Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[CH3:10][C:11]1[NH:12][C:13]([CH3:41])=[C:14]([C:32]([O:34]CCCN(C)C)=[O:33])[CH:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16]=1[C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[O:18].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:10][C:11]1[NH:12][C:13]2[CH2:41][O:34][C:32](=[O:33])[C:14]=2[CH:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16]=1[C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[O:18]
Reactant: CC1=C(C(=O)OCCCN(C)C)C(c2ccccc2)C(C(=O)OCCCN(C)C)=C(C)N1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC1=C(C(=O)OCCCN(C)C)C(c2ccccc2)C2=C(COC2=O)N1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 15.9 %

Procedure:
1.31 grams of 80 percent pyridinium bromide perbromide (3.28 millimoles) was added to a cooled to -20° C. solution of 1.30 grams (2.84 millimoles) of bis(3-dimethylaminopropyl) 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate and 0.4 milliliter of pyridine in 20 milliliters of chloroform. The resulting mixture was stirred at -20° C. for 1/2 hour and then heated at reflux for 2 hours. The mixture was cooled to room temperature and allowed to stir overnight. The crude product was chromatographed on silica gel with 1 percent methanol in chloroform saturated with ammonia as eluant to obtain 161 milligrams of an oil which crystallized when mixed with CDCl3 for NMR analysis. The product was concentrated in vacuo and recrystallized from ethyl acetate-hexane to obtain crystals of m.p. 112°-115° C. after drying 70° C. overnight. The product was a hydrate having elemental analyses as follows:
Reaction SMILES: Cl[C:2]1N2C(=O)NN=C2C(C2C=CC(Cl)=CC=2)=C(C2C=CC(Cl)=CC=2)N=1.[Cl-].ICC.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:42]=[C:41]([N:43]3[CH2:46][C:45]([NH:50][CH2:51][CH3:52])(C(N)=O)[CH2:44]3)[N:40]3[C:53](=[O:58])[N:54]([CH2:56][CH3:57])[N:55]=[C:39]3[C:38]=2[C:59]2[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=2)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:42]=[C:41]([NH:43][CH2:46][C:45]3[CH:44]=[CH:2][CH:52]=[CH:51][N:50]=3)[N:40]3[C:53](=[O:58])[N:54]([CH2:56][CH3:57])[N:55]=[C:39]3[C:38]=2[C:59]2[CH:60]=[CH:61][C:62]([Cl:65])=[CH:63][CH:64]=2)=[CH:33][CH:32]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Reactant: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3nn(CC)c(=O)n23)C1
Agent: [Cl-]
Solvent: CCI
Product: CCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(NCc3ccccn3)n2c1=O

Procedure:
The title compound was prepared in two steps from 5-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one by nucleophilic displacement of chloride with the requisite amine, followed by alkylation with iodoethane, in a manner analogous to that in which 1-(7,8-bis(4-chlorophenyl)-2-ethyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(ethylamino)azetidine-3-carboxamide was prepared. HPLC/MS: retention time=3.623 min, [M+H]30 =491.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4](O)([C:19]([F:22])([F:21])[F:20])[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:7][C:6]=1[CH2:17][CH3:18].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:24])[C:4](=[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:7]=[C:6]1[CH2:17][CH3:18])[C:19]([F:21])([F:22])[F:20]
Reactant: CCc1[nH]n(-c2ccccc2)c(=O)c1C(O)(C(=O)OC)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCC1=NN(c2ccccc2)C(=O)C1=C(C(=O)OC)C(F)(F)F

