Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[O:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Br[CH2:32][CH2:33][CH2:34][OH:35]>C(#N)C>[OH:35][CH2:34][CH2:33][CH2:32][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[O:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:5]1
Reactant: OCCCBr
Reactant: CCOC(=O)CCCOc1ccccc1N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCOc1ccccc1N1CCN(CCCO)CC1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a stirred solution of ethyl 4-(2-(piperazin-1-yl)phenoxy)butanoate 25 (0.48 g, 0.0016 mol) in 60 mL acetonitrile was added DIEA (0.56 mL, 0.0032 mol) followed by 3-bromo-1-propanol 26 (0.14 mL, 0.0016 mol) and the resulting mixture was stirred at 60° C. for 6 h. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was concentrated and the residue was diluted with DCM (50 mL). The reaction mixture was washed with water (50 mL×2), dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography using 0-100% gradient of hexane and ethyl acetate to give the pure ethyl 4-(2-(4-(3-hydroxypropyl)piperazin-1-yl)phenoxy)butanoate 27. Brown oil, 0.39 g (63%). 1H NMR (400 MHz, CDCl3): δ 1.21 (t, J=7.2 Hz, 3H); 2.00 (quintet, J=7.2 Hz, 2H); 2.13 (quintet, J=7.2 Hz, 2H); 2.51 (t, J=7.2 Hz, 2H); 3.08 (broad s, 8H); 3.54 (t, J=6.4 Hz, 2H); 4.02 (t, J=6.4 Hz, 2H); 4.11 (q, J=7.2 Hz, 2H); 4.13-4.18 (m, 2H); 6.83-7.25 (m, 4H). MS (ESI): m/z=351.50 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13](=[NH:16])SC)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[NH2:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21]N1>CC(O)C>[NH2:1][C:2]1[C:3]([C:10]([N:12]=[C:13]2[N:16]3[CH2:21][CH2:22][CH2:23][CH:19]3[CH2:18][NH:17]2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: NC[C@@H]1CCCN1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Solvent: CC(C)O
Product: Nc1nc(N)c(C(=O)N=C2NCC3CCCN23)nc1Cl
Temperature: 60 °C

Procedure:
1-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea (Intermediate A) (195 mg, 0.5 mmol) is suspended in propan-2-ol (10 ml) and (S)-2-(aminomethyl)pyrrolidine (100 mg, 1 mmol) is added. The mixture is heated at 60° C. for 18 hours, allowed to cool to room temperature and the precipitate is removed by filtration. The filtrate is concentrated in vacuo and the residue purified by chromatography (SiO2, DCM/MeOH) to afford the title compound as a light, yellow gum; [M+H]+ 296
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14]C(=O)C)(=[O:3])[CH3:2].[Li+].[OH-].Cl>CO.CCOC(C)=O>[OH:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[NH:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1OC(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1O
Yield: 99.5 %

Procedure:
Acetic acid 2-acetylamino-5-nitro-phenyl ester (416) (21 g, 88.2 mmol) was suspended in MeOH (185 mL) and 2M aqueous LiOH (185 mL) was added. An instantaneous reaction occurred, the solution turned red, everything dissolved and a slight exothermic reaction was felt by the warmth of the flask. TLC (Rf: 0.55 compared to Rf: 0.45 for compound 416 in EtOAc) after 10 minutes indicated complete hydrolysis. Addition of 1.0 M aqueous HCl (500 mL) caused the color to fade and a precipitate to form. Collection of the precipitate via vacuum filtration followed by rinsing with water (2×100 mL) and drying under high vacuum for 16 h gave the desired product (417) as a yellow powder. (17.2 g, 87.8 mmol, 99.5% yield). LC-MS was inconclusive. The product was used in the next step without further characterization
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][CH2:11][CH3:12])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].CC([O-])(C)C.[K+]>C1COCC1.CS(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:21][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][CH2:11][CH3:12])=[CH:4][N:3]=1
Reactant: CCSc1cnc(Cl)cc1C#N
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCSc1cnc(Oc2ccc(Cl)c(Cl)c2)cc1C#N

