Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[Br:11].CC(C)([O-])C.[K+].[F:18][C:19]([F:26])([C:22]([F:25])([F:24])[F:23])[CH2:20][OH:21].Cl>CN(C=O)C.C1COCC1>[Br:11][C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=1[O:21][CH2:20][C:19]([F:26])([F:18])[C:22]([F:25])([F:24])[F:23]
Reactant: O=C(O)c1ccc(Br)c(Cl)n1
Reactant: OCC(F)(F)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Br)c(OCC(F)(F)C(F)(F)F)n1
Temperature: 140 °C
Reaction time: 96 h
Yield: 21.8 %

Procedure:
To a solution of 6-chloro-5-bromo-pyridine-2-carboxylic acid (CAN 959958-25-9, 1.7 g, 7.19 mmol) in DMF (90 mL) and THF (30 mL) was added potassium tert-butoxide (2.02 g, 18.0 mmol) and 2,2,3,3,3-pentafluoropropan-1-ol (5.73 mL, 57.5 mmol). The mixture was stirred at 140° C. for 4 days, cooled and poured into ice-water (100 mL). 2 M Hydrochloric acid (15 mL) was added to adjust the pH to 2-3 and the mixture was extracted with TBME, organic layers were washed twice with water, pooled, dried with Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, ethyl acetate/n-heptane gradient) to give the title compound (548 mg, 22%) as light-brown solid; LC-MS (UV peak area, ESI) 100%, 347.9306 [M−H−].
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH:10]=O)=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2].Cl.[CH3:28][NH:29][CH3:30]>CCOCC.C(Cl)Cl>[CH:1]([C:4]1[C:9]([CH2:10][N:29]([CH3:30])[CH3:28])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCCCc1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CN(C)C)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-4-(4-fluorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) and dimethylamine hydrochloride, according to the procedures described in Example 120. 1H NMR (300 MHz, CDCl3): δ 7.09 (m, 4 H), 3.49 (septet, J=6.6 Hz, 1 H), 3.21 (septet, J=6.6 Hz, 1 H), 3.05 (s, 2 H), 2.22 (t, J=5.2 Hz, 2 H), 1.99 (s, 6 H), 1.18 (m, 18 H), 0.790 (t, J =6.3 Hz, 3 H). FAB-MS: calcd for (C25H37FN2) 384, found 385 (M+H). Anal. Calcd for C23H37FN2: C, 78.08; H, 9.70; N, 7.28; F, 4.94. Found: C, 77.95; H, 9.66; N, 7.12; F, 5.25. mp 69-71° C. Rf=0.4 (20% ether/CH2Cl2).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[CH:16]=[CH:15][C:14]2[O:17][C:18]([CH3:20])=[CH:19][C:13]=2[C:12]1=[O:21].Br[CH2:23][CH2:24][CH2:25][Cl:26].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[Cl:26][CH2:25][CH2:24][CH2:23][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[CH:16]=[CH:15][C:14]2[O:17][C:18]([CH3:20])=[CH:19][C:13]=2[C:12]1=[O:21]
Reactant: Cc1cc2c(=O)n(Cc3nc4ccccc4[nH]3)ccc2o1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc2c(=O)n(Cc3nc4ccccc4n3CCCCl)ccc2o1
Temperature: 25 °C

