Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]([CH2:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH3:14])=[O:12])[S:10][C:3]=12.[OH:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:33]([NH:35][CH3:36])=[O:34])=[C:27]([CH3:32])[N:28]2[CH3:31])=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:19][N:18]([CH3:20])[CH2:17][CH2:16][CH2:15][N:13]([CH3:14])[C:11]([C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[O:21][C:22]2[CH:30]=[C:29]3[C:25]([C:26]([C:33]([NH:35][CH3:36])=[O:34])=[C:27]([CH3:32])[N:28]3[CH3:31])=[CH:24][CH:23]=2)[CH:8]=1)=[O:12]
Reactant: CN(C)CCCN(C)C(=O)c1cc2nccc(Cl)c2s1
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N(C)CCCN(C)C)sc34)ccc12
Yield: 62 %

Procedure:
This material was prepared by the reaction of 7-chloro-N-[3-(dimethylamino)propyl]-N-methylthieno[3,2-b]pyridine-2-carboxamide 32a (0.095 g, 0.32 mmole) with 6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide (0.070 g, 0.32 mmole) 16e and Cs2CO3 (0.104 g, 0.32 mmole) in a manner as described previously for example 1 to give a white solid (0.098 g, 62%). 1H NMR (300 MHz, CD3OD) δ 8.53 (1H, d, J=5.3 Hz), 7.91 (2H, m), 7.38 (1H, s), 7.09 (1H, dd, J=2.1, 8.7 Hz), 6.81(1H, d, J=5.3 Hz), 3.73 (3H, s), 3.66 (2H, m), 3.28 (2H, m), 3.01 (3H, s), 2.68 (9H, m), 2.06 (2H, m), 1.94(3H, s); HRMS (MH+): Calcd: 494.2223. Found: 494.2226.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:31])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19]([CH3:20])=[O:31])[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.7 %

Procedure:
To a stirred solution of 6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole (1.02 g, 2.61 mmol) from Step 3 of this Example in DCM (50 mL) at 0° C. was added 70% meta-chloroperbenzoic acid (707 mg, 2.87 mmol) and the mixture was allowed to warm to rt and stirred for a further 45 min. To the mixture was added saturated aq NaHCO3 and the organic layer was separated. The aqueous layer was extracted with DCM and the combined organic layers were washed with saturated aq NaHCO3. The organic layer was separated, dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure to afford 6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (1.06 g, 100%) as a cream solid which did not require further purification. 1H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.18 (s, 1H), 8.08-8.12 (m, 2H), 7.61 (m, 1H), 7.50 (d, J=9 Hz, 1H), 5.68 (s, 2H), 3.07 (s, 3H); LCMS (ESI) m/z 407 and 409 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([N:8](COC)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:25])=[CH:4][N:3]=1.[C:26]1([OH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:7]2[C:2]([O:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:3][CH:4]=[C:5]([Cl:25])[CH:6]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1)([CH3:20])([CH3:21])[CH3:19]
Reactant: Oc1ccccc1
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2Oc2ccccc2)cc1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A 5 mL pear-shaped flask was charged with N-(2-bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide (134 mg, 0.30 mmol), phenol (85 mg, 0.90 mmol), potassium carbonate (250 mg, 18.0 mmol), and DMA (0.9 mL). The heterogeneous solution was heated to 150° C. and stirred overnight. The crude reaction mixture was subsequently purified via reverse phase HPLC (Column: Varian Dynamax 250×21.4 mm Microsorb100-8 C18, 0.1% TFA/H2O (Eluent A): 0.1% TFA/MeCN (Eluent B)): 1H NMR (400 MHz, CDCl3) δ 7.95 (d, 1H), 7.75 (d, 1H), 7.72 (d, 2H), 7.48 (d, 2H), 7.28-7.34 (m, 2H), 7.17-7.21 (m, 1H), 7.05 (bs, 1H), 6.71-6.76 (m, 2H), 1.34 (s, 9H); MS (ES) M+H expect 417.1. found 417.4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([P:12](=[O:15])([OH:14])[OH:13])([OH:11])[PH2:9]=[O:10])=[CH:4][CH:3]=1.C([Si](C)(C)[O:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][N:30]2[CH:38]=[N:37][C:36]3[C:31]2=[N:32][C:33]([F:40])=[N:34][C:35]=3Cl)[CH:25]=[CH:26][CH:27]=1)(C)(C)C.C(N(CC)C(C)C)(C)C>CS(C)=O>[F:40][C:33]1[N:32]=[C:31]2[C:36]([N:37]=[CH:38][N:30]2[CH2:29][CH2:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([OH:21])[CH:23]=2)=[C:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([P:12](=[O:13])([OH:14])[OH:15])([OH:11])[PH2:9]=[O:10])=[CH:6][CH:7]=2)[N:34]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CCn2cnc3c(Cl)nc(F)nc32)c1
Reactant: Nc1ccc(C(O)([PH2]=O)P(=O)(O)O)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[PH2]C(O)(c1ccc(Nc2nc(F)nc3c2ncn3CCc2cccc(O)c2)cc1)P(=O)(O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.7 %

