Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Reactant: CC(C)(C)N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cncc(Br)c1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
Crude 5-bromopyridine-3-sulfonyl chloride from step 1 above was dissolved in THF (14 L, 8 vol) and then transferred to a 20 L RB flask equipped with mechanical stirrer under inert atmosphere. The solution was cooled to 0-5° C. and tert-butyl amine (1.95 Kg, 26.66 moles) was added at 0-5° C. Upon completion of addition, the reaction mixture was warmed to ambient temperature where it stirred for 2 h. At the conclusion of this period, the reaction progress was monitored by HPLC, which indicated that the reaction was complete. The solvent was evaporated under vacuum to give a thick residue. The residue was dissolved in ethyl acetate (18 L, 12 vol). The organic layer was separated, washed with water (9 L, 5 vol) and then concentrated under vacuum to yield a residue. Hexanes (9 L, 5 vol) were added to the residue and the product precipitated out and was collected by filtration to yield a free flowing yellow solid (1.5 Kg, 54.28% overall yield). 1H NMR (DMSO-D6, 400 MHz, δ ppm); 8.99 (d, J=2 Hz, 1H), 8.81 (d, J=2 Hz, 1H), 8.29 (t, J=2 Hz, 1H). [M++1]=293.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([CH2:17][CH3:18])[C:11](=[O:16])[C:12]([O:14]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH2:1]([O:8][N:9]=[C:10]([CH2:17][CH3:18])[C:11](=[O:16])[C:12]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=NOCc1ccccc1)C(=O)C(=O)OC
Reactant: C1COCCN1
Product: CCC(=NOCc1ccccc1)C(=O)C(=O)N1CCOCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
10.0 g (0.04 mol) of methyl 3-benzyloxyimino-2-oxovalerate and 20 ml of morpholine were combined and the mixture was stirred for 3 hours at 100° C. After distilling the morpholine off under reduced pressure, 100 ml of water was added and the mixture was extracted three times with 100 ml of diethylether. After washing with water and a saturated aqueous sodium chloride followed by anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a residue, which was purified by a column chromatography on a silica gel (n-hexanelethyl acetate) to obtain 6.78 g (yield: 56%) of 4-(3-benzyloxyimino-2-oxovaleryl)morpholine as a white solid.
Reaction SMILES: [Na].[N:2]1([CH2:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl[C:20]1[S:21][C:22]2[C:23]([N:28]=1)=[N:24][CH:25]=[CH:26][N:27]=2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[N:2]1([CH2:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][C:20]4[S:21][C:22]5[C:23]([N:28]=4)=[N:24][CH:25]=[CH:26][N:27]=5)=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: Clc1nc2nccnc2s1
Reactant: Oc1ccc2c(CN3CCOCC3)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na]
Solvent: CN(C)C=O
Product: c1cnc2sc(Oc3ccc4c(CN5CCOCC5)c[nH]c4c3)nc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.4 %

Procedure:
To a solution of 3-morpholin-4-ylmethyl-1H-indol-6-ol sodium salt (130 mg, 0.51 mmol) and 2-chloro-thiazolo[4,5-b]pyrazine (70 mg, 0.41 mmol) in DMF (1.4 mL) was added Cs2CO3 (43 mg, 0.12 mmol) and the resulting suspension was stirred (rt, 16 h). The reaction mixture was filtered and the solid was rinsed with EtOAc. The reaction mixture was concentrated in vacuo. The resulting residue was purified via reverse phase HPLC to provide the title compound as a white powder (38.3 mg, 26%). MS (ESI): mass calculated for C18H17N5O2S, 367.1; m/z found, 368.1 [M+H]+. 1H NMR (600 MHz, CDCl3): 8.51 (d, J=2.6, 1H), 8.32 (d, J=2.6, 1H), 8.21 (s, 1H), 7.83 (d, J=8.6, 1H), 7.45 (d, J=2.2, 1H), 7.21 (d, J=2.3, 1H), 7.12 (dd, J=8.6, 2.2, 1H), 3.75-3.69 (m, 6H), 2.51 (s, 4H).
Reaction SMILES: [O:1]=[C:2]1[C:12]2=[C:13]3[C:8](=[CH:9][C:10]([CH2:14][C:15]([O:17]CC)=[O:16])=[CH:11]2)[CH2:7][CH2:6][CH2:5][N:4]3C1=O.[OH-:21].[Na+].OO.Cl>O>[C:2]([C:12]1[CH:11]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:9]=[C:8]2[C:13]=1[NH:4][CH2:5][CH2:6][CH2:7]2)([OH:1])=[O:21]
Reactant: [OH-]
Reactant: CCOC(=O)Cc1cc2c3c(c1)C(=O)C(=O)N3CCC2
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1cc2c(c(C(=O)O)c1)NCCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
To a solution of ethyl 5,6-dihydro-1,2-dioxo-4H-pyrrolo[3,2,1-ij]quinolin-8-ylacetate (21.5 g) and sodium hydroxide (18.5 g) in water (1 litter) was added 35% hydrogen peroxide solution (10 ml) and stirred for 3 hours at room temperature. The mixture was acidified at pH 2 with concentrated hydrochloric acid, resulting precipitate was collected by filtration, washed with water and dried to yield 17.6 g (95.1%) of the title compound. The compound was recrystallized from ethanol to give pale yellow needles, mp 210°-211° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([CH2:8][N:9]=C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7])([CH3:4])[CH3:3].[CH:23]1(Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[C:2]([O:5][C:6](=[O:7])[CH:8]([NH2:9])[CH:23]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)([CH3:4])([CH3:3])[CH3:1]
Reactant: BrC1CCCCCC1
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(N)C1CCCCCC1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-(diphenylmethylene)glycerine tert-butyl ester (6.83 mmol) and (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphthol[7,6,1,2-cde]azepinium bromide (6.84 μmol) in 45 mL toluene were sequentially added cycloheptyl bromide (8.2 mmol) and CsOH H2O (34.2 mmol) at −10° C. The reaction mixture was stirred at −10° C. for 10 min and then at RT for 4 days. Another portion of (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphthol[7,6,1,2-cde]azepinium bromide (6.84 μmol) was added and stirring was continued at RT for another 24 h. The reaction was quenched with water and extracted 3 times with DCM. The combined organic layers were combined, concentrated and the residue was redissolved in 100 mL THF. A solution of 100 mL aq. 0.5M citric acid solution was added and the mixture was stirred at RT for 4 h. The mixture was concentrated to half of its volume and extracted twice with Et2O. The aqueous layer was basified with solid NaHCO3 and extracted 3 times with DCM. The combined organic layers were dried over MgSO4 and concentrated in vacuo to obtain the desired product as yellow oil.
Reaction SMILES: [NH:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].C([O-])([O-])=O.[K+].[K+].C1C(=O)N([O:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=O)C(=O)C1>O.CC(C)=O>[CH2:27]([O:26][C:24]([N:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4])=[O:23])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: O=C(O)CNCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)CN(CC(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To the solution of iminodiacetic acid XLV (10 g, 75.13 mmol) and K2CO3 (41.53 g, 300.52 mmol) in water (225 mL) was added a solution of CBzOsu (20.6 g, 82.64 mmol) in acetone (150 mL). The mixture was stirred at r.t. overnight. The acetone was evaporated under reduced pressure and the remaining water was washed with ethyl ether (2×). The aqueous layer was acidified to pH=2 with 2 M aq. HCl and then saturated with NaCl, washed with EtOAc (3×). The combined EtOAc was dried over MgSO4 and evaporated under reduced pressure to give 2-{[(benzyloxy)carbonyl](carboxymethyl) amino}acetic acid XLVI (15 g, 56.17 mmol, 75% yield). ESIMS found for C12H13NO6 m/z 290 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([NH:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:17])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Reactant: NC1CCCCC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC3CCCCC3)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and cyclohexanamine as a yellow-brown solid (46%). MS 428 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[CH:7][C:6]=2[CH:11]=1.C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:10][C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=2[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2cc(Cl)ccc2s1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc2sc(CBr)cc2c1
Yield: 97.2 %

Procedure:
A solution of 2.73 g (14.95 mmol) 5-chloro-2-methylbenzothiophene and 2.67 g (15.0 mmol) NBS in 100 ml carbon tetrachloride was heated to 70° C. and a catalytic amount of dibenzoyl peroxide was added. After 30 min reflux solids were removed by filtration. The solvent was removed in vacuo and the residue was suspended in 100 ml hot hexane and filtered. The filtrate was evaporated to dryness to give 3.8 g (97%) of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.N1C=CN=C1.[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C(Cl)Cl>[Si:19]([O:9][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)([C:16]([CH3:18])([CH3:17])[CH3:15])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccnc1Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1Cl
Temperature: 25 °C
Reaction time: 23 h
Yield: 85.5 %

Procedure:
To a solution of 2-chloro-3-pyridylmethanol (2.07 g) in 100 mL CH2Cl2 was added imidazole (1.96 g). TBDMSCl (2.39 g) was added in one portion, and the reaction was stirred at room temperature for 23 h, then filtered through a fritted funnel The liquid filtrate was concentrated and purified via flash chromatography to give 3.18 g of 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloropyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[CH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([Cl:24])=[CH:19][N:18]=1>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:19]2[C:20]([Cl:24])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2nc(Cl)ncc2Cl)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (1.73 g), 2,4,5-trichloro-pyrimidine (0.86 mL), Pd(PPh3)2Cl2 (105 mg), and copper iodide (29 mg) in triethylamine (15 mL) under an argon atmosphere is heated in a microwave oven at 100° C. for 40 min. The solvent is evaporated in vacuo and 1 N citric acid is added. The mixture is extracted with dichloromethane and the combined extracts are washed with water, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 85:15→80:20) to give the title compound. LC (method 7): tR=1.55 min; Mass spectrum (ESI+): m/z=356 [M+H]+.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(C)(C)C.[N:15]1C=CC=CC=1.C1(C)C=CC=CC=1>>[C:8]1([S:11]([NH2:15])(=[O:13])=[O:12])[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccncc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)c1ccccc1

Procedure:
Reaction with p-tert-butylbenzenesulphonyl chloride in pyridine/toluene at room temperature yielded pure 4-tert-butyl-N-[3-(2-tetrahydropyranyloxyethoxy)-2-methoxy-phenoxy)-phenyl]-benzenesulphonamide. MS: Mt /e=555.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]([C:29]2[NH:33][C:32]([CH:34]=O)=[CH:31][CH:30]=2)=[O:28])[CH2:23][CH2:22]1>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:34][C:32]4[NH:33][C:29]([C:27]([N:24]5[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]5)=[O:28])=[CH:30][CH:31]=4)[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1CCN(C(=O)c2ccc(C=O)[nH]2)CC1
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CN1CCN(C(=O)c2ccc(C=C3C(=O)Nc4ncnc(Nc5ccc(F)c(Cl)c5)c43)[nH]2)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 84.2 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 5-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (66.4 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 101.5 mg (84%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.39 (br s, 1H, NH), 11.74 (br s, 1H, NH), 8.81 (br s, 1H), 8.28 (s, 1H), 7.76 (s, 1H), 7.75 (m, 1H), 7.53 (m, 1H), 7.39 (t, J=8.9 Hz, 1H), 6.91 (m, 1H), 6.74 (m, 1H), 3.70 (m, 4H, 2×CH2), 2.37 (m, 4H, 2×CH2), 2.21 (s, 3H, CH3). MS 482 [M++1].
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)([O-:3])=[O:2].Cl.[NH2:15]O.[OH-].[Na+]>C(O)C>[N+:1]([C:4]1[CH:13]=[CH:12][C:11]([NH2:15])=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)([O-:3])=[O:2]
Reactant: NO
Reactant: O=[N+]([O-])c1cccc2cnccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc([N+](=O)[O-])c2ccncc12

