Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:7][O:8][C:9]=1[C:10]([O:12]C)=[O:11])=[O:4].[Li+].[OH-]>CO.O>[CH3:1][NH:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:7][O:8][C:9]=1[C:10]([OH:12])=[O:11])=[O:4]
Reactant: CNC(=O)c1c(-c2ccccc2)noc1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNC(=O)c1c(-c2ccccc2)noc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a suspension of methyl 4-(methylcarbamoyl)-3-phenylisoxazole-5-carboxylate (35 mg, 0.134 mmol) in MeOH (0.8 mL) and water (0.2 mL) was added LiOH, Hydrate (6.77 mg, 0.161 mmol) and the mixture was allowed to stir at rt for 1 hr. during which time the reaction became homogeneous. The volatiles were removed in vacuo and the residue was partitioned between DCM (20 mL) and saturated potassium bisulfate solution (10 mL). The aqueous layer was extracted with DCM (10 mL) and the combined organic layers were dried (MgSO4) and concentrated to afford 4-(methylcarbamoyl)-3-phenylisoxazole-5-carboxylic acid (33 mg, 0.134 mmol, 100% yield) as a slightly off-white foam. HPLC retention time=0.88 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient. MS: (M+H)=247.13.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].N1C=CC=CC=1>ClCCCl.C(Cl)Cl.CN(C=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:19][C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:8])([O-:3])=[O:2]
Reactant: CCOC(=O)c1ccccc1N
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1NC(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A catalytic amount of DMF was added to a stirred solution of 2-nitrobenzoic acid (2.30 g, 13.8 mmol) and oxalyl chloride (6.0 mL, 69 mmol) in 1,2-dichloroethane (70 mL) at r.t. and under nitrogen flow. After 1 h, the reaction was concentrated, re-dissolved in 1,2-dichloroethane and concentrated again. The crude was immediately dissolved in 1,2-dichloroethane (25 mL) before ethyl 2-aminobenzoate (1.00 mL, 6.76 mmol) and pyridine (1.70 mL, 21.0 mmol) was added. The reaction was stirred 45 min at r.t. and under nitrogen atmosphere before being diluted with DCM and washed with HCl (aq., 1M), NaHCO3 (aq., sat., 2×) and brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The crude was purified by column chromatography (SiO2, toluene:acetone 100:0→98:2) to give compound 20 in quant yield (2.24 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH:15]([CH2:33][CH3:34])[CH2:16][O:17][CH2:18][CH2:19][CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>>[NH:23]1[CH2:24][CH2:25][CH:20]([CH2:19][CH2:18][O:17][CH2:16][CH:15]([N:14]2[C:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=[CH:13]2)[CH2:33][CH3:34])[CH2:21][CH2:22]1
Reactant: CCC(COCCC1CCN(C(=O)OC(C)(C)C)CC1)n1cnc2c(N)nc3ccccc3c21
Agent: Cl
Product: CCC(COCCC1CCNCC1)n1cnc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 14 h
Yield: 64.8 %

Procedure:
Under a nitrogen atmosphere, tert-butyl 4-{2-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxylate (1.00 g, 2.1 mmol) and 2N ethanolic hydrochloric acid (10 ml, 20 mmol) were combined and the solution was stirred at ambient temperature for 14 hours. The solvent was removed in vacuo and the resulting tan solid was dissolved in water. Saturated aqueous sodium carbonate was added until the pH reached 10. After extraction with dichloromethane (3×), the organic fractions were combined, washed with brine, dried (Na2SO4), filtered, and the majority of the solvent was removed in vacuo. Hexane was added to form a precipitate. Vacuum filtration yielded 0.5 g of 1-{1-[(2-piperidin-4-ylethoxy)methyl]propyl}-1H-imidazo[4,5-c]quinolin-4-amine as a tan powder.
Reaction SMILES: [H-].[Na+].[O:3]([CH2:10][C:11]1[S:12][C:13]2[C:14](=[O:21])[NH:15][CH2:16][CH2:17][CH2:18][C:19]=2[N:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[O:3]([CH2:10][C:11]1[S:12][C:13]2[C:14](=[O:21])[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17][CH2:18][C:19]=2[N:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1NCCCc2nc(COc3ccccc3)sc21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2sc(COc3ccccc3)nc2CCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A 60% dispersion of sodium hydride in mineral oils (0.014 g, 0.36 mmol) was added to a stirred solution of 5,6,7,8-tetrahydro-2-(phenoxymethyl)-4H-thiazolo[5,4-c]azepin-4-one (0.066 g, 0.24 mmol) in DMF anhydrous (1 mL) at 0° C. and the mixture was stirred at room temperature for 1 hour. Then, benzyl bromide (0.043 mL, 0.36 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with H2O and extracted with DCM. The organic layer was separated, washed with brine, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo to yield 5,6,7,8-tetrahydro-2-(phenoxymethyl)-5-(phenylmethyl)-4H-thiazolo[5,4-c]azepin-4-one (0.084 g, 96% yield) as a colourless oil. C21H20N2O2S LCMS: Rt 3.02, m/z 365 [M+H]+ (using method, LC-MS Method 6).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]3)[C:8]2([NH:14][S:15]([CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])(=[O:17])=[O:16])[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:35]>C(Cl)Cl.CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26]3)[C:8]2([NH:14][S:15]([CH2:18][CH2:19][Si:20]([CH3:23])([CH3:21])[CH3:22])(=[O:17])=[O:16])[C:11]([O:13][CH3:35])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC2(Cc3ccc(Br)cc3C2(NS(=O)(=O)CC[Si](C)(C)C)C(=O)O)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1(NS(=O)(=O)CC[Si](C)(C)C)c2cc(Br)ccc2CC12CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 19 h
Yield: 72 %

Procedure:
A mixture of 6′-bromo-1-(tert-butoxycarbonyl)-1′-(2-(trimethylsilyl)ethylsulfonamido)-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1′-carboxylic acid, obtained as described above, and TMSCHN2 (2.0 Min hexane, 1 mL) in CH2Cl2 (6 mL) and MeOH (3 mL) was stirred at room temperature for 19 h. After the solvent was evaporated under reduced pressure, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford 0.3263 g (72% in three steps) of 1-tert-butyl 1′-methyl 6′-bromo-1′-(2-(trimethylsilyl)ethylsulfonamido)-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1,1′-dicarboxylate as foam. LC-MS tR=2.20 min in 3 min chromatography, m/z 575, 577 (MH+), 547, 549 (MH+-28), 519, 521 (MH+-56).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[NH:15][N:16]=2)[N:13]=1.[F:25][C:26]([F:32])([F:31])[CH2:27][CH2:28][CH2:29]I.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[N:15]([CH2:29][CH2:28][CH2:27][C:26]([F:32])([F:31])[F:25])[N:16]=2)[N:13]=1
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reactant: FC(F)(F)CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: O=c1n(CCCC(F)(F)F)nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 80 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
A suspension of 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (20 mg, 0.056 mmol), 1,1,1-trifluoro-4-iodobutane (20 mg, 0.084 mmol) and solid K2CO3 (12 mg, 0.084 mmol) in anhydrous DMF (0.6 mL) was stirred at 80° C. for 1 h. Analysis by HPLC/MS indicated the reaction was not complete. Additional 1,1,1-trifluoro-4-iodobutane (12 mg, 0.084 mmol) was added, the reaction was allowed to continue at 80° C. for 30 min. After cooling to room temperature, the reaction mixture was diluted with water, and extracted with EtOAc (20 mL×2). The combined EtOAc extracts were washed with water, saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluting with a gradient of EtOAc (0-60%) in hexanes to yield a yellow oily product, which was lyophilized in acetonitrile to afford 19 mg (73%) of the title compound as a yellow powder. HPLC (method B): retention time=7.70 min. 1H NMR (CDCl3, 400 MHz): δ 7.45 (m, 2H), 7.35 (m, 2H), 7.25 (m, 1H), 7.20 (d,J=8.8 Hz, 2H), 7.04 (d,j=8.8 Hz, 2H), 4.17 (t,J=6.1 Hz, 2H), 2.17-2.25 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH2:26][NH2:27])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30]>>[C:28]([NH:27][CH2:26][C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]2=[C:10]([C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[N:9]=1)(=[O:31])[CH:29]=[CH2:30]
Reactant: C=CC(=O)Cl
Reactant: NCc1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Product: C=CC(=O)NCc1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 4 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 1, from 4-(8-amino-3-(aminomethyl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (intermediate 44) and acryloylchloride, to afford the title compound (1.7 mg, 4%). Data: UPLC(C) Rt: 1.22 min; m/z 414.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=2[CH3:29])[CH2:19][CH2:18]1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH3:12])[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=3[CH3:29])[CH2:19][CH2:18]2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: C[C@H](C(=O)O)c1ccc(F)cc1
Solvent: CO
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)[C@@H](C)c2ccc(F)cc2)CC1

Procedure:
Example 168 was prepared from (2S)-2-(4-fluorophenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12; [α]D=+13.5° (C=1.02, MeOH): 1H NMR (400 MHz, CDCl3) δ 7.58–7.49 (m, 2 H), 7.37–7.29 (m, 2 H), 7.26–7.19 (m, 1 H), 7.06 (d, 1 H, J=8.0 Hz), 7.04–6.92 (m, 3 H), 3.56 (t, 1 H, J=6.8 Hz), 3.43–3.23 (m, 2 H), 2.95 (ABq, 2 H), 2.63–2.59 (m, 1 H), 2.59–2.45 (m, 1 H), 2.37 (t, 2 H, J=6.0 Hz), 2.27 (s, 3 H), 2.07–1.90 (m, 2 H), 1.82–1.57 (m, 6 H), 1.50 (d, 3 H, J=7.2 Hz), 1.22 (d, 6 H, J=7.2 Hz); ESMS m/e: 468.3 (M+H)+.
Reaction SMILES: [CH3:1]OC1C=C(O)C(Cl)=CC=1C(OC)=O.[C:15]1([CH3:22])[C:16]([CH3:21])=[CH:17][CH:18]=[CH:19][CH:20]=1.C(N1CCCC1CN)C>CO>[C:15]1([CH3:1])([CH3:22])[CH:20]=[CH:19][CH:18]=[C:17]2[CH2:21][CH:16]12
Reactant: Cc1ccccc1C
Reactant: COC(=O)c1cc(Cl)c(O)cc1OC
Agent: CCN1CCCC1CN
Solvent: CO
Product: CC1(C)C=CC=C2CC21

Procedure:
In a 500 ml flask equipped with a 40 cm Vigreux column, there are put 40 g (0.184 mole) of methyl 2-methoxy-4-hydroxy-5-chlorobenzoate, 160 ml of xylene and 35.5 g of dextro 1-ethyl-2- aminomethylpyrrolidine. It is heated gently. There is complete dissolution when heating begins. The methyl alcohol formed as a methanol - xylene azeotrope is distilled at 61°-63° C. At the end of the reaction, a little xylene is distilled. In 90 minutes, 40 ml containing 7 ml of methyl alcohol are distilled. The excess xylene and amine are then distilled under vacuum. The residue is a solid. It is recovered with 300 ml of water, drained, washed until neutral as indicated by the phenol-phthalein and dried at 60° C. There are obtained 58 g (yield 100%) of N-(1-ethyl-2-pyrrolidylmethyl)-4-hydroxy-5-chlorobenzamide in base state which are transformed to the hydrochloride. This is done by dissolving the base in 200 ml of absolute alcohol and adding an alcohol solution of 14.5 ml of concentrated hydrochloric acid in 40 ml of alcohol. The hydrochloride crystallizes, is drained, washed with alcohol, and air-dried. It is a white solid (m.p. 228° C; [α]D = + 8° (5% water).
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH2:10][C:11]([C:14]([F:17])([F:16])[F:15])(O)[N:12]=2)[C:8]=1[CH3:9]>C(O)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:10]=[C:11]([C:14]([F:16])([F:17])[F:15])[N:12]=2)[C:8]=1[CH3:9]
Reactant: CC1=C(Br)C=CC2=NC(O)(C(F)(F)F)CN21
Agent: Br
Solvent: CCO
Product: Cc1c(Br)ccc2nc(C(F)(F)F)cn12
Yield: 112 %

Procedure:
A mixture of 3.29 g of 6-bromo-5-methyl-2-trifluoromethyl-2,3-dihydroimidazo[1,2-a]pyridin-2-ol hydrobromide and 10 ml of ethanol was stirred under heat-reflux for 3 hours. The cooled reaction mixture was concentrated under reduced pressure, then water was added, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2.72 g of 6-bromo-5-methyl-2-trifluoromethylimidazo[1,2-a]pyridine.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:8][CH:9]=1)[OH:4].[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=2)[C:29](O)=[O:30])[N:20]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[O:8][CH:9]=[C:5]([CH:3]([OH:4])[CH2:2][NH:1][C:29](=[O:30])[C:28]3[CH:32]=[C:24]([C:21]4[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=4)[CH:25]=[N:26][CH:27]=3)[N:6]=2)=[CH:11][CH:12]=1
Reactant: NCC(O)c1coc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCC(O)c1coc(-c2ccc(F)cc2)n1)c1cncc(-c2noc(C(F)(F)F)n2)c1
Yield: 45 %

Procedure:
This compound was synthesized from 2-amino-1-(2-(4-fluorophenyl)oxazol-4-yl)ethanol and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (120 mg, yield 45%). 1H NMR (400 MHz, DMSO-d6) δ 9.35 (d, J=1.8 Hz, 1H), 9.27 (d, J=1.8 Hz, 1H), 9.13-9.10 (t, J=5.6 Hz, 1H), 8.84-8.83 (t, J=1.8 Hz, 1H), 8.11 (s, 1H), 8.03-8.00 (dd, J=8.5 Hz, 5.5 Hz, 2H), 7.39-7.35 (t, J=8.9 Hz, 2H), 5.74-5.73 (d, J=5.2 Hz, 1H), 4.85-4.81 (m, 1H), 3.77-3.71 (m, 1H), 3.56-3.49 (m, 1H). MS (ESI) m/z: Calculated for C20H13F4N5O4: 463.09. found: 464.0 (M+H)+.
Reaction SMILES: NC1N([C@@H]2CC[C@H](C(OC)=O)CC2)C2C=C(CO[Si](C(C)C)(C(C)C)C(C)C)C=CC=2N=1.[CH2:33]([NH:35][C:36]([C@@H:38]1[CH2:43][CH2:42][C@H:41]([N:44]2[C:48]3[CH:49]=[C:50]([CH2:53][N:54]4[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]4)[CH:51]=[CH:52][C:47]=3[NH:46]/[C:45]/2=[N:60]\[C:61](=[O:69])[C:62]2[CH:67]=[CH:66][C:65](F)=[CH:64][CH:63]=2)[CH2:40][CH2:39]1)=[O:37])[CH3:34]>>[CH2:33]([NH:35][C:36]([C@@H:38]1[CH2:43][CH2:42][C@H:41]([N:44]2[C:48]3[CH:49]=[C:50]([CH2:53][N:54]4[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]4)[CH:51]=[CH:52][C:47]=3[N:46]=[C:45]2[NH:60][C:61](=[O:69])[C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH2:40][CH2:39]1)=[O:37])[CH3:34]
Reactant: CCNC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCCCC4)cc32)CC1
Agent: COC(=O)[C@H]1CC[C@@H](n2c(N)nc3ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc32)CC1
Product: CCNC(=O)[C@H]1CC[C@@H](n2c(NC(=O)c3ccccc3)nc3ccc(CN4CCCCC4)cc32)CC1

Procedure:
The title compound was prepared in 5 steps from cis-methyl 4-(2-amino-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate using a method analogous to the preparation of (E)-N-(1-(cis-4-(ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2 (3H)-ylidene)-4-fluorobenzamide. MS m/z=488.2 [M+H]. Calc'd for C29H37N5O2: 487.3.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:1]1([N:7]2[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-n2cccn2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)c1cnn(-c2ccccc2)c1

Procedure:
1-Phenyl-4-acetyl-pyrazole was prepared by acetylation of 1-phenyl-pyrazole with acetic anhydride according to the procedure described in Chemical Abstracts Vol. 63, 16332.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[C:29]([CH2:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)#[N:30]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:36]2[CH:37]=[C:32]([CH2:31][C:29]#[N:30])[CH:33]=[CH:34][CH:35]=2)=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([OH:15])([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)[C:11]([F:12])([F:13])[F:14]
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: N#CCc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CC(c1cc(Oc2cccc(CC#N)c2)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 5, 6-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 1, step 4) was reacted with 3-cyanomethylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as an off-white solid. MS (m/e)=531.1 [M+H+].
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C@H:6]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:5]1=[O:23])[CH:2]=[CH2:3]>[Pd].CO>[O:23]=[C:5]1[N:4]([CH2:1][CH2:2][CH3:3])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C@@H:6]1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: C=CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)COc2ccccc21
Agent: [Pd]
Solvent: CO
Product: CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)COc2ccccc21
Reaction time: 16 h

Procedure:
In an autoclave containing 270 mg of 21 (0.848 mmol), 20 mg of Pd/C (10%) and 5 mL of MeOH, hydrogenation is performed at 4 bar for 16 h at 20° C. After filtration of the catalyst on celite and evaporation of the solvent, 257 mg of expected product 23 are obtained, which product is used directly for the next stage.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:38][O:39][C:40]1[CH:41]=[C:42]([CH2:48][CH2:49][NH2:50])[CH:43]=[CH:44][C:45]=1[O:46][CH3:47]>>[CH3:38][O:39][C:40]1[CH:41]=[C:42]([CH2:48][CH2:49][NH:50][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])[CH:43]=[CH:44][C:45]=1[O:46][CH3:47]
Reactant: COc1ccc(CCN)cc1OC
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Product: COc1ccc(CCNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(-c4ccccc4C)c(OC)c2)C3)cc1OC

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 2-(3,4-dimethoxyphenyl)-ethylamine. Purification was performed using HPLC with a normal phase column. Elution with a mixture of etoxynonafluorobutane and methanol gave the title compound in 97% yield, m.p. 150-154° C. MS [(+)ESI,m/z]: 616.26 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][CH:19]([CH2:22]O)[CH2:18][CH2:17]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:22][CH:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: CN1CCC(CO)CC1
Product: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1

Procedure:
The compound was synthesised according to GP 4 from 4-chloro-7-hydroxy-6-methoxy-quinazoline and (1-Methyl-piperidin-4-yl)-methanol. LC/ESI-MS: m/z=322 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([O:11][CH3:12])[C:4]=1[NH2:5].C(O)=O.[CH:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[C:17]1=O)[CH2:23]2>C1(C)C=CC=CC=1>[CH:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH:17]1[NH:5][C:4]1[C:6]([O:11][CH3:12])=[CH:7][C:8]([CH3:10])=[CH:9][C:3]=1[O:2][CH3:1])[CH2:23]2
Reactant: COc1cc(C)cc(OC)c1N
Reactant: O=C1C2CC3CC(C2)CC1C3
Solvent: O=CO
Solvent: Cc1ccccc1
Product: COc1cc(C)cc(OC)c1NC1C2CC3CC(C2)CC1C3
Yield: 52 %

Procedure:
2.1 g of 2,6-dimethoxy-4-methylaniline are dissolved in 10 ml of toluene, 0.5 ml of formic acid is then added to this solution and the mixture is heated to gentle reflux, under inert atmosphere, and 0.93 g of 2-adamantanone, dissolved in 10 ml of toluene, is added dropwise at this temperature. The reaction mixture is heated at reflux for 48 hours, is then evaporated to dryness and the residue is taken up in 30 ml of 2N hydrochloric acid. The insoluble white crystals are filtered and discarded. The acidic filtrate is extracted with dichloromethane. The organic extracts are washed with a 5% aqueous sodium bicarbonate solution and then with water and the organic phases are then dried over anhydrous sodium sulphate. Evaporation leaves a colourless residue which is purified by flash chromatography on a column of silica gel, eluent: toluene/ethyl acetate 7/3 (v/v) in order to obtain N-(2-adamantyl)-2,6-dimethoxy-4-methylaniline; M.p.=100° C., Yield 52%.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]2[C:17](=[CH:18][C:19](I)=[CH:20][CH:21]=2)[N:16]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.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]>[Cl:14][C:15]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]2[C:17](=[CH:18][C:19]([S:1][C:2]3[CH:3]=[C:4]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=3)=[CH:20][CH:21]=2)[N:16]=1
Reactant: CCC(O)(CC)c1cccc(S)c1
Reactant: Clc1cc(-c2ccccc2)c2ccc(I)cc2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(O)(CC)c1cccc(Sc2ccc3c(-c4ccccc4)cc(Cl)nc3c2)c1
Temperature: 60 °C

Procedure:
10l (900 mg, 4.6 mmol), 2-chloro-7-iodo-4-phenyl-quinoline (10m, 1.6 g, 4.6 mmol), iPr2NEt (1.6 mL, 9.2 mmol), Pd2dba3 (104 mg, 0.1 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (132 mg, 0.2 mmol) were dissolved in 1,4-dioxane (15 mL) and degassed with N2 for 10 minutes. The reaction was heated to 60° C. for 1 hour, and then diluted with saturated aqueous NH4Cl and EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (30% EtOAc in hexanes) to give the desired product, 10n.