Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 88.9 %

Procedure:
To a suspension of 4-chloro-3-nitrobenzoic acid (10 g) and potassium carbonate (7.54 g) in N,N-dimethylformamide (100 mL) was added methyl iodide (3.24 mL) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3.5 hours. The reaction mixture was diluted with ethyl acetate and washed successively with 1 N-hydrochloric acid, water, an aqueous saturated sodium hydrogencarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residual solid was washed with diisopropyl ether to give methyl 4-chloro-3-nitrobenzoate (9.51 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=2)=[O:28])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: CC(C)c1ccc(N=C=O)cc1
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Product: COc1ccc(NC(=O)Nc2ccc(C(C)C)cc2)cc1-c1c(Cl)cnn1C
Yield: 2 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4-isopropylphenyl isocyanate in a similar manner as described in Example 1.53, providing 1.3 mg (2%) of Compound 76 (Note: Compound 76 did not precipitate out). Therefore, the CH2Cl2 was removed under reduced pressure, the residue was dissolved in 5 mL DMSO, and purified by preparative HPLC): LCMS m/z (%)=401 (M+H37Cl, 31), 399 (M+H35Cl, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.63 (s, 1H), 8.52 (s, 1H), 7.59 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.41 (d, J=2 Hz, 1H), 7.37 (dd, J1=12 Hz, J2=2 Hz, 2H), 7.33 (s, 1H), 7.17 (dd, J1=8 Hz, J2=2 Hz, 2H), 7.00 (d, J=12 Hz, 1H), 3.68 (s, 3H), 3.54 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([OH:5])[CH:3]=[CH2:4].C(N(CC)CC)C.[Cl:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([CH2:24][O:25][C:26]3[CH:48]=[CH:47][C:29]4[O:30][CH2:31][C:32]5[CH:45]=[C:44](I)[CH:43]=[CH:42][C:33]=5[CH:34]([O:35][CH:36]5[CH2:41][CH2:40][CH2:39][CH2:38][O:37]5)[C:28]=4[CH:27]=3)=[N:21]2)=[CH:16][C:15]=1[F:49].C(Cl)Cl>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([CH2:24][O:25][C:26]3[CH:48]=[CH:47][C:29]4[O:30][CH2:31][C:32]5[CH:45]=[C:44]([CH2:4][CH2:3][C:2](=[O:5])[CH3:1])[CH:43]=[CH:42][C:33]=5[CH:34]([O:35][CH:36]5[CH2:41][CH2:40][CH2:39][CH2:38][O:37]5)[C:28]=4[CH:27]=3)=[N:21]2)=[CH:16][C:15]=1[F:49]
Reactant: C=CC(C)O
Reactant: Fc1cc2ccc(COc3ccc4c(c3)C(OC3CCCCO3)c3ccc(I)cc3CO4)nc2cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)CCc1ccc2c(c1)COc1ccc(OCc3ccc4cc(F)c(Cl)cc4n3)cc1C2OC1CCCCO1
Temperature: 0 °C
Yield: 61.3 %

Procedure:
0.2 g of (±)-3-buten-2-ol, 1.4 mg of palladium (II) acetate and 0.27 g of triethylamine were added to 1.36 g of 2-(7-chloro-6-fluoroquinolin-2-yl)methoxy-8-iodo-11-(2-tetrahydropyranyloxy)-6,11-dihydrodibenz[b,e]oxepine obtain in Reference example 73 dissolved in 2.5 ml of acetonitrile and the mixture was refluxed under heating for 5.5 hours. After 60 ml of methylene chloride and 60 ml of ice water were added to this reaction mixture, the organic layer was separated, washed with water and dried over anhydrous sodium sulfate. After the solvent was removed, the residue was applied to silica gel column chromatography to obtain 0.76 g of the title compound.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][OH:15])[N:10]=[CH:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[CH2:22][CH2:21][CH2:20]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:17]2[CH:26]=[CH:25][C:24]3[C:23](=[O:27])[CH2:22][CH2:21][CH2:20][C:19]=3[CH:18]=2)[N:10]=[CH:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: CC(C)(C)OC(=O)n1cnc(CCO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cnc(CCOc2ccc3c(c2)CCCC3=O)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 34.2 %

