Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:56])[C:7]([O:10]/[N:11]=[C:12](/[C:43]1[N:44]=[C:45]([NH:48]C(OC(C)(C)C)=O)[S:46][CH:47]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[CH:30]=[C:29]([CH2:31][NH:32][C:33](=[O:42])[CH2:34][N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[N:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.C([SiH](CC)CC)C>C(Cl)Cl>[NH2:48][C:45]1[S:46][CH:47]=[C:43](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:56])=[O:5])/[C:13]([NH:15][C@@H:16]2[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:22])=[O:23])[C@@H:17]2[CH2:25][N:26]2[CH:30]=[C:29]([CH2:31][NH:32][C:33](=[O:42])[CH2:34][N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[N:28]=[N:27]2)=[O:14])[N:44]=1
Reactant: CN1CCN(CC(=O)NCc2cn(C[C@@H]3[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N3S(=O)(=O)O)nn2)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(CC(=O)NCc2cn(C[C@@H]3[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c4csc(N)n4)C(=O)N3S(=O)(=O)O)nn2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10.3 %

Procedure:
To a slurry of (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-((2-(4-methylpiperazin-1-yl)acetamido)methyl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (120 mg, 0.13 mmol) In DCM (1.3 mL) at 0° C. was added TFA: DCM (1:1, 3.9 mL) followed by triethylsilane (62 μL, 0.39 mmol). The reaction mixture was stirred at 0° C. for 30 min and slowly warmed to room temperature. After 2 h at rt it was concentrated in vacuo and triturated with MTBE: Heptane (1:2) whereupon a solid was observed. The crude solid was purified by reverse phase prep HPLC (C18 column, ACN-water solvent system with 0.1% formic acid modifier) to afford the title compound (9 mg). LCMS: m/z=669.75 (M−1); 1H NMR (400 MHz, DMSO-d6) δ 9.40 (d, J=8.7 Hz, 1H), 8.25 (s, 1H), 8.00 (s, 1H), 7.33 (s, 2H), 6.71 (s, 1H), 5.29 (dd, J=8.7, 5.6 Hz, 1H), 4.88-4.60 (m, 2H), 4.34 (d, J=5.7 Hz, 2H), 4.24 (q, J=5.3 Hz, 1H), 3.20-2.87 (m, 8H), 2.77 (s, 3H), 1.34 (s, 3H), 1.30 (s, 3H).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@@H:5]1[N:10]2[C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[CH:13][C:12]=3[N:21]=[C:9]2[CH2:8][O:7][CH2:6]1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:3][CH2:4][C@@H:5]2[N:10]3[C:11]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=[CH:13][C:12]=4[N:21]=[C:9]3[CH2:8][O:7][CH2:6]2)=[CH:25][CH:24]=1
Reactant: OC[C@H]1COCc2nc3cnc4ccccc4c3n21
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Fc1ccc(COC[C@H]2COCc3nc4cnc5ccccc5c4n32)cc1
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 98.5 %

