Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][C@@H:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[O:30][CH2:31][C:32]([O:34]CC)=[O:33].[OH-].[Na+].Cl>C1COCC1.CO>[CH3:1][C:2]1[CH:7]=[C:6]([S:8][C@@H:9]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[O:30][CH2:31][C:32]([OH:34])=[O:33]
Reactant: CCCC[C@@H](Sc1ccc(OCC(=O)OCC)c(C)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCC[C@@H](Sc1ccc(OCC(=O)O)c(C)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.1 %

Procedure:
To a solution of ethyl {[2-methyl-4-({(1R)-1-[4′-(trifluoromethyl)-4-biphenylyl]pentyl}thio)phenyl]oxy}acetate (10 mg, 0.02 mmol) in THF (1 mL) and MeOH (1 mL) was added aqueous NaOH (2M, 1 mL) and the resulting mixture agitated for 1.5 hours at rt. The mixture was then reduced under vacuum, acidified with aqueous HCl (2M), extracted with DCM (2 mL) and reduced to afford the title compound as colourless oil (9 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].Cl.[NH2:13][OH:14]>CO.O>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N:13][OH:14])([O-:3])=[O:2]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccccc1C=NO
Temperature: 30 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
52.9 g (0.35 mol) of o-nitrobenzaldehyde was dissolved in 150 ml of methanol and an aqueous solution of 27.8 g (0.38 mol) of hydroxylamine hydrochloride in 35 ml of water was added dropwise over 30 minutes while maintaining the temperature at 30° C. The mixture was stirred at the same temperature for 2 hours and diluted with 300 ml of water. White crystals deposited were filtered, washed with water and dried. Thus, 53 g of o-nitrobenzaldoxime was obtained. Yield 91%; M.P. 95°-98° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)([OH:3])=O>O>[O:3]=[C:1]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][C:13]([OH:15])=[O:14])[CH:10]=2)[CH2:5][CH2:4]1
Reactant: O=C(O)CCc1ccc(CC(=O)O)cc1
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)C(=O)CC2
Reaction time: 0.5 h

Procedure:
Polyphosphoric acid (1 kg) was stirred and heated to 95°-100° C. and 4-(2-Carboxyethyl)phenylacetic acid (100 g, 0.48 mol) added over 10 minutes. The mixture was stirred for 0.5 hours and poured into ice and H2O; the product was continuously extracted with CHCl3, and recrystallised from benzene to give the title product, m.p. 133°-5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C@:8]23[CH2:15][C@H:14]2[CH2:13][CH2:12][S:11][C:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:9]3)[CH:7]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](O)=[O:33])=[N:30][CH:31]=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C@:8]34[CH2:15][C@H:14]3[CH2:13][CH2:12][S:11][C:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[N:9]4)[CH:7]=2)=[O:33])=[N:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)C[C@H]2CCS1
Reactant: O=C(O)c1ccc(Cl)cn1
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ccc(Cl)cn4)ccc3F)C[C@H]2CCS1
Yield: 50 %

