Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[F:2][C:3]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:4]=1[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1.CS(O[CH2:31][CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1)(=O)=O>CN(C=O)C>[F:2][C:3]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:4]=1[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:31][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:34][CH2:33]3)=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1O
Agent: Br
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 82.5 °C
Yield: 62 %

Procedure:
To a mixture of 4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-ol HBr salt (1.0 g, 2.4 mmol) and K2SO3 (2.5 g) in DMF (15 mL) at rt was added tert-butyl 4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate (1.0 g, 3.4 mmol, and the reaction mixture was heated at 80-85° C. for 4 h. This mixture was directly purified by flash column chromatography on silica gel eluting with hexane:EtOAc/600:400, and then 300:700 to obtain the desired product (786 mg, 62%) as a glassy solid material. 1H NMR (CDCl3) δ 8.57 (d, 1H, J=5.0 Hz), 8.20 (dd, 1H, J=9.9, 2.8 Hz), 8.13 (dd, 1H, J=8.8, 1.7 Hz), 7.43 (d, 2H, J=2.2 Hz), 7.33 (t, 1H, J=7.7 Hz), 6.54 (d, 1H, J=5.0 Hz), 4.20 (m, 2H), 4.04 (d, 2H, J=6.6 Hz), 4.00 (s, 3H), 2.77 (m, 2H), 2.19-1.89 (m, 3H), 1.47 (s, 9H), 1.34 (m, 2H).
Reaction SMILES: CNC(=O)O[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1(O)C=CC=CC=1.C(=O)([O-])N.CN=C=O.[C:27]([O-])(=O)[NH:28][C:29]([NH2:31])=[O:30].NC1C=CC=CC=1>>[CH3:27][NH:28][C:29]([NH:31][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:30]
Reactant: CNC(=O)Oc1ccccc1
Reactant: NC(=O)NC(=O)[O-]
Agent: CN=C=O
Agent: NC(=O)[O-]
Solvent: Nc1ccccc1
Solvent: Oc1ccccc1
Product: CNC(=O)Nc1ccccc1

Procedure:
Following pyrolysis the residual material in the flask had a composition of 25 mole percent phenyl N-methylcarbamate and 75 mole percent phenol. The flask was cooled, a vacuum applied and phenol was stripped at a pressure of 20 mm Hg. Recovered phenol was also chromatographically pure. The residual carbamate remaining after phenol was stripped was returned to the pyrolysis flask. After 3 cycles of pyrolysis and phenol stripping, analysis showed: 96% conversion to methyl isocyanate, 2% unconverted material and 2% conversion to the allophanate. The methyl isocyanate was identified by reaction with aniline to give 1-methyl-3-phenylurea melting at 149°-150.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:18][O:17][CH2:16][CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:36][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].B([O-])[O-]>COCCOC.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:18][O:17][CH2:16][CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13]3)[N:9]=[C:10]([C:44]3[CH:45]=[CH:46][C:41]([O:40][C:37]4[CH:38]=[CH:39][CH:34]=[CH:35][CH:36]=4)=[CH:42][CH:43]=3)[C:3]=12
Reactant: CC1(C)OB(c2ccc(Oc3ccccc3)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCOCC(n2nc(I)c3c(N)ncnc32)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-]B[O-]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 75 °C

Procedure:
tert-butyl 6-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1,4-oxazepane-4-carboxylate (1.18 mmol) is dissolved in ethylene glycol dimethylether (50 mL) and water (10 mL). 4,4,5,5-tetramethyl-2-(4-phenoxyphenyl)-1,3,2-dioxaborolane (1.47 mmol), palladium tetrakistriphenylphosphine (0.059 mmol) and sodium carbonate (2.95 mmol) are added and the reaction is heated for 12-20 hours. Additional boronate and palladium tetrakistriphenylphosphine are added and the reaction is heated at 60-90° C. for a further 20-24 hours. The reaction is concentrated under reduced pressure. The remaining residue was partitioned between dichloromethane and water. The organic layer is dried then concentrated under reduced pressure to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1.C(OCC)(=O)C>CN(C=O)C>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:6]2[C:2]([CH3:1])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:3](=[O:20])[N:4]([C:8]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][CH:11]=3)=[O:9])[C:5]2=[O:7])=[CH:32][CH:31]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC1(c2ccccc2)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(c2ccccc2)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
5-Methyl-3-naphthylcarbonyl-5-phenylimidazolidine -2,4-dione (43 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, 4-fluorobenzyl bromide (24 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 38 mg of white crystals.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[CH:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH:7]1[CH2:13][OH:14].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:14][CH2:13][CH:7]1[CH2:8][CH2:9][CH:10]([CH2:11][O:12][S:2]([CH3:1])(=[O:4])=[O:3])[O:6]1)(=[O:4])=[O:3]
Reactant: OCC1CCC(CO)O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCC(COS(C)(=O)=O)O1
Temperature: 0 °C
Yield: 91.2 %

Procedure:
Methanesulphonyl chloride (307.8 g, 2.7 mol) is added dropwise to a solution of tetrahydrofuran-2,5-dimethanol (118.8 g, 900 mmol) and of triethylamine (454.5 g, 4500 mmol) in 1.54 L of dichloromethane at 0° C. The reaction medium is maintained at 0° C. for 1 hour, ice-cold water is then added and the organic phase is separated out and washed with 500 mL of dilute (1 M) hydrochloric acid solution. The organic phase is separated out and then washed with 500 mL of saturated aqueous NaHCO3 solution. The organic phase is finally separated out and concentrated to give 236.7 g of (tetrahydrofuran-2,5-diyl)bis(methylene) dimethanesulphonate in the form of a brown oil in a purity equal to 96% (determined by LCMS). Reaction yield: 91.0%. A solution of (tetrahydrofuran-2,5-diyl)bis(methylene) dimethanesulphonate (236.7 g, 821.7 mmol) and NaN3 (270.0 g, 4.1094 mol) in DMSO (1.350 L) is heated at 95° C. and stirred overnight. The reaction medium is added to ice-cold water and extracted with 3 times 700 mL of ethyl acetate. The extracts (phase containing ethyl acetate) are successively washed with water, saturated aqueous NaHCO3 solution and dried overnight on MgSO4 and then filtered to remove the MgSO4. The phase containing the ethyl acetate is concentrated to give 166.5 g of 2,5-bis(azidomethyl)tetrahydrofuran in the form of a brown oil. A mixture of 2,5-bis(azidomethyl)tetrahydrofuran (166.5 g) and of Pd-C (10%, 10.8 g) in methanol (2.7 L) is stirred overnight at room temperature under 1 atm of H2. The reaction medium is filtered and the filtrate is concentrated under vacuum to give 90.0 g of 2,5-bis(aminomethyl)tetrahydrofuran in the form of a yellow oil. The total yield for the 3 successive reactions is 75%. The process for synthesizing 2,5-bis(aminomethyl)tetrahydrofuran gives a 90/10 mixture of the cis/trans isomers according to 13C NMR analysis in deuterated methanol.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[N+:13]([C:10]1[CH:11]=[C:1]2[C:2]([O:4][C:5](=[O:12])[NH:6][C:7]2=[CH:8][CH:9]=1)=[O:3])([O-:15])=[O:14]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(=O)o1
