Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[O:15]=[C:16]([CH3:26])[CH2:17][C:18]([O:20][CH2:21][CH:22]1[CH2:25][CH2:24][CH2:23]1)=[O:19].C(O)(=O)C.N1CCCCC1>ClCCl>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:17]([C:16](=[O:15])[CH3:26])[C:18]([O:20][CH2:21][CH:22]1[CH2:25][CH2:24][CH2:23]1)=[O:19]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CC(=O)CC(=O)OCC1CCC1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(=O)OCC1CCC1

Procedure:
700 mg (3.72 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde, 760 mg (4.46 mmol) of cyclobutylmethyl 3-oxobutanoate, 53 μl (0.93 mmol) of acetic acid and 92 μl (0.93 mmol) of piperidine in 25 ml of anhydrous dichloromethane are heated after addition of 4 Å molecular sieves (1.5 g) under reflux for 24 h. After cooling, the suspension is filtered with suction and the filtrate is washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue is purified by preparative HPLC. 962 mg (76% of theory) of the title compound are obtained as an E/Z mixture.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[Cl:20])=[CH:8][CH:7]=1)(=O)C.C1COCC1.CO.O[Li].O>C(OCC)(=O)C.O>[Br:19][C:17]1[CH:16]=[CH:15][C:14]([Cl:20])=[C:13]([CH:18]=1)[CH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][OH:4])=[CH:7][CH:8]=1
Reactant: CC(=O)OCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-bromo-2-chlorobenzyl)benzyl acetate (intermediate AJ) (8.86 g) in 60 mL of a mixture of THF:MeOH:H2O (v/v/v=2:3:1), LiOH.H2O (2.10 g) was added. The solution was stirred at room temperature. After 1 h, H2O (10 mL) and ethyl acetate (100 mL) were added. The aqueous layer was extracted 2× with ethyl acetate. The combined ethyl acetate layers were washed with brine and dried over Na2SO4. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography to obtain pure intermediate AK (6 g).
Reaction SMILES: C([CH:5]1[C:9]([C:10]2[C:18]3[O:17][C:16]([CH:19]4[CH2:21][CH2:20]4)=[N:15][C:14]=3[C:13]([C:22]#[N:23])=[C:12]([CH3:24])[C:11]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:8][CH2:7][N:6]1C(N)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:19]1([C:16]2[O:17][C:18]3[C:14](=[C:13]([C:22]#[N:23])[C:12]([CH3:24])=[C:11]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:10]=3[C:9]3[CH2:5][NH:6][CH2:7][CH:8]=3)[N:15]=2)[CH2:21][CH2:20]1
Reactant: Cc1c(-c2ccccc2)c(C2=CCN(C(N)=O)C2C(C)(C)C)c2oc(C3CC3)nc2c1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2ccccc2)c(C2=CCNC2)c2oc(C3CC3)nc2c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
tert-Butyl 3-(4-cyano-2-cyclopropyl-5-methyl-6-phenyl-1,3-benzoxazol-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxamide (I-327) (52.0 mg, 0.118 mmol) was dissolved in dichloromethane (4 ml), and with cooling with ice, trifluoroacetic acid (2 ml) was added, followed by stirring at room temperature for 2 hours. The reaction liquid was concentrated under reduced pressure, dissolved in chloroform, washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, and the residue obtained by concentration under reduced pressure was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v) and purified in slurry with isopropyl ether to obtain the entitled compound (26.0 mg, 62%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(OC([NH:53][C@@H:54]([CH2:59][C:60]1[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[CH:62][CH:61]=1)[C:55]([O:57][CH3:58])=[O:56])=O)(C)(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][CH2:9][C@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11]([NH:53][C@@H:54]([CH2:59][C:60]1[CH:61]=[CH:62][C:63]([O:66][CH3:67])=[CH:64][CH:65]=1)[C:55]([O:57][CH3:58])=[O:56])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.08 h

Procedure:
To (S)-3-(benzyloxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (1.00 g, 3.39 mmol) in DMF (10 mL) at 0° C. was added HATU (1.42 g, 3.73 mmol). The mixture was stirred for 5 min to dissolve the solids at which time (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-methoxyphenyl)propanoate (0.708 g, 3.39 mmol) and DIEA (1.77 mL, 10.2 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated to provide crude (S)-methyl 2-((S)-3-(benzyloxy)-2-((tert-butoxycarbonyl)amino)propanamido)-3-(4-methoxyphenyl)propanoate as a yellow oil that was carried forward without further purification. MS (EI) for C26H34N2O7, found 387.1 (M-Boc).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=1>C(OCC)(=O)C>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:20])(=[O:21])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=1)=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: Cc1cccc(N)n1
Solvent: CCOC(C)=O
Product: Cc1cccc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2C)n1
Yield: 51 %

Procedure:
4-Hydroxy-2-methyl-N-(6-methyl-2-pyridyl)-2H-naphtho[2,1-e]1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 10 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 2-amino-6-methyl-pyridine. Yield: 51% of theory; m.p.221°-223° C (decomp.; from ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]COC)=[C:4]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([O:21][CH3:22])[CH:15]=2)[CH:3]=1.Cl>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([O:21][CH3:22])[CH:15]=2)[CH:3]=1
Reactant: COCOc1ccc(F)cc1CCc1ccc(F)c(OC)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc(CCc2cc(F)ccc2O)ccc1F
Reaction time: 2 h
Yield: 95.6 %

Procedure:
770 mg of methoxymethyl {4-fluoro-2-[2-(4-fluoro-3-methoxyphenyl)ethyl]phenyl} ether [prepared as described in step (a) above] were dissolved in 4 ml of ethyl acetate, and then 4 ml of a 4N solution of hydrogen chloride in ethyl acetate were added to the resulting solution, whilst ice-cooling. The resulting mixture was then allowed to stand at room temperature for 2 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and purified by silica gel column chromatography, using a 3:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 631 mg (yield 96%) of the title compound as an oily substance.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[S:13][CH:12]=[N:11][CH:10]=1.CCCCCC.C([Li])CCC.CN(C)[CH:27]=[O:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[S:13][C:12]([CH:27]=[O:28])=[N:11][CH:10]=1
Reactant: CN(C)C=O
Reactant: c1ncc(COC2CCCCO2)s1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ncc(COC2CCCCO2)s1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution of 5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazole (7.44 g) in tetrahydrofuran (100 mL) was slowly added a 1.6M n-butyllithium hexane solution (25.6 mL) at −70° C. under a nitrogen atmosphere. The reaction mixture was stirred at −70° C. for 30 min and N,N-dimethylformamide (8.0 g) was added. The reaction mixture was warmed to room temperature, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (6.91 g, yield 82%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). MS: 228 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[N:10]=2)[C:5]([F:8])=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:75]([O:79][C:80]([N:82]1[CH2:87][CH2:86][N:85]([CH2:88][B-](F)(F)F)[C@H:84]([CH3:93])[CH2:83]1)=[O:81])([CH3:78])([CH3:77])[CH3:76].[K+].C(N1CCN[C@H](C)C1)(OC(C)(C)C)=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([C:4]3[CH:3]=[C:2]([CH2:88][N:85]4[CH2:86][CH2:87][N:82]([C:80]([O:79][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:81])[CH2:83][C@H:84]4[CH3:93])[CH:7]=[N:6][C:5]=3[F:8])[N:10]=2)=[CH:19][CH:20]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C[B-](F)(F)F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(CCC)c1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)C[C@H]4C)cnc3F)n2)cc1
Temperature: 85 °C
Yield: 73.7 %

Procedure:
In a 5 mL microwave tube was weighed 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.00 g, 2.084 mmol; Example 313, Step 1), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (0.099 g, 0.208 mmol), cesium carbonate (2.037 g, 6.25 mmol), potassium (R)-((4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)methyl)trifluoroborate (prepared similarly according to Example 270, Step 1, from (R)-4-N-boc-2-methyl-piperazine (Sigma Adrich, Inc.), 0.701 g, 2.188 mmol,), palladium acetate (0.023 g, 0.104 mmol) followed by purging with argon. The solids were then treated with THF (10.00 mL), water (1.0 mL) and heated under a microwave irradiation at 85° C. overnight. The mixture was filtered through a short path of Celite® (diatomaceous earth), washed with ethyl acetate (3×), and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a silica gel column (100% DCM to 5% MeOH in DCM) to obtain the desired product (R)-tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate (1.01 g, 1.535 mmol, 73.7% yield) as a yellow foam. m/z (ESI, +ve ion) 658 (M+H)+.
Reaction SMILES: C[O:2][B:3]([O:6]C)OC.[Cl-].[Mg+2].[Cl:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1.[Cl-]>C(OCC)C>[Cl:10][C:11]1[CH:16]=[C:15]([B:3]([OH:6])[OH:2])[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ccccc1
Reactant: COB(OC)OC
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOCC
Product: OB(O)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of trimethylborate in 200 mL of ethyl ether was cooled to -65° C. 3-Chlorobenzene magnesium chloride (0.8M, 60 mL), i.e., a grignard reagent, was added to the solution in a dropwise manner over 20 minutes. The mixture was kept in the temperature range of -60° C. to -70° C. and stirred. After 30 minutes, the mixture was allowed to warm to 0° C. and stirred for 1 hour. The mixture was quenched with H2O (25 mL) and stirred at room temperature for 1 hour. The solvent was removed and the remaining mass was extracted with ethyl ether (3×100 mL). The organic layers were combined and washed with H2O (2×50 mL), dilute HCl (2×100 mL), H2O (2×50 mL) and brine 1×50 mL). The organic layer was dried with MgSO4 and concentrated, and 100 mL of hexanes was added, and the mixture stirred for 1 hour. The resultant white precipitate was filtered off and allowed to air dry, yielding 4.6 g of 3-chlorobenzene boronic acid, a compound of Formula 4 where R4 is 3-chlorophenyl, as a white solid.
Reaction SMILES: NC1N=C2C(NC=N2)=C([Cl:11])N=1.C(=O)([O-])[O-].[K+].[K+].O.NC1N=C2C(N=CN2[CH:29]2[C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:30]2([Cl:43])[Cl:42])=C(Cl)N=1>CS(C)=O>[Cl:11][C:30]([Cl:42])([Cl:43])[CH:29]=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CCOC(=O)C1(C(=O)OCC)C(n2cnc3c(Cl)nc(N)nc32)C1(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(=CC(Cl)(Cl)Cl)C(=O)OCC
Temperature: 25 °C
Yield: 82.8 %

Procedure:
In a one-liter four-necked flask, 50.0 g (294.9 mmol) of 2-amino-6-chloropurine (manufactured by Sumika Fine Chemicals Co., Ltd.) and 88.2 g (648.0 mmol) of potassium carbonate were added to 650 ml of dimethylsulfoxide, and 26.1 g (1449.9 mmol) of water was then added to the resulting mixture. The resulting mixture was stirred at room temperature. Next, 127.4 g (440.0 mmol) of diethyl 2,2,2-trichloroethylidenemalonate, which was prepared by the process described in U.S. Pat. No. 3,495,012, was added to the resulting mixture, and the mixture was stirred for two hours and a half at room temperature. Thereafter, the reaction mixture was filtered, and the filtrate was poured into water. The precipitated crystals were collected by filtration, washed with 100 ml of water, and then dried under reduced pressure, to give 101.5 g (240.1 mmol) of white crystals of 2-amino-6-chloro-9-(3,3-dicarboethoxy-2,2-dichlorocyclopropyl)purine. The yield was 82.8%.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13](OC)=[O:14]>C1COCC1.CO>[CH3:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[CH2:13][OH:14]
Reactant: COC(=O)c1nc2ccccn2c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CO)nc2ccccn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
Sodium borohydride (1.5 g, 41.6 mmol) was added to a solution of methyl 3-methylimidazo[1,2-a]pyridine-2-carboxylate (2.0 g, 10.5 mmol) in THF (50 mL) and methanol (2.5 ml) at RT. The reaction mixture was stirred at RT for 2 h (the reaction was monitored by TLC) upon which the mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (3-methylimidazo[1,2-a]pyridin-2-yl)methanol (0.8 g, 47.05%) as off-white solid. 1H NMR: 200 MHz, CDCl3: δ 7.45 (d, 1H), 7.6 (d, 1H), 7.2 (t, 1H), 6.8 (t, 1H), 4.85 (s, 2H), 2.45 (s, 3H). MS: [M+H]+: m/z=162.9.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[C:6]=2[C:5]([Cl:14])=[CH:4][CH:3]=1.Cl[C:16](OC(Cl)(Cl)Cl)=[O:17]>C1(C)C=CC=CC=1>[Cl:14][C:5]1[C:6]2[C:7](=[O:13])[C:8]([CH3:11])([CH3:12])[O:9][C:10]=2[C:2]([N:1]=[C:16]=[O:17])=[CH:3][CH:4]=1
Reactant: CC1(C)Oc2c(N)ccc(Cl)c2C1=O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1(C)Oc2c(N=C=O)ccc(Cl)c2C1=O
Yield: 99.9 %

Procedure:
By the method of Example 1, Step F, 2.70 g (0.012 mole) of 7-amino-4-chloro-2,3-dihydro-2,2-dimethylbenzofuran-3-one was reacted with 2.37 g (0.012 mole) of trichloromethyl chloroformate in toluene, yielding 2.85 g of 4-chloro-2,3-dihydro-2,2-dimethylbenzofuran-3-on-7-yl isocyanate.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([O:38][C:39]2[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=2[NH:46][C:47]2[C:48]3[C:55]([CH3:56])=[C:54]([C:57](O)=[O:58])[S:53][C:49]=3[N:50]=[CH:51][N:52]=2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C.[CH3:69][N:70]1[CH:74]=[CH:73][C:72]([NH2:75])=[N:71]1>CN(C=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([O:38][C:39]2[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=2[NH:46][C:47]2[C:48]3[C:55]([CH3:56])=[C:54]([C:57](=[O:58])[NH:75][C:72]4[CH:73]=[CH:74][N:70]([CH3:69])[N:71]=4)[S:53][C:49]=3[N:50]=[CH:51][N:52]=2)[CH2:33]1)=[O:31])([CH3:27])([CH3:28])[CH3:26]
Reactant: Cn1ccc(N)n1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c12
Agent: 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: Cc1c(C(=O)Nc2ccn(C)n2)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU was added into a solution of 4-[2-((S)-1-tert-Butoxycarbonyl-piperidin-3-yloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (100 mg) and DIPEA in anhydrous DMF (2 ml) at 0° C. The reaction was stirred for 0.5 h when 1-methyl-1H-pyrazol-3-amine (100 μl) was added and the reaction allowed to warm to room temperature and stirred for 2 h. The DMF was removed by co-evaporation from toluene and the residue was purified by chromatography to give the intended product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[N:42]1([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([N:45]1[CH2:44][CH2:43][N:42]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:47][CH2:46]1)=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)Cc1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
2-(2,4-Difluorophenyl)acetic acid (5.00 g, 29.1 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (4.46 g, 29.1 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.57 g, 29.1 mmol) and triethylamine (4.05 mL, 29.1 mmol) were stirred in DCM (30 mL) for 15 min. tert-Butyl piperazine-1-carboxylate (2.71 g, 14.5 mmol) was added and the mixture was stirred at room temperature for 8 h. The reaction was diluted with DCM (10 mL) and washed with 1 N NaOH (5 mL), followed by 1 M citric acid (5 mL). The organic extracts were dried over Na2SO4, filtered and concentrated to afford an oil that was purified by RP-HPLC. The best fractions were lyophilized to afford material that was neutralized with NaHCO3 (75 mL), and extracted with EtOAc (2×200 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated to afford the title compound (1.68 g) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 1.42 (s, 9H), 3.25-3.39 (m, 4H), 3.42-3.48 (m, 2H), 3.49-3.56 (m, 2H), 3.74 (s, 2H), 7.02 (dt, J=2.7, 8.5 Hz, 1H), 7.18 (dt, J=2.6, 9.7 Hz, 1H), 7.25-7.33 (m, 1H). Exact mass calculated for C17H22F2N2O3: 340.2. Found: LCMS m/z=341.3 (M+H+).
