Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH2:16])[N:11]=1)[C:4]([NH2:6])=[NH:5].[Na].CS([C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])=O>C(O)C>[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:21]2[NH:22][CH:23]=[CH:24][C:25]=2[N+:26]([O-:28])=[O:27])[N:11]=1)[C:4]([NH2:6])=[NH:5]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: CS(=O)c1[nH]ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: N=C(N)Nc1nc(CSCCNc2[nH]ccc2[N+](=O)[O-])cs1

Procedure:
A solution of 2-(2-guanidino-4-thiazolylmethylthio)-ethylamine dihydrochloride (4 g, 0.013 mole) in ethanol (25 ml) was basified with a solution of sodium (0.65 g, 0.028 mole) in ethanol (20 ml). The mixture was filtered and the filtrate added to 2-methylsulphinyl-3-nitropyrrole (1.5 g, 0.0086 mole). The mixture was refluxed for 5 days, then the solvent was removed in vacuo and the residue chromatographed on a silica-gel column. The product was eluted with ethyl acetate/propan-2-ol (8:2) and recrystallised from methanol/acetone (6:4). Yield: 0.65 g, 22%. M.P. 195.5°-200° C.
Reaction SMILES: [CH:1]1([C:7]2[O:8][C:9]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:10][C:11]=2[CH:12]([O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39]>>[CH:1]1([C:7]2[O:8][C:9]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=3)=[CH:10][C:11]=2[CH:12]([O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:35]([CH3:34])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:20])=[CH:17][CH:16]=2)[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(Oc1ccc(C(=O)O)cc1)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C1CCCCC1
Reactant: CCOC(=O)CCNC
Product: CC(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C1CCCCC1
Yield: 84.3 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-(1-{2-cyclohexyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethoxy)benzoic acid (138 mg) as well as ethyl 3-(methylamino)propanoate (47 mg) to give the title compound (138 mg, 84%) as an amorphous compound.
Reaction SMILES: [C:1]([O:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:6]([OH:8])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[O:28][N:27]=[C:26]([CH3:29])[CH:25]=1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:6](=[O:8])[NH:23][C:24]2[O:28][N:27]=[C:26]([CH3:29])[CH:25]=2)=[CH:10][CH:11]=1
Reactant: Cc1cc(N)on1
Reactant: COc1ccc(C(OC(C)=O)C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(OC(C)=O)C(=O)Nc2cc(C)no2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a suspension of acetoxy-(4-methoxy-phenyl)-acetic acid (79a) (2.78 g, 12.40 mmol) in CH2Cl2 (50 mL), was added 2.0 M oxalyl chloride in CH2Cl2 (9.30 mL, 18.60 mmol), followed by 10 drops of DMF. The mixture was stirred at ambient temperature for one hour, concentrated and further dried under high vacuum. It was re-dissolved in CH2Cl2 (50 mL); to this solution was added 5-amino-3-methylisoxazole (1.34 g, 13.66 mmol), followed by Et3N (2.60 mL, 18.60 mmol). After stirring at ambient temperature overnight, the mixture was concentrated in vacuo and purified by flash column chromatography eluting with 1:1 EtOAc and hexanes to provide 2.70 g yellow solid as the intermediate 79b. 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 7.36 (d, 2H, J=8.67 Hz), 6.90 (d, 2H, J=8.67 Hz), 6.24 (s, 1H), 6.17 (s, 1H), 3.80 (s, 3H), 2.25 (s, 3H), 2.22 (s, 3H). LCMS (ESI—) [M−H]/z Calc'd 303, found 303.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[C:11]([F:16])[C:10]=1[C:17]1[S:21][C:20]([N:22]2[CH2:25][C:24]3([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)[CH2:23]2)=[N:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:46]2[CH:47]=[N:48][NH:49][CH:50]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:46]2[CH:47]=[N:48][NH:49][CH:50]=2)[CH:12]=[C:11]([F:16])[C:10]=1[C:17]1[S:21][C:20]([N:22]2[CH2:25][C:24]3([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)[CH2:23]2)=[N:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3c(F)cc(Br)cc3OCc3ccccc3)s1)C2
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3c(F)cc(-c4cn[nH]c4)cc3OCc3ccccc3)s1)C2
Temperature: 120 °C

