Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[S:24][CH:25]=[CH:26][C:27]=1[CH2:28]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.CCOC(C)=O>[Cl:22][C:23]1[S:24][CH:25]=[CH:26][C:27]=1[CH2:28][O:20][C:17]1[CH:18]=[CH:19][N:14]([C:11]2[CH:12]=[CH:13][C:6]3[N:5]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[N:8]([CH3:9])[C:7]=3[CH:10]=2)[C:15](=[O:21])[CH:16]=1
Reactant: OCc1ccsc1Cl
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccsc4Cl)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
To a mixture of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (2-chloro-3-thienyl)methanol (106 mg) and tributylphosphine (0.264 ml) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine successively, dried over MgSO4, and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc), followed by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH) to give the title compound (42.4 mg) as an off-white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1([O:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[C:14](O)=[O:15])[CH2:9][CH2:8][CH2:7][CH2:6]1>C1(C)C=CC=CC=1>[CH:5]1([O:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[C:14]([Cl:3])=[O:15])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1OC1CCCC1
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Cl)cc1OC1CCCC1
Temperature: 85 °C

Procedure:
Stirring thionyl chloride (20 mL) is treated portionwise with 3-cyclopentyloxy-4-methoxybenzoic acid (5.0 g; that is prepared as described hereinbefore in Reference Example 2) and the solution is then heated at 85° C. for 3 hours. Toluene (50 mL) is added and the mixture is concentrated to give 3-cyclopentyloxy-4-methoxybenzoyl chloride (4.12 g) in the form of an oil which slowly crystallized. [NMR(CDCl3): 1.6-1.7 (m,2H),1.8-1.95(m,4H),1.94-2.05(m,2H),3.94(s,3H),4.85 (m,1H),6.9(d,1H),7.55(d,1H),7.8(q,1H); Elemental analysis: C,61.3; H,5.94; Cl,13.9%; Calculated: C,61.3; H,5.94; Cl,13.92%].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=O)=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.C1C=CC2N(O)N=NC=2C=1.[C:36]([O:40][C:41](=[O:50])[NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[NH2:49])([CH3:39])([CH3:38])[CH3:37]>C(Cl)CCl.C(N(CC)CC)C.O>[C:36]([O:40][C:41](=[O:50])[NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[NH:49][C:18](=[O:20])/[CH:17]=[CH:16]/[C:13]1[CH:14]=[CH:15][N:11]([S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)(=[O:9])=[O:10])[CH:12]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: O=C(O)/C=C/c1ccn(S(=O)(=O)c2cccc(Br)c2)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccn(S(=O)(=O)c2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5.4 g (E)-3-[1-(3-bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid with 300 ml DMF and 2.34 g HOBt.H2O and 21.0 ml Triethylamine is stirred at ambient temperature for 0.5 h. Then it is added 8.8 g EDC.HCL and it is stirred again at ambient temperature for 0.5 h. Finally 3.2 g (2-amino-phenyl)-carbamic acid tert-butyl ester are added and the suspension is stirred at ambient temperature for 24 h. The DMF is evaporated and the residue is extracted with ethyl acetate and water. The organic layer is dried over sodium sulfate. The title product is isolated by flash chromatography. By this method 6.3 g of a yellow foam is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C:25]([F:27])([F:28])[F:26])[C:17]([OH:19])=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC(F)(F)F)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cn(C(CC(F)(F)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
65.0 mg (142 μmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4,4-trifluorobutanoate (racemate) in 1.6 ml of dichloromethane and 411 μl (5.34 mmol) of TFA were reacted according to General Method 6A. Yield: 53 mg (81% of theory)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][CH:12]=1)(=[O:10])=[O:9].[Li]CCCC.[CH3:32][O:33][C:34]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[C:35]=1[CH:36]=[O:37]>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:36]([OH:37])[C:35]1[C:38]([O:42][CH3:43])=[CH:39][CH:40]=[CH:41][C:34]=1[O:33][CH3:32])(=[O:9])=[O:10]
Reactant: COc1cccc(OC)c1C=O
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1csc2ncccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2c(OC)cccc2OC)sc2ncccc12
Yield: 63.6 %

