Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)O1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH:37]2[CH2:39][CH2:38]2)[C:28]=1[O:40][CH3:41]>O1CCOCC1.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>[CH:37]1([CH2:36][O:35][C:29]2[C:28]([O:40][CH3:41])=[C:27]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[C:14](=[O:18])[O:13][CH2:12]4)[CH:32]=[CH:31][C:30]=2[O:33][CH3:34])[CH2:38][CH2:39]1
Reactant: CC1(C)OB(c2ccc3c(c2)COC3=O)OC1(C)C
Reactant: COc1ccc(Br)c(OC)c1OCC1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1OCC1CC1
Temperature: 85 °C
Yield: 42.4 %

Procedure:
A solution of 5(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isobenzofuran-1(3H)-one (325 mg, 1.25 mmol) in dioxane (25 mL) was purged with argon for 1 h, to this was added cesium carbonate (1 g, 3.12 mmol), Pd(PPh3)4 (36 mg, 0.031 mmol) and 1-bromo-3-(cyclopropylmethoxy)-2,4-dimethoxybenzene (300 mg, 1.04 mmol) and the resultant reaction mixture was heated to 80-90° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-10% ethyl acetate in pet ether) afforded a solid (150 mg, 42.5%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[C:11]([OH:14])[CH:10]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24]O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][O:14][C:11]1[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])[O:13][N:12]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: Oc1cc(-c2cccc(Cl)c2Cl)on1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2cccc(Cl)c2Cl)on1
Yield: 76 %

Procedure:
5-(2,3-Dichlorophenyl)-3-hydroxyisoxazole (0.3 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.23 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.37 g, 77%) as a colorless powder.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([NH2:10])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][NH:3]1>C(OC(=O)C)(=O)C>[O:1]=[C:2]1[C:7]([C:8]#[N:10])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][NH:3]1
Reactant: NC(=O)c1cc(-c2ccccc2)n[nH]c1=O
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cc(-c2ccccc2)n[nH]c1=O

Procedure:
A mixture of 2,3-dihydro-3-oxo-6-phenyl-4-pyridazinecarboxamide (4.2 g) in 100 ml of acetic anhydride is heated under reflux for 6 hours. The acetic anhydride is removed by distillation and the residue is partitioned between ammonium hydroxide solution and dichloromethane. The dichloromethane layer is separated and concentrated on the rotary evaporator and the residue is recrystallized from ethanol to give 2,3-dihydro-3-oxo-6-phenyl-4-pyridazinecarbonitrile.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CON(C)[C:10](=[O:24])[C@H:11]([CH:21]([CH3:23])[CH3:22])[N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:13].S([O-])(O)(=O)=O.[K+].C(OCC)C>C1COCC1.O>[C:14]([N:12]([CH3:13])[C@H:11]([CH:10]=[O:24])[CH:21]([CH3:22])[CH3:23])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CON(C)C(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](C=O)N(C)C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 91.7 %

