Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].[Br:4][C:5]1[C:6]([F:23])=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15](I)=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:22]=1>CN(C=O)C.[Cu]I>[Br:4][C:5]1[C:6]([F:23])=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15]([C:1]#[N:2])=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:22]=1
Reactant: [C-]#N
Reactant: NC(=O)c1nc2n(c1I)CCOc1cc(F)c(Br)cc1-2
Agent: [Cu]I
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Temperature: 150 °C

Procedure:
Potassium Cyanide (0.8 eq) and Copper (I) Iodide (0.2 eq) were added to solution of 10-bromo-9-fluoro-3-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (0.05 g) in DMF (3 ml/mmol). The reaction was heated overnight at 150° C., filtered and purified by reverse phase hplc to give 10-bromo-3-cyano-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide. This intermediate was reacted with 2-Methyl-3-butyne-ol similar to as described in Procedure E to afford 12 mg of 3-cyano-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 355 (M)+. 1H NMR (400 MHz, DMSO) δ 8.69-8.56 (m, 1H), 8.04 (s, 1H), 7.64 (s, 1H), 7.14-7.00 (m, 1H), 5.51 (d, J=10.2 Hz, 1H), 4.63-4.57 (m, 2H), 4.56-4.49 (m, 2H), 1.49 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH2:11]O)=[CH:8][C:7]=2[CH:13]=1.P(Br)(Br)[Br:15]>C1(C)C=CC=CC=1>[Br:15][CH2:11][C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:13][C:7]=2[CH:8]=1
Reactant: COc1ccc2oc(CO)cc2c1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: COc1ccc2oc(CBr)cc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
Compound 25 (40 mg, 0.22 mmol) was dissolved in toluene (5 mL) and the solution was cooled to 0° C. PBr3 (21 μL, 0.22 mmol) was added dropwise over 10 min. The reaction mixture was then brought up to room temperature and stirred for 1 h. The solvent was evaporated off in-vacuo. The residue was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (4:1) to give 26 (40 mg, 74%) as an oil. 1H NMR (500 MHz, CDCl3): δ: 7.39 (1H, d, J=8.90 Hz, H-7), 7.01 (1H, d, J=2.55, H-4), 6.94 (1H, dd, J=6.35 & 2.60, H-6), 6.72 (1H, s, H-3), 4.61 (2H, s, 2-CH2), 3.86 (3H, s, OCH3).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:21]([CH2:22][O:23]CC2C=CC=CC=2)[S:20][CH:11](SCC2C=CC=CC=2)[CH2:10]1)C1C=CC=CC=1.BrBr.[CH2:33]([C:35]1[C:36](=[O:42])[NH:37][C:38](=[O:41])[NH:39][CH:40]=1)[CH3:34]>C(Cl)(Cl)(Cl)Cl.C[Si](C)(C)N[Si](C)(C)C.Cl[Si](C)(C)C.[Hg](Br)Br>[CH2:33]([C:35]1[C:36](=[O:42])[NH:37][C:38](=[O:41])[N:39]([CH:40]=1)[C@@H:11]1[S:20][C@H:21]([CH2:22][OH:23])[C@@H:9]([OH:8])[CH2:10]1)[CH3:34]
Reactant: CCc1c[nH]c(=O)[nH]c1=O
Reactant: c1ccc(COC[C@H]2SC(SCc3ccccc3)C[C@@H]2OCc2ccccc2)cc1
Agent: BrBr
Agent: Br[Hg]Br
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CO)S2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Benzyl 3,5-di-O-benzyl-2-deoxy-1,4-dithio-D-erythropentofuranoside (5.6 mmol) was dissolved in CCl4 (30 ml) and bromine (6.2 mmol) in CCl4 (30 ml) was added. After stirring for 5 min. at ambient temperature the solvent was evaporated and the residue re-evaporated from CCl4 (10 ml) to remove excess bromine. To a solution of this crude 1-bromothiosugar in CCl4 (15 ml) was added bis-O-trimethylsilyl-5ethyl uracil (16.6 mmol) [prepared by refluxing 5-ethyluracil (16.6 mmol) in a mixture of hexamethyldisilazane (50 ml) and chlorotrimethylsilane (5 ml) for 2 h., and evaporation of the solvents], HgBr2 (1.99 g; 5.5 mmol) and CdCO3 (2.36 g; 16.6 mmol). The solvent was evaporated and the residue heated at 100° C. for 1 h. The residue was worked up as for the thymidine analogue and the product purified by column chromatography. The benzyl ether protecting groups were removed by treatment with BCl3 as described for the 5-iodo analogue.