Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]([F:28])([F:27])[C:13]1[C:14]([N:19]2[CH:23]=[C:22]([C:24](=[O:26])[CH3:25])[CH:21]=[N:20]2)=[N:15][CH:16]=[CH:17][CH:18]=1.[F:29][C:30]([F:37])([F:36])[C:31](OCC)=[O:32].Cl>C1COCC1>[F:29][C:30]([F:37])([F:36])[C:31](=[O:32])[CH2:25][C:24]([C:22]1[CH:21]=[N:20][N:19]([C:14]2[C:13]([C:12]([F:11])([F:27])[F:28])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:23]=1)=[O:26]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1cnn(-c2ncccc2C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)c1cnn(-c2ncccc2C(F)(F)F)c1
Temperature: -20 °C
Reaction time: 3 h
Yield: 201.4 %

Procedure:
Alternatively, lithium bis(trimethylsilyl)amide (1.0M solution in THF, 1.1 mL, 1.1 mmol) was slowly added to a solution of 1-[1-(3-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-4-yl]-ethanone (240 mg, 0.94 mmol) in 2 mL anhydrous THF at −78° C. under nitrogen. The mixture was then allowed to warm to −20° C. and kept at −20° C. to −5° C. for 3 hrs. After this period of time the mixture was cooled to −78° C. and to it was added ethyl trifluoroacetate (200 mg, 0.41 mmol). The mixture was next allowed to warm to ambient temperature overnight. 1N aqueous HCl was carefully added to adjust the pH 2. Two layers were separated and the aqueous layer was extracted with chloroform three times. The extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 4,4,4-trifluoro-1-[1-(3-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-4-yl]-butane-1,3-dione as a yellow solid (290 mg, 88% yield). The product was used for the next step without purification. 1H-NMR (400 MHz, CDCl3): δ 6.35 (s, 1H), 7.59 (dd, 1H, J=4.80, J=7.83), 8.21 (s, 1H), 8.28 (dd, 1H, J=1.77, J=3.80), 8.75 (dd, 1H, J=4.80, J=1.77), 8.76 (d, 1H, J=0.51)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:28][CH2:29][C:30]2[N:31]=[C:32]([C:35]3[CH:40]=[N:39][CH:38]=[CH:37][N:36]=3)[S:33][CH:34]=2)[CH:27]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:8]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:28][CH2:29][C:30]2[N:31]=[C:32]([C:35]3[CH:40]=[N:39][CH:38]=[CH:37][N:36]=3)[S:33][CH:34]=2)[CH:27]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:8]1
Reactant: CCOC(=O)CCc1cn(Cc2cc(OC)cc(OCc3csc(-c4cnccn4)n3)c2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(Cn2cc(CCC(=O)O)c(-c3ccccc3)c2)cc(OCc2csc(-c3cnccn3)n2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
A mixture of ethyl 3-[1-[3-methoxy-5-[2-(2-pyrazinyl)-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionate (361 mg), 1N aqueous sodium hydroxide solution (1.5 ml), tetrahydrofuran (3 ml), and ethanol (3 ml) was stirred at room temperature for 4 hours, and 1N hydrochloric acid (1.5 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[3-methoxy-5-[2-(2-pyrazinyl)-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionic acid (338 mg, yield: 99%). This was recrystallized from ethanol-hexane. Melting point: 111–112° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.[I:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=[C:2]([N:23]3[CH:24]=[C:20]([I:19])[N:21]=[CH:22]3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: Ic1c[nH]cn1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Product: Fc1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidine (example A.45) (1.5 g, 5.4 mmol) and commercially available 4-iodo-imidazole (1.58 g, 8.15 mmol) according to the general procedure IVa. Obtained as a white solid (2.23 g, 95%). MS (ISP) 435.0 [(M+H)+]; mp 235° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C>Cl[Pd]Cl.O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[CH:11][C:10]([OH:14])=[O:13])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: C=CC(=O)O
Agent: Cl[Pd]Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C=CC(=O)O)cc1
Temperature: 130 °C
Yield: 81.2 %

Procedure:
p-bromo anisole (8.4 g), acrylic acid (3.9 g), water (13.5 g), PdCl2 (0.3 mg) and triethyamine (14.3 g, 89.3% pure by titration, the balance being water, recovered by phase separation from a previous run) were charged into an autoclave and heated for 2 hours at 130° C. The work up detailed in Example 1 gave 6.5 g (81%) of >98% pure p-methoxy cinnamic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:15]1([NH:21][C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NC1CCCCC1

