Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([C:13]#[N:14])=[CH:7][CH:6]=[CH:5][C:4]1=2)=O.[N:15]1(C(OC(C)(C)C)=O)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.COC1C=C(CCN2CCNCC2)C=CC=1C#N>>[N:15]1([CH2:1][CH:3]2[CH2:12][CH2:11][CH2:10][C:9]3[C:8]([C:13]#[N:14])=[CH:7][CH:6]=[CH:5][C:4]2=3)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: N#Cc1cccc2c1CCCC2C=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: COc1cc(CCN2CCNCC2)ccc1C#N
Product: N#Cc1cccc2c1CCCC2CN1CCNCC1

Procedure:
5-(Piperazin-1-ylmethyl)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile was prepared starting from 5-formyl-5,6,7,8-tetrahydronaphthalene-1-carbonitrile and tert-butyl piperazine-1-carboxylate in two steps in an analogous fashion to that described for the synthesis of 2-methoxy-4-[2-(piperazin-1-yl)ethyl]benzonitrile above.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:13])[C@@H:6]([NH2:12])[CH2:7][CH:8]([CH3:11])[CH2:9][CH3:10])[CH3:3].C(N(CC)C(C)C)(C)C.[Cl:23][C:24]1[CH:57]=[CH:56][CH:55]=[CH:54][C:25]=1[O:26][C:27]1[CH2:31]N([C@@H](CC2CCCCC2)C(NC2C=CN(CC(O)(C)C)N=2)=O)[C:29](=[O:53])[CH:28]=1>C(#N)C>[CH2:2]([O:4][C:5](=[O:13])[C@@H:6]([N:12]1[CH2:31][C:27]([O:26][C:25]2[CH:54]=[CH:55][CH:56]=[CH:57][C:24]=2[Cl:23])=[CH:28][C:29]1=[O:53])[CH2:7][CH:8]([CH3:11])[CH2:9][CH3:10])[CH3:3]
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Reactant: CCOC(=O)[C@@H](N)CC(C)CC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)[C@H](CC(C)CC)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 51.9 %

Procedure:
A suspension of (S)-2-amino-4-methyl-hexanoic acid ethyl ester hydrochloride salt (1.05 g, 5.01 mmol) in acetonitrile (6 mL) was treated with N,N-diisopropylethylamine (1.0 mL) and stirred at 60° C. for 15 min. To this mixture was added N,N-diisopropylethylamine (1.2 mL) and a solution of (E)-4-bromo-3-(2-chloro-phenoxy)-but-2-enoic acid ethyl ester (prepared in Example 61, 1.6 g, 5.0 mmol) in acetonitrile (4 mL) via a dropping funnel and the resulting mixture refluxed for 20 h. The resulting mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue dissolved in tetrahydrofuran (8 mL). The resulting solution was transferred to an Emrys Optimizer microwave tube and microwaved at 160° C. for 4 h. The mixture was concentrated in vacuo and the residue purified by ISCO flash chromatography (RediSep silica column 80 g, 20% to 80% ethyl acetate/hexanes) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-hexanoic acid ethyl ester (950 mg, 52%).
Reaction SMILES: [CH2:1]([O:4][NH:5][C@H:6]1[C:11]([CH2:12][O:13][CH3:14])=[CH:10][CH:9]([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[NH:8][CH2:7]1)[CH:2]=[CH2:3].C(N(C(C)C)C(C)C)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.CCOC(C)=O>[CH2:1]([O:4][N:5]1[C:34](=[O:36])[N:8]2[CH2:7][CH:6]1[C:11]([CH2:12][O:13][CH3:14])=[CH:10][C@H:9]2[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])[CH:2]=[CH2:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCON[C@@H]1CNC(CO[Si](C)(C)C(C)(C)C)C=C1COC
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCON1C(=O)N2CC1C(COC)=C[C@H]2CO[Si](C)(C)C(C)(C)C
Yield: 193.8 %

