Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[N:4][C:5]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)=[N:6][CH:7]=1.[CH3:29][N:30]([CH2:35][C:36](O)=[O:37])[CH2:31][C:32](O)=[O:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:3]1[C:2]([N:1]2[C:36](=[O:37])[CH2:35][N:30]([CH3:29])[CH2:31][C:32]2=[O:33])=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)[N:4]=1
Reactant: Nc1cnc(NCCNc2ccc([N+](=O)[O-])cn2)nc1-c1ccc(Cl)cc1Cl
Reactant: CN(CC(=O)O)CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC(=O)N(c2cnc(NCCNc3ccc([N+](=O)[O-])cn3)nc2-c2ccc(Cl)cc2Cl)C(=O)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1 mmol of [5-amino-4-(2,4-dichlorophenyl)pyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine, and 2 mmol of methyliminodiacetic acid, 4 mmol of HBTU, and 5 mmol of N,N-diisopropylethylamine were added to solution and stirred for six hours at room temperature. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate,dried over sodium sulfate, purified by column chromatography eluting with 5-10% methanol/methylene chloride to obtain 1-[4-(2,4-dichlorophenyl)-2-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)pyrimidin-5-yl]-4-methylpiperazine-2,6-dione.
Reaction SMILES: [C:1]1([CH:7]([CH3:10])[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]([CH:14]=[CH2:15])=[CH2:13]>>[CH3:11][C:12]1[CH2:13][CH:8]([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:10])[O:9][CH2:15][CH:14]=1
Reactant: CC(C=O)c1ccccc1
Reactant: C=CC(=C)C
Product: CC1=CCOC(C(C)c2ccccc2)C1
Yield: 13.3 %

Procedure:
4-Methyl-2-(1-phenylethyl)-3,6-dihydro-2H-pyran was prepared similarly according to EXAMPLE I using 2-phenylpropanal (500 g, 3.72 mol) and 2-methyl-1,3-butadiene (279 g, 4.1 mol). 4-Methyl-2-(1-phenylethyl)-3,6-dihydro-2H-pyran (100 g) was obtained with a boiling point of 115-116° C. at 3 mmHg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:18]=[CH:17][C:16](=[O:19])[NH:15][C:14]2=[O:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:21]N1C(=O)CCC1=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:18]=[C:17]([Br:21])[C:16](=[O:19])[NH:15][C:14]2=[O:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc(=O)[nH]c2=O)C1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c(=O)[nH]c2=O)C1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a mixture of 4 (0.6 g, 2.13 mmol) and N-bromosuccinimide (0.456 g, 2.56 mmol) was added DMF (15 mL) and stirred at ambient temperature for 3-4 h. The solution was partitioned between ethyl acetate (50 mL) and 10% Na2S2O3 (40 mL). Organic layer was separated, washed with brine (3×50 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure. The crude material was purified by flash chromatography over silica gel (70% ethyl acetate-dichloromethane) to give pure 5.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[C:21]([N:18]1[CH2:17][CH2:16][N:15]([C:9]2[C:10]([C:12](=[O:14])[CH3:13])=[CH:11][C:2]([Cl:1])=[C:3]3[C:8]=2[N:7]=[CH:6][CH:5]=[CH:4]3)[CH2:20][CH2:19]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccccc2)CC1
Reaction time: 2 h
Yield: 129.5 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with benzoyl chloride (0.018 mL, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4 and concentrated. The resulting residue was purified on silica gel (eluting with 0 to 5% MeOH in dichloromthane) to give the desired product (51 mg). LCMS calculated for C22H21ClN3O2 (M+H)+: m/z=394.1; Found: 394.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][CH2:19][CH:20]5[CH2:25][C:24]([O:30][Si:31]([CH2:36][CH3:37])([CH2:34][CH3:35])[CH2:32][CH3:33])([C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]5([CH:38]=[O:39])[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.P([O-])(O)(O)=[O:41].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][CH2:19][CH:20]5[CH2:25][C:24]([O:30][Si:31]([CH2:36][CH3:37])([CH2:32][CH3:33])[CH2:34][CH3:35])([C:26]([F:29])([F:27])[F:28])[CH2:23][CH2:22][C:21]5([C:38]([OH:41])=[O:39])[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC[Si](CC)(CC)OC1(C(F)(F)F)CCC2(C=O)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCCC2C1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC[Si](CC)(CC)OC1(C(F)(F)F)CCC2(C(=O)O)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCCC2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
