Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([Cl:26])[CH:20]=2)[N:16]([CH3:27])[N:15]=1.Cl[C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=3)=[C:21]([Cl:26])[CH:20]=2)[N:16]([CH3:27])[N:15]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(Oc2ccc(C(F)(F)F)cn2)c(Cl)c1
Temperature: 120 °C
Yield: 76 %

Procedure:
To N,N-dimethylformamide (50 ml) are added 3-(2-chloro-6-fluorophenyl)-5-(3-chloro-4-hydroxyphenyl)-1-methyl-1H-1,2,4-triazole (3.04 g), 2-chloro-5-trifluoromethyl pyridine (1.70 g) and potassium carbonate (1.40 g), which is heated at 120° C. for 2 hours with stirring. After cooling to room temperature, the reaction solution is poured into water and extracted with ethyl acetate, and the layer is washed with water and dried over anhydrous magnesium sulfate. After the concentration under reduced pressure, the crude solid is purified by silica gel column chromatography using mixed solution of hexane-ethyl acetate as eluent to give 3.30 g of desired compound (melting point: 116.0°-117.0° C.).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH2:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:11][Si:10]([C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([C:25]#[C:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=2)=[CH:3][CH:4]=1)([CH3:13])[CH3:12]
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Reactant: C#Cc1ccc(CCCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.7 %

Procedure:
4-iodophenytrimethyl silylacetylene (5.0 g, 16.6 mmol), 4-n-butylphenylacetylene (2.67 g, 16.0 mmol), CuI (32 mg, 0.16 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.35 g, 0.48 mmol), triethylamine (50 mL) and THF (50 mL) were added together and stirred at ambient temperature under N2 for 18 h. The reaction mixture was filtered to remove solids and concentrated to dryness, redissolved in CHCl3, washed with water (2×), brine, dried with MgSO4, filtered, concentrated and the solid recrystallized from hexanes to give 2.10 g (40%) product. The crude product could also be purified by washing with MeOH. This gave 1.94 g additional product for a total yield of 79%. 1H NMR (CDCl3) δ: 7.46 (m, 6H), 7.20 (d, J=8.1 Hz, 2H); 2.63 (t, J=7.6 Hz, 2H); 1.62 (m, 2H); 1.38 (m, 2H); 0.95 (t, J=7.2 Hz, 3H); 0.28 (s, 9H). 13C{1H} NMR (CDCl3): 143.7, 131.9, 131.6, 131.3, 128.5, 123.6, 122.7, 120.1, 104.7, 96.1, 91.6, 88.4, 35.6, 33.4, 22.3, 14.0, −0.1 ppm.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([F:8])[O:7][C:4]1([F:6])F.[F-:11].[K+]>>[C:2]([C:3]([C:4]([F:6])=[O:7])([F:8])[F:11])([F:10])([F:9])[F:1]
Reactant: FC(F)(F)C1(F)OC1(F)F
Reactant: [F-]
Agent: [K+]
Product: O=C(F)C(F)(F)C(F)(F)F

Procedure:
CF3CF2COF (b.p. -28° C.) is prepared by flowing hexafluoropropylene oxide through a stainless steel reactor tube containing active carbon carrying 3% by weight of potassium fluoride kept at 150° C.
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=1>>[CH3:17][C:2]1[N:20]2[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]2=[N:18][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1
Reactant: Cc1ccc(N)nc1
Reactant: CC(Br)C(=O)c1ccc2c(c1)NC(=O)C(C)O2
Product: Cc1ccc2nc(-c3ccc4c(c3)NC(=O)C(C)O4)c(C)n2c1
Yield: 72.8 %

