Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[S:13][CH:14]=[CH:15][C:16]=3[CH2:17]Br)=[N:9][C:8]=2[CH:19]=1)([O-:3])=[O:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[S:13][CH:14]=[CH:15][C:16]=3[CH2:17][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:9][C:8]=2[CH:19]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2oc(-c3sccc3CBr)nc2c1
Reactant: C1COCCN1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc2oc(-c3sccc3CN3CCOCC3)nc2c1
Yield: 78.8 %

Procedure:
A mixture of 5-nitro-2-(3-bromomethyl-2-thienyl)-benzoxazole (5.0 g, 0.0147 mole) and morpholine (2.6 g, 0.03 mole) in 200 ml of benzene is refluxed for 24 hours. The precipitated morpholine hydrobromide is removed by filtration and the benzene evaporated under vacuum yielding 4.0 g of solid. Crystallization from ethanol yields 3.4 g of product, melting point 143°-145° C.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C([O:32][C:33]([CH:35]1[O:40][CH2:39][CH2:38][NH:37][CH2:36]1)=[O:34])C1C=CC=CC=1>>[CH:18]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8](=[O:9])[NH:10][C:11]2[S:12][C:13]([CH2:16][N:37]3[CH2:38][CH2:39][O:40][CH:35]([C:33]([OH:34])=[O:32])[CH2:36]3)=[CH:14][N:15]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: O=C(OCc1ccccc1)C1CNCCO1
Agent: Cl
Product: O=C(O)C1CN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CCO1

Procedure:
Prepared 11 mg (58%) following the general procedures (P) and (F) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (70 mg. 0.21 mmol) and morpholine-2-carboxylic acid benzyl ester hydrochloride (77 mg, 0.30 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([SH:16])=[N:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][C:26]([O:28][CH2:29][CH2:30][CH3:31])=[O:27].C(OCC)(=O)C>CN(C=O)C.O>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][S:16][C:13]1[CH:14]=[CH:15][C:10]([C:9](=[O:17])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:11][N:12]=1)[CH2:30][CH3:31]
Reactant: CCCOC(=O)CBr
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(S)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOC(=O)CSc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of N-(4-fluoro-phenyl)-6-mercapto-nicotinamide (0.024 g, 0.097 mmol, see Example 1) in 2 mL of DMF was added cesium carbonate (0.094 g, 0.29 mmol) and propyl bromoacetate (0.025 μL). The mixture was stirred for 30 minutes and poured into ethyl acetate and water. The organic layer was removed, dried over sodium sulfate, filtered, and the solvents removed in vacuo. Purification by trituration using ethyl acetate/hexanes gave 34 mg (76%) of the titled product as a white solid:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[C:11]2[CH:12]=[CH:13][N:14](C(OCC3C=CC=CC=3)=O)[C:10]=2[CH:9]=[CH:8][N:7]=1)=[O:4]>C(O)C.[Pd]>[NH:14]1[C:10]2[CH:9]=[CH:8][N:7]=[C:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[C:11]=2[CH:12]=[CH:13]1
Reactant: COC(=O)Nc1nccc2c1ccn2C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)Nc1nccc2[nH]ccc12
Reaction time: 1 h
Yield: 90.75 %

Procedure:
To a stirred solution of benzyl 4-[(methoxycarbonyl)amino]-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (264 mg, 0.82 mmol, Step a) in ethanol (10 mL) was added catalytic amount of palladium on carbon (10% wet). The reaction mixture was stirred under an atmosphere of hydrogen gas (atmospheric pressure) for 1 hour. The reaction mixture was filtered over celite and the residue washed with ethanol. The filtrate was concentrated to yield methyl 1H-pyrrolo[3,2-c]pyridin-4-ylcarbamate as a white powder (141 mg, 90.75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](CC3C=CC(CCC(O)=O)=CC=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4]([O:31][CH2:32]C2CCCC2)[CH:3]=1.ClC1C=CC(C2N(CC3C=C(C=CC=3)C(O)=O)C3C=C(F)C(F)=CC=3N=2)=C(OCC2CCCC2)C=1.[CH3:73][O:74][C:75](=[O:84])[C:76]1[CH:81]=[CH:80][C:79]([CH2:82]Br)=[CH:78][CH:77]=1>>[CH3:73][O:74][C:75](=[O:84])[C:76]1[CH:81]=[CH:80][C:79]([CH2:82][N:12]2[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[O:31][CH3:32])=[CH:78][CH:77]=1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C(O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1
Product: COC(=O)c1ccc(Cn2c(-c3ccc(Cl)cc3OC)nc3cc(F)c(F)cc32)cc1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and 4-bromomethyl-benzoic acid methyl ester (CAS Reg. No. 2417-72-3). Brown solid (33%). MS (Turbo Spray): m/z=443.2 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][CH:7]=[N:6]1.C(=O)([O-])[O-].[K+].[K+].[N+:16]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22])([O-:18])=[O:17]>>[N:5]1([CH2:4][CH2:3][CH2:2][NH:1][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[N+:16]([O-:18])=[O:17])[CH:9]=[CH:8][CH:7]=[N:6]1
Reactant: NCCCn1cccn1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(NCCCn1cccn1)c1ccccc1[N+](=O)[O-]

Procedure:
The subtitled compound was prepared substantially in accordance with the method detailed in Example 24A using 6.0 g (0.030 mol) of N-(3-aminopropyl)pyrazole, 8.5 g of potassium carbonate and 2.65 g (O.013 mol) of o-nitrobenzoyl chloride with the exception that the final product was purified by crystallization from a cyanomethane/diethyl ether solution, followed by recrystallization from an ethanol/diethyl ether solution, to provide 6.62 g of the desired subtitled intermediate (m.p. 78°-81° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[C:19]=1[N+:35]([O-:37])=[O:36]>CN(C)C(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:18]2[C:19]([N+:35]([O-:37])=[O:36])=[C:20]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][CH:30]=3)[N:21]=[CH:22][N:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(Cl)c2[N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(COc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
3-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.65 mmol, 131 mg) and sodium hydride (1.3 mmol, 31 mg) were dissolved in N,N-dimethyl acetamide (1.5 mL) and stirred for 30 minutes at room temperature. Then, (6-chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (0.26 mmol, 84 mg) was added. The reaction was stirred at 70° C. for 30 minutes. Its progress was monitored by thin layer chromatography and LCMS. Sodium hydride was quenched with water and the desired compound was extracted in ethyl acetate. Organic solvents were evaporated in vacuo. Flash chromatography (Silica gel 60; 50/50 EtoAc/Hexanes) provided Compound A16 as a yellow solid (96 mg, 54%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.21 (s, 1H), 8.41 (s, 1H), 7.97 (d, 2H), 7.86 (d, 2H), 4.52 (m, 2H), 3.49 (m, 2H), 3.11 (s, 3H), 2.75 (m, 1H), 1.84 (m, 2H), 1.65 (m, 2H), 1.46 (s, 9H). LCMS (ESI), m/z 394.1 (M+H+, 100%).
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.Cl[CH2:7][CH2:8][N:9]([CH2:32][CH2:33]Cl)[C:10]1[CH:30]=[C:29]([Cl:31])[C:13]2[O:14][C:15]3[C:24]([CH3:25])=[CH:23][C:22]([C:26]([OH:28])=[O:27])=[CH:21][C:16]=3[S:17](=[O:20])(=[O:19])[CH2:18][C:12]=2[CH:11]=1>CO>[Cl:31][C:29]1[C:13]2[O:14][C:15]3[C:24]([CH3:25])=[CH:23][C:22]([C:26]([OH:28])=[O:27])=[CH:21][C:16]=3[S:17](=[O:20])(=[O:19])[CH2:18][C:12]=2[CH:11]=[C:10]([N:9]2[CH2:8][CH2:7][N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH2:33][CH2:32]2)[CH:30]=1
Reactant: NCC1CC1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N(CCCl)CCCl)cc1CS2(=O)=O
Solvent: CO
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N3CCN(CC4CC4)CC3)cc1CS2(=O)=O

