Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.CS(C)=O.[C:10](Cl)(=[O:14])[C:11](Cl)=O.[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([N:33]3[C@@H:38](CO)[CH2:37][O:36][CH2:35][C@H:34]3[C:41]3[CH:46]=[CH:45][C:44]([F:47])=[C:43]([F:48])[CH:42]=3)=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1>[Cl-].[NH4+].C(N(CC)CC)C>[CH:25]1[C:26]2[CH:27]([CH2:29][O:30][C:31]([N:33]3[C@@H:38]([CH:10]([OH:14])[CH3:11])[CH2:37][O:36][CH2:35][C@H:34]3[C:41]3[CH:46]=[CH:45][C:44]([F:47])=[C:43]([F:48])[CH:42]=3)=[O:32])[C:28]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1[C@@H](CO)COC[C@H]1c1ccc(F)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(O)[C@H]1COC[C@@H](c2ccc(F)c(F)c2)N1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, a tetrahydrofuran (35 mL) solution containing dimethylsulfoxide (530 μL) was cooled to −78° C. To the reaction solution was then dropwise added oxalyl chloride (608 μL), and this solution was stirred at the same temperature for 5 minutes. A solution of tetrahydrofuran (25 mL) containing (3R,5S)-3-(3,4-difluorophenyl)-5-hydroxymethylmorpholine-4-carboxylic acid 9H-fluorene-9-ylmethyl ester (2.5 g) was then dropwise added thereto, and the solution was stirred at the same temperature for 30 minutes. To the reaction solution was then added triethylamine (3.7 mL), and the reaction mixture was stirred at the same temperature for 30 minutes followed by stirring at room temperature for 1 hour. The resultant solution was diluted with saturated aqueous ammonium chloride, and this solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure. The resultant residue was diluted with tetrahydrofuran (15 mL), and the resultant solution was cooled to −78° C. To the reaction solution was dropwise added methylmagnesium bromide (8.33 mL, 0.97 M tetrahydrofuran solution), and the resultant solution was stirred at the same temperature for 1 hour. The solution was then diluted with saturated aqueous ammonium chloride and ethyl acetate, and the organic layer was partitioned. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate 95/5→1/1), to thereby obtain the titled compound (950 mg). The physical properties of this crude product were as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([Si](CC)(CC)CC)[NH:8][C:5]2=[N:6][CH:7]=1.BrC1C2C(=NC=CC=2)N(S(C2C=CC(C)=CC=2)(=O)=O)C=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC[Si](CC)(CC)c1cc2cc(Cl)cnc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)n2cc(Br)c3cccnc32)cc1
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
Compound 41 (4.37 g, 0.0164 mol) was dissolved in THF. Molecular sieve (10 g of 3 A) was added followed by TBAF (32.75 mL, 0.0328). The reaction mixture was stirred for 5 h at rt. Diluted with ethyl acetate and washed several times with water, brine and the organic layer was dried and concentrated in vacuo to an oil that was subjected to flash chromatography (30% EtOAc-70% hexanes) to give 02.3 g (90%) of the desired material 42. 