Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[C:4]([CH3:10])[N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[C:17]([CH:19]([O:22][CH3:23])[C:20]#[CH:21])[CH:16]=[C:15]([O:24][CH3:25])[C:14]=1[O:26][CH3:27]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:21]#[C:20][CH:19]([O:22][CH3:23])[C:17]2[CH:16]=[C:15]([O:24][CH3:25])[C:14]([O:26][CH3:27])=[C:13]([O:12][CH3:11])[CH:18]=2)=[C:4]([CH3:10])[N:3]=1
Reactant: C#CC(OC)c1cc(OC)c(OC)c(OC)c1
Reactant: Cc1nc(N)nc(N)c1I
Product: COc1cc(C(C#Cc2c(C)nc(N)nc2N)OC)cc(OC)c1OC
Yield: 93.5 %

Procedure:
2,4-Diamino-5-iodo-6-methylpyrimidine (250 mg) was allowed to react with 1,2,3-Trimethoxy-5-(1-methoxyprop-2-ynyl)benzene (473 mg) as per the general procedure to afford 2,4-Diamino-5-(3-methoxy-3-(3,4,5-trimethoxyphenyl)prop-1-ynyl)-6-methylpyrimidine as a yellow powder (335 mg, 93%): Rf=0.29 (9:1, CHCl3:MeOH); mp=127-129° C.; 1H NMR (DMSO-d6) δ 6.84 (s, 2H), 6.37 (s, 2H), 5.34 (s, 1H), 3.78 (s, 6H), 3.66 (s, 3H), 3.35 (s, 3H), 2.23 (s, 3H); 13C NMR (DMSO-d6) δ 167.6, 164.3, 161.1, 152.8, 137.2, 134.8, 104.6, 95.7, 87.5, 81.8, 73.1, 60.0, 55.8, 55.3, 22.4; HRFAB [M+Li] 359.1701 (calculated C18H22N4O4Li: 359.1719). (R)-4-Isopropyl-3-(2-(3,4,5-trimethoxyphenyl)acetyl)oxazolidin-2-one. To a flame-dried 100 mL round-bottom flask was added 3,4,5-trimethoxyphenylacetic acid (2.10 g, 9.29 mmol). THF (25 mL) was added followed by Et3N (1.42 mL, 10.22 mmol). The solution was cooled to −78° C. Pivaloyl chloride (1.26 mL, 10.22 mmol) was added dropwise and the solution warmed to 0° C. and stirred for 1 h. In a separate flame-dried 50 mL round-bottom flask was added (R)-4-isopropyloxazolidin-2-one (1.0 g). THF (20 mL) was added and the solution cooled to −78° C. n-BuLi (6.83 mL, 9.29 mmol, 1.36 M) was added dropwise and the solution stirred at −78° C. for 15 min and then warmed to 25° C. where it was stirred for 15 min. The organolithium solution was transferred to the solution of the mixed anhydride via cannula at −78° C. The reaction was stirred at −78° C. for 15 min, warmed to 0° C., and stirred for 1 h. Water (10 mL) was added and the aqueous layer extracted with EtOAc (2×10 mL). The combined organics were washed with brine (10 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 30 g) using 25% EtOAc in hexanes as the eluent to afford trimethoxyphenyl)acetyl)oxazolidin-2-one as a colorless oil (2.30 g, 88%): Rf=0.28 (1:1, Hex:EtOAc); 1H NMR (CDCl3) δ 6.55 (s, 2H), 4.44-4.41 (m, 1H), 4.29-4.24 (m, 2H), 4.19 (dd, J) 9.0, 3.0 Hz, 1H), 4.12-4.07 (m, 1H), 3.82 (s, 6H), 3.80 (s, 3H), 2.36-2.30 (m, 1H), 0.87 (d, J) 6.8 Hz, 3H), 0.78 (d, J) 7.1 Hz, 3H); 13C NMR (CDCl3) δ 171.2, 154.1, 153.2, 129.4, 106.7, 63.4, 60.9, 58.6, 56.2, 41.6, 28.4, 18.0, 14.7, 14.3; HRFAB [M+Li] 344.1686 (calculated C17H23NO6Li: 344.1686).
Reaction SMILES: Cl.[C:2]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH3:25][N:26]1[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[N:28]=[CH:27]1>C(Cl)Cl>[CH3:25][N:26]1[CH:30]=[C:29]([S:31]([N:13]2[CH2:14][CH2:15][CH:10]([C:2]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)(=[O:33])=[O:32])[N:28]=[CH:27]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: O=C(c1ccccc1)C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)N2CCC(C(=O)c3ccccc3)CC2)c1
Reaction time: 18 h
Yield: 92.6 %

