Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([C:13]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]2[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:15]=2[N:14]=1)[CH3:12])C1C=CC=CC=1>[Pd]>[CH3:28][C:24]1[C:16]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:13]([C@@H:11]([NH2:10])[CH3:12])=[N:14][C:15]=2[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cccc2nc([C@H](C)NC(=O)OCc3ccccc3)n(-c3ccccc3)c12
Agent: [Pd]
Product: Cc1cccc2nc([C@H](C)N)n(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 144.2 %

Procedure:
A mixture of [(S)-1-(7-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid benzyl ester (1.5 g, 3.89 mmol) and 10% Pd/C (150 mg) in IMS (25 mL) was degassed with a stream of nitrogen and, after addition of HCl (1M, 2.5 mL), was stirred at RT (room temperature) under a hydrogen atmosphere for 5.5 h. The suspension was then filtered through a pad of Celite® and the filtrate was concentrated in vacuo. The resulting residue was partitioned between DCM (dichloromethane) and water, the organic layer was then washed with a saturated solution of NaHCO3, dried (Na2SO4) and concentrated in vacuo affording (S)-1-(7-Methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine as a brown solid (1.41 g, 96%). LCMS: RT 2.07 min [M−NH2]1 235.1
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(Cl)Cl>[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([NH:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:14]
Reactant: CCOC(=O)c1ccc(C)c(N)c1
Reactant: CC1=C(C(=O)O)SCCO1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(C)c(NC(=O)C2=C(C)OCCS2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
Thionyl chloride (4.5 g, 0.038 mole) was added to a stirred mixture of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid (6.0 g, 0,037 mole) and methylene chloride (100 ml). The mixture was warmed to 30°-35° C. for 3 hours, then evaporated under reduced pressure. The residue, crude 5,6-dihydro-2-methyl-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride (100 ml), and the ice-chilled solution treated dropwise with a solution of ethyl 3-amino-4-methylbenzoate (6.7 g, 0,037 mole) and tziethylamine (4.0 g, 0,040 mole) in methylene chloride (100 ml). The reaction mixture was stirred overnight at room temperature and then worked up by washing in sequence with water, dilute hydrochloric acid, water, 2% sodium hydroxide and water. Evaporation of the solvent gave an oil, which solidified. After recrystallization from ethanol (30 ml), the product (7.1 g, 59% yield) melted at 105°-107° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:3]1.[CH:11]1([O:15][C:16]2[CH:17]=[C:18]([N:24]3[CH2:29][CH2:28][NH:27][C@@H:26]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:25]3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:14][CH2:13][CH2:12]1>>[CH:11]1([O:15][C:16]2[CH:17]=[C:18]([N:24]3[CH2:29][CH2:28][N:27]([C:8](=[O:10])[CH2:7][C:5]4[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=4)[C@@H:26]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:25]3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:12][CH2:13][CH2:14]1
Reactant: Cn1cnc(CC(=O)O)c1
Reactant: COc1ccc(N2CCN[C@@H](CC(C)C)C2)cc1OC1CCC1
Product: COc1ccc(N2CCN(C(=O)Cc3cn(C)cn3)[C@@H](CC(C)C)C2)cc1OC1CCC1

Procedure:
Prepared by the method outlined for Example 189 using 2-(1-methyl-1H-imidazol-4-yl)acetic acid and (S)-1-(3-cyclobutlyoxy-4-methoxy-phenyl)-3-isobutyl-piperazine (Example 34, Compound 122) as starting materials. Product as an oil (13.5%). LC/MS (Method B) 2.6 min, [M+1]+ 441.1. Potency class B.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: CCc1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccccc3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-ethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-ethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[Br:11][C:12]1[CH:13]=[N:14][NH:15][CH:16]=1.CN(C=O)C>CCOC(C)=O>[Br:11][C:12]1[CH:13]=[N:14][N:15]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][CH:9]=[CH:10][C:3]=23)[CH:16]=1
Reactant: Brc1cn[nH]c1
Reactant: Brc1ccnc2[nH]ccc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1cnn(-c2ccnc3[nH]ccc23)c1
Temperature: 150 °C

Procedure:
A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (1.10 g, 0.00558 mol) and 4-bromo-1H-pyrazole (1.2 g, 0.0084 mol) was heated neat to 150° C. for 2 h. DMF was added to dissolve the crude residue. This residue was taken up in EtOAc and washed with IN NaOH. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give a crude 4-(4-bromo-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-b]pyridine residue, LC/MS (M+H)+: 263, 265.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[CH2:35]([S:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])=[O:38])[CH3:36]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:43]3[CH2:42][CH2:41][N:40]([S:37]([CH2:35][CH3:36])(=[O:38])=[O:39])[CH2:45][CH2:44]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Reactant: CCS(=O)(=O)N1CCNCC1
Product: CCS(=O)(=O)N1CCN(C(=O)N2C(c3ccc(OC)cc3OC(C)C)=N[C@@H](c3ccc(Cl)cc3)[C@H]2c2ccc(Cl)cc2)CC1

Procedure:
[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-ethanesulfonyl-piperazin-1-yl)-methanone was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 6) and 1-ethanesulfonyl-piperazine (prepared from 1-tert-butyloxycarbonyl-piperazine and ethanesulfonyl chloride) in an analogous manner as described in example 8. LR-MS: 659.2 [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:23])=[C:6]([C:8]([NH:11][C:12]([N:14]2[CH:20]3[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]3)[CH2:16][CH2:15]2)=[O:13])([CH3:10])[CH3:9])[CH:7]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:23][C:5]1[CH:4]=[CH:3][C:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:7][C:6]=1[C:8]([NH:11][C:12]([N:14]1[CH:20]2[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])[CH3:9]
Reactant: CC(C)(NC(=O)N1CCN2CCC1CC2)c1cc(Br)ccc1F
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(NC(=O)N1CCN2CCC1CC2)c1cc(-c2ccccc2)ccc1F
Yield: 28.3 %

Procedure:
Using general procedure E, N-(2-(5-bromo-2-fluorophenyl)propan-2-yl)-1,4-diazabicyclo[3.2.2]nonane-4-carboxamide (100 mg, 0.261 mmol), phenyl boronic acid (30 mg, 0.25 mmol) and palladium (II) acetate gave the title compound as an off-white solid (27 mg, 39%). 1H NMR (400 MHz, CDCl3) δ 7.56-7.51 (m, 3H), 7.41-7.37 (m, 3H), 7.32-7.30 (m, 1H), 7.03 (m, 1H), 4.90 (s, 1H), 4.00 (br s, 1H), 3.59 (m, 2H), 3.11-2.92 (m, 6H), 2.04-1.98 (m, 2H) 1.78 (s, 6H), 1.73-1.67 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3) δ 161.8, 159.4, 155.9, 140.9, 137.2, 134.6, 128.9, 127.4, 127.3, 127.2, 127.1, 127.0, 116.9, 57.9, 54.4, 48.1, 46.5, 46.5, 41.4, 29.9, 29.3, 27.5, 27.5 ppm. Purity: >99% UPLCMS (210 nm); retention time 0.90 min; (M+1) 400.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C@H:13](O)[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.[F:17]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.F.F.F.C(N(CC)CC)C.C(N(CC)CC)C>C1COCC1.O.CCOC(C)=O.CCCCCCC>[F:17][C@H:13]([C@H:12]1[CH2:11][O:10][C:9](=[O:16])[N:8]1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[N:7]=1)[CH3:14]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C[C@@H](O)[C@H]1COC(=O)N1c1ccnc(F)n1
Agent: F
Solvent: O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: C[C@H](F)[C@H]1COC(=O)N1c1ccnc(F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.5 %

Procedure:
To a round bottom flask containing a solution of (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (1.52 g, 6.69 mmol) in THF (22 mL) was added perfluorobutanesulfonyl fluoride (3.6 mL, 20.1 mmol) followed by the addition of triethylamine trihydrofluoride (3.3 mL, 20.1 mmol) and triethylamine (8.4 mL, 60.2 mmol). The resulting reaction mixture allowed to stir at room temperature for 2 hr. The reaction mixture was then diluted with water and the aqueous mixture was extracted with EtOAc. The organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 60%) provided a white crystalline of (R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (207 mg, 0.90 mmol, 14% yield). 1H NMR (400 MHz, CDCl3) δ 1.44 (dd, J=23.48, 6.26 Hz, 3H) 4.47-4.57 (m, 1H) 4.66 (dd, J=8.80, 3.33 Hz, 1H) 4.71-4.86 (m, 1H) 5.22-5.45 (m, 1H) 8.21 (dd, J=5.48, 3.91 Hz, 1H) 8.52 (dd, J=5.48, 1.96 Hz, 1H). LCMS m/z 230.1 (M+H)+, Rt 0.63 min.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][N:8]([C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[O:14])[CH2:7][CH2:6][C:5]=2[C:4]=1[CH:21]=[O:22].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][N:8]([C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[O:14])[CH2:7][CH2:6][C:5]=2[C:4]=1[CH:21]=[O:22]
Reactant: COc1ccc2c(c1C=O)CCN(C(=O)c1cccnc1)C2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1c(O)ccc2c1CCN(C(=O)c1cccnc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of 6-methoxy-2-(pyridine-3-carbonyl)-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde (62 mg, 0.21 mmol) in dichloromethane (5 mL) stirred under argon at −78° C. was added boron tribromide (0.12 mL, 0.31 g, 1.25 mmol). The reaction was stirred for 1 h, allowed to warm to room temperature and stirred for 2 h. The reaction was quenched by addition of methanol (2 mL) at −78° C. and the mixture was stirred for 1 h. After warming to room temperature, ethyl acetate (3 mL) and diethyl ether (30 mL) were added, upon scratching the product started to precipitate. The mixture was allowed to stand refrigerated overnight, the product was collected, washed with ethyl acetate and dried over P2O5 to give the title compound (48 mg, 0.13 mmol, 61.9%) as a beige powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]([OH:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:16])=[CH:4][C:3]=1[CH2:17][CH2:18][OH:19]>C1C=CC=CC=1.[O-2].[O-2].[Mn+4]>[NH2:1][C:2]1[C:3]([CH2:17][CH2:18][OH:19])=[CH:4][C:5]([Cl:16])=[CH:6][C:7]=1[C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:15]
Reactant: Nc1c(CCO)cc(Cl)cc1C(O)c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: Nc1c(CCO)cc(Cl)cc1C(=O)c1ccccc1
Yield: 78.3 %

Procedure:
A suspension of 14 g (0.05 mole) of 2-amino-5-chloro-3-[hydroxy(phenyl)methyl]benzene ethanol in 500 ml of benzene was treated with 23 g (0.25 mole) of activated manganese dioxide and brought to reflux in a vessel fitted with a Dean-Stark trap. After 5 hours the hot mixture was filtered through Celite and the benzene stripped to yield a yellow material. This material was recrystallized from ethanol:pet. ether (30:60) to give 10.8 g of the titled compound, m.p. 135°-137° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:27]([O-:29])=[O:28])[C:18]([NH:19][C@H:20]4[CH2:25][CH2:24][CH2:23][C@H:22]([OH:26])[CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S(N2C3=NC=C([N+]([O-])=O)C(N[C@@H]4CCC[C@H](O)C4)=C3C=C2)(=O)=O)C=CC=CC=1>>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:27]([O-:29])=[O:28])[C:18]([NH:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH:22]([OH:26])[CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@H]1CCC[C@H](O)C1
Agent: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@@H]1CCC[C@H](O)C1
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCC(O)C1

Procedure:
A stirred suspension of 1-Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (40.00 g, 118.4 mmol) and 3-amino-cyclohexanol (13.99 g, 121.5 mmol, mixture of four stereoisomers) in isopropyl alcohol (150 ml) was treated with N,N-diisopropylethylamine (30.94 ml, 117.65 mmol) and heated at about 82° C. overnight. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified in four batches by ISCO column chromatography (0-100% Ethyl acetate in heptane), to afford 8.84 g of the trans racemic product as a yellow solid (16.2% yield), and 27.97 g of the cis racemic product as a yellow solid (52.5% yield). In addition 8.66 g of a mixture of cis and trans racemic products (42% trans, 58% cis) was obtained as a yellow solid. Trans (racemic) 3-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanol. LCMS (Method M, ESI): RT=2.61 min, m+H=417.2; 1H NMR (400 MHz, DMSO) δ 8.88 (d, J=11.4 Hz, 1H), 8.12 (d, J=8.0 Hz, 1H), 7.83 (d, J=4.1 Hz, 1H), 7.76 (t, J=7.3 Hz, 1H), 7.65 (t, J=7.7 Hz, 1H), 7.18 (d, J=4.2 Hz, 1H), 4.77 (d, J=3.5 Hz, 1H), 4.36 (s, 1H), 3.99 (d, J=8.4 Hz, 1H), 1.99 (s, 1H), 1.90 (s, 1H), 1.77 (s, 1H), 1.66 (t, J=10.8 Hz, 1H), 1.59-1.46 (m, 2H), 1.25 (s, 1H), 0.85 (d, J=7.0 Hz, 1H). Cis (racemic) 3-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanol. LCMS (Method M): RT=2.47 min, m+H=417.3; 1H NMR (400 MHz, DMSO) δ 8.89 (s, 1H), 8.12 (d, J=7.8 Hz, 2H), 7.85-7.72 (m, 2H), 7.65 (t, J=7.8 Hz, 2H), 6.99 (d, J=4.2 Hz, 1H), 4.89 (d, J=3.8 Hz, 1H), 4.26-4.14 (m, 1H), 3.77 (d, J=3.6 Hz, 1H), 2.05 (d, J=12.4 Hz, 1H), 1.84 (s, 1H), 1.74 (d, J=13.0 Hz, 2H), 1.60-1.28 (m, 5H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[C:8]([O:12][C:13]([NH:15][C@H:16]([CH3:23])[CH2:17]OS(C)(=O)=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].O>CN(C=O)C.C(OCC)(=O)C>[C:8]([O:12][C:13](=[O:14])[NH:15][C@H:16]([CH3:17])[CH2:23][N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)([CH3:11])([CH3:10])[CH3:9]
Reactant: C[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](Cn1cccn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
1H-Pyrazole (70 mg, 1.03 mmol) was dissolved in DMF (5 ml) and cooled in an ice bath. Sodium hydride (60% dispersion in mineral oil, 41 mg, 1.03 mmol) was added and the reaction was stirred for 15 min. Methanesulfonic acid (R)-2-tert-butoxycarbonylamino-propyl ester (200 mg, 0.79 mmol) was then added and the mixture was stirred at 50° C. for 16 h. The reaction was cooled to room temperature and water and ethyl acetate were added. The aqueous layer was extracted twice more with ethyl acetate and the combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) to give 129 mg (72%) of ((R)-1-methyl-2-pyrazol-1-yl-ethyl)-carbamic acid tert-butyl ester. (M+H)+=226.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:27](Cl)=[O:28]>>[CH:1]1([CH2:7][C:8]2[S:12][C:11]([NH:13][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:24]([O:23][CH3:22])[CH:25]=3)=[N:10][C:9]=2[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(-c2nc(N)sc2CC2CCCCC2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Product: COc1ccc(-c2nc(NC(=O)c3ccc(OC)c(OC)c3)sc2CC2CCCCC2)cc1
Yield: 67.5 %

Procedure:
A procedure similar to that in Example 4 was used. 5-cyclohexylmethyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 47 and 3,4-dimethoxy-benzoyl chloride prepared in the step 1 of Example 12 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to give a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (20:1) to obtain a product as a white solid in a yield of 67.5%, mp: 171-172 └. 1H-NMR (CDCl3, 400 MHz) δ: 0.82˜0.98 (2H, m), 1.08˜1.28 (3H, m), 1.58˜1.88 (6H, m), 2.74 (2H, d, J=7.28 Hz, CHCH2Ar), 3.82 (3H, s, OCH3), 3.89 (3H, s, OCH3), 3.94 (3H, s, OCH3), 6.82˜6.89 (3H, m, ArH), 7.35˜7.47 (4H, m, ArH), 11.00 (1H, br, CONH); EI-MS m/e (%): 466.2 (M+, 46), 383.2 (29), 165.1 (100); HREI-MS Calcd. for C26H30N2O4S: 466.1926. found: 466.1920. Anal. Calcd. for C26H30N2O4S: C, 66.93; H, 6.48; N, 6.00. found: C, 66.88; H, 6.68; N, 6.02.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C(OC(Cl)=O)C(C)C.[N:22]1([C:28]([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35](=[O:40])[CH2:34][CH2:33]3)=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[Cl-].[Na+]>CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([N:25]1[CH2:26][CH2:27][N:22]([C:28]([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35](=[O:40])[CH2:34][CH2:33]3)=[O:29])[CH2:23][CH2:24]1)=[O:8]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.4 %

Procedure:
To a solution of 4.8 g of 3,4-dimethoxybenzoic acid and 4 ml of triethylamine in 50 ml of dimethylformamide, a solution of 3.87 g of isobutylchloroformate in 2 ml of dimethylformamide was added dropwise. After the reaction mixture was stirred at a room temperature for 30 minutes, then a solution of 8.1 g of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril in 3 ml of dimethylformamide was added dropwise to the reaction mixture and stirred at a room temperature for 30 minutes, and further stirred at 50°-60° C. for 1 hour. After the reaction was completed, the reaction mixture was poured into a voluminous amount of a saturated sodium chloride aqueous solution and then extracted with chloroform and the chloroform extract was washed with water and dried. The solvent was removed by distillation, and the residue was recrystallized from ethanol-chloroform to obtain 2.5 g of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. Colorless granular crystals. Melting point: 238°-239.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:13])[CH:8]=[CH:7]2.[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21].N1C=CN=C1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]([O:13][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:8]=[CH:7]2
Reactant: OC(Cn1ccc2cccc(Br)c21)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(Cn1ccc2cccc(Br)c21)c1ccccc1
Temperature: 25 °C
Reaction time: 25 h
Yield: 96.5 %

Procedure:
To 2-(7-bromo-1H-indol-1-yl)-1-phenylethanol (0.70 g) were added DMF (7.0 mL), tert-butyl(chloro)dimethylsilane (0.47 g), and imidazole (0.23 g), followed by stirring at room temperature for 25 hours. To the reaction mixture was added a 10% aqueous citric acid solution (15 mL), followed by extraction with ethyl acetate, and the obtained organic layer was washed with brine. After drying over anhydrous sodium sulfate and concentrating under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=99/1-90/10) to obtain 7-bromo-1-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-phenylethyl)-1H-indole (0.92 g).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[S:11][C:10](N)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[BrH:14].BrBr.N([O-])=O.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[Br:14][C:10]1[S:11][C:12]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]=1
Reactant: Nc1nc2cccc([N+](=O)[O-])c2s1
Reactant: Br
Agent: BrBr
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc2nc(Br)sc12
Reaction time: 2 h

Procedure:
To a suspension of 7-nitro-1,3-benzothiazol-2-ylamine (1.80 g, 9.22 mmol) in acetic acid (AcOH) (20 ml) was added 48% hydrogen bromide in H2O (10 ml) with ice-cooling. Bromine (0.157 ml) was added dropwise followed by sodium nitrite (177 mg, 23.9 mmol) in H2O (1 ml). The temperature was kept at 0 to 5° C. The mixture was stirred for 2 h with ice-cooling and then was made alkaline by dropwise addition of 6N NaOH solution. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 1.91 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>C(O)C>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:13][CH:10]2[CH2:12][CH2:11]2)[C:7]=1[NH2:8]
Reactant: NC1CC1
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: CCO
Product: Nc1c(Cl)ncnc1NC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
A stirred solution of 4,6-dichloropyrimidin-5-amine (10 g, 60.9 mmol) and cycloproplyamine (10.44 g, 182.93 mmol, 12.7 mL) in absolute ethanol (100 mL) wee heated at 125° C. in a sealed tube for 4 days. The reaction mixture was then concentrated under reduced pressure to give a yellow solid which was triturated with cold water (200 mL). The resulting slurry was stirred for one hour at room temperature and then filtered. The isolated solid was washed with water (2×25 mL) and dried under reduced pressure to give 11.32 g of the title compound as a pale yellow solid, which was used without any further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:22]([CH:23]=[CH:24][CH:25]=O)=[CH:21][C:20]=1[O:29][CH3:30].[O:31]1[CH2:35][C:34](=[O:36])[NH:33][C:32]1=[O:37]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:22]([CH2:23][CH2:24][CH2:25][CH:35]2[O:31][C:32](=[O:37])[NH:33][C:34]2=[O:36])=[CH:21][C:20]=1[O:29][CH3:30]
Reactant: COc1cc(C=CC=O)ccc1OCc1nc(-c2ccc3ccccc3c2)oc1C
Reactant: O=C1COC(=O)N1
Product: COc1cc(CCCC2OC(=O)NC2=O)ccc1OCc1nc(-c2ccc3ccccc3c2)oc1C

Procedure:
In substantially the same manner as in Working Example 11, 4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]-3-methoxycinnamaldehyde was condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic hydrogenation to yield 5-[3-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]-3-methoxyphenyl]propyl]-2,4-oxazolidinedione. The product was recrystallized from chloroform-methanol-ether to give colorless prisms, m.p.173-174° C.