Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([N:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH3:21])[N:16]=[CH:17]2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([N:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:24][CH:23]=3)[CH3:21])[N:16]=[CH:17]2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(C)Br
Reactant: CN(c1ccc(O)cc1)c1cc2ccc(Cl)cc2cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3cn2)cc1
Yield: 80.4 %

Procedure:
A mixture of ethyl 2-bromopropionate (0.64 g), 4-[N-(7-chloroisoquinolin-3-yl)-N-methylamino]phenol (0.92 g), anhydrous potassium carbonate (0.49 g) and methyl ethyl ketone was heated under reflux for a period of 5 hours. The solution was cooled, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the product was purified by column chromatography over silica gel (eluant dichloromethane) to give ethyl 2-{4-[N-(7-chloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (1.00 g) as a green oil. The assigned structure was confirmed by proton magnetic resonance spectroscopy and mass spectrometry. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.25 (3H, t); 1.60 (3H, d); 3.45 (3H, s); 4.22 (2H, q); 4.75 (1H, q); 6.52 (1H, s); 6.8-7.4 (6H, m); 7.62 (1H, m); 8.75 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([CH2:6][CH:7]3[CH2:11][C:10](=O)[NH:9][CH:8]32)=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([CH2:6][CH:7]3[CH2:11][C:10](=[S:16])[NH:9][CH:8]32)=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CC2Cc3ccc(Cl)cc3C2N1
Solvent: c1ccncc1
Product: S=C1CC2Cc3ccc(Cl)cc3C2N1
Temperature: 90 °C
Reaction time: 1 h
Yield: 225.8 %

Procedure:
To a solution of 4.2 g of 7-chloro-1,2,3,3a,4,8b-hexahydro-indeno[1,2-b]pyrrol-2-one in 100 ml of pyridine is added 2.2 g of diphosphorus pentasulfide, and the mixture is stirred at 90° C. for 1 hour. The reaction mixture is then cooled, poured into ice-cold water and extracted with ethyl acetate. The extract is washed with water and dried over sodium sulfate, and the solvent is distilled off. The residual oil is chromatographed over silica gel with chloroform eluant. The purified product is crystallized with isopropyl ether and recrystallized from the same solvent to give 2.5 g of 7-chloro-1,2,3,3a,4,8b-hexahydro-indeno[1,2-b]pyrrol-2-thione, melting at 225°-227° C.
Reaction SMILES: [CH2:1]([N:3]([CH3:24])[C:4]([CH:6]1[CH2:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:13]([F:23])[CH:12]=2)(O)[CH2:7]1)=[O:5])[CH3:2].[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>ClCCCl>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[CH2:1]([N:3]([CH3:24])[C:4]([CH:6]1[CH2:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:13]([F:23])[CH:12]=2)=[CH:7]1)=[O:5])[CH3:2]
Reactant: CCN(C)C(=O)C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCN(C)C(=O)C1C=C(c2ccc(CN3CCCC3)c(F)c2)C1

Procedure:
3-(3-Fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-3-hydroxy-cyclobutanecarboxylic acid ethyl-methyl-amide (Example 14, 35.15 g, 105.1 mmol) was dissolved in a mixture of 1,2-dichloroethane (1 L) and trifluoroacetic acid (150 mL) and refluxed for 16 h. The resulting dark brown solution was cooled and concentrated to yield a brown oil (94.46) of crude title compound, N-ethyl-3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-N-methylcyclobut-2-enecarboxamide trifluoroacetate salt, with residual TFA, which was used in the next step without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35](=[O:55])[CH2:36][C:37]1([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:39][CH2:38]1)[CH3:33]>>[CH2:32]([O:34][C:35](=[O:55])[CH2:36][C:37]1([C:40]2[CH:45]=[CH:44][C:43]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([O:24][Si:25]([C:28]([CH3:30])([CH3:29])[CH3:31])([CH3:27])[CH3:26])[CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:6][CH:7]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38]1)[CH3:33]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(CCCc1ccccc1)O[Si](C)(C)C(C)(C)C
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(CCCc4ccccc4)O[Si](C)(C)C(C)(C)C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 5-(4-bromo-phenyl)-4-[1-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-3-methyl-isoxazole and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1.[H-].[Na+].[C:22]1([C:28](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>CN(C)C=O>[Br:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[N:6]=[C:5]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1
Reactant: COc1c(Br)ccc2[nH]nc(-c3cccc(F)c3)c12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1c(Br)ccc2c1c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 107.3 %

