Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([S:14][CH2:15][CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)=[CH:8][C:7]=1[CH3:26].[H-].[Na+].[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1.Cl>CN(C=O)C>[CH3:13][O:12][C:10]1[C:9]([S:14][CH2:15][CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:36][C:35]3[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:40])[F:41])=[CH:39][CH:38]=3)[CH:18]=2)=[CH:8][C:7]([CH3:26])=[C:6]([CH:11]=1)[O:5][CH2:4][C:3]([OH:2])=[O:27]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)COc1cc(OC)c(SCCc2c[nH]c3ccccc23)cc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OCC(=O)O)c(C)cc1SCCc1cn(Cc2ccc(C(F)(F)F)cc2)c2ccccc12
Reaction time: 0.5 h

Procedure:
The compound 54A (0.300 g, 0.778 mmol) was dissolved in 5 ml DMF. NaH was added and stirred for ½ h. 4-trifluoromethylbenzyl bromide (0.223 g, 0.934 mmol) was added and the reaction was stirred for 1.5 h. 10 ml 2N HCl was added to pH<4. The DMF solution was partitioned between 30 ml water and 30 ml ethyl acetate. The organic solution was washed 2×30 ml water 1×30 ml brine, dried over sodium sulfate, decanted, concentrated and purified by MPLC to give the title product. MS m/z 544 (M+1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)O1.Br[C:17]1[C:18]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][C:28]=2[Cl:33])=[N:19][C:20]([NH2:26])=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1>>[Cl:33][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:27]=1[C:18]1[C:17]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[CH:22][C:21]([N+:23]([O-:25])=[O:24])=[C:20]([NH2:26])[N:19]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: Nc1nc(-c2ccncc2Cl)c(Br)cc1[N+](=O)[O-]
Product: Nc1nc(-c2ccncc2Cl)c(-c2ccncc2)cc1[N+](=O)[O-]
Yield: 85 %

Procedure:
Following the same procedure as in Intermediate 1 (step a), but using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 3-bromo-3′-chloro-5-nitro-2,4′-bipyridin-6-amine was converted to the title compound as yellowish solid (0.84 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[C:7]([O:15][CH3:16])=[CH:6][C:3]=1[CH:4]=[O:5].[OH-].[K+].[O-:19][Mn](=O)(=O)=O.[K+]>O1CCOCC1>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[C:7]([O:15][CH3:16])=[CH:6][C:3]=1[C:4]([OH:19])=[O:5]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COCCOc1cc(F)c(C=O)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCCOc1cc(F)c(C(=O)O)cc1OC
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
2-Fluoro-5-methoxy-4-(2-methoxyethoxy)benzaldehyde (0.36 g, 1.6 mmol) was suspended in a mixture of dioxane (1.5 mL) and KOH (16 mL of 0.2 M, 3.2 mmol). KMnO4 (370 mg, 2.4 mmol) was added and the mixture was stirred vigorously for 30 minutes. The reaction mixture was filtered and the filtrate was concentrated to 10 mL (blue soln). HCl (4M, mL) was added and the resulting precipitate was filtered and washed with 1M HCl and then water (1 mL) to yield 2-fluoro-5-methoxy-4-(2-methoxyethoxy)benzoic acid (300 mg, 78%) as a white solid. ESI-MS m/z calc. 244.1, found 245.1 (M+1)F. Retention time: 1.01 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 12.96 (s, 1H), 7.30 (d, J=7.0 Hz, 1H), 6.98 (d, J=12.5 Hz, 1H), 4.20-4.13 (m, 2H), 3.78 (s, 3H), 3.71-3.63 (m, 2H), 3.31 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([C:20]([OH:23])([CH3:22])[CH3:21])[CH2:16][CH2:15]3)[N:8]2[CH3:11])=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=1.[CH2:30]([C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:30]([C:32]1[N:33]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]4[CH2:15][CH2:16][CH:17]([C:20]([OH:23])([CH3:21])[CH3:22])[CH2:18][CH2:19]4)[N:8]3[CH3:11])=[C:4]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:3]=2)[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31]
Reactant: Cn1c(CCN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCN3CCC(C(C)(C)O)CC3)n(C)c2n1
Temperature: 120 °C
Yield: 49.7 %

Procedure:
A mixture of 2-{1-[2-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]-piperidin-4-yl}propan-2-ol (71 mg, 0.17 mmol), 2-ethylbenzimidazole (27 mg, 0.19 mmol), Pd2(dba)3 (3.8 mg, 2.5 mol %), Xphos (8.0 mg, 10 mol %) and Cs2CO3 (82 mg, 0.25 mmol) in dioxane (1 0 mL) was purged with argon gas then heated at 120° C., for 19 h, in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PCC, 0-10% MeOH in DCM) to give 367 (45 mg, 50%) as a yellow solid. LCMS: (Method G): RT 6.09 min; [M+H]+ 533.3. 1H NMR (400 MHz, CHCl3-d): δ 8.01-7.97 (m, 1 H), 7.77-7.72 (m, 1 H), 7.29-7.23 (m, 2 H), 4.49-4.15 (m, 4H), 3.88-3.83 (m, 4 H), 3.78 (s, 3 H), 3.34 (q, J=7.5, 2 H), 3.14 (m, 4 H), 2.93-2.75 (m, 2H), 2.20-2.08 (m, 2 H), 1.85-1.78 (m, 2 H), 1.44 (t, J=7.5 Hz, 3 H), 1.40-1.21 (m, 3 H), 1.24-1.18 (m, 6 H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 27.5 %

Procedure:
A mixture of 1-(4-pyridyl)piperazine (4.05 g), 4-fluorobenzonitrile (3.00 g) and potassium carbonate (7.00 g) in N-methylpyrrolidone (25 ml) was heated at 80° C. with stirring for 18 hours. The solvent was then evaporated and the residue was partitioned between dichloromethane and water. The organic layer was washed with water, dried over magnesium sulphate and evaporated. The residue was crystallised from ethanol to give the title compound (1.80 g), m.p. 155°-158° C. Found: C,72.50; H,5.96; N,21.24. C16H16N4 requires: C,72.70; H,6.10; N,21.20%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19](O)=[O:20])=[CH:11]2)=[CH:7][C:6]([C:22]([F:25])([F:24])[F:23])=[CH:5][N:4]=1.Cl.[F:27][CH2:28][CH2:29][NH2:30].C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>ClCCl.O>[F:27][CH2:28][CH2:29][NH:30][C:19]([C:12]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:18]2[N:10]([CH2:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([C:22]([F:23])([F:25])[F:24])[CH:7]=2)[CH:11]=1)=[O:20]
Reactant: COc1ncc(C(F)(F)F)cc1Cn1cc(C(=O)O)c2ncccc21
Reactant: NCCF
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ncc(C(F)(F)F)cc1Cn1cc(C(=O)NCCF)c2ncccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
See FIG. 19(a). To a stirred solution of 1-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (60 mg, 0.177 mmol) in dichloromethane (5 mL) were added 2-fluoroethan-1-amine hydrochloride (26 mg, 0.26 mmol), triethylamine (0.053 g, 0.531 mmol) and T3P (0.33 g, 0.531 mmol) and reaction mixture was stirred for 16 h at room temperature. Then the reaction mixture was poured in to water and extracted with dichloromethane. The reaction mixture was poured into water and extracted with dichloromethane. The combined organic layer was washed with water,brine and solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using silica gel column chromatography to afford N-(2-fluoroethyl)-1-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide as a white solid. Yield: 15 mg. (22.3%). ES+MS m/z: 397. 1H NMR (400 MHz, DMSO-d6): δ ppm 3.66-3.70 (m, 2H), 3.72-3.76 (m, 2H), 4.00 (s, 3H), 4.50-4.52 (m, 2H), 4.62-4.64 (m, 2H), 5.76 (s, 2H), 7.30-7.33 (m, 1H), 7.92 (s, 1H), 8.11 (d, 1H, J=8.3 Hz), 8.32 (s, 1H), 8.50-8.52 (m, 1H), 8.66-8.67 (m, 1H), 8.94 (t, 1H, J=5.6 Hz).
Reaction SMILES: C([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26]5=[O:34])[C:20]=4[CH3:35])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)=O.S(=O)(=O)(O)[OH:37].OO.[OH-].[Na+]>CO.O>[OH:37][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26]5=[O:34])[C:20]=4[CH3:35])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(C=O)ccc4c23)cccc1N1Cc2ccccc2C1=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(O)ccc4c23)cccc1N1Cc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 23 h
Yield: 15.5 %

Procedure:
Step 3 A suspension of 7-formyl-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (30 mg, 0.052 mmol) in methanol (1 mL) was treated with sulfuric acid (4.2 mL, 0.078 mmol) followed by 30% aqueous hydrogen peroxide (0.032 mL, 0.313 mmol), and stirred at rt for 23 h, The mixture was treated with 1 M aqueous sodium hydroxide (200 mL) and stirred for 1 h. The mixture was diluted with water and the precipitate was collected by filtration, washed with water and dried. The residue was purified by preparative HPLC to provide 7-hydroxy-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide as a tan powder (3.6 mg, 15%). 1H NMR (400 MHz, methanol-d4) δ 7.90 (1 H, d, J=7.5 Hz), 7.86 (1 H, d, J=7.9 Hz), 7.65-7.76 (2 H, m), 7.48-7.63 (3 H, m), 7.42 (1H, d, J=6.6 Hz), 7.03 (1 H, d, J=7.9 Hz), 6.98 (1 H, s), 6.92 (1 H, d, J=8.8 Hz), 6.54 (1H, d, J=9.0 Hz), 4.97 (2 H, s), 1.94 (3 H, s). Mass spectrum m/z 448.1 (M+H)+.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][C:9](=[O:18])[N:8]2[CH2:19][C:20]([O:22]CC)=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O1CCCC1.O>[C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][C:9](=[O:18])[N:8]2[CH2:19][C:20]([OH:22])=[O:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CN1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
Ethyl (4,5-cis-diphenyl-2-oxo-3-oxazolidinyl)acetate (40.6 g, 125 mmol) was dissolved in tetrahydrofuran (100 ml) and a solution of sodium hydroxide (6 g, 150 mmol) in water (40 ml) was added thereto. The mixture was stirred at room temperature for 15 minutes. To the homogeneous solution was added water (150 ml) and the mixture was washed twice with diisopropyl ether (20 ml). The aqueous layer was adjusted to pH 2 with a 10-fold dilution of concentrated hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate and filtered. The filtrate was concentratred and the residue was recrystallized from methylenechloride-n-hexane mixture to give the title compound (29.1 g) as white crystals.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([N:12]2[CH2:21][C:20]3[CH:19]=[N:18][N:17]([CH3:22])[C:16]=3[NH:15][C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]2=3)=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:27][CH2:28][C:29]([N:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]1)=[O:30]>CO.C(O)(=O)C>[OH:37][CH:34]1[CH2:33][CH2:32][N:31]([C:29](=[O:30])[CH2:28][CH2:27][C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:21][C:20]4[CH:19]=[N:18][N:17]([CH3:22])[C:16]=4[NH:15][C:14]4[CH:23]=[CH:24][CH:25]=[CH:26][C:13]3=4)=[O:11])=[CH:9][C:4]=2[CH3:3])[CH2:36][CH2:35]1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
Sodium borohydride (4 mg, 0.1 mmol) was added to a solution of 1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-piperidin-4-one (Compound number 701) (50 mg, 0.11 mmol) in methanol/acetic acid (99:1, v/v, 100 ml) and the mixture was stirred at room temperature for 1 h. Sodium borohydride (4 mg, 0.11 mmol) was added again and the mixture was stirred for 1 h at room temperature then concentrated in vacuo. The residue was dissolved in di-chloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo to give a white powder identified as the title compound (28 mg, 56%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([OH:11])=[CH:5][C:4]=1[N:12]=[CH:13][N:14]([CH3:16])[CH3:15])#[N:2].[C:17]([O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31]O)[CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[C:17]([O:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][CH:27]([CH2:30][CH2:31][O:11][C:6]2[C:7]([O:9][CH3:10])=[CH:8][C:3]([C:1]#[N:2])=[C:4]([N:12]=[CH:13][N:14]([CH3:15])[CH3:16])[CH:5]=2)[CH2:28][CH2:29]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1O
Reactant: CC(C)(C)OCCN1CCC(CCO)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(C#N)c(N=CN(C)C)cc1OCCC1CCN(CCOC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
N′-(2-cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethylimidoformamide (876 mg, 4 mmol) in dichloromethane (2 ml) was reacted with 2-(1-(2-tert-butoxyethyl)piperidin-4-yl)ethanol (916 mg, 4.4 mmol) in the presence of triphenylphosphine (1.2 g, 4.6 mmol) by slow addition of a solution of di-tert-butyl azodicarboxylate (1.058 g, 4.6 mmol) in dichloromethane (5 ml). The mixture was stirred for 2 hours at ambient temperature and purified by chromatography. Elution with dichloromethane:ethyl acetate:methanol (5:4:1) yielded N′-(5-{2-[1-(2-tert-butoxyethyl)piperidin-4-yl]ethoxy}-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide (720 mg, 42% yield):
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2)[CH3:5].[F:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][C:33]([NH2:37])=[CH:34][CH:35]=3)[CH:30]=[N:29]2)=[CH:23][CH:22]=1>>[F:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][C:33]([NH:37][C:9]4[C:8]5[C:13](=[CH:14][CH:15]=[CH:16][C:7]=5[O:6][C@H:4]([CH3:5])[C:3]([N:2]([CH3:19])[CH3:1])=[O:18])[N:12]=[CH:11][N:10]=4)=[CH:34][CH:35]=3)[CH:30]=[N:29]2)=[CH:23][CH:22]=1
Reactant: C[C@@H](Oc1cccc2nc[nH]c(=O)c12)C(=O)N(C)C
Reactant: Nc1ccc2c(cnn2Cc2ccc(F)nc2)c1
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccc(F)nc4)c3)c12)C(=O)N(C)C
Yield: 60.2 %

Procedure:
Using the same procedure as in Example 18, (2R)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide (200 mg, 0.77 mmol) and 1-[(6-fluoropyridin-3-yl)methyl]-1H-indazol-5-amine (204 mg, 0.84 mmol) were reacted to give the title compound as a white solid (225 mg, 60%); NMR Spectrum (CDCl3) 1.73 (d, 3H), 3.07 (s, 3H), 3.15 (s, 3H), 5.44 (q, 1H), 5.59 (s, 2H), 6.84 (m, 2H), 7.37 (d, 1H), 7.8-7.45 (m, 3H), 7.87 (dd, 1H), 8.07 (s, 1H), 8.21 (s, 1H), 8.44 (s, 1H), 8.62 (s, 1H); Mass spectrum 486.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.CCN=C=NCCCN(C)C.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:14])=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: Nc1nc(-c2ccco2)c2ncn(CC(=O)O)c2n1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: Nc1nc(-c2ccco2)c2ncn(CC(=O)Nc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 30.5 %

Procedure:
A solution of 2-amino-6-(2-furyl)-9H-purine-9-acetic acid (129 mg, 0.5 mmol) in DCM (2 mL) was treated with EDCI (96 mg, 0.5 mmol) and aniline (45 μL, 0.5 mmol), stirred at room temperature for 3 days, diluted with DCM, washed with water, dried (MgSO4), concentrated in vacuo and purified by chromatography (SiO2; 1% MeOH in EtOAc) to give the title compound (51 mg, 31%) as a white solid.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28]([N:30]1[CH2:34][C:33]([F:36])([F:35])[CH2:32][C@H:31]1[CH2:37][OH:38])=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:23]([O:27][C:28]([N:30]1[CH2:34][C:33]([F:35])([F:36])[CH2:32][C@H:31]1[CH:37]=[O:38])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C=O
Reaction time: 2 h
Yield: 93 %

Procedure:
Dess Martin Periodinane (0.9 g, 0.0021 mol) was added in one portion to a solution of (S)-4,4-difluoro-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.4 g, 0.0016 mol) in DCM (50 mL) under an inert atmosphere. The reaction was stirred until completion (about 2 h) and then quenched with saturated solution of sodium thiosulphate, extracted with DCM (3×100 mL) washed with brine (50 mL), dried over anhydrous sodium sulphate, and concentrated using a rotary evaporator to afford 0.35 g of the desired (S)-4,4-difluoro-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a light brown colored oil product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([NH2:11])=[C:6]([NH2:12])[CH:5]=1.CO[C:16](=[NH:21])[C:17]([Cl:20])([Cl:19])[Cl:18]>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([CH3:10])[C:7]2[NH:11][C:16]([C:17]([Cl:20])([Cl:19])[Cl:18])=[N:12][C:6]=2[CH:5]=1)=[O:13].[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([CH3:10])[C:7]2[NH:11][C:16]([C:17]([Cl:18])([Cl:19])[Cl:20])=[N:21][C:6]=2[CH:5]=1)=[O:13]
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(C)c(N)c(N)c1
Product: COC(=O)c1cc(C)c2[nH]c(C(Cl)(Cl)Cl)nc2c1

Procedure:
7-Methyl-2-trichloromethyl-1H-benzoimidazole-5-carboxylic acid methyl ester 7-Methyl-2-trichloromethyl-1H-benzoimidazole-5-carboxylic acid methyl ester was prepared by a procedure according to example 5 (i) starting from 404.0 mg (2.20 mmol) 3,4-Diamino-5-methyl-benzoic acid methyl ester and 0.39 mL (3.08 mmol) 2,2,2-trichloro-acetimidic acid methyl ester.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.[C:9](Cl)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]>C(Cl)Cl.CCN(CC)CC>[CH2:12]([O:11][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4]1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCC1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a stirred solution of 3-hydroxymethylpiperidine (1 g, 8.7 mmol) in CH2Cl2 (50 mL) and Et3N (1.12 mml) at 0° C. was added dropwise CbzCl (1.24 mL, 8.7 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by chromatography with hexane-EtOAc (2:1) to give a colorless oil (2 g, 94%). 1H NMR (CDCl3) δ 7.35 (m, 5H), 5.12 (m, 2H), 4.20-3.60 (m, 2H), 3.47 (m, 2H), 3.20-2.20 (m, 3H), 1.82-1.10 (m, 5H); 13C NMR (CDCl3) δ 155.55, 136.73, 128.38, 127.85, 127.69, 66.96, 64.31, 46.74, 44.71, 38.01, 26.77, 24.05.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([O:34][CH3:35])([O:32][CH3:33])[CH2:30][F:31])[N:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([O:32][CH3:33])([O:34][CH3:35])[CH2:30][F:31])[N:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: COC(CF)(OC)c1cccc(Br)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: COC(CF)(OC)c1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared in the same manner described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (100 mg, 0.32 mmol) and 2-bromo-6-(2-fluoro-1,1-dimethoxyethyl)pyridine (85 mg, 0.32 mmol) as starting materials.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([F:12])=[CH:7][C:6]=1[CH3:13].[OH-].[Na+]>CO>[Br:11][C:9]1[C:8]([F:12])=[CH:7][C:6]([CH3:13])=[C:5]([CH2:4][C:3]([OH:14])=[O:2])[CH:10]=1
Reactant: COC(=O)Cc1cc(Br)c(F)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(F)c(Br)cc1CC(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5-bromo-4-fluoro-2-methyl-phenyl)-acetic acid methyl ester (10.3 g) in methanol (50 ml) is added 1N aqueous sodium hydroxide (47.4 ml) and the reaction mixture is stirred at room temperature for 18 hours. The mixture is concentrated, the residue treated with 1N hydrochloric acid, the resulting precipitate filtered off, washed with ice-water and dried. Yield: 8.60 g of (5-bromo-4-fluoro-2-methyl-phenyl)-acetic acid as a solid, mp: 100-101° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:12][NH:11][C:10](=O)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:12][N:11]=1
Reactant: Cc1cccc(-c2cc(=O)[nH]cc2-c2ccncc2)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cccc(-c2cc(Cl)ncc2-c2ccncc2)c1

Procedure:
4-(3-methylphenyl)-5-(4-pyridyl)-1H-pyrid-2-one (33 mg, 0.13 mmole) in POCl3 (2 mL) was heated to 105° C. for 12 hr. POCl3 was removed under reduced pressure. The residue was diluted with methylene chloride and was carefully quenched with aqueous sodium carbonate. Standard work up, followed by purification (silica gel, hexane/ethyl acetate) gave the title compound. MS (m/z): Calcd. C17H13N2Cl (M+): 280.5, found (M+H)+: 281 and 283.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:16][CH3:17])(=[O:15])[C:9]#[C:10][C:11]([O:13][CH3:14])=[O:12].C(O)(=O)C.O=O>CN(C)C(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]1[C:8]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1[nH]c2ccccc2c1C(=O)OC
Temperature: 115 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
A solution of aniline (3.91 ml, 43.0 mmol) and dimethyl but-2-ynedioate (5.28 ml, 43.0 mmol) in N,N-dimethylacetamide (DMA) (194 ml)/acetic acid (64.8 ml) was degassed with O2 for 5 min and treated with Pd(OAc)2 (0.964 g, 4.30 mmol). The reaction mixture was heated to 115° C. and placed under and atmosphere of O2. After 18 h, the reaction was cooled to ambient temperature, filtered through a pad of Celite™, diluted with EtOAc and washed with H2O. The organic was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by ISCO (0-50% EtOAc-hexanes: 220 g SiO2) to afford dimethyl 1H-indole-2,3-dicarboxylate (5.5 g, 23.58 mmol, 54.9% yield) as a yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ=9.32 (br. s., 1 H), 8.08 (d, J=8.2 Hz, 1 H), 7.48-7.44 (m, 1 H), 7.42-7.37 (m, 1 H), 7.29 (s, 1 H), 4.01 (d, J=2.0 Hz, 6 H); LCMS (m/z) ES+=234 (M+1).