Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].[C:13]([Si:17]([CH3:28])([CH3:27])[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([NH2:26])[CH:20]=1)([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[SH:2][C:1]1[NH:26][C:21]2[CH:20]=[C:19]([O:18][Si:17]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:28])[CH3:27])[CH:24]=[CH:23][C:22]=2[N:25]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)c(N)c1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2nc(S)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
1,1′-Thiocarbonyldiimidazole (1.87 g, 10.5 mmol) is added by portions to a solution of 4-(tert-butyl-dimethyl-silanyloxy)-ortho-phenylenediamine (2.5 g, 10.5 mmol) in 25 ml of tetrahydrofuran and the mixture is stirred at room temperature for 16 hours. The reaction mixture is then concentrated under reduced pressure, dissolved in 300 ml of ethyl acetate and washed with water (2×100 ml). The organic phase is then dried over MgSO4, filtered and concentrated. The residue is triturated in diisopropylether and pentane and dried under vacuum to yield 2.07 g of 2-mercapto-5-(tert-butyl-dimethyl-silanyloxy)-benzimidazole. Yield=70%. Analytical LC/MS (method B): retention time=4.79 min. m/z=281.36 (positive ion mode).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1.N1C=CC=C[CH:25]=1.Cl.S(Cl)(Cl)=O>CO>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:25])=[O:12])=[CH:5][C:4]=1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1
Reactant: c1ccncc1
Reactant: COc1ccc(CCC(=O)O)cc1-c1ccc2ccccc2c1
Agent: Cl
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1ccc(O)c(-c2ccc3ccccc3c2)c1

Procedure:
According to the procedure described in the synthesis method of Intermediate 20 in Reference Example 6 (Step f), Intermediate 35 (551 mg), pyridine and concentrated hydrochloric acid (5 ml each) were reacted and treated. According to the procedure described in the synthesis method of Intermediate 1 in Reference Example 1 (Step c), the obtained residue was reacted with thionyl chloride (0.33 ml) in methanol to obtain the title compound (Intermediate 36, 531 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-])=[O:9])=[CH:6][CH:5]=1.C1C=CC=CC=1.[N:20]1C=CC=C[CH:21]=1.C(Cl)(=O)C(Cl)=O>ClCCl.CO>[CH3:21][NH:20][C:8]([C:7]1[CH:11]=[CH:12][C:4]([C:3]([O:2][CH3:1])=[O:13])=[CH:5][CH:6]=1)=[O:9]
Reactant: c1ccncc1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: c1ccccc1
Product: CNC(=O)c1ccc(C(=O)OC)cc1
Reaction time: 0.25 h
Yield: 37 %

Procedure:
Monomethylterephthalate (Aldrich, 5.0 g, 0.028 mol) was added to 80 mL of dry benzene in a 250-mL round-bottom flask under argon and fitted with a calcium chloride drying tube. Dry pyridine (4.4 g, 0.056 mol) was added and the mixture was stirred for 15 min. Oxalyl chloride (3.66 g, 0.029 mol) was added by drop over 10 min. The mixture bubbled vigorously during the addition and a heavy white precipitate formed. The mixture was vigorously stirred for 40 min and followed by TLC (three solvent systems: dichloromethane, 2% methanol, and 5% methanol). Anhydrous methylamine was bubbled into the mixture for 10 min. The precipitate dissipated somewhat and the solution color changed from colorless to green and finally to yellow. The mixture was then stirred overnight. The remaining white precipitate was collected on a filter and washed with benzene. The filtrate was washed with water and dried over sodium sulfate. The drying agent was removed by filtration, washed with benzene, and the solvent concentrated to give a white solid. The solids were combined and dissolved in 300 mL dichloromethane. The solution was washed 3 times with 5% HCl, 3×5% sodium bicarbonate, 3×water, 1×brine, and then dried over sodium sulfate. The drying agent was removed by filtration and the filtrate concentrated to give a white solid which was dried in vacuo. This white solid was recrystallized from methanol to give 2 g (37%) of methyl 4-(methylaminocarbonyl)benzoate, mp 126° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][CH:4]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][N:23]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Li+].[OH-].Cl>O.O1CCCC1>[CH3:1][CH:2]([CH3:32])[CH2:3][CH:4]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][N:23]=1)[NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(C(CC(C)C)Nc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
Methyl 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-ylamino)butyl)nicotinate (190 mg, 0.429 mmol) was dissolved in water (3 mL) and tetrahydrofuran (3 mL). 1N LiOH (54.0 mg, 1.29 mmol) was added. The reaction was stirred at room temperature for 2 hours. The reaction was neutralized with 1N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to give 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-ylamino)butyl)nicotinic acid (180 mg, 98%) as a yellow solid. 1H NMR (400 MHz, CD3OD, δ): 9.08 (s, 1H), 8.25 (d, 1H), 7.59-7.63 (m, 5H), 7.38 (d, 2H), 6.63 (d, 2H), 4.65 (m, 1H), 1.85 (m, 2H), 1.65 (m, 1H), 1.00 (m, 6H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:28]=[CH:27][C:10]2[CH2:11][C@@H:12]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:13](=[O:21])[N:14]([CH2:16]C(F)(F)F)[CH2:15][C:9]=2[CH:8]=1>C(Cl)Cl>[OH:6][C:7]1[CH:28]=[CH:27][C:10]2[CH2:11][C@@H:12]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:13](=[O:21])[N:14]([CH3:16])[CH2:15][C:9]=2[CH:8]=1
Reactant: COC(=O)C[C@@H]1Cc2ccc(OC)cc2CN(CC(F)(F)F)C1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)C[C@@H]1Cc2ccc(O)cc2CN(C)C1=O
Temperature: -5 °C
Reaction time: 1.5 h
Yield: 118.1 %

Procedure:
A solution of boron tribromide in CH2Cl2 (1.0 M, 250 mL, 250 mmol) was added dropwise over 30 min to a solution of methyl (S)-8-methoxy-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (21.5 g, 62.3 mmol) in anhydrous CH2Cl2 (230 mL) at −20° C. under argon. After an additional 1.5 hr at −15 to −20° C., the reaction was recooled to −20° C. and quenched by careful dropwise addition of MeOH (250 mL). The reaction was stirred at −10 to 0° C. for 1 hr, then was concentrated on the rotavap. The residue was reconcentrated from MeOH (2×). Purification by flash chromatography on silica gel (50% ethyl acetate/hexanes) gave the title compound (19.38 g, 94%) as a white solid: [α]D −130.50 (c 1.0, MeOH); TLC (silica, 40% EtOAc/hexane) Rf 0.40; MS (ES) m/e 332.1 (M+H)+; 1H NMR (400, CDCl3+2% DMSO-d6) δ 6.92 (d, J=8.3 Hz, 1 H), 6.71 (dd, 1H), 6.58 (d, J=2.5 Hz, 1H), 5.29 (d, J=16.7 Hz, 1 H), 4.21-3.98 (m, 2H), 3.96 (d, J=16.7 Hz, 1H), 3.82 (m, 1H), 3.68 (s, 3H), 2.98 (dd, 1H), 2.94 (dd, 1H), 2.83 (dd, 1H), 2.46 (dd, 1H). Anal. Calcd for C15H16F3NO4: C, 54.38; H, 4.87; N, 4.23. Found: C, 54.40; H, 4.96; N, 4.22.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:9]1[NH:17][C:12]2=[CH:13][N:14]=[CH:15][CH:16]=[C:11]2[CH:10]=1)[OH:8]>O1CCCC1.[O-2].[O-2].[Mn+4]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[NH:17][C:12]2=[CH:13][N:14]=[CH:15][CH:16]=[C:11]2[CH:10]=1)=[O:8]
Reactant: OC(c1ccccn1)c1cc2ccncc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=C(c1ccccn1)c1cc2ccncc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 112 %