Procedure:
A mixture of tert-butyl 2-(5-(2-(benzyloxy)-4-bromo-6-fluorophenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (150 mg, 0.254 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (74 mg, 0.382 mmol) in dioxane (2 mL) was stirred under nitrogen atmosphere. To this suspension was added Pd(PPh3)4 (15 mg, 0.013 mmol) followed by a solution of Na2CO3 (81 mg, 0.763 mmol) in water (0.5 mL). The reaction mixture was sealed and heated at 120° C. for 1 hour under microwave irradiation. A further 1.5 eq of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (74 mg, 0.382 mmol) was added and the reaction was heated for an additional hour at 120° C. under microwave irradiation. A further 1.5 eq of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (74 mg, 0.382 mmol) was added, followed by an additional 0.05 eq of Pd(PPh3)4 (15 mg, 0.013 mmol) and the reaction mixture was heated for 1 hour at 120° C. under microwave irradiation. The reaction mixture was diluted with water (15 mL) and extracted with DCM (20 mL). The organic phase was concentrated in vacuo to afford the crude product as a pale brown oil. The crude material was purified by flash chromatography using a 24 g silica cartridge running a MeOH/DCM gradient to afford a pale brown oil. The oil was purified using a 24 g silica running an EtOAc/heptane gradient to afford the title compound as a clear glass-like solid (86 mg, 58% yield). MS m/z 577.2 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.39 (d, J=1.8 Hz, 1H), 8.09 (d, J=2.0 Hz, 1H), 7.47-7.57 (m, 2H), 7.33-7.44 (m, 4H), 7.28 (dd, J=11.6, 1.5 Hz, 1H), 5.35 (s, 2H), 3.82 (s, 4H), 3.18-3.32 (m, 4H), 1.63-1.77 (m, 4H), 1.40 (s, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[C:3]([CH:10]=O)=[CH:2]1.[O:12]=[C:13]1[CH2:17][O:16][C:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:14]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].N1CCCCC1>C(O)C>[NH:1]1[C:9]2=[N:8][CH:7]=[CH:6][CH:5]=[C:4]2[C:3]([CH:10]=[C:17]2[O:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:13]2=[O:12])=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccccc2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccccc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 49.5 %

Procedure:
To a solution of 7-azaindole-3-carboxaldehyde (0.10 g, 0.70 mmol) and ethyl 4-oxo-2-(phenylamino)-4,5-dihydrofuran-3-carboxylate (0.18 g, 0.70 mmol) in ethanol (3.0 mL), piperidine (0.083 mL, 0.84 mmol) was added at ambient temperature. The mixture was refluxed for 12 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with cold ethanol and isopropyl ether then dried to afford the titled compound (0.13 g, y. 48%).
Reaction SMILES: C(OC(OCC)C(=O)CC1C=CC(C)=CC=1)C.[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[NH:34][C:33]([C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)=[CH:32][N:31]3[C:26]=2[N:27]=[C:28]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=2)[C:29]3=[O:30])=[CH:20][CH:19]=1.Cl>O1CCOCC1.O>[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[C:26]3[N:31]([CH:32]=[C:33]([C:35]4[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=4)[N:34]=2)[C:29]([OH:30])=[C:28]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=2)[N:27]=3)=[CH:20][CH:19]=1
Reactant: O=c1c(Cc2ccc(O)cc2)nc2c(Cc3ccccc3)[nH]c(-c3ccc(O)cc3)cn1-2
Agent: CCOC(OCC)C(=O)Cc1ccc(C)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccc(Cc2nc3c(Cc4ccccc4)nc(-c4ccc(O)cc4)cn3c2O)cc1
Temperature: 0 °C
Reaction time: 14 h
Yield: 60.4 %

