Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].[C:26]([O:30][C:31](=[O:42])[NH:32][CH2:33][C:34]1[CH:39]=[C:38]([NH2:40])[CH:37]=[CH:36][C:35]=1[Br:41])([CH3:29])([CH3:28])[CH3:27].[Si:43]([O:50][C:51]1[C:52]([F:61])=[C:53]([CH:56]=[C:57]([CH2:59][CH3:60])[CH:58]=1)[CH:54]=O)([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44].C[Si]([C:66]#[N:67])(C)C>ClCCl>[C:26]([O:30][C:31](=[O:42])[NH:32][CH2:33][C:34]1[CH:39]=[C:38]([NH:40][CH:54]([C:53]2[CH:56]=[C:57]([CH2:59][CH3:60])[CH:58]=[C:51]([O:50][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[C:52]=2[F:61])[C:66]#[N:67])[CH:37]=[CH:36][C:35]=1[Br:41])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)OC(=O)NCc1cc(N)ccc1Br
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Product: CCc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(C#N)Nc2ccc(Br)c(CNC(=O)OC(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of Yb(OTf)3 (0.399 g) and dichloromethane (20 mL) there were added (5-amino-2-bromobenzyl)carbamic acid t-butyl ester (1.95 g), 3-(t-butyldimethylsilanyloxy)-5-ethyl-2-fluorobenzaldehyde (1.83 g), MS3A (2.6 g) and trimethylsilyl cyanide (1.29 mL) in that order under a nitrogen atmosphere, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, ethyl acetate (200 mL) and water (100 mL) were added to the residue, and after sufficiently shaking the mixture, the organic layer was separated off, washed with saturated aqueous sodium chloride (100 mL) and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane mixture) to obtain the target compound (3.09 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]([CH3:30])([C:14]2[N:18]([CH3:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])=[N:16][N:15]=2)[CH3:13])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C1C=N[C:34]2[N:37](O)N=N[C:33]=2[CH:32]=1.C1(N)CC1.O>CN(C=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]([CH3:30])([C:14]2[N:18]([CH3:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:27])([F:28])[F:29])=[N:16][N:15]=2)[CH3:13])=[C:6]([CH:10]=1)[C:7]([NH:37][CH:34]1[CH2:33][CH2:32]1)=[O:8]
Reactant: On1nnc2cccnc21
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)O
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: O
Product: Cl
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)NC1CC1
Reaction time: 2 h
Yield: 124 %

Procedure:
5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzoic acid (300 mg) was dissolved in DMF (9 ml), and WSC•monohydrochloride (200 mg), HOAt (140 mg) and cyclopropylamine (0.235 ml) were added thereto, followed by stiffing at room temperature for 2 hours. Water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and then saturated brine in this order, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting oily product was purified by silica gel column chromatography (chloroform:methanol=100:1). The resulting oily product was dissolved in ethyl acetate and 4M hydrogen chloride-ethyl acetate (1 ml) was added thereto, followed by concentrating under reduced pressure. The resulting solid was washed with ethyl acetate to obtain, as a white solid, 5-chloro-N-cyclopropyl-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzamide monohydrochloride (218 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:7][C:6]2=[C:16]([C:18]([OH:20])=O)[CH:17]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:45][C@H:46]1[CH:51]2[CH2:52][CH2:53][N:48]([CH2:49][CH2:50]2)[CH2:47]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:48]12[CH2:53][CH2:52][CH:51]([CH2:50][CH2:49]1)[C@H:46]([NH:45][C:18]([C:16]1[CH:17]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]3[O:9][C:8]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[N:7][C:6]=13)=[O:20])[CH2:47]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: COc1cc(C(=O)O)c2nc(-c3ccccc3)oc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N[C@@H]2CN3CCC2CC3)c2nc(-c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
A mixture of 6-methoxy-2-phenylbenzoxazole-4-carboxylic acid (50 mg, 0.18 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (71 mg, 0.37 mmol), 1-hydroxybenzotriazole (50 mg, 0.37 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (46 mg, 0.23 mmol) in DMF (3 mL) was stirred at room temperature for 10 min, then triethylamine (0.10 mL, 0.72 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-6-methoxy-2-phenylbenzoxazole-4-carboxamide (55 mg, 76%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.56 (d, J=7.2 Hz, 1H), 8.21-8.17 (m, 2H), 7.79 (d, J=2.5 Hz, 1H), 7.60-7.52 (m, 3H), 7.26-7.24 (m, 1H), 4.34-4.30 (m, 1H), 3.94 (s, 3H), 3.56-3.51 (m, 1H), 3.16-3.05 (m, 2H), 2.95-2.84 (m, 3H), 2.20-2.18 (m, 1H), 2.15-2.03 (m, 1H), 1.82-1.76 (m, 2H), 1.70-1.55 (m, 1H); MS (ESI+) m/z 378 (M+H); HPLC>99% (AUC), tR=12.90 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:22][OH:23])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26]I>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:22][O:23][CH3:26])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(=O)N1CCC(c2nc(CO)c(-c3ccc(F)cc3)o2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1nc(C2CCN(C(C)=O)CC2)oc1-c1ccc(F)cc1
Reaction time: 0.08 h
Yield: 75.7 %

Procedure:
A solution of 1-{4-[5-(4-fluoro-phenyl)-4-hydroxymethyl-oxazol-2-yl]-piperidin-1-yl}-ethanone (1.0 g; 3.14 mmol) in dry tetrahydrofuran (12 ml) is treated with sodium hydride (0.16 g; 4.09 mmol) in small portions. After 5 minutes, it is added methyl iodide (0.31 ml; 5.02 mmol) and the mixture is stirred for 45 minutes. The reaction is partitioned between ethyl acetate (40 ml) and water (15 ml). The aqueous phase is washed with ethyl acetate (15 ml). The combined organic phases are washed with saturated brine (10 ml), dried over sodium sulfate and concentrated to dryness. Purification by radial chromatography on silica gel using a methanol/ethyl acetate gradient (5%-20%) afforded the product as a light yellow oil (0.79 g; 75%). HNMR (CDCl3): 7.53 (m, 2H), 7.04 (t, 2H, J=8.7 Hz), 4.43 (m, 1H), 4.37 (s, 2H), 3.80 (m, 1H), 3.37 (s, 3H), 3.15 (m, 1H), 3.0 (ttt, 1H, J=10.8; 4.1 Hz), 2.79 (m, 1H), 2.04 (m, 2H), 2.02 (s, 3H), 1.77 (m, 2H). Mass spectrum: m/e calculated (MNa+)=355; observed (MNA+)=355.
Reaction SMILES: I[C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN([CH:48]=[O:49])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:22]([NH:25][C:48]([C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1)=[O:49])([CH3:24])[CH3:23]
Reactant: CN(C)C=O
Reactant: Cc1onc(-c2ccccc2)c1CNc1ccc(I)nn1
Reactant: CC(C)N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)NC(C)C)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
To a solution of (6-iodo-pyridazine-3-yl)-(5-methyl-3-phenyl-isoxazol-4ylmethyl)-amine (300 mg, 0.76 mmol) in DMF (3 mL) was added isopropylamine (0.66 ml, 7.6 mmol), triphenylphosphine (20 mg, 0.08 mmol) and palladium(II) acetate (17 mg, 0.08 mmol). The resulting mixture was stirred at room temperature for 16 h under a carbon monoxide atmosphere. After evaporation of the solvent the residue was extracted (ethyl acetate/water). The organic phase was dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 20:80) to afford the title compound (55 mg, 20%) as a light yellow oil. MS: m/e=352.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:20][NH:21][O:22][CH3:23].CN1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16](=[O:18])[N:21]([O:22][CH3:23])[CH3:20])[CH2:14][CH2:15]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)[C@H]1CC[C@H](CNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 81 g (314.77 mmol) trans-4-[(tert-Butoxyformamido)methyl]cyclohexanecarboxylic acid in 4 l CH2Cl2 was treated with 50.13 g (503.63 mmol) N,O-dimethyl-hydroxylamine hydrochloride, 55.37 ml (503.63 mmol) N-methylmorpholine and at 0° C. with 78.45 g (409.2 mmol) EDCI and 9.67 g (62.95 mmol) HOBT. The reaction mixture was stirred 16 h at room temperature, evaporated and extracted with aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried over Na2SO4 to yield 100.03 g (quantitative) of trans-[4-(Methoxy-methyl-carbamoyl)-cyclohexylmethyl]-carbamic acid tert-butyl ester, MS: 301 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:24]=[C:23]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: OB(O)c1cccc(Cl)c1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(Cl)c2)cn1
Yield: 29 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 3-chlorophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (49 mg, 29%) which was obtained as a white solid. MS (ESI): m/e=335.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][C@@H:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@H:16]1[NH:24][S:25]([CH3:28])(=[O:27])=[O:26].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:14][C@@H:15]1[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@H:16]1[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CS(=O)(=O)N[C@@H]1c2ccccc2C[C@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.2 %

Procedure:
5-Chloro-1H-indol-2-carboxylic acid (196 mg, 1.0 mmol), N-[(1R,2R)-2-amino-2,3-dihydro-1H-inden-1-yl]methanesulfonamide (Method 2; 226 mg, 1.0 mmol), DIPEA (0.17 ml, 1.0 mmol), and HOBT (130 mg, 1.0 mmol) was stirred in DCM (10 ml) for one minute. EDCI (240 mg, 1.25 mmol) was added and the mixture stirred at room temperature for 20 hours. The mixture was diluted with EtOAc, washed with water (2×25 ml), dried over magnesium sulphate and evaporated to give the title compound (320 mg, 79%) as a foam.
