Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:11])([CH3:10])[CH2:8][O:9][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1
Reactant: C1=COCCC1
Reactant: CC(C)(CO)CCCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(CCCCCBr)COC1CCCCO1
Yield: 46.5 %

Procedure:
According to the method described for the synthesis of 207d, 206g (36.0 g, 161 mmol) was treated with 3,4-dihydro-2H-pyran (18.5 g, 220 mmol) and p-toluenesulfonic acid hydrate (0.28 g, 1.5 mmol) in CH2Cl2 (60 mL). After filtration through neutral aluminum oxide (200 g) and concentration, the crude product was purified by column chromatography (silica gel; hexanes/ethyl acetate=50/1), affording 207g (23.0 g, 46%) as an oil. 1H NMR (CDCl3): δ 4.54 (t, 1H, J=3.0), 3.84 (m, 1H), 3.51-3.39 (m, 4H), 2.98 (d, 1H, J=9.3), 1.89-1.80 (m, 3H), 1.70-1.40 (m, 7H), 1.29-1.22 (m, 4H), 0.89 (s, 6H). 13C NMR (CDCl3): δ 99.3, 76.6, 62.1, 39.3, 34.3, 34.2, 33.0, 30.8, 29.2, 25.7, 24.7, 23.2, 19.6. HRMS (LSIMS, gly): Calcd for C14H28BrO2 (MH+): 307.1272, found: 307.1245.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[B-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C(Cl)Cl.C(O)(=O)C>[N:17]1([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:1]3[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=3)=[CH:10][CH:11]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(-c2ccc(C=O)cc2)cc1
Agent: CC(=O)O[B-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=Cc1ccc(-c2ccc(CN3CCCC3)cc2)cc1
Reaction time: 16 h

Procedure:
A solution of biphenyl-4,4′-dicarbaldehyde (0.21 g), pyrrolidine (83 μL), and acetic acid (57 μL) in DCM (5 mL) was treated with sodium triacetoxyborohyride (0.34 g). After 16 hours, the resulting mixture was treated with 3M NaOH (1.5 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried over sodium sulfate and evaporated. The residue was purified via preparative thin layer chromatography eluting with 5% MeOH/DCM to give the title compound (42.5 mg). 1H NMR (400 MHz, CDCI3)δ10.05 (s, 1 H), 7.94 (d, J=8.0, 2 H), 7.75 (d, J=8.0, 2 H), 7.60 (d, J=8.0, 2 H), 7.47 (d, J=8.0, 2 H), 3.72 (s, 2 H), 2.61 (br s, 4 H), 1.84 (br s, 4 H).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15](Cl)[CH:14]=[CH:13][C:3]=1[O:4][C:5](=[CH:10][O:11][CH3:12])[C:6]([O:8][CH3:9])=[O:7].[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>>[Br:18][CH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5](=[CH:10][O:11][CH3:12])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC=C(Oc1ccc(Cl)cc1C)C(=O)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: COC=C(Oc1ccccc1CBr)C(=O)OC

Procedure:
A mixture of 5.13 g of methyl 2-(2-methyl-4-chlorophenoxy)-3-methoxyacrylate, 3.56 g of N-bromosuccinimide, and a catalytic amount of azobisisobutyronitrile was heated at reflux with light irradiation for 4 hours. The mixture was filtered through silica gel, and the solvent evaporated to give a crude sample of methyl 2-(2-bromomethylphenoxy)-3-methoxyacrylate. A mixture of this crude material and 2.46 g of sodium acetate in N,N-dimethylformamide was heated at 100 C. for 4 hours. Water was added and the mixture extracted with ethyl acetate, dried with anhydrous sodium sulfate, evaporated and the residue purified by silica gel column chromatography to give methyl 2-(2-acetyloxymethyl-4-chlorophenoxy)-3-methoxyacrylate) (3.2 