Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:21])([CH3:20])[C:5]([N:7]1[CH2:19][CH2:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH2:8]1)=[O:6].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:22]1([S:28]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]3[CH2:18][CH2:19][N:7]([C:5](=[O:6])[C:4]([CH3:21])([CH3:20])[CH3:3])[CH2:8][C:9]2=3)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)C(=O)N1CCc2c([nH]c3ccccc23)C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)C(=O)N1CCc2c(n(S(=O)(=O)c3ccccc3)c3ccccc23)C1
Reaction time: 0.25 h
Yield: 56.2 %

Procedure:
To a well-agitated suspension of sodium hydroxide (0.81 g, 20.2 mmol) in methylene chloride (10 mL) is added 2,2-dimethyl-1-(1,3,4,9-tetrahydro-pyrido[3,4-b]indol-2-yl)-propan-1-one (2.3 g, 8.98 mmol). The reaction mixture is stirred for 15 min, and then benzenesulfonyl chloride (1.89 g, 10.7 mmol) is added. The solution is stirred at room temperature for 1 h. The reaction is diluted with methylene chloride, washed with water then a saturated sodium chloride solution, dried with sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (50% ethyl acetate-hexane) provides 2.0 g (56.2%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]12[C:14]([Cl:16])([Cl:15])[C:5]([Cl:17])([C:6]3[C:7]([OH:13])=[CH:8][CH:9]=[C:10]([OH:12])[C:11]=31)[C:4]([Cl:18])=[C:3]2[Cl:19].[C:20](O)(=[O:22])[CH3:21]>>[CH3:21][C:20]([C:8]1[C:7]([OH:13])=[C:6]2[C:11](=[C:10]([OH:12])[CH:9]=1)[C:2]1([Cl:1])[C:14]([Cl:15])([Cl:16])[C:5]2([Cl:17])[C:4]([Cl:18])=[C:3]1[Cl:19])=[O:22]
Reactant: Oc1ccc(O)c2c1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Reactant: CC(=O)O
Product: CC(=O)c1cc(O)c2c(c1O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Temperature: 40 °C

Procedure:
76 g. of 1,2,3,4,9,9-hexachloro-1,4-dihydro-1,4-methanonaphthalene-5,8-diol, prepared according to Example 2, were suspended in 100 ml. of acetic acid and then 20 ml. of boron trifluoride-diethyl ether complex were added. This mixture was heated at 100°-105° C. for 5 hours. After being cooled to 40° C., the mixture was poured into ice water. After repeated recrystallization from benzene white crystals were obtained, m.p. 135°-140° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]([NH:27][C:28](=[O:37])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[C:17]([C:18](=[O:23])C(Cl)(Cl)Cl)[C:10]=12.[NH2:38][CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1>CN(C=O)C>[N:42]1[CH:43]=[CH:44][CH:45]=[C:40]([CH2:39][NH:38][C:18]([C:17]2[C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:24][C:25]([NH:27][C:28](=[O:37])[CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[O:26])=[CH:3][C:2]=3[F:1])[NH:15][CH:16]=2)=[O:23])[CH:41]=1
Reactant: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccnc3[nH]cc(C(=O)C(Cl)(Cl)Cl)c23)c(F)c1
Reactant: NCc1cccnc1
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccnc3[nH]cc(C(=O)NCc4cccnc4)c23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of 1-(3-fluoro-4-(3-(2,2,2-trichloroacetyl)-1H-pyrrolo[2,3-b]pyridine 4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea (7.0 mg, 0.012 mmol, Example 270) in 0.5 mL of DMF was added 3-(aminomethyl)pyridine (10 mg, 0.092 mmol, Aldrich). The reaction mixture was stirred at rt for 1 h, and quenched by the addition of 1 mL of cold water. The precipitate that formed was collected by filtration, washed with cold water (1 mL) and cold acetonitrile(1 mL) and dried under vacuum to afford the desired product (4.3 mg, 64%) as a white solid. 1H NMR (DMSO-d6) δ 12.38 (s, 1H), 11.03 (s, 1H), 10.57 (s, 1H), 8.48 (s, 1H), 8.40 (t, 1H, J=5.5 Hz), 8.34 (d, 1H, J=3.3 Hz), 8.11 (d, 1H, J=5.5 Hz), 8.00 (s, 1H), 7.73 (d, 1H, J 13.2 Hz), 7.65 (d, 1H, J=7.7 Hz), 7.37–7.29 (m, 4H), 7.16 (t, 3H, J=8.8 Hz), 6.34 (d, 1H, J=5.5 Hz), 4.48 (d, 2H, J=5.5 Hz), 3.74 (s, 2H); MS(ESI+) m/z 567.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[C:13]([C:17]1[CH:32]=[CH:31][C:20]([C:21]([NH:23][C:24]2[C:25]([NH2:30])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:22])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:30][C:25]1[C:24]([NH:23][C:21](=[O:22])[C:20]2[CH:31]=[CH:32][C:17]([C:13]([CH3:15])([CH3:14])[CH3:16])=[CH:18][CH:19]=2)=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:8])([O-:3])=[O:2]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc([N+](=O)[O-])c2)cc1
Yield: 56.8 %

Procedure:
Using the procedure described in Example 93, Part A, 3-nitrobenzoyl chloride (2.2 mmol) and N1-(4-tert-butylbenzoyl)-1,2-benzenediamine (1.8 mmol) yielded 427 mg (56%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.Cl[CH2:12][CH:13]=O.C(=O)(O)[O-].[Na+].C>C(OCC)C>[CH3:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]2[CH:12]=[CH:13][N:1]=[C:2]2[CH:7]=1
Reactant: O=CCCl
Reactant: CSc1nc(C)cc(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CSc1nc(C)cc2nccn12
Temperature: 80 °C

Procedure:
A mixture of 5 g (32 mmole) of 4-amino-6-methyl-2-methylthiopyrimidine and 10 g (64 mmole) of a 50% aqueous solution of chloroacetaldehyde was heated at 80° C. for one hour. The mixture was cooled with an ice bath and immediately neutralized with sodium bicarbonate. The mixture was extracted with chloroform and the extracts were dried over magnesium sulfate and evaporated to provide an oil. The oil was extracted with hot ethyl acetate, and the extracts were filtered and then evaporated. The residue was dissolved in hot benzene, treated with decolorizing charcoal, and filtered, and the filtrate was evaporated. The residue thereby obtained was dissolved in hot diethyl ether, treated with decolorizing charcoal, and filtered, the filtrate then being evaporated. The residue obtained was recrystallized first from a benzene/hexane mixture and then from cyclohexane, each time accompanied by treatment with decolorizing charcoal. The solid was purified on a preparative scale high pressure liquid chromatograph using ethyl acetate as the eluent. The solid obtained was recrystallized from hexanes to give white crystals of 7-methyl-5-methylthioimidazo[1,2-c]pyrimidine, m.p. 67°-69° C. Analysis: Calculated for C8H9N3S: %C, 53.6; %H, 5.1; %N, 23.4; Found: %C, 53.2; %H, 5.0; %N, 23.8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](O)([CH3:19])[CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=1>[Pd].C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=1
Reactant: CC(O)(CCO)c1ccc(-c2ccc(F)cc2F)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(CCO)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
2.78 g. of 3-(2',4'-difluoro-4-biphenylyl)butane-1,3-diol are dissolved in 30 ml. of acetic acid and hydrogenated at 20° and under 1 atmosphere on 0.5 g of 10% Pd-C until the reaction has ceased. Filtering and evaporating gives 3-(2',4'-difluoro-4-biphenylyl)butan-1-ol.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])=[O:8])C>CO.O.Cl>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[N:9]1[CH:4]=[CH:5][NH:6][C:7]1=[O:8]
Reactant: CCOC(CNC(=O)Nc1ccc(F)cc1F)OCC
Agent: Cl
Solvent: CO
Solvent: O
Product: O=c1[nH]ccn1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.4 %

Procedure:
This urea (37.5 g) was dissolved in a mixture of 560 ml of methanol and 280 ml of water, and 300 ml of 0.48M hydrochloric acid was added thereto and the resulting mixture was stirred for three days at room temperature. The reaction solution was concentrated under reduced pressure. The crystals thus separated out were washed with a mixture of water and methanol (5:1) to give 22.8 g of 1-(2,4-difluorophenyl)-2(1H,3H)-imidazolone as a colorless powder.
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([NH:14][C@@H:15]([CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[C:16]([O:18]C)=[O:17])=[O:13])[CH:7]=[C:8]([CH3:10])[CH:9]=1.O>CO>[CH3:10][C:8]1[CH:7]=[C:6]([CH2:11][C:12]([NH:14][C@@H:15]([CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[C:16]([OH:18])=[O:17])=[O:13])[CH:5]=[C:4]([CH3:3])[CH:9]=1
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)Cc1cc(C)cc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C)cc(CC(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 93 %

