Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][C:9]1[C:18]2[CH:19]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:16]3[C:17]=2[C:12]([C:13](=O)[CH2:14][CH2:15]3)=[CH:11][CH:10]=1>FC(F)(F)C(O)=O>[CH3:8][C:9]1[C:18]2[CH:19]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:16]3[C:17]=2[C:12]([CH2:13][CH2:14][CH2:15]3)=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1cc2c(C)ccc3c2n1CCC3=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2c(C)ccc3c2n1CCC3
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.1 %

Procedure:
Triethylsilane (3.07 g, 26.4 mmol) was added dropwise to a mixture of ethyl 5,6-dihydro-9-methyl-6-oxo-4H-pyrrolo [3,2,1-ij]quinoline-2-carboxylate (1.70 g, 6.61 mmol) and trifluoroacetic acid (20 ml) at room temperature. Then, the reaction mixture was stirred at room temperature for 3 hours and distilled under reduced pressure to remove the solvent. Ice water was added to the residue, followed by extraction with ethyl acetate (twice). The extract solution was washed with a 5% aqueous sodium hydrogencarbonate solution and then a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane= 3/97) to obtain 0.87 g of ethyl 5,6-dihydro-9-methyl-4H-pyrrolo[3,2,1-ij]quinoline-2-carboxylate. M.p. 51°-52° C. (after recrystallization from n-hexane).
Reaction SMILES: C([O:5][C:6](=[O:18])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:17])[CH:13]([CH3:16])[CH2:14][SH:15])(C)(C)C.C(OC(=O)[C@@H]1CCCN1C(=O)CCS)(C)(C)C>>[SH:15][CH2:14][CH:13]([CH3:16])[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:18])=[O:5])=[O:17]
Reactant: CC(CS)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)CCS
Product: CC(CS)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
By substituting 1-(3-mercapto-2-methylpropanoyl)-L-proline tert.butyl ester for the 1-(3-mercaptopropanoyl-L-proline tert.butyl ester in the procedure of Example 18C, 1-(3-mercapto-2-methylpropanoyl)-L-proline is obtained. Rf 0.35 (Silica gel, Benzene/acetic acid 3:1), Rf 0.5 (Silica gel, Methyl-ethylketone/Acetic acid/Pyridine/Water 14:1:2:1), identical to the compound of Example 34.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:18]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C@H:13]([CH3:17])[C:14]([NH2:16])=[O:15])[CH:6]=[CH:5]2.C(O)C.[Cl-].[NH4+].O>[Fe].C(OCC)(=O)C>[NH2:18][C:3]1[C:2]([Cl:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]([C@H:13]([CH3:17])[C:14]([NH2:16])=[O:15])[C:8]2=[O:12]
Reactant: C[C@H](C(N)=O)n1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: C[C@H](C(N)=O)n1ccc2c(N)c(Cl)ccc2c1=O
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-2-(6-chloro-5-nitro-1-oxoisoquinolin-2(1H)-yl)propanamide (120 mg, 0.00040 mol) in ethanol (4 mL, 0.07 mol) was added ammonium chloride (200 mg, 0.004 mol) in water (4 mL, 0.2 mol). The reaction was heated at 85° C. and iron (90 mg, 0.002 mol) was added in two portions 5 minutes apart. The reaction was stirred for 30 minutes and ethyl acetate was added and decanted. the solvent was removed under reduced pressureunder reduced pressure to afford the product as a yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CCO>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:31]=[N:30][C:29]([CH3:28])=[N:34][CH:33]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: Cc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)cn1
Reaction time: 2 h

