Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[CH:11]=[CH:10][C:9]2[N:8](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:7][C@@H:6]3[CH2:31][C@H:32]([N:34]([CH2:38][CH2:39][CH3:40])[CH2:35][CH2:36][CH3:37])[CH2:33][C:4]=1[C:5]=23)=O.S([CH2:51][N+:52]#[C-:53])(C1C=CC(C)=CC=1)(=O)=O.[C:54](=[O:57])([O-])[O-].[K+].[K+]>CO>[O:57]1[C:54]([C:3]2[CH:11]=[CH:10][C:9]3[NH:8][CH2:7][C@@H:6]4[CH2:31][C@H:32]([N:34]([CH2:35][CH2:36][CH3:37])[CH2:38][CH2:39][CH3:40])[CH2:33][C:4]=2[C:5]=34)=[CH:53][N:52]=[CH:51]1
Reactant: O=C([O-])[O-]
Reactant: CCCN(CCC)[C@@H]1Cc2c(C=O)ccc3c2[C@@H](C1)CN3C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Solvent: CO
Product: CCCN(CCC)[C@@H]1Cc2c(-c3cnco3)ccc3c2[C@H](CN3)C1
Yield: 153.6 %

Procedure:
A reaction mixture of (-)(2aR,4S)-6-formyl-1-trityl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (1.06 g, 2 mmol), tosylmethyl isocyanide (390 mg, 2 mmol) and potassium carbonate (304 mg, 2.2 mmol) in 100 ml of methanol was stirred at reflux temperature under a nitrogen atomosphere for 16 hours. The reaction mixture was concentrated to dryness and water was added to the residue. The aqueous mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with a saturated brine solution, dried over magnesium sulfate and concentrated to dryness to yield 1 g of an oil. The oil was dissolved in 20 ml of tetrahydrofuran and 50 ml of 5N hydrochloric acid solution. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted twice with ethyl acetate and the acidic solution was then made alkaline by addition of excess concentrated ammonium hydroxide solution. The basic mixture was extracted twice with ethyl acetate. The ethyl acetate solution was washed with a saturated brine solution, dried over magnesium sulfate and concentrated to dryness to provide 0.5 g of an oil. The oil was purified by silica gel chromatography, with ethyl acetate as eluent, to give 0.3 g of title compound. MS (FD) m/e/325
Reaction SMILES: BrC1[CH:3]=[N:4][CH:5]=C(C)C=1.CON(C)[C:12](=[O:14])[CH3:13].[Li][CH2:17][CH2:18][CH2:19][CH3:20]>C(OCC)C>[CH3:20][C:19]1[CH:18]=[C:17]([C:12](=[O:14])[CH3:13])[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cncc(Br)c1
Reactant: [Li]CCCC
Reactant: CON(C)C(C)=O
Solvent: CCOCC
Product: CC(=O)c1cncc(C)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To 3-bromo-5-methylpyridine 1-1 (2 g, 11.63 mmol) in diethyl ether (30 ml) at −78° C. was added uLi (8.72 ml, 13.95 mmol) dropwise. After 30 min, N-methoxy-N-methylacetamide n-BuLi was added. The resulting mixture was stirred at −78° C. for 2 h then at rt overnight, quenched with saturated NH4Cl solution and diluted with EtOAc. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to give a yellow residue, which was purified by column chromatography (0-65% EtOAc in hexane) to give the desired product 1-2: 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.62 (s, 1H), 8.04 (s, 1H), 2.63 (s, 3H), 2.41 (s, 3H).
Reaction SMILES: [C:1]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[CH:11][C:10]3[N:13](COCC[Si](C)(C)C)[C:14]([O:16][C@@H:17]4[CH2:21][O:20][C@@H:19]5[C@H:22]([O:25][Si](C(C)(C)C)(C)C)[CH2:23][O:24][C@H:18]45)=[N:15][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl.O>[C:1]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[CH:11][C:10]3[NH:13][C:14]([O:16][C@H:17]4[C@H:18]5[O:24][CH2:23][C@@H:22]([OH:25])[C@H:19]5[O:20][CH2:21]4)=[N:15][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(-c3ccc(-c4ccccc4)cc3)ncc2n1COCC[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(-c3ccc(-c4ccccc4)cc3)ncc2[nH]1
Temperature: 25 °C
Reaction time: 52 h

