Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH:11]1[CH:15]=[CH:14][N:13]=[N:12]1.CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I.O>[N:11]1[N:12]([C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[CH:5]=[O:7])[N:13]=[CH:14][CH:15]=1
Reactant: c1c[nH]nn1
Reactant: O=C(O)c1cccc(I)c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc(-n2nccn2)c1
Temperature: 120 °C

Procedure:
In a sealed tube, a mixture of commercially available 3-iodobenzoic acid (2.000 g; 8.06 mmol), 1H-1,2,3-triazole (1.113 g; 16.12 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (236 mg; 1.61 mmol), Cs2CO3 (5.362 g; 16.12 mmol), and CuI (76 mg; 0.40 mmol) in anh. DMF (10 ml) was heated to 120° C. for 16 h. After cooling to rt, water was added, and the mixture was extracted with AcOEt. The separated aq. layer was acidified with aq. 1 M HCl, and extracted with AcOEt (3×). The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH/AcOH=20/1/0.1) afforded the two pure isomers:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]2[NH2:23])[CH2:12][CH2:11]1.[CH3:24][O:25][C:26](OC)(OC)OC.C(O)(=O)CC>>[CH3:24][O:25][C:26]1[N:16]([CH:13]2[CH2:12][CH2:11][N:10]([C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)[CH2:15][CH2:14]2)[C:17]2=[N:23][CH:21]=[CH:20][CH:19]=[C:18]2[N:22]=1
Reactant: COC(OC)(OC)OC
Reactant: NC1=CC=CN(C2CCN(c3nc4ccccc4s3)CC2)C1N
Solvent: CCC(=O)O
Product: COc1nc2cccnc2n1C1CCN(c2nc3ccccc3s2)CC1
Temperature: 90 °C
Yield: 13.4 %

Procedure:
N1-(1-(Benzo[d]thiazol-2-yl)piperidin-4-yl)pyridine-2,3-diamine (200 mg, 0.61 mmol) was combined with tetramethylorthocarbonate (2 mL) and propionic acid (8 mg) and heated at 90° C. for 2 hours. After that, the reaction solution was concentrated under reduced pressure and the residue was purified by silica chromatography to give 2-(4-(2-methoxy-3H-imidazo[4,5-b]pyridine-3-yl)piperidin-1-yl)benzo[d]thiazole (30 mg, 0.082 mmol, 13.4% yield). M+1: 366.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][CH3:8])[CH2:6][O:5][CH2:4]1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.CCCCCC.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][O:1][CH2:2][C:3]1([CH2:7][CH3:8])[CH2:6][O:5][CH2:4]1
Reactant: CCC1(CO)COC1
Reactant: BrCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: CCC1(COCCCCBr)COC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 45 %

Procedure:
Into a 2 L egg plant type flask were charged 46.3 g (0.40 mol) of 3-hydroxymethyl-3-ethyloxetane (product name: OXT-101 manufactured by Toagosei Co., Ltd.), 250.3 g (1.16 mol) of 1,4-dibromobutane (reagent, manufactured by Tokyo Kasei Kogyo Co., Ltd.), and 275 ml of hexane. 500 ml of a 33% sodium hydroxide aqueous solution containing 2 g of tetra-n-butylammonium bromide (reagent, manufactured by Tokyo Kasei Kogyo Co., Ltd.) was added to the mixture and vigorously stirred for 5 hours. After the mixture was refluxed at a temperature of 80° C. for one hour, 500 ml of deionized water was added thereto so as to separate the mixture into an organic phase and an aqueous phase. The aqueous phase was extracted three times with 160 ml of hexane. After the organic phase and the extracted phase were dried over magnesium sulfate, the solvent was distilled out in a vacuum. The resulting transparent liquid was distilled in a vacuum thereby obtaining 44.5 g (0.18 mol) of 3-[(4-bromobutoxy)methyl]-3-ethyloxetane as a distillate at 109° C./532 Pa (yield: 44%, identified with 1H-NMR).
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:36])[CH:15]([N:22]3[CH2:26][C:25]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:34])=[CH:24][C:23]3=[O:35])[CH2:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:9]2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:36])[CH:15]([N:22]2[CH2:26][C:25]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])=[CH:24][C:23]2=[O:35])[CH2:16][CH2:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[N:9]1
Reactant: CC(C)(C)CCC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)(C)CCC(C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Yield: 78.3 %

