Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.[NH2:13][C:14]1[C:15](Cl)=[N:16][CH:17]=[CH:18][CH:19]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:15]2[C:14]([NH2:13])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: Nc1cccnc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CC#N
Product: COc1ccc(Cl)cc1-c1ncccc1N
Temperature: 25 °C

Procedure:
The 500 mL round-bottom flask, equipped with magnetic stirrer and reflux condenser was charged with 5-chloro-2-methoxyphenylboronic acid (9.78 g, 52 mmol), 3-amino-2-chloropyridine (7.00 g, 55 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos, 0.43 g, 2 mol %), palladium (II) acetate (112 mg, 1 mol %), potassium carbonate (21.7 g, 157 mmol), 180 mL of acetonitrile and 20 ml of water. The flask was filled with nitrogen and heated to reflux under nitrogen atmosphere for 24 hours. Then the reaction was cooled down to room temperature, diluted with 500 mL of water and extracted with ethyl acetate (5×40 mL). Organic fractions were combined, dried over sodium sulfate, filtered and evaporated. The residue was subjected to column chromatography on silica gel with eluent hexane/ethyl acetate gradient mixture, providing 2-(5-chloro-2-methoxyphenyl)pyridin-3-amine as white crystals (9.5 g, NMR confirmed the structure).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](O)=[O:11].S(Cl)(Cl)=O.C[N:27](C=O)C>>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([NH2:27])=[O:11]
Reactant: O=C(O)c1cc(Oc2ccc(F)cc2F)ccc1[N+](=O)[O-]
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cc(Oc2ccc(F)cc2F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of compound (1B) (53 g, 0.18 mol), thionyl chloride (51.3 mL) and DMF (1 mL) was stirred at room temperature for 18 h, then concentrated in vacuo to dryness. This acid chloride (60.7 g) was dissolved in THF (400 mL), and NH4OH (235 mL) was added. The mixture was then stirred for 18 h and concentrated in vacuo. The residue was purified by flash chromatography eluting with hexane:EtOAc (4:1) to afford 27.7 g of 5-(2,4-difluoro-phenoxy)-2-nitro-benzamide (1C).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]([CH3:15])([CH2:13][OH:14])[CH2:11][OH:12].[BH4-].[Na+].[OH-].[Na+]>CO.C(OCC)(=O)C>[CH2:1]([NH:9][C:10]([CH3:15])([CH2:13][OH:14])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(N)(CO)CO
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(CO)(CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzaldehyde (17.4 ml) was added dropwise to a solution of 2-amino-2-methyl-1,3-propanediol (20 g) in methanol (200 ml) at 0° C. and the whole was stirred at room temperature for 2 hours. Sodium borohydride (11.5 g) was added thereto in portions at 0° C. and the mixture was stirred for 10 minutes. 1N Sodium hydroxide solution and ethyl acetate were added and the organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo to give 2-benzylamino-2-methyl-1,3-propanediol (28.54 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([CH2:11][CH2:12][CH2:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Cl:31].O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:21])[C:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Cl:31])([CH2:11][CH2:12][CH2:13][C:14]([F:19])([F:20])[C:15]([F:17])([F:18])[F:16])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: ClCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCCCCCl)(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
To a solution of (4,4,5,5,5-pentafluoropentyl)malonic acid diethyl ester (1 g, 3.12 mmol) in tetrahydrofuran (15 ml) was added sodium hydride (175 mg, 4.37 mmol), which was then stirred for 30 min at rt. 1-Bromo-6-chlorohexane (0.7 ml, 4.68 mmol) was added to this reaction mixture and the reaction mixture was refluxed overnight. When the reaction was completed, water was added to the reaction mixture and extracted with ethyl acetate. Then, the organic layer was washed with water and saturated sodium chloride solution. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=30:1) to give the title compound (760 mg, yield: 56%) as a colorless liquid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[NH:15][CH2:14][CH2:13][NH:12][C:11]2=[O:16])=[CH:2]1.[CH3:17][O:18]C=O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[N:15]([CH:17]=[O:18])[CH2:14][CH2:13][NH:12][C:11]2=[O:16])=[CH:2]1
Reactant: COC=O
Reactant: O=C1NCCNC1c1c[nH]c2ccccc12
Product: O=CN1CCNC(=O)C1c1c[nH]c2ccccc12

