Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:11]([O:15]C)(=[O:14])[CH:12]=[CH2:13].[Li+].[OH-].Cl>C(O)(=O)C.CO>[N:1]1([CH2:13][CH2:12][C:11]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C=CC(=O)OC
Reactant: c1ccc2c(c1)CCCN2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)CCN1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A mixture of 1,2,3,4-tetrahydroquinoline (3.0 g, 22.5 mmol) and methyl acrylate (3.9 g, 45.0 mmol) in acetic acid (15 mL) was refluxed for 16 hours. Upon cooling, volatiles were removed in the rotary evaporator and the residue obtained was co-evaporated with methanol (3×20 mL) and then dissolved in methanol (15 mL). To this mixture an aqueous solution of LiOH (1.9 g, 45 mmol) was added and it was stirred at room temperature for 2 hours. Reaction mixture was acidified with conc. HCl to pH˜3 and extracted with ethyl acetate. The organic layer was washed twice with water and brine, dried over MgSO4 and evaporated to dryness to yield 2.91 g of Compound 7 as a dark brown viscous liquid. This product was used without any further purification. The structure of Compound 7 is given below:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>O1CCCC1.C(O)C>[N:1]1([C:2]2[N:3]=[CH:4][C:5]3[NH:6][C:7]4[C:12]([C:13]=3[CH:14]=2)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Nc1cc2c(cn1)[nH]c1ccccc12
Reactant: BrCCCCCBr
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: C1CCOC1
Solvent: CCO
Product: c1ccc2c(c1)[nH]c1cnc(N3CCCCC3)cc12
Yield: 6.6 %

Procedure:
549 mg of 3-amino-β-carboline are refluxed for 4 hours with 1.5 g of 1,5-dibromopentane and 1 g of diazabicycloundecene in 25 ml of tetrahydrofuran and 5 ml of absolute ethanol. After evaporation, the product is chromatographed on silica gel with cyclohexane/ethyl acetate=1:1 as eluant. 50 mg of 3-piperidino-β-carboline are obtained as oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]4)[N:18]=2)[CH:14]=[CH:13][S:12]3)[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-:37].[Na+]>C(O)C>[C:33]([O:32][C:30]([N:26]1[CH2:27][CH2:28][CH2:29][C@@H:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[N:15]4[C:11]([S:12][CH:13]=[CH:14]4)=[N:10][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1](=[O:37])[NH2:2])[CH:4]=3)[CH:22]=[CH:21][N:20]=2)[CH2:25]1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nccc(-c3c(-c4cccc(C#N)c4)nc4sccn34)n2)C1
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nccc(-c3c(-c4cccc(C(N)=O)c4)nc4sccn34)n2)C1
Temperature: 75 °C
Yield: 82.7 %

Procedure:
To a solution of tert-butyl (3R)-3-({4-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxylate (0.204 g, 0.407 mmol) in ethanol (5 mL) was added 25% aqueous sodium hydroxide (0.072 mL, 0.448 mmol). The mixture was heated at 75° C. for 20 hours. Solvent was removed to dryness. Residue was taken into dichloromethane (20 mL), washed with water (5 mL), dried over sodium sulfate and concentrated. Product was purified by flash chromatography on silica gel eluting with 5% methanol in dichloromethane to afford 0.175 g (83%) of the title compound as an off-white solid. M.p.=161-165° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.70 (br. s, 1H), 8.14 (s, 1H), 8.10 (d, J=5.6 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H). 7.54(t, J=7.6 Hz, 1H), 7.44 (d, J=4.4 Hz, 1H), 7.30-7.14 (bs, 2H), 7.15 (d, J=6.8 Hz, 1H), 6.33 (d, J=5.2 Hz, 1H), 3.96 (bs, 1H), 3.81-3.77 (m, 1H), 3.68 (bs, 1H), 2.94-2.90 (m, 2H), 2.00-1.97 (m, 1H), 1.80-1.77 (m, 1H), 1.59-1.53 (m, 1H), 1.46-1.40 (m, 1H), 1.34 (s, 9H); LCMS: 520 [M+H].
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][C:9]12[CH2:20][CH2:19][CH2:18][C:16]3[C:17]1=[C:12]([CH:13]=[CH:14][CH:15]=3)[NH:11][C:10]2=[O:21])=[O:5])C.[OH-].[Na+]>C(COC)OC>[C:4]([CH2:6][CH2:7][CH2:8][C:9]12[CH2:20][CH2:19][CH2:18][C:16]3[C:17]1=[C:12]([CH:13]=[CH:14][CH:15]=3)[NH:11][C:10]2=[O:21])([OH:5])=[O:3]
Reactant: CCOC(=O)CCCC12CCCc3cccc(c31)NC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: O=C(O)CCCC12CCCc3cccc(c31)NC2=O
Yield: 97 %

