Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]2[C:11](=O)[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[O:7][C:6]=12.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:3][CH:4]=[C:5]2[C:11]([Cl:18])=[N:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[O:7][C:6]=12
Reactant: O=C1Nc2ccccc2Oc2c1csc2Cl
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: ClC1=Nc2ccccc2Oc2c1csc2Cl

Procedure:
A 4.0 g. portion of 3-chlorothieno[3,4-b][1,5]benzoxazepin-10(9H)-one (Example 12) and 4.0 g. of phosphorus pentachloride in 103 ml. of dry toluene is refluxed for 41/2 hours. The reaction temperature is concentrated, then is triturated with toluene to give 3,10-dichlorothieno[3,4-b][1,5]benzoxazepine. A 25 ml. amount of dry N-(2-hydroxyethyl)piperazine and 25 ml of dry toluene is added to the product above and the mixture is heated at 120° C. for 16 hours. The reaction mixture is concentrated to a thick oil, the oil is dissolved in hot 2N aqueous acetic acid, treated with activated charcoal and filtered through diatomaceous earth. The filtrate is cooled and precipitated with concentrated ammonium hydroxide. The precipitate is collected and extracted into methylene chloride, the organic solution is dried over anhydrous sodium sulfate and eluted through magnesium silicate with 2.5 liters of methylene chloride followed by one liter of 1:1 ethyl acetate:methylene chloride. The combined organic solvents are evaporated to yield 2.0 g. of 4-(3-chlorothieno[3,4-b][1,5]-benzoxazepin-10-yl)-1-piperazineethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][CH2:9][C@H:10]2[CH2:14][O:13]C(C)(C)[O:11]2)=[CH:5][CH:4]=1.Cl.C(=O)([O-])O.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][CH2:9][C@H:10]([OH:11])[CH2:14][OH:13])=[CH:17][CH:18]=1
Reactant: COc1ccc(COC[C@H]2COC(C)(C)O2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ccc(COC[C@H](O)CO)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
The crude product of (S)-(+)-4-(4-methoxybenzyloxymethyl)-2,2-dimethyl-1,3-dioxolane (4.1 g) was dissolved in methanol (10 mL). The solution was added with 1N hydrochloric acid and stirred at room temperature for one day. The solution was adjusted to pH 6 by addition of saturated aqueous sodium hydrogen carbonate, and extracted four times with dichloromethane. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed and the residue was purified by silica gel column chromatography to obtain (R)-(+)-3-(4-methoxybenzyloxy)-1,2-propanediol (2.4 g, 69%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[F:20][C:21]([F:34])([F:33])[O:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30](O)=[O:31])[CH:26]=[CH:27][CH:28]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:30](=[O:31])[CH2:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][C:21]([F:33])([F:20])[F:34])[CH:24]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cccc(OC(F)(F)F)c1
Product: O=C(Cc1cccc(OC(F)(F)F)c1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-[3-(trifluoromethoxy)phenyl]acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.41-8.43 (m, 1H), 7.95-8.02 (m, 2H), 7.73-7.75 (m, 1H), 7.63-7.64 (m, 4H), 7.50 (t, J=7.9 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.38-7.40 (bs, 1H), 7.27-7.30 (m, 1H), 3.79 (s, 2H); MS (ESI−) M/Z 472 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:16][N:15]4[C:24]([C:27]#[N:28])=[CH:25][N:26]=[C:14]4[N:13]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.[OH:29]O>CS(C)=O.CC(=O)OCC>[NH2:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:16][N:15]4[C:24]([C:27]([NH2:28])=[O:29])=[CH:25][N:26]=[C:14]4[N:13]=3)=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: OO
Reactant: N#Cc1cnc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cn12
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: NC(=O)c1cnc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cn12
Temperature: 60 °C

Procedure:
To a suspension of compound 4-10 (40 mg 0.11 mmol.) and K2 CO3 (30 mg, 0.22 mmol) in DMSO (1.0 mL) was added 0.1 mL of H2O2(30% aq.) and the mixture was heated at 60° C. for 3 h. After cooling, the mixture was diluted with 20 mL of EA, the combined organic phase was washed with sat.NaHSO3 (aq) and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.HPLC to give 19 mg of 4-11.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(=O)(O)[O-].[Na+].C([O:19][C:20](=O)/[CH:21]=[C:22](/[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])\[CH2:23]Br)C>C(O)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])=[CH:21][C:20]1=[O:19])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CCOC(=O)/C=C(\CBr)Oc1ccccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 147.2 %

Procedure:
To a solution of (L)-leucine methyl ester hydrochloride salt (152.6 g, 0.840 mol) in ethanol (200 proof denatured, 2500 mL) was added sodium bicarbonate (115.3 g, 1.37 mol) at room temperature and the resulting mixture stirred for 15 min. To this mixture was added (E)-4-bromo-3-(2-chloro-phenoxy)-but-2-enoic acid ethyl ester (87.7% pure by HPLC, 200 g, 0.549 mol). The resulting cloudy solution was heated to reflux and approx. 500 mL of solvent was removed via a Dean Stark trap before reflux was continued overnight. To this solution was added glacial acetic acid (200 mL) and the solution was heated to reflux for an additional 2 h. The reaction mixture was cooled to room temperature and methyl t-butyl ether (2.7 L) and water (2 L) were added. The mixture was separated and the organic phase washed with a 20% sodium chloride solution (2 L). The solution was evaporated, the residue treated with toluene (2 L) and evaporated again to give (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (83.3% pure by HPLC, 273 g) as a dark orange oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([OH:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([O:15][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Product: C[C@@H](Oc1ccc(F)cc1[N+](=O)[O-])[C@H](NC(=O)OC(C)(C)C)C(=O)O

Procedure:
In analogous manner to that described in example 5a), the reaction of (2S,3R)-2-tert-butoxycarbonylamino-3-hydroxy-butyric acid and 2,5-difluoro-nitrobenzene yielded (72% of theory) the title compound as a brown oil, MS m/e (%): 357.1 (M−H+, 100).
Reaction SMILES: C=O.[H-].[Na+].[F:5][C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][CH2:15][N:14]3[N:18]=[C:19](/[CH:21]=[CH:22]/[C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]5)=[C:25]([O:35][CH3:36])[CH:24]=4)[N:20]=[C:13]23)[CH:9]=[CH:10][CH:11]=1.O.[C:38](=O)(O)[O-:39].[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:5][C:6]1[CH:7]=[C:8]([C:12]2([CH2:38][OH:39])[CH2:17][CH2:16][CH2:15][N:14]3[N:18]=[C:19](/[CH:21]=[CH:22]/[C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]5)=[C:25]([O:35][CH3:36])[CH:24]=4)[N:20]=[C:13]23)[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cc(/C=C/c2nc3n(n2)CCCC3c2cccc(F)c2)ccc1-n1cnc(C)c1
Reactant: O=C([O-])O
Agent: C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3(CO)c2cccc(F)c2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Paraformaldehyde (186 mg) and sodium hydride (containing 40% of mineral oil, 28.7 mg) were added to a solution of 8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine synthesized by the method in Examples 1 and 2 (154 mg) in DMF (3 mL), and the reaction solution was stirred at room temperature for 30 minutes. Thereafter, ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 204 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [Cl-].[NH4+].[F:3][C:4]1([F:22])[O:9][C:8]2[CH:10]=[C:11]([F:17])[C:12]([N+:14]([O-])=O)=[CH:13][C:7]=2[N:6]([CH2:18][C:19]#[CH:20])[C:5]1=[O:21]>O.CO.O1CCCC1.[Fe]>[NH2:14][C:12]1[C:11]([F:17])=[CH:10][C:8]2[O:9][C:4]([F:3])([F:22])[C:5](=[O:21])[N:6]([CH2:18][C:19]#[CH:20])[C:7]=2[CH:13]=1
