Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.P([O-])([O-])([O-])=O.[Al+3]>>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: OC1CCc2ccccc21
Agent: O=P([O-])([O-])[O-]
Agent: [Al+3]
Product: C1=Cc2ccccc2C1
Yield: 91.8 %

Procedure:
To a 25 ml one-neck round bottom flask are added 1-indanol (10 g, 75 mmol) and aluminum phosphate (ALPO4, 1.0 g, 8.2 mmol). The contents of the flask are heated under partial vacuum (5-10 mm Hg) to distill over indene and water. The water is removed by pipette, with the last traces being removed by drying over anhydrous magnesium sulfate to give indene (8 g) in an isolated yield of 92 mole percent.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:25][C@H:26]1[NH:31][CH2:30][CH2:29][NH:28][C:27]1=[O:32]>>[F:24][C:14]1[C:13]([C@@H:11]([C:8]2[N:6]3[N:7]=[C:2]([N:31]4[CH2:30][CH2:29][NH:28][C:27](=[O:32])[C@H:26]4[CH3:25])[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: C[C@@H](c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reactant: C[C@H]1NCCNC1=O
Product: C[C@@H](c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCNC(=O)[C@H]3C)nn12

Procedure:
The title compound was prepared in analogy to Example 18, using enantiomerically pure 6-[(S)-1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate B, 50 mg, 0.145 mmol) and (R)-3-methyl-piperazin-2-one (33.1 mg, 0.29 mmol) instead of the racemates and flash chromatography for the purification. 2:1 mixture of title compound with compound of Example 60 (tR 3.59 min (conditions 5), tR 8.66 and 10.19 min (conditions 3, 90% n-hexane and 10% isopropanol), MH+=423.1, 1H-NMR in DMSO-d6: 8.91 (m, 1H); 8.42 (d, 1H); 7.90 (s, 1H); 7.80 (d, 1H); 7.69-7.50 (m, 3H); 7.05 (d, 1H); 4.93 (m, 1H); 4.50 and 4.28 (q, 1H); 3.87 (m, 1H); 3.43-2.89 (m, 3H); 1.84 (m, 3H); 1.30 and 0.93 (d, 3H)).
Reaction SMILES: [C:1]12([C:11]([O:13][CH:14]3[CH:18]4[O:19][C:20](=[O:30])[CH:21]5[CH:22]([C:23]([O:25]C(C)(C)C)=[O:24])[CH:15]3[CH2:16][CH:17]45)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>C(O)=O>[C:1]12([C:11]([O:13][CH:14]3[CH:18]4[O:19][C:20](=[O:30])[CH:21]5[CH:22]([C:23]([OH:25])=[O:24])[CH:15]3[CH2:16][CH:17]45)=[O:12])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CC(C)(C)OC(=O)C1C2CC3C(OC(=O)C31)C2OC(=O)C12CC3CC(CC(C3)C1)C2
Solvent: O=CO
Product: O=C(O)C1C2CC3C(OC(=O)C31)C2OC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 40 °C
Reaction time: 10 h
Yield: 95 %

Procedure:
The ester (22) obtained in Synthesis Example 1-1-1, 388 g, was dissolved in 1,900 g of formic acid, followed by stirring at 40° C. for 10 hours. The formic acid was distilled off in vacuum and the residue was recrystallized from ethyl acetate, obtaining 319 g of the target compound (yield 95%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]2[C:10]([C:13]3[CH:14]=[CH:15][C:16]([F:27])=[C:17]([C:19]4[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:18]=3)=[CH:11][N:12]=[C:6]2[N:5]=1)(=O)[CH3:2].[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[C:49]([NH2:52])(=[S:51])[CH3:50].C(OCC)C>C(Cl)(Cl)Cl>[F:27][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[N:7]3[CH:8]=[CH:9][C:4]([C:1]4[S:51][C:49]([CH3:50])=[N:52][CH:2]=4)=[N:5][C:6]3=[N:12][CH:11]=2)=[CH:18][C:17]=1[C:19]1[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)c1ccn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2n1
Reactant: CC(N)=S
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Cc1ncc(-c2ccn3c(-c4ccc(F)c(-c5ccccc5C#N)c4)cnc3n2)s1
Temperature: 50 °C
Reaction time: 16 h
Yield: 11 %

Procedure:
5′-(7-Acetylimidazo[1,2-α]pyrimidin-3-yl)-2′-fluorobiphenyl-2-carbonitrile (80 mg, 0.22 mmol) and pyridinium tribromide (110 mg, 0.34 mmol) in chloroform (5 ml) was stirred at 50° C. for 3 h. Thioacetamide (33 mg, 0.44 mmol) was then added and the reaction stirred at 50° C. for 16 h. The resulting mixture was partitioned between dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue was purified by preparative thin-layer chromatography eluting with dichloromethane containing 5% methanol and 1% conc. ammonia to give a foam. Trituration with diethyl ether afforded 2′-fluoro-5′-[7-(2-methylthiazol-5-yl)imidazo[1,2-α]pyrimidin-3-yl]biphenyl-2-carbonitrile as a yellow solid (10 mg, 11%): δH (400 MHz, DMSO) 2.75 (3H, s), 7.56-7.68 (5H, m), 7.81-7.92 (3H, m), 7.98-8.05 (2H, m), 8.40 (1H, s), 9.12 (1H, s); m/z (ES+) 412 (M++H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[NH:9][N:8]=2)[CH:2]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[S:29][C:28]([S:30](Cl)(=[O:32])=[O:31])=[CH:27][CH:26]=1>N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:9]([S:30]([C:28]3[S:29][C:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=4)=[CH:26][CH:27]=3)(=[O:31])=[O:32])[N:8]=2)[CH:2]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Reactant: Oc1ccccc1C1CC(c2cccnc2)=NN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: O=S(=O)(c1ccc(-c2ccccn2)s1)N1N=C(c2cccnc2)CC1c1ccccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
To 2-(3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-5-yl)phenol (29.85 mg, 0.1149 mmol) placed in a sealed tube was added a solution of 5-pyridin-2-ylthiophene-2-sulfonyl chloride (29.85 mg, 0.1045 mmol) in pyridine (0.5 mL). The reaction mixture was shaken at rt for 18 h. The reaction mixture was diluted with a saturated solution of sodium bicarbonate (2.0 mL) and extracted with DCM. The organic solutions were combined, dried over MgSO4, filtered, and concentrated. The residue was purified by RP-HPLC to give 2-{3-pyridin-3-yl-1-[(5-pyridin-2-yl-2-thienyl)sulfonyl]-4,5-dihydro-1H-pyrazol-5-yl}phenol (I-126) (14.50 mg, 30.0%). 1H NMR (300 MHz, d6-DMSO) δ: 9.77 (s, 1H), 8.87 (bd, 1H), 8.64 (dd, 1H), 8.56 (bd, 1H), 8.12 (dt, 1H), 8.03 (d, 1H), 7.87-7.92 (m, 2H), 7.72 (d, 1H), 7.48 (dd, 1H), 7.35-7.40 (m, 2H), 7.11-7.17 (m, 1H), 6.81-6.85 (m, 2H), 5.24 (dd, 1H), 3.74 (dd, 1H), and 3.20 (dd, 1H). LCMS: (FA) ES+ 463.0, ES-460.9.
Reaction SMILES: [OH:1][PH2:2]=[O:3].[OH2:4].C([O-])(=O)C.[Ca+2:9].C([O-])(=O)C.[OH2:14].O.O.O.O.[N+]([O-])([O-])=O.[Ca+2].[N+]([O-])([O-])=O>C(O)(=O)C>[P:2]([O-:14])([O-:4])([O-:1])=[O:3].[Ca+2:9].[P:2]([O-:14])([O-:4])([O-:1])=[O:3].[Ca+2:9].[Ca+2:9]
Reactant: O=[PH2]O
Reactant: O
Agent: *CC*
Agent: CC(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: CC(=O)O
Product: O=P([O-])([O-])[O-]
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
An aqueous solution of 8.51 g 50 wt % H3PO2 was combined with 8.00 g of 25.0 wt % aqueous solution of calcium acetate monohydrate, Ca(O2CCH3)2.H2O (ACS reagent, Aldrich Chemical Co., Inc. #40,285-0, CAS 5743-26-0), equivalent to 5.69 wt % Ca, to give a clear, colorless solution contained in a 250 ml Pyrex beaker. To this solution was added 20.17 g Ca(NO3)24.H2O salt. The molar ratio of Ca/phosphate in this mixture was 3/2 and the equivalent solids level [as Ca3(PO4)2] was 27.3 wt %. Endothermic dissolution of the calcium nitrate tetrahydrate salt proceeded giving a homogeneous solution once the sample warmed to room temperature. Further warming of this solution to >25° C. on a hotplate initiated a reaction which proceeded as described in Example 1. After approximately three minutes, the reaction was essentially complete leaving a moist, white, crumbly solid which was hot to the touch and which smelled of acetic acid. After cooling to room temperature, the solid was stored in a polyethylene vial.
Reaction SMILES: C[Si](C)(C)CCO[C:6]([C:8]1([N:14]=[C:15]=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:25][NH:26][C:27]([C@H:29]([C@@H:39]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:40]([NH:42][NH2:43])=[O:41])[CH2:30]/[CH:31]=[CH:32]/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:28].CN1CCOCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C.CN(C)C=O.ClCCl>[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:25][NH:26][C:27]([C@H:29]([C@@H:39]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:40]([NH:42][N:43]1[C:6](=[O:7])[C:8]2([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[NH:14][C:15]1=[O:16])=[O:41])[CH2:30]/[CH:31]=[CH:32]/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:28]
Reactant: C[Si](C)(C)CCOC(=O)C1(N=C=O)CCCCC1
Reactant: CC(C)C[C@@H](C(=O)NN)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NN1C(=O)NC2(CCCCC2)C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
A solution of 0.269 g of 2-(trimethylsilyl)ethyl-1-isocyanato-1-cyclohexane carboxylate and 0.403 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-4-methylvalerohydrazide in 6 ml of a 5:1 mixture of dichloromethane and dimethylformamide was treated with 0.15 ml of N-methylmorpholine and was stirred for 2 hours at room temperature. The solution was then washed with 5% citric acid solution and then saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (2:1) followed by hexane/ethyl acetate (1:1) for the elution. The product obtained was dissolved in 5 ml of tetrahydrofuran and 1.6 ml of a 1.0M solution of tetrabutylammonium fluoride in tetrahydrofuran added. The mixture was stirred for 1.5 hours at room temperature, then diluted with ethyl acetate and washed successively with 5% citric acid and brine, dried and evaporated. The residue was triturated with ether and there was obtained 0.25 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-4-methyl-N-(2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)valeramide in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([SH:11])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:19](Br)[CH:20]=[CH2:21]>C(=O)([O-])O.[Na+]>[CH2:21]([S:11][C:4]1[CH:5]=[C:6]([CH:10]=[C:2]([NH2:1])[C:3]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]([OH:9])=[O:8])[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: Nc1cc(C(=O)O)cc(S)c1Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCSc1cc(C(=O)O)cc(N)c1Oc1ccccc1

Procedure:
A solution of 5-amino-3-mercapto-4-phenoxybenzoic acid (2.6 g) in saturated sodium hydrogen carbonate (120 ml) is cooled to 4°C. While cooling and stirring, allyl bromide (1 g) is added, and the reaction mixture is kept under nitrogen. After additional stirring for 10 minutes, 3-allylthio-5-amino-4-phenoxybenzoic acid is precipitated by addition of hydrochloric acid until pH 3. After collection by filtration, recrystallisation from aqeuous ethanol, and drying in vacuo, the compound is obtained with a melting point of 142°-143°C.
