Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][N:6]2[C:7](=[O:10])[C:8]=1[I:9].[C:15]([O-:18])(=[O:17])[CH3:16].[K+].O>CN(C=O)C>[C:15]([O:18][CH2:2][C:3]1[N:4]=[C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][N:6]2[C:7](=[O:10])[C:8]=1[I:9])(=[O:17])[CH3:16]
Reactant: O=c1c(I)c(CCl)nc2ccccn12
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc2ccccn2c(=O)c1I
Temperature: 40 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
A mixture of 20.0 g (62.4 mmol) of the product from Step 2 (12) and 9.2 g (93.6 mmol) of potassium acetate in 200 mL DMF was stirred at 40° C. under nitrogen for three hours. The reaction mixture was allowed to cool to ambient temperature and the addition of excess water to the reaction solution caused the product to precipitate out of solution. The product was filtered, washed with water (3×), and drying under reduced pressure at 40° C. overnight yielded 19.4 g (56.4 mmol, 90%) of (3-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl acetate (13) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].O>CN(C=O)C>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:1]/[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc2cccnc2c1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1ccc2cccnc2c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 56.7 %

Procedure:
A solution of 7-methyl-8-nitroquinoline (6 g, 31.9 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (4.27 ml, 31.9 mmol) in DMF (15 ml) was heated at 140° C., under nitrogen, for 16 h. After cooling to room temperature, water (15 ml) was added and the resulting precipitate was collected by filtration, washed with EtOAc and dried to give the title compound (4.4 g, 57%). The compound could not be detected by HPLCMS therefore structure was confirmed by 1H NMR.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][NH:15][C:16]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][N:27]=4)[N:22]=[CH:21][CH:20]=3)=O)[CH:9]=2)[C@H:3]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[N:22]1[C:23]2[C:28](=[N:27][CH:26]=[CH:25][CH:24]=2)[C:19]([NH:18][C:16]2[N:11]3[CH:12]=[CH:13][C:8]([N:4]4[C@@H:3]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:2]([CH3:35])([CH3:1])[O:6][C:5]4=[O:7])=[CH:9][C:10]3=[N:14][N:15]=2)=[CH:20][CH:21]=1
Reactant: CC1(C)OC(=O)N(c2ccnc(NNC(=O)Nc3ccnc4cccnc34)c2)[C@H]1c1ccccc1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)OC(=O)N(c2ccn3c(Nc4ccnc5cccnc45)nnc3c2)[C@H]1c1ccccc1
Reaction time: 1 h
Yield: 1.7 %

Procedure:
A mixture of (S)-2-(4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)pyridin-2-yl)-N-(1,5-naphthyridin-4-yl)hydrazinecarboxamide (150 mg, 0.319 mmol) and POCl3 (292 μL, 3.19 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) in toluene (6.390 mL) was heated at 100° C. After stirring for 1 hour, an additional 1.5 mL of POCl3 was added to the reaction solution. After stirring for another 3 hours, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by reverse-phase preparative HPLC using 0.1% TFA in ACN/H2O, gradient 20% to 90% over 20 minutes to provide a material which was further purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 10% MeOH in DCM, to provide (S)-3-(3-((1,5-naphthyridin-4-yl)amino)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one (2.41 mg, 5.34 μmol, 1.671% yield) as greenish solid. 1H NMR (500 MHz, DMSO-d6) δ 10.06-10.13 (m, 1H), 8.95-9.00 (m, 1H), 8.64 (br. s, 1H), 8.34-8.39 (m, 1H), 8.28 (d, J=6.09 Hz, 1H), 7.81-7.87 (m, 1H), 7.55 (d, J=9.62 Hz, 1H), 7.46-7.51 (m, 1H), 7.38-7.44 (m, 3H), 7.31-7.37 (m, 3H), 5.63 (s, 1H), 1.67 (s, 3H), 0.95 (s, 3H). m/z (ESI) 452.2 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[Na+].[O:7]=[C:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=2)[NH:9]1.Cl[C:22]1[C:31]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=2[N:25]=[CH:24][N:23]=1>>[CH3:20][O:19][C:17]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([OH:7])=[C:16]2[C:22]1[C:31]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=2[N:25]=[CH:24][N:23]=1)=[O:18]
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: Clc1ncnc2c1CCCC2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: COC(=O)c1ccc2[nH]c(O)c(-c3ncnc4c3CCCC4)c2c1