Reactant: C#CCN1C(=O)C(F)(F)Oc2cc(F)c([N+](=O)[O-])cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(N)cc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To ammonium chloride (3.96 g, 74.0 mmol) in water was added iron powder (325 mesh; 4.13 g, 74.0 mmol). To the resulting mixture was added 2,2,7-trifluoro-6-nitro-4-(prop-2-ynyl)-2Hbenzo[b][1,4]oxazin-3(4H)-one (7.06 g, 24.67 mmol) in methanol/tetrahydrofuran. The resulting mixture was stirred vigorously at 70° C. for 2 hours. The reaction was quenched in water/ethyl acetate under stirring. The resulting 2 phase system was filtered and the layers were separated. The water layer was subsequently extracted with ethyl acetate. The combined organic phases were washed with brine, dried with Na2SO4 and concentrated to yield 5.15 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[NH:12]C(C2C=CC=C3C=2N=C(NCC(F)(F)F)C(C)=N3)=C[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:39][C:40]([C:42]1[C:51]([F:52])=[CH:50][CH:49]=[C:48]2[C:43]=1[N:44]=[C:45]([NH:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:46]([CH3:53])=[N:47]2)=O.[C:59](OC(NC1(C(=O)CC(OCC)=O)CC1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>CCO.C1COCC1.CC(O)=O>[C:1]([O:5][C:6]([NH:8][C:9]1([C:11]2[NH:12][C:40]([C:42]3[C:51]([F:52])=[CH:50][CH:49]=[C:48]4[C:43]=3[N:44]=[C:45]([NH:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:46]([CH3:53])=[N:47]4)=[CH:39][C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:59]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nc2ccc(F)c(C(=O)CBr)c2nc1NC(C)(C)C
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NCC(F)(F)F)nc23)[nH]c1C(C)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)CC(=O)C1(NC(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2c(F)ccc3nc(C)c(NC(C)(C)C)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
This compound (230 mg, 0.44 mmol, 58% yield) as a yellow foam was prepared according to the procedures described for Intermediate 293b, using 2-bromo-1-(3-(tert-butylamino)-6-fluoro-2-methylquinoxalin-5-yl)ethanone (605) (268 mg, 0.76 mmol), ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-3-oxopropanoate (604) (619 mg, 2.28 mmol) and K2CO3 (525 mg, 3.80 mmol) in EtOH (2 mL) and THF (2 mL) was stirred at RT for 2 days, followed by subsequent treatment of the resulting 295a (light-yellow oil, m/z (ESI, +ve) 545.2 (M+H)+) with NH4OAc (469 mg, 6.08 mmol) in EtOH (5 mL) and HOAc (3 mL) at 60° C. for 18 h. 1H NMR (400 MHz, CDCl3) δ ppm 7.64 (dd, J=8.90, 5.97 Hz, 1H), 7.17 (dd, J=11.74, 9.00 Hz, 1H), 4.86 (s, 1H), 4.34 (q, J=7.04 Hz, 2H), 2.52 (s, 3H), 1.64 (s, 9H), 1.40 (t, J=7.14 Hz, 3H), 1.36 (s, 9H), 1.20-1.33 (m, 4H). 19F NMR (376 MHz, CDCl3) δ ppm −109.93 (s, 1F). m/z (ESI, +ve) 526.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[K+:13].[S:14](=[O:18])(=[O:17])([OH:16])[OH:15]>O>[K+:13].[K+:13].[OH:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[OH:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([S:14]([OH:16])(=[O:18])=[O:15])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5]
Reactant: O=C(O)c1cccc(O)c1O
Reactant: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1cc(S(=O)(=O)O)cc(O)c1O
Temperature: 20 °C

Procedure:
2,3-Dihydroxybenzoic acid (15.4 g, 0.1 moles) was dissolved in small portions at 5° C. in 80 ml of sulfuric acid containing 30% sulfur trioxide. The mixture was allowed to warm to 20° C. over 1 h and was then poured slowly into 1L of vigorously stirred ice water. The pH was adjusted to 4.5 with 30% potassium hydroxide and the solid formed was removed by filtration. The filtrate was diluted with a 1.5 fold volume of methanol and filtered again. This filtrate was evaporated to 200 ml and the pH was adjusted to 6.0 with potassium hydroxide. Acetone (500 ml) was added and the resulting white precipitate was filtered and dried to give 18 g of crude product. Chromatography of this solid on HP20 in water gave 12.8 g of pure title compound after lyophilization.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:13]3=[N:14][NH:15][CH:16]=[C:12]3[C:11](=[O:17])[N:10]([CH3:18])[C:9]2=[O:19])=[CH:5][CH:4]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Br)=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:15]2[CH:16]=[C:12]3[C:13]([N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=4)[C:9](=[O:19])[N:10]([CH3:18])[C:11]3=[O:17])=[N:14]2)=[CH:25][CH:24]=1
