Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH2:1][CH:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([O:9][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10])=[O:8]
Reactant: CCCCCCCCCCCCO
Reactant: CC(C)CC(N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)C(N)CC(C)C
Yield: 102.2 %

Procedure:
To a stirred solution of DL-leucine 42 (20 g, 152 mmol) in toluene (400 mL) was added 1-dodecanol 2 (25.56 g, 137.2 mmol) in one lot, followed by pTSA (31.9 g, 167.7 mmol). After addition, the temperature of the reaction mixture was slowly raised to reflux temperature, the water was separated azeotropically, and the reaction mixture was monitored by TLC. The reaction mixture was concentrated under vacuum, the obtained residue was taken in ethyl acetate (200 mL) and washed with aqueous 5% Na2CO3 (3×50 mL) followed by brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford crude 43 (42 g, yield: 91.9%) as a liquid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][C:17]=3[O:30][CH3:31])=[C:11]([CH2:32][CH2:33][CH3:34])[N:10]3[N:35]=[CH:36][CH:37]=[C:9]23)[CH2:4][CH2:3]1.[N+](=[CH:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[N-].C(OCC)(=O)C.O>C(Cl)Cl.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]#[N:29])=[CH:18][C:17]=3[O:30][CH3:31])=[C:11]([CH2:32][CH2:33][CH3:34])[N:10]3[N:35]=[CH:36][CH:37]=[C:9]23)[CH2:6][CH2:7]1)[CH3:45]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2OC)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2OC)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ccnn12
Reaction time: 3 h

Procedure:
To a solution of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-methoxybiphenyl-2-carbonitrile (0.93 g) and rhodium acetate (dimer, 0.020 g) in methylene chloride (10 mL) was added dropwise ethyl diazoacetate (0.86 mL), and the mixture was stirred for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.52 g, 47%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12](O)=[O:13])=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[CH2:12][OH:13])=[CH:7][CH:8]=1
Reactant: O=C(O)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.4 %

Procedure:
Carboxylic acid 2.1 (13.3 g, 50 mmol) in anhydrous THF (100 mL) was added dropwise to LiAlH4 (2.9 g, 75 mmol) in anhydrous THF (150 mL) at 0° C. over 30 minutes. The resulting mixture was slowly warmed to room temperature and stirred for 4 hours. The reaction was slowly quenched with water (2.9 mL) at 0° C., 15% NaOH aqueous solution (2.9 mL) and another portion of water (8.7 mL). The mixture was dried over Na2SO4 and concentrated to give 2.2 as a white solid (11.9g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([NH:20][S:22]([CH3:21])(=[O:24])=[O:23])[CH:17]=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(N)c2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NS(C)(=O)=O)c2)C1
Product: Cl

Procedure:
The process is analogous to the method described in example 82, starting from the compound of example 35 and methanesulfonyl chloride.
Reaction SMILES: [CH:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2].[H-].[Na+].Cl[C:12]1[N:13]=[C:14]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[C:15]2[S:20][C:19]([CH2:21][N:22]3[CH2:27][CH2:26][N:25](S(C)(=O)=O)[CH2:24][CH2:23]3)=[CH:18][C:16]=2[N:17]=1>CN(C)C=O.C(OCC)(=O)C>[CH:1]([C:4]1[N:5]([C:12]2[N:13]=[C:14]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[C:15]3[S:20][C:19]([CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:18][C:16]=3[N:17]=2)[CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC(C)c1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1nccn1-c1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To 2-isopropylimidazole (28 mg) in dry N,N-dimethylformamide (1 ml) was added sodium hydride (10 mg, 60% dispersion in mineral oil). After 30 minutes, 2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was added and the reaction mixture was heated in the microwave for 45 minutes at 120° C. The reaction mixture was diluted with ethyl acetate, washed with water, dried (MgSO4) and the solvent removed in vacuo and the residue purified using flash chromatography to yield 176. NMR (400 MHz CDCl3): 1.19 (1H, s, CH), 1.30 (6H, d (J=6.84), 2.61-2.63 (4H, m, CH2), 2.74 (3H, s, CH3), 3.23-3.25 (4H, m, CH2), 3.79-3.82 (6H, m, CH2), 3.92-3.94 (4H, m, CH2), 6.92 (1H, s, ar), 7.18 (1H, s, ar), 7.66 (1H, d (J=1.49), ar). MH+ 506.30
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]([O-])(=[O:23])[CH:21]=C.[C:25](O)(=O)C>>[C:20]([N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH3:25])(=[O:23])[CH3:21]
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Reactant: CC(=O)O
Reactant: C=CC(=O)[O-]
Product: CCCCCCCC/C=C\CCCCCCCCN(C)C(C)=O

Procedure:
When an amide of a fatty amine is desired, i.e. a compound wherein X is --CH2 --NR4R5, it is convenient to acylate and, optionally, alkylate a compound such as oleyl amine and then hydroformylate and acrylate as described above. For example, oleyl amine can be acetylated with acetic acid and methylated to form N-acetyl-N-methyl oleyl amine. This unsaturated amine can then be reacted with carbon monoxide and hydrogen to prepare N-acetyl-N-methyl-10(11)-formyl octadecanamine. This formylated amine can then be reduced to prepare N-acetyl-N-methyl-10(11)-hydroxymethyloctadecanamine which is finally reacted with an acryloyl compound to prepare N-acetyl-N-methyl-10(11)-acryloxymethyloctadecacamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([F:12])[CH:6]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([F:12])[CH:6]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCc2ccccc2)c(F)c1
Temperature: 60 °C
Yield: 86.6 %

Procedure:
To a solution of (3-fluoro-4-hydroxy-phenyl)-acetic acid methyl ester (15 g, 54.3 mmol) and benzyl bromide (9.28 g, 54.3 mmol) in DMF (50 mL), was K2CO3 (7.24 g, 54.3 mmol) added at an ambient temperature. The reaction mixture was heated to 60° C. and maintained for 2 hours. The reaction was cooled to room temperature and poured into H2O (150 mL). The organic compound was extracted with ether (150 mL) and washed with sat NaHCO3 (100 mL). The ether layer was dried over MgSO4, and concentrated under vacuum to afford the desired compound (12.9 g, 87.9%) as a white crystal. The crude compound was used for the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.41-7.49 (m, 5H), 7.15-7.23 (m, 2H), 7.02-7.04 (m, 1H), 5.19 (s, 2H), 3.65 (s, 2H), 3.63 (s, 3H). LCMS 273.4 [MH+].
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[NH:17][C:18](=[O:21])[CH2:19]Cl)[C:9]2=[O:22])[CH2:6][CH2:5][C:4](=[O:23])[NH:3]1.[N-:24]=[N+:25]=[N-:26].[Na+].[Na+].[I-]>CC(C)=O.ClCCl.O>[N:24]([CH2:19][C:18]([NH:17][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH2:16][N:8]([CH:7]1[CH2:6][CH2:5][C:4](=[O:23])[NH:3][C:2]1=[O:1])[C:9]2=[O:22])=[O:21])=[N+:25]=[N-:26]
Reactant: O=C1CCC(N2Cc3c(NC(=O)CCl)cccc3C2=O)C(=O)N1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: [N-]=[N+]=NCC(=O)Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 18 h
Yield: 92.9 %

Procedure:
To a stirred suspension of N-[2-(2,6-dioxo(3-piperidyl))-1-oxoisoindolin-4-yl]-2-chloroacetamide (4.64 g, 13.8 mmol) in acetone (60 ml) was added sodium azide (1.35 g, 20.7 mmol). The mixture was heated to reflux for 18 hours. After 18 hours, to the reaction mixture was added NaI (2.05 g, 13.8 mmol) and additional sodium azide (0.90 g, 13.8 mmol). The mixture was heated at reflux for an additional 18 hours. The solvent was evaporated in vacuo to give an off-white solid which was slurried in a mixture of dichloromethane (50 ml) and H2O (50 ml). This slurry was filtered to give 4.39 g (93%) of product: 1H NMR (DMSO-d6) δ 11.50-9.52 (bs, 2H), 7.87-7.84 (m, 1H), 7.59-7.50 (m, 2H), 5.17 (dd, J=5.0 and 13.1 Hz, 1H), 4.44 (d, J=17.6 Hz, 1H), 4.34 (d, J=17.6 Hz, 1H), 4.13 (s, 2H), 3.00-2.86 (m, 1H), 2.65-2.59 (m, 1H), 2.44-2.29 (m, 1H), 2.07-2.02 (m, 1H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[PH+](C)C.[C:12]([C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([O:27][CH3:28])=[C:21]2[C:24](=O)[CH3:25])=[CH:16][CH:15]=1)#[N:13]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:12]([C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[C:21]([C:24]([CH3:1])=[CH2:25])[C:20]([O:27][CH3:28])=[CH:19][CH:18]=2)[CH:23]=1)#[N:13]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2ccc(C#N)cc2c1C(C)=O
Agent: C[PH+](C)C
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=C(C)c1c(OC)ccc2ccc(C#N)cc12
Temperature: 100 °C
Yield: 93.7 %