Procedure:
(RS)-2a-(3-ethoxycarbonylpropyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (6.20 g, 21.6 mmol) was dissolved in dimethoxyethane (70 ml). Then, 1N sodium hydroxide solution (22 ml, 22 mmol) was added thereto to effect a reaction at 25° C. for 18 hours. Successively the resulting solution was concentrated and aqueous hydrochloric acid was added to the residue obtained to effect crystallization, followed by filtration. Thus, the crystal was obtained in an amount of 5.45 g (yield 97%). MW 259.30 (C15H17NO3); mass spectrum EIMS m/z 259(M)+
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([O:12][CH2:13][CH2:14][CH3:15])[CH:3]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[C:4]([O:12][CH2:13][CH2:14][CH3:15])[CH:3]=1
Reactant: CCCOc1cc(I)ccc1C(=O)OC
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CCCOc1cc(I)ccc1CO

Procedure:
The procedure is the same as that described above, using 14 g of methyl 4-iodo-2-propoxybenzoate, 450 ml of toluene and 87.5 ml of DiBAlH. The product is purified by chromatography on a silica column, eluted with a heptane/ethyl acetate 9:1 mixture. After evaporation of the solvents, 11.3 g (88%) of the expected compound are recovered in the form of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7](O)=[O:8])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Br:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[N:47]=[C:48]([C@@H:51]3[CH2:55][C@H:54]([S:56][CH3:57])[CH2:53][NH:52]3)[NH:49][CH:50]=2)=[CH:42][CH:41]=1.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:7]([N:52]1[CH2:53][C@@H:54]([S:56][CH3:57])[CH2:55][C@H:51]1[C:48]1[NH:49][CH:50]=[C:46]([C:43]2[CH:44]=[CH:45][C:40]([Br:39])=[CH:41][CH:42]=2)[N:47]=1)=[O:8])[CH:10]([CH3:12])[CH3:11]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CS[C@@H]1CN[C@H](c2nc(-c3ccc(Br)cc3)c[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](SC)C[C@H]1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of (S)-2-methoxycarbonylamino-3-methyl-butyric acid (156 mg, 0.89 mmol) and HATU (407 mg, 1.07 mmol) was stirred in DMA (3.0 mL) for 10 min, then 4-(4-bromo-phenyl)-2-((2S,4S)-4-methylsulfanyl-pyrrolidin-2-yl)-1H-imidazole di-HCl (367 mg, 0.89 mmol; Preparation 18) and N,N-diisopropylethylamine (777.3 μL, 4.46 mmol) were added. The resulting mixture was stirred at RT overnight, concentrated, and purified by silica gel chromatography (0 to 90% EtOAc/hexane). Fractions with desired product were combined and concentrated to give the title intermediate (366 mg, 82% yield). (m/z): [M+H]+ calcd for C21H27BrN4O3S 495.10; 497.10. found 495.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([CH3:13])=[CH:8][C:7]=1[Cl:14])C.[BH4-].[Li+].Cl.[OH-].[Na+]>C1COCC1>[NH2:12][C:10]1[C:9]([CH3:13])=[CH:8][C:7]([Cl:14])=[C:6]([CH2:5][CH2:4][OH:3])[CH:11]=1
Reactant: CCOC(=O)Cc1cc(N)c(C)cc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(CCO)cc1N
Temperature: 0 °C
Yield: 100.3 %

