Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:17]([OH:19])=[O:18])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].O=S(Cl)Cl.[CH3:31][CH2:32]O>>[NH2:1][C@H:2]([CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])[C:17]([O:19][CH2:31][CH3:32])=[O:18]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H](N)CCCNC(=O)OCc1ccccc1
Temperature: -10 °C
Yield: 55 %

Procedure:
Boc-Orn(Z)—OH (1 equivalent, 0.4 g, 1.1 mmol) was dissolved in EtOH (4 mL). The reaction mixture was cooled at −10° C., and SOCl2 (1.5 equivalent, 119 μl, 1.65 mmol) was added dropwise. The mixture was allowed to warm to room temperature, then heated at 40° C. for 20 h (TLC control). The reaction mixture was concentrated and the crude was purified by flash chromatography (CH2Cl2/MeOH) to afford the compound 188 (178 mg, 55%) as a white solid Rf=0.23 (CH2Cl2/MeOH 90/10). 1H NMR (300 MHz, CDCl3): δ 7.37-7.27 (m, 5H), 5.54 (broad s, 1H), 5.05 (s, 2H), 4.17 (q, J=6.9 Hz, 2H), 3.95 (broad s, 1H), 3.30-3.13 (m, 2H), 2.10-1.85 (m, 2H), 1.85-1.55 (m, 2H), 1.22 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[CH3:2].ClC1C=C(C=CC=1)C(O)=O.C(NCC)C.[CH3:30][Si:31](Cl)([CH3:33])[CH3:32]>>[Cl:11][C:7]1[C:6]([Si:31]([CH3:33])([CH3:32])[CH3:30])=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([N:3]([CH2:1][CH3:2])[CH2:13][CH3:14])=[O:12]
Reactant: CCN(CC)C(=O)c1cccc(Cl)c1
Reactant: C[Si](C)(C)Cl
Agent: O=C(O)c1cccc(Cl)c1
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cccc(Cl)c1[Si](C)(C)C
Yield: 94.4 %

Procedure:
N,N-diethyl-3-chlorobenzamide (10.45 g, 50 mmol) (prepared from 3-chlorobenzoic acid and diethylamine using the procedures described above) was reacted with TMSCl (16.30 g, 150 mmol) using General Method A to afford 13.4 g of the title compound as an orange oil in 95% yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]Br.C1(=O)[NH:17][C:16](=O)[C:15]2=[CH:19][CH:20]=[CH:21]C=C12.[K].[I-].[K+].[NH:27]1CCCCC1>CC(C)=O>[N:17]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:27])[CH2:16][CH2:15][CH2:19][CH2:20][CH2:21]1
Reactant: C1CCNCC1
Reactant: BrCCCCCCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CC(C)=O
Product: NCCCCCCCCCCN1CCCCC1

Procedure:
The synthesis was performed according to the procedure described in example 157 using reagents 1,10-dibromodecane (30 mmol), potassium phthalimide (15 mmol), and catalytic amounts of potassium iodide in the first step. The product (12.5 mmol), piperidine (50 mmol) and catalytic amounts of potassium iodide were refluxed in acetone for 12 hours. Solvent and piperidine were evaporated. The residue was treated with hydrochloric acid (2N), with potassium carbonate solution and then extracted with methylene chloride. The solvent was removed under reduced pressure, and the residue was refluxed in hydrochloric acid (6N) for 12 hours. The solution was neutralized with potassium carbonate solution and extracted with methylene chloride. The organic layer was evaporated, and the final product purified by flash chromatography (eluent: methylene chloride/triethylamine/methanol (90/10/2)). The solvent was removed under reduced pressure. The residue was crystallized with oxalic acid from diethyl ether/ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[C:11]([NH:13][C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH3:15])=[O:12].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.C1COCC1>[CH3:33][S:34]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[C:11]([NH:13][C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH3:15])=[O:12])(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(NC(=O)c1cccc(-c2ccncc2N)c1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(NC(=O)c1cccc(-c2ccncc2NS(C)(=O)=O)c1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution containing 3-(3-aminopyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide (1.7 g, 5.1 mmol), triethylamine (5.2 g, 51.3 mmol), and dichloromethane (85 mL) was added methanesulfonylchloride (0.90 mL, 11.3 mmol) in dichloromethane (75 mL) dropwise over 3 min. The solution was maintained at room temperature for 1 h and concentrated to remove all solvent. The residue thus obtained was dissolved in THF (51 mL) and tetrabutylammoniumfluoride (24 mL, 1.0 M in THF) was added in a steady stream via syringe. The solution was maintained at 60° C. for 18 h, concentrated and dissolved in ethyl acetate (75 mL). The solution was washed with water (5×50 mL), washed with brine (50 mL), dried over MgSO4, filtered and concentrated. Purification on silica gel (0-8% methanol/dichloromethane, 60 min gradient) afforded 3-(3-(methylsulfonamido)pyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide as a pale yellow foam. 1H NMR (500 MHz, DMSO-D6) δ ppm 9.42 (s, 1H), 8.64 (s, 1H), 8.56 (d, J=4.88 Hz, 1H), 8.45 (s, 1H), 8.03 (s, 1H), 7.90 (d, J=7.63 Hz, 1H), 7.71 (d, J=7.63 Hz, 1H), 7.58 (t, J=7.78 Hz, 1H), 7.49 (d, J=4.88 Hz, 1H), 7.40 (d, J=7.93 Hz, 2H), 7.29 (t, J=7.63 Hz, 2H), 7.17 (t, J=7.17 Hz, 1H), 2.85 (s, 3H), 1.69 (s, 6H). LCMS: retention time: 1.277 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters-Sunfire, 5u, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 410 (MH+).
Reaction SMILES: [Li]CCCC.[CH2:6]([O:9][CH2:10][C:11]([O:13]CC)=O)[CH:7]=[CH2:8].I[CH2:17][Cl:18].CC(O)=O>C1COCC1.CCOCC>[CH2:6]([O:9][CH2:10][C:11]([CH2:17][Cl:18])=[O:13])[CH:7]=[CH2:8]
Reactant: C=CCOCC(=O)OCC
Reactant: ClCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: C=CCOCC(=O)CCl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of iPr2Net (3.1 eq) in THF at −78° C. was added dropwise BuLi (1.4 M. in hexanes, 3.1 eq). The resulting mixture was stirred at 0° C. for 15 min, cooled again to −78° C. and added via cannula to a solution of ethyl (allyloxy)acetate from Step 1(1 eq) and iodochloromethane (2.5 eq) in Et2O at −78° C. After stirring 30 min at −78° C., a solution of AcOH (25 eq.) in THF was added dropwise and the resulting mixture was stirred at RT for 15 min and partitioned between Et2O and brine. The organic layer was washed with sat. aq. NaHCO3, brine, dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by SiO2 gel chromatography (hexane/Et2O=9/1) to give the title compound as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 5.90 (m, 1H), 5.35-5.25 (m, 2H), 4.30 (s, 2H), 4.24 (s, 2H), 4.07 (d, J 5.5, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)([CH2:14]OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=[CH:29][N:28]=[N:27]1.[Na].[CH3:32][N:33](C)C=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)([CH2:14][N:28]2[CH:29]=[N:33][CH:32]=[N:27]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1c[nH]nn1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)(C2CCCCC2)CC1
Agent: [Na]
Product: CC(C)(C)OC(=O)N1CCC(Cn2cncn2)(C2CCCCC2)CC1
Temperature: 100 °C
Yield: 79.7 %

Procedure:
To a solution of 4-cyclohexyl-4-methansulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester (39 g, 103.8 mmol) in N,N-dimethylformamide (200 mL) is added sodium triazole (38 g, 415.2 mmol). The resulting solution is heated to 100° C. for 24 hours then cooled to room temperature. The solvent is removed under reduce pressure and the crude product purified over silica (80:20 EtOAc:hexane) to afford 28.7 g (79.7% yield) of the desired compound as a colorless solid. 1H NMR (CD3OD) δ 0.95–1.90 (m, 15H), 1.46 (s, 9H), 3.45–3.55 (m, 4H), 4.34 (s, 2H), 7.99 (s, 1H), 8.48 (s, 1H). MS (ESI) m/z 349, (M+H+), 371(M+Na+)
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11]/[CH:12]=[C:13]2/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[S:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([N:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[CH:23][C:22]/2=3)[CH2:6][CH2:5]1.C(Cl)Cl>O>[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11]/[CH:12]=[C:13]2\[C:14]3[C:19]([S:20][C:21]4[CH:26]=[CH:25][C:24]([S:27]([N:30]([CH3:31])[CH3:32])(=[O:28])=[O:29])=[CH:23][C:22]\2=4)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:6][CH2:5]1
Reactant: CN1CCN(CC/C=C2/c3ccccc3Sc3ccc(S(=O)(=O)N(C)C)cc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CN1CCN(CC/C=C2\c3ccccc3Sc3ccc(S(=O)(=O)N(C)C)cc32)CC1
Temperature: 25 °C
Yield: 100 %

Procedure:
5N aqueous sodium hydroxide was added to a suspension of thiothixene.2H3PO4 (63.96 g., 100 mmoles, ca. 85% trans/ 15% cis) in water (750 ml.)/methylene chloride (750 ml.) until the aqueous phase was strongly basic. The phases were separated and the aqueous phase extracted with an additional 200 ml. portion of methylene chloride. The combined methylene chloride extract was dried (Na2SO4), filtered and evaporated in vacuo to a light brown oil (ca. 45 g., ca. 100% yield, ca. 85% trans/15% cis). The oil was dissolved in warm acetonitrile (100 ml.) and the solution cooled to room temperature. Some solids, probably trans-thiothixene, formed upon cooling. Potassium t-butoxide (1.1 g., 9.8 mmoles) was added and the mixture stirred overnight at room temperature. Analysis of the reaction mixture, which contained solids, showed a ca. 85% cis/ 15% trans ratio of isomers. Water (10 ml.) was then added and the reaction mixture stirred briefly at room temperature. The tan cis-thiothixene solids were then filtered, washed with acetonitrile, and dried (35.0 g., 78.9% yield, 5% trans, m.p. 143°-145° C.).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:7]=2)[CH2:3][CH2:2]1.Br[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30](=[O:34])[N:29]([CH2:35][CH:36]1[CH2:38][CH2:37]1)[CH:28]=[C:27]2[CH:39]=[O:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[C:30](=[O:34])[N:29]([CH2:35][CH:36]3[CH2:38][CH2:37]3)[CH:28]=[C:27]4[CH:39]=[O:40])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=Cc1cn(CC2CC2)c(=O)c2ccc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Temperature: 80 °C

Procedure:
A mixture of N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.47 g) [prepared as described in US2005020590], the product of step ii) (0.4 g), tetrakis(triphenylphosphine)palladium(0) (0.15 g) and potassium carbonate (0.54 g) in DMF (10 mL) were heated at 80° C. for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organics were dried over magnesium sulphate and evaporated. The residue was purified (SiO2, eluting with 1:1 ethyl acetate: isohexane) to give the sub-title compound (0.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[CH2:11]O.[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BrH:32]>C(O)(=O)C.C1C=CC=CC=1>[Br-:32].[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[CH2:11][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(Cl)c(CO)c(Cl)c1
Reactant: Br
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COc1cc(Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1
Product: [Br-]
Yield: 100 %

Procedure:
A solution of (2,6-dichloro-4-methoxyphenyl)methanol (3.00 g, 14.5 mmol) in 30% HBr in acetic acid (45 mL) was stirred at 20° C. for 3 h, then poured onto ice-water (120 mL) and extracted with pentane (6×100 mL). The extracts were washed with water (3×200 mL), backextracting with pentane (100 mL). Removal of the solvent gave the crude bromide as white crystals, which was immediately redissolved in benzene (80 mL) and treated with triphenylphosphine (5.70 g, 21.7 mmol), stirring at reflux for 15 h. After cooling, the precipitate was collected by filtration, washing thoroughly with dry benzene, then pentane, and dried under vacuum at 50° C. to give the phosphonium salt (521) as a white solid (7.75 g, 100%), mp (CH2Cl2/benzene) 188–190° C. 1H NMR (CDC3) δ 7.83–7.60 (m, 15H), 6.74 (s, 2H), 5.37 (d, J=13.5 Hz, 2H), 3.76 (s, 3H). Found: C, 58.40; H, 4.35. C26H22BrCl2OP requires C, 58.67; H, 4.17.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[NH:8][C:7]2=[O:17].C([O-])([O-])=O.[K+].[K+].[CH3:24][C@@H:25]1[C:29]2[NH:30][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:32][C:28]=2[C:27](=[O:42])[NH:26]1.O1CCOCC1>C(Cl)Cl.O>[C:13]([NH:12][C:9]1[NH:8][C:7](=[O:17])[C:6]2[C:11](=[C:2]([C:31]3[NH:30][C:29]4[C@@H:25]([CH3:24])[NH:26][C:27](=[O:42])[C:28]=4[CH:32]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)[nH]c(NC(C)(C)C)nc34)[nH]c21
Yield: 8.1 %

Procedure:
Argon was bubbled into a mixture of 8-bromo-2-(tert-butylamino)quinazolin-4(3H)-one (408a, 62 mg, 0.21 mmol), K2CO3 (0.116 g, 0.84 mmol), dichlorobis(p-dimethylamino-phenylditbutylphosphine)palladium (ii) (Aldrich; 0.030 g, 0.042 mmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (706; 0.110 g, 0.419 mmol) and 2 mL dioxane and 0.4 mL water for 1 min. The reaction was sealed and placed in a 100° C. oil bath for 30 min. The reaction was cooled and partitioned between sat'd aq. NH4Cl and DCM. The aqueous layer was extracted with 5% IPA/CHCl3 three times and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. This material was dissolved in DMSO, filtered, and purified by RPHPLC, Phenomenex Gemini 150×30 mm C18 column, 10-70% ACN/H2O with 0.1% TFA; product-containing fractions were treated with saturated aqueous NaHCO3 and DCM. The aqueous layer was extracted 3×DCM and combined organics dried over Na2SO4, filtered, and concentrated in vacuo to give 21 mg as a tan solid. The material was sonicated in 0.5 mL DCM for 2 min, then filtered, rinsing 2×DCM. The solid was collected and dried in vacuo to give (R)-2-(tert-butylamino)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (6 mg, 0.017 mmol, 8% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.21 (1H, br. s.), 10.63 (1H, s), 7.95 (1H, dd, J=7.6, 1.6 Hz), 7.82 (1H, dd, J=7.8, 1.6 Hz), 7.62 (1H, s), 7.16 (1H, t, J=7.7 Hz), 6.79 (1H, d, J=1.4 Hz), 6.30 (1H, s), 4.54 (1H, d, J=6.7 Hz), 1.47 (9H, s), 1.36 (3H, d, J=6.7 Hz). m/z (ESI, +ve ion) 352.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C@:9]([CH3:27])([C:23]([F:26])([F:25])[F:24])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:29]([C:31]1[CH:32]=[C:33]([CH3:40])[C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1)#[N:30].CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C@:9]([CH3:27])([C:23]([F:26])([F:25])[F:24])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:37]([C:34]3[C:33]([CH3:40])=[CH:32][C:31]([C:29]#[N:30])=[CH:36][N:35]=3)=[O:38])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C#N)cnc1C(=O)O
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CO[C@@]1(C)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)CO[C@@](C)(C(F)(F)F)C(NC(=O)OC(C)(C)C)=N2)c1
Reaction time: 16 h

Procedure:
To a solution of [(2R,5R)-5-(5-amino-2-fluoro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (82 mg, 0.20 mmol) in DMF (2 ml) was added 5-cyano-3-methyl-pyridine-2-carboxylic acid (42 mg, 0.26 mmol), EDC.HCl (51 mg, 0.26 mmol), HOAt (31 mg, 0.22 mmol) and DIPEA (0.09 ml, 0.52 mmol) and the reaction mixture was kept at 25° C. for 16 h. The mixture was concentrated, the residue dissolved in EtOAc and washed with saturated NaHCO3 solution and brine, dried over MgSO4, filtered and purified by chromatography on silica gel (hexane-EtOAc 20:1 to 1:1) to provide the title compound as a light yellow foam: TLC (hexane-EtOAc 1:1): Rf=0.81; UPLC RtH5=1.437 min; ESIMS: 550 [(M+H)+]; 1H NMR (360 MHz, CDCl3): δ 10.96 (br s, 1H), 9.95 (br s, 1H), 8.63 (s, 2H), 7.88 (m, 1H), 7.71 (m, 1H), 7.54 (dd, 1H), 7.08 (dd, 1H), 4.34 (d, 1H), 4.02 (d, 1H), 2.77 (s, 3H), 1.63 (s, 3H), 1.47 (m, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:32][NH:33][O:34][CH3:35].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:33]([O:34][CH3:35])[CH3:32])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Reactant: CNOC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN(C)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.7 %

Procedure:
A mixture of 1 g of the 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide (2.04 mmol, 1 equiv.), 1.2 g of N,O-Dimethylhydroxylamine hydrochloride (12.25 mmol, 9 equiv.), and 1.5 g of sodium bicarbonate (18.38 mmol, 9 equiv.) in DMF (10 ml) was stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction mixture, and the crude product was filtered. After flash chromatography (ethyl acetate:methanol:triethylamine 40:4:1), 0.486 g of the title compound was isolated (50.7% yield); mp 210-217° C.
Reaction SMILES: [O:1]=[C:2]1[NH:15][CH:14]=[C:5]2[S:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[NH:9][C:4]2=[C:3]1[C:16]#[N:17].S(=O)(=O)(O)[OH:19].[N+:23]([O-])([OH:25])=[O:24]>O>[N+:23]([C:12]1[CH:11]=[CH:10][C:8]2[NH:9][C:4]3[C:5](=[CH:14][NH:15][C:2](=[O:1])[C:3]=3[C:16]#[N:17])[S:6](=[O:19])[C:7]=2[CH:13]=1)([O-:25])=[O:24]
Reactant: N#Cc1c2c(c[nH]c1=O)Sc1ccccc1N2
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])O
Solvent: O
Product: N#Cc1c2c(c[nH]c1=O)S(=O)c1cc([N+](=O)[O-])ccc1N2

Procedure:
To a solution of 5 parts of 2,3-dihydro-3-oxo-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitrile in 90 parts of concentrated sulfuric acid at 0° is slowly added, with stirring, 7 parts of concentrated nitric acid. The resultant mixture is stirred at room temperature for 1 hour, whereupon 2 volumes of water is slowly stirred in. The light yellow precipitate which forms is filtered out and recrystallized from aqueous N,N-dimethylformamide to give needles of 2,3-dihydro-8-nitro-3-oxo-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitrile 10-oxide solvated 1:1 with N,N-dimethylformamide which melts above 310°. The solvent of crystallization can be removed by prolonged heating at around 200° in vacuo.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH3:44])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([N:35]3[C:39]4=[N:40][CH:41]=[CH:42][CH:43]=[C:38]4[CH:37]=[CH:36]3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:45](OC1C(C(O)=O)=NC(CC2(N3C4=NC=CC=C4C=C3)CCCC2)=NC=1O)[C:46]1[CH:51]=CC=CC=1.[Si](OCCNCC1CC1)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH2:44][CH:51]1[CH2:46][CH2:45]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([N:35]3[C:39]4=[N:40][CH:41]=[CH:42][CH:43]=[C:38]4[CH:37]=[CH:36]3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Reactant: O=C(O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)(C)[Si](C)(C)OCCNCC1CC1
Product: CC(C)(C)[Si](C)(C)OCCN(CC1CC1)C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
5-Benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropylmethyl-amide (413) was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (405) from 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (404) (200 mg, 0.45 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropylmethyl-amine (134 mg, 0.58 mmol) (8i) to get an off-white sticky solid (180 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:28])([CH3:27])[C:9]([NH:11][NH:12][C:13]([C:15]2[C:16]([CH3:26])=[N:17][C:18]3[C:23]([C:24]=2[CH3:25])=[CH:22][CH:21]=[CH:20][CH:19]=3)=O)=[O:10])=[CH:4][CH:3]=1.COC(CC[N+](S(=O)(=O)N)(CC)CC)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9]2[O:10][C:13]([C:15]3[C:16]([CH3:26])=[N:17][C:18]4[C:23]([C:24]=3[CH3:25])=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:12][N:11]=2)([CH3:27])[CH3:28])=[CH:6][CH:7]=1
Reactant: Cc1nc2ccccc2c(C)c1C(=O)NNC(=O)C(C)(C)c1ccc(Cl)cc1
Agent: CC[N+](CC)(CCC(=O)OC)S(N)(=O)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc2ccccc2c(C)c1-c1nnc(C(C)(C)c2ccc(Cl)cc2)o1
Temperature: 60 °C
Yield: 36.2 %

Procedure:
To a solution of N′-(2-(4-chlorophenyl)-2-methylpropanoyl)-2,4-dimethylquinoline-3-carbohydrazide (592 mg, 1.5 mmol) in dry tetrahydrofuran (5 ml) was added Burgess's reagent (methoxycarbonyl-sulfamoyltriethylammonium inner salt; 714 mg, 3.0 mmol). The mixture was heated at 60° C. for 1 hour, diluted with ethyl acetate, and washed with water, saturated sodium bicarbonate, and then brine. The organic phase was separated, and the solvent removed under reduced pressure, to provide 2-(2-(4-chlorophenyl)propan-2-yl)-5-(2,4-dimethylquinolin-3-yl)-1,3,4-oxadiazole (205 mg, 36%) as a white powder. 1H NMR (CDCl3, 400 MHz) δ 8.03 (app t, 2H, J=8.2 Hz); 7.78 (app t, 1H, J=7.0 Hz); 7.58 (app t, 1H, J=7.0 Hz); 7.30 (app q, 4H); 2.56 (s, 3H); 2.51 (s, 3H); 1.90 (s, 6H). LCMS (CI) M+H 378.