Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[N:25]=[CH:24][C:23]([C:26]([O:28]C)=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.[OH-].[Na+]>O1CCCC1>[CH:1]1([CH:7]([NH:19][C:20]2[N:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCCC2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)O)cn2)C2CCCCC2)oc2ccc(F)cc12
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a mixture of methyl 6-{[cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}pyridine-3-carboxylate (547 mg) synthesized above, ethanol (10 mL) and tetrahydrofuran (10 mL) was added 1N aqueous sodium hydroxide solution (10 mL), and the mixture was stirred overnight with heating under reflux. In addition, 1N aqueous sodium hydroxide solution (5.00 mL) was added, and the mixture was stirred with heating under reflux for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (15 mL) was added at 0° C. The resulting precipitate was collected by filtration, and the obtained pale-brown solid was dissolved in ethyl acetate. The solution was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (478 mg, 90%) as a pale-brown solid.
Reaction SMILES: Cl.C([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([Cl:17])[C:8]=1[NH2:18])(C)(C)C>CO>[ClH:17].[Cl:17][C:9]1[C:8]([NH2:18])=[C:7]([NH2:6])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: CC(C)(C)Nc1c(N)c(Cl)nc2ccccc12
Agent: Cl
Solvent: CO
Product: Nc1c(Cl)nc2ccccc2c1N
Temperature: 75 °C
Yield: 211.4 %

Procedure:
Methanol (200 mL) and hydrochloric acid (22 mL of 6 N) were added to N4-(tert-butyl)-2-chloroquinoline-3,4-diamine (16.6 g, 66.5 mmol), and the reaction was heated overnight at 75° C. and concentrated under reduced pressure at 100° C. The solid residue was further dried under high vacuum for three hours and then mixed with diethyl ether. The solid was isolated by filtration, washed with diethyl ether, and dried under reduced pressure to provide 16.17 g of 2-chloroquinoline-3,4-diamine hydrochloride.
Reaction SMILES: C1CCN(C(/N=N/C(N2CCCCC2)=O)=O)CC1.C(P(CCCC)CCCC)CCC.[C:32]([O:36][C:37](=[O:46])[NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([OH:45])[CH:40]=1)([CH3:35])([CH3:34])[CH3:33].[CH2:47]([O:54][C:55]([N:57]1[CH2:62][CH2:61][CH:60](O)[CH2:59][CH2:58]1)=[O:56])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C1COCC1>[CH2:47]([O:54][C:55]([N:57]1[CH2:62][CH2:61][CH:60]([O:45][C:41]2[CH:42]=[CH:43][CH:44]=[C:39]([NH:38][C:37]([O:36][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:46])[CH:40]=2)[CH2:59][CH2:58]1)=[O:56])[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(OC2CCN(C(=O)OCc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 57.9 %

