Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([N:17]2[CH:22]3[CH2:23][CH2:24][CH:18]2[CH2:19][O:20][CH2:21]3)[CH:3]=1.Cl.[CH:26]12[NH:33][CH:30]([CH2:31][CH2:32]1)[CH2:29][O:28][CH2:27]2.C(=O)([O-])[O-].[K+].[K+].CCN(C(C)C)C(C)C>O1CCOCC1.ClCCl>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]([N:17]3[CH:22]4[CH2:23][CH2:24][CH:18]3[CH2:19][O:20][CH2:21]4)[CH:3]=[C:2]([N:33]3[CH:26]4[CH2:32][CH2:31][CH:30]3[CH2:29][O:28][CH2:27]4)[N:7]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)cc(N3C4CCC3COC4)n2)cc1
Reactant: C1CC2COCC1N2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(-c2nc(N3C4CCC3COC4)cc(N3C4CCC3COC4)n2)cc1
Temperature: 220 °C
Yield: 45.9 %

Procedure:
In a 2-5 mL microwave vial was placed 8-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (36, 214 mg, 0.617 mmol) in dioxane (4 ml) to give a yellow suspension. 3-Oxa-8-azabicyclo[3.2.1]octane hydrochloride (33, 277 mg, 1.851 mmol), potassium carbonate (341 mg, 2.469 mmol) and DIPEA (0.647 ml, 3.70 mmol) were added. The reaction was heated under microwave irradiation at 220° C. for 1 h. The reaction mixture was diluted with dichloromethane and washed with sat NaHCO3. The organic phase was dried over MgSO4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with ethyl acetate in hexanes (10-40%) to give the title compound (120 mg) as a yellow solid. In addition, mixed fractions were concentrated, applied to a silica gel column and eluted with methanol in dichloromethane (2-5%) to give an additional 19 mg of title compound for a combined yield of 139 mg (0.33 mmol, 53%). HRMS: [M+H]+ mass error=0.6 mDa or 1.45 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=2)[CH:3]=1.[CH2:15](O)[CH2:16][OH:17].[OH-].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3([CH3:13])[O:17][CH2:16][CH2:15][O:14]3)[CH:8]=2)[CH:3]=1
Reactant: CC(=O)c1ccc2cc(Br)ccc2c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC1(c2ccc3cc(Br)ccc3c2)OCCO1
Yield: 79.7 %

Procedure:
A mixture of 13.0 g of 2-bromo-6-acetylnaphthalene, 20 g of ethylene glycol, 200 ml of benzene, and 530 mg of p-toluenesulfonic acid was heated at reflux for 18 hours using a Dean-Stark trap to effect continuous removal of water. The cooled reaction mixture was added to 100 ml of 0.1N sodium hydroxide solution and the resulting mixture extracted with three 75 ml portions of diethyl ether. The combined organic extract was washed with 100 ml saturated sodium chloride solution and then dried over sodium sulfate. The solvent is removed under vacuum and the residue recrystallized from hexane to give 12.2 g of 2-bromo-6-(2-methyl-1,3-dioxolan-2-yl)naphthalene, m.p. 80°-82° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([CH3:11])=[CH:7][CH:8]=[CH:9][CH:10]=1)=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)C#N.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:3]1[C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:11]=[C:1]([C:20]2[CH:19]=[CH:16][CH:15]=[C:14]([O:13][CH3:12])[CH:21]=2)[N:2]=1
Reactant: CNC(=O)c1ccccc1C
Reactant: COc1cccc(C#N)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cccc(-c2cc3ccccc3c(Cl)n2)c1

