Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=3[F:25])[CH2:12][CH2:11]2)[CH2:4][CH2:3]1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](O)=[O:32]>>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([O:16][CH:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][C:31]([C:27]4[S:26][CH:30]=[CH:29][CH:28]=4)=[O:32])[CH2:3][CH2:4]3)[CH2:15][CH2:14]2)=[C:18]([F:25])[CH:19]=1)#[N:22]
Reactant: N#Cc1ccc(OC2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)c(F)c1
Reactant: O=C(O)c1cccs1
Product: N#Cc1ccc(OC2CCN(CC[C@H]3CC[C@H](NC(=O)c4cccs4)CC3)CC2)c(F)c1

Procedure:
According to the synthesis of example 1, the title compound was prepared from Trans 4-{1-[2-(4-Amino-cyclohexyl)-ethyl]-piperidin-4-yloxy}-3-fluoro-benzonitrile and Thiophene-2-carboxylic acid. Preparative HPLC on reversed phase eluting with acetonitrile/water yielded the title compound. MS (m/e): 456.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[SH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].N12CCCN=C1CCCCC2>>[NH2:1][C:2]1[N:3]=[C:4]([S:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)NCCSc1ccc([N+](=O)[O-])c(N)n1

Procedure:
tert-Butyl {2-[(6-amino-5-nitropyridin-2-yl)thio]ethyl}carbamate (Example 43A) is prepared in analogy to Example 42A from 2-amino-6-chloro-3-nitropyridine (500 mg, 2.9 mmol), tert-butyl (2-mercaptoethyl)carbamate (255 mg, 1.4 mmol) and 1,8-diazabicyclo(5.4.0)undec-7-ene (439 mg, 2.9 mmol). 422 mg (93% of theory) of product are obtained.
Reaction SMILES: C(S[C:4]1[N:8]2[C:9]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)=[CH:10][CH:11]=[CH:12][C:7]2=[CH:6][N:5]=1)C>[Ni].C(O)C>[C:13]1([C:9]2[N:8]3[CH:4]=[N:5][CH:6]=[C:7]3[CH:12]=[CH:11][CH:10]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCSc1ncc2cccc(-c3cccc4ccccc34)n12
Agent: [Ni]
Solvent: CCO
Product: c1ccc2c(-c3cccc4cncn34)cccc2c1

Procedure:
Raney Nickel suspension (1 mL, Fluka Cat. No. 83440) is added to a solution of the title D compound, 3-ethylsulfanyl-5-naphthalen-1-yl-imidazo[1,5-a]pyridine (268 mg, 0.88 mmol) in ethanol (15 mL) and heated at reflux overnight. Additional Raney Nickel (1 mL) is added, and the reaction mixture is heated at reflux for three days further, until MS showed complete disappearance of the starting material. The catalyst is filtered off and washed with ethanol. The combined filtrates are concentrated under reduced pressure. The residue is purified by flash column chromatography on silica using ethyl ether as the eluant to yield 5-naphthalen-1-yl-imidazo[1,5-a]pyridine as an amber film. The hydrochloride salt is prepared in acetone by addition of an ethereal solution of HCl (1.2 eq.). The resulting precipitate is re-crystallized from acetonitrile to yield 5-naphthalen-1-yl-imidazo[1,5-a]pyridine hydrochloride (m.p. 222–223° C.): 1H-NMR, (MeOH-d4) δ 8.71 (s, 1H), 8.21 (d, J=8.1, 1H), 8.16 (s, 1H), 8.13 (d, J=16.3, 1H), 8.04 (d, J=17, 1H), 7.98–7.70 (m, 2H), 7.61 (dt, J=5.6, 1.2, 1H); 7.53–7.40, m, (3H); 7.28 (d, J=7.7, 1H); 13C-NMR (MeOH-d4) δ 135.8, 135.53, 132.84, 132.68, 131.96, 130.34, 130.13, 129.81, 129.11, 128.15, 127.04, 126.18, 125.60, 124.79, 120.93, 119.43, 116.50, 112.96; MS (M+1)+ 245.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C@H:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][CH:6]=[CH2:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].[O-]S([O-])(=O)=O.[Mg+2]>O1CCCC1>[CH3:1][NH:2][CH2:3][C@H:4]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:5][CH:6]=[CH2:7]
Reactant: C=CC[C@H](C(=O)NC)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C=CC[C@H](CNC)c1ccccc1
Reaction time: 24 h

