Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([S:13][CH3:14])=[N:11][C:10]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[CH:27]=O.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH3:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[CH2:27][NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([S:13][CH3:14])=[N:11][C:10]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccsc1C=O
Reactant: CSc1nc(-c2ccncc2)nn1-c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CSc1nc(-c2ccncc2)nn1-c1ccc(NCc2sccc2C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A stirred solution of 1-(4-aminophenyl)-5-methylthio-3-(4-pyridyl)-1H-1,2,4-triazole (Example 1) (100 mg, 0.35 mmol) and 3-methylthiophene-2-carboxaldehyde (44 mg, 0.35 mmol) in 5% acetic acid in MeOH (4 mL) at room temperature was treated with sodium cyanoborohydride (55 mg, 0.88 mmol) and the reaction mixture was further stirred at room temperature for 48 h. The reaction mixture was concentrated, diluted with EtOAc, washed with NaHCO3 solution, brine and dried (MgSO4). The residue obtained on concentration was flash chromatographed on silica gel and eluted with a gradient of dichloromethane/acetone (9/1 to 3/1). The title compound was obtained as a white solid (85 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C>O1CCCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:21]([OH:26])[OH:22])=[CH:3][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-bromoanisole (2 g) in tetrahydrofuran (THF, 32 ml), which was cooled to -78° C., was added a hexane solution of n-butyllithium (0.83 M, 13.5 ml). The solution was stirred 15 minutes, at which time triisopropyl borate (8.6 ml) was added. The solution was stirred for 15 minutes, at which time the solution was allowed to warm to room temperature. Stirring was continued for 12 hrs. The solution was then washed into a hydrochloric acid solution (1M, 60 ml) with a small amount of THF. This solution was stirred an additional 2 hours, and was then extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate, and the solvent was removed in vacuo to yield a white solid.
Reaction SMILES: [N:1]#[C:2]Br.Cl.[CH3:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7].C(N(CC)CC)C>C(Cl)Cl>[CH3:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([C:2]#[N:1])[CH2:25][CH2:24]3)=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)(=[O:8])=[O:7]
Reactant: N#CBr
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C#N)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
Cyanogen bromide (3.0M in CH2Cl2, 0.1 mL, 0.3 mmol) was added dropwise to a mixture of 4-({[4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)piperidine hydrochloride (prepared as in Example 2, Step 1, 100 mg, 0.3 mmol) and triethylamine (0.083 mL, 0.6 mmol) in CH2Cl2 (5 mL) at ambient temperature. The reaction mixture was stirred at ambient temperature for 1 h and concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 5% MeOH/CH2Cl2 to give 60 mg (54%) of 4-({[4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)-1-piperidinecarbonitrile as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.97 (d, 2H, J=8.4 Hz), 7.72 (d, 2H, J=8.6 Hz), 7.55 (d, 2H, J=8.8 Hz), 6.98 (d, 2H, J=8.6 Hz), 3.87 (d, 2H, J=6.2 Hz), 3.58-3.47 (m, 2H), 3.08 (s, 3H), 1.96-1.86 (m, 2H), 1.53 (bs, 5H); LRMS (ESI), m/z 393 (M+Na).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:39]([O:40][CH3:41])=[CH:38][C:26]2[CH2:27][CH2:28][N:29]([CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[CH2:30][CH2:31][C:25]=2[CH:24]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:22][C:23]2[C:39]([O:40][CH3:41])=[CH:38][C:26]3[CH2:27][CH2:28][N:29]([CH2:32][C:33](=[O:34])[N:35]([CH3:36])[CH3:37])[CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1cc(OC)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Product: CNC(=O)c1cc(OC)ccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(=O)N(C)C)CC3)ncc1Cl