Procedure:
In a round bottom flask under argon was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5-dimethyl-hexanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (14 mg, 0.026 mmol) in methanol (2 mL). To this mixture was then added p-toluenesulfonic acid monohydrate (1 mg, 0.004 mmol) and stirred at 25° C. for 16 h. After this time period, the mixture was concentrated in vacuo and purified by AnaLogix IntelliFlash flash chromatography (4 g column, 100% ethyl acetate to 40% methanol/ethyl acetate) To afford 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5-dimethyl-hexanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]amide (10 mg, 77%) as a white foam: HR-ES-MS m/z calculated for C24H31N4O5Cl [M+H]+ 491.2056, observed 491.2052; 1H NMR (300 MHz, CDCl3) δ ppm 0.91 (br. s., 9H), 1.04-1.35 (m, 2H), 1.79 (br. s., 1H), 1.99 (br. s., 1H), 3.38-3.84 (m, 2H), 3.97-4.29 (m, 4H), 4.41 (d, J=17.8 Hz, 1H), 4.66 (br. s., 1H), 4.86 (br. s., 1H), 6.65 (br. s., 1H), 7.26 (br. s., 4H), 7.47 (br. s., 1H), 9.56 (br. s., 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])([O:3][CH3:4])=[O:2].[NH2:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([O:26][C:27]([F:30])([F:29])[F:28])[N:19]=1>ClCCCl>[CH3:25][O:24][C:22]1[N:21]=[C:20]([O:26][C:27]([F:30])([F:28])[F:29])[N:19]=[C:18]([NH:17][C:15]([NH:14][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:1]([O:3][CH3:4])=[O:2])(=[O:12])=[O:13])=[O:16])[N:23]=1
Reactant: COc1nc(N)nc(OC(F)(F)F)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)nc(OC(F)(F)F)n1
Temperature: 22 °C
Reaction time: 12 h

Procedure:
3.6 g (0.015 mol) of 2-carbomethoxybenzenesulfonyl isocyanate in 4 ml of 1,2-dichloroethane were added over the course of 5 minutes to a stirred mixture of 3.15 g (0.015 mol) of 2-amino-4-methoxy-6-trifluoromethoxy-1,3,5-triazine and 150 ml of 1,2-dichloroethane at 22° C., and the mixture was stirred at 22° C. for 12 hours. It was then concentrated under reduced pressure and crystallized using 1:1 methyl tert-butyl ether/petroleum ether, and the product was filtered off with suction and washed with petroleum ether to yield 5.1 g (75.4% of theory) of the title compound of melting point 149° C. (decomposition).
Reaction SMILES: [OH-].[K+:2].[CH2:3]([P:21](=[O:24])([OH:23])[OH:22])[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][CH2:18][CH2:19][CH3:20]>O>[CH2:3]([P:21](=[O:22])([O-:24])[O-:23])[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][CH2:18][CH2:19][CH3:20].[K+:2].[K+:2]
Reactant: CCCCCCCCCCCCCCCCCCP(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCCCP(=O)([O-])[O-]
Temperature: 60 °C

