Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([N+:21]([O-])=O)[CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:6].CC(O)=O.C(OCC)C>C1COCC1.[Pt]>[NH2:21][C:19]1[CH:18]=[C:4]([CH:3]=[C:2]([Br:1])[CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:6]
Reactant: COCCOCCOCCNC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCCOCCOCCNC(=O)c1cc(N)cc(Br)c1
Reaction time: 5 h
Yield: 90 %

Procedure:
The product from step (i) above (1 kg, 2.56 mol) was dissolved in THF (3.5 L) and AcOH (500 mL) and hydrogenated at 3 MPa (30 bar) H2 at up to 60° C. with 5% Pt/C (30 g of JM type 18 MA, 55% water). Analysis after 5 hrs showed a 1:1 ratio of ArNHOH and ArNH2. The reaction reached completion after being left overnight, with 1H NMR analysis showing 3% des-bromo side product. The catalyst was filtered off, then the residue was diluted with ethyl acetate (3 L) and washed with 20% potassium carbonate solution (3.5 L). The organics were then dried, filtered and concentrated in vacuo to provide a residue that was then slurried in 5 volumes of diethyl ether overnight to reduce the level of the des-bromo species (<2% after the slurry). The sub-title compound was obtained in 90% yield with a purity of 86% by LC.
Reaction SMILES: [CH:1]1[S:5][CH:4]=[CH:3][C:2]=1[CH2:6][NH:7][CH2:8][CH:9](O)[C:10]1[C:15]([F:16])=[CH:14][C:13]([O:17][CH3:18])=[C:12]([O:19][CH3:20])[CH:11]=1.S(=O)(=O)(O)O>FC(F)(F)C(O)=O>[F:16][C:15]1[C:10]([CH:9]2[CH2:8][NH:7][CH2:6][C:2]3[CH:3]=[CH:4][S:5][C:1]2=3)=[CH:11][C:12]([O:19][CH3:20])=[C:13]([O:17][CH3:18])[CH:14]=1
Reactant: COc1cc(F)c(C(O)CNCc2ccsc2)cc1OC
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)c(C2CNCc3ccsc32)cc1OC
Yield: 69.5 %

Procedure:
1.16 g of α-[[(3-thenyl)amino]methyl]-6-fluoro-3,4-dimethoxybenzyl alcohol was dissolved in 11 ml of trifluoroacetic acid, and after adding thereto 0.31 ml of conc. sulfuric acid under ice cooling, the mixture was stirred for 4 hours. The reaction solution was concentrated, and chloroform and water were added to the residue. The mixture was basified by addition of 10 ml of conc. aqueous ammonia under ice cooling. The chloroform layer was collected after a separating procedure, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized form ethanol, affording 0.76 g of 7-(6-fluoro-3,4-dimethoxyphenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, m.p. 108°-111° C.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[CH:9]1([CH2:12]O)[CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)(=O)C>[CH:9]1([CH2:12][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)[CH2:11][CH2:10]1
Reactant: OCC1CC1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccn(CC2CC2)n1
Yield: 57.4 %

Procedure:
The 3-Nitro-1H-pyrazole (prepared in example 3, 255 mg, 2.26 mmol) was dissolved in tetrahydrofuran (11 mL) and cyclopropyl-methanol (163 mg, 2.26 mmol) was added followed by triphenylphosphine (592 mg, 2.26 mmol). While stirring, diisopropyl azodicarboxylate (667 μL, 3.39 mmol) was added dropwise. A mild exotherm was observed. The reaction continued to stir for 30 min. The solution was diluted with ethyl acetate (100 mL), washed with water (2×35 mL), 1.0 M aqueous hydrochloric acid solution (35 mL), saturated aqueous brine solution (35 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded 1-cyclopropylmethyl-3-nitro-1H-pyrazole (217 mg, 58%) as a yellow oil: H1-NMR (400 MHz, CDCl3) δ 0.44 (2H, qt, J=5.6 Hz), 0.73 (2H, qt, J=6.8 Hz), 1.30-1.40 (1H, m), 4.07 (2H, d, J=7.6 Hz), 6.89 (1H, d, J=2.8 Hz), 7.57 (1H, d, J=2.4 Hz).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(=O)([O-])[O-].[K+].[K+].[CH3:11][CH:12]1[CH2:18][C:17]2[CH:19]=[C:20]3[O:25][CH2:24][O:23][C:21]3=[CH:22][C:16]=2[C:15]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[C:28]([CH3:35])[CH:27]=2)=[N:14][N:13]1[C:36](O)=[O:37].[N-]1C=CN=C1>CN(C)C=O>[CH3:11][CH:12]1[CH2:18][C:17]2[CH:19]=[C:20]3[O:25][CH2:24][O:23][C:21]3=[CH:22][C:16]=2[C:15]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[C:28]([CH3:35])[CH:27]=2)=[N:14][N:13]1[C:36](=[O:37])[NH:4][O:3][CH3:2]
Reactant: CON
Reactant: Cc1cc(C2=NN(C(=O)O)C(C)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CONC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc3c(cc2CC1C)OCO3
Reaction time: 16 h
Yield: 77.1 %