Procedure:
To an ice-cooled solution of 1,1-(azodicarbonyl) dipiperidine (18.08 g, 71.7 mmol) in anhydrous THF (200 mL) is added via syringe tributylphosphine (17.69 mL, 79.7 mmol) and allowed to stir for 2.5 hours. To this ice-cooled mixture is added a solution of (3-hydroxy-phenyl)-carbamic acid tert-butyl ester (10.0 g, 47.8 mmol) and 4-hydroxy-piperidine-1-carboxylic acid benzyl ester (7.23 mL, 47.8 mmol) in anhydrous THF (30 mL) causing a light yellow precipitate to form. The mixture is warmed to room temperature and stirred overnight. The mixture is filtered through a fritted funnel and washed solid with THF (3×15 mL). After removal of solvent, the residue is purified on a silica gel chromatography with ethyl acetate-hexanes to provide a clear oil (11.8 g, 57.9% yield, ES+(m/z) 427.2 [M+H]).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][CH2:22][C:23]1[N:24]([C@@H:29]2[CH2:38][C:37]3[C:32](=[C:33]([F:40])[CH:34]=[C:35]([F:39])[CH:36]=3)[O:31][CH2:30]2)[C:25](=[S:28])[NH:26][CH:27]=1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.SCC(O)=O.[OH-].[K+].O>CN(C)C=O.CO.O>[CH2:1]([NH:8][CH2:21][CH2:22][C:23]1[N:24]([C@@H:29]2[CH2:38][C:37]3[C:32](=[C:33]([F:40])[CH:34]=[C:35]([F:39])[CH:36]=3)[O:31][CH2:30]2)[C:25](=[S:28])[NH:26][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCc1c[nH]c(=S)n1[C@H]1COc2c(F)cc(F)cc2C1)Cc1ccccc1
Agent: O=C(O)CS
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: Fc1cc(F)c2c(c1)C[C@@H](n1c(CCNCc3ccccc3)c[nH]c1=S)CO2
Temperature: 22.5 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of (R)—N-benzyl-N-(2-(3-(6,8-difluorochroman-3-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-yl)ethyl)-2-nitrobenzenesulfonamide (compound K′, 8 g, 13.64 mmol) and 2-mercaptoacetic acid (2.84 ml, 40.9 mmol) in dimethylformamide (DMF) (80 ml) was added 10N potassium hydroxide (10.23 ml, 102 mmol) in one portion with water cooling and the mixture was stirred at 20-25° C. under HPLC control for 3 hours. Methanol-water 1:1 (160 ml) was slowly added with stirring, the mixture was stirred for 2 hours at 20-25° C. Precipitate was collected, washed with MeOH-water 1:1 (80 ml), dried to give (R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione (4.96 g, 12.35 mmol, 91% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13])[CH3:11])([O-:3])=[O:2].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([NH2:28])[N:21]=1>C(#N)C>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([NH:28][C:16]([NH:15][S:12]([CH:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH3:11])(=[O:14])=[O:13])=[O:17])[N:21]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: CC(c1ccccc1[N+](=O)[O-])S(=O)(=O)N=C=O
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)C(C)c2ccccc2[N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4.0 g of the product from Example 15 and 2.2 g of 4,6-dimethoxy-2-aminopyrimidine in 29 ml dry acetonitrile was heated to ca. 60° C. for 11/2 hours and then stirred at room temperature overnight. The product, which had precipitated, was collected and washed with 1-chlorobutane and then dried in vacuo. The yield of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-1-(2-nitrophenyl)ethanesulfonamide was 3.1 g white solid, m.p. 168°-170° C.
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([CH3:18])=[N:5][CH:6]=[C:7]([CH2:16][OH:17])[C:8]=1[CH:9]=[CH:10][C:11]([O:13]CC)=[O:12].Cl>[OH-].[Na+]>[OH:2][C:3]1[C:4]([CH3:18])=[N:5][CH:6]=[C:7]([CH2:16][OH:17])[C:8]=1[CH:9]=[CH:10][C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)C=Cc1c(CO)cnc(C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ncc(CO)c(C=CC(=O)O)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
A mixture of 3.0 g of ethyl 3-(3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridyl)acrylate hydrochloride in 15 ml of 1N aqueous sodium hydroxide solution is stirred at room temperature for 1 hour. The reaction mixture is adjusted to pH 4 with 10% hydrochloric acid, and the resulting precipitate is collected to give 2.2 g of 3-(3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridyl)acrylic acid.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([CH3:25])([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:27][C:28]1[O:32][C:31]([C:33]2([CH3:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[N:30][C:29]=1[CH2:40][CH2:41]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:25][C:5]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:41][CH2:40][C:29]2[N:30]=[C:31]([C:33]3([CH3:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[O:32][C:28]=2[CH3:27])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:26]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3(C)CCCCC3)oc2C)cc1
Product: Cc1oc(C2(C)CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc(C(F)(F)F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 3-(4-hydroxyphenyl)-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester and toluene-4-sulfonic acid 2-[5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl)-ethyl ester using the procedure of Example 50. 1H NMR (400 MHz, CDCl3) δ 7.49 (d, 2H, J=8.60 Hz), 7.15 (d, 2H, J=8.60 Hz), 6.94 (d, 2H, J=8.60 Hz), 6.78 (d, 2H, J=8.60 Hz), 4.13 (t, 2H, J=6.25 Hz), 3.25 (d, 1H, J=14.08 Hz), 3.15 (d, 1H, J 14.08 Hz), 2.99 (t, 2H, J=6.25 Hz), 2.33 (s, 3H), 2.14-2.06 (m, 2H), 1.61-1.41 (m, 8H), 1.49 (s, 3H), 1.30 (s, 3H); MS (ES+) calcd for C30H35NO5F3: Found m/e 546.3 (M+1, 100%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](OC2C=CC=C(C=O)C=2OCCO)[CH:3]=1.CN.C([BH3-])#N.[Na+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(O)(=O)C.CO>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[C:6](#[N:7])[C:5]1[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1OCCO
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccccc1

