Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]1([C:8]([OH:10])=O)[CH2:6][O:5][C:4](=[O:7])[O:3]1.C(Cl)(=O)C([Cl:14])=O.CN(C=O)C>ClCCl>[CH3:1][C@@:2]1([C:8]([Cl:14])=[O:10])[CH2:6][O:5][C:4](=[O:7])[O:3]1
Reactant: C[C@@]1(C(=O)O)COC(=O)O1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@]1(C(=O)Cl)COC(=O)O1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the compound prepared in Example 184 (330 mg) in dichloromethane (11 mL) were added oxalyl chloride (290 μL) and DMF (0.1 mL) and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated in vacuum condition to give the title compound (2.0 g) having the following physical data as a coarse product. This compound was used for the next reaction without being purified.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:9])C)=[C:4]([CH3:10])[CH:3]=1.[BH4-].[Na+].Cl>C(O)C>[Br:1][C:2]1[S:6][C:5]([CH2:7][OH:9])=[C:4]([CH3:10])[CH:3]=1
Reactant: CC(=O)c1sc(Br)cc1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Br)sc1CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(5-bromo-3-methylthien-2-yl)ethanone (intermediate 82, 5.13 g) in ethanol (50 ml) was treated with sodium borohydride (0.947 g). The reaction was stirred at 0° C. for 60 minutes and warmed to room temp for 30 minutes. 2M Aqueous hydrochloric acid was added and the reaction mixture was extracted with ethyl acetate twice. The organic solutions were combined and dried with brine and over magnesium sulfate. The title compound was isolated after removal of the desiccant and evaporation of the solvent.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:3]=1.[CH:15]1([C:18](=O)[CH2:19][C:20](=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[CH:15]1([C:18]2[CH:19]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]3[C:2]([CH3:1])=[N:3][N:4]([CH:8]4[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]4)[C:5]=3[N:7]=2)[CH2:16][CH2:17]1
Reactant: Cc1cc(N)n(C2CCN(C)CC2)n1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CCN(C)CC1
Temperature: 70 °C

Procedure:
3-Methyl-1-(1-methyl-4-piperidinyl)-1H-pyrazol-5-amine (500 mg, 2.57 mmol) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (474 mg, 2.57 mmol) were suspended in Toluene (10 mL) and heated at 70° C. for 5 h. The solvent was removed in vacuo and the crude residue was purified via silica gel chromatography (eluent: gradient of 0 to 10% MeOH:DCM). The final product was collected as a solid, 0.722 g (76%). LCMS E-S (M+H)=343.1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.11 (m, 4H), 1.38 (t, J=7.07 Hz, 3H), 1.83 (d, J=6.06 Hz, 2H), 2.12-2.22 (m, 4H), 2.27 (s, 3H), 2.35 (m, J=7.83, 7.83, 5.05, 4.80 Hz, 1H), 2.54 (s, 3H), 2.94 (d, J=6.57 Hz, 2H), 4.42 (q, J=7.16 Hz, 2H), 4.57-4.73 (m, 1H), 7.46 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.I[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3Cl)c(=O)c12
Reactant: CC(C)CCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)CCn1c2c(c(=O)n1-c1ccc(F)cc1Cl)[C@@H]1CC[C@@]2(C)C1(C)C
Temperature: 80 °C
Yield: 16.9 %

Procedure:
A mixture of (4R,7S)-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 43; 150 mg, 0.47 mmol), tetrabutylammonium iodide (174 mg, 0.47 mmol) and 1-iodo-3-methylbutane (230 μL, 1.75 mmol) in dimethylformamide (3 mL) was heated at 80° C. for 4 days. The solvent was evaporated and dichloromethane (50 mL) was added. The solution was washed with water (2×20 mL), saturated aqueous sodium thiosulfate (20 mL), and brine (20 mL), dried (magnesium sulfate), filtered, concentrated, purified by chromatography, eluting with 60-80% ethyl acetate/petroleum ether, and dried under high vacuum overnight to give (4R,7S)-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1-(3-methyl-butyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (31 mg, 17%) as a tacky oil. APCI(+)-MS (M+H) 391.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:32])[C:11]1[CH:16]=[C:15]([O:17]COC)[CH:14]=[C:13]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:12]=1>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:32])[C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([O:21][C:22]2[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)[CH:12]=1
Reactant: COCOc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(O)cc(Oc2ccc(S(C)(=O)=O)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.9 %

