Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]([O:17][C:18]([N:20]1[CH2:28][CH:27]([OH:29])[CH2:26][C@H:21]1[C:22]([O:24][CH3:25])=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[Na+]>O1CCCC1>[C:13]([O:17][C:18]([N:20]1[CH2:28][C@H:27]([O:29][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:26][C@H:21]1[C:22]([O:24][CH3:25])=[O:23])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1CC(O)CN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
2.02 ml of methanesulfonyl chloride, followed by 3.65 ml of triethylamine were added, whilst ice-cooling, to a solution of 6.1 g of methyl 1-(t-butoxycarbonyl)-4-hydroxyprolinate [prepared as described in step (6) above] dissolved in 120 ml of dry tetrahydrofuran. The mixture was stirred first at 0° to 5° C. for 1 hour and then at room temperature for 1 hour, after which it was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to afford 8.13 g of the title compound as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:9][CH:8]=1.[CH2:28]([NH:30][CH2:31][CH2:32][OH:33])[CH3:29]>CC(N(C)C)=O>[CH2:28]([N:30]([CH2:31][CH2:32][OH:33])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:9][CH:8]=1)[CH3:29]
Reactant: CN(c1ccc(OCCCCBr)cc1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCNCCO
Solvent: CC(=O)N(C)C
Product: CCN(CCO)CCCCOc1ccc(N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.9 %

Procedure:
A solution of 466 mg (1 mmol) of N-[4-(4-Bromo-butoxy)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide 69-9844 in 3.5 ml DMA was treated at 0° C. with 0.195 ml (2 mmol) of 2-ethylaminoethanol and stirred at RT for 15 h. The reaction mixture was cooled (0° C.) again, treated with 0.195 ml (2 mmol) of 2-ethylaminoethanol and stirred at RT for further 24 h. The solution was concentrated, the residual oil was dissolved in water/acetontrile 1:1/5% formic acid and purified by prep. HPLC: RP-18, acetonitrile/water, 10%-60% acetonitrile. The pure fractions were collected, dissolved in EtOAc, washed with aqueous sat. NaHCO3 solution, and the organic phase was dried (Na2SO4) and evaporated to yield 360 mg (76%) of N-(4-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-phenyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide, MS: 475 (MH+).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:16][N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29](S(C4C=CC(C)=CC=4)(=O)=O)[CH:28]=3)=[N:18]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CCO>[NH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]([C:19]2[C:20]3[C:21](=[N:22][CH:23]=[N:24][C:25]=3[NH2:26])[N:17]([CH2:16][C:8]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[N:18]=2)=[CH:28]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nn(Cc4nc5ccccc5n4-c4ccccc4)c4ncnc(N)c34)c3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ncnc2c1c(-c1c[nH]c3ccccc13)nn2Cc1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
A solution of 1-(1-phenyl-1H-benzoimidazol-2-ylmethyl)-3-[1-(toluene-4-sulfonyl)-1H-indol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine in EtOH (20 mL) was added NaOH (2 M, 20 mL). After stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was added H2O and extracted with CH2Cl2. The combined organic layers were evaporated and the residue was purified by P—HPLC to give 154 (500 mg, yield 51%) as a white solid. LCMS (ESI), M+H+=455.18. 1HNMR (400 MHz, DMSO) δ 5.891 (s, 2H), 7.033-7.068 (t, J=7 Hz, 1H), 7.111-7.186 (m, 2H), 7.233-7.284 (m, 2H), 7.458-7.513 (m, 6H), 7.622-7.642 (d, J=8 Hz, 1H), 7.682-7.703 (d, J=1.8 Hz, 1H), 7.724-7.731 (d, J=2.8 Hz, 1H), 8.367 (s, 1H), 11.639-11.644 (d, J=2 Hz, 1H)
Reaction SMILES: C(=O)(O)[O-].[K+].COP([CH2:12][C:13](=[O:21])[CH2:14][P:15]([O:19][CH3:20])([O:17][CH3:18])=[O:16])(OC)=O.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[O:34]>O.C(O)(C)(C)C>[CH3:20][O:19][P:15]([CH2:14][C:13](=[O:21])[CH:12]=[CH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[O:34])([O:17][CH3:18])=[O:16]
Reactant: COP(=O)(CC(=O)CP(=O)(OC)OC)OC
Reactant: O=CCCCCCCCCCCC=O
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: COP(=O)(CC(=O)C=CCCCCCCCCCCC=O)OC
Reaction time: 2 h

