Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH:6]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[CH3:7].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH:6]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:49][CH2:50][C:51]2[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=2[CH3:57])=[O:14])=[CH:15][CH:16]=1)[CH3:7]
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(Oc1cccc(Br)c1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3cccc(Br)c3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.1 %

Procedure:
To a solution of 4-(1-(3-bromophenoxy)ethyl)benzoic acid (0.9 g, 2.8 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.77 g, 4.0 mmol) and 1-hydroxybenzotriazole (0.54 g, 4.0 mmol) in dichloromethane (20 mL) was added triethylamine (0.8 g, 8.0 mmol). The reaction mixture was stirred for 15 minutes at room temperature, then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.76 g, 5 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was washed with water (20 mL), concentrated and purified by column chromatography (silica gel: dichloromethane: methanol=20:1) to give pure product 4-(1-(3-bromophenoxy)ethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (1.2 g, 93%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH:10](C(OC)=O)[C:9]2=[O:19])[CH:2]=1.C(#N)C>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C:9]2=[O:19])[CH:2]=1
Reactant: COC(=O)C1C(=O)CCN(Cc2cccnc2)C1=O
Solvent: O
Solvent: CC#N
Product: O=C1CCN(Cc2cccnc2)C(=O)C1
Yield: 100.6 %

Procedure:
A mixture of methyl 1-(3-pyridylmethyl)-2,4-dioxopiperidine-3-carboxylate (8.50 g), acetonitrile (100 ml) and water (1.4 ml) is refluxed for one hour. The mixture is distilled to remove the solvent to give 1-(3-pyridylmethyl)-2,4-dioxopiperidine (6.66 g, quantitative) as crystals, m.p. 55°-60° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[NH:14][C@H:15]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)[C:16]([N:18]1[CH2:21][C:20]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[CH2:19]1)=[O:17])(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:14][C@H:15]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)[C:16]([N:18]1[CH2:21][C:20]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[CH2:19]1)=[O:17]
Reactant: CCCCOC1(c2ccccc2F)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC1(c2ccccc2F)CN(C(=O)[C@H](N)Cc2ccc(OC)cc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
1 ml of trifluoroacetic acid is added to a solution of 94 mg (0.2 mmol) of tert-butyl[(R)-2-[3-butoxy-3-(2-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]carbamate in 10 ml of dichloromethane, cooled beforehand to 0° C. After stirring for 1 h 30 at ambient temperature, the reaction medium is evaporated off under a stream of nitrogen. 119 mg of (R)-2-amino-1-[3-butoxy-3-(2-fluorophenyl)azetidin-1-yl]-3-(4-methoxy-phenyl)propan-1-one trifluoroacetate are obtained in the form of a yellow oil with a yield of 100%.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[C:9]([F:15])[CH:8]=1.COC(OC)CN(CC1C=CC(F)=CC=1)[S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>>[CH3:17][O:16][CH:3]([O:2][CH3:1])[CH2:4][N:5]([CH2:6][C:7]1[CH:8]=[C:9]([F:15])[C:10]([F:14])=[C:11]([F:13])[CH:12]=1)[S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24]
Reactant: COC(CNCc1cc(F)c(F)c(F)c1)OC
Reactant: COC(CN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1)OC
Product: COC(CN(Cc1cc(F)c(F)c(F)c1)S(=O)(=O)c1ccc(C)cc1)OC

Procedure:
Starting from (2,2-Dimethoxy-ethyl)-(3,4,5-trifluoro-benzyl)-amine (99), the title compound was prepared following the method described for N-(2,2-dimethoxy-ethyl)-N-(4-fluoro-benzyl)-4-methyl-benzene-sulfonamide (4). Rt=1.76 min (Method #4). Detected mass: 372.1 (M+H+).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[C:5]([F:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:21][C:22]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:23]=1[NH2:24]>>[CH3:21][C:22]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:23]=1[NH:24][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[C:5]([F:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(F)ccc1N
Reactant: CN(c1ccccc1)c1nc(Cl)nc2c(F)cccc12
Product: Cc1cc(F)ccc1Nc1nc(N(C)c2ccccc2)c2cccc(F)c2n1

