Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)Cc1ccc(Br)cc1
Yield: 73.1 %

Procedure:
To a stirred solution of 4-bromo-phenyl acetic acid (25 g, 116 mmol) in dichloromethane (250 ml) was added thionyl chloride (13 ml, 170 mmol). The mixture was heated under reflux for 24 hours and then the solvent and the excess reagent were removed. The residue was distilled under reduced pressure (110° C./2 mmHg) to yield 19.8 g (73%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:29]Cl>CN(C=O)C>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:29][N:7]1[C:8]2[C:13](=[C:12]([CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:11]=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1cc2c(COC3CCCCO3)cccc2[nH]1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(COC3CCCCO3)cccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 56 %

Procedure:
Ethyl-4-(2-tetrahydropyranyloxy)methylindole-2-carboxylate (5.1 g) (Chung-gi Shen et al., Heterocycles, 43, 1996, 891-898) and sodium hydride (741 mg, 60% in mineral oil) were stirred in DMF (100 ml) under argon at ambient temperature for 0 minutes. 3,4-Dichlorobenzyl chloride (2.79 ml) was added and the mixture stirred overnight, then partitioned between ethyl acetate (150 ml) and water (150 ml). The organic phase was washed with water (2×150 ml), dried (MgSO4), concentrated in vacuo and the residue purified by column chromatography using iso-hexane, then ethyl acetate:iso-hexane (5/95) as eluent to give the product as a yellow oil (4.39 g, 56%); NMR δ(CDCl3) 1.40 (t, 3H), 1.50-2.00 (m, 6H), 3.60 (m, 1H), 4.00 (m, 1H), 4.35 (q, 2H), 4.75 (m, 1H), 4.85 (d, 1H), 5.10 (d, 1H), 5.80 (s, 2H), 6.85 (m, 1H), 7.15-7.40 (m, 5H), 7.50 (s, 1H); M/z (+) 462.5 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12]C)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br>C(O)(=O)C>[F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1cc(C(=O)O)c(F)cc1C
Agent: Br
Solvent: CC(=O)O
Product: Cc1cc(F)c(C(=O)O)cc1O
Temperature: 140 °C

