Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:10](=[O:11])[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7](=[CH:16][C:17]#[C:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.CO.[BH4-].[Na+]>O>[C:12]([C:9]1[CH:8]=[C:7]([CH2:16][C:17]#[C:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=2)[CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)C1=CC(=CC#Cc2ccc(C(=O)O)cc2)C=C(C(C)(C)C)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CC#Cc2ccc(C(=O)O)cc2)cc(C(C)(C)C)c1O

Procedure:
756 mg (2 mmol) of 4-[3-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-1-ylidene)-1-propynyl]benzoic acid and 50 ml of a mixture (50/50) of THF and methanol are introduced into a three-necked flask. 152 mg (4 mmol) of sodium borohydride are added at 0° C. and the mixture is allowed to return to room temperature. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is triturated from refluxing heptane, filtered and dried. 510 mg (64%) of 4-[3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-1-propynyl]benzoic acid are collected, with a melting point of 198-9° C.
Reaction SMILES: [NH2:1][C:2]([CH3:15])([CH3:14])[CH2:3][C:4]1[N:8]([CH2:9][CH3:10])[N:7]=[C:6]([C:11]#[N:12])[C:5]=1[Br:13].[CH:16]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH2:17]>C1(C)C=CC=CC=1>[Br:13][C:5]1[C:6]([C:11]#[N:12])=[N:7][N:8]([CH2:9][CH3:10])[C:4]=1[CH2:3][C:2]([CH3:14])([NH:1][CH2:17][CH2:16][S:18]([CH3:21])(=[O:20])=[O:19])[CH3:15]
Reactant: C=CS(C)(=O)=O
Reactant: CCn1nc(C#N)c(Br)c1CC(C)(C)N
Solvent: Cc1ccccc1
Product: CCn1nc(C#N)c(Br)c1CC(C)(C)NCCS(C)(=O)=O
Temperature: 25 °C
Yield: 48.3 %

Procedure:
A solution of 5-(2-amino-2-methylpropyl)-4-bromo-1-ethyl-1H-pyrazole-3-carbonitrile (4.1 g, 15.1 mmol) and methyl vinyl sulfone (3.2 g, 30.2 mmol) in toluene (30 mL) was heated at reflux for 15 hours, allowed to cool to room temperature, and concentrated under reduced pressure. The crude product was purified twice by column chromatography on silica gel (eluting first with 5% methanol in dichloromethane and secondly with ethyl acetate) to provide 2.75 g of 4-bromo-1-ethyl-5-(2-methyl-2-{[2-(methylsulfonyl)ethyl]amino}propyl)-1H-pyrazole-3-carbonitrile as a colorless oil.
Reaction SMILES: C1C(N2C(=O)COCC2)=CC=C(N2C(=O)O[C@@H](CNC(C3SC(Cl)=CC=3)=O)C2)C=1.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][C:38]2=[O:43])=[CH:33][CH:32]=1.[O:44]1[CH2:46][C@@H:45]1[CH2:47][N:48]1[C:56](=[O:57])[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49]1=[O:58]>>[OH:44][C@H:45]([CH2:46][NH:30][C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][C:38]2=[O:43])=[CH:35][CH:36]=1)[CH2:47][N:48]1[C:49](=[O:58])[C:50]2[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:56]1=[O:57]
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Agent: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Product: O=C1c2ccccc2C(=O)N1C[C@H](O)CNc1ccc(N2CCOCC2=O)cc1

