Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:36][CH2:35][NH:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.[CH3:37][C:38]1[C:42]([CH:43]=O)=[CH:41][NH:40][N:39]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:36][CH2:35][N:34]([CH2:43][C:42]4[C:38]([CH3:37])=[N:39][NH:40][CH:41]=4)[CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12
Reactant: Cc1n[nH]cc1C=O
Reactant: COc1cc(-c2nn(C3CCNC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: COc1cc(-c2nn(C3CCN(Cc4c[nH]nc4C)C3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.3 %

Procedure:
A suspension of N2-[4-(4-amino-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide (0.200 g, 0.415 mmol) in dichloroethane (5 mL) was treated with 3-methyl-1H-pyrazol-4-carboxaldehyde (0.091 g, 0.83 mmol) and sodium triacetoxy borohydride (0.176 g, 0.83 mmol). The reaction mixture was stirred at room temperature for 24 h under a nitrogen atmosphere. Sodium hydroxide (1N, 15 mL) was added to the reaction mixture and was stirred for 1 h. The organic layer was removed under reduced pressure and dichloromethane was added. The layers were partitioned and the aqueous layer was extracted with dichloromethane (100 mL) and ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using 10% methanol in dichloromethane (15 min), 15% methanol in dichloromethane (10 min), 20% methanol in dichloromethane (10 min) and 50% methanol in dichloromethane (8 min) as the eluent. The column afforded 0.106 g (44%) of pure N2-[4-(4-amino-1-{1-[(3-methyl-1H-4-pyrazolyl)methyl]tetrahydro-1H-3-pyrrolyl}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide. 1H NMR (DMSO-d6, 400 MHz) δ 9.446 (s, 1H), 8.247 (s, 1H), 8.1275-8.1071 (d, 1H, J=8.16 Hz), 7.72-7.7003 (d, 1H, J=7.96 Hz), 7.6004-7.5793 (d, 1H, J=8.44 Hz), 7.398-7.286 (m, 5H), 7.172-7.134 (m, 1H), 5.379 (m, 1H), 4.0443 (s, 3H), 3.962 (s, 3H), 3.492 (m, 2H), 3.1 (m, 1H), 2.75 (m, 3H), 2.352-2.335 (m, 2H), 1.909 (s, 31); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.17 min (100%), MH+ 577.3.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]\[C:39]([OH:41])=[O:40]>C(#N)C.C(O)C>[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]\[C:39]([OH:41])=[O:40].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])[CH2:26][CH2:25][CH3:24])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1ccccc1CCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: CCCC(c1ccccc1OC)N1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.36 g, 10.7 mmole), K2CO3 (2 g, 14.5 mmol) and 2-(4-bromobutyl)anisole (2.4 g, 10 mmol) in acetonitrile (100 ml) was heated at reflux for 2.5 hours. At the end of reaction, the solvent was removed. The residue was extracted into dichloromethane (200 ml) and filtered. The dichloromethane solution was concentrated. The crude oil obtained was purified on a flash chromatography column. The material thus purified was a light yellow oil (2.73 g, 53%). This oil was dissolved in ethanol and treated with maleic acid (607 mg, 1.0 eq) in ethanol. The 4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-(2'-methoxyphenyl)butylpiperidine maleate crystals formed on concentration and subsequent cooling to 0° C. These were collected and dried to yield 2.05 g, m.p.=132°-133° C.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[CH2:32]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O)[CH2:33][CH3:34]>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[O:35][CH2:32][CH2:33][CH3:34])[CH:24]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Reactant: CCCOc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCOc1ccccc1-c1cc(F)ccc1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 74.1 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-propoxyphenylboronic acid (33 mg, 0.183 mmol) and Pd[PPh3]4 (27 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified first on a silica gel column with a 20-30% ethyl acetate/hexanes gradient and then by RP HPLC to afford the product as a white solid (42 mg, 74%). MS m/e 407.23 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17](F)=[CH:18][CH:19]=2)[C:3]=1[CH3:21].Cl.[F:23][C:24]1([F:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([N:27]3[CH2:28][CH2:29][C:24]([F:30])([F:23])[CH2:25][CH2:26]3)=[CH:18][CH:19]=2)[C:3]=1[CH3:21]
Reactant: FC1(F)CCNCC1
Reactant: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccc(N3CCC(F)(F)CC3)nc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C
Reaction time: 66.5 h

