Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCCCC1C(O)=O.C1C=NC2[N:17](O)[N:18]=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.C([O:55][C@@H:56]([C:75]1[S:76][CH:77]=[C:78]([C:80](=[O:83])[NH:81][CH3:82])[N:79]=1)[CH2:57][C@@H:58]([N:62]([CH2:71][CH2:72][O:73][CH3:74])[C:63](=[O:70])[C@@H:64]([NH2:69])[C@@H:65]([CH3:68])[CH2:66][CH3:67])[CH:59]([CH3:61])[CH3:60])(=O)C>ClCCl>[N:69]([C@@H:64]([C@@H:65]([CH3:68])[CH2:66][CH3:67])[C:63]([N:62]([C@@H:58]([CH:59]([CH3:61])[CH3:60])[CH2:57][C@H:56]([C:75]1[S:76][CH:77]=[C:78]([C:80]([NH:81][CH3:82])=[O:83])[N:79]=1)[OH:55])[CH2:71][CH2:72][O:73][CH3:74])=[O:70])=[N+:17]=[N-:18]
Reactant: CC[C@H](C)[C@H](N)C(=O)N(CCOC)[C@H](C[C@@H](OC(C)=O)c1nc(C(=O)NC)cs1)C(C)C
Reactant: On1nnc2cccnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN1CCCCC1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N=[N+]=[N-])C(=O)N(CCOC)[C@H](C[C@@H](O)c1nc(C(=O)NC)cs1)C(C)C
Reaction time: 0.08 h
Yield: 127.6 %

Procedure:
To a suspension of N-methyl pipecolinic acid (0.15 mmole, 21 mg) in dichlbromethane (5 mL) were subsequently added, in the order, HOAt (0.11 mmole, 15 mg), HATU (0.11 mmole, 42 mg) and Et3N (0.21 mmole, 29 μL). After stirring for 5 minutes, a solution in dichloromethane (1 mL) of the compound obtained in example 15.3 (0.1 mmole, 46 mg) was added. The reaction mixture was stirred for 4 hours, At the end dichloromethane was removed under vacuum. The crude product was dissolved in ethyl acetate (10 mL) and washed, in the order, with a NaHCO3 saturated aqueous solution (1×10 mL) and with brine (1×10 mL). The organic phase were dried over Na2SO4, filtered and concentrated under vacuum. The product was purified by flash chromatography (eluent chloroform:methanol 97:3 volume/volume). 58 mg (99% yield) of pure 2-((1R,3R)-3-((2S,3S)-2-azido-N-(2-methoxyethyl)-3-methylpentanamido)-1-hydroxy-4-methylpentyl)-N-methylthiazole-4-carboxamide were isolated. Rf=0.37 (chloroform/methanol 97:3 volume/volume). 1HNMR (400 MHz, CDCl3) δ: 8.07 (s, 1H), 7.62 (m, 1H), 7.57 (m, 1H), 5.75 (dd, 1H), 4.61 (dd, 1H), 4.11 (m, 1H), 3.70-3.48 (m, 4H), 3.22 (s, 3H), 3, 20-3.08 (m, 1H), 2.92 (m, 3H), 2.88-2.78 (m, 1H), 2.40 (m, 1H), 2.2-2.09 (m, 6H), 2.09-1.81 (m, 5H), 1.69-1.48 (m, 5H), 1.39-1.30 (m, 1H), 1.26-1.09 (m, 1H), 1.08-0.86 (m, 12H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][S:25]([NH:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)(=[O:27])=[O:26].[OH-].[Na+]>CN(C=O)C.CO>[CH3:24][S:25]([NH:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:31][CH:30]=1)(=[O:27])=[O:26]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: CS(=O)(=O)Nc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-methylsulphonylamino-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: ClN1C(=O)CCC1=O.[Br:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=[N:21][OH:22])=[CH:12][CH:11]=1.[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:27]=[C:26]([Cl:36])[CH:25]=1.C(N(CC)CC)C>CN(C=O)C.O>[Br:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]2[CH2:31][C:30]([C:28]3[CH:27]=[C:26]([Cl:36])[CH:25]=[C:24]([Cl:23])[CH:29]=3)([C:32]([F:33])([F:35])[F:34])[O:22][N:21]=2)=[CH:12][CH:11]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: ON=Cc1ccc(Br)c2ccccc12
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(Br)c3ccccc23)=NO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-chlorosuccinimid (134 mg) is added to a solution of crude 4-bromo-naphthalene-1-carbaldehyde oxime (250 mg) in DMF (3 ml). After 1 hour at 40° C., the reaction is cooled down to 0° C. and 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (240 mg) and triethylamine (0.15 ml) are added. The reaction is further reacted at room temperature for 16 hours. Water is added and the reaction mixture is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 3-(4-bromo-naphthalen-1-yl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole as colorless crystals: m.p. 127-130° C.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C@H:12]1[O:17][C@:16]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH3:36])=[C:30]([F:37])[C:29]=3[F:38])[CH:21]=2)([O:18][CH3:19])[C@H:15]([OH:39])[C@@H:14]([OH:40])[C@@H:13]1[OH:41])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH2:42](Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:6]([Si:3]([CH3:5])([CH3:4])[O:10][CH2:11][C@@H:12]1[C@@H:13]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@H:14]([O:40][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:15]([O:39][CH2:16][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@:16]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH3:36])=[C:30]([F:37])[C:29]=3[F:38])[CH:21]=2)([O:18][CH3:19])[O:17]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: BrCc1ccccc1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 453.1 %

Procedure:
To a suspension of sodium hydride (3.18 g, 32.65 mmol, 60% dispersion in Mineral oil) in anhydrous tetrahydrofuran (15 mL) was added a solution of (2S,3R,4S,5S,6R)-6-[[tert-butyl (dimethyl)silyl]oxymethyl]-2-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 23h (11.16 g, 18.95 mmol) in anhydrous tetrahydrofuran (80 mL) slowly at 0° C. The mixture was stirred at 0° C. for 1 hour, and then benzyl bromide (20.3 mL, 170.55 mmol) was added. The mixture was warmed up to room temperature and tetrabutylammonium iodide (0.70 g, 1.90 mmol) was added. The mixture was stirred for 12 hours. The reaction mixture was quenched with water (100 mL) at 0° C. and extracted with ethyl acetate (100 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 23i as yellow oil (36.90 g, 100%). This material was not further purified.
Reaction SMILES: C(OC1C=CC=CC=1N1CCCN([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][C:28](=[O:32])[NH:29]3)=[CH:24][CH:23]=2)CC1)C.[Na+].[I-].Cl.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[N:44]1[CH2:49][CH2:48][N:47]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][C:28](=[O:32])[NH:29]3)=[CH:24][CH:23]=2)[CH2:46][CH2:45]1
Reactant: CCOc1ccccc1N1CCCN(CCCCOc2ccc3c(c2)NC(=O)CC3)CC1
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCCCOc2ccc3c(c2)NC(=O)CC3)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.9 %

Procedure:
A mixture of intermediate 12 (314 mg, 0.48 mmol) and NaI (150 mg, 0.96 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 55 (228 mg, 0.48 mmol) and anhydrous K2CO3 (138 mg, 1.92 mmol) were added to the mixture. The resulting mixture was heated to reflux and stirred for 4 h. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=30:1) to give 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (compound 37) (98 mg, 60%). 1H NMR (300 MHz, CDCl3): δ 7.55 (s, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.02-6.85 (m, 3H), 6.37-6.34 (m, 1H), 4.29-4.20 (m, 2H), 3.86 (s, 3H), 3.11 (brs, 4H), 2.86 (t, J=6.9 Hz, 2H), 2.67-2.61 (m, 5H), 2.48 (t, J=7.2 Hz, 1H), 1.82-1.62 (m, 6H). HPLC: 99%, RT 2.109 min. MS (ESI) m/z 411.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:9](=[C:10]([OH:22])[C:11]4[N:12]=[CH:13][CH:14]=[N:15][C:16]=4[C:17]=3[OH:21])[C:8]2=[O:23])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C=O)C>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:8](=[O:23])[C:9]3[C:18](=[C:17]([OH:21])[C:16]4[N:15]=[CH:14][CH:13]=[N:12][C:11]=4[C:10]=3[O:22][C:33](=[O:34])[O:35][CH2:36][CH3:37])[C:19]2=[O:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: O=C1c2c(c(O)c3nccnc3c2O)C(=O)N1Cc1ccc(F)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)Oc1c2c(c(O)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Reaction time: 16 h
Yield: 98 %

Procedure:
7-(4-Fluoro-benzyl)-5,9-dihydroxy-pyrrolo [3,4-g]quinoxaline-6,8-dione 242 (1 g, 2.95 mmol, 1 equiv.) was dissolved in DMF (30 ml, 0.1 M) and pyridine (477 μL, 5.89 mmol, 2 equiv.) before ethyl chloroformate was added (237 μL, 2.95 mmol, 1 equiv.). The reaction was stirred for 16 hours before being quenched with HCl (30 ml, 1 N) and extracted with ethyl acetate (2×30 mL). The organic layer washed several times with water (4×30 mL), saturated NaHCO3 (50 mL), brine solution (50 mL). It was dried over Na2SO4, filtered and concentrated in vacuo. Recrystallization was carried out in ethyl acetate and Hexanes to yield carbonic acid ethyl ester 7-(4-fluoro-benzyl)-9-hydroxy-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoxalin-5-yl ester 243 as a light brown solid (98%, 1.20 g, 2.89 mmol). 1H NMR (300 MHz) CDCl3 δ 9.09 (d, J=6 Hz, 1 H), 8.97 (d, J=6 Hz, 1 H), 8.65 (bs, 1 H), 7.46 (d, J=4.8 Hz, 2 H), 7.03 (d, J=4.8 Hz, 2 H), 4.85 (s, 2 H), 4.04 (q, J=2.8 Hz, 2 H), 1.43 (q, J=2.8 Hz, 3 H). MS: 412.6 (M+1).
Reaction SMILES: C(NC(C1SC(N2C(O)CN(CC3C=CC(F)=CC=3)C2=O)=NC=1C)=O)C1C=CC=CC=1.[F:32][C:33]1[CH:63]=[CH:62][C:36]([CH2:37][CH2:38][N:39]2[CH2:43][CH:42](O)[N:41]([C:45]3[S:46][C:47]([C:51]([NH:53][CH2:54][C:55]4[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=4)=[O:52])=[C:48]([CH3:50])[N:49]=3)[C:40]2=[O:61])=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:37][CH2:38][N:39]2[CH:43]=[CH:42][N:41]([C:45]3[S:46][C:47]([C:51]([NH:53][CH2:54][C:55]4[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=4)=[O:52])=[C:48]([CH3:50])[N:49]=3)[C:40]2=[O:61])=[CH:62][CH:63]=1
Reactant: Cc1nc(N2C(=O)N(CCc3ccc(F)cc3)CC2O)sc1C(=O)NCc1cccnc1
Agent: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)CC2O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2ccn(CCc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 14 %

Procedure:
Following the procedure as described in Example 17, making variations as required to replace N-benzyl-2-(3-(4-fluorobenzyl)-5-hydroxy-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide with 2-(3-(4-fluorophenethyl)-5-hydroxy-2-oxoimidazolidin-1-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide 2, the title compound was obtained as a colorless solid in 14% yield: mp 160-162° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.72 (d, J=5.8 Hz, 1H), 8.50-8.49 (m, 1H), 8.42 (dd, J=4.7, 1.8 Hz, 1H), 7.68 (td, J=7.8, 1.8 Hz, 1H), 7.34-7.30 (m, 1H), 7.22-7.17 (m, 3H), 7.11-7.03 (m, 2H), 6.84 (d, J=3.2 Hz, 1H), 4.38 (d, J=5.8 Hz, 2H), 3.83 (t, J=7.1 Hz, 2H), 2.92 (t, J=7.1 Hz, 2H), 2.48 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 163.0, 161.9, 159.8, 153.8, 151.6, 150.3, 149.3, 148.5, 135.6, 135.3, 134.6, 131.0, 123.9, 120.7, 115.7, 106.7, 44.6, 40.9, 33.8, 17.4; MS (ES+) m/z 438.3 (M+1).
Reaction SMILES: C(#N)C.[Cl:4][C:5]1[C:10]([S:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]([OH:17])=[C:7]([F:18])[CH:6]=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OC(=O)C)C.CCCCCC>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:17][C:8]1[CH:9]=[C:10]([S:11][CH2:12][C:13]([F:14])([F:15])[F:16])[C:5]([Cl:4])=[CH:6][C:7]=1[F:18]
Reactant: BrCCCCCBr
Reactant: Oc1cc(SCC(F)(F)F)c(Cl)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Fc1cc(Cl)c(SCC(F)(F)F)cc1OCCCCCBr
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To 60 ml of acetonitrile were added 3.0 g (11.5 mmol) of 4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenol, 13.2 g (57.4 mmol) of 1,5-dibromopentane, 2.1 g (15.0 mmol) of potassium carbonate and 0.37 g (1.15 mmol) of tetra-n-butylammonium bromide. The mixture was refluxed for 1.5 hour under heating. The mixture was allowed to cool to room temperature, and insoluble matters were removed by filtration. Then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane ethyl acetate=20:1), to obtain 4.2 g (yield: 89%) of an intended product.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH2:6][S:7][C:8]1[C:17]([CH3:18])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:23][N:3]([CH3:2])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH2:6][S:7]([C:8]1[C:17]([CH3:18])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=[O:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nc2ccccc2nc1SCc1ccccc1N(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1nc2ccccc2nc1S(=O)Cc1ccccc1N(C)C
Yield: 31.3 %

Procedure:
In a mixture of 10 ml of chloroform and 10 ml of methanol was dissolved 1.73 g of 2-(2-dimethylaminobenzylthio)-3-methylquinoxaline hydrochloride. To the chilled solution kept at a temperature of lower than 0° C. (temperature of solution) was portionwise added 1.14 g of m-chloroperbenzoic acid (purity: 80%). After the reaction was complete, chloroform and saturated aqueous NaHCO3 solution were added to the reaction mixture. The organic layer was separated and dried over sodium sulfate. The sodium sulfate was then removed by filtration, and the solvent was evaporated under reduced pressure from the filtrate. The residue was purified by silica gel column chromatography (chloroform/methanol), and recrystallized from ethyl acetate/hexane to give 0.51 g of 2-(2-dimethylaminobenzylsulfinyl)-3-methylquinoxaline as a pale brown crystalline powder, m.p. 68°-70° C. (decompn.).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9](Cl)([Cl:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C1(C)C=CC=CC=1>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:9]([Cl:11])=[O:10]
Reactant: CNc1ccccc1
Reactant: O=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CN(C(=O)Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
A vigorously stirred solution of 10.7 g (0.1 mole) of N-methylaniline in 100 ml of acetonitrile was added dropwise under a nitrogen atmosphere to a cold mixture of 155 ml (0.3 mole) of a 1.93M solution of phosgene in toluene and 83.0 g (0.6 mole) of anhydrous potassium carbonate in 200 ml of acetonitrile. After the final addition, the mixture was stirred at ambient temperature for 16 h, filtered, and the filtrate concentrated under reduced pressure. The residue was recrystallized from benzene/petroleum ether (60°-110° C.) to yield 15.9 g (94%) of white solid, mp 85°-86° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[N:14][CH:15]=3)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C(O[Na])(C)(C)C>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]>[Cl:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH:38][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[N:14][CH:15]=3)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)c2)c2cnc(NCCN3CCOCC3)nc21
Reactant: NCc1ccccc1Cl
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3ccccc3Cl)c2)c2cnc(NCCN3CCOCC3)nc21

Procedure:
To a stirred solution of [3-(3-bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 40 supra) (250 mg, 0.468 mmol), 2-chlorobenzylamine (80 mg, 0.564 mmol), DavePhos (37 mg) and t-BuONa (54 mg, 0.564 mmol) in 1,4-dioxane (10 mL), Pd2(dba)3 (42 mg, 0.073 mmol) was added in one portion under N2 atmosphere. The resultant mixture was stirred at 100° C. for 6 hours. The mixture was cooled and filtered; the filtrate was evaporated under reduced pressure to give the crude product. It was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH, 100:1, v/v) to give [3-[3-(2-chloro-benzylamino)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine. (Yield 120 mg, 43%).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[N:13]=[C:12]([O:14][Si](C)(C)C)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.Br[CH2:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([O:28][CH3:29])=[O:27].CN(C=O)C.O1CCOCC1>CO>[CH3:29][O:28][C:26]([C:25]1[CH:24]=[C:23]([CH:32]=[CH:31][CH:30]=1)[CH2:22][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12](=[O:14])[NH:13][C:4]1=[O:3])=[O:27]
Reactant: C[Si](C)(C)Oc1nc(O[Si](C)(C)C)c2ccccc2n1
Reactant: COC(=O)c1cccc(CBr)c1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1cccc(Cn2c(=O)[nH]c(=O)c3ccccc32)c1
Temperature: 122.5 °C
Yield: 83.7 %

Procedure:
The intermediate product 2,4-di(trimethylsilyloxy)quinazoline, methyl 3-(bromomethyl)benzoate (2.1 g, 9.2 mmol) and DMF (1 mL) were added in turn into a 50 mL single-mouth flask, and then the temperature were raised to 115-130° C. and reacted for 3 hours. 1,4-dioxane (6 mL) and methanol (10 mL) were added after the reaction mixture was cooled to 100° C. Then the mixture was refluxed for 30 minutes. The mixture was filtered after it was cooled to room temperature. The precipitate was washed with water (20 mL) and methonal (10 mL), respectively, and dried to give the title compound (1.6 g, 83.7% yield) as white powder. 1H NMR (DMSO-d6): 11.76 (s, 1H), 8.00 (dd, J=7.8 and 1.2 Hz, 1H), 7.89 (s, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.65-7.43 (m, 3H), 7.25-7.20 (m, 2H), 5.36 (s, 2H), 3.80 (s, 3H). MS: m/z 311.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:49]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]1([C:60]([O:62][CH3:63])=[O:61])[CH2:59][CH2:58]1)#[CH:50].CCN(CC)CC>CN(C=O)C.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.[Cu]I>[CH3:63][O:62][C:60]([C:57]1([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=2[C:49]#[C:50][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]4)=[CH:15][CH:14]=3)[N:3]=2)[CH2:59][CH2:58]1)=[O:61]
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)C1
Reactant: C#Cc1ccccc1C1(C(=O)OC)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C1(c2ccccc2C#Cc2nc(Nc3ccc(C4CN(C(=O)OC(C)(C)C)C4)cc3)ncc2C(F)(F)F)CC1
Temperature: 120 °C
Yield: 100 %