Procedure:
2.03 g (25.0 millimoles) of methoxy-amine hydro-chloride and 3.45 g (25.0 millimoles) of potassium carbonate are stirred in 75 ml of anhydrous dimethyl formamide for half an hour whereupon 2.17 g (5.0 millimoles) of (±)-7,8-dihydro-8-methyl-5-(3-methyl-4-nitro-phenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-7-carboxylic acid-imidazolide are added. The reaction mixture is stirred for 16 hours, whereupon the solvent is evaporated at a pressure of 55 Pa. The residue is suspended in 100 ml of water, stirred for half an hour, washed with 50 ml of water and dried. The crude product is recrystallized from 30 ml of acetonitrile and washed with 10 ml of diethyl ether. Thus 1.59 g of the desired compound are obtained, yield 77%, mp.: 192–195° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([S:11]([CH2:13][CH:14]=[CH2:15])=[O:12])=[CH:7][C:5]=1[NH2:6])([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+].N.O>C(O)C>[CH2:13]([S:11]([C:8]1[CH:9]=[CH:10][C:4]([NH2:1])=[C:5]([NH2:6])[CH:7]=1)=[O:12])[CH:14]=[CH2:15]
Reactant: C=CCS(=O)c1ccc([N+](=O)[O-])c(N)c1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCS(=O)c1ccc(N)c(N)c1

Procedure:
To a suspension of 0.0075 mole of 2-nitro-5-(2-propenylsulfinyl)aniline in 75 ml of absolute ethanol under N2 there is added a solution of 4.9 g of Na2S2O4, 4.9 ml of concentrated NH3 and 30 ml of water. The mixture is refluxed for 15 minutes and an additional 0.4 g of Na2S2O4 is added. After 15 minutes of reflux the ethanol is evaporated. The aqueous residue is made basic (pH 12) and extracted with dichloromethane. The combined, dried extracts are evaporated and the resulting oily residue is used immediately in the next reaction.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH2:12][C@@H:11]([NH:23][C:24]2[CH:29]=[C:28]([NH:30][C@@H:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33][C@@H:32]3[O:40][CH3:41])[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(O)=O>C1COCC1.O>[Si:1]([O:8][C@@H:9]1[CH2:10][C@@H:11]([NH:23][C:24]2[CH:29]=[C:28]([NH:30][C@H:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33][C@H:32]3[O:40][CH3:41])[N:27]=[CH:26][N:25]=2)[CH2:12][C@@H:13]1[CH2:14][OH:15])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CO[C@H]1Cc2ccccc2[C@H]1Nc1cc(N[C@@H]2C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@H]1Cc2ccccc2[C@@H]1Nc1cc(N[C@H]2C[C@H](CO)[C@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a solution of N-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]-N′-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrimidine-4,6-diamine (0.188 g, 0.314 mmol) in THF (1.70 mL) and H2O (1.70 mL) was added AcOH (5.08 mL). The solution was stirred overnight then concentrated in vacuo and purified by flash chromatography (0 to 5% MeOH/EtOAc) to obtain the title compound (0.112 g, 74%). LC/MS: Rt=1.46 min, ES+ 485 (Formic Acid).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:13]([C:16]1[CH:17]=[N:18][C:19]([N:22]2[CH2:27][CH2:26][CH:25]([O:28][C:29]3[CH:34]=[CH:33][NH:32][C:31](=[O:35])[CH:30]=3)[CH2:24][CH2:23]2)=[N:20][CH:21]=1)[CH2:14][CH3:15].N1C2C(=CC=CC=2O)C=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O.C(Cl)Cl.[Cu]I>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([N:32]3[CH:33]=[CH:34][C:29]([O:28][CH:25]4[CH2:26][CH2:27][N:22]([C:19]5[N:18]=[CH:17][C:16]([CH2:13][CH2:14][CH3:15])=[CH:21][N:20]=5)[CH2:23][CH2:24]4)=[CH:30][C:31]3=[O:35])=[CH:3][CH:4]=2)[CH:12]=[N:11][CH:10]=[N:9]1
Reactant: CCCc1cnc(N2CCC(Oc3cc[nH]c(=O)c3)CC2)nc1
Reactant: Brc1ccc(-n2cncn2)cc1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(-n5cncn5)cc4)c(=O)c3)CC2)nc1
Temperature: 160 °C
Reaction time: 0.08 h
Yield: 32.8 %