Procedure:
The title compound was prepared by the method of Example 4(B) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyeth-oxymethyl)thieno[2,3-b]pyridine-3-sulfonamide (0.15 g, 0.35 mmoles) [Example 4(A)], THF (5 ml), n-BuLi (2.5M, 0.16 ml, 0.41 mmoles) and 2,6-dimethoxybenzaldehyde (88 mg, 0.53 mmoles). Flash chromatography (50% EtOAc/hexanes) provided 0.13 g (62%) of the title compound as a pink oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:9][C:8]2[CH:10]=[C:11]([NH:14][C:15]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:21][CH:22]=3)=[O:16])[CH:12]=[CH:13][C:7]=2[N:6]=1)=[O:4].[Li+].[OH-]>CO.O.O1CCCC1>[C:23]1([C:20]2[N:19]=[CH:18][C:17]([C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:7]4[N:6]=[C:5]([C:3]([OH:4])=[O:2])[NH:9][C:8]=4[CH:10]=3)=[O:16])=[CH:22][N:21]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1nc2ccc(NC(=O)c3cnc(-c4ccccc4)nc3)cc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc2nc(C(=O)O)[nH]c2c1)c1cnc(-c2ccccc2)nc1
Yield: 72.7 %

Procedure:
A solution of 6-[(2-phenyl-pyrimidin-5-carbonyl)-amino]-1H-benzoimidazole-2-carboxylic acid methyl ester (0.44 mmol) and LiOH (4.40 mmol) in MeOH/water/tetrahydrofuran (1:1:1, 60 mL) is stirred at room temperature overnight. MeOH and THF are evaporated in vacuo and the aqueous mixture is acidified with 5% HCl to pH ˜2. The resulting precipitate is filtered, washed with water (10 mL) and dried to give 6-[(2-phenyl-pyrimidin-5-carbonyl)-amino]-1H-benzoimidazole-2-carboxylic acid as a solid (115 mg). MS: 360 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 7.52-7.70 (m, 5H), 8.30 (s, H), 8.48 (m, 3H), 9.28 (S, H), 9.38 (s, 2H), 10.73 (s, N—H).
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([CH2:7][C:8]2([NH:15][C:16]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+]>C1(C)C(C)=CC=CC=1>[Cl:26][C:21]1[CH:20]=[C:19]([N:18]2[C:9]3=[CH:10][CH2:11][CH2:12][CH2:13][C:8]3([CH2:7][C:6]3[CH:27]=[CH:28][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[NH:15][C:16]2=[O:17])[CH:24]=[C:23]([Cl:25])[CH:22]=1
Reactant: N#Cc1ccc(CC2(NC(=O)Nc3cc(Cl)cc(Cl)c3)CCCCC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: N#Cc1ccc(CC23CCCC=C2N(c2cc(Cl)cc(Cl)c2)C(=O)N3)cc1
Yield: 50.2 %

Procedure:
A suspension of 1-[1-(4-cyano-benzyl)-2-oxocyclohexyl]-3-(3,5-dichlorophenyl)-urea (3.7 g) (0.009 mol), K2CO3 (2.6 g) (2.1 eq) and molecular sieves 4A (10 g) in xylene (500 ml) was refluxed 16 h. After cooling, the reaction mixture was filtered on paper, concentrated in vacuo, and the residue purified on SiO2 chromatography (eluent EtOAc/cyclohexane-3/7) to yield 4-[1-(3,5-Dichlorophenyl)-2-oxo-1,2,3,4,5,6-hexahydro-benzimidazol-3a-ylmethyl]benzonitrile (1.8 g) as a white solid. 1H NMR (CDCl3): 7.6 (2H, d), 7.35 (2H, d), 7.15 (1H, m), 6.95 (2H, m), 5.65 (1H, bs), 4.95 (1H, m), 3.1 (1H, d), 2.9 (1H, d), 2.5-2.1 (2H, m), 2.1-1.65 (4H, m).
Reaction SMILES: [C:1]1([N:7]2[CH:15]=[C:14]3[C:9]([N:10]=[CH:11][C:12]([NH:16][S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])=[CH:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>CCOC(C)=O.[OH-].[Pd+2].[OH-]>[C:1]1([N:7]2[CH:15]=[C:14]3[C:9]([NH:10][CH2:11][CH:12]([NH:16][S:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)(=[O:18])=[O:19])[CH2:13]3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Nc1cnc2nn(-c3ccccc3)cc2c1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=S(=O)(NC1CNc2nn(-c3ccccc3)cc2C1)c1ccccc1
Reaction time: 5 h

