Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.C(N1CCOCC1)C.[CH2:35]([NH2:40])[CH2:36][CH2:37][CH2:38][CH3:39]>O1CCCC1>[CH2:35]([NH:40][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCN
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: CCCCCNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 16 h

Procedure:
12.46 g (0.05 mol) of N-benzyloxycarbonyl-L-proline were dissolved in 100 ml of dry tetrahydrofuran and the solution was cooled to -10° C. The solution was stirred and there were added thereto 6.56 ml (0.05 mol) of isobutyl chloroformate and 6.35 ml (0.05 mol) of N-ethylmorpholine. The mixture was then stirred at -10° C. for 15 minutes. 5.76 ml (0.05 mol) of n-pentylamine were then added and the resulting mixture was stirred at 0° C. for 1 hour and then at room temperature for 16 hours. The mixture was evaporated to an oil and 400 ml of water were added. The resulting mixture was extracted with two 150 ml portions of ethyl acetate, the organic layers were combined and washed successively with two 100 ml portions of 5% citric acid solution, once with 100 ml of water, twice with 100 ml portions of 5% sodium bicarbonate solution and once with 100 ml of water. The organic layer was dried over sodium sulphate, evaporated to an oil and triturated with 350 ml of petroleum ether. On scratching, the product crystallized out, was filtered off and washed with 100 ml of petroleum ether. There were thus obtained 10.16 g (64%) of N-benzyloxycarbonyl-L-proline n-pentylamide of melting point 74°-76° C. A second crop (0.800 g) of melting point 76°-79° C. was obtained from the mother liquor.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:12](=[O:30])[C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:29])[C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)=[CH:15][CH:14]=2)[CH2:3]1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>ClCCl>[C:31]([NH:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:12](=[O:30])[C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:29])[C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)=[CH:17][CH:18]=2)[CH2:3]1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: NC1Cc2ccccc2N(C(=O)c2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2)C1
Solvent: ClCCl
Product: CC(=O)NC1Cc2ccccc2N(C(=O)c2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2)C1
Reaction time: 1 h
Yield: 62.2 %

Procedure:
To 3-amino-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.44 g) are added dichloromethane (5 ml) and acetic anhydride (0.12 g) and the mixture is stirred for 1 hour. The reaction mixture is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane→dichloromethane:methanol=50:1) to give 3-acetylamino-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.3 g) as colorless amorphous.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26](O)=[O:27])=[CH:20][CH:19]=1>>[C:18]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:19]=[CH:20][C:21](/[CH:24]=[CH:25]/[C:26]([NH:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:9]=[CH:10]3)=[O:27])=[CH:22][CH:23]=1
Reactant: Nc1ccc2c(cnn2CCN2CCCC2)c1
Reactant: O=C(O)C=Cc1ccc(-c2ccccc2)cc1
Product: O=C(/C=C/c1ccc(-c2ccccc2)cc1)Nc1ccc2c(cnn2CCN2CCCC2)c1

Procedure:
1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-ylamine and 3-biphenyl-4-yl-acrylic acid were processed as described in Example 17 to provide the title compound. MS (DCI/NH3) MS m/z 437 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ ppm 1.84 (m, 2 H), 1.99 (m, 2 H), 3.06 (m, 2 H), 3.53 (m, 2 H), 3.72 (m, 2 H), 4.76 (t, J=5.93 Hz, 2 H), 6.91 (m, 1 H), 7.40 (m, 1 H), 7.50 (m, 2 H), 7.64 (m, 2 H), 7.75 (m, 7 H), 8.18 (s, 1 H), 8.31 (s, 1 H), 9.56 (br s, N H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([Sn](CCCC)(CCCC)[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)CCC.N#N>CN(C)C(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1
Reactant: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CC(=O)N(C)C
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1-c1ccncc1
Temperature: 80 °C

Procedure:
A solution of 3-(3-bromo-4-fluorophenyl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (70 mg, 0.19 mmol) and 4-(tri-n-butylstannyl)pyridine (107 mg, 0.29 mmol) in N,N-dimethylacetamide (3 ml) was degassed with N2. Tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol) and copper(I) iodide (15 mg, 0.079 mmol) was added and the mixture heated at 80° C. for 6 h. The solvent was evaporated in vacuo and the residue partitioned between dichloromethane and water, separated and the aqueous re-extracted with dichloromethane. The combined organics were washed with brine, dried (MgSO4) and evaporated. The residue was purified using preparative thin-layer chromatography on silica gel, using 30% ethyl acetate/dichloromethane as the eluent, to give a yellow solid. Further purification using preparative thin-layer chromatography on silica gel, eluting with 2% methanol/dichloromethane, afforded 3-[4-fluoro-3-(pyridin-4-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a cream solid: δH (360 MHz, DMSO) 7.52 (1H, d, J 7), 7.63 (1H, dd, J 10 and 8), 7.71-7.73 (2H, m), 7.90 (1H, ddd, J 9, 5 and 2), 8.04 (1H, dd, J 7 and 2), 8.33 (1H, s), 8.72 (2H, m), 9.37 (1H, d, J 7); m/z (ES+) 359 (M++H).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:28])[C:8]=1[NH:9][C:10]([C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH2:26][CH3:27])=[N:17][N:18]2[CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:14][CH:13]=1)=[O:11].I[CH3:30]>CN(C=O)C.O>[Cl:28][C:7]1[CH:6]=[N:5][CH:4]=[C:3]([Cl:2])[C:8]=1[N:9]([CH3:30])[C:10]([C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH2:26][CH3:27])=[N:17][N:18]2[CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:14][CH:13]=1)=[O:11]
Reactant: CI
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3c(Cl)cncc3Cl)ccc12
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn(C2CCCC2)c2cc(C(=O)N(C)c3c(Cl)cncc3Cl)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
5.2 mg (0.130 mmol, 1.05 equiv) sodium hybride, 60% oil dispersion, were added to a room temperature solution of 50 mg (0.124 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid (3,5-dichlor-pyridin-4-yl)-amide in 3 mL anhydrous DMF. After 30 min. 7.7 μl (0.124 mmol, 1.0 equiv) iodomethane were added and the mixture stirred at room temperature for 4 h. The reaction mixture was diluted with 50 mL H2O and extracted 2×20 mL ethyl acetate. The ethyl acetate extracts were combined, washed 2×5 mL H2O, 1×5 mL brine, and dried over Na2SO4. Filtration, concentration of filtrate and drying gave a yellow oil, which was purified on a silica gel column (25% ethylacetate/hexanes, flash) to give 27 mg (52%) of a white crystalline solid: mp 118-119° C.; HRMS calcd for C21H22N4OCl3+H: 417.12519. Found: 417.12270.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:9][C:10]([C:12]1[CH:20]=[C:16]([C:17]([NH2:19])=[O:18])[C:15]([OH:21])=[CH:14][CH:13]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C1(C)C=CC(S(O[CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH3:48])(=O)=O)=CC=1>CN(C)C=O>[CH2:22]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH3:48])=[C:16]([CH:20]=1)[C:17]([NH2:19])=[O:18])=[O:11])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NC(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1O
Reactant: CCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCOCCOc1ccc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)cc1C(N)=O
Yield: 93.1 %

Procedure:
A solution of 5-(N,N-dibenzylglycyl)salicylamide (10 g.) in dimethylformamide (75 ml) was added dropwise to a stirred suspension of sodium hydride (0.875 g) in dimethylformamide (25 ml). 2-(2 -Ethoxyethoxy)ethyl p-toluenesulphonate (12.75 g) was then added and the solution heated at 100° for 2 hours. The solvent was evaporated to give a yellow oily solid which was partitioned between ethyl acetate and water. The ethyl acetate layer was dried (MgSO4), concentrated to 30 ml and chromatographed on alumina (60 g.). The column was eluted with ethyl acetate (100 ml portions). The first fraction was discarded and the subsequent four fractions yielded an oil (12.2 g) which crystallised from ethanol to give the ether as colourless plates (5.8 g) m.p. 91.5°-92.5°. Recrystallisation of a sample raised the m.p. to 92.5°-94°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.O>C(O)C.[NH4+].[Cl-].[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N=Nc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: COc1ccc(NNc2ccccc2)cc1
Yield: 100.3 %

