Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:16])[CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Oc1ccc(Br)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
12 g of 2-Benzyloxyphenol was dissolved in 300 ml of acetonitrile, 10.7 g of N-bromosuccinimide was added thereto, and the mixture was stirred at room temperature for 2 hours. Additional N-bromosuccinimide (1 g) was added thereto and the mixture was stirred for 1 hour, and further additional N-bromosuccinimide (1 g) was added thereto and the mixture was stirred for 2 hours. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography, to give 14.927 g of the title compound in the 10:1 hexane-ethyl acetate fraction.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:20]=[CH:19][N:10]([C@@H:11]2[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[CH2:12]2)[C:9](=[O:21])[N:8]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:22][O:23][C:24]1[CH:45]=[CH:44][C:27]([C:28](Cl)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[CH:26][CH:25]=1.CO>N1C=CC=CC=1>[C:1]([NH:6][C:7]1[CH:20]=[CH:19][N:10]([C@@H:11]2[O:18][C@H:15]([CH:16]([C:28]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:27]3[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:45][CH:44]=3)[OH:17])[C@@H:13]([OH:14])[CH2:12]2)[C:9](=[O:21])[N:8]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(C(c2ccccc2)(c2ccc(OC)cc2)C(O)[C@H]2O[C@@H](n3ccc(NC(=O)C(C)C)nc3=O)C[C@@H]2O)cc1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
2.5 mmol of compound 5 are dried by successive additions and evaporations of anhydrous pyridine. There is taking up with 25 ml of pyridine, cooling to 0° C. and the addition of 2.75 mmol (1.1 equivalent) of 4,4'-dimethoxy trityl chloride in 25 ml of pyridine at 0° C. The reaction is allowed to continue for 17 hours at 5° C. and then 2 ml of methanol are added to the reaction medium. After 30 minutes, the solvent is expelled with the rotary evaporator and the oily residue taken up by 100 ml of ethyl acetate, followed by washing 3 times with 50 ml of aqueous 5% NaHOO solution and once with 50 ml of bidistilled water. The organic phase is then dried on sodium sulphate and concentrated. By fractionating on a silica gel column, the thus obtained compound 6 is isolated and corresponds to formula (I), in which B is radical of formula (III) derived from cytosine, R1 and R2 are methyl radicals, R3 the 4,4'-dimethoxy trityl radical, R4 a hydrogen atom and R a hydrogen atom.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH:13]1[O:21][CH:12]21)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>[OH-].C([N+](C)(C)C)C1C=CC=CC=1>[CH2:1]([O:3][P:4]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[C@@H:13]([OH:21])[C@@H:12]2[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]1=[O:22])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(OCC)c1ccc2c(c1)C1OC1C(C)(C)O2
Reactant: Oc1ccccn1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Product: CCOP(=O)(OCC)c1ccc2c(c1)[C@@H](n1ccccc1=O)[C@H](O)C(C)(C)O2

Procedure:
A mixture containing 5.6 g of 6-diethylphosphono-2,2-dimethyl-3,4-epoxychromane, 2.5 g of 2-hydroxypyridine and 4 drops of benzyltrimethylammonium hydroxide is refluxed for 48 hours. After the dioxane has been concentrated, the residue is taken up in methylene chloride and the mixture is washed twice with water and then dried over sodium sulfate and concentrated to dryness. Ethyl ether is added and the product crystallizes. After recrystallization from ethyl acetate, 1.5 g of the expected product are obtained. Melting point: 130° C. (capillary tube)
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][C@H:33]([CH:38]([CH3:40])[CH3:39])[C:34]([O:36][CH3:37])=[O:35].[C:41]1([C:47]2[CH:52]=[CH:51][C:50](O)=[CH:49][CH:48]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1>[C:41]1([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:46]=[CH:45][C:44]([O:32][C@@H:33]([CH:38]([CH3:40])[CH3:39])[C:34]([O:36][CH3:37])=[O:35])=[CH:43][CH:42]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)[C@H](O)C(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H](Oc1ccc(-c2ccccc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethylazodicarboxylate (11.5 ml) in dry tetrahydrofuran (40 ml) was added dropwise over 30 minutes to a stirred solution of triphenylphosphine (22 g), methyl (R)-2-hydroxy-3-methylbutanoate (11.2 g, J.Am.Chem.Soc., (1990), 112, 21, 7659) and 4-phenylphenol (14.5 g) in dry tetrahydrofuran (120 ml). The resulting solution was stirred at room temperature overnight and was then concentrated under reduced pressure. A mixture of isohexane:ether (9:1) (750 ml) was added to the residue and the mixture stirred at room temperature for 30 minutes. The solution was filtered and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with isohexane:dichloromethane (1:4) then (1:1) to give the sub-title compound as a solid, which was recrystallised from hexane to give a crystalline solid (7.9 g).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][N:5]=1.[OH-].[Na+].[Cl:16][C:17]1[CH:26]=[CH:25][C:20]2[NH:21][C:22]([SH:24])=[N:23][C:19]=2[CH:18]=1>CO.O>[Cl:16][C:17]1[CH:26]=[CH:25][C:20]2[NH:21][C:22]([S:24][CH2:3][C:4]3[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][N:5]=3)=[N:23][C:19]=2[CH:18]=1
Reactant: Sc1nc2cc(Cl)ccc2[nH]1
Reactant: COc1ccnc(CCl)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccnc(CSc2nc3cc(Cl)ccc3[nH]2)c1OC