Procedure:
A 100-mL, round-bottomed flask, under an atmosphere of N2, was charged with sodium hydride (60% oil dispersion, 72 mg, 1.78 mmol). The sodium hydride was washed with 3 portions of hexanes to remove the oil and then 20 mL of anhydrous THF was added. The reaction mixture was cooled to 0° C. and (11S)-11-hydroxymethyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (413 mg, 1.62 mmol) was added. After stirring for 75 minutes, 4-fluorobenzyl bromide (215 μL, 1.78 mmol) was added. The reaction was allowed to warm to ambient temperature overnight. After 20 hours the reaction mixture was treated with 20 mL of saturated NaHCO3 solution and 20 mL of ethyl acetate and the layers were separated. The organic portion was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated under reduce pressure to give (11S)-11-{[(4-fluorobenzyl)oxy]methyl}-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (580 mg) as a light-yellow, glassy solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[N:11](C3CCCCO3)[N:10]=2)[C:5]([Cl:21])=[CH:4][N:3]=1.C(OC([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]([NH2:45])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=O)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)=[N:7][C:2]([NH:45][C:38]2[C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:35]([CH:32]3[CH2:31][CH2:30][NH:29][CH2:34][CH2:33]3)=[CH:36][CH:37]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)nn1C1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c3ccccc23)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(Nc3ccc(C4CCNCC4)c4ccccc34)ncc2Cl)n[nH]1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A mixture of 2,5-dichloro-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidin-4-amine (202.7 mg, 0.62 mmol), tert-butyl-4-(4-aminonaphthalen-1-yl)piperidine-1-carboxylate (202.0 mg, 0.62 mmol), Xantophos (35.9 mg, 0.062 mmol), padallium acetate (II) (7.0 mg, 0.031 mmol), and cesium carbonate (40.3 mg, 0.12 mmol) in 5.0 mL of THF was heated at 150° C. in a microwave reactor for 25 min. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude product was dissolved in 5 mL of DCM and 4 mL of TFA. This reaction mixture was stirred at room temperature for 2 h followed by concentration in vacuo. The crude product is purified by RP-HPLC to afford 5-chloro-N4-(5-methyl-1H-pyrazol-3-yl)-N2-(4-(piperidin-4-yl)naphthalene-1-yl)pyrimidine-2,4-diamine; ESMS m/z 434.2 (M+H+)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2Br)cc1
Product: CS(=O)(=O)c1ccc(-c2ccccc2-c2ccc(C(F)(F)F)cc2)cc1
Yield: 77.7 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 4.0 g (13 mmol) of 1-bromo-2-[4-(methylsulfonyl)phenyl]benzene (Example 4, Step 2) was reacted with 3.8 g (20 mmol) of 4-(trifluoromethyl)phenylboronic acid (Step 1). Purification by silica gel chromatography (Waters Prep-500A) with ethyl acetate/hexane (1:3) and subsequent recrystallization from ethyl acetate/hexane gave 3.80 g (77%) of 1-[4-(trifluoromethyl)phenyl]-2-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 172.8°-173.5° C.; NMR (CDCl3) δ 3.06 (s, 3H), 7.23 (d, J=8 Hz, 2H), 7.33 (d, J=9 Hz, 2H), 7.41-7.46 (m, 2H), 7.48-7.54 (m, 4H), 7.81 (d, J=9 Hz, 2H). MS (ES): m/e 383 (M+Li); HRMS Calc'd for C20H15F3O2S: 376.0745. Found: 376.0766.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>>[ClH:1].[C:18]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[C:5]([C:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=2)=[CH:6]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CC=C(c2c[nH]c3ccc(Cl)cc23)CC1
Agent: Cl
Product: CN1CC=C(c2cn(C(=O)c3ccccc3)c3ccc(Cl)cc23)CC1

Procedure:
(20 mg, 59%) from 5-chloro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4d, 25 mg, 0.1 mmol) and benzoyl chloride (21.1 mg, 0.15 mmol), m.p 256-7° C., HRMS-FAB+ for C21H19N2OCl.HCl, calculated MH+ (--HCl): 351.1264; found: 351.12595.
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[CH:7](Br)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:20]3[C:27]([CH3:28])=[C:26]([C:29]([O:31][CH3:32])=[O:30])[S:25][C:21]=3[N:22]=[CH:23][N:24]=2)=[C:14]([OH:33])[CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[CH3:32][O:31][C:29]([C:26]1[S:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([NH:18][C:15]3[CH:16]=[CH:17][C:12]([F:11])=[CH:13][C:14]=3[O:33][CH:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:10])[CH3:8])[C:20]=2[C:27]=1[CH3:28])=[O:30]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O)c2c1C
Reactant: CC(Br)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C(=O)OC(C)(C)C)c2c1C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-Bromopropionic acid tert-butyl-ester (1.4 g) was added to methyl 4-(4-fluoro-2-hydroxyphenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (Intermediate III) (2.00 g) and cesium carbonate (4.8 g) in ACN (50 ml) and stirred at 60° C. for 2 hours. The mixture was diluted with water, filtrated and washed with water.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([O:24][C:25]([C:27]1([CH2:42]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:31][CH2:30][N:29]([C:32](=[O:41])[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[CH2:28]1)=[O:26])[CH3:23]>CS(C)=O>[CH2:22]([O:24][C:25]([C:27]1([CH2:42][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:31][CH2:30][N:29]([C:32](=[O:41])[C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)[CH2:28]1)=[O:26])[CH3:23]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)C1(COS(=O)(=O)c2ccc(C)cc2)CCN(C(=O)c2ccc(OC)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C1(COc2ccc(-c3ccc(C#N)cc3)cc2)CCN(C(=O)c2ccc(OC)cc2)C1
Temperature: 80 °C
Yield: 93.6 %