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-methoxy-N-methyl-benzamide of Example 607 was reacted with 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide, in a similar manner as Example 601b, to yield desired product 2-[5-Chloro-2-(3-dimethylcarbamoylmethyl-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-5-methoxy-N-methyl-benzamide as a lyophylate (29%); 1H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H, exchangeable), 9.85 (bs, 1H, exchangeable), 8.77 (d, J=4.72 Hz, 1H, exchangeable), 8.39 (d, J=8.84 Hz, 1H) 8.27 (s, 1H, exchangeable), 8.17 (s, 1H), 7.66 (s, 1H), 7.31 (s, 1H), 6.98 (m, 2H), 4.33 (s, 2H), 3.86 (s, 3H), 3.82 (s, 3H), 3.7-3.5 (m, 2H), 3.4-3.0 (m, 4H), 2.95 (s, 6H), 2.80 (d, J=4.30 hz, 3H); MS (m/e) 568.43 (M+H).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1.CN(C)C(=O)C>O>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Yield: 77 %

Procedure:
A mixture of 17.6 parts of 1-(phenylmethyl)piperazine, 8.4 parts of ethyl 4-fluorobenzoate and 45 parts of N,N-dimethylacetamide was stirred and refluxed for 22 hours. The reaction mixture was cooled and poured onto 500 parts of water. The product was extracted three times with benzene. The combined extracts were washed three times with a lot of water, dried, filtered and evaporated. The residue was stirred in hexane. The product was filtered off, washed with hexane and dried in vacuo, yielding 12.5 parts (77%) of ethyl 4-[4-(phenylmethyl)-1-piperazinyl]benzoate (intermediate 2).
Reaction SMILES: COC[O:4][C:5]1[C:6]([C:16](=[O:18])[CH3:17])=[CH:7][C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:9][CH:10]=1.CC(O)C.C1COCC1>Cl>[OH:4][C:5]1[C:6]([C:16](=[O:18])[CH3:17])=[CH:7][C:8]([CH2:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[N:9][CH:10]=1
Reactant: COCOc1cnc(CC(C)(C)C)cc1C(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(=O)c1cc(CC(C)(C)C)ncc1O

Procedure:
A solution of 1-(5-(methoxymethoxy)-2-neopentylpyridin-4-yl)ethanone (21.6 g, 86 mmol) in (2:1:1) 5 M HCl:i-PrOH:THF (800 mL) was stirred 4 h at rt. The mixture was concentrated to remove the THF and i-PrOH. The resulting solution consisting of the product in aqueous HCl was quenched by slow addition to a solution of saturated aqueous NaHCO3 (500 mL) containing excess solid NaHCO3 (50 g). The aqueous layer was extracted with CH2Cl2 (3×250 mL), the organic layers combined and washed with saturated aqueous NaCl (250 mL), dried (MgSO4), and concentrated to give 1-(5-hydroxy-2-neopentylpyridin-4-yl)ethanone as a brown oil.
Reaction SMILES: Br.[CH3:2][C:3]1[N:4]=[C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2C(OCC2C=CC=CC=2)=O)[O:6][CH:7]=1.CCOCC>CC(O)=O>[CH3:2][C:3]1[N:4]=[C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[O:6][CH:7]=1
Reactant: Cc1coc([C@H]2CCCN2C(=O)OCc2ccccc2)n1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1coc([C@H]2CCCN2)n1
Reaction time: 1 h

Procedure:
HBr in AcOH (60 mL) was added to (R)-benzyl 2-(4-methyloxazol-2-yl)pyrrolidine-1-carboxylate (neat) at room temperature. After 1 h, ether (20 mL) was added slowly with vigorous string. Stirring was continued for 10 min and allowed to settle for 5-10 min. The supernatant was decanted. This process was repeated 3-4 times until the supernatant was colourless. The semi-solid was dissolved in water (50 mL) and brought to pH ˜8 with 1N LiOH and extracted with 5% MeoH/95% CHCl3
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:9][CH:10]=2)[N+:5]([O-:17])=[CH:4][CH:3]=1.[OH-:18].[K+]>>[OH:18][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:9][CH:10]=2)[N+:5]([O-:17])=[CH:4][CH:3]=1
Reactant: [O-][n+]1ccc(Cl)c2ccc(OC(F)(F)F)cc21
Reactant: [OH-]
Agent: [K+]
Product: [O-][n+]1ccc(O)c2ccc(OC(F)(F)F)cc21