Procedure:
After adding 60 ml of trifluoroacetic acid to a solution of 30.9 g (84.3 mmol) of the obtained 3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl ester in methylene chloride (100 ml) while cooling on ice, the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:acetic acid ethyl ester=1:1) to obtain 15.2 g of 5-hydroxy-3-(4-methanesulfonyl-phenoxy)benzoic acid methyl ester (yield: 56%) as a white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.Cl.[NH2:14][OH:15].[OH-].[Na+].Cl>CCO.O>[CH:1]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[N:14]/[OH:15])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=Cc1ccc2cnccc2c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O/N=C/c1ccc2cnccc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To a solution of isoquinoline-6-carbaldehyde (2.48 g, 15.8 mmol) (prepared as shown in Example 6) in 160 mL of 1:2 EtOH:H2O was added hydroxylamine hydrochloride (1.21 g, 17.4 mmol). The mixture was cooled to 0° C., and 50 wt % NaOH in H2O (3.2 mL, 0.2 mL per mmol of aldehyde) was added dropwise. The mixture was then stirred at 0° C. for 2 hours, at which time the pH was adjusted to about 6 with 10% aqueous HCl. The resulting biphasic mixture was then transferred to a separatory funnel and extracted five times with 150 mL of DCM. The combined organic layers were dried over MgSO4. Concentration under reduced pressure afforded (E)-isoquinoline-6-carbaldehyde oxime (2.14 g, 78.8% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 9.20 (s, 1H), 8.44 (d, J=5.9 Hz, 1H), 8.28 (s, 1H), 8.06 (s, 2H), 7.99 (s, 1H), 7.83 (s, 5.9 Hz, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:23])[O:6][C:7]2[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH3:18])[CH:12]=[C:11]([O:19][CH2:20][CH2:21][CH3:22])[C:8]=2[C:9]=1[CH3:10].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][C:4]2[C:5](=[O:23])[O:6][C:7]3[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH3:18])[CH:12]=[C:11]([O:19][CH2:20][CH2:21][CH3:22])[C:8]=3[C:9]=2[CH3:10])[CH2:34][CH2:33]1
Reactant: CCCOc1cc(OCCC)c2c(C)c(CCCl)c(=O)oc2c1
Reactant: COc1ccccc1N1CCNCC1
Product: CCCOc1cc(OCCC)c2c(C)c(CCN3CCN(c4ccccc4OC)CC3)c(=O)oc2c1
Yield: 47 %

Procedure:
Process B; starting materials: 3-(2-chloroethyl)-4-methyl-5,7-dipropoxy-2H-1-benzopyran-2-one (Example 38) and 1-(2-methoxyphenyl)piperazine; yield 47% of crude product.
Reaction SMILES: [CH3:1]C(N(C)C)=O.[NH2:7][C:8]1[C:9]([OH:27])=[C:10]([N:16]2[C:21](=[O:22])[N:20]([CH3:23])[C:19](=[S:24])[N:18]([CH3:25])[C:17]2=[O:26])[C:11]([F:15])=[CH:12][C:13]=1[Cl:14]>CO>[Cl:14][C:13]1[C:8]2[N:7]=[CH:1][O:27][C:9]=2[C:10]([N:16]2[C:21](=[O:22])[N:20]([CH3:23])[C:19](=[S:24])[N:18]([CH3:25])[C:17]2=[O:26])=[C:11]([F:15])[CH:12]=1
Reactant: CC(=O)N(C)C
Reactant: Cn1c(=S)n(C)c(=O)n(-c2c(F)cc(Cl)c(N)c2O)c1=O
Solvent: CO
Product: Cn1c(=S)n(C)c(=O)n(-c2c(F)cc(Cl)c3ncoc23)c1=O

Procedure:
5.0 g (48.1 mmol) of trimethylformamide were added dropwise to a solution of 502 mg (1.50 mmol) of 3-(3-amino-4-chloro-6-fluoro-2-hydroxyphenyl)-1,5-dimethyl-6-thioxo-[1,3,5]-triazinane-2,4-dione in 10 ml of methanol. The mixture was then heated at reflux temperature for 9 hours. The reaction mixture was subsequently concentrated under reduced pressure. The resulting crude product was purified by means of column chromatography (mobile phase: cyclohexane/ethyl acetate=20:1). Yield: 240 mg (46%); m.p.: 209-211° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].N>C(O)C.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: N#Cc1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCc1ccc(N2CCN(c3ccncc3)CC2)cc1
Yield: 71.1 %

