Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:14].B(Br)(Br)Br>ClCCl>[CH3:14][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH2:9][C:10]([F:11])([F:12])[F:13])[C:3]=1[OH:2]
Reactant: COc1c(C)cccc1CC(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cccc(CC(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.3 %

Procedure:
2-Methoxy-1-methyl-3-(2,2,2-trifluoro-ethyl)-benzene(6.0 g) was dissolved in dichloromethane (100 ml) and BBr3 (100 ml) added. The reaction was allowed to stir at room temperature for 12 hrs, after which time it was quenched slowly with cHCl. The mixture was then made basic with 2N NaOH solution and the organics discarded. The aqueous was acidified with 1N HCl and the product extracted with ethyl acetate to afford the title compound as a brown oil (4.43 g). LCMS: APCI−VE=189
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([NH:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([NH:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH:24][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(F)c4)n3n2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CS(=O)(=O)N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(F)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of trans-N1-(3-(3-fluorophenyl)imidazo[1,2-b]pyridazin-6-yl)cyclohexane-1,4-diamine (180 mg, 0.55 mmol) and DIPEA (213.2 mg, 1.65 mol) in DMSO (2.8 mL) was added dropwise MeSO2Cl (63.4 mg, 0.55 mmol). The resulting mixture was stirred at room temperature overnight. LCMS showed most of starting material was converted. The mixture was partitioned between brine (100 mL) and EtOAc (50 mL) and separated. The aqueous layer was extracted with EtOAc (50 mL*3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give EX. 8-89 (13 mg, 6%) as a brown solid.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.[C:18]1([CH3:27])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>>[CH3:27][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2
Reactant: BrC=C1c2ccccc2CCc2ccccc21
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1C=C1c2ccccc2CCc2ccccc21

Procedure:
Combine 5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.5 g, 1.75 mmol) and o-tolylboronic acid (0.238 g, 1.75 mmol) using procedures essentially as described in Example 219, below. Pass through a plug of silica gel equilibrated with hexanes. Concentrate the filtrate to give the title product: MS (m/e) 296 (M+); Analysis for C23H20: Calcd: C, 93.19 H, 6.80. Found: C, 93.42 H, 6.79.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH2:30][CH2:31][CH3:32])=[O:28])=[C:22]([Cl:33])[CH:21]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:34][CH3:35])C1C=CC=CC=1.CS(O)(=O)=O>FC(F)(F)C(O)=O>[Cl:33][C:22]1[CH:21]=[C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:34][CH3:35])[CH:11]=3)[N:16]=[CH:15][N:14]=2)[CH:25]=[CH:24][C:23]=1[NH:26][C:27]([NH:29][CH2:30][CH2:31][CH3:32])=[O:28]
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCc4ccccc4)c(OC)cc23)cc1Cl
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(O)c(OC)cc23)cc1Cl
Temperature: 100 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-N′-propylurea (42.2 g) was dissolved in trifluoroacetic acid (200 ml). Methanesulfonic acid (11.1 ml) was then added to the solution, and the mixture was stirred at 100° C. for 4 hr. The reaction solution was cooled to room temperature, and trifluoroacetic acid was removed by distillation under the reduced pressure. Chloroform and methanol were added to the mixture as the residue, followed by extraction with a 10% aqueous sodium hydroxide solution three times. The aqueous layer was neutralized with concentrated hydrochloric acid to precipitate a solid. The solid was washed with water, methanol, and ether in that order, and was then dried in vacuo through a vacuum pump to give 20.7 g (yield 60%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]#[C:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:8][C:9]=1[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].C[N:25]1C(=O)CCC1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]#[C:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:8][C:9]=1[N:10]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[NH2:25])=[O:4]
Reactant: CN1CCCC1=O
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1NC(=O)OC(C)(C)C
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(N)C(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
To a solution of 3-tert-butoxycarbonylamino-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (4.3 g, 12.8 mmol) in NMP (64 mL) was added K-OtBu (1.6 g, 14.1 mmol). After 10 min a solution of 0-4-nitrobenzoylhydroxylamine (3.0 g, 16.6 mmol) in NMP (16 mL) was added dropwise and the reaction was allowed to stir for 16 h. The reaction was quenched with LiCl solution (5% in water, 50 mL) and diluted with EtOAc (50 mL). The crude product was washed 3×50 mL with 5% LiCl solution, dried over Na2SO4, and purified by silica gel chromatography 0-30% EtOAc/hexanes to give 3-(N-tert-butoxycarbonyl-hydrazino)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (2.6 g, 7.4 mmol).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([NH2:22])=[CH:11][CH:10]=1)C1C=CC=CC=1.CO[C:25](OC)(OC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([C:25]2[N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:22]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccc(OCc2ccccc2)nc1Nc1ccccc1
Reactant: COC(OC)(OC)c1ccccc1
Product: Oc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2n1

