (30 mg, 30%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.20 (s, 1H), 8.06 (d, J=7.5 Hz, 1H), 7.84 (m, 1H), 7.76 (m, 1H), 7.69 (s, 1H), 7.30 (m, 1H), 7.21 (m, 1H), 5.56 (s, 2H), 4.82 (m, 1H), 3.50 (m, 1H), 3.36 (m, 1H), 3.19 (s, 3H), 2.01 (m, 1H), 1.87 (m, 1H), 1.56-1.67 (m, 2H), 1.11-1.31 (m, 4H); LCMS (ESI) m/z 457 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([CH2:25][OH:26])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@@H:9]1[C@@H:13](/[CH:14]=[CH:15]/[CH2:16][C:17]([OH:23])([CH3:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]1=[O:24].[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[O:1]=[C:2]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@@H:9]1[C@@H:13](/[CH:14]=[CH:15]/[CH2:16][C:17]([OH:23])([CH3:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]1=[O:24]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC(C)(O)C/C=C/[C@H]1C=CC(=O)[C@@H]1CCCCCCC(=O)CO
Solvent: c1ccncc1
Product: CCCCC(C)(O)C/C=C/[C@H]1C=CC(=O)[C@@H]1CCCCCCC(=O)COC(C)=O
Reaction time: 18 h

Procedure:
To a solution of 0.1 g of 1,9-dioxo-16-hydroxy-1-hydroxymethyl-16-methyl-10,13-trans-prostadiene (Example 1214) in 0.75 ml of pyridine is added 0.026 g of acetic anhydride. After 18 hr. at room temperature, the solvent is removed at reduced pressure and the residue is chromatographed on silica gel to give the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[N:4]=1.[C:27]([NH2:31])([CH3:30])([CH3:29])[CH3:28]>ClCCl>[C:27]([NH:31][CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[N:4]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: COc1ccc(-c2nc(CCl)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: COc1ccc(-c2nc(CNC(C)(C)C)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 13 h
Yield: 39.4 %

Procedure:
A mixture of 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline (1.78 g), tert-butylamine (17.4 g) and dichloromethane (40 ml) was stirred at room temperature for 13 hours. The reaction mixture was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with dichloromethane-ethanol (30:1, v/v) gave 2-(tert-butylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline (0.77 g, 40%). This compound was recrystallized from ethyl acetate - hexane. Colorless prisms, mp. 120°-122° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:35]3[N:34]=[C:32]([NH2:33])[NH:31][C:29](=[O:30])[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:36][CH2:37][CH2:38][OH:39])[C@@H:21]1[OH:40])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C[Si](C)(C)Cl.[C:52](Cl)(=[O:56])[CH:53]([CH3:55])[CH3:54]>CCOC(C)=O.O>[Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:35]3[N:34]=[C:32]([NH:33][C:52](=[O:56])[CH:53]([CH3:55])[CH3:54])[NH:31][C:29](=[O:30])[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:36][CH2:37][CH2:38][OH:39])[C@@H:21]1[OH:40])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)[C@H](OCCO)[C@@H]1O)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](O)[C@H]2OCCO)c(=O)[nH]1
Temperature: 5 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
Dried 5′-O-t-butyldiphenylsilyl-2′-O-(hydroxyethyl)-guanosine (55.9 g, <69 mmol) as a crude product was dissolved in anhydrous pyridine (494 mL, 6.11 mol) with cooling to 5° C. and trimethylchlorosilane (62.7 mL, 494 mmol) was added slowly to give a suspension. The reaction mixture was allowed to slowly warm to ambient temperature, and after 1 hour was again cooled to 5° C. Isobutyryl chloride (51.8 mL, 494 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After 2 hours the reaction mixture was cooled to 5° C. and cold water (100 mL) was slowly added. After stirring for 12 hours, the solvent was evaporated in vacuo at 40° C. to give an oil which was dissolved in EtOAc (2000 mL) and water (200 mL). The mixture was shaken, the organic was separated, washed twice with water (2×200 mL), then with brine (200 mL), and dried with MgSO4. The solvent was evaporated in vacuo to a volume of about 500 mL after which there was a flocculent white solid which was filtered, washed with cold EtOAc (3×5 mL), and dried in vacuo (0.5 torr) at 45° C. with P2O5 for 28 hours to afford the title compound as a white solid (26.74 g, 60%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[CH:13]([OH:14])[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:2]=1.[C:17]1(O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:17]1([O:14][CH:13]2[CH:12]3[CH2:11][CH2:10][N:9]([CH2:16][CH2:15]3)[CH:8]2[CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC1C2CCN(CC2)C1Cc1cccnc1
Reactant: Oc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: c1ccc(OC2C3CCN(CC3)C2Cc2cccnc2)cc1

