Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2([CH2:27][NH2:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2([CH2:27][NH:28][C:9](=[O:11])[CH2:8][S:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:23][CH2:24][CH2:25][CH2:26]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Reactant: O=C(O)CSc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C2(CNC(=O)CSc3ccccc3)CCCC2)cc1OC
Reaction time: 16 h
Yield: 14.6 %

Procedure:
Phenylsulfanyl-acetic acid (33.6 mg, 0.200 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (47.1 g, 0.200 mmol) were dissolved in acetonitrile (1 mL) containing triethylamine (83.6 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (76.0 mg, 0.200 mmol) was added and the solution was allowed to stir for 16 hours. The mixture was then purified by reverse phase preparative liquid chromatography to yield the pure product (11.3 mg, 0.0293 mmol, 14.6%) ESI-MS m/z calc. 385.2, found 386.0 (M+1)+. Retention time of 3.12 minutes.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[O:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11](Cl)=[O:12]>C(Cl)(Cl)Cl>[N:1]1([C:11]([C@H:7]2[CH2:8][CH2:9][CH2:10][O:6]2)=[O:12])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=C(Cl)[C@H]1CCCO1
Solvent: ClC(Cl)Cl
Product: O=C([C@H]1CCCO1)n1ccnc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
21.8 g (32 mmol) imidazole are placed in 400 ml chloroform and cooled to 0° C. 21.3 g (15.0 mol) (R)-tetrahydrofuran-2-carbonyl chloride are added dropwise, then the mixture is stirred for 1.5 hours at ambient temperature. After cooling again to 0° C. the reaction mixture is extracted with semisaturated sodium chloride solution. The organic phase is dried and evaporated to dryness. Yield: 24.0 g
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].Cl[CH2:6][C:7](=O)[CH2:8][C:9]([O:11][CH3:12])=[O:10]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:2][C:1]1[O:3][CH:6]=[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[N:4]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: CC(N)=O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1coc(C)n1
Temperature: 120 °C

Procedure:
A mixture of acetamide (1.312 g, 22.21 mmol) and methyl chloroacetoacetate in 20 mL of 1,4-dioxane and 20 mL of toluene was heated at 120° C. for 4 hours. The solution was concentrated and the residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated compound (a pale yellow oil). 1H NMR (CDCl3, 500 MHz) δ 7.58 (1H, s), 3.78 (3H, s), 3.64 (2H, s), 2.51 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18](O)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:24]=4[O:23][CH3:22])[CH2:29]3)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1OC)CCNC2
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccccc12
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3ccc(F)cc3)nc3ccccc13)C2
Yield: 10 %

Procedure:
Reaction of 2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 3 (10% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.72 and 2.98 (2t, 2H), 3.49 and 4.03 (2t, 2H), 3.68 and 3.75 (2s, 3H), 3.76 and 3.81 (2s, 3H), 4.42 and 4.93 (2s, 2H), 6.63 and 7.01 (2d, 1H), 6.81 and 7.08 (2d, 1H), 7.37-7.44 (m, 2H), 7.76-7.79 (m, 1H), 7.89-7.99 (2d, 1H), 8.07-8.15 (m, 2H), 8.53-8.62 (m, 2H); MS (ESI) m/z 444 ([M+H]+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:12]1([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24]3[N:29]=[CH:28][C:27](Br)=[CH:26][N:25]=3)[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1.[NH:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]1=[O:37]>[Cu](I)I.O>[CH:12]1([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24]3[N:29]=[CH:28][C:27]([N:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]4=[O:37])=[CH:26][N:25]=3)[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=c1cccc[nH]1
Reactant: Brc1cnc(OC2CCN(C3CCCC3)CC2)nc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccccn1-c1cnc(OC2CCN(C3CCCC3)CC2)nc1
Temperature: 150 °C
Reaction time: 3 h
Yield: 16.2 %