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][CH:21]=[C:20]([C:23]([OH:25])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:38][CH2:37][C@@H:36]([NH2:39])[CH2:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:34][CH2:35][C@@H:36]([NH:39][C:23]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:15]=3[NH:22][CH:21]=2)=[O:25])[CH2:37][CH2:38]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: COc1ccc(-c2ncnc3c(C(=O)O)c[nH]c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A73) and cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[C:16]4[O:17][CH2:18][CH2:19][NH:20][C:15]=4[CH:14]=[CH:13][CH:12]=3)[NH:8][C:7]=2[CH:21]=1.[Br:24][C:25]1[CH:26]=[CH:27][C:28](Cl)=[N:29][CH:30]=1.ClC1C(Cl)=CC=CN=1>>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([N:20]2[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([C:9]4[NH:8][C:7]5[CH:21]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=[CH:5][C:6]=5[N:10]=4)[C:16]=3[O:17][CH2:18][CH2:19]2)=[N:29][CH:30]=1
Reactant: FC(F)(F)c1ccc2nc(-c3cccc4c3OCCN4)[nH]c2c1
Reactant: Clc1ccc(Br)cn1
Agent: Clc1cccnc1Cl
Product: FC(F)(F)c1ccc2nc(-c3cccc4c3OCCN4c3ccc(Br)cn3)[nH]c2c1
Yield: 91 %

Procedure:
The procedure of Example 6 was repeated except for using 8-(6-(trifloromethyl)-1H-benzo[d]imidazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine and 5-bromo-2-chloropyridine instead of 4-(5-tert-butyl-1H-benzo[d]imidazol-2-yl)benzenamine and 2,3-dichloropyridine in Example 6 respectively to obtain the title compound (4.3 g, yield: 91%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:39])[N:4]([C:19]2[CH:20]=[C:21]([CH:36]=[CH:37][CH:38]=2)[CH2:22][NH:23][C:24](=O)[O:25]C2C=CC([N+]([O-])=O)=CC=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].ClCCl.[CH3:43][NH:44][CH3:45]>O1CCCC1>[Br:1][C:2]1[C:3](=[O:39])[N:4]([C:19]2[CH:20]=[C:21]([CH:36]=[CH:37][CH:38]=2)[CH2:22][NH:23][C:24](=[O:25])[N:44]([CH3:45])[CH3:43])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cccc(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cccc(CNC(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
To a reaction vessel (borosilicate culture tube) was added 4-nitrophenyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzylcarbamate (from step 1) (0.150 g, 0.250 mmol) and dichloromethane (2.5 mL). The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 15 minutes. A stock solution of N,N-dimethylamine in tetrahydorfuran (0.15 mL, 2.0 M) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. The reaction mixture was concentrated and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) which afforded an off white solid (0.065 g, 51%). 1H NMR (400 MHz, DMF-d6) δ 7.58 (app q, J=7.79 Hz, 1H), 7.42 (app t, J=7.65 Hz, 1H), 7.37 (app d, J=7.79 Hz, 1H), 7.08 (s, 1H), 7.03 (app dt, J=1.58, 5.37 Hz, 1H), 6.96 (app dt, J=2.55, 8.39 Hz, 1H), 6.88-6.83 (m, 1H), 6.06 (s, 1H), 5.24 (s, 2H), 4.95 (app t, J=5.57 Hz, 1H), 4.42 (app dddd, J=5.10, 5.71, 10.20, 15.17 Hz, 2H), 2.90 (s, 6H), 1.96 (s, 3H). ES-HRMS m/z 506.0848 (M+H C23H22BrF2N3O3 requires 506.0885).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[NH2:30].