Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](C(OC(C)(C)C)=O)[CH:14]=[C:13]3[C:26]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:29]=[CH:28][N:27]=2)=[N:7][N:6]=1)(=O)=O.[NH3:38].O>CS(C)=O>[O:35]1[CH2:34][CH2:33][N:32]([C:30]2[CH:29]=[CH:28][N:27]=[C:26]([C:13]3[C:12]4[C:16](=[CH:17][CH:18]=[C:10]([C:8]5[S:9][C:5]([NH2:38])=[N:6][N:7]=5)[CH:11]=4)[NH:15][CH:14]=3)[N:31]=2)[CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)n1cc(-c2nccc(N3CCOCC3)n2)c2cc(-c3nnc(S(C)(=O)=O)s3)ccc21
Reactant: N
Solvent: O
Solvent: CS(C)=O
Product: Nc1nnc(-c2ccc3[nH]cc(-c4nccc(N5CCOCC5)n4)c3c2)s1
Temperature: 110 °C
Yield: 5 %

Procedure:
A sealed tube was charged with tert-butyl 5-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)-3-(4-morpholinopyrimidin-2-yl)-1H-indole-1-carboxylate (1.7 g, 3.3 mmol) in DMSO (17 mL) saturated with NH3. The reaction was heated at 110° C. for 7 h, then the mixture was poured into H2O. The mixture was extracted with EtOAc and the combined organic layers were dried, filtered and concentrated. The residue was purified with silica gel chromatography to give 5-(3-(4-morpholinopyrimidin-2-yl)-1H-indol-5-yl)-1,3,4-thiadiazol-2-amine (65 mg, 5%). MS (ESI, pos. ion) m/z: 380.1 (M+1). 1H-NMR (DMSO-d6, 300 MHz) δ: 11.89 (1H, s), 8.79 (1H, s), 8.28 (1H, d, J=6.3 Hz), 8.24 (1H, d, J=2.4 Hz), 7.75 (1H, dd, J=8.4, 1.5 Hz), 7.52 (1H, d, J=8.7 Hz), 7.32 (2H, s), 6.66 (1H, d, J=6.3 Hz), 3.81 (8H, brs).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[OH:8])[CH:2]=1.O1C[CH2:20][CH2:19][CH2:18]1.[H-].[Na+].C(Br)C=C>O>[CH2:20]([O:8][CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])[CH:19]=[CH2:18]
Reactant: C1CCOC1
Reactant: OC(c1cccnc1)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C=CCBr
Solvent: O
Product: C=CCOC(c1cccnc1)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 250 ml single neck round bottom flask equipped with a reflux condensor and an argon inlet was added 3.56 gm of the 3-pyridyl-2,4-dichlorophenylcarbinol and 60 ml of anhydrous tetrahydrofuran. The system was cooled to 0° C. and after cooling 0.37 gm sodium hydride added. The system was stirred for 75 additional minutes and 1.45 ml of allyl bromide was then added. The system was allowed to come to room temperature over 1/2-hour and stirred there for an additional 1 hour. Afterwards the system was heated at reflux for 18 hours. At this time, water was added to the system and the product extracted with methylene chloride. The methylene chloride was then washed with water and then dried over sodium sulfate. The methylene chloride was removed by stripping to give 1.73 gm of the 3-pyridyl-2,4-dichlorophenylcarbinol allylether and listed as compound number 3 in Table I.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]3[CH2:18][CH2:19][NH:20][CH2:21][C:5]=3[C:4]=2[CH:3]=1.[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[CH2:23].C(O)(=O)C>CO>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[C:6]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:22][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:21][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccccn1
Reactant: Fc1ccc(-n2c3c(c4cc(F)ccc42)CNCC3)cc1
Solvent: CC(=O)O
Solvent: CO
Product: Fc1ccc(-n2c3c(c4cc(F)ccc42)CN(CCc2ccccn2)CC3)cc1
Yield: 89.9 %

Procedure:
A mixture of 8-fluoro-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (3 g, 0.01 mole), 2-vinylpyridine (1.7 g, 0.01 mol) and 2 mL of glacial acetic acid were refluxed for 48 hours in 30 mL of methanol. The solvent was removed in vacuo and the separated solid was purified by HPLC using ethyl acetate as the eluant to afford 3.5 g (89.9% yield) of the title compound. It was converted to the dihydrochloride salt; mp. 267°-270° C.
Reaction SMILES: Br[C:2]1[C:15]([OH:16])=[CH:14][C:13]2[CH:12]3[CH:7]([CH2:8][CH2:9][CH2:10][CH2:11]3)[CH:6]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH2:5][C:4]=2[CH:3]=1.C[O-].[Na+].CN([CH:30]=[O:31])C>C(OCC)(=O)C>[OH:23][C:20]1[CH:19]=[CH:18][C:17]([CH:6]2[CH2:5][C:4]3[CH:13]=[C:14]([O:31][CH3:30])[C:15]([OH:16])=[CH:2][C:3]=3[CH:12]3[CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]3)=[CH:22][CH:21]=1
Reactant: Oc1ccc(C2Cc3cc(Br)c(O)cc3C3CCCCC23)cc1
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1O)C1CCCCC1C(c1ccc(O)cc1)C2
Yield: 100 %

Procedure:
Combine 2-Bromo-9-(4-hydroxy-phenyl)-4b,5,6,7,8,8a,9,10-octahydro-phenanthren-3-ol (chiral) (0.033 g, 0.09 mmol), CuCl2 (0.008 g, 0.06 mmol), 5 M NaOMe (in methanol, 1.5 ml), DMF (0.5 ml) and heat 15 hours at 110° C. Cool, add ethyl acetate and wash with 1N HCl, then water. Dry organic layer over anhydrous sodium sulfate and remove solvent in vacuo. Chromatograph over silica gel 2× first with 20% ethyl acetate/hexanes, then 5-20% ethyl acetate/hexanes to yield the titled compound (0.010 g, 100%). 1H NMR (CDCl3): 7.21 (d, J=8.4 Hz, 2H), 7.0 (s, 1H), 6.85 (d, J=8.8 Hz, 2H), 6.69 (s, 1H), 3.91 (s, 3H), 3.2 (m, 4H), 2.85 (dd, J=4 and 11 Hz, 1H), 2.45 (d, J=14.9 Hz, 1H), 2.1-0.8 (m, 7H). MS m/z 323(M−1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH:20]=C)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CC[O:24]C(C)=O>CC(O)C.O.O=[Os](=O)(=O)=O>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH:20]=[O:24])[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: C=CCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCOC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)C1(CC=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
4-Allyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (2.97 g, 10 mmol) was dissolved in iPrOH (50 mL) and H2O (10 mL). To this was added a aqueous solution of NaIO4 (4.68 g, 21.8 mmol) in water (40 mL), followed by addition of OsO4 (8.4 mg, crystals, in one portion) at rt. The solution was stirred at rt. After 30 min, milky cloudy formed. Stirring was continued overnight. TLC and LC/MS did not detect the SM, but it was still very milky. The reaction mixture was poured into ice water (20 mL) and EtOAc (30 mL). The two layers were separated and the aqueous layer was extracted with EtOAc (3×15 mL). The combined extracts were washed with brine, and concentrated to dryness to obtain a liquid. The liquid was subject to a distillation under reduced pressure to remove isopropanol. The remaining liquid was purified on a 50 g silica gel column, eluted with MeOH in DCM (0-5%). Note: the product is not UV active. Anisaldehyde visualization was used. The product fractions were collected and concentrated to yield 1.03 g (34% yield) of the title compound as a liquid.
Reaction SMILES: [Cl:1][C:2]1N=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[Cl-].Cl[C:33]1C=CC(C[Zn+])=CN=1>>[Cl:1][C:2]1[CH:33]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Reactant: Clc1ccc(C[Zn+])cn1
Agent: [Cl-]
Product: O=c1c2cc(Cc3ccc(Cl)cc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O

Procedure:
6-(4-Chlorobenzyl)-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one was prepared by the procedure described for the synthesis of 6-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one in Example 1, substituting 4-chlorobenzylzinc chloride for (2-chloro-5-pyridyl)methylzinc chloride.
Reaction SMILES: [Cl:1][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.C(O[Cl:15])(C)(C)C>CO>[Cl:15][N:4]1[C:3]([CH2:2][Cl:1])([CH3:9])[CH2:7][O:6][C:5]1=[O:8]
Reactant: CC1(CCl)COC(=O)N1
Reactant: CC(C)(C)OCl
Solvent: CO
Product: CC1(CCl)COC(=O)N1Cl
Temperature: 25 °C

Procedure:
A solution of 4-(chloromethyl)-4-methyloxazolidin-2-one (13.39 g, 89.52 mmol) in MeOH (100 ml) was cooled to 0° C., and tert-butylhypochlorite (12.0 ml, 101 mmol) was added dropwise over 15 min. The solution was warmed to RT over 45 min, and concentrated in vacuo. The residue was crystallized by dissolution in ˜80 ml CH2Cl2 followed by careful layering of 60 ml hexanes to afford the title compound as white, fan-shaped crystals (12.31 g, 66.89 mmol, 75%). 1H NMR (CDCl3, 400 MHz) δ1.50 (s, 3H), 3.55 (d, J=12.0 Hz, 1H), 3.75 (d, J=12.0 Hz, 1H), 4.19 (d, J=8.8 Hz, 1H), 4.53 (d, J=8.4 Hz, 1H). 13C NMR (CDCl3, 100 MHz) δ 20.4, 46.7, 64.1, 155.7. LRMS (ESI/APCI): 225 [M+H+CH3CN]+, 191 [M+H−Cl+CH3CN]+, 184 [M+H]+, 150 [M+H−Cl]+.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[Cl:19][C:20]1[C:21]([O:28][CH:29]([F:31])[F:30])=[N:22][CH:23]=[C:24]([CH:27]=1)[CH:25]=O>>[Cl:19][C:20]1[CH:27]=[C:24]([CH2:25][N:1]2[CH:2]([C:9]3[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=3[O:17][CH3:18])[CH2:3][CH2:4][C:5]2=[O:7])[CH:23]=[N:22][C:21]=1[O:28][CH:29]([F:31])[F:30]
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cnc(OC(F)F)c(Cl)c1
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cnc(OC(F)F)c(Cl)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with 5-chloro-6-(difluoromethoxy)nicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 413.32 g/mol.
Reaction SMILES: [PH:1]([CH2:4][CH3:5])[CH2:2][CH3:3].N([C:13]([CH3:17])([CH3:16])C#N)=NC(C)(C)C#N>>[CH2:17]([P:1]([CH2:4][CH2:5][P:1]([CH2:4][CH3:5])[CH2:2][CH3:3])[CH2:2][CH2:3][P:1]([CH2:4][CH3:5])[CH2:2][CH3:3])[CH2:13][CH3:16]
Reactant: CCPCC
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCP(CCP(CC)CC)CCP(CC)CC
Yield: 5502.7 %

Procedure:
A mixture of n-PrP(CH=CH2)2 (1.29 g, 10.0 mmol), Et2PH (2.25 g, 25.0 mmol) and 2,2'-azobis(isobutyronitrile) (AIBN, 30 mg) in a closed flask under inert atmosphere was irradiated by a GE Sunlamp (275 W) one foot away for 24 hours. The resulting colorless liquid was stripped of volatiles under vacuum and vacuum distilled to give 3.1 g (97% yield) of product collected at 132-135° C./0.35 mm Hg. 31P-NMR (toluene): δ--18.5 (2P); δ--22.8 (1P).
Reaction SMILES: I[C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:21]=[CH:20][C:10]([O:11][CH:12]3[CH:17]4[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]4)[CH2:13]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[NH:25][NH2:26].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:29]([O:28][C:24]([N:25]([C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:21]=[CH:20][C:10]([O:11][CH:12]3[CH:17]4[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]4)[CH2:13]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1)[NH2:26])=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: Ic1ccc(Oc2ccc(OC3CN4CCC3CC4)cc2)cc1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(N)c1ccc(Oc2ccc(OC3CN4CCC3CC4)cc2)cc1

Procedure:
The product of Example 38A (420 mg, 1.0 mmol) was coupled with tert-butyl carbazate (Aldrich, 158 mg, 1.2 mmol) under the catalysis of Cul (Strem Chemicals, 9.5 mg, 0.05 mmol) with Cs2CO3 (Strem Chemicals, 489 mg, 1.4 mmol) in DMF (anhydrous, Aldrich, 5 mL) at 80° C. overnight. The mixture was diluted with EtOAc (50 mL) and washed with water (2×10 mL). The organic solution was concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:2, Rf. 0.20) as an oil (190 mg, yield, 45%). 1H NMR (MeOH-d4, 300 MHz) δ 1.46 (s, 9H), 1.76–2.16 (m, 3H), 2.20–2.39 (m, 1H), 2.41–2.54 (m, 1H), 3.16–3.47 (m, 5H), 3.66–3.86 (m, 1H), 4.70–4.84 (m, 1H), 6.77–6.93 (m, 2H), 6.94–7.04 (m, 4H), 7.25–7.48 (m, 2H) ppm. MS (DCl/NH3) m/z 426 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[N:10][CH:11]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].C(Cl)(Cl)Cl>C(O)(=O)C.S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH2:4][N:5]([C:6]1[CH:11]=[N:10][CH:9]=[N:8][CH:7]=1)[C:17](=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ccc(CNc2cncnc2)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)N(Cc1ccc(Cl)cc1Cl)c1cncnc1
Yield: 68.5 %

Procedure:
2.80 g (11 mmol) of N-(2,4-dichlorobenzyl)-N-(pyrimidin-5-yl)amine are dissolved in 5 ml of glacial acetic acid and then 5 ml of acetic anhydride and 3 drops of concentrated sulfuric acid are added to the solution. With stirring, the reaction mixture is boiled under reflux for 11/2 hours and subsequently cooled. 30 ml of chloroform are added to the mixture, the acetic acid is removed by extraction with water and the separated solution of chloroform is dried over sodium sulfate. The sodium sulfate is filtered off and the chloroform is then evaporated off in vacuo at 80° C. and the residue is recrystallised from a mixture of 5 ml of toluene and 5 ml of cyclohexane, affording 2.23 g (68.5% of theory) of N-(2,4-dichlorobenzyl)-N-(pyrimidin-5-yl)acetamide, m.p. 134°-136° C. A further 0.90 g (27.6% of theory) of pure product is obtained by purifying the product formed in the filtrate through a column of silica gel (eluant: ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:17])=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1.C([Li])(CC)C.[CH3:23][CH:24]([CH3:27])[CH:25]=[O:26].[Cl-].[NH4+]>O1CCCC1>[OH:26][CH:25]([CH:24]([CH3:27])[CH3:23])[CH2:17][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)C=O
Reactant: COc1ccc(C)c(NC(=O)OC(C)(C)C)c1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(CC(O)C(C)C)c(NC(=O)OC(C)(C)C)c1
Reaction time: 0.25 h
Yield: 50.2 %

Procedure:
Under an argon atmosphere, to a solution of tert-butyl (5-methoxy-2-methylphenyl)carbamate (1.42 g) in tetrahydrofuran (30 mL) was slowly added dropwise sec-butyllithium (1.06 mol/L hexane-cyclohexane solution, 12.5 mL) at −40° C., and the mixture was stirred for 15 minutes. Then, a solution of 2-methylpropionaldehyde (476 mg) in tetrahydrofuran (3 mL) was added dropwise thereto, and the mixture was stirred at −40° C. for 15 minutes, and then stirred at room temperature for additional 40 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (929 mg). 1H-NMR (CDCl3) δ ppm: 0.96-1.06 (6H, m), 1.52 (9H, s), 1.70-1.83 (1H, m), 1.90 (1H, d, J=3.8 Hz), 2.57-2.75 (2H, m), 3.48-3.59 (1H, m), 3.80 (3H, s), 6.59 (1H, dd, J=2.8, 8.5 Hz), 7.00 (1H, d, J=8.5 Hz), 7.43 (1H, br s), 7.91 (1H, br s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.Br[CH2:12][C:13]#[N:14]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][CH2:12][C:13]#[N:14])=[CH:5][CH:4]=1
Reactant: N#CCBr
Reactant: COc1ccc(CN)cc1
Solvent: C1CCOC1
Product: COc1ccc(CNCC#N)cc1
Temperature: 10 °C
Reaction time: 12 h
Yield: 76.4 %

Procedure:
A mixture of TEA (55.9 ml, 401 mmol), (4-methoxyphenyl)methanamine (50 g, 364 mmol) and 2-bromoacetonitrile (43.7 g, 364 mmol) in THF (500 ml) was stirred at about 10° C. for about 12 h in a 500 ml round-bottomed flask. The reaction was filtered through a pad of silica gel. The crude material was deposited onto silica gel, loaded onto a silica gel column and eluted with Hex/EtOAc (1:1) to afford the title compound (49 g, 278 mmol, 76% yield). 1H-NMR (CDCl3, 400 MHz): δ=3.55 (s, 2H), 3.81 (s, 3H), 3.87 (s, 2H), 6.88 (d, 2H, J=8.4 Hz), 7.26 (d, 2H, J=8.0 Hz)
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:20][OH:21])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH2:18][CH3:19])=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C(O)(=O)C>C1C=CC=CC=1>[OH:1][CH2:2][CH:3]1[CH:4]2[C:13]3[C:8]([CH2:7][CH2:6][N:5]2[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:21][CH2:20]1)=[CH:9][C:10]([O:17][CH2:18][CH3:19])=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3
Reactant: O=Cc1ccccc1
Reactant: CCOc1cc2c(cc1OCC)C(C(CO)CO)NCC2
Agent: Cl
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOc1cc2c(cc1OCC)C1C(CO)COC(c3ccccc3)N1CC2
Yield: 70 %

Procedure:
10 mmoles (2.8 g) of 1-[bis(hydroxymethyl)-methyl]-6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline and 11 mmoles (1.17 g) of freshly distilled benzaldehyde are refluxed in 50 ml of absolute benzene, in the presence of a catalytic amount of hydrochloric acid or acetic acid for 4 hours. The solvent is distilled off and the residual pale-yellow oil is crystallized by trituration with ether. The aimed compound is obtained in a yield of 70%.
Reaction SMILES: Br[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[CH:3]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[N:18]1([C:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:6](=[O:13])[C:5]3[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=3[CH:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=c1c2ccccc2cc(Br)c2ccccc12
Reactant: C1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=c1c2ccccc2cc(N2CCCCC2)c2ccccc12

Procedure:
A mixture of 71.3 g of 10-bromo-5H-dibenzo[a,d]cyclohepten-5-one, 50 ml. of piperidine, 1 liter of t-butanol and finally 33.6 g of potassium t-butoxide was stirred under reflux 2 hours, then at room temperature overnight. The mixture was filtered, and concentrated to dryness. The residue was slurried with water and decanted. The residue was slurried with methanol and filtered to give 59.8 g of 10-(1-piperidyl)-5H-dibenzo[a,d]cyclohepten-5-one, m.p. 103°-105° C.
Reaction SMILES: [C:1]1([C:13]([OH:15])=[O:14])([C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[CH2:16]1[O:18][CH2:17]1>C(C(C)=O)C(C)C>[OH:8][CH2:7][CH2:2][O:14][C:13]([C:1]1([C:10]([O:12][CH2:17][CH2:16][OH:18])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:1][CH2:10][OH:11])=[O:8])=[O:15]
Reactant: O=C(O)C1CCCCC1(C(=O)O)C(=O)O
Reactant: C1CO1
Solvent: CC(=O)CC(C)C
Product: O=C(OCCO)C1CCCCC1(C(=O)OCCO)C(=O)OCCO

Procedure:
Cyclohexanetricarboxylic acid was allowe to react under pressure with ethylene oxide and 0.15% of the catalyst of Example II (based on the total wt. of system) in the presence of methyl isobutyl ketone at 150°-160° C for 2 hours. A viscous oil of good purity was obtained after charcoal treatment and evaporation of a methyl isobutyl ketone solution. The infrared spectra and elements analysis were consistent with the desired product.
Reaction SMILES: [C:1]([N:5]([C:7]([C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1)=[O:8])[NH2:6])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])=[CH:19][CH:18]=1.CCOCC>C(Cl)Cl>[C:1]([N:5]([C:7]([C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1)=[O:8])[NH:6][C:27]([NH:26][S:23]([C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1)(=[O:24])=[O:25])=[O:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Cc1cccc(C(=O)N(N)C(C)(C)C)c1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cccc(C(=O)N(NC(=O)NS(=O)(=O)c2ccc(Cl)cc2)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N'-t-butyl-N'-3-toluoyl hydrazine (4.03 g, 0.02 mol) in methylene chloride (25 ml) under nitrogen was added 4-chlorobenzenesulfonyl isocyanate (5 g, 80%, 0.02 mol) at room temperature. The exothermic reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure to give an oil. A precipitate appeared after treating with ether. The pure product was collected by suction-filtration and washed with a small amount of ether affording 4.8 g of 1-t-butyl-1-(3-toluoyl)-4-(4-chlorobenzenesulfonyl)semicarbazide as a white solid: m.p. 184°-188° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[OH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:28]2[CH2:27][CH2:26][N:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[OH:18])[CH2:30][CH2:29]2)[N:3]=1
Reactant: Oc1ccccc1N1CCNCC1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCO)nc(NCCO)nc1N1CCN(c2ccccc2O)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-(2-hydroxy-phenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 60° C. to yield 2,4-bis-(2-hydroxy-ethylamino)-6-[4-(2-hydroxy-phenyl)-piperazin-1-yl]-pyrimidine-5-carbonitrile as a white lyophilisate; MS: [M+H]+=399.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[CH:31][C:27]=1[C:28]([OH:30])=O.C(N(CC)CC)C.Cl.[O:55]1[CH2:59][CH2:58][CH2:57][CH:56]1[CH2:60][O:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C)C=O>[F:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[CH:31][C:27]=1[C:28]([N:65]1[CH2:66][CH2:67][CH:62]([O:61][CH2:60][CH:56]2[CH2:57][CH2:58][CH2:59][O:55]2)[CH2:63][CH2:64]1)=[O:30]
Reactant: C1COC(COC2CCNCC2)C1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OCC2CCCO2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
O-Benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (509 mg, 1.34 mmol) was added, in one portion, to 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (200 mg, 0.67 mmol) and triethylamine (0.206 mL, 1.48 mmol) in N,N-dimethylformamide (2.5 mL), at 25° C. under an air atmosphere. The resulting solution was stirred at 25° C. for 10 minutes. A solution of 4-((tetrahydrofuran-2-yl)methoxy)piperidine hydrochloride (164 mg, 0.74 mmol) and triethylamine (0.206 mL, 1.48 mmol) in N,N-dimethylformamide (1 mL) was then added dropwise and the resulting solution stirred at 25° C. for 10 hours. The crude mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound as a solid (238 mg, 76%); 1H NMR (400.132 MHz, DMSO) δ 1.01 (2H, dt), 1.31-1.37 (1H, m), 1.43-1.50 (1H, m), 1.51-1.58 (1H, m), 1.68-1.73 (1H, m), 1.74-1.93 (4H, m), 3.00-3.07 (1H, m), 3.17-3.18 (1H, m), 3.39 (2H, d), 3.53-3.59 (1H, m), 3.70-3.75 (1H, m), 3.90 (2H, ddd), 4.33 (2H, s), 7.21 (1H, t), 7.33-7.35 (1H, m), 7.39-7.43 (1H, m), 7.83 (1H, td), 7.89 (1H, td), 7.97 (1H, d), 8.27 (1H, dd), 12.56 (1H, s) m/z (LC-MS, ESI+), RT=1.71 (M+H 466.5).