Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[N:14][N:15]([CH2:17][C:18]3[CH:19]=[N:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([CH3:28])[CH:22]=4)[CH:16]=2)=[O:11])=[C:6]([CH3:29])[N:5]=[C:4]([NH:30]C(=O)OC(C)(C)C)[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[NH2:30][C:4]1[N:5]=[C:6]([CH3:29])[C:7]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[N:14][N:15]([CH2:17][C:18]3[CH:19]=[N:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([CH3:28])[CH:22]=4)[CH:16]=2)=[O:11])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1ccc2cc(Cn3cc(C(=O)NCc4c(C)cc(NC(=O)OC(C)(C)C)nc4C)nn3)cnc2c1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2cc(Cn3cc(C(=O)NCc4c(C)cc(N)nc4C)nn3)cnc2c1
Temperature: 23 °C

Procedure:
To a solution of tert-butyl (4,6-dimethyl-5-((1-((7-methylquinolin-3-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)pyridin-2-yl)carbamate (70 mg, 0.140 mmol) in DCM (1 ml) was added TFA (0.215 ml, 2.79 mmol). Reaction mixture was stirred over a weekend at 23° C. Reaction mixture was evaporated to afford a crude product, which was purified by preparative HPLC (Sunfire C18-ODB, 5 μm, 100×30 mm, elution with A=water+0.1% HCOOH and B=ACN+0.1% HCOOH, gradient from 10% to 100% B in 25 min, flow: 40 mL/min). Fractions were combined and solvents were evaporated to afford athe product as a formic acid salt, which was dissolved in methanol and eluted through a PL-HCO3 MP-resin column (Stratosphere SPE) in order to remove salt. The eluted solution was evaporated and dried overnight under high vacuum (dessicator, 50° C.) to afford the title compound as a free base. 1H-NMR (DMSO-d6, 400 MHz) δ 8.90 (s, 1H), 8.72 (s, 1H), 8.30 (broad s, 1H), 8.26 (s, 1H), 7.89 (d, 1H), 7.83 (s, 1H), 7.49 (d, 1H), 6.10 (s, 1H), 5.87 (s, 2H), 5.61 (broad s, 2H), 4.33 (d, 2H), 2.54 (s, 3H), 2.31 (s, 3H), 2.18 (s, 3H); HPLC (Method G) Rt=1.079 min; MS (Method V) [M+H]+=402.4.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:16]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:15])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[N:6]=1.B1([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH:34]=2)OC(C)(C)C(C)(C)O1>>[NH2:16][C:4]1[S:3][C:2]([C:37]2[CH:38]=[CH:33][CH:34]=[C:35]([CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH:36]=2)=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=1)=[O:15]
Reactant: CC1(C)OB(c2cccc(CN3CCOCC3)c2)OC1(C)C
Reactant: Cn1cc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)cn1
Product: Cn1cc(NC(=O)c2nc(-c3cccc(CN4CCOCC4)c3)sc2N)cn1
Yield: 36 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 2-bromo-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate and 3-(4-morpholinomethyl)phenylboronic acid pinacol ester gave 356 as an off-white solid (31 mg, 36% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 9.80 (s, 1H), 7.98 (s, 1H), 7.80-7.73 (m, 2H), 7.65 (s, 1H), 7.49-7.38 (m, 3H), 7.35 (d, J=7.6 Hz, 1H), 3.82 (s, 3H), 3.60 (t, J=4.5 Hz, 4H), 3.53 (s, 2H), 2.45-2.33 (m, 4H). LCMS (ES+) m/z 399 (M+1)
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:35](=[O:36])[N:6]2[C:7]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([CH2:20][OH:21])[N:17]=[C:18]([CH3:19])[N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]>ClCCl.[O-2].[O-2].[Mn+4]>[CH:20]([C:16]1[N:17]=[C:18]([CH3:19])[N:13]2[CH:12]=[C:11]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:35](=[O:36])[N:6]4[C:7]=3[C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=3)=[O:23])[S:15][C:14]=12)=[O:21]
Reactant: Cc1nc(CO)c2sc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)cn12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1nc(C=O)c2sc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)cn12
Temperature: 25 °C
Reaction time: 14 h
