Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:14](Cl)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[C:17]([O:21][C:22]([NH:24][C@H:25]1[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28][NH:27][C:26]1=[O:33])=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:17]([O:21][C:22]([NH:24][C@H:25]1[CH2:31][CH2:30][C@@H:29]([O:32][C:14]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:15])[CH2:28][NH:27][C:26]1=[O:33])=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CNC1=O
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OC(=O)C2CCCCC2)CNC1=O
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Triethylamine (8.4 mL, 60 mmol) is added to a solution of cyclohexanecarbonyl chloride (6.3 g, 43.0 mmol), (3S, 6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-hydroxy-2H-azepin-2-one (7.0 g, 28.7mmol) and 100 mL of CH2Cl2 at 50° C. The reaction mixture is stirred at room temp. overnight. The reaction mixture is then partitioned with water, and the organic layer is dried (Na2SO4), and concentrated with rotary evaporation. The resulting residue is chromatographed (5% EtOAc—CH2Cl2) to give 10.1 g (99.5% of (3S, 6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-(cyclohexanecarbonyl)oxy-2H-azepin-2-one as a white solid: 1H NMR (CDCl3): δ 5.89 (d, J=5.27 Hz, 1H), 5.65 (t, J=4.90 Hz, 1H), 4.89 (s, 1H), 4.30 (q, J=4.14 Hz, 1H), 3.49 (m, 2H), 2.31 (tt, J=10.92 Hz and 3.39 Hz, 1H), 2.13 (d, J=14.32 Hz, 1H), 1.98 (d, J=13.56 Hz, 2H), 1.88 (d, J=14.31 Hz, 2H), 1.75 (d, J=11.30 Hz, 2H), 1.66 (s, 2H), 1.45 (s, 9H), 1.30 (m, 5H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.Cl.[CH3:15]O>>[CH3:15][O:10][C:9](=[O:11])[CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([NH2:2])=[CH:13][CH:12]=1
Reactant: Nc1ccc(OCC(=O)O)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)COc1ccc(N)cc1
Yield: 58.5 %

Procedure:
To a mixture of (4-Aminophenoxy)acetic acid HCl 14 (250 g, 1.228 mol), in methanol (5 L) was passed dry HCl gas at 10° C. for 1 hour and refluxed for 10 hours. Methanol (3.5 liters) was distilled off, ice water (1 liter) was added and the pH was adjusted to 7.5 with K2CO3. Crude 15 was filtered, dried and recrystallised from a mixture of chloroform:hexane (1:5) to give pure 15 (130 g, 58.5%) as a light brown powder. The melting point was found to be 65-66.8° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1.O>CC(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([C@H:12]2[CH2:13][CH2:14][C@H:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17]2)[CH2:10][CH2:11]1
Reactant: CCOC(=O)[C@H]1CC[C@H](N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)[C@H]1CC[C@H](N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Reaction time: 0.5 h

Procedure:
trans Ethyl 4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-cyclohexanecarboxylate (0.8 g) was dissolved in t-BuOH (180 ml) at 38° C. To this was added Candia rugosa lipase powder (3 g). This was stirred for 30 minutes then water (20 ml) was added over 4 h. The mixture was then stirred for 48 h and filtered. The enzyme was washed with 9:1 t-BuOH-water (2×20 ml) and the filtrate was evaporated. Ethyl acetate was added to the residue and then decanted. The resultant solid was dissolved in methanol/DMSO and was purified by HPLC (Waters XTerra® column with at-column dilution of sample) (gradient (5% MeCN/NH3(aq) (0.2%) to 40% MeCN//NH3(aq) (0.2%)] gave the title compound (0.44 g) as a white solid.
Reaction SMILES: [C:1]([SH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH2:12]>C(Cl)(Cl)(Cl)Cl>[C:1]([S:9][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:12])[CH3:10])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)c1ccccc1
Reactant: S=C(S)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(SC(=S)c1ccccc1)c1ccccc1
Temperature: 70 °C
Yield: 32.6 %