Procedure:
A solution of 1-N-Boc-4-(2-hydroxyethyl)imidazole (1.06 g, 5.0 mmol), 6-hydroxytetralone (0.811 g, 5.0 mmol), and triphenylphosphine (1.44 g, 5.5 mmol) in 10 mL of freshly distilled THF was cooled in an ice bath for 10 minutes and then treated with neat diethyl azodicarboxylate (0.87 mL, 5.5 mmol) added via syringe through a rubber septum. The ice bath was permitted to melt and the reaction continued at room temperature for 5 hours. The solvent was removed in vacuo and the residue was chromatographed (silica gel, 500 g; 1:1, EtOAc:hexanes), and the pure fractions were pooled to afford 0.61 g (33%) of the title compound as a clear, colorless, viscous oil: CI-MS m/e 357 (M++1).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.[CH2:8]([O:10][C:11](=[O:41])[CH2:12][C:13]1[CH:22]=[C:21]([C:23](=[O:39])[C:24]2[CH:29]=[CH:28][C:27]([S:30]([N:33]3CCNCC3)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:40])[CH:19]=2)[CH:14]=1)[CH3:9].C=O.C([BH3-])#N.[Na+]>C(#N)C.C(O)(=O)C>[CH2:8]([O:10][C:11](=[O:41])[CH2:12][C:13]1[CH:22]=[C:21]([C:23](=[O:39])[C:24]2[CH:25]=[CH:26][C:27]([S:30]([N:33]3[CH2:7][CH2:6][N:3]([CH3:1])[CH2:4][CH2:5]3)(=[O:32])=[O:31])=[CH:28][CH:29]=2)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:40])[CH:19]=2)[CH:14]=1)[CH3:9]
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc(S(=O)(=O)N3CCNCC3)cc2)c2cc(F)ccc2c1
Reactant: CCN(CC)CC
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)Cc1cc(C(=O)c2ccc(S(=O)(=O)N3CCN(C)CC3)cc2)c2cc(F)ccc2c1
Reaction time: 0.25 h
Yield: 59 %

Procedure:
Triethylamine (0.04 mL, 0.27 mmol) was added to a stirred mixture of {6-fluoro-4-[4-(piperazine-1-sulfonyl)-benzoyl]-naphthalen-2-yl}-acetic acid ethyl ester (0.10 g, 0.17 mmol) in acetonitrile (4 mL) at 0° C. and the reaction mixture was stirred for 15 minutes. Formaldehyde (0.02 mL, 0.83 mmol) and sodium cyanoborohydride (0.017 g, 0.27 mmol) were added to the reaction mixture at 0° C., then the mixture was stirred for another 15 minutes. The reaction mixture was neutralized to pH ˜7 by gradual addition of acetic acid. The reaction mixture was concentrated, and the residue was made alkaline by the addition of a 2.0 N aqueous solution of KOH. The resulting mixture was extracted with diethyl ether (2×15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. Silica gel (100-200 mesh) column chromatography (4:1 ethyl acetate-hexanes) afforded 0.05 g (60%) of {6-fluoro-4-[4-(4-methyl-piperazine-1-sulfonyl)-benzoyl]-naphthalen-2-yl}-acetic acid ethyl ester as an off-white sticky solid. MS cald. for C26H27FN2O5S ([M+H]+) 499, obsd. 499.3.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH2:11][CH2:12][CH2:13][CH3:14].O1[CH2:19][CH2:18][CH2:17][CH2:16]1>[Pd].BrCC1C=CC(C#N)=CC=1.[Zn].O>[CH2:11]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:2]=1[CH2:16][C:17]1[CH:13]=[CH:12][C:11]([C:3]#[N:4])=[CH:19][CH:18]=1)[CH2:12][CH2:13][CH3:14]
Reactant: C1CCOC1
Reactant: CCCCc1nc2ccccn2c1Br
Agent: [Pd]
Agent: N#Cc1ccc(CBr)cc1
Agent: [Zn]
Solvent: O
Product: CCCCc1nc2ccccn2c1Cc1ccc(C#N)cc1

