Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](S(C)=O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]1[C:32]2[CH:33]=[C:34]([NH2:37])[CH:35]=[CH:36][C:31]=2[N:30]=[CH:29]1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:37][C:34]4[CH:35]=[CH:36][C:31]5[N:30]=[CH:29][N:28]([CH3:27])[C:32]=5[CH:33]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Reactant: Cn1cnc2ccc(N)cc21
Product: Cn1cnc2ccc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)NC(C)(C)C)c5)n4n3)cc21

Procedure:
Following the synthetic and purification procedures described in Example 1293d, N-tert-butyl-3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (103 mg, 0.262 mmol) was coupled with 3-methyl-3H-benzimidazol-5-ylamine (66 mg, 0.45 mmol) at 105° C. for 120 h to afford the title compound. Yield of TFA salt: 78 mg (50%) of brown powder; LC/MS: 476 (M+H); HPLC: 97% pure, RT=2.64 min; 1H NMR: (DMSO, δ) 10.04 (s, 1H), 9.38 (s, 1H), 9.12 (s, 1H), 8.49 (s, 1H), 8.41 (d, J=8.0, 1H), 8.31 (s, 1H), 7.87 (d, J=8.0, 1H), 7.79 (m, 3H), 7.61 (s, 1H), 7.24 (d, J=4.9, 1H), 7.07 (d, J=4.9, 1H), 3.81 (s, 3H), 1.08 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH2:12][CH3:13])[N:10]=[C:9]([CH3:14])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[NH2:15][CH2:16][CH2:17][OH:18].C(N(CC)CC)C>C(Cl)Cl>[CH2:12]([N:11]1[C:3]2[C:2]([NH:15][CH2:16][CH2:17][OH:18])=[N:7][C:6]([CH3:8])=[N:5][C:4]=2[C:9]([CH3:14])=[N:10]1)[CH3:13]
Reactant: CCn1nc(C)c2nc(C)nc(Cl)c21
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1nc(C)c2nc(C)nc(NCCO)c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.7 %

Procedure:
A solution of 12 g (0.057 mol) of 7-chloro-3,5-dimethyl-1-ethyl-1H-pyrazolo[4,3-d]pyrimidine in 150 ml of methylene dichloride is treated with 12 g (0.2 mol) of 2-aminoethanol and 8 ml of triethyamine and stirred at room temperature 48 hours. The mixture is filtered to give 7.6 g (56%) of 2-[1-ethyl-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl]aminoethanol, mp 181°-183° C. from ethyl acetate.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[CH3:19][O:20][C:21](=[O:38])[C@@H:22]1[CH2:26][C@@H:25]([OH:27])[CH2:24][N:23]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:19][O:20][C:21](=[O:38])[C@@H:22]1[CH2:26][C@@H:25]([O:27][S:14]([C:11]2[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=2)(=[O:16])=[O:15])[CH2:24][N:23]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
37.5 ml (270 mmol) of triethylamine, 49.04 g (257 mmol) of p-toluenesulfonyl chloride and 2.99 g (24.5 mmol) of 4-dimethylaminopyridine were added in turn to a solution of 77.70 g (245 mmol) of (2S,4R)-1-benzyloxycarbonyl-4-hydroxyproline methyl ester in 600 ml of methylene chloride, and the resulting mixture was then stirred at room temperature overnight. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was purified by chromatography on a silica gel column using a 1:1 by volume mixture of hexane and ethyl acetate as the eluant to afford 106.18 g (quantitative yield) of (2S,4R)-1-benzyloxycarbonyl-4-(p-toluenesulfonyloxy)proline methyl ester as a yellow oil.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[S:17][CH:18]=[C:19]([CH3:25])[C:20]=1[C:21]([O:23][CH3:24])=[O:22]>>[CH3:25][C:19]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:16]([NH:15][C:12](=[O:14])[CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[S:17][CH:18]=1
Reactant: COC(=O)c1c(C)csc1N
Reactant: O=C(O)Cc1cccc2ccccc12
Product: COC(=O)c1c(C)csc1NC(=O)Cc1cccc2ccccc12

Procedure:
The title compound was prepared from 2-(naphthalen-1-yl)acetic acid (10 g, 54 mmol) and methyl 2-amino-4-methylthiophene-3-carboxylate (9.2 g, 54 mmol) according to protocol A (15.4 g, 85%) as a white solid. 1H NMR (CDCl3) δ 11.0 (s, 1H), 8.05-7.85 (m, 3H), 7.63-7.50 (m, 4H), 6.36 (s, 1H), 4.29 (s, 2H), 3.57 (s, 3H), 2.28 (s, 3H); 13C NMR (CDCl3) δ 168.3, 165.6, 149.3, 135.0, 134.0, 132.1, 129.8, 128.9, 128.6, 127.0, 126.2, 125.7, 123.7, 112.9, 112.2, 51.1, 41.9, 17.7; MH+ 340.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([Cl:10])=[O:9].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22]2)[CH:16]=1.O>C(O)(C)C>[ClH:10].[F:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:21]([C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)[CH:22]=1)=[O:9]
Reactant: c1cncc(-n2ccc3ccccc32)c1
Reactant: O=C(Cl)c1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(C)O
Solvent: O
Product: Cl
Product: O=C(c1ccccc1F)c1cn(-c2cccnc2)c2ccccc12
Reaction time: 2 h

Procedure:
To a stirred mixture of 58 g. (0.93 mole) of aluminum chloride in 240 ml. of MDC was added a solution of 28.6 g. (0.18 mole) of 2-fluorobenzoyl chloride in 100 ml. of MDC. The resulting mixture was stirred for two hours and then added dropwise to a solution of 29 g. (0.149 mole) of 1-(3-pyridinyl)-1H-indole in 200 ml. of MDC. When addition was complete the reaction mixture was stirred for fifteen minutes and then poured into 1 liter of water. The organic layer was separated, washed with aqueous sodium bicarbonate, dried over magnesium sulfate and taken to dryness in vacuo to give 50 g. of a red oil. The latter was dissolved in 200 ml. of isopropanol, the solution was treated with 10 ml. of concentrated hydrochloric acid, and the solid which separated was collected and dried to give 24.8 g. of product which was recrystallized from ethanol to give 3-(2-fluorobenzoyl)-1-(3-pyridinyl)-1H-indole hydrochloride, m.p. 205°-212° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-])=O.C(O)(=O)C.[C:20]1(=O)[O:25][C:23](=[O:24])[CH:22]=[CH:21]1>[OH-].[Na+].[Pd].O1CCOCC1>[C:20]1(=[O:25])[N:1]([C:4]2[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([CH:12]=2)[C:9]([OH:11])=[O:10])[C:23](=[O:24])[CH:22]=[CH:21]1
Reactant: O=C(O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: O=C1C=CC(=O)O1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C(O)c1cc(C(=O)O)cc(N2C(=O)C=CC2=O)c1

Procedure:
211.2 g (1.0 mol) of 5-nitroisophthalic acid are dissolved in 1,590 g of aqueous sodium hydroxide (90.0 g of sodium hydroxide in 1,500 ml of water) and the solution is rendered neutral with 15 ml of anhydrous acetic acid and hydrogenated in the presence of 10 g of a palladium-on-charcoal catalyst (5% by weight of Pd). The catalyst is filtered off and a solution of 118.0 g (1.2 mols) of maleic anhydride in 150 ml of dioxane is added to the filtrate in the course of 2 hours, whilst stirring vigorously. A white suspension is formed and is stirred overnight at 20°-25° C., 250 ml of acetic acid are then added and the mixture is stirred for a further 2 hours. The amide-acid which has precipitated is filtered off, washed with water and methanol and dried at 30° C. in vacuo for 24 hours. The reaction product (315 g) is then heated, in 2,500 ml of acetic anhydride, whilst stirring, to 80°-85° C. for 30 minutes. About 1.8 liters of liquid (acetic acid + acetic anhydride) are distilled off under a waterpump vacuum. The residual suspension is poured onto 2,000 g of ice and the mixture is stirred overnight. The reaction product which has precipitated is filtered off, washed with water and methanol and dried at 60° C. in vacuo for 12 hours. 210 g of white, crystalline 5-maleimidylisophthalic acid are obtained; melting point > 300° C. (= 80% of theory, based on the nitroisophthalic acid).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][C:25]4[CH2:26][NH:27][CH:28]([CH3:32])[CH2:29][C:30]=4[N:31]=3)=[O:22])[CH:17]([C:33]([O:35]CC)=[O:34])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C(O)C.[OH-].[Na+].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][C:25]4[CH2:26][NH:27][CH:28]([CH3:32])[CH2:29][C:30]=4[N:31]=3)=[O:22])[CH:17]([C:33]([OH:35])=[O:34])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1nc2c(s1)CNC(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3C(=O)O)sc2CN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In tetrahydrofuran (10 ml), 4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-(ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine (2.08 g) was dissolved, followed by the addition of ethanol (20 ml) and a 1N aqueous solution (3.70 ml) of sodium hydroxide. The resulting mixture was stirred at room temperature for 1 hour. After concentration of the reaction mixture under reduced pressure, the residue was added with water (20 ml). The precipitate thus formed was collected by filtration, whereby the title compound (1.39 g) was obtained as a pale yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]([Cl:17])=[N:11][C:12](Cl)=[CH:13][C:14]=1[Cl:15].C([Sn](CCCC)(CCCC)[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1)CCC>CN(C)C=O.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]([Cl:17])=[N:11][C:12]([C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:13][C:14]=1[Cl:15]
Reactant: Fc1cccc(Cl)c1-c1c(Cl)cc(Cl)nc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Fc1cccc(Cl)c1-c1c(Cl)cc(-c2ncccn2)nc1Cl

Procedure:
14.6 g (0.047 mol) of 3-(2-chloro-6-fluorophenyl)-2,4,6-trichloropyridine (see Example Ab), 20.0 g (0.051 mol) of 2-tri-n-butylstannylpyrimidine and 1.1 g (0.94 mmol) of tetrakistriphenylphosphinepalladium(0), dissolved in 70 ml of dimethylformamide and 50 ml of 1,4-dioxane, were kept at 110° C. for 10 h. After removal of the volatile components under reduced pressure, the product was purified on silica gel using cyclohexane/ethyl acetate. Yield 2.0 g of yellow crystals (m.p. 147° C.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([OH:20])[CH2:19][CH2:18][C:13]4([O:17]CCO4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.[CH3:22]O>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([O:20][CH3:22])[CH2:11][CH2:12][C:13](=[O:17])[CH2:18][CH2:19]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OC1(c2ccc3c(c2)OCO3)CCC2(CC1)OCCO2
Reactant: CO
Agent: Cl
Product: COC1(c2ccc3c(c2)OCO3)CCC(=O)CC1
Yield: 70 %

Procedure:
A solution of 8-(1,3-Benzodioxol-5-yl)-1,4-dioxa-spiro[4.5]decan8-ol (5.0 g, 1.8 mmole) in 100 mL methanol with 1 mL conc. hydrochloric acid was stirred for 22 hr and the solution concentrated in vacuo. The residue was purified by chromatography on silica eluting with ethyl acetate-hexane (1:19) to give the product (70%, mp: 84°-85 ° C.).
Reaction SMILES: O=[CH:2][C:3]([OH:5])=[O:4].[NH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1B(O)O>C(#N)C>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[CH:2]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: O=CC(=O)O
Reactant: C1CCNCC1
Solvent: CC#N
Product: O=C(O)C(c1ccc(F)cc1F)N1CCCCC1
Yield: 63.3 %