Yield: 32 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6((1R)-1-Hydroxyethyl)-2-(7-hydroxymethyl-5-methylimidazo-[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (279 mg) was dissolved in 30 ml of dichloromethane. Manganese dioxide (500 mg) was added to the solution. The mixture was stirred at room temperature for 14 hr. The reaction solution was filtered. The filtrate was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel to give 89 mg of 4-nitrobenzyl (1S,5R,6S)-2-(7-formyl-5-methylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:35])[C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([S:19][C:20]3[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:30])=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:26]([C:24]1[CH:25]=[C:20]([S:19][CH:16]2[CH2:17][CH2:18][N:13]([S:10]([C:7]3[N:6]([CH3:35])[C:5]([CH2:3][OH:2])=[CH:9][CH:8]=3)(=[O:12])=[O:11])[CH2:14][CH2:15]2)[CH:21]=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:23]=1[OH:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: COC(=O)c1ccc(S(=O)(=O)N2CCC(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)n1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(CO)ccc1S(=O)(=O)N1CCC(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
To 5-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (Ex. 4a, 440 mg, 0.84 mmol) in 5 mL of THF was added LiAlH4 (128 mg, 3.4 mmol) in 4 portions. The mixture was stirred for 2 h at room temperature and then quenched with saturated NH4Cl (30 mL) and extracted with Ethyl acetate (2×3 0 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. Chromatography (10-60% Ethyl acetate/hexanes) gave the title compound as a light-pink solid (195 mg, 47%), mp 64-65° C. 1H NMR (400 MHz, CDCl3): δ 7.27 (s, 2H), 7.07 (d, J=2 Hz, 1H), 6.32 (d, J=2 Hz, 1H), 5.30 (s, 1H), 4.59 (s, 2H), 3.73 (s, 3H), 3.57 (m, 2H), 2.77 (m, 1H), 2.48 (m, 2H), 1.99 (m, 2H), 1.70 (m, 2H), 1.41 (s, 18H). ESI/CI-MS m/z 495 ([M+H]+), 493 ([M−H]−). Three HPLC (reverse-phase, C18) methods were used to determine the purity of the title compound. Method 1: gradient elution, 50% to 99% solvent B (A=aqueous 0.1% H3PO4, B=MeCN) in 15 min. Purity (UV-VIS): 98.7% (215 nm), 97.6% (254 nm), 98.6% (280 nm); Method 2: gradient elution, 40% to 95% solvent B (A=10 mM NH4OAc, B=MeCN) in 6 min. Purity (UV-VIS λ): 98.0% (215 nm), 97.8% (254 nm), 97.8% (280 nm); Method 3: gradient elution, 60% to 85% solvent B (A=aqueous 0.1% H3PO4, B=MeCN) in 15 min. Purity (UV-VIS): 98.3% (238 nm).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[C@H:7]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:8][CH2:9][CH:10]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C)C=O>[C:14]([O:13][C:11](=[O:12])[C@@H:10]([NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:9][CH2:8][C:7]([C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:36])[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:42][CH:41]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC(CC[C@@H](C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(OCc2ccccc2)cc1)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 157.2 %

Procedure:
1.00 g (1.97 mmol) (2S)-2-Benzyloxycarbonyl-5-tert.-butoxycarbonylamino-hexane dioic acid di-tert.-butyl ester were dissolved in 25 mL dimethylformamide, 87 mg (2.2 mmol) NaH (60% in mineral oil) added and stirred at room temperature for 30 min. 601 mg (2.17 mmol) 4-benzloxy benzyl bromide 1 mL dimethylformamide were added and the reaction stirred for 1 h at 60° C. The solvent was removed i. vac. And the residue partitioned between ethyl acetate and brine. The organic phase was adsorbed on Isolute and directly chromatographed on a Biotage Isolera system (SNAP 100 g, A=n-Hexane, B=ethyl acetate. A 3 CV, A to 25% B in 10 CV, 4.7 CV 25% B, 50 mL/min, Fr. a 18 mL). Fractions 68 to 75 were collected to give 1.09 g (79%) of (2S,5SR)-5-Benzyloxycarbonyl-6-(4-benzyloxy-phenyl)-5-tert.-butoxycarbonyl-2-tert.-butoxycarbonylamino-hexanoic acid tert.-butyl ester.
