Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:15]O>>[CH3:15][O:7][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][CH:2]([OH:1])[CH3:9]
Reactant: CC(O)CCCC(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCC(C)O
Yield: 78 %

Procedure:
5-Hydroxy hexanoic acid 3 (1 g, 7.69 mmoles) is dissolved in 30 mL of methanol, mixed with a catalytic amount of sulfuric acid and heated until the reaction is completed. Subsequently, the solvent is removed under vacuum and the residue distilled under the vacuum of an oil pump. 870 mg (6.00 mmoles) of methyl-5-hydroxyhexanoate 4 is obtained which represents a yield of 78%.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][N:13]([CH3:20])[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:7][C:6]1[CH:8]=[C:2]([N:17]2[CH2:18][CH2:19][CH:14]([N:13]([CH3:20])[CH3:12])[CH2:15][CH2:16]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CN(C)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 140 °C
Reaction time: 5 h
Yield: 87.3 %

Procedure:
To 5-chloro-2-nitroaniline (16.9 mmol) in DMF (56 mL) was added 4-(dimethylamino)piperidine (18.5 mmol) and K2CO3 (18.5 mmol). The reaction was stirred at 140° C. overnight after which another further 9.2 mmol of the amine was added. Stirring at 140° C. was continued for a further 5 hours. The mixture was allowed to cool and then the precipitate was collected by filtration. The precipitate was washed with EtOAc and then the combined filtrates were evaporated to dryness. The residue suspended in water and the resulting precipitate collected by filtration. The product was washed with water and then dried to give a [1-(3-amino-4-nitro-phenyl)-piperidin-4-yl]-dimethyl-amine as a brown/orange solid (3.9 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[C:14]([O:47][CH3:48])=[CH:15][C:16]2[CH2:22][CH2:21][CH2:20][C:19]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]4[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([O:42][CH3:43])[CH:33]=4)[CH2:27][CH:26]3[CH2:44]O)=[O:24])=[CH:18][C:17]=2[CH:46]=1.[CH2:49]([N:51](CC)[CH2:52]C)C>C(Cl)Cl>[CH3:11][O:12][C:13]1[C:14]([O:47][CH3:48])=[CH:15][C:16]2[CH2:22][CH2:21][CH2:20][C:19]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]4[CH:33]=[C:34]([O:42][CH3:43])[C:35]([O:40][CH3:41])=[C:36]([O:38][CH3:39])[CH:37]=4)[CH2:27][CH:26]3[CH2:44][N:51]([CH3:52])[CH3:49])=[O:24])=[CH:18][C:17]=2[CH:46]=1
Reactant: CCN(CC)CC
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1CO)=C2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1CN(C)C)=C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
To a solution of oxalyl chloride (175 mg) in methylene chloride (1 ml) is added dropwise at -78° C. a solution of dimethyl sulfoxide (215 mg) in methylene chloride (1 ml), and the mixture is stirred for 10 minutes. To the reaction mixture is added a solution of 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzyl)piperazine-2-methanol (500 mg) in methylene chloride (2 ml), and the mixture is stirred for 10 minutes. To the reaction mixture is added triethylamine (650 mg), then the reaction temperature is raised up to room temperature. To the reaction mixture is then added water, followed by extraction with methylene chloride. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is dissolved in methanol (5 ml). To the mixture are added dimethylamine hydrochloride (200 mg) and sodium cyanoborohydride (130 mg). The reaction mixture is stirred for 48 hours at room temperature and then poured into a 1N NaOH solution, followed by extraction with methylene chloride. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is purified by means of a silica gel column chromatography (eluent:methanol ethyl acetate=15:85) to give 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -2-dimethylaminomethyl-4-(3,4,5-trimethoxybenzyl) piperazine (200 mg). This product is converted to its hydrochloride, followed by recrystallization from ethanol to give colorless prisms, m.p. 167-169° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=O)[C:16]3[C:11](=[CH:12][C:13]([OH:20])=[C:14]([Cl:19])[CH:15]=3)[O:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:21]([CH2:23][CH2:24][OH:25])[NH2:22]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:16]3[CH:15]=[C:14]([Cl:19])[C:13]([OH:20])=[CH:12][C:11]=3[OH:10])=[N:22][N:21]([CH2:23][CH2:24][OH:25])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NNCCO
Reactant: O=c1c(-c2ccc(Br)cc2)coc2cc(O)c(Cl)cc12
Solvent: CCO
Product: OCCn1cc(-c2ccc(Br)cc2)c(-c2cc(Cl)c(O)cc2O)n1