Procedure:
A solution of 1-(4-cyanophenyl)-4-(4-pyridyl)piperazine (1.8 g) in ethanol saturated with ammonia gas (150 ml) was hydrogenated at 150 atmospheres and 100° C. (using Raney Nickel as catalyst) in a high pressure hydrogenation apparatus for 18 hours. The solution was filtered through diatomaceous earth and the filtrate evaporated to give a solid which was purified by flash chromatography on alumina (ICN Alumina N 32-63) using a mixture of 95:5 dichloromethane:methanol as eluant. The residue was recrystallised from tetrahydrofuran/isohexane to give 1-(4-aminomethylphenyl)-4-(4-pyridyl)piperazine (1.3 g) m.p.168-170° C.; microanalysis, found: C,71.5; H,7.6; N,20.5%; C16H20N4 requires: C,71.6; H,7.5; N,20.9%; NMR: 3.2-3.4(m,4H), 3.4-3.6(m,4H), 3.65(s,2H), 6.8-6.9(d,2H), 6.9-7.0(d,2H), 7.15-7.25(d,2H), 8.15-8.25(d,2H); MS: m/z 269 (MH)+.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][NH:6][CH3:7].CCN(C(C)C)C(C)C.[N:18]([C:21]([CH3:27])([CH3:26])[CH2:22][C:23](Cl)=[O:24])=[N+:19]=[N-:20].[OH-].[Na+]>ClCCCl>[N:18]([C:21]([CH3:27])([CH3:26])[CH2:22][C:23]([N:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:8])[CH3:1])[CH3:7])=[O:24])=[N+:19]=[N-:20]
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Reactant: CNCCCN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CN(C)CCCN(C)C(=O)CC(C)(C)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a stirred ice cold solution of N1,N1,N3-trimethylpropane-1,3-diamine (5.0 g, 1 equiv, 43.0 mmol) and DIEA (11.2 mL, 1.5 equiv, 64.5 mmol) in anhydrous DCE (200 mL) was added 3-azido-3-methylbutanoyl chloride (6.95 g, 43.0 mmol) in small portions. The reaction was stirred and left at 0° C. for 1 h. Aqueous NaOH (5N, 4 equiv, 34.5 mmol) was added to the reaction mixture. The solvent and DIEA was removed via rotovap to give an oily aqueous mixture. The contents of the flask was poured into a separatory funnel and extracted with DCM (2×100 mL). The organic layer was dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a crude oil (8.71 g, 84.0%). This material was used without further purification. 1H NMR (D2O, 400 MHz): δ 1.34 (t, J=7.2, 3H), 1.43 (s, 6H), 2.11-2.15 (m, 2H), 3.09 (s, 3 H), 3.35 (s, 2H), 3.41 (dt, J=7.2, 4H). LRMS (ESI+) for C11H23N5O (241.2); Found: 241 (M+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]2[O:12][C:11](=[O:13])[CH:10](O)[C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1>O>[C:1]([C:5]1[CH:6]=[C:7]([C:16]([CH3:19])([CH3:17])[CH3:18])[C:8]2[O:12][C:11](=[O:13])[CH:10]([C:26]3[CH:25]=[C:24]([CH3:27])[CH:23]=[CH:22][C:21]=3[CH3:20])[C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C)cc1
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Solvent: O
Product: Cc1ccc(C)c(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)c1
Yield: 80.1 %

Procedure:
To a solution of 262.3 g (1.00 mol) of 5,7-di-tert-butyl-3-hydroxy-3H-benzofuran-2-one (compound (201), Table 2, Example 1a) in 500 ml (4.05 mol) of p-xylene are added 40 g of Fulcat 22B and the mixture is refluxed for 15 hours on a water separator. The Fulcat 22B catalyst is then removed by filtration and excess p-xylene is removed by distillation on a vacuum rotaray evaporator. Crystallisation of the residue from 400 ml of methanol yields 280.6 g (80%) of 5,7-di-tert-butyl-3-(2,5-dimethylphenyl)-3H-benzofuran-2-one, m.p. 93-97° C. (compound (101), Table 1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][C:21]#[C:22][CH3:23])[C:18]([C:24]([O:26]CC)=[O:25])=[CH:17][N:16]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>[OH-].[K+].O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][C:21]#[C:22][CH3:23])[C:18]([C:24]([OH:26])=[O:25])=[CH:17][N:16]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC#CCn1c(C(=O)OCC)cnc1N1CCCC(NC(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC#CCn1c(C(=O)O)cnc1N1CCCC(NC(=O)OC(C)(C)C)C1