Procedure:
(Pyridin-2-yl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (Example 117) (55 mg, 0.24 mmol) was dissolved in tetrahydrofuran (4 mL). Manganese dioxide (210 mg, 2.42 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered through diatomaceous earth and the filter cake was washed thoroughly with tetrahydrofuran. The organic filtrate was concentrated to a yellow solid. Drying under vacuum at 40° C. produced (pyridin-2-yl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (60 mg, quant.): mp 219-222° C.; 1H NMR (500 MHz, CD3OD) δ7.66-7.76 (2H, m), 7.85 (1H, m), 8.04-8.08 (1H, m), 8.14-8.21 (2H, m), 8.82-8.43 (1H, m), 8.92 (1H, s); ESI MS m/z=224 [C13H9N30+H]+; HPLC (Method A) 95.4% (AUC), tR=13.1 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9]/[CH2:10][OH:11])=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.[CH2:31]([O:33][C:34](=[O:47])[C@@H:35]([O:44][CH2:45][CH3:46])[CH2:36][C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1)[CH3:32]>C1C=CC=CC=1>[CH2:31]([O:33][C:34](=[O:47])[C@@H:35]([O:44][CH2:45][CH3:46])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:11][CH2:10]/[CH:9]=[C:8](/[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)\[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:39][CH:38]=1)[CH3:32]
Reactant: OC/C=C(\c1ccccc1)c1ccc(Br)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\c2ccccc2)c2ccc(Br)cc2)cc1)OCC
Yield: 90.3 %

Procedure:
Reaction of (E)-3-(4-bromophenyl)-3-phenyl-prop-2-en-1-ol (289 mg, 1.0 mmol), tributylphosphine (0.37 ml, 1.5 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (262 mg, 1.10 mmol) and azodicarboxylic dipiperidide (378 mg, 1.5 mmol) in benzene in an identical manner to example 3 gave the title compound (460 mg, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH2:32]([O:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH3:33]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:40]5[CH2:41][CH2:42][N:37]([CH2:36][CH2:35][O:34][CH2:32][CH3:33])[CH2:38][CH2:39]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CCOCCN1CCNCC1
Product: CCOCCN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-ethoxy-ethyl)-piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1-(2-ethoxy-ethyl)-piperazine following General Procedure C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([C@H:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]([NH2:18])=[O:17])[C:9]2=[O:14])([O-])=O.CO>>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([C@H:15]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:16]([NH2:18])=[O:17])[C:9]2=[O:14]
Reactant: NC(=O)[C@@H](c1ccccc1)n1ccc2c([N+](=O)[O-])cccc2c1=O
Solvent: CO
Product: NC(=O)[C@@H](c1ccccc1)n1ccc2c(N)cccc2c1=O
Reaction time: 1.5 h

Procedure:
A round bottom flask was charged with (R)-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)-2-phenylacetamide (2.3 g, 0.0071 mol), methanol (30 mL, 0.7 mol) palladium, 10% weight on charcoal (110 mg, 0.00090 mol) was added and the flask was evacuated of air and stirred under hydrogen atmosphere (1 atm) for 1.5 h. The reaction mixture was filtered over celite and the solvent removed under pressure. The residue was purified by flash chromatography (40 g silica, 0-10% MeOH/DCM) to obtain the product as a light yellow solid. MS m/z=294.5 (M+H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:12]=[C:13]([C:23]2[N:28]=[C:27]([C:29]3[CH:30]=[C:31]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:32]=[C:33]([Cl:35])[CH:34]=3)[N:26]=[C:25]([C:42]3[CH:47]=[C:46](Br)[CH:45]=[C:44](Br)[CH:43]=3)[N:24]=2)[CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.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>[Cl:10][C:11]1[CH:12]=[C:13]([C:23]2[N:28]=[C:27]([C:29]3[CH:30]=[C:31]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:32]=[C:33]([Cl:35])[CH:34]=3)[N:26]=[C:25]([C:42]3[CH:47]=[C:46]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:45]=[C:44]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:43]=3)[N:24]=2)[CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1cc(-c2ccccc2)cc(-c2nc(-c3cc(Br)cc(Br)c3)nc(-c3cc(Cl)cc(-c4ccccc4)c3)n2)c1
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: [Cs+]
Solvent: C1CCOC1
Product: Clc1cc(-c2ccccc2)cc(-c2nc(-c3cc(Cl)cc(-c4ccccc4)c3)nc(-c3cc(-c4ccccc4)cc(-c4ccccc4)c3)n2)c1
Yield: 84 %