Procedure:
2-Oxoacetic acid (141 mg, 1.90 mmol) and piperidine (0.16 ml, 1.90 mmol) were dissolved in acetonitrile (10 ml). 2,4-Difluorophenylboronic acid (300 mg, 1.90 mmol) was added and the mixture was stirred at reflux for 4 hours. The solvent was evaporated and the crude was purified by flash chromatography (DCM/MeOH=85/25) to obtain the title compound (307 mg, 63% yield) as an off-white solid.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][C:7]1[C:8]([CH3:28])=[N:9][C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Br:2][CH2:6][C:7]1[C:8]([CH3:28])=[N:9][C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1
Reactant: Cc1nc(-c2ccccc2)cc(-c2cccc([N+](=O)[O-])c2)c1CO
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)cc(-c2cccc([N+](=O)[O-])c2)c1CBr
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 37.2 %

Procedure:
To a solution of phosphorus tribromide (0.93 g) in tetrahydrofuran (10 ml) was dropwise added a suspension of 3-hydroxymethyl-2-methyl-4-(3-nitrophenyl)-6-phenylpyridine (1.65 g) in tetrahydrofuran (10 ml) at 5°-10° C. After stirring for 1.5 hours at the same temperature, the reaction mixture was poured into ice-water (20 ml), adjusted to pH 9.5 with saturated aqueous potassium carbonate and extracted with ethyl acetate (40 ml). The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to a column chromatography on silica gel eluting with chloroform. The fraction containing the desired compound were combined and evaporated in vacuo to give 3-bromomethyl-2-methyl-4-(3-nitrophenyl)-6-phenylpyridine (0.49 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:27])[N:16]([CH3:26])[C:17]3[C:22]([C:23]=2[O:24][CH3:25])=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:30]=1[C:31](O)=[O:32]>>[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:30]=1[C:31]([NH:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:27])[N:16]([CH3:26])[C:17]3[C:22]([C:23]=2[O:24][CH3:25])=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4])=[O:32]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(OC)c3ccccc3n(C)c2=O)cc1
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)c3ccccc3n(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl

Procedure:
The compound obtained as an intermediate in Process 3 of Example 6, that is, methyl (2S)-2-amino-3-[4-(4-methoxy-1-methyl-2-oxo-1,2-dihydro-3-quinolinyl)phenyl]propionate (50 mg) was acylated with 2-chloro-6-methylbenzoic acid by the same procedure as that of Process 1 of Example 17 to obtain methyl (2S)-2-[(2-chloro-6-methylbenzoyl)amino]-3-[4-(4-methoxy-1-methyl-2-oxo-1,2-dihydro-3-quinolinyl)phenyl]propionate (38 mg).
Reaction SMILES: [CH2:1]1[O:21][C:20]2[C:3](=[CH:4][C:5]3[C:11](=[O:12])[C:10]4[CH:13]=C(C#N)[CH:15]=[CH:16][C:9]=4[CH2:8][O:7][C:6]=3[CH:19]=2)[O:2]1.Cl.[C:23]([OH:26])(=[O:25])[CH3:24]>>[CH2:1]1[O:21][C:20]2[C:3](=[CH:4][C:5]3[C:11](=[O:12])[C:10]4[CH:13]=[C:24]([C:23]([OH:26])=[O:25])[CH:15]=[CH:16][C:9]=4[CH2:8][O:7][C:6]=3[CH:19]=2)[O:2]1
Reactant: CC(=O)O
Reactant: N#Cc1ccc2c(c1)C(=O)c1cc3c(cc1OC2)OCO3
Agent: Cl
Product: O=C(O)c1ccc2c(c1)C(=O)c1cc3c(cc1OC2)OCO3

Procedure:
Heat a mixture of 4.98 gm. (0.0178 mole) of 6,11-dihydro-2,3-methylenedioxy-11-oxodibenz[b,e]-oxepin-9-carbonitrile, 90 ml. of acetic acid, 9 ml. of concentrated hydrochloric acid under reflux of 74 hours. Cool the reaction mixture and separate the solids by filtration and dry (yield 3.45 gm.). Suspend the solids in water and treat with N-methylpiperazine. Remove base insolubles by filtration and acidify the filtrate with concentrated hydrochloric acid to the Congo Red end point. Separate the solids by filtration and dry. Purify by recrystallization from acetic acid to obtain the title product (m.p. 320°-321° C.)
Reaction SMILES: [NH:1]([CH2:5][CH2:6]O)CCO.II.[C:10]1(=[O:16])O[C:13](=O)[CH:12]=[CH:11]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20](S(O)(=O)=O)=[CH:19][CH:18]=1>>[N-:1]=[C:10]=[O:16].[N-:1]=[C:10]=[O:16].[C:17]1([CH2:27][C:6]2[CH:5]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1C=CC(=O)O1
Reactant: OCCNCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: II
Product: [N-]=C=O
Product: c1ccc(Cc2ccccc2)cc1

Procedure:
The above amounts of diethanolamine and iodine were added to the above amount of soybean oil with stirring. The mixture was stirred for 24 hours at a temperature between about 200° F. and about 226° F. Then, the above amounts of maleic anhydride and p-toluenesulphonic acid were added with stirring. The mixture was stirred under vacuum for 20 hours at a temperature between about 200° F. and about 226° F. to give a liquid soybean oil based polyol with a hydroxyl number of 55. A reaction mixture of about 10.00 grams of the polyol and the above indicated amount of diphenylmethane diisocyanate yielded a solid soybean oil based polyurethane material.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[NH:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1C(O)=O.[CH2:19]([N:23]1[C:27](=[O:28])[CH:26]=[CH:25][C:24]1=[O:29])[CH2:20][CH2:21][CH3:22]>>[CH2:19]([N:23]1[C:27](=[O:28])[CH:26]2[CH:7]([C:6]3[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[N:11]3[CH:12]([CH:25]2[C:24]1=[O:29])[CH2:16][CH2:17][CH2:18]3)[CH2:20][CH2:21][CH3:22]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCCCN1C(=O)C=CC1=O
Product: CCCCN1C(=O)C2C(C1=O)C(c1ccc(C#N)cc1)N1CCCC21

Procedure:
7.B)c) (3aRS,4RS,8aSR,8bSR)-4-(2-Butyl-decahydro-1,3-dioxo-pyrrolo[3,4-a]pyrrolizin-4-yl)-benzonitrile was prepared analogously to Example 4.B)g) from 4-cyano-benzaldehyde, L-proline and N-butylmaleimide. Yellow oil. 1 H-NMR (DMSO-D6): 7.74 (d, ArH); 7.49 (d, ArH); 4.22 (d, 4-H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.C([Li])CCC.Cl[C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:18]=[C:17]([N:27]2[C:31]3[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:30]=3[N:29]=[C:28]2[CH:38]([F:40])[F:39])[N:16]=1>C1COCC1.C(O)(=O)C.O>[F:40][CH:38]([F:39])[C:28]1[N:27]([C:17]2[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:20]=[C:15]([NH:1][C:2]3[CH:7]=[N:6][C:5]([F:8])=[CH:4][CH:3]=3)[N:16]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:30]=2[N:29]=1
Reactant: Nc1ccc(F)nc1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Nc2ccc(F)nc2)nc(N2CCOCC2)n1
Reaction time: 0.17 h
Yield: 40.2 %

Procedure:
To 0.240 g (2.14 mmol) of 5-amino-2-fluoropyridine in THF (5 mL) was added 0.94 mL of n-butyllithium (2.5 M solution in hexanes), and the mixture was stirred for 10 min. A solution of 0.283 g (0.71 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) in THF (5 mL) was added. The resulting mixture was stirred at room temperature for 1 hr. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed successively with water and aqueous NH3, and dried. Removal of the solvent followed by chromatography on alumina eluting first with hexanes/EtOAc (1:1) and then CH2Cl2/EtOAc (1:3) gave a brown powder. Recrystallization from ethanol/CH2Cl2 gave 0.135 g (40% yield) of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-(6-fluoro-3-pyridinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 261-263° C.; 1H NMR (CDCl3) δ8.44 (br s, 1H), 8.03-8.01 (m, 1H), 7.90 (br s, 1H), 7.61-7.31 (m, 2H), 7.07 (br s, 1H), 6.99 (dd, J=8.3, 3.4 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 4.05 (s, 3H), 3.93-3.88 (m, 4H), 3.80 (s, 4H); Anal. Calcd. for C21H19F3N8O2: C, 53.4; H, 4.05; N, 23.7. Found: C, 53.5; H, 4.0; N, 23.8%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8]SCC)[CH:7]=1.O[O:13][S:14]([O-:16])=O.[K+].[CH3:18][C:19](C)=O>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][S:14]([CH2:18][CH3:19])(=[O:16])=[O:13])[CH:7]=1
Reactant: CC(C)=O
Reactant: O=S([O-])OO
Reactant: CCSCc1cncc(Br)c1
Agent: [K+]
Product: CCS(=O)(=O)Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the title compound from Example 62 Step B (96 mg, 0.41 mmol) in acetone (2.0 mL) was added OXONE® (763 mg, 1.24 mmol). The reaction was stirred at room temperature overnight, then filtered and concentrated under reduced pressure to provide the title compound: LCMS m/z 265.91 [M+2+H]+; 1H NMR (500 MHz, CDCl3) δ 8.72 (s, 1H), 8.53 (s, 1H), 8.00 (s, 1H), 4.19 (s, 2H), 2.96 (q, J=7.4, 2H), 1.43 (t, J=7.4, 3H).
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].COC[O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH:21]=O.O.[C:24]([O:27][CH2:28][CH3:29])(=[O:26])[CH3:25]>O1CCCC1>[OH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH:21]=[CH:1][CH2:2][CH2:25][C:24]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: COCOc1c(C=O)ccc2ccccc12
Reactant: CCOC(C)=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCC=Cc1ccc2ccccc2c1O
Reaction time: 0.75 h
Yield: 17 %

Procedure:
A mixture of potassium t-butoxide (2.10 g, 0.019 mole) and 4-carbethoxypropyl-triphenylphosphonium bromide (prepared according to the procedure of P. E. Sonnet, J. Org. Chem. 34, 1147 (1964); 8.40 g, 0.018 mole) in dry tetrahydrofuran (15 mL) was stirred at 0°. After 45 minutes, a solution of 1-methoxymethoxy-2-naphthaldehyde (2.00 g, 0.009 mole) in dry tetrahydrofuran (7.5 mL) was added over 10 minutes. The resulting mixture was stirred at 0° for 2 hours, then was poured into water. The crude material was isolated by extraction with ethyl acetate and chromatographed with 10% ether/petroleum ether, then was dissolved in absolute ethanol (200 mL), treated with 3 drops of sulfuric acid, and heated at reflux for 18 hours. After cooling, the solution was diluted with water and the crude product mixture isolated by extraction with ethyl acetate. This was chromatographed with 85:15 petroleum ether/ether to provide two different solids. The first one to elute was recrystallized (hexane) to provide the Z isomer of the title compound (0.43 g, 17%) as a pale yellow solid, mp 75°-77°. The second solid was recrystallized (hexane) to provide the E isomer (0.23 g, 9%) as a white solid, mp 63°-64°.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)C=C.Cl[C:20]1[CH:25]=CC=C[C:21]=1Cl>>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[C:10]([CH2:25][CH:20]=[CH2:21])[CH:9]=2)=[CH:17][CH:16]=1
Reactant: Clc1ccccc1Cl
Reactant: C=CCOc1ccc(Oc2ccc(C)cc2)cc1
Product: C=CCc1cc(Oc2ccc(C)cc2)ccc1O

Procedure:
4-(4′-Methylphenoxy)phenyl allyl ether (4.00 g, 16.37 mmol) was taken up in 1,2-dichlorobenzene (50 mL) and refluxed for 20 h. After cooling, the solvent was removed in vacuo and the resulting crude oil was chromatographed on silica gel (15% ethyl acetate hexane) to afford 4-(4′-methylphenoxy)-2-allylphenol.