Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[C:24]#[N:25])=[N:20][CH:21]=1.Cl>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:24]([C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[C:19]1[N:20]=[CH:21][C:16]([CH2:15][CH:5]([C:4](=[O:3])[CH2:11][CH2:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:17][CH:18]=1)#[N:25]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: N#Cc1ccccc1-c1ccc(CCl)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)nc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a mixture of 60% sodium hydride in oil (1.64 g) and tetrahydrofuran (30 mL) was added dropwise a mixture of ethyl 3-oxohexanoate (8.10 g) in tetrahydrofuran (20 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. Then, 2-[5-(chloromethyl)pyridin-2-yl]benzonitrile (2.25 g) and tetrabutylammonium iodide (1.25 g) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 M hydrochloric acid (50 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a yellow oil (2.20 g, 62%).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:5]2[CH:13]=[C:14]([Cl:25])[C:15]([S:17][C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[CH:16][C:4]=2[N:3]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:37]([O:39][C:40]([C:42]1[CH:43]=[N:44][NH:45][CH:46]=1)=[O:41])[CH3:38]>[Cl-].[Na+].O>[CH2:37]([O:39][C:40]([C:42]1[CH:43]=[N:44][N:45]([C:2]2[N:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:5]3[CH:13]=[C:14]([Cl:25])[C:15]([S:17][C:18]4[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=4)=[CH:16][C:4]=3[N:3]=2)[CH:46]=1)=[O:41])[CH3:38]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: COCCOCn1c(Cl)nc2cc(Sc3cccc(C)c3)c(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2nc3cc(Sc4cccc(C)c4)c(Cl)cc3n2COCCOC)c1
Temperature: 80 °C

Procedure:
To a mixture of 2,6-dichloro-1-(2-methoxy-ethoxymethyl)-5-m-tolylsulfanyl-1H-benzoimidazole (0.500 g, 1.26 mmol) and DMF (2.52 mL) was added cesium carbonate (0.820 g, 2.52 mmol) and 1H-pyrazole-4-carboxylic acid ethyl ester (0.194 g, 1.38 mmol). The mixture was heated at 80° C. for 2 h in a sealed tube. The mixture was cooled to 23° C. and poured into brine (40 mL), and extracted with EtOAc (3×50 mL). The organic layers were washed with brine (40 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (0-50% EtOAc/hexanes) to yield the titled compound as a 1:1 mixture of regioisomers (0.387 g, 61%). 1H NMR (500 MHz, CDCl3): 8.84 (s, 1H), 8.79 (s, 1H), 8.14 (s, 2H), 7.77 (s, 1H), 7.68 (s, 1H), 7.44 (s, 1H), 7.41 (s, 1H), 7.23-7.18 (m, 4H), 7.18-7.16 (m, 1H), 7.12 (d, J=7.6 Hz, 2H), 7.09 (d, J=7.5 Hz, 1H), 6.09 (s, 2H), 5.98 (s, 2H), 4.36-4.27 (m, 4H), 3.66-3.60 (m, 2H), 3.55-3.50 (m, 2H), 3.48-3.42 (m, 2H), 3.38-3.34 (m, 2H), 3.28 (s, 3H), 3.24 (s, 3H), 2.32 (s, 3H), 2.31 (s, 3H), 1.38-1.30 (m, 6H).
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[I:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[S:32]>>[I:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:12]=[CH:13][C:8]3[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=3[N:10]=2)[CH2:15][CH2:16]1)=[S:32]
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Reactant: S=C=Nc1ccccc1I
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4ccccc4I)CC3)nc21

Procedure:
Pipemidic acid (25 mg, 0.0824 mmol) and 2-iodophenyl isothiocyanate (21.5 mg, 0.0824 mmol) were used. Purification on silica yielded compound 26 in Table 1, below (35 mg, 75%). 1H NMR (300 MHz, CDCl3) δ 9.36-9.30 (m, 1H), 8.69-8.65 (m, 1H), 7.89-7.82 (m, 1H), 7.62-7.55 (m, 1H), 7.41-7.32 (m, 1H), 7.00-6.92 (m, 1H), 4.40-4.01 (m, 10H), 1.53-1.44 (m, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:11](O)([C:13]([F:16])([F:15])[F:14])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:11]([C:13]([F:16])([F:15])[F:14])=[N:9][C:4]=2[C:3]=1[Cl:10]
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ccc(Br)c(Cl)c1N
Product: FC(F)(F)c1nc2c(Cl)c(Br)ccc2[nH]1

Procedure:
Synthesized as described in Example 195C from 4-bromo-3-chloro-1,2-benzenediamine and TFA: MS (ESI) m/z 301 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:4][CH2:3]1>C1COCC1.O>[CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)=[CH:7][C:6]=2[C:5]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C(C)(C)C)=CCC3(C)C)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
A solution of 24.0 mg (0.06 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)-naphth-3-yl)ethynyl]benzoate (Compound 71) and 6.5 mg (0.16 mmol) of LiOH--H2O in 3 mL THF/water (3:1, v/v) was stirred overnight (22 hours) at room temperature. The reaction mixture was extracted with Et2O and the layers were separated. The aqueous layer was acidified with HCl (1M aqueous solution) and then extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][NH:8][C:9](=[O:22])[C@@H:10]([NH:14]C(=O)OC(C)(C)C)[CH:11]([CH3:13])[CH3:12])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:14][C@@H:10]([CH:11]([CH3:13])[CH3:12])[C:9]([NH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][CH:23]=1)=[O:22]
Reactant: COc1ccc(CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CNC(=O)[C@@H](N)C(C)C)cc1
Temperature: 0 °C
Reaction time: 7 h
Yield: 73.1 %

Procedure:
A solution of (S)-tert-butyl 1-(4-methoxybenzylamino)-3-methyl-1-oxobutan-2-ylcarbamate (1.50 g, 4.46 mmol) in dichloromethane (15 mL) was cooled to 0° C. Trifluoroacetic acid (2 mL) was added and the mixture stirred at 0° C. for 7 hours. The reaction mixture was concentrated and the residue taken up in dichloromethane and washed with saturated aqueous NaHCO3 solution. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification of the crude material by column chromatography, eluting with 4% MeOH/dichloromethane with 0.1% NH4OH, provided (S)-2-amino-N-(4-methoxybenzyl)-3-methylbutanamide (0.770 g, 73%). LCMS (APCI+) m/z 237 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)=[O:5])[CH3:2]>CCOC(C)=O.CO.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][CH:7]1[CH2:16][CH2:15][C:10]2([O:11][CH2:12][CH2:13][O:14]2)[CH2:9][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C=C1CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 8-ethoxycarbonylmethylidene-1,4-dioxaspiro[4.5]decane (crude, 172.9 g) 10% Pd—C (53.2% wet, 6.5 g) in EtOAc/MeOH (1250 mL and 400 mL) is stirred under H2 atmosphere at room temperature for 4 hours. The reaction mixture is filtered, and the filtrate is concentrated in vacuo to afford crude 8-ethoxycarbonylmethyl-1,4-dioxaspiro[4.5]decane. The crude product is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[S:9][C:10]([NH2:12])=[N:11][C:6]2=[CH:5][CH:4]=1.[C:13]([N:16]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH2:30][CH3:31])[CH:27]=3)[N:22]([C:32](=[O:37])C(F)(F)F)[CH2:21]2)[CH2:17]1)(=[O:15])[CH3:14]>>[C:13]([N:16]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH2:30][CH3:31])[CH:27]=3)[N:22]([C:32]([NH:12][C:10]3[S:9][C:7]4[C:6]([N:11]=3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=4)=[O:37])[CH2:21]2)[CH2:17]1)(=[O:15])[CH3:14]
Reactant: CCOc1ccc2c(c1)C1(CCN(C(C)=O)C1)CN2C(=O)C(F)(F)F
Reactant: COc1ccc2nc(N)sc2n1
Product: CCOc1ccc2c(c1)C1(CCN(C(C)=O)C1)CN2C(=O)Nc1nc2ccc(OC)nc2s1

Procedure:
The captioned compound was obtained in the form of a reddish brown solid by performing the same reactions and/or treatments as those in Step 4 of Example 198, with the exceptions that 5-methoxythiazolo[5,4-b]pyridin-2-amine was used instead of the 2-amino-5-chlorothiazole hydrochloride in Example 1, which was cited in Example 57, and that 1-(1′-acetyl-5-ethoxyspiro[indoline-3,3′-pyrrolidin]-1-yl)-2,2,2-trifluoroethanone was used instead of 1-(1′-acetyl-5-(4-fluorophenoxy)phenoxyspiro[indoline-3,3′-pyrrolidin]-1-yl)-2,2,2-trifluoroethanone.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[OH:16])[N:12]=[CH:11][CH:10]=[C:9]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][CH3:28])=[O:26])=[C:20]([Cl:29])[CH:19]=1)=[O:5])[CH3:2].Br[CH2:31][CH:32]1[CH2:37][CH2:36][N:35]([C:38](OC(C)(C)C)=O)[CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].C=O.C([BH3-])#N.[Na+]>CN(C)C=O.C(OCC)(=O)C.CCCCCC.C(O)(=O)C.O>[CH2:1]([NH:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:31][CH:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][CH3:28])=[O:26])=[C:20]([Cl:29])[CH:19]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1cc2c(Oc3ccc(NC(=O)NC)c(Cl)c3)ccnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=O)c1cc2c(Oc3ccc(NC(=O)NC)c(Cl)c3)ccnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
N6-Ethyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide) (80.0 mg, 0.193 mmol), tert-butyl 4-(bromomethyl)-1-piperidinecarboxylate (80.5 mg, 0.289 mmol) and potassium carbonate (33.3 mg, 0.241 mmol) were heated and stirred in dimethylformamide (1 ml) at 60° C. for 15 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained product was stirred in trifluoroacetic acid (1 ml) at room temperature for 1 hour, and then the reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol and triethylamine was added dropwise for neutralization. After distilling off the solvent, the residue was dissolved in a tetrahydrofuran (2 ml)-methanol (2 ml) mixed solvent, and then a 37% formaldehyde aqueous solution (0.360 ml), acetic acid (0.070 ml) and sodium cyanoborohydride (36.3 mg, 0.579 mmol) were added in that order at room temperature and the mixture was stirred for 15 minutes. After adding basic silica gel to the reaction solution and concentrating it, it was subjected to silica gel column chromatography, the target fraction was concentrated under reduced pressure, the obtained crude product was suspended in ethyl acetate, the suspension was diluted with hexane, and the crystals were filtered out, washed with hexane and blow-dried to obtain the title compound (57.5 mg, 0.109 mmol, 57%) as white crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N=C=NC(C)C)(C)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH2:36][CH2:37][NH2:38])[CH:33]=[CH:34][CH:35]=1>CN(C)C=O>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH2:36][CH2:37][NH:38][C:16](=[O:18])[CH2:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][CH:13]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: COc1cccc(CCN)c1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COc1cccc(CCNC(=O)Cc2ccc(OCc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
To a solution of 4-benzyloxyphenylacetic acid (4.85 g 20 mmol) in dimethylformamide (30 mL) under nitrogen was added 1,3-diisopropylcarbodiimide. After 2 hours, to the solution was added 2-(3-methoxyphenyl)ethylamine (3.02 g, 20 mmol) and stirred at room temperature for 20 hours. The reaction was quenched with a saturated sodium carbonate solution and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 30-70% ethyl acetate/hexane) to provide the title compound (5.74 g, 76% yield): 1H NMR (CDCl3) 7.38 (m, 5H), 7.14 (t, 1H), 7.07 (d, 2H), 6.91 (d, 2H), 6.74 (dd, 1H), 6.62 (m, 2H), 5.37 (br, 1H), 5.06 (s, 2H), 3.77 (s, 3H), 3.47 (s, 2H), 3.44 (t, 2H), 2.70 (t, 2H); ES-MS (m/z) 376 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:7](=[O:15])[C:6]3=[CH:16][CH:17]=[CH:18][C:4]([C:5]=23)=[CH:3][CH:2]=1>C(O)C.[Pt]>[OH:15][C:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[C:10]2[N:1]=[CH:2][CH:3]=[C:4]3[CH2:18][CH2:17][CH2:16][C:6]=1[C:5]=23
Reactant: O=C1c2ccccc2-c2nccc3cccc1c23
Agent: [Pt]
Solvent: CCO
Product: Oc1c2c3c(ccnc3c3ccccc13)CCC2
Temperature: 25 °C
Reaction time: 23 h
Yield: 63.8 %

Procedure:
7H-Dibenzo[de,h]quinol-7-one (17.4 g) and Adams platinum (5.8 g) suspended in ethanol (394 cc) are placed under an initial hydrogen pressure of 10 bars at 25° C. The mixture is stirred for 23 hours at 25° C. The catalyst is filtered off and washed four times with dimethylformamide (total 1000 cc). The combined organic solutions are evaporated to dryness. The residue (22.1 g) is stirred for one hour with distilled water (500 cc) and then the precipitate is filtered off, washed twice, successively, with ethanol (total of 20 cc) and then dried under reduced pressure (20 mm Hg) at 20° C. A crude product (15.8 g) is obtained which is recrystallised from a mixture (300 cc) of equal parts of ethanol and dimethylformamide. After cooling for 20 hours at about 5° C., the crystals are filtered off, washed three times with diethyl ether (total 60 cc) and dried under reduced pressure (1 mm Hg) at 100° C. The product obtained (12.1 g) is recrystallised a second time from butyl acetate (410 cc). After cooling for 16 hours at 5° C., the crystals are filtered off, washed twice with ethyl acetate (total 20 cc) and dried under reduced pressure (1 mm Hg) at 100° C. for 8 hours. 7-Hydroxy-5,6-dihydro-4H-dibenzo[de,h]quinoline (11.3 g), melting at 260° C., is thus obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[CH:13]=2)=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4([C:36]([OH:38])=O)[CH2:35][CH2:34]4)=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[O:4][N:3]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH3:50][S:51]([NH2:54])(=[O:53])=[O:52].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:1][C:2]1[C:6]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[CH:13]=2)=[C:5]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4([C:36]([NH:54][S:51]([CH3:50])(=[O:53])=[O:52])=[O:38])[CH2:34][CH2:35]4)=[CH:29][CH:28]=3)=[CH:25][CH:26]=2)[O:4][N:3]=1
Reactant: Cc1cccc(-c2cncc(Nc3c(C)noc3-c3ccc(-c4ccc(C5(C(=O)O)CC5)cc4)cc3)c2)c1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(-c2cncc(Nc3c(C)noc3-c3ccc(-c4ccc(C5(C(=O)NS(C)(=O)=O)CC5)cc4)cc3)c2)c1
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(4′-{3-methyl-4-[5-(3-methyl-phenyl)-pyridin-3-ylamino]-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (0.050 g, 0.1 mmol) in DCM (1 mL) at RT was added DMF (1 μL, 0.01 mmol) and oxalyl chloride (17 μL, 0.15 mmol). After 1 hr, the mixture was concentrated to dryness and re-dissolved in DCM (1 mL). To this solution was added methanesulfonamide (0.014 g, 0.15 mmol), DIEA (60 μL, 0.35 mmol), and DMAP (0.001 g). The resulting mixture was stirred for 5 min, then diluted with EtOAc (20 mL) and extracted with H2O (2×10 mL). The combined aqueous layers were back-extracted with EtOAc (10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The crude residue was purified on reverse-phase preparative HPLC to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24]([CH2:26][N:27]5[CH2:30][CH:29]([C:31]([O:33]C)=[O:32])[CH2:28]5)=[CH:23][C:22]=4[CH:35]=3)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[OH-].[K+]>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24]([CH2:26][N:27]5[CH2:28][CH:29]([C:31]([OH:33])=[O:32])[CH2:30]5)=[CH:23][C:22]=4[CH:35]=3)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3ccc4oc(CN5CC(C(=O)OC)C5)cc4c3)no2)cc1OCC
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOc1ccc(-c2nc(-c3ccc4oc(CN5CC(C(=O)O)C5)cc4c3)no2)cc1OCC
Yield: 54.8 %

Procedure:
A mixture of the product of Step A (0.06 g; 0.126 mmol) and 10% KOH (0.1 ml) in dioxane (2 ml) was refluxed for 1 h and solvents were evaporated to dryness. The residue was treated with AcOH (0.5 ml) and evaporated to dryness in vacuo. The residue was purified by FCC (SiO2, CH2Cl2 saturated with concentrated NH4OH and MeOH, 85:15) to give the title compound (0.032 g; 55%), as a colourless solid. 1H-NMR (CD3OD+CDCl3) 8.37 (d, 1H, J=3 Hz); 8.09 (dd, 1H, J=3, 6 Hz); 7.77 (dd, 1H, J=3, 9 Hz); 7.68 (s, 1H); 7.6 (d, 1H, J=9 Hz); 7.02-7.07 (m, 2H); 4.38 (s, 2H); 4.05-4.21 (m, 8H); 1.44-1.49 9m, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH:26]1[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]1.C(OC(N1CCC2NN(C3CCC(C)CC3)C(C3C=CC(Cl)=CC=3)C=2CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH:26]3[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: CC1CCC(Br)CC1
Agent: CC1CCC(N2NC3=C(CCN(C(=O)OC(C)(C)C)CC3)C2c2ccc(Cl)cc2)CC1
Product: CC1CCC(n2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)CC1
Yield: 10.7 %

Procedure:
The title compound (11 mg) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.30 mmol) using 1-bromo-4-methyl-cyclohexane (1.0 mmol) in place of chloro-cyclobutane. The reaction sequence also yielded 3-(4-chlorophenyl)-2-(4-methyl-cyclohexyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C20H26ClN3, 343.18; found, m/z 344.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.40-7.34 (m, 4H), 4.10-4.06 (m, 1H), 3.39-3.37 (m, 2H), 3.28-3.26 (m, 2H), 3.17-3.15 (m, 2H), 2.94-2.91 (m, 2H), 1.96-1.89 (m, 2H), 1.83-1.76 (m, 4H), 1.52-1.10 (m, 2H), 0.91-0.87 (m, 4H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]2[N:23]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[O:9])[NH:21][C:20]=2[C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)=[CH:26][CH:27]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(Sc3ccccn3)[nH]c2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccccn3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 3.90 g of 4,5-bis(4-methoxyphenyl)-2-(2-pyridylthio)imidazole in 100 ml of dichloromethane. The solution is stirred for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated under vacuum to dryness. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus producing 3.42 g of 4,5-bis(4-methoxyphenyl)-2-(2-pyridylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([C:10]#[N:11])[CH2:8][O:7][CH2:6]1)=[O:4].O=S(Cl)Cl.O>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH2:6][O:7][CH2:8][C:9]=1[C:10]#[N:11])=[O:4]
Reactant: COC(=O)C1COCC1C#N
Solvent: c1ccncc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)C1=C(C#N)COC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
4-Cyano-tetrahydro furane 3-carboxylic acid methyl ester was dissolved in 4.9 ml of pyridine and treated with 4.4 ml (60 mmol) of SOCl2 during 90 min under nitrogen at 4° C. The resulting solution was warmed to room temperature, stirred for 6 hours and poured into 40 ml water at 4° C. and extracted with benzene. Combined extracts were dried and concentrated in vacuo to give 90% yield of 4-cyano-2,5-dihydro furane 3-carboxylic acid methyl ester.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:11][C:12]=1[F:17]
Reactant: Clc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNc2ncccn2)C1
Yield: 66.5 %

Procedure:
A solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate (120.7 mg), 2-chloropyrimidine (40.5 mg) and potassium carbonate (46.5 mg) in ethanol (3 mL) was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water, and the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (97.8 mg).