Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].I[CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:20]([CH3:22])[CH3:21])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(O)c(F)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(F)c1
Temperature: 60 °C

Procedure:
To methyl 3-fluoro-4-hydroxy-benzoate (2.00 g, 11.8 mmol) in DMF (12.5 mL) was added K2CO3 (6.50 g, 47.0 mmol) followed by 2-iodopropane (2.35 mL, 23.5 mmol). The mixture was heated at 60° C. for 1.5 h. The mixture was filtered using EtOAc and the filtrate was evaporated under reduced pressure. The residue was dissolved in EtOAc and was washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give methyl 3-fluoro-4-isopropoxybenzoate. ESI-MS m/z calc 212.1, found 213.3 (M+1)+. Retention time: 1.70 minutes (3 min run).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[SH:10][CH2:11][CH2:12][CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][CH2:11][S:10][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: OCCCS
Product: N#Cc1ccc(SCCCO)cc1

Procedure:
5 g of 4-fluorobenzonitrile was used in Procedure Q with 3-mercapto-1-propanol to afford 4-(3-hydroxypropylthio)benzonitrile. 1.8 g of 4-(3-hydroxypropylthio)benzonitrile was reacted via Procedure T to give 4-(3-hydroxypropylthio)benzoic acid. 1.2 g of 4-(3-hydroxypropylthio)benzoic acid was reacted via Procedure R to give 4-(3-hydroxypropylsulfonyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(3-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-hydroxypropylsulfonyl)benzamide. MS (Q1) 431.3 (M)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.[Cl:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[O:25][CH2:26][C@@H:27]([NH:29][CH3:30])[CH3:28])[N:18]=[CH:17][N:16]=2)[CH:11]=[CH:10][C:9]=1[OH:31]>>[Cl:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[O:25][CH2:26][C@@H:27]([N:29]([CH3:30])[C:4](=[O:6])[CH2:3][O:2][CH3:1])[CH3:28])[N:18]=[CH:17][N:16]=2)[CH:11]=[CH:10][C:9]=1[OH:31]
Reactant: COCC(=O)O
Reactant: CN[C@@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Product: COCC(=O)N(C)[C@@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Yield: 49 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using methoxyacetic acid and 2-chloro-4-[(5-{[(2S)-2-(methylamino)propyl]oxy}quinazolin-4-yl)amino]phenol (obtained as described in Example 56, preparation of starting materials) to give N-[(1S)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-2-methoxy-N-methylacetamide in 49% yield; Mass spectrum MH+ 429.2.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH2:15]([C:18]1[C:26]2[O:25][N:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:22]=2[CH:21]=[CH:20][C:19]=1[O:31][CH2:32][CH2:33][CH2:34]Br)[CH2:16][CH3:17]>>[CH3:1][C:2]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:6][C:5](=[O:7])[N:4]([CH2:34][CH2:33][CH2:32][O:31][C:19]2[CH:20]=[CH:21][C:22]3[C:23]([C:27]([F:29])([F:30])[F:28])=[N:24][O:25][C:26]=3[C:18]=2[CH2:15][CH2:16][CH3:17])[C:3]1=[O:8]
Reactant: CC1(c2ccccc2)NC(=O)NC1=O
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Product: CCCc1c(OCCCN2C(=O)NC(C)(c3ccccc3)C2=O)ccc2c(C(F)(F)F)noc12

