Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:37])[C@@H:6]([OH:36])[C@@H:7]([NH:10][C:11]([C@@H:13]2[CH2:17][C@@H:16]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=3[CH3:28])(=[O:20])=[O:19])[CH2:15][N:14]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:12])[CH2:8][CH3:9])[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5](=[O:37])[C:6](=[O:36])[C@@H:7]([NH:10][C:11]([C@@H:13]2[CH2:17][C@@H:16]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=3[CH3:28])(=[O:19])=[O:20])[CH2:15][N:14]2[C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[O:12])[CH2:8][CH3:9])[CH2:3][CH2:2]1
Reactant: CC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(C)cc2C)CN1C(=O)OC(C)(C)C)[C@H](O)C(=O)NC1CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(C)cc2C)CN1C(=O)OC(C)(C)C)C(=O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2S,4R)-tert-butyl 2-((2S,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxopentan-3-ylcarbamoyl)-4-(2,4-dimethylphenylsulfonyl)pyrrolidine-1-carboxylate (64 mg, 119 μmol, Eq: 1.00) and Dess-Martin periodinane (572 mg, 202 μmol, Eq: 1.7) were combined with CH2Cl2 (1 ml). The reaction was stirred overnight at RT. Dess-Martin periodinane (280 mg) was added again and stirred for 5 h, until near complete conversion. The reaction was extracted with 15 ml CH2Cl2 and 2×5 ml satd. Na2S2O3. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by preparative HPLC. The title compound was obtained as a light yellow gum (52.5 mg, 82.3%, MS (m/e)=536.24 [M+H+]).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[O:16][N:15]=[C:14]([CH3:17])[C:13]=2[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[CH2:24]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[O:16][N:15]=[C:14]([CH3:17])[C:13]=2[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1noc(NS(=O)(=O)c2ccc(N)cc2)c1C
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1noc(NS(=O)(=O)c2ccc(NCc3ccccc3)cc2)c1C
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
To a mixture of 4-amino-N-(3,4-dimethyl-5-isoxazolyl)benzenesulfonamide (1.0 g, 3.74 mmol) and sodium bicarbonate (310 mg, 4.48 mmol) suspended in ethanol was added benzyl bromide (770 mg, 4.48 mmol). After 10 min of stirring at 70° C., the mixture became homogeneous. The reaction was stirred at 70° C. for 2 h and the solvent and volatiles were evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with brine (2×25 ml). After drying over magnesium sulfate, evaporation of the solvent left a viscous yellow oil which was chromatographed on silica gel to give 960 mg (72% yield) clear, colorless oil. Further purification by HPLC gave a white solid, m.p. 47°-8° C.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:6]=1)=[O:4].C1(C2(C3C=CC=CC=3)OB(C)N3CCC[C@H]23)C=CC=CC=1.C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[Br:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:6]=1)[OH:4]
Reactant: CS(=O)(=O)Nc1cc(C(=O)CBr)ccc1OCc1ccccc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Temperature: -30 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
Under nitrogen atmosphere, a solution of 2-bromo-1-[4-(phenyl-methoxy)-3-[(methylsulfonyl)amino]phenyl]ethanone (J. Med. Chem., vol. 23, no. 7, p. 738 (1980)) (977 mg, 2.45 mmol) and (R)-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine (170 mg, 0.61 mmol) in tetrahydrofuran is stirred for 30 minutes. The mixture is cooled to −30° C., and thereto is added a 2M borane-dimethylsulfide complex in tetrahydrofuran (1.84 mL, 3.68 mmol), and the mixture is stirred at −25° C. for 2 days. The reaction solution is warmed to room temperature, and ethyl acetate and a saturated aqueous ammonium chloride solution are added thereto, and the mixture is stirred. The organic layer is collected and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (ethyl acetate/chloroform=1/50) to give the desired (R)-2-bromo-1-[4-(phenylmethoxy)-3-[(methylsulfonyl)-amino]phenyl]ethanol (881 mg, yield: 90%).
Reaction SMILES: [C:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH2:30])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:31])[CH2:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9])(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:35][CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39].O>CN(C)C=O>[C:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH:30][CH2:35][CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:31])[CH2:5][CH2:6][CH2:7][N:8]([CH3:9])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(C)CCCBr
Reactant: CC(=O)N(CCCN(C)C)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(CCCN(C)C)c1ccc(-c2cc(=O)c3c(NCCCC(C)C)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
1.01 g (2.33 mmol) of 2-[4-[N-acetyl-N-(3-dimethylaminopropyl) amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one obtained in Example 127 (2) was dissolved in 20 mL of dimethylformamide under argon atmosphere, 190 mg (4.75 mmol) of sodium hydride (60% oil dispersion) and 0.66 mL (4.7 mmol) of 1-bromo-4-methylpentane were added under ice-cooling and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and mixture was extracted twice with ethyl acetate. The organic layer was washed once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1-9:1) to give 595 mg of 2-[4-[N-acetyl-N-(3-dimethylaminopropyl)amino]-3-fluorophenyl]-6,8-difluoro-5-(4-methylpentylamino)-4H-1-benzopyran-4-one (yield: 49%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[CH:13][N:14]=[C:7]3[C:6]=2[CH:15]=1.[F:16][C:17]1[C:22](B(O)O)=[CH:21][CH:20]=[CH:19][N:18]=1.C([O-])(=O)C.[K+]>CN(C=O)C.O.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:16][C:17]1[C:22]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[CH:13][N:14]=[C:7]4[C:6]=3[CH:15]=2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: Brc1ccc2c(c1)-c1nccn1CCO2
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ncccc1-c1ccc2c(c1)-c1nccn1CCO2
Temperature: 100 °C

