Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[N:12]([C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=3)[N:13]=[C:14]([CH2:23][OH:24])[C:15]=2[CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[CH:7]=[CH:8][CH:9]=1.Br.Br[CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[N:12]([C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=3)[N:13]=[C:14]([CH2:23][O:24][CH2:32][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[C:15]=2[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCc1c(CO)nn2c(CC)ccc2c1-c1cccc(Cl)c1
Reactant: BrCc1ccncc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc2c(-c3cccc(Cl)c3)c(CCC(=O)O)c(COCc3ccncc3)nn12
Reaction time: 1 h
Yield: 10.3 %

Procedure:
To a solution of sodium hydride (93.1 mg) in DMF (4 mL) was added ethyl 3-[4-(3-chlorophenyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate (150 mg) under ice water cooling and the mixture was stirred at this temperature for 1 hour. To this was added 4-(bromomethyl)pyridine hydrobromide (196 mg) and the mixture was stirred for 1 hour at ambient temperature. The reaction was quenched by adding water. The mixture was extracted with CHCl3. The organic layer was washed with water and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of CHCl3-MeOH=30-1 to give 3-{4-(3-chlorophenyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid (18 mg) as a yellow solid.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:20]([CH3:21])[C:19](=[O:22])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:23][CH3:24])[CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)(=O)C>N>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:20]([CH3:21])[C:19](=[O:22])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:23][CH3:24])[CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc2nc(-c3ccc(OC(C)=O)cc3)n(C)c(=O)c2c1
Agent: N
Product: COc1ccc2nc(-c3ccc(O)cc3)n(C)c(=O)c2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
80.3 gm (0.247 mol) of 2-(4-acetoxy-phenyl)-3-methyl-6-methoxy-3,4-dihydro-quinazolin-4-one were suspended in 800 ml of concentrated aqueous ammonia, and the suspension was heated for 1.5 hours on a steam bath, whereby at first a clear solution was obtained, and after about 60 minutes the formation of a white precipitate began. After cooling to 0° C., the product was suction-filtered off, washed with water and dried at 80° C. in a circulating air drier.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([NH2:9])[N:6]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>C(Cl)Cl>[CH:1]([C:4]1[CH:8]=[C:7]([NH:9][C:23](=[O:24])[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:6]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(N)n(-c2cccnc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cccnc2)n1
Yield: 75.6 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-isopropyl-1-(pyridin-3-yl)-1H-pyrazol-5-amine (179 mg, 0.89 mmol) and potassium carbonate (159 mg, 1.2 mmol) in anhydrous DCM (3 ml) was added dropwise phenyl chloroformate (0.33 ml, 2.6 mmol) as a solution in DCM (0.2 ml). The crude was purified by silica gel chromatography (DCM/MeOH 0-10%) to afford phenyl 3-isopropyl-1-(pyridin-3-yl)-1H-pyrazol-5-ylcarbamate (217 mg, 76%). 1H NMR (300 MHz, CDCl3) δ 1.29 (s, 6H), 2.99 (m, 1H), 6.39 (s, 1H), 6.67 (s, 1H), 7.08-7.32 (m, 6H), 7.99 (d, J=7 Hz, 1H), 8.34 (s, 1H), 8.45 (d, J=7 Hz, 1H); LC-MS (ESI) m/z 323 (M+H)+.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:19][CH:20]([O:23][CH3:24])[O:21][CH3:22]>CN(C=O)C.CCOC(C)=O>[CH3:22][O:21][CH:20]([O:23][CH3:24])[CH2:19][O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(CBr)OC
Reactant: OC1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(COC1CCCCC1)OC
Yield: 30.6 %

Procedure:
Dissolve cyclohexanol (2.00 mL, 19.1 mmol) in DMF (9.6 mL), then add NaHMDS (1 M solution in THF, 21.0 mL, 21.0 mmol), and stir the solution at room temperature for 5 min. Add 2-bromo-1,1-dimethoxyethane (2.26 mL, 19.1 mmol), then stir the mixture at room temperature under a nitrogen atmosphere for three days. Dilute the mixture with EtOAc (250 mL) and wash with saturated aqueous NaCl (2×250 mL). Dry the organic phase over MgSO4, filter, and concentrate the filtrate under reduced pressure. Subject the resulting crude material to silica gel chromatography eluting with a gradient of 0% to 10% EtOAc/hexanes. Concentrate the fractions containing the desired product under reduced pressure to furnish the title compound as a pale yellow oil (1.10 g, 31% yield). 1H NMR (400 MHz, CDCl3): δ 4.47 (t, J=5.3 Hz, 1H), 3.49 (d, J=5.3 Hz, 2H), 3.39 (s, 6H), 3.25 (tt, J=9.2, 3.7 Hz, 1H), 1.94-1.87 (m, 2H), 1.76-1.69 (m, 2H), 1.55-1.49 (m, 1H), 1.34-1.17 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[NH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:27]1(I)[CH2:31][CH2:30][CH2:29][CH2:28]1>O>[CH:27]1([N:7]2[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:15])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COC(=O)c1c[nH]c(=O)c2ccccc12
Reactant: IC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(C2CCCC2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.3 %

Procedure:
To a solution of methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylate (780 mg, 3.8 mmol, Bionet), potassium carbonate (650 mg, 4.7 mmol, Aldrich), and 6 mL of DMF was added cyclopentyl iodide (0.52 mL, 4.5 mmol, Aldrich). The solution was stirred at RT for 4 h, then diluted with 50 mL of water. The solids were filtered and washed with CH2Cl2 and EtOAc. The filtrate was concentrated in vacuo and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with 0% to 15% EtOAc:hexane to give 240 mg (23%) of methyl 2-cyclopentyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylate as an off-white solid. MS m/z: 272.3 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])=[CH:2]1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: CCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCOC(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of indole-3-carboxylic acid, 1-bromononane and potassium carbonate in N,N-dimethylformamide was stirred at room temperature for 15 hours. After insoluble materials were filtered off, the filtrate was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated. The solid was collected and washed with hexane to give nonyl indole-3-carboxylate.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)(O)O.[NH2:27][C:28]([NH2:30])=[NH:29]>CN1CCCC1=O.CCOCC>[N:11]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:29][C:28]([NH2:30])=[NH:27])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: N=C(N)N
Reactant: O=S(=O)(c1ccc(F)cc1)N1CCOCC1
Agent: O=C(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: N=C(N)Nc1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 87.5 °C
Reaction time: 24 h

Procedure:
A mixture of 4-[(4-fluorophenyl)sulfonyl]morpholine (0.25 g, 1 mmol), cesium carbonate (1.30 g, 4 mmol), and guanidine carbonate (1.08 g, 6 mmol) in 2 ml of 1-methyl-2-pyrrolidinone (NMP) is stirred at 85 to 90° C. for 24 hrs. It is then cooled to room temperature and diluted with ether. The resulting suspension is filtered, and the precipitate extracted with tetrahydrofuran (THF) to yield, after evaporation of solvent, 0.12 g of a yellow solid; mp 102-105° C.; MS (ESI) m/z 285.1 (M+H); HRMS: calcd for C11H16N4O3S, 284.0943; found (ESI_FT), 285.1011 (M+H).
Reaction SMILES: [Cl-].[CH2:2]([NH2+:9][CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:15]=[C:16]([N:21]=[C:22]=[S:23])[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([N:21]=[C:22]2[N:9]([CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:10][CH2:11][S:23]2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: ClCC[NH2+]Cc1ccccc1
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Product: Clc1ccc(N=C2SCCN2Cc2ccccc2)cc1Cl

Procedure:
2-Hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give N-benzyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-benzyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3,4-dichlorophenyl isothiocyanate to give 2-(3,4-dichlorophenylimino)-3-benzyl-1,3-thiazolidine.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:11]3[CH:12]=[CH:13][CH:14]=[C:10]3[O:9][C:8]=2CC#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([OH:22])(=[O:21])[CH3:20].S(=O)(=O)(O)O>O>[C:1]1([C:7]2[CH:15]=[C:11]3[CH:12]=[CH:13][CH:14]=[C:10]3[O:9][C:8]=2[CH2:20][C:19]([OH:22])=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1oc2cccc-2cc1-c1ccccc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1oc2cccc-2cc1-c1ccccc1