Procedure:
A mixture of dithiobenzoic acid (10.59 g), a-methylstyrene (10 g) and carbon tetrachloride (40 mL) was heated at 70° C. for 4 hours. The resultant mixture was reduced to a crude oil which was purified by column chromatography (aluminium oxide (activity III), n-hexane eluent) to give 2-phenylprop-2-yl dithiobenzoate (5) (6.1 g, 32.6% yield) as a dark purple oil. 1H-nmr (CDCl3) d (ppm): 2.03 (s, 6H); 7.20-7.60 (m, 8H) and 7.86 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[C:6]([CH3:12])=[CH:5][C:4]=1[NH:13]C=O)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[OH-].[NH4+]>CO>[NH2:13][C:4]1[CH:5]=[C:6]([CH3:12])[C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:3]=1[CH2:1][CH3:2]
Reactant: CCc1c(NC=O)cc(C)c2nc[nH]c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCc1c(N)cc(C)c2nc[nH]c12
Temperature: 25 °C

Procedure:
A mixture of 4-ethyl-5-formamido-7-methylbenzimidazole (1.7 g, 8.36 mmol), potassium carbonate (2.0 g, 14.4 mmol) and 6N hydrochloric acid (34 mL) in methanol (34 mL) is heated to reflux for 1 hour. The mixture is cooled to room temperature, brought to pH 9 with ammonium hydroxide and rotary evaporated. The residue is purified by flash chromatography on silica gel (chloroform:methanol 9:1) to afford 5-amino-4-ethyl-7-methylbenzimidazole as a tan solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:33](O)[C:34]([F:37])([F:36])[F:35]>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:17])[C@@H:4]([C:5]#[C:6][C:7](=[O:9])[O:8][CH2:33][C:34]([F:37])([F:36])[F:35])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: OCC(F)(F)F
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)OCC(F)(F)F)C1(C)C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
4 g of the product of Step A and 3.5 g of dicyclohexylcarbodiimide were added to a solution of 20 ml of methylene chloride and 1 ml of pyridine and the reaction mixture was stirred for 1 hour. 2.15 g of trifluoroethanol and 5 ml of methylene chloride were then added to the mixture which was stirred at 20° C. for 16 hours and was filtered. The filtrate was rinsed with methylene chloride and the filtrate was evaporated to dryness. The residue was taken up in ether and the solution was washed with N hydrochloric acid, then with water and dried and evaporated to dryness. The 5 g of residue was chromatographed over silica gel and was eluted with a 95-5 benzene-ethyl acetate mixture to obtain 3.5 g of 1,1-dimethylethyl (1R,cis) 2,2-dimethyl-3-[3-oxo-3-(2,2,2-trifluoroethoxy)-1-propynyl]-cyclopropane-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13](=[CH2:17])[CH2:14][CH2:15]O.CCOC(/N=N/C(OCC)=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1C=CC=CC=1.O>[CH3:17][C:13](=[CH2:12])[CH2:14][CH2:15][O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)CCO
Reactant: CC(=O)Nc1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccccc1
Product: C=C(C)CCOc1cccc(NC(C)=O)c1
Temperature: 25 °C
Yield: 52 %

Procedure:
A suspension of the mixture of N-(3-hydroxy-phenyl)-acetamide and acetic acid 3-fonnylamino-phenyl ester (18.12 g, 0.12 mol), 3-methyl-but-3-en-1-ol (8.6 g, 0.1 mol), DEAD (87 g, 0.2 mol) and Ph3P (31.44 g, 0.12 mol) in benzene (250 mL) was heated at reflux overnight and then cooled to room temperature. The reaction mixture was poured into water and the organic layer was separated. The aqueous phase was extracted with EtOAc (300×3 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give N-[3-(3-methyl-but-3-enyloxy)-phenyl]-acetamide (11 g, 52%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][NH:19]2)=[CH:15][CH:14]=1>C(O)CCC>[NH:19]1[C:20]2[C:16](=[CH:15][CH:14]=[C:13]([NH:12][C:2]3[N:3]=[C:4]([NH:12][C:13]4[CH:21]=[C:20]5[C:16]([CH:17]=[N:18][NH:19]5)=[CH:15][CH:14]=4)[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=3)[CH:21]=2)[CH:17]=[N:18]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Solvent: CCCCO
Product: c1cc2c(Nc3ccc4cn[nH]c4c3)nc(Nc3ccc4cn[nH]c4c3)nc2[nH]1
Temperature: 116 °C
Reaction time: 8 h
Yield: 8.3 %

Procedure:
A mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (90 mg, 0.48 mmol) and 6-aminoindazole (127 mg, 0.95 mmol) in n-butyl alcohol (n-BuOH) (4 mL) was stirred at 116° C. overnight. The mixture was purified by reverse phase HPLC using a gradient of 7-50% CH3CN in water over 10 min. The title compound was recovered to give a powder (15 mg). MS 382.4 (M+H) (Compound 4-1).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:15]([NH:18][CH2:19][CH2:20][CH3:21])[CH2:16][CH3:17]>CN(C)C=O>[CH2:15]([N:18]([CH2:19][CH2:20][CH3:21])[C:2]1[C:3]2[N:4]([CH:12]=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:16][CH3:17]
Reactant: CCCNCCC
Reactant: Clc1nc2ccccc2n2cnnc12
Solvent: CN(C)C=O
Product: CCCN(CCC)c1nc2ccccc2n2cnnc12
Yield: 41 %

Procedure:
4-Chloro-[1,2,4]triazolo[4,3-a]-quinoxaline (2.0 g., 0.01 mole), the product of Example 2, and 3.0 g. (0.03 mole) of di-n-propylamine in N,N-dimethylformamide (50 ml.) were stirred for 3 hours at room temperature. The solution was poured over ice to form a precipitate which was separated by filtration and air dried. Recrystallization from cyclohexane (250 ml.) afforded 1.1 g. (41% yield) of 4-di-n-propylamino-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 240°-242° C. Mass spectrum: m/e, 269 (P).
Reaction SMILES: CC1(C)COC2(CCC(CCN[C@H](C3C=CC=CC=3)C)(O)CC2)OC1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CC1(C)CO[C:42]2([CH2:61][CH2:60][C:45]3([O:50][C:49](=[O:51])[N:48]([C@H:52]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[CH3:53])[CH2:47][CH2:46]3)[CH2:44][CH2:43]2)[O:41]C1>>[C:54]1([C@@H:52]([N:48]2[CH2:47][CH2:46][C:45]3([CH2:60][CH2:61][C:42](=[O:41])[CH2:43][CH2:44]3)[O:50][C:49]2=[O:51])[CH3:53])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: C[C@@H](c1ccccc1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Agent: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccccc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: C[C@@H](c1ccccc1)N1CCC2(CCC(=O)CC2)OC1=O

Procedure:
The title compound is prepared from 3,3-dimethyl-9-{2-[(S)-1-phenyl-ethylamino]-ethyl}-1,5-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; the crude product, a mixture of the title compound and 12,12-dimethyl-3-[(S)-1-phenyl-ethyl]-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one, obtained thereafter is treated as described in Step 10 of Intermediate 2 to convert the intermediate to the title compound as well. Yield: 49% of theory; LC (method 6): tR=1.06 min; Mass spectrum (ESI+): m/z=288 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([N:10]([CH2:21][CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Br:30])[CH:25]=2)O)[CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(OC(=O)C)C>[C:1]1([S:7]([N:10]2[CH2:21][CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Br:30])[CH:25]=3)[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12](=[O:13])[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CN(CC(O)c1cccc(Br)c1)S(=O)(=O)c1ccccc1)Nc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: O=C1CN(S(=O)(=O)c2ccccc2)CC(c2cccc(Br)c2)N1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
At 0° C. to a solution of 2-{benzenesulfonyl-[2-(3-bromo-phenyl)-2-hydroxy-ethyl]-amino}-N-phenyl-acetamide (1.15 g) and triphenylphosphine (678 mg) in ethylacetate (10 mL) was added a solution of diethylazodicarboxylate (0.4 mL) in ethylacetate (5 mL) dropwise. After 15 min. the cooling bath was removed and the mixture was stirred at RT for 3 h. Additional amounts of triphenylphosphine (31 mg) and diethylazodicarboxylate (0.18 mL) were added, and stirring was continued for 1 h. The mixture was diluted with water and ethyl acetate, the phases were separated, and the inorganic one was extracted with ethyl acetate (×2). The organic layers were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, n-heptane/ethyl acetate 7:3) to give 4-benzenesulfonyl-6-(3-bromo-phenyl)-1-phenyl-piperazin-2-one (0.99 g, 89%) as a white foam, MS: 471.4 (M+H, 1Br)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][CH:4]([OH:6])[CH3:5].C(Cl)Cl.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>O>[CH3:1][CH:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][C:4](=[O:6])[CH3:5]
Reactant: CC(C)CCCC(C)CC(C)O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)CC(C)CCCC(C)C
Reaction time: 3 h

Procedure:
A solution of 47 g. of 4,8-dimethylnonan-2-ol in 250 ml. of methylene chloride is cooled to about 10° as a solution of 46.4 g. of sodium dichromate in 125 ml. of water is added. The mixture is maintained at about 10° as a solution of 46.3 g. of sulfuric acid in 100 ml. of water is added over about 45 minutes. The mixture is allowed to attain room temperature and, after about 3 hours, the organic layer is separated and the aqueous layer is extracted with methylene chloride. The combined organic materials are washed with saturated potassium bicarbonate, water and saturated sodium chloride, dried over magnesium sulfate and evaporated to yield 4,8-dimethylnonan-2-one.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](I)[CH:12]=1>CS(C)=O.[NH4+].[Cl-].[Cu]>[CH2:6]([O:5][C:3](=[O:4])[C:2]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([Cl:10])[CH:12]=1)([F:9])[F:8])[CH3:7]
Reactant: Clc1cccc(I)c1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1cccc(Cl)c1
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a mixture of copper bronze (2.93 g, 46.1 mmol) in DMSO (5.0 mL) was added ethyl bromodifluoroacetate (3.2 mL, 25 mmol) under argon at room temperature (see Sato, K. et al; Chem. Pharm. Bull. 47:1013-1016, 1999). After stirring for 1 h, 1-chloro-3-iodobenzene (2.57 mL, 20.8 mmol) was added under argon at room temperature. After shaking for 3 days, the mixture was diluted with saturated NH4Cl (50 mL) and extracted with ether (25 mL). The biphasic mixture was filtered through a pad of Celite, and the filter cake was washed with ether (25 mL). The organic layer was separated from the filtrate, and the aqueous layer was extracted with ether (25 mL). The combined organic layers were washed with saturated NH4Cl (2×15 mL) and brine (15 mL), dried (Na2SO4), and concentrated to afford the title compound (4.77 g, 97%) as a clear yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.63-7.59 (m, 1H), 7.53-7.45 (m, 2H), 7.43-7.36 (m, 1H), 4.31 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10](OS(C(F)(F)F)(=O)=O)=[C:9]2[C:4]([CH2:5][N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:7][CH2:8]2)=[N:3]1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu](Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:1][N:2]1[C:10]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=2)=[C:9]2[C:4]([CH2:5][N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:7][CH2:8]2)=[N:3]1
Reactant: CC1(C)OB(c2ccccn2)OC1(C)C
Reactant: Cn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl[Cu]Cl
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: CN(C)C=O
Product: Cn1nc2c(c1-c1ccccn1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 100 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a solution of tert-butyl 2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydro-2H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (1.0 g, 2.60 mmol) in DMF (25 mL) was added pyridine-2-boronic acid pinacol ester (1.33 g, 6.49 mmol), cesium carbonate (3.42 g, 10.38 mmol), copper chloride (257 mg, 0.259 mmol), palladium acetate (29 mg, 0.130 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (145 mg, 0.259 mmol). The reaction was stirred at 100° C. overnight under an atmosphere of N2. The reaction was poured into ice water and extracted with CH2Cl2 three times. The combined organic layers were dried over anhydrous MgSO4, filtered and evaporated. Chromatography on silica gel (0-100% ethyl acetatehexanes) provided the desired product (145 mg, 17%). MS (ESI) mass calcd. C17H22N4O2, 314.2. m/z found, 315.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.73-8.70 (m, 0.5H), 7.80-7.76 (m, 0.5H), 7.40-7.35 (m, 2H), 7.31-7.24 (m, 1H), 4.66-4.44 (m, 2H), 4.07 (s, 2H), 3.84 (s, 1H), 3.70-3.56 (m, 2H), 2.73-2.55 (m, 2H), 1.54-1.42 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][N:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12](=O)[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[CH:12]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[N:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10][CH2:9]2
Reactant: COc1cccc(CCN(C(=O)c2ccncc2)c2ccccc2)c1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CCN(c1ccccc1)C2c1ccncc1

Procedure:
The title compound was prepared by analogy to Preparation 65 except that N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-isonicotinamide was used instead of 4-methoxy-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-benzamide, and the final residue was subjected to flash chromatography using hexanes:EtOAc from 4:1 to 2:1.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=3)[C:8]=2[CH2:7][CH2:6][N:5]1[C:19](=[O:21])[CH3:20].CN(C=[O:26])C>>[C:19]([N:5]1[CH2:6][C:7]2[C:8](=[O:26])[C:9]3[CH:10]=[C:11]([O:17][CH3:18])[CH:12]=[CH:13][C:14]=3[NH:15][C:16]=2[CH:4]1[CH3:3])(=[O:21])[CH3:20]
Reactant: COc1ccc2[nH]c3c(c2c1)CCN(C(C)=O)C3C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2[nH]c3c(c(=O)c2c1)CN(C(C)=O)C3C
Reaction time: 48 h
Yield: 45 %

Procedure:
NaH (1.2 eq; 60% suspension in oil) is added to a solution of 1-methyl-2-acetyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline (1.56 g; 6.0 mmol) in DMF (20 ml). The mixture is stirred under an oxygen atmosphere for 48 hours, further NaH (1.1 eq) is then added and stirring is continued overnight. The DMF is then distilled off under reduced pressure. The crude product is taken up in water and then filtered. Saturated NH4Cl solution is added to the aqueous phase. The mixture is stirred for 30 minutes. The precipitate is filtered off and then washed successively with water, an MeOH/CH2Cl mixture (10/90), acetone and then ethyl acetate. After drying, 2-acetyl-7-methoxy-3-methyl-9-oxo-1,3,4,9-tetrahydropyrrolo[3,4-b]quinoline is obtained (yield=45%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C1COCC1.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]([S:28]([CH3:27])(=[O:30])=[O:29])[S:28]([CH3:27])(=[O:30])=[O:29])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCc1ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
Compound 52 (0.16 g, 0.605 mmol) was dissolved in anhydrous THF (5 mL). To the clear solution were sequentially added triethylamine (0.18 mL, 1.21 mmol) and 4-dimethylaminopyridine (15 mg, 0.121 mmol). The mixture was cooled to about −10° C. for 15 min by a methanol-ice bath. To the cold solution was slowly added methanesulfonyl chloride (51 μL). The solution was further stirred at the temperature (about −10° C.) for an additional 30 min, then allowed to slowly warm up to room temperature by removing the cooling bath. The reaction mixture was concentrated under reduced pressure. The residue was chromatographed over silica gel, eluting with a mixture of ethyl acetate (0-35%) and hexanes (100-65%), to afford 0.212 g (83%) of the product 53 as a white solid. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.52-1.70 (m, 4H), 2.68 (t, J=7.4 Hz, 2H), 3.13-3.18 (m, 2H), 3.40 (s, 6H), 4.53 (br s, 1H), 7.27 (s, 4H). m/z (APCI)=321 [C17H28N2O6S2−Boc+H]+.
Reaction SMILES: C(O)C.[C:4]([C:8]1[C:9](=[O:30])[CH2:10][CH:11]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH2:25][CH2:26][CH2:27][Cl:28])[C:19]=3[CH:29]=2)[CH2:12][C:13]=1[OH:14])(=O)[CH2:5][CH3:6].Cl.[CH2:32]([O:34][NH2:35])[CH3:33].C([O-])(=O)C.[Na+]>O.CC(C)=O.CCCCCC>[CH2:32]([O:34][N:35]=[C:4]([C:8]1[C:9](=[O:30])[CH2:10][CH:11]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH2:25][CH2:26][CH2:27][Cl:28])[C:19]=3[CH:29]=2)[CH2:12][C:13]=1[OH:14])[CH2:5][CH3:6])[CH3:33]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc3c(c2)N(CCCCl)C(=O)CO3)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Solvent: CC(C)=O
Product: CCON=C(CC)C1=C(O)CC(c2ccc3c(c2)N(CCCCl)C(=O)CO3)CC1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To 50 mL of absolute ethanol were added in sequence 1.6 g (4.1 mmol) of 2-propionyl-3-hydroxy-5-(N-(3-chloropropyl)-3-oxo-(2H)-1,4-benzoxazin-6-yl)-cyclohex-2-en-1-one, 0.32 g (3.4 mmol) of ethoxyamine hydrochloride and 0.27 g (3.3 mmol) of anhydrous sodium acetate. The resulting mixture was stirred at ambient temperature for 2.5 hours. The reaction mixture was then diluted with 200 mL of water and extracted twice with 50 mL portions of dichloromethane. The extracts were combined, dried over MgSO4 and filtered. Evaporation off of the solvent gave the crude product as a yellow oily residue. Flash chromatography on silica gel eluting with 20 percent acetone/hexane afforded the above-named product as a pale glassy oil in a yield of 1.0 g (56 percent of theoretical). 1H NMR (CDCl3): d1.05-1.43 (m, 6H, both --CH2CH3 's), 2.15 (p, J=7 Hz, 2H,--CH2CH2Cl and --CH2Cl), 4.57 (s, 2H, --OCH2C=O), 6.83-7.00 (m, 3H, aromatic H's), 14.9 (broad s, 1H, enol H); (Compound 9).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[C:9]([CH2:14][NH:15]C(=O)C(Cl)Cl)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2]>Cl>[CH:1]([C:4]1[C:13]2[C:8](=[C:9]([CH2:14][NH2:15])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nccc2c(CNC(=O)C(Cl)Cl)cccc12
Agent: Cl
Product: CC(C)c1nccc2c(CN)cccc12
Reaction time: 1 h
Yield: 67.6 %

Procedure:
Twenty grams of 1-isopropyl-5-dichloroacetylaminomethylisoquinoline was dissolved in 100 ml of conc. hydrochloric acid. The solution was heated with stirring for 1 hour. The reaction mixture was concentrated, made weakly alkaline with an aqueous solution of sodium hydroxide, and extracted with benzene to afford 8.7 g of 1-isopropyl-5-aminomethylisoquinoline as an oil.