Procedure:
A mixture of 2 g of the product of Stage D, 100 ml of tetrahydrofuran and 1 -g of [tetra-bis(triphenylphosphine)] palladium was added to 35.9 ml of zinc 4-bromomethyl benzonitrile at ambient temperature and the mixture was refluxed for one hour. The mixture was allowed to return to ambient temperature, poured into water and extracted with ethyl acetate. The extracts were washed with a saturated aqueous solution of sodium chloride, dried, filtered and brought to dryness to obtain after chromatography on silica (ethyl acetate), 1.1 g of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4([C:23]([CH3:29])([CH3:28])[C:24]([O:26]C)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C-]#N.[K+].[Li+].[I-]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4([C:23]([CH3:29])([CH3:28])[C:24]([OH:26])=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)C1(c2ccc3c(cnn3-c3ccc(F)cc3)c2)CCCCC1
Agent: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: c1ccncc1
Product: CC(C)(C(=O)O)C1(c2ccc3c(cnn3-c3ccc(F)cc3)c2)CCCCC1
Temperature: 180 °C

Procedure:
Methyl 2-(1-(1-(4-fluorophenyl)-1H-indazol-5-yl)cyclohexyl)-2-methylpropanoate (635 mg, 1.61 mmol) was dissolved in 4 mL pyridine and transferred to a microwave reactor. Potassium cyanide (419 mg, 6.45 mmol) and LiI (864 mg, 6.45 mmol) were added and the reactor was sealed under nitrogen and heated in a microwave for 30 min at 180° C. The reaction was extracted from 1 M HCl using EtOAc×4 (lots of black, insoluble precipitate). The organic layers were dried, concentrated, and purified by MPLC on SiO2 using 1:1 EtOAc/hexanes. Obtained 115 mg (19%) of off white powder 2-(1-(1-(4-fluorophenyl)-1H-indazol-5-yl)cyclohexyl)-2-methylpropanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCCC)[NH:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[C:33]([O:37][C:38]([N:40]1[CH2:43][CH:42]([NH:44][CH3:45])[CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([N:40]1[CH2:41][CH:42]([N:44]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][C:4]=3[C:29]([F:32])([F:30])[F:31])[N:8]=[CH:9]4)[C:18](=[O:26])[N:19]=2)[CH3:45])[CH2:43]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CNC1CN(C(=O)OC(C)(C)C)C1
Reactant: CCCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1)C1CN(C(=O)OC(C)(C)C)C1

Procedure:
3-({5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-azetidine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazolidin-4-one and 3-Methylamino-azetidine-1-carboxylic acid tert-butyl ester following General Procedure B.
Reaction SMILES: [C:1]1([CH3:60])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:18][CH2:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][CH2:14][N:13]([CH2:29][CH2:30][N:31]3[CH2:39][CH2:38][N:37](S(C4C=CC(C)=CC=4)(=O)=O)[CH2:36][CH2:35][N:34]([S:50]([C:53]4[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=4)(=[O:52])=[O:51])[CH2:33][CH2:32]3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.S(=O)(=O)(O)O>>[C:56]1([CH3:59])[CH:55]=[CH:54][C:53]([S:50]([N:34]2[CH2:35][CH2:36][NH:37][CH2:38][CH2:39][N:31]([CH2:30][CH2:29][N:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18][N:10]([S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:60])=[CH:2][CH:3]=4)(=[O:9])=[O:8])[CH2:11][CH2:12]3)[CH2:32][CH2:33]2)(=[O:51])=[O:52])=[CH:58][CH:57]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(CCN3CCN(S(=O)(=O)c4ccc(C)cc4)CCN(S(=O)(=O)c4ccc(C)cc4)CC3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Product: Cc1ccc(S(=O)(=O)N2CCNCCN(CCN3CCNCCN(S(=O)(=O)c4ccc(C)cc4)CC3)CC2)cc1