Procedure:
rac-5-Methyl-5-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione was prepared as for Example 10 from 5-methyl-5-phenylimidazolidine-2,4-dione and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(=O)([O-])[O-].[Na+].[Na+].[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>O>[S:17]([NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:10])=[O:9])([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2C(=O)O)cc1
Temperature: 78 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
In a 1 L reaction flask equipped with a condenser, 34.25 g (0.25 mol) of anthranilic acid, 411 g of water and 63.59 g (0.6 mol) of sodium carbonate were heated. The resulting reaction solution was maintained at an inner temperature of 78° C. for 30 minutes and then cooled to 67° C., and 57.2 g (0.3 mol) of tosyl chloride was added in two portions. The reaction solution gradually generated heat upon addition of tosyl chloride and turned homogeneous at 78° C. The reaction solution was aged at 80° C. for 1 hour. Crystals started to separate out in the first ten or so minutes of the aging. The completion of the reaction was confirmed by liquid chromatography, and the reaction solution was carefully neutralized with concentrated hydrochloric acid and allowed to cool. The crystals were collected by filtration at room temperature and washed with 100 ml of dilute hydrochloric acid at pH 3 and with 125 ml of water. Recrystallization from 247 g of n-propanol afforded 56.97 g of tosylanthranilic acid in a 78.3% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:5])[O:4][CH2:3]1.[F:6][C:7]1[CH:12]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[C:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[O:23][C:20]2=[CH:21][N:22]=1>CO.ClCCl>[F:6][C:7]1[CH:12]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[C:24]([CH:26]3[CH2:31][CH2:30][N:29]([CH2:3][C:2]([CH3:5])([OH:4])[CH3:1])[CH2:28][CH2:27]3)[O:23][C:20]2=[CH:21][N:22]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc3cc(C4CCNCC4)oc3cn2)c(F)c1
Reactant: CC1(C)CO1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(O)CN1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4F)ncc3o2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
1,1-Dimethyloxirane (55 μL) is added to a solution of 5-(2-fluoro-4-methanesulfonyl-phenyl)-2-piperidin-4-yl-furo[2,3-c]pyridine (0.15 g) in methanol (2 mL) and dichloromethane (3 mL) at room temperature. The solution is stirred at 50° C. overnight. The solution is concentrated to give the crude title compound that is used without further purification. LC (method 4): tR=0.98 min; Mass spectrum (ESI+): m/z=447 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[C:4]#[N:5].C(=O)(O)[O-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C.[I-].[Na+]>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][NH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[C:4]#[N:5])[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(N)c(C#N)cc1OC
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1cc(OC)c(OC)cc1C#N
Temperature: 25 °C
Yield: 20.4 %

Procedure:
Under N2 suspend 2-amino-4,5-dimethoxybenzonitrile (2.0 g, 12.25 mmol) in ethanol (50 mL), and add sodium bicarbonate (3.09 g, 36.78 mmol) in one portion. By syringe, slowly add ethyl bromoacetate (2.72 mL, 24.5 mmol), and then sodium iodide (10 mg). Heat the reaction at 65° C. and then cool to ambient temperature. Filter the resulting solid and wash with ethyl acetate to dissolve the organics. Concentrate the filtrate to obtain 0.66 g (23%) of the title compound; MS 265(M+H).
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([NH2:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C(C)=CC=CC=1>O>[CH2:8]([N:17]1[C:4](=[O:5])[CH:3]=[CH:2][C:1]1=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCCCCCCN
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCCCCCCN1C(=O)C=CC1=O
Temperature: 120 °C

Procedure:
One equivalent each of maleic anhydride and n-nonylamine are charged into a 1 liter 3-neck round bottom glass flask containing 300 ml xylene, a reflux condenser with a Dean-Stark attachment, Teflon-coated magnetic stirring bar, and a thermometer. The contents are heated to 120° C. for about 15 hours, the reaction extent being monitored by the amount of water collected. After 1 equivalent of water is collected, the reaction solvent is flash distilled off. The absence of an infrared absorbance at 1830 cm-1 and 1791 cm-1 is evidence of anhydride consumption; the presence of an infrared absorbance at 1772 cm-1 is evidence of imide formation.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[N:6]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[C:15]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:13])[N:8]=[CH:7]1)[CH3:2]>[Pd]>[CH2:1]([O:3][C:4](=[O:34])[CH:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[N:6]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[C:15]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:13])[N:8]=[CH:7]1)[CH3:2]
Reactant: CCCCCCC(C(=O)OCC)n1cnc(NC(=O)c2cccc([N+](=O)[O-])c2C(=O)OCC)c1
Agent: [Pd]
Product: CCCCCCC(C(=O)OCC)n1cnc(NC(=O)c2cccc(N)c2C(=O)OCC)c1
Yield: 98.4 %

