Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:39]([O:46][C:47]1[CH:48]=[C:49]([C:54]2[CH:55]=[C:56]([CH:64]3[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]3)[N:57]3[C:62]=2[C:61]([NH2:63])=[N:60][CH:59]=[N:58]3)[CH:50]=[C:51]([F:53])[CH:52]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:39]([O:46][C:47]1[CH:48]=[C:49]([C:54]2[CH:55]=[C:56]([CH:64]3[CH2:69][CH2:68][N:67]([C:4](=[O:5])[CH2:3][N:2]([CH3:7])[CH3:1])[CH2:66][CH2:65]3)[N:57]3[C:62]=2[C:61]([NH2:63])=[N:60][CH:59]=[N:58]3)[CH:50]=[C:51]([F:53])[CH:52]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CN(C)CC(=O)O
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3cc(F)cc(OCc4ccccc4)c3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CC(=O)N1CCC(c2cc(-c3cc(F)cc(OCc4ccccc4)c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
The solution of N,N-dimethylglycine (100 mg, 0.24 mmol) in DCM (1 mL) was treated with N,N-diisopropylethylamine (83 uL, 0.48 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (55 mg, 0.29 mmol) and 1-hydroxybenzotriazole (38.8 mg, 0.29 mmol) followed by 5-[3-(benzyloxy)-5-fluorophenyl]-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.24 mmol). The mixture was stirred at rt overnight then purified by HPLC. 20 mg (17%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 7.91 (s, 1H), 7.47-7.35 (m, 5H), 6.88 (s, 1H), 6.82 (d, 1H), 6.75 (d, 1H), 6.50 (s, 1H), 5.49 (s, 2H), 5.13 (s, 2H), 4.66 (d, 1H), 4.23 (d, 1H), 3.48 (m, 1H), 3.25-3.15 (m, 2H), 3.12-3.04 (m, 1H), 2.76 (td, 1H), 2.29 (s, 6H), 2.17 (s, 2H), 1.72-1.61 (m, 2H); LC-MS m/z [M+H]+ 503.3, RT 2.34 min.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[C@@H:3]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:18]([O-])=O)[C:9]1=[O:21])[C:4]([O:6][CH3:7])=[O:5].CO>[Pd]>[NH2:18][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH:16]=[CH:17][N:8]([C@H:3]([CH:2]([CH3:22])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])[C:9]2=[O:21]
Reactant: COC(=O)[C@@H](C(C)C)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H](C(C)C)n1ccc2c(N)cccc2c1=O

Procedure:
(R)-methyl 3-methyl-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)butanoate (2.8 g, 0.0091 mol) was stirred with palladium 10% wt. on calcium carbonate (0.23 g, 0.00011 mol) in methanol (40 mL, 1 mol) under hydrogen (balloon) over 1 h at room temperature. The catalyst was filtered, the filtrate was concentrated to dryness and yielded a yellow oil. MS m/z 274.8 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:17]1[CH:22]=[CH:21][C:20]2[O:23][CH2:24][O:25][C:19]=2[CH:18]=1)[C:3]#[C:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:6].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:24]1[O:23][C:20]2[CH:21]=[CH:22][C:17]([C:2]([C:3]#[C:4][C:5]([O:7][CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)=[O:6])=[O:1])=[CH:18][C:19]=2[O:25]1
Reactant: COc1ccc(COC(=O)C#CC(O)c2ccc3c(c2)OCO3)cc1
Agent: [Mn+4]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(COC(=O)C#CC(=O)c2ccc3c(c2)OCO3)cc1
Reaction time: 1 h

Procedure:
A solution of 53 g (155 mmol) of 4-methoxybenzyl 4-hydroxy-4-(3,4-methylenedioxyphenyl)-2-butynoate in 400 ml of methylene chloride was added dropwise at 0° to a suspension of 338 g (3.9 mol) of manganese dioxide in 800 ml of methylene chloride The reaction mixture was stirred at 0° for 1 hour, treated with 4 spatula tips of sodium sulphate, suction filtered over Dicalit and concentrated. Crystallization of the residue from ether yielded 4-methoxybenzyl 3-[3,4-(methylenedioxy)benzoyl]propiolate of melting point 113°-114°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][C:3]=1[F:15].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][O:14][S:24]([CH3:23])(=[O:26])=[O:25])[O:10][N:9]=2)=[CH:4][C:3]=1[F:15]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CC(c2ccc(Br)c(F)c2)=NO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CC(c2ccc(Br)c(F)c2)=NO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
[3-(4-Bromo-3-fluoro-phenyl)-4,5-dihydro-isoxazol-5-yl]-methanol (30 g, 112.4 mmol) was added to anhydrous dichloromethane (300 ml) followed by addition of triethylamine (21.8 ml, 157.3 mmol). The solution was cooled to 0° C. followed by drop wise addition of methane sulfonyl chloride (10.4 ml, 134.8 mmol). The reaction was stirred for 2 hours at 0° C. and then aqueous sodium bicarbonate (100 ml) was added. After further extraction with dichloromethane (2×100 ml), the organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give the desired product (38.7 g).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:3]=1[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH2:19](C([Sn])=C(CCCC)CCCC)[CH2:20]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:9]([Si:6]([CH3:8])([CH3:7])[O:5][CH2:4][C:3]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:2]=1[CH:19]=[CH2:20])([CH3:12])([CH3:11])[CH3:10]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COc1ccc(Br)c(CO[Si](C)(C)C(C)(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(OC)cc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 33.63 9 (0.10 mol) of (2-bromo-5-methoxy-benzyloxy)-tert-butyl-dimethyl-silane (14), 32.18 9 (0.10 mol) of tributylvinyl tin and 4.7 g (0.004 mol) of tetrakis(triphenylphosphine)palladium(0) were combined in 250 mL of toluene, and the solution was heated to reflux for 6 hours. The reaction was allowed to cool to ambient temperature and was quenched with 5% NH4OH (2×100 mL). The organic layer was washed with water (1×200 mL) and brine (1×200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to yield crude product. The crude product was chromatographed on a silica gel column, first with hexane, then with 20% CHCl3 in hexane, and finally with 40% CHCl3 in hexane to afford 25.0 9 (89%) of tert-butyl-dimethyl-(2-vinyl-5-methoxy-benzyloxy)-silane (15).
Reaction SMILES: O.[CH3:2][C:3]1[C:4]([CH2:22][S:23][C:24]2[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[N:25]=2)=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]1[CH2:16][O:15][C:14]2([CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[O:13][CH2:12]1.C(N(CC)C(C)C)(C)C.[O-]O.C1(C(C)C)C=CC=CC=1.C(=O)([O-])[OH:54].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C1(C)C=CC=CC=1>[CH3:2][C:3]1[C:4]([CH2:22][S:23]([C:24]2[NH:25][C:26]3[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=3[N:28]=2)=[O:54])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]1[CH2:16][O:15][C:14]2([CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[O:13][CH2:12]1
Reactant: O=C([O-])O
Reactant: Cc1c(OCC2COC3(CCOCC3)OC2)ccnc1CSc1nc2ccccc2[nH]1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(OCC2COC3(CCOCC3)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 82.4 %

Procedure:
To a toluene (dehydrated) (1.5 ml)-water (1.47 μl, 81.5 μmol) solution of the 2-(((3-methyl-4-(1,5,9-trioxaspiro[5.5]undec-3-ylmethoxy)pyridin-2-yl)methyl)thio)-1H-benzimidazole (300 mg, 679 μmol) separately obtained in the same manner as described in the steps (10a) to (10d) of Example 10, L-(+)-diethyl tartrate (51.2 μl, 299 μmol) was added and the mixture was stirred at 50° C. for 5 minutes in a nitrogen atmosphere. Titanium (IV) isopropoxide (40.1 μl, 136 μmol) was added and the resultant mixture was stirred for further one hour. After cooled on ice and N,N-diisopropylethylamine (37.8 μl, 217 μmol) was added, and cumene hydroperoxide (376 μl, 2.04 mmol as the content was regarded as 80%) was added dropwise in a nitrogen atmosphere, the mixture was stirred at 0° C. to room temperature for 5.5 hours. After a saturated aqueous solution of sodium hydrogen carbonate was added, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate/methanol) to obtain the title compound (256 mg, yield: 82.4%) as a light yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[I:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:24][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([I:19])[CH:21]=1)=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NCc1cccc(I)c1
Product: O=C(NCc1cccc(I)c1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-(3-iodobenzyl)isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.23 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.43 mmol of 3-iodobenzylamine. LC/MS [6.37 min; 574 (M+1)]
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[CH2:9][NH:8][CH2:7][C@H:6]1[NH:10][C:11](=[O:26])[CH2:12][NH:13][C:14](=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[CH:2]=[CH2:3].[N:27]1([C:33]([C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]3)=[CH:37][CH:36]=2)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:1]([O:4][C@@H:5]1[CH2:9][N:8]([CH:44]2[CH2:43][CH2:42][N:41]([C:38]3[CH:37]=[CH:36][C:35]([C:33]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:34])=[CH:40][CH:39]=3)[CH2:46][CH2:45]2)[CH2:7][C@H:6]1[NH:10][C:11](=[O:26])[CH2:12][NH:13][C:14](=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=1)[CH:2]=[CH2:3]
Reactant: O=C1CCN(c2ccc(C(=O)N3CCOCC3)cc2)CC1
Reactant: C=CCO[C@@H]1CNC[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: C=CCO[C@@H]1CN(C2CCN(c3ccc(C(=O)N4CCOCC4)cc3)CC2)C[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To the solution of rel-N-(2-{[(3R,4R)-4-(allyloxy)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide (60 mg, 0.16 mmol) in methanol (5 mL) was added 1-[4-(morpholin-4-ylcarbonyl)phenyl]piperidin-4-one (70 mg, 0.24 mmol) and sodium triacetoxyborohydride (68.5 mg, 0.32 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched by adding water (5 mL), and mixture then was extracted with EtOAc (15 mL×3). The organic phases were combined, dried over MgSO4, filtered, concentrated under reduced pressure and subjected to column chromatography (ethyl acetate, methanol and ammonium hydroxide (85:15:1) to afford the title compound (57 mg, 55%) as a white solid. 1H-NMR (CDCl3) δ: 1.44-1.62 (m, 2H), 1.79-1.88 (m, 2H), 2.00-2.18 (m, 2H), 2.24-2.37 (m, 2H), 2.61-2.68 (m, 4H), 3.25-3.33 (r, 1H), 3.59-3.68 (m, 8H), 3.78-3.79 (m, 1H), 3.92-3.99 (m, 1H), 4.05 (d, J=4.8 Hz, 2H), 4.08-4.16 (m, 1H), 4.27 (b, 1H), 5.09-5.25 (m, 2H), 5.76-5.89 (m, 1H), 6.81 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 7.47-7.52 (m, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 8.03 (s, 1H). MS m/z: 644 (M+1).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.CC([O-])(C)C.[K+]>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]>[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:3]=2)=[CH:27][CH:26]=1
Reactant: Cc1ccc(O)cc1
Reactant: COc1ccc(CNc2nc(Cl)nc3c2ncn3C(C)C)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc(CNc2nc(Oc3ccc(C)cc3)nc3c2ncn3C(C)C)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
Phenol coupling: A 10 mL flame-dried Schlenk flask equipped with a magnetic stir bar was charged with 2-chloro-6-(4-methoxybenzylamino)-9-isopropylpurine (0.193 g, 0.5 mmol, 1.0 equiv), 4-methylphenol (0.081 g, 0.75 mmol, 1.5 equiv), Pd2(dba)3 (0.0069 g, 0.0075 mmol, 0.015 equiv.), ligand 1 (0.0051 g, 0.015 mmol, 0.03 equiv.) and KOtBu (0.112 g, 1.0 mmol, 2.0 equiv.). The Schlenk flask was evacuated and backfilled with argon and charged with anhydrous 1,4-dioxane (2.0 mL). The reaction was stirred under argon at 90° C. and monitored by TLC. When the reaction was complete after 8 hours, the solvent was removed in vacuo and the reaction crude was purified by flash column chromatography (2% methanol in dichloromethane) to afford desired 2-(4-methylphenoxy)-6-(4-methoxy-benzylamino)-9-isopropylpurine (180 mg, 90%): 1H NMR (400 MHz, CDCl3) δ 1.53 (d, 6H, J=6.8 Hz), 2.37 (s, 3H), 3.79 (s, 3H), 4.54 (br, 2H), 4.71 (m, 1H, J=6.8 Hz), 6.35 (br, 1H), 6.81 (d, 2H, J=8.4 Hz), 7.10–7.18 (m, 6H), 7.65 (s, 1H); HRMS (MALDI-FTMS) [MH+] C23H26N5O2 404.2081, found: 404.2080.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](Br)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:6]=2[CH:22]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:6]=2[CH:22]=1
Reactant: Clc1ccc2c(c1)C(c1ccccn1)=NCc1nnc(Br)n1-2
Reactant: CN1CCNCC1
Product: CN1CCN(c2nnc3n2-c2ccc(Cl)cc2C(c2ccccn2)=NC3)CC1

Procedure:
In the manner given in Example 1, 8-chloro-1-bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with 1-methylpiperazine to give 8-chloro-1-(4-methylpiperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][CH:20]([OH:25])[C:21]([O:23][CH3:24])=[O:22])[CH:15]=2)[N:10]=1.Br[CH2:27][C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:35].[H-].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:34][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:35])[C:28]=1[CH2:27][O:25][CH:20]([CH2:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH:18]=[CH:17]2)[C:21]([O:23][CH3:24])=[O:22]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: COC(=O)C(O)Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)OCc1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of methyl 3-[2-(2,6-dichlorophenyl)-6-quinolinyl]-2-hydroxypropanoate 55 (0.159 g) and α-bromo-2,6-dichlorotoluene (1.05 g) in DMF (3.5 ml) is added 17 mg of NaH (60% dispersion in mineral oil) and Ag2O (0.102 g). The solution is stirred for 1 night at room temperature. A saturated solution of NaHCO3 is added. The aqueous phase is extracted with AcOEt (3×10 ml). The organic phases are washed with water (2×10 ml), with brine and dried over MgSO4. After concentration, the residue is purified twice over silica gel using AcOEt/petroleum ether 10/90 then 15/85 as eluent to give methyl 2-[(2,6-dichlorobenzyl)oxy]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate 56.
Reaction SMILES: C[O-].[Na+].[C:4](=[O:9])(OC)[O:5]C.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][CH2:23][C:24]3=O)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>Cl>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][C:23]([C:4]([OH:5])=[O:9])=[CH:24]3)=[CH:19][CH:18]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)OC
Reactant: Cc1ccc(-c2ccc3c(c2)C(=O)CCC3)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CC3)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of sodium methoxide (5.63 g), dimethyl carbonate (33 ml) and 7—(4-methylphenyl)-1-tetralone (4.93 g) was refluxed for 30 minutes. The reaction mixture was cooled to 0° C., and to the mixture was gradually added 3N hydrochloric acid(80 ml). 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 dissolved in THF (30 ml), and to the mixture was added sodium boron hydride (494 mg) at 0° C. and then was dropwise added methanol (3 ml) for 30 minutes. The reaction mixture was stirred at 0° C. for 4 hours, and to the mixture was added water (500 ml). 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 dissolved in methanol (20 ml), and to the mixture was added 1N sodium hydroxide (20 ml). The mixture was refluxed for 4 hours, cooled, acidified with concentrated hydrochloric acid, and 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 dissolved in Diglyme (20 ml), and to the mixture was added concentrated hydrochloric acid (4 ml). The mixture was stirred at 100° C. for 2 hours, and to the mixture was added water (500 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, and concentrated under reduced pressure. The residue was dissolved in 0.5N sodium hydroxide (400 ml), and the mixture was washed with diethylether. The aqueous layer was separated and acidified with concentrated hydrochloric acid. 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 recrystallized from ethyl acetate-diisopropylether to give 7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxylic acid (1.96 g) as pale brown crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:18]4[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=4[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[CH:22]([OH:27])[C:23]([O:25][CH3:26])=[O:24].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:18]4[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=4[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[C:22](=[O:27])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C(O)c1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(=O)c1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
To a mixture of methyl 2-(7-chloro-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (2.5 g, 6.48 mmol) in CH2Cl2 (70 mL) was added Dess-Martin periodinane (3.02 g, 7.13 mmol) and the resulting mixture was stirred at rt for 1 hr. Then diluted with ethyl acetate (500 mL), washed with sat. NaHCO3 (100 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel chromatography (5-30% EtOAc/hexane) to afford desired methyl 2-(7-chloro-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (1.1 g, 2.87 mmol, 44.2% yield) as off-white solid. 44% yield based on 2 steps. 1H NMR (500 MHz, CDCl3) δ: 7.77-7.71 (m, 2H), 7.20 (d, J=7.6 Hz, 1H), 7.00 (s, 1H), 4.02 (s, 3H), 2.89-2.83 (m, 4H), 2.64 (s, 3H), 1.86 (dt, J=6.5, 3.3 Hz, 4H). LCMS (M+H)=384.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:18])[CH2:9]NC(=O)OC(C)(C)C)=[N:6][CH:7]=1.Cl.O1CCOCC1.CO>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:18])[CH3:9])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccc(Br)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 140.1 %

Procedure:
To a reaction mixture of tert-butyl 2-(5-bromopyridin-2-yl)-2-oxoethylcarbamate (0.36 g, 1.142 mmol) in DCM was added 4 M hydrogen chloride in dioxane (2 ml, 8.00 mmol) and some MeOH. The reaction was stirred at rt for 3 hrs. The reaction mixture was concentrated to dryness to yield 2-amino-1-HCl salf of (5-bromopyridin-2-yl)ethanone (0.32 g) as a yellow solid. LC/MS (Cond. N-1): [M+H]+ 215.13, RT=0.945 min.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])[O:6]1)=[C:2]=[O:3].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1COCC1>[O:23]=[C:15]1[C:14](=[C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]([CH2:4][NH:1][C:2]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:3])[O:6]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16]1
Reactant: O=C=NCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Reactant: C1CCNCC1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=C1OC(CNC(=O)N2CCCCC2)c2ccccc21
Yield: 24.8 %

Procedure:
A solution of 3-(3-isocyanatomethyl-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (95 mg, 0.31 mmol) and piperidine (92.8 μl, 0.94 mmol) in THF (2.0 ml) was stirred at room temperature for 4 hours. The reaction was partitioned between EtOAc and water. The organic layer was washed with dilute HCl aqueous solution, water, saturated NaHCO3 aqueous solution, water, brine, dried with anhydrous Na2SO4, and rotary evaporated to a brown film. The brown film was chromatographed through silica gel column (CHCl3 to 4% MeOH/CHCl3 gradient) to produce piperidine-1-carboxylic acid [3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-ylmethyl]-amide as a yellow solid (30 mg, 25%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:58]1([CH2:61][N:62]2[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]2)[CH2:60][CH2:59]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:23]=[C:24]([F:33])[C:25]([C:26]([N:65]5[CH2:66][CH2:67][N:62]([CH2:61][CH:58]6[CH2:60][CH2:59]6)[CH2:63][CH2:64]5)=[O:28])=[CH:29][C:30]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: C1CN(CC2CC2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N2CCN(CC3CC3)CC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid as described in the general procedure for amide bond synthesis using HATU and 1-(cyclopropylmethyl)piperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.07 (d, J=4.55 Hz, 2 H) 0.45 (d, J=8.08 Hz, 2 H) 0.75-0.87 (m, 1 H) 1.47-1.77 (m, 6 H) 1.92 (br. s., 2 H) 2.20 (d, J=6.57 Hz, 2 H) 2.32-2.43 (m, 2 H) 3.22-3.31 (m, 2 H) 3.64 (br. s., 2 H) 3.88 (s, 3 H) 4.06 (t, J=13.77 Hz, 3 H) 4.70-4.84 (m, 1 H) 6.97 (d, J=6.06 Hz, 1 H) 8.04 (s, 1 H) 8.16 (d, J=11.87 Hz, 1 H) 8.28 (s, 1 H). [M+H] calculated for C29H36F3N7O3, 588; found 588.