Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C12BC(CCC1)CCC2.[CH:10]([C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:14][CH:13]=1)=[CH2:11].[OH-:25].[Na+].OO>O1CCCC1.O>[OH:25][CH2:11][CH2:10][C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[CH:14][CH:13]=1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 9-borabicyclo[3.3.1]nonane (9-BBN, 5.65 g, 46.3 mmol) in anhydrous tetrahydrofuran was added to a solution of t-butyl 4-vinylbenzoate (8.47 g, 42.1 mmol) prepared in the Preparative Example 102 in anhydrous tetrahydrofuran in a nitrogen stream. The obtained mixture was stirred at room temperature for 3 hours. 15 ml of water and 17 ml of 3N NaOH were added to the reaction mixture successively, followed by the dropwise addition of 30% aqueous hydrogen peroxide at 50° C. or below. The obtained mixture was stirred as such for one hour and poured into water. The mixture thus obtained was extracted with ethyl acetate. The organic phase was washed with an aqueous solution of common salt, dehydrated and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography (developer: n-hexane/ethyl acetate=1:1) to give the objective compound. yield: 8.71 g
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[SH:11].[C:12](O)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1>C(Cl)(Cl)Cl>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[S:11][C:12]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[N:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: O=C(O)c1cccnc1
Reactant: Nc1cc([N+](=O)[O-])ccc1S
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc2sc(-c3cccnc3)nc2c1
Yield: 44 %

Procedure:
2-Amino-4-nitrobenzenethiol,17 g, 0.10 mole, and nicotinic acid, 18.7 g, 0.15 mole, are heated 2 hours at reflux in 250 cc of CHCl3 containing 100 g of PPE. The solution is concentrated in vacuo, and the residue slurried in H2O. The pH is adjusted to 11 with 50% NaOH solution. The precipitate is filtered, washed with H2O and dried in vacuo to yield 11.2 g of tan solid m.p. 196°-198°, 44% of theory.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[NH:8][C:9](=[O:20])[CH2:10][C:11](=[O:19])[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=1)([O-])=O.[H][H]>C(O)C.[Ni]>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]2[NH:8][C:9](=[O:20])[CH2:10][C:11](=[O:19])[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=1
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc([N+](=O)[O-])ccc2N1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc2c(c1)N(c1ccccc1)C(=O)CC(=O)N2

Procedure:
29.7 g of 7-nitro-5-phenyl-1H-1,5-benzodiazepine-2,4-dione in 200 ml ethanol containing 1.0 g of Raney nickel is hydrogenated at room temperature at an initial hydrogen pressure of 50 p.s.i. The reaction is stopped after 0.3 moles of hydrogen has been absorbed. The reaction mixture is filtered and the filtrate evaporated to give 7-amino-5-phenyl-3H-1,5-benzodiazepine-2,4-dione.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18](CC)(C)C)[CH:15]=[C:14]([C:23]([CH2:26]C)([CH3:25])[CH3:24])[C:13]=1[OH:28])([O-])=O.[N+](C1C(N=NC2C=CC=C(C(C)(C)C)C=2O)=CC([Cl:39])(C)CC=1)([O-])=O>>[Cl:39][C:7]1[CH:8]=[CH:9][C:4]2=[N:1][N:11]([C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:23]([CH3:26])([CH3:24])[CH3:25])[C:13]=3[OH:28])[N:10]=[C:5]2[CH:6]=1
Reactant: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Reactant: CC1(Cl)C=C(N=Nc2cccc(C(C)(C)C)c2O)C([N+](=O)[O-])=CC1
Product: Cc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1

Procedure:
When in Example 1, the 2-nitro-2'-hydroxy-3',5'-di-tert-amylazobenzene is replaced by an equivalent amount of 2-nitro-5-chloro-2'-hydroxy-3'-tert-butyl-5-methylazobenzene, the above noted product is obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[CH2:12][N:11]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][C@@H:25]([CH3:30])[C:26]([F:29])([F:28])[F:27])=[O:17])[CH2:10]3)[CH2:3][CH2:2]1.[Cl:31][S:32](O)(=[O:34])=[O:33]>ClCCCl>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[CH2:12][N:11]([C:16]([C:18]2[CH:23]=[C:22]([S:32]([Cl:31])(=[O:34])=[O:33])[CH:21]=[CH:20][C:19]=2[O:24][C@@H:25]([CH3:30])[C:26]([F:29])([F:27])[F:28])=[O:17])[CH2:10]3)[CH2:3][CH2:2]1
Reactant: O=S(=O)(O)Cl
Reactant: C[C@H](Oc1ccccc1C(=O)N1Cc2ccc(C3CCOCC3)cc2C1)C(F)(F)F
Solvent: ClCCCl
Product: C[C@H](Oc1ccc(S(=O)(=O)Cl)cc1C(=O)N1Cc2ccc(C3CCOCC3)cc2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
A solution of 0.2 g (0.47 mmol) [5-(tetrahydro-pyran-4-yl)-1,3-dihydro-isoindol-2-yl]-[2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone in 2 ml of 1,2-dichloroethane was added dropwise to 0.32 ml (4.7 mmol) chlorosulfonic acid under ice bath cooling. The mixture was stirred at room temperature for 30 minutes and then at 55° C. for 30 minutes. The mixture was cooled in an ice bath and quenched by dropwise addition of 2 ml water. The mixture was diluted with dichloromethane. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined dichloromethane extracts were dried over Na2SO4, filtered and concentrated in vacuo. The obtained foam was stirred with ethylacetate. The solid was filtrated. The filtrate was washed twice with a saturated solution of NaHCO3, dried over Na2SO4, filtered and concentrated in vacuo to provide 0.12 g (51%) of the title compound as light yellow foam. MS (m/e): 517.1 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])[O:8][CH:7]([C:17]([F:20])([F:19])[F:18])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2.[H-].[Na+].I[CH3:29].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([CH3:15])([CH3:16])[CH2:13][O:14][CH3:29])[O:8][CH:7]([C:17]([F:20])([F:19])[F:18])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(C(C)(C)CO)cc2OC1C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(C(C)(C)COC)cc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 6-chloro-7-(2-hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylate (205 mg, 0.584 mmole) in 8 mL of dry DMF was added 86 mg of 60% NaH, and 0.5 mL of iodomethane. The mixture was stirred overnight at room temperature. Water was added, the mixture extracted with DCM, the combined organic extracts dried over Na2SO4, filtered, and evaporated. Chromatography of the residue over silica gel using DCM as eluent gave the title compound, 49 mg, as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[NH3:21]>>[NH2:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1cnc2ccc(OC(C)C)cc2c1Cl
Reactant: N
Product: CCOC(=O)c1cnc2ccc(OC(C)C)cc2c1N

Procedure:
Prepared as in Example 1a from ethyl 4-chloro-6-isopropoxyquinoline-3-carboxylate (Example 10b) and ammonia as an off white solid (75%). MS 275 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:14]4=[N:15][CH:16]=3)=[N:7][N:8]2[CH2:39][CH:36]2[CH2:38][CH2:37]2)=[CH:4][CH:3]=1
Reactant: BrCC1CC1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CC4)c4cc(Cl)ccc34)nc12
Temperature: 0 °C
Reaction time: 15 h
Yield: 74.5 %

Procedure:
2-(6-Chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (120 mg, 247 μmol) was dissolved in DMF (1 mL) and cooled to 0° C. Sodium hydride (12.9 mg, 322 μmol) was added. After 30 min cyclopropylmethyl bromide (50.1 mg, 0.0360 mL, 371 μmol) was added and the mixture warmed to room temperature. After 15 h, the mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica, 40 g Analogix column, 20-50% ethyl acetate in hexanes, 15 min gradient) to give 2-(6-chloro-1-(cyclopropylmethyl)-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (99 mg, 184 μmol, 74.2%) as a yellow powder. 1H NMR (CDCl3) δ: 9.27 (s, 1H), 8.43-8.50 (m, 2H), 8.31 (d, J=8.3 Hz, 1H), 7.54 (s, 1H), 7.23 (s, 1H), 5.73 (s, 2H), 4.40-4.56 (m, 1H), 4.35 (d, J=6.8 Hz, 2H), 3.54-3.64 (m, 2H), 1.42 (d, J=6.4 Hz, 7H), 0.89-1.00 (m, 2H), 0.62-0.71 (m, 2H), 0.51 (q, J=4.9 Hz, 2H), −0.07-−0.01 (m, 9H)
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[C:6]1([C@@H:12]([NH2:14])[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[CH:1](=[N:14]/[C@H:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:13])\[CH2:2][CH2:3][CH3:4]
Reactant: C[C@H](N)c1ccccc1
Reactant: CCCC=O
Solvent: ClCCl
Product: CCC/C=N/[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.7 %

