Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:18]([OH:21])([CH3:20])[CH3:19])[CH2:4][CH2:3]1.[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][C@H:27]([CH:32]=O)[CH2:26]2>>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][C@H:27]([CH2:32][NH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=4[N:10]=[C:9]3[C:18]([OH:21])([CH3:19])[CH3:20])[CH2:6][CH2:7]1)[CH2:26]2
Reactant: CC(C)(O)c1nc2cc(Cl)ccc2n1[C@H]1CC[C@@H](N)CC1
Reactant: O=C[C@H]1Cc2ccc(Br)cc2C1
Product: CC(C)(O)c1nc2cc(Cl)ccc2n1[C@H]1CC[C@@H](NC[C@H]2Cc3ccc(Br)cc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of cis-2-[1-(4-amino-cyclohexyl)-5-chloro-1H-benzoimidazol-2-yl]-propan-2-ol and (S)-5-bromo-indan-2-carbaldehyde. LC-MS showed a single peak, C26H31BrClN3O (m/e) calcd 515.1339, obsd 516.1 (M+H). 1H-NMR (CD3OD) □ 7.96 (d, 1H), 7.59 (s, 1H), 7.36 (s, 1H), 7.26 (d, 1H), 7.18 (d, 1H), 7.12 (d, 1H), 5.38 (m, 1H), 3.16 (m, 2H), 3.03 (br s, 1H), 2.67-2.83 (m, 7H), 2.07 (m, 2H), 1.72 (br s, 10H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]N)=[CH:6][CH:5]=1.[F:12][C:13]1[CH:35]=[CH:34][C:16]([CH2:17][NH:18][C:19]([C:21]2[N:22]=[C:23]3[C:31]([C:32]#[N:33])=[CH:30][NH:29][N:24]3[C:25](=[O:28])[C:26]=2[OH:27])=[O:20])=[CH:15][CH:14]=1.FC1C=CC(CCl)=CC=1>CN(C=O)C>[F:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][NH:18][C:19]([C:21]2[N:22]=[C:23]3[C:31]([C:32]#[N:33])=[CH:30][N:29]([CH2:8][C:7]4[CH:10]=[CH:11][C:4]([F:3])=[CH:5][CH:6]=4)[N:24]3[C:25](=[O:28])[C:26]=2[OH:27])=[O:20])=[CH:34][CH:35]=1
Reactant: NCc1ccc(F)cc1
Reactant: N#Cc1c[nH]n2c(=O)c(O)c(C(=O)NCc3ccc(F)cc3)nc12
Agent: Fc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cn(Cc2ccc(F)cc2)n2c(=O)c(O)c(C(=O)NCc3ccc(F)cc3)nc12
Temperature: 90 °C
Yield: 37.5 %

Procedure:
Sodium hydride (11.0 mg, 0.367 mmol) was added in one portion to a stirred suspension of 3-Cyano-6-hydroxy-7-oxo-1,7-dihydro-pyrazolo[1,5-a]pyrimidine-5-carboxylic acid 4-fluoro-benzylamide compound with 4-fluorobenzylamine (Example 3.1) (100 mg, 0.306 mmol) in DMF (2 mL) under nitrogen at room temperature. The mixture was stirred for 30 min before p-fluorobenzyl chloride (40 μL, 0.366 mmol) was added and the mixture heated at 90° C. for 2 days. After this time, the reaction was cooled to room temperature and partitioned between ethyl acetate (10 mL) and aqueous hydrochloric acid (1M, 10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organics were washed with water (3×10 mL), brine (10 mL) and then concentrated. The residue was purified by column chromatography (95:5:1 dichloromethane:methanol:aqueous ammonia) to afford the desired product (50 mg, 36%).
Reaction SMILES: [C:1]([O:5][P:6]([O:13][CH2:14][C:15]([NH:18]C(=O)OCC1C=CC=CC=1)([CH3:17])[CH3:16])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[H][H]>[OH-].[OH-].[Pd+2].CO>[P:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:13][CH2:14][C:15]([NH2:18])([CH3:17])[CH3:16])=[O:7]
Reactant: CC(C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(N)COP(=O)(OC(C)(C)C)OC(C)(C)C
Yield: 94.8 %

Procedure:
The product of Example 95B (0.40 g, 0.96 mmol) and 20% palladium hydroxide on carbon (0.21 g) in a ethyl acetate (10 mL) and methanol (1 mL) was stirred under a an atmosphere of hydrogen for 0.5 hours. The reaction was filtered through a bed of celite and concentrate to give the title product (0.256 g).
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[CH2:35]([C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][N:19]([C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)[C:45](=[O:46])[C:44]3[CH:48]=[CH:49][C:41]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:42][CH:43]=3)=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCCCc1ccc(C(=O)Cl)cc1
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: Cl
Product: CCCCCCc1ccc(C(=O)N(Cc2ccc(C#Cc3ccc(CCCC)cc3)cc2)c2ccc3c(c2)C(=O)OC(C)(C)O3)cc1

Procedure:
The titled compound was prepared following the procedure K using 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one hydrochloride and 4-hexylbenzoyl chloride as a yellow oil (85%). HPLC, Rt: 6.45 min (Purity: 99.8%).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[C:5](=[O:12])[N:4]1[C:13]1[CH:22]=[N:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.[C:23]([O:28][C@@H:29]([C:31]1[N:36]=[C:35](Cl)[CH:34]=[CH:33][N:32]=1)[CH3:30])(=[O:27])[CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(O)(C)C>[C:23]([O:28][C@@H:29]([C:31]1[N:32]=[C:33]([N:8]2[CH2:9][CH2:10][C:11]3[N:3]([CH3:2])[N:4]([C:13]4[CH:22]=[N:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[C:5](=[O:12])[C:6]=3[CH2:7]2)[CH:34]=[CH:35][N:36]=1)[CH3:30])(=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Reactant: Cn1c2c(c(=O)n1-c1cnc3ccccc3n1)CNCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCCC(=O)O[C@H](C)c1nccc(N2CCc3c(c(=O)n(-c4cnc5ccccc5n4)n3C)C2)n1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a stirred solution of 1-methyl-2-quinoxalin-2-yl-1,2,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one hydrochloride (prepared according to the method of Example 75, Step C, 175 mg, 0.55 mmol) and (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 126 mg, 0.55 mmol) in isopropanol (6 mL) was added triethylamine (230 μL, 1.66 mmol). This mixture was heated to reflux overnight, cooled to room temperature, and evaporated. The residue was diluted, with saturated aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1.5% methanol/chloroform) to give 248 mg (95%) of the title compound of Example 75, Step D as a yellow oil. 1H NMR (CDCl3, 250 MHz) δ 9.70 (s, 1H), 8.29 (d, 1H), 8.15 (dd, 1H), 8.03 (m, 1H), 7.82-7.70 (c, 2H), 6.48 (d, 1H) 5.72 (q, 1H), 4.36 (s, 2H), 4.35-4.15 (c, 2H), 3.42 (s, 3H), 2.77-2.82 (c, 2H), 2.43 (t, 2H), 1.79-1.60 (c, 2H), 1.61 (d, 3H), 0.99 (t, 3H); MS (APCI) 474 (MH+).
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH:19]=O)[N:15]3[CH3:18])=[C:11]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:10]=2)[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)([CH3:3])[CH3:2].[CH:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][C:35]1=[O:40])([CH3:33])[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:31]([N:34]1[CH2:39][CH2:38][N:37]([CH2:19][C:14]2[N:15]([CH3:18])[C:16]3[C:12]([N:13]=2)=[C:11]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[N:10]=[C:9]([N:8]2[C:7]4[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=4[N:5]=[C:4]2[CH:1]([CH3:2])[CH3:3])[N:17]=3)[CH2:36][C:35]1=[O:40])([CH3:33])[CH3:32]
Reactant: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CC(C)N1CCNCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)C)C(=O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
A mixture of 2-(2-isopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.15 g, 0.37 mmol), 1-isopropylpiperazin-2-one (0.078 g, 0.44 mmol) and 4 Å molecular sieves (0.372 g) in DCE (3 mL) was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.157 g, 0.74 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 10:90) to give 555 as an off-white solid (0.168 g, 84%). LCMS (Method I): RT=3.43 min, [M+H]+ 532.3. 1H NMR (400 MHz, DMSO-d6): δ 7.93-7.89 (m, 1 H); 7.68-7.63 (m, 1 H); 7.28-7.23 (m, 2 H); 4.64-4.58 (m, 1 H); 4.29-4.21 (m, 4 H); 3.97-3.90 (m, 1 H); 3.90 (d, J=4.6 Hz, 2 H); 3.80 (s, 3 H); 3.78 (t, J=4.6 Hz, 4 H); 3.21-3.15 (m, 4 H); 2.78-2.75 (m, 2 H); 1.36 (d, J=6.8 Hz, 6 H); 1.05 (d, J=6.8 Hz, 6 H)
Reaction SMILES: [CH3:1][NH:2][C@@H:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][OH:5].[CH2:13](Br)[C:14]#[CH:15]>>[CH3:1][N:2]([CH2:15][C:14]#[CH:13])[C@@H:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][OH:5]
Reactant: C#CCBr
Reactant: CN[C@H](CO)Cc1ccccc1
Product: C#CCN(C)[C@H](CO)Cc1ccccc1

Procedure:
Compound 1c is synthesized according to general procedure H from starting material 1b using 2.5 mmol of propargyl bromide (298 mg). The desired compound is obtained in 60% yield (243 mg, 1.2 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24](Br)[N:23]=2)[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.O.[CH3:36][N:37](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:36]#[N:37])[N:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N(c2ccc(F)c(Cl)c2)c2cccc(Br)n2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](N(c2ccc(F)c(Cl)c2)c2cccc(C#N)n2)C1
Temperature: 110 °C
Reaction time: 9 h

Procedure:
3(S)-[(6-bromopyridin-2-yl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 1.06 mmol), zinc cyanide (250 mg, 2.12 mmol) and tetrakis(triphenylphosphine)palladium (122 mg, 0.106 mmol) were suspended in 8 ml of dimethylformamide (DMF), followed by stirring under a nitrogen atmosphere at 110° C. for 9 hours. After cooling to room temperature, ethyl acetate and water were added to the reaction solution to separate the solution into layers. The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1→3:1). The solvent was distilled off from the purified product under reduced pressure to thereby obtain 398 mg of oily colorless 3(S)-((3-chloro-4-fluorophenyl)-(6-cyanopyridin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].C(O)(C)C>O>[C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1)(=[O:22])[CH3:21]
Reactant: Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(C)O
Product: CC(=O)Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1

Procedure:
To a 0.33 g. sample of 5-amino-2-nitro-3-phenylbenzofuran is added 1 ml. of acetic anhydride, and the mixture is heated for 5 minutes on a steam bath. About 10 ml. of isopropanol is added, and the mixture is again heated on a steam bath to dissolve the solid. It is then saturated with hot water and cooled to provide yellow needles of 5-acetamido-2-nitro-3-phenylbenzofuran, m.p. 204°-207° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([C:16]3[CH:17]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:20][CH:21]=3)=[CH2:15])[CH:5]=[CH:4][C:3]1=2.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:26][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH:14]([C:16]3[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=3)[C:22]([O:24][CH3:25])=[O:23])[CH3:15])[CH:5]=[CH:4][C:3]1=2
Reactant: C=C(c1cccc(C(=O)OC)c1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(C(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)c1

Procedure:
A solution of methyl 3-[1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)vinyl]phenylcarboxylate (1.2 g, 3.45 mmol) in ethyl acetate, in the presence of palladium-on-charcoal (0.3 g) at a pressure of 6 bar of hydrogen, is stirred at room temperature for 4 h. The mixture is filtered through Celite and then concentrated on a rotary evaporator under vacuum at 40° C.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:22])[CH2:20]O)=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)[O:22][CH:19]([C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)[CH2:20][O:4]1
Reactant: OCC(O)c1ccc(Cl)cc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Clc1ccc(C2COC(CBr)(c3ccc(Cl)cc3)O2)cc1

Procedure:
A mixture of 11.7 parts of 2-bromo-4'-chloroacetophenone, 9 parts of 1-(p-chlorophenyl)-1,2-ethanediol, 0.5 parts of p-toluenesulfonic acid and 80 parts of benzene is stirred and refluxed for 2 days with water-separator. The reaction mixture is cooled and washed successively twice with a sodium hydrogen carbonate solution and once with water. The organic phase is dried and evaporated. The residue is triturated in petroleum ether and cooled on ice. The precipitated product is filtered off, crystallized from methanol, stirred in acetonitrile while cooling on ice, filtered off again and washed once more with acetonitrile, yielding 2-(bromomethyl)-2,4-bis(p-chlorophenyl)-1,3-dioxolane.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([Na:10])[CH:9]=[CH:8][CH:7]=[CH:6]1)=[O:4].Cl[C:12]([O:14][CH3:15])=[O:13]>O1CCCC1>[CH3:15][O:14][C:12]([C:6]1[C:5]([C:3]([O:2][CH3:1])=[O:4])([Na:10])[CH:9]=[CH:8][CH:7]=1)=[O:13]
Reactant: COC(=O)C1([Na])C=CC=C1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)C1=CC=CC1([Na])C(=O)OC
Yield: 28.5 %

Procedure:
To a tetrahydrofuran solution of methoxycarbonyl cyclopentadienyl sodium (28 mmol/28 ml) preparated by the Rausch method, a tetrahydrofuran solution of methyl chloroformate (2 g/30 ml) was added under cooling with ice. When the solution reached room temperature, it was filtered and concentrated under reduced pressure. Then, methylene chloride was added thereto to precipitate slightly pink precipitates. The precipitates were collected by filtration and dried to obtain 1.23 g of dimethoxycarbonylcyclopentadienyl sodium.
Reaction SMILES: C1C=CC2[C:17](=[O:18])[C:16]3C4C(C=CN=3)=CC=NC=4C=2C=1.[Br:19][C:20]1[C:29]2[C:24]3=[C:25]([C:30]4[C:35]([C:36](=[O:37])[C:23]3=[N:22][CH:21]=1)=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:26]=[CH:27][CH:28]=2.C1C=C[NH+]=CC=1.Br[Br-]Br>C(Cl)(Cl)Cl>[CH:32]1[CH:31]=[C:30]2[C:25]3[C:24]4[C:23]([C:36](=[O:37])[C:35]2=[CH:34][CH:33]=1)=[N:22][CH:21]=[C:20]([Br:19])[C:29]=4[CH:28]=[CH:27][N:26]=3.[CH3:16][CH2:17][O:18][C:21]1[N:22]=[C:23]2[C:24]3[C:25]([C:30]4[C:35]([C:36]2=[O:37])=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:26][CH:27]=[CH:28][C:29]=3[C:20]=1[Br:19]
Reactant: O=C1c2ccccc2-c2nccc3ccnc1c23
Agent: O=C1c2ccccc2-c2nccc3c(Br)cnc1c23
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CCOc1nc2c3c(nccc3c1Br)-c1ccccc1C2=O
Yield: 1 %

Procedure:
Electrophilic Bromination of Sampangine: Preparation of 4-Bromo-7H-naphtho[1,2,3-ij] [2,7]naphthyridin-7-one [4-Bromosampangine, 5] and 4-Bromo-5-ethoxy-7H-naphtho[1,2,3-ij][2,7]naphthyridin-7-one[4-Bromo-5-ethoxysampangine, 20]. A mixture of pyridinium bromide perbromide (4.80 g, 15.0 mmol) and sampangine (2.32 g, 10.0 mmol) in CHCl3 (100 mL) was heated at reflux for 24 h. After cooling, the mixture was poured into a separatory funnel and washed with saturated aqueous NaHCO3 solution (2×250 mL). The organic layer was dried (K2CO3) and concentrated to dryness. The residual solids were subjected to flash silica gel chromatography while eluting with CHCl3 to give pure 4-bromosampangine (5) (2.00 g, 64%) and 4-bromo-5-ethoxysampangine (20) (0.05 g, 1%). An analytical sample of 20 was obtained by crystallization from CHCl3. Compound 5: mp 244°-246° C.; IR (KBr) 1670, 1590, 1400, 1320, 1310, 1275, 1230, 980, 790, 755, 720 cm-1 ; 1H NMR (CDCl3) δ 7.72 (ddd, 1H, J=7.9, 7.9, 1.4 Hz), 7.86 (ddd, 1H, J=7.9, 7.9, 1.4 Hz), 7.96 (d, 1H, J=5.9 Hz), 8.46 (dd, 1H, J=7.9, 1.4 Hz), 8.85 (dd, 1H, J=7.9, 1.4 Hz), 8.99 (d, 1H, J=5.9 Hz), 9.28 (s,1H); 13C NMR (CDCl3) 118.3 (1), 120.5 (0), 123.7 (0), 125.8 (1), 128.7 (1), 131.8 (1), 132.3 (0), 135.0 (1), 135.1 (0), 138.6 (0), 146.7 (0), 148.6 (1), 150.2 (1), 151.7 (0), 181.6 (0) ppm; Anal. (exact mass, HREIMS) calcd for C15H7BrN2O m/e 309.9741, found 309.9747; Anal. calcd for C15H7BrN2O: C 57.90, H 2.27, N 9.00; found C 57.70, H 2.27, N 9.26. Compound 20: mp 200°-201° C.; IR (KBr) 1670, 1592, 1570, 1430, 1382, 1365, 1330, 1270, 1212, 1080, 1070, 1042, 980, 845, 762, 755, 720, 710, 635 cm-1 ; 1H NMR (CDCl3) δ 1.56 (t, 3H, J=7.1 Hz), 4.79 (q, 2H, J=7.1 Hz), 7.67 (ddd, 1H, J=7.3, 7.3, 1.4 Hz), 7.79 (ddd, 1H, J=7.3, 7.3, 1.4 Hz), 7.82 (d, 1H, J=6.1 Hz), 8.36 (dd, 1H, J=7.3, 1.4 Hz), 8.72 (d, 1H, J=6.1 Hz), 8.75 (dd, 1H, J=7.3, 1.4 Hz); 13C NMR (CDCl3) 14.6 (3), 64.7 (2), 107.4 (0), 117.5 (0), 117.8 (1), 125.5 (1), 128.2 (1), 131.4 (1), 132.2 (0), 134.5 (1), 135.0 (0), 140.9 (0), 144.6 (0), 147.2 (1), 151.7 (0), 159.9 (0), 181.4 (0) ppm; Anal. calcd for C17H11BrN2O: C 57.48, H 3.12, N 7.88; found C 57.09, H 3.37, N 7.75.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.Cl[CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>>[O:19]=[S:18]1(=[O:20])[CH2:17][CH2:16][CH2:15][N:1]1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)c1ccc(N)cc1OC
Product: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)O

