Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C@H:11]2[NH2:19])[CH:6]=[CH:7][C:8]=1[Cl:9].C(OC(OCC)CBr)C.C(=O)([O-])[O-].[K+].[K+].CCOCC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH:11]2[NH2:19])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: COc1cc([C@@H]2c3ccccc3C[C@H]2N)ccc1Cl
Agent: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1cc(C2c3ccccc3CC2N)ccc1Cl
Temperature: 150 °C
Reaction time: 4 h

Procedure:
A mixture of 1.0 grams(3.65 mmol) of Compound L from step B, 0.55 mL (3.65 mmol) 2-bromoacetaldehyde diethyl acetal, and 1.0 grams (7.3 mmol) anhydrous potassium carbonate in 35 mL dry DMF was stirred at 150° C. for 4 hours. After cooling to room temperature, the mixture was poured into 300 mL ether, washed with three 50 mL portions of water, dried (MgSO4) and evaporated. The residue was purified by flash chromatography, eluting with 1:1 hexane-ethyl acetate to give 1.1 grams (77%) of N-(2,2-diethoxyethyl)-trans-1-(3-methoxy-4-chlorophenyl-2-indanamine (Compound M) as an oil, 200 MHz NMR(CDCl3) d 1.15 (tr,6H,J=7 Hz), 2.70-290(m,3H), 3.20-3.70 (m,6H), 4.09 (d,1H,J=8 Hz), 4.55(tr,1H,J=5 Hz), 6.70-6.90 (m,3H), 7.10-7.30 (m,4H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([NH:27]C(=O)OC(C)(C)C)[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10]([C:35]1[CH:40]=[C:39]([F:41])[C:38]([OH:42])=[C:37]([Cl:43])[CH:36]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].Cl>ClCCl.C(OCC)C>[NH2:27][CH:23]1[CH2:24][CH2:25][CH2:26][N:21]([C:18]2[N:19]=[CH:20][C:15]([NH:14][C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([C:35]5[CH:40]=[C:39]([F:41])[C:38]([OH:42])=[C:37]([Cl:43])[CH:36]=5)[CH:11]=4)[N:6]=[CH:5][C:4]=3[C:1](=[O:3])[CH3:2])=[CH:16][CH:17]=2)[CH2:22]1
Reactant: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCCC(N)C2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.9 %

Procedure:
tert-butyl 1-(5-(3-acetyl-6-(3-chloro-5-fluoro-4-hydroxyphenyl)quinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (80 mg, 0.132 mmol) was dissolved in dichloromethane (5 mL). To this solution was added a 2.0 M HCl solution in diethyl ether (2 mL) the mixture was stirred for 16 h at room temperature where a precipitate formed. The precipitate was filtered off, washed with dichloromethane (10 mL), dried under vacuum to obtain the desired product as the HCl salt (30 mg, 45%) as a yellow-orange solid: 1H NMR (500 MHz, MeOD) δ 9.26 (s, 1H), 8.24 (d, J=2.9 Hz, 1H), 8.20 (dd, J=8.9, 1.9 Hz, 1H), 7.99 (d, J=8.9 Hz, 1H), 7.95 (d, J=2.0 Hz, 1H), 7.68 (dd, J=9.1, 2.8 Hz, 1H), 7.11 (d, J=9.1 Hz, 1H), 7.04 (m, 2H), 4.54 (s, 1H), 4.02 (d, J=12.7 Hz, 1H), 2.80 (s, 3H), 2.18 (m, 1H), 1.94 (m, 1H), 1.74 (m, 2H); ESI MS m/z 506, [C27H25ClFN5O2+H]+; HPLC 95.2% (AUC), tR=10.84 min.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][CH:22]=[N:23]3)=[CH:18][CH:17]=2)[CH:10]=1.B(Br)(Br)Br>ClCCl>[N:23]1[C:24]2[C:19](=[CH:18][CH:17]=[C:16]([O:15][C:11]3[N:12]=[CH:13][N:14]=[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[OH:2])[CH:10]=3)[CH:25]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Temperature: -78 °C

