Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[CH:27][CH:26]=3)[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:14]([CH3:42])[C:13]=2[CH:43]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH2:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[CH:29][CH:30]=3)[CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[C:14]([CH3:42])[C:13]=2[CH:43]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(NCc4ccccc4)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(NCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To a mixture of ethyl 3-[{[4-({[5-(benzylamino)-3-methyl-1-benzofuran-2-yl](cyclohexyl)methyl}amino)phenyl]carbonyl}(methyl)amino]-propanoate (354 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 1.5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (310 mg, 92%) as a white solid.
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[N:5][N:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.C([Li])CCC>O1CCCC1>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]1[C:2]([B:16]([OH:21])[OH:17])=[C:3]2[CH2:15][CH2:14][CH2:13][N:4]2[N:5]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1c(-c2ccccn2)nn2c1CCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 54.8 %

Procedure:
Place tetrahydrofuran (60.0 mL) in a 100 mL round-bottom flask equipped with a temperature probe, a magnetic stirrer, and a septum and put under a nitrogen atmosphere. Add 3-bromo-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (Preparation 3-D; 3.00 g, 11.4 mmol) and triisopropyl borate (6.80 mL, 29.5 mmol). Cool the mixture to −78° C. using a dry ice/acetone bath. Add 1.41M n-butyllithium in hexanes (19.3 mL, 27.3 mmol) dropwise via a syringe pump over 10 min keeping the temperature below −40° C. Remove the dry ice/acetone bath and allow the reaction mixture to warm to room temperature. Add saturated aqueous ammonium chloride (20 mL) and extract with chloroform (2×150 mL). Combine the organic layers, dry over solid sodium chloride, and remove the solvent under reduced pressure to afford an oil. Purify by normal phase flash chromatography (120 g Biotage KP-Sil 40L: ethyl acetate for 25 min, 0-10% methanol in ethyl acetate in ramp over 15 min, then 10% methanol in ethyl acetate) to obtain 1.43 g (55%) of the title product. MS ES+ m/e 230 (M+1).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20](=[O:22])[CH3:21])=[CH:12][CH:11]=1.[Cl:23][C:24]1[CH:25]=[C:26]([C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[CH:27]=[C:28]([Cl:30])[CH:29]=1.Cl>O1CCCC1>[Br:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20](=[O:22])[CH2:21][C:31]([C:26]2[CH:27]=[C:28]([Cl:30])[CH:29]=[C:24]([Cl:23])[CH:25]=2)([OH:36])[C:32]([F:35])([F:34])[F:33])=[CH:12][CH:11]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1ccc(Br)c2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(Br)c2ccccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
Lithium diisopropylamide (Aldrich Chemical Company, 2M in tetrahydrofuran/ethylbenzene, 4 mL, 7.94 mmol) was added to tetrahydrofuran (4 mL) at −78° C. A solution of 1-(4-bromo-1-naphthalenyl)ethanone (1.8 g, 7.22 mmol) in tetrahydrofuran (4 mL) was added dropwise to the mixture. When the addition was complete the mixture was stirred for 30 min at −78° C. Then a solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (1.75 g, 7.20 mmol) in tetrahydrofuran (4 mL) was added dropwise to the mixture at such a rate that the temperature of the reaction mixture did not exceed −55° C. The mixture was allowed to warm to ambient temperature over 120 min. The mixture was then poured into 1N hydrochloric acid (100 mL) and extracted with ethyl acetate (2×100 mL). The combined extracts were dried and evaporated. Chromatography on silica gel (eluted with 1:9 ethyl acetate/hexanes) and crystallization from hexanes gave the title product as a white solid (1.1 g, 40% yield) melting at 74.5-75° C. (after recrystallization from hexanes).
