Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([Cl:23])[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([S:14]([CH2:17][CH:18]3[CH2:20][CH2:19]3)(=[O:16])=[O:15])[CH:8]=2)=[C:4]([Cl:24])[CH:3]=1.C(N(CC)CC)C.C([CH:34]([C:38](Cl)=[O:39])[C:35](Cl)=[O:36])C.C1C[O:44][CH2:43][CH2:42]1>>[CH2:43]([O:44][C:38](=[O:39])[CH2:34][C:35]([NH:1][C:2]1[CH:3]=[C:4]([Cl:24])[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([S:14]([CH2:17][CH:18]3[CH2:20][CH2:19]3)(=[O:16])=[O:15])[CH:8]=2)=[C:21]([Cl:23])[CH:22]=1)=[O:36])[CH3:42]
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: Nc1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)CC3CC3)c2)c(Cl)c1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)Nc1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)CC3CC3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(4-amino-2,6-dichloro-phenoxy)-2-cyclopropylmethane-sulfonyl-phenol (43 mg, 0.11 mmol) in THF (2 mL) was added triethylamine (17 μL, 0.12 mmol) and ethyl malonyl chloride (14 μL, 0.11 mmol). The resulting mixture was stirred at RT for 3 h. The solution was concentrated and the residue was purified by preparative TLC (2% MeOH in CH2Cl2) to give the title compound of Step F (42 mg). MS (APCI−) Calc.: 501.0, Found: 500.3 (M−1).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:18])([F:17])[F:19])=[N:14][N:15]=4)[CH:12]=3)[CH2:6][CH2:5]2)=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)cn12
Product: Fc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4c3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine with 4-fluorobenzaldehyde was carried out according to General Synthetic Method 9. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([N:12]=C(C1C=CC=CC=1)C1C=CC=CC=1)=[CH:7]2.Cl.C(=O)(O)[O-:28].[Na+]>O1CCCC1>[NH2:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([OH:28])=[CH:3][CH:4]=[N:5]2)=[N:10][CH:9]=1
Reactant: O=C([O-])O
Reactant: Clc1ccnc2cc(N=C(c3ccccc3)c3ccccc3)cnc12
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cnc2c(O)ccnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A round bottom flask under nitrogen was charged with 8-chloro-N-(diphenylmethylene)-1,5-naphthyridin-3-amine (315 mg, 0.92 mmol), 2M aqueous HCl (1.42 mL, 2.84 mmol), and tetrahydrofuran (0.25M, 3.67 mL). This was stirred at RT for 30 minutes. Reaction basified with aq. sodium bicarbonate solution and product extracted with dichloromethane. This was dried over sodium sulfate and concentrated to afford orange solid; which was purified via ISCO silica gel chromatography, 40 g column, 30% (90/10/1 DCM:MeOH:NH4OH)/DCM over 40 minutes to afford 7-amino-1,5-naphthyridin-4-ol (140 mg, 95% yield) as yellow solid. MS[M+H]=180.2. Calc'd for C8H6ClN3=179.6.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13](=O)[CH3:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O1CCOCC1.[C:22]([NH2:26])(=[O:25])[CH:23]=[CH2:24].CC(C)([O-])C.[K+]>O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH2:24][CH2:23][C:22](=[O:25])[NH:26][C:13]=3[CH3:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)Cc1ccc(-n2ccnc2)cc1
Reactant: C=CC(N)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC1=C(c2ccc(-n3ccnc3)cc2)CCC(=O)N1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 3 g 1-[4-(1-imidazolyl)-phenyl]-2-propanone (EPA 102 227, example 4), 30 ml 1,4-dioxane, 1,2 g acrylic acid amide and 1.73 g potassium tert-butoxide is stirred for 40 minutes at room temperature and subsequently for 2 hours at 100° C. After cooling it, water is added, the precipitated solid is sucked off, washed with water, dried and purified by column chromatography (silica gel/dichloromethan/methanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O)[C:5]([O:7][CH3:8])=[O:6].[H][H]>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)c(F)c1
