Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1C(C)=C2C(CCC(CCCC(CCCC(CCCC(C)C)C)C)(C)O2)=C(C)[C:3]=1O.P(Cl)(Cl)(Cl)=O.[Br:37][C:38]1[C:39](=[O:54])[NH:40][C:41](=[O:53])[N:42]([CH:52]=1)[C@@H:43]1[O:51][C@H:48]([CH2:49][OH:50])[C@@H:46]([OH:47])[C@H:44]1[OH:45].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.N1C=CC=CC=1.C1C=CC=CC=1>[C:2](=[C:49]([OH:50])[C@H:48]1[O:51][C@@H:43]([N:42]2[CH:52]=[C:38]([Br:37])[C:39](=[O:54])[NH:40][C:41]2=[O:53])[C@H:44]([OH:45])[C@@H:46]1[OH:47])([CH3:3])[CH3:1]
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1Br
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)=C(O)[C@H]1O[C@@H](n2cc(Br)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O

Procedure:
The phosphrylation reaction described in Example 1 is repeated except that 4.3 g (0.01 mol) of DL-alpha-tocopherol, 4 g of pyridine, 3.06 g of phosphorus oxychloride, and 50 ml of benzene are used. Separately, 5-bromouridine is treated with p-toluene-sulfonic acid in aceton to give isopropylidene-5-bromouridine and 4.35 g (0.012 mol) of this isopropylidene-5-bromouridine and 2 g of pyridine are dissolved in 60 ml of tetrahydrofuran. Then, the reaction and workup procedures of Example 1 are followed to give the potassium salt and, then, the free acid. The free acid is recrystallized from ethanol to give 2.5 g of colorless crystals melting at 177°-178° C.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([CH2:12][C:13]([OH:15])=O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[CH:16]12[N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:20]([CH2:21][CH2:22]1)[CH2:19][NH:18][CH2:17]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.O>[O:11]=[C:10]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7](=[O:8])[N:9]1[CH2:12][C:13]([N:18]1[CH2:17][CH:16]2[N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:20]([CH2:21][CH2:22]2)[CH2:19]1)=[O:15]
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)CN1C(=O)c3ccccc3C1=O)C2
Reaction time: 8 h
Yield: 75.6 %

Procedure:
To a stirred solution of N-phthaloylglycine (725 mg, 3.53 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 2.36 mmol) in CH2Cl2 (20 mL) were added HOBt (481 mg, 3.53 mmol) and WSC (677 mg, 3.53 mmol) at room temperature and the mixture was stirred overnight. To the mixture was added H2O (5 mL) and the organic layer was separated, washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 230-400 mesh, 309, CH2Cl2-MeOH=98/2 to 92/8) afforded the product as a white solid (713 mg, 81%).
Reaction SMILES: O=P(Cl)(Cl)Cl.[Br:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.CN([CH:19]=[O:20])C>>[Br:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([CH:19]=[O:20])=[CH:10][NH:11]2
Reactant: Brc1cccc2[nH]ccc12
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2cccc(Br)c12
Temperature: 35 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
POCl3 (1.02 g, 6.63 mmol) was added dropwise to ice cold DMF (3 mL) and stirred for 15 min. 4-Bromoindole (1.00 g, 5.10 mmol) in DMF (1 mL) was added slowly. The mixture was heated to 35° C. with continuous stirring for 1.20 h (yellow precipitation was formed). The reaction mixture was cold on ice and treated with ice and 20% W/w aq. NaOH to pH 14 (pink color). Heating at reflux for 15 min. afforded a yellow clear solution, which formed a white precipitation when allowed to attain rt. The precipitation was filtered off, rinsed with ice cold water and dried under reduced pressure over weekend to give the title compound (1.14 g, 65%) as an off white solid. MS (ESI+) for C9H6BrNO m/z 224 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:4][C:3]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[F:27].[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.[F-].[Cs+].[NH4+].[Cl-]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCOC(C)=O>[F:27][C:19]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=1[O:17][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[C:31]1[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=1)[N:8]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:7]=[CH:6]2
Reactant: OB(O)c1ccncc1
Reactant: O=[N+]([O-])c1ccc(Oc2cc3cnn(C4CCCCO4)c3cc2Br)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2cc3cnn(C4CCCCO4)c3cc2-c2ccncc2)c(F)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A mixture of 6-bromo-5-(2-fluoro-4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (5.0 g, 11.5 mmol), 4-pyridineboronic acid (3.0 g, 24.3 mmol), PdCl2(dppf) (1.8 g, 2.25 mmol) and CsF (5.0 g, 33.0 mmol) in 1,4-dioxane (100 mL) is stirred at 110° C. overnight. Then, aqueous NH4Cl and EtOAc are added. The organic phase is separated, dried over anhydrous MgSO4 and concentrated. The residue is purified by silica gel column chromatography eluting with PE:EtOAc (3:1) to give the desired product (2.8 g, 56% yield). MS (m/z): 435.1 (M+H).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:16][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CBr)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.4 %

Procedure:
To a solution of 1,1-dimethylethyl 3-(hydroxymethyl)-1-pyrrolidinecarboxylate (0.56 g, 2.8 mmol) with carbon tetrabromide (1.39 g, 4.2 mmol) in methylene chloride (10 mL) was added drop wise a solution of triphenyl phosphine (0.73 g, 2.8 mmol in 5 mL of methylene chloride). Upon completion the mixture was stirred 18 h at room temperature. The solvent was removed at reduced pressure and the residue stirred in 10% ethyl acetate 90% hexane. The mixture was filtered and the resulting solution chromatographed on silica eluting with a gradient of 0-25% EtOAc in hexane to afford the desired compound (0.41 g, 55%). MS (ES+) m/z 264 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]([CH3:16])[CH3:15])=[C:2]=[O:3].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]2[CH2:29][C:28](=[O:30])[CH:27]=[CH:26][NH:25]2)=[CH:20][CH:19]=1>>[CH:14]([C:5]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([O:10][CH3:11])=[CH:9][C:4]=1[NH:1][C:2]([N:25]1[CH:26]=[CH:27][C:28](=[O:30])[CH2:29][C@H:24]1[C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)=[O:3])([CH3:16])[CH3:15]
Reactant: O=C1C=CN[C@H](c2ccc(F)cc2)C1
Reactant: COc1cc(N=C=O)c(C(C)C)cc1OC
Product: COc1cc(NC(=O)N2C=CC(=O)C[C@H]2c2ccc(F)cc2)c(C(C)C)cc1OC

Procedure:
1-Isocyanato-2-isopropyl-4,5-dimethoxy-benzene was reacted with (S)-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one following the procedure of step 3 of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][CH2:28][C@@H:29]([OH:31])[CH3:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][CH2:28][C@@H:29]([OH:31])[CH3:30])=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: C[C@H](O)CN
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: C[C@H](O)CNC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to (S)-1-amino-2-propanol via Procedure G. The product was purified on reverse phase HPLC to yield (S)-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(2-hydroxypropyl)terephthalamide. MS (Q1) 444 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].[Cl:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]Cl)[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOCC>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][Cl:14])[CH:17]=1
Reactant: COC(=O)CCc1ccccc1O
Reactant: ClCc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)CCc1ccccc1OCc1cccc(CCl)c1
Yield: 54.6 %

Procedure:
A mixture of 1.8 g (10 mmol) of 2-hydroxybenzenepropanoic acid methyl ester, 14 g (80 mmol) of α,α'-dichloro-m-xylene, 4.25 g (30.8 mmol) of anhydrous, granular potassium carbonate, and 70 mL of acetonitrile was stirred and refluxed for 4 hr. After being cooled, the resulting mixture was diluted with 200 mL of ether and filtered with suction. The solids were washed thoroughly with ether and then the filtrate and washes were combined and concentrated in vacuo. The oily residue was chromatographed on 100 g of silica gel. Elution with 19:1 hexane-ether afforded 1.74 g (54.6%) of 2-[3-(chloromethyl)phenylmethoxy]benzenepropanoic acid methyl ester as a colorless oil.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:12]([OH:16])[CH2:13][CH2:14][OH:15]>N1C=CC=CC=1>[CH3:8][C:7]1[CH:9]=[CH:10][C:4]([S:1]([O:15][CH2:14][CH2:13][CH2:12][O:16][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])(=[O:3])=[O:2])=[CH:5][CH:6]=1
Reactant: OCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 82.9 %

Procedure:
To a solution of 116.36 g (610.37 mmol) of tosyl chloride in 200 mL of anhydrous pyridine add 19.26 g (253.09 mmol) of 1,3-propanediol in 50 mL of anhydrous pyridine dropwise over the period of two hours at 0-10° C. Stir the reaction mixture for an additional four hours, then pour it into 500 mL of ice cold water. Collect the white precipitate that forms by filtration, wash filter cake with water, dilute aqueous sulfuric acid (10 wt. %), dilute aqueous sodium carbonate (1M), and again with water. Crystallize the wet product from acetone to afford 80.68 g (83%) of 1,3-propanediol bis(4-methylbenzenesulfonate) as off white powder. 1H NMR (400 MHz, CDCl3) δ 7.77-7.69 (m, 4H), 7.37-7.30 (m, 4H), 4.05 (t, J=6.0 Hz, 4H), 2.44 (s, 6H), 1.99 (p, J=6.0 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 145.01, 132.65, 129.92, 127.84, 65.83, 28.67, 21.61. MS (m/e): 408 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([N:13]([CH3:15])[CH3:14])[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][CH3:24])=[CH:19][CH:18]=2)[N:3]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[Cl:42][C:43]1[CH:51]=[CH:50][C:46]([C:47](O)=[O:48])=[CH:45][CH:44]=1>CCOC(C)=O>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]([C:47](=[O:48])[C:46]3[CH:50]=[CH:51][C:43]([Cl:42])=[CH:44][CH:45]=3)[CH3:24])=[CH:19][CH:18]=2)=[N:5][C:6]=1[N:13]([CH3:14])[CH3:15]
Reactant: CNc1ccc(Cc2nc(Cl)c(CC(=O)OC)c(N(C)C)n2)cc1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc(N(C)C(=O)c3ccc(Cl)cc3)cc2)nc1N(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of methyl {4-chloro-6-(dimethylamino)-2-[4-(methylamino)benzyl]pyrimidin-5-yl}acetate (0.080 g, 0.23 mmol), 1-hydroxybenzotriazole (0.043 g, 0.32 mmol), triethylamine (0.11 mL, 0.80 mmol), and 4-chlorobenzoic acid (0.043 g, 0.28 mmol) was treated with WSCI (0.066 g, 0.34 mmol) at room temperature and the reaction mixture was stirred at room temperature for 16 hours. EtOAc was then added and the organic layer was washed sequentially with 0.5N HCl, saturated NaHCO3, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the crude product methyl[4-chloro-2-{4-[(4-chlorobenzoyl)(methyl)amino]benzyl}-6-(dimethylamino)pyrimidin-5-yl]acetate.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[O:3]1.[CH2:15](I)[CH3:16]>>[CH2:15]([N:11]1[CH:12]=[CH:13][C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)=[N:10]1)[CH3:16]
Reactant: CC1(C)OB(c2cc[nH]n2)OC1(C)C
Reactant: CCI
Product: CCn1ccc(B2OC(C)(C)C(C)(C)O2)n1

Procedure:
This compound was prepared by using procedure analogous to those described for the synthesis of Example 85A, Step 1 starting from 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and ethyl iodide. LCMS (M+H−82)+: m/z=141.1.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[O:13].O>Br.C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[O:13]
Reactant: COc1ccc2c(c1)C(=O)CCO2
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCOc2ccc(O)cc21
Reaction time: 4 h
Yield: 93.2 %

Procedure:
A mixture of 50.0 g (281 mmol) of 6-methoxychroman-4-one in 350 mL 48% HBr and 350 mL acetic acid was heated to reflux under N2. After 4 hours, the reaction mixture was cooled to room temperature in a Rotovap (trademark) and 1 L H2O was added. The suspension was kept at 0° C. overnight. The mixture was filtered, and the precipitate washed two times with H2O, two times with hexanes and then dried under vacuum to give 43.0 g of the title product as a dark purple/black solid. 93% yield.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[C:15]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]1[CH2:11][NH:12][CH2:13][CH2:14]2.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:1]([N:12]1[CH2:13][CH2:14][C:15]2([O:9][CH:10]2[CH2:11]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc(C23CCNCC2O3)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: c1ccc(CN2CCC3(c4ccccc4)OC3C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
22.5 Ml of benzyl bromide was added dropwise to a stirred solution of 32.3 g of 3,4-epoxy-4-phenylpiperidine and 38.1 ml of triethylamine in 254 ml of benzene. A precipitate appeared during the addition. The whole reaction mixture was then stirred at room temperature for three hours. The residual solid was removed by filtration and the solvent evaporated to give 53.4 g of 1-benzyl-3,4-epoxy-4-phenyl-piperidine.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12].FC1C=CC([B:23]([OH:25])[OH:24])=C(O[C@H](CC=C)C)C=1>>[CH3:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([B:23]([OH:25])[OH:24])=[C:3]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])[CH:4]=1
Reactant: C=CC[C@H](C)Oc1cc(C)c(C)cc1Br
Reactant: C=CC[C@H](C)Oc1cc(F)ccc1B(O)O
Product: C=CC[C@H](C)Oc1cc(C)c(C)cc1B(O)O
Yield: 85 %