Procedure:
6-(3,6-Dimethylimidazo[1,2-a]pyridin-2-yl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.8 g) was prepared in substantially the same manner as that of Example 16 from 6-(2-bromopropionyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.4 g) and 2-amino-5-methylpyridine (2.6 g). mp. 232° C. (dec.).
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[O:19])[CH2:9][CH2:8]1)(C)(C)C>C(O)C>[OH:6][C@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[O:19])[CH2:11][CH2:12]1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N2CCCCC2=O)CC1
Solvent: CCO
Product: O=C1CCCCN1[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve trans-1-(4-[tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-piperidin-2-one (10 g, 21.1 mmol) in ethanol containing concentrated hydrochloric acid (5% v/v, 30 mL) and stir at room temperature for 18 hours. Evaporate the solvent, take the residue up in DCM (300 mL) and wash with saturated aqueous NaHCO3 (100 mL). Dry the organic layer over anhydrous Na2SO4 and remove the solvent to obtain the desired intermediate as a clear oil (4.0 g, 95%): MS (ES+) m/z=198 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]N(C)C)[C:12]=2[S:21][CH2:22][CH3:23])[CH:3]=1.[Cl:24]C(OCC)=O.O.C(OCC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][Cl:24])[C:12]=2[S:21][CH2:22][CH3:23])[CH:3]=1
Reactant: CCSc1c(CN(C)C)cccc1Oc1cc(Cl)ccc1C#N
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCSc1c(CCl)cccc1Oc1cc(Cl)ccc1C#N
Temperature: 0 °C
Reaction time: 17 h
Yield: 43.3 %

Procedure:
Under a nitrogen atmosphere, 4-chloro-2-(3-dimethylaminomethyl-2-ethylsulfanyl-phenoxy)-benzonitrile (570 mg, 1.64 mmol) was dissolved in anhydrous toluene (10 mL). The solution was cooled to 0° C. and ethyl chloroformate (480 μL, 5 mmol) was slowly added. The reaction mixture was stirred for 17 h, allowing it to reach room temperature. Water (5 mL) and diethyl ether (5 mL) were added and the organic layer was separated and dried with MgSO4. After filtration, the solvent was removed in vacuo to yield crude material (340 mg) that was then dissolved in ethyl acetate and absorbed in vacuo onto silica gel (1.5 g). This material was chromatographed on an ISCO CombiFlash Chromatography System to yield 4-chloro-2-(3-chloromethyl-2-ethylsulfanyl-phenoxy)-benzonitrile as a clear oil (240 mg, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH2:25][NH2:26])=[CH:17][N:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].C(N(CC)CC)C.[C:38](O)(=[O:41])[CH2:39][CH3:40]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:28])([F:29])[F:30])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[C:18]([CH2:25][NH:26][C:38](=[O:41])[CH2:39][CH3:40])=[CH:17][N:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: CCC(=O)O
Reactant: NCc1cnc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NCc1cnc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
