Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].Br[CH2:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18](C)=O>>[CH2:17]([C:3]([CH2:9][CH3:10])([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])[CH3:18]
Reactant: CC(C)=O
Reactant: CC(=O)CC(C)=O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC(CC)(C(C)=O)C(C)=O
Temperature: 25 °C

Procedure:
25 g of 2,4-pentandione, 98.3 g of bromo-ethane, 80 g of potassium carbonate, and 175 ml of acetone were mixed and refluxed for 39.5 hours. The solid was filtered off and washed with petroleum ether and acetone. To the liquid layer, 2.0 g of 1,8-diazabicyclo-[5.4.0]-undec-7-ene was added and the mixture was refluxed for two days. After addition of an additional 11.6 g of 1,8-diazabicyclo-[5.4.0]-undec-7-ene and refluxing for seven hours, 25 g of ethyl acrylate was added and the mixture was stirred at room temperature, and the solvent was distilled off and the mixture was refluxed for 8 hours. The base was neutralized by adding acetic acid, washed with an aqueous potassium carbonate solution, and extracted with diethyl ether. The ether layer was dried and the product was isolated by fractional distillation to yield 9 g of product (boiling point 190° C./1000 mbar; purity: 75%; colorless).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].C(OC1C=CC=CC=1C(=O)NC1SC=C(S(C)=O)N=1)(=O)C.[C:28]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38](=[O:47])[NH:39][C:40]1[S:41][C:42]([S:45][CH3:46])=[CH:43][N:44]=1)(=[O:30])[CH3:29]>>[C:28]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38](=[O:47])[NH:39][C:40]1[S:41][C:42]([S:45]([CH3:46])=[O:1])=[CH:43][N:44]=1)(=[O:30])[CH3:29]
Reactant: CSc1cnc(NC(=O)c2ccccc2OC(C)=O)s1
Reactant: O=S([O-])OO
Agent: CC(=O)Oc1ccccc1C(=O)Nc1nc(S(C)=O)cs1
Agent: [K+]
Product: CC(=O)Oc1ccccc1C(=O)Nc1ncc(S(C)=O)s1

Procedure:
Using the Oxone® procedure as described in section 1.5.1.7 for the synthesis of compound (1), 518 (1.1 g, 3.57 mmol), affords 11 as a white solid.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[C:11]([C:23]([CH3:25])=[O:24])[CH:10]=1>OS(O)(=O)=O.C([O-])(O)=O.[Na+]>[OH:7][CH2:8][C:9]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[C:11]([C:23]([CH3:25])=[O:24])[CH:10]=1
Reactant: CC(=O)c1cc(COC2CCCCO2)c2c(c1)-c1ccccc1C2=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)c1cc(CO)c2c(c1)-c1ccccc1C2=O
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
1-(2-Tetrahydropyranyl)oxymethyl-3-methylcarbonyl-9-fluorenone (197 mg) was dissolved in 1% H2SO4 (5 ml) and allowed to stand at room temperature for 0.5 hr. The reaction mixture was diluted with excess NaHCO3 soln (10%). The MeOH was removed under reduced pressure and the residue was extracted with EtOAc, dried and evaporated which gave the product (135 mg).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C:14]23[O:21][CH:18]([CH2:19]C2)[CH:17]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:15]3)[N:6]=1.[F:40][C@H]1[C@H](NC(=O)OC(C)(C)C)CC[C@@H](C2N(C)N=CC=2[N+]([O-])=O)OC1>>[Br:1][C:2]1[S:3][C:4]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:15][CH2:16][C@@H:17]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[C@H:18]([F:40])[CH2:19][O:21]2)[N:6]=1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1C12CCC(NC(=O)OC(C)(C)C)C(CC1)O2
Product: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1

Procedure:
Following the procedure for Intermediate 65, starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80) gave tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O.CO>[O:11]1[CH2:12][CH2:13][CH2:14][CH:8]([C:7]2[C:2]([O:31][C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:16]4[S:15][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=5[N:17]=4)=[CH:30][CH:29]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: Fc1ncccc1C1CCCOCC1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CO
Product: c1cnc(Oc2ccc(Nc3nc4ccccc4s3)cc2)c(C2CCCOCC2)c1
Temperature: 120 °C
Reaction time: 17 h