Procedure:
A sealed pressure flask, flushed with N2, containing a mixture of crude [(4-Amino-phenyl)-hydroxy-phosphinoylmethyl]-phosphonic acid (8.29 mmol), 9-{2-[3-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-ethyl}-6-chloro-2-fluoro-9H-purine (3.37 g, 8.29 mmol), and N,N-diisopropylethylamine (7.2 mL, 41.5 mmol) in 45.0 mL DMSO was heated at 110–120° C. for 13 h. Upon removing excess N,N-diisopropylethylamine (N2 flow, slight heat) the slightly brown solution was cooled to ambient temperature and added ˜500 mL of H2O to produce a milky, off-white solution. Further precipitation occurred upon addition of TFA (final pH=1–2), at which time the mixture was heated (100° C. hot plate) and stirred vigorously for ˜20 min, filtered while hot, then washed with acidified H2O (TFA, pH=1–2; 4×20 mL), EtOH (2×20 mL), and Et2O (4×20 mL). Isolation of a second crop from the concentrated filtrate in the same manner as described above, followed by removal of excess solvent (in vacuo) provided 2.47 g of an off-white solid: m/z 506 (M−H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>>[O:15]1[CH2:14][CH:13]1[CH2:11][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: ClCC1CO1
Product: c1cc2cc(OCC3CO3)ccc2[nH]1

Procedure:
The title compound was prepared from 5-hydroxyindole and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[O:11][C:12]([C:14]([OH:16])=O)=[CH:13][C:3]1=2.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[O:11][C:12]([C:14]([Cl:19])=[O:16])=[CH:13][C:3]1=2
Reactant: Cn1c2ccccc2c2oc(C(=O)O)cc21
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cn1c2ccccc2c2oc(C(=O)Cl)cc21
Temperature: 50 °C

Procedure:
To a suspension of sodium hydride (2.5 g) in dimethylformamide (100 ml), a solution of ethyl furo[3,2-b]indole-2-carboxylate (20 g) in dimethylformamide (100 ml) was added dropwise with stirring, then the mixture was stirred for 0.5 hour at room temperature. Methyl iodide (30 g) was added, and the resulting mixture was stirred for 5 hours at room temperature to give ethyl 4-methyl-furo[3,2-b]indole-2-carboxylate (18 g), which was hydrolyzed in a solution of sodium hydroxide (20 g) in water (200 ml) with stirring for an hour to give 4-methyl-furo[3,2-b]indole-2-carboxylic acid (15 g). This carboxylic acid was treated with thionyl chloride (50 ml) in benzene (70 ml) with stirring for an hour at 50° C. to give 4-methyl-furo[3,2-b]indole-2-carbonyl chloride (12 g).
Reaction SMILES: Cl[CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)[CH2:4]1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O.O>[N:16]([CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)[CH2:4]1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1O[C@@H](CCl)CN1c1ccc(Cl)cn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(Cl)cn2)C(=O)O1
Yield: 93.2 %

Procedure:
A mixture of (5R)-5-(chloromethyl)-3-(5-chloropyridin-2-yl)-1,3-oxazolidin-2-one (2.32 g, INTERMEDIATE 7) and sodium azide (1.22 g) was heated to 100° C. in 75 ml of dimethylformamide for 15 h. The mixture was then diluted with 500 ml of water and extracted with 500 ml of ethyl acetate (3×). The combined organic layers were washed with water (250 ml) and brine (250 ml). They were then dried over sodium sulfate and concentrated in vacuo to provide 2.22 g (93%) of the title compound in >95% purity via LC/MS. Mass spectrum (ESI) 254.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])OC1C=CC=CC=1.Cl.[CH2:20]([O:22][C:23](=[O:26])[CH2:24][NH2:25])[CH3:21]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:25][CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:26])=[O:18]
Reactant: O=C(Nc1ccc(F)cc1F)Oc1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)CNC(=O)Nc1ccc(F)cc1F
Temperature: 80 °C
Yield: 88.4 %