Procedure:
21.5 g (0.1 mol) of 3-(3-indolyl)-piperazin-2-one (Example 30) are formylated with methylformate, as described in Example 5.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[O:4]1[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[CH2:27]([OH:30])[CH2:28][OH:29]>O>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:29][CH2:28][CH2:27][OH:30]
Reactant: CCCCCCCCCCC1CO1
Reactant: OCCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Solvent: O
Product: OCCCCCCCCCCCCOCCO
Temperature: 52.5 °C
Reaction time: 0.25 h
Yield: 98.1 %

Procedure:
Separately, a 100 ml mixing vessel equipped with a calcium chloride-containing tube was charged with 36.9 g (0.20 mole) of 1,2-epoxydodecane. While the charged 1,2-epoxydodecane was stirred and cooled with water, concentrated sulfuric acid was gradually dropped in an amount of 0.4 g (0.004 mole) into the cooled 1,2-epoxydodecane. After stirring for 15 minutes, the resultant mixture was placed into the dropping apparatus attached to the reaction vessel and was dropped into the ethylene glycol contained in the reaction vessel and maintained at a temperature of 50 to 55° C. over a time of 2 hours. Then the reaction of the mixture was carried out at a temperature of 50 to 55° C. for one hour. After the exhaustion of the starting material, namely 1,2-epoxydodecane, was confirmed by a thin-layer chromatography, the reaction was stopped. A saturated aqueous sodium hydrogen carbonate solution was mixed in an amount of 50 ml into the resultant reaction liquid in the reaction vessel, the resultant mixture was stirred for 10 minutes to neutralize the reaction liquid. The reaction liquid was subjected to an extraction procedure using diethyl ether to extract the reaction product. The resultant extraction liquid was concentrated by using a rotary evaporator. An ethylene glycol monohydroxydodecyl ether mixture was obtained in an amount of 48.3 g (yield: 98.1%).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[Br:7][C:8]1[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][CH:9]=1.C(N(CC)CC)C>C1COCC1>[OH:4][CH2:3][CH:2]([NH:1][S:13]([C:11]1[S:12][C:8]([Br:7])=[CH:9][CH:10]=1)(=[O:15])=[O:14])[CH2:5][OH:6]
Reactant: NC(CO)CO
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(NC(CO)CO)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
To a stirred solution of 2-amino-1,3-propanediol (1.26 g, 13.8 mmol) in THF (20 ml) was added at 0° C. (ice water bath) commercially available 5-bromo-thiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) and triethylamine (0.71 ml, 5.07 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) to yield the title compound (0.87 g, 72%) as a white solid. MS (ISN) 313.9 [(M−H)−], mp 80° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)N.N([O-])=[O:12].[Na+]>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([OH:12])[CH:8]=1
Reactant: O=N[O-]
Reactant: Cc1cc(Br)cc(N)c1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(Br)cc(O)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.6 %

Procedure:
10.00 g of 5-bromo-2,3-dimethylaniline (3-11) was dissolved in a mixed solution of 50 ml of 25% sulfuric acid and 50 ml of toluene, and under cooling with ice, 20 ml of aqueous solution of 3.80 g of sodium nitrite was dropped thereto. The resulting mixture was stirred at the same temperature for 1 hour, and then stirred at 100° C. for 1 hour, and thereafter, the reaction solution was poured into ice water and extracted with ethyl acetate and the resulting organic layer was washed with saturated salt water, and thereafter, the resulting organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=9:1) to obtain 5.49 g of 5-bromo-2,3-dimethylphenol (3-17).
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:45])[N:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]4[CH:26]=[C:25]([NH:27][C:28]5[CH:33]=[CH:32][C:31]([C:34]([N:36]6[CH2:41][CH2:40][O:39][CH2:38][CH2:37]6)=[O:35])=[CH:30][N:29]=5)[C:24](=[O:42])[N:23]([CH3:43])[N:22]=4)[C:16]=3[CH3:44])[CH:11]=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+]>CO.Cl>[C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:45])[N:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]4[CH:26]=[C:25]([NH:27][C:28]5[CH:33]=[CH:32][C:31]([C:34]([N:36]6[CH2:41][CH2:40][O:39][CH2:38][CH2:37]6)=[O:35])=[CH:30][N:29]=5)[C:24](=[O:42])[N:23]([CH3:43])[N:22]=4)[C:16]=3[CH3:44])[CH2:11][NH:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)n2)cccc1-n1cnc2cc(C(C)(C)C)ccc2c1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)n2)cccc1N1CNc2cc(C(C)(C)C)ccc2C1=O
Reaction time: 0.75 h
Yield: 61.1 %