Procedure:
To a solution of (5-amino-2-chloro-4-methyl-phenyl)-acetic acid ethyl ester (0.25 g, 1.09 mmol) in THF (15 ml) was added lithium borohydride (0.059 g, 2.74 mmol) and the mixture was heated at reflux for three hours. The mixture was cooled to 0° C. and acidified to pH 1 with aqueous 2N HCl. The mixture was taken to pH7 by addition of aqueous 2N NaOH and the mixture was extracted with EtOAc. The combined extracts were washed with water and brine dried, over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the crude product by flash chromatography (hexanes:EtOAc 1:1) gave 0.203 g (99%) of 2-(5-amino-2-chloro-4-methyl-phenyl)-ethanol as a white solid.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:17])[CH:15]=[CH2:16])[C:6]([O:8][CH3:9])=[O:7])=O>C(Cl)Cl.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[CH3:17][CH:14]1[CH:15]=[CH:16][C:3]2[C:12](=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)[O:13]1
Reactant: C=CC(C)Oc1ccc(C(=O)OC)cc1C=O
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)C=CC(C)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
To a stirred solution of methyl 3-formyl-4-[(1-methylprop-2-enyl)oxy]benzoate (370 mg, 1.59 mmol) in CH2Cl2 (8 mL) at rt is added benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (56 mg, 0.068 mmol). The mixture is stirred at rt overnight. The reaction mixture is concentrated in vacuo to a dark residue. The crude product is purified by flash chromatography on SiO2. Elution with hexanes-EtOAc (95:5) gives 225 mg (69%) of methyl 2-methyl-2H-chromene-6-carboxylate as a clear oil: 1H NMR (400 MHz, CDCl3) δ 7.82, 7.68, 6.79, 6.41, 5.71, 5.11, 3.89, 1.48.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C@H:20]([C:22]([OH:24])=O)[CH3:21])=[O:18])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[Na+].[Na+]>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:22](=[O:24])[C@H:20]([CH3:21])[NH:19][C:17]3=[O:18])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[C@H](NC(=O)Nc1ccc(Oc2ccc(F)c(Cl)c2)cc1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@@H]1NC(=O)N(c2ccc(Oc3ccc(F)c(Cl)c3)cc2)C1=O
Temperature: 100 °C
Yield: 12 %

Procedure:
A mixture of N-[({4-[(3-chloro-4-fluorophenyl)oxy]phenyl}amino)carbonyl]-L-alanine (Intermediate 10, 352 mg) in 15 mL of 3N HCl was heated at 100° C. for 16 hours. Then sodium carbonate was added and the mixture was adjusted to pH=8. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine and dried with magnesium sulphate. Removal of the solvent afforded crude compound which was purified by column chromatography (MeOH/DCM=1/50) to give 40 mg of the title compound as a white solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1.OC1C=CC(O)=CC=1C(=O)C.[F:31][C:32]([F:42])([F:41])C1C=CC(C=O)=CC=1>>[OH:19][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:4]1[CH:5]=[CH:6][C:7]([C:32]([F:42])([F:41])[F:31])=[CH:2][CH:3]=1)[CH2:17][C:16]2=[O:18]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Agent: CC(=O)c1cc(O)ccc1O
Product: O=C1CC(c2ccc(C(F)(F)F)cc2)Oc2ccc(O)cc21

Procedure:
6-Hydroxy-2-(4-trifluoromethylphenyl)chroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 2.0 g of 2′,5′-dihydroxyacetophenone and 2.1 ml of 4-trifluoromethylbenzaldehyde. The product was purified by column chromatography using heptane-ethyl acetate (2:1) as an eluant. Further purification was carried out by column chromatography using toluene-ethyl acetate (4:1) as an eluant. Finally the product was crystallised from ethanol. 1H NMR (400 MHz, d6-DMSO) δ: 9.47 (s, 1H), 7.82-7.76 (m, 4H), 7.13 (d, 1H, J 3.0 Hz), 7.06 (dd, 1H, J 8.8, 3.0 Hz), 6.99 (d, 1H, J 8.8 Hz), 5.70 (dd, 1H, J 12.9, 2.9 Hz), 3.16 (dd, 1H, J −16.9, 12.9 Hz), 2.86 (dd, 1H, J −16.9, 2.9 Hz).
Reaction SMILES: O.[C:2]1([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[H][H]>[Pd].O1CCCC1.C(O)C>[C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCCC(=O)c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: c1ccc(CCCCCCc2ccccc2)cc1
Yield: 94.5 %