Procedure:
To a solution of 4-benzoylpiperidine hydrochloride (1.50 g, 6.64 mmol) and DIPEA (2.74 mL, 15.3 mmol) in CH2Cl2 (35 mL) was added 1-methylimidazole-4-sulfonyl chloride (1.31 g, 7.31 mmol) and stirred for 18 h. The reaction was washed with 2 N NaOH (30 mL), dried over MgSO4 and concentrated under vacuum to afford 4 as a white solid (2.05 g, 93%); 1H-nmr (400 MHz, CDCl3) δ 7.81-7.78 (m, 2H), 7.52-7.36 (m, 5H), 3.86-3.78 (m, 2H), 3.71 (s, 3H), 3.26-3.17 (m, 1H), 2.82 (td, J=11.0, 3.0 Hz, 2H), 1.92-1.84 (m, 4H); m/z 334.0 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)[CH2:14][OH:15])[CH2:10]2)=[CH:4][CH:3]=1.Cl[C:32]([O:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:33]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:32](=[O:33])([O:34][C:35]1[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=1)[O:15][CH2:14][C:13](=[C:11]1[CH2:12][N:9]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[CH2:10]1)[C:16]1[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: OCC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 320 mg (0.717 mmol) of 2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-2-(3,5-difluorophenyl)ethanol (Example 31) and 175 mg (1.43 mmol) of 4-dimethylaminopyridine in 10 mL of methylene chloride was added 217 mg (1.076 mmol) of 4-nitrophenyl chloroformate, and the reaction mixture was stirred for 4 h at rt. The reaction mixture was concentrated and the residue was purified by silica gel chromatography with hexanes/ethyl acetate=12:1 to afford the title compound as a white solid; Mass Spectrum m/e=613 (M+1 35Cl, 35Cl) and 615 (M+1 35Cl, 37Cl).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[N:9]=[C:10](Cl)[C:11]([C:25]#[N:26])=[C:12]3[C:17]=2[C:16]=1[NH:15][C:14](=[O:18])[N:13]3[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[O:5])[CH3:2].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1B(O)O.O1CCOCC1>C([O-])(O)=O.[Na+].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>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[N:9]=[C:10]([C:34]3[CH:33]=[C:32]([F:35])[CH:31]=[CH:30][C:29]=3[Cl:28])[C:11]([C:25]#[N:26])=[C:12]3[C:17]=2[C:16]=1[NH:15][C:14](=[O:18])[N:13]3[C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1cc(F)ccc1Cl
Reactant: CCOC(=O)c1sc2nc(Cl)c(C#N)c3c2c1NC(=O)N3c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1sc2nc(-c3cc(F)ccc3Cl)c(C#N)c3c2c1NC(=O)N3c1ccncc1