Procedure:
To a toluene solution (5 ml) of 3-ethyl-α-hydroxy-2,5-dihydro-5-oxo-1-phenyl-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (172 mg, 0.5 mmol), thionyl chloride (0.365 ml, 5.0 mmol) was added and the mixture was stirred under reflux for 3 hours. After concentrating the liquid reaction mixture under reduced pressure, the title compound was obtained as a reddish brown solid (163 mg).
Reaction SMILES: [BrH:1].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16]C(=O)C)[C:14](=[O:20])[N:13]([CH2:21][CH2:22][NH:23][CH3:24])[C:12]3[CH:25]=[CH:26][CH:27]=[CH:28][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].C(O)C>O>[BrH:1].[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:20])[N:13]([CH2:21][CH2:22][NH:23][CH3:24])[C:12]3[CH:25]=[CH:26][CH:27]=[CH:28][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CNCCN1C(=O)[C@H](OC(C)=O)[C@H](c2ccc(C)cc2)Sc2ccccc21
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNCCN1C(=O)[C@H](O)[C@H](c2ccc(C)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
A mixture of 0.8 g of (±)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(N-methylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin- 4(5H)-one hydrobromide, 10 ml of 5% aqueous sodium hydroxide solution and 5 ml of ethanol is stirred at room temperature for 1 hours. After the reaction is completed, the mixture is diluted with water and the aqueous mixture is extracted with chloroform. The extract is washed with aqueous saturated sodium chloride solution, dried and evaporated to remove solvent. The residue is converted to its hydrobromide and recrystallized from ethanol, whereby 0.58 g of (±)-cis-2-(4-methylphenyl)-3-hydroxy-5-[2-(N-methylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrobromide is obtained as prisms.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])#[N:2].[Cl:14][C:15]([Cl:19])([Cl:18])[S:16]Cl.C(N(CC)CC)C.CCCCCC>C(Cl)Cl>[C:1]([CH2:3][N:4]([S:16][C:15]([Cl:19])([Cl:18])[Cl:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])#[N:2]
Reactant: N#CCNC(=O)c1ccccc1Cl
Reactant: ClSC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: N#CCN(SC(Cl)(Cl)Cl)C(=O)c1ccccc1Cl
Reaction time: 0.42 h

Procedure:
To a stirred mixture of 5.0 g (0.026 mole) N-Cyanomethyl-2-chlorobenzamide (the product of Example 8) and 5.3 g (0.029 mole) trichloromethylsulfenyl chloride in 125 ml methylene chloride, 3.2 g (0.032 mole) triethylamine in 25 ml methylene chloride were dropped in over 35 minutes. The reaction mixture was stirred about 25 minutes. The reaction mixture was washed three times with 75 ml water, dried over magnesium sulfate and stripped to give a brown oil. Hexane (25 ml) was added to the oil which crystallized when cooled in an ice bath.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:19][CH:20]1[CH:27]2[CH2:28][C:23]3([OH:30])[CH2:24][CH:25]([CH2:29][CH:21]1[CH2:22]3)[CH2:26]2>>[OH:30][C:23]12[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:29][CH:21]([CH:20]3[NH:19][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[C:10]([O:9][CH2:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:11]=3)[CH2:22]1)[CH2:24]2
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Reactant: O=C(O)c1cccc(OCCc2ccccc2)c1
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1cccc(OCCc2ccccc2)c1

