Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])=[CH:7][C:6]=2[C:5]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[C:4]([F:24])[CH:3]=1.C1C(=O)N([Br:32])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:32][CH2:11][C:8]1[O:9][C:10]2[C:2]([Cl:1])=[CH:3][C:4]([F:24])=[C:5]([C:12]3[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:19])([F:21])[F:20])=[CH:16][CH:17]=3)[C:6]=2[CH:7]=1
Reactant: Cc1cc2c(-c3ccc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1c(C(F)(F)F)ccc(-c2c(F)cc(Cl)c3oc(CBr)cc23)c1=O
Yield: 78.8 %

Procedure:
0.98 g (2.72 mmol) of 3-(7-chloro-5-fluoro-2-methylbenzofuran-4-yl)-1-methyl-6-trifluoromethyl-2-(1H)-pyridone was dissolved in 25 ml of carbon tetrachloride, and 0.51 g (2.86 mmol) of NBS and 0.04 g (0.27 mmol) of 2,2′-azobisisobutyronitrile were added thereto, followed by refluxing for 2 hours. Succinic acid imide was removed by filtration. Then, carbon tetrachloride was distilled off under reduced pressure, and the obtained residue was poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the obtained crude crystals were washed with n-hexane to obtain 0.94 g (yield: 79%) of the desired product. Melting point: 142-144° C. 1H-NMR (300 MHz, CDCl3) δ value: 3.73(3H,s), 4.56(2H,s), 6.66(1H,s), 6.80(1H,d), 7.20(1H,d), 7.55(1H,d)ppm.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(Cl)Cl>O>[NH2:9][C:3]1[NH:4][C:5](=[O:8])[N:6]=[CH:7][C:2]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Nc1nc(=O)[nH]cc1Br
Reactant: C1CCNCC1
Solvent: ClCCl
Solvent: O
Product: Nc1[nH]c(=O)ncc1N1CCCCC1
Yield: 89 %

Procedure:
Method 8 was followed using 1 eq. of 5-bromocytosine and 15 eq. of piperidine (as solvent). The reaction was cooled and added to CH2Cl2 and H2O. The solid was filtered, rinsed with H2O, and dried yielding 6-amino-5-(piperidin-1-yl)pyrimidin-2(1H)-one as a solid (89%). LCMS (m/z): 195.0 (MH+); LC Rt=1.28 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[CH:15]([OH:26])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3]1.C(N(CC)CC)C.S(=O)(=O)=O.[NH+]1C=CC=CC=1>CS(C)=O.O>[CH3:1][C:2]1([CH3:27])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15](=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:3]1
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(C(O)CCCCc2ccccc2)c1
Agent: O=S(=O)=O
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(C2=NC(C)(C)CO2)c(C(=O)CCCCc2ccccc2)c1
Reaction time: 6 h
Yield: 59.6 %

Procedure:
A solution of 1-[2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5-methoxy-phenyl]-5-phenyl-pentan-1-ol (0.62 g, 1.7 mmoles), prepared as described in example 17, in DMSO (10 ml) was added with triethylamine (35 ml) and, after 30 minutes, with pyridinium sulfur trioxide (1.62 g, 10.2 mmoles). After 6 hours, the mixture was diluted with 10 volumes of water and twice extracted with ethyl ether. The organic phases were washed with water, discoloured with charcoal, anhydrified and concentrated. The residue was flash chromatographed (eluent: petrolatum/ethyl acetate 7:3) to give 0.37 g of the title compound (yield: 60%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:30][NH:31][O:32][CH3:33]>CN(C=O)C.C(Cl)Cl>[CH3:33][O:32][N:31]([CH3:30])[C:11](=[O:13])[CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:14]
Reactant: CNOC
Reactant: C[C@H](CC(=O)O)NC(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: ClCCl
Product: CON(C)C(=O)C[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.7 %

Procedure:
To a solution of (R)-3-(tert-butoxycarbonylamino)butanoic acid (4.30 g, 21.16 mmol) in DMF (20 mL) and DCM (20.00 mL) was added EDC (4.46 g, 23.27 mmol) and HOBt (4.21 g, 27.5 mmol). The mixture was stirred at rt for 15 min, then N,O-dimethylhydroxylamine hydrochloride (3.10 g, 31.7 mmol) was added, followed by TEA (5.90 mL, 42.3 mmol) dropwise. The resulting light yellow suspension was stirred at rt for 7 hr. The reaction was quenched with addition of water (100 mL). The mixture was extracted with EtOAc (2×). The combined EtOAc extracts were washed with water (2×), 0.3 M aqueous KHSO4, saturated aqueous NaHCO3 (2×), saturated aqueous NaCl (2×), dried over Na2SO4, filtered and concentrated to give (R)-tert-butyl 4-(methoxy(methyl)amino)-4-oxobutan-2-ylcarbamate (2.48 g, 10.1 mmol, 47.6% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 5.32 (s, 1H), 4.14-3.96 (m, 1H), 3.68 (s, 3H), 3.18 (s, 3H), 2.71 (dd, J=15.6, 4.6 Hz, 1H), 2.61-2.49 (m, 1H), 1.41 (d, J=17.2 Hz, 9H), 1.24 (d, J=6.7 Hz, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:21]C(OCC2C=CC=CC=2)=O)[C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:10]=1[O:32][C:33]([N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:34])C1C=CC=CC=1.C([Cl:47])C1C=CC=CC=1>CO.[C].[Pd]>[Cl-:47].[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH3+:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:10]=1[O:32][C:33]([N:35]1[CH2:36][CH2:37][CH2:38][CH2:39]1)=[O:34]
Reactant: ClCc1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OC(=O)N2CCCC2)c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]([NH3+])Cc1ccc(O)c(OC(=O)N2CCCC2)c1
Product: [Cl-]
Reaction time: 3 h

Procedure:
Pyrrolidine-1-carboxylic acid 2-benzyloxy-5-((S)-2-benzyloxycarbonylamino-2-methoxycarbonyl-ethyl)-phenyl ester (364 mg) was dissolved in methanol (15 ml) containing benzyl chloride (95 mg) and 5% palladium-carbon (50 mg). The mixture was stirred for 3 hours under an atmosphere of hydrogen gas. The catalyst was removed by filtration and washed with methanol. Evaporation of the filtrate gave a gum which was crystallised by trituration with ether. (S)-2-[4-Hydroxy-3-(pyrrolidine-1-carbonyloxy)-phenyl]-1-methoxycarbonyl-ethyl-ammonium chloride was obtained as a white solid, 212 mg; NMR (500 MHz, d6 DMSO) 1.82-1.92 (4H, m), 2.97 (1H, dd J 14, 7), 3.05 (1H, dd J 14, 6), 3.31 (2H, t J 7), 3.49 (2H, t J 7), 3.67 (3H, s), 4.19 (1H, t J ca 6), 6.85-6.88 (3H, m), 8.54 (3H, br s exch D2O), 9.54 (1H, s, exch D2O); HPLC/MS retention time 3.04 min, m/z 309 (MH+).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[CH2:4][C:5](O)=[O:6].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.Cl.Cl.[NH2:35][CH2:36][C:37]1[N:42]=[C:41]([C:43]2[N:44]=[C:45]([N:48]=[C:49]([NH2:51])[NH2:50])[S:46][CH:47]=2)[CH:40]=[CH:39][CH:38]=1>CN(C)C=O.C(N(CC)CC)C>[NH2:50][C:49](=[N:48][C:45]1[S:46][CH:47]=[C:43]([C:41]2[CH:40]=[CH:39][CH:38]=[C:37]([CH2:36][NH:35][C:5](=[O:6])[CH2:4][N:3]([CH3:8])[CH3:2])[N:42]=2)[N:44]=1)[NH2:51]
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CC(=O)NCc1cccc(-c2csc(N=C(N)N)n2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
A mixture of N,N-dimethylglycine hydrochloride (1.5 g), 1-hydroxybenzotriazole hydrate (1.5 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.1 g) in N,N-dimethylformamide (15 ml) was stirred for 1 hour at ambient temperature. The above mixture was added to a mixture of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole trihydrochloride (3.0 g) and triethylamine (3.5 ml) in N,N-dimethylformamide (45 ml) and the mixture was stirred for 2 hours at ambient temperature. The solvent was removed by concentration and the residue was dissolved in a mixture of tetrahydrofuran, ethyl acetate and water. The mixture was adjusted to pH 13.5 With 5N-sodium hydroxide. The separated organic layer was washed with brine and evaporated in vacuo. The residue was triturated with ethyl acetate to give 2-(diaminomethyleneamino)-4-(6-dimethylaminoacetylaminomethylpyridin-2-yl)thiazole (1.96 g).
Reaction SMILES: [C:1]([C@@H:4]([NH:12][S:13]([C:16]1[S:17][C:18]([Cl:21])=[CH:19][CH:20]=1)(=[O:15])=[O:14])[C@H:5]([CH3:11])[CH2:6][C:7]([F:10])([F:9])[F:8])(=[O:3])[CH3:2].[CH3:22][Mg]Br.CCOC(C)=O.CCCCCC>C1COCC1>[Cl:21][C:18]1[S:17][C:16]([S:13]([NH:12][C@H:4]([C:1]([OH:3])([CH3:22])[CH3:2])[C@H:5]([CH3:11])[CH2:6][C:7]([F:10])([F:9])[F:8])(=[O:15])=[O:14])=[CH:20][CH:19]=1
Reactant: CC(=O)[C@@H](NS(=O)(=O)c1ccc(Cl)s1)[C@H](C)CC(F)(F)F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@H](CC(F)(F)F)[C@H](NS(=O)(=O)c1ccc(Cl)s1)C(C)(C)O
Temperature: 25 °C
Reaction time: 19 h
Yield: 46.9 %

Procedure:
A solution of N-[(1S,2R)-1-acetyl-4,4,4-trifluoro-2-methylbutyl]-5-chlorothiophene-2-sulfonamide (prepared as in Example 17, 0.100 g, 0.275 mmol) in THF (5 mL) was stirred under nitrogen at 0° C. Methyl magnesium bromide (3.0 M in ethyl ether, 0.266 mL, 0.824 mmol,) was added dropwise and the resulting solution was stirred for 19 h at 25° C. After this time period, the reaction was complete by TLC (1:2 EtOAc/hexane). The solution was quenched with saturated aqueous NH4Cl (10 mL) and extracted with ether (40 mL). The organic layer washed with brine (20 mL) and then dried over MgSO4 to obtain a crude oil (0.110 g). The crude product was purified by the Biotage Flash™ 40 chromatography system, eluent: 1:4 EtOAc-hexanes, to afford 5-chloro-N-[(1S,2R)-4,4,4-trifluoro-1-(1-hydroxy-1-methylethyl)-2-methylbutyl]thiophene-2-sulfonamide as a white solid (0.049 g, 46.6%). Mass Spectrum (−ESI): 378 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[CH:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:32][CH2:31][CH:27]([C:28]([Cl:30])=[O:29])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[ClH:30].[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:25][CH2:26][CH:27]([C:28]([NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)=[O:17])=[O:29])[CH2:31][CH2:32]2)=[CH:20][CH:19]=1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Br)cc1
Product: Cl
Product: O=C(Nc1ccc(Br)cc1)c1ccccc1NC(=O)C1CCN(c2ccncc2)CC1
Yield: 76.5 %

Procedure:
Using the procedure described in Example 138, N-(4-bromophenyl)-2-aminobenzamide (0.97 mmol) and N-(4-pyridyl)isonipecotoyl chloride (1.9 mmol), purifying with RPHPLC Method A, yielded 383 mg (77%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]2[NH:9][C:10]([CH2:12][CH:13]3[CH2:16][CH:15]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])[CH2:14]3)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:31][Si:32]([CH3:39])([CH3:38])[CH2:33][CH2:34][O:35][CH2:36]Cl>CN(C)C=O>[C:1]([C:5]1[CH:24]=[CH:23][C:8]2[N:9]([CH2:36][O:35][CH2:34][CH2:33][Si:32]([CH3:39])([CH3:38])[CH3:31])[C:10]([CH2:12][CH:13]3[CH2:16][CH:15]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])[CH2:14]3)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)C1CC(Cc2nc3cc(C(C)(C)C)ccc3[nH]2)C1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CC(Cc2nc3cc(C(C)(C)C)ccc3n2COCC[Si](C)(C)C)C1
Reaction time: 1 h
Yield: 53.6 %

Procedure:
To a solution of 3-[(5-tert-butyl-1H-1,3-benzodiazol-2-yl)methyl]-N-methoxy-N-methylcyclobutane-1-carboxamide (80%, 2.02 g, 4.91 mmol) in N,N-dimethylformamide (40 ml) under N2 was added potassium carbonate (1.36 g, 9.81 mmol) and the reaction was stirred for 1 h. 2-(Trimethylsilyl)ethoxymethyl chloride (1.31 ml, 7.36 mmol) was added slowly, and stirring maintained for 20 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was taken up in EtOAc (50 ml) and washed with water (3×50 ml), then brine (50 ml) before being dried (MgSO4) and concentrated. The crude material was purified by silica flash column chromatography, eluting with 50-100% EtOAc in heptane to afford the title compound (1.21 g, 54%) as a colourless gum: MS (ESI+) for C25H41N3O3Si m/z 461.0 [M+H]+; LC purity 97% (UV), 100% (ELS), (ret. time, 1.98 min); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.58-7.89 (m, 1 H), 7.33 (s, 2 H), 5.39-5.53 (m, 2 H), 3.65 (s, 3 H), 3.49-3.58 (m, 2 H), 3.41 (br. s., 1 H), 3.10-3.23 (m, 3 H), 3.03 (s, 3 H), 2.32-2.63 (m, 2 H), 2.00-2.18 (m, 2 H), 1.32-1.45 (m, 9 H), 0.91 (td, J=8.1, 4.9 Hz, 2 H), −0.13-0.07 (m, 9 H).
Reaction SMILES: C([C:4]1[CH:5]=[CH:6][C:7]2[CH:11]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:9][C:8]=2[CH:16]=1)(=O)C.[N-:17]=[N+]=[N-].[Na+].[CH3:21][C:22]([O-:24])=O.[Na+]>C(O)(=O)C.OS(O)(=O)=O>[C:22]([NH:17][C:4]1[CH:5]=[CH:6][C:7]2[CH:11]=[C:10]([S:12](=[O:13])(=[O:14])[NH2:15])[S:9][C:8]=2[CH:16]=1)(=[O:24])[CH3:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)c1ccc2cc(S(N)(=O)=O)sc2c1
Reactant: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2cc(S(N)(=O)=O)sc2c1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A solution of 6-acetylbenzo[b]thiophene-2-sulfonamide (5.1 g, 0.02 mole) in glacial acetic acid (50 ml) and concentrated H2SO4 (20 ml) was stirred and heated to 65° C. Sodium azide (5.0 g, 0.077 mole) was added in portions over a 1 hour period. After heating the mixture at 80° C. for another 3 hours, it was poured into a stirred, saturated NaOAc solution (500 ml) cooled in an ice bath. The resulting mixture was refrigerated overnight. The solid was collected, resuspended in water (300 ml), and recollected to obtain 5.25 g (97%) of crude product, m.p. 214°-217° C. Recrystallizations from CH3OH with charcoal decolorization and from CH3CN afforded 1.5 g of 6-acetamido-2-sulfamoylbenzo[b]thiophene, m.p. 231°-232.5° C.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH:5]([NH:19][CH:20]=[O:21])[CH2:6][CH2:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=O.[H-].[Na+].CI.[CH2:26]1COCC1.O>C1COCC1>[CH3:1][O:3][CH2:4][CH:5]([N:19]([CH3:26])[CH:20]=[O:21])[CH2:6][CH2:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: C1CCOC1
Reactant: O=CNC(CCOc1cccc2ccccc12)COC=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCC(CCOc1cccc2ccccc12)N(C)C=O
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A solution of 2-(formylamino)-4-(1-naphthyloxy)-1-butanol formate, described in Example 3, in THF (30 ml) is added dropwise to a suspension of 51% sodium hydride (600 mg) in THF (30 ml). The mixture is heated at 40° C for 11/2 hours and then cooled to room temperature. A solution of methyl iodide (2.4 g) in THF (10 ml) is added and the mixture stirred at room temperature for 18 hours. Excess sodium hydride is decomposed by the addition of THF/water (9:1). The mixture is filtered through diatomaceous earth (Celite). The filtrate is dried and evaporated to dryness. The oily residue is subjected to chromatography on silica gel. Elution with methanol-chloroform (1:30) gives the title compound, nmr (CDCl3)δ2.05 (m, 2H), 2.85 (s, 3H), 3.35 (s, 3H), 3.6 (m, 1H), 4.15 (m, 4H), 6.75 - 8.35 (7H), 8.15 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([F:14])[CH:3]=1.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([C:24]([OH:26])=O)=[N:16]1.[CH:27]1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C.Cl>[Cl:8][C:7]1[C:2]([NH:1][C:24]([C:17]2[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:15][N:16]=2)=[O:26])=[CH:3][C:4]([F:14])=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:27])=[O:11])[CH:6]=1
Reactant: O=C(O)c1nsc2ccccc12
Reactant: COC(=O)Cc1cc(Cl)c(N)cc1F
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2nsc3ccccc23)cc1F
Temperature: 80 °C
Reaction time: 10 h

Procedure:
Methyl 4-amino-5-chloro-2-fluorophenylacetate (753 mg, 3.25 mmol), benzo(d)isothiazole-3-carboxylic acid (583 mg, 3.25 mmol), HOBt (834 mg, 6.18 mmol), EDC HCl (934 mg, 4.88 mmol) and DMAP (catalytic amount) were dissolved in DMF (16 ml). The resulting solution was stirred for 10 hours at 80° C. After cooling, the reaction mixture was poured in 1M HCl, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (middle pressure, n-hexane/ethyl acetate 9:1, 15 ml/min, φ 50×300 mm) to give ethyl (5-chloro-2-fluoro-4-((3-benzo(d)isothiazolylcarbonyl)amino)phenyl)acetate. The resulting ester was dissolved in THF/methanol (4 ml, 3:1), and to the resulting solution was added 1M NaOH (1 ml). The mixture was stirred for 18 hours at room temperature. The solvent was distilled off under reduced pressure, and the residue was poured in 1M HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (5-chloro-2-fluoro-4-((3-benzo(d)isothiazolylcarbonyl)amino)phenyl)acetic acid (354 mg, 30%) as a colorless solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:16][C:15]([CH3:18])([CH3:17])[C:14](=[O:19])[N:13]([CH3:20])[C:12]3[C:7]2=[N:8][C:9]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=2[O:31][CH3:32])=[N:10][CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:33]1([CH:38]2[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40][CH2:39]2)[CH2:37][CH2:36][CH2:35][CH2:34]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([N:6]2[CH2:16][C:15]([CH3:17])([CH3:18])[C:14](=[O:19])[N:13]([CH3:20])[C:12]3[C:7]2=[N:8][C:9]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH:44][CH:41]4[CH2:40][CH2:39][CH:38]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[CH2:43][CH2:42]4)=[O:28])=[CH:24][C:23]=2[O:31][CH3:32])=[N:10][CH:11]=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NC1CCC(N2CCCC2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCC(N3CCCC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C

Procedure:
To a solution of 4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-3-methoxy-benzoic acid (Intermediate 236; 83 mg, 0.19 mmol) in DMF (3 mL) was added a solution of 4-pyrrolidin-1-ylcyclohexan-1-amine (Intermediate 237; 78 mg, 0.46 mmol). DIPEA (100 uL, 0.57 mmol) was added, followed by HATU (107 mg, 0.28 mmol). The resultant mixture was stirred at ambient temperature for 2 hours. The reaction mixture was evaporated to a gum, which was partitioned between DCM (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The organic phase was separated by gravity elution through a PTFE filter cup and evaporated to an amber gum which was purified by base modified reverse phase preparative HPLC to yield the title compound as an off white solid (34 mg, 30%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([CH3:11])[C:5]([CH3:12])=[C:4]([CH3:13])[C:3]=1[CH3:14].[CH3:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([CH3:25])[C:23]=1[OH:24])[CH:19]=O>>[CH3:11][C:6]1[C:5]([CH3:12])=[C:4]([CH3:13])[C:3]([CH3:14])=[C:2]([CH3:1])[C:7]=1[C:8](=[O:10])[CH:9]=[CH:19][C:18]1[CH:21]=[C:22]([CH3:25])[C:23]([OH:24])=[C:16]([CH3:15])[CH:17]=1
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: CC(=O)c1c(C)c(C)c(C)c(C)c1C
Product: Cc1cc(C=CC(=O)c2c(C)c(C)c(C)c(C)c2C)cc(C)c1O

Procedure:
This compound was synthesized from pentamethylacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described earlier.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26]>>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:3][C:2]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[CH:25]=[O:26])=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1
Reactant: CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: O=Cc1cccc(B(O)O)c1
Product: CN1CCN(Cc2cc3nc(-c4cccc(C=O)c4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 3-formyl phenyl boronic acid in General Procedure A. Purification on silica yielded 3-[6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-benzaldehyde. This was then treated with methylmagnesium bromide in THF to give the desired compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][C:12]([F:15])([F:14])[CH2:11][N:10]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C1C[O:26][CH2:25]C1.N12CCCN=C1CCCCC2.[CH:39]([NH2:42])([CH3:41])[CH3:40]>CCOC(C)=O.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[F:14][C:12]1([F:15])[CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[C:25](=[O:26])[NH:42][CH:39]([CH3:41])[CH3:40])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@@H]1c1cc(F)ccc1Br
Reactant: CC(C)N
Reactant: C1CCOC1
Agent: [Mo]
Agent: [C-]#[O+]
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)NC(=O)c1ccc(F)cc1[C@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Temperature: 150 °C

Procedure:
To a nitrogen-flushed microwave vial was added (R)-tert-butyl 2-(2-bromo-5-fluorophenyl)-4,4-difluoro-pyrrolidine-1-carboxylate (I-49) (304 mg, 0.80 mmol), molybdenum hexacarbonyl (211 mg, 0.80 mmol), trans-di-μ-acetatobis[2-di-o-tolylphosphino)benzyl]-dipalladium(II) (Palladacycle) (30 mg, 4 mol %), THF (1.6 mL), 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) (239 μL, 1.6 mmol) and isopropylamine (171 μL, 2.0 mmol). The vial was capped and then heated at 150° C. for 30 minutes in a Biotage microwave reactor. The cooled reaction mixture was diluted with EtOAc and filtered through Celite. The combined filtrates were washed successively with saturated aqueous NH4Cl, water, 2% citric acid and brine, then dried over sodium sulfate and concentrated. The residue was purified by silica chromatography with EtOAc/Hex (5-30%) as eluent, to yield (R)-tert-butyl 4,4-difluoro-2-(5-fluoro-2-(isopropylcarbamoyl)phenyl)pyrrolidine-1-carboxylate (I-50) as an off-white foam. 1H NMR (400 MHz, CDCl3) δ 7.44 (bs, 1 H), 7.11 (bs, 1 H), 7.00 (td, J=2.5, 8.2 Hz, 1 H), 5.31 (t, J=7.7 Hz, 1 H), 4.23 (bs, 1 H), 4.09-3.87 (m, 2 H), 2.91 (bs, 1 H), 2.41 (bs, 1 H), 1.45 (bs, 6 H), 1.26 (d, J=6.5 Hz, 6 H), 1.19 (bs, 3 H). MS m/z 331.1 (M−55)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([C:19]([OH:21])=O)[CH:13]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[C:14]([C:19](=[O:21])[NH:22][C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:27][CH:28]=3)[CH:15]=[CH:16][C:17]=2[Cl:18])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cc(C(=O)O)ccc2Cl)cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cc(C(=O)Nc3ccc(N4CCOCC4)cc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
A mixture of 6-chloro-biphenyl-3,4′-dicarboxylic acid 4′-ethyl ester (800 mg), N-(4-aminophenyl)morpholine (469 mg), EDAC (504 mg), HOBT (355 mg) and N-methylmorpholine (578 μl) in DMF (10 ml) was stirred at room temperature. After 1 h, water (80 ml) was added and the resulting suspension filtered. The residue was then purified by chromatography. Elution with 1:1 ethyl acetate:petrol gave a yellow crystalline solid (437 mg).