Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[N:13]=[C:14]([C:22]#[CH:23])[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:10])([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[N:28]=[CH:29][S:30][CH:31]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.[Cu]I.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>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([CH3:24])[C:9](=[O:10])[NH:11][C:12]1[N:13]=[C:14]([C:22]#[C:23][C:27]2[N:28]=[CH:29][S:30][CH:31]=2)[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Brc1cscn1
Reactant: C#Cc1nc(NC(=O)C(C)NC(=O)OC(C)(C)C)cc2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc2ccccc2c(C#Cc2cscn2)n1

Procedure:
A mixture of tert-butyl-N-[1-[(1-ethynylisoquinolin-3-yl)amino]-1-oxopropan-2-yl]-carbamate D4a (50 mg, 0.15 mmol), 4-bromo-1,3-thiazole (24 mg, 0.15 mmol), copper(I) iodide (3 mg, 0.02 mmol), Dichlorobis(triphenylphosphine)palladium(II) (10 mg, 0.01 mmol) and DIPEA (75 μl, 0.44 mmol) is stirred under argon atmosphere in NMP (1 ml) for 2 h at 80° C. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 12 mg (19%). HPLC-MS: M+H=423; tR=1.84 min (*Method—4).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24]([OH:26])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([NH2:40])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([O:13][CH3:14])[C:10]([F:12])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[NH:23][CH:22]=2)=[O:26])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1cc(-c2ncnc3c(C(=O)O)c[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Product: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)c[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A79) and (R)-3-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C@:2]([C:6]([NH:8][C@H:9]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:35](O)=[O:36])[CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:25])[CH2:21][CH2:22][CH3:23])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH2:4][CH3:5])[CH3:3].C[N-]OC.[H-].[H-].[H-].[H-].[Li+].[Al+3].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].S(=O)(=O)(O)O>C1COCC1.CC(=O)OCC>[NH2:1][C@:2]([C:6]([NH:8][C@H:9]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([CH:35]=[O:36])[CH2:28][CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)=[O:25])[CH2:21][CH2:22][CH3:23])=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH2:4][CH3:5])[CH3:3]
Reactant: CCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@](C)(N)CC)C(=O)N[C@@H](CC1CCCCC1)C(=O)O
Agent: C[N-]OC
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@](C)(N)CC)C(=O)N[C@H](C=O)CC1CCCCC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 79.6 %

Procedure:
A solution of 640 mg (1.18 mmol) of Iva-Phe-Nva-Cha-N,O-dimethylhydroxylamide in 3.2 ml of absolute THF is added dropwise to a suspension of 60.8 mg (1.59 mmol) of LAH in 1.6 ml of absolute THF at -5° C.; after 2.5 hours at 0° C., a further 30.5 mg (0.8 mmol) of LAH are added, and the mixture is stirred at 0° C. for a further 30 minutes, cooled to -10° C. and 1.08 ml of saturated Seignette salt solution is slowly added dropwise, and the mixture is stirred for 30 minutes and then 2.46 ml of 2N sulfuric acid are added dropwise. EA is poured onto the reaction mixture, which is stirred for 30 minutes, the solution is decanted off from the precipitate, and the residue is extracted twice with EA. The combined organic phases are washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried and concentrated at R.T. 470 mg of the title compound are obtained and rapidly reacted further.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[H-].[Na+].Br[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:10]=1.O>C1COCC1.[Cl-].[Cl-].[Zn+2].C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[F:16][C:15]([F:17])([F:18])[C:13]1[CH:14]=[C:9]([C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)[CH:10]=[C:11]([C:19]([F:20])([F:21])[F:22])[CH:12]=1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Reactant: c1cc[nH]c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(-c2ccc[nH]2)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 147.5 %

Procedure:
A 500 mL 3-neck round-bottomed flask was charged with a solution of pyrrole (5.15 g, 76.79 mmol) in THF (120 mL) at rt and cooled to 0° C. NaH(2.21 g, 92.12 mmol) was added portionwise and the reaction mixture was stirred at 0° C. for 1 h. To this reaction mixture, ZnCl2 (10.4 g, 77 mmol) was added and stirred at 0° C. for 1 h. 1-Bromo-3,5-bis(trifluoromethyl)benzene (5.0 g, 17.0 mmol) was added and reaction was properly degassed for 10 min and palladium diacetate (0.172 g, 0.76 mmol) and 2-(dicyclohexyl phosphino)biphenyl (0.269 g, 0.76 mmol) were added and reaction was refluxed for 48 h. Reaction mixture was transferred into water (100 mL) and extracted with EtOAc (3×300 mL) and the combined organic layers were washed with saturated brine solution (3×150 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford 7 g of crude 2-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrrole which was purified by chromatography to afford 0.8 g of pure product. LCMS calcd for: C12H6F6N [M−H]− 278.18. found 278.19 (retention time 3.383 min)
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH2:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH:31][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([N:2]([CH3:1])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1
Reactant: CN(c1ccccc1)c1cccc(C(=O)O)c1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccccc1)c1cccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 3 %

Procedure:
A solution of 3-(methyl(phenyl)amino)benzoic acid (0.056 g, 0.246 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.057 g; 0.246 mmol), HATU (0.102 g; 0.271 mmol) and N,N-diisopropylethylamine (0.106 mL; 0.616 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.003 g (3%) of the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([O:10]C(C)(C)C)=[O:9]>FC(F)(F)C(O)=O>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9]
Reactant: CC(C)(C)OC(=O)[C@@H](c1ccccc1)N1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H](c1ccccc1)N1CCCC1=O
Yield: 103 %

Procedure:
The product of example 128C (245 mg, 0.89 mmol) in trifluoroacetic acid (5 mL) was stirred at ambient temperature for 2 hours. The mixture was concentrated to afford 201 mg (100%) of the title compound. MS (ESI) m/z 276 (M+H)+.
Reaction SMILES: O.NN.Cl.NO.C[N:8](C)/[CH:9]=[CH:10]/[C:11]([C:13]1[S:17][C:16]([N:18]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[C:19]2=[O:34])=[N:15][C:14]=1[CH3:35])=[O:12]>>[O:12]1[C:11]([C:13]2[S:17][C:16]([N:18]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)[C:19]3=[O:34])=[N:15][C:14]=2[CH3:35])=[CH:10][CH:9]=[N:8]1
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)/C=C/N(C)C
Agent: Cl
Agent: NN
Agent: NO
Solvent: O
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1-c1ccno1
Yield: 76 %

Procedure:
Following the procedure as described in Example 38, making variations as required to replace hydrazine monohydrate with hydroxylamine hydrochloride to react with (E)-1-(5-(3-(dimethylamino)acryloyl)-4-methylthiazol-2-yl)-3-(4-(trifluoromethyl)benzyl)imidazolidin-2-one, the title compound was obtained as a colorless solid in 76% yield: mp 153-154° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J=1.8 Hz, 1H), 7.67 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 6.23 (d, J=1.8 Hz, 1H), 4.53 (s, 2H), 4.17-4.04 (m, 2H), 3.54-3.41 (m, 2H), 2.53 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.2, 158.4, 155.5, 150.5, 148.1, 139.7, 128.5, 125.9, 125.8, 122.1, 111.8, 99.4, 47.6, 42.1, 41.9, 17.1; MS (ES+) m/z 409.1 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]3[C:13](=[O:14])[N:12]([C:15]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]5[CH:28]=[C:27]([NH:29][C:30]6[CH:35]=[CH:34][C:33]([C:36]([N:38]7[CH2:43][CH2:42][O:41][CH2:40][CH2:39]7)=[O:37])=[CH:32][N:31]=6)[C:26](=[O:44])[N:25]([CH3:45])[CH:24]=5)[C:16]=4[CH:17]=[O:18])[CH2:11][CH2:10][NH:9][C:8]=3[CH:46]=2)[CH2:3][CH2:2]1.C(O)C.[BH4-].[Na+]>C1COCC1>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]3[C:13](=[O:14])[N:12]([C:15]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]5[CH:28]=[C:27]([NH:29][C:30]6[CH:35]=[CH:34][C:33]([C:36]([N:38]7[CH2:43][CH2:42][O:41][CH2:40][CH2:39]7)=[O:37])=[CH:32][N:31]=6)[C:26](=[O:44])[N:25]([CH3:45])[CH:24]=5)[C:16]=4[CH2:17][OH:18])[CH2:11][CH2:10][NH:9][C:8]=3[CH:46]=2)[CH2:2][CH2:3]1
Reactant: Cn1cc(-c2cccc(N3CCNc4cc(C5CC5)ccc4C3=O)c2C=O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1cc(-c2cccc(N3CCNc4cc(C5CC5)ccc4C3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reaction time: 1 h
Yield: 56.9 %

Procedure:
To a mixture of 2-(8-Cyclopropyl-5-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzaldehyde (350 mg, 0.566 mmol) in 40 mL 1:1 absolute ethanol and THF cooled to 0 C was added sodium borohydride (22 mg, 0.566 mmol, 1 eq) and the reaction was stirred for 1 hour at 0 C. The reaction was quenched with water and 2 drops glacial acetic acid, and stirred for 5 min. The mixture was concentrated in vacuo to remove THF and Ethanol, neutralized with a few drops of aqueous saturated sodium bicarbonate, then concentrated to dryness. The residue was loaded directly on an analogix 40 g column using 10% methanol in CH2Cl2, and eluted with a gradient of 5% to 10% methanol in CH2Cl2 to give a solid. Repurification using HPLC gave 200 mg 8-Cyclopropyl-4-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one, as a solid, 63% yield.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=1)C>>[CH:10]1([S:9][C:5]2[N:4]=[C:3]([CH2:2][O:26][C:23]3[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][C:17]([OH:28])=[O:16])=[CH:21][C:22]=3[F:27])[CH:8]=[CH:7][CH:6]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1
Reactant: ClCc1cccc(SC2CCC2)n1
Product: O=C(O)CCc1ccc(OCc2cccc(SC3CCC3)n2)c(F)c1
Yield: 85 %

Procedure:
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 37 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.043 g, 84%).
Reaction SMILES: [CH2:1](O)[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:36])C(=O)C1>CN(C=O)C>[Br:36][CH2:1][CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCC#CCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCCC#CCCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
To a solution of oct-3-yn-1-ol (1.26 g, 10.0 mmol) in DMF (25 mL) was added triphenylphosphine (2.92 g, 11.2 mmol). The solution was cooled to 0° C. and NBS (1.92 g, 10.8 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (1 mL). The solution was diluted with ether (150 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford 1-bromo-oct-3-yne (1.35 g, 71%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 3.40 (2H, d, J=7.2 Hz), 2.78 (2H, m), 2.15 (2H, m), 1.22 (4H, m), 0.88 (3H, t, J=6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 82.83, 77.05, 31.18, 30.63, 23.68, 22.20, 18.67, 13.89.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([O:14][C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25]4)=[CH:20][CH:19]=3)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.N1C=CC=CC=1.[NH2:41][C:42]1[CH:43]=[C:44]([S:48]([O:51][C:52]2[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=2)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=1>C(Cl)(Cl)Cl>[CH:10]1[C:11]2[CH:12]([O:14][C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[CH:23][C:24]([C:28]([NH:41][C:42]5[CH:43]=[C:44]([S:48]([O:51][C:52]6[CH:53]=[CH:54][C:55]([CH3:58])=[CH:56][CH:57]=6)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=5)=[O:29])=[CH:25]4)=[CH:20][CH:19]=3)=[O:16])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1ccc2ccc(C(=O)O)cc2c1)OC1c2ccccc2-c2ccccc21
Reactant: Cc1ccc(OS(=O)(=O)c2cccc(N)c2)cc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(OS(=O)(=O)c2cccc(NC(=O)c3ccc4ccc(NC(=O)OC5c6ccccc6-c6ccccc65)cc4c3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 104 mg (0.026 mmol) of compound 107 was added 6.5 mL of chloroform, 1.3 mL of thionyl chloride, and 100 μL of pyridine. The reaction was allowed to stir at ambient temperature for 3 hours and then all volatiles were removed in vacuo. The residue was stripped in vacuo from chloroform twice. To the resulting solid, suspended in 15 mL of chloroform was added 74 mg (0.028 mmol) of 4-methylphenyl 3-aminobenzenesulfonate (compound 5) and 27 μL (0.033 mmol) of pyridine as a solution in 1.5 mL of chloroform. The reaction was allowed to stir at ambient temperature for 16 hours, after which it was partitioned between ethyl acetate and 1 N HCl (aqueous). The organic layer was dried (magnesium sulfate), filtered, and the volatiles were removed in vacuo. The resulting residue was treated with diethyl ether. and the solid precipitate collected by vacuum filtration. This provided 110 mg of compound 108.
Reaction SMILES: [C:1]1([CH2:9][OH:10])[C:2]([CH2:7][OH:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C12COCC1=CC=CC=2.[N+]([O-])(O)=O.O>C(O)(=O)C>[CH:9](=[O:10])[C:1]1[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:7]=[O:8]
Reactant: OCc1ccccc1CO
Agent: c1ccc2c(c1)COC2
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1ccccc1C=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
In a 1000-ml three-neck flask equipped with a thermometer, a reflux condenser and a stirrer were placed 13.3 g of o-xylylene glycol, 36.7 g of o-xylylene oxide, 85.1 g of 60% by weight nitric acid, 165.5 g of water, and 199.5 g of acetic acid. The mixture was raised in temperature to 70° C. on an oil bath and was stirred under these conditions for 1 hour. After cooling, the reaction mixture was analyzed by gas chromatography to find that the raw material o-xylylene glycol was completely absent and that phthalaldehyde was formed in a yield of 84%. The obtained reaction mixture was extracted with two portions of toluene, the organic layer was distilled and thereby yielded phthalaldehyde in a yield of 67% on the basis of o-xylylene glycol. Gas chromatographic analysis revealed that phthalaldehyde had a purity of 98.8%. In addition, phthalide was formed in a yield of 11%.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[NH2:17][CH2:18][C:19]1[CH:20]=[C:21]([OH:32])[C:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1>>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:23]=[CH:24][C:19]([CH2:18][NH:17][CH:14]=[C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=4)[C:8](=[O:12])[NH:7][C:6]3=[O:13])=[CH:20][C:21]=2[OH:32])=[CH:30][CH:29]=1
Reactant: NCc1ccc(-c2ccc(F)cc2)c(O)c1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Product: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccc(F)cc2)c(O)c1
Yield: 60 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione-2, the title compound is prepared from 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (90 mg, 0.27 mmol) and 4-Aminomethyl-4′-fluoro-biphenyl-2-ol (66 mg, 0.3 mmol) in 60% yield: MS (ESI): 513.1 (M−1)−1.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].C(N(CC)CC)C.[N:27]1[N:36]2[C:30]([CH2:31][NH:32][C:33]3[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=3[CH2:35]2)=[CH:29][CH:28]=1>C(Cl)Cl.C(OCC)(=O)C>[N:27]1[N:36]2[C:30]([CH2:31][N:32]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[CH3:1])=[CH:8][CH:9]=3)=[O:12])[C:33]3[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=3[CH2:35]2)=[CH:29][CH:28]=1
Reactant: c1ccc2c(c1)Cn1nccc1CN2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a mixture of 1.37 g of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 15 ml of methylene chloride, cooled to 0° C. is added 1.5 ml of triethylamine. To the mixture is added 5 mmol of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine. The reaction mixture is allowed to stir at room temperature for 48 hours and the volatiles are removed in vacuo to give a residue. The residue is dissolved in 100 ml of ethyl acetate and washed with water, 2N citric acid, aqueous NaHCO3 and brine. The solution is dried with Na2SO4 and the solvent removed in vacuo. The residue is purified by flash chromatography on silica gel with ethyl acetate-hexane to give the desired product, m.p. 142°-146° C.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[N:23]1([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=2[NH:39][C:40](=O)[C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[OH-].[Na+]>C1(C)C=CC=CC=1>[N:23]1([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=2[NH:39][C:40](=[S:10])[C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1N1CCCCC1)c1ccncc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(N2CCCCC2)c(NC(=S)c2ccncc2)c1
Temperature: 100 °C
Yield: 33.7 %

Procedure:
Lawesson's reagent (328 mg, 0.811 mmol, commercially available product) was added to a toluene (2.5 ml) solution of N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (SRPIN-1, GIF-0340) (528 mg, 1.51 mmol), obtained as described in Referential Example 1-3, and the resulting mixture was stirred with refluxing at 100° C. for 12 hours. The mixture was cooled to room temperature, and then an aqueous solution of 2 M sodium hydroxide was added thereto to alkalify the solution. The mixture was reverse extracted three times with an aqueous solution of 12 M sodium hydroxide. 2 M hydrochloric acid was added to the aqueous layer to acidify the solution. Then, the resulting mixture was extracted three times with ether. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50 g, hexane/ethyl acetate=1/1). Thus, N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]isonicotinthioamide (GIF-0616) (186 mg, 33.7%) was yielded as a colorless solid.
Reaction SMILES: [N:1]([CH:4]1[CH2:7][N:6]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH:17]3[CH2:20][CH2:19][CH2:18]3)[CH2:12][CH2:11]2)=[O:9])[CH2:5]1)=[N+]=[N-].O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH:17]1([N:13]2[CH2:14][CH2:15][CH2:16][N:10]([C:8]([N:6]3[CH2:5][CH:4]([NH2:1])[CH2:7]3)=[O:9])[CH2:11][CH2:12]2)[CH2:20][CH2:19][CH2:18]1
Reactant: [N-]=[N+]=NC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Reaction time: 16 h
Yield: 40.4 %

Procedure:
1-[(3-azidoazetidin-1-yl)carbonyl]-4-cyclobutyl-1,4-diazepane (140 mg, 0.50 mmol), was dissolved in THF (5 ml) and water (0.28 ml, 5 mmol) was added. PPh3 was then added as a solid and the reaction was stirred for 16 hours giving a clear solution. The reaction was concentrated in vacuo and purified by FCC (DCM/MeOH/MH3 gradient, 95:5:1 to 70:30:1) to provide the title compound as pale yellow solid (51 mg, 40%).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1>CCO.[Pd]>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(C2=CCOCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ccc(C2CCOCC2)cc1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
450 mg (2.43 mmol) 4-(3,6-dihydro-2H-pyran-4-yl)benzonitrile was dissolved in 15 ml EtOH and 50 mg 10% Pd/C was added. The reaction mixture was stirred under H2 (4 bar) over night at room temperature. The mixture was filtered through celite with EtOAc washing. The filtrate was concentrated and the crude product 340 mg (75% yield) was used directly in the next step.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]=[N:19][C:20]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[C:21]([CH3:24])[C:22]=3[CH3:23])[CH2:13][C@H:12]2[CH3:32])=[N:9][CH:10]=1)=[O:4].[Li+].[OH-].O.C1COCC1>CO>[CH2:25]([C:20]1[N:19]=[N:18][C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:8]3[CH:7]=[N:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][N:9]=3)[C@H:12]([CH3:32])[CH2:13]2)=[C:22]([CH3:23])[C:21]=1[CH3:24])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c(C)c3C)C[C@H]2C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(Cc2ccccc2)nnc(N2CCN(c3cnc(C(=O)O)cn3)[C@H](C)C2)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.9 %

Procedure:
(R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (1.8 g, 4.16 mmol) is combined with LiOH (998 mg, 42 mmol), H2O (20 mL), THF (20 mL), and MeOH (10 mL). The combined mixture is allowed to stir at room temperature for 16 h. It is concentrated to remove organic solvents in vacuo. Additional water is added and the pH is adjusted to 4.0 with HCl or phosphate buffer. The solution is extracted with EtOAc and the combined organic extracts are washed with brine. The extract is dried over sodium sulfate and filtered to remove the drying agent. The filtrate is concentrated to afford the title compound (1.46 g, 84%).