Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:20][CH2:19][C:11]2([O:16][C@@H:15]([CH3:17])[CH2:14][C@H:13]([CH3:18])[O:12]2)[C@H:10]([CH3:21])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[CH3:17][C@H:15]1[CH2:14][C@H:13]([CH3:18])[O:12][C:11]2([CH2:19][CH2:20][NH:8][CH2:9][C@H:10]2[CH3:21])[O:16]1
Reactant: [H][H]
Reactant: C[C@@H]1CN(Cc2ccccc2)CCC12O[C@@H](C)C[C@H](C)O2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1CNCCC12O[C@@H](C)C[C@H](C)O2
Reaction time: 4 h
Yield: 98 %

Procedure:
To a solution of (2S,4S,7R)-9-benzyl-2,4,7-trimethyl-1,5-dioxa-9-azaspiro[5.5]undecane from Example 1A (20.30 g, 70.20 mmol) in methanol (300 mL) was added palladium hydroxide (0.986 g, 7.02 mmol) and the mixture stirred under 60 psi pressure of hydrogen. After 4 hours, the mixture was filtered and concentrated to provide 13.71 g (98%) of the title compound as an oil. 1H NMR (300 MHz, CDCl3) δ 4.06-3.97 (m, 2H), 2.94 (dd, 1H, J=12.7, 4.0 Hz), 2.87 (dd, 2H, J=5.2, 5.2 Hz), 2.66 (dd, 1H, J=12.7, 5.6 Hz), 1.92-1.85 (m, 1H), 1.82-1.73 (m, 1H), 1.63-1.53 (m, 4H), 1.20 (d, 3H, J=6.4 Hz), 1.19 (d, 3H, J=6.4 Hz), 0.96 (d, 3H, J=7.1 Hz); MS (DCI/NH3) m/e 200 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=O.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1cccc(F)c1
Reactant: Cc1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a solution of ethyl 3-fluorobenzoate (2.0 g, 11.9 mmol) and 4-methylpyridine (1.1 mL, 1.0 g, 10.8 mmol) in THF (9 mL) at 0° C. under nitrogen atmosphere was added dropwise lithium bis(trimethylsilyl)amide (23.8 mL, 1.0M in hexane, 23.8 mmol) During the addition a precipitate was formed and the suspension was stirred at room temperature overnight. The reaction was diluted with hexane (40 mL) and filtered. The solid was partitioned between ethyl acetate and a saturated solution of ammonium chloride. The organic phase was dried (MgSO4) and evaporated under reduced pressure to give the title compound as a yellow solid (2.09 g, 82%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.Br[C:19]1[C:20]2[C:21]3[CH:34]=[CH:33][S:32][C:22]=3[C:23](=[O:31])[NH:24][C:25]=2[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[CH3:30][O:29][C:28]1[CH:27]=[CH:26][C:25]2[NH:24][C:23](=[O:31])[C:22]3[S:32][CH:33]=[CH:34][C:21]=3[C:20]=2[C:19]=1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Yield: 49.3 %

Procedure:
Following General Procedure E, tert-butyl 1-(4-bromophenyl)ethylcarbamate (3.0 g, 10 mmol) was reacted with 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (2.8 g, 9.0 mmol) to afford the desired product (2.0 g, 50%) as a brown solid: ESI MS m/z 451 [C25H26N2O4S+H]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33](O)=[C:32]([CH3:38])[CH:31]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33]([O:1][CH2:2][CH:3]2[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[CH2:4]2)=[C:32]([CH3:38])[CH:31]=1
Reactant: CN1CCCC(CO)C1
Reactant: Cc1cc(Br)cc(C)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1OCC1CCCN(C)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 66.2 %

Procedure:
3-Hydroxymethyl-1-methylpiperidine (0.4 mL, 3.14 mmol) and triphenylphosphine (1.01 g, 3.85 mmol) were added to a solution of 4-bromo-2,6-dimethylphenol (517 mg, 2.57 mmol) in tetrahydrofuran (10 mL) at 0° C. under dry nitrogen, followed by the dropwise addition of diethyl azodicarboxylate (0.57 mL, 3.60 mmol). The mixture was stirred at 0° C. for 4 hours and the solvent removed in vacuo. The residue was purified on silica gel, eluting with 5% methanol in dichloromethane containing 0.25% ammonium hydroxide, to give 3-(4-bromo-2,6-dimethylphenoxymethyl)-1-methylpiperidine as an oil (531 mg, 66%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=3)[NH:12][C:11]=2[C:20]([O:22]CC)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+:26]>[OH-].[NH4+]>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=3)[NH:12][C:11]=2[C:20]([NH2:26])=[O:22])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [OH-]
Product: NC(=O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Temperature: 100 °C

