Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH:22]([C:28]([O:30]CC)=O)[C:23]([O:25]CC)=O)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH2:34][NH2:35]>C(O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH:22]5[C:28](=[O:30])[NH:35][NH:34][C:23]5=[O:25])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Reactant: NN
Solvent: CCO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3C(=O)NNC3=O)cc1OCC2
Temperature: 75 °C

Procedure:
A mixture of 181 mg (0.40 mmol) of diethyl 2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)malonate and 0.314 mL (10.0 mmol) of hydrazine in 4.0 ml of Ethanol was heated at 75° C. for 18 hours. The mixture was concentrated, the residue triturated with acetic acid. A precipitate was filtered off, washed with acetic acid, ethyl ether and recrystallized from ethyl ether/ethanol mixture to give 360. Yield 59 mg (37.5%). M/z 394.1, calc. 393.15. 1H NMR (400 MHz, DMSO) δ 10.20 (s, 2H), 8.29 (d, J=8.6, 1H), 7.89 (d, J=12.9, 2H), 7.70 (d, J=8.5, 1H), 7.63 (s, 1H), 5.93 (dt, J=13.1, 6.7, 1H), 4.48 (d, J=7.2, 4H), 1.49 (d, J=6.6, 6H)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)=[O:4].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(CO)cc1
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A stirred solution of p-methoxycarbonylbenzaldehyde (Description 35, 0.82 g, 5.0 mmol) in methanol (10 ml) at 0° under argon was treated with sodium borohydride (50 mg, 1.25 mmol), added in portions over 5 minutes. After stirring overnight the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and dried (MgSO4). Removal of the solvent gave the desired product as a colourless solid (0.78 g, 94%). δH (CDCl3) 1.83 (1H, t, J 5.9 Hz), 3.93 (3H, s), 4.78 (1H, d, J 5.9 Hz), 7.45 (2H, d, J 8.1 Hz), 8.04 (2H, d, J 8.1 Hz) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].C1N=CN([C:16](N2C=NC=C2)=[O:17])C=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[O:17]=[C:16]1[NH:10][C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[NH:1]1
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N#Cc1ccc2[nH]c(=O)[nH]c2c1
Temperature: 125 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
To a solution of 3,4-diaminobenzonitrile (350 mg) in toluene (5.5 ml) was added CDI (554 mg), followed by stirring at 125° C. for 2 hours. To the reaction mixture was added a 1M aqueous NaOH solution (0.117 ml), followed by extraction with EtOAc. The organic layer was dried over anhydrous MgsO4, and then filtered, and the filtrate was concentrated. It was powdered/washed with IPE/IPA to obtain 2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile (423 mg) as colorless powders.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:15][CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9]C.B(Br)(Br)Br.O.C(=O)(O)[O-].[Na+]>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:17][CH2:18]2)[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(CCN2CCN(CCCc3ccccc3)CC2)cc1OC
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(CCN2CCN(CCCc3ccccc3)CC2)cc1O
Temperature: 0 °C
Reaction time: 5 h
Yield: 74.4 %

Procedure:
To a solution of 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine (0.829 g, 2.25 mmol) in dichloromethane (DCM, 20 mL) is added boron tribromide (BBr3) drop wise at −78° C. under nitrogen. After the addition had been completed, the reaction solution is slowly warmed to 0° C., stirred for 5 h and then cooled to −10° C. To the cooled reaction mixture is added water cautiously. The resulting mixture is neutralised with sodium bicarbonate at ambient temperature and extracted with ethyl acetate/THF. The organic layer is separated, filtered through silica gel, dried over sodium sulfate, concentrated, and dried in a vacuum oven. The residue is then purified by column chromatography eluting with dichloromethane-methanol to afford 0.57 g of 1-[2-(3,4-dihydroxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine. This material is then dissolved in ethanol and treated with 6 N hydrogen chloride aqueous solution to pH=3. The resultant crystals are filtered, washed with cold ethanol, and dried to give 212 mg of the title compound (25% from 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([N+:21]([O-:23])=[O:22])=[CH:8][CH:9]=2)[N:4]=1.O.[SH:25][C:26]1[N:34]=[CH:33][N:32]=[C:31]2[C:27]=1[NH:28][CH:29]=[N:30]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([N+:21]([O-:23])=[O:22])=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:2][S:25][C:26]1[N:34]=[CH:33][N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][NH:30]2
Reactant: Sc1ncnc2nc[nH]c12
Reactant: O=c1c2ccc([N+](=O)[O-])cc2nc(CCl)n1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2ccc([N+](=O)[O-])cc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 73.8 %

Procedure:
Prepared according to Procedure C using Intermediate 2o (216 mg, 0.617 mmol), 6-mercaptopurine monohydrate (116 mg, 0.681 mmol), K2CO3 (94 mg, 0.680 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 212 mg of a yellow crystalline solid (74%), mp 218.0-218.3° C. (decomposes). 1H NMR (DMSO-d6) δ: 13.56 (br s, 1H); 8.49 (s, 1H); 8.42 (s, 1H); 8.38-8.45 (m, 2H); 8.31 (d, J=8.4 Hz, 1H); 7.81 (d, J=6.5 Hz, 1H); 7.68 (d, J=6.7 Hz, 1H); 7.43-7.58 (m, 2H); 4.53 (s, 2H). 13C NMR (DMSO-d6) ppm: 157.7, 154.4, 153.3, 149.8, 149.3, 147.6, 145.2, 141.4, 131.5, 129.8, 129.7, 129.2, 128.4, 127.1, 126.7, 122.7, 120.3, 119.4, 29.9. MS (ES): m/z 466.0 (M+). Anal. calcd. for C20H12ClN7O3S.0.4C2H6O.0.05KCl: C, 51.19; H, 2.97; Cl, 7.63; N, 20.09; S, 6.57. Found: C, 51.27; H, 2.88; Cl, 7.40; N, 20.04; S, 6.52.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][C:24]1[S:28][C:27]([C:29](=O)[CH2:30][NH:31][C:32](=O)[C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:23][C:24]1[S:28][C:27]([C:29]2[S:10][C:32]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=3)=[N:31][CH:30]=2)=[CH:26][CH:25]=1
Reactant: Cc1ccc(C(=O)CNC(=O)c2ccc(C(F)(F)F)cc2)s1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cnc(-c3ccc(C(F)(F)F)cc3)s2)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.9 %

Procedure:
To a stirred suspension of Lawesson's Reagent (2.3 g, 0.0057 mole) in approximately 40 ml of toluene was added a mixture of N-[2-(5-methylthienyl)-2-oxoethyl]-4-trifluoromethylbenzamide (3.0 g, 0.011 mole) in toluene (35 ml). After complete addition the reaction mixture was heated at reflux for approximately four hours, then was allowed to cool to room temperature and stirred for two days. The solvent was removed from the reaction mixture by evaporation under reduced pressure, leaving an oil. The oil was dissolved in a small amount of methylene chloride and purified by column chromatography on silica gel, eluting with methylene chloride, yielding 1.0 g of 5-(5-methylthien-2-yl)-2-(4-trifluoromethylphenyl)thiazole as a solid, m.p. 150°-152° C.
Reaction SMILES: C[O:2][C:3]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][C@@H:6]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[O:7][C@H:8]2[CH2:14][NH:15][CH:16]=[O:17].Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:35]([O:34][C:32](=[O:33])[CH:31]([N:21]1[CH2:20][CH2:19][CH:18]([C@@H:6]2[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:12]([CH3:13])[C:3]=3[OH:2])[C@H:8]([CH2:14][NH:15][CH:16]=[O:17])[O:7]2)[CH2:23][CH2:22]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:25]=1)[CH3:36]
Reactant: CCOC(=O)Cc1ccccc1Br
Reactant: COc1c(C)ccc2c1C[C@@H](C1CCNCC1)O[C@H]2CNC=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(c1ccccc1)N1CCC([C@@H]2Cc3c(ccc(C)c3O)[C@H](CNC=O)O2)CC1

Procedure:
Stir a solution of N-((1R,3S)-5-methoxy-6-methyl-3-(4-piperidinyl)-1-isochromanyl-methyl)formamide (200 mg, 0.58 mmole), ethyl 2-bromophenylacetate (229 mg, 0.94 mmole) and diisopropylethylamine (243 mg, 1.88 mmole) in acetonitrile overnight at room temperature. Add ethyl acetate and water (2 mL each), then separate the organic phase and dry over Na2SO4. Purify the crude product on a 4 g silica gel column (eluting with ethyl acetate:heptane 3:1). Collect the appropriate fractions and concentrate to obtain the title compound. It was used without further purification in the next step.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=O)=O)=CC=1.[OH-].[K+]>N1C=CC=CC=1.CCOC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])=[CH:4][CH:3]=1
Reactant: Sc1ccc(I)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC1CSc1ccc(I)cc1
Reaction time: 4 h
Yield: 52.6 %