Procedure:
A suspension of 3D (50 mg, 0.142 mmol) and palladium hydroxide (20% wt of Pd) on carbon (50 mg) in EtOAc (5 mL)/methanol(2 mL) was stirred under a hydrogen balloon for 5 hours, then filtered via a pad of Celite. The filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with 2.0 M NH3 in MeOH/CH2Cl2 (3:97 ratio) to give the desired product, which was further purified using preparative HPLC to give the title compound as a TFA salt (15 mg, 22% yield). LC/MS (method A): retention time=2.75 min, (M+H)+=355.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([C:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[O:19])[CH:15]=[C:14]([C:27]([O:29]C)=[O:28])[CH:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH3:32]O>[OH-].[Na+].O>[CH3:32][C:13]1[C:14]([C:27]([OH:29])=[O:28])=[CH:15][C:16]([C:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[O:19])=[CH:17][C:12]=1[C:9]1[CH:8]=[CH:7][C:6]([S:3]([N:2]([CH3:31])[CH3:1])(=[O:4])=[O:5])=[CH:11][CH:10]=1
Reactant: CO
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2ccc(S(=O)(=O)N(C)C)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(C(=O)O)c(C)c(-c2ccc(S(=O)(=O)N(C)C)cc2)c1
Temperature: 22.5 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 4′-[(dimethylamino)sulfonyl]-5-[(dipropylamino)carbonyl][1,1′-biphenyl]-3-carboxylate (XXXVIII, step 2, 555 mg, 1.24 mmol) in methanol (6 mL) and sodium hydroxide (2 mL of a 6.0 M mixture in water, 12 mmol) is stirred at 20-25 degrees C. for 4 hours. The reaction mixture is partitioned between ethyl acetate (40 mL) and water (40 mL). The aqueous phase is acidified to pH=4 with hydrochloric acid (1N), extracted with ether (3×100 mL), and the combined organic phases are concentrated under reduced pressure to give methyl 4′-[(dimethylamino)sulfonyl]-5-[(dipropylamino)carbonyl][1,1′-biphenyl]-3-carboxylic acid (IX-XXXIX), NMR (300 MHz, CDCl3): δ 8.37, 8.12, 7.89, 7.80, 3.51, 3.22, 2.76, 1.74, 1.59, 1.02 and 0.79.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=4)[CH2:13][CH2:12]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=1>>[CH3:37][C:32]1[CH:31]=[C:30]([N:1]2[C:9]3[C:4](=[C:5]([CH2:10][N:11]4[CH2:16][CH2:15][CH:14]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=5)[CH2:13][CH2:12]4)[CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:35]=[CH:34][C:33]=1[CH3:36]
Reactant: Cc1ccc(I)cc1C
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Product: Cc1ccc(-n2ccc3c(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)cccc32)cc1C

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 4-iodo-1,2-dimethylbenzene: ESMS m/e: 480.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[C:11]([CH2:20][C:21]([OH:23])=[O:22])=[C:10]2[CH3:24])=[CH:4][CH:3]=1.[CH2:25](OC(=O)CC1C2C(=CC=C(OC)C=2)NC=1C)[CH3:26].[H-].[Na+].ClC1C=CC(CCl)=CC=1>>[CH2:25]([O:22][C:21](=[O:23])[CH2:20][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[N:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:10]=1[CH3:24])[CH3:26]
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2Cc1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Agent: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cc1c(C)n(Cc2ccc(Cl)cc2)c2ccc(OC)cc12