Procedure:
A suspension of ethyl 3-phenylsulfonyl-5-chloroindole-2-carboxylate (596 mg, 1.64 mmol) in aqueous conc. ammonium hydroxide (10 mL) containing ammonium chloride (28 mg) was heated at 100° C. for 3 hours in a sealed screw-top tube. The sealed tube was cooled in an ice bath as product crystallized out. The product was collected by filtration, rinsed with ice water, and dried to give the product, mp 253°-254° C.
Reaction SMILES: F[B-](F)(F)F.C(O[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])=[NH2+:10])C.[O-]CC.[Na+].[N:22]#[C:23][NH2:24]>C(O)C>[C:23]([N:24]=[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[NH2:10])#[N:22]
Reactant: CCOC(=[NH2+])c1ccccc1C
Reactant: N#CN
Agent: CC[O-]
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCO
Product: Cc1ccccc1C(N)=NC#N
Yield: 18.8 %

Procedure:
To a solution of Example 19A (2.5 g 10.00 mmol) in 10 ml of absolute ethanol was added a solution of sodium ethoxide (681 mg, 10 mmol) in 3.7 ml of absolute ethanol. The precipitate was filtered and the filtrate was treated with a solution of cyanamide (420 mg, 10 mmol) in 10 ml of absolute ethanol. The reaction mixture was refluxed for 3 days and the solvent removed under reduced pressure. The crude mixture was purified by silica gel chromatography, eluting with a gradient of 0-50% ethyl acetate in methylene chloride to provide the 0.3 g of title compound. MS (ESI+) m/z 160 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([NH2:10])=[O:9].Cl.[N:20]([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:3]2[C:2]3[N:1]=[N:20][NH:10][C:8](=[O:9])[C:7]=3[CH:6]=[CH:5][N:4]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2nccc(C(N)=O)c2N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2nccc3c(=O)[nH]nnc23)cc1
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
300 mg of 3-amino-2-(4-methoxyphenyl)-4-pyridinecarboxamide were stirred at 0° C. in 5 ml of glacial acetic acid and 1 ml of concentrated hydrochloric acid during the addition of 128 mg of sodium nitrite in 2 ml of water. The cooling bath was removed, 3 ml of water were added, the mixture was stirred for 0.5 hour and the precipitated product was removed by filtration. Recrystallization from aqueous dimethylformamide yielded 275 mg of 8-(4-methoxyphenyl)pyrido[3,4-d]-1,2,3-triazin-4(3H)-one as yellow needles of melting point 226° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:13])([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>O>[C:20]([O:13][C:8]([C:6]1[CH:5]=[CH:4][C:3]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:2]([F:1])[CH:7]=1)([CH3:12])[C:9]([OH:11])=[O:10])(=[O:22])[CH3:21]
Reactant: CC(O)(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)OC(C)(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Reaction time: 2 h

Procedure:
The product from Example 1 (5 g.) was added to acetic anhydride (50 ml.) and the mixture heated on a steam bath for 2 hours after the acid had all dissolved. The mixture was then cooled and poured into water (200 ml.). The aqueous mixture was allowed to stand for 2 hours and the product collected recrystallised from a mixture of ether and light petroleum (b.p. 62°-68° C.) gave 2-acetoxy-2-(2-fluoro-4-biphenylyl)propionic acid, m.p. 141°-142° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([OH:26])=O)[CH:21]=[CH:20][S:19]3)[CH2:3][CH2:2]1.[F:27][C:28]([F:38])([F:37])[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([NH:34][C:33]2[CH:35]=[CH:36][C:30]([O:29][C:28]([F:27])([F:37])[F:38])=[CH:31][CH:32]=2)=[O:26])[CH:21]=[CH:20][S:19]3)[CH2:3][CH2:2]1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)Nc2ccc(OC(F)(F)F)cc2)c1OCC1CC1