Procedure:
A solution of 50 g (0.22 mol) of 2-nitro-4-trifluoromethyl-1-chlorobenzene, 22 g (0.22 mol) of cyclohexylamine and 61 g (0.44 mol) of potassium carbonate in 600 ml of ethanol was refluxed for 4 hours. The reaction mixture was concentrated and then the crude product was washed with water and ether. The organic phase was worked up, and the product was purified by column chromatography on silica gel (mobile phase: heptane/ethyl acetate=5/1).
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH:7]=[N:8]O.C1N=CN(C(N2C=NC=C2)=O)C=1>O1CCCC1>[F:1][CH:2]([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]#[N:8]
Reactant: ON=Cc1cccc(OC(F)F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: N#Cc1cccc(OC(F)F)c1
Reaction time: 8 h
Yield: 54.8 %

Procedure:
A solution of 4.95 g of 3-(difluoromethoxy)benzaldehyde oxime in 50 ml of dry tetrahydrofuran was treated with 4.30 g of N,N-carbonyldiimidazole. After the effervescence had subsided, the reaction solution was allowed to stand overnight, then concentrated in vacuo. The residue was taken up in 75 ml of water and the pH adjusted to 4 with hydrochloric acid. The nitrile was extracted into ether, dried over sodium sulfate and concentrated, giving a yellow oil which upon distillation gave 2.45 g of the desired compound as a colorless oil, bp 73°-75° C./0.3 mm.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([C@H:27]3[CH2:31][CH2:30][NH:29][CH2:28]3)[C:11]2=[O:32])[CH:7]=[CH:8][CH:9]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([C@H:27]3[CH2:31][CH2:30][N:29]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:28]3)[C:11]2=[O:32])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n([C@H]3CCNC3)c12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n([C@H]3CCN(S(C)(=O)=O)C3)c12

Procedure:
3-(3-Chloro-phenyl)-1-((S)-1-methanesulfonyl-pyrrolidin-3-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (27 mg) was prepared according to general procedure H from (S)-3-(3-chloro-phenyl)-7-methoxy-1-pyrrolidin-3-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione.dihydrochloride (42 mg, 0.1 mmol) and methanesulfonyl chloride. LCMS: m/z 501 [M+1]+.
Reaction SMILES: [I-].C[N+]1C=CN([C:8](=[O:30])/[N:9]=[C:10]2\[S:11][C:12]([CH3:29])=[CH:13][N:14]\2[C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[O:22][C:17]=3[CH:16]=2)C=1.Cl.[F:32][C@@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1.CCN(C(C)C)C(C)C>C(#N)C>[F:32][C@@H:33]1[CH2:37][CH2:36][N:35]([C:8](/[N:9]=[C:10]2\[S:11][C:12]([CH3:29])=[CH:13][N:14]\2[C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:26])([F:25])[C:21]([F:23])([F:24])[O:22][C:17]=3[CH:16]=2)=[O:30])[CH2:34]1
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)n2cc[n+](C)c2)s1
Reactant: F[C@@H]1CCNC1
Agent: Cl
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)N2CC[C@@H](F)C2)s1
Temperature: 30 °C
Reaction time: 12 h

