Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH2:30]([C@H:34]1[CH2:39][CH2:38][C@H:37]([C@H:40]2[CH2:45][CH2:44][C@H:43]([CH:46]=O)[CH2:42][CH2:41]2)[CH2:36][CH2:35]1)[CH2:31][CH:32]=[CH2:33]>C1COCC1>[CH3:2][O:3][CH:4]=[CH:46][C@H:43]1[CH2:42][CH2:41][C@H:40]([C@H:37]2[CH2:36][CH2:35][C@H:34]([CH2:30][CH2:31][CH:32]=[CH2:33])[CH2:39][CH2:38]2)[CH2:45][CH2:44]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C=O)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C=COC)CC2)CC1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
A mixture of 66.4 g (193.7 mmol) of methoxymethyltriphenyl phosphonium chloride and 600 ml of THF was cooled to −50° C. under a gas stream of nitrogen. To the mixture, 20.1 g (179.1 mmol) of t-BuOK was added and stirred for 1 hour. To the mixture, a solution of 37.0 g (148.9 mmol) of trans-4-(trans-4-(3-_butenyl)cyclohexyl)cyclohexane carbaldehyde in 400 ml of THF was added dropwise with maintaining the temperature below −50° C. After dropwise addition, the reaction temperature was increased gradually to the room temperature, and stirring was carried out further for 5 hours. The solvent was distilled off under a decresed pressure, 250 ml of water was added and the mixture was extracted with 300 ml of toluene. The organic layer was washed with 200 ml of water for three times and dried with anhydrous magnesium sulphate. The solvent was distilled off under a decreased pressure, and the residue was subjected to silica gel column chromatography (eluent: a mixed solvent of toluene/heptane=3/7), to obtain 16.1 g of crude 1-(2-methoxyethenyl)-trans-4- (trans-4-(3-butenyl) cyclohexyl) cyclohexane.
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:12]=[C:11]([NH:18][C:19]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([NH:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34])=[CH:25][CH:24]=3)=[O:20])[CH:10]=1)=[O:8])(=[NH:3])[NH2:2].Cl.[N:37]1([C:42](N)=[NH:43])C=CC=N1>>[C:1]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:12]=[C:11]([NH:18][C:19]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([NH:30][C:31](=[O:35])[CH2:32][CH2:33][NH:34][C:42]([NH2:43])=[NH:37])=[CH:25][CH:24]=3)=[O:20])[CH:10]=1)=[O:8])(=[NH:2])[NH2:3]
Reactant: N=C(N)n1cccn1
Reactant: CC(C)Cn1cc(NC(=O)c2cc3cc(NC(=O)CCN)ccc3[nH]2)cc1C(=O)NCCC(=N)N
Agent: Cl
Product: CC(C)Cn1cc(NC(=O)c2cc3cc(NC(=O)CCNC(=N)N)ccc3[nH]2)cc1C(=O)NCCC(=N)N
Yield: 26 %

Procedure:
Compound 114 was treated with 1H-pyrazole-1-carboxamidine hydrochloride according to the procedure for 47 to give compound 115. Yield: 26%. MS: 262.17 (M/2+H+). 1H-NMR (DMSO-d6): 11.51 (s, 1H), 10.25 (s, 1H), 9.93 (s, 1H), 8.89 & 8.60 (2br s, 3H), 8.25 (t, 1H), 7.99 (s, 1H), 7.51 (t, 1H), 7.37 (d, 1H), 7.26 (d, 1H), 7.25 (s, 1H), 7.19 (d, 1H), 6.92 (d, 1H), 4.11 (d, 2H), 2.59 (t, 2H), 1.98 (m, 1H), 0.80 (d, 6H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([F:23])=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[O:30][CH2:31][CH2:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(C)=O>[F:23][C:13]1[C:12]([CH2:11][C:8]2[N:6]3[N:7]=[C:2]([C:36]4[CH:35]=[N:34][N:33]([CH2:32][CH2:31][O:30][CH:25]5[CH2:26][CH2:27][CH2:28][CH2:29][O:24]5)[CH:37]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[C:21]([F:22])[CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2
Reactant: Fc1cc2ncccc2c(F)c1Cc1cnc2ccc(Cl)nn12
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Fc1cc2ncccc2c(F)c1Cc1cnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nn12
Temperature: 150 °C

