Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:14]([OH:15])=[C:13]([C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH2:8][CH2:9]Br)[CH2:2][CH3:3].[SH:19][CH2:20][CH:21]1[CH2:25][O:24][C:23]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[S:22]1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:16]([C:13]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][S:19][CH2:20][CH:21]2[CH2:25][O:24][C:23]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[S:22]2)=[C:4]([CH2:1][CH2:2][CH3:3])[C:14]=1[OH:15])(=[O:18])[CH3:17]
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)OCC(CS)S1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCSCC2COC(CCC(=O)OCC)(CCC(=O)OCC)S2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.4 %

Procedure:
3-(2-n-Propyl-3-hydroxy-4-acetylphenoxy)-1-bromopropane (2.0 g, 0.006 mol), prepared by the method described in U.S. Pat. No. 4,565,882, Example 14, incorporated herein by reference, was dissolved in methyl ethyl ketone (20 ml). To this solution was added the thiol of Example 1 (2.0 g, 0.006 mol) and anhydrous potassium carbonate (2.5 g) and the reaction mixture was refluxed with stirring under a nitrogen atmosphere for 24 hrs. The reaction was cooled to room temperature, filtered and the filtrate concentrated on the rotary evaporator. The residue was chromatographed on silica gel using 25% ethyl acetate/hexane as eluent to give 3.3 g (95%) of the title compound as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.CCN(CC)CC.Cl[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17]>C(Cl)Cl>[OH:7][CH:4]1[CH2:5][CH2:6][N:1]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:2][CH2:3]1
Reactant: CC(C)OC(=O)Cl
Reactant: OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a stirring solution of piperidin-4-ol (5.22 g, 51.6 mmol, Aldrich), Et3N (13.2 mL, 95 mmol, Aldrich) in CH2Cl2 (50 mL) at 0° C. was added a solution of Isopropyl chloroformate (1 Molar in Toluene, 43.0 mL, 43.0 mmol, Aldrich) dropwise. The reaction mixture was stirred at room temperature for 1 h and washed with 1N HCl in H2O. The H2O layer was extracted with DCM (2×). The organic layers were combined and concentrated in vacuo to yield 5.71 g of the desired product as a light brown oil. MS (ESI) 188 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH2:11][CH2:12][CH2:13][OH:14])[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: NCCCO
Reactant: Cc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cnc(Cl)nc1NCCCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
To a solution of 2,4-dichloro-5-methylpyrimidine (8.00 g, 49.1 mmol) and 3-amino-1-propanol (4.50 mL, 58.9 mmol) in ethanol (200 mL) was added sodium carbonate (26.0 g, 245 mmol). The solution was vigorously stirred at rt for 24 h. The mixture was filtered over Celite® and the filtrate concentrated under reduced pressure. The resulting solid was triturated with Et2O to give the product as a white solid (9.80 g, 99%). 1H NMR (400 MHz, CDCl3) δ 1.86 (qt, 2H), 2.00 (s, 3H), 3.55 (t, 2H), 3.64 (t, 2H), 4.92 (broad, 2H), 7.68 (s, 1H).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][CH2:14][NH:13][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: NCCc1ccccn1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CNCCc1ccccn1

Procedure:
The product was made from D-glucose and 2-(β-aminoethyl)-pyridine comparable as in Example A. A wax-like, colorless product was obtained.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C=O)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([O:5][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1

Procedure:
While cooling on ice, Boc-L-Pro-OH (1.08 g, 5.0 mmol) and benzyl bromide (0.893 ml, 75 mmol) were reacted in DMF (10 ml) in the presence of triethylamine (10.5 ml, 75 mmol) to obtain Boc-L-Pro-OBzl as an oily product. This product was reacted under ice-cooling with 2 N HCl/dioxane (5 eq.) for three hours to obtain H-L-Pro-OBzl-HCl.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])=[CH:9][C:8]=1[F:40].Cl>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:41])=[O:4])=[C:8]([F:40])[CH:9]=2)=[C:14]([CH3:39])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:33])([CH3:34])[CH3:32])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)O)c(F)c2)c(C)c1
Temperature: 100 °C
Yield: 103.3 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.20 mL) was added to a solution of optically active (4′-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-fluoro-2′-methyl-biphenyl-4-yl)-acetic acid methyl ester (Example 141-(1); 33.0 mg, 38%, >99.8% e.e.) in methanol (1.0 mL), and the mixture was stirred with microwave heating at 100° C. for five minutes. A 2 N hydrochloric acid aqueous solution (0.30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate and washing with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (dichloromethane:methanol=100:0 to 90:10) to give the target compound as a colorless oil (33.2 mg, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.O=[S:19](Cl)Cl>ClCCl>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[C:4]([CH:3]=1)=[N:10][S:19][N:9]=2
Reactant: Nc1cc(F)c(F)cc1N
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1cc2nsnc2cc1F
Temperature: 25 °C
Yield: 58.1 %

