Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(C[Br:25])=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][N:40]([CH2:43][C:44]([C:46]3[CH:51]=[CH:50][C:49]([CH2:52]O)=[CH:48][C:47]=3[CH3:54])=[O:45])[C:39](=[O:55])[CH:38]=2)=[N:33][CH:34]=1>>[Br:25][CH2:52][C:49]1[CH:50]=[CH:51][C:46]([C:44](=[O:45])[CH2:43][N:40]2[CH:41]=[CH:42][C:37]([O:36][CH2:35][C:32]3[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][N:33]=3)=[CH:38][C:39]2=[O:55])=[C:47]([CH3:54])[CH:48]=1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccc(Cl)cn2)cc1=O
Product: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccc(Cl)cn2)cc1=O

Procedure:
1-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-chloro-pyridin-2-ylmethoxy)-1H-pyridin-2-one is prepared following preparation 1d employing 4-(5-chloro-pyridin-2-ylmethoxy)-1-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6](=[O:17])(=[O:16])[C:5]=2[CH:4]=[C:3]([C:18](O)=[O:19])[CH:2]=1.C1C2C=CC3C=CC=CC=3S(=O)(=O)C=2C=C(C(O)=O)C=1>>[OH:19][CH2:18][C:3]1[CH:2]=[CH:1][C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6](=[O:17])(=[O:16])[C:5]=2[CH:4]=1
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1CC2
Agent: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Product: O=S1(=O)c2ccccc2CCc2ccc(CO)cc21

Procedure:
Repeat the process of Example 6, substituting an equivalent quantity of 10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid-5,5-dioxide for the dibenzo[b,f]thiepin-3-carboxylic acid-5,5-dioxide, to obtain the title product (m.p., 128°-130° C.).
Reaction SMILES: [CH3:1][C:2]([CH3:22])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:21])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:20])=[CH:11]/[CH2:12][S:13][CH2:14][C@H:15]([NH2:19])[C:16]([OH:18])=[O:17].C([O-])([O-])=O.[K+].[K+].[C:29]1(=[O:35])[O:34][C:32](=[O:33])[CH:31]=[CH:30]1.Cl>C1COCC1>[C:16]([C@@H:15]([NH:19][C:29](=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33])[CH2:14][S:13][CH2:12]/[CH:11]=[C:10](\[CH3:20])/[CH2:9][CH2:8]/[CH:7]=[C:6](\[CH3:21])/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:22])[CH3:1])([OH:18])=[O:17]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Reactant: O=C1C=CC(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)/C=C/C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of S-trans, trans-farnesyl-L-cysteine (500 mg, 1.54 mmol) in THF and first portion of K2CO3 (3 mmol) was cooled to 5° C. with vigorous stirring. To this stirred solution was added maleic anhydride (302 mg, 3.07 mmol) portions wise while maintaining the PH at 9-10 with another portion of K2CO3 (3 mmol). The mixture was stirred at room temperature for 3 h, HPLC analysis showed completion of the reaction. The pH of the reaction mixture then adjusted to 2 by the addition of 2N HCl solution. The acidic solution was extracted three times with 15 ml of ethyl acetate. The combined organic extract was washed with water, brine and dried over sodium sulfate and then concentrated to afford crude product, which was further purified by preparative HPLC (552 mg, 85% yield): 1H-NMR (500 MHz, CD3OD) δ 1.50 (bs, 6H), 1.57 (s, 3H), 1.59 (s, 3H), 1.85-2.10 (m, 8H), 2.68 (dd, J=6.5, 14.5, 1H), 2.95 (dd, J=4.5, 14.0 Hz, 1H), 3.07 (dd, J=7.0, 13.0 Hz, 1H), 3.17 (dd, J=8.5, 13.5 Hz, 1H), 4.59 (dd, J=4.5, 8.5), 4.97-5.02 (m, 2H), 5.12 (t, J=7.5, 1H), 6.21 (d, J=13.0 Hz, 1H), 6.47 (d, J=13.0 Hz, 1H); 13C-NMR (125 MHz, CDCl3) δ 16.2, 16.3, 17.8, 25.3, 26.0, 27.4, 27.8, 30.3, 33.3, 40.8, 40.9, 54.0, 121.5, 125.1, 125.5, 132.1, 133.3, 134.4, 136.3, 140.7, 167.7, 168.0, 172.9; ES-MS: mass calcd for Chemical Formula: C22H33NO5S 423.6 (M+). Found (M+Na) m/z 446.
Reaction SMILES: N[C:2]1[C:6]([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])=CNN=1.[CH3:14][N:15](C)[CH:16]=CC(C1C=C(N(C)C(=O)C)C=CC=1)=O>C(O)(=O)C>[CH3:14][N:15]([CH3:16])[C:6](=[CH2:2])[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8]
Reactant: CC(=O)N(C)c1cccc(C(=O)C=CN(C)C)c1
Reactant: Nc1n[nH]cc1C(=O)c1cccs1
Solvent: CC(=O)O
Product: C=C(C(=O)c1cccs1)N(C)C
Yield: 70 %

Procedure:
A mixture of (3-amino-1H-pyrazol-4-yl)-2-thienylmethanone (4) (1.93 g, 10 mmol) and N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]-phenyl]-N-methylacetamide (6) (2.46 g, 10 mmol) in glacial acetic acid (100 mL) is refluxed for 8 hrs. Evaporation of all volatiles on a rotary evaporator gives a residue which is partitioned between aqueous saturated sodium bicarbonate and methylene chloride. The methylene chloride layer is dried over sodium sulfate and filtered. Two additional volumes of methylene chloride are added and the solution is warmed to reflux. Hexane is added until crystallization is observed. The mixture is cooled and filtered to give Compound 1 as a yellow solid (2.57 g, 7 mmol, 70%).
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([OH:16])=[O:15])=[CH:5][N:4]=1.O>Br>[OH:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([OH:16])=[O:15])=[CH:5][N:4]=1
Reactant: COc1ncc(C(=O)O)c2c(C)cccc12
Agent: Br
Solvent: O
Product: Cc1cccc2c(O)ncc(C(=O)O)c12
Yield: 53.7 %

Procedure:
A solution of 1-methoxy-5-methylisoquinolin-4-carboxylic acid (Intermediate-8) (1.2 g, 5.5 mmol) in HBr (48% aq. solution, 20 mL) was stirred at RT for 24 h. After completion (TLC), the reaction mixture was poured into water, filtered, washed with water (4×25 mL), and then dried to afford title compound (600 mg, 52%).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:21])[O:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].CI.[C:26](=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:26][N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[C:18](=[O:21])[O:19][CH3:20]
Reactant: O=C([O-])O
Reactant: COC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)N(C)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 0.5 h

Procedure:
A mixture of 1.27 g of [3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]carbamic acid, methyl ester, 100 ml of dry dimethylformamide and 0.129 g of sodium hydride was stirred under argon, for 30 minutes, then 0.31 ml of methyl iodide was added. This mixture was stirred for 2 hours, then poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane. The extracts were combined, dried and evaporated. The residue was dissolved in dichloromethane:methanol (95:5) and filtered through a short plug of silica gel. The filtrate was concentrated and the resulting solid chromatographed on a column of 500 g of silica gel, eluting with dichloromethane:methanol (97:3). Fractions containing product were combined, evaporated and the solid recrystallized from dichloromethane-hexane, giving 0.92 g of the desired product as off-white crystals, mp 164°-166° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:26][CH2:27][CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[OH:29]>CO.[Pd]>[OH:29][CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:27][NH:26][CH:22]1[CH2:23][CH2:24][N:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][S:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)(=[O:10])=[O:11])=[CH:14][CH:15]=2)[CH2:20][CH2:21]1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NCC(O)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NCC(O)c4ccccc4)CC3)cc2)cc1
Yield: 61.3 %

Procedure:
A mixture of 4-methoxy-N-[4-(4-oxo-piperidine-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 218) (0.16 g, 0.44 mmol) and 2-amino-1-phenylethanol (0.18 g, 1.3 mmol) in 75 mL of methanol was hydrogenated in the presence of 100 mg of 10% Pd/C under H2 (5˜20 psi) for overnight. The catalyst was then removed by filtering through a short pad of silica gel. The filtrate was concentrated and purified by silica gel chromatography using 5-10% MeOH/CH2Cl2 as eluent to give 0.13 g (61%) of the title compound as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.78-1.92 (m, 2H), 2.50-2.80 (m, 5H), 3.60-3.70 (m, 2H), 3.79 (s, 3H), 4.56-4.60 (m, 1H), 5.26 (brs, 1H), 6.76 (d, J=9.0 Hz, 2H), 6.86 (d, J=9.0 Hz, 2H), 7.04 (d, J=9.0 Hz, 2H), 7.20-7.25 (m, 1H), 7.25-7.36 (m, 4H), 7.58 (d, J=9.0 Hz, 2H); MS (ES) m/z: 482.4 (MH+); HRMS Calcd. for C26H31N3O4S(M+): 481.2035. Found: 481.2028.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH2:9](B(O)O)[CH2:10][CH2:11][CH2:12][CH3:13]>>[CH2:9]([C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=Cc1ccc(Br)s1
Reactant: CCCCCB(O)O
Product: CCCCCc1ccc(C=O)s1
Yield: 67.4 %

Procedure:
The compound was synthesized as in Example 3.1 using 5-bromothiophene-2-carbaldehyde (250 mg, 1.31 mmol) in place of 5-bromo-2-formylfuran and pentylboronic acid (250 mg, 2.16 mmol) in place of hexylboronic acid to give 5-pentylthiophene-2-carbaldehyde (161 mg, 67%). Used without further characterization.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH3:11])[C:5](=[O:9])[NH:6][C:7]=1[CH3:8].[CH3:12]I>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([O:9][CH3:12])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CCc1cc(Br)c(C)[nH]c1=O
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)c(C)nc1OC
Reaction time: 72 h
Yield: 6287.1 %

Procedure:
5-Bromo-3-ethyl-6-methyl-1H-pyridin-2-one (25 g, 115.7 mmol) was dissolved in 200 ml of chloroform to form an orange solution. Silver carbonate (31.9 g, 115.7 mmol) was added and the mixture was vigorously stirred. Methyl iodide (10.8 ml, 1.5 mmol) was added to this suspension, which was then stirred in the dark at RT under nitrogen. After 3 days, the mixture was filtered and the solution was concentrated in a rotary evaporator. The residue was chromatographed on silica gel with n-heptane as mobile phase and afforded a colorless oil (21.7 g, 82%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl.[Cl:9][CH2:10][C:11]1[C:16]([CH3:17])=[C:15]([S:18][CH2:19][CH2:20][CH2:21][Cl:22])[CH:14]=[CH:13][N:12]=1>C(O)(C)C>[ClH:9].[Cl:22][CH2:21][CH2:20][CH2:19][S:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([CH2:10][S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:16]=1[CH3:17]
Reactant: Sc1ccncc1
Reactant: Cc1c(SCCCCl)ccnc1CCl
Agent: Cl
Solvent: CC(C)O
Product: Cc1c(SCCCCl)ccnc1CSc1ccncc1

Procedure:
According to the procedure described in Example A1., reaction of 4-mercaptopyridine with 2-chloromethyl-4-(3-chloropropylthio)-3-methylpyridine hydrochloride in isopropanol gives a hydrochloride of the title compound as a colorless solid. After dissolving in water, a pH of 10 is adjusted, the mixture is extracted 2× with dichloromethane, the organic phases are washed with sodium carbonate solution and dried (magnesium sulfate), the solvent is concentrated on a rotary evaporator and the residue is crystallized from dichloromethane/diisopropyl ether. The title compound is obtained as a colorless solid; Yield 78of theory; m.p. 88-91° C.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1.Cl(O)(=O)(=O)=O.C([C@@H]1N[C@H](C2OC(C)=CC=2)N(C)C1=O)C1C=CC=CC=1>O>[C@@H:10]12[CH2:11][C@H:12]([CH:8]=[CH:9]1)[C@@H:3]1[C@@H:2]2[C:1](=[O:7])[CH2:6][CH2:5][CH2:4]1
Reactant: O=C1C=CCCC1
Reactant: C1=CCC=C1
Agent: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: O=C1CCC[C@H]2[C@H]1[C@H]1C=C[C@H]2C1
Yield: 81 %

Procedure:
Prepared according to general procedure A from 2-cyclohexen-1-one (58 μL, 0.60 mmol), cyclopentadiene (74 μL, 0.90 mmol), 70% aqueous perchloric acid (10.3 μL, 0.12 mmol), and (2S, 5S)-5-benzyl-3-methyl-2-(5-methyl-furan-2-yl)-imidazolidin-4-one (32.4 mg, 0.15 mmol) in water (150 μL) for 17 hours at 0° C. Purification by silica gel chromatography (5:1 pentane:ether) provided the title compound as a colorless oil in 81% yield (79 mg, 0.49 mmol); 12:1 endo:exo, endo 63% ee. For the purposes of characterization, the endo isomer was separated from the exo isomer by silica gel chromatography. IR (film) 3061, 2961, 2935, 2867, 1701, 1570, 1453, 1406, 1358, 1337, 1315, 1236, 1172, 1115, 1018, 910.6, 823.8, 779.2, 733.6, 561.5 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.15 (dd, J=5.7, 3.0 Hz, 1H, CH═CH), 5.99 (dd, J=5.7, 3.0 Hz, 1H, CH═CH), 3.24 (m, 1H, CHCH═CH), 2.85 (m, 1H, CHCH═CH), 2.66 (m, 2H, CH(H)CO and CHCO), 2.30 (m, 1H, one of CH2CO), 1.79 (m, 4H, CHCHCH2, COCH2CH2 and one of CHCHCH2), 1.42 (ddd, J=8.4, 1.8, 1.8 Hz, 1H, one of CHCH2CH), 1.28 (m, 1H, one of CHCH2CH), 0.73 (m, 1H, one of CHCHCH2); 13C NMR (75 MHz, CDCl3) δ215.7, 137.8, 135.1, 52.0, 48.7, 46.8, 45.5, 41.7, 39.7, 28.4, 22.2; HRMS (CI) exact mass calc'd for (C11H14O) requires m/z 162.1045, found m/z 162.1049. [α]D=+120.6 (c=1.0, CHCl3). Product ratios were determined by GLC analysis (130° C., 23 psi); (1R, 2R, 7R, 8R) endo isomer tr=13.4 min, and (1S, 2S, 7S, 8S) endo isomer tr=13.2 min, exo isomers tr=11.7, 12.3 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([C:27]([CH3:29])=[CH2:28])=[CH:15][C:10]=1[C:11]([O:13]C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([C:27]([CH3:29])=[CH2:28])=[CH:15][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)c1cc(C(=O)OC)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=C(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 89 %

Procedure:
Methyl 2,4-bis-benzyloxy-5-isopropenyl-benzoate (700 mg, 1.80 mmol) was dissolved in methanol (20 ml), a solution of potassium hydroxide (286 mg, 5.1 mmol) in water (4 ml) was added and the mixture was stirred and held at reflux for 3 hours. Upon cooling the solvent was removed in vacuo and the mixture acidified to pH 2 or below by the addition of 2M hydrochloric acid. The mixture was extracted with dichloromethane, the organic layer was separated and the solvent removed in vacuo to afford 2,4-bis-benzyloxy-5-isopropenyl-benzoic acid (600 mg, 89%) as a colourless solid. 1H NMR (DMSO-d6) 7.52 (2H, d), 7.47-7.29 (9H, m), 6.82 (1H, s), 5.20 (2H, s), 5.17 (2H, s), 5.06 (1H, s), 5.04 (1H, s), 2.03 (3H, s). MS: [M+H]+ 375.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][CH:11]1[CH2:16][CH2:15][C:14]([C:22]#[N:23])([C:17](OCC)=[O:18])[CH2:13][CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>C1COCC1.O.C1COCC1>[CH2:3]([O:10][CH:11]1[CH2:16][CH2:15][C:14]([CH2:17][OH:18])([C:22]#[N:23])[CH2:13][CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1(C#N)CCC(OCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC1(CO)CCC(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 116.9 %

Procedure:
To a solution of sodium borohydride (186 mg, 4.92 mmol, 2.5 equiv) in THF/H2O (5/0.5 mL) was added a solution of ethyl 4-(benzyloxy)-1-cyanocyclohexanecarboxylate (565 mg, 1.97 mmol, 1.0 equiv) in THF (dry, 3 mL) dropwise. The reaction mixture was stirred at room temperature for 18 hrs. It was concentrated to give the white solid. H2O (20 mL) was added. The aqueous phase was extracted with EtOAc (4×30 mL). The combined organic solution was washed with brine (30 mL), dried over anhydrous Na2SO4 and then concentrated to give 565 mg of crude 4-(benzyloxy)-1-(hydroxymethyl)cyclohexanecarbonitrile as a colorless sticky oil which was not purified and submitted for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.Br[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([O:8][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH:7]=1
Reactant: OCc1ccc(Cl)cc1O
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1cc(Cl)ccc1CO)c1ccccc1
Temperature: 100 °C
Yield: 76.7 %

Procedure:
Charged 5-chloro-2-(hydroxymethyl)phenol (787 mg, 4.96 mmol), (bromoethyl)benzene (1.01 g, 5.46 mmol), K2CO3 (1.37 g, 9.93 mmol) and DMF (8 mL) to a flask, heated to 100° C. overnight. Poured into ice water, and extracted with ethyl acetate twice, and washed the organic phase with water twice, brine and dried with anhydrous Na2SO4. Solvent was then removed and purified by flash column chromatograph to give 1.0 g of the title compound (77%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:22][S:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[C:28]([CH3:35])[C:27]=1[CH2:36][O:37][CH3:38])(=[O:25])=[O:24].[C:39]1(=[O:46])[CH2:44][CH2:43][CH2:42][C:41](=[O:45])[CH2:40]1>C(O)(CC)(C)C>[CH3:22][S:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([CH:40]2[C:41](=[O:45])[CH2:42][CH2:43][CH2:44][C:39]2=[O:46])=[O:32])=[C:28]([CH3:35])[C:27]=1[CH2:36][O:37][CH3:38])(=[O:24])=[O:25]
Reactant: COCc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Reactant: O=C1CCCC(=O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: COCc1c(S(C)(=O)=O)ccc(C(=O)C2C(=O)CCCC2=O)c1C
Temperature: 80 °C
Reaction time: 11 h
Yield: 7.3 %

Procedure:
1.3 g of potassium carbonate and 3.0 g of N,N'-dicyclohexylcarbodiimide were added to a solution mixture comprising 2.0 g of 4-methanesulfonyl-3-methoxymethyl-2-methylbenzoic acid, 0.9 g of 1,3-cyclohexanedione and 100 ml of t-amyl alcohol. The mixture was stirred at 80° C. for 11 hours. It was concentrated under reduced pressure, and then an aqueous potassium carbonate solution was added. Then, insoluble substances were removed by filtration. The filtrate was washed with chloroform, then acidified by an addition of concentrated hydrochloric acid and extracted with chloroform. The chloroform layer was washed with water and with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.1 g of a crude desired product. This crude product was recrystallized from ethanol to obtain 0.2 g of the desired product. Melting point: 192-198° C.
Reaction SMILES: S([CH2:11][N+:12]#[C-:13])(C1C=CC(C)=CC=1)(=O)=O.[N:14]1([CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3([CH:35]=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CO>[N:14]1([CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3([C:35]4[O:36][CH:13]=[N:12][CH:11]=4)[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[CH:25][CH:24]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ncc(C2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 2.1 %

Procedure:
Tosylmethyl isocyanide (370 mg, 1.89 mmol) was added to a solution of 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (500 mg, 1.58 mmol) and potassium carbonate (652 mg, 4.73 mmol) in methanol (7 ml). The reaction mixture was heated at reflux for 3 hours. The reaction mixture was partitioned between ethyl acetate (2×75 ml) and water (20 ml). The organic layers were combined, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was taken up in 2N hydrochloric acid (3 ml) and stirred at room temperature for 1.5 hours. The mixture was then partitioned between aqueous sodium carbonate and dichloromethane (2×75 ml). The combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 by volume) to provide the title compound (12 mg, 2%). 1H NMR (400 MHz, CD3OD) δ 1.81-1.85 (m, 4H), 1.97-2.02 (m, 2H), 2.25-2.31 (m, 2H), 2.38-2.43 (m, 2H), 2.60-2.63 (m, 4H), 2.69 (t, 2H), 3.61 (t, 2H), 3.78-3.83 (m, 2H), 4.01 (t, 2H), 6.87 (d, 2H), 6.98 (s, 1H), 7.22 (d, 2H), 8.09 (s, 1H). LRMS APCI+ m/z 357 [MH]+.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccccc1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Product: N=C(OCc1ccccc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and benzyl alcohol, there is obtained benzyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as an oil, mas spectrum m/e: M+ 328 (4), 237 (44), 194 (100), 179 (21), 165 (30), 91 (62);
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[F:8][C:9]1[CH:10]=[C:11]([CH:24]2[C:33]([CH3:35])([CH3:34])[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:36](O)=[O:37])[CH:30]=3)[NH:25]2)[CH:12]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)[CH:14]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[F:8][C:9]1[CH:10]=[C:11]([CH:24]2[C:33]([CH3:35])([CH3:34])[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:36]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:37])[CH:30]=3)[NH:25]2)[CH:12]=[C:13]([N:15]2[CH2:16][CH2:17][N:18]([CH:21]([CH3:22])[CH3:23])[CH2:19][CH2:20]2)[CH:14]=1
Reactant: CS(N)(=O)=O
Reactant: CC(C)N1CCN(c2cc(F)cc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(c2cc(F)cc(C3Nc4ccc(C(=O)NS(C)(=O)=O)cc4CC3(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
To a suspension of methanesulfonic acid amide (266 mg, 2.8 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (112 mg, 2.8 mmol). The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-[3-fluoro-5-(4-isopropyl-piperazin-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (120 mg, 0.28 mmol), and 1,1′-carbonyldiimidazole (91.5 mg, 0.56 mmol) in N,N-dimethylformamide (2 mL) was stirred at 70° C. for 1 h. The above suspension of methanesulfonic acid amide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{2-[3-Fluoro-5-(4-isopropyl-piperazin-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}methanesulfonamide (20 mg, 14%) as a white solid: LC/MS m/e calcd for C26H35FN4O3S (M+H)+: 503.7, observed: 503.3.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].C(O)CCCCC.N#N.[C:15](OCCCCCC)([CH3:18])([CH3:17])[CH3:16]>>[C:1]([O:5][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: CCCCCCOC(C)(C)C
Agent: N#N
Solvent: CCCCCCO
Product: CC(C)(C)OC(C)(C)C
Reaction time: 17 h

Procedure:
300 mmoles of t-butanol, 100 mmoles of 1-hexanol and 2.5 g of Ti-Si-catalyst powder are stirred in a 100 ml autoclave at a pressure of 40 bar N2 and a temperature of 150° C. over a period of 17 h, 17% of n hexanol were converted into hexyl t-butyl ether with a selectivity of 90%.