Procedure:
5-(1H-Benzimidazol-2-ylmethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one(0.75 g), 1-bromo-3-chloropropane(1.3 ml), and potassium carbonate(0.95 g) were added to 50% hydrous acetonitrile(16 ml). The mixture was heated overnight under reflux. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1→0:1). The purified product was condensed to dryness under reduced pressure to give the title compound(0.18 g) as a colorless oily matter.
Reaction SMILES: N#N.C[O:4][C:5]1[CH:6]=[C:7]([C:15]2[C:16]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[S:34][C:33]([CH2:35][C:36]([OH:38])=[O:37])=[CH:32][CH:31]=3)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([O:13]C)[C:10]=1[O:11]C.B(Br)(Br)Br.O>C(Cl)Cl>[OH:4][C:5]1[CH:6]=[C:7]([C:15]2[C:16]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[S:34][C:33]([CH2:35][C:36]([OH:38])=[O:37])=[CH:32][CH:31]=3)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([OH:13])[C:10]=1[OH:11]
Reactant: COc1cc(-c2ccccc2C(=O)Nc2ccccc2-c2ccc(CC(=O)O)s2)cc(OC)c1OC
Agent: BrB(Br)Br
Agent: N#N
Solvent: ClCCl
Solvent: O
Product: O=C(O)Cc1ccc(-c2ccccc2NC(=O)c2ccccc2-c2cc(O)c(O)c(O)c2)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 19.7 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Dissolve (5-{2-[(3′,4′,5′-Trimethoxy-biphenyl-2-carbonyl)-amino]-phenyl}-thiophen-2-yl)-acetic acid (86) (55 mg, 0.11 mmol) in anhydrous DCM (3.2 mL) at −78° C., add dropwise a 1M solution of BBr3 in DCM (730 μL, 0.73 mmol) and stir for additional 30 min at −78° C. After slowly warming up stir the reaction solution for additional 4 h at rt. Cool reaction mixture to 0° C., add dropwise water. Extract the mixture with EtOAc (3×), wash combined organic layer with brine and dry it with Na2SO4. Purify the crude product by preparative RP HPLC (gradient, water/CH3CN 95:5 to 5:95) to obtain (5-{2-[(3′,4′,5′-Trihydroxy-biphenyl-2-carbonyl)-amino]-phenyl}-thiophen-2-yl)-acetic acid (87) (10 mg, 18%) as a yellow solid. 1H NMR (400 MHz, CD3OD): 3.88 (s, 2H); 6.50 (s, 2H); 6.66 (d, 1H, J=3.5 Hz); 6.93 (d, 1H, J=3.5 Hz); 7.23 (t; 1H, J=7.3 Hz); 7.35 (t, 1H, J=7.6 Hz); 7.38-7.46 (m, 3H); 7.50 (t, 1H, J=7.3 Hz); 7.62 (d, 1H, J=8.0 Hz); 7.84 (d, 1H, J=8.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:26]=[CH:27][CH:28]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[C:21]([C:23]([OH:25])=[O:24])[S:22][C:15]=12)=[O:8].Br[CH2:30][CH2:31][CH2:32][OH:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:26]=[CH:27][CH:28]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[C:21]([C:23]([O:25][CH2:30][CH2:31][CH2:32][OH:33])=[O:24])[S:22][C:15]=12)=[O:8]
Reactant: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc3cc(C(=O)O)sc23)c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc3cc(C(=O)OCCCO)sc23)c1
Temperature: 50 °C

Procedure:
To a stirred solution of 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylic acid (120 mg, 0.30 mmol) in anhydrous DMF (10 ml) were added 3-bromo-1-propanol (63 mg, 0.45 mmol) and potassium carbonate (83 mg, 0.60 mmol). The mixture was heated at 50° C. for 5 hours and poured into 100 ml of water. The precipitates were filtered, washed with water and dried to give the crude, which was purified by silica gel chromatography eluting with 3˜5% of methanol in chloroform to give 3-hydroxypropyl 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate as white solid. Yield: 25 mg, 18%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].C([Li])CCC.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1.O>[C:14]1([CH2:13][CH:3]2[CH2:4][CH2:5][CH2:6][NH:1][C:2]2=[O:7])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCCCN1
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1NCCCC1Cc1ccccc1
Temperature: -40 °C
Reaction time: 12 h
Yield: 53.9 %

Procedure:
To a stirred solution of 2-piperidone (40 g, 0.404 mol) in tetrahydrofuran (800 ml) at 0° C. was added, over a period of 2 hours, n-butyl lithium (2.5 M in hexane, 356 ml, 0.889 mol). The reaction was cooled to -40° C. and a solution of benzyl bromide (48 ml, 0.404 mol) in tetrahydrofuran (200 ml) was added dropwise over a period of 2 hours. The reaction was allowed to warm slowly to room temperature and stirred for 12 hours. Water (100 ml) and saturated aqueous ammonium chloride (100 ml) were added and the aqueous phase separated and extracted with ethyl acetate (3×100 ml). The combined organic phases were washed with brine (200 ml), dried with sodium sulphate and evaporated in vacuo. The resulting solid was recrystallised from toluene to give the desired product as white needles (41.2 g), m.pt. 120°-123° C. Low resolution mass spectroscopy revealed the mass/charge ratio of the parent molecule ion, M+, to be 190 thereby confirming the molecular of the product to be 190.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][N:31]([CH3:37])[C:32](=[O:36])[C:33](O)=[O:34]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:33]([C:32]([N:31]([CH3:37])[CH3:30])=[O:36])=[O:34])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)C(=O)O
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(=O)N(C)C)c1