Procedure:
4-Chloro-7-trifluoromethoxyquinoline-1-oxide (9.4 g) and potassium hydroxide (20.0 g) were dissolved in industrial methylated spirit (320 ml) and the solution was heated under reflux for 90 minutes. The solvent was removed by evaporation and the residue dissolved in water (100 ml). Glacial acetic acid (40 ml) was added at 0 to 5°, the precipitate collected, washed with water (2×10 ml) and crystallised from methanol (120 ml) to give the novel compound 4-hydroxy-7-trifluoromethoxyquinoline-1-oxide, m.p. 80°-181°.
Reaction SMILES: Br/[C:2](=[CH:8]\[CH3:9])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:6]([O:5][C:3](=[O:4])/[CH:2]=[CH:8]/[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:7]
Reactant: C/C=C(\Br)C(=O)OCC
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)/C=C/CN1CCCCC1
Yield: 79.6 %

Procedure:
A mixture of ethyl bromocrotonate (193 mg), piperidine (94 mg) and potassium carbonate (276 mg) in acetonitrile (10 ml) was stirred and heated at reflux for 3 hours. The reaction mixture was cooled and the solvent was removed in vacuo. The residue was partitioned between water (2×15 ml) and ethyl acetate (20 ml). The organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as an orange oil (157 mg). Tlc Silica. (100:8:1)Mixture of dichloromethane, ethanol and ammonia (S.G=0.88) Rf=0.55 Mass spec MH+ (found)=198 MH+ (calculated)=198.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH:10]1[C:15]([C:16]2[C:25](=[O:26])[C:24]3[CH:23]=[CH:22][C:21]([OH:27])=[CH:20][C:19]=3[O:18][CH:17]=2)=[CH:14][CH:13]=[C:12]([OH:28])[CH:11]=1.O>C(O)C>[OH:27][C:21]1[CH:20]=[C:19]2[C:24]([C:25](=[O:26])[C:16]([C:15]3[CH:10]=[CH:11][C:12]([OH:28])=[C:13]([N+:6]([O-:9])=[O:7])[CH:14]=3)=[CH:17][O:18]2)=[CH:23][CH:22]=1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: O=c1c(-c2ccc(O)c([N+](=O)[O-])c2)coc2cc(O)ccc12

Procedure:
20 ml of a mixture of concentrated sulfuric acid and nitric acid (3:1) are added dropwise to a solution of 1 g of daidzein in 200 ml of dry ethanol at room temperature while stirring vigorously. The mixture is stirred for another 2 hours, and 400 ml of water are then added. The compound precipitates, is filtered off with suction and washed with water until neutral. The yellow product is recrystallized from alcohol.
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.Br[CH2:9][CH2:10][CH2:11]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:9][CH2:10][CH2:11][S:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)=[N:5][N:4]=[N:3]1
Reactant: BrCCCBr
Reactant: Cn1nnnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCSc1nnnn1C
Yield: 66.7 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (4.6 g) and 1,3-dibromopropane (4 g) are dissolved in acetone (50 ml). To the mixture is added potassium carbonate (5.5 g), and the mixture is refluxed for 3 hours. After acetone is distilled off, water is added to the residue, and the precipitated crystals are separated by filtration and recrystallized from ethanol to give 1-methyl-5-[3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiopropyl]thio-1,2,3,4-tetrazole (3.6 g) as colorless prisms, m.p. 141.5°-143.5° C.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:19])(=O)=O>C(Cl)(Cl)Cl>[Cl:19][C:4]1[CH:3]=[C:2]([F:1])[CH:15]=[CH:14][C:5]=1[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(=O)c1ccc(F)cc1Cl
Yield: 88.3 %