Procedure:
To a mixture of 7-tert-Butyl-3-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-3H-quinazolin-4-one (11 mg, 0.018 mmol) and sodium cyanoborohydride (1.3 mg, 0.019 mmol) in 1 mL methanol was added 1 drop of 2M hydrochloric acid in methanol to bring the pH to 3. After stirring for 45 minutes, the resulting mixture was partitioned between ethylacetate and dilute aqueous NaHCO3. The ethylacetate layer was washed with brine, dried over anhydrous MgSO4, concentrated in vacuo, and purified by preparative TLC (5% MeOH/CH2Cl2) to yield 7-tert-Butyl-3-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2,3-dihydro-1H-quinazolin-4-one (6.5 mg, 0.011 mmol). MS (ESI) 608 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:26]=[CH:27][CH:28]=2)[C:19]([F:34])=[CH:18][N:17]=1>C(O)CCC>[C:30]([NH:29][C:25]1[CH:24]=[C:23]([NH:22][C:20]2[C:19]([F:34])=[CH:18][N:17]=[C:16]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=3)[N:21]=2)[CH:28]=[CH:27][CH:26]=1)(=[O:33])[CH:31]=[CH2:32]
Reactant: C=CC(=O)Nc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: CCOC(=O)COc1ccc(N)cc1
Solvent: CCCCO
Product: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(OCC(=O)OCC)cc3)ncc2F)c1
Yield: 19.5 %

Procedure:
A solution of ethyl 2-(4-aminophenoxy)acetate (0.801 g) and N-(3-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)acrylamide (1.0 g) in 1-butanol (10 mL) was heated to 135° C. for 2 hr. The reaction was monitored on TLC using hexanes:ethyl acetate (3:7) as mobile phase. After completion of the reaction, butanol was removed under reduced pressure and water was added. The mixture was extracted with ethyl acetate and the organic layer was dried over sodium sulfate and solvent was removed under reduced pressure. Crude material was purified by Combiflash chromatography and eluted with 29% ethyl acetate in hexane to give 0.30 g of ethyl 2-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)acetate.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].C(O)C>CCN(CC)CC>[CH3:1][O:2][CH2:3][C@H:4]([OH:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: COCC(=O)CC(=O)OC
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC[C@H](O)CC(=O)OC
Yield: 99.8 %

Procedure:
In a 10 liter autoclave were put 1473 g (10.08 mol) of methyl 4-methoxy-3-oxobutyrate, 2210 ml of ethanol, and 4.59 g (5.09 mmol) of Ru2Cl4((S)-Tol-BINAP)2.NEt3, and asymmetric hydrogenation was carried out at 100° C. under a hydrogen pressure of 4000 kPa for 4 hours (conversion: 100%). The solvent was removed by evaporation to yield 1490 g of the title compound as liquid.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9]C)=[O:8])[O:4][N:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.[OH-].[Na+].Cl>CN(C=O)C>[CH3:11][O:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[O:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)no1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COc1cc(C(=O)O)on1
Temperature: 25 °C

Procedure:
To a solution of methyl 3-hydroxyisoxazole-5-carboxylate (958 mg, 6.69 mmol) in DMF (10 ml) was added potassium carbonate (935 mg, 6.76 mmol) at −5° C. Then dimethyl sulfate (644 μL, 6.76 mmol) was added slowly. The reaction mixture was allowed to warm to room temperature and was stirred over night. Then 2N NaOH (5.02 mL, 10.0 mmol) was added and the mixture was stirred for 4 h. After slow addition of 2N HCl (6.69 mL, 13.4 mmol), the mixture was extracted three times with diethyl ether. The combined organic extracts were washed with brine and evaporated. The remaining yellow oil was co-evaporated four times with toluene to give a solid that was dried for 4 h at 40° C. under high vacuum. The title compound as obtained as light brown solid (576 mg, 60%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([NH:9][CH2:10][CH3:11])[CH:8]=1)#[N:2].Cl.[CH2:13]([OH:16])[CH2:14][CH3:15]>>[CH2:10]([NH:9][C:7]1[CH:8]=[C:3]([C:1](=[NH:2])[O:16][CH2:13][CH2:14][CH3:15])[CH:4]=[N:5][CH:6]=1)[CH3:11]
Reactant: CCCO
Reactant: CCNc1cncc(C#N)c1
Agent: Cl
Product: CCCOC(=N)c1cncc(NCC)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Into a solution of 3-cyano-5-ethylaminopyridine (380 mg, 2.59 mmol) in 1-propanol (40 ml) was passed hydrogen chloride gas under ice-cooling for 30 minutes. The reactor was tight sealed, and the mixture was stirred at room temperature for 20 hours and concentrated under reduced pressure. After the residue was neutralized with a saturated aqueous sodium carbonate solution and extracted with chloroform (50 ml×3). The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product of propyl 5-ethylamino-3-pyridinecarboximidate. The crude product was then dissolved in acetonitrile (5 ml) and an aqueous solution (18 ml) of cyanamide (210 mg, 5.0 mmol), Na2HPO4 (355 mg, 2.5 mmol) and NaH2PO4 ·2H2O (1.56 g, 10 mmol) was added to the solution, and the mixture was stirred at room temperature over night. After the reaction was completed, the reaction mixture was extracted with chloroform (30 ml×3), and the chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (Wako Gel C-200, 30 g; eluted with hexane/ethyl acetate) to give propyl N-cyano-5-ethylamino-3-pyridinecarboximidate (322 mg, 1.38 mmol) as a colorless oil (Yield 54%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:21])=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>CN(C)C=O>[Br:1][C:2]1[C:3]([O:21][CH2:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(Br)c(O)cc2N1
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CN=C(c2ccccc2Cl)c2cc(Br)c(OCCCN3CCOCC3)cc2N1
Temperature: 50 °C
Reaction time: 73 h
Yield: 69.8 %