Procedure:
As an illustration of an acid hydrolysis of nitrile intermediates a mixture of 5 g. of 3-phenyl-7-benzofuranacetonitrile in 30 ml. of acetic acid, 20 ml. of water and 20 ml. of sulfuric acid is stirred and heated at reflux overnight. On cooling and diluting with water one obtains 3-phenyl-7-benzofuranacetic acid, purified by crystallization from benzenehexane.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.[CH3:8][O:9][C:10](=[O:25])[C@H:11]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH2:15].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.Cl.COC(=O)[C@H](CC1C=CC=CC=1)N>>[CH3:8][O:9][C:10](=[O:25])[C@H:11]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH:15][C:5](=[O:7])[CH2:4][CH:1]1[CH2:2][CH2:3]1
Reactant: O=C(O)CC1CC1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)CC1CC1

Procedure:
Following General Procedure U and using cyclopropylacetic acid (Lancaster) and N-(L-alaninyl)-L-phenylalanine methyl ester (prepared by coupling N-BOC-L-alanine (Bachem) with L-phenylalanine methyl ester hydrochloride (Bachem) using General Procedure U, followed by removal of the BOC-group using General Procedure Y), the title compound was prepared as a solid (mp=128-131° C.). The reaction was monitored by tlc (Rf=0.14 in 1:1 EtOAc/hexanes).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:9]([C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1)=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5]2.O.C(O)C>[Zn].C(O)(=O)C>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([C:10]2[N:9]3[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]3)=[CH:3][C:2]=2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: Cc1cc2ccccn2c1C(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc2ccccn2c1C(=O)c1ccc(N)cc1
Temperature: 80 °C
Yield: 81.4 %

Procedure:
5.66 g (86.57 mmol) of zinc and 20.63 ml (360.71 mmol) of glacial acetic acid are added to 6.74 g (24.05 mmol) of (2-methylindolizin-3-yl)(4-nitrophenyl)methanone in 120 ml of a 2/1 mixture of water and ethanol. The reaction medium is heated at 80° C. for 4 hours. 0.57 g (8.7 mmol) of zinc and 2.06 ml of glacial acetic acid are added. Refluxing is maintained for 1 hour. At ambient temperature, the reaction medium is filtered off. The residue obtained is rinsed with ethyl acetate and with methyl THF. The organic phase is washed with a saturated aqueous solution of sodium hydrogen carbonate and then with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, and then concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (90/10) mixture. 4.9 g of a yellow solid are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[N:28]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=1)=[C:29]=[O:30]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:29](=[O:30])[NH:28][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1ccc(N=C=O)cc1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a stirred suspension of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (200 mg, 0.476 mmol) in anhydrous DCM (10 ml), a solution of DMAP (87 mg, 0.714 mmol) and 4-isocyanato-1,2-dimethoxybenzene (171 mg, 0.952 mmol) in anhydrous DCM (5 ml) was added dropwise within 10 minutes. The reaction mixture was stirred at RT overnight. After 18 hours, the reaction mixture was diluted with DCM (10 ml) and washed with HCl 0.5M. The organic layer was dried over Na2SO4 and evaporated. The crude material was purified by flash chromatography on silica gel (EtOAc 100%) affording the desired product as a white solid (200 mg, 0.334 mmol, 70.1% yield, [α]D=−27.6, c=0.45, DCM).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([CH3:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[C:35]([CH2:36][O:37]C3CCCCO3)=[N:34][CH:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:37][CH2:36][C:35]1[N:31]([C:27]2[CH:26]=[C:25]([C:24]3[CH2:23][C:22](=[O:45])[NH:21][C:9]4[CH:10]=[C:11]([CH3:20])[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]=4[N:7]=3)[CH:30]=[CH:29][CH:28]=2)[N:32]=[CH:33][N:34]=1
Reactant: Cc1cc(NC(=O)CC(=O)c2cccc(-n3ncnc3COC3CCCCO3)c2)c(NC(=O)OC(C)(C)C)cc1N(C)CC(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1N(C)CC(C)C)N=C(c1cccc(-n3ncnc3CO)c1)CC(=O)N2
Yield: 73.5 %

Procedure:
Prepared from (RS)-[5-(isobutyl-methyl-amino)-4-methyl-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,4]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M116) (0.96 g, 1.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a pale brown solid (480 mg, 73%).
Reaction SMILES: [C:1]([CH:4]([NH:13][C@H:14]([C:16]([N:18]1[C@H:26]([C:27]([OH:29])=[O:28])[CH2:25][C:20]2([S:24][CH2:23][CH2:22][S:21]2)[CH2:19]1)=[O:17])C)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2].[OH-].[Na+]>>[C:1]([CH:4]([NH:13][CH2:14][C:16]([N:18]1[C@H:26]([C:27]([OH:29])=[O:28])[CH2:25][C:20]2([S:24][CH2:23][CH2:22][S:21]2)[CH2:19]1)=[O:17])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2]
Reactant: C[C@H](NC(CCc1ccccc1)C(=O)O)C(=O)N1CC2(C[C@H]1C(=O)O)SCCS2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(CCc1ccccc1)NCC(=O)N1CC2(C[C@H]1C(=O)O)SCCS2

Procedure:
As described in Example 2, hydrolyze 7-[N-(1-carboethoxy-3-phenylpropyl)glycyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid (prepared as described in Example 2) with sodium hydroxide to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=2[CH3:14])[N:5]=[CH:4][C:3]=1[C:15]([NH2:17])=[O:16].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:25][C:26](OC)=O)[CH:22]=[CH:23][CH:24]=1.[H-].[Na+].Cl.[Cl-].[Na+]>C(O)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[CH2:25][C:26]1[NH:17][C:15](=[O:16])[C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=3[CH3:14])[C:2]=2[N:1]=1
Reactant: COC(=O)Cc1cccc(Cl)c1
Reactant: Cc1cccc(-n2ncc(C(N)=O)c2N)c1C
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CCO
Product: Cc1cccc(-n2ncc3c(=O)[nH]c(Cc4cccc(Cl)c4)nc32)c1C
Temperature: 25 °C

Procedure:
0.1 g (0.43 mmol) of 5-amino-1-(2,3-dimethylphenyl)-1H-pyrazole-4-carboxamide (Example 17A) is dissolved under argon in 6 ml of absolute ethanol and 0.24 g (1.3 mmol) of methyl 3-chlorophenylacetate and 0.17 g (4.34 mmol) of 60% sodium hydride (suspension in mineral oil) are added. The reaction mixture is heated to reflux overnight. Cooling to room temperature is followed by acidification with concentrated hydrochloric acid. The mixture of sodium chloride and the product precipitated thereby is filtered off and washed several times with water and diethyl ether. Drying under high vacuum results in 97 mg (61% of theory) of the product as colourless solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:10][C:11]([OH:13])=[O:12])[C:8]=1[CH3:9])(=[O:3])[CH3:2].[C:14]1(C)C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C.CCOCC>CO>[C:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: Cc1ccccc1
Reactant: CC(=O)c1cnn(CC(=O)O)c1C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)Cn1ncc(C(C)=O)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 2-(4-acetyl-5-methyl-1H-pyrazol-1-yl)acetic acid (1.17 g, 6.42 mmol, as a mixture of regioisomers from the previous step) in MeOH (8.8 ml)-Toluene (30.6 ml) was added a 2 M solution of (trimethylsilyl)diazomethane in ether (4.8 ml, 9.6 mmol) dropwise at 0° C. The resulting solution was allowed to warm to rt and stirred for 120 min. The reaction was quenched by addition of AcOH (3 ml) and the solvent was concentrated in vacuo. The crude product was purified by silica gel column chromatography (CH2Cl2:MeOH=30:1) to give the desired product along with a mixture of regioisomers (>99% yield). 1H NMR (270 MHz, CDCl3) δ 2.45 (3H, s), 2.53 (3H, s), 3.79 (3H, s), 4.90 (2H, s), 7.88 (1H, s).
Reaction SMILES: [F:1][C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:3][O:4][CH2:5]Cl.Br(F)(F)[F:13].[OH-].[Na+]>>[F:1][C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:3][O:4][CH2:5][F:13]
Reactant: FC(F)(F)C(F)(F)COCCl
Agent: [Na+]
Agent: [OH-]
Product: FCOCC(F)(F)C(F)(F)F
Temperature: -5 °C