Procedure:
Under nitrogen atmosphere, 0.62 g of potassium t-butoxide was suspended in 10 ml of toluene, and 2.26 g of trimethylphosphonium iodide was added to the resulting suspension at room temperature. The resulting mixture was stirred under heating at 100° C. for one hour to give a yellow suspension. Then, 0.84 g of 7'-cyano-2'-methoxy-1'-acetonaphthone was added to the yellow suspension, and the resulting mixture was further stirred at 10° C. for 30 minutes, cooled to room temperature by allowing to stand, diluted with ethyl acetate, and filtered through Celite. The filtrate was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography to give 0.78 g of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Cl.[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]1.C(N(CC)CC)C.[OH-].[Na+]>CN1CCCC1=O.O>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:14][C@H:15]3[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: O
Product: O[C@H]1CC[C@H](Nc2ccnc3cc(Cl)ccc23)CC1

Procedure:
414.2 g of 4,7-dichloroquinoline, 380 g of trans-4-amino-cyclohexanol hydrochloride and 255 9 of triethylamine were heated to reflux overnight in 1.05 l of 1-methyl-2-pyrrolidone under an argon atmosphere. After cooling the reaction mixture 3.8 l of water and 380 ml of 28% sodium hydroxide solution were added thereto while stirring and cooling. The separated reaction product was filtered off under suction, washed with water until the wash water was neutral and dried at 100° C./12 mbar. Yield 491 g (84.9%) of trans-N-(7-chloro-quinolin-4-yl)-4-aminocyclohexanol.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:37])[CH:10]([OH:36])[CH2:11][NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:29]([O:31]C(C)(C)C)=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.[Cl:45]CCl>>[ClH:45].[ClH:45].[NH2:8][C@@H:9]([CH3:37])[CH:10]([OH:36])[CH2:11][NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:29]([OH:31])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NCC(O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NCC(O)[C@H](C)N)C(=O)O
Product: Cl
Reaction time: 1 h

Procedure:
To a solution of N-[N-[(3S)-3-[[(t-butyloxy)carbonyl]amino]-2-hydroxybutyl]-L-phenylalanyl-L-leucine, t-butyl ester (faster isomer) (0.33 g, 0.64 mmol) in 3.5 ml of dichloromethane was added trifluoroacetic acid (2 ml). The resulting solution was stoppered and allowed to stand for 1 hour at room temperature, and the solvent was then evaporated. Analysis of the residue by 13C-NMR showed a considerable amount of unreacted t-butyl ester. The recovered material was treated with 10 ml of ~1.5N hydrogen chloride in acetic acid for 1.5 hours at room temperature. The solvent was evaporated (<25° C., vacuum pump) and the residue was triturated with ether yielding a white solid. Analysis by 13C-NMR again revealed t-butyl resonances, although diminished in intensity. The aforementioned hydrogen chloride/acetic acid treatment was repeated three more times, finally yielding 200 mg of the title compound as a white solid, melting point 174°-177° C. (changes form 127°-131° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([NH:16][NH2:17])=[O:15])[CH:5]=[CH:4][C:3]1=2.[C:19]([N:26]1[CH2:31][CH2:30]N(C(O)=O)[CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN1CC[O:62][CH2:61][CH2:60]1>CN(C=O)C.O>[C:22]([O:21][C:19]([N:26]1[CH2:27][CH2:28][CH:60]([C:61]([NH:17][NH:16][C:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:18])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=3[CH:7]=2)=[O:15])=[O:62])[CH2:30][CH2:31]1)=[O:20])([CH3:23])([CH3:24])[CH3:25]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)O)CC1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)NN)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NNC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.2 g (6.22 mmol) of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid hydrazide from step b were suspended in 15 ml of DMF together with 1.43 g (6.22 mmol) of 1-Boc-piperazine-4-carboxylic acid (preparation analogous to Bioorganic & Medicinal Chemistry Letters, 2001, vol. 11, #24 p. 3161-3164), 2.41 g (12.45 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 867 mg (6.22 mmol) of 1-hydroxybenzotriazole hydrate. 1.40 ml (12.45 mmol) of 4-methylmorpholine were added to the reaction mixture, which was then stirred at room temperature overnight, stirred into 350 ml of water. The resultant precipitate was filtered off with suction, dissolved in DCM, dried, stripped off to dryness and purified by means of flash chromatography on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:28]3[CH:29]=[C:30](/[CH:34]=[CH:35]/[C:36]([O:38]CCCC)=[O:37])[CH:31]=[CH:32][CH:33]=3)=[C:7]([CH2:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][C:3]=1[CH3:43].C(O)C.[OH-].[Na+].Cl>CC(C)=O>[CH3:5][C:10]([CH3:11])=[O:9].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:28]3[CH:29]=[C:30](/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37])[CH:31]=[CH:32][CH:33]=3)=[C:7]([CH2:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[C:24]([F:25])([F:27])[F:26])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][C:3]=1[CH3:43]
Reactant: CCCCOC(=O)/C=C/c1cccc(-c2c(CC(=O)Nc3ccc(F)cc3C(F)(F)F)c(=O)oc3cc(Cl)c(C)cc23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: Cc1cc2c(-c3cccc(/C=C/C(=O)O)c3)c(CC(=O)Nc3ccc(F)cc3C(F)(F)F)c(=O)oc2cc1Cl
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 168.8 %

