Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.Cl[C:12]([F:17])([F:16])C([O-])=O.[Na+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:16][CH:12]([F:17])[O:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: Cc1cc(O)cnc1C#N
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(OC(F)F)cnc1C#N

Procedure:
A solution of 5-hydroxy-3-methyl-pyridine-2-carbonitrile (CAS registry 228867-86-5) (228 mg, 1.70 mmol), sodium chlorodifluoroacetate (CAS registry 1895-39-2) (518 mg, 3.40 mmol) and K2CO3 (705 mg, 5.10 mmol) in DMF (7 ml) was stirred for 0.5 h at 100° C. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl soln. and brine. The aqueous layers were reextracted with EtOAc, the combined organic layers dried over Na2SO4, filtrated and the filtrate was concentrated. The title compound was obtained as a colourless oil after flash chromatography on silica gel (cyclohexane/EtOAc gradient 0-3 min 95:5, 3-35 min 95:5 to 60:40).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([F:14])[CH:4]=1.C(N(CC)CC)C.[F:22][S:23]([F:37])([F:36])([F:35])([F:34])[C:24]1[CH:33]=[CH:32][C:27]([CH2:28][N:29]=[C:30]=[S:31])=[CH:26][CH:25]=1>CN(C)C=O>[F:22][S:23]([F:34])([F:35])([F:36])([F:37])[C:24]1[CH:25]=[CH:26][C:27]([CH2:28][NH:29][C:30](=[S:31])[NH:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([F:14])[CH:4]=2)=[CH:32][CH:33]=1
Reactant: FS(F)(F)(F)(F)c1ccc(CN=C=S)cc1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(CNC(=S)NCc2ccc(S(F)(F)(F)(F)F)cc2)cc1F
Temperature: 25 °C

Procedure:
N-(4-aminomethyl-2-fluoro-phenyl)-methane sulphonamide (237 mg, 1.09 mmol) was dissolved in dimethylformamide (1 ml) and to this was added triethylamine (132 mg, 1.30 mmol) and 4-(pentafluorosulphanyl)benzylisothiocyanate (300 mg, 1.09 mmol) dissolved in dimethylformamide (1 ml). The reaction mixture was stirred over night at room temperature, the solvent removed under vacuum and the residue dissolved in a little methanol. Following column chromatographic cleaning (silica gel, hexane/ethyl acetate 1:5), the product was obtained as a solid (305 mg, 57% of the theoretical amount).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([OH:19])[CH:5]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([O:19][C:21](=[O:23])[CH3:22])[CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(O)c(N=Nc2ccccc2)c(O)c1
Solvent: CC(=O)O
Product: COC(=O)c1cc(O)c(N=Nc2ccccc2)c(OC(C)=O)c1

Procedure:
A mixture of 27 g. of 3,5-dihydroxy-4-phenylazo-benzoic acid methyl ester, 250 ml. of glacial acetic acid and 21 g. of acetic anhydride was stirred at 100° C. for 3 hours, complete solution occurring. The resulting solution was evaporated to dryness under reduced pressure. The residue was taken up in methanol and again evaporated to dryness. The residue was recrystallized from dimethylformamide/methanol and there was obtained 3-acetoxy-5-hydroxy-4-phenylazo-benzoic acid methyl ester having a melting point of 162° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)=[O:4].C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:19][CH2:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(CBr)c1
Temperature: 40 °C
Yield: 91.7 %

Procedure:
To a mixture of methyl-m-toluate (180 g, 1.2 mol) and N-bromosuccimide (235 g, 1.32 mol) in CCl4 (2 L) was added in portion benzoyl peroxide (18 g, 0.1 times) at 50° C. The mixture was refluxed for 5 h. Then the mixture was allowed to cool down to 40° C. and the solid was filtered off. The filtrate was concentrated to give methyl 3-(bromomethyl)benzoate (252 g, 91%) as light yellow liquid.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[OH-].[NH4+:10].[OH-].[Na+]>O>[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[NH4+:10]
Reactant: O=C(O)/C=C/C(=O)O
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])/C=C/C(=O)O
Reaction time: 0.25 h

