Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:22](Br)[CH:23]=[CH2:24].O>CN(C=O)C>[CH2:24]([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[CH:23]=[CH2:22]
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cc(C(=O)OC)cc(C(=O)OC)c1
Reaction time: 14 h
Yield: 100.8 %

Procedure:
To a mixture of dimethyl 5-hydroxy-isophthalate (10 g, 47.577 mmol), Cs2CO3 (31 g, 95.2 mmol) in DMF was added allyl bromide (4.83 mL, 57.1 mmol) drop-wise. After stirring the mixture for 14 hours, the reaction was treated with water, extracted with EtOAc (2×). The combined organic extract was dried over sodium sulfate, filtered and evaporated to provide the desired product as white solid (12 g, 100% yield). The crude product was used without further purification. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.94 (s, 6 H) 4.56-4.71 (m, 2 H) 5.33 (dd, J=10.46, 1.41 Hz, 1 H) 5.39-5.53 (m, 1 H) 5.96-6.17 (m, 1 H) 7.76 (d, J=1.32 Hz, 2 H) 8.28 (t, J=1.41 Hz, 1 H); LC-MS: (ESI)+m/z=251.00 (M+1)+.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17]1[N:18]=[C:19]2[N:23]([CH:24]=1)[CH:22]=[CH:21][S:20]2>CN(C=O)C.O>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17]1[N:18]=[C:19]2[N:23]([C:24]=1[I:8])[CH:22]=[CH:21][S:20]2
Reactant: Fc1ccc(-c2cn3ccsc3n2)c(F)c1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc3sccn3c2I)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
NIS (5.56 g, 24.7 mmol) was added to 6-(2,4-difluorophenyl)imidazo[2,1-b]thiazole (5.84 g, 24.72 mmol) in DMF (60 mL) then stirred at ambient temperature for about 30 min. The mixture was diluted with water (about 500 mL), filtered, and washed with ether to give the title compound (5.17 g, 58%): LC/MS (Table 1, Method a) Rt=2.13 min; MS m/z: 363.0 (M+H)+.
Reaction SMILES: [I:1]/[CH:2]=[CH:3]/[CH2:4][C:5]([OH:11])([CH3:10])[CH2:6][CH2:7][CH2:8][CH3:9].N1C=CN=C1.CN(C)C=O.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>CCCCCC>[I:1]/[CH:2]=[CH:3]/[CH2:4][C:5]([CH3:10])([O:11][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(C)(O)C/C=C/I
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCCC(C)(C/C=C/I)O[Si](C)(C)C
Reaction time: 8 h

Procedure:
To a stirred mixture of 24.5 g (55.6 mmoles) of 1-iodo-4-hydroxy-4-methyl-trans-1-octene (Example 130), 13.6 g (200 mmoles) of imidazole, and 75 ml of dimethylformamide is added 10.9 g (100 moles) of chlorotrimethylsilane. After standing overnight the mixture is poured into 250 ml of hexane. The mixture is washed thoroughly with water followed by brine and dried over magnesium sulfate. After removal of the solvent, the product is distilled to give a colorless liquid, bp 67.5°-68° C. (0.07 mm).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC)(C)(C)C.C(Br)(Br)(Br)[Br:41]>CCCCCC>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Br:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCCCOCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: CCCCCC
Product: BrCCCCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
7.0 g of 5-hydroxypentyl benzyl ether and 10.6 g of triphenylphosphine were added to 50 ml of methyl tert-butyl ether and then cooled to 0° C. Further, 13.2 g of carbon tetrabromide was added and the mixture was stirred at room temperature for 3 hours. Thereafter, 100 ml of hexane was added and the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 5.5 g of 5-bromopentyl benzyl ether.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:8]([CH3:30])=[C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[C:10]2[N:11]([N:13]=[C:14]([NH:16]C(=O)C)[N:15]=2)[CH:12]=1)=O.[NH:32]([C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][C:35]=1[S:42]([CH3:45])(=[O:44])=[O:43])[NH2:33].Cl.CCOC(C)=O>C(O)CCC>[NH2:16][C:14]1[N:15]=[C:10]2[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)=[C:8]([CH3:30])[C:7]([C:5]3[N:32]([C:34]4[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][C:35]=4[S:42]([CH3:45])(=[O:44])=[O:43])[N:33]=[CH:3][CH:4]=3)=[CH:12][N:11]2[N:13]=1
Reactant: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)C=CN(C)C)cn2n1
Reactant: CS(=O)(=O)c1cc(C#N)ccc1NN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2S(C)(=O)=O)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Yield: 3.2 %

Procedure:
N-[6-(3-Dimethylamino-acryloyl)-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-acetamide (Int. 25, 247 mg, 0.573 mmol) and 4-hydrazino-3-methanesulfonyl-benzonitrile (Int. 22, 181 mg, 0.86 mmol) were heated at 100° C. in a mixture of n-butanol (10 mL) and conc. HCl (0.3 mL) for 1.5 h. EtOAc was added and the mixture was concentrated in vacuo. The resultant residue was purified by preparative C18 HPLC, eluting with a gradient of 40-90% MeCN in water (+0.1% formic acid) to give the title compound as a yellow solid (10 mg).
Reaction SMILES: [Na].C(O)C.[NH2:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1.[CH3:17][CH:18]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])CCO>C1CCCCC1>[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH2:13][CH2:14][CH:18]([CH3:17])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:11])=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC(CCO)CC(C)(C)C
Agent: [Na]
Solvent: C1CCCCC1
Solvent: CCO
Product: CC(CCOC(=O)c1ccc(N)cc1)CC(C)(C)C

Procedure:
Sodium metal (1 g cat.) was added to ethanol (30 mL) to give a solution which was added to a suspension of ethyl 4-aminobenzoate (175 g, 1.06 mol) and 3,5,5 trimethyl hexanol (200 g, 1.4 mol) in cyclohexane (300 mL). The suspension was heated under reflux for 24 hours with the azeotropic removal of ethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH3:12]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: N
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Fluorobenzenesulfonylchloride (25 g) were dissolved in dichloromethane (250 ml) and treated at 0° C. with an aqueous solution of ammonia (25%, 50 ml). The mixture was stirred for 2 hours with cooling and overnight at room temperature. The reaction mixture was acidified and the organic solvent evaporated. The residue was extracted with ethyl acetate to yield 20 g 4-fluorobenzenesulfonamide, which were dissolved in water (300 ml), treated with 1-benzyl-piperazine (102 g) and refluxed for 24 hours. The reaction mixture was filtered to yield 26 g of the title compound. (mass spec APCI [M+H]=332)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:51]=[CH:52][CH:53]=1)[CH2:5][C@@H:6]([C:23]([NH:25][C:26](=[O:50])[C@H:27]([CH2:29][S:30]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[NH2:28])=[O:24])[NH:7][C:8](=[O:22])[CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:51]=[CH:52][CH:53]=1)[CH2:5][C@@H:6]([C:23]([NH:25][C:26](=[O:50])[C@H:27]([CH2:29][SH:30])[NH2:28])=[O:24])[NH:7][C:8](=[O:22])[CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc(C[C@H](NC(=O)C(c2ccccc2)c2ccccc2)C(=O)NC(=O)[C@@H](N)CSC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(C[C@H](NC(=O)C(c2ccccc2)c2ccccc2)C(=O)NC(=O)[C@@H](N)CS)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-[3-methyl-N-(2,2-diphenylacetyl)-L-phenylalanyl]-S-trityl-L-cysteinamide (0.68 g, 0.95 mmol) in CH2Cl2 (20 mL) is added triethylsilane (0.30 mL, 1.9 mmol), in one portion, followed by dropwise addition of trifluoroacetic acid (10 mL). The yellow solution is stirred at room temperature for 1 hour, after which time solvent is evaporated, and the residue is suspended in water (30 mL), filtered, and the collected solid is washed with water and ether (100 mL each), and dried in vacuo, to yield of N-[3-methyl-N-(2,2-diphenylacetyl)-L-phenylalanyl]-L-cysteinamide, as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[N:8][CH:7]=1.[C:13]1([CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.N1C=CC=CC=1>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:5]([NH:4][CH2:3][CH2:2][O:1][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: O=C(NCCO)c1cccnc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCCc1ccccc1)OCCNC(=O)c1cccnc1
Temperature: 2 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
N-(2-Hydroxy-ethyl)-nicotinamide (3.3 g, 20.0 mmol, 1.0 eq.) was dissolved in DCM (100 mL) and pyridine (20 mL). The light yellow solution was cooled to 2° C. A solution of 4-phenylbutanoylchloride (3.65 g of 20 mmol, 1.0 eq.) in DCM (25 mL) was slowly added. The reaction mixture was stirred for 1 h at 0° C. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in water (100 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (75 mL). The combined organic layers were washed with a saturated aqueous solution of NaHCO3 (50 mL) and of brine (50 mL). The organic layer was dried over Na2SO4, filtrated and evaporated under reduced pressure. The yellow, oily residue was dried at high vacuum at room temperature to give 6.2 g (100%) of the product as yellow oil. The crude product was purified by flash chromatography over silica gel with ethyl acetate to yield the pure 4-phenyl-butyric acid 2-[(pyridine-3-carbonyl)amino]-ethyl ester 5.6 g (89%) as a light yellow oil. 1H NMR (CDCl3) δ=1.87-1.95 (m, 2H), 2.29-2.34 (m, 2H), 2.58-2.63 (m, 2H), 3.67-3.72 (m, 2H), 4.25-4.29 (m, 2H), 7.11-7.41 (m, 7H), 8.08-8.12 (m, 1H), 8.65-8.67 (q, 1H), 8.99-9.00 (d, 1H). 13C NMR (CDCl3) δ=26.3, 33.4, 35.0, 39.6, 62.9, 123.5, 126.0, 128.4, 128.4, 130.0, 135.2, 141.1, 148.1, 152.1, 165.8, 173.9. MS (ESI) m/z=313.2 (100) [M+H+]. DC (silica gel/ethyl acetate): RF=0.32.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[Li]CCCC.C1C[O:20][CH2:19]C1>CCCCCC>[F:1][C:2]1[C:3]([CH:19]=[O:20])=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(F)cc1OC
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: COc1ccc(F)c(C=O)c1OC
Reaction time: 3 h

Procedure:
To a solution of 4-fluoro-1,2-dimethoxy-benzene (20.0 g, 128.07 mmol) in anhydrous THF (200 mL) under nitrogen at −78° C. was added dropwise a 2.5M solution in hexane of n-BuLi (102.4 mL, 256.14 mmol) for duration 30 min and the reaction mixture was further stirred at the same temperature for 3 h. The reaction mixture was quenched carefully with DMF (100 mL) at −65° C. to −40° C. and left overnight. 2N HCl (300 mL) was added dropwise at −60° C. and the mixture stirred for 30 min. The two layers were separated and the aqueous layer extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. Purification was completed by flash column chromatography (20% EtOAc/hexane). Yield 18.0 g (85%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.39 (s, 1H), 7.09 (dd, J=9.4, 5.1 Hz, 1H), 6.84 (t, J=9.6 Hz, 1H), 3.98 (s, 3H), 3.88 (s, 3H). 19F NMR (376 MHz, CHLOROFORM-d): −126 ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]([CH3:14])[CH3:13])[C:6]2=[O:11].C1C(=O)N([Cl:22])C(=O)C1.O>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:22])=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]([CH3:14])[CH3:13])[C:6]2=[O:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)N1Cc2c(N)cccc2C1=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1Cc2c(N)ccc(Cl)c2C1=O
Yield: 29.7 %

Procedure:
A solution of 2.8 grams (0.015 mole) of 4-amino-2-(1-methylethyl)isoindolin-1-one and 2.0 grams (0.015 mole) of NCS in 80 mL of DMF was stirred at 25° C. for about 18 hours. The reaction mixture was then poured into water, and the mixture was extracted repeatedly with diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel using mixtures of EtOAc and methylene chloride as eluants. The fractions containing product were combined and concentrated under reduced pressure, yielding about 1.0 gram of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C1(=O)[N:5]([C@@H:6]2[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[O:12][C@H:7]2[O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:19])[C:3]2=CC=CC=C12.C(N)CCC>CO>[C:4]([NH:5][C@@H:6]1[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[O:12][C@H:7]1[O:8][CH2:9][CH:10]=[CH2:11])(=[O:19])[CH3:3]
Reactant: C=CCO[C@@H]1O[C@H](CO)[C@@H](O)C[C@H]1N1C(=O)c2ccccc2C1=O
Solvent: CO
Solvent: CCCCN
Product: C=CCO[C@@H]1O[C@H](CO)[C@@H](O)C[C@H]1NC(C)=O
Reaction time: 3 h
Yield: 54 %

Procedure:
A mixture of allyl 2,3-dideoxy-2-phthalimido-β-D-glucopyranoside, Compound 22, (100 mg, 0.30 mmol) and BuNH2 (4 mL) in MeOH (20 mL) was refluxed for 10 hours, then cooled and evaporated. Acetic anhydride (2 mL) was added to a solution of the residue in MeOH (10 mL) at 0°-5° C., and the mixture was stirred for three hours at 0°-5° C. The mixture was concentrated, and the residue was triturated in MeOH with Et2O to give Compound 1i (40 mg, 54 percent).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].Cl.[CH3:12][NH:13][O:14][CH3:15].CN(C)CCCN=C=NCC.N1C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([N:13]([O:14][CH3:15])[CH3:12])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1ccnc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 82.4 %

Procedure:
In a round-bottomed flask, 2.0 g of 2-bromoisonicotinic acid, 1.1 g of N,O-dimethylhydroxylamine hydrochloride, 3.8 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 3.2 ml of pyridine are placed in 50 ml of tetrahydrofuran. The mixture is stirred at ambient temperature for 40 h. The mixture is concentrated, and the residue is taken up in 50 ml of ethyl acetate and 50 ml of water. The organic phase is washed with 50 ml of a 1N solution of sodium hydroxide and 50 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. 2.0 g of compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:12])[CH:11]=1)[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].C(#N)C.O.Cl[C:25]([F:35])([F:34])C(C1C=CC=CC=1)=O>>[F:34][CH:25]([F:35])[O:12][C:10]1[CH:11]=[C:2]([F:1])[CH:3]=[C:4]2[C:9]=1[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(F)cc(O)c2n1
Reactant: O=C(c1ccccc1)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc2cc(F)cc(OC(F)F)c2n1
Temperature: 80 °C

Procedure:
To a mixture of 6-fluoro-2-methylquinolin-8-ol (0.15 g, 0.85 mmol) and potassium carbonate (4.2 g, 30 mmol) in acetonitrile (3.4 mL, 0.85 mmol) and water (3.4 mL, 0.85 mmol) was added 2-chloro-2,2-difluoroacetophenone (0.62 mL, 4.2 mmol). The vessel was sealed and the mixture was heated at 80° C. for 4 hours. The cooled reaction mixture was extracted with diethyl ether (2×30 mL), and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure at ambient temperature The resulting residue was purified by reverse phase chromatography on a C18 column (0-100% acetonitrile/water). Aqueous fractions containing the product were combined and extracted with diethyl ether (2×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure at ambient temperature providing the title compound. Presence of water was noted and the material taken on as is assuming theoretical yield obtained (0.19 g, 100%).
Reaction SMILES: Cl[S:2]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:4])=[O:3].[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([O:20][C:21]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:22]=2[NH2:23])[N:13]=1.N1C=CC=CC=1>ClCCl>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([O:11][CH3:10])[N:13]=[C:14]([O:20][C:21]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:22]=2[NH:23][S:2]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:4])=[O:3])[N:15]=1
Reactant: COc1cc(OC)nc(Oc2cccc(F)c2N)n1
Reactant: COC(=O)CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)Nc1c(F)cccc1Oc1nc(OC)cc(OC)n1
Reaction time: 8 h

Procedure:
Methyl (chlorosulfonyl)acetate (13.0 g) in dichloromethane (20 ml) was aaded dropwise with stirring and cooling to 2-(4,6-dimethoxypyrimidin-2-yloxy)-6-fluoroaniline (20 g) and pyridine (6.3 g) in dichloromethane (120 ml). After stirring for 2 hours, the mixture was allowed to stand at room temperature overnight. Washing with dilute hydrochloric acid and water, dryiny over magnesium sulfate, and running down, gave an oil which was triturated with ether. The resulting off-white solid was separated by filtration to qive 20.4 of the desired product, mp 111°-114° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)=[CH:6][CH:5]=1.[Cl:21][C:22]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:21][C:22]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:23]=1[C:24]([N:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:19])[F:20])=[CH:5][CH:6]=1)[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1)=[O:25]
Reactant: O=C(O)c1csc(Nc2ccc(OC(F)(F)F)cc2)n1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1csc(N(C(=O)c2ccc(F)cc2Cl)c2ccc(OC(F)(F)F)cc2)n1
Temperature: 50 °C
Reaction time: 48 h
Yield: 111.8 %

Procedure:
A mixture of 2.0 g (6.6 mmol) 2-(4-(trifluoromethoxy)phenylamino)-thiazole-4-carboxylic acid, 3.17 g (16.4 mmol) 2-chloro-4-fluorobenzoyl chloride and 0.92 g (6.6 mmol) potassium carbonate in 50 mL THF was stirred at 50° C. for 48 h. After evaporation of the volatiles the residue was partitioned between water and ethyl acetate. Organic phases were pooled, dried with MgSO4 and the solvent was removed in vacuo. Crystallisation from n-heptane/ethyl acetate yielded 3.4 g of the title compound which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:13]([CH3:14])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C@@H:8]([NH2:10])[CH3:9].[NH2:15][C:16]1[N:21]=[C:20](Cl)[C:19]([C:23]#[N:24])=[C:18]([CH3:25])[N:17]=1.CCN(C(C)C)C(C)C>C(#N)C>[NH2:15][C:16]1[N:21]=[C:20]([NH:10][C@H:8]([C:7]2[N:6]=[C:5]3[CH:11]=[CH:12][N:13]([CH3:14])[C:4]3=[CH:3][C:2]=2[Br:1])[CH3:9])[C:19]([C:23]#[N:24])=[C:18]([CH3:25])[N:17]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Reactant: Cc1nc(N)nc(Cl)c1C#N
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2Br)c1C#N
Temperature: 75 °C
Yield: 93.8 %

Procedure:
A microwave vial was charged with (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (2 g, 7.87 mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (1.592 g, 9.44 mmol), acetonitrile (40 mL), and DIPEA (5.50 mL, 31.5 mmol). The reaction mixture was heated to 75° C. for 1 hour in an oil bath and then cooled to room temperature. A precipitate was isolated by vacuum filtration and washed with acetonitrile to give the title compound as an off-white solid (2.85 g, 94%). ESI-MS m/z [M+H]+ calc'd for C16H16BrN7, 386. found 386.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:33])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17]([OH:19])=O)[C:9]2=[O:14])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.O>O1CCCC1>[F:28][CH:27]([F:29])[O:26][C:23]1[CH:24]=[CH:25][C:20]([CH:15]([N:8]2[C:7](=[O:33])[C:6]3[C:10](=[CH:11][CH:12]=[CH:13][C:5]=3[NH:4][C:1](=[O:3])[CH3:2])[C:9]2=[O:14])[CH2:16][C:17]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[O:19])=[CH:21][C:22]=1[O:30][CH2:31][CH3:32]
Reactant: C1COCCN1
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C(CC(=O)N2CCOCC2)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
To a solution of 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (400 mg, 0.86 μmmol) in tetrahydrofurane was added carbonyldiimidazole (160 mg, 1 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added morpholine (0.12 ml, 1.3 mmol). The resulted mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×10 ml), water (10 ml), brine (10 ml) and was dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was purified by HPLC (acetonitrile:water=45:55) to give N-{2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-3-morpholin-4-yl-3-oxo-propyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide as a white solid (200 mg, 44%): mp, 109-111° C.; 1H NMR (CDCl3): 1.44 (t, J=7.5 Hz, 3H, OCH2CH3), 2.26 (s, 3H, CH3CO), 3.02 (dd, J=5, 17.5 Hz, 1H, CHHCO), 3.49-3.68 (m, 8H, morpholine ring), 3.9 (dd, J=7.5, 17.5 Hz, 1H, CHHCO), 4.09 (q, J=7.5 Hz, 2H, OCH2CH3), 5.84 (dd, J=5, 10 Hz, 1H, CHN), 6.54 (t, JH-F=75 Hz, 1H, OCF2H), 7.11-7.16 (m, 3H, Ar), 7.45 (d, J=7.5 Hz, 1H, Ar), 7.63 (t, J=7.5 Hz, 1H, Ar), 8.75 (d, J=7.5 Hz, 1H, Ar), 9.50 (s, 1H, NHCO). 13C NMR (CDCl3): 15.3, 25.6, 35.1, 42.7, 46.6, 51.9, 65.5, 67.2, 67.5, 112.6, 114.4, 115.9, 116.7, 118.6, 120.8, 120.9, 123.5, 125.5, 131.9, 136.6, 138.2, 138.5, 140.6, 151.3, 168.6, 168.7, 169.9, 170.6; Anal. Calcd. for C26H27F2N3O7: C, 58.75; H, 5.12; N, 7.91; Found: C, 58.48; H, 5.09; N, 7.79;
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([C:30]2[O:34][N:33]=[C:32]([CH2:35][CH2:36][OH:37])[N:31]=2)=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:30]3[O:34][N:33]=[C:32]([CH2:35][CH2:36][OH:37])[N:31]=3)=[C:27]([CH3:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Cc1nc(Cl)ccc1-c1nc(CCO)no1
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1-c1nc(CCO)no1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (51 mg, 0.17 mmol) and 2-[5-(6-chloro-2-methylpyridin-3-yl)-1,2,4-oxadiazol-3-yl]ethanol (40 mg, 0.17 mmol) as starting materials.