Procedure:
1-[(4-Chlorophenyl)methyl]-5-methoxy-2-methyl-1H-indole-3-acetic acid. The procedure in Example 63, Part B, was used to react 1.35 g (5.5 mmol) of 5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester with 240 mg (6 mmol) of 60% NaH/mineral oil and 970 mg (6 mmol) of p-chlorobenzyl chloride to give 1.4 g of 1-[(4-chlorophenyl)methyl]-2-methyl-5-methoxy-1H-indole-3-acetic acid ethyl ester that had been chromatographed on silica (20% ether/hexane→35% ether/hexane). This ester was hydrolyzed with 3 mL of 5N NaOH to give 1.23 g of crude 1-[(4-chlorophenyl)methyl]-5-methoxy-2-methyl-1H-indole-3-acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](Cl)=[O:9].[NH2:16][C:17]1[C:18](=[O:37])[N:19]([CH3:36])[C:20]2[C:25]([C:26]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:33])=[CH:24][C:23]([CH3:34])=[CH:22][C:21]=2[CH3:35].N1C=CC=CC=1.C1COCC1>O>[OH2:2].[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:26]1[C:25]2[C:20](=[C:21]([CH3:35])[CH:22]=[C:23]([CH3:34])[CH:24]=2)[N:19]([CH3:36])[C:18](=[O:37])[C:17]=1[NH:16][C:8](=[O:9])[CH:7]=[CH:6][C:5]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(C=CC(=O)Cl)cc1OC
Reactant: Cc1cc(C)c2c(c1)c(-c1ccccc1Cl)c(N)c(=O)n2C
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)Nc2c(-c3ccccc3Cl)c3cc(C)cc(C)c3n(C)c2=O)cc1OC
Temperature: 25 °C
Reaction time: 96 h
Yield: 65.4 %

Procedure:
A mixture of 3,4-dimethoxycinnamoyl chloride (678 mg), 3-amino-4-(2-chlorophenyl)-1,6,8-trimethyl-2(1H)-quinolone (511 mg), pyridine (0.28 ml) and THF (10 ml) was stirred at room temperature for four days. Then, the mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The solvent was removed and the residue was purified by a silica gel chromatography with benzene-acetone (4:1) to give crystals of 4-(2-chlorophenyl)-3-(3,4-dimethoxycinnamoylamino)-1,6,8-trimethyl-2(1H)-quinolone hydrate (510 mg, 65.6%). The crystals were recrystallized from ethanol to afford colorless prisms.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[N:13]1[C:18]2[NH:19][C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[NH:22][CH2:23][C:17]=2[CH:16]=[CH:15][CH:14]=1>C(OCC)C>[N:13]1[C:18]2[NH:19][C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[N:22]([C:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][CH2:3][C:4]=4[CH:9]=3)=[O:12])[CH2:23][C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: O=C(O)c1ccc2c(c1)CCO2
Solvent: CCOCC
Product: O=C(c1ccc2c(c1)CCO2)N1Cc2cccnc2Nc2ccccc21