Procedure:
WO 01/47919, application disclosed the Rivaroxaban with applications for prevention and treatment of various thromboembolic diseases. Further this patent describes a method for preparation of Rivaroxaban of formula (I), wherein 4-(4-aminophenyl)morpholin-3-one is reacted with 2-[(2S)-oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione, in presence of solvent to obtain 2-[(2R)-2-hydroxy-3-{[4(3-oxomorpholin-4-yl)phenyl]amino}propyl]-1H-isoindole-1,3(2H)-dione which is further converted to 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione by phosgene equivalent. Departing of the pthalamide group affords 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one, which is finally coupled with 5-chlorothiophene-2-carbonyl chloride to give 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide i.e. Rivaroxaban of formula (I) as shown in scheme-1;
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH2:8][CH2:9][N:10]=[CH:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[CH:7]=1.[BH4-].[Na+].O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH2:8][CH2:9][NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(C=NCCc2cc(F)ccc2OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(CNCCc2cc(F)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.30 g (16.8 mmol) of methyl 4-({[2-(5-fluoro-2-methoxyphenyl)ethyl]imino}-methyl)benzoate are dissolved in 48.4 ml of methanol, and 1.27 g (33.6 mmol) of sodium borohydride are added. The solution is stirred at RT for 2 hours, and water is then added and the solution is extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is taken up in ethyl acetate and extracted with diluted HCl. The aqueous phase is made alkaline and extracted with ethyl acetate, and the extract is dried over magnesium sulphate, filtered and concentrated under reduced pressure.
Reaction SMILES: ClC1C=CC([C:8]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)(OC)[C:9]2[CH:14]=[C:13]([OH:15])[C:12]([C:16](C3C=CC(Cl)=CC=3)([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)OC)=[CH:11][C:10]=2[OH:33])=CC=1>[N+](C1C=CC=CC=1)([O-])=O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]2[C:16]([C:36]3[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=3)=[C:12]3[C:13](=[CH:14][C:9]4[C:10]([O:33][C:24]5[C:19]([C:8]=4[C:36]4[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=4)=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=5)=[CH:11]3)[O:15][C:20]=2[CH:21]=1
Reactant: COC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1cc(O)c(C(OC)(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1O
Solvent: O=[N+]([O-])c1ccccc1
Product: Clc1ccc(C2=c3cc4c(cc3Oc3cc(Cl)ccc32)=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2O4)cc1

Procedure:
A solution of the product from example a (2,5-bis-[bis-(4-chloro-phenyl)-methoxy-methyl]-benzene-1,4-diol, 1.0 g, 1.56 mmol) is dissolved in nitrobenzene (5 ml) and the solution heated at reflux. The initially colourless solution turns red and later deeply violet. After one hour at reflux, the mixture is allowed to cool and then filtered. The product (violet needles) is washed with plenty of methanol and dried. MS shows the correct mass and isotopic pattern of four chlorines.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([N:12]2[C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:19])=O)=[N:6][CH:7]=1.N1C=CC=CC=1.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+].C>C1(C)C=CC=CC=1.CO.O>[CH3:19][C@H:13]1[CH2:14][CH2:15][CH2:16][C@@H:17]([CH3:18])[N:12]1[C:10]1[N:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]2=[N:8][N:9]=1
Reactant: C[C@@H]1CCC[C@H](C)N1C(=O)NNc1ccc(F)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(F)cn12
Temperature: 50 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a suspension of Intermediate 3b (27.4 g, 102.9 mmol) and pyridine (25 mL, 309.1 mmol) in toluene (250 mL) at 50° C. was added POCl3 (11.0 mL, 118 mmol) in 3 portions at 30 s intervals. (CARE: exotherm to 70° C.). The brown suspension was stirred at 50° C. for 1 h, then cooled to RT. Water (100 mL) and sat. aqueous NaHCO3 solution (100 mL) were added (CARE: gas evolution) and the mixture stirred at RT for 30 min. The aqueous was extracted with EtOAc (2×250 mL), then the combined organics washed with brine (250 mL), dried (Na2SO4), filtered and concentrated in vacuo to leave a brown oil (26.3 g, overweight). The oil was redissolved in MeOH (150 mL) then charcoal (6 g) was added and the mixture swirled for 30 min. The suspension was filtered through Celite and the filtercake washed with MeOH (25 mL). The filtrate was concentrated in vacuo to leave a red oil. this was azeotroped with pentane (25 mL) (24.0 g). The solid was slurried in diethyl ether/pentane (1:1, 40 mL), filtered and dried in vacuo to leave Intermediate 3c (20.6 g, 81%). The mother liquor was concentrated in vacuo, the residue dissolved in hot cyclohexane (50° C., 30 mL), then cooled to RT and allowed to stand for over the weekend. The mixture was filtered, the solid washed with cyclohexane (5 mL) then dried in vacuo at 45° C. to leave additional Intermediate 3c (1.8 g, 6%). LCMS: Rt 3.30 min, m/z 249 [MH+]. 1H NMR (300 MHz, CDCl3): 0.68 (6H, d, J=6.2 Hz), 1.36-1.49 (2H, m), 1.52-1.68 (1H, m), 1.75-1.90 (3H, m), 3.29-3.40 (2H, m), 7.16 (1H, ddd, J=10.0, 7.6, 2.3 Hz), 7.67 (1H, dd, J=10.0, 4.7 Hz), 8.03 (1H, t, J=2.7 Hz).
Reaction SMILES: [OH-].[Na+].[C:3]([CH:6]1[CH2:11][CH2:10][C:9]([CH3:16])([C:12]([O:14]C)=[O:13])[CH2:8][CH2:7]1)(=[O:5])[CH3:4].Cl>C(O)C>[C:3]([CH:6]1[CH2:11][CH2:10][C:9]([CH3:16])([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: COC(=O)C1(C)CCC(C(C)=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)C1CCC(C)(C(=O)O)CC1
Yield: 71.7 %