Procedure:
A mixture of 5.1 g of a-hexyl-4-{[(3-nitro-2-ethoxycarbonylphenyl)carbonyl]amino}imidazole-1-acetic acid ethyl ester and 2.1 g of 5% palladium-on-carbon were hydrogenated in the presence of 150 ml of methanol until consumption of hydrogen ceased. The catalyst was removed by filtration and the filtrate concentrated in vacuo to provide 4.7 g of the desired subtitled intermediate. NMR.
Reaction SMILES: FC(F)(F)C(O)=O.[SH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1.O[CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH:20]([S:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=1)[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: COc1ccccc1C(O)Cn1ccnc1
Reactant: COC(=O)c1ccc(S)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccccc2OC)cc1
Reaction time: 2.7 h

Procedure:
8.3 ml of trifluoroacetic acid were added, whilst ice-cooling, to a mixture of 578 mg of methyl 4-mercaptobenzoate and 500 mg of 1-[2-hydroxy-2-(2-methoxyphenyl)ethyl]imidazole, and the mixture was stirred at a temperature between 0° and 5° C. for 2.7 hours, and then at room temperature for 2.5 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([O:16]CC)=[O:15])[NH:11][N:10]=2)=[C:5]2[NH:19][CH:20]=[C:21]([C:22](=[O:42])[C:23](=[O:41])[N:24]3[CH2:29][CH2:28][N:27]([C:30]4[N:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:33]=[N:32][N:31]=4)[CH2:26][CH2:25]3)[C:4]=12.O[Li].O.Cl>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[NH:11][N:10]=2)=[C:5]2[NH:19][CH:20]=[C:21]([C:22](=[O:42])[C:23](=[O:41])[N:24]3[CH2:25][CH2:26][N:27]([C:30]4[N:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:33]=[N:32][N:31]=4)[CH2:28][CH2:29]3)[C:4]=12
Reactant: CCOC(=O)c1cc(-c2ncc(OC)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)n[nH]1
Agent: Cl
Agent: [Li]O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cnc(-c2cc(C(=O)O)[nH]n2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c12
Temperature: 120 °C

Procedure:
To a suspension of ethyl 3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate (0.124 g, 0.217 mmol) in DMF (1.5 mL) and H2O (1.5 mL) was added LiOH monohydrate (0.027 g, 0.651 mmol). The mixture was heated to 120° C. for 24 h. The reaction was not complete, so an additional 0.05 g of LiOH hydrate along with 2 mL of H2O were added to the mixture, and it was again heated to 120° C. After 24 h of heating, the reaction was nearly complete by LCMS, so it was cooled to rt, and made acidic (pH =1) with 6N HCl. The mixture was diluted with H2O, and partitioned with EtOAc. The product precipitated from between the two layers, and was collected by filtration. The solids were washed with cold MeOH and H2O. The 3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylic acid (0.08 g) was collected as a light yellow solid. LCMS: m/e 542.97 (M+H)+, ret time 1.86 min (method 2). 1H NMR (500 MHz, DMSO-D6) δ ppm 12.10-12.22 (s, 1 H) 8.25 (s, 1 H) 8.10 (s, 1 H) 7.56-7.77 (m, 5 H) 7.39 (s, 1 H) 3.99 (s, 3 H) 3.67-3.72 (m, 2 H) 3.40-3.46 (m, 2 H) 3.29-3.36 (m, 2 H) 3.14-3.20 (m, 2 H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.O>CS(C)=O>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])=[CH:22][CH:21]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1OCc1ccc(F)cc1
Reaction time: 8 h

Procedure:
N-Hydroxyphthalimide (12.0 g) in 130 ml dimethyl sulphoxide is treated with anhydrous finely divided potassium carbonate (6.6 g), when the dark red colour of the anion develops. The mixture is then treated dropwise at room temperature with p-fluorobenzyl chloride (20 g) and the mixture is stirred overnight or until the red colour is discharged. The reaction mixture is poured into water, and the resultant crystalline product is filtered off. Recrystallisation from ethanol gives N-p-fluorobenzyloxyphthalimide in pure form as white needles. (16.4 g, 82%), m.p. 156°-157° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N+:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)([O-:30])=[O:29]>>[N+:28]([C:31]1[CH:36]=[C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:9]=3)[CH:3]=2)[CH:34]=[CH:33][CH:32]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1
Product: O=[N+]([O-])c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1

