Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C2C(=CC=CC=2)C=C1[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1.[NH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]C1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl>[NH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:11]1[CH:12]=[CH:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=1
Reactant: c1ccc2c(c1)CCCN2
Reactant: c1ccc2c(c1)CCCN2c1cc2ccccc2[nH]1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: c1ccc2nc(-c3cc4ccccc4[nH]3)ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The indolyl-tetrahydroquinoline was made according to the established lanthanide triflate catalyzed Kobayashi chemistry (for a leading reference, see Kobayashi, S.; Ishitani, H.; Nagayama, S. Synthesis, 1995, 1195-1202). The tetrahydroquinoline (50.0 mg, 0.102 mmol) was dissolved in 10 mL anhydrous dichloromethane and the solution was cooled to 0° C. under nitrogen atmosphere. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (47.6 mg, 0.210 mmol) in 2 mL dichloromethane was then added in a drop-wise fashion. The reaction mixture was stirred at 0° C. for additional 30 minutes. The reaction crude was filtered through celite and the solvent was evaporated in vacuo to supply a yellow solid. Further purification by flash column chromatography (alumina basic, CH2Cl2/MeOH=20:1) yielded 27.5 mg of indolyl-quinoline 517.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:15][C:16]#[CH:17])C(=O)OC(C)(C)C)=[CH:5][N:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:6]([NH:7][CH2:15][C:16]#[CH:17])=[CH:5][N:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1
Reactant: C#CCN(C(=O)OC(C)(C)C)c1cn(-c2cccnc2)nc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CCNc1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of tert-butyl (3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(prop-2-yn-1-yl)carbamate (2.2 g, 6.61 mmol) in dichloromethane (DCM; 8.3 ml) was added 2,2,2-trifluoroacetic acid (12.06 g, 106 mmol) and the reaction mixture was stirred at ambient temperature for 1 h. The reaction was quenched by the addition of saturated sodium bicarbonate (NaHCO3). The organic layer was extracted with DCM (2×20 mL). The organic layers were combined and dried over sodium sulfate (Na2SO4), filtered and concentrated to afford the title compound as a beige solid (1.5 g, 6.12 mmol, 93%): 1H NMR (400 MHz, CDCl3) δ 8.89 (d, J=2.3 Hz, 1H), 8.50 (dd, J=4.7, 1.4 Hz, 1H), 8.01-7.93 (m, 1H), 7.54 (s, 1H), 7.37 (ddd, J=8.3, 4.8, 0.7 Hz, 1H), 3.90 (s, 2H), 3.38 (s, 1H), 2.44-2.09 (m, 1H); ESIMS m/z 233 ([M+H]+).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH2:26][CH:27]=[CH2:28])[C:22](OC)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[CH3:4][O:3][P:2]([CH2:1][C:22](=[O:23])[C@@H:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:26][CH:27]=[CH2:28])([O:5][CH3:6])=[O:7]
Reactant: COP(C)(=O)OC
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)CP(=O)(OC)OC
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a solution of dimethyl methylphosphonate (15.85 mL, 148 mmol) in THF (99 mL) at −78° C. was added n-butyllithium (93 mL, 148 mmol) slowly. After addition was completed, the reaction mixture was stirred for 30 min and then a solution of (S)-methyl 2-(tert-butoxycarbonylamino)pent-4-enoate (6.8 g, 29.7 mmol) in THF (15 mL) was added slowly. Stirring was continued for another 40 min at −78° C. The reaction was then quenched by adding water and diluted with EtOAc. The organic layer was washed with 1 M HCl, saturated NaHCO3 and brine. The organic layer was then dried over MgSO4, filtered and concentrated to give a clear oil. The crude product was then purified by silica gel chromatography to give the desired product (9.3 g, 98%) as colorless oil. MS (ESI) m/z: 599.0 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][C:11]=1[C:18]1[N:22]([CH:23]([CH3:25])[CH3:24])[CH:21]=[N:20][N:19]=1.O=S(Cl)[Cl:28]>C(Cl)Cl.CN(C=O)C>[Cl:28][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[C:11]([C:18]2[N:22]([CH:23]([CH3:25])[CH3:24])[CH:21]=[N:20][N:19]=2)[CH:12]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2-c2nncn2C(C)C)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(CCl)cc2-c2nncn2C(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
To a room temperature solution of 29.5 (60 mg, 176 μmol) in DCM was added one drop of DMF followed by SOCl2(63 mg, 527 μmol). The mixture was stirred at room temperature for 2.0 hours. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel with 0-5% MeOH/EtOAc provided 29.6 as a colorless oil (44 mg, 70%).
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C@@H:15]([O:21][C:22](=[O:25])[CH2:23][CH3:24])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:26])[CH2:5][CH2:4]2.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[O:26]=[C:6]1[CH2:5][CH2:4][C@@:3]2([CH:2]=[O:1])[C:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[O:21][C:22](=[O:25])[CH2:23][CH3:24])=[CH:7]1
Reactant: CCC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(CO)[C@H]3CC[C@]12C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CCC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C=O)[C@H]3CC[C@]12C

Procedure:
To a solution of 14 g of 19-hydroxy-17β-(1-oxopropoxy)androst-4-en-3-one in 1 liter of acetone cooled in an ice bath is added 13.3 ml of Jones reagent over one hour after which the reaction mixture is poured into a large volume of water and extracted with ether. The ether extract is dried over magnesium sulfate, filtered and the solvent removed. The residue is crystallized from acetone-hexane to give 3-oxo-17β(1-oxopropoxy)-androst-4-en-19-al, M.P. 119°-121° C.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[NH2:17][CH2:18][CH2:19][SH:20]>>[CH3:10][O:9][C:8]1[C:3]([CH2:2][S:20][CH2:19][CH2:18][NH2:17])=[N:4][CH:5]=[CH:6][C:7]=1[O:11][CH3:12]
Reactant: COc1ccnc(CO)c1OC
Reactant: NCCS
Solvent: O=S(Cl)Cl
Product: COc1ccnc(CSCCN)c1OC

Procedure:
3-Fluoro-2-methyl-4-nitropyridine N-oxide is treated with an excess of sodium methoxide and the product is heated in acetic anhydride and deacetylated to give 2-hydroxymethyl-3,4-dimethoxypyridine. 2-Hydroxymethyl-3,4-dimethoxypryidine is treated with thionyl chloride and the product is treated with cysteamine to give 2-(3,4-dimethoxy-2-pyridylmethylthio)ethylamine.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[N:3]1[C:8]1[N:13]=[C:12]([NH:14][C:15]2[C:16]3[N:17]([CH:31]=[CH:32][N:33]=3)[N:18]=[C:19]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=3)[C:24]([O:26]C)=[O:25])[CH:20]=2)[CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>O1CCOCC1.O>[CH3:7][CH:4]1[CH2:5][CH2:6][CH:2]([CH3:1])[N:3]1[C:8]1[N:13]=[C:12]([NH:14][C:15]2[C:16]3[N:17]([CH:31]=[CH:32][N:33]=3)[N:18]=[C:19]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=3)[C:24]([OH:26])=[O:25])[CH:20]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1cccc(-c2cc(Nc3cccc(N4C(C)CCC4C)n3)c3nccn3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC1CCC(C)N1c1cccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A mixture of methyl 3-(8-(6-(2,5-dimethylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (150 mg, 0.34 mmol) and NaOH (150 mg, 3.75 mmol) in 1,4-dioxane (5 mL) and water (5 mL) was stirred for 2 h at 40° C. Then the mixture was concentrated to 5 mL then adjusted to pH=2 with 2M HCl. The precipitate was filtered and the solid was washed with water (2 mL) and dichloromethane (3 mL) to give 3-(8-(6-(2,5-dimethylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (86 mg, 59%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.79 (s, 1H), 9.13 (s, 1H), 8.62 (s, 1H), 8.49 (s, 1H), 8.32-8.14 (m, 3H), 7.75 (t, 1H, J=7.8 Hz), 7.54 (t, 1H, J=8.1 Hz), 6.74 (d, 1H, J=7.8 Hz), 6.23 (d, 1H, J=8.7 Hz), 4.12 (s, 2H), 2.13-2.08 (m, 2H), 1.74-1.68 (m, 2H), 1.18 (s, 3H), 1.16 (s, 3H). LC-MS: [M+H]+, 429, tR=1.708 min, HPLC: 97.23% at 214 nm, 95.49% at 254 nm, tR=6.248 min.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH3:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:27])[CH:16]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:17][O:18]2)=[CH:13][CH:12]=1.IC.[NH4+].[Cl-]>O1CCCC1>[CH3:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:27])[C:16]([CH3:2])([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:17][O:18]2)=[CH:13][CH:12]=1
Reactant: COc1ccc2c(c1)OCC(c1ccncc1)C2=O
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc2c(c1)OCC(C)(c1ccncc1)C2=O
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
To a solution of LDA (2.0 mol/l, 0.863 ml, 1.73 mmol) in tetrahydrofuran (1.5 ml) was added at −78° C. a solution of 7-methoxy-3-(4-pyridyl)chroman-4-one (220 mg, 0.863 mmol) in tetrahydrofuran (2 ml), which was then stirred for 30 minutes. Iodomethane (0.537 ml, 8.63 mmol) was added to -the reaclion solution, which was warmed to −10° C. and stirred for 3 hours. After the reaction was completed, the reaction solution was neutralized under ice-cooling using saturated aqueous NH4Cl solution, extracted with ethyl acetate, and washed with saturated saline solution. The organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=1:2) to give 7-methoxy-3-methyl-3-(4-pyridyl)chroman-4-one (131 mg, yield 56%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].[H-].[Na+].[CH3:13]I>CN(C=O)C>[CH3:13][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6]
Reactant: Cc1ccc(C#N)cc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C#N)ccc1C
Temperature: 0 °C
Yield: 91.4 %

Procedure:
15 g (0.11 mol) of 3-hydroxy-4-methylbenzonitrile dissolved in 30 ml of DMF were added dropwise to a suspension of 0.11 mol of NaH and 30 ml of DMF, and the mixture was stirred until no further H2 evolution was observed. Then 10.6 ml (0.17 mol) of methyl iodide were added dropwise, and the mixture was stirred at RT for 1 h. The solution was poured into ice-water, and the product was extracted with ether/ethyl acetate 7:1. After the solvent had been stripped off, the product began slowly to crystallize. 14.8 g (89%) of the product were obtained. 1H-NMR (CDCl3; δ in ppm): 7.2 (m, 2H); 7.02 (s, 1H); 3.85 (s, 3H); 2.25 (s, 3H)
Reaction SMILES: Cl.C([O:5][C:6]1[C:7]([CH3:14])=[N:8][CH:9]=[C:10]([CH2:12][OH:13])[CH:11]=1)(=O)C.Cl.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O.N1C=CC=CC=1>[OH:5][C:6]1[C:7]([CH3:14])=[N:8][CH:9]=[C:10]([CH2:12][O:13][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH:11]=1
Reactant: CC(=O)Oc1cc(CO)cnc1C
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ncc(COC(=O)c2ccncc2)cc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2.4 g. of 3-acetoxy-5-hydroxymethyl-2-methylpyridine hydrochloride in 20 ml. of pyridine was added a solution of 2.0 g. of isonicotinoyl chloride hydrochloride in 15 ml. of dimethylformamide under cooling and the resulting mixture was stirred at room temperature for 16 hours. Then, the reaction mixture was poured into ice-water and the mixture was extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off to give an oily substance. The substance was taken into 25 ml. of 2N HCl and the resulting mixture was stirred at 80°C. for 30 minutes. The mixture was neutralized with sodium bicarbonate, filtered and recrystallized from methanol to give 0.9 g. of the desired product. m. p. 180° - 180.5°C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[CH3:27][O:28][C:29]1[N:34]=[C:33]([CH3:35])[N:32]=[C:31]([N:36](C2C=CC=CC=2)[C:37](=O)[O-:38])[N:30]=1>O1CCOCC1>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([S:12]([NH:15][C:37]([NH:36][C:31]3[N:30]=[C:29]([O:28][CH3:27])[N:34]=[C:33]([CH3:35])[N:32]=3)=[O:38])(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:2][CH2:3]1
Reactant: COc1nc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Reactant: NS(=O)(=O)c1cccnc1OCC1CC1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cccnc2OCC2CC2)n1
Reaction time: 0.33 h
Yield: 87.6 %

Procedure:
4.56 g of 2-cyclopropylmethoxypyridin-3-ylsulfonamide and 3.13 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene are suspended in 50 ml of dioxan and to this suspension are added 5.46 g of N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)phenylcarbamate. The mixture is stirred for 20 minutes and concentrated by evaporation. The residue is triturated with 10 ml of 2N hydrochloric acid and the precipitated solid is isolated and washed with water and ether, affording 6.90 g of N-(2-cyclopropylmethoxypyridin-3-ylsulfonyl)-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea with a melting point of 165°-167° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:19])[C:9]2([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11][CH2:10]2)=[CH:4][C:3]=1[NH:20][C:21](=[O:36])[C@H:22]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C@@H:23]([CH3:28])[C:24]([F:27])([F:26])[F:25].[CH:37](OCC)=[CH2:38]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:19][CH:37]=[CH2:38])[C:9]2([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:10][CH2:11]2)=[CH:4][C:3]=1[NH:20][C:21](=[O:36])[C@H:22]([C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C@@H:23]([CH3:28])[C:24]([F:27])([F:25])[F:26]
Reactant: C[C@H]([C@H](C(=O)Nc1cc(C(O)C2(C(=O)OC(C)(C)C)CC2)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F
Reactant: C=COCC
Solvent: ClCCl
Product: C=COC(c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1)C1(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
Under argon, 473 mg (0.87 mmol) of tert-butyl 1-[(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)(hydroxy)methyl]cyclopropanecarboxylate (as diastereomer mixture) were dissolved in 2.4 ml of dichloromethane, and 1.24 ml (13 mmol) of ethyl vinyl ether and 11 mg (0.03 mmol) of)bis(acetato)(1,10-phenanthrolin-N1,N10)palladium [J. Org. Chem. 62, 1560-1562 (1997)] were added at room temperature. The reaction solution was then heated to 50° C. and stirred at this temperature for two days. Another 1.24 ml (13 mmol) of ethyl vinyl ether and 11 mg (0.03 mmol) of)bis(acetato)(1,10-phenanthrolin-N1,N10)palladium were then added, and stirring of the reaction mixture was continued at 50° C. overnight. This procedure was repeated two more times. The reaction solution was then cooled to room temperature and concentrated to dryness under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/dichloromethane 1:1). This gave 298 mg of the target compound (60% of theory).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[OH:15].[C:16]([C:18]1[CH:32]=[CH:31][C:21]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)=[CH:20][C:19]=1[F:33])#[CH:17]>>[CH3:30][O:29][C:27]([CH:25]1[CH2:26][N:23]([CH2:22][C:21]2[CH:31]=[CH:32][C:18]([C:16]3[O:15][C:3]4[CH:4]=[CH:5][C:6]([CH2:8][C:9]5[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=5)=[CH:7][C:2]=4[CH:17]=3)=[C:19]([F:33])[CH:20]=2)[CH2:24]1)=[O:28]
Reactant: C#Cc1ccc(CN2CC(C(=O)OC)C2)cc1F
Reactant: Oc1ccc(Cc2cccnc2)cc1I
Product: COC(=O)C1CN(Cc2ccc(-c3cc4cc(Cc5cccnc5)ccc4o3)c(F)c2)C1

Procedure:
Synthesized according to Scheme B3 and general procedure G from 2-iodo-4-(pyridin-3-ylmethyl)phenol (0.305 g, 0.98 mmol) and methyl 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-carboxylate (0.220 g, 0.89 mmol): yellow solid. MS (ESI) m/z: Calculated: 430.2; Observed: 431.5 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[CH3:14][O:15][C:16](=[O:27])[C@H:17]([CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:20])[NH2:18]>>[CH3:14][O:15][C:16](=[O:27])[CH:17]([NH:18][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13])[CH:19]([OH:20])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)[C@@H](N)C(O)c1ccccc1
Product: COC(=O)C(NC(=O)c1cc2cc(Cl)ccc2[nH]1)C(O)c1ccccc1

Procedure:
From 5chloro-1H-indole-2-carboxylic acid and (+)-threo b-phenylserine methyl ester.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH:6]([CH3:8])[NH2:7])[CH3:3].[CH2:10]([O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)[C:11]#[C:12][CH3:13]>>[CH2:2]([O:4][C:5](=[O:9])[CH:6]([NH:7][S:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:10][C:11]#[C:12][CH3:13])=[CH:20][CH:19]=1)(=[O:23])=[O:22])[CH3:8])[CH3:3]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C(C)N
Agent: Cl
Product: CC#CCOc1ccc(S(=O)(=O)NC(C)C(=O)OCC)cc1
Yield: 57.6 %

Procedure:
According to the procedure of Example 20, 1.00 g (6.51 mmol) of D,L-alanine ethyl ester hydrochloride reacted with 1.75 g (7.16 mmol) of 4-but-2-ynyloxy-benzenesulfonyl chloride to provide 1.22 g (58%) of the sulfonamide as a white solid. Electrospray Mass Spec: 325.9 (M+H)+
Reaction SMILES: Br[C:2]1[C:6]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][NH2:16]>CO.C(OCC)(=O)C>[CH3:11][C:7]1[C:6]2[C:2]([NH:12][CH2:13][CH2:14][CH2:15][NH2:16])=[N:3][S:4][C:5]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc2snc(Br)c12
Reactant: NCCCN
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cccc2snc(NCCCN)c12
Temperature: 25 °C

Procedure:
3-Bromo-4-methylbenzo[d]isothiazole (2.70 g, 11.84 mmol), and 1,3-diaminopropane (10.0 g, 135 mmol) in methanol (15 ml) was heated at 64° C. for 1.5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Lyophilization of the crude sample in acetonitrile/water yielded N1-(4-methylbenzo[d]isothiazol-3-yl)propane-1,3-diamine sample. 1H NMR (300 MHz, DMSO-d6): 7.70 (d, 1H), 7.30 (t, 1H), 7.15 (dd, 1H), 6.58 (t, 1H), 3.47 (t, 2H), 2.96 (t, 2H), 2.73 (s, 3H), 1.92 (t, 2H), 1.56 ppm (m, 2H). MW=221 confirmed by LC-MS, tr=2.30 min (Method E) MH+=222.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[N:16])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CCOCC>C1COCC1>[NH2:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:9][CH2:8][CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:12][CH2:11]1
Reactant: N#CCCN1CCC(C2CCCCC2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCCCN1CCC(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a stirred solution of 3-(4-cyclohexylpiperidin-1-yl)propionitrile (5.11 g, 23.3 mmol, 1.0 equiv) in anhydrous THF (15 mL) under argon was added a solution of BH3 in THF (1.0M, 82 mL, 3.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours, then cooled to room temperature and concentrated to a volume of about 30 mL. Aqueous HCl (6N, 55 mL) was added and stirring was continued for 2 hours at 55-60° C. The mixture was basified to pH 9 by addition of 6N aq. NaOH and extracted with CH2Cl2 (3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was dissolved in CH2Cl2 (20 mL) and treated with HCl in ether (1.0M, 58 mL, 2.5 equiv). The solvents were removed, ether (40 mL) was added, the mixture was filtered, and the filter cake was washed with ether (2×20 mL). Water (40 mL) was added to the resulting white solid, the pH was adjusted to 10 with 1M NaOH, and the aqueous phase was extracted with CH2Cl2 (3×80 mL). The combined organic solutions were dried over MgSO4 and concentrated to give 4.63 g (88%) of colorless oil, which was characterized spectroscopically.
Reaction SMILES: CO[N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([OH:7])=[O:6].[ClH:13].[H][H]>CO.O>[ClH:13].[NH2:3][CH:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([OH:7])=[O:6]
Reactant: [H][H]
Reactant: CON=C(C(=O)O)c1csnn1
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(C(=O)O)c1csnn1
Reaction time: 1 h

Procedure:
A solution of 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (mixture of syn- and anti-isomers) (500 mg) [prepared by the method described in Belgian Pat. No. 859384 (1978)] in a mixture of methanol (10 cm3) and water (2.3 cm3) was treated with 1N hydrochloric acid (2.7 cm3) and hydrogenated under 50 psi of hydrogen with 5% rhodium-on-charcoal (500 mg) for one hour. A further portion of catalyst (500 mg) was added and hydrogenation continued for one hour. After filtration the filtrate was evaporated to dryness in vacuo and the residue triturated with ether to give the title compound as an off-white solid, (490 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[CH:4][CH:3]=1.Cl.[NH2:13][OH:14].C(=O)([O-])O.[Na+]>CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7]/[C:8](=[N:13]/[OH:14])/[NH2:9])=[CH:4][CH:3]=1
Reactant: N#CCOc1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N/C(COc1ccc(Cl)cc1)=N\O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(4-chlorophenoxy)acetonitrile (1.35 g, 8.06 mmol), hydroxylamine hydrochloride (0.840 g, 12.1 mmol), and sodium hydrogencarbonate (3.38 g, 40.3 mmol) in methanol (15 mL) was heated to reflux. After 16 hours, the reaction mixture was cooled to ambient temperature and filtered. The filtrate was diluted with ethyl acetate (125 mL) and washed with 1 N aqueous HCl and saturated aqueous NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo to furnish the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.28 (s, 1H), 7.36-7.28 (m, 2H), 7.06-6.98 (m, 2H), 5.60 (bs, 2H), 4.39 (s, 2H); MS (DCI+) m/z 201 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:28]([N:30]([C:34]1([C:40]#[CH:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:31][CH2:32][OH:33])[CH3:29]>>[CH2:28]([N:30]([C:34]1([C:40]#[C:41][C:16]2[CH:15]=[CH:14][C:13]3[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:26])([F:27])[F:1])=[CH:8][CH:7]=4)=[N:10][S:11][C:12]=3[CH:17]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:31][CH2:32][OH:33])[CH3:29]
Reactant: C#CC1(N(CC)CCO)CCCCC1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Product: CCN(CCO)C1(C#Cc2ccc3c(-c4ccc(C(F)(F)F)cc4)nsc3c2)CCCCC1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and 2-[Ethyl-(1-ethynyl-cyclohexyl)-amino]-ethanol were converted to yield 2-(Ethyl-{1-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-ylethynyl]-cyclohexyl}-amino)-ethanol as brown oil, MS: 473.3 (MH+).