Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=4)C=C3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O>O1CCCC1.FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:22]3[CH:17]=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=3)[CH2:10][CH2:9]2)=[CH:24][CH:25]=1
Reactant: Fc1ccc(CCN2CCC(n3ccc4ccc(Br)cc43)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(CCN2CCC(Nc3cccc(Br)c3)CC2)cc1
Reaction time: 3 h
Yield: 54.5 %

Procedure:
Under ice cooling, a 1 M solution (20 ml) of a borane/tetrahydrofuran complex in tetrahydrofuran was added dropwise into a solution of 1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-bromoindole (3.9 g) in trifluoroacetic acid (50 ml) followed by stirring for 3 hr. After adding water thereto and concentrating under reduced pressure, the reaction mixture was basified by adding ethanol and a 5 N aqueous solution of sodium hydroxide and then stirred for 30 min. Next, a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added thereto and the layers were separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The residue was then purified by silica gel column chromatography (toluene/acetone system) to give the title compound (2.0 g) as a white powder (yield: 51%).
Reaction SMILES: I[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[OH:32][C:33]1[N:34]([CH3:38])[CH:35]=[CH:36][N:37]=1>C(=O)([O-])[O-].[Ag+].[Ag+].C1C=CC=CC=1>[CH3:29][O:28][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:30][CH3:31])[N:4]=[C:3]([CH2:2][O:32][C:33]1[N:34]([CH3:38])[CH:35]=[CH:36][N:37]=1)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1
Reactant: CCOC(=O)c1c(CI)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: Cn1ccnc1O
Agent: [Ag+]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: CCOC(=O)c1c(COc2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 9.4 %

Procedure:
A mixture of ethyl 2-iodomethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (9.0 g), 2-hydroxy-1-methylimidazole (1.8 g), silver (I) carbonate (Ag2CO3)(5.1 g) and benzene (100 ml) was stirred at 50° C. for 18 hours. The insoluble solid was filtered off. The filtrate was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residual oil was subjected to column chromatography on silica gel. The fractions eluted with chloroform/ethyl acetate (5/1, v/v) gave ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[(1-methyl-2-imidazolyl)oxymethyl]quinoline-3-carboxylate (0.8 g, 9%) which was then recrystallized from ethyl acetate-hexane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=1)=[O:30]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)=[O:30])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C(Cl)OCc1cccc(Cl)c1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1cccc(Cl)c1

Procedure:
Prepared according to the procedure described in Example 56, Step 2, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 3-chlorobenzyl chloroformate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[CH2:9][CH2:8]1>[Pd].CO>[NH:10]1[CH2:11][CH2:12][CH:7]([C@H:5]2[CH2:6][C@H:4]2[CH2:3][CH2:2][OH:1])[CH2:8][CH2:9]1
Reactant: O=C(OCc1ccccc1)N1CCC([C@H]2C[C@H]2CCO)CC1
Agent: [Pd]
Solvent: CO
Product: OCC[C@@H]1C[C@@H]1C1CCNCC1

Procedure:
Benzyl 4-((1R,2S)-2-(2-hydroxyethyl)cyclopropyl)piperidine-1-carboxylate (75.0 g, 247 mmol) and palladium on activated carbon (10%, wet, 10.0 g) in methanol (1000 mL) were stirred under an atmosphere of hydrogen (1 atm) at RT for 48 h. The mixture was filtered through Celite® and the filter cake washed with methanol. The filtrate was concentrated to dryness under reduced pressure to afford the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ 3.74 (m, 2H), 3.15-3.05 (m, 2H), 2.56 (m, 2H), 1.91-1.87 (m, 2H), 1.76-1.72 (m, 3H), 1.36-1.28 (m, 3H), 0.92-0.87 (m, 1H), 0.84-0.76 (m, 1H), 0.67-0.61 (m, 1H), 0.60-0.56 (m, 1H), −0.18 (q, J=4.5 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]([O:21]C(C)(C)C)=[O:20]>CC#N>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][CH2:18][C:19]([OH:21])=[O:20])[CH:10]=2)[CH:6]=[CH:7]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Oc1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)COc1ccc2cc[nH]c2c1
Reaction time: 20 h

Procedure:
6-Hydroxyindole (1.0 g, 7.51 mmol) in degassed MeCN (10 mL) was added K2CO3 (1.14 g, 8.26 mmol) followed by tert-butyl bromoacetate (1.16 g, 8.26 mmol) and the reaction mixture was stirred for 20 hours under N2. The precipitate was filtered off and the solvent was removed in vacuo to give (1-H-indole-6-yloxy)-acetic acid. This was converted to [1-Cyclopropylmethyl-3-(thiazol-2-ylcarbamoyl)-1H-indol-6-yloxy]-acetic acid tert-butyl ester following general procedure (A). [1-Cyclopropylmethyl-3-(thiazol-2-ylcarbamoyl)-1H-indol-6-yloxy]-acetic acid was obtained by treating the intermediate with TFA-DCM (1:1) (2 mL) for 90 min before the solvent was removed in vacuo.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[CH:4][N:3]=1.[I:11]N1C(=O)CCC1=O>CN(C=O)C>[I:11][C:10]1[C:5]2[C:6](=[N:7][C:2]([CH3:1])=[N:3][CH:4]=2)[NH:8][N:9]=1
Reactant: Cc1ncc2cn[nH]c2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Cc1ncc2c(I)n[nH]c2n1
Temperature: 80 °C

Procedure:
2.180 g (purity 73%, approx. 11.82 mmol) of 6-methyl-1H-pyrazolo[3,4-d]pyrimidine and 3.987 g (17.72 mmol) of N-iodosuccinimide were dissolved in 30 ml DMF and heated for 2 h at 80° C. After cooling, the mixture was concentrated in the rotary evaporator and the residue was mixed with dichloromethane, filtered with suction and dried under high vacuum. 7.950 g (approx. 38% purity) of the target compound was obtained.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[CH:9]=[N:8]1.ClC(Cl)(O[C:50](=[O:56])OC(Cl)(Cl)Cl)Cl.[NH3:58]>C(Cl)(Cl)Cl.C1COCC1.O>[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][N:30]([C:50]([NH2:58])=[O:56])[CH2:31][CH2:32]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:34])=[O:35])[CH:13]=2)[CH:9]=[N:8]1
Reactant: N
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(N)=O)CC5)cc4)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.4 %

Procedure:
To a solution of 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (step 1 example 103) (150 mg. 0.233 mmol) in chloroform (10 mL) triethyl amine (0.16 mL, 1.165 mmol) was added at 0° C. drop wise. This solution was added to a solution of triphosgene (59 mg, 0.233 mmol) in chloroform (10 mL) and stirred at RT for 30 minutes. Ammonia in THF was added to this solution drop wise and stirred at RT overnight. This was diluted with water and extracted in chloroform and distilled out the solvent to afford the 40 mg (26.4% yield) of the titled compound after purification with preparative TLC (silicagel-1000 micron) using 3% methanol in DCM as eluent. MS: m/z=649.7 (M+1).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[O:13]([CH2:20][CH2:21][CH2:22]Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[O:13]([CH2:20][CH2:21][CH2:22][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCCOc1ccccc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(CCCOc3ccccc3)cccc21
Temperature: 165 °C
Yield: 59.4 %

Procedure:
A mixture of 7.41 g (40.0 mmol) of potassium phthalimide and 6.30 mL (40.0 mmol) of 3-phenoxypropylbromide in 100 mL DMF was stirred at reflux (165° C.) under N2(g) for 90 min. Mixture was cooled and filtered, filtrate was condensed in vacuo. Residue was recrystallized from 95% ethanol to give 44 (6.68 g, 58%) as a white solid. UV λmax 222 (41700, 95% ETHANOL). 1H NMR (400 MHz, CDCl3) δ 7.85 (m, 2H), 7.72 (m, 2H), 7.24 (t, J=10 Hz, 2H), 6.92 (t, J=7 Hz, 4H), 6.82 (d, J=4 Hz, 2H), 4.03 (t, J=6 Hz, 2H), 3.92 (t, J=4 Hz, 2H), 2.20 (t, J=3 Hz, 2H); 13C NMR (CDCl3) δ 168.7, 134.7, 134.3, 132.6, 129.7, 124.0, 123.6, 121.1, 114.9, 65.9, 35.9, 28.7; IR (drift) 2474 (w), 2431 (w), 2417 (w), 2339 (w), 2305 (w), 1770, 1705 (s), 1600, 1397, 1388, 1249 (s), 1233, 756, 721 (s), 712, cm−1. HRMS (FAB) calcd for C17H15NO3+H1 282.1130, found 282.1129.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[H-].[Na+].[Cl:9][C:10]1(C(F)=O)[N:15]=[C:14]([NH:16][CH2:17][CH3:18])[CH:13]=[CH:12][NH:11]1.CN([CH:25]=[O:26])C>>[NH2:2][C:1]1[N:16]([CH2:17][CH3:18])[C:14]2[N:15]=[C:10]([Cl:9])[N:11]=[CH:12][C:13]=2[C:25](=[O:26])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CCNC1=NC(Cl)(C(=O)F)NC=C1
Reactant: CN(C)C=O
Reactant: N#CCC(N)=O
Agent: [H-]
Agent: [Na+]
Product: CCn1c(N)c(C(N)=O)c(=O)c2cnc(Cl)nc21
Temperature: 3.5 °C
Reaction time: 0.25 h
Yield: 73.4 %

Procedure:
To a solution, cooled to 2-5°C. on an ice bath, of 6.29 g (74.78 mmol) of cyanoacetamide in 140 mL of anhydrous DMF are added portionwise 5.98 g (149.55 mmol) of 60% sodium hydride. The mixture is stirred for 15 minutes at 2-5°C. and this suspension is then added rapidly to the solution of 14.5 g (71.22 mmol) of the acid fluoride prepared in step 2.5 in 155 mL of anhydrous DMF, precooled to 2-5°C. on an ice bath. The mixture is stirred overnight at room temperature and then cooled to 2-5°C., and 2.99 g (74.78 mmol) of 60% sodium hydride are added portionwise. The medium is stirred for 4 hours at room temperature, ice is then added slowly to destroy the excess hydride, and the reaction medium is poured into an ice-water mixture. The resulting mixture is acidified by adding aqueous 0.1 N HCl solution. The precipitate formed is isolated by filtration, rinsed with water and then dried in an oven, followed by rinsing with pentane. 14.0 g of expected product are finally obtained in the form of a pale orange solid. Yield=73.4%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.O.[C:12]1(=[O:17])[CH2:16][CH2:15][CH:14]=[CH:13]1>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:14]2[CH2:15][CH2:16][C:12](=[O:17])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: O=C1C=CCC1
Solvent: C1COCCO1
Solvent: O
Product: O=C1CC[C@H](c2ccc(Br)cc2)C1
Temperature: 35 °C
Yield: 88.7 %

Procedure:
Alternatively, a 3 L three-necked round-bottomed flask equipped with a temperature probe and a nitrogen bubbler was charged with 4-bromophenylboronic acid (100 g, 498 mmol) and hydroxy[(S)-BINAP]rhodium(I) dimer (6.20 g, 4.17 mmol) in dioxane (1667 mL) and water (167 mL) at room temperature. The resulting suspension was degassed with nitrogen and 2-cyclopenten-1-one (27.8 mL, 332 mmol) was added in one portion. The mixture was further degassed for 5 minutes and heated at 35° C. for about 16 hours. The reaction mixture was cooled to room temperature and concentrated. The brown residue was treated with EtOAc (500 mL) and filtered. The filtrate was washed with a saturated solution of NaHCO3 (500 mL) and brine (500 mL), dried over MgSO4, filtered, and concentrated to afford a dark brown solid. The crude reaction product was purified by silica gel chromatography (1:9 EtOAc:heptane as eluant). Fractions containing product were combined and concentrated to afford (S)-3-(4-bromo-phenyl)-cyclopentanone (70.4 g, 89%, 95% ee as determined by chiral HPLC) as an ivory solid.
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([F:18])=[C:4](F)[C:3]=1[F:20].[CH3:21][O:22][C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:24]=1[NH2:25]>>[CH3:21][O:22][C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:24]=1[NH:25][C:4]1[C:3]([F:20])=[C:2]([F:1])[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]=1[F:18].[CH3:21][O:22][C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:24]=1[NH:25][C:4]1[C:3]([NH:25][C:24]2[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:23]=2[O:22][CH3:21])=[C:2]([F:1])[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]=1[F:18]
Reactant: O=C1c2ccccc2C(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: COc1cccc(C)c1N
Product: COc1cccc(C)c1Nc1c(F)c(F)c2c(c1F)C(=O)c1ccccc1C2=O
Product: COc1cccc(C)c1Nc1c(F)c2c(c(F)c1Nc1c(C)cccc1OC)C(=O)c1ccccc1C2=O
Reaction time: 4 h

Procedure:
2 g of 1,2,3,4-Tetrafluoroanthraquinone and 25 g of 2-methoxy-6-methylaniline were charged in a 5 cc, four necked flask and then the reaction was carried out at 80° C. for about 4 hours. After completion of reaction, 2-methoxy-6-methylaniline was distilled out from the reaction solution, and a column purification using a column with a silica gel was effected to give rise to 1.04 g of 2-(2-methoxy-6-methylanilino)-1,3,4-trifluoroanthraquinone (Dye 7') (yield 36.7 mol %) and 1.05 g of 2,3-bis(2-methoxy-6-methylanilino)-1,4-difluoroanthraquinone (Dye 20') (yield 28.6 mol %). The physical properties of Dye 7' and analytical values defining the compound are tabulated in Table 23 and the physical properties of Dye 20' and analytical values defining the compound are tabulated in Table 24.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)=[CH2:3].CN1C=CN=C1.[N+](=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N-]>C1(C)C=CC=CC=1>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:2]2([CH3:3])[CH2:1][CH:21]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5][CH:6]=1)(=[O:12])[CH3:11]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=C(C)c1ccc(C(C)=O)cc1
Agent: Cn1ccnc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1(C)c1ccc(C(C)=O)cc1
Yield: 21.6 %

Procedure:
To a stirred solution of 1-[4-(1-methylethenyl)phenyl]ethanone (711 mg, 4.44 mmol, trans) (Org. Lett., 2002, 4(1), 107-109), N-methylimidazole (1.06 ml, 13.3 mmol) and Co(TPP) (89 mg, 0.13 mmol) in toluene (10 ml) was added ethyl diazoacetate (0.65 ml, 6.21 mmol) in one portion at ambient temperature. The same procedure as described in Example 2H was performed to give the title compound (236 mg, 22%) as dark yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@@H:14]2[CH3:19])[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[BH-](O[C:30]([CH3:32])=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.COC(OC)OC>ClCCCl.CC(O)=O>[CH3:19][C@H:14]1[CH2:15][O:16][CH2:17][CH2:18][N:13]1[C:4]1[C:5]2[S:10][C:9]([CH2:11][N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)=[CH:8][C:6]=2[N:7]=[C:2]([C:30]2[CH:32]=[N:7][CH:2]=[N:3][CH:4]=2)[N:3]=1
Reactant: CN1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2cc(C=O)sc12
Agent: [Na+]
Solvent: ClCCCl
Solvent: COC(OC)OC
Solvent: CC(=O)O
Product: C[C@H]1COCCN1c1nc(-c2cncnc2)nc2cc(CN3CCN(C)CC3)sc12

Procedure:
Following General Procedure D, (S)-2-chloro-4-(3-methylmorpholino)thieno[3,2-d]pyrimidine-6-carbaldehyde (100 mg, 0.34 mmol), HOAc (25 mg), NaBH(OAc)3 (80 mg, 0.37 mmol), N-methylpiperazine (41 mg, 0.40 mmol), 1,2-dichloroethane (1.0 mL), trimethylorthoformate were reacted at room temperature. The crude product was used in the next step without purification. MS (Q1) 382 (M)+. Following General Procedure A, crude product from above, pyrimidine-5-boronic acid (27 mg), Pd(PPh3)4 (20 mg), MeCN (1 mL) and 1M KOAc in H2O (1 mL) were irradiated at 150° C. for 30 min. The reaction mixture was diluted with CH2Cl2, and filtered. The filtrate was concentrated to give crude 422 which was purified by reverse phase HPLC. (14 mg) MS (Q1) 426 (M)+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([NH2:21])[CH:13]=1.Cl>CC(N(C)C)=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([NH2:21])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Nc1cc(Sc2ccc(O)cc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
A solution of 4-hydroxybenzenethiol (46 g; 328 mmol) in DMA (500 ml) under argon was cooled to 0° C. and treated portionwise with NaH (28.9 g; 722 mmol; 60 % dispersion in oil). The mixture was stirred at room temperature for 2 hours and then solid 4-chloro-2-amino-nitrobenzene (56.6 g; 328 mmol) was added rapidly portionwise. The mixture was stirred and heated at 80° C. for 30 minutes and allowed to cool overnight. The mixture was poured into aqueous HCl (2 N) and the precipitate was filtered, washed with water, then pentane and dried in vacuo to give 4-(4-hydroxyphenylsulphanyl)-2-amino-nitrobenzene as a beige solid (86.6 g).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:18]([OH:21])([CH3:20])[CH3:19])[CH2:4][CH2:3]1.[CH2:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH:23]1[CH:31]=O>>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C@H:5]3[CH2:4][CH2:3][C@@H:2]([NH:1][CH2:31][CH:23]4[CH2:22][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24]4)[CH2:7][CH2:6]3)[C:9]([C:18]([OH:21])([CH3:19])[CH3:20])=[N:10][C:11]=2[CH:16]=1
Reactant: CC(C)(O)c1nc2cc(Cl)ccc2n1[C@H]1CC[C@@H](N)CC1
Reactant: O=CC1Cc2ccccc2C1
Product: CC(C)(O)c1nc2cc(Cl)ccc2n1[C@H]1CC[C@@H](NCC2Cc3ccccc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of cis-2-[1-(4-amino-cyclohexyl)-5-chloro-1H-benzoimidazol-2-yl]-propan-2-ol and indan-2-carbaldehyde. 1H-NMR is consistent with the assigned structure, LC-MS showed a single peak, C26H32ClN3O (m/e) calcd 437.2234, obsd 438.2 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:51])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:49][CH3:50])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:37]=4[C:38]([NH:40][CH:41]([CH3:43])[CH3:42])=[O:39])[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].O.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:51][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:49][CH3:50])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:37]=4[C:38]([NH:40][CH:41]([CH3:43])[CH3:42])=[O:39])[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(=O)NC(C)C)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(=O)NC(C)C)c3ccnc-3[nH]1)N(C(=O)CN(C)C)CC2
Temperature: 120 °C
Yield: 72.8 %

Procedure:
2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-(1-methylethyl)benzamide (210 mg, 0.294 mmol) was dissolved in 1,4-dioxane (10 mL) and transferred to a 20 ml microwave vessel. Water (3 mL) and a solution of 6M NaOH (3 ml) was added and reaction heated in microwave at 120° C. for 10 minutes. Resulting brown solution was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a brown solid that was purified via chromatography on SiO2 to afford 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-(1-methylethyl)benzamide (120 mg, 0.214 mmol) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (d, J=6.50 Hz, 6 H), 2.25 (s, 6 H), 3.05-3.22 (m, 4 H), 3.77 (s, 3 H), 4.03-4.13 (m, 1 H), 4.18 (t, J=8.29 Hz, 2 H), 6.26 (br. s., 1 H), 6.84-7.01 (m, 3 H), 7.25-7.38 (m, 1 H), 7.57 (s, 1 H), 8.25 (d, J=8.33 Hz, 1 H), 8.45 (d, J=7.60 Hz, 1 H), 8.64 (s, 1 H), 9.69 (s, 1 H), 11.25 (br. s., 1 H). (ESIMS (M+H)+=561)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH3:16])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:7]=2[CH:24]=1)#[CH:2].Br[C:26]1[CH:27]=[N:28][CH:29]=[N:30][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:8]1[C:7]2[CH:24]=[C:3]([C:1]#[C:2][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)[CH:4]=[CH:5][C:6]=2[N:12]2[C:13]([CH3:16])=[N:14][N:15]=[C:11]2[CH2:10][N:9]=1
Reactant: C#Cc1ccc2c(c1)C(c1ccccc1F)=NCc1nnc(C)n1-2
Reactant: Brc1cncnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nnc2n1-c1ccc(C#Cc3cncnc3)cc1C(c1ccccc1F)=NC2
Reaction time: 24 h

Procedure:
A mixture of 316 mg (1 mmol) of 8-ethynyl-6-(2-fluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine 200 mg (1.25 mmol) of 5-bromopyrimidine, 45 mq of triphenylphosphine, 10 mg of cuprous iodide, 0.5 ml of triethylamine and 10 ml of dimethylformamide was stirred and degassed for 10 minutes by a slow stream of argon. Palladium acetate, 15 mg, was then added and stirring under argon was continued for 24 hours. The reaction mixture was partitioned between aqueous sodium bicarbonate solution and methylene chloride. The organic layer was washed with water, dried and evaporated, at the end azeotropically with xylene. The residue was chromatographed over 20 g of silica gel (Merck 70-230 mesh) using 5% of ethanol in methylene chloride. The combined clean fractions were evaporated and the residue was crystallized from ethyl acetate to give off-white crystals of the title compound with m.p. 143°-146° C.