Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=[O:3].[CH:7]1([C:10](OC)=[O:11])[CH2:9][CH2:8]1.C[O-].[Na+]>CS(C)=O>[CH:7]1([C:10](=[O:11])[CH2:1][C:2]([CH:4]2[CH2:6][CH2:5]2)=[O:3])[CH2:9][CH2:8]1
Reactant: CC(=O)C1CC1
Reactant: COC(=O)C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(CC(=O)C1CC1)C1CC1
Temperature: 52.5 °C

Procedure:
Cyclopropyl methyl ketone (2.5 mL; 25 mmol) was dissolved in DMSO (12.5 mL) and methyl cyclopropanecarboxylate (5.0 mL; 50 mmol; 2 equiv) was added. The reaction mixture was cooled in ice-water and sodium methoxide (2.70 g; 50 mmol; 2 equiv) was added. The reaction mixture was stirred for 5 min in the ice-water bath, the bath was removed, and the mixture was heated to 50-55° C. for 8 h. The reaction mixture was diluted with toluene (12.5 mL), cooled in ice-water, and 6 N HCl (9 mL) was added dropwise such that the temperature remained below 25 ° C. The layers were separated and the aqueous solution was extracted with additional toluene (10 mL). The combined organic solution was washed with aqueous sodium bicarbonate (10 mL), dried with sodium sulfate and concentrated to afford 3.50 g (92%) yield of 1,3-dicyclopropyl-1,3-propanedione.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.[CH2:21]([N:23]([CH2:26][CH2:27][CH2:28][NH2:29])[CH2:24][CH3:25])[CH3:22]>C(O)C>[CH2:21]([N:23]([CH2:26][CH2:27][CH2:28][NH:29][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1)[CH2:24][CH3:25])[CH3:22]
Reactant: CCN(CC)CCCN
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Solvent: CCO
Product: CCN(CC)CCCNCc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1

Procedure:
Using the method of Example 1, 5-bromomethyl-2-nitro-3-phenylbenzofuran is reacted with 3-(N,N-diethylamino)propylamine in ethanol to provide light tan crystals of 5-[3-(N,N-diethylamino)propylaminomethyl]-2-nitro-3-phenylbenzofuran dihydrochloridemonohydrate, m.p. 143°-150° C., having the structure
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:28])[C:15](=[O:27])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([SH:26])[CH:17]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.Br[CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C(#N)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:28])[C:15]([C:16]2[CH:17]=[C:18]([S:26][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=2)=[O:27])=[C:4]([O:29][CH3:30])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(S)cc(C(F)(F)F)c1
Reactant: O=C(O)CCCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCCCC(=O)O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-3-mercapto-N-methyl-5-(trifluoromethyl)benzamide (0.05 g, 115 μmol, Example 216, intermediate a) in acetonitrile (1 mL) were added 4-bromobutanoic acid (36.4 mg, 218 μmol) and DIPEA (29.6 mg, 40.0 μL, 229 μmol). After the addition of DIPEA the white suspension turned to a light yellow solution, which was stirred at room temperature for 24 hours before another batch of DIPEA (29.6 mg, 40.0 μL, 229 μmol) was added (white suspension turned into light yellow solution). The reaction mixture was stirred at room temperature for another 20 hours and then poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered and evaporated. The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless solid (0.01 g; 16%). MS (ESI): m/z=523.13 [M+H]+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:75][N:76]([CH3:81])[CH2:77][CH2:78][CH2:79][NH2:80]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:80][CH2:79][CH2:78][CH2:77][N:76]([CH3:81])[CH3:75])=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CCCN
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCCNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)c(F)c1
Reaction time: 0.17 h
Yield: 62.2 %