Reactant: COc1ccc(Cn2c(=O)n(C)c(=O)c3c[nH]nc32)cc1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2c(=O)n(C)c(=O)c3cn(Cc4ccc(Br)cc4)nc32)cc1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A suspension of 7-(4-methoxybenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (161 g, 562 mmol), 1-bromo-4-(bromomethyl)benzene (157 g, 628 mmol) and K2CO3 (93.2 g, 674 mmol) in DMF (800 mL) is stirred at room temperature until the reaction is complete. The reaction mixture is poured into water (5 L). After filtration, the filter cake is washed with water and ethanol successively, and then dried under vacuum to give 226 g of product (yield: 88%). MS (ESI) m/z 455.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[S:14][N:13]=[C:12]([C:15]3([Cl:18])[CH2:17][CH2:16]3)[N:11]=2)[C:6]([CH3:19])=[CH:5][C:3]=1[NH2:4].CO[CH:22](OC)[N:23]([CH2:25][CH3:26])[CH3:24]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[S:14][N:13]=[C:12]([C:15]3([Cl:18])[CH2:16][CH2:17]3)[N:11]=2)[C:6]([CH3:19])=[CH:5][C:3]=1[N:4]=[CH:22][N:23]([CH2:25][CH3:26])[CH3:24]
Reactant: CCN(C)C(OC)OC
Reactant: Cc1cc(N)c(Cl)cc1Oc1nc(C2(Cl)CC2)ns1
Solvent: Cc1ccccc1
Product: CCN(C)C=Nc1cc(C)c(Oc2nc(C3(Cl)CC3)ns2)cc1Cl
Yield: 86.5 %

Procedure:
0.63 g (1.86 mmol) of 2-chloro-4-{[3-(1-chlorocyclopropyl)-1,2,4-thiadiazol-5-yl]oxy}-5-methylaniline is dissolved in 5 ml of toluene and treated with 0.50 g (3.71 mmol) of N-ethyl-N-methylformamide dimethyl acetal. The reaction mixture is refluxed for 12 h, subsequently cooled, freed from solvent under vacuum and purified by column chromatography. 0.62 g of product is obtained (82.0% purity, 71.3% yield; log P (pH 2.3)=1.62).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(N(CC)[C:16](Cl)=[S:17])C.Cl>C1(C)C=CC=CC=1>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)=[C:16]=[S:17]
Reactant: CCN(CC)C(=S)Cl
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N=C=S)cc1
Yield: 74.5 %

Procedure:
82.5 g of ethyl p-aminobenzoate was dissolved in 500 ml of toluene, to the solution was added 83.4 g of N,N-diethylthiocarbamoyl chloride and the mixture was refluxed by heating for 8 hours. After cooling with ice, 100 ml of concentrated hydrochloric acid was added to the reaction mixture and then the toluene layer was separated and washed with water. The toluene was distilled off under reduced pressure and the residual oily product was crystallized from methanol to obtain 77.1 g of ethyl p-isothiocyanatobenzoate. Yield: 74.5%. Melting Point: 52° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)=[CH:10][C:4]=2[S:3]1.[CH3:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:20][CH:19]=1>C(OCC)C>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:13](=[O:15])[C:12]([NH:11][C:9]3[CH:8]=[CH:7][C:5]4[NH:6][C:2](=[O:1])[S:3][C:4]=4[CH:10]=3)=[O:16])[CH2:25][CH2:24]2)=[CH:29][CH:30]=1
Reactant: Cc1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)C(=O)Nc1ccc2[nH]c(=O)sc2c1
Solvent: CCOCC
Product: Cc1ccc(CC2CCN(C(=O)C(=O)Nc3ccc4[nH]c(=O)sc4c3)CC2)cc1

Procedure:
The title compound is prepared from N-(2-oxo-2,3-dihydro-benzothiazol-6-yl)-oxalamic acid (Example 61b) and 4-(4-methyl-benzyl)-piperidine according to the method described in Example 1c. Melting Point: 221-222° C. (diethylether)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5](Br)=[CH:4][CH:3]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12].O1CCOCC1.O>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(OCC)(=O)C>[CH3:8][C:6]1[N:7]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=1[C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10]
Reactant: Cc1nc(N)ccc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(N)ccc1C#C[Si](C)(C)C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
To a mixture of 6-amino-3-bromo-2-methylpyridine (200 mg, 1.0 mmol), trimethylsilylacetylene (0.22 mL, 1.6 mmol), copper (I) iodide (9.9 mg, 0.052 mmol), and 1,4-dioxane (1.5 mL) was added bis(triphenylphosphine)palladium (II) chloride (73 mg, 0.10 mmol), which was stirred under nitrogen atmosphere for 3 hours and 30 minutes at 100° C. The reaction mixture was allowed to room temperature, water was added to the reaction mixture at the same temperature, ethyl acetate was added, and the mixture was filtered through a Celite pad. The organic layer of the filtrate was separated and washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure, and the residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (140 mg, 57%, purity: 86%).