Procedure:
To a solution of 4,5-difluorobenzene-1,2-diamine (2.0 g, 0.014 mol) and triethylamine (7.8 mL, 0.056 mol) in dichloromethane (80 mL) was added SOCl2 (4.04 mL, 0.055 mol) dropwise at room temperature. The resulting reaction mixture was heated to reflux overnight. The reaction mixture was then allowed to cool to room temperature, and quenched with water carefully. The resulting mixture was extracted with dichloromethane, dried over Na2SO4 and concentrated on a rotary evaporator to give a white solid as the crude compound. The crude product was purified by flash column chromatography (silica gel, hexanes) to afford 5,6-difluorobenzo[1,2,5]thiadiazole as a white crystalline solid (1.4 g, 58% yield). 1H NMR (CDCl3 500 MHz): δ: 7.76 (t, 2H, J=8.5 Hz). 13C NMR (CDCl3, 500 MHz): δ 154.94, 154.78, 152.86, 152.70, 150.89, 150.85, 150.81, 106.26, 106.21, 106.14, 106.09. Anal. calcd. for (C6H2F2N2S): C, 41.86; H, 1.17; N, 16.27. Found: C, 41.41; H, 1.22; H, 15.87. m.p: 64-65° C.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1CCN2C(=NCCC2)CC1.N#N>C1(C)C=CC=CC=1>[C:12]([O:11][C:9](=[O:10])[CH2:8][O:5][C:1](=[O:6])[C:2]([CH3:4])=[CH2:3])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C=C(C)C(=O)O
Agent: N#N
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: C=C(C)C(=O)OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methacrylic acid (8.06 g, 0.10 mole), t-butyl bromoacetate (19.50 g, 0.10 mole) and 1,8-diazabicyclo[5.4.0]undoc-7-ene, DBU, (15.20 g, 0.10 mole) and 150 ml toluene were combined in a 500 ml 3-neck flask equipped with condenser, nitrogen inlet, thermometer and magnetic stirrer bar. The reaction mixture was stirred at room temperature for one hour. The reaction was continued at 90° C. overnight under a blanket of N2 flow. The mixture was cooled to room temperature and the salt was removed by filtration. The toluene solution was washed with 75 ml saturated NaCl solution and 2×75 ml Dl-water respectively before dried on MgSO4 overnight. The solid was filtered out and the toluene was removed at rotavap. An oily residue was distilled to a final clear liquid at reduced pressure.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH:11]=[O:12]>C1COCC1>[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH:11]([OH:12])[CH3:1]
Reactant: O=Cc1ccncc1Br
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1ccncc1Br
Temperature: 0 °C

