Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3](O)[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6].C(O)CCC.S(=O)(=O)(O)O.ClC(Cl)=C(Cl)Cl.Cl>O>[O:8]=[C:7]1[O:9][C@H:3]([C@H:2]([CH2:1][OH:13])[OH:12])[C:4]([OH:10])=[C:5]1[OH:6]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClC(Cl)=C(Cl)Cl
Solvent: CCCCO
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Temperature: 85 °C
Reaction time: 17 h

Procedure:
742 g (3.75 mol) of anhydrous 2-keto-L-gulonic acid were suspended in 1.5 l (17 mol) of n-butanol and, after addition of 8 g of concentrated sulfuric acid, the mixture was evacuated to 200 mbar. After heating to 85° C., 1.1 l of water-containing n-butanol were distilled off after 2 hours. The viscous, golden-yellow-colored melt was mixed with 906 ml (8.9 mol) of perchloroethylene and rearranged at 72 to 75° C. for 17 hours after addition of 84 ml of conc. hydrochloric acid. The precipitated L-ascorbic acid was filtered off with suction, washed with n-butanol and dried in vacuo. 588 g (88%) of a pale gray crude product having a purity of 98.5% were obtained. The crude product dissolved in water. After clarifying filtration, a colorless solution was obtained from which it was possible to isolate L-ascorbic acid in a manner known from the literature. The residue (0.9%) consisted mainly of carbon.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9]([CH:11]=O)=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][NH2:25])=[CH:18][CH:17]=1>>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][NH:25][CH2:11][CH:9]([OH:10])[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(CCCN)cc1
Reactant: O=CC(=O)c1cccc(C(F)(F)F)c1
Product: Cc1ccc(CCCNCC(O)c2cccc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared in the manner described in Example 9 using 3-trifluoromethylphenylglyoxal and 3-(4-methylphenyl)propanamine. Recrystallization of the chromatographed material from hexane gave the title compound m.p. 96-98. τ(CDCl3) 8.0-8.5 (2H, m), 7.7 (3H, s), 7.0-7.5 (6H, m+2H, disappears with D2O), 5.3 (1H, dd), 2.9 (4H, s), 2.3-2.7 (4H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:14]I>C1(C)C=CC=CC=1>[CH3:14][O:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cc(C)nc(O)c1
Reactant: CI
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C)nc(OC)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 77.7 %

Procedure:
20.0 g (111.4 mmol) of ethyl 2-hydroxy-6-methylisonicotinate (20a) were suspended in 330 ml of toluene. After addition of 36.54 g (132.5 mmol) of Ag2CO3 and 23.5 g (165.6 mmol) of methyl iodide, the mixture was heated to 100° C. with KPG stirring. After 4 hours, the reaction mixture was allowed to cool to RT and it was filtered through Celite. The filtrate was washed twice with water, dried with Na2SO4 and concentrated, 16.9 g of the title compound being isolated as a yellowish oil.
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(C(C)C)CC)(C)C.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37]>C(Cl)Cl>[CH2:14]([N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:35](=[O:38])[CH:36]=[CH2:37])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCNCCCCCCCCCCCC
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N(CCCCCCCCCCCC)CCCCCCCCCCCC
Temperature: 0 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
To a solution of didodecylamine 66 (25 g, 70.7 mmol) and diisopropylethylamine (18 g, 141 mmol) in anhydrous CH2Cl2 (700 mL) at −10° C., a solution of acryloyl chloride (7.68 g, 85 mmol) in CH2Cl2 (100 mL) was added dropwise over a period of 20 min. After the completion of the addition the reaction mixture was stirred for 4 h at 0° C. after which the TLC of the reaction mixture showed the completion of the reaction. The reaction mixture was washed with satd. NaHCO3 solution (200 mL), water (200 mL), brine (100 mL) and dried over NaSO4. Concentration of the organic layer provided the product 71 (28.4 g, 100%) which was used as such in the next step. 1H NMR CDCl3 δ 0.94 (t, J=6.5 Hz, 6H), 1.05-1.69 (m, 40H), 3.15-3.60 (dt, 4H), 5.64 (d, 1H), 6.36 (d, 1H), 6.63 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:8]=[CH:9][C:10](O)=[O:11])[CH:7]=1.S(Cl)([Cl:16])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:8]=[CH:9][C:10]([Cl:16])=[O:11])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=Cc1cc(Br)ccc1F
Product: O=C(Cl)C=Cc1cc(Br)ccc1F
Temperature: 100 °C
Reaction time: 2 h

Procedure:
3-(5-Bromo-2-fluoro-phenyl)-acrylic acid (1.3 g, 5.0 mmol) prepared in Step 1 was added to thionyl chloride (10.0 mL). The reaction mixture was stirred at 100° C. for 2 hours and then concentrated under reduced pressure. The resulting residue was concentrated under reduced pressure three times, along with using toluene, to give 1.4 g of the titled compound as an unpurified dark brown liquid.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:13]1[C:18]([NH2:19])=[CH:17][N:16]=[C:15]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][O:29][CH3:30])[CH2:23][CH2:22]2)[N:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])C>CC(O)=O>[C:9]([O:8][C:6]([CH:5]1[C:13]2[N:14]=[C:15]([NH:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][O:29][CH3:30])[CH2:23][CH2:22]3)[N:16]=[CH:17][C:18]=2[NH:19][C:4]1=[O:3])=[O:7])([CH3:11])([CH3:10])[CH3:12]
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1nc(NC2CCN(CCOC)CC2)ncc1N
Solvent: CC(=O)O
Product: COCCN1CCC(Nc2ncc3c(n2)C(C(=O)OC(C)(C)C)C(=O)N3)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 133.7 %

Procedure:
2-{5-Amino-2-[1-(2-methoxy-ethyl)-piperidin-4-ylamino]-pyrimidin-4-yl}-malonic acid tert-butyl ester ethyl ester (6, 658 mgs, 1.5 mmol) was dissolved in AcOH (8.0 mls) and stirred at room temperature for approximately 4 hrs. The reaction mixture was concentrated in vacuo and dried under high vacuum overnight to give 2-[1-(2-methoxy-ethyl)-piperidin-4-ylamino]-6-oxo-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid tert-butyl ester (7, 785 mgs, ˜100%) as a mixture of acetate salts which was used as is in the next reaction without further purification. LC/MS Calcd for [M+H]+ 392, found 392.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[S:30][CH2:29][CH2:28][CH2:27][C:17]=3[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:20]=2)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([N:24]1[CH2:25][CH2:26][N:21]([C:19]2[N:20]=[C:15]([N:12]3[CH2:13][CH2:14][O:9][CH2:10][CH2:11]3)[C:16]3[S:30][CH2:29][CH2:28][CH2:27][C:17]=3[N:18]=2)[CH2:22][CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: C1CSc2c(nc(N3CCNCC3)nc2N2CCOCC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(CN2CCN(c3nc4c(c(N5CCOCC5)n3)SCCC4)CC2)cc1
Yield: 80.7 %

Procedure:
1.6 g of benzyl chloride was added dropwise to a mixture of 3 g of 4-morpholino-2-piperazino-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine, 4 g of potassium carbonate and 30 ml of N,N-dimethylformamide at room temperature under stirring, followed by stirring for 5 hours. The reaction solution was extracted with ethyl acetate, and the extract was washed with water and dried. The solvent was then distilled off and the resulting crystals were recrystallized from a mixture of diethyl ether-petroleum ether to obtain 3.1 g (82% yield) of 2-(N-benzylpiperazino)-4-morpholino-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine as pale yellow prisms having a melting point of 125° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)=[O:10])[CH:3]=1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:4]([C:9]([C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:15]=2)=[O:10])[CH:3]=1
Reactant: O=C(c1cnn(-c2ccccc2)c1)c1cc(F)ccc1O
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1ccc(F)cc1C(=O)c1cnn(-c2ccccc2)c1
Yield: 91 %