Procedure:
2-Chloro-5-ethylthio-4-pyridinecarbonitrile (4.0 g) was reacted with 3.6 g of 3,4-dichlorophenol in the presence of 2.6 g of t-BuOK in 40 ml of THF and 4 ml of DMSO. 5.5 g (84.6%) of the desired, 2-(3,4-dichlorophenoxy)-5-ethylthio-4-pyridinecarbonitrile was recovered, m.p. 68°-69° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[CH3:43][N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1>C(OCC)(=O)C.C(OC(C)C)(C)C>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][N+:44]4([CH3:43])[CH2:48][CH2:47][CH2:46][CH2:45]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CN1CCCC1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1nsc(N)n1
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[N+]3(C)CCCC3)CS[C@H]12)c1nsc(N)n1
Reaction time: 1 h
Yield: 12.2 %

Procedure:
To a solution of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (IX-1) (Z/E=2/1, 150 mg, 0.21 mmole) in ethyl acetate (2 ml) was added a solution of 1-methylpyrrolidine (36 mg, 0.42 mmole) in ethyl acetate (1 ml) in one portion with stirring. The mixture was stirred for 15 minutes and diluted with isopropyl ether (10 ml) to form a precipitate, which was collected by filtration. A mixture of the solid (130 mg), formic acid (1 ml) and concentrated HCl (0.1 ml) was stirred at room temperature. After 1 hour, the reaction mixture was concentrated under reduced pressure, diluted with water (20 ml) and filtered. The aqueous solution was passed through a reverse phase column (the packing of PrepPAK-500/C18 cartridge, 100 ml), eluting with water and 10% CH3OH. The desired fractions were collected, and concentrated in vacuo to a small volume and freeze-dried to give 13 mg (12%) of the title compound (I-1A) (Z/E=1/1), melting at >280° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].Cl.Cl[CH2:35][C:36]#[C:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:35][C:36]#[C:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7]
Reactant: ClCC#Cc1cccnc1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CC#Cc2cccnc2)C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 50 °C
Reaction time: 5 h
Yield: 29.8 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]piperazine (0.67 g), 1-chloro-3-(3-pyridyl)-2-propyne hydrochloride (0.3 g) and potassium carbonate (0.52 g) in N,N-dimethylformamide (5 ml) was stirred for 5 hours at 50° C. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[3-(3-pyridyl)-2-propynyl]piperazine (0.25 g) as a syrup.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[H-].[Na+].Cl[C:18]1[N:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=1.O>C1COCC1>[CH3:24][C:21]1[N:20]=[N:19][C:18]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:23][CH:22]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: Cc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(OCc2c(-c3ccccc3)noc2C)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.6 %

Procedure:
To a solution of (5-methyl-3-phenyl-4-isoxazolyl)methanol (0.50 g, 2.64 mmol) in THF (8 mL) was added sodium hydride (55% dispersion in mineral oil, 0.16 g, 3.17 mmol) at 0° C. The reaction mixture was stirred for 30 min while it was allowed to warm up to room temperature. 3-Chloro-6-methylpyridazine (0.36 g, 2.77 mmol) was added and stirring was continued for 2 h. Water (10 mL) was added and the mixture was extracted with ethyl acetate (40 mL). The combined organic layers were washed with brine (10 mL) and dried over sodium sulfate. Concentration and purification of the residue by chromatography (SiO2, heptane:ethyl acetate=100:0 to 50:50) afforded the title compound (220 mg, 30%) as a yellow oil. MS: m/e=282.3 [M+H]−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1.[CH3:21][Mg+].[Br-]>C1COCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Reactant: C[Mg+]
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 53 %