Procedure:
A slurry of 11.6 g (0.1 mole) fumaric acid was dissolved in 30 ml water was mixed with 13 g of 30% aqueous solution of ammonium hydroxide (0.11 mol NH3). Carefully warming the slurry to boiling gave a dear solution. This solution was boiled to dryness over a period of 15 minutes to give a white crystalline solid. The solid was tumbled under nitrogen at 100 Torr, at 190°-200° C. for 4 hours to give a water insoluble, tan grasslike solid weighing 12.0 g. This solid was dissolved in 40 g of an aqueous solution containing 4.0 g of sodium hydroxide to form a pale yellow solution, pH 7.0, containing 25% solids.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][CH2:15][CH:16]([OH:31])[C:17]2[N:18]=[C:19]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:20][CH:21]=2)=[CH:8][CH:7]=1)([O:3]CC)=[O:2].[OH-].[Na+]>>[C:1]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][NH:14][CH2:15][CH:16]([OH:31])[C:17]2[N:18]=[C:19]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:20][CH:21]=2)=[CH:10][CH:11]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)c1ccc(CCNCC(O)c2csc(NC(=O)c3ccccc3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(CCNCC(O)c2csc(NC(=O)c3ccccc3)n2)cc1

Procedure:
Prepared analogously to Example 2 by reaction of N-[2-(4-carboethoxyphenyl)ethyl]-2-hydroxy-2-(2-benzoylamino-thiazol-4-yl)ethanamine with 1N sodium hydroxide solution, followed by purification of the crude product on a silica gel column using chloroform/methanol =1:1 and trituration with water/ethanol =9:1.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[N:33]1([C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:32])[F:31])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:30])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: C1CCNC1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc2cc(C(=O)N3CCCC3)cnc2c1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 48.3 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with pyrrolidine (9 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane and allowed to react overnight. The reaction mixture was concentrated, the residue was suspended in water, and the solid was collected by vacuum filtration. This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 26 mg of the title compound as a colorless solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[N:14]\[O:15][CH3:16])/[C:10]([NH:12][CH3:13])=[O:11].CN(C=O)C.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1[OH:30].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1[O:30][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[N:14]\[O:15][CH3:16])/[C:10]([NH:12][CH3:13])=[O:11]
Reactant: CNC(=O)/C(=N/OC)c1ccccc1CBr
Reactant: Cc1ccc(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cc(C)ccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
To (E)-2-(2-bromomethylphenyl)-2-methoxyimino-N-methylacetamide (0.72 g, 2.5 mmol), added were dry DMF (5.0 ml), 2,5-dimethylphenol (0.46 g, 3.75 mmol) and potassium carbonate (0.69 g, 5.0 mmol), and the reaction mixture was stirred at room temperature for 4 hours. Then, water (100 ml) was added to the reaction mixture which was then extracted with ethyl acetate (100 ml). The extract was washed with water (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give (E)-2-[2-(2,5-dimethylphenoxy-methyl)phenyl]-2-methoxyimino-N-methylacetamide (0.57 g) as colorless crystals (yield, 69.8%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@H:19]2[CH2:23][CH2:22][N:21]([CH3:24])[C:20]2=[O:25])[CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].[N:26]1([C:30]([C:32]2[CH:33]=[N:34][C:35](Cl)=[C:36]([Cl:38])[CH:37]=2)=[O:31])[CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[N:26]1([C:30]([C:32]2[CH:37]=[C:36]([Cl:38])[C:35]([O:1][C:2]3[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@H:19]4[CH2:23][CH2:22][N:21]([CH3:24])[C:20]4=[O:25])[CH:17]=3)[C:5]([NH:7][C:8]3[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])=[N:34][CH:33]=2)=[O:31])[CH2:29][CH2:28][CH2:27]1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cnc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Temperature: 120 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A mixture of 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide (Intermediate 18) (136 mg, 0.4 mmol), azetidin-1-yl-(5,6-dichloropyridin-3-yl)methanone (Intermediate 21) (103 mg, 0.44 mmol) and potassium carbonate (111 mg, 0.8 mmol) in DMA (5 mL) was stirred at 120° C. for 2 hours. The solution was evaporated under reduced pressure, the residue dissolved in ethyl acetate (40 mL) washed with water (2×20 mL), brine (20 mL), dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography on silica, eluting with a gradient of 0-4% methanol in DCM to afford the product (188 mg, 87%). 1H NMR δ (300 MHz, CDCl3) 2.16-2.29 (m, 1H), 2.40 (quintet, 2H), 2.50-2.72 (m, 4H), 2.95 (s, 3H), 3.36-3.58 (m, 2H), 4.18-4.42 (m, 4H), 4.95 (t, 1H), 7.15 (s, 1H), 7.37 (s, 1H), 7.55 (s, 1H), 8.15 (s, 2H), 8.25 (s, 1H), 8.55 (s, 1H), 9.54 (s, 1H); m/z 537 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:18][C:19](=O)[CH3:20]>C(O)C>[CH3:20][C:19]1[C:12]2[C:13](=[O:15])[CH2:14][CH:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:10][C:11]=2[O:16][CH:18]=1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Cc1coc2c1C(=O)CC(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15 %

