Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13](O)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]([O:24][CH3:25])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccc(O)c([N+](=O)[O-])c1)c1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Cc1ccc(OC(=O)c2ccccc2)cc1[N+](=O)[O-]
Yield: 63436.2 %

Procedure:
A mixture of 4-hydroxy-3-nitrophenyl benzoate (48.8 g, 0.19 mol), methyl bromoacetate (28.8 g, 0.19 mmol), anhydrous potassium carbonate (33.8 g, 0.24 mol) and acetone (700 mL) was heated at reflux for 24 h. The mixture was evaporated in vacuo and the residue partitioned between aqueous NaOH (1 M, 1 L) and dichloromethane (3×200 mL). The combined organic extracts were washed with aqueous NaOH (1 M, 500 mL), water (500 mL) and brine (250 mL), then dried (Na2SO4) and evaporated in vacuo to give a solid. Crystallisation from methanol with charcoal treatment gave the title compound (38 g, 61%) as pale yellow needles.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Cl[CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:17][C:18](=[O:19])[N:20]([CH3:22])[CH3:21])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CN(C)C(=O)CCl
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(OCC(=O)N(C)C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.2 %

Procedure:
A mixture of 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (2 g, 10 mmol), 2-chloro-N,N-dimethylacetamide (1.33 g, 11 mmol) and cesium carbonate (9.8 g, 30 mmol) ) in dimethylformamide (20 mL) was stirred at room temperature for 16 hours. The reaction was diluted with ethyl acetate (150 mL), washed with water (5×50 mL) and brine, dried and concentrated. The residue was recrystallized from ethyl acetate and hexane to give 1.4 g of 5-dimethylcarbamoylmethoxy-1H-indole-2-carboxylic acid ethyl ester as a brown solid.
Reaction SMILES: [Cl:1][C:2]1(Cl)[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]3[C:17]([C:5]=2[CH2:4][CH2:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=3.O.O.O.C([O-])(=O)C.[Na+].[H][H]>C(O)(=O)C.[Pd]>[Cl:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]3[C:17]([C:5]=2[CH2:4][CH2:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: O=C1Nc2ccc3ccccc3c2CCC1(Cl)Cl
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1Nc2ccc3ccccc3c2CCC1Cl
Reaction time: 0.08 h
Yield: 31.4 %

Procedure:
A solution of 3,3-dichloro-4-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b]azepine (6.2 g, 22 mmol) in glacial acetic acid (200 ml) was placed under an atmosphere of nitrogen. Sodium acetate trihydrate (3.8 g, 28 mmol) was added. After 5 minutes palladium on carbon (10%, 0.6 g) was added and the reaction mixture was hydrogenated at atmospheric pressure and room temperature using 450 ml of hydrogen gas. The reaction mixture was filtered through Celite and the solvent was evaporated in vacuo. After reevaporation with toluene (250 ml), the residue was suspended in water (100 ml), stirred for 5 minutes and the solid was isolated by filtration and dried in vacuo to afford 1.7 g of 3-chloro-4-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b]azepine.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>ClC1C=CC=CC=1Cl.[Cu]>[Br:14][C:15]1[CH:16]=[C:17]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1cccc(I)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Product: Brc1cccc(-n2c3ccccc3c3ccccc32)c1
Temperature: 100 °C

Procedure:
4 g of carbazole, 8.08 g of 1-bromo-3-iodobenzene, 13.2 g of potassium carbonate, 3.08 g of copper powder and 0.63 g of dibenzo-18-crown-6 were dissolved in 30 mL of o-dichlorobenzene, and the resulting solution was refluxed at a steady 100° C. After completion of the reaction, the reaction mixture was extracted with dichloromethane and distilled water, and the solvent was dried. The resulting solid was filtered and purified, yielding 9-(3-bromophenyl)-9H-carbazole as an intermediate.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:26](=[O:31])[NH:27][CH:28]([CH3:30])[CH3:29])([CH3:25])[CH3:24])[CH:17]=1)[C:10]([CH3:33])([CH3:32])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH:28]([NH:27][C:26]([C:23]([NH:22][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:33])([CH3:32])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1)([CH3:25])[CH3:24])=[O:31])([CH3:30])[CH3:29]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)NC(C)C)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)NC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 32.7 %