Procedure:
Combine (S)-2-phenylpent-4-enoic acid, N-methyl amide (1.35 g, 7.13 mmol) and tetrahydrofuran (20 mL). Cool in an ice bath, add a solution of lithium aluminum hydride (17 mL, 1.0 M in tetrahydrofuran, 17 mmol). After the addition is complete, heat the reaction mixture to reflux. After 24 hours, cool in an ice bath and carefully quench with water (0.6 mL), an aqueous 15% sodium hydroxide solution (0.6 mL) and then water (2 mL). Dilute the quenched reaction mixture with diethyl ether (50 mL), add MgSO4, and stir. After 2 hours, filter through celite and rinse the solids with dichloromethane. Dry the filtrate with MgSO4, and evaporate in vacuo to give (S)-N-methyl-(2-phenylpent-4-enyl)amine: Rf =0.51 (silica gel, 18/2/0.2 dichloromethane/methanol/concentrated aqueous ammonia).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5]O.[CH2:9]([N:11](CC)CC)C.CS(Cl)(=O)=O.CCCCC>CCOCC>[F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5][C:9]#[N:11]
Reactant: CCN(CC)CC
Reactant: OCCCC(F)(F)F
Agent: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCCCC
Product: N#CCCCC(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 6.40 g (50.3 mM) 4,4,4-trifluorobutanol, prepared in Example 45d, and 7.71 ml (55.3 mM) triethylamine in 1.50 ml Et2O at 0° C. under N2, was added 4.28 ml (55.3 mM) methanesulfonyl chloride dropwise. A white precipitate formed and was stirred 60 minutes at 0° C. An equal volume of pentane was added and the reaction mixture was filtered through celite, followed by concentration on a rotary evaporator without heat. The crude mesylate was mixed with 8.19 g (126 mM) KCN and catalytic KI in 150 ml dimethysulfoxide at rt. The reaction mixture was then heated to 80° C. for 3 hours, turning deep orange and gelling. After cooling, the orange gel was poured into 100 ml of stirring H2O, extracted into Et2O, washed with saturated NaCl, dried over MgSO4, filtered and volatiles distilled. The crude liquid residue was 5.12 g (75%).
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH3:14])=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=1)[OH:4])#[CH:2].O[C:20]1[CH:29]=[C:28](I)[CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]>>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH3:14])=[C:7]([C:15]([CH3:17])([CH3:16])[CH3:18])[CH:6]=1)[C:1]#[C:2][C:28]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:29]=1
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: C#CC(O)c1ccc(OCCC)c(C(C)(C)C)c1
Product: CCCOc1ccc(C(O)C#Cc2ccc(C(=O)OC)cc2)cc1C(C)(C)C
Yield: 86.3 %

Procedure:
Following the basic procedure of Example 11(d), by reacting 3.3 g (13.4 mmol) of α-ethynyl-3-tert-butyl-4-(propyloxy)benzenemethanol with 3.8 g (13.4 mmol) of methyl 2-hydroxy-4-iodobenzoate, 4.4 g (83%) of methyl 4-[3-hydroxy-3-(3-tert-butyl-4-propyloxyphenyl)-1-propynyl]benzoate were obtained in the form of a dark brown oil.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:23]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=[CH:22]3)[C:16]=2C(OC)=O)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C1(B(O)O)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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:25]1([C:24]2[C:23]3[C:17]([CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:16][C:15]=2[C:12]2[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:10][CH:11]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)c1c2cccccc-2c(-c2ccccc2)c1-c1ccc(S(=O)(=O)NC(C)(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)c1ccc(-c2cc3cccccc-3c2-c2ccccc2)cc1
Temperature: 0 °C

Procedure:
Methyl 2- (4-t-butylaminosulfonylphenyl) -3-phenylazulene-1-carboxylate: To a solution of methyl 3-bromo-2-(4-t-butylaminosulfonylphenyl) azulene-1-carboxlate (0.56 g) in toluene (10.0 ml) was added phenylboronic acid (0.34 g), tetrakis(triphenylphosphine)palladium (0) (0.07 g) and 2M aqueous Na2CO3 (2.3 ml), and the reaction mixture was heated under reflux for 2 hr. The reaction mixture was poured into ice-water, followed by extracted with EtOAc. The combined EtOAc extracts were washed with water and brine, dried over Na2SO4, and concentrated. The crude product was purified by SiO2 column chromatography (benzenee/EtOAc, 20:1) to give the title compound (0.47 g) as violet crystals; mp 76°-77° C.
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]4[O:22][CH:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].[H][H]>O.C(O)(=O)C.[Pd]>[CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]4[O:22][C@H:6]5[C:7]([CH2:9][CH2:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8]
Reactant: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Yield: 79 %