Reaction SMILES: [N:1]1([CH:6]([CH3:12])C(OCC)=O)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].C1C[O:24][CH2:23]C1>>[N:1]1([CH2:6][CH2:12][CH2:23][OH:24])[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: CCOC(=O)C(C)n1ccnn1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCCn1ccnn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of ethyl (1H-1,2,3-triazol-1-yl)propanoate (8.96 g, 53 mmol) in THF (50 ml) was added dropwise to a suspension of lithium aluminium hydride (3 g, 79 mmol) in THF (250 ml) cooled at 0° C. After stirring for 1 hour at 5° C., the mixture was stirred for 1 hour at ambient temperature. The mixture was cooled at 0° C. and 4N sodium hydroxide (30 ml) was added dropwise. The mixture was filtered and the solid was washed with THF followed by ethyl acetate. The filtrate was dried (MgSO4) and evaporated. The residue was purified by column chromatography, eluting with methylene chloride/methanol (94/6) to give 3-(1,2,3-triazol-1-yl)propan-1-ol (6.2 g, 92%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11](Cl)(=[O:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:15]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].CCCCCC>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH2:22]([N:21]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[S:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([CH3:1])[S:3][C:4]=2[CH:10]=1)(=[O:13])=[O:12])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: Cc1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: CCCCCCNCCCCCC
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCCCN(CCCCCC)S(=O)(=O)c1ccc2nc(C)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
A solution of Compound 2 (5.0 g, 20.2 mmol) from step (b) of Example 1 dissolved in chloroform (30 ml) was added drop wise to a solution of dihexylamine (4.5 g, 24.2 mmol) in chloroform (20 ml). The combined mixture was stirred at room temperature for 2 hours. The reaction mixture was then washed with water (2×, 50 ml) and brine (1×, 50 ml). The organic layer was then dried with sodium sulfate and evaporated. The residue thus obtained was suspended in ca. 5 ml hot ethyl acetate and this solution was then slowly added to 40 ml hexane. The white solid that precipitated was filtered and the filtrate evaporated to dryness to provide 7.76 g (97%) of Compound 20 as a syrupy liquid, Rf=0.43 (30% ethyl acetate in hexane). The structure of this compound is given below:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:40][O:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][C:51]=1[O:52][CH3:53])[N:48]=[CH:47][CH:46]=[C:45]2[O:54][C:55]1[CH:60]=[CH:59][C:58]([NH2:61])=[CH:57][C:56]=1[F:62]>CN(C=O)C>[CH3:40][O:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][C:51]=1[O:52][CH3:53])[N:48]=[CH:47][CH:46]=[C:45]2[O:54][C:55]1[CH:60]=[CH:59][C:58]([NH:61][C:14]([C:10]2[C:9](=[O:17])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:13]=[CH:12][CH:11]=2)=[O:16])=[CH:57][C:56]=1[F:62]
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)c2cc1OC
Temperature: 25 °C
Yield: 36.7 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (45 mg, 0.19 mmol), HOBt (20 mg) and EDCI.HCl (80 mg, 0.31 mmol) in DMF (2.5 mL) was added 4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorobenzenamine (56 mg, 0.18 mmol) at rt, and the reaction mixture was stirred over the weekend at rt. It was directly purified by preparative HPLC to afford the product (35 mg, 30%) as a beige-colored TFA salt solid. 1H NMR (CD3OD) δ 12.21 (s, 1H), 8.60 (dd, 2H, J=9.9, 1.6 Hz), 8.01 (d, 1H, J=12.6 Hz), 7.90 (dd, 1H, J=7.6, 1.6 Hz), 7.74 (s, 1H), 7.45-7.37 (m, 5H), 7.24 (t, 2H, J=8.2 Hz), 6.89 (d, 1H, J=6.6 Hz), 6.65 (t, 1H, J=6.6 Hz), 4.03 (s, 3H), 4.00 (s, 3H); MS(ESI+) m/z 530.2 (M+H)+.
Reaction SMILES: C(C1(CC)C2CCCC=2C2C([O:21][C:22](=[O:32])[CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=CC(CCCCC)=CC=2O1)C.[CH2:35](C1C=C(OC(=O)CCCN2CCSCC2)C2C3C=C(C)CCC3C(C)(C)OC=2C=1)CCCC.C(C1C=C(OC(=O)CCN2CCCC2)C2C3CC(C)=CCC3C(C)(C)OC=2C=1)CCCC.O1CCN(CCCC(OC2C3C4CCCCC4COC=3C=C(CCCCC)C=2)=O)CC1>>[CH3:35][CH:23]([CH2:24][CH2:25][N:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[C:22]([OH:21])=[O:32]
Reactant: CCCCCc1cc(OC(=O)CCCN2CCSCC2)c2c(c1)OC(C)(C)C1CCC(C)=CC21
Reactant: CCCCCc1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(CC)(CC)C1=C2CCC1
Agent: CCCCCc1cc(OC(=O)CCN2CCCC2)c2c(c1)OC(C)(C)C1CC=C(C)CC21
Agent: CCCCCc1cc2c(c(OC(=O)CCCN3CCOCC3)c1)C1CCCCC1CO2
Product: CC(CCN1CCCCC1)C(=O)O

Procedure:
Some of the compounds produced according to the invention are: 4,4-diethyl-7-n-pentyl-9-[4-(piperidino)-butyryloxy]-1,2,3,4-tetrahydrocyclopenta[c][1]benzopyran, 4,4-di-(1-hexyl)-7-(3-methyl-2-octyl)-9-[4-(morpholino)-butyryloxy]-1,2,3,4,12,13-hexahydrocyclopenta[c][1]benzopyran, 4,4-dimethyl-7-(3-methyl-2-octyl)-9-[4-(piperidino)-butyryloxy]-1,2,3,4,12,13-hexahydrocyclopenta[c][1]benzopyran, 4,4-diethyl-7-octadecyl-9-[3-pyrrolidino)-propionyloxy]-1,2,3,4,12,13-hexahydrocyclopenta[c][1]benzopyran, 3-pentyl-1-[4-(thiomorpholino)-butyryloxy]6a,7,8,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran, 3-pentyl-1-[3-(pyrrolidino)-propionyloxy]-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran, 1-[4-(homopiperidino)-butyryloxy]-7,8,9,10-tetrahydro-6H-dibenzo-[b,d]pyran and 1-[4-(morpholino)-butyryloxy]-3-pentyl-6a, 7,8,9,10,10a hexahydro-6H-dibenzo[b,d]pyran.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([C:14]1[CH:29]=[CH:28][C:17]2[CH2:18][CH2:19][C:20]3[C:21]([C:26](=[O:27])[C:16]=2[CH:15]=1)=[N:22][CH:23]=[CH:24][CH:25]=3)#[N:13]>C(Cl)(Cl)Cl>[C:12]([C:14]1[CH:29]=[CH:28][C:17]2[CH2:18][CH2:19][C:20]3[C:21]([C:26](=[O:27])[C:16]=2[CH:15]=1)=[N+:22]([O-:9])[CH:23]=[CH:24][CH:25]=3)#[N:13]
Reactant: N#Cc1ccc2c(c1)C(=O)c1ncccc1CC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2c(c1)C(=O)c1c(ccc[n+]1[O-])CC2

Procedure:
In a manner similar to that described in Example II, 1.19 grams (0.0055 mole) of m-chloroperbenzoic acid is added to a solution of 1.29 grams (0.005 mole) of 9-cyano-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyridin-11-one in 20 milliliters of chloroform and the resulting mixture stirred at ambient temperature for several days with an addition of an about 0.5 gram portion of m-chloroperbenzoic acid after the first 24 hours. At the end of this period the mixture is washed, dried and evaporated to obtain a 9-cyano-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]-pyridin-11-one N-oxide intermediate as residue.