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[C:24]1([NH:30][CH2:31][CH2:32][NH2:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>COCCOC>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:33][CH2:32][CH2:31][NH:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]=1[N+:16]([O-:18])=[O:17]
Reactant: NCCNc1ccccc1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Solvent: COCCOC
Product: Nc1nc(NCCNc2ccccc2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester and N-phenylethylenediamine in DME. ES-MS m/e (%): 363 (M+Na+, 20), 341 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:12])=[O:9])=[CH:4][C:3]=1[C:29]#[C:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH2:37])[CH:32]=1.[C:38]1([CH3:47])[CH:43]=[CH:42][CH:41]=[C:40]([C:44](O)=[O:45])[CH:39]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:12])=[O:9])=[CH:4][C:3]=1[C:29]#[C:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:44](=[O:45])[C:40]2[CH:41]=[CH:42][CH:43]=[C:38]([CH3:47])[CH:39]=2)[CH:32]=1
Reactant: COC(=O)CCCCS(=O)(CCCCC(=O)OC)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Reactant: Cc1cccc(C(=O)O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)CCCCS(=O)(CCCCC(=O)OC)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3cccc(C)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To the reaction solution of dimethyl 5,5′-[N-({6-amino-5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbonyl)sulfonimidoyl]dipentanoate (80 mg, 0.15 mmol, 1.0 equiv.), m-toluic acid (60 mg, 0.2 mmol, 1.3 equiv.), and DIPEA (0.11 mL, 0.6 mmol, 4.0 equiv.) in anhydrous DMF (1 mL) was added BOP (120 mg, 0.27 mmol, 1.8 equiv.) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for overnight. It was then diluted with EtOAc, washed with sat. aq. NaHCO3, aq. NH4Cl, and brine, and finally dried with anhydrous Na2SO4. The solution was decanted, concentrated, and the oily residue was subject to a gradient column chromatography (from EtOAc-Hex 1:3 to 4:1) to afford the title compound as clear oil (76 mg). 1H NMR (DMSO-d6) δ: 10.29 (s, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.07 (t, J=1.8 Hz, 1H), 8.04 (d, J=2.3 Hz, 1H), 7.79 (s, 1H), 7.74-7.78 (m, 2H), 7.38-7.46 (m, 4H), 7.00 (br. s., 2H), 3.54-3.63 (m, 10H), 2.41 (s, 3H), 2.39 (t, J=7.3 Hz, 4H), 1.71-1.86 (m, 4H), 1.64-1.71 (m, 4H)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([OH:14])[C@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26]Br.C([O-])(O)=O.[Na+]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([O:14][CH2:26][C:25]2[CH:28]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:30]=[C:23]([C:22]([F:21])([F:35])[F:36])[CH:24]=2)[C@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: O[C@H]1OCCN(Cc2ccccc2)[C@@H]1c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [I-]
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(CO[C@H]2OCCN(Cc3ccccc3)[C@@H]2c2ccccc2)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 59.1 %

Procedure:
To a suspension of 0.592 g (14.8 mmol) of Nail in 30 mL of dry THF at 0° C. was added 3.32 g (12.3 mmol) of 4-benzyl-2-(S) -hydroxy-3-(R)-phenyl-morpholine prepared in step A. After 15 min 0.915 g of tetrabutylammonium iodide (2.47 mmol) and 2.4 mL (13 mmol) of 3,5-bis(trifluoromethyl)benzyl bromide were added. The resulting mixture was stirred at ice-bath temperature for 1 h, then poured into saturated NaHCO3 solution and extracted with ethyl acetate (EtOAc). The organic layers were combined, washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the resiue was chromatographed on a Waters Prep500 HPLC system using 50% EtOAc/Hexane to isolate 3.6 g (59%) of 4-Benzyl-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine.
Reaction SMILES: C([O:8][C:9](=[O:37])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:36])[CH2:16][CH2:17][C:18](=[O:35])[C@@H:19]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.CO.[Pd]>[C:21]1([CH2:20][C@H:19]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:18](=[O:35])[CH2:17][CH2:16][C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]([OH:37])=[O:8])=[O:36])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)O
Yield: 89.9 %

Procedure:
To a stirred solution of the benzyl ester 10 (100 mg, 0.1968 mmol) in dry EtOAc-MeOH (3:1 ratio) (10 mL) was added 10% Pd/C (50 mg) and the resulting mixture stirred at room temperature under 1 atmosphere of hydrogen for 24 h. Filtration of the black Pd residue and evaporation of the filtrate gave a crude residue. Column chromatography on silica gel elution with 20% MeOH-EtOAc afforded (5S)-6-phenyl-5-[(tert-butyloxycarbonyl)-amino]-4-oxo-hexanoyl-L-proline 11a as a pale colourless oil (74 mg, 90%); Rf 0.23 (20% MeOH-EtOAc); IR (liquid film) ν 1720 (CO), 3000 (broad, COOH) cm−1; 1H NMR (300 MHz, CDCl3) δH 1.39 (9H, s, (CH3)3), 2.04 (2H, m, —CH2—), 2.44 (1H, br-s, —COOH), 2.62 (4H, m,), 2.94 (3H, m), 3.16 (1H, m), 3.60 (2H, m, —CH2N—), 4.52 (2H, m, 2×—CH—), 5.08 (1H, m, —NH—) and 7.14-7.35 (5H, m, Ar—H); 13C NMR (75 MHz, CDCl3) δC 21.0, 22.6, 24.7, 28.0, 29.2, 30.9, 31.4, 34.6, 46.9, 58.7, 60.4, 126.8, 127.0, 128.5, 128.7, 129.5, 136.4, 155.3, 171.8, 173.7, 207.5 and 208.0; HRMS m/z calcd for C22H30N2O6 (M+) 418.21734, found 418.21039.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[C:29]([N+:42]([O-:44])=[O:43])[CH:28]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:30]4[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][C:29]=4[N+:42]([O-:44])=[O:43])=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c([N+](=O)[O-])c1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: COc1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)c([N+](=O)[O-])c1
Yield: 1 %

Procedure:
4-[4-(3,4-Dichloro-phenyl)-thiazol-2-yl]-4′-methoxy-2′-nitro-biphenyl-2-carboxylic acid was prepared in 1% yield (for two steps) from 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6) and 2-(4-methoxy-2-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (available from Combi-Blocks Inc.) using General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode. 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.49 (s, 1H), 8.45 (s, 1H), 8.31-8.36 (m, 1H), 8.27 (d, J=7.9 Hz, 1H), 8.03-8.13 (m, 1H), 7.73-7.80 (m, 1H), 7.67 (s, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.37 (d, J=4.5 Hz, 1H), 3.92 (s, 3H).
Reaction SMILES: COC1C=CC=CC=1C[Mg]Cl.CN(C)C1SC2C=C(OC)C=CC=2C=1[C:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:29][CH:28]=1)=[O:26]>C1COCC1>[N:36]1([CH2:35][CH2:34][O:33][C:30]2[CH:29]=[CH:28][C:27]([CH:25]=[O:26])=[CH:32][CH:31]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Agent: COc1ccccc1C[Mg]Cl
Solvent: C1CCOC1
Product: O=Cc1ccc(OCCN2CCCCC2)cc1
Reaction time: 0.5 h
Yield: 257.9 %

Procedure:
Add a solution of 2-methoxybenzylmagnesium chloride (5 mL of 0.25 M/THF) to a stirred solution of (2-dimethylamino-6-methoxy-benzo[b]thiophen-3-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (500 mg, 1.14 mmol) in THF (5 mL) at −78° C. After 30 min, add additional 2-methoxybenzyl-magnesium chloride (5 mL). After 30 min, quench with water and dilute with iPrOH/CHCl3(1:3). Wash the organic phase with water and brine, dry over MgSO4, filter and concentrate to yield 6-methoxy-2-(2-methoxy-benzyl)-benzo[b]thiophen-3-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (686 mg). Use the crude product without further purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[CH:12]#[C:13][CH2:14]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:14]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:10])([F:11])[F:1])[C:13]#[CH:12]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(trifluoromethyl)phenol (50.0 g, 0.31 mol) and progargyl bromide (44.0 g, 0.37 mol) in ACN (500 mL) was added K2CO3 (51.0 g, 0.37 mol) and the mixture was stirred overnight at rt, concentrated, diluted with water and extracted with Et2O. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA=40/1) to give compound P33a (59.7 g, 97%) as an oil.
Reaction SMILES: [CH3:1][CH:2]1[S:6][CH:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:4][C:3]1=[O:13].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[H-].[Na+].[Na+].[Cl-]>CN(C)C=O>[CH2:19]([O:18][C:16]([CH2:15][N:4]1[C:3](=[O:13])[CH:2]([CH3:1])[S:6][CH:5]1[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:17])[CH3:20]
Reactant: CC1SC(c2cccnc2)NC1=O
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C(C)SC1c1cccnc1
Reaction time: 1 h
Yield: 55 %

Procedure:
5-Methyl-2-(3-pyridyl)thiazolidin-4-one (10 g, 51.5 mmol) and ethyl bromoacetate (6.85 ml, 61.8 mmol) were dissolved in dry dimethylformamide (50 ml), and 60% sodium hydride (2.16 g, 54.1 mmol) was added in limited amounts to the solution at 0° to 10° C. This reaction mixture was kept between those temperatures for 1 hour. The mixture, after addition of aqueous NaCl, was extracted with ethyl acetate. The extract was washed with aqueous NaCl, dried, and the solvent was removed in vacuo. The residue was chromatographed on silica gel, giving the cis-isomer (5.8 g) (compound No. 9) and the trans-isomer (2.1 g) (compound No. 10) of the title compound (55% yield). Compound No. 9: cis-isomer NMR (CDCl3, δ) [ppm]; 1.24 (3 H, t, J=7.2 Hz), 1.67 (3 H, d, J=7.1 Hz), 5.81 (1 H, s). IR (CHCl3) [cm-1 ]; 2950, 1740, 1683, 1587, 1575, 1441, 1370, 1014. Compound No. 10: trans-isomer NMR (CDCl3, δ) [ppm]; 1.25 (3 H, t, J=7.2 Hz), 1.68 (3 H, d, J=7.1 Hz), 5.83 (1 H, d, J=1.7 Hz). IR (CHCl3) [cm-1 ]; 2950, 1739, 1685, 1585, 1572, 1370, 1345, 1012.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.[O:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[O:7]1[CH2:12][CH2:11][CH:10]([NH:6][C:3]2[NH:4][CH:5]=[N:1][N:2]=2)[CH2:9][CH2:8]1
Reactant: Nc1nc[nH]n1
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: c1nnc(NC2CCOCC2)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.4 %