Procedure:
Prepared in an analogous manner as described for intermediate rac-A9a from tert-butyl (1S,7S)-1-(5-amino-2-fluorophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-ylcarbamate (intermediate (−)-A8a) (85 mg, 0.24 mmol) and 5-chloro-2-pyridinecarboxylic acid to give the tert-butyl (1S,7S)-1-(5-(5-chloropicolinamido)-2-fluorophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-ylcarbamate (70 mg, 50% yield) as a light yellow oil. MS (ISP): m/z=391.0 [(M-Boc+H)+] and 393.1 [(M-Boc+2+H)+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][C:10]=1[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][OH:31])=[O:27])=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:33].[Na+]>CO.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:16])=[O:33])=[CH:11][C:10]=1[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][OH:31])=[O:27])=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1ccc(OCc2ccccc2)c(CCCc2ccc(C(=O)NCCO)cc2)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)c1ccc(OCc2ccccc2)c(CCCc2ccc(C(=O)NCCO)cc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
A slurry of 4-[3-(2-benzyloxy-5-methylthiophenyl)-propyl]-N-(2-hydroxyethyl)benzenecarboxamide (0.22 g) in methanol (10 ml) was added to a stirred solution of sodium metaperiodate (0.113 g) in water (1 ml) maintained at 0° C. by external cooling. The reaction mixture was stirred at 0° C. for 2 hours, then concentrated to a volume of approximately 2 ml. This residue was dissolved in ethyl acetate (10 ml), the ethyl acetate solution was dried (anhydrous magnesium sulphate) and the solution evaporated to dryness. The residue was subjected to chromatography on silica (Merck) eluted with a mixture of methanol/ethyl acetate (1:9 v/v). The only porduct obtained was triturated with ethyl acetate (2 ml) to give 4-[3-(2-benzyloxy-5-methylsulphinylphenyl)propyl]-N-(2-hydroxyethyl)-benzenecarboxamide (mp. 105°-108° C.; 43% yield).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:19](Cl)(=[O:21])[CH3:20]>C(=S)=S>[C:19]([C:9]1[CH:8]=[CH:7][C:6]([O:5][C:4]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:3]=2[C:2]([F:1])([F:17])[F:18])=[CH:11][CH:10]=1)(=[O:21])[CH3:20]
Reactant: FC(F)(F)c1cc(Cl)ccc1Oc1ccccc1
Reactant: CC(=O)Cl
Solvent: S=C=S
Product: CC(=O)c1ccc(Oc2ccc(Cl)cc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
In this preparation 23.18 g (0.085 mol) of 4-(2-trifluoromethyl-4-chlorophenoxy)-benzene and 6.66 g (0.085 mol) of acetyl chloride are admixed with 200 ml of carbon disulfide and then 27.52 g (0.17 mol) of ferric chloride is added and the resulting mixture stirred at room temperature for about 23 hours. The mixture is then washed three times with ice-water, dried over magnesium sulfite and filtered. The filtrate is evaporated to dryness and the residue chromatographed on a silica gel column eluting with hexane; 5 vol.% tetrahydrofuran-hexane; and then 10 vol.% tetrahydrofuran-hexane, affording 1-acetyl-4-(2-trifluoromethyl-4-chlorophenoxy)-benzene.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH2:12])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([CH2:15][C:16](O)=[O:17])#[N:14].CCN=C=NCCCN(C)C.Cl>C(#N)C.Cl>[C:13]([CH2:15][C:16]([NH:12][C:10]1[S:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=1)=[O:17])#[N:14]
Reactant: Nc1nnc(-c2ccccc2)s1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Product: N#CCC(=O)Nc1nnc(-c2ccccc2)s1

Procedure:
5-phenyl-1,3,4-thiadiazol-2-amine (600 mg, 3.3 mmol), cyano acetic acid (300 mg, 3.6 mmol), and EDC-HCl (861 mg, 4.5 mmol) were stirred in acetonitrile (15 mL) at room temperature for 2 hours. The mixture was diluted with aqueous 1N HCl and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with ethyl acetate/hexanes (1/9) to afford 2-cyano-N-(5-phenyl-1,3,4-thiadiazol-2-yl)acetamide as a white solid which was used without further purification.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[C@H:6]([CH2:8][SH:9])[NH2:7])[CH3:3].[C:11](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[CH2:2]([O:4][C:5](=[O:10])[C@H:6]([CH2:8][S:9][C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH2:7])[CH3:3]
Reactant: CCOC(=O)[C@@H](N)CS
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 87.9 %

Procedure:
L-Cysteine ethyl ester hydrochloride (5.0 g, 27.03 mmol, 1 eq.) and trityl chloride (11.3 g, 40.55 mmol, 1.5 eq) were stirred in 20 mL of DMF for 2 days at room temperature. The reaction was purified by direct injection into RP-HPLC using 50-100% water/acetonirile gradient (no TFA added) over 20 min. After drying in vacuo, 9.3 g (88%) of 203 was obtained as a white powder. 1H NMR (500 MHz, CD3OD): δ=7.23-7.41 (m, 15H), 4.18 (q, 2H, J=7.5 Hz), 3.17 (m, 1H), 2.58 (dd, 1H, J=8.5 Hz, 12 Hz), 2.48 (dd, 1H, J=5 Hz, 12 Hz), 1.35 (t, 3H, J=7.5 Hz). 13C NMR (125 MHz, CD3OD) δ 171.9, 145.9, 130.7, 129.0, 127.9, 68.1, 62.5, 53.3, 30.8, 14.3. EI-MS (m/z): [M+1] calculated for C24H27NO2S 392.2. found 393.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=3)=[C:9]([CH2:11][S:12]([CH2:15][C:16]([O:18]CC)=[O:17])(=[O:14])=[O:13])[N:10]=2)[CH:7]=1.[OH-].[Na+].O.C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:31])([F:32])[F:33])[CH:24]=3)=[C:9]([CH2:11][S:12]([CH2:15][C:16]([OH:18])=[O:17])(=[O:14])=[O:13])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)CS(=O)(=O)Cc1nc2ccc(Cl)cn2c1C#Cc1cccc(OC(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CS(=O)(=O)Cc1nc2ccc(Cl)cn2c1C#Cc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.4 %

Procedure:
100 mg (0.200 mmol) of ethyl 2-((6-chloro-3-((3-(trifluoromethoxy)phenyl)-ethynyl)imidazo[1,2-a]pyridin-2-yl)methylsulfonyl)acetate were dissolved in 2 ml of ethanol before adding 0.060 ml (0.599 mmol) of a 32% sodium hydroxide aqueous solution. The mixture was stirred at r.t. for 16 h. The solution was poured into 10 ml of water, acidified to an acid pH with acetic acid, extracted with 2×5 ml of dichloromethane, the combined organic phases were dried on Na2SO4 which was then removed by filtration and the obtained filtrate was concentrated in vacuo. 76 mg (yield=80%) of 2-((6-chloro-3-((3-(trifluoromethoxy)phenyl)ethynyl)-imidazo[1,2-a]pyridin-2-yl)methylsulfonyl)acetic acid were obtained as a yellow solid. LC-MS: m/z=473 (MH+) UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 14.72-12.20 (m, 1H), 9.00 (d, J=1.2 Hz, 1H), 7.88-7.76 (m, 3H), 7.62-7.45 (m, 3H), 4.96 (s, 2H), 4.42 (s, 2H).
Reaction SMILES: NC(CCCCCCCCC(N)C(C)C)C(C)C.C(C1CC=CCCC=CCC(C(C)C)N=N1)(C)C.[CH3:37][CH:38]([CH:41]1[CH2:52][CH:51]=[CH:50][CH2:49][CH2:48][CH:47]=[CH:46][CH2:45][CH:44]([CH:53]([CH2:55][CH3:56])[CH3:54])[N:43]=[N:42]1)[CH2:39][CH3:40]>>[NH2:42][CH:41]([CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH:44]([NH2:43])[CH:53]([CH3:54])[CH2:55][CH3:56])[CH:38]([CH3:37])[CH2:39][CH3:40]
Reactant: CCC(C)C1CC=CCCC=CCC(C(C)CC)N=N1
Agent: CC(C)C(N)CCCCCCCCC(N)C(C)C
Agent: CC(C)C1CC=CCCC=CCC(C(C)C)N=N1
Product: CCC(C)C(N)CCCCCCCCC(N)C(C)CC
Yield: 84.7 %

Procedure:
If there are used in the manner described under (a), instead of 250 g (1 mol) of 3,12-diisopropyl-1,2-diaza-1,5,9-cyclododecatriene, 87.3 g (0.31 mol) of 3,12-di-(2-butyl)-1,2-diaza-1,5,9-cyclododecatriene (diastereoisomeric mixture) and correspondingly reduced amounts of catalyst and solvent, with otherwise the same procedure, there is obtained, as the main fraction, 74.7 g (85% of theory) of 4,13-diamino-3,14-dimethylhexadecane in the form of colourless oil [b.p. 143°-5° C./0.05 Torr; nD20 =1.4639; IR (liquid) inter alia bands at 3330 and 1626 cm-1 ].
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=2)O1.Br[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[C:20]([F:31])[CH:19]=1>C(O)CCC.C(OCC)(=O)C.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:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])=[C:20]([F:31])[CH:19]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1F
Reactant: CC1(C)OB(c2cccnc2N)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2cccnc2N)cc1F
Temperature: 130 °C
Yield: 42.9 %

Procedure:
A degassed mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (2.4 g, 10.91 mmol), tert-butyl 4-bromo-2-fluorobenzoate (3.30 g, 12.00 mmol), Pd(PPh3)4 (0.63 mg, 0.0.545 mmol), 2.0 M Na2CO3aqueous solution (10.91 mL) in n-butanol (26 mL) was microwave heated to 130° C. for 10 min. The reaction was diluted with ethyl acetate (30 mL), and then washed with water (10 mL) and brine (10 mL). The organics were dried over sodium sulfate, filtered, concentrated, and then purified by flash chromatography (10-60% ethyl acetate/heptane eluent) to provide tert-butyl 4-(2-aminopyridin-3-yl)-2-fluorobenzoate (1.35 g, 43% yield). LCMS (m/z): 289.4 (MH+), 0.67 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[N:6]([CH2:20][C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22])[C:5]2=[O:27].[C:28]([N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[CH2:41][CH2:42]O)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl.CN(C=O)C>[C:31]([O:30][C:28]([N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[CH2:41][CH2:42][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[N:6]([CH2:20][C:21](=[O:22])[NH:23][CH:24]([CH3:25])[CH3:26])[C:5]2=[O:27])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: COc1cccc(-c2nc3ccc(O)cc3c(=O)n2CC(=O)NC(C)C)c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(-c2nc3ccc(OCCC4CCCCN4C(=O)OC(C)(C)C)cc3c(=O)n2CC(=O)NC(C)C)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
A mixture of 2-[6-hydroxy-2-(3-methoxy-phenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropyl-acetamide (INTERMEDIATE IV.4) (200 mg, 0.55 mmol), N-Boc-2-piperidine ethanol (250 mg, 1.09 mmol) and resin-bound triphenylphosphine (˜3 mmol/g, 543 mg, 1.63 mmol) in dichloromethane (4.5 mL) and DMF (0.5 mL) was cooled to 0° C. and diisopropylazodicarboxylate (DIAD) (0.21 mL, 1.09 mmol) was added dropwise with stirring. The reaction mixture was allowed to warm to room temperature and stirring was continued for 16 h. The mixture was then filtered and concentrated in vacuo. The crude residue was dissolved in dichloromethane (100 mL) and washed with 1 N NaOH (aq.) and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography on silica gel with ethyl acetate:hexane (2:1, v/v) afforded 2-{2-[3-(isopropylcarbamoylmethyl)-2-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yloxy]ethyl}piperidine-1-carboxylic acid tert-butyl ester (65 mg, 0.11 mmol, 20%).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]=1[C:19]1[N:20]=[CH:21][N:22]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[CH:23]=1>>[CH:1]1([NH:6][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([N:22]3[CH:23]=[C:19]([C:9]4[C:10]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)=[N:11][O:12][C:8]=4[CH3:7])[N:20]=[CH:21]3)[CH:25]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C(=O)O)c2)cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C(=O)NC3CCCC3)c2)cn1
Yield: 41 %

Procedure:
As described for Example 71, cyclopentylamine was converted, using 3-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (49 mg, 41%) which was obtained as an off-white solid. MS: m/e=413.0 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=1)([O-])=O.[Sn]>Cl.O>[NH2:1][C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=1
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2o1
Agent: Cl
Agent: [Sn]
Solvent: O
Product: Nc1ccc2[nH]c(=O)oc2c1
Yield: 35.5 %

Procedure:
A solution of 6-Nitro-3H-benzooxazol-2-one (8.4 grams, 46.0 mmole) and Tin (16.0 g) in concentrated hydrochloric acid (100 ml) was stirred at 60° C. for 2 hours. The mixture was diluted with water, basified to pH 12 and extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered, and concentrated to give an orange solid (2.45 g). MW 150; MS (m/e) 151 (M++1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=2)[CH2:4][CH2:3]1>[Pd].CO>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(Nc2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCC(Nc2cccc(N)c2)CC1
Yield: 109.7 %

Procedure:
Alternatively, charge a 2 L Parr bottle with 1-methyl-4-(3-nitrophenylamino)piperidine (100 g; 0.425 mol), 10% Pd/C (5 g) and methanol (1 L). Shake the mixture overnight under an initial hydrogen pressure of 4 atm, keeping the temperature below 35° C. Filter off the catalyst and wash with methanol (100 mL). Concentrate the filtrates under reduced pressure to provide 1-methyl-4-(3-aminophenylamino)piperidine as a red oil (95.7 g, 100% yield) which crystallizes upon standing at room temperature.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:23]([NH:25][CH3:26])=[O:24])[CH:17]=[CH:16]2.[CH:27]1[N:31]=[CH:30][N:29]2[CH2:32][CH2:33][C:34](=[O:35])[C:28]=12.[Cl-].[NH4+]>C1COCC1>[OH:35][C:34]1([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([C:23]([NH:25][CH3:26])=[O:24])[CH:17]=[CH:16]3)[C:28]2[N:29]([CH:30]=[N:31][CH:27]=2)[CH2:32][CH2:33]1
Reactant: CNC(=O)c1ccc2cc(Br)ccc2c1
Reactant: O=C1CCn2cncc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2cc(C3(O)CCn4cncc43)ccc2c1
Reaction time: 1 h
Yield: 36.6 %

Procedure:
Dry THF (150 ml) was cooled to −65° C. in a dry ice-acetone bath under an argon atmosphere and n-butyl lithium hexane solution (1.6M: 45.2 ml) was added. A solution of 6-bromo-N-methyl-2-naphthamide (8.68 g) in dry THF (700 ml) cooled to 10° C. was added to this solution at not more than −55° C., and the mixture was stirred for 1 h. A dry THF solution (60 ml) of 5,6-dihydro-7H-pyrrolo[1,2-c]imidazol-7-one (3.65 g) was added dropwise. The mixture was stirred at the same temperature for 1.5 h and saturated aqueous ammonium chloride solution (120 ml) was added to stop the reaction. The solvent was evaporated under reduced pressure and an ethanol-soluble material was extracted from the resulting residue and the solvent was evaporated again. The residue was purified by flash silica gel column chromatography (eluent, chloroform/methanol containing ammonia (7%), 19/1→9/1). The eluate was recrystallized from methanol to give the title compound (3.36 g) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.O[CH:10]1[CH2:14][CH2:13][O:12][CH2:11]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)=[CH:4][N:3]=1
Reactant: OC1CCOC1
Reactant: Oc1ccc(Br)nc1
Product: Brc1ccc(OC2CCOC2)cn1

Procedure:
The title compound was prepared from 2-bromo-5-hydroxypyridine and rac-3-hydroxy-tetrahydrofuran in analogy to Example 9c): MS (EI): 243 and 245 M+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.BrC1C=C(C(=O)C)C=CC=1.[OH-].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: CC(=O)c1cccc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cccc(Br)c4)ccc3c1)n2C1CCCCC1
Yield: 12 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(3-bromo-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (15 mg, 12% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O-])=O.O[N:31]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:32]([C:34]1[CH:35]=[N:36][C:37]2[C:42]([C:43]=1[OH:44])=[CH:41][C:40]([F:45])=[CH:39][CH:38]=2)=[O:33]>CN(C)C=O>[F:45][C:40]1[CH:39]=[CH:38][C:37]2[N:36]=[CH:35][C:34]3[C:32](=[O:33])[N:31]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[O:44][C:43]=3[C:42]=2[CH:41]=1
Reactant: O=C(c1cnc2ccc(F)cc2c1O)N(O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=c1c2cnc3ccc(F)cc3c2on1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 14.7 %

Procedure:
Into a mixture of 8.81 g of triphenylphosphine and 50 ml of dimethylformamide, 5.58 g of ethyl azodicarboxylate were poured at 10°-15° C. and after continued stirring for 15 minutes, 6.68 g of the product of Step A were added in small fractions. Stirring was maintained for 2 hours at 0° C. and for 16 hours at ambient temperature and the crystallized product was separated. The filtrate was poured into iced water, and extracted with dichloromethane. The organic phase was washed with water, dried and the solvent was eliminated. The residue was chromatographed on silica and eluted with a methylene chloride-ethyl acetate mixture (9-1) to obtain 0.92 g of 8-fluoro-2-phenylisoxazolo(4,5-c)quinolin-3-(2H)-one melting at 174° C.
Reaction SMILES: C([S:4][CH2:5][CH2:6][N:7]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:8](=[O:21])[NH:9][C@@H:10]([CH3:20])[C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])(=O)C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[SH:4][CH2:5][CH2:6][N:7]([CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:8](=[O:21])[NH:9][C@@H:10]([CH3:20])[C:11]([N:13]1[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12]
Reactant: CC(=O)SCCN(CCc1ccccc1)C(=O)N[C@@H](C)C(=O)N1CCN(C)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](NC(=O)N(CCS)CCc1ccccc1)C(=O)N1CCN(C)CC1
Reaction time: 0.17 h

Procedure:
1-[(2S)-2-[3-[2-(Acetylthio)ethyl]-3-phenethylureido]propionyl]-4-methylpiperazine (Compound No. 13-2, 36.6 g) is dissolved in methanol (87 ml) under a nitrogen atmosphere, and the solution is cooled with ice. A 1 N aqueous sodium hydroxide solution (87 ml) is added dropwise thereto, and the mixture is stirred under ice cooling for 10 minutes. A 10% aqueous citric acid solution is added to the reaction mixture under ice cooling to adjust pH to 7. The mixture is concentrated under reduced pressure, a10% aqueous sodium hydrogencarbonate solution (300 ml) is added to the concentrate, and the whole is extracted with ethyl acetate. The organic layer is washed with water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give the titled compound (Compound No. 30-1).