Procedure:
In a 2-liter three-necked flask equipped with a stirring device and a nitrogen substituting device, 5 g of a Pd-C catalyst (a 5% product, containing 55.9% of water) and a solution of 100.9 g of 1,6-diphenylhexane-1,6-dione in 400 milliliters of tetrahydrofuran and 400 milliliters of denatured ethanol as well as 5 milliliters of 6N-hydrochloric acid were introduced, stirred at a normal pressure and contacted with hydrogen gas. After absorption of hydrogen was stopped, the catalyst was filtered off and the solution was concentrated. The concentrate was dissolved in ethyl acetate, washed with a dilute aqueous solution of sodium hydrogencarbonate and water, and thereafter dried with anhydrous sodium sulfate. After removing off the solvent by a rotary evaporator, a distillation under a decreased pressure was carried out, to obtain 85.3 g of 1,6-diphenylhexane as colorless liquid.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[C:13]1([CH2:19][O:20][C:21]([C:23]2([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.[C:40]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:45]=[CH:44][C:43]([C:46](O)=[O:47])=[CH:42][CH:41]=1>C(Cl)Cl>[C:13]1([CH2:19][O:20][C:21]([C:23]2([NH:29][C:46]([C:43]3[CH:44]=[CH:45][C:40]([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)=[CH:41][CH:42]=3)=[O:47])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:22])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
2.11 g (11 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 2.33 g (10 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester, 1.68 g (11 mmol) of 1-hydroxybenzotriazole and 3.23 g (10 mmol) of 4-biphenylcarboxylic acid in 120 ml of methylene chloride under ice-cooling. After the mixture was stirred at room temperature overnight, the reaction solution was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography to obtain 3.51 g (85%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[Cl:22][C:23]1[CH:29]=[C:28]([P:30]([CH3:33])([CH3:32])=[O:31])[CH:27]=[CH:26][C:24]=1[NH2:25].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:25][C:24]2[CH:26]=[CH:27][C:28]([P:30]([CH3:32])([CH3:33])=[O:31])=[CH:29][C:23]=2[Cl:22])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: CP(C)(=O)c1ccc(N)c(Cl)c1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2ccc(P(C)(C)=O)cc2Cl)nnc1Cl
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 2-Chloro-4-(dimethylphosphoryl)aniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:12]=[CH:11][N:10]([CH3:13])[C:5]2=[C:6]([O:8][CH3:9])[N:7]=1.[I:14]N1C(=O)CCC1=O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([I:14])=[CH:11][N:10]([CH3:13])[C:5]2=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1nc(Br)cc2ccn(C)c12
Solvent: CN(C)C=O
Product: COc1nc(Br)cc2c(I)cn(C)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
The product from Example 91B (0.82 g, 3.40 mmol) and N-iodosuccinimide (0.918 g, 4.08 mmol) were combined in dimethylformamide (17.01 mL), stirred for two hours at ambient temperature, and quenched with 100 mL of 10% aqueous sodium thiosulfate. The mixture was stirred for 15 minutes and the resulting solid was collected by filtration, washed repeatedly with water and dried to constant mass to afford the title compound (1.17 g, 94%).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:39][CH3:40])=[C:7]([CH:28]=[C:29]([N:31]2[CH:36]=[CH:35][C:34](=[O:37])[NH:33][C:32]2=[O:38])[CH:30]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=1[CH2:21][NH:22]CCC(C)C)([CH3:4])([CH3:3])[CH3:2].[C:41](=O)(O)[O-:42].[Na+].Cl>CCO>[C:1]([C:5]1[C:6]([O:39][CH3:40])=[C:7]([CH:28]=[C:29]([N:31]2[CH:36]=[CH:35][C:34](=[O:37])[NH:33][C:32]2=[O:38])[CH:30]=1)[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])=[CH:12][C:11]=1/[CH:21]=[N:22]/[O:42][CH3:41])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C([O-])O
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2CNCCC(C)C)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CO/N=C/c1cc(NS(C)(=O)=O)ccc1C=Cc1cc(-n2ccc(=O)[nH]c2=O)cc(C(C)(C)C)c1OC
Temperature: 70 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution of the product from Example 30, Part A (35 mg, 0.070 mmol) in EtOH (2 ml) was added O-methoxylamine hydrochloride (29 mg, 0.35 mmol) and sodium bicarbonate (30 mg, 0.35 mmol). The resulting mixture was stirred at 70° C. for 2 h. To the mixture was added 1 N aq. HCl (1 ml) to give a colorless precipitate that was filtered and dried to give the title compound as a colorless solid (24 mg, 64%). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.43 (d, J=2.21 Hz, 1 H) 9.94 (s, 1 H) 8.74 (s, 1 H) 7.79-7.85 (m, 2 H) 7.76 (d, J=7.72 Hz, 1 H) 7.57-7.65 (m, 2 H) 7.32 (dd, J=8.64, 2.39 Hz, 1 H) 7.23 (d, J=2.57 Hz, 1 H) 7.18 (d, J=116.18 Hz, 1 H) 5.66 (dd, J=7.72, 2.21 Hz, 1 H) 3.93 (s, 3 H) 3.79 (s, 3 H) 3.03 (s, 3 H) 1.38 (s, 9 H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:12]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCBr
Reactant: O=C1CCCCCN1
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCN1CCCCCC1=O
Yield: 89.7 %