Procedure:
4-Chloro-2-[3-formyl-2-(2-hydroxyethoxy)phenoxy]benzonitrile (0.29 g, 0.91 mmol), methylamine (2M in methanol, 2.0 mL, 4.0 mmol) and sodium cyanoborohydride (70 mg, 1.1 mmol)-were stirred at ambient temperature in a 0.1% acetic acid/methanol solution (25 mL) for 24 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.11 g, 0.95 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-[2-(2-hydroxyethoxy)-3-methylaminomethyl)phenoxy]-benzonitrile fumarate (250 mg, 61%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[N+:13]([O-])=O)[CH3:2]>C1C=CC=CC=1.O=[Pt]=O>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH2:13])[CH3:2]
Reactant: CCOC(=O)Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: c1ccccc1
Product: CCOC(=O)Cc1cc(Cl)ccc1N
Yield: 63.8 %

Procedure:
(5-Chloro-2-nitro-phenyl)-acetic acid ethyl ester (5.9 g, 24.2 mmol) in benzene (125 mL) containing PtO2 (500 mg) was placed on a Parr hydrogenator at 40 psi H2. After 18 h the mixture was filtered through celite and evaporated to give a clear brown liquid. The liquid was purified (silica, 25% EtOAc/hexanes) to give 3.3 g (64%) of a clear golden liquid. TLC (silica, 25% EtOAc/hexanes): Rf=0.30. MS (electrospray): exact mass calculated for C10H12ClNO2, 213.06. m/z found, 214.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.20-7.10 (m, 2H), 6.78 (d, J=8.3 Hz, 1H), 4.26 (q, J=7.2, 2H), 1.18 (t, J=7.1 Hz, 3H).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:47])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:46])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:45])[NH:31][C@@H:32]4[CH2:36][CH2:35][C@H:34]([CH2:37][N:38]5[CH2:43][CH2:42][CH2:41][CH:40]([CH3:44])[CH2:39]5)[CH2:33]4)[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:49])[CH3:48])(=O)C.[OH-].[Na+]>C1COCC1>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:47])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:46])[CH2:12][CH2:13][C@@:14]3([C:30]([NH:31][C@@H:32]4[CH2:36][CH2:35][C@H:34]([CH2:37][N:38]5[CH2:43][CH2:42][CH2:41][CH:40]([CH3:44])[CH2:39]5)[CH2:33]4)=[O:45])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:48])[CH3:49]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCCC(C)C4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCCC(C)C4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.1 %

Procedure:
(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((1R,3S)-3-((3-methylpiperidin-1-yl)methyl)cyclopentylcarbamoyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 49, 0.5 g) in MeoH:THF (8:8 ml) and cooled the contents to 0° C. then sodium hydroxide (0.12 g in 4 ml water) was added and stirred for about 6 hours at room temperature. Completion of the reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure and the residue was taken in water, and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.31 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57-0.97 (m, 19H); 1.18-1.21 (m, 8H); 1.25-1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65-1.82 (m, 10H); 1.85-1.98 (m, 4H); 2.56-2.69 (m, 2H); 3.29-3.38 (m, 1H); 3.89-3.90 (m, 1H); 4.25-4.70 (m, 4H); 5.78 (s, 1H); MASS: 635 (100%).
Reaction SMILES: [N+]([CH2:4][C@H:5]([C@@H:7]([C@H:9]([C@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8])[OH:6])([O-])=O.S(=O)(=O)(O)[OH:16].[OH-].[Ba+2].[OH-]>[OH-].[Na+].O>[OH:16][C@@H:4]1[O:12][C@@H:11]([CH2:13][OH:14])[C@H:9]([OH:10])[C@@H:7]([OH:8])[C@@H:5]1[OH:6]
Reactant: O=[N+]([O-])C[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO
Reactant: O=S(=O)(O)O
Agent: [Ba+2]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC[C@@H]1O[C@@H](O)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
1-Deoxy-1-nitro-L-glucitol (5.0 g.) was dissolved in 2 N sodium hydroxide (15 ml.) and the solution was immediately added dropwise to a stirred, cooled (ice-bath) solution of sulfuric acid (7.5 ml.) in water (9.0 ml.). The solution was then diluted with water (175 ml.) and neutralized to Congo Red with warm barium hydroxide solution. The precipitated barium sulfate was removed by centrifugation and the remaining sulfate was precipitated with a slight excess of barium acetate. The solution was then filtered through a pad of Celite® and the filtrate de-ionized by passage through a column containing 50 ml. of Dowex® 50W-X8 (H+) resin. The effluent and washings were evaporated under reduced pressure to a syrup which was diluted with a few drops of ethanol, warmed to 50°, seeded (seed crystals obtained from previous experiments) and allowed to crystallize. The resulting crystals were filtered with the aid of cold ethanol to give, after recrystallization, α-L-glucopyranose (2.4 g.), m.p. 146°-147°, [α]D -100°→-53.3° (24 hr.; c 2.15, water), compared to m.p. 146°-147°, [α]D -53° (at equilibrium; c 2.6, water). The filtrate containing L-glucose (t.l.c., n-propanol/ethyl acetate/water v/v 3:1:1) was retained for use in subsequent preparations of L-glucose.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:39])[C:14]([N:16]([CH3:38])[C:17]2[C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])=[CH:19][C:20]([NH:23][C:24]([CH2:26][O:27]C(=O)C)=[O:25])=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:43][Si](C)(C)[N-][Si](C)(C)C.[K+].CI.[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:40])[C:14]([N:16]([C:17]2[CH:22]=[N:21][C:20]([N:23]([C:24](=[O:25])[CH2:26][OH:27])[CH3:43])=[CH:19][C:18]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[CH3:38])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: CC(=O)OCC(=O)Nc1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccccc1-c1cc(N(C)C(=O)CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 18 %