Procedure:
In a procedure analogous to that of Example 41 2-chloro-4-(N-methylphenylamino)-8-fluoroquinazoline and 2-methyl-4-fluoroaniline are reacted together to give the title compound.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:16](OC)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[SH:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:24]=[C:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[S:19][C:1]([C:3]2[N:8]=[C:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)c1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 72.1 %

Procedure:
A mixture of tert-butyl 6-cyano-2-pyridinecarboxylate (1.1 g, 5.3 mmol), methyl thiosalicylate (1.8 g, 10.7 mmol), triethylamine (2.0 ml, 14.3 mmol) and toluene (4 ml) was refluxed for 12 hrs. After cooling, the precipitated crystals were collected by filtration, recrystallized from tetrahydrofuran-hexane to give the titled compound (1.3 g, 70%).
Reaction SMILES: FC(F)(F)CC(O[C:7]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:8]=1[F:17])=O.[CH:20]1[C:32]2[CH:31]([CH2:33][O:34][C:35]([N:37]([CH3:64])[C:38]([CH3:63])([C:40]([NH:42][C@H:43]([C:47]([N:49]([C@@H:51]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C@H:52]([O:57][CH3:58])[CH2:53][C:54]([OH:56])=[O:55])[CH3:50])=[O:48])[CH:44]([CH3:46])[CH3:45])=[O:41])[CH3:39])=[O:36])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1>ClCCl>[CH:29]1[C:30]2[CH:31]([CH2:33][O:34][C:35]([N:37]([CH3:64])[C:38]([CH3:63])([C:40]([NH:42][C@H:43]([C:47]([N:49]([C@@H:51]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C@H:52]([O:57][CH3:58])[CH2:53][C:54](=[O:56])[O:55][C:7]3[C:8]([F:17])=[C:9]([F:16])[C:10]([F:15])=[C:11]([F:14])[C:12]=3[F:13])[CH3:50])=[O:48])[CH:44]([CH3:45])[CH3:46])=[O:41])[CH3:39])=[O:36])[C:32]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]=2[CH:26]=[CH:27][CH:28]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reactant: O=C(CC(F)(F)F)Oc1c(F)c(F)c(F)c(F)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Temperature: 25 °C
Yield: 98.3 %

Procedure:
Pentafluorophenyl 3,3,3-trifluoropropanoate (2.44 mL, 13.4 mmol, 2.0 eq.) was added to a solution of #128 (4.18 g, 6.70 mmol, 1.0 eq.) in 50 mL of dichloromethane followed by pyridine (1.61 mL, 20.1 mmol, 3.0 eq.). Reaction was allowed to stir at room temperature for -12 hours. Reaction was concentrated in vacuo and the residue was purified by silica chromatography (Gradient: 0%-70% acetone in heptanes) producing #135 (5.2 g, 98%) as a white foam. LC-MS (Protocol Q1): m/z 812.1 [M+Na+] retention time=1.24 minutes.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:8]([C:10]1[CH:21]=[CH:20][C:13]2[N:14]([CH3:19])[C:15]([CH2:17][NH2:18])=[N:16][C:12]=2[CH:11]=1)=[O:9].FC(F)(F)C([O-])=O.C(N(C(C)C)C(C)C)C.Cl[C:46]1[CH:51]=[CH:50][C:49]([C:52]#[N:53])=[CH:48][N:47]=1.Cl>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:8]([C:10]1[CH:21]=[CH:20][C:13]2[N:14]([CH3:19])[C:15]([CH2:17][NH:18][C:46]3[N:47]=[CH:48][C:49]([C:52]#[N:53])=[CH:50][CH:51]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN)n2C)c1ccccn1
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cn1)n2C)c1ccccn1
Temperature: 100 °C

