Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19]1>>[CH3:17][N:13]1[CH2:14][CH2:15][CH2:16][C@@H:12]1[CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:20]3[CH:21]=[CH:22][S:18][CH:19]=3)[CH:10]=2)[CH:6]=[CH:7]1
Reactant: CN1CCC[C@H]1Cn1ccc2ccc(Br)cc21
Reactant: OB(O)c1ccsc1
Product: CN1CCC[C@@H]1Cn1ccc2ccc(-c3ccsc3)cc21

Procedure:
(39.9 mg, 79%); from (S)-6-bromo-1-((N-methylpyrrolidin-2-yl)methyl)indole (50.0 mg, 0.17 mmol) and thiophene-3-boronic acid (43.6 mg, 0.34 mmol).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[Si:23]([O:40][C:41]1[CH:42]=[C:43]([CH:51]=[CH:52][CH:53]=1)[CH2:44][CH:45]1[CH2:49][CH2:48][O:47][C:46]1=[O:50])([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)(=O)C>C1COCC1.O>[C:1]1([C:7]2[N:8]=[C:9]([CH:46]([OH:50])[CH:45]([CH2:49][CH2:48][OH:47])[CH2:44][C:43]3[CH:42]=[C:41]([O:40][Si:23]([C:36]([CH3:38])([CH3:39])[CH3:37])([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:53]=[CH:52][CH:51]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](Oc1cccc(CC2CCOC2=O)c1)(c1ccccc1)c1ccccc1
Reactant: c1ccc(-c2ncoc2-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](Oc1cccc(CC(CCO)C(O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a solution of 4,5-diphenyloxazole (5.3 g) in THF (50 ml) at −78° C. under N2 was added n-butyllithium (1.6 M in hexane, 9.2 ml). After 30 minutes, a solution of 3-(3-t-butyldiphenylsilyloxybenzyl)-2-oxotetrahydrofuran (3.3 g) in THF (30 ml) was added thereto and stirred for 1 hour at the same temperature. The reaction mixture was poured into the mixture of ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3 and brine, dried over MgSO4, and evaporated in vacuo. The oily residue was dissolved in THF (100 ml) and LiAlH4 was added to the solution at 0° C. After being stirred for 2 hours, the mixture was poured into a mixture of ethyl acetate and 1N-HCl solution. The organic layer was washed with sat. NaHCO3 and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 3-[3-(4,5-diphenyloxazol-2-yl)-3-hydroxy-2-(2-hydroxyethyl)propyl]-1-(t-butyldiphenylsilyloxy)benzene (4.3 g).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[F:6][C:7]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=3)[S:18][C:11]=12.C([O-])([O-])=O.[K+].[K+]>>[F:6][C:7]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[CH2:20][CH2:21][N:22]([C:1](=[O:4])[CH:2]=[CH2:3])[CH2:23][CH:24]=3)[S:18][C:11]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(C4=CCNCC4)sc23)c(F)c1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CC(=O)N1CC=C(c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.1 %

Procedure:
Acryloyl chloride (131.3 mL, 1.62 mmol) was added to a suspension of 7-(2-fluoro-4-nitrophenoxy)-2-(1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-b]pyridine (85) [US 2007/0004675 A1] (150 mg, 0.40 mmol) and K2CO3 (223.4 1.62 mmol) and the mixture was stirred overnight at room temperature. It was then filtered and concentrated under reduced pressure affording title compound 98 (172 mg, 100% yield) that was used in the next step without further purification. MS (m/z): 426.1 (M+1)
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[H][H].C(OC(N1C[C@H]2[C@H](CCCC2)C1)=O)C>[C].[Rh].C(O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][C@H:8]2[C@@H:13]([CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)N1Cc2ccccc2C1
Agent: [Rh]
Agent: CCOC(=O)N1C[C@H]2CCCC[C@H]2C1
Solvent: CCO
Product: CCOC(=O)N1C[C@@H]2CCCC[C@H]2C1
Yield: 0.6 %