Procedure:
A mixture of butyl(2E)-3-{3-[7-chloro-3-(2-{[4-fluoro-2-(trifluoromethyl)phenyl]amino}-2-oxoethyl)-6-methyl-2-oxo-2H-chromen-4-yl]phenyl}acrylate (3.0 g), ethanol (9 ml) and 2N NaOH (9 ml) was stirred at 50° C. for 1.5 hours. After completion of the reaction, acetone (27 ml) was added to the reaction mixture at 50° C., and 6N HCl (3.5 ml) was added dropwise thereto to adjust pH to 0.6. The mixture was stirred at 50° C. for 30 minutes and then at 25° C. for 1 hour, and crystals were collected by filtration, and washed with acetone/water (2/1, 6 ml). To a mixture of the resulting crystals (2.79 g), acetone (2 ml) and water (6 ml) was added dropwise 5% aqueous ammonia (2.1 ml) with stirring at room temperature to adjust pH to 9.2 and dissolve the mixture. Toluene (4.5 ml) was added to the resulting solution and the mixture was stirred for 5 minutes and allowed to stand for 5 minutes to separate an aqueous layer. Acetone (12 ml) and activated charcoal (0.15 g) were added to the obtained aqueous layer and the mixture was stirred at room temperature for 15 minutes. The activated charcoal was removed by filtration, and washed with acetone (6 ml). The filtrate and washings were combined and warmed to 50° C., and 6N HCl (1.25 ml) was added dropwise thereto with keeping the temperature almost the same and stirring to adjust pH to 0.5 and precipitate crystals. The mixture was stirred at 50° C. for 30 minutes and then at about 25° C. for 1 hour, and the crystals were collected by filtration and washed with acetone/water (2/1, 6 ml) to obtain the title compound (2.54 g, yield 84.8%). This product contained 0.9 mol of acetone.
Reaction SMILES: [N+:1]([C:4]1[N:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[P:17]([O:25][CH2:26][CH2:27][C:28]#[N:29])[N:18]([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20]>C1COCC1>[C:28]([CH2:27][CH2:26][O:25][P:17]([N:18]([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:20])[CH3:21])[C:7]1[NH:6][N:5]=[C:4]([N+:1]([O-:3])=[O:2])[N:8]=1)#[N:29]
Reactant: CC(C)N(C(C)C)P(Cl)OCCC#N
Reactant: O=[N+]([O-])c1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)N(C(C)C)P(OCCC#N)c1nc([N+](=O)[O-])n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a stirred solution of 3-nitro-1,2,4-triazole (9.64 g, 84.50 mmol) and triethylamine (14.0 mL, 10.26 g, 101.4 mmol) in THF (200 mL) was added dropwise chloro-2-cyanoethoxy-N,N-diisopropylaminophosphine (20.0 g, 84.50 mmol) at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was filtered to remove the resulting salt, and the solvent was removed under reduced pressure to give the crude product as a pale brown oil (24.9 g, 95%). After standing at room temperature, the oil becomes a pale yellow wax-like solid. 1H NMR (CDCl3 δ 8.39 (s, 1H), 4.09 (m, 2H), 3.51 (m, 2H), 2.81 (m, 2H), 1.19 (d, J=6.0 Hz, 6H), 1.07 (d, J=9.0 Hz, 6H). 31P NMR (CDCl3) δ 133.9.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([CH3:13])[CH:4]=1.[I:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[I:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:2][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]=[C:5]([CH3:13])[CH:4]=2)=[CH:17][CH:16]=1
Reactant: Oc1ccc(I)cc1
Reactant: Cc1cc(CCl)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(COc2ccc(I)cc2)c2ccccc2n1
Yield: 100 %

