Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]([C:5]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][C@@H:22]([CH3:26])[CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:35][CH2:36][OH:37]>>[CH3:33][N:2]([CH3:1])[C:3]([C:5]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH2:35][CH2:36][OH:37])[C@@H:22]([CH3:26])[CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: OCCBr
Reactant: C[C@H]1CN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CCN1
Product: C[C@H]1CN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CCN1CCO
Yield: 40.6 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-[5-((S)-3-methyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (74 mg, 0.17 mmol) and 2-bromo ethanol (23 mg, 0.18 mmol) gave 7-cyclopentyl-2-{5-[(S)-4-(2-hydroxy-ethyl)-3-methyl-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (34 mg, 42%). MS (ESI) m/z 493.3 (M+H)+
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH3:26])[CH:5]([OH:25])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([CH3:24])[CH:15]=2)=[CH:8][CH:7]=1.[OH-:28].[K+].[NH2:30]O.CO.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>>[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35].[OH:25][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([CH3:24])[CH:15]=2)=[CH:8][CH:7]=1)[CH:4]([CH3:26])[C:3]([NH:30][OH:28])=[O:2]
Reactant: COC(=O)C(C)C(O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Reactant: NO
Reactant: [OH-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1cc(COc2ccc(C(O)C(C)C(=O)NO)cc2)c2ccccc2n1
Reaction time: 1 h

Procedure:
3-Hydroxy-2-methyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-propionic acid methyl ester (0.10 g, 0.27 mmol) was added to a solution of KOH/NH2OH/MeOH (2 mL) under a nitrogen atmosphere at room temperature. The reaction was stirred for 1 h and was acidified with TFA. The solution was concentrated and the product was purified by HPLC on a C-18 column eluting with an acetonitrile:water:TFA gradient to give the title compound as two separated diasteromers (0.063 g, 48%) and (0.035 g, 27%) as a white solid. MS found: (M+H)+=367.
Reaction SMILES: OCCO[C:5]1[CH:10]=[CH:9][C:8]([C:11]2([C:24]3[CH:29]=[CH:28][C:27](OCCO)=[CH:26][CH:25]=3)C3C=CC=CC=3C3C2=CC=CC=3)=[CH:7][CH:6]=1.[CH2:34]1[O:36][CH2:35]1.[OH:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2([C:57]3C=C[C:60]([OH:63])=[CH:59][CH:58]=3)[C:56]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[C:50]3[C:45]2=[CH:46][CH:47]=[CH:48][CH:49]=3)=[CH:40][CH:39]=1.OCCCOC1C=CC(C2(C3C=CC(OCCCO)=CC=3)C3C=CC=CC=3C3C2=CC=CC=3)=CC=1.ClCCCO>>[OH:63][C:60]1[CH:59]=[CH:58][CH:57]=[CH:44][C:45]=1[C:50]1([C:49]2[CH:48]=[CH:47][CH:46]=[CH:35][C:34]=2[OH:36])[C:28]2[CH:29]=[CH:24][CH:25]=[CH:26][C:27]=2[C:56]2[C:51]1=[CH:52][CH:53]=[CH:54][CH:55]=2.[C:38]1(=[O:37])[C:39]2[C:40]([C:7]3[C:8]([CH:11]=2)=[CH:9][CH:10]=[CH:5][CH:6]=3)=[CH:41][CH:42]=[CH:43]1
Reactant: Oc1ccc(C2(c3ccc(O)cc3)c3ccccc3-c3ccccc32)cc1
Reactant: OCCOc1ccc(C2(c3ccc(OCCO)cc3)c3ccccc3-c3ccccc32)cc1
Reactant: C1CO1
Agent: OCCCCl
Agent: OCCCOc1ccc(C2(c3ccc(OCCCO)cc3)c3ccccc3-c3ccccc32)cc1
Product: O=C1C=CC=C2C1=Cc1ccccc12
Product: Oc1ccccc1C1(c2ccccc2O)c2ccccc2-c2ccccc21