Procedure:
Prepared as described in Example 76 using (1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (51 mg, 0.13 mmol) and 2-(dimethylamino)-2-oxoacetic acid (13 mg, 0.13 mmol). Yield 44 mg (69%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[Br:12]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:12][C:10]1[C:2]([F:1])=[CH:3][C:4]([OH:11])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)c1ccc(F)cc1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Br)c(F)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.5 %

Procedure:
To a stirring solution of 4-fluoro-2-hydroxy-benzoic acid (5.58 g, 35.7 mmol) in dimethyl formamide (72 mL, 0.5 M) was added N-bromosuccinimide (7.08 g, 39.3 mmol). The mixture was allowed to stir for 24 h at room temperature. Next, the mixture was diluted with 300 mL of ethyl acetate and washed successively with water (3×330 mL) and saturated aq LiCl (4×200 mL). The organic layer was dried over Na2SO4, filtered and concentrated to afford 5-bromo-4-fluoro-2-hydroxy-benzoic acid (8.1 g, 96%) as a beige powder. Please note, the product may contain up to 20% of a dibrominated impurity which may be separated from the desired product after coupling with a benzylamine or upon methylation (Example 50): Rf 0.32 (20% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 mHz) δ 8.00 (d, J=8.1 Hz, 1 H), 7.05 (d, J=10.5 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:19])[CH2:15][CH2:16][CH:17]=[CH2:18])=[CH:4][CH:3]=1.I[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:19])[CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccccc1
Reactant: C=CCCC(O)c1c(C)noc1-c1ccc(Br)cc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)CC/C=C/c1ccccc1

Procedure:
Prepared according to the procedure described in Example 168, Step 1, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-pent-4-en-1-ol and iodobenzene.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN1CCOCC1>CO>[CH2:21]([NH:28][S:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:3]3[C:4]([CH3:7])=[N:5][NH:6][C:2]=3[NH2:1])[S:9][C:10]=2[CH:16]=1)(=[O:19])=[O:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CO
Solvent: CN1CCOCC1
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCc3ccccc3)cc2s1
Yield: 13.4 %

Procedure:
the title compound (16 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), benzylamine (66 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 400.5 (M+1, 100%). Yield=13%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[C:4]2[CH2:12][CH2:13][C:14](=[N:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]1=2.N12CCCN=C1CCCCC2.[CH3:34][N:35]=[C:36]=[O:37]>C(Cl)Cl>[CH3:34][NH:35][C:36](=[O:37])[O:11][C:7]1[CH:8]=[CH:9][C:10]2[N:2]([CH3:1])[C:3]3[C:14](=[N:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:13][CH2:12][C:4]=3[C:5]=2[CH:6]=1
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=NCc1ccccc1
Reactant: CN=C=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CNC(=O)Oc1ccc2c(c1)c1c(n2C)C(=NCc2ccccc2)CC1
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To a stirred solution of 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol (2.0 g) in CH2Cl2 (40 n-A) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 g) followed by the dropwise addition of methyl isocyanate (0.39 g) in CH2Cl2 (10 ml). The reaction was monitored via TLC and after 3 hours the solution was concentrated and the precipitate was collected and recrystallized from acetonitrile to give 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl methylcarbamate (1.85 grams).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].[N+:20]([C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[CH2:25][CH2:26]Br)([O-:22])=[O:21]>C(O)C>[C:1]([NH:4][C:5]([CH2:26][CH2:25][C:24]1[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=1[N+:20]([O-:22])=[O:21])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1CCBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1[N+](=O)[O-])(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of diethyl acetamidomalonate (33.2 g) in ethanol (150 ml) was added to a solution of sodium ethoxide in ethanol [prepared from sodium (3.8 g) and ethanol (200 ml)]. The reaction mixture was stirred at room temperature for 30 minutes and a solution of 2-nitrophenethyl bromide (J. Med. Chem. 20, 1020 (1977), 40.0 g) in ethanol (100 ml) was added dropwise during 20 minutes. After addition was complete, the reaction mixture was refluxed for 18 hours, then cooled to room temperature and evaporated under reduced pressure. The residue was dissolved in water (350 ml) and the solution extracted with ethyl acetate (2×350 ml). The combined ethyl acetate extracts were washed with water (200 ml) and dried over magnesium sulfate. Removal of the solvent under reduced pressure gave diethyl 2-acetamido-2-(o-nitrophenethyl)malonate as a low melting solid, used without further purification for the next synthetic step.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:12]([N:14](CC)CC)C.ClC(OC(Cl)(Cl)Cl)=O.CN>ClCCl.CCO>[NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH:14][CH3:12])=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: CCN(CC)CC
Agent: CN
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCO
Solvent: ClCCl
Product: CNC(=O)c1cc(Br)cnc1N
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-amino-5-bromonicotinic acid (Combi-Blocks, San Diego, USA, 1.355 mmol) and triethylamine (0.378 ml) in dichloromethane (10 ml) cooled with an ice-bath was added a solution of trichloromethyl chloroformate (Acros, Basel, Switzerland, 0.677 mmol) in dichloromethane (10 ml). After 40 min stirring at 0° C., was added a solution 8 M of methylamine in EtOH (1.7 ml). The RM was stirred for 30 min at rt then was diluted with dichloromethane, washed with saturated aqueous NaHCO3, with brine, dried over Na2SO4, filtered and evaporated. The residue was taken in DMF and purified by preparative HPLC. The fractions containing product were basified with NaHCO3, concentrated and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as a white solid. (HPLC: tR 1.69 min (Method A); M+H=230, 232 MS-ES)
Reaction SMILES: C(OC([C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[CH:32])[CH:26]=2)=[N:17][CH:18]=[N:19]3)[CH2:9][C@@H:8]1[C:33]([O:35][CH3:36])=[O:34])=O)C=C.[NH2:37][C@@H]1CCN(CC2C=CC=C3C=2C(NC2C=CC=C(OC)C=2)=NC=N3)C[C@H]1C(NC)=O>CO>[NH2:37][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[CH:32])[CH:26]=2)=[N:17][CH:18]=[N:19]3)[CH2:9][C@H:8]1[C:33]([O:35][CH3:36])=[O:34]
Reactant: CNC(=O)[C@@H]1CN(Cc2cccc3ncnc(Nc4cccc(OC)c4)c23)CC[C@H]1N
Reactant: C#Cc1cccc(Nc2ncnc3cccc(CN4CC[C@@H](C(=O)OCC=C)[C@@H](C(=O)OC)C4)c23)c1
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3cccc(CN4CC[C@@H](N)[C@H](C(=O)OC)C4)c23)c1