Procedure:
Potassium carbonate (40 mg) and copper iodide (40 mg) were added to a DMF solution (5 ml) of 2-(1-cyclopentylpiperidin-4-yloxy)-5-bromopyrimidine (130 mg) and 1H-pyridin-2-one (19 mg), and stirred at 150° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added to it and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, chloroform:methanol=9:1) to obtain the entitled compound (11 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4](Cl)[N:3]=1.Cl.[CH3:12][O:13][C:14]1[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=1>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:19][C:16]2[CH:15]=[C:14]([O:13][CH3:12])[NH:18][N:17]=2)[C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1
Reactant: COc1cc(N)n[nH]1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)n1
Agent: Cl
Solvent: CCO
Product: COc1cc(Nc2nc(Cl)nc(Cl)c2Cl)n[nH]1
Temperature: 25 °C
Yield: 25.8 %

Procedure:
To a solution of 2,4,5,6-tetrachloro-pyrimidine (2.18 g) in absolute ethanol (100 mL) was added DIEPA (4.4 mL) and 5-methoxy-1H-pyrazol-3-amine hydrogen chloride salt (1.50 g). The resulting solution was stirred at room temperature for over night. The solvent was evaporated under reduced pressure. The crude compound was purified by Gilson (10-60% MeCN/H2O, 15 minutes) to give the titled compound as solid (0.76 g). m/z 294.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.F[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(-n2cncn2)cc1
Temperature: 90 °C
Yield: 73.2 %

Procedure:
1,2,4-Triazole (0.82 g, 0.01 mol), ethyl 4-fluorobenzoate (2 g, 0.01 mol) and anhydrous potassium carbonate (1.43 g, 0.01 mol) was dissolved in DMSO (30 ml) and heated to 90° C. for 18 h. The solution was poured into water (50 ml), extracted with ethyl acetate (50 ml), dried (sodium sulphate), filtered and evaporated to dryness under reduced pressure. The white solid was purified by flash column chromatography (silica, diethyl ether) to afford a white solid (1.59 g, 73%).
Reaction SMILES: [F:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:15]#[N:16])[C:9]=2[C:11]([F:14])([F:13])[F:12])[NH:4][C:3]=1[CH3:17].Cl[CH2:19][C:20]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[O:22][N:21]=1>>[F:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:15]#[N:16])[C:9]=2[C:11]([F:13])([F:12])[F:14])[N:4]([CH2:19][C:20]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)[O:22][N:21]=2)[C:3]=1[CH3:17]
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: Cc1[nH]c2ccc(C#N)c(C(F)(F)F)c2c1F
Product: Cc1c(F)c2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 23 from 3-fluoro-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: MS (ES) m/z 469 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]([O:14]C)=[O:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl>[OH-].[Na+].CO.CS(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]([OH:14])=[O:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)C(c1ccccc1)C(c1ccccc1)c1ccc2[nH]ncc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: O=C(O)C(c1ccccc1)C(c1ccccc1)c1ccc2[nH]ncc2c1
Yield: 82 %

Procedure:
Methyl 3-(1H-indazol-5-yl)-2,3-diphenylpropanoate was heated to 100° C. overnight in a mixture of 2 M NaOH/MeOH/DMSO (1:1:1). The next day, the reaction was cooled, acidified to pH 5 with HCl and extracted 2×EtOAc. The organic layers were washed with water×2, dried over MgSO4, filtered, concentrated in vacuo, and purified by HPLC to give 10 mg (82% yield) and 30 mg of the diastereomers of acid 3-(1H-indazol-5-yl)-2,3-diphenylpropanoic acid. MS found: (M+H)+=343.
Reaction SMILES: [C:1](Cl)(=O)C.[CH3:5][C:6]1[CH:7]=[C:8]([CH2:25][C:26]([OH:28])=[O:27])[CH:9]=[C:10]([CH3:24])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=1>CO>[CH3:5][C:6]1[CH:7]=[C:8]([CH2:25][C:26]([O:28][CH3:1])=[O:27])[CH:9]=[C:10]([CH3:24])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=1
Reactant: COc1ccc(Oc2c(C)cc(CC(=O)O)cc2C)cc1C(C)C
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)Cc1cc(C)c(Oc2ccc(OC)c(C(C)C)c2)c(C)c1
Temperature: 25 °C
Yield: 46.9 %