Procedure:
A solution of 4.40 g ethyl 2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-3-(but-2-ynyl)-3H-imidazole-4-carboxylate in 28 ml 4 M potassium hydroxide solution and 20 ml of tetrahydrofuran is stirred for 14 h at 100° C. Then the solution is neutralized with 2 M hydrochloric acid and extracted with dichloromethane. The combined organic extracts are dried over sodium sulphate and evaporated to dryness.
Reaction SMILES: [FH:1].C(N(C(C)C)CC)(C)C.O.[F:12][C:13]([F:23])([F:22])[CH:14]([O:19][CH2:20]Cl)[C:15]([F:18])([F:17])[F:16]>>[CH2:20]([F:1])[O:19][CH:14]([C:15]([F:18])([F:17])[F:16])[C:13]([F:23])([F:22])[F:12]
Reactant: F
Reactant: FC(F)(F)C(OCCl)C(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: FCOC(C(F)(F)F)C(F)(F)F
Temperature: 10 °C
Yield: 95 %

Procedure:
In an efficient fume hood, liquid hydrogen fluoride (85.1 g, 4.25 mol) was transferred into a 1 liter Teflon® reaction vessel chilled in a dry ice/acetone cold bath. The vessel was fitted with a dry ice condenser, thermocouple, and addition funnel and a portion of chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether (80.1 g) was added. A solution of diisopropylethylamine (249.0 g, 1.93 mol) in chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether (271.0 g) was slowly added while maintaining the internal temperature in the range of -5°to 10° C. After completing the addition, the mixture was transferred to a 2 liter glass boiling flask and the Teflon® vessel was rinsed out with a solution of diisopropylethylamine (307.0 g, 2.38 mol) in chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether (180.0 g) which was also transferred to the glass flask. An additional 850 g of chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether was added to the reaction flask to bring the total to 1381.1 g (6.38 mol). This mixture was heated at reflux for 16 hours. After cooling to ambient temperature, water (700 mL) was added to the reaction mixture and, after vigorous shaking, the resultant layers were separated. The lower organic layer was further washed with 700 mL of dilute hydrochloric acid (35 mL of 12 N HCl in 665 mL of water). The organic layer (1259.7 g) was analyzed by NMR and gas chromatography and was shown to consist of 63.6% fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether (sevoflurane) and 35.4% recovered chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether, giving a 95% yield of sevoflurane based on starting material consumed.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH2:24][CH2:25][S:26][CH2:27][CH:28]=3)[S:20][C:19]=2[CH2:29][CH3:30])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36]>>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH2:24][CH2:25][S:26][CH2:27][CH:28]=3)[S:20][C:19]=2[CH2:29][CH3:30])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:32]([CH3:31])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:14])=[CH:16][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: CCc1sc(C2=CCSCC2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Product: CCc1sc(C2=CCSCC2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 32 %

Procedure:
An operation similar to that in Example 69 (9) was performed using 4-{cyclohexyl[5-(3,6-dihydro-2H-thiopyran-4-yl)-2-ethylthiophen-3-yl]methoxy}benzoic acid (234 mg) synthesized in Example 85 (4) and ethyl 3-(methylamino)propanoate (79.8 mg) to give the title compound (89.2 mg, 33%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:23]=[C:22]([O:24][CH3:25])[C:21]([F:26])=[CH:20][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13].[CH3:27]OC(OC)N(C)C.C(OCC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2[C:11](=[CH:20][C:21]([F:26])=[C:22]([O:24][CH3:25])[N:23]=2)[C:12](=[O:13])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:27]1
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1cc(F)c(OC)nc1Nc1ccc(F)cc1F
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(OC)c(F)cc2c1=O
Yield: 63.3 %