Procedure:
Compound 18B was prepared from 18A in a similar way as 15F. It has an analytical HPLC retention time=1.546 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) and a LC/MS M++H=416+.
Reaction SMILES: [OH:1]O.[C:3]([C:7]1[CH:12]=[C:11]([CH2:13][S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:10]=[C:9]([CH3:23])[C:8]=1[OH:24])([CH3:6])([CH3:5])[CH3:4]>CC(C)=O>[C:3]([C:7]1[CH:12]=[C:11]([CH2:13][S:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:1])[CH:10]=[C:9]([CH3:23])[C:8]=1[OH:24])([CH3:5])([CH3:6])[CH3:4]
Reactant: OO
Reactant: CCCCCCCCSCc1cc(C)c(O)c(C(C)(C)C)c1
Solvent: CC(C)=O
Product: CCCCCCCCS(=O)Cc1cc(C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 26 h
Yield: 72.1 %

Procedure:
5.7 g of 30% hydrogen peroxide are added dropwise at 0° C. to 16.1 g (0.05 mol) of 2-tert-butyl-6-methyl-4-(n-octylthiomethyl)phenol, dissolved in 120 ml of acetone. After stirring at room temperature for 26 hours, the solvent is distilled off under reduced pressure. Chromatography on silica gel using methylene chloride/ethyl acetate in a ratio of 9:1 as eluent gives 12.2 g of 2-tert-butyl-6-methyl-4-(octylsulfinylmethyl)phenol as a yellowish oil.
Reaction SMILES: C([CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[C:6](N)=[O:7])CCC.[OH-:16].[Na+].C(N)CCC.Cl>[Ni].O>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:5][C:6]([OH:7])=[O:16]
Reactant: [OH-]
Reactant: CCCCC(C(N)=O)c1ccccc1Cl
Agent: [Ni]
Agent: Cl
Agent: [Na+]
Solvent: CCCCN
Solvent: O
Product: O=C(O)Cc1ccccc1Cl
Yield: 95 %