Procedure:
2-(3′-Nitro-biphenyl-3-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.3) (1.79 g, 4.0 mmol) and commercially available 3-nitro-phenylboronic acid (0.8 g, 4.8 mmol) according to the general procedure VI. Obtained as a light grey solid (1.74 g, 89%). MS (EI) 489.2 [(M)+]; mp 219° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.O.[NH2:14][NH2:15]>C(O)C>[Cl:8][C:7]1[C:2]([NH:14][NH2:15])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1ncc(C(F)(F)F)cc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 113.6 %

Procedure:
To a solution of 2,3-dichloro-5-(trifluoromethyl)pyridine (6.8 g) in ethanol (50 mL) was added hydrazine hydrate (3.15 g) in an ice bath, and the mixture was stirred overnight at 50° C. The mixture was allowed to be cooled to room temperature, and the solvent was evaporated under reduced pressure. The obtained residue was treated with IPE, and the precipitated solid was collected by filtration to give the title compound (7.57 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:12]=3[C:11]=2[CH2:10][CH2:9][CH2:8]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:12]2[C:11]3[CH2:10][CH2:9][CH2:8][N:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][NH:1][C:29](=[O:31])[CH3:30])[C:16]=3[CH2:15][CH2:14][C:13]=2[CH:17]=1
Reactant: CC(=O)Cl
Reactant: NCCCC(=O)N1CCCC2=C1CCc1cc(Cl)ccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCC(=O)N1CCCC2=C1CCc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 5.09 g (0.015 mol) of 4-(4-aminobutyryl) -8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline in 50 mI of methylene chloride are added 5 ml (0.036 mol) of triethylamine and then at 0° 1.33 ml (0.019 mol) of acetyl chloride dissolved in 15 ml of methylene chloride, and the mixture is stirred at room temperature for 1 hour. Then, the mixture is extracted with methylene chloride/ water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Crystallization from methylene chloride/ether, chromatography on silica gel with ethyl acetate/methanol (9:1) and renewed crystallization from methylene chloride/ether gives N-[4-[8-chloro-2,3,5,6-tetrahydrobenzo[f]quinolin-4(1H)-yl]-4-oxobutyl]acetamide as white crystals with melting point 142-143°.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([S:10]([OH:13])(=O)=[O:11])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.P(Cl)(Cl)([Cl:16])=O>C(Cl)Cl>[N:1]1[CH:2]=[C:3]([S:10]([Cl:16])(=[O:13])=[O:11])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1cnc2ccccn12
Solvent: ClCCl
Product: O=S(=O)(Cl)c1cnc2ccccn12
Temperature: 25 °C