Procedure:
(Z)-3-Methyl-1-(5-methyl-3-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2(3H)-ylidenecarbamoyl)-1H-imidazol-3-ium iodide (Example 81A, 250 mg, 0.45 mmol), (R)-3-fluoropyrrolidine hydrochloride (62 mg, 0.49 mmol) and Hunig's base (0.078 mL, 0.45 mmol) in acetonitrile (5 mL) were stirred at 55° C. for 3 hours. The reaction mixture was then cooled to 30° C. with continued stirring for 12 hours. The mixture was evaporated to dryness and purified by reverse phase HPLC to give the title compound. 1H NMR (CDCl3) δ ppm 2.00 (2H), 2.20 (3H), 3.35-3.85 (4H), 5.10-5.30 (1H), 6.60 (1H), 7.20 (1H), 7.35 (1H), 7.45 (1H); MS (ESI) m/z 436(M+H)+.
Reaction SMILES: Cl.[S:2]1[C:6]([NH2:7])=[CH:5][C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]1=2.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1.C(Cl)Cl>[S:2]1[C:6]([NH:7][S:19]([C:16]2[CH:17]=[CH:18][C:13]([Br:12])=[CH:14][CH:15]=2)(=[O:21])=[O:20])=[CH:5][C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]1=2
Reactant: Nc1cc2ccccc2s1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc2ccccc2s1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
To a stirred solution of compound 1-C (9.28 g, 49.9 mmol) in pyridine (100 mL) and methylene chloride (50 mL), cooled on an ice bath, was added 4-bromobenzene-1-sulfonyl chloride (12.8 g, 49.9 mmol), portion-wise over a period of 4 minutes. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction mixture was concentrated under reduced pressure, the crude residue partitioned between EtOAc (500 mL) and 1N HCl (250 mL), the layers separated, the organic phase washed with 1N HCl (125 mL), brine, dried over MgSO4, filtered and evaporated in vacuo. The crude residue was purified by flash column chromatography (SiO2) eluting with an EtOAc-Heptane gradient to afford 13.5 g of compound 361-A as a tan powder. 1H-NMR (DMSO-d6) δ: 6.89 (s, 1H), 7.33-7.20 (m, 2H), 7.75-7.64 (m, 3H), 7.84-7.76 (m, 3H), 11.30 (s, 1H); MS: m/z 366.1 (M-H)−.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[N:20]([CH3:21])[NH:19][C:18]([O:23][CH3:24])(O)[C:17]=1[C:25]1[CH:33]=[CH:32][C:28]2[O:29][CH2:30][O:31][C:27]=2[CH:26]=1.CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[O:29]1[C:28]2[CH:32]=[CH:33][C:25]([C:17]3[C:18]([O:23][CH3:24])=[N:19][N:20]([CH3:21])[C:16]=3[NH:15][S:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)(=[O:13])=[O:12])=[CH:26][C:27]=2[O:31][CH2:30]1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC1(O)NN(C)C(N)=C1c1ccc2c(c1)OCO2
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: COc1nn(C)c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1-c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 6 %

Procedure:
4-(tert-butyl)benzenesulfonyl chloride (190 mg) was added at room temperature under an atmosphere of nitrogen to a solution of 5-amino-4-(1,3-benzodioxol-5-yl)-3-methoxy-1-methyl-1H-pyrazol-3-ol (Preparation 43) (100 mg) and dimethylaminopyridine (50 mg) in anhydrous pyridine (4 ml). The reaction was stirred overnight. The mixture was concentrated under reduced pressure, then a saturated solution of ammonium chloride (6 ml), ethyl acetate (6 ml), and brine (6 ml) were sequentially added. The aqueous phase was extracted with ethyl acetate (2×8 ml) and the combined organic fractions were washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified to yield the title compound (10 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: BrCc1ccccc1
Product: COc1ccc(N(Cc2ccccc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 86.8 %

Procedure:
Using general procedure H, 4-(4-methoxyphenylamino)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 77) (612 mg, 2.00 mmol) and benzyl bromide (410 mg, 2.40 mmol) gave 4-[benzyl-(4-methoxyphenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil (688 mg, 87%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:23][CH3:24])=[C:7]([CH:22]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)=[O:9])=[O:2].CC(C)=[O:27].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>O>[CH3:24][O:23][C:6]1[CH:5]=[CH:4][C:3]([C:1]([OH:27])=[O:2])=[CH:22][C:7]=1[C:8](=[O:9])[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=1
Reactant: COc1ccc(C=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1ccc(C(=O)O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Reaction time: 0.42 h

