Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N:8]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[N:9]1.[CH2:16]([Cl:18])[Cl:17]>CN(C=O)C>[Cl:17][CH:16]([Cl:18])[C:11]1[CH:10]=[N:9][N:8]([CH3:7])[C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: ClCCl
Reactant: Cn1nccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ncc(C(Cl)Cl)c1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
To a solution of potassium tert-butoxide (157 ml, 1.0M in THF) and anhydrous DMF (40 ml) at −78° C. was added a mixture of 1-methyl-5-nitro-1H-pyrazole (5.0 g, 39 mmol) in anhydrous methylene chloride (3.5 mL) and anhydrous DMF (25 mL) via dropwise addition. The reaction was stirred at −78° C. for 30 minutes and quenched by the careful addition of acetic acid (20 mL) in methanol (40 mL). The resulting mixture was allowed to warm to room temperature and poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water and brine and dried over by sodium sulfate. Chromatography on silica gel with hexanes and ethyl acetate (3:12:1) gave 1.47 g of 4-dichloromethyl-1-methyl-5-nitro-1H-pyrazole (18%): 1H NMR (300 MHz, CDCl3) δ 7.88 (s, 1H), 6.85 (s, 1H), 4.23 (s, 3H); MS (m/e): 210.2 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OC(CC(C)C)[C:13]#[N:14].OS([O-])=O.[Na+].[C-]#N.[Na+]>O>[OH:10][CH:9]([CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]#[N:14]
Reactant: O=CCCc1ccccc1
Reactant: CC(C)CC(O)C#N
Agent: O=S([O-])O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#CC(O)CCc1ccccc1

Procedure:
2-Hydroxy-4-phenylbutanenitrile is prepared from 3-phenylpropionaldehyde according to the protocol described for 2-Hydroxy-4-methylpentanenitrile; (11.14 g, 83.2 mmol) 3-phenylpropionaldehyde, NaHSO3 (17.7 ml of solution at 37%, 83 mmol), (4.08 g, 83.2 mmol) of NaCN in H2O (18 ml). The product, a yellow oil, is used with no other purification (12.4 g, 93%); 1H NMR (100 MHz, CDCl3) δ: 2.02-2.25 (m, 2H), 2.76-2.91 (m, 2H), 3.98 (s, 1H), 4.39 (t, J=8 Hz, 1H), 7.26 (d, J=3 Hz, 5H); 13C NMR (25 MHz, CDCl3) δ: 30.49, 36.37, 59.92, 120.04, 126.28, 128.28, 128.49, 139.60. Analysis calculated for C10H11NO: C, 74.51; H, 6.88; N, 8.69. Experimental: C, 74.38; H, 6.97; N, 8.42.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([CH:11]1O[CH:14]=[N:13][CH:12]1S(C1C=CC(C)=CC=1)(=O)=O)[CH3:10].[NH3:26]>>[CH3:8][C:7]1[C:2]([CH3:1])=[C:3]([CH:9]([C:11]2[N:26]=[CH:14][NH:13][CH:12]=2)[CH3:10])[CH:4]=[CH:5][CH:6]=1
Reactant: N
Reactant: Cc1ccc(S(=O)(=O)C2N=COC2C(C)c2cccc(C)c2C)cc1
Product: Cc1cccc(C(C)c2c[nH]cn2)c1C
Temperature: 110 °C
Yield: 88.7 %