Procedure:
Compounds for introducing the unit (A3) can be obtained by reacting 9,9-bis(hydroxyphenyl)fluorenes with compounds (alkylene oxide, haloalkanol, etc.) corresponding to the groups R3 and R4. For example, 9,9-bis[4-(2-hydroxyethoxy)phenyl]fluorene can be obtained by adding ethylene oxide to 9,9-bis(4-hydroxyphenyl)fluorene, and 9,9-bis[4-(3-hydroxypropoxy)phenyl]fluorene can be obtained, for example, by reacting 9,9-bis[4-hydroxyphenyl]fluorene with 3-chloropropanol under an alkaline condition. In addition, 9,9-bis(hydroxyphenyl)fluorene can be obtained by a reaction between a fluorenone (9-fluorenone, etc.) and a corresponding phenol, and 9,9-bis(4-hydroxyphenyl)fluorene can be obtained, for example, by a reaction between a phenol and 9-fluorenone.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:10][C:11]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:4][CH:3]=1.Cl[CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:33][C:32]1[O:31][C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:29][C:28]=1[CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:10][C:11]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: COC(=O)CCc1sc(Sc2ccc(O)cc2)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1sc(Sc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
A mixture of methyl 3-[2-(4-hydroxyphenylthio)-4-phenyl-5-thiazolyl]propionate (350 mg), 4-chloromethyl-5-methyl-2-phenyloxazole (196 mg), potassium carbonate (260 mg) and N,N-dimethylformamide (4 ml) was stirred at 50° C. for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylthio]-4-phenyl-5-thiazolyl]propionate (400 mg, yield 78%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: ClCCl.N1C=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([SH:15])[NH:13][N:14]=2)[CH:5]=1.I[CH3:17].[CH2:18]([N:20](CC)CC)C>>[CH3:17][S:15][C:12]1[NH:13][N:14]=[C:10]([C:6]2[CH:5]=[CH:18][N:20]=[CH:8][CH:7]=2)[N:11]=1
Reactant: Sc1nc(-c2cccnc2)n[nH]1
Reactant: CI
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CSc1nc(-c2ccncc2)n[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a dichloromethane solution of 5-pyridin-3-yl-2H-[1,2,4]triazole-3-thiol (Step B, Example 1) triethylamine was added followed by iodomethane. This solution was stirred at room temperature for 2 h, during which period the reaction was complete by RP-HPLC. The solvent was evaporated and the residue was purified by RP-HPLC affording the desired intermediate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[Cl:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C)C=O.C(Cl)(Cl)Cl>[Cl-:13].[Cl-:13].[CH2:18]([O:17][C:15]([CH2:14][N+:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][N+:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1)=[O:16])[CH3:19]
Reactant: c1cc(-c2ccncc2)ccn1
Reactant: CCOC(=O)CCl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C[n+]1ccc(-c2cc[n+](CC(=O)OCC)cc2)cc1
Product: [Cl-]
Temperature: 120 °C

Procedure:
4,4'-Bipyridyl (156 g) was heated with ethyl chloroacetate (245 g) in dry dimethylformamide (400 ml) to 90°- 100° C. After 2 hours a further quantity of ethyl chloroacetate (123 g) was added and the mixture heated a further 2.5 hours at 120° C. The solution was cooled, diluted with chloroform (400 ml), stirred a short time at 0° C., and the solid collected, washed with chloroform and dried. The 1,1'-di-ethoxycarbonylmethyl-4,4'-bipyridylium dichloride so obtained (340 g) was dissolved in concentrated hydrochloric acid and heated under reflux for 3 hours. The mixture was cooled to 0° C., acetone (200 ml) slowly added, and the grey solid collected, washed with acetone, and dried, giving 1,1'-dicarboxymethyl-4,4'-bipyridylium dichloride.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][C:8](=[O:28])[NH:9][CH:10]([C:21](=[O:27])[NH:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:11][S:12][CH2:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:15])[C:3](O)=[O:4].[C:29]1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:40][OH:41]>>[CH3:40][O:41][C:3](=[O:4])[CH:2]([NH2:1])[CH2:6][CH2:7][C:8](=[O:28])[NH:9][CH:10]([C:21](=[O:27])[NH:22][CH2:23][C:24]([O:26][CH3:29])=[O:25])[CH2:11][S:12][CH2:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:15]
Reactant: CCOC(=O)C(=O)CSCC(NC(=O)CCC(N)C(=O)O)C(=O)NCC(=O)O
Reactant: CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)C(=O)CSCC(NC(=O)CCC(N)C(=O)OC)C(=O)NCC(=O)OC

Procedure:
A mixture of 2-Amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid (200 mg) and p-toluenesulfonic acid (30 mg) in methanol (100 mL) was heated to reflux for 72 h. The solvent was then evaporated and the residue was dried under high vacuum to afford the desired product, 2-amino-4-[2-(2-ethoxycarbonyl-2-oxo-ethylsulfanyl)-1-(methoxycarbonylmethyl-carbamoyl)-ethylcarbamoyl]-butyric acid methyl ester, as a yellowish sticky solid. 1H-NMR (D3COD, 300 MHz) δ (ppm): 6.24 (d, J=10.5 Hz, 0.22H), 4.49-4.4.33 (m, 1H), 4.15-3.91 (m, 3H), 3.76 (s, 3H), 3.65-3.57 (m, 2H), 3.51 (s, 3H), 3.21-2.73 (m, 2.8H), 2.45-2.43 (m, 2H), 2.10-1.92 (m, 2H, 1.13-1.03 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:37][CH3:38])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH2:25][NH:26]C(=O)OCC5C=CC=CC=5)[CH2:18]4)=[CH:16][C:9]=23)[CH:7]=1.[H][H]>O1CCCC1.CO.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:37][CH3:38])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH2:25][NH2:26])[CH2:18]4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCCN(CCCNC(=O)OCc4ccccc4)C3)cc12
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCCN(CCCN)C3)cc12

Procedure:
To a solution of Example 127 (100 mg, 0.194 mmol) in tetrahydrofuran (20 mL) and methanol (10 mL) was added 20% palladium hydroxide on carbon (wet, 20 mg, 0.015 mmol). The mixture was heated under 50 psi hydrogen at 45° C. for 3 hours and cooled. The insoluble material was filtered off and the filtrate was concentrated. The residue was purified by reverse phase HPLC, and was eluted with 10-70% acetonitrile in 0.1% trifluoroacetic acid/water to afford the title compound. LCMS: 383.23 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 1.58-1.74 (m, 3H) 1.82-1.93 (m, 1H) 1.95-2.07 (m, 2H) 2.18 (d, 1H) 2.81-2.97 (m, 4H) 3.14-3.23 (m, 2H) 3.48 (t, 2H) 3.74 (s, 3H) 6.10 (s, 1H) 7.08 (d, 1H) 7.17-7.23 (m, 2H) 7.25-7.34 (m, 1H) 8.22 (d, 1H) 10.17 (s, 1H) 11.88 (s, 1H).
Reaction SMILES: [Br-].[CH3:2][Si:3]([CH3:13])([CH3:12])[C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][PH3+].[CH:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=O.C[O-].[Na+].CO>CO>[CH3:2][Si:3]([CH3:13])([CH3:12])[C:4]1[CH:5]=[C:6]([CH:7]=[CH:14][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: C[Si](C)(C)c1cccc(C[PH3+])c1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C=Cc2cccc([Si](C)(C)C)c2)cc1
Reaction time: 17 h
Yield: 24.7 %

Procedure:
(m-Trimethylsilylbenzyl)phosphonium bromide (758 mg, 1.50 mmol) and methyl 4-formylbenzoate (258 mg, 1.57 mmol) were added to a NaOMe-methanol solution, which was prepared from 40 mg (1.74 mmol) of Na metal and 15 ml of dry methanol, and the mixture was stirred for 17 hours. The precipitate (trans form) was collected by filtration, washed with a cooled mixture of MeOH and n-hexane, and dried in vacuo to give 115 mg of white crystals. The mother liquors were evaporated and dissolved in CH2Cl2. The insoluble substance was filtered off and the filtrate was evaporated. The residue was purified by column chromatography to give 60 mg of colorless oil (cis form, yield 13%), 158 mg of white crystals (trans form, total yield 59%) and 110 mg of interfraction (yield 23%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:40].C[N:42]([CH:50]1CCNC[CH2:51]1)[C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46].C([N:58]([CH2:61][CH3:62])[CH2:59][CH3:60])C>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:58]3[CH2:59][CH2:60][CH:51]([CH2:50][NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:62][CH2:61]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([C:22]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH:32]=[CH:33][C:34]=3[CH3:35])[C:13]=2[CH2:12][NH:11][C:10]1=[O:40]
Reactant: CCN(CC)CC
Reactant: Cc1ccc(C(=O)NCc2ccccc2)cc1-c1nc(S(C)(=O)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NCc2ccccc2)cc1-c1nc(N2CCC(CNC(=O)OC(C)(C)C)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Reaction time: 96 h

Procedure:
Compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide (0.0811 g, 0.144 mmol) was dissolved in CH2Cl2 (5 mL) and 1,1-dimethylethyl methyl(4-piperidinyl)carbamate (0.0394 g, 0.18 mmol) and triethylamine (0.029 g, 0.288 mmol) were added. The reaction mixture was stirred for 4 days. Additional 1,1-dimethylethyl methyl(4-piperidinyl)carbamate (0.0788 g, 0.36 mmol) and triethylamine (0.058 g, 0.576 mmol) were added and the mixture was stirred under argon at room temperature for an additional 7 days. The solvents were pumped off in vacuo, and the residue taken up in EtOAc and washed with 1 N NaOH, brine, dried over anhydrous Na2SO4 filtered and evaporated. The residue was flash chromatographed on silica gel (20 g) eluted with 0-70% EtOAc/hexane. Some impurities remained, so the material was rechromatographed on silica gel (20 g) eluted with 0-50% EtOAc/hexane to give the title compound as a white amorphous solid. mp (dec) 146-150° C. LC-MS m/z 698 (M+H)+, 2.66 min (ret time).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22](Br)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:31]4[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=4)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(Br)ccc3C2=O)cc1
Reactant: OB(O)c1cccnc1
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(-c4cccnc4)ccc3C2=O)cc1
Reaction time: 0.33 h
Yield: 59 %