Procedure:
Prepared from 3-phenethyloxy-benzoic acid and 4-amino-1-hydroxyadamantane to give the title compound as a mixture of two isomers. 1H NMR (300 MHz, CDCl3): δ 7.20-7.39 (m, 8H), 7.13 (dd, 0.3H), 7.02 (dd, 0.7H), 6.22-6.38 (m, 1H), 4.09-4.28 (m, 3H), 3.11 (t, 2H), 2.24 (t, 2H), 1.47-2.00 (m, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH3:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH3:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1CN1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Reaction time: 8 h
Yield: 8.7 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.188 g, 0.383 mmol) in methylene chloride (6 mL) was added with trifluoroacetic acid (6 mL) at room temperature, and the mixture was stirred overnight. The solvent was evaporated, then the residue was dissolved in methanol (8 mL), the solution was added with a 5% solution of hydrochloric acid in methanol (2 mL), and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, and added to saturated aqueous sodium hydrogencarbonate, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated to obtain the objective (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0130 g, 8%).
Reaction SMILES: [Br:1][C:2]1[N+:10]([O-:11])=[CH:9][C:8]2[N:7]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]3=[N+:20]([O-])[CH:21]=[CH:22][CH:23]=[C:5]3[C:4]=2[CH:3]=1.CS([Cl:29])(=O)=O>CN(C)C=O.C(OCC)(=O)C.O>[Br:1][C:2]1[N+:10]([O-:11])=[CH:9][C:8]2[N:7]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]3[N:20]=[CH:21][CH:22]=[C:23]([Cl:29])[C:5]=3[C:4]=2[CH:3]=1.[Br:1][C:2]1[N+:10]([O-:11])=[CH:9][C:8]2[N:7]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]3[N:20]=[C:21]([Cl:29])[CH:22]=[CH:23][C:5]=3[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c2c[n+]([O-])c(Br)cc2c2ccc[n+]([O-])c21
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1c2c[n+]([O-])c(Br)cc2c2c(Cl)ccnc21
Product: C[Si](C)(C)CCOCn1c2c[n+]([O-])c(Br)cc2c2ccc(Cl)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-bromo-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-1,7-dioxide (1 g, 2.4 mmol) in N,N-dimethylformamide (19 mL) was treated with methanesulfonyl chloride (0.38 mL, 4.9 mmol) and the reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was then diluted with ethyl acetate (150 mL) and water (200 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 40 g, ISCO, 5-85% ethyl acetate in heptane) to afford the title compound as a 4:1 mixture with 6-bromo-2-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-7-oxide respectively as an off-white solid (100 mg, 10%). The mixture was used in the next step without any further purification.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]([OH:25])[CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][N:20]2[CH3:24])[CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]([O:25][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][N:20]2[CH3:24])[CH:14]=[CH:15][CH:16]=1
Reactant: COc1cccc(C(O)CC2CCCN2C)c1
Reactant: CCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCC(=O)OC(CC1CCCN1C)c1cccc(OC)c1
Reaction time: 2 h
Yield: 90.5 %

Procedure:
A solution of 0.7 g of hexanoyl chloride in 10 ml of methylene chloride is added drop by drop to a mixture of 1.17 g of 1-(3-methoxyphenyl)-2-(1-methyl-2-pyrrolidinyl)-ethanol and 0.5 g of triethyl amine in 20 ml methylene chloride. The mixture is stirred for 2 hours and subsequently treated with water. The organic phase is separated, dried over sodium sulphate and concentrated. There are obtained 1.5 g of the title compound as tough, light oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH:19]=3)=[CH:10][C:9]=2[F:20])=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:28][CH2:29][C:30](Cl)=[O:31]>ClCCl.CN(C)C=O>[Cl:28][CH2:29][C:30]([N:17]1[CH2:16][CH:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:6]=[CH:7][C:2]([F:1])=[CH:3][N:4]=3)=[C:9]([F:20])[CH:10]=2)[CH2:19][CH2:18]1)=[O:31]
Reactant: O=C(Cl)CCl
Reactant: Fc1cnc(-c2ccc(C3=CCNCC3)cc2F)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCl)N1CC=C(c2ccc(-c3ncc(F)cn3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5-Fluoro-2-[2-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-pyrimidine (22AB) (1.94 g, 7.1 mmol, 1 equiv) was dissolved in a (3v:1v) mixture of dichloromethane (30 mL) and N,N-dimethyl formamide (10 mL) and triethylamine (862 mg, 1.19 mL, 8.52 mmol, 1.2 equiv) was added, followed by slow addition of chloroacetyl chloride (962 mg, 678 uL, 8.52 mmol, 1.2 equiv) at room temperature. The mixture was then stirred for about 4 hours at room temperature.
Reaction SMILES: O[N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2N=N1.[CH:11]1([N:17]=C=NC2CCCCC2)CCCC[CH2:12]1.CS(NC1C=CC(C(=O)CCC(O)=O)=CC=1)(=O)=O>CN(C)C=O>[CH3:12][C:11]1[N:17]=[C:8]([CH2:7][CH2:6][NH2:2])[CH:9]=[CH:10][CH:5]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: On1nnc2ccccc21
Agent: CS(=O)(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Solvent: CN(C)C=O
Product: Cc1cccc(CCN)n1
Reaction time: 1 h
Yield: 100 %

