Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:10]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:11][C:12]([CH3:29])=[C:13]([CH3:28])[C:14]=1[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].[CH2:37]([O:39][CH2:40][C:41](Cl)=[O:42])[CH3:38]>ClCCl>[CH2:37]([O:39][CH2:40][C:41]([NH:8][C:9]1[C:10]([O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[N:11][C:12]([CH3:29])=[C:13]([CH3:28])[C:14]=1[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:42])[CH3:38]
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCCCNC(=O)OC(C)(C)C)c1C
Reactant: CCOCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCC(=O)Nc1c(Oc2ccccc2)nc(C)c(C)c1NCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (3.3 mL, 23.7 mmol) was added to a chilled (0° C.) mixture of tert-butyl 4-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]butylcarbamate (8.60 g, 21.5 mmol) and anhydrous dichloromethane (200 mL). Ethoxyacetyl chloride (2.76 g, 22.5 mmol) was added. After one hour the reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to provide tert-butyl 4-({3-[(ethoxyacetyl)amino]-5,6-dimethyl-2-phenoxypyridin-4-yl}amino)butylcarbamate as a brown oil. The oil was combined with pyridine (130 mL) and heated at reflux overnight. The reaction mixture was concentrated under reduced pressure to provide a brown oil. The oil was dissolved in dichloromethane and was washed with water. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in diethyl ether and then concentrated under reduced pressure to provide 8.21 g of tert-butyl 4-[2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]butylcarbamate.
Reaction SMILES: [F:1][C:2]([F:15])([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:3](OCC)=[O:4].[NH2:16][NH2:17].O>CCO>[F:1][C:2]([F:15])([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:3]([NH:16][NH2:17])=[O:4]
Reactant: CCOC(=O)C(F)(F)Cc1ccccn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)C(F)(F)Cc1ccccn1
Reaction time: 1 h

Procedure:
The product of Example 66 (0.18 g, 0.84 mmol) was dissolved in 5 mL of EtOH. To the solution was added NH2NH2.H2O (0.084 g, 1.7 mmol). The reaction was complete in 1 hour. The solvent-was removed under vacuum. The structure was confirmed by 1H NMR.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[O:11][CH:10]=[C:9]([C:19](O)=[O:20])[C:8]2=[O:22])(=[O:3])[CH3:2].C1C=CC=CC=1.S(Cl)([Cl:31])=O.CN(C)C=O>CCCCCC>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[O:11][CH:10]=[C:9]([C:19]([Cl:31])=[O:20])[C:8]2=[O:22])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2occ(C(=O)O)c(=O)c2cc1OC(C)=O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2occ(C(=O)Cl)c(=O)c2cc1OC(C)=O
Temperature: 25 °C
Yield: 90.3 %

Procedure:
A mixture of 6,7-diacetoxychromone-3-carboxylic acid (18.4 g, 60 mmol), benzene (450 ml), thionyl chloride (8.6 g, 72 mmol) and dimethylformamide (3 ml) was refluxed for one hour, and cooled to room temperature. After the addition of n-hexane (300 ml), the resulting precipitate was collected to give the desired compound (17.6 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.CO.[OH-].[K+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1-c1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1nc(-c2ccc(F)cc2)oc1-c1cccs1
Yield: 91.3 %