Procedure:
Lithium aluminum hydride (875 mg, 23 mmol) was added to a solution of Nα-Boc-Nα-methyl-L-valine N-methoxy-N-methylamide (12) (2.0 g, 7.7 mmol) in dry THF (8 mL) and the reaction mixture was stirred for 20 min. The mixture was poured into a stirring solution of potassium hydrogen sulfate (3.14 g, 23 mmol) in water (100 mL). Diethyl ether (75 mL) was added, the layers separated and the aqueous layer extracted with diethyl ether (3×50 mL). The organic layers were combined, and washed sequentially with 3 N hydrochloric acid (3×30 mL), saturated aqueous sodium hydrogen carbonate (3×30 mL), and saturated aqueous sodium chloride (3×30 mL). The organic layer was dried with magnesium sulfate and the solvent was evaporated to yield the crude aldehyde 13 (1.52 g, 92% yield). Aldehyde 13 was used without further purification. Note: 13 can be stored under argon for ˜2 weeks, but when stored in organic solvents at room temperature, undergoes slow decomposition. 1H-NMR (200 MHz, CDCl3) 0.73 (d, J=6.9 Hz, 3H, CH3), 0.91 (d, J=6.9 Hz, 3H, CH3), 1.27 (s, 9H, Boc-(CH3)3), 2.02-2.15 (m, 1H, CH), 2.63 (s, 2H, NCH3), 2.72 (s, 1H, NCH3), 3.44 (d, J=9.5 Hz, 0.5H, CH), 3.86 (d, J=9 Hz, 0.5H, CH), 9.45 (s, 1H, CH); Exact mass calc'd for C11H22NO3 (M+H)+: 216.15997; Found (DCI): 216.15996; Optical rotation obtained was [α]D25 −104.2 (c 5.5, CHCl3).
Reaction SMILES: OCCCN1C=C(C2C=CC(N[C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=C3C=2CN(C)C3=O)C=N1.[NH2:50][C:51]1[C:52]([C:67]([NH:69][CH3:70])=[O:68])=[N:53][C:54]([C:57]2[CH:58]=[N:59][N:60]([CH2:62][CH:63]([CH3:66])[CH2:64][OH:65])[CH:61]=2)=[CH:55][CH:56]=1>>[OH:65][CH2:64][CH:63]([CH3:66])[CH2:62][N:60]1[CH:61]=[C:57]([C:54]2[N:53]=[C:52]([C:67](=[O:68])[NH:69][CH3:70])[C:51]([NH:50][C:26]3[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:25]=3)=[CH:56][CH:55]=2)[CH:58]=[N:59]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CNC(=O)c1nc(-c2cnn(CC(C)CO)c2)ccc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CC(C)CO)c4)nc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
Prepared analogously to Compound 1B using replacing compound 1C with 3-amino-6-[1-(3-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-N-methylpyridine-2-carboxamide (Compound 18C). 1H NMR (CD3OD, 400 MHz): δ=8.92 (br. s., 1H) 8.51 (s, 1H) 8.37 (br. s., 1H) 8.31 (s, 1H) 7.77 (d, J=8.8 Hz, 1H) 7.54 (d, J=7.8 Hz, 1H) 7.17 (s, 1H) 7.04 (d, J=7.8 Hz, 1H) 4.29 (dd, J=13.8, 6.44 Hz, 1H) 4.00-4.16 (m, 5H) 3.89 (s, 3H) 3.47 (d, J=5.6 Hz, 2H) 3.37 (d, J=21.7 Hz, 2H) 3.00 (s, 3H) 2.26 (dq, J=12.8, 6.4 Hz, 1H) 1.27 (t, J=7.1 Hz, 6H) 0.94 (d, J=6.8 Hz, 3H). MS (ESI): m/z=707.70 [M+H]+. UPLC: tR=1.29 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: CO[C:3]1[S:4][CH:5]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[N+:13]([O-:15])=[O:14])[N:7]=1.C(=O)(O)[O-].[Na+].O=P(Cl)(Cl)[Cl:23]>O>[Cl:23][C:3]1[S:4][CH:5]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[N+:13]([O-:15])=[O:14])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1nc(-c2sccc2[N+](=O)[O-])cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccsc1-c1csc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-methoxy-4-(3-nitrothiophen-2-yl)thiazole (403 mg, 1.66 mmol) in POCl3 (2 mL) was heated at 60° C. for 1 h then to 100° C. for a further 2 h. The resulting solution was cooled to room temperature and diluted with cold H2O then saturated aqueous sodium bicarbonate. The mixture was extracted with methylene chloride and the combined organic phases were dried (Na2SO4), filtered and concentrated under vacuum to give 2-chloro-4-(3-nitrothiophen-2-yl)thiazole. Retention time (min)=2.550, method [1], MS(ESI) 246.9 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7].[CH2:14]=O.Cl.[NH4+].[OH-]>O>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[C:6](=[O:8])[O:7][CH2:14]2
Reactant: C=O
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(cc1OC)C(=O)OC2
Reaction time: 8 h
Yield: 58.4 %

Procedure:
Under mechanical stirring a slurry of 3,4-dimethoxybenzoic acid (353.5 g, 1.94 moles) in HCHO (1.71, 24.5 moles) was prepared and cooled in ice, saturated with gaseous HCl (340 g, 9.32 moles), then gradually brought to 60° C. After 1 night the temperature was brought to room value and further HCl (300 g) was gurgled therein, then the temperature was brought to 60° C. again overnight. The mixture was brought to small volume, taken up in water (1 l), neutralized with 28% NH4OH (1.5 l) and kept at cold for 2 hours, then filtered. The filtrate was washed with water till neutrality, then crystallized from methanol (2 l) and dried under vacuum at 60° C. to give 220 g of the title product (yield: 58.65%).
Reaction SMILES: CCOCC.[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13]1([C:19]2[O:20][CH2:21][CH2:22][N:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[C:13]1([C:19]([NH:23][CH2:22][CH2:21][O:12][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(C2=NCCO2)cc1
Reactant: Oc1ccccc1
Solvent: CCOCC
Solvent: O
Product: O=C(NCCOc1ccccc1)c1ccccc1

Procedure:
In German Pat. No. 1,062,253, A. Jager describes the preparation of various ether and carboxamide compounds by treating certain substituted oxazolines with certain phenols, with the exclusion of water. A mixture of phenol and 2-phenyloxazoline refluxed for 7 hours yielded PhCONHCH2CH2OPh as a product. Similarly, p-bis(oxazolinyl)benzene and phenol gave N,N'-bis(β-phenoxyethyl)terephthalamide. Finally, Jager found that a mixture of 2-phenyl-2-oxazoline and hydroquinone produced 1,4-bis(β-benzamidoethoxy)benzene.
Reaction SMILES: [C:1]([C:3]1[CH:45]=[CH:44][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4C(OC(C)(C)C)=O)([O:15][CH3:16])[C:11]([F:14])([F:13])[F:12])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OC)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)(OC)C(F)(F)F)N(COCC[Si](C)(C)C)C=2C=1)#N>>[F:13][C:11]([F:12])([F:14])[C:10]([C:8]1[NH:7][C:6]2[CH:44]=[CH:45][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:9]=1)([O:15][CH3:16])[C:17]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(OC)(c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(OC)(c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C)C(F)(F)F
Product: COc1cc(C)c2[nH]ccc2c1C(OC)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F

Procedure:
The title compound was synthesized from a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-methoxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-methoxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate using the same procedure as described in Example 24-B. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.76-13.01 (m, 1H) 11.06 (br. s., 1H) 8.27 (s) 7.82-7.92 (m) 7.50-7.66 (m, 2H) 7.36 (t, J=2.78 Hz, 1H) 6.65-6.79 (m, 2H) 3.19 (s, 3H) 3.10 (s, 3H). HRMS calcd. for C21H17F3N4O2 (M+H)+ 415.1379. found 415.1376.
Reaction SMILES: [C:1]([C@@H:3]([NH:5][C:6](=[O:12])OC(C)(C)C)[CH3:4])#[N:2].[C:13](Cl)(=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]C>>[C:1]([C@@H:3]([NH:5][C:6](=[O:12])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:4])#[N:2]
Reactant: C[C@@H](C#N)NC(=O)OC(C)(C)C
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@@H](C)C#N
Yield: 53 %

Procedure:
General procedures D was used to deprotect 1.17 mmols of (S)-tert-butyl 1-cyanoethylcarbamate to the corresponding amine. General procedure F was then use to couple to amine to 1.521 mmols of oleoyl chloride. After standard purification techniques, 0.62 mmols (53%) of the title product was recovered. 1H NMR (500 MHz, CDCl3) δ 6.08 (s, 1H), 5.40-5.28 (m, 2H), 5.00-4.90 (m, 1H), 4.12 (q, J=7.2, 0H), 2.20 (dd, J=6.6, 8.5, 2H), 2.00 (dd, J=6.3, 12.0, 4H), 1.68-1.58 (m, 2H), 1.54 (d, J=7.2, 3H), 1.38-1.20 (m, 24H), 0.87 (t, J=6.9, 3H). 13C NMR (126 MHz, CDCl3) δ 172.49, 130.02, 129.66, 119.35, 36.11, 35.63, 31.88, 29.74, 29.68, 29.50, 29.31, 29.20, 29.14, 29.08, 27.20, 27.14, 25.30, 22.67, 19.43, 14.11.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:11])=[CH:5][C:4]=1[O:32][CH3:33].[CH3:34][S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1.ClCCl>[CH3:33][O:32][C:4]1[CH:5]=[C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)=[O:11])[CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][S:35]([CH3:34])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(C)C(=O)NCc2ccc(C(F)(F)F)nc2-c2cccc(C)c2)ccc1CN
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(C(C)C(=O)NCc2ccc(C(F)(F)F)nc2-c2cccc(C)c2)ccc1CNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 21.5 %

Procedure:
To a stirred solution of 2-(4-(aminomethyl)-3-methoxyphenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (151 mg, 0.33 mmol) in pyridine, cooled to 0° C., were added methanesulfonyl chloride (151 mg). The resulting reaction mixture was stirred for 15 h at room temperature. The mixture dissolved in dichloromethane and washed with 1N HCl. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(3-Methoxy-4-(methylsulfonamidomethyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (example 78) (38 mg) was obtained as 22% yield.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]([CH3:32])[C:7]([CH2:20][NH:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[CH:8][C:9](=[O:19])[C:10]=1[O:11]CC1C=CC=CC=1)=[O:4].C1(S(C(N)C2N(C)C(C(O)=O)=C(O)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH3:1][NH:2][C:3]([C:5]1[N:6]([CH3:32])[C:7]([CH2:20][NH:21][S:22]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)(=[O:23])=[O:24])=[CH:8][C:9](=[O:19])[C:10]=1[OH:11])=[O:4]
Reactant: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccc(Cl)cc2)n1C
Agent: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(O)c1C(=O)O
Product: CNC(=O)c1c(O)c(=O)cc(CNS(=O)(=O)c2ccc(Cl)cc2)n1C
Yield: 66.1 %

Procedure:
6-[(4-Chloro-benzenesulfonylamino)-methyl]-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide (16-07) (375.0 mg, 65.95%, purified by Prep-HPLC) was synthesized as a light pink solid from 3-benzyloxy-6-[(4-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-07) (700.0 mg, 1.47 mmol) following the procedure described for 6-(benzene sulfonyl amino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-01).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([OH:24])=O)[CH2:18][CH2:17]2)[N:4]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH2:34].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:6]=[C:5]([NH:15][C@H:16]2[CH2:17][CH2:18][C@H:19]([C:22]([NH:34][CH2:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[C:26]([F:25])([F:35])[F:36])=[O:24])[CH2:20][CH2:21]2)[N:4]=1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CNc1nc(N[C@H]2CC[C@H](C(=O)O)CC2)nc(-c2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CNc1nc(N[C@H]2CC[C@H](C(=O)NCc3ccccc3C(F)(F)F)CC2)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of trans-4-{[4-(methylamino)-6-phenyl-1,3,5-triazin-2-yl]amino}cyclohexanecarboxylic acid (40 mg, 0.12 mmol) was added 1-[2-(trifluoromethyl)phenyl]methanamine (22 mg, 0.12 mmol), EDCI (24 mg, 0.12 mmol), HOBt (17 mgs, 0.12 mmol), and N-methylmorpholine (13 mg, 0.12 mmol). The mixture was stirred at rt for 20 h. The solvent was removed under vacuum, and the resulting residue was purified by HPLC to provide 20 mg (34% yield) of the desired material. MS (ES+): m/e 485.3 [M+H]+.
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH3:32])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[O:34]1C[CH2:37][CH2:36][C@@H:35]1C(NN)=O>>[CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([C@H:32]4[CH2:37][CH2:36][CH2:35][O:34]4)=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Reactant: NNC(=O)[C@H]1CCCO1
Product: Cc1cc(C2CCC2)c(-c2nnc([C@H]3CCCO3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 152), using (R)-tetrahydrofuran-2-carbohydrazide (compound 174.1) in place of acetohydrazide. m/z (ES+) 496 (M+H)+. 1H NMR (300 MHz, CD3OD) δ 7.70 (d, 2H), 7.49-7.41 (m, 4H), 5.15 (t, 1H), 4.89-4.80 (m, 1H), 4.14-3.92 (m, 3H), 3.65-3.51 (m, 1H), 3.33-3.27 (m, 1H), 3.03-2.95 (m, 2H), 2.47-2.37 (m, 4H), 2.24-1.91 (m, 9H), 1.83-1.71 (m, 4H).
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]([O:44][C:45](=[O:80])[CH2:46][CH2:47][CH2:48][CH2:49][CH:50]1[S:79][C@H:53]2[CH2:54][C@@H:55]([O:72]C3CCCCO3)[C@H:56](/[CH:57]=[CH:58]/[C@@H:59]([O:65]C3CCCCO3)[CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[C@H:52]2[CH2:51]1)[CH2:23][O:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])(=[O:19])[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][CH2:16][CH2:17][CH3:18]>CO>[C:1]([O:20][CH2:21][CH:22]([O:44][C:45](=[O:80])[CH2:46][CH2:47][CH2:48][CH2:49][CH:50]1[S:79][C@H:53]2[CH2:54][C@@H:55]([OH:72])[C@H:56](/[CH:57]=[CH:58]/[C@@H:59]([OH:65])[CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[C@H:52]2[CH2:51]1)[CH2:23][O:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])(=[O:19])[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][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCCCC)OC(=O)CCCCC1C[C@@H]2[C@@H](/C=C/[C@H](CCCCC)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2S1
Solvent: CO
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCCCC)OC(=O)CCCCC1C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]2S1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 66.6 %

