Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:29])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[NH:19][C:20]2[CH:28]=[C:27]3[C:23]([CH:24]=[N:25][NH:26]3)=[CH:22][CH:21]=2)=[CH:7][C:6]=1[N+:30]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>CCO>[NH2:30][C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:29])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[NH:19][C:20]2[CH:28]=[C:27]3[C:23]([CH:24]=[N:25][NH:26]3)=[CH:22][CH:21]=2)[CH:9]=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Solvent: CCO
Product: CC(C)(C)c1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The title compound was prepared from N-(4-tert-butyl-3-nitro-phenyl)-2-(1H-indazol-6-ylamino)-nicotinamide by dissolving in EtOH (20 ml) and adding Sn(II)Cl2 (12.58 g) and stirred at RT for 5 h and at 0° C. overnight. The mix was warmed to RT and quenched by pouring onto ice, neutralized with NaHCO3 and basified with 6N NAOH. An emulsion formed upon addition of EtOAc which was filtered through Celite® and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with H2O, brine and dried over MgSO4 then purified by flash chromatography (3-5% MeOH to afford the product as a orange-yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14]>C(Cl)Cl>[F:14][C:13]([F:15])([F:16])[CH2:12][CH2:11][C:4]1[C:5]([OH:9])=[CH:6][CH:7]=[CH:8][C:3]=1[OH:2]
Reactant: COc1cccc(OC)c1CCC(F)(F)F
Solvent: ClCCl
Product: Oc1cccc(O)c1CCC(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
30.5 g (0.13 mole) of 1,3-dimethoxy-2-(3,3,3-trifluoropropyl)-benzene in 275 ml of methylene chloride are introduced into a 1.5 l sulfonating flask with a thermometer, bubble counter, dropping funnel with cooling jacket and argon connection and cooled to -75°. 340 ml of a precooled 1 molar solution of boron tribromide in methylene chloride are now added dropwise such that the reaction temperature does not rise above -70° (about 90 minutes). After subsequently stirring at room temperature for 6 hours, the red reaction solution is poured onto 800 ml of ice-water. The organic base is separated off, the aqueous phase is extracted again with ether and the combined organic phases are washed with brine, dried over magnesium sulfate and evaporated. 2-(3,3,3-Trifluoropropyl)-resorcinol is obtained in the form of red crystals of melting point 82°-84° (yield 100%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][C:2]1=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.O1CCCCC1[O:32][CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[C:41](=O)[O:40][CH2:39]2.OS(O)(=O)=O.[OH-].[Na+]>O1CCCC1>[OH:32][CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[C:41](=[C:3]1[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][C:2]1=[O:10])[O:40][CH2:39]2
Reactant: O=C1OCc2cc(CCCOC3CCCCO3)ccc21
Reactant: O=C1Cc2cccnc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ncccc2C1=C1OCc2cc(CCCO)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9 %

Procedure:
To a stirred solution of 1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (193 mg (1.44 mmol) in anhydrous tetrahydrofuran (10 ml) under N2 was added 1.0M LiHMDS/THF solution (2.9 ml, 2.9 mmol). The mixture was stirred at room temperature for 10 minutes, then 5-[3-(tetrahydro-pyran-2-yloxy)-propyl]-3H-isobenzofuran-1-one (200 mg, 0.72 mmol) was added. The mixture was stirred at room temperature for 2.5 hours and poured into 1M H2SO4 solution (20 ml). The mixture was heated at 55° C. for 15 minutes, cooled to room temperature and poured into an ice water (200 ml). The mixture was basified to pH 9 with NaOH solution and stirred overnight. The solid was filtered, washed with water and dried under vacuum to give 3-[5-(3-hydroxy-propyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one as a brown solid (20 mg, 9%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6]/[CH:7]=[C:8](\[CH3:11])/[CH:9]=[O:10].[C-]#N.[Na+].[C:18](O)(=[O:20])C>CO.[O-2].[O-2].[Mn+4]>[OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6]/[CH:7]=[C:8](\[CH3:11])/[C:9]([O:20][CH3:18])=[O:10]
Reactant: C/C(C=O)=C\COc1cccc(O)c1
Reactant: CC(=O)O
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)/C(C)=C/COc1cccc(O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1.00 g of (E)-4(3-hydroxyphenoxy)-2-methyl-2-buten-1-al, 7.31 g active manganese dioxide, 1.26 g sodium cyanide and 0.4 g glacial acetic acid in 40 ml methanol is stirred at room temperature for about 16 hours, filtered and the filtrate evaporated to dryness using an aspirator and a concentrated aqueous sodium hydroxide trap. During the volume reduction, the filtrate is stirred in a water bath at about 35° C. The red oil residue is treated with 50 ml diethylether and 50 ml distilled water and the mixture stirred vigorously for about one hour. The phases are separated and the water layer is washed with 50 ml diethylether. The organic layers are combined and washed with two 150 ml portions of distilled water. The ether layer is dried over anhydrous magnesium sulfate, treated with activated charcoal and filtered. The filtrate is evaporated to dryness to yield 0.68 g light yellow oil which crystallizes on standing which is taken up in 40 ml diethylether and heated under a stream of nitrogen as 15 ml hexanes is slowly added. When the volume reaches 25 ml, it is treated with activated charcoal and filtered. The filtrate is reduced in volume to 200 ml, allowed to cool to room temperature and is placed in a freezer. Bright yellow solid forms and is collected by nitrogen pressure filtration and is dried under a stream of nitrogen yielding 0.27 g product, m.p. 79°-81° C. Elemental Analysis. Calculated: C,64.85; H,6.35. Found: C,64.74; H,6.37.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1([C:7]([O:9]CC)=[O:8])[CH2:6][CH2:5][CH2:4]1.[OH-].[Na+]>C(O)C.C1COCC1.O>[F:1][CH:2]([F:12])[C:3]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)C1(C(F)F)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)C1(C(F)F)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.3 %

Procedure:
To a stirred solution of Intermediate 235A (0.24 g, 1.347 mmol) in ethanol (3.5 mL), THF (3.5 mL) was added NaOH (0.162 g, 4.04 mmol) in water (3 mL) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated and the residue was diluted with water (3 mL) and extracted with ethyl acetate. The aqueous layer was then acidified to pH 3-4 using an aqueous solution of 1.5 N HCl and extracted with ethyl acetate (3×25 mL) The combined organic layer was washed with water, dried over Na2SO4, filtered and the filtrate concentrated. The residual mass was then azeotroped with toluene to afford Intermediate 235B as a brown solid (0.12 g, 59% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.33 (s, 1H), 6.55-5.94 (m, 1H), 3.28-3.03 (m, 2H), 2.41-2.10 (m, 2H), 2.00-1.68 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:30][C:31]([F:38])([F:37])[C:32](OCC)=[O:33]>C(Cl)Cl>[F:30][C:31]([F:38])([F:37])[C:32]([NH:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)=[O:33]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21)C(F)(F)F
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of (1-((1-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.199 mmol, 62.1 mg) and triethylamine (0.399 mmol, 0.056 mL, 40.4 mg) in DCM (1.2 mL) was added a solution of ethyl 2,2,2-trifluoroacetate (0.199 mmol, 0.024 mL, 28.3 mg) and the whole stirred at room temperature for 60 h. The reaction mixture was concentrated under reduced pressure and the residue purified by RP-HPLC to give a clear film (30.0 mg, 0.074 mmol, 36.9%). MS (ESI): m/z [M+H]+ 408.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)(=[O:9])=[O:8].C(=O)(O)[O-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)(=[O:8])=[O:9]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2ccccn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)c2ccccn2)cc1
Temperature: 0 °C
Yield: 88.8 %

Procedure:
A stirred solution of 4-nitrophenyl 2-pyridyl sulfone (6.50 g, 24.6 mmol) and stannous chloride dihydrate (27.72 g, 123.0 mmol) in absolute ethanol (200 mL) was heated at reflux for 25 min. The reaction mixture was poured into ice water, and the aqueous solution basified with sodium bicarbonate (pH=8-9) and extracted with ethyl acetate (2×400 mL). The organics were combined, dried (MgSO4), filtered, and the solvent distilled to yield the title benzenamine (5.12 g, 89%) as a white solid; mp 158°-160° C. 1H-NMR (300 MHz, d6 -DMSO): 6.27 (broad s, 2H, NH2), 6.66 (d, 2H, J=8.7 Hz, aromatic), 7.61 (m, 3H, aromatic), 8.08 (d, 2H, J=4.9 Hz, aromatic), 8.68 (d, 1H, J=4.9, aromatic). MS (CI, CH4): 235(M+1).
Reaction SMILES: [CH2:1]([N:8]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:28])[NH:23][CH2:22][CH2:21]2)[S:9]([C:12]1[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:32][CH3:33]>C1COCC1>[CH2:1]([N:8]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:28])[N:23]([CH2:32][CH3:33])[CH2:22][CH2:21]2)[S:9]([C:12]1[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: Cn1ccc(S(=O)(=O)N(Cc2ccccc2)c2ccc3c(c2)CCNC3=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCc2cc(N(Cc3ccccc3)S(=O)(=O)c3ccn(C)n3)ccc2C1=O
Temperature: 110 °C
Yield: 42.8 %

Procedure:
To a suspension of 1-methyl-1H-pyrazole-3-sulfonic acid benzyl-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide (9 mg, 0.022 mmol) and sodium hydride (2 mg of a 60% dispersion in mineral oil, 0.045 mmol) in anhydrous THF (0.5 ml) was added iodoethane (2 μl, 0.045 mmol) and the reaction heated to 110° C. in a microwave for 0.5 hrs. The solvent was evaporated in vacuo and the resulting residue purified by preparative HPLC (Method B) to yield the title compound as a colourless solid (4 mg, 24%). HPLC retention time 4.14 min. Mass spectrum (ES+) m/z 425 (M+H).
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13](O)=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:21])=O>C1C=CC=CC=1>[C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13]([Cl:21])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C(=O)O)c1ccc(C(=O)c2cccs2)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C(=O)Cl)c1ccc(C(=O)c2cccs2)cc1

Procedure:
A mixture of 5.2 parts of p-(2-thenoyl)hydratropic acid, 4.8 parts of thionyl chloride and 32 parts of anhydrous benzene is stirred and refluxed for 3h. 30. The reaction mixture is evaporated and the residue is evaporated once more from benzene, yielding p-(2-thenoyl)hydratropoyl chloride as a residue.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=O)[NH:19][CH:20]=[N:21]2)=[C:16]([O:25][CH2:26][C@H:27]2[CH2:31][CH2:30][CH2:29][N:28]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([Cl:3])=[N:19][CH:20]=[N:21]2)=[C:16]([O:25][CH2:26][C@H:27]2[CH2:31][CH2:30][CH2:29][N:28]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(OCc2ccccc2)cc2nc[nH]c(=O)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(OCc2ccccc2)cc2ncnc(Cl)c12
Temperature: 50 °C

Procedure:
Phosphorous oxychloride (520 μl) was added dropwise to a mixture of tert-butyl (2R)-2-({[7-(benzyloxy)-4-oxo-3,4-dihydroquinazolin-5-yl]oxy}methyl)pyrrolidine-1-carboxylate (500 mg) and N,N-diisopropylethylamine (52 μl) in DCM (10 ml) and the reaction mixture was heated at 50° C. for 62 hours. The reaction mixture was concentrated in vacuo and then water and saturated aqueous sodium carbonate (cooled to 4° C.) was added. The aqueous mixture was then extracted with DCM and the organic layer was dried (MgSO4) and concentrated in vacuo to leave tert-butyl (2R)-2-({[7-(benzyloxy)-4-chloroquinazolin-5-yl]oxy}methyl)pyrrolidine-1-carboxylate as a brown oil, which was used without further purification.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]([CH3:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][CH2:49][O:48]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]([CH3:52])[CH2:46][C@@H:47]2[CH2:51][CH2:50][CH2:49][O:48]2)=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C[C@@H]1CCCO1)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)C[C@@H]2CCCO2)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 42.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N—[(S)-tetrahydrofuran-2-ylmethyl]acetamide (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.9 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:24]([CH:25]=[O:26])=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[S:22][N:21]=2)=[CH:16][CH:15]=1>CCOCC.C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:24]([CH:25]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[OH:26])=[C:23]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[S:22][N:21]=2)=[CH:18][CH:19]=1
Reactant: Brc1cccnc1
Reactant: O=Cc1c(-c2ccc(Cl)cc2)nsc1-c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1cccnc1)c1c(-c2ccc(Cl)cc2)nsc1-c1ccccc1
Reaction time: 0.25 h
Yield: 105.5 %

Procedure:
A solution of 3-bromopyridine (103 mg) in 2.5 ml of ether is cooled to −78° C. under N2 and to this is added drop-wise a BuLi solution (0.375 ml, 1.6 M in hex). After stirring for 15 min, a solution of 15 (150 mg) in THF is added drop-wise. Stirring is continued for 20 min at −78° C., the red colored reaction mixture is quenched with water (5 ml) and the cooling bath is removed. Water (25 ml) and EtOAc (30 ml) are added. After washing, the layers are separated, the organic layer is washed with brine, dried and concentrated to afford an orange foam (200 mg). The material is purified by flash column chromatography (2% MeOH in CH2Cl2). Desired compound 16 is obtained as white foam showing the expected mass in LCMS (M+1:379 and its isotopes at 380; 381 and 382).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([C:10]2[N:15]=[C:14]([O:16][C:17]3C=CC=C[CH:18]=3)[C:13]([CH3:23])=[CH:12][N:11]=2)[N:8]=[CH:7][C:6]=1[C:24]([NH:26][CH2:27][C:28]1[N:32]([CH3:33])[CH:31]=[N:30][CH:29]=1)=[O:25])[CH2:2][CH2:3][CH3:4]>C(O)C>[CH2:1]([C:5]1[N:9]([C:10]2[N:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13]([CH3:23])=[CH:12][N:11]=2)[N:8]=[CH:7][C:6]=1[C:24]([NH:26][CH2:27][C:28]1[N:32]([CH3:33])[CH:31]=[N:30][CH:29]=1)=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(C(=O)NCc2cncn2C)cnn1-c1ncc(C)c(Oc2ccccc2)n1
Solvent: CCO
Product: CCCCc1c(C(=O)NCc2cncn2C)cnn1-c1ncc(C)c(OCC)n1

Procedure:
Compound 16 was prepared following procedures described for compound 15 with the exception of substituting phenol with ethanol. 1H NMR (CDCl3) δ 0.88-0.91 (t, 3H), 1.35-1.39 (m, 2H), 1.44-1.47 (t, J=7.0 Hz, 3H), 1.60-1.63 (m, 2H), 2.20 (s, 3H), 3.49-3.52 (m, 2H), 3.66 (s, 3H), 4.48-4.52 (q, 2H), 4.64-4.65 (d, J=5.5 Hz, 2H), 7.02 (s, 1H), 7.47 (s, 1H), 7.83 (s, 1H), 8.33 (s, 1H). LCMS (ES+) m/z 398 (M+1).
Reaction SMILES: O[CH2:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[NH2:17][CH2:18][CH2:19][SH:20]>>[CH3:10][O:9][C:8]1[C:3]([CH2:2][S:20][CH2:19][CH2:18][NH2:17])=[N:4][CH:5]=[CH:6][C:7]=1[O:11][CH3:12]
Reactant: COc1ccnc(CO)c1OC
Reactant: NCCS
Solvent: O=S(Cl)Cl
Product: COc1ccnc(CSCCN)c1OC

Procedure:
3-Fluoro-2-methyl-4-nitropyridine N-oxide is treated with an excess of sodium methoxide and the product is heated in acetic anhydride and deacetylated to give 2-hydroxymethyl-3,4-dimethoxypyridine. 2-Hydroxymethyl-3,4-dimethoxypyridine is treated with thionyl chloride and the product is treated with cysteamine to give 2-(3,4-dimethoxy-2-pyridylmethylthio)ethylamine.
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:49]([O:51][C:52](=[O:73])[C@@H:53]([O:55][C:56]1[CH:61]=[C:60](Cl)[N:59]=[C:58]([S:63][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[C:67]([F:71])[C:66]=2[F:72])[N:57]=1)[CH3:54])[CH3:50]>CCOC(C)=O.CCCC(C)C.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].O1CCOCC1>[CH2:49]([O:51][C:52](=[O:73])[C@@H:53]([O:55][C:56]1[CH:61]=[C:60]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[N:59]=[C:58]([S:63][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[C:67]([F:71])[C:66]=2[F:72])[N:57]=1)[CH3:54])[CH3:50]
Reactant: CCOC(=O)[C@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: NS(=O)(=O)N1CCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCCC(C)C
Product: CCOC(=O)[C@H](C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of azetidine-1-sulfonamide (prepared according to patent WO 2004/011443, 0.13 g), tris(dibenzylideneacetone)dipalladium (0) (58 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (42 mg), cesium carbonate (0.31 g), 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2S)-propanoic acid ethyl ester (product of step i) (0.25 g) and dioxane (10 mL), Purification was by column chromatography on silica gel using EtOAc/isohexane (3:7) as eluent to give the subtitle compound as clear, colourless oil. Yield: 0.28 g
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][C:24]2=[O:33])[CH2:19][CH2:18]1)=[O:16])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH3:13])=[N:10][CH:11]=1.O.[OH-].[Li+].Cl.[NH:39]1[CH2:44][CH2:43][CH:42]([N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1.[PH2](Cl)=O>CO.O.C(Cl)Cl.C(N(CC)CC)C>[N:45]1([CH:42]2[CH2:43][CH2:44][N:39]([C:3](=[O:2])[CH:4]([NH:14][C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[NH:25][C:24]4=[O:33])[CH2:19][CH2:18]3)=[O:16])[CH2:5][C:6]3[CH:11]=[N:10][C:9]([O:12][CH3:13])=[N:8][CH:7]=3)[CH2:40][CH2:41]2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: COC(=O)C(Cc1cnc(OC)nc1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reactant: C1CCN(C2CCNCC2)CC1
Agent: Cl
Agent: O=[PH2]Cl
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-(2-methoxy-pyrimidin-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester (99 mg) in methanol (6 mL) was added a solution of lithium hydroxide monohydrate (18 mg) in water (1 mL). The reaction was stirred at room temperature for 4 h and cooled to 0° C. The reaction was treated with 1N hydrochloric acid (0.4 mL), concentrated. The residue obtained was dissolved in methylene chloride (3 mL), and treated sequentially with 4-piperidyl-piperidine (50 mg), triethylamine (88 μL), and bis-2-oxo-3-oxazolidinyl)phoshinic chloride (71 mg). The reaction was stirred overnight, concentrated, and purified by prep HPLC to give 103 mg (45%). LC/MS: tR=1.23 min, 605.54 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[NH:9][CH:8]=[CH:7][C:6]2=O.O=P(Cl)(Cl)[Cl:25].[OH-].[K+]>C(#N)C>[Cl:25][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(=O)cc[nH]c2cc1OCCCN1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: COc1cc2c(Cl)ccnc2cc1OCCCN1CCCC1
Temperature: 85 °C
Yield: 87.3 %

Procedure:
Intermediate VI (63 g, 0.198 mol) and POCl3 (5 v/w, 315 in L) were added to acetonitrile (5 v/w, 315 mL). The mixture was warmed up to 85° C. to react under reflux for 6 h. After completion of the reaction, the reaction solution was cooled. POCl3 and acetonitrile were evaporated off to produce a grey viscous solid. This solid was added to a great deal of ice-water mixture, adjusted with a 10% KOH solution to a pH of 10, and extracted with CH2Cl2 (200 mL×3). The organic layer was collected, dried over anhydrous sodium sulfate, and cooled after evaporating off the solvate to produce an off-white solid (58 g) in a yield of 87.3%.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:3].FC(F)(F)C([NH2:18])=O.[O-2].[Mg+2].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>ClCCl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH3:1][S:2]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])(=[NH:18])=[O:3]
Reactant: NC(=O)C(F)(F)F
Reactant: COC(=O)c1cccc(S(C)=O)c1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: COC(=O)c1cccc(S(C)(=N)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.2 %

Procedure:
A solution of methyl 3-(methylsulfinyl)benzoate (3.23 g, 16.3 mmol), 2,2,2-trifluoroacetamide (3.69 g, 32.6 mmol), magnesium oxide (1.97 g, 48.9 mmol), rhodium(II) acetate dimer (0.18 g, 0.408 mmol), and iodobenzene diacetate (7.88 g, 24.5 mmol) in 150 ml dichloromethane was stirred at room temperature. After 16 hours, the mixture was filtered past filter agent (Celite), rinsed with chloroform, and rotary evaporated. The sample was dissolved in EtOAc, washed with brine/dilute HCl, brine, dried with anhydrous Na2SO4 and rotary evaporated. The yellow-orange oil was dissolved in 60 ml MeOH, K2CO3 (6.76 g, 48.9 mmol) added, and the mixture stirred at room temperature for 12 minutes. The MeOH filtrate was decanted from the solids, which were then rinsed with MeOH and EtOAc. The pH of the combined organic filtrates were adjusted to pH 2 using 4% HCl, then the aqueous layer diluted by adding H2O. The aqueous layer was washed with 30% EtOAc in hexane, then the pH adjusted to pH 9 with saturated Na2CO3. The aqueous layer was extracted with CHCl3, the combined CHCl3 layers washed with brine, dried with anhydrous Na2SO4 and rotary evaporated to give the title compound as a light tan solid (2.58 g, 74%).