Procedure:
To 2-fluoro-5-methoxy-4-methylbenzoic acid (650 mg, 3.53 mmol) was added 49% aqueous HBr (6.5 mL) and glacial acetic acid (5.5 mL). The mixture was heated overnight at 140° C., cooled to RT, diluted with ice water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated to yield 2-fluoro-5-hydroxy-4-methylbenzoic acid. MS m/z=171 [M+1]+. Calc'd for C8H7FO3: 170.20.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([CH3:10])[CH:8]=1)[C:3](=[O:14])[N:21]([CH2:20][C:19]1[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=1)[CH2:12]2
Reactant: COC(=O)c1c(C)cc(Br)cc1CBr
Reactant: NCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Temperature: 100 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-6-methyl-benzoic acid methyl ester (0.966 g, 3.0 mmol), 4-chloro-benzylamine (0.462 mL, 3.8 mmol), and K2CO3 (0.829 g, 6.0 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-bromo-7-methyl-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.725 g, 69%). GC-MS: m/z 350 (M)+, 314 (M−36)+.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:13][S:14][C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:6]([NH:24][CH3:25])[CH2:5][CH2:4]1)[CH3:2].[CH:26]([CH:28]=O)=[O:27]>CO>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH:6]([N:24]([CH3:25])[CH2:28][CH2:26][OH:27])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC(NC)c2cccc(CSc3nc4ccccc4[nH]3)c21
Reactant: O=CC=O
Solvent: CO
Product: CCN1CCC(N(C)CCO)c2cccc(CSc3nc4ccccc4[nH]3)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-ethyl-4-methylamino-8-(2-benzimidazolyl)thiomethyl-1,2,3,4-tetrahydroquinoline (900 mg) in methanol (20 ml) was added glyoxal (10 ml) and the mixture was stirred for 3 hours at room temperature. The solvent was distilled off and the resulting residue was dissolved in methanol, and to this mixture was added gradually sodium borohydride (1 g). After stirring the mixture for 1 hour at room temperature, the reaction mixture was concentrated. The resulting residue was extracted with dichloromethane and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography [eluent:dichloromethane-methanol (99:1)] to give 1-ethyl-4-[N-methyl-N-(2-hydroxyethyl)amino]-8-(2-benzimidazolyl)thiomethyl-1,2,3,4-tetrahydroquinoline (510 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)=O.[CH3:18][C:19]1[CH:23]=[C:22]([CH2:24][C:25](Cl)=[O:26])[O:21][N:20]=1.Cl.CC1C=C(CC(O)=O)ON=1.C(Cl)(=O)C(Cl)=O>C(Cl)Cl.C(N(CC)CC)C.CN(C)C=O>[Cl:17][C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[NH:1][C:25](=[O:26])[C:24]([C:22]1[O:21][N:20]=[C:19]([CH3:18])[CH:23]=1)=[C:4]2[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1
Reactant: Cc1cc(CC(=O)Cl)on1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccc(O)c1
Agent: Cc1cc(CC(=O)O)on1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(-c2c(-c3cccc(O)c3)c3cc(Cl)ccc3[nH]c2=O)on1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A mixture of 2-amino-5-chloro-3′-hydroxybenzophenone (0.1 g, 0.4 mmol), (3-methyl-isoxazol-5-yl)-acetyl chloride (1.18 mmol) [synthesized from the reaction between (3-methyl-isoxazol-5-yl)-acetic acid hydrochloride and oxalyl chloride catalyzed by N,N-dimethylformamide in DCM], triethylamine (Et3N) (0.20 mL) and DCM (10 mL) was heated to reflux overnight. The mixture was then cooled to room temperature and concentrated, and the residue was purified by flash chromatography on silica gel (5% methanol in DCM) to give 6-chloro-4-(3-hydroxyphenyl)-3-(3-methyl-isoxazol-5-yl)-1H-quinolin-2-one (99 mg, 70%). 1H NMR (300 MHz, DMSO-d6) δ 9.68 (s, 1H), 7.68-7.60 (m, 2H), 7.43 (d, J=10.0 Hz, 1H), 7.25 (t, J=10.0 Hz, 1H), 7.01-6.97 (m, 1H), 6.88-6.80 (m, 1H), 6.68-6.59 (m, 1H), 6.47 (s, 1H), 2.15 (s, 3H). MS: 353.2 (M+H).
Reaction SMILES: [C:1](/[C:4](/[CH3:29])=[CH:5]/[C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=2[O:27][CH3:28])=[CH:8][CH:7]=1)([OH:3])=[O:2].[H][H]>[Pd].O1CCCC1>[C:1]([CH:4]([CH3:29])[CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=2[O:27][CH3:28])=[CH:8][CH:7]=1)([OH:3])=[O:2]
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(/C=C(\C)C(=O)O)cc23)c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2cccc3ccc(CC(C)C(=O)O)cc23)c(OC)c1
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A mixture of 10% (w/w) palladium on carbon (0.75 g) and methyl E-4-[7-(2-carboxyprop-1-enyl)naphth-1-ylmethyl]-3-methoxybenzoate (4.38 g), in tetrahydrofuran (100 ml) was hydrogenated under 3.7 bar of hydrogen for 2 h. To the reaction mixture was added a slurry of 10% (w/w) palladium on carbon (0.75 g) and tetrahydrofuran (20 ml). After hydrogenating for 2 h more, the reaction mixture was filtered through diatomaceous earth with tetrahydrofuran washes. The solvent was evaporated and the residue was dissolved in ether. Evaporation and vacuum drying overnight afforded methyl 4-[7-(2-carboxypropyl)naphth-1-ylmethyl]-3-methoxybenzoate (4.22 g, 96%) as a colorless glassy solid; mp 110.0°-129.0° C.; MS(CI), m/e=393(M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.C1CCCCC=1>C(O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CN(C)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CN(C)c1ccc(N)c(C(=O)O)c1
Yield: 61.1 %

Procedure:
The mixture of 2.1 g of 2-nitro-5-dimethylaminobenzoic acid, 7 mL of cyclohexene and 1.5 g of Pd/C (10%) is heated under reflux conditions in 60 mL of ethanol for 6 hours. The hot reaction mixture is filtered through celite filter. The filtrate is evaporated to obtain 1.1 g of the title compound. M.p.: 232° C.
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].C(N(C(C)C)CC)(C)C.Cl[C:36]([O:38][CH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:37]>C(#N)C>[CH:39]1([O:38][C:36]([N:9]2[CH2:10][C@H:11]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:23])[F:24])(=[O:15])=[O:14])[CH2:12][C@H:8]2[C:6](=[O:7])[NH:5][CH2:4][C:2]#[N:3])=[O:37])[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)OC1CCCC1
Reaction time: 2 h