Yield: 99.7 %

Procedure:
In 150 ml ethyl acetate was dissolved 5.74 grams methyl 3-fluoro-4-nitrobenzoate and the resulting solution was hydrogenated in the Parr apparatus (45 psi) over 600 mg 10% Pd-on-C for about 45 minutes, when the hydrogen uptake ceased. The catalyst was removed by filtration and the solvent was removed in vacuo to give 4.86 grams methyl 3-fluoro-4-aminobenzoate as an off-white solid, m.p. 107°-110° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:11](OCC)(=[O:16])[CH2:12][C:13]([CH3:15])=O>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:11](=[O:16])[CH:12]=[C:13]([CH3:15])[NH:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1ccc(NN)cc1C
Solvent: CC(=O)O
Product: Cc1cc(=O)n(-c2ccc(C)c(C)c2)[nH]1
Yield: 156.7 %

Procedure:
A solution of 3,4-dimethylphenylhydrazine (7.3 g; 0.053 mol.) and ethyl acetoacetate (6.9 g; 0.053 mol.) in glacial acetic acid (50.0 mL) was stirred and heated at 100° for 24h. The solvent was evaporated and the product purified by chromatography (silica gel, 50% ethyl acetate/hexanes) to afford the title compound (16.8 g; 64%). MS(ES) m/z 203 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:13]=[CH:14]/[C:15]([O:17]CC)=[O:16])[N:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@@H:8]2[CH3:12])[CH:6]=1.[OH-].[Na+].CO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[N:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@@H:8]2[CH3:12])[CH:6]=1
Reactant: CCOC(=O)/C=C/c1cc(Br)cn1[C@@H]1CCC[C@@H]1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H]1CCC[C@H]1n1cc(Br)cc1/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.2 %

Procedure:
To a solution of ethyl (2E)-3-(4-bromo-1-(cis-2-methylcyclopentyl)-1H-pyrrol-2-yl)acrylate (800 mg) in THF (7.36 mL) were added 1N aqueous sodium hydroxide solution (7.36 mL) and methanol (10 mL) at room temperature, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure to evaporate the methanol and THF, and the remaining aqueous solution was washed with diethyl ether (100 mL). The obtained aqueous layer was acidified with 1N hydrochloric acid (7.36 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (711 mg).
Reaction SMILES: C([O-])(=O)C.[Na+].[O:6]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[O:9][CH2:8][CH2:7]1.Cl.[NH2:25][OH:26].C(O)C>O>[O:6]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[N:25][OH:26])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[O:9][CH2:8][CH2:7]1
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 70 °C
Reaction time: 10 h
Yield: 118.7 %

Procedure:
A solution of sodium acetate (6.64 g, 60.72 mmol) in water (10 mL) was added into a mixture of 4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzaldehyde (5.0 g, 20.24 mmol) benzaldehyde(Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606), hydroxylamine hydrochloride (4.22 g, 60.72 mmol), ethyl alcohol (300 mL), and water (50 mL). The mixture was stirred at 70° C. for 10 hours, then poured into water and extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/ethyl acetate 2/1) gave a white solid (6.3 g, 90% yield); mp 151-152° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.63 (m, 4H), 3.35 (m, 4H), 3.90 (s, 4H), 6.96 (m, 2H), 7.40 (m, 2H), 7.96 (s, 1H), 10.75 (s, 1H); MS (ES) m/z: 263 (MH+); Anal. Calcd. for C14H18N2O3: C, 64.11; H, 6.92; N, 10.68. Found: C, 64.24; H, 6.81; N, 10.64.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)=[CH:6][C:5]([C:22]#[N:23])=[CH:4][C:3]=1[NH:24][C:25]1[N:30]=[C:29]([N:31]([CH:41]2[CH2:43][CH2:42]2)CC2C=CC(OC)=CC=2)[C:28]2=[N:44][CH:45]=[C:46]([C:47]#[N:48])[N:27]2[N:26]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[O:15])[CH2:9]2)=[CH:6][C:5]([C:22]#[N:23])=[CH:4][C:3]=1[NH:24][C:25]1[N:30]=[C:29]([NH:31][CH:41]2[CH2:43][CH2:42]2)[C:28]2=[N:44][CH:45]=[C:46]([C:47]#[N:48])[N:27]2[N:26]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCOC(C(=O)N5CCOCC5)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCOC(C(=O)N3CCOCC3)C2)c1
Temperature: 25 °C
Yield: 24.4 %

Procedure:
To a round bottom flask charged with 2-((2-chloro-5-cyano-3-(2-(morpholine-4-carbonyl)morpholino)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (64.9 mg, 0.097 mmol) in dichloromethane (485 μl) was added anisole (21.19 μl, 0.194 mmol), followed by TFA (224 μl, 2.91 mmol). The reaction mixture was stirred at rt ON. Additional TFA (224 μl, 2.91 mmol) was added. Stir at rt ON. Additional TFA (224 μl, 2.91 mmol) was added and the reaction mixture was stirred at rt ON. Excess TFA was removed by concentration in vacuo. The crude residue was taken up in methanol and free based using a Phenomenex Strata 1 g SCX column. The column was flushed with 3 column volumes methanol and 3 column volumes 3.5 N ammonia/methanol. The ammonia layers were concentrated in vacuo. The crude material was purified by neutral phase preparatory LC/MS chromatography to provide (+/−) 2-((2-chloro-5-cyano-3-(2-(morpholine-4-carbonyl)morpholino)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (13 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[O:9][C:8]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=1)=[CH:7]2.[F:26][C:27]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:7][C:8](=[O:9])[C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[C:11]=1[C:10]([NH:30][CH2:29][C:28]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:27]=1[F:26])=[O:12]
Reactant: NCc1ccc(F)cc1F
Reactant: O=c1oc(-c2ccc(Oc3ccccc3)cc2)cc2cccc(Cl)c12
Solvent: Cc1ccccc1
Product: O=C(Cc1cccc(Cl)c1C(=O)NCc1ccc(F)cc1F)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
Alternatively, 8-chloro-3-(4-phenoxyphenyl)isochromen-1-one (48 mg, 0.14 mmol) and 2,4-difluorobenzylamine (24 μL, 0.20 mmol) were combined in toluene (2.0 mL) in a round-bottomed flask under nitrogen. To the resulting mixture was added a solution of methyl aluminoxane (0.11 mL, of a 1.5 M solution in toluene, 0.16 mmol). The resulting yellow solution was then heated to reflux. TLC of the reaction mixture after 1 hour at reflux showed no 8-chloro-3-(4-phenoxyphenyl)isochromen-1-one remaining. Heating was discontinued and the reaction was allowed to cool to ambient temperature. The reaction was then quenched by the addition of 1N HCl (aq.) (5 mL), and diluted with EtOAc (25 mL). The layers were separated and the acidic aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with H2O (10 mL), saturated aqueous NaHCO3 (10 mL), then brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a white solid. The crude solid was purified by silica gel column chromatography by adsorbing the material onto silica gel from a CH2Cl2 solution, loading the resulting solid onto the column and eluting with a gradient from 0% to 20% EtOAc/hexane. The main peak that eluted was collected to afford a compound of formula (W), 2-chloro-N-(2,4-difluorobenzyl)-6-[2-oxo-2-(4-phenoxyphenyl)ethyl]benzamide, (54 mg, 79% yield) as a white solid; 1H-NMR (400 MHz, CDCl3): δ 7.87-7.82 (2H, m), 7.46-7.41 (2H, m), 7.35-7.21 (4H, m), 7.14-7.10 (2H, m), 7.05-7.02 (1H, m), 7.01-6.96 (2H, m), 6.66-6.60 (1H, m), 6.53-6.47 (1H, m), 6.43 (1H, t, J=6.1 Hz), 4.49 (2H, d, J=6.1 Hz), 4.25 (2H, s); which could be used in the next step to produce a corresponding compound of formula (Id).
Reaction SMILES: CN(P(N(C)C)(N(C)C)=O)C.[CH3:12][C:13]1([CH3:21])[O:18][C:17](=[O:19])[CH:16]=[C:15]([CH3:20])[O:14]1.[CH2:22]([O:29][CH2:30][C:31](Cl)=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Li+].CC([N-]C(C)C)C.Cl>C(OCC)(=O)C.CCOCC>[CH3:12][C:13]1([CH3:21])[O:18][C:17](=[O:19])[CH:16]=[C:15]([CH2:20][C:31](=[O:32])[CH2:30][O:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:14]1
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: O=C(Cl)COCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1(C)OC(=O)C=C(CC(=O)COCc2ccccc2)O1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
In an argon gas stream, 13.75 ml of n-butyl lithium (1.6M solution in hexane) were added to 60 ml of an ether solution containing 2.35 g (0.022 mol) of diisopropylamine at -20° C. to form LDA. After stirring for 30 minutes, the solution was cooled to -78° C., and 6.93 ml (0.04 mol) of HMPA were added thereto, followed by stirring for 15 minutes. Afterward, a mixture of 2.84 g (0.02 mol) of 2,2-dimethyl-6-methyl-1,3-dioxin-4-one and 60 ml of ether as well as 60 ml of an ether solution containing 1.85 g (0.01 mol) of benzyloxyacetyl chloride were added to LDA. After the temperature was gradually returned to room temperature, 10% hydrochloric acid was added thereto to neutralize the solution, and extraction was then carried out with ether. The resultant organic layer was dried over anhydrous magnesium sulfate. Next, the used solvent was distilled off, and the residue was then subjected to column chromatography (an eluent of hexane:ethyl acetate =4:1), thereby obtaining 1.95 g (yield 67%) of 2,2-dimethyl-6-(3-benzyloxy-2-oxopropyl)-1,3-dioxin-4-one.
Reaction SMILES: [Br:1]CC1[CH:4]=[C:5]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:17][CH:16]=2)=O)[CH:6]=[CH:7][CH:8]=1.[CH3:36][C:37]1[S:41][CH:40]=[N:39][CH:38]=1.[CH3:42][CH2:43][O:44]CC>C1(C)C=CC=CC=1>[Br-:1].[C:43]([N:12]([CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:19][CH:20]=1)[C:10]1[CH:9]=[C:5]([CH2:4][N+:39]2[CH:38]=[C:37]([CH3:36])[S:41][CH:40]=2)[CH:6]=[CH:7][CH:8]=1)(=[O:44])[CH3:42]
Reactant: Cc1cncs1
Reactant: CCOCC
Reactant: CCCCCCCCCCCCCCOc1ccc(CCNC(=O)Cc2cccc(CBr)c2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCOc1ccc(CCN(C(C)=O)c2cccc(C[n+]3csc(C)c3)c2)cc1
Product: [Br-]

Procedure:
A mixture of 2.5 g N-[3-(bromomethyl)phenyl-N-[2-[4-(tetradecyloxy)phenyl]ethyl]acetamide and 2.28 g of 5-methylthiazole in 50 ml of toluene is refluxed for 5 hours, cooled and ether added. The solid is collected by centrifugation and washed several times with ether then vacuum dried to give 1.8 g of the desired product as a white solid, m.p. 136°-140° C.
