Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]=[CH:11][C:10]=2[CH:14]=1.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:30])(=O)=O)=CC=1.O>C1COCC1.C(OCC)(=O)C>[F:30][C:12]1[O:13][C:9]2[CH:8]=[CH:7][C:6]([CH:2]3[O:3][CH2:4][CH2:5][O:1]3)=[CH:14][C:10]=2[CH:11]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: c1cc2cc(C3OCCO3)ccc2o1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1cc2cc(C3OCCO3)ccc2o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 138.6 %

Procedure:
5-[1,3]Dioxolan-2-yl-benzofuran (50 mg, 0.26 mmol) was dissolved in THF (2 mL) and the solution was cooled down to −78° C. Butyl lithium (180 uL, 1.1 eq.) was added dropwise. This mixture was stirred 30 min at 25° C. Then the reaction mixture was cooled down to −78° C. and N-fluorodibenzenesulfonamide (91 mg, 1.1 eq.), dissolved in 1 mL THF, was added dropwise to the reaction mixture. The mixture was stirred overnight between −78° C. and room temperature. Water and ethyl acetate were added to the mixture and the aqueous layer was extracted 3 times. Combined organic phases was dried over MgSO4, filtrated and evaporated, to give the 2-Fluoro-5-[1,3]dioxolan-2-yl-benzofuran (75 mg) mixed with side products. However it was sufficiently pure to be used for the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][C:3]1=[O:9].[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH:15]=O.[NH2:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1>>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]2[C:4]3[C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[CH2:7][CH2:6][C:5]=3[NH:21][C:22]3=[CH:26][CH:25]=[N:24][N:23]23)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: Nc1cc[nH]n1
Product: CC1(C)CCC2=C(C1=O)C(c1ccc(F)c(Br)c1)n1nccc1N2

Procedure:
4,4-Dimethyl-1,3-cyclohexanedione, 3-bromo-4-fluorobenzaldehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH:6]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[CH3:7].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:42][CH2:43][C:44]1[C:45]([OH:52])=[N:46][C:47]([CH3:51])=[CH:48][C:49]=1[CH3:50]>O.ClCCl.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH:6]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:42][CH2:43][C:44]2[C:45]([OH:52])=[N:46][C:47]([CH3:51])=[CH:48][C:49]=2[CH3:50])=[O:14])=[CH:15][CH:16]=1)[CH3:7]
Reactant: CC(Oc1cccc(F)c1)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3cccc(F)c3)cc2)c(O)n1
Temperature: 25 °C
Yield: 34.2 %

Procedure:
A mixture of 4-(1-(3-fluorophenoxy)ethyl)benzoic acid (260 mg, 1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (382 mg, 2 mmol), N-hydroxybenzotriazole (270 mg, 2 mmol), triethylamine (0.3 mL) and dichloromethane (15 mL) were stirred at 25° C. for half an hour. And then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (152 mg, 1 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (20 mL) was added and the mixture was extracted with dichloromethane (30 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 4-(1-(3-fluorophenoxy)ethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (Compound I-42) (135 mg, 34%). LRMS (M+H+) m/z: calcd. 394.17. found 394. HPLC purity (214 nm): 91%. 1H NMR (300 MHz, d6-DMSO): δ 11.44 (s, 1H), 8.30 (t, J=4.8 Hz, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 7.20 (q, J=8.1 Hz, 1H), 6.77-6.64 (m, 3H), 5.83 (s, 1H), 5.57 (q, J=6.3 Hz, 1H), 4.27 (d, J=4.8 Hz, 2H), 2.15 (s, 3H), 2.10 (s, 3H), 1.53 (d, J=6.0 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[C:7]2[OH:13].[CH3:14][C:15]([NH2:18])([CH3:17])[CH3:16]>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:18][C:15]([CH3:17])([CH3:16])[CH3:14])[NH:8][C:7]2=[O:13]
Reactant: Oc1nc(Cl)nc2c(Br)cccc12
Reactant: CC(C)(C)N
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)[nH]1
Temperature: 80 °C
Yield: 56.1 %

