Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:8]([CH2:9][OH:10])=[CH:7][N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:5]=1.F[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.O>CN(C)C=O>[CH3:3][C:4]1[C:8]([CH2:9][O:10][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)=[CH:7][N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:5]=1
Reactant: Cc1nn(-c2ccccn2)cc1CO
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(-c2ccccn2)cc1COc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Sodium hydride (60%, oily, 0.80 g) was added to a solution of [3-methyl-1-(2-pyridyl)-1H-pyrazol-4-yl]methanol (3.20 g) in N,N-dimethylformamide (50 ml) at 0° C., and the mixture was stirred at room temperature for one hour. 4-fluorobenzaldehyde (2 ml) was added to the reaction mixture, and the mixture was stirred overnight at 50° C. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and 4-[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-ylmethoxy]benzaldehyde (4.26 g, yield: 86%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 84–85° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([S:20](O)(=[O:22])=[O:21])[CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O=P(Cl)(Cl)[Cl:27].N1C=CC=CC=1.O>CN1CCN(C)C1=O>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([S:20]([Cl:27])(=[O:22])=[O:21])[CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)CC(c1ccccc1)c1ccc(OC)c(S(=O)(=O)O)c1
Solvent: CN1CCN(C)C1=O
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CC(c1ccccc1)c1ccc(OC)c(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(4-methoxy-3-sulfo-phenyl)-3-phenyl-propionic acid methyl ester (850 mg, 2.43 mmol) in 1,3-dimethyl-2-imidazolidinone (25 mL) is added POCl3 (0.57 ml, 6.06 mmol) and pyridine (0.33 mL, 4.13 mmol). The reaction mixture is stirred at RT for 1 h. After this time, water (50 mL) is added and the reaction mixture is extracted with DCM (3×50 mL). The combined organic phases are washed with brine (30 mL) then dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as an oil.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[NH:26][C:25](=[O:27])[C:24]3[NH:28][CH:29]=[N:30][C:23]=3[CH:22]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[NH:26][C:25](=[O:27])[C:24]3[N:28]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:29]=[N:30][C:23]=3[CH:22]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3nc[nH]c3c(=O)[nH]2)CC1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1cnc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)[nH]c(=O)c21
Reaction time: 8 h

Procedure:
ClCH2COOEt (1 equiv.) in dimethylforamide was added drop-wise to a solution of 4-(4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-6-yl)piperazine-1-carboxylic acid tert-butyl ester, 3 and potassium carbonate (0.8 equiv.) in dimethylforamide. The solution was stirred overnight. The mixture was then diluted with water and extracted with methylene chloride. The combined organic layers were dried over magnesium sulfate, and the solvents were evaporated. The product was further purified over a silica column chromatography, eluting with ethyl acetate, to give 4 as a solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:21]([O:25][C:26](N=[N+]=[N-])=[O:27])([CH3:24])([CH3:23])[CH3:22]>O.O1CCCC1>[C:21]([O:25][C:26]([N:9]([C:6]1[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:8][CH:7]=1)[CH2:10][C:11]([OH:13])=[O:12])=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: O=C(O)CNc1ccc(CO)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N(CC(=O)O)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a solution of p-hydroxymethylphenylglycine (8.0 g, 0.044 mole) and triethylamine (8.8 g., 0.087 mole) in 160 ml water was added t-butoxycarbonyl azide (6.95 g., 0.049 mole) dissolved in 120 ml tetrahydrofuran. After stirring overnight at room temperature, the reaction mixture was washed twice with 200 ml. portions of ether. The aqueous layer was covered with ether and in an ice bath was acidified to pH 3-3.5 with 3N hydrochloric acid. The acidic solution was extracted three times with 200 ml portions of ether. The combined ether layers were washed with saturated sodium chloride solution, dried, and the ether evaporated under reduced pressure. The resulting oil was triturated with chloroform-hexane and the solid filtered off to give N-t-butoxycarbonyl-p-hydroxymethylphenylglycine (7.74 g, 63% yield), m.p. 139°-141.5° (dec.).