Procedure:
Zinc powder (10.0 g; 0.15 mol) was added to a stirred mixture of 4-methoxyazobenzene (4.24 g; 20.0 mmol) in 96% ethanol (75 ml) and saturated NH4Cl solution (2.0 ml) at 0° C. (bath temperature). Two more portions of saturated NH4Cl solution (2.0 ml) were added at 1.5 h intervals. The yellowish solution was poured into cold water (100 ml) and filtered. The residue was extracted with methylene chloride (5×50 ml). The combined aqueous phases were extracted with methylene chloride (3×25 ml). The combined organic solutions were,dried (Na2SO4), filtered and evaporated to give 4.3 g crude 1-(4-methoxyphenyl)-2-phenylhydrazine as a reddish oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][NH:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)(C)(C)C.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[OH:30][C:24]([C:26]([F:29])([F:28])[F:27])=[O:25].[C:17]1([C@@H:8]([NH2:7])[CH2:9][NH:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC1CCOCC1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CNC1CCOCC1)c1ccccc1

Procedure:
A solution of the tert-butyl carbamate (333 mg, 1.04 mmol) and TFA (1.0 ml) in CH2Cl2 (6.0 ml) was stirred at room temperature for 50 minutes. The excess solvent was removed under reduced pressure, giving the crude (R)-1-phenyl-N2-(tetrahydro-pyran-4-yl)-ethane-1,2-diamine TFA salt as a pale yellow oil (849 mg).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]1([N:29]=[C:30]=[S:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([NH:29][C:30](=[S:31])[NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[O:17])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: S=C=NC1CCCCC1
Product: O=C(NCCCOc1cccc(CN2CCCCC2)c1)NNC(=S)NC1CCCCC1

Procedure:
The compound is prepared by a method analogous to that of Example 17 from N-[3-[3-(1-piperidinylmethyl) phenoxy]propyl]-hydrazine carboxamide and cyclohexyl isothiocyanate. The analytical values are summarized in Table I.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:57][N:58]1[CH2:63][CH2:62][CH:61]([NH2:64])[CH2:60][CH2:59]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:64][CH:61]5[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46-1.78 (m, 10 H) 1.98 (m, 4 H) 2.18 (s, 3 H) 2.79 (d, J=11.4 Hz, 2 H) 3.33 (s, 3 H) 3.74 (m, 1 H) 3.94 (s, 3 H) 4.04 (t, J=14.0 Hz, 2 H) 4.75 (q, J=7.9 Hz, 1 H) 7.50 (s, 1 H) 7.47 (d, J=1.5 Hz, 1 H) 7.94 (s, 1 H) 8.09 (d, J=7.8 Hz, 1 H) 8.27 (d, J=8.1 Hz, 1 H) 8.26 (s, 1 H). [M+H] calc'd for C27H35F2N7O3, 544; found 544.
Reaction SMILES: [CH2:1]([C@@:4]1(C)[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:5]1=[O:29])C=C.C(Cl)(Cl)(Cl)Cl.I([O-])(=O)(=O)=O.[Na+].Cl.CC[O:45][C:46]([CH3:48])=[O:47]>C(#N)C.O.[Ru](Cl)(Cl)Cl.O>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:6]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:5](=[O:29])[C@:4]([CH2:48][C:46]([OH:45])=[O:47])([CH3:1])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)CC)C1=O
Reactant: CCOC(C)=O
Agent: Cl[Ru](Cl)Cl
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: O
Product: CCC(CC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of 725 mg (1.63 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one (Example 3, Step A) in a mixture of acetonitrile (4 mL), carbon tetrachloride (4 mL) and water (5.9 mL) added 1.40 g (6.53 mmol) of sodium periodate followed by 44 mg (0.20 mmol) of ruthenium(III) chloride hydrate. The dark brown biphasic mixture was stirred vigorously at room temperature for 21 h, and then was acidified with 1 N HCl. The mixture was diluted with EtOAc and filtered through a pad of Celite® (J. T. Baker, Phillipsberg, N.J., diatomaceous earth). After filtration, the layers were separated and the aqueous layer was extracted with EtOAc (1×). The combined organic layers were washed with saturated aqueous sodium chloride (1×), then were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (0 to 25% MeOH/DCM, gradient elution) provided the title compound as a white solid.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][SH:3].C[O-].[Na+].Cl[CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1>C(O)C>[N:11]1([CH2:10][CH2:9][S:3][CH2:2][CH2:1][SH:4])[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCCn1ccnc1
Reactant: SCCS
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: SCCSCCn1ccnc1