Procedure:
1.5 g (3.25 mmol) of 1-methyl-2-aminomethyl-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-trifluoracetate were stirred into 10 ml of N-ethyl-diisopropylamine and heated to 100° C. for 15 minutes. After the addition of 720 mg (5.25 mmol) of 2-chloro-5-cyano-pyridine the reaction mixture was heated to 125° C. for 2 hours. After cooling to ambient temperature and stirring with about 20 ml of water, the pH was adjusted to 4 by the addition of 1N hydrochloric acid and the mixture was extracted 3 times with ethyl acetate. The combined organic phases were washed with saline solution and dried over sodium sulphate. After evaporation of the solvent the crude product was chromatographed on silica gel, eluting first with methylene chloride, later with methylene chloride/ethanol (25:1) and (19:1). The desired fractions were combined and evaporated down.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][N+:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1SC.[CH2:25]([N:32]1[C:36](=[O:37])[CH2:35][S:34][C:33]1=[N:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[NH:47][CH2:48][CH3:49])[C:42]#[N:43])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[C:36](=[O:37])[C:35](=[C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]2[CH3:12])[S:34][C:33]1=[N:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[NH:47][CH2:48][CH3:49])[C:42]#[N:43])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CSc1ccc2ccccc2[n+]1C
Reactant: CCNc1ccc(C#N)cc1N=C1SCC(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2C=Cc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 45, intermediate 1-methyl-2-methylthioquinolinium p-toluenesulfonate was condensed with 3-(3-benzyl-4-oxothiazolidin-2-ylideneamino)-4-ethylaminobenzonitrile to afford the title compound. 1H-NMR (CDCl3): δ 7.41–7.58 (4H, m), 7.20–7.38 (9H, m), 6.49 (1H, d), 5.16 (2H, s), 3.79 (3, brs), 3.01 (2H, q), 1.02 (3H, t); MS(ESI): 492 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O>CCOC(C)=O.C(OCC)C>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:7]2[CH:15]=[CH:16][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:10]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cccnc2)cc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Nc1ccc(Oc2cccnc2)cc1
Reaction time: 3.5 h
Yield: 95.4 %

Procedure:
A solution of 3-(4-nitrophenoxy)pyridine (5.00 g, 23.13 mmol) in EtOAc (100 mL) in a 250 ml Parr bottle was purged with nitrogen. To this solution was added EtOAc-moistened 10% Pd/C catalyst (500 mg, 10% by weight). The reaction flask was placed in a Parr hydrogenation apparatus, purged with nitrogen (5×), evacuated, and then pressurized to 40 psi with hydrogen and shaken for 3.5 h. The reaction mixture was then purged with nitrogen, and filtered through a pad of Celite®, rinsing with ethyl acetate (3×) and ethanol (3×). The filtrate was evaporated at reduced pressure to give a brown crystalline residue. The residue was stirred in diethyl ether at room temperature for 16 h and then filtered to provide 4.11 g (95%) of the desired product as light brown crystals. 1H-NMR (DMSO-d6) δ 8.21 (m, 2H), 7.30 (ddd, J=8.4, 4.6, 0.7 Hz, 1H), 7.18 (ddd, J=8.4, 2.9, 1.4 Hz, 1H), 6.79 (d, J=8.8 Hz, 2H), 6.58 (d, J=9.0 Hz, 2H), 5.05 (br s, 2H); MS LC-MS [M+H]+=187, RT=1.03 min.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:19])[S:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][CH3:18])[CH:10]=2)=[O:5])C.[NH2:20][CH2:21][C:22]([O-:24])=[O:23].[Na+]>COCCO>[OH:16][C:15]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=2)[S:8][C:7](=[O:19])[C:6]=1[C:4]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:5]
Reactant: CCOC(=O)c1c(O)c2ccc(OC)cc2sc1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Solvent: COCCO
Product: COc1ccc2c(O)c(C(=O)NCC(=O)O)c(=O)sc2c1
Yield: 78 %