Procedure:
Under an argon atmosphere, 1,1-diethoxy-3-(4-methylphenyl)propan-2-one (33) (216 mg, 914 μmol) was dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). To this was added coelenteramine (196 mg, 707 μmol) and, after cooling to 0° C., conc. hydrochloric acid (0.20 mL) was further added thereto, and then stirred overnight (14 hours) at 100° C. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography in an argon flow (n-hexane/ethyl acetate═1/2→ethyl acetate→ethyl acetate/methanol═50/1→20/1). The solid obtained was further reprecipitated (n-hexane/acetone) to give me-coelenterazine (34, me-CTZ) as a yellow powder (180 mg, 427 μmol, 60.4%).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[C:11]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[N:10]=[C:9]([CH3:26])[N:8]=1)[CH2:4][CH3:5])[CH3:2].Cl>>[CH2:1]([CH:3]([NH:6][C:7]1[C:12]([NH2:13])=[C:11]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[N:10]=[C:9]([CH3:26])[N:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1nc(C)nc(Oc2c(C)cc(C)cc2C)c1[N+](=O)[O-]
Agent: Cl
Product: CCC(CC)Nc1nc(C)nc(Oc2c(C)cc(C)cc2C)c1N

Procedure:
The title compound was prepared by hydrogenation of (1-ethyl-propyl)-[2-methyl-5-nitro-6-(2,4,6-trimethyl-phenoxy)-pyrimidin-4-yl]-amine by the method analogous to that described in Example 93. 1H NMR(CDCl3) δ 6.88(s,2H), 4.52(d,1H), 4.10(m,1H), 2.94(brs,2H), 2.30(s,3H), 2.23(s,3H), 2.09(s,6H), 1.4–1.8(m,4H), 0.95(t,6H) ppm. The corresponding HCl salt, mp 248–250° C. 1H NMR(CD3OD) δ 6.91(s,2H), 4.00(m,1H), 2.39(s,3H), 2.28(s,3H), 2.07(s,6H), 1.6–1.8(m,4H), 1.00(t,6H) ppm.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[CH:4]=[CH:3]1.[C:14](Cl)(=[O:18])[C:15]([Cl:17])=[O:16]>CCOCC>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4]([C:14](=[O:18])[C:15]([Cl:17])=[O:16])=[CH:3]1
Reactant: Cn1ccc2ccc([N+](=O)[O-])cc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: Cn1cc(C(=O)C(=O)Cl)c2ccc([N+](=O)[O-])cc21
Reaction time: 3 h
Yield: 94.4 %

Procedure:
To a solution of 1.33 g (7.55 mmol) of 1-methyl-6-nitro-1H-indole (2) in 40 ml of ether were added 1.5 ml (17.2 mmol) of oxalyl chloride at 0-5° C. under Argon. A precipitate was formed. After 3 hours stirring, the resulting solid was filtered, washed with a small amount of ether and dried to yield 1.9 g (95%) of (1-methyl-6-nitro-1H-indol-3-yl)-oxo-acetyl chloride (3) as a yellow solid. This material was used without purification.
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[CH:5]([C:10]([OH:12])=[O:11])[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.[OH:15]O.C(#N)C>O.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[CH:5]([C:10]([OH:12])=[O:11])[C:6]([CH3:9])([CH3:8])[S:7](=[O:15])[C@H:3]12
Reactant: OO
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1C(=O)O
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC1(C)C(C(=O)O)N2C(=O)C(N)[C@H]2S1=O
Reaction time: 1 h