Procedure:
To a stirred cold solution of methanol (15 mL) and acetyl chloride (3 mL, 86.0 mmol) at 0° C. was added dropwise a solution of 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)phenylacetic acid (0.7 g, 4.3 mmol) in methanol (5 mL). The reaction mixture was heated under reflux for 5 h and cooled to room temperature. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (100 mL). The organic solution was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated with hexane, filtered and dried under reduced pressure to afford methyl 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)phenylacetate as a yellow solid (0.69 g, 95%): 1H NMR (300 MHz, CDCl3): δ 7.02 (s, 2 H), 6.82 (d, J=2.7 Hz, 1 H), 6.66 (d, J=8.7 Hz, 1 H), 6.38 (dd, J=3.3, 8.7 Hz, 1 H), 3.79 (s, 3 H), 3.75 (s, 3 H), 3.60 (s, 2 H), 3.28-3.25 (m, 1 H), 2.14 (s, 6 H), 1.20 (d, J=7.2 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (1:1); Rf=0.6.
Reaction SMILES: C[N:2]([CH3:21])[CH:3]=[C:4]([C:10](=[O:20])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([Cl:18])=[CH:13][C:12]=1[Cl:19])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:22]1(N)C[CH2:23]1>C1(C)C=CC=CC=1>[CH:21]1([NH:2][CH:3]=[C:4]([C:10](=[O:20])[C:11]2[CH:16]=[C:15]([F:17])[C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:23][CH2:22]1
Reactant: NC1CC1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)cc1Cl
Yield: 93.9 %

Procedure:
33.4 g of ethyl 3-dimethylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylate are heated to boiling under reflux with 7 g of cyclopropylamine and 120 ml of toluene for 1 hour. The gas evolution, the onset of which is initially violent, is then finished. The toluene is removed by distillation in vacuo, and the solid residue is recrystallized from light petroleum. 32.5 g of ethyl 3-cyclopropylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylate of melting point 89°-91° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]2[N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:15][CH2:16][CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][CH2:32][C:31]2[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=2)[CH:10]2[N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:15][CH2:16][CH:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CC(O)C2C1CCN2C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(OCc2ccc(F)cc2)C2C1CCN2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
Bicyclic alcohol 43 (4.2 g, 11.59 mmol) and 4-fluoro-benzyl bromide (2.2 mL, 17.4 mmol) were dissolved in DMF (115 mL) and cooled to 0° C. Sodium hydride (930 mg, 23.2 mmol) was added and, after ˜5 min, the ice bath was removed. After 15 min, the reaction mixture was diluted with toluene (250 mL) and saturated aqueous NH4Cl (500 mL) and extracted with 1:1 Et2O/hexanes (600 mL). The organic layer was washed successively with 1N HCl, water, saturated aqueous NaHCO3, water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (10:1 to 1:1 hexanes/EtOAc) to afford 5.15 g of 44 as a viscous oil (94%): 1H NMR (300 MHz, CDCl3): δ7.36 (m, 6H), 7.07-6.92 (m, 3H), 5.15 (m, 2H), 4.63 (m, 1H), 4.50 (m, 1H), 4.32 (m, 1H), 4.19 (m, 1H), 3.97 (m, 1H), 3.87-3.64 (m, 2H), 3.25-3.08 (m, 2H), 2.35 (m, 0.5H), 2.17 (m, 0.5H), 1.88 (m, 1H), 1.46 (s, 9H) ppm. Mass spectrum, m/z [414.7] (M−t-Bu)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:6](O)[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[O:3]1.[NH:13]1[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[N:15]=[CH:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.Cl.O1CCOCC1>C1COCC1>[CH3:21][O:20][C:18]([C:16]1[N:15]([CH:6]2[C:5]3[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=3[O:3][C:2]2([CH3:12])[CH3:1])[CH:14]=[N:13][CH:17]=1)=[O:19]
Reactant: COC(=O)c1c[nH]cn1
Reactant: CC1(C)Oc2ccccc2C1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COC(=O)c1cncn1C1c2ccccc2OC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2,2-dimethyl-2,3-dihydro-benzofuran-3-ol (375 mg, 2.28 mmol) in THF (20 mL) is added methyl 4-imidazolecarboxylate (CAS#17325-26-7, 432 mg, 3.42 mmol), followed by triphenylphosphine (896 mg, 3.42 mmol). The reaction is cooled to 0° C. and di-t-butyl azodicarboxylate (787 mg, 3.42 mmol) is added. The reaction is permitted to warm to room temperature and stirred for 2 hours. The reaction mixture is then cooled to 0° C. and quenched with 4 N HCl in dioxane (5 mL, 20 mmol) and stirred for 30 minutes. The reaction is concentrated to near dryness and diluted with ethyl acetate. The organic layer is extracted three times with 1 N aqueous HCl. The aqueous extracts are combined, neutralized with Na2CO3, and extracted three times with ethyl acetate. The combined organic layers are dried with Na2SO4, filtered and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 1:5) to furnish 3-(2,2-dimethyl-2,3-dihydro-benzofuran-3-yl)-3H-imidazole-4-carboxylic acid methyl ester; HRMS: (ESI) m/z 245.0934 [(M+H)+: Calcd for C13H13N2O3: 245.0926]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05 (s, 3H), 1.57 (s, 3 H), 3.92 (s, 3 H), 6.32 (s, 1 H), 6.92 (d, J=8.1 Hz, 1 H), 6.95-7.02 (m, 2 H), 7.25 (s, 1 H), 7.32-7.40 (m, 1 H), 7.80 (s, 1 H).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:29])[NH:7][C:8]2[CH:28]=[CH:27][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:4][NH:5][C:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[O:13])=[CH:27][CH:28]=2)=[O:29])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(NC(=O)NCC3CC3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCNCC2)cc1
Reaction time: 1 h
Yield: 94.9 %

