Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH2:7]([O:6][C:1]([CH:2]([CH3:4])[CH2:3][NH:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:8]
Reactant: NCc1ccccc1
Reactant: C=C(C)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(C)CNCc1ccccc1
Yield: 31.6 %

Procedure:
350 ml (2.8 moles) of ethyl methacrylate were added to a solution of 150 g (1.4 moles) of benzylamine dissolved in 400 ml of ethanol. The mixture was heated under reflux for 4 hours, and then 175 ml (1.4 mole) of ethyl methacrylate were added to it, after which it was heated under reflux for 24 hours. The solvent and the unreacted materials were then removed from the mixture by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel eluted with a 1:1 by volume mixture of ethyl acetate and toluene, to afford 98.0 g of N-(2-ethoxycarbonylpropyl)benzylamine as a red oil.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1.C1C(=O)N([Br:23])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:15])=[CH:5][C:6]=1[C:11]([F:14])([F:13])[F:12]
Reactant: COC(=O)c1ccc(C)c(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=C(O)c1ccc(CBr)c(C(F)(F)F)c1
Yield: 140.4 %

Procedure:
4-Methyl-3-(trifluoromethyl)benzoic acid methyl ester (3.73 g, 18.3 mmol) in CCl4 (40 mL) with NBS (3.9 g, 22 mmol) and benzoylperoxide with 25% of water (0.55 g, 1.7 mmol) were stirred and heated to reflux for 6 h. Solvent was evaporated, a water solution of K2CO3 was added and product is extracted with EtOAc to obtain a pale yellow solid (7.64 g, 25.7 mmol). Yield=140% (crude).
Reaction SMILES: [CH2:1]([P:3](Cl)([CH2:5][O:6][S:7]([C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])(=[O:9])=[O:8])=[O:4])[CH3:2].[CH:19]([OH:23])([CH2:21][CH3:22])[CH3:20].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([P:3]([CH2:5][O:6][S:7]([C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])(=[O:9])=[O:8])(=[O:4])[O:23][CH:19]([CH2:21][CH3:22])[CH3:20])[CH3:2]
Reactant: CCP(=O)(Cl)COS(=O)(=O)c1c(C)cccc1Cl
Reactant: CCC(C)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)OP(=O)(CC)COS(=O)(=O)c1c(C)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
To a solution of 5.83 g of P-ethyl[[(2-chloro-6-methylphenyl)sulfonyloxy]-methyl]phosphinoyl chloride (Example 51) and 0.2 g of 4-dimethylaminopyridine (DMAP) in 15 ml of methylene chloride at 10° C. was added dropwise over 10 minutes a solution of 1.52 g of sec-butanol and 2.32 g of triethylamine in 8 ml of methylene chloride. After 1 hour, the cooling bath was removed and the reaction was warmed to room temperature and stirred an additional two hours. The reaction mixture was diluted with ethyl acetate, 20 ml, ether, 50 ml, and water, 60 ml, and the organic phase was separated, washed with an additional 50 ml of water, dried with magnesium sulfate, filtered and concentrated. The resulting oil was dissolved in 4 ml of methylene chloride and flash chromatographed on Merck silica gel using blends of ethyl acetate and hexanes. Similar fractions were combined to yield 3.2 g of desired product as a tan oil.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[NH:11][NH2:12].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.Cl>[N:12]1([NH:11][C:10](=[O:13])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=[CH:7][CH:6]=[CH:5]1
Reactant: COC1CCC(OC)O1
Reactant: CC(C)(C)OC(=O)NN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nn1cccc1
Temperature: 85 °C
Reaction time: 21 h
Yield: 49.9 %

Procedure:
Under an atmosphere of nitrogen, a solution of 2,5-dimethoxytetrahydrofuran (400 g, 3.03 mol) and tert-butyl carbazate (364 g, 2.75 mol) in 1,4-dioxane (2.5 L) were combined in a flask. Then, aqueous hydrochloric acid solution (2N, 35.8 mL, 71.5 mmol) was added dropwise and the reaction mixture was stirred for 21 hours at 85° C. The reaction mixture was treated with saturated sodium carbonate aqueous solution (120 mL) at room temperature. The quenched mixture was filtered to give a precipitate which was dried to give the title compound as a gray solid (250 g). The organic phase of the filtrate was concentrated and the resultant precipitate was washed with diisopropyl ether (200 mL) and filtered to give the title compound as a gray solid (60 g). The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1→3:1→2:1) to obtain the title compound (47 g). A total of 357 g of the title compound having the following physical data was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]([OH:20])[C:18]#[CH:19])[CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].I[C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:17]([OH:20])[C:18]#[C:19][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC(O)c1ccc(N2CCCCC2)c(C(C)(C)C)c1
Reactant: O=C(O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CC(C)(C)c1cc(C(O)C#Cc2ccc(C(=O)O)cc2)ccc1N1CCCCC1
Yield: 46.1 %

