Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])(CC)C.[CH3:43][Si:44](Cl)([CH3:46])[CH3:45]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][Si:20]([CH:21]([CH3:22])[CH3:23])([CH:24]([CH3:26])[CH3:25])[CH:27]([CH3:29])[CH3:28])[CH:17]=2)[CH:12]=[CH:11][C:10]=1[Si:44]([CH3:46])([CH3:45])[CH3:43])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)[Si](Oc1ccc2cccc(NC(=O)OC(C)(C)C)c2c1)(C(C)C)C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1ccc2ccc([Si](C)(C)C)c(NC(=O)OC(C)(C)C)c2c1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1-(tert-butoxycarbonylamino)-7-(triisopropylsilyloxy) naphthalene, as described above in Step A, (12.47 g, 30.0 mmol) and N,N,N′,N′-tetramethylethylenediamine (10.0 mL, 66.0 mmol) in THF (300 mL) at −78° C. was added sec-butyllithium (1.3 M in cyclohexane, 24.2 mL, 31.5 mmol) dropwise. The reaction mixture was stirred at −78° C. for 5 min, then trimethylsilyl chloride (4.2 mL, 33.0 mmol) was added dropwise and stirring was continued for 30 min. sec-Butyllithium (1.3 M in cyclohexane, 24.2 mL, 31.5 mmol) was added and the mixture was stirred dropwise was stirred at −78° C. for 5 hours, then quenched with saturated aqueous NH4Cl (400 mL) and extracted with CH2Cl2 (2×500 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of hexane—30% to 50% CH2Cl2 to yield the above-titled product.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:19]=[CH:18][C:7]2[C:8]([C:11]3[CH:12]=[C:13](O)[CH:14]=[CH:15][CH:16]=3)=[N:9][O:10][C:6]=2[CH:5]=1.CC1C=CC(S([O:30][CH2:31][C@@H:32]2[O:34][CH2:33]2)(=O)=O)=CC=1.O>CN(C)C=O>[F:3][C:4]1[CH:19]=[CH:18][C:7]2[C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:30][CH2:31][C@H:32]4[CH2:33][O:34]4)=[CH:15][CH:16]=3)=[N:9][O:10][C:6]=2[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: Oc1cccc(-c2noc3cc(F)ccc23)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
To a cold (0° C.) solution of sodium hydride (1.80 g, 45.0 mmol) in dimethylformamide (anhydrous,40 mL) and under a nitrogen atmosphere, add dropwise a solution of 3-(6-fluoro-benzo[d]isoxazol-3-yl)-phenol (10 g, 43.63 mmol) in dimethylformamide (anhydrous, 50 mL). Precipitate forms. Cool (0° C.) reaction mixture for 20 minutes and the material solidifies. Add dimethylformamide (anhydrous, 120 mL) and (2R)-(−)-glycidyl tosylate (10.47 g, 45.87 mmol) dissolved in dimethylformamide (40 mL), dropwise, over a period of time of 0.5 hours, while cooling with an ice bath. After this addition, the reaction mixture becomes homogeneous. Warm reaction mixture to room temperature and stir overnight. Pour reaction mixture into cold water (600 mL), stir for 1 hour under an ice bath, filter and wash the filter cake with water to obtain an off-white solid. Add dichloromethane (200 mL) to the off-white solid, wash with saturated sodium chloride and dry (MgSO4). Directly purify by column (silica) chromatography (dichloromethane) and triturate with pentane to give the title compound as an off-white solid (9.70 g, 78% Yield). MS shows [M+H]+=286. NMR and microanalysis (C, H, N) are consistent with the final, desired compound. mp=132-133° C.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[C:13]1([NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19]>C1COCC1>[NH:19]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:20][C:1]1=[O:2]
Reactant: Nc1ccccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2[nH]1
Temperature: 5 °C
Reaction time: 16 h
Yield: 54.5 %

Procedure:
A mixture of 1,1'-carbonyldiimidazole (10.7 g) and THF (100 ml) was added to a mixture of 1,2-phenylenediamine (6.48 g) and THF (150 ml) which had been cooled to approximately 5° C. in an ice-water bath. The mixture was stirred at ambient temperature for 16 hours. The precipitate was filtered off giving 2,3-dihydrobenzimidazol-2-one (4.38 g, 55%), m.p. >290° C.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][CH2:25][C:26]2=O)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:32]([O:35][CH2:36][CH3:37])(=[O:34])[CH3:33].O>C(COC)OC>[Si:3]([O:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][CH:25]=[C:26]2[CH2:33][C:32]([O:35][CH2:36][CH3:37])=[O:34])([C:16]([CH3:19])([CH3:17])[CH3:18])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC2=O)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)CC1=CCCc2c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cccc21
