Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](Br)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Mg].[C:17]([C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=1)([CH3:20])([CH3:19])[CH3:18].Cl[P:34](Cl)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[P:41](Cl)Cl>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([P:34]([C:7]2[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[P:41]([C:7]2[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=2)[C:23]2[CH:22]=[C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:24]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Reactant: ClP(Cl)c1ccccc1P(Cl)Cl
Reactant: CC(C)(C)c1cc([Mg]Br)cc(C(C)(C)C)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(P(c2cc(C(C)(C)C)cc(C(C)(C)C)c2)c2ccccc2P(c2cc(C(C)(C)C)cc(C(C)(C)C)c2)c2cc(C(C)(C)C)cc(C(C)(C)C)c2)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,5-Di-tert-butylbromobenzene (12.50 g, 46.43 mmol) was added dropwise to magnesium (1.70 g, 69.96 mmol) and THF (50 mL) in an argon atmosphere. After the dropwise addition, the mixture was heated under reflux for 1 hour. The reaction mixture was cooled to ambient temperature and filtered, and the thus-obtained THF solution of 3,5-di-tert-butylphenylmagnesium bromide, and 1,2-bis(dichlorophosphino)benzene (2.00 g, 7.15 mmol) were reacted as in Production Example 1. The reaction was allowed to proceed overnight at 60° C. After purification, the title compound was obtained as a white powder (4.66 g, yield 73%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[C:10]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=23)=[N:11][C:12]([NH:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19](F)=[CH:18][C:17]=2[O:26][CH3:27])=[N:13][CH:14]=1>FC(F)(F)CO>[Cl:8][C:9]1[C:10]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=23)=[N:11][C:12]([NH:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:18][C:17]=2[O:26][CH3:27])=[N:13][CH:14]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: CN1CCNCC1
Solvent: OCC(F)(F)F
Product: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 140 °C
Yield: 99.5 %

Procedure:
1-Methylpiperazine (0.267 mL, 2.41 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 500 mg, 1.21 mmol) in 2,2,2-trifluoroethanol (6 mL). The mixture was heated in a microwave at 140° C. for 1 h. The mixture was then loaded onto a SCX column, and the column was washed with CH3OH. The column was then eluted with 2M methanolic ammonia and appropriate fractions were combined and concentrated in vacuo. Further purification by FCC, eluting with 0-10% CH3OH in CH2Cl2 gave the title compound (596 mg, 100%), as an orange foam; 1H NMR: (CDCl3) 2.37 (3H, s), 2.57-2.68 (4H, m), 3.08-3.14 (4H, m), 4.00 (3H, s), 6.64 (1H, s), 6.98 (1H, t), 7.34-7.43 (1H, m), 7.53 (1H, s), 8.41 (1H, s), 8.49 (1H, d), 8.53-8.6 (1H, m), 8.93 (1H, s), 9.04 (1H, s); m/z: ES+ MH+ 495.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[C:14](I)[CH:15]=[CH:16][C:7]=3[C:6]=2[N:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32]>CN1CCCC1=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[C:14]([NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[C:29]([O:28][CH3:27])[CH:30]=4)[CH:15]=[CH:16][C:7]=3[C:6]=2[N:18]=1
Reactant: Nc1ncc2c(n1)-c1ccc(I)cc1NC(=O)C2
Reactant: COc1cccc(N)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cccc(Nc2ccc3c(c2)NC(=O)Cc2cnc(N)nc2-3)c1
Temperature: 90 °C
Yield: 60.8 %