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 60 mg, 0.134 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (44.4 mg, 0.202 mmol), Pd(PPh3)2Cl2 (9.44 mg, 0.013 mmol) and Na2CO3 (42.8 mg, 0.403 mmol) were added to a MW vial and treated with DME (570 μL), EtOH (81 μL) and water (163 μL). The vial was sealed, evacuated/purged with argon, and subjected to MW irradiation at 80° C. with stirring for 2 h, diluted with THF (1 mL), treated with Si-Thiol (Silicycle, 1.27 mmol/g, 52.9 mg, 0.067 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 12, 20% for 0.2 min then 20% to 50% in 12 min) to yield the title compound as a white solid. UPLC-MS (condition 1) tR=1.82 min, m/z=458.2 [M+H]+, m/z=443.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.80 (m, 1H) 1.79-1.92 (m, 1H) 2.69 (s, 3H) 2.91 (d, J=11.00 Hz, 1H) 3.14-3.49 (m, 3H) 4.13-4.28 (m, 1H) 4.83 (br. s, 1H) 7.34 (d, J=8.56 Hz, 2H) 7.80-7.91 (m, 2H) 8.05 (d, J=2.45 Hz, 1H) 8.75 (s, 2H) 8.78 (d, J=2.20 Hz, 1H) 10.14 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[N:18]2[CH2:23][CH2:22][CH2:21][CH:20]([NH2:24])[CH2:19]2)=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[CH3:25][N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[N:18]2[CH2:23][CH2:22][CH2:21][CH:20]([NH:24][CH:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[CH2:19]2)=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: CN1CCC(=O)CC1
Reactant: Nc1ncc(Br)nc1C(=O)Nc1cnccc1N1CCCC(N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCC(NC2CCCN(c3ccncc3NC(=O)c3nc(Br)cnc3N)C2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
To a solution of 3-amino-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-bromopyrazine-2-carboxamide in CH2Cl2 at room temperature was added 1-methylpiperidin-4-one (1.5 eq) followed by sodium triacetoxyborohydride (5.0 eq). The reaction was stirred at room temperature for 12 hours, concentrated, purified by reverse phase HPLC and lyophilized to provide 3-amino-6-bromo-N-(4-(3-(1-methylpiperidin-4-ylamino)piperidin-1-yl)pyridin-3-yl)pyrazine-2-carboxamide, (66%). LCMS (m/z): 489.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=O)[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[CH3:35][S:36]([OH:39])(=[O:38])=[O:37]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[O:9][CH3:10])[C:14]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)([CH2:35][S:36]([OH:39])(=[O:38])=[O:37])[NH:13][CH2:12][CH2:11]2
Reactant: CS(=O)(=O)O
Reactant: COc1ccc(CCNC(=O)CCc2ccc(C(F)(F)F)cc2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C(CCc1ccc(C(F)(F)F)cc1)(CS(=O)(=O)O)NCC2
Temperature: 90 °C

Procedure:
The compound 3 is suspended in toluene and heated to 80-100° C. After addition of 1.5 equivalents phosphorus oxychloride the mixture is heated for 6 hours to 80-100° C. and then cooled within 3 hours to 20° C. The suspension is added to water while maintaining the pH of the aqueous layer during addition and subsequent stirring between 7-8 by addition of a sodium hydroxide solution. The mixture is stirred until all precipitate is dissolved. After phase separation the water is removed by azeotropic distillation. Then 1.0 equivalent of methanesulfonic acid is added, the formed suspension stirred for some time and then slowly cooled to 0-10° C. and stirred at this temperature for another couple of hours. After filtration the product is washed with toluene and dried in vacuo.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[NH2:9][C:10]1[C:19]2[N:20]=[C:21]([CH2:28][CH2:29][CH2:30][CH3:31])[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[C:18]=2[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1>>[NH2:9][C:10]1[C:19]2[N:20]=[C:21]([CH2:28][CH2:29][CH2:30][CH3:31])[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[C:18]=2[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Reactant: O=C(Cl)c1ccco1
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)c1ccco1
Yield: 29.2 %

Procedure:
Using the general method of Example 47, furoyl chloride (15.8 μL, 0.16 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.05 g, 0.16 mmole) to provide 0.019 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-furamide as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.58 (dd, J=4.4, 1.5 Hz, 1 H), 8.06 (dd, J=8.6, 1.6 Hz, 1 H), 7.41 (dd, J=8.5, 4.4 Hz, 1 H), 7.33 (m, 1 H), 7.08 (dd, J=3.5, 0.6 Hz, 1 H), 6.84 (m, 1 H), 6.47 (dd, J=3.5, 1.7 Hz, 1 H), 4.86 (apparent t, J=7.7 Hz, 2 H), 3.59 (apparent q, J=6.5 Hz, 2 H), 2.92 (apparent t, J=7.8 Hz, 2 H), 1.7-2.1(m, 6 H), 1.51 (m, 2 H); 1.00 (t, J=7.3 Hz, 3 H); HRMS (EI) calcd for C22H26N6O2 (M+) 406.2117, found 406.2121.
Reaction SMILES: O[C@@H:2]([CH3:35])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].CS(O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:33][O:32][CH2:31][C@H:30]([CH3:34])[O:29][C:14]1[CH:13]=[C:12]([C:9]2[NH:8][C:7]([C:5]3[O:6][C@H:2]([CH3:35])[CH2:3][N:4]=3)=[CH:11][CH:10]=2)[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=2)[CH:15]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NC[C@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NC[C@@H](C)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 56.4 %