Procedure:
To a solution of 70 mg (0.12 mmol) acetic acid (5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-ylcarbamoyl)-methyl ester in 4 ml tetrahydrofuran at room temperature under argon were added dropwise 0.13 ml (0.12 mmol) of a 1 M solution of potassium hexamethyldisilazide in tetrahydrofuran. Stirring was continued for 1 h at room temperature and 17 mg (0.12 mmol) methyl iodide were added. After stirring overnight, saturated ammonium chloride solution was added and the aqueous layer was extracted with diethyl ether. The diethyl ether layer was dried with sodium sulfate, evaporated, and the residue was purified by flash-chromatography to give 12 mg (18%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([NH:14][CH:15]=[N:16]2)=[C:12](Cl)[N:11]=1>C(O)CCCC.C(O)(C)C>[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([NH:14][CH:15]=[N:16]2)=[C:12]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=2)[N:11]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CC(C)O
Solvent: CCCCCO
Product: Clc1cccc(Nc2nc(Cl)nc3nc[nH]c23)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
1.4 ml (13 mmol) of 3-chloro-aniline are added to a suspension of 650 mg (3.44 mmol) of 2,6-dichloro-purine in 5 ml of 1-pentanol. The reaction mixture is stirred at 100° C. (oil bath temperature) for 3 hours. After cooling to room temperature, the mixture is diluted with isopropanol and stirred at 10° C. for 90 minutes. The precipitate is filtered off and rinsed with isopropanol and diethyl ether. The crystals are partitioned between 50 ml of 2 N (two normal) sodium hydroxide solution, 100 ml of water and 700 ml of ethyl acetate. The aqueous phase is subsequently extracted twice with ethyl acetate. The combined organic extracts are washed twice with water and once with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate is concentrated under reduced pressure. The crude product is stirred with diethyl ether and the crystals are dried at 50° C. under an HV. 2-Chloro-6-(3-chloro-phenyl-amino)-purine is obtained; Rf=0.47 (ethyl acetate:hexane=3:1); APCI-MS: (M+H)+=280; HPLC: tret(grad 20/1)=10.26 minutes.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH2:12])=[N-]>CCOCC>[CH:1]1([CH2:6][C:7]([O:9][CH3:12])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCCC1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)CC1CCCC1
Temperature: 0 °C
Yield: 62.5 %

Procedure:
To an ice-cooled and stirred solution of cyclopentylacetic acid (7.9 g, 0.062 mol) in 30 ml of ether was added an excess solution of diazomethane in ether. After concentration, the residue was distilled under reduced pressure to give a colorless transparent liquid of methyl cyclopentylacetate (yielded amount 5.5g, 0.039 mol, yield 62.5%, b.p. 64°-65° C./15 mmHg). Then, a solution of n-butyl lithium in hexane (1.58N, 55.7 ml, 0.088 mol) was added dropwise to a stirred solution of dimethyl methylphosphonate (10.9 g, 0.088 mol) in 100 ml of anhydrous THF under argon atmosphere at -78° C. After 30 minutes, the above-mentioned methyl cyclopentylacetate (5.0 g, 0.035 mol) in 10 ml of anhydrous THF was further added dropwise, and the mixture was stirred in situ for 30 minutes. This reaction mixture was allowed to warm to 0° C., diluted with 5.3 ml of acetic acid and 20 ml of water, and concentrated. 30 ml of water was added to the residue. The mixture was extracted with ethyl acetate (50 ml×2), and the combined ethyl acetate layers were washed with water (20 ml×1) and brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled under reduced pressure to give a colorless transparent oil of dimethyl 3-cyclopentyl-2-oxo-propylphosphonate (7.8 g, 0.033 mol, yield 94.7%, b.p. 110°-112° C./0.13 mmHg), which was assigned the structure by the following data:
Reaction SMILES: [C:1](Cl)(=[O:13])[O:2][CH:3]1[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2.[CH3:15][C:16]([NH2:29])([C:25]([O:27][CH3:28])=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.Cl.CCOC(C)=O.C(N(CC)CC)C>C1COCC1>[CH3:15][C:16]([C:25]([O:27][CH3:28])=[O:26])([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[NH:29][C:1]([O:2][CH:3]1[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2)=[O:13]
Reactant: COC(=O)C(C)(N)Cc1ccc(O)cc1
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(Cc1ccc(O)cc1)NC(=O)OC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tricyclo[3.3.1.13,7 ]dec-2-yl carbonchloridate [5.77 g, 0.026 mmol, prepared from 2-adamantanol and his (trichloromethyl)carbonate (Horwell, D. C., et al, J. Med. Chem. 1991, 34,404-414)] in 60 mL THF, a solution of DL-α-methyltyrosine methyl ester (5.0 g, 0.0238 mol, prepared from the DL-α-methyltyrosine methyl ester hydrochloride using 1M K2CO3 and EtOAc) in 320 mL THF was added dropwise via an addition funnel, keeping the temperature below 25° C. A solution of triethylamine (4.81 g, 0.047 mol) in 120mL THF was then added dropwise and the heterogeneous reaction mixture was stirred for 16 hours at room temperature under a nitrogen atmosphere. The amine salt was filtered and the filtrate was concentrated in vacuo to givea tan, fluffy solid. Purification by flash chromatography (silica gel, 10% EtOAc/hexane) yielded the title compound. MS: 388 (MH+); 387 (M+).
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[N:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[N:12]=[C:11]([CH3:13])[N:10]=[C:9]2[C:8]=1[NH:24][C:33](=[O:35])[N:14]2[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1nc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(CC)Oc1nc(C)nc2c1[nH]c(=O)n2-c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 254.8 %

Procedure:
A mixture of 6-(1-ethyl-propoxy)-2-methyl-N4-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5-diamine (182 mg, 0.554 mmol), triethylamine (39 mg, 0.388 mmol) and triphosgene (58 mg, 0.196 mmol) in 6 ml of dry THF was stirred at room temperature for 30 min. The mixture was quenched with water and extracted with chloroform. The organic layer was dried and concentrated to give 177 mg (90%) of the title compound as a white solid, mp 159–160° C. 1H NMR(CDCl3) δ 8.50(s,1H), 6.99(s,2H), 5.30(m,1H), 2.47(s,3H), 2.32(s,3H), 2.08(s,6H), 1.73(m,4H), 0.94(t,6H) ppm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]=2[S:8][C:7]=1[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:16][N:12]1[C:13](=[O:15])[C:14]2[C:6]([S:5][CH2:4][CH2:3][CH2:2][NH:1][C:36](=[O:37])[CH2:35][O:34][CH3:33])=[C:7]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[S:8][C:9]=2[N:10]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:11]1=[O:17]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCN)c(Cc3cccc4ccccc34)sc21
Reactant: COCC(=O)Cl
Product: COCC(=O)NCCCSc1c(Cc2cccc3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Yield: 52 %

Procedure:
Prepared from 5-[(3-aminopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (10 mg) and methoxyacetyl chloride (53 mg) following the method of Example 41 to give the title compound (6 mg).