Procedure:
7-chloro-6-cyano-4-oxo-5-pyridin-4-yl-4,5-dihydro-3H-1-thia-3,5,8-triaza-acenaphthylene-2-carboxylic acid ethyl ester Compound 3a (537 mg, 1.35 mmol), prepared using the procedure of Example 1, was combined with 2-chloro-5-fluorophenyl-boronic acid (468 mg, 2.69 mmol), Pd(Ph3P)4 (156 mg, 0.135 mmol), sat'd NaHCO3 (15 mL) and 1,4-dioxane (40 mL). The reaction mixture was refluxed for 2 hrs then diluted with sat'd NaHCO3 and extracted with EtOAc. The organic layer was dried (MgSO4) and evaporated. The solid was recrystallized from EtOAc to give 7-(2-chloro-5-fluoro-phenyl)-6-cyano-4-oxo-5-pyridin-4-yl-4,5-dihydro-3H-1-thia-3,5,8-triaza-acenaphthylene-2-carboxylic acid ethyl ester Compound 15 (440 mg) as a pale yellow solid. LC/MS 494, 496 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([CH3:18])[CH:17]=2)[C:14](=[O:19])[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)[CH2:12]3)[CH:6]=[N:7][CH:8]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:18][C:16]1[CH:17]=[C:9]([C:5]2[CH:4]=[C:3]([CH2:2][O:1][S:40]([CH3:39])(=[O:42])=[O:41])[CH:8]=[N:7][CH:6]=2)[CH:10]=[C:11]2[C:15]=1[C:14](=[O:19])[N:13]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][C:28]([F:30])([F:31])[F:29])=[CH:25][CH:26]=1)[CH2:12]2
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(-c2cncc(CO)c2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(-c2cncc(COS(C)(=O)=O)c2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
5-(5-Hydroxymethyl-pyridin-3-yl)-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (72 mg, 0.168) was diluted with dichloromethane (5 mL) and the solution was cooled to 0° C. in an icebath. Triethyl amine (47 μL, 0.168 mmol) and methanesulfonyl chloride (19 μL, 0.252 mmol) were added and stirring continued for 1 hr at 0° C. The mixture was quenched with cold saturated sodium bicarbonate and the organics were dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound as black oil (70 mg, 100%). 1H NMR (300 MHz, CDCl3): δ 8.01 (s, 1H), 7.43-7.37 (m, 5H), 7.23-7.20 (m, 3H), 5.37 (s, 2H), 4.83 (s, 2H), 4.34 (s, 2H), 3.09 (s, 3H), 2.86 (s, 3H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10](=[O:12])[CH3:11])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCC2
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.1 %

Procedure:
A mixture of 2,3-dihydro-1H-indene (100.0 g, 0.85 mol) and acetic anhydride (104.2 g, 1.35 mol) was added drop-wise to a slurry of AlCl3 (272.0 g, 2.04 mol) in CH2Cl2 (1000 ml) at 0° C. over a period of 3 h. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 15 h. Then the reaction mixture was poured into ice water (500 mL) and extracted with ethyl acetate (500 mL×3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4 and evaporated in vacuo. The residue that was purified by column chromatography (petroleum ether:ethyl acetate=20:1) to give the product (120.0 g, 88%). 1H NMR (400 MHz, CDCl3) δ 2.08-2.15 (m, 2H), 2.58 (s, 3H), 2.95 (t, J=7.2, 4H), 7.28 (d, J=8.0, 1H), 7.75 (d, J=8.0, 1H) 7.82 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]([CH2:19][O:20][CH3:21])[CH2:17][CH3:18])[C:10]=2[NH2:22])=[C:5]([CH3:23])[CH:4]=1.[C:24](OC)(=[O:28])[C:25]([CH3:27])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[N:22]=[C:25]([CH3:27])[C:24](=[O:28])[N:15]([CH:16]([CH2:19][O:20][CH3:21])[CH2:17][CH3:18])[C:11]=3[N:12]=[CH:13][CH:14]=2)=[C:5]([CH3:23])[CH:4]=1
Reactant: CCC(COC)Nc1nccc(-c2ccc(OC)cc2C)c1N
Reactant: COC(=O)C(C)=O
Product: CCC(COC)n1c(=O)c(C)nc2c(-c3ccc(OC)cc3C)ccnc21
Yield: 3.3 %