Procedure:
To 500 mg of 5-formyl-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide were added 20 ml of acetone and 0.5 ml of Jones reagent under cooling with ice, and the mixture was stirred for 25 minutes. Then, 0.2 ml of Jones reagent were added further and the mixture was stirred for 35 minutes. To the reaction mixture were added 100 ml of water, which was extracted (100 ml×2) with methylene chloride (small quantity of acetone was added). After washed with 50 ml of saturated brine, the organic layer was dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and the residue obtained was purified by means of column chromatography (silica gel, methylene chloride:methanol=100:1, quantity of methanol was increased gradually), then recrystallized from hexane-acetone to obtain 270 mg of aimed product as white crystals.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C:8]([CH3:9])=[CH:7][C:6](=[O:10])[C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]1[CH2:19][O:20][CH3:21].[CH3:22]OC(C1OC(C)=CC(=O)C=1OCC1C=CC=CC=1)C>>[ClH:1].[CH3:2][N:3]1[C:8]([CH3:9])=[CH:7][C:6](=[O:10])[C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]1[CH:19]([O:20][CH3:21])[CH3:22]
Reactant: COC(C)c1oc(C)cc(=O)c1OCc1ccccc1
Reactant: COCc1c(OCc2ccccc2)c(=O)cc(C)n1C
Agent: Cl
Product: COC(C)c1c(OCc2ccccc2)c(=O)cc(C)n1C

Procedure:
The title compound was prepared by the method outlined for 1,6-dimethyl-2-methoxymethyl-3-benyloxy-pyridin-4(1H)-one hydrochloride, using 3.56 g (13 mmol, 1 eq.) of 2-(1-methoxyethyl)-3-benzyloxy-6-methyl-pyran-4(1H)-one to yield the pure product 2.64 g (62.8%) after recrystallisation from methanol/diethyl ether, as a white crystalline solid m.p 17-19° C.
Reaction SMILES: [Cl:1][C:2]1[NH:13][C:5]2[C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH:10](O)[C:4]=2[C:3]=1[Cl:14].S(O)(O)(=O)=O.[NH2:20][C:21]1[NH:22][CH:23]=[CH:24][N:25]=1.CCOCC>CS(O)(=O)=O>[NH2:20][C:21]1[NH:25][C:24]([CH:10]2[CH2:9][CH2:8][NH:7][C:6](=[O:12])[C:5]3[NH:13][C:2]([Cl:1])=[C:3]([Cl:14])[C:4]2=3)=[CH:23][N:22]=1
Reactant: O=C1NCCC(O)c2c1[nH]c(Cl)c2Cl
Reactant: Nc1ncc[nH]1
Agent: CS(=O)(=O)O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: Nc1ncc(C2CCNC(=O)c3[nH]c(Cl)c(Cl)c32)[nH]1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of 2,3-dichloro-4-hydroxy-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one (60 mg, 0.256 mmol), prepared as in reference 2, in methanesulfonic acid (0.5 mL) is added 2-aminoimidazole sulfate (40.5 mg, 0.153 mmol). The mixture is stirred at 45° C. overnight, cooled to room temperature and Et2O (5 mL) is added resulting in brown oil. After discarding the supernatant, the oil is purified by silica gel column chromatography and eluted with MeOH—CH2Cl2 to give 4-(2-amino-3H-imidazol-4-yl)-2,3-dichloro-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one; 1H NMR (Methanol-d4) δ 2.09-2.17 (m, 1H), 2.23-2.31 (m, 1H), 3.20-3.29 (m, 2H), 4.23 (t, 1H, J=3.6 Hz), 6.18 (s, 1H); m/z [M++1] 300.0.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3([C:18]([O:20]C)=[O:19])[CH2:17][CH2:16][CH2:15]3)=[CH:9][CH:8]=2)=[N:5][N:4]=[N:3]1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14]3([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:12]=2)=[N:5][N:4]=[N:3]1
Reactant: COC(=O)C1(Cc2ccc(-c3nnnn3C)cc2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nnnc1-c1ccc(CC2(C(=O)O)CCC2)cc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
To a solution of methyl 1-[[4-(1-methyltetrazol-5-yl)phenyl]methyl]cyclobutane carboxylate (0.33 g, 1.15 mmol) in a mixture of THF (7 mL) and methanol (7 mL) was added 1 N sodium hydroxide (7 mL). The mixture was heated to 55° C. and stirred for 4 h at which point TLC analysis indicated the absence of starting material. After cooling to room temperature, the solvent was removed under vacuum and the residue was diluted with water and extracted with ethyl acetate to remove any neutral impurities. Then, the aqueous layer was neutralized with 1 N hydrochloric acid and the product was extracted with ethyl acetate (2×50 mL). The combined extracts were washed with saturated brine and dried over sodium sulfate. After filtration, the solution was concentrated under vacuum and the residue was dried under high vacuum to afford 1-[[4-(1-methyl-5-tetrazolyl)phenyl]methyl]cyclobutane carboxylic acid (180 mg, 57%) as a light yellow syrup.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=2)[NH:9]1.[NH2:23][C:24]1([C:27]([O-:29])=[O:28])[CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:27]([C:24]1([NH:23][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH2:26][CH2:25]1)([OH:29])=[O:28]
Reactant: NC1(C(=O)[O-])CC1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccccc1Br
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccccc1NC1(C(=O)O)CC1
Temperature: 120 °C
Reaction time: 16 h
Yield: 80.1 %