Procedure:
L21. To a suspension of (2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride (0.13 mmole) from experiment K2 in acetonitrile (1 ml) was added at 22° C. diisopropyl ethyl amine (0.40 mmole) and cyclopentyl chloroformate (0.15 mmole) and stirring was continued for 2 h. The mixture was quenched with methanol, acidified with acetic acid and subjected to prep. HPLC (RP-18) using a mixture of acetonitrile and water to give (2S,4R)-2-(cyanomethyl-carbamoyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-1-carboxylic acid cyclopentyl ester as a colorless oil. MS: 474.1 [M+H]+.
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:5]=[C:6]([C:11]2[C:12]([C:17]#[N:18])=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:8][C:9]=1[CH3:10]>ClCC(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:3][C:4]1[CH:5]=[C:6]([C:11]2[C:12]([C:17]#[N:18])=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][Br:1]
Reactant: Cc1ccc(-c2ccccc2C#N)cc1Br
Reactant: BrBr
Agent: ClCC(Cl)(Cl)Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: N#Cc1ccccc1-c1ccc(CBr)c(Br)c1
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
5.6 g (0.035 mol) of bromine, dissolved in 20 ml of tetrachloroethane, are added dropwise at 100-110° with UV irradiation to a solution of 8.9 g (0.033 mol) of 3'-bromo-4'-methyl-1,1'-biphenyl-2-carbonitrile in 900 ml of tetrachloroethane after addition of 0.1 g of benzoyl peroxide. After 30 minutes, the reaction mixture is cooled and evaporated in vacuo. The crystalline residue is recrystallized from ethyl acetate and gives 4.1 g of the title compound of m.p. 152-153°.
Reaction SMILES: [N:1]1([C:6]2[CH:28]=[CH:27][C:9]([CH2:10][C:11]3[C:12]([N:23]4[CH2:26][CH2:25][CH2:24]4)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](Br)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Li]CCCC.[CH3:34][N:35]1[C:39]([CH:40]=[O:41])=[CH:38][N:37]=[C:36]1[CH3:42]>C1COCC1>[N:23]1([C:12]2[C:11]([CH2:10][C:9]3[CH:27]=[CH:28][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:7][CH:8]=3)=[C:20]([Cl:21])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:40]([C:39]4[N:35]([CH3:34])[C:36]([CH3:42])=[N:37][CH:38]=4)[OH:41])[CH:18]=3)[N:13]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: Clc1c(Cc2ccc(-n3cccn3)cc2)c(N2CCC2)nc2ccc(Br)cc12
Reactant: Cc1ncc(C=O)n1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ncc(C(O)c2ccc3nc(N4CCC4)c(Cc4ccc(-n5cccn5)cc4)c(Cl)c3c2)n1C
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
3-(4-(1H-Pyrazol-1-yl)benzyl)-2-(azetidin-1-yl)-6-bromo-4-chloroquinoline (1.03 g, 2.27 mmol, Intermediate 17) and THF (15 mL) were combined in the reaction vessel under an N2 atmosphere and cooled to −78° C. in a dry ice acetone bath. n-BuLi (1.6 M in hexanes, 1.70 mL, 2.72 mmol) was then added dropwise via syringe over approximately one minute and contents were allowed to stir at −78° C. for an additional 5 minutes. 1,2-Dimethyl-1H-imidazole-5-carbaldehyde (0.31 g, 2.5 mmol) in THF (5 mL) was then cannulated into the reaction vessel and the reaction was stirred at −78° C. for 10 minutes. The dry ice bath was removed and replaced by an ice water bath and the reaction continued for approximately one hour at 0° C. The reaction was then quenched with a saturated, aqueous NH4Cl solution, then transferred to a separatory funnel with EtOAc. The organic phase was separated and the aqueous layer was back extracted with EtOAc, then the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-10% DCM/(10% of a 2 M NH3 MeOH in DCM)) to provide the title compound. MS (ESI): mass calcd. for