1-{2-[3-(3,4,5-Trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)pyrimidin-5-yl}methanamine (0.1 g) and triethylamine (0.05 g) were added to dichloromethane (20 mL), and then dichloromethane solution (10 mL) comprising anhydrous propionic acid (0.05 g) was added dropwise thereto under ice cooling. After the dropwise addition was completed, the reaction solution was stirred at room temperature for one hour. The solvent was evaporated off under reduced pressure, and the residue was then purified by a silica gel chromatography to obtain the title compound (0.1 g, 90%).
Reaction SMILES: Cl.[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1.N>>[ClH:13].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][C:14]([Cl:13])=[CH:15][CH:16]=3)[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(Cl)cc1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 4-chlorobenzoic acid (Aldrich) according to methods A and C; yield 49 mg, 0.17 mmol (63%): 1H NMR (300 MHz, methanol-d4) δ 1.96 (d, J=14 Hz, 2H), 2.20 (s, 1H), 2.32 (d, J=14 Hz, 2H), 2.46 (s, 2H), 3.57 (s, 2H), 3.67 (s, 4H), 4.39 (s, 1H), 7.49 (d, J=8 Hz, 2H), 7.83 (d, J=8 Hz, 2H); MS (DCI/NH3) m/z 291 (M+H)+; Anal. C16H19ClN2O.HCl: C, H, N.
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([C:11]1[C:12]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([C:35]([F:38])([F:37])[F:36])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[N:13][N:14]([C:16]2([CH2:22][C:23]#[N:24])[CH2:21][CH2:20][NH2+:19][CH2:18][CH2:17]2)[CH:15]=1)(=[O:10])[NH2:9].CCN(C(C)C)C(C)C.Cl[C:49]([O:51][CH3:52])=[O:50]>C(Cl)Cl>[C:8]([C:11]1[C:12]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([C:35]([F:38])([F:36])[F:37])(=[O:33])=[O:34])=[CH:28][CH:27]=2)=[N:13][N:14]([C:16]2([CH2:22][C:23]#[N:24])[CH2:21][CH2:20][N:19]([C:49]([O:51][CH3:52])=[O:50])[CH2:18][CH2:17]2)[CH:15]=1)(=[O:10])[NH2:9]
Reactant: COC(=O)Cl
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(S(=O)(=O)C(F)(F)F)cc3)n2)CC[NH2+]CC1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccc(S(=O)(=O)C(F)(F)F)cc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[4-Carbamoyl-3-({4-[(trifluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-7) (30 mg, 0.053 mmol) was dissolved in DCM (1.0 mL). DIPEA (0.055 mL, 0.32 mmol) was added, followed by methyl chloroformate (0.024 mL, 0.32 mmol). The resulting mixture was allowed to stir at ambient temperature for 30 minutes. The solvent was removed in vacuo and the crude residue was purified by reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound, Example #27-1, as a solid.
Reaction SMILES: C(O[CH:5]([C:28]1[CH:29]=[CH:30][C:31]2[N:35]=[C:34]3[S:36][CH2:37][CH2:38][CH2:39][N:33]3[C:32]=2[CH:40]=1)[C:6]1(Br)[C:12](=[O:13])[N:11]2[C@@H:7]1[S:8][CH:9]=[C:10]2[C:14]([O:16]CC1C=CC([N+]([O-])=O)=CC=1)=[O:15])(=O)C.[H][H]>C1COCC1.P([O-])([O-])([O-])=O>[S:36]1[C:34]2=[N:35][C:31]3[CH:30]=[CH:29][C:28](/[CH:5]=[C:6]4\[C@@H:7]5[N:11]([C:12]\4=[O:13])[C:10]([C:14]([OH:16])=[O:15])=[CH:9][S:8]5)=[CH:40][C:32]=3[N:33]2[CH2:39][CH2:38][CH2:37]1
Reactant: [H][H]
Reactant: CC(=O)OC(c1ccc2nc3n(c2c1)CCCS3)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: O=C(O)C1=CS[C@@H]2/C(=C\c3ccc4nc5n(c4c3)CCCS5)C(=O)N12
Yield: 18.4 %