Temperature: 41 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
Isatoic Anhydride (25.0 g, 153.25 mmol) is suspended in acetic acid (50 mL) with efficient stirring. The reaction vessel is placed in a pre-heated oil bath at 40° C. and red fuming nitric acid (99.5%, 75 mL, 1.67 mol) is added over 35 minutes (Caution: Exothermic). The reaction mixture is stirred for an additional 4 hours at 38-44° C., then cooled to 20° C. using an ice bath. The reaction mixture is poured on ice (400 mL). After the ice melts, the yellow solid is isolated by vacuum filtration and washed with cold water (5×100 mL). The yellow solid is dried under high vacuum to constant weight at 60-70° C. affording 27.92 g (87%) of product; 1H-NMR (300 MHz, DMSO-d6); δ12.33 (s, 1H), 8.58 (d, J=2.5 Hz, 1H), 8.53 (dd, J=2.6 Hz, 9.0 Hz, 1H), 7.31 (d, J=8.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[Cl:9].[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:21](=[O:30])[C:22]#[C:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=1>>[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)/[C:22](=[C:23](\[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[Cl:9])/[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)/[C:21]2=[O:30])[CH:14]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Reactant: Clc1cccc(I)c1Cl
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3cccc(Cl)c3Cl)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1,2-dichloro-3-iodobenzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.00 (s, 1H), 7.92 (d, 1H), 7.33-7.54 (m, 9H), 7.23 (dd, 1H), 7.10 (t, 1H), 6.74 (t, 1H), 6.66 (d, 1H), 6.55 (d, 1H), 4.95 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:11]=[C:12]([N:15]2[CH2:18][CH:17]([S:19][C:20]3[C@H:21]([CH3:44])[C@@H:22]4[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:23]4[C:24]=3[C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)=[O:26])[CH2:16]2)[S:13][CH:14]=1)(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][C:10]1[N:11]=[C:12]([N:15]2[CH2:16][CH:17]([S:19][C:20]3[C@H:21]([CH3:44])[C@@H:22]4[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:23]4[C:24]=3[C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=3)=[O:26])[CH2:18]2)[S:13][CH:14]=1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(CO[Si](C)(C)C(C)(C)C)cs4)C3)[C@H](C)[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(CO)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-[1-(4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (719 mg, 1.09 mmol) (obtained as described in Example 20(1)) in anhydrous tetrahydrofuran (36 ml) were added sequentially acetic acid (0.19 ml, 3.3 mmol) and a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (3.3 ml, 3.3 mmol) in an ice bath. The resulting mixture was stirred at room temperature overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate and the aqueous layer was further extracted with ethyl acetate. The organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate: methanol (15:1) as the eluant to afford the desired compound p-nitrobenzyl (1R,5S,6S)-2-[1-(4-hydroxymethyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (426.2 mg, yield 72%) as a yellow syrup.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6](=[O:24])[C@H:7]([CH3:23])[N:8]([C:16](=[O:22])[CH2:17][O:18]C(=O)C)[C:9]1[C:13]([CH3:14])=[CH:12][S:11][C:10]=1[CH3:15].O.Cl>CO>[CH3:4][O:5][C:6](=[O:24])[C@H:7]([CH3:23])[N:8]([C:16](=[O:22])[CH2:17][OH:18])[C:9]1[C:13]([CH3:14])=[CH:12][S:11][C:10]=1[CH3:15]
Reactant: COC(=O)[C@H](C)N(C(=O)COC(C)=O)c1c(C)csc1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](C)N(C(=O)CO)c1c(C)csc1C

Procedure:
A solution of 5.4 g (0.1 mol) sodium methanolate in 50 ml dry methanol is slowly added to a mixture of 62.6 g (0.2 mol) N-(acetoxyacetyl)-N-(2,4-dimethylthien-3-yl)-alanine methylester (=Ex. 3.5) in 750 ml dry methanol with stirring. The mixture is stirred for two hours at room temperature, then freed of solvent in vacuo. The residue is poured into water and the pH adjusted to pH 2 with 2 N aqueous HCl. The product is extracted with CHCl3, the organic phase washed with water, dried over Na2SO4, and evaporated in vacuo to yield the title compound, m.p. 69°-70°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[CH3:26])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:35]([O:37][CH3:38])=[O:36]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:25][C:23]1[CH:22]=[CH:21][C:20]([CH3:26])=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:35]([O:37][CH3:38])=[O:36])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:24]=1
Reactant: COC(=O)Cl
Reactant: Cc1ccc(F)cc1[C@H](OCCN)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCO[C@@H](c1cc(F)ccc1C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 11.1 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(5-fluoro-2-methylphenyl)methyl)piperidine-1-carboxylate (3.1 g, 8.5 mmol) and DMAP (0.54 g) in dry CH2Cl2 (45 mL), Et3N (2.58 g, 3.6 mL) was added. The resulting mixture was cooled to 0-5° C. under ice-water bath, a solution of methyl chloroformate (4.0 g, 43 mmol, 5 eq) in dry CH2Cl2 (50 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 h at 0-5° C. The reaction was quenched with water (50 mL). The aqueous layer was extracted with CH2Cl2 (3×30 mL), the combined organic layers were washed with 10% citric acid (2×50 mL) and brine, then dried over Na2SO4, filtered and concentrated to the crude product, which was purified by preparative HPLC to afford (R)-tert-butyl 3-((R)-(5-fluoro-2-methylphenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (400 mg, HPLC≧98%). 1H NMR (CDCl3) δ 7.2 (m, 1H), 7.1 (m, 1H), 6.9 (m, 1H), 4.4 (m, 1H), 4.1 (m, 1H), 3.7 (m, 1H), 3.6 (s, 3H), 3.2 (m, 2H), 2.9 (m, 2H), 2.3 (s, 3H), 1.75 (m, 1H), 1.6 (m, 1H), 1.4 (s, 9H), 1.25 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)c1ccc(Br)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of compound 68b (5 g, 0.02 mol) in THF (100 mL) was added a 1 M THF solution of NaHMDS (22.6 mL, 22.6 mmol) at 0° C. under a nitrogen atmosphere. The resulting solution was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was then cooled to 0° C. and iodomethane (3.19 g, 22.5 mmol) was added dropwise. The ice-water bath was removed and stirring was continued for an additional hour at room temperature. The reaction mixture was then treated with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford compound 68c as brown oil. Mass Spectrum (GCMS, ESI pos.): Calcd. for C11H13BrO2: 256.0 (M). found: 256.0.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1[N:50]=[N:49][C:44]2[CH:45]=[CH:46][CH:47]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1(N)CCCC1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:50][N:49]5[CH2:44][CH2:45][CH2:46][CH2:47]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN1CCCC1
Product: COc1cc(C(=O)NN2CCCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and pyrrolidin-1-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.45 (m, 3 H) 1.55-1.90 (m, 7 H) 2.02 (br. s., 4 H) 3.33 (s, 3 H) 3.52 (br. s., 4 H) 3.97 (s, 3 H) 4.14 (t, 2 H) 4.49 (quin, 1 H) 7.48 (d, 1 H) 7.52 (s, 1 H) 8.26 (s, 1 H) 8.31 (d, 1 H) 8.42 (s, 1 H). [M+H] calc'd for C26H33F2N7O3 530; found 530.