Procedure:
To a mixture of 0.070 g (0.161 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-benzoic acid (I-182) and 4 mL of dimethylformamide was added 0.0346 g (0.256 mmole) of 1-hydroxybenzotriazole, 0.0950 g (0.250 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1253 g (0.936 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0246 g (0.242 mmole) of 3-(dimethylamino)-propylamine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.052 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-3-fluoro-benzamide (I-227) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])C.[Li+].[I-]>N1C=CC=CC=1>[Cl:22][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1c(N2CCCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(O)c1c(N2CCCC2)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 20 step D from 6-chloro-4-phenyl-2-pyrrolidin-1-yl-quinoline-3-carboxylic acid ethyl ester (100 mg, 0.26 mmol) and LiI (351.4 mg, 2.63 mmol) in pyridine. Pale yellow solid (74 mg, 80%). LC-MS: 351 (M−H)−.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[C:13]3[C:14]([O:18][CH3:19])=[N:15][CH:16]=[CH:17][C:12]=3[N:11]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:10]=2)[CH:6]=[C:5]1[C:39]([OH:41])=[O:40])([CH3:3])[CH3:2].I[CH:43]([CH3:45])[CH3:44].C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>C1COCC1.O>[CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[C:13]3[C:14]([O:18][CH3:19])=[N:15][CH:16]=[CH:17][C:12]=3[N:11]([C:20]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:10]=2)[CH:6]=[C:5]1[C:39]([O:41][CH:43]([CH3:45])[CH3:44])=[O:40])([CH3:3])[CH3:2]
Reactant: CC(C)I
Reactant: COc1nccc2c1c(-c1cc(C(=O)O)n(C(C)C)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1nccc2c1c(-c1cc(C(=O)OC(C)C)n(C(C)C)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 46.2 %

Procedure:
A mixture of 1-isopropyl-4-(4-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)-1H-pyrrole-2-carboxylic acid (200 mg, 0.37 mmol), 2-iodopropane (310 mg, 1.80 mmol), Cs2CO3 (360 mg, 1.1 mmol) in THF (50 mL) was stirred at reflux for 6 hours. After cooling down, ethyl acetate (100 mL) and water (50 mL) were added. The organic layer was separated and washed by water (30 mL) and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound as a yellowish oil (100 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C@@H:9]2[CH:16]3[CH2:17][N:12]4[CH2:13][CH:14]([CH2:18][CH:10]2[CH2:11]4)[CH2:15]3)=[N:6][CH:7]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH3:28][C:29]1[CH:30]=[CH:31][C:32]([S:35]([OH:38])(=[O:37])=[O:36])=[CH:33][CH:34]=1.N>>[C:29]1([CH3:28])[CH:30]=[CH:31][C:32]([S:35]([OH:38])(=[O:36])=[O:37])=[CH:33][CH:34]=1.[C:19]1([C:2]2[CH:3]=[CH:4][C:5]([O:8][C@@H:9]3[CH:16]4[CH2:17][N:12]5[CH2:13][CH:14]([CH2:18][CH:10]3[CH2:11]5)[CH2:15]4)=[N:6][CH:7]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc(OC2C3CC4CC2CN(C4)C3)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Product: c1ccc(-c2ccc(OC3C4CC5CC3CN(C5)C4)nc2)cc1

Procedure:
The free base of the title compound was prepared from the product of Example 10C (45 mg, 0.14 mmol) and phenylboronic acid (25 mg, 0.20 mmol) according to Method F, and converted to the p-toluenesulfonate salt using the procedure of Method H: 1H NMR (300 MHz, methanol-D4) δ ppm 1.94 (d, J=13.2 Hz, 2H), 2.20 (s, 1H), 2.36 (s, 5H), 2.41 (s, 1H), 2.57 (s, 2H), 3.58 (s, 2H), 3.70 (s, 4H), 5.47 (t, J=3.4 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 7.22 (d, J=7.8 Hz, 2H), 7.30-7.41 (m, 1H), 7.42-7.51 (m, 2H), 7.56-7.63 (m, 2H), 7.67-7.75 (m, 2H), 8.07 (dd, J=8.6, 2.5 Hz, 1H), 8.40 (d, J=2.4 Hz, 1H). MS (DCI/NH3) m/z=307 (M+H)+; Anal. Calcd. for C20H22N2O.1.3C7H8O3S.0.5H2O: C, 64.81; H, 6.24; N, 5.19 Found: C, 64.77; H, 6.30; N, 5.15.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH2:16](Br)[C:17]#[CH:18].C(Cl)(Cl)Cl>CN(C)C=O>[C:1]([N:4]([C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[C:16]#[C:17][CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc2ccccc2s1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC#CN(C(C)=O)c1nc2ccccc2s1
Temperature: 50 °C
Yield: 62 %

Procedure:
2-Acetylaminobenzothiazole (e) (6.0 g) was dissolved in dimethylformamide (50 ml) and 50% sodium hydride (1.648 g) was added thereto in small portions with stirring under ice-cooling. The mixture was heated at 50° C. for 1 hour, then cooled to room temperature and 2-propynyl bromide (3.0 ml) was added thereto. The mixture was heated at 60° C. for 4 hours and evaporated to remove the solvent. After addition of water, the residue was extracted with benzene. The extract was washed with water, and evaporated to remove the solvent. The residue was applied to column chromatography on silica gel (120 g) to give 2-(N-acetyl-N-propynylamino)benzothiazole (f) (4.43 g, yield 62%) from chloroform eluate:
Reaction SMILES: [F:1][C:2]1[C:30]([F:31])=[CH:29][C:5]2[N:6]([C:19](=[O:28])[CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[NH:12][N:13]=3)[C:4]=2[CH:3]=1.[Na].[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41]Cl)[CH2:36][CH2:35]1>CN(C)C=O.C1(C)C(C)=CC=CC=1>[F:1][C:2]1[C:30]([F:31])=[CH:29][C:5]2[N:6]([C:19](=[O:28])[CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[N:12]([CH2:41][CH2:40][N:37]4[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]4)[N:13]=3)[C:4]=2[CH:3]=1
Reactant: CN1CCN(CCCl)CC1
Reactant: CCCN(CCC)CC(=O)N1c2cc(F)c(F)cc2-n2c(n[nH]c2=O)-c2cccnc21
Agent: [Na]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: CCCN(CCC)CC(=O)N1c2cc(F)c(F)cc2-n2c(nn(CCN3CCN(C)CC3)c2=O)-c2cccnc21
Reaction time: 22 h

Procedure:
In the manner given in Example 25, to 6,7-difluoro-2,9-dihydro-9-[ (dipropylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one in dimethylforamide is added a solution of sodium hydrided in mineral oil. The mixture is allowed to react at about 95°C. for 40 minutes and after cooling [2-(4-methylpiperazino)-ethyl]chloride in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in example 25 to give 6,7-difluoro-2.9-dihydro-2-[2-(4-methylpiperazino)ethyl]-9-[(dipropylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]-benzodiazepin-3-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](O)=[O:15])[C:9]2=[O:17])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=1.CN1CCOCC1>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:38][C:35]3[CH:34]=[CH:33][C:32]([Cl:31])=[CH:37][N:36]=3)=[O:15])[C:9]2=[O:17])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)Nc1ccc(Cl)cn1
Reaction time: 0.5 h

Procedure:
To a suspension of 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.168 g, 0.506 mmol; Example 58D) was added a catalytic amount of N,N-dimethylformamide followed by oxalyl dichloride (0.404 mL, 0.809 mmol). After stirring for 30 minutes, the reaction was concentrated and dried under high vacuum for 10 minutes. The residue was dissolved in dichloromethane (0.5 mL) and 5-chloropyridin-2-amine (0.052 g, 0.404 mmol) and 4-methylmorpholine (0.089 mL, 0.809 mmol) were added. After 30 minutes, the reaction was loaded onto a GraceResolv™ 40 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 10% ethyl acetate/hexanes to 40% ethyl acetate/hexanes (Flow=40 mL/minute) over 40 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 8.24-8.20 (m, 1H), 8.09 (d, J=8.8, 1H), 7.65 (dd, J=2.7, 8.8, 1H), 7.36-7.28 (m, 4H), 7.05-6.96 (m, 4H), 4.19 (s, 2H), 3.54 (t, J=6.5, 2H), 2.82 (t, J=6.5, 2H); MS (ESI+) m/z 442.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([OH:16])[CH:15]=[C:10]3[CH:9]=[C:8]2[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:3]=1.Cl.Cl[CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([O:16][CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)[CH:15]=[C:10]3[CH:9]=[C:8]2[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=1
Reactant: CCOC(=O)CCc1cc2cc(O)cnc2n1Cc1ccc(Cl)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cc2cc(OCc3ccc4ccccc4n3)cnc2n1Cc1ccc(Cl)cc1
Temperature: 55 °C

Procedure:
To a solution of the aforementioned Ethyl 3-[1-(4-chloro-benzyl)-5-hydroxy-1H-pyrrolo[2,3-b]pyridin-2-yl]-propionate (68 mg, 0.190 mmol) in DMF (1 mL) was added 2-chloromethylquinoline hydrochloride (49 mg, 0.228 mmol), cesium carbonate (124 mg, 0.380 mmol) and catalytic TBAI. The mixture was then heated to 55° C. for 12 hours after which it was partitioned between EtOAc and water, the aqueous layer extracted with EtOAc, the combined organic phases dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 30% EtOAc in hexanes to afford the title ester.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[O:17])=[CH:11][CH:10]=1>>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH:3]2[C:4](=[O:7])[CH2:5][CH2:6][S:1][CH2:2]2)=[O:17])=[CH:11][CH:10]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: O=C1CCSCC1
Product: O=C1CCSCC1C(=O)Cc1ccc(F)cc1
Yield: 78 %