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 1 (95 mg, 0.256 mmol) with 4-(trifluoromethoxy)aniline (54 mg, 0.307 mmol) in the presence of EDCI hydrochloride (98 mg, 0.512 mmol) and DMAP (47 mg, 0.384 mmol) in a mixture of DCM and DMF (4:1, 5 mL) to give 68 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.23-0.26 (m, 2H), 0.43-0.47 (m, 2H), 1.13-1.15 (m, 1H), 3.73 (d, J=6.6 Hz, 2H), 3.78 (s, 3H), 6.92-6.96 (m, 1H), 7.04 (t, J=7.8 Hz, 1H), 7.22-7.25 (m, 1H), 7.35-7.38 (m, 3H), 7.44 (d, J=16.2 Hz, 1H), 7.77-7.81 (m, 2H), 7.86 (d, J=16.2 Hz, 1H), 8.01 (d, J=4.2 Hz, 1H), 10.47 (s, 1H); ESI-MS (m/z) 530.37 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]([OH:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1>CCCCCC.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@@H:9]1[CH:21]([OH:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCCCCC
Product: CC(O)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C

Procedure:
To compound 1K (0.1M solution in 10% CH3CN in DCM) add NMO (2 equiv) followed by TPAP (0.05 equiv). Provide sufficient ventilation and take care to watch for exotherm. Stir reaction at rt for 3-5 h. Dilute by half with hexane and allow TPAP to precipitate. Flash filter through silica gel plug (20 fold mass of starting alcohol) and elute with 10% EtOAc/Hex until product is not observed in eluent. Removal of solvents gave the title compound. MS (ES) m/z 344.31 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[C:10]([CH2:15][CH3:16])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.[Pd]>[C:1]([O:5][C:6]([NH:8][NH:9][CH:10]([CH2:15][CH3:16])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(=NNC(=O)OC(C)(C)C)C(C)(C)C
Agent: [Pd]
Solvent: ClCCl
Product: CCC(NNC(=O)OC(C)(C)C)C(C)(C)C

Procedure:
Approximately 10.3 g N′-(1-ethyl-2,2-dimethyl-propylidene)-hydrazinecarboxylic acid tert-butyl ester was mixed with 4.14 g (3.9 mmol) 10% Pd/C in CH2Cl2 under an atmosphere of hydrogen in a Parr shaker for four hours. The reaction was monitored by TLC (12 indicator), and the crude product was twice chromatographed using 10% ether in hexane to yield N′-(1-ethyl-2,2-dimethyl-propyl)-hydrazinecarboxylic acid tert-butyl ester. 1H NMR (CDCl3, 500 MHz) δ (ppm): 6.05 (br, 1H), 3.9 (br, 1H)), 2.45 (m, 1H), 1.6 (m, 1H), 1.5 (s, 9H), 1.25 (m, 1H), 1.1 (t, 3H), 0.92 (s, 9H).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[CH2:20][CH:19]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]#[N:28])[CH2:23][CH2:22]4)[O:18][C:15]3=[CH:16][N:17]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[OH:29][NH:30][C:31](=N)[CH2:32][CH2:33][CH3:34]>>[CH3:1][S:2]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[C:14]3[CH2:20][CH:19]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]5[O:29][N:30]=[C:31]([CH2:32][CH2:33][CH3:34])[N:28]=5)[CH2:23][CH2:22]4)[O:18][C:15]3=[CH:16][N:17]=2)=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: CCCC(=N)NO
Reactant: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCN(C#N)CC2)C3)cc1
Product: CCCc1noc(N2CCC(C3Cc4cc(-c5ccc(CS(C)(=O)=O)cc5)ncc4O3)CC2)n1

Procedure:
The title compound is prepared from 4-[5-(4-methanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile and N-hydroxy-butyramidine following a procedure analogous to that described in Example 2. LC (method 6): tR=1.46 min; Mass spectrum (ESI+): m/z=483 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1O)=[CH:11][C:10]([CH3:15])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:18])=O>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[Cl:18])=[CH:11][C:10]([CH3:15])=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc2ccc(C)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CC(=O)c1cnc2ccc(C)cc2c1Cl

Procedure:
3-Acetyl-4-hydroxy-6-methylquinoline (0.02 mol), prepared according to R. K. MAPARA and C. M. DESAI (CA 50 1011 b) is added to 40 ml of freshly distilled phosphorus oxychloride. The mixture is brought to reflux for 10 minutes. The solution is brought back to room temperature and then poured onto an ice/caustic soda mixture. After extraction with dichloromethane, the ogranic phase is decanted, washed until neutral, dried and concentrated. The 3-acetyl-4-chloro-6-methylquinoline (m.p. 145° C.) is used without further purification for the following stage.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([Br:25])=[CH:20][C:19]=1Br)[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2].[CH2:27]=[N:28]O.[N+](C1C=CC=CC=1)([O-])=O>[Cu]I.C(N(CC)CC)C>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([Br:25])=[CH:20][C:19]=1[C:27]#[N:28])[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: CCN(CC)c1ccc(N=Nc2c(C)cc(Br)cc2Br)c(NC(C)=O)c1
Reactant: C=NO
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O=[N+]([O-])c1ccccc1
Product: CCN(CC)c1ccc(N=Nc2c(C)cc(Br)cc2C#N)c(NC(C)=O)c1
Temperature: 90 °C