Procedure:
To a stirred solution of 4-chloro-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinoline (0.10 g, 0.32 mmol) in DMF (2 mL) was added 4,4-difluoropiperidine hydrochloride (0.056 g, 0.36 mmol) followed by potassium carbonate (0.090 g, 0.65 mmol). The reaction was stirred at 100° C. and stirring continued for 66.5 h. After which, the reaction mixture was cooled to rt and water was added. The crude reaction mixture was extracted with EtOAc and dried over magnesium sulfate and concd in vacuo. The crude material was purified on silica gel, eluting with 0-30% EtOAc in hexanes to provide 4-chloro-2-(6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-5,7-difluoro-3-methylquinoline as a brown solid. Mass Spectrum (ESI) m/e=410.0 (M+1).
Reaction SMILES: C(/N=[CH:6]/[C:7]1[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:15])CCC.S(=O)(=O)(O)[OH:17]>O.C(OCC)(=O)C>[Cl:15][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][CH3:14])[C:7]=1[CH:6]=[O:17]
Reactant: CCCC/N=C/c1c(Cl)cccc1CC
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cccc(Cl)c1C=O
Temperature: 25 °C
Yield: 77 %

Procedure:
To a solution of 19.7 g (88.1 mmol) butyl-[1-(2-chloro-6-ethyl-phenyl)-meth-(E)-ylidene]-amine in 70 ml water at 0° C. was added dropwise 18.9 ml concentrated sulphuric acid. The mixture was then heated at reflux for 90 min before being cooled to room temperature and diluted with ethyl acetate. The mixture was then washed sequentially with water, saturated aqueous sodium bicarbonate solution, and saturated brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate/heptane 1:30) to afford 11.4 g (77%) of the title compound as a yellow oil. 1H-NMR (CDCl3): 1.22 (3H, t, CH3), 2.97 (2H, q, CH2), 7.20 (1H, d, ArH), 7.30 (1H, d, ArH), 7.39 (1H, dd, ArH), 10.65 (1H, s, CHO).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH:6]([O:9][P:10]([CH:16]([CH:18]=[O:19])[CH3:17])(=[O:15])[O:11][CH:12]([CH3:14])[CH3:13])([CH3:8])[CH3:7]>C(Cl)(Cl)(Cl)Cl>[CH:12]([O:11][P:10]([C:16]([CH:18]=[O:19])([Cl:4])[CH3:17])(=[O:15])[O:9][CH:6]([CH3:7])[CH3:8])([CH3:13])[CH3:14]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)OP(=O)(OC(C)C)C(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)OP(=O)(OC(C)C)C(C)(Cl)C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
At 10° C., a solution of 14 g (0.104 mole) of sulfuryl chloride in 50 ml of carbon tetrachloride is dripped into a solution of 22.2 g (0.1 mole) of α-formylethanephosphonic acid diisopropyl ester in 150 ml of carbon tetrachloride. The reaction mixture is stirred for 3 hours at room temperature and the solvent is then distilled off under reduced pressure. The residue is taken up in ether, washed with 5% sodium bicarbonate solution and then with saturated sodium chloride solution, and dried over sodium sulfate. The ether is stripped off under reduced pressure. There is obtained 24 g (93.5% of theory) of α-formyl-α-chloroethanephosphonic acid diisopropyl ester.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([C:7]1[CH:22]=[CH:21][C:10]2[O:11][C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[CH2:14][C:15](=[O:16])[C:9]=2[CH:8]=1)[CH3:6])C.[OH-].[K+]>C(O)C.O>[O:16]=[C:15]1[CH2:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][C:10]2[CH:21]=[CH:22][C:7]([CH:5]([CH3:6])[C:4]([OH:23])=[O:3])=[CH:8][C:9]1=2
Reactant: CCOC(=O)C(C)c1ccc2c(c1)C(=O)Cc1ccccc1O2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1ccccc1O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
To 151 mg of ethyl2-(10,11-dihydro-11-oxo dibenzo[b,f]-oxepin-2-yl)-propionate in 2ml of ethanol was added 400 mg of potassium hydroxide in 2 ml of water and the mixture was stirred at room temperature for 0.5 hour. After the completion of the reaction, to this was added water and the mixture was extracted with benezene. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain pale brown oil, which was chromatographed over silica gel, eluted with chloroform and there was obtained 112 mg of 2-(10,11-dihydro-11-oxo dibenzo[b,f]oxepin-2-yl)-propionic acid as pale yellow oil. This was crystallized from the mixed solvent of ethyl acetate-n-hexane to give pale yellow crystals having a melting point of 156°-157° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[C:22]([Cl:24])[C:21]([NH2:25])=[CH:20][C:19]=4[F:26])=[C:11]3[C:10]([NH:27][CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[N:9]2)=[CH:5][CH:4]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]2[C:49](=[O:50])[C:48]([C:51](O)=[O:52])=[CH:47][CH:46]=[N:45]2)=[CH:40][CH:39]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[C:19]([F:26])=[CH:20][C:21]([NH:25][C:51]([C:48]5[C:49](=[O:50])[N:44]([C:41]6[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=6)[N:45]=[CH:46][CH:47]=5)=[O:52])=[C:22]([Cl:24])[CH:23]=4)=[C:11]3[C:10]([NH:27][CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[N:9]2)=[CH:35][CH:36]=1
Reactant: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4cc(Cl)c(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4cc(Cl)c(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.1 %

Procedure:
A solution of 1-(4-methoxybenzyl)-4-(4-amino-5-chloro-2-fluorophenoxy)-N-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (130 mg, 0.254 mmol) in CH2Cl2 (1 mL) was added into a solution of 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (119 mg, 0.509 mmol, obtained from Example 19 Step C), triethylamine (0.213 ml, 1.53 mmol), EDCI (293 mg, 1.53 mmol) and HOBT (206 mg, 1.53 mmol) in CH2Cl2 (2 mL). The reaction mixture was stirred for 12 hours at ambient temperature. The reaction was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 and brine. The organic layer obtained was dried with Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (5% MeOH in CH2Cl2) to afford the product (100 mg, 54.1% yield) as a yellow solid. LRMS (APCI pos) m/e 727.2 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-])=O.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br.ClC1C2C=C(N(C)C)N=CC=2N=CN=1.N>C(O)C.ClCCl>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][O:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Fc1cccc(CBr)c1
Agent: CN(C)c1cc2c(Cl)ncnc2cn1
Agent: N
Solvent: CCO
Solvent: ClCCl
Product: Nc1ccc(OCc2cccc(F)c2)cc1

Procedure:
4-(3-Fluorobenzyloxy)aniline was prepared from 4-nitrophenol (Aldrich) and 3-fluorobenzylbromide (Aldrich) according to Procedure D. This was reacted with 4-chloro-6-(N,N-dimethylamino)pyrido[3,4-d]pyrimidine according to Procedure A to give the product; tic (dichloromethane:ethanol:aq.ammonia, 100:8:1) Rf 0.48; m/z (M+1 )+390.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[C:4]2[N:9]([Si](C(C)(C)C)(C)C)[CH:10]=[CH:11][C:3]=12.C([Li])(C)(C)C.[C:24](=[O:26])=[O:25]>O1CCCC1>[Cl:8][C:5]1[C:4]2[NH:9][CH:10]=[CH:11][C:3]=2[C:2]([C:24]([OH:26])=[O:25])=[CH:7][N:6]=1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2c(Br)cnc(Cl)c21
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)c2[nH]ccc12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-bromo-1-(tert-butyl-dimethyl-silanyl)-7-chloro-1H-pyrrolo[2,3-c]pyridine (500 mg) in dry tetrahydrofuran (25 ml) at −78° C. under an atmosphere of nitrogen was added tert-butyllithium (1.7M in pentane, 1.88 ml). After addition, the reaction mixture was stirred for 15 minutes at −78° C. then poured onto crushed pellets of carbon dioxide. The mixture was allowed to warm to room temperature and then evaporated. The residue was dissolved in water and the aqueous washed twice with diethyl ether. The aqueous was then acidified with 2M hydrochloric acid and extracted twice with ethyl acetate. The organic layer was dried (MgSO4) and evaporated to give the title compound as a yellow solid (120 mg).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]2[CH:17]=[C:18]([C:20]([O-])=[O:21])[S:19][C:12]=12.[Li+]>>[N:1]1([CH2:7][CH2:8][NH:9][C:20]([C:18]2[S:19][C:12]3[C:13](=[N:14][CH:15]=[CH:16][C:11]=3[Cl:10])[CH:17]=2)=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCN1CCCCC1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: O=C(NCCN1CCCCC1)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from 2-piperidin-1-yl-ethyl amine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 324/326 (MH+); HPLC Rf: 3.64 min.; HPLC purity 93%.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[C:25]([Cl:32])[CH:24]=1.O>CN(C)C=O>[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([C:15]2[C:8]3[NH:7][C:6]4[N:1]=[CH:2][CH:3]=[CH:4][C:5]=4[CH2:11][NH:10][C:9]=3[CH:12]=[CH:13][CH:14]=2)=[O:28])=[C:25]([Cl:32])[CH:24]=1
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: O=C(Cl)c1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Br)cc1Cl)c1cccc2c1Nc1ncccc1CN2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.9 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5] benzodiazepine (3 g, 15.2 mmol) in N,N-dimethylformamide under nitrogen were added solid potassium carbonate (6.3 g, 45.6 mmol). The mixture was treated dropwise with a solution of the crude 4-bromo-2-chlorobenzoyl chloride (22.9 mmol) in N,N-dimethylformamide. After stirring at room temperature for 15 minutes, water was added under stirring. The resulting solid was collected, dissolved in chloroform, and the solution washed with 1N NaOH and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue (purple foam) was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with 20% ethyl acetate in hexane provided 3.4 g of the title compound as a foam which crystallized as a white solid by trituration from ethanol-ether, m.p. 165-168° C.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[C:6]([C:16]([OH:18])=O)=[CH:5]1)([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:55][C:56]1[S:57][CH:58]=[CH:59][N:60]=1>C(Cl)Cl>[S:57]1[CH:58]=[CH:59][N:60]=[C:56]1[NH:55][C:16]([C:6]1[C:7]2[C:12](=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:18]
Reactant: Nc1nccs1
Reactant: CC(C)n1cc(C(=O)O)c2ccc([N+](=O)[O-])cc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)n1cc(C(=O)Nc2nccs2)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 4.9 %

Procedure:
A solution of 1-isopropyl-6-nitro-1H-indole-3-carboxylic acid (200 mg, 0.81 mmol) in methylene chloride (4 mL) and N,N-diisopropylethylamine (0.32 mL, 1.85 mmol) at 25° C. was treated with benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluoro-phosphate (463 mg, 1.05 mmol). The reaction was stirred at 25° C. for 20 min. At this time, the reaction was treated with 2-aminothiazole (186 mg, 1.85 mmol) and was stirred at 25° C. for 24 h. At this time, the reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL) and was treated with a 1N aqueous hydrochloric acid solution (25 mL). The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dissolved in a hot solution of 1/1 hexanes/ethyl acetate and then filtered. The filtrate was cooled in the freezer for 1 h. At this time, the resulting solid was collected by filtration. The filtrate was concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 1-isopropyl-6-nitro-1H-indole-3-carboxylic acid thiazol-2-ylamide (13 mg, 4.9%) as a yellow solid: mp 236-239° C.; EI-HRMS m/e calcd for C15H14N4O3S (M+) 330.0786, found 330.0792.
Reaction SMILES: [OH-].[K+].[OH:3][NH:4]C(=O)OC(C)(C)C.[N+]([C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:16]=1[C:17]#[N:18])([O-])=O.O>CN(C=O)C>[NH2:18][C:17]1[C:16]2[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][CH:21]=[CH:22][C:15]=2[O:3][N:4]=1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NO
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1noc2cccc([N+](=O)[O-])c12
Reaction time: 20 h
Yield: 21.7 %

Procedure:
To potassium hydroxide (0.58 g, 10.3 mmol) and tert-butyl N-hydroxycarbamate (1.38 g, 10.3 mmol) in DMF (30 iml) was added 2,6-dinitrobenzonitrile (2.0 g, 10.3 nmmol) and the mixture was stirred for 20 h. Water was added. The whole was extracted with ether, the ether was dried (sodium sulphate) and evaporated. Flash column chromatography on silica gel, eluting with ethyl acetate/dichloromethane, gave the product (0.4 g), MS (+CI) 180 ([M+H]+), 1H NMR (CDCl3) 8.13 (1H, d), 7.78 (1H, d), 7.68 (1H, dd), 5.43 (2H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([F:27])[CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[N:34]=[CH:35][S:36][CH:37]=1)CCC.[Cl-].[Li+]>O1CCOCC1.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>[F:27][C:19]1[CH:18]=[C:17]([N:9]2[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([C:33]3[N:34]=[CH:35][S:36][CH:37]=3)=[CH:3][CH:4]=2)[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(Br)cc2)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(-c3cscn3)cc2)cc1F
Yield: 87.5 %

Procedure:
To a stirred solution of 2-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole (0.361 g, 0.78 mmol) in 1,4-dioxane (12 mL) was added 4-(tributylstannyl)thiazole (0.35 g, 0.94 mmol ), lithium chloride (0.083 g, 1.95 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.090 g, 0.078 mmol) at room temperature under nitrogen. The mixture was heated at reflux temperature for 3 hours. After cooling, volatiles were removed by evaporation. The residue was redissolved in ethyl acetate (30 mL) and the whole washed with water and brine. After dried over MgSO4 and concentration in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (3/1). The resulting solid was recrystallized from ethyl acetate-hexane to give the title compound (0.319 g, 87.6% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([CH:20]=[CH:21][CH:22]=3)[C:14]([NH:16][CH:17]3[CH2:19][CH2:18]3)=[O:15])[C:6]=2[N:7]=1.Cl[C:24]1[N:29]=[C:28]([CH3:30])[N:27]=[C:26]([N:31]2[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][OH:39])[CH2:33][CH2:32]2)[CH:25]=1>>[CH:17]1([NH:16][C:14](=[O:15])[C:13]2[CH:20]=[CH:21][CH:22]=[C:11]([C:8]3[C:6]4[N:7]=[C:2]([NH:1][C:24]5[CH:25]=[C:26]([N:31]6[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][OH:39])[CH2:33][CH2:32]6)[N:27]=[C:28]([CH3:30])[N:29]=5)[N:3]=[CH:4][C:5]=4[S:10][CH:9]=3)[CH:12]=2)[CH2:18][CH2:19]1
Reactant: Nc1ncc2scc(-c3cccc(C(=O)NC4CC4)c3)c2n1
Reactant: Cc1nc(Cl)cc(N2CCN(CCO)CC2)n1
Product: Cc1nc(Nc2ncc3scc(-c4cccc(C(=O)NC5CC5)c4)c3n2)cc(N2CCN(CCO)CC2)n1
Yield: 47.1 %

Procedure:
N-Cyclopropyl-3-(2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thieno[3,2-d]pyrimidin-7-yl)benzamide (16 mg, 47% yield) was prepared in the same manner as Step 10 of Example 1 using 3-(2-aminothieno[3,2-d]pyrimidin-7-yl)-N-cyclopropylbenzamide (20 mg, 0.064 mmol) and 2-(4-(6-chloro-2-methylpyrimidin-4-yl)piperazin-1-yl)ethanol (17 mg, 0.064 mmol).