Procedure:
From 6-(benzyloxy)-N2-phenylpyridine-2,3-diamine and trimethyl orthobenzoate, prepared in a similar manner as the one described in Example 1.117, the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.61 (d, J=8.3 Hz, 1H), 7.29-7.57 (m, 10H), 8.00 (d, J=8.6 Hz, 1H), 11.07 (broad s, 1H).
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH2:16]([N:18]1[C:24]2[CH:25]=[C:26]([F:30])[C:27]([NH2:29])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20][CH2:19]1)[CH3:17].Cl[C:32]1[N:37]=[C:36]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:41][C:40]=2[O:51][CH3:52])[C:35]([Cl:53])=[CH:34][N:33]=1.C(=O)([O-])[O-]>C(O)(C)C.C(Cl)Cl>[Cl:53][C:35]1[C:36]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH2:46][CH2:47][O:48][CH2:49][CH2:50]3)=[CH:41][C:40]=2[O:51][CH3:52])=[N:37][C:32]([NH:29][C:27]2[C:26]([F:30])=[CH:25][C:24]3[N:18]([CH2:16][CH3:17])[CH2:19][CH2:20][CH2:21][O:22][C:23]=3[CH:28]=2)=[N:33][CH:34]=1
Reactant: CCN1CCCOc2cc(N)c(F)cc21
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCN1CCCOc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)c(F)cc21
Reaction time: 1 h

Procedure:
10-Camphorsulfonic acid (70.5 mg, 0.303 mmol) was added to 9-Ethyl-2-fluoro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamine (58 mg, 0.28 mmol) and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (98 mg, 0.28 mmol) in Isopropyl alcohol (2 mL). The mixture was irradiated in a CEM microwave (140° C., 30 min). MP-Carbonate (2.69 mmol/g loading; 0.21 g, 0.57 mmol) and DCM (2 mL) were added and the mixture stirred for 1 h, then filtered onto a 5 g SiO2 cartridge, which which was air dried. The sample was chromatographed (ISCO, 2×12 g SiO2, 0-50% EtOAc:Hex) to afford 5-Chloro-N*2*-(9-ethyl-2-fluoro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-yl)-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine as a lavender film (43 mg, 29%). LCMS 529 (M+H), 1H-NMR (CDCl3): 8.23 (d, 1H, J=8.7 Hz), 8.00 (s, 1H), 7.77 (d, 1H, J=8.7 Hz), 7.58 (s, 1H), 6.75 (s, 1H), 6.60 (d, 1H, J=13.2 Hz), 6.55 (m, 2H), 4.08 (t, 2H, J=5.6 Hz), 3.91 (s, 3H), 3.88 (t, 4H, J=4.6 Hz), 3.17 (m, 8H), 1.98 (m, 2H), 1.21 (t, 3H, J=7.0 Hz); 19F-NMR: −135.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:22][CH2:23][CH2:24]O)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:26]1[CH:30]=[N:29][CH:28]=[N:27]1>>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:22][CH2:23][CH2:24][N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1nc[nH]n1
Reactant: OCCCc1ccccc1OCc1coc(/C=C/c2ccccc2)n1
Product: C(=C/c1nc(COc2ccccc2CCCn2cncn2)co1)\c1ccccc1
Yield: 54 %

