Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([I:15])=[CH:12][CH:13]=2)[C:8](=[O:16])[C:7]([C:17]([O:19]CC)=O)=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>>[C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([I:15])=[CH:12][CH:13]=2)[C:8](=[O:16])[C:7]([C:17]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=2)=[O:19])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2ccc(I)cc2c1=O
Reactant: NCc1ccc(Cl)cc1
Product: CC(C)(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Temperature: 25 °C
Yield: 88.7 %

Procedure:
A slurry of 1.11 g of ethyl 1-(tert-butyl)-6-iodo4oxo-1,4-dihydro-3-quinolinecarboxylate from Preparation No. 30 in 2.0 g of 4-chlorobenzylamine is heated under argon at 160° C. for 18 h, then cooled to room temperature and triturated with 1N HCl. The solid is filtered, washed well with water, and dried under vacuum. Flash chromatography using 20% ethyl acetate in dichloromethane provides 1.22 g of the title compound as a white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].Cl>CO.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.5 %

Procedure:
To a solution of Example 7 (0.095 g, 0.240 mmol) in methanol (1.4 ml), lithium hydroxide (0.028 g, 1.20 mmol) in water (0.36 ml) was added and stirred at RT. After 12 h, the pH was adjusted to (approx) 7.5 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as an off-white solid (0.070 g, 76%). M.P.: 245-247° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 13.18 (s, 1H), 8.88 (dd, J=4.1, 1.7 Hz, 1H), 8.71 (d, J=8.7 Hz, 1H), 8.39 (d, J=1.1 Hz, 1H), 8.36 (d, J=8.5 Hz, 2H), 8.21 (d, J=8.7 Hz, 1H), 8.10 (d, J=8.5 Hz, 2H), 8.03 (d, J=9.2 Hz, 2H), 7.84 (dd, J=8.7, 2.0 Hz, 1H), 7.53 (dd, J=8.4, 4.2 Hz, 1H), 6.22 (s, 2H). MS (m/z): 381.88 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:22][C@H:23]4[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]4)[C:15]([C:17]([CH:19]([CH3:21])[CH3:20])=[CH2:18])=[N:16][C:12]=3[CH:11]=[C:10]([C:30]3[NH:34][C:33](=[O:35])[O:32][N:31]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:36][S:37]([O-:39])=[O:38].[Na+].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:22][C@H:23]4[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]4)[C:15]([CH:17]([CH2:18][S:37]([CH3:36])(=[O:39])=[O:38])[CH:19]([CH3:20])[CH3:21])=[N:16][C:12]=3[CH:11]=[C:10]([C:30]3[NH:34][C:33](=[O:35])[O:32][N:31]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C=C(c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1)C(C)C
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)C(CS(C)(=O)=O)c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 60 °C

Procedure:
To a stirred solution of 3-{4-(5-chloropyridin-3-yl)-2-(3-methylbut-1-en-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (synthesized in a manner similar to Example 9.1; 20 mg, 0.046 mmol) in dry ethanol (0.7 mL) was added sodium methanesulfinate (47 mg, 0.46 mmol) followed by acetic acid (27 μL, 0.046 mmol). The reaction mixture was heated to 60° C. for 12 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by reverse phase prep-HPLC (Kromasil C18, water/MeOH+0.1% TFA) to give 3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-{2-methyl-1-[(methylsulfonyl)methyl]propyl}-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one (TFA salt, racemate). 1H NMR (400 MHz, DMSO-d6): δ 12.90 (br s, 1H), 8.86 (s, 1H), 8.85 (s, 1H), δ 8.43 (s, 1H), 8.24 (s, 1H), 4.07-3.96 (m, 2H), 3.84-3.79 (m, 1H), 3.67-3.64 (m, 2H), 3.02 (s, 3H), 2.21-2.16 (m, 1H), 1.39 (d, J=11.6 Hz, 2H), 1.22-1.15 (m, 2H), 1.04 (d, J=6.7 Hz, 3H), 0.83 (d, J=6.7 Hz, 3H), 0.70 (d, J=6.5 Hz, 3H), 0.78-0.41 (m, 6H). MS ES/APCl calc'd. for C27H33ClN6O4S [M+H]+ 573. found 573.
Reaction SMILES: [OH:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18].[Se](=O)=[O:20]>O1CCOCC1>[OH:1][C@H:2]1[C@@H:16]([OH:20])[CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18]
Reactant: O=[Se]=O
Reactant: CC1=C2C[C@@]3(C)C(=CC[C@H](O)[C@@H]3C)C=C2OC1=O
Solvent: C1COCCO1
Product: CC1=C2C[C@@]3(C)C(=C[C@H](O)[C@H](O)[C@@H]3C)C=C2OC1=O
Temperature: 50 °C
Reaction time: 48 h
Yield: 85.8 %

Procedure:
The compound prepared in Example B1 (5 mg, 0.02 mmol) was dissolved in dioxane (1 ml), selenium dioxide (22 mg, 0.20 mmol) was added thereto, and the mixture was stirred at 50° C. for 2 days. The reaction solution was filtered, and the solvent was removed by distillation under reduced pressure. The residue was purified by preparative TLC (hexane:ethyl acetate=1:1) to give the title compound (4.5 mg, 86%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH2:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[S:30]1[C:34]([CH:35]=O)=[CH:33][N:32]=[CH:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:35][C:34]4[S:30][CH:31]=[N:32][CH:33]=4)[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)CC(C(=O)OC)=CC=N3)cc1
Reactant: O=Cc1cncs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cncs2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.9 %

Procedure:
In 1,2-dichloroethane (15 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-benzazepine-4-carboxylate (0.50 g). To the solution were added 1,3-thiazole-5-carbaldehyde 10.43 g) and sodium triacetoxyborohydride (0.80 g), and the mixture was stirred at room temperature for 24 hours. To the mixture was added sodium triacetoxyborohydride (0.27 g), and the mixture was stirred for 6 hours. The solvent was removed under reduced pressure, the resulting residue was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=3/2→2/3) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(1,3-thiazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.50 g).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=[O:11])=O)(C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:25][O:26][CH2:27][CH2:28][O:29][C:30]1[CH:55]=[CH:54][C:33]2[N:34]([C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[C:40]([N:47]5[CH2:52][CH2:51][CH:50]([NH2:53])[CH2:49][CH2:48]5)[CH:41]=[CH:42][CH:43]=4)[N:38]=3)[CH:35]=[N:36][C:32]=2[CH:31]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH2:8][CH2:9][C:10]([NH:53][CH:50]1[CH2:49][CH2:48][N:47]([C:40]2[CH:41]=[CH:42][CH:43]=[C:44]3[C:39]=2[N:38]=[C:37]([N:34]2[C:33]4[CH:54]=[CH:55][C:30]([O:29][CH2:28][CH2:27][O:26][CH3:25])=[CH:31][C:32]=4[N:36]=[CH:35]2)[CH:46]=[CH:45]3)[CH2:52][CH2:51]1)=[O:11]
Reactant: COCCOc1ccc2c(c1)ncn2-c1ccc2cccc(N3CCC(N)CC3)c2n1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COCCOc1ccc2c(c1)ncn2-c1ccc2cccc(N3CCC(NC(=O)CN)CC3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
N-(tert-butoxycarbonyl)glycine (105 mg, 0.600 mMol) was dissolved in 3 mL of DCM under an atmosphere of dry N2. To this mixture was added 1,1′-carbonyldiimidazole (100 mg, 0.61 mMol) and the reaction mixture was stirred at ambient temperature for 30 minutes. To this solution was then added 4-dimethylaminopyridine (8.0 mg, 0.065 mMol) and 1-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine 33 (170 mg, 0.408 mMol). The reaction mixture was subsequently stirred overnight at ambient temperature. The reaction mixture was then partitioned between DCM and saturated aqueous NaHCO3. The organic layer was saved and washed again with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated under vacuum to give a yellow foam. The residue was chromatographed on flash silica gel eluting with MeOH/DCM (397) to give 182 mg of a yellow residue. The residue was dissolved in 0.5 ml of TFA and stirred at ambient temperature for 30 minutes under an atmosphere of dry N2. The reaction mixture was subsequently concentrated under vacuum and then partitioned between 0.1 N aqueous NaOH. The organic layer was saved and washed again with 0.1 N aqueous NaOH, dried over Na2SO4, filtered and concentrated under vacuum to give a yellow foam. The foam was chromatographed on flash silica gel eluting with MeOH/DCM (595) to give 75 mg of the title compound as 54 a yellow solid.
Reaction SMILES: [C:1]([NH:20][CH2:21][CH2:22]O)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:57][C:58]1[CH:59]=[C:60]([N:65]2[C:69](=[O:70])[O:68][N:67]=[C:66]2[C:71]2[C:72]([NH:76]C(=O)C(F)(F)F)=[N:73][O:74][N:75]=2)[CH:61]=[CH:62][C:63]=1[F:64]>O1CCCC1.C(OC)(C)(C)C>[Cl:57][C:58]1[CH:59]=[C:60]([N:65]2[C:69](=[O:70])[O:68][N:67]=[C:66]2[C:71]2[C:72]([NH:76][CH2:22][CH2:21][NH:20][C:1]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:73][O:74][N:75]=2)[CH:61]=[CH:62][C:63]=1[F:64]
Reactant: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1)C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=c1onc(-c2nonc2NCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)n1-c1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
A solution of 2-(tritylamino)ethanol (10 g, 33 mmol) [EP599220 and J. Org. Chem. (2001), 66, 7615] and triphenylphosphine (8.7 g, 33 mmol) in tetrahydrofuran (65 mL) at 0° C. was treated with diisopropyl azodicarboxylate (7.0 mL, 35 mmol) dropwise. The reaction mixture was stirred at 0° C. for 15 min, treated with a solution of N-{4-[4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-2,2,2-trifluoroacetamide (9.3 g, 24 mmol) in tetrahydrofuran (28 mL), and stirred at 25° C. for 16 h. The reaction mixture was concentrated, diluted with ethyl acetate (350 mL), cooled to 0° C., treated with 1 N HCl (200 mL), and stirred at 25° C. for 1 h. The reaction mixture was treated with additional 1 N HCl (150 mL) and stirred at 25° C. for 3 h. The organic layer was separated, washed with saturated sodium bicarbonate (200 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a yellow foam which was reconcentrated from hexanes to give an oily solid. The oily solid was treated with methyl tert-butyl ether (50 mL) and stirred to give a heterogeneous mixture. The solid was filtered, washed with methyl tert-butyl ether (30 mL), and dried to give the desired product (10 g, 74%) as a white solid. LCMS for C31H24ClFN6O3Na (M+Na)+: m/z=605.2. 1H NMR (300 MHz, DMSO-d6): δ 7.97 (dd, J=6.7, 2.6 Hz, 1H), 7.71-7.66 (m, 1H), 7.60 (dd, J=9.1, 8.8 Hz, 1H), 7.40-7.37 (m, 6H), 7.28-7.23 (m, 6H), 7.18-7.12 (m, 3H), 6.59 (dd, J=5.9, 5.6 Hz, 1H), 3.37-3.31 (m, 2H), 2.96 (dd, J=7.6, 7.6 Hz, 1H), 2.27-2.19 (m, 2H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14].[C:15](Cl)(=[O:19])[CH2:16][CH2:17][CH3:18]>ClCCCl>[C:15]([C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[NH:5][C:6](=[O:14])[CH2:7]2)(=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: CCCC(=O)Cl
Reactant: O=C1Cc2ccccc2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 50 °C
Yield: 26.2 %

Procedure:
To 15 g aluminum chloride suspended in 30 mL 1,2-dichloroethane in an ice bath was added 7.5 g of 2-oxindole and then 12 g of butanoyl chloride. The resulting suspension was heated to 50° C. overnight. The mixture was poured into ice water and extracted 3 times with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over sodium sulfate, and concentrated to dryness to give a brown solid. The solid was chromatographed on silica gel (50% ethyl acetate in hexane) to give 3 g (25%) of the title compound as a yellow solid.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[NH:4][N:3]=1.[CH3:13]C([O-])(C)C.[K+].CI>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[N:4]([CH3:13])[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2[nH]nc(I)c2c1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc2c(c1)c(I)nn2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a solution of 3-iodo-5-methoxy-1H-indazole (442 mg, 1.61 mmol) in THF (10.0 mL) at 0° C. was added KOtBu 1M in THF (2.26 mL, 2.26 mmol) and the mixture stirred at 0° C. for 30 min where it became a pale brown reddish solution then added MeI (320 mg, 141 μL, 2.26 mmol). The reaction mixture was stirred at 0° C. for 30 min then warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride in water and extracted with dichloromethane (3×30 mL), organics dried over MgSO4 and concentrated to a clear oil. Then dissolved in toluene and purified by chromatography (80 g column, 50 μm from Analogix, 0-20% EtOAc in hexanes over 20 min to afford 3-iodo-5-methoxy-1-methyl-1H-indazole (355 mg, 1.23 mmol, 76.4%) as an off-white solid. MS (M+H)+=288.9 (>90% purity); 1H NMR (CDCl3) δ: 7.24 (d, J=9.1 Hz, 1H), 7.10 (dd, J=9.1, 2.6 Hz, 1H), 6.75 (d, J=2.6 Hz, 1H), 4.06 (s, 3H), 3.88 (s, 3H). The regioisomer 3-iodo-5-methoxy-2-methyl-2H-indazole (89 mg, 309 μmol, 19.2%) was also obtained as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9]O)=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC>C(Cl)(Cl)Cl>[Br:12][CH2:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: OCCCc1ccncc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: BrCCCc1ccncc1
Reaction time: 2 h
Yield: 111.1 %

Procedure:
3.0 g of 4-pyridinepropanol was dissolved in 90 ml of chloroform, 9.4 g of carbon tetrabromide and 7.5 g of triphenylphosphine was added under ice cooling, and the mixture was stirred for 2 hours. Ether was added to the reaction solution, and the mixture was extracted with 1N hydrochloric acid, and then the aqueous layer was washed with ether. The aqueous layer was adjusted to be basic with 6N sodium hydroxide, and extracted with ether. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure to give 4.86 g of 4-(3-bromopropyl)pyridine.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:20]Br.[C:22]([C:24]1[CH:25]=[C:26]([CH2:30][CH:31]=[CH:32]O)[CH:27]=[CH:28][CH:29]=1)#[N:23]>CC#N>[C:22]([C:24]1[CH:25]=[C:26]([CH2:30][CH:31]=[CH:32][Br:20])[CH:27]=[CH:28][CH:29]=1)#[N:23]
Reactant: BrBr
Reactant: N#Cc1cccc(CC=CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: N#Cc1cccc(CC=CBr)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 101.8 %

Procedure:
To a suspension of Ph3P (1.0 g) in 40 mL of MeCN at 0° C. was added bromine (0.6 g) and the mixture was stirred at 0° C. for 15 minutes and then warmed to ambient temperature. To the suspension of Br2PPh3 was then added 3-cyano-1-(3-hydroxyprop-2-en-1yl)benzene (0.5 g) in 10 mL MeCN dropwise. The resulting solution was stirred at 60° C. for 30 minutes, cooled to ambient temperature and concentrated. The residue was triturated with 10% hexane in ethyl acetate. The mixture was filtered through a silica gel pad and the filtrate was concentrated to afford 0.71 g of 3-cyano-1-(3-bromoprop-2-en-1yl)benzene as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[F:27][CH:28]([F:32])[C:29](=[O:31])[CH3:30]>C1COCC1>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=3)[C:6]([CH2:18][C:29]([CH3:30])([OH:31])[CH:28]([F:32])[F:27])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: Cc1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Reactant: CC(=O)C(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)(Cc1nn(-c2ccnc(N)n2)c2cc(Br)ccc12)C(F)F
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-(6-bromo-3-methyl-1H-indazol-1-yl)pyrimidin-2-amine (500 mg, 1.64 mmol) in dry THF (5 mL) at −78° C. under an atmosphere of nitrogen, was introduced lithium diisopropylamide (2.1 mL of a 2M solution in THF, 4.11 mmol). After 5 minutes, a solution of 1,1-difluoropropan-2-one (0.4 mL, 4.93 mmol) in dry THF (2 mL) was added. The reaction mixture was warmed to RT after 20 minutes at −78° C. After 30 minutes at RT, the reaction mixture was quenched (5 mL of sat. aq. ammonium chloride) and concentrated in vacuo. The residue was diluted with DCM (10 mL), washed with water (2 mL) and the organic extract dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography (Biotage, elution with DCM containing a 1-12% gradient of MeOH) furnished the title compound as a yellow solid: 1H NMR (500 MHz, CDCl3) delta 1.36 (3H, s), 3.19 (1H, d, J=15.1 Hz), 3.34 (1H, d, J=14.9 Hz), 3.40 (1H, s), 5.17 (2H, s), 5.67 (1H, t, J=56.3 Hz), 7.24 (1H, d, J=8.5, 1.5 Hz), 7.45 (1H, dd, J=8.5, 1.5 Hz), 7.61 (1H, d, J=8.5 Hz), 8.32 (1H, d, J=5.6 Hz), 9.00 (1H, d, J=1.4 Hz); LC-MS: m/z=+397.90/399.90 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][C:12]([N+:18]([O-])=O)=[CH:13][CH:14]=2)[C:9]1=[O:21]>CO.C(O)(=O)C.[Pd]>[NH2:18][C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][CH2:17][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:21])=[CH:14][CH:13]=1
Reactant: Cc1ccncc1-n1ccc2ccc([N+](=O)[O-])cc2c1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccncc1N1CCc2ccc(N)cc2C1=O

Procedure:
Using analogous reaction conditions as described in Example 24, 2-(4-methyl-pyridin-3-yl)-7-nitro-2H-isoquinolin-1-one (I-24b: 120 mg, 0.4240 mmol) in methanol (10 mL) and acetic acid (0.1 mL) was reduced using Pd/C (40 mg) at 50 PSI in a Parr hydrogenator at room temperature for 3.30 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH3:27])=[O:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:47]1([CH:53](O)[CH2:54][CH3:55])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:55][CH2:54][CH2:53][N:47]4[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH3:27])=[O:24]
Reactant: CCC(O)N1CCCCC1
Reactant: CCNC(=O)Nc1ccc(Oc2ncnc3cc(O)c(OC)cc23)cc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(Oc2ncnc3cc(OCCCN4CCCCC4)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N′-ethylurea (2.7 g) was dissolved in N,N-dimethylformamide (30 ml), and triphenylphosphine(3.6 g), piperidinopropanol (1.2 g), and diethyl azodicarboxylate (2.4 g) were added to the solution. The mixture was stirred at room temperature for 2 hr. Triphenylphosphine(3.6 g), piperidinopropanol (0.8 g), and diethyl azodicarboxylate (1.9 g) were then again added to the reaction solution. The mixture was stirred at room temperature for additional 10 hr. The solvent was removed by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel by development with chloroform/methanol (20/1) to give 1.5 g (yield 42%) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[CH:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[C:20]3[CH:28]([F:30])[F:29])[N:16]=[C:15]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:14]=2)[CH2:8][CH2:7]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH:43]1([NH2:47])[CH2:46][CH2:45][CH2:44]1.O>CN(C)C=O>[CH:43]1([NH:47][CH2:2][C:3]([NH:5][C@H:6]2[CH2:11][CH2:10][C@H:9]([O:12][C:13]3[CH:18]=[C:17]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[C:20]4[CH:28]([F:30])[F:29])[N:16]=[C:15]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[N:14]=3)[CH2:8][CH2:7]2)=[O:4])[CH2:46][CH2:45][CH2:44]1
Reactant: O=C(CBr)N[C@H]1CC[C@H](Oc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1
Reactant: NC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CNC1CCC1)N[C@H]1CC[C@H](Oc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-N-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]acetamide (100 mg) was suspended in dimethylformamide (2 mL), and potassium carbonate (30 mg) and cyclobutylamine (60 μL) were added thereto, followed by stirring at room temperature overnight. To the reaction solution was added water, followed by extraction with ethyl acetate. The extracts were washed with water and saturated brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by amino silica gel chromatography (hexane:ethyl acetate=40:60-10:90) to obtain N2-cyclobutyl-N-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]glycinamide (79 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[OH-].[K+]>CO.O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(Cl)cc(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Cl)cc(C(=O)O)c1
Yield: 21.1 %

Procedure:
In a 5 liter 3-necked round-bottomed flask were placed 5-chloroisophthalic acid dimethyl ester (146.4 g) and methanol (2.5 liters). To the resulting solution was added (dropwise) a solution of potassium hydroxide (42.8 g) in methanol (500 ml) with vigourous stirring under nitrogen. The resulting mixture was refluxed 2 hours, cooled down and the solvent was then eliminated in the rotavap. The residue was taken up in water (800 ml), the pH brought to 8 and the resulting solution washed with ethyl ether. The aqueous solution was made acidic with aqueous hydrochloric acid and extracted with ethyl acetate (3×400 ml). The combined organic layers were dried (magnesium sulfate) and the solvent was then eliminated in the rotavap. The solid residue was stirred in 1.3 liters of chloroform overnight and filtered. The solvent was then evaporated yielding 5-chloroisophthalic acid monomethyl ester as a white solid (29 g).