Reaction SMILES: BrCCCC1C=CC=[C:7]2[C:8]([NH:10]C(=O)[C:6]=12)=O.[CH3:16][O:17][C:18]1[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=1>>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][CH2:6][CH2:7][CH2:8][NH2:10]
Reactant: O=C1NC(=O)c2c(CCCBr)cccc21
Reactant: COc1ccccc1N
Product: COc1ccccc1NCCCN
Yield: 33.5 %

Procedure:
By using 3-bromopropylphthalimide (25.0 g) and o-anisidine (10 g) as starting materials, the title compound (4.9 g) was obtained in the same manners as those of Reference Example 57, (1) and Reference Example 54, (4).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[C:7]([CH:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH2:10]1)=[O:8].Br.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:10]=1)=[O:8]
Reactant: Cc1cccc(C(=O)C2CNc3ccccc3C2=O)c1
Reactant: BrCc1ccccn1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)c2cn(Cc3ccccn3)c3ccccc3c2=O)c1
Yield: 31 %

Procedure:
Compound 4w was prepared following the procedure outlined in Step 3 of Example 1 using 52 mg (1.3 mmol) of sodium hydride (60%), 132 mg (0.5 mmol) of 3-(3-methyl-benzoyl)-2,3-dihydro-1H-quinolin-4-one 3g, 3 mL of anhydrous dimethylformamide, and 164 mg (0.65 mmol) of 2-bromomethylpyridine hydrobromide. The crude product was purified by flash chromatography to yield 55 mg of a pale yellow solid 4w: Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=1.913 min; LC-MSD, m/z for C23H18N2O2, [M+H]+=355.4, [M+2H]+=356.4; 1H NMR (400 MHz, CDCl3/HCl): δ 2.40 (s, 3H), 5.50 (s, 2H), 7.12 (d, 1H), 7.22-7.35 (m, 3H), 7.38-7.46 (m, 2H), 7.56-7.68 (m, 4H), 8.56 (s, 1H), 8.46 (d, 1H), 8.62 (d, 1H).
Reaction SMILES: N.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:12][C:13]#[N:14])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1>>[N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([CH:12]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=2)[C:13]#[N:14])=[CH:17][CH:18]=1
Reactant: Clc1ccnc2ccccc12
Reactant: COc1ccc(CC#N)cc1OC
Agent: N
Product: COc1ccc(C(C#N)c2ccnc3ccccc23)cc1OC
Reaction time: 2 h

Procedure:
To 500 ml of liquid NH3 was added 35.4 g (0.2 mol) of 3,4-dimethoxyphenylacetonitrile and 11.7 g (0.3 mol) of NaNH2. The mixture was stirred for two hours, maintaining a temperature at -25° to -30°C by cooling in a dry ice/acetone bath. 4-Chloroquinoline (16.4 g, 0.1 mol) was added and the resulting mixture was allowed to stir at room temperature until all excess NH3 had evaporated. Benzene was added to the residue and water was added slowly to destroy excess NaNH2. The phases were separated and the aqueous phase was extracted with benzene. The combined benzene extracts were extracted with 9M HCl (2×150 ml). The acidic phase was washed with Et2O (500 ml), cooled and basified with concentrated NH4OH. The aqueous mixture was extracted with CHCl3 (500 ml). The CHCl3 extract was dried with MgSO4 and evaporated to give a quantitative yield of crude α-(4 -quinolinyl)-α-(3,4-dimethoxyphenyl)acetonitrile intermediate.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[NH:13][CH2:14][C:15]1[C:16]([NH:23][CH3:24])=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=1.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[F:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([F:5])[C:7]=1[N:13]1[CH2:14][C:15]2[C:16](=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=2)[N:23]([CH3:24])[C:1]1=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CNc1nc(SC)ncc1CNc1c(F)cccc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1c(F)cccc1F)C2
Reaction time: 1 h
Yield: 87.4 %

Procedure:
A stirred solution, cooled in ice, of 0.7 ml (1.3 mmol) of phosgene (20% in toluene) in 5 ml of tetrahydrofuran was treated dropwise with a solution of 210 mg (0.71 mmol) of 5-(2,6-difluorophenyl)aminomethyl-4-methylamino-2-methylthiopyrimidine and 0.2 ml (1.4 mmol) of triethylamine in 5 ml of tetrahydrofuran. The mixture was stirred for 1 hour. To the mixture were added 20 ml of tetrahydrofuran and 20 ml of saturated aqueous ammonium chloride solution and the phases were separated. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 200 mg (87%) of 3-(2,6-difluorophenyl)-7-methylthio-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid. [Mass spectrum (ESI) MH+ =323].