Procedure:
To 6-([1,1′-biphenyl]-4-yl)-2-(((3R,3aR,6R,6aS)-6-((tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c]pyridine (26.0 mg, 0.039 mmol) in anhydrous DCM (1.23 mL) was added TFA (0.91 mL, 11.82 mmol). The solution stirred at RT for 52 h. The reaction solution was evaporated under reduced pressure. The residue extracted into EtOAc (35 mL) and washed with 1N NaOH (6.0 mL, 6 mmol) and water (10 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure to afford the title compound. LC-MS: calculated for C24H21N3O4 415.15 observed m/e: 416.16 (M+H)+ (Rt 1.34/2.0 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]2[CH3:14])=[CH:4][C:3]=1[O:15][CH3:16].[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([CH2:31][C:32](O)=[O:33])[N:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:32](=[O:33])[CH2:31][N:24]3[C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:30]4[C:22]([C:18]4[NH:17][CH:21]=[CH:20][N:19]=4)=[N:23]3)[CH2:10][C@@H:9]2[CH3:14])=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Reactant: COc1cc(N2CCNC[C@@H]2C)ccc1Cl
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)C[C@@H]2C)ccc1Cl

Procedure:
The title compound was prepared following protocol A. (S)-1-(4-Chloro-3-methoxyphenyl)-2-methylpiperazine and [3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]acetic acid were used as the coupling components. The crude product was purified by silica gel chromatography (1% to 7% MeOH in CH2Cl2) to provide 1-[(S)-4-(4-chloro-3-methoxyphenyl)-3-methylpiperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid: 1H NMR (CDCl3, 400 MHz) δ□ 8.77 (d, 0.6H), 8.66 (d, 0.3H), 8.57-8.54 (m, 1H), 7.30-7.19 (m, 4H), 6.48-6.40 (m, 2H), 5.54-5.36 (m, 2H), 4.25 (br. d, 0.6H), 4.00 (br. d, 0.6H), 3.88 (s, 1.3H), 3.86 (s, 1.7H), 3.82-3.48 (m, 3.2H), 3.36-3.29 (m, 0.6H), 3.17-3.13 (m, 2H), 1.51-1.43 (m, 3H); LC/MS m/z (M+H)+ 466.4.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7](OC)[C:6]=1[O:16][CH3:17].C1C=CC=CC=1.[CH3:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].Cl.[O:32]1CCC[CH2:33]1>CCCCCC>[CH3:33][O:32][C:13]1[CH:12]=[C:8]([C:9](=[O:11])[CH2:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:7]=[C:6]([O:16][CH3:17])[C:5]=1[O:4][CH3:3]
Reactant: CC(=O)C(C)(C)C
Reactant: COc1ccc(C(=O)O)c(OC)c1OC
Reactant: C1CCOC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COc1cc(C(=O)CC(=O)C(C)(C)C)cc(OC)c1OC
Reaction time: 5 h
Yield: 74 %

Procedure:
In a 200 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and a nitogen-inlet tube, 3.0 gm (75 mmol) of 60% sodium hydride, 10 gm (44.3 mmol) of methyl 3,4,5-oxopentanoyl)benzene trimethoxybenzoate, and 80 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream, and refluxed with heating while 5.3 gm (53.2 mmol) of pinacolone was added dropwise. Refluxing under heat was continued for 5 hours. After cooling the reaction mixture, 45 ml of 2N hydrochloric acid was added, the mixture was extracted twice with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed by evaporation to give a crude product. Hexane was added to the crude product and insoluble substances were filtered off. The filtrate was concentrated by evaporation, and recrystallization afforded 9.6 gm of the target compound as colorless needles (yield: 74%).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([CH3:23])([CH3:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][CH:8]=1.CN(C)[CH:26]=[O:27].O>CCCCC.O1CCCC1>[CH:26]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([CH3:23])([CH3:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][CH:8]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(C=O)cc1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 50.5 %

Procedure:
At −75° C., 13.5 ml (22.98 mmol) of a 1.7 M tert-butyllithium solution in pentane are slowly added to a solution of 6.00 g (19.16 mmol) of tert-butyl 3-(4-bromophenyl)-2,2-dimethylpropionate (Example I-2) in 80 ml of tetrahydrofuran, the temperature being kept below −60° C. The mixture is stirred for 15 min, and 1.82 g (24.90 mmol) of N,N-dimethylformamide are then added and the mixture is stirred at −75° C. for a further 4 h. The mixture is slowly warmed to −20° C. and, with vigorous stirring, admixed with 20 ml of water, and then warmed to room temperature. The aqueous phase is extracted 3× with diethyl ether and the combined organic phases are dried over sodium sulphate/sodium carbonate and freed from the solvent under reduced pressure. Distillation of the residue under oilpump vacuum gives 2.54 g (51%) of tert-butyl 3-(4-formylphenyl)-2,2-dimethylpropionate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:28])[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[C:29]([O:33]C)(=[O:32])[CH:30]=[CH2:31]>CO.C(COC)OC>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH:14]=[CH:13][CH2:12][C:11]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:10](=[O:28])[CH:9]=[CH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:31][CH2:30][C:29]([OH:33])=[O:32])=[CH:20][CH:19]=1
Reactant: C=CC(=O)OC
Reactant: O=C(C=Cc1ccc(Cl)cc1)C(CC=Cc1ccc(Cl)cc1)c1ccccc1
Solvent: CO
Solvent: COCCOC
Product: O=C(O)CCC(CC=Cc1ccc(Cl)cc1)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Reaction time: 24 h

Procedure:
Triton B (1 ml., 40% in MeOH) is added to a stirred solution of 1,7-bis-(p-chlorophenyl)-4-phenyl-1,6-heptadien-3-one (16.10 g., 0.039 mole) in glyme (150 ml.), followed by addition of methyl acrylate (3.87 g., 0.045 mole) in glyme (25 ml.). After stirring for 24 hours, the solvent is removed in vacuo and water (600 ml.) and dilute hydrochloric acid (25 ml.) are added to the residue. The organic material is extracted into ether and these extracts are washed with water, saturated brine and dried (Na2SO4). After removal of the solvent, the residue is heated on a steam bath with a solution of 20% sodium hydroxide (20 ml.) in methanol (300 ml.) for 20 hours. The methanol is removed in vacuo and the residue is dissolved in water (1200 ml.). Extraction with ether removes unreacted ketone. Ether is expelled from the aqueous phase by warming. The solution is cooled in an ice bath, acidified with dilute hydrochloric acid (25 ml.) and the solid (yellowish) that precipitates is filtered and air-dried; yield 16.5 g., m.p. 75°-173°C. Several recrystallizations from n-butyl chloride gives material with m.p. 178.5°-180°C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1F)=[O:4].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:25]([NH2:27])[CH3:26])[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:24][O:23][C:21]1[CH:20]=[C:19]([CH:25]([NH:27][C:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=2[C:3](=[O:4])[C:2]([F:14])([F:13])[F:1])[CH3:26])[CH:18]=[C:17]([O:16][CH3:15])[CH:22]=1
Reactant: COc1cc(OC)cc(C(C)N)c1
Reactant: O=C(c1ccc(F)cc1F)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC)cc(C(C)Nc2cc(F)ccc2C(=O)C(F)(F)F)c1
Yield: 33.7 %

Procedure:
2,2,2-Trifluoro-1-(2,4-difluorophenyl)ethanone (1.0 g, 4.8 mmol), 1-(3,5-dimethoxyphenyl)ethanamine (0.95 g, 5.2 mmol) and N,N-diisopropylethylamine (1.2 g, 9.6 mmol) were stirred at 60° C. in dry acetonitrile (50 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and purified by silica chromatography in 20% ethyl acetate in hexanes to collect the title compound (600 mg, 34% yield). 1H NMR (400 MHz, CDCl3): δ 9.27 (s, 1H), 7.79 (t, 1H), 6.44 (s, 2H), 6.35 (m, 2H), 6.23 (d, 1H), 4.48 (m, 1H), 3.77 (s, 6H), 1.61 (d, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7]O.[C:9]1([NH:15][C:16]2([C:22](=[O:25])[CH2:23][CH3:24])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[C:9]1([NH:15][C:16]2([C:22](=[O:25])[CH2:23][CH3:24])[CH2:21][CH2:20][N:19]([CH2:7][CH2:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH2:18][CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCC(=O)C1(Nc2ccccc2)CCNCC1
Reactant: OCCc1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CCC(=O)C1(Nc2ccccc2)CCN(CCc2cccs2)CC1
Temperature: 25 °C

Procedure:
A mixture of 4.1 parts of 2-thiopheneethanol, methanesulfonate ester, 3.5 parts of 1-[4-(phenylamino)-4-piperidinyl]-1-propanone, 5.3 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone is stirred and refluxed for 18 hours. After cooling to room temperature, the reaction mixture is poured onto water and the layers are separated. The organic phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 1-{4-(phenylamino)-1-[2-(2-thienyl)ethyl]-4-piperidinyl}-1-propanone; mp. 127.1° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[N:15]=[CH:14][C:13]3[NH:16]/[C:17](=[N:25]\[C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)/[N:18]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:12]=3[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][CH:42]([CH3:44])[CH3:43]>CN(C=O)C>[CH2:41]([N:22]1[CH2:21][CH2:20][CH:19]([N:18]2[C:12]3[CH:11]=[C:10]([O:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[N:15]=[CH:14][C:13]=3[NH:16]/[C:17]/2=[N:25]\[C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:23]1)[CH:42]([CH3:44])[CH3:43]
Reactant: CC(C)CBr
Reactant: O=C(/N=c1\[nH]c2cnc(OCCN3CCCCC3)cc2n1C1CCNCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CN1CCC(n2/c(=N/C(=O)c3ccccc3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
A suspension of (E)-N-(6-(2-(piperidin-1-yl)ethoxy)-1-(piperidin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide (0.089 g, 0.198 mmol) and potassium carbonate (0.082 g, 0.595 mmol) in DMF (2 mL) was cooled to 0° C. under nitrogen. To this mixture was added 1-bromo-2-methylpropane (0.054 g, 0.397 mmol). The ice bath was removed, and the resulting mixture was stirred for 16 hours at RT. The reaction mixture was diluted with water (10 mL) and DCM (30 mL), and the organic layer was collected, concentrated and purified by silica gel chromatography (5-30% MeOH/DCM) to afford (E)-N-(1-(1-isobutylpiperidin-4-yl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide as an off-white solid (20 mg, 19.97% yield). MS m/z=505.2 [M+H]. Calc'd for C29H40N6O2: 504.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:41][O:42][C:43](=[O:62])[C@@H:44]([NH2:61])[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][C:53]2[CH:58]=[CH:57][N:56]=[C:55]([CH3:59])[C:54]=2[CH3:60])=[CH:48][CH:47]=1>>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:19])[NH:61][C@H:44]([C:43]([O:42][CH3:41])=[O:62])[CH2:45][C:46]2[CH:47]=[CH:48][C:49]([O:52][C:53]3[CH:58]=[CH:57][N:56]=[C:55]([CH3:59])[C:54]=3[CH3:60])=[CH:50][CH:51]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](N)Cc1ccc(Oc2ccnc(C)c2C)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCC2CCCCC2)cc1)O3
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3

Procedure:
(3S,8S)-3-(4-Cyclohexylmethoxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester was coupled with (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester bis hydrochloride according to General Procedure L furnished (3S,8S)-3-(4-Cyclohexylmethoxy-phenyl)-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester. This compound was converted to (S)-2-{[(3S,8S)-3-(4-cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester bis hydrochloride according to General ProcedureC. LCMS (m/z) 707.
Reaction SMILES: C(OC([NH:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:48][O:49][CH2:50][CH3:51])[N:24]([CH2:25][C:26]([O:29][C:30](=[O:47])[CH2:31][N:32](CC3C=CC=CC=3)CC3C=CC=CC=3)([CH3:28])[CH3:27])[C:20]=2[C:19]2[CH:18]=[CH:17][C:16]([CH2:52][CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:15][C:14]=2[N:13]=1)=O)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:48][O:49][CH2:50][CH3:51])[N:24]([CH2:25][C:26]([O:29][C:30](=[O:47])[CH2:31][NH2:32])([CH3:28])[CH3:27])[C:20]=2[C:19]2[CH:18]=[CH:17][C:16]([CH2:52][CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:15][C:14]=2[N:13]=1
Reactant: CCOCc1nc2c(NC(=O)OCc3ccccc3)nc3cc(CCC(=O)OCC)ccc3c2n1CC(C)(C)OC(=O)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOCc1nc2c(N)nc3cc(CCC(=O)OCC)ccc3c2n1CC(C)(C)OC(=O)CN
Temperature: 25 °C
Reaction time: 20 h
Yield: 5.5 %

Procedure:
Ethyl 3-(4-(benzyloxycarbonylamino)-1-(2-(2-(dibenzylamino)acetoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoate (182 mg, 232 μmol) was combined with ethyl acetate (20 mL) to give a light yellow solution. Palladium on carbon 10% (600 mg, 232 μmol) was added and the mixture was stirred for 20 h at room temperature under H2. Afterwards the mixture was filtered through celite® and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 30% methanol in THF) to 27 mg of an impure sample that was further purified by preparative HPLC to give the title compound (6 mg, 5%) as light yellow oil; LC-MS (UV peak area, ESI) 79%, 516.5 (MHCOO−).
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([C:22]2[N:23]=[N:24][N:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:26]=2)=[N:20][C:19]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH:42]([CH3:44])[CH3:43])(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[CH:18][N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O.CC#N>C(Cl)Cl>[CH:42]([S:39]([C:36]1[CH:35]=[CH:34][C:33]([C:19]2[N:20]=[C:21]([C:22]3[N:23]=[N:24][N:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:26]=3)[C:16]([NH2:8])=[N:17][CH:18]=2)=[CH:38][CH:37]=1)(=[O:41])=[O:40])([CH3:44])[CH3:43]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cn(-c4ccccc4)nn3)n2)cc1
Solvent: CC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3cn(-c4ccccc4)nn3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-N-[5-(4-isopropylsulfonylphenyl)-3-(1-phenyltriazol-4-yl)pyrazin-2-yl]carbamate (193 mg, 0.3109 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was concentrated in vacuo, more DCM was added and concentrated in vacuo to leave a yellow solid. The solid was sonicated in a small amount of MeCN and solid collected by filtration and dried by suction to provide the sub-titled product 5-(4-(isopropylsulfonyl)phenyl)-3-(1-phenyl-1H-1,2,3-triazol-4-yl)pyrazin-2-amine Compound I-1 as a pale yellow solid (105 mg, 80%). 1H NMR (400.0 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.85 (s, 1H), 8.46 (d, 2H), 8.12 (d, 2H), 7.91 (d, 2H), 7.74 (br s, 2H), 7.67 (t, 2H), 7.58 (t, 1H), 3.47 (quintet, 1H) and 1.19 (d, 6H) ppm; LC/MS m/z 421.1 [M+H]+.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[F:24])[CH:13]=[CH:14][CH3:15].B(OC)(OC)[O:26]C.OO>O.C1COCC1>[CH2:12]([O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:26])=[C:19]([F:23])[C:18]=1[F:24])[CH:13]=[CH:14][CH3:15]
Reactant: CC=CCOc1cccc(F)c1F
Reactant: COB(OC)OC
Agent: OO
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC=CCOc1ccc(O)c(F)c1F
Temperature: -50 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
225 mL of 2.67 M butyllithium hexane solution was added dropwise to THF (500 mL) solution containing 96.0 g of 1-(2-butenoxy)-2,3-difluorobenzene under vigorous stirring at −50° C. or lower, while keeping the internal temperature, and then the stirring was continued for 1 hour at −50° C. While keeping the internal temperature, THF (60 mL) solution containing 63.3 g of trimethyl borate was added dropwise. The stirring was continued for 30 minutes while keeping the temperature, and then the temperature was increased to 0° C. While keeping the internal temperature, 120 mL of water was added dropwise, and then 160 mL of 15% hydrogen peroxide solution was further added dropwise. The stirring was continued for 1 hour at 0° C. The solution was heated to room temperature, and the stirring was further continued for 2 hours. Then, saturated saline was added to separate the organic phase, and extraction was performed from the water phase with toluene (twice). The organic phase was collected, then washed with 10% sodium thiosulfate aqueous solution, 3M hydrochloric acid, water, saturated aqueous solution of sodium hydrogencarbonate, and saturated saline in this order, and dried over anhydrous magnesium sulfate. The solvent was evaporated. The obtained residue was purified by column chromatography, and was subjected to recrystallization, to thereby obtain 42.7 g of 4-(2-butenoxy)-2,3-difluorophenol in the form of pale yellow needle-like crystals (E/Z ratio=99/1, according to 1H-NMR analysis).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[C:14]1([CH:20]2[CH2:25][C:24](=[O:26])[CH2:23][C:22](=[O:27])[CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.CC(C)(O)C#N>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH:23]2[C:22](=[O:27])[CH2:21][CH:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:25][C:24]2=[O:26])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC(c2ccccc2)CC(=O)C1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.5 %

Procedure:
A solution of 4-chloro-2-nitrobenzoyl chloride (4.4 g) in dry dichloromethane (5 ml) was added at 5°-10° C. to a stirred solution of 5-phenylcyclohexane-1,3-dione [3.7 g] and triethylamine (2.8 ml) in dry dichloromethane (50 ml), and the mixture was stirred at ambient temperature for 18 hours. Triethylamine (8.4 ml) and acetone cyanohydrin (0.4 ml) were added successively to the solution and the mixture was stirred at ambient temperature for 4 hours. The resulting solution was washed successively with 2N hydrochloric acid (25 ml) and water (3×25 ml), dried over sodium sulphate and evaporated under reduced pressure to give a brown solid which was recrystallised from acetonitrile to give 2-(4-chloro-2-nitrobenzoyl)-5-phenylcyclohexane-1,3-dione (4.2 g), mp 144°-145° C., as a light cream crystalline solid.