Procedure:
Under an atmosphere of nitrogen, a mixture of 51 mg of (13E)-(6RS,9α,11α,15S)-6,9-epithio-11,15-bis-(tetrahydropyran-2-yloxy)prost-13-enoic acid 1,3-bisstearoyloxy-2-propyl ester, 2.5 mg of p-toluenesulphonic acid-pyridine complex and 2 ml of methanol was stirred at 50° C. for 1.5 hours, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (2:1) as eluent to give 29 mg of the title compound having the following physical characteristics:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[F:10][C:11]([F:17])([F:16])[CH2:12][N:13]=[C:14]=[S:15]>C(#N)C>[F:10][C:11]([F:17])([F:16])[CH2:12][NH:13][C:14](=[S:15])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1
Reactant: CSc1nccc(N)n1
Reactant: FC(F)(F)CN=C=S
Solvent: CC#N
Product: CSc1nccc(NC(=S)NCC(F)(F)F)n1
Reaction time: 72 h
Yield: 51.2 %

Procedure:
A mixture of 4-amino-2-methylthiopyrimidine (2.1 g.), 2,2,2-trifluoroethylisothiocyanate (2.8 g.) and acetonitrile (5 ml.) was stirred at 70° for 72 hours and then cooled, and the solid that crystallised was collected to give 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-methylthiopyrimidine (2.15 g.) which was used without further purification.
Reaction SMILES: [Cl-].[NH4+:2].[CH:3]1[CH:8]=[C:7]([C:9](O)=O)[C:6]([Cl:12])=[CH:5][CH:4]=1>>[CH:3]1[CH:8]=[C:7]([C:9]#[N:2])[C:6]([Cl:12])=[CH:5][CH:4]=1
Reactant: [NH4+]
Reactant: O=C(O)c1ccccc1Cl
Agent: [Cl-]
Product: N#Cc1ccccc1Cl
Temperature: 225 °C
Yield: 880.8 %

Procedure:
OCBTC (230 g, 1.0 mol), ammonium chloride (59 g, 1.10 eq), and OCBA (15.7 g) were added to a 500 mL reactor equipped with thermocouple, overhead stirrer, and reflux condenser. The reaction mixture was stirred, heated upto 225° C., and maintained at that temperature while the reaction was periodically followed by gas chromatography (GC). After a reaction time of about 8 h, OCBN (121.5 g, 88.4%) was obtained by distillation (melting point: 45°-46° C.).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([CH2:37][O:38]C(=O)C)=[O:36]>>[OH:38][CH2:37][C:35]([NH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:36]
Reactant: CC(=O)OCC(=O)Cl
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Product: O=C(CO)NC1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from trans-4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A140) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [Li+].[BH4-].Cl[Si](C)(C)C.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:21]=2[CH3:28])=[C:13]([CH:17]=1)[C:14](O)=[O:15]>C1COCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:21]=2[CH3:28])=[C:13]([CH2:14][OH:15])[CH:17]=1
Reactant: COc1cccc(CCc2ccc(Br)cc2C(=O)O)c1C
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(CCc2ccc(Br)cc2CO)c1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Into a dry 100 mL flask was weighed LiBH4 (0.55 g; 25.0 mmol). THF (25 mL) was added and the suspension was cooled to 0° C. To the chilled suspension was added chlorotrimethylsilane (6.36 mL; 50.0 mmol). Then solid 5-bromo-2-[2-(3-methoxy-2-methylphenyl)-ethyl]-benzoic acid 7 (4.37 g; 12.5 mmol) was added portion-wise, slowly enough to control bubbling of the mixture. After addition, the ice bath was removed and the suspension was stirred at ambient temperature overnight. The mixture was quenched by slowly adding methanol until the bubbling stopped and the solution turned clear. The solvents were evaporated and the residue was stirred in water, basified using 2.5 N NaOH solution and extracted with dichloromethane. The organic extracts were combined, dried over Na2SO4 and evaporated to obtain the compound 8 as a low-melting solid (4.19 g crude).