Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:21])[CH:17]=3)[C:12]2=[O:22])[CH:10]=1.O.[NH2:25][NH2:26]>C(O)C>[Cl:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:22])[N:11]([C:9]1[CH:10]=[C:5]([CH2:4][C:3]([NH:25][NH2:26])=[O:2])[CH:6]=[N:7][CH:8]=1)[CH2:20][CH2:19]2
Reactant: COC(=O)Cc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)Cc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 90 °C

Procedure:
[5-(6-Chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-acetic acid methyl ester (100 mg, 0.30 mmol) and hydrazine monohydrate (0.75 mL) were dissolved in ethanol (8.0 mL) and the reaction mixture was heated at 90° C. for 3 h before it was cooled and concentrated in vacuo to give a crude product (100 mg, quant.) as light yellow oil. MS: 331.1 (M+H+).
Reaction SMILES: [N:1]([CH:4]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5]1)=[N+]=[N-]>CO.[Pd]>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([NH2:1])[C:10]=12
Reactant: [N-]=[N+]=NC1CCCCc2cccnc21
Agent: [Pd]
Solvent: CO
Product: NC1CCCCc2cccnc21
Yield: 88 %

Procedure:
To a solution of the azide (23.18 g, 0.123 mol) in methanol (150 mL) was added Palladium, 10 wt. % on activated carbon (1.95 g) and the resultant mixture was hydrogenated at 40 psi on a Parr shaker. The mixture was vacuum filtered through celite and the cake was washed with methanol. The solvent was removed from the filtrate under reduced pressure and the oil obtained was distilled (Kugelrohr, by 105-140° C. @ 0.2 Ton) to provide 17.56 g (88%) of 6,7,8,9-Tetrahydro-5H-cyclohepta[b]pyridin-9-ylamine as a pale yellow oil. 1H NMR (CDCl3) δ 1.23-1.37 (m, 1H), 1.43-1.57 (m, 1H), 1.78-2.10 (m, 6H) including 2.04 (s, 2H), 2.71-2.85 (m, 2H), 4.19 (dd, 1H, J=10.0, 1.5), 7.05 (dd, 1H, J=7.4, 4.9 Hz), 7.36 (d, 1H, J=5.9 Hz), 8.38 (d, 1H, J=4.9 Hz).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH:30]=O>>[CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:30][C:29]3[CH:32]=[CH:33][C:34]([Cl:35])=[C:27]([Cl:26])[CH:28]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)nnc3c(Cl)cccc23)c1
Product: Clc1ccc(CNc2cccc(-c3c(Cc4ccccc4)nnc4c(Cl)cccc34)c2)cc1Cl

Procedure:
The title compound was prepared from [3-(3-benzyl-8-chlorocinnolin-4-yl)phenyl]amine and 3,4-dichlorobenzaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 504.6.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:25]3[N:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: Clc1ncccn1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ncccn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 2-chloro-pyrimidine following a procedure analogous to that described in Example 19. LC (method 5): tR=1.89 min; Mass spectrum (ESI+): m/z=390 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].C1C(=O)N([Br:19])C(=O)C1>CC(O)=O>[Br:19][C:3]1[C:2]([F:1])=[CH:8][C:6]([NH2:7])=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: Nc1cc(F)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
A solution of 5-fluoro-2-nitroaniline (1.5 g, 9.61 mmol) and NBS (1.7 g, 9.55 mmol) in HOAc (75 mL) was heated at reflux for 90 min. The reaction mixture was then poured into ice water (300 mL) and stirred for 10 min. A bright yellow precipitate was collected by filtration and dried in vacuo overnight to afford 1.57 g (76%) of 4-bromo-5-fluoro-2-nitroaniline (96): MS (ESI) m/z=235 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=1.[CH3:23][CH:24]([CH3:28])[CH2:25][CH:26]=O.[BH4-].[Na+]>CO.O>[CH3:23][CH:24]([CH3:28])[CH2:25][CH2:26][NH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=1
Reactant: NCc1cccc2c(Oc3ccc(C(N)=O)cc3)ccnc12
Reactant: CC(C)CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)CCNCc1cccc2c(Oc3ccc(C(N)=O)cc3)ccnc12
Temperature: 50 °C

