Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:3](=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[O:18])[NH:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=32)[CH2:2]1.[H-].[Na+].[CH2:21](Br)[C:22]#[CH:23].[OH-].[Na+]>CN(C)C=O>[CH2:23]([N:9]1[C:8](=[O:18])[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2][CH2:1][N:12]([C:13]=23)[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]1=2)[C:22]#[CH:21]
Reactant: O=C1Nc2ccccc2N2CCc3cccc1c32
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)c2cccc3c2N(CC3)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 19.8 %

Procedure:
A mixture prepared from 1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]-benzodiazepin-6-one (8.3 gm, 35 mmole) and sodium hydride (1.65 gm, 50% in oil, 1.0 eq) in dimethylformamide (DMF, 80 ml) was stirred at room temperature for 1.5 hours under N2. It was cooled to ~0° C. To this solution was charged propargyl bromide (16.5 gm, 80% in toluene, 3 eq) and the mixture was stirred for another 1.5 hours at 0° C. At the end of the reaction, the solution was poured into 10% NaOH (250 ml), and extracted with dichloromethane (DCM 1 l). The DCM solution was washed with NaOH (250 ml), water (2×300 ml) and brine (2×300 ml), then dried over MgSO4 and concentrated to an oil. Purification was accomplished by flash chromatography (SiO2 column, 200 gm, eluted with 1:1 hexane:DCM, 4 l). The material thus purified weighed 7.1 gm, (74%) as an oil. It turned to solid upon trituration with ether. A 3 gram portion of this material was recrystallized from ether (150 ml) to afford 1.9 gm of yellow crystals, m.p. 104°-105° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[Cl:25])[O:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]1.[NH2:26][C:27]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:28]=1[C:29](O)=[O:30].Cl>>[NH2:26][C:27]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:28]=1[C:29]([NH:21][CH2:20][CH2:19][N:16]1[CH2:15][CH2:14][CH:13]([O:12][C:11]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:9]([Cl:8])[CH:10]=2)[CH2:18][CH2:17]1)=[O:30]
Reactant: NCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: COc1ccc(N)c(C(=O)O)c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N)c(C(=O)NCCN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c1
Yield: 75.4 %

Procedure:
Prepared by the method of Example 2 using the product from Example 1 step (iv) (1.0 g) and 2-amino-5-methoxybenzoic acid (0.418 g) without the addition of 1.0M ethereal hydrogen chloride solution to give an oil which was purified by chromatography (dichloromethane:methanol, 95:5) to give the sub-titled product as an oil (0.82 g).
Reaction SMILES: [Na].[N:2]1([CH2:7][C:8]([NH:10][CH:11]2[C:18](=[O:19])[N:17]3[CH:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:29]([CH3:30])[N:28]=[N:27][N:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3]1.[C:31]([NH:36][CH2:37]Cl)(=[O:35])[CH2:32][CH2:33][CH3:34]>CN(C)C=O>[C:31]([NH:36][CH2:37][O:21][C:20]([C:16]1[N:17]2[CH:12]([S:13][CH2:14][C:15]=1[CH2:23][S:24][C:25]1[N:29]([CH3:30])[N:28]=[N:27][N:26]=1)[CH:11]([NH:10][C:8](=[O:9])[CH2:7][N:2]1[CH:3]=[CH:4][CH:5]=[CH:6]1)[C:18]2=[O:19])=[O:22])(=[O:35])[CH2:32][CH2:33][CH3:34]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cn3cccc3)C2SC1
Reactant: CCCC(=O)NCCl
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCC(=O)NCOC(=O)C1=C(CSc2nnnn2C)CSC2C(NC(=O)Cn3cccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To dimethylformamide is added the sodium salt of 7-[[(1-pyrryl)acetyl]amino]-3-[[(1-methyltetrazol-5-yl) thio]methyl] -8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid, one equivalent, and an equivalent amount of N-butyrylaminomethyl chloride. The mixture is stirred at room temperature for about one hour after which it is carefully poured into ice water. The product precipitates and is recovered by filtration. The solid is dissolved in ethyl acetate and washed with aqueous sodium bicarbonate and then with water. The organic layer is dried over magnesium sulfate, filtered and evaporated to dryness in vacuo to give the title compound.
Reaction SMILES: [C:1]([C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[N:6][NH:7][C:8]2=[O:15])#[CH:2].Cl.BrC1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>C(NCC)C.O.[Cu]I>[CH3:14][O:13][C:12]1[C:3]([CH2:1][C:2]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:15])[NH:7][N:6]=[CH:5]2
Reactant: C#Cc1c(OC)ccc2c(=O)[nH]ncc12
Reactant: Brc1ccncc1
Agent: [Cu]I
Agent: Cl
Solvent: O
Solvent: CCNCC
Product: COc1ccc2c(=O)[nH]ncc2c1Cc1ccncc1
Temperature: 75 °C
Yield: 89.2 %