Procedure:
A mixture of 1.8281 g (0.005 mole) of 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-hydroxy-2H-1,4-benzodiazepin-2-one (Ipp) from the previous step, 0.636 g of sodium carbonate, 0.9818 g (0.006 mole) of 4-(3-chloropropyl)-morpholine and 50 mL of dimethylformamide was stirred at 50° C., under an argon atmosphere for 73 hours. The mixture was then cooled and partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous layer was then reextracted with ethyl acetate. The ethyl acetate layers were washed successively with saturated sodium bicarbonate, water, brine and then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-(3-(4-morpholinyl)propoxy)-2H-1,4-benzodiazepin-2-one (Ij). Pure 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-(3-(4-morpholinyl)propoxy)-2H-1,4-benzodiazepin-2-one (Ij) (1.721 g) was obtained by silica gel chromatography eluting with ethyl acetate-methanol (90:10). MH+/Z=492.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:4]([NH:13][CH:14]2[CH2:16][CH2:15]2)[CH:3]=1.[CH:17]([O-])([O-])OCC>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[S:9](=[O:10])(=[O:11])[N:12]=[CH:17][N:13]([CH:14]3[CH2:16][CH2:15]3)[C:4]=2[CH:3]=1
Reactant: CCOC([O-])[O-]
Reactant: NS(=O)(=O)c1cc(Cl)c(Cl)cc1NC1CC1
Product: O=S1(=O)N=CN(C2CC2)c2cc(Cl)c(Cl)cc21
Temperature: 150 °C

Procedure:
In a round-bottom flask, a mixture of 4,5-dichloro-2-cyclopropylaminobenzenesulphonamide from the Step above (2.5 g) and ethyl orthoformate (25 mL) is heated in the open state at 150° C. for 1 hour. The suspension obtained is cooled on an ice bath, and the insoluble material is collected by filtration, washed with ether and dried. The solid is re-dissolved in a mixture of acetone and methanol in the hot state and the hot solution is treated with absorbent carbon and then filtered and concentrated to dryness. The residue is recrystallised from methanol.
Reaction SMILES: [Br:1]Br.[CH:3]([S:6]([N:9]1[C:13]2[CH:14]=[C:15]([C:18]3[N:22]([CH:23]4[CH2:25][CH2:24]4)[CH:21]=[N:20][C:19]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH2:33])(=[O:8])=[O:7])([CH3:5])[CH3:4]>C(Cl)(Cl)Cl>[CH:3]([S:6]([N:9]1[C:13]2[CH:14]=[C:15]([C:18]3[N:22]([CH:23]4[CH2:24][CH2:25]4)[C:21]([Br:1])=[N:20][C:19]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH2:33])(=[O:8])=[O:7])([CH3:5])[CH3:4]
Reactant: BrBr
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3c(-c4ccccc4F)ncn3C3CC3)cc21
Solvent: ClC(Cl)Cl
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3c(-c4ccccc4F)nc(Br)n3C3CC3)cc21
Reaction time: 18 h
Yield: 78.1 %

