Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:14][C:15]([N:17]1[C@@H:30]([C:31]#[C:32]/[CH:33]=[CH:34]\[C:35]#[CH:36])[C@:29]23[O:37][C@:24]2([C@@H:25]([OH:43])[C:26]([O:41][CH3:42])([O:39][CH3:40])[CH2:27][C@@H:28]3[CH3:38])[C:23]2[CH:22]=[C:21]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH:20]=[CH:19][C:18]1=2)=[O:16])[CH:12]=[CH2:13].C(N(CC)CC)C.P([O-])([O-])([O-])=O>ClCCl>[CH2:11]([O:14][C:15]([N:17]1[C@@H:30]([C:31]#[C:32]/[CH:33]=[CH:34]\[C:35]#[CH:36])[C@:29]23[O:37][C@:24]2([C:25](=[O:43])[C:26]([O:39][CH3:40])([O:41][CH3:42])[CH2:27][C@@H:28]3[CH3:38])[C:23]2[CH:22]=[C:21]([O:44][Si:45]([C:48]([CH3:49])([CH3:51])[CH3:50])([CH3:46])[CH3:47])[CH:20]=[CH:19][C:18]1=2)=[O:16])[CH:12]=[CH2:13]
Reactant: C#C/C=C\C#C[C@@H]1N(C(=O)OCC=C)c2ccc(O[Si](C)(C)C(C)(C)C)cc2[C@@]23O[C@@]12[C@@H](C)CC(OC)(OC)[C@@H]3O
Agent: O=C(Cl)C(=O)Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: C#C/C=C\C#C[C@@H]1N(C(=O)OCC=C)c2ccc(O[Si](C)(C)C(C)(C)C)cc2[C@@]23O[C@@]12[C@@H](C)CC(OC)(OC)C3=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
Dimethyl sulfoxide (4.22 mL, 59.5 mmol, 15.0 equiv) was added to a solution of oxalyl chloride (3.46 mL, 39.7 mmol, 10.0 equiv) in dichloromethane (75 mL) at -78° C. After stirring at -78° C. for 20 min, a solution of allyl(6S,6aS,7S,10R,10aS)-2-(tert-butyldimethylsiloxy)-6-[(Z)-3-hexene-1,5-diynyl]-7,8,9,10-tetrahydro-10-hydroxy-9,9-dimethoxy-7-methyl-6a,10a-epoxyphenanthridine-5(6H)-carboxylate (23, 2.30 g, 3.97 mmol, 1 equiv) in dichloromethane (75 mL) was added over 10 min via cannula to the cold reaction solution. The reaction mixture was warmed to -40° C. and was held at that temperature for 10 h. The reaction mixture was then cooled to -78° C., triethylamine (16.6 mL, 119 mmol, 30.0 equiv) was added, and the resulting solution was stirred in an ice bath for 30 min. The product solution was poured into aqueous phosphate buffer solution (pH 7, 0.05M in sodium hydrogen phosphate and 0.05M in potassium dihydrogen phosphate, 150 mL). The aqueous layer was separated and extracted further with dichloromethane (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated. The residue was purified by flash column chromatography (2% ethyl acetate-dichloromethane initially, grading to 5% ethyl acetate-dichloromethane) to afford allyl(6S,6aS,7S,10aR)-2-(tert-butyldimethylsiloxy)-6-[(Z)-3-hexene-1,5-diynyl]-7,8,9,10-tetrahydro-9,9-dimethoxy-7-methyl-10-oxo-6a,10a-epoxyphenanthridine-5(6H)-carboxylate (24) as a light brown foam (2.10 g, 92%). ##STR35##
Reaction SMILES: [N:1]1([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:16]1[C:25]2[C:20](=[C:21]([CH:26]([CH3:30])[C:27](O)=[O:28])[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[N:1]1([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][NH:13][C:27](=[O:28])[CH:26]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:20]=3[CH:19]=[CH:18][N:17]=[CH:16]4)[CH3:30])=[CH:14][CH:15]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCc1ccc(N2CCCCCC2)cc1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(N2CCCCCC2)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-(1-azepanyl)benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 388 (M+H)+; MS (ESI−) m/z 366 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.53 (m, 7H), 1.72 (m, 4H), 3.85 (s, 2H), 4.03 (q, J 7.1, 1H), 6.76 (m, 3H), 7.26 (m, 2H), 7.58 (m, 1H), 1H), 8.10 (m, 2H), 8.72 (t, J 5.8, 1H), 9.91 (s, 1H); Anal. Calcd for C25H29N3O+2.15 HCl+2 H2O: C, 59.82; H, 7.06. Found: C, 59.59; H, 728.
Reaction SMILES: [CH2:1]([N:7]1[CH:12]=[C:11](I)[C:10]([CH3:14])=[C:9]([N+:15]([O-:17])=[O:16])[C:8]1=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:19]([O-:22])(=[O:21])C.[K+].[CH3:24]S(C)=O>CO.C(OCC)(=O)C.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]>[CH2:1]([N:7]1[CH:12]=[C:11]([C:19]([O:22][CH3:24])=[O:21])[C:10]([CH3:14])=[C:9]([N+:15]([O-:17])=[O:16])[C:8]1=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)[O-]
Reactant: CCCCCCn1cc(I)c(C)c([N+](=O)[O-])c1=O
Reactant: CS(C)=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCn1cc(C(=O)OC)c(C)c([N+](=O)[O-])c1=O
Temperature: 60 °C
Yield: 75 %

Procedure:
A mixture of 1-hexyl-5-iodo-4-methyl-3-nitro-2-pyridone (0.500 g, 1.37 mmol), tris(dibenzylideneacetone)dipalladium (0.003 g), diphenylphosphinoferrocence (0.154 g) and potassium acetate (0.565 g) in DMSO (10 mL) and methanol (10 mL) was stirred and heated at 60° C. under an atmosphere of carbon monoxide for 4 hours. The mixture was diluted with ethyl acetate, washed with aqueous sodium bicarbonate, dried (MgSO4), filtered, and evaporated. Chromatography of the residue over silica gel (30% ethyl acetate/petroleum ether) gave 1-hexyl-4-methyl-3-nitro-5-methoxycarbonyl-2-pyridone (0.305 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>COCCOC.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:15])[CH:9]([CH2:24][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1cccc(Cl)n1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.9 %

Procedure:
To a solution of ethyl 3-(6-chloro-2-pyridyl)-3-oxopropionate (7.6 g, 33.4 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60% in oil, 1.34 g, 33.4 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hrs. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (7.98 g, 33.4 mmol) in 1,2-dimethoxyethane (50 ml), and the mixture was stirred overnight at room temperature. The reaction solution was poured into water (200 ml), saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene) to give ethyl 3-(6-chloro-2-pyridyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (13.0 g, 100%) as a colorless oil.
Reaction SMILES: [Al](Br)(Br)Br.[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[C:10]([N+:22]([O-:24])=[O:23])[CH:9]=1)(=[O:7])[CH3:6].CCCCCC.C(OCC)(=O)C>C1C=CC=CC=1>[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[C:10]([N+:22]([O-:24])=[O:23])[CH:9]=1)(=[O:7])[CH3:6]
Reactant: COc1ccc(-c2ccc(C(C)=O)cc2[N+](=O)[O-])cc1
Agent: Br[Al](Br)Br
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CC(=O)c1ccc(-c2ccc(O)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of AlBr3 (12.6 g, 47.4 mmole) in benzene (45 mL) is added dropwise under nitrogen a solution of the methylether (5 g, 18.45 mmole) of Step A in benzene (12 mL) over 30 minutes. The resulting solution is stirred at room temperature for 3.5 hours. (TLC, 8:2 hexane-ethyl acetate). The mixture is cooled in an ice bath and the complex is decomposed by the dropwise addition of 6N-HC1 (ca. 37 mL). The organic layer is separated and the aqueous phase is reextracted with ether (3x). The combined extracts are concentrated to a small volume and extracted again with 2.5N-NaOH (2×50 mL +1×10 mL). The basic extracts are cooled and acidified with concentrated HCl (to pH 2). The solid is collected and dried (4.27 g, 90% ). It is used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:4]([NH:6][NH:7][C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([I:15])[CH:10]=2)=O)[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>C(#N)C>[CH:1]1([C:4]2[O:16][C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([I:15])[CH:10]=3)=[N:7][N:6]=2)[CH2:2][CH2:3]1
Reactant: O=C(NNC(=O)C1CC1)c1cccc(I)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: Ic1cccc(-c2nnc(C3CC3)o2)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 98.7 %

Procedure:
N′-Cyclopropanecarbonyl-3-iodobenzoic hydrazide (535 mg, 1.62 mmol) obtained in Step 1 was suspended in acetonitrile (20 mL), and the mixture was stirred at 60° C. for 6 hours after adding triphenylphosphine (850 mg, 3.24 mmol), carbon tetrachloride (0.63 mL, 6.48 mmol), and triethylamine (0.45 mL, 3.24 mmol). The residue obtained upon concentration under reduced pressure was then purified by silica gel column chromatography to give 2-cyclopropyl-5-(3-iodophenyl)-1,3,4-oxadiazole (499 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH2:9][C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Cl)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=O)CC(=O)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To an ice-cold solution of 1-(3-chlorophenyl)ethanone (16.79 mL, 129 mmol) and diethyl oxalate (18.05 mL, 136 mmol) in DMF (78.0 mL) was added, portionwise over 30 min., NaH (6.09 g, 155 mmol, 60% dispersion in mineral oil) and the resultant mixture was stirred at that temperature for 20 min. and then at room temperature for 16 h. The reaction mixture was diluted with water and acidified to pH=4-5 with 1N aq. HCl. The mixture was further diluted with copious amounts of water. The aq. layer was extracted with EtOAc (4×100 mL) and the combined organic layer was washed with water, brine, dried over anhydrous MgSO4, filtered and the filtrate was concentrated under reduced pressure to provide a crude residue. It was purified by silica gel chromatography (220 g REDISEP® column, eluting with a 0 to 15% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate A1C (27.1 g, 84%) as a solid. MS(ES): m/z=277.10 [M+Na]+; 1H NMR (400 MHz, chloroform-d) δ ppm 7.99 (t, J=1.8 Hz, 1H), 7.95-7.86 (m, 1H), 7.60 (ddd, J=8.0, 2.1, 1.0 Hz, 1H), 7.48 (t, J=7.9 Hz, 1H), 7.06 (s, 1H), 4.43 (q, J=7.3 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([C:4]1[S:5][C:6]([NH2:9])=[CH:7][N:8]=1)[CH2:2][CH3:3].[CH3:10][C:11]1([CH3:19])[O:18][C:16](=[O:17])[CH2:15][C:13](=[O:14])[O:12]1.[CH2:20](OC(OCC)OCC)C>C(O)C>[CH3:10][C:11]1([CH3:19])[O:18][C:16](=[O:17])[C:15](=[CH:20][NH:9][C:6]2[S:5][C:4]([CH2:1][CH2:2][CH3:3])=[N:8][CH:7]=2)[C:13](=[O:14])[O:12]1
Reactant: CCOC(OCC)OCC
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCc1ncc(N)s1
Solvent: CCO
Product: CCCc1ncc(NC=C2C(=O)OC(C)(C)OC2=O)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
A solution of the product of Example 5D (212.7 mg, 1.496 mmol) in anhydrous ethanol (5 mL) was treated with Meldrum's acid (237 mg, 1.645 mmol) and triethylorthoformate (0.25 mL, 1.496 mmol) at room temperature, and the reaction was heated in a preheated 100° oil bath. After 15 minutes, the reaction was cooled to room temperature and the solvent removed by rotary evaporation under vacuum. Purification by silica gel flash chromatography with a gradient of 10% to 20% ethyl acetate/methylene chloride afforded the title compound as an off-white solid (240 mg, 0.8099 mmol, 54%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][Br:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([P:20]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>C1(C)C=CC=CC=1>[Br-:14].[C:1]([O:5][C:6]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][P+:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9][CH:8]=1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCP(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Solvent: Cc1ccccc1
Product: CCCC[P+](CCCC)(CCCC)Cc1ccc(C(=O)OC(C)(C)C)cc1
Product: [Br-]
Temperature: 60 °C
Reaction time: 1.17 h

Procedure:
To a solution of 4-(bromomethyl)benzoic acid tert-butyl ester (22.1 g) in toluene (440 ml), tri-n-butylphosphine (30.5 ml) was added, and the mixed solution was stirred at 60° C. for 70 min. The reaction solution was removed by evaporation under reduced pressure, and to the resulting crude product, n-hexane was added and stirred. The resulting solid was filtered out to give [4-(tert-butoxycarbonyl)benzyl](tributyl)phosphonium bromide (36.0 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[N:7]=1.C(N(C(C)C)C(C)C)C.Cl.[CH2:24]([O:26][C:27](=[O:30])[CH2:28][NH2:29])[CH3:25].O>CN(C)C=O>[CH2:24]([O:26][C:27](=[O:30])[CH2:28][NH:29][C:11]([C:9]1[N:10]=[C:5]2[N:6]([N:7]=[C:2]([Cl:1])[CH:3]=[CH:4]2)[N:8]=1)=[O:13])[CH3:25]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1nc2ccc(Cl)nn2n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1nc2ccc(Cl)nn2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
2.86 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine-2-carboxylic acid and 2.72 ml of N-ethyldiisopropylamine were suspended in 30 ml of N,N-dimethylformamide; 2.63 g of N,N′-carbonyldiimidazole was added, followed by stirring at room temperature for 1 hour. To the reaction mixture, 2.21 g of glycine ethyl ester hydrochloride was added, followed by stirring at room temperature for 5 hours. Water was added; the crystal precipitated was collected by filtration, washed with water and ether and dried to yield 2.93 g of the title compound.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[N:15]=[C:14]([NH:16][C@:17]([CH3:23])([CH2:21][CH3:22])[C:18](O)=[O:19])[CH:13]=[CH:12][N:11]=2)=[CH:2]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[F:42][C:43]([F:47])([F:46])[CH2:44][NH2:45].C([O-])([O-])=O.[Na+].[Na+]>CC1OCCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[N:15]=[C:14]([NH:16][C@:17]([CH3:23])([CH2:21][CH3:22])[C:18]([NH:45][CH2:44][C:43]([F:47])([F:46])[F:42])=[O:19])[CH:13]=[CH:12][N:11]=2)=[CH:2]1
Reactant: NCC(F)(F)F
Reactant: CC[C@@](C)(Nc1ccnc(-c2c[nH]c3ncccc23)n1)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC1CCCO1
Product: CC[C@@](C)(Nc1ccnc(-c2c[nH]c3ncccc23)n1)C(=O)NCC(F)(F)F
Temperature: 62.5 °C
Reaction time: 0.5 h

Procedure:
To (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoic acid (4a) (limiting reagent) charge 2-methylTHF (7.5 vol), then charge T3P® (2.0 eq, 50% w/w in 2-MeTHF). Heat the mixture to 60-65° C. and maintain this temperature for no less than 3 hrs and the solids are completely dissolved. Cool to 20-25° C. then charge 2,2,2-trifluoroethylamine (2.0 eq). Continue agitation for no less than 6 hrs at 20-25° C. and until HPLC analysis showed <1.0% of (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoic acid (4a). Slowly charge a Na2CO3 solution (15 vol, 1.165M) while maintaining a batch temperature <30° C. Stir the mixture for 30 min then separate the phases. Wash the organic phase with water (4 vol). Emulsions have been observed at this point and can be addressed through addition of NaCl solution. Charge methanol (7 vol) then distill to 4 vol. Repeat 3 times. Prior to crystallization, adjust the total volume to approximately 11 vol. Heat the mixture to 50-55° C. then add water (2.45 vol, final solvent composition 22% water in methanol) over 30 min. Seed the batch with (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (Ia) (1 wt % seed based on the compound of Formula (4a)). Stir for 4 hrs at 50-55° C. then add water over 24 h until the mixture is approximately 58 wt % water in methanol. Cool to 20-25° C., stir 1 h, then filter. Wash the cake with water (2 vol). Dry the solids at 60-65° C. to give (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (Ia).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[O:10]1[C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1>>[CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]1[S:4][C:5]([C:17]2([OH:20])[CH2:18][CH2:19][C:14]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:15][CH2:16]2)=[CH:6][N:7]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C[Si](C)(C)c1nccs1
Product: C[Si](C)(C)c1ncc(C2(O)CCC3(CC2)OCCO3)s1

Procedure:
The title compound was prepared as white solid from 2-trimethylsilanyl-thiazole and 1,4-dioxa-spiro[4.5]decan-8-one using the similar procedure described in Step A of Example 24.
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:21][CH2:20]1)[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[CH:7]=[C:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10]>C(O)C>[OH:1][C@@H:2]([CH2:18][N:19]1[CH2:20][CH2:21][CH:22]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:23][CH2:24]1)[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1/[CH:7]=[C:8]1\[C:9]([O:11][CH2:12][CH2:13]\1)=[O:10]
Reactant: O=C1OCCC1=Cc1ccccc1OC[C@@H](O)CN1CCC(c2ccc3ccccc3c2)CC1
Solvent: CCO
Product: O=C1OCC/C1=C/c1ccccc1OC[C@@H](O)CN1CCC(c2ccc3ccccc3c2)CC1
Reaction time: 6 h
Yield: 15 %

Procedure:
(S)-α-(2′-(2-Hydroxy-3-(4-(naphthalen-2-yl) piperidino) propyloxy) benzylidene)-γ-butyrolactone (2.0 g) was dissolved in ethanol (300 ml) and exposed to the sunlight for 6 hr. The solvent was concentrated under reduced pressure and the obtained oil was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (0.3 g).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([NH:13][CH2:14][CH2:15][NH:16][CH2:17][C:18]1[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][CH:19]=1)[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28](=O)(ON1C(=O)CCC1=O)[O:29]N1C(=O)CCC1=O.C(N(CC)CC)C>ClCCCl.ClC(Cl)C>[C:1]([O:5][C:6]([C@@H:8]([N:13]1[CH2:14][CH2:15][N:16]([CH2:17][C:18]2[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][CH:19]=2)[C:28]1=[O:29])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cccc(CNCCN[C@@H](C(=O)OC(C)(C)C)C(C)(C)C)n1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)c1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Yield: 86.3 %

Procedure:
A solution of the product of Example 50-3 (92 g, 243 mmol), disuccinimidyl carbonate (78 g, 304 mmol), and triethylamine (41 mL, 294 mmol) in 1,2-dichloroethane (1.8 L) was stirred at room temperature for 16 hours. The mixture was diluted with dichloroethane (200 mL), washed with saturated NaHCO3 (2×500 mL), and brine (200 mL), dried over MgSO4, filtered and concentrated. The residue was triturated with hexane (550 mL) and ethyl acetate (50 mL) at room temperature for two hours to give the title compound as a white solid (85 gm, 98% yield). 1H NMR (CDCl3): δ ppm 1.10 (s, 9 H), 1.48 (s, 9 H), 3.34 (m, 2 H), 3.62 (m, 1 H), 3.88 (m, 1 H), 4.00 (s, 3 H), 4.42 (s, 1 H), 4.64 (s, 2 H), 7.52 (d, 1 H), 7.81 (t, 1 H), 8.03 (d, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].S(Cl)(Cl)=O.O.[CH3:25]O>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:25])=[O:7])=[CH:4][C:3]=1[S:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)(=[O:13])=[O:12]
Reactant: CO
Reactant: O=C(O)c1ccc(O)c(S(=O)(=O)N2CCOCC2)c1
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(O)c(S(=O)(=O)N2CCOCC2)c1
Temperature: 0 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
The 4-hydroxy-3-(morpholine-4-sulfonyl)-benzoic acid (4.0 g, 14 mmol) was dissolved in methanol and cooled to 0° C. Thionyl chloride (5 mL) was added slowly to the stirring solution. The solution was allowed to stir 15 h under nitrogen at room temperature. Water (10 mL) was added slowly to neutralize the thionyl chloride, and the solvent was removed under reduced vacuum. The concentrated oil was partitioned between ethyl acetate and water, and the ethyl acetate phase was washed with saturated sodium bicarbonate solution twice. The ethyl acetate was washed with brine, and dried using magnesium sulfate. Solvent was removed under vacuum to yield the crude oil. The crude was purified using silica gel (eluent 40% ethyl acetate/hexane) to provide the title compound (3.73 g,86%) as a white solid: 1HNMR (DMSO-d6) δ11.8-11.9 (bs, 1H), 8.22 (d, J=2 Hz, 1H), 8.05 (dd, J=9 Hz, 2 Hz, 1H), 7.14 (d, 9 Hz, 1H), 3.84 (m, 3H), 3.62 (m, 4H), 3.11 (m, 4H); MS (EI): M+ 301; Anal.Calc. for C12H15NO6S: C, 47.83; H, 5.02; N, 4.65. Found: C, 47.58; H, 4.95; N, 4.65.
Reaction SMILES: [OH-].[Na+].[C:3]([OH:12])(=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6].[CH3:13][C:14]1[N:15]=[N:16][S:17][C:18]=1[C:19](Cl)=[O:20]>O>[CH3:13][C:14]1[N:15]=[N:16][S:17][C:18]=1[C:19]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[C:3]([OH:12])=[O:11])=[O:20]
Reactant: Cc1nnsc1C(=O)Cl
Reactant: Nc1ccccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nnsc1C(=O)Nc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
In 50 ml of water were dissolved 1.2 g (31 mmol) of sodium hydroxide and 4.2 g (31 mmol) of anthranilic acid. While cooling the solution with ice, 5 g (31 mmol) of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid chloride was dropwise added thereto over a period of 30 minutes. After the dropping, the resulting mixture was reacted with stirring at room temperature for 30 minutes. After the reaction was completed, the crystalline product deposited from the reaction mixture was collected by filtration and washed with methanol and ethyl acetate. Thus, 7.1 g of the objective compound was obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:24][CH:25]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]1)[C:11]1[CH:12]=[C:13]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]O)[CH:14]=[CH:15][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:51]1(=[O:61])[NH:55][C:54](=[O:56])[C:53]2=[CH:57][CH:58]=[CH:59][CH:60]=[C:52]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:24][CH:25]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]1)[C:11]1[CH:12]=[C:13]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:55]2[C:51](=[O:61])[C:52]3[C:53](=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:54]2=[O:56])[CH:14]=[CH:15][CH:16]=1
Reactant: CN1CCC(OC(c2cccc(SCCCCCO)c2)c2nc3ccccc3[nH]2)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(OC(c2cccc(SCCCCCN3C(=O)c4ccccc4C3=O)c2)c2nc3ccccc3[nH]2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentan-1-ol (35 mg) in tetrahydrofuran are added triphenylphosphine (31 mg) and phthalimide (18 mg). The reaction mixture is cooled to 0° C. and diethyl azodicarboxylate (31 μL) is added. The reaction mixture is stirred at 0° C. for 30 minute. The mixture is evaporated to dryness and the residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 98/2/0.2 to 95/5/0.5) to give 2-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentyl)isoindole-1,3-dione (example 305B).