Procedure:
A mixture of 1-(4-bromophenyl)-1H-1,2,4-triazole (45 mg, 0.20 mmol), 4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H) -one (58 mg, 0.18 mmol), quinolin-8-ol (11 mg, 0.074 mmol, Alfa Aesar), potassium carbonate (33 mg, 0.24 mmol), Copper(I) iodide (14 mg, 0.074 mmol, Alfa Aesar) in DMSO (2 mL) was heated under microwave condition at 160° C. for 30 min. The resulting mixture was diluted with H2O and extracted with EtOAc (2×). The combined organic layers were concentrated in vacuo to a green oil. The oil was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2 and then SiO2, 0 to 10% MeOH in CH2Cl2) to yield an off-white solid. The solid was dissolved in DCM and 1 eq of HCl (1N HCl in Et2O) was added, the resulting mixture stirred for 5 min and then concentrated in vacuo to give 27 mg of desired product as an off-white solid. MS (ESI) 458 (M+H).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH:26]=O)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[NH2:36][CH2:37][CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH2:26][NH:36][CH2:37][CH2:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3]
Reactant: NCCc1cccnc1
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc(-c2cc3cc(CNCCc4cccnc4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Yield: 66.3 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (100 mg, 0.200 mmol) was dissolved in acetonitrile (5.8 mL), and the solution was treated with 3-(2-aminoethyl)pyridine (0.235 mL, 2.00 mmol), acetic acid (0.229 mL, 4.00 mmol) and sodium triacetoxyborohydride (127 mg, 0.599 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=4/1) to obtain 4-methanesulfonyloxy-5-methoxy-7-{1-(tert-butoxycarbonyl)-5-[(2-(pyridin-3-yl)ethyl)aminomethyl]indol-2-yl}isoindolinone (80.5 mg, yield 66%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:15])[CH2:13]Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[OH-].[Na+]>CCOCC>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:13][CH:12]([CH3:15])[CH2:11][C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[CH2:19][CH2:18]1
Reactant: CC(CCl)Cc1ccc(C(C)(C)C)cc1
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(Cc1ccc(C(C)(C)C)cc1)CN1CCN(C)CC1
Yield: 93.6 %

Procedure:
533 g of 3-(4-tert.butylphenyl)-2-methylpropyl chloride and 714 g of 4-methylpiperazine were stirred for 7 hours at 140° C. and then cooled to +10° C. in an ice bath, and 400 ml of 50% strength sodium hyroxide solution were added slowly, followed by the addition of 500 ml of ether. The organic phase was separated off, dried over sodium hydroxide and distilled to give 640 g of 1-methyl-4-[3-(4-tert.-butylphenyl)-2-methylpropyl]-piperazine of boiling point 135°-140° C./0.3 mbar.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][C:13]2[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=2)=[CH:4][CH:3]=1.[CH2:23](Br)[CH:24]=[CH:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:23]([NH:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][C:13]2[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=2)=[CH:4][CH:3]=1)[CH:24]=[CH:25][CH3:26]
Reactant: COC(=O)c1nc(N)ccc1Oc1nc(OC)cc(OC)n1
Reactant: CC=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC=CCNc1ccc(Oc2nc(OC)cc(OC)n2)c(C(=O)OC)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 36.6 %