Procedure:
A stirred mixture of 3-acetylamino-4-(2', 4'-dibromo-6'-methylphenylazo)-N,N-diethylaniline (4.8 parts), copper (I) iodide (2.0 parts), formaldoxime trimer (1.8 parts), triethylamine (1.5 parts), and nitrobenzene (100 parts) was heated to 90° C. for 11/2 hours when thin layer chromatography showed reaction to be complete. Isolation by the method of Example 3 gave 3-acetylamino-4-(2'-cyano-4'-bromo-6'-methylphenylazo)-N,N-diethylaniline, infra red spectrum identical with that of authentic material.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:49])[C:32]([C:47]#[N:48])=[CH:33][C:34]([N:37]([CH2:45][CH3:46])C(=O)OC(C)(C)C)([CH3:36])[CH3:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:33][C:34]([NH:37][CH2:45][CH3:46])([CH3:35])[CH3:36])[C:47]#[N:48])=[O:49])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CCN(C(=O)OC(C)(C)C)C(C)(C)C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: O=C(O)C(F)(F)F
Product: CCNC(C)(C)C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 5-((R)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl(ethyl)carbamate (60 mg, 0.089 mmol) DCM (10 mL) was added 2.5 mL of CF3COOH. The mixture was stirred for 2 h at room temperature. The volatile phase was removed under reduced pressure and the residue was purified on Prep-HPLC. Conditions: (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm. This resulted 12 mg (16%) of the title compound as a white solid and bis TFA salt. LC-MS: m/z 569 (M+H+). H-NMR (400 MHz, CD3OD, ppm). 8.37 (s, 1H), 7.72 (s, 1H), 7.57 (t, J=8.4 Hz, 1H), 7.48 (t, J=8.0 Hz, 2H), 7.28 (t, J=7.2 Hz, 1H), 7.17 (d, 8.0 Hz, 2H), 6.97 (dd, J=8.4 Hz, 2.0 Hz, 1H), 6.91 (dd, J=11.6 Hz, 2.0 Hz, 1H), 4.95-4.82 (m, 2H), 4.70-4.65 (m, 1H), 3.71-3.65 (m, 3H), 3.59-3.55 (m, 1H), 2.15-2.11 (m, 1H), 2.02-1.93 (m, 2H), 1.81-1.79 (m, 1H), 1.53 (s, 3H), 1.47 (s, 3H), 1.29 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1.[NH2:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CC(N(C)C)=O>[CH3:13][O:12][C:10](=[O:11])/[CH:9]=[CH:8]/[C:5]1[N:6]=[CH:7][C:2]([NH:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)=[N:3][CH:4]=1
Reactant: COC(=O)/C=C/c1cnc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)/C=C/c1cnc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cn1
Temperature: 92.5 °C
Reaction time: 6 h
Yield: 60.7 %

Procedure:
A mixture of methyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (10.00 g), tert-butyl (3R)-3-amino-1-pyrrolidinecarboxylate (14.01 g) and potassium phosphate (21.30 g) in DMA (25 mL) was stirred at 90-95° C. for 6 hours under nitrogen atmosphere. After addition of water, the reaction mixture was extracted with AcOEt. Water was added to the organic layer and the mixture was adjusted to pH 8 with 1N HCl aq., washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by silica gel (chromatorex NH) (hexane-AcOEt 60:40 v/v) to give tert-butyl (3R)-3-({5-[(1E)-3-methoxy-3-oxo-1-propen-1-yl]-2-pyrazinyl}amino)-1-pyrrolidinecarboxylate as a solid (10.64 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[OH:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=1.[OH-].[K+]>CS(C)=O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([O:12][C:13]2[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH2:21])=[O:20])=[CH:23][CH:24]=2)=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: CC(Oc1ccc(O)cc1)C(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(N)=O
Reaction time: 5 h
Yield: 50 %

