Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](=[O:8])[C:6]=1[Br:7].Cl.[NH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>O>[Br:7][C:6]1[C:5](=[O:8])[N:4]([CH3:9])[C:3](=[O:10])[C:2]=1[N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1
Reactant: CN1C(=O)C(Br)=C(Br)C1=O
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN1C(=O)C(Br)=C(N2CCC(=O)CC2)C1=O
Yield: 93.4 %

Procedure:
To a stirred solution of 3,4-dibromo-1-methyl-1H-pyrrole-2,5-dione (100 mg, 0.373 mmol) in AcN (20 mL) was added piperidin-4-one hydrochloride (101 mg, 0.746 mmol) at room temperature followed by K2CO3 (102 mg, 7.46 mol). The reaction mixture was then refluxed for 2 h, diluted with water, extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude material was purified via silica gel column chromatography eluting with 30% EtOAc in hexanes to afford 3-bromo-1-methyl-4-(4-oxopiperidin-1-yl)-1H-pyrrole-2,5-dione (100 mg, 99%) as a pale yellow solid.
Reaction SMILES: C1(O)C=CC=CC=1.[OH:8][C@@H:9]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1)[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].S(O[CH2:38][CH:39]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]1)(C1C=CC(C)=CC=1)(=O)=O>>[C:15]([O:14][C:13]([NH:12][CH2:11][CH2:10][C@H:9]([C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][CH2:38][CH:39]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:49])([CH3:51])[CH3:50])=[O:46])[CH2:41][CH2:40]1)[OH:8])=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCC2CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
Alkylation of phenol (7, Intermediate I) with tert-butyl 4-((tosyloxy)methyl)piperidine-1-carboxylate following the method used in Example 11 gave (R)-tert-butyl 4-((3-(3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenoxy)methyl)piperidine-1-carboxylate as a colorless oil. Yield (0.70 g, 80%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2O)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: Cc1ccc2ccnc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc2ccnc(Cl)c2c1
Yield: 85 %

Procedure:
The solution of POCl3 (10 mL) and 7-methyl-isoquinolin-1-ol (3.55 g, 22.3 mmol) was refluxed under nitrogen for 5 h. The residue, after removal of POCl3 by distillation, was quenched with iced water and extracted with methylene chloride (3×). Purification by flash silica gel column using 10-25% EtOAc in hexane as elute gave 3.40 g (85% yield) of desired product. 1H-NMR (300 MHz, CDCl3) δ 8.21 (d, 1H), 8.11 (s, 1H), 7.75 (d, 1H 7.60 (d, 1H), 7.55 (d, 1H), 2.60 (s, 3H).
Reaction SMILES: [CH:1]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1.Cl>CC(C)=O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:9][S:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:8])=[O:7])=[O:21])=[CH:15][CH:14]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: NS(=O)(=O)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Br)cc1)NS(=O)(=O)C1CCCC1
Reaction time: 2 h
Yield: 83.2 %

Procedure:
The general method of procedure A was followed with cyclopentanesulfonamide (3 g), acetone (100 ml), 1N sodium hydroxide (21 ml), and 4-bromophenyl isocyanate (3.7 g) dissolved in acetone (50 ml). After two hours, 1N HCl (21 ml) was added. The resulting precipitate was collected, washed with water and dried at 60° C. under vacuum to provide 5.4 g of product.
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:13]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19](C)(C)[C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)(=O)=O)=CC=1.[NH:26]1[CH2:30]C[C@@H:28]([NH:31][C:32](=O)OC(C)(C)C)[CH2:27]1>>[N:26]1([C:12]2[C:13]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)[CH2:27][CH2:28][NH:31][CH2:32][CH2:30]1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCCC3(C)C)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Product: Nc1nc2c(c(N3CCNCC3)n1)CCCCC2

Procedure:
The title compound was prepared according to the procedure of Example 1E, substituting the product from Example 13C for the product of Example 1D and substituting piperazine for (R)-tert-butyl pyrrolidin-3-ylcarbamate. 1H NMR (300 MHz, CD3OD) δ 3.38 (m, 4H), 3.21 (, 4H), 2.74 (m, 2H), 2.62 (m, 2H), 1.86 (m, 2H), 1.57-1.71 (m, 4H). MS (DCI+) m/z 248 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[NH:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[N:23]=3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[NH:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[CH2:21][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[N:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: [H][H]
Reactant: c1ccc(COc2ccc(N3CCN(Cc4nc5ccccc5[nH]4)CC3)nc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1ccc(N2CCN(Cc3nc4ccccc4[nH]3)CC2)nc1