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:48])[CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2[N:23]=[C:22]([NH:24][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[N:30](C(OC(C)(C)C)=O)[N:29]=[CH:28]4)[C:21]3[C:16](=[CH:17][C:18]([O:46][CH3:47])=[C:19]([O:41][CH2:42][CH2:43][O:44][CH3:45])[CH:20]=3)[N:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:30]1[C:31]2[C:27](=[CH:26][C:25]([NH:24][C:22]3[C:21]4[C:16](=[CH:17][C:18]([O:46][CH3:47])=[C:19]([O:41][CH2:42][CH2:43][O:44][CH3:45])[CH:20]=4)[N:15]=[C:14]([C:10]4[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=4)[O:7][CH2:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:48])[N:23]=3)=[CH:33][CH:32]=2)[CH:28]=[N:29]1
Reactant: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(OCC(=O)NC(C)C)c3)nc2cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1cc2c(Nc3ccc4[nH]ncc4c3)nc(-c3cccc(OCC(=O)NC(C)C)c3)nc2cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude tert-butyl 5-(2-(3-(2-(isopropylamino)-2-oxoethoxy)phenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate from the previous step was taken up in CH2Cl2 (2 mL) and TFA (5 mL). The mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo and a portion of the residue was purified by preparative HPLC (10-35-90, 10-30-90, 0-15-90, 5-20-90 and 20-40-90 methods) to give 2-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)-quinazolin-2-yl)phenoxy)-N-isopropylacetamide (0.039 g, 68.4 mmol). MS 557 (M+1). HPLC retention time 5.48 mins.
Reaction SMILES: [C:1]([CH:4]1[N:9]([C:10]2[CH:15]=[C:14]([C:16](=[O:18])[NH2:17])[N:13]=[C:12]([Cl:19])[N:11]=2)[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)(=[O:3])[NH2:2].CO>O1CCOCC1.Cl>[ClH:19].[C:1]([CH:4]1[CH2:5][NH:6][CH2:7][CH2:8][N:9]1[C:10]1[N:11]=[C:12]([Cl:19])[N:13]=[C:14]([C:16]([NH2:17])=[O:18])[CH:15]=1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(C(N)=O)nc(Cl)n2)C(C(N)=O)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC(=O)c1cc(N2CCNCC2C(N)=O)nc(Cl)n1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-carbamoyl-4-(6-carbamoyl-2-chloropyrimidin-4-yl)piperazine-1-carboxylate (4.744 g, 12.33 mmol) in dioxane (25 mL) was added 4M HCl in dioxane (5.0 mL, 20.0 mmol). After stirring overnight the reaction was diluted with additional dioxane (25 mL) and 4M HCl in dioxane (5.0 mL, 20.0 mmol). After 5 h, MeOH (10 mL) was added. After stirring overnight more MeOH (10 mL) was added. After stirring one more night the reaction was evaporated in vacuo to give crude 6-(2-carbamoylpiperazin-1-yl)-2-chloropyrimidine-4-carboxamide hydrochloride. The crude hydrochloride salt was suspended in THF (50 mL). To this was added iPr2NEt (7.10 mL, 40.8 mmol) and methyl iodide (0.85 mL, 13.7 mmol). The reaction vessel was sealed and heated at 70° C. for 5 h. The reaction mixture was cooled and partitioned between EtOAc (100 mL) and water (50 mL). The organics were isolated and saved. 1N aqueous NaOH was added to the aqueous layer then it was extracted with EtOAc (100 mL). These organics were also isolated and saved. Once more, 1N aqueous NaOH was added to the aqueous layer then it was extracted with EtOAc (100 mL). The organics were isolated and combined with the other batches of organic extracts. The combined organics were dried over Na2SO4, filtered, and evaporated in vacuo. The solid residue was triturated with MeOH (5 mL), filtered, and washed with MeOH (1×2 mL). The solid was dried under vacuum at 40° C. to give 6-(2-carbamoyl-4-methylpiperazin-1-yl)-2-chloropyrimidine-4-carboxamide as a cream-colored powder (0.924 g, 3.09 mmol, 25% yield). LC/MS: m/z=299.1 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].O[N:27]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][C:37]([F:40])([F:39])[F:38])[NH2:29].CCN(C(C)C)C(C)C>>[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:22][N:29]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][C:37]([F:38])([F:39])[F:40])[N:27]=2)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccccc3OC(F)(F)F)no2)cc1[N+](=O)[O-]

