Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[CH2:35]([O:37][CH2:38][CH2:39][N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[N:49]1[CH2:55][CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)[CH3:36].C(N(CC)C(C)C)(C)C.CO.C(OCC)(=O)C>C(#N)C.C(OCC)(=O)C>[CH3:33][O:32][C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:52]2[CH2:53][CH2:54][CH2:55][N:49]([C:41]3[N:40]([CH2:39][CH2:38][O:37][CH2:35][CH3:36])[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)[CH2:50][CH2:51]2)([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3cccc(Cl)c3)C2)cc(OC)c1OC
Agent: I
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOCCn1c(N2CCCN(CCC3(c4cccc(Cl)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 48 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3-chlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.82 g, 1.65 mmol), 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (1.04 g, 1.91 mmol), and N,N-diisopropylethylamine (1.3 mL, 7.43 mmol) in acetonitrile (50 mL). Heat to reflux. After 2 days, cool and dilute the reaction mixture with ethyl acetate (300 mL). Extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 24% methanol/ethyl acetate containing concentrated aqueous ammonia (20 mL/3L) to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][C:16]([CH3:26])([CH2:19][C:20]1([CH3:25])[O:24][CH2:23][CH2:22][O:21]1)[CH2:17][NH2:18].C(N(CC)CC)C>ClCCl>[CH3:15][C:16]([CH3:26])([CH2:19][C:20]1([CH3:25])[O:21][CH2:22][CH2:23][O:24]1)[CH2:17][NH:18][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)(CN)CC1(C)OCCO1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CNc1c([N+](=O)[O-])cnc2ccccc12)CC1(C)OCCO1
Yield: 99.9 %

Procedure:
The general method described in Part A of Example 28 was used to react 4-chloro-3-nitroquinoline (21.8 g, 104 mmol), 2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propylamine (19.8 g, 114 mmol) and triethylamine (15.2 g, 150 mmol) in dichloromethane for 75 hours to provide [2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-(3-nitroquinolin-4-yl)amine (35.9 g) as a yellow solid that was used directly in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:14][CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[CH:20][C:19]=2[Cl:32])[OH:17])[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]>C(O)C.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:14][CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=2[Cl:32])[OH:17])[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(CC(C)NCC(O)c2ccc(OCc3ccccc3)cc2Cl)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(CC(C)NCC(O)c2ccc(O)cc2Cl)cc1

Procedure:
N-(2-[4-Carbomethoxyphenyl]-1-methylethyl)-2-(4-benzyloxy-2-chlorophenyl)-2-hydroxyethanamine was hydrogenated in ethanol at atmospheric pressure and room temperature in the presence of 5% palladium on charcoal. The catalyst was removed and the product was recrystallised as the hydrochloride from ethyl acetate as a 28:72 mixture of diastereoisomers, mp 194°-195°. τ (d6DMSO) 8.79 (3H, d, J=6 Hz), 6.20-7.50 (6H, m), 6.16 (3H, s), 4.67 (1H, m), 2.30-3.30 (5H, m), 2.07 (2H, d, J=8 Hz), 0.67 (1H, br).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C.[Ti+4]>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][C:10](=[O:11])[NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)=[CH:15][CH:14]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: N#Cc1cccc(N=C=O)c1
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: N#Cc1cccc(NC(=O)OCCc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
Titanium tetra-tert-butoxide (0.080 mL, 0.21 mmol) was added dropwise to a solution of 3-cyanophenylisocyanate (228 mg, 1.58 mmol) and 2-(4-bromophenyl)ethanol (606 mg, 3.01 mmol) in toluene (10 mL). A precipitate formed immediately and the reaction was stirred for 2 h at rt. The reaction was quenched with saturated ammonium chloride solution and extracted with DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo. The residual solid was triturated with DCM hexane to give 11A (543 mg, 100%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.95 (t, J=6.81 Hz, 2 H), 4.38 (t, J=6.81 Hz, 2 H), 6.68 (s, 1 H), 7.11 (d, J=8.35 Hz, 2 H), 7.31-7.35 (m, 1 H), 7.38 (t, J=7.91 Hz, 1 H), 7.44 (d, J=8.35 Hz, 2 H), 7.52 (d, J=7.03 Hz, 1 H), 7.76 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15](B(O)O)[CH3:16].C([O-])([O-])=O.[K+].[K+].CC(=O)OCC>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:15]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH3:16]
Reactant: CCB(O)O
Reactant: CS(=O)(=O)c1ccc(Br)c([N+](=O)[O-])c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Yield: 41.1 %

Procedure:
bromo-4-methylsulfonyl-2-nitrobenzene (2 g, 7.0 mmol), ethylboronic acid (0.57 g, 7.7 mmol), K2CO3 (3.0 g, 21 mmol), Pd(dppf)Cl2 (0.29 g, 0.35 mmol) in 1,4-dioxane/water (4:1) (24 mL) were heated at 85° C. under N2 overnight. Silica gel chromatography (PE:EA=6:1) gave the title compound (0.66 g, 40%) as a brown solid.
Reaction SMILES: N#N.C([SiH2][O:8][C:9](C)(C)[C:10]1[S:11][CH:12]=[C:13]([C:15]2([CH3:20])[O:19][CH2:18][CH2:17][O:16]2)[N:14]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[CH3:20][C:15]1([C:13]2[N:14]=[C:10]([CH2:9][OH:8])[S:11][CH:12]=2)[O:19][CH2:18][CH2:17][O:16]1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1nc(C2(C)OCCO2)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(c2csc(CO)n2)OCCO1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(tert-butyl-dimethyl-silanyloxymethyl)-4-(2-methyl-[1,3]dioxolan-2-yl)-thiazole (1.30 g, 4.12 mmol) in dry THF (10 mL) was treated at 0° C. with TBAF (6.2 mL of a 1M solution in THF, 6.20 mmol). The reaction mixture was stirred at 0° C. for 5 min and at rt for 1 h30. The mixture was then diluted with EA (10 mL), washed with brine (3×10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (5:1->1:3 hept-EA) gave the title compound as a yellow oil. TLC:rf (1:2 hept-EA)=0.20. LC-MS-conditions 02: tR=0.59 min; [M+H]+=202.48.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([OH:12])=O)[S:7][C:6]=2[C:13]=1[N+:14]([O-:16])=[O:15].S(Cl)(Cl)=O.[C:23]1([CH3:29])C=CC=CC=1>CN(C)C=O>[OH:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([N:14]3[CH2:29][CH2:23][O:1][CH2:2][CH2:13]3)=[O:12])[S:7][C:6]=2[C:13]=1[N+:14]([O-:16])=[O:15]
Reactant: COc1cc2cc(C(=O)O)sc2c([N+](=O)[O-])c1O
Reactant: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc2cc(C(=O)N3CCOCC3)sc2c([N+](=O)[O-])c1O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
6-Hydroxy-5-methoxy-7-nitro-benzo[b]thiophene-2-carboxylic acid (2.7 g) was dissolved in toluene (45 ml). Thionyl chloride (1.2 ml) and N,N-dimethylformamide (4 drops) were added. The solution was stirred at 80° C. for two hours and after that it was evaporated. The residue was dissolved into dichloromethane (45 ml) and morpholine (1.4 ml) and triethylamine (1.2 ml) added. The reaction solution was stirred at room temperature overnight. The solution of water and 2M HCl was added to the solution. The solid was washed with water and dried under vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C@@H:13]3[CH:17]=[C:16]([CH:18]4[CH2:20][CH2:19]4)[CH2:15][NH:14]3)[NH:11][CH:12]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:30][O:31][C:32]([NH:34][C@@H:35]([CH:39]([CH3:41])[CH3:40])[C:36](O)=[O:37])=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:30][O:31][C:32](=[O:33])[NH:34][C@H:35]([C:36]([N:14]1[CH2:15][C:16]([CH:18]2[CH2:20][CH2:19]2)=[CH:17][C@H:13]1[C:10]1[NH:11][CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[N:9]=1)=[O:37])[CH:39]([CH3:41])[CH3:40]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: Brc1ccc(-c2c[nH]c([C@@H]3C=C(C4CC4)CN3)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CC(C2CC2)=C[C@H]1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-bromo-phenyl)-2-((S)-4-cyclopropyl-2,5-dihydro-1H-pyrrol-2-yl)-1H-imidazole (1.8 g, 5.45 mmol) in DCM (30 mL) was added DIPEA (3.52 g, 27.25 mmol), (S)-2-methoxycarbonylamino-3-methyl-butyric acid (1.14 g, 6.54 mmol) and HATU (2.49 g, 6.54 mmol). The mixture was stirred at RT overnight washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated. The resulting material was combined with the product of a separate batch prepared at the 0.61 mmol scale by the same process and purified by column chromatography (20%-50% EtOAc in petroleum ether) to give the desired product, which was purified by SFC separation to give the title intermediate (800 mg, 30% yield). m/z): [M+H]+ calcd for C23H27BrN4O3 487.13, 489.12 found 487.1.