Procedure:
20 ml of a 2N aqueous sodium hydroxide solution was added to a solution of 2.1 g of methyl 4-acetyl-1-methyl-1-cyclohexanecarboxylate (Example 35) in 20 ml of ethanol. The solution was reacted for 4 hours, while it was refluxed. After reaction, 2N hydrochloric acid was added to the reaction solution, acidifying the solution. The solution was extracted three times with 50 ml of ethyl acetate. The organic layer obtained was washed twice with an aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed in vacuo, and the product obtained was recrystallized from ethyl acetate/hexane, yielding 1.4 g of 4-acetyl-1-methyl-1-cyclohexanecarboxylic acid as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:8]([Cl:16])[CH:7]=1)=O.[CH:18]1([O:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>CO>[CH3:1][O:2][C:3](=[O:17])/[C:4](/[C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:8]([Cl:16])[CH:7]=1)=[N:24]/[O:23][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NOC1CCCC1
Reactant: COC(=O)C(=O)c1ccc(S(C)(=O)=O)c(Cl)c1
Solvent: CO
Product: COC(=O)/C(=N/OC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
(3-Chloro-4-methanesulfonyl-phenyl)-oxo-acetic acid methyl ester (1.75 g, 6.32 mmol) was stirred in methanol (14 mL) and warmed in a 70° C. oil bath. O-Cyclopentyl-hydroxylamine (1.09 g, 7.92 mmol) was added. After 2 h, the reaction mixture was allowed to cool and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 □m; 20% ethyl acetate/hexanes) gave (E)-(3-chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid methyl ester (1.01 g, 44%) eluting second as a clear, colorless oil which solidified over time: H1-NMR (400 MHz, CDCl3) δ=1.62 (4H, m), 1.85 (4H, m), 3.31 (3H, s), 3.91 (3H, s), 4.96 (1H, m), 7.48 (1H, dd, J=8.2 Hz, J=1.3 Hz), 7.59 (1H, d, J=1.2 Hz), 8.17 (1H, d, J=8.2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([OH:16])=O)=[CH:8]2)=[O:4].[OH-].[NH4+:18]>O1CCCC1>[C:14]([C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=2)(=[O:16])[NH2:18]
Reactant: [NH4+]
Reactant: COC(=O)c1ccc2[nH]c(C(=O)O)cc2c1
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2[nH]c(C(N)=O)cc2c1
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 5-(methoxycarbonyl)-1H-indole-2-carboxylic acid (2.50 g, 11.4 mmol) in tetrahydrofuran (20 mL) was added 1,1-carbonyldiimidazole (3.70 g, 22.8 mmol). The yellow suspension was stirred for 2 hours. Then concentrated ammonium hydroxide (20 mL) was added and the mixture was stirred at room temperature for 5 hours. The pale green suspension was filtered, washed with water and 5 mL of methanol, and air dried to give methyl 2-carbamoyl-1H-indole-5-carboxylate (2.04 g, 82%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6, δ): 11.93 (br. s., 1 H), 8.32 (d, J=1.2 Hz, 1 H), 8.06 (br. s., 1 H), 7.79 (dd, J=8.6, 1.6 Hz, 1 H), 7.48 (d, J=8.6 Hz, 1 H), 7.45 (br. s., 1 H), 7.27 (s, 1 H), 3.32 (s, 3 H).
Reaction SMILES: C1(COC([N:11]2[CH2:16][CH:15]3[CH2:17][CH:12]2[CH2:13][N:14]3[CH2:18][CH:19]([OH:31])[C:20]2[CH:29]=[CH:28][C:23]3[C:24](=[O:27])[O:25][CH2:26][C:22]=3[C:21]=2[CH3:30])=O)C=CC=CC=1>CCOC(C)=O.[Pd]>[CH:15]12[CH2:17][CH:12]([NH:11][CH2:16]1)[CH2:13][N:14]2[CH2:18][CH:19]([C:20]1[CH:29]=[CH:28][C:23]2[C:24](=[O:27])[O:25][CH2:26][C:22]=2[C:21]=1[CH3:30])[OH:31]
Reactant: Cc1c(C(O)CN2CC3CC2CN3C(=O)OCc2ccccc2)ccc2c1COC2=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1c(C(O)CN2CC3CC2CN3)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of isomers B of phenylmethyl-5-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (470 mg, 1.114 mmol) in 50 mL of EtOAc was added 100 mg of Pd/C under Ar, and the mixture was stirred at ambient temperature under H2 atmosphere overnight. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by prep-TLC (MeOH/DCM=1:15) to give isomers B of 5-[2-(2,5-diazabicyclo[2.2.1]hept-2-yl)-1-hydroxyethyl]-4-methyl-2-benzofuran-1(3H)-one. MS m/z 289 (M+1)+.
Reaction SMILES: [CH2:1]([NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:18]1[O:20][CH:19]1[CH2:21][OH:22]>C(O)C>[OH:20][CH:19]([CH2:21][OH:22])[CH2:18][NH:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OCC1CO1
Reactant: CCCCCCCCCCCCCCCCN
Solvent: CCO
Product: CCCCCCCCCCCCCCCCNCC(O)CO
Reaction time: 8 h

Procedure:
Hexadecylamine (5.00 g, 0.024 moles) was dissolved in absolute ethanol, and glycidol (3.07 g, 0.041 moles) was added dropwise. The reaction was refluxed under nitrogen for 4 hours then allowed to stir overnight. After 22 hours of refluxing, the reaction was stopped and a white solid formed during the cooling stage. The solid was recovered and recrystallized in hot hexane. (yield=2.02g)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=1.[O:8]1[C:12]2([CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1>C1COCC1>[Br:1][C:2]1[C:3]([C:15]2([OH:18])[CH2:16][CH2:17][C:12]3([O:11][CH2:10][CH2:9][O:8]3)[CH2:13][CH2:14]2)=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Cn1cc(Br)cn1
Solvent: C1CCOC1
Product: Cn1cc(Br)c(C2(O)CCC3(CC2)OCCO3)n1

Procedure:
The title compound was prepared as a white solid from 4-bromo-1-methyl-1H-pyrazole, as prepared in the previous step, and 1,4-dioxa-spiro[4.5]decan-8-one in THF using the procedure described in Step A of Example 1.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][N:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:27]([C:24]1[CH:23]=[N:22][C:21]([NH:19][CH2:18][CH:15]2[CH2:14][CH2:13][N:12]([C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:11])[CH2:17][CH2:16]2)=[N:26][CH:25]=1)[CH3:28]
Reactant: CCc1cnc(Cl)nc1
Reactant: NCC1CCN(C(=O)[C@@H]2C[C@H]2c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cnc(NCC2CCN(C(=O)[C@@H]3C[C@H]3c3ccccc3)CC2)nc1
Temperature: 150 °C

