Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)([CH3:7])=[O:6].[C:9]([O:12][CH2:13][C:14]([NH:28][C:29](=[O:31])[CH3:30])([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:15][O:16][C:17](=[O:19])[CH3:18])(=[O:11])[CH3:10]>ClCCCl>[C:17]([O:16][CH2:15][C:14]([NH:28][C:29](=[O:31])[CH3:30])([CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:5](=[O:6])[CH3:7])=[CH:26][CH:27]=1)[CH2:13][O:12][C:9](=[O:11])[CH3:10])(=[O:19])[CH3:18]
Reactant: CC(=O)NC(CCc1ccccc1)(COC(C)=O)COC(C)=O
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)NC(CCc1ccc(C(C)=O)cc1)(COC(C)=O)COC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of AlCl3 (16 mmol) in DCE (20 mL) is added AcCl (8 mmol) in one portion. After stirring at room temperature for 30 minutes, to the solution is added acetic acid 2-acetoxymethyl-2-acetylamino-4-phenyl-butyl ester (2 mmol) in DCE (5 mL). After an additional 30 minutes, the mixture is poured into ice-cold 1 N NaOH and is extracted with DCM. The organic phase is washed with 1 N HCl, brine and dried over Na2SO4. After concentrating, the crude material is purified by column chromatography using EtOAc/hexane (2/1) to give acetic acid 2-acetoxymethyl-2-acetylamino-4-(4-acetyl-phenyl)-butyl ester as a white solid. MS: (ES+): 364.2 (M+1)+.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:29])[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([O:23][CH:24]([CH2:27][F:28])[CH2:25][F:26])[CH:22]=3)[C:17](O)=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[NH2:36][C:37]1[CH:42]=[N:41][C:40]([CH3:43])=[CH:39][N:38]=1>C(Cl)Cl>[N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:29])[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([O:23][CH:24]([CH2:25][F:26])[CH2:27][F:28])[CH:22]=3)[C:17]([NH:36][C:37]3[CH:42]=[N:41][C:40]([CH3:43])=[CH:39][N:38]=3)=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cnc(N)cn1
Reactant: O=C(O)c1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(OC(CF)CF)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cnc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(OC(CF)CF)c2)cn1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 57.9 %

Procedure:
1-Chloro-N,N-2-trimethylpropenylamine (0.08 mL, 0.60 mmol) was added to a solution of 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}benzoic acid (215 mg, 0.5 mmol) in DCM (5 mL) and the reaction stirred at RT for 30-40 minutes. Pyridine (0.08 mL, 1.0 mmol) and 2-amino-5-methylpyrazine (108 mg, 1.0 mmol) were added and the reaction stirred for 16 hours before being concentrated in vacuo and water (20 mL) added. The mixture was extracted with ethyl acetate (3×20 mL), washed with 1N hydrochloric acid (20 mL), a saturated solution of sodium hydrogen carbonate (20 mL), brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed on silica, eluting with a gradient of 0-10% methanol in DCM, to give the desired compound as a white solid (150 mg). 1H NMR δ (CDCl3): 2.40 (quintet, 2H), 2.56 (s, 3H), 4.22-4.31 (m, 2H), 4.32-4.40 (m, 2H), 4.62-4.82 (m, 5H), 7.06 (t, 1H), 7.38 (t, 1H), 7.47 (t, 1H), 8.15 (s, 1H), 8.17 (s, 1H), 8.25 (d, 1H), 8.46 (s, 1H), 9.55 (s, 1H); m/z 518 (M+H)+, 516 (M−H)−
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:29]([O:30]C(=O)C)[C@H:28]([O:34]C(=O)C)[C@@H:27]([CH2:38][O:39]C(=O)C)[O:26][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([CH2:14][O:15][CH3:16])[CH:11]=[CH:10][C:9]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=O)C.C[O-].[Na+]>CO>[O:7]([C:8]1[CH:13]=[C:12]([CH2:14][O:15][CH3:16])[CH:11]=[CH:10][C:9]=1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[C@@H:6]1[O:26][C@H:27]([CH2:38][OH:39])[C@@H:28]([OH:34])[C@H:29]([OH:30])[C@H:5]1[OH:4]
Reactant: COCc1ccc(Cc2ccc(OC)cc2)c(O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1ccc(Cc2ccc(OC)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of 2-(4-methoxybenzyl)-5-methoxymethylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.14 g) in methanol (3 mL) was added sodium methoxide (28% methanol solution, 0.047 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by column chromatography on benzenesulfonylpropyl silica gel (eluent: methanol) to give 2-(4-methoxybenzyl)-5-methoxymethylphenyl β-D-glucopyranoside (0.084 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([Cl:12])[C:6]=2[N:7]=1>C1CCCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][C:16]3[C:15](=[CH:4][CH:5]=[CH:6][CH:8]=3)[CH2:14]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([Cl:12])[C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCCCC2)c2ncnc(Cl)c2n1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: Clc1nc(N2CCc3ccccc3C2)c2ncnc(Cl)c2n1

Procedure:
2,8-dichloro-4-piperidino-pyrimido [5,4-d]-pyrimidine Rf value: 0.66 (silica gel; cyclohexane/ethyl acetate=2:1)
Reaction SMILES: N=C=N.[CH3:4][O:5][CH2:6][C:7]([OH:9])=O.ON1C2C=CC=CC=2N=N1.[NH2:20][CH2:21][C:22]1[CH:23]=[C:24]([N:28]2[C:33]([CH3:34])=[CH:32][C:31]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=3[F:44])=[C:30]([Br:45])[C:29]2=[O:46])[CH:25]=[CH:26][CH:27]=1.CN=C=O>CN(C)C(=O)C.CN1CCOCC1.ClCCCl>[Br:45][C:30]1[C:29](=[O:46])[N:28]([C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[CH2:21][NH:20][C:7](=[O:9])[CH2:6][O:5][CH3:4])[C:33]([CH3:34])=[CH:32][C:31]=1[O:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=1[F:44]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cccc(CN)c1
Reactant: COCC(=O)O
Agent: CN=C=O
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: COCC(=O)NCc1cccc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28 %

Procedure:
To a reaction vessel (borosilicate culture tube) was added approximately 2.87 g of polymer bound carbodiimide resin (0.96 mmol/g) followed by a stock solution of methoxyacetic acid (8.0 mL, 0.10 M) in N,N-dimethylacetamide. A stock solution of 1-hydroxybenzotriazole in N,N-dimethylacetamide (3.0 mL, 0.10 M) and N-methylmorpholine (6.0 mL, 0.10 M) in 1,2-dichloroethane were added to the reaction vessel. The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 4 hours. A stock solution of EXAMPLE 293 in N,N-dimethylacetamide (5.0 mL, 0.10 M) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. At this time the reaction was diluted with 1,2-dichloroethane (10 mL) and treated with approximately 1.70 g of polyamine resin (2.63 mmol/g) and approximately 0.84 g of methylisocyanate functionalized polystyrene (1.50 mmol/g) and the orbital shaking was continued at 200 RPM at room temperature for 4 hours. The reaction vessel was then opened and the solution phase products were separated from the insoluble quenched byproducts by filtration and collection into a vial. After partial evaporation the insoluble byproducts were rinsed with N,N-dimethylacetamide (2×5 mL). The filtrate was evaporated by blowing N2 over the vial while heating (60° C.) in a reaction block (KEM-Lab Parallel Reactor) and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) afforded an off white solid (0.081 g, 28%). 1H NMR (400 MHz, DMF-d6) δ 7.59 (q, J=7.65 Hz, 1H), 7.46 (app t, J=7.55 Hz, 1H), 7.40-7.37 (m, 1H), 7.11-7.07 (m, 2H), 7.00 (t, J=8.56 Hz, 2H), 6.54 (s, 1H), 5.30 (s, 2H), 4.43 (s, 2H), 3.88 (s, 2H), 3.35 (app d, J=0.80 Hz, 2H), 1.97 (s, 3H). ES-HRMS m/z 507.0699 (M+H C23H21BrF2N2O4 requires 507.0726).
Reaction SMILES: [O:1]=[O+][O-].[OH:4][CH:5]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:16]([CH3:27])[C:15]1=[O:28])/[CH:6]=C/C1C=CC=CC=1>CO.ClCCl>[OH:4][CH:5]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH:16]([CH3:27])[C:15]1=[O:28])[CH:6]=[O:1]
Reactant: O=[O+][O-]
Reactant: CC1C(=O)C(C(O)/C=C/c2ccccc2)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CO
Product: CC1C(=O)C(C(O)C=O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ozone gas was bubbled into a solution of 0.450 g (1.30 mmol) of tert-butyl 4-[(2E)-1-hydroxyl-3-phenylprop-2-enyl]-2-methyl-3-oxopiperidine-1-carboxylate (Step D) in 10 mL of methanol and 10 mL of dichloromethane at −78° C. until the solution turned blue. The reaction was quenched with dimethyl sulfide, warmed to ambient temperature, and stirred for 1 h. The mixture was concentrated in vacuo and purified by flash chromatography on a Biotage® system (silica gel, eluting with 20% ethyl acetate/hexane to 60% ethyl acetate/hexane), affording the title compound.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[NH:14][CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:1]1([CH2:7][C:8]([C:10]2[NH:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c[nH]c(C(=O)Cc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(C(=O)Cc2ccccc2)c1

Procedure:
All of the methyl 5-phenylacetylpyrrole-3-carboxylate prepared by Example 80 was boiled with methanol (20 ml.) and 1N sodium hydroxide (15 ml.) for 90 minutes. The aqueous residue was cooled, acidified with conc. hydrochloric acid, and crude product (1.2 g.) recovered by filtration. Chromatography on 30 g. of silica gel, employing ethyl acetate-1/hexane-5/5% acetic acid as eluant, gave, on evaporation of the initial, ultraviolet absorbing fractions, purified 5-phenylacetylpyrrole-3-carboxylic acid (470 mg., m.p. 205°-207° C., m/e 229).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:9]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:10]([S:12][CH3:13])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].I[CH2:25][CH2:26][CH3:27].O>CN(C)C=O>[Br:1][C:2]1[C:3]2[N:4]([C:9]([N:14]([CH2:25][CH2:26][CH3:27])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[C:10]([S:12][CH3:13])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCCI
Reactant: CSc1nc2c(Br)cc(C)cn2c1NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(C(=O)OC(C)(C)C)c1c(SC)nc2c(Br)cc(C)cn12
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
tert-Butyl N-[8-bromo-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-yl]carbamate (123 mg) was dissolved in N,N-dimethylformamide (10 mL), then sodium hydride (65% in oil; 15 mg) was added thereto under ice-cooling, and the mixture was stirred for 10 minutes. Iodopropane (67 mg) was added thereto under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The extracted organic layers were combined, dried over anhydrous magnesium sulfate and evaporated, to give the title compound (133 mg) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[C@H:4]([CH2:23][O:24][C:25]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:5]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>N1CCCCC1>[CH3:1][O:2][C:3](=[O:44])[C@H:4]([CH2:23][O:24][C:25]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH2:5]
Reactant: COC(=O)[C@H](COC1(c2ccccc2)c2ccccc2-c2ccccc21)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Product: COC(=O)[C@@H](N)COC1(c2ccccc2)c2ccccc2-c2ccccc21
Reaction time: 0.5 h
Yield: 97 %

Procedure:
The crude Nα -(9-fluorenylmethoxycarbonyl)-O-(9-phenyl-9H-fluoren-9-yl)-L-serine methyl ester from Step 1 (Method A) was dissolved in piperidine (5 mL) and the mixture stirred at 60 (C for 0.5 h. After evaporation of the solvent the residue was chromatographed on silica gel with ethyl acetate to give 6.96 g (yield 97%) O-(9-phenyl-9H-fluoren-9-yl)-L-serine methyl ester as a viscous oil. 1H NMR (CDCl3, 300 MHz) δ: 7.65 (d, 2H), 7.40-7.05 (m, 11H), 3.65 (s, 3H), 3.46 (t, 1H), 3.30-3.10 (m, 2H), 1.80 (br s, 2H); 13C NMR (CDCl3, 75 MHz) δ: 174.1, 146.4, 146.2, 142.7, 140.4, 129.0, 128.9, 128.1, 127.9, 126.9, 125.2, 125.1, 124.9, 119.8, 119.7, 88.1, 65.1, 54.6, 51.8, 51.7, 13.9.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=O)([CH3:4])([CH3:3])[CH3:2].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:43]>CO>[ClH:43].[C:1]([C:5]1[CH:6]=[C:7]([C:14]2[N:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][N:15]=2)[C:8]([OH:13])=[C:9]([CH2:10][NH:28][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:12]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2nccc(C(F)(F)F)n2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)NCc1cc(C(C)(C)C)cc(-c2nccc(C(F)(F)F)n2)c1O
Reaction time: 1 h
Yield: 38 %

Procedure:
To a solution of 5-(tert-butyl)-2-hydroxy-3-(4-(trifluoromethyl)pyrimidin-2-yl)benzaldehyde (324 mg, 1.00 mmol) and tert-butylamine (0.21 mL, 2.00 mmol) in methanol (10 mL) was added sodium triacetoxyborohydride (254 mg, 1.20 mmol). The solution was stirred at 25° C. for one hour at which time a second portion of sodium triacetoxyborohydride (254 mg, 1.20 mmol) was added. After one hour a third portion of sodium triacetoxyborohydride (254 mg, 1.20 mmol) was added and the mixture was stirred for one hour. The solution was brought to pH 1 by the addition of 1N solution of hydrochloric acid and then partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate solution (25 mL). The organic phase was separated, concentrated under reduced pressure and purified using flash chromatography on silica eluting with a solvent gradient of 100:0 to 0:100 v/v 100% dichloromethane to a solution of 10% methanol, 1% ammonium hydroxide, 89% dichloromethane. The product was further purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% acetone in hexanes. The residue was dissolved in an excess of a 1N solution of hydrochloric acid in ethanol, the solvent was removed under reduced pressure and the solid was triturated with ether to give 4-(tert-butyl)-2-((tert-butylamino)methyl)-6-(4-(trifluoromethyl)pyrimidin-2-yl)phenol hydrochloride (156 mg, 38% yield) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:22]=3[Cl:31])[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:31][C:22]1[C:23]([C:27]([F:29])([F:28])[F:30])=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]([NH:19][C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:36]([CH:33]4[CH2:35][CH2:34]4)=[O:37])=[N:10][C:9]3=[CH:8][CH:7]=2)[CH:13]=1)=[O:32]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2Cl)cc1Oc1ccc2nc(N)sc2n1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2Cl)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.4 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methylphenyl}-2-chloro-3-(trifluoromethyl)benzamide (200 mg, 0.417 mmol) in pyridine (5 mL) was added cyclopropanecarbonyl chloride (57.4 μL, 0.835 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The residue was filtered through a pad filled with silica gel, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→70/30), and recrystallized from tetrahydrofuran to give the title compound (115 mg, 50%) as white crystals.
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]=2[CH:14]=1)=O.[NH2:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>C(#N)C>[CH3:15][C:2]1[N:18]2[CH:19]=[CH:20][CH:21]=[N:22][C:17]2=[N:16][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]=2[CH:14]=1
Reactant: CC(Br)C(=O)c1ccc2sc(=O)[nH]c2c1
Reactant: Nc1ncccn1
Solvent: CC#N
Product: Cc1c(-c2ccc3sc(=O)[nH]c3c2)nc2ncccn12
Temperature: 25 °C
Yield: 50.7 %

Procedure:
A solution of 5-(2-bromopropionyl)-2-benzothiazolinone (2.9 g) and 2-aminopyrimidine (2.9 g) in acetonitrile (100 ml) was refluxed for 15 hours with stirring. The reaction mixture was cooled to ambient temperature to give a precipitate, which was collected by filtration. The precipitate was added to a mixture of water and ethyl acetate and the resulting mixture was adjusted to pH 8.0 with 20% aqueous potassium carbonate solution. The precipitate was collected by filtration, washed successively with water and ethanol and dried over phosphorus pentoxide to give 5-(3-methylimidazo-[1,2-a]pyrimidin-2-yl)-2-benzothiazolinone (1.45 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][CH:15]=[C:13]([CH2:12][Cl:11])[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccc(Br)cc1
Product: ClCc1coc(-c2ccc(Br)cc2)n1
Yield: 14 %

Procedure:
This compound was synthesized from 4-bromobenzamide and 1,3-dichloroacetone as described in example 74 step 1 (1.5 g, yield 14%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.92-7.89 (d, J=8.8 Hz, 2H), 7.71 (s, 1H), 7.61-7.59 (d, J=8.8 Hz, 2H), 4.57 (s, 2H). MS (ESI) m/z: Calculated for C10H7BrClNO: 272.94. found: 273.8 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20](=[O:22])[CH3:21])=[CH:14][C:13]=2[F:23])[NH:4][CH:3]=1.C([Li])CCC.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20](=[O:22])[CH3:21])=[CH:14][C:13]=2[F:23])[N:4]([S:35]([C:32]2[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH:3]=1
Reactant: CC(=O)Nc1cc(F)c(Oc2ccnc3[nH]cc(Br)c23)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(F)c(Oc2ccnc3c2c(Br)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
1.37 g (3.58 mmol) of N-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}acetamide are dissolved in 200 ml of THF and cooled to −78° C. 1.6 ml (4.0 mmol) of a 2.5M n-butyllithium solution are added dropwise, and the mixture is stirred for 15 min. 752 mg (3.94 mmol) of p-toluenesulfonyl chloride as a solution in 7.5 ml of THF are then added dropwise. The reaction solution is allowed to warm to RT and stirred for one hour. The mixture is then partitioned between ethyl acetate and 0.1N aqueous sodium hydroxide solution. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure. The product is purified by column chromatography on silica gel (mobile phase: dichloromethane/acetone 20:1 to 10:1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)[CH3:21])=[O:19])[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[NH:12][N:11]=[CH:10]2)[CH3:2].[CH2:32](I)[CH3:33]>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([CH2:17][C:18]([N:20]([N:22]1[CH2:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30]1)[CH3:21])=[O:19])[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]([CH2:32][CH3:33])[N:11]=[CH:10]2)[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc2cn[nH]c2cc1C
Product: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc2cnn(CC)c2cc1C
Yield: 69 %

Procedure:
Using the compound (746 mg, 1.77 mmol) of Example 241, step B and ethyl iodide (0.26 n2, 3.23 mmol), and according to the method of Example 241, step C, the title compound (549 mg, yield 69%) was obtained as a colorless amorphous solid.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:15][CH:14]=3)[N:10]=[C:9]([NH:29][CH:30]3[CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:32]1[CH2:33][CH:30]([NH:29][C:9]2[N:8]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([NH:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:28])=[CH:17][CH:18]=3)[N:10]=2)[CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2nc(-c3ccc(NC(=O)Nc4ccccc4)cc3)nc(N3CCOCC3)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccccc1)Nc1ccc(-c2nc(NC3CNC3)nc(N3CCOCC3)n2)cc1
Reaction time: 24 h

Procedure:
To a stirred solution of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(phenylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate 30 mg (0.055 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at room temperature and stirred for 24 hours. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. Yield: 20 (83%); (M+H) 447.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH:10]=O)[CH:8]=1)([O-:3])=[O:2].[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>CC#N>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: O=CCn1cc([N+](=O)[O-])cn1
Reactant: c1ccc2c(c1)CCN2
Solvent: CC#N
Product: O=[N+]([O-])c1cnn(CCN2CCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(4-nitro-1H-pyrazol-1-yl)acetaldehyde (1.02 g, 4.97 mmol) in MeCN (18.0 mL), indoline (0.56 mL, 4.95 mmol) dissolved in MeCN (6 mL) was added. The resulting orange solution was stirred at rt for 5 min, then STAB (2.10 g, 9.90 mmol) was added in portions. After stirring at rt for 1 h, the reaction mixture was quenched with water and extracted with DCM (2×). The combined org. layers were concentrated and purification was performed by FC (EtOAc/toluene 2:8) to yield 1-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)indoline as a brown solid. LC-MS conditions A: tR=0.85 min, [M+H]+=259.14.