Procedure:
4.76 g (35.3 mmol) of 1-hydroxybenzotriazole and 7.27 g (35.3 mmol) of dicyclohexylcarbodiimide were added to a solution of 7.02 g (29.4 mmol) of 4-(4-methylsulfonylaminophenyl)-4-oxobutyric acid in 60 ml of dimethylformamide at 0° C. and the mixture was stirred at that temperature for 1 h. 4.80 g (35.3 mmol) of 2-(6-methyl-2-pyridyl)ethylamine obtained in the above step (2) was added thereto. The mixture was stirred at room temperature for 12 h and then filtered. The filtrate was concentrated. The solid residue thus obtained was washed with a solvent mixture of chloroform/acetic acid/ethanol to give 9.39 g (yield: 89%) of the intended compound in the form of white crystals.
Reaction SMILES: [N+]([O-])(O)=O.[OH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:18])=[C:13](C)[C:14]=2C)[O:9][C:8](=[O:19])[CH:7]=1.[CH:20](Cl)(Cl)Cl>>[CH3:18][C:12]1[C:11]([CH3:20])=[C:10]2[C:15]([C:6]([OH:5])=[CH:7][C:8](=[O:19])[O:9]2)=[CH:14][CH:13]=1
Reactant: Cc1cc2oc(=O)cc(O)c2c(C)c1C
Reactant: ClC(Cl)Cl
Solvent: O=[N+]([O-])O
Product: Cc1ccc2c(O)cc(=O)oc2c1C
Reaction time: 0.5 h

Procedure:
Fuming nitric acid (18 ml) was added to a stirred suspension of 4-hydroxy-5,6,7-trimethylcoumarin (m.p. 262°-4°; 3.38g) in chloroform (250 ml) at room temperature over 1.5 hours. After a further 30 minutes, the solvent was removed in vacuo at room temperature and 6N hydrochloric acid (70 ml) added to the residue. Filtration gave the product, m.p. 134°-7°(d), (C12H11NO5 requires C, 57.83; H, 4.45; N, 5.62. Found: C, 57.92; H, 4.57; N, 5.65).
Reaction SMILES: O[CH:2]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:7]([O:8][C@@H:9]2[O:17][C@H:16]([CH2:18][OH:19])[C@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[C@H:5]([OH:6])[C@H:3]1[OH:4].[CH2:24]([NH2:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH3:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][NH:34][CH:2]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:7]([O:8][C@@H:9]2[O:17][C@H:16]([CH2:18][OH:19])[C@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CCCCCCCCCCN
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Product: CCCCCCCCCCNC1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O

Procedure:
The process was carried out in essentially the same manner as in Step (a) of Example 5, using 21 g of lactose and 15.2 g of decylamine.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCOCCCCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCCOCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
To a solution of Intermediate 12 (1.0 g, 4.8 mmol) in CH2Cl2 (20 mL) was added Dess-Martin periodinane (2.4 g, 5.76 mmol) and the reaction was stirred 2 hours at room temperature. The solution was then diluted with CH2Cl2 (40 mL), washed with water (2×20 mL), saturated solution of sodium bicarbonate (2×20 mL), and water (20 mL), dried (Na2SO4), and concentrated. The residue was purified by column chromatography (methylene chloride/acetone, 20:1) to afford the title compound (550 mg, 58%) as oil.
Reaction SMILES: [Br:1]Br.[CH2:3]([CH:5]1[CH2:16][C:15]2[C:7](=[CH:8][C:9]3[O:13][CH2:12][O:11][C:10]=3[CH:14]=2)[C:6]1=[O:17])C.CC([O-])=O.[Na+]>C(Cl)Cl.O>[Br:1][C:14]1[C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=[C:7]2[C:15]=1[CH2:16][CH:5]([CH3:3])[C:6]2=[O:17]
Reactant: BrBr
Reactant: CCC1Cc2cc3c(cc2C1=O)OCO3
Agent: CC(=O)O[Na]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC1Cc2c(cc3c(c2Br)OCO3)C1=O
Reaction time: 24 h
Yield: 58 %