Procedure:
4′-hydroxy-4-biphenyl carbonitrile (107.0 g, 549 mmol) and potassium carbonate (94.9 g, 687 mmol) were added to a stirred solution of 1-(4-methoxy-benzoyl)-3-(toluene-4-sulfonyloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (211.3 g, 457.8 mmol) (see Preparation 11) in dimethylsulphoxide (422 mL). The reaction mixture was heated at 80° C. for 18 hours then partitioned between ethyl acetate (2000 mL) and water (2000 mL). The organic layer was washed with water (2000 mL) then separated and concentrated under reduced pressure to afford the title compound as an orange oil (207.7 g, 93%). (>99.5% e.e.)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(C(C)C)CC)(C)C.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[C:33]1([S:39]([N:21]2[CH2:22][CH2:23][CH:18]([C:17]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:8]3[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=3)[CH2:19][CH2:20]2)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ncccc1-c1[nH]c2ccccc2c1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ncccc1-c1[nH]c2ccccc2c1C1CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.1 %

Procedure:
To a solution of 2-(2-methoxy-pyridin-3-yl)-3-piperidin-4-yl-1H-indole (0.12 g, 0.39 mmol) in dichloromethane (10 ml) and diisopropylethylamine (0.20 ml, 1.17 mmol) was added phenylsulfonyl chloride (52 μl, 0.41 mmol). The reaction was stirred at room temperature for 4 h and quenched by adding water. The organic layer was separated, washed with aqueous sodium hydroxide, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by a flash chromatography (SiO2, 30% EtOAc in hexane) to give the desired product as a white solid (0.042 g, 24%); M.p.=231-234° C.; 400 MHz 1H NMR (DMSO-d6) δ: 11.00 (s, 1H), 8.20 (dd, J1=0.8 Hz, J2=4.8 Hz, 1H), 7.77 (m, 3H), 7.66 (m, 3H), 7.29 (m, 2H), 7.07 (m, 2H), 6.92 (m, 1H), 3.84 (m, 5H), 2.56 (m, 1H), 2.42 (m, 2H), 2.00 (m, 2H), 1.66 (m, 2H); LCMS: 448.69 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([Cl:10])[N:7]([C@@H:11]3[O:23][C@H:22]([CH2:24][O:25]C(=O)C)[C@@H:17]([O:18]C(=O)C)[C@H:12]3[O:13]C(=O)C)[C:6]=2[CH:29]=1>N.CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([Cl:10])[N:7]([C@@H:11]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:17]([OH:18])[C@H:12]3[OH:13])[C:6]=2[CH:29]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3ccc(N)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: Nc1ccc2nc(Cl)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2c1