Procedure:
2-chloromethyl-3,4-dimethoxypyridine hydrochloride (896 mg, 0.004 mol) was dissolved in 25 ml MeOH and treated with NaOH (390 mg, 0.008 mol) dissolved in 1.5 ml H2O. 5-chloro-2-mercapto-1H-benzimidazole (812 mg, was added and the resulting mixture allowed to react for 2h at room temperature. The solvent was evaporated and the residue partitioned between 50 ml 2.5 % NaOH and 75 ml CH2Cl2. The aqueous layer was separated and extracted twice with 25 ml CH2Cl2. The organic layers were combined, washed with 25 ml H2O, dried over MgSO° and the solvent was evaporated.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[Li+].[Li+].Br[CH2:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[F:27]>CN(C)C=O>[OH:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[O:8][CH2:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[F:27]
Reactant: CC(=O)c1ccc(O)c(O)c1
Reactant: Fc1cccc(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2c(F)cccc2F)c(O)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3′,4′-dihydroxyacetophenone (25.0 g, 164.3 mmol), lithium carbonate (12.1 g, 164.3 mmol), and α-bromo-2,6-difluorotoluene (34.0 g, 164.3 mmol) in dimethyl formamide (400 mL) is stirred at room temperature for 2 days. The mixture is then filtered through celite, and the filtrate is concentrated in vacuo. The residue is diluted with H2O(200 mL), and the mixture is filtered. The collected solid is recrystallized from ethanol to give 3′-hydroxy-4′-(2,6-difluorobenzyloxy)-acetophenone.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]([NH:15]C(=O)OC(C)(C)C)=[N:11][CH:12]=[CH:13][CH:14]=2)O1.Br[C:25]1[S:33][C:28]2[C:29](=[O:32])[NH:30][CH2:31][C:27]=2[CH:26]=1>CCCCO.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:15][C:10]1[C:9]([C:25]2[S:33][C:28]3[C:29](=[O:32])[NH:30][CH2:31][C:27]=3[CH:26]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=C1NCc2cc(Br)sc21
Reactant: CC(C)(C)OC(=O)Nc1ncccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: Nc1ncccc1-c1cc2c(s1)C(=O)NC2
Temperature: 110 °C
Yield: 72 %

Procedure:
A solution of tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carba mate (736 mg, 2.3 mmol), 2-bromo-4H-thieno[2,3-c]pyrrol-6(5H)-one (500 mg, 2.3 mmol) and Pd(PPh3)4 (40 mg, 0.035 mmol) in n-BuOH (5 mL) and 2.0 M Na2CO3 (4.6 mL) was degassed and the resulting reaction mixture was refluxed at 110° C. for 2 h. Upon completion, the reaction was cooled to room temperature, filtered, and washed with MeOH (10 mL) and water (2×10 mL). The solid was dried under high vacuum yielding 2-(2-aminopyridin-3-yl)-4H-thieno[2,3-c]pyrrol-6(5H)-one (383 mg, 72% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40 (br. s., 1H), 8.00 (dd, J=5.0, 1.8 Hz, 1H), 7.52 (dd, J=7.3, 1.8 Hz, 1H), 7.36 (s, 1H), 6.66 (dd, J=7.4, 4.9 Hz, 1H), 5.99 (s, 2H), 4.32 (s, 2H); MS (EI) m/z=232.3 [M+1]+.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]([CH:6]([CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])[CH2:7][CH:8]=[O:9])[CH3:5].Cl>CCOCC>[CH2:4]([CH:6]([CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])[CH2:7][CH:8]([OH:9])[C:1]#[N:2])[CH3:5]
Reactant: [C-]#N
Reactant: CCC(CC=O)C(C)[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: CCC(CC(O)C#N)C(C)[N+](=O)[O-]
Yield: 92.3 %

