Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[NH:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][C:13]([O:22][CH3:23])=[CH:14][C:15]=3[O:20][CH3:21])[N:10]=2)=[CH:4][C:3]=1[CH3:24].[CH:25]([N:28]([CH:31](C)C)[CH2:29]C)(C)C.CS(Cl)(=O)=O>CN(C=O)C.CCOC(C)=O>[CH3:21][O:20][C:15]1[CH:14]=[C:13]([O:22][CH3:23])[CH:12]=[C:11]2[C:16]=1[C:17](=[O:19])[NH:18][C:9]([C:5]1[CH:6]=[C:7]([CH3:8])[C:2](/[N:1]=[CH:25]/[N:28]([CH3:31])[CH3:29])=[C:3]([CH3:24])[CH:4]=1)=[N:10]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(N)c(C)c3)nc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(/N=C/N(C)C)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.7 %

Procedure:
To a solution of 2-(4-amino-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.096 g, 0.295 mmol) and diisopropylethylamine (61.7 μL, 0.354 mmol), in DMF (2.96 mL) was added dropwise methanesulfonyl chloride (25.2 μL, 0.325 mmol). After stirring at room temperature for 18 h, the mixture was diluted with EtOAc (300 mL), washed with saturated aqueous sodium bicarbonate (2×75 mL), saturated aqueous LiCl (2×75 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified over silica gel (12 g, CH2Cl2/CH3OH) to provide (E)-N′-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-N,N-dimethylformimidamide (0.0502 g, 45%) as a white solid. Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.68 (s, 1H), 7.87 (s, 2H), 7.40 (s, 1H), 6.72 (d, J=2.31 Hz, 1H), 6.48 (d, J 2.31 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 2.97 (s, 6H), 2.12 (s, 6H); MS (APCI) m/z 381 [M+H]+.
Reaction SMILES: [CH3:1][C@@:2]1([O:36][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:6]([O:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:5]([CH2:16][O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:4][C@H:3]1[N:26]1[C:30]2=[CH:31][N:32]=[N:33][C:34](=O)[C:29]2=[N:28][CH2:27]1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)[Cl:57]>>[Cl:57][C:34]1[N:33]=[N:32][CH:31]=[C:30]2[N:26]([C@@H:3]3[O:4][C@H:5]([CH2:16][O:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C@@H:6]([O:7][C:8](=[O:15])[C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[C@@:2]3([CH3:1])[O:36][C:37](=[O:44])[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:27]=[N:28][C:29]=12
Reactant: C[C@@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1N1CN=C2C(=O)N=NC=C21
Reactant: ClP(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: C[C@@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(Cl)nncc21

Procedure:
A solution containing the compound from Step A (300 mg, 0.50 mmol), the N,N-diethylaniline (1.2 mL) and freshly distilled phosphorus chloride (24 mL) was stirred at reflux for 1 hour. The reaction mixture was evaporated to dryness. Dichloromethane was added to the residue and the organic layer poured over cracked ice/water. The aqueous layer was extracted with dichloromethane. The organic layer was washed with sodium hydrogenocarbonate 5%, water and was evaporated to dryness. The crude product was purified on silica gel using diethyl ether/petrol ether (1/1) as eluant to give the title compound (295 mg) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:13]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]2=[O:21])[CH:5]=[CH:6][C:7]=1[S:8][C:9]([F:12])([F:11])[F:10].[H-].[Na+].[Cl:24][C:25]1[CH:30]=[C:29]([CH2:31]Cl)[CH:28]=[CH:27][N:26]=1>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[C:4]([N:13]2[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:31][C:29]3[CH:28]=[CH:27][N:26]=[C:25]([Cl:24])[CH:30]=3)[C:14]2=[O:21])[CH:5]=[CH:6][C:7]=1[S:8][C:9]([F:12])([F:10])[F:11]
Reactant: ClCc1ccnc(Cl)c1
Reactant: CC1(C)NC(=O)N(c2ccc(SC(F)(F)F)c(N)c2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(c2ccc(SC(F)(F)F)c(N)c2)C(=O)N1Cc1ccnc(Cl)c1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 89.7 %

Procedure:
To a solution of 0.4 g of 3-{3-amino-4-[(trifluoro-methyl)thio]phenyl}-5,5-dimethylimidazolidine-2,4-dione obtained in stage c) below in 20 mL of dimethylformamide are added, under argon, 53 mg of 60% sodium hydride and stirring is continued for 20 minutes at room temperature. To this solution are added 2.85 g of 2-chloro-4chloromethylpyridine obtained in stage b) of Example 3 dissolved in 5 mL of dimethylformamide, and the reaction mixture is then heated at 70° C. for 3.5 hours and then poured into 100 mL of ice-water and extracted with three times 100 mL of ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is taken up in 100 mL of diethyl ether, washed with water, dried over magnesium sulphate, filtered and concentrated under vacuum to give 500 mg of 3-{3-amino-4-[(trifluoromethyl)thio]phenyl}-1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethylimidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:21])C=1.ClC1C=C(C=CC=1)C(O)=O>C(Cl)(Cl)Cl>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:12])=[O:21])=[CH:7][CH:6]=1)=[O:4]
Reactant: CSc1ccc(C(=O)CBr)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccc(C(=O)CBr)cc1
Yield: 33.2 %

Procedure:
A solution of 2-bromo-1-(4-methylsulphanylphenyl)-1-ethanone (3.7 g, 15 mmol) in CHCl3 (50 ml) is maintained at a temperature of −5° C. A solution of m-chloroperbenzoic acid (70%, 3.7 g, 15 mmol) in CHCl3 (30 ml) cooled to 0° C. is added dropwise while maintaining an IT of −5° C. to 0° C. After stirring for ½ hour in the cold, the deposited m-chlorobenzoic acid is filtered off. The filtrate is first washed with NaHCO3 solution (8% strength, 50 ml) until acid-free and then rewashed with water (50 ml). The CHCl3 phase dried over Na2SO4 sicc. is concentrated in vacuo. A yellowish residue (1.3 g) results.
Reaction SMILES: C(#N)C.[Br:4][CH2:5][C:6]([CH3:10])=[CH:7][CH:8]=[O:9].Br[Si:12]([CH3:15])([CH3:14])[CH3:13]>CCCCC.C(N(CC)CC)C>[Br:4][CH:5]=[C:6]([CH3:10])[CH:7]=[CH:8][O:9][Si:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: C[Si](C)(C)Br
Reactant: CC(=CC=O)CBr
Solvent: CCCCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C=CO[Si](C)(C)C)=CBr
Temperature: 20 °C
Reaction time: 48 h
Yield: 25.8 %

Procedure:
Pentane (120 cc), acetonitrile (120 cc), 4-bromo-3-methyl-2-butenal (9 g, 107 mmol) and triethylamine (13 g) are introduced under an argon atmosphere into a 500-cc three-necked round-bottomed flask. The temperature is kept at 0° C. and bromotrimethylsilane (19.6 g) is then added over 20 minutes. The mixture is stirred for 2 days at a temperature in the region of 20° C. The pentane solution is sampled with a syringe and is then replaced with an equivalent quantity of pentane. The operation is repeated 4 times. The various pentane solutions are combined and the pentane is removed, any entry of air being excluded. The residue obtained is purified by distillation. 1-Bromo-2-methyl-4-trimethylsilyloxybutadiene (6.5 g) is thus obtained (B.P.0.25 =59° C.).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21]>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:15][C:14]=1[C:20]([F:21])([F:22])[F:23]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(C=O)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 4-chloro-3-(trifluoromethyl)phenol.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:18])[C:12]1=[O:26].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>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>[O:26]=[C:12]1[C:13]([C:17]([NH:19][C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[O:18])=[CH:14][CH:15]=[CH:16][N:11]1[CH:6]1[C:7]2[C:3](=[C:2]([C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1ccncc1)c1cccn(C2CCc3c(Br)cccc32)c1=O
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
Product: O=C(Nc1ccncc1)c1cccn(C2CCc3c(-c4cccnc4)cccc32)c1=O

Procedure:
2-oxo-1-(4-(pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide was prepared by heating a mixture of 1-(4-bromo-2,3-dihydro-1H-inden-1-yl)-2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (35.1 mg, 0.0855 mmol, 1.0 eq.), pyridin-3-ylboronic acid (12.8 mg, 0.104 mmol, 1.2 eq.), Pd(PPh3)4 (5.6 mg, 0.0048 mmol, 0.056 eq.), and potassium carbonate (15.1 mg, 0.109 mmol, 1.3 eq.) in 0.80 mL of dioxanes and 0.20 mL of H2O in a microwave at 140° C. for 5 min. The crude material was filtered through celite and the filtrate was purified by reverse phase HPLC using the method of 5-35% ACN/H2O in 40 min The purified material was concentrated and dried under vacuum to give 2-oxo-1-(4-(pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide as a clear colorless oil. Retention time (min)=8.051, method [8], MS (ESI) 409.2 (M+H); 1H NMR (300 MHz, CDCl3) δ 9.19 (m, 1H), 8.90 (m, 1H), 8.67 (m, 2H), 8.53 (m, 2H), 8.24 (d, J=7.1 Hz, 2H), 8.06 (m, 1H), 7.53 (m, 2H), 7.32 (m, 1H), 6.71 (t, J=7.7 Hz, 1H), 6.62 (t, J=7.1 Hz, 1H), 3.20 (m, 3H), 2.95 (m 1H), 2.19 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)=[N:4][C:3]=1[NH2:25].[CH3:26][C:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[C:8]([C:5]2[N:6]=[N:7][C:2]([C:31]3[CH:30]=[CH:29][N:28]=[C:27]([CH3:26])[CH:32]=3)=[C:3]([NH2:25])[N:4]=2)=[N:9]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1Cl
Reactant: Cc1cc(B(O)O)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: C1COCCO1
Product: Cc1cc(-c2nnc(-c3nn(Cc4ccccc4F)c4ncccc34)nc2N)ccn1
Reaction time: 0.17 h

Procedure:
Under an argon atmosphere, 140 mg (purity 65%, 0.256 mmol) of 6-chloro-3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1,2,4-triazine-5-amine were suspended in 5 ml of absolute dioxane. 105 mg (0.767 mmol) of (2-methylpyridin-4-yl)boronic acid, 1.023 ml (1.023 mmol) of 1N aqueous potassium carbonate solution and 14 mg (0.051 mmol) of tricyclohexylphosphine were added and argon was passed through the suspension for 10 min with stirring. Then, 28 mg (0.038 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride were added and the reaction mixture was stirred for 30 min in the microwave at 140° C. Again, 19 mg (0.026 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride were added and the reaction mixture was stirred for 40 min in the microwave at 150° C. After cooling, the mixture was filtered over an Extrelut cartridge and after-washed with a mixture of dichloromethane/methanol (v/v=20:1). The filtrate was concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 20:80→100:0). This gave 53 mg of the target compound (purity 92%; 41% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[C:33]1[S:34][CH:35]=[C:36]([CH3:38])[N:37]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:33]3[S:34][CH:35]=[C:36]([CH3:38])[N:37]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1csc(I)n1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1csc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)n1
Temperature: 90 °C
Reaction time: 43 h
Yield: 36 %

Procedure:
A mixture containing 3.2 mmol 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester, 15.9 mmol potassium carbonate, 3.8 mmol 2-Iodo-4-methyl-thiazole (CAS: 34203-25-3) and 0.1 mmol tetrakistriphenylphosphine in 11 ml deglazed DMF was stirred at 90° C. for 43 hours. The solvent was removed in vacuo. The residue was taken in ethyl acetate. The mixture was washed twice with water. The aqueous layer was extracted once with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was purified on a 50 g Flashpack cartridge (Eluent: Heptane/AcOEt) to afford the title compound as a white solid (36% yield). MS (m/e): 316.1 (M+, 100%)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[NH2:12])=[CH:4][C:3]=1[O:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(O)(=O)C.CN(C)C=O>[CH2:20]([N:17]1[CH2:18][CH2:19][CH:14]([O:13][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:2]=2[CH3:1])[C:9]([NH2:12])=[N:8][CH:7]=[CH:6]3)[CH2:15][CH2:16]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc2c(N)nccc2cc1OC1CCNCC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(N)nccc2cc1OC1CCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
A couple of drops of glacial acetic acid was added to a solution of 7-methyl-6-(piperidin-4-yloxy)isoquinolin-1-ylamine (30 mg, 0.117 mmol) in N, N-dimethylformamide (1 ml), followed by addition of benzaldehyde (50 μL). The mixture was then treated with sodium triacetoxyborohydride (100 mg) and stirred for 2 h. Water (1 ml) was added, the mixture was stirred for 30 min and then purified by prep-HPLC to give 6-(1-benzyl-piperidin-4-yloxy)-7-methylisoquinolin-1-ylamine (24 mg), El-MS: m/z=348.3 [M+H]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:27])[CH:20]=[C:21]([C:22]4[CH:26]=[CH:25][S:24][CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:28]=[N+:29]=[N-:30].[Na+]>>[N:28]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([Cl:27])[CH:20]=[C:21]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)[C:15]=2[O:14]1)=[N+:29]=[N-:30]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4ccsc4)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2cc(Cl)cc(-c3ccsc3)c2O1
Yield: 103.6 %

Procedure:
Treatment of (±)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.18 g, 0.43 mmol) with sodium azide (0.11 g, 1.72 mmol) generally according to the procedure described for Intermediate 98 provided 0.13 g of (±)-2-(azidomethyl)-5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (120 mg, 5 wt. %) generally according to the procedure described for Example 1 gave 0.11 g (85%) of (±)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a light yellow solid, hydrochloride salt. mp 230° C. (dec); Anal. calcd. for C13H12ClNOSHCl: C, 51.66; H, 4.34; N, 4.63. Found: C, 45.27; H, 4.19; N, 3.93.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]([NH:21][C:22](=[O:24])[CH3:23])[CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH:32]1[C:44]2[CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]=2[CH:35]=[CH:34][C:33]=1[N:45]=[C:46]=[O:47]>O1CCCC1>[CH:32]1[C:44]2[CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]=2[CH:35]=[CH:34][C:33]=1[NH:45][C:46]([N:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH:13]([NH:21][C:22](=[O:24])[CH3:23])[CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=2)[CH2:20][CH2:19]1)=[O:47]
Reactant: CC(=O)NC(COc1ccc2sc(C)nc2c1)CN1CCNCC1
Reactant: O=C=Nc1ccc2c(c1)Cc1ccccc1-2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC(COc1ccc2sc(C)nc2c1)CN1CCN(C(=O)Nc2ccc3c(c2)Cc2ccccc2-3)CC1
Temperature: 55 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
To a solution of N-[2-(2-methylbenzothiazol-5-yloxy)-1-(piperazinylmethyl)ethyl]-acetamide (18.4 mg) in tetrahydrofuran (1 ml) was added triethylamine (25.6 μl) and 2-fluorenyl isocyanate (9.5 mg). The reaction mixture was stirred at 55° C. for 4 hours, producing a white precipitate. The precipitate was filtered off, and solvent removed from the filtrate under reduced pressure. The residue was purified by thin layer chromatography, developing with 4% methanol/methylene chloride, to provide N-{2-[4-(N-fluoren-2-ylcarbamoyl)piperazinyl]-1-[(2-methylbenzothiazol-5-yloxy)methyl]ethyl}acetamide (11.2 mg), a compound of Formula I.
Reaction SMILES: [C:1](=[O:22])([O:3][C@H:4]([CH:8]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:5]([NH2:7])=[S:6])[NH2:2].C(=O)([O-])O.[K+].Cl[CH2:29][C:30](=[O:32])[CH3:31]>C(COC)OC>[C:1](=[O:22])([O:3][C@@H:4]([C:5]1[S:6][CH2:29][C:30]([OH:32])([CH3:31])[N:7]=1)[CH:8]([C:18]([CH3:19])([CH3:21])[CH3:20])[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[NH2:2]
Reactant: CC(=O)CCl
Reactant: CC(C)(C)C(c1c[nH]c2ccccc12)[C@@H](OC(N)=O)C(N)=S
Agent: O=C([O-])O
Agent: [K+]
Solvent: COCCOC
Product: CC1(O)CSC([C@H](OC(N)=O)C(c2c[nH]c3ccccc23)C(C)(C)C)=N1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A solution of (R)-tert-butyl-1-amino-3-(1H-Indol-3-yl)-1-thioxopropan-2-yl carbamate (6.49 g, 20.3 mmol) in anhydrous dimethoxyethane (100 mL) was mixed with powdered potassium hydrogencarbonate (10.1 g, 101 mmol) and chloroacetone (9.69 g, 8.4 mL, 101 mmol) and stirred for 8 h at 70° C. and over the weekend at 45° C. The reaction mixture was then filtered and the filtrate concentrated to low volume in a vacuum.
Reaction SMILES: C[O:2][C:3]([CH:5]([N:14]1[CH2:17][CH:16]([NH:18][C:19](=[O:45])[C:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH:33]([C:41]([O:43]C)=[O:42])[NH:34]C(=O)C(F)(F)F)=[CH:26][CH:25]=2)=[N:21][O:22][CH3:23])[C:15]1=[O:46])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:4].[OH-].[Na+]>CC(C)=O>[C:3]([CH:5]([N:14]1[CH2:17][CH:16]([NH:18][C:19](=[O:45])[C:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH:33]([NH2:34])[C:41]([OH:43])=[O:42])=[CH:26][CH:25]=2)=[N:21][O:22][CH3:23])[C:15]1=[O:46])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)([OH:4])=[O:2]
Reactant: CON=C(C(=O)NC1CN(C(C(=O)OC)c2ccc(OC)cc2)C1=O)c1ccc(OCCC(NC(=O)C(F)(F)F)C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CON=C(C(=O)NC1CN(C(C(=O)O)c2ccc(OC)cc2)C1=O)c1ccc(OCCC(N)C(=O)O)cc1
Reaction time: 0.08 h
Yield: 13 %

Procedure:
1-(α-Methoxycarbonyl-4-methoxybenzyl)-3-[2-[4-{3-methoxycarbonyl-3-(2,2,2-trifluoroacetamido)propoxy}phenyl]-2-methoxyiminoacetamido]-2-azetidinone (0.19 g.) was dissolved in acetone (2 ml.). 1 N-Sodium hydroxide aqueous solution (0.9 ml.) was added to the solution at ambient temperature, and the mixture was stirred for 5 minutes. The acetone was distilled off from the reaction mixture, and the remaining solution was adjusted to pH 3 with 10% hydrochloric acid. The separated oil material was isolated by decantation, washed with acetone and water, and then pulverized with acetonitrile to give 1-(α-carboxy-4-methoxybenzyl)-3-[2-{4-(3-amino-3-carboxypropoxy)phenyl}-2-methoxyiminoacetamido]-2-azetidinone (0.02 g.). Mp 170° to 176° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Yield: 97.8 %

Procedure:
To a solution of 10% Pd-C (5 g) in ethanol (500 ml) is added 1-(4-nitrobenzoyl)-1,2,3,4-tetrahydroquinoline (53.4 g) and the mixture is subjected to catalytic reduction at ordinary temperature under atmospheric pressure of hydrogen. After the reduction, 10% Pd-C is removed by filtration, and the filtrate is concentrated under reduced pressure to give 1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline (46.7 g) as yellow powder, m.p. 185°-188° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]([C:17]2[N:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][C:25]=1[CH3:33]>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([NH:14][C:15]([C:17]3[N:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:16])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:26][C:25]=1[CH3:33]
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnn1
Reactant: Cc1cc(B(O)O)ccc1Cl
Product: Cc1cc(-c2cc(NC(=O)c3cccnn3)cnc2OCC(F)(F)F)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example 39, using pyridazine-3-carboxylic acid[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 62 a) and B-(4-chloro-3-methylphenyl)-boronic acid (CAN 161950-10-3) as starting materials; LC-MS (UV peak area/ESI) 94.2%, 423.0828 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9](O[C@@H](C)CC)=[N:10][C:11]=2[NH2:17].FC(F)(F)C(O)=O.[CH3:30][C@@H:31]([NH:35]C1NC2C(N=C(OC)N=2)=C(N)N=1)[CH2:32][CH2:33][CH3:34].BrCCCCCl>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([NH:35][C@H:31]([CH3:30])[CH2:32][CH2:33][CH3:34])=[N:10][C:11]=2[NH2:17]
Reactant: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Reactant: CCC[C@@H](C)Nc1nc(N)c2nc(OC)nc-2[nH]1
Agent: ClCCCCBr
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Nc1nc(N)c2nc(OC)n(CCCCCl)c2n1

Procedure:
Prepared similarly to Intermediate 44 from N2-[(1R)-1-methylbutyl]-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate and 1-bromo-4-chlorobutane.
Reaction SMILES: [CH:1]1([C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[O-:6])[CH2:3][CH2:2]1.[Na+].CN1CCN(C)C1=O.[OH:21][C:22]1[CH:27]=[C:26]([Cl:28])[N:25]=[N:24][C:23]=1Cl.C1(C2C=CC=C(C)C=2O)CC1>C1(C)C=CC=CC=1.O>[Cl:28][C:26]1[N:25]=[N:24][C:23]([O:6][C:5]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:22]([OH:21])[CH:27]=1
Reactant: Cc1cccc(C2CC2)c1[O-]
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cc1cccc(C2CC2)c1O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN1CCN(C)C1=O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a mixture of 27.4 g (purity: 92.9%; 149 mmol) of sodium 2-cyclopropyl-6-methylphenoxide and 12.5 g of 1,3-dimethyl-2-imidazolidinone was added 2.5 g (purity: 98.5%; 14.9 mmol) of 4-hydroxy-3,6-dichloropyridazine at room temperature. Then, the resultant mixture was heated from room temperature to 140° C. to effect a reaction for 7 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 120 g of pure water and 100 g of toluene were added to the cooled mixture, and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. Then, the resultant aqueous phase containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was quantitatively determined by an HPLC internal standard analysis method, which showed that 3.58 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 86.9%) and 17 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.4%) were obtained.