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC(N(C)C)=O.[CH2:40]([O:42][C:43](=[O:64])[C@H:44]([OH:63])[CH2:45][N:46]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[C:59]([Cl:61])[CH:58]=[CH:57][C:56]=2[F:62])=[CH:51][CH:50]=1)[NH2:47])[CH3:41].CCN(C(C)C)C(C)C>>[CH2:40]([O:42][C:43](=[O:64])[C@H:44]([OH:63])[CH2:45][N:46]([CH2:48][C:49]1[CH:50]=[CH:51][C:52]([C:55]2[CH:60]=[C:59]([Cl:61])[CH:58]=[CH:57][C:56]=2[F:62])=[CH:53][CH:54]=1)[NH:47][C:7]([C:4]1[S:3][C:2]([OH:1])=[N:6][CH:5]=1)=[O:9])[CH3:41]
Reactant: O=C(O)c1cnc(O)s1
Reactant: CCOC(=O)[C@H](O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cnc(O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
2-Hydroxy-5-thiazolecarboxylic acid (9.0 mg, 62 μmol) and HATU (28.3 mg, 74 μmol) were stirred in DMA (0.5 mL, 5 mmol) for 10 minutes. (R)-3-[N-(5′-Chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid ethyl ester (22.7 mg, 62 μmol) and DIPEA (32.4 μL, 186 μmol) were added, and resulting mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure and the residue was dissolved in 50% AcOH-water (1.5 mL), filtered, purified by reverse phase preparative HPLC, and lyophilized to yield the title compound (11.9 mg, purity 96%) as a TFA salt. MS m/z [M+H]+ calc'd for C22H21ClFN3O5S, 494.09. found 494.4.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:18](Cl)(=[O:22])C(Cl)=O.[NH3:24]>C(Cl)Cl.O>[O:17]=[C:14]1[CH2:15][CH2:16][CH:11]([C:5]2[CH:10]=[CH:9][C:8]([C:18]([NH2:24])=[O:22])=[CH:7][CH:6]=2)[CH2:12][CH2:13]1
Reactant: N
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1ccc(C2CCC(=O)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
14.24 g (107 mmol) AlCl3 was added portionwise to a solution of 6.98 g (40 mmol) 4-phenylcyclohexanone and 4.51 ml (53.3 mmol) oxalylchloride in 200 ml CH2Cl2 at 0° C. Stirred at 0° C. for 1 h and at r.t. for 2 h. Cooled to 0° C. and aqueous NH3 was added carefully until pH>10. The mixture was diluted with CH2Cl2 and water. The mixture was filtered to remove solids. The phases were separated. The organic phase was dried (MgSO4) and concentrated. Gave 4.8 g (55%) of the title compound. Used in the next step without further purification.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1)([O-:3])=[O:2].[CH2:21]([OH:23])C.[CH2:24]=[O:25].C(N(CC)CC)C>C(OCC)(=O)C.CCCCCC>[N+:1]([C:4]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:12]=1)([CH2:21][OH:23])[CH2:24][OH:25])([O-:3])=[O:2]
Reactant: CCO
Reactant: C=O
Reactant: CCCCCCCCc1ccc(CCC[N+](=O)[O-])cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCc1ccc(CCC(CO)(CO)[N+](=O)[O-])cc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
1-(3-nitropropyl)-4-octylbenzene (43 g) and absolute ethanol (400 mL) are charged into a round bottom flask equipped with a condenser and calcium guard tube. Paraformaldehyde (43 g) and triethylamine (64.8 mL) are added. The mixture is heated to 70° C., stirred for 3 hours, and is concentrated under reduced pressure at 50° C. to obtain a solid. The solid is dissolved in ethyl acetate (300 mL), the solution is washed with cold water (2×200 mL), and the organic layer is dried over anhydrous sodium sulphate. The organic layer is concentrated under reduced pressure to obtain a yellow solid. Hexane (500 mL) is added and the mixture is cooled to −20° C. and stirred for 20 minutes. The formed solid is separated by filtration and washed with cold hexane (2×100 mL) to obtain the title compound as an off-white solid. Yield: 26 g.