Procedure:
N-[(2S)-2-Hydroxypropyl]-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxamide (285 mg, 0.567 mmol) synthesized in Example (33a) was dissolved in tetrahydrofuran (10 mL), and anhydrous methanesulfonic acid (130 mg, 0.746 mmol) and triethylamine (0.24 mL, 1.72 mmol) were added, followed by stirring at room temperature for 21 hours under nitrogen atmosphere. A saturated aqueous sodium hydrogencarbonate solution (10 mL) was added, and the solution was separated with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-70%) to afford the desired product (155 mg, yield 56%) as a white solid.
Reaction SMILES: Cl.[C:2]1([CH2:8][O:9][C:10]([NH:12][C@@H:13]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:14](=[O:35])[CH2:15][NH:16][C@H:17]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>O1CCCC1.O>[C:2]1([CH2:8][O:9][C:10]([NH:12][C@@H:13]([CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:14]([OH:35])[CH2:15][NH:16][C@H:17]([C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26])[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)CN[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)C(O)CN[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 0.08 h
Yield: 97 %

Procedure:
A solution of N-[(3S)-3-[[(phenylmethoxy)carbonyl]amino]-2-oxo-4-phenylbutyl]-L-phenylalanine, phenylmethyl ester, hydrochloride (2.12 g, 3.6 mmol) in 72 ml of 3:1 tetrahydrofuran-water was cooled to 0° C. Sodium borohydride (681 mg, 18 mmol) was added in approximately seven portions over 5-10 minutes. The reaction mixture was allowed to stir an additional 5 minutes and then poured into 150 ml of water. This mixture was extracted with 300 ml of ethyl acetate-ether (5:3). The organic extract was washed with water (2×50 ml) and brine (50 ml) and then dried (sodium sulfate) and evaporated to give 1.93 g of a colorless oil. This material was purified by flash chromatography on 150 g of Merck silica gel (230-400 mesh), eluting with hexane-ethyl acetate (1.25:1), to afford 1.14 g of the title compound as a white solid. The 13C-NMR spectrum was consistent with an approximately 2:1 mixture of alcohol diastereomers.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[S:11]([N:21]1[CH2:27][CH2:26][CH2:25][C@H:22]1[CH2:23][OH:24])([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[CH3:18][C:17]1[CH:19]=[CH:20][C:14]([S:11]([N:21]2[CH2:27][CH2:26][CH2:25][CH:22]2[CH:23]=[O:24])(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2CO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)N2CCCC2C=O)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5 g (0.0394 mol) of oxalyl chloride in 50 ml of CH2Cl2 at -60° is added dropwise 7 g (0.0833 mol) of DMSO. The solution is stirred 30 minutes at -60° and then 10 g (0.039 mol) of N-tosylprolinol is added over five minutes at 60° and 15 ml of triethylamine is added. The solution is warmed to 25° and stirred one hour. The solution is then washed with H2O, dried over MgSO4 and the solvents removed. The residual oil, 10 g, is purified using a silica gel column and CHCl3 :MeOH (90:10) as the eluates. An oil is obtained which solidifies, 9.5 g (96%), mp 139°-140°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[N:10]2)[N:3]=1.[CH3:18][O-:19].[Na+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[N:10]2)[N:5]=[C:6]([O:19][CH3:18])[CH:7]=1
Reactant: FC(F)(F)c1ccn(-c2nc(Cl)cc(Cl)n2)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)nc(-n2ccc(C(F)(F)F)n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a stirred solution of compound 304 (1 g, 3.53 mmol) in MeOH (10 mL) at 0° C. was added NaOMe (760 μL) dropwise. The mixture was stirred at room temperature for 2 hrs. Methanol was evaporated. The residue was dissolved in DCM, washed sequentially with water and brine. Organics were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography to yield compound 305 as a white solid in 68% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 4.11 (s, 3H), 6.71-6.72 (m, 2H), 8.58 (dd, J=2.78 Hz and J=1.00 Hz, 1H); 19F NMR (CDCl3, 376 MHz) δ (ppm) −62.54 (s, 3F).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:29])([CH3:28])[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8]CC.[OH-].[K+].CN1CCN(C)C1=O.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:29])([CH3:28])[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:16]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOc1ccc(C(C)(C)COCc2cccc(Oc3ccccc3)c2)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccc(O)c(Cl)c1
Temperature: 150 °C
Reaction time: 18 h
Yield: 48.9 %

Procedure:
100 g of 3-phenoxybenzyl 2-(3-chloro-4-ethoxyphenyl)-2-methylpropyl ether and 25 g of 97% potassium hydroxide were added to 300 ml of 1,3-dimethyl-2-imidazolidinone (hereinafter referred to as DMI) and the mixture was stirred at 150° C. for 18 h. After cooling to room temperature, the mixture was poured into water and made acidic with a concentrated aqueous hydrochloric acid solution. After extraction with benzene, the benzene solution was washed with water and dried. Benzene was distilled off under reduced pressure and the obtained oily residue was purified according to a column chromatography (silica gel, developer: benzene) to obtain 45.6 g of 3-phenoxybenzyl 2-(3-chloro-4-hydroxyphenyl)-2-methylpropyl ether (m.p. 68° to 69° C.).
Reaction SMILES: [H-].[Na+].O.[NH:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.Br[CH2:10][C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][N:12]=1>CCCCCC.CN(C)C=O>[N:4]1([CH2:10][C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: BrCc1noc2ccccc12
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(Cn3ccnc3)noc2c1
Temperature: 85 °C

Procedure:
Sodium hydride (50% in mineral oil, 3.4 g, 0.071 mole) is washed free of mineral oil with hexane (3×30 mL) and suspended in dimethylformamide (100 mL). This suspension is well stirred and maintained near room temperature (water bath) during the dropwise addition of a solution of imidazole (4.8 g, 0.071 mole) in dimethylformamide (25 mL). The reaction mixture is stirred at room temperature for 1 hour when 3-bromomethyl-1,2-benzisoxazole (15.0 g, 0.071 mole) is added all at once. The mixture is then heated at 85° C. for 8 hours. The solvent is evaporated in vacuo and the residue is taken up in methylene chloride (200 mL) and washed with water (3×50 mL). The organic solution is dried over anhydrous sodium sulfate, filtered and evaporated to give 3-[(1H-imidazol-1-yl)methyl]-1,2-benzisoxazole, which is purified by recrystallisation from isopropanol, m.p. 52-55° C. The free base is converted to the hydrochloride salt m.p. 145-146° C., when its solution in isopropanol is treated with a small excess of ethereal hydrogen chloride.
Reaction SMILES: Cl.Cl.CN([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)C.C([N:14]([CH2:17]C)[CH2:15]C)C.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[C:23](Cl)=[O:24]>ClCCl>[CH3:17][N:14]([CH3:15])[CH:10]1[CH2:9][CH2:8][CH2:7][N:6]([C:23](=[O:24])[C:22]2[CH:21]=[C:20]([Cl:19])[CH:28]=[C:27]([Cl:29])[CH:26]=2)[CH2:11]1
Reactant: CCN(CC)CC
Reactant: CN(C)N1CCCCC1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: CN(C)C1CCCN(C(=O)c2cc(Cl)cc(Cl)c2)C1
Reaction time: 0.25 h

Procedure:
A mixture of 3 dimethylaminopiperidine dihydrochloride (0 9 g, 0.005 mol), triethylamine (1.5 g, 0.015 mol) and dichloromethane (20 ml) was stirred for 15 min. 3,5-Dichlorobenzoylchloride (1.05 g, 0.005 mol) was then added and stirring continued for a further 2 h. The solution was then washed with aqueous sodium carbonate solution, dried and evaporated. The residue was dissolved in isopropyl alcohol (15 ml) and acidified with ethanolic hydrogen chloride to precipitate the crystalline hydrochloride 1.3 g, mp 242-244° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH2:10][OH:11].Cl>N>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: Oc1ccc(S)cc1
Agent: Cl
Agent: N
Product: OCCSc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
280 ml of 28% aqueous ammonia was added to a mixture of 50 g of 4-hydroxythiophenol and 54.56 g of ethylene bromohydrin and the mixture was stirred vigorously at room temperature for 2 h. 225 ml of concentrated hydrochloric acid was added thereto under cooling with ice to adjust the pH of the aqueous phase to 1. After extraction with ethyl acetate, the ethyl acetate layer was washed with a saturated aqueous common salt solution and then dried over anhydrous magnesium sulfate. The resulting solution was filtered and the filtrate was concentrated and subjected to silica gel column chromatography to obtain 44.77 g (yield: 66%) of the intended compound having the following physical properties:
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Al](C)(C)C.C1(C)C=CC=CC=1.[ClH:21].[CH3:22][NH2:23]>>[CH3:22][NH:23][C:4](=[NH:5])[C:3]1[CH:6]=[CH:7][C:8]([Cl:21])=[N:9][CH:2]=1
Reactant: CN
Reactant: Cl
Reactant: N#Cc1cccnc1Cl
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CNC(=N)c1ccc(Cl)nc1
Yield: 76.7 %

Procedure:
Using a method similar to Example 380, Part D, using 2-chloronicotinonitrile (1.00 g, 7.32 mmol), 2.0 M Al(CH3)3 in toluene (11 mL, 22.0 mmol) and methylamine hydrochloride (1.48 g, 22.0 mmol) gives the title compound (0.952 g, 76.7%): MS ES+ 171.8 (M+H)+, MS ES− 168.0 (M−H)−; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=5.0 min, 97.0% purity.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:15]3[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=3)=[N:9][N:10]3[CH2:14][CH2:13][S:12][C:11]=23)=[CH:3][CH:2]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C(Cl)Cl>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:8]([C:15]3[CH:16]=[C:17]([NH:21][C:31]([NH:30][C:27]4[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:29][CH:28]=4)=[O:32])[CH:18]=[CH:19][CH:20]=3)=[N:9][N:10]3[CH2:14][CH2:13][S:12][C:11]=23)=[CH:5][CH:6]=1
Reactant: Nc1cccc(-c2nn3c(c2-c2ccncc2)SCC3)c1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1cccc(-c2nn3c(c2-c2ccncc2)SCC3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
3-(7-Pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazol-6-yl)-phenylamine (52 mg, 0.177 mmol) was dissolved in dry DCM under nitrogen atmosphere. p-trifluoromethyl-phenylisocyanate (0.030 mL, 0.212 mmol, 1.2 eq) was added and the mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluant: DCM/MeOH 96:4) to give 73 mg (86%) of 1-[3-(7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazol-6-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea as white powder.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:14][C@@H:15]1[C@@H:23]([C@@H:24]([OH:26])[CH3:25])[O:22][C@H:21]2[C@H:17]([N:18]=[C:19]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[S:20]2)[C@H:16]1[O:36][CH2:37][CH:38]=[CH2:39])[CH:12]=[CH2:13].C(N(CC)CC)C>ClCCl>[C:24]([C@H:23]1[O:22][C@H:21]2[C@H:17]([N:18]=[C:19]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33])[S:20]2)[C@@H:16]([O:36][CH2:37][CH:38]=[CH2:39])[C@@H:15]1[O:14][CH2:11][CH:12]=[CH2:13])(=[O:26])[CH3:25]
Reactant: C=CCO[C@H]1[C@H](OCC=C)[C@H]2N=C(N(C)C(=O)OC(C)(C)C)S[C@H]2O[C@@H]1[C@H](C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCO[C@@H]1[C@H]2N=C(N(C)C(=O)OC(C)(C)C)S[C@H]2O[C@H](C(C)=O)[C@H]1OCC=C
Temperature: -20 °C
Reaction time: 4 h
Yield: 72.6 %

Procedure:
A solution of DMSO (52 g, 672 mmol) in dichloromethane (500 mL) was treated with oxalyl dichloride (64 g, 505 mmol) at −78° C. for 1 hour, then a solution of 117 (36 g, 84 mmol) in dichloromethane (150 mL) was added. The resulted solution was stirred for 4 hours at −20° C. followed by the addition of triethylamine (85 g, 841 mmol) at −78° C. After stirring at −20° C. for additional 1 hour, the reaction was quenched with water (600 mL), extracted with dichloromethane (2×300 mL). The organic layers combined, washed with brine (2×200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by silica gel column, eluted with 3% 20% ethyl acetate in petroleum ether to afford 118 (26 g, 73%) as a yellow syrup; [M+H]+ 427.0; 1H NMR (300 MHz, CDCl3) δ 6.02 (d, J=6.3 Hz, 1H), 5.82-5.99 (m, 2H), 5.17-5.35 (m, 4H), 4.20-4.29 (m, 1H), 4.03-4.29 (m, 5H), 3.71-3.77 (m, 2H), 3.25 (s, 3H), 2.14 (s, 3H), 1.52 (s, 9H).