1H NMR DMSO d6 11.8 (bs, 1H), 8.2 (s, 1H), 8.1 (s, 1H), 7.5 (s, 1H), 6.5 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:11]\[OH:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O/N=C\c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a suspension of 4-chlorobenzaldehyde (25.0 g, 178 mmol) and hydroxylamine hydrochloride (13.7 g, 198 mmol) in ethanol (14.1 mL) and water (42.9 mL) was added ice (82 g). Then a solution of sodium hydroxide (18.1 g, 454 mmol) in water (21.4 mL) was added dropwise within a 10 min period (temperature rises from −8° C. to +7° C.) whereupon most of the solid dissolves. After 30 min stirring at room temperature a white solid precipitated and the resulting mixture was then diluted with water and acidified with HCl (4 N). The white precipitate was then filtered off, washed with water and dried under high vacuum to afford the title compound (27.0 g, 97%) which was obtained as an off white solid. MS m/e (EI): 155.1 [M]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][C@H:6]([OH:23])[C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[C@@H:9]3[CH2:22][C@@H:10]3[C:11]2=[O:21])[CH2:3]1.N1C=CN=C1.[C:29]([Si:33]([CH3:36])([CH3:35])Cl)([CH3:32])([CH3:31])[CH3:30]>CN(C)C=O>[C:29]([Si:33]([CH3:36])([CH3:35])[O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][C@H:6]([OH:23])[C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[C@@H:9]3[CH2:22][C@@H:10]3[C:11]2=[O:21])[CH2:3]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@]12CC[C@H](O)CC1=C[C@H](O)[C@H]1[C@@H]3[C@@H]4C[C@@H]4C(=O)[C@@]3(C)CC[C@@H]12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=C[C@H](O)[C@H]3[C@@H]4[C@@H]5C[C@@H]5C(=O)[C@@]4(C)CC[C@@H]32)C1
Temperature: -20 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
A solution of 120 g of 3β,7β-dihydroxy-15β,16β-methylene-5-androsten-17-one in 1,000 ml of dimethylformamide is combined with 31 g of imidazole and cooled to -20° C. Within 2 hours, 63 g of tert.-butyldimethylchlorosilane in 450 ml of dimethylformamide is added dropwise to the reaction mixture, and the latter is agitated for another hour. The reaction product is precipitated with sodium-chloride-containing water, filtered off, washed with water, and dissolved in methylene chloride. The solution is dried over sodium sulfate and evaporated. After chromatography on silica gel with hexane-acetone, 128.8 g of 3β-(tert.-butyldimethylsilyloxy)-7β-hydroxy-15β,16β-methylene-5-androsten-17-one is obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1.Cl.[CH3:15][C:16]1([CH3:35])[C:20]([CH3:22])([CH3:21])[O:19][B:18]([C:23]2[CH:24]=[N:25][N:26]([C:28]3([CH2:32][C:33]#[N:34])[CH2:31][NH:30][CH2:29]3)[CH:27]=2)[O:17]1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[C:33]([CH2:32][C:28]1([N:26]2[CH:27]=[C:23]([B:18]3[O:19][C:20]([CH3:22])([CH3:21])[C:16]([CH3:35])([CH3:15])[O:17]3)[CH:24]=[N:25]2)[CH2:31][N:30]([C:2]2[N:3]=[CH:4][C:5]([C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=2)[CH2:29]1)#[N:34]
Reactant: CC1(C)OB(c2cnn(C3(CC#N)CNC3)c2)OC1(C)C
Reactant: CC(C)NC(=O)c1cnc(Cl)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1cnc(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cn1
Temperature: 100 °C
Yield: 57.6 %

