Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1.C[O:11][C:12](=[O:30])[C@@H:13]1[CH2:17][C@@H:16](OS(C)(=O)=O)[CH2:15][N:14]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].O>CO>[C:23]([N:14]1[CH2:15][C@@H:16]([S:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:17][C@H:13]1[C:12]([OH:30])=[O:11])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reactant: SCc1ccc(Br)cc1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](SCc2ccc(Br)cc2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a solution of Na (0.25 g) (0.011 mol) in 3 mL of MeOH was added 4-bromobenzyl mercaptan (2.2 g) (0.011 mol). The reaction mixture was stirred for 1 h. Trans-N-Boc-4-methanesulfonyloxy-L-proline methyl ester (1.2 g) (0.0037 mol) (Preparation 9) was added and the mixture refluxed for 18 hrs. Upon cooling to RT, 40 mL of water was added and the mixture was extracted with EtOAc. The aqueous layer was acidified with 1 N HCl and extracted with DCM. The combined organic extracts were washed with water, dried over MgSO4, and the solvent evaporated in vacuo to afford cis-N-Boc-4-(4-bromobenzyl thio)-L-proline (1.08 g). NMR (CDCl3, 200 MHz): 10.65 (1H, COOH), 7.4 (2H, d), 7.15 (2H, d), 4.15-4.35 (1H, m), 3.65 (2H, s), 2.95-3.35 (2H, m), 2.4-2.6 (1H, m), 1.85-2.2 (1H, m), 1.3-1.5 (9H). To a solution of cis-N-Boc-4-(4-bromobenzyl thio)-L-proline (1.08 g) in 10 mL of MeOH was added dropwise SOCl2 (0.2 mL), and the mixture was stirred for 72 hrs at RT. The solvent was evaporated under reduced pressure and the residue dissolved in DCM. The organic layer was washed with dilute aqueous NaHCO3, water, and dried over MgSO4. The solvent was evaporated in vacuo to afford cis-4-(4-bromo-benzylthio)-L-proline methyl ester (0.6 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]2([CH3:26])[CH2:21][CH2:20][C:19]3[C:14](=[C:15]([CH3:25])[C:16]([CH3:24])=[C:17]([OH:23])[C:18]=3[CH3:22])[O:13]2)=[O:11])[CH:5]=[CH:4][N:3]=[CH:2]1.[O:27]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].CCOC(C)=O>C(C#N)(C)=O.C(Cl)Cl.O>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:11])[C:12]([OH:27])([CH3:26])[CH2:21][CH2:20][C:19]2[C:14](=[O:13])[C:15]([CH3:25])=[C:16]([CH3:24])[C:17](=[O:23])[C:18]=2[CH3:22])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCCn1ccnc1)O2
Agent: CC(=O)C#N
Agent: [Ce+4]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCCn2ccnc2)=C(C)C1=O
Reaction time: 0.08 h
Yield: 93.2 %

Procedure:
To a solution of N-(3-(1H-imidazol-1-yl)propyl)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (100.7 mg, 0.282 mmol) in 6 mL AcCN and 6 mL CH2Cl2, cooled to 0° C., was added a cooled solution of CAN (340 mg, 0.620 mmol) in 2 mL H2O, dropwise over 5 minutes. The reaction was immediately treated with 5 mL EtOAc and washed 3×3 mL H2O. The aqueous layer was basified with 6 mL saturated NaHCO3 solution and extracted 6×3 mL EtOAc. The combined organics were dried over Na2SO4 and concentrated to a yellow oil. Flash chromatography yielded 98.1 mg of N-(3-(1H-imidazol-1-yl)propyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:6]([CH3:7])[N:5]([CH2:8][CH2:9][C:10]#[N:11])[C@H:4]([CH2:12][OH:13])[CH2:3]1.C(N(CC)[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[CH3:25])C>>[CH3:1][C@H:2]1[C@@H:6]([CH3:7])[N:5]([CH2:8][CH2:9][C:10]2[NH:11][C:17](=[O:26])[C:18]3[C:19]([CH:25]=2)=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[C@H:4]([CH2:12][OH:13])[CH2:3]1
Reactant: C[C@@H]1C[C@@H](CO)N(CCC#N)[C@@H]1C
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Product: Cc1cccc2c(=O)[nH]c(CCN3[C@H](CO)C[C@@H](C)[C@H]3C)cc12