Procedure:
To 60% sodium hydride (0.22 g, washed with hexane thrice) was added ethanol (30 ml). To the mixture was added 5-phenylcyclohexane-1,3-dione (1.0 g) and then was added chloroacetone (0.49 g) at 0° C., and the mixture was stirred at room temperature for 20 minutes and refluxed for 13 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give colorless crystals of 3-methyl-6-phenyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.18 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@@H:10]([NH2:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH3:2].C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:42]([C:38]2[CH:37]=[C:36]3[C:41](=[CH:40][CH:39]=2)[N:33]([CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:21]4[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:31][CH:30]=2)[C:34]([CH3:46])=[C:35]3[CH3:45])=[O:43])[CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: CCOc1cccc([C@H](C)N)c1
Product: CCOc1cccc([C@H](C)NC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(3-ethoxyphenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 545 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH2:37]([S:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])=[O:40])[CH3:38]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:45]3[CH2:44][CH2:43][N:42]([S:39]([CH2:37][CH3:38])(=[O:40])=[O:41])[CH2:47][CH2:46]3)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([CH3:30])([CH3:31])[C:32]#[N:33])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CCS(=O)(=O)N1CCNCC1
Product: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(S(=O)(=O)CC)CC1

Procedure:
2-{3-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-(4-ethanesulfonyl-piperazine-1-carbonyl)-4,5-dihydro-1H-imidazol-2-yl]-4-ethoxy-phenyl}-2-methyl-propionitrile was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12e) and 1-ethanesulfonyl-piperazine (example 14) in an analogous manner as described in example 25. LR-MS: 682.3 [(M+H)+]
Reaction SMILES: [C@H:1]1([CH2:11][OH:12])[C@@H:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.O>CN(C=O)C>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:12][CH2:11][C@H:1]2[C@@H:10]3[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]3)[CH2:4][CH2:3][CH2:2]2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OC[C@@H]1CCCN2CCCC[C@H]12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OC[C@@H]2CCCN3CCCC[C@H]23)cc1
Reaction time: 2 h

Procedure:
(1R,9aR)-1-(Octahydroquinolizin-1-yl)methanol (2.5 g) was added to a suspension of sodium hydride (60% in oil, 710 mg) in DMF (20 ml) and, after gas evolution ceased, 4-fluoronitrobenzene (2.51 g) was added. After 2 hours, the reaction mixture was hydrolyzed with water and then partitioned between ethyl acetate and dilute hydrochloric acid. The aqueous phase was made alkaline with sodium hydroxide solution and extracted twice with ethyl acetate. The two ethyl acetate phases were combined, dried over magnesium sulfate and concentrated. The product with the molecular weight of 290.37 (C16H22N2O3); MS (ESI): 291 (M+H+) was obtained in this way.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][CH:6]1[CH:15]=[CH:14][C:13]2[CH:12]=[N:11][CH:10]=[CH:9][C:8]=2[C:7]1=O>Cl>[NH:3]1[C:7]2[C:8]3[CH:9]=[CH:10][N:11]=[CH:12][C:13]=3[CH2:14][CH2:15][C:6]=2[NH:5][C:2]1=[O:1]
Reactant: N#C[O-]
Reactant: NC1C=Cc2cnccc2C1=O
Agent: Cl
Agent: [K+]
Product: O=c1[nH]c2c([nH]1)-c1ccncc1CC2
Reaction time: 2 h
Yield: 25.8 %

Procedure:
Potassium cyanate (8.63 g, 0.106 mole) was added to a solution of 6-aminoisoquinolin-5-one (5.0 g, 0.0213 mole) in hydrochloric acid (pH=1) while maintaining the acidity constant by subsequent addition of concentrated hydrochloric acid. After stirring for about 11/2 hours, the product precipitated andwas obtained by filtration. Recrystallization from 50% aqueous ethanol gave 1.03 g (25%) of the desired product, m.p. >310° C.
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([C:20]([OH:22])=O)=[C:5]([C:15](OCC)=[O:16])[CH:6]=[N:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.[NH2:24][NH2:25]>C(O)C>[OH:2][C:3]1[C:4]2[C:20](=[O:22])[NH:25][NH:24][C:15](=[O:16])[C:5]=2[CH:6]=[N:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1cnc(-c2ccccc2)c(O)c1C(=O)O
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=c1[nH][nH]c(=O)c2c(O)c(-c3ccccc3)ncc12

Procedure:
A mixture of 2 g. ethyl 5-hydroxy-6-phenylpyridine3,4-dicarboxylate. hydrochloride, 40 ml ethanol and 4 ml hydrazine hydrate was refluxed for 4 hours. After cooling, the pale yellow crystals were recovered by filtration, suspended in 20 ml of water and made acid with dilute hydrochloric acid. The crystals were recovered by filtration, rinsed with water and dried. The procedure provided 1.2 g of 8-hydroxy-7-phenylpyrido[3,4-d]pyridazine-1,4-(2H,3H)-dione, melting point: more than 300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:5]([NH2:6])=[C:4]([F:12])[C:3]=1[F:13].[H][H]>[Ni].C(O)C>[Cl:1][C:2]1[C:3]([F:13])=[C:4]([F:12])[C:5]([NH2:6])=[C:7]([NH2:9])[CH:8]=1
Reactant: Nc1c([N+](=O)[O-])cc(Cl)c(F)c1F
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(Cl)c(F)c(F)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-2,3-difluoro-6-nitroaniline (11.4 g, 54.4. mmol), Raney nickel (Aldrich, Milwaukee, slurry in water, 2.2 g wet) and ethanol (200 mL) were combined in a stirred Parr reactor which was pressurized with hydrogen (250 psig). The mixture was allowed to stir at rt overnight, after which time the reactor was depressurized and the mixture was filtered through Celite and the solvents were removed in vacuo. The remaining residue was dissolved in ethyl acetate, dried over magnesium sulfate and the solvents were removed in vacuo to afford a brownish solid (11.6 g, crude weight); 1H NMR (DMSO-d6) δ: 6.43 (d, J=5.7 Hz, 1H, Ar—H), 5.25 (very br s, 4H, overlapping NH2).
Reaction SMILES: [NH2:1][C@@:2]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH2:6][C@@H:5]([O:7][CH3:8])[CH2:4][C@H:3]1[CH2:9][OH:10].[C:18]1([CH2:31][O:32][C:33]([N:35]=[C:36]=[S:37])=[O:34])[C:30]2[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1>ClCCl>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C@:2]1([NH:1][C:36]([NH:35][C:33](=[O:34])[O:32][CH2:31][CH:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:30][C:29]=3[C:28]3[C:27]2=[CH:26][CH:25]=[CH:24][CH:23]=3)=[S:37])[CH2:6][C@@H:5]([O:7][CH3:8])[CH2:4][C@H:3]1[CH2:9][OH:10]
Reactant: CO[C@H]1C[C@@H](CO)[C@](N)(c2ccccc2F)C1
Reactant: O=C(N=C=S)OCc1cccc2c1Cc1ccccc1-2
Solvent: ClCCl
Product: CO[C@H]1C[C@@H](CO)[C@](NC(=S)NC(=O)OCC2c3ccccc3-c3ccccc32)(c2ccccc2F)C1
Yield: 67.4 %