Procedure:
3-(2-(4-Fluorophenyl)acetyl)dihydro-2H-thiopyran-4(3H)-one (508 mg, 78%) was obtained from tetrahydrothiopyran-4-one and 4-fluorophenylacetyl chloride by the general procedure for the preparation of diketones. MS (ES+) m/z 253.1 (M+H)+
Reaction SMILES: C(OC=[C:6]1[O:24][CH2:23][C@:9]2([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:12][CH2:13][C@@H:8]2[CH2:7]1)(=O)C.I([O-])(=O)(=O)=[O:34].[Na+].ClCCCl.O>C(#N)C.[Ru](Cl)(Cl)Cl>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[C@:9]12[CH2:23][O:24][C:6](=[O:34])[CH2:7][C@H:8]1[CH2:13][S:12][C:11]([NH:14][C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[N:10]2
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(=O)OC=C1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CC#N
Product: O=C1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of [(4aR,8aS)-2-(benzoylamino)-8a-(2,4-difluorophenyl)-4a,5,8,8a-tetrahydropyrano[3,4-d][1,3]thiazin-6(4H)-ylidene]methyl acetate (C11) (430 mg, 0.938 mmol), ruthenium(III) chloride (5.8 mg, 28 μmol) and sodium periodate (98.5%, 407 mg, 1.87 mmol) in acetonitrile (0.5 mL) and a 1:1 mixture of 1,2-dichloroethane and water (5 mL) was stirred for 3 hours at room temperature, then allowed to stand for 18 hours without stirring. After dilution with saturated aqueous sodium thiosulfate solution (25 mL), the mixture was extracted with ethyl acetate (3×50 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 80% ethyl acetate in heptane) provided the product as a white solid. Yield: 237 mg, 0.589 mmol, 63%. LCMS m/z 403.1 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.99 (br d, J=8 Hz, 2H), 7.49-7.54 (m, 1H), 7.43 (br dd, J=8, 7 Hz, 2H), 7.32 (ddd, J=9.0, 9.0, 6.3 Hz, 1H), 6.81-6.93 (m, 2H), 4.85 (d, J=11.7 Hz, 1H), 4.24 (d, J=11.5 Hz, 1H), 3.35-3.44 (m, 1H), 2.87-2.97 (m, 2H), 2.80 (dd, half of ABX pattern, J=18.7, 7.5 Hz, 1H), 2.63 (dd, J=13.1, 3.1 Hz, 1H).
Reaction SMILES: [Li]CCCC.I/[CH:7]=[CH:8]/[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>[Cu]>[C:8]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)#[CH:7]
Reactant: I/C=C/Oc1ccc(-c2ccccc2)cc1
Agent: [Cu]
Agent: [Li]CCCC
Product: C#COc1ccc(-c2ccccc2)cc1
Yield: 70 %

Procedure:
For the synthesis of the 1,2-diheteroatom-substituted olefins (See Scheme 3), four-step scheme was developed where 4-phenylphenol 1 was used in one side. First, 4-phenylphenol was vinylated using 1,1,2-trichloroethylene45 to give the corresponding 4-((1,2-dichlorovinyl)oxy)-1,1′-biphenyl 2 with yield of more than 85%.46, 47 Then, 4-(ethynyloxy)-1,1′-biphenyl 3 was prepared by elimination reaction using n-BuLi in 70% yield.46,47 Although 1 was used in this paper, other types of alcohols and phenols can also be converted to the alkyne form.46 Hydrozirconation and iodinolysis of 3 led to 2-iodoenol ether 4 in 55% yield.48, 49 Using the copper-catalyzed coupling reaction, 4 were linked with various substrates bearing the different functional groups.36,50, 51
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([NH:8][C:9](=[O:17])[O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][C@H:5]2[C@@H:3]1[CH2:4]2.Cl[C:19]1[N:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:29]3[C:34]([Cl:35])=[C:33]([O:36][CH3:37])[CH:32]=[C:31]([O:38][CH3:39])[C:30]=3[Cl:40])[CH:25]=2)[N:20]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(OCC)(=O)C>[Cl:35][C:34]1[C:33]([O:36][CH3:37])=[CH:32][C:31]([O:38][CH3:39])=[C:30]([Cl:40])[C:29]=1[C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([NH:1][C@H:2]1[C@@H:7]([NH:8][C:9](=[O:17])[O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:16])[CH3:15])[CH2:6][C@H:5]3[C@@H:3]1[CH2:4]3)[N:28]=[CH:27]2
Reactant: C[Si](C)(C)CCOC(=O)N[C@H]1C[C@@H]2C[C@@H]2[C@H]1N
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(Cl)ncc3c2)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4[C@H]5C[C@H]5C[C@@H]4NC(=O)OCC[Si](C)(C)C)ncc3c2)c1Cl
Temperature: 25 °C
Yield: 62.5 %