Procedure:
The manner in which 3-(phenyloxy)-2-(3-pyridylmethyl)-1-azabicyclo[2.2.2]octane of the present invention is synthesized can vary. For example, pyridine-3-carboxaldehyde and quinuclidin-3-one hydrochloride (commercially available from Aldrich) are reacted together in the presence of methanolic potassium hydroxide as described in Neilsen and Houlihan, Org. React. 16: 14-38 (1968). This aldol condensation product, 2-(3-pyridylmethylene)-1-azabicyclo[2.2.2]octan-3-one, is then dissolved in methanol and hydrogenated in the presence of Raney nickel catalyst to afford 2-(3-pyridylmethyl)-1-azabicyclo[2.2.2]octan-3-ol. This alcohol is then etherified with phenol via Mitsunobu coupling with diethylazidocarboxylate and triphenylphosphine, as described by Guthrie et al., J. Chem. Soc., Perkin Trans I45: 2328 (1981), to afford the desired product, 3-(phenyloxy)-2-(3-pyridylmethyl)-1-azabicyclo[2.2.2]octane.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:8]2[CH:9]3[CH2:12][CH2:13][CH:7]2[C:6]([CH3:14])([C:10]3=[CH2:11])[CH2:5][CH2:4][CH2:3]1.BrCC(O)=O>>[CH:2]([CH:3]1[CH2:4][CH:5]2[C:6]3([CH3:14])[CH2:7][CH2:8][CH2:9][CH:12]2[CH2:13][C:10]13[CH3:11])([CH3:15])[CH3:1]
Reactant: C=C1C2CCC3C2C(C)(C)CCCC13C
Agent: O=C(O)CBr
Product: CC(C)C1CC2C3CCCC2(C)C1(C)C3
Yield: 19.8 %