Procedure:
To a stirred solution of Intermediate 121 (2.04 g, 5.96 mmol) in acetonitrile (500 mL), N-ethyl-N-isopropylpropan-2-amine (4.15 mL, 23.82 mmol) was added triphosgene (0.721 g, 2.38 mmol) as a solution in 20 mL CH3CN via syringe pump (0.1 ml/min) at 0° C. The reaction was stirred and allowed to warm from 0° C. to rt overnight. LCMS showed complete conversion to product. The solution was concentrated to give a residue, which was then taken up in 150 mL EtOAc and washed with 5% citric acid, NaHCO3, brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column (40 g, 0-60% Hex/EA) to afford the title compound (1.700 g, 77%) as an oil.
Reaction SMILES: C[O:2][C:3](=[O:46])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:18]=2)=[CH:6][C:5]=1[NH:33][C:34](=[O:45])[C:35]1[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=1.[OH-].[Na+]>C(O)C.O.O1CCCC1>[CH2:26]([N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](/[CH:16]=[N:15]/[O:14][CH2:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:46])=[O:2])=[C:5]([NH:33][C:34](=[O:45])[C:35]3[CH:36]=[CH:37][C:38]([C:41]([CH3:43])([CH3:42])[CH3:44])=[CH:39][CH:40]=3)[CH:6]=2)=[CH:18]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(OCCCO/N=C/c2cn(Cc3ccccc3)c3ccccc23)cc1NC(=O)c1ccc(C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)Nc2cc(OCCCO/N=C/c3cn(Cc4ccccc4)c4ccccc34)ccc2C(=O)O)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-[3-({[(1E)-(1-benzyl-1H-indol-3-yl)methylidene]amino}oxy)-propoxy]-2-[(4-tert-butylbenzoyl)amino]benzoic acid methyl ester (0.229 g, 0.47 mmol) in ethanol/water/tetrahydrofuran (8/3/1) was added 2.5 N NaOH (6 mL, 15 mmol) and the reaction was heated at reflux for 45 minutes until all starting material was gone. It was cooled to room temperature, concentrated to a small volume in vacuo and acidified to pH 1 with 2N HCl solution. It was extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (10/90 to 20/80) to the title compound (0.200 g, 70%) as an off-white solid. mp=180.9-182.5° C. mass spectrum (+ES, M+H) m/z 604. 1H NMR (400 MHz, DMSO-d6); δ 13.40 (bs, 1H), 12.40 (bs, 1H), 8.65 (d, 1H), 8.39 (s, 1H), 7.98 (d, 2H), 7.87 (d, 2H), 7.82 (s, 1H) 7.60 (d, 2H), 7.48 (d, 1H), 7.30 (m, 2H), 7.2-2 (m, 4H), 7.09 (m, 1H), 6.78 (dd, 1H), 5.42 (s, 2H), 4.26 (t, 2H), 4.22 (t, 2H), 2.20 (m, 2H), 1.31 (s, 9H) Elemental analysis: Calcd. for C37H37N3O5: C, 73.61; H, 6.18; N, 6.96. Found: C, 72.91; H, 6.22; N, 6.70.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]=2[CH:15]=1)[CH:2]([CH3:4])[CH3:3].[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:16][C:7]1[C:8]2[O:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=2[CH:15]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:6]=1
Reactant: CC(C)Cc1ccc2c(c1)C(C)(C)CO2
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)Cc1cc(Br)c2c(c1)C(C)(C)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
To a solution of 5-isobutyl-3,3-dimethyl-2,3-dihydro-benzofuran (1.59 g, 7.78 mmol) in dichloromethane (40 mL) was added pyridinium tribromide (2.49 g, 7.78 mmol) and the reaction mixture stirred at room temperature overnight. The solution was washed with water and brine, dried (Mg2SO4), filtered and evaporated. The residue was purified on silica gel (0% to 2% ethyl acetate in hexane) to give 1.51 g of 7-bromo-5-isobutyl-3,3-dimethyl-2,3-dihydro-benzofuran (68%). 1H NMR (300 MHz; CDCl3): δ 0.90 (d, J=6.3 Hz, 6 H), 1.33 (s, 6 H), 1.77 (m, 1 H), 2.39 (d, J=7.5 Hz, 2 H), 4.30 (s, 2 H), 6.80 (d, J=1.5 Hz, 1 H), 7.05 (d, J=1.5 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](/[CH:8]=[N:9]/[CH:10]2[CH2:14][CH2:13][N:12]([CH3:15])[C:11]2=[O:16])[CH:3]=1.[CH:17]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[CH2:18]>C1COCC1.C([O-])(=O)C.[Ag+]>[C:22]1([S:19]([CH:17]2[CH2:18][C:10]3([CH2:14][CH2:13][N:12]([CH3:15])[C:11]3=[O:16])[NH:9][CH:8]2[C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=2)(=[O:21])=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C=CS(=O)(=O)c1ccccc1
Reactant: CN1CCC(/N=C/c2cc(Br)ccn2)C1=O
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: CN1CCC2(CC(S(=O)(=O)c3ccccc3)C(c3cc(Br)ccn3)N2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-[(E)-(4-bromo-2-pyridyl)methyleneamino]-1-methyl-pyrrolidin-2-one (which may be prepared as described in Description 1) (564.3 mg, 2 mmol) and phenyl vinyl sulfone (339.8 mg, 2.02 mmol) in THF (10 mL) was treated with silver acetate (333.99 mg, 2 mmol). The mixture was stirred at room temp for 2 hours, filtered through Celite and concentrated to give the title compound (D2) as a brown gum;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[S:28](Cl)(=[O:30])=[O:29].C(N(C(C)C)CC)(C)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:28]([C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=3)(=[O:30])=[O:29])[CH2:12][CH2:13]2)=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CS(=O)(=O)c1cc(F)ccc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(F)ccc1N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 61.8 %

Procedure:
Sulfonylation of 1-(4-fluoro-2-(methylsulfonyl)phenyl)piperazine (316.6 mg, 1.23 mmol) with naphthalene-2-sulfonyl chloride (278 mg, 1.54 mmol) was carried out according to a similar procedure described for example 3A using anhydrous dichloromethane (5 mL) as solvent and diisopropylethylamine (0.256 mL, 1.47 mmol) as base. 1-[4-fluoro-2-(methylsulfonyl)phenyl]-4-(2-naphthylsulfonyl)piperazine was obtained in 61.8% yield (340 mg) as white solid.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([CH:28]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:29]2[CH2:30][CH2:31][N:32]([C:15](=[O:17])[CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)[CH2:33][CH2:34]2)=[CH:26][CH:27]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-[(4-chloro-phenyl)-phenyl-methyl]-piperazine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C29H31ClN2O5 [M+H]+: 524.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].[OH:11][C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:9]=1)[C:5]#[N:6]
Reactant: Oc1cncnc1
Reactant: N#Cc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(F)cc(Oc2cncnc2)c1
Yield: 48.5 %

Procedure:
3,5-Difluorobenzonitrile (1.0 g, 7.2 mmol, 1.0 eq), 5-hydroxypyrimidine (691 mg, 7.19 mmol, 1.00 eq), K2CO3 (1.2 g, 8.7 mmol, 1.2 eq) and DMF (17 mL) were added to a microwave vial and microwaved at 150° C. for 15 minutes. The reaction was filtered and concentrated on silica gel (5 g). The silica gel was loaded on top a fresh bed of silica gel and washed with 50% ethyl acetate/hexane. The solvents were removed in vacuo and the crude mixture was purified by flash chromatography on silica gel afforded 750 mg (48%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.75 (s, 2H), 7.71 (ddd, J=8.4, 2.2, 1.2 Hz, 1H), 7.62-7.61 (m, 1H), 7.56 (dt, J=10.0, 2.3 Hz, 1H); [M+1]+: 216.1.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8](CO)C=[C:6](Cl)[C:3]=1[CH:4]=[O:5].[O:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH3:8][CH2:9][CH2:2][CH:3]([CH3:6])[CH3:4].[C:14]([O:13][CH2:17][CH3:16])(=[O:5])[CH3:15]
Reactant: C1CCOC1
Reactant: O=Cc1c(Cl)cc(CO)cc1Cl
Product: CCCC(C)C
Product: CCOC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
21.0 mg (0.8 mmol) Phosporous tribromide was added to a stirred solution of 480 mg (2.3 mmol) A3 in 20 ml dry tetrahydrofurane, and the solution was stirred for 3 hours at room temperature. After hydrolysis (15 ml) the phases were separated and the organic layer was washed with saturated NaCl (10 ml) and dried over magnesium sulfate. 236 mg (0.9 mmol) A16 was obtained by column chromatography on SiGel (iso-hexane/ethyl acetate 9:1).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:12]=[C:13]([C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH:14]=[C:9]3[C:10]=2[N:5]([CH2:6][CH2:7][O:8]3)[C:4](=[O:25])[CH:3]=1.[H-].[Na+].S(OC)(O[CH3:32])(=O)=O.C(O)C>CN(C)C=O.O>[CH3:1][C:2]1[C:11]2[CH:12]=[C:13]([C:15]([O:24][CH3:32])([C:16]([F:17])([F:18])[F:19])[C:20]([F:23])([F:22])[F:21])[CH:14]=[C:9]3[C:10]=2[N:5]([CH2:6][CH2:7][O:8]3)[C:4](=[O:25])[CH:3]=1
Reactant: Cc1cc(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)F)cc13)OCC2
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: COC(c1cc2c3c(c1)c(C)cc(=O)n3CCO2)(C(F)(F)F)C(F)(F)F
Reaction time: 24 h

