Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:19][C:20]([CH3:35])([CH3:34])[CH2:21][CH2:22][O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[C@@H:10]([OH:18])[CH2:11][CH:12]([CH:15]([CH3:17])[CH3:16])[CH:13]=[CH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[C:37]1(C)[CH:42]=CC(S(O)(=O)=O)=C[CH:38]=1.COC(OC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([CH2:19][C:20]([CH3:34])([CH3:35])[CH2:21][CH2:22][O:23][Si:24]([CH:25]([CH3:26])[CH3:27])([CH:28]([CH3:30])[CH3:29])[CH:31]([CH3:33])[CH3:32])[C@H:10]([CH2:11][CH:12]([CH:15]([CH3:17])[CH3:16])[CH:13]=[CH2:14])[O:18][C:37]1([CH3:42])[CH3:38])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=CC(C[C@H](O)[C@H](CC(C)(C)CCO[Si](C(C)C)(C(C)C)C(C)C)NC(=O)OC(C)(C)C)C(C)C
Solvent: COC(C)(C)OC
Solvent: ClCCl
Solvent: O
Product: C=CC(C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CCO[Si](C(C)C)(C(C)C)C(C)C)C(C)C

Procedure:
4.4 g of 6(S)-tert-butoxycarbonylamino-8,8-dimethyl-5(S)-hydroxy-3(R,S)-isopropyl-10-triisopropylsilyloxydec-1-ene and 134 mg of p-toluenesulfonic acid hydrate are stirred in 25 ml of methylene chloride and dimethoxypropane at room temperature for 2 h. After the reaction mixture has been concentrated, the residue is purified over 500 g of silica gel by means of FC (mobile phase D): Rf (D)=0.61.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH3:25][C:26]1[O:30][C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:28][C:27]=1[CH2:37][O:38][C:39]1[CH:59]=[CH:58][C:42]([CH2:43][N:44]2[C:56]3[CH:55]=[CH:54][CH:53]=[C:52]([OH:57])[C:51]=3[C:50]3[C:45]2=[CH:46][CH:47]=[CH:48][CH:49]=3)=[CH:41][C:40]=1[O:60][CH3:61]>C(O)C.O>[CH3:61][O:60][C:40]1[CH:41]=[C:42]([CH:58]=[CH:59][C:39]=1[O:38][CH2:37][C:27]1[N:28]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:30][C:26]=1[CH3:25])[CH2:43][N:44]1[C:56]2[CH:55]=[CH:54][CH:53]=[C:52]([O:57][CH:2]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:51]=2[C:50]2[C:45]1=[CH:46][CH:47]=[CH:48][CH:49]=2
Reactant: COc1cc(Cn2c3ccccc3c3c(O)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCOC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)C(Oc1cccc2c1c1ccccc1n2Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)c1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 180.4 %

Procedure:
5.26 g of ethyl α-bromophenylacetate and 4.23 g of potassium carbonate (powder) were added to N,N-dimethylformamide (50 mL) suspension of 10.0 g of 9-{4-[(5-methyl-2-phenyloxazole-4-yl)methoxy]-3-methoxybenzyl}-9H-carbazole-4-ol, and stirred at 60° C. for 2 hours. After the reaction mixture was allowed to cool, water and ethanol were added, the crystalline precipitate was isolated by filtration, and 24 g of ethyl (±)-2-{9-[3-methoxy-4-((5-methyl-2-phenyl-oxazole-4-yl)methoxy)-benzyl]-9H-carbazole-4-yloxy}-2-phenylacetate (undried) was prepared. This was dissolved in mixture of ethanol-tetrahydrofuran, 4.1 mL of 5 N sodium hydroxide solution was added and stirred at 60° C. for 1 hour. The reaction mixture was allowed to cool, and then adjusted to pH3 with 1 N hydrochloric acid, the crystalline precipitate was isolated by filtration, washed with ethyl acetate, dried under reduced pressure, and 10.6 g of the subject compound was prepared as white crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[NH:11][CH2:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:5])[CH3:2].B.N1C=CC=CC=1.C(OC([C@@H]1CCC[C@H]1NCCC(C)(C)C)=O)C>C(O)(=O)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:11][CH2:12][CH2:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(NCCC(C)(C)C)CCC1
Agent: B
Agent: CCOC(=O)[C@@H]1CCC[C@H]1NCCC(C)(C)C
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H]1CCC[C@@H]1NCCC(C)(C)C
Reaction time: 0.25 h
Yield: 7.3 %