Procedure:
A solution of methylmagnesium bromide (10.00 ml, 30.0 mmol) was added dropwise to a solution of 3-Bromo-pyridine-4-carbaldehyde (1.860 g, 10.00 mmol) in THF (30 mL) at −78° C. The resulting mixture was slowly warmed up to 0° C. over 3 h of period. The reaction was quenched by saturated NH4Cl solution. After extraction with ethyl acetate (50 mL×4), the combined extracts were dried over Na2SO4. After filtration and concentration, an oil residue was obtained, which turned into solid after standing (2.1 g). 1H NMR (400.3 MHz, CDCl3): δ 0.23 (d, J=8 Hz, 3H), 3.91 (m, 1H), 6.29 (d, J=4 Hz, 1H), 7.26 (d, J=4 Hz, 1H), 7.37 (s, 1H).
Reaction SMILES: [O:1](S(C(F)(F)F)(=O)=O)[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([CH3:27])[CH2:26][O:25][CH2:24]2)=[CH:19][C:18]=1O.N1C=CC=CC=1>C(Cl)Cl>[F:6][C:5]([F:8])([F:7])[S:2]([O:1][C:18]1[CH:19]=[C:20]([C:23]2([CH3:27])[CH2:26][O:25][CH2:24]2)[CH:21]=[CH:22][C:17]=1[CH3:16])(=[O:4])=[O:3]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1ccc(C2(C)COC2)cc1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(C2(C)COC2)cc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Tf2O (3.07 mL, 18.2 mmol) was added dropwise to a solution of 2-methyl-5-(3-methyloxetan-3-yl)phenol (2.70 g, 15.2 mmol) and pyridine (1.71 mL, 21.2 mmol) in DCM (25 mL) at 0° C. The red/orange mixture was stirred at 0° C. for 1.5 h, then partitioned between DCM and water. The aqueous layer was extracted with DCM (2×). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (0-40% EtOAc/heptane) to provide 2-methyl-5-(3-methyloxetan-3-yl)phenyl trifluoromethanesulfonate. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.38 (d, J=8.08 Hz, 1 H) 7.26 (dd, J=7.96, 1.89 Hz, 1 H) 7.14 (d, J=1.77 Hz, 1 H) 4.89 (d, J=5.56 Hz, 2 H) 4.66 (d, J=5.81 Hz, 2 H) 2.41 (s, 3 H) 1.75 (s, 3 H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:5](=[N:15][N:16]([CH3:18])[N:17]=2)[NH:6][C:7]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:8]=2[N:9]=1.CS(C)=O.[CH3:23][N:24]1[CH2:29][CH2:28]N[CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[F:14][C:11]1[CH:12]=[CH:13][C:7]2[NH:6][C:5]3=[N:15][N:16]([CH3:18])[N:17]=[C:4]3[C:3]([N:2]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)=[N:9][C:8]=2[CH:10]=1
Reactant: CN1CCNCC1
Reactant: Cn1nc2c(n1)C(N)=Nc1cc(F)ccc1N2
Agent: Cl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CN1CCN(C2=Nc3cc(F)ccc3Nc3nn(C)nc32)CC1
Temperature: 125 °C

Procedure:
10-Amino-7-fluoro-2-methyl-2,4-dihydro-1,2,3-triazolo[4,5-b][1,5]benzodiazepine hydrochloride (2.68 g) was added to a mixture of dry dimethyl sulphoxide (10 ml), toluene (10 ml) and dry N-methyl piperazine (3.3 ml), which had been degassed with nitrogen for 20 minutes. The stirred solution was then heated at 125° C. (oil-bath) under nitrogen for five hours, cooled to room temperature, and distilled water (33.3 ml) added, keeping the temperature below 25° C. After stirring at 5° C. for half an hour, the suspension obtained was filtered off and dried at 70° C. under reduced pressure to leave a yellow crystalline solid, which was recrystallised from ethyl acetate/n hexane, melting point 195°-197° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[F:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][CH2:15][C@H:16]2[CH2:25][N:20]3[CH2:21][CH2:22][NH:23][CH2:24][C@@H:19]3[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.Cl>>[F:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][C@H:16]2[CH2:25][N:20]3[CH2:21][CH2:22][N:23]([C:5]4[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:24][C@@H:19]3[CH2:18][CH2:17]2)=[CH:26][CH:27]=1
Reactant: Fc1ccc(OC[C@@H]2CC[C@H]3CNCCN3C2)cc1
Reactant: Clc1ccc(Cl)nn1
Agent: Cl
Product: Fc1ccc(OC[C@@H]2CC[C@H]3CN(c4ccc(Cl)nn4)CCN3C2)cc1

Procedure:
The title compound was prepared according to Preparation 3 with 3,6-dichloropyridazine and (7R,9aS)-7-(4-fluorophenoxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine. mp (.HCl) 265–270° C. 13C NMR (base, CDCl3): δ 26.8, 29.0, 36.4, 45.1, 50.4, 54.4, 58.6, 60.3, 71.5, 115.2, 115.3, 115.4, 115.6, 115.9, 128.7, 146.7, 155.0, 155.6, 158.76, 158.82. HRMS calcd for C19H22ClFN4O: 376.1461; found: 376.1453.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O-:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-]>>[C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cc1ccccc1

Procedure:
Using the procedure in Example 2, methyl 3-chloro-4-(3-(2-methyl-2-phenylpropyl)-7-(n-propyl)-6-benz[4,5]isoxazoloxy)propylthio)-phenylacetate was saponified with LiOH to form 3-chloro-4-(3-(2-methyl-2-phenylpropyl)-7-propyl-6-benz[4,5]isoxazoloxy)propylthio)phenylacetic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:7][O:6][C:5]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([N+:20]([O-])=O)[CH:14]=2)([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[O:4][CH2:3]1.[H][H]>[Ni].CO>[CH3:1][C:2]1([CH3:23])[CH2:3][O:4][C:5]([C:13]2[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=2)([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[O:6][CH2:7]1
Reactant: CC1(C)COC(c2ccc(N)c([N+](=O)[O-])c2)(c2cccs2)OC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CC1(C)COC(c2ccc(N)c(N)c2)(c2cccs2)OC1
Yield: 100 %