Procedure:
14.0 g of ethyl 2-[2-(4-fluorophenyl)-5-(2-thienyl)-4-oxazolyl]acetate, 300 ml of methanol, 30 ml of water and 5.6 g of potassium hydroxide are treated in the same manner as described in Example 8. 11.7 g of 2-[2-(4-fluorophenyl)-5-(2-thienyl)-4-oxazolyl]acetic acid are thereby obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:13][CH:14]([F:16])[F:15])CC=C)=[CH:4][CH:3]=1>C(O)CCC.[Pd]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:13][CH:14]([F:16])[F:15])=[CH:4][CH:3]=1
Reactant: C=CCN(Cc1ccc(Cl)nc1)CC(F)F
Agent: [Pd]
Solvent: CCCCO
Product: FC(F)CNCc1ccc(Cl)nc1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
An amount of 2 g (7.38 mmol) of N-[(6-chloropyridin-3-yl)methyl]-N-(2,2-difluoroethyl)prop-2-en-1-amine is placed in 20 ml of n-butanol and treated with 100 mg of 10% palladium-on-charcoal (water-moistened). The mixture is subsequently stirred and heated at reflux for 18 h until complete conversion has been achieved. The reaction mixture is cooled to ambient temperature and then filtered through celite. The solvent is removed under vacuum. An amount of 1.3 g of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethanamine is obtained (corresponds to 84% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](OC)[N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:22])=O>CN(C)C=O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:22])[N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@H](c2cccc(OC)n2)CC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@H](c2cccc(Cl)n2)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of trans-4-(6-methoxy-pyridin-2-yl)-cyclohexanecarboxylic acid ethyl ester (0.55 g, 2.1 mmol) in N,N-dimethylformamide (21 ml) was added phosphorus oxychloride (0.96 ml, 10 mmol) at room temperature. Stirring for 2 h at 90° C. was followed by stirring for 24 h at 120° C. After cooling to room temperature the reaction mixture was poured onto crushed ice, stirred for 10 minutes and extracted with three 100-ml portions of ethyl acetate. The combined organic layers were washed with two 50-ml portions of water and one 50-ml portion of brine, dried over anhydrous sodium sulfate and concentrated to dryness. Purification by flash-chromatography gave the title compound (0.20 g, 36%) as light yellow oil. MS m/e: 268 ([M+H]+)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](COS(C)(=O)=O)C1
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (0.48 mL) was added to a solution of (S)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (1.10 g) and triethylamine (1.42 mL) in DCM (20 mL) at 0° C. under nitrogen. The reaction was stirred for 2 h before being partitioned between DCM (200 mL) and water (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford the subtitle product (1.20 g) as a yellow oil.
Reaction SMILES: [C:1]([S:5](/[N:7]=[C:8](/[C:10]1[N:11]=[N:12][N:13]([C:15]2[CH:16]=[C:17]([CH:30]=[C:31]([N:33]([S:37]([CH3:40])(=[O:39])=[O:38])[CH2:34][CH2:35][CH3:36])[CH:32]=2)[C:18]([NH:20][C@@H:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:22])=[O:19])[CH:14]=1)\[CH3:9])=[O:6])([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.[CH2:45]([Li])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C1(C)C=CC=CC=1>[C:1]([S:5]([NH:7][C:8]([C:10]1[N:11]=[N:12][N:13]([C:15]2[CH:16]=[C:17]([CH:30]=[C:31]([N:33]([S:37]([CH3:40])(=[O:38])=[O:39])[CH2:34][CH2:35][CH3:36])[CH:32]=2)[C:18]([NH:20][C@@H:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:22])=[O:19])[CH:14]=1)([CH3:9])[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:6])([CH3:2])([CH3:4])[CH3:3]
Reactant: [Li]Cc1ccccc1
Reactant: CCCN(c1cc(C(=O)N[C@H](C)c2ccc(F)cc2)cc(-n2cc(/C(C)=N/S(=O)C(C)(C)C)nn2)c1)S(C)(=O)=O
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCCN(c1cc(C(=O)N[C@H](C)c2ccc(F)cc2)cc(-n2cc(C(C)(Cc3ccccc3)NS(=O)C(C)(C)C)nn2)c1)S(C)(=O)=O
Reaction time: 1 h
Yield: 23.4 %