Procedure:
6-(6-Chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-5,7-difluoro-quinoline (Stage 171.2, 90 mg, 0.272 mmol) was introduced in a microwave reactor together with 1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Stage 171.4, 88 mg, 0.272 mmol), tetrakis-(triphenylphosphine)-palladium (15.72 mg), 2 M Na2CO3 (0.490 mL) and DME (0.9 mL). The mixture was heated at 150° C. under microwave irradiation for 30 min. The RM was taken up with EtOAc and washed with 10% Na2CO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in MeOH and filtered through a cartridge of PL-Thiol to remove the palladium. The filtrate was then purified by preparative HPLC with acetonitrile and water (+0.1% TFA) to afford the title compound (tR 1.1 min (conditions 2), MH+=491).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:26][C@H:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][CH3:29])[CH2:5][C:6]1[CH:25]=[CH:24][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.C=O.F[C:40](F)(F)C(O)=O.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:5][C:6]2[CH:7]=[C:8]3[O:13][CH2:12][C@H:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:19]=4)[O:10][C:9]3=[CH:24][C:25]=2[CH2:40][N:26]1[C@H:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][CH3:29])=[O:36]
Reactant: CC[C@H](N[C@@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OC(C)=O)cc1)O2)C(=O)OC)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(OC(C)=O)cc1)O3
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(S)-3-[(S)-2-(4-Acetoxy-phenyl)-2,3-dihydro-benzo[1,4]dioxin-6-yl]-2-((S)-1-phenyl-propylamino)-propionic acid methyl ester (110 mg) was dissolved in 32 mL dry dioxane and 20 mg paraformaldehyde and 8 mL trifluoroacetic acid were added. The reaction stirred 48 h at rt. NaHCO3 was added until a pH of 7 was achieved, then the mixture was extracted with EtOAc. The organic extract was washed with brine and dried over Na2SO4 and evaporated. The residue was purified by silica gel flash chromatography (9:1 to 8:2 hexanes/EtOAc) to give 120 mg desired product. LCMS (m/z): 503.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>CO>[CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(-n2cnnn2)ccc1SC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1ccc(-n2cnnn2)cc1C(=O)O
Reaction time: 2 h