Procedure:
In the same manner as in Example 1b (a) and using ethyl (2S,4R,5R)-4,5-dimethylpyrrolidine-2-carboxylate described in Tetrahedron Lett., Vol. 34, No. 3, pp. 537-540 (1993), ethyl (2S,4R,5R)-1-tert-butoxycarbonyl-4,5-dimethylpyrrolidine-2-carboxylate is obtained. In the same manner as in Example 1b (b) and using ethyl (2S,4R,5R)-1-tert-butoxycarbonyl-4,5-dimethylpyrrolidine-2-carboxylate, (2S,4R,5R)-1-tert-butoxycarbonyl-4,5-dimethyl-2-hydroxymethylpyrrolidine is obtained. In the same manner as in Example 1b (c) and using (2S,4R,5R)-1-tert-butoxycarbonyl-4,5-dimethyl-2-hydroxymethylpyrrolidine, (2S,4R,5R)-4,5-dimethyl-2-hydroxymethylpyrrolidine-hydrochloride is obtained. In the same manner as in Example 1b (d) and using (2S,4R,5R)-4,5-dimethyl-2-hydroxymethylpyrrolidine hydrochloride, 3-[(2S,4R,5R)-4,5-dimethyl-2-hydroxymethylpyrrolidin-1-yl]propionitrile is obtained. In the same manner as in Example 1b (e) and using 3-[(2S,4R,5R)-4,5-dimethyl-2-hydroxymethylpyrrolidin-1-yl]propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-(2-[(2S,4R,5R)-4,5-dimethyl-2-hydroxymethylpyrrolidin-1-yl]ethyl)-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:10][C:9]=2[N+:21]([O-])=O)[CH:7]=1.O.[Cl-].[NH4+]>C(O)C.ClCCl.[Fe]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19])[N:11]=[CH:10][C:9]=2[NH2:21])[CH:7]=1
Reactant: COc1ccc(F)cc1-c1c([N+](=O)[O-])cnn1CCOC[Si](C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: COc1ccc(F)cc1-c1c(N)cnn1CCOC[Si](C)(C)C
Temperature: 75 °C
Reaction time: 6 h
Yield: 70.2 %

Procedure:
To a solution of 5-(5-fluoro-2-methoxyphenyl)-4-nitro-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazole (1.0 g, 2.7 mmol) in 8 mL ethanol was added 16 mL water, ammonium chloride (570 mg, 10.8 mmol), and iron powder (760 mg, 13.5 mmol). The reaction mixture was stirred at 75° C. for 6 hours. After cooling to room temperature, the reaction was diluted with dichloromethane and filtered through a celite pad, rinsing with more dichloromethane. The filtrate was added to 150 mL saturated aqueous sodium bicarbonate and extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated to yield 640 mg (70%) of 5-(5-fluoro-2-methoxyphenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-amine, which was carried forward without purification. LCMS (ESI) m+H=338.1. 1H NMR (400 MHz, CDCl3) δ: 7.37 (m, 2H), 7.20 (t, 1H), 7.04 (dd, 1H), 5.42 (t, 2H), 3.90 (d, 3H), 3.65 (t, 2H), 0.96 (t, 2H), 0 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][CH3:18])=[O:7])=[CH:4][C:3]=1[Cl:11]
Reactant: CCO
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Br)c(Cl)c1

Procedure:
To a suspension of 4-bromo-3-chlorobenzoic acid (5.00 g, 21.2 mmol) in ethanol (50 mL) was added sulphuric acid (5 mL) and the resultant mixture heated to reflux for 60 h. The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with further ethyl acetate and the combined organic fractions dried (phase separator) and concentrated in vacuo to give the title compound as a brown oil/solid (5.09 g, 19.3 mmol). δH (d6-DMSO, 400 MHz): 8.06 (1H, d), 7.96 (1H, d), 7.80 (1H, dd), 4.33 (2H, q), 1.33 (3H, t). MS (ES): no mass ion observed.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]C(=O)CCCC)=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:23]([O:29][CH3:30])(=[O:28])[CH2:24][C:25]([CH3:27])=[O:26].[H-].[Na+].[CH2:33]([Li])[CH2:34][CH2:35][CH3:36]>C1COCC1>[CH2:33]([C:30]1([CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[O:29][C:23](=[O:28])[CH:24]=[C:25]([OH:26])[CH2:27]1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCC(=O)CCc1ccc(OCc2ccccc2)cc1
Reactant: [Li]CCCC
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC1(CCc2ccc(O)cc2)CC(O)=CC(=O)O1