Procedure:
4-(4-Methoxy-2-methyl-phenyl)-N2-(1-methoxymethyl-propyl)-pyridine-2,3-diamine (0.08 g, 0.25 mmol) and methyl pyruvate (33 μL, 0.38 mmol) were treated substantially as in Part E of Example 67a to give 3.0 mg of 8-(4-methoxy-2-methyl-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 74a): 1H NMR (400 MHz, CDCl3) δ ppm 8.46 (d, J=4.89 Hz, 1 H), 7.15 (d, J=8.31 Hz, 1 H), 7.12 (d, J=4.40 Hz, 1 H), 6.85 (d, J=6.60 Hz, 1 H), 6.83 (d, J=12.23 Hz, 1 H), 5.89 (m, 1 H), 4.38 (m, 1 H), 3.86 (s, 3 H), 3.77 (m, 1 H), 3.32 (s, 3 H), 2.46 (s, 3 H), 2.11 (s, 3 H), 1.77 (m, 2 H), 0.86 (t, J=7.34 Hz, 2 H). MS (EI) 368.30 [(M+H)+, 100]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[C:28]([O:32][C:33](=[O:38])[CH2:34][C:35](O)=[O:36])([CH3:31])([CH3:30])[CH3:29].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:28]([O:32][C:33](=[O:38])[CH2:34][C:35]([O:10][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[CH2:8][C:7]1[C:6]([Cl:26])=[CH:5][N+:4]([O-:27])=[CH:3][C:2]=1[Cl:1])=[O:36])([CH3:31])([CH3:30])[CH3:29]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A mixture of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (1 g, 2.380 mmol), 3-tert-butoxy-3-oxopropanoic acid (0.457 g, 2.86 mmol), EDC (1.369 g, 7.14 mmol), and DMAP (0.291 g, 2.380 mmol) in DCM (50 ml) was stirred at RT overnight. The reaction mixture was washed with HCl 1N, NaHCO3 5% and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography on silica gel column (DCM:EtOAc=40:60) affording (S)-4-(2-(3-tert-butoxy-3-oxopropanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (1.1303 g, 2.010 mmol, 84% yield, MS/ESI+ 562.0 [MH]+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:20][OH:21])[C@H:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1.CCOC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:20][O:21][S:23]([CH3:22])(=[O:25])=[O:24])[C@H:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](OC(C)(C)C)[C@@H](CO)NC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C[C@@H](OC(C)(C)C)[C@@H](COS(C)(=O)=O)NC(=O)OCc1ccccc1
Reaction time: 5.5 h
Yield: 100.7 %

Procedure:
To a solution of (1R,2R)-N-(benzyloxycarbonyl)-1-(hydroxymethyl)-2-(tert-butoxy)propanamine (1.6 g, 5.4 mmol) in anh. pyridine (30 mL) at 4° C. was added methanesulfonyl chloride (0.75 mL, 9.7 mmol) dropwise. The reaction was stirred for 5.5 h, then was diluted with EtOAc (200 mL) and washed with a 1N HCl solution (4×200 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to yield (1R,2R)-N-(benzyloxycarbonyl)-1-(methanesulfonyloxymethyl)-2-(tert-butoxy)propanamine as an oil (2.03 g, 100%): TLC (25% EtOAc/hex) Rf0.31.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[N:15]([CH2:16][C:17]([OH:19])=O)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1.[C:20](N1C=CN=C1)([N:22]1C=CN=[CH:23]1)=O.CNC.C(OC(C)C)(C)C>O1CCCC1.C(O)(C)C>[CH3:20][N:22]([CH3:23])[C:17](=[O:19])[CH2:16][N:15]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:5]1[S:6][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(-c2nc3cccnc3n2CC(=O)O)s1
Agent: CNC
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CC(C)OC(C)C
Product: Cc1ccc(-c2nc3cccnc3n2CC(=O)N(C)C)s1
Temperature: 40 °C
Yield: 20.6 %

