Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13].C1C[O:18][CH2:17]C1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[CH2:10]([NH:14][C:17](=[O:18])[CH:7]([OH:8])[C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1)[CH2:11][CH2:12][CH3:13]
Reactant: C1CCOC1
Reactant: Cc1ccc(C=O)cc1
Reactant: CCCCN
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: CCCCNC(=O)C(O)c1ccc(C)cc1
Reaction time: 0.08 h
Yield: 94 %

Procedure:
To a solution of p-tolualdehyde (131 mg, 1.0 mmol) and 1 (216 mg, 1.2 mmol) in acetonitrile (3 ml) was added n-butylamine (80 mg, 1.1 mmol) at 0° C. After stirring for 5 min, the reaction mixtures was added dropwise THF solution of tetrabutylammonium fluoride (1.0 N, 1.5 ml, 1.5 mmol), and then stirred at 0° C. for 20 min. The resulting reaction solution was concentrated and purified with silica gel column chromatography by using hexane-ethyl acetate (3/1) as an eluent to give N-butyl-2-hydroxy-2-(4-methylphenyl)acetamide as a colorless powder (218 mg, 0.94 mmol, 94%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].CN(C=O)C.[Br:16][CH2:17][C:18](Br)=[O:19]>O1CCOCC1>[Br:16][CH2:17][C:18]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])=[O:19]
Reactant: O=C(Br)CBr
Reactant: Nc1ccccc1C(=O)O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(CBr)Nc1ccccc1C(=O)O
Temperature: 0 °C
Reaction time: 5 h
Yield: 87.8 %

Procedure:
A solution of anthranilic acid (50 g, 364.6 mmol) in anhyd DMF (125 mL) and dioxane (125 mL) in a 1 L Morton flask equipped with a mechanical stirrer and a constant addition funnel was cooled with an ice-bath to 0° C. Freshly distilled bromoacetyl bromide (73.6 g, 31.77 mL, 364.6 mmol) was added dropwise keeping the internal temperature between 0-1.5° C. over a 2.5 hour period. After addition of the bromoacetyl bromide was completed, the ice-bath was removed and stirring at rt was continued for 5 h. The reaction mixture was cooled in an ice-bath and slowly diluted with water (300 mL). A white precipitate formed, which was filtered, washed sequentially with 5% HBr solution (500 mL) and water (500 mL), and then dried in a vacuum desiccator. Further drying in a vacuum oven at 60° C. afforded 82.61 g (87.8%) of the title compound as a white powder, mp 164.6-167.6° C. [lit 165.5-172° C. (Hoffman LaRoche U.S. Pat. No. 3,244,698)]; 1H NMR (DMSO-d6) δ 13.7 (bs, 1H), 11.60 (s, 1H), 8.44 (d, J=8.0, 1H), 8.00 (dd, J=8.0, J=1.6, 1H), 7.62 (dt, J=8.0, J=1.6, 1H), 7.21 (t, J=8.0, 1H); 4.26 (s, 2H); 13C NMR (DMSO-d6) δ 169.20, 165.05, 139.95, 134.08, 131.13, 123.46, 120.02, 117.09, 30.67; MS (EI, m/z) 256.9 (M+), 258.9 (M+ 2+).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[N:19][NH:20][CH:21]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[NH:19]1[CH:18]=[C:17]([C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)[CH:21]=[N:20]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=Cc1cnc(Br)s1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=Cc1cnc(-c2cn[nH]c2)s1
Temperature: 70 °C
Yield: 53.7 %

Procedure:
To a solution of 2-bromothiazole-5-carbaldehyde (500 mg, 2.6 mmol) in toluene (15 mL) and ethanol (7 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (606 mg, 3.1 mmol), 2M sodium carbonate solution (7.3 mL) and Pd(PPh3)4 (30 mg, 0.02 mmol). The reaction mixture was purged with argon for 15 min and the resulting mixture was heated at 70° C. for 4 h. The reaction mixture was concentrated, diluted with water (100 mL), and extracted with ethyl acetate (2×200 mL). The combined extracts were washed with brine solution (20 mL), dried over Na2SO4, filtered and concentrated to under vacuum to obtain crude product. The crude product was purified by flash chromatography (60-120μ; 50% ethyl acetate in hexane) to afford 2-(1H-pyrazol-4-yl)thiazole-5-carbaldehyde as yellow solid (250 mg, 54% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.49 (br s, 1H), 10.00 (s, 1H), 8.61 (s, 1H), 8.55 (s, 1H), 8.09 (s, 1H); LC-MS m/z calculated for [M+H]+ 180.02, found 180.1.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[S:10]1>O1CCCC1>[OH:27][C:24]1[CH:25]=[CH:26][C:21]([C:9]2([S:10][C:11]3[CH:12]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14](=[O:15])[N:13]([CH3:16])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[S:7]2)=[CH:22][CH:23]=1
Reactant: CN1C(=O)C(Cl)(c2ccc(O)cc2)Sc2ccccc21
Reactant: Sc1ccccc1
Solvent: C1CCOC1
Product: CN1C(=O)C(Sc2ccccc2)(c2ccc(O)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a stirred solution of thiophenol (6.7 ml) in tetrahydrofuran (15 ml), 2-chloro-3,4-dihydro-2-(4-hydroxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (4.0 g, compound No. 2) is added. The mixture is stirred for 3 hours at room temperature, and then concentrated in vacuo. The residue is purified by silica gel column chromatography to give 4.5 g (90.0%) of the titled compound.
Reaction SMILES: [C:1](NN)(=O)C.[Br:6][C:7]1[C:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:9][C:10]2[N:11]([C:13]([CH2:16][C:17]3[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)=[N:14][N:15]=2)[CH:12]=1>C(O)(=O)C.FC(C1C=CC=CC=1)(F)F>[Br:6][C:7]1[C:8]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[CH:9][C:10]2[N:11]([C:13]([CH2:16][C:17]3[C:18]([CH3:1])=[N:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=3)=[N:14][N:15]=2)[CH:12]=1
Reactant: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(Br)cn23)cn1
Reactant: CC(=O)NN
Solvent: CC(=O)O
Solvent: FC(F)(F)c1ccccc1
Product: Cc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(Br)cn12
Yield: 60 %

Procedure:
The title compound (61 mg, 60%) as a white powder was prepared from N′-(5-bromo-4-(4-chlorophenyl)pyridin-2-yl)-2-(2-methyl-6-trifluoromethyl)pyridin-3-yl)acetohydrazide (100 mg, 0.20 mmol) in glacial acetic acid (0.6 mL) and (trifluoromethyl)benzene (1.8 mL) by the procedures analogous to those described for 6-bromo-7-(4-chlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (Example 56D). LC/MS (method B): retention time 1.83 min, [M+H]+=481.0.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.Cl.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][NH:29][CH2:28]2>>[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][N:29]([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]1)[CH2:28]2
Reactant: Clc1ccc2c(c1)CNC2
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Agent: Cl
Product: O=C(O)c1ccnc(-c2cn(CCN3Cc4ccc(Cl)cc4C3)cn2)c1
Yield: 17 %

Procedure:
The title compound was prepared in 17% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 5-chloroisoindoline hydrogen chloride according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 3.08 (2H, t, J=5.9 Hz), 3.90 (2H, s), 3.92 (2H, s), 4.20 (2H, t, J=6.0 Hz), 7.24 (2H, s), 7.31 (1H, s), 7.56 (1H, d, J=4.8 Hz), 7.80 (1H, s), 7.88 (1H, s), 8.27 (1H, s), 8.61 (1H, d, J=4.9 Hz). [M+H] Calc'd for C19H17ClN4O2, 369. Found, 369.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=1.[H-].[Na+].F[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([N+:31]([O-:33])=[O:32])=[CH:23][CH:22]=1.O>C1COCC1.CCOC(C)=O>[N+:31]([C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([O:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH:5]=2)=[CH:22][CH:23]=1)([O-:33])=[O:32]
Reactant: CC(C)(C)OC(=O)Nc1cc(CCO)ccn1
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(CCOc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.6 %

Procedure:
To a solution of tert-butyl 4-(2-hydroxyethyl)pyridin-2-ylcarbamate (11) (6.00 g, 25.2 mmol) in THF (70 mL) was added sodium hydride (2.52 g, 63.0 mmol, 60 wt %) at 0° C. The bright yellow suspension was stirred for 20 min at 0° C. before the addition of 1-fluoro-4-nitronaphthalene (4.81 g, 25.2 mmol) in a single portion. After stirring at RT for 2 hr, water (100 mL) was added followed by EtOAc (100 mL). The solid formed between the layers was collected by filtration and the organic phase was washed with saturated aq NaHCO3 (100 mL), brine (100 mL) and dried. The volatiles were removed to give an orange solid. The solids were combined and triturated from MeOH (50 mL) to give tert-butyl 4-(2-(4-nitronaphthalen-1-yloxy)ethyl)pyridin-2-ylcarbamate (12) as a yellow solid (11.0 g, 98%): m/z 410 (M+H)+ (ES+).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1>CC#N.C(Cl)(Cl)Cl>[Br-:23].[F:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][O:26][CH2:25][CH2:24][N+:1]23[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)([CH2:3][CH2:2]2)[CH2:7][CH2:8]3)=[CH:33][CH:32]=1
Reactant: Fc1ccc(COCCBr)cc1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCOCc3ccc(F)cc3)(CC1)CC2
Product: [Br-]
Temperature: 60 °C
Yield: 16.8 %

Procedure:
1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (30 mg, 0.102 mmol) was added to a solution of 1-{[(2-bromoethyl)oxy]methyl}-4-fluorobenzene (33 mg, 0.143 mmol) in 2:3 CH3CN/CHCl3 (3 mL), and the reaction was heated at 60° C. for 96 h. The reaction was concentrated, and the crude product was washed with EtOAc (3×1 mL). The product was dried under high vacuum to give the title compound (9 mg, 16%). LC/MS ESI RT 1.89 min M+ 446
Reaction SMILES: C(N(CC)CC)C.Cl.[O:9]([NH2:11])[CH3:10].Cl[C:13]1[C:22]([C:23]([C:25](=[CH:31]N(C)C)[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:24])=[CH:21][C:20]2[C:15](=[CH:16][C:17]([F:36])=[C:18]([F:35])[CH:19]=2)[N:14]=1>ClC(Cl)Cl>[CH2:29]([O:28][C:26]([C:25]1[C:23](=[O:24])[C:22]2[CH:21]=[C:20]3[CH:19]=[C:18]([F:35])[C:17]([F:36])=[CH:16][C:15]3=[N:14][C:13]=2[N:11]([O:9][CH3:10])[CH:31]=1)=[O:27])[CH3:30]
Reactant: CON
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)cc2nc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(OC)c2nc3cc(F)c(F)cc3cc2c1=O
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 79.8 %

Procedure:
2.13 g of triethylamine are added to a suspension of 1.7 g of methoxylamine hydrochloride in 40 cm3 of trichloromethane. After stirring for 15 minutes at a temperature close to 20° C., 3.69 g of ethyl 2-(2-chloro-6,7-difluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate are added to the solution obtained and the mixture is stirred for 4 hours and a half at about 20° C. The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) at a temperature close to 50° C. The residue is taken up in 70 cm3 of ethanol and 3.6 g of triethylamine and the mixture is heated for 30 minutes at a temperature close to 75° C. After cooling to about 20° C., the precipitate obtained is drained and washed with 3 times 30 cm3 of ethanol. 2.67 g of 3-ethoxycarbonyl-7,8-difluoro-1-methoxy-4-oxo-1,4-dihydro-benzo [b][1,8]naphthyridine are obtained in the form of a pale yellow solid melting at 266°-268° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.C(O[C:32]1(O[Si](C)(C)C)[CH2:34][CH2:33]1)C.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][N:10]=[C:11]([N:19]3[CH2:20][CH2:21][N:22]([CH:32]4[CH2:34][CH2:33]4)[CH2:23][CH2:24]3)[C:12]=2[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: Clc1ccc(-c2n[nH]c(N3CCNCC3)c2-c2ccncc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Clc1ccc(-c2[nH]nc(N3CCN(C4CC4)CC3)c2-c2ccncc2)cc1
Reaction time: 0.08 h
Yield: 63 %