Procedure:
To a 50-mL, round-bottomed flask containing 7-[6-(2-methoxy-phenyl)-pyrimidin-4-yloxy]-quinoline, (Example 109), (0.09 g, 0.27 mmol) was added dichloromethane (3 mL). The solution was cooled to −78° C. and BBr3 (0.82 mL, 0.82 mmol, 1 N in dichloromethane, Aldrich) was added. The reaction mixture was allowed to warm to room temperature over 1 h and then cooled to −78° C. and quenched with satd sodium bicarbonate (10 mL). The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (2×100 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuum. The resulting solid was suspended in methanol (15 mL) and the remaining solid was collected by filtration, and dried under vacuum to obtain the title compound as a white solid. Mp: 188–191° C. MS (ESI, pos. ion.) m/z: 316 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[Cl:25][C:26]1[CH:34]=[C:33]([OH:35])[CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:11][CH:12]=1)[NH:5][C:28]([C:27]1[CH:31]=[CH:32][C:33]([OH:35])=[CH:34][C:26]=1[Cl:25])=[O:29]
Reactant: O=C(O)c1ccc(O)cc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccc(O)cc1Cl
Yield: 35 %

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[(2-chloro4-hydroxyphenyl)carbonyl]-L-phenylalanine methyl ester was prepared in 35% yield from 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester and 2-chloro-4-hydroxybenzoic acid using the general procedure described in example 3. HR MS: Obs. mass, 521.0433. Calcd. mass, 521.0438 (M+H).
Reaction SMILES: C1C2C(COC([N:18]3[C:23]4[CH:24]=[CH:25][C:26]([C:28]5[NH:29][C:30]([C:33]#[N:34])=[CH:31][CH:32]=5)=[CH:27][C:22]=4[C:21]([CH3:36])([CH3:35])[O:20][CH:19]3[CH3:37])=O)C3C(=CC=CC=3)C=2C=CC=1.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>N1CCCCC1.CN(C=O)C>[CH3:37][CH:19]1[O:20][C:21]([CH3:36])([CH3:35])[C:22]2[CH:27]=[C:26]([C:28]3[NH:29][C:30]([C:33]#[N:34])=[CH:31][CH:32]=3)[CH:25]=[CH:24][C:23]=2[NH:18]1
Reactant: CC1OC(C)(C)c2cc(-c3ccc(C#N)[nH]3)ccc2N1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC1Nc2ccc(-c3ccc(C#N)[nH]3)cc2C(C)(C)O1
Yield: 56.1 %

