Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:10]1[CH2:15][C:14]2[C:16]3[C:29]([OH:30])=[CH:28][C:27]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[C:39]=4[CH3:45])=[CH:26][C:17]=3[O:18][C:19]([CH2:23][CH2:24][CH3:25])([CH2:20][CH2:21][CH3:22])[C:13]=2[CH2:12][CH2:11]1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:46].[N:47]1([CH2:52][CH2:53][CH2:54][C:55](O)=[O:56])[CH2:51][CH2:50][CH2:49][CH2:48]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:46].[CH2:1]([N:10]1[CH2:15][C:14]2[C:16]3[C:29]([O:30][C:55](=[O:56])[CH2:54][CH2:53][CH2:52][N:47]4[CH2:51][CH2:50][CH2:49][CH2:48]4)=[CH:28][C:27]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[C:39]=4[CH3:45])=[CH:26][C:17]=3[O:18][C:19]([CH2:23][CH2:24][CH3:25])([CH2:20][CH2:21][CH3:22])[C:13]=2[CH2:12][CH2:11]1)[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCC1(CCC)Oc2cc(CCCCCCCc3cccc(C)c3C)cc(O)c2C2=C1CCN(CC=Cc1ccccc1)C2
Reactant: O=C(O)CCCN1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCC1(CCC)Oc2cc(CCCCCCCc3cccc(C)c3C)cc(OC(=O)CCCN3CCCC3)c2C2=C1CCN(CC=Cc1ccccc1)C2

Procedure:
2-Cinnamyl-8-(2,3-dimethylphenyl-n-heptyl)-5,5-di(n-propyl)-10-hydroxy-1,2,3,4-tetrahydro-5H[1]benzopyrano [3,4-d]pyridine, γ-pyrrolidinobutyric acid hydrochloride and dicyclohexylcarbodiimide are reacted in equimolar amounts according to Example 1 to form the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[N:11]=[C:10]([C:19]([OH:21])=O)[CH:9]=2)=[CH:4][CH:3]=1.[I-].ClC1C=CC=C[N+:25]=1C.[Br:31][C:32]1[CH:40]=[CH:39][C:35](C(O)=O)=[CH:34][N:33]=1>C1COCC1.CCN(C(C)C)C(C)C>[Br:31][C:32]1[N:33]=[C:34]([NH:25][C:19]([C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[N:11]=2)=[O:21])[CH:35]=[CH:39][CH:40]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: C[n+]1ccccc1Cl
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)n(C2CCCCO2)n1
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(Br)n1)c1cc(-c2ccc(F)cc2)n(C2CCCCO2)n1
Reaction time: 72 h
Yield: 29.5 %

Procedure:
To a suspension of 5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid 1 (400 mg, 1.37 mmol) and 2-chloro-1-methylpyridinium iodide (524 mg, 2.0 mmol) in THF (20 ml), DIPEA (0.46 ml) followed by 6-bromopyridin-2-amine 2 (237 mg, 1.37 mmol) were added. The suspension was stirred for 72 hrs. Then the reaction mixture was concentrated, diluted in water (10 ml) and extracted with dichloromethane (50 ml×2). All organic phases were washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified on a silica gel column (EtOAc: pet-ether 1:4) to give N-(6-bromopyridin-2-yl)-5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide 3 (180 mg) as a white solid. Mp. 151-152° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[C:14]([C:15]([OH:17])=[O:16])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.C(N(CC)CC)C.C1(OS(OC2CCCC2)(=O)=O)CCCC1>>[O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[CH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[CH:14]1([C:15]([O-:17])=[O:16])[CH2:10][CH2:11][CH2:2][CH2:13]1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Agent: O=S(=O)(OC1CCCC1)OC1CCCC1
Solvent: CCN(CC)CC
Product: O=C([O-])C1CCCC1
Product: O=c1[nH]c2ccccc2c2cc[nH]c12