Procedure:
In a 3-liter GL autoclave fitted with a electromagnetic stirrer are added 207 g of N-ethoxycarbonylisoindoline, 793 g of ethylalcohol and 20 g of 5% rhodium-carbon catalyst (50% water-containing). The reaction mixture is subjected to a hydrogen-pressure of 25 kg/cm2 and a temperature of 130° C. After a 10 hour hydrogen introduction, the drop in the rate of the hydrogen-absorption is observed, at this point the introduction of hydrogen is ceased to terminate the reaction. After the termination of reaction, the catalyst is filtered out from the reacted solution. By the result of the capillary chromatographic analysis, the yield of cis-hexahydro-N-ethoxycarbonylisoindoline is 95.3%. In addition, 0.6% of trans-hexahydro-N-ethoxycarbonylisoindoline is formed.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([CH3:8])=[CH:5][CH2:6]O.[C:9]([O:17]CC)([O:14][CH2:15][CH3:16])(OCC)[CH3:10].C(O)(=O)CC>C(O)C>[Cl:1][CH2:2][CH2:3][C:4]([CH3:8])([CH:5]=[CH2:6])[CH2:10][C:9]([O:14][CH2:15][CH3:16])=[O:17]
Reactant: CC(=CCO)CCCl
Reactant: CCOC(C)(OCC)OCC
Solvent: CCC(=O)O
Solvent: CCO
Product: C=CC(C)(CCCl)CC(=O)OCC
Reaction time: 0.08 h
Yield: 76 %

Procedure:
To a solution of 1.97 parts of a 2:1 mixture of E/Z stereoisomers of 5-chloro-3-methyl-2-penten-1-ol in 20 parts by volume of triethyl orthoacetate is added 0.14 part of propionic acid. This solution is heated for 40 hours in an oil bath (~150°) in such a manner that the ethanol that forms during the reaction is slowly distilled through a Vigreaux column. After cooling the solution, 20 parts by volume of pentane and 20 parts by volume of 1 M sulfuric acid are added, and this mixture is stirred vigorously for 5 minutes to hydrolyze the excess triethyl orthoacetate. The mixture is then diluted with 150 parts by volume of water and the product is isolated by pentane extraction. The pentane extracts are washed with saturated sodium bicarbonate, 10% sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. Removal of the pentane, followed by fractional distillation, yields 2.27 parts (76%) of ethyl 3-[2-chloroethyl]-3-methyl- 4-pentenoate. The formula is: ##STR2##
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19][O:20][C:21](=[O:25])[CH2:22][CH2:23][NH2:24].C(N(CC)CC)C.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:19][O:20][C:21](=[O:25])[CH2:22][CH2:23][NH:24][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCNC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.1 %

Procedure:
To a mixture of 4-benzyloxybenzoic acid (8.92 g, 39.08 mmol) and 3-amino-propionic acid methyl ester hydrochloride (6.00 g, 42.98 mmol) in CH2Cl2 (100 mL) was added DMAP (catalytic), triethylamine (6.60 mL, 47.35 mmol), and EDCI (9.00 g, 46.94 mmol). The mixture was stirred at RT for 12 h. The mixture was diluted with CH2Cl2. The organics were washed with 1N HCl, 2N NaOH, water, and brine (1×100 mL each), and dried with MgSO4 to yield 11.28 g (92%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:27]=[N:26][CH:25]=[CH:24][C:5]=1[C:6]([CH2:12][S:13]([N:16]([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:15])=[O:14])=[N:7]2.[OH-:28].[Na+]>C(O)(=O)C.O>[CH3:23][N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[S:13]([CH2:12][C:6]1[C:5]2[CH:24]=[CH:25][N:26]=[CH:27][C:4]=2[C:3]2[C:2](=[O:28])[NH:11][CH:10]=[CH:9][C:8]=2[N:7]=1)(=[O:14])=[O:15]
Reactant: [OH-]
Reactant: CN(c1ccccc1)S(=O)(=O)Cc1nc2ccnc(Cl)c2c2cnccc12
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN(c1ccccc1)S(=O)(=O)Cc1nc2cc[nH]c(=O)c2c2cnccc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(1-chloropyrido[4,3-c]-1,6-naphthyridin-6-yl)-N-methyl-N-phenylmethanesulfonamide (45 mg, 0.113 mmol) in acetic acid (2790 μl) and water (1196 μl) was heated to 100° C. and stirred for 2 h. After cooling to room temperature, the reaction mixture was added to aqueous sodium hydroxide (1M). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA, to afford N-methyl-1-(1-oxo-1,2-dihydropyrido[4,3-c]-1,6-naphthyridin-6-yl)-N-phenylmethanesulfonamide as a yellow solid. 1H NMR (500 MHz, C2D6SO) δ 12.17 (s, 1H), 11.19 (s, 1H), 8.87 (d, 1H), 8.30 (d, 1H), 7.71 (t, 1H), 7.48 (d, 2H), 7.38 (t, 2H), 7.29 (t, 1H), 6.95 (d, 1H), 5.36 (s, 2H), 3.22 (s, 3H). LRMS (APCI) calc'd for (C14H14N3O) [M+H]+, 381.1; found 381.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)[CH:10]=[CH:9][C:8]=1[CH3:19])[CH3:2].[F:21][C:22]([F:39])([F:38])[C:23]1[CH:37]=[CH:36][C:26]([CH2:27][O:28][C:29](N2C=CN=C2)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[F:21][C:22]([F:38])([F:39])[C:23]1[CH:37]=[CH:36][C:26]([CH2:27][O:28][C:29]([N:15]2[CH2:16][CH2:17][CH2:18][CH:13]([C:11]3[CH:10]=[CH:9][C:8]([CH3:19])=[C:7]([NH:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH:12]=3)[CH2:14]2)=[O:30])=[CH:25][CH:24]=1
Reactant: O=C(OCc1ccc(C(F)(F)F)cc1)n1ccnc1
Reactant: CCOC(=O)CNc1cc(C2CCCNC2)ccc1C
Solvent: Cc1ccccc1
Product: CCOC(=O)CNc1cc(C2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)ccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.3 %