Procedure:
A mixture of 10.5 g (0.05 mole) of ethyl p-fluorobenzoylacetate, 6.7 g (0.05 mole) of sulfuryl chloride and 30 ml. of chloroform was held at reflux for 18 hours and cooled. The chloroform solution was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 10.8 g (88%) of ethyl 2-chloro-(p-fluoro)-benzoylacetate as an oil. A mixture of 10.8 g (0.441 mole) of ethyl 2-chloro-(p-fluoro)-benzoylacetate, 3.36 g (0.0441 mole) of thiourea, 20 ml. of water and 10 ml. of ethanol was held at reflux for 3 hours. Ethanol was removed under reduced pressure. The residue was made basic with saturated sodium bicarbonate. The solid was filtered, washed with water and recrystallized from ethanol to give 8.9 g (76%) of ethyl 2-amino-4-(p-fluorophenyl)-5-thiazolecarboxylate as white prisms, m.p. 205°-208° C.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[O:6]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[O:6]([C:13]1[CH:14]=[CH:15][C:16]([N:17]([CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])[CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])=[CH:18][CH:19]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: ClCC1CO1
Solvent: CCO
Product: OC(CCl)CN(CC(O)CCl)c1ccc(Oc2ccccc2)cc1
Reaction time: 6 h

Procedure:
To a four-necked flask equipped with a thermometer, a dropping funnel, a cooling tube, and a stirrer was charged with 610.6 g (6.6 mol) of epichlorohydrin, and then the inside of the four-necked flask was purged with nitrogen. In 1018.5 g of ethanol was dissolved 203.7 g (1.1 mol) of 4-phenoxyaniline powder. The temperature of the epichlorohydrin was raised to 70° C. and the ethanolic solution of 4-phenoxyaniline was dropped over 4 hours. Moreover, the reaction was continued at 70° C. for six hours under stirring to produce 4-phenoxy-N,N-bis(2-hydroxy-3-chloropropyl)aniline.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][CH2:8][C@@H:9]([NH:15][C:16](=O)OC(C)(C)C)[C@H:10]([OH:14])[CH2:11][S:12][CH3:13]>O1CCCC1>[CH3:16][NH:15][C@@H:9]([C@H:10]([OH:14])[CH2:11][S:12][CH3:13])[CH2:8][OH:7]
Reactant: CSC[C@@H](O)[C@@H](CO)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN[C@H](CO)[C@H](O)CSC
Reaction time: 8 h
Yield: 55.9 %

Procedure:
Lithium aluminium hydride (3 ml, 2M in THF, 6.0 mmol) was added dropwise to a solution of tert-butyl(2R,3S)-1,3-dihydroxy-4-(methylthio)butan-2-ylcarbamate (316 mg, 1.3 mmol) in tetrahydrofuran (5 ml) and the resulting suspension heated to reflux and left overnight. The reaction was cooled to ambient, quenched with water (0.25 ml), 15% aq NaOH (0.25 ml), and water (0.75 ml) and the resulting white suspension left to stir for 30 minutes. The suspension was then filtered through Celite®, washed with hot ethyl acetate, and the filtrate concentrated in vacuo to afford a mobile oil. The residue was purified by flash chromatography on silica gel eluting with 5% 7 N NH3 in MeOH/DCM to afford the title compound as an oil (120 mg, 57%). 1H NMR (CDCl3) δ 3.78 (m, 2H), 3.58 (dd, J=11.5, 3.9 Hz, 1H), 2.78 (dd, J=13.6, 4.3 Hz, 1H 1H), 2.64 (dd, J=13.6, 8.2 Hz, 1H), 2.50 (m, 1H), 2.47 (s, 3H), 2.15 (s, 3H). 13C NMR (CDCl3) δ 70.4, 64.5, 61.0, 39.7, 35.3, 16.6.
Reaction SMILES: [C:1]([CH:4]([S:6][C:7](=[N:9][OH:10])[CH3:8])[CH3:5])(=[O:3])[NH2:2].[CH3:11][N:12]=[C:13]=[O:14]>C(N(CC)CC)C.CC(C)=O>[CH3:11][NH:12][C:13]([O:10][N:9]=[C:7]([S:6][CH:4]([C:1](=[O:3])[NH2:2])[CH3:5])[CH3:8])=[O:14]
Reactant: CN=C=O
Reactant: CC(=NO)SC(C)C(N)=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CNC(=O)ON=C(C)SC(C)C(N)=O
Reaction time: 48 h
Yield: 74 %

