Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C1(C)C=CC=CC=1>[C:15]1([C:2]2[C:7]3[O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: Ic1cccc2c1oc1ccccc12
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(-c2cccc3c2oc2ccccc23)cc1
Temperature: 25 °C

Procedure:
4-iododibenzo[b,d]furan (4 g, 13.60 mmol), phenylboronic acid (1.99 g, 16.32 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (0.447 g, 1.08 mmol), Pd2(dba)2 (0.250 g, 0.272 mmol), K3PO4 (10.1 g, 47.6 mmol), 150 mL toluene and 15 mL water were charged in a 250 mL flask. The reaction mixture was degassed by bubbling N2 for 30 minutes and then heated to reflux under N2 overnight. The reaction was cooled to room temperature and the crude product was purified by silica gel column to yield 3.3 g (99%), which was confirmed by GC-MS.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:18][S:19][C@H:20]4[C:23](=[O:24])[N:22]([C:25]5[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=5)[C@@H:21]4[C:32]4[CH:46]=[CH:45][C:35]([O:36][CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])=[CH:34][CH:33]=4)OCC(C)(C)C[O:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1>C(O)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:11])[CH2:18][S:19][C@H:20]3[C:23](=[O:24])[N:22]([C:25]4[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=4)[C@@H:21]3[C:32]3[CH:46]=[CH:45][C:35]([O:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:34][CH:33]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(N2C(=O)[C@H](SCC3(c4ccc5c(c4)OCO5)OCC(C)(C)CO3)[C@H]2c2ccc(OCC(=O)OC(C)(C)C)cc2)cc1
Solvent: O=CO
Product: Cc1ccc(N2C(=O)[C@H](SCC(=O)c3ccc4c(c3)OCO4)[C@H]2c2ccc(OCC(=O)O)cc2)cc1
Reaction time: 0.5 h

Procedure:
tert-Butyl {4-[(2R,3R)-3-({[2-(1,3-benzodioxol-5-yl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl}thio)-1-(4-methylphenyl)-4-oxoazetidin-2-yl]phenoxy}acetate (Method 21) (0.21 g, 0.32 mmol) was dissolved in formic acid (10 mL) at room temperature and stirred for 30 minutes. The mixture was concentrated under reduced pressure (temperature<30° C.) and this crude oil was purified by flash-chromatography (heptane:acetone:formic acid 6:4:0.01) to afford the title compound.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]([NH:36][CH:37]([C:40](=[O:43])[CH2:41][CH3:42])[CH2:38][CH3:39])=O)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].P(Cl)(Cl)(Cl)=O>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[O:43][C:40]([CH2:41][CH3:42])=[C:37]([CH2:38][CH3:39])[N:36]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(C(=O)NC(CC)C(=O)CC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1nc2c(C)cc(-c3nc(CC)c(CC)o3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 170 from tert.butyl 4'-[[2-n-propyl-4-methyl-6 -[N-(1-propionyl-n-propyl)-aminocarbonyl]-1H-benzimidazol-1-yl ]-methyl]-biphenyl-2-carboxylate and phosphorusoxychloride
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][S-:12].[Na+]>C1(C)C=CC=CC=1>[F:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([S:12][CH3:11])[CH:9]=1
Reactant: O=Cc1ccc(F)cc1F
Reactant: C[S-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CSc1cc(F)ccc1C=O
Temperature: 80 °C
Reaction time: 7 h
Yield: 37.6 %

Procedure:
To a solution of 2,4-difluorobenzaldehyde (3.0 g, 21.1 mmol, CAS RN 1550-35-2) in toluene (29 mL) was added sodium thiomethoxide (2.03 g, 28.9 mmol) and the resulting suspension was stirred at 80° C. for 7 hours. Heating was removed and stirring continued at room temperature for another 18 hours. The reaction mixture was treated with diethyl ether (50 mL) and water (15 mL) and the layers were separated. The aqueous layer was extracted twice with ethyl acetate (50 mL each). The organic layers were washed with saturated aqueous sodium hydrogencarbonate solution and with brine, dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in 50 mL n-heptane and 50 mL diethyl ether and the clear solution was evaporated slowly until a turbid solution formed. The originally oily precipitation turned into a white solid which was filtered, washed with n-heptane and dried under high vacuum to give the compound as a colourless solid (1.35 g, 37%). MS (ESI+): m/z=170.0 ([M+H]+).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[C:10](=S)=[S:11].N#CCl>C(Cl)Cl.O>[CH:1]1([N:7]=[C:10]=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=C=S
Reactant: NC1CCCCC1
Agent: N#CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: S=C=NC1CCCCC1
Yield: 98.4 %

Procedure:
In one hour 0.5 mole of cyclohexyl amine, 0.5 mole of sodium hydroxide and 60 grams of water were treated with 0.5 mole of carbon disulfide. The N-cyclohexyl sodium dithiocarbamate solution was stirred for a further hour at 50° C. There were added 1,000 cc of water, 20 grams of sodium hydroxide and 250 cc of methylene chloride. Under stirring there were led in at 6° C, 0.515 mol of cyanogen chloride. After the separation the methylene chloride layer was distilled. There were isolated 69.5 grams of cyclohexyl isothiocyanate (B.P. 98.5° C/13 mm Hg), corresponding to a yield of 98.4% of theory.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:7][N:6]1[S:20]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)(=[O:22])=[O:21])=O.O.[NH2:34][NH2:35]>CO>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][S:10][C@H:8]2[CH2:7][N:6]([S:20]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)(=[O:22])=[O:21])[C@H:5]([C:3]([NH:34][NH2:35])=[O:2])[CH2:9]2)=[CH:13][CH:14]=1
Reactant: COC(=O)[C@@H]1C[C@@H](SCc2ccc(OC)cc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Reactant: NN
Solvent: O
Solvent: CO
Product: COc1ccc(CS[C@@H]2C[C@@H](C(=O)NN)N(S(=O)(=O)c3ccc4ccccc4c3)C2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(step 8) To a solution of 5 g (10.6 mmol, 1 eq) (2S,4R)-4-(4-Methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester in 20 ml methanol were added 6.45 ml (110 mmol, 10 eq) hydrazine-hydrate and the solution was stirred at RT for 3 days. The solvent was evaporated, followed by solving and evaporating with EtOH, ether and hexane. The light yellow solid was dried in vacuo giving (2S,4R)-4-(4-Methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid hydrazide, mp 130° C., MS: 472 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=[O:11])[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>>[OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[NH:5][C:4](=[O:11])[C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: CC(C)c1cc(O)cc(=O)[nH]1
Product: CC(C)c1cc(O)c([N+](=O)[O-])c(=O)[nH]1
Temperature: 0 °C
Reaction time: 84 h

Procedure:
A solution of 4-hydroxy-6-isopropyl-1H-pyridin-2-one (1.76 g, 11.5 mmol) in 55-60 mL of 50% aq HNO3 is stirred at 70° C. for 2.5 h. After cooling, the reaction mixture is poured into ice-cold H2O (˜100 mL). The resulting solution is allowed to sit in the refrigerator for 3.5 days. The solid that precipitates is collected by filtration, washed with water, and dried to afford 4-hydroxy-6-isopropyl-3-nitro-1H-pyridin-2-one as yellow crystals. 1H NMR (DMSO-d6, 300 MHz) δ 12.30 (br s, 1H), 11.82 (br s, 1H), 5.82 (d, J=1.2 Hz, 1H), 2.71 (sept, J=6.9 Hz, 1H), 1.13 (d, J=6.9 Hz, 6H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:60])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH:45]([C:47]#[N:48])[CH2:44][N:43]6[C:49](=[O:59])[CH:50]([NH:54][C:55]([O:57][CH3:58])=[O:56])[CH:51]([CH3:53])[CH3:52])=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C(N1CC[CH2:68][C@H:64]1[C:65](O)=O)#N.COC(NC(C1C=CC=CC=1)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:60])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH:45]([C:47]#[N:48])[CH2:44][N:43]6[C:49](=[O:59])[CH:50]([NH:54][C:55]([O:57][CH3:58])=[O:56])[C:51]6[CH:53]=[CH:68][CH:64]=[CH:65][CH:52]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: N#CN1CCC[C@H]1C(=O)O
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(C#N)CN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: COC(=O)NC(C(=O)O)c1ccccc1
Product: COC(=O)NC(C(=O)N1CC(C#N)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1

Procedure:
Synthesized similar to [1-(2-{5-[6-(4-{2-[4-Cyano-1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester, reverting the order of Suzuki coupling and reaction introduction of the amino acid moiety on the cyano proline using methoxycarbonylamino-phenyl-acetic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[CH:4][N:3]=1.[NH3:17]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:17])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[CH:4][N:3]=1
Reactant: Nc1ncc(-c2cccc(Cl)c2Cl)c(Cl)n1
Reactant: N
Product: Nc1ncc(-c2cccc(Cl)c2Cl)c(N)n1
Temperature: 125 °C

Procedure:
To 2-amino-4-chloro-5-(2,3-dichlorophenyl)pyrimidine (6.73 gms) was added ethanolic ammonia (30 equiv. in 50 ml EtOH) and the mixture sealed in a Parr reaction vessel and heated to 125° C. for 38 hours. After cooling, the mixture was concentrated in vacuo and the residue mixed with 1N NaOH (75 ml), filtered, washed with water and dried in vacuo, 6.14 gms, mp. 208°-211° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[N:18][C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:28][O:29]C1C=CC=CC=1B(O)O.O1C2C=CC(C3(C(NC4C=NC(Br)=CC=4)=O)CC3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[N:18][C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[O:29][CH3:28])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccccc1B(O)O
Reactant: O=C(Nc1ccc(-c2ccccc2)nc1)C1(c2ccc3c(c2)OCO3)CC1
Agent: O=C(Nc1ccc(Br)nc1)C1(c2ccc3c(c2)OCO3)CC1
Product: COc1ccccc1-c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cn1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-(2-methoxyphenyl)pyridin-3-yl)cyclopropanecarboxamide was synthesized using the procedure of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-phenylpyridin-3-yl)cyclopropanecarboxamide from 2-methoxyphenylboronic acid and 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-3-yl)cyclopropanecarboxamide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][N:12]=[C:11](O)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:11]1[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)[N:14]=[CH:13][N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cccc(-c2cc(O)ncn2)c1
Product: N#Cc1cccc(-c2cc(Cl)ncn2)c1

Procedure:
6-(3-cyanophenyl)-4-hydroxypyrimidine is boiled under reflux with phosphorus oxychloride to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][N:8]([CH2:7][C:6]1[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:9]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: COc1cccc(CBr)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Product: COc1ccc(CN(Cc2cccc(OC)c2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-10b) and 3-methoxybenzyl bromide. MS (M−H, 440.50); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.58 (s, 3H), 3.68 (s, 3H), 4.24 (s, 2H), 4.25 (s, 2H), 6.50 (s, 1H), 6.64 (d, J=4 Hz, 1H), 6.73 (m, 1H), 6.77 (d, J=8 Hz, 2H), 7.00 (d, J=8 Hz, 2H), 7.12 (t, J=8 Hz, 1H), 7.94 (d, J=8 Hz, 2H), 8.09 (d, J=8 Hz, 2H), 13.49 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH3:14])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].Cl.N1C=CC=CC=1.[NH4+].[OH-]>C(OC(O)C)C.O>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH3:14])[N:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][CH:24]=1
Reactant: CCOc1ccc2ncc(C#N)c(Cl)c2n1
Reactant: Nc1cccc(Br)c1
Agent: CCOC(C)O
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: c1ccncc1
Product: CCOc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2n1

Procedure:
4-Chloro-6-ethoxyl-[1,5]naphthyridine-3-carbonitrile (500 mg, 2.14 mmol) was heated at reflux with m-bromoaniline (0.69 ml, 3 eq) in the presence of pyridine HCl salt (250 mg, 1.1 eq) in ethoxyethanol (20 ml) under argon for 3 hrs. After cooling the mixture was diluted with water, made basic with NH4OH, and extracted with CH2Cl2. The extracts were washed (Brine), dried (Na2SO4), and concentrated. The remaining solid was triturated with a mixture of CH2Cl2 and ether, giving the title compound as a yellow solid. mass spectrum (electrospray, m/e): 370.9 (M+H); IR cm-1: 3305, 2217; H-NMR δ (DMSO-d6): 1.365 (3H, t, CH3), 4.585 (2H, q, CH2), 7.327 (1H, d, C8-H), 7.395 (2H, m, C4′ and C6 Hs in bromoaniline), 7.503, (1H, m, C5′-H), 7.618 (1H, s, C2′-H), 8.194 (1H, d, C7-H), 8.516 (1H, s, C2-H), 9.684 (1H, bs, NH).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18](=[O:19])[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:16]([CH3:27])[NH:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C1CC=CCC=1>CCO.[OH-].[OH-].[Pd+2]>[CH2:20]([C:17]1[C:18](=[O:19])[N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[NH:15][C:16]=1[CH3:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1[nH]n(C2CCN(Cc3ccccc3)CC2)c(=O)c1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: Cc1[nH]n(C2CCNCC2)c(=O)c1Cc1ccccc1
Yield: 110.2 %

Procedure:
To a solution of 0.52 g of 1-benzyl-4-(4-benzyl-5-methyl-1H-pyrazol-3(2H)-on-2-yl)-piperidine in 20 mL of EtOH under nitrogen was added 0.2 g of Pearlman's catalyst and 2.5 mL of 1,4-cyclohexadiene. This mixture was refluxed for 3 hours, filtered through Celite and concentrated under reduced pressure to give 0.43 g of 4-(4-benzyl-5-methyl-1H-pyrazole-3(2H)-on-2-yl)-piperidine. ESI-MS 271.9 (M+H); HPLC A: 1.68 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[N:29]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[C:30]=[O:31]>C(Cl)Cl>[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([NH:29][C:30]([N:9]2[CH2:10][CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:31])[CH:33]=1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=C=Nc1cccnc1
Solvent: ClCCl
Product: CC(C)(C)CC1CN(C(=O)Nc2cccnc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 30 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (40 mg, 0.095 mmol) and 3-isocyanatopyridine (Oakwood, 29.1 mg, 0.242 mmol) in CH2Cl2 (5 mL) was stirred at rt for 17 hrs. The reaction mixture was then purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid pyridin-3-ylamide (15.5 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([O:18]CC)=[O:17])=[N:11][CH:10]=[C:9]([OH:21])[C:8]=2[C:7]1=[O:22].[Li+].[OH-].Cl>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([OH:18])=[O:17])=[N:11][CH:10]=[C:9]([OH:21])[C:8]=2[C:7]1=[O:22]
Reactant: CCOC(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ncc(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 60 °C

Procedure:
To a solution of ethyl 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (27.0 g, 71 mmol) in THF (333 mL) and MeOH (166 mL) was added LiOH (5.21 g, 214 mmol) dissolved in enough water to make a 1N solution (total volume 213 mL) and the reaction was heated to 60° C. overnight. HPLC showed completion. A white precipitate was observed. The reaction was neutralized with 1N HCl and the more volatile solvents removed, leaving the water solution. 300 mL water was added the solution was acidified to pH 1 with 1 N HCl. A large amount of solids had precipitated. The resulting slurry was stirred vigorously with 100 mL CHCl3. Most of the solid had precipitated from the partitioning and the entire mix was filtered and dried over the weekend to give product. Additional less pure product was recovered from extraction of the filtrate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].B([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)(O)O.C(N(CC)CC)C>CN(C=O)C.[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>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]([CH3:12])=[C:2]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH:3]=1)=[O:6]
Reactant: COC(=O)c1ccc(C)c(Br)c1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-c2ccc(C(=O)O)cc2)c1
Temperature: 100 °C
Yield: 71.3 %

Procedure:
A stirred solution of methyl 3-bromo-4-methylbenzoate (2.6 g, 0.011 mole) in dry DMF (20 ml) under argon was treated with 4-boronobenzoic acid (1.85 g, 0.011 mole) and tetrakis (triphenylphosphine) palladium(0) (400 mg), followed by triethylamine (4.68 ml, 0.046 mole). The mixture was heated at 100° C. for 18 hours, then concentrated in vacuo. The residue was treated with ethyl acetate and extracted with 10% NaHCO3 solution. The basic extract was acidified with dil. HCl and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to afford the title compound as a light orange solid (2.12 g, 85%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[CH:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]1)[CH3:14].C(N(CC)CC)C.O>CS(C)=O>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[CH:13]([N:15]1[CH2:16][CH2:17][CH:18]([CH:21]=[O:22])[CH2:19][CH2:20]1)[CH3:14]
Reactant: CC(c1ccc(C(F)(F)F)cc1C(F)(F)F)N1CCC(CO)CC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CC(c1ccc(C(F)(F)F)cc1C(F)(F)F)N1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.8 %

Procedure:
To a solution of (1-{1-[2,4-bis(trifluoromethyl)phenyl]ethyl}piperidin-4-yl)methanol (2.0 g) and triethylamine (2.35 mL) in DMSO (22.5 mL) was added sulfur trioxide pyridine complex (2.69 g). The reaction mixture was stirred at room temperature for 1.5 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by so silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.15 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18])[CH2:6]O.S(Cl)([Cl:27])=O>>[Cl:27][CH2:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(CO)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: O=S(Cl)Cl
Product: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Yield: 126.4 %

Procedure:
In substantially the same manner in Reference Example 94, 3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol (6.00 g) was reacted with thionyl chloride (1.58 g) to obtain 4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (5.77 g, yield 91%) as crystals.
Reaction SMILES: [C:1]([CH2:4][S:5][C:6]1[CH:34]=[CH:33][C:9]2[CH:10](O)[C:11]3[CH:18]=[C:17]([O:19][CH2:20][C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][C:25]([Cl:31])=[CH:26][CH:27]=5)[N:22]=4)[CH:16]=[CH:15][C:12]=3[O:13][CH2:14][C:8]=2[CH:7]=1)([OH:3])=[O:2].[SH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39]>>[C:38]([CH2:37][CH2:36][S:35][CH:10]1[C:9]2[CH:33]=[CH:34][C:6]([S:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:7][C:8]=2[CH2:14][O:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][C:25]([Cl:31])=[CH:26][CH:27]=4)[N:22]=3)=[CH:18][C:11]1=2)([OH:40])=[O:39]
Reactant: O=C(O)CSc1ccc2c(c1)COc1ccc(OCc3ccc4ccc(Cl)cc4n3)cc1C2O
Reactant: O=C(O)CCS
Product: O=C(O)CCSC1c2ccc(SCC(=O)O)cc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21

Procedure:
8-carboxymethylthio-2-(7-chloroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [N:1]1([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=2)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1>N.CO.C1COCC1.[Ni]>[N:1]1([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=2)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: N#CCc1ccc(-n2cnc3cnc4ccccc4c32)cc1
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: NCCc1ccc(-n2cnc3cnc4ccccc4c32)cc1

Procedure:
1.3 g (4.6 mmol) of (4-imidazo[4,5-c]quinolin-1-yl-phenyl)-acetonitrile (Example 8) and 0.7 g Raney-Ni in 220 ml 10% NH3 in methanol/THF 1:1 are hydrogenated for 6 h at 45° C. and 1.012 bar. The catalyst is filtered off and washed with methanol. The solvent is partially evaporated and diethyl ether is added. The precipitated material is filtered off and discarded. The mother liquor is concentrated to dryness and the title compound is isolated as colorless crystals. MS: 289 (M++1); HPLC: tret=7.57 min (Grad 3).