Procedure:
Compound of formula (23) (3.16 g, 8.84 mmol), prepared according to example 4, was dissolved in ammonia-saturated ethanol (40 ml, containing approximately 160 mmol ammonia) and heated to 110° C. for 3 h. The mixture was then evaporated to dryness, and the residue was mixed with an aqueous, saturated solution of NaHCO3 (20 ml). The mixture was extracted with toluene (2×20 ml), and the combined extracts were washed with water (2×20 ml). The combined extracts were then extracted with 10% aqueous HCl (3×20 ml), and the combined acidic extracts were basified with gaseous ammonia, and extracted with toluene (2×20 ml). The combined organic extracts were dried over Na2SO4, and concentrated under reduced pressure, to yield compound of formula (XX) (1.57 g, 89%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29](C)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:33]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:33])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N
Reactant: CC(C)OCCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Product: CC(C)OCCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3,4-difluorophenyl)-4-[2-(2-propoxy)ethoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 110 mg, 34%). mp 54-56° C. 1H NMR (300 MHz, DMSO-d6) δ 1.0 (d, 6H), 3.43 (m, 1H), 3.54 (m, 2H), 4.63 (m, 2H), 7.5 (m, 3H), 7.6 (m, 1H), 7.8 (m, 1H), 7.95 (m, 4H), 8.2 (s, 1H). MS (DCI/NH3) m/z 466 (M+H)+, 483 (M+NH4)+. Anal. calc. for C21H21F2N3O5S: C, 54.19; H, 4.55; N, 9.03. Found, C, 54.29; H, 4.67; N, 8.95.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11]O)[CH:5]=[C:6]([F:10])[C:7]=1[S:8][CH3:9].[Br-:13].FC1C=C(C=C(F)C=1SC)C=O>>[Br:13][CH2:11][C:4]1[CH:5]=[C:6]([F:10])[C:7]([S:8][CH3:9])=[C:2]([F:1])[CH:3]=1
Reactant: [Br-]
Reactant: CSc1c(F)cc(CO)cc1F
Agent: CSc1c(F)cc(C=O)cc1F
Product: CSc1c(F)cc(CBr)cc1F

Procedure:
The product from step B was converted to the bromide according to the procedure from intermediate 5 (step A). 1H NMR (500 MHz, CDCl3) δ 7.36 (d, J 7.5 Hz, 2H), 4.82 (s, 2H), 2.88 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:12]([OH:14])=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:12]([Cl:17])=[O:14])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C1(c2ccc(Cl)c(Cl)c2)CC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C1(c2ccc(Cl)c(Cl)c2)CC1

Procedure:
1-(3,4-Dichloro-phenyl)-cyclopropanecarboxylic acid (1 g, 4.35 mmol) was stirred in thionyl chloride (2 ml) at 37° for 72 h then the thionyl chloride was removed under reduced pressure the residue was rotovapped from benzene (×3) affording the title compound as a yellow oil. (1.1 g, quant) 1H NMR(400 MHz, CDCl3) δ 7.46 (dd, J=8.3 Hz, 4.4 Hz, 2H), 7.23 (d, J=8.3, 1H), 2.00 (dd, J=4.6, Hz, 7.6 Hz, 2H), 1.485(dd, J=4.6, Hz, 7.6 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:21]1[CH2:30][C@H:29]([O:31][CH2:32][CH2:33][OH:34])[CH2:28][C@H:22]1[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[C:39]([O:47][C:48]([F:51])([F:50])[F:49])[CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:43]([C:40]1[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][C:39]=1[O:47][C:48]([F:49])([F:50])[F:51])(=[O:45])=[O:44])[C:6](=[O:11])[C:5]2([N:21]1[CH2:30][C@H:29]([O:31][CH2:32][CH2:33][OH:34])[CH2:28][C@H:22]1[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccc(C)cc1C1(N2C[C@H](OCCO)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@H](OCCO)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 4.3 %

Procedure:
With 750 mg of the compound obtained in Step 141-4 and 491 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting material, 49 mg of the title compound (amorphous) was obtained by a similar procedure to Example 2. [α]D25=−113° (c=0.150, CHCl3)
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].N([O-])=O.[Na+].[N-:14]=[N+:15]=[N-].[Na+]>FC(F)(F)C(O)=O.O>[N:1]([C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccccc1CO
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: [N-]=[N+]=Nc1ccccc1CO
Reaction time: 0.75 h
Yield: 72.3 %

Procedure:
To a solution of 2-aminobenzyl alcohol (12.0 g, 97.4 mmol) in 50 mL of trifluoroacetic acid at 0° C. was added sodium nitrite (7.39 g, 107.2 mmol). This solution was stirred for 45 min and then there was added sodium azide (6.33 g, 97.4 inmol) dropwise as a solution in water. The resulting mixture was stirred at 0° C. for 45 min and then was carefully quenched by slow addition of potassium carbonate. The reaction mixture was diluted with ethyl acetate, washed with brine, dried (MgSO4), filtered through a pad of silica gel and concentrated to afford 10.5 g (72%) of the title compound which was used without further purification. 1H NMR (CDCl3) δ7.33 (m, 2H), 7.14 (m, 2H), 4.59 (s, 2H), 2.69 (broad s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4].[C:10]([OH:18])(=[S:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+].Cl>C(O)C>[C:10]([S:17][CH2:2][C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4])(=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OC(=S)c1ccccc1
Reactant: O=C(O)CNC(=O)CCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CNC(=O)CSC(=O)c1ccccc1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a stirring solution under argon at 0° C. of (1.50g, 10mmoles) N-chloroacetylglycine in (25 mL) ethanol was added (1.41 ml, 12 mmoles) thiobenzoic acid, followed by (7.0 mL, 3N, 21 mmoles) potassium hydroxide over 3 minutes. The reaction was allowed to heat to room temperature for 20 minutes followed by reflux under argon at 50° C. for 2 hours. The reaction was cooled to room temperature and acidified with (5 mL, 2N) hydrochloric acid. The ethanol was rotavapped off to leave N-(S-benzoylmercaptoacetyl)-glycine (m.p. 140.5°-141.5° C.), a white solid, which was washed with water, filtered, and dried in vacuo (2.46g, 98% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=2)=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.[CH3:50][S:51]([CH2:54][CH2:55][C:56](O)=[O:57])(=[O:53])=[O:52]>C(Cl)Cl.C(Cl)Cl.CO>[Cl:1][C:2]1[C:3]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=2)=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:56](=[O:57])[CH2:55][CH2:54][S:51]([CH3:50])(=[O:53])=[O:52])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1cnc(-c2cc(N3CCNCC3)ncc2Cl)c(C)c1
Reactant: CS(=O)(=O)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1cnc(-c2cc(N3CCN(C(=O)CCS(C)(=O)=O)CC3)ncc2Cl)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
To a solution of 5′-chloro-3,5-dimethyl-2′-(piperazin-1-yl)-2,4′-bipyridine (2.3 g, 15.1 mmol) and HOBT (2.55 g, 18.9 mmol) in CH2Cl2 (60 mL) was added NMM (5.67 g, 56.7). After stirring for 30 min at room temperature, EDCI (3.63 g, 18.9 mmol) and 3-(methylsulfonyl)propanoic acid (3.9 g, 12.6 mmol) were added and the mixture was stirred at 30° C. for 18 hours. TLC (CH2Cl2/MeOH=10:1) showed the starting material was consumed completely. After removal of the solvent in vacuo, the residue was dissolved in CH2Cl2 (180 mL), washed with saturated aq. NaHCO3 (40 mL), saturate aq. NH4Cl (40 mL) and brine (40 mL). The resulting material was dried over Na2SO4 and concentrated in vacuo to give title compound (4.8 g, 90%) as white solid. 1H NMR (400 MHz, CDCl3): δ 8.28 (s, 1H), 8.15 (s, 1H), 7.36 (s, 1H), 6.53 (s, 1H), 3.69-3.66 (m, 2H), 3.58-5.53 (m, 4H), 3.48-3.46 (m, 2H), 3.41-3.37 (m, 2H), 2.94 (s, 3H) 2.89-2.86 (m, 2H), 2.31 (s, 3H), 2.10 (s, 3H); m/z for C20H25ClN4O3S 437.3 (M+H)+.
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]1[CH2:10][C@H:9]([CH:11]([NH:13]S(C(C)(C)C)=O)[CH3:12])[CH2:8]1)(C)(C)C.[ClH:22]>CO>[ClH:22].[NH2:13][CH:11]([C@@H:9]1[CH2:10][C@H:7]([OH:6])[CH2:8]1)[CH3:12]
Reactant: CC(NS(=O)C(C)(C)C)[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: Cl
Solvent: CO
Product: CC(N)[C@H]1C[C@@H](O)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid {1-[cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclobutyl]-ethyl}-amide (200 mg, 0.60 mmol) in MeOH (3 mL) was added hydrogen chloride (4.0M in 1,4-dioxane, 0.30 mL, 1.2 mmol). The reaction mixture was stirred at room temperature for 20 min then concentrated to afford cis-3-(1-aminoethyl)-cyclobutanol hydrochloride as an off-white semisolid which was used without further purification. 1H NMR (METHANOL-d4, 300 MHz): δ (ppm) 4.09 (quind, J=7.5, 3.8 Hz, 1H), 3.17 (dt, J=6.0, 3.0 Hz, 1H), 2.36-2.56 (m, 2H), 1.78-1.96 (m, 1H), 1.59-1.77 (m, 2H), 1.22 (dd, J=6.8, 3.8 Hz, 3H).
Reaction SMILES: [C:1]([C:3](=[C:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH:17]=[CH:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)[C:4]([OH:6])=[O:5])#[N:2].[BH4-].[Na+]>CO>[C:1]([CH:3]([C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH:17]=[CH:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)[C:4]([OH:6])=[O:5])#[N:2]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=C(C#N)C(=O)O)CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2C(C#N)C(=O)O