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25].CO>C(Cl)Cl.O1CCOCC1>[ClH:25].[ClH:25].[N:19]1([CH2:18][CH2:17][CH2:16][N:11]2[C:12](=[O:15])[CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N(CCCN2CCCCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: O=C1CCNCCN1CCCN1CCCCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 7.3 g (21.50 mmol) of 5-oxo-4-(3-piperidin-1-yl-propyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester was dissolved in 140 ml CH2Cl2, cooled to 0° C. and treated with 54 ml (215.03 mmol) of 4M HCl in dioxane, then warmed to RT. After 3 h, 40 ml of MeOH were added to dissolve the precipitation and stirring was continued over night. The solution was evaporated, dissolved in toluene and evaporated (2×) to yield 7.71 g (quantitative) of the title compound as a white solid. MS: 240.1 (MH+).
Reaction SMILES: N([O-])=O.[Na+].[I:5][C:6]1[C:10]([C:11]2[CH:16]=[CH:15][N:14]=[C:13](N)[N:12]=2)=[CH:9][N:8]([CH:18]([CH3:20])[CH3:19])[N:7]=1.FC(F)(F)C(O)=[O:24]>>[I:5][C:6]1[C:10]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([OH:24])[N:12]=2)=[CH:9][N:8]([CH:18]([CH3:20])[CH3:19])[N:7]=1
Reactant: CC(C)n1cc(-c2ccnc(N)n2)c(I)n1
Reactant: O=C(O)C(F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Product: CC(C)n1cc(-c2ccnc(O)n2)c(I)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium nitrite (314 mg, 4.55 mmol) was added in portions to a stirred mixture of Intermediate 4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-amine (500 mg, 1.52 mmol) and trifluoroacetic acid (15 ml) at 0° C. The mixture was allowed to warm to rt and was stirred for 1 h, then the solvent was removed under vacuum. The crude mixture was diluted with ethyl acetate and washed with saturated aqueous potassium carbonate solution and brine to provide the title compound as a solid. MS m/z 331.0 (M+1).
Reaction SMILES: C[Al](C)C.CCCCCC.[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12].[Cl:19][C:20]1[CH:21]=[C:22]([NH:35][C:36]2[C:37]3[C:44]4[CH:45]=[CH:46][C:47](/[CH:49]=[CH:50]/[C:51]([O:53]C)=O)=[CH:48][C:43]=4[S:42][C:38]=3[N:39]=[CH:40][N:41]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1.[NH4+].[Cl-]>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:19][C:20]1[CH:21]=[C:22]([NH:35][C:36]2[C:37]3[C:44]4[CH:45]=[CH:46][C:47](/[CH:49]=[CH:50]/[C:51]([N:16]5[CH2:17][CH2:18][N:13]([CH2:11][CH3:12])[CH2:14][CH2:15]5)=[O:53])=[CH:48][C:43]=4[S:42][C:38]=3[N:39]=[CH:40][N:41]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1
Reactant: CCN1CCNCC1
Reactant: COC(=O)/C=C/c1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCN1CCN(C(=O)/C=C/c2ccc3c(c2)sc2ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
To a stirred and cold (0° C.) solution of toluene (5 mL) was added trimethyl aluminum in hexane (2M, 0.77 mL, 1.54 mmol, 4 equiv) and stirred for 10 min at 0° C. followed by addition of 1-ethyl piperazine (48 mg, 0.42 mmol, 1.1 equiv). The resulting mixture was stirred for an additional 5 min at 0° C. and then warmed to rt. A suspension of methyl (2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)[1]benzothieno[2,3-d]pyrimidin-7-yl]acrylate (200 mg) in toluene was added to the above generated mixture. The resulting mixture were heated at 100° C. for 16 h. after cooled to rt, it poured into a cold mixture (0° C.) of NH4Cl aq solution and EtOAc. The resulting gel-like mixture was filtered through a pad of Celite® and pad was washed with EtOAc. The combined EtOAc layers were dried over MgSO4 and concentrated in vacuo. The residue was carefully triturated with ether to yield a yellow solid (200 mg, 86%). 1H-NMR (DMSO-d6) δ 9.08 (s, 1H), 8.54 (m, 3H), 7.92 (dd, 1H), 7.74 (d, 1H), 7.62 (d, 1H), 7.52 (dd, 1H), 7.45 (m, 2H), 7.32 (m, 2H), 7.24 (d, 1H), 7.17 (m, 1H), 5.28 (s, 2H), 3.74 (m, 2H), 3.58 (m, 2H), 2.35 (m, 6H), 1.0 (t, 3H); LCMS RT=3.03 min, [M+H]+=602.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][NH2:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20](OCC)(OCC)(OCC)[CH3:21]>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:20]([CH3:21])=[N:13][N:12]=[C:7]1[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNc1cc(-c2ccccc2)c2cc(Br)ccc2n1
Reactant: CCOC(C)(OCC)OCC
Solvent: Cc1ccccc1C
Product: Cc1nnc2cc(-c3ccccc3)c3cc(Br)ccc3n12

Procedure:
In the manner given in Example 2, 6-bromo-4-phenyl-2-hydrazinoquinoline and triethyl orthoacetate are refluxed in xylene to give 7-bromo-1-methyl-5-phenyl-s-triazolo[4,3-a]quinoline.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][OH:9])[CH:6]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C.CCOC(C)=O>[Si:19]([O:9][CH2:8][CH2:7][N:5]1[CH:6]=[C:2]([I:1])[CH:3]=[N:4]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCn1cc(I)cn1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCCn1cc(I)cn1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 111.4 %

Procedure:
A solution of 2-(4-iodo-1H-pyrazol-1-yl)ethanol (Preparation 57) (1.01 g, 4.24 mmol) in DMF (21 mL) was treated with imidazole (410 mg, 6.03 mmol) followed by tert-butylchlorodiphenylsilane (1.321 mL, 5.09 mmol) and the mixture was stirred to room temperature for 18 hours. The mixture was diluted with EtOAc and quenched with brine. The aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 10% EtOAc in cyclohexane to give the title compound (2.25 g, quant).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.CN(C)C=O.OC[C:32]1[CH2:33][C@@H:34]2[C@H:37]([CH:38]=1)[C@@:36]([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])([CH2:39][N+:40]([O-:42])=[O:41])[CH2:35]2>O>[Cl:24][CH2:20][C:32]1[CH2:33][C@@H:34]2[C@H:37]([CH:38]=1)[C@@:36]([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])([CH2:39][N+:40]([O-:42])=[O:41])[CH2:35]2
Reactant: CC(C)(C)OC(=O)C[C@]1(C[N+](=O)[O-])C[C@@H]2CC(CO)=C[C@@H]21
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C[C@]1(C[N+](=O)[O-])C[C@@H]2CC(CCl)=C[C@@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triphenylphosphine (1.85 g, 7.05 mmol) and carbon tetrachloride (0.78 mL, 8.14 mmol) were added to a dimethylformamide solution (8.0 mL) of tert-butyl(±)-[(1R,5R,6R)-3-(hydroxymethyl)-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (807 mg, 2.71 mmol), and the mixture was stirred at room temperature for 1 hour. To the reaction solution, water was added, followed by extraction with diethyl ether. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the obtained crude product of tert-butyl(±)-[(1R,5R,6R)-3-(chloromethyl)-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate was dissolved in dimethylformamide (10 mL). To the solution, sodium thiomethoxide (570 mg, 8.14 mmol) was added with stirring at 0° C., and the mixture was stirred at this temperature for 4 hours. The reaction solution was diluted with ethyl acetate and separated into aqueous and organic layers. The organic layer was washed with a 1 M aqueous sodium hydroxide solution, water, and saturated saline and then dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the obtained crude product was purified by silica gel column chromatography to obtain the compound of interest as an oil substance (632 mg, 71%).
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH:15]2[C:17]([OH:19])=O)=[O:13])=[CH:7][CH:6]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:35][CH:36]([CH3:43])[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C=O)C>[NH2:2][N:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH:15]2[C:17]([NH:35][CH:36]([CH3:43])[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:19])=[O:13])=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(C)N
Reactant: NN=Cc1ccc(NC(=O)C2CC2C(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)NC(=O)C1CC1C(=O)Nc1ccc(C=NN)cc1
Reaction time: 8 h

Procedure:
To 1.0 g (0.0035 mol) 2-[[[4-(aminoiminomethyl)phenyl]amino]carbonyl]cyclopropyl-carboxylic acid hydrochloride in 100 mL dry DMF was added 0.36 g (0.39 mL, 0.0035 mol) N-methylmorpholine and 0.48 g (0.46 mL, 0.0035 mol) isobutylchloroformate. The reaction was allowed to proceed for ten minutes at room temperature then 0.515 g (0.576 mL , 0.0035 mol) ethyl 3-aminobutyrate was added. The reaction was allowed to proceed overnight. The volatiles were removed under vacuum at 55° C. until a viscous oil remained. The residue was dissolved in water (60 mL) and purified by preparative RPHPLC. Two diastereomers were obtained and separated by HPLC. The faster eluting diastereoisomer, isomer 1, was collected and lyophilized to 0.9 g of a white solid: 1H NMR (300 MHz) d6 -DMSO δ 1.17 (m, 8H), 2.07 (m, 1H), 2.38 (m, 1H), 4.04 (m, 3 H), 7.77 (s, 4H), 8.28 (d, J=7.9), 8.80 (bs, 2H), 9.16 (bs , 2H), 10.78 (s , 1H); MS (FAB) 361.3 (MH+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].OS([O-])(=O)=O.[Na+]>C(O)CCC>[CH2:18]([O:19][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=1)[CH2:14][CH2:13][CH3:12]
Reactant: O=C(O)c1cc(Cl)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCCCO
Product: CCCCOc1ccnc(C(=O)O)c1
Temperature: 150 °C
Reaction time: 1 h
Yield: 182.4 %

Procedure:
Sodium bis(trimethylsilyl)amide (28.8 g, 157 mmol) was added slowly to anhydrous n-butanol (52 mL). After 1 h, 4-chloro-pyridine-2-carboxylic acid (3.00 g, 19.1 mmol) was added and the reaction was heated to 150° C. for 3 h. Potassium bis(trimethylsilyl)amide (7.80 g, 39.2 mmol) in n-butanol (30 mL) was added to the reaction mixture and this was heated o.n. The mixture was cooled to r.t and pH was adjusted to 5 with 1N NaHSO4 solution. The mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to give the title compound (3.40 g, 94% yield) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.ClC1C=CC(C2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[O:19]N=2)=CN=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[O:19][N:9]=2)=[N:6][CH:7]=1
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(Cl)nc3)no2)cc1
Reactant: N#Cc1ncc(Cl)cn1
Product: CC(C)Cc1ccc(-c2nc(-c3ncc(Cl)cn3)no2)cc1

Procedure:
The title compound was prepared from 5-chloropyrimidine-2-carbonitrile by procedures analogous to those described in Example 4A-4B for the preparation of 2-Chloro-5-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]pyridine.
Reaction SMILES: [CH:1]([S:4][C:5]1[S:6][C:7]([C:18]([O:20]CC)=[O:19])=[C:8]2[CH2:17][CH2:16][C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[C:9]=12)([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>C(O)C>[CH:1]([S:4][C:5]1[S:6][C:7]([C:18]([OH:20])=[O:19])=[C:8]2[CH2:17][CH2:16][C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[C:9]=12)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1sc(SC(C)C)c2c1CCc1nc(C)oc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc2c(o1)-c1c(SC(C)C)sc(C(=O)O)c1CC2
Temperature: 50 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Ethyl 4,5-dihydro-8-isopropylthio-2-methylthieno[3,4-g]benzoxazole-6-carboxylate (0.71 g) was dissolved in ethanol (30 ml); a 2 N aqueous solution of sodium hydroxide (2.1 ml) was added at 50° C. After the reaction mixture was stirred at 50° C. for 1 hour, the solution obtained was poured over water, acidified with 1 N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off to yield 4,5-dihydro-8-isopropylthio-2-methylthieno[3,4-g]benzoxazole-6-carboxylic acid (0.57 g, 66%), which was then recrystallized from ethyl acetate-hexane. Yellow prisms. Melting point 277-278° C.