Procedure:
6.0 mL of a 100 mM solution of KOH was titrated into a dispersed solution of octadecylphosphonic acid (100 mg, 0.3 mmol) in 30 mL of water while stirring. The mixture was then heated to 60° C. while stirring until the water was evaporated (about 3 hours). The resulting white solid was then dried under vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:15]#[C:16][Si](C)(C)C>CN(C=O)C.[Cu]I>[NH:1]1[C:2]2[C:3](=[CH:4][C:5]([C:8]3([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]3)=[CH:6][CH:7]=2)[CH:15]=[CH:16]1
Reactant: COC(=O)C1(c2ccc(N)c(C#C[Si](C)(C)C)c2)CC1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
To a degassed solution of methyl 1-(4-amino-3-((trimethylsilyl)ethynyl)phenyl)cyclopropanecarboxylate (4.69 g, 0.02 mol) in DMF (20 mL) was added CuI (1.5 g, 0.008 mol) under N2 at room temperature. The mixture was stirred for 3 hr at room temperature. The insoluble solid was filtered off and washed with EtOAc (50 mL×3). The filtrate was evaporated under reduced pressure to give a residue, which was purified by chromatography column on silica gel (petroleum ether/ethyl acetate=20:1) to give methyl 1-(1H-indol-5-yl)cyclopropanecarboxylate (2.2 g, 51%). 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1 H), 7.33 (d, J=8.4 Hz, 1 H), 7.23-7.18 (m, 2 H), 6.52-6.51 (m, 1 H) 3.62 (s, 3 H), 1.65-1.62 (m, 2 H), 1.29-1.23 (m, 2 H).
Reaction SMILES: [SH:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][SH:8])=[O:4].[C:14](O)(=O)C>CCOCC.[N+](=C)=[N-]>[CH3:14][O:10][C:9](=[O:11])[C@H:6]([CH2:7][SH:8])[NH:5][C:3](=[O:4])[C:2]([SH:1])([CH3:13])[CH3:12]
Reactant: CC(C)(S)C(=O)N[C@@H](CS)C(=O)O
Reactant: CC(=O)O
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)[C@H](CS)NC(=O)C(C)(C)S
Yield: 94 %

Procedure:
To a solution of N-(2-mercapto-2-methylpropionyl)-L-cysteine (1.0 g) in ether(3 ml), diazomethane dissolved in ether(12 ml) was added dropwise under ice-cooling. After the addition, acetic acid was added to the reaction mixture. The reaction mixture was washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 1.0 g(94%) of the titled compound.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].O.[OH-].[Li+]>CO.O>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][NH:24][C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=2[O:22][CH3:23])[C:15]([NH:14][C:5]2([C:3]([OH:4])=[O:2])[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13]2)=[O:33])=[CH:27][CH:28]=1
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(NCc3ccc(F)cc3)c2)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1NCc1ccc(F)cc1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
The compound of step 1 (30 mg, 0.053 mmol) was dissolved in methanol (3 ml) and water (1 ml). Lithium hydroxide hydrate (3.8 mg, 0.09 mmol) was added, and the mixture was stirred at room temperature until LC/MS analysis showed complete conversion. The mixture was filtered, the filtrate subjected to preparative RP HPLC (water/ACN gradient), and the fractions containing the title compound freeze-dried to give 19 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]=[C:21]1[O:25][C:23](=[O:24])[CH2:22]1.O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:23]([O:17][CH2:16][C:15]([CH3:19])([CH3:18])[CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]1)(=[O:24])[CH2:22][C:21]([CH3:20])=[O:25]
Reactant: CC(C)(CO)CN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C=C1CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)CC(=O)OCC(C)(C)CN1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
3.7 g of 3-[4-(tert-butyloxycarbonyl)-1-piperazinyl]-2,2-dimethylpropanol and 30 mg of 4-dimethylaminopyridine were dissolved in 10 ml of methylene chloride, and diketene was added while cooling the solution with ice. After stirring the solution for 30 minutes under cooling with ice, water was added and the solution was extracted with methylene chloride. The resulting extract was concentrated under reduced pressure to give 4.7 g of an oily product (yield: 97%). The IR and NMR data of the compound thus obtained are as follows: ##STR59##
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.C(OC)(OC)OC.[CH2:18]([O:20][C:21](=[O:27])[CH:22]=[C:23]1[CH2:26][CH2:25][CH2:24]1)C>CO.S(=O)(=O)(O)O>[OH:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([S:1][C:23]2([CH2:22][C:21]([O:20][CH3:18])=[O:27])[CH2:26][CH2:25][CH2:24]2)=[CH:3][C:4]=1[CH3:10]
Reactant: Cc1cc(S)cc(C)c1O
Reactant: CCOC(=O)C=C1CCC1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: COC(OC)OC
Product: COC(=O)CC1(Sc2cc(C)c(O)c(C)c2)CCC1
Yield: 68.2 %