Procedure:
To a solution (70 mL) of 1H-1,2,4-triazol-3-amine (3.7 g) and tetrahydro-4H-pyran-4-one (5.2 g) in acetic acid was added sodium cyanoborohydride (14 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (0.92 g, 10%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:22])[C@H:6]([N:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[N+:18]([O-])=O)[C:9]2=[O:21])[CH3:7])[CH2:3][CH2:2]1.CO>[Pd]>[NH2:18][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH:16]=[CH:17][N:8]([C@H:6]([CH3:7])[C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:22])[C:9]2=[O:21]
Reactant: C[C@H](C(=O)NC1CC1)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: CO
Product: C[C@H](C(=O)NC1CC1)n1ccc2c(N)cccc2c1=O

Procedure:
(R)-N-Cyclopropyl-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)propanamide (0.6 g, 0.002 mol) was stirred with palladium 10% wt. on calcium carbonate (0.1 g, 0.00005 mol) in methanol (30 mL, 0.7 mol) under hydrogen (balloon) over 1 h at room temperature. The catalyst was filtered, the filtrate was concentrated to dryness gave a brown solid. MS m/z 271.7 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[CH:12][CH:11]=2)=[C:4]([CH3:19])[N:3]=1.[CH:20]([C:23]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[C:25]([CH:32]([CH3:34])[CH3:33])[C:24]=1[S:35](Cl)(=[O:37])=[O:36])([CH3:22])[CH3:21].C1N2CCN(CC2)C1.O>C1COCC1.C(#N)C>[NH2:1][C:2]1[N:7]=[C:6]([O:8][S:35]([C:24]2[C:25]([CH:32]([CH3:33])[CH3:34])=[CH:26][C:27]([CH:29]([CH3:31])[CH3:30])=[CH:28][C:23]=2[CH:20]([CH3:22])[CH3:21])(=[O:37])=[O:36])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[CH:12][CH:11]=2)=[C:4]([CH3:19])[N:3]=1
Reactant: Cc1nc(N)nc(O)c1Cc1ccc(CC#N)cc1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(N)nc(OS(=O)(=O)c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1Cc1ccc(CC#N)cc1
Temperature: 30 °C
Reaction time: 7 h

Procedure:
A suspension of the product from step (ii) (6.0 g, 23.6 mmol), 2,4,6-triisopropylbenzenesulfonyl chloride (9.28 g, 30.6 mmol) and DABCO (4.76 g, 42.5 mmol) in THF (48.0 g) was stirred at 30° C. for 7 hours. Water (9.6 g) was added to the mixture and the organic layer was separated and concentrated under reduced pressure to give a solid. The solid was dissolved in acetonitrile (57.0 g) and heated to 60° C. Water (36.0 g) was added to the solution and the mixture was stirred at 60° C. for 1 hour. Water (36.0 g) was added to the mixture and the mixture was cooled to 5° C. and stirred at 5° C. for 1 hour. The resulting precipitate was collected by filtration, washed duplicate with combined solution of water (9.0 g) and acetonitrile (3.6 g), and dried to give the subtitle is compound as a solid, 11.6 g.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([S:5][C:6]1[NH:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)=[O:4].[H-].[Na+].Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1>CN(C)C=O>[CH3:1][N:2]([CH3:17])[C:3]([S:5][C:6]1[N:7]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=2)[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)=[O:4]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CN(C)C(=O)Sc1nc(-c2ccccc2)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)Sc1nc(-c2ccccc2)cn1-c1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a solution of 0.25 g (1.0 millimole) of 2-(N,N-dimethylcarbamoylthio)-4-phenylimidazole in 10 ml of N, N-dimethylformamide was added 0.04 g (1.0 millimole) of sodium hydride, and the mixture was stirred at room temperature for 1 hour. Then, 0.16 g (1.0 millimole) of 2-chloro-5-nitropyridine was added to the mixture, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure and washed with water and ethyl acetate to obtain 0.27 g (yield=73%) of intended 2-(N,N-dimethylcarbamoylthio)-1-(5-nitropyridinyl)-4-phenylimidazole (compound No. 28) in the form of a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14]C(OC)=O)[C:9]1=[O:19])([CH3:4])([CH3:3])[CH3:2].[C:21]1(=[O:27])[O:26][C:24](=[O:25])[CH2:23][CH2:22]1>CN(C)C=O>[C:1]([O:5][C:6]([CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:24](=[O:25])[CH2:23][CH2:22][C:21]([OH:26])=[O:27])[C@:10]([CH3:14])([C:6]([O:5][CH3:1])=[O:20])[C:9]1=[O:19])=[O:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C[C@@H]1NCCN(CC(=O)OC(C)(C)C)C1=O
Reactant: O=C1CCC(=O)O1
Solvent: CN(C)C=O
Product: COC(=O)[C@]1(C)C(=O)N(CC(=O)OC(C)(C)C)CCN1C(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 192.7 %

Procedure:
A mixture of (S)-(3-methoxycarbonylmethyl-2-oxo-piperazin-1-yl)acetic acid tert-butyl ester (1.0 g) and succinic anhydride (0.7 g) in dimethylformamide (15 ml) was stirred for 5 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in water (10 ml) and purified by means of CHP-20 column chromatography (H2O→30% acetonitrile aqueous solution) to give the titled compound (1.3 g) as a colorless oily product.
Reaction SMILES: [Na].[NH2:2][C:3]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[Cl:14])=[CH:4][C:5]#[N:6].[C:15](=O)([O:19]CC)[O:16][CH2:17][CH3:18].Cl>C(O)C.O.C(OCC)(=O)C>[CH2:17]([O:16][C:15](=[O:19])[NH:2]/[C:3](/[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[Cl:14])=[CH:4]\[C:5]#[N:6])[CH3:18]
Reactant: CCOC(=O)OCC
Reactant: N#CC=C(N)c1ccc(F)cc1Cl
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)N/C(=C\C#N)c1ccc(F)cc1Cl

Procedure:
At 40° C., 982 mg (42.7 mmol) of sodium were dissolved in ethanol (53 ml). 5.6 g (28.5 mmol) of 3-amino-3-(2-chlor-4-fluorophenyl)prop-2-enonitrile and 7.4 g (62.7 mmol) of diethyl carbonate were added, and the reaction solution was stirred under reflux for 4 h. 200 ml of ethyl acetate and 150 ml of water were added to the reaction mixture, and the pH was adjusted to pH=5 with hydrochloric acid. The organic phase was separated off, dried over magnesium sulfate and concentrated on a rotary evaporator. Removal of the solvent gave 6.77 g (88% of theory) of the product as a mixture of E and Z isomers.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH:29]2[C:24]([CH2:25][N:26]([CH2:30][C:31]#[CH:32])[CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:23])([OH:22])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1.[H][H]>C(O)C>[CH3:33][C:2]1([CH3:1])[CH:29]2[C:24]([CH2:25][N:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:23])([OH:22])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1
Reactant: [H][H]
Reactant: C#CCN1CCC2C(=C3C(=CC(C(C)CCCc4ccc(F)cc4)=CC3(O)O)OC2(C)C)C1
Solvent: CCO
Product: CCCN1CCC2C(=C3C(=CC(C(C)CCCc4ccc(F)cc4)=CC3(O)O)OC2(C)C)C1

Procedure:
5,5-Dimethyl-8-(4-p-fluorophenyl-1-methylbutyl)-2-(2-propynyl)-10-hydroxy-1,2,3,4-tetrahydro-5H[1]benzopyrano [4,3-c]pyridin-10-ol was hydrogenated in ethanol using 5% palladium on carbon as a catalyst. When two equivalents of hydrogen were taken up, the catalyst was filtered and solution concentrated to give the desired product.