Procedure:
Combine methyl 2-methylthio-5-(1H-tetrazol-1-yl)benzoate (0.5 g, 2.0 mmol) and a 1 M aqueous solution of sodium hydroxide (20 mL, 20 mmol) in methanol (20 mL). After 2 hours, adjust the pH to about 2 using a 1 M aqueous hydrochloric acid solution and extract with ethyl acetate. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to give the title compound: Rf=0.70 (silica gel, 10% methanol/85% chloroform/5% acetic acid).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]([F:51])([F:50])[C:14]1[CH:15]=[C:16]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:17][N:18]1[C:22]([N:23]2[CH2:28][CH2:27][S:26][CH2:25][CH2:24]2)=[C:21]([C:29]2[N:33]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[Cl:41])[C:32]([CH3:42])=[N:31][N:30]=2)[N:20]=[N:19]1>C1COCC1>[F:51][C:13]([F:50])([F:12])[C:14]1[CH:15]=[C:16]([CH:43]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:45]=1)[CH2:17][N:18]1[C:22]([N:23]2[CH2:28][CH2:27][S:26](=[O:9])[CH2:25][CH2:24]2)=[C:21]([C:29]2[N:33]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[Cl:41])[C:32]([CH3:42])=[N:31][N:30]=2)[N:20]=[N:19]1
Reactant: Cc1nnc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2N2CCSCC2)n1Cc1ccccc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: Cc1nnc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2N2CCS(=O)CC2)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add m-chloro-perbenzoic acid (29 mg, 0.13 mmol) to a solution of 4-{3-(3,5-bis-trifluoromethyl-benzyl)-5-[4-(2-chloro-benzyl)-5-methyl-4H-[1,2,4]triazol-3-yl]-3H-[1,2,3]triazol-4-yl}-thiomorpholine (69 mg, 0.11 mmol) in THF (1 mL) at −78° C. After 30 minutes, quench with 1N Na2S2O3 at −78° C., warm to RT. Dilute with 20% i-PrOH/CHCl3, wash with 1N HCl, saturated NaHCO3 solution, and brine. Dry the combined organic layers over MgSO4 and concentrate. Purify the residue by flash chromatography on silica gel eluting with 0-4% MeOH/CHCl3 to afford the title compound: MS(IS) 618 (M+1). TLC: Rf=0.18 (5% MeOH/CHCl3).
Reaction SMILES: B(F)(F)F.CCOCC.[F:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21](O)([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C@@H:22]([C:26]2[CH:38]=[CH:37][C:29]([C:30]([O:32]C(C)(C)C)=[O:31])=[CH:28][CH:27]=2)[CH2:23][CH2:24][CH3:25])=[CH:13][CH:12]=1>C(Cl)Cl.CCOC(C)=O>[F:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]([C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[C@@H:22]([C:26]2[CH:38]=[CH:37][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)[CH2:23][CH2:24][CH3:25])=[CH:13][CH:12]=1
Reactant: CCC[C@H](c1ccc(C(=O)OC(C)(C)C)cc1)C(O)(c1ccc(OC)cc1)c1ccc(F)c2ccccc12
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCC[C@H](c1ccc(C(=O)O)cc1)C(c1ccc(OC)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Boron trifluoride diethyl etherate (0.074 mL, 0.583 mmol) was added dropwise to a solution of tert-butyl 4-{(1R)-1-[(4-fluoro-1-naphthyl)(hydroxy)(4-methoxyphenyl)methyl]butyl}benzoate (150 mg, 0.291 mmol) in DCM (2 mL) at 0° C. The solution was allowed to warm to RT and stirred overnight. The solution was diluted with EtOAc (30 mL) then washed with water and brine. The organic layer was dried over MgSO4, filtered, then concentrated to provide the title compound which was used directly in the next step without further purification. LC1 1.20 min. [M+H]+ 442.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:22]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[CH:3]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc(N)ccn2)CC1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccnc(N2CCN(C(=O)OCC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,2-Dimethylpropyl 4-(4-aminopyridin-2-yl)-1-piperazinecarboxylate (105 mg) obtained in Example 20 was dissolved in pyridine (2 mL), acetic anhydride (0.1 mL) was added thereto, and stirred at room temperature for 3 hours, and the reaction liquid was diluted with chloroform, washed with saturated sodium hydrogencarbonate and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (chloroform/methanol=19/1) to obtain 52 mg of the entitled compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:41])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)(=[O:32])=[O:31])=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:44]1([CH2:50][CH2:51][NH:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:41])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:47]3[CH2:48][CH2:49][N:44]([CH2:50][CH2:51][NH:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH2:45][CH2:46]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)(=[O:31])=[O:32])=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(S(=O)(=O)N2CCCC2)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)NCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(S(=O)(=O)N2CCCC2)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(pyrrolidine-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with N-(2-piperazin-1-yl-ethyl)-methanesulfonamide dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C37H46N6O6S2Cl2 [(M+H)+] 805.2370, observed 805.2372.
Reaction SMILES: C[O:2][P:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:6])[O:4]C>Cl>[C:9]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][P:3](=[O:2])([OH:6])[OH:4]
Reactant: COP(=O)(Cc1ccccc1-c1ccccc1)OC
Agent: Cl
Product: O=P(O)(O)Cc1ccccc1-c1ccccc1
Yield: 64.8 %

Procedure:
A solution of ([1,1 '-Biphenyl]-2-ylmethyl)phosphonic acid dimethyl ester (Compound 6, 515 mg, 1.87 mM) in concentrated hydrochloric acid (5 mL) is heated at reflux temperature for six hours. The reaction is then allowed to stand at room temperature until a white precipitate is formed. The aqueous HCl is removed under reduced pressure. The white solid is recrystallized from water to yield 300 mg of title compound as white crystals, mp 168.5°-169° C.
Reaction SMILES: C(O)=O.[O:4]1CCCO[CH:5]1[CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([CH:18]2[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[CH2:20][CH2:19]2)[CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[F:33][C:32]([F:34])([F:35])[C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][CH:21]2[CH2:20][CH2:19][CH:18]([CH:15]3[CH2:16][CH2:17][CH:12]([CH2:11][CH2:10][CH:5]=[O:4])[CH2:13][CH2:14]3)[CH2:23][CH2:22]2)=[CH:31][CH:30]=1
Reactant: FC(F)(F)c1ccc(CCC2CCC(C3CCC(CCC4OCCCO4)CC3)CC2)cc1
Solvent: O=CO
Solvent: Cc1ccccc1
Product: O=CCCC1CCC(C2CCC(CCc3ccc(C(F)(F)F)cc3)CC2)CC1
Yield: 95 %

Procedure:
Formic acid (1.5 g, 33 mmol) and toluene (10 ml) were added to the above 4-(4-(1,3-dioxan-2-ylethyl)cyclohexyl)-1-(2-(4-trifluoromethylphenyl)ethyl)cyclohexane (1.46 g, 3.23 mmol), followed by refluxing the mixture for 5 hours, washing the organic layer successively with a saturated, aqueous solution of sodium bicarbonate and water, drying over magnesium sulfate, and distilling off the solvent, to obtain 3-(4-(4-(2-(4-trifluoromethylphenyl)ethyl)cyclohexyl)cyclohexyl)propanal (1.21 g, 3.07 mmol). Yield: 95.0%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:13][C:14](=O)[CH3:15])[CH:11]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C([O-])(=O)C.[NH4+:21].C(O)(=O)C>C1(C)C(C)=CC=CC=1>[CH3:15][C:14]1[N:21]=[CH:11][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:13]=1
Reactant: CC(=O)CN(C=O)c1cccc([N+](=O)[O-])c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: Cc1cn(-c2cccc([N+](=O)[O-])c2)cn1
Reaction time: 0.17 h
Yield: 83.8 %

Procedure:
A suspension of N-(3-nitrophenyl)-N-(2-oxo-propyl)-formamide (265 mg), ammonium acetate (919 mg) and acetic acid (0.3 ml) in xylene (5 ml) was refluxed for 2.5 hours and then evaporated under reduced pressure. To the residue were added ethyl acetate and an aqueous solution of sodium hydroxide (1N, 25 ml), and the mixture was stirred for 10 minutes. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated to give 4-methyl-1-(3-nitrophenyl)imidazole (203 mg, 83.9%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[O:6][CH2:5]2.[CH3:24][N:25](C)C=O.C(N)CN>C1(C)C=CC=CC=1>[CH3:22][N:21]([CH2:20][CH2:19][CH2:18][C:7]1([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[O:6][CH2:5][C:4]2[CH:3]=[C:2]([C:24]#[N:25])[CH:10]=[CH:9][C:8]1=2)[CH3:23]
Reactant: CN(C)C=O
Reactant: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(Br)ccc21
Solvent: NCCN
Solvent: Cc1ccccc1
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 145 °C

Procedure:
Cuprous cyanide (85.4 g, 0.95 mol) was added to 5-bromo-1-(3-dimethylaminopropyl) 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran (200 g, 0.53 mol) and contents were heated to 140-150° C. After completion of reaction, N,N-dimethylformamide (200 ml) was added and reaction mass was further diluted with toluene (500 ml). The reaction mixture was cooled to 80° C. where aqueous ethylenediamine (50% w/v) was added and layers were separated. The organic layer was washed sequentially with aqueous EDTA (2% w/v) and water (2×200 ml). The organic layer was concentrated under reduced pressure to remove toluene. The residue was distilled in vacuum and crude Citalopram was obtained as oil. Yield: 110 g. The crude product contained 7% of desmethyl citalopram by HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:12])[CH:3]=1.[CH3:13][Mg]Cl>C1COCC1>[Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]([CH3:13])[OH:7])=[C:4]([F:12])[CH:3]=1
Reactant: C[Mg]Cl
Reactant: COc1cc(C=O)c(F)cc1Cl
Solvent: C1CCOC1
Product: COc1cc(C(C)O)c(F)cc1Cl
Temperature: 25 °C
Yield: 95.6 %

Procedure:
A stirred solution of 10.4 g of 4-chloro-2-fluoro-5-methoxybenzaldehYde in 150 mL of anhydrous THF was cooled in a dry ice-acetone bath and treated with 35 mL of a 3M solution of methyl magnesium chloride in THF over a period of one minute. The ice bath was removed and the mixture allowed to warm to room temperature. After warming, the solution was slowly poured into ice water. The water slurry was extracted three times with diethyl ether, the ether extracts dried and concd to afford a crude oil. Crystallization from hexanes yielded 10.8 g (95.6%) of 4-chloro-2-fluoro-5-methoxy-α-methylbenzenemethanol: mp 68.5°-69.5° C. This benzenemethanol intermediate was dissolved in 100 mL of acetone, cooled in an ice water bath and treated dropwise with 50 mL of freshly prepared Jones' reagent (prepared from 6.7 g of CrO3, 6 mL of H2SO4 and 50 mL of water), keeping the temperature below 10° C. After stirring for 2 hrs, the solution was diluted with water and extracted three times with methylene chloride. The organic extracts were dried and concd to give a crude product. Recrystallization from methanol yielded 9.66 g (90.3%) of 1-(4-chloro-2-fluoro-5-methoxyphenyl)ethanone as a white solid: mp 96.5°-98.5° C.; 1HNMR (CDCl3) δ2.50 (d, 3H, 5.4 Hz), 3.80 (s, 3H), 7.10 (d, 1H, 10.1 Hz), 7.30 (d, 1H, 6.3 Hz).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[C:13]1([CH3:23])[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][NH2:22])=[O:20])[CH:14]=1>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:22][NH:21][C:19](=[O:20])[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH3:23])[CH:14]=1
Reactant: Cc1cccc(C(=O)NN)c1
Reactant: O=Cc1ccc2ccccc2n1
Solvent: CCO
Product: Cc1cccc(C(=O)NN=Cc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 36.2 %

Procedure:
A mixture of 3.3 gm (0.021 mole) of 2-quinolinecarboxaldehyde, 3.15 gm (0.021 mole) of m-toluic acid hydrazide and 150 ml of absolute ethanol is refluzed 10 hr. The hot solution is filtered then diluted with water until cloudy. The mixture is cooled to room temperature and then chilled. The solid is collected to give 2.2 gm (36%) of the title compound having a melting point of 187.5°-188° C. after recrystallizing from methylene chloride/diethyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)([SH:15])[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:25].[OH-].[K+].[NH2:28]OS(O)(=O)=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C:10]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=3)([C:11]([F:14])([F:13])[F:12])[S:15][N:28]=2)=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(C(=O)CC(S)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Reactant: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cc(C2=NSC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-Bromo-3-methyl-phenyl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-mercapto-butan-1-one (382 mg) in a solution of potassium hydroxide (162 mg in 8 mL of water) was added a solution of Hydroxylamine-O-sulfonic acid (2 equiv.) in a solution of potassium hydroxide (243 mg in 16 mL of water). After stirring at room temperature for 30 minutes, the mixture was diluted with ethyl acetate, and washed with brine. The collected organic phases were dried over magnesium sulfate, filtered and the filtrate was evaporated under vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/dichloromethane) to give 3-(4-Bromo-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isothiazole (184 mg).
Reaction SMILES: N1C2C(=CC=CC=2)C=NC=1.N1C2C(=CC=CC=2)N=CC=1.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[N:23][N:22]=1.N1C2C(=CC=CN=2)C=CC=1>>[N:22]1[C:21]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:25]=[CH:24][N:23]=1
Reactant: c1ccc2cnncc2c1
Agent: c1ccc2nccnc2c1
Agent: c1ccc2ncncc2c1
Agent: c1cnc2ncccc2c1
Product: c1ccc2nnccc2c1

Procedure:
quinazoline; quinoxaline; phthalazine; or naphthyridine;
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35]CC=C)=[CH:31][CH:30]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:39][O:40][C:41](=[O:43])[CH3:42])[CH2:7][O:8]2)(=[O:3])[CH3:2].CN1C(=O)CC(=O)N(C)C1=O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:39][O:40][C:41](=[O:43])[CH3:42])[CH2:7][O:8]2)(=[O:3])[CH3:2]
Reactant: C=CCOc1ccc(Cc2cc([C@]34OC[C@](COC(C)=O)(O3)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc2Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: C1CCOC1
Product: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(O)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Temperature: 90 °C
Yield: 94.4 %

Procedure:
To a solution of (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(3-(4-(allyloxy)benzyl)-4-chlorophenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (0.6 g, 0.973 mmol) in dry THF (10 mL), was added Pd(PPh3)4 (337 mg, 0.29 mmol) followed by 1,3-dimethyl barbituric acid (1.57 g, 9.73 mmol). The reaction mixture was then refluxed at 90° C. for 1 h. After the completion of reaction as monitored by TLC, the reaction was quenched with saturated solution of NaHCO3 (10 mL), diluted with ethyl acetate (100 mL) and then washed with water (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4 and volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 5:5 Ethyl acetate:Pet. Ether) to provide title compound (0.53 g, 94%).