Procedure:
A total of 530 mg of 5-bromo-3-(3-fluoro-phenyl)-4-methoxy-1H-indazole obtained in Production Example II-2-c was dissolved in 8.3 ml of dimethylformamide, and 99 mg of sodium hydride (60% content) was added under ice-cooling and stirring. After stirring for 15 minutes, 483 mg of triphenylmethyl chloride was added. After stirring at room temperature for 1 hour, saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:8), to give 998 mg of the title compound as pale yellow crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:12]([CH:15]=[N:16][OH:17])=[C:11](Cl)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](OCC)(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[H-].[Na+]>[Cu]Br>[CH2:24]([O:23][C:21]([C:20]1[C:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:14][CH2:13][C:12]=2[CH:15]=[N+:16]([O-:17])[C:19]=1[OH:26])=[O:22])[CH3:25]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ON=CC1=C(Cl)CCN(Cc2ccccc2)CC1
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c2c(c[n+]([O-])c1O)CCN(Cc1ccccc1)CC2

Procedure:
Prepared from 1-benzyl-4-chloro-5-hydroxyiminomethyl-2,3,6,7-tetrahydro-1H-azepine by reaction with diethyl malonate in the presence of sodium hydride and catalytic amounts of copper(I) bromide at 100° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.Cl[C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:23])[CH:12]=[CH:11][N:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:16]=1[O:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:7][C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[CH:14]=1
Reactant: Cc1csc(N)n1
Reactant: Cc1cccc(C)c1Oc1ccnc(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1csc(Nc2cc(Oc3c(C)cccc3C)ccn2)n1
Yield: 43.5 %

Procedure:
Using the method of Example 3, Step B, 4-methylthiazol-2-amine (0.244 g, 2.14 mmol), 2-chloro-4-(2,6-dimethylphenoxy)pyridine (0.500 g, 2.14 mmol), potassium phosphate (0.500 g, 2.35 mmol), Pd2(dba)3 (0.098 g, 0.107 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.062 g, 0.107 mmol) were reacted to provide N-(4-(2,6-dimethylphenoxy)pyridin-2-yl)-4-methylthiazol-2-amine (0.290 g, 44% yield). 1H NMR (d6-DMSO) δ 10.93 (s, 1H), 8.13 (d, 1H), 7.15-7.22 (m, 3H), 6.50 (s, 1H), 6.40 (d, 1H), 6.39 (s, 1H), 2.19 (s, 3H), 2.08 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[C:13]#[N:14])([O-])=O.[CH2:15]([N:17]1[CH2:22][CH2:21]N[CH2:19][CH2:18]1)[CH3:16].O>CN(C=O)C>[CH2:15]([N:17]1[CH2:22][CH2:21][N:1]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=2[C:13]#[N:14])[CH2:19][CH2:18]1)[CH3:16]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CCN1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCN(c2cccc([N+](=O)[O-])c2C#N)CC1
Temperature: 90 °C

Procedure:
2,6-Dinitrobenzenecarbonitrile (1.0 eq) and ethylpiperazine (3.6 eq) were dissolved in DMF. The resulting solution heated at 90° C. for 2 hours. The solution was cooled to room temperature and poured into H2O. A precipitate formed which was filtered to yield the desired product as a brown solid. LC/MS m/z260.1 (MH+), Rf 1.69 minutes. 6-Amino-2-(4-ethylpiperazinyl)benzenecarbonitrile
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11](Br)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])[CH3:21].C(O[K])(C)(C)C.O>CS(C)=O.[Hg]>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([CH2:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:22])[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CC(=O)c1ccccc1
Agent: CC(C)(C)O[K]
Agent: [Hg]
Solvent: O
Solvent: CS(C)=O
Product: CCN1CCN(c2nc(CC(=O)c3ccccc3)cc3ccccc23)CC1
Yield: 89.1 %

Procedure:
A mixed solution of 1-(4-ethylpiperazin-1-yl)-3-bromoisoquinoline (1.00 g), acetophenone (1.50 g) and tert-butoxypotassium (1.40 g) in dimethyl sulfoxide (50 ml) was irradiated with light (450 W; mercury-vapor lamp) at room temperature for 5 hr. Water (200 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with water and brine, and then extracted with a 2N aqueous solution of hydrochloric acid (100 ml). The resulting aqueous layer was basified with sodium carbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was removed, to give 1-(4-ethylpiperazin-1-yl)-3-phenacylisoquinoline (1.0 g) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2[O:20][CH3:21])=O)=[CH:5][CH:4]=1.Cl.[F:23][C:24]1[CH:25]=[C:26]([CH:31]([NH2:33])[CH3:32])[CH:27]=[C:28]([F:30])[CH:29]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[F:23][C:24]1[CH:25]=[C:26]([CH:31]([NH:33][CH:9]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2[O:20][CH3:21])[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH3:32])[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: CC(N)c1cc(F)cc(F)c1
Reactant: COc1ccc(C(=O)c2cc([N+](=O)[O-])ccc2OC)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cc([N+](=O)[O-])ccc2OC)cc1
Yield: 92.5 %

Procedure:
Following a similar procedure to that described in Example (1a), 1.29 g of 2-methoxy-5-nitrophenyl 4-methoxyphenyl ketone, 1.74 g of 1-(3,5-difluorophenyl)ethylamine hydrochloride, 3.76 ml of triethylamine, 0.59 ml of titanium tetrachloride, 1.25 g of sodium cyanoborohydride and 0.39 ml of acetic acid were reacted, to obtain 1.78 g of the title compound as a yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[S:30][C:29]([NH:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)=[N:28][C:27]=1[C:42]([NH2:44])=[O:43]>C1COCC1.N1C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:25][C:26]2[S:30][C:29]([NH:31][C:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:35]=[CH:34][CH:33]=3)=[N:28][C:27]=2[C:42]([NH2:44])=[O:43])=[O:11])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Reactant: NC(=O)c1nc(Nc2cccc3ccccc23)sc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)Nc2sc(Nc3cccc4ccccc34)nc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
To a mixture of 4-acetamidobenzoic acid (0.151 g, 0.845 mmol) and a catalytic amount of DMF in dry THF (8 mL) was added dropwise oxalyl chloride (0.12 mL, 1.40 mmol) at 0° C., and the mixture was stirred for 2 hrs at rt. The solvent was evaporated, and the residual oxalyl chloride was removed with azeotropic distillation using toluene under nitrogen atmosphere. The resulting acid chloride was then dissolved in pyridine (5 mL) and cooled to 0° C. To this solution, a solution of 5-amino-2-(naphthalene-1-ylamino)thiazole-4-carboxamide (0.2 g, 0.70 mmol) in pyridine (5 mL) was added at 0° C., and the mixture was stirred for 12 hrs at rt. The solvent was evaporated, and the residue was suspended into I M HCl, and the resulting solids were collected and dried. The crude solids were purified by silica gel column chromatography eluted with 3% MeOH in DCM to give 91 mg (29% yield) of the titled compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH:33]2[CH2:36][CH2:35][CH2:34]2)[CH2:29][CH2:28]1)=[O:26].C([O-])([O-])=O.[K+].[K+].O>CC#N.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2([CH2:21][CH2:20][N:19]([CH2:24][C:25]([N:27]3[CH2:32][CH2:31][N:30]([CH:33]4[CH2:36][CH2:35][CH2:34]4)[CH2:29][CH2:28]3)=[O:26])[CH2:18][CH2:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C2(CCNCC2)N1Cc1ccccc1
Reactant: O=C(CCl)N1CCN(C2CCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CN1CCC2(CC1)c1ccccc1C(=O)N2Cc1ccccc1)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-benzylspiro[isoindole-1,4′-piperidin]-3(2H)-one (1.84 mmol) and 1-(chloroacetyl)-4-cyclobutylpiperazine (1.84 mmol) in CH3CN (8 ml) is added K2CO3 (761 mg, 5.52 mmol). The resulting suspension is stirred at rt overnight. Water (10 ml) and EtOAc (10 ml) is added and the layers are separated. The aqueous layer is extracted with EtOAc (20 ml) and the combined extracts are washed with brine (20 ml), dried over Na2SO4 and evaporated. The residue is purified by flash column to give 2-benzyl-1′-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]spiro[isoindole-1,4′-piperidin]-3(2H)-one as an off-white solid (LC-MS (M+1): 472.3) and 2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl 2-benzyl-3-oxo-2,3-dihydro-1′H-spiro[isoindole-1,4′-piperidine]-1′-carboxylate as a minor product.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([OH:12])=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C(=O)(O)[O-].[K+].CS(O[CH:27]([C:42]#[N:43])[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:29]=1)(=O)=O>C1COCC1.CN(C=O)C.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH:9]([C:10]([O:12][CH:27]([C:42]#[N:43])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:29]=3)=[O:11])[C:8]2([CH3:13])[CH3:14])=[CH:15][CH:16]=1
Reactant: CS(=O)(=O)OC(C#N)c1ccc(F)c(Oc2ccccc2)c1
Reactant: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)O
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)OC(C#N)c1ccc(F)c(Oc2ccccc2)c1
Reaction time: 48 h

Procedure:
3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylic acid (0.82 g, 3.40 mmol) is stirred together with 0.34 g (3.40 mmol) potassium bicarbonate in 10 ml THF/DMF (1:1) for 15 minutes. Then 1.0 g (3.40 mmol) α-cyano-4-fluoro-3-phenoxybenzyl methanesulfonate in 5 ml THF/DMF (1:1) is added and the mixture stirred for approximately 48 hours. The reaction is diluted with ether, washed with water (3×) and sat. NaCl, dried and solvent is removed. The crude product is purified by prep. TLC developing with 10% ethyl acetate/hexane to yield α-cyano-4-fluoro-3-phenoxybenzyl 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: N(OCCCC)=O.[C:8]([O:16][C@@H:17]1[C@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:20]([C:31]([NH:33][CH2:34][CH3:35])=[O:32])[O:19][C@H:18]1[N:36]1[CH:44]=[N:43][C:42]2[C:37]1=[N:38][C:39](N)=[N:40][C:41]=2[Cl:45])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.II.[I:49]CI>C1COCC1.[Cu]I>[C:8]([O:16][C@@H:17]1[C@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:20]([C:31]([NH:33][CH2:34][CH3:35])=[O:32])[O:19][C@H:18]1[N:36]1[CH:44]=[N:43][C:42]2[C:37]1=[N:38][C:39]([I:49])=[N:40][C:41]=2[Cl:45])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ICI
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: [Cu]I
Agent: CCCCON=O
Agent: II
Solvent: C1CCOC1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
n-Butyl nitrite (4.65 ml, 39.7 mmol) was added to a suspension of (2R,3R,4S,5S)-2-(2-amino-6-chloro-9H-purin-9-yl)-4-(benzoyloxy)-5-[(ethylamino)carbonyl]-tetrahydro-3-furanyl benzoate (Preparation 46) (8.10 g, 14.7 mmol), iodine (3.73 g, 14.7 mmol), copper(I) iodide (6.16 g, 32.3 mmol) and diiodomethane (12.55 ml, 155.8 mmol) in THF (100 ml) and the mixture was heated under reflux for 2.5 hours. The solution was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between 5% w/w aqueous sodium metabisulfite solution (100 ml) and dichloromethane (100 ml). The organic layer was separated, filtered through Arbocel (Trade Mark), dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol (99:1 by volume) to afford the title compound as a yellow foam (7.55 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[F:26][C:27]([F:41])([F:40])[O:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][N:33]=[C:32]2[CH:38]=O.N1CCCCC1>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:38]/[C:32]3[C:31]4[C:35](=[CH:36][CH:37]=[C:29]([O:28][C:27]([F:40])([F:26])[F:41])[CH:30]=4)[NH:34][N:33]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ccc(OC(F)(F)F)cc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ccc(OC(F)(F)F)cc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 39.9 %

Procedure:
A solution of tert-butyl 4-[1-(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.103 g, 0.295 mmol) in methanol (1.2 mL) was added with 5-(trifluoromethoxy)-1H-indazole-3-carbaldehyde (0.0680 g, 0.295 mmol), and piperidine (0.00251 g, 0.0295 mmol) at room temperature, and the mixture was stirred at 60° C. for 3 hours. The solvent was evaporated, and then the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-[(6-hydroxy-3-oxo-2-{[5-(trifluoromethoxy)-1H-indazol-3-yl]methylene}-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0660 g, 40%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([OH:22])=O)[CH:17]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[N:15]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:30][C@H:31]1[CH2:36][O:35][CH2:34][CH2:33][NH:32]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][C@@H:31]4[CH3:30])=[O:22])[CH:17]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[N:15]=3)=[CH:10][CH:9]=2)[CH2:2][CH2:3]1
Reactant: C[C@H]1COCCN1c1cc(C(=O)O)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Reactant: C[C@H]1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COCCN1C(=O)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-[4-(Cyclopropylcarbamoylamino)phenyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine-4-carboxylic acid (95 mg) was dissolved in DMF (3 mL) and (3S)-3-methylmorpholine added. DIPEA (0.125 mL) and HATU (137 mg) were added and the reactions stirred at RT for 3 h before being concentrated in vacuo and partitioned between DCM (25 mL) and water (25 mL). The organic layer was dried over magnesium sulphate, filtered and evaporated to dryness to give the desired material as a solid (88 mg).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[N:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>CO.O>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CCOC(=O)c1csc(-c2ccc(S(N)(=O)=O)cc2)n1
Solvent: CO
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2nc(C(=O)O)cs2)cc1
Temperature: 75 °C

Procedure:
In an oven-dried, 100-mL, round-bottomed flask was placed ethyl 2-(4-aminosulfonylphenyl)thiazole-4-carboxylate (1300 mg, 4.2 mmol), LiOH monohydrate (350 mg, 8.3 mmol) in MeOH (40 mL) and H2O (4 mL). The solution was heated to 75° C. for 3 h, cooled to RT, and concentrated. The resulted yellow solid was dissolved in H2O (10 mL), extracted with EtOAc (1×15 mL). The aqueous layer was acidified with 2N aqueous HCl (4.15 mL). The precipitate was filtered, and washed with H2O (10 mL) to afford the title compound as a light-yellow solid. MS m/z: 285 (M+H).