Procedure:
In a stream of argon, phenylboronic acid (904 mg), 4,6-bis(5-chlorobiphenyl-3-yl)-2-(3,5-dibromophenyl)-1,3,5-triazine (1.70 g), cesium carbonate (2.41 g) and tetrakis(triphenylphosphine)palladium (114 mg) were suspended in tetrahydrofuran (80 mL), and the mixture was refluxed for 18 hours. The reaction mixture was left to stand at room temperature, and then low-boiling ingredients were distilled away under a reduced pressure. Methanol was added to the reaction mixture, and the solid precipitate was recovered by filtration, and purified by silica gel chromatography using a chloroform/hexane (1:2 to 1:0) mixed liquid as a developing solvent to give 1.42 g of the target 2,4-bis(5-chlorobiphenyl-3-yl)-6-[(1,1′:3′,1″)-terphenyl-5′-yl]-1,3,5-triazine as a yellowish white powder (yield: 84%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([N:32]2[CH2:37][CH2:36]S[CH2:34][CH2:33]2)=[O:31])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:10]=2)=[N:6][CH:7]=1.O[O:39][S:40]([O-:42])=O.[K+]>C1COCC1.CO.O>[O:39]=[S:40]1(=[O:42])[CH2:36][CH2:37][N:32]([C:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[CH:10]=3)[N:4]=2)=[O:31])[CH2:33][CH2:34]1
Reactant: O=S([O-])OO
Reactant: O=C(c1ccccc1Nc1nc(Nc2cccc(CCN3CCOCC3)c2)ncc1F)N1CCSCC1
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccccc1Nc1nc(Nc2cccc(CCN3CCOCC3)c2)ncc1F)N1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5-fluoro-N2-{3-[2-(4-morpholinyl)ethyl]phenyl}-N4-[2-(4-thiomorpholinylcarbonyl)phenyl]-2,4-pyrimidinediamine (100 mg, 0.19 mmoles) was dissolved in 5 mL of THF and 5 mL of methanol, and treated with a solution of OXONE® reagent (15 equivalents) in 5 mL water. The system was stirred for 48 h at room temperature, and then filtered and concentrated to dryness. The residue was immobilized onto silica gel and purified by flash chromatography on silica gel, using a gradient of 100% A to 90% A-10% B, where “A” is chloroform and “B” is 10:90:1 methanol-chloroform-concentrated aqueous ammonium hydroxyde). The title compound was isolated and characterized. MS: M(C27H31FN6O4S)=554.2, (M+H)+=555.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH3:2].[H-].[Na+].Cl.O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:11]1)[CH3:2]
Reactant: CCOC(=O)C=CCCCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC1CCCCO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
To a solution of 7-hydroxy-hept-2-enoic acid ethyl ester (99.9 g, 0.58 mol) in tetrahydrofuran prepared in the previous step, cooled with ice-water bath, was added sodium hydride (4.80 g, 0.12 mol, 60%) in two portions. The mixture was stirred at 0° C. for 2 h and then at room temperature for 2 h. The mixture was neutralized with a 1 M aqueous hydrochloric acid solution (pH ˜5.0-6.0). Water (1 L) was then added and the mixture was extracted with ethyl acetate (3×1 L). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was treated with hexanes/ethyl acetate (3×800 mL, hexanes/ethyl acetate=10/1, v/v). The mixture was filtered and dried over anhydrous sodium sulfate. The filtrate was concentrated and the crude product was purified by flash column chromatography (QingDao silica gel, 200-300 mesh, 10% ethyl acetate/hexanes) to afford (tetrahydro-pyran-2-yl)-acetic acid ethyl ester (77.1 g, 77% yield).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][NH2:42]>>[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][NH:42][C:29](=[O:30])[CH:28]([N:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:33])([F:1])[F:34])=[O:6])[CH:9]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)[CH:24]=[N:25]1)[CH3:32]
Reactant: NCc1ccccn1
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Product: CC(C(=O)NCc1ccccn1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and 2-pyridinemethanamine (Aldrich and Cat. No. A65204). LCMS (M+H)+: m/z=564.2.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[OH-].[NH4+:16]>C(O)C>[NH2:16][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3]
Reactant: [NH4+]
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Agent: [OH-]
Solvent: CCO
Product: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
5-Chlorosulfonyl-2-oxindole (2.1 g) was added to 10 mL of ammonium hydroxide in 10 mL of ethanol and stirred at room temperature overnight. The mixture was concentrated and the solid collected by vacuum filtration to give 0.4 g (20% yield) of the title compound as an off-white solid.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[NH:46]1[CH:50]=[C:49]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[N:48]=[N:47]1>O1CCCC1>[CH2:54]([O:53][C:51]([C:49]1[CH:50]=[N:46][N:47]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[N:48]=1)=[O:52])[CH3:55]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCOC(=O)c1c[nH]nn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
To a solution of t-butyl 4-hydroxypiperidine-1-carboxylate (0.43 g, 3.3 mmol) and triphenylphosphine (1.05 g, 4.0 mmol) in tetrahydrofuran (15 mL) at 0° C. was added dropwise diethyl azodicarboxylate (0.63 mL, 4.0 mmol). After 5 minutes ethyl 1H-1,2,3-triazole-4-carboxylate (0.43 g, 3.0 mmol, prepared according to D. R. Buckle, C. J. M. Rockell, J. Chem. Soc., Perkin Transaction 1 1982, 2, 627-630) was added in tetrahydrofuran (5 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified by medium pressure liquid chromatography (HPLC) using 15 to 40% ethyl acetate in hexanes as eluant to afford 0.42 g of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:14][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)cc1C(F)(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)c(C(F)(F)F)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
A mixture of 4-methyl-3-trifluoromethyl-benzonitrile (370 mg, 2 mmol), N-Bromosuccinimide (356 mg, 2 mmol) and benzoyl peroxide (15 mg) in CCl4 (8 mL) was stirred at 85° C. for 16 hrs. The reaction mixture was then partitioned between saturated aqueous NaHCO3 and DCM. DCM layer was dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid which was purified via flash chromatography (15% EtOAc in n-heptane) to yield the title compound as a solid (460 mg, 85%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH3:2].[CH2:15]([C:17]1[CH:22]=[C:21]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[C:19]([CH2:32][CH3:33])[C:18]=1O)[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:15]([C:17]1[CH:22]=[C:21]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[C:19]([CH2:32][CH3:33])[C:18]=1[O:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:12][CH2:13][CH3:14])[CH3:16]
Reactant: CCc1cc(OC(=O)c2ccccc2)cc(CC)c1O
Reactant: CCOC(COCCCCO)OCC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(COCCCCOc1c(CC)cc(OC(=O)c2ccccc2)cc1CC)OCC
Yield: 97.9 %