Procedure:
A mixture of 2-(2-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (150 mg, 0.42 mmol), copper(I) iodide (24 mg, 0.13 mmol), 1-amino-cyclopropane-1-carboxylate (170 mg, 1.7 mmol) and potassium carbonate (174 mg, 1.26 mmol) in dimethyl sulfoxide (3 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[2-(1-carboxy-cyclopropylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (128 mg, 80%) as a white solid: LC/MS m/e calcd for C22H24N2O4 (M+H)+: 381.46, observed: 381.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]([CH2:36][CH2:37][OH:38])[CH2:33][CH2:34][OH:35])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[OH:35][CH2:34][CH2:33][N:32]([CH:29]1[CH2:30][CH2:31][N:26]([C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:14]([C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:12]=3[CH3:13])=[O:16])=[CH:25][C:22]=2[C:23]#[N:24])[CH2:27][CH2:28]1)[CH2:36][CH2:37][OH:38]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Reactant: N#Cc1cc(N)ccc1N1CCC(N(CCO)CCO)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N(CCO)CCO)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 9.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.0 g) and 5-amino-2-{4-[N,N-bis(2-hydroxyethyl)amino]piperidin-1-yl}benzonitrile (1.2 g), the title compound (0.2 g) was obtained, melting point: 230–233° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([CH:22]([CH3:24])[CH3:23])=[CH:15][C:16]=1[C:17](OCC)=[O:18]>CO>[CH3:24][CH:22]([C:14]1[S:13][C:12]2[N:11]=[C:2]3[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[CH:6][N:7]3[C:17](=[O:18])[C:16]=2[CH:15]=1)[CH3:23]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CCOC(=O)c1cc(C(C)C)sc1N
Solvent: CO
Product: CC(C)c1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Yield: 20.1 %

Procedure:
A mixture of 24.0 g (0.1538 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) and 32.8 g (0.1538 mol) of 2-amino-5-(1-methylethyl)-3-thiophenecarboxylic acid, ethyl ester (Tetrahedron, Vol. 33, pages 2089-2092, 1977) is heated in a wax bath at 178°-182° C. for two hundred five minutes and then at 180°-196° C. for sixty-five minutes under nitrogen. The mixture is cooled, suspended in hot methanol and filtered to give 8.9 g of 2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 280°-282° C. after recrystallization from dimethylformamide.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28](Br)=[CH:27][N:26]=4)=[O:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[CH:27][N:26]=4)=[O:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NC1CCC(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)CC1)c1ccc(Br)cn1
Reactant: C1COCCN1
Product: O=C(NC1CCC(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)CC1)c1ccc(N2CCOCC2)cn1

Procedure:
The title compound, MS: m/e=523.2 (M+H+), was prepared in accordance with the general method of example 30A65, step 2 from 5-bromo-pyridine-2-carboxylic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide and morpholine.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[C:27]([O:28][CH3:29])=[CH:26][C:20]([CH:21]=[CH:22][C:23](O)=O)=[C:19]([N+:30]([O-:32])=[O:31])[CH:18]=1>>[CH3:15][O:16][C:17]1[C:27]([O:28][CH3:29])=[CH:26][C:20](/[CH:21]=[CH:22]/[C:23]2[NH:1][C:2]3[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=3[N:8]=2)=[C:19]([N+:30]([O-:32])=[O:31])[CH:18]=1
Reactant: COc1cc(C=CC(=O)O)c([N+](=O)[O-])cc1OC
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cc(OC)c(OC)cc3[N+](=O)[O-])nc2n(CC)c1=O
Yield: 38.8 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 1.50 g (7.57 mmol) of 5,6-diamino-1,3-diethyluracil and 2.11 g (8.33 mmol) of 4,5-dimethoxy-2-nitrocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 1.22 g (yield 39%) of Compound 124 as orange needles.