Procedure:
3.0 g (9.8 mmol) of methyl 6-amino-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate, 1.5 g (10.8 mmol) of 2-butenyl bromide and 1.6 g (11.8 mmol) of potassium carbonate were added to 10 ml of DMF, and the mixture was stirred at 100° C. for one hour. After completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate, dried and concentrated. Then, the obtained residue was purified by column chromatography and crystallized to obtain a solid, which was washed with diisopropyl ether to obtain the desired product as colorless prism crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([O:32][CH3:33])=[C:4]([C@H:8]([CH2:30][CH3:31])[CH2:9][C@@:10]([C:26]([F:29])([F:28])[F:27])([OH:25])[CH:11]=NC2C=C(F)C=C3C=2C=CC(C)=N3)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.C([O-])(O)=[O:39].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:3]([O:32][CH3:33])=[C:4]([C@H:8]([CH2:30][CH3:31])[CH2:9][C@:10]([OH:25])([C:26]([F:27])([F:28])[F:29])[CH:11]=[O:39])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: CC[C@H](C[C@@](O)(C=Nc1cc(F)cc2nc(C)ccc12)C(F)(F)F)c1cccc(F)c1OC
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1cccc(F)c1OC
Temperature: -40 °C

Procedure:
The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are dried over sodium sulphate and the solvent is removed in vacuo to give 205 mg of (2R,4R)-4-(3-fluoro-2-methoxyphenyl)-1-[(7-fluoro-2-methylquinolin-5-yl)imino]-2-(trifluoromethyl)-hexan-2-ol as a crude product. The crude imine is dissolved in 18 ml of CH2Cl2 and the solution is cooled to −40° C. 3.4 ml (3.4 mmol) of a 1 M BBr3 solution in dichloromethane are added slowly dropwise over 5 minutes and the mixture is allowed to warm to 0° C. over 1 hour, and after 30 minutes at 0° C. is poured onto a mixture of saturated NaHCO3 and ice. It is extracted repeatedly with ethyl acetate and the extracts are washed with saturated NaCl solution and dried over Na2SO4. Purification by column chromatography on silica gel (150 ml) with ethyl acetate affords 37 mg of product (analytical HPLC: Rt=9.2 min (Chiralcel OD 5μ, 250×4.6 mm, hexane/ethanol 10%, 1 ml/min flow rate) as the (−)-enantiomer.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@H:6]([NH:20][C:21](=[O:31])[CH2:22][CH2:23][C:24](=O)[NH:25][CH2:26][CH2:27][C:28]#[N:29])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C[Si]([N:70]=[N+:71]=[N-:72])(C)C>C1COCC1>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@H:6]([NH:20][C:21](=[O:31])[CH2:22][CH2:23][C:24]1[N:25]([CH2:26][CH2:27][C:28]#[N:29])[N:72]=[N:71][N:70]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)NCCC#N
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCc1nnnn1CCC#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
Next, to a solution of (R)-4-biphenyl-4-yl-3-[3-(2-cyano-ethylcarbamoyl)-propionylamino]-butyric acid ethyl ester (204 mg, 0.468 mmol) in THF (10 mL) at room temperature is added Ph3P (307 mg, 1.17 mmol) and the mixture is stirred at room temperature for 10 minutes. Then to the mixture at ice bath temperature is added DIAD (0.228 ml, 1.171 mmol) and trimethylsilyl azide (0.155 ml, 1.171 mmol). The resulting mixture is slowly warmed up to room temperature and stirred for 16 hours. The reaction mixture is concentrated under reduced pressure. The obtained residue is purified by flash chromatography (silica gel, 1% to 3% EtOH/DCM) to give (R)-4-biphenyl-4-yl-3-{3-[1-(2-cyano-ethyl)-1H-tetrazol-5-yl]-propionylamino}-butyric acid ethyl ester (137 mg, 64% yield). HPLC retention time=1.61 minutes (condition C); MS=461 (m+1).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[O:15][CH2:14]2)[NH:21][C:20]([CH2:25][CH3:26])=[CH:19]4)(=O)=O)=CC=1.[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[C:38]1[CH2:39][CH2:40][NH:41][CH2:42][CH:43]=1>CS(C)=O.C(OCC)(=O)C>[CH2:25]([C:20]1[NH:21][C:22]2[C:18]([CH:19]=1)=[C:17]1[O:27][CH:13]([CH2:12][N:41]3[CH2:42][CH:43]=[C:38]([C:32]4[C:31]5[C:35](=[CH:36][CH:37]=[C:29]([F:28])[CH:30]=5)[NH:34][CH:33]=4)[CH2:39][CH2:40]3)[CH2:14][O:15][C:16]1=[CH:24][CH:23]=2)[CH3:26]
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: CCc1cc2c3c(ccc2[nH]1)OC[C@H](COS(=O)(=O)c1ccc(C)cc1)O3
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCc1cc2c3c(ccc2[nH]1)OCC(CN1CC=C(c2c[nH]c4ccc(F)cc24)CC1)O3