t-Butanol (20 mL) and water (4 mL) were added to rac-(3R,4aR,12bS)-9-(4-fluorophenyl)-3-((triethylsilyl)oxy)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carb aldehyde (40, R1=4-Fluorophenyl, R3=Trifluoromethyl) (0.360 g, 0.642 mmol). After cooling to about 0° C., sodium dihydrogenphosphate (0.770 g, 6.42 mmol), 2-methyl-but-2-ene (0.270 g, 3.85 mmol), and sodium chlorite (0.348 g, 3.85 mmol) were added sequentially. After about 30 min, the ice bath was removed and the reaction was allowed to warm to rt. After about 3 h, a 1:1 solution of sat. aq. Na2SO3 and sat. aq. NaCl (50 mL) was added. Water (30 mL) was added. The mixture was extracted with EtOAc (3×50 mL). The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (40 g) using a gradient of 0-20% EtOAc in heptane. The product fractions were combined and concentrated under reduced pressure to give rac-(3R,4aR,12bS)-9-(4-fluorophenyl)-3-((triethylsilyl)oxy)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carboxylic acid (43, R1=4-Fluorophenyl, R3=Trifluoromethyl) (0.267 g, 72% yield); LC/MS, method 4, Rt=2.39 min.; MS m/z: 577 (M+H)+. 1H NMR (400 MHz, DMSO) δ 12.57 (s, 1H), 8.26 (d, J=0.7 Hz, 1H), 7.90 (s, 1H), 7.82-7.75 (m, 2H), 7.54 (s, 1H), 7.45-7.35 (m, 2H), 2.95-2.71 (m, 2H), 2.60-2.48 (m, 1H), 2.42-2.15 (m, 4H), 2.03-1.78 (m, 3H), 1.73-1.52 (m, 2H), 1.34-1.20 (m, 1H), 0.99-0.90 (m, 9H), 0.69-0.59 (m, 6H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]Br)[CH:18]=1.C(N(CC)CC)C>CC#N.O>[Br:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[CH2:23][N:13]1[CH2:14][CH2:15][N:10]([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:3]=2[Cl:2])[CH2:11][CH2:12]1
Reactant: BrCc1cccc(Br)c1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: Clc1cccc(N2CCN(Cc3cccc(Br)c3)CC2)c1Cl
Yield: 55 %

Procedure:
A mixture of 1-(2,3-dichlorophenyl)piperazine hydrochloride (intermediate 41) (294 mg, 1.1 mmol), 1-bromo-3-(bromomethyl)benzene (250 mg, 1 mmol) and anhydrous triethylamine (253 mg, 2.5 mmol) was dissolved in CH3CN and the solution was heated to reflux for 4 h. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aq NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE/EtOAc=8:1) to give 1-(3-bromobenzyl)-4-(2,3-dichlorophenyl)piperazine (intermediate 53) (220 mg, 74%) as a white solid.
Reaction SMILES: [OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][CH:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:37]4[CH2:38][CH2:39][CH:35]([F:34])[CH2:36]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1
Reactant: FC1CCNC1
Reactant: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(F)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.16 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 1H), 0.83 (d, 3H). m/z: 420 [M+H]
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][CH2:20][CH3:21])=[C:6]([C:8]2[N:16]=[C:15]3[C:11](=[N:12][N:13]=[N:14]3)[C:10](=[O:17])[N:9]=2)[CH:7]=1.[OH-:22].[Na+].[Mn]([O-])(=O)(=O)=[O:25].[K+]>O>[C:1]([C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][CH2:20][CH3:21])=[C:6]([C:8]2[N:16]=[C:15]3[C:11](=[N:12][N:13]=[N:14]3)[C:10](=[O:17])[N:9]=2)[CH:7]=1)([OH:25])=[O:22]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCOc1ccc(C)cc1C1=NC(=O)C2=NN=NC2=N1
Reactant: [OH-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CCCOc1ccc(C(=O)O)cc1C1=NC(=O)C2=NN=NC2=N1

Procedure:
A suspension of 2-(5-methyl-2-propoxyphenyl)-8-azapurin-6-one (2.85 g; prepared as described in the specifications of British Pat. No. 1338235 and U.S. Pat. No. 3,819,631) in water (80 ml) was treated with sodium hydroxide (1.0 g). Potassium permanganate (6.3 g) was then added to the resulting solution, and the mixture was stirred and heated at reflux for 150 minutes. The hot mixture was filtered through diatomaceous earth to remove manganese dioxide and the filtrate was acidified with concentrated hydrochloric acid. The solid precipitate was then dissolved in hot aqueous ammonia solution (2 N) and then acidified again with concentrated hydrochloric acid. The resulting hot suspension was then filtered and the white solid formed was washed with water. The solid was treated with ethanol (50 ml) and the resulting suspension was brought to reflux and the 2-(5-carboxy-2-propoxyphenyl)-8-azapurin-6-one (1.8 g), m.p. 271°-272° C. (with decomposition), was filtered off from the hot mixture.
Reaction SMILES: C([NH:11][CH2:12][C:13]([NH:15][C:16]([C:24]([N:26]1[CH2:31][CH2:30][NH:29][C:28](=[O:32])[CH:27]1[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:25])=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])(OCC1C=CC=CC=1)=O.Br>C(O)(=O)C>[NH2:11][CH2:12][C:13]([NH:15][C:16]([C:24]([N:26]1[CH2:31][CH2:30][NH:29][C:28](=[O:32])[CH:27]1[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:25])=[CH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:14]
Reactant: CC(C)CC1C(=O)NCCN1C(=O)C(=Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CC(C)CC1C(=O)NCCN1C(=O)C(=Cc1ccccc1)NC(=O)CN

Procedure:
4-[N-carbobenzyloxyglycyldehydropohenylalanyl]-3-(2-methylpropyl)piperazinone (XXXVI, Example 69, 0.5 g.) is added to a solution of hydrogen bromide (32%) in acetic acid (5 ml.). After 1 hour the diluents are evaporated to give the title compound as the hydrobromide salt.
Reaction SMILES: Cl[C:2]([O:4][N:5]=[C:6]([C:12]#[N:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:3].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[CH:17][C:16]=1[OH:23].N1C=CC=CC=1>C1C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[CH:17][C:16]=1[O:23][C:2]([O:4][N:5]=[C:6]([C:12]#[N:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:3]
Reactant: CCOC(=O)C(C#N)=NOC(=O)Cl
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=NOC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a solution of ethyl 2-chlorocarbonyloxyimino-2-cyanoacetate (0.05 mol) prepared as in Example 11 (1), a solution of 2,4,5-trichlorophenol (9.9 g) and pyridine (3.9 g) in benzene (50 ml) is dropwise added under cooling with icewater. The resulting mixture is stirred for 1 hour and allowed to stand over night. The reaction mixture is washed with water, dried and concentrated. The residue is admixed with petroleum ether and filtered to collect crystals, which is dried and recrystallized from a benzene-petroleum ether mixture to give ethyl 2-(2,4,5-trichlorophenyl)oxycarbonyloxyimino-2-cyanoacetate (12.0 g). M.P. 101 to 103°C.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH2:3][CH2:4][CH2:5][CH:6]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][CH2:24][C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=3)=[O:22])=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:34]=[CH:35][CH:36]=[CH:37][C:7]1=2.O[N:40]1[C:44](=[O:45])[CH2:43][CH2:42][C:41]1=[O:46].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[O:46]=[C:41]1[CH2:42][CH2:43][C:44](=[O:45])[N:40]1[O:30][C:29](=[O:31])[C:28]1[CH:27]=[CH:26][C:25]([CH2:24][NH:23][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][O:17][C:15]2[CH:14]=[CH:13][C:12]3[CH:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:38])[C:7]4[CH:37]=[CH:36][CH:35]=[CH:34][C:8]=4[CH2:9][CH2:10][C:11]=3[CH:16]=2)=[CH:33][CH:32]=1
Reactant: O=C1CCC(=O)N1O
Reactant: CN(C)CCCC1c2ccccc2CCc2cc(OCCCC(=O)NCc3ccc(C(=O)O)cc3)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN(C)CCCC1c2ccccc2CCc2cc(OCCCC(=O)NCc3ccc(C(=O)ON4C(=O)CCC4=O)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
A solution of 87 mg (0.169 mmol) of the acid (15) in 10 ml of CH2Cl2 was treated with 40 mg (0.348 mmol) of N-hydroxysuccinimide and 87 mg (0.454 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl and stirred at room temperature overnight. The reaction was washed with H2O, saturated NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel using 10% ether in CH2Cl2 as eluent to give 34 mg (33%) of 16 as a white amorphous solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([CH:17]=[C:18]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]1)#[N:16].N12CCCN=C1CCCCC2>C(#N)C>[C:15]([CH2:17][C:18]1([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]1)#[N:16]
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.06 g, 0.0158 mol) in acetonitrile (50 mL) was added tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (3.06 g, 0.0158 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (2.36 mL, 0.0158 mol). The resulting mixture was stirred at room temperature overnight. After evaporating to dryness, the residue was purified on silica gel, eluting with 0-100% EtOAc in hexanes, to give the desired product (5.40 g, 88%). LCMS (M+H) 389.1.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][N:15]=1.[C:20]([C:22]1[CH:36]=[CH:35][C:25]([O:26][C:27]([CH3:34])([CH3:33])[C:28](OCC)=[O:29])=[CH:24][CH:23]=1)#[N:21]>CCCCCC.O1CCCC1>[OH:29][C:28](=[CH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][N:15]=1)[C:27]([CH3:34])([CH3:33])[O:26][C:25]1[CH:35]=[CH:36][C:22]([C:20]#[N:21])=[CH:23][CH:24]=1
Reactant: Cc1ccncn1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C#N)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(C#N)cc1)C(O)=Cc1ccncn1
Temperature: -78 °C

Procedure:
10 ml of a 1.2M solution of butyllithium in n-hexane were added to a solution of 1.68 ml of diisopropylamine in 50 ml of tetrahydrofuran while stirring at -78° C. under a nitrogen atmosphere. The solution was stirred for a further 15 minutes and a solution of 4-methylpyrimidine in 20 ml of tetrahydrofuran was then added. The solution was allowed to warm to 20° C. and was stirred for 2 hours. The solution was then cooled to -78° C., 2.33 g of ethyl 2-(4-cyanophenoxy)-2-methylpropionate in 30 ml of tetrahydrofuran were added to and the mixture was allowed to warm to 20° C. and was stirred for 16 hours. The mixture was then partitioned between ethyl acetate and water. The organic phase was washed with sodium chloride solution and evaporated. The residue was chromatographed on silica gel using ethyl acetate for the elution to give 0.69 g of 4-[2-hydroxy-1,1-dimethyl-3-(4-pyrimidinyl)-2-propenyloxy]benzonitrile in the form of a yellow solid of melting point 115°-117° C. (from ethyl acetate/n-hexane).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3](=[S:14])[S:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7].C=O.[C:18](=S)=S.CN(C)C(=S)[S-].C[NH2+]C>CO>[CH3:1][N:2]([CH3:15])[C:3](=[S:4])[SH:14].[C:6]([CH:5]=[CH2:18])(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: S=C=S
Reactant: CN(C)C(=S)SCC(=O)c1ccccc1
Agent: C=O
Agent: CN(C)C(=S)[S-]
Agent: C[NH2+]C
Solvent: CO
Product: C=CC(=O)c1ccccc1
Product: CN(C)C(=S)S
Temperature: 0 °C

Procedure:
A solution of phenacyl dimethyldithiocarbamate (12.0 grams, 0.050 mole), formaldehyde (4.1 grams of 37% aqueous solution, 0.050 mole), carbon disulfide (1.9 grams, 0.025 mole), and dimethylammonium dimethyldithiocarbamate (8.3 grams, 0.050 mole) in methanol (50 ml.) was stirred and heated at 38° C.-40° C. for 2.5 hours. The reaction mixture was then cooled to 0° C. and the precipitated product was filtered off, washed with cold methanol and dried in air. The yield of product melting at 106° C.-108.5° C. was 17.6 grams (94%). Repeated recrystallization from methylene chloride-methanol and acetone-2-propanol solution without heat gave pure 1-benzoylethylene dimethyldithiocarbamate melting at 106° C.-109.5° C. The structure was determined from the infrared spectrum and elemental analysis.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].Cl.[CH3:13]O>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:13])=[O:10]
Reactant: O=C(O)Cc1ccccc1O
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
2-Hydroxyphenylacetic acid (50 g) was added to a solution of hydrogen chloride in methanol [prepared from acetyl chloride (25 ml) and methanol (250 ml)]. The solution was stirred at room temperature for three hours and then allowed to stand overnight (fifteen hours). The resulting mixture was concentrated under reduced pressure, and the residue was taken up in ether (250 ml) and washed with an aqueous solution of sodium bicarbonate until effervescence ceased. The ethereal solution was dried and then concentrated under reduced pressure and the resulting solid was recrystallized from ether/petrol to afford methyl 2-hydroxyphenylacetate (50 g; 92% yield) as white, powdery crystals, M.P. 70°-72° C.; infrared maxima (nujol mull): 3420, 1715 cm-1 ; 1H nmr (CDCl3, 90 MHz): delta 3.70 (2H, s), 3.75 (3H, s), 6.80-6.95 (2H, m), 7.05-7.10 (1H, m), 7.15-7.25 (1H, m), 7.40 (1H, s) ppm.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([OH:16])=O)[N:2]=1.[Mg].[CH2:18](Br)[CH3:19].[Cl-].[NH4+].O1CC[CH2:25][CH2:24]1>C(OCC)C>[CH2:24]([C:14]([C:3]1[N:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3)([OH:16])[CH2:18][CH3:19])[CH3:25]
Reactant: O=C(O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: C1CCOC1
Reactant: CCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC(O)(CC)c1cc2c(cn1)[nH]c1ccccc12

Procedure:
480 mg of β-carboline-3-carboxylic acid estyl ester are dissolved in 40 ml of tetrahydrofuran and added drop by drop to a Grignard solution consisting of 144 mg of magnesium chips and 660 mg of ethylbromide in 10 ml of diethyl ether. After 2 hours of reflux it is mixed with aqueous ammonium chloride solution and extracted with methylene chloride. After drying, filtering and evaporation, the residue is chromatographed on silica gel with toluene/glacial acetic acid/water=10:10:1 as eluant. 120 mg of 3-(1-ethyl-1-hydroxy-propyl)-β-carboline are obtained as oil.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:21][CH:20]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][CH:24]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CC(=O)OCC)c(Cc2ccc(C(=O)OC(C)(C)C)cc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc(Cl)c(CC(=O)OCC)c(Cc2ccc(C(=O)O)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
160 mg of the product of Example 3 were introduced into 4 ml of methylene chloride and 1 ml of trifluoroacetic acid and after the mixture was stirred at ambient temperature for 2 hours 30 minutes, it was diluted with 20 ml of methylene chloride, washed twice with 10 ml of water, extracted again with 20 ml of methylene chloride and evaporated to dryness under reduced pressure to obtain 140 mg of product which was crystallized from 1 ml of methylene chloride with 3 ml of isopropyl ether added to it. After standing at rest for approximately 16 hours, separation took place to obtain 77 mg of the expected product melting at 130° C.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([C:7]23[CH2:12][CH:11]2[CH2:10][CH2:9][C:8]3=O)=[CH:3][CH:2]=1.[CH3:15][NH:16][CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:32]CCl>Cl[Ti](Cl)(Cl)Cl>[ClH:32].[CH3:15][N:16]([CH3:17])[CH:8]1[CH2:9][CH2:10][CH:11]2[C:7]1([C:4]1[CH:5]=[CH:6][C:1]([CH3:14])=[CH:2][CH:3]=1)[CH2:12]2
Reactant: ClCCl
Reactant: Cc1ccc(C23CC2CCC3=O)cc1
Reactant: CNC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1ccc(C23CC2CCC3N(C)C)cc1
Product: Cl
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 42 %

Procedure:
A mixture of 1-p-tolyl-bicyclo[3.1.0]hexan-2-one (139 mg, 0.75 mmol) in dichloromethane (6 mL) was cooled to 0° C. and dimethylamine (2M solution in THF, 1.1 mL, 2.2 mmol) and TiCl4 (71 mg; 0.37 mmol) were added sequentially. After stirring at 0° C. for 45 min, the mixture was warmed to reflux and was stirred overnight. The reaction was then cooled to room temperature, and treated with sodium triacetoxyborohydride (226 mg, 1.06 mmol) at room temperature. The reaction mixture was stirred for 5 h, the reaction mixture was quenched with water (10 mL). The layers were filtered, and the pH was adjusted to 9 using saturated NaHCO3. The layers were then separated, and the aqueous layer was re-extracted with CH2Cl2 (2×), dried over sodium sulfate, filtered and concentrated in vacuo. The oily crude residue was converted to HCl salt using HCl/diethyl ether to give the desired compound (79 mg; 42%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (m, 1 H) 1.50-1.66 (m, 1 H) 1.83-1.92 (m, 1 H) 2.01-2.21 (m, 4 H) 2.39-2.44 (m, 1 H) 2.55-2.90 (m, 6 H) 3.89-4.02 (m, 1 H) 7.01-7.33 (m, 4 H) 11.99 (bs, 1H). 13C NMR (100 MHz, CHLOROFORM-d) d ppm 11.54 (s, 1 C) 21.18 (s, 1 C) 25.78 (s, 1 C) 26.25 (s, 1 C) 30.67 (s, 1 C) 32.84 (s, 1 C) 43.01 (s, 1 C) 44.82 (s, 1 C) 75.27 (s, 1 C) 128.06 (s, 2 C) 130.02 (s, 2 C) 137.04 (s, 1 C) 138.76 (s, 1 C). MS (M+1) 216, HPLC Purity 95% (AUC).