Procedure:
To a solution of 5-bromo-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (400 mg, 1.20 mmol, Step 12a above) in THF (10 mL) at 0° C. was added a catalytic amount of [1,3-bis(diphenylphosphino)-propane]nickel(II) chloride (3.8 mg) followed by MeMgBr (0.8 mL of a 3.0 M solution in THF, Aldrich). The mixture was refluxed for 3 hours, cooled to ambient temperature, and quenched with saturated aqueous ammonium chloride. The volatile components were evaporated and the residue was diluted with CH2Cl2 and saturated aqueous ammonium chloride. The organic extract was dried over MgSO4 and concentrated. The residue was chromatographed (silica gel; CH2Cl2 /MeOH, 10:0.2 to 10:0.5) to afford the 5-methyl-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethyloxy)pyridine as an oil (177 mg, 53%): 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 9H), 2.20-2.40 (m, 2H), 3.90 (t, J=8.33 Hz, 2H), 4.14 (m, 1H), 4.31 (m, 1H), 4.51 (m, 1H), 7.04 (s, 1H), 8.06 (s, 1H), 8.18 (d, J=3.33 Hz, 1H); MS (CI/NH3) m/z 279 (M+H)+. To a solution of the above product (170 mg, 0.6 mmol) in CH2Cl2 (2 mL) at 0° C. was added TFA (1.0 mL). After stirring for 30 minutes the solution was basified with 15% aqueous NaOH and extracted with CH2Cl2. The combined organic extracts were dried over MgSO4 and concentrated. The crude product was chromatographed (silica gel; CH2Cl2 /MeOH, 10:1) to afford 5-methyl-3-(azetidinyl-(2S)-methoxyl)pyridine as an oil (93 mg, 64%): 1H NMR (CDCl3, 300 MHz) δ 2.28 (m, 1H), 2.36 (s, 3H), 2.39 (m, 1H), 3.43 (m, 1H), 3.65 (q, J=3.33 Hz, 1H), 3.98-4.02 (m, 2H), 4.22 (m, 1H), 7.12(m, 1H), 8.04 (s, 1H), 8.14 (d, J=3.33 Hz, 1H); MS (CI/NH3) m/z: 179 (M+H)+. The above product was slurried in Et2O and HCl in Et2O was added dropwise. The solvent was removed and the resultant solid was recrystallized from MeOH/Et2O to afford the title compound as a light yellow, very hygroscopic solid: 1H NMR (D2O, 300 MHz) δ 2.36 (s, 3H), 2.67 (q, J=8.33 Hz, 2H), 4.04-4.21 (m, 2H), 4.40 (d, J=3.40 Hz, 2H), 4.90 (m, 1H), 7.40 (s, 1H), 8.04 (s, 1H), 8.14 (s, 1H). MS (CI/NH3) m/z: 179 (M+H+)+. Anal. Calcd. for C10H14N2.1.5 HCl: C, 51.57; H, 6.71; N, 12.03. Found: C, 51.53; H, 6.86; N, 12.03.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][C:22]([F:27])=[C:23]([F:26])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C(=CC=C(F)C=3)N=CC2=O)CC1>ClCCl>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][C:22]([F:27])=[C:23]([F:26])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3cc(F)c(F)cc32)CC1
Agent: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(CCn2c(=O)cnc3cc(F)c(F)cc32)CC1

Procedure:
tert-Butyl{1-[2-(6,7-difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 151, 500 mg, 1.23 mmol) was reacted with trifluoroacetic acid in dichloromethane as described for Intermediate 140 to give 380 mg (quantitative) of the crude product as an oil.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:21])[NH:6][C@@H:7]1[CH2:20][C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:28][O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Cl>CN(C=O)C.O>[CH:1]([O:4][C:5](=[O:21])[NH:6][C@@H:7]1[CH2:20][C:10]2[N:11]([CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=3[O:29][CH3:28])[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: COc1ccccc1CCl
Reactant: CC(C)OC(=O)N[C@@H]1Cc2[nH]c3ccc(C#N)cc3c2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1Cn1c2c(c3cc(C#N)ccc31)C[C@H](NC(=O)OC(C)C)C2
Temperature: 50 °C
Yield: 98.3 %

Procedure:
A mixture of ((S)-7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester (2.0 g, 7.06 mmol) and cesium carbonate (3.22 g, 9.88 mmol) in DMF (40 mL) is treated with 2-methoxybenzyl chloride (1.16 g, 7.41 mmol). The reaction is heated at 50° C. for 18 h. The reaction is cooled to room temperature and diluted with water (300 mL). The white solid is collected and washed with water. The solid is dried in a 40° C. vacuum oven. After drying, 2.80 g (98%) product is obtained as a white solid. LC-ES/MS m/z 404 [M+H]+, TR=2.83 min.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14](=[O:16])[CH3:15])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[Br:17]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:17][C:11]1[C:10]2[C:9]([CH3:12])([CH3:13])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([C:14](=[O:16])[CH3:15])[C:2]=1[OH:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1cc2c(cc1O)C(C)(C)CCC2
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cc2c(c(Br)c1O)C(C)(C)CCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(3-hydroxy-5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone (Compound A-88, 13.3 g, 61 mmol) in N,N-dimethylformamide (120 mL) was added N-bromosuccinimide (10.9 mg, 61 mmol). The mixture was stirred at room temperature for 16 h. The mixture was then diluted with water and extracted with diethyl ether. The combined ethereal layers were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. Recrystallization from diethyl ether and flash column chromatography (silica gel, 5% ethyl acetate in hexane) afforded the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH2:19]([NH2:25])[C:20]1[O:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH2:19][CH:20]1[CH2:21][CH2:22][CH2:23][O:24]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: NCc1ccco1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NCC1CCCO1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (300 mg, 1.13 mmol) was treated with furfurylamine following general procedure B to afford 8-methoxy-4-[(tetrahydro-furan-2-ylmethyl)-amino]-quinoline-3-carboxylic acid ethyl ester (280 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (220 mg) following general procedure E. The above ethylamide (0.67 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-7-methoxy-1-(tetrahydro-furan-2-ylmethyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (30 mg). LCMS: m/z 356 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.N1C=CC=CC=1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>C(Cl)Cl>[C:19]1([O:18][C:16](=[O:17])[NH:1][C:2]2[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cnc(N)cn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cnc(NC(=O)Oc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.7 %

Procedure:
2-Amino-5-methylpyrazine (5.16 g, 47 mmol) was dissolved in CH2Cl2 (52 mL), stirred and cooled to 0° C. under N2. To this, pyridine (4.8 mL, 59 mmol) was added followed by phenyl chloroformate (6.2 mL, 59 mmol), dropwise, over 15 min, causing a precipitate to form. The mixture was stirred at 0° C. for 1 h. Then the reaction was quenched with 0.25 M HCl (40 mL) and anhydrous ether (50 mL), and stirred at 0° C., for 30 min. The precipitate was isolated by filtration, washed with DI H2O (20 mL) and ether (2×25 mL), and dried under vacuum to give the product (7.4 g) as a white fluffy powder.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]OS(C)(=O)=O)=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)=[CH:4][CH:3]=1.[N:31]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[C:40]([O:39][C:37]([N:31]1[CH2:36][CH2:35][N:34]([CH2:14][C:11]2[C:12](=[O:13])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:30][CH:29]=3)[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)[CH:10]=2)[CH2:33][CH2:32]1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Yield: 78.8 %