Procedure:
To a solution of 3-(4-chlorophenyl)-4-(4-pyridyl)-5-(4-piperazinyl)pyrazole (1.95 g; 5.8 mmoles; prepared as set forth in Example A-169) and acetic acid (3.6 g, 60 mmol) containing 5A molecular sieves (6 g) was added [(1-ethoxycyclopropyl)oxy]trimethylsilane (6 g, 35 mmol). After stirring for 5 minutes, sodium cyanoborohydride (1.7 g, 26 mmol) was added and the mixture was refluxed under a nitrogen atmosphere for 6 hours. The reaction mixture was filtered hot and the filtrate concentrated in vacuo. Water (50 mL) was added and the solution made basic with 2N sodium hydroxide. The resultant gel was extracted with dichloroethane and the combined organic extracts dried (MgSO4). Evaporation again yielded a gel which was treated with hot methanol. Upon cooling, the product crystallized to give 1.4 g (63%) of 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl)-4-cyclopropylpiperazine, m.p. 264-265° C. Anal. Calc'd. for C21H22ClN5.1.5H2O: C, 61.99; H, 6.19; N, 17.21. Found: C, 62.05; H, 5.81; N, 16.81.
Reaction SMILES: C(#N)C.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([F:22])=[C:9]([CH:11](Cl)[C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[CH:16]=2)[CH:10]=1.[BH4-].[Na+].[OH-].[Na+]>O>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([F:22])=[C:9]([CH:10]=1)[CH2:11][C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[CH:16]=1
Reactant: Fc1ccc(Br)cc1C(Cl)c1cc2ccccc2s1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Fc1ccc(Br)cc1Cc1cc2ccccc2s1
Temperature: 40 °C
Reaction time: 17.5 h
Yield: 80.9 %

Procedure:
Acetonitrile (1,260 ml) was added to 2-[(5-bromo-2-fluorophenyl)(chloro)methyl]-1-benzothiophene (265.69 g) and the mixture was heated to 40° C. The resulting solution was added to a water (1,260 ml) solution of sodium borohydride (113.0 g) and sodium hydroxide (14.9 g) at 59.0 to 67.9° C., followed by stirring at 24.1 to 67.5° C. for 17.5 hours. To the reaction mixture were added 36% hydrochloric acid (340.5 g), water (1,260 ml) and toluene (1,260 ml), and extraction was conducted. The organic layer was washed with a 5% aqueous sodium hydrogencarbonate solution (1,260 ml) and subjected to vacuum distillation to distil off the solvent. To the residue were added 2-propanol (378 ml) and methanol (756 ml), and the residue was dissolved with heating. To the solution was added, as a seed crystal, 2.7 g of the 2-(5-bromo-2-fluorobenzyl)-1-benzothiophene produced by the method of Reference Example 2, at 39.7° C., followed by stirring at 0.7 to 5.0° C. for 13 hours. The separated-out crystals were collected by filtration, washed with methanol (251 ml), and vacuum-dried to obtain, as white crystals, 2-(5-bromo-2-fluorobenzyl)-1-benzothiophene [194.05 g, yield: 80.9%, purity: 99% (HPLC)].
Reaction SMILES: [O:1]1[C:5]2[NH:6][CH2:7][C:8]3[N:9]([CH:11]=[CH:12][CH:13]=3)[CH2:10][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C(Cl)Cl.C(OCC)(=O)C>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([N:6]2[C:5]3[O:1][CH:2]=[CH:3][C:4]=3[CH2:10][N:9]3[CH:11]=[CH:12][CH:13]=[C:8]3[CH2:7]2)=[O:29])=[CH:31][CH:32]=1)([O-:23])=[O:22]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1cc2n(c1)Cc1ccoc1NC2
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2Cc2ccoc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.0 mmol of 9,10-dihydro-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine in 10 ml of methylene chloride under argon is added 1.5 mmol of triethylamine followed by ice bath cooling. A solution of 1.1 mmol of 4-nitrobenzoyl chloride in 5 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture is stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, 1N HCl, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give desired product as a solid.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:27]3[N:23]([C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:25][N:26]=3)[C:22]3[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=3[N:20]([CH2:38][C:39](=[O:52])[N:40]([CH:49]([CH3:51])[CH3:50])[C:41]3[CH:42]=[N:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=3)[C:19]2=[O:53])=[N:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:27]3[N:23]([C:24]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[N:25][N:26]=3)[C:22]3[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=3[N:20]([CH2:38][C:39]([N:40]([CH:49]([CH3:50])[CH3:51])[C:41]3[CH:42]=[N:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=3)=[O:52])[C:19]2=[O:53])=[N:9]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)c3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3n[nH]c4ccccc34)c3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product of Step A, 3-(6-{[isopropyl-(6-methoxy-pyridin-3-yl)-carbamoyl]-methyl}-5-oxo-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-4-ylmethyl)-indazole-1-carboxylic acid tert-butyl ester, was dissolved in CH2Cl2 (8 mL) and TFA (2 mL) was added. The reaction was stirred at room temperature for 24 hours and was concentrated in vacuo. Purification by medium pressure chromatography eluting with a solvent gradient (1% MeOH in EtOAc to 5% MeOH in EtOAc) provided 172 mg of 2-[4-(1H-indazol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. 1H NMR (CD3OD) δ 8.04 (d, 1H), 7.88 (d, 1H), 7.64 (m, 2H), 7.56 (d, 2H), 7.49 (t, 2H), 7.39 (q, 3H), 7.31 (t, 1H), 7.19 (t, 1H), 7.11 (t, 1H), 6.95 (d, 1H), 6.86 (m, 1H), 4.72 (m, 1H), 4.59 (m, 1H), 4.41 (t, 1H), 3.99-4.12 (m, 2H), 3.90 (m, 4H), 0.95 (m, 6H); MS 613.8 (M+1), 611.5 (m−1).
Reaction SMILES: NO.C(=O)/C=C/CC.[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(C)(C)C.C([Zn]CC)C.[C:24]([O:27]C(=O)C)(=[O:26])[CH3:25]>CCCCCC.C1(C)C=CC=CC=1>[C:24]([O:27][CH:16](/[CH:17]=[CH:18]/[CH2:13][CH3:9])[CH2:15][CH3:14])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1ccccc1
Agent: CC/C=C/C=O
Agent: CC[Zn]CC
Agent: NO
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC/C=C/C(CC)OC(C)=O
Reaction time: 48 h

Procedure:
A vial was charged with aminoalcohol 1 (0.0032 g, 0.011 mmol) prepared as in Example 1. To the vial was added 1.62 mL of a stock solution containing trans-2-pentenal (0.34 g), t-butylbenzene internal standard (0.25 g), 1 M diethylzinc in hexane (8.0 mL), and toluene (4.0 mL). After 48 h, acetic anhydride (0.200 mL) was added. After an additional 72 h, a sample of the solution was analyzed by gas chromatography at 80° C. on a Cyclodex B stationary phase. The product trans4hepten-3-yl acetate was formed 85% enantiomeric excess.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH2:22][CH2:21][C:20]=3[N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[C:18](=[O:37])[N:17]2[CH:38]([CH3:42])[C:39]([OH:41])=O)=[CH:12][CH:11]=1)#[N:9].F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.[CH2:65]([CH2:67][NH2:68])[OH:66]>CN(C)C=O>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH2:22][CH2:21][C:20]=3[N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:36])[F:34])[CH:28]=3)[C:18](=[O:37])[N:17]2[CH:38]([CH3:42])[C:39]([NH:68][CH2:67][CH2:65][OH:66])=[O:41])=[CH:12][CH:11]=1)#[N:9]
Reactant: NCCO
Reactant: CC(C(=O)O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C(=O)NCCO)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (55 μL, 0.40 mmol) is added to a solution of 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazolin-3(4H)-yl)-propanoic acid (intermediate 59, 50 mg, 0.10 mmol) in N,N-dimethylformamide, and the mixture is stirred for 10 min at room temperature. N,N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (33 mg, 0.10 mmol) is added, and the mixture is stirred for 15 min. Ethanolamine (15 μL, 0.25 mml) is added, and the mixture is stirred for 1 h, diluted with N,N-dimethylformamide and purified by preparative HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 39 mg; ESI mass spectrum [M+H]+=527; Retention time HPLC: 0.86 min (Z018_S04).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:16]#[N:17])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](O)([CH3:21])([CH3:20])[CH3:19].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:16]#[N:17])[C:13]([O:15][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)O
Reactant: N#CC(NC(=O)OCc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(C#N)NC(=O)OCc1ccccc1
Yield: 67.4 %

Procedure:
To a mixture of 2-benzyloxycarbonylamino-2-cyanoacetic acid (2.00 g, 8.54 mmol), toluene (20 ml) and t-butyl alcohol (6.33 g, 85.4 mmol), was added trifluoroacetic acid anhydride (7.17 g, 34.2 mmol) dropwise and the solution was stirred for half an hour. The reaction solution was neutralized by adding 10% NaOH aqueous solution (18 g), the organic layer was separated and washed with water three times, dried over sodium sulfate, insoluble materials were filtered and the filtrate was condensed to give t-butyl 2-benzyloxycarbonylamino-2-cyanoacetate (1.67 g, yield 67.4%) as a pale yellow oil.