Procedure:
A mixture of 2-[3-(1-isopropylcarbamoyl-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.85 g, 1.88 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (10 mL) was stirred at 50° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(1-isopropylcarbamoyl-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (260 mg, 30%) as a white solid: LC/MS m/e calcd for C25H33N3O3 (M+H)+: 424.56, observed: 424.1.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]([C@H:11]([CH2:13][N:14]([CH3:16])[CH3:15])[CH3:12])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1.CC(=O)CC.C[Si](C)(C)[Cl:24]>O>[CH3:1][CH2:2][C@H:3]([C@H:11]([CH2:13][N:14]([CH3:16])[CH3:15])[CH3:12])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1.[ClH:24]
Reactant: C[Si](C)(C)Cl
Agent: CC[C@@H](c1cccc(O)c1)[C@@H](C)CN(C)C
Solvent: CCC(C)=O
Solvent: O
Product: Cl
Temperature: 22.5 °C

Procedure:
Tapentadol free base (2.1 g) was added to 2-butanone (32 ml), the mixture was heated to reflux and followed by the addition of water (0.22 ml) and trimethylchlorosilane (1.6 ml) at the same temperature and then maintaining for 1 hour. The resulting mass was cooled at 20-25° C. The resulting solid was filtered, the product was washed with pre-cooled 2-butanone (4 ml) and then the solid was dried at 25° C. for 3 hours to produce 1.8 g of tapentadol hydrochloride salt (Purity by HPLC: 97.78%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:14][CH:15]([NH:17][CH2:18][CH2:19]O)[CH3:16])[S:10]([CH3:13])(=[O:12])=[O:11].[ClH:21]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:14][CH:15]([NH:17][CH2:18][CH2:19][Cl:21])[CH3:16])[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: Cc1cccc(C)c1N(CC(C)NCCO)S(C)(=O)=O
Reactant: Cl
Product: Cc1cccc(C)c1N(CC(C)NCCCl)S(C)(=O)=O
Yield: 87 %

Procedure:
The title compound is prepared as described in Example 50, with the difference that 1-[N-(2,6-dimethylphenyl)-methane-sulfonamido]-2-(2-hydroxy-ethylamino)-propane, prepared according to Example 46, is applied as starting substance. The product is obtained with a yield of 87%; its hydrochloride melts at 185°-190° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][N:25]1[C:29]2=[N:30][CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=[C:28]2[N:27]=[CH:26]1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:33]=[C:28]6[N:27]=[CH:26][N:25]([CH3:24])[C:29]6=[N:30][CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: Cn1cnc2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc5c(c4)ncn5C)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine (Stage 74.1.1) to give the title compound as a white solid. (HPLC: tR 2.26 min (Method A); M+H=425 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.52-8.46 (m, 2H), 8.20-8.08 (m, 3H), 8.05-7.98 (m, 1H), 7.60-7.55 (m, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:19])[C:14]([O:16]CC)=[O:15])=[CH:9][CH:8]=1)(=[O:4])=[O:3].O1CCCC1.O.[OH-].[Na+]>C(OCC)(=O)C.C(O)(=O)C>[CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:19])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)C(C)c1ccc(CNS(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(CNS(C)(=O)=O)cc1
Temperature: 25 °C
Yield: 25.2 %

Procedure:
To a stirred solution of ethyl 2-(4-(methylsulfonamidomethyl)phenyl)propanoate (325 mg, 1.139 mmol) in co-solvent with tetrahydrofuran and water (1:1) were added sodium hydroxide (114 mg, 2.8475 mmol). The reaction mixture was refluxed for 16 h, then cooled to room temperature, acidified to pH 3-4 with acetic acid. The residue dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography to give 2-(4-(methylsulfonamidomethyl)phenyl)propanoic acid (74 mg, 25%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[O:8][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[CH2:10][C:3]=12.[CH2:18]([NH2:21])[CH2:19][NH2:20]>>[NH2:20][CH2:19][CH2:18][NH:21][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[O:8][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[CH2:10][C:3]=12
Reactant: Clc1ccnc2c1CC1(CN3CCC1CC3)O2
Reactant: NCCN
Product: NCCNc1ccnc2c1CC1(CN3CCC1CC3)O2
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of 74 mg (0.295 mmol) of 4′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] in 10 mL of ethylenediamine was heated to reflux under a nitrogen atmosphere and stirred for 4 days. Upon cooling to ambient temperature, the solvent was removed in vacuo. The residue was dissolved in 20 mL of saturated aqueous sodium carbonate and extracted with chloroform (3×25 mL). The combined organic extract was dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound as a dark oil, 80 mg (100%): electrospray MS (m/z, relative intensity) 275 ([MH]+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.[C:21]1([CH3:31])[CH:26]=[CH:25][CH:24]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:22]=1>>[C:21]1([CH3:31])[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:10]=3[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]4)[CH2:3][CH2:2]2)(=[O:29])=[O:28])[CH:22]=1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Product: Cc1cccc(S(=O)(=O)N2CCC(COc3cccc4nc(N)nc(N)c34)CC2)c1
Yield: 83 %