Procedure:
6-amino-2,2-dimethylpenam-3-carboxylic acid (1.06 g.) was suspended in water (6 cc), and sodium tungstate dihydrate (10 mg.) was added thereto. To the stirred mixture was added, dropwise, 30% hydrogen peroxide (0.8 cc) while cooling in an ice bath over a period of 20 minutes, and the mixture was stirred for 1 hour at the same temperature. To this mixture was added, dropwise, cooled acetonitrile (90 cc), and the precipitate was collected by filtration and dried under reduced pressure to yield a pale yellowish powder (0.85 g.) of 6-amino-2,2-dimethylpenam-3-carboxylic acid-1-oxide.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[N:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[C:29]1[O:33][CH:32]=[N:31][CH:30]=1)[C:23](O)=[O:24]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[N:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([C:29]3[O:33][CH:32]=[N:31][CH:30]=3)=[C:20]([F:19])[CH:21]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(-c2cnco2)c(F)c1
Reactant: CCc1cnc(N2CCC(NC3CC3)CC2)cn1
Product: CCc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)c(F)c3)C3CC3)CC2)cn1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-ethyl-pyrazin-2-yl)-piperidin-4-yl]-amine and 3-fluoro-4-oxazol-5-yl-benzoic acid following a procedure analogous to that described in Example 17. LC (method 1): tR=1.18 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[N:17]=[C:16]2[C:12]([NH:13][CH:14]=[N:15]2)=[C:11](Cl)[N:10]=1>C(O)CC>[Cl:8][C:9]1[N:17]=[C:16]2[C:12]([NH:13][CH:14]=[N:15]2)=[C:11]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:10]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: Nc1ccccc1
Solvent: CCCO
Product: Clc1nc(Nc2ccccc2)c2[nH]cnc2n1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Aniline (4.66 g; 0.05 mol) was added to a suspension of 2,6-dichloropurine (5.67 g; 0.03 mol) in n-propanol (60 ml) and N,N-ethyldiisopropylamine (6.44 g; 0.05 mol) was added. The reaction mixture was stirred at 100° C. for 4 hours. After cooling to room temperature the precipitate was filtered off, washed with n-propanol (2×10 ml) and water (3×10 ml) and dried in the drying oven at 60° C. into constant weight. Yield: 6.26 g yellowish substance (84.9%). TLC (chloroform-methanol; 85:15): one single spot; free of the starting material, HPLC purity: 98+%
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:29])[C:7]([CH2:18][NH:19][C:20]([NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:29])[C:7]([CH2:18][NH:19][C:20]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([S:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:38])=[O:37])[CH2:25][CH2:24]3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1CCNCC1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1CCN(S(=O)(=O)c2ccccc2)CC1

Procedure:
1-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3-(1-phenylsulfonyl-piperidin-4-yl)-urea was prepared starting from intermediate N and benzenesulfonyl chloride. MS calcd. for C28H28ClN4O4S [(M+H)+] 551.1, obsd. 551.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)([O-:3])=[O:2].[Li+].[Cl-].FC(F)(F)S(O[C:21]1[CH2:26][CH2:25][NH:24][CH:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:22]=1)(=O)=O.C(OC(N1CCC(=O)CC1)=O)(C)(C)C.[Li+].CC([N-]C(C)C)C.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:21]1[CH2:26][CH2:25][NH:24][CH:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:22]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)C1C=C(OS(=O)(=O)C(F)(F)F)CCN1
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1C=C(c2ccccc2[N+](=O)[O-])CCN1
Temperature: 90 °C

Procedure:
To a 100 mL round-bottomed flask equipped with stirring was added 2-nitrophenyl boronic acid (Combi-Blocks Chemical Company) (210 mg, 1.3 mmol), LiCl (Aldrich) (168 mg, 4 mmol), tetrakis(triphenyl-phosphine)palladium (O) (Strem Chemical Company) (69 mg, 0.06 mmol) and tert-butyl 4-[(trifluoromethyl)-sulfonyloxy]-1,2,5,6-tetrahydro-pyridinecarboxylate [prepared by the method of Wustrow, D. J. and Wise, L. D., Synthesis 1991, 993-995, from tert-butyl-4-oxopiperidine-1-carboxylate (Aldrich), LDA (Aldrich) and N-phenyltrifluoromethancsulfonimide (Aldrich)] (397 mg, 1.2 mmol) in DME (5 mL). The reaction mixture was purged with N2 and a 2 M soln of Na2CO3 (1.8 mL, 3.6 mmol) was introduced. After heating the mixture to 90° C. for 3 h, the reaction was cooled to 25° C. and diluted with EtOAc (15 mL). The organic layer was separated, washed with 10% Na2CO3, H2O and satd NaCl and dried over Na2SO4, filtered and concentrated in vacuo to afford a dark yellow oil. The crude material was purified by column chromatography (3:1 hexane:EtOAc) to give the title compound as a white solid (240 mg). MS (ESI, pos. ion) m/z: 305 (M+1). Calc'd for C16H20N2O4: 304.34.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5](O)=O)[CH2:3][CH3:4].CN1CCOCC1.ClC(OCC(C)C)=O.[Br:30][C:31]1[CH:32]=[C:33]([NH2:38])[C:34]([NH2:37])=[CH:35][CH:36]=1.C(O)(=O)C>C(#N)C>[Br:30][C:31]1[CH:36]=[CH:35][C:34]2[NH:37][C:5]([C@@H:2]([NH:1][C:8](=[O:9])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH3:4])=[N:38][C:33]=2[CH:32]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CC[C@H](NC(=O)OC(C)(C)C)c1nc2cc(Br)ccc2[nH]1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
To a solution of Boc-Abu-OH (2.979 g, 14.66 mmol) in acetonitrile (50 mL) and 4-methylmorpholine (1.78 mL, 16.2 mmol) cooled to −20° C. was added isobutyl chloroformate (1.92 mL, 14.8 mmol) dropwise. The mixture was stirred for an additional 90 minutes at −20° C. and then 4-bromo-1,2-benzenediamine (2.86 g, 15.3 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 5 hours. The solvent was evaporated, redissolved in ethyl acetate, washed with water, saturated aqueous solution of sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in acetic acid (5.0 mL, 88 mmol) and stirred at room temperature for 18 hours. The acetic acid was removed in vacuo and purified by silica gel column chromatography eluting with a 0-100% ethyl acetate/hexanes gradient. The residue was recrystallised from a mixture of ethyl acetate/hexanes to afford the title compound (2.65 g, 51%) as a white solid.
Reaction SMILES: [CH:1]([S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:33]=[CH:32][C:15]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[N:27]([CH:28]([CH3:30])[CH3:29])[C:26]([CH3:31])=[N:25][CH:24]=4)[CH:20]=[CH:19][N:18]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])=[CH2:2].[OH-].[Ba+2].[OH-].[O:37]1CCOCC1>O>[OH:37][CH2:2][CH2:1][S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:33]=[CH:32][C:15]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[N:27]([CH:28]([CH3:29])[CH3:30])[C:26]([CH3:31])=[N:25][CH:24]=4)[CH:20]=[CH:19][N:18]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5]
Reactant: C1COCCO1
Reactant: C=CS(=O)(=O)N1CCN(c2ccc(Nc3nccc(-c4cnc(C)n4C(C)C)n3)cc2)CC1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Product: Cc1ncc(-c2ccnc(Nc3ccc(N4CCN(S(=O)(=O)CCO)CC4)cc3)n2)n1C(C)C