Procedure:
5.2 g. of the methyl ester of 20-cyano-3-oxo-1,4,17(20)-pregnatriene-21-oic acid is reacted, under the conditions indicated in Example 9(b), in 150 ml. of methanol at 0° C. with 200 mg. of sodium borohydride. After a reaction time of 7 hours, the reaction mixture is worked up as described in Example 9(b), and after recrystallization from methanol, 4.92 g. of the methyl ester of 20-cyano-3-oxo-1,4-pregnadiene-21-oic acid is produced, m.p. 208°-210° C.
Reaction SMILES: S(=O)(=O)(O)N.[O:6]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl([O-])=[O:22].[Na+]>O.CC(C)=O>[O:6]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([OH:22])=[O:18])=[CH:19][CH:20]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: [O-][Cl+][O-]
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(Oc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 74 %

Procedure:
Sulfamic acid (7.35 g, 75.7 mmol) in water (5 mL) was added to a stirred solution of 4-phenoxy benzaldehyde (5 g, 25.23 mmol) in acetone (25 mL) at 4° C. Sodium chlorite (9.13 g, 100.9 mmol) in water (5 mL) was then added slowly resulting in formation of a yellow solid with effervescence. The mixture was stirred at the same temperature for 30 minutes. The reaction mixture was then diluted with cold water and the product extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated under reduced pressure to afford 4 g (74% yield) of 4-phenoxy benzoic acid. 1H NMR (DMSO): δ 7.98-7.92 (d, 2H), 7.5-7.44 (t, 2H), 7.28-7.2 (t, 1H), 7.16-7.1 (d, 2H), 7.06-7.0 (d, 2H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]=[CH:10][C:11](=[O:13])[CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:14]S(C)=O>>[C:3]1([CH:9]2[CH2:14][CH:10]2[C:11](=[O:13])[CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)C=Cc1ccccc1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Product: CC(=O)C1CC1c1ccccc1
Yield: 97 %