Procedure:
Phenyl 2,4-difluorophenylcarbamate (5.0 g) and 4.2 g of glycine ethyl ester hydrochloride were dissolved in 30 ml of pyridine and the solution was heated at 80° C. for 14 hours. The reaction solution was concentrated under reduced pressure and to the residue were added 80 ml of ethyl acetate and 20 ml of water. The ethyl acetate layer was washed with 10 ml of an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Hexane (50 ml) was added to the residue and the solid separated out was collected by filtration to give 4.58 g of N-(2,4-difluorophenyl)-N'-ethoxycarbonylmethylurea as a colorless powder.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6]2.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6]2
Reactant: COc1ccc2c(c1)CNC2=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C1NCc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.9 %

Procedure:
A mixture of 5-methoxy-2,3-dihydro-isoindol-1-one (3.7 g, 23 mmol) and boron tri-bromide (1 M in CH2Cl2, 15.2 mL, 88 mmol) in CH2Cl2 (30 mL) at −78° C. was stirred for 16 h at RT. The mixture was then cooled to −78° C. and MeOH (25 mL) was added. After 1 h at −78° C. the mixture was evaporated and the residue purified by chromatography (SiO2, CH2Cl2:2N NH3-MeOH 98:2 to 90:10) to afford the title product (2.5 g, 72%) as an off-white solid. MS m/e=148.0 (M−H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]2[CH:19]=[CH:18][N:17]=[CH:16][C:7]=2[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC[O:22][CH2:23][CH3:24]>>[OH:22][CH:23]([C:24]1[CH:7]=[CH:6][CH:5]=[CH:9][CH:10]=1)[C:16]1[C:7]2[S:8][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:6]=2[CH:19]=[CH:18][N:17]=1
Reactant: COCOc1c(-c2ccccc2)sc2cnccc12
Reactant: CCOCC
Product: COCOc1c(-c2ccccc2)sc2c(C(O)c3ccccc3)nccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
A solution of 1.0 g (3.7 mmol) of 3-methoxymethoxy-2-phenyl-6-azabenzo[b]thiophene in 5 mL of dry ether was added and the solution was kept at -60° for 3 hours. The reaction was quenched with 0.5 mL of benzaldehyde and allowed to warm to room temperature. The mixture was partitioned between ether and water and the aqueous layer was washed with ether. The combined extracts were dried and concentrated to an oil. Chromatography on silica gel (30% ethyl acetate-hexane) afforded 0.62 g (44%) of a colorless oil, NMR (200 MHz, CDCl3) δ3.4 (s, 3H), 5.0 (s, 2H), 5.95 (s, 1H, --OH), 7.2-7.8-(m, 12H), 8.52 (d, J=6Hz, IH), Mass Spec m/e 377 (M+).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3](=[O:12])[C:4](=[N:10][OH:11])[C:5](=[N:7][O:8][CH3:9])[CH3:6].[CH3:14][N:15]=[C:16]=[O:17].C1N2CCN(CC2)C1>C(Cl)Cl>[CH3:13][N:2]([CH3:1])[C:3](=[O:12])[C:4](=[N:10][O:11][C:16](=[O:17])[NH:15][CH3:14])[C:5](=[N:7][O:8][CH3:9])[CH3:6]
Reactant: CON=C(C)C(=NO)C(=O)N(C)C
Reactant: CN=C=O
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: CNC(=O)ON=C(C(=O)N(C)C)C(C)=NOC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 34 parts of N,N-dimethyl-2-hydroxyimino-3-methoxyiminobutyramide, 350 parts of methylene chloride, 13 parts of methyl isocyanate and one-tenth part triethylenediamine was stirred at 25° C. for 3 hours and then refluxed for 1 hour. The solvent was removed by stripping under reduced pressure (15 mm.) at 50° bath temperature, thereby affording the solid crude product. Recrystallization from a benzene-acetonitrile mixture gave 32 parts of N,N-dimethyl-3-methoxyimino-2-[(methylcarbamoyl)oximino]butyramide, m.p. 172°-173° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[CH3:23]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH3:23])[C:14]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:15])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(NC(=O)C2CCCC2)c1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)cc(N(C)C(=O)C2CCCC2)c1C
Reaction time: 0.25 h

Procedure:
To a stirred solution of methyl 5-chloro-3-(cyclopentanecarboxamido)-2-methylbenzoate (0.3 g, 1.01 mmol) in DMF, sodium hydride (0.060 g, 0.0015 mmol) was added at 0° C. and reaction mixture was allowed to stir for 15 min. Methyl iodide (0.32 mL, 0.50 mmol) was added and reaction mixture and was stirred at room temperature. After complete consumption of starting material, the reaction was quenched with addition of water and extracted with ethyl acetate. The combined organic layer was the washed with brine, dried (Na2SO4) and concentrated. The crude compound was used for the next step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=2)[N:20]([CH3:31])[C:19](=[O:32])[C:18]=1[C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[CH:34]=1)=O)(C)(C)C>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[Cl:30][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][CH2:15][CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[C:18]([C:33]3[CH:34]=[C:35]([CH3:40])[CH:36]=[C:37]([CH3:39])[CH:38]=3)[C:19](=[O:32])[N:20]2[CH3:31])=[CH:25][C:24]=1[N+:27]([O-:29])=[O:28]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc([N+](=O)[O-])c(Cl)cc3n(C)c2=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3)c3cc([N+](=O)[O-])c(Cl)cc3n(C)c2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-1-methyl-6-nitro-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (ca. 100 mg crude from EXAMPLE17, StepB in a mixture of 1 mL trifluoroacetic acid and 0.01 mL anisole) was stirred at room temperature for 1 hour. The mixture was then concentrated in vacuo, resolvated in methylene chloride and washed with saturated sodium bicarbonate. The concentrated organics were purified by flash chromatography on silica gel (chloroform:1% ammonium hydroxide in methanol:, 9:1) to give the title compound (22 mg). MASS: 470 (M+H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:20]2[CH:32]=[CH:33][CH:34]=[CH:35][C:19]=2[O:18][CH2:17]1)[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:2].CCOCC>C(OCC)(=O)C.Cl>[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([OH:27])=[O:26])[C:20]2[CH:32]=[CH:33][CH:34]=[CH:35][C:19]=2[O:18][CH2:17]1)[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCC1CCCCC1)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)[C@H](CCC1CCCCC1)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Reaction time: 4 h
Yield: 83.6 %

Procedure:
In 10 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 0.5 g of tert-butyl 3(S)-[1(S)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate obtained in Example 49, and the solution is allowed to stand at room temperature for 4 hours. To the solution is added 200 ml of petroluem ether and the resulting mixture is shaken thoroughly. After the supernatant is removed by decantation, the residue is diluted with 50 ml of water and extracted three times with 100 ml each of ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl ether is added to the viscous residue to give 0.37 g of 3(S)-[1(S)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid as colorless crystals melting at 135°-139° C.
Reaction SMILES: [CH2:1]([C:11]1[CH:16]=[C:15]([O:17][CH3:18])[N:14]=[C:13]([N:19]([CH3:21])[CH3:20])[N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:22]N1C(=O)CCC1=O>C(#N)C>[Br:22][C:16]1[C:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[N:12][C:13]([N:19]([CH3:20])[CH3:21])=[N:14][C:15]=1[O:17][CH3:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCCCc1cc(OC)nc(N(C)C)n1
Solvent: CC#N
Product: CCCCCCCCCCc1nc(N(C)C)nc(OC)c1Br
Temperature: 23 °C
Reaction time: 5 h

Procedure:
To a stirred solution containing 1.22 g (4.16 mmol) of 4-decyl-6-methoxy-N,N-dimethylpyrimidin-2-amine in 20 mL of acetonitrile were added 808 mg (4.54 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 23° C. and protected from light for 5 h. The reaction mixture was concentrated under diminished pressure and the residue was dissolved into 100 mL of ethyl acetate. The organic solution was washed with a 100-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with 9:1 hexanes-ethyl ether afforded the expected product as white solid: yield 1.27 g (82%); mp: 45-46° C.; silica gel TLC Rf 0.75 (9:1 hexanes-ethyl ether); 1H-NMR (CDCl3) δ 0.86 (t, 3H, J=6.8 Hz), 1.33-1.24 (br m, 14H), 1.65 (quint, 2H, J=7.2 Hz), 2.68 (dd, 2H, J=7.6, 7.6 Hz), 3.12 (s, 6H) and 3.92 (s, 3H); 13C NMR (CDCl3) δ 14.09, 22.67, 27.62, 29.32, 29.37, 29.45, 29.57, 29.60, 31.89, 36.70, 36.94, 36.94, 53.97, 91.17, 160.07, 165.06 and 169.05.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9](#[N:12])[CH:10]=[CH2:11].CC(N=NC(C#N)(C)C)(C#N)C.P([O-])([O-])([O-])=O.[Ca+2].[Ca+2].[Ca+2].P([O-])([O-])([O-])=O>O>[CH:1]([CH:11]=[CH:10][C:9]#[N:12])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CC#N
Reactant: C=Cc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=P([O-])([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: N#CC=CC=Cc1ccccc1

Procedure:
76 parts by weight of styrene, 24 parts by weight of acrylonitrile, and 120 parts of deionized water are mixed. To the mixture, 0.17 parts by weight of azobisisobutylonitrile (AIBN), 0.4 parts by weight of t-dodecyl mercaptan chain transfer agent, and 0.5 parts by weight of tricalciumphosphate are added. The mixture is suspension polymerized at 75° C. for 5 hours, and a styrene-acrylonitrile (SAN) copolymer resin is obtained. The resultant copolymer is washed, dehydrated and dried to obtain SAN copolymer resin having a weight average molecular weight of 150,000 g/mol in powder form.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:5]([N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6].[CH2:24]([N:26]([CH2:31]C)[CH2:27][CH2:28][CH2:29][NH2:30])C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:24][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH:30][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:5]([N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6]
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CCN(CC)CCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(NCCCN(C)C)c1
Yield: 68 %

Procedure:
A mixture of 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide (2.5 g, 1 eq, prepared according to Example A1), 3-diethylamino-propylamine (877 mg, 1.1 eq) and potassium carbonate (2.13 g, 2 eq) in acetonitrile (80 ml) is heated under reflux for hours then concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (130 ml) and water (50 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: dichloromethane/methanol 9:1) produces the expected compound in the form of a yellow oil (2.1 g mg; 68% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[CH:13]1([C:9]2[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6](=[O:20])[N:5]3[C:10]=2[C:11]([CH3:12])=[C:2]([C:26]2[CH:27]=[CH:28][C:23]([N:22]([CH3:32])[CH3:21])=[CH:24][CH:25]=2)[CH:3]=[CH:4]3)[CH2:15][CH2:14]1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N(C)C)cc3)ccn2c1=O
Yield: 39.8 %

Procedure:
Methyl 1-cyclopropyl-8-(4-(dimethylamino)-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (77 mg, 0.26 mmol) and (4-(dimethylamino)-phenyl)-boronic acid (56 mg, 0.34 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (39 mg, 31%). ESI-MS m/z: 377 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].S(OC)(O[CH3:15])(=O)=O>[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][CH3:15]
Reactant: Cc1cc(Br)cc(Br)c1O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: COc1c(C)cc(Br)cc1Br
Reaction time: 0.08 h

Procedure:
To a stirred solution of the product of stage (a) (266 g) in 4 N aqueous sodium hydroxide (900 ml), dimethyl sulphate (192 ml) was added whilst maintaining the temperature at 35°-40° C. The mixture was stirred for 5 minutes, then 4 N aqueous sodium hydroxide (450 ml) was added and dimethyl sulphate (96 ml) was added dropwise. The temperature rose to 55° C. The mixture was then stirred overnight, and the product was extracted into dichloromethane, washed with water, dried over magnesium sulphate, filtered, and the solvent evaporated off to give a brown oil (280 g). Distillation gave the title product as a colourless oil, bp 96°-98° C./0.3 mm Hg.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[CH2:7][CH2:8][O:9][C:5]=2[CH:4]=1.[C-:12]#[N:13].[K+]>CS(C)=O.O>[O:9]1[C:5]2[CH:4]=[C:3]([CH2:2][C:12]#[N:13])[CH:11]=[CH:10][C:6]=2[CH2:7][CH2:8]1
Reactant: [C-]#N
Reactant: ClCc1ccc2c(c1)OCC2
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1ccc2c(c1)OCC2
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a solution of 6-(chloromethyl)-2,3-dihydrobenzofuran (12.3 g, 73 mmol) in DMSO (100 mL) was added KCN (7.1 g, 109.5 mmol). The reaction mixture was stirred at 100 □ for 2 hours. The mixture was diluted with water and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine, dried, concentrated in vacuo and purified by column chromatography on silica gel (5-10% ethyl acetate in petroleum ether) to afford 2-(2,3-dihydrobenzofuran-6-yl)acetonitrile (8.4 g, 70.4% yield). 1H NMR (400 MHz, CDCl3) δ: 7.16 (d, J=7.6, 1H), 6.79 (d, J=7.2, 1H), 6.72 (s, 1H), 4.58 (t, J=8.4, 2H), 3.67 (s, 2H), 3.19 (t, J=8.4, 2H).