Procedure:
3-(4-Methoxyphenyl)isoquinolin-1-one obtained by reacting N-methyl-o-toluamide (1.49 g) and 3-methoxybenzonitrile (1.33 g) according to Example 10-1 was reacted with phosphorous oxychloride (10 ml) according to Example 10-2, to give 1-chloro-3-(3-methoxyphenyl)isoquinoline. Then, it was reacted with N-ethylpiperazine (10 ml) at 120° C. for 6 hr. The reaction solution was evaporated, and ethyl acetate and water were added to the resulting residue. The resulting organic layer was washed with water and brine, and then dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give the free compound of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5](O)=[N:6][C:7]=1[CH3:8].P(Cl)(Cl)([Cl:15])=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[Cl:15][C:5]1[C:4]([N+:10]([O-:12])=[O:11])=[CH:3][C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc([N+](=O)[O-])c(O)nc1C
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Product: Cc1cc([N+](=O)[O-])c(Cl)nc1C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
A mixture of 5,6-dimethyl-3-nitropyridin-2-ol (7.09 g, 42.2 mmol), benzyltriethylammonium chloride (4.82 g, 21.1 mmol) and acetonitrile (90 mL) at room temperature was slowly treated with phosphorus oxychloride (11.8 mL, 125 mmol) then heated to reflux and stirred overnight. The mixture was concentrated under reduced pressure and treated with ice-water (220 mL) and basified with concentrated ammonium hydroxide (100 mL). The mixture was extracted with dichloromethane (3×100 mL) and the combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 2-chloro-5,6-dimethyl-3-nitropyridine (7.28 g, 92%). Mp. 72-76° C.; 400 M Hz 1H NMR (CDCl3) δ: 8.01 (s, 1H), 2.58 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si](C(C)C)(C(C)C)C(C)C)=[CH:4][C:3]=1[OH:20].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOCC>C1COCC1>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([OH:20])[CH:4]=1)#[CH:9]
Reactant: CC(C)[Si](C#Cc1ccc(F)c(O)c1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#Cc1ccc(F)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-fluoro-5-((triisopropylsilyl)ethynyl)phenol is dissolved in THF and tetrabutyl ammoniumflouride is added. The solution is stirred overnight at RT. Et2O is added and the solution is washed with H2O, Brine, dried, and the solvent removed. This material is used without any further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[N:15]=[N:16][N:17]([CH2:19][C:20]([O:22]CC)=[O:21])[N:18]=3)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[N:15]=[N:16][N:17]([CH2:19][C:20]([OH:22])=[O:21])[N:18]=3)=[CH:10][N:9]=2)[CH2:6][CH2:7]1
Reactant: Oc1cc(F)ccc1Cl
Reactant: CCOC(=O)Cn1nnc(-c2cnc(N3CCC(O)CC3)nc2)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(O)Cn1nnc(-c2cnc(N3CCC(Oc4cc(F)ccc4Cl)CC3)nc2)n1

Procedure:
The title compound was prepared in a similar manner as that described for Example 3 (step 4) from ethyl {5-[2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl]-2H-tetrazol-2-yl}acetate, 2-chloro-5-fluorophenol, triphenylphosphine and diethyl azodicarboxylate.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH:6][C:7](=[O:14])OCC(Cl)(Cl)Cl)=[N:2]1.[C:15]1([C:21]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:15]1([C:21]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][N:29]([C:7]([NH:6][C:3]4[N:4]=[CH:5][NH:1][N:2]=4)=[O:14])[CH2:28][CH2:27]3)[S:23][N:22]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1nc[nH]n1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1nc[nH]n1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
A mixture of 2,2,2-trichloroethyl 1H-1,2,4-triazol-3-ylcarbamate (265 mg, 0.609 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (300 mg, 1.22 mmol) and diisopropylethylamine (0.106 ml, 1.22 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 8 hours. Water was poured into the reaction mixture. A crystal formed was collected by filtration and recrystallized from a mixed solvent of hexane and tetrahydrofuran to obtain the desired product (61.8 mg, 28.5%) as a solid.
Reaction SMILES: [Na][Na].[N+:3]([C:6]1[CH:7]=[C:8]([S:27]([OH:30])(=[O:29])=[O:28])[C:9]([CH:12]=[CH:13][C:14]2[C:15]([S:23]([OH:26])(=[O:25])=[O:24])=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[CH:10][CH:11]=1)([O-])=O.[Na].N>>[N+:20]([C:17]1[CH:16]=[C:15]([S:23]([OH:26])(=[O:24])=[O:25])[C:14]([CH:13]=[CH:12][C:9]2[C:8]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:7][C:6]([NH2:3])=[CH:11][CH:10]=2)=[CH:19][CH:18]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc([N+](=O)[O-])cc2S(=O)(=O)O)c(S(=O)(=O)O)c1
Agent: N
Agent: [Na]
Agent: [Na][Na]
Product: Nc1ccc(C=Cc2ccc([N+](=O)[O-])cc2S(=O)(=O)O)c(S(=O)(=O)O)c1

Procedure:
An aqueous solution of the disodium salt of 4,4'-dinitro-stilbene-2,2'-disulphonic acid is treated with an equivalent amount, relative to the nitro group to be reduced, of sodium bisulphide solution at 75°-85° C., ammonia being added. The course of the reaction can be followed by known analytical methods. When the partial reduction has ended, the 4-nitro-4'-amino-stilbene-2,2'-disulphonic acid formed is isolated as the disodium salt or as an inner salt. The amount of 4,4'-diamino-stilbene-2,2'-disulphonic acid contained as an impurity is less than 1% and the residual content of 4,4'-dinitro-stilbene-2,2'-disulphonic acid is less than 0.1%. 4-Nitro-4'-aminostilbene-2,2'-disulphonic acid is a known intermediate product for dyestuffs.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[C:5](=[C:10]([NH:14][CH2:15][C:16]2[O:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].COCCNC1C=CC=C(C(O)=O)C=1C(O)=O>>[CH3:21][C:18]1[O:17][C:16]([CH2:15][NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:22])=[O:2])[C:5]=2[C:6]([OH:8])=[O:7])=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc(NCc2ccc(C)o2)c1C(=O)OC
Agent: COCCNc1cccc(C(=O)O)c1C(=O)O
Product: Cc1ccc(CNc2cccc(C(=O)O)c2C(=O)O)o1

Procedure:
3-[(5-Methyl-furan-2-ylmethyl)-amino]-phthalic acid dimethyl ester (5 mmol) was treated in the same manner as described above for the synthesis of 3-(2-methoxy-ethylamino)-phthalic acid. The product of the reaction, which contained a mixture of diacid and monomethyl esters, was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][C:5](=O)[CH3:6].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][CH2:30][OH:31])=[CH:21]1.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1.O>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][C:5]1([CH3:6])[C:21]2[CH2:20][C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:22]=2[CH2:29][CH2:30][O:31]1
Reactant: OCCC1=CCc2ccccc21
Reactant: CC(=O)CCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CN(C)CCC1(C)OCCC2=C1Cc1ccccc12
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-dimethylamino-3-butanone (1.0 g) dissolved in toluene (10 ml), p-toluenesulfonic acid (1.3 g) is added. The suspension is stirred for 10 min. Indene-3-ethanol (1.0 g) in toluene (5 ml) is added to the suspension and the resulting solution stirred for 2 hr. Boron trifluoride etherate (0.25 ml) is added together with ca. 0.5 g of hydrated alkali-aluminum silicate. The mixture is heated at 80° C for 30 min. The mixture is cooled and diluted with water. The organic layer is separated and the aqueous layer extracted with toluene. The organic layers are washed with water. The combined aqueous phase is rendered alkaline with conc.NH4OH and extracted with toluene. The latter extract is treated with charcoal and then concentrated to afford the title compound, identical to the compound of the same name described in Example 284.
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:6][N:5]1[CH2:17][C:18]([NH:20][C:21]1[C:26]([Cl:27])=[CH:25][C:24]([N+:28]([O-])=O)=[CH:23][C:22]=1[Cl:31])=[O:19])=[O:3].S1C=CC=C1>CO.[Pt]>[NH2:1][C:2]([CH:4]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:7][CH2:6][N:5]1[CH2:17][C:18]([NH:20][C:21]1[C:26]([Cl:27])=[CH:25][C:24]([NH2:28])=[CH:23][C:22]=1[Cl:31])=[O:19])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)Nc2c(Cl)cc([N+](=O)[O-])cc2Cl)C(C(N)=O)C1
Agent: [Pt]
Solvent: c1ccsc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)Nc2c(Cl)cc(N)cc2Cl)C(C(N)=O)C1
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
A solution of 2-(aminocarbonyl)-N-(4-nitro-2,6-dichlorophenyl)-4-(tert-butoxycarbonyl)-1-piperazineacetamide (1.0 g, 2.1 mmol) in 30 mL of methanol containing methanolic 4% thiophene (0.25 mL) and 5% platinum on charcoal catalyst (450 mg) was hydrogenated using a Parr apparatus at 50° C. and 25 psi for 30 minutes. After cooling and removal of catalyst by filtration, the solvent was removed from the filtrate in vacuo to yield III as an amorphous solid (0.88 g, 94% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>O>[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:29][CH:28]=1
Reactant: OCCCCCCCCCCCCCCCCBr
Reactant: Oc1ccc(-c2cccc(F)c2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: OCCCCCCCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Yield: 85 %

Procedure:
First, 3 g of 16-bromo-1-hexadecanol, 1.9 g of 2,3-difluoro-4'-hydroxybiphenyl, 2.6 g of potassium carbonate, and 50 ml of methyl ethyl ketone were placed in a 100 ml flask. The reaction mixture was stirred under reflux for 32 hours. The reaction mixture was poured into water, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was recrystallized from acetone to obtain 3.5 g of 2,3-difluoro-4'-(16-hydroxyhexadecyl)oxybiphenyl (Y: 84%). The compound thus obtained had a purity of 97.4% by GC.
Reaction SMILES: Cl.C(OC([NH:9][C@@:10]1([C:34]([OH:36])=[O:35])[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[C@@H:14]([NH:26][C:27](=[O:30])[CH2:28][OH:29])[C@@H:13]2[C@H:11]1[C@H:12]2[C:31]([OH:33])=[O:32])=O)(C)(C)C>O1CCOCC1.O>[ClH:24].[NH2:9][C@@:10]1([C:34]([OH:36])=[O:35])[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[C@@H:14]([NH:26][C:27](=[O:30])[CH2:28][OH:29])[C@@H:13]2[C@H:11]1[C@H:12]2[C:31]([OH:33])=[O:32]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)O)[C@@H]2[C@@H](C(=O)O)[C@@H]2[C@H](NC(=O)CO)[C@H]1OCc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: N[C@]1(C(=O)O)[C@@H]2[C@@H](C(=O)O)[C@@H]2[C@H](NC(=O)CO)[C@H]1OCc1ccc(Cl)c(Cl)c1
Yield: 133.3 %

Procedure:
Add 4N hydrogen chloride (3.0 mL, 12.0 mmol) in 1,4-dioxane to a mixture of (1S,2R,3R,4S,5R,6S)-2-(tert-butoxycarbonylamino)-3-[(3,4-dichlorophenyl)methoxy]-4-[(2-hydroxyacetyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (0.032 g, 0.06 mmol) in water (0.3 mL). Wash the solid with acetonitrile and diethylether on a fritted funnel Sequentially wash the solid with acetonitrile and diethylether and then further dry in a vacuum oven overnight at 50° C. to provide the title compound as a white solid (0.018 g, 0.04 mmol, 65%). MS (m/z): 433 (M+H).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:39])[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:26][CH:25]=2)=[O:22])=[CH:16][C:15]=1[O:40][CH3:41].[NH:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44][CH2:43]1>ClCCl.C(N(CC)CC)C>[N:42]1([C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]([CH3:39])[CH2:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[CH:26][CH:25]=3)=[O:22])=[CH:16][C:15]=2[O:40][CH3:41])=[O:11])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44][CH2:43]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1ccc2c(c1)CCN2
Reactant: COc1cc(CC(=O)Nc2ccc(C(C)CC(=O)OC(C)(C)C)cc2)ccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CC(=O)Nc2ccc(C(C)CC(=O)OC(C)(C)C)cc2)ccc1NC(=O)N1CCc2ccccc21
Reaction time: 1 h

Procedure:
Triphosgene (150 mg) was added to a stirred solution of tert-butyl 3-[4-({4-amino-3-methoxyphenyl}acetylamino)phenyl]butyrate (540 mg, Reference Example 2) in dichloromethane (50 ml) at 0-5° C. under an atmosphere of nitrogen. After stirring for one hour the mixture was treated with a solution of indoline (0.15 ml) in dichloromethane (2.5 ml) and triethylamine (0.51 ml). This mixture was allowed to stand at room temperature overnight and then evaporated. The residual gummy solid was suspended in water and the suspension was acidified to pH 1 by addition of hydrochloric acid. The resulting pale green solid was filtered and then subjected to flash chromatography on silica eluting with 0.2% to 1% methanol in dichloromethane to give the title compound (580 mg) as an off-white solid.
Reaction SMILES: Cl[C:2]1[NH:3][S:4](=[O:14])(=[O:13])[C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>O>[Cl:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:2]([N:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]3)[NH:3][S:4](=[O:14])(=[O:13])[C:5]=2[CH:11]=1
Reactant: CN1CCNCC1
Reactant: O=S1(=O)NC(Cl)=Nc2ccc(Cl)cc21
Solvent: O
Product: CN1CCN(C2=Nc3ccc(Cl)cc3S(=O)(=O)N2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a stirred suspension of 10.0 g of 3,7-dichloro-2H-1,2,4-benzothiadiazine 1,1-dioxide in 100 ml of water is added 8.0 g of 1-methylpiperazine, while the mixture is cooled in an ice bath. After the addition, the mixture is stirred at 60° C. for 1 hour. The crystalline precipitate collected is recrystallized from a mixture of dimethylformamide and water to give 11.0 g of the desired product, m.p. above 300° C.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH:8]([OH:10])[C:7]2[S:11][CH:12]=[CH:13][C:6]=2[CH2:5]1)[CH:2]=[CH2:3].[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1F>>[ClH:14].[CH2:1]([N:4]1[CH2:9][CH:8]([O:10][C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:14])[C:20]=2[Cl:21])[C:7]2[S:11][CH:12]=[CH:13][C:6]=2[CH2:5]1)[CH:2]=[CH2:3]
Reactant: Fc1cccc(Cl)c1Cl
Reactant: C=CCN1Cc2ccsc2C(O)C1
Product: C=CCN1Cc2ccsc2C(Oc2cccc(Cl)c2Cl)C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 5-allyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 16) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:14])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.CS(O[CH:20]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]1)(=O)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)[O:14][CH:20]1[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: Oc1ccc(CN2CCCC2)c(F)c1
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(CN3CCCC3)c(F)c2)C1
Yield: 79.4 %

Procedure:
Using a similar protocol as described in Example 29C employing 31A (6.6 g, 33.8 mmol) and tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate (10.2 g, 40.6 mmol) as starting materials afforded 9.4 g (80%) of 31B as a solid. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 1.77 (m, 4H), 2.52 (m, 4H), 3.61 (s, 2H), 3.99 (m, 2H), 4.27 (m, 2H), 4.84 (m, 1H), 6.43 (dd, 1H), 6.49 (dd, 1H), 7.27 (t, 1H), MS (APCI+) m/z 351 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[CH3:51][O:52][C:53]1[CH:54]=[C:55]([CH:58]=[CH:59][C:60]=1[O:61][CH3:62])CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][C:58]2[CH:55]=[CH:54][C:53]([O:52][CH3:51])=[C:60]([O:61][CH3:62])[CH:59]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(CO)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(COC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(C)c2C)cc1OC
Temperature: 25 °C
Yield: 70.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (65 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (107 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3,4-dimethoxybenzyl alcohol (60 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (73 mg, yield 55%).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[CH:36]=O)[CH:29]=[CH:28]1>>[CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:36][C:34]3[CH:33]=[CH:32][CH:31]=[C:30]4[C:35]=3[N:27]([CH3:26])[CH:28]=[CH:29]4)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: Cn1ccc2cccc(C=O)c21
Product: Cn1ccc2cccc(CNc3cccc(-c4c(Cc5ccccc5)nnc5c(Cl)cccc45)c3)c21

Procedure:
The title compound was prepared from 3-(3-benzyl-8-chloro-cinnolin-4-yl)-phenylamine and 1-methyl-1H-indole-7-carbaldehyde according the procedure of Example 5 Step 5. MS (ESI) m/z 489.
Reaction SMILES: C[O:2][C:3]1[C:8](OC)=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=[CH:5][C:4]=1[C:15]1[N:20]=[CH:19][N:18]=[C:17]([O:21][C:22]2[C:27]3[N:28]=[C:29]([NH2:31])[S:30][C:26]=3[CH:25]=[CH:24][CH:23]=2)[CH:16]=1.B(F)(F)F.CCOCC>ClCCl>[NH2:31][C:29]1[S:30][C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([O:21][C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:4]4[CH:5]=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][C:3]=4[OH:2])[CH:16]=3)[C:27]=2[N:28]=1
Reactant: COc1c(-c2cc(Oc3cccc4sc(N)nc34)ncn2)ccc(C(F)(F)F)c1OC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4O)ncn3)cccc2s1
Temperature: -78 °C

Procedure:
To a 100-mL, round-bottomed flask containing a solution of 4-[6-(2-methoxy-methoxy-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 135(c)), (1.8 g, 3.9 mmol) in dichloromethane (39 mL) was added boron trifluoride diethyl etherate (1.5 mL, 12 mmol, Aldrich) with stirring at −78° C. The reaction mixture was then stirred at 0° C. for 1 h and at room temperature for 3 h. The mixture was quenched with satd sodium bicarbonate at 0° C. and extracted with dichloromethane (2×100 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuum. The crude material was purified by silica gel chromatography (gradient: 0–3% 2 N ammonia in methanol/dichloromethane) to yield the title compound as an amorphous, white solid. MS (ESI, pos. ion.) m/z: 406 (M+1).