Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[S:30][C:29]([NH:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)=[N:28][C:27]=1[C:42]([NH2:44])=[O:43]>C1COCC1.N1C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:25][C:26]2[S:30][C:29]([NH:31][C:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:35]=[CH:34][CH:33]=3)=[N:28][C:27]=2[C:42]([NH2:44])=[O:43])=[O:11])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: NC(=O)c1nc(Nc2cccc3ccccc23)sc1N
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)Nc2sc(Nc3cccc4ccccc34)nc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
To a mixture of 4-acetamidobenzoic acid (0.151 g, 0.845 mmol) and a catalytic amount of DMF in dry THF (8 mL) was added dropwise oxalyl chloride (0.12 mL, 1.40 mmol) at 0° C., and the mixture was stirred for 2 hrs at rt. The solvent was evaporated, and the residual oxalyl chloride was removed with azeotropic distillation using toluene under nitrogen atmosphere. The resulting acid chloride was then dissolved in pyridine (5 mL) and cooled to 0° C. To this solution, a solution of 5-amino-2-(naphthalene-1-ylamino)thiazole-4-carboxamide (0.2 g, 0.70 mmol) in pyridine (5 mL) was added at 0° C., and the mixture was stirred for 12 hrs at rt. The solvent was evaporated, and the residue was suspended into I M HCl, and the resulting solids were collected and dried. The crude solids were purified by silica gel column chromatography eluted with 3% MeOH in DCM to give 91 mg (29% yield) of the titled compound.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[C:27]([O-:38])(=[O:37])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[Na+]>CC(C)=O.O>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:38][C:27](=[O:37])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CCCCCCCCCC(=O)[O-]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCC(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Yield: 71.3 %

Procedure:
To 200 ml of acetone-water (1:1) are added 6.0 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 5.2 g of sodium n-decanoate and the mixture is refluxed for 10 hours. The solvent is distilled off under reduced pressure and the residue is extracted with 300 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 750 ml of diisopropyl ether-n-hexane (1:9), elution is carried out with 1000 ml of a 1:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 5.2 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]([CH3:23])([N:6]([CH2:20][CH2:21][CH3:22])[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])(=[O:9])=[O:8])[CH3:5].C1COCC1.CO.O[Li].O>O>[CH3:23][C:4]([N:6]([CH2:20][CH2:21][CH3:22])[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])(=[O:9])=[O:8])([CH3:5])[C:3]([OH:24])=[O:2]
Reactant: CCCN(C(C)(C)C(=O)OC)S(=O)(=O)c1ccccc1C(F)(F)F
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCN(C(C)(C)C(=O)O)S(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.8 %

Procedure:
Methyl-2-methyl-2-(N-propyl-2-(trifluoromethyl)phenylsulfonamido)propanoate (340 mg, 0.93 mmol) was charged, and dissolved through addition of THF (4 ml), and methanol (4 ml). LiOH.H2O dissolved in H2O (4 ml) was added thereto, followed by stirring for 12 hours at room temperature. After stirring for 12 hours, the resultant solution was vacuum-evaporated, acidified with 2N—HCl to pH 2-3, and extracted with EA (×2). The organic layer was dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed so as to obtain 2-methyl-2-(N-propyl-2-(trifluoromethyl)phenylsulfonamido)propionic acid (320 mg, 0.91 mmol, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][N:14]2C(OC)=O)=[O:8].[OH-].[K+].C(Cl)Cl.O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2)=[O:8]
Reactant: COC(=O)n1ncc2c(NC(=O)NCc3ccc(Cl)c(Cl)c3)cccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1cccc2[nH]ncc12
Temperature: 25 °C

Procedure:
The product of Example 90C (0.25 g, 0.6 mmol) was heated at reflux in methanol (5 mL) and 0.5N KOH (1 mL) for 0.5 hours. The reaction mixture was allowed to cool to ambient temperature, pH was adjusted to 5, and volume was reduced under reduced pressure. Methylene chloride and water was added, the phases were separated, and the organic phase concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 4.38 (d, 2H), 6.9 (t, 1H), 7.05 (d, 1H), 7.19 (t, 1H), 7.35 (dd, 1H), 7.6 (m, 2 H), 8.06 (s, 1H), 8.82 (s, 1H). MS (DCI+) m/z 336 (M+H)+; Anal. Calcd. For C15H13N4Cl2O: C, 53.75; H, 3.62; N, 16.72. Found: C, 53.84, H, 3.44; N, 16.88.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([CH3:23])[CH:22]=2)[O:15][CH2:16][CH2:17][CH2:18][OH:19])(=[O:10])=[O:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([CH3:23])[CH:22]=2)[O:15][CH2:16][CH2:17][CH:18]=[O:19])(=[O:10])=[O:9])[CH:7]=1
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cc(F)ccc2C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cc(F)ccc2C)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
To a cooled (0° C.), stirred solution of 528 mg (1.44 mmol) of 3-[3-(5-fluoro-2-methylphenylsulfonyloxy)-5-methylphenoxy]propanol, as prepared in the preceding step, 527 μL (3.02 mmol) of N,N-diisopropylethylamine and 307 μL (4.32 mmol) of anhydrous dimethyl sulfoxide in 6.0 mL of anhydrous dichloromethane was added 459 mg (2.88 mmol) of sulfur trioxide pyridine complex. The mixture was warmed to ambient temperature over 30 min and stirred for 16 h. The mixture was then poured into 15 mL of dichloromethane and washed with 5% (w/v) aqueous citric acid (2×25 mL). Each wash was extracted with 5 mL of dichloromethane and the combined extracts were washed with brine (25 mL), dried over Na2SO4 and concentrated. The resulting material was chromatographed on 35 g of silica gel with dichloromethane followed by 3% ethyl acetate-dichloromethane to afford 320 mg (61%) of the title compound as a colorless syrup: Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C17H17FO5S: 375.1 (M+Na). Found: 375.0.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]2([CH:23](B(O)O)[CH2:22][CH2:21][CH2:20]2)[C:12]1=[O:27].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>COCCOC.O>[C:1]([C:3]1[CH:4]=[C:5]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[NH:11][C:12](=[O:27])[C:13]23[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2]
Reactant: O=C1Nc2ccccc2C12CCCC2B(O)O
Reactant: N#Cc1cc(F)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cc(F)cc(-c2ccc3c(c2)C2(CCCC2)C(=O)N3)c1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A solution of 3-cyano-5-fluoro-bromobenzene (0.5 g, 2.6 mmol), and tetrakis (triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2 for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (0.9 g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the subtitled compound (0.35 g, 44%) as white needles. mp: 235–237° C.; 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.1 (s, 1H), 8.0 (dt, 1H, J=1.7, 2.0, 7.0 Hz), 7.8–7.7 (m, 2H), 7.6 (dd, 1H, J=1.8, 6.4 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0–1.9 (m, 8H); MS (EI) M+ @ m/z 306.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]=[CH:6][CH:7]([N:19]([CH3:36])[C:20](=[O:35])[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)C.[OH-].[Li+]>CO.O1CCCC1.O>[CH3:36][N:19]([CH:7]([CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[CH:6]=[CH:5][C:4]([OH:37])=[O:3])[C:20](=[O:35])[C:21]1[CH:22]=[C:23]([C:31]([F:33])([F:34])[F:32])[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1
Reactant: CCOC(=O)C=CC(Cc1ccc2ccccc2c1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C=CC(=O)O)Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 23.0 g of 4-[N-methyl-N-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(naphth-2-yl)-pent-2-enoic acid ethyl ester [see example 20d)] and 9.23 g of lithium hydroxide (monohydrate) in 240 ml of methanol, 175 ml of tetrahydrofuran and 72 ml of water is stirred at room temperature for 120 minutes and then concentrated by evaporation. The residue is dissolved in 200 ml of water, acidified to pH=2 with 0.1N hydrochloric acid and extracted three times using 200 ml of ethyl acetate each time. The combined organic phases are washed with water and saturated NaCl solution, dried (magnesium sulfate) and concentrated by evaporation. Filtration of the residue over silica gel with hexane/ethyl acetate 1:1 yields the title compound in the form of a yellow foam. Rf value=0.41 (methylene chloride/methanol 19:1). IR(CH2Cl2) cm-1 : 3050,1709, 1644, 1402, 1337,1277, 1183,1142, 905, 849, 821
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17].[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2.N1CCCCC1>C(O)C>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=[C:23]3[C:22]4[C:26](=[CH:27][CH:28]=[C:20]([F:19])[CH:21]=4)[NH:25][C:24]3=[O:29])=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CC2
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C=C2C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(CCN(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
A stirred solution of 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (67 mg, 0.267 mmol), 5-fluoro-1,3-dihydro-indol-2-one (40 mg, 0.267 mmol) in 0.66 ml of ethanol was added dropwise with anhydrous piperidine (0.1 ml). The mixture was stirred at room temperature overnight. The resulting solid was filtered under reduced pressure, washed with ethanol (1 ml×3) and purified by silica gel column chromatography with triethylamine:methanol:dichloromethane (1:20:500) as eluents to give 5-(2-dimethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (60 mg, 54.8%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26]>>[OH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)(=[O:27])=[O:26])=[CH:3][CH:4]=1
Reactant: Nc1ccc(CO)cc1
Reactant: O=S(=O)(Cl)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Nc1ccc(CO)cc1)c1ccccn1
Yield: 47 %

Procedure:
Reaction of (4-Amino-phenyl)-methanol (249 mg, 2.03 mmol), N,N-diisopropylethylamine (294 uL, 1.69 mmol), and pyridine-2-sulfonyl chloride (300 mg, 1.69 mmol) for 1 h at room temperature followed by column chromatography on silica gel (CH2Cl2/MeOH 194:3) gave the title compound (210 mg, 47%) as a red solid. 1H NMR (300 MHz, CDCl3) δ 4.60 (d, 2H, J=6.0 Hz), 7.07 (br s, 1H), 7.15 (d, 2H, J=8.4 Hz), 7.23 (d, 2H, J=8.7 Hz), 7.44-7.48 (m, 1H), 7.83 (ddd, 1H, J=7.5, 7.5, 1.8 Hz), 7.89 (d, 1H, J=7.8 Hz), 8.72 (d, 1H, J=4.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:21]([O-:23])=[O:22])=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].COC1C([N+]([O-])=O)=C(C=CC=1)C=O.CO[CH2:39][N:40]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:41][Si](C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:46]([N:40]1[CH2:41][CH:6]([C:5]2[CH:18]=[CH:19][CH:20]=[C:3]([O:2][CH3:1])[C:4]=2[N+:21]([O-:23])=[O:22])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:39]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CCOC(=O)C(=Cc1cccc(OC)c1[N+](=O)[O-])C(=O)OCC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: COc1cccc(C=O)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(C(=O)OCC)CN(Cc2ccccc2)CC1c1cccc(OC)c1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a solution of diethyl 2-(3-methoxy-2-nitrobenzylidene)malonate, which was prepared from 3-methoxy-2-nitrobenzaldehyde following the procedure described in Example 1, Part C (162 mg, 0.5 mmol) in 10 mL of methylene chloride was added added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (237 mg, 1.0 mmol) and trifluoroacetic acid (0.010 mL, 0.125 mmol). The solution was allowed to stir at 40° C. for 18 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography (elution with 4:1 hexane/EtOAc) to afford 201 mg (88%) of the title compound. 1H NMR (CDCl3): δ 7.40-7.25 (m, 7H), 6.93-6.85 (m, 1H), 4.36-4.30 (m, 1H), 4.32-4.15 (m, 2H), 3.87 (s, 3H), 3.77 (q, 2H), 3.69 (s, 2H), 3.60-3.50 (m, 1H), 3.05-2.97 (m, 1H), 2.85-2.78 (m, 1H), 2.75-2.68 (m, 1H), 1.23 (t, 3H, J=7.2 Hz), 0.83 (t, 3H, J=7.2 Hz). LRMS (ESI): 457.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]OS(C)(=O)=O)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:28]([CH2:31][NH2:32])[CH:29]=C.[CH3:33]N(C=O)C>>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:32]([CH2:31][CH:28]=[CH2:29])[CH3:33])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: C=CCCN
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(CCCCCOS(C)(=O)=O)ccc21
Product: C=CCN(C)CCCCCc1ccc2c(c1)CCCN2C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To 560 mg (1.4 mmol) 6-(5-Methanesulfonyloxy-pentyl)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester in 5 ml DMF were added 2.5 ml (26.0 mmol) N-allylmethylamine. The solution was stirred at 70° C. for 2 h, concentrated and dissolved in water and CH2Cl2. 2M NaOH was added and the inorganic phase was extracted with CH2Cl2. The organic phase was washed with water and dried over Na2SO4. Purification by column chromatography with CH2Cl2/MeOH 20:1 yielded 470 mg (89%) 6-[5-(Allyl-methyl-amino)-pentyl]-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as yellow oil, MS: 373 (MH+).
Reaction SMILES: O.NN.O=C1C2C(=CC=CC=2)C(=O)[N:6]1[CH2:15][C@@H:16]([NH:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:40]([CH3:41])[N:39]=[CH:38][N:37]=2)=[CH:32][CH:31]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25]>C(Cl)Cl.CO>[NH2:6][CH2:15][C@@H:16]([NH:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:40]([CH3:41])[N:39]=[CH:38][N:37]=2)=[CH:32][CH:31]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25]
Reactant: Cn1ncnc1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cn1ncnc1-c1ccc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)cc1

Procedure:
Hydrazine hydrate (0.028 ml, 0.58 mmol) was added to a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-1,2,4-triazol-5-yl)benzamide (67.3 mg, 0.116 mmol) in DCM/MeOH (1/0.1 ml).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:8]=2[CH:26]([OH:29])CO)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.CCOC(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([N:23]([CH3:24])[CH3:25])=[O:22])[C:8]=2[CH:26]=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(C(O)CO)n(CC(=O)N(C)C)c2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(C=O)n(CC(=O)N(C)C)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To a solution of methyl 3-cyclohexyl-2-(1,2-dihydroxyethyl)-1-[2-(dimethylamino)-2-oxoethyl]-1H-indole-6-carboxylate (from Step 3) in THF/water (0.05 M, 1:1, v:v) cooled to 0° C. was added sodium periodate (1.2 eq.). The resulting mixture was allowed to warm to RT and left stirring for a further 3 h. The mixture was diluted with EtOAc and 5% aq. citric acid solution. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were extracted with aqueous citric acid (2% solution), sat. aq. NaHCO3 solution and brine. The organic phase was then dried over Na2SO4 and evaporated in vacuo. The residual material was then crystallised from EtOAc with PE. The product was obtained as an off-white solid (83%).
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:13](=[O:14])[C@H:12]3[CH2:15][CH2:16][CH2:17][C@H:11]3[N:10]([C:18](=[O:31])[CH2:19][N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[C:9]3[CH:32]=[CH:33][CH:34]=[CH:35][C:8]2=3)=[CH:4][CH:3]=1.[C:38](Cl)(=[O:40])[CH3:39].C([O-])(O)=O.[Na+]>ClCCl>[C:38]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:13](=[O:14])[C@H:12]3[CH2:15][CH2:16][CH2:17][C@H:11]3[N:10]([C:18](=[O:31])[CH2:19][N:20]3[C:21](=[O:30])[C:22]4=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]4[C:24]3=[O:25])[C:9]3[CH:32]=[CH:33][CH:34]=[CH:35][C:8]2=3)=[CH:36][CH:37]=1)(=[O:40])[CH3:39]
Reactant: Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.5 %

Procedure:
To a suspension of (3aR*,10aS*)-9-(4-aminobenzyl)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (198 mg, 0.4 mmol) in dichloromethane (1 mL) was added acetyl chloride (43 μL, 0.6 mmol) and the mixture was stirred at room temperature for 20 minutes. This reaction mixture was diluted with dichloromethane (3 mL) and, after saturated aqueous NaHCO3 solution (2 mL) was added, the mixture was further stirred. The aqueous layer was then separated and the organic layer was washed with water, dried over MgSO4, and concentrated under reduced pressure. The residue was crystallized from dichloromethane-ethanol and recrystallized from chloroform-ethanol to provide 72 mg (yield 34%) of the title compound. m.p. 303°-306° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH2:9][O:10][CH3:11])([CH3:8])[C:5]([OH:7])=O.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:42]([O:44][CH:45]([O:49][CH2:50][CH3:51])[CH2:46][CH2:47][NH2:48])[CH3:43]>C(Cl)Cl.C1COCC1>[CH2:42]([O:44][CH:45]([O:49][CH2:50][CH3:51])[CH2:46][CH2:47][NH:48][C:5](=[O:7])[C:4]([CH2:3][O:2][CH3:1])([CH3:8])[CH2:9][O:10][CH3:11])[CH3:43]
Reactant: COCC(C)(COC)C(=O)O
Reactant: CCOC(CCN)OCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(CCNC(=O)C(C)(COC)COC)OCC
Temperature: 25 °C
Reaction time: 23 h
Yield: 80.7 %

Procedure:
5 g of 3-methoxy-2-methoxymethyl-2-methyl-propionic acid (prepared as in EP609058) were dissolved in 49 mL of DCM and 12 mL of THF. 11.4 mL of DIPEA, 5.84 g of HOBt, 7.07 g of EDCI and 5.45 g of 3,3-diethoxy-propylamine were added sequentially. The mixture was stirred for 23 h at rt, diluted with DCM and washed with sat. NaHCO3. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using heptane/EtOAc from 3/1 to 0/1 as eluant to yield 7.25 g of N-(3,3-diethoxy-propyl)-3-methoxy-2-methoxymethyl-2-methyl-propionamide as a yellowish oil.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])C.[Li]N.[CH3:8][O:9][C:10]([CH3:16])([O:12][CH2:13]C#C)[CH3:11].C(I)C>CCCCCC>[CH3:8][O:9][C:10]([CH3:16])([O:12][CH2:13][C:5]#[C:3][CH2:2][CH3:1])[CH3:11]
Reactant: C=CC(=C)C
Reactant: C#CCOC(C)(C)OC
Agent: [Li]N
Solvent: CCI
Solvent: CCCCCC
Product: CCC#CCOC(C)(C)OC
Reaction time: 1 h
Yield: 120.6 %

Procedure:
0.89 g (127 mmol) of granulated lithium were added within 15 minutes to 100 ml (4 mol) of liquid ammonia at −37° C. The mixture was stirred until no more lithium floated (after approximately 15 minutes). A dark blue solution of lithium in liquid ammonia was obtained. 5.94 g (86.3 mmol) of isoprene were added portion wise within 30 minutes. The end of the formation of LiNH2 could be recognized by the de-coloration of the reaction mixture and 10.69 g (70.1 mmol) of 3-(1-methoxy-1-methyl-ethoxy)-propyne were added to the reaction mixture at −37° C. within 30 minutes. The reaction mixture was held at −37° C. for about 1 hour. Ethyl iodide (20.05 g, 126 mmol) was added with a dropping funnel to the reaction mixture within 30 minutes. The reaction mixture was subsequently stirred for 1 hour. n-Hexane (100 ml) was added to the reaction mixture and the liquid ammonia was evaporated under normal pressure within 1.5 hours. Water (50 ml) was added to the reaction mixture at 22° C., and the mixture was vigorously stirred until all salt was dissolved. The water layer was extracted twice with 50 ml n-hexane. The organic layer was dried over 5 g of anhydrous sodium sulfate. The solution was concentrated under reduced pressure (40° C., 60 mbar) and the crude product was analyzed by GC. Crude 1-(1-methoxy-1-methyl-ethoxy)-pent-2-yne (13.21 g) were obtained with a purity of 72.95% (88.0% yield based on 3-(1-methoxy-1-methyl-ethoxy)-propyne).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[H][H].[CH3:7][CH:8]([CH2:10][CH:11]([OH:13])[CH3:12])[CH3:9].O=C(C=C(C)C)C>CC(CC(C)=O)C.C(O)(C)C>[CH2:10]([C:11]([CH2:12][CH:2]([CH3:4])[CH3:1])=[O:13])[CH:8]([CH3:9])[CH3:7]
Reactant: CC(C)CC(C)O
Reactant: [H][H]
Reactant: CC(C)=O
Solvent: CC(C)O
Solvent: CC(=O)CC(C)C
Solvent: CC(=O)C=C(C)C
Product: CC(C)CC(=O)CC(C)C

Procedure:
As demonstrated by entries 4 and 5 in Table 1, at about 130° C., the conversion of the three-carbon feedstock starting from acetone and hydrogen is 16.4% and from isopropanol is 8.6%. Isopropanol becomes the major reaction product, while MIBC predominates over MIBK in the aldol product. Small amounts of mesityl oxide are also seen, however, no diisobutylketone is formed. Thus, 130° C. favors secondary alcohols over ketones and the conversion of three-carbon feedstock to aldol products is poor.