Procedure:
The product from Step 1 (0.10 g, 0.5 mmol) was treated with phosphorus oxychloride (3 mL) and heated to reflux overnight. The reaction mixture was cooled to RT and treated with DCM (50 mL), poured into ice-water (100 mL), and then extracted with DCM (4×100 mL). The organic layers were combined and dried (Na2SO4), filtered, and concentrated to dryness under vacuum to give the title compound (0.10 g). 1H NMR (DMSO-d6) δ 8.87 (m, 1 H), 8.25 (s, 1 H), 7.98 (m, 2 H), 7.57 (m, 1 H).
Reaction SMILES: [OH-].[Na+].O.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH2:19][NH:20][CH2:21][CH2:22][O:23]C(=O)C(C)(C)C)[CH:9]=[CH:10][C:11]=1[CH:12]=[CH:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1>C(O)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH2:19][NH:20][CH2:21][CH2:22][OH:23])[CH:9]=[CH:10][C:11]=1[CH:12]=[CH:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1cc(CNCCOC(=O)C(C)(C)C)ccc1C=Cc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(CNCCO)ccc1C=Cc1cccs1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
NaOH (4.3 g, 107 mmol) was dissolved in ethanol (25 ml), and water (7 ml) was added thereto. Next, 2,2-dimethylpropionic acid 2-{[3-methoxy-4-(2-thiophene-2-ylvinyl)phenyl]methylamino}ethyl ester (4.0 g, 10.7 mmol) was dissolved in ethanol (8 ml) and added dropwise to the mixture. The mixture was stirred at room temperature for 2 hours and further at 45° C. for 1 hour. After the solvent was evaporated off, water (100 ml) was added and the oily matter was subjected to extraction with ethyl acetate. After 2 times of washing with water, drying over Na2SO4 and concentration were performed. The residue was purified by silica gel chromatography to give a yellow oily matter (yield: 3.1 g (100%)).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]2[N:3]=1.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].CCN(C(C)C)C(C)C>O1CCCC1>[CH:9]1([NH:8][C:6]2[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]3[N:3]=[C:2]([NH:1][C:20](=[O:21])[C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[F:17])[CH:7]=2)[CH2:11][CH2:10]1
Reactant: Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Reactant: O=C(Cl)c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=Cc1cnn2c(NC3CC3)cc(NC(=O)c3ccccc3F)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5-amino-7-(cyclopropylamino) pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (step b) (30 mg, 0.138 mmol) in 1.0 mL tetrahydrofuran, stirring under nitrogen, was added 2-fluoro benzoyl chloride (33 ul, 0.275 mmol) and DIPEA (28.8 ul). The reaction mixture was stirred at room temperature for one hour. The reaction was then partitioned between ethyl acetate and water, the organic layer was dried under sodium sulfate concentrated on high vacuum to yield N-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)-2-fluorobenzamide. The crude product was further dissolved in 1.0 mL ethanol, added hydantoin (41.2 mg, 0.411 mmol) and pipperdine (40.0 ul). The reaction was heated to 80° C. for three hours. Cooled the reaction mixture and yellow precipitate was filtered, washed with ethanol to yield 10 mg (40% yield, two steps) (Z)-N-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)-2-fluorobenzamide. LCMS (M+1=422)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[O-2].[Mg+2].O.Cl[C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14]>C(OCC)(=O)C>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][C:13](=[O:14])[O:15][CH:16]([CH3:18])[CH3:17])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(O)c1
Reactant: CC(C)OC(=O)Cl
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)OC(=O)Nc1cccc(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
A mixture of 3-aminophenol (109 g), magnesium oxide (25 g), water (350 ml) and ethyl acetate (100 ml) was stirred vigorously at room temperature while isopropyl chloroformate (123 g) was added slowly. An ice bath was employed to ensure that the temperature did not exceed 30° C. After stirring for one hour at room temperature, the mixture was filtered to remove insoluble particles. These were washed thoroughly with ether, then the filtrates were combined, then separated, and the organic layers were dried over magnesium sulphate. Evaporation under reduced pressure gave a viscous, pale yellow oil which was crystallised from toluene to give 162.7 g of desired product, mp 75°-77° C.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:15]1([C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:15]1([C:21](=[N:22][CH:23]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=2)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(N=C(c1ccccc1)c1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
Tert-butyl 4-bromobenzoate (10.3 g, 40.1 mmol), ethyl N-(diphenylmethylene)glycinate (14.99 g, 56.1 mmol), potassium phosphate (25.5 g, 120 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.409 g, 0.801 mmol) were stirred in toluene (120 mL) at 100° C. under nitrogen for 3 days. Room temperature was attained and the mixture filtered through Celite and concentrated in vacuo. The residue was purified by MPLC to give the desired product as a yellow oil. 1H NMR (DMSO-d6, 600 MHz) δ 7.86 (d, J=7.8 Hz, 2H), 7.58 (m, 2H), 7.51 (m, 3H), 7.48 (d, J=7.8 Hz, 2H), 7.45 (m, 1H), 7.41 (t, J=7.5 Hz, 2H), 7.08 (m, 1H), 5.08 (s, 1H), 4.00 (m, 2H), 1.51 (s, 9H), 1.05 (t, J=6.9 Hz, 3H).