Procedure:
4-nitrobenzyl (5R)-6-[(acetyloxy)(3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazol-7-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (700 mg, 1.1 mmol) was suspended in 20 ml THF and 20 ml pH=6.5 aqueous phosphate buffer. The mixture was then subjected to 45 psi hydrogen for two hours. Then it was filtered through a pad of celite and concentrated in vacuo to remove most of the THF. The solution was then cooled to zero degree and basified to pH=8 with 1 N sodium hydroxide. Then it was purified via reverse phase HPLC using 1 liter of water followed by 5%-25% acetonitrile and water. Water was then removed through concentrate in vacuo and 75 mg of product (Yield 18%) was collected. MP: >250° C., H-NMR (D2O): δ 7.08 (m, 6H), 3.70 (m, 2H), 4.05 (m, 2H), 3.13 (m, 2H), 2.22 (m, 2H); MS: 372.1 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[F-:10].[K+]>CN1CCCC1=O.[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.O>[F:10][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=1)[C:8]#[N:9]
Reactant: [F-]
Reactant: N#Cc1ccnc(Cl)c1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1ccnc(F)c1
Temperature: 100 °C
Yield: 43.3 %

Procedure:
Treat a solution of 2-chloro-4-cyanopyridine (6.0 g, 43.5 mmol) and potassium fluoride (7.56 g, 130.3 mmol) in 1-methyl-2-pyrrolidinone (20 mL) with tetrabutylphosphonium bromide (14.8 g, 43.7 mmol) and heat to 100° C. for 18 hours. Dilute with water and extract with EtOAc. Wash EtOAc with water, brine, dry with Na2SO4, and concentrate to give the title compound (2.3 g, 43%). MS (ES) 123.1 (M+1)+. 1H NMR (400 MHz, CHCl3) δ 8.43 (d, 1H, J=5.2 Hz), 7.45 (m, 1H), 7.22 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].O.[Se](=O)=[O:12]>O1CCOCC1>[C:1]([C:3]1[C:4]([CH:9]=[O:12])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1ncccc1C#N
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cccnc1C=O
Yield: 9.7 %

Procedure:
To a solution of 3-cyano-2-picoline (166 mg, 1.41 mmol) in dioxane (3 mL) was added water (0.2 mL) and selenium(IV) oxide (228 mg, 2.05 mmol) and the mixture stirred at reflux overnight. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (Hexanes/ether, 3:1 then 1:1) to afford the title compound (18 mg, 10%) as a pale yellow solid. 1H NMR (CDCl3): δ7.69 (dd, 1H, J=9,6 Hz), 8.20 (d, 1H, J=9 Hz), 9.00 (d, 1H, J=3 Hz), 10.13 (s, 1H).
Reaction SMILES: CN(C)C=O.[N:6]1([CH:12]([CH3:26])[CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[C:17]([NH2:25])=[N:16]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.Br.Br[CH2:29][CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[N:6]1([CH:12]([CH3:26])[CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[C:17]([NH:25][CH2:29][CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[N:16]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCN(CC)CCCBr
Reactant: CC(CCn1nc(N)c2cc(Cl)ccc21)N1CCCCC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nn(CCC(C)N2CCCCC2)c2ccc(Cl)cc12
Temperature: 180 °C
Reaction time: 12 h
Yield: 50.9 %

Procedure:
To 60 ml of anhydrous N,N-dimethylformamide were added 9.90 g of the 1-(3-piperidinobutyl)-3-amino-5-chloroindazole, 8.98 g of 3-bromopropyldiethylamine hydrobromide and 7.89 g of anhydrous potassium carbonate, and the mixture was stirred for 12 hours at 180° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochloric acid layer was washed with diethyl ether. The pH of the layer was adjusted to at least 11 with potassium carbonate, and the alkali layer was extracted three times with chloroform. The chloroform layer was dried with anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography (alumina: 200 g) using chloroform as the developing solvent to give 6.90 g of 1-(3-piperidinobutyl)-3-(3-diethylaminopropylamino)-5-chloroindazole having the following analytical values in a yield of 51 %.
Reaction SMILES: [CH:1]1([O:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:28][Si](C)(C)C>ClCCl.CN(C)C=O>[CH:1]1([O:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:9]([NH2:28])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=C(O)C(OC1CCCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)C(OC1CCCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
A solution of rac-cyclohexyloxy-(3,4-dichloro-phenyl)-acetic acid (Example 2; 364 mg, 1.20 mmol) in dichloromethane (10 mL) and N,N-dimethylformamide (one drop) cooled to 0° C. was treated with oxalyl chloride (2.OM solution in dichloromethane, 0.84 mL, 1.68 mmol). The reaction was stirred at 0° C. for 1 h, then 1,1,1,3,3,3-hexamethyldisilazane (0.90 mL, 4.20 mmol) was added and the cloudy mixture was stirred at 25° C. for 16 h. At this time, the reaction was quenched with methanol (10 mL), washed with an aqueous solution of 5% sulfuric acid (2×15 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine (1×10 mL), then were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The product was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) to afford rac-2-cyclohexyloxy-2-(3,4-dichloro-phenyl)-acetamide (311 mg, 76% yield) as a colorless oil: FAB-HRMS m/e calcd for C14H17NCl2O2 (M+H)+302.0714, found 302.0728.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11](O)=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][CH2:17][S:16](=[O:21])(=[O:20])[CH2:15]1.C(Cl)CCl.C1C=CC2N(O)N=[N:32]C=2C=1.N.O1CCOCC1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:32])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][CH2:17][S:16](=[O:21])(=[O:20])[CH2:15]1
Reactant: O=C(O)c1cc(Br)cc2c(C3CCCS(=O)(=O)C3)c[nH]c12
Reactant: On1nnc2ccccc21
Agent: N
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: NC(=O)c1cc(Br)cc2c(C3CCCS(=O)(=O)C3)c[nH]c12
Temperature: 100 °C
Yield: 87.3 %

