Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]([F:22])([F:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:7]=1[F:23])C.[Li+].[OH-].Cl>CO>[F:22][C:14]([F:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH2:13][NH:12][C:8]1[C:7]([F:23])=[C:6]([CH2:5][C:4]([OH:24])=[O:3])[CH:11]=[CH:10][N:9]=1
Reactant: CCOC(=O)Cc1ccnc(NCC(F)(F)c2ccccn2)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1ccnc(NCC(F)(F)c2ccccn2)c1F
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 0.159 g (0.469 mmol) ethyl {2-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]-3-fluoropyridin-4-yl}acetate 29-2 in 1 mL MeOH was added 469 uL (0.469 mmol, 1M aqueous solution) LiOH. The reaction was stirred at room temperature for 23 h. To the reaction was added 38.7 uL (0.469 mmol, 12M aqueous solution) HCl. The mixture was stirred for 10 min, concentrated in vacuo, and placed under vacuum alongside P2O5 to yield {2-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]-3-fluoropyridin-4-yl}acetic acid 29-3. 1H NMR (CD3OD, 400 MHz) δ8.606 (d, 1H, J=4.77 Hz, ArH); 7.894 (t, 1H, J=7.83 Hz, ArH); 7.692 (d, 1H, J=7.69 Hz, ArH); 7.609 (d, 1H, J=5.22 Hz, ArH); 7.458 (t, 1H, J=6.05 Hz, ArH); 6.499 (t, 1H, J=4.99 Hz, ArH); 4.324 (t, 2H, J=13.92 Hz, CH2); 3.572 (s, 2H, CH2); MS (Electrospray): m/z 312.0 (M+H).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][SH:3].[H-].[Na+].Br[C:9]1[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]2[C:16]([N:17]=1)=[C:15]([NH2:18])[N:14]=[CH:13][N:12]=2>CN(C=O)C>[C:1]([CH2:2][S:3][C:9]1[N:10]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:11]2[C:16]([N:17]=1)=[C:15]([NH2:18])[N:14]=[CH:13][N:12]=2)([OH:5])=[O:4]
Reactant: Nc1ncnc2c1nc(Br)n2Cc1ccccc1
Reactant: O=C(O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1nc(SCC(=O)O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
A solution of thioglycolic acid (0.05 mL, 0.68 mmol) and NaH (0.05 g, 1.35 mmol, 60% in oil) in anhydrous DMF (3 mL) was stirred for 30 min at 0° C. under argon, then 23 (0.13 g, 0.45 mmol) in DMF (3 mL) was added. After stirring overnight at room temperature, the reaction mixture was concentrated to dryness, and the crude product was purified by reverse phase HPLC (5-50% ACN in TEAA over 20 min) to give 24 (0.07 g, 50%). Rt (0-10% A in B over 20 min.) 10.36 min.; 1H NMR (DMSO-d6) δ: 4.17 (s, 2H, SCH2), 5.31 (s, 2H, CH2), 7.10 (bs, 2H, NH2), 7.29 (m, 3H, H arom.), 7.35 (m, 2H, H arom.), 8.12 (s, 1H, H2); 13C NMR (DMSO-d6) δ: 34.91 (SCH2), 45.97 (CH2), 119.17 (C5), 127.77, 128.22 and 129.15 (CH), 136.63 (Cq), 147.77 (C8), 152.02 (C4), 152.51 (C2), 154.62 (C6); 169.85 (CO); HRMS (ESI-TOF) m/z calcd for [C14H13N5O2S+H]316.0868; found 316.0855.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+:24]([O-])([OH:26])=[O:25]>ClCCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([N+:24]([O-:26])=[O:25])[C:21]([F:23])=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cc(F)ccc3O2)cc1
Reactant: O=[N+]([O-])O
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)OCC2COc3cc(F)c([N+](=O)[O-])cc3O2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 19.0 g (56.2 mmole) of {(2R)-6-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate in 200 mL of 1,2-dichloro-ethane in an ice/water bath was added dropwise a solution of 8.35 mL (0.197 mole) of fuming nitric acid (d 1.49) and the mixture was stirred for 2 hours at 0° C. After the reaction was complete, it was quenched with ice and diluted with 500 mL of methylene chloride. After the ice had melted, the organic layer was separated and washed with equal volumes of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum to a crude yellow solid. This was column chromatographed on silica gel with 1:1 hexane/methylene chloride as eluant to give 18.6 g of the (R)-enantiomer of the title compound as a light yellow solid (m.p. 106-107° C.).
Reaction SMILES: [C:1]1([P:9]([C:43]2[CH:48]=[C:47]([CH3:49])[CH:46]=[C:45]([CH3:50])[CH:44]=2)([C:11]2[CH:42]=[CH:41][CH:40]=[CH:39][C:12]=2[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[P:21]([C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[CH:32]=2)([C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=2)=O)=[O:14])=O)[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.C(N(CC)CC)C.Cl[SiH](Cl)Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:31]1([P:21]([C:23]2[CH:24]=[C:25]([CH3:30])[CH:26]=[C:27]([CH3:29])[CH:28]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13]([C:12]2[CH:39]=[CH:40][CH:41]=[CH:42][C:11]=2[P:9]([C:1]2[CH:2]=[C:3]([CH3:8])[CH:4]=[C:5]([CH3:7])[CH:6]=2)[C:43]2[CH:48]=[C:47]([CH3:49])[CH:46]=[C:45]([CH3:50])[CH:44]=2)=[O:14])[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[CH:32]=1
Reactant: Cc1cc(C)cc(P(=O)(c2cc(C)cc(C)c2)c2ccccc2C(=O)c2ccccc2P(=O)(c2cc(C)cc(C)c2)c2cc(C)cc(C)c2)c1
Agent: Cl[SiH](Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(P(c2cc(C)cc(C)c2)c2ccccc2C(=O)c2ccccc2P(c2cc(C)cc(C)c2)c2cc(C)cc(C)c2)c1
Yield: 20 %