Procedure:
In substantially the same manner as in Working Example 1, 3-[2-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol was allowed to react with 1,2,4-triazole to give 1-[3-[2-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-1,2,4-triazole. The yield was 54%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 72-73° C.
Reaction SMILES: [CH:1]([S:4]([CH2:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[N:9]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34]>O1CCOCC1>[CH:1]([S:4]([CH2:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:33](=[O:34])[O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:24][CH:25]=2)[N:9]=1)(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)S(=O)(=O)Cc1cc(N2CCOCC2)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)Cc1cc(N2CCOCC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
(4-{4-[(Isopropylsulfonyl)methyl]-6-morpholin-4-ylpyrimidin-2-yl}phenyl)amine (1.5 g, 3.98 mmol) was dissolved in dioxane (10 mL). Sodium bicarbonate (503 mg, 5.98 mmol) was added, followed by phenyl chloroformate (0.502 mL, 3.98 mmol) and the reaction stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the resultant oil partitioned between 10 mL DCM and 10 mL water. The organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo. The cream solid obtained was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM, to give the desired material as a white solid (1.5 g).
Reaction SMILES: Cl.CC(OC([N:9]1[C:17]2[C:12](=[C:13]([F:21])[CH:14]=[CH:15][C:16]=2[C:18]([OH:20])=[O:19])[CH2:11][CH2:10]1)=O)(C)C>C(Cl)Cl>[F:21][C:13]1[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[C:17]2[C:12]=1[CH2:11][CH2:10][NH:9]2
Reactant: CC(C)(C)OC(=O)N1CCc2c(F)ccc(C(=O)O)c21
Agent: Cl
Solvent: ClCCl
Product: O=C(O)c1ccc(F)c2c1NCC2
Reaction time: 2 h

Procedure:
A solution of 1 M HCl (1 mL, 1 mmol) was added to a solution of 1-{[(1,1-Dimethylethyl)oxy]carbonyl}-4-fluoro-2,3-dihydro-1H-indole-7-carboxylic acid (50 mg, x mmol) in DCM at room temperature. The reaction was stirred for 2 h, and additional 1 M HCl (1 mL, 1 mmol) was added. The reaction was stirred overnight, and the mixture was evaporated and dried under high vacuum, giving the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[F:17][CH:18]([F:24])[C:19]([F:23])([F:22])[CH2:20]I>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:20][C:19]([F:23])([F:22])[CH:18]([F:24])[F:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: FC(F)C(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCC(F)(F)C(F)F)cc1
Temperature: 105 °C
Yield: 71.1 %

Procedure:
To a solution of 4-nitro phenol (860 mg, 6.1 mmol) in DMF (10 ml) was added potassium carbonate (1.4 g, 10 mmol) and 1,1,2,2-tetrafluoro-3-iodo-propane (500 mg, 2 mmol). The reaction mixture was heated at 100-110° C. for 6 hr, then cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (100 ml), then washed once with 5% sodium hydroxide solution, several times with water, and finally brine. The organic layer was then dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 1-nitro-4-(2,2,3,3-tetrafluoro-propoxy)-benzene (360 mg, 68%) as solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.B(O)(O)[C:24]1[CH:29]=[CH:28][C:27](C(O)=O)=[CH:26][CH:25]=1>>[CH2:15]([C:11]1([CH2:17][CH2:18][OH:19])[C:8]2[NH:9][C:10]3[C:6]([C:7]=2[CH2:14][CH2:13][O:12]1)=[CH:5][C:4]([CH:20]([CH3:22])[CH3:21])=[CH:3][C:2]=3[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:16]
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: CCC1(CCO)OCCc2c1[nH]c1c(-c3ccccc3)cc(C(C)C)cc21

Procedure:
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 4-carboxylphenylboronic acid in step 1 F.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:20]4[C:21]5[S:28][C:27]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)=[CH:26][C:22]=5[N:23]=[CH:24][N:25]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=O)=O)C=CC=CC=1.[CH2:35]([N:37]([CH:40](O)[CH2:41][CH3:42])[CH2:38][CH3:39])[CH3:36]>>[CH2:35]([N:37]([CH2:38][CH3:39])[CH2:40][CH2:41][CH2:42][N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[C:21]4[S:28][C:27]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:26][C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1)[CH3:36]
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Nc3ncnc4cc(-c5ccccc5)sc34)ccc21
Reactant: CCC(O)N(CC)CC
Product: CCN(CC)CCCn1ccc2cc(Nc3ncnc4cc(-c5ccccc5)sc34)ccc21

Procedure:
The title compound was prepared from [1-benzenesulfonyl-1H-indol-5-yl]-(6-phenyl-thieno[3,2-d]pyrimidin-4-yl )-amine (246 mg, 1.00 mmol) and diethylamino-propanol (120 mg, 0.939 mmol) by a procedure analogous to example 69. RP18-HPLC RT: 4.55 minutes; API MS: 455.63 (M+1) MP: 178-180° C.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2[N:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]1=[O:17].[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[CH2:25]([O:24][C:22]([CH2:21][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:17])[C:4]2[CH:16]=[CH:15][CH:14]=[N:13][C:5]1=2)=[O:23])[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: CN1C(=O)c2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1c2ccccc2N(C)C(=O)c2cccnc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 18.2 %

Procedure:
To 1.0 g (4.4 mmoles) of 5,6-dihydro-6-methyl-11H-pyrido[2,3-b][1,5]benzodiazepin-5-one in 50 ml of dimethylformamide was added 0.25 g (5 mmol) of 50% sodium hydride in oil. The reaction mixture was then stirred at 50° C. for an additional 2 h and then 0.6 ml (5 mmol) of ethyl bromoacetate was added. The reaction mixture was then stirred at 50° C. for an additional 3 h. It was then cooled to room temperature and the solvent was evaporated. The residue was dissolved in methylene chloride, washed with water, dried over anhydrous sodium sulfate and evaporated to obtain 2.0 g of the crude product. It was further purified by column chromatography (silica gel) using 10% ethyl acetate/methylene chloride as eluent to obtain 250 mg of pure 5,6-dihydro-11-(ethoxy-carbonyl)methyl-6-methyl-11H-pyrido[2,3-b][1,5]benzodiazepin-5-one, m.p. 99°-100° C.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[C:55]([C:59]1[CH:60]=[C:61]([C:69](=[O:71])[CH3:70])[CH:62]=[C:63]([O:66][CH2:67][CH3:68])[C:64]=1[OH:65])([CH3:58])([CH3:57])[CH3:56]>C(Cl)Cl.CO>[Br:1][CH2:70][C:69]([C:61]1[CH:62]=[C:63]([O:66][CH2:67][CH3:68])[C:64]([OH:65])=[C:59]([C:55]([CH3:56])([CH3:58])[CH3:57])[CH:60]=1)=[O:71]
Reactant: [Br-]
Reactant: CCOc1cc(C(C)=O)cc(C(C)(C)C)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: CCOc1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
Tetra-n-butylammonium tribromide (321 mg, 0.666 mmol) was added to a solution of the 1-[3-(tert-butyl)-5-ethoxy-4-hydroxyphenyl]-1-ethanone (150 mg, 0.635 mmol) in methylene chloride-methanol (4 ml:1 ml) and the mixture was stirred at room temperature for 8 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (60 mg) as colorless crystals.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:34])[CH2:7][CH:8]([N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([CH2:22][C:23]2[C:24]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:25]=3[S:26][CH:27]=2)[C:14]1=[O:33])[CH2:9][C:10]([OH:12])=[O:11].Cl>O.CO>[CH3:32][C:31]1[C:24]2[C:23]([CH2:22][N:15]3[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:13]([CH:8]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][C:6]([OH:34])=[O:5])[C:14]3=[O:33])=[CH:27][S:26][C:25]=2[CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)CC(CC(=O)O)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cccc2scc(Cn3c(=O)n(C(CC(=O)O)CC(=O)O)c4ccccc43)c12
Reaction time: 2 h
Yield: 86.8 %

Procedure:
Lithium hydroxide monohydrate (7.2 mg, 0.17 mmol) is dissolved in water (1.0 mL) and it is added into the solution of 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-pentanedioic acid monomethyl ester (25 mg, 0.057 mmol) in methanol (1.0 mL) at room temperature. The mixture is stirred for 2 hr and then 1.0 M HCl solution (0.5 mL) is added along with water (10 mL). The mixture is extracted with EtOAc (3×10 mL) and the organic layers are combined, dried over MgSO4 and concentrated to give crude product. Purification by preparative TLC using 5% MeOH in CH2Cl2 with 1% acetic acid afforded 21 mg (87%) of 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-pentanedioic acid. LCMS (ESMS): m/z 425.22 (M+H+).
Reaction SMILES: CC1(C)[N:6]2[C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH2:9][C@@H:5]2[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:3][CH2:4][C@@H:5]1[NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH2:9]1
Reactant: CC1(C)C[C@@H]2COC(C)(C)N2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC1(C)C[C@H](CO)NC1=O
Yield: 90.1 %

Procedure:
Prepared according to WO patent: 2013004290. To a solution of (R)-3,3,6,6-tetramethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (4.13 g, 22.54 mmol) in MeOH (90 mL) was added p-toluenesulfonic acid monohydrate (0.429 g, 2.254 mmol). The resulting mixture was heated at reflux for 2 h. The solvent was removed under reduced pressure (rotary evaporator) and the crude material was absorbed onto a plug of silica gel and purified by chromatography on an ISCO Combiflash™ RF (40 g Grace Reverlis column, using a gradient of 0-20% MeOH in DCM) affording (R)-5-(hydroxymethyl)-3,3-dimethylpyrrolidin-2-one (2.91 g, 20.31 mmol, 90% yield) as a white semi-solid. MS (ESI) 144.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[C:18]([CH3:29])[CH:17]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(N(CC)CC)C>C1COCC1>[CH3:29][C:18]1[CH:17]=[C:16]([NH:15][C:8]2[C:7]3[C:12](=[CH:13][CH:14]=[C:5]([CH:4]=[CH:3][CH2:2][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:6]=3)[N:11]=[CH:10][N:9]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cc(Nc2ncnc3ccc(C=CCCl)cc23)ccc1Oc1cccnc1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(Nc2ncnc3ccc(C=CCN4CCOCC4)cc23)ccc1Oc1cccnc1
Temperature: 85 °C

Procedure:
To a suspension of 0.035 g (0.091 mmol) of 3-{4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-en-1-ol in 0.5 mL of methylene chloride and 1 mL of ethylene dichloride was added 1 mL of thionyl chloride. The reaction was heated at 100° C. for 1 hour and the solvents were evaporated to provide [6-(3-chloro-propenyl)-quinazolin-4-yl]-[3-methyl-4-(pyridin-3-yloxy)-phenyl]-amine [MS: M+ 403.1] which was dissolved in THF and used directly in the next reaction. To the solution of [6-(3-chloro-propenyl)-quinazolin-4-yl]-[3-methyl-4-(pyridin-3-yloxy)-phenyl]-amine was added 0.10 mL of morpholine and 0.044 mL of triethylamine. The mixture was heated at 85° C. for 16 hours, cooled to room temperature, and partitioned between 10% aqueous potassium carbonate and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and the combined organics were dried and evaporated to yield 57 mg of material. The product was purified on a silica gel prep plate, eluting with 96:4:0.1 chloroform/methanol/concentrated ammonium hydroxide to afford 26 mg of the title compound; 1H NMR (CDCl3): δ 8.71 (s, 1), 8.33 (m, 2), 7.94 (s, 1), 7.80 (m, 2), 7.69 (s, 1), 7.58 (m, 1), 7.20 (m, 1), 6.94 (d, J8.7 Hz, 1), 6.68 (d, J=15.8 Hz, 1), 6.46 (m, 1), 3.79 (m, 4), 3.26(m, 2), 2.63 (m, 4), 2.25 (s, 3).
Reaction SMILES: C([N:20]1[C:24]2=[N:25][CH:26]=[CH:27][C:28]([C:29]3[S:30][CH:31]=[C:32]([CH2:34][C:35]#[N:36])[N:33]=3)=[C:23]2[CH:22]=[N:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:20]1[C:24]2=[N:25][CH:26]=[CH:27][C:28]([C:29]3[S:30][CH:31]=[C:32]([CH2:34][C:35]#[N:36])[N:33]=3)=[C:23]2[CH:22]=[N:21]1
Reactant: N#CCc1csc(-c2ccnc3c2cnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCc1csc(-c2ccnc3[nH]ncc23)n1
Yield: 15.7 %

Procedure:
A solution of 2-[2-(1-tritylpyrazolo[5,4-b]pyridin-4-yl)thiazol-4-yl]acetonitrile (83 mg, 0.1716 mmol) in DCM (3 ml) was treated with triethylsilane (0.5 ml) followed by TFA (0.5 mL). After 15 minutes the mixture was concentrated in vacuo and purified by column chromatography (70:9:1 DCM/MeOH/NH4OH) to give the product as a light tan solid (6.5 mg, 16% Yield). 1H NMR (DMSO, 400 MHz) δ 4.37 (2H, s), 7.72 (1H, d), 7.94 (1H, s), 8.63 (1H, s), 8.66 (1H, d), 13.98 (1H, br s); MS (ES+) 242.00