Procedure:
Prepared from 4-fluoro-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenol (282 mg) and ethyl bromoacetate according to GP2 to give 335 mg (91%) yellow solid: LC/MS (an10n8): Rt 3.16, m/z 339.0 [M−H]−; 1H NMR (CDCl3): δ 1.26 (t, J=7.0 Hz, 3H), 4.23 (t, J=7.1 Hz, 2H), 4.63 (s, 2H), 6.81 (dd, J=9.0, 4.0 Hz, 1H), 7.13 (ddd, J=8.9, 4.5, 3.0 Hz, 1H), 7.21 (dd, J=8.1, 3.2 Hz, 1H), 7.31-7.37 (m, 1H), 7.24-7.50 (m, 2H), 7.72-7.78 (m, 2H), 8.18 (s, 1H), 8.58 (s, 1H); 13C NMR (CDCl3): δ14.3, 61.8, 66.1, 114.0 (d, JCF=7.6 Hz), 116.8 (d, JCF=24.5 Hz), 118.3 (d, JCF=23.5 Hz), 119.7, 125.2, 127.7, 129.7, 131.8, 139.6, 142.8, 151.1 (d, JCF=2.2 Hz), 157.6 (d, JCF=241.1 Hz), 168.7, 187.1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[F:13].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OCC)(=O)C>C1COCC1.C(=O)([O-])[O-].[Ag+2]>[CH2:14]([O:12][C:9]1[C:10]2[C:5](=[CH:4][C:3]([F:13])=[C:2]([Cl:1])[CH:11]=2)[CH:6]=[CH:7][N:8]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=c1[nH]ccc2cc(F)c(Cl)cc12
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cc2ccnc(OCc3ccccc3)c2cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-Chloro-6-fluoro-2H-isoquinolin-1-one (prepared according to WO 2007/012422; 52.2 g) was dissolved in THF (1 L). After addition of silver carbonate (145.5 g) and benzyl bromide (40.6 mL), the mixture was stirred at room temperature overnight. Another 6.2 mL of benzyl bromide were added and the mixture was stirred at 70° C. for 2 h. After cooling down to room temperature, the reaction mixture was diluted by addition of 1 L of ethyl acetate and filtered over celite. The filter cake was washed thoroughly, the organic layer was evaporated and subjected to silica gel chromatography (n-heptanes: methyl tert. butyl ether) to give 27.8 g of the title compound 1. Rt=3.73 min (Method A). Detected mass: 288.1 (M+H+).
Reaction SMILES: [I:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:4]([CH3:17])[C:3]=1[C:18]([OH:20])=O.[N:21]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]1>>[OH:27][CH:24]1[CH2:23][CH2:22][N:21]([CH:28]2[CH2:33][CH2:32][N:31]([C:18]([C:3]3[N:4]([CH3:17])[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=4)=[N:6][C:2]=3[I:1])=[O:20])[CH2:30][CH2:29]2)[CH2:26][CH2:25]1
Reactant: Cn1c(-c2cccc(C(F)(F)F)c2)nc(I)c1C(=O)O
Reactant: OC1CCN(C2CCNCC2)CC1
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCC(O)CC2)CC1

Procedure:
In analogy to the procedure described for example 2, 5-iodo-3-methyl-2-(3-trifluoromethyl-phenyl)-3H-imidazole-4-carboxylic acid (example 36) was coupled with [1,4′]bipiperidinyl-4-ol to give the title compound as light red solid. MS: 563.2 (MH+).
Reaction SMILES: ClC1C=CC2N(C(C(F)F)=NN=2)N=1.[F:14][C:15]1[CH:16]=[C:17]([CH:38]=[C:39]([S:41]([CH3:44])(=[O:43])=[O:42])[CH:40]=1)[CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[CH:27][C:28]3[N:29]([C:31]([C:34](F)([F:36])[F:35])=[N:32][N:33]=3)[N:30]=2)[CH2:21][CH2:20]1>>[F:36][CH:34]([F:35])[C:31]1[N:29]2[N:30]=[C:25]([N:22]3[CH2:23][CH2:24][N:19]([CH2:18][C:17]4[CH:38]=[C:39]([S:41]([CH3:44])(=[O:42])=[O:43])[CH:40]=[C:15]([F:14])[CH:16]=4)[CH2:20][CH2:21]3)[CH:26]=[CH:27][C:28]2=[N:33][N:32]=1
Reactant: CS(=O)(=O)c1cc(F)cc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Agent: FC(F)c1nnc2ccc(Cl)nn12
Product: CS(=O)(=O)c1cc(F)cc(CN2CCN(c3ccc4nnc(C(F)F)n4n3)CC2)c1
Yield: 55 %

