Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][S:6]([C:9]2[CH:26]=[CH:25][C:12]3[N:13]([CH2:21][CH:22]4[CH2:24][CH2:23]4)[C:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:15][C:11]=3[CH:10]=2)(=[O:8])=[O:7])[CH2:2]1.C(N(CC)CC)C.C[Si]([N:38]=[C:39]=[O:40])(C)C>ClCCl>[CH:22]1([CH2:21][N:13]2[C:12]3[CH:25]=[CH:26][C:9]([S:6]([CH2:5][CH:3]4[CH2:2][N:1]([C:39]([NH2:38])=[O:40])[CH2:4]4)(=[O:8])=[O:7])=[CH:10][C:11]=3[N:15]=[C:14]2[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:23][CH2:24]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CNC3)ccc2n1CC1CC1
Reactant: C[Si](C)(C)N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CN(C(N)=O)C3)ccc2n1CC1CC1
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To the solution of 5-(azetidin-3-ylmethylsulfonyl)-1-(cyclopropylmethyl)-2-neopentyl-1H-benzo[d]imidazole (STEP F, 350 mg, 0.780 mmol) and triethylamine (395 microL, 2.81 mmol) in dichloromethane (5 mL) was added trimethylsilyl isocyanate (162 microL, 1.02 mmol) at room temperature. The resulting solution was stirred for 1 h. The reaction mixture was concentrated in vacuo. The residue was extracted with ethyl acetate (15 mL) and washed with water (30 mL). The organic layer was dried over magnesium sulfate. The crude product was purified with silica gel column chromatography (ethyl acetate-methanol=100:1 to 100:8) to give the title compound (198 mg, 61%).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=O)[O:4][C:2]2=[O:3].[CH3:13][NH2:14]>>[CH3:13][N:14]1[C:2](=[O:3])[C:1]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:4]
Reactant: CN
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: Cn1c(=O)[nH]c2ccccc2c1=O

Procedure:
6 g isatoic anhydride was stirred in 100 ml dry tetrahydrofurane(THF) and methylamine was passed through the mixture for 5 min. The resulting solution was evaporated and the residue was again dissolved in THF (100 ml) and charged with 15 ml 30% phosgene solution in toluene. The mixture was heated to reflux and additional 15 ml phosgene solution was added. After 4 hours reflux the mixture was cooled and evaporated to dryness. The residue was treated with water and the crystals were collected by filtration. The yield was 3.5 g. M.p. 240.4°-240.5° C.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[C:2]#[CH:3].[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>C1COCC1.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>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[C:2](=[CH2:3])[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CC(=O)OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C(=O)OCc1ccccc1)[Sn](CCCC)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of 6.42 g (40.1 mmol) of benzyl propiolate from step A in 25 ml of anhydrous TI-IF was added 0.93 g (0.80 mmol) of tetrakis(triphenylphosphine)palladium(0) followed by a solution of 12.6 g (42.1 mmol) of tributyltin hydride in 25 mL of anhydrous THF over 15 min. After stirring at room temperature overnight the solvent was removed under reduced pressure. The residue was filtered through a pad of Celite® which was then washed with hexanes. The filtrate was concentrated in vacuo and the crude product was purified by silica gel chromatography eluting with a 0-15% ethyl acetate in hexane gradient to afford the title compound as a colorless oil (13 g, 73%). 1H NMR (CDCl3, 500 MHz) δ 7.39 (m, 5H), 6.99 (d, J=2.7 Hz, 1H), 5.98 (d, J=2.7 Hz, 1H), 5.20 (s, 2H), 1.47 (m, 6H), 1.30 (m, 6H), 0.96 (m, 6H), 0.89 (t, J=7.4 Hz, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1B(O)O>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:40]5[CH:41]=[C:36]([F:35])[CH:37]=[CH:38][C:39]=5[F:42])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)c1cc(F)ccc1F
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cc(F)ccc5F)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2,5-difluoro-phenylboronic acid.
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7](Cl)=[O:8])(=O)C.Cl.[CH3:15][N:16]([CH3:18])[OH:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:15][N:16]([O:17][C:7]([C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[OH:4])=[O:8])[CH3:18]
Reactant: CN(C)O
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)OC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
6.00 Grams of acetylsalicylic acid chloride was dissolved in 70 ml of methylene chloride, and 7.37 g of N,N-dimethylhydroxylamine hydrochloride was added. Then, 9.16 of triethylamine was added dropwise thereto with stirring at room temperature. After completion of addition, stirring was carried out at room temperature for further 6 hours. The reaction mixture was washed with a 0.5N hydrochloric acid and then twice with water, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue obtained was subjected to column chromatography to obtain 3.10 g of 2-(N,N-dimethylaminooxycarbonyl)phenol.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=O)[CH2:10][C:4]=2[CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[CH:10][C:4]=2[CH:3]=1
Reactant: O=C1Cc2cc(Cl)ccc2Oc2ccccc21
Reactant: CN1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CN1CCN(C2=Cc3cc(Cl)ccc3Oc3ccccc32)CC1
Yield: 79.9 %