Procedure:
To a solution of 2-(3,3-dimethylbutylamino)-cyclopent-1-enecarboxylic acid ethyl ester (5.59 g, 23.4 mmol) in acetic acid (70 mL) was added a 8.0 M solution of borane in pyridine (3.2 mL, 25.6 mmol) at 25° C. After stirring for 15 min, the reaction mixture was concentrated in vacuo. The crude material was triturated with 1.0 M aqueous hydrochloric acid solution (25 mL) and stirred for 0.5 h (until the gas evolution ceased). The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude material was purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-10% methanol in dichloromethane) to afford cis-2-(3,3-dimethylbutylamino)-cyclopentanecarboxylic acid ethyl ester as a yellowish oil (0.40 g, 1.7 mmol, 7%) and trans-2-(3,3-dimethylbutylamino)-cyclopentanecarboxylic acid ethyl ester and an off-white solid (2.37 g, 9.8 mmol, 42%). cis-2-(3,3-Dimethylbutylamino)-cyclopentanecarboxylic acid ethyl ester: 1H NMR (400 MHz, CDCl3) δ 0.91 (9H, s), 1.28 (3H, t, J=7.0 Hz), 1.35-1.50 (2H, m), 1.56-1.73 (2H, m), 1.80-2.03 (4H, m), 2.60-2.75 (2H, m), 2.98-3.02 (1H, m), 3.35 (1H, q, J=7.4 Hz), 4.15 (2H, q, J=6.9 Hz), 6.38 (1H, s). trans-2-(3,3-Dimethylbutylamino)-cyclopentanecarboxylic acid ethyl ester: 1H NMR (400 MHz, CDCl3) δ 0.94 (9H, s), 1.29 (3H, t, J=7.0 Hz), 1.66-2.01 (6H, m), 2.11-2.27 (2H, m), 2.86 (2H, t, J=8.6 Hz), 3.10 (1H, q, J=7.8 Hz), 3.68 (1H, q, J=7.0 Hz), 4.18 (2H, q, J=7.0 Hz). LC-MS (ESI) calcd for C14H27NO2 241.20, found 242.4 [M+H+].
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[CH3:7][O:8][C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[O:11][CH2:12][CH:13]1[NH:17][CH2:16][CH2:15][S:14]1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([N:17]1[CH2:16][CH2:15][S:14][CH:13]1[CH2:12][O:11][C:10]1[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=1[O:8][CH3:7])=[O:4]
Reactant: COc1ccccc1OCC1NCCS1
Reactant: CC(Br)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1OCC1SCCN1C(=O)C(C)Br
Reaction time: 1 h

Procedure:
α-Bromopropionyl chloride (0.97 ml) in methylene chloride (15 ml) is added dropwise to a mixture of 2-(o-methoxyphenoxy)methyl-thiazolidine (2 g) and triethylamine (1.35 ml) in CH2Cl2 (30 ml) at 0°-5° C. After 1 hour, the mixture is washed with water and the usual work-up gives 3-α-bromopropionyl-2-(o-methoxyphenoxy)methyl-thiazolidine as a colourless oil.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[S:6](=O)(=[O:9])([OH:8])[O-:7].[Na+:11]>>[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][S:6]([O-:9])(=[O:8])=[O:7].[Na+:11]
Reactant: ClCC1CO1
Reactant: O=S(=O)([O-])O
Agent: [Na+]
Product: O=S(=O)([O-])CC(O)CCl