Procedure:
Using methyl 4-amino-2-methoxybenzoate (1.01 g) and 3-chloropropane-1-sulfonyl chloride (0.9 mL) and by the reaction and treatment in the same manner as in Preparation Example 16, the title compound (839 mg) was obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:25]([F:26])=[CH:24][N:23]=[C:22]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([N:34]4[CH2:39][CH2:38][N:37]([C:40](=[O:42])[CH3:41])[CH2:36][CH2:35]4)=[CH:30][CH:29]=3)[N:21]=2)[CH2:16][CH2:15]1>C(Cl)Cl.CN(C=O)C>[C:40]([N:37]1[CH2:38][CH2:39][N:34]([C:31]2[CH:32]=[CH:33][C:28]([NH:27][C:22]3[N:21]=[C:20]([N:17]4[CH2:16][CH2:15][CH:14]([NH:13][C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH2:19][CH2:18]4)[C:25]([F:26])=[CH:24][N:23]=3)=[CH:29][CH:30]=2)[CH2:35][CH2:36]1)(=[O:42])[CH3:41]
Reactant: N#CCC(=O)O
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(N)CC4)n3)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(NC(=O)CC#N)CC4)n3)cc2)CC1
Reaction time: 0.5 h
Yield: 14.7 %

Procedure:
To a suspension of cyanoacetic acid (85 mg, 1.00 mmol) in CH2Cl2 (2 mL) (containing 2 drops of DMF) at room temperature, oxalyl chloride (0.082 mL, 0.94 mmol) was added. Gas evolved and suspension became clear. It was then stirred for 30 min. To the above solution cooled in an ice bath, a solution of 1-(4-(4-(4-(4-aminopiperidin-1-yl)-5-fluoropyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (70 mg, 0.17 mmol) and TEA (0.478 mL, 3.43 mmol) in DMF (2 mL) was added drop wise. The mixture was then stirred at room temperature for 3 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (12 mg). MS 481.5 (M+H); UV 204.7, 266.3 nm
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)=[O:7])[CH2:3][CH2:2]1.[F:22][C:23]([F:40])([F:39])[C:24]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)([OH:29])[C:25]([F:28])([F:27])[F:26].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:1]1([CH2:4][NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([C:34](=[O:35])[C:33]4[CH:32]=[CH:31][C:30]([C:24]([OH:29])([C:23]([F:22])([F:39])[F:40])[C:25]([F:26])([F:27])[F:28])=[CH:38][CH:37]=4)[CH2:18][CH2:17]3)=[CH:11][CH:10]=2)=[O:7])[CH2:2][CH2:3]1
Reactant: O=C(NCC1CC1)Nc1ccc(OC2CCNCC2)cc1
Reactant: O=C(O)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CC1)Nc1ccc(OC2CCN(C(=O)c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.1 %

Procedure:
1-(cyclopropylmethyl)-3-(4-(piperidin-4-yloxy)phenyl)urea (1.037 mmol, 300 mg), 4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzoic acid (1.037 mmol, 299 mg) and triethylamine (3.11 mmol, 0.432 mL, 315 mg) were combined and stirred at room temperature in dichloromethane (5 mL). 1-Propanephosphonic acid cyclic anhydride (1.555 mmol, 0.926 mL, 990 mg; 50% solution in ethyl acetate) was added and the reaction stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution and the organic layer was separated, dried and concentrated under vacuum. The residue was dissolved in dichloromethane and purified by silica column chromatography (eluent 2-8% methanol in dichloromethane) to afford the title compound (24 mg). MS (ESI) m/z 560.2 [M+H]+
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[C:5]([F:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](B(O)O)[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[Cl:13][C:10]1[C:9]2[C:4](=[C:5]([F:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2c(F)cccc2c1Cl
Reactant: OB(O)c1cccnc1
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: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2cccnc2)nc2c(F)cccc2c1Cl

Procedure:
Prepared according to general Procedure F using 2,4-dichloro-8-fluoro-3-methylquinoline (250 mg, 1.1 mmol), 3-pyridylboronic acid (134 mg, 1.1 mmol), tetrakis(triphenylphosphine)palladium(0) (126 mg, 0.11 mmol), sodium carbonate (202 mg, 1.90 mmol) in toluene:water (5 mL:2 mL) and heating at 130° C. overnight. After purification 4-chloro-8-fluoro-3-methyl-2-(pyridin-3-yl)quinoline was obtained as a white solid. Mass Spectrum (ESI) m/e=273.0 (M+1).