Procedure:
The product from Example 29D (800 mg) in ethyl acetate (35 mL) was treated with 10% palladium on carbon (85 mg) under a blanket of hydrogen gas at 23° C. until TLC indicated consumption of starting material. The mixture was filtered and the filter cake washed with with methanol and CH2Cl2. The filtrates were combined and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 90:10:0.1 CH2Cl2:methanol:NH4OH) to provide the title compound pure as a white solid (566 mg, 92%). mp 144-145° C.; Rf=0.08; (95:5 CH2Cl2:methanol:0.1% NH4OH); MS 310 (M+H)+; 1H NMR (300 MHz, MeOD) δ 7.72 (d, 1H, J=2.7 Hz), 7.53 (m, 2H), 7.21 (m, 2H), 7.12 (dd, 1H, J=9, 3 Hz), 6.75 (d, 1H, J=9 Hz), 3.85 (s, 2H), 3.40 (t, 4H, J=5.1 Hz) 2.69 (t, 4H, J=5.1 Hz); Analysis calculated for C17H19N5O (1.0 equivalent methanol, 0.1 equivalent dichloromethane): C, 62.13; H, 6.68; N, 20.01. Found: C, 62.04; H, 6.57; N, 19.67.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][C:15](=[O:18])[N:14]2[C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22](O)=[O:23])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClCCl.[CH3:31][NH2:32]>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][C:15](=[O:18])[N:14]2[C:19]2[CH:27]=[CH:26][CH:25]=[C:21]([C:22](=[O:23])[NH:32][CH3:31])[CH:20]=2)=[O:12])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CN
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCC(=O)N2c2cccc(C(=O)O)c2)no1
Solvent: ClCCl
Product: CNC(=O)c1cccc(N2C(=O)CC[C@H]2C(=O)Nc2cc(C(C)(C)C)on2)c1

Procedure:
To a stirred solution of 3-[(S)-2-(5-tert-butyl-isoxazol-3-ylcarbamoyl)-5-oxo-pyrrolidin-1-yl]-benzoic acid (75 mg, 0.2 mmol) in dichloromethane (1 mL) 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC hydrochloride) (42 mg, 0.22 mmol) is added at room temperature. After 5 minutes methylamine (0.5 mL of 2 M solution in tetrahydrofuran, 1 mmol) is added. After 2 h solvent is removed in vacuo and the crude is purified by chromatography over silica gel eluting with methanol/dichloromethane to give the title compound as a white solid, ESI m/z 385 [M+H]+.
Reaction SMILES: S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[F:12][C:13]1[CH:14]=[C:15]([CH2:20][CH2:21][CH2:22]O)[CH:16]=[C:17]([F:19])[CH:18]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>N1C=CC=CC=1.O>[F:12][C:13]1[CH:14]=[C:15]([CH2:20][CH2:21][CH2:22][N:24]=[N+:25]=[N-:26])[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: OCCCc1cc(F)cc(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: [N-]=[N+]=NCCCc1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
Tosyl chloride (0.0814 mol) was added to a cooled (0°) solution of 3-(3,5-difluorophenyl)propanol (0.0407 mol) in pyridine (75 ml). The reaction was stirred 2 hours at 25°, then it was poured into ice/water and extracted into ethyl ether. The ethereal extracts were washed with 3N aqueous hydrogen chloride and water, then were dried over sodium sulfate and concentrated. The residue was dissolved in dimethylformamide (75 ml) and sodium azide (0.0814 mol) was added. The reaction was stirred 8 hours, then was diluted with water and extracted into ethyl acetate. The organic extract was washed with 3N aqueous hydrogen chloride and water, then dried over sodium sulfate and concentrated to yield 6.7 g (64%) of an oily product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:18]([O:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][C:26]([Cl:32])=[CH:27][CH:28]=4)[N:23]=3)=[CH:19][C:6]1=2.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:33]1([S:39]([NH:1][CH2:2][CH2:3][S:4][CH:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][O:8][C:7]3[CH:16]=[CH:17][C:18]([O:20][CH2:21][C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][C:26]([Cl:32])=[CH:27][CH:28]=5)[N:23]=4)=[CH:19][C:6]2=3)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Product: O=S(=O)(NCCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21)c1ccccc1