Procedure:
A solution of 2-(trimethylsilyl)ethyl (1S,2R,3S,5S)-2-aminobicyclo[3.1.0]hexan-3-ylcarbamate (250 mg, 0.977 mmol), 2-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazoline (300 mg, 0.814 mmol) and sodium bicarbonate (205 mg, 2.442 mmol) in N-methyl-2-pyrrolidone (10 mL) was stirred at 100° C. overnight. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL) and washed with water (eight times) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to afford a crude product, which was purified by silica gel column chromatography (ethyl acetate:petroleum ether=4:2) to afford the title compound (300 mg, 52%) as a yellow solid. MS (ES+) C28H34Cl2N4O4Si requires: 588, 590, found: 589, 591 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=1)[CH3:2].C1COCC1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[C:8]([N:34]2[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc2c1CCCC2
Reactant: CN1CCNCC1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cc(N2CCN(C)CC2)cc2c1CCCC2
Reaction time: 24 h

Procedure:
To a solution of compound of step d) (0.5 g, 1.36 mmol) in dry THF (10 ml) K3PO4 (405 mg, 1.90 mmol), N-methylpiperazine (180 μl, 163 mmol), tris(dibenzylideneacetoneacetone)-dipalladium(0) (60 mg, 0.07 mmol) and 2-(di-t-butylphosphino)biphenyl (21 mg, 0.07 mmol) are added under argon. The reaction is kept under argon at 80° C. for 24 hours. After filtration DMF is removed under reduced pressure and the crude residue is purified on silica gel (methylene chloride/methanol 95/5) affording the pure compound.
Reaction SMILES: [O:1]=[C:2]([OH:14])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([C:11]([O-:13])=[O:12])[OH:10])O)[OH:6])[OH:4].[K+].[K]>O>[O:12]=[C:11]([OH:13])[C@@H:9]([C@H:7]1[O:14][C:2](=[O:1])[C@@H:3]([OH:4])[C@H:5]1[OH:6])[OH:10]
Reactant: O=C([O-])[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(=O)O
Agent: [K+]
Agent: [K]
Solvent: O
Product: O=C1O[C@H]([C@@H](O)C(=O)O)[C@H](O)[C@@H]1O
Reaction time: 3 h
Yield: 63297.5 %

Procedure:
Acid form cation exchange resin (20 mL, 40 meq. of total exchange capacity, Rexyn 100(H), Fisher) that had been prewashed with deionized water was added to a mixture of monopotassium D-glucarate (10.00 g, 39.89 mmol, Sigma) and deionized water (100 mL). The potassium salt dissolved within 10 min, the mixture was stirred for 3 h and the resin was removed by filtration and washed with deionized water (3×10 mL). The resin was left aside for regeneration to its acid form and the filtrate was concentrated to a syrup at 60° C. The syrup was seeded with pure D-glucaro-3,6-lactone and solidified as a cake in two-three days. The cake was triturated with acetone (15 mL), the white solid was removed by filtration and air-dried to yield D-glucaro-6,3-lactone (4,851 g, 63.3%). When this experiment was scaled up to 50.00 g of monopotassium D-glucarate, D-glucaro-6,3-lactone was obtained in 69.1% yield (26.49 g, 137.9 mmol): mp 130°-135° C. [Smith, J. Chem. Soc., 633 (1944); 138-142 ° C.]; IR (KBr) 3365 cm-l (broad, OH), 2913 cm-1 (C--H, stretch), 1780 cm-l (C=O, five membered ring lactone), 1725 cm-l (C=O, acid); 1H NMR (CD3OD) δ4.59 (dd, 1H, H-3, J2,3 = 6.73 Hz, J3,4 =2.12), 4.53 (m, 2H, H-2, H-5,), 4.51 (m, 1H, H-2); proton decoupled 13C NMR (D2O)δ178.8 (lactone C=O), 174.5 (acid C=O), 81.61 (C-3), 71.65 (C-5), 71.31 (C-2), and 69.89 (C-4).