Procedure:
Obtained in 55% yield by General Synthetic Method 5, starting from 6-chloro-3-difluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine and 3-fluoro-5-methylsulfonylbenzaldehyde (obtained as described in Example 778, preparation of starting materials).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:23]2[C:22](=[O:28])[CH2:21][C@@:20]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:19])[CH2:13][CH:14](OC)[O:15]C)[CH2:3]1>C(O)(=O)C.O>[CH:14]([CH2:13][C:12](=[O:19])[C@@H:11]1[C@:20]2([CH3:29])[C@H:8]([C@H:7]3[C@H:23]([C:22](=[O:28])[CH2:21]2)[C@:24]2([CH3:27])[C@H:4]([CH2:3][C@H:2]([OH:1])[CH2:26][CH2:25]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1)=[O:15]
Reactant: COC(CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C)OC
Solvent: O
Solvent: CC(=O)O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CC=O)[C@@]3(C)CC(=O)[C@@H]12
Yield: 49.5 %

Procedure:
A solution of 3α-hydroxy-21-dimethoxymethyl-5α-pregnane-11,20-dione (900 mg.) in glacial acetic acid (13 ml) and water (1.3 ml) was stirred at 75° C for 6 hours, then poured into a mixture of ice and water. The product was collected, washed with water and dried in vacuo to give title compound (395 mg), [α]D + 100.5° (c, 0.4), λmax. 268 nm (ε 6,325).
Reaction SMILES: [CH3:1][C:2]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(N(CC)C(C)C)(C)C.Cl[C:27](=[O:32])[C:28]([O:30][CH3:31])=[O:29]>C1COCC1.CCOC(C)=O>[CH3:8][C:2]([N:9]([C:27](=[O:32])[C:28]([O:30][CH3:31])=[O:29])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([CH3:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(=O)Cl
Reactant: COC(=O)CC(C)(C)NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CC(C)(C)N(Cc1ccccc1)C(=O)C(=O)OC
Temperature: 0 °C
Yield: 91.2 %

Procedure:
To a solution of methyl 3-methyl-3-[(phenylmethyl)amino]butanoate (5.5853 g, 25.24 mmol) in THF (125 mL) was added N,N-diisopropylethylamine (6.6 mL, 37.89 mmol). The solution was cooled to 0° C., and methyl chloro(oxo)acetate (2.55 mL, 27.73 mmol) was added dropwise. The mixture was then allowed to stir and warm to room temperature overnight. The mixture was diluted with EtOAc (200 mL) and washed with 1 N aq. HCl (100 mL), followed by sat. aq. NaHCO3 (100 mL). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was crystallized from EtOAc—hexanes to give a white solid that was collected by vacuum filtration and washed with hexanes. The resulting methyl 3-methyl-3-[[(methyloxy)(oxo)acetyl](phenylmethyl)amino]butanoate (7.0709 g, 91%) was obtained as a white solid. LCMS: (M+H)+: 308.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:23])/[CH:14]=[C:15]2\[O:16][C:17]([CH3:22])([CH3:21])[O:18][C:19]\2=[O:20])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:25]1C=C(/C=C/CCN)C=CC=1Cl>>[Cl:8][C:7]1[CH:6]=[C:5](/[CH:4]=[CH:9]/[CH2:10][CH2:11][NH:12][C:13](=[O:23])/[CH:14]=[C:15]2\[O:16][C:17]([CH3:21])([CH3:22])[O:18][C:19]\2=[O:20])[CH:25]=[CH:3][C:2]=1[Cl:1]
Reactant: CC1(C)OC(=O)/C(=C/C(=O)NCCCc2ccc(Cl)c(Cl)c2)O1
Reactant: NCC/C=C/c1ccc(Cl)c(Cl)c1
Product: CC1(C)OC(=O)/C(=C/C(=O)NCC/C=C/c2ccc(Cl)c(Cl)c2)O1
Yield: 54 %