Procedure:
A four neck flask of 2 L was charged with 1000 g of the same longifolene as in Production Example 4 and 100 g of bromoacetic acid to carry out reaction at 170° C. for 18 hours. This reaction mixture was washed with a saturated sodium hydrogencarbonate aqueous solution and water and refined by distillation, and after refined by distillation, it was charged into an autoclave of 2 L together with 18 g of a palladium-carbon catalyst for hydrogenation to carry out hydrogenation (hydrogen pressure: 6 MPa·G, reaction temperature: 100° C., reaction time: 2 hours). After finishing the reaction, the catalyst was separated by filtration, and the filtrate was precisely distilled to thereby obtain 200 g of targeted 2-isopropyl-1,7a-dimethyl-octahydro-1,4-methano-indene (synthetic oil II: fluid C). The measurement results of general properties and a traction coefficient of the fluid C are shown in Table 4.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[C:3]=1[CH:13]1[N:18]([CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[C:17](=[O:30])[CH2:16][CH2:15][CH2:14]1>CO>[NH2:8][C:7]1[C:2]([OH:1])=[C:3]([CH:13]2[N:18]([CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[C:17](=[O:30])[CH2:16][CH2:15][CH2:14]2)[C:4]([O:11][CH3:12])=[CH:5][CH:6]=1
Reactant: COc1ccc([N+](=O)[O-])c(O)c1C1CCCC(=O)N1Cc1ccc2ccccc2n1
Solvent: CO
Product: COc1ccc(N)c(O)c1C1CCCC(=O)N1Cc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A mixture of 6-(2-hydroxy-6-methoxy-3-nitrophenyl)-1-(quinolin-2-ylmethyl)piperidin-2-one (340 mg; 0.83 mmol), and 10% Pd(C) (34 mg; 10% in mass) in anh. MeOH (15 ml) was stirred at rt, under hydrogen atmosphere (1 atm), for 5.5 h. Filtration over a pad of celite, concentration to dryness under reduced pressure, and additional drying under HV afforded 6-(3-amino-2-hydroxy-6-methoxyphenyl)-1-(quinolin-2-ylmethyl)piperidin-2-one as a red solid (302 mg; 96%). LC-MS (conditions A): tR=0.41 min.; [M+H]+: 378.38 g/mol.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[C:30]([CH3:33])[CH2:31]O)=[CH:25][CH:24]=1>C(#N)C>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[C:30]([CH3:33])[CH2:31][Br:20])=[CH:25][CH:24]=1
Reactant: BrBr
Reactant: CC(=Cc1ccc(Br)cc1)CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(=Cc1ccc(Br)cc1)CBr
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To an acetonitrile solution (180 mL) of triphenylphosphine (24.3 g, 92.7 mmol) was added dropwise bromine (4.78 mL, 185 mmol) at 0° C. and the mixture was stirred at the same temperature for 30 minutes. To the solution was added the acetonitrile solution (60 mL) of 3-(4-bromophenyl)-2-methyl-2-propen-1-ol obtained in Reference Example 106 (20.1 g, 88.3 mmol) and the mixture was stirred at 0° C. for 1 hour. The reaction solution was concentrated under reduced pressure, diethyl ether (200 mL) was added to the residue, and the insolubles were filtered off. The solution was washed with a saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure to obtain 25.0 g (yield 98%) of the title compound as an oily matter.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[N:22]1([C:2]2[CH:3]=[C:4]([C:12]3[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=3[CH3:21])[CH:5]=[CH:6][C:7]=2[S:8]([CH3:11])(=[O:10])=[O:9])[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: c1c[nH]cn1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(-n3ccnc3)c2)s1
Temperature: 140 °C

Procedure:
A stirred mixture of N-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) (0.1 g, 0.30 mmol), imidazole (0.069 g, 0.90 mmol) and caesium carbonate (0.198 g, 0.60 mmol) in dry DMSO is heated under argon at 140° C. for 2 hours. The solvent is removed and water (30 ml) is added. The product is extracted with ethyl acetate (2×30 ml) and the combined organic extracts are washed with brine (20 ml) and dried (MgSO4). Removal of the solvent and trituration with methanol affords the titled compound as an orange solid. 377.9721
Reaction SMILES: S(Cl)(Cl)=O.CC1C=CC(C(O)=O)=CN=1.CC1N=CC(C(Cl)=O)=CC=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][N:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1.[CH3:47][C:48]1[N:53]=[CH:52][C:51]([C:54]([N:56]=[C:57]=[S:58])=[O:55])=[CH:50][CH:49]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][N:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH:44][C:57]([NH:56][C:54]([C:51]2[CH:52]=[N:53][C:48]([CH3:47])=[CH:49][CH:50]=2)=[O:55])=[S:58])=[CH:42][CH:41]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1ccc(C(=O)N=C=S)cn1
Agent: Cc1ccc(C(=O)Cl)cn1
Agent: Cc1ccc(C(=O)O)cn1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)nc4)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 6-methylnicotinic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 6-methyl-3-pyridinecarbonyl isothiocyanate was prepared using the resultant 6-methyl-3-pyridinecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 6-methyl-3-pyridinecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (71 mg, yield 89%).
Reaction SMILES: [C:1]([C:3](=[C:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[CH2:4][CH2:5][C:6]([OH:8])=[O:7])#[N:2].[OH-:26].[Na+].Cl>C(O)CO>[C:1]([C:3](=[C:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH2:4][CH2:5][C:6]([OH:8])=[O:7])(=[O:26])[NH2:2]
Reactant: [OH-]
Reactant: COc1ccc(C(=C(C#N)CCC(=O)O)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: OCCO
Product: COc1ccc(C(=C(CCC(=O)O)C(N)=O)c2ccc(OC)cc2)cc1

