Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:43])([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH:17]([NH:19][C:20]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][C:29](=[O:32])[N:28]4[CH2:33][CH:34]=[C:35]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[N:36]=[C:27]34)[CH:23]=[CH:22][N:21]=2)[CH3:18])[CH:11]=1)[CH3:9])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([C:10]1[CH:11]=[C:12]([CH2:16][CH:17]([NH:19][C:20]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][C:29](=[O:32])[N:28]4[CH2:33][CH:34]=[C:35]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[N:36]=[C:27]34)[CH:23]=[CH:22][N:21]=2)[CH3:18])[CH:13]=[CH:14][CH:15]=1)([CH3:9])[CH3:43]
Reactant: CC(Cc1cccc(C(C)(C)NC(=O)OC(C)(C)C)c1)Nc1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(Cc1cccc(C(C)(C)N)c1)Nc1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of [1-methyl-1-(3-{2-[4-(4-oxo-8-phenyl-3,4-dihydro-2H, 6H-pyrimido[1,2-a]pyrimidin-1-yl)-pyrimidin-2-ylamino]-propyl}-phenyl)-ethyl]-carbamic acid tert-butyl ester (0.25 g, 0.42 mmol) and trifluoroacetic acid (1 mL) in dichloromethane (2 mL) was stirred at room temperature for 30 min. The mixture was washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and was purified by chromatography on silica gel using 0-8% 2 M NH3 MeOH/CH2Cl2. M+1=496. 1NMR (CDCl3) d (3H, 1.23 ppm), s (6H, 1.47 ppm), m (2H, 2.21 ppm), m (1H, 2.82 ppm), m (1H, 2.98 ppm), s (1H, 3.48 ppm), m (4H, 4.12 ppm), m (1H, 4.35 ppm), d (1H, 4.95 ppm), s (1H, 6.60 ppm), d (1H, 7.09 ppm), d (1H, 7.21 ppm), m (2H, 7.36 ppm), m (3H, 7.44 ppm), dd (2H, 7.91 ppm), d (1H, 8.16 ppm).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH2:9][C:10]([NH:12][NH2:13])=[O:11])[S:8][C:4]=2[CH:3]=1.C1N=CN([C:21](N2C=NC=C2)=[O:22])C=1>ClCCCl>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH2:9][C:10]3[O:11][C:21]([OH:22])=[N:13][N:12]=3)[S:8][C:4]=2[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)Cc1nc2ccc(Br)cc2s1
Solvent: ClCCCl
Product: Oc1nnc(Cc2nc3ccc(Br)cc3s2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
To a suspension of 2-(6-bromobenzo[d]thiazol-2-yl)acetohydrazide (500 mg, 1.75 mmol) (described in WO 2011/074560) in 1,2-dichloroethane (15 mL) at 0° C. was added CDI (340 mg, 2.10 mmol) then the reaction mixture allowed to warm to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and the residue purified on silica gel chromatography eluting with 0 to 10% MeOH/DCM to give Compound 51a (296 mg, 54% yield) as a white solid. LCMS=0.84 min using analytical method (M), 502.0 (M+H). 1H NMR (400 MHz, CDCl3 containing CD3OD) δ 8.02 (d, J=1.8 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.59 (dd, J=8.7, 1.9 Hz, 1H), 4.38 (s, 2H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:26][C:27]1[CH:28]=[C:29]([NH:38][C:39]([C@H:41]2[C:50]3[C:45](=[CH:46][C:47]([CH2:51][O:52][CH3:53])=[CH:48][CH:49]=3)[CH2:44][CH2:43][NH:42]2)=[O:40])[CH:30]=[C:31]2[C:35]=1[C:34]([CH3:37])([CH3:36])[CH2:33][CH2:32]2.[C:54]([O:58][C:59](=[O:68])[CH2:60][C@@H:61]1[CH2:64][C@H:63]([C:65](O)=[O:66])[CH2:62]1)([CH3:57])([CH3:56])[CH3:55].CCN(C(C)C)C(C)C>O.CN(C=O)C>[F:26][C:27]1[CH:28]=[C:29]([NH:38][C:39]([C@H:41]2[C:50]3[C:45](=[CH:46][C:47]([CH2:51][O:52][CH3:53])=[CH:48][CH:49]=3)[CH2:44][CH2:43][N:42]2[C:65]([C@@H:63]2[CH2:62][C@H:61]([CH2:60][C:59]([O:58][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:68])[CH2:64]2)=[O:66])=[O:40])[CH:30]=[C:31]2[C:35]=1[C:34]([CH3:37])([CH3:36])[CH2:33][CH2:32]2
Reactant: COCc1ccc2c(c1)CCN[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of HATU (100 mg, 0.26 mmol), (R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (100 mg, 0.24 mmol), cis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (56.3 mg, 0.26 mmol), DIEA (0.094 mL, 0.53 mmol) and DMF (2 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give tert-butyl 2-(cis-3-((R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (130 mg, 0.225 mmol, 94%) as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-].C(OCC)(=O)C>C1COCC1.[Cl-].[Na+].O>[N:19]1[CH:18]=[CH:17][C:16]([NH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:4][OH:3])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Nc1ccncc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1[nH]c2ccccc2c1Nc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
At 0° C. stir a solution of 3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid ethyl ester (1.4 g, 5 mmol) in THF (15 mL) and add a 1M solution of LAH in THF (8 mL, 8 mmol). Allow the reaction to warm to room temperature and stir for an additional 0.5 h. Add aqueous NH4Cl solution, ethyl acetate and brine. Filter the solid that forms in the biphasic mixture to obtain 0.56 g (47%) of the title compound as a beige solid: MS 240(M+H); HPLC: Rt=1.04 min; TLC (silica gel, dichloromethane/MeOH, 4:1), Rf=0.6.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C@H:12]([NH:23]C(OCC2C=CC=CC=2)=O)[C:13]([O:15]CC2C=CC=CC=2)=[O:14])=[N:8][CH:9]=1)([O-])=O.C.[H][H]>CO.O.[Pd]>[NH2:23][C@@H:12]([CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][N:8]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(N[C@@H](CCc1ccc([N+](=O)[O-])cn1)C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: Nc1ccc(CC[C@H](N)C(=O)O)nc1
Yield: 91.3 %