Procedure:
The ether XXVII was refractionated to obtain a sample (56.8 g, 0.286 mole) of <99% purity by GLC. This sample was cooled to -5°C and stirred in a teflon bottle as bromine trifluoride (15.6 g, 0.114 mole) was added dropwise. The product was stirred with ice and dilute sodium hydroxide solution to remove halogens and acids, separated, washed with distilled water, freeze-dried at -20°C and then dried at 0°C over type 3A molecular sieve. The V so obtained was 99.0% by GLC; micro b760 62.2°C; d42 1.41; yield 45 g (87% of theory). The molecular sieve type 3A is manufactured and sold by the Linde Division of Union Carbide Company.
Reaction SMILES: [H][H].[NH:3]1[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[N:25]O)[C:16]=2[CH:15]=[CH:14][CH:13]=1>C(O)C.O1CCCC1.[Ni]>[NH:3]1[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([NH2:25])[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: [H][H]
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2c([nH]1)CCCC2
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: NC1c2ccccc2-c2c(-c3nc4c([nH]3)CCCC4)cccc21
Yield: 97.3 %

Procedure:
The procedure used in Example 6 is followed. In a 25 ml autoclave, dissolve 43 mg of 4-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, in a mixture of 4 ml of ethanol and 4 ml of tetrahydrofuran, add a spatula of Raney activated nickel and then subject to a hydrogen pressure of 1 bar and heat the autoclave at 600 for 12 hours. After cooling, the volume of hydrogen absorbed is 12 ml. After filtration of the catalyst, concentration to dryness under reduced pressure and purification by formation of a paste with diisopropyl ether, in this way we obtain 40 mg of 4-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)-9H-fluoren-9(R,S)-ylamine, in the form of a beige powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[N+:10]([CH2:13][C:14]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[F:23])=[O:15])([O-:12])=[O:11].I[CH2:25][C:26]([CH2:28]I)=[CH2:27]>CN(C)C=O>[CH2:25]=[C:26]1[CH2:28][C:13]([N+:10]([O-:12])=[O:11])=[C:14]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])[O:15][CH2:27]1
Reactant: O=C(C[N+](=O)[O-])c1cc(F)ccc1F
Reactant: C=C(CI)CI
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C1COC(c2cc(F)ccc2F)=C([N+](=O)[O-])C1
Temperature: 60 °C

Procedure:
N,N-diisopropylethylamine (184 mL) was added to a solution of 2-nitro-1-(2,5-difluorophenyl)ethanone (92.7 g, 461 mmol) in N,N-dimethylformamide (1000 mL) and 3-iodo-2-(iodomethyl)prop-1-ene (156 g, 507 mmol). The mixture was heated at 60° C. for 2 h, evaporated and purified by chromatography (silica gel, gradient 0-30% dichloromethane in hexane) to yield 3-methylene-5-nitro-6-(2,5-difluorophenyl)-3,4-dihydro-2H-pyran.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][CH2:18][O:19][CH:20]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(#N)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:20]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[O:19][CH2:18][CH2:17][N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]2)=[CH:22][CH:23]=1
Reactant: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1
Reactant: OCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: OCCN1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
To a refluxing mixture of 1.05 g (0.0081 mol) N-(2-hydroxy-ethyl)piperazine, 0.75 g (0.0054 mol) dry potassium carbonate and 5 ml toluene, a solution of 0.76 g (0.0027 mol) 1-[(2-chloroethoxy)(4-fluorophenyl)methyl]-4-fluorobenzene in 3 ml toluene was added dropwise. The reaction mixture was refluxed for 11 h and then cooled to room temperature. It was diluted with toluene (100 ml) and extracted with 2N hydrochloric acid (100 ml). The acidic extract was washed with one portion of toluene, then rendered basic by addition of 4N sodium hydroxide solution (75 ml) and extracted with toluene (100 ml). The toluene solution was washed successively with two portions of water and once with brine. Evaporation in vacuo gave a yellowish oil, which was redissolved in acetonitrile (20 ml). The title compound was precipitated as the dimaleate salt with an excess of a maleic acid solution in acetonitrile. By recrystallization from hot acetonitrile/methanol 1.29 g (78% of the theoretical yield) of the title compound was obtained as white crystals, m.p. 163° C.