Procedure:
Into 10 ml of toluene was dissolved 252 mg (0.36 mmol) of 2,2′-bis{di-(3,5-xylyl)phosphinyl}benzophenone, and further 2.0 ml (14.4 mmol) of triethylamine was added thereto, and the resultant solution was cooled to 0° C. Thereto was added 360 μl (3.6 mmol) of trichlorosilane, and then the resultant solution was stirred for 30 minutes while the temperature thereof was kept at 0° C. Thereafter, the temperature thereof was slowly raised to a temperature at which the solution was allowed to be refluxed. The solution was then refluxed for 4 hours. The reaction mixture was cooled, and thereto was dropwise added 10 ml of 25% aqueous sodium hydroxide slowly. The aqueous phase was extracted with 10 ml of methylene chloride. The organic phases were combined, washed with 1N hydrochloric acid two times and then dried over magnesium sulfate. The resultant was concentrated under reduced pressure to distill off the solvent, and then purified by column chromatography on silica gel (ethyl acetate:hexane=1:6) to give 47.7 mg (yield: 20%) of the title compound in the form of a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:9]([OH:19])[CH2:10][O:11][Si](C(C)(C)C)(C)C)(C)(C)C.[ClH:27].O1CCOCC1>CO>[ClH:27].[NH2:7][C@H:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:9]([OH:19])[CH2:10][OH:11]
Reactant: CC(C)(C)OC(=O)N[C@H](c1ccccc1)[C@H](O)CO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@H](c1ccccc1)[C@H](O)CO
Reaction time: 2 h

Procedure:
To a solution of 300 mg of tert-butyl[(1R,2S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxy-1-phenylpropyl]carbamate and 5 ml of methanol was added 5 ml of a 4 M hydrogen chloride/dioxane solution, followed by stirring for 2 hours. The solvent was evaporated under reduced pressure to obtain 171 mg of (2S,3R)-3-amino-3-phenylpropane-1,2-diol hydrochloride.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:17][C:18]([O:20][CH2:21][CH:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([O:37][C:38]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39])[CH3:36].C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:35]([O:37][C:38]([N:40]1[CH2:41][CH2:42][N:43]([C:14](=[O:15])[C@@H:13]([NH:17][C:18]([O:20][CH2:21][CH:22]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=3[C:29]3[C:34]2=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:44][CH2:45]1)=[O:39])[CH3:36]
Reactant: O=C(N[C@@H](CCCCOCc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CCOC(=O)N1CCNCC1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCCCOCc2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reaction time: 3 h