Procedure:
Following the procedure of Example 1(10), 2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 78.8%).
Reaction SMILES: C[O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([CH:9]2[CH2:12][CH2:11][CH:10]2[C:13]([OH:15])=[O:14])=[O:8])=[CH:5][CH:4]=1.Br.[C:19](O)(=O)[CH3:20]>O>[CH2:19]([O:15][C:13]([CH:10]1[CH2:11][CH2:12][CH:9]1[C:7](=[O:8])[C:6]1[CH:16]=[CH:17][C:3]([OH:2])=[CH:4][CH:5]=1)=[O:14])[CH3:20]
Reactant: CC(=O)O
Reactant: COc1ccc(C(=O)C2CCC2C(=O)O)cc1
Agent: Br
Solvent: O
Product: CCOC(=O)C1CCC1C(=O)c1ccc(O)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To 2-(4-methoxy-benzoyl)-cyclobutanecarboxylic acid (10.28 g, 43.88 mmol) was added 48% hydrogen bromide in water (50 mL) and acetic acid (50 mL). After overnight stirring at 120° C., the reaction was concentrated, stirred with ethanol a few times, and the product was purified using a Single Step column (7:3 hexanes:ethyl acetate) to obtain 7.70 g (71%); MS m/z 247 (M−H)
Reaction SMILES: [F:1][C:2]1[CH:38]=[C:37]([NH:39][C:40]([NH:42][C:43](=[O:51])[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[S:41])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:29][CH:30]4[CH2:34][CH2:33][CH2:32][O:31]4)C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)[S:13][C:6]=12>C1(C)C=CC=CC=1.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:38]=[C:37]([NH:39][C:40]([NH:42][C:43](=[O:51])[CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[S:41])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH2:29][CH:30]4[CH2:34][CH2:33][CH2:32][O:31]4)=[CH:16][CH:15]=3)[S:13][C:6]=12
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1)CC1CCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(CNCC5CCCO5)cc4)sc23)c(F)c1
Reaction time: 8 h

Procedure:
To a solution of 80 (200 mg, 0.28 mmol) in toluene (5 mL), TFA (excess) was added. The reaction mixture was allowed to stir overnight, the solvent was removed under reduced pressure and the remained solid was triturated with diethyl ether to afford title compound 81 as the di-TFA salt (130 mg, 57% yield). 1H NMR (DMSO) δ (ppm): 12.47 (s, 1H), 11.83 (s, 1H), 9.06 (s, 2H), 8.53 (dd, J=2.0 and 5.5 Hz, 1H), 8.13 (s, 1H), 8.0 (d, J=12.1 Hz, 1H), 7.97 (d, J=8.7 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H), 7.53 (m, 2H), 7.32 (m, 4H), 7.27 (m, 1H), 6.68 (d, J=5.8 Hz, 1H), 4.23 (m, 1H), 3.82 (s, 2H), 3.78 (m, 1H), 3.71 (m, 1H), 3.11 (m, 1H), 2.95 (m, 1H), 2.0 (m, 1H), 1.98 (m, 2H), 1.56 (m, 1H). MS (m/z) 627.3 (M+H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][C@H:28]1[NH:33][CH2:32][CH2:31][N:30]([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=2)[CH2:29]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:33]2[CH2:32][CH2:31][N:30]([C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)[CH2:29][C@H:28]2[CH3:27])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: C[C@@H]1CN(c2ccc3ccccc3n2)CCN1
Product: C[C@@H]1CN(c2ccc3ccccc3n2)CCN1CCCCC1(C(=O)NCC(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-[(R)-3-methyl-piperazin-1-yl]-quinoline
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[Cl:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44](Cl)=[O:45]>>[Cl:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)=[O:45]
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3cccc(Cl)c3)CN2C1=O
Yield: 96.1 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 3-chlorobenzoyl chloride (45 μL, 0.35 mmol). The final trituration (diethyl ether/hexane) and filtration gave 119 mg (94%) of 18-(3-chorobenzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.4% pure (HPLC), MS m/z 705 (M−H)−, HRMS: calcd. 707.2518 and found 707.2531 (M+H)+, mp 154-156° C.