Procedure:
The title compound was prepared according the General Method 6 using 4.0 g (13 mmol) of 1-(4-benzyloxyphenyl)-heptan-3-one (prepared in Example U), 6.3 g (54 mmol) of methyl acetoacetate, 2.2 g (54 mmol) of 60% NaH dispersion in mineral oil, 33 mL (1.64 M, 54 mmol) of n-butyllithium and 110 mL of THF. The reaction mixture was quenched with 0.1 NH4Cl, and the mixture was worked up in the normal fashion.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:27]=[C:26]([CH3:28])[C:20]([O:21][CH2:22][CH2:23][CH2:24][NH2:25])=[C:19]([CH2:29][CH3:30])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:31][CH3:32])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:33](O)(=[O:36])[CH2:34][OH:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:27]=[C:26]([CH3:28])[C:20]([O:21][CH2:22][CH2:23][CH2:24][NH:25][C:34](=[O:35])[CH2:33][OH:36])=[C:19]([CH2:29][CH3:30])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:31][CH3:32])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCCN
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCCNC(=O)CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.2 %

Procedure:
To a solution of 3-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)propan-1-amine (200 mg, 0.458 mmol), glycolic acid (52 mg, 0.687 mmol) and DIPEA (178 mg, 1.37 mmol) in DMF (5 mL), TBTU (191 mg, 0.596 mmol) is added. The mixture is stirred at rt for 18 h before it is diluted with EA (50 mL) and washed twice with sat. aq. NaHCO3 solution (50 mL) followed by brine (50 mL). The org. extract is dried over Na2SO4, filtered, and concentrated. The crude product is purified by prep. HPLC to give the title compound (116 mg) as a pale yellow oil; LC-MS: tR=1.14 min, [M+H]+=495.25; 1H NMR (CD3OD): δ 7.85 (s, 1H), 7.83 (s, 1H), 7.53 (s, 1H), 7.28 (s, 1H), 4.01 (s, 2H), 4.00 (s, 3H), 3.94 (t, J=6.1 Hz, 2H), 3.57 (t, J=6.9 Hz, 2H), 3.24-3.31 (m, 1H), 2.77 (q, J=7.6 Hz, 2H), 2.38 (s, 3H), 2.05-2.16 (m, 4H), 1.86-1.96 (m, 4H), 1.72-1.82 (m, 2H), 1.31 (t, J=7.5 Hz, 3H).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.CNCCNC.[I-:34].[Na+]>O1CCOCC1.ClCCl.[Cu]I>[I:34][C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: [I-]
Reactant: Brc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Ic1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 110 °C
Yield: 99.6 %

Procedure:
A mixture of 6-bromo-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (250 mg, 0.6 mmol), copper (I) iodide (23 mg, 0.12 mmol), N,N′-dimethyl-1,2-ethanediamine (0.013 mL, 0.12 mmol), and sodium iodide (360 mg, 2.4 mmol) in 1,4-dioxane was heated at 110° C. for 3 days. The reaction was diluted with dichloromethane (20 mL), filtered, and concentrated to afford a residue that was purified by flash chromatography (silica, 10 g column, Biotage, 0-10% methanol in (DCM containing 1% 2M ammonia in methanol)) to afford the title compound as an orange solid (280 mg, 100%).
Reaction SMILES: [ClH:1].[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].[S:14]([O-:18])([O-:17])(=[O:16])=[O:15].[Zn+2:19]>O>[Cl-:1].[Zn+2:19].[S:14]([OH:18])([O-:17])(=[O:16])=[O:15].[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5]
Reactant: Cl
Reactant: O=S(=O)([O-])[O-]
Agent: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: [Zn+2]
Solvent: O
Product: O=S(=O)([O-])O
Product: [Cl-]

Procedure:
Example 1 was repeated using 1855 g of purified water, 431.5 g (2 moles) of glucosamine hydrochloride and 287.5 g (1 mole) of zinc sulfate (heptahydrate) instead of the sodium sulfate. After freeze drying, glucosamine sulfate zinc chloride was obtained as a white powder in a yield of 540 g (95% of theoretical).
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)=[C:2]=[O:3].Cl.[NH2:15][C@H:16]([C:21]([O:23]C)=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19].[OH-].[Na+].Cl>CCN(CC)CC>[O:3]=[C:2]1[N:15]([C@@H:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:21]([OH:23])=[O:22])[C:6](=[O:8])[C:5]2[C:4](=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:1]1
Reactant: COC(=O)c1ccccc1N=C=O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C(=O)O)n1c(=O)[nH]c2ccccc2c1=O
Temperature: 80 °C

Procedure:
Refer to Scheme 1, a mixture of methyl 2-isocyanatobenzoate (0.5 g, 2.82 mmol) and (S)-methyl leucinate HCl (0.52 g, 2.82 mmol) salt and 1 mL of Et3N was heated to 80° C. for 2 hours. 2 mL of 2M NaOH aqueous solution was added to above mixture and then heated to 100° C. overnight. The mixture was neutralized with concentrated HCl. Extracted by EtOAc and dried over MgSO4. Removing solvent gave the crude product, which used for next step without further purification. [M+H] calc'd for C14H16N2O4, 277; found, 277.
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4]([OH:6])=[O:5])[CH2:3][CH2:2]1.S(Cl)(Cl)=O.[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>O1CCCC1.C(N(CC)CC)C>[CH2:14]([O:5][C:4]([C:1]1([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)C1(C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(O)C1(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Yield: 74 %

Procedure:
1,1-Cyclopropanedicarboxylic acid (5.02 g) was dissolved in tetrahydrofuran (50 ml) under a nitrogen atmosphere, and triethylamine (5.38 ml) was added dropwise with stirring and cooling in an ice water bath. After stirring at the same temperature for 30 minutes, thionyl chloride (2.82 ml) was added dropwise with cooling in ice water bath. After stirring at the same temperature for 30 minutes, a solution of benzyl alcohol (4.39 ml) in tetrahydrofuran (25 ml) was added with cooling in an ice water bath, and the reaction mixture was gradually brought to room temperature and stirred overnight. A 2N aqueous solution of sodium hydroxide (100 ml) was added to the reaction mixture, and tetrahydrofuran was distilled off under reduced pressure. tert-Butyl methyl ether (25 ml) was added to the resultant aqueous solution, followed by stirring. The organic layer and the aqueous layer were separated. The aqueous layer was cooled in an ice water bath, and 2N hydrochloric acid (50 ml) was added to adjust pH 4. Ethyl acetate (150 ml) was added, and the reaction mixture was stirred for a while. The organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was dried under reduced pressure to give the title compound (6.29 g, 74%) as a pale yellow oil.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:18]([CH:19]=1)=[N:17][C:16]1[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22]Cl)[CH:15]=1)[CH:10]=2.[CH2:24]([NH2:28])[CH2:25][CH2:26][CH3:27]>>[ClH:2].[ClH:1].[ClH:2].[CH2:24]([NH:28][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:18]([CH:19]=1)=[N:17][C:16]1[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22][NH:17][CH2:16][CH2:15][CH2:14][CH3:13])[CH:15]=1)[CH:10]=2)[CH2:25][CH2:26][CH3:27]
Reactant: ClCCOc1ccc2cc3ccc(OCCCl)cc3nc2c1
Reactant: CCCCN
Agent: Cl
Product: CCCCNCCOc1ccc2cc3ccc(OCCNCCCC)cc3nc2c1

Procedure:
The compound is prepared from 3,6-bis(2-chloroethoxy)acridine hydrochloride and n-butylamine as described in Example 15, giving 1.45 g. of the desired product as yellow crystals, m.p. 254°-256° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[CH3:12][S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[C:21]2Cl)(=[O:15])=[O:14]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:21]1[C:20]2[C:25](=[C:16]([S:13]([CH3:12])(=[O:14])=[O:15])[CH:17]=[CH:18][CH:19]=2)[N:24]=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)c1cccc2c(Cl)ccnc12
Reactant: Cc1cc2cc(F)ccc2[nH]1
Product: Cc1[nH]c2ccc(F)cc2c1-c1ccnc2c(S(C)(=O)=O)cccc12