Procedure:
(2-Methyl-5-piperidin-3-yl-phenylamino)-acetic acid ethyl ester (63 mg, 0.23 mmol) was dissolved in 3 mL toluene and imidazole-1-carboxylic acid 4-trifluoromethyl-benzyl ester (93 mg, 0.34 mmol) was added. The reaction was stirred for 18 h at room temperature under nitrogen. The reaction was flash chromatographed with 15% ethyl acetate/hexanes to yield 40 mg (37%) of the desired 3-[3-(ethoxycarbonylmethyl-amino)-4-methyl-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([NH:20][C@H:21]([C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])[C:10]([NH:12][C:13]1C=CC=CC=1O)=[O:11].[C:30](N1C=CN=C1)(N1C=CN=C1)=S.[NH2+]1C2C=CC=CC=2N=N1.CNC>ClCCl.O1CCCC1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:20][C@H:21]([C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])[C:10]([N:12]([CH3:13])[CH3:30])=[O:11]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)[C@H](CC(C)C)N[C@@H](C(=O)Nc1ccccc1O)c1ccc(F)cc1F
Agent: CNC
Agent: c1ccc2c(c1)N=N[NH2+]2
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C)C)NC(C(=O)N(C)C)c1ccc(F)cc1F
Reaction time: 18 h
Yield: 58.5 %

Procedure:
A solution of methyl N-{(1R)-1-(2,4-difluorophenyl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-L-leucinate (203 mg) and 1,1′-thiocarbonyldiimidazole (100 mg) in dichloromethane (5 ml) was left to stand for 18 hours. Water (10 □l) was added to the reaction mixture and this was then stirred rapidly for 30 minutes. After this, 1H-Benzotriazolium, 1-[bis(dimethylamino)methylene]-, tetrafluoroborate(1-), 3-oxide (TBTU, 321 mg) and a solution of dimethylamine in tetrahydrofuran (0.5 ml of 2M solution) were added. The reaction mixture was stirred for a further 18 hours and was then passed down an SPE (5 g, silica) eluting with a gradient (8:1 to 1:2 cyclohexane:ethyl acetate). The required fractions were combined and evaporated to furnish methyl N-[1-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucinate (100 mg).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O.[CH:12]12[O:18][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]2.[S:19]1[CH2:23][CH2:22][NH:21][CH2:20]1>C(#N)C>[S:19]1[CH2:23][CH2:22][N:21]([C@H:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C@@H:12]2[OH:18])[CH2:20]1
Reactant: C1CSCN1
Reactant: C1CCC2OC2C1
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: O[C@H]1CCCC[C@@H]1N1CCSC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.9 %