Procedure:
Oxalyl chloride (118 μL; 1.40 mmol; 3 eq.), Intermediate 22 (120 mg; 0.47 mmol; 1 eq.), Intermediate 2 (103 mg; 0.47 mmol, 1 eq.) and DIEA (103 μL; 1.40 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 90/10) afforded the title compound as a yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[SH:6].Cl[C:8]1[S:12][C:11]([C:13](=[O:15])[CH3:14])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O>[N+:16]([C:9]1[CH:10]=[C:11]([C:13](=[O:15])[CH3:14])[S:12][C:8]=1[S:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)([O-:18])=[O:17]
Reactant: Sc1nccs1
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2nccs2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.9 %

Procedure:
To a solution of thiazole-2-thiol (0.05 g, 0.5 mmol) in toluene (10ML), was added 1-(5-Chloro-4-nitro-2-thienyl)ethanone (0.102 g, 0.5 mmol) and K2CO3 (0.69 g, 5 mmol). The resulting reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water (10 mL) and was extracted with ethyl acetate. The organic extract was dried (Na2SO4), concentrated under vacuum and the residue purified by silica gel chromatography using a mixture of 70:30 ethyl acetate and hexane as eluent to afford the title product as a solid (60 mg, 43% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.51 (2H, s), 8.26 (2H, dd), 8.23 (2H, dd), 2.54 (3H, s). MS m/z: 287.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:14](=[O:16])[CH3:15])=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([CH3:13])[C:11]=2[CH:12]=1.[CH3:17][Mg]Br>C1COCC1>[CH3:1][O:2][C:3]1[C:4]([C:14]([OH:16])([CH3:17])[CH3:15])=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([CH3:13])[C:11]=2[CH:12]=1
Reactant: COc1cc2c(cc1C(C)=O)CCCC2C
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1cc2c(cc1C(C)(C)O)CCCC2C
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
1-(3-Methoxy-5-methyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone (5.1 g, 23.37 mmol) was dissolved in 50 mL dry THF under nitrogen atmosphere, and the resulting solution was cooled in an ice bath. Methyl magnesium bromide (11.69 mL, 35.1 mmol in diethyl ether) was added dropwise, and the solution was stirred for one hour at 0° C., then for four hours at room temperature. The reaction mixture was poured into ice water and extracted with dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide 5.38 g of 2-(3-methoxy-5-methyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-propan-2-ol as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31]Br)[CH2:26][C@@H:25]2[CH3:34])=[C:20]([CH:35]=[CH:36][CH3:37])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:38]1[C:42]2[CH:43]=[C:44]([C:47]3([CH3:54])[NH:51][C:50](=[O:52])[NH:49][C:48]3=[O:53])[CH:45]=[CH:46][C:41]=2[CH2:40][CH2:39]1>>[CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31][N:49]3[C:48](=[O:53])[C:47]([C:44]4[CH:45]=[CH:46][C:41]5[CH2:40][CH2:39][O:38][C:42]=5[CH:43]=4)([CH3:54])[NH:51][C:50]3=[O:52])[CH2:26][C@@H:25]2[CH3:34])=[C:20]([CH:35]=[CH:36][CH3:37])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=Cc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)C[C@@H]1C
Reactant: CC1(c2ccc3c(c2)OCC3)NC(=O)NC1=O
Product: CC=Cc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc4c(c3)OCC4)C2=O)C[C@@H]1C

Procedure:
(S)-1-(4-{4-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-2-(prop-1-en-1-yl)phenyl}-3-methylpiperazin-1-yl)-2-bromoethanone and 5-(2,3-dihydrobenzofuran-6-yl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Example 14-1, and the title compound was obtained as a yellow oil.