Procedure:
The sub-title compound was prepared by the method of Example 40 step a, using 5-fluoro-2-methyl-1H-indole and 8-methanesulphonyl-4-chloroquinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2COS(C)(=O)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:29]([CH2:31][NH2:32])[OH:30].[CH2:33](O)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:11][C@H:10]2[CH2:33][NH:32][CH2:31][CH2:29][OH:30])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](COS(C)(=O)=O)C1
Reactant: CCO
Reactant: NCCO
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CNCCO)C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6S,7R)-7-(3,4-dichlorophenyl)-6-{[(methylsulfonyl)oxy]methyl}-1,4-oxazepane-4-carboxylate (1.9 g) in ethanol (41.8 mL) was added ethanolamine (7.57 mL), and the mixture was stirred at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, distilled water was added, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.65 g).
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:20]=[CH:19][C:18](=[O:21])[C:17]([C:22]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:25]=[CH:24][CH:23]=3)=[N:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+].[OH2:35].[CH3:36]O>>[CH2:2]([N:9]1[CH2:10][CH:11]=[C:12]([N:15]2[CH:20]=[C:19]([O:35][CH3:36])[C:18](=[O:21])[C:17]([C:22]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:25]=[CH:24][CH:23]=3)=[N:16]2)[CH2:13][CH2:14]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CO
Reactant: O
Reactant: O=c1ccn(-c2cc[n+](Cc3ccccc3)cc2)nc1-c1ccnn1-c1ccccc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Product: COc1cn(C2=CCN(Cc3ccccc3)CC2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzyl-4-[4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]pyridinium bromide (0.73 g) in methanol (30 mL) was added sodium borohydride (0.21 g) at 0° C., and the mixture was stirred at room temperature overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate and recrystallized from ethyl acetate to give the title compound (0.15 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:21][C:22]([F:25])([F:24])[F:23])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2.IC.[C:28]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH3:28][O:1][C:2]1[CH:3]=[C:4]([O:21][C:22]([F:25])([F:23])[F:24])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:13])([F:14])[F:15])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(O)c2OC1C(F)(F)F
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(OC)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of ethyl 8-hydroxy-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 621w, Step 2 (165 mg, 0.442 mmole), iodomethane (82.8 uL, 1.33 mmole), KI (7.34 mg, 0.0442 mmole), K2CO3 (184 mg, 1.33 mmole) in anhydrous DMF (5.0 mL) was stirred at room temperature for 17 hrs. The mixture was then poured into brine (100 mL) and extracted with EtOAc (2×100 mL). The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give a tan solid. The crude product was purified by silica chromatography (0%-25% EtOAc in hexanes) to give an assumed quantitative yield of the product as an off-white crystalline solid: EIHRMS m/z 386.0593 (M+, C15H12F6O5, Calc'd 386.0589).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[C:7](=[C:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)([CH3:9])[CH3:8].[I-].C[S+](C)(C)=O>CS(C)=O>[C:7](=[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]21[O:4][CH2:2]2)([CH3:9])[CH3:8]
Reactant: CC(C)=C1CCC(=O)CC1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)=C1CCCCC12CO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
Potassium t-butoxide (3.3 g, 29.4 mmol) was added to a mixture of ketone (3, 2.5 g, 18.1 mmol) and trimethylsulfoxonium iodide (6.45 g, 29.4 mmol) in dry dimethyl sulfoxide (40 mL) under nitrogen atmosphere at room temperature. The mixture was stirred for 4.0 h at room temperature. The reaction was quenched by the addition of cold water (40 mL) and extracted with ethyl acetate (2×60 mL). The combined organic layer was washed with water (75 mL) followed by brine (75 mL) and dried over sodium sulfate. The filtered organic layer was concentrated under vacuum to give an oil. Weight: 2.13 g. Weight yield: 77%. 1H-NMR (400 MHz, CDCl3): δ 1.42-1.50 (m, 2H), 1.55-1.61 (m, 2H), 1.65 (s, 6H), 2.31 (t, 4H), 2.61 (s, 2H). MS (APCI method): No molecular ion peak was observed.
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2:10].[Na+].[Na+].Cl[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.Br[C:21]1[S:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][N:25]=1.O>CN(C)C=O>[N+:26]([C:23]1[S:22][C:21]([S:10][C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)=[N:25][CH:24]=1)([O-:28])=[O:27]
Reactant: Clc1cnccn1
Reactant: [S-2]
Reactant: O=[N+]([O-])c1cnc(Br)s1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(Sc2cnccn2)s1
Temperature: 40 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 60.0 g (0.25 mol) of sodium sulfide nonahydrate in 500 ml of dimethyl formamide was gradually added 29 g (0.25 mol) of chloropyrazine in 100 ml of dimethyl formamide. The solution was stirred overnight at approximately 40° C. following which 52.5 g (0.25 mol) of 2-bromo-5-nitrothiazole was added as a solid. This reaction mixture was stirred at room temperature for 4 hours. After this period it was poured into water. The resulting precipitate was collected by suction filtration, washed with water and dried. The crude product was crystallized from methanol to yield 38 g (72% yield) of yellowish-gold crystals, m.p. 129°-130° C. A sample was subjected to elemental analysis. The results obtained were as follows:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8](Br)[C:9]#[CH:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:10]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]#[CH:8]
Reactant: C#CCBr
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1ccccc1
Temperature: 85 °C
Yield: 84 %

Procedure:
Referring to FIG. 39, phenol (14.6 g. 0.155 mol), propargyl bromide (19 m 0.171 mol) and potassium carbonate (32.1 g, 0.232 mol) in DMF (100 mL) were heated at 85° C. overnight. The reaction was diluted with water and extracted with ether. The extract was washed with brine, dried (MgSO4) and evaporated. The residue was purified by Biotage flash column chromatography (10% EtOAc/Hep) to give product as an oil (17.2 g, 84%).