Procedure:
To a 0° C. suspension of 0.03 g (0.05 mmol) 3-{4-[(1E)-N-(tert-butylsulfinyl)ethanimidoyl]-1H-1,2,3-triazol-1-yl}-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[(methylsulfonyl)(propyl)amino]benzamide in 5 mL toluene was added 0.1 mL (0.2 mmol, 2M solution in toluene) trimethylaluminum followed by 1 mL (approx. 0.2 mmol, 0.2 mM solution in ether) benzyllithium. The reaction mixture was stirred for 1 hr, then 0.4 mL more benzyllithium was added and the reaction mixture stirred for another hour at 0° C. The reaction was quenched by addition of 1 mL of saturated sodium sulfate solution and 50 mL EtOAc and stirred vigorously. To this was added MgSO4 and the resulting mixture was filtered through celite and concentrated. Purification by flash chromatography (1×8 cm silica gel, linear gradient 30-100% EtOAc/hexanes) afforded 8 mg 3-(4-{1-[(tert-butylsulfinyl)amino]-1-methyl-2-phenylethyl}-1H-1,2,3-triazol-1-yl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[(methylsulfonyl)(propyl)amino]benzamide which was dissolved in 1 mL methanol. To this was added 0.7 mL 2M HCl in ether. After 30 minutes the mixture was concentrated and purified by preparative HPLC (5->95% CH3CN/H2O over 30 min, 0.1% added TFA, C18 PRO YMC 20×150 mm) to afford 3 mg 3-[4-(1-amino-1-methyl-2-phenylethyl)-1H-1,2,3-triazol-1-yl]-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[(methylsulfonyl)(propyl)amino]benzamide as its trifluoroacetate salt. 1H NMR (CD3OD, 500 MHz) δ 8.55 (s, 1H), 8.28 (s, 1H), 8.04 (s, 1H), 7.99 (m, 1H), 7.42 (m, 2H), 7.26 (m, 3H), 7.07 (m, 2H), 7.00 (m, 2H), 5.25 (m, 1H), 3.77 (t, J=6.83 Hz, 2H), 3.47 (d, J=13 Hz, 1H), 3.27 (d, J=13 Hz, 1H), 3.01 (s, 3H), 1.76 (s, 3H), 1.59 (d, J=7.18 Hz, 3H), 1.53 (m, 2H), 0.95 (t, J=7.33 Hz, 3H). High resolution mass spec (FT/ICR) calc M+H=579.2548 found 578.2560.
Reaction SMILES: [C:1]([O:5]C(N1C[C@@H](C)N2[C@H](CC3C2=NC(Br)=CC=3)C1)=O)(C)(C)[CH3:2].[C:23]([O:27][C:28]([N:30]1[CH2:42][C@@H:41]([CH3:43])[N:40]2[C@H:32]([CH2:33][C:34]3[C:39]2=[N:38][C:37]([OH:44])=[CH:36][CH:35]=3)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].[H-].[Na+].BrCCO>>[C:23]([O:27][C:28]([N:30]1[CH2:42][C@@H:41]([CH3:43])[N:40]2[C@H:32]([CH2:33][C:34]3[C:39]2=[N:38][C:37]([O:44][CH2:2][CH2:1][OH:5])=[CH:36][CH:35]=3)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(O)nc3N21
Agent: OCCBr
Agent: [H-]
Agent: [Na+]
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(OCCO)nc3N21

Procedure:
This compound was prepared in analogy to Example 22 intermediate b), from (4R,9aR)-6-hydroxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and 2-bromoethanol.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([NH:17][C:18]3[C:26]4[O:25][CH2:24][O:23][C:22]=4[C:21]([C:27]#[C:28][CH2:29][O:30][CH3:31])=[CH:20][C:19]=3[Cl:32])=[N:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:33][CH3:34].C(N(CC)CC)C.[C:42]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:44])[CH3:43].COC(O)C>>[C:42]([N:45]1[CH2:50][CH2:49][N:48]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:17][C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[C:21]([C:27]#[C:28][CH2:29][O:30][CH3:31])=[CH:20][C:19]=4[Cl:32])=[N:12][CH:13]=[N:14]3)=[CH:9][C:8]=2[O:33][CH3:34])[CH2:47][CH2:46]1)(=[O:44])[CH3:43]
Reactant: CC(=O)N1CCNCC1
Reactant: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCCl)c(OC)cc23)c2c1OCO2
Agent: COC(C)O
Solvent: CCN(CC)CC
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCN4CCN(C(C)=O)CC4)c(OC)cc23)c2c1OCO2
Reaction time: 7 h
Yield: 17.2 %

