Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:9]=[CH:8][C:7]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[C:21]([OH:30])[CH:20]=1)=[O:18])[CH:2]([CH3:4])[CH3:3].[H-].[Na+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:9]=[CH:8][C:7]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[C:21]([CH:20]=1)[O:30][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:18])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(O)c2)c(OCC(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C(=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
In 9 ml of N,N-dimethylformamide is dissolved 0.86 g of (2,4-diisobutoxyphenyl)(3-hydroxy-4-isobutoxyphenyl)methanone, to which is added 0.12 g of 60% sodium hydride. After elevating the temperature to 80° C., 0.52 ml of ethyl 2-bromoacetate is added, and the mixture thus obtained is stirred at 80-90° C. for 30 minutes. The reaction mixture is cooled to ambient temperature and added to a mixture of ethyl acetate and water, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 1.00 g of ethyl 2-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenoxy]acetate as a light yellow oily product.
Reaction SMILES: O(S(C)(=O)=O)S(C)(=O)=O.[CH2:10]([O:12][C:13]([C:15]1[CH:19]=[CH:18][N:17]([CH:20]([CH3:22])[CH3:21])[C:16]=1[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)O)=[O:14])[CH3:11].CCN(CC)CC.[NH2:39][C:40]1[C:41](=[O:48])[N:42]([CH3:47])[CH:43]=[C:44]([Cl:46])[CH:45]=1>C(Cl)Cl.O>[CH2:10]([O:12][C:13]([C:15]1[CH:19]=[CH:18][N:17]([CH:20]([CH3:22])[CH3:21])[C:16]=1[CH:23]([NH:39][C:40]1[C:41](=[O:48])[N:42]([CH3:47])[CH:43]=[C:44]([Cl:46])[CH:45]=1)[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(Cl)cc1
Reactant: Cn1cc(Cl)cc(N)c1=O
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccn(C(C)C)c1C(Nc1cc(Cl)cn(C)c1=O)c1ccc(Cl)cc1
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
Ms2O (18.65 mmol) was added at −30° C. to a solution of 2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step E4) (9.32 mmol) and Et3N (46.6 mmol) in CH2Cl2 (60 mL) and stirred at −30° C. for 15 min. 3-Amino-5-chloro-1-methyl-1H-pyridin-2-one (Step L4) (11.19 mmol) was added and the mixture was stirred at −10° C. for 30 min. The mixture was diluted with H2O and extracted with CH2Cl2 (3×). The combined organic phases were washed successively with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography to afford the title compound as a white solid. ESI-MS: tR=1.37 min, [M+]+462/464 (LC-MS 1).
Reaction SMILES: [Li+].CC([N-][CH:6]([CH3:8])[CH3:7])C.[CH2:9]([O:11][C:12](=[O:16])C(C)C)[CH3:10].Br[CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22].O>C1COCC1>[CH2:9]([O:11][C:12](=[O:16])[C:6]([CH3:7])([CH3:8])[CH2:22][CH2:21][CH2:20][CH:19]=[CH2:18])[CH3:10]
Reactant: C=CCCCBr
Reactant: CCOC(=O)C(C)C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCC(C)(C)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of LDA (2M, 5 mL) in THF (5 mL), at −78° C., is added a solution of isobutyric acid ethyl ester (1.16 g, 10 mmol) in THF (3 mL) dropwise. After the addition, the solution is slowly warmed to RT and stirred for 20 min. The temperature is then reduced to −78° C. and a solution of 5-bromo-pent-1-ene (5 mL, 10 mmol) in THF (3 mL) is added dropwise. The solution is warmed to RT and stirred for 18 h. The mixture is poured into water and extracted with EtOAc. The organic layer is dried, filtered and the solvent is removed under reduced pressure. The residue is purified by flash chromatography using(hexane/EtOAc (10:1) as eluent to give the product as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])[C:9](=[O:10])[N:8]([CH3:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[S:5]1)([CH3:3])[CH3:2].[Br:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH:1]([C:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:28][CH2:27][O:26][CH2:25][CH2:24][Br:23])[C:9](=[O:10])[N:8]([CH3:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[S:5]1)([CH3:3])[CH3:2]
Reactant: BrCCOCCBr
Reactant: CC(C)C1(c2ccccc2O)Sc2ccccc2N(C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)C1(c2ccccc2OCCOCCBr)Sc2ccccc2N(C)C1=O

Procedure:
9.4 g (30 mmol) of 3,4-dihydro-2-isopropyl-4-methyl-2-(2-hydroxyphenyl)-2H-1,4-benzothiazin-3-one are boiled for 8 hours under reflux with 22 g (94 mmol) of 1,5-dibromo-3-oxapentane and 12.9 g (90 mmol) of potassium carbonate in 75 ml of 2-butanone. The mixture is then filtered with suction, and the filtrate is concentrated, finally in a high vacuum. This gives 12.4 g of an almost colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[NH:35][C:36]([NH:38][C:39]1[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][C:40]=1[F:46])=[O:37])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:17][C@@H:18]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:19]([O:21]C)=[O:20])=[O:16])[S:14][C:7]=12.[OH-].[Na+].O.Cl>C1COCC1.CO>[C:28]([O:27][C:25](=[O:26])[CH2:24][CH2:23][C@H:18]([NH:17][C:15]([C:13]1[S:14][C:7]2[C:8](=[N:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]2[CH:32]=[CH:33][C:34]([NH:35][C:36]([NH:38][C:39]3[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][C:40]=3[F:46])=[O:37])=[C:2]([F:1])[CH:3]=2)[CH:12]=1)=[O:16])[C:19]([OH:21])=[O:20])([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)O)sc34)cc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-tert-butyl 1-methyl (2S)-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]pentanedioate (260 mg, 0.40 mmol) in a mixture of THF/MeOH (10 ml/10 ml) was added 1M NaOH solution (2 ml, 2 mmol). The mixture was stirred at room temperature for 1 hour and poured into 100 ml of water. 1M HCl was added with stirring until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give (2S)-5-tert-butoxy-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoic acid as off-white solid. Yield: 230 mg, 91%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])[C:19]([Cl:34])=[CH:18][N:17]=1>>[Cl:34][C:19]1[C:20]([NH:22][C:23]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[N:21][C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=3[CH:14]=2)=[N:17][CH:18]=1
Reactant: CN1C(=O)OCCc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(C)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(C)c1Nc1nc(Nc2ccc3c(c2)CCOC(=O)N3C)ncc1Cl

Procedure:
Following a procedure analogous to Example 1742a, 2-amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3,N-dimethyl-benzamide were converted to 2-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-3,N-dimethyl-benzamide. TFA salt: 1H NMR (300 MHz, CDCl3) δ 11.84 (bs, 1H), 9.91 (s, 1H), 7.90 (s, 1H), 7.53-7.33 (m, 5H), 6.91 (d, 1H), 6.52 (bq, 1H), 4.46 (bs, 2H), 3.43 (s, 3H), 3.08 (d, 3H), 2.83 (bt, 2H), 2.32 (s, 3H); MS (m/e) 467 (M+1).
Reaction SMILES: [C:1]1(C)C=CC(S([O-])(=O)=O)=C[CH:2]=1.[CH2:12]([C:19]1[S:20][C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[N+:23]=1CC)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].N1C=CC=CC=1>O>[CH2:1]([C:26]1[C:22]2[NH:23][C:19](=[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:30]([CH3:31])=[O:32])[S:20][C:21]=2[CH:29]=[CH:28][CH:27]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CC[n+]1c(Cc2ccccc2)sc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: CCc1cccc2c1NC(=C(C(C)=O)c1ccccc1)S2

Procedure:
2-Benzyl-3-ethylbenzothiazolium p-toluenesulfonate (34 g, 0.08 mol), acetic anhydride (8.9 g, 0.088 mol) and dry pyridine (100 ml) are heated at reflux for 15 min., cooled and diluted with 1 liter of water. The oil which separates becomes crystalline on stirring. It is collected on a filter and washed with water. Yield 22.8 g (97%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:29]=[CH:28][C:11]2[CH2:12][C:13]3([O:27][C:10]=2[CH:9]=1)[C:22]1[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:16][N:15]([C:23](=O)[CH2:24][CH3:25])[CH2:14]3>O1CCCC1.CCOCC>[ClH:7].[Cl:7][C:8]1[CH:29]=[CH:28][C:11]2[CH2:12][C:13]3([O:27][C:10]=2[CH:9]=1)[C:22]1[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:16][N:15]([CH2:23][CH2:24][CH3:25])[CH2:14]3
Reactant: CCC(=O)N1Cc2ccccc2C2(Cc3ccc(Cl)cc3O2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCN1Cc2ccccc2C2(Cc3ccc(Cl)cc3O2)C1
Product: Cl

Procedure:
To a refluxing suspension of lithium aluminum hydride (1.4 g) in tetrahydrofuran (100 ml) is slowly dropped 6-chloro-2'-propionylspiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (6.1 g) in tetrahydrofuran (50 ml). The reaction mixture is heated under reflux for four hours, cooled and quenched by the dropwise addition of saturated ammonium chloride solution (100 ml). The mixture is filtered, diluted with ether, washed with water (2X), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the solvent is removed to yield an oil which is dissolved in ether and converted to the product hydrochloride salt (6.0 g, 90%). The salt is recrystallized from ethyl acetate/methanol to yield the analytical sample as a white solid, mp 227°-228° (dec.).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C(OCC)(=O)C>[CH2:1]([NH:8][C:19](=[O:20])[CH2:18][CH2:17][Br:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCBr
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CCBr)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of benzylamine (6.49 ml) and triethylamine (8.26 ml) in ethyl acetate (60 ml) was added dropwise to a solution of 3-bromopropionyl chloride (6 ml) in ethyl acetate (10 ml) at 0° C. The reaction mixture was stirred to room temperature for 1 hr. The organic phase was washed with water (2×150 ml), saturated brine (150 ml) and dried over magnesium sulphate. Removal of the solvent produced the amide as a crystalline solid.
Reaction SMILES: N([CH:4]([NH2:16])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[C:7]([F:15])[CH:6]=1)=[N+]=[N-].[CH3:17]O>>[F:15][C:7]1[CH:6]=[C:5]([CH:4]([NH2:16])[CH3:17])[CH:10]=[CH:9][C:8]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CO
Reactant: [N-]=[N+]=NC(N)c1ccc(C(F)(F)F)c(F)c1
Product: CC(N)c1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Yield: 34 %

Procedure:
C-Azido-C-(3-fluoro-4-trifluoromethyl-phenyl)-methylamine (0.4 g) was dissolved in methanol (6 mL). The flask was evacuated and filled with nitrogen atmosphere before catalytic amount of Pd/C was added to the flask. The reaction was put under hydrogen atmosphere and stirred at r.t. over night. The flask was evacuated and filled with nitrogen before the reaction mixture was filtered through a celite pad. The solvent was removed and the crude product was purified on a colon (silica, CH2Cl2 followed by CH2Cl2/MeOH, 9:1) yielding 120 mg (34%) of 1-(3-Fluoro-4-trifluoromethyl-phenyl)-ethylamine. 1H NMR δ (CDCl3): 1.42 (3H, d), 4.22 (1H, q), 7.21-7.30 (m, 2H), 7.58 (1H, t).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[C:22](S(C)=O)[N:21]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:29]([NH2:32])([CH3:31])[CH3:30]>>[CH:29]([NH:32][C:2]1[N:7]2[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:21][CH:20]([CH3:25])[CH3:9])[N:21]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:7][CH:6]([CH3:10])[CH3:5])[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1)([CH3:31])[CH3:30]
Reactant: CC(C)N
Reactant: CS(=O)c1nccc(-c2nn3c(Cl)cccc3c2-c2ccnc(S(C)=O)n2)n1
Product: CC(C)Nc1nccc(-c2nn3c(NC(C)C)cccc3c2-c2ccnc(NC(C)C)n2)n1

Procedure:
N-Isopropyl-2,3-bis[2-(isopropylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine was prepared by treating 7-chloro-2,3-bis[2-(methylsulfinyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine with isopropylamine as described in Example 7. 1H NMR, (CDCl3): δ 8.39 (d, 1H), 8.14 (d, 1H), 7.52 (m, 1H), 7.36 (d, 1H), 6.96 (m, 1H), 6.60 (d, 1H), 6.06 (d, 1H), 5.99 (d, 1H), 5.08 (m, 1H), 4.99 (m, 1H), 4.05–4.25 (m, 2H), 3.80–3.99 (m, 1H), 1.42 (d, 6H), 1.30 (d, 6H), 1.24 (m, 6H); MS m/z 446 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[C:21]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:33]2[CH2:32][CH2:31][N:30]([C:27]3[CH:26]=[CH:25][C:24]([C:21](=[O:23])[CH3:22])=[CH:29][CH:28]=3)[CH2:35][CH2:34]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Product: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2ccc(C(C)=O)cc2)CC1

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(4-acetylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:23][CH:22]=2)=[N:6][C:7]=1[C:8](=O)[NH:9][NH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[N:14]=1)=[O:12].CCN(C(C)C)C(C)C.BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>C(#N)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:22]=[CH:23][C:24]([C:25]([N:27]([CH3:28])[CH3:29])=[O:26])=[CH:30][CH:31]=2)=[N:6][C:7]=1[C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[N:14]=2)=[N:10][N:9]=1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)NNC(=O)c3cccc(N)n3)n2)cc1
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4cccc(N)n4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
To a suspension of 4-[5-amino-6-[[(6-aminopyridine-2-carbonyl)amino]carbamoyl]pyrazin-2-yl]-N,N-dimethyl-benzamide (80 mg, 0.1903 mmol) in anhydrous acetonitrile (1.600 mL) cooled in an ice bath, was added DIPEA (73.78 mg, 99.43 μL, 0.5709 mmol) followed by dibromo(triphenyl)phosphorane (104.4 mg, 0.2474 mmol) portionwise. The resulting mixture was stirred at room temperature for 30 min. The precipitate was isolated by filtration, washed with small amount of acetonitrile giving a pale yellow solid. The solid was triturated in hot acetonitrile, cooled, filtered and washed acetonitrile then ether to give the pure product (36.1 mg, 54% yield); 1H NMR (400 MHz, DMSO) d 2.98-3.02 (m, 6H), 6.53 (br s, 2H), 6.69 (m, 1.5H), 7.16 (m, 0.51H), 7.16 (m, 1H), 7.53-7.66 (m, 3H), 8.11 (m, 2H) and 8.94 (s, 1H) ppm; MS (ES+) 403.29
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7]([C:9](Cl)(Cl)Cl)=[N:8][C:4]=2[CH:3]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C1C[O:24]CC1>>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7]([C:9]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:24])=[N:8][C:4]=2[CH:3]=1
Reactant: Clc1ccc2[nH]c(C(Cl)(Cl)Cl)nc2c1
Reactant: C1CCOC1
Reactant: C1CNCCN1
Product: O=C(c1nc2cc(Cl)ccc2[nH]1)N1CCNCC1
Yield: 10 %

Procedure:
The reaction was carried out as described in General Procedure 2 with commercially available 5-chloro-2-trichloromethyl-1H-benzoimidazole (100 mg, 0.37 mmol) and piperazine (64 mg, 0.75 mmol) in THF (3 mL). Purification afforded 10 mg (10%) of the title compound. MS (ESI): mass calculated for C12H13ClN4O, 264.08; m/z found, 265.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 13.29 (s, 1H), 7.67 (br s, 2H), 7.33 (d, J=8.6 Hz, 2H), 4.50-4.47 (m, 2H), 3.71 (t, J=4.6 Hz, 2H), 2.41-2.39 (m, 4H), 2.22 (s, 3H).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(Cl)(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>O>[N:17]1[CH:16]=[CH:15][C:14]([C:13]2[O:20][C:2]3[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=3[N:12]=2)=[CH:19][CH:18]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1O)c1ccncc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: FC(F)(F)c1ccc2nc(-c3ccncc3)oc2c1
Temperature: 25 °C
Yield: 33.4 %

Procedure:
A mixture of 0.8 g of N-(2-hydroxy-4-trifluoromethylphenyl)isonicotinamide, 15 ml of carbon tetrachloride, 2.23 g of triphenylphosphine and 0.86 g of triethylamine was heated to reflux for five hours. The mixture was cooled to room temperature. Then, water was poured into the mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 2-(pyridin-4-yl)-6-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 15”).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:13])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:13])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc(O)c(C)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)c(C)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 3, 5-dihydroxy-4-methylbenzoate (3.5 g, 19.22 mmol, 1.0 eq) was dissolved in 300 ml of DMF. To this solution potassium carbonate (2.52 g, 18.26 mmol, 0.95 eq) was added. To this stirred suspension, benzyl bromide (3.12 g, 18.26 mmol, 0.95 eq) (diluted with 50 ml of DMF) was added dropwise over a period of 3 h. The solution was stirred overnight at ambient temperature. Then DMF was evaporated under reduced pressure. The residue was washed with water and the product was extracted thrice with DCM. The combined DCM layers was dried over sodium sulphate and evaporated under vacuum. The required product was purified by silica gel (240-400) column chromatography using 10% ethyl acetate/hexane as the eluent. Yield: 1.6 g (30%). 1H NMR (400 MHz, DMSO-d6): δ 2.07 (s, 3H), 3.81 (s, 3H), 5.14 (s, 2H), 7.08 (s, 1H), 7.14 (s, 1H), 7.33-7.35 (d, 1H, J=7.04 Hz), 7.39-7.42 (t, 2 H, J=7.40 Hz), 7.46-7.48 (d, 2H, J=7.48 Hz), 9.78 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:17]([Br:18])=[CH:16][C:5]2[C:6]([C:12]([NH:14][CH3:15])=[O:13])=[C:7]([CH:9]3[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl.N1C=CC=CC=1.O>[Br:18][C:17]1[C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:3][C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[C:6]([C:12]([NH:14][CH3:15])=[O:13])[C:5]=2[CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)c1c(C2CC2)oc2cc(N)c(Br)cc12
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CNC(=O)c1c(C2CC2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a degassed solution of 6-amino-5-bromo-2-cyclopropyl-N-methylbenzofuran-3-carboxamide (4.0 g, 13 mmol) in DCM/Pyridine (80 mL/10 mL) was added MsCl (4.5 g, 39 mmol) under N2 at 0° C. over a period of 30 min. The reaction mixture was stirred at 25° C. for 8 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine and dried over Na2SO4. After concentration, the residue was purified by column chromatography (PE) to give crude product of 5-bromo-2-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (4.5 g, yield: 90%). 1H-NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.71 (s, 1H), 6.79 (s, 1H), 5.93 (s, 1H), 3.06 (d, J=4.8 Hz, 3H), 2.96 (s, 3H), 2.59˜2.61 (m, 1H), 1.13˜1.14 (m, 2H), 1.16˜1.20 (m, 2H). MS (M+H)+: 387/389.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[C:19]3[CH2:18][O:17][CH2:16][C:15]=3[CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.O.NN>C(O)C.[Pd]>[CH2:16]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([O:10][C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[C:19]=2[CH2:18][O:17]1
Reactant: O=[N+]([O-])c1ccc(Oc2cccc3c2COC3)cc1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2cccc3c2COC3)cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
A solution of 4-[(4-nitrophenyl)oxy]-1,3-dihydro-2-benzofuran (Intermediate 4, 208 mg), hydrazine hydrate (0.051 ml, 1.618 mmol) and Pd/C (172 mg, 0.162 mmol) in ethanol (6 ml) was stirred under argon at 90° C. After 1.5 hour the mixture was cooled to room temperature and then filtered over celite. The celite was washed with methanol. The organic phase was concentrated to afford title compound (136 mg).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)=[C:6]([O:30][CH3:31])[CH:5]=1)=[S:3].Cl[CH2:33][C:34](N(C)C)=[O:35].[CH3:39][CH:40](O)[CH3:41]>>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C@H:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]3[CH:28]=[CH:29][C:4]([C:2]4[S:3][CH:33]=[C:34]([O:35][CH:40]([CH3:41])[CH3:39])[N:1]=4)=[CH:5][C:6]=3[O:30][CH3:31])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)[CH3:27]
Reactant: CC(C)O
Reactant: CN(C)C(=O)CCl
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C(N)=S)cc3OC)ccc21
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc(OC(C)C)cs4)cc3OC)ccc21
Temperature: 25 °C
Yield: 49 %

Procedure:
A solution of ethyl ((1S)-5-{3-[4-(aminocarbonothioyl)-2-methoxyphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (500 mg, 1.1 mmol) (Example 146) and 2-chloro-N,N-dimethylacetamide (800 mg, 6.6 mmol) in i-PrOH (anhydrous, 15 mL) was stirred at 70° C. for 8 h. The reaction was cooled to rt, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc:hexane (v/v)=1:2) gave 292 mg (49%) of the title compound as a yellow oil. LC-MS: RT=4.27 min; (M+H)+:526.1.