Procedure:
DMAP (122.2 mg, 0.5 mmol) and DIC (N,N-diisopropylcarbodiimide) (235 μl, 1.5 mmol) were added to a solution of tryptophan methyl ester (255 mg, 1.0 mmol) and 3,5-dimethylphenylacetic acid (164 mg, 1.0 mmol) in dry DCM (11 ml). After 17 h at room temperature the solvent was removed under reduced pressure and the crude product was purified by flash chromatography (DCM containing 1% EtOH) to afford (S)-methyl 2-(2-(3,5-dimethylphenyl)acetamido)-3-(1H-indol-3-yl)propanoate. An aqueous solution of LiOH (1N, 4.5 ml, 4.5 mmol) was added to a solution of (S)-methyl 2-(2-(3,5-dimethylphenyl)acetamido)-3-(1H-indol-3-yl)propanoate (365 mg, 1 mmol) in methanol (24.5 ml) and the reaction mixture was stirred at room temperature for 4.5 h. Then water was added and methanol was removed under reduced pressure. The aqueous residue was washed with DCM (5×20 ml), treated with HCl 2N to obtain a pH 4 and extracted with DCM (3×25 ml). The organic phases were dried with anhydrous Na2SO4 and the solvent was removed under reduced pressure to afford (S)-2-(2-(3,5-dimethylphenyl)acetamido)-3-(1H-indol-3-yl)propionic acid (93% c.y.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=[CH:6]2.OO.[Br:19]Br>CO>[Br:19][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cccc2cc(OC)ccc12
Reactant: BrBr
Agent: OO
Solvent: CO
Product: COC(=O)c1cccc2c(Br)c(OC)ccc12
Temperature: 70 °C
Yield: 166.8 %

Procedure:
108 g (0.50 mol) of methyl 6-methoxy-1-naphthoate are dissolved in 2500 ml of methanol, and 30 g of 35% hydrogen peroxide solution are added. 42 g (0.26 mol) of bromine are then added dropwise at 35° C. in the course of 60 minutes. The mixture is subsequently heated at 70° C. When the reaction has ended, the mixture is concentrated in vacuo to a total volume of approximately 500 ml, allowed to cool to 20° C. and subjected to filtration with suction, and the filter cake is washed with methanol and water. Drying in vacuo at 60° C. gives 128.0 g of methyl 5-bromo-6-methoxy-1-naphthoate in the form of fine white needles.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[C:6]([Cl:16])[N:5]=[CH:4][N:3]=1.[Cl-].[OH:18][C@@H:19]1[C@H:23]([OH:24])[C@@H:22]([CH2:25][OH:26])[CH2:21][C@H:20]1[NH3+:27].CCN(CC)CC>C(O)C>[Cl:16][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:27][C@@H:20]2[CH2:21][C@H:22]([CH2:25][OH:26])[C@@H:23]([OH:24])[C@H:19]2[OH:18])[C:7]=1[CH2:8][CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]
Reactant: [NH3+][C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CCOC(Cc1c(Cl)ncnc1Cl)OCC
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(Cc1c(Cl)ncnc1N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O)OCC

Procedure:
A mixture of 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (5.35 g, 20.2 mmol) and (1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentanaminium chloride (9.29 g, 24.3 mmol) was taken up in ethanol (236 mL), treated with Et3N (11.2 mL, 80.8 mmol) and heated at reflux for 23 h; HPLC/LC MS indicated consumption of starting materials and presence of product. The reaction mixture was concentrated to afford a tan slurry, which was carried on crude: MS (ESI+) for C16H26ClN3O5 m/z 376.2 (M+H)+; MS (ESI−) for C16H26ClN3O5 m/z 374.2 (M−H)−; HPLC purity >95% (ret. time, 2.436 min). Variation on route from J. Med. Chem. 10, 665 (1967).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.O>C1COCC1>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In THF (250 ml) was dissolved 4-nitrobenzylbromide (25.0 g), and to the mixture was added morpholine (25.2 ml) at 0° C. The reaction mixture was stirred for 15 hours at room temperature. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) to give 4-(4-nitrobenzyl)morpholine (25.5 g) as pale yellow crystals. A portion of the crystals was recrystallized from diisopropylether to give pale yellow crystals which were used for various analyses. mp 79-80° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:33])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]2)=[O:26])=[CH:20][CH:19]=1)[NH:6]C(=O)C1C(C)=CC=CC=1Cl.CCN(C(C)C)C(C)C.[OH:43][C:44]1[CH:51]=[CH:50][C:47]([CH:48]=O)=[CH:46][CH:45]=1>C1COCC1>[CH3:2][O:3][C:4](=[O:33])[C@H:5]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:25](=[O:26])[C@@H:27]3[CH2:32][CH2:31][CH2:30][CH2:29][N:28]3[CH:48]2[C:47]2[CH:50]=[CH:51][C:44]([OH:43])=[CH:45][CH:46]=2)=[CH:22][CH:23]=1)[NH2:6]
Reactant: O=Cc1ccc(O)cc1
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)C2CCCCN2)cc1)NC(=O)c1c(C)cccc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](N)Cc1ccc(N2C(=O)[C@@H]3CCCCN3C2c2ccc(O)cc2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 15.5 %