Procedure:
A mixture of 4-hydroxy-7-methoxy-2-oxo-2H-thiochromene-3-carboxylic acid ethyl ester (47 mg, 0.17 mmol) and sodium glycinate (81 mg, 0.84 mmol) in 2-methoxyethanol (5.6 mL) was refluxed overnight (20 h). The reaction mixture was concentrated, and the crude residue dissolved in water (60 mL), acidified to pH 3-4 using 1 N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to provide [(4-hydroxy-7-methoxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid (41 mg). MS ESI(−) m/e: 308.06 (M−1).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([CH:18]=[O:19])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1.[BH4-].[Na+].Cl.[CH3:25]O>>[CH3:25][O:19][CH2:18][C:17]1[CH:16]=[N:15][N:14]2[C:9]([C:5]3[CH:4]=[C:3]([C:2]([F:20])([F:1])[F:21])[CH:8]=[CH:7][CH:6]=3)=[CH:10][CH:11]=[N:12][C:13]=12
Reactant: CO
Reactant: O=Cc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: COCc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 1.35 g. of 7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine-3-carboxaldehyde in 90 ml. of absolute methanol is treated with 0.175 g. of sodium borohydride. After stirring for 2 hours at room temperature, excess 1 N aqueous hydrochloric acid is added and the mixture with the methanol is concentrated under reduced pressure. The solid that separates is dissolved in methylene chloride and this solution is washed with a saturated sodium bicarbonate solution and then dried (sodium sulfate). Addition of hexane to this refluxing solution causes the desired compound to crystallize, m.p. 114°-116° C.
Reaction SMILES: C(Cl)(Cl)Cl.C([O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:23]([O:25][CH:26]([C:31]([F:34])([F:33])[F:32])[CH2:27][CH2:28][CH2:29][CH3:30])=[O:24])[CH2:17][CH2:16]2)C1C=CC=CC=1.I[Si](C)(C)C>CO>[OH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:23]([O:25][C@@H:26]([C:31]([F:32])([F:33])[F:34])[CH2:27][CH2:28][CH2:29][CH3:30])=[O:24])[CH2:17][CH2:16]2
Reactant: CCCCC(OC(=O)C1=Cc2ccc(OCc3ccccc3)cc2CC1)C(F)(F)F
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCC[C@@H](OC(=O)C1=Cc2ccc(O)cc2CC1)C(F)(F)F
Yield: 61 %

Procedure:
To 10 ml of a chloroform solution of 0.23 g (0.5 mmol) of the (R) 1-trifluoromethylpentyl 6-benzyloxy-3,4-dihydro-2-naphthalenecarboxylate obtained in the third step was added 0.1 ml (0.7 mmol) of iodotrimethylsilane in a nitrogen atmosphere with stirring, and the mixture was reacted at room temperature for two and a half hours with stirring. Then, 10 ml of methanol was added, and the mixture was rapidly concentrated at room temperature under reduced pressure. The concentrate was separated by column chromatography, to obtain 0.11 g of (R)1-trifluoromethylpentyl 6-hydroxy-3,4-dihydro-2-naphthalenecarboxylate as a white solid (yield: 61%). The 1H-NMR data of this compound are described below.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:11])[NH:9][N:10]=[C:4]2[C:3]=1I.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:11])[NH:9][N:10]=[C:4]3[C:3]=2[C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=c1[nH]nc2c(I)c(Br)ccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ccn12
Temperature: 150 °C
Yield: 51.7 %

