Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][C:7](Cl)=[CH:6][N:5]=1)([OH:3])=[O:2].P(Cl)(Cl)(Cl)=[O:12]>>[C:1]([C:4]1[CH:9]=[N:8][C:7]([OH:12])=[CH:6][N:5]=1)([OH:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1cnc(Cl)cn1
Product: O=C(O)c1cnc(O)cn1

Procedure:
For example the compound 2-carboxy-5-chloro-pyrazine can be prepared by treating with an excess of phosphorus oxychloride, at the reflux temperature, the 2-carboxy-5-hydroxy-pyrazine compound in its turn obtained in the manner described in Helv. Chim. Acta 47, 873 (1964).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH2:12]([C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16])[CH3:13]>>[CH2:12]([C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10])[CH3:13]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CCc1ccccc1N
Product: CCc1ccccc1Nc1ccccc1CC(=O)O

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-ethylaniline to yield 2-[(2-ethylphenyl)amino]phenylacetic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33](Br)[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][N:39]1[CH2:44][CH2:43][N:42]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([N:48]3[CH2:47][CH2:46][CH:45]([N:42]4[CH2:41][CH2:40][N:39]([CH3:38])[CH2:44][CH2:43]4)[CH2:50][CH2:49]3)[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)c1cc(C(=O)N2Cc3ccc(Br)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CN1CCN(C2CCNCC2)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=C(C)c1cc(C(=O)N2Cc3ccc(N4CCC(N5CCN(C)CC5)CC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 120 °C
Yield: 44.4 %

Procedure:
A solution of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-(5-bromo-1,3-dihydro-isoindol-2-yl)-methanone (200 mg; 0.36 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (80 mg; 1.2 equiv.) in toluene (5 ml) was treated with (2-biphenyl)-di-tert-butylphosphine (6 mg; 5 mol %), tris(dibenzylidene)palladium(0) (10 mg; 2.5 mol %) and sodium tert-butoxide (50 mg; 1.4 equiv.) then heated at 120° C. for 30 minutes in a CEM explorer microwave synthesiser. The reaction mixture was diluted with DCM, washed with brine, dried (MgSO4) and evaporated. Purification by flash column chromatography (Biotage SP4—25S, 25 ml/min) eluting with DMAW 240-120-90 followed by evaporation of product containing fractions gave 105 mg of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-{5-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-1,3-dihydro-isoindol-2-yl}-methanone as the acetic acid salt.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=2)[CH:9]=1)(=[O:5])=[O:4].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:46]([C:48]1[N:49]=[C:50]([C:61]([O-])=[O:62])[N:51]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[CH:52]=1)#[N:47].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:15]1([C:10]2[CH:9]=[C:8]([CH2:7][CH2:6][S:3](=[O:4])(=[O:5])[NH:2][CH3:1])[CH:13]=[CH:12][C:11]=2[NH:14][C:61]([C:50]2[N:51]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[CH:52]=[C:48]([C:46]#[N:47])[N:49]=2)=[O:62])[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CNS(=O)(=O)CCc1ccc(N)c(C2=CCCCC2)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNS(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 123 mg (0.418 mmol) of 2-(4-amino-3-cyclohex-1-enyl-phenyl)-ethanesulfonic acid methylamide (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 292 mg (0.627 mmol) of PyBroP, 140 mg (0.460 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), and 218 μL (1.25 mmol) of DIEA. The mixture was stirred at RT for 2 h, diluted with CH2Cl2 (20 mL) and washed with saturated aqueous NaHCO3 (1×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 50% EtOAc-hexane afforded 177 (71%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C26H37N5O4SSi, 544.2 (M+H). found 543.9.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:10][C:11]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[C:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:12]=1[OH:25]>>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[O:10][C:11]1[CH:16]=[C:15]([C:17]([CH3:18])([CH3:19])[CH3:20])[CH:14]=[C:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:12]=1[O:25][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])#[N:5]
Reactant: CC(C)(C)c1cc(O)c(O)c(C(C)(C)C)c1
Reactant: N#Cc1ccccc1F
Product: CC(C)(C)c1cc(Oc2ccccc2C#N)c(Oc2ccccc2C#N)c(C(C)(C)C)c1
Yield: 90.1 %

Procedure:
The compound 1,2-bis-(2-cyanophenoxy)-3,5-di-tert-butylbenzene was prepared, according to the procedure of Example 1, by reacting 2-fluorobenzonitrile with 1,2-dihydroxy-3,5-di-tert-butyl benzene. The product was recrystallized from ethanol to give a 90.1% yield of the title compound with the formula: ##STR12##
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[C:14]([C:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([S:29][Si](C(C)C)(C(C)C)C(C)C)[CH:24]=2)[CH2:21][CH2:20][O:19][CH:18]([CH3:22])[CH2:17]1)#[N:15].CC(C)([O-])C.[K+]>C(O)C.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:14]([C:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([S:29][C:10]3[CH:11]=[CH:12][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[CH:8][CH:9]=3)[CH:24]=2)[CH2:21][CH2:20][O:19][CH:18]([CH3:22])[CH2:17]1)#[N:15]
Reactant: CC1CC(C#N)(c2cccc(S[Si](C(C)C)(C(C)C)C(C)C)c2)CCO1
Reactant: Cc1nccn1-c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1nccn1-c1ccc(Sc2cccc(C3(C#N)CCOC(C)C3)c2)cc1
Yield: 92.6 %

Procedure:
To a stirred solution of 4-(2-methylimidazol-1-yl)phenyl iodide (1.21 g, 3.1 mmol) and (2SR, 4RS)-4-cyano-2-methyl-4-(3-triisopropylsilylthiophenyl)-3,4,5,6-tetrahydro-2H-pyran (795 mg, 2.8 mmol) in ethanol (20 ml) was added tetrakis(triphenylphosphine)palladium(0) (215 mg, 0.2 mmol) and potassium tert-butoxide (383 mg, 3.4 mmol) under a nitrogen atmosphere. The resulting mixture was heated at reflux temperature for 15.5 h, then cooled and concentrated in vacuo. The residue was diluted in ethyl acetate (100 ml), and washed with water (2×100 ml), brine (100 ml) and dried (MgSO4) and concentrated. Purification by silica-gel column chromatography, eluting with dichloromethane-methanol (25:1), gave 1.01 g (93%) of the titled compound as a yellow gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=2)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: COc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2cc(Cl)nc(SC)n2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 658.1 %

Procedure:
To a solution of 4,6-dichloro-2-(methyl thio)pyrimidine (75 g, 38.4 mmol, Sigma-Aldrich) in DMF (750 mL) was added p-methoxybenzyl alcohol (58.38 g, 42.1 mmol) and K2CO3 (212.3 g, 1538 mmol). The reaction was stirred at 60° C. for 12 h, then cooled to RT. Water (500 mL) was added to the mixture and the resulting suspension was filtered. The solid was dried and triturated with Hexanes to give 4-Chloro-6-(4-methoxy-benzyloxy)-2-methylsulfanyl-pyrimidine (75 g, 66.4% yield) as a white solid. MS (ESI, pos. ion) m/z: 297.0 (M+1); 1H NMR (400 MHz, CDCl3): δ 7.30-7.37 (m, 3H), 6.89-6.93 (m, 2H), 5.36 (s, 2H), 3.82 (s, 3H), 2.57 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].C(N(CC1C=NC=CC=1)C(NC)=S)C1C=CC=CC=1.[Cl:30][C:31]1[N:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33][CH:32]=1>CCO>[Cl:30][C:31]1[N:36]=[CH:35][C:34]([CH2:37][NH:38][C:3]([N:2]([CH3:10])[CH3:1])=[CH:4][N+:5]([O-:7])=[O:6])=[CH:33][CH:32]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: CSC(=C[N+](=O)[O-])N(C)C
Agent: CNC(=S)N(Cc1ccccc1)Cc1cccnc1
Solvent: CCO
Product: CN(C)C(=C[N+](=O)[O-])NCc1ccc(Cl)nc1

Procedure:
The 1-dimethylamino-1-methylthio-2-nitroethylene (1.0 g) prepared in (1) and 1.0 g of 6-chloro-3-pyridylmethylamine were refluxed in 30 ml of EtOH for 2 hours. The EtOH was then distilled off and the residue was subjected to silica gel column chromatography using CHCl3 --MeOH (10:1) as an eluent. The crystals obtained were recrystallized from EtOH to recover 0.82 g of the title compound as pale yellow crystals.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C@H:6]([NH2:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[N:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[C:22]=[O:23]>CO>[O:30]([C:27]1[CH:26]=[CH:25][C:24]([NH:21][C:22](=[O:23])[NH:11][C@@H:6]([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[CH2:7][C:8]([O-:10])=[O:9])=[CH:29][CH:28]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C[N+](C)(C)C[C@H](N)CC(=O)[O-]
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)Nc1ccc(Oc2ccccc2)cc1
Reaction time: 18 h

Procedure:
To a solution of (R)-aminocarnitine (27 mg, 0.17 mmol) and diisopropylethylamine (88 uL, 0.51 mmol) in MeOH (2 mL) was added 1-isocyanato-4-phenoxybenzene (71 mg, 0.34 mmol) and the reaction stirred for 18 h. The MeOH was removed in vacuo and the residue stirred with 1:1 ether/EtOAc. Impurities were dissolved in the ether/EtOAc and discarded and the remaining material was taken up into 90:10 CH2Cl2/MeOH and then loaded onto a short SiOH plug. The title compound was eluted by increasing MeOH content in 10% steps to 60%. The compound was then taken up into 90:10 CH2Cl2/MeOH and filtered through a plug of celite which gave after drying the title compound as a white powder (10 mg, 16%). 1H NMR (400 MHz, CD3OD) δ 7.37-7.30 (m, 4H), 7.07 (t, 1H, J=7.2 Hz), 6.95-6.92 (m, 4H), 4.73-4.71 (m, 1H), 3.80-3.54 (m, 2H), 3.26 (s, 9H), 2.81-2.68 (m, 2H); MS ESI 372.2 [M+H]+, calcd for [C20H25N3O4+H]+ 372.43.
Reaction SMILES: Br[CH2:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][C:4]=1[N+:19]([O-:21])=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:41]([C:43]1[C:48]([CH3:49])=[CH:47][C:46](/[CH:50]=[CH:51]/[C:52]([O:54][CH3:55])=[O:53])=[CH:45][C:44]=1[CH3:56])=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:55][O:54][C:52](/[CH:51]=[CH:50]/[C:46]1[CH:45]=[C:44]([CH3:56])[C:43](/[CH:41]=[CH:2]/[C:3]2[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])=[CH:5][C:4]=2[N+:19]([O-:21])=[O:20])=[C:48]([CH3:49])[CH:47]=1)=[O:53]
Reactant: COC(=O)/C=C/c1cc(C)c(C=O)c(C)c1
Reactant: O=C(OCc1ccccc1)c1ccc(CBr)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/c1cc(C)c(/C=C/c2ccc(C(=O)OCc3ccccc3)cc2[N+](=O)[O-])c(C)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of benzyl 4-bromomethyl-3-nitrobenzoate (2.06 g, 5.88 mmol) and triphenylphosphine (1.54 g, 5.87 mmol) in DMF (10 mL) was heated at 100° C. for 1 h. To this solution was added methyl (E)-3-(4-formyl-3,5-dimethylphenyl)-acrylate (1.28 g., 5.86 mmol) and potassium carbonate (1.63 g, 11.8 mmol) and the mixture was heated and stirred at 100° C. for 18 h. The reaction was poured into ethyl acetate and extracted with water once and brine.five times. The organic layer was dried, filtered, and the solvent was removed under reduced pressure. The residue was purified by chromatography using a 0-40% gradient of heptane/ethyl acetate to give benzyl 4-{(E)-2-[4-((E)-2-methoxycarbonylvinyl)-2,6-dimethylphenyl]-vinyl}-3-nitrobenzoate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([F:24])[CH:15]=3)[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:29]([NH:33][S:34]([C:37]1[S:38][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:40][CH:41]=1)(=[O:36])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([NH:33][S:34]([C:37]1[S:38][C:39]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([C:25]([F:26])([F:27])[F:28])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[C:16]([F:24])[CH:15]=4)[N:13]=3)[CH:3]=2)=[CH:40][CH:41]=1)(=[O:35])=[O:36])([CH3:30])([CH3:31])[CH3:32]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Fc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(F)c4)cc(C(F)(F)F)n3)c2)s1

Procedure:
N-tert-Butyl-5-{3-[6-(3-fluoro-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromophenyl)-4-(3-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.109) (0.465 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-sulfonamide (example F.1) (0.414 g, 1.2 mmol) according to the general procedure VI. Obtained as an off-white solid (0.32 g), which was subsequently deprotected.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[CH2:22]1[CH2:24][CH:23]1[CH2:25][O:26][C:27]1C=CC=CC=1C=O.[O-]CC.[Na+]>C(O)C>[CH2:22]1[CH2:24][CH:23]1[CH2:25][O:26]/[CH:27]=[CH:1]/[C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][CH:9]=1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccccc1OCC1CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1c(-c2ccc(C(F)(F)F)cc2)c(/C=C/OCC2CC2)nc2sccn12
Yield: 47.6 %

Procedure:
A solution of Intermediate 5 (400 mg, 1.289 mmol), (2-cyclopropylmethoxy)benzaldehyde (356 mg, 2.025 mmol) and sodium ethoxide (183 mg, 2.108 mmol) in ethanol (20 ml) was refluxed for 15 h. The reaction mixture was concentrated, the residue extracted with ethyl acetate, washed with water and brine to afford crude solid which was purified by column chromatography to afford 241 mg of the desired compound as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.12-0.20 (m, 2H), 0.27-0.32 (m, 2H), 0.78-0.83 (m, 1H), 3.74 (d, J=6.9 Hz, 2H), 6.90-6.97 (m, 2H), 7.18-7.26 (m, 2H), 7.39 (d, J=6.9 Hz, 1H), 7.52 (d, J=4.8 Hz, 1H), 7.58 (d, J=7.8 Hz, 2H), 7.80 (d, J=7.5 Hz, 2H), 7.91-7.97 (m, 1H), 8.00 (d, J=4.5 Hz, 1H); ESI-MS (m/z) 469.22 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH:4]=[CH:3][CH:2]=1.[N:18]1([C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26]=[CH:27][NH:28]3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[NH:28]1[C:29]2[C:25](=[C:24]([N:18]3[CH2:23][CH2:22][N:21]([CH:14]4[CH2:15][CH2:16][N:11]([C:9]5[CH:8]=[CH:7][CH:6]=[C:5]6[C:10]=5[N:1]=[CH:2][CH:3]=[CH:4]6)[CH2:12][CH2:13]4)[CH2:20][CH2:19]3)[CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1cnc2c(N3CCC(N4CCN(c5cccc6[nH]ccc56)CC4)CC3)cccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
To a solution of 0.270 g of 1-quinolin-8-yl-piperidin-4-one (Example A, Step 6, above) and 0.240 g of 4-piperazino-indole (commercially available) in 15 mL CH2Cl2 was added 0.327 g of sodium triacetoxyborohydride and 0.2 mL acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2Cl2. The organic phase was washed with water, dried over magnesium sulfate and evaporated. The product crystallized to give 0.200 g of the desired product. Mp: 256° C.; MS (ES) m/z (relative intensity): 412 (M++−H, 100).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[S:12])SC)(=[O:3])[CH3:2].[N-:13]=[N+:14]=[N-:15].[Na+]>O1CCOCC1.O>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:9]([SH:12])=[N:15][N:14]=[N:13]1)(=[O:3])[CH3:2]
Reactant: CSC(=S)NCCCNC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)NCCCn1nnnc1S
Reaction time: 4 h
Yield: 48.7 %

Procedure:
A mixture of a solution of methyl N-(3-acetamidopropyl)dithiocarbamate (193 g) in dioxane (610 ml) and a solution of sodium azide (79.42 g) in water (500 ml) was refluxed under stirring for 4 hours. Dioxane was distilled off and the remaining aqueous layer was washed with diethyl ether (150 ml×2), adjusted to pH 1 with 17.5% hydrochloric acid, and cooled in an ice bath. Precipitates were collected by filtration and washed with ice-water to give white powder of 1-(3-acetamidopropyl)-1H-tetrazol-5-thiol (91.75 g), mp. 152° to 154° C.
Reaction SMILES: [ClH:1].C(OC([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2([NH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=3)[CH2:21][CH2:20]2)[C:14](=[O:38])[CH2:13]1)=O)C1C=CC=CC=1>C(OCC)(=O)C.C(O)C.[C].[Pd]>[ClH:1].[CH2:36]([O:35][C:33]([NH:32][C:19]1([CH2:18][N:15]2[CH2:16][CH2:17][NH:12][CH2:13][C:14]2=[O:38])[CH2:20][CH2:21][N:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=2)[CH2:23][CH2:24]1)=[O:34])[CH3:37]
Reactant: CCOC(=O)NC1(CN2CCN(C(=O)OCc3ccccc3)CC2=O)CCN(c2ccnc(C)c2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)NC1(CN2CCNCC2=O)CCN(c2ccnc(C)c2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A 4N hydrochloric acid solution in ethyl acetate (0.7 ml) and 10% palladium carbon (500 mg) were added to a solution of 4-benzyloxycarbonyl-1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidiny]methyl}-2-piperazinone (1.3 g) in ethanol (50 ml), and the mixture was stirred at room temperature for 15 hours under a nitrogen atmosphere. After the catalyst was removed, the solvent was distilled off to obtain the colorless amorphous title compound (1.15 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]2[O:20][N:19]=[C:18]([C:21]3[S:25][C:24]([CH2:26]O)=[CH:23][C:22]=3[CH2:28][CH3:29])[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:55]1[CH2:58][CH:57]([C:59]([O:61][CH3:62])=[O:60])[CH2:56]1.C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:16]2[O:20][N:19]=[C:18]([C:21]3[S:25][C:24]([CH2:26][N:55]4[CH2:58][CH:57]([C:59]([O:61][CH3:62])=[O:60])[CH2:56]4)=[CH:23][C:22]=3[CH2:28][CH3:29])[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1
Reactant: COC(=O)C1CNC1
Reactant: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3cccc(F)c3)c(Cl)c2)n1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3cccc(F)c3)c(Cl)c2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using (5-{5-[3-chloro-4-(3-fluorophenoxy)phenyl]-1,2,4-oxadiazol-3-yl}-4-ethyl-2-thienyl)methanol (0.15 g, 0.34 mmol) that was obtained in Example 16 (16b), carbon tetrabromide (0.16 g, 0.51 mmol), triphenylphosphine (0.13 g, 0.51 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.073 g, 0.51 mmol), and N,N-diisopropylethylamine (0.14 mL, 0.84 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:8 to 5:15) as the eluent to afford the title compound (0.16 g) in a yield of 88% as a colourless oily product.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:20]#[N:21])[C:10]([CH3:19])=[C:11]([C:14]([O:16]CC)=[CH2:15])[C:12]=3[F:13])[N:8]=2)[CH2:3][CH2:2]1.Cl.[O:23]1C=CN=C1.CO>O1CCCC1>[C:14]([C:11]1[C:12]([F:13])=[C:6]([OH:5])[C:7]([NH:8][C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:23])=[C:9]([C:20]#[N:21])[C:10]=1[CH3:19])(=[O:16])[CH3:15]
Reactant: c1cocn1
Reactant: C=C(OCC)c1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1c(C)c(C#N)c(NC(=O)C2CC2)c(O)c1F
Temperature: 25 °C
Reaction time: 19 h

Procedure:
2-Cyclopropyl-6-[1-(ethoxy)ethenyl]-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-78) (1.0 g, 3.49 mmol) was dissolved in tetrahydrofuran (10 ml), aqueous 1 N hydrochloric acid solution (2.0 ml) was added, followed by stirring at room temperature for 19 hours. At this point in time, it was known that a mixture with an oxazole-opened compound is given, and for complete ring opening, methanol (5 ml) was added followed by stirring overnight at room temperature. The solvent was concentrated under reduced pressure, ethyl acetate was added to the resulting residue, followed by fractionation with water.
Reaction SMILES: ClC1C=C(C=CC=1Cl)C([NH:7][CH:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:9]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N+:44]([C:47]1[CH:54]=[CH:53][CH:52]=[CH:51][C:48]=1[CH:49]=O)([O-:46])=[O:45].C(=O)(O)[O-].[Na+]>ClCCl.C(O)(=O)C>[N+:44]([C:47]1[CH:54]=[CH:53][CH:52]=[CH:51][C:48]=1[CH2:49][NH:7][CH:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:9]1)([O-:46])=[O:45]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1ccc(Cl)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2C(c2ccccc2)=NC1NCc1ccccc1[N+](=O)[O-]
Reaction time: 18 h
Yield: 72.5 %

Procedure:
A solution of Intermediate 3 (50 mg) and sodium (triacetoxy)borohydride (106 mg) in dichloromethane (6 ml) and acetic acid (1 ml) was treated with 2-nitro-benzaldehyde (45 mg). The resulting mixture was stirred under nitrogen for 18 h. Saturated sodium bicarbonate solution was carefully added, and the mixture extracted with dichloromethane. The organic layer was passed through a hydrophobic frit, and evaporated. The residue was then purified on a silica gel SPE cartridge. Gradient elution with 10-18% ethyl acetate in petrol gave the title compound as a colourless solid (33 mg) LC/MS RT=4.83 min Found ES+=387
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([OH:26])[CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C(O)C.C(O)(=O)C.[Pd]>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2([OH:26])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(NC(=O)C2(O)CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)c1ccc(NC(=O)C2(O)CCNCC2)cc1

Procedure:
A mixture of 33 mg (0.09 mmol) 1-benzyl-4-hydroxy-piperidine-4-carboxylic acid (4-isopropyl-phenyl)-amide in 15 mL ethanol and 10 uL acetic acid was hydrogenated over Pd/C with 1 bar H2 for 2 h at room temperature. The mixture was filtered, the catalyst washed with ethanol and the filtrate evaporated to dryness yielding 33 mg (70% purity) of the title compound. MS (m/e): 263.1 [(M+H)+].