Reaction SMILES: C[NH:2][C:3]([CH3:9])=[CH:4][C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[Cl:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>O1CCCC1>[Cl:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]2[O:23][N:2]=[C:3]([CH3:9])[C:4]=2[C:5]([O:7][CH3:8])=[O:6])=[CH:20][CH:19]=1
Reactant: CNC(C)=CC(=O)OC
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)c1c(C)noc1-c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
Methyl 3-oxobutanoate (29.4 g) was dissolved in methanol (30.0 ml), and a 40%-methylamine-methanol solution (32.0 ml) was added dropwise at room temperature. The mixture was stirred for 1 hour. After the completion of the reaction, the reaction solution as such was concentrated, and then dried using a vacuum pump. Thus, methyl 3-(methylamino)-2-butenoate (31.8 g, yield 97%) was obtained. Subsequently, methyl 3-(methylamino)-2-butenoate (5.38 g) was dissolved in tetrahydrofuran (100 ml), and pyridine (5.0 ml) was added dropwise at room temperature. Under ice cooling, p-chloromethyl benzoyl chloride (8.0 g) was added dropwise and the mixture was stirred at room temperature for 4 hours. After the completion of the reaction, distilled water was added, and the product was extracted by liquid separation using ether and then washed with saturated aqueous solution of sodium chloride. The product was dried over sodium sulfate to concentrate and the residue was dried using a vacuum pump. Subsequently, the residue was dissolved in acetic acid (30.0 ml). Hydroxylamine hydrochloride (2.8 g) was added at room temperature, and the mixture was heated under reflux for 1 hour and 30 minutes. After the completion of the reaction, saturated aqueous solution of sodium hydrogencarbonate was added to neutralize the reaction system, and the product was extracted by liquid separation using ether. The resultant organic layer was washed with saturated solution of sodium chloride and dried over sodium sulfate to concentrate. The residue was purified through a column using a hexane-acetone elution system. Thus, methyl 5-[4-(chloromethyl)phenyl]-3-methyl-4-isoxazole carboxylate (5.42 g, yield 49.0%) was obtained.
Reaction SMILES: [Li].C[Si]([N-:6][Si](C)(C)C)(C)C.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:16]#[N:17].Cl>C1COCC1>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:16]([NH2:6])=[NH:17]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1cc(C#N)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Product: COc1cc(C(=N)N)ccc1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
99 ml (99 mmol) lithium-bis-trimethylsilylamide solution (1 mol/l in THF) are diluted with 640 ml THF, cooled to 10° C. and combined with 8.3 g (46.591 mmol) 3-methoxy-4-nitro-benzonitrile. The reaction mixture is stirred for 10 min at 20° C. The mixture is cooled to 0° C. and combined with 80 ml 3 N hydrochloric acid. The reaction mixture is evaporated down in vacuo and extracted with water and ethyl acetate. The aqueous phase is adjusted to pH 14 with 3 N sodium hydroxide solution. The product is then suction filtered.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:17]=1[O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[C:22]([N:24]([CH3:26])[CH3:25])=[O:23]>C(O)C>[Cl:34][C:32]1[CH:31]=[CH:30][C:17]([O:18][C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=2)[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:33]=1
Reactant: CN(C)C(=O)c1cccc(Oc2ccc(Cl)cc2N)c1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: CCCc1ccc2c(Nc3cc(Cl)ccc3Oc3cccc(C(=O)N(C)C)c3)ccnc2n1

Procedure:
The product from Example 2g (177 mg, 0.86 mmol) was reacted with the product from Example 168d (249 mg, 0.86 mmol) in ethanol (5 mL) at 85° C. in a sealed tube for 18 h giving the crude title compound which was purified by HPLC with TFA providing the product as the trifluoroacetic acid (100 mg, 20.2%). 1H NMR (500 MHz, DMSO-D6) δ ppm: 8.86 (d, J=8.79 Hz, 1H) 8.52 (d, J=6.84 Hz, 1 H) 7.74 (d, 1 H) 7.72 (d, 1H) 7.60 (dd, J=8.79, 2.93 Hz, 1 H) 7.28-7.33 (m, 1 H) 7.27 (d, 2H) 7.06 (d, J=7.81 Hz, 1 H) 6.99 (dd, J=8.06, 2.69 Hz, 1 H) 6.71 (d, J=6.84 Hz, 1 H) 2.96 (t, 2 H) 2.91 (s, 3 H) 2.70 (s, 3 H) 1.79-1.86 (m, 2 H) 0.96 (t, J=7.49 Hz, 3 H); MS (ESI+) m/z 461 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2B(O)O)[CH2:18][CH2:17]1>>[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)[CH2:17][CH2:18]1
Reactant: OB(O)c1ccc(F)cc1OCC1CC1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(F)cc1OCC1CC1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 2) and 2-(cyclopropylmethoxy)-4-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C20H17FN4O, 349. Found, 349.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:55])[C@@H:20]([NH:36][C:37](=[O:54])[C@@H:38]([NH:42][C:43](=[O:53])[C@H:44]([CH3:52])[C@H:45]([O:50][CH3:51])[CH2:46][CH2:47]C=C)[CH:39]([CH3:41])[CH3:40])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH:23]=3)[NH:14]2)=[O:12])[CH:4]=1)=[CH2:2]>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.ClCCCl>[C:32]([Si:29]([CH3:30])([CH3:31])[O:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][C@H:20]1[C:19](=[O:55])[N:15]2[NH:14][C@@H:13]([CH2:18][CH2:17][CH2:16]2)[C:11](=[O:12])[O:10][CH2:9][C:5]2=[CH:4][C:3](=[CH:8][CH:7]=[N:6]2)[CH:1]=[CH:2][CH2:47][CH2:46][C@@H:45]([O:50][CH3:51])[C@@H:44]([CH3:52])[C:43](=[O:53])[NH:42][C@@H:38]([CH:39]([CH3:41])[CH3:40])[C:37](=[O:54])[NH:36]1)([CH3:35])([CH3:33])[CH3:34]
Reactant: C=CCC[C@@H](OC)[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)OCc2cc(C=C)ccn2)N1)C(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: CO[C@@H]1CC/C=C/c2ccnc(c2)COC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1C
Solvent: ClCCCl
Product: CO[C@@H]1CCC=Cc2ccnc(c2)COC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1C
Temperature: 80 °C

Procedure:
Hoveyda-Grubbs 2nd generation catalyst (22 mg, 0.035 mmol) was added to a stirred solution of (S)-1-{(S)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-[(S)-2-((2R,3R)-3-methoxy-2-methyl-hept-6-enoylamino)-3-methyl-butyrylamino]-prop ionyl}-hexahydro-pyridazine-3-carboxylic acid 4-vinyl-pyridin-2-ylmethyl ester (276 mg, 0.35 mmol) in 1,2-dichloroethane (130 mL) and the reaction mixture was heated at 80° C. under nitrogen for 3 hours. The reaction mixture was cooled to room temperature, silica gel was added and the solvent was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:1 to neat ethyl acetate to afford (E)-(1S,14R,15R,18S,21S)-21-[3-(tert-butyl-dimethyl-silanyloxy)-benzyl]-18-isopropyl-14-methoxy-15-methyl-3-oxa-6,17,20,23,27-pentaaza-tricyclo[21.3.1.1*5,9*]octacosa-5(28),6,8,10-tetraene-2,16,19,22-tetraone (160 mg, 61%) as a white solid. LCMS (m/z) 750 [M+H], Tr=5.58 min.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:23])=[CH:6][C:7]([CH3:22])([CH3:21])[NH:8]2.[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[C:3]([CH2:2][S:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:22])([CH3:21])[CH:6]=[C:5]2[CH3:23]
Reactant: Sc1ccccc1
Reactant: COc1ccccc1-c1ccc2c(c1CCl)C(C)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1ccc2c(c1CSc1ccccc1)C(C)=CC(C)(C)N2