Procedure:
In Scheme 13, commercially available 5-nitroisoquinoline is aminated with hydroxylamine hydrochloride and sodium hydroxide in ethanol at 50° C. to yield the 5-nitro-isoquinolin-8-ylamine, which may be diazotized with a mixture of sodium nitrite in a strong acid such as hydrochloric, sulfuric or hydrofluoroboric acid. The diazonium salt may be heated with an appropriate copper salt such a copper chloride, copper bromide or copper cyanide to yield the 8-Cl, 8-Br or 8-CN nitro isoquinolines respectively. The diazonium salt may also be heated in with potassium iodide to yield the 8-iodo intermediate or heated in the presence of an aqueous acid such as sulfuric acid to yield the 8-OH nitroisoquinoline. The tetrafluoroborate diazonium salt may be heated to yield the 8-F nitroisoquinoline. In addition, the diazonium salt may be reacted with a sulfur nucleophile to yield the 8-thioalkyl nitroisoquinoline which may be further oxidized to the 8-sulfoxide or 8-sulfone. Any of the nitroisoquinolines described above may then be reduced by hydrogenation with a suitable catalyst or another suitable reducing agent such as tin(II) chloride and then further elaborated by the chemistry illustrated in Schemes 5 and 6 to the target ureas.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[F:9].[Cl-].[Al+3].[Cl-].[Cl-].[C:14](Cl)(=[O:16])[CH3:15].Cl>>[Br:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([C:14](=[O:16])[CH3:15])=[C:6]([F:8])[CH:7]=1
Reactant: Fc1ccc(F)c(Br)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(F)c(Br)cc1F
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
To a stirred mixture of 2-bromo-1,4-difluorobenzene (3.24 g, 16.81 mmol) and aluminium chloride (5.82 g, 43.7 mmol) at 60° C. under nitrogen was added dropwise acetyl chloride (1.98 g, 25.28 mmol 1). The mixture was stirred at 95° C. for 1.5 hr and then poured into ice (50 mL). To the mixture was added HCl (3 mL) followed by extraction into ether (20 mL×2). The ether extracts were washed with brine (20 mL) and then concentrated under reduced pressure to obtain the desired crude product (brown oil) as mixture with starting material (55:45) (2.67 g, 33%); 1H NMR (250 MHz, CHLOROFORM-d) delta 2.64 (3H, d, J=5.18 Hz), 7.42 (1H, dd, J=9.44, 5.18 Hz), 7.65 (1H, dd, J=8.45, 6.17 Hz).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].CCN(C(C)C)C(C)C.[NH:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18]>>[C:26]([O:25][C:23]([NH:14][C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:20]([O:22][CH2:2][C:3]#[N:4])=[O:21])=[O:24])([CH3:27])([CH3:29])[CH3:28]
Reactant: N#CCCl
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N
Reaction time: 12 h
Yield: 96 %

Procedure:
Chloroacetonitrile (5 mL) and DIPEA (160 mg, 0.21 mL, 1.2 mmol) were added to Boc-Leu-OH (252 mg, 1.09 mmol) and stirred for 12 h. The solvent was removed under reduced pressure and SiO2 flash chromatography (20% ethyl acetate in hexanes) afforded 284 mg of a pale yellow oil in 96% yield. Rf 0.5 in 20% ethyl acetate in hexanes. 1H NMR (500 MHz, CDCl3): δ 5.00 (d, J=7.7 Hz, 1H), 4.80-4.65 (m, 2H), 4.30-4.29 (m, 1H), 1.70-1.65 (m, 1H), 1.60-1.47 (m, 2H), 1.39 (s, 9H), 0.91-0.89 (m, 6H); 13C NMR (125 MHz, CDCl3): δ 172.2, 155.5, 114.21, 80.3, 53.2, 52.0, 41.0, 28.3, 24.8, 22.8, 21.7; HRMS (ESI) m/z calcd for C13H22N2O4Na [M+Na]+ 293.147. found 293.151.
Reaction SMILES: [C:1]([OH:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:7]([CH2:9][NH2:10])[OH:8]>N1C=CC=CC=1>[OH:8][CH2:7][CH2:9][NH:10][CH:2]([CH2:3][CH3:4])[C:1]([OH:6])=[O:5]
Reactant: C/C=C/C(=O)O
Reactant: NCCO
Solvent: c1ccncc1
Product: CCC(NCCO)C(=O)O

Procedure:
A solution of 86 g of crotonic acid (1 mole) and ethanolamine (1 mole) in pyridine (200 ml) is refluxed for 2-3 hours and subsequently cooled. The resulting product is filtered and recrystallized to yield the title compound having m.p. 178-180° C. (Compound 1.1, Table 1).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:32])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=4[O:30][CH3:31])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:33][NH2:34]>>[Cl:32][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])[C:15]2[O:14][CH:13]([CH2:12][NH:34][CH3:33])[CH2:17][C:16]=2[CH:18]=1
Reactant: CN
Reactant: COc1ccc(-c2cc(Cl)cc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c(OC)c1
Product: CNCC1Cc2cc(Cl)cc(-c3ccc(OC)cc3OC)c2O1

Procedure:
The title compound was prepared (0.052 g, 68%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.099 g, 0.21 mmol) and methylamine (0.065 g, 2.1 mmol). mp 206-208° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2].[Li]CCCC.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]=[O:28]>C1COCC1>[CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([C:9]2[S:10][C:11]([CH:27]([OH:28])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(-c2cccs2)c(C)[nH]c1=O
Reactant: O=Cc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(-c2ccc(C(O)c3ccccn3)s2)c(C)[nH]c1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-ethyl-6-methyl-5-thiophen-2-yl-1H-pyridin-2-one prepared in accordance with the procedures of Example 24, Step 3 (97 mg, 0.442 mmol) in anhydrous THF (1 ml) is cooled to −78° C., and n-BuLi (2.5 M in hexane, 0.4 ml, 1 mmol) is added. The resulting dark green mixture is stirred for 30 min, and then pyridine-2-carbaldehyde (80 mg, 0.746 mmol) is added. The cooling bath is removed after 20 min, and the reaction mixture is slowly warmed to room temperature. After 3 hr, water (5 ml) is added to the mixture, and it is extracted with ethyl acetate. The organic phases are washed and dried, and the residue is purified on silica gel to afford a yellow solid (60 mg). MS: m/e=327 (M+H). 1H-NMR (D6-DMSO, δ ppm) 11.65 (s, 1H); 8.51 (d, 1H); 7.85 (d, 1H); 7.61 (d, 1H); 7.29 (m, 1H); 7.21 (s, 1H); 6.88 (m, 2H); 6.43 (d, 1H); 5.88 (d, 1H); 2.38 (q, 2H); 2.24 (s, 3H); 1.06 (t, 3H, J=7.4 Hz).
Reaction SMILES: C([N:20]1[N:24]=[N:23][C:22]([C:25]2([C:33]#[N:34])[C:27]3([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:26]2)=[N:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>CO.C1COCC1.O=[Pt]=O>[NH:23]1[C:22]([C:25]2([CH2:33][NH2:34])[C:27]3([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:26]2)=[N:21][N:20]=[N:24]1
Reactant: N#CC1(c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CC12CCCCC2
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: NCC1(c2nnn[nH]2)CC12CCCCC2
Reaction time: 20 h
Yield: 80.7 %

Procedure:
To a solution of the 1-(2-trityl-2H-tetrazol-5-yl)-spiro[2.5]octane-1-carbonitrile (2.40 g, 2.39 mmol) in 100 mL MeOH:THF (1:1) was added PtO2 (0.15 g), concentrated HCl (1.67 g), and the mixture was hydrogenated in a Parr shaker at 48 psi for 20 h. The mixture was filtered and concentrated. Flash chromatography of the residue on silica gel (0.25:1.25:3.5 conc. NH4OH (aq):MeOH:CH2Cl2) furnished 0.40 g (36%) of C-[1-(1H-tetrazol-5-yl)-spiro[2.5]oct-1-yl]-methylamine as a colorless solid. 1H NMR (CD3OD) δ 3.77 (d, J=13.2 Hz, 1H, —CH2H2), 3.07 (d, J=13.2 Hz, 1H, —CH2H2), 1.66 (m, 1H), 1.53 (d, J=5.1 Hz, 1H, cyclopropyl —CHH), 1.47-1.59 (m, 4H), 1.22-1.42 (m, 3H), 1.06 (m, 1H), 0.97 (m, 1H), 0.88 (d, J=5.1 Hz, 1H, cyclopropyl —CHH). 13C NMR (CD3OD) δ 161.18, 31.61, 31.51, 26.00, 25.76, 25.30, 24.78, 21.67. LRMS: m/z 206.1 (M−1). Anal. Calc'd for C10H17N5: C, 57.95; H, 8.27; N, 33.79. Found: C, 56.83; H, 8.24; N, 33.40.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][C:8]3[N:9]2[CH:12]=[N:13][N:14]=3)=[CH:4][CH:3]=1.[SH:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([OH:27])=[O:26].CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:15]1([C:6]2[C:5]3[C:10](=[CH:11][C:2]([S:21][C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=[O:26])=[CH:3][CH:4]=3)[N:9]3[CH:12]=[N:13][N:14]=[C:8]3[CH:7]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1cccc(S)c1
Reactant: Ic1ccc2c(-c3ccccc3)cc3nncn3c2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cccc(Sc2ccc3c(-c4ccccc4)cc4nncn4c3c2)c1
Temperature: 70 °C

Procedure:
8-Iodo-5-phenyl-[1,2,4]triazolo[4,3-a]quinoline (250 mg, 0.67 mmol), 3-mercaptobenzoic acid (120 mg, 0.81 mmol), iPr2NEt (0.36 mL, 2.1 mmol), Pd2dba3 (15 mg, 0.02 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (19 mg, 0.03 mmol) were dissolved in 1,4-dioxane and degassed with N2. The reaction was then sealed and heated to 70° C. for 30 minutes, followed by cooling to room temperature, filtration, and concentration to give the desired product, 11a.