Procedure:
The sulfonamide was obtained by reacting 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) and m-toluenesulfonyl chloride (71 mg; 0.37 mmol) via Method AA to yield 131 mg. (83% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.54 (m, 4H), 7.47 (t, J=8.4 Hz, 1H), 7.10 (br s, 2H), 6.75 (d, J=8.4 Hz, 1H), 6.49 (d, J=8.0 Hz, 1H), 5.93 (br s, 2H), 3.95 (d, J=6.0 Hz, 2H), 3.69 (br d, J=11.6 Hz, 2H), 2.42 (s, 3H), 2.23 (t, J=12.0 Hz, 2H), 1.86 (m, 3H), 1.36 (m, 2H). MS m/z (ESI) 428 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][O:13][CH3:14])[CH:8]=[C:7]([O:15][CH2:16][O:17][CH3:18])[CH:6]=1.[Br:19]N1C(=O)CCC1=O.O>CN(C)C=O>[CH3:18][O:17][CH2:16][O:15][C:7]1[C:8]([Br:19])=[C:9]([CH2:11][CH2:12][O:13][CH3:14])[CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCc1cc(OCOC)cc(OCOC)c1
Solvent: CN(C)C=O
Solvent: O
Product: COCCc1cc(OCOC)cc(OCOC)c1Br
Temperature: 4 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
1,3-Bis(methoxymethoxy)-5-(2-methoxyethyl)benzene (5.00 g, 19.5 mmol) obtained in Example 1, Step 3 was dissolved in N,N-dimethylformamide (40 mL). After the solution was cooled to 4° C., N-bromosuccinimide (3.47 g, 19.5 mmol) was added thereto, followed by stirring for 1 hour. To the reaction mixture was added water (0.10 L), and the mixture was extracted with a mixed solvent of hexane and ethyl acetate (hexane/ethyl acetate=1/1, 0.30 L). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9-1/2) to obtain 3,5-bis(methoxymethoxy)-2-bromo-1-(2-methoxyethyl)benzene (5.7 g, 87%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[CH3:8].[CH3:9][S-:10].[Na+]>CO>[CH3:8][C:3]1[N:4]=[C:5]([NH2:7])[S:6][C:2]=1[S:10][CH3:9]
Reactant: C[S-]
Reactant: Cc1nc(N)sc1Br
Agent: [Na+]
Solvent: CO
Product: CSc1sc(N)nc1C
Reaction time: 8 h

Procedure:
5-Bromo-4-methyl-thiazol-2-ylamine (1.35 g, 7 mmol,) was dissolved in methanol abs. (13.5mL) and sodium methanethiolate (0.6 g, 7.7 mmol) 1.1 equiv.) was added portionwise at rt. After stirring overnight, the dark colored mixture was concentrated under reduced pressure and purified over a 50 g silica cartridge (NH2-modified) with ethyl acetate as eluent. The desired fractions were evaporated to give the title compound as a light yellow solid: 180 mg, MS (ISP): m/e 161.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:22][CH:23]3[CH2:40][CH:39]4[N:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]5[C:36]([C:42](O)=[O:43])([NH:37][C:38]4=[O:41])[CH2:35]5)[CH2:24]3)=[N:8][C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:10]2)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.[CH3:58][C:59]1([S:62]([NH2:65])(=[O:64])=[O:63])[CH2:61][CH2:60]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:22][CH:23]3[CH2:40][CH:39]4[N:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]5[C:36]([C:42]([NH:65][S:62]([C:59]6([CH3:58])[CH2:61][CH2:60]6)(=[O:64])=[O:63])=[O:43])([NH:37][C:38]4=[O:41])[CH2:35]5)[CH2:24]3)=[N:8][C:9]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: CC1(S(N)(=O)=O)CC1
Reactant: COc1ccc(-c2nc(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)c3ccc(OC)c(C)c3n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1ccc(-c2nc(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6(C)CC6)CC5C=CCCCCN(C)C(=O)N4C3)c3ccc(OC)c(C)c3n2)cc1
Temperature: 25 °C
Yield: 21.5 %

Procedure:
The acid (130) (35 mg, 0.056 mmol) was dissolved in DCM (2 ml). EDAC (13 mg, 0.067 mmol) was added and the mixture was stirred at room temperature over night. Methylcyclopropanesulfonic acid amide (8.2 mg, 0.061 mmol) and DBU (18 μl, 0.117 mmol) was added and the reaction mixture was stirred at room temperature over night. 5% Citric acid was added to the reaction mixture, and the mixture was extracted with brine, dried over Na2SO4 and purified by HPLC to give the title compound (9 mg, 22%). MS (M+H)=747.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4](O)=O)[CH3:3].[NH2:14][C:15]1[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=1[NH2:21].C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1.CCOC(C)=O.CC(O)=O>[F:22][C:17]1[CH:18]=[CH:19][C:20]2[N:21]=[C:4]([C@@H:2]([NH:1][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:3])[NH:14][C:15]=2[CH:16]=1
Reactant: Nc1ccc(F)cc1N
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Boc-L-Ala-OH (3.00 g, 15.86 mmol) and 3,4-diamino-1-fluorobenzene (2.00 g, 15.86 mmol) were mixed in pyridine (52.9 mL). EDCBCl (9.12 g, 47.6 mmol) was added and the mixture was stirred at ambient temperature for 20 min. The reaction mixture was diluted with EtOAc, washed with water, 1.0 N HCl and brine. The organic layer was dried with Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography on a 120 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane as eluent. The desired fractions were combined and concentrated under reduced pressure to give the crude amide intermediate. The amide was dissolved in AcOH (26.9 mL) and heated in an oil bath at 70° C. for about 30 min. The reaction mixture was diluted with EtOAc and carefully neutralized with aq. K2CO3. The organic layer was washed with NaCl, dried with Na2SO4, and filtered. The filtrate was concentrated to dryness to yield (S)-tert-butyl 1-(6-fluoro-1H-benzo[d]imidazol-2-yl)ethylcarbamate: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.23 (1H, br. s.), 7.15-7.61 (3H, m), 6.98 (1H, t, J=8.5 Hz), 4.78-4.89 (1H, m), 1.46 (3H, d, J=7.0 Hz), 1.40 (9H, s); LC-MS (ESI) m/z 280.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[CH3:11].[C:12]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[CH3:11][C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][O:6][C:2]=1[NH:1][S:18]([C:15]1[CH:14]=[CH:13][C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Cc1c(C(F)(F)F)noc1N
Product: Cc1c(C(F)(F)F)noc1NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Yield: 78 %

Procedure:
N-(4-Methyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylsulfonamide was prepared, as described in Example 194, from 5-amino-4-methyl-3-trifluoromethylisoxazole and 4-biphenyisulfonyl chloride in 78% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a white solid, m.p. 139-140° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][S:11][CH3:12]>>[CH3:12][S:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: CSCCCl
Reactant: O=C1CCNCC1
Product: CSCCN1CCC(=O)CC1

Procedure:
1-(2-Methylthioethyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-2-methylthioethane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: C(N1C2C(=CC(N)=CC=2)CC1)(=O)C.[C:14]([N:17]1[C:25]2[CH:24]=[C:23]3[C:26](=[O:30])[C:27](=[O:29])[NH:28][C:22]3=[CH:21][C:20]=2[CH2:19][CH2:18]1)(=[O:16])[CH3:15].[CH:31]1[C:36]([NH:37][NH2:38])=[CH:35][CH:34]=[C:33]([S:39]([NH2:42])(=[O:41])=[O:40])[CH:32]=1.Cl>O>[C:14]([N:17]1[C:25]2[CH:24]=[C:23]3[C:26](=[O:30])[C:27](=[O:29])[NH:28][C:22]3=[CH:21][C:20]=2[CH2:19][CH2:18]1)(=[O:16])[CH3:15].[C:14]([N:17]1[C:25]2[CH:24]=[C:23]3[C:26](=[N:38][NH:37][C:36]4[CH:35]=[CH:34][C:33]([S:39]([NH2:42])(=[O:40])=[O:41])=[CH:32][CH:31]=4)[C:27](=[O:29])[NH:28][C:22]3=[CH:21][C:20]=2[CH2:19][CH2:18]1)(=[O:16])[CH3:15]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: CC(=O)N1CCc2cc(N)ccc21
Agent: CC(=O)N1CCc2cc3c(cc21)C(=O)C(=O)N3
Agent: Cl
Solvent: O
Product: CC(=O)N1CCc2cc3c(cc21)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N3

Procedure:
5-Acetyl-1,5,6,7-tetrahydro-pyrrolo[2,3-f]indole-2,3-dione was prepared from 1-acetyl-5-aminoindoline according to Procedure A in 90% yield: mp>250° C.; 1H NMR (DMSO-d6): δ 2.11 (s,3H), 3.16 (t, J=8.4 Hz, 2H), 4.06 (t, J=8.4 Hz, 2H), 6.78 (s, 1H), 8.02 (s, 1H), 10.87 (s, 1H); APCI−MS: m/z 229 (M−H)−. Anal. Calcd for C12H10N2O3.0.3 H2O: C, 61.17; H, 4.53; N, 11.89. Found: C, 60.91; H, 4.62; N, 12.10. The title compound was prepared from 5-acetyl-1,5,6,7-tetrahydro-pyrrolo[2,3-f]indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 53% yield: mp>250° C.; 1H NMR (DMSO-d6):d2.13 (s,3H), 3.13 (t, J=8.4 Hz, 2H), 4.06 (t, J=8.4 Hz, 2H), 6.79 (s, 1H), 7.22 (s, 2H), 7.48 (d, J=8.7 Hz, 2H), 7.76 (d, J=8.7 Hz, 2H), 8.24 (s, 1H), 10.96 (s, 1H), 12.78 (s, 1H); APCI−MS: m/z 422 (M+Na)+. Anal. Calcd for C18H17N5O4S: C, 54.13; H, 4.29; N, 17.53; S, 8.03. Found: C, 53.85; H, 4.23; N, 17.28; S, 7.89.
Reaction SMILES: Cl[P:2]1(=[O:7])[O:6][CH2:5][CH2:4][O:3]1.[Si:8]([O:15][CH2:16][CH2:17][OH:18])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[Si:8]([O:15][CH2:16][CH2:17][O:18][P:2]1(=[O:7])[O:6][CH2:5][CH2:4][O:3]1)([C:11]([CH3:13])([CH3:14])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OCCO
Reactant: O=P1(Cl)OCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCOP1(=O)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of freshly prepared 2-chloro-2-oxo-1,3,2-dioxaphospholane (14.2 g, 0.1M) in dry dichloromethane (30 ml) was added, drop-wise, to a stirred mixture of 2-(tert-butyldimethylsilyloxy)ethanol (17.6 g, 0.1M), triethylamine (18.1 ml), 0.13M) in dry dichloromethane (30 ml) at 0° C. under a nitrogen atmosphere. The mixture was allowed to warm to ambient temperature and was stirred for a further 2 hours. The mixture was filtered and the filtrand washed with n-hexane. The filtrate was evaporated in vacuo, diluted with n-hexane (30 ml) filtered and the filtrate evaporated in vacuo to give a brown oil.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)=[O:6])[CH2:2]1.CCN(C(C)C)C(C)C.[O:27]1[CH2:32][CH2:31][CH:30]([CH2:33][C:34](Cl)=[O:35])[CH2:29][CH2:28]1.Cl>C(Cl)Cl.O>[CH:14]1([N:10]2[CH2:11][CH2:12][CH2:13][N:7]([C:5]([CH:3]3[CH2:2][N:1]([C:34](=[O:35])[CH2:33][CH:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)[CH2:4]3)=[O:6])[CH2:8][CH2:9]2)[CH2:17][CH2:16][CH2:15]1
Reactant: O=C(Cl)CC1CCOCC1
Reactant: O=C(C1CNC1)N1CCCN(C2CCC2)CC1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CC1CCOCC1)N1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 2.5 %

Procedure:
To a stirred solution of 1-(azetidin-3-ylcarbonyl)-4-cyclobutyl-1,4-diazepane (30 mg, 0.13 mmol) and DIPEA (42 μl, 0.25 mmol) in DCM (1 ml) was added tetrahydropyran-4-yl acetyl chloride (21 mg, 0.13 mmol) in DCM (1 ml). The reaction mixture stirred at RT for 16 hrs. Upon completion, water and 1M HCl were added and the reaction mixture was washed with DCM (3×5 ml). The combined organic phases were dried (MgSO4), filtered and concentrated at reduced pressure. The residue was purified by preparative HPLC to afford the title compound as colourless oil (1.2 mg, 3% yield).