Procedure:
To a suspension of sodium cyanide (4.5 g) and 3-ethyl-4-nitro-pentanal (7.5 g) in ether (50 ml) was added conc. hydrochloric acid (7.5 ml) at 0° C. with stirring. The resulting mixture was stirred at 0° C. for an hour, diluted with ether, washed successively with water and brine, dried over magnesium sulfate, and then evaporated to dryness in vacuo to give 4-ethyl-2-hydroxy-5-nitro-hexanenitrile (8.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([N:39]=[C:40]=[O:41])=[O:38])=[CH:32][CH:31]=1>O1CCCC1.C(N(C(C)C)CC)(C)C>[CH3:26][N:24]([CH3:25])[CH2:23][CH2:22][N:19]1[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:40]([NH:39][C:37](=[O:38])[CH2:36][C:33]4[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=4)=[O:41])=[CH:28][CH:27]=3)[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:21][CH2:20]1
Reactant: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3)ccn2)CC1
Reaction time: 8 h
Yield: 29 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(2-dimethylaminoethyl)piperazin-1-yl]carbonylamino}pyridine (86.7 mg) in tetrahydrofuran (2.5 ml) were added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 5.4 ml) and diisopropylethylamine (0.235 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5) to provide the titled compound (36.2 mg, 29%) as white powder.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:17][NH:18][O:19][CH3:20].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[CH3:17][N:18]([O:19][CH3:20])[C:10](=[O:12])[C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To a solution of 30 g Boc-proline and 13.6 g N,O-dimethylhydroxylamine hydrochloride in 250 ml of dichloromethane was added 26.73 g 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, 18.83 g N-hydroxy-benzotriazol and 49.34 g N-methyl-morpholine at 0° C. The mixture was stirred overnight at room temperature. The reaction mixture was washed sequentially with saturated sodium bicarbonate, a 5% aqueous solution of citric acid and brine. The organic phase was dried over sodium sulfate. After filtration, the solvent was removed in vacuo to give 22.9 g N-methyl-N-methoxy-(Boc-proline)-amide.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.Cl.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.NC1C=CC(C(F)(F)F)=CC=1>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1cc2ncnc(Nc3ccc(C(F)(F)F)cc3)c2cn1
Temperature: 180 °C
Reaction time: 0.03 h
Yield: 63.2 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (390 mg, 2.03 mmol), 4-aminobenzotrifluoride hydrochloride (0.40 g, 2.02 mmol) and 4-aminobenzotrifluoride (1.61 g, 10.0 mmol) is stirred at 180° C. for 2 min. The resulting product is neutralized with excess NaHCO2, dissolved in MeOH/CHCl3, dried onto alumina and chromatographed over alumina (4-7% MeOH/CH2Cl2) to give 7-amino-4-(4-trifluoromethylanilino)pyrido[4,3-d]pyrimidine (390 mg, 63%) as a cream solid. Analytically pure material was obtained by further chromatography over silica gel (5% MeOH/CH2Cl2) to give pale yellow needles. 1H NMR (DMSO) δ 10.09 (1H, brs), 9.40 (1H, s), 8.48 (1H, s), 8.13 (2H, d, J=8.2 Hz), 7.74 (2H, d, J=8.7 Hz), 6.72 (2H, brs), 6.40 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](SC)=[CH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.[CH3:20][NH:21][CH3:22]>C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([N:21]([CH3:22])[CH3:20])=[CH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CSC(=CC(=O)C(F)(F)F)NCc1ccc(Cl)nc1
Solvent: CCO
Product: CN(C)C(=CC(=O)C(F)(F)F)NCc1ccc(Cl)nc1
Temperature: 20 °C

Procedure:
The product of Example 6, 1-(6-chloro-3-pyridylmethyl) amino-1-methylthio-4,4,4-trifluoro-1-buten-3-one, (2.0 g, 0.0065 mol) and dimethylamine (1.5 ml) were dissolved in ethanol (15 ml). The resulting solution was heated under reflux for 2 hours. The resulting mixture was cooled to ambient temperature (20° C.) and solvent removed by evaporation under reduced pressure. The solid residue was recrystallized from ether to give the product, 1-(6-chloro-3-pyridylmethyl)amino-1-dimethylamino-4,4,4-trifluoro-1-buten-3-one, in a yield of 0.3 g (16%), melting point 85° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5]C=CC=2)[C:3](=[O:10])[CH2:2]1.[CH:11]1(N)[CH2:13][CH2:12]1>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[NH:1]1[C:2]2[C:13](=[CH:12][CH:5]=[CH:4][C:3]=2[OH:10])[CH:11]=[CH:9]1
Reactant: NC1CC1
Reactant: O=C1CNc2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Oc1cccc2cc[nH]c12
Temperature: -10 °C
Reaction time: 8 h

Procedure:
7-Chloroacetyloxy-1,4-dihydro-4-methylcyclopent b!indol-3(2H)-one (15.0 g) and cyclopropylamine (9.6 g) were dissolved in 300 ml toluene and cooled to -10° C. Titanium tetrachloride (6.3 g) dissolved in 50 ml toluene was added slowly to the first solution. The reaction mixture was allowed to come up to room temperature and stirred overnight. The next day another 1.5 equivalents of the amine (4.6 g) was added to the reaction mixture and the mixture was stirred for one hour. The reaction mixture was filtered through a pad of silica gel, eluting with 3:1 hexane/ethyl acetate, giving a yellow oil after removal of solvents. 3-Cyclopropylamino-4-methyl-1,2,3,4-tetrahydrocyclopent b!-indol-7-ol was isolated as a light yellow solid (3.3 g) after flash chromatography and recrystallization from ethyl acetate.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:21]2[CH2:29][C@@H:28]3[C@@H:23]([CH2:24][CH2:25][CH2:26][NH:27]3)[CH2:22]2)=[C:5]([F:20])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[C:8]2=[O:19])#[N:2].[C:30]([O:34][CH2:35][CH3:36])(=[O:33])[C:31]#[CH:32]>>[C:1]([C:3]1[C:4]([N:21]2[CH2:29][C@@H:28]3[C@@H:23]([CH2:24][CH2:25][CH2:26][N:27]3[CH:32]=[CH:31][C:30]([O:34][CH2:35][CH3:36])=[O:33])[CH2:22]2)=[C:5]([F:20])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:14][CH2:15]1)[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[C:8]2=[O:19])#[N:2]
Reactant: N#Cc1c(N2C[C@@H]3CCCN[C@@H]3C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C#CC(=O)OCC
Product: CCOC(=O)C=CN1CCC[C@H]2CN(c3c(F)cc4c(=O)c(C(=O)O)cn(C5CC5)c4c3C#N)C[C@H]21