Procedure:
To a stirred mixture of p-iodothiophenol (1.75 g, 7.43 mmol) and N-(tert-butoxycarbonyl)-2-pyrrolidinylmethyl p-toluenesulfonate (2.39 g, 6.75 mmol) in pyridine (12.7 mL) was added 8N KOH (1.27 mL) at room temp, and the resulting mixture was stirred for 4 hr at the same temp. The reaction mixture was diluted with EtOAc. The solution was washed with H2O, sat NH4Cl, brine, and dried over Na2SO4. The organic layer was concentrated under a reduced pressure. The residue was chromatographed on silica-gel with n-hexane-EtOAc (5:1, v/v) as eluent to afford 1.49 g (53%) [N-(tert-butoxycarbonyl)-2-pyrrolidinyl]methyl 4-iodophenyl sulfide as a pale yellowish oil. 1H-NMR (400 MHz, CDCl3) δ(s, 9H), 1.78-2.01(br m, 4H), 2.71 (dt, 1H), 3.32-3.49 (br m, 3H), 3.90-4.02 (br m, 1H), 7.12 (d, J=7.8 Hz, 1H), 7.18 (d, J=7.8 Hz, 1), 7.57 (dd, J=2.0, 8.3 Hz, 2H); MS (FAB) m/z 420(M++1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[C:5]#[N:6].[S:11]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([C:13]2[CH:14]=[CH:15][S:11][CH:12]=2)[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Br)cc(Br)c1
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: N#Cc1cc(Br)cc(-c2ccsc2)c1
Temperature: 25 °C

Procedure:
A mixture of 3,5-dibromobenzonitrile (3 g, 11.5 mmol), thiophene-3-boronic acid (2.35 g, 18 mmol), dichlorobis(triphenylphosphine)palladium(II)(1.21 g, 1.7 mmol), tri-o-tolylphosphine (0.524 g, 1.7 mmol), sodium carbonate (3.46 g, 33 mmol) in aqueous acetonitrile (1:10), 110 mL) was refluxed under nitrogen for 6 hours, cooled to room temperature, concentrated under reduced pressure, suspended in hydrochloric acid (2N, 50 mL), and extracted with diethyl ether (3×80 mL). The combined organic extracts were washed with water (150 mL), saturated aqueous sodium bicarbonate (150 mL), and brine (50 mL), dried over magnesium sulfate, adsorbed onto silica, chromatographed on silica and eluted with a mobile phase of ethyl acetate in hexane. The first fraction was concentrated under reduced pressure to leave 3-bromo-5-(thien-3-yl)benzonitrile in the form of a yellow amorphous solid. Yield 1.47 g (48 percent). mp 62-63° C.; 1H NMR (CDCl3) δ 7.94 (t, J=1.8 Hz, 1H), 7.79 (t, J=1.5 Hz, 1H), 7.69 (t, J=1.8 Hz, 1H), 7.54 (dd, J1=3.0 Hz, J2=1.5 Hz, 1H), 7.46 (dd, J1=5.1 Hz, J2=3.0 Hz, 1H), 7.34(dd, J1=4.8 Hz, J2=1.5 Hz, 1H); EI/MS 265 m/e (M+); IR (KBr) σ cm−1 2230.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:24]([OH:26])=O)[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:73][C@@H:74]([NH2:81])[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1>C(#N)C.C(Cl)Cl>[C:1]([NH:8][C@@H:9]([C:24]([NH:81][C@@H:74]([C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[CH3:73])=[O:26])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: C[C@@H](N)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Product: C[C@@H](NC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccccc1
Reaction time: 8 h
Yield: 96.7 %