Procedure:
The title compound was synthesized according to the procedure described for Example 9 using sodium tert-butoxide (48 mg, 0.5 mmol), methyl 2-oxo-5-indolinecarboxylate (21 mg, 0.11 mmol) and 4-chloro-5,6,7,8-tetrahydroquinazoline solution (0.1 mL, 1 M in N-methylpyrrolidinone, corresponding to 17 mg, 0.1 mmol; described in: Budesinsky Z., Roubinek F. Collect. Czech. Chem. Commun., 1964, 29, 2341). The crude oil was purified on SCX-column pre-rinsed with methanol using ethyl acetate, methylene chloride, methylene chloride/methanol 1:1, and methanol/ammonia (2 M, aq) as elution solvents.
Reaction SMILES: P(Br)(Br)[Br:2].[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([Br:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:22]([CH3:24])[CH3:23])[CH:16]=1)[CH2:9]O>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([Br:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:22]([CH3:24])[CH3:23])[CH:16]=1)[CH2:9][Br:2]
Reactant: BrP(Br)Br
Reactant: CC(C)c1cc(Oc2c(Br)cc(CO)cc2Br)ccc1O
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Br)cc(CBr)cc2Br)ccc1O
Yield: 72.1 %

Procedure:
A solution of PBr3 (125 mg, 0.463 mmol) in 5 ml of CH2Cl2 was added dropwise, under nitrogen, to a stirred solution of 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)-benzylalcohol (Example 12) (385 mg, 0.925 mmol) in 20 ml CH2Cl2 at 0° C. The reaction mixture was left to stand at room temperature over night and then diluted with CH2Cl2. The organic phase was washed with water, dried over MgSO4 and concentrated. The residue was purified by column chromathography (silica gel, 75:25 petroleum-ether/EtOAc) to give 160 mg (36%) of 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzylbromide.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[N:4]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[CH:6]([C:12]1[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:21])[CH:19]=3)[NH:14][CH:13]=1)[CH2:5]2>CN(C)C=O.O=[Mn]=O>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11]1)[CH:6]([C:12]1[C:20]3[C:15](=[CH:16][CH:17]=[C:18]4[NH:21][C:1]([CH3:2])=[N:3][C:19]4=3)[NH:14][CH:13]=1)[CH2:5]2
Reactant: CCN
Reactant: Nc1ccc2[nH]cc(C3CN4CCC3CC4)c2c1
Agent: O=[Mn]=O
Solvent: CN(C)C=O
Product: Cc1nc2c(ccc3[nH]cc(C4CN5CCC4CC5)c32)[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2 mmol of ethylamine and 10 mmol of MnO2 are added to a solution of 1 mmol of 3-(1-azabicyclo[2.2.2]oct-3-yl)-1H-indol-5-ylamine in 20 ml of dimethylformamide (DMF), and the mixture is stirred at room temperature for 12 hours. The suspension is filtered through Celite and washed with DMF. After the solvent has been distilled, the mixture is subjected to conventional work-up, giving 8-(1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-3,6-dihydroimidazo[4,5-e]indole; ESI 281.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12.C(O)(=O)C.[Br:37]Br.C(O)(=O)C>O>[Br:37][C:7]1[C:2]([OH:1])=[C:3]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH2:19]3)[C:4]2=[N:5][CH:6]=1
Reactant: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(O)ccnc32)CC1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c2ncc(Br)c3O)CC1
Reaction time: 0.17 h
Yield: 71 %

Procedure:
To a solution of the title compound from Example 252 (0.19 grams) and glacial acetic acid (4 mL) was added a 0.7 M bromine-acetic acid solution (0.7 mL) at 25° C. under N2. After 10 minutes, water was added and the resulting solid was filtered and washed with water several times and dried to give the title compound (0.18 grams, 71%, MH+ 526).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:8]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:8]=1
Reactant: CC(C)(C)OC(=O)n1cc([N+](=O)[O-])cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)n1cc(N)cn1
Yield: 95.7 %

Procedure:
A solution of tert-butyl 4-nitro-1H-pyrazole-1-carboxylate (1.0 g, 4.7 mmol) in MeOH (120 ml) was passed through the H-Cube with full hydrogen mode at 60° C. and 1 bar with a 10% Pd/C cartridge using 1 ml/min flow rate. The solution was then passed through the H-Cube for a second time using identical conditions and the solvent removed in vacuo to afford tert-butyl 4-amino-1H-pyrazole-1-carboxylate (0.82 g, 4.5 mmol, 95%). 1H NMR (DMSO) δ 1.54 (9H, s), 4.42 (2H, s), 7.33 (1H, s), 7.35 (1H, s). LCMS (2) Rt: 1.45 min; m/z (ES+) 206 M+Na+.
Reaction SMILES: [CH2:1]([CH:4]1[S:8][C:7]2[C:9]([CH3:19])=[C:10]([O:15]COC)[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1)[CH:2]=[CH2:3].S(=O)(=O)(O)O>C(O)(=O)C>[CH2:1]([CH:4]1[S:8][C:7]2[C:9]([CH3:19])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1Oc2c(C)c(C)c(OCOC)c(C)c2S1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: C=CCC1Oc2c(C)c(C)c(O)c(C)c2S1
Temperature: 50 °C