Procedure:
To a solution of 4-(8-aminomethylquinolin-4-yloxy)benzamide (23 mg, 0.08 mmol, Preparation 90) in MeOH (5 mL) was added 3-methylbutyraldehyde (8.5 μL, 0.08 mmol) and 4 Å molecular sieves (500 mg). The resulting mixture was heated to 50° C. for 16 h then cooled to rt and NaBH4 (6 mg, 0.16 mmol) was added. After 3 h a few drops of water were added, the mixture filtered and washed with MeOH. Solvent was removed in vacuo and the residue purified by column chromatography (0.25% NH4OH(aq), 5% MeOH in DCM) to give the title compound: RT=2.65 min; m/z (ES+)=364.2 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N+:9]=[N-:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].NCCC[CH:18]([NH:22][CH3:23])[CH2:19][CH2:20][NH2:21]>CCOCC>[NH2:8][CH2:5][CH2:4][CH2:3][N:22]([CH3:23])[CH2:18][CH2:19][CH2:20][NH:21][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N+:9]=[N-:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: [N-]=[N+]=Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: CNC(CCN)CCCN
Solvent: CCOCC
Product: CN(CCCN)CCCNc1ccc(N=[N+]=[N-])cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
The reaction was carried out in the dark. A solution of 4-fluoro-3-nitrophenyl azide (0.91 g, 5.0 mmol, Sigma) in 10 ml dry ether was added dropwise with stirring to a solution of 3.2 ml of N-(3-aminopropyl-N-methyl-1,3-propanediamine (10 mmol, Aldrich) in 20 ml dry ether and the mixture was stirred for 30 min. The reaction was monitored using TLC (alumina, elution with methanol). The solvent was removed and the red oil was dissolved in 25 ml water, 25 ml 1.0M HaOH and then extracted into ethyl acetate (2×50 ml). The organic phase was dried over MgSO4 and the solvent then removed in vacuum. TLC: (I) alumina, eluted with methanol, Rf=0.43 (II) silica gel, elution with 1:9 AcOH/H2O, Rf between Rf=0.23 and Rf=0.55. 1H NMR (CDCl3 /TMS) δ: 1.45 (2H, broad s, NH), 1.64 (2H, m, CH2), 1.87 (2H, p, J=6.52 Hz, CH2), 2.25 (3H, s, CH3), 2.43 (2H, t, CH2), 2.47 (2H, t, J=6.46 Hz, CH2), 2.73 (2H, t, J=6.89 Hz, CH2), 3.37 (2H, m, J=6.61 Hz, CH2), 6.89 (1H, d, J=9.23 Hz, ArH), 7.10 (1H, dd, J=2.73, 9.20 Hz, ArH), 7.79 (1H, d, J=2.74 Hz, ArH), 8.47 (1H, m, NH). 13C NMR (CDCl3 /TMS) δ: 143.123 (Q), 131.24 (Q), 127.91 (CH), 127.16 (Q), 115.73 (CH), 115.44 (CH), 55.70 (CH2), 55.40 (CH2), 42.03 (CH2), 41.90 (CH3), 40.50 (CH2), 30.94 (CH2), 26.20 (CH2).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:35])[CH2:21][CH2:20]2)=[O:18])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.CCN=C=NCCCN(C)C.[N:47]12[CH2:54][CH2:53][CH:50]([CH2:51][CH2:52]1)[CH:49](O)[CH2:48]2>CN(C)C1C=CN=CC=1.CN(C)C=O>[N:47]12[CH2:54][CH2:53][CH:50]([CH2:51][CH2:52]1)[CH:49]([O:14][C:13](=[O:15])[CH:12]([NH:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:35])[CH2:23][CH2:24]1)=[O:18])[CH2:11][C:4]1[CH:5]=[C:6]3[C:10](=[C:2]([CH3:1])[CH:3]=1)[NH:9][N:8]=[CH:7]3)[CH2:48]2
Reactant: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc2cn[nH]c12
Reactant: OC1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)OC2CN3CCC2CC3)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid (50 mg, 0.105 mmol), EDCI (100 mg), and 4-dimethylaminopyridine (0.2 equiv.) in dimethylformamide was added aza-bicyclo[2.2.2]oct-3-yl alcohol (0.525 mmol, 5 equiv.). The mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate, washed with brine, dried over magnesium sulfate, and purified by preparative HPLC to yield the desired compound. LC/MS: tR=1.62 min, 586.41 (MH)+.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6](N)[CH2:5][CH2:4]1.O=[C:16]([CH2:20][CH2:21]C(O)=O)[C:17]([OH:19])=[O:18]>C(O)(=O)C>[CH3:2][C:3]1([CH3:14])[C:12]2[C:7]3=[C:8]([C:20]([CH2:16][C:17]([OH:19])=[O:18])=[CH:21][N:6]3[CH2:5][CH2:4]1)[CH:9]=[CH:10][CH:11]=2
Reactant: O=C(O)CCC(=O)C(=O)O
Reactant: CC1(C)CCN(N)c2ccccc21
Agent: Cl
Solvent: CC(=O)O
Product: CC1(C)CCn2cc(CC(=O)O)c3cccc1c32
Yield: 33.9 %

Procedure:
To a solution of glacial acetic acid (80 mL) and concentrated hydrochloric acid (9 mL) was added 3,4-dihydro-4,4-dimethyl-1-(2H)-quinolinamine (9.5 g, 53.9 mmol) and 2-ketoglutaric acid (9.7 g, 65.1 mmol) and the suspension heated at reflux for 3 hours. After cooling the solvents were removed under reduced pressure and the residue dissolved in 500 mL of ethyl acetate. The ethyl acetate solution was washed with water (3×150 mL) and saturated aqueous sodium chloride (1×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 1-4% methanol in dichloromethane. Fractions containing product were combined and concentrated under reduced pressure to provide 4.45 g (34%) of the desired compound as a tan foam. An impure fraction was extracted with 1N sodium hydroxice (2×50 mL) and the combined aqueous layers washed with diethyl ether (20 mL) and made acidic with concentrated hydrochloric acid (8 mL). This aqueous mixture was extracted with dichloromethane (2×100 mL), followed by drying (Na2SO4) to provide an additional 2.55 g (19%) of desired product
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:4]=1.Cl[CH2:18][CH2:19][CH:20]([OH:29])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[O:22]([CH2:21][CH:20]([OH:29])[CH2:19][CH2:18][N:12]1[CH2:13][CH2:14][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH2:10][CH2:11]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: OC(CCCl)COc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: OC(CCN1CCN(c2cccc(C(F)(F)F)c2)CC1)COc1ccccc1
Yield: 65.9 %

Procedure:
This compound was prepared according to the procedure of Example 6. A mixture of 3.5 g (0.015 mole) of N-(α, α, αtrifluoro-m-tolyl)piperazine, 3.0 g (0.015 mole) of 4-chloro1-phenoxy-2-butanol and 5.3 g (0.05 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 3.9 g (66%) of white powder, m.p. 83°-84° C. The recrystallizing solvent used in isopropyl alcohol.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1.Br[C:35]1[CH:36]=[C:37]([CH2:42][C:43]([OH:45])=[O:44])[CH:38]=[CH:39][C:40]=1[F:41]>>[F:41][C:40]1[C:35]([C:16]2[CH:17]=[CH:18][C:19]([C:21]([F:23])([F:22])[F:24])=[CH:20][C:15]=2[CH2:14][N:3]2[C@@H:2]([CH3:1])[C@@H:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:5][C:4]2=[O:13])=[CH:36][C:37]([CH2:42][C:43]([OH:45])=[O:44])=[CH:38][CH:39]=1
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(O)Cc1ccc(F)c(Br)c1
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1F

Procedure:
Prepared according to the procedure described in Example 7, Step 2, using the following starting materials: (4S,5R)-4-methyl-5-phenyl-3-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-oxazolidin-2-one and 3-bromo-4-fluorophenylacetic acid. M+H is 488.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1.[CH3:18][CH:19]([OH:23])[CH2:20][CH2:21][CH3:22].[H-].[Na+]>>[CH3:18][CH:19]([O:23][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(C)O
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Agent: [H-]
Agent: [Na+]
Product: CCCC(C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
In a separate flask, a suspension of 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (500 mg) and 2-pentanol (3.8 mL) was heated to 50° C. Sodium hydride (396 mg, 60% dispersion) was added in portions and the reaction was stirred at 50° C. for 72 h. The reaction was cooled and quenched with water (10 mL) and was extracted with EtOAc (3×25 mL). The combined organics were washed with brine (30 mL), dried over MgSO4, filtered and concentrated in vacuo to give crude title compound as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([OH:15])[CH:9]=1)(C)(C)C.[CH3:17][N:18]1[CH2:22][CH2:21][C@H:20](O)[CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][C:10]=1[O:15][C@@H:20]1[CH2:21][CH2:22][N:18]([CH3:17])[CH2:19]1
Reactant: CN1CC[C@H](O)C1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)c(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CC[C@@H](Oc2cc(N)ccc2Cl)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.7 %

Procedure:
To a cooled (0° C.) solution of 4-chloro-3-hydroxyphenylcarbamic acid tert-butyl ester (55 g, 0.23 mol), (S)-1-methyl-pyrrolidin-3-ol (24 g, 0.24 mol), and triphenylphosphine (89 g, 0.34 mol) in THF (1.1 L) was added dropwise via addition funnel a solution of DIAD (67 mL, 0.34 mol) in THF (100 mL) over 1 h. The resultant solution was allowed to slowly warm to ambient temperature and maintained for 16 h. The THF was removed in vacuo and the residue treated with 6 N HCl (650 mL). The resultant mixture was stirred at room temperature for 4 h, at which time it was diluted with water (500 mL) and the filtered to remove the triphenylphosphine oxide. The filtrate was washed with EtOAc (3×1 L) and chloroform (5×1 L) to remove additional reaction by-products. The aqueous layer was then basified with solid NaOH pellets and extracted with ether (2×1 L) and EtOAc (2×1 L). The combined organic layers were washed with saturated NaHCO3 (2×1 L) and brine (1 L), dried (MgSO4), and concentrated to give 40 g (80%) of the title compound: MS (ES+) m/e [M+H]+ 227.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[C:7]([OH:13])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:17][S:18](Cl)(=[O:20])=[O:19]>O>[CH3:17][S:18]([O:13][C:7]1[C:6](=[O:14])[C:5]2[C:10](=[CH:11][CH:2]=[CH:3][CH:4]=2)[N:9]([CH3:12])[CH:8]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(O)c(=O)c2ccc(F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1cc(OS(C)(=O)=O)c(=O)c2ccccc21
Temperature: 0 °C

Procedure:
7-Fluoro-3-hydroxy-1 -methyl-4-quinolone (4.5 g) was added to a solution of sodium hydroxide (12 g) in water (56 ml) and the mixture stirred at 0 to 5° with ice/water cooling. Methanesulphonyl chloride (4 ml) was added over a period of 1 5 minutes followed by aqueous sodium hydroxide (5M, 3 ml). The resultant solid was collected by filtration, washed with water (2×20 ml), and crystallised from industrial methylated spirit (220 ml) to give the novel compound 7-fluoro-]-methyl-4-oxo-1,4-dihydroquinol-3-yl methanesulphonate, m.p. 212°-213°.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:6][CH2:5][CH2:4][NH:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C=O)C>[O:1]=[C:2]1[CH:7]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)CBr
Reactant: O=C1NCCCC1CCc1ccc2cccnc2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCCC(CCc2ccc3cccnc3n2)C1=O
Reaction time: 0.5 h

Procedure:
A solution of 1-5 (0.28 g, 1.1 mmol) and DMF (10 mL) at −15° C. was treated with NaN(TMS)2 (1.2 mL, 1.2 mmol, 1M in hexanes) to give a red solution. After 30 min, the red solution was treated with ethyl bromoacetate (128 μL, 1.2 mmol), followed by continued stirring for 1 h. The reaction mixture was then quenched with sat. NH4Cl and then extracted with EtOAc (3×). The combined extracts were washed with brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 10% CH3OH/EtOAc) gave 1-6 as a yellow gum.
Reaction SMILES: C(O[K])(C)(C)C.F[C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][OH:30].Cl>C1COCC1.CCOC(C)=O>[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1cccnc1F
Reactant: COCCOCCOCCOCCO
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOCCOCCOCCOc1ncccc1C(=O)O
Temperature: 100 °C
Yield: 89.9 %

Procedure:
A solution of tBuOK in THF (20% wt, 561.0 uL, 1.0 mmol) was added to a mixture of 2-fluoronicotinic acid (70.6 mg, 0.50 mmol) and tetraethyleneglycol monomethyl ether (105.5 μL, 0.50 mmol) in THF (2.0 mL) at ambient temperature under N2. The mixture was heated at 100° C. for 3 h. The reaction mixture was diluted with EtOAc. The organic phase was acidified with 1 N HCl solution, washed with saturated NaCl solution, then dried over Na2SO4. Filtration and concentration in vacuo provided compound D as light yellow liquid (148.1 mg, 90%) for next step without further purification. ESMS: 330.0 [M+H]+, 352.0 [M+Na]+, 368.0 [M+K]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][C:5]([C:9](O)=[O:10])=[C:6]([CH3:8])[N:7]=1.[Cl:14]C(OC(Cl)(Cl)Cl)=O>ClC1C=CC=CC=1.N1C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[C:3]1[S:4][C:5]([C:9]([Cl:14])=[O:10])=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1nc(C(F)(F)F)sc1C(=O)O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Solvent: c1ccncc1
Product: Cc1nc(C(F)(F)F)sc1C(=O)Cl
Reaction time: 2 h
Yield: 98 %

Procedure:
In a similar apparatus to Example 1, 4.2 g (0.02 mole) of 2-trifluoromethyl-4-methylthiazole-5-carboxylic acid were suspended in 100 ml of chlorobenzene, followed by the addition of 0.04 g of pyridine. Under heating and reflux, 9.9 g (0.05 mole) of trichloromethyl chloroformate were added dropwise over 5 hours. After completion of the dropwise addition, stirring was continued for additional 2 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 4.5 g of 2-trifluoromethyl-4-methylthiazole-5-carboxylic acid chloride. Its purity and yield were 98.7% and 98.0%, respectively.
Reaction SMILES: [CH:1]([CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>CN(C)C=O.O>[CH:1]([CH:4]1[C:9](=[O:10])[N:8]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1Oc2ccccc2NC1=O
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C(C(C)C)Oc2ccccc21

Procedure:
To a solution of 2-isopropyl-2H-1,4-benzoxazin-3(4H)-one (19.1 g) in N,N-dimethylformamide (200 ml), sodium hydride (60% in oil, 4.0 g) was added and stirred at room temperature for 30 minutes, to which a solution of methyl bromoacetate (10 ml) in N,N-dimethylformamide (200 ml) was added dropwise with ice-cooling. After stirring with ice-cooling for 1 hour, the reaction mixture was diluted with water and subjected to extraction with ethyl acetate. The extract was washed with water, dried (MgSO4) and evaporated to dryness, to give methyl 3,4-dihydro-2-isopropyl-3-oxo-2H-1,4-benzoxazine-4-acetate as an oil. Yield was 26.0 g (98.9%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[C:7]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5])[CH3:2].[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:35]3[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[C:7]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1cccc(OC)c1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1cccc(OC)c1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(3-methoxyphenyl)indole-3-carboxylic acid ethyl ester (183 mg, 0.46 mmol, see step (b) Example 5) and 4-trifluoromethylphenylboronic acid (129 mg, 0.68 mmol). Yield 170 mg (68%).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])[CH3:14].C[O-].[Na+].Cl>CO.CCOC(C)=O>[CH3:4][O:3][C:1](=[O:2])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:14][C:13](=[O:15])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(C=CC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-carbomethoxybenzaldehyde (79 mg, 0.48 mmol) and acetophenone (56 μL, 0.48 mmol) in anhydrous methanol (1.6 mL), was added neat sodium methoxide (26 mg, 0.48 mmol). The mixture was stirred at room temperature overnight then heated to reflux for 1 hour, cooled down to room temperature and added HCl 1N and EtOAc. The layers were separated and the organic layer dried over anhydrous MgSO4 and filtered. The solvent was evaporated under vacuum to afford a yellow solid, which was recrystallized from acetonitrile/water to give a pale yellow crystalline solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20](=[O:25])[NH:21][CH2:22][CH2:23][F:24])=[O:14])[N:8]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:7]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.O>[F:24][CH2:23][CH2:22][NH:21][C:20]([C@@H:16]1[CH2:17][CH2:18][CH2:19][N:15]1[C:13](=[O:14])[CH2:12][O:11][C:9]1[N:8]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1)=[O:25]
Reactant: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCCF)n(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCCF)n(-c2ccccc2)n1
Reaction time: 2 h

Procedure:
To a solution of 1.50 g 5-[2-((S)-2-(2-Fluoro-ethylcarbamoyl)-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester in 28 ml THF and 7 ml water were added 1.7 ml aqueous NaOH (2 M) portionwise at 0° C. After 2 h the solution was neutralized with Amberlite IR-120 ion exchange resin, filtered and washed with methanol. The crude product obtained after evaporation of the solvents was used in the subsequent reaction. Yield: 1.38 g.