Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([NH:27][NH2:28])=[O:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]4[O:26][C:29](=[O:30])[NH:28][N:27]=4)[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc2c(Cc3cccc(C(=O)NN)n3)c(-c3ccccc3)[nH]c2c1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc2c(Cc3cccc(-c4n[nH]c(=O)o4)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
To a suspension of 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carbohydrazide (258 mg) in tetrahydrofuran (3.5 mL) was added 1,1′-carbonyldiimidazole (135 mg), and this mixture was stirred at room temperature for 3 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (270 mg). 1H-NMR (DMSO-d6) δ ppm: 3.77 (3H, s), 4.34 (2H, s), 6.63 (1H, dd, J=2.3, 8.5 Hz), 6.87 (1H, d, J=2.3 Hz), 7.27-7.40 (3H, m), 7.42-7.53 (2H, m), 7.68-7.90 (4H, m), 11.20 (1H, s), 12.76 (1H, br s). ESI-MS (m/z): 399 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:25])=[N:5][C:6]([NH2:24])=[N:7][C:8]=1[O:9][CH2:10][CH2:11][O:12][CH2:13][P:14]([O:20][CH:21]([CH3:23])[CH3:22])([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])#N.S(=O)(=O)(O)[OH:27]>O.[Pd]>[CH:1]([C:3]1[C:4]([NH2:25])=[N:5][C:6]([NH2:24])=[N:7][C:8]=1[O:9][CH2:10][CH2:11][O:12][CH2:13][P:14]([O:20][CH:21]([CH3:23])[CH3:22])([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[O:27]
Reactant: O=S(=O)(O)O
Reactant: CC(C)OP(=O)(COCCOc1nc(N)nc(N)c1C#N)OC(C)C
Agent: [Pd]
Solvent: O
Product: CC(C)OP(=O)(COCCOc1nc(N)nc(N)c1C=O)OC(C)C
Yield: 42 %

Procedure:
5-Cyano-2,4-diamino-6-[2-(diisopropoxyphosphorylmethoxy)ethoxy]pyrimidine (1.5 g, 4 mmol) was hydrogenated in water (36 ml) and sulfuric acid (6 ml) over 5% palladium on charcoal (0.25 g) under stirring for 20 h at room temperature. The mixture was filtered through a pad of Celite and the catalyst was washed with hot water and hot methanol (100 ml each). The filtrate was neutralized with aqueous NaOH and solvents evaporated. The residue was mixed with hot methanol, salts were filtered off and the mixture was taken down. Product was purified by column chromatography on silica gel (elution with 3% MeOH in CHCl3) to give 0.63 g (42%) of 5-formyl-2,4-diamino-6-[2-(diisopropoxyphosphorylmethoxy)ethoxy]pyrimidine.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:21])[C:14]=2[N+:18]([O-])=O)[C:9]1=[O:22])[CH3:7])(=[O:3])[CH3:2].C(O)C.[Cl-].[NH4+].O>[Fe]>[C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:21])[C:14]=2[NH2:18])[C:9]1=[O:22])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)OC[C@@H](C)n1ccc2c(N)c(Cl)ccc2c1=O
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with (R)-2-(6-chloro-5-nitro-1-oxoisoquinolin-2(1H)-yl)propyl acetate (160.0 mg, 0.0004927 mol) and ethanol (7 mL, 0.1 mol), and the reaction was heated at 85° C. Ammonium chloride (264 mg, 0.00493 mol) in water (7 mL, 0.4 mol) was added, followed by iron (110 mg, 0.0020 mol) in two portions. The reaction was stirred at that temperature for one hour. The reaction mixture was then poured onto dichloromethane (60 mL) and extracted. The extracts were washed with brine, dried, and the solvent removed under reduced pressure to afford the product as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@@H:18]2[NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1.[C:30](O)(=[O:32])[CH3:31]>>[C:30]([N:22]1[C@@H:18]([CH2:17][O:16][C:14]2[CH:13]=[C:12]([O:24][CH3:25])[CH:11]=[C:10]3[C:15]=2[C:6]([NH:5][C:4]2[CH:26]=[CH:27][C:28]([F:29])=[C:2]([Cl:1])[CH:3]=2)=[N:7][CH:8]=[N:9]3)[CH2:19][C@H:20]([OH:23])[CH2:21]1)(=[O:32])[CH3:31]
Reactant: CC(=O)O
Reactant: COc1cc(OC[C@H]2C[C@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Product: COc1cc(OC[C@H]2C[C@H](O)CN2C(C)=O)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 59 %

Procedure:
The procedure described in Example 20 was repeated using (3S,5R)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol (120 mg) with acetic acid (18 μl) to give the title compound as a white solid in 59% yield; NMR spectrum (DMSO-d6) 9.95 (s, 1H), 8.46 (s, 1H), 8.16-8.14 (m, 1H), 7.73-7.70 (m, 1H), 7.46 (t, 1H), 6.85 (s, 1H), 6.84 (s, 1H), 5.10 (m, 1H), 4.67-4.63 (m, 1H), 4.47-4.38 (m, 2H), 4.26-4.21 (m, 1H), 3.94 (s, 3H), 3.59 (dd, 1H), 3.41 (dd, 1H), 2.11-2.05 (m, 2H), 2.00 (s, 3H); Mass spectrum MH+ 461.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[N:10]O)[CH2:7][CH2:8][CH2:9][C:2]1=2.[H-].C([Al+]CC(C)C)C(C)C.[F-].[Na+].O>ClCCl>[S:1]1[C:2]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:10][C:3]=2[CH:4]=[CH:5]1
Reactant: ON=C1CCCc2sccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [F-]
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: c1cc2c(s1)CCCCN2
Reaction time: 3 h
Yield: 52.9 %

Procedure:
A solution of 6,7-dihydro-5H-benzo[b]thiophen-4-one oxime (1.67 g) in dry dichloromethane (100 mL) was cooled to 0°. Following dropwise addition of diisobutylaluminum hydride (50 ml, 1M in hexanes), the mixture was stirred at 0° for three hours and then diluted with dichloromethane (50 mL). Sodium fluoride (8.4 g) was added, followed by water (2.7 mL). The reaction mixture was stirred vigorously for 30 minutes, then filtered. and concentrated to provide the title compound (0.81 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:30](Cl)(=[O:32])=[O:31])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:30]([C:24]2[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=2)(=[O:32])=[O:31])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Product: COc1ccc(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)cc1OC

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 3,4-dimethoxybenzene-1-sulfonyl chloride.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH2:13])[N:4]=1)[CH3:2].[F:14][C:15]1[CH:16]=[CH:17][C:18]([O:33][CH3:34])=[C:19]([C:21]([CH3:32])([CH3:31])[CH2:22][C:23]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH:24]=O)[CH:20]=1>C(O)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:13]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])([OH:30])[CH2:22][C:21]([C:19]2[CH:20]=[C:15]([F:14])[CH:16]=[CH:17][C:18]=2[O:33][CH3:34])([CH3:31])[CH3:32])[N:4]=1)[CH3:2]
Reactant: CCc1ccc2c(N)cccc2n1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCc1ccc2c(N=CC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Yield: 80.1 %

Procedure:
Analogously to Example 37, 334 mg (1.94 mmol) of 2-ethylquinolin-5-ylamine is reacted with 500 mg (1.62 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanal in 2.20 ml of concentrated acetic acid and 15 ml of toluene. After purification on silica gel with hexane-ethyl acetate (0–100%), 600 mg (80% of theory) of the corresponding imine is obtained.
Reaction SMILES: [CH2:1]([NH:19][CH:20]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:25]([OH:26])[C@H:23]([OH:24])[C@H:21]1[OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:31](Cl)(=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>>[CH:20]1([N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:31](=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[O:28][C@H:27]([CH2:29][OH:30])[C@@H:25]([OH:26])[C@H:23]([OH:24])[C@H:21]1[OH:22]
Reactant: CCCCCCCCCCCCCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
Preparation in analogy to Example 6 from N-octadecylglucopyranosylamine and stearoyl chloride.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][C:6]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])=[C:5]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[N:4]=1.[CH3:38][O:39][CH2:40][C:41](Cl)=[O:42]>>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([C:5]2[N:4]=[C:3]([CH2:2][NH:1][C:41](=[O:42])[CH2:40][O:39][CH3:38])[C:8]([CH2:9][NH:10][C:11](=[O:22])[C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=3)=[CH:7][C:6]=2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])=[CH:36][CH:35]=1
Reactant: COCC(=O)Cl
Reactant: NCc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)cc1CNC(=O)c1ccc(C(F)(F)F)cc1
Product: COCC(=O)NCc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)cc1CNC(=O)c1ccc(C(F)(F)F)cc1
Yield: 77.6 %

Procedure:
0.35 g of N-{[6-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-{[(methoxyacetyl)amino]methyl}pyrid-3-yl]methyl}-4-(trifluoromethyl)benzamide is prepared from 0.40 g of N-{[2-(aminomethyl)-6-(4-chlorophenyl)-5-(2,4-dichlorophenyl)pyrid-3-yl]methyl}-4-(trifluoromethyl)benzamide and 0.084 g of methoxyacetyl chloride, using a procedure similar to that of step E) of Example 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:22](O)=[O:23]>O>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([F:8])[C:3]=1[OH:9])[CH:22]=[O:23]
Reactant: Oc1c(F)cccc1F
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1cc(F)c(O)c(F)c1

Procedure:
A solution of 2,6-difluorophenol (25 g, 192 mmol), hexamethylenetetramine (26 g, 192 mmol) and trifluoroacetic acid (190 mmol) was refluxed overnight. The reaction was cooled and diluted with water (200 mL) and extracted with dichloromethane (3×100 mL). The organic layer was washed with 10% aqueous potassium carbonate (2×100 mL). The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield 3,5-difluoro-4-hydroxybenzaldehyde as a white solid. Upon sitting the desired product began to precipitate from the original aqueous layer that was extracted with dichloromethane. The layer was filtered to provide the product (6) as long white crystals.
Reaction SMILES: [CH2:1]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[CH2:17]([Li])CCC.IC>C(OCC)C.CCCCCC>[CH2:1]([N:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: COc1cccc(CNc2ccccc2)c1
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CI
Product: COc1cccc(CN(C)c2ccccc2)c1

Procedure:
5.15 g of N-(3-Anisyl)-N-phenyl-amine were dissolved in 25.0 ml of anhydrous diethylether. 11.0 g of a 2.50 M solution of n-butyl lithium in n-hexane was added with stirring. After completion of the addition the reaction mixture was heated to reflux for 30 min 3.90 g of iodomethane are added and the reaction mixture was heated to reflux for additional 4 hours. After extraction with 2.00 N sodium hydroxide solution (three times) the organic layer was dried with anhydrous sodium sulfate. After filtration the solvent was removed in vacuo and the crude product purified by fractionated distillation in vacuo. At a temperature of 70-90° C./0.01 mbar 2.40 g (45.0%) of APMA was collected as yellow liquid.
Reaction SMILES: [Li].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:15]([O-])=[CH:16][C:17](=O)[C:18]([O:20]CC)=[O:19])[CH:7]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:9]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:48][C:49]1[CH:54]=[C:53]([NH:55][NH2:56])[CH:52]=[CH:51][N:50]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:15]2[N:55]([C:53]3[CH:52]=[CH:51][N:50]=[C:49]([Cl:48])[CH:54]=3)[N:56]=[C:17]([C:18]([OH:20])=[O:19])[CH:16]=2)[CH:7]=[C:8]([O:10][C:11]([F:12])([F:13])[F:14])[CH:9]=1
Reactant: NNc1ccnc(Cl)c1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(OC)cc(OC(F)(F)F)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: COc1cc(OC(F)(F)F)cc(-c2cc(C(=O)O)nn2-c2ccnc(Cl)c2)c1

Procedure:
500 mg (1.29 mmol) of the compound of Example 10A is reacted analogously to the synthesis of the compound of Example 20A with 256 mg (1.42 mmol) of 2-chloropyridin-4-yl-hydrazine hydrochloride. After hydrolysis, 149 mg (28% of theory) of the title compound is obtained.
Reaction SMILES: C([CH:3]([CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:24])[CH:10]=1)[C:4]([OH:6])=[O:5])C.[OH-].[Na+]>C(O)C>[CH3:23][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:24])[C:17]=1[CH2:16][O:15][C:11]1[CH:10]=[C:9]([CH:8]=[CH:7][CH2:3][C:4]([OH:6])=[O:5])[CH:14]=[CH:13][CH:12]=1
Reactant: CCC(C=Cc1cccc(OCc2c(C)cccc2C)c1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1COc1cccc(C=CCC(=O)O)c1

Procedure:
To a solution of Ethyl 4-(3-(2,6-dimethylbenzyloxy)phenyl)-3-butenoic acid: ethanol at low temp, add aqueous sodium hydroxide, after an hour, concentrate and purify by flash chromatography on silica gel column (chloroform:methanol 95:5 spiked with acetic acid).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][OH:26])[C:5]1=[O:29])[CH:2]=[CH2:3].[H-].[Na+].I[CH3:34]>C1COCC1>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][O:26][CH3:34])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)COC)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 50 mg (0.112 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B) in 0.5 mL of THF was added 60% sodium hydride (8.96 mg, 0.244 mmol) at 0° C. After being stirred at 0° C. for 30 min, iodomethane (14.01 uL, 0.244 mmol) was added. The reaction was allowed to warm to 25° C., and stirred for an additional 2 h until completion. The reaction was quenched with saturated aqueous NH4Cl solution, extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC[N:32]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH2:32])=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ccc(Nc2nc(-c3cccc(C(=O)O)c3)nc3scnc23)cc1OC
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Nc2nc(-c3cccc(C(N)=O)c3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.6 %

Procedure:
To a mixture of 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (100 mg, 0.25 mmol), EDCI (70 mg, 0.37 mmol), HOBt (50 mg, 0.37 mmol) and Et3N (49 mg, 0.49 mmol) in DCM (20 mL) was bubbled ammonia until saturation. The mixture was stirred at room temperature for 3 h, then was filtered and the filtrate was concentrated to give residue which was purified by column chromatography (DCM:MeOH=50:1) to afford 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamide (22 mg, 14%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.13 (s, 1H), 9.37 (s, 1H), 8.88 (t, 1H, J=1.5 Hz), 8.51 (d, 1H, J=7.8 Hz), 8.10 (s, 1H), 7.98 (d, 1H, J=7.5 Hz), 7.86 (d, 1H, J=2.4 Hz), 7.58 (t, 1H, J=7.8 Hz), 7.49-7.44 (m, 2H), 7.99 (d, 1H, J=8.7 Hz), 3.82 (s, 3H), 3.77 (s, 3H). LC-MS: 408 [M+H]+, tR=1.39 min. HPLC: 97.78% at 214 nm, 97.42% at 254 nm, tR=1.39 min. LC-MS: 408 [M+H]+, tR=1.392 min. HPLC: 95.38% at 214 nm, 96.23% at 254 nm, tR=3.53 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[C:5]#[N:6].[CH2:11](Cl)[O:12][CH3:13].[H-].[Na+]>CN(C)C=O>[I:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[O:1][CH2:11][O:12][CH3:13]
Reactant: N#Cc1ccc(I)c(O)c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cc(C#N)ccc1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-hydroxy-4-iodobenzonitrile (500 mg, 2.04 mmol) and MOMCl (350 mg, 4.37 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL) and cooled to 0° C. NaH (100 mg, 60% suspension in mineral oil, 2.5 mmol) is then added. The resulting mixture is allowed to stir at room temperature for 1 h before TLC analysis suggested the consumption of the starting iodide. Ether is then added and washed with H2O (3×20 mL) and brine. After drying over Na2SO4, the ether is removed and the residue is purified through chromatography to afford the desired MOM ether (570 mg, 96%). 1H NMR (300 MHz, CDCl3) δ 7.90 (1H, d, J=8.01 Hz), 7.32 (1H, d, J=1.7 Hz), 7.03 (1H, dd, J=8.01 and 1.71 Hz), 5.27 (2H, s), 3.51 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9](Br)[CH:8]=[C:7]([CH3:12])[C:6]=1[Cl:13].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[CH:8]=[C:7]([CH3:12])[C:6]=1[Cl:13]
Reactant: CN1CCNCC1
Reactant: COC(=O)Cc1cc(Br)cc(C)c1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc(N2CCN(C)CC2)cc(C)c1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
(5-Bromo-2-chloro-3-methyl-phenyl)-acetic acid methyl ester (2.0 g, 7.2 mmol), N-methylpiperazine (960 μL, 8.6 mmol) and Cs2CO3 (3.3 g, 10.1 mmol) are suspended in toluene (80 mL). Pd(OAc)2 (81 mg, 0.36 mmol) and BINAP (224 mg, 0.36 mmol) are added and the reaction is stirred at 100° C. overnight. The mixture is filtered through Celite and the solvent is evaporated. The residue is purified by FCC (AcOEt/AcOH/H2O 60:15:15) to afford 2-[2-chloro-3-methyl-5-(4-methyl-piperazin-1-yl)-phenyl]-acetic acid methyl ester. The ester is suspended in NH4OH 25% (60 mL). The mixture is stirred overnight at RT and the precipitate is filtered off to yield the amide. 1H NMR (DMSO, 400 MHz) δ 2.20 (s, 3H), 2.27 (s, 3H), 2.40-2.45 (m, 4H), 3.07-3.13 (m, 4H), 3.48 (s, 2H), 6.78 (s, 1H), 6.82 (s, 1H), 6.91 (br s, 1H), 7.34 (br s, 1H).
Reaction SMILES: C(S[CH:6]([C:10](=[O:15])CC(C)C)[CH:7](C)[CH3:8])C(=C)C.C(SC(C(=O)CC(C)C)C(C)C)C=CC.[CH2:31]([S:34][CH:35]([C:39](=[O:44])[CH2:40][CH:41]([CH3:43])[CH3:42])[CH:36]([CH3:38])[CH3:37])[CH:32]=[CH2:33]>>[CH2:32]([CH:31]([S:34][CH:35]([CH:36]([CH3:38])[CH3:37])[C:39]([CH2:40][CH:41]([CH3:43])[CH3:42])=[O:44])[C:10]([CH2:6][CH2:7][CH3:8])=[O:15])[CH3:33]
Reactant: C=CCSC(C(=O)CC(C)C)C(C)C
Reactant: C=C(C)CSC(C(=O)CC(C)C)C(C)C
Agent: CC=CCSC(C(=O)CC(C)C)C(C)C
Product: CCCC(=O)C(CC)SC(C(=O)CC(C)C)C(C)C