Procedure:
A solution of 9H-fluoren-9-ylmethyl-6-[5-cyano-1H-pyrrol-2-yl]-2,4,4-trimethyl-2H-3,1-benzoxazine-1(4H)-carboxylate (0.1 g, 0.2 mmol) in 20% piperidine in DMF (5 mL) was stirred at room temperature under nitrogen for 10 minutes. The mixture was poured into a saturated ammonium sulfate solution (30 mL) and extracted with diethyl ether (3×30 mL). The combined organic layers were dried (MgSO4) and evaporated. The residue was purified by a silica gel column chromatography (hexane:ethyl acetate/3:1) to afford the title compound as a white solid (0.03 g, 56%): mp 201-202° C.; 1H-NMR (DMSO-d6) δ 12.27 (s, 1H), 7.44 (d, 1H, J=2.1 Hz), 7.32 (dd, 1H, J=8.3, 1.1 Hz), 6.92 (dd, 1H, J=4.1, 2.6 Hz), 6.57 (d, 1H, J=8.3 Hz), 6.50 (dd, 1H, J=4.2, 2.6 Hz), 6.40 (s, 1H), 4.77-4.80 (m, 1H), 1.51 (s, 3H), 1.46 (s, 3H), 1.27 (d, 3H, J=5.7 Hz); MS (ESI) m/z 266 [M−H]−.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:12])[CH2:6][CH2:5]2.[CH:21]#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>[Cu]I>[C:21]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:12])[CH2:6][CH2:5]2)#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCOC(=O)CCNC(=O)N1CCc2cc(I)ccc21
Reactant: C#CCCCCCC
Agent: [Cu]I
Product: CCCCCCC#Cc1ccc2c(c1)CCN2C(=O)NCCC(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
A mixture of the product of Step B (0.16 g; 0.41 mmol), 1-octyne (0.073 ml; 0.49 mmol), Cl2Pd(PPh3)2 (0.02 g; 0.028 mmol) and CuI (0.005 g; 0.026 mmol) was degassed under reduced pressure and saturated with dry N2. After addition of DIPEA (0.5 ml), the resulting mixture was stirred for 2 h at room temperature under N2. The solvents were removed in vacuo and the residue was diluted to 15 ml with EtOAc and washed with 5% citric acid, 5% NaHCO3, H2O, brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO2; CH2Cl2) to give the title compound (0.1 g; 65%) as a brownish solid. 1H-NMR (CDCl3) 7.75 (d, 1H, J=8.4 Hz); 7.16 (d, 1H, J=8.4 Hz); 7.1 (s, 1H); 5.34 (t, 1H, J=5.8 Hz); 4.11 (q, 2H, J=7.1 Hz); 3.82 (t, 2H, J=8.8 Hz); 3.52 (m, 2H); 3.06 (t, 2H, J=8.8 Hz); 2.56 (t, 2H, J=5.8 Hz); 2.33 (t, 2H, J=7.1 Hz); 1.53 (m, 2H); 1.52 (m, 2H); 1.26 (m, 6H); 1.23 (t, 2H, J=7.1 Hz); 0.86 (t, 3H, J=6.9 Hz).
Reaction SMILES: [N:1]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28](O)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[NH2:41][C@@H:42]([C:53]([NH:55][C@H:56]([C:61]([N:63]([CH3:72])[C@H:64]([C:69]([NH2:71])=[O:70])[CH2:65][CH2:66][S:67][CH3:68])=[O:62])[CH2:57][CH:58]([CH3:60])[CH3:59])=[O:54])[CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1.FC(C(O)=O)(F)F.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>>[N:1]1([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:33][CH2:32][CH2:31][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:41][C@@H:42]([C:53]([NH:55][C@H:56]([C:61]([N:63]([CH3:72])[C@H:64]([C:69]([NH2:71])=[O:70])[CH2:65][CH2:66][S:67][CH3:68])=[O:62])[CH2:57][CH:58]([CH3:60])[CH3:59])=[O:54])[CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@@H](C(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@@H](C(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 60 %

Procedure:
Condensation of BocPro-DTrp-PheOH (Example 33, 1.49 g.) and HDTrp-Leu-MeMetNH2 trifluoroacetate salt (1.25 g.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave BocPro-DTrp-Phe-DTrp-Leu-MeMetNH2 in 60% yield. De-t-butoxycarbonylation of BocPro-DTrp-Phe-DTrp-Leu-MeMetNH2 (1.50 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HPro-DTrp-Phe-DTrp-Leu-MeMetNH2, which was isolated as the amorphous white solid phosphate (1:2) salt dihydrate in 57% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:4]=1[NH2:5].O.O.O.O.[NH:16]1[C:24](=[O:25])[C:22](=[O:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18]>O>[NH2:5][C:4]1[C:6]([O:10][CH3:11])=[CH:7][C:8]([C:22]2([OH:23])[C:20](=[O:21])[NH:19][C:17](=[O:18])[NH:16][C:24]2=[O:25])=[CH:9][C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(OC)c1N
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Solvent: O
Product: COc1cc(C2(O)C(=O)NC(=O)NC2=O)cc(OC)c1N
Reaction time: 1 h
Yield: 91.7 %

Procedure:
25 g of 2,6-dimethoxyaniline were added to a solution of 35 g of alloxan tetrahydrate in 120 ml of water. While stirring vigorously, the initially heterogeneous mixture changed after one hour into a brown solution from which grey crystals separated after a short time. The reaction mixture was stirred at room temperature for an additional 24 hours until dimethoxyaniline was no longer detectable according to thin-layer chromatography (cyclohexane/ethyl acetate/water=60:30:1). The reaction mixture was suction filtered, the residue on the suction filter was suspended with 4 portions of water to 80 ml and sucked dry. The solid was dried at 100°/16 mbar for 16 hours. There were obtained 44.2 g of 5-(4-amino-3,5-dimethoxyphenyl)-5-hydroxybarbituric acid as a light grey powder of m.p. 240°-243° (under decomposition). For purification, the powder can be recrystallized from 1-butanol, there being obtained a product of m.p. 242°-244° (decomposition).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33]N>>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: NNc1ccccc1F
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1ccccc1F
Yield: 65 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 2-fluoro-phenylhydrazine according to the method described for Example 1 in 65% yield. MS: M=417.0 (M+H)+
Reaction SMILES: C([O:4][CH:5]1[C:11]2[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][CH:7]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[N:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)=[O:19])[CH2:6]1)(=O)C.[Li+].[OH-]>C1COCC1.O>[Cl:36][C:32]1[CH:31]=[C:30]2[C:35]([C:26]([N:23]3[CH2:24][CH2:25][N:20]([C:18]([NH:17][CH:7]4[CH2:6][CH:5]([OH:4])[C:11]5[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=5[CH2:9][CH2:8]4)=[O:19])[CH2:21][CH2:22]3)=[CH:27][CH:28]=[N:29]2)=[CH:34][CH:33]=1
Reactant: CC(=O)OC1CC(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)CCc2ccc(F)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC1CCc2ccc(F)cc2C(O)C1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-[9-(acetyloxy)-2-fluoro-6,7,8,9-tetrahydro-5H-benzo[α]cyclohepten-7-yl]-4-(7-chloro-4-quinolinyl)-1-piperazinecarboxamide (30.0 mg, 0.0588 mmol) in THF:H2O (3:1, 2 mL) was added LiOH (8 mg). The reaction mixture was stirred at rt for 3 h, then THF was evaporated in vacuo. The reaction mixture was diluted with AcOEt (100 mL), washed with brine, and dried. Concentration followed by flash chromatography afforded the title product. LC-MS: 469 (M++1). δ 1H NMR (CDCl3) δ 8.70 (d, 1H), 8.05 (s, 1H), 7.95 (d, 1H), 7.45 (d, 1H), 7.05 (m, 2H), 6.85 (m, 2H), 4.95 (m, 1H), 4.35 (m, 1H), 3.65 (m, 4H), 3.20 (m, 4H), 3.15 (m, 1H), 2.60 (m, 1H), 2.20 (m, 2H), 1.8 (m, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17].C(Cl)Cl>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:16]([N:18]([CH2:19][CH3:20])[C:9](=[O:11])[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:17]
Reactant: O=C(O)CCc1ccccc1
Reactant: CCNCC
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a suspension of 3-phenylpropionic acid (455 mg, 3 mmol, Aldrich), in toluene (2 mL) at RT was slowly added thionyl chloride (0.44 mL, 6 mmol, 2 eq., Aldrich). DMF (2 drops) was added and the solution was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in CH2Cl2 (5 mL). Diethylamine (0.78 mL, 7.5 mmol, 2.5 eq., Aldrich) was added dropwise to the CH2Cl2 solution at 0° C. and the reaction mixture was warmed and stirred at RT for 30 min. After evaporation under reduced pressure, the resulting residue was sequentially treated with H2O (5 mL) and EtOAc (5 mL). The organic and aqueous layers were separated and the aqueous layer was extracted with EtOAc (2×5 mL). The combined organic layers were washed with brine, dried with MgSO4 and concentrated under reduced pressure. Purification of the residue was performed using a short silica gel column (silica gel 60, 230-400 mesh) with EtOAc/hexanes as eluent. N,N-diethyl-3-phenylpropanamide (608 mg, 99% yield) was obtained as a colorless oil. Further purification using flash column chromatography was deemed unnecessary. 1H NMR (400 MHz, CDCl3) δ ppm: 7.34-7.14 (m, 5H), 3.38 (q, J=7.09 Hz, 2H), 3.22 (q, J=7.12 Hz, 2H), 2.98 (t, J=7.92 Hz, 2H), 2.59 (t, J=7.90 Hz, 2H), 1.16-1.03 (m, 6H); 13C NMR (101 MHz, CDCl3) δ ppm: 171.16, 141.51, 128.37, 128.35, 125.97, 41.81, 40.13, 35.01, 31.59, 14.20, 13.01.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([OH:9])[C:5]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[CH3:14].[C:15]1([CH2:21][C:22](O)=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:21]([C:22]1[NH:8][C:7]2[C:6]([OH:9])=[C:5]([C:10]([CH3:11])([CH3:13])[CH3:12])[CH:4]=[C:3]([CH3:14])[C:2]=2[N:1]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Cc1cc(C(C)(C)C)c(O)c(N)c1N
Product: Cc1cc(C(C)(C)C)c(O)c2[nH]c(Cc3ccccc3)nc12
Yield: 51.1 %