Temperature: 50 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A mixture of 5-chloromethyl-6-(2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 5-1, 80 mg, 0.24 mmol), thiophenol (148 μL, 1.44 mmol) and potassium carbonate (266 mg, 1.92 mmol) was suspended in anhydrous N,N-dimethylformamide (2 mL), and the reaction mixture was stirred at 50° C. overnight. After cooling down, it was diluted with ethyl acetate (50 mL). The whole was washed with water (50 mL) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (53 mg) as a colorless solid. (Yield 55%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:35])[C:32]([CH3:34])=[CH2:33]>C1COCC1>[CH3:34][C:32](=[CH2:33])[C:31]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1)=[O:35]
Reactant: C=C(C)C(=O)Cl
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3)c12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (50 mg, 0.18 mmol) and DIPEA (93 μL, 0.53 mmol) in THF (1.8 mL) at room temperature was added methacryloyl chloride (27.8 mg, 0.266 mmol) and the solution stirred for 1 hour. The reaction was quenched with ethanol (0.1 mL). The desired product was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. The combined fractions with the desired product were concentrated until only the water layer remained. The water layer was neutralized with 2M aqueous potassium bicarbonate and the mixture was extracted with ethyl acetate (×5). The combined organic fractions were dried over sodium sulfate, filtered and concentrated under reduced pressure to give ethyl 4-{3-[(2-methylacryloyl)amino]phenyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C19H19N4O3 [M+H]+: 351, found 351. 1H NMR (600 MHz, DMSO-D6) δ 13.0 (s, 1H), 9.91 (s, 1H), 8.91 (s, 1H), 8.30 (s, 1H), 8.05 (s, 1H), 7.84 (d, 1H, J=7.04 Hz), 7.40 (t, 1H, J=7.63 Hz), 7.32 (d, 1H, J=7.04 Hz), 5.82 (s, 1H), 5.53 (s, 1H), 3.86 (q, 2H, J=7.04 Hz), 1.95 (s, 3H), 0.85 (t, 3H, J=7.04 Hz).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:17][C@H:16]([OH:18])[CH2:15][C@H:14]1[C:19](=[O:21])[NH2:20])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.[Cl-].[Na+]>O1CCCC1>[C:6]([O:10][C:11]([N:13]1[CH2:17][C@H:16]([O:18][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][C@H:14]1[C:19](=[O:21])[NH2:20])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(N)=O
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(N)=O
Reaction time: 1 h

Procedure:
1.85 ml of methanesulfonyl chloride was added, whilst ice-cooling, to a solution of 5.0 g of (2S, 4R)-1-(t-butoxycarbonyl)-2-carbamoyl-4-hydroxypyrrolidine [prepared as described in step (2) above] in 250 ml of dry tetrahydrofuran, followed by 3.31 ml of triethylamine. The mixture was then stirred at 0° to 5° C. for 1 hour, after which it was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography through silica gel (eluted with a 9:1 by volume mixture of ethyl acetate and methanol) to afford 5.5 g of the title compound as colorless crystals.
Reaction SMILES: [NH2:1][CH:2]([CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][CH2:5][CH:6]([NH2:16])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:40])[CH2:34][O:35][CH2:36][C:37](Cl)=[O:38]>ClCCl>[CH2:19]([O:18][CH2:17][CH:2]1[CH2:3][NH:4][CH2:5][CH:6]([CH2:7][O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:16][C:37](=[O:38])[CH2:36][O:35][CH2:34][C:33](=[O:40])[NH:1]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)COCC(=O)Cl
Reactant: NC(CNCC(N)COCc1ccccc1)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1COCC(=O)NC(COCc2ccccc2)CNCC(COCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,5-diamino-1,5-dibenzyloxymethyl-3-aza-pentane (0.57 g, 1.7 mmol) (Example 6 (d)) and triethylamine (0.34 g, 3.4 mmol) in dichloromethane (10 ml) and a solution of diglycolic acid dichloride (0.29 g, 1.7 mmol) in dichloromethane (10 ml) were added simultaneously over 2.5 hours to vigorously stirred dichloromethane (10 ml) at 0° C. The solution was stirred at ambient temperature overnight, washed with water (2×30 ml), dried with sodium sulphate and evaporated. Yield 0.59 g (78%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)([CH3:12])[CH3:11].[Br:26][C:27]1[N:32]2[CH:33]=[CH:34][N:35]=[C:31]2[C:30](Br)=[N:29][CH:28]=1>CC(O)C>[Br:26][C:27]1[N:32]2[CH:33]=[CH:34][N:35]=[C:31]2[C:30]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([CH:16]3[CH2:15][CH2:14][N:13]([CH:10]([CH3:12])[CH3:11])[CH2:18][CH2:17]3)=[CH:24][CH:23]=2)=[N:29][CH:28]=1