Procedure:
A mixture of 7-(4-chlorobutoxy)-N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-6-methoxyquinazolin-4-amine (0.23 g, 0.4 mmol), triethylamine (0.22 ml, 1.6 mmol), N-acetyl piperazine (0.205 g, 1.6 mmol) in 2 methoxyethanol (2 ml) was heated to 80 C for 12 hours and then at 100 C for 7 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. Flash chromatography on silica eluting with a mixture of 2-10% methanol in dichloromethane gave the product as a light orange solid (0.041 g, 17%). NMR Spectrum: (DMSOd6 at 373k+d4 acetic acid) 1.73 (m, 2H), 1.88 (m, 2H), 1.98 (s, 3H), 2.67 (t, 4H), 3.09 (t, 2H), 3.37 (s, 3H), 3.55 (t, 4H), 3.96 (s, 3H), 4.18 (t, 2H), 4.32 (s, 2H), 6.09 (s, 2H), 7.05 (s, 1H), 7.21 (s, 1H), 7.80 (s, 1H), 8.25 (s, 1H). Mass Spectrum: M+H+ 596 and M+H− 594.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].CS[C:14](=[N:19][CH3:20])[S:15]([O-:18])(=[O:17])=[O:16]>C(#N)C>[CH3:20][NH:19][C:14]([S:15]([OH:18])(=[O:17])=[O:16])=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1]
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CN=C(SC)S(=O)(=O)[O-]
Solvent: CC#N
Product: CNC(=NCCSCc1nc[nH]c1C)S(=O)(=O)O

Procedure:
A solution of 1.43 g (0.0085 mole) of 2-(5-methyl-4-imidazolylmethylthio)ethylamine in dry acetonitrile (150 ml) was added dropwise, with stirring, to a solution of 1.43 g (0.0084 mole) of 1-methylthio-1-methyliminomethanesulphonate in dry acetonitrile (150 ml) at 50°, giving an immediate white precipitation.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]([C:15]2[S:16][C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19](=[O:21])[N:20]=2)[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)(Cl)Cl>[CH2:1]([S:8]([C:9]1[N:14]=[C:13]([C:15]2[S:16][C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19](=[O:21])[N:20]=2)[CH:12]=[CH:11][CH:10]=1)=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1nc(-c2cccc(SCc3ccccc3)n2)sc2ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=c1nc(-c2cccc(S(=O)Cc3ccccc3)n2)sc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
2-(6-Benzylthio-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.18 g, 0.50 mmol) was dissolved in chloroform (30 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.11 g, 0.50 mmol) in chloroform (10 ml) was added dropwise thereto. The reaction mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.057 g, 30%) as pale yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].Br[CH2:15][CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>>[C:21]([Si:18]([O:17][CH2:16][CH2:15][O:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=1[N+:1]([O-:3])=[O:2])([CH3:20])[CH3:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=[N+]([O-])c1cccc(O)c1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Product: CC(C)(C)[Si](C)(C)OCCOc1cccc([N+](=O)[O-])c1[N+](=O)[O-]