Procedure:
To a suspension of 10 g 3 Å MS in CH2Cl2 (150 mL) under N2 at rt was added butyraldehyde (4.96 mL, 55 mmol) followed by (S)-(−)-1-phenylethylamine (6.45 mL, 50 mmol). The mixture was stirred at rt for 1.5 h, filtered over celite and the solvent removed under reduced pressure to give 9 g of the crude imine, which was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[CH:23]=O)[CH:16]=[CH:15]1>O1CCCC1.C(OCC)(=O)C>[C:3](/[CH:5]=[CH:23]/[C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]=1[NH:14][CH:15]=[CH:16]2)#[N:4]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=Cc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#C/C=C/c1cccc2cc[nH]c12
Reaction time: 0.25 h

Procedure:
Sodium hydride, 60% dispersion in mineral oil (0.10 g, 2.5 mmol) was added in portions over 10 minutes to a stirred solution of diethyl cyanomethylphosphonate (0.44 g, 2.5 mmol) in tetrahydrofuran (10 ml) cooled in ice. The mixture was stirred for 15 minutes then a solution of 7-indole carboxaldehyde (0.30 g, 2.1 mmol) in tetrahydrofuran (2 ml) was added dropwise. The mixture was stirred for 30 minutes, diluted with ethyl acetate, washed with water, dried and evaporated. The residue was chromatographed on silica in ethyl acetate-hexane (1:3) to give the product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:37][CH2:36][O:35][C:34]1=[O:38]>>[O:38]=[C:34]1[N:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH2:26][NH:25][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:20])[CH3:21])=[O:24])[CH2:37][CH2:36][O:35]1
Reactant: NCc1ccccc1N1CCOC1=O
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccccc1N1CCOC1=O)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and 3-(2-(aminomethyl)phenyl)oxazolidin-2-one, derived from reduction of intermediate 116, 2-(2-oxooxazolidin-3-yl)benzonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.90 (1H, t, J=6.0 Hz), 7.58–7.32 (7H, m), 7.22 (2H, t, J=7.5 Hz), 5.08 (2H, s), 4.48 (2H, t, J=7.8 Hz), 4.44 (2H, d, J=6.0 Hz), 4.06–3.97 (4H, m), 3.88 (2H, m), 1.56 (6H, s); LCMS (M+H)+ m/z 505.
Reaction SMILES: [C:1]([CH2:9][C:10](=O)[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C(OCC)(=O)C>[N:13]1(/[C:10](/[CH3:11])=[CH:9]\[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: C1CCNC1
Solvent: CCOC(C)=O
Product: C/C(=C/C(=O)c1ccccc1)N1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.2 %

Procedure:
To a solution of 17.4 g of benzoylacetone in 100 ml of ethyl acetate is added a solution of 7.35 g of pyrrolidine in 50 ml of ethyl acetate. The reaction mixture is stirred at room temperature for 16 hours. The precipitated compound is collected by filtration to give 20.30 g of 3-(1-pyrrolidinyl)crotonophenone.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[CH3:24])[C:6]=2[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: Cc1c(Cl)cccc1CBr
Reactant: Cc1nc2c(Br)cc([N+](=O)[O-])cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1Cn1c(C)nc2c(Br)cc([N+](=O)[O-])cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
A mixture of 4-bromo-2-methyl-6-nitro-1H-benzo[d]imidazole (67 g, 258 mmol), 1-(bromomethyl)-3-chloro-2-methylbenzene (68 g, 309 mmol), prepared as described in example 1, step b, and cesium carbonate (126 g, 387 mmol) in DMF (800 mL) was stirred at 80° C. for 2 h. After cooled to room temperature, the mixture was poured into 1.5 L of water. The resulting precipitate was filtered, washed with water (300 mL), ether (100 mL) and dried in vacuo to give the crude product (100 g, 98%) as a brown solid; LC/MS: MS (ES+) m/e 394 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 2.48 (s, 3H), 2.54 (s, 3H), 5.73 (s, 2H), 6.06 (d, J=7.8 Hz, 1H), 7.06 (t, J=7.8 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H), 8.30 (d, J=1.8 Hz, 1H), 8.60 (d, J=1.8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:12][C:11]=1[C:20]([F:23])([F:22])[F:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:24](#N)[CH3:25].O>>[C:5]1([CH2:4][CH2:3][CH2:2][CH2:1][O:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:12][C:11]=2[C:20]([F:21])([F:22])[F:23])[CH:25]=[CH:24][CH:8]=[CH:7][CH:6]=1
Reactant: CCCCCCCCOc1ccc(C(=O)NN)cc1C(F)(F)F
Reactant: CC#N
Solvent: O
Product: NNC(=O)c1ccc(OCCCCc2ccccc2)c(C(F)(F)F)c1
Yield: 95 %

Procedure:
The title compound was prepared analogously to 4-(octyloxy)-3-(trifluoromethyl)-benzo-hydrazide (12a) in >95% yield. MS (ESI): 353.11 (MH+); HPLC retention time on a C8(2) column (30×3.00 mm, 3μ) is 2.30 min with gradient 20-98% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase.
Reaction SMILES: [ClH:1].[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.[S:13]1[C:17]2=[CH:18][N:19]=[C:20]([C:22](O)=[O:23])[CH:21]=[C:16]2[CH:15]=[CH:14]1.N>>[ClH:1].[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:22]([C:20]3[CH:21]=[C:16]4[CH:15]=[CH:14][S:13][C:17]4=[CH:18][N:19]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1cc2ccsc2cn1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cc2ccsc2cn1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and thieno[2,3-c]pyridine-5-carboxylic acid (Tetrahedron Lett. 1999, 40, 7935) according to methods A and C; yield 73 mg, 0.18 mmol (51%): 1H NMR (300 MHz, methanol-d4) δ 2.12-2.33 (m, 5H), 2.55 (s, 2H), 3.53 (d, J=12 Hz, 2H), 3.59 (s, 2H), 3.99 (d, J=13 Hz, 2H), 4.40 (s, 1H), 7.94 (d, J=5 Hz, 1H), 8.65 (d, J=5 Hz, 1H), 9.15 (s, 1H), 9.59 (s, 1H); MS (DCI/NH3) m/z 296 (M+H)+; Anal. C17H19N3OS.2HCl.0.6H2O: C, H, N.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)#[N:6].[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][CH2:15]1.Cl>C(Cl)(Cl)C(Cl)Cl>[C:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[C:11]([CH:12]=1)[C:14]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:20])#[N:6]
Reactant: O=C1CCC(=O)O1
Reactant: N#Cc1ccc(O)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)C(Cl)Cl
Product: N#Cc1ccc(O)c(C(=O)CCC(=O)O)c1

Procedure:
Aluminium chloride (148 g, 1.11 mole) was added to a stirred mixture of 4-cyanophenol (44 g, 0.37 mole), succinic anhydride (33.3 g, 0.33 mole), and sym-tetrachloroethane (260 ml), and the mixture was then heated at 135° for 2 hours. The resultant complex was decomposed with ice and hydrochloric acid, and 3-(5-cyano-2-hydroxybenzoyl)propionic acid was isolated by standard procedures.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]#[N:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.Cl.[NH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[NH2:1][C:2]1[S:3][C:4]([C:13]([NH:16][OH:17])=[NH:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: N#Cc1sc(N)nc1-c1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1sc(N)nc1-c1ccccc1

Procedure:
2-Amino-4-phenyl-thiazole-5-carbonitrile (0.13 g, 0.6 mmol) was suspended in 1:1 water/ethanol (v/v) (24 mL) and added hydroxylamine hydrochloride (1.47 g, 21 mmol) and potassium carbonate (1.86 g, 13 mmol). The reaction mixture was heated at reflux for 3 days, then the solvent was reduced and the aqueous phase was extracted with dichloromethane. The organic layer was washed with water and brine, and was dried over sodium sulfate. The solvent was evaporated to yield a yellow solid. Yield: 0.1 g, 66%.
Reaction SMILES: O=S(Cl)Cl.[Br:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[C:13]([F:16])[C:12]([CH2:17][C:18](O)=[O:19])=[C:11]([F:21])[CH:10]=2.COC(=O)CC1C(F)=C2C(=CC=1F)N=CC(Br)=C2.[NH2:40][NH2:41]>CO>[Br:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[C:13]([F:16])[C:12]([CH2:17][C:18]([NH:40][NH2:41])=[O:19])=[C:11]([F:21])[CH:10]=2
Reactant: NN
Reactant: O=C(O)Cc1c(F)cc2ncc(Br)cc2c1F
Agent: COC(=O)Cc1c(F)cc2ncc(Br)cc2c1F
Solvent: CO
Solvent: O=S(Cl)Cl
Product: NNC(=O)Cc1c(F)cc2ncc(Br)cc2c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 402.6 %

Procedure:
SOCl2 (394 mg, 3.31 mmol) was added dropwise to a stirred solution of (3-bromo-5,7-difluoro-quinolin-6-yl)-acetic acid (500 mg, 1.65 mmol) in 12 ml of methanol at 0° C. under N2. After stirring for 2 hours at room temperature the solvent was evaporated and the crude (3-bromo-5,7-difluoro-quinolin-6-yl)-acetic acid methyl ester was used directly in the next step. To a mixture of (3-bromo-5,7-difluoro-quinolin-6-yl)-acetic acid methyl ester (2.29 g, 7.22 mmol) in methanol (100 mL) was added anhydrous hydrazine (2.31 g, 72.2 mmol). The mixture was heated at 55° C. for 4 hours. Additional anhydrous hydrazine (1.16 g, 36.1) was added and the mixture was heated at 55° C. for 2 hours. The reaction mixture was cooled to room temperature to give a white solid. The white solid was filtered and washed with cold methanol to obtain 2.1 g of the title compound (92% yield). MS: m/z 318 [M+H+]. 1H NMR (500 MHz. DMSO-d6): δ 1.99 (2H, s), 4.25 (2H, bs), 7.72 (1H, d), 8.74 (1H, s), 9.03 (1H, s), 9.35 (1H, s).
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].C(N(CC)CC)C.[CH3:13][Si:14](Cl)([CH3:16])[CH3:15]>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-].C1(C=CC(O)=CC=1)O>[CH3:13][Si:14]([CH3:16])([CH3:15])[O:5][CH:1]=[CH:2][CH:3]=[CH2:4]
Reactant: C[Si](C)(C)Cl
Reactant: C/C=C/C=O
Agent: Oc1ccc(O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CC=CO[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a solution of crotonaldehyde (31.8 g, 0.454 mole) and triethylamine (51.4 g, 1.1 eq) in benzene at 25° C., was added hydroquinone (0.95 g) and zinc chloride (0.75 g) rapidly with efficient stirring. This was followed by the addition of freshly distilled trimethylsilyl chloride (46 ml, 0.9 eq) over 1-2 minutes, whereupon a white precipitate rapidly formed. After stirring the mixture for 30 minutes at 25° C., a further 0.2 eq of trimethylsilyl chloride were added. The reaction was then warmed to 70° C. and stirred at this temperature for 12 hours. It was then cooled to 0° C., quenched by addition of saturated aq. NaHCO3 (75 ml), poured into a separatory funnel, and the organic layer separated. The aqueous layer was extracted with further portions of benzene (3×50 ml), the organic extracts combined, washed with 10% KHSO4, and the benzene removed in vacuo to leave a dark brown liquid. Distillation through a short Vigreaux column yielded 28.4 g (46%) of pure 1-trimethylsilyloxy-1,3-butadiene as a colorless liquid (bp 78°-80° C./68 mm Hg). 1H NMR (200 MHz, CDCl3): δ 6.66(1H,d,J=11.9 Hz), 6.35(1H,dt,J=17.1, 10.6Hz), 5.84(1H,t,J=11.4 Hz), 5.11(1H,dd,J=16.8, 1.8 Hz), 4.94(1H,dd,J=10.3, 1.8 Hz), 0.37(9H, s).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]3[N:23]([N:27]=[C:28]([NH2:30])[N:29]=3)[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]3[N:23]([N:27]=[C:28]([NH:30][CH:10]4[CH2:11][CH2:12][N:7]([C:5]5[S:4][N:3]=[C:2]([CH3:1])[N:6]=5)[CH2:8][CH2:9]4)[N:29]=3)[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1
Reactant: Nc1nc2c(-c3ccc(F)cc3)cccn2n1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Product: Cc1nsc(N2CCC(Nc3nc4c(-c5ccc(F)cc5)cccn4n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting with 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 8-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (example 1f). The title compound was obtained as a white solid (yield=28%).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[CH:15]([C:16]([O:18]CC)=[O:17])[S:14][CH2:13][C:12](=[O:21])[C:11]=3[CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].O>CO>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[CH:15]([C:16]([OH:18])=[O:17])[S:14][CH2:13][C:12](=[O:21])[C:11]=3[CH:22]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C1SCC(=O)c2cc(C3CCCCC3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1CSC(C(=O)O)c2ccc(C3CCCCC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
In methanol (200 ml) was suspended ethyl 6-cyclohexyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylate (52 g) followed by addition of 2N-KOH (100 ml). The mixture was stirred at room temperature for one hour, poured into water, acidified and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and the solvent was distilled off to give 6-cyclohexyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (33 g, yield 73%). Recrystallization from ethyl acetate-hexane gave colorless plates.