Procedure:
(S)-N-(2-chloro-6-methylbenzoyl)-4-[[(2-piperidinyl)carbonyl]amino]-L-phenylalanine methyl ester hydrochloride (100 mg, 0.2 mmol), DIPEA (0.10 mL, 0.54 mmol) and 4-hydroxybenzaldehyde (30 mg, 0.25 mmol) was added to a suspension of activated 3 Å molecular sieves (100 mg) in THF (1.5 mL). The resulting mixture was stirred room temperature overnight and at 60° C. for 3 hr. After it was cooled to room temperature, the mixture was transferred onto a silica gel column and eluted with ethyl acetate:hexane (2:1) to give N-[(2-chloro-6-methylphenyl)carbonyl]]-4-[(8aS)-hexahydro-3-(4-hydroxyphenyl)-1-oxoimidazo[1.5-a]pyridin-2-yl]-L-phenylalanine methyl ester (17.5 mg, 0.031 mmol) as a foam. The methyl ester (17.5 mg, 0.031 mmol) was hydrolyzed with 1N NaOH (0.1 mL, 0.1 mmol) in 0.5 mL of ethanol at room temperature for 6 hr. The reaction mixture was acidified to pH<2 with TFA and was purified on RP-HPLC to give N-[(2-chloro-6-methylphenyl)carbonyl]-4-[(8aS)-hexahydro-3-(4-hydroxyphenyl)-1-oxoimidazo[1.5-a]pyridin-2-yl]-L-phenylalanine (8.3 mg, 0.015 mmol), in 7.5% yield. HRMS: calcd. 548.1952. Obs. 548.1938 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[CH:13]=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=23)=[O:11])[C:6]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[O:28][CH:29]([F:31])[F:30])=[N:5]1.[CH3:32][S:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1.[BH3-]C#N.[Na+]>CO>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH:29]([F:30])[F:31])=[C:21]([C:6]2[C:7]([NH:9][C:10]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[N:17][C:16]=34)=[O:11])=[CH:8][N:4]([CH2:3][CH2:2][NH:1][CH2:38][C:37]3[CH:40]=[CH:41][C:34]([S:33][CH3:32])=[CH:35][CH:36]=3)[N:5]=2)[CH:26]=1
Reactant: NCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: CSc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CSc1ccc(CNCCn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)cc1
Reaction time: 2 h