Procedure:
To a stirring mixture of 7-bromo-8-iodo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (1.0 g, 2.9 mmol) in 15 mL dioxane and 5 mL of water at 20° C. was added 4-chlorophenylboronic acid (1.4 g, 8.8 mmol), K2CO3 (0.8 g, 5.9 mmol), and tetrakis(triphenylphosphine)palladium (0.17 g, 0.15 mmol). The resulting reaction mixture was degassed and then heated in a microwave reactor at 150° C. for 40 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was allowed to cool to room temperature and was concentrated under reduced pressure. The crude product was purified by trituration with methylene chloride to obtain the title compound (0.52 g, 1.5 mmol) as a light yellow solid. MS: [M+H]+=356. 1H NMR (CD3OD): δ 7.89 (d, J=1.9 Hz, 1H), 7.37-7.24 (m, 8H), 5.48 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].[H-].[Na+].Cl[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1>C1COCC1>[CH3:9][C@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[N:13]=[C:14]([CH3:24])[S:15][C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[O:11])[C@H:3]1[CH2:2][O:1][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CO)c(-c2ccc(F)cc2)s1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2COc2ccc(C(F)(F)F)cn2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of rac-cis-(2-(hydroxymethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone in THF was added NaH (4 eq) at 0° C. and stirred for 30 min at RT. 2-Chloro-5-(trifluoromethyl)pyridine (2 eq) was then added and solution refluxed for 2 h. The reaction was cooled and quenched with saturated NH4Cl and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 493.7 (M+H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]1[CH:10]=[C:11]([CH:15]([OH:26])[CH2:16][O:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:12]=[CH:13][CH:14]=1>N1C=CC=CC=1>[C:1]([O:26][CH:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH3:8])[CH:10]=1)[CH2:16][O:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)(=[O:3])[CH3:2]
Reactant: Cc1cccc(C(O)COCCN2CCOCC2)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(COCCN1CCOCC1)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.65 ml of pyridine and 0.99 ml of acetic anhydride were added to 1 g of 1-(3-methylphenyl)-2-[2-(morpholin-4-yl)ethoxy]ethanol. The mixture was stirred for 3 hours at room temperature. The reaction mixture was subjected to distillation under reduced pressure to remove the solvent. To the residue were added 20 ml of ethyl acetate and 10 ml of water. The mixture was adjusted to pH 10 with potassium carbonate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: chloroform/ethanol=30/1) to obtain 1 g of oily 1-acetoxy-1-(3-methylphenyl)-2-[2-(morpholin-4-yl)ethoxy]ethane (compound No. 178).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:18]=3[N+:25]([O-:27])=[O:26])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH2:23][N:46]4[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]4)[CH:20]=[CH:19][C:18]=3[N+:25]([O-:27])=[O:26])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: NC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc([N+](=O)[O-])c(Nc3nc(-c4ccc(Cl)cc4)c(C(N)=O)s3)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.1 %

Procedure:
To a mixture of 0.16 g (0.40 mmole) of 4-(4-chloro-phenyl)-2-(5-formyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.19b), 0.51 g (2.38 mmole) of sodium triacetoxy-borohydride and 15 mL of dichloromethane was added 0.07 mL (0.60 mmole) of 1-methylpiperazine. The mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 0:100-15:85) to give 0.16 g of 4-(4-chloro-phenyl)-2-[5-(4-methyl-piperazin-1-ylmethyl)-2-nitro-phenylamino]-thiazole-5-carboxylic acid amide (VI.19c).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](OCC)=[O:14].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CCCCCC>O1CCCC1>[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](=[O:14])[CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: Cc1ccncc1
Reactant: CCOC(=O)c1ccco1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)c1ccco1
Reaction time: 2 h
Yield: 70.3 %

Procedure:
To a solution of 4-picoline (4.6 g, 49.4 mmol) and ethyl 2-furancarboxylate (7.7 g, 54.9 mmol) in tetrahydrofuran (40 ml) was dropwise added lithium bis(trimethylsilyl)amide (100 ml, 100 mmol) over 1 hour at 0° C. under an atmosphere of nitrogen gas, followed by stirring as it was for 2 hours. Hexane (140 ml) was added to the reaction mixture, and the resulting crystals were collected by filtration. The resulting crystals were dissolved in ethyl acetate and a saturated aqueous ammonium chloride solution. The organic layer was washed with a saturated aqueous ammonium chloride solution twice and brine, dried over anhydrous sodium sulfate and concentrated. Hexane was added to the residue, and the resulting precipitates were collected by filtration and washed with hexane, to give the title compound (6.5 g, 70%) as a pale yellow solid.