Procedure:
400 mg (1.01 mmol) of 8-cyano-1-cyclopropyl-7-((1S,6S)-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1.03 ml (10.1 mmol) of ethyl propiolate are heated at 120° C. in 7.5 ml of methylglycol for 1 hour. The reaction solution is concentrated in vacuo and the residue is stirred with water and filtered off with suction. The resulting crude product is recrystallized from ethanol.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:14][CH3:15])=[C:7](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)[CH:8]=1)#[N:2].C(N(CC)CC)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:45]([O:52][C:53](=[O:72])[CH2:54][C@@H:55]([NH2:71])[CH2:56][N:57]1[CH2:62][CH2:61][CH:60]([O:63][C:64]2[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=2)[CH2:59][CH2:58]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(Cl)Cl>[CH2:45]([O:52][C:53](=[O:72])[CH2:54][C@@H:55]([NH:71][C:11](=[O:13])/[CH:10]=[CH:9]/[C:7]1[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=1[O:14][CH3:15])[CH2:56][N:57]1[CH2:58][CH2:59][CH:60]([O:63][C:64]2[CH:65]=[CH:66][C:67]([F:70])=[CH:68][CH:69]=2)[CH2:61][CH2:62]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: COc1ccc(C#N)cc1/C=C/C(=O)O
Reactant: N[C@H](CC(=O)OCc1ccccc1)CN1CCC(Oc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C#N)cc1/C=C/C(=O)N[C@H](CC(=O)OCc1ccccc1)CN1CCC(Oc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (E)-3-(5-cyano-2-methoxy-phenyl)-acrylic acid (0.916 g, 4.51 mmol), triethylamine (1.257 ml, 9.02 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (1.44 g, 4.51 mmol) in DCM (10 ml) is treated with (R)-3-amino-4-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-butyric acid benzyl ester. The reaction mixture is stirred at ambient temperature for 2 hours, then is washed with water, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with 2:1 ethylacetate:hexane) to afford (R)-3-[(E)-3-(5-cyano-2-methoxy-phenyl)-acryloylamino]-4-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-butyric acid benzyl ester. [MH]+ 572.1.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2([OH:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]2[NH:21][CH2:22][CH2:23][CH2:24]O)[CH:9]=[CH:10][CH:11]=1>C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2([OH:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]2[NH:21][CH2:22][CH2:23][CH2:24][Cl:3])[CH:9]=[CH:10][CH:11]=1
Reactant: OCCCNC1=Nc2ccccc2C1(O)c1cccc(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: OC1(c2cccc(Cl)c2)C(NCCCCl)=Nc2ccccc21

Procedure:
Thionylchloride (2.2 g., 1.36 ml.) was added dropwise to a stirred suspension of 3-(m-chlorophenyl)-2-(3-hydroxypropylamino)-3H-indol-3-ol (3.16 g.) in chloroform (25ml.) at 0°C. The reaction mixture was heated under reflux for 45 minutes. the mixture was then cooled and the chloroform evaporated off at reduced pressure. Toluene (25 ml.) was added to the residue and after evaporation the procedure was repeated with a second quantity of toluene. The residue was then dissolved in the minimum quantity of isopropyl alcohol and a small quantity of ether was added to give the title compound as the hydrochloride, colourless rhombs (2.20 g.), m.p. 199° to 203°C.(decomp.). (Found C, 55.15; H, 4.6; N, 7.5. C17H16N2Cl2O2HCl requires C, 54.9; H, 4.6; N, 7.5%)
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1.CC(C)=[O:14]>[N+]([O-])([O-])=O.[Ag+]>[OH:14][CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1
Reactant: CC(C)=O
Reactant: COC(=O)c1csc(CCl)c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: COC(=O)c1csc(CO)c1

Procedure:
A solution of methyl 5-(chloromethyl)-3-thiophenecarboxylate (1.7 g) in 50% aqueous acetone (60 ml) was treated with silver nitrate (1.52 g). After 2 h the resulting precipitate was filtered and the filtrate was evaporated. The residue was extracted with diethyl ether, and the ethereal extract was washed with water. Evaporation of the solvent gave an oily residue, which was chromatographed on silica with ethyl acetate-light petroleum 60°-80°; (1:1) to give the title compound as an oil (0.3 g) b.p. 110/0.1 mm m.p. 38°-40°.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:10][S:11]([NH:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=[O:22])[CH2:20]Br)=[CH:17][CH:16]=1)(=[O:13])=[O:12].C(N(CC)CC)C>C(O)C>[CH3:10][S:11]([NH:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=[O:22])[CH2:20][N:2]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH3:1])=[CH:17][CH:16]=1)(=[O:13])=[O:12]
Reactant: CNCc1ccccc1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(CC(=O)c1ccc(NS(C)(=O)=O)cc1)Cc1ccccc1

Procedure:
N-Methylbenzylamine (22.43 g), 4-methanesulphonamidophenacyl bromide (50 g) (see J. Med. Chem. 1966, 9, 88) and triethylamine (17 g) in ethanol (500 ml) were stirred at room temperature for 18 hours. The solvent was removed, the residue was taken up in dilute hydrochloric acid, washed with ethyl acetate and the organic layer was discarded. The aqueous layer was neutralised with sodium bicarbonate and then extracted three times with ethyl acetate. The combined organic extracts were evaporated and the residue chromatographed on silica [Merck `Kieselgel 60` (Trade Mark)] eluting with hexane containing ethyl acetate (0% up to 100%). The title compound was obtained as an oil by collection and evaporation of appropriate fractions. The oil solidified when triturated with ether, yield of the title compound 32 g.