Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][N:7]([C:9]2[N:13]3[C:14]4[CH:20]=[CH:19][NH:18][C:15]=4[N:16]=[CH:17][C:12]3=[N:11][CH:10]=2)[C@H:6]([CH2:21][CH3:22])[CH2:5]1)=[N+]=[N-].BrCC(OC(C)(C)C)=O.Cl.N([C@@H]1CN[C@H](C)C1)=[N+]=[N-].N([C@@H]1CN(C(OC(C)(C)C)=O)[C@H](C)C1)=[N+]=[N-].[OH-].[Na+].[H][H]>CCO.[OH-].[OH-].[Pd+2]>[CH2:21]([C@H:6]1[N:7]([C:9]2[N:13]3[C:14]4[CH:20]=[CH:19][NH:18][C:15]=4[N:16]=[CH:17][C:12]3=[N:11][CH:10]=2)[CH2:8][C@@H:4]([NH2:1])[CH2:5]1)[CH3:22]
Reactant: CC[C@@H]1C[C@H](N=[N+]=[N-])CN1c1cnc2cnc3[nH]ccc3n12
Reactant: [H][H]
Agent: [Pd+2]
Agent: CC(C)(C)OC(=O)CBr
Agent: C[C@@H]1C[C@H](N=[N+]=[N-])CN1
Solvent: CCO
Product: CC[C@@H]1C[C@H](N)CN1c1cnc2cnc3[nH]ccc3n12
Yield: 89 %

Procedure:
To the solution of 8-((2R,4S)-4-azido-2-ethylpyrrolidin-1-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (0.136 g, 0.459 mmol, prepared using S from Example #3 Step E and tert-butyl bromoacetate, E with HCl, H with (2R,4S)-4-azido-2-methylpyrrolidine (prepared from (2R,4S)-tert-butyl 4-azido-2-methylpyrrolidine-1-carboxylate as detailed in Rosen, T.; Chu, D. T. W.; Lico, I. M.; Fernandes, P. B.; Marsh, K.; Shen, L.; Cepa, V. G.; Pernet, A. G. J. Med. Chem. 1988, 31, 1598-1611, then E with HCl), OO, D with NaOH) in EtOH (15 mL), 20% palladium hydroxide on carbon (0.05 g, 0.071 mmol) was added and the reaction mixture was stirred under atmospheric pressure of hydrogen for 2 h. The catalyst was removed by filtration through a pad of Celite® and the solvent was removed under reduced pressure to yield (3S,5R)-5-ethyl-1-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidin-3-amine (0.11 g, 89%) as an off-white amorphous solid. LC/MS (Table 1, Method a) Rt=1.00 min; MS m/z 271 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[C:7]1([C@@H:13]2[CH2:17][O:16][C:15](=[O:18])[NH:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH3:4]/[CH:3]=[CH:2]/[C:1]([N:14]1[C@H:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:17][O:16][C:15]1=[O:18])=[O:5]
Reactant: O=C1N[C@H](c2ccccc2)CO1
Reactant: C/C=C/C(=O)Cl
Product: C/C=C/C(=O)N1C(=O)OC[C@H]1c1ccccc1
Yield: 81.1 %

Procedure:
trans-Crotonoyl chloride (2.67 g, 10.24 mmol, Aldrich) was coupled with (R)-4-phenyl-2-oxazolidinone (1.46 g, 8.9 mmol) according to the procedure of Example 1c to afford the title compound (1.67 g). MS m/z 232 (M+H)+, 249 (M+NH4)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:13]3=[C:14]4[S:20][CH:19]=[CH:18][C:15]4=[N:16][CH:17]=[C:12]3[N:11]=[C:10]2[CH2:21][C:22]#[N:23])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(Cl)Cl>[C:22]([CH2:21][C:10]1[N:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([CH2:2][NH:1][C:32](=[O:33])[O:34][CH2:35][CH3:36])[CH2:4][CH2:5]2)[C:13]2=[C:14]3[S:20][CH:19]=[CH:18][C:15]3=[N:16][CH:17]=[C:12]2[N:11]=1)#[N:23]
Reactant: N#CCc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NC[C@H]1CC[C@H](n2c(CC#N)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {1-[trans-4-(aminomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}acetonitrile (9.5 mg, 0.029 mmol) and triethylamine (20. μL, 0.14 mmol) in methylene chloride (1 mL) was added ethyl chloroformate (3.3 μL, 0.035 mmol). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (1.9 mg, 16%). LCMS calculated for C20H24N5O2S (M+H)+: m/z=398.2. Found: 397.8.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](O)[N:5]2[N:9]=[CH:10][N:11]=[C:4]2[CH:3]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:6]1[N:5]2[N:9]=[CH:10][N:11]=[C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: Oc1nc(Cl)cc2ncnn12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc2ncnn2c(Cl)n1

Procedure:
The mixture of 7-Chloro-[1,2,4]triazolo[1,5-c]pyrimidin-5-ol (35 mg) in POCl3 was heated at reflux for 3 hours. After removal of the volatiles, the residue was purified by a short plug column eluting with 1:1 EtOAc/hexane to give 5,7-Dichloro-[1,2,4]triazolo[1,5-c]pyrimidine as an off-white solid (11 mg). 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H) 7.72 (s, 1H). [M+H] calc'd for C5H2Cl2N4, 189; found, 189.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=1>>[CH3:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[CH2:30][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Cc1cccc(CBr)c1
Product: Cc1cccc(CN2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)c1

Procedure:
Compound 133 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1-(bromomethyl)-3-methylbenzene and conditions outlined in procedure V. LCMS: 406 [M+H]; Rt=1.02 min.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[N:4]=[C:5]([CH:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21]CC3C=CC=CC=3)=[CH:17][CH:16]=2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])[S:6][CH:7]=1.B(F)(F)F.CCOCC>CCS>[F:30][C:2]([F:1])([F:29])[C:3]1[N:4]=[C:5]([CH:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])[S:6][CH:7]=1
Reactant: COC(=O)CC(Cc1ccc(OCc2ccccc2)cc1)c1nc(C(F)(F)F)cs1
Agent: FB(F)F
Solvent: CCS
Solvent: CCOCC
Product: COC(=O)CC(Cc1ccc(O)cc1)c1nc(C(F)(F)F)cs1
Temperature: 0 °C
Reaction time: 18 h
Yield: 80.9 %

Procedure:
To a solution of methyl (±)-3[4-(trifluoromethyl)thiazol-2-yl]-4-(4-benzyloxyphenyl)butanoate (0.44 mmole, crude) in EtSH (5 mL) at RT was added BF3.OEt2 (0.3 mL). After 18 hr. additional BF3.OEt2 (0.3 mL) was added. After another 18 hr, the mixture was cooled to 0° C. and carefully quenched with saturated NaHCO3. The resulting mixture was extracted with CH2Cl2 (3×25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel (30% EtOAc/hexanes) to give the title compound (123 mg, 81% over 3 steps) as a yellow oil: MS (ES) m/e 346 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28]([OH:30])=O)=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:31]([O:38][CH2:39][CH2:40][NH:41][CH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH:42]1[CH2:43][CH2:44][CH2:45][CH2:46]1)[C:28]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:30])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: O=C(O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCNC1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)C1CCCC1
Yield: 61.6 %

Procedure:
To a stirred solution mixture of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (283) (100 mg, 0.25 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopentyl-amine (8e) (72 mg, 0.29 mmol) in dimethylformamide (2.5 mL) were added N,N-diisopropylethylamine (0.1 mL, 0.74 mmol) and HATU (141 mg, 0.37 mmol). Stirring was continued at room temperature for 20 h, whereafter water (25 mL) was added and the mixture extracted with ethyl acetate (3×20 mL). The combined organic part was washed with water (3×50 mL) and brine (2×30 mL) and dried and concentrated. The crude product was purified by Combi-Flash column (eluted at 20-30% ethyl acetate in hexane) to get 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopentyl-amide (288) (97 mg, 62.28%) as a light yellow sticky solid.
Reaction SMILES: C([O:3][P:4]([C:9]([O:22]CC)([P:11]([O:19]CC)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])[CH3:10])(=[O:8])[O:5]CC)C.Cl.C(OP(C(O)(P(O)(C1C=CC=CC=1)=O)C)(=O)OCC)C>>[OH:22][C:9]([P:4](=[O:3])([OH:5])[OH:8])([P:11]([OH:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])[CH3:10]
Reactant: CCOC(C)(P(=O)(OCC)OCC)P(=O)(OCC)c1ccccc1
Agent: CCOP(=O)(OCC)C(C)(O)P(=O)(O)c1ccccc1
Agent: Cl
Product: CC(O)(P(=O)(O)O)P(=O)(O)c1ccccc1
Temperature: 120 °C

Procedure:
[1-Ethoxy-1-(ethoxy-phenyl-phosphinoyl)-ethyl]phosphonic acid diethyl ester (7c) (67 mg, 1.9 mmol) was combined with concentrated HCl (2 mL). The solution was heated to reflux (120° C.) for 20 hours. The following morning HPLC indicated that all [1-Hydroxy-1-(hydroxy-phenyl-phosphinoyl)-ethyl] phosphonic acid diethyl ester was gone. Excess HCl was removed under a stream of N2 at 100° C. The residue was placed on the high vac for further drying and then dissolved in 6 mL 1:1 CH3CN/H2O. The solution was filtered through a 0.45 μm syringe filter. The resulting solution was purified by RP HPLC. Lyophilization left a white solid (18 mg, 35%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C@@H:9]([C:15]2[N:16]=[CH:17][N:18]([CH2:20][C:21]3[CH:25]=[C:24]([C:26]4[S:27][C:28]([Cl:31])=[CH:29][CH:30]=4)[O:23][N:22]=3)[CH:19]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.O>Cl>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C@@H:9]([C:15]2[N:16]=[CH:17][N:18]([CH2:20][C:21]3[CH:25]=[C:24]([C:26]4[S:27][C:28]([Cl:31])=[CH:29][CH:30]=4)[O:23][N:22]=3)[CH:19]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H](Cc1ccc(N)nc1)c1cn(Cc2cc(-c3ccc(Cl)s3)on2)cn1
Agent: Cl
Solvent: O
Product: Nc1ccc(C[C@H](C(=O)O)c2cn(Cc3cc(-c4ccc(Cl)s4)on3)cn2)cn1
Yield: 74.6 %