Procedure:
18 g of p-chloro-α,α,α-trifluorotoluene and 18 g of α-(p-hydroxyphenoxy)propionamide were dissolved in 50 ml of dimethyl sulfoxide, and 5.6 g of potassium hydroxide was added. The reaction was performed at 130° to 150° C. for about 5 hours. After the reaction, the reaction product was purified in a customary manner to afford the final product having a melting point of 157° to 158° C. The yield was 50%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.CO.Cl[CH2:15]Cl.C[Si](C=[N+]=[N-])(C)C>C1COCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:15])=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: ClCCl
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 2-(4-aminophenyl)acetic acid (170 mg, 1.1 mmol) in a mixture of THF (4 ml), MeOH (1 ml) and dichloromethane (1 ml) in a 20-mL vial was added dropwise (trimethylsilyl)diazo-methane (1 ml, 2N in hexane) at 0° C. After the addition was complete, the resulting mixture was stirred at room temperature for 1 hr. The volatile material was removed under reduced pressure and the residue was purified by chromatography on silica gel using hexane/dichloromethane (2:1) followed by dichloromethane as eluent to give methyl 2-(4-aminophenyl)acetate as an yellowish oil (97 mg, 53% yield).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(C(C)C)CC)(C)C.[CH3:30][N:31]([CH3:38])[C:32](=[O:37])[CH2:33][CH2:34][NH:35][CH3:36]>ClCCl>[C:19]([C:7]1[C:5]2[N:6]=[C:2]([N:35]([CH3:36])[CH2:34][CH2:33][C:32]([N:31]([CH3:38])[CH3:30])=[O:37])[O:3][C:4]=2[C:10]([F:11])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[CH3:18])#[N:20]
Reactant: CNCCC(=O)N(C)C
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccccc2)c(F)c2oc(N(C)CCC(=O)N(C)C)nc2c1C#N

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.20 g, 0.84 mmol) was dissolved in dichloromethane (10 ml), and diisopropylethylamine (0.16 ml, 0.94 mmol) and N,N-dimethyl-3-(methylamino)propionamide (I-149) (0.11 g, 0.84 mmol) were added. After heated under reflux for 3 hours, this was diluted with dichloromethane.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].N[C:10]1[C:15]([C:16]#[N:17])=[N:14][C:13]([C:18]2[C:26]3[O:25][C:24]([CH3:28])([CH3:27])[CH:23]([OH:29])[C:22]=3[CH:21]=[CH:20][CH:19]=2)=[CH:12][N:11]=1>CO>[NH2:7][C:6]1[N:8]=[C:16]([NH2:17])[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:18]3[C:26]4[O:25][C:24]([CH3:27])([CH3:28])[CH:23]([OH:29])[C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[N:5]=1
Reactant: N=C(N)N
Reactant: CC1(C)Oc2c(-c3cnc(N)c(C#N)n3)cccc2C1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1(C)Oc2c(-c3cnc4nc(N)nc(N)c4n3)cccc2C1O
Reaction time: 0.08 h

Procedure:
A solution of 2.8 grams (0.052 mole) of sodium methoxide in 100 mL of methanol is stirred, and 1.9 grams (0.019 mole) of guanidine hydrochloride is added. Upon completion of addition, the reaction mixture is stirred for about 5 minutes and then is filtered to remove sodium chloride. The filtrate is then added to 4.5 grams (0.01 6 mole) of 2-amino-3-cyano-5-(2,3-dihydro-3-hydroxy-2,2-dimethylbenzofuran-7-yl)pyrazine. The stirring reaction mixture is then heated to reflux where it is stirred for about 18 hours. After this time the reaction mixture is cooled and filtered. The filter cake is washed with water and dried, yielding 2,4-diamino-6-(2,3-dihydro-3-hydroxy-2,2-dimethylbenzofuran-7-yl)pteridine.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21].Cl>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:13]=[CH:14][C:15]([C:20](=[O:21])[CH2:19][Cl:18])=[CH:16][CH:17]=1
Reactant: Clc1ccccc1-c1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)c1ccc(-c2ccccc2Cl)cc1
Reaction time: 18 h
Yield: 90.3 %

Procedure:
293.7 g (2.2 mols) of aluminium chloride are introduced in portions to a solution of 377 g (2 mols) of 2-chlorobiphenyl in 160 ml (2 mols) of chloroacetyl chloride and 1,000 ml of methylene chloride. After 18 hours, the reaction mixture is poured onto ice and hydrochloric acid. The organic phase is seperated off, washed, dried over sodium sulphate and concentrated in vacuo by distilling off the solvent. The oil which remains is purified by distillation. 478.7 g (90% of theory) of 4(2-chlorophenyl)phenacyl chloride of melting point 47° C. are obtained.