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:30][C:23]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=2[Br:21])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(Br)c(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(Br)c(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (2.9 g, 12.68 mmol) was dissolved in dry methylene chloride (19 mL) and dry pyridine (2.61 mL). To the reaction mixture was then added thionyl chloride (1.81 g, 15.22 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture was then added successively, under nitrogen atmosphere, 2-bromo-5-methoxy-phenylamine (2.82 g, 13.95 mmol), dry triethylamine (4.49 g, 44.40 mmol), dry methylene chloride (23 mL), 4-(dimethylamino)pyridine (0.15 g, 1.26 mmol) and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was then partitioned with aqueous 2N HCl and tert-butyl methyl ether. The organic layer was washed with aqueous 2N HCl, aqueous NaHCO3, brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (25% ethyl acetate/hexanes) to yield the title compound as a solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:13])=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1.OOS([O-])=O.[K+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH:1]1([N:4]2[C:5]3[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=3[N:13]=[C:20]2[C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(NC2CC2)c(N)c1
Reactant: O=Cc1cccnc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)nc(-c1cccnc1)n2C1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N1-cyclopropyl-4-methoxy-benzene-1,2-diamine (0.2 g, 0.0011 mol) and pyridine-3-carbaldehyde (0.12 g, 0.0011 mol) in DMF (5 ml) and H2O (2 ml) was added OXONE® monopersulphate (0.81 g, 0.00132 map. Reaction mass was stirred at room temperature for 3 h. The reaction mixture was basified with 10% K2CO3 solution to pH˜8-10 and extracted with EtOAc (3×20 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated under vacuum to afford the crude compound which was purified by column chromatography to obtain title compound 1-cyclopropyl-5-methoxy-2-(pyridin-3-yl)-1H-benzimidazole (376). 1H NMR (400 MHz, DMSO-d6), δ: 9.16 (s, 1H), 8.70 (s, 1H), 8.37 (d, J=8.8 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.23 (s, 1H), 6.96 (d, J=8.8 Hz, 1H), 3.80 (s, 3H), 1.10 (d, J=6.4 Hz, 2H), 0.64 (s, 2H). MS (M+1): 266.1, Purity 98.98%.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH2:15])=[O:14])[CH2:4][CH2:3]1.C(O)C.[BH4-].[Na+]>O>[OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH2:15])=[O:14])[CH2:4][CH2:3]1
Reactant: NC(=O)NC1CCC(=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)NC1CCC(O)c2ccccc21
Reaction time: 5 h

Procedure:
To a stirred solution of 4.6 g. of 1,2,3,4-tetrahydro-4-oxo-1-naphthylurea in 230 ml. of ethanol 0.85 g. of sodium borohydride is added. The reaction mixture is stirred for about 5 hours and after standing overnight 50 ml. water is added while stirring. The mixture is then evaporated in vacuo to remove the solvent. Water (50 ml.) is added, then glacial acetic acid is added, until the foaming caused by the acid ceases. The solution is evaporated to dryness in vacuo, alcohol is added and the whole evaporated to dryness in vacuo. Then 30 ml. of ethanol is added to the residue and the mixture stirred and filtered. The collected insoluble solid is air dried. This solid is heated with 300 ml. of acetone and filtered. The filtrate is concentrated in vacuo to afford 0.55 g. of the title compound, melting point 170°- 176° C. On further work-up of the acetone mother liquor, 0.2 g. of the title compound, melting point 169°-174° C., is recovered.