Procedure:
A mixture of 5.04 parts of 4-[5,5-dimethyl-2-(2-thienyl)-1,3-dioxan-2-yl]-2-nitrobenzenamine and 120 parts of methanol is hydrogenated at normal pressure and at room temperature with 3 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 4.5 parts (100%) of 4-[5,5-dimethyl-2-(2-thienyl)-1,3-dioxan-2-yl]-1,2-benzenediamine; mp. 178° C.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:21]=[CH:22][C:23]([O:27][CH3:28])=[C:24]([OH:26])[CH:25]=1.[K+].[Br-]>CCOC(C)=O>[OH:26][C:24]1[CH:25]=[C:20]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:21]=[CH:22][C:23]=1[O:27][CH3:28]
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: COc1ccc(N)cc1O
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2ncnc3ccc4nc(C#N)sc4c23)cc1O
Yield: 54 %

Procedure:
Prepared from VII and 5-amino-2-methoxyphenol. Flash chromatography eluent (EtOAc). Yield: 54%; yellow solid; mp 248° C.; IR (KBr) νmax/cm−1 2921, 2851, 2227, 1724, 1647, 1616, 1583, 1509, 1460, 1334, 1287, 1263, 1218, 1172, 1148, 1120, 1036, 973, 953, 864, 833; 1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, 1H, J=8.7 Hz), 8.05 (m, 1H), 7.77 (d, 1H, J=8.7 Hz), 7.94 (d, 2H, J=8.7 Hz), 6.65 (m, 1H), 3.77 (s, 3H); HRMS calcd for C17H12N5O2S (M+H+): 350.0712, found 350.0715.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:9](=[O:10])[C:8](=[O:11])[C:7]=1OCCCC)[CH2:2][CH2:3][CH3:4].[OH-].[NH4+:18]>O1CCCC1.CO>[NH2:18][C:7]1[C:8](=[O:11])[C:9](=[O:10])[C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(OCCCC)c(=O)c1=O
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1c(N)c(=O)c1=O
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
Preparation A: A solution of 1,2-dibutoxy-1-cyclobutene-3,4-dione (6.09, 0.027 mole) in 40 mL of tetrahydrofuran was cooled to 5° C. in an ice-water bath and treated dropwise over a period of 9 minutes with a solution of 1.8 mL of concentrated ammonium hydroxide in a mixture of 8 mL of tetrahydrofuran and 1 mL of methanol. After stirring at 5° C. for 30 minutes and at ambient temperature for 90 minutes the mixture was concentrated under reduced pressure to a slurry. A small amount of Skellysolve B was added and the product was collected by filtration after 16 hours of standing at 0° C. to give 3.26 g of the title compound. A sample (8.54 g) was partly dissolved in acetone, filtered and cooled to give 4.51 g of purified title compound; mp=165.5°-168° C. (clear melt).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.O[NH:38][C:39]([C:41]1[CH:50]=[CH:49][CH:48]=[C:47]2[C:42]=1[CH2:43][CH2:44][CH2:45][C@@H:46]2[NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[NH:40]>CN(C=O)C.CC(=O)OCC>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:40]=[C:39]([C:41]3[CH:50]=[CH:49][CH:48]=[C:47]4[C:42]=3[CH2:43][CH2:44][CH2:45][C@@H:46]4[NH:51][C:52](=[O:58])[O:53][C:54]([CH3:56])([CH3:55])[CH3:57])[N:38]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCc2c(C(=N)NO)cccc21
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@@H]4NC(=O)OC(C)(C)C)no2)cc1C#N
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
Prepared using General Procedure 2. To a stirring solution of 3-cyano-4-isopropoxybenzoic acid (556 mg, 2.72 mmol) in DMF (10 mL) was added HOBt (476.6 mg, 3.53 mmol) and EDCI (677.9 mg, 3.53 mmol). After stirring for 30 min, (S)-tert-butyl (5-(N-hydroxycarbamimidoyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate INT-10 (3.56 g crude, approximately 2.99 mmol) was added. After stirring at room temperature for an additional 90 min, the mixture was heated to 90° C. for 15 h. The mixture was diluted with EA and washed with NaHCO3. The combined organic layers were dried, concentrated, and chromatographed (EA/hexanes) to provide 1.89 g (46%) (S)-tert-butyl (5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate INT-12 as a white solid. LCMS-ESI (m/z) calculated for C27H30N4O4: 474.6; no M/Z observed, tR=4.23 min. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J=2.1 Hz, 1H), 8.33 (dd, J=8.9, 2.2 Hz, 1H), 7.92 (dd, J=7.7, 1.1 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.32 (dd, J=20.3, 12.6 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 4.94 (d, J=6.0 Hz, 1H), 4.88-4.72 (m, 1H), 3.23-3.08 (m, 1H), 3.07-2.94 (m, 1H), 2.06 (d, J=12.6 Hz, 1H), 1.97-1.78 (m, 3H), 1.53-1.43 (m, 15H). 13C NMR (101 MHz, CDCl3) δ 172.64, 169.40, 162.69, 155.43, 138.65, 137.55, 134.04, 133.83, 131.68, 129.55, 126.08, 125.97, 116.74, 115.20, 113.53, 103.87, 79.44, 72.69, 48.97, 29.73, 28.40, 21.68, 19.71, 14.14.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][NH:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14](Br)=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+]>CO.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:9][NH:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: CNc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Reactant: Cc1ccc(N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CNc1ccc(Nc2ccc(C)cc2)c2c1C(=O)c1ccccc1C2=O
Reaction time: 6 h
Yield: 82 %

Procedure:
In a reactor were charged p-toluidine (80 parts) , 1-methylamino-4-bromoanthraquinone (15.8 parts), sodium acetate (7.5 parts) and copper acetate (0.5 part) and the mixture was kept at 115° to 120° C. for 6 hours under a nitrogen atmosphere. Thereafter, the reaction mixture was diluted with methanol (100 parts) and cooled. The precipitate produced was filtrated, washed with methanol (500 parts) and then water (200 parts), and dried at 80° to 90° C. to obtain 1-methylamino-4- (4 '-methylanilino) -anthraquinone (yield 82% ).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][CH:15]=[N:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([I:24])C(=O)C1>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][C:15]([I:24])=[N:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]cnc2C1
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2[nH]c(I)nc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
To a solution of 1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (Preparation 20, 18 g, 80.62 mmol) in THF (300 mL) was added NIS (27.2 g, 121 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (800 mL), washed with sodium thiosulfate aqueous solution (3×700 mL) and brine (500 mL), dried over MgSO4 and concentrated in vacuo to give the title compound as a yellow solid (18.25 g) in a 64.8% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:10])[CH3:9])=[N:6][CH:7]=1
Reactant: CC(=O)c1ccc(Br)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
To a solution of 1-(5-bromopyridin-2-yl)ethanone (1.1 g, 5.5 mmol) in ethanol (100 mL) was added sodium borohydride (2.5 g, 66.1 mmol). The reaction mixture was stirred at room temperature for 24 hours. The mixture was filtered, the filtrate was acidified and the solvent removed on a rotary evaporator. The residue was taken up with water (50 mL) and extracted with dichloromethane (50 mL). The combined extract was dried over sodium sulfate, filtered, concentrated and purified by column chromatography to give 1-(5-bromopyridin-2-yl)ethanol (1.0 g, 90.0%) as a yellow oil. LRMS (M+H+) m/z: calcd 201.98. found 202. 1H NMR (300 MHz, CD3OD) δ 8.54 (d, J=2.4 Hz, 1H), 7.98 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 4.85 (m, 1H), 1.45 (d, J=6.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][C:23](F)=[CH:22][C:21]=2[O:27][CH:28]([CH3:30])[CH3:29])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[CH3:32][N:33]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][C:23]([N:36]3[CH2:37][CH2:38][CH2:39][N:33]([CH3:32])[CH2:34][CH2:35]3)=[CH:22][C:21]=2[O:27][CH:28]([CH3:30])[CH3:29])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: CC(C)Oc1cc(F)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: CN1CCCNCC1
Product: CC(C)Oc1cc(N2CCCN(C)CC2)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Yield: 99.9 %

Procedure:
Prepared from 5-fluoro-2-(4-fluoro-2-isopropoxybenzoylamino)-N-(5-chloropyridin-2-yl)benzamide (159 mg, 0.356 mmol) and 1-methyl-hexahydro-1,4-diazepine (203 mg, 1.77 mmol, 5 eq) to provide 192 mg (82%) of the title compound.