Procedure:
Prepared from 2,3-dihydro-benzofuran-5-carboxylic acid (0.328 g, 2 mmol) and 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (0.398 g, 2 mmol) in a manner essentially identical to that of Example 1. The title compound was obtained as an off-white solid, m.p. 188° C., upon recrystallization from diethyl ether.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10](=[O:25])[NH:11][CH2:12][C@@H:13]([NH:17]C(OC(C)(C)C)=O)[CH:14]([CH3:16])[CH3:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:28]>O1CCOCC1>[ClH:28].[N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10](=[O:25])[NH:11][CH2:12][C@@H:13]([NH2:17])[CH:14]([CH3:15])[CH3:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)[C@@H](CNC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@H](N)CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
To a solution of ((2S)-2-t-butoxycarbonylamino-3-methylbutyl)-carbamic acid p-nitrobenzyl ester (3.13 g, 8.21 mmol) (obtained as described in Reference Example 61(3)) in 1,4-dioxane (31 ml) was added a 4N solution of hydrogen chloride in 1,4-dioxane (31 ml) in an ice bath, and the mixture was stirred at room temperature for 4 hours. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the resulting mixture was filtered off and washed with ethyl acetate to give ((2S)-2-amino-3-methylbutyl)carbamic acid p-nitrobenzyl ester hydrochloride (1.82 g, yield 70%) as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([CH:8]2[S:13][CH2:12][CH2:11][CH2:10][S:9]2)[CH:7]=1.[Li+].CC([N-]C(C)C)C.[O:23]=[C:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.[NH4+].[Cl-]>C1COCC1>[C:33]([O:32][C:30]([N:27]1[CH2:28][CH2:29][C:24]([C:8]2([C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[F:14])[S:9][CH2:10][CH2:11][CH2:12][S:13]2)([OH:23])[CH2:25][CH2:26]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Fc1ccc(Br)cc1C1SCCCS1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(C2(c3cc(Br)ccc3F)SCCCS2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
A solution of 2-(5-bromo-2-fluoro-phenyl)[1,3]dithiane (19 g, 64.84 mmol) in THF (100 ml) was added to a degassed and stirred 2 M solution of LDA (32.42 ml, 64.84 mmol) in THF dry (150 ml) at −78° C. and the reaction was carried out at −20° C. for 30 min. The reaction was cooled down again to −78° C. and tert-butyl 4-oxo-1-piperidinecarboxylate (13.03 g, 65.5 mmol) in THF (100 ml) was added dropwise. After 30 min, a further portion of tert-butyl 4-oxo-1-piperidinecarboxylate was added (0.5 g, 0.25 mmol). After 1 h, the reaction mixture was poured into a saturated NH4Cl solution (200 ml) and extracted with AcOEt. The combined organic fractions were washed with water (100 ml), brine (100 ml), dried over Na2SO4, then filtered and evaporated to give a yellow oil. The crude product was purified by column chromatography (AcOEt/hexane 30/70) to give 4-[2-(5-bromo-2-fluoro-phenyl)-[1,3]dithian-2-yl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester as a white solid (13 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([N:18]=[C:19]=S)[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC1CC2C(CC=1)=CC=CC=2N=C=S)C.[N:38]([CH2:41][C:42]([C:44]1[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][C:45]=1[F:54])=[O:43])=[N+]=[N-].N(CC(C1C=CC(C(F)(F)F)=CC=1)=O)=[N+]=[N-]>>[C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([NH:18][C:19]3[O:43][C:42]([C:44]4[CH:49]=[CH:48][C:47]([C:50]([F:51])([F:52])[F:53])=[CH:46][C:45]=4[F:54])=[CH:41][N:38]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=NCC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: CC(C)(C)OC(=O)NC1CCc2cccc(N=C=S)c2C1
Agent: CCOC1=CCc2cccc(N=C=S)c2C1
Agent: [N-]=[N+]=NCC(=O)c1ccc(C(F)(F)F)cc1
Product: CC(C)(C)OC(=O)NC1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4F)o3)c2C1
Yield: 16 %

Procedure:
The title compound was prepared using the procedure as described in Example 1H, substituting the product of Example 20F (415 mg, 1.36 mmol) for the product of Example 1F and the product of Example 22A (404 mg, 1.63 mmol) for the product of Example 1G. The crude product was purified by flash chromatography eluting with 20% to 60% EtOAc/hexanes which gave 107 mg (16%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.CO[CH:15]1[CH2:19][CH2:18][CH:17](OC)O1>C(O)(=O)C>[Cl:12][C:4]1[CH:3]=[C:2]([N:1]2[CH:15]=[CH:19][CH:18]=[CH:17]2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-n2cccc2)cc1Cl