Reaction SMILES: [CH:1]([C:3]1([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:5][CH2:4]1)=[CH2:2]>C(OCC)(=O)C.[Pt](=O)=O>[CH2:1]([C:3]1([C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:5][CH2:4]1)[CH3:2]
Reactant: C=CC1(C(=O)OCc2ccccc2)CC1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCC1(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a solution of benzyl 1-vinylcyclopropanecarboxylate B-40a (100 mg, 0.494 mmol) in ethyl acetate (10 mL) was added platinum (IV) oxide (28.1 mg, 0.124 mmol). The reaction mixture was stirred for 1 h at 25° C. under hydrogen atmosphere (bladder pressure). After completion of reaction, it was filtered through the celite bed and washed the bed with EtOAc (2×20 mL). The solvent was removed under reduced pressure to obtain benzyl 1-ethyl-cyclopropanecarboxylate B-42a (70 mg, 0.343 mmol, 69.3% yield) as a colorless liquid. 1H NMR (CDCl3, δ=7.26 ppm, 400 MHz): δ 7.36-7.30 (m, 5H), 5.10 (s, 2H), 1.59 (q, J=7.2 Hz, 2H), 1.21 (app. q, J≈3.6 Hz, 2H), 0.99 (t, J=7.2 Hz, 3H), 0.69 (app. q, J≈3.6 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)(=[O:12])=[O:11].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccnc(Cl)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccnc(-c2ccc(S(C)(=O)=O)cc2)c1
Temperature: 120 °C
Yield: 73.8 %

Procedure:
To a mixture of 2-chloro-4-methylpyridine (3 g, 23.5 mmol), 4-(methylsulfonyl)phenylboronic acid (5.64 g, 28.2 mmol), potassium phosphate (12.0 g, 56.4 mmol) and DMF (50 mL) under an atmosphere of nitrogen was added palladium tetrakistriphenylphosphine (1.36 g, 1.18 mmol). After heating at 120° C. for 14 hours, the reaction was cooled and the DMF removed in vacuo. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL), separated and the organic layer dried over sodium sulfate and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of ethyl acetate in cyclohexane gave the title compound (4.29 g, 74%) TLC RF 0.19 (1:1 ethyl acetate:cyclohexane) LC retention time 2.36 mins, MS m/z 248 (MH+)
Reaction SMILES: Cl[Si](C)(C)C.[CH3:6][O:7][C:8](=[O:14])[CH:9]=[C:10]1[CH2:13][O:12][CH2:11]1.[CH3:15][Mg]Cl>C1COCC1.[Cu]I>[CH3:6][O:7][C:8](=[O:14])[CH2:9][C:10]1([CH3:15])[CH2:13][O:12][CH2:11]1
Reactant: COC(=O)C=C1COC1
Reactant: C[Mg]Cl
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: COC(=O)CC1(C)COC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Chlorotrimethylsilane (74 μl, 0.58 mmol) was solved in 1.5 ml THF. Copper(I) iodide (7 mg, 0.04 mmol) and oxetan-3-ylidene-acetic acid methyl ester (50 mg, 0.39 mmol) in 0.5 ml THF were added at room temperature and the mixture was stirred for 15 minutes at room temperature. The reaction mixture was cooled to −15° C. and 3N methylmagnesiumchloride-solution (0.52 ml, 1.56 mmol) was added drop wise. The reaction mixture was stirred for 1 hour at room temperature, quenched then with saturated NH4Cl-solution and extracted with dichloromethane. The organic extracts were washed with brine, dried with sodium sulfate, filtered and evaporated to give 65 mg (92%) light yellow oil. The crude product was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(Cl)c(O)c([N+](=O)[O-])c1
Reaction time: 0.17 h
Yield: 44 %

Procedure:
Sulphuric acid (83%, 20 ml) was cooled in an ice-bath, and 3-chloro-4-hydroxybenzoic acid (4 g, 22 mM) stirred in. After 10 minutes, nitric acid (70%, 1.43 ml, 22 mM) was run in, and the mixture stirred at 0° for 2 hours. After pouring onto ice, the solid was filtered, and recrystallised from aqueous ethanol to give title compound as yellow crystals (2.1 g, 44%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[NH2:11])[CH3:2].[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=1[CH2:22][C:23](Cl)=[O:24]>C1(C)C=CC=CC=1.C(OCC)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[NH:11][C:23](=[O:24])[CH2:22][C:15]1[C:16]([F:21])=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[F:13])[CH3:2]
Reactant: CCOC(=O)c1cccnc1N
Reactant: O=C(Cl)Cc1c(F)cc(F)cc1F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)c1cccnc1NC(=O)Cc1c(F)cc(F)cc1F
Temperature: 25 °C
Yield: 92.5 %

Procedure:
2-Aminonicotinic acid ethyl ester (2.4 g) was suspended in dry toluene (50 ml). To the stirred suspension, 2,4,6-trifluorophenylacetyl chloride (3.0 g) in dry toluene (20 ml) was added. The resulting suspension was heated to reflux for 8 hours. The reaction mixture was cooled to ambient temperature, diluted with diethyl ether (100 ml), washed with water and brine, and the organic layer was dried over magnesium sulphate. The solvent was evaporated to give 2-[2-(2,4,6-trifluorophenyl)-acetylamino]-nicotinic acid ethyl ester as a yellow solid (4.5 g, 93%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](NN)[CH2:9][N:8]=[C:7](C3C(F)=CC=CC=3F)[C:6]=2[CH:22]=1.ClCC(Cl)=O.C([O-])(=O)C.[Na+]>>[NH:11]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:22][C:6]=2[CH:7]=[N:8][CH:9]=[CH:10]1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2c(F)cccc2F)=NC1
Agent: CC(=O)[O-]
Agent: O=C(Cl)CCl
Agent: [Na+]
Product: C1=CNc2ccccc2C=N1

Procedure:
In the manner given in Preparation 10, 7-chloro-5(2,6-difluorophenyl)-3H-1,4-benzodiazepin-2-yl hydrazine is reacted with chloroacetyl chloride and after 1.5 hours with sodium acetate, then the mixture is refluxed to give 8-chloro-1-(chloromethyl)-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4-benzodiazepine. Preparation 14 8-Nitro-1-(bromomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: C(OC[N:10]1[C:14]2[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[C:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:11]1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH:39]2[CH2:41][CH2:40]2)[CH:29]=1)C1C=CC=CC=1.C(OCN1C2C=NNC(=O)C=2C(CC2C=CC=CC=2F)=C1C1C=CC(OC(F)F)=C(OC2CC2)C=1)C1C=CC=CC=1>>[CH:39]1([O:38][C:30]2[CH:29]=[C:28]([C:11]3[NH:10][C:14]4[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=4[C:12]=3[CH2:20][C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH:33]=[CH:32][C:31]=2[O:34][CH:35]([F:37])[F:36])[CH2:41][CH2:40]1
Reactant: O=c1[nH]ncc2c1c(Cc1ccc(F)cc1)c(-c1ccc(OC(F)F)c(OC3CC3)c1)n2COCc1ccccc1
Agent: O=c1[nH]ncc2c1c(Cc1ccccc1F)c(-c1ccc(OC(F)F)c(OC3CC3)c1)n2COCc1ccccc1
Product: O=c1[nH]ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(Cc3ccc(F)cc3)c12
Yield: 29.4 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 22-(b) except for using 184 mg (0.531 mmol) of 1-benzyloxymethyl-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-(4-fluorobenzyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 24-(a) in place of 1-benzyloxymethyl-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-(2-fluorobenzyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 69 mg of the title compound was obtained as a white solid. (Yield: 24%)
Reaction SMILES: C(=O)(O)[O-].[Na+].[C:6]1(O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](O)=[N:8][N:7]=1.[CH2:18]([S:26][S:27]C(=N)N)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>O.CO>[CH2:18]([S:26][S:27][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([S:27][S:26][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[N:8][N:7]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCSSC(=N)N