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:5])[CH3:4].[CH:6]1([N:9]([CH:36]2[CH2:38][CH2:37]2)[C:10]([C:12]2[N:33]([CH2:34][CH3:35])[C:15]3=[N:16][C:17]([NH:24][C:25]4[S:26][C:27]([C:30]([OH:32])=O)=[CH:28][N:29]=4)=[C:18]4[N:22]=[CH:21][N:20]([CH3:23])[C:19]4=[C:14]3[CH:13]=2)=[O:11])[CH2:8][CH2:7]1>>[CH:6]1([N:9]([CH:36]2[CH2:38][CH2:37]2)[C:10]([C:12]2[N:33]([CH2:34][CH3:35])[C:15]3=[N:16][C:17]([NH:24][C:25]4[S:26][C:27]([C:30]([N:2]([CH:3]([CH3:5])[CH3:4])[CH3:1])=[O:32])=[CH:28][N:29]=4)=[C:18]4[N:22]=[CH:21][N:20]([CH3:23])[C:19]4=[C:14]3[CH:13]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: CNC(C)C
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C(=O)O)s3)nc21
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C(=O)N(C)C(C)C)s3)nc21

Procedure:
This compound was prepared according to Example 20 using N-methylpropan-2-amine and 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)thiazole-5-carboxylic acid (example 20A) to provide 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-N-isopropyl-N-methylthiazole-5-carboxamide
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N:10]([CH2:13][C:14](=O)[CH3:15])[CH:11]=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:21].C(OCC)(=O)C.[OH-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N:10]2[CH:13]=[C:14]([CH3:15])[N:21]=[CH:11]2)=[CH:4][CH:3]=1
Reactant: COc1nc(Br)ccc1N(C=O)CC(C)=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1nc(Br)ccc1-n1cnc(C)c1
Temperature: 140 °C
Yield: 14.5 %

Procedure:
A mixture of N-(6-bromo-2-methoxypyridin-3-yl)-N-(2-oxopropyl)formamide (7072 mg, 24.63 mmol) and ammonium acetate (8714 mg, 113 mmol) in 16 mL of acetic acid was heated at 140° C. for 1 h. The reaction mixture was cooled to rt and poured into a mixture of icewater and ethyl acetate. The pH of the resulting mixture was brought to pH 9 with a 50% aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 6-bromo-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine (959.0 mg, 3.58 mmol, 14.52% yield) as brown solid. LC-MS (M+H)+=270.0.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[S:18][CH:19]=[C:20]([C:22]([OH:24])=[O:23])[N:21]=3)[CH2:13][CH2:12]2)=[O:10])[N:4]=1.[CH3:27][C:28]([CH3:33])([CH3:32])[CH2:29][CH2:30]O>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[S:18][CH:19]=[C:20]([C:22]([O:24][CH2:30][CH2:29][C:28]([CH3:33])([CH3:32])[CH3:27])=[O:23])[N:21]=3)[CH2:13][CH2:12]2)=[O:10])[N:4]=1
Reactant: CC(C)(C)CCO
Reactant: O=C(O)c1csc(C2CCN(C(=O)Cn3ccc(C(F)(F)F)n3)CC2)n1
Product: CC(C)(C)CCOC(=O)c1csc(C2CCN(C(=O)Cn3ccc(C(F)(F)F)n3)CC2)n1

Procedure:
A solution of 2-(1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-2, 200 mg) is reacted analogously to Example I-811 with 3,3-dimethylbutan-1-ol (68.0 mg). This gives, after chromatographic purification, 3,3-dimethylbutyl 2-(1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (98 mg, 40%).
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:29])[CH2:18][CH:19]2[CH2:27]Cl)[C:14](=[CH2:30])[CH2:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]>C1CCCCC=1.C(O)C.[Pd]>[C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:29])[C@@H:18]4[CH2:27][C@@H:19]42)[C@@H:14]([CH3:30])[CH2:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: C=C1C[C@H]2[C@@H]3CC[C@](OC(C)=O)(C(C)=O)[C@@]3(C)CC[C@@H]2[C@]2(C)C1=CC(=O)CC2CCl
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A suspension of 533 mg of 10% Pd/C in 31 ml of cyclohexene and 46 ml of ethanol is stirred for one hour at 80° C. bath temperature. To this mixture is added 7.5 g of 17-acetoxy-1-chloromethyl-6-methylene-4-pregnene-3,20-dione and the mixture is further stirred for 18 hours at 80° C. Subsequently the catalyst is suctioned off, washed with warm ethanol, and the filtrate is combined with 7 ml of concentrated hydrochloric acid. The mixture is concentrated to one-third of the reaction volume and poured on an ice water-sodium chloride solution. After the usual working-up step, the crude product is purified on 700 g of silica gel with a hexane-ethyl acetate gradient. Yield: 4.3 g of 17α-acetoxy-6α-methyl-1α,2α-methylene-4-pregnene-3,20-dione, mp 198°-200° C.