Procedure:
tert-Butyl-[2-(2,3-dinitro-phenoxy)-ethoxy]-dimethyl-silane was prepared by a procedure according to example 108 (i) starting from 500 mg (2.72 mmol) 2,3-dinitro-phenol and 1.00 g (4.18 mmol) (2-Bromo-ethoxy)-tert-butyl-dimethyl-silane.
Reaction SMILES: [C:1]([C:17]([NH:19][CH2:20][CH2:21][OH:22])=[O:18])([C:4]([C:7]([C:10]([C:13]([F:16])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[C:23]([O:26][CH2:27][CH3:28])(=[O:25])C>O>[C:1]([C:17]([NH:19][CH2:20][CH2:21][OH:22])=[O:18])([C:4]([C:7]([C:10]([C:13]([F:16])([F:14])[F:15])([F:11])[F:12])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[NH2:19][C:23]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(C)=O
Agent: O=C(NCCO)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: O
Product: CCOC(N)=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A 500 mL round bottom flask equipped with a magnetic stirrer and fitted with a condenser was charged with C5F11CONHC2H4OH (30.0 grams), ethyl acetate (46.3 grams) and N3300 (16.3 grams). Upon dissolution, the mixture was heated to 80° C., DBTDL (one drop) was added, and heating was continued for 16 hours. The reaction was monitored by FTIR analysis, which showed the disappearance of the —NCO band at approximately 2289 wavenumbers. A solution of Witconate DS-10 (2.3 grams) in DI water (220.0 grams) was slowly added to the solution in the 500 mL flask with vigorous stirring, keeping the temperature between 65° C. and 73° C. during addition. Upon completion of addition, the solution was sonicated with a Cole-Parmer ultrasonic homogenizer (model CPX 600, available from Cole-Parmer, Vernon Hills, Ill.) for 8 minutes. The ethyl acetate was removed using a rotary evaporator, yielding C5F11CONHC2H4OH/N3300 Urethane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([C:24]([NH2:26])=[NH:25])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([C:24](=[NH:25])[NH2:26])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCN(C(=N)N)C4)n3)c3cc(Cl)cnc32)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N=C(N)N1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]piperidine-1-carboxamidine, 57b, (0.18 g, 0.32 mmol) in MeOH (5 mL) was added sodium methanolate (3 mL of 25% w/v, 13.88 mmol) and the reaction was stirred at room temperature. After 5 min, the mixture was concentrated in vacuo to light yellow solid. The crude residue was purified via preparatory HPLC (MeOH/1% aqueous HCl) to afford the desired product.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][C:8]([CH3:52])([CH2:50][CH3:51])[CH2:9][C:10]1[N:11]=[C:12]([CH2:34][CH:35]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][N:44]=3)=[CH:39][CH:38]=2)[OH:36])[N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1.CI>C(O)(C)(C)C>[CH3:7][C:8]([CH3:52])([CH2:50][CH3:51])[CH2:9][C:10]1[N:11]=[C:12]([CH2:34][CH:35]([C:37]2[CH:38]=[CH:39][C:40]([C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][N:44]=3)=[CH:41][CH:42]=2)[O:36][CH3:1])[N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:14]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)c2ccc(-c3ccc(F)cn3)cc2)n1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CI
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(OC)c2ccc(-c3ccc(F)cn3)cc2)n1
Reaction time: 8 h

Procedure:
Potassium tert-butoxide (21 mg, 0.19 mmol) was added to a solution of 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethanol (104 gm, 0.17 mmol) and methyl iodide (19 μL, 0.31 mmol) in tert-butanol (17 mL) at ambient temperature. After stirring overnight, the reaction mixture was washed with brine (100 mL), dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded 2-(4-{2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-methoxyethyl}phenyl)-5-fluoropyridine as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:17]([C:18]#[CH:19])=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1.[CH2:20]([O:22][C:23](=[O:42])[C@H:24]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[NH:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1)[CH3:21].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.[Pd](Cl)Cl.O>[CH2:20]([O:22][C:23](=[O:42])[C@H:24]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[NH:25][C:26](=[O:34])[C:27]1[CH:28]=[CH:29][C:30]([C:19]#[C:18][C:17]2[C:3]3[C:2]([OH:1])=[N:7][C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:5][C:4]=3[NH:15][CH:16]=2)=[CH:31][CH:32]=1)[CH3:21]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(I)cc1)C(=O)OCC
Reactant: C#Cc1c[nH]c2nc(NC(=O)C(C)(C)C)nc(O)c12
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C#Cc2c[nH]c3nc(NC(=O)C(C)(C)C)nc(O)c23)cc1)C(=O)OCC
Temperature: 25 °C
Yield: 84.6 %

Procedure:
To a suspension of 3.33 g (12.9 mmol) of N-(4-hydroxy-5-ethynyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropionamide in 64 mL of acetonitrile stirred under nitrogen was added 5.77 g (28.4 mmol) of BSA and the resulting mixture was stirred at 40° C. for 2 hours, then cooled to ambient temperature. To the resulting solution was added sequentially 5.58 g (12.9 mmol) of N-4-iodobenzoyl-L-glutamic acid diethyl ester, 2.6 g (25.8 mmol) of triethylamine, and a mixture of 0.114 g (0.65 mmol) of palladium(II) chloride and 0.338 g (1.29 mmol) of triphenylphosphine in 16 mL of acetonitrile. The resulting mixture was heated under reflux overnight (18 hours), after which time HPLC analysis of an aliquot indicated complete conversion of the (acetylenic) starting material. The mixture was cooled to ambient temperature and 2 mL of water was added. The resulting suspension was stirred for 30 minutes, filtered, and the precipitate washed with acetonitrile and dried, affording 6.15 g (85%) of N-[4-[2-[2-(2,2-dimethylpropionyl)amino-4-hydroxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl ]ethynyl]benzoyl]-L-glutamic acid diethyl ester as a tan solid. The melting point and NMR spectral data for the product were in agreement with data obtained on an authentic sample prepared by the procedure of Example 3.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]1[C:13]([P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][S:11][CH2:10]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]>C1C=CC=CC=1.[O-2].[Mn+4].[O-2]>[CH2:17]([O:16][P:14]([C:13]1[C:9]([P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])=[CH:10][S:11][CH:12]=1)([O:19][CH2:20][CH3:21])=[O:15])[CH3:18]
Reactant: CCOP(=O)(OCC)C1=CSCC1P(=O)(OCC)OCC
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: CCOP(=O)(OCC)c1cscc1P(=O)(OCC)OCC
Temperature: 25 °C
Yield: 85.4 %

Procedure:
In benzene, 9.740 g (112 mmols) of commercially available manganese (IV) oxide was dissolved, to which 2.010 g (5.60 mmols) of 3,4-bis(diethoxyphosphoryl)-2,3-dihydrothiophene was added at room temperature. Thereafter, the reaction mixture was heated and stirred under reflux for 29 hours. After the reaction, the reaction mixture was cooled down to room temperature and the solid was removed by celite filtration. The filtrate was distilled off under reduced pressure to remove the solvent, and the resulting crude product was purified with a silica gel column (ethyl acetate:methanol=15:1) to obtain the specified substance in the form of a brown solid at a yield of 1.700 g (yield: 85.4%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21](Br)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>>[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: N#Cc1ccc(-c2ccc(Cn3ccnc3)cn2)cc1

Procedure:
Synthesized using 4-cyanophenylboronic acid (185 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 110 mg, 0.42 mmol, 67%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.22 (s, 2H), 6.93 (s, 1H), 7.14 (s, 1H), 7.54 (dd, J=8.2, 2.3 Hz, 1H), 7.60 (s, 1H), 7.75-7.78 (m, 3H), 8.11 (d, J=8.2 Hz, 2H), 8.62 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.0, 112.9, 118.6, 119.0, 121.0, 127.4, 130.5, 131.5, 132.6, 136.0, 137.3, 142.6, 148.8, 150.4; MS (ESI): m/z=261.03 [M+H]+.