Reactant: Oc1nnc(O)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCCSSc1nnc(SSCCCCCCCC)c2ccccc12
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of sodium bicarbonate (4.30 8, 0.05 mole) in water (60 ml) was added dropwise to a stirred suspension of the phthalazine-1,4-diol prepared as above (2.91 g, 0.015 mole) and S-n-octylthioisothiourea obtained in step (A) (7.695 g, 0.03 mole) in methanol (70 ml) at 60°-65° C. over 30 minutes. The mixture was stirred at room temperature for a further hour, then filtered giving a yellow solid, which was washed with water and dried giving the duct as yellow crystals (6.56 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=[O:12])[CH2:7][CH:6]([CH2:14][CH2:15][OH:16])[CH2:5]2.[N:17]#[C:18][NH2:19].[CH]Cl.[OH-].[Na+]>>[NH2:19][C:18]1[N:17]=[N+:11]([O-:12])[C:10]2[CH:9]=[C:8]3[C:4]([CH2:5][CH:6]([CH2:14][CH2:15][OH:16])[CH2:7]3)=[CH:3][C:2]=2[N:1]=1
Reactant: N#CN
Reactant: Nc1cc2c(cc1[N+](=O)[O-])CC(CCO)C2
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc2cc3c(cc2[n+]([O-])n1)CC(CCO)C3
Temperature: 100 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
A mixture of nitroaniline 156 (17.6 g, 79 mmol) and cyanamide (19.8 g, 471 mmol) were melted together at 60° C. and cHCl (35 mL) was added dropwise. The solution was heated to 100° C., stirred for 1 h, cooled to ca. 50° C. and the mixture made strongly basic with 7.5 M NaOH solution. The mixture was heated to 100° C. for 3 h, cooled to 20° C. and diluted with ice/water. The resulting precipitate was filtered, washed with H2O (100 mL) and Et2O (30 mL), and dried to give 1-oxide 157 (18.4 g, 94%) as a yellow-green solid: mp 230-235° C.; 1H NMR [(CD3)2SO] δ 7.92 (s, 1H, H-9), 7.33 (s, 1H, H-5), 7.11 (br s, 2H, NH2), 4.45 (br s, 1H, OH), 3.49 (t, J=6.6 Hz, 2H, CH2O), 3.06-3.15 (m, 2H, H-6, H-8), 2.59-2.69 (m, 2H, H-6, H-8), 2.49-2.54 (m, 1H, H-7), 1.63 (q, J=6.6 Hz, 2H, CH2); HRMS calcd for C12H14N4O2 (M+) m/z 246.1117, found 246.1115.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:13]=[C:14]([C@H:18]2[C@H:22]([CH2:23][OH:24])[CH2:21][N:20]([CH2:25][C:26]3([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:19]2)[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[F:11][C:12]1[CH:13]=[C:14]([C@H:18]2[C@H:22]([CH:23]=[O:24])[CH2:21][N:20]([CH2:25][C:26]3([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)[CH2:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(OCc1ccccc1)C1(CN2C[C@@H](CO)[C@H](c3cccc(F)c3)C2)CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C[C@@H]1CN(CC2(C(=O)OCc3ccccc3)CCCCC2)C[C@H]1c1cccc(F)c1
Reaction time: 0.33 h

Procedure:
A solution of oxalyl chloride (0.6 mL, 7 mmol) in 35 mL CH2Cl2 was cooled to −78° C. and DMSO (1 mL, 14.1 mmol) was added dropwise. After stirring for 20 min a solution of Benzyl 1-{[(3R,4S)-3-(3-fluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]methyl}cyclohexane carboxylate (2.5 g, 5.88 mmol, from Step C) in 35 mL CH2Cl2 was added. The mixture was stirred for 20 min more then triethylamine (4 mL, 29.5 mmol) was added. The cooling bath was removed and the mixture was stirred for 4h. 100 mL CH2Cl2 was added and the mixture was washed with 1 M NaOH then water and sat'd sodium chloride. The organic layer was dried over magnesium sulfate and concentrated. Flash chromatography (90 g silica, 5/1 hexane/EtOAc) gave the desired aldehyde. 1H NMR (500 MHz, CDCl3) δ1.25-1.43 (m, 6H), 1.58-1.63 (m, 4H), 2.15-2.19 (m, 2H), 2.62-2.73 (m, 2H), 2.83-2.87 (m, 1H), 2.92-3.01 (m, 2H), 3.44-3.51 (m, 1H), 5.11-5.21 (dd, 2H), 6.9-6.97 (m, 1H), 6.98-7.13 (m, 2H), 7.23-7.4 (m, 6H), 9.6 (s, 1H).