Procedure:
A mixture of 4.0 g (0.0247 m) of 1-(1-carbamoylethylthio)acetaldoxime, 75 ml of dry acetone, 4.0 g (0.07 m) of methyl isocyanate, and 2 drops of triethylamine was allowed to stand at room temperature, with occasional shaking, for two days. The acetone and excess methyl isocyanate were removed from the product under reduced pressure. The white solid residue was recrystallized from ethanol and then dried at room temperature to give 4.0 g (74% yield) of 1-(1-carbamoylethylthio]acetaldehyde O-(methylcarbamoyl)oxime; melting point=161°-163° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([Cl:18])[CH:12]=3)[CH:7]=1.C([O-])(O)=O.[Na+].Cl[C:30]([O:32][C:33]([CH3:35])=[CH2:34])=[O:31]>CCOC(C)=O>[Cl:22][C:5]1[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([Cl:18])[CH:12]=3)=[CH:7][C:2]([NH:1][C:30](=[O:31])[O:32][C:33]([CH3:35])=[CH2:34])=[C:3]([F:23])[CH:4]=1
Reactant: C=C(C)OC(=O)Cl
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(Cl)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(Cl)cc3n(CC)c2=O)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A bi-phasic mixture of Example A3 (250 mg, 0.710 mmol) in EtOAc (10 mL) and satd. NaHCO3 (15 mL) was treated with isopropenyl chloroformate 9120 mg, 0.984 mmol) and stirred at RT for 2 h. The layers were separated, the organic layer washed with water, then brine, dried over Na2SO4 and concentrated to dryness to afford prop-1-en-2-yl (4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)carbamate (292 mg, 94% yield). MS (ESI) m/z: 436.0 [M+H]+.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:14]=[C:15]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].C([O:29][B:30](OCC)[O:31]CC)C.[Cl-].[NH4+]>O1CCCC1>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][C:15]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:14][C:13]=1[B:30]([OH:31])[OH:29]
Reactant: COc1ccc(-c2ccncc2)cc1Br
Reactant: CCOB(OCC)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccncc2)cc1B(O)O
Temperature: -80 °C
Reaction time: 0.25 h

Procedure:
A solution of n-butyllithium in hexane (1.7 mL of 2.5 M, 4.25 mmol) is added to a stirred solution of 4-(3-bromo-4-methoxyphenyl)pyridine (Example 1 b; 1.06 g, 4 mmol) and triethylborate (0.62 g, 4.2 mmol) in dry tetrahydrofuran (20 mL) at -85° C. under an argon atmosphere. The mixture is stirred for 15 min at -80° C., then treated with a saturated aqueous solution of ammonium chloride (60 mL) and extracted with ethyl acetate (2×80 mL). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from ethyl acetate-hexane to give 2-methoxy-5-(pyridin-4-yl)phenylboronic acid as a beige crystalline solid. m.p. 194-200° C. and having the following physical characteristics:
Reaction SMILES: [C:1]1([C:7]2[N:20]=[N:19][C:18]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:11](=O)[NH:10][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:23]>P(Cl)(Cl)(Cl)=O>[Cl:23][C:11]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[C:18]2[N:19]=[N:20][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9]=2[N:10]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cc(-c3ccccc3)nnc2c2ccccc12
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nc2cc(-c3ccccc3)nnc2c2ccccc12
Reaction time: 3.5 h
Yield: 80 %