Procedure:
A solution of tert-butyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate (K4) (260 mg, 0.606 mmol), PdCl2(PPh3)2 (21 mg, 0.030 mmol), PPh3 (16 mg, 0.061 mmol), CuI (12 mg, 0.061 mmol) and methyl 1-(2-ethynylphenyl)cyclopropanecarboxylate (K2) (146 mg, 0.728 mmol) in DMF (3.0 mL) was degassed with nitrogen for 10 minutes. Et3N (1.0 mL) was added and the resulting mixture heated under microwave irradiation at 120° C. for 20 minutes. The resulting mixture was adsorbed onto silica and purified by silica gel column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-25% EtOAc in petroleum benzine 40-60° C.) to give the title compound A7 as an orange oil (359 mg, >95%); 1H NMR (400 MHz, d6-DMSO) δ 10.45 (s, 1H), 8.82 (s, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.61 (dd, J=7.5, 1.0 Hz, 1H), 7.55-7.38 (m, 3H), 7.32 (d, J=8.6 Hz, 2H), 4.32-4.17 (m, 2H), 3.89-3.74 (m, 3H), 3.52 (s, 3H), 1.64 (q, J=4.0 Hz, 2H), 1.40 (s, 9H), 1.29 (q, J=4.2 Hz, 2H). LCMS-A: rt 6.550 min; m/z 593 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[NH:10][C:9]=1[C:18]([NH2:20])=[O:19])(=[O:7])=[O:6].C(N(CC)CC)C.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>CCOC(C)=O>[Br:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:18]([NH2:20])=[O:19])=[C:8]2[S:5]([NH:4][CH2:3][CH2:2][NH:1][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])(=[O:6])=[O:7]
Reactant: NCCNS(=O)(=O)c1c(C(N)=O)[nH]c2ccc(Br)cc12
Reactant: CCS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NCCNS(=O)(=O)c1c(C(N)=O)[nH]c2ccc(Br)cc12
Temperature: 65 °C
Reaction time: 60 h

Procedure:
A solution of the product from Example 63 (15 mg, 0.038 mmol), triethylamine (0.017 mL, 0.11 mmol) and ethanesulfonyl chloride (0.004 mL, 0.04 mmols) were combined in a sealed tube and heated to 65° C. overnight. The solvent was removed under a stream of N2 and replaced with DMF. After adding an additional 3 equivalents of ethanesulfonyl chloride and triethylamine, the reaction was heated to 65° C. for 8 hours and stirred at room temperature for 60 hours. The mixture was diluted with EtOAc and washed with 10% Na2CO3 and brine, dried over Na2SO4, filtered and concentrated in vac o. Purification by reversed-phase preparative HPLC gave the titled compound. ESI+ MS: 453 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[C:13]([CH3:18])=[C:14]([CH2:16][OH:17])[S:15][C:3]=12.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>Cl>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:8]([C:7]2[C:2]([OH:1])=[C:3]3[S:15][C:14]([CH2:16][OH:17])=[C:13]([CH3:18])[C:4]3=[N:5][CH:6]=2)=[O:10])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cnc2c(C)c(CO)sc2c1O
Reactant: NCc1ccc(F)cc1
Agent: Cl
Product: Cc1c(CO)sc2c(O)c(C(=O)NCc3ccc(F)cc3)cnc12
Temperature: 80 °C
Yield: 85.5 %

Procedure:
A suspension of 140 mg (0.52 mmol) ethyl 7-hydroxy-2-(hydroxymethyl)-3-methylthieno[3,2-b]pyridine-6-carboxylate in 1.28 mL (11.2 mmol) 4-fluorobenzylamine was heated to 80° C. for 24 hours. The mixture was then cooled to room temperature and added to 10 mL of 1N HCl and then cooled in the refrigerator for three hours. The resulting mixture was then filtered and the obtained solid was washed with 1N HCl several times (50 mL total volume) and dried in a vacuum oven at 60° C. over night to provide 154 mg of the title compound as a tan solid.