Procedure:
To a solution of 4-mercapto-2,6-dimethylphenol (2.5 g) in anhydrous methanol (40 mL) containing trimethyl orthoformate (3 mL), was added cyclobutylidene-acetic acid ethyl ester (7.6 g) and then 5 drops of concentrated sulfuric acid. The solution was deoxygenated by bubbling with nitrogen, and was allowed to reflux for 4 days. The mixture was concentrated, washed with saturated NaHCO3 and extracted with ethyl acetate. After concentrated in vacuo, the residue was purified by flash chromatography eluted with 10-20% ethyl acetate in hexane to give 3.1 g of methyl {1-[(4-hydroxy-3,5-dimethylphenyl)thio]cyclobutyl}acetate as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[C:10]([CH3:14])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16])[CH3:2].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:10]([CH3:14])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)CNc1cc(F)c(C)cc1[N+](=O)[O-]
Solvent: c1ccncc1
Product: CCOC(=O)CNc1cc(-n2ccnc2)c(C)cc1[N+](=O)[O-]
Yield: 39.6 %

Procedure:
By using 1.00 g of N-(5-fluoro-4-methyl-2-nitrophenyl)glycine ethyl ester, 266 mg of imidazole and 10 ml of pyridine, 470 mg (39%) of N-[5-(1H-imidazol-1-yl)-4-methyl-2-nitrophenyl]glycine ethyl ester was obtained.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH:15]1([CH2:21][C:22](Cl)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[C:1]([C:5]1[C:6]([NH:14][C:22](=[O:23])[CH2:21][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Reactant: O=C(Cl)CC1CCCCC1
Product: CC(C)(C)c1c(NC(=O)CC2CCCCC2)nn2cccnc12

Procedure:
The product from Example 105B and 2-cyclohexylacetyl chloride were processed using the method analogous to that described in Example 105C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92-1.03 (m, 2H), 1.11-1.29 (m, 3H), 1.44 (s, 9H), 1.59-1.81 (m, 6H), 2.18 (d, J=6.1 Hz, 2H), 6.99 (dd, J=7.1, 4.1 Hz, 1H), 8.47 (dd, J=4.1, 1.7 Hz, 1H), 8.92 (dd, J=7.1, 1.7 Hz, 1H), 9.64 (s, 1H); MS (DCI) m/z 315 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:21][CH2:22][C:23]([O:25]C)=[O:24])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+:28]>CO.O1CCCC1>[Na+:28].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:21][CH2:22][C:23]([O-:25])=[O:24])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: COC(=O)CNc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C([O-])CNc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
Into a solution of 0.46 g of methyl N-[2-(4-chlorophenyl)sulfonylaminoindan-5-yl]glycinate dissolved in 20 ml of a mixture of methanol-tetrahydrofuran (1:1) is added 1.22 ml of an aqueous 1 N sodium hydroxide solution, and the mixture is stirred at room temperature overnight, and further at 60° C. for 3 hours. After the reaction, the solvent is evaporated, and the residue is recrystallized from an isopropyl alcohol-water mixture to give 0.37 g of N-[2-(4-chlorophenyl)sulfonylaminoindan-5-yl]glycine sodium salt as colorless crystals.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[CH:13]1([C:16](=O)[CH2:17][C:18]([O:20]C)=[O:19])[CH2:15][CH2:14]1>>[CH:13]1([C:16]2[O:1][N:2]=[C:3]([CH:4]3[CH2:11][CH2:10][CH2:9][CH2:8][C:5]43[CH2:7][CH2:6]4)[C:17]=2[C:18]([OH:20])=[O:19])[CH2:15][CH2:14]1
Reactant: COC(=O)CC(=O)C1CC1
Reactant: ON=C(Cl)C1CCCCC12CC2
Product: O=C(O)c1c(C2CCCCC23CC3)noc1C1CC1

