Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>CN(C=O)C.O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[CH:4][CH:5]=2)=[O:10])=[CH:12][CH:13]=1
Reactant: CCOP(OCC)OCC
Reactant: COc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(C(=O)c2ccc(OC)cc2)cc1)OCC
Temperature: 150 °C
Reaction time: 10 h
Yield: 72 %

Procedure:
(4-(bromomethyl)phenyl)(4-methoxyphenyl)methanone, 32-c, (3 g, 10 mmol) and triethyl phosphite (2 g, 11.9 mmol) was dissolved in DMF (20 ml), and then stirred for 10 h at 150° C. The resulting mixture was cooled to ambient temperature, diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). The organic layer was combined, washed with brine (2×100 ml), dried over Na2SO4 anhydrous, purified by chromatography on silica gel (petroleum ether/ethyl acetate=1:1.5). The pure product, 32-d, was obtained as a colorless oil (2.6 g, 72% yield). 1H NMR (300 MHz, CDCl3) δ 1.20-1.27 (m, 6H), 2.80-2.88 (d, J=22.8, 2H) 3.81 (s, 3H), 3.93-4.07 (m, 4H), 6.86-6.90 (m, 2H), 7.31-7.35 (m, 2H), 7.62-7.93 (m, 4H). LC-MS 363 [MH]+.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(N(CC)CC)C.[Cl:19][C:20]1[N:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[Cl:19][C:20]1[N:25]=[CH:24][C:23]([S:26]([N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][N:2]([CH3:11])[CH3:1])[CH2:6][CH2:7]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CN(C)CCN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCN1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
To a solution of N,N-dimethyl-N-(2-piperazin-1-ylethyl)amine (0.80 g, 5.0 mmol) and triethylamine (1.0 g, 10 mmol) in dichloromethane (7 mL) was added 6-chloropyridine-3-sulfonyl chloride (1.0 g, 5.0 mmol; described in: Naegeli et al. Helv. Chim. Acta, 1938, 21, 1746, 1750) in dichloromethane (3 mL) at room temperature. After stirring over night at room temperature the solvent was removed in vacuo, the residue was partitioned between aqueous sodium hydroxide (2 M), diethyl ether (3×15 mL), and dichloromethane (3×15 mL). The combined extracts were dried (MgSO4), and the solvents were removed in vacuo to afford 1.3 g of the crude product. The residue was purified on a silica gel column using acetonitrile/triethylamine, (90:10), as the eluent to afford 1.0 g (60% yield) of title compound: 1H NMR (CDCl3, 400 MHz) δ 8.73 (d, J=2 Hz, 1H), 7.95 (dd, J=8, 2 Hz, 1H), 7.48 (d, J=8 Hz, 1H), 3.08 (t, J=5 Hz, 4H), 2.56 (t, J=5 Hz, 4H), 2.47 (t, J=7 Hz, 2H), 2.35 (t, J=7 Hz, 2H), 2.19 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 155.8, 148.8, 137.8, 131.3, 124.6, 56.7, 56.0, 52.4, 45.8, 45.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]3[CH2:11][C:12]4[C:17]([C:9]3=[C:8]([CH:18]=[CH:19][N+:20]([O-:22])=[O:21])[C:7]=2[N:23]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4.C(Cl)(Cl)Cl.[BH4-].[Na+].C(O)(=O)C>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]3[CH2:11][C:12]4[C:17]([C:9]3=[C:8]([CH2:18][CH2:19][N+:20]([O-:22])=[O:21])[C:7]=2[N:23]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4
Reactant: COc1ccc2c(n1)c(C=C[N+](=O)[O-])c1n2Cc2ccccc2-1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(n1)c(CC[N+](=O)[O-])c1n2Cc2ccccc2-1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon and in an anhydrous medium, 660 mg (2.15 mmol) of the compound obtained in Step F are suspended in 10 ml of isopropanol and 30 ml of chloroform in the presence of 1.5 g of 230-400 mesh silica; 408 mg (10.75 mmol) of sodium borohydride are added slowly. After 30 minutes' stirring at room temperature, acetic acid is added and the reaction mixture is filtered through a glass frit. After removal of the solvents by evaporation, the residue is diluted in dichloromethane and washed with water. The organic phase is then dried over magnesium sulphate, filtered and concentrated to yield the title compound in the form of a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6](S)[C:5]=3[CH:12]=[CH:13][CH:14]=2.[N:15]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH:19]=[CH:18][N:17]=[CH:16]1>C(O)C>[Br:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([NH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[C:5]=3[CH:12]=[CH:13][CH:14]=2
Reactant: NCCCCCn1ccnc1
Reactant: SC1=Nc2ccc(Br)c3cccc1c23
Solvent: CCO
Product: Brc1ccc2c3c(cccc13)C(NCCCCCn1ccnc1)=N2
Yield: 19.5 %

Procedure:
A mixture of 5.3 g of 6-bromo-benz(cd)indole-2-thiol, 3.1 g of 5-(1H-imidazol-l-yl) pentanamine, 100 ml of ethanol and 6.3 g of mercuric acetate was reacted as described in Example 1, giving 1.5 g of the desired product, mp 138° C.-140° C.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:37])[C@@H:15]([O:34][CH2:35][CH3:36])[C@@H:16]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:20][C:19]=1[CH3:33])[OH:17])C1C=CC=CC=1.[CH3:38][O-:39].[Na+]>CO>[CH3:38][O:39][C:14](=[O:37])[C@@H:15]([O:34][CH2:35][CH3:36])[C@@H:16]([C:18]1[C:19]([CH3:33])=[CH:20][C:21]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][C:23]=1[CH3:24])[OH:17]
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1c(C)cc(OCc2ccccc2)cc1C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCO[C@H](C(=O)OC)[C@H](O)c1c(C)cc(OCc2ccccc2)cc1C

Procedure:
In analogy to the procedure described in example 1 b], (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2,6-dimethyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one was treated with sodium methoxide in methanol to give (2S,3R)-3-(4-benzyloxy-2,6-dimethyl-phenyl)-2-ethoxy-3-hydroxy-propionic acid methyl ester as colorless liquid. According to 1H-NMR spectroscopy, one single diastereomer was obtained.
Reaction SMILES: [O:1]=[C:2]([N:6]1[C@@H:10]([CH:11]([CH3:13])[CH3:12])[CH2:9][O:8][C:7]1=[O:14])[CH2:3][CH2:4][CH3:5].C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.Br[CH2:36][S:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1>[O:1]=[C:2]([N:6]1[C@@H:10]([CH:11]([CH3:13])[CH3:12])[CH2:9][O:8][C:7]1=[O:14])[C@@H:3]([CH2:36][S:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:4][CH3:5]
Reactant: CCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Reactant: BrCSCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC[C@H](CSCc1ccccc1)C(=O)N1C(=O)OC[C@@H]1C(C)C
Yield: 123.3 %

Procedure:
A solution of the N-acylated product of Step 6 (36.9 g, 185 mmol) in anhydrous THF (70 mL) was added to a magnetically stirred, cooled (-78° C.) solution of LDA (lithium diisopropylamide) (prepared from 28.6 mL (20.6 g, 204 mmol) of diisopropylamine and 127.5 mL (1.6M in hexane, 204 mmol) of n-butyllithium) in anhydrous THF (240 mL). After stirring for 0.5 h at -78° C. the resultant lithium enolate was treated with benzyl bromomethyl sulfide (52.3 g, 241 mmol) for 2 h at -20° C. The reaction was quenched by the addition of half-saturated aq NH4Cl (200 mL). Volatiles were removed in vacuo and the product was extracted into CH2Cl2 (3×). The combined organic extracts were successively washed with 1M aqueous sodium bisulfate (2×), 1M aqueous KHCO3 (2×) and brine, dried over MgSO4 and concentrated in vacuo to give 76.5 g of a yellow liquid. This crude material was roughly purified by flash chromatography on silica with EtOAc: hexane 1:99, 2:98, 5:95, 10:90 and 15:85 to give the title compound as a colorless liquid (48.9 g), which was used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[N:4][CH:5]=[CH:6][N:7]=1.N1C=CC=CC=1.[Br:22]Br.O>CC(O)=O>[Br:22][C:6]1[N:7]=[C:2]([Cl:1])[C:3]([NH:8][NH:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14])=[N:4][CH:5]=1
Reactant: BrBr
Reactant: O=C(NNc1nccnc1Cl)C(F)(F)F
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: O
Product: O=C(NNc1ncc(Br)nc1Cl)C(F)(F)F
Temperature: 0 °C

Procedure:
A solution of 2.40 g of the product of Step A and 1.97 g of pyridine in AcOH (10.0 mL) at 0° C. was stirred as a solution of 1.92 g of bromine in AcOH (1.0 mL) was added dropwise. The resulting mixture was stirred at 0° C. for one h and then warmed to ambient temperature and stirred for an additional 16 h. The reaction mixture was poured into water and extracted with EtOAc (2×). The combined organic extracts were washed with water, dried over magnesium sulfate, filtered, and concentrated to an oil that was purified by silica gel chromatography to provide trifluoroacetic acid N′-(5-bromo-3-chloro-pyrazin-2-yl)-hydrazide as a white solid. MS (M+H+)=320.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[C:12](=[O:15])[NH:13]Cl)=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C@@H:43](N)[CH3:44])=[CH:39][CH:38]=1>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[C:12]([NH:13][C@H:43]([C:40]2[CH:41]=[CH:42][C:37]([Cl:36])=[CH:38][CH:39]=2)[CH3:44])=[O:15])=[CH:6][CH:5]=1
Reactant: C[C@H](N)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(CN(C(=O)NCl)c2ccc(C3CCCCC3)cc2)cc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(CN(C(=O)N[C@@H](C)c2ccc(Cl)cc2)c2ccc(C3CCCCC3)cc2)cc1
Reaction time: 2 h

Procedure:
A 2 L reaction flask equipped with mechanical stirring was charged with N-chlorocarbamoyl-4-[(4-cyclohexylphenylamino)methyl]benzoic acid methyl ester (94 g, 0.244 mmol), N-methyl-2-pyrrolidinone (1.0 L) and triethylamine (68 mL, 0.487 mol). To the clear solution was added drop wise (S)-1-(4-chlorophenyl)ethylamine (38.0 g, 0.244 mol), keeping the internal reaction temperature below 30° C. Stirring was continued for 2 hours, then the reaction mixture was partitioned between water (1.0 L) and ethyl acetate (1.0 L). After extensive mixing, the organic layer was separated, and washed with a 5% aqueous solution of citric acid (500 mL), and saturated ammonium chloride (500 mL), before drying with anhydrous sodium sulphate. Solvent was removed, and the residual oil was evaporated once from acetonitrile. This product was sufficiently pure for further synthesis. Yield: 103 g (84%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([NH:12]C(=O)C(F)(F)F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=1[F:8]>C([O-])([O-])=O.[K+].[K+].CO.O>[Cl:1][C:2]1[C:3]([F:19])=[C:4]([C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=1[F:8])[NH2:12]
Reactant: O=C(Nc1c([N+](=O)[O-])cc(F)c(Cl)c1F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Nc1c([N+](=O)[O-])cc(F)c(Cl)c1F
Yield: 6.9 %

Procedure:
A solution of 6.35 g (20.8 mmol) of 3-chloro-2,4-difluoro-6-nitro-(trifluoroacetamido)benzene in 60 mL of 7% K2CO3 methanol/water (3:2) was stirred at 25° C. for 4 h. The solution was evaporated to remove the methanol. Solid was observed in the residue and it was filtered and washed by water, and dried to leave 301 mg of crystalline yellow solid, mp 96°-97° C. 1H NMR (CDCl3), 6.07 (mb, 2), 7.815 (dd, 1, J=1.92, 9.13). More solid was observed after the mother aqueous solution was allowed to stand at room temperature overnight. It was filtered and washed by water, and dried to leave yellow solid (1.01 g). More solid was crystallized from the mother solution. It was collected three more times to leave 2.48 g of a yellow solid. 1H NMR is identical with above, total yield 3.80 g (87%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([F:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:18][C:19]1([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH2:28]([O:27][C:25]([C:19]1([CH2:18][N:13]2[CH2:12][CH2:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])([F:16])[CH2:15][CH2:14]2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(OCc1ccccc1)C1(CI)CCOCC1
Reactant: CC(C)(C)OC(=O)NCC1(F)CCNCC1
Product: CC(C)(C)OC(=O)NCC1(F)CCN(CC2(C(=O)OCc3ccccc3)CCOCC2)CC1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 3 from 4-tert-butoxycarbonylaminomethyl-4-fluoropiperidine (step 4 of Example 15) and benzyl 4-iodomethyltetrahydropyran-4-yl-carboxylate (step 2 of Example 15).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:14]1)[CH:6]=2
Reactant: O=[N+]([O-])c1cc(Br)cc2[nH]ncc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)cc2nn(C3CCCCO3)cc12
Temperature: 25 °C

Procedure:
A mixture of 6-bromo-4-nitro-1H-indazole (10.0 g, 0.041 mol), 3,4-dihydropyran (8.52 ml, 0.09 mol) and pyridinium para-toluene sulfonate (125 mg, 0.50 mol) in dichloromethane (150 ml) was heated at reflux for 4.5 hours. The reaction was allowed to cool to room temperature and was poured onto saturated aqueous sodium bicarbonate (200 ml). The layers were separated and the aqueous layer extracted with dichloromethane (2×100 ml). The combined organic layers were washed with 5% aqueous citric acid (w/v, 100 ml) and brine (100 ml) then dried over magnesium sulphate. Solvent was removed in vacuo to give the title compound which was used in subsequent reactions without further purification (12.89 g).
Reaction SMILES: [CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(C)C=CC=CC=1>C1COCC1.O>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:9][C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30].[CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCCC[C@H](C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC[C@@H](C)OC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
After (S)-2-octanol (300 mg, 2.30 mmol), triphenylphosphine (724 mg, 2.76 mmol), 4-nitrobenzoic acid (465 mg, 2.76 mmol), and THF (12 ml) were added to a 50 ml flask, a 40% azodicarboxylic acid diisopropyl ester-toluene solution (1.45 ml, 2.76 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for two hours. Water (0.5 mL) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was then carried out using diethyl ether (10 ml, ×2). Then, the organic layer was washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 5% ethyl acetate-hexane solution) to give (R)-2-(4-nitrobenzoyloxy)octane as a pale yellow liquid substance (616 mg, yield: 96%/(S)-2-octanol).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][Cl:6].[OH:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]2)=[CH:10][CH:9]=1.[OH-].[Na+].O>CC(N(C)C)=O.C1CCCCC1>[Cl:6][CH2:5][CH2:4][CH2:3][CH2:2][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]2)=[CH:10][CH:9]=1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: ClCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C1CCc2ccc(OCCCCCl)cc2N1
Temperature: 25 °C

Procedure:
1-bromo-4-chloro butane (500 ml) was added to a stirred solution of 7-hydroxy-3,4-dihydrocarbostyril (100 gm) in dimethylacetamide (500 ml) at ambient temperature. The reaction mixture was heated at 36° to 40° C. Sodium hydroxide (33.1 gm) was added to the reaction mixture at the interval of 30 min (Complete the addition of sodium hydroxide in 9 equal fractions in 4.0 hours). The reaction mixture was cooled at ambient temperature and D.M Water was added to it. The reaction mixture was extracted with ethylacetate. Organic layer was separated and washed with 5% brine and finally dried over sodium sulphate. The organic layer was evaporated to dryness under reduced pressure (10 mm) at 45° C. to obtain residue. To the residue cyclohexane (1000 ml) was added to give of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH2:7])[CH3:2].[C:13](O)(=O)[C:14]1C(=CC=C[CH:20]=1)N>>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:7][CH:14]([CH3:20])[CH3:13])[CH3:2]
Reactant: Nc1ccccc1C(=O)O
Reactant: CCOC(=O)c1ccccc1N
Product: CCOC(=O)c1ccccc1NC(C)C

Procedure:
Following the reaction procedure of Example 8 but substituted a molar equivalent amount of anthranilic acid ethyl ester for the anthranilic acid, there is obtained N-isopropylanthranilic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([NH:19][CH2:20][CH2:21][C:22]3[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:24][CH:23]=3)=[O:18])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:35].[Na+].Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([NH:19][CH2:20][C:21]([C:22]3[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[C:24]([O:26][CH2:27][C:28]([OH:30])=[O:29])[CH:23]=3)=[O:35])=[O:18])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)COc1ccc(CCNC(=O)c2cc3c(s2)CCN(C(=O)OC(C)(C)C)C3)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2sc(C(=O)NCC(=O)c3ccc(OCC(=O)O)c(OCC(=O)O)c3)cc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 107.8 %

Procedure:
To the solution of the compound prepared in Example 17 (a) (2 g) in THF (50 ml) was added an aqueous solution (50 ml) of sodium hydroxide (240 mg), and the mixture was stirred at room temperature for 20 minutes. After THF was evaporated under reduced pressure, the concentrated reaction mixture was acidified to pH 3.5 with 5N hydrochloric acid. Crystals deposited were collected by filtration and dried to give 1.21 g of [[4-[[[(5-t-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]amino]acetyl]-o-phenylene]dioxy]diacetic acid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:9]2=[O:18])[CH2:4][CH2:3]1.F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O.CO>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][N:15]([C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=4)[CH2:14][CH2:13]3)[C:9]2=[O:18])[CH2:6][CH2:7]1
Reactant: O=C1N([C@H]2CC[C@H](O)CC2)CCC12CCNCC2
Reactant: N#Cc1ccc(F)cc1
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CCC3(CC2)CCN([C@H]2CC[C@H](O)CC2)C3=O)cc1

Procedure:
A mixture of 2-(trans-4-hydroxycyclohexyl)-2,8-diazaspiro[4.5]decan-1-one (20 mg, 0.00008 mol), 4-fluorobenzonitrile (12.3 mg, 0.000102 mol) and N,N-diisopropylethylamine (44 μL, 0.00025 mol) in N-methylpyrrolidinone (0.5 mL) was irradiated under microwave at 200° C. for 15 min. The mixture was diluted with methanol (1.3 mL), and purified by Prep-HPLC to give 4-[2-(trans-4-hydroxycyclohexyl)-1-oxo-2,8-diazaspiro[4.5]dec-8-yl]benzonitrile. LCMS: (M+H)+=354.2.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:9]([OH:10])=[C:7]([OH:8])[CH:6]=1.[CH:13]1([C:16](Cl)=[O:17])[CH2:15][CH2:14]1>N1C=CC=CC=1>[OH:8][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][NH:2][C:16]([CH:13]2[CH2:15][CH2:14]2)=[O:17])[CH:12]=[CH:11][C:9]=1[OH:10]
Reactant: NCCc1ccc(O)c(O)c1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(NCCc1ccc(O)c(O)c1)C1CC1
Reaction time: 5 h

Procedure:
Dissolve 15.0 g. of dopamine hydrochloride in 200 ml. of pyridine. Add with stirring 24.96 g. of cyclopropane-carboxylic acid chloride portionwise over a 2-hour period at room temperature. Stir at room temperature overnight. Add methanol (200 ml.), water (75 ml.) and concentrate ammonium hydroxide solution (50 ml.) to the reaction mixture and allow the clear solution to stand for 5 hours at room temperature. Pour the solution into 2 liters of of 2N hydrochloric acid and ice with vigorous agitation. Extract the oily precipitate with ethyl acetate. Wash the extract with saturated aqueous sodium bicarbonate solution, dry over sodium sulfate and evaporate to a residue. Dissolve the residue from ethyl acetate-ethyl ether and crystallize to obtain the title compound, m.p. 174.5°-176° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39]([OH:41])=O)=[CH:36][CH:37]=3)[C:32]([CH3:42])=[C:31]2[CH3:43])=[CH:25][CH:24]=1)=[O:16])(C)(C)C>>[CH3:43][C:31]1[N:30]([CH2:29][C:26]2[CH:27]=[CH:28][C:23]([C:18]3[C:17]([C:15]([OH:14])=[O:16])=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:24][CH:25]=2)[C:38]2[C:33]([C:32]=1[CH3:42])=[CH:34][C:35]([C:39](=[O:41])[NH:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([CH3:1])[CH:3]=1)=[CH:36][CH:37]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: Cc1cccc(CN)c1
Product: Cc1cccc(CNC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 3-methylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.O=[Pt]=O.C(O)C>[CH:1]1([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: O=C(O)C1(c2ccccc2)CC1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)C1(C2CCCCC2)CC1
Yield: 57.8 %

Procedure:
To 1-phenyl-cyclopropanecarboxylic acid (0.500 g) in acetic acid (2 mL) was added Adams catalyst (0.050 g) in ethanol (0.3 mL). The reaction was left to stir for 48 hours under 5 bar of hydrogen. The reaction was filtered, washing with ethanol (10 mL) and water (10 mL). The resulting solid was collected by filtration and subsequently washed with water (10 mL) to afford the sub-titled compound (0.3 g).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=[O:4])=[O:3].[Br:6][C:7]1[CH:16]=[CH:15][C:10]2[O:11][CH:12]([CH3:14])[CH2:13][C:9]=2[CH:8]=1>C(Cl)(Cl)Cl>[Br:6][C:7]1[CH:16]=[C:15]([O:3][S:2]([Cl:1])(=[O:5])=[O:4])[C:10]2[O:11][CH:12]([CH3:14])[CH2:13][C:9]=2[CH:8]=1
Reactant: CC1Cc2cc(Br)ccc2O1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: CC1Cc2cc(Br)cc(OS(=O)(=O)Cl)c2O1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.7 %

Procedure:
470 g (4.03 moles) of chlorosulfonic acid are added dropwise over 20 minutes at -7° C. to a solution of 106 g (0.5 mole) of 5-bromo-2,3-dihydro-2-methylbenzo[b]furan in 300 ml of chloroform, and the mixture is then stirred for a further 15 minutes at 20°-25° C. The reaction mixture is taken up in ice/water, the organic phase is separated, and aqueous phase is extracted with two 500 ml portions of chloroform. The combined organic phases are washed with two 250 ml portions of water, dried over sodium sulfate, and concentrated, affording 101 g (65% of theory) of 5-bromo-2,3-dihydro-2-methyl-7-benzo[b]furanylsulfochloride.