Procedure:
Phosphorus oxychloride (760 ml), 3-phenyl-pyridazino[4,3-c]isoquinolin-6(5H)-one (74 g, 0.27 mol) and phosphorus pentachloride (58 g, 0.278 mol) in a 2 litre flask are heated to reflux temperature with stirring. Heating is continued for about 3.5 hours, then a solution is obtained which is evaporated under reduced pressure to eliminate the phosphorus oxychloride excess. The solid is taken up with benzene and then evaporated to dryness in order to eliminate all the unreacted phosphorus oxychloride. Then the reaction mass is taken up with methylene chloride (1500 ml) and washed with 10% aqueous ammonium acetate (two times; first with 800 ml and then with 400 ml), and subsequently with water up to neutrality. The methylene chloride phase is dried on magnesium sulfate and the solvent is evaporated under reduced pressure. The solid residue is disaggregated and washed with methylene chloride (300 ml) and filtered, yielding 6-chloro-3-phenyl-pyridazino-[4,3-c]isoquinoline (63 g). By concentrating the mother liquors to dryness and crystallizing the obtained solid from acetone, 11 g of the same product is obtained. These two crops of 6-chloro 3-phenylpyridazino[4,3-c]isoquinoline derivatives are pooled and recrystallized from acetone, with a 90% overall yield. The product has a melting point of 177°-178° C.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:35]2[CH2:34][CH2:33][N:32]([C:25]3[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:24]=3[O:23][CH3:22])[CH2:37][CH2:36]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: COc1ccc(N2CCNCC2)c(OC)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccc(OC)cc3OC)CC2)c(OC)nc1C
Yield: 77 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,4-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]([NH:14][NH2:15])=[O:13])[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1.[N-]=C=O>ClCCl>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:15][NH:14][C:12](=[O:13])[CH2:11][C@@H:8]2[CH2:9][CH2:10][N:6]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:7]2)=[O:25])=[CH:19][CH:18]=1
Reactant: NNC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Reactant: O=C=Nc1ccc(Br)cc1
Agent: [N-]=C=O
Solvent: ClCCl
Product: O=C(C[C@@H]1CCN(C(=O)C2CC2)C1)NNC(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 27 h
Yield: 67.1 %

Procedure:
In a round bottom flask under nitrogen, a solution of 2-[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (52.6 g, 249 mmol) in dichloromethane (356 mL) was cooled to 0° C. and 4-bromophenylisocyanate (49.3 g, 249 mmol) was added. Once the isocyanate dissolved, the cooling bath was removed and the reaction was allowed to warm to room temperature and was stirred for 27 h. White precipitate formed quickly. The reaction was filtered to collect the white precipitate, washed with 50 mL cold dichloromethane, and air dried. The white solid was washed with additional cold dichloromethane (300 mL) and dried under vacuum suction overnight to provide the title compound (108.29 g, 63% pure, 167 mmol, 67% yield). MS(ES)+ m/e 409.2, 411.2 [M+H]+.
Reaction SMILES: C[CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[CH2:15](Cl)Cl>[O-2].[O-2].[Mn+4]>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:2][C:3]([O:5][CH3:15])=[O:4])=[CH:8][CH:9]=1)=[O:14]
Reactant: CC(Cc1ccc(CO)cc1)C(=O)O
Reactant: ClCCl
Agent: [Mn+4]
Agent: [O-2]
Product: COC(=O)CCc1ccc(C=O)cc1
Reaction time: 0.25 h

Procedure:
To a solution of Intermediate B (300 mg, 1.54 mmol) in DCM (25 mL) was added manganese dioxide (2.98 g, 34 mmol). The mixture was stirred for 15 minutes, and then filtered through Celite and washed with additional DCM (100 mL). The filtrate was concentrated to yield the desired product. This was used directly in the next stage without further purification or characterisation.