Procedure:
2-Fluoro-3-(oxepan-4-yl)pyridine (0.055 g, 0.28 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (0.20 g, 0.85 mmol), and cesium carbonate (0.28 mL, 0.85 mmol) were mixed in NMP (0.75 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at 120° C. for 17 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic layers were washed with 1 M aqueous sodium hydroxide, washed with sat. sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to yield an orange solid. The solid was slurried in MeOH and filtered to give N-(4-(3-(oxepan-4-yl)pyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine. MS (ESI, pos. ion) m/z: 418.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:20]1[CH2:25][CH2:24]/[C:23](=[N:26]\[N:27]([CH3:29])[CH3:28])/[CH:22]([CH3:30])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CI>C1COCC1.ClCCl>[CH2:13]([N:20]1[CH2:25][CH:24]([CH3:1])[C:23](=[N:26][N:27]([CH3:29])[CH3:28])[CH:22]([CH3:30])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)NC(C)C
Reactant: CC1CN(Cc2ccccc2)CC/C1=N\N(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: ClCCl
Product: CC1CN(Cc2ccccc2)CC(C)C1=NN(C)C
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
Diisopropylamine (3.3 ml, 23.5 mmol) is dissolved in 20 ml of THF and cooled to −5° C. A 1.6M solution of n-butyllithium in THF (14.7 ml, 23.5 mmol) is added dropwise within 10 min. After additional 10 min at −5° C., a solution of 42 (4.8 g, 19.6 mmol) in 30 ml of THF is added within 20 min (the color of the reaction mixture changed to red). Now, the solution is cooled to −78 C. Methyliodide (1.33 ml, 21.5 mmol) is added dropwise within 15 min and the mixture is allowed to warm to room temperature over night. Dichloromethane is added and the solution is washed with water. Evaporation gave 5 g of a colorless oil, which is further purified by flash-chromatography (silicagel, ethyl acetate/hexanes 1:1)
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6](COS(C2C=CC(C)=CC=2)(=O)=O)[CH2:5][N:4]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:3]1.[N-:27]=[N+:28]=[N-:29].[Na+].CN(C=[O:35])C>CCOC(C)=O>[N:27]([CH2:7][C@@H:6]1[O:35][C@H:2]([CH3:1])[CH2:3][N:4]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:5]1)=[N+:28]=[N-:29]
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@H](C)CN(C(=O)OC(C)(C)C)C2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](CN=[N+]=[N-])O1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (3S,5R)-tert-butyl 3-methyl-5-((tosyloxy)methyl)piperidine-1-carboxylate (0.860 g, 2.232 mmol) in DMF (7 mL) at rt was added sodium azide (0.218 g, 3.347 mmol) after which time the reaction was warmed to 80° C. and stirred an additional 3 h. The completed reaction was cooled to rt, diluted with EtOAc (25 mL) and washed three times with water (5 mL each). The resultant organic layer was dried over anhydrous Na2SO4, filtered, concentrated after which time the crude product was purified over silica gel (Biotage eluting with 0 to 15% EtOAc in heptane gradient) to provide (2R,6R)-tert-butyl 2-(azidomethyl)-6-methylmorpholine-4-carboxylate, 37 (0.545 g, 2.126 mmol, 95.3% yield) as a colorless crystalline solid after concentration of the desired combined fractions and drying in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10](=O)[C:9]3[CH:13]=[C:14]([S:17][CH3:18])[CH:15]=[CH:16][C:8]=3[O:7][C:6]=2[CH:19]=1.[Cl-:20].[Ca+2].[Cl-].Cl>C1C=CC=CC=1>[Cl:20][CH:10]1[C:9]2[CH:13]=[C:14]([S:17][CH3:18])[CH:15]=[CH:16][C:8]=2[O:7][C:6]2[CH:19]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[CH2:11]1
Reactant: [Cl-]
Reactant: CSc1ccc2c(c1)C(=O)Cc1ccc(C)cc1O2
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: CSc1ccc2c(c1)C(Cl)Cc1ccc(C)cc1O2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7.5 G. of 10,11-dihydro-3-methyl-8-methylthio-dibenz[b,f]oxepin-10-one are dissolved in 75 ml. of benzene. 7.5 G. of anhydrous calcium chloride are added thereto and the mixture is saturated with hydrogen chloride. Then, the resulting mixture is stirred at room temperature for 16 hours and filtered. The filtrate is evaporated in vacuo and there is obtained 10-chloro-10,11-dihydro-3-methyl-8-methylthio-dibenz[b,f]oxepin.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([O:11][CH3:12])[C:3]=1C=O.ClC1C=CC=C(C(OO)=[O:21])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[OH:21]
Reactant: COc1ccc(F)c(F)c1C=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(F)c(F)c1O
Reaction time: 0.33 h
Yield: 70.8 %

Procedure:
To a solution of 2,3-difluoro-6-methoxybenzaldehyde (2.58 g) in methylene chloride (45 mL) was added 3-chloroperbenzoic acid (5.97 g) under ice-cooling, and the mixture was heated for reflux overnight. The reaction mixture was cooled in ice. To the mixture was added 10% aqueous sodium sulfite solution, and the resulting mixture was stirred for 20 minutes. The organic layer was separated and washed with water twice, a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL)-methanol (7.5 mL). To the solution was added sodium methoxide (28% methanol solution, 3.75 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=2/3) and column chromatography on aminopropylated silica gel (eluent: ethyl acetate/methanol=9/1−3/2) successively to give the title compound (1.7 g).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[NH:12][C:13]2[CH:19]=[C:18]([C:20]([OH:22])=O)[CH:17]=[CH:16][C:14]=2[N:15]=1)([CH3:3])[CH3:2].[N:23]1([CH2:29][CH2:30][O:31][C:32]2[C:40]3[C:35](=[CH:36][C:37]([NH2:41])=[CH:38][CH:39]=3)[NH:34][N:33]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[N:23]1([CH2:29][CH2:30][O:31][C:32]2[C:40]3[C:35](=[CH:36][C:37]([NH:41][C:20]([C:18]4[CH:17]=[CH:16][C:14]5[N:15]=[C:11]([NH:10][C:5]6[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=6[CH:1]([CH3:2])[CH3:3])[NH:12][C:13]=5[CH:19]=4)=[O:22])=[CH:38][CH:39]=3)[NH:34][N:33]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: CC(C)c1ccccc1Nc1nc2ccc(C(=O)O)cc2[nH]1
Reactant: Nc1ccc2c(OCCN3CCOCC3)n[nH]c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)c1ccccc1Nc1nc2ccc(C(=O)Nc3ccc4c(OCCN5CCOCC5)n[nH]c4c3)cc2[nH]1

Procedure:
2-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid (0.3 mmol; see Example 66) was coupled with aforementioned 3-(2-morpholin-4-ylethoxy)-1H-indazol-6-ylamine (0.3 mmol) using HBTU as described in general procedure D to afford the desired product, 2-(2 isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid [3-(2-morpholin-4-ylethoxy)-1H-indazol-6-yl]-amide. MS: m/z 540 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH:12]=[O:13])[C:9]([CH2:14][N:15]3[CH2:20][CH2:19][C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)=[N:8]2)=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][OH:13])[C:9]([CH2:14][N:15]3[CH2:16][CH2:17][C:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:19][CH2:20]3)=[N:8]2)=[CH:33][CH:34]=1
Reactant: O=Cc1cn(Cc2ccc(Cl)cc2)nc1CN1CCC(c2ccccc2)(c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: OCc1cn(Cc2ccc(Cl)cc2)nc1CN1CCC(c2ccccc2)(c2ccccc2)CC1
Reaction time: 20 h
Yield: 55.8 %

Procedure:
The product of Example 15 (0.05 g) was dissolved in dichloromethane (5 ml) and sodium triacetoxyborohydride (0.068 g) added. After 20 hours at room temperature, brine and dichloromethane were added, the organic phase was separated, dried and the solvent removed by evaporation to give a residue. Trituration under ether gave the product as a solid (0.028 g), m.p. 104-105° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Sn](CCCC)(CCCC)CCCC)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].Br[C:31]1[N:32]=[C:33]([N:41]2[CH2:46][CH2:45][N:44]([CH2:47][CH3:48])[CH2:43][CH2:42]2)[C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[CH:36][CH:35]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:47]([N:44]1[CH2:43][CH2:42][N:41]([C:33]2[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:40]=[C:31]([C:14]3[CH:13]=[CH:12][C:11]([C@H:8]4[CH2:7][CH2:6][C@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:10][CH2:9]4)=[CH:16][CH:15]=3)[N:32]=2)[CH2:46][CH2:45]1)[CH3:48]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1[C@H]1CC[C@H](OC(C)=O)CC1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc([C@H]4CC[C@H](OC(C)=O)CC4)cc3)cc3ccccc23)CC1

Procedure:
Trans-4-(tributylstannylphenyl)cyclohexyl acetate(0.56 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (0.46 g) -were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.06 g) in xylene in nitrogen atmosphere overnight. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate. Then, it was adjusted to pH 10 by a 8N aqueous solution of sodium hydroxide, extracted with ethyl acetate, washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give a mixture (0.44 g) of 1-(4-ethylpiperazin-1-yl)-3-[4-(trans-4-acetoxycyclohexyl)phenyl]isoquinoline as a brown viscous oil and the starting material.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[C:10]([Cl:11])=[CH:9][C:8]([O:12][CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)=[CH:7][C:6]=1[Cl:26].[OH-].[Na+]>CO.O1CCCC1.O>[Cl:11][C:10]1[CH:9]=[C:8]([O:12][CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:7]=[C:6]([Cl:26])[C:5]=1[C:4](=[O:27])[C:3]([OH:28])=[O:2]
Reactant: COC(=O)C(=O)c1c(Cl)cc(OCCOc2ccc3ccccc3c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(=O)c1c(Cl)cc(OCCOc2ccc3ccccc3c2)cc1Cl
Yield: 91.4 %

Procedure:
A solution of 2,6-dichloro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester(0.6 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from acetone-hexane provided 0.53 g of purified 2,6-dichloro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid as a colorless solid, mp 155°-156° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:22]([O:26][C:27]([NH:29][CH2:30][C:31](=[CH2:35])[C:32](O)=[O:33])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:22]([O:26][C:27]([NH:29][CH2:30][C:31](=[CH2:35])[C:32]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1)=[O:33])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: C=C(CNC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(CNC(=O)OC(C)(C)C)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (300 mg, 1.06 mmol), 2-((tert-butoxycarbonylamino)methyl)acrylic acid (321 mg, 1.60 mmol), HATU (606 mg, 1.59 mmol) and DIPEA (371 μL, 2.13 mmol) in DMF (5.0 mL) was stirred at room temperature for 3 hours. The resulting mixture was diluted with ethyl acetate (15 mL) and washed with saturated aqueous bicarbonate, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier to give ethyl 4-(3-(2-((tert-butoxycarbonylamino)methyl)acrylamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C24H28N5O5 [M+H]+: 466, found 466.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C(N(CC)CC)C.Cl[C:37]([O:39][CH3:40])=[O:38]>ClCCl.CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:27][CH3:28])=[C:16]([CH:23]4[CH2:24][N:25]([C:37]([O:39][CH3:40])=[O:38])[CH2:26]4)[C:17]([C:18]#[N:19])=[C:20]([Cl:22])[CH:21]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: COC(=O)Cl
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CC(c2c(C#N)c(Cl)cc(C(C)n3nc(C)c4c(N)ncnc43)c2OC)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (chiral intermediate from Example 261) (20 mg, 0.05 mmol) in dichloromethane (1 mL) was treated with triethylamine (20 μL, 0.14 mmol) followed by methyl chloroformate (4.7 μL, 0.06 mmol) and stirred at room temperature for 1 h. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (12 mg, 52%). The product was isolated as a single enantiomer. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.51 (s, 1H), 7.34 (br s, 2H), 6.25 (q, J=7.0 Hz, 1H), 4.53-4.38 (m, 1H), 4.36-4.17 (m, 4H), 3.71 (s, 3H), 3.55 (s, 3H), 2.55 (s, 3H), 1.73 (d, J=7.1 Hz, 3H). LCMS for C21H23ClN7O3 (M+H)+: m/z=456.2; Found: 456.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][CH3:16].N([O-])=O.[Na+].[BrH:21]>O1CCOCC1.O.[Cu]Br>[Br:21][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][CH3:16])[CH:4]=1
Reactant: CSc1ccccc1-c1cc(N)ccc1F
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1ccccc1-c1cc(Br)ccc1F
Temperature: 4 °C
Reaction time: 0.67 h
Yield: 57 %

Procedure:
To a solution of 2-fluoro-2′-(methylthio)biphenyl-5-ylamine (397 mg, 1.70 mmol) in 1,4-dioxane (2.1 ml) was added 48% aqueous hydrobromic acid (8 ml) and the mixture was cooled to 3° C. before the dropwise addition of sodium nitrite (137 mg, 1.98 mmol) in water (0.5 ml) over 5 min, while the temperature was kept below 5° C. The resulting mixture was stirred at 4±1° C. for 2 h 40 min then more sodium nitrite (26 mg, 0.37 mmol) in water (0.1 ml) was added dropwise and the mixture was stirred at 3° C. for 50 min. A cooled (3° C.) solution of copper(I) bromide (744 mg, 5.19 mmol) in 48% hydrobromic acid (2.4 ml) was added and the mixture was stirred at 3° C. for 15 min then heated to 50° C. for 1 h. The mixture was cooled to ambient temperature, diluted with water (50 ml) and extracted with ethyl acetate (4×35 ml). The combined organics were washed with 1M aqueous sodium sulphite solution (30 ml), then saturated aqueous ammonium chloride solution (30 ml), dried over anhydrous magnesium sulphate and evaporated to give a brown oil. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (0-2%) gave 5-bromo-2-fluoro-2′-(methylthio)biphenyl as a white solid (287 mg, 57%): δH (360 MHz, CDCl3) 2.40 (3H, s), 7.04 (1H, t, J 9), 7.16-7.24 (2H, m), 7.32 (1H, d, J 8), 7.36-7.51 (4H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:17][CH:18]([OH:21])[CH2:19][OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].C(N(CC)CC)C>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:17][CH:18]([OH:21])[CH2:19][O:20][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(CC(O)CO)c1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc(CC(O)CO[Si](C)(C)C(C)(C)C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83 %

Procedure:
To a solution of (±)-3-[2-(benzyloxy)-3-methoxyphenyl]propane-1,2-diol (50.23 g, 0.174 mol) in N,N-dimethylformamide (600 mL) was added tert-butyldimethylsilyl chloride (28.88 g, 0.192 mol) followed by triethylamine (22.03 g, 0.218 mol) and 4-(dimethylamino)pyridine (2.12 g, 0.017 mol) and the reaction mixture was allowed to stir at room temperature for 6 h. The reaction mixture was quenched by the addition of water (1000 mL) and was extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with water (4×300 mL), aqueous hydrogen chloride (1.0 N, 400 mL), saturated aqueous sodium chloride (300 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 3:7) provided 58.14 g (83%) of (±)-1-[2-(benzyloxy)-3-methoxyphenyl]-3-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ol as a colorless oil. Rf=0.48 (silica, ethyl acetate:hexanes 3:7); Anal. calcd. for C23H34O4Si: C, 68.62; H, 8.51. Found: C, 69.20; H, 8.91.