C28H27ClN6O, 498.2; m/z found, 499.5 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 8.16-8.12 (m, 1H), 7.88 (dd, J=2.5, 0.6 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.70 (dd, J=1.8, 0.6 Hz, 1H), 7.62-7.54 (m, 3H), 7.19 (d, J=8.5 Hz, 2H), 6.53 (s, 1H), 6.44 (dd, J=2.5, 1.8 Hz, 1H), 5.97 (s, 1H), 4.33 (s, 2H), 4.19-4.12 (m, 4H), 3.49 (s, 3H), 2.34 (s, 3H), 2.27-2.18 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:28]#[N:29])=[N:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[C:12]([C:24]([F:27])([F:26])[F:25])[CH:11]=2)=[CH:6][C:7]=1[NH:8][CH3:9].Cl.[N:31]([O-])=O.[Na+].C(OCC)(=O)C>CN1C(=O)CCC1.O>[CH3:9][N:8]1[C:7]2[CH:6]=[C:5]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[C:12]([C:24]([F:27])([F:26])[F:25])[CH:11]=3)[N:4]=[C:3]([C:28]#[N:29])[C:2]=2[N:1]=[N:31]1
Reactant: O=N[O-]
Reactant: CNc1cc(-c2ccc(OCc3ccccn3)c(C(F)(F)F)c2)nc(C#N)c1N
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCc4ccccn4)c(C(F)(F)F)c3)cc21
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
To 3-amino-4-(methylamino)-6-(4-(pyridin-2-ylmethoxy)-3-(trifluoromethyl)-phenyl)picolinonitrile (1.7 g) in NMP (20 ml) was added 1M hydrochloric acid (22 ml) and cooled to 5-10° C. with an ice bath. To above solution was then added dropwise a solution of sodium nitrite (0.59 g) in water (5 ml) during 5 minutes. The mixture was stirred at room temperature for another 1 hour. After adding ethyl acetate (200 ml), the mixture washed with water (4×100 ml), brine (50 ml), solvent removed under reduced pressure. Upon addition of methanol (20 ml) to the residue, the desired product precipitated and collected by filtration to give 1-methyl-6-(4-(pyridin-2-yl-methoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (480 mg) as a white solid. 1H NMR (CDCl3) δ: 8.61 (d, 1H), 8.35 (s, 1H), 8.29 (d, 1H), 7.98 (s, 1H), 7.78 (t, 1H), 7.60 (d, 1H), 7.27 (t, 1H), 7.22 (d, 1H), 5.40 (s, 2H), 4.44 (s, 3H). MS m/z 411 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(OC([N:37]([CH2:44][CH3:45])[C:38]1([C:41](O)=[O:42])[CH2:40][CH2:39]1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:41]([C:38]4([NH:37][CH2:44][CH3:45])[CH2:40][CH2:39]4)=[O:42])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: CCN(C(=O)OC(C)(C)C)C1(C(=O)O)CC1
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: CCNC1(C(=O)N2CCC(c3cc(F)c(Nc4ncc(Cl)c(Nc5cc(C)[nH]n5)n4)cc3C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (67.3 mg, 0.17 mmol), 1-(tert-butoxycarbonyl(ethyl)amino)cyclopropanecarboxylic acid (38.0 mg, 0.17 mmol), HATU (63.0 mg, 0.17 mmol) and diisopropylethylamine (57 μL, 0.34 mmol) in 1 mL of DMF was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and water, the combined organic extracts were dried (Na2SO4) and then concentrated in vacuo. The resulting crude mixture was dissolved in 5 mL of DCM and 4 mL of TFA and was then stirred for 2 h followed by concentration in vacuo. The crude product was purified by RP-HPLC to afford (4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)(1-(ethylamino)cyclopropyl)methanone; ESMS m/z 527.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([NH2:11])[CH:10]=[C:4]2[CH2:3]1.Br[C:13]1[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=[C:17]([Br:19])[CH:18]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[Br:19][C:17]1[CH:18]=[C:13]([NH:11][C:9]2[CH:10]=[C:4]3[CH2:3][N:2]([CH3:1])[CH2:7][CH2:6][N:5]3[N:8]=2)[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=1
Reactant: CN1CCn2nc(N)cc2C1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Temperature: 120 °C
Yield: 44.8 %

