Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21]Cl.[CH3:23][C:24]1([CH3:34])[O:28][C:27]2[CH:29]=[CH:30][CH:31]=[C:32](O)[C:26]=2[O:25]1.C(=O)([O-])[O-:36].[K+].[K+].O>CN(C=O)C>[CH3:23][C:24]1([CH3:34])[O:28][C:27]2[CH:29]=[CH:30][C:31]([O:36][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:3]3[C:4]([Cl:16])=[CH:5][C:6]([O:8][CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[CH:7][C:2]=3[Cl:1])=[CH:32][C:26]=2[O:25]1
Reactant: ClCCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: O=C([O-])[O-]
Reactant: CC1(C)Oc2cccc(O)c2O1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)Oc2ccc(OCCCCOc3c(Cl)cc(OCc4ccccc4)cc3Cl)cc2O1
Yield: 71.4 %

Procedure:
A stirred solution of 0.3 gram (0.00083 mole) of 1,3-dichloro-2-(4-chlorobutoxy)-5-(phenylmethoxy)benzene, 0.17 gram (0.00100 mole) of 2,2-dimethylbenzo[d]1,3-dioxolan-4-ol, and 0.17 gram (0.00125 mole) of potassium carbonate in 10 mL of DMF was heated at 80° C. for about 18 hours. After this time, the reaction mixture was cooled and 30 mL of water was added. The mixture was then extracted with three 20 mL portions of diethyl ether. The combined extracts were washed with 20 mL of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:1 methylene chloride:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.29 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: COC[O:4][C:5]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=[CH:9][C:8]([C:18](=[O:36])[NH:19][CH2:20][C:21]2([CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:23][CH2:22]2)=[CH:7][C:6]=1[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=1.C[Si](Br)(C)C>C(Cl)Cl>[Cl:17][C:13]1[CH:12]=[C:11]([C:10]2[CH:9]=[C:8]([C:18](=[O:36])[NH:19][CH2:20][C:21]3([CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:22][CH2:23]3)[CH:7]=[C:6]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=3)[C:5]=2[OH:4])[CH:16]=[CH:15][CH:14]=1
Reactant: COCOc1c(-c2cccc(Cl)c2)cc(C(=O)NCC2(COCCCCc3ccccc3)CC2)cc1-c1cccc(Cl)c1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=C(NCC1(COCCCCc2ccccc2)CC1)c1cc(-c2cccc(Cl)c2)c(O)c(-c2cccc(Cl)c2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of (3,3″-dichloro-5′-{[1-(4-phenylbutoxymethyl)-cyclopropylmethyl]-carbamoyl}-[1,1′;3′1″]terphenyl-2′-yloxy)methyl methyl ether (0.681 g, 1.10 mmol) in CH2Cl2 (15 mL) at −30° C. containing 4 Å molecular sieves was added trimethylsilyl bromide (0.581 mL, 4.40 mmol). After stirring at this temperature for 1 h, it was warmed to 0° C. and stirred an additional 5 h. Only slight conversion to product so warmed to room temperature and stirred at this temperature for 18 h. At this point, the mixture was quenched with sat. aq. NaHCO3 (10 mL) and extracted with EtOAc (250 mL). The organic layer was washed with brine (25 mL) and dried (MgSO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (10 to 30% EtOAc/petroleum ether gradient) to afford the product (0.455 g, 72%) as a solid; 1H NMR (DMSO-d6) δ 0.32-0.41 (m, 2H), 0.47-0.55 (m, 2H), 1.40-1.62 (m, 4H), 2.46-2.58 (m, 2H), 3.28 (s, 2H), 3.28-3.42 (m, 4H), 7.11-7.20 (m, 3H), 7.20-7.29 (m, 2H), 7.42-7.55 (m, 6H), 7.65 (s, 2H), 7.79 (s, 2H), 8.34 (t, J=6.3 Hz, 1H), 9.19 (s, 1H); mass spectrum [(+) ESI], m/z 574 (M)+.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:15]F.[F-].[Na+]>C(#N)C.ClC(Cl)(Cl)C(F)(F)F>[C:1]1([CH:7]([F:15])[C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FF
Reactant: CCOC(=O)C(=O)Cc1ccccc1
Agent: [F-]
Agent: [Na+]
Solvent: FC(F)(F)C(Cl)(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)C(=O)C(F)c1ccccc1
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 40 %

Procedure:
Ethyl 3-phenylpyruvate (10 g; 0.052 mol) is dissolved in a mixture of acetonitrile (60 g) and trichlorotrifluoroethane (410 g), and the resulting solution is cooled to -10° C. Then, fluorine gas (0.067 mol) diluted with nitrogen to 10% concentration is introduced therein over a period of 2.5 hours while stirring vigorously. After addition of sodium fluoride (2 g), the solvent is distilled off under reduced pressure, and the residue is rectified to give ethyl 3-phenyl-3-fluoropyruvate (4.37 g). Boiling point, 90°-95° C./1 mmHg.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:12]([O-])([O-:14])=[O:13].[NH4+].BrCC(C1C=CC=CC=1)=O>S(=O)(=O)(O)O.C(N)=O>[N+:12]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)=[CH:6][CH:5]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])[O-]
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: O=C(CBr)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: NC=O
Product: O=[N+]([O-])c1ccc(-c2c[nH]cn2)cc1

Procedure:
Prepared by nitrogenating 4-phenyl-imidazole in concentrated sulphuric acid with ammonium nitrate analogously to Example D (64% of theory; melting point: 220° C.) or by heating ω-bromo-acetophenone in formamide (160° C., 2.5 hours) (53% of theory; melting point: 220-222° C.).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]([CH:18]([CH3:20])[CH3:19])[C@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]1[OH:17].C([O-])([O-])=O.[K+].[K+]>ClCCl.O>[Cl:1][CH2:2][C:3]([O:17][C@@H:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:8]1[N:7]([CH3:6])[CH:18]([CH3:20])[CH3:19])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CC(C)N(C)[C@H]1c2ccccc2C[C@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(C)N(C)[C@H]1c2ccccc2C[C@H]1OC(=O)CCl
Temperature: 35 °C
Reaction time: 0.08 h
Yield: 96.3 %

Procedure:
2.00 grams (17.5 mmol) of chloroacetyl chloride was added drop by drop, in 5 minutes, to a solution of 3.00 grams (14.6 mmol) of (1S,2R)-N-methyl,N-i-propyl-1-amino-2-indanol in 40 ml of dichloromethane at room temperature. The temperature increased to 35° C. The reaction was stirred for 15 hours at room temperature. This was followed by the addition of 50 ml of a 5% K2CO3 solution in water and extraction. The basic water layer was once again extracted using 30 ml of dichloromethane. After the collected organic layers had been washed with water, dried using Na2SO4 and evaporated, 3.96 grams (85%) of product was isolated as a yellow oil. 1H NMR (200 MHz, CDCl3): 1.05 (2*d, 6H), 2.09 (s, 3H), 2.96 (dd, J=8.6 and 3.5 Hz +septet, 2H), 3.14 (dd, J=8.6 and 3.5 Hz, 1H), 3.99 (s, 2H), 4.47 (d, J=3,1 Hz, 1H), 5.47 (dt, J=3,1 and 3.5 Hz, 1H) and 7.10-7.25 (m, 4H). 13C NMR (50.31 MHz, CDCl3): 20.59 (q), 33.00 (q), 37.06 (t), 41.10 (t), 53.61 (d), 66.08 (d), 78.47 (d), 124.84 (d), 125.81 (d), 126.62 (d), 127.61 (d), 138.96 (s), 140.46 (s) and 166.85 (s).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:11][N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@@H:5]2[CH2:4]1.Cl[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC(C)C>[OH:1][CH2:2][C@@H:3]1[CH2:11][N:6]2[CH2:7][CH2:8][N:9]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=3)[CH2:10][C@@H:5]2[CH2:4]1
Reactant: Clc1ccc(Cl)nc1
Reactant: OC[C@H]1C[C@H]2CNCCN2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: OC[C@H]1C[C@H]2CN(c3ccc(Cl)cn3)CCN2C1
Yield: 29.2 %

Procedure:
A mixture of 0.50 g (3.2 mmol) of (7S,8aS)-7-hydroxymethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 13, Step A), 2.37 g (16.0 mmol) of 2,5-dichloropyridine, 0.85 g (8.0 mmol) of sodium carbonate and 35 mL of isoamyl alcohol was refluxed for 48 hours. The hot solution was filtered and the filtrate evaporated. Purification by flash silica gel chromatography with 9:1 chloroform:methanol gave 0.25 g (29%) of the title compound. 13C NMR (CDCl3): d 31.1, 37.3, 44.7, 49.7, 51.2, 57.2, 62.5, 66.9, 107.9, 119.9, 137.1, 146.1, 157.6. m/z (MH+) 268.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]([CH:13]3[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]3)=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.[Br:26]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([Br:26])[CH:9]=[C:10]([C:11]([CH:13]3[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]3)=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)c2ccc3c(N)ncnn23)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(C(=O)c2cc(Br)c3c(N)ncnn23)C1
Reaction time: 1 h

Procedure:
A solution of tert-butyl 2-[(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)carbonyl]morpholine-4-carboxylate (0.66 g, 1.90 mmol) in THF (5 mL) was cooled to −50° C. and stirred for 1 h before adding 1.3-dibromo-5,5-dimethylhydantoin (0.27 g, 0.94 mmol) in portions. The reaction was then quenched with satd. Na2SO3 solution. The product was extracted with EtOAc, dried (MgSO4) and concentrated. The crude solid was triturated with EtOAc and filtered. An off-white solid was isolated (530 mg, 65%). 1H-NMR (DMSO-d6) δ 8.10 (s, 1 H), 7.54 (s, 1 H), 5.05-4.95 (m, 1 H), 4.00-3.89 (m, 2H), 3.69-3.55 (m, 2 H), 3.10-3.00 (m, 2 H), 1.33 (bs, 9 H).
Reaction SMILES: [OH-].[K+].[CH2:3]([C:9]1[C:10]2[NH:14][C:13]([C:15]([C:49]3[CH:54]=[CH:53][C:52]([C:55]([O:57]C)=[O:56])=[CH:51][CH:50]=3)=[C:16]3[N:48]=[C:19]([C:20]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([O:46]C)=[O:45])=[CH:40][CH:39]=4)=[C:21]4[NH:37][C:24](=[C:25]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:26]5[CH:27]=[CH:28][C:29]=1[N:30]=5)[CH:23]=[CH:22]4)[CH:18]=[CH:17]3)=[CH:12][CH:11]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.Cl>CO.C1COCC1>[C:44]([C:41]1[CH:42]=[CH:43][C:38]([C:20]2[C:21]3[NH:37][C:24]([C:25]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[C:26]4[N:30]=[C:29]([C:9]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[C:10]5[NH:14][C:13](=[C:15]([C:49]6[CH:50]=[CH:51][C:52]([C:55]([OH:57])=[O:56])=[CH:53][CH:54]=6)[C:16]6[CH:17]=[CH:18][C:19]=2[N:48]=6)[CH:12]=[CH:11]5)[CH:28]=[CH:27]4)=[CH:23][CH:22]=3)=[CH:39][CH:40]=1)([OH:46])=[O:45]
Reactant: CCCCCCc1c2nc(c(CCCCCC)c3ccc([nH]3)c(-c3ccc(C(=O)OC)cc3)c3nc(c(-c4ccc(C(=O)OC)cc4)c4ccc1[nH]4)C=C3)C=C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCCCc1c2nc(c(CCCCCC)c3ccc([nH]3)c(-c3ccc(C(=O)O)cc3)c3nc(c(-c4ccc(C(=O)O)cc4)c4ccc1[nH]4)C=C3)C=C2
Reaction time: 48 h

Procedure:
In a typical experiment, a solution of KOH (200 mg, 3.6 mmol) in methanol (1 ml) was added to a stirred solution of 5,10-dihexyl-15,20-bis-(4-methoxycarbonylphenyl)-porphyrin (34 mg, 0.05 mmol) in THF (8 ml) and the reaction mixture was stirred for 2 d. Water (50 ml) and hydrochloric acid were then added until the pH was adjusted to 4-6. The aqueous layer was extracted with dichloromethane (2×100 ml) and the organic layer was separated, washed with water until neutral and dried over sodium sulfate. The solvent was evaporated and the title compound 5,10-bis-(4-carboxyphenyl)-15,20-dihexyl-porphyrin was obtained after recrystallization from dichloromethane/aqueous methanol (26 mg, 79%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:24]([F:27])([F:26])[F:25])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[O:17][C:16]([C:18]([NH2:20])=O)=[CH:15][CH:14]=1)[C:7]([CH2:21][CH2:22][CH3:23])=[CH:6]2)#[N:2].N1C=CC=CC=1.O=P(Cl)(Cl)Cl>C(Cl)Cl>[C:18]([C:16]1[O:17][C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:24]([F:26])([F:27])[F:25])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:21][CH2:22][CH3:23])=[CH:14][CH:15]=1)#[N:20]
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1ccc(C(N)=O)o1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1ccc(C#N)o1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
A solution containing 5-{[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]methyl}-2-furancarboxamide (Example 271B) (0.388 g, 1.03 mmol), pyridine (10 mL) and CH2Cl2 (25 mL) was cooled to 0-5° C. This mixture was mixed with POCl3 (0.792 g, 5.17 mmol) and the resulting mixture was stirred at rt for 2 h. The reaction mixture was then partitioned between CH2Cl2 and saturated NaHCO3. The organics were washed with 1.0N HCl, dried (MgSO4) and concentrated to dryness. The residue was purified by flash chromatography (0-10% EtOAc-hexanes gradient) to afford a pure product (0.204 g, 55% yield): MS (ES) m/z 357 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][N:12]1[CH:15](SC)[CH2:14][C:13]1=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19]Cl>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([CH2:11][N:12]1[CH:15]([Cl:19])[CH2:14][C:13]1=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC1CC(=O)N1CC(=O)OCc1ccccc1
Reactant: ClCl
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CN1C(=O)CC1Cl)OCc1ccccc1
Yield: 104.6 %

Procedure:
1-Benzyloxycarbonylmethyl-4-methylthioazetidin-2-one (2.65 g) was dissolved in methylene dichloride (50 ml) and the solution was stirred and ice cooled while a solution of chlorine (0.71 g) in carbon tetrachloride (7 ml) was added in one portion. The mixture was stirred for 3 minutes and then the solvent was evaporated under reduced pressure to yield 1-benzyloxycarbonylmethyl-4-chloroazetidin-2-one as a pale yellow oil (2.65 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:10]([N+:11]([O-])=O)=[CH:9][C:6]([C:7]#[N:8])=[C:5]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([F:23])([F:22])[F:21])[CH2:16][CH2:15]2)[CH:4]=1.CCOC(C)=O>[Pd].CCO>[NH2:11][C:10]1[C:3]([NH:2][CH3:1])=[CH:4][C:5]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([F:21])([F:22])[F:23])[CH2:16][CH2:15]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(C#N)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1cc(N2CCC(C(F)(F)F)CC2)c(C#N)cc1N

Procedure:
H2 (1 atm) was passed through a mixture of 4-(methylamino)-5-nitro-2-(4-trifluoromethyl-piperidin-1-yl)benzonitrile (204 mg, 0.62 mmol), Pd/C (66 mg, 0.062 mmol), EtOAc (10 mL) and EtOH (10 mL) at rt for 1 h. The mixture was filtered through celite and concentrated. Crystallization from Et2O/PE gave the sub-title compound.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][CH2:5][CH:6]=[O:7].[O:10]1CCOCC1.[Se](=O)=O.O>C(O)(=O)C>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](=[O:10])[CH:6]=[O:7]
Reactant: C1COCCO1
Reactant: O=CCCCC(F)(F)F
Agent: O=[Se]=O
Solvent: O
Solvent: CC(=O)O
Product: O=CC(=O)CCC(F)(F)F
Temperature: 90 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Combine 5,5,5-trifluoropentanal (2.01 g, 14.35 mmol), 1,4-dioxane (10 mL), selenium dioxide (1.62 g, 1.0 eq), water (0.51 mL), and acetic acid (0.69 mL). Heat the mixture at 90° C. and stir overnight. Allow the reaction mixture to cool to room temperature. Filter, wash the solids with dioxane. Combine the filtrate and washings to give 5,5,5-trifluoro-2-oxopentanal (2.21 g, 100%). GCMS m/z=154.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])[CH2:11][NH:10][C:9]1=[O:22])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:34][C:35]([F:40])([F:39])[C@@H:36]1[CH2:38][O:37]1>O1CCCC1.CN1CCCC1=O.O>[F:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C@H:12]1[CH2:11][N:10]([CH2:38][C@H:36]([OH:37])[C:35]([F:40])([F:39])[F:34])[C:9](=[O:22])[C@@H:8]([NH:7][C:6](=[O:23])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=O
Reactant: FC(F)(F)[C@@H]1CO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CN(C[C@H](O)C(F)(F)F)C1=O
Temperature: -30 °C
Reaction time: 2 h

Procedure:
To a pre-cooled −30° C. solution of tert-butyl[(3S,5S)-5-(2,3-difluorophenyl)-2-oxopiperidin-3-yl]carbamate (described in Intermediate 11, step B, 56 mg, 0.172 mmol) in tetrahydrofuran:N-methyl-2-pyrrolidinone (2:1, 0.8 mL) was added lithium bis(trimethylsilyl)amide (0.22 mL, 0.22 mmol, 1 M in THF) and the mixture was stirred at −30° C. for 30 min. (2S)-2-(Trifluoromethyl)oxirane (19 mg, 0.172 mmol) was added and the resulting mixture was stirred at −30° C. for 2 h. The mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% ethyl acetate→90% ethyl acetate/hexane) afforded the title compound. MS: m/z=461.2 (M+Na).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.O=[C:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[N:1]([CH:17]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16]1)[CH2:2][CH2:3]2)#[N:11]
Reactant: N#Cc1ccc2c(c1)CCN2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3cc(C#N)ccc32)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of indoline-5-carbonitrile (110 mg, 0.75 mmol) in 2.5 mL of MeOH was added tert-butyl 3-oxopyrrolidine-1-carboxylate (166 mg, 0.90 mmol) and HOAc (0.11 mL, 1.88 mmol) subsequently. After stirring at room temperature for 10 minutes, NaCNBH3 (57 mg, 0.90 mmol) was added and the mixture was then stirred at ambient temperature for 2 days. The volatiles were removed under vacuum. The residue was diluted with EtOAc, then washed with 1 N NaOH solution and brine, dried over Na2SO4, and evaporated in vacuo to afford the crude title compound for the next step use without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.C(Cl)Cl.C(O[C@@H:17]1[O:29][C@H:28]([CH3:30])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[C:20]([O:19][C@@H:18]1[C@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@@H:28]([CH3:30])[O:29][C@H:17]1[N:6]1[CH:7]=[C:2]([F:1])[C:3]([NH2:9])=[N:4][C:5]1=[O:8])(=[O:22])[CH3:21]
Reactant: Nc1nc(=O)[nH]cc1F
Reactant: CC(=O)O[C@@H]1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cc(F)c(N)nc1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
5-Fluorocytosine (2.42 g, 18.8 mmol) was suspended in toluene (10 ml) and hexyamethyl-disilazane (3.03 g, 18.8 mmol). The mixture was heated at 100° C. overnight. After concentrating the reaction mixture under reduced pressure, methylene chloride (30 ml) and 5-deoxy-1,2,3-tri-O-Acetyl-β-D-ribofuranoside (4) (5.16 g, 18.8 mmol) were added to the residue. Then, anhydrous stannic chloride (4.90 g, 18.8 mmol) was added dropwise to the ice-cooled reaction mixture over a period of 20 min. After stirring the mixture at room temperature for an additional 2 h, sodium bicarbonate (10 g) was added, followed by the dropwise addition of water (20 ml). After stirring the resulting mixture at room temperature overnight, 4% sodium bicarbonate solution was poured into the reaction mixture and stirred for additional 1 h. The mixture was then extracted with water-methylene chloride. The organic layer was collected, dried with Na2SO4, the solvent was removed under reduced pressure to give brown syrup. The residue was then partially purified by silica gel chromatography using CH2Cl2:MeOH (5:1) as an eluent to yield crude target compound (5) (4.455 g, 13.5 mmol, 72%). 1H NMR in DMSO-d6: δ1.34 (d, 3H, J=6.4 Hz, H-5), 2.05, 2.06 (2s, each 3H, OMe), 4.14 (q, 1H, J=5.0 Hz, H-4), 5.10 (t, 1H, J=6.4 Hz, H-2), 5.43 (dd, 1H, J=6.31 Hz, H-3), 5.77 (dd, 1H, J=1.0 Hz, H-1), 7.71 (br s, 1H, N—CH═C—F), 7.97 (br s, 1H, NH), 8.02 (d, 1H, J=7.0 Hz, NH).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([C:29]3([CH3:36])[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:28])[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>C(Cl)Cl>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([C:29]3([CH3:36])[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:28])[CH:24]=2)[NH:19][N:18]=1
Reactant: CN1CCC(C)(C(=O)Nc2ccc3c(c2)c(-c2nc4ccccc4[nH]2)nn3C2CCCCO2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC(C)(C(=O)Nc2ccc3[nH]nc(-c4nc5ccccc5[nH]4)c3c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.5 %

Procedure:
TFA (0.1 mL, 1.587 mmol) was added to a solution of N-(3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1,4-dimethylpiperidine-4-carboxamide (5 mg, 0.010 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (2 mg) as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.49 (bs, 1H), 7.64 (m, 4H), 7.29 (m, 2H), 3.49 (m, 2H), 3.18 (m, 2H), 2.91 (s, 3H), 2.59 (m, 2H), 1.46 (m, 2H), 1.28 (s, 3H); ESI-MS [M+H]+: 389.3.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[CH2:4][CH2:3]1.[Cl:16][C:17]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:30]=2)=[O:28])=[CH:22][C:18]=1[C:19](O)=[O:20]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH:12][C:19](=[O:20])[C:18]3[CH:22]=[C:23]([NH:26][C:27]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([N:35]5[CH2:36][CH2:37][O:38][CH2:39][CH2:40]5)[CH:30]=4)=[O:28])[CH:24]=[CH:25][C:17]=3[Cl:16])[CH:13]=[CH:14][CH:15]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2cccc(N)c2)CC1
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1ccnc(N2CCOCC2)c1
Product: CN1CCN(Cc2cccc(NC(=O)c3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3Cl)c2)CC1

Procedure:
Using an analogous procedure to that described in Example 4, 3-(4-methylpiperazin-1-ylmethyl)aniline was reacted with 2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)benzoic acid to give the title compound in 32% yleld; NMR Spectrum: (DMSOd6) 2.13 (s, 3H), 2.31-2.35 (m, 8H), 3.42 (s, 2H), 3.49-3.53 (m, 4H), 3.69-3.72 (m, 4H), 7.02 (d, 1H), 7.1 (d, 1H), 7.22-7.3 (m, 2H), 7.57-7.65 (m, 3H), 7.84-7.94 (m, 2H), 8.28 (d, 1H), 10.47 (s, 1H), 10.52 (s, 1H); Mass Spectrum: M+H+ 549 and 551.
Reaction SMILES: CC1NC2C(C=1)=CC(OC1C3C(=CC(OCC4CCNCC4)=CC=3)N=CN=1)=CC=2.C(OC([N:37]1[CH2:42][CH2:41][CH:40]([CH2:43][CH2:44][O:45][C:46]2[CH:55]=[C:54]3[C:49]([C:50]([O:56][C:57]4[CH:58]=[C:59]5[C:63](=[CH:64][CH:65]=4)[NH:62][C:61]([CH3:66])=[CH:60]5)=[N:51][CH:52]=[N:53]3)=[CH:48][C:47]=2[O:67][CH3:68])[CH2:39][CH2:38]1)=O)(C)(C)C>>[CH3:68][O:67][C:47]1[CH:48]=[C:49]2[C:54](=[CH:55][C:46]=1[O:45][CH2:44][CH2:43][CH:40]1[CH2:41][CH2:42][NH:37][CH2:38][CH2:39]1)[N:53]=[CH:52][N:51]=[C:50]2[O:56][C:57]1[CH:58]=[C:59]2[C:63](=[CH:64][CH:65]=1)[NH:62][C:61]([CH3:66])=[CH:60]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cc1cc2cc(Oc3ncnc4cc(OCC5CCNCC5)ccc34)ccc2[nH]1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCC1CCNCC1
Yield: 87.5 %

Procedure:
Using an analogous procedure to that described for the synthesis of 4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline, (prepared as described in Example 122), 7-(2-(1-tert-butoxycarbonylpiperidin-4-yl)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (400 mg, 0.75 mmol), (prepared as described in Example 126), was used to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(piperidin-4-yl)ethoxy)quinazoline (284 mg, 87%).