Procedure:
To Me3SOI (2.2 g, 10 mmol) in DMSO (20 mL) was added NaH (50%, 480 mg, 10 mmol). 4-Phenyl-but-3-en-2-one (1.13 g, 7.7 mmol) was added after 10 min. The reaction mixture was quenched after 30 min with water, extracted with EtOAc, and washed with water (3×30 mL). The organic extract was dried over MgSO4 and concentrated to give 1-(2-Phenyl-cyclopropyl)-ethanone (1.5 g, 97%).
Reaction SMILES: [NH2:1][C:2]1=[N:3][C:4](=[O:30])[N:5]([CH3:29])/[C:6]/1=[CH:7]/[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[C:25]([F:28])([F:27])[F:26])[CH2:10][CH2:9]1.[CH2:31](N)[C:32]#[CH:33]>C1(C)C=CC=CC=1>[F:27][C:25]([F:26])([F:28])[C:16]1[CH:17]=[C:18]([C:21]([F:22])([F:23])[F:24])[CH:19]=[CH:20][C:15]=1[CH2:14][N:11]1[CH2:12][CH2:13][CH:8](/[CH:7]=[C:6]2\[C:2]([NH:1][CH2:33][C:32]#[CH:31])=[N:3][C:4](=[O:30])[N:5]\2[CH3:29])[CH2:9][CH2:10]1
Reactant: CN1C(=O)N=C(N)/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: C#CCN
Solvent: Cc1ccccc1
Product: C#CCNC1=NC(=O)N(C)/C1=C/C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a solution of (5E)-4-amino-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-1-methyl-1,5-dihydro-2H-imidazol-2-one (133 mg) in toluene (1 mL) was added propargylamine (843 mg) at room temperature. The reaction mixture was stirred at 100° C. overnight. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (87 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:25](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:17][C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:25])[C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CNCc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](N[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-3-Methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5.4 g, 25.3 mmol) was dissolved in dichloromethane (75 mL). S-(−)-□-Methylbenzylamine (3.1 g, 3.2 mL, 25.3 mmol) was added followed by sodium triacetoxyborohydride (10.7 g, 50.6 mmol). The reaction was stirred at room temperature overnight. LC/MS analysis revealed four components, with only one component clearly separated. The reaction was diluted with dichloromethane (150 mL) and extracted water (2x), brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to afford a white foam that was purified by flash column chromatography (84.5:15:0.5 dichloromethane:acetonitrile:NH4OH) to afford a clear oil. This material was rechromatographed (89.5:10:0.5 dichloromethane:acetonitrile:NH4OH) to afford the title compound as a clear oil. Wt.: 820 mg (10%). 1H NMR (300 MHz, CDCl3) δ 7.31 (m, 3H), 7.22 (m, 2H), 3.85 (m, 3H), 2.68 (m, 1H), 2.46 (m. 1H), 2.17 (m, 1H), 1.67 (m, 1H), 1.40 (s, 9H), 1.30 (d, 3H), 1.08 (m, 2H), 0.97 (d, 3H); LC/MS m/z 319 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8](Br)[CH2:7][CH2:6]1.[Cl:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][SiH:26](Cl)[CH2:25][CH2:24]2)=[CH:16][C:15]=1[F:30]>>[Cl:13][C:14]1[C:15]([F:30])=[CH:16][C:17]([O:21][CH2:22][C@H:23]2[CH2:24][CH2:25][Si@H:26]([C@H:8]3[CH2:9][CH2:10][C@H:5]([CH2:4][CH2:3][CH:2]([CH3:12])[CH3:1])[CH2:6][CH2:7]3)[CH2:27][CH2:28]2)=[CH:18][C:19]=1[F:20]
Reactant: Fc1cc(OCC2CC[SiH](Cl)CC2)cc(F)c1Cl
Reactant: CC(C)CCC1CCC(Br)CC1
Product: CC(C)CC[C@H]1CC[C@H]([Si@H]2CC[C@H](COc3cc(F)c(Cl)c(F)c3)CC2)CC1