Procedure:
4-Oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-cyclopentyl carboxylate was prepared according to method of esterification C from 194 mg (0.85 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid, 1.29 mL (12.75 mmol) of triethylamine and 1.99 g (8.5 mmol) of dicyclopentylsulfate to give, after precipitation in water, 250 mg (98%) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-cyclopentyl carboxylate in the form of a beige solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH:22]=[CH2:23])[CH:5]1[CH2:9][CH:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:7][CH:6]1O)[CH:2]=[CH2:3].C([N:26](CC)CC)C.CS(Cl)(=O)=O.[OH-].[NH4+]>CC(OC)(C)C>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][O:10][CH:8]2[CH2:9][CH:5]([N:4]([CH2:21][CH:22]=[CH2:23])[CH2:1][CH:2]=[CH2:3])[CH:6]([NH2:26])[CH2:7]2)=[CH:13][CH:14]=1
Reactant: CCN(CC)CC
Reactant: C=CCN(CC=C)C1CC(OCc2ccc(OC)cc2)CC1O
Agent: CS(=O)(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: C=CCN(CC=C)C1CC(OCc2ccc(OC)cc2)CC1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[bis(prop-2-en-1-yl)amino]-4-[(4-methoxyphenyl)methoxy]cyclopentan-1-ol (8.75 g, 27.6 mmol) in dry MTBE (92 ml) at 0° C. under nitrogen was added triethylamine (7.68 ml, 55.1 mmol) and methanesulfonyl chloride (2.58 ml, 33.1 mmol). The reaction mixture was stirred at 0° C. for 30 minutes. To this was then added further triethylamine (7.68 ml, 55.1 mmol) and the reaction was stirred at 0° C. for 30 minutes followed by the addition of ammonium hydroxide (25% aq, 82 ml, 590 mmol). The reaction was warmed to room temperature for 17 hours then partitioned between MTBE and water. The aqueous layer was re-extracted with MTBE. The combined organics were dried over magnesium sulphate, filtered and concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[N:12][CH3:13])=[C:3]1[CH3:14].[BH4-].[Na+]>C(O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:12][CH3:13])=[C:3]1[CH3:14]
Reactant: CN=Cc1c(C)n(C)c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNCc1c(C)n(C)c2ccccc12
Temperature: 25 °C
Yield: 68 %

Procedure:
1,2-Dimethyl-3-(methyliminomethyl)-1H-indole was taken up in ethanol (200 mL) and NaBH4 (2.6 g, 68.7 mmole) was added portionwise with stirring at RT (vigorous gas evolution). After 16 h the reaction was concentrated under vacuum, and the residue was basified with aqueous 1.0 N NaOH (200 mL). The mixture was extracted with Et2O (250 mL), and the combined Et2O extracts were washed with brine, dried (Na2SO4) and concentrated. Purification by flash chromatography on silica gel (5-10% (5% NH4OH/MeOH)/CHCl3) gave the title compound (8.47 g, 68%) as an oil which solidified in the freezer 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J=7.7 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.19 (t, 1H), 7.12 (t, 1H), 3.93 (s, 2H), 3.69 (s, 3H), 2.49 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1(O)[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10]1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.CCCCCC>C(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10]1
Reactant: OC1(c2cccc(F)c2F)CCC=CCC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(C2CCC=CCC2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
In a 250 mL round-bottomed flask (t=g) was added (Z)-1-(2,3-difluorophenyl)cyclohept-4-enol (2.05 g, 9.14 mmol) in CH2Cl2 (40 mL) to give a colorless solution. Triethylsilane (7.30 mL, 45.7 mmol) was added, followed by TFA (20 mL). The mixture was stirred at room temperature for 3 hours: TLC showed a complete conversion (Rf=0.42 by pure hexane). It was concentrated down to a bi-layer oil (the lower layer wasn't hexane-soluble). Purification by FCC using only hexane afforded the desired product as a colorless oil (1.684 g, 88%). 1H NMR (400 MHz, CDCl3) δ 7.00-6.90 (m, 3H), 5.90-5.82 (m, 2H), 3.20-3.05 (m, 1H), 2.40-2.15 (m, 4H), 1.90-1.78 (m, 2H), 1.60-1.40 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]#N)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[OH-].[K+].CI.O>C(O)C>[CH3:12][S:11][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CCO
Solvent: O
Product: CSc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 0.08 h
Yield: 95.1 %

Procedure:
2-Nitro-4-thiocyanato-aniline (17.6 g.) was added portionwise to a stirred solution of potassium hydroxide (13.4 g.) in ethanol (210 ml.) cooled below 15° C. After 5 minutes, methyl iodide (12.8 g.) was added to the purple solution and the mixture was allowed to stand overnight at room temperature. The mixture was then poured into water (1100 ml.) and the deep red solid was filtered off, washed with water, and dried to give 4-methylthio-2-nitroaniline (15.8 g.), m.p. 72°-73° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][C@@H:15]2[CH2:17][C@H:12]1[CH2:13][NH:14]2.[CH2:18]=O>C(O)=O>[NH3:1].[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][C@@H:15]2[CH2:17][C@H:12]1[CH2:13][N:14]2[CH3:18]
Reactant: c1ccc2nc(N3C[C@@H]4C[C@H]3CN4)ccc2c1
Reactant: C=O
Solvent: O=CO
Product: CN1C[C@@H]2C[C@H]1CN2c1ccc2ccccc2n1
Product: N

Procedure:
A mixture of 2-(2-quinolinyl)-(1S,4S)-2,5-diazabicyclo-[2.2.1]-heptane (0.39 g; 1.73 mmol), formaldehyde (2 ml; 37%) and formic acid (2 ml) was stirred at reflux for 24 hours. The solvent was evaporated. Aqueous sodium hydroxide (50 ml; 1 M) was added, followed by extraction with diethyl ether (3×50 ml). Chromatography on silica gel with dichloromethane, methanol and conc. ammonia (89:10:1) gave the title compound as free base. Yield 0.35 g (85%).
Reaction SMILES: [C:1]([CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=O)[CH2:9][CH2:8]3)#[N:2].Cl.[NH2:19][OH:20].C(N(CC)CC)C.C([OH:30])C>>[CH3:15][C:13]1[CH:14]=[C:5]2[CH2:4][CH:3]([C:1]([NH2:2])=[O:30])[O:17][C:6]2=[C:7]2[C:12]=1[NH:11][C:10](=[N:19][OH:20])[CH2:9][CH2:8]2
Reactant: CCO
Reactant: NO
Reactant: Cc1cc2c(c3c1NC(=O)CC3)OC(C#N)C2
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cc2c(c3c1NC(=NO)CC3)OC(C(N)=O)C2
Temperature: 90 °C