Procedure:
A solution of 5 g of potassium bicarbonate in 150 ml of water was added to a mixture of 8.22 g (30 mMole) of 1,3-bis(dimethylphosphono)propan-2-one and 5.94 g (80 mMole) of dodecan-1,12-dial in 150 ml of t-butanol. After 21/2 h stirring at 27° under nitrogen water was added and the mixture was extracted with ether. The organic layer was separated, washed with brine, dried over sodium sulphate and evaporated. The residue was chromatographed on 150 g of silica gel. Hexane-ethyl acetate 1:1 eluted 2.68 g of unreacted dodecan-1,12-dial and ether eluted 4.38 g (42%, resp. 75% when based on recovered dial) of the title compound as a viscous oil.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:11]=1[CH2:12][NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]([CH2:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])[C:16](=[O:30])[CH:15]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:15]1[C:16](=[O:30])[N:17]([CH2:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])[C:18]([CH3:20])=[CH:19][C:14]=1[NH:13][CH2:12][C:11]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:10]=1[F:9]
Reactant: Cc1cc(NCc2ccc(F)cc2F)cc(=O)n1Cc1cccc(C#N)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(NCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1cccc(C#N)c1
Reaction time: 2 h
Yield: 19.2 %

Procedure:
N-Chloro succinimide (36 mg, 0.27 mmol) was added to a solution of the product of Step 5 (0.125 g, 0.26 mmol) in methylene chloride (10 mL). After stirring at 25 C for 2 h, the reaction was complete by LC-MS. The reaction mixture was poured into saturated aqueous NaHCO3. The aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous Na2SO4, and concentrated in vacuo. The residue was triturated with acetonitrile to give the title compound as a tan solid (20 mg, 13%). 1H NMR (400 MHz, CD3OD) δ 7.61 (d, J=8.4 Hz, 1H), 7.49 (m, 2H), 7.40 (d, J=8.4 Hz, 1H), 7.33 (q, J=8.4 and 14.8 Hz, 1H), 6.94 (m, 2H), 6.00 (s, 1H), 5.34 (s, 2H), 4.56 (s, 2H), 2.21 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −114.00 (1F), −116.89 (1F) ppm. LC/MS, tr=5.49 minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 400 (M+H).
Reaction SMILES: C([N:4]([C:30](=[O:32])[CH3:31])[C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[CH2:7][N:8]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C:9](=[CH2:14])[C:10]([O:12][CH3:13])=[O:11])(=O)C.C(=O)(O)[O-].[Na+]>CO>[C:30]([N:4]1[C:5]2[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=2[CH2:7][N:8]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:14]1)(=[O:32])[CH3:31]
Reactant: C=C(C(=O)OC)N(Cc1ccccc1N(C(C)=O)C(C)=O)S(=O)(=O)c1ccc(OC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CN(C(C)=O)c2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a solution of 0.70 g (1.52 mmol) of methyl 2-[(2-diacetylaminobenzyl)-(4-methoxybenzenesulfonyl)amino]acrylate in 5 ml of anhydrous methanol was added 0.332 g (3.95 mmol) of anhydrous sodium bicarbonate. The mixture was stirred at room temperature overnight and the solvent removed under vacuum. To the residue was added ethyl acetate and H2O. The organic layer was separated, washed with brine and dried with Na2SO4. The solvent was removed and the residue dried under vacuum to give 0.59 g of white crystals, m.p. 150-155° C. Anal. for C20H22N2O6S: Calc'd: C,57.4; H,5.3; N,6.7; S,7.7; Found: C,56.6; H,5.2; N,6.5; S,7.5; Mass spectrum (ES) 419.9 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.[C:26]([O-])([O-])=[O:27].[K+].[K+]>CO>[CH3:26][O:27][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [K+]
Solvent: CO
Product: COc1nc(Nc2ccc(OC)c(Cl)c2)nc(NC2CCCCCC2)n1

Procedure:
To 6-chloro-N-(3-chloro-4-methoxyphenyl)-N′-cycloheptyl-[1,3,5]triazine-2,4-diamine (5 g) dissolved in methanol was added K2CO3 (3.2 g) and refluxed for about 6-8 h. TLC was monitored. After the completion of the reaction, the reaction mass was filtered through vacuum and the filtrate was evaporated to yield the title compound. (Wt. 4.7 g Y: 95%)
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([OH:14])=O.C(Cl)Cl.C(Cl)CCl.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([N:31]1[CH2:32][CH2:33][N:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:29][CH2:30]1)=[O:14]
Reactant: Cc1c(C(=O)O)sc2nc[nH]c(=O)c12
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(C(=O)N2CCN(c3ccccc3)CC2)sc2nc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
To a solution of 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid, (0.42 g, 2 mmol) in 1:1 DCM and DMF (10 mL) was added EDC (0.764 g, 4 mmol), DMAP (cat.) and 4-phenylpiperazine (0.324 g, 2 mmol). The reaction was stirred at RT overnight and DCM was removed. The resultant residue was partitioned between EtOAc (50 mL) and H2O (50 mL). The organic layer was dried over Na2SO4 and concentrated to provide 0.4 g 5-methyl-6-(4-phenylpiperazine-1-carbonyl)thieno[2,3-d]pyrimidin-4(3H)-one, (yield: 57%).
Reaction SMILES: [S:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][CH:5]=1)C#N.C(S)[C@@H](O)[C@@H](O)CS.[CH2:18]([O:20][C:21](=[O:26])[C:22](Br)([CH3:24])[CH3:23])[CH3:19].C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O.O>[CH2:18]([O:20][C:21](=[O:26])[C:22]([S:1][C:4]1[S:8][C:7]([NH2:9])=[N:6][CH:5]=1)([CH3:24])[CH3:23])[CH3:19]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: N#CSc1cnc(N)s1
Agent: O=C([O-])[O-]
Agent: O[C@H](CS)[C@@H](O)CS
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
In a nitrogen atmosphere 5-thiocyanato-thiazol-2-ylamine (10 g, 64 mmol) dissolved in MeOH (300 mL) was added 2,3-dihydroxy-1,4-dithiolbutane (DTT, 9.8 g, 64 mmol) and stirred at room temperature for 11/2 h. Then 2-bromo-2-methyl-propionic acid ethyl ester (13.6 g, 70 mmol) and K2CO3 (10.5 g, 76 mmol) was added and the reaction mixture was stirred for further 13H. Addition of water (500 mL) and EtOAc (500 mL). Separation of the organic phase followed by extraction of the aqueous phase with EtOAc (2×300 mL). The combined organic phases were washed with water (500 mL) and brine (2×400 mL) and dried (MgSO4), filtered and evaporated. The crude product was dissolved in a small amount of DCM and purified by flash chromathography (heptane/EtOAc 2:1→1:2). Fractions containing the product were pooled and evaporated to a product containing impurities of DDT. This product was dissolved in diethyl ether (100 mL) and washed with water several times. The ether phase was dried (MgSO4), filtered and evaporated to give 8.45 g (54%) of 95% pure 2-(2-aminothiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester as light brown crystals.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[N:7][C:8]([F:12])=[C:9]([CH3:11])[CH:10]=1)(=O)C>[OH-].[Na+]>[F:12][C:8]1[C:9]([CH3:11])=[CH:10][C:5]([OH:4])=[CH:6][N:7]=1
Reactant: CC(=O)Oc1cnc(F)c(C)c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(O)cnc1F
Yield: 86.8 %

Procedure:
The product of step 32d (3.6 g, 21.3 mmol) was dissolved in 20% aqueous NaOH (25 mL). After complete consumption of the starting material the solution was neutralized by addition of HCl. The aqueous mixture was extracted with ethyl acetate. The organic extracts were dried (MgSO4), and the solvent was evaporated. The crude product was triturated with hexane to yield 2.35 g (87%) of the title compound: MS (CI/NH3) m/z: 128 (M+H)+, 145 (M+NH4)+ ; 1H NMR (CDCl3, 300 MHz) δ: 7.61(t, J=2.2 Hz, 1H), 7.17 (m, 1 H), 2.25 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.[F:43][C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=1[CH2:51][C:52]([OH:54])=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[F:43][C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=1[CH2:51][C:52]([N:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][S:18][C:9]1[NH:10][C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:54]
Reactant: O=C(O)Cc1ccc(F)cc1F
Reactant: CCCCCCCNCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCN(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)Cc1ccc(F)cc1F
Reaction time: 2.5 h
Yield: 88 %

Procedure:
To a solution of N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-1-heptanamine (2.2 g, 0.005 mol), 1-hydroxybenzotriazole hydrate (0.81 g, 0.006 mol), and 2,4-difluorophenylacetic acid (1.12 g, 0. 0065 mol) in N,N-dimethylformamide (50 mL) at 0° was added, portionwise as a solid, dicyclohexylcarbodiimide (1.24 g, 0.006 mol). The reaction mixture was stirred at 0° for 2.5 hours, then at ambient temperature for 72 hours . The solids were filtered and washed with chloroform. The filtrate was concentrated under vacuum and the residue (5.2 g) was chromatographed with 7:3 hexane-ethyl acetate. The resulting solid was triturated with hexane to give the title compound (2.59 g, 0.0044 mol) as a yellow oil. 1H NMR (CDCl3) δ 7.6-7.0(m,11H), 6.8-6.5(m,2H), 3.7(d,2H,J=13.7 Hz), 3.5(t,2H,J=6.4 Hz), 3.4-3.0(m,3 H), 2.9(t,2H,J=6.1 Hz), 1.8-1.1(m,17H), 0 0.9(t,3H,J=6.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[C:13]1[C:21]2[C:16](=[C:17]([O:22][CH3:23])[N:18]=[CH:19][CH:20]=2)[N:15]([CH3:24])[CH:14]=1.[NH:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:30]2[CH2:31][CH2:32][CH:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:34][CH2:35]2)=[CH:7][C:6]=1[C:13]1[C:21]2[C:16](=[C:17]([O:22][CH3:23])[N:18]=[CH:19][CH:20]=2)[N:15]([CH3:24])[CH:14]=1
Reactant: COc1nccc2c(-c3cc(C=O)ccc3Oc3ccc(F)cc3F)cn(C)c12
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1nccc2c(-c3cc(CN4CCC(NC(=O)OC(C)(C)C)CC4)ccc3Oc3ccc(F)cc3F)cn(C)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 426.9 %

Procedure:
A solution of Example 105B (125 mg, 0.317 mmol), tert-butyl piperidin-4-ylcarbamate (190 mg, 0.951 mmol) and acetic acid (0.181 mL, 3.17 mmol) in dichloromethane (3 mL) was heated at 50° C. for 1 hour. The reaction mixture was cooled in an ice bath and the sodium triacetoxyborohydride (134 mg, 0.634 mmol) was added portionwise over a few minutes. The reaction mixture was stirred 2 hours while warming to ambient temperature. The reaction mixture was quenched with 1 M sodium hydroxide (2 mL) and partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (50 mL). The layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (783 mg, 100% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH:9]=[CH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)[CH2:3][CH2:2]1.[H][H]>[Pt].C(O)C>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)[CH2:3][CH2:2]1
Reactant: O=C1CCc2cc(C=CCCN3CCOCC3)ccc2N1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: O=C1CCc2cc(CCCCN3CCOCC3)ccc2N1
Yield: 81.2 %

Procedure:
2.8 Grams of 6-(4-chloro-4-butenyl)-3,4-dihydrocarbostryil and 2.1 g of sodium iodide were mixed into 40 ml of dimethylformamide and the mixture was stirred at 50° C. for 1 hour. Then into the reaction mixture was added 2.0 g of morpholine and 2.0 ml of triethylamine and was stirred at 50° C. for 1 hours. The reaction mixture was concentrated under a reduced pressure to obtain a residue and 50 ml of 5%-sodium hydrogencarbonate aqueous solution was added therein and stirred. Next, the insoluble matters formed in the mixture were collected by filtration, and were washed with water and then recrystallized from ethanol to obtain 2.2 g of 6-(4-morpholino-1-butenyl)-3,4-dihydrocarbostyril, having the melting point of 136°-139° C. in colorless needle-like crystals. Next, 2.2 g of 6-(4-morpholino-1-butenyl)-3,4-dihydrocarbostyril and 0.2 g of platinum black were mixed into 100 ml of ethanol and was subjected to catalytic reduction under 3 kg/cm2 of hydrogen gas at a room temperature for 5 hours. The reaction mixture was filtered and the mother liquor was concentratd under a reduced pressure to obtain a residue. The residue was recrystallized from ligroinbenzene to obtain 1.8 g of 6-(4-morpholinobutyl)-3,4-dihydrocarbostyril, in colorless flake-like crystals. Melting point: 130°-132° C.
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]1[CH2:15]O.[CH:18]1([N:21]2[C:29]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[NH:23][C:22]2=[O:30])[CH2:20][CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O-])=O)=NC([O-])=O>C1COCC1>[CH:18]1([N:21]2[C:29]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[N:23]([CH2:15][C:7]3[N:6]([CH2:5][CH2:4][CH2:3][CH:2]([F:17])[F:1])[C:14]4[C:9]([N:8]=3)=[N:10][CH:11]=[CH:12][CH:13]=4)[C:22]2=[O:30])[CH2:20][CH2:19]1
Reactant: O=c1[nH]c2cnccc2n1C1CC1
Reactant: OCc1nc2ncccc2n1CCCC(F)F
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1n(Cc2nc3ncccc3n2CCCC(F)F)c2cnccc2n1C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.4 %

Procedure:
To a suspension of (1-(4,4-difluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)methanol 43-5 (470 mg, 1.9 mmol), 1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one 10-d (431 mg, 2.3 mmol) and triphenylphosphine (613 mg, 2.3 mmol) in 14 ml dry THF was added (E)-diïsopropyl diazene-1,2-dicarboxylate (0.6 ml, 2.9 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The precipitate was filtered off and washed with some diethyl ether to obtain the title product as a white powder (450 mg, 58%). m/z=399 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][O:43][C:44]1[C:49]([CH3:50])=[CH:48][CH:47]=[CH:46][C:45]=1[O:51][CH3:52]>>[CH3:52][O:51][C:45]1[CH:46]=[CH:47][CH:48]=[C:49]([CH3:50])[C:44]=1[O:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C)c1OCCCBr
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4c(C)cccc4OC)cc3)cc21

Procedure:
Analogously to Method I, 0.100 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.065 g of 2-(3-bromopropoxy)-1-methoxy-3-methylbenzene are used to prepare the title compound. Rf=0.26 (2:1 EtOAc-heptane); Rt=6.05.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]([NH2:12])=[S:11])[CH:7]=[CH:8][N:9]=1.[Br:13][C:14]1[CH:23]=[CH:22][C:17]([C:18](=O)[CH2:19]Br)=[CH:16][CH:15]=1>CCO>[Br:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]2[N:12]=[C:10]([C:6]3[CH:7]=[CH:8][N:9]=[C:4]([CH2:3][CH2:2][CH3:1])[CH:5]=3)[S:11][CH:19]=2)=[CH:16][CH:15]=1
Reactant: CCCc1cc(C(N)=S)ccn1
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: CCO
Product: CCCc1cc(-c2nc(-c3ccc(Br)cc3)cs2)ccn1
Temperature: 70 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
As shown in FIG. 27, in reaction (a) a mixture of prothionamide (9.01 g, 50.0 mmol) and 4-bromophenacyl bromide 6a (13.9 g, 50.0 mmol) in EtOH (400 mL) was stirred at 70° C. for 1 h. After cooled to room temperature, the precipitation was filtered off with EtOAc and washed with EtOAc and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give 4-(4-bromophenyl)-2-(2-propylpyridin-4-yl)thiazole 2 (14.3 g, 79%) as a light-yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:24]3[C:19](=[C:20]([O:25]CC4C=CC=CC=4)[CH:21]=[CH:22][CH:23]=3)[C:18]([CH3:33])=[N:17]2)[CH:5]=[CH:6][C:7]=1[O:8]CC1C=CC=CC=1>[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:25])[C:19]=3[C:18]([CH3:33])=[N:17]2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: Cc1nn(-c2ccc(OCc3ccccc3)c(F)c2)c2cccc(OCc3ccccc3)c12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1nn(-c2ccc(O)c(F)c2)c2cccc(O)c12
Reaction time: 18 h
Yield: 56.6 %

Procedure:
A mixture of 1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-3-methyl-4-[(phenylmethyl)oxy]-1H-indazole (D31) (0.45 g) and 10% palladium on charcoal (150 mg) in ethyl acetate (30 mL) was hydrogenated at atmospheric pressure for about 18 hrs. The mixture was filtered, concentrated and chromatographed (silica gel, 0-100% ethyl acetate in hexane) to give the title compound as a white solid (0.15 g) (E15).