Procedure:
A mixture of 8-bromo-2-chloroquinazolin-4-ol (407c, 0.20 g, 0.77 mmol) in 2-methylpropan-2-amine (1.62 mL, 15.42 mmol) was sealed and heated to 80° C. overnight. The reaction was transferred to a microwave vessel and heated to 170° C. for 30 min. The reaction was transferred to a flask with DCM/MeOH and concentrated in vacuo. The material was taken up in DCM/MeOH and adsorbed onto 1.3 g silica gel and dried in vacuo. The material was purified by silica gel chromatography (24 g column) using 0-100% EtOAc/hexanes. The product-containing fractions were concentrated to afford 8-bromo-2-(tert-butylamino)quinazolin-4(3H)-one (408a, 0.128 g, 0.432 mmol, 56% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.59 (1H, s), 7.85-7.90 (2H, m), 7.00 (1H, t, J=7.7 Hz), 6.22 (1H, s), 1.48 (9H, s). m/z (ESI, +ve ion) 296.0/298.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[CH3:24])[CH2:6][CH2:5][CH2:4]1.[H][H]>C(O)C.[Pt]=O>[CH3:26][N:2]([CH3:1])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH3:24])[CH2:6][CH2:5][CH2:4]1
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)N1CCCC(N(C)C)c2ccccc21
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: Cc1cc(N)ccc1C(=O)N1CCCC(N(C)C)c2ccccc21
Yield: 15.6 %

Procedure:
5-Dimethylamino-1-(2-methyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (86.0 g) is dissolved in ethanol (800 ml), and thereto is added platinum oxide (10 g). The mixture is subjected to hydrogenation at ordinary temperature under atmospheric pressure of hydrogen for 4 hours. The catalyst is removed by filtration, and the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=200:1→100:1), and further purified by silica gel thin layer chromatography (developer; chloroform:methanol=10 :1), and recrystallized from methanol/diethyl ether to give 5-dimethylamino-1-(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (G) (Rf:0.52, 27.4 g) and 5-dimethylamino-1-(2-methyl-4-amino-benzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (H) (Rf:0.48, 12.3 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:18].O1CCOCC1>[Cu-]=O.O>[C:11]1([CH3:16])[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH:9]=[CH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:18])[CH:7]=1
Reactant: [NH4+]
Reactant: Cc1ccccc1C=Cc1ccnc(Br)c1
Agent: O=[Cu-]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccccc1C=Cc1ccnc(N)c1
Temperature: 150 °C

Procedure:
A 2 mL microwave reaction tube is charged with the mixture of E and Z 2-bromo-4-(2-o-tolyl-vinyl)-pyridine (510 mg, 1.9 mmol), Copper (I) oxide (53 mg, 0.37 mmol), Ammonium Hydroxide (28%, 0.5 mL) and 1-4-dioxane (0.5 mL). The reaction mixture is heated at 150° C. for 30 min in a microwave reactor. Then water (5 mL) is added and the mixture is extracted with EtOAc (3×20 mL). The combined organic layers are washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude is purified by silica flash column chromatography eluting with EtOAc in Heptane (gradient from 0% to 100%) to give the desired mixture of products (210 mg).
Reaction SMILES: S1C2CN[CH2:8][CH2:9][C:4]=2C=C1.C(C1C=[CH:16][C:15]([OH:18])=[CH:14]C=1)#N>O1CCOCC1>[CH:15]([O:18][CH:9]([CH3:8])[CH3:4])([CH3:16])[CH3:14].[CH:15]([OH:18])([CH3:16])[CH3:14]
Reactant: N#Cc1ccc(O)cc1
Reactant: c1cc2c(s1)CNCC2
Agent: *CO*
Solvent: C1COCCO1
Product: CC(C)O
Product: CC(C)OC(C)C
Temperature: 80 °C
Reaction time: 4 h
Yield: 23 %

Procedure:
A mixture of 4,5,6,7-tetrahydro-thieno[2,3-c]pyridine (1 g; 7.2 mmoles), p-cyano-phenol (95% purity; 0.9 g; 7.2 mmoles), polyoxymethylene (0.43 g; 14.4 mmoles) and dioxan (20 cc) is stirred at 80° C. during 4 hours. After concentration in vacuo, the residue is taken up into 2N hydrochloric acid. The aqueous phase is extracted with ether, made basic with concentrated ammonia and again extracted with methylene chloride. The organic extracts are washed with water, dried over sodium sulfate and concentrated in vacuo. The residue is recrystallized from isopropyl ether-isopropanol (M.p. 134° C.; yield: 23%).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=[CH2:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]2[N:46]([C:47]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:45]=[N:44][N:43]=2)=[CH:32][CH:31]=1>O1CCCC1>[CH2:1]([C:5]1[N:14]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]3[N:46]([C:47]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[N:45]=[N:44][N:43]=3)=[CH:34][CH:35]=2)[C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:16]=[CH2:17])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=Cc1ccc2[nH]c(CCCC)nc(=O)c2c1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=Cc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c(=O)c2c1
Temperature: 25 °C
Yield: 69.1 %

Procedure:
To a suspension of 4.49 g of 2-Butyl-6-ethenyl-4(1H)-quinazolinone in 70 ml of dry tetrabydrofuran at room temperature is rapidly added 23.63 9 of a 1.0M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran. After stirring for 20 minutes at room temperature 21.94 g of 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazole is rapidly added in one portion and the reaction mixture heated at reflux for 48 hours. After cooling to room temperature, the reaction mixture is concentrated in vacuo to a residue which is purified by chromatography on silica gel by eluting with 1:3 ethyl acetate-hexanes to give 9.58 g of the desired product as a yellow solid. FAB MASS SPEC 705 (M+H)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1)=[O:4].[OH-].[Na+].O>O1CCCC1>[O:14]=[C:11]1[NH:10][C:9]2[CH:15]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=2[S:13][CH2:12]1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)CS2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CSc2ccc(C(=O)O)cc2N1
Reaction time: 2.5 h
Yield: 98.2 %

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid methyl ester (6.74 g) was suspended in tetrahydrofuran (100 mL) and 2M sodium hydroxide (30 mL) was added followed by water (20 mL). The solution was stirred for 2.5 hours, evaporated to half volume and acidified with 2M hydrochloric acid. The product was collected, washed with water and dried in vacuo, to give a white solid (6.2 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10](/[CH:14]=[CH:15]/[CH:16]([C:21]3[CH:26]=[C:25]([Cl:27])[C:24]([F:28])=[C:23]([Cl:29])[CH:22]=3)[C:17]([F:20])([F:19])[F:18])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].[F:30][C:31]([F:37])([F:36])[CH2:32][C:33](O)=[O:34].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:27][C:25]1[CH:26]=[C:21]([CH:16]([C:17]([F:19])([F:20])[F:18])/[CH:15]=[CH:14]/[C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[N:5]([C:3](=[O:4])[CH2:2][NH:1][C:33](=[O:34])[CH2:32][C:31]([F:37])([F:36])[F:30])[CH:6]=[CH:7]3)[CH:22]=[C:23]([Cl:29])[C:24]=1[F:28]
Reactant: O=C(O)CC(F)(F)F
Reactant: NCC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CC(F)(F)F)NCC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To a stirred solution of (E)-2-amino-1-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indol-1-yl) ethanone (0.04 g, 0.09 mmol) in DCM (5.0 ml) was added 3,3,3-trifluoropropanoic acid (17.5 mg, 0.136 mmol), PyBOP (70 mg, 0.135 mmol) and DIEA (29 mg, 0.225 mmol) and the reaction was stirred at RT for 16 h. The reaction mixture was diluted with DCM, and the DCM layer was washed with water and saturated brine solution. The separated DCM layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound, which was purified by column chromatography (SiO2, 100-200 mesh; 10% ethyl acetate/petroleum ether) to afford the title compound as an off-white solid (30 mg, 60%): mp 121-126° C.; 1H NMR (400 MHz, CDCl3) δ 8.33 (br, 1H), 7.59 (s, 1H), 7.45 (m, 4H), 6.72 (d, J=3.6 Hz, 3H), 6.39 (m, 1H), 4.71 (t, J=7.2 Hz, 2H), 4.15 (m, 1H), 3.51 (m, 1H), 3.28 (m, 1H); ESIMS m/z 553.06 ([M−H]−).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=[O:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[CH3:18][Mg]Br>O1CCCC1.C(OCC)C>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]([OH:17])[CH3:18])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: C[Mg]Br
Reactant: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCc1nc(=O)c2cc(C(C)O)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.60 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazoline-carboxaldehyde in 30 ml of dry tetrahydrofuran, cooled to 0° C. is added dropwise, 2.61 ml of a 3.0M solution of methylmagnesium bromide in diethyl ether. The reaction is stirred at 0° C. for 30 minutes and then quenched with 10 ml of aqueous ammonium chloride. After diluting with 10 ml of water, the reaction mixture is extracted with 9:1 chloroform-methanol. The combined extracts are dried with magnesium sulfate, filtered and concentrated to yield 0.64 g of the desired product. CI MASS SPEC 247(MH+).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH3:25][Mg]Br.Cl>O1CCCC1.C(=O)=O.CC(C)=O.O>[F:24][C:2]([F:1])([F:23])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]([OH:20])[CH3:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: C[Mg]Br
Agent: Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)=O
Product: CC(O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde (8.49 g, 25.5 mmol) in anhydrous tetrahydrofuran (102 mL) in dry ice/acetone bath was added methylmagnesium bromide (1 M in butyl ether, 25.5 mL, 25.5 mmol). The solution was then warmed to room temperature and stirred overnight. The reaction was acidified with hydrogen chloride (2 N, 10 mL) until pH 2, diluted with water, and extracted with ethyl acetate (2×). The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound as an orange liquid (8.80 g, 94%): 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.27-8.11 (m, 2H), 7.90-7.68 (m, 2H), 7.49 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.3 Hz, 2H), 4.98 (q, J=6.5 Hz, 1H), 1.54 (d, J=6.5 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 350 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]([Si:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][CH2:7][CH:8]([OH:14])[CH:9]([OH:13])[CH2:10][CH:11]=[CH2:12])([CH3:4])[CH3:3].C(=O)(O)[O-].[Na+].[I:32]I>C(OCC)C.O>[CH3:4][C:2]([Si:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][CH2:7][C@H:8]1[O:14][C@H:11]([CH2:12][I:32])[CH2:10][C@H:9]1[OH:13])([CH3:1])[CH3:3]
Reactant: II
Reactant: C=CCC(O)C(O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)[Si](OC[C@H]1O[C@H](CI)C[C@H]1O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.3 %

Procedure:
A 0° C. solution of 14.67 g of product from Example 274 in 200 ml of 3:1 diethyl ether/water is treated with 4.99 g of sodium bicarbonate and 15.07 g of iodine. The reaction mixture is stirred vigorously for 24 hours at room temperature, quenched with 15 ml of saturated sodium sulfite, and diluted with 100 ml of water. the reaction mixture is extracted with diethyl ether, dried, concentrated in vacuo, and purified by chromatography (silica gel: 0-10% ethyl acetate/hexane) to give 15.0 g of the desired product.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:8]([S:11][CH3:12])=[N:9][CH:10]=1)=[O:5])C.[OH-].[K+:22]>>[K+:22].[CH3:12][S:11][C:8]1[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19])[C:6]([C:4]([O-:5])=[O:3])=[CH:10][N:9]=1
Reactant: CCOC(=O)c1cnc(SC)n1COCC[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Product: CSc1ncc(C(=O)[O-])n1COCC[Si](C)(C)C
Temperature: 60 °C

Procedure:
To a solution of 2-methylsulfanyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazole-4-carboxylic acid ethyl ester (99 mg, 0.31 mmol)(as prepared in the previous step) was added 2 N KOH (0.16 mL, 0.32 mmol) and the mixture heated to 60° C. for 3 h. The mixture was concentrated and dried under vacuum to give the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C11H19KN2O3SSi, 289.1 (M−K+2H). found 288.7.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13]([S:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(OCC)(=O)C.[ClH:38]>C(OCC)(=O)C.CC(O)C>[ClH:38].[CH3:24][NH:23][CH2:22][C:11]1[CH:10]=[C:9]([C:8]2[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=2)[N:13]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:12]=1
Reactant: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2cccs2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2cccs2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of tert-butyl {[5-(2-cyanopyridin-3-yl)-1-(2-thienylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (195 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 140 mg, 84%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][C:8]([C:12](=[CH2:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[OH-:20].[Na+].OO.Cl>C1COCC1.O>[CH3:19][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:18][OH:20])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: C=C(CCCCC)c1ccc2c(c1)OCCC2(C)C
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC(CO)c1ccc2c(c1)OCCC2(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4,4-dimethyl-7-(1-methylene-hexyl)-chroman (0.442 g, 1.71 mmole) in 8 mL of THF at 0° C. was treated with 1.71 mL of 1M BH3.THF complex. The reaction mixture was stirred at room temperature for three hours and then cooled to 0° C. The mixture was treated successively with 0.3 mL of water, 0.34 mL of 3M sodium hydroxide and 0.34 mL of 30% hydrogen peroxide, stirred at room temperature for two hours and then diluted with 10 mL of water. The pH was adjusted to 4.0 with 10% HCl and extracted with three 12.5 ML portions of ether. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a pale yellow oil. The product was purified by flash chromatography (SiO2, 10-20% ethyl acetate in hexanes) to yield 0.366 g of 2-(4,4-dimethyl-chroman-7-yl)-heptan-1-ol as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:20]([C:22]1[NH:23][C:24]([CH:32]([CH3:34])[CH3:33])=[CH:25][C:26]=1[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:20][C:22]4[NH:23][C:24]([CH:32]([CH3:34])[CH3:33])=[CH:25][C:26]=4[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)c1cc(CCC(=O)O)c(C=O)[nH]1
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)c1cc(CCC(=O)O)c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.7 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3-(2-formyl-5-isopropyl-1H-pyrrol-3-yl)-propionic acid (54.4 mg, 0.26 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 2 days. The precipitate was collected by vacuum filtration, washed with water, 1N HCl, water and finally ethanol, dried in vacuum oven to give 83 mg (71%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 13.44 (br s, 1H, NH), 12.15 (br s, 1H, COOH), 11.69 (br s, 1H, NH), 9.02 (br s, 1H), 8.29 (s, 1H), 7.77 (dd, J=2.5 & 6.4 Hz, 1H), 7.47 (s, 1H), 7.43 (m, 1H), 7.33 (t, J=8.9 Hz, 1H), 6.14 (d, J=2 Hz, 1H), 3.01 (m, 1H, CH(CH3)2), 2.83 (t, J=7.2 Hz, 2H, CH2), 2.48 (m, 2H, CH2), 1.21.27 (d, J=6.8 Hz, 6H, CH(CH3)2). MS 469 [M++1].
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:29]=[CH:28][C:7]2[N:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[C:14]([N:21]5[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]5)[CH:15]=[CH:16][CH:17]=4)[N:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1)[CH3:2].[CH:30]1([NH2:33])[CH2:32][CH2:31]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:30]1([NH:33][CH:24]2[CH2:23][CH2:22][N:21]([C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:13]=3[N:12]=[C:11]([N:8]3[C:7]5[CH:28]=[CH:29][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=5[N:10]=[CH:9]3)[CH:20]=[CH:19]4)[CH2:26][CH2:25]2)[CH2:32][CH2:31]1
Reactant: CCOc1ccc2c(c1)ncn2-c1ccc2cccc(N3CCC(=O)CC3)c2n1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOc1ccc2c(c1)ncn2-c1ccc2cccc(N3CCC(NC4CC4)CC3)c2n1
Reaction time: 0.17 h
Yield: 103.2 %

Procedure:
1-[2-(5-Ethoxy-benzoimidazol-1-yl)quinolin-8-yl]-piperidin-4-one 18 (130 mg, 0.340 mMol) was dissolved in 1.5 mL of DCE under an atmosphere of dry N2. To this solution was added cyclopropyl amine (110 μL, 1.70 mMol) and 200 μL of AcOH and the solution was stirred for 10 minutes. To this solution was added NaHB(OAc)3 (107 mg, 0.50 mMol) and the solution was stirred at ambient temperature for 5 hours. The reaction mixture was then partitioned between DCM and aqueous 0.1 N NaOH. The DCM layer was again washed with aqueous 0.1 N NaOH, dried over Na2SO4, filtered and concentrated under vacuum to give 150 mg of a green foam. The foam was chromatographed on flash silica gel eluting with a gradient from MeOH/DCM (299) to MeOH/DCM (496) to give the title compound 20 as a yellow solid.