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17](=[O:19])[CH3:18])[CH:13]=2)[N:8]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:7]=1)=[O:5])C.[OH-].[Na+].O.Cl>C(O)C>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:8]2[C:9]3[C:14](=[CH:13][C:12]([C:17](=[O:19])[CH3:18])=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(F)cc2)c2ccc(C(C)=O)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)c1ccc2c(c1)c(=O)c(C(=O)O)cn2Cc1ccc(F)cc1
Yield: 81.6 %

Procedure:
A solution of compound 9 (0.46 g, 1.3 mmol) and 20% aqueous NaOH (4.3 mL) in ethanol (3 mL) was stirred for 18 hours at room temperature, then was poured into water (100 mL) and treated with 1N HCl until pH 3. The precipitate was filtered, washed with dry ethanol and light petroleum ether to give compound 12 (0.36 g, 88%); mp 206-208° C. (washed with dry ethanol).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[CH:21]1([C:24]2[NH:25][CH:26]=[CH:27][N:28]=2)[CH2:23][CH2:22]1>[Pd]>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([N:25]4[CH:26]=[CH:27][N:28]=[C:24]4[CH:21]4[CH2:23][CH2:22]4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reactant: c1c[nH]c(C2CC2)n1
Agent: [Pd]
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3C3CC3)nc2N1C1CCCC1

Procedure:
Intermediate B was reacted via palladium coupling with 2-cyclopropyl-1H-imidazole (synthesized according to U.S. Pat. No. 6,610,723, column 91, Example 409, the disclosure of which is hereby incorporated by reference with respect to this compound) to provide the title compound. 1H NMR (CD3OD) δ: 8.05 (s, 1H), 8.04 (d, J=2.2 Hz, 1H), 7.46 (d, J=2.2 Hz, 1H), 4.43 (pent, J=3.7 Hz, 2H), 3.40 (s, 3H), 3.21 (pent, J=3.3 Hz, 1H), 2.20-2.05 (m, 1H), 2.05-1.77 (m, 7H), 1.75-1.60 (m, 2H), 1.36 (d, J=7.5 Hz, 2H), 1.30-1.10 (m, 2H), 0.87 (t, J=7.5 Hz, 3H); LCMS: 367.1 m/z (M+H)+; ret. Time: 6.70 min (Analytical Method C).
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[O:18])[O:16][C:15](=[O:19])[NH:14][C:13]=2[CH:20]=1.IC>O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[O:18])[O:16][C:15](=[O:19])[N:14]([CH3:3])[C:13]=2[CH:20]=1
Reactant: CN(C)C=O
Reactant: O=c1[nH]c2cc(Br)ccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1c(=O)oc(=O)c2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
Sodium hydride (0.47 g, 12 mmol) was added to a 3 neck 250 mL RBF under nitrogen and then washed with hexanes. Once the hexanes were decanted, N,N-dimethylformamide (20.0 mL, 11 mmol) was added. The resulting mixture was cooled to 0° C. using an ice-water bath, and then 7-bromo-1H-benzo[d][1,3]oxazine-2,4-dione (2.7 g, 11 mmol) was added in one batch. After stirring at room temperature for 1 hour, iodomethane (0.70 mL, 11 mmol) was added dropwise to the yellow solution, and the reaction mixture was stirred for 16 hours. Water (50 mL) was added, and the resulting precipitate that formed was collected via filtration. The solid was washed with additional water (100 mL), followed by ether (100 mL). Drying in a vacuum oven overnight at 50° C. afforded the desired product as an off-white solid (2.1 g, 74% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:50][N:51]([CH3:56])[CH2:52][CH2:53][NH:54][CH3:55]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([N:54]([CH2:53][CH2:52][N:51]([CH3:56])[CH3:50])[CH3:55])=[O:36])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:48][CH:49]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Reactant: CNCCN(C)C
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N(C)CCN(C)C)cc3)cn2)cc1
Yield: 56.6 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (46.5 mg, 0.0705 mmol) obtained in Step A in Example 1-D-19 and N,N,N′-trimethyl ethylenediamine (36.7 μl, 0.282 mmol) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, amidation was carried out, to obtain a crude product of 4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-dimethylamino-ethyl)-N-methyl-benzamide as a yellow liquid (29.7 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-84) as a colorless powder (14.0 mg, 39%).