Procedure:
A mixture of 2,3-diamino-4-hydroxy-5-tert-butyltoluene (Description 11) (prepared from 12 g of 2,3-dinitro-4-hydroxy-5-tert-butyltoluene) and phenylacetic acid (30 g) was heated for 1 h at 120°-130° C. under nitrogen. The reaction product was extracted with chloroform, washed with 10% sodium carbonate, water, and dried (Na2SO4). The chloroform solution was evaporated to dryness in vacuo, and recrystallised from chloroformethylacetate-pentane to afford the title compound (9.3 g), m.p. 226°-228° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:21])[C:11]3=[CH:12][NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[CH3:22][N:23]=[C:24]=[O:25]>CO>[CH3:22][NH:23][C:24]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:21])[C:11]3=[CH:12][NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1)=[O:25]
Reactant: CN=C=O
Reactant: Nc1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Solvent: CO
Product: CNC(=O)Nc1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Reaction time: 8 h

Procedure:
The mixture of 0.7 g of 2-(p-aminophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one, 1.4 g of methylisocyanate and 25 ml of methanol is refluxed for 7 hours and allowed to stand at room temperature overnight. It is evaporated, the residue treated with diluted aqueous sodium hydroxide and diethyl ether, the aqueous solution separated, washed with diethyl ether and its pH adjusted to 8.5 with ammonium chloride. The precipitate formed is collected, washed with methanol, then with diethyl ether and dried, to yield the 2-(p-methylcarbamoylaminophenyl)-pyrazolo[4,3-c]quinolin3(5H)-one, showing IR-peaks of 895, 869, 850, 825, 816, 812, 785, 780, 767 and 738 cm-1.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.O.O[N:12]1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.N>CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]([NH2:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(Br)s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
A solution of 5-bromo-thiophene-2-carboxylic acid (4.51 g, 21.78 mmol), 3-hydroxybenzotriazole hydrate (3.24 g, 23.96 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (4.6 g, 23.96 mmol) in DMF (70 mL) is stirred at room temperature for 2 hours. The reaction mixture is then cooled to 0° C. and aq. 35% NH3 (2.2 mL) is added. The mixture is stirred at room temperature overnight. The solvent is removed in vacuo and the residue dissolved in EtOAc, washed with 1N NaHCO3, and brine. The organic layers are combined, dried over MgSO4, filtered and concentrated to afford the title compound (3.78 g, 84%). HPLC (254 nm): Rt 2.46 min (96.5%).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.Cl[C:18]1[N:23]=[CH:22][C:21]([CH2:24][CH2:25][CH3:26])=[CH:20][N:19]=1.BrC1C=CC2N=C(OC3CCN(C4N=CC(CCC)=CN=4)CC3)SC=2C=1>>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:18]4[N:23]=[CH:22][C:21]([CH2:24][CH2:25][CH3:26])=[CH:20][N:19]=4)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: Brc1ccc2nc(N3CCNCC3)sc2c1
Reactant: CCCc1cnc(Cl)nc1
Agent: CCCc1cnc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)nc1
Product: CCCc1cnc(N2CCN(c3nc4ccc(Br)cc4s3)CC2)nc1