Procedure:
From 1,2-bis(4,7-di-p-toluenesulfonyl-1,4,7-triazacyclonon-1-yl)ethane (1.1.30) and sulphuric acid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([Cl:19])[C:5]=1[C:6]([O:8]CC)=[O:7]>O.C(O)C>[Cl:3][C:4]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[C:11]([Cl:19])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 71.7 %

Procedure:
A solution of sodium hydroxide (41.6 g) in water was added to a solution of ethyl 2,6-dichloro-4-trifluoromethylbenzoate (96.3 g) in ethanol. The mixture was heated at reflux for 2.5 hours then cooled and evaporated. It was diluted with water and extracted with ether. The aqueous layer was acidified to pH1 and extracted with ether, washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with n-hexane and filtered to give 2.6-dichloro-4-trifluoromethylbenzoic acid (62.3 g) as a white solid mp 138.5°-139° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:20](O)=[O:21])=[N:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:37][C:38]1[CH:46]=[CH:45][C:41]([CH2:42][NH:43][CH3:44])=[CH:40][CH:39]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:20]([N:43]([CH2:42][C:41]2[CH:45]=[CH:46][C:38]([F:37])=[CH:39][CH:40]=2)[CH3:44])=[O:21])=[N:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCn2nc(C(=O)O)c(OCc3ccccc3)c2C1=O
Reactant: CNCc1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN(Cc1ccc(F)cc1)C(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-benzyloxy-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid (50 mg, 0.166 mmol) in DMF (2 mL) were added EDC (32 mg, 0.166 mmol), HOBT (27 mg, 0.199 mmol), and 4-fluoro-N-methylbenzylamine (23 mg, 0.166 mmol). The reaction was stirred at room temperature overnight and partitioned between EtOAc and brine. The aqueous layer was extracted several times with EtOAc, and the combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA) and collection and concentration of the appropriate fractions afforded the title product. 1H NMR (400 MHz, CDCl3) δ 7.44-7.42 (m, 1H), 7.38-7.29 (m, 4H), 7.16-7.12 (m, 1H), 6.98-6.92 (m, 3H), 5.30-5.24 (m, 4H), 4.39-4.34 (m, 2H), 3.80-3.73 (m, 2H), 3.19-3.17 (d, 3H), 2.89-2.86 (d, 3H); ES MS (M+1)=423.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([CH3:21])[CH:15]=3)=[N:11][C:10]=2[CH:22]=1.C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[F:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:1](=[O:3])[CH3:2])=[C:16]([CH3:21])[CH:15]=3)=[N:11][C:10]=2[CH:22]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(-c2nc3cc(F)ccc3s2)ccc1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(-c2nc3cc(F)ccc3s2)cc1C
Reaction time: 0.5 h

Procedure:
Acetyl Chloride (0.09g, 1.55 mmol) was added to a solution of 5-fluoro2-(4′-amino-3′-methylphenyl)benzothiazole (0.2 g, 0.78 mmol) in chloroform (5 ml) containing triethylamine (86 mg, 0.85 mmol). The resulting solution was stirred for 30 min, then poured into water (20 ml). The organic layer was removed, dried (Na2SO4) and evaporated. Recrystallisation from ethanol gave a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2([C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH3:27])=[C:21]([CH3:28])[N:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH3:27])=[C:21]([CH3:28])[N:20]=1)[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:33]2[CH:34]=[N:29][CH:30]=[N:31][CH:32]=2)[CH:7]=1
Reactant: OB(O)c1cncnc1
Reactant: COc1c(C)cc(C2(c3ccnc(Br)c3)N=C(N)c3c(F)cccc32)nc1C
Product: COc1c(C)cc(C2(c3ccnc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)nc1C
Yield: 7 %