Procedure:
The 14-hydroxycodeinone (39.45 g of the damp solid) was dissolved in water (81.13 ml) and 80% acetic acid (16.17 ml). 10 wt % palladium on carbon catalyst (0.33 g wet weight, 0.16 g dry weight) was added and hydrogen was passed through the mixture for about 6 hours at about 12 psi. The mixture was filtered to remove the catalyst. An ammonium hydroxide solution was added to the mixture up to pH 9. The solid precipitate was washed with water and with ethanol, and was dried. The product was oxycodone (18.8 g, 79% yield).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)=[CH:4][CH:3]=1.[CH3:18][CH:19]([C:21](=O)[CH2:22][C:23](=O)[CH:24]([CH3:26])[CH3:25])[CH3:20].ClC1C=CC(OCCCC2N=C(N)NN=2)=CC=1.FC1C=CC(O)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]2[N:14]=[C:13]3[N:15]=[C:21]([CH:19]([CH3:20])[CH3:18])[CH:22]=[C:23]([CH:24]([CH3:26])[CH3:25])[N:12]3[N:11]=2)=[CH:16][CH:17]=1.[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)=[CH:16][CH:17]=1
Reactant: CC(C)C(=O)CC(=O)C(C)C
Agent: Nc1nc(CCCOc2ccc(Cl)cc2)n[nH]1
Agent: Nc1nc(CCCOc2ccc(F)cc2)n[nH]1
Agent: Oc1ccc(F)cc1
Product: CC(C)c1cc(C(C)C)n2nc(CCCOc3ccc(F)cc3)nc2n1
Yield: 61 %

Procedure:
The title compound was prepared according to the experimentals described for Example 22 above from 3-[3-(4-fluorophenoxy)propyl]-1H-1,2,4-triazol-5-amine and 2,6-dimethyl-3,5-heptanedione in 61% yield. The reagent 3-[3-(4-fluorophenoxy)propyl]-1H-1,2,4-triazol-5-amine was prepared by a similar procedure for the synthesis of 3-[3-(4-chlorophenoxy)propyl]-1H-1,2,4-triazol-5-amine in Example 22 above, beginning from 4-fluorophenol instead of 4-chlorophenol. EM (calc.): 356.2; MS (ESI) m/e: 357.4 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([F:21])=[C:5]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1)#N.CC(C[AlH]CC(C)C)C.[O:31]1CCCC1>>[CH3:18][N:17]([CH3:19])[C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH:1]=[O:31])[C:4]=2[F:21])=[O:20])=[CH:12][CH:13]=1
Reactant: CN(C)c1ccc(C(=O)Nc2cccc(C#N)c2F)cc1
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Product: CN(C)c1ccc(C(=O)Nc2cccc(C=O)c2F)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of N-(3-cyano-2-fluorophenyl)-4-(dimethylamino)benzamide (2.18 g, 7.70 mmol) in tetrahydrofuran (150 mL) at −78° C. was added DIBAL-H (23.09 mL, 23.09 mmol) over 20 min. The mixture was stirred at −78° C. for 1 h before it was allowed to warm to room temperature and stirred at room temperature for 4 hr. The mixture was poured into ice/water (600 mL) and stirred at room temperature for 30 min. The mixture was extracted with CH2Cl2 (4×100 mL). The combined extract was filtered through CELITE®, washed with brine (80 mL), and dried over anhydrous MgSO4. Evaporation of the solvent under vacuum provided a crude product (1.83 g) as a pale yellow solid. This product was used in the next step without further purification.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O)(=O)C.[CH2:9]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH:25]=O)[CH2:21][CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([BH3-])#N.[Na+]>CO>[CH2:9]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH:4][CH:1]2[CH2:3][CH2:2]2)[CH2:21][CH2:20]1)=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCC(CNC2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
Cyclopropylamine (1.4 g, 24.4 mmol) and acetic acid (0.5 ml) were added to a solution of 4-formyl-piperidine-1-carboxylic acid benzyl ester from Example E33.2 (5.5 g, 22.2 mmol) in methanol (49.5 ml) and the mixture was stirred for 1 h at room temperature. Sodium cyanoborohydride (1.84 g, 28.9 mmol) was added and the mixture was stirred for 20 h at room temperature under an inert atmosphere. Solvents were removed in vacuo and azeotroped with toluene. The residue was dissolved in EtOAC, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% methanol:90% dichloromethane) to yield the title compound (3.0 g, 47%).
Reaction SMILES: [CH2:1]([CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)O)[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)Br.Cl.[CH:39]1([NH:45][C:46]([CH:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)=[O:47])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:39]1([NH:45][C:46]([CH:48]2[CH2:49][CH2:50][N:51]([CH:3]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=3)[CH2:1][CH3:2])[CH2:52][CH2:53]2)=[O:47])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: CCC(O)c1cccc([N+](=O)[O-])c1
Reactant: O=C(NC1CCCCC1)C1CCNCC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(c1cccc([N+](=O)[O-])c1)N1CCC(C(=O)NC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.5 %

Procedure:
A solution of α-ethyl-3-nitro-benzenemethanol (0.54 g, 2.98 mmol) in DCM (10 mL) is treated with PPh3 (1.6 g, 6.1 mmol).) and CBr4 (2 g, 6.03 mmol). The yellowish solution is stirred at RT for 2 h 30. Piperidine-4-carboxylic acid cyclohexylamide hydrochloride J-1 (0.82 g) is added at once, as well as DIPEA (2 mL). The RM is stirred at RT overnight then heated to 70° C. for 1H. The RM is evaporated under reduced pressure. The residue is partitioned between DCM (25 mL) and sat. aq. NaHCO3 (25 mL). The organic layer is washed twice with sat. aq. NaHCO3, dried over MgSO4 and evaporated under reduced pressure. The crude residue is purified by flash chromatography on silica gel using a gradient of DCM/MeOH/NH4OH 95:5:1 to 90:10:1. After concentration of the product-containing fractions, the title compound (0.173 g, 16%) is obtained as a colorless solid LC-MS A: tR=0.68 min; [M+H]+=374.21.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:18][C:17]=1[CH3:33].Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:18][C:17]=1[CH3:33]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4ccccc4)cc3C)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4ccccc4)cc3C)c2cc1OC
Temperature: 0 °C
Yield: 80 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methylphenyl}-2-phenoxyacetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%). Mass spectrometry value (ESI-MS, m/z): 434 (M++1)
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][C:5]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]2[C:8]([N:9]=[C:10]3[C:15](=[N:16]2)[CH:14]=[CH:13][CH:12]=[CH:11]3)=[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=12>CO>[CH3:3][O:4][C:5]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]2[C:8]([N:9]=[C:10]3[C:15](=[N:16]2)[CH:14]=[CH:13][CH:12]=[CH:11]3)=[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=12
Reactant: C=[N+]=[N-]
Reactant: CCOC(=O)c1c(O)c2ccccc2c2nc3ccccc3nc12
Solvent: CO
Product: CCOC(=O)c1c(OC)c2ccccc2c2nc3ccccc3nc12
Reaction time: 8 h
Yield: 91.5 %

Procedure:
An excess amount of diazomethane ethereal solution was added to a suspension of 640 mg of ethyl 5-hydroxybenzo[a]-phenazine-6-carboxylate in 8 ml of methanol and the mixture was left to stand overnight. The solvent was evaporated off under reduced pressure and the residual powder was recrystallized from ethanol to give 626 mg (91.5% yield) of ethyl 5-methoxybenzo[a]phenazine-6-carboxylate as orange prisms, m.p. 155°-157° C., Anal. Calcd. (%) for C20H16N2O3 : C, 72.28; H, 4.85; N, 8.43; Found: C, 72.41; H, 4.66; N, 8.18
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([F:19])[C:17]=1F)[C:12]([OH:14])=[O:13].Cl>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:17]2[C:16]([F:19])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[F:8])[CH2:3][CH2:2]1
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Reactant: OCC1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(F)c(OCC2CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of cyclopropylmethanol (5.62 mL) in DMF (30 mL) was added sodium hydride (60% oil, 2.84 g), and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added 3,4,5-trifluorobenzoic acid (5.00 g), and the mixture was stirred at room temperature for 30 min. The reaction mixture was neutralized with 6 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in DMF (20 mL) were added potassium carbonate (3.92 g) and methyl iodide (1.77 mL), and the mixture was stirred with heating at 60° C. for 40 min. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate). To a solution of the obtained oil in a mixed solvent of THF (20 mL) and methanol (20 mL) was added 2 M aqueous sodium hydroxide solution (28.8 mL), and the mixture was stirred with heating at 60° C. for 40 min. The reaction mixture was allowed to cool to room temperature, and neutralized with 6 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was washed with hexane to give the title compound (5.32 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH:7]=O.[CH3:9][C:10]([S@@:13]([NH2:15])=[O:14])([CH3:12])[CH3:11].S([O-])(O)(=O)=O.[K+]>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH:7]=[N:15][S@:13]([C:10]([CH3:12])([CH3:11])[CH3:9])=[O:14]
Reactant: O=Cc1ncccn1
Reactant: CC(C)(C)[S@@](N)=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)[S@](=O)N=Cc1ncccn1
Temperature: 50 °C
Yield: 80.5 %

Procedure:
A mixture of 2-pyrimidine-carboxaldehyde (11.5 g, 107 mmol), (S)-(−)-2-methyl-2-propanesulfinamide (12.9 g, 107 mmol) and potassium hydrogensulfate (14.5 g, 107 mmol) in toluene (57 ml) was heated at 50° C. overnight. After decanting the solution, the solid residue is washed 3 times with dichloromethane, the washings combined with the decanted solution and solvents are evaporated in vacuo to give 18.2 g (81%) of (S)-2-methyl-propane-2-sulfinic acid 1-pyrimidin-2-yl-methylideneamide. LC/MS (method 3): Rt=1.29 min; m/z=212.09 (M+H+).
Reaction SMILES: I[C:2]1[C:3]([CH3:12])=[N:4][O:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[OH:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>[Pd](Cl)Cl.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.CN(C=O)C>[OH:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:3]([CH3:12])=[N:4][O:5][C:6]=2[CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: COC(=O)Cc1onc(C)c1I
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1onc(C)c1-c1ccc(O)cc1
Temperature: 85 °C
Yield: 64.7 %

Procedure:
To a 50 mL two neck RB flask fitted with magnetic stirrer was charged with 5 mL of DMF. To the stirred solvent were added methyl (4-iodo-3-methyl-1,2-oxazol-5-yl)acetate (0.7 g, 2.5 mmol), (4-hydroxyphenyl)boronic acid (0.34 g, 2.5 mmol) and 1 mL of aqueous NaHCO3 solution (0.62 g, 7.47 mmol) under argon atmosphere. After purging the argon gas about 10 minutes was added bis-(triphenylphosphine) palladium(II)chloride (0.21 g, 0.3 mmol) and heated at 85° C. for 4 h. The RM was filtered through celite and washed with cold water and extracted with ethyl acetate (25 mL). The organic layer was washed with water (20 mL) and saturated brine solution (20 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude material was purified by silica gel column chromatography using ethyl acetate and petroleum ether as eluents. The product was obtained as brown solid (0.4 g, yield: 66.6%). 1H NMR (300 MHz, CDCl3): δ 7.07-7.10 (d, 2H), 6.84-6.86 (d, 2H), 5.82 (s, 1H), 3.69 (s, 2H), 3.66 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]2[C:6]([CH2:9][C:10](OC)=[O:11])=[N:7][CH:8]=[C:2]12.[BH4-].[Li+].CO.Cl>C(O)C>[OH:11][CH2:10][CH2:9][C:6]1[N:3]2[C:2]([S:1][CH:5]=[CH:4]2)=[CH:8][N:7]=1
Reactant: COC(=O)Cc1ncc2sccn12
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCO
Product: OCCc1ncc2sccn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To a solution of 1.10 g (5.62 mmol) of methyl (imidazo-[5,1-b]thiazol-5-yl)acetate in 15 ml of ethanol was added 61 mg (2.8 mmol) of lithium borohydride with ice-cooling, and the mixture was stirred at room temperature for 30 minutes. To this was added 130 mg (5.6 mmol) of lithium borohydride. The mixture was stirred at room temperature for 3 hours, and allowed to stand overnight in a refrigerator. 20 ml of methanol and 2 ml of concentrated hydrochloric acid were added to the reaction solution with ice-cooling. The mixture was stirred, and then concentrated under reduced pressure. To this was added 30 ml of methanol, and the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was concentrated to approximately half the original volume under reduced pressure. The crystals precipitated were collected by filtration to give 640 mg of the title compound.