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[CH3:12][N:13]([CH3:27])[C:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1.CI>C1COCC1>[CH3:12][N:13]([CH3:27])[C:14]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:19][CH2:18][C:17](=[O:20])[CH:16]([CH3:1])[CH2:15]1
Reactant: [Li]CCCC
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1CC(c2ccccc2)(N(C)C)CCC1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Diisopropylamine (2.1 ml, 15 mmol) was provided in dry THF in argon and mixed with n-butyl lithium in hexane (2.5M, 6 ml, 15 mmol) at 30° C. The reaction mixture was cooled to −78° C. 4-(dimethylamino)-4-phenylcyclohexanone (2.17 g, 10 mmol), dissolved in 10 ml of dry THF, was added in drops to this solution within 10 min. The batch was stirred for 30 min at −78° C. and then mixed with methyl iodide (1.86 ml, 30 mmol). It was heated to RT and stirred for a further 18 h. The solvent was removed at the rotary evaporator and the residue taken up in DCM. Extraction was conducted with 1N HCl (3×30 ml). The aqueous phase was basified with 5N NaOH (20 ml) and extracted with DCM (3×30 ml). The combined organic phases were washed with H2O (2×10 ml) and dried over Na2SO4. The semisolid residue (1.2 g) obtained after removal of the solvent was recrystallised from ethyl acetate (1 ml).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14].Cl>C1COCC1>[Cl:8][C:6]1[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]2[O:12][C:13](=[O:14])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)cc([N+](=O)[O-])c1O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)cc([N+](=O)[O-])c2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-amino-4-chloro-6-nitrophenol (2.00 g, 10.6 mmol) in THF (50 mL) was added 1,1′-carbonyldiimidazole (2.06 g, 12.7 mmol) and the resulting mixture was stirred at ambient temperature for 1 h. The mixture was poured into 1 N hydrochloric acid and the precipitate was isolated by filtration, washed with H2O, then hexanes, and dried in vacuo to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27].O>ClCCl>[N+:12]([C:3]1[C:4]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])=[N:5][C:6]2[C:11]([CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCCCCO
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc2ccccc2nc1NCCCCO
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a stirred mixture of 4-chloro-3-nitroquinoline (100.0 g, 479 mmol) and triethylamine (72.8 g, 719 mmol) in dichloromethane (700 mL) was added dropwise 4-amino-1-butanol (42.7 g, 479 mmol). After the addition was complete, water (500 mL) was added to the reaction mixture to cause the product to precipitate. More water (2 L) was added, and the mixture was stirred overnight and then filtered. The organic solution was dried over sodium sulfate, concentrated under reduced pressure, and combined with the product isolated by filtration to provide 4-(3-nitroquinolin-ylamino)butan-1-ol (113 g) as a bright yellow solid.
Reaction SMILES: C([O:8][C:9]1[C:10](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:11][CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[C:10]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)/C=C/c1ncccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ncccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
To a solution of (E)-ethyl 3-(3-(benzyloxy)pyridin-2-yl)acrylate (3.00 g) in MeOH was added a catalytic amount of 10% Pd/C. The reaction mixture was stirred for 2 h at room temperature under H2 and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (1.34 g, 65.00%), and the crude product was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 196.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 9.41 (bs, 1H), 8.15-8.21 (m, 1H), 7.3-7.0 (m, 2H), 4.15-4.05 (m, 2H), 3.15 (t, J=4.2 Hz, 2H), 2.85 (t, J=8.0 Hz, 2H), 1.2 (t, J=4.2 Hz, 2H) ppm.