Procedure:
To a solution of 500 mg (S)-6-Benzyloxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoic acid in 7 ml DMF were added at 0° C. 172 mg piperazine-1-carboxylic acid ethyl ester, 0.14 ml N-ethylmorpholine and 357 mg TOTU. After stirring for 3 h the solution was diluted with ethyl acetate and subsequently washed with aqueous LiCl (4%) and half-saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification. Yield: 663 mg.
Reaction SMILES: [Cl:1][C:2](C)([CH3:5])[CH:3]=O.C(O)C.C(O[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])C>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>[CH2:18]([O:17][CH:13]([O:14][CH2:15][CH3:16])[C:2]([Cl:1])([CH3:5])[CH3:3])[CH3:19]
Reactant: CC(C)(Cl)C=O
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(OCC)C(C)(C)Cl
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a mixture of 45 g (0.424 mol) of 2-chloro-2-methylpropanal, 99.6 ml (1.69 mol) of ethanol, 81.6 g (0.55 mol) of triethylorthoformate in 100 ml of methylene chloride was added 800 mg (4.2 mmol) of p-toluenesulfonic acid and the mixture was stirred at room temperature. After adding 2 g of potassium carbonate to the above mixture, the reaction mixture was stirred (2 min.), and filtered. The filtrate was concentrated (80° C.) to remove methylene chloride and the residue was distilled (2×) to afford 52 g (68.2%) of 2-chloro-2-methylpropanal diethyl acetal, b.p. 55°-65° C./25 mm.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:10]=1)=O)C.[OH-].[NH4+:33]>>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([S:19]([NH:18][C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[N:9]2[CH:10]=[C:6]([C:4]([NH2:33])=[O:3])[CH:7]=[N:8]2)(=[O:21])=[O:20])=[CH:23][CH:24]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)c1cnn(-c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2cc(C(N)=O)cn2)cc1

Procedure:
1-[2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (synthesized according to general procedure D, 55 mg, 0.119 mmol) and 1 mL of ammonium hydroxide were stirred at 70° C. for 18 hours. The resultant solution was partitioned between saturated sodium bicarbonate and dichloromethane, and the aqueous layer extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was subsequently purified by flash column chromatography (0-100% ethyl acetate in hexanes) to yield 1-[2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-phenyl]-1H-pyrazole-4-carboxylic acid amide: MS (ES) M+H expected 433.1, found 433.0.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH:10]=[CH:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[C:6](=[O:15])[C:5]=12.[Cl-].[Al+3].[Cl-].[Cl-].[C:20](Cl)(=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[C:20]([C:2]1[CH:1]=[C:5]2[N:4]([CH:3]=1)[CH:10]=[CH:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[C:6]2=[O:15])(=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCC(=O)Cl
Reactant: O=c1c2ccccc2ccn2cccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC(=O)c1cc2c(=O)c3ccccc3ccn2c1

Procedure:
11H-Pyrrolo[2,1-b][3]benzazepin-11-one (1.0 g.) is dissolved in 20 ml. of methylene chloride and 2.66 g. of aluminum chloride is added with cooling. At room temperature there is added little by little 720 mg. of pentanoyl chloride. Fifteen minutes after the addition is complete the mixture is poured onto ice. The organic phase is separated, filtered, dried and concentrated to dryness. The residue is triturated with ether, collected and dried to give 2-pentanoyl-11H-pyrrolo[2,1-b] [3]benzazepin-11-one.
Reaction SMILES: [N+:1]([C:4]12[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5]2)([O-:3])=[O:2].[BH4-].[Na+].CCOCC.[ClH:22]>CO>[ClH:22].[OH:14][CH:13]1[C:4]2([N+:1]([O-:3])=[O:2])[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:10][CH2:11][CH2:12]1
Reactant: O=C1CCCC2CCCCC12[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: O=[N+]([O-])C12CCCCC1CCCC2O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8a-nitrodecahydronapthalen-1-one [P. Dampawan and W. W. Zajac Jr. Synthesis, 545, 1983] (1.2 g, 6.1 mmol) in MeOH (10 ml) at 0° C., add sodium borohydride (0.09 g) and warm to RT. After 0.5 hr, add ether and 1N HCl. Dry and concentrate the organic layer. Dissolve the residue in EtOH (50 ml) and add this to Raney Nickel (1.2 g, wet weight) and place under 60 psi of H2 at 55° C. After 24 hr., filter though celite and concentrate to dryness. Dissolve the resultant oil in Et2O add dry HCl in MeOH and collect the title compound as a colorless precipitate EI MS: M+=169.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[CH3:32][C:33]1[CH:34]=[CH:35][C:36]2[N:37]([CH:39]=[N:40][C:41]=2[Sn](CCCC)(CCCC)CCCC)[CH:38]=1>CN(C=O)C.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.[Cu]I>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:41]4[N:40]=[CH:39][N:37]5[CH:38]=[C:33]([CH3:32])[CH:34]=[CH:35][C:36]=45)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncn2cc(C)ccc12
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3cnc4c(n3)c(C(=O)N[C@H](C)C(=O)N3CC(C#N)C3)cn4COCC[Si](C)(C)C)ncn2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (100 mg, 0.20 mmol) and 6-methyl-1-tributylstannyl-imidazo[1,5-a]pyridine (crude from step 5, 307 mg, 0.36 mmol) were dissolved in DMF (1.8 ml). The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium (0) (12 mg, 0.010 mmol) and copper (I) iodide (8 mg, 0.042 mmol) were added. The reaction mixture was stirred at 90° C. in an oil bath overnight then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-3% MeOH) to afford 98 mg (89%) of 2-(6-methyl-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:32])[C:28]([O:30]C)=O)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:36][NH2:37]>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:32])[C:28]([NH:37][CH3:36])=[O:30])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Reactant: CN
Product: CNC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Yield: 55 %

