Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][CH:4]([C:8]([NH:10][CH2:11][C:12]2[C:17]([CH3:18])=[N:16][CH:15]=[CH:14][N:13]=2)=O)[CH2:3]1.N.C(OCC)(=O)C.CO>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CO>[CH3:1][N:2]1[CH2:3][CH:4]([C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:17]([CH3:18])[C:12]3=[CH:11][N:10]=2)[CH2:5][C:6]1=[O:7]
Reactant: Cc1nccnc1CNC(=O)C1CC(=O)N(C)C1
Agent: CS(=O)(=O)O
Agent: N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nccn2c(C3CC(=O)N(C)C3)ncc12
Temperature: 60 °C
Reaction time: 18 h
Yield: 108.8 %

Procedure:
1-Methyl-N-((3-methylpyrazin-2-yl)methyl)-5-oxopyrrolidine-3-carboxamide (330 mg, 1.329 mmol) was dissolved in Eaton's reagent (2 ml) and the reaction mixture was stirred at 60° C. for 18 hour. Then the reaction mixture was poured into an ice-bath and basified with 7N ammonia in methanol (20 ml). The resulting mixture was extrated with chloroform/iso-propanol (9/1) five times. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The residue (280 mg) was stripped with toluene twice and with dichloromethane twice. An additional crop (53 mg) was obtained by extraction of the water layer with chloroform/iso-propanol (9/1) twice and drying and concentrating as described before. In total 333 mg of crude 1-methyl-4-(8-methylimidazo[1,5-a]pyrazin-3-yl)pyrrolidin-2-one was obtained which was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2C(=O)[O:12][N:11]=[C:10]2[C:15]2[C:19]([CH2:20][OH:21])=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+]>CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:15]2[C:19]([CH2:20][OH:21])=[N:18][O:17][N:16]=2)=[N:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=c1onc(-c2nonc2CO)n1-c1ccc(F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
4-(3-Chloro-4-fluorophenyl)-3-[4-(hydroxymethyl)-1,2,5-oxadiazol-3-yl]-1,2,4-oxadiazol-5(4H)-one (20 mg, 0.064 mmol) was dissolved in anhydrous EtOH (0.6 mL) followed by addition of 2 M of sodium hydroxide in water (60 μL). Reaction was stirred at 50° C. for 4 hrs. Consumption of starting material was monitored by TLC. The sample was quenched with acetic acid, diluted with MeOH and purified by preparative LCMS. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash silica column chromatography to yield the desired product (16 mg, 87%). 1H NMR (400 MHz, DMSO-d6) δ: 11.49 (s, 1H), 9.02 (s, 1H), 7.18 (dd, J=9.1, 9.1 Hz, 1H), 6.97 (dd, J=6.6, 2.7 Hz, 1H), 6.69 (m, 1H), 5.68 (t, J=6.2 Hz, 1H) 4.72 (d, J=5.8 Hz, 2H); MF═C10H8ClFN4O3; LCMS calculated for C10H9ClFN4O3 (M+H)+: m/z=287.035.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH:9]([CH3:21])[C:10](=[O:20])[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[CH3:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:26]([C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[CH3:23])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][C:10](=[O:20])[C:9]=1[CH3:21]
Reactant: CC(C(=O)CC(=O)c1ccccc1)C(=O)c1ccccc1Cl
Reactant: Cc1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cc1ccccc1-n1c(-c2ccccc2)cc(=O)c(C)c1-c1ccccc1Cl

Procedure:
In 500 ml of xylene were dissolved 37.7 g (0.012 mole) of 1-(2-chlorophenyl)-2-methyl-5-phenyl-1,3,5-pentanetrione, 38.6 g (0.36 mole) of 2-methylaniline, 22.8 g (0.12 mole) of para-toluenesulfonic acid and 30 g of Molecular Sieves 5A, followed by refluxing the resulting mixture for 8 hours. After cooling, solid matter was filtered off and the organic layer was washed first with 100 ml of 10% hydrochloric acid and then with 100 ml of a 10% aqueous solution of sodium hydroxide. After washing the organic layer further with water, it was dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was subjected to chromatography on a silica gel column (eluent: ethyl acetate). As result, two atrop-isomers of 2-(2-chlorophenyl)-3-methyl-1-(2-methylphenyl)-6-phenyl-4(1H)-pyridinone, namely, Compound 338 and Compound 339 were obtained in yields of 1.2 g and 8.0 g, respectively. Their melting points were 227°-229° C. and 222°-225° C., respectively.
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].[NH2:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=1>CN(C)C=O>[OH:22][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([NH:16][CH:3]=[C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[NH:6][C:5]2=[O:15])=[CH:18][CH:19]=1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Reactant: Nc1ccc(CO)cc1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc2C1=CNc1ccc(CO)cc1
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 89.5 %