Procedure:
0.9 g of 2-allyl-5-methoxymethoxy-4,6,7-trimethyl-1,3-benzoxathiole (prepared as described in Example 89) was dissolved in 8 ml of acetic acid, and 3 drops of 10% v/v aqueous sulfuric acid were added to the resulting solution, which was then heated at 50° C. for 30 minutes. The solution was then cooled down to room temperature, and the reaction mixture was condensed by evaporation under reduced pressure. The condensate was dissolved in benzene, and the solution was washed with water and then dried over anhydrous sodium sulfate. The benzene was distilled off, and the resulting crude product was purified by silica gel Lobar column chromatography. The title compound, melting at 78.5°-79.5° C., was obtained from the fraction eluted with benzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=O)[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:19][O:20][CH2:21][CH2:22][NH2:23]>>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([NH:23][CH2:22][CH2:21][O:20][CH3:19])=[O:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COCCN
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Product: COCCNC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Yield: 50 %

Procedure:
Prepared in a similar manner to Example 3 from 2-(2-fluorobiphenyl-4-yl)propanoic acid and 2-methoxyethanamine. Yield: 50%. 1H NMR (500 MHz, CDCl3): δ 1.54-1.56 (d, 3H), 3.30 (s, 3H), 3.38-3.45 (m, 4H), 3.55 (q, 1H), 5.58 (s br, 1H), 7.11-7.16 (m, 2H), 7.36-7.45 (m, 5H), 7.54 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8][CH3:9])=[C:6]([S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[CH:4][C:3]=1[NH:15][C:16](=[O:24])[C@:17]([OH:23])([CH3:22])[C:18]([F:21])([F:20])[F:19].ClC1C=C(C=CC=1)C(OO)=[O:30].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:13]([S:10]([C:6]1[CH:5]=[CH:4][C:3]([NH:15][C:16](=[O:24])[C@:17]([OH:23])([CH3:22])[C:18]([F:19])([F:21])[F:20])=[C:2]([Cl:1])[C:7]=1[S:8]([CH3:9])=[O:30])(=[O:12])=[O:11])[CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1SC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1S(C)=O
Reaction time: 16 h
Yield: 132.3 %

Procedure:
To a stirred solution of (R)-N-[4-ethylsulphonyl-3-methylsulphanyl-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 28) (0.636 g) in DCM was added metachloroperoxybenzoic acid (0.17 g). After 1 hour at ambient temperature a further portion of meta-chloroperoxybenzoic acid (0.14 g) was added and stirring was continued at ambient temperature for 16 hours. Further meta-chloroperoxybenzoic acid (0.08 g) was added and after 30 minutes sodium hydrogen carbonate solution (50 ml) was added. The organic layer was separated, dried and volatile material was removed by evaporation. The residue was purified by chromatography on a Mega Bond Elut column (20 g) eluting with 10-80% EtOAc/isohexane to give the title compound (0.55 g) as a white foam. NMR: 1.19 (t, 3H), 1.62 (s, 3H), 3.14 (s, 3H), 3.52-3.60 (m, 2H), 8.00 (d, 1H), 8.14 (brs, 1H), 8.45-8.49 (m, 1H), 10.11 (brs, 1H); m/z: 420.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28].C(N(CC)CC)C>ClCCl>[CH2:30]([O:29][C:27](=[O:28])[NH:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:15])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1)[CH2:31][CH2:32][CH3:33]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: CCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
To a stirred solution of [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethyl-phenyl)methanone (100 mg, 0.285 mmol) in dichloromethane (5 mL) was added n-butyl chloroformate (0.285 mmol) in the presence of triethylamine (0.313 mmol) at 0° C. The resulting mixture was stirred at ambient temperature for 24 h and then quenched with water (10 mL). The organic phase was washed with water, saturated NaCl, dried over MgSO4 and then concentrated in vacuo to afford the desired product as a white solid (0.095 g, 74% yield). 1H NMR (500 MHz, CDCl3) δ 8.10, 7.73, 7.63, 7.55, 7.36, 7.04, 4.19, 3.96-4.02, 3.89-3.95, 3.61-3.66, 3.52-3.56, 3.32, 1.64-1.70, 1.38-1.46, 0.95.
Reaction SMILES: [OH:1][C@@H:2]1[C@@:26]2([CH3:27])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:28])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([O:29][C:30](=[O:32])[CH3:31])[C@@H:3]1[OH:33]>C(OC(=O)C)(=O)C.N1C=CC=CC=1>[C:2]([O:1][C@@H:2]1[C@@:26]2([CH3:27])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:28])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20])[CH2:5][C@@H:4]([O:29][C:30](=[O:32])[CH3:31])[C@@H:3]1[O:33][C:4](=[O:29])[CH3:5])(=[O:1])[CH3:3]
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O)[C@H]1O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]1OC(C)=O
Yield: 147.4 %