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 1.18 g (4.4 mmol) of 1-(3-tert-butyl-4-piperidin-1-ylphenyl)prop-2-yn-1-ol with 890 mg (3.6 mmol) of 4-iodobenzoic acid, 35 mg (0.18 mmol) of copper iodide and 63 mg (0.09 mmol) of bis(triphenylphosphine)palladium chloride. 650 mg of 4-[3-(3-tert-butyl-4-piperidin-1-ylphenyl)-3-hydroxyprop-1-ynyl]benzoic acid are obtained in the form of a beige solid (Mp=112° C., yield=46%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[C:42]([CH3:47])=[N:43][O:44][C:45]=1[CH3:46])=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[C:42]([CH3:47])=[N:43][O:44][C:45]=2[CH3:46])=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1c(C)noc1C
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Product: Cc1noc(C)c1C(=O)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3) and N-methoxy-N,3,5-trimethyl-1,2-oxazole-4-carboxamide
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:25]2[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=2)[CH2:28][NH:29]C(=O)OC(C)(C)C)[C:5]2[N:6]([N:8]=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[N:10]=2)[CH:7]=1.[ClH:40]>C(Cl)Cl.CCOCC>[ClH:40].[ClH:40].[NH2:29][CH2:28][C:27]1[CH:26]=[C:25]([C:4]2[C:5]3[N:6]([N:8]=[C:9]([NH:11][CH:12]4[CH2:13][CH2:14][N:15]([C:18]5[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20][N:19]=5)[CH2:16][CH2:17]4)[N:10]=3)[CH:7]=[C:2]([CH3:1])[CH:3]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: Cc1cc(-c2cccc(CNC(=O)OC(C)(C)C)c2)c2nc(NC3CCN(c4cc(C)ncn4)CC3)nn2c1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(-c2cccc(CN)c2)c2nc(NC3CCN(c4cc(C)ncn4)CC3)nn2c1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of tert-butyl 3-(6-methyl-2-(1-(6-methylpyrimidin-4-yl)piperidin-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzylcarbamate (46 mg, 87.0 μmol) in methylene chloride (1 mL) was added 2 M solution of HCl in Ether (500 μL). The suspension was stirred at room temperature over night. The solvent was decanted and the residue was digerated with diethyl ether three times. The title compound was dried under reduced pressure and was obtained as a yellow solid (39 mg, 89%). MS ISP (m/e): 429.3 (100) [(M+H)+], 412.4 (57).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([NH:12][C:13]([C:15]1[C:20]([I:21])=[C:19]([N:22]2[CH2:26][CH2:25][CH:24](Br)[C:23]2=[O:28])[C:18]([I:29])=[C:17]([C:30]([NH:32][CH:33]([CH2:39][O:40][C:41](=[O:43])[CH3:42])[CH2:34][O:35][C:36](=[O:38])[CH3:37])=[O:31])[C:16]=1[I:44])=[O:14])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]>C(O)(=O)C.C([O-])(=O)C.[Ag+]>[C:1]([O:4][CH2:5][CH:6]([NH:12][C:13]([C:15]1[C:20]([I:21])=[C:19]([N:22]2[CH2:26][CH2:25][CH:24]([O:4][C:1](=[O:3])[CH3:2])[C:23]2=[O:28])[C:18]([I:29])=[C:17]([C:30]([NH:32][CH:33]([CH2:39][O:40][C:41](=[O:43])[CH3:42])[CH2:34][O:35][C:36](=[O:38])[CH3:37])=[O:31])[C:16]=1[I:44])=[O:14])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c(I)c(N2CCC(Br)C2=O)c1I
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c(I)c(N2CCC(OC(C)=O)C2=O)c1I
Yield: 163.4 %