Procedure:
In this example, sultaine derivatives are formed using the products of Example 2. In general, epichlorohydrin is reacted with sodium bisulfate (NaHSO3) to form sodium 3-chloro-2-hydroxypropanesulfonate. This product is then reacted with the alkylamidoalkylamine composition (e.g., from Example 2) to provide the corresponding hydroxysultaine.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH2:19]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:20]>>[C:22]([N:21]([CH2:19][CH3:20])[C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCNC(C)(C)C
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Product: CCN(C(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 23b, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and N-ethyl-2-methylpropan-2-amine (CAN 4432-77-3) as starting materials and isolated (50 mg, 47%) as a light yellow solid; MS (ESI, m/z): 345.7 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([NH2:17])[CH3:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:17][CH2:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a stirred solution of 1-tert-butoxycarbonyl-4-piperidone (3.99 g, 20 mmol) in THF (40 mL) were added ethylamine (20 mL of a 2.0 M solution in THF, 40 mmol), acetic acid (1.15 mL, 20 mmol) and sodium triacetoxyborohydride (8.48 g, 40 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with 1 N aqueous sodium hydroxide (120 mL) at 0° C. and stirred at room temperature for 30 minutes. The organic solvent was evaporated under reduced pressure, and the remaining aqueous layer was extracted with ethyl acetate (40 mL, 2×20 mL). The combined organic layers were washed with brine (2×20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford the title compound (4.54 g, 19.9 mmol, 99%) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:22][C:21]2[N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]([C:27]([OH:29])=O)=[CH:17][C:16]=2[CH2:15][CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:70]([NH2:74])([CH3:73])([CH3:72])[CH3:71]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:22][C:21]2[N:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[C:18]([C:27]([NH:74][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:29])=[CH:17][C:16]=2[CH2:15][CH2:14]1)=[O:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCc2cc(C(=O)O)c(C(F)(F)F)nc2C1)Cc1cc(F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cc2c(nc1C(F)(F)F)CN(C(=O)C[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the product (33 mg, 0.061 mmol) from Example 3, Step B, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC; 12 mg, 0.063 mmol), 1-hydroxybenzotriazole (HOBt; 9 mg, 0.067 mmol) and N,N-diisopropylethyl amine (0.026 mL, 0.15 mmol) in 1.0 mL of dichloromethane was added tert-butylamine (0.011 mL, 0.100 mmol). The solution was stirred at room temperature for 18 h. The reaction mixture was subjected directly to flash chromatography (silica gel; 35 to 75% ethyl acetate/hexanes step-gradient elution) to afford the title compound as a white foam.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC(C([O:9][C@@H:10]2[CH2:18][C@@H:13]3[O:14][C:15](=[O:17])[CH2:16][C@@H:12]3[C@H:11]2/[CH:19]=[CH:20]/[C@H:21]([C:23]2[S:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[CH:24]=2)[OH:22])=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.C1COCC1>[S:27]1[C:23]([C@H:21]([OH:22])/[CH:20]=[CH:19]/[C@@H:11]2[C@@H:12]3[C@@H:13]([O:14][C:15](=[O:17])[CH2:16]3)[CH2:18][C@H:10]2[OH:9])=[CH:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]1=2
Reactant: O=C1C[C@@H]2[C@@H](/C=C/[C@@H](O)c3cc4ccccc4s3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1C[C@@H]2[C@@H](/C=C/[C@@H](O)c3cc4ccccc4s3)[C@H](O)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.1 %

Procedure:
A mixture consisting of (3aR,4R,5R,6aS)-4-((R,E)-3-(benzo[b]thiophen-2-yl)-3-hydroxyprop-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate (intermediate 28, 0.343 g, 0.672 mmol) and potassium carbonate (0.046 g, 0.336 mmol), and 1:1 methanol-THF (12 mL) was stirred at room temperature for 18 hours. The reaction mixture turned from colorless to red-orange. After complete consumption of starting material, as judged by TLC, the reaction mixture was diluted with ethyl acetate (300 mL), washed with 1:1 saturated ammonium chloride-water (2×50 mL) and brine (50 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give a yellow solid. The material was triturated in 10% ethyl acetate in hexanes (200 mL) for three days. The product was collected to give an off-white solid which was rinsed with hexanes and dried to afford the title intermediate 29 (189 mg, 85% triturated yield) as an off-white solid; MS (ESI+) m/z 313 (m+H—H2O), (ESI−) m/z 389 (m+AcO−); 1H NMR (d6-DMSO) δ 7.83-7.93 (m, 1H), 7.72-7.83 (m, 1H), 7.24-7.38 (m, 2H), 7.19-7.24 (s, 1H), 5.94-6.01 (m, 1H), 5.65-5.82 (m, 2H), 5.31-5.38 (m, 1H), 4.94-5.01 (m, 1H), 4.84-4.93 (m, 1H), 3.80-3.91 (m, 1H), 2.74-2.88 (m, 1H), 2.56-2.69 (m, 1H), 2.22-2.37 (m, 3H), 1.64-1.80 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[OH-].[Na+].[CH2:13]([OH:18])[CH2:14][CH2:15][CH2:16][CH3:17].C1(C)C=CC=CC=1>O>[CH2:13]([O:18][C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10])[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: CCCCCO
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCOc1cc[n+]([O-])c(C)c1C
Temperature: 25 °C
Yield: 125.1 %

Procedure:
17.0 g (0.11 mol, 1.0 eq.) of 4-chlor-2,3-dimethylpyridine-N-oxide, 8.6 g (0.225 mol, 2.0 eq.) of caustic soda, and 19.0 g (0.22 mol, 2.0 eq.) of 1-pentanol were added to 68 mL of toluene, and the mixture as heated to reflux for 5 hours, and then cooled to room temperature. 15 mL of water was added to the reaction liquid, and the mixture was concentrated, to obtain a residue in the form of a black paste. Subsequently, the residue was dissolved in 500 mL of water, and then the aqueous solution was extracted three times with 670 mL of chloroform. The extract was dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure, to obtain 28.8 g of 4-pentyloxy-2,3-dimethylpyridine-N-oxide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:21][C:22](=[O:35])[CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=2)[CH:13]=[CH:14][C:15]=1[S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:36][C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=1.O.[C:46]([OH:50])(=[O:49])[CH:47]=O>>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:21][C:22](=[O:35])[CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH:47]([NH:36][C:37]3[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=3)[C:46]([OH:50])=[O:49])=[CH:28][CH:27]=2)[CH:13]=[CH:14][C:15]=1[S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1CNC(=O)OC(C)(C)C
Reactant: O=CC(=O)O
Solvent: O
Product: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(C(Nc3ccc(C#N)cc3)C(=O)O)cc2)cc1CNC(=O)OC(C)(C)C

Procedure:
Using a procedure analogous to that used to prepare 2D, 15C (0.101 g, 0.20 mmol) was reacted with 4-aminobenzonitrile (0.024 g, 0.2 mmol) and glyoxylic acid monohydrate (0.018 g, 0.2 mmol) to give, after purification by reverse phase HPLC, 15D (78 mg, 62%) as a white solid. MS (ESI) m/z 634.9 (M+H)+.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[CH3:21][S:22]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NS(C)(=O)=O)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and methanesulfonyl chloride, there is obtained ethyl N-(methylsulfonyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 136.5°-138° C.;
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:33]3[CH2:37][CH:36]([OH:38])[CH:35]=[CH:34]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[H][H]>[Pd].C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:33]3[CH2:34][CH2:35][CH:36]([OH:38])[CH2:37]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(C3C=CC(O)C3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(-c2nn(C3CCC(O)C3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Yield: 68.4 %

Procedure:
A mixture of N1-{4-[4-amino-1-(4-hydroxy-2-cyclopentenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-trifluoromethylbenzamide (0.10 g, 0.19 mmol) and 10% palladium on carbon (0.03 g) in ethanol (10 mL) was stirred at ambient temperature under one atmosphere of hydrogen overnight. The mixture was filtered and the filtrate was purified by preparative HPLC to yield N1-{4-[4-amino-1-(3-hydroxycyclopentyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-trifluoromethylbenzamide (0.07 g, 0.13 mmol) as a white sold: 1H NMR (DMSO-d6, 400 MHz) δ 9.91 (dd, 1H), 8.31(d, 1H), 8.24 (s, 1H), 8.00 (t, 1H), 7.89 (d, 1H), 7.75 (d, 1H), 7.34 (s, 1H), 7.30 (d, 1H), 6.90 (br, 2H), 5.17 (m, 1H), 4.97 (m, 1H), 4.22 (m, 1H), 3.94 (s, 3H), 1.79-2.41 (m, 6H); MS: MH+ 531.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>CCO.O>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: OC1CCNCC1
Reactant: Brc1ccncc1
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC1CCN(c2ccncc2)CC1
Yield: 53.2 %

Procedure:
A solution of 4-hydroxypiperidine (7.80 g, 77 mmol), 4-bromopyridine (15.0 g, 77 mmol), and triethylamine (32 mL, 231 mmol) in 90 mL of EtOH and 30 mL of H2O was heated at 150° C. in a sealed tube for 4 days. The mixture was concentrated and the residue partitioned between CH2Cl2 and H2O. The organic layer was washed with 1 N NaOH (2×), diluted with EtOAc and the resulting solid collected by filtration affording 7.30 g (53%) of the title compound.
Reaction SMILES: [C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([CH2:21][C@H:22]([O:23]C(=O)C)[C@:5]12[CH3:6])[C@:18]1([CH3:19])[C@@H:13]([CH2:14][C@H:15]([O:27]C(=O)C)[CH2:16][CH2:17]1)[CH2:12][C@H:11]3[O:31]C(=O)C)(=[O:3])[CH3:2].O.[OH-].[Li+]>CO.O.O1CCCC1>[C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([CH2:21][C@H:22]([OH:23])[C@:5]12[CH3:6])[C@:18]1([CH3:19])[C@@H:13]([CH2:14][C@H:15]([OH:27])[CH2:16][CH2:17]1)[CH2:12][C@H:11]3[OH:31])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](C1)C[C@@H](OC(C)=O)[C@@H]1[C@@H]2C[C@H](OC(C)=O)[C@]2(C)[C@@H](C(C)=O)CC[C@@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 17β-acetyl-3α,7α,12α-triacetoxy-5β-androstane (9.48 g) and lithium hydroxide monohydrate (4.0 g) in methanol (20 ml), water (20 ml) and tetrahydrofuran (20 ml) is stirred at room temperature for about 19 hours, concentrated in vacuo, diluted with ethyl acetate and washed with brine. The organic solution is dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude is purified by flash chromatography in ethyl acetate to give the desired product.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[C:15]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:10]([CH3:27])=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu][C:30]#[N:31].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:30]#[N:31])[C:15]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:10]([CH3:27])=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(OCc3ccc(F)cc3)c(Br)cnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(C)n(Cc2ccccc2)c2c(OCc3ccc(F)cc3)c(C#N)cnc12
Temperature: 25 °C
Yield: 22.7 %

Procedure:
1-Benzyl-6-bromo-7-(4-fluorobenzyloxy)-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine hydrochloride prepared in Example 273 was neutralized with a saturated sodium carbonate solution to obtain 1-benzyl-6-bromo-7-(4-fluoro-benzyloxy)-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine (1.4 g, 3.18 mmol). A solution of 1-benzyl-6-bromo-7-(4-fluoro-benzyloxy)-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine (1.4 g, 3.18 mmol) and copper (I) cyanide (700 mg, 7.52 mmol) in anhydrous N,N-dimethylformamide (30 ml) was refluxed for 48 hours and then cooled to room temperature. Ethyl acetate was added to the reaction mixture, which was then filtered to discard insoluble solid. Water was added to the resulting solution, which was then extracted with ethyl acetate. The resulting organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/methanol=10/1, v/v) to give 278 mg of the titled compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:10]([N:13]2[C:18](=[O:19])[CH2:17][CH2:16][CH2:15][C@H:14]2[C:20]#N)[CH2:11][OH:12])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].C(=O)(O)[O-:23].[Na+].C(Cl)(Cl)Cl.Cl.[CH2:32]([OH:34])[CH3:33]>>[OH:12][CH2:11][CH:10]([N:13]1[C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH:14]1[C:20]([O:34][CH2:32][CH3:33])=[O:23])[C:4]1[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=1
Reactant: O=C([O-])O
Reactant: N#C[C@@H]1CCCC(=O)N1[C@@H](CO)c1cc(F)c(F)c(F)c1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCCC(=O)N1C(CO)c1cc(F)c(F)c(F)c1

Procedure:
A solution of (S*) 1-[(R*)-1-(3,4,5-trifluorophenyl)-2-hydroxyethyl]-6-oxopiperidine-2-carbonitrile (2.0 g) in saturated hydrochloric acid-ethanol (30 mL) was stirred at room temperature for nine days. A saturated sodium bicarbonate solution and chloroform were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 1.48 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH:1]([S:4]([C:7](=[C:10]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)SC)[C:8]#[N:9])(=[O:6])=[O:5])([CH3:3])[CH3:2].[NH2:22][CH:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:24]>>[CH:1]([S:4]([C:7](=[C:10]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[NH:22][CH:23]([CH3:24])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:8]#[N:9])(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: COc1cccc(NC(SC)=C(C#N)S(=O)(=O)C(C)C)c1
Reactant: CC(N)C(C)(C)C
Product: COc1cccc(NC(NC(C)C(C)(C)C)=C(C#N)S(=O)(=O)C(C)C)c1
Yield: 80 %

Procedure:
2-Isopropylsulfonyl-3-(3-methoxyphenylamino)-3-methylsulfanyl-2-propenenitrile (0.500 g, 1.53 mmol) was stirred in 2-amino-3,3-dimethylbutane (2 ml) for 48 h at 100° C. under nitrogen in a sealed flask. The reaction mixture was concentrated and the residue dissolved in dichloromethane,washed twice with 1N aqueous HCl, once with brine, and once with water. The organic phase was dried (sodium sulphate) and evaporated to afford 450 mg (80%) of the title compound as white crystals. Mp 59-62° C. 1H NMR (200 MHz, CDCl3): δ=0.84 (s, 9H), 0.96 (d, 3H), 1.40 (d, 6H), 3.00-3.33 (m, 2H), 3.82 (s, 3H), 6.64 (dd, 1H), 6.81 (dd, 1H), 7.31 (dd, 1H), 7.73-7.94 (m, 1H) 8.95 (br s, 1H).