Procedure:
A mixture of 2-{4-[4-(vinylsulphonyl)piperazin-1-yl]anilino}-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl) pyrimidine (Example 29; 260 mg 0.56 mmol) and barium hydroxide (560 mg 3.27 mmol) in water (10 ml) was heated at 65° C.-90° C. over 6 hours. 1,4-dioxane (1 ml) was added after 1, 2, 3 and 5 hours. After evaporation under reduced pressure, the residue was treated with water (10 ml) and saturated sodium hydrogen carbonate solution (10 ml). The suspension was extracted with DCM (30 ml and 2×20 ml) and EtOAc (25 ml). Both extracts were washed (separately) with brine (10 ml) and dried (Na2SO4). The extracts were combined and evaporated. After chromatography on silica gel using MeOH:DCM (4:96 to 8:92), the title compound was obtained as a yellow solid (108 mg 40%). NMR: 1.40 (d, 6H), 2.49 (s, 3H), 3.13 (m, 4H), 3.23 (t, 2H), 3.30 (m, 4H), 3.76 (q, 2H), 5.01 (t, 1H), 5.69 (septuplet, 1H), 6.93 (d, 2H), 6.96 (d, 1H), 7.39 (s, 1H), 7.48 (d, 2H), 8.31 (d, 1H), 9.18 (s, 1H); m/z 486.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[C:13](N)(=[NH:15])[CH3:14]>C(OCCO)C>[Cl:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:13]([CH3:14])[N:15]=[C:4]2[OH:6]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: CC(=N)N
Agent: Cl
Solvent: CCOCCO
Product: Cc1nc(O)c2cc(Cl)ccc2n1
Yield: 38.6 %

Procedure:
2-Amino-5-chlorobenzoic acid (3.58 g, 20.9 mmol, 1 eq.), acetamidine hydrochloride (2.36 g, 25.1 mmol, 1.2 eq.) and 2-ethoxyethanol (70 mL) were mixed and refluxed for 48 h. The resultant solids were filtered and dried to yield 1.57 g of yellow solid product. MS (ES+)=195/197 (M+H)++.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])(O)=O.[Na+].[Cl-].[Na+].O>>[NH:25]([C:13]1[N:14]=[CH:15][C:16]2[C:17](=[O:18])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]3[N:10]([CH:22]=[CH:23][N:24]=3)[C:11]=2[N:12]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=c1c2cnc(Nc3ccccc3)nc2n2ccnc2n1-c1ccccc1Cl

Procedure:
A mixture of Example 1E (70.0 mg, 0.195 mmol) and aniline (39.1 μl, 0.428 mmol) was heated in a capped vial at 90° C. for 1 hour. After cooling, the residue was treated with saturated NaHCO3/brine and extracted with ethyl acetate (2×). The combined organic layers were dried over MgSO4, filtered, concentrated, and purified on a 12 g column using the ISCO Companion flash system eluting with CH2Cl2/ethyl acetate (8:2 to 7:3) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.08 (d, J=1.83 Hz, 1H), 7.14 (t, J=7.48 Hz, 1H), 7.42 (t, J=7.63 Hz, 2H), 7.54-7.59 (m, 2H), 7.61-7.66 (m, 1H), 7.70-7.74 (m, 1H), 7.79-7.90 (m, 3H), 9.14 (s, 1H), 10.78 (s, 1H). MS (ESI+) m/z 389.2 (M+H)+.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[O:9]=[C:10]1[CH2:13][CH:12]([C:14](O)=[O:15])[CH2:11]1.C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C>[O:9]=[C:10]1[CH2:13][CH:12]([C:14]([O:1][N:2]2[C:6](=[O:7])[CH2:5][CH2:4][C:3]2=[O:8])=[O:15])[CH2:11]1
Reactant: O=C1CC(C(=O)O)C1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C1CC(C(=O)ON2C(=O)CCC2=O)C1
Temperature: 16 °C
Reaction time: 2 h

Procedure:
Into a 5 L reactor equipped with a nitrogen flow and an overhead stirrer was added N-hydroxysuccinimide (250.0 g, 2.172 mol) and 3-oxo-cyclobutanecarboxylic acid (248 g, 2.17 mol). Ethyl acetate (3.4 L) was added and the reaction was cooled to 16° C. A solution of 25% DCC in EtOAc (2.17 mol) was added slowly via an addition funnel to the reaction mixture over 7 minutes then the mixture was then heated at 45° C. After 2 h, the mixture was filtered and the filtrate was washed once with EtOAc (1 L×1) and evaporated to dryness in vacuo to afford the desired product. 1H NMR (400 MHz, DMSO-d6) δ 2.83 (bs, 4H), 3.30-3.39 (m, 2H), 3.52-3.60 (m, 2H) and 3.67-3.73 (m, 1H).