Procedure:
Br2 (11.42 ml, 221.44 mmol) was added dropwise at 0° C. into well stirred mixture of 6-ethyl-6,7-dihydro-5H-indeno[5,6-d][1,3]dioxol-5-one (40.01 g, 210.37 mmol) solution in CH2Cl2 (93 ml) and NaOAc (35.32 g, 430 6 mmol) solution in water (62 ml). After 20 h of stirring at room temperature, 11.5 g of AcONa and 3.42 ml of Br2 (30% of starting amount) were added. This procedure was repeated after 24 h, the resulting mixture was stirred for additional 48 h. The resulting mixture was diluted by CH2Cl2 (200 ml), the organic layer was separated, washed with water (350 ml), dried over MgSO4 and evaporated. The residue was recrystallized from hexane-benzene (3:1) yielding 32.83 g (58%) of white-yellow solid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[OH-:11].[Na+].[C:13](Cl)(=[O:23])[C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=O)=[CH:16][CH:15]=1.O>C(C(C)=O)C(C)C>[C:14]1([C:13]2[O:23][C:1](=[O:11])[C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=3[N:4]=2)[CH:22]=[CH:21][C:17]([C:18]2[O:9][C:1](=[O:10])[C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=3[N:4]=2)=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: [OH-]
Reactant: Nc1ccccc1C(=O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=c1oc(-c2ccc(-c3nc4ccccc4c(=O)o3)cc2)nc2ccccc12

Procedure:
Anthranilic acid (1 part by weight) and 0.35 parts of NaOH were dissolved in approximately 5.5 parts of methyl isobutyl ketone (MIBK). With stirring, a solution of 0.7 parts of terephthaloyl dichloride in 3 parts of MIBK was slowly added at approximately 60 to 70° C. to the mixture. After the addition, the mixture was reacted at 60 to 70° C. for 2 hours. Water was distilled off and approximately 2 parts of acetic anhydride was added. The mixture was then reacted for 7 hours at reflux conditions. Water was then added, the batch was refluxed for 0.5 hours and then the MIBK was distilled off. Approximately 1 part of 50% NaOH solution was then added and the reaction mixture was cooled, filtered and dried to give 2,2′-p-phenylenebis(3,1-benzoxazin-4-one).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH:27]=4)[N:20]=3)=[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:38]1(/[CH:44]=[CH:45]/[CH2:46]Cl)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C1C[O:51][CH2:50]C1>C(Cl)Cl>[CH3:37][N:35]([CH3:36])[CH2:34][CH2:33][O:32][C:28]1[CH:27]=[C:26]([NH:25][C:21]2[N:20]=[C:19]([C:18]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:50]([C:44]5([C:38]6[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=6)[CH2:46][CH2:45]5)=[O:51])[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=34)[CH:24]=[CH:23][N:22]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: ClC/C=C/c1ccccc1
Reactant: C1CCOC1
Reactant: COc1ccc2c(-c3ccnc(Nc4cccc(OCCN(C)C)c4)n3)c(-c3cccc(N)c3)nn2c1
Solvent: ClCCl
Product: COc1ccc2c(-c3ccnc(Nc4cccc(OCCN(C)C)c4)n3)c(-c3cccc(NC(=O)C4(c5ccccc5)CC4)c3)nn2c1
Reaction time: 1 h
Yield: 45 %

Procedure:
4-[2-(3-Aminophenyl)-6-(methyloxy)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-{[2-(dimethylamino)ethyl]oxy}phenyl)-2-pyrimidinamine (97 mg, 0.20 mmol) and (2E)-3-phenyl-2-propenyl chloride (40 mg, 0.24 mmol) were combined in THF (2 mL) and stirred for 1 h. The mixture was diluted with DCM and TEA (2 drops), absorbed onto silica gel, and purified by silica gel chromatography to afford the title compound as a yellow solid (56 mg, 45%). 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.55 (s, 1H), 8.57 (d, J=2.0 Hz, 1H), 8.45 (d, J=9.3 Hz, 1H), 8.23 (d, J=5.6 Hz, 1H), 7.97 (br s, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.62-7.59 (m, 3H), 7.55-7.53 (m, 1H), 7.47-7.39 (m, 4H), 7.30-7.26 (m, 3H), 7.14 (m, 1H), 6.81 (d, J=15.6 Hz, 1H), 6.52 (dd, J=8.2, 2.5 Hz, 1H), 6.48 (d, J=5.3 Hz, 1H), 3.99 (t, J=6.0 Hz, 3H), 3.87 (s, 3H), 2.68-2.64 (m, 2H), 2.23 (s, 6H). ES-LC/MS m/z=626 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:29])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:4][CH2:5][CH2:6][CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:14][OH:15].[OH:30]O>C(O)(=O)C.O>[OH:1][CH2:2][C:3]([CH3:29])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:4][CH2:5][CH2:6][CH2:7][S:8]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:14][OH:15])=[O:30]
Reactant: CC(CO)(CCCCSCCCCC(C)(CO)c1ccccc1)c1ccccc1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: CC(CO)(CCCCS(=O)CCCCC(C)(CO)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 87.2 %

Procedure:
To a solution of 6-(6-hydroxy-5-methyl-5-phenylhexylsulfanyl)-2-methyl-2-phenylhexan-1-ol (3.0 g, 7.0 mmol) in glacial acetic acid (20 mL) was added hydrogen peroxide (50 wt. % in water; 0.5 mL, 7.0 mmol). The reaction mixture was stirred at rt for 22 h, then diluted with water (100 mL), and extracted with chloroform (3×80 mL). The combined organic phases were subsequently washed with saturated NaHCO3 solution (3×80 mL) and saturated NaCl solution (80 mL), dried over MgSO4, concentrated in vacuo, and dried in high vacuo to give crude 6-(6-hydroxy-5-methyl-5-phenylhexylsulfinyl)-2-methyl-2-phenylhexan-1-ol (2.63 g 88%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 7.42-7.12 (m, 10 H), 3.78-3.58 (m, 2 H), 3.58-3.45 (m, 2 H), 2.90-2.70 (m, 2 H), 2.68-2.39 (m, 2 H), 1.95-1.50 (m, 8 H), 1.50-1.00 (m, 10 H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 144.5, 144.4, 128.4, 128.3, 126.5, 126.2, 126.1, 72.2, 72.1, 71.9, 52.4, 52.0, 43.2, 37.8, 37.7, 23.2, 22.9, 22.4, 21.7, 21.5. HRMS (LSIMS, nba): Calcd. for C26H39O3S1 (MH+): 431.2620, found: 431.2611.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH:19]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1)[N+]([O-])=O.[CH2:37]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[CH2:41][CH2:40][NH:39][CH2:38]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH2:19][N:39]2[CH2:38][CH2:37][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[CH2:41][CH2:40]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccccc1
Reactant: c1ccc2c(c1)CCNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(CN2CC(CN3CCc4ccccc4CC3)C(c3ccccc3)C2)cc1
Yield: 49.1 %

Procedure:
The title compound was prepared from 20 mg of 1-Benzyl-3-(SR)-formyl-4-(SR)-phenylpyrrolidine, 28 mg of 2, 3, 4, 5-tetrahydro-1H-benzo[d]-azepine-picrate salt, 0.013 mL of DIEA and 24 mg of sodium triacetoxyborohydride using a procedure analogous to that described in Example 9, Step B to provide 14.5 mg of the title compound. RF : 0.53 (50% EtOAc in hexanes). 1H NMR (300 MHz, CDCl3): δ2.42-3.02 (m, 16H), 3.67 (ABq, J=13 Hz, 2H), 7.00-7.38 (m, 14H). Mass Spectrum (ESI): 397.1 (M+H).