Procedure:
Prepared in 85% yield from (S)-1-bromo-4,5-dimethyl-2-(pent-4-en-2-yloxy)benzene following the procedure for (S)-(4-fluoro-2-(pent-4-en-2-yloxy)phenyl)boronic acid. 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 6.72 (s, 1H), 5.93-5.82 (m, 1H), 5.81 (d, J=5.8 Hz, 2H), 5.22-5.13 (m, 2H), 4.68-4.55 (m, 1H), 2.60-2.42 (m, 2H), 2.28 (s, 3H), 2.22 (s, 3H), 1.38 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[NH:8][C:7]([C:16]([O:18]C)=[O:17])=[CH:6]2.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[NH:8][C:7]([C:16]([OH:18])=[O:17])=[CH:6]2
Reactant: COC(=O)c1cc2cc(OC)c(OC)c(OC)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2cc(C(=O)O)[nH]c2c(OC)c1OC
Reaction time: 3 h

Procedure:
Methyl 5,6,7-trimethoxyindole-2-carboxylate (700 mg) was dissolved in methanol (13 mL), potassium hydroxide powder (450 mg) was added to the solution, and the mixture was stirred for 3 hours under reflux. After allowing the reaction mixture to cool, it was concentrated under reduced pressure, and water was added to the residue. The resultant water layer was washed with ether and then neutralized with diluted hydrochloric acid. Crystals deposited were collected by filtration and dried to obtain the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][N:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][N:16]=1
Reactant: COC(=O)c1ccc(OCC2CCCN2C(=O)OC(C)(C)C)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC2CCCN2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a stirred solution of methyl 2-[[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methyloxy]pyridine-5-carboxylate (232.3 mg, 0.691 mmol) in CH2Cl2 (4.6 mL) was added TFA (0.9 mL) at 0° C., and the reaction mixture was stirred at room temp for 2 hr. The solvent was removed under a reduced pressure and the residue was made basic by the addition of 1N NaOH. The aqueous solution was extracted with CHCl3, washed with brine, and the dried over Na2SO4. The solvent was evaporated under a reduced pressure to afford 146.2 mg (90%) methyl 2(2-pyrrolidinyl)methoxypyridine-5-carboxylate as an oil. 1H-NMR (400 MHz, CDCl3) δ1.49-1.58 (m, 1H), 1.72-2.18 (m, 3H), 2.92-3.05 (m, 2H), 3.50-3.57 (m, 1H), 3.91 (s, 3H), 4.23 (dd, J=8.0, 10.7 Hz, 1H), 4.38 (dd, J=4.4, 10.3 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 8.15 (dd, J=2.4, 8.8 Hz, 1H), 8.80 (d, J=2.4 Hz, 1H); MS (FAB) m/z 237 (M++1).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C@H:16]2[CH2:21][N:20]([CH:22]3[CH2:25][CH2:24][CH2:23]3)[CH2:19][CH2:18][N:17]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.O>[Pd].C(O)C>[CH:22]1([N:20]2[CH2:19][CH2:18][N:17]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:16]([C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])[CH2:21]2)[CH2:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCC2)C[C@@H]1C(=O)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C2CCC2)C[C@@H]1C(=O)N1CCNCC1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
10% Palladium on carbon (900 mg) was added to tert-butyl (2R)-2-[(4-benzylpiperazin-1-yl)carbonyl]-4-cyclobutylpiperazine-1-carboxylate (5.12 g) and water (10 ml). Under an argon atmosphere, ethanol (250 μl) was added and the mixture stirred at room temperature under a hydrogen filled balloon. After 4 hours the catalyst was removed by filtration and washed with a small quantity of non-flammable solvent (dichloromethane). The combined filtrate was concentrated in vacuo, azeotroped once with toluene and dried under vacuum to give tert-butyl (2R)-4-cyclobutyl-2-(piperazin-1-ylcarbonyl)piperazine-1-carboxylate as an off-white foam (4.08 g).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=O)[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][CH:18]=[N:19][C:4]1=2)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[S:29])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][CH:18]=[N:19][C:4]1=2)[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCN1c2ncccc2C(=O)N(C)c2cccnc21
Solvent: Cc1ccccc1
Product: CCN1c2ncccc2C(=S)N(C)c2cccnc21
Yield: 162.8 %