Procedure:
N,N'-bis-[2-acetyloxy-1-(acetyloxymethyl)ethyl]-5-[3-bromo-2-oxo-1-pyrrolidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide (4.00 g, 3.92 mmol) of example 4a was dissolved in glacial acetic acid (40 ml) and treated with silver acetate (3.25 g, 19.50 mmol) at 133°-135° for 26 hours under a nitrogen atmosphere. The suspended solids were filtered off and the solvent was removed in vacuo. The resulting crude residue was treated with acetic anhydride (30 ml) and pyridine (42 ml), after which the volatile components were completely removed Under high vacuum. The resulting product was purified by silica gel flash chromatography to obtain N,N'-bis-[2-acetyloxy-1-(acetyloxymethyl)ethyl]-5-[3-acetyloxy-2-oxo-1-pyrrolidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide as a pale orange foam (3.20 g, 82% yield).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[Cl:28][C:29]1[C:34]([F:35])=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])(O)=O.[Na+]>COCCOC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:28][C:29]1[N:30]=[CH:31][C:32]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)=[CH:33][C:34]=1[F:35]
Reactant: CC1(C)OB(c2cnc(Cl)c(F)c2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cnc(Cl)c(F)c2)c1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 300 mg, 0.672 mmol) and 2-chloro-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (346 mg, 1.345 mmol) were dissolved in DME (2.7 mL). A solution of 2 M NaHCO3 (1.01 mL, 2.03 mmol) was added, the RM was flushed with argon and Pd(PPh3)2Cl2 (56.6 mg, 0.081 mmol) was added. The RM was stirred under argon at 95° C. for 2 h in a capped pressure safe tube. After cooling to RT, the RM was dissolved in EtOAc, and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH), followed by a second purification (RediSep® Silica gel column, n-hexane/EtOAc, 50 to 100% EtOAc) and treatment with Si-Thiol (200 mg) in MeOH to afford the title compound as a white powder. HPLC (Condition 4) tR=5.63 min, UPLC-MS (Condition 7) m/z=497.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.80 (m, 1H) 1.80-1.91 (m, 1H) 2.87 (d, J=10.56 Hz, 1H) 3.18-3.28 (m, 2H) 3.33-3.50 (m, 1H) 4.20 (br. s, 1H) 4.86 (d, J=3.52 Hz, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.84 (d, J=8.99 Hz, 2H) 7.99-8.11 (m, 2H) 8.34 (s, 1H) 8.77 (d, J=2.35 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: [CH2:1]([N:13]([CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:20]([OH:30])[CH:19]=1)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:31]O>>[CH2:1]([N:13]([CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:20]([O:30][CH3:31])[CH:19]=1)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CO
Reactant: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)OC)c(O)c1
Product: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)OC)c(OC)c1
Yield: 91.6 %

Procedure:
3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-hydroxyphenyl]propanoic acid, methyl ester (500 mg, 1.18 mmol) and methanol (0.096 ml, 2.37 mmol) were reacted under Mitsunobu conditions as described in example 1 and afforded the title compound (471 mg, 81%) as a pale yellow oil.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]([CH3:40])[N:20]=[CH:21][C:22]=2[NH:23][C:24]([C:26]2[N:27]=[C:28](Br)[S:29][C:30]=2[NH:31]C(OC(C)(C)C)=O)=[O:25])[CH2:13][CH2:12]1)C1C=CC=CC=1.[CH:42]1([C:45]2[CH:50]=[CH:49][C:48](B3OC(C)(C)C(C)(C)O3)=[C:47]([F:60])[CH:46]=2)[CH2:44][CH2:43]1>>[NH2:31][C:30]1[S:29][C:28]([C:48]2[CH:49]=[CH:50][C:45]([CH:42]3[CH2:44][CH2:43]3)=[CH:46][C:47]=2[F:60])=[N:27][C:26]=1[C:24]([NH:23][C:22]1[CH:21]=[N:20][N:19]([CH3:40])[C:18]=1[N:14]1[CH2:15][CH2:16][CH2:17][C@@H:11]([NH2:10])[CH2:12][CH2:13]1)=[O:25]
Reactant: CC1(C)OB(c2ccc(C3CC3)cc2F)OC1(C)C
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Product: Cn1ncc(NC(=O)c2nc(-c3ccc(C4CC4)cc3F)sc2N)c1N1CCC[C@@H](N)CC1
Yield: 37.8 %