Procedure:
Two grams of the acid obtained in Example 4 was heated with 10 ml of a 5N aqueous solution of NaOH in 50 ml of ethylene glycol at 150° C. for 12 hours. The product mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was treated with the chromatography of silicagel to obtain 0.5 g of the above intended compound.
Reaction SMILES: Cl.[CH2:2]([N:5]([CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:14]([O:17]C)=[C:13]2[C:9]=1[C:10]([OH:19])=[N:11][NH:12]2)[CH2:3][CH3:4].[BrH:23]>>[BrH:23].[OH:19][C:10]1[C:9]2[C:13](=[C:14]([OH:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6][N:5]([CH2:20][CH2:21][CH3:22])[CH2:2][CH2:3][CH3:4])[NH:12][N:11]=1
Reactant: CCCN(CCC)CCc1ccc(OC)c2[nH]nc(O)c12
Agent: Br
Agent: Cl
Product: CCCN(CCC)CCc1ccc(O)c2[nH]nc(O)c12

Procedure:
Under argon, 480 mg of N,N-dipropyl-N-[2-(3-hydroxy-7-methoxy-1H-indazol-4-yl)ethyl]amine, hydrochloride, is heated to 120° C. in 5 ml of aqueous hydrogen bromide (65%) for 4 hours. The mixture is concentrated and once distilled with water. The residue is dried, triturated with diethyl ether, and repeatedly recrystallized from ethanol/acetone/diethyl ether, thus obtaining 340 mg of N-[2-(3,7-dihydroxy-1H-indazol-4-yl)ethyl]-N,N-dipropylamine, hydrobromide, decomposition point 242°-244° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C@H:19]([O:21][CH2:22][C:23]3([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:28][CH2:27][N:26]([C:29](OC(C)(C)C)=O)[CH2:25][CH2:24]3)[CH3:20])[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O.C(Cl)Cl.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:29][N:26]1[CH2:25][CH2:24][C:23]([CH2:22][O:21][C@@H:19]([C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=2)[CH3:20])([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:28][CH2:27]1
Reactant: C[C@@H](OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(-c2ccc(C#N)cc2)cc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](OCC1(c2ccccc2)CCN(C)CC1)c1cc(-c2ccc(C#N)cc2)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(R)-tert-Butyl 4-((1-(4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate (300 mg, 0.53 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 6 mL) for 1 h. The solvent was removed in vacuo and the resulting crude product dissolved in acetonitrile (5 mL), cooled to 0° C. and treated with formaldehyde (37 wt. % solution in water, 1.1 mL). The reaction was treated with sodium cyanoborohydride (163 mg, 2.58 mmol) and a few drops of acetic acid. The reaction was stirred at 0° C. for 30 min and at room temperature for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvents were evaporated to afford 222 mg (73%). 1H-NMR (CDCl3, 300 MHz) δ 7.71 (s, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 7.53 (s, 1H), 7.51 (s, 1H), 7.21-7.35 (m, 6H), 7.09-7.14 (m, 1H), 4.27 (q, J=6.6 Hz, 1H), 3.29 (d, J=9.2 Hz, 1H), 3.24 (d, J=8.8 Hz, 1H), 2.50-2.57 (m, 2H), 2.15 (s, 3H), 1.93-2.22 (m, 6H), 1.32 (m, 3H); 13C-NMR (CDCl3, 76 MHz) δ 146.5, 149.8, 140.0, 132.6, 131.4 (d, J=32.2 Hz), 128.0, 127.8, 127.7, 125.9, 123.8 (q, J=272.4 Hz), 122.8, 122.7, 122.0, 118.5, 111.6, 51.8, 50.2, 46.1, 40.1, 32.3, 31.9, 23.9. Mass spec.: 479.19 (MH)+.