Procedure:
5-Cyclopropyl-3-(spiro[2.5]octan-4-yl)isoxazole-4-carboxylic acid (I-11K) was prepared from N-hydroxyspiro[2.5]octane-4-carbimidoyl chloride and methyl 3-cyclopropyl-3-oxopropanoate following the same protocol as described for I-6E. MS m/z 262.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:28])([CH2:25][CH2:26][SH:27])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].[Cl:29][CH2:30][CH2:31]Cl.[OH-].[Na+]>O>[C:2]([CH2:25][CH2:26][S:27][CH2:31][CH2:30][Cl:29])([C:3]([C:4]([C:5]([C:6]([C:7]([C:8]([C:9]([F:12])([F:11])[F:10])([F:14])[F:13])([F:16])[F:15])([F:17])[F:18])([F:20])[F:19])([F:21])[F:22])([F:23])[F:24])([F:28])[F:1]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCS
Reactant: ClCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCSCCCl
Reaction time: 5 h

Procedure:
2-(Perfluorooctyl)ethanethiol (RF =C8F17, 4.80 g, 10.0 mmle) and 1,2-dichloroethane (29.67 g, 300 mmole) and 10 ml of water was stirred by magnet bar under nitrogen at ambient temperature, while sodium hydroxide (0.67 g, 16.7 mmole) in 20 ml of water was added dropwise during a half hour. An exotherm carried the temperature from 24.0° to 25.2°. A thick, white slurry was formed. After 5 hours of stirring at 23.5°, the white slurry had not separated into two liquid layers as in the procedures used above. Stirring was continued for 29 hours and a sample removed for analysis. After 39 hours the thick white paste was made acidic by the addition of 5.0 ml of 6N hydrochloric acid, and the white solid collected on a Buchner funnel, and washed with water. When dry the solid weighed 3.45 g, mp (sinter 82°) 83°-88°, 70% of theory for C8F17CH2CH2SCH2CH2SCH2CH2C8F17. A 1.00-g sample was recrystallized from hot chloroform, that was first filtered while hot, from insoluble salt; 0.54 g, mp (sinter 90°) 92°-94°. The filtrate deposited 0.26 g of less pure solid. The original filtrate containing water and 1,2-dichloroethane (above) was separated into layers, and the organic layer evapd off to give white solid, mp 30°-33°, 1.18 g, 21.7% of theory for C8F17CH2CH2SCH2CH2Cl.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:12])[CH2:9][CH2:10][CH3:11])[CH:5]=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:33]([CH3:34])=[C:32]([C:35](Cl)=[O:36])[CH:31]=[N:30]2)=[CH:25][CH:24]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:12][C:35]([C:32]2[CH:31]=[N:30][N:29]([C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=3)[C:33]=2[CH3:34])=[O:36])[CH2:9][CH2:10][CH3:11])[CH:5]=[N:6][CH:7]=1
Reactant: CCCC(N)c1cncc(Br)c1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(NC(=O)c1cnn(-c2ccc(Cl)cc2)c1C)c1cncc(Br)c1
Reaction time: 15 h
Yield: 75.4 %

Procedure:
A solution of 1-(5-bromo-pyridin-3-yl)-butylamine (470 mg, 2.0 mmol), diisopropylethylamine (0.82 mL, 4.7 mmol) and DMAP (19 mg, 0.16 mmol) in CH2Cl2 (20 mL) is treated with 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carbonyl chloride (400 mg, 1.6 mmol) and stirred for 15 hours. The reaction mixture is then diluted with CH2Cl2 (50 mL), washed with saturated aqueous ammonium chloride (2×50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material is purified by flash chromatography on silica gel (eluted with 20 to 50% EtOAc/hexanes) to provide 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid [1-(5-bromo-pyridin-3-yl)-butyl]amide as a colorless foam-solid (540 mg, 78%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:18]([CH3:22])[C:19](=O)[CH3:20]>CO>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[O:15][C:18]([CH3:22])=[C:19]([CH3:20])[N:16]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)C(C)Cl
Solvent: CO
Product: Cc1nc(C2CCN(Cc3ccccc3)CC2)oc1C