Procedure:
tert-Butyl 4-(4-(3-(cyclopropylmethyl)ureido)benzoyl)piperazine-1-carboxylate (46.7 mmol, 18.78 g) was dissolved in dichloromethane (30 mL) and trifluoroacetic acid (233 mmol, 17.33 ml, 26.6 g) was added. The reaction was stirred for 1 hour and then was concentrated under reduced pressure. The crude material was triturated with ether to give a white powder after high vacuum drying. The white powder was taken up in water and carefully taken to pH 10 with sodium carbonate. The aqueous was then extracted with dichloromethane and the combined organic phases were dried, filtered and concentrated under reduced pressure to give the title compound (13.4 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](I)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])[CH3:2].[C:27]([Cu])#[N:28]>CN1C(=O)CCC1.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:27]#[N:28])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(I)c2cc(Oc3cc(F)ccc3Cl)ccc2c1O
Reactant: N#C[Cu]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1nc(C#N)c2cc(Oc3cc(F)ccc3Cl)ccc2c1O
Temperature: 130 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
A mixture of 7-(2-chloro-5-fluoro-phenoxy)-4-hydroxy-1-iodo-isoquinoline-3-carboxylic acid ethyl ester (180 mg) and CuCN (66 mg) in NMP (2 mL) was stirred at 130° C. for 1 h; then cooled, diluted with DCM, filtered, then washed with water, dil. NaCl solution, dried over sodium sulphate, filtered, concentrated, the residue was column purified to give the desired product (120 mg). LC MS ESI: 387 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:27]([Cu])#[N:28]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:27]#[N:28])[N:11]=1)=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2-c1ccc(OC)cc1
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2-c1ccc(OC)cc1

Procedure:
Prepared in analogy to that of Example 105(a) from 2,3,7-tribromo-4-hydroxy-1-(4-methoxy-phenyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and CuCN. The title compound, ESI MS (m/z): 494 (M+H)+.
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[N:9]([CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:8]2=[O:22])([O-:4])=[O:3].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:35][O:34][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:36][CH3:37])[N:27]=[CH:26][N:25]=[C:24]2[N:19]1[CH2:18][CH2:17][CH:16]([N:9]2[C:8](=[O:22])[C:7]3[C:12](=[CH:13][CH:14]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[NH:11][C:10]2=[O:15])[CH2:21][CH2:20]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(=O)n1C1CCNCC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Temperature: 80 °C