Procedure:
The procedure of Example 2 was repeated except that N-(2-aminophenyl)-4-((5-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 56 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 3-pyridyl boronic acid instead of phenyl boronic acid were used, and the reaction was performed for 20 mins, to obtain the title compound (59%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:40])[C@H:10]([NH:20]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.[OH-].[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:1]([O:8][C@H:9]([CH3:40])[C@H:10]([NH2:20])[CH2:11][O:12][Si:13]([C:16]([CH3:18])([CH3:17])[CH3:19])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](OCc1ccccc1)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H](OCc1ccccc1)[C@H](N)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
(2R,3R)-3-(benzyloxy)-1-{[tert-butyl(dimethyl)silyl]oxy}-N-tritylbutan-2-amine (3.26 g, 5.92 mmol) was dissolved in 75 mL of anhydrous CH2Cl2 and 9.6 mL of glacial acetic acid. The reaction mixture was cooled to 0° C. under an atmosphere of N2 and boron trifluoride diethyl etherate (790 μL, 5.92 mmol) was added dropwise over several minutes. After stirring for 4 hours, the reaction mixture was treated with 90 mL of cold, aqueous 10% NaOH solution. The layers were separated and the aqueous portion was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 0-5% methanol/CHCl3) gave 1.83 g of (2R,3R)-3-(benzyloxy)-1-{[tert-butyl(dimethyl)silyl]oxy}butan-2-amine as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[C:20]([CH:27]=[CH:28]C=3C)[C:21]([NH:23][CH:24]3[CH2:26][CH2:25]3)=[O:22])=[CH:15][CH:16]=2)[CH2:11][NH:10][C:9]1=[O:31].[C:32](C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[CH2:46]([Cl:48])Cl>>[CH:24]1([NH:23][C:21](=[O:22])[C:20]2[CH:27]=[CH:28][C:46]([Cl:48])=[C:18]([C:14]3[CH:13]=[C:12]4[C:17](=[CH:16][CH:15]=3)[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:32])[C:9](=[O:31])[N:10]=[CH:11]4)[CH:19]=2)[CH2:26][CH2:25]1
Reactant: ClCCl
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(c1)CNC(=O)N2c1ccccc1Cl
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Product: Cc1ccccc1-n1c(=O)ncc2cc(-c3cc(C(=O)NC4CC4)ccc3Cl)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3-(1-(2-chlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl)-N-cyclopropyl-4-methylbenzamide (0.1233 g, 285 μmol) in DCM was added DDQ (71 mg, 314 μmol) and the resulting dark-colored mixture was stirred at RT for 3 h. The reaction was quenched with NaHCO3(aq) and water (10 mL each) and the separated aqueous layer was extracted with 5% MeOH in DCM (3×6 mL). The combined organic layers were washed with, 1N NaOH(aq), brine, dried (Na2SO4), and concentrated to give the crude residue. Flash column chromatographic purification (5% MeOH in DCM) of the crude residue followed by washing the concentrated pure product fractions with ethyl acetate provided N-cyclopropyl-4-chloro-3-(2-oxo-1-o-tolyl-1,2-dihydroquinazolin-6-yl)benzamide as a white solid. MS m/e 430 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:16]=[CH:15][N:14]=[C:13]3[C:9]=2[NH:10][C:11](=[O:17])[NH:12]3)[CH2:4][CH2:3]1.[C:18]1([CH2:24][CH:25]=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(O)(=O)C.ClCCCl.CO>[CH2:25]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:16]=[CH:15][N:14]=[C:13]3[C:9]=2[NH:10][C:11](=[O:17])[NH:12]3)[CH2:4][CH2:3]1)[CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC1CCN(c2ncnc3[nH]c(=O)[nH]c23)CC1
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=c1[nH]c2ncnc(N3CCC(NCCc4ccccc4)CC3)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.3 %

Procedure:
A mixture of 6-(4-aminopiperidin-1-yl)-7,9-dihydropurin-8-one (Example 4B, 0.045 g, 0.20 mmol), phenylacetaldehyde (0.025 ml, 0.20 mmol), NaBH(OAc)3 (0.065 g, 0.30 mmol) and acetic acid (5 drops) in 1,2-dichloroethane (2 ml) and MeOH (0.5 ml) was stirred at room temperature for 2 hours. The solution was absorbed onto a 5 g SCX-II acidic resin cartridge and eluted with MeOH, then 1M NH3-MeOH. The basic eluant was concentrated. Preparative thin layer chromatography (t.l.c.), eluting with 1% NH3 (aq)/9% MeOH/90% CH2Cl2 gave the product as an off white solid (0.007 g, 10%). LC/MS: (LCT) Rt 3.62 [M+H]+339.
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[SH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].CC(C)([O-])C.[K+].Cl>CN(C=O)C>[F:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]([C:5]2[CH:16]=[CH:17][C:2]([S:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[N:3][CH:4]=2)=[O:7])=[CH:10][CH:11]=1
Reactant: O=C(O)CCS
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CCSc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Temperature: 60 °C
Yield: 66.3 %

Procedure:
To a solution of 6-chloro-N-(4-fluoro-phenyl)-nicotinamide (0.20 g, 0.80 mmol) in 10 mL of DMF was added 3-mercaptopropionic acid (0.10 mL, 1.2 mmol) and potassium tert-butoxide (0.31 g, 2.8 mmol) and the mixture heated to 60° C. After 9 h the reaction mixture was poured into ice water, HCl (1 M, aq) added to adjust to pH 6, and the solids removed via filtration. The filtrate was then taken to pH 10 with NaOH (4M, aq) and extracted with ethyl acetate. HCl (6M, aq) was then added to the filtrate to adjust the pH to 4 and extracted with ethyl acetate, dried over sodium sulfate, and the solvents removed in vacuo to yield a white solid. Purification by recrystallization using ethyl acetate gave 0.17 g (66%) of the titled product as a white solid; MS (EI) m/z 319.20 (M−H)−.
Reaction SMILES: N[C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:27].[Na+]>C(COC)OC.O.C(OCC)(=O)C>[I:27][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CC(=O)c1ccc(Oc2ccc(N)cc2)cc1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CC(=O)c1ccc(Oc2ccc(I)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
To a solution of 1-(4-(4-aminophenoxy)phenyl)ethanone (6.0 g, 26.43 mmol), in dimethoxyethane (80 mL), was added a solution of sulphuric acid (10.9 mL, 206.19 mmol) in water (54.5 mL) dropwise. The resulting reaction mixture was cooled to 0° C. and a solution of sodium nitrite (2.74 g, 39.64 mmol) in water (18 mL) was added dropwise. The reaction mixture was stirred at 0-5° C. for additional 30 min and a solution of sodium iodide (19.81 g, 132.15 mmol) in water (54 mL) was added dropwise. The reaction mixture was stirred for additional 30 min. After the completion of reaction as confirmed by TLC, the reaction mixture was diluted with ethyl acetate (300 mL). The organic layer was separated, washed with water (100 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 3:7 EtOAc:Pet Ether) to afford the title compound (6.8 g, 76%) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]3[O:18][CH2:17][O:16][C:14]3=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].[CH3:19][NH2:20]>O1CCCC1.CO>[ClH:1].[CH3:19][NH:20][CH2:2][C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]3[O:18][CH2:17][O:16][C:14]3=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(CCl)N1CCc2cc3c(cc2CC1)OCO3
Reactant: CN
Solvent: C1CCOC1
Solvent: CO
Product: CNCC(=O)N1CCc2cc3c(cc2CC1)OCO3
Product: Cl
Reaction time: 20 h

Procedure:
13.5 g (0.05 mole) of 3-chloroacetyl-2,3,4,5-tetrahydro-7,8-methylenedioxy-1H-3-benzazepine was dissolved in 250 ml of dry tetrahydrofuran and the solution added to approximately 150 ml of liquid methylamine at -78°. The mixture was stirred for 20 hours allowing the temperature to rise to 22° during this interval after which it was warmed on the steambath to drive out the excess methylamine. The white solid that had formed was filtered off and washed with tetrahydrofuran. Distillation of the solvent in the rotary evaporator left 18.2 g of a thick yellow syrup which was dissolved in a minimum of hot isopropanol. Chilling gave a white salt, mp 250°-252° dec. The salt was dissolved in 30 ml of hot methanol, the solution filtered and diluted with 210 ml of ethyl acetate. On standing at room temperature white crystals of the above-named product separated, mp 253°-254°(dec.).