Procedure:
To a mixture of 16.0 g of 4-(2,2-diethoxyethoxy)butanol, 18.9 g of 2,6-diehtyl-4-benzoyloxyphenol (which had been produced according to the method as described in JP-A 8-337549/1996), 20.2 g of triphenylphosphine, and 200 ml of tetrahydrofuran was slowly added dropwise 17.0 g of diisopropyl azodicarboxylate with stirring under ice cooling in a stream of nitrogen gas. After stirring at room temperature for 6 hours, the reaction mixture was concentrated to give a residue. This residue was subjected to silica gel chromatography, which afforded 31.4 g (yield, 88%) of 3,5-diethyl-1-benzoyloxy-4-(4-(2,2-diethoxyethoxy)butyloxy)benzene, nD24.8 1.5129.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C([O:38][C:39](=[O:42])[CH2:40]Br)C1C=CC=CC=1.COC(C)(C)C>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[C:1]([O:4][C@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[O:7][CH2:40][C:39]([OH:42])=[O:38])(=[O:3])[CH3:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(=O)OC[C@H]1OC(O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: CC(=O)OC[C@H]1OC(OCC(=O)O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C

Procedure:
A mixture that consists of 34.83 g (100 mmol) of 2,3,4,6-tetra-O-acetyl-mannopyranose, 1.70 g (5 mmol) of tetrabutylammonium hydrogen sulfate and 82.93 g (600 mmol) of fine-powder potassium carbonate in 350 ml of dioxane is cooled to 0° C. At 0° C., 34.36 g (150 mmol) of bromoacetic acid benzyl ester is added in drops over 10 minutes while being stirred vigorously. It is stirred for one hour at 0° C. 250 ml of MTB (methyl-tert-butyl ether) is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of ethanol. 5 g of palladium (10%) on activated carbon is added thereto and hydrogenated until no more hydrogen is taken up by the solution. Catalyst is filtered out, it is rewashed with ethanol, and the combined solutions are evaporated to the dry state in a vacuum.