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]([CH:10]3[CH2:15][NH:14][CH2:13][CH2:12][NH:11]3)=[C:8]([CH3:9])[C:4]=2[CH:3]=1.Cl[C:19]1[CH:28]=[C:27]2[C:22]([C:23](=[O:34])[C:24]([C:31]([OH:33])=[O:32])=[CH:25][N:26]2[CH2:29][CH3:30])=[CH:21][C:20]=1[F:35]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]([CH:10]3[NH:11][CH2:12][CH2:13][N:14]([C:19]4[CH:28]=[C:27]5[C:22]([C:23](=[O:34])[C:24]([C:31]([OH:33])=[O:32])=[CH:25][N:26]5[CH2:29][CH3:30])=[CH:21][C:20]=4[F:35])[CH2:15]3)=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: Cc1c(C2CNCCN2)sc2ccc(Cl)cc12
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4sc5ccc(Cl)cc5c4C)C3)cc21

Procedure:
A 3.0 g portion of 2-(5-chloro-3-methylbenzo[b]-thien-2-yl)piperazine was added to 5 ml of pyridine. A 1.01 g portion of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added and the mixture was heated in a pressure bottle, under argon at 130°-135° C. for 18 hours, then cooled and placed in an ice bath. The resulting crystals were collected, washed with cold pyridine, dichloromethane and ether and recrystallized from dimethylformamide, giving 401 mg of the desired product, mp 300°-305° C.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1[CH2:12]Br.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH2:15]([N:22]1[CH2:12][C:5]2[C:4](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH3:11])[C:3]1=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cccc(OC)c1CBr
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1cccc2c1CN(Cc1ccccc1)C2=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
A mixture of 2-bromomethyl-3-methoxy-benzoic acid methyl ester (0.119 g, 0.5 mmol), benzylamine (0.065 mL, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-benzyl-4-methoxy-2,3-dihydro-isoindol-1-one (0.078 g, 61.4%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.83 (s, 3H), 4.21 (s, 2H), 4.69 (s, 2H), 6.98 (d, 1H), 7.25-7.51 (m, 7H). GC-MS: m/z 253 (M)+, 176 (M-77)+.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH3:8][S:9]([O:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=2)(=[O:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:8][S:9]([O:12][C:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][C:18]([C:24]([F:27])([F:25])[F:26])=[CH:19][CH:20]=2)[N:15]([CH3:5])[CH:14]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Oc1cnc2cc(C(F)(F)F)ccc2c1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cn1cc(OS(C)(=O)=O)c(=O)c2ccc(C(F)(F)F)cc21

Procedure:
Dimethyl sulphate (26.1ml) was added to a stirred suspension of 4-hydroxy-7-trifluoromethylquinol-3-yl methanesulphonate (7.19 g) and potassium carbonate (75.5 g) in dry 2-butanone (350 ml) and the resultant mixture was heated under reflux for 5 hours. The solvent was removed by distillation and the resultant residue was extracted with dichloromethane (600 ml then 400 ml). The combined extracts were dried over magnesium sulphate and the solvent was removed by distillation. The residue was purified by flash chromatography on a silica gel column eluted with dichloromethane:methanol (75:1) followed by flash chromatography on a silica gel column eluted with ethyl acetate and crystallisation from industrial methylated spirit (150 ml) to give the novel compound 1-methyl-4-oxo-7-trifluoromethyl-1,4-dihydroquinol-3-yl methanesulphonate, m.p. 218°.