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:20][CH2:19]2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5](O)=[O:6].[CH2:34]([NH2:36])[CH3:35]>>[CH2:34]([N:36]1[CH:2]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[CH:25]=4)[CH2:20][CH2:19]3)=[CH:12][CH:13]=2)[CH2:3][CH2:4][C:5]1=[O:6])[CH3:35]
Reactant: O=C(O)CCC(=O)c1ccc(CCCCN2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1
Reactant: CCN
Product: CCN1C(=O)CCC1c1ccc(CCCCN2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1

Procedure:
4-Oxo-4-[4-(4-(4-(3-trifluoromethylphenyl)piperazin-1-yl)butyl)phenyl]butyric acid and ethylamine are reacted together to give N-ethyl-5-[4-(4-(4-(3-trifluoromethylphenyl)piperazin-1-yl)butyl)phenyl ]pyrrolidin-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](O)(=[O:12])[CH:10]=[CH2:11].C1C2NC3C(=CC=CC=3)SC=2C=CC=1>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:8][CH2:11][CH2:10][C:9]2=[O:12]
Reactant: C=CC(=O)O
Reactant: Oc1ccc(Br)cc1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: O=C1CCOc2ccc(Br)cc21
Temperature: -78 °C
Reaction time: 6 h

Procedure:
Following the procedure of Example 1, para-bromophenol (43.25 grams), acrylic acid (27 grams) and phenothiazine (0.02 grams) were added to the pressure reactor. The system was closed and evacuated before being cooled to -78° C. and the anhydrous hydrogen fluoride (110 grams) was added. After the mixture was heated and stirred for six hours at 100° C., 140 psig, the excess hydrogen fluoride was vented and the reaction mixture cooled to 0°-5° C. After washing the mixture with D.I. water, HPLC analysis indicated one major product which was separated and characterized as 6-Bromo-4-Chromanone.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]([OH:13])[C:5]1[CH:6]=[CH:7][C:8]([OH:12])=[C:9]([OH:11])[CH:10]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:37][O:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[CH:45]=[C:44]([CH:49]([CH3:53])[C:50]([OH:52])=O)[CH:43]=[CH:42]2>C(#N)C>[OH:11][C:9]1[CH:10]=[C:5]([CH:4]([OH:13])[CH2:3][N:2]([CH3:1])[C:50](=[O:52])[CH:49]([C:44]2[CH:43]=[CH:42][C:41]3[C:46](=[CH:47][CH:48]=[C:39]([O:38][CH3:37])[CH:40]=3)[CH:45]=2)[CH3:53])[CH:6]=[CH:7][C:8]=1[OH:12]
Reactant: CNC[C@H](O)c1ccc(O)c(O)c1
Reactant: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: COc1ccc2cc(C(C)C(=O)N(C)CC(O)c3ccc(O)c(O)c3)ccc2c1
Reaction time: 0.17 h

Procedure:
Epinephrine (Aldrich, 3.18 grams [g], 17.3 millimoles [mmol]), 1-hydroxylbenzotriazole hydrate (Aldrich, 1.76 g, 12.9 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl (Aldrich, 2.49 g, 12.9 mmol) were added to acetonitrile (200 milliliters [ml]). After stirring for 10 minutes, a solution of 6-methoxy-α-methyl-2-naphthaleneacetic acid (Aldrich, 2.0 g, 8.66 mmol), in 50 ml of acetonitrile, was added dropwise. After stirring for 16 hours, the reaction mixture was concentrated in vacuo (under reduced pressure), and the residue was partitioned between water (100 ml) and methylene chloride (100 ml). The layers were separated and the aqueous layer was extracted with methylene chloride (2×50 ml) and ethyl acetate (50 ml). The combined organic extracts were treated with methanol until a clear solution was formed. This solution was dried (magnesium sulfate) and concentrated in vacuo. Flash chromatography of the residue (silica gel, 95:5, volume:volume [v:v], methylene chloride:methanol), and concentration of the appropriate fractions resulted in the formation of a solid. The solid was recrystallized from a mixture of ethyl acetate and hexane to give N-(2(3,4-dihydroxyphenyl)-2-hydroxyethyl)-N-methyl-2-(6-methoxy-2-naphthyl)propionamide, a mixture of diastereomers, as a white solid (0.95 g, 27% yield).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]4)=[O:26])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.[P:38](=[O:42])([OH:41])([OH:40])[OH:39]>C(Cl)Cl>[CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:28][CH2:29][C:30]([F:34])([F:33])[CH2:31][CH2:32]4)=[O:26])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.[P:38]([O-:42])([O-:41])([O-:40])=[O:39]
Reactant: O=P(O)(O)O
Agent: Cc1nnc(C(C)C)n1[C@@H]1C[C@H]2CC[C@@H](C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Solvent: ClCCl
Product: O=P([O-])([O-])[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Maraviroc (10 gm) was dissolved in methylene chloride (100 ml) and stirred for 30 minutes at room temperature. To the solution was added phosphoric acid (2 gm) and stirred for 11 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 11 gm of crystalline form 1 of maraviroc phosphate.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:16]=2[NH:15][C:14](=[O:17])[CH:13]3SC)=[O:7])=[CH:4][CH:3]=1.[Sn].Cl>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:16]=2[NH:15][C:14](=[O:17])[CH2:13]3)=[O:7])=[CH:20][CH:21]=1
Reactant: CSC1C(=O)Nc2c(C(=O)c3ccc(F)cc3)cccc21
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: O=C1Cc2cccc(C(=O)c3ccc(F)cc3)c2N1

Procedure:
A mixture of 40.0 g (0.133 mole) of 7-(4-fluorobenzoyl)-3-methylthioindolin-2-one and 40.0 g (0.34 mole) of tin powder in one liter of 95% ethanol was heated to reflux and 100 ml of concentrated hydrochloric acid was added. The mixture was heated for 6 hrs, then filtered while hot. The filtrate was cooled and the precipitate was collected and recrystallized from isopropyl alcohol to yield 24.5 g (72%) as off-white needles, m.p. 185°-187.0° C.
Reaction SMILES: CO[C:3](=O)[NH:4][C:5]1[CH:6]=[N:7][C:8]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].COCCO[AlH2-]OCCOC.[Na+].[OH-].[Na+].C(OCC)(=O)C>ClCCl.C1(C)C=CC=CC=1>[CH3:3][NH:4][C:5]1[CH:6]=[N:7][C:8]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: COC(=O)Nc1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CNc1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
A solution of 0.5 g (1.4 mMol) [6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-carbamic acid methyl ester in 3.0 ml dichloromethane was added over 10 minutes to a solution of 1.98 ml (6.9 mMol ) Red-Al® (70% in toluene) and 2.5 ml toluene (exothermic, cool with a water bath to avoid temperature to go >50° C.). The reaction mixture was stirred 2 hours at 50° C., cooled to 0° C., and 4 ml aqueous NaOH 1N were carefully (exothermic) added over 15 minutes, followed by 20 ml ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with deionized water and brine, dried (Na2SO4) and concentrated under reduced pressure to yield 0.37 g (89%) methyl-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-amine as an orange resin.
Reaction SMILES: [CH:1]([C:4]1([CH3:19])[S:8][C:7]([NH:9][C@H:10]2[CH2:15][C@H:14]3[CH2:16][C@@H:11]2[CH2:12][C:13]3=[O:17])=[N:6][C:5]1=[O:18])([CH3:3])[CH3:2].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[OH:17][C@@H:13]1[CH2:12][C@H:11]2[CH2:16][C@@H:14]1[CH2:15][C@@H:10]2[NH:9][C:7]1[S:8][C:4]([CH:1]([CH3:3])[CH3:2])([CH3:19])[C:5](=[O:18])[N:6]=1
Reactant: CC(C)C1(C)SC(N[C@H]2C[C@H]3C[C@@H]2CC3=O)=NC1=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C1(C)SC(N[C@H]2C[C@H]3C[C@@H]2C[C@H]3O)=NC1=O
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 5-isopropyl-5-methyl-2-((1R,2S,4R)-5-oxobicyclo[2.2.1]heptan-2-ylamino)thiazol-4(5H)-one (0.380 g, 1.36 mmol) in anhydrous THF (20 mL) was added L-Selectride (1.0 M solution in THF, 4.07 mL, 4.07 mmol) in anhydrous THF at −78° C. under nitrogen. After stirring at −78° C. for 3 h., the reaction was quenched with hydrogen peroxide (35 wt % solution in water, 4 mL) and NaOH (10% aqueous, 7 mL). The mixture was warmed to ambient temp. and then in a 65° C. bath overnight. The volatiles were removed in vacuo. The residue was partitioned between CHCl3/i-PrOH (v/v=3/1) and brine. The organic portion was separated, dried over MgSO4, filtered, and conc. in vacuo. The residue was purified by flash column chromatography (0 to 5% of MeOH in EtOAc) to give the title compound as a white solid.