Procedure:
To a solution of N-[1-(2-aminoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (130 mg, 0.29 mmol) in methanol (5 mL) was added 4-(methylsulfanyl)benzaldehyde (66.3 mg, 0.44 mmol). The mixture was stirred for 2 hr, then NaBH3CN (27.5 mg, 0.44 mmol) was added. The resulting solution was stirred at room temperature overnight and quenched with water (1 mL). The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (30.0% up to 37.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 30.0% in 2 min); Detector, UV 254/220 nm. This resulted in 39.6 mg (23%) of the formic acid salt of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-([[4-(methylsulfanyl)phenyl]methyl]amino)-ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 20) [M+H]+=584.2, RT=2.23 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.74 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.67 (m, 2H), 8.37 (s, 1H), 7.61 (dd, 1H, J=2.8, 8.8 Hz), 7.59 (d, 1H, J=2.8 Hz), 7.44 (d, 1H, J=8.8 Hz), 7.31-7.27 (m, 3H), 7.18 (d, 2H, J=8.0 Hz), 7.07 (t, 1H, J=73.6 Hz), 4.25 (t, 2H, J=5.2 Hz), 3.70 (s, 2H), 2.95-2.92 (m, 2H), 2.50 (s, 3H).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([O:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:31]([C:32]#[N:33])=[C:30]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[N:29]=[C:28]([S:39][CH2:40][C:41]3[N:42]=[C:43]([C:46]4[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=4)[S:44][CH:45]=3)[C:27]=2[C:53]#[N:54])=[CH:22][CH:21]=1)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C.[F:55][C:56]([F:61])([F:60])[C:57]([OH:59])=[O:58]>ClCCl>[F:55][C:56]([F:61])([F:60])[C:57]([OH:59])=[O:58].[NH2:8][C@H:9]([C:14]([O:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[C:31]([C:32]#[N:33])=[C:30]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[N:29]=[C:28]([S:39][CH2:40][C:41]3[N:42]=[C:43]([C:46]4[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=4)[S:44][CH:45]=3)[C:27]=2[C:53]#[N:54])=[CH:24][CH:25]=1)=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](N)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.37 g (1.74 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl N-(tert-butoxycarbonyl)-L-leucinate were initially charged in 15 ml of dichloromethane, and 15.00 ml (194.70 mmol) of trifluoroacetic acid were added. The mixture was stirred at room temperature for 1 h. After removal of the solvent under reduced pressure, the residue was dissolved in 5.00 ml of dichloromethane and 10.00 ml of diethyl ether were added. The residue formed was filtered off with suction. Drying gave 1.09 g (76.1% of theory) of the desired target compound.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH3:28])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:29].[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=2)[CH2:33][CH2:32]1>C1COCC1>[CH3:30][N:31]1[CH2:32][CH2:33][N:34]([C:37]2[CH:42]=[CH:41][C:40]([NH:43][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([CH2:12][C:13]5[CH:14]=[C:15]([NH:19][C:20]([C:22]6[N:23]([CH3:28])[N:24]=[C:25]([CH3:27])[CH:26]=6)=[O:21])[CH:16]=[CH:17][CH:18]=5)=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:29])=[CH:39][CH:38]=2)[CH2:35][CH2:36]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1cc(C(=O)Nc2cccc(Cc3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(Cc3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 34.9 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indol-6-ylmethyl)-phenyl]-amide (prepared below, 50 mg, 0.129 mmol) and THF (1 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (24.6 mg, 0.129 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was dissolved in EtOAc. The resulting solution was diluted with Hexanes to initiate the precipitation of the product. The solid precipitate that formed was filtered then washed with ˜3 mL of i-prOH yielding 35% (25.3 mg, 0.045 mmol) of the title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:20]=[CH:19][C:14]2[O:15][CH2:16][C:17](=[O:18])[C:13]=2[CH:12]=1>ClCCl>[CH3:9][O:10][C:11]1[CH:20]=[CH:19][C:14]2[O:15][C:16](=[CH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:17](=[O:18])[C:13]=2[CH:12]=1
Reactant: COc1ccc2c(c1)C(=O)CO2
Reactant: O=Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)C(=Cc1ccccc1)O2
Temperature: 25 °C

Procedure:
36.5 mmol (3.9 g) of benzaldehyde are added to a solution of 30.5 mmol (5 g) of 5-methoxy-3-benzo[b]furanone in 150 ml of dichloromethane. With vigorous stirring and at ambient temperature, 25 g of basic alumina are then added. Stirring is maintained at ambient temperature for 30 minutes. The mixture is then filtered, the filtrate is concentrated and the residue obtained is washed with a minimum amount of ethanol to yield the expected compound. Melting point: 134° C.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:7]([CH3:14])[CH:6]=[C:5]([CH3:15])[C:3]=1[NH2:4].N1C=CC=CC=1.[C:22]1([S:28]([N:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[C:36](Cl)=[O:37])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>ClCCl>[C:22]1([S:28]([N:31]2[CH2:35][CH2:34][CH2:33][C@H:32]2[C:36]([NH:4][C:3]2[C:5]([CH3:15])=[CH:6][C:7]([CH3:14])=[C:8]([N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[C:2]=2[CH3:1])=[O:37])(=[O:29])=[O:30])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cc(C)c(N2CCCC2)c(C)c1N
Reactant: O=C(Cl)C1CCCN1S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C)c(N2CCCC2)c(C)c1NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of the 2,4,6-trimethyl-3-pyrrolidin-1-ylaniline (220 mg, 1.00 mmol) in of anhydrous dichloromethane (20 mL), were added pyridine (0.100 mL, 1.3 mmol) and 1-benzenesulfonyl-pyrrolidine-2-carbonyl chloride (0.297 g, 1.0 mmol). The reaction mixture was stirred overnight at room temperature. The solution was acidified with HCl (1N, 20 mL) and extracted with CH2Cl2 (2×20 mL). The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate (10 mL) and dried over magnesium sulfate (MgSO4). The organic layers were filtered and concentrated under reduced pressure to give a brown solid. The residue was further purified by flash chromatography (silica gel) using 95–5% hexane/ethyl acetate as the mobile phase (gradient) and semi-preparative HPLC to give ′1-(Phenylsulfonyl)-N-(2,4,6-trimethyl-3-pyrrolidin-1-ylphenyl)prolinamide (157 mg) as an off-white solid. MS m/z (M+H)+: calculated (m/z) 442.22, found (m/z) 442.25.