Procedure:
Thirty grams of 2-chlorodibenzo[b,f]oxepin-10(11H)-one, prepared in accordance with the procedure of Example 3, 45 grams of N-methylpiperazine and a solution of 8 grams of p-toluenesulfonic acid monohydrate in 150 ml of xylene are refluxed for a period of 22 hours in a reflux apparatus equipped with a Dean-Stark trap in order to remove the water that forms. The reaction mixture is cooled, treated with a solution of sodium bicarbonate, washed with water until the water washings are neutral, dried over anhydrous sodium sulfate and filtered through a column of neutral aluminum oxide. The filtrate is concentrated to dryness in vacuo and the residue, 46 grams, crystallized from ethanol to yield 32 grams of 1-(2-chlorodibenzo[b,f]oxepin-10-yl)-4-methylpiperazine having an m.p. of 119°-121° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(=NC1CCCCC1)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[C:26]([CH:29]([CH3:31])[CH3:30])C=O)=[CH:21][CH:20]=1.[O:39]1C[CH2:42][CH2:41][CH2:40]1>>[F:38][C:35]1[CH:34]=[CH:33][C:32]([C:25]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[C:26]([CH:29]([CH3:31])[CH3:30])[CH:42]=[CH:41][CH:40]=[O:39])=[CH:37][CH:36]=1
Reactant: CC(C)C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: CC=NC1CCCCC1
Agent: [Li+]
Product: CC(C)C(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Lithium diisopropylamide (9 mL of 1.8M solution, 15 mmol) was added to N-ethylidenecyclohexanamine (7.5 mL of 2M solution, 15 mmol) in tetrahydrofuran at -40° C. After stirring for 30 minutes and cooling to -70° C., 3,3-bis(4-fluorophenyl)-2-(1-methylethyl)propenal (1.43 g, 5.0 mmol) was added. The reaction was stirred -70° for 1.5 hrs. and quenched with 2N hydrochloric acid. The mixture was extracted with diethyl ether and the extracts concentrated in vacuo. The residue was stirred for 64 hours with a mixture of 50 mL of benzene, 35 mL acetic acid and 15 mL of water. The layers were separated and the aqueous layer extracted with diethyl ether. The combined organic solution was washed with saturated sodium bicarbonate solution, water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 1% ethyl acetate in hexane and the material obtained crystallized from hexane to give 0.55 g of the title compound as a yellow solid; m.p. =105°-107° C.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].O=[CH:10][C:11]([Cl:14])([Cl:13])[Cl:12]>C(#N)C>[Cl:12][C:11]([Cl:14])([Cl:13])[CH:10]1[N:1]2[CH2:8][CH2:7][CH2:6][CH:2]2[C:3](=[O:5])[O:4]1
Reactant: O=C(O)[C@H]1CCCN1
Reactant: O=CC(Cl)(Cl)Cl
Solvent: CC#N
Product: O=C1OC(C(Cl)(Cl)Cl)N2CCCC12
Reaction time: 18 h

Procedure:
To a solution of D-proline (100.0 g) in acetonitrile (400 ml) was added dropwise chloral (169 ml) at room temperature, and the mixture was stirred for 18 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. To the resulting residue was added water, and the mixture was extracted with chloroform. The separated organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was slurry-washed with n-hexane/ethyl acetate (20/1, 900 ml) to give the titled compound (159.7 g).
Reaction SMILES: [Br:1]Br.[C:3]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:5][CH2:6][CH3:7])=[O:4].Br>O.C1COCC1>[CH2:6]([O:5][C:3]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH:12]([Br:1])[CH2:13]1)=[O:4])[CH3:7]
Reactant: BrBr
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: Br
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(=O)C(Br)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 108 %

Procedure:
Bromine (2.83 mL, 55 mmol) was added dropwise to a stirred solution of N-carbethoxy-4-piperidone (7.54 mL, 50 mmol) and a 48% solution of HBr in H2O (1.41 mL) in THF (88 mL) at 0° C. The mixture was stirred at room temperature for 15 minutes and then quenched with a saturated solution of Na2S2O3, basified with a saturated solution of Na2CO3 and extracted with diethyl ether. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield 3-bromo-4-oxo-1-piperidinecarboxylic acid ethyl ester (13.5 g, 54% yield, 50% pure) as a dark brown oil that was used in the next step without further purification. C8H12BrNO3 GCMS (EI): Rt 3.77, MW (theor) 249; m/z [M]+ 249 (using method, GC-MS Method 2).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[F:9])[CH:7]=1
Reactant: OB(O)c1ccccc1F
Reactant: Brc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccccc1-c1cncc(Br)c1
Yield: 47 %

Procedure:
3,5-Dibromopyridine (ABCR Product List AB115322) (250 mg; 2.1 mmol), 2-fluorophenylboronic acid (Sigma-Aldrich, order number 445223)(147 mg; (2.1 mmol), Pd(PPh3)2Cl2 (148 mg; 0.4 mmol) are combined in DMF (8 ml) and 2N Na2CO3 (1.3 ml) and heated to 160° C. in an oil bath for 20 minutes. The reaction mixture is evaporated to dryness, taken up in TBME/CH2Cl2 (30 ml/10 ml), diluted with hexanes (50 ml), filtered and evaporated to dryness. The solid white residue is dissolved in TBME (10 ml), diluted with hexanes, filtered, and purified via chromatography (SiO2, TBME/hexanes 5:95) to yield the title compound as white crystals (125 mg; 47%). MS (m/z) ES+: 252, 254 (MH+). Retention time: 2.79 minutes (LC-MS method 3).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:14][N:15]([CH3:17])[CH3:16])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[O:18]1[CH:22]=[CH:21][C:20]([C:23]2[S:27][C:26]([S:28](Cl)(=[O:30])=[O:29])=[CH:25][CH:24]=2)=[N:19]1>>[CH3:17][N:15]([CH3:16])[CH2:14][C@H:2]([NH:1][S:28]([C:26]1[S:27][C:23]([C:20]2[CH:21]=[CH:22][O:18][N:19]=2)=[CH:24][CH:25]=1)(=[O:29])=[O:30])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccon2)s1
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(-c2ccon2)s1
Yield: 84 %

Procedure:
According to the method described in example S20a, (R)-benzyl 3-amino-4-(dimethylamino)butanoate (27 mg, 0.086 mmol) was reacted with 5-(isoxazol-3-yl)thiophene-2-sulfonyl chloride to yield the title compound as a white solid (38 mg, 84%). MS ESI 450.2 [M+H]+, calcd for [C20H23N3O5S2+H]+ 450.11
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8].[NH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[NH2:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:3]=[C:4]([O:9][CH2:10][C@H:11]3[CH2:15][CH2:14][CH2:13][N:12]3[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=2[Cl:8])[CH:27]=[CH:26][CH:25]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(-c2cccc(N)c2)c1
Yield: 29.8 %

Procedure:
To a solution of 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 69a (520 mg, 1.33 mmol) and 3-aminophenylboronic acid (310 mg, 2.0 mmol) in toluene (8mL) was added Pd(0) (50 mg) and Na2CO3 (2.5 mL of a 2M solution), and the mixture was heated at reflux for 16 hours. The solvent was removed under vacuum, and the residue was purified by chromatography on a silica gel column, eluting with chloroform:ether 100:5-100:4 to afford 160 mg of the title compound. MS (DCI/NH3) m/z 404 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.44 (s, 9H), 1.88 (m, 1H), 2.03 (m, 2H), 3.37 (m, 2H), 3.76 (m, 2H), 4.16 (m, 2H), 6.75 (m, 2H), 6.82 (m, 1H), 7.22 (m, 2H), 8.08 (m, 1H).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH:9]1([C@H:13]([NH:15][C:16]2[C:21]3[N:22]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[CH:23]=[N:24][C:20]=3[CH:19]=[C:18]([C:36]#[N:37])[N:17]=2)[CH3:14])[CH2:12][CH2:11][CH2:10]1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:8][C:19]1[C:20]2[N:24]=[CH:23][N:22]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=3)[C:21]=2[C:16]([NH:15][C@@H:13]([CH:9]2[CH2:12][CH2:11][CH2:10]2)[CH3:14])=[N:17][C:18]=1[C:36]#[N:37]
Reactant: C[C@@H](Nc1nc(C#N)cc2ncn(Cc3ccc(C(F)(F)F)cc3)c12)C1CCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C[C@@H](Nc1nc(C#N)c(Br)c2ncn(Cc3ccc(C(F)(F)F)cc3)c12)C1CCC1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
NBS (73.5 mg, 0.413 mmol) was added to a stirred, room temperature mixture of (R)-4-((1-cyclobutylethyl)amino)-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (150 mg, 0.376 mmol) in degassed chloroform (3 ml) in a sealed tube. The mixture was heated to 45° C. and stirred under Ar for 1 hour. The mixture was cooled to room temperature and diluted with DCM. The mixture was then transferred to a separatory funnel, washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting dark orange oil was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford (R)-7-bromo-4-((1-cyclobutylethyl)amino)-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd for C21H19BrF3N5 [M+H]+ 479. found 479.
Reaction SMILES: FC(F)(F)S(O[Si:7]([CH3:10])([CH3:9])[CH3:8])(=O)=O.[Si:13]([O:30][CH:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:26]([Si:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[O:30][CH:31]1[CH2:36][CH2:35][C:34]([O:37][Si:7]([CH3:10])([CH3:9])[CH3:8])=[CH:33][CH2:32]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)[Si](OC1CCC(=O)CC1)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](OC1CC=C(O[Si](C)(C)C)CC1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Trimethylsilyl trifluoromethanesulfonate (45.0 g; 198.8 mmol) is dropped into a solution of known 4{[tert-butyl(diphenyl)silyl]oxy}cyclohexanone [Okamura, W. H.; Elnagar, H. Y.; Ruther, M.; Dobreff, S. J. Org. Chem. 1993, 58, 600] (58.4 g, 165.5 mmol) and triethylamine (55.4 mL; 397.6 mmol) in dichloromethane (500 mL) at −78° C. under an atmosphere of nitrogen. After one hour the reaction mixture is allowed to warm to 0° C. and quenched with saturated NaHCO3-solution (120 mL). The organic layer is separated, dried over MgSO4 and concentrated under reduced pressure. A 1:1-mixture of tert-BuOMe and hexane is added to the biphasic residue. The organic layer is separated, washed with saturated NaHCO3-solution and dried over MgSO4. The solvent is removed under reduced pressure to deliver 69.0 g of the title compound as colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH:20]2[CH3:26]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:18][CH2:17][C:16]4[C:21](=[C:22]([F:25])[CH:23]=[CH:24][C:15]=4[F:14])[CH:20]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c(F)ccc(F)c21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2c(F)ccc(F)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5,8-Difluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [F:1][C:2]([F:28])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]1[NH:4][C:5](=[O:21])[C:6]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8][C:7]=2[N:20]=1.F[B-](F)(F)F.[CH3:34][O+](C)C>>[F:1][C:2]([F:28])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]1[N:4]=[C:5]([O:21][CH3:34])[C:6]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:7]=2[N:20]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(C(F)(F)c3ccccc3)[nH]c(=O)c2CC1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Product: COc1nc(C(F)(F)c2ccccc2)nc2c1CCNCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-[difluoro(phenyl)methyl]-4-oxo-3,4,5,6,8,9-hexahydro-7H-pyrimido[4,5-d]azepine-7-carboxylate of Preparation 8, Step A (535 mg, 1.37 mmol) was added trimethyloxonium tetrafluoroborate (3 eq, 606 mgs 4.10 mmol) and the reaction mixture was stirred overnight at room temperature, after which time an orange solid had precipitated. The reaction mixture was quenched with saturated NaHCO3 (aq) and stirred rapidly until a complete solution was attained. The organic layer was collected, dried over MgSO4, filtered and dried in vacuo to give a brown oil. This material was chromatographed on silica, eluting with ethyl acetate/10% methanol, then dichloromethane/methanol/ammonia, 95/5/0.5. The relevant fractions were combined and evaporated in vacuo to give a coloured oil (quantitative yield).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[Cl:17][C:18]1[CH:19]=[C:20]([F:42])[C:21]([C:40]#[N:41])=[C:22]([C:24]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)=[N:25]S(C(C)(C)C)=O)[CH:23]=1.Cl.CO>C1COCC1>[Cl:17][C:18]1[CH:23]=[C:22]2[C:21]([C:40]([NH2:41])=[N:25][C:24]2([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)[C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)=[C:20]([F:42])[CH:19]=1
Reactant: FC(F)(F)c1cc(Br)ccn1
Reactant: COc1cccc(C(=NS(=O)C(C)(C)C)c2cc(Cl)cc(F)c2C#N)c1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(C2(c3ccnc(C(F)(F)F)c3)N=C(N)c3c(F)cc(Cl)cc32)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39.2 %

Procedure:
tert-Butyllithium (1.7 M in pentane, 6.59 mL, 11.20 mmol) was added dropwise to THF (10 mL) at −100° C. under an argon atmosphere. A solution of 4-bromo-2-trifluoromethylpyridine (1.266 g, 5.60 mmol) in THF (1 mL) was added dropwise followed by the addition of N-((5-chloro-2-cyano-3-fluorophenyl)(3-methoxyphenyl)methylene)-2-methylpropane-2-sulfinamide (2 g, 5.09 mmol) in THF (6 mL). The resulting reaction mixture was left on the thawing cooling bath for 30 min then the cooling bath was removed and the mixture was stirred at rt for 1.5 h. Hydrogen chloride in methanol solution (20.36 mL, 25.45 mmol) was added and the mixture was stirred at rt for 1 h. The mixture was concentrated and purified on a silica gel column eluted with 0-10% 0.1M NH3 in MeOH in DCM to afford 870 mg (39%) of the title compound.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:20][C:21]1[C:26](=[O:27])[NH:25][C:24]([C:28](O)=[O:29])=[C:23]([CH3:31])[CH:22]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:1]([N:8]([CH2:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:28]([C:24]1[NH:25][C:26](=[O:27])[C:21]([Br:20])=[CH:22][C:23]=1[CH3:31])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCNCc1ccccc1
Reactant: Cc1cc(Br)c(=O)[nH]c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Br)c(=O)[nH]c1C(=O)N(CCCO[Si](C)(C)C(C)(C)C)Cc1ccccc1
Reaction time: 16 h

Procedure:
To a stirred solution of N-benzyl-3-((tert-butyldimethylsilyl)oxy)propan-1-amine (2, 3.0 g, 12.9 mmol) in dimethylformamide (50 mL), 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (3, 3.6 g, 12.9 mmol), HBTU (6.4 g, 16.9 mmol) and N,N-diisopropylethylamine (2.2 g, 16.9 mmol) were added at room temperature. The mixture was stirred for 16 h. TLC showed completion of reaction. The reaction mixture was quenched with aqueous sodium bicarbonate solution and extracted with ethyl acetate (250 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to afford N-benzyl-5-bromo-N-(3-((tert-butyldimethylsilyl) oxy) propyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (4) as yellow liquid. Yield: 3.0 g, 47%; MS (ESI) m/z 495.24 [M−1]−.