Procedure:
A mixture of 5-chloro-N-isopropylpyrazine-2-carboxamide (200 mg, 1.00 mmol), {3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile HCl salt (325 mg, 1.00 mmol, from Example 1, step 3) and N,N-diisopropylethylamine (401 μL, 2.30 mmol) in 1,4-dioxane (5.0 mL) was heated at 100° C. for 2 h. After cooling, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexane (gradient: 20-80%) to afford the desired product (0.26 g, 58%). LCMS cacld. for C22H31BN7O3 (M+1)+: m/z=452.3. Found: 452.2.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:13])[NH:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH3:28][C:29]([CH3:31])=[O:30]>>[CH2:20]([O:12][C:9]1[CH:10]=[CH:11][C:2]([O:1][CH2:28][C@@H:29]2[CH2:31][O:30]2)=[C:3]2[C:8]=1[NH:7][C:6](=[O:13])[CH2:5][CH2:4]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCc2c(O)ccc(O)c2N1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1CCc2c(OC[C@@H]3CO3)ccc(OCc3ccccc3)c2N1
Reaction time: 4 h

Procedure:
5,8-Dihydroxy-3,4-dihydro-2(1H)-quinolinone (2.0 g, 11.16 mol) and potassium carbonate (1.8 g, 13.02 mol) were stirred at reflux in acetone (35 mL). Benzyl bromide (1.33 mL, 11.2 mmol) was added and refluxing continued for 4 hours. The solvents were removed and the reaction mixture partitioned between chloroform and water. The organic phase was washed with brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent evaporated to dryness in vacuo. The residue was purified by flash chromatography on silica gel Merck-60 (eluant: 1:1 hexane-ethyl acetate) to yield the title compound (0.80 g, 2.97 mmol).
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[CH3:27][N:28]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(O)C>[ClH:1].[ClH:1].[CH3:27][N:28]1[CH2:34][CH2:33][CH2:32][N:31]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:30][CH2:29]1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: CN1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CN1CCCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Product: Cl

Procedure:
8.6 gm of 11-chloroacetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 3.5 gm of sodium carbonate and 4.5 gm of hexahydro-1-methyl-1H-1, 4-diazepine were refluxed in 100 ml of ethanol for 2.5 hours. Then the hot mixture was suction-filtered, the alcohol was distilled off, and the residue was triturated with dioxane. The precipitated crystals were dissolved in ethanol and converted into the dihydrochloride by addition of concentrated hydrochloric acid. After recrystallization from 94% ethanol:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:10][C:11]1[CH:37]=[CH:36][CH:35]=[CH:34][C:12]=1[C:13]([C:15]1[C:22](=[O:23])[N:18]2[CH2:19][CH2:20][CH2:21][N:17]2[C:16]=1[C:24]1[CH:29]=[CH:28][N:27]=[C:26](S(C)(=O)=O)[N:25]=1)=[O:14]>C1COCC1.C([O-])(O)=O.[Na+]>[Cl:10][C:11]1[CH:37]=[CH:36][CH:35]=[CH:34][C:12]=1[C:13]([C:15]1[C:22](=[O:23])[N:18]2[CH2:19][CH2:20][CH2:21][N:17]2[C:16]=1[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:25]=1)=[O:14]
Reactant: CS(=O)(=O)c1nccc(-c2c(C(=O)c3ccccc3Cl)c(=O)n3n2CCC3)n1
Reactant: Oc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1Cl)c1c(-c2ccnc(Oc3ccccc3)n2)n2n(c1=O)CCC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of phenol (0.04 g, 0.43 mmol) in THF (1 mL) is added sodium hydride (0.02 g of a 60% dispersion in mineral oil, 0.32 mmol). After stirring 5 min at room temperature a solution of 2-(2-chloro-benzoyl)-3-(2-methanesulfonyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 24, (0.09 g, 0.21 mmol) in THF (2 mL) is added to the reaction mixture. After stirring 1.5 hours at room temperature, the mixture is diluted with aqueous saturated NaHCO3. The aqueous phase is extracted three times with CHCl3 and the combined organic phases are washed with aqueous saturated NaHCO3, dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified over silica (10% MeOH/CHCl3) to afford 30 mg of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.77 (d, J=5.1 Hz, 1H), 8.04 (d, J=5.1 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.41-7.20 (m, 9H), 4.00 (t, J=7.2 Hz, 2H), 3.95 (t, J=7.2 Hz, 2H), 2.54 (dddd, J=7.5, 7.5, 7.5, 7.5 Hz, 2H); ESI− MS: m/z (rel intensity) 431.1 (100, M+−H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CNCCC1C=CC=CC=1.Cl[C:21]1[N:26]=[N:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]([F:44])([F:43])[F:42])=[O:34])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH2:8]([NH:9][C:21]1[N:26]=[N:25][C:24]([N:27]2[CH2:28][CH2:29][N:30]([C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]([F:42])([F:44])[F:43])=[O:34])[CH2:31][CH2:32]2)=[CH:23][CH:22]=1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(Cl)nn2)CC1
Agent: CNCCc1ccccc1
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(NCCc3ccccc3)nn2)CC1

Procedure:
Following the procedure set forth above in Example 1, only making variations using 2-phenylethylamine to replace N-methyl-2-phenylethylamine to react with [4-(6-chloropyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (11.8 mg, 15% yield). 1H NMR (CDCl3, 400 MHz) δ 7.74, 7.62-7.68, 7.52-7.57, 7.33-7.37, 7.28-7.32, 7.40-7.46, 6.83, 6.18, 3.95, 3.68-3.70, 3.30-3.50, 2.96. MS (ES+) m/z 456.4 (M+1).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.CC[Mg+].[Br-].[F:16][C:17]1[C:26]([CH:27]=[O:28])=[C:25]([F:29])[CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[N:22]2>C1COCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([CH:27]([C:26]3[C:17]([F:16])=[C:18]4[C:23](=[CH:24][C:25]=3[F:29])[N:22]=[CH:21][CH:20]=[CH:19]4)[OH:28])=[CH:3][N:4]=2)[N:7]=1
Reactant: O=Cc1c(F)cc2ncccc2c1F
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: OC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of 3-bromo-6-chloro-imidazo[1,2-b]pyridazine (2.40 g, 10.35 mmol) in 30 mL of THF was added EtMgBr (1 M in THF, 12.43 mL, 12.42 mmol) solution at rt. The solution was stirred for 30 min and a solution of 5,7-difluoroquinoline-6-carbaldehyde (2.0 g, 10.35 mmol) in 10 mL of THF was added. The resulting mixture was stirred at rt for additional 2 h and then quenched with 50 mL of NH4Cl solution. The solution was extracted with EtOAc and the combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo to afford 3.48 g (97%) of the title compound. LCMS (method B): [MH]+=347, tR=1.23 min.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][C:14](=[O:16])[NH:13][C:12]=3[CH:17]=2)[CH2:4][CH2:3]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[O:16]=[C:14]1[NH:13][C:12]2[CH:17]=[C:8]([CH:5]3[CH2:6][CH2:7][CH:2]([N:18]4[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=5)=[O:24])[CH2:19]4)[CH2:3][CH2:4]3)[CH:9]=[CH:10][C:11]=2[O:15]1
Reactant: O=C1CCC(c2ccc3oc(=O)[nH]c3c2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccc4oc(=O)[nH]c4c3)CC2)C1

Procedure:
The title compounds were prepared as white solids from reductive amination of 5-(4-oxo-cyclohexyl)-3H-benzooxazol-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:25]([O:29][C:30](=[O:43])[N:31]=[C:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])SC)([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>CN(C=O)C.[Hg](Cl)Cl>[C:39]([O:38][C:36]([NH:35][C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:23][CH:24]=1)=[N:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:43])=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: CCO[C@@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl[Hg]Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
3-{4-[(4-Aminophenethyl)oxy]phenyl}-2(S)-ethoxypropanoic acid (223 mg, 0.61 mmol) and tert-butyl-[(tert-butoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate (186 mg, 0.64 mmol) were mixed in 3 ml DMF. Triethylamine (0.34 ml, 2.44 mmol) was added. The mixture was then cooled in an ice-bath. Mercury (II)chloride (180 mg, 0.66 mmol) was added. After 30 minutes, the cooling bath was removed. The reaction mixture was stirred overnight. Water and ethyl acetate were added into the mixture. The organic phase was separated, dried with magnesium sulfate and the solvent was evaporated in vacuum. Column chromatography of the residue on silica gel using ethyl acetate/heptane (10:90, then 25:75) as eluant gave 135 mg, yield 39% of the desired product.
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4].[C:16]([O:25][CH3:26])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH2:19].N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>O>[ClH:1].[CH3:26][O:25][C:16]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:13]([C@H:10]1[CH2:9][CH2:8][C@H:7]([CH2:6][NH:2][C:3]([NH2:5])=[NH:4])[CH2:12][CH2:11]1)=[O:15])=[O:24]
Reactant: COC(=O)c1ccccc1N
Reactant: N=C(N)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1NC(=O)[C@H]1CC[C@H](CNC(=N)N)CC1