Procedure:
3-(4-Bromo-phenyl)-6-chloro-7-hydroxy-chromen-4-one (0.1 g, 0.28 mmol), and 2-Hydrazino-ethanol (0.04 g) were suspended in ethanol (10 ml) and refluxed for 1 hr. 4-[4-(4-Bromo-phenyl)-1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-6-chloro-benzene-1,3-diol precipitated out on quenching as a white solid (0.09 g, 78.8%).
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:22][C:23]2([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[C:9]#[C:10][CH3:11].C(N(CC)CC)C>C(Cl)Cl>[CH2:32]([O:31][C:29]([C:23]1([CH2:22][S:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:8][C:9]#[C:10][CH3:11])=[CH:18][CH:17]=2)(=[O:21])=[O:20])[CH2:24][CH2:25][N:26]([C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:27][CH2:28]1)=[O:30])[CH3:33]
Reactant: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCNCC2)cc1
Reactant: CC(C)(C)N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCN(C(=O)NC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
To a solution of tert-butylisocyanate (0.097 ml, 0.85 mmol) in 8.0 mL of CH2Cl2, was added 4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-4-piperidinecarboxylic acid ethyl ester (prepared from example 36, step 2) (0.337 g, 0.81 mmol) and triethylamine (0.135 ml, 0.97 mmol) and stirred at room temperature for 2 h. The reaction was diluted with CH2Cl2 and washed with H2O, brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with ether:hexanes (1:1) to provide 0.284 g (73%) of the desired product as a white solid. Electrospray Mass Spec: 479.2 (M+H)+.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C1(NC(C)(C)C)C=CC=CC=1.NC(N)=O.C(NN[CH2:27][C:28]([C:30]1[CH:31]=[CH:32][C:33]([OH:39])=[C:34]([CH2:36][C:37]#[N:38])[CH:35]=1)=[O:29])(C)(C)C>>[OH:39][C:33]1[CH:32]=[CH:31][C:30]([CH:28]([OH:29])[CH2:27][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:35][C:34]=1[CH2:36][C:37]#[N:38]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)NNCC(=O)c1ccc(O)c(CC#N)c1
Agent: CC(C)(C)Nc1ccccc1
Agent: NC(N)=O
Product: CC(C)(C)NCC(O)c1ccc(O)c(CC#N)c1

Procedure:
The procedure of Example 1(c) is repeated with substitution of an equimolar amount of t-butylamine for phenyl-t-butylamine in that example. The resulting aminoketone, 5-[N-(t-butylamino)glycyl]-2-hydroxyphenylacetonitrile is reduced according to the procedure of Example 1(d) to yield 2-hydroxy-5-[1-hydroxy-2-(t-butylamino)ethyl]-benzeneacetonitrile.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:6]=1[CH2:7][C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[CH3:30]O>>[Cl:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:6]=1[CH2:7][C:8]([O:10][CH3:30])=[O:9]
Reactant: Cc1ccc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1c(Cl)nc(-c2ccccc2)n1Cc1ccc(C)cc1
Reaction time: 2 h

Procedure:
In 100 ml of methanol was dissolved 1.8 g of 4-chloro-1-(4-methylbenzyl)-2-phenylimidazole-5-acetic acid, and 0.5 ml of concentrated sulfuric acid was added to the solution to boil for 2 hours. The reaction solution was evaporated to dryness under reduced pressure, and 50 ml each of ethyl acetate and a 10% aqueous sodium bicarbonate solution were added to the residue to shake. The ethyl acetate layer, after washing with water, was evaporated to dryness under reduced pressure. The residue was dissolved in a small amount of methanol and there was obtained, upon standing, 1.5 g of methyl 4-chloro-1-(4-methylbenzyl)-2-phenylimidazole-5-acetate as colorless, prism-formed crystals, m.p. 92°-95° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([C:9]2[N:13](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:12]=[N:11][CH:10]=2)O)=[CH:3][CH:2]=1.[CH3:33][CH:34](O)[CH3:35].[OH-].[Na+]>I.C(Cl)(Cl)Cl>[NH:13]1[C:9]([CH:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH2:33][C:34]2[CH:35]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:10][N:11]=[CH:12]1
Reactant: CC(C)O
Reactant: OC(c1ccncc1)c1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: c1ccc(CC(c2ccncc2)c2cnc[nH]2)cc1
Temperature: 160 °C

Procedure:
A mixture of pyridin-4-yl(1-trityl-1H-imidazol-5-yl)methanol, (Intermediate 4) (526 g, 1.03 mmol) in 57% aqueous HI (10 mL) and iPrOH (2 mL) was added red phosphorus (318 mg, 10.3 mmol) in a resealable tube was heated at 160° C. for 16 h. The mixture was then cooled to room temperature and poured into ice-water, which was then basified with NaOH and diluted with CHCl3. The residue was isolated in a typical aqueous workup using CHCl3 and purified by MPLC with 5 to 15% MeOH: CH2Cl2 to give 4-(1-(1H-imidazol-5-yl)-2-phenylethyl)pyridine (AGN214418) as a solid, 36 mg. 1HNMR (CD3OD, 300 MHz) δ 6.98 (s, 1H), 7.20-7.11, (m, 9H), 7.61 (s, 1H), 4.38 (t, J=9 Hz, 1H), 3.43 (dd, J=6 Hz, 12 Hz, 1H), 3.19 (dd, J=9 Hz, 15 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([OH:21])=O)=[CH:4][C:3]=1[C:22]1[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=1.CN(C(O[N:36]1N=[N:43][C:38]2C=CC=C[C:37]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC(N(C)C)=O.Cl.NCC#N>O1CCOCC1>[C:37]([CH2:38][NH:43][C:19]([C:5]1[C:6](=[O:18])[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=2)[C:2]([CH3:1])=[C:3]([C:22]2[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=2)[CH:4]=1)=[O:21])#[N:36]
Reactant: Cc1c(-c2ccnn2C)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: Cc1c(-c2ccnn2C)cc(C(=O)NCC#N)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
The compound obtained in step (a) (0.2 g, 0.53 mmol) was dissolved in 1,4-dioxane (5 ml), HBTU (0.19 g, 0.5 mmol) and DMA (0.32 g, 2.5 mmol). The mixture was stirred for 10 minutes and aminoacetonitrile hydrochloride (0.55 g, 0.6 mmol) was added. After 1 h the mixture was evaporated and the residue purified by chromatography on silica to give the amide (0.15 g, 72%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([Cl:20])=[CH:14][C:13]=2[F:21])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].S(=O)(=O)(O)O.[N+:27]([O-])([OH:29])=[O:28]>>[Cl:1][C:2]1[C:3]([C:12]2[C:13]([F:21])=[CH:14][C:15]([Cl:20])=[C:16]([O:18][CH3:19])[C:17]=2[N+:27]([O-:29])=[O:28])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: COc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1c(Cl)cc(F)c(-c2nn(C)c(C(F)(F)F)c2Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Chloro-3-(4-chloro-2-fluoro-5-methoxyphenyl)-1-methyl-5-trifluoromethyl-1H-pyrazole (1.2 g, 3.5 mmol) was slurried with 4 ml of con. sulfuric acid and was slowly added to a stirred 4 ml mixture of con. sulfuric acid-con. nitric acid (9:1) at −15° C. Solution was allowed to stir at ambient temperature for 2 hr and then added to ice water. Extraction with ethyl acetate and removal of the solvent afforded a crude product which was chromatographed on silica gel. Elution of the column with hexane-methylene chloride (4:6) furnished the title compound (0.72 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:22]=1[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[O:26])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:22]=1[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C=Cc1ccc(OC)cc1CN(Cc1ccc(C(F)(F)F)cc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(OC)cc1CN(Cc1ccc(C(F)(F)F)cc1)C(=O)OC(C)(C)C
Reaction time: 7 h
Yield: 98.5 %

Procedure:
To 10% Pd/C (5 g, 4.7 mmol, prewetted with DMF) was added a solution of methyl 2-[N-(tert-butoxycarbonyl)-N-(4-trifluoromethylbenzyl)aminomethyl]-4-methoxycinnamate (34.52 g, 72 mmol) in methanol (100 mL). The mixture was shaken under hydrogen (50 psi) in a Parr apparatus for 7 hr, then was filtered through a pad of celite® to remove the catalyst. The filtrate was concentrated to afford the title compound (34.15 g, 98%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=8.1 Hz, 2H), 7.31 (br s, 2H), 7.09 (d, J=8.4 Hz, 1H), 6.76 (dd, 1H), 6.66 (s, 1H), 4.47 (br s, 2H), 4.40 (br s, 2H), 3.76 (s, 3H), 3.63 (s, 3H), 2.79 (br s, 2H), 2.47 (t, 2H), 1.48 (s, 9H.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[F:36][C:37]1[CH:38]=[C:39]([C:43]2[NH:44][C:45](=[O:53])[C:46]3[CH:52]=[CH:51][CH:50]=[N:49][C:47]=3[N:48]=2)[CH:40]=[CH:41][CH:42]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:51]4[CH:50]=[N:49][C:47]5[N:48]=[C:43]([C:39]6[CH:40]=[CH:41][CH:42]=[C:37]([F:36])[CH:38]=6)[NH:44][C:45](=[O:53])[C:46]=5[CH:52]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=c1[nH]c(-c2cccc(F)c2)nc2ncccc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cnc4nc(-c5cccc(F)c5)[nH]c(=O)c4c3)cc12
Temperature: 80 °C
Reaction time: 5 h
Yield: 13.5 %

Procedure:
To a mixture of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (90 mg, 0.18 mmol), 2-(3-fluorophenyl)pyrido[2,3-d]pyrimidin-4(3H)-one (63 mg, 0.19 mmol) and K3PO4.3H2O (143 mg, 0.54 mmol) in 1,4-dioxane/H2O (3 mL/0.3 mL), Pd2(dba)3 and X-Phos (10 mg/10 mg) were added under N2 protection. After being stirred at 80° C. for 5 h, the reaction mixture was concentrated in vacuo, suspended in water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC give the product of 2-(4-fluorophenyl)-5-(2-(3-fluorophenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (15 mg, yield: 13%). 1H-NMR (DMSO-d6, 400 MHz) δ 12.97 (br s, 1H), 9.03 (d, J=2.4 Hz, 1H), 8.50˜8.60 (m, 2H), 8.16 (s, 1H), 8.12 (d, J=7.6 Hz, 1H), 8.00˜8.09 (m, 3H), 7.79 (s, 1H), 7.65 (dd, J=14.0, 8.0 Hz, 1H), 7.46˜7.52 (m, 1H), 7.43 (t, J=8.8 Hz, 2H), 3.26 (s, 3H), 3.02 (s, 3H), 2.85 (d, J=4.8 Hz, 3H). MS (M+H)+: 616.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[O:13]1[C:17]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].C(#N)C>O.CCOCC>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([N:20]2[CH2:21][CH2:22][C:17]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:18][CH2:19]2)=[CH:3][CH:4]=1)[CH3:10]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 30.5 %

Procedure:
A mixture of 50 g (0.349 mol) of ethyl p-fluorobenzoate, 185 g (1.29 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, 73 g (0.5282 mol) of K2CO3, and 400 ml of acetonitrile is stirred at 90°-100° C. for three days. The reaction mixture is allowed to cool to ambient temperature, diluted with water, and extracted with methylene chloride. The combined organic extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo to give a pasty solid. Trituration with ether furnishes 31 g (23%) of title compound: IR (KBr) 1695 and 1610 cm-1 ; NMR (CDCl3) δ 7.98 (d, 2H), 6.96 (m, 2H), 4.36 (q, 2H), 4.02 (s, 4H), 3.58-3.48 (m, 4H), 1.92-1.80 (m, 4H), and 1.38 (t, 3H).
Reaction SMILES: [ClH:1].C(O[C:7]([N:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([F:23])=[C:18]([F:22])[C:19]=2[F:21])[C:14](=[O:24])[C:13]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:12]1)C)=O)(C)(C)C.C(OC(C)C)(C)C>C(OCC)(=O)C>[ClH:1].[F:23][C:17]1[CH:16]=[C:15]2[C:20](=[C:19]([F:21])[C:18]=1[F:22])[N:11]([NH:9][CH3:7])[CH:12]=[C:13]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:14]2=[O:24]
Reactant: CCOC(=O)c1cn(N(C)C(=O)OC(C)(C)C)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: CCOC(=O)c1cn(NC)c2c(F)c(F)c(F)cc2c1=O
Reaction time: 2 h

Procedure:
To 4N hydrochloric acid solution (46 ml) in ethyl acetate was added ethyl 1-(N-tert-butoxycarbonyl-N-methylamino)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (9.20 g) under ice-cooling and the mixture was stirred at the same condition for 2 hours. Diisopropyl ether (90 ml) was added to the mixture to give a solid. The solid was collected by filtration, and dried over phosphorus pentaoxide under reduced pressure to give ethyl 6,7,8-trifluoro-1-methylamino-1,4-dihydro -4-oxoquinoline-3-carboxylate hydrochloride(6.26 g).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[C:10](=[O:26])[N:11]([CH2:14][C:15]3[N:24]=[C:23]([CH3:25])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[N:12]=[CH:13][C:8]=2[N:7]=[C:6]1[N:27]1[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33]C(=O)OC(C)(C)C)[CH2:28]1)[C:2]#[C:3][CH3:4].FC(F)(F)C(O)=O>ClCCl>[NH2:33][C@@H:29]1[CH2:30][CH2:31][CH2:32][N:27]([C:6]2[N:5]([CH2:1][C:2]#[C:3][CH3:4])[C:9]3[C:10](=[O:26])[N:11]([CH2:14][C:15]4[N:24]=[C:23]([CH3:25])[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[N:16]=4)[N:12]=[CH:13][C:8]=3[N:7]=2)[CH2:28]1
Reactant: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2cnn(Cc3nc(C)c4ccccc4n3)c(=O)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCn1c(N2CCC[C@@H](N)C2)nc2cnn(Cc3nc(C)c4ccccc4n3)c(=O)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 17.2 g (31.7 mmol) tert-butyl (R)-{1-[1-(but-2-ynyl)-6-(4-methyl-quinazolin-2-ylmethyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]-piperidin-3-yl}-carbamate in 400 ml dichloromethane was combined with 85 ml trifluoroacetic acid and stirred for three hours at ambient temperature. The mixture was evaporated to dryness at 30° C., the residue was dissolved in dichloromethane and the solution was made basic with ice-cooled saturated sodium carbonate solution. The organic phase was separated off and the aqueous phase was extracted twice more with dichloromethane. The combined organic phases were dried over sodium sulphate and the solvent was removed. The residue was purified by chromatography on silica gel (dichloromethane/methanol/ammonium hydroxide 95:5:0.1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([NH2:17])=[CH:11][CH:12]=[C:13]([O:15][CH3:16])[CH:14]=2)=[CH:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=O)[CH:19]=1>>[CH3:16][O:15][C:13]1[CH:12]=[CH:11][C:10]2[N:17]=[C:24]([C:20]3[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=3)[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:9]=2[CH:14]=1
Reactant: COc1ccc(N)c(Nc2ccc(F)cc2)c1
Reactant: O=Cc1cccnc1
Product: COc1ccc2nc(-c3cccnc3)n(-c3ccc(F)cc3)c2c1

Procedure:
N2-(4-Fluorophenyl)-4-methoxybenzene-1,2-diamine was reacted analogously to Example 11d with pyridine-3-carbaldehyde.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.Br[CH2:31][CH:32]([OH:37])[C:33]([F:36])([F:35])[F:34].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH2:31][CH:32]([OH:37])[C:33]([F:36])([F:35])[F:34])[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: OC(CBr)C(F)(F)F
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O)C(F)(F)F)c2nc(C)nn12
Temperature: 100 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
A mixture of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.91 g), 3-bromo-1,1,1-trifluoropropan-2-ol (1.2 mL), cesium carbonate (3.8 g) and N,N-dimethylacetamide (20 mL) was stirred at 100° C. for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.76 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=2)=[N:10]1.C1C(=O)N([Br:37])C(=O)C1>>[Br:37][CH2:20][C:13]1[NH:12][C:11]([C:21]2[S:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=2)=[N:10][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(C)NC(c2nc(C(F)(F)F)cs2)=NC1c1ccc(Cl)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1=C(CBr)NC(c2nc(C(F)(F)F)cs2)=NC1c1ccc(Cl)cc1Cl
Yield: 70.5 %

Procedure:
Ethyl 4-(2,4-dichlorophenyl)-6-methyl-2-(4-(trifluoromethyl)thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.44 g, 0.94 mmol) was reacted with NBS (0.21 g, 0.94 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.36 g, 70%). The compound was characterized by the following spectroscopic data: