Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O-:19])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(Cl)(=O)C(Cl)=O.[CH2:26]1[N:31]([CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]3[CH:43]=[CH:44][C:45]([NH:47][C:39]=3[CH:38]=2)=O)[CH2:30][CH2:29][N:28]([C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=2[Cl:55])[CH2:27]1.CC(C)([O-])C.[K+]>ClCCl.CN(C)C=O>[P:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:19][C:45]1[CH:44]=[CH:43][C:40]2[C:39](=[CH:38][C:37]([O:36][CH2:35][CH2:34][CH2:33][CH2:32][N:31]3[CH2:30][CH2:29][N:28]([C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=4[Cl:55])[CH2:27][CH2:26]3)=[CH:42][CH:41]=2)[N:47]=1)=[O:2]
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Agent: CC(C)(C)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=P(OCc1ccccc1)(OCc1ccccc1)Oc1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of dibenzyl phosphate (2.48 g, 8.91 mmol) in dichloromethane (25 ml) was added dimethyl formamide (1 drop) followed by oxalyl chloride (0.75 mL, 8.91 mmol). After 2 hours the reaction mixture was concentrated in vacuo. The residue was dissolved in 2-methyltetrahydrfuran (5 mL) and added to a suspension of dehydro-aripiprazole (1.66 g, 3.71 mmol) and potassium t-butoxide (0.92 g, 8.17 mmol) in 2-methyltetrahydrfuran (35 mL) at 0° C. under Ar (g) then allowed to gradually warm to room temperature. After stirring overnight the reaction was quenched with water (25 mL) and 28% aq NH3 (15 mL) and stirred for 10 minutes. The reaction mixture was then extracted with ethyl acetate (2×40 mL). The combined organics were washed with water (50 mL) and brine (50 mL) then dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by column chromatography eluting with 5% methanol (1:1 ethyl acetate/dichloromethane) to give the product. The 1H-NMR showed minor impurities still present (impurities not observed by LCMS). Various further purifications were attempted but failed to remove these impurities.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[CH2:29][CH:30]([CH3:32])[CH3:31]>CN(C=O)C>[CH3:31][CH:30]([CH3:32])[CH2:29][CH2:28][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 80 °C
Yield: 129.3 %

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 50.7 mg, 0.1 mmol), K2CO3 (49.5 mg, 0.36 mmol), and isoamyl bromide (32 uL, 0.27 mmol) in DMF (1.0 mL). Heat at 80° C. for 6 hours. Pass through an SCX column, washing with methanol and then eluting with 2.0 M NH3 in MeOH. Concentrate the eluant and purify by flash chromatography, eluting with 70:22:8 EtOAc/CH2Cl2/2.0 M NH3 in MeOH to afford the title compound (45.7 mg, 72%): MS ES+ 354.0 (M+H)+, HRMS calcd for C21H28N3O2 354.2182 (M+H)+, found 354.2182, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=6.39 min, 100% purity; Anal. Calcd for C21H27N3O2.0.2CH2Cl2.0.1MeOH: C, 69.59; H, 5.98; N, 11.43. Found: C, 69.47; H, 6.25; N, 11.30.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:24])[CH:11]=2)[N:6]=1)(=O)[CH3:2].C(O)C.Cl>C1COCC1>[Cl:24][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[C:5]([NH:4][CH2:1][CH3:2])[CH:14]=[C:13]2[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CC(=O)Nc1cc(-c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2n1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CCNc1cc(-c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
500 mg of 2-acetylamino-6-chloro-4-(4-nitrophenyl)quinoline (compound 1c) were suspended in 10 ml of THF and, under argon, added in portions to 2.9 ml of borane-THF complex. Foaming was followed by formation of a yellow solution. After stirring at room temperature for 12 hours, the solution was mixed with 5 ml of ethanol and 2 ml of concentrated HCl and heated on a water bath, cooled and distilled to remove water. The residue was mixed with water, made alkaline with 2N NaOH, extracted with ethyl acetate and washed with water. The product was purified by MPLC chromatography using an MPRC cartridge with a mixture of 1 part by volume of ethyl acetate, 2 parts by volume of toluene. A yellow solid product was isolated.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[N:7]([O-])=O.[Na+].Cl.[NH2:12][C:13]1[N:17]2[CH2:18][CH2:19][CH2:20][N:16]2[C:15](=[O:21])[CH:14]=1.C([O-])(=O)C.[Na+]>Cl.O.C(O)C>[NH2:12][C:13]1[N:17]2[CH2:18][CH2:19][CH2:20][N:16]2[C:15](=[O:21])[C:14]=1/[N:7]=[N:1]/[C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: O=N[O-]
Reactant: Nc1nccs1
Reactant: Nc1cc(=O)n2n1CCC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1c(/N=N/c2nccs2)c(=O)n2n1CCC2
Reaction time: 0.17 h

Procedure:
0.57 g of 2-aminothiazole is solubilized in 3 ml of 6N hydrochloric acid. The medium is cooled to zero degrees, and then a solution of 0.39 g of sodium nitrite in 3 ml of water is added over 3 minutes. The medium is then kept stirring for 10 minutes between 0 and 5° C. A mixture of 1 g of 3-amino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one hydrochloride, 5 ml of ethanol, 5 ml of water and 1.7 g of sodium acetate is added to the reaction medium.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]C(OCC)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:19][O:20][P:21]([CH2:25][C:26](=[O:40])CC(O[Si](C(C)(C)C)(C)C)CCC)(=[O:24])[O:22][CH3:23]>>[CH3:19][O:20][P:21]([CH2:25][C:26](=[O:40])[CH:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH2:10][CH2:11][CH2:12][CH3:13])(=[O:24])[O:22][CH3:23]
Reactant: CCOC(=O)CCCCCO[Si](C)(C)C(C)(C)C
Reactant: CCCC(CC(=O)CP(=O)(OC)OC)O[Si](C)(C)C(C)(C)C
Product: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)CP(=O)(OC)OC
Yield: 60 %

Procedure:
Dimethyl(3-((tert-butyldimethylsilyl)oxy)-2-oxoheptyl)phosphonate 9 (1.55 g) was prepared in 60% yield using compound 8 according to the procedures described for compound 3 (see Schemes 1-3).
Reaction SMILES: [OH:1][CH:2]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][C:23]=1[F:34])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH:6]1[CH2:18][C:19]([OH:21])=[O:20].S(Cl)([Cl:37])=O>CO>[ClH:37].[ClH:37].[OH:1][CH:2]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][C:23]=1[F:34])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH:6]1[CH2:18][C:19]([OH:21])=[O:20]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2ncc(F)c(C(O)CCC3CCN(C(=O)OC(C)(C)C)CC3CC(=O)O)c2c1
Solvent: CO
Product: COc1ccc2ncc(F)c(C(O)CCC3CCNCC3CC(=O)O)c2c1
Product: Cl
Reaction time: 0.5 h

Procedure:
A solution of 940 mg of (3RS,4RS) and (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-acetic acid in 20 cm3 of methanol was cooled to a temperature in the region of −25° C., with stirring and under an inert atmosphere. 0.43 cm3 of thionyl chloride were added to this solution over 5 minutes. The mixture was brought to a temperature in the region of 20° C. while the stirring was continued for a further 1 hour 30 minutes. The reaction mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. and then 30 cm3 of methanol were added. This series of operations was repeated 3 times. 920 mg of methyl (3RS,4RS) and (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate dihydrochloride were obtained in the form of a yellow foam.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[O:15][CH2:16][CH3:17].[OH-].[Li+].Cl>O1CCCC1.O>[CH2:16]([O:15][C:5]1[CH:6]=[C:7]([O:10][C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:9][C:4]=1[C:3]([OH:18])=[O:2])[CH3:17]
Reactant: CCOc1cc(OC(F)(F)F)ccc1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(OC(F)(F)F)ccc1C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
590 mg 2-Ethoxy-4-trifluoromethoxy-benzoic acid methyl ester was dissolved in a mixture of 30 ml tetrahydrofuran and 10 ml water. 367 mg lithium hydroxide were added and the reaction mixture stirred at 60° C. for two hours. The cooled reaction mixture was acidified by dropwise addition of concentrated hydrochloric acid, then the mixture was extracted three times with portions of 80 ml ethyl acetate. The combined organic layers were dried over MgSO4. The solvent was removed in vacuo to obtain 518 mg 2-ethoxy-4-trifluoromethoxy-benzoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:18])=[O:5])[CH3:2].[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH2:18][Br:19])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)nc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2)nc1CBr
Temperature: 25 °C
Yield: 100.9 %

Procedure:
A mixture of 2-(4-chloro-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester (2.50 g, 8.88 mmol), N-bromosuccinimide (2.13 g, 12.0 mmol) and benzoyl peroxide (150 mg, 0.62 mmol) in carbon tetrachloride (50 mL) was refluxed for 24 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (3.23 g, product is 69% pure by 1H NMR, impurities are starting material and dibromonated compound): 1H NMR (CDCl3, 200 MHz): δ=7.90 (d, 2H), 7.44 (d, 2H), 4.96 (s, 3H), 4.38 (q, J=7.0 Hz, 2H), 1.44 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)=[CH:4][CH:3]=1.CN(C)[CH:16]=[C:17]([N:23]=[CH:24]N(C)C)[C:18]([O:20][CH2:21][CH3:22])=[O:19].FC(F)(F)C(O)=O>C(O)(=O)C>[F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[C:11]3[CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:23]=[CH:24][C:10]=3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=CN(C)C)N=CN(C)C
Reactant: Fc1ccc(Cn2cccc2)cc1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2c(ccn2Cc2ccc(F)cc2)cn1
Yield: 19 %

Procedure:
A solution of 1-(4-fluorobenzyl)-1H-pyrrole (11.1 g, 63.4 mmol), ethyl 3-dimethylamino-2-(dimethylamino-methyleneamino)-acrylate (14.84 g, 69.7 mmol) [prepared according to W. Kantlehner, F. Wagner, H. Bredereck, Liebigs Ann. Chem. 1980, 344-357] and trifluoroacetic acid (19.4 mL, 253.6 mmol) in acetic acid (80 mL) was stirred for 16 h at ambient temperature. Then the solution was heated to reflux for 4 hr. After cooling down, it was concentrated. The residue was poured into satd. potassium carbonate solution (1000 mL) and extracted with ethyl acetate (3×500 mL). The combined organic extracts were washed with brine (2×500 mL), dried over sodium sulfate, and concentrated. Purification by column chromatography with toluene:acetonitrile (2:1) provided the title compound. (3.6 g, 19% yield). 1H NMR (CDCl3) δ ppm 9.15 (s, 1H), 8.23 (s, 1H), 7.37 (d, 1H, J=3.0 Hz), 7.0-7.11 (m, 4H), 6.83 (d, 1H, J=3.0 Hz), 5.40 (s, 2H), 4.52 (q, 2H, J=7.0 Hz), 1.48 (t, 3H, J=7.0 Hz). LCMS (APCI, M+H+): 299.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:12]([O:16][C:17](=[O:35])[NH:18][CH:19]1[CH2:24][CH2:23][N:22]([S:25]([C:28]2[CH:29]=[N:30][C:31](Cl)=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH2:21][CH2:20]1)([CH3:15])([CH3:14])[CH3:13]>CN(C=O)C>[C:12]([O:16][C:17](=[O:35])[NH:18][CH:19]1[CH2:20][CH2:21][N:22]([S:25]([C:28]2[CH:29]=[N:30][C:31]([O:11][CH2:3][CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH2:23][CH2:24]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: OCCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(OCCc3ccccc3)nc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 78 %

Procedure:
Sodium hydride (0.03 g, 1.15 mmol, 60% suspension in mineral oil) was added in portion wise to a cool (0° C.), stirred solution of phenethyl alcohol (0.08 g, 0.64 mmol) in DMF (5 ml) and the mixture was stirred at this temperature for 5 minutes. After this time, [1-(6-chloro-pyridine-3-sulfonyl)piperidin-4-yl]-carbamic acid tert-butyl ester (0.2 g, 0.5 mmol) was added in one portion and the mixture was warmed to room temperature stirred at this temperature under a nitrogen atmosphere for 12 hours. After this time the mixture was cooled to room temperature, concentrated and the resulting residue was diluted with DCM (50 ml) and washed sequentially with HCl (1M solution, 20 ml), NaOH (1M solution, 20 ml) and brine (20 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the title compound (0.18 g, 75% yield) as a white solid. Tr=2.32 min, m/z (ES+) (M+H)+ 462.
Reaction SMILES: [I-].[CH3:2][N+:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]3=2)[C:5]([CH3:17])([CH3:16])[C:4]=1[CH3:18].[OH-].[Na+].[CH3:21][O:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29]([OH:35])=[C:30]2[N:33]=O)=[CH:25][CH:24]=1>CCCCCC>[CH3:21][O:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29]3[O:35][C:4]4([C:5]([CH3:17])([CH3:16])[C:6]5[C:11](=[C:10]6[CH:12]=[CH:13][CH:14]=[CH:15][C:9]6=[CH:8][CH:7]=5)[N:3]4[CH3:2])[CH:18]=[N:33][C:30]=32)=[CH:25][CH:24]=1
Reactant: COc1ccc2ccc(O)c(N=O)c2c1
Reactant: CC1=[N+](C)c2c(ccc3ccccc23)C1(C)C
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Product: COc1ccc2ccc3c(c2c1)N=CC1(O3)N(C)c2c(ccc3ccccc23)C1(C)C
Reaction time: 0.5 h

Procedure:
To a solution of 1.05 grams (3.0 mmole) of 1,2,3,3-tetramethyl-3H-benz[g] indolium iodide in 15 milliliters (ml) of hexane at 25° C. was added 10 ml (50 mmole) of 20% sodium hydroxide. The two phase mixture was stirred vigorously under nitrogen for about 30 minutes. The organic layer was separated, transferred to a reaction flask equipped with a reflux condenser and diluted with 15 ml of absolute ethanol. To this solution was added 0.61 grams (3.0 mmole) of 7-methoxy-1-nitroso-2-naphthol and the resulting reaction mixture refluxed under nitrogen for about 6 hours. The reaction mixture was cooled, the volume reduced under vacuum and 0.29 grams (0.71 mmole) of the product, 9'-methoxy-1,3,3-trimethylspiro [benz[g] indoline-2,3'-[3H] naphth [2,1-b][1,4] oxazine] was obtained as yellow-orange crystals. A solution of the crystals dissolved in ethanol or toluene was colorless. The solution turned blue when irradiated with ultraviolet light.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH2:27][C:28]#[CH:29])[C:23]([O:25]C)=[O:24].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:27][C:28]#[CH:29])[C:23]([OH:25])=[O:24]
Reactant: C#CCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Temperature: 60 °C
Yield: 1.6 %

Procedure:
To a solution of methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pent-4-yn-oate (0.146 g; 0.362 mmol) in methanol (3.6 mL) was added a solution of sodium hydroxide 5 N (0.72 mL) and the mixture was heated at 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was acidified with HCl (1N) until pH 1. The organic layer was washed with brine, water, dried over magnesium sulphate and concentrated under reduced pressure. Purification by preparative HPLC (HPLC method 1) furnished 0.0023 g (2%) of the title compound as a light yellow solid.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:24])[C@@H:14]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:15])[NH:8]1)=[O:6].O.[OH-].[Li+]>O1CCCC1.O>[C:20]([O:19][C:17]([NH:16][C@@H:14]([CH3:15])[C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:7]([C:5]([OH:6])=[O:4])[NH:8]1)=[O:24])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H](C(=O)O)N1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A cooled (0° C.) solution of (S)-1-((S)-2-tert-butoxycarbonylamino-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (3.007 g, 6.948 mmol) in tetrahydrofuran/water (60 mL, 5:1) was treated with lithium hydroxide monohydrate (874.4 mg, 20.844 mmol). After stirring at 0° C. for 40 minutes the reaction was quenched with hydrochloric acid (1 M, 50 mL). The aqueous layer was extracted with ethyl acetate (2×). The organics were combined, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. Residual trichlorethanol was azeotroped off with toluene (3×) to provide (S)-1-((S)-2-tert-butoxycarbonylamino-propionyl)-hexahydro-pyridazine-3-carboxylic acid as a white solid which was then combined with (R)-1-(7-bromo-quinolin-2-yl)-ethylamine hydrochloride (1.998 g, 6.948 mmol) and suspended in anhydrous acetonitrile (60 mL) and tetrahydrofuran (10 mL). The suspension was cooled to 0° C. and subsequently treated with N,N-diisopropylethylamine (6 mL, 34.740 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (3.699 g, 9.727 mmol). After slowly warming to room temperature and stirring for 16 h, the reaction was quenched at 0° C. with hydrochloric acid (1 M, 70 mL). The aqueous layer was extracted with ethyl acetate (2×). The organics were combined, washed with a saturated solution of sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 1:4 to afford the title compound (3.702 g, 99%) as a white foam. 1H NMR (300 MHz, CDCl3) δ 1.38 (d, J=6.9 Hz, 3H), 1.43 (s, 9H), 1.47-1.55 (m, 2H), 1.58 (d, J=6.9 Hz, 3H), 1.60-1.78 (m, 2H), 2.22-2.31 (m, 1H), 2.65-2.78 (m, 1H), 3.39-3.52 (m, 1H), 4.55 (d, J=13.4 Hz, 1H), 5.18-5.34 (m, 2H), 5.36-5.45 (m, 1H), 7.37 (d, J=8.5 Hz, 1H), 7.65 (dd, J=8.5, 1.6 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 8.04 (d, J=6.5 Hz, 1H), 8.14 (d, J=8.5 Hz, 1H), 8.36 (s, 1H). LCMS (m/z) 536.1, 537.1 [M+H], Tr=2.58 min.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([O:4][C:5]([NH:7][CH:8]([CH:23]([CH3:25])[CH3:24])[C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=1)=[O:10])=[O:6])[CH3:3].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[C:35][CH2:36]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:30][CH:29]=1.C[O-].[Na+]>CO>[CH3:3][C:2]([CH3:26])([O:4][C:5]([NH:7][CH:8]([CH:23]([CH3:24])[CH3:25])[C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:36][C:35]#[C:34][C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)=[C:16]([O:21][CH3:22])[CH:15]=1)=[O:10])=[O:6])[CH3:1]
Reactant: COc1cc(CCNC(=O)C(NC(=O)OC(C)(C)C)C(C)C)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCC#Cc2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CCNC(=O)C(NC(=O)OC(C)(C)C)C(C)C)ccc1OCC#Cc1ccc(Cl)cc1

Procedure:
A mixture 2-(1,1-dimethylethoxycarbonylamino)-N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-3-methylbutyramide (4.0 g), toluene-4-sulfonic acid 3-(4-chloro-phenyl)-prop-2-ynyl ester (5.3 g) and 1M sodium methoxide solution in methanol (18 ml) in methanol (100 ml) is heated to reflux for 3 hours . Then the solvent is removed by distillation. Water (300 ml) is added. The mixture is extracted with ethyl acetate (2×200 ml) and washed with brine (100 ml). The organic layers are collected, dried (MgSO4) and evaporated. 2-(1,1-dimethylethoxycarbonylamino)-N-{2-[3-methoxy-4-(4-chlorophenyl-prop-2-ynyloxy)-phenyl]-ethyl}-3-methylbutyramide is obtained which is purified by flash column chromatography on silica gel (ethyl acetate/hexane 1:1) and recrystallisation (ethyl acetate/hexane), m.p. 141-142° C.
Reaction SMILES: [OH:1][CH:2]([CH:23]([CH3:25])[CH3:24])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:12][N:13]=2)[N:10]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:24][CH:23]([CH3:25])[C:2](=[O:1])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[N:12][N:13]=2)[N:10]=1
Reactant: CC(C)C(O)C#Cc1ccc2nnc(CNC(=O)OC(C)(C)C)n2n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)C(=O)C#Cc1ccc2nnc(CNC(=O)OC(C)(C)C)n2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.7 %

Procedure:
tert-Butyl (6-(3-hydroxy-4-methylpent-1-ynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (1.82 g, 5.27 mmol) and manganese dioxide (activated) (9.16 g, 105 mmol) were dissolved in DCM (263 mL) and stirred at room temperature over two days. Additional manganese dioxide (activated) (4.58 g, 52.7 mmol) was added and stirring continued overnight. The reaction mixture was filtered over a plug of Celite and washed with DCM to yield tert-butyl (6-(4-methyl-3-oxopent-1-ynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.917 g, 50.7% yield) after concentration in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][NH2:12])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:20](F)(F)[CH2:21][N+:22]([O-:24])=[O:23]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:10][CH2:11][NH:12][C:20]2=[CH:21][N+:22]([O-:24])=[O:23])=[CH:4][N:3]=1
Reactant: NCCNCc1ccc(Cl)nc1
Reactant: O=[N+]([O-])CC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=[N+]([O-])C=C1NCCN1Cc1ccc(Cl)nc1
Temperature: 20 °C
Reaction time: 5 h
Yield: 67.1 %

Procedure:
5 g (26.9 mmol) of N-(2-chloro-5-pyridylmethyl)ethylene-diamine and 11.7 g (84.6 mmol) of potassium carbonate are placed in 40 ml of methanol. A solution of 3.64 g (28.2 mmol) of 1,1,1-trifluoro-2-nitro-ethane in 20 ml of methanol is added dropwise at 5° C. to 10° C. within 30 minutes. After the addition is complete, the mixture is stirred for 5 hours at 20° C. The mixture is then concentrated by removal of the solvent by distillation in vacuo, and the residue is taken up in methylene chloride, washed with a small amount of water, dried, concentrated and recrystallized from methanol. 4.6 g (70.1% of theory) of 1-(2-chloro-5-pyridylmethyl)-2-(nitromethylene)-imidazoline of a melting point of 160° C. to 161° C. are obtained.