Reaction time: 0.5 h

Procedure:
To a solution of diethyiphosphoric acid ethyl ester (19 g) in dimethoxyethane (200 ml) was added NaH (3.4 g, 60%) in oil) at 0° C. under N2. After being stirred for 30 minutes, 5-t-butyidiphenylsilyloxy-1-oxo-1,2,3,4-tetrahydronaphthalene (20 g) was added to the mixture. After being stirred for 12 hours at 80° C., the solution was poured hnto a mixture of ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was dissolved into a mixture of toluene (100 ml and 1,8-diazabicyclo[5.4.0]-7-undecene (17 ml) and the mixture was stirred for 3 days at 100° C. The solution was washed with 1N-HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 5-t-butyldiphenylsilyloxy-1-ethoxycarbonylmethyl-3,4-dihydronaphthalene (20.3 g).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1.O>CS(C)=O>[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][CH2:11][CH:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)=[CH:31][CH:30]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CNCC2COc3ccc4c(c3O2)CC(=O)N4)cc1
Temperature: 85 °C
Yield: 56.3 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.00 g, 2.66 mmole) and 4-methoxybenzylamine (1,40 ml, 10.7 mmole) were combined in 10 ml of dry DMSO and heated to 85° C. for 3.5 hours under a nitrogen atmosphere. After cooling to room temperature, 150 ml of water was added and the mixture was extracted twice with 250 ml portions of 35% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an oil, which was column chromatographed on silica gel using 2% methanol/CH2Cl2 as eluant. The free base of the title compound (0.51 g, 64%) was obtained as an oil upon concentration in vacuum. The product was crystallized from ethanol with the addition of one equivalent of fumaric acid to give 0.44 g of the (S) enantiomer of the title compound as an off-white solid fumarate, one-quarter hydrate, m.p. 205°-205.5° C.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([CH3:28])[O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([OH:27])[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16])(C(C)(C)C)(C)C.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37].C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[O:27][C:25]1[CH:24]=[C:14]([CH:13]=[C:12]([O:11][C@@H:10]([CH3:28])[CH2:9][OH:8])[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Oc2cc(O[C@@H](C)CO)cc(C(=O)Nc3ccn(C)n3)c2)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 30.9 %

Procedure:
A solution of 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (0.30 g, 0.74 mmol), 3-fluoro-4-methoxyphenylboronic acid (255 mg, 1.5 mmol), copper (II) acetate (0.202 g, 1.11 mmol), triethylamine (0.517 mL, 3.71 mmol) and freshly activated 4 Å molecular sieves (1 g) in DCM (40 mL) was stirred at ambient temperature and under ambient atmosphere for 2 days. The reaction mixture was filtered through celite, washed with DCM (2×10 mL), the DCM removed in vacuo. The residue was partitioned between ethyl acetate and a saturated solution of sodium bicarbonate, the organic layer washed with brine, dried (MgSO4) and concentrated in vacuo. 3.5M Hydrochloric acid (0.5 mL) was added to a solution of the residual oil dissolved in methanol (5 mL) and stirred at RT for 20 minutes, then the solution neutralised with saturated sodium bicarbonate. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed on silica, eluting with ethyl acetate, to give the desired compound (95 mg).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])=[C:20]([CH:24]=1)[C:21](O)=[O:22]>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])=[C:20]([CH:24]=1)[C:21]([NH:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4])=[O:22]
Reactant: O=C(O)c1cc(Cl)ccc1Oc1c(F)cccc1F
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2c(F)cccc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5) and 5-chloro-2-(2,6-difluorophenoxy)benzoic acid (step 4): 1H-NMR (CDCl3) δ 8.16 (1H, d, J=2.8 Hz), 8.00 (2H, d, J=8.4 Hz), 7.83–7.74 (1H, m), 7.45 (2H, d, J=8.4 Hz), 7.35–7.23 (2H, m), 7.16–7.04 (2H, m), 6.67–6.61 (1H, m), 5.48–5.33 (1H, m), 3.90 (3H, s), 1.59 (3H, d, J=7.0 Hz)); MS (ESI) m/z 446 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=3)[C:11]=2[CH2:12]P(OCC)(OCC)=O)=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].[C:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=O)[CH3:35].O>C1COCC1>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=3)[C:11]=2/[CH:12]=[C:34](/[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)\[CH3:35])=[O:6])[CH2:2][CH2:3]1
Reactant: CC(=O)c1ccccc1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CP(=O)(OCC)OCC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2/C=C(\C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a suspension of N-cyclopropyl-5-(diethylphosphonomethyl)-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (450 mg, 1.00 mmol) obtained in Example 321b) in THF (5 ml) was added sodium hydride (50% oil dispersion, 75 mg) at 0° C., and the mixture was stirred at room temperature for 1 hr. A solution of acetophenone (117 μl) in THF (5 ml) was added to the obtained reaction mixture, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was stirred at 60° C. for 15 hr and cooled to 0° C. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/4 to ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound as a colorless powder (150 mg, 36%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][C@@H:6]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:45])[C@H:26]([CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:27][C:28]([O:30][CH3:31])=[O:29])[O:5][CH2:4]1.[C:46]1([N:52]=[C:53]=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(Cl)Cl>[CH3:31][O:30][C:28]([NH:27][C@H:26]([C:25]([NH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][CH2:16][C@H:6]1[O:5][CH2:4][C@@H:3]([CH2:2][NH:1][C:53](=[O:54])[NH:52][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[N:8]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7]1)=[O:45])[CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:29]
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CN)CO1)C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CNC(=O)Nc2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (2R,5R)-5-(aminomethyl)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-4-carboxylate (1 eq.) in DCM (0.1M) was added phenyl isocyanate (2.2 eq). The reaction mixture was stirred for 16 hrs at room temperature, diluted with CH2Cl2 and the organic layer was washed with aqueous saturated sodium bicarbonate. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by automated silica gel flash chromatography system eluted with a gradient 10% to 100% of EtOAc/Hex to afford title compound.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5](Br)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)CCC>O1CCCC1>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([C:19]2[S:18][CH:17]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Brc1ccc(Br)c2nsnc12
Solvent: C1CCOC1
Product: c1csc(-c2ccc(-c3cccs3)c3nsnc23)c1

Procedure:
An analogous process is described by Kim et al. in “Journal of Material Chemistry” (2008), Vol. 18, pages 5223-5229, in which 4,7-di-2-thienyl-2,1,3-benzothia-diazole (DTB) can be prepared by reacting 4,7-dibromo -2,1,3-benzothiadiazole and tri-n-butyl(thien-2-yl)stannane, in the presence of tetrahydrofuran, at 66° C., for 3 hours. Bis(triphenylphosphine)palladium-(II)chloride [PdCl2(PPh3)2] is used as catalyst. Also in this case, at the end of the reaction, the solvent is removed by evaporation at reduced pressure and the residue obtained is purified by elution on a silica gel chromatographic column using a mixture of methylene chloride/hexane (1/1 vol/vol) as eluent, obtaining 4,7-di-2-thienyl-2,1,3-benzothiadiazole (DTB) with a yield equal to 88%.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:15]3[N:16]=[CH:17][NH:18][C:14]=3[CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28](O)=[O:29])=[CH:22][CH:21]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C:28]([N:11]2[CH2:12][CH2:13][C:14]3[NH:18][CH:17]=[N:16][C:15]=3[CH:10]2[C:7]2[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)=[O:29])=[CH:24][CH:25]=1
Reactant: O=C(O)CCc1ccc(F)cc1
Reactant: CC(C)c1ccc(C2NCCc3[nH]cnc32)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)c1ccc(C2c3nc[nH]c3CCN2C(=O)CCc2ccc(F)cc2)cc1
Yield: 33.3 %

Procedure:
A mixture of histamine dihydrochloride (1.85 g, 10.0 mmol), water (10 mL), potassium hydroxide (1.72 g, 30.0 mmol), ethanol (25 mL) and 4-isopropylbenzaldehyde (1.62 g, 10.91 mmol) was heated to reflux for 1.5 h. Ethanol was evaporated and the residue was diluted with water (40 mL). Extraction (5×25 mL DCM), washing of the combined extracts (2×50 mL brine) and drying (MgSO4) yielded 2.29 g (87%) of crude 4-(4-isopropylphenyl)-4,5,6,7-tetrahydro-imidazo[4,5-c]pyridine, which was used for the next synthetic step without further purification. This amine (0.48 g, 1.99 mmol) was dissolved in DCM (5 mL) and added to a 30 min old mixture of 3-(4-fluorophenyl)propionic acid (0.31 g, 1.84 mmol), HOBt (0.27 g, 1.20 mmol) and EDC (0.42 g, 12.19 mmol) in DCM (10 mL). After 18 h the mixture was washed with water (50 mL), dried (MgSO4) and concentrated. The crude product was purified by column chromatography (silica gel, gradient elution with DCM/methanol). 0.24 g (33%) of the title amide was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([C:13](O)=[O:14])[N:12]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1.S(Cl)(Cl)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([C:13]([N:25]=[N+:26]=[N-:27])=[O:14])[N:12]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1oc(-c2cnc(Cl)cc2NC(C)C)nc1C(=O)O
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Product: Cc1oc(-c2cnc(Cl)cc2NC(C)C)nc1C(=O)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylic acid (30a) (750 mg, 2.54 mmol) and thionyl chloride (12.68 mmol) were refluxed at 100° C. for 20 h. Thionyl chloride was removed under reduced pressure. The resulting solid acid chloride was dissolved in acetone (15 mL) and cooled to 0° C. Sodium azide (7.61 mmol) dissolved in water (3 mL) was added to the reaction mixture at 0° C. and stirred for 30 min. The reaction temperature was raised to room temperature and stirred for 5 h. The reaction mixture was concentrated to remove the solvent. The compound precipitated in the aqueous layer was filtered and dried under vacuum to obtain the desired compound 2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carbonyl azide. LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 μm; Solvent A=10% MeOH: 90% H2O: 0.1% TFA; Solvent B=90% MeOH: 10% H2O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time); retention time: 2.363 min.
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1.[H-].[Na+].[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.O>[Br:1][C:2]1[N:6]([S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])[CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1
Reactant: O=Cc1c[nH]c(Br)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(Br)n(S(=O)(=O)c2ccccc2)c1
Reaction time: 0.17 h
Yield: 85.5 %

Procedure:
To a solution of 5-bromo-1H-pyrrole-3-carbaldehyde (3.50 g) in tetrahydrofuran (70 mL) was added sodium hydride (60% in oil, 1.21 g) at room temperature, and the mixture was stirred for 10 min. Benzenesulfonyl chloride (4.27 g) was added, and the mixture was further stirred for 1 hr, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→7:3) and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 5.4 g, 85%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19]Cl)[C:5]=2[CH:4]=1.C(N(CC)CC)C.[NH:30]1[CH2:35][CH2:34][CH:33]([O:36][CH2:37][CH2:38][OH:39])[CH2:32][CH2:31]1>C(C(C)=O)C.[I-].[Na+]>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19][N:30]3[CH2:35][CH2:34][CH:33]([O:36][CH2:37][CH2:38][OH:39])[CH2:32][CH2:31]3)[C:5]=2[CH:4]=1
Reactant: OCCOC1CCNCC1
Reactant: FC(F)(F)c1ccc2c(c1)N(CCCCl)c1ccccc1S2
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: OCCOC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1

Procedure:
40 g of 2-trifluoromethyl-10-(3-chloropropyl)-phenothiazine were dissolved in 350 ml of methyl ethyl ketone and 17.6 g of sodium iodide, 11.8 g of triethylamine, then 17 g of 2-(4-piperidyloxy)-ethanol were successively added to this solution. It was refluxed for 20 hours and after cooling, the precipitate was removed by vacuum filtration. The filtrate was evaporated to dryness to obtain 2-trifluoromethyl-10-[3-(4-β-hydroxyethoxypiperidino)-propyl]-phenothiazine as an oil which was added to a mixture of ether and dilute hydrochloric acid. The formed precipitate was recovered by vacuum filtration and was crystallized from 95% ethanol to obtain 40.5 g of 2-trifluoromethyl-10-[-3(4-β-hydroxyethoxypiperidino)-propyl]-phenothiazine hydrochloride as white crystals. Then a current of ammonia was led into an ether suspension of this product and the formed precipitate was removed by filtration. The filtrate was evaporated to dryness to obtain 2-trifluoromethyl-10-[3-(4-β-hydroxyethoxypiperidino)-propyl]-phenothiazine as an oil.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:20][CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][CH2:12]2)[CH:3]=1.[NH3:21]>CO.C(Cl)Cl>[O:18]1[C:14]2([CH2:19][CH2:20][CH:11]([C:4]3[CH:3]=[C:2]([NH2:21])[N:7]4[N:8]=[CH:9][CH:10]=[C:6]4[N:5]=3)[CH2:12][CH2:13]2)[O:15][CH2:16][CH2:17]1
Reactant: N
Reactant: Clc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Solvent: ClCCl
Solvent: CO
Product: Nc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Temperature: 100 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
7-chloro-5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidine (5.58 mmol, 1.64 g) is charged to 10-20 mL microwave vessel. To this vessel is added 10 mL ˜7N NH3 in methanol. The vessel was sealed and heated at 100° C. for 18 hours. After 18 hours, the reaction mixture was cooled to room temperature and diluted with 100 mL DCM. The resulting solution is washed with saturated NaHCO3(aq) and extracted with DCM twice more. The combined organics were dried over Na2SO4 and the solvent removed in vacuo to yield 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-7-amine (1.52 g, 99% yield) as pale orange solid.
Reaction SMILES: O.NN.[C:4]1([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:16][CH2:15]2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1>C(O)C>[C:4]1([N:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH2:22])[CH2:18][CH2:19]2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCN(c2cccc3ccccc23)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCN1CCN(c2cccc3ccccc23)CC1

Procedure:
0.17 ml (3.55 mmol) of hydrazine monohydrate is added slowly at room temperature to a solution of 1.14 g (2.96 mmol) of 2-{2-[4-(1-naphthyl)-1-piperazinyl]ethyl}-1H-isoindole-1,3(2H)-dione, prepared in step 1.1, in 15 ml of ethanol. The reaction mixture is then refluxed for 1 hour.
Reaction SMILES: C([O:4][C:5]([CH3:7])=[CH2:6])(=O)C.[CH3:8][CH2:9][CH2:10][CH2:11][CH2:12]C>>[C:7]1([C@@H:5]([OH:4])[CH3:6])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=C(C)OC(C)=O
Reactant: CCCCCC
Product: C[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
(R, S)-1-Phenylethanol (0.244 gram, 2 mmol) and isopropenyl acetate (0.2 gram, 2 mmol) were dissolved in 10 ml of n-hexane dried in advance on Molecular Sieve 4A for one day. To the resulting solution was added 1 gram of an enzyme (Amano P: Product of Amano Seiyaku K. K.), and the mixture was stirred at 25° C. and 150 r.p.m. for 4 hours. The reaction mixture was filtered, and the filtrate was subjected to HPLC using an optically active column. (S)-1-phenylethanol was obtained in an optical purity of 100% with a theoretical yield of 100%.