Procedure:
The stirred reaction mixture of (1-{[(1R,2R)-2-phenylcyclopropyl]carbonyl}piperidin-4-yl)methylamine (EXAMPLE 154, STEP 2) (0.100 g, 0.387 mmol), 2-chloro-5-ethyl-pyrimidine ([111196-81-7], 0.055 g, 0.387 mmol) and cesium carbonate (0.252 g, 0.774 mmol) in DMF (5 mL) was heated at 150° C. for 7 h. The reaction mixture was cooled to RT, diluted with ethyl acetate (100 mL), washed with water (5×20 mL), and brine (10 mL), then dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel 60, eluting with 10:1–20:89–70 CH2Cl2:2-propanol:hexane to give the title compound. M.S. (M+1): 365.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2.[F:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1.[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][NH:32][C:31](=[O:35])[C:30]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:27]>CN(C=O)C.[Cu](I)I>[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][N:32]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[C:31](=[O:35])[C:30]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:27]
Reactant: CCOC(=O)c1c(OCC)cc[nH]c1=O
Reactant: Fc1ccc(I)cc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCC)ccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.1 %

Procedure:
DMF (9 L) and cesium carbonate (3.1 kg) were charged under nitrogen to a reactor and stirred for 10 min at room temperature. To this mixture, a solution of 8-hydroxyquinoline (0.275 kg) in DMF (1 L), copper iodide (0.27 kg) and 1-fluoro-4-iodobenzene (1.576 kg) were added under nitrogen. Then, ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate (1 kg) was added and the reaction mixture was heated to 100° C. for 20 hrs under nitrogen. After completion of the reaction, the mixture was filtered through celite. To the filtrate, water (100 L) was added and the mixture was extracted three times with DCM (25 L). The combined DCM layers were washed two times with water (20 L), two times with 1.5 N HCl (5 L), and one time with brine (10 L), and then dried over sodium sulfate and concentrated to dryness. Petroleum ether (5 L) was added to the concentrate and the resulting slurry was stirred for 30 min. The solids were filtered and dried at room temperature in vacuum to give 1.1 kg crude ethyl 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)([CH3:9])[CH3:8])[CH3:2].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:26])C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([OH:26])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)([CH3:8])[CH3:9])[CH3:2]
Reactant: CCOC(=O)CCC(C)(C)c1cccc(OC)c1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(O)CC(C)(C)c1cccc(OC)c1
Temperature: -70 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
27.2 g (108.65 mmol) of ethyl-4-(3-methoxyphenyl)-4-methylpentanoate is dissolved in 380 ml of tetrahydrofuran, and the reaction mixture is cooled to −70° C. to −65° C. Within two hours, 304 ml of a 0.5 molar solution of potassium-bis-(trimethylsilylamide) in toluene is added in drops, and the reaction mixture is then stirred for 75 more minutes at −70° C. 39.7 g (152.11 mmol) of Davis reagent, dissolved in 380 ml of tetrahydrofuran, is now added in drops within 90 minutes. After two hours of stirring at −70° C., 195 ml of saturated ammonium chloride solution is slowly added in drops, the cold bath is removed and it is stirred vigorously for thirty minutes. After extraction with diethyl ether (twice with 800 ml each), the combined organic extracts are treated as usual with water and brine. After the solvent is spun off, the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 20.9 g (72.4%) of the desired compound is isolated.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[O:21]COCCOC.Cl>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[OH:21]
Reactant: COCCOCOc1cc(-c2ccc3nc(NC(C)=O)sc3c2)cnc1Cl
Agent: Cl
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(O)c3)cc2s1
Yield: 104.2 %