Procedure:
A mixture of 5.16 g (11.5 mmol) of phenylmethyl (S)-5-nitro-α-[[(phenylmethoxy)carbonyl]amino]-2-pyridinebutanoate, 2 g of active charcoal and 0.77 g of active palladium-on-charcoal in 100 ml of methanol and 100 ml of water is stirred for 4 days at 50 psi of hydrogen at room temperature. The reaction medium is filtered through a cake of Celite and the cake is rinsed with 3×50 ml of boiling water. The aqueous phases are combined and concentrated under reduced pressure. 2.05 g of (S)-α,5-diamino-2-pyridinebutanoic acid are thus obtained in the form of a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12]>O.C(Cl)Cl.CO>[CH2:11]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:15][CH2:14]1)[CH3:12]
Reactant: CCN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C
Yield: 88.7 %

Procedure:
A mixture of 1-bromo-4-nitrobenzene (6 g, 29.7 mmol) and 1-ethylpiperazine (7.6 ml, 59.4 mmol, 2 eq.) is heated to 80° C. for 15 h. After cooling to RT, the reaction mixture is diluted with water and DCM/MeOH, 9:1. The aqueous layer is separated and extracted with DCM/MeOH, 9:1. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/MeOH+1% NH3aq, 9:1) affords 6.2 g of the title compound as a yellow solid: ESI-MS: 236.0 [MH]+; tR=2.35 min (purity: 100%, gradient J); TLC: Rf=0.50 (DCM/MeOH+1% NH3aq, 9:1).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccccc2Cl)cc1
Yield: 38.2 %

Procedure:
The title compound (125 mg, 38%) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (300 mg, 0.89 mmol, prepared in example 1), 2-chlorobenzeneboronic acid (170 mg, 1.09 mmol), tetrakis(triphenylphosphine)palladium(0) (5.6 mg, 0.005 mmol), 2 M sodium carbonate (320 mg in 1.5 mL water) and 1,4-dioxane (9 mL) in a manner analogous to the procedure described in Example 2.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13](S(C)(=O)=O)=[N:14][N:15]=2)[CH:8]=[C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[OH:24])([CH3:4])[CH3:3].[NH2:25][NH2:26]>C(O)(C)C>[CH3:22][C:20]([C:7]1[CH:8]=[C:9]([C:11]2[S:12][C:13]([NH:25][NH2:26])=[N:14][N:15]=2)[CH:10]=[C:5]([C:2]([CH3:3])([CH3:1])[CH3:4])[C:6]=1[OH:24])([CH3:21])[CH3:23]
Reactant: NN
Reactant: CC(C)(C)c1cc(-c2nnc(S(C)(=O)=O)s2)cc(C(C)(C)C)c1O
Solvent: CC(C)O
Product: CC(C)(C)c1cc(-c2nnc(NN)s2)cc(C(C)(C)C)c1O
Yield: 73.1 %

Procedure:
To a solution of 2,6-bis(1,1-dimethylethyl)-4-[5-(methylsulfonyl)-1,3,4-thiadiazole-2-yl]-phenol (4.1 g, 0.0111 mole) in isopropyl alcohol (30 ml) is added hydrazine (5.0 g, 0.10 mole). The resulting mixture is heated at reflux for four hours. The mixture is cooled and concentrated in vacuo. The residue is dissolved in 1:1 ethyl acetate/ether and washed with saturated aqueous NaCl and dried over MgSO4. Filtration and concentration in vacuo provides a solid which is recrystallized from ethanol/water to give 2.6 g of 2,6-bis(1,1-dimethylethyl)-4-(5-hydrazino-1,3,4-thiadiazol-2-yl)phenol after drying in vacuo (3.6 g theor., 73%), mp 109°-122° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=NC1CCCCC1)=NC1CCCCC1.N1(O)C2C=CC=CC=2N=N1.[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48](O)[CH2:47]2>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:10]([O:12][C@@H:48]1[CH:49]2[CH2:52][CH2:53][N:46]([CH2:51][CH2:50]2)[CH2:47]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COc1ccc(C(NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1ccc(C(NC(=O)OC(C)(C)C)C(=O)O[C@H]2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.7 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-(4-methoxyphenyl)acetic acid (I43) (1.39 g, 4.94 mmol) in dry THF (60 ml), were added N,N′-methanediylidenedicyclohexanamine (1.22 g, 5.94 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (802 mg, 5.94 mmol), and (R)-quinuclidin-3-ol (755 mg, 5.94 mmol). The reaction was stirred at RT for 15 hours, and the solvent was evaporated. The residue was taken up with DCM, the insoluble solid was filtered off, and the organic solution was washed twice with aq. Na2CO3 and then brine, dried over Na2SO4 and evaporated. The crude was purified by flash chromatography (DCM/MeOH=95/5 to 93/7) to obtain (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-(4-methoxyphenyl)acetate (630 mg; 33% yield).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][CH2:17][CH2:18][CH2:19]O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CS(Cl)(=O)=O.C(C(C(C(O)=O)O)O)(O)=O.[CH2:36]([O:38][C:39]([C@@H:41]1[CH2:46][CH2:45][CH2:44][NH:43][CH2:42]1)=[O:40])[CH3:37].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CC(C)=O.O.C(N(CC)CC)C>[CH2:36]([O:38][C:39]([CH:41]1[CH2:46][CH2:45][CH2:44][N:43]([CH2:19][CH2:18][CH2:17][CH2:16][N:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]2=3)[CH2:42]1)=[O:40])[CH3:37]
Reactant: OCCCCN1c2ccccc2CCc2ccccc21
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: CS(=O)(=O)Cl
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCCN(CCCCN2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
The above alcohol (5.4 g, 0.02 mol) was dissolved in toluene (160 ml) and triethylamine (7 ml) was added. Methanesulfonyl chloride (2.5 ml, 0.032 mol) was added dropwise and when addition was complete the reaction mixture was stirred for 2 h. Water was added and the phases were separated. The organic phase was dried (MgSO4) and the solvent evaporated in vacuo affording a residue which was dissolved in acetone (85 ml). To this solution (R)-3-piperidinecarboxylic acid ethyl ester tartrate (9.0 g, 0.03 mol) and potassium carbonate (7.0 g, 0.051 mol) were added and the mixture was heated at reflux temperature for 16 h. After cooling to room temperature and filtration on filter aid (celite) the solvent was removed by evaporation. The residue was dissolved in diethyl ether (100 ml) and extracted with a 5% tartaric acid solution (3×125 ml). The combined aqueous extracts were washed with diethyl ether and pH was adjusted to 7-8 with a potassium carbonate solution. The neutralised aqueous mixture was extracted with ethyl acetate (4×200 ml). The combined ethyl acetate extracts were washed with water, brine and dried (MgSO4). The solvent was evaporated in vacuo affording 2.6 g (32%) of 1-(4-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-butyl]-3-piperidinecarboxylic acid ethyl ester, obtained as an oil. The residue was purified further by column chromatography on silica gel (65 g) using a mixture of dichloromethane and methanol (99.2:0.8) as eluent. Rf : 0.20 (SiO2 ; n-heptane/ethyl acetate=1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][C:8](=O)[NH:9]2)=[CH:4][CH:3]=1>C1COCC1>[CH3:13][C:6]1([CH3:14])[C:5]2[C:10](=[CH:11][C:2]([NH2:1])=[CH:3][CH:4]=2)[NH:9][CH2:8][CH2:7]1
Reactant: CC1(C)CC(=O)Nc2cc(N)ccc21
Solvent: C1CCOC1
Product: CC1(C)CCNc2cc(N)ccc21

Procedure:
A mixture of 7-amino-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (1.07 g, 5.62 mmol) and borane dimethylsulfide complex (1.60 ml, 16.9 mmol) in 40 ml of anhydrous THF was heated at reflux under N2 for 15 h. The solvents were removed under reduced pressure. The residue was heated at reflux in 20 ml of MeOH for 2 h, then 0.80 g of NaHCO3 was added, and the mixture was heated at reflux for 2 h. The mixture was filtered, condensed, and the residue was purified by flash column chromatography (5 to 10% of EtOAc in CH2Cl2). The titled compound was obtained as a viscous oil. MS(ES+): 176.9 (M+H)+. Calc'd for C11H16N—176.26.
Reaction SMILES: [CH:1]([O:14][C:15]1[C:16]2[C:35](=[O:36])[N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:33][C:17]=2[C:18](OS(C(F)(F)F)(=O)=O)=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:51][O:52][C:53]1[C:58](B(O)O)=[CH:57][CH:56]=[CH:55][N:54]=1.CCOC(C)=O.CCCCCC>C1(C)C=CC=CC=1.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]([O:14][C:15]1[C:16]2[C:35](=[O:36])[N:34]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[CH2:33][C:17]=2[C:18]([C:58]2[C:53]([O:52][CH3:51])=[N:54][CH:55]=[CH:56][CH:57]=2)=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2c(c(OS(=O)(=O)C(F)(F)F)c3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Reactant: COc1ncccc1B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ncccc1-c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Temperature: 120 °C

Procedure:
Alternatively, according to a modified Suzuki coupling method of C. H. Chen; Tetrahedron Letter; EN; 44; 5747-5750; 2003, to a solution of trifluoro-methanesulfonic acid 9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester 46 (266.2 mg, 0.428 mmol) dissolved in toluene (5 mL) was added Na2CO3 (2M in water, 500 μl), 2-methoxypyridine-3-boronic acid (164 mg, 1.07 mmol) and tetrakis-(triphenylphosphine)-palladium(0)(100 mg, 0.086 mmol). The reaction mixture in the flask was flashed with argon three times. It was then heated to 120° C. under argon 4 hours. The reaction was monitored by TLC (EtOAc/hexane 3/7) (Rf1=0.6, Rf17=0.1) and LC/MS. After cooling to room temperature, the mixture was diluted with EtOAc (20 mL) and washed with 1N HCl, saturated NaHCO3 and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with EtOAc/Hexane (1/1) to afford pure 9-benzhydryloxy-7-(4-fluoro-benzyl)-5-(2-methoxy-pyridin-3-yl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 288, 125 mg, 50%. 1H NMR (CDCl3) δ 9.0 (dd, 1H), 8.3 (dd, 1H), 8.2 (s, 1H), 7.8 (dd, 4H), 7.7 (dd, 1H), 7.4 (dd, 1H), 7.3-7.1 (m, 8H), 7.0 (m, 2H+1H), 4.7 (dd, 2H), 4.1(dd, 2H), 3.8 (s, 1H); MS: 582 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13].S(=O)(=O)(O)O>[N+](C)([O-])=O>[CH3:1][C:2]1[C:10]([N+:12]([O-:14])=[O:13])=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C)c1C(=O)O
Agent: O=S(=O)(O)O
Solvent: C[N+](=O)[O-]
Product: Cc1ccc([N+](=O)[O-])c(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
2,6-Dimethylbenzoic acid (15 g) dissolved in 350 ml of nitromethane was cooled in an ice bath and treated with 18.9 ml of 70% nitric acid and then 14 ml of concentrated sulfuric acid. The bath was removed and the mixture was stirred at room temperature for 22 hr. The mixture was poured into ethyl acetate, washed several times with water, dried, evaporated, and 17.2 g of 2,6-dimethyl-3-nitrobenzoic acid, mp 115.9-116.5° C., was obtained. ##STR141##
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:3]=12.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>N1C=CC=CC=1>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:14]2[CH2:15][CH2:16][C:3]3[C:4](=[N:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[CH3:1])[CH2:12][CH2:13]2)=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1c2c(nc3ccccc13)CCNCC2
Solvent: c1ccncc1
Product: Cc1c2c(nc3ccccc13)CCN(C(=O)c1ccc(Cl)cc1)CC2
Yield: 65 %