Procedure:
The title compound was synthesized as described in Example 33 in 7% yield starting from 1-(2-Bromopyridin-4-yl)-4-fluoro-1-(5-methoxy-4,6-dimethylpyridin-2-yl)-1H-isoindol-3-amine (200 mg, 0.45 mmol) and pyrimidin-5-ylboronic acid (61.8 mg, 0.50 mmol).
Reaction SMILES: Cl.Cl[C:3]1[CH:21]=CC=C[C:4]=1C(OC1CNC1)C1C=CC=CC=1Cl.[N-]=C=O.[Cl:25][C:26]1[CH:51]=[CH:50][CH:49]=[CH:48][C:27]=1[CH:28]([O:36][CH:37]1[CH2:40][N:39]([C:41]([NH:43][C:44]([CH3:47])([CH3:46])C)=[O:42])[CH2:38]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35]>>[Cl:25][C:26]1[CH:51]=[CH:50][CH:49]=[CH:48][C:27]=1[CH:28]([O:36][CH:37]1[CH2:38][N:39]([C:41]([NH:43][CH:44]2[CH2:46][CH2:21][CH2:3][CH2:4][CH2:47]2)=[O:42])[CH2:40]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35]
Reactant: Clc1ccccc1C(OC1CNC1)c1ccccc1Cl
Reactant: CC(C)(C)NC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1
Agent: Cl
Agent: [N-]=C=O
Product: O=C(NC1CCCCC1)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1

Procedure:
This material was prepared from 3-(2,2′-dichlorobenzhydryloxy)azetidine hydrochloride (68) and the corresponding commercially available isocyanate using the procedure described for compound (69).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].Br[CH2:11][C:12]1[CH:25]=[CH:24][C:23]2[C:22](=[O:26])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:27])[C:14]=2[CH:13]=1>C(#N)C>[CH3:11][C:12]1[CH:25]=[CH:24][C:23]2[C:22](=[O:26])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:27])[C:14]=2[C:13]=1[N:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]=[CH:4]1
Reactant: O=C1c2ccccc2C(=O)c2cc(CBr)ccc21
Reactant: Clc1nc[nH]c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1ccc2c(c1-n1cnc(Cl)c1Cl)C(=O)c1ccccc1C2=O
Yield: 40 %

Procedure:
4,5-Dichloroimidazole (0.18 g, 1.33 mmol) and potassium hydroxide (0.08 g, 1.46 mmol) were combined in a round bottom flask. Acetonitrile (2 mL) was added and the mixture was stirred at reflux for 30 min, dissolving the remaining solid. Concurrently, 2-(Bromomethyl)anthraquinone (0.4 g, 1.33 mmol) was added to 30 mL acetonitrile and stirred at reflux for 30 min, partially dissolving the solid. The solution in the initial flask was added to the 2-(bromomethyl)anthraquinone mixture, and the solution was returned to reflux for 3 h. The mixture was filtered hot, and a precipitate quickly formed in the tan filtrate. The precipitate was collected by a second filtration and washed with cold acetonitrile to yield a yellow powder (0.19 g, 40% yield). 1H NMR (300 MHz, DMSO-d6) 8.20 (3H, m, Ar), 8.10 (1H, s, NCHN), 8.01 (1H, d, Ar), 7.89-7.95 (2H, m, Ar), 7.74 (1H, dd, Ar), 5.51 (2H, s, CH2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([O:17][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: O=C(CBr)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)OCC(=O)c1ccccc1
Yield: 95.2 %

Procedure:
The title compound (7.07 g) was prepared from (RS)-2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (5.0 g) and 2-bromoacetophenone (4.18 g) according to the method of description 36.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][CH2:8][CH:7]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6]1)[CH2:2][CH:3]=[CH2:4].Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH:4]=[CH:3][CH2:2][CH2:1][N:5]2[CH2:9][CH2:8][CH:7]([S:10]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)(=[O:12])=[O:11])[CH2:6]2)[CH:22]=1
Reactant: Brc1cccnc1
Reactant: C=CCCN1CCC(S(=O)(=O)c2ccc(O)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(O)cc1)C1CCN(CCC=Cc2cccnc2)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 78.6 %

Procedure:
(RS)-4-(1-But-3-enyl-pyrrolidine-3-sulfonyl)-phenol (100 mg, 0.355 mmol), 3-bromopyridine (62 mg, 0.39 mmol), PdCl2(dppf)2-dichloromethane complex (9.3 mg, 0.01 mmol), and K2CO3 (95 mg, 0.69 mmol) were suspended in DMF (1.5 ml). After 5 hours stirring at 80° C., the reaction mixture was cooled to room temperature and concentrated. The residue was chromatographed over silica gel (CH2Cl2/MeOH 97:3 then 19/1) to provide (RS)-4-[1-(4-pyridin-3-yl-but-3-enyl)-pyrrolidine-3-sulfonyl]-phenol (100 mg, 78%) as a light orange foam, MS: m/e=359.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Cl[C:11]([O:13][CH2:14][CH2:15][CH3:16])=[O:12]>C(#N)C>[CH2:14]([O:13][C:11](=[O:12])[NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])[CH2:15][CH3:16]
Reactant: Cc1cccc(C)c1N
Reactant: CCCOC(=O)Cl
Solvent: CC#N
Product: CCCOC(=O)Nc1c(C)cccc1C
Temperature: 150 °C
Yield: 95 %

Procedure:
2,6-Dimethyl-aniline (3.0 mL) and propyl chloroformate (4.1 mL) were dissolved in acetonitrile (15 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. The reaction mixture was concentrated in vacuo to furnish 4.79 g (95% yield) of the title compound as a brown solid. The crude product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]([CH2:17][CH2:18][F:19])([CH2:12][CH2:13][C:14](=[O:16])[CH3:15])[C:8]2=O)=[CH:4][C:3]=1[O:20][CH3:21].C(O)(=O)C.N1CCCC1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:20][CH3:21])[CH2:6][C:7]1([CH2:17][CH2:18][F:19])[C:8]2=[CH:15][C:14](=[O:16])[CH2:13][CH2:12]1
Reactant: COc1cc2c(cc1Cl)C(=O)C(CCF)(CCC(C)=O)C2
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNC1
Product: COc1cc2c(cc1Cl)C1=CC(=O)CCC1(CCF)C2
Temperature: 95 °C

Procedure:
To a solution of 6-chloro-2-(2-fluoroethyl)-5-methoxy-2-(3-oxobutyl)indan-1-one (32 g, 102 mmol) in toluene (1000 mL) were added acetic acid (7.0 mL, 120 mmol) and pyrrolidine (10 mL, 120 mmol) and the solution was heated at 95° C. for 2 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (1000 mL), washed with water and saturated aqueous NaHCO3, and dried over MgSO4. Filtration through a pad of silica gel and removal of the solvent under vacuum gave 6-chloro-9a-(2-fluoroethyl)-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8]C>Br.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cc1F
Agent: Br
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2ccc(O)c(F)c2)cc1
Yield: 95.1 %

Procedure:
Subsequently, 6.8 g of 3'-fluoro-4'-methoxybiphenyl-4-carboxylic acid was heated under reflux for 14 hours in 150 ml of 48% hydrobromic acid and 80 ml of dioxane. The volatile components were removed by evaporator, and the residue was washed several times with water to give 6.10 g (yield 95%) of the desired 3'-fluoro-4'-hydroxybiphenyl-4-carboxylic acid.