Procedure:
Following the procedures from Example 210 and shown in FIG. 3, using ((R)-1-{4-[(2-bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl)-amino]-2-methyl-2H-pyrazol-3-yl}-perhydro-azepin-4-yl)-carbamic acid benzyl ester and 2-(4-cyclopropyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as starting materials, 222 was obtained in 37.8% yield over two steps: 1H NMR (400 MHz, DMSO) δ 8.86 (s, 1H), 8.10 (t, J=8.2 Hz, 1H), 7.53 (s, 1H), 7.35 (s, 2H), 7.06 (dd, J=19.7, 10.7 Hz, 2H), 3.65 (s, 3H), 3.21-2.99 (m, 5H), 2.05-1.95 (m, 1H), 1.90-1.73 (m, 4H), 1.65-1.47 (m, 3H), 1.06-0.99 (m, 2H), 0.81-0.75 (m, 2H); MS (ESI) m/z: 470.2 [M+H]+
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3](O)=[O:4].O1CCCC1.C(OC(Cl)=O)C.[CH2:21]([N:23](CC)CC)C>>[C:21]([C:2]([CH3:1])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][OH:4])#[N:23]
Reactant: CCCCC(C)C(=O)O
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCCCC(C)(C#N)CO
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 48.5 %

Procedure:
A mixture of 1.25 g (8.1 mM) of (-)-2-methylhexanoic acid ([α]D26 -6.15 degrees (c 1.073, methanol)), 20 ml of dry tetrahydrofuran and 0.90 g (8.9 mM) of dry triethylamine was cooled on an ice bath, and 0.84 g (8.1 mM) of ethyl chloroformic acid was added dropwise thereto in 5 minutes, followed by 1 hour of stirring at 0° C. A white salt precipitated at this time was removed by filtration. To a mixture of 0.46 g (12.1 mM) of sodium borohydride and 8 ml of distilled water under stirring at 0° C., the above filtrate was added dropwise in 20 min., followed by stirring at room temperature for 3 hours. After the reaction, 2N-hydrochloric acid was added to give pH 1, and the organic layer was separated. The remaining aqueous layer was subjected to extraction with ether, and the ether extract was mixed with the organic layer. The mixture was washed with 1N-sodium bicarbonate aqueous solution and dried on sodium sulfate. After the removal of solvent by distillation, the product was subjected to distillation by a Kugelrohr distiller. At 95° C./4 mmHg, (+)-2-cyano-2-methyl-1-hexanol was obtained in an amount of 0.55 g (Yield:48.5%), [α]D26 +0.66 degree (c 1.823, ether).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:14]1[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:13]=1[F:12])=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1c(F)cccc1F
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1c(F)cccc1F
Yield: 90.8 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-(2,6-difluorophenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2,6-difluoro phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (0.91 g, 91%). EI-MS rm/z 308 (M−H)−
Reaction SMILES: [CH:1]([O:4][C:5](=[O:33])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH:29]3[CH2:32][CH2:31][CH2:30]3)[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24][CH2:25][CH2:26][CH2:27]Cl)[CH:16]=3)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].[I-].[Na+].[Na].[NH:37]1[CH:41]=[N:40][CH:39]=[N:38]1>CC#N>[CH:1]([O:4][C:5](=[O:33])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH:29]3[CH2:32][CH2:31][CH2:30]3)[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24][CH2:25][CH2:26][CH2:27][N:37]2[CH:41]=[N:40][CH:39]=[N:38]2)[CH:16]=3)=[CH:9][CH:8]=1)([CH3:3])[CH3:2]
Reactant: c1nc[nH]n1
Reactant: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCCCl)cc3n2C2CCC2)cc1
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CC#N
Product: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCCn4cncn4)cc3n2C2CCC2)cc1