Procedure:
A suspension of 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine 101e (1 g, 6.6 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.7 g, 6.6 mmol), XantPhos (380 mg, 0.66 mmol), Pd2(dba)3 (602 mg, 0.66 mmol) and Cs2CO3 (4 g, 13.2 mmol) in dioxane (30 mL) was heated in a sealed tube at 120° C. for 2 h under nitrogen. After reaction the solvent was filtered and the filtrate was evaporated in vacuo to give a yellow solid. The yellow solid was washed with EtOAc (10 mL×3) to give 146a as a yellow solid (1 g, 45%), which was used without further purification. MS: (M+H)+ 338.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:27]2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: Clc1cccc2c1CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1c(F)c(N2Cc3cccc(Cl)c3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 24 %

Procedure:
268 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 154 mg of 4-chloroisoindoline, 274 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 93 mg of the target compound.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]12([CH:19]=O)[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.[BH4-].[Na+]>CO.C(OCC)(=O)C>[C:9]12([CH2:19][NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[NH2:8])[CH2:10][CH:11]3[CH2:17][CH:15]([CH2:14][CH:13]([CH2:12]3)[CH2:18]1)[CH2:16]2
Reactant: Nc1ccccc1N
Reactant: O=CC12CC3CC(CC(C3)C1)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccccc1NCC12CC3CC(CC(C3)C1)C2
Reaction time: 2 h
Yield: 10.1 %

Procedure:
1,2-Phenylenediamine (5 g) was added to a solution of 1-adamantanecarboxaldehyde (7.6 g) in methanol (100 ml). The solution was stirred at 23° for 2 h, then sodium borohydride (3.5 g) was added portionwise. The resulting mixture was stirred at 230 for 2 h, then diluted with ethyl acetate (400 ml) and filtered. The organic layer was washed with brine (300 ml), dried and concentrated in vacuo to a residue, which was taken up in ethyl ether and the inorganic salts still present were removed by filtration. The filtrate was concentrated in vacuo and purified by flash chromatography to give the title compound as a beige solid (1.2 g). M.p.86°-7° T.l.c. CH-EA (7:3), Rf 0.6.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:16]=[CH:15][NH:14][N:13]=2)[N:7]=1>C(Cl)(Cl)Cl.CO>[NH:14]1[CH:15]=[CH:16][C:12]([C:8]2[N:7]=[C:6]([CH:2]=[O:1])[CH:11]=[CH:10][CH:9]=2)=[N:13]1
Reactant: c1cc(-c2cc[nH]n2)nc(C2OCCO2)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=Cc1cccc(-c2cc[nH]n2)n1

Procedure:
The deprotection of the acetal function of 2-[1,3]dioxolan-2-yl-6-(1H-pyrazol-3-yl)pyridine is carried out on 0.65 g of product (2.99 mmol) according to a protocol similar to that used in stage 5 of Example 7. The title compound is isolated by chromatography on a silica column (eluent: chloroform/methanol; 98:2). 0.31 g of a white foam is obtained.
Reaction SMILES: [NH:1]([C:31]([O:33]CC1C=CC=CC=1)=O)[C@H:2]([C:15]([NH:17][C@H:18]([C:27]([O:29][CH3:30])=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:16])[CH2:3][C:4](=[O:14])[O:5]C(C1C=CC=CC=1)=O.[NH:41]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42]C(O)=O>CO.Cl.[Pd].[C]>[NH:41]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][C:31]([NH:1][C@H:2]([C:15]([NH:17][C@H:18]([C:27]([O:29][CH3:30])=[O:28])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)=[O:16])[CH2:3][C:4](=[O:14])[OH:5])=[O:33]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CC(=O)OC(=O)c1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CC(=O)O)NC(=O)CNC(=O)OC(C)(C)C
Yield: 73.4 %

Procedure:
4.81 g (0.009 mole) of Z-Asp(OBz)-Tyr-OMe [m.p. 126°-127° C. [α]D24 =-4.8° (C=1, methanol). Anal. Calcd. (%) for C29H30N2O8 : C, 65.16; H, 5.66; N, 5.24. Found (%): C, 65.14; H, 5.71; N, 5.18] was dissolved in a mixture of 150 ml of methanol and 9 ml of 1N HCl and hydrogenated over 0.9 g of a 10% Pd-carbon catalyst at room temperature for 6 hours. Then the catalyst was filtered off, and the filtrate was distilled in vacuo to dryness. The resulting dipeptide was condensed with a mixed anhydride which had been prepared from 1.89 g of Boc-Gly-OH in the same manner as in (1) of Example 2. The product was recrystallized from ethyl acetate-ether, giving 3.09 g of Boc-Gly-Asp-Tyr-OMe; yield 71.8%, m.p. 97°-99° C.