Procedure:
2-Amino-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (200 mg, 0.568 mmol, 1.0 equiv), anhydrous K3PO4 powder (241 mg, 1.14 mmol, 2.0 equiv) and palladium bis-tri-t-butyl phosphine (58 mg, 0.1136 mmol, 20 mol %) were combined in a sealable vial with a magnetic stir bar under a nitrogen atmosphere (glove box). 3-Methoxyaniline (209 mg, 1.70 mmol, 3.0 equiv) was added, followed by 6 mL of anhydrous N-methylpyrrolidinone. The vial was sealed with a silicone lined crimp cap and removed from the glove box. The vial was sonicated for 2 minutes and then heated to 90° C. (oil bath temperature) for 18 hours. The dark brown solution was diluted with 50 mL of water and the brown solids were collected by filtration and washed with water and then diethyl ether. Purification by silica gel chromatography (10% methanol, 85% dichloromethane, 5% formic acid) afforded an orange powder, which was recrystallized from methanol and diethyl ether to yield 120 mg (61%) of 2-amino-9-(3-methoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-225) as a yellow-orange powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:16]=[C:17]([O:21][CH2:22][C:23](O)=[O:24])[CH:18]=[CH:19][CH:20]=3)[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:26].[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][NH2:36])[CH2:29][CH2:28]1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCC[N+](C)(C)C.[I-]>ClC(Cl)C.CN(C)C=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:16]=[C:17]([O:21][CH2:22][C:23]([NH:36][CH2:35][CH2:34][CH2:33][N:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)=[O:24])[CH:18]=[CH:19][CH:20]=3)[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:26]
Reactant: NCCCN1CCOCC1
Reactant: Cc1cc(-c2cc(-c3cccc(OCC(=O)O)c3)[nH]c(=O)n2)ccc1O
Agent: CCN=C=NCCC[N+](C)(C)C
Agent: On1nnc2ccccc21
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: Cc1cc(-c2cc(-c3cccc(OCC(=O)NCCCN4CCOCC4)c3)[nH]c(=O)n2)ccc1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 20.9 %

Procedure:
({3-[6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl]phenyl}-oxy)acetic acid (Compound 222, 17 mg, 48 umol) and 3-morpholinopropan-1-amine (5.8 mg, 40 umol) were dissolved in dichloroethane (1.25 mL) and N,N-dimethylformamide (0.79 mL). To this solution was added 1-hydroxybenzotriazole (6.8 mg, 50 umol) followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (17.8 mg, 60 umol). The reaction mixture was stirred at room temperature for 15 hours and was concentrated in vacuo. The reaction mixture was purified by reverse phase HPLC to give 4 mg of product. 1H NMR (400 MHz, d6-DMSO): δ 8.31 (s, 1H), 8.17 (t, 1H), 7.96 (s, 1H), 7.87 (dd, 1H), 7.75 (d, 1H), 7.68 (s, 1H), 7.47 (t, 1H), 7.38 (s, 1H), 7.17 (dd, 1H), 6.92 (d, 1H), 4.61 (s, 2H), 3.61 (t, 4H), 3.21-3.16 (m, 2H), 2.30-2.22 (m, 6H), 2.20 (s, 3H), 1.63-1.57 (m, 2H). MS (EI): 480 (MH+).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[N:5][CH:4]=1)=[O:2].[NH2:16][C@H:17]([C:19]([NH:21][C@H:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH3:23])=[O:20])[CH3:18].Cl.C(Cl)CCl.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>C(Cl)Cl>[CH:1]([C:3]1[S:7][C:6]([NH:8][CH:9]([CH:13]([CH3:15])[CH3:14])[C:10]([NH:16][C@@H:17]([CH3:18])[C:19]([NH:21][C@@H:22]([CH3:23])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:20])=[O:12])=[N:5][CH:4]=1)=[O:2]
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Reactant: CC(C)[C@H](Nc1ncc(C=O)s1)C(=O)O
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)C(Nc1ncc(C=O)s1)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.1 %