Procedure:
to a solution of 2,3-dihydro-7-methyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-5H-pyrido[1,2,3-de]-1,4-benzoxazin-5-one in dimethylformamide is added sodium hydride and dimethyl sulfate. The solution is stirred for 24 hours, treated with ethanol and added to water. The resultant recipitate is filtered, triterated with 10% sodium hydroxide solution and filtered. The residual solid is recrystallized to give 2,3-dihydro-7-methyl-9-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl) ethyl]-5H-pyrido[1,2,3-de]-1,4-benzoxazin-5-one. If desired sodium hydride may be replaced by a base such as potassium carbonate or potassium t-butoxide and dimethyl sulfate may be replaced by methyl iodide.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[C:4]([F:10])[CH:3]=1.C(O[CH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])C.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:14]([O:15][CH2:16][CH3:17])[O:18][CH2:19][CH3:20])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCOC(OCC)c1ccc(Br)cc1F

Procedure:
The title compound was prepared as described in Example 15, Step 2 using 4-bromo-2-fluorobenzaldehyde (102 g, 0.5 mol), triethylorthoformate (88.8 g, 0.6 mol), and PPTS (2.52 g, 0.05 mol) as starting materials. 1H NMR (400 MHz, CDCl3): δ 7.41 (d, 1H), 7.21 (d, 1H), 7.14 (d, 1H), 5.60 (s, 1H), 3.68 (q, 2H), 3.49 (q, 2H), 1.17 (t, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C[O-].[Na+].[C:14]([O:18]C)(=O)[CH:15]=[CH2:16].[CH3:20][C:21]1C=CC=CC=1C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:16][CH2:15][C:14](=[O:18])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: Cc1ccccc1C
Reactant: C=CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: N#CC1(c2ccc(F)cc2)CCC(=O)CC1
Reaction time: 0.08 h

Procedure:
A mixture of 221 parts of 4-fluorobenzeneacetonitrile, 700 parts of sodium methoxide solution 30% and 900 parts of dimethylbenzene is stirred for 5 minutes. Then there are added dropwise 309 parts of methyl 2-propenoate (exothermic reaction: temperature rises to 65° C.). Upon completion, stirring is continued overnight at reflux temperature. The methanol is distilled off till an internal temperature of 110° C. is reached. After cooling, 1000 parts of a hydrochloric acid solution 6 N are added dropwise and the whole is stirred and refluxed for 5 minutes. Upon cooling, the layers are separated. The organic phase is dried, filtered and evaporated. The residue is stirred and refluxed for 4 hours together with 500 parts of acetic acid, 500 parts of water and 500 parts of a hydrochloric acid solution. After cooling, the product is extracted with trichloromethane. The extract is washed successively with water, with a diluted sodium hydroxide solution and again with water till neutralization, dried, filtered and evaporated. The residue is crystallized from 2-propanol, yielding 134.5 parts of 1-(4-fluorophenyl)-4-oxocyclohexanecarbonitrile; mp. 91.8° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N+:17]([O-:19])=[O:18])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N+:17]([O-:19])=[O:18])=[C:12]([CH:16]=1)[C:13]([O:15][CH3:1])=[O:14]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 99.9 %

Procedure:
Potassium carbonate (515 gm) was added to a solution of 5-chloro-2-nitro benzoic acid (500 gm) in acetone (2750 ml) at room temperature. Dimethyl sulphate (306.5 gm) was added to the reaction mixture slowly and heated to reflux for 30 minutes. The reaction mass was filtered and then concentrated to obtain a residual mass. The residual mass was poured to the ice water and extracted with methylene chloride. The solvent was distilled off under reduced pressure to obtain a residual solid of methyl 5-chloro-2-nitrobenzoate (534 gm).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9]O)=[O:5].CS([O-])(=O)=O.[NH:24]1[CH2:29][CH2:28][C:27]2([C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][O:30]2)[CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][N:24]1[CH2:29][CH2:28][C:27]2([C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][O:30]2)[CH2:26][CH2:25]1)=[O:5]
Reactant: c1ccc2c(c1)COC21CCNCC1
Reactant: O=C(CCCCO)c1cc(C(F)(F)F)ccc1Cl
Agent: CS(=O)(=O)[O-]
Product: O=C(CCCCN1CCC2(CC1)OCc1ccccc12)c1cc(C(F)(F)F)ccc1Cl

Procedure:
4-(2-Chloro-5-trifluoromethylbenzoyl)-1-butanol, prepared as described in EXAMPLE 17, was converted to the corresponding methanesulfonate by the method described in EXAMPLE 2. Treatment with spiro[isobenzofuran-1(3H),4'-piperidine] according to the method described in EXAMPLE 2 gave 1'-[4-(2-chloro-5-trifluoromethylbenzoyl)-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine]. Conversion to the corresponding hydrazone and ring closure according to the method described in EXAMPLE 17 gave the title compound, 18, mp: 146-47° C.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:7]([C:22](OCC)=[O:23])=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2].O>C1(C)C=CC=CC=1.O1CCCC1>[OH:11][CH2:10][C:9]1[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][C:6]([CH:27]([CH3:28])[CH3:29])=[C:7]([CH2:22][OH:23])[C:8]=1[C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nc(C(C)C)c(CO)c(-c2ccc(F)cc2)c1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
22.8 ml (80 mmol) of a 3.5 molar solution of sodium bis-(2-methoxyethoxy)-dihydroaluminate in toluene are added under nitrogen to a solution of 4.6 g (11.4 mmol) of the compound from Example 3 in 100 ml of dry tetrahydrofuran at -10° C. to -5° C. The mixture is stirred overnight at room temperature and then warmed to 40° C. for 5 h. After cooling again to 0° C., 100 ml of water are cautiously added dropwise and the mixture is extracted three times using 100 ml of ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue is chromatographed on a column (100 g of silica gel 70-230 mesh, φ3.5 cm, using ethyl acetate/petroleum ether (6:4)).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:4][OH:5].[Br:10][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[C:14](Cl)=[N:15][CH:16]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH2:8]([O:7][C:3](=[O:6])[CH2:4][O:5][C:14]1[C:13]([N+:18]([O-:20])=[O:19])=[CH:12][C:11]([Br:10])=[CH:16][N:15]=1)[CH3:9]
Reactant: CCOC(=O)CO
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)COc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
Sodium hydride (55% dispersion in mineral oil, 603 mg, 13.8 mmol) was added to a solution of ethyl glycolate (1.43 g, 13.8 mmol) in 1,4-dioxane, and the reaction mixture was heated at 70° C. for 1 h, then 5-bromo-2-chloro-3-nitropyridine (Eur. Pat. Appl. EP 122109 (1984); 1.64 g, 6.91 mmol) was added, and stirring was continued at 70° C. for 1 h and at room temperature for 16 h. The reaction mixture was then neutralized with sat. aq. sodium hydrogencarbonate solution and extracted three times with dichloromethane. The organic layers were pooled, dried (Na2SO4), and evaporated. Chromatography (SiO2, hexane-ethyl acetate gradient) furnished (5-bromo-3-nitropyridin-2-yloxy)-acetic acid ethyl ester (1.03 g, 49%). Light yellow liquid, MS (ISP)=305.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)=[O:27])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(C=CCCCNC(=O)C3CCCC3)c2CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCCCCNC(=O)C3CCCC3)c2CC1

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-[5-(cyclopentanecarbonyl-amino)-pent-1-enyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as obtained in the previous step in EtOAc (20 mL) and add 10% Pd/C (Degussa type, 200 mg). Then apply a pressure of 70 psi of hydrogen while shaken vigorously. Filter the crude mixture through a short pad of Celite® and concentrate in vacuo. Purify the resulting material by preparative HPLC to obtain the desired intermediate as a clear oil (311 mg, 87% for the two previous steps). MS (ES+) m/z=485.2 (M+Na)+.