Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.F[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[C:38]([C:39]([OH:41])=[O:40])=[C:37]([CH3:42])[N:36]=[C:35]([CH3:43])[C:34]=1C(O)=O>CCCCCC>[CH3:43][C:35]1[CH:34]=[C:33]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:40][C:39](=[O:41])[C:38]2=[C:37]([CH3:42])[N:36]=1
Reactant: Cc1nc(C)c(C(=O)O)c(-c2ccccc2F)c1C(=O)O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: Cc1cc2c(c(C)n1)c(=O)oc1ccccc12
Reaction time: 0.83 h
Yield: 28.9 %

Procedure:
To 1400 ml of Dowtherm A heated to 240°-245° C. was added over a 10 minute period 113 g of 4-(2-fluorophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylic acid and the reaction mixture was boiled for 50 minutes, cooled and allowed to stand at room temperature overnight. The crystalline solid, a by-product identified below, was filtered off and the filtrate was extracted with 700 ml of 3N hydrochloric acid followed by a second extraction with 300 ml of 3N hydrochloric acid. The combined acidic extracts were made basic by adding aqueous ammonium hydroxide and the alkaline mixture was extracted with 800 ml of chloroform. Evaporation of the chloroform yielded a brown mixture of solid and liquid, to which was added 300 ml of n-hexane and the mixture chilled. The solid was filtered off and dried. This solid, a by-product, was combined with the above noted solid by-product to yield 25.4 g (29%) of 2,4-dimethyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one, m.p. 194°-197° C. The filtrate was concentrated to dryness on a steam bath, the residue taken up with ethanol and the solution concentrated on a rotary evaporator to yield, as a liquid, 55.2 g (70%) of 4-(2-fluorophenyl)-2,6-dimethylpyridine.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Cl:11][C:12]1[CH:31]=[CH:30][C:15]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([OH:29])=[C:24](OC)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[C:14]([F:32])[CH:13]=1.[C:33](=O)([O-])[O-:34].[K+].[K+]>CN(C=O)C>[ClH:2].[Cl:11][C:12]1[CH:31]=[CH:30][C:15]([NH:16][C:17]2([O:34][CH3:33])[C:26]3[C:21](=[CH:22][C:23]([O:29][CH2:3][CH2:4][N:5]4[CH2:10][CH2:9][O:8][CH2:7][CH2:6]4)=[CH:24][CH:25]=3)[N:20]=[CH:19][NH:18]2)=[C:14]([F:32])[CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: ClCCN1CCOCC1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COC1(Nc2ccc(Cl)cc2F)NC=Nc2cc(OCCN3CCOCC3)ccc21
Temperature: 100 °C
Yield: 53 %

Procedure:
4-(2-Chloroethyl)morpholine hydrochloride (40 mg, 2.1 mmol) was added to 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (63 mg, 0.2 mmol), (prepared as described for the starting material in Example 4), and potassium carbonate (95 mg, 0.69 mmol) in DMF (3 ml) and the mixture heated at 100° C. for 3 hours. The mixture was allowed to cool, the volatiles were removed by evaporation and the residues partitioned between water and methylene chloride. The organic phase was separated, passed through phase separating paper and the solvent was removed by evaporation. The residue was dissolved in acetone, and hydrogen chloride in ether (0.2 ml of a 1M solution, 0.2 mmol) was added. The precipitated product was collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)4-methoxy-7-(2-morpholinoethoxy)quinazoline hydrochloride (50 mg, 50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=2[O-])[CH:5]=[CH:6][CH:7]=1.COS(OC)(=O)=O.[C-:24]#[N:25].[Na+]>CC(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]2[N:11]=[C:12]([C:24]#[N:25])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: [O-][n+]1ccccc1C=Cc1cccc(F)c1
Agent: [Na+]
Solvent: CC(C)O
Solvent: COS(=O)(=O)OC
Product: N#Cc1cccc(C=Cc2cccc(F)c2)n1

Procedure:
Following the general method described in example 2b, 2-[2-(3-fluoro-phenyl)-vinyl]-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and crystallization the title compound was obtained as a beige crystalline material. Mp. 111–112° C. (iPrOH), MS: m/e=224 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.[Br:31]N1C(=O)CCC1=O>C(OCC)(=O)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][Br:31])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2CBr)cc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a heterogeneous, refluxing solution of 2-(4-fluorophenyl)-4-methyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (590 mg, 1.65 mmol) and carbon tetrachloride (24 mL) was quickly added N-bromosuccinimide (yield: 308 mg, 1.73 mmol) followed by benzoyl peroxide (12 mg, 0.05 mmol). After 1 hour the reaction had only run to near 50% completion. Additional benzoyl peroxide (12 mg, 0.05 mmol) was added, and the reaction checked after another 1 hour. The reaction was still not complete, and so more benzoyl peroxide (4 mg, 0.017 mmol) was added. After 30 minutes, the reaction was completed. The mixture was cooled to 23° C. and diluted with ethyl acetate. The acetate solution was washed with saturated NaHCO3, water, and brine. The solution was dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes gradient 1:1 to 4:1) to provide the product (yield: 530 mg, 74%). 1H NMR (300 MHz, CDCl3) δ 3.16 (s, 3H), 4.34 (s, 2H), 7.20 (dd, J=8.8, 8.8 Hz, 2H), 7.67–7.74 (m, 2H), 7.82 (d, J=8.7 Hz, 2H), 7.86 (s, 1H), 8.17 (d, J=8.7 Hz, 2H). MS (APCI+) m/z 437 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH2:13][S:14][C:15]3[N:19]([CH3:20])[C:18]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)=[N:17][N:16]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.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>[O:26]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]([C:8]3[O:12][N:11]=[C:10]([CH2:13][S:14][C:15]4[N:19]([CH3:20])[C:18]([C:21]5[S:22][CH:23]=[CH:24][CH:25]=5)=[N:17][N:16]=4)[N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:27]1
Reactant: OB(O)c1ccoc1
Reactant: Cn1c(SCc2noc(-c3cccc(I)c3)n2)nnc1-c1cccs1
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: CCOC(C)=O
Solvent: COCCOC
Product: Cn1c(SCc2noc(-c3cccc(-c4ccoc4)c3)n2)nnc1-c1cccs1
Temperature: 90 °C
Yield: 59.3 %

Procedure:
To 5-(3-Iodo-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole (50 mg, 0.10 mmol) in a vial was added 3-furan boronic acid (17 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.0052 mmol), ethylene glycol dimethyl ether (1 ml) and 2 M sodium carbonate (1 ml). The vial was then sealed and heated at 90° C. for 1 h with vigorous stirring. The reaction was cooled, diluted with ethyl acetate, washed with water and saturated brine, filtered and concentrated. The residue was purified by flash column chromatography using 70% ethyl acetate in hexanes. Additional purification by trituration with a mixture of diethyl ether and hexanes and then filtration afforded the title compound as a beige solid 25 mg (57%). 1H NMR (CDCI3), δ (ppm): 8.18 (s, 1H), 7.98 (d, 1H), 7.79 (s, 1H), 7.71 (d, 1H), 7.51 (m, 4H), 7.17 (m, 1H), 6.74 (s, 1H), 4.55 (s, 2H), 3.73 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.Cl.C(NCC)C.[N+:17]([CH2:20][C:21](OC)=[O:22])([O-:19])=[O:18]>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:10][C:21](=[O:22])[C:20]([N+:17]([O-:19])=[O:18])=[CH:7]2
Reactant: O=Cc1cc(F)ccc1O
Reactant: COC(=O)C[N+](=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCNCC
Product: O=c1oc2ccc(F)cc2cc1[N+](=O)[O-]
Yield: 55.4 %

Procedure:
5-Fluoro-2-hydroxybenzaldehyde (7.14 g, 50.96 mmol), diethyl amine hydrochloride (6.70 g, 61.15 mmol) and methyl nitroacetate (5.62 mL, 61.15 mmol) were added together in toluene (90 mL) and stirred together at reflux under a N2 atmosphere. A Dean-Stark apparatus was fitted to the system to remove the H2O generated by the reaction. The reaction was allowed to reflux overnight, after which the mixture was cooled and diluted with H2O. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated. Purification by flash chromatography on silica gel afforded the product as an orange solid (5.90 g, 55%)
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH:11]([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1>>[F:12][CH:11]([F:13])[C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:20]3[CH:19]=[C:18]([C:21]4[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:17]=[CH:16][C:15]=3[F:14])=[CH:3][N:4]=[C:5]2[N:10]=1
Reactant: FC(F)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2cc(-c3ccccc3C#N)ccc2F)OC1(C)C
Product: N#Cc1ccccc1-c1ccc(F)c(-c2cnc3nc(C(F)F)ccn23)c1
Yield: 49 %

Procedure:
3-Bromo-7-difluoromethylimidazo[1,2-α]pyrimidine (124 mg, 0.50 mmol) was coupled with 4′-fluoro-3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3′-(7-difluoromethylimidazo[1,2-α]pyrimidin-3-yl)-4′-fluorobiphenyl-2-carbonitrile (180 mg, 49%) as a yellow powder: δH (400 MHz, CDCl3) 6.69 (1H, t, J 55), 7.32 (1H, d, J 7), 7.42-7.57 (3H, m), 7.64-7.76 (3H, m), 7.84 (1H, dd, J 8 and 1), 8.13 (1H, d, J 1), 8.79 (1H, dd, J 7 and 2); m/z (ES+) 365 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].Cl.[NH2:15][CH:16]([P:21]([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[C:17]([O:19][CH3:20])=[O:18].CN1CCOCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:26]([O:25][P:21]([O:22][CH2:23][CH3:24])[CH:16]([NH:15][C:5](=[O:6])[C:4]1[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[CH:9][C:8]=1[O:12][CH3:13])[C:17]([O:19][CH3:20])=[O:18])[CH3:27]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: CCOP(OCC)C(N)C(=O)OC
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOP(OCC)C(NC(=O)c1c(OC)cccc1OC)C(=O)OC
Reaction time: 8 h

Procedure:
2,6-Dimethoxybenzoyl chloride (1.28 g, 6.42 mmol) was added to a mixture of methyl 2-amino-2-(diethoxyphosphino)acetate hydrochloride [1.5 g, 6.11 mmol, prepared by the method of Y. Nasukawa, et al, J. Org. Chem, (1992) 57, 5453] and NMM (1.5 ml, 13.44 mmol) in CH2Cl2 (30 ml). The mixture was stirred overnight at room temperatue then poured into 10% citric acid. The mixture was extracted with CH2Cl2 (×2) and the combined organic extracts washed with sodium hydrogen carbonate solution (×2) and brine, dried (MgSO4) and evaporated in vacuo to give a brown solid (1.62 g). δH (DMSO-d6) 8.82 (1H, dd, J 9.1, 2.5 Hz), 7.29 (1H, t, J 8.4 Hz), 6.65 (2H, d, J 8.4 Hz), 5.20 (1H, dd, J 20.0, 9.2 Hz), 4.15-4.03 (4H, m), 3.72 (3H, s), 3.71 (6H, s), 1.39-1.20 (6H, m); m/z (ESI) 390 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][N:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[C:31]([OH:32])=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[C:26]([CH3:33])[NH:27]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:32][C:31]3[C:23]([F:22])=[C:24]4[C:28](=[CH:29][CH:30]=3)[NH:27][C:26]([CH3:33])=[CH:25]4)=[CH:14][N:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)cnnc2cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCc1ccccc1
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 38.5 %

Procedure:
A mixture of 7-benzyloxy-4-chloro-6-methoxy cinnoline (2 g, 6.66 mmol), (prepared as described for the starting material in Example 1), 4-fluoro-5-hydroxy-2-methylindole (1.32 g, 7.99 mmol), (prepared as described for the starting material in Example 1), and cesium carbonate (3.2 g, 9.98 mmol) in DMF (40 ml) was heated at 95° C. for 1.5 hours. 4-Fluoro-5-hydroxy-2-methylindole (82 mg, 0.5 mmol) and cesium carbonate (3.2 g, 9.98 mmol) were added. The mixture was stirred for 1.5 hours at 115° C. The mixture was cooled, the solid was filtered and the filtrate was evaporated under vacuum. The residue was purified by column chromatography, eluting with methylene chloride/ethyl acetate (90/10 followed by 80/20) followed by methylene chloride/ethyl acetate/methanol (80/18/2). The fractions containing the expected product were combined and evaporated and the residue was triturated with ether/pentane (1/1). The solid was filtered, washed with pentane and dried under vacuum to give 7-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline (1.1 g, 39%).
Reaction SMILES: [K+].[C:2]1(=[O:17])[N:6]([CH2:7][S:8]([O-])(=[O:10])=[O:9])[C:5](=[O:12])[C:4]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:3]12.P(Cl)(Cl)(Cl)(Cl)[Cl:19]>C1C=CC=CC=1>[C:2]1(=[O:17])[N:6]([CH2:7][S:8]([Cl:19])(=[O:10])=[O:9])[C:5](=[O:12])[C:4]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:3]12
Reactant: O=C1c2ccccc2C(=O)N1CS(=O)(=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [K+]
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1CS(=O)(=O)Cl
Reaction time: 1.5 h

Procedure:
To 41.7 g. (0.15 mol.) of phthalimidomethanesulfonic acid potassium salt in 220 ml. of dry benzene is added 22.5 g. (0.132 mol.) of phosphorus pentachloride. The reaction mixture is refluxed on a steam bath for 1 hour, then an additional 22.5 g. of phosphorus pentachloride is added and heating is continued for 1.5 hours. The reaction mixture is evaporated to dryness, crushed ice is added to the residue and the slurry is filtered. The product is washed with water to give phthalimidomethanesulfonyl chloride.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[CH2:23]([N:15]1[CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH:10]1[CH2:9][OH:8])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNC(CO)C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(CO)C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Triethylamine (0.58 mL, 4.2 mmol) was added to a mixture of racemic tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (0.60 g, 2.8 mmol, racemic, AstaTech) and benzyl bromide (0.36 mL, 3.0 mmol) in acetonitrile (5.0 mL). The mixture was heated to 80° C. in an oil bath for 4 h, then allowed to cool and stir at ambient temperature overnight. Solvent was removed in vacuo and the residue was dissolved in methylene chloride. The solution was washed with 0.1N NaOH, dried over sodium sulfate and concentrated. Flash chromatography, using a 40 g silica gel cartridge and eluting with a gradient from 0-60% EtOAc in hexanes afforded product as a viscous oil (630 mg, 71%). 1H NMR (300 MHz, CDCl3): δ 7.37-7.22 (m, 5H), 4.02 (d, 1H), 3.87 (dd, 1H), 3.69 (dd, 1H), 3.63-3.50 (m, 2H), 3.41 (d, 1H), 3.41-3.27 (br m, 1H), 3.22-3.06 (br m, 1H), 2.84-2.71 (br m, 1H), 2.64-2.50 (br m, 1H), 2.27 (ddd, 1H), 1.45 (s, 9H); LCMS (M+H)+: 307.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[NH:20])[NH:13][O:14][C:15](OCC)=[O:16])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[NH:20][C:15](=[O:16])[O:14][N:13]=2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)ONC(=N)c1ccc(CC(C(=O)OC)c2cccc(C(F)(F)F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(-c2noc(=O)[nH]2)cc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.5 %

Procedure:
A mixture of 3-[4-(N-ethoxycarbonyloxycarbamimidoyl)-phenyl]-2-(3-trifluoromethyl-phenyl)-propionic acid methyl ester (30 mg, 68 μmol), sodium carbonate (2.0 g), dimethylformamide (10 ml), and water (10 ml) was stirred at room temperature for 2 days. The reaction mixture was evaporated, and the residue solved in potassium hydrogen sulfate solution and ethyl acetate. The organic layer was evaporated and gave after lyophilization 22 mg of the desired product (85% yield). MS m/z: 379.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[CH2:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][CH:34]=[N:35][CH:36]=2)[CH:26]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:22](=[O:21])[CH2:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[N:35][CH:34]=[N:33][CH:32]=2)[CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cncnc2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1NC(=O)CC(=O)c1cccc(-c2cncnc2)c1

Procedure:
The title compound was prepared from (2-amino-4-chloro-phenyl)-carbamic acid tert-butyl ester (Example J4) (243 mg, 1.0 mmol) and 3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionic acid tert-butyl ester (Example K13) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown solid (350 mg, 75%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@:4]([C:7]1[N:8]=[CH:9][C:10]2[N:11]([S:20]([CH3:23])(=[O:22])=[O:21])[C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH3:6])[NH2:5].[CH:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH:26]1[O:35][C:36](Cl)=[O:37])[CH2:32]2.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[C@:4]([C:7]1[N:8]=[CH:9][C:10]2[N:11]([S:20]([CH3:23])(=[O:22])=[O:21])[C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH3:6])[NH:5][C:36]([O:35][CH:26]1[CH:25]2[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]1[CH2:28]3)[CH2:32]2)=[O:37]
Reactant: COC(=O)[C@](C)(N)c1cc2c3ccccc3n(S(C)(=O)=O)c2cn1
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@](C)(NC(=O)OC1C2CC3CC(C2)CC1C3)c1cc2c3ccccc3n(S(C)(=O)=O)c2cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-[9-(methylsulfonyl)-β-carbolin-3-yl]-alanine methylester (0.5 g, 1.4 mmol) in THF (10 mL) was added 2-adamantyloxycarbonyl chloride (345 rag, 1.7 mmol) and the solution was treated with diisopropyl ethylamine (219 mg, 1.7 mmol) in THF (5 mL). The reaction mixture was stirred for 4 hours at room temperature, evaporated in vacuum and partitioned between ethyl acetate (100 mL) and water (50 mL). The organic layer was separated,washed successively with 7.5% citric acid solution (50 mL), 8% NaHCO3 solution (50 mL) and then dried over Na2SO4. The solvent was evaporated in vacuum and N-(2-adamantyloxy-carbonyl)-2-[9-(methylsulfonyl)-β-carbolin-3-yl]-alanine methylester was isolated as a yellow oil which solidified upon drying(0.73 g, 97.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:15][CH:16]([CH2:20][Cl:21])[C:17](Cl)=[O:18]>C(Cl)(Cl)Cl>[Cl:15][CH:16]([CH2:20][Cl:21])[C:17]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:18]
Reactant: O=C(Cl)C(Cl)CCl
Reactant: Nc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)cc1)C(Cl)CCl
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
To a stirred solution of 12.8 grams (0.10 mole) of 4-chloroaniline in 85 ml of chloroform was added 8 ml of pyridine. The mixture was cooled to 10° and 16.1 grams (0.10 mole) of 2,3-dichloropropionyl chloride was added dropwise at such a rate that the reaction mixture temperature did not exceed 35°. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to a solid residue. The solid was slurried with water and collected by filtration. The dried solid was recrystallized from methylcyclohexane-ethyl acetate using silica gel as a decolorant to give 19.7 grams of 2,3-dichloro-N-(4-chlorophenyl)propanamide; mp 127.5°-129°.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH2:13])=O)[CH:9]=2)[N:4]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:3]=1.COC(OC)[N:23]([CH3:25])C.C(O)(=O)C.[NH2:32]N>O>[NH:23]1[CH:25]=[N:32][C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:3]=[C:2]3[Br:1])=[N:13]1
Reactant: NN
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1ccc2c(c1)c(Br)nn2C1CCCCO1
Solvent: CC(=O)O
Solvent: O
Product: Brc1nn(C2CCCCO2)c2ccc(-c3nc[nH]n3)cc12
Temperature: 80 °C
Yield: 93 %

Procedure:
The title compound was prepared by reacting 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (15.13 g, 46.67 mmol) with N,N-dimethylformamide dimethyl acetal (134 mL) and heating to 80° C. for 3 hours. The reaction was allowed to cool to room temperature, and condensed to a brown oil that was exposed to atmospheric conditions minimally. To the crude oil was added glacial acetic acid (220 mL) and hydrazine (23 mL), and then the mixture was heated to 115° C. for 1.5 hours. The reaction was allowed to cool to room temperature, and subsequently added to water (500 mL) resulting in the formation of a white precipitate which was filtered and dried in a vacuum oven (15.05 g, 93% yield): ES-MS (m/z) 350 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH3:15])[N:7]=[C:6]2OC1C=CC([N+]([O-])=O)=CC=1.[CH:26]([O-:28])=O.[NH4+:29]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8]([CH3:15])([O:28][C:26]1[CH:5]=[CH:4][C:3]([NH2:29])=[CH:12][CH:11]=1)[N:7]=[CH:6]2
Reactant: COc1cc2nc(C)nc(Oc3ccc([N+](=O)[O-])cc3)c2cc1OC
Reactant: [NH4+]
Reactant: O=C[O-]
Solvent: CCO
Product: COc1cc2c(cc1OC)NC(C)(Oc1ccc(N)cc1)N=C2
Temperature: 70 °C
Reaction time: 3 h
Yield: 2499 %

Procedure:
A mixture of 6,7-dimethoxy-2-methyl-4-(4-nitro-phenoxy)quinazoline (0.081 g, 0.236 mmole), Pt/S (0.008 g, 15 mol %), ammonium formate (0.098 g, 1.56 mmol) and EtOH (3 mL) was heated with stirring at 70° C. for 3 hours. The reaction mixture was then filtered while hot and washed with hot EtOH. The crude product of 4-(6,7-dimethoxy-2-methyl-quinazolinyloxy)-phenylamine (0.924 g) was obtained as a yellow solid, which was used in the next reaction without further purification. LC/MS: m/z 312 (M+H).