Procedure:
To a material from Example 20 (560 mg, 1.227 mmol), H-Ala-Ala-OtBu.HCl (300 mg, 1.187 mmol), EDC (341 mg, 1.780 mmol), and 1-hydroxy-7-azabenzotriazole (97 mg, 0.712 mmol) in CH2Cl2 (12 mL) is added N-methylmorpholine (0.783 mL, 7.12 mmol) and the resulting solution is allowed to stir at room temp for 18 h. The solvent is removed in vacuo and the residue is purified by BIOTAGE® Silica gel chromatography on a 25 g Thompson Single Step silica cartridge using a linear gradient from 100% CH2Cl2 to 100% EtOAc over 12 column volumes to give 213 mg (42.1%) of the title compound as an off-white solid. LC/MS (Condition A): ret. T=3.17 min, (M+H)+ 427.22.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[N:2].Cl[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]>C(O)C>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCO
Product: N#Cc1ccc(Nc2ccncc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
According to the method of J.C.S. Perkin Trans. I, 1979, 135, p-cyanoaniIine (6 894 g, 58.4 mmol) was added to a solution of 4-chloro-3-nitropyridine (9.26 g, 58.4 mmol) in ethanol (200 ml) and the mixture was stirred at room temperature for 18 hours. The resulting yellow suspension was poured into 500 ml of ice-cold dilute ammonia and filtered The solid was treated with 150 ml of boiling ethanol, cooled in ice, and filtered to give the title compound as a bright yellow powder, (12.15 g), m.p. 210°-211° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[CH:11])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH2:16].[N:18]1[CH:23]=[CH:22]N=N[N:19]=1>ClCCCl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]2[CH:22]=[CH:23][N:18]=[N:19][CH:11]=2)[C:7]([C:12]([F:13])([F:15])[F:14])=[CH:6][C:5]=1[NH2:16]
Reactant: C#Cc1cc(C(=O)OC)c(N)cc1C(F)(F)F
Reactant: c1cnnnn1
Solvent: ClCCCl
Product: COC(=O)c1cc(-c2ccnnc2)c(C(F)(F)F)cc1N
Temperature: 25 °C
Yield: 40.2 %

Procedure:
A solution of 2-amino-5-ethynyl-4-trifluoromethyl-benzoic acid methyl ester (150 mg, 0.62 mmol) and tetrazine (55.7 mg, 0.68 mmol) in 1,2-dichloroethane (3 mL) in a sealed tube was heated in the microwave at 130° C. for 40 min and at 120° C. for 40 min. After cooling to r.t., the solvent was removed in vacuo. The residue was purified by flash chromatography (10 g silica gel, hexanes→EtOAc:hexanes (2:3)) to provide 2-amino-5-pyridazin-4-yl-4-trifluoromethyl-benzoic acid methyl ester (74 mg, 40%) as a solid. API-ES: m/z 298 [M+H]+, rt 3.54 min.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:18]O>>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: CO
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc([N+](=O)[O-])c1C
Temperature: 0 °C

Procedure:
To 2-methyl-3-nitrobenzoic acid (10.0 g) is added methanol (100 ml) and thereto thionyl chloride (8 ml) is added dropwise at room temperature. After reflux for 2 hours, the reaction mixture is poured into ice-water and extracted with dichloromethane. The solvent is concentrated to give methyl 2-methyl-3-nitrobenzoate (10.8 g).
Reaction SMILES: C([N:8]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:25])[CH:19]=2)[C:15]2[C:10](=[C:11]([NH:27][CH:28]=[O:29])[C:12]([OH:26])=[CH:13][CH:14]=2)[CH2:9]1)C1C=CC=CC=1.[ClH:30]>C(O)C>[ClH:30].[OH:25][C:20]1[CH:19]=[C:18]([CH:16]2[C:15]3[C:10](=[C:11]([NH:27][CH:28]=[O:29])[C:12]([OH:26])=[CH:13][CH:14]=3)[CH2:9][NH:8][CH2:17]2)[CH:23]=[CH:22][C:21]=1[OH:24]
Reactant: O=CNc1c(O)ccc2c1CN(Cc1ccccc1)CC2c1ccc(O)c(O)c1
Agent: Cl
Solvent: CCO
Product: O=CNc1c(O)ccc2c1CNCC2c1ccc(O)c(O)c1
Yield: 82.4 %

Procedure:
450 mg of 2-benzyl-4-(3,4-dihydroxyphenyl)-8-formamido-7-hydroxy-1,2,3,4-tetrahydroisoquinoline was dissolved in 9 ml of ethanol, and after adding thereto 0.86 ml of 2N hydrochloric acid 0.05 g of 10% paradium-carbon, hydrogenation reaction was performed at room temperature. The hydrogenation reaction was over, the reaction mixture was filtered, and concentrated. The residue was changed to precipitates with treatment of isopropyl alcohol and acetonitrile, and the precipitates was collected by filtration, affording 320 mg of 4-(3,4-dihyroxyphenyl)-8-formamido-7-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][C:6]2[CH:7]([O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.C(N(CC)CC)C.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][C:6]2[CH:7]([O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=3)[CH2:8][N:9]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CCOC(=O)Cl
Reactant: COc1cc2c(cc1OC)C(Oc1ccc(C(F)(F)F)cc1)CNCC2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCc2cc(OC)c(OC)cc2C(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C

Procedure:
To a cooled solution of 7,8-dimethoxy-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine (5.5 g, 0.015 mole) and triethylamine (1.7 g, 0.017 mole) in chloroform (70 ml) was slowly dropped a solution of ethyl chloroformate (1.0 g, 0.017 mole) in chloroform (20 ml). After stirring twenty hours at ambient temperature the reaction mixture was concentrated to an oil which was dissolved in ether, washed with water, dilute HCl, again twice with water, then dried (saturated NaCl, anhydrous MgSO4). The solution was filtered then concentrated to a solid (5.0 g, 76%, m.p. 120° C.) of which a sample was twice recrystallized from hexanes to yield 7,8-dimethoxy-3-ethoxycarbonyl-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine, m.p. 130°-131° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][C:6]([CH2:9][N:10]=[C:11]=[O:12])([CH3:8])[CH2:5][CH:4]([N:13]=[C:14]=[O:15])[CH2:3]1.[OH2:17].[CH3:18][CH:19]([OH:21])[CH3:20]>>[CH3:1][C:2]1([CH3:16])[CH2:7][C:6]([CH2:9][N:10]=[C:11]=[O:12])([CH3:8])[CH2:5][CH:4]([N:13]=[C:14]=[O:15])[CH2:3]1.[CH3:3][CH:4]([NH2:13])[CH2:5][O:17][CH2:18][CH:19]([O:21][CH2:18][CH:19]([O:21][CH2:5][CH:4]([NH2:13])[CH3:3])[CH3:20])[CH3:20]
Reactant: CC(C)O
Reactant: O
Agent: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Product: CC(N)COCC(C)OCC(C)OCC(C)N

Procedure:
The same experimental procedures were repeated. A mixture of IPDI (22.2 g, 0.10M) in i-PrOH (11.2 g) was added into the solution of D-230 (46 g, 0.20M) in i-PrOH (18 g) and water (5 g) over a 3 hour period at 20°-30° C. The resulting product solution was analyzed to be 1.88 meq/g for amine (calc. 1.95 meq/g).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[C:10](=[O:20])[C:11]4[C:16]([O:17][C:18]=3[CH:19]=2)=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:4][N:3]=[N:2]1.[N+:21]([O-])([O-:23])=[O:22].[K+]>S(=O)(=O)(O)O>[N+:21]([C:13]1[CH:14]=[CH:15][C:16]2[O:17][C:18]3[C:9](=[CH:8][CH:7]=[C:6]([C:5]4[NH:1][N:2]=[N:3][N:4]=4)[CH:19]=3)[C:10](=[O:20])[C:11]=2[CH:12]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1c2ccccc2oc2cc(-c3nnn[nH]3)ccc12
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1c2ccc(-c3nnn[nH]3)cc2oc2ccc([N+](=O)[O-])cc12
Temperature: 20 °C
Reaction time: 1 h

Procedure:
3-(5-Tetrazolyl)xanthone (1.0 g) was dissolved in concentrated sulphuric acid (10.0 ml) and the resulting solution cooled to below 15° C. Potassium nitrate (0.50 g) was added in small portions over 10 min. with cooling to maintain the temperature between 10° and 15° C. and the reaction mixture was then stirred at 20° C. for 1 hr. The reaction mixture was poured on to ice and the precipitated product filtered off, washed with water and recrystallised from dimethylformamide. The crystallised product was washed with methanol and dried at 156° C./20 mm Hg to yield 0.78 g, mpt. ca. 280° C. with decomposition.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.FC(F)(F)C(O)=O.[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][N:29]([CH2:32][CH2:33][CH2:34][CH3:35])[C:28](=[O:36])[CH:27]=1.C(N(CC)CC)C>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][N:29]([CH2:32][CH2:33][CH2:34][CH3:35])[C:28](=[O:36])[CH:27]=1
Reactant: CCCCn1ccc(CN)cc1=O
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCCCn1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1=O

Procedure:
A mixture of (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (170 mg, 0.51 mmol) and 4-aminomethyl-1-butyl-1H-pyridin-2-one trifluoroacetate (150 mg, 0.51 mol) is stirred in dimethylformamide (2.7 mL) at room temperature in the presence of triethylamine (0.33 mL) for 18 hours. The reaction mixture is concentrated under reduced pressure. The residue is purified via semi-preparative HPLC (Prodigy ODS3 column, 5% acetonitrile/95% water/0.01% trifluoroacetic acid to 100% acetonitrile at 10 mL/min) to give (4Z)-6-iodo-4-({[(1-butyl-2-oxo-1,2-dihydropyridin-4-yl)methyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione as an peach colored solid (25 mg, 10% due to substantial loss of material during HPLC malfunction).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.CN(C=[N:16][S:17]([CH2:20][CH:21]([CH:24]([CH3:26])[CH3:25])[CH2:22][OH:23])(=[O:19])=[O:18])C>>[ClH:1].[CH:24]([CH:21]([CH2:20][S:17](=[O:19])(=[O:18])[NH2:16])[CH2:22][O:23][C:2]1[C:3]([CH3:11])=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1)([CH3:26])[CH3:25]
Reactant: Cc1cc2nccn2nc1Cl
Reactant: CC(C)C(CO)CS(=O)(=O)N=CN(C)C
Product: Cc1cc2nccn2nc1OCC(CS(N)(=O)=O)C(C)C
Product: Cl

Procedure:
Using 0.8 g of 6-chloro-7-methylimidazo[1,2-b]pyridazine and 1.29 g of 3-(N,N-dimethylaminomethylene)aminosulfonyl-2-isopropyl-1-propanol, 1.37 gof the title compound was obtained in the same manner as in Examples 14 and
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N#C[Cl:22].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1>C1C=CC=CC=1>[Cl-:22].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][P+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:26][CH:25]=1
Reactant: Cc1ccc(S)cc1
Reactant: N#CCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Cc1ccc(S[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Cl-]
Reaction time: 0.33 h

Procedure:
To a suspension of 10.8 g. of the triphenylphosphine/cyanogen chloride reaction product, (C6H5)3P(CN)Cl in 100 ml. of benzene at 5°-10°C. was added a solution of 4.2 g. of p-methylthiophenol in 15 ml. of benzene. After addition was complete, the clear solution was held at 45°C. for 20 minutes. The benzene was removed in vacuo at room temperature to leave p-methylphenylthiotriphenylphosphonium chloride.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].C=O.[CH:24](O)=O.[OH-].[Na+]>O.C(O)C>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=1)[CH3:24])[CH2:20][CH3:21]
Reactant: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCN(CCC)CCCCN(C)Cc1ccc(C#N)cc1
Yield: 94.8 %

Procedure:
16 g (56 mmol, 1.0 equivalent) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a), 50 ml of ethanol, 11.9 g (139 mmol, 2.5 equivalents) of a formaldehyde aqueous solution (35%), and 12.8 g (278 mmol, 5 equivalents) of formic acid were charged in a 300 ml four-necked flask. The mixture was reacted at 80° C. for one hour. The raw material was then disappeared. The reaction solution was slowly added to a solution prepared by dissolving 40 g of sodium hydroxide in 200 ml of distilled water. The reaction solution was extracted with 200 ml of chloroform. This operation was repeated twice. The chloroform layer was then dried over anhydrous sodium sulfate. The solvent was then concentrated, thereby obtaining 16 g of 4-[(4-dipropylaminobutyl)methylamino]methylbenzonitrile (2b) as a slightly yellow oily substance (yield: 95%). [HPLC: 99% (HPLC measurement conditions A)]
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Oc1ccc(F)cc1F
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(F)cc1F
Reaction time: 2 h
Yield: 97 %

Procedure:
104 g (796 mmol) of 2,4-difluorophenol was dissolved in 800 ml of dichloromethane, 132 ml of triethylamine and 92.0 ml of ethyl chloroformate were added under ice-cooling and the mixture was stirred at -10° to 0° C. for 2 hours. The reaction solution was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 156 g (97%) of 2,4-difluoro-O-ethoxycarbonylphenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:19]=[N+]=[N-])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[ClH:42]>O1CCCC1.C(OCC)(=O)C>[ClH:42].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:19])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(N=[N+]=[N-])c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(N)c2cccc([N+](=O)[O-])c2)cc1

Procedure:
Triphenylphosphinie (20.5 g) was added in small portions to a solution of α-(4-methoxyphenyl)-3-nitrobenzyl azide (18.5 g) [prepared as described in step (a) above] in anhydrous tetrahydrofuran (100 ml). When the triphenylphosphine was dissolved and the evolution of nitrogen had ceased, water (20 ml) was added to the reaction mixture and this mixture was heated under reflux for 6 hours. At the end of this time, the tetrahydrofuran of the reaction mixture was removed by evaporation under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column using a 2:1 by volume mixture of hexane and ethyl acetate as the eluant, to afford a colorless oil. This oil was dissolved in a solution of hydrogen chloride in ethyl acetate (4N). The ethyl acetate was evaporated to dryness. The residue was suspended in diisopropyl ether and filtered to afford the title compound (13.8 g) as a white solid.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[CH2:26][C:27]([OH:29])=[O:28].C(N(CC)CC)C>O>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26](=[CH:14][C:13]1[CH:16]=[CH:17][C:10]([S:9][CH3:8])=[CH:11][CH:12]=1)[C:27]([OH:29])=[O:28]
Reactant: CSc1ccc(C=O)cc1
Reactant: O=C(O)Cc1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CSc1ccc(C=C(C(=O)O)c2ccc(F)cc2F)cc1
Temperature: 90 °C
Yield: 42.2 %

Procedure:
A mixture of acetic anhydride (50 mL), 4-(methylthio)benzaldehyde (3.75 g, 24.6 mmol), 2,4-difluorophenylacetic acid (4.41 g, 24.6 mmol), and triethylamine (2.80 g, 27.7 mmol) was heated to reflux for 3.5 hours. The reaction was cooled to 90° C., and water (100 mL) was added through an addition funnel. A yellow oil formed that solidified upon stirring. The solid was collected by filtration, and dissolved in ethyl acetate, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The solid thus obtained was recrystallized from toluene to give the desired acid (3.18 g, 42%): mp 165°-171° C. 1H NMR (acetone-d6) 300 MHz 7.95 (s,1H), 7.08-7.18 (m, 7H), 2.47 and 2.31 (s, 3H); 19F NMR (acetone-d6) -110.81 (m) -111.75 (m). Mass spectrum: M+H=306.