Procedure:
A solution of 0.283 g (0.665 mmole) of 77 in 10 mL of NH3 /MeOH was stirred in a pressure bottle at room temperature for 5 hr. The reaction mixture was evaporated and coevaporated with MeOH (3×, bath temperature <40° C.), The residue was recrystallized from MeOH to give 0.170 g (2 crops, 85%) of 79 as beige crystals. MP ~170° C. (dec.), MS (El) m/e 299.0862 (16%, M+ =299.0673), 1H NMR (DMSO-d6): d 7.25 (d, 1, 4-H, J4-5 =8.5 Hz), 6.87 (d, 1, 7-H, J7-5 =2.0 Hz), 6.57 (dd, 1, 5-H), 5.75 (d, 1, 1'-H, J1'-2' 7 5 Hz), 5.43 (d, 1, 2'-OH, J2'-2'OH =6-5 Hz), 5.18 (d, 1, 3'-OH, J3'-3'OH =5.0 Hz), 5.04 Hz), (s, 2, 6-NH2) 5.03 (t, 1, 5'-OH, J5'-5'OH =5.5 Hz), 4.48 (m, 1, 2'-H, J2'-3' =6.0 Hz), 4.07 (m, 1, 3'-H, J3'-4' =3.0 Hz), 3.90 (m, 1, 4'-H, J4'-5' =4.0 Hz, J4'-5" =5.0 Hz), 3.66 (m, 2, 5'-H and 5"-H, J5'-5" =12.0 Hz), 13C NMR (DMSO-d6): d 145.34 (C6), 135.63 (C2), 133.34 (C7a), 133.18 (C3a), 118.83 (C4), 111.71 (C5), 95.79 (C7), 88.79 (C1'), 85.24 (C4'), 70.17 (C2'), 69.70 (C3'), 61.55 (C5'),
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:28])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][O:13][C:14]2[CH:27]=[CH:26][C:17]([CH:18]=[C:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[CH:16][CH:15]=2)=[CH:7][CH:6]=1.C(O)(=O)C>CN(C)C=O.[Pd]>[CH3:1][NH:2][C:3](=[O:28])[NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][O:13][C:14]2[CH:27]=[CH:26][C:17]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[CH:16][CH:15]=2)=[CH:9][CH:10]=1
Reactant: CNC(=O)Nc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CNC(=O)Nc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Yield: 58.9 %

Procedure:
1.2 g (3.02 mmole) 5-(4-[2-(4-methylureidophenyl)ethoxy]benzylidene)thiazolidine-2,4-dione was hydrogenated for 18 hours in 100 ml dimethylformamide and 10 ml acetic acid with 1 g Pd/C (10%) as catalyst. The catalyst was filtered off and the solvent was evaporated in vacuo. Ethyl acetate was added and the product was extracted with potassium carbonate in water. A black precipitate was filtered off and the ethyl acetate phase was extracted with more potassium carbonate solution. The water phase was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated in vacuo and recrystallized in methanol to give 0.71 g (yield 59%) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[C:3]=1[CH2:4]O.C(N(CC)CC)C.S([Cl:25])(C)(=O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[C:3]=1[CH2:4][Cl:25]
Reactant: CC(=O)Nc1cccc(C)c1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cccc(C)c1CCl
Reaction time: 0.5 h

Procedure:
To a suspension of 2-methyl-6-acetamidobenzyl alcohol (30 g) and triethylamine (46.54 ml) in methylene chloride (300 ml) was added dropwise mesyl chloride (14.25 ml) below 8° C. The mixture was stirred under ice cooling for 30 minutes and then at room temperature for 20 minutes. The reaction mixture was washed with 1N-hydrochloric acid solution, water and saturated sodium bicarbonate aqueous solution, dried over magnesium sulfate and evaporated in vacuo. The residue was suspended in n-hexane and the precipitates were collected by filtration and dried to give 2-methyl-6-acetamidobenzyl chloride (19.28 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6]=2[N:17]=1.[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[N:10]([CH3:20])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6]=2[N:17]=1
Reactant: Cc1ccc2c(n1)Nc1ccccc1NC2=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(n1)Nc1ccccc1N(C)C2=O
Temperature: 30 °C
Reaction time: 1 h

Procedure:
A mixture consisting of 11.3 gm (0.05 mol) of 6,11-dihydro-2-methyl-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-one (prepared according to C.A. 74, 53868y, 1971), 150 ml of dimethyl formamide, and 2.8 gm of 50% sodium hydride in mineral oil was stirred at 30° C. in a nitrogen atmosphere for 1 hour. Then, a solution of 10.7 gm (0.075 mol) of methyl iodide in 30 ml of dimethyl formamide was added dropwise while stirring, and the mixture was heated on an oil bath at 100° C. for 3 hours while stirring and then evaporated in vacuo, and an aqueous sodium carbonate solution was stirred into the residue. The mixture was suction-filtered, and the filter cake was washed with water and recrystallized from xylene, yielding 80% of theory of the compound named in the heading, which had a melting point of 192°-194° C.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([C:12]2[N:17]=[C:16]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[CH:15]=[CH:14][CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:3].Cl[C:26]1[N:34]=[CH:33][N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1.COCCO.CCN(C(C)C)C(C)C>>[Cl:10][C:8]1[C:7]([CH3:11])=[C:6]([C:12]2[N:17]=[C:16]([C:18]([N:20]([CH3:21])[CH3:22])=[O:19])[CH:15]=[CH:14][CH:13]=2)[C:5]([O:23][CH3:24])=[C:4]([CH:2]([NH:1][C:26]2[N:34]=[CH:33][N:32]=[C:31]3[C:27]=2[N:28]=[CH:29][N:30]3[CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH3:3])[CH:9]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1-c1cccc(C(=O)N(C)C)n1
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1-c1cccc(C(=O)N(C)C)n1
Temperature: 105 °C

Procedure:
The 6-{3-[1-aminoethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (0.025 g, 0.072 mmol) was combined with 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.022 g, 0.14 mmol, from Example 176, Step 4) in 2-methoxyethanol (1.0 mL, 13 mmol) and DIPEA (0.037 g, 0.29 mmol) in a sealed tube. The reaction was heated to 105° C. in an oil bath for 18 hours. Without workup, the reaction was carried into the next step.
Reaction SMILES: F[C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]([C:11]#[N:12])=[C:4]([F:13])[C:3]=1[F:14].[F-].[K+].[CH:17]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(#N)C>[F:10][C:6]1[C:5]([C:11]#[N:12])=[C:4]([F:13])[C:3]([F:14])=[C:2]([O:23][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:7]=1[C:8]#[N:9]
Reactant: OC1CCCCC1
Reactant: N#Cc1c(F)c(F)c(F)c(C#N)c1F
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1c(F)c(F)c(OC2CCCCC2)c(C#N)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
A 5.0 g amount of tetrafluoroisophthalonitrile and 2.18 g of potassium fluoride were dissolved in 25 ml of acetonitrile, and 3.83 g of cyclohexanol was then dropwise added to the mixture. After the dropwise addition, the mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered, the filtrate was concentrated in vacuo, and the concentrated liquid was poured to 50 ml of water. The resultant mixture was extracted with carbon tetrachloride. After washing with water, the extract was dried with anhydrous magnesium sulfate and the solvent was then distilled off. Thus, 6.2 g (88% yield) of the desired compound No. 47 was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([C:18](=[O:20])[CH3:19])=[CH:15][CH:16]=3)[C:11]([CH3:22])([CH3:21])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[C:23]([C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)([OH:25])=[O:24].[OH-].[Na+]>CO>[O:20]=[C:18]([C:14]1[CH:15]=[CH:16][C:17]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[CH:9][CH2:10][C:11]([CH3:22])([CH3:21])[C:12]=2[CH:13]=1)[CH:19]=[CH:30][C:29]1[CH:32]=[CH:33][C:26]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CC=C2c1ccc(C)cc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C2=CCC(C)(C)c3cc(C(=O)C=Cc4ccc(C(=O)O)cc4)ccc32)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 78.7 mg (0.272 mmol) 3,4-dihydro-1-(4-methylphenyl)-4,4-dimethyl-6-acetylnaphthalene (Compound 100G) in 4.0 ml of MeOH was added 53.1 mg (0.354 mmol) of 4-carboxy benzaldehyde, and 80. mg (2.00 mmol; 2.0 ml of 1M aqueous NaOH). The resulting solution was stirred at room temperature for 12 hours, concentrated under reduced pressure, and the residual oil dissolved in EtOAc. The solution was treated with 10% HCl, and the organic layer was washed with H2O, and saturated aqueous NaCl, then dried over Na2SO4. Removal of the solvents under reduced pressure gave the title compound as a colorless solid which was purified by recrystallization from CH3CN. 1H NMR (acetone-d6): δ 8.00 (7H, m), 7.83 (1H, d, J=15.6 Hz), 7.24 (4H, s), 7.13 (1H, d, J=8.1 Hz), 6.12 (1H, t, J=4.5 Hz), 2.42 (2H, d, J=4.8 Hz), 2.38 (3H, s), 1.41 (6H, s).
Reaction SMILES: Cl.[NH:2]([C:9]1[C:14]([Cl:15])=[CH:13][N:12]=[C:11](Cl)[N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.CC(C)=O>S1(CCCC1)(=O)=O>[NH:2]([C:9]1[C:14]([Cl:15])=[CH:13][N:12]=[C:11]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2)n1
Agent: Cl
Solvent: CC(C)=O
Solvent: O=S1(=O)CCCC1
Product: O=C(O)c1ccc(Nc2ncc(Cl)c(Nc3ccccc3)n2)cc1
Temperature: 140 °C
Yield: 96.5 %

Procedure:
Ethereal hydrogen chloride (1.0M; 10 ml, 10.0 mmol) was added to a solution of 4-anilino-2,5-dichloropyrimidine (Method 2; 2.41 g, 10.0 mmol) and 4-aminobenzoic acid (1.10 g, 8.0 mmol) in sulpholane (10 ml) and the mixture was heated at 140° C. for 3 hours. The mixture was left to cool and acetone (75 ml) was added. The insoluble solid was collected by filtration and washed with acetone (50 ml) to give the product (2.63 g, 97%). NMR: 7.25 (t, 1H), 7.4 (t, 2H), 7.55-7.65 (m, 4H), 7.7 (d, 2H), 8.35 (s, 1H), 9.6 (br s, 1H), 10.4 (br s, 1H); MS (MH+): 341, 343.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[N:7]=[CH:6][CH:5]=1)[CH3:2].[NH2:16][C:17]1[S:18][CH2:19][C:20](=[O:22])[N:21]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:16][C:17]1[S:18]/[C:19](=[CH:14]\[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:6][CH:5]=[C:4]3[O:3][CH2:1][CH3:2])/[C:20](=[O:22])[N:21]=1
Reactant: NC1=NC(=O)CS1
Reactant: CCOc1ccnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOc1ccnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 34 was used, starting with 4-ethoxy-quinoline-6-carbaldehyde (example 3b), 2-amino-thiazol-4-one, sodium acetate and acetic acid to give 2-Amino-5-[1-(4-ethoxy-quinolin-6-yl)-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 300 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([CH:9]=1)[CH2:7]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:36]NC(=O)CCC(N)=O>C1COCC1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([CH:9]=1)[CH2:7][Br:36]
Reactant: COCCOCOc1ccc(I)cc1CO
Reactant: NC(=O)CCC(=O)NBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOCOc1ccc(I)cc1CBr
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-iodo-2-(2-methoxy-ethoxymethoxy)-benzyl alcohol (7.5 g, 22 mmol) in 60 mL of THF at 15° C. is added triphenylphospine (6.35 g, 24 mmol) followed by N-bromosuccinamide (4.3 g, 24 mmol). The solution is stirred for 5 min. The solution is allowed to warm to ambient temperature. After 20 min, the solution is concentrated. The crude product is purified by column chromatography eluting with EtOAc:CH2Cl2 :hexane (3:1:6).