Procedure:
A suspension of 5-ethynyl-6-methoxy-2H-phthalazin-1-one (1.9 g, 9.49 mmoles), prepared as described in example 140, 4-bromopyridine hydrochloride (2.214 g, 11.39 mmoles), bis(triphenylphosphine)PdCl2 (133 mg, 0.1998 mmole) and CuI (36 mg, 0.1898 mmole) in diethylamine (40 ml) was heated at 75° C. for 1 hour, cooled, diluted with water (40 ml) and the solid was filtered after 30 minutes under stirring. The solid was suspended in acetone, stirred for 15 minutes, filtered again and dried in oven at 45° C. under vacuum giving 2.263 g of the title compound (yield: 86%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:21])[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:6][C:5]=1[F:22])(=[O:3])[CH3:2].[Br:23]([O-])(=O)=O.[K+].Br>C(O)(=O)C>[Br:23][CH2:2][C:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:21])[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:6][C:5]=1[F:22])=[O:3]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: CCOC(=O)c1cn(CC)c2cc(C(C)=O)c(F)cc2c1=O
Agent: Br
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(CC)c2cc(C(=O)CBr)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 271.2 %

Procedure:
A solution of 2.45 g (8.0 mmol) ethyl 7-acetyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 50 ml acetic acid was treated with 0.46 g potassium bromate, and then 3.8 ml 48% hydrobromic acid was added dropwise over one half hour. The mixture was stirred 24 hours at room temperature and poured into 200 ml ice water. The precipitate was filtered, washed with water and dried to afford 2.87 g ethyl 7-bromoacetyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[CH2:24]([N:26](C(C)C)C(C)C)C>ClCCl.O1CCCC1>[C:24]([N:21]1[CH2:22][CH2:23][CH:18]([N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:19][CH2:20]1)#[N:26]
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Temperature: 25 °C

Procedure:
Bromonitirile (1.96 g) is added to a solution of N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide (3.50 g) and ethyldiisopropylamine (9.60 mL) in dichloromethane (125 mL) and tetrahydrofuran (125 mL) and the reaction mixture is stirred over night at room temperature. The reaction mixture is washed with water and the organic phase is dried over Na2SO4 and concentrated in vacuo. The residue is triturated with diethyl ether to afford the title compound. LC (method 3): tR=1.55 min; Mass spectrum (ESI+): m/z=337 [M+H]+.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[CH:8]=2)[S:4][N:3]=1.[CH3:18][O:19][C:20]1[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.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>[Cl:17][C:9]1[CH:8]=[C:7]([C:5]2[S:4][N:3]=[C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])[C:20]=3[O:19][CH3:18])[N:6]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1Cl
Reactant: CO/C=C/c1cccc(B(O)O)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CO/C=C/c1cccc(-c2nsc(-c3ccc(OC(C)C)c(Cl)c3)n2)c1OC
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 60.9 %

Procedure:
A mixture of 3-bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazole (D43) (200 mg, 0.599 mmol), {2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}boronic acid (D101) (187 mg, 0.899 mmol), tripotassium phosphate (318 mg, 1.499 mmol) and Pd(Ph3P)4 (69.3 mg, 0.060 mmol) in N,N-Dimethylformamide (DMF) (5 mL) and Water (2 mL) was stirred at 120° C. (Microwave) for 10 min. The reaction mixture was poured to water. Then the mixture was extracted with EA. The combined organic layers were washed with water and then dried over anhydrous sodium sulphate. After filtration and concentration, the residue was purified by column chromatography to give 5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-3-{2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,2,4-thiadiazole (D102) (152 mg). MS (ES): C21H21ClN2O3S requires 416.1. found 417.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:14])=[C:9](/[CH2:12][CH3:13])\[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH2:15]([O:17][C@@H:18]([CH2:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH3:14])=[C:9](/[CH2:12][CH3:13])\[CH2:10][O:11][C:28]2[CH:27]=[CH:26][C:25]([CH2:24][C@H:18]([O:17][CH2:15][CH3:16])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:30][CH:29]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: CC/C(CO)=C(\C)c1ccc(Br)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C(CC)=C(/C)c2ccc(Br)cc2)cc1)OCC
Yield: 81 %

Procedure:
The title compound (535 mg, 81%) was prepared from (Z)-3-(4-bromophenyl)-2-ethyl-but-2-en-1-ol (prepared as described in example 96b) (355 mg, 1.39 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (348 mg, 1.46 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17]([N:19]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:20]3=[O:30])=[O:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[CH:40][N:39]=1>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>[CH3:15][C:14]1[N:13]=[C:12]([NH:16][C:17]([N:19]2[CH2:23][CH2:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:20]2=[O:30])=[O:18])[CH:11]=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:42]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:37])[CH:43]=2)[CH:7]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: Cc1nc(NC(=O)N2CCN(C3CCOCC3)C2=O)ccc1Oc1ccnc(Cl)c1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)nc3C)ccn2)ccn1
Temperature: 80 °C
Yield: 35.4 %

Procedure:
A mixture of Example C3 (0.377 g, 0.873 mmol) and K2CO3 (0.362 g, 2.62 mmol) in dioxane (4 mL) and water (1 mL) was sparged with Ar, treated with 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.201 g, 0.917 mmol) and Pd(Ph3P)4 (0.101 g, 0.087 mmol), sparged again with Ar and heated at 80° C. overnight. The mixture was cooled to RT, diluted with EtOAc, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc). The material was treated with Et2O, stirred at RT and the resulting solid collected via filtration and dried to afford N-(6-methyl-5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (151 mg, 35%). 1H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1 H), 8.56 (d, J=5.6 Hz, 1 H), 8.52 (d, J=5.2 Hz, 1 H), 7.93-7.88 (m, 2 H), 7.79 (dd, J=5.3, 1.6 Hz, 1 H), 7.66-7.63 (m, 2 H), 6.86 (dd, J=5.6, 2.4 Hz, 1 H), 3.93-3.77 (m, 5 H), 3.49-3.34 (m, 4 H), 2.52 (s, 3 H), 2.26 (s, 3 H), 1.78-1.66 (m, 2 H), 1.63-1.57 (m, 2H); MS (ESI) m/z: 489.2 (M+H+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:28])([CH3:27])[C:21]=3[CH:29]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH:30]O>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:28])([CH3:27])[C:21]=3[CH:29]=2)=[O:30])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1
Reactant: OO
Product: CC(=O)Nc1ccc(S(=O)CCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-acetamido-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:14]([NH:16][C@H:17]1[CH2:36][N:21]2[C:22]3[C:27]([C:28]([CH2:29][C:30]([O:32]CCC)=[O:31])=[C:20]2[CH2:19][CH2:18]1)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:15]>>[CH2:14]([N:16]([C:11]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)=[O:13])[C@H:17]1[CH2:36][N:21]2[C:22]3[C:27]([C:28]([CH2:29][C:30]([OH:32])=[O:31])=[C:20]2[CH2:19][CH2:18]1)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:15]
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NCC)CC2
Reactant: O=C(O)C1(c2ccc(F)cc2)CC1
Product: CCN(C(=O)C1(c2ccc(F)cc2)CC1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 1-(4-fluorophenyl)cyclopropanecarboxylic acid and propyl [(7R)-7-(ethylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 435.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([O:17][CH2:18][CH:19]3[O:21][CH2:20]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:22])=[CH:4][CH:3]=1.[CH:23]([NH2:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([O:17][CH2:18][CH:19]([OH:21])[CH2:20][NH:26][CH:23]([CH3:25])[CH3:24])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: O=C1c2ccccc2C(OCC2CO2)N1c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CC(C)NCC(O)COC1c2ccccc2C(=O)N1c1ccc(Cl)cc1

Procedure:
A solution of 2-(4-chlorophenyl)-3-(2,3-epoxypropoxy)-isoindolin-1-one (15 g.) and isopropyl-amine (75 cc.) in anhydrous toluene (250 cc.) is heated under reflux for 5 days. The reaction mixture is then evaporated to dryness under reduced pressure and the residue obtained is recrystallised from ethyl acetate (60 cc.). After drying, 2-(4-chlorophenyl)-3-(2-hydroxy-3-isopropylamino-propoxy)-isoindolin-1-one (13 g.), melting at 107° C., is obtained.
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:11][C:12]1[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=1[C:14]([CH:16]1[CH2:21][CH2:20][N:19](C)[CH2:18][CH2:17]1)=[O:15]>C1(C)C=CC=CC=1>[O:7]([C:8]([N:19]1[CH2:20][CH2:21][CH:16]([C:14](=[O:15])[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[F:11])[CH2:17][CH2:18]1)=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1CCC(C(=O)c2ccccc2F)CC1
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1F)C1CCN(C(=O)Oc2ccccc2)CC1
Temperature: 25 °C

Procedure:
47.0 g of phenylchloroformate are added to a stirring solution of 57.5 g of 4-(2-fluorobenzoyl)-1-methyl piperidine in 750 ml of toluene. The reaction mixture is refluxed for 5 hours, cooled to ambient temperature, filtered, and the solvent is removed leaving a light colored oil. Theoil is triturated with hexane to give a crystalline material which is recrystallized twice from an ethanol-water mixture and once from ethanol The oil give the compound, mp 95°-96° C., 1-phenoxycarbonyl-4-(2-fluorobenzoyl)piperidine.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[S:8][C:7]=1[C:17]([NH2:19])=[O:18])[CH2:2][CH2:3][CH3:4].[CH3:20][C:21]([CH3:23])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([N:5]1[C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[S:8][C:7]=2[C:17](=[O:18])[NH:19][C:21]1([CH3:23])[CH3:20])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(-c2ccncc2)sc1C(N)=O
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCN1c2cc(-c3ccncc3)sc2C(=O)NC1(C)C
Temperature: 70 °C
Reaction time: 72 h
Yield: 70 %

Procedure:
A mixture of 3-(butylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.100 g, 0.400 mmol), acetone (3.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 3 days at 70° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (100 mL). Extraction with ethyl acetate-tetrahydrofuran (2:1, 100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. The oil was purified by column chromatography (Combiflash, 12 g silica gel, hexane to ethyl acetate) to afford the title compound (0.0879 g, 70%) as a yellow solid:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[C:11](OC([O-])=O)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:11](=[O:12])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1cccc(CN)c1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: C1CCOC1
Product: COc1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Methoxybenzylamine (23 g) was dissolved in 150 ml of tetrahydrofuran, and a solution of 32 g of t-butyl dicarbonate in tetrahydrofuran (50 ml) was added thereto. The mixture was stirred at room temperature for 1 hour, and then the solvent was evaporated. The residue was dissolved in ethyl acetate and successively washed with 1N hydrochloric acid and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated to give t-butyl N-(3-methoxybenzyl)carbamate. The resulting t-butyl N-(3-methoxybenzyl)carbamate was then dissolved in 250 ml of acetonitrile, 30 g of N-bromosuccinimide was added thereto under ice-cooling, the mixture was stirred at room temperature for 3 hours, and then the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with water and then with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by a silica gel column, to give 36 g of the title compound in the 2:1 hexane-diethyl ether fraction.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[N:15]1[N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]2[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=[CH:4][CH:3]=2)[N:18]=[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=12
Reactant: CNc1cccc(Br)n1
Reactant: C#CCCn1nc2ccccc2n1
Product: CNc1cccc(C#CCCn2nc3ccccc3n2)n1
Yield: 14285.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from (6-bromo-pyridin-2-yl)-methyl-amine (105 mg, 0.56 mmol) and 2-but-3-ynyl-2H-benzo[d][1,2,3]triazole (96 mg, 0.56 mmol, Example 109(D)). Reaction time: 3 hours. The crude residue was purified by C18 flash chromatography (water to water/acetonitrile 3:2) to yield 22 mg (80 mmol, 14%) of 6-(4-(2H-benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)-N-methylpyridin-2-amine as a white solid (M.P.=150-154° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:21]=[C:11]3[NH:12][C:13](=[O:20])[C:14]4[C:19]([N:10]3[N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1.[N:22]1([CH2:28][CH2:29][C:30](O)=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:20]=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]2[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:7]=[CH:6][CH:5]=3)[CH:21]=[C:11]2[NH:12]1
Reactant: Nc1cccc(-c2cc3[nH]c(=O)c4ccccc4n3n2)c1
Reactant: O=C(O)CCN1CCCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCN1CCCCC1)Nc1cccc(-c2cc3[nH]c(=O)c4ccccc4n3n2)c1

Procedure:
A solution of EXAMPLE 12 (0.1 g, 0.4 mmol), 3-piperidinopropionic acid (60 mg, 0.4 mmol), 1-hydroxybenzotriazole (0.098 g, 0.7 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (0.377 g, 0.7 mmol) and diisopropylethylamine (0.4 mL, 2.2 mmol) in N,N′-dimethylformamide (4 mL) was heated in a microwave at 100° C. for 15 minutes. The mixture was concentrated and purified by flash chromatography on silica gel with 10% methanol/dichloromethane to provide the title compound. 1H NMR (CD3OD) δ 8.23-8.27 (m, 3H), 7.89 (td, J=7.8, 1.5 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.59 (dd, J=7.1, 2.2 Hz, 1H), 7.48-7.56 (m, 1H), 7.42 (t, J=8.0 Hz, 1H), 6.33 (s, 1H), 3.62 (s, 2H), 3.51 (t, J=6.6 Hz, 2H), 3.04 (s, 2H), 2.96 (t, J=6.8 Hz, 2H), 1.98 (d, J=3.4 Hz, 2H), 1.82 (s, 3H), 1.58 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH:3]([CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)=[CH2:4].[C:11]([C@H:19]([CH3:23])[C:20](Cl)=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C1(C)C=CC=CC=1>[C:11]([C@H:19]([CH3:23])[C:20]([N:9]1[C@H:5]([CH:3]=[CH2:4])[CH2:6][CH2:7][C:8]1=[O:10])=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@H](C(=O)Cl)C(=O)c1ccccc1
Reactant: C=CC1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C[C@@H]1CCC(=O)N1C(=O)[C@@H](C)C(=O)c1ccccc1
Temperature: 25 °C
Yield: 45 %

Procedure:
To 60% sodium hydride (336 mg, 10.0 mmol) in toluene (20 mL) at 0° C. was added dropwise a solution of 5-vinylpyrrolidin-2-one (1.0 mg, 9.0 mmol) in toluene (10 mL) over a 10 min period. The cooling bath was removed and the solution was allowed to warm to 25° C. to ensure complete generation of the anion. To the anion at 25° C. was added dropwise a solution of (2S)-2-benzoylpropanoyl chloride (21, 2.7 g, 12.6 mmol) in toluene (10 mL) over a 10 min period. TLC indicated that the reaction was complete upon addition of the acid chloride (silica gel plates; hexane and t-butyl methyl ether, 1:1). Water (50 mL) as added to the reaction mixture and the phases were separated. The aqueous phase was extracted with diethyl ether (2×40 mL). The combined organic phases were washed with a saturated aqeous sodium bicarbonate solution (1×100 mL) and dried (MgSO4). Concentration and purification by flash chromatography on silica gel (EM 60, 0.040-0.063 partical size, 230-400 Mesh, column size: 6.5 cm diameter×20 cm length) using hexane and t-butyl methyl ether (10:1) afforded 1.1 g (42%) of (5S)-N-((2S)-2-benzoylpropanoyl)-5-ethenylpyrrolidin-2-one (24a) as a thick oil: 1H NMR (CDCl3) δ1.44-1.46 (d, J=6.5 Hz ,3 H), 1.64-1.80 (m, 1 H), 2.12-2.20 (m, 1 H), 2.42-2.84 (m, 2 H), 4.12-4.21 (q, J=6.4 Hz, 1 H), 4.38-4.47 (m, 1 H), 4.58-4.67 (m, 1 H), 4.89-4.91 (m, 1 H), 5.06-5.19 (m, 2 H), 5.77-5.85 (m, 1 H), 7.28-7.40 (m, 5 H); 13C NMR (CDCl3) δ174.8, 173.5, 137.7, 135.3, 128.0, 127.7, 127.4, 115.1, 74.6, 71.6, 31.3, 24.0, 18.1; IR (neat) 3066 (w), 3033 (w), 2939 (w), 1740 (vs), 1708 (vs), 1455 (s), 1370 (s), 1277 (s), 1148 (s), 1113 (s), 739 (s) cm-1.