Procedure:
To 10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (140 mg, 0.53 mmol) in DMF (20 mL) and water (2 mL) was added 2-Fluoropyridine-3-boronic acid (89 mg, 0.632 mml), Potassium acetate (207 mg, 2.11 mmol) and Tetrakis(triphenylphosphine)palladium (30 mg, 0.0264 mmol). The reaction mixture was degassed for 5 minutes, and heated at 100° C. overnight. LCMS showed desired product peak. The reaction was allowed to cool to room temperature, diluted with EtOAc, and filtered through a thin pad of celite. The filtrate was washed with water followed by brine, dried over MgSO4 and concentrated. The crude residue was purified by Prep HPLC to provide 10-(2-fluoropyridin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine. LC/MS (ESI+): m/z 282 (M+H)
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([CH3:17])[CH:11]=1>CC(N(C)C)=O>[CH3:8][O:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:1](=[O:3])[CH3:2])=[C:12]([CH3:17])[CH:11]=1
Reactant: COc1ccc(N)c(C)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1ccc(NC(C)=O)c(C)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 88 %

Procedure:
Acetic anhydride (50 ml) was added dropwise to a solution of 4-methoxy-2-methylaniline (49.7 g, 360mmol) in DMA (200 ml) at 5° C. and the mixture stirred for 4.5 hours at ambient temperature. The solvent was removed by evaporation and the resulting solid washed with water and dried under vacuum to give N-(4-methoxy-2-methylphenyl)acetamide (57.3 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.Cl[C:13]1[N:18]=[C:17]([Cl:19])[N:16]=[C:15]2[N:20]([CH3:23])[N:21]=[CH:22][C:14]=12>>[Cl:19][C:17]1[N:16]=[C:15]2[N:20]([CH3:23])[N:21]=[CH:22][C:14]2=[C:13]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=2)[N:18]=1
Reactant: COc1ccc(N)cc1OC
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Product: COc1ccc(Nc2nc(Cl)nc3c2cnn3C)cc1OC

Procedure:
Reaction of 4-aminoveratrole with 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 5 by General Procedure B gave (6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(3,4-dimethoxy-phenyl)-amine.
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11]([F:23])=[C:12]([C:14]3[C:15]([C:21]#[N:22])=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[CH:13]=2)OC1.Br[C:26]1[N:30]2[N:31]=[CH:32][C:33]([C:35]([F:38])([CH3:37])[CH3:36])=[N:34][C:29]2=[N:28][CH:27]=1.CCOC(C)=O.CCCC(C)C>>[F:20][C:17]1[CH:16]=[C:15]([C:21]#[N:22])[C:14]([C:12]2[CH:13]=[C:8]([C:26]3[N:30]4[N:31]=[CH:32][C:33]([C:35]([F:38])([CH3:36])[CH3:37])=[N:34][C:29]4=[N:28][CH:27]=3)[CH:9]=[CH:10][C:11]=2[F:23])=[CH:19][CH:18]=1
Reactant: CC1(C)COB(c2ccc(F)c(-c3ccc(F)cc3C#N)c2)OC1
Reactant: CC(C)(F)c1cnn2c(Br)cnc2n1
Solvent: CCOC(C)=O
Solvent: CCCC(C)C
Product: CC(C)(F)c1cnn2c(-c3ccc(F)c(-c4ccc(F)cc4C#N)c3)cnc2n1

Procedure:
5′-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-4,2′-difluorobiphenyl-2-carbonitrile was coupled to 7-bromo-3-(1-fluoro-1-methylethyl)imidazo[1,2-b][1,2,4]triazine in 77% yield using a similar procedure to that described in Example C, step f, to give a yellow solid: mp 156-159° C. (EtOAc-isohexane); 1H NMR (400 MHz, CDCl3) δ1.84 (6H, d, J 22.0 Hz), 7.36-7.46 (2H, m), 7.54 (1H, dd, J7.8, 2.7 Hz), 7.57-7.60 (1H, m), 8.10-8.16 (2H, m), 8.30 (1H, s), 8.79 (1H, d, J 1.2 Hz); MS (ES+) m/z 394 [M+H]+. Anal. Found: C, 64.07; H, 3.66; N, 17.60%. Required for C21H14F3N5: C, 64.12; H, 3.59; N, 17.80%.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(F)cc2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2ccc(F)cc21
Yield: 96.4 %

Procedure:
1,1-Dimethylethyl N-((7-fluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (590 mg, 1624 μmol) was stirred in TFA (3 mL, 40386 μmol) at room temperature for 15 minutes. Water was added. The resulting precipitate was filtered and washed with water to give the desired product as a white solid (481 mg). MS (m/e)=308.1 (M+H)+. Calculated for C15H14FNO5 307.09.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[SiH3]Cl.[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].Cl.C(N(CC)CC)C>C(N(CC)CC)C.C1CCCCC1>[Si:1]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Cl:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OCCCCCCCl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: [SiH3]Cl
Solvent: C1CCCCC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCCCCCCl
Temperature: 25 °C

Procedure:
A 250 ml, three-necked flask was fitted with a large magnetic, egg-shaped stir bar, a thermocouple, a small, pressure-equalizing addition funnel, a reflux condenser, and an argon inlet. This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon. The flask was charged with 16.20 grams (0.108 mole, 1.00 equivalents) of t-butyldimethylsilyl chloride, and 100 grams of cyclohexane. The silyl chloride rapidly dissolved, endothermically. 6-Chloro-1-hexanol, 15.06 grams (0.108 mole, 1.00 equivalent) was then added dropwise in five minutes. Triethylamine, 10.93 grams (0.108 mole, 1.00 equivalent) was then added dropwise to the reaction mixture. An exotherm was noted, and fumes of triethylamine hydrochloride were observed. A fine, white precipitate rapidly developed. The reaction mixture was stirred at room temperature, and monitored by GC analysis. An aliquot of the clear supernatant was injected into the GC. After one and a half hours, both starting materials were still present, and the conversion to the desired product was only 27.8%. The reaction mixture was stirred overnight at room temperature, under a blanket of argon. The sample after 21 hours indicated only a 53.3% conversion to the desired product. After 161.5 hours stirring, the conversion was still only 88.0%.
Reaction SMILES: [C:1]([O:5][CH:6]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)[CH:7]1[C:16](OCC)=[O:17])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Al+3].[Li+]>C1COCC1>[C:1]([O:5][CH:6]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)[CH:7]1[CH2:16][OH:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1C(OC(C)(C)C)C1c1ccc(C)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(C2C(CO)C2OC(C)(C)C)nc1
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
The solution of ethyl 2-tert-butoxy-3-(5-methylpyridin-2-yl)cyclopropanecarboxylate (12-4) (350 mg, 1.26 mmol) in THF (2 mL) was cooled to 0° C. Then lithium aluminium tetrahydride (72 mg, 1.89 mmol) was added to the solution at 0° C. and it was stirred for 30 min before restored to the room temperature for 1 h. The reaction was quenched in sequence with 0.1 mL water, 0.05 mL 15% NaOH aqueous, 0.1 mL water. The resulting mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by Pre-TLC (PE/EA=1/1). The product was obtained as a white solid (200 mg, 68%). 1H NMR (400 MHz, MeOD) δ 8.24 (s, 1H), 7.55 (dd, J=8.2, 1.7 Hz, 1H), 7.11 (d, J=8.2 Hz, 1H), 3.66-3.58 (m, 3H), 2.33 (s, 3H), 2.13 (t, J=6.6 Hz, 1H), 1.80 (dd, J=6.4, 3.7 Hz, 1H), 1.06 (s, 9H); LRMS (ES) calculated M+H for C14H22NO2: 236.3. Found: 236.2.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:27])[C@@H:6]([O:24][CH2:25][CH3:26])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)[CH3:3].Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>O1CCCC1>[CH2:2]([O:4][C:5](=[O:27])[C@@H:6]([O:24][CH2:25][CH3:26])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:29]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:30])=[CH:21][CH:22]=2)=[CH:10][CH:9]=1)[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)OCC
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(NC(=O)Oc3ccccc3)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.8 %

Procedure:
3-{4-[2-(4-Aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid ethyl ester hydro chloride (described in Example 41b) (0.55 g; 1.4 mmole) was dissolved in tetrahydrofuran (5 ml). Phenyl chloroformat (0.675 g; 3 mmole) was added slowly. The reaction mixture was stirred at room temperature and continuosly checked with HPLC and after 3 days was all the starting material consumed. Water was added, tetrahydrofuran evaporated and the residue extracted three times with ethyl acetate. The organic phase was dried with magnesium sulfate and evaporated. Purification of the crude product with preparative HPLC (Kromasil C8, 7 μm, 50×250 mm) using acetronitrile (70%) in ammonium acetate buffer (pH 7) as mobil phase gave 0.46 g (96.3% yield) (S)-2-ethoxy-3-(4-{2-[4-(phenoxycarbonylamino)phenyl]ethoxy]phenyl)propanoic acid ethyl ester.
Reaction SMILES: CO[N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH:6]=1.C(=O)=O.C(O)=O.[H][H]>C(O)C.O1CCCC1.[Pd]>[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([O:14][Si:15]([CH:19]([CH3:21])[CH3:20])([CH:22]([CH3:24])[CH3:23])[CH:16]([CH3:17])[CH3:18])[CH:6]=1
Reactant: [H][H]
Reactant: CON=Cc1ccc([N+](=O)[O-])c(O[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: [Pd]
Agent: O=C=O
Solvent: CCO
Solvent: O=CO
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1cc(CN)ccc1N)(C(C)C)C(C)C

Procedure:
A solution of 4-nitro-3-[(triisopropylsilyl)oxy]benzaldehyde O-methyloxime (0.70 g, 2.0 mmol) in ethanol (13 mL) and tetrahydrofuran (3 mL) is degassed with solid carbon dioxide, then charged with 5% palladium on carbon (100 mg) and 88% formic acid (0.8 mL). The mixture is stirred under 1 atm hydrogen gas overnight. The mixture is then filtered through a pad of diatomaceous earth, and the filtrate is concentrated under reduced pressure to give {4-(aminomethyl)-2-[(triisopropylsilyl)oxy]phenyl}amine as its diformic acid salt. This material is used in the subsequent step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH2:7]([O:11][CH3:12])[CH:8]1[O:10][CH2:9]1>>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:9][CH:8]([OH:10])[CH2:7][O:11][CH3:12])[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: COCC1CO1
Product: COCC(O)Cn1cc(Br)cn1
Temperature: 25 °C
Yield: 51.6 %

Procedure:
A solution of 4-bromopyrazole (200 mg, 1.36 mmol) in methyl glycidyl ether (510 mg, 5.79 mmol) was heated at 100° C. for 70 minutes. After cooling to r.t., the excess methyl glycidyl ether was removed in vacuo to give the title compound (165 mg, 52%) as a clear yellow liquid. δH (CDCl3) 3.21-3.24 (1H, m), 3.31-3.35 (2H, m), 3.38 (3H, s), 4.08-4.30 (3H, m), 7.47-7.50 (2H, m). LCMS (ES+) 235, 237 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:16][C:15](=[O:17])[C:14]2=[C:18]([CH3:26])[N:19]=[C:20]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[N:13]2[N:12]=1)[CH2:2][CH3:3].[S:27](Cl)([Cl:30])(=[O:29])=[O:28]>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:27]([Cl:30])(=[O:29])=[O:28])=[CH:7][C:6]=1[C:11]1[NH:16][C:15](=[O:17])[C:14]2=[C:18]([CH3:26])[N:19]=[C:20]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[N:13]2[N:12]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Reactant: O=S(=O)(Cl)Cl
Product: CCCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 0.7 g (2 mmol) of 2-(2-propoxyphenyl)-5-methyl-7-cyclopentyl-3H-imidazo-[5,1-f][1,2,4]-triazin-4-one (Example 17A). This gives 0.8 g (89.3%) of sulphonyl chloride as a white foam which is directly reacted further.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:23]=[CH:22][C:10]([O:11][Si](C(C)C)(C(C)C)C(C)C)=[CH:9][C:8]=2[CH:24]([CH3:26])[CH3:25])[CH2:6][CH2:5]1)[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][C:4]1([C:7]2[CH:23]=[CH:22][C:10]([OH:11])=[CH:9][C:8]=2[CH:24]([CH3:25])[CH3:26])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC1(c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC1(c2ccc(O)cc2C(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a solution of [4-(1-ethoxycyclopropyl)-3-isopropyl-phenoxy]-triisopropyl-silane (Intermediate 99, 360.0 mg, 0.96 mmol) in 3 mL THF at 0° C. was added tetrabutylammonium fluoride (625.0 mg, 2.39 mmols, 2.4 mL of a 1 M solution in THF). The solution was stirred at 0° C. for 30 minutes and then quenched by the addition of H2O. The mixture was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound (180 mg, 86%) was isolated from the residue by column chromatography (4-10% EtOAc-hexanes) as a colorless solid.
Reaction SMILES: [C:1]([CH2:5][NH:6][C:7]([CH2:9][N:10]1[C:14]([CH2:15][N:16]=[N+]=[N-])=[C:13]([CH3:19])[N:12]=[CH:11]1)=[O:8])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([CH2:5][NH:6][C:7]([CH2:9][N:10]1[C:14]([CH2:15][NH2:16])=[C:13]([CH3:19])[N:12]=[CH:11]1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ncn(CC(=O)NCC(C)(C)C)c1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ncn(CC(=O)NCC(C)(C)C)c1CN

Procedure:
A solution of 1-t-butylmethylaminocarbonylmethyl-4-methyl-5-azidomethylimidazole (400 mg) and 10% Pd/C (400 mg) in ethyl acetate (60 ml) was hydrogenated at atmospheric pressure for 4 h. The solution was filtered through Celite and the solvents removed in vacuo to give the title compound. 1H NMR (CDCl3) d 0.80 (s, 9 H), 1.61 (br s, 2 H), 2.23 (s, 3 H), 2.99 (d, J=6.1 Hz, 2 H), 3.86 (s, 2 H), 4.63 (s, 2 H), 7.50 (s, 1 H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[CH:18]=[C:17]([C:19]([O-:21])=O)[NH:16][C:13]3=[N:14][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=N1.N1CCCC1.C(N(CC)C(C)C)(C)C>>[N:30]1([C:19]([C:17]2[NH:16][C:13]3=[N:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:11]=[C:12]3[CH:18]=2)=[O:21])[CH2:31][CH2:36][CH2:35][CH2:34]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C([O-])c1cc2cc(OCCCN3CCCC3)cnc2[nH]1
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc2cc(OCCCN3CCCC3)cnc2[nH]1)N1CCCC1
Yield: 53 %

Procedure:
The title compound was synthesized in analogy to example 1 from lithium 5-(3-pyrrolidin-1-yl-propoxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, pyrrolidine and N,N-diisopropylethylamine to give the desired product as a light yellow solid (53%).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:19]1([CH3:29])[CH:24]=[CH:23][CH:22]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:20]=1>>[C:19]1([CH3:29])[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]4)[CH2:2][CH2:3]2)(=[O:27])=[O:26])[CH:20]=1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Product: Cc1cccc(S(=O)(=O)N2CCN(c3cccc4nc(N)nc(N)c34)CC2)c1
Yield: 41 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and m-toluenesulfonyl chloride (78.2 mg; 0.41 mmol) to obtain 32.3 mg. (41% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.58 (m, 4H), 7.38 (t, J=8.0 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 5.92 (br s, 2H), 3.74 (br d, J=11.6 Hz, 2H), 3.44 (m, 1H), 3.1 (br d, J=12 Hz, 2H), 2.85 (m, 2H), 2.53 (m, 4H). ESIMS+399.6 m/z