Procedure:
Cyclopropylmethyl amine (0.30 mL, 3.34 mmol) was added to a solution of Example 102j (0.2 g, 0.42 mmol) in methanol (5 mL), followed by the addition of n-tetrabutylammonium iodide (0.01 g, 0.020 mmol) in an atmosphere of nitrogen and sealed in a pressure reactor vessel at 110° C. for 10 h. The reaction mixture was brought to room temperature, concentrated, treated with water and extracted with n-butanol. The organic layer was washed with water, brine, dried, concentrated and purified by crystallisation (ethylacetate-pet-ether). Yield: 0.114 g, (53.7%). 1H NMR (DMSO-d6): δ 0.1 (d, 2H, CH2), 0.50 (d, 2H, CH2), 0.90 (m, 1H, CH), 2.30 (d, 2H, CH2), 2.70 (s, 3H, CH3), 3.20-3.25 (m, 4H, 2CH2), 5.15 (s, 2H, CH2), 7.10 (s, 1H, Ar), 7.15 (s, 1H, Ar), 8.0 (s, 1H, Ar), 8.20 (s, 1H, Ar).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][CH:9]([C:24]1[N:25]=[CH:26][N:27]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([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:28]=1[CH3:29])[CH:10]1[C:22](=[O:23])[N:14]2[C:15]3[C:20]([CH:21]=[C:13]2[CH2:12][CH2:11]1)=[CH:19][CH:18]=[CH:17][CH:16]=3.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:1]([O:8][CH:9]([C:24]1[N:25]=[CH:26][N:27]([C:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:28]=1[CH3:29])[CH:10]1[C:22](=[O:23])[N:14]2[C:15]3[C:20]([CH:21]=[C:13]2[CH2:12][CH2:11]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:3])[CH3:2]
Reactant: Cc1c(C(O)C2CCc3cc4ccccc4n3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)OC(c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C)C1CCc2cc3ccccc3n2C1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (1.26 g) was added to a solution of 8,9-dihydro-7-[(hydroxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (1.34 g, a mixture of the isomers A and B) in pyridine (20 ml). After being stirred at 60° C. for 2 hours, the solution was evaporated in vacuo. The residue obtained was diluted with chloroform and neutralized with an aqueous sodium hydrogencarbonate solution. The separated organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to give 7-[(acetoxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-8,9-dihydropyrido[1,2-a]indol-6(7H)-one as an oil, which was used in the next reaction without purification.
Reaction SMILES: CC(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:11]=[C:10]([S:33][CH3:34])[CH:9]=1)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:34][S:33][C:10]1[CH:9]=[C:8]([NH2:7])[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:11]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(NC(=O)OC(C)(C)C)cc(SC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(SC)c1
Yield: 87 %

Procedure:
A solution of 2.65 g (5.2 mmol) of 3-(methylthio)-5-(octadecyloxy)phenylcarbamic acid dimethylethyl ester and2.0 ml (26 mmol) of trifluoroacetic acid in 50 ml of methylene chloride waskept at room temperature for 24 hours. The mixture was concentrated at reduced pressure and the residue was treated with excess NaHCO3 solution. The product was extracted with methylene chloride and the dried extract was concentrated and recrystallized from methylene chloride-hexaneto give 1.85 g (87% yield), nap 75°-77° of 3-(methylthio)-5-(octadecyloxy)benzenamine. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: O=[C:2]1[CH2:7][S:6][C:5]2[CH:8]=[CH:9][C:10]([C:12](OC)=[O:13])=[N:11][C:4]=2[NH:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.CCOCC.C(Cl)(Cl)Cl>[S:6]1[CH2:7][CH2:2][NH:3][C:4]2[N:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:5]1=2
Reactant: COC(=O)c1ccc2c(n1)NC(=O)CS2
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: OCc1ccc2c(n1)NCCS2
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
A solution of methyl 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate (31a) (1.0 g) in dry tetrahydrofuran (170 ml) was treated with a 1M solution of lithium aluminium hydride in ether (14 ml) and the mixture was heated under reflux for 18 hours. It was cooled and a slight excess of 2N sodium hydroxide was added followed by chloroform and anhydrous sodium sulphate and the mixture was stirred for 30 minutes and filtered. The solution was evaporated to dryness to give a semi-solid (0.482 g)
Reaction SMILES: [CH2:1]([OH:6])/[CH:2]=[CH:3]\[CH2:4][OH:5].[CH2:7](I)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[NH4+].[Cl-]>CCOCC>[CH2:7]([O:5][CH2:4]/[CH:3]=[CH:2]\[CH2:1][OH:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: OC/C=C\CO
Reactant: CCCCCCCI
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCCCOC/C=C\CO

Procedure:
A 50% oil dispersion of NaH (9.4 g) was washed three times with 20 ml of dry THF under argon and the remaining oil-free NaH was suspended in 600 ml of dry THF. cis-2-Butene-1,4-diol (50 ml, 46.7 g, 530 mmole) was then added slowly by syringe to the suspension. After a small amount of diol was added a gelatinous precipitate began to form, most of which went back into solution by the end of the addition. The mixture was allowed to stir for an additional hour and n-heptyliodide (30.4 ml, 42.0 g, 186 mmole) was added in one portion. The reaction was allowed to stir overnight. Aqueous NH4Cl was added to the mixture followed by 600 ml of ether. The organic layer was separated, washed with 200 ml of NaHCO3, 200 ml of brine, dried over MgSO4, filtered and the solvent evaporated to yield a pale yellow oil. Distillation afforded 23.82 g, bp 106-10° C. (0.1 mm). 1H NMR δ 5.76 (m, 2), 4.20 (t, 2, J=6 Hz), 4.04 (d, 2, J=6 Hz), 3.44 (t, 2, J=7 hz), 2.22 (t, 1, J=6 Hz), 1.59 (br t, 2, J=7 hz) 1.29 (br, 8), 0.88 (t, 3, J=7 hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([CH2:13][OH:14])([CH2:11][OH:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].P(=O)(O)(O)O.[CH3:21][C:22]([CH3:24])=O>C1C=CC=CC=1>[CH3:21][C:22]1([CH3:24])[O:12][CH2:11][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:13][O:14]1
Reactant: CC(C)=O
Reactant: CCOC(=O)C(CO)(CO)C(=O)OCC
Agent: O=P(O)(O)O
Solvent: c1ccccc1
Product: CCOC(=O)C1(C(=O)OCC)COC(C)(C)OC1
Yield: 87 %

Procedure:
To diethyl-bis-(hydroxymethyl)malonate (50 g) in acetone (50 ml) and benzene (200 ml) is added phosphoric acid (10 g). . The mixture is refluxed while stirring and separating water which distills. When water evolution is complete, the reaction mixture is cooled and the organic layer is separated, stirred with solid sodium carbonate (10 g), filtered and evaporated to give the title product (52 g) (87%) nD26 1.4412.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH3:16])[C:10]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]([C:23]1([CH2:26]OS(C)(=O)=O)[CH2:25][CH2:24]1)=[O:22])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:18]([O:20][C:21]([C:23]1([CH2:26][O:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([CH3:17])[C:11]=2[CH3:16])[CH2:25][CH2:24]1)=[O:22])[CH3:19]
Reactant: Cc1c(O)ccc(OCc2ccccc2)c1C
Reactant: CCOC(=O)C1(COS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(COc2ccc(OCc3ccccc3)c(C)c2C)CC1
Temperature: 130 °C
Reaction time: 6 h

Procedure:
A suspension of 4-benzyloxy-2,3-dimethyl-phenol (960 mg), 1-methanesulfonyloxymethyl-cyclopropanecarboxylic acid ethyl ester, prepared as in Step 1 (890 mg) and cesium carbonate (1.5 g) in DMF (20 mL) was stirred at 130 ° C for 6 h, and the mixture was partitioned between EtOAc and water. The organic layer was washed with water, dried over MgSO4 and evaporated. The residue was purified by silica gel column eluting with 10% EtOAc in hexane to give 0.78 g of 1-(4-benzyloxy-2,3-dimethyl-phenoxymethyl)-cyclopropanecarboxylic acid ethyl ester as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[NH2:32][C@H:33]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34]1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([NH:32][C@H:33]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34]3)=[O:28])[CH2:10]2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N[C@H]3CCN(C(=O)OC(C)(C)C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
3.05 g of N,N'-carbonyldiimidazole were added to a solution of 7.99 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid in 80 ml of dry acetonitrile, and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was cooled to 0° C., after which a solution of 3.34 g of (3S)-3-amino-1-t-butoxycarbonylpyrrolidine in 30 ml of dry acetonitrile was added, and the mixture was stirred at the same temperature for 20 minutes; it was then stirred at room temperature for a further 1.4 hours and at 32° C. for 45 minutes. The reaction mixture was then concentrated by evaporation under reduced pressure, and the concentrate was diluted with 200 ml of ethyl acetate. The resulting ethyl acetate solution was washed twice with water and then once with a saturated aqueous solution of sodium chloride. The solution was then dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was recrystallized from diethyl ether, to give 9.11 g of the title compound, as a powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[C:18](=[O:29])[N:19]([CH2:26][CH2:27][F:28])[CH:20]4[CH3:25])[C:12]([C:30]([F:33])([F:32])[F:31])=[CH:11][N:10]=2)=[C:4]([O:34][CH3:35])[CH:3]=1.C(N(CC)CC)C.[C:43](Cl)(=[O:46])[CH:44]=[CH2:45]>C1COCC1.C(OCC)(=O)C>[C:43]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[C:18](=[O:29])[N:19]([CH2:26][CH2:27][F:28])[CH:20]4[CH3:25])[C:12]([C:30]([F:32])([F:33])[F:31])=[CH:11][N:10]=2)=[C:4]([O:34][CH3:35])[CH:3]=1)(=[O:46])[CH:44]=[CH2:45]
Reactant: COc1cc(N)ccc1Nc1ncc(C(F)(F)F)c(Nc2cccc3c2C(=O)N(CCF)C3C)n1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC(=O)Nc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3C(=O)N(CCF)C4C)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
311 mg (0.634 mmol) 2-(4-amino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine are dissolved in 10 ml THF and combined with 115 μl (0.824 mmol) triethylamine and 62 μl (0.761 mmol) acrylic chloride. This mixture is stirred for 1 h at ambient temperature. Then it is diluted with ethyl acetate and extracted three times with water. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]([CH3:45])[C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38]>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:42]4[CH2:41][CH2:40][N:39]([C:37](=[O:38])[N:36]([CH3:35])[CH3:45])[CH2:44][CH2:43]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C(=O)N1CCNCC1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(=O)N(C)C)CC4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (30.0 mg, 0.058 mmol) was added piperazine-1-carboxylic acid dimethylamide (36.6 mg, 0.232 mmol) in 1,4-dioxane (1 mL). The reaction mixture was stirred at 40° C. for 4 h, then at room temperature overnight. The reaction mixture was filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+ calc'd for C32H38ClN6O4S (M+H+): 637.2; Found: 637.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([C:10](=O)[NH:11][C:12]1[CH:13]=[CH:14][C:15]([F:23])=[C:16]2[C:21]=1[NH:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)[CH3:9])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O>[C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([C:10]1[N:20]2[C:21]3[C:16]([CH2:17][CH2:18][CH:19]2[CH3:22])=[C:15]([F:23])[CH:14]=[CH:13][C:12]=3[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CCc2c(F)ccc(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c2N1
Solvent: CC(=O)O
Product: CC1CCc2c(F)ccc3nc([C@H](C)NC(=O)OC(C)(C)C)n1c23
Yield: 40.1 %

Procedure:
A solution of [(S)-1-(5-fluoro-2-methyl-1,2,3,4-tetrahydroquinolin-8-ylcarbamoyl)ethyl]carbamic acid tert-butyl ester (63.6 mg, 0.181 mmol) in AcOH (5 mL) was stirred at 80° C. for 2.5 h, then concentrated in vacuo. The residue was purified by column chromatography (Si—PCC, gradient 20-50% EtOAc in cyclohexane) affording the title compound as a colourless gum (24.2 mg, 40%) LCMS (Method B): RT 2.45 min [M+H]+ 334
Reaction SMILES: B1C2CCCC1CCC2.[CH2:10]([C:14]1[C:15]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:21][S:20][C:16]=2[N:17]=[CH:18][N:19]=1)[CH2:11][CH:12]=[CH2:13].[OH-:30].[Na+].OO>O1CCCC1.C(OCC)(=O)C.C(O)C>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]2[C:15]3[C:14]([CH2:10][CH2:11][CH2:12][CH2:13][OH:30])=[N:19][CH:18]=[N:17][C:16]=3[S:20][CH:21]=2)=[CH:28][CH:27]=1
Reactant: C=CCCc1ncnc2scc(-c3ccc(F)cc3)c12
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: OCCCCc1ncnc2scc(-c3ccc(F)cc3)c12
Temperature: 50 °C
Yield: 47 %

Procedure:
9-BBN (0.236 g, 0.00193 mol) in tetrahydrofuran (5.00 mL) was treated with 4-but-3-en-1-yl-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine (0.500 g, 0.00176 mol) in tetrahydrofuran (3.0 mL) at 50° C. for 1 h. Ethanol (1.0 mL), 6 N sodium hydroxide (0.33 mL) and 30% hydrogen peroxide (0.67 mL) were then added successively and the resulting mixture was maintained at 50° C. for 1 h. The reaction was then cooled to room temperature, diluted with ethyl acetate (50 mL) and washed with sodium bicarbonate (2×30 mL). The organic layers were combined, concentrated and purified by column chromatography over silica gel (using ethyl acetate/hexane 1:5-1:1 as an eluent) to afford 4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butan-1-ol as a white solid in 47% yield.