Procedure:
225.5 g (1 mol) of N-t.-butyl-(2-chlorophenyl)-acetamide (melting point: 128°-130° C.) and 281 g of 15% strength NaOH (1.05 mols) are heated at 260° C., while stirring, for 3 hours in a 0.7 l nickel autoclave. The autoclave is cooled and the reaction mixture is run into a distillation apparatus. Distillation through a 30 cm column up to a head temperature of 100° C. gives 71.5 g of t.-butylamine of 97% purity, corresponding to a yield of 95% of the theoretical yield. 200 ml of water and 100 ml of 30% strength hydrochloric acid are added to the distillation bottom product. The acid which has been precipitated is filtered off with suction and dried in vacuo. 157.8 g of o-chlorophenylacetic acid of melting point 95° C. are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:30])[CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=2)[N:9]=[C:8]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:7]=1.C([O-])(=O)C.[K+].[N:36]#[C:37]Br.Cl>O.CO>[NH2:36][C:37]1[O:30][CH:3]([CH2:4][NH:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[N:9]=[C:8]([N:17]3[CH2:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]3)[CH:7]=2)[CH2:2][N:1]=1
Reactant: N#CBr
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(O)CN)c2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3CN=C(N)O3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.4 %

Procedure:
A mixture of 1-amino-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-2-ol (80 mg, 0.18 mmol, prepared in analogy to Example 9-7) and potassium acetate (89 mg, 0.91 mmol) in a mixture solution of methanol and water (7 ml, V/V=6/1) was added cyanogen bromide (89 mg, 0.84 mmol) at 0° C. After being stirred at room temperature for 3 hours, the mixture was stirred further with concentrated hydrochloric acid (3 mL) for 1 hour, and then concentrated in vacuo. The residue was dissolved in a saturated aqueous solution of sodium bicarbonate (10 mL) and extracted with dichloromethane (15 mL×3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column (10% methanol in dichloromethane) to afford 32 mg of the desired product as a white solid. MS obsd. (ESI+) [(M+H)+] 452, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92-7.87 (m, J=4.6 Hz, 2 H), 7.72 (s, 1 H), 7.65-7.62 (t, J=3.7 Hz, 1 H), 7.49-7.45 (t, J=3.9 Hz, 1 H), 7.32 (d, J=2.1 Hz, 1 H), 7.23 (d, J=2.1 Hz, 1 H), 6.85 (t, J=2.6 Hz, 1 H), 6.46 (brs, 2 H), 6.10 (s, 1 H), 5.10 (s, 2 H), 4.82-4.77 (m, J=4.8 Hz, 1 H), 4.49 (brs, 2 H), 3.75 (m, 1 H), 3.63 (s, 2 H), 3.52 (m, 3 H), 2.35 (s, 3 H).
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:27]=[CH:26][C:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)=[CH:24][C:18]=1[O:19][CH2:20][C:21](O)=[O:22])[C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:38][C:39]1[CH:40]=[C:41]([CH:47]=[CH:48][CH:49]=1)[C:42]([O:44][CH2:45]C)=[O:43].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC>CN(C=O)C>[CH2:1]([N:8]([CH2:16][C:17]1[CH:27]=[CH:26][C:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)=[CH:24][C:18]=1[O:19][CH2:20][C:21]([NH:38][C:39]1[CH:40]=[C:41]([CH:47]=[CH:48][CH:49]=1)[C:42]([O:44][CH3:45])=[O:43])=[O:22])[C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)N(Cc1ccccc1)Cc1ccc(-c2cccc3ccccc23)cc1OCC(=O)O
Reactant: CCOC(=O)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)N(Cc1ccccc1)Cc1ccc(-c2cccc3ccccc23)cc1OCC(=O)Nc1cccc(C(=O)OC)c1
Reaction time: 5 h

Procedure:
A room temperature solution of Example 21A (50 mg, 0.10 mmol) in DMF (1.0 mL) was treated with ethyl 3-aminobenzoate (20 μL, 0.13 mmol), HOBT (23 mg, 0.14 mmol), EDCI (29 mg, 0.15 mmol), and Et3N (21 μL, 0.15 mmol), stirred for 5 hours, and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 2:5 hexanes/ethyl acetate to provide the desired product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[NH:24]C(=O)OC(C)(C)C)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:24][C:18]1[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]([NH:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1c(F)cccc1C(=O)NC1CCN(Cc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1c(F)cccc1C(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-(1-benzylpiperidin-4-ylcarbamoyl)-6-fluorophenylcarbamate (67.0 g, 157 mmol) in dichloromethane (700 mL) at 0° C. was added trifluoroacetic acid (100 mL). The ice bath was removed and the reaction stirred at room temperature overnight. The reaction was concentrated and partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous portion was extracted with ethyl acetate (2×), which were washed with water (3×), then brine, dried over magnesium sulfate, and concentrated to give 47.6 g (93%) as a white solid which was used without purification. Mass spec.: 328.33 (MH)+.