Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1.C(N(CC)CC)C>CCCCO>[Br:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CC(C)CC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CC(C)CC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Yield: 39.2 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylbutanamide (177 mg, 0.563 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (339 mg, 1.69 mmol), and triethylamine (157 μL, 1.13 mmol) in n-BuOH (5 mL) was processed as in Example 56, Step B, and the crude was purified by C-18 reverse phase chromatography (Biotage 25M+) on Biotage SP4 unit eluting with a gradient of 15-85% CH3CN/water (25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(3-methylbutanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (109 mg, 39% yield) as a solid. LCMS (APCI+) m/z 494, 496 (M+H)+, Retention time=3.92 minutes (Method 2).
Reaction SMILES: N1(C(N)=O)CC[O:4]CC1.[Cl:10][C:11]1[C:12]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:13][C:14]([O:21][CH3:22])=[C:15]([CH2:17][C:18]([OH:20])=S)[CH:16]=1>C(O)(=O)C.Cl.O>[Cl:10][C:11]1[C:12]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:13][C:14]([O:21][CH3:22])=[C:15]([CH2:17][C:18]([OH:4])=[O:20])[CH:16]=1
Reactant: COc1cc(N2CCCCC2)c(Cl)cc1CC(O)=S
Reactant: NC(=O)N1CCOCC1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(N2CCCCC2)c(Cl)cc1CC(=O)O

Procedure:
A solution of 11.07 g (30 mmoles) of 5-chloro-2-methoxy-4-(piperidin-1-yl)-phenylthioacetic acid morpholinamide in 120 ml of glacial acetic acid and 30 ml of concentrated hydrochloric acid is boiled under reflux for 22 hours. The reaction mixture is cooled, diluted with water and extracted with methylene chloride. The combined methylene chloride phases are washed with water, dried over sodium sulphate and concentrated by evaporation in a high vacuum rotary evaporator. Chromatography over silica gel with chloroform/methanol (19:1) yields 5-chloro-2-methoxy-4-(piperidin-1-yl)-phenylacetic acid which, after recrystallisation with methylene chloride/hexane, melts at 120°-122°.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]1[CH:18]([C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:17][CH2:16][CH2:15][CH:14]1[C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=1.[Li+].[BH4-]>C1COCC1.CO.[OH-].[Na+]>[CH3:25][C:24]1[C:19]([CH:18]2[CH2:17][CH2:16][CH2:15][CH:14]([C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=3)[N:13]2[CH2:12][C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[CH2:3][OH:2])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1cc(C#N)ccc1CN1C(c2ncccc2C)CCCC1c1ncccc1C
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccc(C#N)cc1CO
Temperature: 25 °C
Yield: 85.9 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.260 g, 0.98 mmol), 2-bromomethyl-5-cyano-benzoic acid methyl ester (0.360 g, 1.42 mmol), KI (37 mg, 0.22 mmol), and DIPEA (0.35 mL, 2.01 mmol) in DMF (5 mL) was heated at 60° C. for 17 hours. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) provided 415 mg (96%) of 5-cyano-2-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester as a tan solid. To a cold (0° C.) solution of 5-Cyano-2-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester (0.409 g, 0.937 mmol) in THF (4.5 mL) and MeOH (9 mL) was added LiBH4 (229 mg, 10.52 mmol) and the mixture was allowed to warm to room temperature overnight. The mixture was diluted with 1.0 N NaOH (10 mL) and extracted with CH2Cl2 (5×25 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.332 g (87%) of COMPOUND 56 as a white foam. 1H NMR (CDCl3) δ 1.61-1.77 (m, 3H), 2.05-2.14 (m, 1H), 2.30-2.44 (m, 2H), 2.51 (s, 6H), 3.71 (s, 2H), 4.11 (d, 2H, J=10.8 Hz), 4.46 (s, 2H), 4.94 (br s, 1H), 6.87-6.96 (m, 4H), 7.22-7.27 (m, 3H), 8.21 (d, 2H, J=4.2 Hz). 13C NMR (CDCl3) δ 19.35, 25.70, 28.19, 51.31, 62.24, 67.36, 109.58, 119.48, 122.56, 129.25, 130.02, 132.00, 132.24, 138.53, 139.79, 145.29, 146.76, 159.25; ES-MS m/z 413 (M+H). Anal. Calcd. For C26H28N4O.1.0H2O2: C, 72.53; H, 7.02; N, 13.01. Found: C, 72.46; H, 6.73; N, 12.91.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([NH2:17])=[CH:12][N:11]=1>CO>[Cl:9][C:10]1[N:11]=[CH:12][C:13]2[N:17]=[C:7]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])[S:8][C:14]=2[N:15]=1
Reactant: CCOC(=O)N=C=S
Reactant: Nc1cnc(Cl)nc1Cl
Solvent: CO
Product: CCOC(=O)Nc1nc2cnc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.3 %

Procedure:
Ethoxycarbonyl isothiocyanate (4.32 mL, 36.6 mmol) and 2,4-dichloro-pyrimidin-5-ylamine (3.00 g, 18.29 mmol) were mixed neat and sonicated for 5 minutes to help dissolve. The mixture was stirred at ambient temperature for 10 minutes, at which time the entire mixture had solidified. Methanol (100 mL) was added and the mixture was refluxed for 30 minutes, cooled to ambient temperature and the solids were collected by filtration to afford ethyl 5-chlorothiazolo[5,4-d]pyrimidin-2-ylcarbamate (3.8 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.64 (s, 1H) 9.05 (s, 1H) 4.31 (q, J=7.19 Hz, 2H) 1.32 (t, J=7.15 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CCOCC>[Br:13][CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(C)cccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1c(C)cccc1CBr
Reaction time: 0.33 h

Procedure:
To a solution of methyl 2,6-dimethyl-benzoate (22.0 g, 134 mmol, example 1) in CCl4 (250 mL) is added N-bromo-succinimide (19 g, 107 mmol) followed by benzoyl peroxide (1.0 g, 4.0 p mmol). The resulting solution is warmed to reflux and stirred at this temperature for 20 min. The reaction mixture is then allowed to cool before being diluted with ether (200 mL), filtered and concentrated. The residue is purified by flash chromatography (silica, 4% acetone in hexanes) to give the title compound. This product (approx. 85% purity, remainder is methyl 2,6dimethyl benzoate) is used without further purification. MS (EI) 242, 244 (M+, Br pattern).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]#[N:18])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([S:12]([C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[C:17]#[N:18])(=[O:14])=[O:13])[CH:6]=[CH:5]3)=[CH:26][CH:25]=1
Reactant: N#Cc1ccccc1S(=O)(=O)c1ccc2cc(Br)ccc2c1
Reactant: OB(O)c1ccc(F)cc1
Product: N#Cc1ccccc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1

Procedure:
Prepared from 2-[(6-bromo-2-naphthyl)sulfonyl]benzonitrile (Step 3) and 4-fluorobenzeneboronic acid according to the method of Example 2 Step 1. 1H NMR (500 MHz, CDCl3) δ 8.80 (1H, s), 8.42 (1H, d, J=7.9 Hz), 8.11 (1H, d, J=8.6 Hz), 8.00 (2H, t, J=9.0 Hz), 7.93 (1H, dd, J=1.7, 8.7 Hz), 7.85-7.79 (3H, m), 7.70-7.64 (3H, m), 7.19 (2H, t, J=8.6 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[C:5]=1[N+:20]([O-])=O)([O-])=O.[OH-].[Na+].[H][H]>[C].[Pd]>[NH2:1][C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[C:5]=1[NH2:20]
Reactant: O=C1c2ccccc2C(=O)c2c1ccc([N+](=O)[O-])c2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc2c(c1N)C(=O)c1ccccc1C2=O
Reaction time: 5 h
Yield: 98 %

Procedure:
A 500 ml. electromagnetically stirred glass reactor was charged with 5.0 g (0.0167 mole) of dinitroanthraquinone (a mixture of 1,5-isomer and 1,8-isomer), 100 g (0.1 mole) of a 4% aqueous solution of sodium hydroxide and 0.25 g of 5% palladium-carbon. The inside of the reactor was purged with hydrogen, and the dinitroanthraquinone was hydrogenated at 30° C. with stirring. In 5 hours, 0.1169 mole of hydrogen was absorbed, the reaction was stopped. The reaction mixture was filtered in an atmosphere of nitrogen to separate the catalyst. Then, the filtrate was oxidized with air with stirring at 20° to 30° C. for 2 hours. The resulting crystals were filtered and dried to afford 3.9 g of diaminoanthraquinone (a mixture of 1,5-isomer and 1,8-isomer) in a yield of 97.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:18][C:20](=[O:21])[O:22][CH2:23][CH3:24])[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1cc(Cl)c(Oc2cc(Cl)cc(Cl)c2)c(Cl)c1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cc(Cl)c(Oc2cc(Cl)cc(Cl)c2)c(Cl)c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
3,5-Dichloro-4-(3,5-dichlorophenoxy)benzenamine (0.1 mole) and pyridine (50 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer and are cooled to about 5° C. Ethyl chloroformate (0.125 mole) is added, with stirring, at about 5° C. Stirring is continued for a period of about 30 minutes at about 5° C., then for an additional 16 hours at room temperature. The mixture is then washed with 2 portions of water (50 ml), dried and the solventis then removed to yield the desired product ethyl [3,5-dichloro-4-(3,5-dichlorophenoxy)phenyl]carbamate.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[OH:40].C(OC([N:48]1[CH2:53][CH2:52][CH:51](O)[CH2:50][CH2:49]1)=O)(C)(C)C.Cl>C1COCC1>[Cl:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[O:40][CH:51]1[CH2:52][CH2:53][NH:48][CH2:49][CH2:50]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc(F)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(OC2CCNCC2)c(Cl)c1
Reaction time: 16 h
Yield: 85.9 %

Procedure:
DEAD (0.90 ml) was added to a solution of triphenylphosphine (1.44 g), 2-chloro-4-fluorophenol (0.806 g) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.0 g) in THF at RT. The reaction was stirred for 16 hrs, HCl (2 ml, 4M in dioxan) added and the mixture stirred at RT for 16 hrs. The mixture was then evaporated to dryness, triethylamine (5 ml) added, re-evaporated, dissolved in methanol (10 ml) and placed on to a SCX cartridge (Varian, 10 g), eluted first with methanol then with 10% NH3 in methanol. The basic fractions were combined and evaporated to give the sub-title compound as an oil (0.98 g)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1.C([N-]C(C)C)(C)C.[Li+].[O:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:30]3([OH:33])[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)[N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1ncn2C
Reactant: O=C1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1(O)CCOCC1)n2C
Temperature: -78 °C
Yield: 80.9 %

Procedure:
To (S)-4-(2-chloro-9-methyl-9H-purin-6-yl)-3-methylmorpholine (100.0 mg, 0.374 mmol) in anhydrous THF (4.0 mL) at −78° C. under N2 was added freshly prepared lithium diisopropylamide in THF (2.0 eq.), and the reaction mixture was stirred at −78° C. After stirring for 2 h tetrahydro-4H-pyran-4-one (68.6 μL, 0.75 mmol, 2.0 eq.) was added. The reaction was then stirred at RT for 16 h and quenched with saturated aqueous sodium ammonium chloride solution. Volatile solvent was evaporated in vacuo, and the crude was diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and brine, then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 5 to 100% ethyl acetate in hexane). Crystallization from ether-hexane afforded the product (b-1) as a solid (111.3 mg, 81.0%). 1H NMR (CDCl3, 400 MHz). δ ppm 5.3 (broad s, 1H), 4.98 (broad s, 1H), 4.00 (dd, J=3.4 Hz, 1H), 3.97 to 3.79 (m, 7H), 3.79 to 3.71 (m, 2H), 3.60 (td, J=11.6, 2.7 Hz, 1H), 3.45 (broad s, 1H), 2.39 (m, 2H), 1.86 (d, J=13.2 Hz, 2H), 1.38 (d, J=6.8 Hz, 3H); LC-MS m/z (method A)=368/370 [M+H]+, RT=1.93 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:39]3[S:40][CH:41]=[C:42]([CH2:44][CH2:45][CH2:46][O:47][Si](C(C)(C)C)(C)C)[N:43]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:37][CH2:36]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:39]3[S:40][CH:41]=[C:42]([CH2:44][CH2:45][CH2:46][OH:47])[N:43]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:36][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3nc(CCCO[Si](C)(C)C(C)(C)C)cs3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2CC(c3nc(CCCO)cs3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C
Yield: 96.1 %

Procedure:
A sol. of compound E3 (1.23 g, 1.50 mmol) and TBAF (1.0 M in THF, 1.88 mL, 1.88 mmol) in THF (20 mL) was stirred at 0° C. for 3.5 h. The mixture was diluted with EtOAc and was then washed with brine (4×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:4→1:2→1.1→EtOAc) yielded the title compound (1.02 g, 96%). LC-MS: tR=1.11 min, ES+: 707.33.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](=O)(O)[O-].[Na+].IC>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C([O-])O
Reactant: Cc1c(Br)cccc1C(=O)O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Br)c1C
Temperature: 60 °C
Yield: 103.3 %

Procedure:
A mixture of 3-bromo-2-methylbenzoic acid (16 g, 74.4 mmol), sodium bicarbonate (12.5 g, 148.8 mmol) and iodomethane (21.2 g, 148.8 mmol) in DMF (160 mL) was heated at 60° C. for 2 hours. The mixture was cooled to room temperature and poured into ice water (400 mL). The mixture was extracted with ethyl acetate (4×100 mL). The EtOAc solution was washed with water (3×100 mL), brine (100 mL) and dried (MgSO4). Solvent was removed to give methyl 3-bromo-2-methylbenzoate (17.6 g, 100%) as an oil: 1H NMR (CDCl3) δ 7.70 (t, J=7.6 Hz, 2H), 7.08 (t, J=7.9 Hz, 1H), 3.90 (s, 3H), 2.67 (s, 3H).
Reaction SMILES: C(OC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].Cl.C([O-])(=O)C.[K+].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([S:25][CH:26]([CH3:30])[CH2:27][CH:28]=[O:29])[CH:22]=[CH:23][CH:24]=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:29][CH:28]([CH2:27][CH:26]([S:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=1)[CH3:30])[CH2:2][C:3](=[O:4])[CH3:5]
Reactant: COC(=O)CC(C)=O
Reactant: COc1cccc(SC(C)CC=O)c1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(SC(C)CC(O)CC(C)=O)c1
Reaction time: 3 h
Yield: 89.6 %

Procedure:
9.86 Grams of methyl acetoacetate were dissolved in 15 ml of water, and 12.67 g of a 30% aqueous sodium hydroxide solution was added thereto by drops while cooling the mixture to 25° C. or less. After having been stirred at 30°-35° C. for 3 hours, the mixture was adjusted to pH 7.0 with a concentrated aqueous hydrochloric acid solution. Thereafter, 0.74 g of potassium acetate and 2.42 g of tetrabutylammonium bromide were added thereto, and then an additional concentrated aqueous hydrochloric acid was added thereto so that the mixture had a pH of 6.9. Further, 28.00 g of a toluene solution containing 38.0% of 3-(3-methoxyphenylthio)butanal were added thereto and the resulting mixture was stirred at 45°-50° C. for 9 hours. The organic layer separated from the mixture was washed with a 5% aqueous acetic acid solution and then with a saturated aqueous sodium chloride solution. Then it was dried over anhydrous magnesium sulfate. Removing the solvent from the layer under reduced pressure gave 13.39 g of crude 4-hydroxy-6-(3-methoxyphenylthio)-2-heptanone (purity 90.9%, yield: 89.6%). A purified product was obtained by column chromatography. The purified product had an nD21 of 1.5530.
Reaction SMILES: C(O[C@H]1C2C(=CC(OCCC)=CC=2)[C@@H](N)C1)C=C.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[F:33][C:34]([F:50])([F:49])[C:35]([NH:37][CH:38]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([CH3:47])[CH:45]=2)[C:40](=[O:48])[CH2:39]1)=[O:36].CC[C@@H]1C(=O)OC[C@@H]1CC1N(C)C=NC=1.Cl>C1COCC1>[F:33][C:34]([F:49])([F:50])[C:35]([NH:37][CH:38]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([CH3:47])[CH:45]=2)[CH:40]([OH:48])[CH2:39]1)=[O:36]
Reactant: Cc1ccc2c(c1)C(NC(=O)C(F)(F)F)CC2=O
Agent: C=CCO[C@@H]1C[C@H](N)c2cc(OCCC)ccc21
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: CC[C@@H]1C(=O)OC[C@@H]1Cc1cncn1C
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C(NC(=O)C(F)(F)F)CC2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Step BJ (1): L-Selectride (1 M/THF, 18.5 mL, 18.5 mmol) was added dropwise (over 30 min) to a solution of 2,2,2-trifluoro-N-(6-methyl-3-oxo-2,3-dihydro-1H-inden-1-yl)acetamide [Quermonne, M. A.; Dallemagne, P.; Louchahi-Raoul, J.; Pilo, J. C.; Rault, S.; Robba, M. Eur. J. Med. Chem. 1992, 27, 961-965] (3.97 g, 15.4 mmol) in THF (80 mL) at −78° C. After 2 hr at −78° C., the reaction mixture was quenched with saturated aqueous NH4Cl solution (2 mL) and allowed to warm to rt. The crude mixture was concentrated in vacuo. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3 solution followed by brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford 3.4 g (85% yield) of racemic 2,2,2-trifluoro-N-(3-hydroxy-6-methyl-2,3-dihydro-1H-inden-1-yl)acetamide. LC-MS (M+H)+=260.091H NMR (500 MHz, CDCl3) δ 9.16-9.12 (t, 1H) 7.31-7.29 (m, 1H) 7.02 (m, 1H) 6.94 (s, 1H) 4.98 (t, 1H) 4.10 (bs, 2H) 2.38-2.28 (m, 4H) 2.07-2.01 (m, 1H).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][C:7]1([CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][O:8]1.[Cl:19][C:20]1[NH:21][CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[N:24]=1>C(O)C>[Cl:19][C:20]1[N:21]([CH2:9][C:7]([OH:8])([CH3:6])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[N:24]=1
Reactant: CC(C)(C)OC(=O)CCC1(C)CO1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)(CCC(=O)OC(C)(C)C)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 78.4 %

Procedure:
Sodium acetate (0.59 g, 7.18 mmol) was added to a suspension of tert-butyl 3-(2-methyloxiran-2-yl)propionate (1.00 g, 5.39 mmol) and 2-chloro-4-nitro-1H-imidazole (0.53 g, 3.59 mmol) in ethanol (5 ml) followed by stirring under reflux for 6 hours. Insoluble matters were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford tert-butyl 5-(2-chloro-4-nitroimidazol-1-yl)-4-hydroxy-4-methylpentanoate (0.94 g, yield 78%) as a light yellow oil.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH3:20])[C:10]2[C:14]3[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:21][N:22]=[C:23]=[O:24].CO.C(Cl)Cl>CCOC(C)=O.[Cu]Cl>[CH3:21][NH:22][C:23](=[O:24])[O:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([N:9]([CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH3:20])=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: CN(CCN1CCOCC1)c1noc2cc(O)ccc12
Reactant: CN=C=O
Agent: Cl[Cu]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)Oc1ccc2c(N(C)CCN3CCOCC3)noc2c1
Yield: 49.8 %

Procedure:
To a stirred solution of 3-[[2-(4-morpholinyl)ethyl]methylamino]-1,2-benzisoxazol-6-ol (2 g) and copper(I)chloride (0.3 g) in EtOAc (60 ml) was added methyl isocyanate (0.5 g). After 3.5 hours thin layer chromatography (TLC) (silica gel, 10% MeOH/DCM) showed no starting material. The reaction was filtered through neutral alumina eluting with EtOAc (2 l) and the filtrate was concentrated in vacuo to yield 1.2 g of the product, m.p. 94°-95° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:36]([O:38][C:39]1[CH:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([CH:51]([CH3:53])[CH3:52])[CH2:47][CH2:46]2)[CH:42]=[CH:41][C:40]=1[NH2:54])[CH3:37].Cl.O1CCOCC1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:54][C:40]3[CH:41]=[CH:42][C:43]([N:45]4[CH2:50][CH2:49][N:48]([CH:51]([CH3:52])[CH3:53])[CH2:47][CH2:46]4)=[CH:44][C:39]=3[O:38][CH2:36][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: CCOc1cc(N2CCN(C(C)C)CC2)ccc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 175 °C
Yield: 60 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.20 mmol) and {2-(ethyloxy)-4-[4-(1-methylethyl)-1-piperazinyl]phenyl}amine (Example 171, step B) (54 mg, 0.20 mmol) in 2,2,2-trifluoroethanol (1.0 mL) was added 4 M HCl in dioxane (102 μL, 0.41 mmol). The mixture was stirred and heated on a Biotage microwave at 175° C. for 30 min, then cooled to rt. The mixture was neutralized with 0.5M sodium methoxide in MeOH. The mixture was concentrated under vacuum and the residue purified by silica gel chromatography to give a yellow oil. The oil was dissolved in minimal DCM, then hexane was added until a precipitate was formed. The slurry was cooled at −10° C. for 30 min, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (86 mg, 0.12 mmol, 60%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.79 (s, 1H), 9.33 (br s, 1H), 8.37 (s, 1H), 8.23 (d, 1H, J=5.32 Hz), 8.11 (d, 1H, J=2.02 Hz), 7.77 (dd, 1H, J=2.02 and 8.61 Hz), 7.70 (d, 1H, J=8.98 Hz), 7.35-7.47 (m, 3H), 7.28 (d, 1H, J=8.61 Hz), 7.19 (t, 2H, J=8.06 Hz), 6.93 (t, 1H, J=6.96 Hz), 6.66 (d, 1H, J=2.20 Hz), 6.55 (d, 1H, J=5.13 Hz), 6.47 (dd, 1H, J=2.38 and 8.80 Hz), 4.06 (q, 2H, J=6.96 Hz), 3.99 (s, 3H), 3.08-3.16 (m, 4H), 2.55-2.75 (m, 5H), 1.24 (t, 3H, J=6.96 Hz), 1.02 (d, 6H, J=6.42 Hz). MS (ESI): 719 [M+H]+.