Procedure:
The compound obtained in Example 262 (0.63 g, 2.76 mmol) was dissolved in ethanol (50 ml), to which hydroxylamine hydrochloride (0.38 g, 5.5 mmol) and triethylamine (1.15 ml, 8.3 mmol) were added. The mixture was refluxed with heat at 90° C. for 1 hour. The solvent was distilled off under reduced pressure. To the residue, water and chloroform were added. The precipitate was collected by filtration, and washed with water and chloroform. Subsequently, the washed material was dissolved in hot methanol and chloroform, followed by drying over magnesium sulfate. When the solvent was distilled off under reduced pressure, 0.47 g of the title compound was obtained as a white solid (65%). This solid was recrystallized from methanol--ether to obtain colorless crystals (mp.: 251°-254° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([CH3:39])[CH:34]=2)[CH:28]=1)=[O:26])(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([CH3:39])[CH:34]=2)[CH:28]=1)=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(C)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (257 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) according to the general procedure M. Obtained as an off-white foam (470 mg, 95%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[C:29](Cl)[CH:28]=[CH:27][C:26]=1[C:32]1[CH:37]=CC=[CH:34][CH:33]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[P:38]([O:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][N:56]([CH2:59][CH2:60][C@@H:61]([NH:70][C:71]2[CH:76]=[CH:75][C:74]([S:77](=[O:80])(=[O:79])[NH2:78])=[CH:73][C:72]=2[S:81]([C:84]([F:87])([F:86])[F:85])(=[O:83])=[O:82])[CH2:62][S:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:55][CH2:54]1)([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].[CH2:88]([Cl:91])[CH2:89]Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[P:38]([O:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][N:56]([CH2:59][CH2:60][C@@H:61]([NH:70][C:71]2[CH:76]=[CH:75][C:74]([S:77](=[O:79])(=[O:80])[NH:78][C:20](=[O:21])[C:19]3[CH:23]=[CH:24][C:16]([N:13]4[CH2:12][CH2:11][CH:10]([C@@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3])[C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:32]5[CH:37]=[CH:89][C:88]([Cl:91])=[CH:34][CH:33]=5)[CH2:15][CH2:14]4)=[CH:17][CH:18]=3)=[CH:73][C:72]=2[S:81]([C:84]([F:87])([F:86])[F:85])(=[O:83])=[O:82])[CH2:62][S:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:55][CH2:54]1)([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1cc(Cl)ccc1-c1ccccc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CC(C)(C)OP(=O)(OCCN1CCN(CC[C@H](CSc2ccccc2)Nc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CC1)OC(C)(C)C
Reactant: ClCCCl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OP(=O)(OCCN1CCN(CC[C@H](CSc2ccccc2)Nc2ccc(S(=O)(=O)NC(=O)c3ccc(N4CCC([C@@H](O[Si](C)(C)C(C)(C)C)c5ccccc5-c5ccc(Cl)cc5)CC4)cc3)cc2S(=O)(=O)C(F)(F)F)CC1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(R)-4-(4-((tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 170 mg, 0.32 mmol), (R)-di-tert-butyl 2-(4-(4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butyl)piperazin-1-yl)ethyl phosphate (INTERMEDIATE 61, 275 mg, 0.35 mmol), DMAP (116 mg, 0.95 mmol) and EDC (122 mg, 0.63 mmol) were dissolved in DCM (3.2 ml). The reaction mixture was stirred at r.t. for 72 hours. The mixture was diluted with DCM (10 ml) and washed with NaHCO3 solution (saturated, aq., 5 ml) and brine (5 ml). The collected organic layer was dried over Na2SO4 and concentrated to give the title compound (446 mg, yield: almost quantitative). The title compound was used in the preparation of EXAMPLE 10 without further purification.
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.C(NC1C=[C:51]2[C:55](=[CH:56][CH:57]=1)[NH:54][C:53]([C:58]([OH:60])=O)=[CH:52]2)(=O)C.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:58]([C:53]2[NH:54][C:55]([CH2:56][CH3:57])=[N:2][C:52]=2[CH3:51])=[O:60])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(=O)Nc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc(C)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.1 %

Procedure:
HATU (114 mg, 0.3 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (62 mg, 0.2 mmol), 5-(acetylamino)-1H-indole-2-carboxylic acid (31 mg, 0.2 mmol) and diisopropylethylamine (52 uL, 0.3 mmol) in DMF (1 mL). The reaction mixture was stirred at RT overnight and was extracted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (0-5% 2M NH3 solution of MeOH in DCM) and preparative TLC (5% 2M NH3 solution of MeOH in DCM) to afford the title compound (5.5 mg) as a white solid. 1H NMR (400 MHz, CDCl3-d): δ ppm 8.85 (s, 1H) 7.54 (s, 1H) 7.31-7.38 (m, 2H) 7.20-7.27 (m, 1H) 7.14 (s, 1H) 7.01 (s, 1H) 4.62 (d, J=6.41 Hz, 2H) 2.67 (q, J=7.69 Hz, 2H) 2.55 (s, 3H) 1.29 (t, J=7.69 Hz, 3H). LCMS: m/z 447 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:3]=1.[I-].[K+].CCN(C(C)C)C(C)C.[CH3:34][C:35]1[NH:39][N:38]=[C:37]([NH2:40])[CH:36]=1>CN(C=O)C.O>[F:21][C:13]([F:22])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:4]1[N:3]=[C:2]([NH:40][C:37]2[CH:36]=[C:35]([CH3:34])[NH:39][N:38]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Fc1ccc(C(F)(F)c2nc(Cl)c3ccc(F)cc3n2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cc3)nc3cc(F)ccc23)n[nH]1
Temperature: 50 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
To a solution of 4-chloro-2-(difluoro(4-fluorophenyl)methyl)-7-fluoroquinazoline (0.160 g, 0.492 mmol) in DMF (2 mL) at rt were added potassium iodide (0.082 g, 0.492 mmol), DIEA (0.094 mL, 0.541 mmol) and 5-methyl-1H-pyrazol-3-amine (0.048 g, 0.492 mmol). After stirring the reaction mixture at 50° C. overnight, the mixture was cooled to rt and H2O (15 mL) was added. The precipitate was collected by filtration and washed with H2O. The crude product was purified on HPLC (Phenomenex phenylhexyl reverse phase column, eluted with gradient of solvent B=0.05% HOAc/CH3CN and solvent A=0.05% HOAc/H2O) to afford 2-(difluoro(4-fluorophenyl)methyl)-7-fluoro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine as a white powder (36 mg, 19%). 1H NMR (300 MHz, DMSO-d6) δ 2.26 (s, 3H), 6.27 (s, 1H), 7.35 (t, 2H), 7.56 (m, 1H), 7.72-763 (m, 3H), 8.78 (m, 1H), 10.82 (s, 1H), 12.23 (s, 1H); LC-MS (ESI) m/z 388 (M+H)+.
Reaction SMILES: FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.[F:22][C:23]1[CH:52]=[CH:51][C:26]([C:27]([NH:29][N:30]=[CH:31][C:32]2[CH:37]=[CH:36][C:35]([C@@H:38]3[O:43][CH2:42][CH2:41][N:40]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:39]3)=[CH:34][CH:33]=2)=[O:28])=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]2[O:28][C:31]([C:32]3[CH:33]=[CH:34][C:35]([C@@H:38]4[O:43][CH2:42][CH2:41][N:40]([C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[CH2:39]4)=[CH:36][CH:37]=3)=[N:30][N:29]=2)=[CH:51][CH:52]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(C=NNC(=O)c3ccc(F)cc3)cc2)C1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(-c3nnc(-c4ccc(F)cc4)o3)cc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 65.8 %

Procedure:
[Bis(trifluoroacetoxy)iodo]benzene (90.5 mg, 0.211 mmol) was dissolved in chloroform (5 ml), then (S)-tert-butyl 2-(4-((2-(4-fluorobenzoyl)hydrazono)methyl)phenyl)morpholine-4-carboxylate (75 mg, 0.175 mmol) was added and the mixture was stirred at room temperature for 20 min. The solvent was evaporated and the residue was purified by flash chromatography (10 g silica gel, 10 to 20% ethyl acetate in heptane) to yield a white solid (49 mg, 66%). MS (ISP): 370.1 ([M-tBu+H]+), 426.1 ([M+H]+).
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[O:14])=[CH:8][CH:7]=1.[F:16][C:17]1[CH:18]=[C:19]([NH2:36])[CH:20]=[CH:21][C:22]=1[O:23][CH:24]1[C:29]2=[C:30]([CH:33]([CH3:35])[CH3:34])[CH:31]=[CH:32][N:28]2[N:27]=[CH:26][NH:25]1.C1COCC1.ClCCl>C(OCC)(=O)C>[F:16][C:17]1[CH:18]=[C:19]([NH:36][C:2]([NH:3][C:13](=[O:14])[CH2:12][C:9]2[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=2)=[S:1])[CH:20]=[CH:21][C:22]=1[O:23][CH:24]1[C:29]2=[C:30]([CH:33]([CH3:34])[CH3:35])[CH:31]=[CH:32][N:28]2[N:27]=[CH:26][NH:25]1
Reactant: N#C[S-]
Reactant: CC(C)c1ccn2c1C(Oc1ccc(N)cc1F)NC=N2
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1ccn2c1C(Oc1ccc(NC(=S)NC(=O)Cc3ccc(F)cc3)cc1F)NC=N2
Reaction time: 2 h
Yield: 74.4 %

Procedure:
To a homogeneous solution of sodium thiocyanate (0.037 g, 0.46 mmol, 3.3 equiv) in ethyl acetate (1 mL), at room temperature under a nitrogen atmosphere, was added 4-fluorophenyl-acetyl chloride (0.048 ml, 0.35 mmol, 2.5 equiv). The mixture was stirred for 2 h before being added directly to a homogeneous solution of 3-fluoro-4-(5-isopropyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (0.040 g, 0.139 mmol, 1.0 equiv) in anhydrous 1/1 THF/dichloromethane (3 mL), under a nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 16 h before being quenched with 1 N HCl. The solution was extracted with CH2Cl2 (3×50 ml), the combined organic fractions washed with 1 N NaOH (50 ml), dried (Na2SO4), filtered and concentrated in vacuo. Purification by silica gel (Merck KGaA, 230–400 mesh particle size) flash chromatography, eluting with 4/1 hexane/ethyl acetate, afforded the title compound (0.050 g, 75%). 1H NMR (CDCl3) δ 12.34 (s, 1H), 8.47 (m, 1H), 7.65–7.78 (m, 2H), 7.63–7.64 (m, 1H), 7.19–7.32 (m, 4H) 703–7.08 (m, 2H), 6.66–6.67 (m, 1H), 3.65 (s, 2H), 3.40–3.50 (m, 1H), 1.28–1.30 (m, 6H); HRMS(ESI) 482.1462, calc, (M+H)+ 482.1461 found. Elemental Analysis: C24H21N5O2SF2. 0.23 H2O. calc: C, 59.35; H, 4.45, N, 14.42, found. C, 59.36; H, 4.44; N, 14.03.
Reaction SMILES: [CH2:1]([C:8]1[CH:35]=[CH:34][CH:33]=[CH:32][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][NH:14][CH:15]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:37][C:38]#[N:39]>>[CH2:1]([C:8]1[CH:35]=[CH:34][CH:33]=[CH:32][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:37][C:38]#[N:39])[CH:15]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: COc1ccc(C(NCCCOc2ccccc2Cc2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(c2ccc(OC)cc2)N(CC#N)CCCOc2ccccc2Cc2ccccc2)cc1

Procedure:
By following similar procedure as described in Preparation 93, N-alkylation of [3-(2-benzyl-phenoxy)-propyl]-[bis-(4-methoxy-phenyl)-methyl]-amine with bromoacetonitrile gives the title compound as oil. FABMS: m/z 506 (M)+, 507 (M+H)+.
Reaction SMILES: [Cl:1]Cl.[CH2:3]=[C:4]1[O:8][C:6](=[O:7])[CH2:5]1.[CH2:9]([OH:11])[CH3:10]>C(Cl)(Cl)(Cl)Cl>[CH2:9]([O:11][C:6](=[O:7])[CH2:5][C:4]([CH2:8][Cl:1])=[O:3])[CH3:10]
Reactant: C=C1CC(=O)O1
Reactant: ClCl
Reactant: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)CC(=O)CCl
Yield: 94 %

Procedure:
72 g (1 mol) of chlorine were passed into a solution of 84 g (1 mol) of diketene in dry carbon tetrachloride at -20° C. and the reaction solution was then added dropwise, while stirring, to 200 ml of ethanol, during which addition the temperature was not permitted to exceed 0° C.; the solvent was then stripped off on a rotary evaporator and the residue was distilled. 155 g (94% of theory) of γ-chloroacetoacetic acid ethyl ester of boiling point 90° C./7 mm Hg were obtained.