Reaction SMILES: CC(O)C.[CH3:5][C:6]1([CH3:20])[CH2:10][C:9]2[CH:11]=[CH:12][C:13]([S:17]([O-:19])=[O:18])=[C:14]([O:15][CH3:16])[C:8]=2[O:7]1.[Li+].[Cl:22]N1C(=O)CCC1=O>O>[CH3:5][C:6]1([CH3:20])[CH2:10][C:9]2[CH:11]=[CH:12][C:13]([S:17]([Cl:22])(=[O:19])=[O:18])=[C:14]([O:15][CH3:16])[C:8]=2[O:7]1
Reactant: COc1c(S(=O)[O-])ccc2c1OC(C)(C)C2
Reactant: O=C1CCC(=O)N1Cl
Agent: [Li+]
Solvent: CC(C)O
Solvent: O
Product: COc1c(S(=O)(=O)Cl)ccc2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension composed of 100 ml of water and 100 ml of 2-propanol and containing 24.8 g of lithium 2,3-dihydro-2,2-dimethyl-7-methoxy-6-benzofuransulfinate is added portionwise 14.7 g of N-chlorosuccinimide. The reaction temperature is maintained at 15°-20° during the addition by occasional cooling with an ice-water bath. After addition is complete, the suspension is stirred at ambient temperature for one hour and then is diluted with water. The aqueous mixture is extracted twice with methylene chloride. The combined organic extractions are dried over sodium sulfate and then the solvent is evaporated under reduced pressure to afford crude 2,3-dihydro-2,2-dimethyl-7-methoxy-6-benzofuransulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[C:16]=1[OH:25].[CH3:26]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].CI>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[C:16]=1[O:25][CH3:26]
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2c([N+](=O)[O-])cnc3ccc(Cl)cc23)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1ccc(-c2c([N+](=O)[O-])cnc3ccc(Cl)cc23)c(OC)c1OC
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
A mixture of 6-chloro-4-(2-hydroxy-3,4-dimethoxyphenyl)-3-nitroquinoline (1.20 g), N,N-dimethylformamide (20 ml), potassium carbonate powder (0.92 g) and methyl iodide (0.41 ml) was stirred for 10 mins. at 0° C. and for 2 hrs. at room temperature, and then diluted with water, extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was recrystallized from methanol to give 6-chloro-4-(2,3,4-trimethoxyphenyl)-3-nitroquinoline as yellow crystals (1.12 g, 89.6%). m.p. 114°-116° C.
Reaction SMILES: [H-].[Na+].CCO.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:35])[C:14]([NH:16][C:17]2[N:22]=[C:21]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:20]=[C:19]([O:29][CH2:30][C:31](F)(F)F)[N:18]=2)=[O:15])=[CH:9][CH:8]=1.C(O)(=O)C>CN(C=O)C>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:35])[C:14]([NH:16][C:17]2[N:18]=[C:19]([O:29][CH2:30][CH3:31])[CH:20]=[C:21]([O:23][CH2:24][C:25]([F:27])([F:26])[F:28])[N:22]=2)=[O:15])=[CH:9][CH:8]=1
Reactant: CN(C(=O)Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOc1cc(OCC(F)(F)F)nc(NC(=O)N(C)c2ccc(Br)cc2)n1
Temperature: 60 °C
Yield: 20.7 %

Procedure:
To a suspension of NaH (320 mg, 8.0 mmol, 60% dispersion in mineral oil) in anhydrous DMF (5 mL) under an N2 atmosphere was added anhydrous EtOH (583 μL, 10 mmol). To this solution was added a solution of N-(4-bromophenyl)-N′-[4,6-bis(2,2,2-trifluoroethoxy)pyrimidin-2-yl]-N-methylurea (1.0 g, 2.0 mmol), prepared in a manner similar to 7, in anhydrous DMF (3 mL). The resulting solution was heated (ca. 60° C.) for 2 h, the heat was removed and the solution cooled to room temperature. The solution was diluted with EtOAc (100 mL) and extracted with 2 N HCl (2×50 mL). The organics were dried over MgSO4, filtered and concentrated to afford a brown oil. The brown oil was eluted through a plug of silica using a mixture of hexane and EtOAc and the resulting organic solution concentrated to afford a yellow oil. The yellow oil was further purified by reverse phase chromatography (HPLC grade acetonitrile and water, both with 0.1% acetic acid) to afford 103 as a yellow tacky oil (186 mg, 41% yield): 1H NMR (CDCl3) δ 7.64 (d, 2H, J=8.8 Hz), 7.24 (d, 2H, J=8.8 Hz), 6.84 (s, 1H), 4.81-4.72 (q, 2H, J=8.5 Hz), 4.33-4.26 (q, 2H J=7.1 Hz), 1.39-1.37 (t, 3H, J=7.1 Hz); ESI/MS 449, 451 (M+H), 447, 449 (M−H).