Procedure:
A solution of [(1R*,2S*,4S*)-2-amino-2-(2-fluorophenyl)-4-methoxycyclopentanyl]methanol (225 mg) and fluorenylmethyloxycarbonyl isothiocyanate (316 mg) in dichloromethane (18 mL) was stirred at room temperature for three days. The reaction solution was purified by silica gel column chromatography to obtain the title compound (330 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([CH2:15][CH3:16])[CH:9]([OH:14])[CH2:10][N+:11]([O-:13])=[O:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][Si:26](Cl)([CH3:28])[CH3:27]>ClCCl>[C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([CH2:15][CH3:16])[CH:9]([O:14][Si:26]([CH3:28])([CH3:27])[CH3:25])[CH2:10][N+:11]([O-:13])=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C[N+](=O)[O-]
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(NC(=O)OC(C)(C)C)C(C[N+](=O)[O-])O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.7 %

Procedure:
To a mixture of (1-ethyl-2-hydroxy-3-nitro-propyl)-carbamic acid tert-butyl ester (1.83 g, 7.37 mmol) and triethylamine (1.49 g, 14.75 mmol) in dry dichloromethane (25 mL) under N2 is added trimethylsilyl chloride (1.20 g, 11.05 mmol). The mixture is stirred at room temperature for 24 h, then diluted with 40 mL of dichloromethane and washed with water (40 mL). The organic layer is dried over magnesium sulfate and concentrated in vacuum. The residue is purified over 110 g silica gel, eluted with ethyl acetate: heptane (1:4) to afford (1-ethyl-3-nitro-2-trimethylsilanyloxy-propyl)-carbamic acid tert-butyl ester (1.505 g, 86%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[CH:5][P:4](C2C=CC=CC=2)[CH:3]=1.[C:14]1([C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:7][C:6]1[C:2]2([CH3:1])[CH2:3][P:4]([C:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:20]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cp(-c2ccccc2)cc1C
Reactant: C(#Cc1ccccc1)c1ccccc1
Product: CC1=C(c2ccccc2)P2CC1(C)C(c1ccccc1)=C2c1ccccc1

Procedure:
The starting compound 3,4-dimethyl-2,5,6-triphenyl-1-phosphanorbornadiene required for the preparation of NORBOS can be obtained according to the prior art in good yield in a two-stage synthesis. In the first process step, phenyldichlorophosphine or phenyldibromophosphine, or a mixture thereof, is reacted with dimethylbutadiene to give the 1-halo-2,5-dihydrophospholium salt, which is dehydrohalogenated by 2-methylpyridine to give 3,4-dimethyl-1-phenylphosphole. The reaction of the phosphole with diphenylacetylene in the second process step produce 3,4-dimethyl-2,5,6-triphenyl-1-phosphanorbornadiene.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2I)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:30][CH:31]1[CH2:36][CH2:35][CH:34](B(O)O)[CH:33]([CH3:40])[NH:32]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2[C:34]2[C:33]([CH3:40])=[N:32][C:31]([F:30])=[CH:36][CH:35]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC1NC(F)CCC1B(O)O
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-(6-chloro-4-iodo-3-pyridinyl)-N,2-dimethylpropanamide (200 mg, 0.363 mmol), 2-fluoro-6-methylpiperidine-5 boronic acid (73 mg, 0.472 mmol), sodium carbonate solution (0.4 mL, 2M), tetrakistriphenylphosphinepalladium (4 mg, 0.00363 mmol) in dioxan (2 mL) were heated together in the microwave at 110° C. for 30 minutes. The mixture was partitioned between EtOAc and sat NaHCO3 solution. Aqueous layer extracted with EtOAc×3. Combined extracts dried and evaporated. Residue purified on a 12+M horizon column eluting with Pet Et2O to 60% EtOAc/Pet Et2O, Solvent evaporated under reduced pressure to afford the title compound in quantitative yield.