Procedure:
The general procedure of Example 36 was repeated using 4-(3-methylbutyl)cyclohexyl bromide and 4-(4-chloro-3,5-difluorophenyloxyrnethyl)-1-chloro-1-silacyclohexane, thereby obtaining the intended product.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH2:15]([NH:22][C:23](=[O:26])[CH:24]=[CH2:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>>[CH2:15]([NH:22][C:23](=[O:26])[CH2:24][CH2:25][N:11]1[CH2:12][CH2:13][C:14]2=[C:2]([CH3:1])[C:3]3[C:8]([CH:9]2[CH2:10]1)=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1=C2CCNCC2c2ccccc21
Reactant: C=CC(=O)NCc1ccccc1
Agent: Cl
Product: CC1=C2CCN(CCC(=O)NCc3ccccc3)CC2c2ccccc21

Procedure:
1,3,4,9b-Tetrahydro-5-methyl-2H-indeno[1,2-c]pyridine and N-benzyl acrylamide are reacted in accordance with the process described in Example 6. Reaction period 8 hours. M.P. of the hydrochloride of the title compound 211°-212.5° from ethanol (decomp.).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C)C=O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH:21]([O:27][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:19]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(O)Cc1ccc(OCCN2CCOc3ccccc32)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCCN2CCOc3ccccc32)cc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
A solution of ethyl 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate (0.5 g, 1.34 mmol) obtained in example 13 in dry dimethyl formamide (5 mL) was added to a stirred ice cooled suspension of sodium hydride (60% dispension in oil) (0.08 g, 1.66 mmol) in dry dimethyl formamide (3 mL) under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 30 minutes followed by the addition of benzyl bromide (0.46 g, 2.69 mmol). The mixture was allowed to warm to 25° C. and stirring was continued for fuirther 18 h. Water (25 mL) was added and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with water (50 mL), brine (50 mL) and dried Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (2:8) as eluent to afford the title compound (0.3 g) along with benzyl 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoate. This mixture (1:1) is used in example 47 without any separation.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]([CH3:44])=[C:6]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:7]([C:14]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=2[O:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]2C(=O)C3=CC=CC=C3C2=O)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].O.NN>C(O)C>[NH2:28][CH2:27][CH2:26][CH2:25][CH2:24][O:23][C:15]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=1[CH:7]1[C:6]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:5]([CH3:44])[NH:4][C:3]([CH2:1][CH3:2])=[C:8]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1=C(C)NC(CC)=C(C(=O)OCC)C1c1cc([N+](=O)[O-])ccc1OCCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(CC)=C(C(=O)OCC)C1c1cc([N+](=O)[O-])ccc1OCCCCN
Yield: 65.7 %

Procedure:
A solution of 12.4 g of diethyl 2-ethyl-4-[2-(4-phthalimidobutoxy)-5-nitrophenyl]-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate and 10.4 g of hydrazine monohydrate in 270 ml of 95% ethanol (water: 5%) was refluxed under heating for 10 hours. After cooling the reaction solution, the solution was concentrated under reduced pressure, and the residue was extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Crude crystals thus obtained were recrystallized from chloroform-ether to give 6.4 g of diethyl 4-[2-(4-aminobutoxy)-5-nitrophenyl]-2-ethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:13][Br:14])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(Br)ccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(Br)ccc1CBr
Temperature: 70 °C
Yield: 76.1 %

Procedure:
A mixture of ethyl 5-bromo-2-methylbenzoate (7.52 g, 30.9 mmol), N-bromosuccinimide (6.05 g, 34.0 mmol) and benzoyl peroxide (0.75 g, 3.10 mmol) in carbon tetrachloride (150 ml) was heated to 70° C. in an oil bath for 18 h. After this time, the mixture was cooled to room temperature and the solids removed by filtration. The filtrate was then concentrated under reduced pressure and purified by flash chromatography (silica, gradient 1-10%, ethyl acetate/hexanes) afforded ethyl 5-bromo-2-(bromomethyl)benzoate (7.57 g, 76%) as a clear oil: 1H NMR (300 MHz, CDCl3) 8.09 (d, J=2.2 Hz, 1H), 7.61 (dd, J=8.3, 2.2 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 4.90 (s, 2H), 4.42 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H).