Procedure:
Trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride (3 g, 0.013 mole) (which is prepared by the method as disclosed in Japanese Patent First Publication No. 19694/1977, C.A., 87, 53269x) and methyl anthranilate (2.3 g, 0.015 mole) are added to pyridine (20 ml), and the mixture is stirred for a while, and thereto is added dicyclohexylcarbodiimide (3.1 g, 0.015 mole), and the mixture is stirred at room temperature for 72 hours. After the completion of the reaction, water (10 ml) is added to the reaction mixture, and the mixture is stirred for 30 minutes, and the undissolved materials are filtered off. The filtrate is concentrated to dryness. The resulting residue is washed with ethyl acetate (100 ml) and recrystallized from water to give the title compound (2.23 g) as white crystals. m.p. 118.5°-120.5° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[NH:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:21]([O:27][CH2:28]Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH2:28][O:27][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=c1[nH]c(=O)c2c(ncn2Cc2ccccc2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-Benzylxanthine (8.66 g) was dissolved in N,N-dimethylformamide (300 ml); sodium hydride (1.57 g) and chloromethyl pivalate (7.7 ml) were added to the solution; and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and washed with water and 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then, the solvent was removed by distillation. The residue was purified by silica gel column chromatography to give 2.66 g of the title compound from the elution fraction of hexane-ethyl acetate 1:1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15]O.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15][N:27]1[CH2:28][CH2:29][N:24]([C:22]([C:18]2[O:17][CH:21]=[CH:20][CH:19]=2)=[O:23])[CH2:25][CH2:26]1
Reactant: COc1cc2c(cc1OC)C(=CO)C(=O)N2
Reactant: O=C(c1ccco1)N1CCNCC1
Product: COc1cc2c(cc1OC)C(=CN1CCN(C(=O)c3ccco3)CC1)C(=O)N2

Procedure:
3.0 g. of 5,6-Dimethoxy-3-hydroxymethylene oxindole was reacted with 4.0 g. N-furoyl piperazine as described in Example 2 except that 0.10 g. toluene sulfone acid was added as a catalyst. Yield 3.46 g. of product, m.p. 158°-160° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:7](=[O:17])[CH:6]=[CH:5]2.[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])#[CH:19]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:17]=[C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:19]#[C:18][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=2)[N:8]1[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)Cn1c(=O)ccc2cc(Br)ccc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cn1c(=O)ccc2cc(C#C[Si](C)(C)C)ccc21
Temperature: 80 °C

Procedure:
Methyl 2-(6-bromo-2-oxoquinolin-1(2H)-yl)acetate (0.67 mmol), CuI (0.67 mmol) and PdCl2(PPh3)2 (0.40 mmol) were dissolved in triethylamine (3 mL) in a glass pressure tube and nitrogen gas was bubbled through the solution via a gas dispersion tube for 5 minutes. Ethynyltrimethylsilane (3.5 mmol) was added to the reaction mixture and the tube was sealed and placed into an oil bath pre-heated to 80° C. for 8 h. The resulting solution was concentrated under vacuum and purified via an isco column. Retention time (min)=2.759, method [1], MS (ESI) 314.1 (M+H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1.[CH3:20][C:21]([CH3:27])([CH2:24][CH:25]=[CH2:26])[CH:22]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:1]1([CH:20]([NH:17][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:21]([CH3:27])([CH3:22])[CH2:24][CH:25]=[CH2:26])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: c1ccc2[nH]nnc2c1
Reactant: C=CCC(C)(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CCC(C)(C)C(NC(=O)c1ccc(Cl)cc1)n1nnc2ccccc21

Procedure:
Benzotriazole, 4-chlorobenzamide, 2,2-dimethyl-4-pentenal, and p-toluenesulfonic acid were processed as in Example 53A to provide Example 67A.