Procedure:
11-(2-Aminoethylthio)-2-(7-chloroquinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine and phenylsulfonyl chloride were used and reacted in the same manner as in Example 34 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:14][CH2:15][N:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH2:17][CH2:18]Cl.O>CS(C)=O>[Cl:1][C:2]1[C:3]([C:8]2([C:9]#[N:10])[CH2:18][CH2:17][N:16]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[CH2:15][CH2:14]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1ncccc1Cl
Reactant: COc1ccc(CN(CCCl)CCCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CN2CCC(C#N)(c3ncccc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of 3-chloro-2-pyridylacetonitrile [prepared by the method described in JP08295663] (1.46 g, 9.57 mmol) in DMSO (19 mL) was slowly added to NaH (60% oil dispersion, 1.01 g, 25.3 mmol), and the mixture was stirred at room temperature for 1 h. A solution of N,N-bis(2-chloroethyl)-p-methoxybenzylamine (2.21 g, 8.43 mmol) in DMSO (19 ml,) was added, and the resulting mixture was stirred at 75° C. for 4 h. After cooling, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2) to give 4-(3-chloro-2-pyridyl)-4-cyano-1-(4-methoxyphenyl)methylpiperidine 1 (1.91 g, 60%) as an orange oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])/[CH:3]=[CH:4]/[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:13](O)[C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1.O>CCCCCC>[CH3:1][CH:2](/[CH:3]=[CH:4]/[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:13][C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1)=[O:10])[CH3:12]
Reactant: COc1cc(CO)ccc1O
Reactant: CC(C)/C=C/CCCCC(=O)O
Solvent: O
Solvent: CCCCCC
Product: COc1cc(COC(=O)CCCC/C=C/C(C)C)ccc1O
Temperature: 50 °C
Reaction time: 16 h
Yield: 86.7 %

Procedure:
trans-8-Methyl-6-nonenoic acid (1.00 g, 5.87 mmol), vanillyl alcohol (1.085 g, 7.04 mmol), and Novozym 435 (100 mg) were measured and placed in a flask (25 ml). The mixture in the flask free of a plug was heated with stirring in an oil bath at 50° C. for 16 hours. After 2 to 3 hours of stirring with heating, attachment of water on the wall of the upper part of the flask was observed. The reaction mixture was returned to room temperature, hexane (25 ml) was added, and Novozym 435 and precipitated vanillyl alcohol were removed by filtration. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml) and saturated brine (25 ml), and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Since production of polar impurity other than vanillyl alcohol was confirmed by TLC, the residue was dissolved in 50 ml of hexane and passed through a short column packed with 1.5 g of silica gel, and the silica gel was sufficiently washed away with a mixed solvent of hexane and ethyl acetate (volume ratio 10:1). The above-mentioned impurity was not detected in the eluent by TLC. The eluent was concentrated under reduced pressure to give capsiate (1.56 g, yield 86.6%) as a colorless oil. This capsiate contained a trace amount of trans-8-methyl-6-nonenoic acid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:35])[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][NH:19][C:20]([C:22]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[O:24][C:23]=3[CH3:34])=[O:21])[CH:14]=2)[CH:9]=1.O.Cl>C1COCC1>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]2[O:24][C:23]([CH3:34])=[C:22]([C:20]([NH:19][CH2:18][C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH:9]=[C:8]([O:7][CH2:6][C:5]([OH:35])=[O:4])[CH:17]=[CH:16]4)=[O:21])[CH:26]=2)=[CH:32][CH:31]=1
Reactant: COC(=O)COc1ccc2cc(CNC(=O)c3cc(-c4ccc(Cl)cc4)oc3C)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(Cl)cc2)cc1C(=O)NCc1ccc2cc(OCC(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
1 N NaOH (514 μL, 0.514 mmol) was added under nitrogen to a solution of [6-({[5-(4-chloro-phenyl)-2-methyl-furan-3-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid methyl ester (239 mg, 0.514 mmol), prepared in the previous step, in 30 mL of THF plus 15 mL of water. After the addition the reaction was stirred at room temperature for 20 h (overnight). 1 N HCl (1 mL) was added and the reaction then concentrated under reduced pressure to remove the THF. The solid present was removed by filtration and dried under reduced pressure to give the title compound (190 mg, 83%) as a tan solid, mp 177-181° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[NH:12][C:11](=[O:16])[C:10]=1[CH2:17][NH:18][C:19]([C:21]1[CH:29]=[C:28]([C:30]2[CH:31]=[CH:32][C:33]([N:36]3[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][C@H:37]3[CH3:49])=[N:34][CH:35]=2)[CH:27]=[C:26]2[C:22]=1[C:23]([CH3:53])=[CH:24][N:25]2[CH:50]([CH3:52])[CH3:51])=[O:20]>C(Cl)Cl>[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[NH:12][C:11](=[O:16])[C:10]=1[CH2:17][NH:18][C:19]([C:21]1[C:22]2[C:23]([CH3:53])=[CH:24][N:25]([CH:50]([CH3:52])[CH3:51])[C:26]=2[CH:27]=[C:28]([C:30]2[CH:35]=[N:34][C:33]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][C@H:37]3[CH3:49])=[CH:32][CH:31]=2)[CH:29]=1)=[O:20]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)C[C@H]4C)nc3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCNC[C@H]4C)nc3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
Added trifluoroacetic acid (1 ml, 12.98 mmol) to a solution of (R)-tert-butyl 4-(5-(4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-1-isopropyl-3-methyl-1H-indol-6-yl)pyridin-2-yl)-3-methylpiperazine-1-carboxylate (57 mg, 0.091 mmol) in DCM (3 mL) and let stir at RT for 1 hour. Concentrated on rotovap. Partitioned between DCM and sat′d Na2CO3, separated and washed DCM phase with water, brine, dried (MgSO4), filtered and rotovapped off DCM. Obtained 25 mg of the title compound as a tan solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 (d, 2H), 1.46-1.59 (m, 6H), 2.21 (s, 3H), 2.27 (s, 3H), 2.44 (s, 3H), 2.83 (dd, J=12.13, 3.54 Hz, 1H), 2.96-3.29 (m, 4H), 3.90 (br. s., 1H), 4.47-4.76 (m, 5H), 6.00 (s, 1H), 6.51 (d, J=8.59 Hz, 1H), 7.05 (s, 1H), 7.45 (s, 1H), 7.68 (dd, J=8.72, 2.40 Hz, 1H), 8.43 (d, J=2.27 Hz, 1H), 10.11-12.70 (m, 1H). LCMS: [M+H]+ 527.5.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([N:24]2[CH2:38][C:27]3=[C:28]4[N:33]([N:34]=[C:26]3[C:25]2([CH3:40])[CH3:39])[C:32]([CH3:35])=[C:31]([Cl:36])[C:30]([CH3:37])=[N:29]4)=[O:23])[CH2:11][CH2:10]1)=O)(C)(C)C.O>O1CCOCC1>[ClH:36].[Cl:36][C:31]1[C:30]([CH3:37])=[N:29][C:28]2[N:33]([N:34]=[C:26]3[C:25]([CH3:39])([CH3:40])[N:24]([C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[O:15][CH:12]4[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]4)=[O:23])[CH2:38][C:27]3=2)[C:32]=1[CH3:35]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)C(C)(C)N(C(=O)c1ccccc1OC1CCN(C(=O)OC(C)(C)C)CC1)C3
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2c3c(nn2c(C)c1Cl)C(C)(C)N(C(=O)c1ccccc1OC1CCNCC1)C3
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.2 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (0.55 mL; 2.21 mmol; 4 eq.) was added to a suspension of 4-[2-(6-chloro-1,1,5,7-tetramethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (306 mg; 0.55 mmol; 1 eq.) in 1,4-dioxane (6 mL) followed by water (604) and the resulting mixture was stirred at room temperature for 16 hours. A 4M solution of HCl in 1,4-dioxane (0.55 mL; 2.21 mmol; 4 eq.) was added and the resulting mixture was stirred at room temperature for 3 hours. Concentration in afforded the title compound (34 mg, quantitative) as an orange solid. 1H NMR (DMSO-d6) δ 9.09 (br s, 1H), 8.76 (br s, 1H), 7.48-7.38 (m, 1H), 7.37-7.17 (m, 2H), 7.06 (t, J=7.1 Hz, 1H), 4.85-4.67 (m, 1H), 4.41 (s, 2H), 3.05 (s, 4H), 2.84 (s, 3H), 2.54 (s, 3H), 2.06 (br s, 2H), 1.90 (s, 6H), 1.87-1.71 (m, 2H). HPLC (max plot) 99.8%, Rt 3.09 min. UPLC/MS: (MS+) 454.5 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[S:12][C:11]([N:13]=[C:14]=[O:15])=[N:10][N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:16][NH:17][CH2:18][CH:19]=[O:20]>C(OCC)(=O)C>[CH3:16][N:17]([CH2:18][CH:19]=[O:20])[C:14]([NH:13][C:11]1[S:12][C:8]([C:2]2([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[N:9][N:10]=1)=[O:15]
Reactant: CNCC=O
Reactant: CC1(c2nnc(N=C=O)s2)CCCCC1
Solvent: CCOC(C)=O
Product: CN(CC=O)C(=O)Nc1nnc(C2(C)CCCCC2)s1

Procedure:
A mixture of 5-(1-methylcyclohexyl)-1,3,4-thiadiazol-2-yl isocyanate dimer (7.5 grams), the dimethyl acetal of 2-methylaminoacetaldehyde (5 grams) and ethyl acetate (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. After this time the mixture is stripped of solvent under reduced pressure to yield the desired product the dimethyl acetal of 2-{1-methyl-3[5-(1-methylcyclohexyl)-1,3,4-thiadiazol-2-yl]ureido}acetaldehyde.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([C:6]([NH2:11])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[Si](C)(C)C.CC([Mg]Cl)C.[O:22]1[C:26]2([CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]2)[O:25][CH2:24][CH2:23]1>C1COCC1>[NH2:11][C:6]1[C:5]2=[CH:4][CH:3]=[C:2]([C:29]3([OH:32])[CH2:30][CH2:31][C:26]4([O:25][CH2:24][CH2:23][O:22]4)[CH2:27][CH2:28]3)[N:10]2[N:9]=[CH:8][N:7]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Nc1ncnn2c(Br)ccc12
Agent: CC(C)[Mg]Cl
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: Nc1ncnn2c(C3(O)CCC4(CC3)OCCO4)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7-Bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (9.20 g, 35.41 mmol) was dissolved in THF (105 mL) under argon at room temperature. Chlorotrimethylsilane (9.08 mL, 7.77 g, 70.82 mmol, 2 eq.) was added, and the mixture was stirred at room temperature for 3 h. It was then cooled to 0° C., and 2-propyl magnesium chloride (74 mL of a 2.0 M solution in THF, 149 mmol, 4.2 eq.) was added. The mixture was stirred for further 3 h while warming up to room temperature. Then, 1,4-dioxaspiro[4.5]decan-8-one (8.38 g, 53.12 mmol, 1.5 eq.) was added, and stirring was continued for another 16 h. The reaction was quenched with a 1:1 mixture of concentrated aqueous ammonium chloride solution and ice until the pH value reached 6-7. The mixture was extracted with two portions of ethyl acetate, and the combined organic extracts were dried over anhydrous sodium carbonate and concentrated to dryness. The title compound was crystallized from diethyl ether. Yield: 6.05 g (58% of th.).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH:13]2[CH:9]1[CH2:10][N:11]([C:15]1[CH:24]=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=1)[CH2:12]2)=O)(C)(C)C.Cl>O1CCOCC1.ClCCl>[CH:13]12[CH2:14][NH:8][CH:9]1[CH2:10][N:11]([C:15]1[CH:24]=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=1)[CH2:12]2
Reactant: CC(C)(C)OC(=O)N1CC2CN(c3cnc4ccccc4n3)CC21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1ccc2nc(N3CC4CNC4C3)cnc2c1

Procedure:
3-Quinoxalin-2-yl-3,6-diaza-bicyclo[3.2.0]heptane-6-carboxylic acid tert-butyl ester (0.52 mmol) was treated with 4M HCl in dioxane (2 mL) in dichloromethane (2 mL) to give the title compound. MS (ESI) mass calcd. for C13H14N4, 226.28; m/z found 227.2 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11](CC1C=CC=CC=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>>[CH2:9]([N:14]1[CH:13]=[C:12]2[C:7](=[CH:8][CH:9]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[C:10](=[O:22])[NH:11]2)[C:6]([OH:31])=[C:5]1[C:3]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ncc2c(cc(-c3cccc(OC)c3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: COc1cccc(C2C=C3C(=CN(Cc4ccccc4)C(C(=O)NCCC(=O)O)=C3O)NC2=O)c1
Temperature: 25 °C
Yield: 150.2 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.084 mmol), β-alanine (600 mg, 6.7 mmol) and NaOMe solution (10 mL, 5.0 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 30 mg of the title compound as a yellow solid. MS: (+) m/z 474.36 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]([N:14]([CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[C:24]([NH2:26])=[O:25])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[O:13])=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.[CH3:35][NH:36][CH3:37]>>[CH3:1][C:2]1[C:3]([C:12]([N:14]([CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[C:24]([NH2:26])=[O:25])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[O:13])=[N:4][C:5]([N:36]([CH3:37])[CH3:35])=[N:6][CH:7]=1
Reactant: COc1cccc(C(C(N)=O)N(Cc2ccc(C)cc2)C(=O)c2nc(S(C)(=O)=O)ncc2C)c1
Reactant: CNC
Product: COc1cccc(C(C(N)=O)N(Cc2ccc(C)cc2)C(=O)c2nc(N(C)C)ncc2C)c1

Procedure:
This was prepared in the same manner as the product of example 244, using the sulfone from example 253 and dimethylamine as the amine, to give the title compound as a foam, 0.14 g, (74%).