Procedure:
By appropriate application of method used to synthesize Intermediate 5, Intermediate 6 (41 mg, 0.19 mmol) was converted to Example 143 A (38 mg, 0.10 mmol, 54% yield). HPLC/MS (Method D) RT=1.06 min, [M+H]+ 370.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1([C:17]#[N:18])[CH2:16][CH2:15]1>>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1([C:17]([NH2:18])=[O:2])[CH2:15][CH2:16]1
Reactant: O=S(=O)(O)O
Reactant: N#CC1(c2c(F)cccc2Cl)CC1
Product: NC(=O)C1(c2c(F)cccc2Cl)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A reaction vessel containing 25 ml of concentrated sulfuric acid was cooled in ice bath. Then, 1-(2-chloro-6-fluorophenyl)cyclopropane carbonitrile (8.9 g, 0.046 mole) was slowly added to the reaction vessel. The reaction mixture was allowed to 15 warm to room temperature and stirred for 21/2 days. The mixture was poured into 100 ml of ice water mixture and then extracted with methylene chloride. The organic layer was washed with water (2×100 ml), brine (100 ml) and dried over magnesium sulfate. The solvent was removed and the product was chromatographed over 120 g silica gel with a cyclohexane:ethyl acetate (70:30) eluent to give 7.6 g of product (M.P. 98°-102° C.). ##STR6## where Xn =2-bromo
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.Cl.CN(C)CCCN=C=NCC.O.O[N:26]1[C:30]2C=[CH:32][CH:33]=[CH:34][C:29]=2N=N1.N1CCCCC1.[Cl-].[NH4+]>C(Cl)(Cl)Cl>[N:26]1([C:1]([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)=[O:3])[CH2:32][CH2:33][CH2:34][CH2:29][CH2:30]1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Solvent: O
Product: O=Cc1ccc(C(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.3 %

Procedure:
To a solution of 4-carboxybenzaldehyde (1.06 g) in chloroform (14.1 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.03 g), 1-hydroxybenzotriazole monohydrate (1.62 g) and piperdine (1.05 mL) were added. After stirring the mixture at room temperature for 15 hours, a saturated aqueous solution of ammonium chloride was added. After extraction with ethyl acetate, the combined organic layers were washed with saturated brine. The washed organic layers were dried over anhydrous magnesium sulfate and after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=85:15-30:70) to give the titled compound as a colorless oil (1.57 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]#[C:12][Si](C)(C)C)[C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2]>CN(C)C(=O)C.[Cu]I>[N+:1]([C:4]1[CH:5]=[C:6]2[CH:11]=[CH:12][NH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)C#Cc1cc([N+](=O)[O-])cnc1N
Agent: [Cu]I
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1cnc2[nH]ccc2c1
Yield: 82.3 %

Procedure:
5-Nitro-3-trimethylsilanylethynyl-pyridin-2-ylamine (0.7 g, 2.98 mmol) and copper(I) iodide (114 mg, 0.60 mmol) were dissolved in N,N-dimethylacetamide (14 mL). The mixture was irradiated in a microwave reactor at 190° C. for 30 min. The mixture was evaporated to remove N,N-dimethylacetamide in vacuo. The residue was dissolved in hot tetrahydrofuran (50° C., 250 mL) and filtered through a short pad of silica gel (from QingDao, 200-300 mesh). The filtrate was concentrated to afford 5-nitro-1H-pyrrolo[2,3-b]pyridine (0.4 g, 83%) as a yellow solid: LC/MS m/e calcd for C7H5N3O2 [M+H]+ 164.14, observed 164.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=2[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:10]([C:29](N2C3CC4C(C)(C)C3(CC4)CS2(=O)=O)=[O:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:45].[Li+].Cl>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[C:14]=2[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[C@@H:10]([C:29]([OH:30])=[O:45])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)OC(=O)c1c(C2CN(C(=O)OC(C)(C)C)CC2C(=O)N2C3CC4CCC3(CS2(=O)=O)C4(C)C)cccc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)OC(=O)c1c([C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2C(=O)O)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 138.9 %

Procedure:
To a solution of 3-(10,10-Dimethyl-3,3-dioxo-3λ6-thia-4-aza-tricyclo[5.2.1.01,5]decane-4-carbonyl)-4-(2-isopropoxycarbonyl-3-trifluoromethyl-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (625 mg, 0.97 mmol)) in 20 mL of 2:1 THF/H2O was added lithium hydroxide (70 mg, 2.91 mmol). The reaction mixture was allowed to stir at ambient temperature for 18 h. The reaction was acidified with 1 N HCl and extracted with EtOAc. The EtOAc layer was washed with brine, dried (MgSO4) and concentrated to afford 0.60 g of a mixture of the title compound and (1R)-(+)-2,10-camphorsultam, which was used without purification. LRMS (ES)+: 446.28 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[H-].[K+].Br[CH2:19][CH:20]=[CH:21][CH3:22]>O1CCCC1>[CH2:19]([N:9]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:20]=[CH:21][CH3:22]
Reactant: CC=CCBr
Reactant: Clc1ccc(CNc2cccnc2)cc1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC=CCN(Cc1ccc(Cl)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
A solution of 4.4 g of N-[(4-chlorophenyl)methyl]-(3-pyridyl)amine dissolved in 50 ml of tetrahydrofuran was added to a suspension of 4 g of a 24.6% suspension of potassium hydride in oil in tetrahydrofuran. The mixture was allowed to stir at room temperature for approximately 30 minutes whereupon 4 g of 1-bromo-2-butene was added dropwise to the reaction mixture. The mixture was allowed to stir at room temperature overnight at which time the solution was evaporated to dryness. The residue was dissolved in dichloromethane and washed with water. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The oil residue was chromatographed over silica gel. Fractions containing the major component were combined and the solvent was evaporated therefrom to provide 3 g of N-(2-butenyl)-N-[(4-chlorophenyl)methyl]-(3-pyridyl)amine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]#[N:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13](=[N:16][OH:17])[NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ccc(-c2ccc(Cl)cc2)o1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NC(=NO)c1ccc(-c2ccc(Cl)cc2)o1

Procedure:
A mixture of 51 g (0.25 mole) of 5-(p-chlorophenyl)-2-furonitrile, 19 g (0.27 mole) of hydroxylamine hydrochloride, 18 g (0.27 mole) of potassium hydroxide and 750 ml of absolute ethanol was heated under reflux for 1 hour. The reaction mixture was concentrated on a rotary evaporator and cooled in ice overnight. The solid was collected by filtration and washed with anhydrous ether to give 43 g (73%). Two recrystallizations from absolute ethanol gave an analytical sample, m.p. 167°-169°.
Reaction SMILES: [O:1]=[C:2]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=[CH:28][CH:27]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.[BH4-].[Na+].Cl>CO.O>[OH:1][CH:2]([C:26]1[CH:27]=[CH:28][C:29]([C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=[CH:30][CH:31]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:25])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][CH2:7]1
Reactant: CC(C)(CO)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(CO)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
Dissolve 2-(4-(1-oxo-4-(4-(hydroxydiphenylmethyl)-1-piperidinyl)-butyl)-phenyl)-2-methylpropanol in methanol (450 mL) and stir for 15 minutes at room temperature. Add, -by dropwise addition, a solution of sodium borohydride (2.25 g, 0.06 mol) in water (10 mL) over 15 minutes. Stir for another 30 minutes and cool in an ice-bath. Slowly add concentrated hydrochloric acid (4 mL) and water (8 mL) and stir for an additional 20 minutes. Evaporate the solvent in vacuo and partition the residue between methylene chloride (150 mL) and water (70 mL). Separate the organic phase and extract the aqueous phase with methylene chloride (25 mL). Wash the combined organic layers with water (2×50 mL), evaporate the solvent in vacuo and recrystallize (acetone) to give the title compound as white needles (9.53 g, 79%).