Procedure:
In ethanol (30 ml) was dissolved 1-(2-chloroethyl)imidazole, to which were added 1,2-ethanedithiol (25 ml) and sodium methoxide (28% methanol solution) (16.6 ml), and the mixture was heated for 30 minutes under reflux. Insoluble substances were filtered off, and the filtrate was concentrated under reduced pressure. To the concentrate was added dichloromethane (300 ml). The organic layer was washed with water, then with a saturated aqueous sodium chloride solution, followed by drying (sodium sulfate). The solvent was distilled off, and the residue was subjected to a silica gel column chromatography (3.0×40 cm:ethyl acetate→ethyl acetate:methanol=10:1) to give 2-[2-(1 -imidazolyl)ethylthio]ethanethiol (3.0 g) as a pale yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][OH:13])[CH:7]=1.[C:15]1([N:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:22](=[O:23])[N:21]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COC(=O)COc1cccc(CO)c1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)COc1cccc(COC(=O)N(c2ccccc2)c2ccccc2)c1
Yield: 73.5 %

Procedure:
(3-Hydroxymethylphenoxy)acetic acid methyl ester (400 mg, 2 mmol) and diphenylcarbamyl chloride (580 mg, 2.5 mmol) were combined in pyridine (2 ml). The resultant yellow solution was allowed to stand for ten days under nitrogen. The mixture was then poured into water, extracted with dichloromethane, and evaporated. Purification of the residue by silica gel chromatography, eluting with 5% acetone/dichloromethane, gave {3-[(diphenyl-carbamoyloxy)methyl]phenoxy}acetic acid methyl ester as a colorless solid (575 mg, 73%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27](=O)[NH:26][N:25]=[N:24]2)=[CH:19][CH:18]=1.FC1C=C(F)C=CC=1[C@]1(OC1)[C@H](N1C(=O)N(C2C=CC(C(F)(F)F)=CC=2)N=N1)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([O:14][C:27]2[N:23]([C:20]3[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:29])[F:30])=[CH:22][CH:21]=3)[N:24]=[N:25][N:26]=2)[CH3:13])[CH2:11][O:10]1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]nnn1-c1ccc(C(F)(F)F)cc1
Agent: C[C@@H](n1nnn(-c2ccc(C(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](Oc1nnnn1-c1ccc(C(F)(F)F)cc1)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 7.2 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.41 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.30 g of 1-(4-trifluoromethylphenyl)-5(1H,4H)-tetrazolone, 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(4-trifluoromethylphenyl)-5-(1H,4H)-tetrazolone (1.38 g) and 0.168 g of (2R)-2-(2,4-difluorophenyl)-2-[(1R)-1-[1-(4-trifluoromethylphenyl)-1H-tetrazol-5-yloxy]ethyl]oxirane were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:20]1([CH2:23][C:24](O)=[O:25])[CH2:22][CH2:21]1>>[C:12]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][C:24](=[O:25])[CH2:23][CH:20]1[CH2:22][CH2:21]1)=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Reactant: O=C(O)CC1CC1
Product: O=C(CC1CC1)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 114 employing 3-amino-2-benzoyl-6-chloroindole (Example 1) and cyclopropylacetic acid. m.p.: 72-75° C.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]([C:20]2[C:21]([F:26])=[N:22][CH:23]=[CH:24][CH:25]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[N+:17]([O-])=O)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH-].[NH4+]>O1CCOCC1.O>[C:1]([C:5]1[NH:6][C:7]([C:20]2[C:21]([F:26])=[N:22][CH:23]=[CH:24][CH:25]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[NH2:17])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(-c2ccc(F)cc2[N+](=O)[O-])c(-c2cccnc2F)[nH]1
Agent: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1nc(-c2ccc(F)cc2N)c(-c2cccnc2F)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.9 %

Procedure:
To a solution of 3-[2-tert-butyl-4-(4-fluoro-2-nitrophenyl)-1H-imidazol-5-yl]-2-fluoropyridine (0.13 g, 0.36 mmol) in 1,4-dioxane (4 mL) was added a solution of sodium dithionite (0.5 g, 0.003 mol) and ammonium hydroxide (0.5 mL, 0.004 mol) in water (4 mL). The reaction was stirred at 25° C. for 4 h and was then extracted with EtOAc. The combined extracts were washed with water 2×, dried over MgSO4 and concentrated in vacuo to give 0.098 g of the desired product. 1H NMR (500 MHz, CD3OD): δ 8.28-8.29 (m, 1H), 7.95-7.99 (m, 1H), 7.45-7.46 (m, 1H), 7.34-7.35 (m, 1H), 6.77-7.11 (m, 2H), 6.73-6.77 (m, 1H), 1.56 (s, 9H). MS [M+H]=329.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18](Br)=[CH:19][N:20]=[CH:21]3)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[NH3:54].O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18]([NH2:54])=[CH:19][N:20]=[CH:21]3)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2cccc3cncc(Br)c23)CC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2cccc3cncc(N)c23)CC1
Temperature: 70 °C
Reaction time: 22 h

Procedure:
A suspension of Intermediate 121 (100 mg), tris(dibenzylideneacetone)dipalladium(0) (22.1 mg), 2-(di-tert-butylphosphino)biphenyl (33.9 mg) and sodium tert-butoxide (35.3 mg) in 0.5 N ammonia/dioxane solution (2 ml) was stirred at 70° C. for 22 hours. The reaction mixture was filtered through a Celite layer, and the solvent was evaporated under reduced pressure. Then, the residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to obtain the title compound (36.1 mg).
Reaction SMILES: [CH3:1][C:2]1[C:17]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:5]2[O:6][CH:7]([CH2:9][N:10]=[N+]=[N-])[CH2:8][C:4]=2[CH:3]=1>[Pd]>[CH3:1][C:2]1[C:17]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:5]2[O:6][CH:7]([CH2:9][NH2:10])[CH2:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(c3c1CCC3)OC(CN=[N+]=[N-])C2
Agent: [Pd]
Product: Cc1cc2c(c3c1CCC3)OC(CN)C2
Yield: 80 %

Procedure:
Treatment of (±)-(5-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methyl 4-methylbenzenesulfonate (0.862 g, 2.40 mmol) with sodium azide (0.469 g, 7.21 mmol) generally according to the procedure described for Intermediate 24 gave (±)-(5-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methyl azide. Treatment of the azide with palladium on carbon (10 wt. %, 0.055 g) generally according to the procedure described for Example 2 gave 0.460 g (80%) of (±)-1-(5-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. mp>200° C. (dec.); Anal. calcd. for C13H17NOHCl: C, 65.13; H, 7.57; N, 5.84. Found: C, 64.97; H, 7.61; N, 5.67.