Reaction SMILES: COC1C=CC(COC2C(=O)[N:13]3[C:16]4(CCCCC4)[NH:17][C:18](=[O:19])[C:12]3=[C:11]([CH3:25])C=2)=CC=1.[CH2:28]([Li])CCC.Cl[C:34]1[CH:39]=[C:38](NC2N=CN=C(NC(C3CC3)=O)C=2)[C:37](=[O:53])[N:36]2[C:54]([C:59]3[CH:64]=[CH:63][CH:62]=C(F)C=3)([CH3:58])[NH:55][C:56](=[O:57])[C:35]=12>O1CCCC1>[CH3:28][C:34]1[CH:39]=[C:38]([C:18]([C:12]2[CH:11]=[CH:25][N:17]=[CH:16][N:13]=2)=[O:19])[C:37](=[O:53])[N:36]2[C:54]3([CH2:58][CH2:62][CH2:63][CH2:64][CH2:59]3)[NH:55][C:56](=[O:57])[C:35]=12
Reactant: COc1ccc(COc2cc(C)c3n(c2=O)C2(CCCCC2)NC3=O)cc1
Reactant: CC1(c2cccc(F)c2)NC(=O)c2c(Cl)cc(Nc3cc(NC(=O)C4CC4)ncn3)c(=O)n21
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)c2ccncn2)c(=O)n2c1C(=O)NC21CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6′-bromo-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-c]pyridine]-1′,5′-dione (2, 2 g, 6.43 mmol) in tetrahydrofuran (30 mL) at −78° C. is added n-butyllithium (1.6 M in hexanes, 12.06 mL, 19.29 mmol) dropwise, followed by N-methoxy-N-methylpyrimidine-4-carboxamide (1, 1.29 g, 7.72 mmol). The reaction is slowly warmed to room temperature and stirred for 4 h. The reaction is quenched via the slow addition of water. The mixture is warmed to room temperature and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated. The crude is purified via column chromatography to afford 8′-methyl-6′-(pyrimidine-4-carbonyl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (3).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:10])[CH3:9])[N:5]=[C:4]([O:11][CH3:12])[N:3]=1.[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1.C=O.[C:24](O)(=O)C>C(O)C>[N:13]1([CH2:24][NH:1][C:2]2[N:7]=[C:6]([N:8]([CH3:9])[CH3:10])[N:5]=[C:4]([O:11][CH3:12])[N:3]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1
Reactant: COc1nc(N)nc(N(C)C)n1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC(=O)O
Agent: C=O
Solvent: CCO
Product: COc1nc(NCn2nnc3ccccc32)nc(N(C)C)n1

Procedure:
With stirring, a mixture of 16.9 g (0.1 mole) of 2-amino-4-dimethylamino-6-methoxy-1,3,5-triazine, 12 g (0.1 mole) of benztriazole, 9.4 g (0.11 mole) of aqueous 35% formaldehyde and 1 g of acetic acid in 100 ml of ethanol is heated under reflux for 2 hours. The still hot solution is clarified by filtration and crystals of the title compound precipitate from the cooled solution. The precipitate is filtered with suction and dried, affording 25 g (83% of theory) of crystalline product with a melting point of 222°-224° C.
Reaction SMILES: C(OC([N:8]([C:13]1[CH:14]=[C:15]([C:20]2[CH:21]=[C:22]3[C:28]([C:29]4[C:30]([CH3:44])=[N:31][N:32]([CH2:35][C:36]5[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([F:43])[CH:37]=5)[C:33]=4[CH3:34])=[CH:27][N:26](C(OC(C)(C)C)=O)[C:23]3=[N:24][CH:25]=2)[CH:16]=[CH:17][C:18]=1[F:19])[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C>Cl.O1CCOCC1.CO>[F:42][C:40]1[CH:41]=[C:36]([CH:37]=[C:38]([F:43])[CH:39]=1)[CH2:35][N:32]1[C:33]([CH3:34])=[C:29]([C:28]2[C:22]3[C:23](=[N:24][CH:25]=[C:20]([C:15]4[CH:16]=[CH:17][C:18]([F:19])=[C:13]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])[CH:14]=4)[CH:21]=3)[NH:26][CH:27]=2)[C:30]([CH3:44])=[N:31]1
Reactant: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1-c1cn(C(=O)OC(C)(C)C)c2ncc(-c3ccc(F)c(N(C(=O)OC(C)(C)C)S(C)(=O)=O)c3)cc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(F)c(NS(C)(=O)=O)c3)cc12
Yield: 42.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 5-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-fluorophenyl)-3-(1-(3,5-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (88 mg, 0.121 mmol) was deprotected in HCl in dioxane/MeOH (5/2 ml). This afforded 27 mg (35% yield) of the titled compound. 1H NMR (CDCl3, 300 MHz): δ 13.6 (s, 1H), 8.42 (s, 1H), 8.26 (s, 1H), 7.80-7.77 (d, 1H), 7.50 (s, 1H), 7.33-7.32 (m, 2H), 6.79-6.69 (m, 4H), 5.33 (s, 2H), 3.09 (s, 3H), 2.24 (s, 3H), 2.18 (s, 3H). MS: m/z=526.2 (M+1), HPLC: 94.82% in method B.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:6]2[NH:7][CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:12])[N:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.[F:22][C:23]1[CH:24]=[C:25]([CH2:30][OH:31])[CH:26]=[CH:27][C:28]=1[F:29]>>[F:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:30][O:31][C:2]1[CH:11]=[C:6]2[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:12])[N:3]=1
Reactant: O=c1nc(Cl)cc2n1CCCN2
Reactant: OCc1ccc(F)c(F)c1
Reactant: Fc1ccc(CBr)cc1
Product: O=c1nc(OCc2ccc(F)c(F)c2)cc2n1CCCN2Cc1ccc(F)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for E2 starting from 8-chloro-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one, 1-(bromomethyl)-4-fluorobenzene and (3,4-difluorophenyl)methanol.
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[OH:3].[CH2:7]([NH2:10])[CH2:8][NH2:9]>O>[CH2:7]([NH:10][C:1](=[O:6])[CH:2]([CH3:4])[OH:3])[CH2:8][NH:9][C:1](=[O:6])[CH:2]([CH3:4])[OH:3]
Reactant: CC(O)C(=O)O
Reactant: NCCN
Solvent: O
Product: CC(O)C(=O)NCCNC(=O)C(C)O
Temperature: 125 °C

Procedure:
Lactic acid (441 g; 4.90 moles) was placed in a reaction flask equipped with a distillation head. Under a nitrogen atmosphere, ethylene diamine (147 g; 2.45 moles) was slowly added with stirring to the reaction flask. During the course of the addition, the reaction mixture turned a deep orange and the temperature reached 140° C. The reaction mixture was then heated at 150° C. overnight with the water being removed by distillation. The reaction mixture was allowed to cool to 125° C. then it was poured into an aluminum pan and allowed to cool to ambient temperature to provide 468 g of crude product. This material was recrystallized from methanol (1.9 L) to provide N,N'-1,2-ethanediylbislactamide, m.p. 188° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[C:14]([O:15][CH3:16])[CH:13]=1.[CH2:22]([NH2:25])[CH2:23][CH3:24]>CCO>[CH2:22]([NH:25][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[C:14]([O:15][CH3:16])[CH:13]=1)[CH2:23][CH3:24]
Reactant: COc1ccc(Cn2cnc3c(Cl)ncnc32)cc1OC
Reactant: CCCN
Solvent: CCO
Product: CCCNc1ncnc2c1ncn2Cc1ccc(OC)c(OC)c1

Procedure:
A reaction mixture containing 5.14 g (16.8 mmol) of 6-chloro-9-veratrylpurine, 7.0 ml (84.9 mmol) of propylamine and 60 ml of EtOH was refluxed for 2.5 hrs. Evaporation of the reaction mixture gave a residual solid which was recrystallized from acetone to give the crude product; yield 4.78 g (87.0%) mp 117°-120°. Further recrystallizations of the crude white material from acetone gave the analytical material; mp 122°-125°.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][N:13]3[C:17]4[C:18]([Cl:23])=[N:19][NH:20][C:21](=[O:22])[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][N:13]3[C:17]4[C:18]([Cl:23])=[N:19][N:20]([CH3:28])[C:21](=[O:22])[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:26][CH:27]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cn2ccc3c(=O)[nH]nc(Cl)c32)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1nc(Cl)c2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.6 %

Procedure:
In DMF (15 ml) was dissolved 1-[4-(4-chlorobenzoyl)benzyl]-7-chloropyrrolo [2,3-d]pyridazin-4(5H)-one (352 mg) followed by addition of potassium carbonate (858 mg). Then, methyl iodide (0.06 ml) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (200 ml). The organic layer was washed with water (100 ml) 3 times and saturated aqueous NaCl solution once and dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration, the solvent was distilled off under reduced pressure and the resulting crystals were rinsed with hexane to provide 290 mg (yield 80%) of the title compound.
Reaction SMILES: [ClH:1].[O:2]1[CH2:6][CH2:5][C:4](=O)[CH2:3]1.[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1.C(=O)C1OC=CC=1>>[O:2]1[CH2:6][CH2:5][CH:4]([NH:8][C@@H:9]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[C:18]4[C:19]([Cl:1])=[CH:20][N:21]=[CH:22][C:23]=4[CH:24]=[CH:25][CH:26]=3)(=[O:16])=[O:15])[CH2:10]2)[CH2:3]1
Reactant: N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reactant: Cl
Reactant: O=C1CCOC1
Solvent: O=Cc1ccco1
Product: O=S(=O)(c1cccc2cncc(Cl)c12)N1CC[C@@H](NC2CCOC2)C1

Procedure:
Hydrochloride of the compound obtained in Example 19-2 and tetrahydrofuran-3-one can be used in the method of Example 4-1 instead of hydrochloride of (S)-3-amino-1-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine and furfural, respectively, to obtain the title compound.
Reaction SMILES: [CH2:1]([C:3]1([CH3:19])[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[O:4]1)[CH3:2].C(O)(=O)C.[Br:24]Br>C(Cl)(Cl)(Cl)Cl>[Br:24][C:6]1[C:7](=[O:8])[C:3]([CH2:1][CH3:2])([CH3:19])[O:4][C:5]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: BrBr
Reactant: CCC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=CC1=O
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CCC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4.5 g of 2-ethyl-2-methyl-5-{4-(methylsufonyl)phenyl}-3(2H)-furanone dissolved in 100 ml carbon tetrachloride, were added acetic acid (3 ml) and bromine (1 ml). The reaction solution was stirred for 1 hour at room temperature. Then the reaction was quenched by adding saturated aqueous sodium thiosulfate solution until the characteristic color of bromine disappeared. The reaction solution was extracted with dichloromethane (30 ml×3) and the organic layer was concentrated in vacuo. The resulting residue was purified by column chromatographic separation (hexane/ethylacetate=1:1) to give 4 g of 4-bromo-2-ethyl-2-methy-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone. NMR: δ0.91 (t, J=7.2 Hz, 3H), 1.52 (s, 3H), 1.95 (qd, J=7.2, 3.0 Hz, 2H), 3.11 (s, 3H), 8.11 (d, J=8.7 Hz, 2H), 8.41 (d, J=8.7 Hz, 2H). IR (cm−1): 2928, 1703, 1583, 1316, 1160, 552.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[CH2:11]([CH:14]1[CH2:19][C:18](=O)[CH2:17][C:16](=[O:21])[CH2:15]1)[CH2:12][CH3:13].[CH3:22]/[C:23](/[NH2:27])=[CH:24]\[C:25]#[N:26]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:17]3[C:16](=[O:21])[CH2:15][CH:14]([CH2:11][CH2:12][CH3:13])[CH2:19][C:18]=3[NH:27][C:23]([CH3:22])=[C:24]2[C:25]#[N:26])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: CCCC1CC(=O)CC(=O)C1
Reactant: C/C(N)=C\C#N
Reactant: O=Cc1ccc(O)c(Br)c1
Solvent: CCO
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1ccc(O)c(Br)c1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of 3-bromo-4-hydroxy-benzaldehyde (13.07 g), 5-propylcyclohexane-1,3-dione (10.02 g) and 3-aminocrotonitrile (5.34 g) in ethanol (165 ml) was stirred at 80° C. for 17 h. A precipitate formed, which was collected by filtration. The filtrate was concentrated in vacuo and then triturated with ethyl acetate. The solids were combined and dried in vacuo.