Procedure:
To a CH3CN (200 mL) solution of 4-chloromethyl-2-methylquinoline (10.22 g, 53.3 mmol) and 4-iodophenol (11.98 g, 1.02 eq) was added K2CO3. The suspension was heated to reflux for 6 h. The mixture was then filtered through Celite® while the solution was still hot. The 4-(4-iodo-phenoxymethyl)-2-methylquinoline (20 g, 100%) was obtained as fine crystals after recrystalization in CH3CN.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)([O-])=O>C(Cl)Cl.N1C=CC=CC=1>[NH2:6][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 107.4 %

Procedure:
To a solution of pyridine (50 mL) and MsCl (15.86 g, 139.13 mmol) in DCM (150 mL) was added the solution of 4-nitrobenzenamine (16.0 g, 115.94 mmol) in pyridine (100 mL) at 0° C. The mixture was stirred at room temperature for 4 h. The volatiles were removed under reduced pressure. The residue was rinsed with water (200 mL×3) and dried under reduced pressure to afford the title compound as a yellow powder (23.20 g, yield 95%).
Reaction SMILES: OS(O)(=O)=O.O[C:7]1([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH2:9][CH2:8]1.[C:17](#[N:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-:25].[Na+]>>[C:17]([NH:24][C:7]1([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH2:9][CH2:8]1)(=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [OH-]
Reactant: N#Cc1ccccc1
Reactant: CCOC(=O)CC1(O)CCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)CC1(NC(=O)c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
H2SO4 (2.20 mL, 41.3 mmol) was slowly added to a mixture of ethyl (1-hydroxycyclobutyl)acetate (6.45 g, 40.8 mmol) and benzonitrile (40 mL, 0.392 mol) at room temperature. The mixture was stirred for 1 hour at room temperature, then for an additional hour at 80° C. The mixture was cooled in an ice-water bath, and 2N NaOH solution was added until the solution reached pH=7. The mixture was extracted with ethyl acetate and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (AcOEt:Hexane=5:1) of the residue gave the title compound as a colorless solid (5.40 g, 51%). 1H-NMR (400 MHz, CDCl3) δ 1.22 (3H, t, J=7.3 Hz), 1.84-2.07 (2H, m), 2.22-2.32 (2H, m), 2.44-2.55 (2H, m), 3.05 (2H, s), 4.11 (2H, q, J=7.3 Hz), 6.73 (1H, s), 7.39-7.52 (3H, m), 7.72-7.79 (2H, m).
Reaction SMILES: P(Cl)([O:6][CH2:7][CH3:8])(OCC)=O.Cl.[CH3:11][N:12](NCC(O)=O)[CH3:13].[Cl-].[CH3:20][C@@H:21]1[CH2:26][CH2:25][C@H:24]([NH3+:27])[CH2:23][CH2:22]1>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH3:20][C@@H:21]1[CH2:26][CH2:25][C@H:24]([NH:27][C:7](=[O:6])[CH2:8][N:12]([CH3:13])[CH3:11])[CH2:23][CH2:22]1
Reactant: C[C@H]1CC[C@@H]([NH3+])CC1
Reactant: CCOP(=O)(Cl)OCC
Reactant: CN(C)NCC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)N[C@H]1CC[C@@H](C)CC1

Procedure:
Using 6.5 ml of diethyl chlorophosphate, 18 ml of triethylamine, 5.2 g of dimethylaminoglycine hydrochloride, 5 g of cis-4-methylcyclohexylammonium chloride, and 0.15 g of 4-dimethylaminopyridine, a reaction similar to that performed in Example 77 was carried out. As a result, 4.8 g of N-(cis-4-methylcyclohexyl)-2-dimethylaminoacetamide was obtained as a pale yellow oil, which had the following physiochemical properties: