Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[C:12]([Cl:16])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH2:17])=[O:5])[CH3:2].[F:18][C:19]1[CH:24]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1OS(C(F)(F)F)(=O)=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[C:12]([Cl:16])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:17][C:20]1[CH:21]=[CH:22][C:23]([Si:25]([CH3:27])([CH3:26])[CH3:28])=[CH:24][C:19]=1[F:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N)c2cncc(Cl)c2n1C
Reactant: C[Si](C)(C)c1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(Nc2ccc([Si](C)(C)C)cc2F)c2cncc(Cl)c2n1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.7 %

Procedure:
A degassed solution of 3-amino-7-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (300 mg, 1.18 mmol), trifluoro-methanesulfonic acid 2-fluoro-4-trimethylsilanyl-phenyl ester (486 mg, 1.53 mmol), Pd2dba3 (54 mg, 0.06 mmol), Xantphos (68 mg, 0.118 mmol) and Cs2CO3 (770 mg, 2.36 mmol) in toluene (10 ml) was heated to reflux then stirred for 16 hours. The reaction mixture was cooled to ambient temperature then filtered through a pad of Celite® washing with toluene. The resultant solution was concentrated in vacuo to give an oil. The oil was purified by flash chromatography (SiO2, cyclohexane:ethyl acetate, gradient 95:5 to 90:10) to provide the title compound as a gum (370 mg, 74%). 1H NMR (CDCl3) 8.64 (1H, s), 8.31 (1H, s), 7.47 (1H, s, br), 7.23 (1H, dd, J=1.5, 110. Hz), 7.10 (1H, dd, J=1.0, 8.0 Hz), 6.97 (1H, t, J=8.0 Hz), 4.42 (2H, q, J=7.0 Hz), 4.35 (3H, s), 1.43 (3H, t, J=7.0 Hz), 0.29 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:3]=[C:2]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[F:30])[CH:29]=[CH:28][CH:27]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: OB(O)c1ccccc1F
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(-c2ccccc2F)c1

Procedure:
Compound is prepared from 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide and 2-fluorophenyl boronic acid according to conditions described in general procedure K. 1H NMR 300 MHz (CDCl3) δ 8.3(d, 1H), 8.15(s, 1H), 7.18-8.05(m, 11H), 6.8(d, 1H, J=10 Hz), 4.3(t, 2H), 3.75(m, 4H), 3.0(t, 2H), 2.6(m, 4H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[N:5]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:4](=[O:29])[C:3]=1[C:30]([O:32]CC)=O.[CH:35]1([NH2:39])[CH2:38][CH2:37][CH2:36]1>>[CH:35]1([NH:39][C:30]([C:3]2[C:4](=[O:29])[N:5]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)[C:6]3[C:11]([C:2]=2[OH:1])=[N:10][CH:9]=[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=3)=[O:32])[CH2:38][CH2:37][CH2:36]1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: NC1CCC1
Product: O=C(NC1CCC1)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2ccc([N+](=O)[O-])cc2)c1=O

Procedure:
This compound was prepared from ethyl 4-hydroxy-1-[(4-nitrophenyl)methyl]-2-oxo-7-(phenylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclobutylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.91 (1H, d, J=7.6 Hz), 8.21 (1H, s), 8.10 (2H, d, J=8.6 Hz), 7.35 (2H, d, J=8.6 Hz), 7.29 (1H, s), 7.14 (3H, m), 7.08 (2H, m), 5.47 (2H, br s), 4.40 (1H, m), 3.91 (2H, s), 2.24 (2H, m), 1.86 (2H, m), 1.67 (2H, m); HRMS calcd for C27H24N4O5+H+: 485.1825. Found: 485.1815.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[NH2:10][CH2:11]CS.C(OC(=O)C)C>C(O)C.CCCCCC>[N+:5]([CH:4]=[C:3]1[NH:10][CH2:11][CH2:1][S:2]1)([O-:7])=[O:6]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCS
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=[N+]([O-])C=C1NCCS1
Yield: 46.6 %

Procedure:
TEA (1.8 mL, 13.20 mmol) was added to a solution of 1,1-bis-methylsulfanyl-2-nitro-ethene (I-1b: 1.45 g, 8.802 mmol) and 2-amino-ethanethiol (1 g, 8.802 mmol) in ethanol (20 mL). The resulting mixture was heated to reflux for 3 hours. The reaction mixture was monitored by TLC (70% ethylacetate in hexane). The reaction mixture was concentrated to afford the crude product. Purification by column chromatography on silica gel (70% ethylacetate in hexane) afforded 0.6 g of the product (31% yield).
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[K+:26]>[Ag].O>[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[K+:26]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Ag]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 85 °C

Procedure:
Using the apparatus shown in FIG. 5, particulate organic silver salt 3-1 was prepared in the following manner. Into a tank (31) containing 83.5 g of behenic acid and 1583.5 g of pure water, while stirring at 85° C., 147.7 ml of 1.5N aqueous KOH solution was added over 5 min. and allowed to react further for 60 min. to obtain a potassium behenate solution. Finally, water was added to make the total amount to 2000 ml. To a tank (32), 2000 ml of aqueous solution containing 37.6 g of silver nitrate was fed and maintained at 10° C. In FIG. 5, the numeral 33 designates the mixing device shown in FIG. 1(a). To the mixing device (33), in which a supply tube and a discharge tube, each had an inside diameter of 4 mm, the foregoing potassium behenate solution and aqueous silver nitrate solution were supplied at a flow rate of 1500 ml/min and allowed to undergo nucleation. During the nucleation, the silver potential was continuously measured and after the variation thereof fell within 2 mV, 1500 ml of nucleus particles (or nucleus particles) was taken out and used in the subsequent stage. The variation of silver potential was 1.8 mV over the entire nucleation time. In FIG. 5, numerals 38 and 39 designate a flowmeter and a pump, respectively.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:24][CH:23]=1
Reactant: COc1cc2c(=O)[nH]c3nccc(Cl)c3c2cc1OC
Reactant: Nc1ccc(F)cc1
Product: COc1cc2c(=O)[nH]c3nccc(Nc4ccc(F)cc4)c3c2cc1OC
Yield: 3.2 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 212 using Compound 211 (50 mg, 0.17 mmol) and 4-fluoroaniline (25 mg, 0.22 mmol) to provide 215 (2 mg, 2% yield) as a white solid. LC-MS (M+H=366, obsd.=366).
Reaction SMILES: [C:1]([C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([O:32][CH2:33][CH3:34])[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([O:41][NH2:42])([CH3:40])([CH3:39])[CH3:38]>>[C:37]([O:41][N:42]=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH:27]([O:32][CH2:33][CH3:34])[C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:25]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CCOC(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)C(=O)OC
Reactant: CC(C)(C)ON
Product: CCOC(Cc1ccc(OCCn2c(=O)sc3cc(C(=NOC(C)(C)C)c4ccccc4)ccc32)cc1)C(=O)OC

Procedure:
Starting from the compound obtained in Step C of Example 1, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-(tert-butyl)hydroxylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.C(N(CC)CC)C.CS(C)=O.[C]=O.[CH3:40][CH2:41][O:42][C:43](C)=[O:44]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:43]([O:42][CH2:41][CH3:40])=[O:44]
Reactant: CCOC(C)=O
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Temperature: 100 °C
Yield: 82 %

Procedure:
Add 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (213 g, 500 mmol), triethylamine (118 g, 1150 mmol), palladium(II) acetate (5.6 g, 25 mmol) and 1,3-bis(diphenylphosphino)propane (6.4 g, 15 mmol) to anhydrous DMSO (2.1 L) and ethanol (640 mL) in a 1 gallon autoclave. Inert the autoclave with nitrogen then charge the mixture with carbon monoxide at 50 psi and heat at 100° C. for 2 h (monitor reaction by HPLC). Cool the autoclave to room temperature and add the dark reaction mixture to a flask containing water (3.2 L) and EtOAc (3.2 L). Collect the organic layer and back extract the aqueous layer with EtOAc (2.1 L). Wash the combined organic extracts with water (2.1 L). Concentrate the organic layer in vacuo to a dark oil. Purify the crude mixture by chromatography on silica gel eluting with heptane/EtOAc (5:1) to give the desired intermediate as a pale green oil (144 g, 82%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[NH:9][C:8](=[O:14])[C:7]3[S:15][CH:16]=[CH:17][C:6]=3[C:5]=2[C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH3:30])[CH2:25][S:26]([NH2:29])(=[O:28])=[O:27])=[CH:20][CH:19]=1.BrB(Br)Br>>[OH:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[NH:9][C:8](=[O:14])[C:7]3[S:15][CH:16]=[CH:17][C:6]=3[C:5]=2[C:4]=1[C:18]1[CH:19]=[CH:20][C:21]([CH:24]([CH3:30])[CH2:25][S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:23]=1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CS(N)(=O)=O)cc1
Agent: BrB(Br)Br
Product: Cc1cc(O)c(-c2ccc(C(C)CS(N)(=O)=O)cc2)c2c1[nH]c(=O)c1sccc12
Yield: 45.4 %

Procedure:
Following General Procedure F, 2-(4-(8-methoxy-6-methyl-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propane-1-sulfonamide (16 mg, 0.036 mmol) was reacted with tribromoborane (1.0 M in methylene chloride, 1.0 mL, 1.0 mmol) to afford the desired product (7.0 mg, 44%) as a light brown solid: 1H NMR (500 MHz, CD3OD) δ 7.68 (d, J=8.4 Hz, 2H), 7.54 (d, J=5.4 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.07 (s, 1H), 6.08 (d, J=5.4 Hz, 1H), 2.57 (s, 3H), 1.86 (s, 6H); ESI MS m/z 429 [C21H20N2O4S2+H]+; HPLC 98.7%, tR=8.51 min.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@H:16]3[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl.[NH:35]1[CH:39]=[C:38]([CH2:40][C:41](O)=[O:42])[N:37]=[CH:36]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:35]1[CH:39]=[C:38]([CH2:40][C:41]([N:21]2[CH2:20][CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[CH2:17][C@H:16]2[C:14](=[O:15])[NH:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:32]=[CH:33][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:12][CH:11]=2)=[O:42])[N:37]=[CH:36]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1
Reactant: O=C(O)Cc1c[nH]cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.3 %

Procedure:
Step (c) A flask was charged with (S)-benzyl 3-(4-(4-fluorophenoxy)phenylcarbamoyl)piperazine-1-carboxylate (1.08 g, 2.41 mmol), 4-imidazoleacetic acid hydrochloride (392 mg, 2.41 mmol), DIEA (1.0 mL, 5.8 mmol), HATU (1.01 g, 2.65 mmol) and DMF (5 mL). The reaction mixture was stirred at ambient temperature for 20 minutes and then quenched with saturated sodium bicarbonate (aq., 10 mL). The mixture was extracted with ethyl acetate (20 mL) and the extract was washed with deionized water (10 mL) and then brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Product was purified from the residue by reverse phase HPLC to give Compound 257, (S)-benzyl 4-(2-(1H-imidazol-4-yl)acetyl)-3-(4-(4-fluorophenoxy)phenylcarbamoyl)piperazine-1-carboxylate (0.80 g, 1.43 mmol, 67% yield), as an off-white solid. 1H-NMR (400 MHz, CDCl3): 10.27 (s, 1H), 9.18 (s, 1H), 7.60-7.49 (m, 3H), 7.47-7.21 (m, 5H), 7.06-6.91 (m, 6H), 5.45 (s, 1H), 5.17 (s, 2H), 5.09-5.00 (m, 2H), 4.04 (m, 2H), 4.09-3.97 (m, 2H), 3.81-3.73 (m, 2H), 3.46-3.77 (m, 1H), 3.17 (dd J=13.6, 4.8 Hz, 1H), 3.13-3.00 (m, 1H). MS (EI) for C30H28FN5O5. found 558.2 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][O:14][C:12]1[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]2[NH:20][C:21](=[O:37])[CH2:22][C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3)c1)=N2

Procedure:
The title compound was prepared from {5-methoxy-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M155) (320 mg, 0.604 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (164 mg, 66%).
Reaction SMILES: [NH2:1][C:2]([CH3:13])([CH3:12])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=O.B.CO>C1COCC1>[CH3:13][C:2]([NH2:1])([CH3:12])[CH2:3][CH2:4][N:6]1[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1
Reactant: CC(C)(N)CC(=O)N1CCOCC1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(N)CCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
3-Amino-3-methyl-1-morpholinobutan-1-one (0.55 g, 2.96 mmol) and borane in THF (1 M, 6 mL, 6 mmol) were mixed together. The mixture was stirred at room temperature overnight, another portion borane in THF (6 mL) was added and the mixture stirred for another day. Methanol (5 mL) was added and the solvent was removed in vacuo. Water (20 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The LC-MS showed still product in the water phase which was now extracted with methylene chloride (2×20 mL). The organic phases were combined, dried over anhydrous sodium sulfate and the solvent was removed in vacuo to give the crude product (0.09 g); MS (EI): m/e=173.2 [M+H]+.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([N:18]1[C:30]2[C:29]([CH3:31])=[C:28]([C:32](OCC)=[O:33])[CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.[OH-].[Na+]>CCCCCC.C(Cl)Cl>[CH2:11]([N:18]1[C:30]2[C:29]([CH3:31])=[C:28]([CH:32]=[O:33])[CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1ccc2c3ccccc3n(Cc3ccccc3)c2c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1c(C=O)ccc2c3ccccc3n(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
1.6 ml of a 1.5M solution of diisobutylaluminum hydride in hexane was added at -78° C. to a solution of 213 mg of ethyl 9-benzyl-1-methylcarbazole-2-carboxylate, as obtained in Example 28, in 5 ml of methylene chloride. The reaction mixture was stirred for 1 hour at this temperature, warmed to room temperature, and then stirred for a further 1 hour at room temperature. After this time, 0.1 ml of water, 0.1 ml of a 1N aqueous solution of sodium hydroxide and 0.3 ml of water were added successively to the reaction mixture. Precipitated crystals were filtered off and the filtrate was then concentrated by evaporation under reduced pressure. 187 mg of pyridinium dichromate and molecular sieve 4A, followed by 2 ml of methylene chloride, were added to 100 mg of the thus obtained residue. The resulting mixture was stirred for two hours at room temperature, filtered using Florisil (trade mark), and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 2 g of silica gel with a 5:1 v/v mixture of hexane and ethyl acetate as the eluent, to yield 94 mg of the title compound as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:11]([N+:20]([O-])=O)=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2>CCO.[Pd]>[NH2:20][C:11]1[C:10]([O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][C:3]=2[O:2][CH3:1])=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2
Reactant: CCOC(=O)Cc1ccc(Oc2ccc3ncccc3c2[N+](=O)[O-])c(OC)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(Oc2ccc3ncccc3c2N)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Pd/C (30 mg) was added to 24.3 (310 mg) in EtOH (10 mL). The mixture was stirred under hydrogen at room temperature for 6 h. The catalyst was removed by filtration through celite. The filtrate was concentrated under vacuum to give 24.4. MS ESI (pos.) m/z: 353.1 (M+H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:20])=[C:15]([C:17](=[O:19])[CH3:18])[CH:16]=1>CN(C=O)C>[Br:1][C:13]1[C:14]([OH:20])=[C:15]([C:17](=[O:19])[CH3:18])[CH:16]=[C:11]([CH2:10][Cl:9])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1cc(CCl)ccc1O
Solvent: CN(C)C=O
Product: CC(=O)c1cc(CCl)cc(Br)c1O
Reaction time: 15 h

Procedure:
A solution of N-bromosuccinimide (10 mmol) in 8 mL of DMF is added dropwise to a solution of 1-(5-chloromethyl-2-hydroxy-phenyl)-ethanone 211 (10 mmol) in 20 mL DMF and the resulting mixture is stirred for 12-18 h. The solvent is evaporated under reduced pressure and the residue is diluted with water resulting in the formation of a solid. The solid is isolated and recrystallized from ethanol to yield 1-(3-Bromo-5-chloromethyl-2-hydroxy-phenyl)-ethanone 212.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: COC(=O)c1ccc2occ(Br)c2c1
Product: COC(=O)c1ccc2occ(-c3ccccc3Cl)c2c1
Yield: 92 %

Procedure:
In the same manner as in Reference Example 19 and using methyl 3-bromo-1-benzofuran-5-carboxylate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and (2-chlorophenyl)boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 92%) was obtained as colorless crystals.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][C@H:3]2[CH2:7][CH2:8][CH2:9][C@@H:2]12.F[C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][N:12]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[I:17][C:14]1[CH:15]=[CH:16][C:11]([N:1]2[C:5](=[O:6])[CH2:4][C@H:3]3[CH2:7][CH2:8][CH2:9][C@@H:2]23)=[N:12][CH:13]=1
Reactant: Fc1ccc(I)cn1
Reactant: O=C1C[C@H]2CCC[C@H]2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1C[C@H]2CCC[C@H]2N1c1ccc(I)cn1
Temperature: 105 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
To a solution of (3aR,6aR)-hexahydrocyclopenta[b]pyrrol-2(1H)-one (210 mg, 1.68 mmol) and 2-fluoro-5-iodopyridine (412 mg, 1.85 mmol, 1.1 equiv.) in toluene (1.1 ml) were added Cs2CO3 (656 mg, 2.01 mmol, 1.2 equiv.) The reaction was stirred for 16 h at 105° C. The residue was taken up in ethyl acetate, the solids were filtered off and washed with ethyl acetate. The filtrate was concentrated in vaccuo and the residue was purified by flash chromatography (SiO2, 20 g) using a 0% to 60% ethyl acetate in heptane gradient. One obtains the title compound, (300 mg 55%), as a colorless oil, MS: m/e=329.4 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][CH2:28][C:23]([OH:29])([CH3:22])[CH2:24][CH2:25]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC1(O)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(O)CCN(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)CC1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 4-methylpiperidin-4-ol hydrochloride (586375-35-1) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=382.6 [MH+].
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:20])(=[O:19])[N:11]([CH2:13][C:14]([O:16][CH2:17]C)=[O:15])[CH3:12])=O.C[O-].[Na+].Cl>>[OH:2][C:3]1[C:5]2[S:6][CH:7]=[CH:8][C:9]=2[S:10](=[O:20])(=[O:19])[N:11]([CH3:12])[C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCOC(=O)CN(C)S(=O)(=O)c1ccsc1C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: COC(=O)C1=C(O)c2sccc2S(=O)(=O)N1C
Reaction time: 0.25 h

Procedure:
13.2 G. (0.041 mol) of the obtained 3-(N-carbethoxymethyl-N-methylsulfamoyl)-thiophene-2-carboxylic acid methyl ester are suspended in 42 ml. of a 1-N methanolic sodium methylate solution in the cold and under a nitrogen atmosphere, everything dissolving after stirring for 15 minutes. The solution is heated to reflux for 25 minutes, cooled, neutralized with concentrated hydrochloric acid and evaporated in vacuo. The residue is taken up in methylene chloride, shaken out once each time with water and a 5% sodium bicarbonate solution, dried and evaporated. The crystalline residue is digested with a small amount of methanol for purification. There is obtained 4-hydroxy-3-methoxycarbonyl-2-methyl-2H-thieno[2,3-e]-1,2-thiazine 1,1-dioxide of melting point 193°-195° C., which can be converted by reaction with 2-aminothiazole in a manner analogous to that described in the last part of Example 1 into the 4-hydroxy-2-methyl-N-(2-thiazolyl)-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide of melting point 217° C. (decomposition).