Procedure:
To a solution of {4-[6-(3-chloro-propoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester (37 mg, 0.08 mmol) in CH3CN (1 mL) is added sodium iodide (71 mg, 0.48 mmol). The resulting mixture is stirred at reflux temperature overnight. The solvent is then evaporated and the residue is diluted with anhydrous DMF (1 mL) and then treated with the sodium salt of 1,2,4-triazole (0.16 mmol) at room temperature overnight. The solvent is removed under reduced pressure and the residue is diluted with ethyl acetate and then washed with water. The organic layer is concentrated and triturated with hexane and the precipitate is collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford {4-[3-cyano-1-cyclobutyl-6-(3-[1,2,4]triazol-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester, compound 1255 (31 mg, 78%).
Reaction SMILES: CO.C(=O)([O-])[O-].[K+].[K+].C([O:12][C:13]1[CH:14]=[C:15]([CH:34]=[CH:35][CH:36]=1)[C:16]([NH:18][C:19]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22])=[O:17])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[OH:12][C:13]1[CH:14]=[C:15]([CH:34]=[CH:35][CH:36]=1)[C:16]([NH:18][C:19]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22])=[O:17]
Reactant: CC(=O)Oc1cccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cccc(O)c1
Reaction time: 2 h
Yield: 90.1 %

Procedure:
0.50 mL of methanol, 0.50 mL of tetrahydrofuran and 8.3 mg of potassium carbonate were added to 15 mg of 2-(3-acetoxybenzamido)-4-phenylbenzoic acid at room temperature sequentially and stirred at the same temperature for 2 hours. 10% citric acid aqueous solution was added to the reaction mixture and a solid substance was separated by filtration to obtain 12 mg of 2-(3-hydroxybenzamido)-4-phenylbenzoic acid as while solid.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([C:11]2[S:15][C:14]([NH2:16])=[N:13][N:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C(OCC)(=O)C>[CH:5]1([C:11]2[S:15][C:14]([N:16]=[C:1]=[O:2])=[N:13][N:12]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=C(Cl)Cl
Reactant: Nc1nnc(C2CCCCC2)s1
Solvent: CCOC(C)=O
Product: O=C=Nc1nnc(C2CCCCC2)s1

Procedure:
A saturated solution of phosgene in ethyl acetate (500 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. 5-Cyclohexyl-2-amino-1,3,4-thiadiazole (6 grams) is added to the reaction vessel and the resulting mixture is stirred and heated at reflux for a period of about 4 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized from a dimethyl formamide-water mixture to yield the desired product 5-cyclohexyl-1,3,4-thiadiazol-2-yl isocyanate dimer having a melting point of 237° to 239° C.
Reaction SMILES: [CH2:1]1[C@@H:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Cl[CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].CC(C)CC(=O)C>[CH2:1]1[C@@H:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][N:2]1[CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)COCCCl
Reactant: c1ccc2c(c1)Cc1ccccc1N1CCNC[C@H]21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)COCCN1CCN2c3ccccc3Cc3ccccc3[C@H]2C1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
32.48 g of (S)-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine (prepared as described in Preparation 3), 22.7 g of ethyl 2-choroethoxyacetate, 48.9 g of sodium carbonate and 0.79 g of sodium iodide were added to 340 ml of 4-methyl-2-pentanone, and the mixture was heated under reflux for 16 hours. At the end of this time, it was cooled to room temperature and was filtered using a Celite filter aid, and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through silica gel eluted with a 1:1 by volume mixture of ethyl acetate and hexane, to give 44.85 g (yield 91%) of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:22]=[CH:21][C:13]([O:14][CH:15]([CH3:20])[C:16](OC)=[O:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[CH2:25]([NH2:28])[CH:26]=[CH2:27]>>[CH2:25]([NH:28][C:16](=[O:17])[CH:15]([O:14][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:24])([F:23])[F:1])=[CH:8][N:7]=2)=[CH:22][CH:21]=1)[CH3:20])[CH:26]=[CH2:27]
Reactant: COC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: C=CCN
Product: C=CCNC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 60 °C

Procedure:
A mixture containing 11.85 g (0.035 mol) of methyl 2-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]-propionate and 11.5 g (0.2 mol) of allylamine is boiled under reflux (about 60° C.) for 10 hours. (The reaction is followed by gas chromatography.) Thereafter, the excess of allylamine is distilled off and the residue is dissolved in benzene. After washing the solution cooled down with 5% aqueous hydrochloric acid and then with saturated sodium chloride solution, the organic phase is dried over anhydrous magnesium sulfate and evaporated. The crude product is recrystallized from petroleum ether (b.p. 120° C.) containing a small amount of toluene.