Procedure:
1α,2α-Dihydroxy-3β-acetoxy-cholesta-5-ene (264 mg) was dissolved in a mixture of acetic anhydride (20 ml) and pyridine (2 ml) and the solution was heated on a boiling water bath for 2 hours to remove acetic anhydride. To the solution was added ice-water and the precipitated crystals were recovered by filtration. Recrystallization of the crystals from methanol yielded 1α,2α,3β-triacetoxycholesta-5-ene (230 mg) having a melting point between 109 and 110° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH:6]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH2:5]2.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[NH:20][NH2:21]>CO.OS(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:21][NH:20][C:19]([O:23][CH2:24][CH3:25])=[O:22])[CH:6]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH2:5]2
Reactant: O=C1c2ccc(F)cc2CC1c1ccc(F)cc1
Reactant: CCOC(=O)NN
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCOC(=O)NN=C1c2ccc(F)cc2CC1c1ccc(F)cc1
Yield: 95 %

Procedure:
To a mixture of 1.5 g of 5-fluoro-2-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-one (prepared by a procedure analogous to Example 1, Step B) and 0.63 g of ethyl carbazate in 20 ml of methanol was added 1 drop of conc. H2SO4 and the reaction was refluxed under nitrogen overnight. The reaction was then partitioned between ethyl acetate and 5% aqueous NaHCO3, the aqueous extracts were washed with ethyl acetate and the combined organic extracts were dried over MgSO4. Concentration of the organic extract afforded 1.9 g of a yellow oil, which was triturated with ether to afford 1.27 g of a white solid, m.p. 139°-141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:19]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([CH2:25][N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:31][CH:30]=3)=[O:18])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Product: O=C(COc1ccc(-c2ccc(Cl)cc2)cc1)Nc1ccc(CN2CCCCC2)cc1

Procedure:
The product was prepared according to general working method I from (4′-chloro-biphenyl4-yloxy)-acetic acid (137a) and 4-piperidin-ylmethyl-phenylamine.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:20][C:9]2[N:10]([CH3:19])[C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=O)C.[CH3:21][NH2:22]>C(O)C>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]2[N:10]([CH3:19])[C:9]3[CH2:20][CH:6]([C:4]([NH:22][CH3:21])=[O:3])[CH2:7][C:8]=3[C:16]=2[CH:15]=1
Reactant: CCOC(=O)C1Cc2c(n(C)c3ccc(OC)cc23)C1
Reactant: CN
Solvent: CCO
Product: CNC(=O)C1Cc2c(n(C)c3ccc(OC)cc23)C1
Temperature: 70 °C
Reaction time: 50 h

Procedure:
To a solution of 1,2,3,4-tetrahydro-4-methyl-7-methoxycyclopent[b]indole-2-carboxylic acid ethyl ester (4.5 g, 0.016 mole) in 100 ml of absolute ethanol, was added methylamine (40% aqueous solution, 15 ml, 6 g, 0.18 mole). The mixture was stirred at 70° C. for 50 hours in a sealed tube. The mixture was concentrated to a brown solid (~5 g) which was eluted on a silica gel column with ethyl acetate/dichloromethane (1:1) via HPLC. The desired fractions were combined and concentrated to a white solid, 3.0 g, mp 164°-165° C. A sample of this material was recrystallized from ethanol to afford the product as a white solid, mp 166°-167° C.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16]CC2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C(=Cc1ccccc1OCc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Oc1ccccc1CCCc1ccccc1
Yield: 83 %

Procedure:
The whole of this benzyl 2-(3-phenyl-1-propenyl)phenyl ether was treated with hydrogen in the presence of 100 mg of 5% w/w palladium-on-carbon in 40 ml of ethanol at room temperature for 3 hours. At the end of this time, insoluble materials were removed by filtration, and the filtrate was concentrated by distillation under reduced pressure, to give 0.230 g (yield 83%) of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Li]CCCC.C(OC([N:21]1[CH2:26][CH2:25][C:24]2([CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)[CH2:23][CH2:22]1)=O)(C)(C)C>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:29]2[CH2:30][CH2:31][C:24]3([CH2:25][CH2:26][NH:21][CH2:22][CH2:23]3)[CH2:27][CH:28]=2)=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Reactant: Clc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1ccc(C2=CCC3(CCNCC3)CC2)cc1
Reaction time: 0.5 h

Procedure:
Was prepared according to method A with the following variation: A solution of 4-bromochlorobenzene (1.15 g, 5.98 mmol) in THF (5 mL) was added drop-wise to a solution of n-BuLi (1.6 M in hexanes (4 mL, 6.4 mmol)) at −78° C. and stirred for 30 min. A solution of 9-oxo-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (500 mg, 1.87 mmol) in THF (5 mL) was added. The mixture was stirred for 1 h. White solid Mp. 104.2-107.1° C.
Reaction SMILES: Cl.Cl.[NH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([NH:13][O:14][CH2:15][C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[CH2:5][NH:4]1.C(N(CC)CC)C.[O:29]=[C:30](Cl)OC(Cl)(Cl)Cl.CN(C1C=CC=CN=1)C>C(#N)C>[O:29]=[C:30]1[N:13]([O:14][CH2:15][C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[CH:6]2[CH2:5][N:4]1[NH:3][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12
Reactant: C=CCOC(=O)CONC1CNNc2ccccc21
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCOC(=O)CON1C(=O)N2CC1c1ccccc1N2
Reaction time: 1 h
Yield: 80.8 %

Procedure:
5.63 g of the product obtained in stage D are dissolved in 2 l of acetonitrile. 8.45 g of triethylamine are slowly added, followed, at 0° C., by 1.658 g of diphosgene and 2.25 g of dimethylaminopyridine. The temperature is allowed to return to ambient temperature. After one hour, the acetonitrile is evaporated and the residue is treated with NaH2PO4 (1M aqueous solution). Extraction is carried out with AcOEt, and the organic phase is washed with water. It is dried over MgSO4 and the solvent is evaporated. The residue is chromatographed on silica (eluent: heptane/AcOEt (4:1)). The compound obtained is crystallized from ether at 0° C. and 1.96 g of the expected product (41%) are isolated.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[N:16][O:17][CH3:18])[C:12]([NH:14][CH3:15])=[O:13].[Br:19][C:20]1[CH:21]=[C:22]([CH3:27])[C:23](F)=[N:24][CH:25]=1.O>C1COCC1>[CH3:18][O:17][N:16]=[C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][O:3][C:23]1[C:22]([CH3:27])=[CH:21][C:20]([Br:19])=[CH:25][N:24]=1)[C:12]([NH:14][CH3:15])=[O:13]
Reactant: CNC(=O)C(=NOC)c1ccccc1CO
Reactant: Cc1cc(Br)cnc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C(=NOC)c1ccccc1COc1ncc(Br)cc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.3 %

Procedure:
Sodium hydride (60%, 0.18 g, 4,5 mmol) was added to a solution of 2-hydroxymethyl-α-methyoxyimino-N-methyl-benzeneacetamide (1.0 g, 4.5 mmol) in dry THF (25 mL) and stirred for 10 minutes at 25° C. under N2 atmosphere. The pyridine product of Example 1 (0.86 g, 4.5 mmol) was added to this reaction mixture and stirred for 16 hours. Water (20 mL) was added and the resulting mixture was extracted with ether (3×50 mL), dried (anhydrous Na2SO4), filtered and concentrated in vacuo to yield crude residue (1.5 g), which was then triturated with ether/pentane to give α-(methoxyimino)-N-methyl-2-[[[5-bromo-3-methyl-2-pyridinyl]oxy]methyl]-benzeneacetamide (1.1 g) as a white solid. M.P. 115-116° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1)[CH3:2].[ClH:12]>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:12])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(CO)cc1
Reactant: Cl
Product: CCOc1ccc(CCl)cc1

Procedure:
4-Ethoxybenzyl alcohol (5 g) and concentrated hydrochloric acid (8.5 cm3) were vigorously stirred together for 30 minutes. The 2 phases were then allowed to separate, and the lower layer separated off, and diluted with chloroform. The organic solution was dried over anhydrous magnesium sulphate, and removal of the solvent by evaporation gave 4-ethoxybenzyl chloride (5.6 g). (This product is not stable on keeping, so was converted immediately to the phosphonium salt--see Example 12).