Procedure:
5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-indole-7-carboxylic acid (0.185 g, 0.497 mmol) was suspended in DMF (2 mL) with EDC (0.286 g, 1.49 mmol, 3 eq) and HOBt (0.076, 0.497 mmol) in a 10 mL microwave reaction vessel. 0.5M ammonia in 1,4-dioxane (1.9 mL, 0.9945 mmol, 2 eq) was added and heated on the microwave at 100° C. for 20 minutes. Reaction was diluted with water and extracted with ethyl acetate. The combined organics were washed with 1N NaOH, water, and brine then dried with magnesium sulfate, to give 0.161 g (87%) of the title compound.
Reaction SMILES: C([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:7]([C@@H:8]([OH:32])[CH2:9][C:10]3[C@H:11]4[C@:23]([CH3:31])([CH2:24][CH2:25][C:26]=32)[C@@H:14]([C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:13][CH2:12]4)[CH2:6]1)(=O)C.[K]>C(O)C>[CH3:21][CH:19]([CH2:18][CH2:17][CH2:16][C@H:15]([C@@H:14]1[C@:23]2([CH3:31])[C@H:11]([C:10]3[CH2:9][C@@H:8]([OH:32])[C@H:7]4[C@:27]([C:26]=3[CH2:25][CH2:24]2)([CH3:30])[CH2:28][CH2:29][C@H:5]([OH:4])[CH2:6]4)[CH2:12][CH2:13]1)[CH3:22])[CH3:20]
Reactant: CC(=O)O[C@H]1CC[C@]2(C)C3=C(C[C@H](O)[C@H]2C1)[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC3
Agent: [K]
Solvent: CCO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C[C@H]1[C@H](O)C3
Reaction time: 2 h
Yield: 85.5 %

Procedure:
3β-(Acetyloxy)-5α-cholest-8-ene-6α-ol (124 mg) is dissolved in 20 ml ethanol. Solid potassium hydroxyde (710 mg) is added and the reaction mixture is stirred for 2 hours. After aqueous work-up, 5β-cholest-8-ene-3β,6β-diol (96 mg) is isolated.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[OH:20])=[N:7][CH:8]=[N:9]2)=[C:4]([CH3:21])[CH:3]=1.[NH:22]=[S:23]1(=[O:27])[CH2:26][CH2:25][CH2:24]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([N:22]=[S:23]4(=[O:27])[CH2:26][CH2:25][CH2:24]4)=[CH:3][C:4]=3[CH3:21])[N:9]=[CH:8][N:7]=2)=[C:14]([OH:20])[CH:15]=1
Reactant: Cc1cc(Br)cc2ncnc(Nc3ccc(F)cc3O)c12
Reactant: N=S1(=O)CCC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Cc1cc(N=S2(=O)CCC2)cc2ncnc(Nc3ccc(F)cc3O)c12
Temperature: 25 °C

Procedure:
1.5 g (4.3 mmol) 2-[(7-bromo-5-methyl-quinazolin-4-yl)amino]-5-fluoro-phenol, 0.45 g (4.3 mmol) 1-iminothietane 1-oxide (IV.6), 0.26 g (0.86 mmol) 2-(di-t-butylphosphino) biphenyl, 0.3 g (0.33 mmol) Pd2dba3 and 0.61 g (6.4 mmol) sodium tert-butoxide in dioxane are heated to 80° C. for 3 h. After cooling to RT the reaction mixture is filtered and evaporated. The residue is purified by FC.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:8][CH2:9][C:10](OCC)=[O:11])=[O:5])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[K+].C(O)(=O)C.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH2:18]([O:17][C:15]([N:7]1[CH2:8][CH2:9][C:10](=[O:11])[CH:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:16])[CH3:19]
Reactant: CCOC(=O)CCN(CC(=O)OCC)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1C(=O)CCN1C(=O)OCC
Reaction time: 0.75 h