Procedure:
To a suspension of 4-Methoxymethylene-4H-isoquinoline-1,3-dione (203 mg, 1.0 mmol) in N,N-dimethylformamide (2.5 mL) is added 4-aminobenzyl alcohol (123.2 mg, 1.0 mmol). The reaction mixture is shaken at 115° C. for 1.5 hours. Upon cooling to ambient temperature, product precipitated out of solution. The product is recovered by filtration, rinsing with diethyl ether, and drying to yield 263.3 mg 4-[(4-Hydroxymethyl-phenylamino)-methylene]-4H-isoquinoline-1,3-dione.
Reaction SMILES: [CH:1]1([NH:9][C:10]2[O:11][CH2:12][C:13]3[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]C1.[CH:21]([N:24]=[C:25]=[O:26])([CH3:23])[CH3:22]>>[CH:1]1([NH:9][C:10]2[O:11][CH2:12][C:13]3[CH:19]=[C:18]([NH:20][C:25]([NH:24][CH:21]([CH3:23])[CH3:22])=[O:26])[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CC(C)N=C=O
Reactant: Nc1ccc2c(c1)COC(NC1CCCCCCC1)=N2
Product: CC(C)NC(=O)Nc1ccc2c(c1)COC(NC1CCCCCC1)=N2
Yield: 19.7 %

Procedure:
Prepared from N2-cyclooctyl-4H-benzo[d][1,3]oxazine-2,6-diamine (210 mg, 0.81 mmol) and isopropyl isocyanate (76 mg, 0.89 mmol) according to the procedure described for Example 16. Obtained the title compound as an off-white foam (55 mg, 20%), MS (ISP) m/e=345.3 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[CH:3]=1.Cl[C:14]([O:16][CH2:17][C:18]#[CH:19])=[O:15]>>[CH2:17]([O:16][C:14]([O:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][C:14]([O:16][CH2:17][C:18]#[CH:19])=[O:15])=[CH:7][CH:8]=2)[CH:3]=1)=[O:15])[C:18]#[CH:19]
Reactant: Oc1ccc2ccc(O)cc2c1
Reactant: C#CCOC(=O)Cl
Product: C#CCOC(=O)Oc1ccc2ccc(OC(=O)OCC#C)cc2c1
Yield: 83.6 %

Procedure:
Analogous to Example 19, 2,7-dihydroxynaphthalene was reacted with propargyl chloroformate to produce the title compound. Yield was 83.6% theory. m.p. 94°-96° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8]O)[CH:7]=1.S(Cl)([Cl:14])=O>ClCCl.CN(C=O)C>[Cl:14][CH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:10][CH3:11]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(F)cc1CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19.0 g (0.12 mol) of (5-fluoro-2-methoxyphenyl)methanol are dissolved in 105 ml of dichloromethane. One drop of DMF is added, and 26.6 ml (0.37 mol) of thionyl chloride are then added slowly. The solution is stirred at RT for 2 hours and evaporated under reduced pressure. The residue is taken up in ethyl acetate, the mixture is cooled and admixed with water and then washed with saturated sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated under reduced pressure.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH3:20])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:50])[C:32]2[CH:37]=[CH:36][C:35]([O:38][CH:39]3[CH2:44][C:43]([CH3:46])([CH3:45])[N:42]([CH3:47])[C:41]([CH3:49])([CH3:48])[CH2:40]3)=[CH:34][N:33]=2)=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:50])[C:32]3[CH:37]=[CH:36][C:35]([O:38][CH:39]4[CH2:44][C:43]([CH3:45])([CH3:46])[N:42]([CH3:47])[C:41]([CH3:49])([CH3:48])[CH2:40]4)=[CH:34][N:33]=3)=[CH:26][CH:25]=2)[N:7]([CH3:20])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1C(C)(C)CC(Oc2ccc(C(=O)Nc3ccc(N)cc3)nc2)CC1(C)C
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1C(C)(C)CC(Oc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4C)cc3)nc2)CC1(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 6 %

Procedure:
A mixture of 3-tert-butyl-1-methyl-1H-pyrazol-5-ylcarbamate from Step 1 of this example (65 mg, 0.24 mmol), N-(4-aminophenyl)-5-(1,2,2,6,6-pentamethylpiperidin-4-yloxy)picolinamide dihydrochloride from Example 49 (90 mg, 0.20 mmol), triethylamine (92 μL, 0.66 mmol), and N,N-dimethylpyridin-4-amine (2 mg, 0.02 mmol) in THF (3 mL) was stirred at rt for 2 d. The solvent was removed under reduced pressure. The crude residue was purified by silica gel flash chromatography, eluting with 9% MeOH/1% NH3 in DCM. The resulting compound was then purified by reverse phase HPLC to afford N-(4-(3-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)ureido)phenyl)-5-(1,2,2,6,6-pentamethylpiperidin-4-yloxy)picolinamide (7 mg, 6% yield). LCMS (ESI) m/z 562 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.76 (br s, 1H), 9.47 (br s, 1H), 8.35-8.34 (d, 1H), 8.11-8.08 (d, 1H), 7.78-7.75 (d, 2H), 7.63-7.59 (d, 1H), 7.47-7.44 (d, 2H), 6.02 (s, 1H), 4.87 (t, 1H), 3.6 (s, 3H), 2.2 (s, 3H), 2.04-1.99 (d, 2H), 1.49-1.42 (t, 2H), 1.21 (s, 9H), 1.13-1.12 (m, 12H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[N:12]4[CH2:20][CH2:19][N:18]=[C:13]4[S:14][C:15]=3[CH:16]=[O:17])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[N:12]4[CH2:20][CH2:19][N:18]=[C:13]4[S:14][C:15]=3[CH2:16][OH:17])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1=C(c2cc3c(Cl)cccc3s2)N2CCN=C2S1
Agent: [BH4-]
Agent: [Na+]
Product: OCC1=C(c2cc3c(Cl)cccc3s2)N2CCN=C2S1

Procedure:
This Example was performed in a similar manner to Example 3. 3-(4-Chlorobenzo[b]thiophen-2-yl)-5,6-dihydroimidazo[2,1-b]-thiazole hydrobromide (1.5 g, see Example 1) was basified to give 3-(4-chlorobenzo[b]thiophen-2-yl)-5,6-dihydroimidazo[2,1-b]thiazole which was brominated to give 2-bromo-3-(4-chlorobenzo[b]thiophen-2-yl)-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide (1.13 g) as a pale yellow solid, m.p. 227-229° C. This was reacted with ethylmagnesium chloride (2.0 M solution in ether; 3.75 ml) in tetrahydrofuran (20 ml) followed by dimethylformamide (0.83 ml) to give 3-(4-chlorobenzo[b]thiophen-2-yl)-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxaldehyde. (0.65 g) as a red-brown solid after flash chromatography. This aldehyde was reduced with sodium borohydride (0.13 g) to give [3-(4-chlorobenzo[b]thiophen-2-yl)-5,6-dihydroimidazo[2,1-b]thiazol-2-yl]methanol (0.22 g) as a yellow solid, m.p. 170-172° C.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17]C(=O)C)[CH2:14][C@H:13]2[CH2:21][C:22]([OH:24])=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC(OCC)=O.[CH3:33][NH2:34].Cl>O1CCCC1.C(OCC)(=O)C.C(O)C.C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([SH:17])[CH2:14][C@H:13]2[CH2:21][C:22]([NH:34][CH3:33])=[O:24])=[O:11])=[CH:25][CH:26]=1)([O-:3])=[O:2]
Reactant: CN
Reactant: CC(=O)S[C@H]1C[C@@H](CC(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CNC(=O)C[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
(2R,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-carboxymethyl-4-acetylthiopyrrolidine (153 mg) was dissolved in 2 ml of dry tetrahydrofuran, and 61 mg of triethylamine was added thereto. Ethyl chloroformate (65 mg) was added thereto at -10° to -15° C. under nitrogen stream, followed by stirring at the same temperature for 30 minutes. A 30% ethanol solution of methylamine (414 mg) was added thereto at -40° C., and stirring was continued at -20° to -30° C. for 1 hour. The reaction mixture was acidified with dilute hydrochloric acid, diluted with ethyl acetate, washed successively with water, a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel thin layer chromatography to obtain (2R,4S)-1-(p-nitrobenzyloxycarbonyl)-2-methylaminocarbonylmethyl-4-mercaptopyrrolidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:32](=[O:33])[N:13]2[CH2:14][CH:15]3[CH2:20][CH2:19][C:18]([NH:21][C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])([C:12]2=[N:11][C:10]=1[C:34]([O:36]CC)=[O:35])[CH2:17][CH2:16]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O[Li].O>CCO>[CH2:1]([O:8][C:9]1[C:32](=[O:33])[N:13]2[CH2:14][CH:15]3[CH2:16][CH2:17][C:18]([NH:21][C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])([C:12]2=[N:11][C:10]=1[C:34]([OH:36])=[O:35])[CH2:19][CH2:20]3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: O=C(NC12CCC(CC1)Cn1c2nc(C(=O)O)c(OCc2ccccc2)c1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a solution of ethyl 3-(benzyloxy)-10-(((benzyloxy)carbonyl)amino)-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate, Intermediate 3 (250 mg, 0.483 mmol) in EtOH (5 mL) was added water (1.250 mL) followed by LiOH—H2O (20.27 mg, 0.483 mmol) and the mixture was stirred at room temp for 16 h. Water (10 mL) was then added and the mixture was extracted with ether (100 mL). The aqueous layer was then acidified with 1N HCl and then extracted with ethyl acetate (2×100 mL), washed with brine, dried (Na2SO4), filtered and concentrated to afford the title compound (180 mg, 76% yield) as a light yellow solid. 1H NMR (500 MHz, CDCl3) δ: 7.51 (d, 2H, J=6.71 Hz), 7.30-7.40 (m, 9H), 5.46 (s, 2H), 5.06 (s, 2H), 4.10-4.15 (m, 2H), 2.47-2.61 (m, 3H), 2.03-2.11 (m, 2H), 1.91-2.01 (m, 2H), 1.63-1.73 (m, 2H). LCMS (M+H)=490.23.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:12]=[C:13]([C:22](O)=[O:23])[CH:14]=[C:15]2[C:19]([CH3:20])=[C:18]([CH3:21])[NH:17][C:16]=12.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[CH3:57][N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1>ClCCl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:12]=[C:13]([C:22]([N:61]2[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]2)=[O:23])[CH:14]=[C:15]2[C:19]([CH3:20])=[C:18]([CH3:21])[NH:17][C:16]=12
Reactant: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(C(=O)O)cc2c1C
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(C(=O)N3CCN(C)CC3)cc2c1C
Yield: 53.1 %

Procedure:
A solution of 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid (450 mg, 1.4 mmol) prepared in Step 1, 1-hydroxybenzotriazole hydrate (284 mg, 2.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (401 mg, 2.1 mmol), diisopropylethylamine (730 μl, 4.2 mmol), and 1-methylpiperazine (234 μl, 2.1 mmol) in dichloromethane (10 ml) was stirred overnight at room temperature and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (dichloromethane/methanol=10/1, v/v) to give 300 mg of the titled compound as a white solid (Yield: 53%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[S:3]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:26])[C:12]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)=[CH:13][O:14]2)=[CH:9][CH:8]=1)(=[O:5])=[O:4].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1>[F:28][C:2]([F:1])([F:27])[S:3]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:26])[C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)=[CH:13][O:14]2)=[CH:9][CH:8]=1)(=[O:5])=[O:4]
Reactant: O=c1c(-c2ccc([N+](=O)[O-])cc2)coc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccc(-c2coc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a suspension of 3-(4-nitrophenyl)-4-oxo-4H-chromen-7-yl trifluoromethanesulfonate (5.0 g, 14.75 mmol) in tetrahydrofuran (20 mL) was added a freshly prepared solution of sodium dithionite (5.13 g in 20 mL). The mixture was stirred at room temperature for 2 hours and then additional sodium dithionite (2.57 g) was added in two portions. The reaction mixture was stirred for 24 hours at room temperature, after which time the reaction was complete. The organic solvent was evaporated under reduced pressure and then water (10 mL) was added to the suspension. The solids in suspension were filtered off and dried under high vacuum. The product was heated with acetonitrile and stirred until room temperature was achieved. The solids were filtered off to provide 3-(4-aminophenyl)-4-oxo-4H-chromen-7-yl trifluoromethanesulfonate (4.1 g), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:43])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[C:40]([F:41])=[CH:39][C:34]([C:35]([O:37]C)=[O:36])=[C:33]([F:42])[CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.[Al](Br)(Br)Br.CSC>C(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@:12]2([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10][C@@H:9]([C:28]([NH:30][C:31]3[C:40]([F:41])=[CH:39][C:34]([C:35]([OH:37])=[O:36])=[C:33]([F:42])[CH:32]=3)=[O:29])[C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:43])=[C:16]([F:22])[CH:17]=1
Reactant: COC(=O)c1cc(F)c(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1F
Agent: Br[Al](Br)Br
Solvent: ClCCl
Solvent: CSC
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cc(F)c(C(=O)O)cc2F)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2,5-difluorobenzoate (75 mg, 0.118 mmol) in methylene chloride (10 ml), AlBr3 (Aldrich, 59 mg, 0.94 mmol) was added followed by dimethyl sulfide (Aldrich, 0.2 ml, 0.63 mmol). The mixture was stirred at rt for 2 hrs. The solvent was removed and the residue was treated with 3 ml of acetonitrile and 10 ml of water. The mixture was then extracted with ethyl acetate. Removal of solvent gave an off white solid. 72 mg. (ES+) m/z Calcd: [(M+H)+]: 622. found: 622.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:31])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19](Cl)=[N:18][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=[O:7].CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][C:43]([NH2:46])=[N:44][CH:45]=2)O1>>[NH2:46][C:43]1[N:44]=[CH:45][C:40]([C:19]2[N:20]=[C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:22]3[S:23][C:15]([CH2:14][N:11]4[CH2:12][CH2:13][N:8]([C:6]([N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:31])=[O:7])[CH2:9][CH2:10]4)=[CH:16][C:17]=3[N:18]=2)=[CH:41][N:42]=1
Reactant: COCCN(C)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: COCCN(C)C(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid (2-methoxy-ethyl)-methyl-amide (Example 27) was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine via General Procedure A. Purification on silica yielded 155. NMR (CDCl3): 2.57-2.60 (m, 4H, 2×CH2), 2.92 (s, 3H, CH3), 3.31-3.33 (m, 4H, 2×CH2), 3.36 (s, 3H, CH3), 3.38-3.41 (m, 4H, 2×CH2), 3.55-3.57 (m, 4H, 2×CH2), 3.86 (s, 2H, CH2), 3.89-3.92 (m, 4H, 2×CH2), 4.04-4.06 (m, 4H, 2×CH2), 5.28 (sbr, 2H, NH2), 7.29 (s, H, ArH), 7.33 (s, H, ArH), 9.29 (s, 2H, 2×ArH). MS: (ESI+): MH+528.44
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.I[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.CC(C)([O-])C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:27][CH:28]=1
Reactant: Ic1ccccc1C1CCOCC1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2C2CCOCC2)cc1
Temperature: 130 °C

Procedure:
A microwave vial was charged N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.120 g, 0.287 μmol), 4-(2-iodophenyl)tetrahydro-2H-pyran (0.124 g, 0.431 μmol), sodium tert-butoxide (0.055 g, 0.575 μmol), tris(dibenzylideneacetone)dipalladium(0) (0.026 g, 0.029 μmol) and xantphos (0.033 g, 0.057 μmol). After purging with N2, toluene (3 mL) was added and the vessel was sealed and heated in the microwave at 130° C. for 30 min. LCMS confirmed coupling product formation. The reaction mixture was concentrated and taken up in DCM, then passed through a 12 g silica gel plug, eluting with 1:1 EtOAC/hex to afford N-(4-methoxybenzyl)-4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as a semi-pure orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.Br[C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[O:27][CH2:26][CH2:25][O:24]2)=[CH:19][N:18]=1>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[O:24]1[CH2:25][CH2:26][O:27][CH:23]1[C:20]1[CH:21]=[CH:22][C:17]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[N:18][CH:19]=1
Reactant: Brc1ccc(C2OCCO2)cn1
Reactant: Clc1ccnc2ccsc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1ccnc2cc(-c3ccc(C4OCCO4)cn3)sc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.7 %

Procedure:
To a solution of 7-chlorothieno[3,2-b]pyridine (14 g, 82.4 mmol) in THF (137 mL) was added, at −78° C., a solution of n-BuLi (34.4 mL, 89.3 mmol, 2.6 M in hexanes) and the reaction mixture was stirred for 10 min. A solution of ZnCl2 (89 mL, 89.3 mmol, 1.0 M in Et2O) was added and the mixture was stirred at RT for 10 min. Pd(PPh3)4 (3.18 g, 2.75 mmol) was added along with a solution of 300 (15.8 g, 68.7 mmol) in THF (50 mL) and the reaction mixture was heated to reflux under an atmosphere of N2 gas for 1 hour. The reaction mixture was then cooled to RT, and partitioned between saturated ammonium hydroxide solution and EtOAc. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated. The resultant material was triturated with EtOAc to afford the title compound 301 (21.4 g, 98% yield) as a beige solid. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.71 (d, J=2.1 Hz, 1H), 8.67 (d, J=5.1 Hz, 1H), 8.49 (s, 1H), 8.36 (d, J=8.1 Hz, 1H), 8.01 (dd, J=8.1, 2.1 Hz, 1H), 7.61 (d, J=5.1 Hz, 1H), 5.91 (s, 1H), 4.16-3.96 (m, 4H).