Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:25][CH:26]=1.O>CN(C)C=O>[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=4)=[N:25][CH:26]=3)=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=[N:4]1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2ccc(COc3ccc(CCCCn4ccnn4)cc3)cn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
23 mg (0.90 mmol) of 95% sodium hydride were added at 0° C. to a solution of 163 mg (0.75 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 4.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 204 mg (0.75 mmol) 5-chloromethyl-2-(4-trifluoromethyl-phenyl)-pyridine (WO 2005/049573) were given to the reaction mixture and stirring continued at r.t for 2 days. After addition of 8 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, methanol/water 1:1, and a small amount of ether. The residue was purified by chromatography on silica (eluent: ethyl acetate) to give 240 mg 71% of the title compound as white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[N-:10]([C:13]#[N:14])[C:11]#[N:12].[Na+]>>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:13]([NH2:14])=[N:10][C:11]#[N:12])=[CH:3][CH:4]=1
Reactant: N#C[N-]C#N
Reactant: COc1ccc(N)cn1
Agent: [Na+]
Product: COc1ccc(NC(N)=NC#N)cn1

Procedure:
A solution of 5-amino-2-methoxypyridine and sodium dicyanamide was processed as described in Example 71A to provide the desired product.
Reaction SMILES: [H-].[Na+].[CH2:3]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:15](O)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:4][CH3:5].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1.[OH2:29]>CN(C)C=O>[CH2:3]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH:25]([O:29][CH:25]([C@H:15]3[CH2:16][CH2:17][C@H:12]([C@H:9]4[CH2:10][CH2:11][C@H:6]([CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]4)[CH2:13][CH2:14]3)[C:24]3[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[C:24]3[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:4][CH3:5]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](O)CC2)CC1
Reactant: COc1ccc(CCl)cc1
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(OC(c3ccc(OC)cc3)[C@H]3CC[C@H]([C@H]4CC[C@H](CCC)CC4)CC3)c3ccc(OC)cc3)CC2)CC1

Procedure:
To 0.6 g of sodium hydride (purity 60%) was added 30 ml of anhydrous N,N-dimethylformamide. While stirring sufficiently, to the solution was added a solution of 3.36 g of trans-4-(trans-4-propylcyclohexyl)cyclohexanol dissolved in 10 ml of anhydrous N,N-dimethylformamide. This mixture was continued to stirring at 50° C. for one hour and then 2.8 g of 4-methoxybenzyl chloride was added thereto, and the mixture was stirred and reacted at the same temperature for 3 hours with stirring. After completion of the reaction, 100 ml of water was added to the reaction mixture, the mixture was extracted with toluene, washed with a saturated NaCl aqua, dried and the solvent was removed under reduced pressure. The residue was purified by silica gel column to obtain 1.0 g of the targeted trans-4-(trans-4-propylcyclohexyl)cyclohexyl-4-methoxybenzyl ether.
Reaction SMILES: [N:1]([C@@H:4]([CH:8]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:5]([OH:7])=[O:6])=[N+]=[N-].CCOC(C)=O>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[NH2:1][C@@H:4]([CH:8]([C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[C:5]([OH:7])=[O:6]
Reactant: [N-]=[N+]=N[C@H](C(=O)O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Solvent: CCOC(C)=O
Product: N[C@H](C(=O)O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 100.1 %

Procedure:
(S)-2-Azido-3,3-bis-(4-chloro-phenyl)-propionic acid (0.98 g, 2.9 mmol), Lindlar's catalyst (307 mg, 5 mol % Pd), and EtOAc (29 mL) was placed in a 500 mL Parr bottle. The bottle was pressurized with 50 psi of H2 and shaken overnight in a Parr shaker apparatus. The mixture was diluted with MeOH, and the catalyst was removed by filtration through diatomaceous earth, rinsing with MeOH. The filtrate was concentrated to provide 0.90 g (100%) of the desired amino acid as a white solid. MS (ESI−): mass calcd. for C15H13Cl2NO2, 309; m/z found, 308 [M−H]−. 1H NMR (400 MHz, CD3OD): 7.41-7.22 (m, 8H), 4.46 (d, J=9.1, 1H), 4.26 (d, J=9.1, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[O:15]=[S:16]1(=[O:39])[CH2:21][CH2:20][CH:19]([O:22][C:23]2[CH:28]=[C:27]([CH3:29])[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36]O)[CH:31]=3)=[C:25]([CH3:38])[CH:24]=2)[CH2:18][CH2:17]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[O:15]=[S:16]1(=[O:39])[CH2:21][CH2:20][CH:19]([O:22][C:23]2[CH:28]=[C:27]([CH3:29])[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][O:1][C:2]4[CH:3]=[CH:4][C:5]([CH:8]5[CH2:10][CH:9]5[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=4)[CH:31]=3)=[C:25]([CH3:38])[CH:24]=2)[CH2:18][CH2:17]1
Reactant: COC(=O)C1CC1c1ccc(O)cc1
Reactant: Cc1cc(OC2CCS(=O)(=O)CC2)cc(C)c1-c1cccc(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)C1CC1c1ccc(OCc2cccc(-c3c(C)cc(OC4CCS(=O)(=O)CC4)cc3C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
A solution of methyl 2-(4-hydroxyphenyl)cyclopropanecarboxylate (0.156 g, 0.813 mmol), {4′-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-2′,6′-dimethylbiphenyl-3-yl}methanol (0.395 g, 0.739 mmol) and tributylphosphine (0.298 g, 1.47 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.372 g, 1.47 mmol) was added, and the mixture was stirred at room temperature for 4 hr. Hexane (15 mL) was added to the reaction mixture and the precipitated insoluble material was filtrated. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-40:60) to give the title compound (0.396 g, yield 91%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.[NH:28]1[CH2:31][CH2:30][CH2:29]1.C(O)(=O)C.ClCCl.CO.C([BH3-])#N.[Na+]>>[N:28]1([CH2:5][C:4]2[CH:7]=[CH:8][C:9]([C:10]3[S:11][C:12]4[C:17]([N:18]=3)=[CH:16][CH:15]=[C:14]([C:19]3([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:21][CH2:20]3)[N:13]=4)=[C:2]([F:1])[CH:3]=2)[CH2:31][CH2:30][CH2:29]1
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: Fc1cc(CN2CCC2)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Reaction time: 0.17 h

Procedure:
A solution of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (0.102 g, 0.27 mmol), azetidine (0.037 mL, 0.54 mmol) and acetic acid (0.063 mL, 1.1 mmol) in dichloromethane (3.00 mL, 0.27 mmol) and methanol (2.00 mL, 0.27 mmol), was stirred for 60 min at ambient temperature. The reaction mixture was treated with sodium cyanoborohydride (0.0086 g, 0.14 mmol) and was stirred for 10 min, concentrated in vacuo, and adsorbed onto silica gel. Silica gel chromatography (20-30% EtOAc/hexanes, followed by 40% (3% Et3N/EtOAc)/hexanes gave the title compound. MS (ESI) m/z: Calculated: 415.2; Observed: 416.1 (M++1).
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][C:5](C=O)=[CH:4][C:3]=1[O:10][CH3:11].BrC[C:14]([NH:16]C1C=CC(Br)=CC=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].C(#N)CC>C(OCC)(=O)C>[O:10]([CH2:11][C:14]([NH2:16])=[O:15])[C:3]1[CH:2]=[CH:9][CH:8]=[CH:5][CH:4]=1
Reactant: O=C(CBr)Nc1ccc(Br)cc1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC#N
Product: NC(=O)COc1ccccc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 190 %

Procedure:
To 4-hydroxy-3-methoxybenzaldehyde (2.02 g, 13.3 mmol), 2-bromo-N-(4-bromophenyl)acetamide (3.00 g, 10.2 mmol) and potassium carbonate (2.12 g, 15.4 mmol) was added propionitrile (10 ml), and the mixture was stirred at 80° C. for one day. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by alumina column chromatography (developing solvent; ethyl acetate), and powderized with ethyl acetate-diisopropyl ether (1:5) to give a phenoxyacetamide derivative (2.93 g). The title compound was obtained by similar operations as in Reference Example 43 and Example 6 and using this compound.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C=O)C>[CH3:15][O:14][C:10](=[O:13])/[CH:11]=[CH:12]/[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: N#Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(C#N)cc1
Yield: 94 %

Procedure:
Table 1, Entry 2. In the reaction tube were mixed 4-bromobenzonitrile (0.182 g, 1.0 mmol), methyl acrylate (0.108 g, 1.25 mmol), palladium acetate (0.00225 g, 0.01 mmol), tri-o-tolylphosphine (0.0122 g, 0.04 mmol), triethylamine (0.127 g, 1.25 mmol) and 0.50 ml DMF.under nitrogen. The contents of the flask were irradiated for 3.50 min with an effect of 60 W. After cooling, the product mixture was poured into 25 ml water and was extracted three times with 25 ml DCM. The combined extracts were washed with 25 ml water and concentrated to an oil. The crude product was purified by column chromatography on silica gel using i-hexane/diethyl ether (1/1) as the eluent. The yield was 94% (pale yellow crystals).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1F)[CH:30]=[O:31]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:34]3[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][C:27]=3[Br:26])=[CH:12][CH:11]=2)=[CH:18][CH:19]=1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
N-(4-chlorophenethyl)-4-hydroxybenzamide (1.5 g, 5.4 mmol) was diluted with DMSO (15 mL) followed by the addition of K2CO3 (0.89 g, 6.4 mmol) and 3-bromo-4-fluorobenzaldehyde (1.0 g, 4.9 mmol). The reaction was stirred at 85° C. overnight and then cooled to ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with twice with 10% sodium carbonate, water and brine, and then concentrated. The crude material was purified by silica gel chromatography eluting with hexanes:ethyl acetate (1:1) and then 100% ethyl acetate to yield N-(4-chlorophenethyl)-4-(2-bromo-4-formylphenoxy)benzamide (1.6 g, 71% yield).
Reaction SMILES: N1C=CC=CC=1.[S:7]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]1.[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>C(Cl)Cl.O>[CH3:22][C:21]1[CH:23]=[CH:24][C:18]([S:15]([O:14][CH2:13][CH:10]2[CH2:11][CH2:12][S:7][CH2:8][CH2:9]2)(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: OCC1CCSCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCSCC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pyridine (7.6 mL, 98.4 mmol) was added at 0° C. to a solution of (tetrahydro-2H-thiopyran-4-yl)methanol (1.3 g, 9.84 mmol) in CH2Cl2 (20 mL) followed by the addition of TsCl (2.0 g, 10.83 mmol). The reaction mixture was stirred at ambient temperature for 18 h, diluted with H2O (200 mL) and extracted with CH2Cl2 (200 mL). Drying over anhydrous Na2SO4 followed by concentration in vacuo gave (tetrahydro-2H-thiopyran-4-yl)methyl 4-methylbenzenesulfonate as an off white solid. The crude was carried forward to the next step without additional purification. Yield (0.75 g, 30%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][CH2:16][C@@H:17]([C:19]([OH:21])=[O:20])[NH2:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.[O-2].[Mg+2].[CH3:25][O:26][C:27]1[CH:39]=[CH:38][C:30]([CH2:31][O:32][C:33](N=[N+]=[N-])=[O:34])=[CH:29][CH:28]=1>O1CCOCC1>[CH3:25][O:26][C:27]1[CH:39]=[CH:38][C:30]([CH2:31][O:32][C:33]([NH:18][C@H:17]([C:19]([OH:21])=[O:20])[CH2:16][O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:34])=[CH:29][CH:28]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Reactant: COc1ccc(COC(=O)N=[N+]=[N-])cc1
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(COC(=O)N[C@@H](COCc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
O-Benzyl-L-serine trifluoroacetic acid salt, 3.09 g. in 20 ml. of water containing 0.8 g. of magnesium oxide is treated with 2.28 g. of p-methoxybenzyloxycarbonyl azide in 20 ml. of dioxane. The mixture is stirred at room temperature for four days. It is then filtered and the filtrate diluted with ethyl acetate and the solution washed with cold 0.2 N hydrochloric acid and with saturated sodium chloride solution. The ethyl acetate solution is dried and evaporated to an oil. The crude product is triturated with isopropyl ether and stored in the cold to yield crystalline material. Separation by filtration gives 1.75 g., mp. 70°-72° C. This product is recrystallized from aqueous ethanol to give 1.54 g. and is again recrystallized from ethyl acetate-hexane to yield 1.25 g. of the above named product, mp. 72°-73° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9].[OH-].[Na+]>Cl>[N:1]1([C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)COC(=O)N1CCNCC1
Reaction time: 18 h
Yield: 58.5 %

Procedure:
A solution of piperazine (8.61 g, 0.1 mol) in 1M HCl (200 mL) at room temperature was treated with isobutyl chloroformate (13.66 g, 13 mL, 0.1 mol), adjusted to pH 3 with 1M NaOH over 1 to 2 hours, stirred for 18 hours, quenched with 4M KOH, and extracted with dichloromethane (2×100 mL). The combined extracts were dried (MgSO4), filtered, and concentrated to provide 10.9 g (59%) the desired product. MS (ESI(+)) m/e 187 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:16])[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([OH:14])[CH:10]=[CH:9][C:8]=2[CH3:15])([CH3:3])[CH3:2].[CH2:17](Br)[CH:18]=[CH:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl.O>CN(C)C=O>[CH2:17]([O:14][C:11]1[CH:10]=[CH:9][C:8]([CH3:15])=[C:7]2[C:12]=1[CH:13]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:16])[NH:6]2)[CH:18]=[CH:19][CH3:20]
Reactant: Cc1ccc(O)c2cc(C(C)C)c(=O)[nH]c12
Reactant: CC=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC=CCOc1ccc(C)c2[nH]c(=O)c(C(C)C)cc12
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 68.4 %

Procedure:
3-Isopropyl-5-hydroxy-8-methyl-1,2-dihydrocarbostyril (2.2 g, 10.13 mmol) was dissolved in dimethylformamide (25 ml). Crotylbromide (1.22ml, 12.11 mmol) and potassium carbonate (2.8 g, 20.26 mmol) were added to the solution, and the mixture was stirred at 70° C. for 2.5 hours. After the mixture was cooled, chloroform-water was added for phase separation. The organic phase was washed with water, and saturated aqueous sodium chloride solution in this order, and dried. The solvent was distilled off under reduced pressure, and the residue was recrystallized from chloroform-n-hexane. As a result, 1.88 g of the title compound was obtained as colorless needles (68%).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[S:17][C:18]4[C:28]5[C:23](=[CH:24][C:25]([CH:29]6[CH2:33][CH2:32][C:31](=O)[CH2:30]6)=[CH:26][CH:27]=5)[CH2:22][CH2:21][C:19]=4[N:20]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[NH3:37].[CH2:38](B1OC(C)(C)C(C)(C)O1)[CH:39]=[CH2:40]>ClCCl>[CH2:38]([C:31]1([NH2:37])[CH2:32][CH2:33][CH:29]([C:25]2[CH:24]=[C:23]3[C:28](=[CH:27][CH:26]=2)[C:18]2[S:17][C:16]([C:10]4[O:9][N:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:11]=4[C:12]([F:14])([F:15])[F:13])=[N:20][C:19]=2[CH2:21][CH2:22]3)[CH2:30]1)[CH:39]=[CH2:40]
Reactant: O=C1CCC(c2ccc3c(c2)CCc2nc(-c4onc(-c5ccccc5)c4C(F)(F)F)sc2-3)C1
Reactant: N
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Solvent: CO
Solvent: ClCCl
Product: C=CCC1(N)CCC(c2ccc3c(c2)CCc2nc(-c4onc(-c5ccccc5)c4C(F)(F)F)sc2-3)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
To a stirred mixture of 3-(2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]thiazol-7-yl)cyclopentanone (prepared according to Preparation 121C from 5-(7-iodo-4,5-dihydronaphtho[2,1-d]thiazol-2-yl)-3-phenyl-4-(trifluoromethyl)isoxazole (Preparation 123A), 200 mg, 0.416 mmol), 7 M methanol solution of ammonia (2 mL, 14.00 mmol), and anhydrous dichloromethane (1.5 mL) was added allylboronic acid pinacol ester (0.117 mL, 0.624 mmol). The mixture was stirred at room temperature overnight. More allylboronic acid pinacol ester (0.1 mL) was added. The mixture was stirred at room temperature for 5 h before being concentrated. The residue was mixed with water (5 mL) and extracted with dichloromethane (4×2 mL). The combined dichloromethane extracts were dried (sodium sulfate) and concentrated under reduced pressure. Purification using reverse phase HPLC (Phenomenex Luna AXIA 5 u c18 30×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA), concentration, neutralization with saturated aqueous sodium bicarbonate solution and extraction with dichloromethane gave 1-allyl-3-(2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]thiazol-7-yl)cyclopentanamine (103 mg, 0.197 mmol, 47.4% yield) as a glassy solid. The compound had an HPLC retention time=3.75 min. (condition C); LC/MS M+1=521.9.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[CH3:12][C:13]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)=[O:14].[OH-].[Na+].Cl>CO>[OH:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:12]/[C:13]([C:15]2[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)=[O:14])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1O
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 3-hydroxy-4-methoxybenzaldehyde (1.1 g, 7.3 mmol) and 3,4,5-trimethoxyacetophenone (1.54 g, 7.3 mmol) in methanol (30 ml) was added a 50% w/v solution of aqueous NaOH (1 ml). The mixture was stirred for 24 hours at room temperature, acidified with 2N HCl and extracted with chloroform (3×30 ml). The combined organic phase was dried over anhydrous MgSO4, filtered, the solvent concentrated under vacou. The product was purified by crystallisation from methanol. 1H-NMR (CDCl3): 7.8 (d, 1H), 7.4 (d, 1H), 7.2-7.3 (m, 3H), 7.1 (dd, 1H), 6.9 (d, 1H), 5.8 (s, 1H) 4.0 (s, 9H) 3.9 (s, 3H); Mass Spectrum m/e (M+1) 329.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=[N:15][S:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17].[BH4-].[Na+].O>CO.C(Cl)Cl>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][NH:15][S:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17]
Reactant: CC(C)(C)S(=O)N=Cc1ccc2oc3ccccc3c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)S(=O)NCc1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of N-(dibenzo[b,d]furan-2-ylmethylene)-2-methylpropane-2-sulfinamide (2.260 g; 7.55 mmol) in anh. MeOH (27 ml) and anh. DCM (57 ml) was treated with NaBH4 (343 mg; 9.06 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 10 min. Water and DCM were added, and the organic layer was then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording N-(dibenzo[b,d]furan-2-ylmethyl)-2-methylpropane-2-sulfinamide as a yellow solid. LC-MS (conditions A): tR=0.82 min.; [M+H]+: 302.01 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)([C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)O)[CH:17]=[CH:18][C:13]=3[N:12]3[N:34]=[N:35][N:36]=[C:11]3[CH2:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:39])=O>>[Cl:39][C:19]([C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)([C:21]1[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=1)[C:16]1[CH:17]=[CH:18][C:13]2[N:12]3[N:34]=[N:35][N:36]=[C:11]3[CH2:10][N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:14]=2[CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)=NCc1nnnn1-2
Product: Cn1cncc1C(Cl)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)=NCc1nnnn1-2
Temperature: 5 °C
Reaction time: 5 h

Procedure:
A mixture of 6-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-4H-tetrazolo[1,5-a][1,4]benzodiazepine-8-methanol (see Example B9) (0.0015 mol) in thionyl chloride (10 ml) was stirred at 5° C. for 5 hours. The solvent was evaporated till dryness. The product was used without further purification, yielding 8-[chloro(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-6-(3-chlorophenyl)-4H-tetrazolo[1,5-a][1,4]benzodiazepine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13](=[C:16]2[C:25]3[CH:24]=[CH:23][S:22][C:21]=3[C:20](=O)[CH2:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]2=3)[CH2:12][CH2:11]1.Cl.[NH2:32][OH:33]>N1C=CC=CC=1>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][C:13](=[C:16]2[C:25]3[CH:24]=[CH:23][S:22][C:21]=3[C:20](=[N:32][OH:33])[CH2:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]2=3)[CH2:14][CH2:15]1
Reactant: NO
Reactant: O=C1Cc2ccccc2C(=C2CCN(CCOCCOCCO)CC2)c2ccsc21
Agent: Cl
Solvent: c1ccncc1
Product: OCCOCCOCCN1CCC(=C2c3ccccc3CC(=NO)c3sccc32)CC1

Procedure:
6.0 g 4-{1-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]piperidin-4-ylidene}-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)one and 0.95 g hydroxylaminehydrochlorid in 70 ml pyridine are refluxed for 12 hours. After elimination of the pyridine by distillation, ethanol and a little water are added to the residue and the title compound is crystallised out as the hydrochlorid (Mt. p. 240°-243°).