Procedure:
Add bromine (0.34 mL, 6.545 mmol) dropwise over 5 minutes to a solution of 1-isopropylsulfonyl-2-amino-6-(1-(cyclopropyl)-4-(2-fluorophenyl)-imidazol-5-yl)-benzimidazole (2.61 g, 5.95 mmol) in chloroform (0.7 L) and stir for 18 hours. Wash with water, saturated sodium bicarbonate, dry with magnesium sulfate, filter and remove solvents under reduced pressure. Purify the residue on silica gel eluting with ethyl acetate/dichloromethane mixtures to provide the title compound (2.41 g). MS(ES+): m/z=518.0 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[CH:20]=[C:19]([CH2:21][N:22]3[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]3)[CH:18]=[CH:17][N:16]=2)[CH:6]=[C:7]([O:13][CH3:14])[C:8]=1[O:9][CH:10]([CH3:12])[CH3:11].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1>>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][C:19]3[CH:18]=[CH:17][N:16]=[C:15]([C:5]4[CH:6]=[C:7]([O:13][CH3:14])[C:8]([O:9][CH:10]([CH3:11])[CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:20]=3)[CH2:23][CH2:24]2)=[CH:33][CH:32]=1
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC(C)C
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC(C)C)c(OC)c4)c3)CC2)cc1

Procedure:
1-[[2-(3,5-dimethoxy-4-isopropoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (350 mg) and p-anisidine (123 mg) were condensed in the same manner as described in Preparation Example 37 to give the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12]C)[C:8](=[O:14])[CH2:7][CH2:6]2.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[OH:12])[C:8](=[O:14])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1CCc2cc(O)c(O)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Asolution of 5,6-dimethoxyindan-1-one (Compound 3a)(19 g, 0.094 mole) in 200 mL of methylene chloride was cooled at −78° C. with a dry-ice/iPrOH bath. To this solution was then added 200 mL (0.2 mole) of a 1 M solution of BBr3 in CH2Cl2 dropwise. The resulting solution was stirred at −78° C. for 1 hr and then at 0° C. for 1 hr. The solution was then cooled back to −78° C. with a dry-ice/iPrOH bath and quenched with 50 mL of MeOH. The solution was evaporated on a rotary evaporator to dryness, the solid was re-dissolved in MeOH and concentrated again for two more times. The red solid, the title compound, was used in subsequent reactions without further purification. MS m/z 165 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[OH:23][C:24]1[CH:32]=[N:31][CH:30]=[CH:29][C:25]=1[C:26](O)=O>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[CH2:26][C:25]3[CH:29]=[CH:30][N:31]=[CH:32][C:24]=3[OH:23])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Reactant: O=C(O)c1ccncc1O
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3Cc3ccncc3O)c21

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 3-hydroxyisonicotinic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.45 (m, 1H), 1.52-1.74 (m, 4H), 1.84 (m, 1H), 3.19 (m, 2H), 4.18 (dd, 1H, J=10.2, 4.0 Hz), 4.64 (t, 1H, J=10.0 Hz), 5.25 (m, 1H), 6.61 (d, 1H, J=8.2 Hz), 6.87 (d, 1H, J=8.2 Hz), 7.08 (d, 1H, J=5.5 Hz), 7.46 (t, 1H, J=8.2 Hz), 7.84 (br s, 1H), 8.07 (d, 1H, J=5.5 Hz), 8.19 (s, 1H), 8.29 (br s, 1H), 10.28 (s, 1H), 10.9 (br s, 1H). MS 432 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][N:6]1[C:13]([NH:14][NH:15][C:16]([NH:18][CH3:19])=S)=[CH:12][C:10](=[O:11])[N:9]([CH2:20][CH2:21][CH3:22])[C:7]1=[O:8].CO>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][N:6]1[C:13]2[NH:14][N:15]=[C:16]([NH:18][CH3:19])[C:12]=2[C:10](=[O:11])[N:9]([CH2:20][CH2:21][CH3:22])[C:7]1=[O:8]
Reactant: CCCn1c(=O)cc(NNC(=S)NC)n(Cc2cccc(Cl)c2)c1=O
Solvent: CN(C)C=O
Solvent: CO
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2cccc(Cl)c2)c1=O
Yield: 71.8 %

Procedure:
A solution of 1-(3-chlorobenzyl)-6-(4-methylthiosemicarbazido)-3-propyluracil (3.81 g, 10 mM) in DMF (40 ml) was stirred at 100° C. for 20 hours. To the reaction solution was added 50% methanol (20 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol gave colorless crystals (2.49 g, 72%), m.p. 263°-265° C.