Procedure:
7 g 1-benzyl-piperidine-4-carboxylic acid amide and 13 mL 3-chlorobutan-2-on were stirred 6 h at 180° C. under microwave conditions. The mixture was diluted in methanol and n-methylpyridinone and purified by HPLC to give 1.48 g of the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][CH2:26][C:25]=2[CH:32]=1>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]3[CH2:30][CH2:29][C:28](=[O:31])[NH:27][CH2:26][C:25]=3[CH:32]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CNC(=O)CC2
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CNC(=O)CC3)ncc1Cl

Procedure:
Following a procedure analogous to Example 1742a, 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methylbenzamide and 8-amino-1,2,4,5-tetrahydro-benzo[c]azepin-3-one were converted to give 2-[5-chloro-2-(3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide: 1H NMR (300 MHz, CDCl3) δ 8.54 (d, 1H), 8.03 (s, 1H), 7.6 (m, 2H), 7.4 (m, 2H), 7.08 (m, 3H), 7.26 (m, 1H), 7.1 (t, 1H), 7.05 (d, 1H). 4.25 (s, 2H), 3.05 (t, 2H), 2.95 (d, 3H), 2.86 (t, 2H); MS (m/e): 437.3 (M+1).
Reaction SMILES: [CH2:1]([C:3]([OH:18])([CH2:6][CH2:7]/[CH:8]=[C:9](\[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)/[CH3:10])[CH2:4][CH3:5])[CH3:2].Br[CH2:20][C:21]1[CH:22]=[C:23]([C:31](OC)=[O:32])[C:24](=[CH:29][CH:30]=1)[C:25](OC)=[O:26]>>[OH:32][CH2:31][C:23]1[CH:22]=[C:21]([CH:30]=[CH:29][C:24]=1[CH2:25][OH:26])[CH2:20][O:17][C:13]1[CH:12]=[C:11](/[C:9](/[CH3:10])=[CH:8]\[CH2:7][CH2:6][C:3]([CH2:4][CH3:5])([OH:18])[CH2:1][CH3:2])[CH:16]=[CH:15][CH:14]=1
Reactant: CCC(O)(CC)CC/C=C(/C)c1cccc(O)c1
Reactant: COC(=O)c1ccc(CBr)cc1C(=O)OC
Product: CCC(O)(CC)CC/C=C(/C)c1cccc(OCc2ccc(CO)c(CO)c2)c1
Yield: 0.1 %

Procedure:
In a manner similar to Example 64(d), by reacting 234 mg (0.95 mmol) of (Z)-3-ethyl-7-(3-hydroxyphenyl)oct-6-en-3-ol with 356 mg (1.24 mmol) of dimethyl 4-bromomethylphthalate, .398 mg (92%) of expected product are obtained in the form of an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH2:9][CH2:10][CH:11]([OH:23])[CH2:12][N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1>CC(O)C>[Cl:8][C:4]1[N:3]=[C:2]([NH:9][CH2:10][CH:11]([OH:23])[CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: NCC(O)CN1CCc2ccccc2C1
Solvent: CC(C)O
Product: OC(CNc1cncc(Cl)n1)CN1CCc2ccccc2C1
Temperature: 130 °C

Procedure:
To a solution of 2,6-dichloropyrazine (150 mg, 1 mmol) in 5 mL i-PrOH was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (206 mg, 1 mmol), the solution sealed and the mixture heated at 130° C. for 2 h. After cooling, the solvent was evaporated and the residue used directly in the next step without purification. LCMS (m/z): 319 (M+1).