Procedure:
In 4 ml of benzene was suspended 200 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinoyl]acetate, and 71 mg of N,N-dimethylformamide dimethylacetal was added thereto, after which the resulting mixture was subjected to reaction under reflux for 9 hours. The solvent was removed by distillation under reduced pressure, and to the residue thus obtained was added 2 ml of diethyl ether, after which the crystals thus deposited were collected by filtration to obtain 130 mg (yield 63.3%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 190°-192° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[H][H]>CO.[Pd]>[NH2:8][C:7]1[C:2]([CH3:1])=[C:3]([C:11]([F:12])([F:13])[F:14])[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1c([N+](=O)[O-])cccc1C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1c(N)cccc1C(F)(F)F
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of 2-methyl-3-nitrobenzotrifluoride (41.0 g, 0.2 m) in methanol (100 ml) was stirred under an atmosphere of dry nitrogen at room temperature and palladium on charcoal catalyst (10% w/w, 1.0 g) was added. The stirred mixture was warmed to 40°-45° and then hydrogen was passed into the solution at atmospheric pressure until the reduction, as observed by thin-layer chromatography, was complete (4-5 hours). The solution was cooled to room temperature and the catalyst removed by filtration. Distillation of the solvent at atmospheric pressure followed by steam distillation of the crude product gave 3-amino-2-methylbenzotrifluoride (32.2 g, 92% yield), as a pale-brown oil which slowly crystallized.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[N+:8]([O-])([O:10]C(=O)C)=[O:9]>C(O)(=O)C.C(OC(=O)C)(=O)C>[N+:8]([CH:2]([C:1]([OH:7])=[O:6])[C:3]([OH:5])=[O:4])([O-:10])=[O:9]
Reactant: CC(=O)O[N+](=O)[O-]
Reactant: O=C(O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)C(C(=O)O)[N+](=O)[O-]

Procedure:
Nitration of malonic acid with acetyl nitrate in acetic acid/acetic anhydride was conducted to obtain nitromalonic acid. To the nitromalonic acid is added urea to obtain a condensation reaction mixture which is refluxed to form dilituric acid in situ. Various salts are separately prepared from the dilituric acid in situ using as cation sources potassium chloride, ammonia, and guanidinium chloride. The potassium diliturate salt, ammonium diliturate, guanidinium diliturate salts are each recovered and isolated by filtration.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][NH:5]2.Cl[CH2:15][C:16]#[N:17]>O1CCCC1.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:11]([C:7]([CH2:8][CH2:9][NH:10][CH2:15][C:16]#[N:17])=[CH:6][NH:5]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc2c(CCN)c[nH]c2c1
Reactant: N#CCCl
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc2c(CCNCC#N)c[nH]c2c1
Reaction time: 15 h

Procedure:
17 g of 6-methyltryptamine were dissolved at 40° C. under inert atmosphere in 500 ml of tetrahydrofuran, and the solution was allowed to return to ambient temperature. 14.6 ml of 1,5-diaza[5,4,0]undec-5-ene were added followed by 6.2 ml of chloroacetonitrile and stirring for 15 hours. The solvent was eliminated under reduced pressure and the residue was taken up in 250 ml of methylene chloride, washed with water, dried and concentrated to dryness. The 25 g of crude product was purified by chromatography on silica (eluent: methylene chloride-ethyl acetate 3-7) to obtain 13.2 g of the expected product melting at 92° C.
Reaction SMILES: [BH4-].[Na+].[C:3]1([C@@H:9]([N:11]=[C:12]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:15]3([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH2:14][CH2:13]2)[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+]>CO>[C:3]1([C@@H:9]([NH:11][C@@H:12]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:15]3([CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:19][CH2:20]3)[CH2:14][CH2:13]2)[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@H](N=C1CCC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21)c1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](N[C@H]1CCC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21)c1ccccc1
Temperature: 0 °C

Procedure:
At −78° C., NaBH4 (760 mg, 20 mmol) was added to a solution of the imine (B1) (7.82 g, 20 mmol) in methanol (100 ml). The reaction mixture was allowed to warm to 0° C. over 2-3 hours then treated with saturated NaHCO3 (ca. 100 ml), concentrated under reduced pressure at <30° C. to remove the solvent. The residue was extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4 and concentrated to give (S)-tert-butyl 4-((S)-1-phenylethylamino)-3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate (B2) as a solid. LC-MS: m/e=421.32 (M+H). Rt=2.20 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:13](=[O:14])[CH2:12][CH2:11][N:10]([C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH2:9][CH2:8]1.[I-:27].[Na+]>>[Cl:25][C:20]1[CH:19]=[C:18](/[CH:17]=[CH:16]/[C:15]([N:10]2[CH2:11][CH2:12][C:13](=[O:14])[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][I:27])[CH2:8][CH2:9]2)=[O:26])[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCCCCl)CC1
Reactant: [I-]
Agent: [Na+]
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCCCI)CC1
Temperature: 90 °C
Reaction time: 20 h

Procedure:
In analogy to the procedure described in example 6D, 4-(5-chloro-pentyl)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one and sodium iodide were stirred at 90° C. for 20 h to give the title compound as orange oil. MS: 509.2 (MH+, 2Cl).