Procedure:
Following example 10, 10.2 g of 50% sodium hydride-mineral oil dispersion (5.1 g of NaH, 0.2125 M), 20 g (0.177 M) of azacycloheptan-2-one and 35.8 g (0.2 M) of 1-bromoheptane on 18 hr. reflux gave 33.5 g (90%) of colorless product; b.p. 155°-158°/0.5 mm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]2[CH2:18][CH2:17][CH2:16]/[C:15](=[CH:19]\[C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]4)=[C:22]([O:32][CH3:33])[CH:21]=3)/[C:14]2=[O:34])[C@H:10]([OH:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(O)(=O)C.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([N:13]2[CH2:18][CH2:17][CH2:16]/[C:15](=[CH:19]\[C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]4)=[C:22]([O:32][CH3:33])[CH:21]=3)/[C:14]2=[O:34])[C@H:10]([OH:35])[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1cc(/C=C2\CCCN([C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]3O)C2=O)ccc1-n1cnc(C)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(/C=C2\CCCN([C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3O)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.3 %

Procedure:
To a THF (5 mL) solution of (E)-trans-3-hydroxy-4-(3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-2-oxopiperidin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (30 mg) obtained in Example 554, diisopropylazodicarboxylate (0.024 mL), triphenylphosphine (33 mg) and acetic acid (0.007 mL) were added, and the reaction solution was agitated at room temperature for 3 hours. Ethyl acetate and a saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 10 mg of the title compound was obtained by purifying the residue by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: ethyl acetate). The physical properties of the compound are as follows.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:18]=2[F:25])[CH2:8][CH2:7]1)[CH3:2].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)=[NH:24])=[CH:19][C:18]=2[F:25])[CH2:10][CH2:11]1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C#N)cc2F)CC1
Product: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C(=N)N3CCN(C)CC3)cc2F)CC1
Yield: 28 %

Procedure:
The same procedure as in Example 45 was performed with ethyl-N-(N-(4-cyano-2-fluorobenzoyl)-βethyl-α,α-dimethyl-β-alanyl)-4-piperidineacetate (1.48 g, 3.3 mmol) by using 1-methylpiperazine (3.7 ml) as an amine to yield the titled compound (514 mg, 28%).
Reaction SMILES: [K].[Cl:2][C:3]1[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH3:13][OH:14]>>[Cl:2][C:3]1[N:11]=[C:10]([O:14][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: [K]
Product: COc1ccc(C(=O)O)c(Cl)n1
Yield: 52 %

Procedure:
Potassium botoxide (483 mg, 4.31 mmol) and MeOH (8 mL) were added to 2,6-dichloro-nicotinic acid (207 mg, 1.07 mmol), and the mixture was stirred using microwave at 60° C. for 1 hour. After the termination of the reaction, the reactant was filtered, and 1N HCl was added thereto at 0° C. to adjust the pH to 3. The solid was dried by N2 gas to obtain the title compound (106 mg, 52%).