Procedure:
To anhydrous magnesium perchlorate (12.93 g, 53.3 mmol) was added a solution of cyclohexene oxide (6.1 mL, 58.6 mmol) in anhydrous acetonitrile (25 mL) and the resulting mixture was stirred at room temperature for 20 min. Then a solution of thiazolidine (5.16 g, 55.0 mmol) in anhydrous acetonitrile was added and the reaction mixture was heated at 35° C. for 16 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between water (350 mL) and diethyl ether (350 mL). The aqueous layer was separated and extracted once more with diethyl ether (350 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to provide the crude product. The crude aminoalcohol was purified by dry-column chromatography with a mixture of ethyl acetate-hexanes (1:1, v/v) as eluent to yield 4.83 g (47% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:5]2Cl.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:5]2[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: Cc1nc2ccc(Br)cc2c(Cl)c1S(C)(=O)=O
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2ccc(Br)cc2c(N2CCOCC2)c1S(C)(=O)=O
Temperature: 80 °C
Yield: 81.5 %

Procedure:
6-Bromo-4-chloro-3-methanesulfonyl-2-methyl-quinoline (compound of example D.1) (11.5 g, 34.4 mmol), morpholine (3.3 mL, 37.8 mmol) and N,N-diisopropyl ethyl amine (6.5 mL, 37.8 mmol) were heated at 100° C. in dry N,N-dimethylformamide (10 mL) for 30 min. The reaction mixture was evaporated to dryness, and the residue extracted with dichloromethane, 10% Na2CO3 and sat. NaCl. The crude product was stirred and heated at 80° C. in ethyl acetate (80 mL) for 10 min, the resulting suspension was cooled in ice, the crystals were filtered off and washed with little cold ethyl acetate. One obtained 10.8 g (81%) of white crystals. MS: m/z=385/387 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:24](=[O:31])[C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1ccccc1
Yield: 85.1 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (155 mg, 0.50 mmol), N-methylpyrrolidone (3 mL) and benzoyl chloride (0.070 mL, 0.60 mmol), and in the same manner as in Example 162, the title compound (176 mg, yield 85%) was obtained. melting point 265° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[CH:27]2.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[NH:29]1[C:30]2[C:26](=[CH:25][C:24]([O:23][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]5[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:32][CH:31]=2)[CH:27]=[CH:28]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OCC1CCN(C)CC1
Temperature: 100 °C
Yield: 63.3 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (110 mg, 0.34 mmol), (prepared as described for the starting material in Example 10), and 5-hydroxyindole (55 mg, 0.41 mmol) in DMF (1.5 ml) containing potassium carbonate (70 mg, 0.51 mmol) was heated at 100° C. for 2 hours. After cooling, water was added and the precipitate was collected by filtration, washed with water followed by ether, and dried under vacuum over phosphorus pentoxide to give 4-(indol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (90 mg, 64%).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.[H-].[Na+].[Cl:15][C:16]1[C:21]2[C:22](=[O:40])[N:23]3[CH2:39][CH2:38][CH2:37][C@H:24]3[C:25]3[N:26]([CH:27]=[N:28][C:29]=3[C:30](N3C=CN=C3)=[O:31])[C:20]=2[CH:19]=[CH:18][CH:17]=1>O>[Cl:15][C:16]1[C:21]2[C:22](=[O:40])[N:23]3[CH2:39][CH2:38][CH2:37][C@H:24]3[C:25]3[N:26]([CH:27]=[N:28][C:29]=3[C:30]([O:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:31])[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OC1CCCCC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 601 mg (6 mmol) of cyclohexanol, 10 ml of dimethylformamide and 288 mg (6 mmol) of sodium hydride (55 percent oil dispersion) is stirred at room temperature for 0.5 hour, the solution obtained is treated with 2.20 g (6 mmol) of (S)-1-[(8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl)carbonyl]imidazole, the mixture is stirred at room temperature for a further 0.5 hour and then poured into about 70 ml of water. The precipitated material is filtered off under suction, washed with water and dried. By recrystallization from ethyl acetate there is obtained cyclohexyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 166°-167°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:12][NH:13][CH3:14])=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CNCC1C2C=CC=CC=2N2CCCC=12.[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([OH:41])=O)=[CH:33][CH:32]=1.Cl.O=C1NC2N=CC(/C=C/C(O)=O)=CC=2CC1>>[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([N:13]([CH2:12][C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[N:8]([CH3:11])[CH:7]=2)[CH3:14])=[O:41])=[CH:33][CH:32]=1
Reactant: CNCc1cn(C)c2cc(F)ccc12
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: CNCc1c2n(c3ccccc13)CCC2
Agent: Cl
Agent: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Product: CN(Cc1cn(C)c2cc(F)ccc12)C(=O)/C=C/c1ccc(N)nc1
Yield: 50.1 %

Procedure:
According to the procedure of Example 24, except substituting 6-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.11 g, 0.59 mmole) for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene, and substituting (E)-3-(6-amino-pyridin-3-yl)acrylic acid (0.098 g, 0.59 mmole) for the (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride salt, the title compound (0.1 g, 27%) was prepared as a white powder: MS (ES) m/e 339 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](C(=O)N3CCCCC3)N(C(=O)OC(C)(C)C)C2)cc1
Yield: 90.4 %

Procedure:
4.7 g (15.7 mmol) (2S,4R)-4-Hydroxy-2-(piperidin-1-ylcarbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 300 ml CH2Cl2 were treated with 4.5 g (23.6 mmol, 1.5 eq) p-toluene sulfonylchloride in the presence of 2.88 g (23.6 mmol, 1.5 eq) DMAP at RT for 48 h. The solution was washed with 1M KHSO4, water, 5% aq. NaHCO3 solution, water and brine, dried over Na2SO4 and was concentrated. Flash chromatography yielded 6.42 g (90%) (2S,4R)-2-(Piperidine-1-carbonyl)-4-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester as white foam.
Reaction SMILES: [C:1]([C:8]1[C:17](=O)[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(=O)([O-])O.[Na+].P(Cl)(Cl)([Cl:28])=O>C(Cl)(Cl)Cl>[Cl:28][C:17]1[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCC(=O)c1c[nH]c2c(OC)cccc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCC(=O)c1cnc2c(OC)cccc2c1Cl

Procedure:
3-hexanoyl-8-methoxy-4(1H)-quinolone (4.6 g, 0.017 mol) was heated under reflux in a mixture of phosphorus oxychloride (8 ml) and chloroform (50 ml) for 1.5 hours. When cool, the mixture was poured into a vigorously stirred mixture of sodium hydrogen carbonate solution, ice and chloroform. The layers were separated and the organic solution was washed with sodium hydrogen carbonate solution and brine. Evaporation of the chloroform solution afforded 4-chloro-3-hexanoyl-8-methoxyquinoline as a yellow-brown oil (5 g).
Reaction SMILES: BrC1C(O)=CC2C(C)(C)CC=C(C)C=2C=1.[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27]C)[C:23]([CH3:30])([CH3:29])[CH2:22][CH:21]=[C:20]2[C:31]([CH3:34])([CH3:33])[CH3:32]>>[Br:16][C:17]1[C:26]([OH:27])=[CH:25][C:24]2[C:23]([CH3:30])([CH3:29])[CH2:22][CH:21]=[C:20]([C:31]([CH3:33])([CH3:32])[CH3:34])[C:19]=2[CH:18]=1
Reactant: COc1cc2c(cc1Br)C(C(C)(C)C)=CCC2(C)C
Agent: CC1=CCC(C)(C)c2cc(O)c(Br)cc21
Product: CC(C)(C)C1=CCC(C)(C)c2cc(O)c(Br)cc21
Yield: 98.8 %

Procedure:
The same procedure as for preparing 3-bromo-5,8,8-trimethyl-7,8-dihydronaphthalen-2-ol (Compound 96) was used with 6-bromo-4-tert-butyl-7-methoxy-1,1-dimethyl-1,2-dihydronaphthalene (Compound 95, 0.57 g, 1.8 mmol) to give 0.55 g (100%) of the title compound as a yellow oil.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[NH:9][CH2:10][CH2:11][C:12]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1>O1CCOCC1.C(OCC)(=O)C>[ClH:1].[ClH:1].[ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[NH:9][CH2:10][CH2:11][C:12]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1
Reactant: CCOC(=O)C1(CCNc2cnccc2C)CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)C1(CCNc2cnccc2C)CCCNC1
Reaction time: 2 h

Procedure:
Hydrogen chloride in 1,4-dioxane (4.0 M, 2.0 mL) was added to a solution of 1-tert-butyl 3-ethyl 3-{2-[(4-methylpyridin-3-yl)amino]ethyl}piperidine-1,3-dicarboxylate (0.036 g, 0.000092 mol) in ethyl acetate (0.5 mL) and the mixture was stirred for 2 h. Then the solvent was removed in-vacuo to afford the product. LC-MS: 292.3 (M+H)+.