Procedure:
A dry 10 mL, round bottom flask was charged with N-(6-(6-chloro-5-((2-methoxyethoxy)methoxy)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.0050 g, 0.012 mmol), a stirbar, and 1 mL dry TFE. To the stirring solution was added a 1 M solution of hydrochloric acid (0.037 ml, 0.037 mmol). The solution was transferred to a 5 mL, conical vial, purged with Ar, and sealed. The solution was irradiated using a Biotage microwave synthesizer for 5 minutes at 100° C. The cooled solution was concentrated in vacuo, and sonicated in 0.5 mL THF. The precipitate was collected using a glass frit under positive pressure nitrogen. The solids were washed with 0.5 mL dry THF, initially dried using a stream of nitrogen, and then at 60° C. and <1.0 mm Hg for 30 minutes to afford N-(6-(6-chloro-5-hydroxypyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.0040 g). 1H NMR (400 MHz, DMF) 5 ppm 2.33 (s, 3H) 7.77 (dd, J=8.41, 1.86 Hz, 1H) 7.82 (d, J=2.25 Hz, 1H) 7.83 (d, J=8.61 Hz, 1H) 8.30 (d, J=2.15 Hz, 1H) 8.38 (d, J=1.76 Hz, 1H) 11.30 (br. s., 1H) 12.43 (br. s., 1H). 13C NMR (101 MHz, DMF) δ ppm 22.67 (s, 1 C) 120.44 (s, 1 C) 121.39 (s, 1 C) 122.26 (s, 1 C) 125.57 (s, 1 C) 132.27 (s, 1 C) 133.46 (s, 1 C) 137.13 (s, 1 C) 137.72 (s, 1 C) 137.88 (s, 1 C) 149.53 (s, 1 C) 150.58 (s, 1 C) 159.48 (s, 1 C) 169.92 (s, 1 C). 91741-17-1 HPLC-MS: retention time=1.56 min (96.0%@215 nm; >99% @254 nm; m/z=319.9, calculated for C14H10ClN3O2S+H+=320.0).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=2)[C:28](O)=[O:29])[N:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=[N:25][CH:26]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: NCCc1csc(-c2ccc(Cl)cc2)n1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCCc1csc(-c2ccc(Cl)cc2)n1)c1cncc(-c2noc(C(F)(F)F)n2)c1
Yield: 23 %

Procedure:
This compound was synthesized from 2-(2-(4-chlorophenyl)thiazol-4-yl)ethanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (13 mg, yield 23%). 1H NMR (400 MHz, CDCl3) δ 9.46 (m, 1H), 9.25 (m, 1H), 8.81-8.80 (t, J=2 Hz, 1H), 7.87-7.84 (m, 2H), 7.40-7.37 (m, 2H), 7.08 (s, 1H), 3.93-3.89 (m, 2H), 3.16-3.13 (m, 2H). MS (ESI) m/z: Calculated for C20H13ClF3N5O2S: 479.04. found: 480.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1(O)[CH2:13][CH2:12][CH2:11][CH2:10]1.[H][H]>C(O)C.[Pd]>[CH:9]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:1])([F:15])[F:16])[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: OC1(c2ccccc2C(F)(F)F)CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: FC(F)(F)c1ccccc1C1CCCC1
Yield: 90.6 %

Procedure:
To a solution of 1-(2-(trifluoromethyl)phenyl)cyclopentanol (5.1 g, 22.15 mmol) in ethanol (32 mL) was added 10% Pd—C (500 mg; Degussa; wet) and the mixture was hydrogenated overnight with a hydrogen balloon. The reaction mixture was filtered through Celite®. The filtrate was poured into ice-water (100 mL) and extracted with CH2Cl2 (2×70 mL). The combined CH2Cl2 layer was washed with water (1×75 mL), dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give the title compound (4.3 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.58-1.67 (m, 4H), 1.81-1.90 (m, 2H), 2.06-2.15 (m, 2H), 3.32-3.43 (m, 1H), 7.22-7.26 (m, 1H), 7.45-7.51 (m, 2H), 7.58 (d, J=8 Hz, 1H).