Procedure:
A solution of 2-(5-methyl-2-thienyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0183 mole) and 1,1'-carbonyldiimidazole (2.97 g, 0.0183 mole) in tetrahydrofuran (100 ml) was stirred at room temperature for 33/4 hours with a stream of nitrogen bubbling through it. A solution of dimethylamine (48 ml of a 2.29M solution in tetrahydrofuran, 0.1098 mole) was added and the mixture was heated at 40° C. overnight under nitrogen. The solvents were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed twice with a saturated sodium chloride solution, twice with a 5% potassium hydroxide solution and twice again with a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, treated with charcoal, filtered and evaporated under reduced pressure to give a residue which was dissolved in hot isopropyl alcohol and brought to the cloud point by addition of isopropyl ether. Upon cooling to room temperature, a solid precipitated which was collected by filtration, rinsed with isopropyl ether, and dried under high vacuum at room temperature to give 1.13 g of title compound (20%), mp 193°-197° C.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:27]=[CH:26][CH:25]=[CH:24][C:8]=2[C:9]=1[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[O:23][CH2:22]2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH3:4].[CH:28]([NH2:31])([CH3:30])[CH3:29]>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[O:6][C:7]2[CH:27]=[CH:26][CH:25]=[CH:24][C:8]=2[C:9]=1[S:10]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]([OH:23])[CH2:22][NH:31][CH:28]([CH3:30])[CH3:29])=[CH:17][CH:18]=1)(=[O:11])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1S(=O)(=O)c1ccc(OCC2CO2)cc1
Reactant: CC(C)N
Solvent: ClC(Cl)Cl
Product: CCCCc1oc2ccccc2c1S(=O)(=O)c1ccc(OCC(O)CNC(C)C)cc1

Procedure:
2-n-Butyl-3-[4-(2,3-epoxypropoxy)phenylsulfonyl]benzofuran (1.9 g.) was dissolved in 30 ml. of freshly distilled isopropylamine and the solution was heated at 100° for 2 hours. After cooling, the solvent was evaporated to give a residue which was dissolved in chloroform. Evaporation of the solvent gave the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].Br[CH2:16]CCCCC(O)=O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:16])=[O:13]
Reactant: O=C(O)CCCCCBr
Reactant: O=C(O)CCCCCCCCCCBr
Product: COC(=O)CCCCCCCCCCBr
Yield: 90 %

Procedure:
12.0 grams (45 mmole) of 11-bromoundecanoic acid was treated in the same manner as described above for 6-bromohexanoic acid to yield greater than 90% methyl 11-bromoundecanoate.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[C:18]([CH3:24])=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1>CC(C)=O>[C:6]([O:5][C:3](=[O:4])[CH2:2][O:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([Br:16])[C:18]=1[CH3:24])([CH3:9])([CH3:8])[CH3:7]
Reactant: Cc1c(O)cccc1Br
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(Br)cccc1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.7 %

Procedure:
Tert-butyl bromoacetate (1.08 mL, 7.27 mmol) and potassium carbonate (2.01 g, 14.55 mmol) were added to a solution of 3-bromo-2-methylphenol (1.29 g, 6.92 mmol) in acetone (17 mL), and the mixture was stirred at room temperature for 5 hours under a nitrogen atmosphere. The mixture was filtered, and the filtrate was evaporated to dryness to give (3-bromo-2-methylphenoxy)acetic acid tert-butyl ester as a pale yellow oil (2.12 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[N:7](C(OCC1C=CC=CC=1)=O)[CH2:6][CH2:5]2.C(O)C.C1CCCCC=1>[Pd].O>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[NH:7][CH:6]=[CH:5]2
Reactant: O=C(OCc1ccccc1)N1CCc2cc(O)c(O)cc21
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Solvent: O
Product: Oc1cc2cc[nH]c2cc1O