Procedure:
A solution of 0.11 g (0.24 mmol) of ethyl (S)-3-(6-aminopyridin-3-yl)-2-{1-[5-(5-chlorothiophen-2-yl)isoxazol-3-ylmethyl]-1H-imidazol-4-yl}propionate in 2 ml of semi-concentrated hydrochloric acid was stirred at RT for 24 h. The reaction mixture was freeze-dried and purified by preparative HPLC. The fractions of value obtained were combined and freeze-dried with 2 equivalents (eq) of 1N HCl (1×) and with 1 eq of 1N HCl and water (1×). This gave 0.077 g (69%) of the title compound as the hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:17][C:18]([CH3:20])=O.C1C=C(C(O)=O)C(C(O)=O)=CC=1.[BH4-].[Na+].[OH-].[Na+]>>[CH:18]([NH:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])([CH3:20])[CH3:17]
Reactant: CC(C)=O
Reactant: Cc1ccc(C(=O)c2ccccc2)c(N)c1
Agent: O=C(O)c1ccccc1C(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: Cc1ccc(C(=O)c2ccccc2)c(NC(C)C)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
422.6 g. (2 moles) of 2 amino-4-methylbenzophenone is dissolved in 2.34 liters (40.29 moles) of acetone, and with stirring 540 gms (3.25 moles) of o-phthalic acid is added. To the resulting suspension is added portionwise 80 gms (2.14 moles) of sodium borohydride over a period of 45 minutes and in a manner such as to keep the reaction mixture at 20°-25° C. At the end of the addition, the cooling is altered such as to allow the temperature to rise to 30°-35° C., and this temperature is maintained for 30 minutes. The cooling is removed and the temperature carefully increased to 50° C., and regulated at 50°-55° C. for 90 minutes. The mixture is then cooled to 15° C., 808 gms of 8% aqueous NaOH (1.625 moles) is added, the phases separated and the acetone phase (upper layer) recovered and concentrated. The water layer is extracted with 1 litre of heptane, and the concentrated acetone phase added to the heptane extract. The heptane solution is washed with 250 mls of H2O, then concentrated by distillation to obtain 496 gms of 2-(N-isopropylamino)-4-methylbenzophenone, b.p. 180°-185° C./5mm (Yield 99%).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[F:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]([N+:17]([O-])=O)[C:11]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>O.C1COCC1>[F:9][C:10]1[C:11]([O:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[C:12]([NH2:17])[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: Cc1ccc([N+](=O)[O-])c(Oc2cccc3ccccc23)c1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(N)c(Oc2cccc3ccccc23)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
A solution of sodium hydrosulfite (25.8 g, 125 mmol) in water (120 mL) was added dropwise to a solution of 1-[(2-fluoro-3-methyl-6-nitrophenyl)oxy]naphthalene (6.2 g, 20.86 mmol) in THF (60 mL) at room temperature. The mixture was stirred at room temperature for 2 hrs. The reaction mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (hexane:ethyl acetate) to give the title compound (3.34 g, 60%) as a light tan oil. 1H NMR (400 MHz, chloroform-d) δ ppm 8.44-8.52 (m, 1H), 7.80-7.90 (m, 1H), 7.45-7.61 (m, 3H), 7.19-7.32 (m, 1H), 6.86 (t, 1H), 6.64 (d, 1H), 6.53 (dd, 1H), 3.59 (br. s., 2H), 2.19 (s, 3H). ES MS m/z 268 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].B(F)(F)F.CCOCC.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.O>ClCCl>[CH3:24][O:23][C:17]1[C:18]([O:21][CH3:22])=[CH:19][C:20]2[C:6]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=3)[C:11]([C:12]#[N:13])=[CH:14][C:15]=2[CH:16]=1
Reactant: COc1ccc(C=C(C#N)c2ccc(OC)c(OC)c2)cc1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: FB(F)F
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: COc1cc2cc(C#N)c3cc(OC)c(OC)cc3c2cc1OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
2,3-Bis-(3,4-dimethoxy-phenyl)-acrylonitile (1.83 g, 5.63 mmol) was dissolved in absolute dichloromethane (100 ml) and the obtained solution was cooled to 0° C. and maintained under nitrogen atmosphere. Boron trifluoride etherate (1.76 g, 12.39 mmol) was dropwise added (within 15 min) to the reaction mixture which was stirred for further 15 min at 0° C. At this temperature, pyridinium chlorochromate (PCC) (2.43 g, 11.26 mmol), was portionwise added (10 portions, 1 portion/min) to the reaction mixture which turned green-brown. After complete addition of PCC, the reaction mixture was stirred for further 10 min, poured into water (200 ml), and extracted with dichloromethane (2×200 ml). The combined organic extracts were dried over magnesium sulphate and evaporated under reduced pressure. The obtained brown residue was chromatographed on silica (CH2Cl2). This afford a yellow material which was further purified by crystallisation in ethanol/dichloromethane: 9/1 to give 2,3,6,7-tetramethoxy-phenanthrene-9-carbonitrile as white powder (yield 1.75 g, 96%).
Reaction SMILES: [C:1]([CH2:3][O:4][C@@H:5]([C:19]1[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)#[N:2].S(C)C.CO>C1COCC1>[NH2:2][CH2:1][CH2:3][O:4][C@@H:5]([C:19]1[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1
Reactant: Cc1cccc([C@H](OCC#N)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: Cc1cccc([C@H](OCCN)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C

Procedure:
(R)-tert-Butyl 3-((R)-(cyanomethoxy)(m-tolyl)methyl)piperidine-1-carboxylate (20 g, 0.04 mol) was dissolved in anhydrous THF (300 mL), and the solution was heated to reflux under nitrogen. A solution of BH3.Me2S (12 mL, 0.12 mol) in THF was added dropwise, and stirring was continued under reflux overnight. The resulting solution was cooled to rt and MeOH was added dropwise to quench the excess borane. After evaporation of the solution, the crude (R)-tert-butyl 3-((R)-(2-aminoethoxy)(m-tolyl)methyl)piperidine-1-carboxylate was obtained and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:34])=[C:4]([N:8]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>CO.C1COCC1>[Cl:1][C:2]1[C:3]([CH3:34])=[C:4]([N:8]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:25])=[O:26])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CNC(=O)CN(c2cccc(Cl)c2C)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2ccc(C(=O)O)cc2)c2cccc(Cl)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 200.8 %

Procedure:
308 mg of methyl 4-[({N-(3-chloro-2-methylphenyl)-N-[(4-methylphenyl)sulfonyl]glycyl}amino)methyl]benzoate was dissolved in 5.00 mL of methanol and 2.00 mL of THF, and 2.40 mL of a 1 M aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature overnight. Then, to the reaction liquid was added 3.00 mL of THF, followed by stirring at 60° C. for 4 hours. The reaction liquid was ice-cooled, acidified by addition of 2.60 mL of 1 M hydrochloric acid, and then extracted with a mixed solvent of chloroform/methanol (5/1), and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 90:10) to obtain 601 mg of 4-[({N-(3-chloro-2-methylphenyl)-N-[(4-methylphenyl)sulfonyl]glycyl}amino)methyl]benzoic acid.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([C:10](OCC)=[O:11])[N:7]=[C:6]([C:15](OCC)=[O:16])[CH:5]=1>CCO>[Br:3][C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[N:7]=[C:6]([CH2:15][OH:16])[CH:5]=1
Reactant: CCOC(=O)c1cc(Br)cc(C(=O)OCC)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc(Br)cc(CO)n1
Yield: 83.7 %

Procedure:
The title compound was synthesized via modification of Acta Chem. Scand. B42, 373, 1988. A mixture of NaBH4 (6.8 g, 180 mmol), diethyl 4-bromopyridine-2,6-dicarboxylate (12.1 g, 40 mmol) in absolute EtOH (500 mL) was heated under reflux for 18 h. The solvent was removed in vacuo and the residue was treated with hot saturated aqueous NaHCO3. The mixture was extracted with EtOAc, the combined organic phase was dried (Na2SO4) and evaporated. The dried material was recrystallized from EtOAc to give 7.3 g (83%) of the title compound as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[CH2:22]1[O:30][CH:23]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[OH:30][CH:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][O:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17]
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cccc(O)c1
Reactant: c1ccc(C2CO2)cc1
Product: O=C1c2ccccc2C(=O)N1CCOc1cccc(OCC(O)c2ccccc2)c1

Procedure:
Alkylation reaction of phenol 24 with styrene oxide gave 2-(2-(3-(2-hydroxy-2-phenylethoxy)phenoxy)ethyl)isoindoline-1,3-dione as yellow oil. Yield (0.85 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=7.2 Hz, 1H), 7.41-7.53 (m, 3H), 7.28-7.38 (m, 5H), 7.12-7.16 (m, 1H), 6.60-6.65 (m, 1H), 6.52 (s, 1H), 6.48 (dd, J=8.0, 2.0 Hz, 1H), 4.79-4.82 (m, 1H), 4.19 (t, J=5.4 Hz, 2H), 3.72-3.84 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:26])[N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=4[OH:25])=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([C@@H:12]([CH3:26])[N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=4[OH:25])=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CC1c2ccccc2-c2ccc(F)cc2N1C(=O)c1ccc(O)cc1O
Solvent: ClC(Cl)Cl
Product: C[C@@H]1c2ccccc2-c2ccc(F)cc2N1C(=O)c1ccc(O)cc1O

Procedure:
The enantiomers of 4-[(3-fluoro-6-methylphenanthridin-5(6H)-yl)carbonyl]benzene-1,3-diol (800 mg, 2.29 mmol) were separated by automated, preparative, normal phase, chiral chromatography on a Chiralpak AS (20 mm×250 mm) column eluting with 15% isopropyl alcohol in hexane at a flow rate of 20 mL/min with. The fractions containing the first peak were combined and concentrated in vacuo, to provide one peak (99.9%) with a retention time of 7.971 minutes was isolated as a white solid (224 mg, 56% based upon a 1:1 ratio of enantiomers with a theoretical maximum amount of 400 mg). mp 184-187° C.; [α]D25=−665° (c=0.0104 g/mL, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (d, J=6.73 Hz, 3 H) 5.65 (m, J=6.73 Hz, 1 H) 6.16 (d, J=1.81 Hz, 1 H) 6.22 (dd, J=8.41, 2.20 Hz, 1 H) 6.75 (d, J=9.83 Hz, 1 H) 6.98 (d, J=8.28 Hz, 1 H) 7.04 (td, J=8.67, 2.59 Hz, 1 H) 7.33 (m, 2 H) 7.39 (m, 1 H) 7.90 (d, J=7.76 Hz, 1 H) 7.94 (dd, J=8.79, 6.21 Hz, 1 H) 9.62 (s, 1 H) 9.70 (s, 1 H); MS (ESI) m/z 350 ([M+H]+); MS (ESI) m/z 348 ([M−H]−); HRMS: calcd for C21H16FNO3, 349.1114 (M), 350.1187 ([M+H]+); found (ESI+), 350.1181.
Reaction SMILES: N[CH2:2]C(C1(O)CCCCC1)C1C=CC=CC=1.[NH2:17][CH2:18][CH:19]([C:28]1([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.Cl.C1(O)CCCCC1>>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH:19]([C:28]2([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:18][NH:17][CH3:2])=[CH:25][CH:24]=1
Reactant: COc1ccc(C(CN)C2(O)CCCCC2)cc1
Reactant: NCC(c1ccccc1)C1(O)CCCCC1
Agent: Cl
Solvent: OC1CCCCC1
Product: CNCC(c1ccc(OC)cc1)C1(O)CCCCC1

Procedure:
By replacing 1-[α-(aminomethyl)benzyl]cyclohexanol with a molar equivalent amount of 1-[2-amino-1-(p-methoxyphenyl)ethyl]cyclohexanol in Example 7, 1-[1-(4-methoxyphenyl)-2-methylamino)ethyl]cyclohexanol hydrochloride (m.p. 164°-166° C.) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][C:13]([OH:24])([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:7]1)=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].CCN=C=NCCCN(C)C>>[OH:24][C:13]1([C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH2:14][CH2:15][CH:10]([N:8]2[CH2:9][CH:6]([NH:5][C:3]([CH2:2][NH:1][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([CH3:25])[CH:27]=3)=[O:4])[CH2:7]2)[CH2:11][CH2:12]1
Reactant: Cc1cccc(C(=O)O)c1
Reactant: COc1ccc(C2(O)CCC(N3CC(NC(=O)CN)C3)CC2)cn1
Agent: CCN=C=NCCCN(C)C
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C)c4)C3)CC2)cn1

Procedure:
The title compound was prepared as yellow solid from 2-amino-N-{1-[4-hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexyl]-azetidin-3-yl}-acetamide, as prepared in Step D of Example 16, and 3-methylbenzoic acid (Aldrich) by EDCI coupling using the procedure described in Step C of Example 16.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][CH3:18])[CH:9]=2)=[O:4]
Reactant: COc1ccccc1B(O)O
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Product: COC(=O)c1c(O)c2ccc(-c3ccccc3OC)cc2sc1=O

Procedure:
4-Hydroxy-7-(2-methoxy-phenyl)-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5e) and 2-methoxyphenylboronic acid under conditions analogous to Example 7(a). MS ESI(−) m/e: 341.07 (M−1).