Procedure:
In 150 ml of DMF was dissolved 3.0 g (8.09 mmol) of 1,2,3,4-tetrahydro-6-nitro-2, 4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide, and 1.7 g (8.09 mmol) of 4-chloro6,7-dimethoxyquinazoline and 1.1 g (24 mmol) of potassium carbonate were added to the solution, followed by heating at 80° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with an aqueous solution of sodium chloride and dried. After the solvent was distilled off, ethanol and ether were added to the residue. The precipitated crystals were collected by filtration and washed with ether to give 3.28 g (yield: 8=%) of Compound 24 as white crystals 1H-HMR (DMSO-d6) δ (ppm) 12.01 (s, 1H, NH), 8.67 (d, 1H, J=2.5 Hz), 8.55 (s, 1H), 8.45 (dd, 1H, J=9.0, 2.5 Hz), 7.34 (d, 1H, J=9.0 Hz), 7.23 (s, 1H), 7.15 (s, 1H), 5.09-5.04 (m, 1H), 4.37-4.32 (br.-d, 2H), 3.95 (s, 3H), 3.93 (s, 3H), 3.27-3.23 (br.-t, 2H), 2.87-2.78 (m, 2H), 1.81-1.77 (br.-d, 2H).
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C@H:2]([C:4](O)=[O:5])[CH3:3].N1C(F)=NC(F)=NC=1[F:19].N1C=CC=CC=1>C(Cl)Cl>[NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C@H:2]([C:4]([F:19])=[O:5])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)F

Procedure:
CBZ-Ala (1 mmole) in dry CH2Cl2 is kept under nitrogen and treated with cyanuric fluoride (8 mmol) and pyridine (1 mmole) to form the corresponding CBZ-Ala-F.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:35])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:19]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:35])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([N:32]([CH3:33])[CH3:34])=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH:19]=1
Reactant: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)Nc3ccccc3N)c2)cc1

Procedure:
Starting materials: (2-{(E)-3-[1-(4-dimethylamino-benzenesulfonyl)-1H-pyrrol-3-yl]-allanoylamino}-phenyl)-carbamic acid tert-butyl ester (compound A8) (0.141 g), CH2Cl2 (10 ml), TFA (1 ml). Reaction conditions: room temperature, 20 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([CH:27]2[CH2:29][CH2:28]2)[CH:3]=1.[NH:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20]([N:30]5[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]5)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([CH:27]2[CH2:28][CH2:29]2)[CH:3]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C3CC3)c2)S1
Reactant: O=C(O)C1CNC1
Product: O=C1NC(N2CC(C(=O)O)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C2CC2)c1

Procedure:
1-(5-[1-(4-Chloro-2-cyclopropyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-dihydro-thiazol-2-yl]-azetidine-3-carboxylic acid was prepared from 5-[1-(4-chloro-2-cyclopropyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and azetidine-3-carboxylic acid following General Procedure C.
Reaction SMILES: [BrH:1].[CH:2]1([N:5]([C:13]2[N:18]3[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:17]3[N:16]=[C:15]([C:24]3[S:25][C:26]([CH2:29]O)=[CH:27][CH:28]=3)[CH:14]=2)C(=O)OC(C)(C)C)[CH2:4][CH2:3]1>ClCCl>[Br:1][CH2:29][C:26]1[S:25][C:24]([C:15]2[CH:14]=[C:13]([NH:5][CH:2]3[CH2:4][CH2:3]3)[N:18]3[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:17]3[N:16]=2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N(c1cc(-c2ccc(CO)s2)nc2c(C=O)cnn12)C1CC1
Reactant: Br
Solvent: ClCCl
Product: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(CBr)s3)nc12
Temperature: 40 °C
Yield: 34 %

Procedure:
Hydrogen bromide (48% in water, 5 mL) was added dropwise to tert-butyl cyclopropyl(3-formyl-5-(5-(hydroxymethyl)thiophen-2-yl)pyrazolo[1,5-a]pyrimidine-7-yl)carbamate (980 mg, 2.4 mmol) suspended in dichloromethane (5 mL). The solution immediately became dark brown and homogeneous upon addition. The reaction was heated to 40° C. for 4 hours, then diluted with dichloromethane (10 mL). The liquid was decanted and the gummy residue was washed with dichloromethane (3×10 mL). The combined liquids were washed successively with sat. NaHCO3 (20 mL) and brine (20 mL), and then dried over MgSO4, filtered and concentrated in vacuo: The residue was triturated with hexanes and then purified via flash column chromatography (10-20% EtOAc/hexanes) to provide 5-(5 -(bromomethyl)thiophen-2-yl)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (300 mg, 34%) as a yellow solid. LCMS (ES): >95% pure, m/z 378 [M+1]+.