Procedure:
11.4 g of benzyl 5,6-dihydroxy-2,3-dihydroindole-1-carboxylate, 60 ml of ethanol, 5.7 g of 10% palladium-on-charcoal, 5.7 ml of water and 23 ml of cyclohexene were mixed together, and the mixture was maintained at reflux for one hour.
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:40][CH3:41])[C:24]([F:42])=[CH:23][N:22]=1>>[F:42][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:29]=2[O:40][CH3:41])=[N:26][C:21]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: CNC(=O)CN1CCc2cc(N)c(OC)cc2CC1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1F
Product: CNC(=O)CN1CCc2cc(Nc3ncc(F)c(Nc4ccc(N5CCOCC5)cc4OC)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N-methyl-acetamide and (2-Chloro-5-fluoro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 61e. Product was isolated as a pale yellow solid (0.044 g, 48%). MP: 82-124° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.29 (d, 1H, J=8.6 Hz), 8.16 (s, 1H), 7.93-7.90 (m, 1H), 7.40 (s, 1H), 7.36-7.29 (m, 1H), 7.22-7.18 (m, 1H), 6.63 (s, 1H), 6.56-6.53 (m, 1H) 6.53-6.48 (m, 1H), 3.93-3.84 (m, 10H), 3.17-3.09 (m, 6H), 2.92-2.82 (m, 7H), 2.74-2.65 (m, 4H). MS: 566.30 (MH)+.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[O:2]1.[Mn]([O-])(=O)(=O)=[O:16].[K+]>O.CC(C)=O>[N+:12]([C:8]1[C:5]([C:6]([OH:16])=[O:7])=[CH:4][C:3]2[O:2][CH2:1][O:11][C:10]=2[CH:9]=1)([O-:14])=[O:13]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=Cc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A mixture of 3,4-(methylenedioxy)-6-nitrobenzaldehyde (25 g, 128 mmol) and potassium permanganate (40 g, 253 mmol) in a mixture of 300 mL water and 200 mL acetone was stirred overnight at ambient temperature and then heated to 100° C. for 1 hour. The reaction mixture was filtered through Celite®, acetone was removed in vacuo, and the product precipitated from the water solution by acidification to pH 1.2 with concentrated hydrochloric acid to give 6-nitro-benzo[1,3]dioxole-5-carboxylic acid [19.88 g (73%)].
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][OH:15])=[C:4]([NH2:16])[N:3]=1.[NH2:17][NH2:18]>>[NH:17]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][OH:15])=[C:4]([NH2:16])[N:3]=1)[NH2:18]
Reactant: NN
Reactant: Nc1nc(Cl)nc2c1ncn2COCCO
Product: NNc1nc(N)c2ncn(COCCO)c2n1
Reaction time: 1 h

Procedure:
2-Chloro-9-(2-hydroxyethoxymethyl)adenine (0.83 g) was added with stirring to 95% hydrazine (11 ml) and the resulting solution stirred 1 hour under nitrogen. Excess hydrazine was removed by distillation in a rotary evaporator at a bath temperature of 30° C. followed by co-evaporation twice with ethyl acetate. The residue was thoroughly triturated with methanol to give a quantitative yield (0.8 g) of white to cream colored-2-hydrazino-9-(2-hydroxyethoxymethyl)adenine, m.p. 220°-222° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:12]2[C:13]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[OH:25])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].Br[CH2:27][CH:28]([CH3:30])[CH3:29]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:12]2[C:13]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[O:25][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CC(C)CBr
Reactant: CCOC(=O)c1ccccc1-c1ccccc1-c1cc(Cl)ccc1O
Product: CCOC(=O)c1ccccc1-c1ccccc1-c1cc(Cl)ccc1OCC(C)C

Procedure:
Prepared as in procedure A from 5-chloro-2-hydroxy-[1,1′;2′,1″]terphenyl-2″-carboxylic acid ethyl ester and 1-bromo-2-methyl-propane.
Reaction SMILES: [CH2:1]([P:3]([OH:5])[OH:4])[CH3:2].[CH:6](=[O:9])[CH:7]=[CH2:8].[O-]S(OOS([O-])(=O)=O)(=O)=O.[Na+].[Na+]>O>[CH2:1]([P:3]([CH2:8][CH2:7][CH:6]=[O:9])(=[O:5])[OH:4])[CH3:2]
Reactant: CCP(O)O
Reactant: C=CC=O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCP(=O)(O)CCC=O
Temperature: 100 °C
Yield: 74.9 %

Procedure:
564 g (6 mol) of ethylphosphonous acid (produced as in Example 1) are dissolved in 860 g of water and initially charged to a 5 l five-neck flask equipped with thermometer, reflux condenser, high-performance stirrer and dropping funnel. The reaction mixture is heated to 100° C. and 392 g (7 mol) of 2-propenal and 500 g of a 5% strength sodium peroxodisulfate solution (1.5 mol % based on 2-propenal) is added dropwise at atmospheric pressure over 1 h. Then, the water is distilled off in vacuo. The residue is taken up in tetrahydrofuran and the insoluble salts are filtered off. The solvent of the filtrate is removed in vacuo to leave 675 g (75% of theory) of ethyl(2-formylethyl)phosphinic acid as oil.