Procedure:
A solution of 0.41 g (0.1.1 mmole) of [(2R)-8-ethyl-2,3-dihydro-7H-[1,4]-dioxino[2,3-e]indol-2-yl]methyl 4-methylbenzenesulfonate and 0.71 g (3.3 mmole) of 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 25 mL of DMSO were heated at 75-80° C. for 4 hours. The mixture was diluted with 300 mL of ethyl acetate, washed with 200 ml portions of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 0-2% methanol in methylene chloride as eluant. The product fractions were combined and concentrated in vacuum, and the residue triturated with ether/hexane (1:1) to give 0.090 g of the (S)-enantiomer of the title compound as a yellow solid hydrate, m.p. 81-82° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24](OC)=[O:25])=[C:12]2[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl.C(Cl)(=O)C(Cl)=O.[BH4-].[Na+]>O1CCCC1.CO.CN(C)C=O.COCCOC.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:13]([CH2:24][OH:25])=[C:12]2[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(-c2cccc(F)c2)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [BH4-]
Solvent: COCCOC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cn1c(CO)c(-c2cccc(F)c2)c2cc(OCc3ccccc3)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.8 %

Procedure:
To a solution of methyl 6-benzyloxy-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (5.97 g, 13 mmol) in tetrahydrofuran (50 mL) and methanol (50 mL) was added an aqueous solution (10 mL) of lithium hydroxide monohydrate (1.64 g, 39 mmol). The obtained mixture was refluxed under heating for 12 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (50 mL), and oxalyl chloride (1.0 mL, 12 mmol) and N,N-dimethylformamide (3 drops) were added thereto. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in tetrahydrofuran (30 mL). The obtained solution was added dropwise to a suspension of sodium tetrahydroborate (1.32 g, 35 mmol) in 1,2-dimethoxyethane (30 mL) at 0° C. The obtained mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 6-benzyloxy-4-(3-fluorophenyl)-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone (1.39 g, 32.2%) as crystals.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Br:19])=[CH:17][C:16]([C:20]([O:22]C)=[O:21])=[CH:15][C:14]=3[Br:24])[C:5]2=[N:4][C:3]=1[CH3:25].CO.[OH-].[Na+].Cl>O.O1CCCC1>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Br:19])=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:14]=3[Br:24])[C:5]2=[N:4][C:3]=1[CH3:25]
Reactant: COC(=O)c1cc(Br)c(COc2cccn3c(Br)c(C)nc23)c(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1nc2c(OCc3c(Br)cc(C(=O)O)cc3Br)cccn2c1Br
Temperature: 60 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a mixture of 3-bromo-8-(2,6-dibromo-4-methoxycarbonylbenzyloxy)-2-methylimidazo[1,2-a]pyridine (550 mg), methanol (10 ml) and tetrahydrofuran (5 ml) was added 1N aqueous solution of sodium hydroxide (1.135 ml), and the mixture was stirred for 1 hour at 60° C. The reaction mixture was adjusted pH 4 with 1N hydrochloric acid, and water was added thereto. The precipitate was collected by filtration to give 3-bromo-8-(2,6-dibromo-4-carboxybenzyloxy)-2-methylimidazo[1,2-a]pyridine (518 mg).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[Li]CCCC.[N+:13]([C:16]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:17]=1[CH:18]=[O:19])([O-:15])=[O:14]>O1CCCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:16]([N+:13]([O-:15])=[O:14])=[C:17]([CH:18]([OH:19])[C:3]#[C:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH:20]=1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C#CC(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(O)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
To a solution of ethyl propiolate (4.05 mL, 40 mmol) in tetrahydrofuran (125 mL) at −78° C. under nitrogen was added n-BuLi (2.5 mL, 40 mmol, 1.6 M in hexane). The reaction mixture was stirred at about −70° C. for 0.5 hours and then 2-nitro-5-chlorobenzaldehyde (6.75 g, 36.4 mmol) was added dropwise. The reaction mixture was stirred at 78° C. for 0.25 hours, warmed to −60° C., quenched with acetic acid (5 mL) and then warmed to room temperature. The reaction mixture was partitioned between ether (250 mL) and water (250 mL). The layers were separated and the organic layer was washed with brine (250 mL) and dried over Na2SO4. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography eluting with hexane/ethyl acetate (4:1) to afford 6.12 g (59%) of the title compound as a yellow oil which solidified on standing.