Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.[H-].[Na+].FC(F)(F)S(O[CH2:25][C:26]([F:29])([F:28])[F:27])(=O)=O.O>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C2COCCN2c2nc(Cl)ncc2N1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
To a solution of 2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (363 mg, 1.509 mmol) in DMF (6 ml) at 0° C. was added NaH (72.4 mg, 1.81 mmol). After 15 minutes of stirring at 0° C., a solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate (525 mg, 2.26 mmol) in DMF (1 ml) was slowly added. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to give a crude oil. The crude residue was purified by silica gel chromatography (hexane/ethyl acetate, 19:1 to 1:1) to afford 2-chloro-5-(2,2,2-trifluoroethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (373 mg, 1.16 mmol, 77% yield) as a yellow solid. MS [M+H] found 323.
Reaction SMILES: [Si]([O:18][CH2:19]/[CH:20]=[CH:21]/[CH2:22][CH:23]([C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[F:41])[S:24]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1.CCCCCC>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([S:24]([CH:23]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[F:41])[CH2:22]/[CH:21]=[CH:20]/[CH2:19][OH:18])(=[O:26])=[O:25])=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](OC/C=C/CC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=S(=O)(c1ccc(Cl)cc1)C(C/C=C/CO)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
The (E)-2-[5-(t-butyldiphenylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-3-pentenyl]-1,4-difluorobenzene (Isomer 246-B) (465 mg, 0.761 mmol) obtained in Example 246 was dissolved in tetrahydrofuran (10 ml), followed by the dropwise addition of a tetrahydrofuran solution (1.0M, 1.5 ml, 1.5 mmol) of tetrabutylammonium fluoride. At room temperature, the mixture was stirred for 1 hour. After addition of water (0.2 ml), the residue obtained by concentrating the resulting mixture under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with hexane, whereby the title compound (225 mg, 0.605 mmol, 80%) was obtained as a white powder.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[F:22])[CH:6]=1)(=[O:4])=[O:3].[C:23]1([CH2:29][C:30]([N:32]=[C:33]=[S:34])=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.CO>[CH3:1][S:2]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:33]([NH:32][C:30](=[O:31])[CH2:29][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[S:34])=[CH:17][C:16]=2[F:22])[CH:6]=1)(=[O:3])=[O:4]
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CS(=O)(=O)c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Reaction time: 2 h
Yield: 31.6 %

Procedure:
To a suspension of 237 (20 mg, 0.059 mmol) in THF (10 mL) was added 2-phenylacetyl isothiocyanate (26 mg, 0.146 mmol). The reaction mixture was stirred for 2 hours, concentrated under reduced pressure and the residue was purified by column chromatography, eluent EtOAc/MeOH (19:1), to afford a solid material that was dissolved in a minimum MeOH and precipitated with hexane to afford title compound 238 (9.6 mg, 31%) as a white solid. 1HNMR: (DMSO-d6) δ (ppm): 12.48 (s, 1H), 11.81 (s, 1H), 8.69(d, J=5.5 Hz, 1H), 8.36 (s, 1H), 8.03(d, J=12.13 Hz, 1H), 7.55 (s, 2H), 7.36-7.30 (m, 2H), 7.30-7.24 (m, 3H), 6.86(d, J=5.5 Hz, 1H), 3.83 (s, 2H), 3.54 (s, 3H). MS (m/z): 516.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[C:4](=[O:15])[CH:3]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)[C:4](=[O:15])[CH:3]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(n2ccc(O)cc2=O)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3ccc(O)cc3=O)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-hydroxy-1-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](O)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:39]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:39])=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2c(O)ncnc2C1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCc2c(Cl)ncnc2C1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 86.7 %

Procedure:
A mixture of 4-hydroxy-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (1.4 g, 5.6 mmol) and triphenylphosphine (2.9 g, 11.1 mmol) was stirred in DCE (41 mL) until the solution became clear, and then carbon tetrachloride (1.6 mL, 16.7 mmol) was added. The reaction mixture was heated to 70° C. and stirred for 2.5 hours. The volatiles were removed in vacuo and the crude material was directly purified by flash chromatography on silica gel (0-50% EtOAc/heptanes) to afford the title compound as an off-white solid (1.31 g, 87% yield). MS (ESI) m/e (M+H+): 269.73
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH:9]=[O:10])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])[O:20][CH2:21][CH3:22].[C:25]1(C)C=CC(S(O)(=O)=O)=C[CH:26]=1>C(O)C>[C:1]([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH:9]([O:20][CH2:21][CH3:22])[O:10][CH2:25][CH3:26])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC([O-])[O-]
Reactant: C=CCOC(=O)NC(C=O)CC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(OCC)OCC

Procedure:
To a solution of 3-allyloxycarbonylamino-4-oxo-butyric acid tert-butyl ester, 102, (13.3 g, 51.7 mmol) in anhydrous ethanol (75 mL) is added ethyl orthoformate (45 mL, 0.270 mol), p-toluenesulfonic acid (0.15 g, cat.) and 4 Å molecular sieves (10 g, kiln dried) under N2. After the consumption of starting material, the sieves are removed by filtration and the solvent removed in vacuo to provide the desired compound as a clear oil which is used directly without further purification. MS (ESI): m/e=332.21 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([NH2:12])=O)[CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:22]2)=CC=1>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10](=[S:22])[NH2:12])[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=S)c1cc(Cl)c(Cl)c(Cl)n1
Yield: 58.7 %

Procedure:
A mixture of 4, 5, 6-trichloropyridine-2-carboxamide (10.4 g, 46 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent, 22.0 g, 54 mmol) in toluene (150 mL) was heated under reflux for two hours. The reaction mixture was cooled, diluted with water (250 mL) and extracted with ethyl acetate (2×150 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (20% ethyl acetate in hexanes) to give 4, 5, 6-trichloropyridine-2-carbothioamide (6.5 g, 27 mmol): mp 168-169° C.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[CH2:15]CS([O-])(=O)=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[ClH:22].[F:23][C:24]([F:57])([F:56])[C:25]1[CH:26]=[C:27]([CH2:35][O:36][C@@H:37]2[CH2:42][CH2:41][CH2:40][N:39](CC3C=[NH+]C=CC=3)[C@@H:38]2[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[ClH:22].[ClH:22].[F:33][C:31]([F:32])([F:34])[C:29]1[CH:28]=[C:27]([CH2:35][O:36][C@H:37]2[CH2:42][CH2:41][CH2:40][N:39]([CH2:15][C:11]3[N:10]([S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:21])=[CH:2][CH:3]=4)(=[O:9])=[O:8])[CH:14]=[CH:13][N:12]=3)[C@H:38]2[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:26]=[C:25]([C:24]([F:57])([F:23])[F:56])[CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccnc2CCS(=O)(=O)[O-])cc1
Reactant: FC(F)(F)c1cc(CO[C@@H]2CCCN(Cc3ccc[nH+]c3)[C@@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccnc2CN2CCC[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2c2ccccc2)cc1
Temperature: 100 °C

Procedure:
((N-p-Toluenesulfonyl)imidazol-2-yl)methylmethanesulfonate (1.6 g) was added to a suspension of the compound of Description 3 (2.47 g) and potassium carbonate (800 mg) in dimethylformamide (10 ml) and the resulting mixture was heated at 100° C. for 2 h. The mixture was cooled, diluted with water (100 ml) and extracted with ethyl acetate (3×20 ml). The organic extracts were combined, washed with brine, dried (MgSO4) and concentrated in vacuo. This afforded a colourless oil which was purified by column chromatography on silica using 25-30% ethyl acetate in hexane. This afforded the product as a white crystalline solid which was recrystallised from dichloromethane/petrol: mp 125°-126° C. 1H NMR (360 MHz, DMSO-d6) d 1.4-1.5 (1H, m, NCH2CH2CHH), 1.5-1.67 (1H, m, NCH2CH2CHH), 1.8-2.0 (1H, m, NCH2CHH), 2.06-2.1 (1H, m, NCH2CHH), 2.35 (3H, s, CH3), 2.4 (1H, mc, NCHH), 2.7-2.86 (1H, m, NCHH), 3.50 (1H, d, J=14.0 Hz, CHH-imidazole), 3.56 (1H, brs, CHO), 3.76 (1H, d, J=1.5 Hz, CHPh), 4.08 (1H, d, J=14.0 Hz, CHH-imidazole), 4.09 (1H, d, J=12.0 Hz, OCHH), 4.48 (1H, d, J=12.0 Hz, OCHH), 6.96 (1H, d, J=1.0 Hz, imidazole-H), 7.12 (2H, d, J=8.5 Hz, ArH), 7.2-7.3 (3H, m, ArH), 7.34 (1H, d, J=1.0 Hz, imidazole-H), 7.46-7.58 (2H, m, ArH), 7.60 (2H, s, ArH), 7.71 (1H, ArH), 7.79 (2H, d, J=8.5 Hz, ArH); MS (CI+) m/z 638 (M+ +1). Found: C, 58.48; H, 4.78; N, 6.72; S, 4.81. Calcd. for C31H29F6N3O3S: C, 58.39; H, 4.58; N, 6.59; S, 5.03%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[C:10]([CH3:18])=[N:9]2)=[CH:5][CH:4]=1.CC1C=CC(S(O[CH2:32][CH2:33][C@@H:34]2[CH2:36][C@@H:35]2[CH:37]2[CH2:42][CH2:41][N:40]([C:43]3[N:48]=[CH:47][C:46]([Cl:49])=[CH:45][N:44]=3)[CH2:39][CH2:38]2)(=O)=O)=CC=1.[I-].[K+]>C(#N)C.O>[Cl:49][C:46]1[CH:45]=[N:44][C:43]([N:40]2[CH2:41][CH2:42][CH:37]([C@H:35]3[CH2:36][C@H:34]3[CH2:33][CH2:32][NH:17][C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=3)[N:9]=[C:10]4[CH3:18])[CH2:38][CH2:39]2)=[N:48][CH:47]=1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Reactant: COc1ccc(Cn2nc(C)c3cc(N)ccc32)cc1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(Cn2nc(C)c3cc(NCC[C@@H]4C[C@@H]4C4CCN(c5ncc(Cl)cn5)CC4)ccc32)cc1
Temperature: 110 °C
Reaction time: 1.33 h

Procedure:
1-(4-methoxybenzyl)-3-methyl-1H-indazol-5-amine (51 mg, 0.34 mmol) from step 2 of this example, 2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate from step 1 of Example 5 (75 mg, 0.17 mmol) and potassium iodide (3 mg, 0.017 mmol) combined and the solids slurried in acetonitrile. The slurry was reacted in the microwave with stirring for 80 minutes at 110° C. using normal power. The mixture was cooled to RT, diluted with 4:1 water:saturated sodium bicarbonate (40 ml), extracted with EtOAc (3×40 ml), the organic fractions combined, washed with brine, dried over Na2SO4, filtered and the volatiles removed in vacuum. The product was purified by chromatography on SiO2 eluting with 10% acetone:DCM to give the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:3]=1[C:4]#[N:5].[Cl-].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][Zn+])=[CH:15][CH:14]=1.NC1C=CC(CC2C=CC=CC=2)=CC=1C#N>>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Clc1ccc(C[Zn+])cc1
Reactant: N#Cc1cc(I)ccc1N
Agent: N#Cc1cc(Cc2ccccc2)ccc1N
Agent: [Cl-]
Product: N#Cc1cc(Cc2ccc(Cl)cc2)ccc1N

Procedure:
From 9 (488 mg, 2 mmol) and 4-chlorobenzylzinc chloride (0.5 M in THF, 10 mL, 5 mmol) by the same method as 10a; white powder (243 mg, 59%): mp 91.5-93° C.; 1H NMR (DMSO-d6) δ 3.79 (s, 2H, CH2), 5.87 (br s, 2H, NH2), 6.68 (d, J=8.0 Hz, 1H, H-3), 7.11 (d, J=8.0 Hz, H-4), 7.18 (d, J=8.4 Hz, 2H, H-2′ and H-6′), 7.20 (s, 1, H-6),7.29 (d, J=8.4 Hz, 2H, H-3′ and H-5′).
Reaction SMILES: C([N:3]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[N:16]=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[S:18][CH:19]=2)=[CH:9][CH:8]=1)C=O)=O.Cl>CO.C(OCC)(=O)C>[NH2:3][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[N:16]=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[S:18][CH:19]=2)=[CH:9][CH:8]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(CN(C=O)C=O)cc2)cs1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(CCc2ccc(CN)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.4 %

Procedure:
To a solution of N-[4-(2-{4-[(diformylamino)methyl]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide (56 mg) in methanol (0.5 ml) was added 4N hydrogen chloride in ethyl acetate (0.5 ml), and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated in vacuo. The residue was separated between chloroform (5 ml) and saturated aqueous sodium hydrogen bicarbonate (5 ml), and the aqueous layer was extracted with chloroform (5 ml). The organic layer was dried over sodium sulfate and concentrated in vacuo to give N-(4-{2-[4-(aminomethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (50 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:2]1.C(N(CC)CC)C.[C:50](OC(=O)C)(=[O:52])[CH3:51]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:23][C:24]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:12][N:13]([C:50](=[O:52])[CH3:51])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:2]1
Reactant: COc1ccccc1CNC[C@@H](Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1CN(C[C@@H](Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)=O
Reaction time: 4 h
Yield: 87 %

Procedure:
To a stirring solution of (R)-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-(N-triphenylmethylamino)propane (0.404 mol) in anhydrous tetrahydrofuran (1.2 L) under a nitrogen atmosphere at 0° C. was added triethylamine (66.5 ml, 0.477 mol) and acetic anhydride (45.0 ml, 0.477 mol). After 4 hours, the mixture was concentrated on a rotary evaporator, redissolved in methylene chloride and ethyl acetate, washed with water (2×) and brine (2×), dried over anhydrous sodium sulfate, filtered, and concentrated to a solid on a rotary evaporator. The resulting solid was dissolved in chloroform and loaded onto silica gel 60 (230-400 mesh) and eluted with a 1:1 mixture of ethyl acetate and hexanes. The product was then crystallized from an ethyl acetate/hexanes mixture. The resulting product of (R)-3-(1H-indol-3-yl)-1-[N-(2-5 methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane was crystallized and isolated over three crops giving 208.97 grams (87% yield) of analytically pure material.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH3:2].[CH2:13]=O.[CH2:15]([OH:18])[C:16]#[CH:17].CO>O1CCOCC1.C(Cl)Cl.Cl[Cu]>[CH2:1]([N:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[CH2:13][C:17]#[C:16][CH2:15][OH:18])[CH3:2]
Reactant: CCNCc1ccc(OC)cc1
Reactant: C=O
Reactant: C#CCO
Agent: Cl[Cu]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: CCN(CC#CCO)Cc1ccc(OC)cc1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A mixture of N-ethyl-4-methoxybenzenemethanamine (13.3 g, 80.6 mmol), paraformaldehyde (3.63 g), propargyl alcohol (6.33 g, 113 mmol) and CuCl (0.311 g) in 350 mL of 1,4-dioxane was stirred at reflux for 30 min. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with 200 mL of 50% NH4OH and extracted with EtOAc. The combined extracts were washed with water, brine, dried and concentrated. The residue was chromatographed on silica gel (elution with 2.5% MeOH in CH2Cl2 and then 5% MeOH in CH2Cl2) to afford the product V (15.1 g, 81% yield) as an oil.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([OH:37])[CH2:21][C:22]([CH3:36])([CH3:35])[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].N1C=CC=CC=1.[C:44](Cl)(=[O:62])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]>C(Cl)Cl>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([O:37][C:44](=[O:62])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:21][C:22]([CH3:35])([CH3:36])[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: COc1ccc(COC(=O)C(C)(C)CC(O)COC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(C)(C)C(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a mixture of 4-methoxybenzyl 5-(N-CBz-L-valyloxy)-4-hydroxy-2,2-dimethylvalerate (20.6 g, 40 mmol), Pyridine (31.6 g, 400 mmol) in CH2Cl2 (500 mL) at 0° C., was added dropwise a solution of stearoyl chloride (18.2 g, 60 mmol) in CH2Cl2 (100 mL). After 1 h at 0° C., the temperature of the reaction mixture was allowed to assume room temperature and then the mixture was stirred for 5 h at room temperature. The mixture was extracted with a 10% aqueous solution of NaHCO3 (300 mL) and the aqueous phase was washed with CH2Cl2 (200 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 1→5% MeOH in CH2Cl2), to give 27.2 g of 4-methoxybenzyl 5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvalerate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[OH:9][C@@H:10]1[CH2:14][CH2:13][O:12][CH2:11]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C@@H:10]2[CH2:14][CH2:13][O:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: Clc1ccc(Br)cn1
Reactant: O[C@@H]1CCOC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1ccc(O[C@@H]2CCOC2)nc1
Temperature: 90 °C
Yield: 46.4 %

Procedure:
To a solution of 5-bromo-2-chloropyridine (10 g, 52.1 mmol) in 100 mL of DMF was added commercially available (R)-(−)-3-hydroxytetrahydrofuran (6.87 g, 78.1 mmol) and Cs2CO3 (33.85 g, 0.104 mol), the resulting mixture was heated 90° C. for 36 hours. The solvent was concentrated and the residue was extracted with EtOAc (500 ml), washed with water (200 ml). The organic layer was dried over Na2SO4, concentrated and purified by chromatography on silica gel (eluting with Petrol ether:EtOAc=100:1) to afford 5-Bromo-2-[(R)-(tetrahydro-furan-3-yl)oxy]-pyridine (5.9 g, yield: 47%) as a solid. 1HNMR (CDCl3 400 MHz): δ 8.15 (d, J=2.4 Hz, 1H), 7.61-7.64 (m, 1H), 6.64 (d, J=8.8 Hz, 1H), 5.47-5.50 (m, 1H), 3.85-4.02 (m, 4H), 2.07-2.28 (m, 2H). [α]D20=+18.5 (C=0.189, CHCl3).
Reaction SMILES: CC([O-])(C)C.[K+].[Br:7][C:8]1[C:17]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[C:16]2[C:11]([CH:12]=[N:13][C:14](Cl)=[N:15]2)=[CH:10][CH:9]=1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1.CC(O)=O>CC(O)C>[Br:7][C:8]1[C:17]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[C:16]2[C:11]([CH:12]=[N:13][C:14]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([S:40](=[O:42])(=[O:41])[NH2:43])=[CH:36][CH:35]=3)=[N:15]2)=[CH:10][CH:9]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(Br)ccc3cnc(Cl)nc23)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(Br)ccc3cnc(Nc4ccc(S(N)(=O)=O)cc4)nc23)CC1
Temperature: 105 °C
Reaction time: 2.5 h
Yield: 36.9 %

Procedure:
Solid KOtBu (442 mg, 3.95 mmole) was added to a solution of tert-butyl 4-(7-bromo-2-chloroquinazolin-8-yloxy)piperidine-1-carboxylate (500 mg, 1.13 mmole) and 4-aminobenzenesulfonamide (777 mg, 4.62 mmole) in IPA (15 mL). The reaction was sealed and heated to 105° C. with stirring. After 2.5 hours, AcOH was added to the reaction to pH 4 and the reaction was evaporated to a solid. The crude product was dissolved in DMSO (15 mL) and purified by prep. HPLC to give 241 mg of product in 37% yield (417 mmole).