Procedure:
2.0 g of methyl 4-amino-2-chlorobenzoate were dissolved in 10 ml of acetic acid, 2.0 ml of 2,5-dimethoxytetrahydrofuran were added thereto, and the mixture was heated under reflux for 15 minutes. After cooling the reaction solution, the solvent was evaporated. The obtained residue was mixed with EtOAc and saturated NaHCO3 aq. and extracted. The organic layer was washed with brine, and dried over sodium sulfate anhydride. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane-EtOAc (4:1)) to obtain 2.1 g of methyl 2-chloro-4-(1H-pyrrol-1-yl)benzoate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12].CCC(C1C=CC=CC=1)=O.[NH2:27][C:28]1[N:29]=[CH:30][NH:31][C:32]=1[C:33]#[N:34]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:29]2[CH:30]=[N:31][C:32]([C:33]#[N:34])=[C:28]2[N:27]=1
Reactant: Cc1ccccc1C(=O)CC(=O)C(F)(F)F
Reactant: N#Cc1[nH]cnc1N
Solvent: CCC(=O)c1ccccc1
Product: Cc1ccccc1-c1cc(C(F)(F)F)n2cnc(C#N)c2n1
Yield: 6.3 %

Procedure:
Reaction of 1-(2-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (230 mg, 1.0 mmol), prepared from commercially available 2-methyl-acetophenone according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (19 mg, 6%). MS (ISP) 303.0 [(M+H)+]; mp 151° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.Cl.Cl.[NH2:23][CH:24]1[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1>>[N:26]12[CH2:31][CH2:30][CH:29]([CH2:28][CH2:27]1)[CH:24]([NH:23][C:18]([C:17]1[C:11]3[O:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[N:13][C:12]=3[CH:14]=[CH:15][CH:16]=1)=[O:20])[CH2:25]2
Reactant: NC1CN2CCC1CC2
Reactant: COc1ccc(-c2nc3cccc(C(=O)O)c3o2)cc1
Agent: Cl
Product: COc1ccc(-c2nc3cccc(C(=O)NC4CN5CCC4CC5)c3o2)cc1
Yield: 24 %

Procedure:
N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-methoxyphenyl)benzoxazole-7-carboxamide was prepared from 2-(4-methoxyphenyl)benzoxazole-7-carboxylic acid and 3-aminoquinuclidine dihydrochloride using the method outlined in Step C of Example 14. This compound was obtained in 24% yield as a white solid: mp 166-167° C.; 1H NMR (500 MHz, CD3OD) δ 8.20 (dd, J=7.0, 2.0 Hz, 2H), 7.86 (d, J=7.9 Hz, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.49 (t, J=7.9 Hz, 1H), 7.14 (dd, J=1.9, 7.0 Hz, 2H), 4.26 (m, 1H), 3.91 (s, 3H), 3.42 (m, 1H), 3.02 (m, 1H), 2.92 (m, 3H), 2.83 (m, 1H), 2.16 (d, J=3.1 Hz, 1H), 2.07 (m, 1H), 1.84 (m, 2H), 1.68 (m, 1H); MS (ESI) m/z 378 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:13][CH:14]=[CH2:15])[C:8]([OH:12])=[CH:9][CH:10]=2)[O:5][C:4](=[O:16])[CH:3]=1.[CH3:17]O>>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:13][CH:14]=[CH2:15])[C:8]([OH:12])=[CH:9][C:10]=2[CH3:17])[O:5][C:4](=[O:16])[CH:3]=1
Reactant: CO
Reactant: C=CCc1c(O)ccc2c(C)cc(=O)oc12
Product: C=CCc1c(O)cc(C)c2c(C)cc(=O)oc12

Procedure:
In a manner analogous to example 23, from 4-methyl-7-hydroxy-8-allylcoumarin (XII) 4-methylangelicin (XXIX; m.p. 194°-5° C. (from MeOH)) was obtained: ##STR32## and from 4,5-dimethyl-7-hydroxy-8-allylcoumarin (XIV) the 4,5-dimethylangelicin (XXX; m.p. 211°-2° (MeOH)) was obtained: ##STR33##