Procedure:
Using the same procedure as in Example 26, methyl (2R)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.42 mmol) was reacted with methylamine to give the title compound as a white solid (110 mg, 55%) except that the crude material was purified on an HPLC column (C18, 5 microns, 19 mm diameter, 100 mm length) of a preparative HPLC-MS system eluting with a mixture of water and acetonitrile containing 2 g/l of ammonium carbonate (gradient). NMR Spectrum 1.65 (d, 3H), 2.67 (d, 3H), 5.16 (q, 1H), 5.71 (s, 2H), 7.00 (d, 1H), 7.04-7.10 (m, 3H), 7.36 (dd, 2H), 7.71-7.77 (m, 3H), 8.17 (s, 1H), 8.37 (m, 1H), 8.53 (s, 1H), 8.55 (s, 1H), 10.68 (br s, 1H); Mass spectrum MH+ 471.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].CC1C=C(I)C=CC=1N.FC1C([Cl:38])=C(C=CN=1)C(O)=O>>[Cl:38][C:18]1[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[C:11]([CH:15]=[CH:16][N:17]=1)[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1ccnc(F)c1Cl
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Agent: Cc1cc(I)ccc1N
Product: O=C(O)c1ccnc(Cl)c1Nc1ccc(I)cc1F

Procedure:
2-Chloro-3-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid was synthesized as outlined in General Method 1 and according to the procedure for the synthesis of intermediate 1 by reacting 4 mmol of 2-methyl-4-iodoaniline with 6 mmol 2-fluoro-3chloro-isonicotinic acid. LC/MS [10.25 min; 390.9 (M−1)-ESI-].
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:13]=1[CH2:14][NH:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>N1C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:13]=1[CH2:14][N:15]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:36](=[O:38])[CH3:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(OCCOCc2ccccc2)c(CNc2cc(F)ccc2Oc2ccccc2)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(OCCOCc2ccccc2)c(CN(C(C)=O)c2cc(F)ccc2Oc2ccccc2)c1
Yield: 79 %

Procedure:
To a solution of 5.08 g (10.7 mmol) crude 2b in 50 ml ml pyridine was added 4.37 g (42.8 mmol) acetic acid anhydride. The reaction mixture was stirred over night and poured into ice-cold ethyl acetate. The organic phase was washed with water, diluted aqueous sodium hydrogen sulfate, water and brine and were dried with magnesium sulfate. The crude product was purified by silica column chromatography (ethyl acetate:hexane gradient 1:8→1:4). The desired product 2c was obtained in 79% yield (4.36 g, 8.45 mmol).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1B(O)O.[Cl:15][C:16]1[NH:17][C:18]2[C:23]([C:24]=1[CH:25]=[O:26])=[CH:22][CH:21]=[CH:20][CH:19]=2.N1C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:15][C:16]1[N:17]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][O:2][CH3:1])[C:18]2[C:23]([C:24]=1[CH:25]=[O:26])=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: COCCOc1ccccc1B(O)O
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COCCOc1ccccc1-n1c(Cl)c(C=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.6 %