Reactant: Brc1ncc(Br)n2ccnc12
Reactant: CC(C)N1CCC(c2ccc(N)cc2)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1

Procedure:
N,N-Diisopropylethylamine (360 μL, 2.2 mmol) is added to a mixture of 4-(1-isopropylpiperidin-4-yl)phenylamine (220 mg, 1.0 mmol) and 5,8-dibromoimidazo[1,2-a]pyrazine (280 mg, 1.0 mmol) in iPrOH (5 mL) and heated at reflux for 48 h. The mixture is cooled and the solvent evaporated under reduced pressure to afford an orange-brown solid. This is partitioned between DCM (50 mL) and water (20 mL) and the layers are separated. The organic phase is washed with citric acid (10% aq., 3×25 mL). The combined washings are extracted with DCM (25 mL) and then made basic by addition of NaHCO3 (s). The mixture is extracted with DCM (3×25 mL) and the combined extracts dried over MgSO4 and evaporated. The material is used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:28]=[CH:29][CH:30]=2)[O:22][CH2:23][C:24]([O:26]C)=O)(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:38][NH2:39]>CO>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:13]1[N:14]([S:16]([C:19]2[CH:30]=[CH:29][CH:28]=[C:21]([O:22][CH2:23][C:24]([NH:39][CH3:38])=[O:26])[CH:20]=2)(=[O:17])=[O:18])[CH:15]=[C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH:12]=1
Reactant: COC(=O)COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Reactant: CN
Solvent: CO
Product: CNC(=O)COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Methyl 2-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetate 1i (110 mg, 0.20 mmol) was dissolved in 10 mL of a solution of methylamine in methanol (33%), and the reaction solution was heated up to 40° C. and stirred for 2 h. The reaction solution was concentrated under reduced pressure to obtain the title product tert-butyl ((5-(2-fluorophenyl)-1-((3-(2-(methylamino)-2-oxoethoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 1j (60 mg, a yellow oil), which was used directly in the next step.
Reaction SMILES: [OH:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:9]([O-])=[CH:8][C:7]=2[N:6]=[C:5]1[NH:18][C:19](=[O:22])[O:20][CH3:21].[OH-].[NH4+:26].C1(S(Cl)(=O)=O)C=CC=CC=1>CO>[NH2:26][C:8]1[C:7]2[N:6]=[C:5]([NH:18][C:19](=[O:22])[O:20][CH3:21])[N:4]([CH2:3][C:2]([OH:1])([CH3:24])[CH3:23])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: [NH4+]
Reactant: COC(=O)Nc1nc2c[n+]([O-])c3ccccc3c2n1CC(C)(C)O
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [OH-]
Solvent: CO
Product: COC(=O)Nc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O
Temperature: 0 °C
Yield: 45.5 %

Procedure:
A suspension of methyl [1-(2-hydroxy-2-methylpropyl)-5-oxido-1H-imidazo[4,5-c]quinolin-2-yl]carbamate (0.80 g, 2.4 mmol) in methanol (10 mL) was stirred vigorously and cooled to 0° C. Concentrated ammonium hydroxide (0.8 mL, 25 mmol) was added followed by benzenesulfonyl chloride (0.9 g, 5 mmol), which was added dropwise. The mixture was stirred for two hours at 0° C. to 5° C. An analysis by LC/MS indicated the reaction was incomplete. Additional benzenesulfonyl chloride (0.9 g) was added, and the reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was purified by automated flash chromatography (40+M silica cartridge, eluting with 0% to 25% CMA in chloroform) followed by recrystallization from ethyl acetate to provide 0.36 g of methyl [4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]carbamate as a white solid, mp 255-258° C. (decomposition).