Reaction SMILES: Cl.[CH:2]1([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[OH-].[Na+].O1CCCC1>[CH2:14]([O:21][C:22]([NH:10][C@H:9]([C:11]([OH:13])=[O:12])[CH2:8][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](CC1CCCCC1)C(=O)O)OCc1ccccc1
Reaction time: 1.5 h
Yield: 68.9 %

Procedure:
To a solution of 3-cyclohexylalanine, hydrochloride (4.75 , 22.8 mmol) in 2N sodium hydroxide (11.4 mL) were added at 0° C., simultaneously, a solution of benzylchloroformate (3.2 mL, 36 mmol) in tetrahydrofuran (10 mL) and 2N sodium hydroxide (11.4 mL). (The pH of the mixture was maintained around 9-10 by addition of 2N sodium hydroxide.) The mixture was stirred for 1.5 hours. The solution was washed with diethyl ether (3×20 mL). The aqueous phase was acidified to pH 2 with 3N aqueous hydrochloric acid and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous magnesium sulphate. Filtration and removal of the solvent in vacuo left 4.80 g of the expected product (yellow oil, 69% yield).
Reaction SMILES: [C@H:1]1([NH:11][C:12]([C@@H:14]2[CH2:23][C:22]3[C:17](=[CH:18][C:19]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:21]=3)[CH2:16][N:15]2C(OC(C)(C)C)=O)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C@H:1]1([NH:11][C:12]([C@@H:14]2[CH2:23][C:22]3[C:17](=[CH:18][C:19]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:21]=3)[CH2:16][NH:15]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)CN(C(=O)OC(C)(C)C)[C@H](C(=O)N[C@@H]1CCCc3ccccc31)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CN[C@H](C(=O)N[C@@H]1CCCc3ccccc31)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a solution of (S)-2-tert-butyl 7-methyl 3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinoline-2,7(1H)-dicarboxylate (1.06 g, 2.28 mmol) in CH2Cl2 (22.8 mL) was added TFA (5.7 mL). The resulting reaction mixture was stirred at room temperature for 1 h and then quenched with sat. aq. NaHCO3 solution. The aqueous layer was extracted with EtOAc (3×), and the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting oil was then lyophilized from MeCN/H2O overnight to give the title compound (0.79 g, 2.18 mmol, 96%) as a light yellow solid. 1H NMR (DMSO-d6) δ 8.39 (d, J=8.6 Hz, 1H), 7.85-7.67 (m, 2H), 7.34 (d, J=7.9 Hz, 1H), 7.24-7.02 (m, 4H), 5.12-4.93 (m, 1H), 4.23-3.97 (m, 2H), 3.86 (s, 3H), 3.73 (dd, J=10.0, 4.7 Hz, 1H), 3.33 (br s, 1H), 3.18-3.05 (m, 1H), 3.03-2.88 (m, 1H), 2.86-2.63 (m, 2H), 2.02-1.83 (m, 2H), 1.81-1.64 (m, 2H); MS (ESI+) m/z 365.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl

Procedure:
The title compound was prepared from (4-chloro-5-methyl-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example A17) (4.45 g, 15.5 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as a yellow solid (3.90 g, 98%).
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C:10](O)=[O:11])=[CH:7][C:6]=1[CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[NH4+].[Cl-]>C(OCC)C.[O-2].[O-2].[Mn+4]>[C:1]([C:5]1[O:9][C:8]([CH:10]=[O:11])=[CH:7][C:6]=1[CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1oc(C(=O)O)cc1CO[Si](C)(C)C(C)(C)C
Agent: [Mn+4]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)c1oc(C=O)cc1CO[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
Under cooling with ice, a solution of methyl ester of 5-tert-butyl-4-tert-butyldimethylsilanyloxymethylfuran-2-carboxylic acid (2.16 g, 6.63 mmol) in diethyl ether (20 ml) was added to a suspension of lithium aluminum hydride (503 mg, 13.3 mmol) in diethyl ether (20 ml), followed by stirring for 1 hour. Under cooling with ice, the mixture was mixed with ethyl acetate and saturated aqueous NH4Cl and filtered. The filtrate was extracted with ethyl acetate and the organic layer was washed with water and saturated brine, dried over magnesium sulfate and evaporated to remove the solvent. The thus obtained residue was dissolved in methylene chloride (80 ml), mixed with manganese dioxide (5.76 g, 66.3 mmol) and stirred overnight. After filtering the reaction mixture, the filtrate was evaporated to remove the solvent to give the titled compound (1.58 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([C:21]3[C:26]([F:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:29](O)=[O:30])[CH2:12]1)(=[O:10])=[O:9].[CH2:32]([NH:39][C:40](=[O:48])[C:41](=[O:47])[C@@H:42]([NH2:46])[CH2:43][CH2:44][CH3:45])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([NH:39][C:40](=[O:48])[C:41](=[O:47])[C@@H:42]([NH:46][C:29]([C@@H:13]1[CH2:12][C@@H:11]([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:9])[CH2:15][N:14]1[C:16]([C:18]1([C:21]2[C:26]([F:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=2)[CH2:19][CH2:20]1)=[O:17])=[O:30])[CH2:43][CH2:44][CH3:45])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCC[C@H](N)C(=O)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1)C(=O)C(=O)NCc1ccccc1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-4-(2-Chloro-benzenesulfonyl)-1-[1-(5-chloro-3-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid and (S)-3-Amino-2-oxo-hexanoic acid benzylamide in step 1. MS (m/e)=703.15 [M+H+].
Reaction SMILES: COC(=O)C1(CCC(C(O)=O)C1(C)C)C.Cl.C[O:18][C:19](=[O:40])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][C:26](NC(=O)C2C(Cl)=CC=CC=2Cl)=[CH:25][CH:24]=1)[NH2:21]>>[NH2:21][C@H:20]([C:19]([OH:40])=[O:18])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Agent: COC(=O)C1(C)CCC(C(=O)O)C1(C)C
Agent: Cl
Product: N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
The preparation follows that of Preparation 37-C-8. The starting materials are: (1R-cis)-1,2,2-trimethylcyclopentane-1,3-dicarboxylic acid 3-methyl ester, 10-A, and 4-[(2,6-dichlorobenzoyl)amino]-L-phenylalanine methyl ester, hydrochloride salt, 37-B-1. Physical properties as follows: m.p. 154-160° C. 1H NMR(300 MHz, MeOH-d4). δ7.58(2H), 7.42(3H), 7.24(3H), 4.74(1H), 3.3(1H), 3.03(1H), 2.75(1H), 2.41(1H), 2.12(1H), 1.80(1H), 1.43(1H), 1.14(3H), 1.11(3H), 0.63(3H); MS−ESI (m/z): 533([M−H−]); MS−ESI (m/z): 535([M+H+]).
Reaction SMILES: [C:1]1([CH:7]([C:12]2[C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:15]=3[NH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN.F[P-](F)(F)(F)(F)F.[N:30]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:34]2C=CC=CC=2N=N1>C(Cl)Cl.CN(C=O)C.C([O-])(O)=O.[Na+]>[CH3:34][NH:30][C:9](=[O:11])[CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[NH:14][CH:13]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)CC(c1ccccc1)c1c[nH]c2ccncc12
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)CC(c1ccccc1)c1c[nH]c2ccncc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To a RT suspension of 3-phenyl-3-(1H-pyrrolo[3,2-c]pyridin-3-yl)-propionic acid (1.1 mmol) in DCM/DMF (3/2, 5 mL) was added TEA (0.23 mL, 1.7 mmol) followed by MeNH2 (2 M in THF, 0.83 mL) and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.58 g, 1.3 mmol). The resulting mixture was stirred at RT overnight, diluted with an aqueous solution of NaHCO3, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (DCM/MeOH/NH40H), affording N-Methyl-3-phenyl-3-(1H-pyrrolo[3,2-c]pyridin-3-yl)-propionamide (0.16 g).
Reaction SMILES: P(O)(O)([O-])=O.[K+].S([O-])([O-])(=O)=O.[Mg+2].[C:13](=[O:16])([O-])[O-:14].[Ca+2].[OH-].[Na+].[CH2:20]([NH:26][C:27](CO)(CO)[CH2:28][OH:29])[CH2:21]S(O)(=O)=O.N1CCC[C@H]1C(O)=O.O=C(CCC(O)=O)C(O)=O.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>C1(C)C(C)=CC=CC=1>[OH:29][C@H:28]1[CH2:27][NH:26][C@H:20]([C:13]([OH:14])=[O:16])[CH2:21]1
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(O)CCNC(CO)(CO)CO
Agent: O=C(O)CCC(=O)C(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: Cc1ccccc1C
Product: O=C(O)[C@@H]1C[C@@H](O)CN1
Reaction time: 0.33 h

Procedure:
Separately, Df1 medium comprising 5% soluble starch, 1.5% soybean meal, 0.05% monopotassium phosphate, 0.05% magnesium sulfate 7 hydrate and 0.5% calcium carbonate, and adjusted to pH 7.0 with 6N NaOH, was put in test tubes (diameter 25 mm×length 200 mm) in an amount of 10 ml each and sterilized at 120° C. for 20 minutes. One ml of the above-mentioned seed culture was inoculated in the medium in each test tube under germ-free condition and cultivated at 28° C. for 2 days with shaking. The thus-obtained culture was centrifuged at 7000×g for 10 minutes at 4° C. The cells thus separated were washed with 80 mM TES [N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid] buffer (pH 7.5) and then recentrifuged. 150 mg of the thus-obtained wet cells was suspended in 1.5 ml of a reaction mixture which had been prepared by adding 1.4% (v/v) of NYMEEN solution [prepared by adding 4 g of NYMEEN S-215 (produced by Nippon Oils & Fats Co.) to 10 ml of xylene] to 80 mM TES buffer (pH 7.5) containing 4 mM L-proline, 8 mM 2-ketoglutaric acid, 4 mM L-ascorbic acid and 2 mM ferrous sulfate] and the mixture was allowed to stand at 30° C. for 2 hours to carry out the enzymatic reaction.
Reaction SMILES: C1(C(C2C=CC=CC=2)(CC=C)CN)C=CC=CC=1.C1(C=O)CCCCC1.[CH2:27]([NH:34][CH2:35][C:36]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:37][CH:38]=[CH2:39])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH:28]1([CH2:27][NH:34][CH2:35][C:36]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:37][CH:38]=[CH2:39])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C=CCC(CNCc1ccccc1)(c1ccccc1)c1ccccc1
Agent: C=CCC(CN)(c1ccccc1)c1ccccc1
Agent: O=CC1CCCCC1
Product: C=CCC(CNCC1CCCCC1)(c1ccccc1)c1ccccc1
Yield: 97 %

Procedure:
N-(Cyclohexylmethyl)-2,2-diphenylpent-4-en-1-amine was prepared from 2,2-diphenylpent-4-enylamine and cyclohexanecarboxaldehyde according to the procedure used for preparation of N-benzyl-2,2-diphenylpent-4-en-1-amine. The product was obtained in a 97% yield as a colorless oil. The compound was purified by column chromatography on silica gel (Hexane/Ethyl acetate=8/1). 1H NMR (400 MHz, CDCl3) δ 0.41 (s, 1H), 0.74-0.83 (m, 2H), 1.08-1.41 (m, 4H), 1.59-1.71 (m, 5H), 2.38 (d, J=6.8 Hz, 2H), 3.05 (d, J=6.8 Hz, 2H), 3.20 (s, 2H), 4.97 (dt, J=10.4, 0.12 Hz, 1H), 5.06 (dt, J=16.8, 1.2 Hz, 1H), 5.36-5.47 (m, 1H), 7.19-7.33 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 26.3, 27.1, 31.6, 37.7, 41.9, 50.4, 56.3, 57.5, 117.8, 126.1, 128.2, 123.3, 135.3, 147.3.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:13]1)=[O:4].[OH-].[Na+]>>[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:13]1)([OH:4])=[O:2]
Reactant: COC(=O)CCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)n1
Yield: 78.9 %

Procedure:
2-(7-Methoxycarbonylheptyl)-4,5-diphenyltriazole (1 g) was reacted with 2N sodium hydroxide in a method similar to Example 58. Recrystallisation from ethanol and water gave 2-(7-carboxyheptyl)-4,5-diphenyltriazole (0.76 g, 79%) as a white solid, m.p. 86°-88° C.