Procedure:
Prepared according to the method described in Example 1(a) above from Nα -Boc-Nδ -Cbz-(R)-ornithine (5.0 g; 13 mmol), BOP reagent (6.0 g; 13 mmol), HOBT (1.8 g; 13 mmol) and DiPEA (7.1 mL; 40.0 mmol) 100 mL of acetonitrile:CH2Cl2 (1:1), followed by 1.8 mL (13 mmol) of (R)-α-methylbenzylamine, then stirred overnight. After work up, the crude product was purified by passing it through a plug of silica gel with EtOAc to give 5.9 g (92%) of the sub-title compound as a light yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C[Al](C)C.N#N.[NH:20](/[C:24](/[CH3:30])=[CH:25]\[C:26](OC)=[O:27])[C:21]([CH3:23])=O>C(Cl)Cl>[CH3:23][C:21]1[N:13]([C:10]2[CH:11]=[N:12][C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:8][CH:9]=2)[C:26](=[O:27])[CH:25]=[C:24]([CH3:30])[N:20]=1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: Nc1ccc(N2CCOCC2)nc1
Agent: C[Al](C)C
Agent: N#N
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)nc2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
To a solution of 6-morpholinopyridin-3-amine (1.79 g, 10 mmol) in CH2Cl2 (100 mL) was added trimethylaluminium (40 mL, 40 mmol, 1 M in heptane) carefully under N2. The mixture was stirred at rt for 30 min, followed by the addition of a solution of methyl 3-acetaminocrotonate (1.89 g, 12 mmol) in CH2Cl2 (5 mL). The reaction was stirred at rt for 6 h, then quenched with saturated NH4Cl aqueous solution (100 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by recrystallized from EtOAc to give the title compound as a pale yellow solid (1.11 g, 39%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([OH:16])=O)[N:2]=1.S(Cl)(Cl)=O>CN(C)C=O>[CH2:1]([N:2]([CH2:3][CH3:4])[C:14]([C:3]1[N:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:16])[CH3:13]
Reactant: O=C(O)c1cc2c(cn1)[nH]c1ccccc12
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1cc2c(cn1)[nH]c1ccccc12
Reaction time: 8 h

Procedure:
A mixture of 2 g of β-carbolin-3-carboxylic acid, 20 ml of thionyl chloride and 2 ml of dimethylformamide is boiled under reflux for 1 hour. The excess thionyl chloride is removed by distillation under reduced pressure. 20 ml of diethylamine is added under cooling to a suspension of the residue in 20 ml of triethylamine and the mixture is concentrated under reduced pressure. The residue is treated with aqueous ammonia (pH 8.5) and the mixture thus obtained is extracted with chloroform (6×25 ml). The extract is washed with water (2×25 ml), dried (K2CO3), decolorized with a small amount of charcoal and filtered. The filtrate is evaporated to dryness and the residue is kept at 60° C. overnight. The solid (1.56 g; 62%) is recrystallized from toluene to form β-carbolin-3-carboxylic acid diethylamide having a melting point of 170.0° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[C:43]([Si:47]([O:50][CH2:51][CH2:52][CH2:53]I)([CH3:49])[CH3:48])([CH3:46])([CH3:45])[CH3:44].CCCCCC>CN(C)C=O.C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1([N:16]([CH2:53][CH2:52][CH2:51][O:50][Si:47]([C:43]([CH3:44])([CH3:46])[CH3:45])([CH3:48])[CH3:49])[S:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)(=[O:18])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCI
Reactant: O=C(OCc1ccccc1)C1(NS(=O)(=O)c2ccc(-c3ccc(F)cc3)cc2)CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCN(C1(C(=O)OCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.2 %

Procedure:
To a solution of 1-(4'-fluorobiphenyl-4-sulfonylamino)cyclopentanecarboxylic acid benzyl ester (23.0 grams, 50.7 mmol) in dry N,N-dimethylformamide (500 ml) at room temperature was added potassium hexamethyldisilazide (12.2 grams, 61.1 mmole) and, after 45 minutes, tert-butyl-(3-iodopropoxy)dimethylsilane (18.3 grams, 60.9 mmol). The resulting mixture was stirred at room temperature for 16 hours. Additional potassium hexamethyidisilazide (3.0 grams, 15 mmole) and tert-butyl-(3-iodopropoxy)-dimethylsilane (4.5 grams, 15 mmol) were then added. Stirring at room temperature was continued for a further 5 hours. The mixture was quenched by addition of saturated ammonium chloride solution. The N,N-dimethylformamide was removed by evaporation under vacuum. The residue was taken up in diethyl ether and washed successively with water, dilute aqueous hydrochloric acid solution and brine. After drying over magnesium sulfate, the diethyl ether was evaporated to afford a yellow oil. To this was added hexane and methylene chloride to induce crystallization of the starting material which was recovered by filtration. Evaporation of solvents from the filtrate afforded crude 1-[[3-(tert-butyl-dimethylsilanyloxy)propyl]-(4'-fluorobiphenyl-4-sulfonyl)amino]-cyclopentanecarboxylic acid benzyl ester as an amber oil (27.35 grams).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[N:8]=[C:7]2[C:32]([OH:34])=O)([O-:3])=[O:2].CN([C:38]([O:42][N:43]1N=NC2C=CC=N[C:44]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNOC.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:38][O:42][N:43]([CH3:44])[C:32]([C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:9]([C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]=1)=[O:34]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc([N+](=O)[O-])cc12
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-nitro-1-trityl-1H-indazole-3-carboxylic acid 20AP (12.06 g, 26.85 mmol) and HATU (10.2 g, 26.85 mmol) was dissolved in DMF (100 ml). After stirring for 10 min at room temperature, N,O-dimethylhydroxylamine hydrochloride 21AP (2.62 g, 26.85 mmol) and DIEA (14.1 ml, 80.55 mmol) was added. It was stirred further for 1 hr at room temperature. Reaction mixture was poured into 300 ml of water. Solid was collected by filtration. This solid was redissolved in EtOAc (300 ml) and 75 ml of sat. NaHCO3 was added. Organic fraction was washed with water (2×75 ml), brine (75 ml) and dried over MgSO4. Solvent was removed under reduced pressure to give desired 5-nitro-1-trityl-1H-indazole-3-carboxylic acid methoxy-methyl-amide 22AP (12.56 g, 95%).
Reaction SMILES: [C:1]1([C@H:7]([CH3:30])[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C@@:17]3([OH:29])[CH2:23][C@H:22]4[CH2:24][C@H:19]([CH2:20][CH2:21]4)[C@@H:18]3[CH2:25][N:26]([CH3:28])[CH3:27])[CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C[Si]([Cl:36])(C)C>CC(=O)CC>[ClH:36].[C:1]1([C@H:7]([CH3:30])[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C@@:17]3([OH:29])[CH2:23][C@H:22]4[CH2:24][C@H:19]([CH2:20][CH2:21]4)[C@@H:18]3[CH2:25][N:26]([CH3:28])[CH3:27])[CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)Cl
Agent: C[C@H](C(=O)Oc1cccc([C@@]2(O)C[C@@H]3CC[C@@H](C3)[C@@H]2CN(C)C)c1)c1ccccc1
Solvent: CCC(C)=O
Solvent: O
Product: Cl

Procedure:
Stir a solution of (S)-2-phenylpropanoic acid (300 mg, 2.0 mmol) in 5 mL of oxalyl chloride for 3 hours at room temperature. After removal of solvent under vacuum, (S)-2-phenylpropanoyl chloride is obtained as pole yellow oil. Dissolve the oil in 10 mL of CH2Cl2. Add (1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-(3-hydroxyphenyl)bicyclo[3.2.1]octan-3-ol (400 mg, 1.45 mmol) and Et3N (293 mg, 2.9 mmol) to the solution. Stir the resultant mixture at room temperature for additional 3 hours. After addition of 20 mL of water, basify the mixture with K2CO3 to pH=10, and extract the aqueous mixture with EtOAc (20 mL×3). The combined organic layers are washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purify the residue by silica gel chromatography (CH2Cl2:MeOH=30:1) to afford (S)-3-((1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-hydroxybicyclo[3.2.1]octan-3-yl)phenyl 2-phenylpropanoate (500 mg, 84.7%; MS (m/z): 408 (M+1)) as yellow oil. Stir (S)-3-((1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-hydroxybicyclo[3.2.1]octan-3-yl)phenyl 2-phenylpropanoate (250 mg, 0.61 mmol) with H2O (11 mg, 0.61 mmol) and TMSCl (66 mg, 0.61 mmol) in 2-butanone (5 mL) for 3 hours. Collect the precipitate by filtration to afford (S)-3-((1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-hydroxybicyclo[3.2.1]octan-3-yl)phenyl 2-phenylpropanoate hydrochlorid (215 mg, Yield: 79.3%) as white solid. The absolute configuration of its hydrochloride salt form was confirmed by x-ray analysis. 1H NMR (400 MHz, DMSO) δ 9.81 (br, 1H), 7.31-7.41 (m, 7H), 7.14 (s, 1H), 6.87-6.90 (m, 1H), 5.01 (s, 1H), 4.08-4.10 (m, 1H), 3.02-3.08 (m, 1H), 2.42-2.58 (m, 4H), 2.12-2.26 (m, 6H), 1.90-1.99 (m, 2H), 1.75-1.80 (m, 2H), 1.51-1.59 (m, 6H).