Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([S:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:4])[CH3:3].C(N(CC)CC)C.[F:19][C:20]([F:34])([F:33])[O:21][C:22]1[CH:32]=[CH:31][C:25](/[CH:26]=[CH:27]/[C:28](Cl)=[O:29])=[CH:24][CH:23]=1>ClCCl>[C:2]([S:5][CH:6]1[CH2:11][CH2:10][N:9]([C:28](=[O:29])/[CH:27]=[CH:26]/[C:25]2[CH:24]=[CH:23][C:22]([O:21][C:20]([F:33])([F:34])[F:19])=[CH:32][CH:31]=2)[CH2:8][CH2:7]1)(=[O:4])[CH3:3]
Reactant: CC(=O)SC1CCNCC1
Reactant: O=C(Cl)/C=C/c1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)SC1CCN(C(=O)/C=C/c2ccc(OC(F)(F)F)cc2)CC1
Yield: 95.2 %

Procedure:
In 17 ml of dichloromethane were suspended 1.28 g (6.53 mmol) of 4-(acetylthio)piperidine hydrochloride, and 2.27 ml (16.3 mmol) of triethylamine were added dropwise to the suspension with stirring under ice-cooling. Then, a solution in which 1.80 g (7.18 mmol) of (E)-4-(trifluoromethoxy)cinnamoyl chloride were dissolved in 6 ml of dichloromethane was added dropwise to the reaction mixture, followed by stirring of the mixture at the same temperature for 1 hour. The reaction mixture was subjected to silica gel column chromatography and eluted with a mixed solvent of hexane-ethyl acetate (2:1 to 1:1) to obtain 2.32 g (yield: 95%) of the desired compound as a slightly yellow solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:28])[CH2:24][C:25]([OH:27])=O)=[N:20][CH:21]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[N:51]1([C:57]([C:59]2[CH:64]=[C:63]([F:65])[C:62]([F:66])=[C:61]([F:67])[CH:60]=2)=[O:58])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1>CN(C=O)C.O>[O:27]=[C:25]([N:54]1[CH2:55][CH2:56][N:51]([C:57](=[O:58])[C:59]2[CH:64]=[C:63]([F:65])[C:62]([F:66])=[C:61]([F:67])[CH:60]=2)[CH2:52][CH2:53]1)[CH2:24][C:23]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:21][N:20]=1)=[O:28]
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cn1
Reactant: O=C(c1cc(F)c(F)c(F)c1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC(=O)N1CCN(C(=O)c2cc(F)c(F)c(F)c2)CC1)Nc1ccc(-c2ccccc2)cn1
Reaction time: 0.03 h
Yield: 15.1 %

Procedure:
DIPEA (453 mg, 3.51 mmol) was added to N-(5-phenyl-pyridin-2-yl)-malonamic acid (300 mg, 1.17 mmol), which was prepared following the synthetic route described in method II, in DMF (3 mL) followed by EDCI (336 mg, 1.75 mmol) and HOBT (189 mg, 1.4 mmol). After 2 minutes, piperazin-1-yl-(3,4,5-trifluoro-phenyl)-methanone hydrochloride (328 mg, 1.17 mmol) was added and stirring was continued at room temperature overnight. Cold water was then added and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by preparative HPLC afforded 85 mg (15% yield) of 3-oxo-N-(5-phenyl-pyridin-2-yl)-3-[4-(3,4,5-trifluoro-benzoyl)-piperazin-1-yl]-propionamide. LC/S [M+H]+: 483.16, 97.03%. 1H NMR (300 MHz, DMSO-d6): δ 10.7 (s, 1H), 8.7 (s, 1H), 8.1 (s, 2H), 7.7 (d, 2H), 7.5 (m, 4H), 7.4 (m, 1H), 3.7-3.1 (bs, 2H), 3.6-3.2 (m, 8H).
Reaction SMILES: [O:1]=[C:2]([NH:5][C:6]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][CH:24]=[CH:23]2)([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9]CC)=O)[CH2:3][CH3:4].[H][H]>C(O)(=O)C.[Pt]=O>[O:9]=[C:7]1[C:6]([NH:5][C:2](=[O:1])[CH2:3][CH3:4])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:17][C:18]2=[CH:19][CH:20]=[CH:21][C:22]3=[C:27]2[N:26]1[CH2:25][CH2:24][CH2:23]3
Reactant: CCOC(=O)C(Cc1cccc2cccnc12)(NC(=O)CC)C(=O)OCC
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOC(=O)C1(NC(=O)CC)Cc2cccc3c2N(CCC3)C1=O
Yield: 77.8 %

Procedure:
A mixture of diethyl ((1-oxopropyl)amino)(8-quinolinylmethyl)propanedioate (17.47 g, 0.047 mol) and platinum oxide (0.72 g) in glacial acetic acid (150 mL) was hydrogenated (50 1b initial pressure) until hydrogen uptake ceased (1.8 equiv). The mixture was filtered through celite and the solvent removed under reduced pressure. The product was crystallized from ethyl acetate to give 12.08 g of crystals, mp 136°-140° C. A sample was recrystallized from ethyl acetate for analysis; mp 137°-141° C. Anal. Calc'd for C18H22N2O4 : C, 65.44; H, 6.71; N, 8.48. Found: C, 65.66; H, 6.64; N, 8.43.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Cl)=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[H-].[Na+].O>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:36][C:35]3[CH:38]=[CH:39][C:32]([O:31][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:33][CH:34]=3)[C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCc2c(n(Cc3ccc(OCc4ccccc4)cc3)c3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
To a stirred solution of 2-benzyloxycarbonyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole (17.75 g, 58.0 mmole) in dry DMF (150 mL) at was added 4-benzyloxybenzylchloride (14.85 g, 63.8 mmole). After 10 min, 60% NaH (2.78 g. 69.6 mmole),was added and the reaction slurry was allowed to warm to RT and stir for 12 hr. The reaction contents were poured into H2O (200 mL) and extracted with EtOAc (2×200 mL). The combined organic phases were washed sequentially with H2O and brine, then were dried over Na2SO4. Concentration under reduced pressure gave a waxy solid. Purification on silica (hexanes/EtOAc, 4:1) afforded the title compound (27.13 g, 93%) as a white solid: MS (ES) m/e 503 (M+H)+.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].Cl.[CH3:27]O>>[CH3:27][O:10][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=1
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: CO
Agent: Cl
Product: CCCCNc1cc(C(=O)OC)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 5 h

Procedure:
A mixture of 3-n-butylamino-4-phenoxy-5-sulphamyl-benzoic acid (3 g) and methanol (60 ml) was saturated with gaseous hydrogen chloride. The reaction mixture was allowed to warm during the saturation. After cooling and standing for 5 hours, the reaction mixture was evaporated in vacuo, and the residue was recrystallized from methanol (12 ml), whereby the methyl-3-n-butylamino-4-phenoxy-5-sulphamyl-benzoate was obtained with a melting point of 148° C.
Reaction SMILES: [Cl-].[NH4+].C[Al](C)C.C.ClC1C(C#N)=[N:11]C=C(Cl)C=1.[F:18][C:19]1[C:20]([C:26]#[N:27])=[N:21][CH:22]=[C:23]([F:25])[CH:24]=1>C1(C)C=CC=CC=1.CO>[F:18][C:19]1[C:20]([C:26](=[NH:11])[NH2:27])=[N:21][CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: N#Cc1ncc(F)cc1F
Reactant: N#Cc1ncc(Cl)cc1Cl
Agent: C
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: CO
Solvent: Cc1ccccc1
Product: N=C(N)c1ncc(F)cc1F
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
33.4 g (0.624 mol) of ammonium chloride are suspended in 1 l of toluene and cooled to 0-5° C. 328 ml of trimethylaluminium (2 M in hexane, 0.624 mol) are added dropwise, and the mixture is stirred at RT until the evolution of methane has ceased. The solution of 3,5-dichloro-pyridine-2-carbonitrile in toluene (solution from Example V) is then added dropwise, and the mixture is then stirred at 80° C. overnight. After cooling to from 0 to −5° C., MeOH is added dropwise until the evolution of gas has ceased, the salts are filtered off with suction and washed to 2× with a little MeOH. The mixture is concentrated using a rotary evaporator and the residue is dissolved in 500 ml of CH2Cl2/MeOH (9:1) and once more filtered off with suction from inorganic salts. The mixture is concentrated using a rotary evaporator, giving 23.6 g (39.1%) of 3,5-difluoro-2-pyridinecarboximidamide as hydrochloride (m.p.: 183° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[Cl:24])[NH2:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:24])=[C:17]([Cl:16])[CH:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Product: Clc1ccc(NC2CCCc3c2[nH]c2ccc(Br)cc32)cc1Cl

Procedure:
6-Bromo-N-(3,4-dichlorophenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (200 mg, 0.76 mmol) and 3,4-dichloroaniline (245 mg, 1.51 mmol) in a similar manner as described above to give 12 mg (4%) of an off-white solid; 1H-NMR (DMSO-d6): δ 11.08 (s, 1H), 7.57 (d, 1H), 7.26 (d, 1H), 7.23 (d, 1H), 7.13 (dd, 1H), 6.92 (d, 1H), 6.70 (dd, 1H), 6.52 (d, 1H), 4.79-4.77 (m, 1H), 2.68-2.52 (m, 2H), 1.99-1.72 (m, 4H); MS m/z (M−1) 409.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][NH2:18])=[N:15][CH:16]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][NH:18][C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])=[N:15][CH:16]=1
Reactant: O=C(Cl)N1CCCCC1
Reactant: NNc1ccc(F)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NNc1ccc(F)cn1)N1CCCCC1
Yield: 84 %

Procedure:
1-Piperidine carbonyl chloride (348 mg, 0.30 mL, 2.36 mmol) was added dropwise to a solution of 5-fluoro-2-hydrazinyl-pyridine (see for reference WO 2010/022076, which is incorporated herein by reference in its entirety; 0.30 g, 2.36 mmol) and DIPEA (1.2 mL, 7.08 mmol) in DCM (10 mL) at RT under nitrogen and the mixture stirred for 2 h. The solution was washed with water (2×15 mL) and dried (Na2SO4). The solvent was evaporated and the residue triturated (diethyl ether) and filtered to afford the title compound as an off-white solid (475 mg, 84%). LCMS (Method 1): Rt 1.82 min, m/z 239 [MH+].
Reaction SMILES: [OH:1][C@H:2]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[CH2:3][N:4]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N+:23]([O-])=O)[CH:19]=2)[O:14]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[BH4-].[Na+]>C1COCC1.C(O)C.[Pd]>[NH2:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[O:14][C@@H:13]([CH2:12][N:4]([CH2:3][C@H:2]([OH:1])[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:22][CH2:21]2
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc([N+](=O)[O-])ccc2O1)C[C@H](O)c1cccnc1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(N)ccc2O1)C[C@H](O)c1cccnc1
Temperature: 0 °C
Yield: 30 %

Procedure:
tert-Butyl (2R)-2-hydroxy-2-(3-pyridinyl)ethyl{[(2R)-6-nitro-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 171, 500 mg, 1.2 mmol) was dissolved in degassed THF, and to the solution was added Pd/C (50 mg, 10%) under argon and cooled to 0° C. NaBH4 was dissolved in ethanol and added to the reaction slowly to avoid excessive bubbling. After gas evolution had stopped, the reaction was warmed to room temperature and monitored by TLC. When complete, the reaction was cooled to 0° C. and quenched by the addition of ice. The black precipitate was then filtered through Celite® and the filtrate was concentrated in vacuo until cloudy. The filtrate was then extracted with ethyl acetate and the crude material was purified via flash chromatography to yield the product (30%). 1H NMR (DMSO-d6, δ): 8.4 (m, 2H), 7.7 (m, 1H), 7.4 (m, 1H), 6.4 (d, 1H), 6.3 (s, 1H), 6.2 (d, 1H), 5.6 (d, 1H), 4.8 (m, 1H), 4.5 (m, 1H), 3.5 (m, 2H), 3.4 (m, 2H), 2.8 (m, 2H), 1.8 (m, 1H), 1.5 (m, 1H), 1.2 (d, 9H); LC/MS: m/z 399, MH+ 400
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([F:15])([F:14])([F:13])([F:12])[F:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[F:11][S:10]([F:12])([F:13])([F:14])([F:15])[C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(S(F)(F)(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(S(F)(F)(F)(F)F)c1

Procedure:
2 g (8 mmol) of 3-nitropentafluorosulfanylbenzene (CAS # 2613-26-5) were dissolved in 20 ml of ethanol, admixed with 0.1 g of palladium on carbon (10%) and hydrogenated at 5.5 bar until the hydrogen uptake had ended. Subsequently, the reaction mixture was filtered and concentrated under reduced pressure. Molecular weight 219.01 (C6H6F5NS); retention time Rt=1.74 min. [C]; MS (ESI): 261.07 (MH++CH3CN).
Reaction SMILES: C(Cl)(=O)[C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:8])=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].CN([CH:20]=[O:21])C.S(=O)(=O)(O)O>O(C1C=CC(C(=O)C2C=CC=CC=2)=CC=1)C1C=CC=CC=1.ClCCCl>[O:21]([C:2]1[CH:3]=[CH:4][C:5]([C:6]([Cl:8])=[O:7])=[CH:9][CH:10]=1)[C:20]1[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Agent: O=C(c1ccccc1)c1ccc(Oc2ccccc2)cc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Solvent: ClCCCl
Product: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 1905.3 %

Procedure:
p-Phenoxybenzoyl chloride (12.633 g, 0.0543 moles) and BPBPTCDI (3.5459 g, 0.0054 moles) were polymerized with terephthaloyl chloride (1.1572 g, 0.0057 moles) in the presence of aluminum chloride (32.84 g, 0.2463 moles), DMF (10.08 mLs, 0.1308 moles), p-phenoxybenzophenone (0.1646 g, 0.0006 moles) and DCE (120 mLs) initially at -30° C., but warming to room temperature over two hours. The reaction mixture was left at room temperature for fifteen hours and then heated at 28°-32° C. for twenty-six hours. After working up as described in Example 4 the copolymer was obtained as a very pale orange fibrous powder (14.33 g, 95.2% yield), IV 0.90 dl/g (c=0.12 g/dL).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1.[NH2:19][C:20]1[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=1[C:22]([NH:24][CH2:25][CH:26]1[CH2:28][CH2:27]1)=[O:23].CCN(CC)CC>CC(O)C>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[N:3]=[C:2]2[NH:19][C:20]1[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=1[C:22]([NH:24][CH2:25][CH:26]1[CH2:28][CH2:27]1)=[O:23]
Reactant: Clc1ccc2nc(-c3cccnc3)nc(Cl)c2c1
Reactant: Nc1ccccc1C(=O)NCC1CC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C(NCC1CC1)c1ccccc1Nc1nc(-c2cccnc2)nc2ccc(Cl)cc12
Temperature: 25 °C

Procedure:
A 100 mL round bottom flask was charged with 4,6-dichloro-2-(pyridin-3-yl)quinazoline (synthesized as described in Scheme 1 and 4, substituting 5-chloro-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid) (150 mg, 0.54 mmol) and 2-amino-N-(cyclopropylmethyl)benzamide) (310 mg, 1.63 mmol) and anhydrous i-PrOH (20 mL) was added and refluxed for 3 h. The reaction mixture was cooled to room temperature and Et3N (3 eq) was added. The solvent was removed in vacuo. To the crude product was added a water-methanol mixture (5:1, 50 mL), and then sonicated for 5 min. The solidified compound was collected by filtration, and the solid was recrystallized from hot methanol and washed with water. The product was dried at 50° C. to give 2-(6-chloro-2-(pyridin-3-yl)quinazolin-4-ylamino)-N-(cyclopropylmethyl)benzamide as a colorless cotton (220 mg, 94%). The structure was confirmed by NMR and elemental analysis. 1H NMR (Bruker 300 MHz, DMSO-d6) ppm 0.20-0.98 (m, 5H), 3.07-3.21 (m, 2H), 7.24-8.26 (m, 7H), 8.68-9.55 (m, 5H), 12.22 (s, 1H). CHN Calcd. C, 67.05; H, 4.69; N, 16.29. Found C, 67.15; H, 4.89; N, 16.25
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:24][C:25]([O:27]C)=[O:26])[CH:7]=[CH:8][C:9]=1[NH:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:22][CH3:23])[CH:14]=1)=[O:12]>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:24][C:25]([OH:27])=[O:26])[CH:7]=[CH:8][C:9]=1[NH:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:22][CH3:23])[CH:14]=1)=[O:12]
Reactant: CCn1cc(C(=O)Nc2ccc(CC(=O)OC)cc2Cl)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCn1cc(C(=O)Nc2ccc(CC(=O)O)cc2Cl)c2ccccc21
Temperature: 50 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
In THF (6.0 ml) was dissolved methyl 3-chloro-4-((1-ethyl-3-indolylcarbonyl)amino)phenylacetate. To the resulting solution was added 0.25N NaOH (6.0 ml) at room temperature. After stirring at 50° C. for 18 hours, the reaction mixture was cooled to room temperature and distilled under reduced pressure to remove the solvent. The residue was acidified with 1N HCl (2.0 ml). The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and then, dried under reduced pressure to give 3-chloro-4-((1-ethyl-3-indolylcarbonyl)amino)phenylacetic acid (250.7 mg, 94%) as a brown amorphous substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[NH:11][CH2:12][CH2:13][OH:14].[CH3:15]O>>[F:1][C:2]1[C:3]2[N:11]([CH2:12][CH2:13][OH:14])[CH:15]=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=[N+]([O-])c1cccc(F)c1NCCO
Product: OCCn1cnc2cccc(F)c21

Procedure:
To a solution of 2-[(2-fluoro-6-nitrophenyl)amino]ethanol (0.78 g ) in methanol (15 mL) 10% palladium on carbon (200 mg) was added. The mixture was hydrogentated at hydrogen pressure 1 bar until the consumption of hydrogen gas ceased (60 min). The reaction mixture was filtered through a pad of Celite, which was further washed with methanol and acetonitrile. The filtrate was concentrated to dryness and the residue was dissolved in formic acid (4 mL). The solution was transferred into a microwave vial, which was sealed and irradiated for 15 min at 135° C. The solvent was removed in vacuum, the residue was dissolved in methanol (4 mL) and a 7 M solution of ammonia in methanol (4 mL) was added. After 10 min the mixture was concentrated to dryness and the residue was purified on a short silica column. Yield 0.65 g (93%). MS (ESI) m/z 181.1 [M+H]. 1H NMR (400 MHz, DMSO-D6) δ ppm: 3.60 (t, J=5.3 Hz, 2H), 4.21 (t, J=5.3 Hz, 2H), 6.92 (dd, J=12.1, 8.1 Hz, 1H), 7.02 (m, 1H), 7.34 (d, J=8.1 Hz, 1H), 8.03 (s, 1H), 8.26 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][N:32]3[CH2:31][CH2:30][N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][CH3:21])[CH2:34][CH2:33]3)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1ccc(C2=NOC(CCC=O)C2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2=NOC(CCCN3CCN(c4ccccc4OC)CC3)C2)cc1OC
Yield: 59.4 %

Procedure:
3-[3-(3,4-Dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl]propanal (25.8 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.5 mg, 0.262 mmol) and diisopropylethylamine (26.9 L, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 22.7 mg (60.0%) of the target compound was obtained.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[CH:17]=2)=[C:12]([OH:23])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[BH4-].[Na+].[Cl-].[Na+].CCOCC>CO>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:21][CH2:20][CH2:19][CH:18]([OH:22])[CH:17]=2)=[C:12]([OH:23])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)(C)c1ccc(C2=CC(=O)CCC2)c(O)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CCCCCCC(C)(C)c1ccc(C2=CC(O)CCC2)c(O)c1
Reaction time: 0.5 h

Procedure:
To a -18° C. solution of 70.0 g (0.20 mol) of 3-[4-(1,1-dimethylheptyl]-2-hydroxyphenyl]-cyclohex-2-enone in 200 ml of methanol is added 7.6 g (0.20 mol) of sodium borohydride. The reaction mixture is stirred for 30 minutes and then added to one liter of saturated sodium chloride-one liter of ether. The ether extract is washed once with 500 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue is purified via column chromatography on 500 g of silica gel eluted with 50% ether-pentane to yield the title compound.
Reaction SMILES: O1CCCC1.C([N-]C(C)C)(C)C.[Li+].[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[Cl:25])[N:21]=[C:20]([O:26][CH3:27])[C:19]([O:28][CH3:29])=[N:18]2.[B:30](OC)([O:33]C)[O:31]C.Cl>O1CCCC1.O>[Cl:25][C:24]1[C:15]([Cl:14])=[CH:16][C:17]2[N:18]=[C:19]([O:28][CH3:29])[C:20]([O:26][CH3:27])=[N:21][C:22]=2[C:23]=1[B:30]([OH:33])[OH:31]
Reactant: COc1nc2cc(Cl)c(Cl)cc2nc1OC
Reactant: COB(OC)OC
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc2cc(Cl)c(Cl)c(B(O)O)c2nc1OC
Reaction time: 1 h
Yield: 26.1 %

Procedure:
Lithium diisopropylamide mono(tetrahydrofuran) (1.5M in cyclohexane, 6.18 mL, 9.26 mmol) was added to a stirred suspension of 6,7-dichloro-2,3-dimethoxyquinoxaline (Preparation 1, 2.0 g, 7.72 mmol) in dry tetrahydrofuran (150 mL) at −78° C., under nitrogen. After 1 hour at −78° C., trimethyl borate (1.47 mL, 2.0 g, 19.3 mmol) was added. The solution was stirred for a further 1 hour and then left to reach room temperature over 18 hours. Water (50 mL) was added, the solution was acidified to pH 1 with 2M aqueous hydrochloric acid solution and extracted with dichloromethane (3×150 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using dichloromethane:methanol (100:0 changing to 99:1, by volume) as the eluent to afford 6,7-dichloro-2,3-dimethoxyquinoxaline-5-boronic acid (0.610 g, 26%) as a light brown solid.
Reaction SMILES: [NH:1]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:15].[BH4-].[Na+]>C(O)C>[OH:14][CH:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:1][C:2](=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCCCC(=O)c2ccccc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CCCCC(O)c2ccccc2N1

Procedure:
A solution of 3,4,5,6-tetrahydro-1H-1-benzazonin-2,7-dione (14.2 g), J. Am. Chem. Soc. 88, 1049 (1966), and sodium borohydride (1.4 g) in ethanol (720 ml) is stirred at room temperature for 18 hours. The ethanol is removed under reduced pressure, and the residue dissolved in dichloromethane (350 ml). The solution is extracted with 2N hydrochloric acid (2×200 ml) and saturated brine (100 ml), and dried over sodium sulfate. The solvent is removed under reduced pressure to give 7-hydroxy-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one.