Procedure:
3-(p-Chloro-benzoyl)-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline was prepared from 1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline and 4-chloro-benzoyl chloride in pyridine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11](=[O:31])[N:10]2[CH2:32][C:33]2[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([O:43]CC)=[O:42])=[CH:35][CH:34]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].Cl>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[N:10]([CH2:32][C:33]3[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42])=[CH:35][CH:34]=3)[C:11](=[O:31])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=3)[C:13]([CH3:20])=[C:14]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)/C=C/c1ccc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)OCC)C2c2ccc(C#N)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(Cc2ccc(/C=C/C(=O)O)cc2)C1c1ccc(C#N)cc1
Reaction time: 0.5 h

Procedure:
A stirred solution of ethyl 4-(4-cyanophenyl)-3-{4-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 40) (100 mg, 0.16 mmol) in ethanol (2 ml) is treated with 10% aq. sodium hydroxide solution (3 ml). After 30 minutes at room temperature, the pH of the solution is adjusted to 2 with 1 N hydrochloric acid, and the crude product is extracted with ethyl acetate (3×150 ml). The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by preparative HPLC (RP18 column; eluent: acetonitrile/0.1% aq. formic acid 10:90→90:10).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:7]=[CH:8][C:9]=1[OH:10])[CH:2]=[CH2:3].[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl.OC1C=CC=CC=1C(CCC(O)=O)=O.[OH-].[Na+]>ClCCl>[CH2:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:18][CH:20]1[O:22][CH2:21]1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C2=NNC(=O)CC2)ccc1O
Reactant: ClCC1CO1
Agent: O=C(O)CCC(=O)c1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CCc1cc(C2=NNC(=O)CC2)ccc1OCC1CO1
Yield: 47 %

Procedure:
A mixture of finely ground 6-(3-allyl-4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (50g, 0.22 mole), epichlorohydrin (200 g, 2.2 mole) and piperidine (2g) was heated on a steam bath for 90 minutes. Evaporation under reduced pressure gave a viscous oil which was dissolved in dichloromethane and stirred for 10 minutes with dilute sodium hydroxide (500 ml). The organic phase was washed with water, dried and evaporated to an oil which slowly solidified. Addition of ethanol-ether gave 6[3-allyl-4-(2,3-epoxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (30g, 47%, m.p. 92.5°-95° C) which was recrystallised from aqueous ethanol to give the pure pyridazinone (m.p. 93.5°-95° C).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[N:14]=[C:13]([C:15]2[C:16]([CH3:25])=[C:17]([C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH:18]=[O:19])[CH:12]=[CH:11][N:10]=1.O.[C:27]([O:30][CH2:31]C)(=[O:29])C>CN(C=O)C.CO>[CH:18]([C:17]1[C:16]([CH3:25])=[C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([C:27]([O:30][CH3:31])=[O:29])[N:14]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH3:24])=[O:19]
Reactant: COc1ccc(-c2ccnc(Cl)n2)c(C)c1C=O
Reactant: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COC(=O)c1nccc(-c2ccc(OC)c(C=O)c2C)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
Triethylamine (656 μL, 4.71 mol) and a [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (256 mg, 0.314 mmol) were added to a solution of the 3-(2-chloropyrimidin-4-yl)-6-methoxy-2-methylbenzaldehyde obtained in Example 75-1 (412 mg, 1.57 mmol) in DMF (4.0 mL) and methanol (4.0 mL) at room temperature, and the mixture thus obtained was then stirred under a carbon monoxide atmosphere at 80° C. for 8 hours. Thereafter, the reaction solution was cooled to room temperature, and water was then added to the reaction solution. The mixed solution was extracted with ethyl acetate twice. The organic layer thus obtained was washed with water and brine, and was then dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to 0:1, v/v) to obtain the title compound (150 mg, yield: 33%).