Procedure:
3-methyl-thio-4-heptanone; 3-propyl-thio-4-heptanone; 3-(methallylthio)-2,6-dimethyl-4-heptanone; 3-crotylthio-2,6-dimethyl-4-heptanone; and 3-allylthio-2,6-dimethyl-4-heptanone.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[C:6](=[CH:7][C:8]([NH2:16])=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.[Cl:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>>[Cl:18][CH2:19][CH2:20][C:21]([NH:16][C:8]1[CH:9]=[CH:10][C:11]2[NH:12][C:13]3[C:4](=[CH:3][C:2]([NH:1][C:21](=[O:22])[CH2:20][CH2:19][Cl:18])=[CH:15][CH:14]=3)[C:5](=[O:17])[C:6]=2[CH:7]=1)=[O:22]
Reactant: Nc1ccc2[nH]c3ccc(N)cc3c(=O)c2c1
Reactant: O=C(Cl)CCCl
Product: O=C(CCCl)Nc1ccc2[nH]c3ccc(NC(=O)CCCl)cc3c(=O)c2c1
Yield: 81 %

Procedure:
A suspension of 2,7-diamino-9(10H)-acridone 12 (13.44 g, 60 mmol), in 3-chloropropionyl chloride (3-CPC) (240 mL) was stirred at 90° C. for 4 hr and then heated under reflux for 2 hr. The resultant mixture was cooled to 0° C. after which the product was collected on a glass sinter. The product was washed with acetone (60 mL) followed by toluene (2×60 mL), more acetone (4×60 mL), dry ether (2×60 mL) and finally hexane (2×60 mL). The product was dried over P2O5 under vacuum to yield an olive-green solid (19.68 g, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[O:11].[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C@@H:37]([NH:39][CH3:40])[CH3:38])[C:28]([O:30][CH3:31])=[O:29].C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C@@H:37]([N:39]([CH3:40])[C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:38])[C:28]([O:30][CH3:31])=[O:29]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1F
Reactant: CN[C@@H](C)COc1ccc(C(=O)OC)cc1Cl
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@H](C)N(C)C(=O)Cc2ccc(NC(=O)Nc3ccccc3F)c(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
A mixture of 3-methoxy-4-[N′-(2-fluorophenyl)ureido]phenylacetic acid (296 mg, 0.93 mmol), methyl (S)-3-chloro-4-(2-methylamino-1-propoxy)benzoate (240 mg, 0.93 mmol), EDC(hydrochloride) (268 mg, 1.40 mmol), HOBt (189 mg, 1.40 mmol), and DMAP (23 mg, 0.19 mmol) in DMF (8 mL) was stirred at room temp for 1.5 hr. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with 5% MeOH in CHCl3 as eluent to give 520 mg (100%) methyl (S)-3-chloro-4-[2-[N-methyl-N-[3-methoxy-4-[N′-(2-fluorophenyl)ureido]phenylacetyl]amino]-1-propoxy]benzoate as a red-brown amorphous solid.