Procedure:
A mixture of 2.66 g (0.01 mol) of 5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido-[3,2-b:2'3'-e] [1,4]diazepin-6-one and 2.10 g (0.005 mol) of Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) in 50 ml of toluene was refluxed for 21/2 h. The solvent was then removed in vacuo and water was added to the residue. The product was extracted with ethyl acetate, dried (anhydrous sodium sulfate), and concentrated in vacuo. Purification was effected on a silica gel column using methylene chloride as the first eluent, followed by ethyl acetate/hexane (1:4). Removal of the solvent in vacuo gave 2.20 g (74% of theory) of 5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-thione as a yellow powder, which was recrystallized from 10% hexane/ethyl acetate to provide 1.1 g of the title compound as yellow needles, m.p. 157°-158° C.
Reaction SMILES: C(C1C=CC(CN)=CC=1)(C)(C)C.O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.[C:28]([C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]=[C:40]=[O:41])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29].[NH2:42][CH2:43][C:44]1[CH:49]=[C:48]([CH:50]=[CH2:51])[C:47]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])=[C:46]([C:57]([F:60])([F:59])[F:58])[CH:45]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:28]([C:32]1[CH:33]=[CH:34][C:35]([CH2:38][NH:39][C:40](=[O:41])[NH:42][CH2:43][C:44]2[CH:49]=[C:48]([CH:50]=[CH2:51])[C:47]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])=[C:46]([C:57]([F:60])([F:58])[F:59])[CH:45]=2)=[CH:36][CH:37]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1ccc(CN=C=O)cc1
Reactant: C=Cc1cc(CN)cc(C(F)(F)F)c1NS(C)(=O)=O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC(C)(C)c1ccc(CN)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=Cc1cc(CNC(=O)NCc2ccc(C(C)(C)C)cc2)cc(C(F)(F)F)c1NS(C)(=O)=O
Reaction time: 5 h
Yield: 36.88 %

Procedure:
4-tert-Butyl-benzylamine (1.5 eq, 15.20 μl, 0.09 mmol), BOC2O (1.5 eq, 0.09 mmol, 20.70 μl), and DMAP (0.2 eq, 0.01 mmol, 1.34 mg) were added to methylene chloride. The reaction mixture was stirred for 5 hr. After confirming the synthesis of the 1-tert-butyl-4-isocyanatomethylbenzene with TLC, N-(4-Aminomethyl-2-trifluoromethyl-6-vinylphenyl)methanesulfonamide (1 eq, 0.06 mmol, 20.5 mg) and TEA (2 eq, 0.12 mmol, 16.72 μl) were added into the reaction mixture. The reaction mixture was stirred for 12 hr and purified with similar procedure to step 7 of example 8 to gave title compound (10.7 mg 36.88%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:19]=[C:16]([CH:17]=O)[C:15]([OH:20])=[CH:14][CH:13]=1.C(O)C>CO>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([OH:20])=[C:16]([CH:19]=1)[CH:17]=[N:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CO
Solvent: CCO
Product: O=C(O)c1ccc(N=Cc2cc(Cl)ccc2O)cc1
Yield: 94 %

Procedure:
Using the procedure of Sheeman et al [J.A.C.S., Vol. 84 (1982), p. 2457], 1.37 g of p-amino-benzoic acid, 2.35 g of 5-chlorosalicylaldehyde, 240 ml of ethanol and 17 ml of anhydrous methanol were reacted to obtain 2.59 g of 4-[(5-chloro-2-hydroxy-benzylidene)amino]-benzoic acid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]=12.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1>>[CH3:12][C:9]1[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]2=[C:2]([O:23][CH2:22][C:21]3[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:26])[F:27])=[CH:25][CH:24]=3)[N:3]=[N:4][CH:5]=[C:6]2[C:10]=1[CH3:11]
Reactant: C=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: OCc1ccc(C(F)(F)F)cc1
Product: C=CCn1c(C)c(C)c2cnnc(OCc3ccc(C(F)(F)F)cc3)c21
Yield: 52.5 %

Procedure:
The title compound was prepared as pale yellow crystals in 52.5% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazine and 4-trifluoromethylbenzyl alcohol.