Procedure:
A solution of 53.9 g of ethyl N-(ethoxycarbonylmethyl)-N-(ethoxycarbonyl)-β-alaninate in 200 ml of toluene is added dropwise to a stirred solution of potassium hexamethyldisilazide (429 ml, 0,653 M) in 125 ml of toluene under nitrogen and cooled to 0° . After 45 minutes at 0°, 21.6 ml of acetic acid is added followed by a solution of 100 g of sodium phosphate (monobasic) in 1 liter of water. The layers are separated, the organic layer is washed with pH 7 buffer, dried over sodium sulfate, filtered, concentrated and purified by flash chromatography using ethyl acetate/hexane (3:7) to yield ethyl 1-ethoxycarbonyl-3-oxo-pyrrolidine-2-carboxylate.
Reaction SMILES: [CH2:1]([C:11]1[NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[N:12]=1)[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH2:1]([C:2]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1)[C:11]1[N:12]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1
Reactant: ClCc1ccccc1
Reactant: c1ccc2[nH]c(Cc3nc4ccccc4[nH]3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(Cn2c(Cc3nc4ccccc4n3Cc3ccccc3)nc3ccccc32)cc1
Yield: 19.4 %

Procedure:
To a flask were added 2.0 g 2,2′-methylenebis(1H-benzimidazole), 2.8 g potassium carbonate, 100 ml N,N-dimethylformamide and the mixture was stirred under nitrogen. 2.5 g benzyl chloride were added and the mixture was heated to 70 C for 16 hours. Another 0.7 g benzyl chloride was added and the reaction was heated to 70 C for another 20 hours. The reaction was cooled to 22 C, quenched with 150 ml water and the product was extracted with ethyl acetate and washed with water. Following removal of solvent, the product was recrystallized from 10 ml ethanol, then 10 ml acetonitrile with 1 ml of water. The product was filtered and dried resulting in 0.67 g tan solid.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]([NH2:14])[CH2:4][CH2:3]1.C[C@@H]1N[C@@H](C2C=CC=CC=2)[C@@H](N)CC1.C[C@H]1N[C@H](C2C=CC=CC=2)[C@H](N)CC1.[CH3:43][O:44][C:45]1[CH:46]=[C:47]2[C:52](=[CH:53][C:54]=1[CH:55]=O)[N:51]([CH3:57])[C:50](=[O:58])[CH2:49][CH2:48]2>>[CH3:43][O:44][C:45]1[CH:46]=[C:47]2[C:52](=[CH:53][C:54]=1[CH2:55][NH:14][CH:5]1[CH2:4][CH2:3][CH:2]([CH3:1])[NH:7][CH:6]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:51]([CH3:57])[C:50](=[O:58])[CH2:49][CH2:48]2
Reactant: CC1CCC(N)C(c2ccccc2)N1
Reactant: COc1cc2c(cc1C=O)N(C)C(=O)CC2
Agent: C[C@@H]1CC[C@@H](N)[C@@H](c2ccccc2)N1
Agent: C[C@H]1CC[C@H](N)[C@H](c2ccccc2)N1
Product: COc1cc2c(cc1CNC1CCC(C)NC1c1ccccc1)N(C)C(=O)CC2

Procedure:
By a procedure similar to the previous examples 9 and 9A: prepared through the reaction of 6-methyl-2-phenyl-piperidin-3-ylamine [or (2S,3S,6S)-6-methyl-2-phenyl-piperidin-3-ylamine or (2R,3R,6R)-6-methyl-2-phenyl-piperidin-3-ylamine] with 6-Methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde.