Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([NH:17][C:18]4[CH:19]=[N:20][CH:21]=[CH:22][C:23]=4[N:24]4[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C@@H:25]4[CH3:38])=[N:15][CH:16]=3)[N:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.FC1C(C2C=CC3N(C(NC4C=NC=CC=4N4CCC[C@H](NC(=O)OC(C)(C)C)[C@H]4C)=NC=3)N=2)=NC=CC=1.P(C)(C)C.N(C1C=NC=CC=1N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1)=C=S.N(C1C=NC=CC=1N1CCC[C@H](NC(=O)OC(C)(C)C)C1C)=C=S>C1COCC1>[F:1][C:2]1[C:3]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([NH:17][C:18]4[CH:19]=[N:20][CH:21]=[CH:22][C:23]=4[N:24]4[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH:25]4[CH3:38])=[N:15][CH:16]=3)[N:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1[C@@H](NC(=O)OC(C)(C)C)CCCN1c1ccncc1Nc1ncc2ccc(-c3ncccc3F)nn12
Agent: CC1[C@@H](NC(=O)OC(C)(C)C)CCCN1c1ccncc1N=C=S
Agent: CP(C)C
Agent: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2N=C=S)C1
Solvent: C1CCOC1
Product: CC1[C@@H](NC(=O)OC(C)(C)C)CCCN1c1ccncc1Nc1ncc2ccc(-c3ncccc3F)nn12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
tert-butyl ((2S,3S)-1-(3-((2-(3-fluoropyridin-2-yl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-2-methylpiperidin-3-yl)carbamate (first eluting diastereomer) and tert-butyl ((2R,3S)-1-(3-((2-(3-fluoropyridin-2-yl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-2-methylpiperidin-3-yl)carbamate (second eluting diastereomer). PMe3 (0.86 mL of 1.0 M solution in THF, 0.86 mmol) was added drop wise to a solution of 3-(azidomethyl)-6-(3-fluoropyridin-2-yl)pyridazine (Preparation XXVIII, 190 mg, 0.82 mmol) in THF (2 mL) at RT. After the reaction mixture stirred for 15 min at RT, it was treated with a suspension of tert-butyl ((3S)-1-(3-isothiocyanatopyridin-4-yl)-2-methylpiperidin-3-yl)carbamate (Preparation XLIX, 288 mg, 0.82 mmol) in THF (2.5 mL) at RT. The resulting mixture was stirred at RT for 15 min; then concentrated to half of its volume. The solution purified by silica gel chromatography (50-100% EtOAc in hexanes followed by 1-3% MeOH in EtOAc) to provide tert-butyl ((3S)-1-(3-((2-(3-fluoropyridin-2-yl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-2-methylpiperidin-3-yl)carbamate as an orange amorphous solid. MS (ESI, pos. ion) m/z: 519.1 (M+1). LCMS indicated the presence of 2 peaks with the same mass at about 1:3 ratio. The above obtained orange amorphous solid was dissolved in 10 mL of DMSO and purified on a preparative reverse-phase HPLC (using Prep HPLC method 3) to provide tert-butyl ((2S,3S)-1-(3-((2-(3-fluoropyridin-2-yl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-2-methylpiperidin-3-yl)carbamate (first eluting diastereomer) and tert-butyl ((2R,3S)-1-(3-((2-(3-fluoropyridin-2-yl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-2-methylpiperidin-3-yl)carbamate (second eluting diastereomer).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([OH:12])[CH2:9][N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([O:12][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:9][N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CC[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.4 %

Procedure:
To a stirred mixture of tert-butyl (2R,4R)-2-(3-ethoxy-3-oxopropyl)-4-hydroxypyrrolidine-1-carboxylate (335 mg, 1.2 mmol, step 2 of Example 8) and triethylamine (0.25 mL, 1.8 mmol) in dichloromethane (5 mL) at 0° C. was added methanesulfonyl chloride (0.14 mL, 1.8 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 3 h. To the mixture was added water (10 mL) and extracted with dichloromethane (100 mL). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give 462 mg (100%) of the title compound as a yellow oil, which was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O)(=[O:11])=[O:10].[CH2:21]1[NH:26][CH2:25][CH2:24][N:23]2[CH2:27][CH2:28][CH2:29][C@H:22]12>CN(C)C(=O)C.CC1CCCO1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([N:26]2[CH2:25][CH2:24][N:23]3[CH2:27][CH2:28][CH2:29][C@@H:22]3[CH2:21]2)=[O:17])[CH:13]=1)(=[O:10])=[O:11]
Reactant: C1C[C@@H]2CNCCN2C1
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2ccccc2F)c1
Solvent: CC1CCCO1
Solvent: CC(=O)N(C)C
Product: O=C(c1cccc(S(=O)(=O)Nc2ccccc2F)c1)N1CCN2CCC[C@@H]2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid (800 mg, 2.71 mmol) and 2-(3H-[1,2,3]triazolo[4,5-h]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1133 mg, 2.98 mmol) in N,N-dimethylacetamide (6.5 mL) and 2-methyltetrahydrofuran (19.5 mL) was added (R)-octahydropyrrolo[1,2-a]pyrazine (479 mg, 3.79 mmol). The reaction was stirred at room temperature for 3 hours, diluted with 2-methyltetrahydrofuran (5 mL), and washed with saturated bicarbonate (2×25 mL). The combined aqueous layers were adjusted to pH 7 with buffer and re-extracted with 2-methyltetrahydrofuran (3×15 mL). The combined organic layers were concentrated under reduced pressure. The residue was taken up in ethanol (25 mL) and concentrated to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH2:13][C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)COCCO.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH2:13][C:14]([OH:16])=[O:15])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: NCC(=O)O
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: OCCOCCO
Product: O=C(O)CNc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 54.1 %

Procedure:
26.2 g (0.137 mol) of 2,5-dichloro-1-nitrobenzene, 20.6 g (0.274 mol) of glycine and 18.9 g (0.137 mol) of potassium carbonate were heated in 200 ml of diethylene glycol at 120° C. for 1 h. After cooling, 100 ml of water were added and the solution was acidified with 1M hydrochloric acid. The precipitate was filtered off with suction. 17.1 g (54%) of the product were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:13].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.CCOC(C)=O>[CH3:14][NH:1][C:2]1[CH:7]=[C:6]([C:8]([CH2:11][CH3:12])([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[OH:13]
Reactant: CCC(C)(C)c1ccc(O)c(N)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: CCC(C)(C)c1ccc(O)c(NC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Amino-4-tert-pentylphenol (5.00 g, 27.8 mmol) and potassium carbonate (3.88 g, 28.1 mmol) were mixed at RT for 2.5 hours in DMF (15 mL). Methyl iodide (1.20 mL, 19.3 mmol) was added and the mixture was stirred overnight at RT. Diluted the mixture with EtOAc and extracted with aqueous sodium bicarbonate and water. Dried the organic layers over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (10-15% MTBE/hexanes). Concentrated the product fractions to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]#[N:14].[CH2:15]([Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[C:18]#[CH:19])[CH3:16].[NH4+].[Cl-]>N(C(C)C)C(C)C.CN(C=O)C.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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:18]([Si:17]([C:15]#[C:16][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]#[N:14])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:19]
Reactant: C#C[Si](CC)(CC)CC
Reactant: N#CCc1ccc(C(F)(F)F)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC[Si](C#Cc1cc(C(F)(F)F)ccc1CC#N)(CC)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
Bis(triphenylphosphine)palladium(II) chloride (0.106 g, 0.151 mmol), copper(I) iodide (0.058 g, 0.303 mmol) and triphenylphospine (0.079 g, 0.303 mmol) are dissolved in a mixture of i-Pr2NH (11.36 ml)/DMF (3.79 ml) (degassed with N2 for 15 min). 2-(2-Bromo-4-(trifluoromethyl)phenyl)acetonitrile (1.1 g, 3.8 mmol) is added to the resultant orange solution. The mixture is stirred at RT for one hour. Triethyl(ethynyl)silane (1.018 ml, 5.68 mmol) is added dropwise, and the batch is warmed to 80° C. After 1 hour, a saturated, aqueous NH4Cl solution (50 ml) is added to the strongly dark-coloured batch. After phase separation, the aqueous phase is extracted three times with 50 ml of ethyl acetate each time. The combined organic phases are dried over Na2SO4 and evaporated to dryness in vacuo. The residue is purified by chromatography on silica gel with a 98:2 mixture of petroleum ether and ethyl acetate, giving 2-(2-((triethylsilyl)ethynyl)-4-(trifluoromethyl)phenyl)acetonitrile (orange oil, 91%, 1.226 g, 3.79 mmol);
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CS(Cl)(=O)=O.[CH:36]([N:39](CC)C(C)C)(C)C.CN.C1COCC1>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:28]=[CH:27][C:26]([CH2:29][NH:39][CH3:36])=[CH:25][CH:24]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CO)cc1
Agent: CN
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNCc1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4′-(hydroxymethyl)-6-methylbiphenyl-3-yl)cyclopropanecarboxamide (610 mg, 1.52 mmol), methanesulfonyl chloride (0.13 mL, 1.7 mmol), and N,N-diisopropylethylamine (0.79 mL, 4.6 mmol) were dissolved in dichloromethane (10 mL) at 25° C. The reaction was stirred for 10 minutes before a 2.0 M solution of MeNH2 in THF (15 mL, 30 mmol) was added. The mixture was stirred for 30 minutes at ambient temperature before it was extracted with 1N HCl (20 mL×2) and saturated NaHCO3 (20 mL×2). The organic extracts were dried over Na2SO4 and evaporated. The crude product was purified by chromatography on silica gel (eluting with 0-20% methanol in dichloromethane) to afford 1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-((methylamino)methyl)biphenyl-3-yl)cyclopropanecarboxamide (379 mg, 60%). ESI-MS m/z calc. 414.5. found 415.5 (M+1)+; retention time 2.44 minutes.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([NH:20]C(=O)OC(C)(C)C)([CH3:19])[CH3:18])[CH:13]=[CH:14][CH:15]=1.C1(C)C=CC=CC=1>C(Cl)Cl>[NH2:20][C:17]([CH3:19])([CH3:18])[CH2:16][C:12]1[CH:11]=[C:10]([CH2:9][OH:8])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(Cc1cccc(CO)c1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(N)Cc1cccc(CO)c1
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl 1-(3-(hydroxymethyl)phenyl)-2-methylpropan-2-ylcarbamate (Example 275, step b) (0.7 g) in DCM (20 mL) and the resultant solution allowed to stand at 20° C. for 30 minutes. Toluene (40 mL) was added and the solvents evaporated under reduced pressure. The residue was partitioned between DCM and 1M aqueous sodium hydroxide, and the aqueous layer was extracted with DCM (×2). The combined organics were dried over sodium sulphate, filtered and the solvent removed under reduced pressure to afford the subtitled compound. Yield 0.440 g.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[NH:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[N:8]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCNc2ccc(C(=O)OC)cc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCN1CCN(S(C)(=O)=O)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold, stirred solution of methyl 4-butyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (180 mg) and triethylamine (62 μL) in methylene chloride (2 mL) was added methanesulfonyl chloride (101 μL) and the mixture was stirred for 1 h. The mixture was warmed to room temperature, diluted with methylene chloride, washed with washed with 1 N hydrochloric acid, and brine. The organic layer was then dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:3 ethyl acetate/hexanes) provided 150 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.57, 7.41, 7.32, 3.90, 3.84, 3.45, 3.38, 1.61, 1.41, 0.98.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.S(Cl)(Cl)=O.CCN(CC)CC.[NH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([C:37]([CH3:43])([CH3:42])[CH2:38][CH2:39][C:40]#[N:41])=[CH:31]2>ClCCl.CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:27][C:28]4[CH:29]=[C:30]5[C:34](=[CH:35][CH:36]=4)[NH:33][C:32]([C:37]([CH3:43])([CH2:38][CH2:39][C:40]#[N:41])[CH3:42])=[CH:31]5)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CC(C)(CCC#N)c1cc2cc(N)ccc2[nH]1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(CCC#N)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (0.068 g, 0.33 mmol) was added thionyl chloride (72 μL, 0.99 mmol) and DMF (20 μL) at room temperature. The mixture was stirred for 30 minutes before the excess thionyl chloride was evaporated under reduced pressure. To the resulting acid chloride, dichloromethane (0.5 mL) and Et3N (230 μL, 1.7 mmol) were added. A solution of 4-(5-amino-1H-indol-2-yl)-4-methylpentanenitrile (0.33 mmol) in dichloromethane (0.5 mL) was added to the acid chloride solution and the mixture was stirred at room temperature for 1.5 h. The resulting mixture was diluted with dichloromethane and washed with 1 N HCl (2×2 mL), saturated aqueous NaHCO3 (2×2 mL) and brine (2×2 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(4-cyano-2-methylbutan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide.
Reaction SMILES: C(N(CC)CC)C.[S:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[CH:10]=[CH:9]1.ClCCl.[C:20]1([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[C:26]([N:13]1[CH2:14][CH2:15][C:16]2[S:8][CH:9]=[CH:10][C:11]=2[CH2:12]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1cc2c(s1)CCNC2
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: c1ccc(C(c2ccccc2)(c2ccccc2)N2CCc3sccc3C2)cc1

Procedure:
20 cm3 (0.079 mole) of triethyl amine are added dropwise to the solution of 10 g (0.072 mole) of 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine and 20 cm3 of dichloro methane at room temperature and 20.02 g (0.072 mole) of triphenyl-methyl-chloride are added. The reaction mixture is kept at room temperature for a night and is poured onto 200 cm3 of water. The phases are separated; the organic phase is dried on sodium sulfate and evaporated to dryness. The residual product is purified by silica gel chromatography using dichloro methane as eluent.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[O:6][C:7]([CH3:11])=[CH:8][C:9]=1[SH:10].Cl[CH:13]([C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15].O>CO>[CH2:14]([CH:13]([S:10][C:9]1[CH:8]=[C:7]([CH3:11])[O:6][C:5]=1[CH3:4])[C:16]([CH2:17][CH2:18][CH3:19])=[O:20])[CH3:15]
Reactant: Cc1cc(S)c(C)o1
Reactant: CCCC(=O)C(Cl)CC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCC(=O)C(CC)Sc1cc(C)oc1C
Temperature: 23 °C
Reaction time: 1 h

Procedure:
Into a 25 ml round bottom 3 neck flask equipped with magnetic stirrer, Y tube, nitrogen inlet, reflux condenser and thermometer is placed a solution of 0.27 g (0.005 moles) of sodium methoxide dissolved in 3 ml absolute methanol. The sodium methoxide solution is cooled using a water bath to 25° C. A solution of 0.64 g (0.005 moles) of 2,5-dimethyl-3-furan thiol in 3 ml of absolute methanol is then added to the sodium methoxide solution dropwise from a pipette while maintaining the temperature of the reaction mass between 22° C and 28° C. While maintaining the temperature of the reaction mass at 23° - 35° C, 3-chloro-4-heptanone (0.74 g; 0.005 moles) in 1 ml absolute methanol is added dropwise. The reaction mass is then stirred for a period of 1 hour while maintaining the temperature at 23° C. After this 1 hour period, 15 ml of water is added with stirring and the reaction mass temperature rises to 28° - 30° C. The reaction mass is cooled to 25° C using a water bath and now exists in an aqueous phase and an organic phase. The aqueous phase (pH=6) is extracted with two 6 ml portions of n-hexane; and the hexane extracts and organic phase are combined, washed with a 4 ml portion of saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The resulting material is gravity filtered and concentrated on a rotary evaporator at 25° - 35° C and 15 mm Hg pressure, yielding a crude yellow oil weighing 1.2 g. The desired product is isolated by GLC trapping (8 foot × 1/4 inch SE-30 Column), and NMR, IR and Mass Spectral analyses yield the information that this material has the structure: ##SPC16##
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8]Br)=[CH:3][CH:2]=1.[C:11]([OH:17])(=[O:16])[C:12](=[N:14][OH:15])[CH3:13]>>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][O:15][N:14]=[C:12]([CH3:13])[C:11]([OH:17])=[O:16])=[CH:3][CH:2]=1
Reactant: Cc1ccc(CCBr)cc1
Reactant: CC(=NO)C(=O)O
Product: CC(=NOCCc1ccc(C)cc1)C(=O)O
Yield: 41 %

Procedure:
2-p-Tolylethyl bromide and pyruvic acid oxime are reacted by the process of Example 1 and the reaction mixture is evaporated when the reaction is complete. The residue is taken up in a little water, washed with diethyl ether and the aqueous solution is acidified. The precipitate obtained is filtered off with suction and dried to give a yield of 41% of theory of 2-(2-p-tolylethyloxyimino)-propionic acid; m.p. 106°-108° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CNC(=O)CCNC(=O)OCc2ccccc2)C1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCNC(=O)OCc1ccccc1)NC[C@H]1CCCNC1
Yield: 89.9 %

Procedure:
To a solution of 1.84 g of 3-(benzyloxycarbonyl)amino-N-({(3R)-1-(tert-butoxycarbonyl)-3-piperidyl}methyl)propanamide in 2 ml of chloroform, 2 ml of trifluoroacetic acid was added at room temperature, followed by an hour's stirring at the same temperature. The reaction liquid was distilled off under reduced pressure, and the residue was rendered basic with 4N aqueous sodium hydroxide solution. Extracting the product with chloroform, the product was dried over anhydrous sodium sulfate. Upon distilling the solvent off under reduced pressure, 1.26 g of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[CH:6]=[C:5]2[C:19](=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1.[OH-].[Na+].CO>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[C:5]2[C:19](=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2cccc([N+](=O)[O-])c2)c2cc(Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)CCCn1cc(C(=O)c2cccc([N+](=O)[O-])c2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.9 %

Procedure:
A mixture of ethyl 4-[5-chloro-3-(3-nitrobenzoyl)indol-1-yl]butyrate (2.00 g), 1N aqueous sodium hydroxide (7.5 ml), methanol (35 ml) and 1,4-dioxane (35 ml) was stirred at 25° C. for 6 hours. After evaporation of the organic solvent, 1N hydrochloric acid (15 ml) was added to the aqueous solution and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The crystalline residue was washed with hot ethanol to give 4-[5-chloro-3-(3-nitrobenzoyl)indol-1-yl]butyric acid (1.77 g) as colorless crystals.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)C=CC=CC=1.C(N(C(C)C)C(C)C)C.[OH:37][C:38]1([CH3:44])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>ClC(Cl)Cl.O1CCCC1>[CH3:26][O:25][C:15]1[C:13]2[N:14]=[C:10]([NH:9][C:8]([N:41]3[CH2:42][CH2:43][C:38]([OH:37])([CH3:44])[CH2:39][CH2:40]3)=[O:27])[S:11][C:12]=2[C:18]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[CH:17][CH:16]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Reactant: CC1(O)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)N3CCC(C)(O)CC3)nc12
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-carbamic acid phenyl ester (3.2 g, 8.3 mmol) and N-ethyl-diisopropyl-amine (4.4 ml, 25 mmol) in trichloromethane (50 ml) is added a solution of 4-hydroxy-4-methyl-piperidine in trichloromethane (3 ml) and tetrahydrofurane (3 ml) and the resulting mixture heated to reflux for 1 h. The reaction mixture is then cooled to ambient temperature and extracted with saturated aqueous sodium carbonate (15 ml) and water (2×5 ml). Final drying with magnesium sulphate and evaporation of the solvent and recrystallization from ethanol afforded the title compound as white crystals (78% yield), mp 236° C. MS: m/e=407(M+H+).