Procedure:
Compound 13C was prepared from Compound 13B and 2-chloro-5-propylpyrimidine in a similar manner to the procedure described for Compound 1C in Example 1. 1H NMR (500 MHz, chloroform-d) δ ppm 8.20 (2H, s), 7.73 (1H, dd, J=1.7, 0.6 Hz), 7.40-7.43 (2H, m), 3.96-4.00 (4H, m), 3.70-3.74 (4H, m), 2.44 (2H, t, J=7.4 Hz), 1.57-1.64 (2H, m), 0.95 (3H, t, J=7.3 Hz). LC/MS (m/z)=419 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]=2[C:15]([NH:17][NH2:18])=[O:16])[CH2:3][CH2:2]1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=O)=[C:22]([O:29][CH3:30])[CH:21]=1>>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]=2[C:15]2[O:16][C:24]([C:23]3[CH:27]=[CH:28][C:20]([F:19])=[CH:21][C:22]=3[O:29][CH3:30])=[N:18][N:17]=2)[CH2:2][CH2:3]1
Reactant: COc1cc(F)ccc1C(=O)O
Reactant: NNC(=O)c1c(-c2ccccc2)noc1C1CC1
Product: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C2CC2)o1
Yield: 31 %

Procedure:
As described for example 2, 5-cyclopropyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (1.32 g, 5.43 mmol) was converted using 4-fluoro-2-methoxy-benzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 631 mg, 31%) which was obtained as a white solid. MS: m/e=319.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:16]12([CH2:26][C:27](Cl)=[O:28])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2>>[C:16]12([CH2:26][C:27]([N:1]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:28])[CH2:23][CH:22]3[CH2:21][CH:20]([CH2:19][CH:18]([CH2:24]3)[CH2:17]1)[CH2:25]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: C1COCCOCCOCCOCCN1
Product: O=C(CC12CC3CC(CC(C3)C1)C2)N1CCOCCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10,13-tetraoxacyclopentadecane and (1-adamantyl)acetyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=1>[Ni].O1CCCC1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N)c(OCc2ccccc2)c1
Reaction time: 5.5 h
Yield: 96.9 %

Procedure:
To a tetrahydrofuran solution (100 mL) of 3-benzyloxy-4-nitro-benzoic acid methyl ester(10.0 g, 34.9 mmol) was added Raney Nickel (wet) (2.0 g). The reaction was pressured to approximately 50 psi at left to shake at room temperature for 5.5 h. An aliquot was removed and TLC deemed the reaction complete. The reaction was filtered through celite and then concentrated under reduced pressure to yield 4-amino-3-benzyloxy-benzoic acid methyl ester as a solid (8.7 g, 97%). 1H NMR (CDCl3) 7.58(m,2H), 7.50-7.30(m,5H), 6.70(d,1H), 5.14(s,2H), 4.84(s,3H).
Reaction SMILES: [Na].Cl[CH2:3][C:4]1[N:5]=[C:6]([OH:14])[C:7]2[S:13][CH2:12][CH2:11][CH2:10][C:8]=2[N:9]=1.[CH3:15][OH:16]>>[OH:14][C:6]1[C:7]2[S:13][CH2:12][CH2:11][CH2:10][C:8]=2[N:9]=[C:4]([CH2:3][O:16][CH3:15])[N:5]=1
Reactant: Oc1nc(CCl)nc2c1SCCC2
Reactant: CO
Agent: [Na]
Product: COCc1nc(O)c2c(n1)CCCS2

Procedure:
Sodium metal (0.46 g, 0.02 gr. atm.) was dissolved in methanol (100 ml) and the product from step A was added. The reaction mixture was refluxed for 4 hours and then most of the solvent was removed in vacuo. The addition of water afforded 1.2 g of title compound which was dried and used in step C without further purification.