Procedure:
To a suspension of 500 mg pulverized molecular sieves (4 Å), the compound of step 2 (761 mg, 3.88 mmol), 2-chloro-1H-indole-3-carbaldehyde (465 mg, 2.59 mmol) and copper(II) acetate (940 mg, 5.18 mmol) in DCM (20 ml) was added pyridine (0.42 ml, 5.18 mmol) and triethylamine (0.72 ml, 5.18 mmol). The reaction mixture was stirred at room temperature for one week. The mixture was diluted with water and extracted with DCM. The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by preparative HPLC. The eluate was lyophilized overnight to give 56 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([CH3:10])[CH:3]=1.[H-].[Na+].Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH4+].[Cl-]>CN(C=O)C>[CH2:17]([O:16][C:14](=[O:15])[NH:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([CH3:10])[C:5]=1[NH2:9])[CH3:18]
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(Br)cc(N)c1N
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1cc(Br)cc(C)c1N
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
To a stirred solution of 5-bromo-3-methylbenzene-1,2-diamine (4 g) in DMF (80 ml) was added NaH (40% oil dispersion, 800 mg) at 0° C., and the reaction mixture was stirred for another 30 min at the same temperature. A solution of ethyl chloroformate (1.9 g) in DMF (10 ml) was added dropwise thereto at 0° C. and then the resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into saturated NH4Cl solution, and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (2.5 g) as a yellow solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH:8]([C:13]([OH:15])=[O:14])[CH2:7]1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[O:12]=[C:11]1[NH:6][CH2:7][CH:8]([C:13]([OH:15])=[O:14])[CH2:9][CH2:10]1
Reactant: COc1ccc(CN2CC(C(=O)O)CCC2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C1CCC(C(=O)O)CN1
Temperature: 80 °C
Reaction time: 6 h
Yield: 94.6 %

Procedure:
To an optically active compound of 1-(2,4-dimethoxybenzyl)-6-oxopiperidine-3-carboxylic acid (1.36 g) were added anisole (758 μl) and trifluoroacetic acid (10 ml), and the mixture was stirred at 80° C. for 6 hours. This reaction solution was cooled to room temperature, and then concentrated under reduced pressure. To the resulting residue was added diisopropyl ether, and the mixture was stirred at room temperature. The insoluble substance was collected by filtration, and dried under reduced pressure to give the titled compound (628 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:6]([CH2:8][C:9](OCC)=[O:10])=O.[CH3:19][NH:20][NH2:21]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[CH2:8][C:9](=[O:10])[N:20]([CH3:19])[N:21]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(OC)c1
Reactant: CNN
Solvent: CCO
Product: COc1ccc(C2=NN(C)C(=O)C2)cc1OC
Yield: 40.1 %

Procedure:
Using General Procedure A; ethyl 3,4-dimethoxybenzoylacetate (5.00 g, 19.8 mmol, 1.1 equ.) in ethanol (60 mL) was treated at 0° C. with methylhydrazine (0.95 mL, 19.8 mmol, 1.0 equiv.) to give 3-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrazol-5(4H)-one (1.86 g, 7.94 mmol, 44%) after purification by chromatography on silica gel (hexanes:ethyl acetate; 4:1 to 1:1) as a light yellow powder. 1H-NMR (400 MHz) CDCl3: 7.35-7.35 (d, 1H), 7.06-7.04 (dd, 1H), 6.87-6.85 (d, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.57 (s, 2H), 3.39 (s, 3H), 13C-NMR (100 MHz) CDCl3: 171.6, 154.1, 151.1, 149.4, 124.1, 119.6, 110.7, 107.3, 55.9, 55.9, 38.0, 31.3; LC/MS-MS: 235.1→219.0 m/z; GS1 and GS2 at 30, DP=66, CE=33, CXP=14, tR=3.26 min.
Reaction SMILES: CN(C)CCC1C2C(O)=CC=C(F)C=2N(C)C=1.[CH2:18]([N:25]1[C:33]2[C:28](=[C:29]([O:35]CC3C=CC=CC=3)[CH:30]=[CH:31][C:32]=2[F:34])[C:27]([CH2:43][CH2:44][N:45]([CH3:47])[CH3:46])=[CH:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([N:25]1[C:33]2[C:32]([F:34])=[CH:31][CH:30]=[C:29]([OH:35])[C:28]=2[C:27]([CH2:43][CH2:44][N:45]([CH3:46])[CH3:47])=[CH:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN(C)CCc1cn(Cc2ccccc2)c2c(F)ccc(OCc3ccccc3)c12
Agent: CN(C)CCc1cn(C)c2c(F)ccc(O)c12
Product: CN(C)CCc1cn(Cc2ccccc2)c2c(F)ccc(O)c12

Procedure:
Following the procedure used to prepare compound 1-9c (step 8 scheme 1), compound 7-2 gave compound 7-3 (table 7).