Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]([CH3:15])[C@H:9]([CH:13]=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:16]([CH2:21][CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:18][CH2:19][CH3:20])=[O:17]>C(Cl)Cl.O>[C:1]([N:8]([CH3:15])[C@@H:9]([CH:10]([CH3:12])[CH3:11])/[CH:13]=[C:21](\[CH3:22])/[C:16]([O:18][CH2:19][CH3:20])=[O:17])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)[C@@H](C=O)N(C)C(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
To a solution of aldehyde 13 (1.75 g, 8.7 mmol) in dry CH2Cl2 (9.0 mL) under an argon atmosphere at room temperature was added (carbethoxyethylidene)triphenylphosphorane (4.19 g, 11.3 mmol) and stirring was continued for a 4 h. The reaction mixture was diluted with water (100 mL) and extracted with diethyl ether (3×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (100 mL), dried with magnesium sulfate and concentrated in vacuo. The crude oil was purified by flash chromatography (silica gel, 2:23 diethyl ether-pet. ether) to afford the required E-2-alkenoate 14 as a colourless oil (2.13 g, 82% yield). 1H-NMR (200 MHz, CDCl3) 0.74 (d, J=6 Hz, 3H, CH3), 0.79 (d, J=6 Hz, 3H, CH3), 1.17 (t, J=0.7 Hz, 3H, CH3), 1.34 (s, 9H, Boc-(CH3)3), 1.72 (m, 1H, CH), 1.78 (s, 3H, —CH3), 2.60 (bs, 3H, NCH3), 4.08 (q, J=7 Hz, 2H, CH2), 4.15-4.20 (m, 0.5H, CH), 4.21-4.32 (m, 0.5H, CH), 6.54 (d, J=8 Hz, 1H, CH); Exact mass calc'd for C16H30N04 (M+H)+: 300.21750; Found (DCI): 300.21754. Optical rotation obtained was [α]D25 +61.1 (c 9.1, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([F:19])=[C:15]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[NH:14][C:13]2=[O:27])=[C:4]([F:28])[CH:3]=1.[C:29](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([F:19])=[C:15]([C:20]([F:25])([F:26])[C:21]([F:24])([F:23])[F:22])[N:14]([CH3:29])[C:13]2=[O:27])=[C:4]([F:28])[CH:3]=1
Reactant: O=C([O-])O
Reactant: CC(C)Oc1cc(-n2c(=O)[nH]c(C(F)(F)C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CC(C)Oc1cc(-n2c(=O)c(F)c(C(F)(F)C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-fluoro-6-pentafluoroethyl-2,4(1H,3H)-pyrimidinedione in acetone with sodium bicarbonate and dimethyl sulphate there is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-fluoro-1-methyl-6-pentafluoroethyl-2,4(1H,3H)-pyrimidinedione, m.p. 107°-109° C.;
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][NH:14][C:13]1=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][O-].[Na+].Cl[O-]>ClCCl.O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][N:14]([Cl:17])[C:13]1=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-]Cl
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(N[C@H]1CN(Cl)C1=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of (S)-3-benzyloxycarbonylamino-2-azetidinone (440 mg) in dichloromethane (15 ml) was combined with a solution of borax (1.53 g) in water (10 ml) and cooled in an ice-bath to 0°-5° C. While stirring vigorously, a 5.07% solution of sodium hypochlorite (3.2 ml) was added; after 1 hour another portion (1.6 ml) of hypochlorite solutionwas added and stirring was continued for 1 hour at 0°-5° C. The organic layer was separated and the aqueous solution was extracted with dichloromethane. The combined extracts were dried (sodium sulfate) and solvent was removed in vacuo giving (S)-3-benzyloxycarbonylamino-1-chloroazetidin-2-one as an oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:26])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH:15]1[C:24]2[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1)[CH3:3].CCN(C(C)C)C(C)C.Cl[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38]>C(Cl)Cl>[CH2:40]([O:39][C:37]([N:16]1[CH2:17][CH2:18][C:19]2[C:24](=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:15]1[C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[O:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:26])=[O:38])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1NCCc2cc(F)ccc21
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(Cl)cc1C1c2ccc(F)cc2CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an-ice cooled solution of (±)-[4-chloro-2-(6-fluoro-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (900 mg, 2.25 mmol, 1.0 eq.) and DIPEA (1.16 mL, 6.75 mmol, 3.0 eq.) in DCM (30 mL), benzyl chloroformate (0.43 mL, 2.92 mmol, 1.3 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the solution was stirred at r.t. for 3 hours. The reaction was quenched with 1M aq. citric acid soln. (25 mL). The layers were separated. The aq. phase was extracted with DCM (3×50 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash master (column: 50 g, flow: 40 mL/min, Heptane+10% EtOAc to Heptane+50% EtOAc) to yield the title compound.
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[CH:10][C:9]([C:12]3[CH:25]=[CH:24][C:15]([O:16][C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=4)=[CH:14][CH:13]=3)=[N:8]2)=[CH:3][CH:2]=1.Br[C:28]1([CH2:37][CH2:38][O:39][CH2:40]C)[C:33](=[O:34])[NH:32][C:31](=[O:35])[NH:30][C:29]1=[O:36]>>[CH3:40][O:39][CH2:38][CH2:37][C:28]1([O:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[CH:24]=[CH:25][C:12]([C:9]4[CH:10]=[CH:11][N:7]([C:4]5[CH:3]=[CH:2][C:1]([CH3:26])=[CH:6][CH:5]=5)[N:8]=4)=[CH:13][CH:14]=3)=[CH:18][CH:19]=2)[C:29](=[O:36])[NH:30][C:31](=[O:35])[NH:32][C:33]1=[O:34]
Reactant: CCOCCC1(Br)C(=O)NC(=O)NC1=O
Reactant: Cc1ccc(-n2ccc(-c3ccc(Oc4ccc(O)cc4)cc3)n2)cc1
Product: COCCC1(Oc2ccc(Oc3ccc(-c4ccn(-c5ccc(C)cc5)n4)cc3)cc2)C(=O)NC(=O)NC1=O

Procedure:
By the same procedure as Example 1, Part C, 4-[4-(1-p-Tolyl-1H-pyrazol-3-yl)-phenoxy]-phenol and 5-bromo-5-(2-methoxyethyl)-pyrimidine-2,4,6-trione (from Preparation 3B) were converted to the title compound. MS m/z: ESI+ 527.2 (M+H)+, ESI− 525.4 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[Cl:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]([NH:18][C:12]2[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:10]([C:3]3[N:4]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:6][C:2]=3[Cl:1])[CH:11]=2)=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C(C)C
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)c(Cl)c2)cc1-c1c(Cl)cnn1C(C)C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a solution of 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1 g, 0.433 mmol) in CH2Cl2, was added 3-chloro-4-fluoro-phenyl isocyanate (0.082 g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 56 as a colorless solid (0.052 g, 28%). LCMS m/z (%)=439 M+H+ (37Cl, 29), 437 M+H+ (35Cl, 46), 1H NMR (400 MHz, acetone-d6) δ: 8.764 (bs, 1H), 8.673 (bs, 1H), 8.31-8.28 (m, 1H), 8.110 (d, J=2.72 Hz, 1H), 8.088 (d, J=2.71 Hz, 1H), 7.974 (s, 1H), 7.878 (d, J=2.68 Hz, 1H), 7.828-7.788 (m, 1H), 7.68-7.64 (m, 1H), 7.635-7.563 (m, 1H), 4.668 (m, 1H), 4.246 (s, 3H), 1.874 (d, J=6.61 Hz, 3H), 1.713 (d, J=6.61 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([Se:16][C:17]#[C:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.CCCCCCC>C1COCC1.[OH-].[Na+]>[CH3:1][C:2]1[C:3]([Se:16][C:17]#[C:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: COC(=O)c1ccc(C#C[Se]c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: Cc1cc2c(cc1[Se]C#Cc1ccc(C(=O)O)cc1)C(C)(C)CCC2(C)C
Yield: 80.4 %

Procedure:
In a manner similar to that of Example 7, by reaction of 1.35 g (3.07 mmol) of methyl 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-napthylselanylethynyl)benzoate in 20 ml of THF and 3 g of sodium hydroxide, and after trituration from heptane, 1.05 g (80%) of the expected compound are obtained in the form of a white solid. m.p.=240° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([OH:14])=O.[O:15]1[CH2:20][CH2:19][NH:18][C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]1=2>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:18]1[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[O:15][CH2:20][CH2:19]1)=[O:14]
Reactant: O=C(O)CSc1nc2ccccc2s1
Reactant: c1ccc2c(c1)NCCO2
Product: O=C(CSc1nc2ccccc2s1)N1CCOc2ccccc21
Yield: 78 %

Procedure:
The title compound was synthesized according to General Procedure B using 2-(benzo[d]thiazol-2-ylthio)acetic acid and 3,4-dihydro-2H-benzo[b][1,4]oxazine to yield 44 as a white solid (78%): MS m/z: 343 (M+H)+. Anal. Calcd. For, C17H14N2O2S2: C, 59.63; H, 4.12; N, 8.18; S, 18.73. Found: C, 59.73; H, 4.17; N, 8.18; S, 18.76.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].Br[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([Cl:16])=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:13][C:12]=2[CH:22]=1.CN(C)C=O>O1CCCC1>[Cl:16][C:15]1[C:11]2[CH:10]=[CH:9][C:8]([CH2:7][O:4][C:1]([CH3:2])=[O:3])=[CH:22][C:12]=2[S:13][C:14]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1sc2cc(CBr)ccc2c1Cl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1sc2cc(COC(C)=O)ccc2c1Cl
Temperature: 80 °C
Yield: 63 %

Procedure:
Sodium acetate (3.3 g, 40.5 mmol) was added to a stirred solution of ethyl 6-bromomethyl-3-chlorobenzo[b]thiophene-2-carboxylate (Preparation 10, 4.5 g, 13.5 mmol) in a mixture of anhydrous dimethylformamide (20 ml) and anhydrous tetrahydrofuran (10 ml), under a nitrogen atmosphere. The mixture was heated at 80° C. for 20 hours, then the mixture was partitioned between diethyl ether and water. The organic layer was separated and washed with more water, dried (magnesium sulfate), and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using dichloromethane as eluant to give the title compound as a colourless gum (2.66 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([CH3:19])[N:15]=2)=[CH:10][C:9]=1[OH:20].[CH2:21]([O:23][C:24]([C:26]1[C:27]2[S:35][CH:34]=[C:33]([CH2:36]Br)[C:28]=2[C:29]([Cl:32])=[N:30][CH:31]=1)=[O:25])[CH3:22]>O1CCCC1.CN(C)C=O>[CH2:21]([O:23][C:24]([C:26]1[C:27]2[S:35][CH:34]=[C:33]([CH2:36][O:20][C:9]3[CH:10]=[C:11]([C:14]4[O:18][N:17]=[C:16]([CH3:19])[N:15]=4)[CH:12]=[CH:13][C:8]=3[CH3:7])[C:28]=2[C:29]([Cl:32])=[N:30][CH:31]=1)=[O:25])[CH3:22]
Reactant: CCOC(=O)c1cnc(Cl)c2c(CBr)csc12
Reactant: Cc1noc(-c2ccc(C)c(O)c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4nc(C)no4)ccc3C)csc12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A suspension of cesium carbonate (1.02 g, 3.13 mmol), 2-methyl-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenol (0.42 g, 2.20 mmol) (from Example 52 supra) in tetrahydrofuran/N,N-dimethylformamide (5:2, 21 mL) was heated at 70° C. for 2 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.68 g, 2.04 mmol) (from Example 1 supra) was added. Heating was continued for 1 hour. The reaction mixture was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (2×). The combined organic phase washed with water and brine, dried (magnesium sulfate) and concentrated. The residue was purified by flash chromatography eluting with 5-10% ethyl acetate in dichloromethane to give 4-chloro-3-[2-methyl-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.51 g, 57%).
Reaction SMILES: C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[NH:22][CH:23]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]O)[CH:26]=1>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[N:22]([CH2:31][C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)[CH:23]=1
Reactant: OCc1cccnc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CN(C)C=O
Product: O=c1ncc(Cl)cn1Cc1cccnc1
Temperature: 90 °C

Procedure:
N,N-Dimethylformamide dineopentyl acetal (1.8 ml) was added to a stirred suspension of 5-chloropyrimidin-2-one (522 mg) and 3-pyridylcarbinol (0.55 ml) in dry N,N-dimethylformamide (10 ml) under nitrogen and the mixture was then heated at 90° C. After 1 h the reaction mixture was evaporated to a brown solid which was subjected to column chromatography on silica developing one eluting with chloroform-ethanol, 14:1. This gave a pale yellow solid which was crystallised from acetone to give off white needles of the title pyrimidinone (387 mg), m.p. 191°-193° C., λmax (EtOH) 229.5 nm (ε 8,930), 334 nm (ε 2,530).
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([C@@H:17]1[CH2:22][C@@H:21]([N:23]([CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH2:20][CH2:19][NH:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C>[CH2:10]([C@@H:17]1[CH2:22][C@@H:21]([N:23]([CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([F:27])([F:28])[F:26])[CH2:20][CH2:19][N:18]1[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=CCc1ccccc1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN(CCc2ccccc2)[C@H](Cc2ccccc2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
209 μl (0.936 mmol) of phenylacetaldehyde are added dropwise over the course of 10 minutes to a solution of 100 mg (0.233 retool) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine, 58 mg (0.702 mmol) of sodium acetate, 44 mg (0.702 mmol) of sodium cyanoborohydride and 67 μl (1.17 mmol) of acetic acid in 2 ml of ethanol at room temperature. The reaction mixture is left to stir at room temperature for 16 hours. The residue after evaporation in a rotary evaporator is taken up in ethyl acetate, and the organic phase is washed with water and with brine, dried over magnesium sulfate and evaporated to dryness. The yellow oil is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia (2000:50:1). The title compound is obtained as oil. TLC: methylene chloride/methanol/conc. ammonia (2000:50:1) Rf =0.33, FD-MS: M+ =531.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)[OH:4].[CH2:17]([N:19]1[C:23]2=[N:24][C:25]([CH2:47][CH3:48])=[C:26]([CH2:35][NH:36][C:37](=[O:46])[C:38]3[CH:43]=[CH:42][C:41]([CH:44]=O)=[CH:40][CH:39]=3)[C:27]([NH:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:22]2[CH:21]=[N:20]1)[CH3:18]>>[CH2:17]([N:19]1[C:23]2=[N:24][C:25]([CH2:47][CH3:48])=[C:26]([CH2:35][NH:36][C:37](=[O:46])[C:38]3[CH:39]=[CH:40][C:41]([CH2:44][NH:1][CH2:2][C@H:3]([OH:4])[C:5]4[CH:14]=[CH:13][C:12]([OH:15])=[C:11]5[C:6]=4[CH:7]=[CH:8][C:9](=[O:16])[NH:10]5)=[CH:42][CH:43]=3)[C:27]([NH:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:22]2[CH:21]=[N:20]1)[CH3:18]
Reactant: NC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(C=O)cc1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CNC[C@H](O)c2ccc(O)c3[nH]c(=O)ccc23)cc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 43, using Intermediate 4 in place of Intermediate 8 and Intermediate 31 in place of Intermediate 29.
Reaction SMILES: [H-].[Na+].[CH:3](=[C:10]1/[C:11](=[O:29])[NH:12][C:13](=[O:28])/[C:14]/1=[CH:15]/[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)\[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:30][O:31][CH2:32]Cl>CN(C)C=O>[CH3:30][O:31][CH2:32][N:12]1[C:13](=[O:28])/[C:14](=[CH:15]/[C:16]2[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=2)/[C:10](=[CH:3]\[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:11]1=[O:29]
Reactant: COc1cc(/C=C2/C(=O)NC(=O)/C2=C/c2ccccc2)cc(OC)c1OC
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCN1C(=O)C(=C/c2ccccc2)/C(=C\c2cc(OC)c(OC)c(OC)c2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a suspension of 63.2% sodium hydride (0.38 g) in dimethylformamide (10 ml) is added dropwise a solution of (3E,4E)-3-benzylidene-4-(3,4,5-trimethoxybenzylidene)-2,5-pyrrolidinedione (3.65 g) in dimethylformamide (10 ml) under ice-cooling, and the mixture is stirred at room temperature for one hour. To the mixture is added dropwise methoxymethyl chloride (0.84 ml) under ice-cooling, and the mixture is stirred at room temperature overnight. The mixture is evaporated to remove the solvent, and to the residue is added ethyl acetate. The mixture is washed, dried, and evaporated to remove the solvent. The resulting residue is purified by silica gel column chromatography (solvent; n-hexane:trichloromethane:ethyl acetate=5:5:4) to give (3E,4E)-1-methoxymethyl-3-benzylidene-4-(3,4,5-trimethoxybenzylidene)-2,5-pyrrolidinedione (3.0 g) as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:24])[CH2:9][C:10]([N:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][O:14][C:13]2=[O:23])=[O:11])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Br:34]N1C(=O)CCC1=O>ClCCl>[Br:34][C@H:9]([C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH3:24])[C:10]([N:12]1[C@H:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15][O:14][C:13]1=[O:23])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@H](CC(=O)N1C(=O)OC[C@H]1c1ccccc1)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccc(Br)cc1)[C@@H](Br)C(=O)N1C(=O)OC[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the product from Step B (2.87 g, 7.39 mmol) in dichloromethane (40 mL) was added N,N-diisopropylethylamine (1.93 mL, 11.1 mmol) and dibutylborontriflate (9.6 mL, 1M solution in dichloromethane, 9.60 mmol) at −78° C. The light yellow solution was stirred at −78° C. for 15 min, 0° C. for 1 h and recooled to −78° C. for 15 min. The above solution was transferred to a precooled suspension of N-bromosuccinimide (3.93 g, 22.2 mmol) in dichloromethane (40 mL) via cannula. The resultant mixture was stirred at −78° C. for 1 h and 0° C. for 3 h. The reaction was quenched by addition of 0.5N aqueous sodium bisulfite solution. The organic phase was separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic layers were washed with brine and concentrated in vacuo. Purification by flash chromatography (silica gel, 83:17 hexanes/ethyl acetate) afforded the desired product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:22]([C:24]1[CH:37]=[CH:36][C:27]([CH2:28][N:29]2[C:33]([CH:34]=O)=[CH:32][N:31]=[CH:30]2)=[CH:26][CH:25]=1)#[N:23].CCOC(C)=O>ClCCCl>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:29]2[C:33]([CH2:34][NH:6][CH2:5][C:4]([O:3][CH3:2])=[O:7])=[CH:32][N:31]=[CH:30]2)=[CH:36][CH:37]=1)#[N:23]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Reactant: COC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)CNCc1cncn1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of glycine methyl ester hydrochloride (595 mg, 4.74 mmol) in 1,2-dichloroethane at 0° C. was added 4 Å powdered molecular sieves (3 g), followed by sodium triacetoxyborohydride (1.51 g, 7.1 mmol). The 1-(4-cyanobenzyl)-5-imidazolecarboxaldehyde from Step E of Example 1 (1.00 g, 4.74 mmol) was added, and the reaction was stirred overnight, allowing it to warm to room temperature. The reaction was poured into EtOAc, washed with sat. aq. NaHCO3, and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was taken up in CH2Cl2, and propylamine (20 vol %) was added. The reaction was stirred for one hour, then concentrated in vacuo, and purified by silica gel chromatography (95:5; CHCl3:MeOH) to provide the titled amine product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3ccccc3s2)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2nc3ccccc3s2)cc1
Yield: 112.7 %

Procedure:
A mixture of 2-(4-nitrophenyl)benzothiazole (105 mg, 0.40 mmol) and tin(II) chloride dihydrate (205 mg, 0.91 mmol) in ethanol (20 mL) was refluxed under N2 for 4 hrs. After removing ethanol by vacuum evaporation. The residue was dissolved into ethyl acetate (20 ml), and washed with NaOH solution (1N, 3×20 ml) and water (3×20 ml), dried and evaporated to dryness to give 102 mg (97%) of the product
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.Br[CH2:31][CH:32]1[CH2:34][CH2:33]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:32]1([CH2:31][O:1][C:2]2[C:3](=[O:29])[C:4]([C:18]3[N:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:21]=[CH:20][CH:19]=3)=[N:5][N:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:9]=3)[CH:7]=2)[CH2:34][CH2:33]1
Reactant: BrCC1CC1
Reactant: O=c1c(O)cn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(OCC2CC2)cn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.1 %

Procedure:
A suspension of 5-hydroxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (100 mg, 0.25 mmol), (bromomethyl)cyclopropane (0.048 mL, 0.50 mmol), and K2CO3 (104 mg, 0.75 mmol) in DMF (1 mL) was stirred for 20 h at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane/AcOEt (1/1) and crystallized from MeOH to give the title compound (103 mg, 91% yield) as colorless prisms: mp 72-78° C.; 1H NMR (300 MHz, CDCl3): δ ppm 0.32-0.47 (2H, m), 0.60-0.76 (2H, m), 1.26-1.39 (1H, m), 4.06 (2H, d, J=7.2 Hz), 7.04 (1H, dd, J=2.3, 8.3 Hz), 7.18 (1H, s), 7.33-7.46 (7H, m), 7.55 (1H, d, J=7.9 Hz), 7.80 (1H, d, J=1.9 Hz), 7.99 (1H, s). LC-MS (ESI) m/z 453 [M+H]+. Anal. Calcd for C24H0F3N4O2.0.5H2O: C, 62.47; H, 4.37; N, 12.14. Found: C, 62.19; H, 4.41; N, 12.15.