Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O-:21])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:58]([C:61]1[N:66]=[CH:65][C:64]([NH:67][CH:68]2[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]2)=[CH:63][CH:62]=1)([O-:60])=[O:59]>CN(C)C=O.ClCCl.O1CCCC1>[N+:58]([C:61]1[N:66]=[CH:65][C:64]([NH:67][CH:68]2[CH2:73][CH2:72][N:71]([C:19](=[O:21])[CH2:18][CH2:17][CH2:16][N:13]3[CH2:14][CH2:15][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([F:2])([F:22])[F:23])=[CH:5][CH:6]=4)[CH2:11][CH2:12]3)[CH2:70][CH2:69]2)=[CH:63][CH:62]=1)([O-:60])=[O:59]
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cn1
Reactant: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])nc2)CC1
Reaction time: 0.08 h

Procedure:
4-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid lithium salt (35 mg; 0.11 mmol, prepared in accordance with Example 3), diisopropylethyl amine (174 μL; 1.0 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (37 mg; 0.1 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution of (6-nitro-pyridin-3-yl)-piperidin-4-yl-amine hydrochloride (27 mg; 0.1 mmol, prepared in accordance with Example 94) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 90 minutes at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (3×5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (48 mg; 0.09 mmol). The structure was confirmed using Protocol II-A. Calculated mass=521; observed mass=521; HPLC retention time=3.08 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][N:5]([C:7]([NH:20][CH2:21][CH3:22])=[N:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[CH:13]=2)(=[O:11])=[O:10])[N:4]=[CH:3]1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1([CH3:23])[CH2:6][N:5]([C:7]([NH:20][CH2:21][CH3:22])=[N:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)(=[O:11])=[O:10])[N:4]=[CH:3]1
Reactant: CCNC(=NS(=O)(=O)c1cccc(OC)c1)N1CC(C)(C)C=N1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCNC(=NS(=O)(=O)c1cccc(O)c1)N1CC(C)(C)C=N1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
In 20 mL DCM, 2.32 g N-[(4,4-Dimethyl-4,5-dihydro-pyrazol-1-yl)-ethylamino-methylene]-3-methoxy-benzenesulfonamide was dissolved, and 13.7 mL of a 1M solution of BBr3 in DCM was added. The mixture was stirred over weekend at room temperature. A 5% aqueous NaHCO3 solution was added to quench the mixture that contained a sticky precipitate; after quenching, this was dissolved by gently heating the mixture. The organic layer was separated and the aqueous layer was extracted once more with DCM. The combined organic layers were dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (DCM/MeOH 99:1→98:2) to yield 1.24 g (56%) N-[(4,4-Dimethyl-4,5-dihydro-pyrazol-1-yl)-ethylamino-methylene]-3-hydroxybenzenesulfonamide as of a beige powder. 1HNMR (400 MHz, CDCl3) δ 1.09 (t, J=7 Hz, 3H), 1.14 (s, 6H), 3.40-3.50 (m, 2H), 3.58 (br.s., 2H), 6.72 (s, 1H), 6.79 (br.s., 1H), 6.97-7.03 (m, 1H), 7.25-7.34 (m, 2H), 7.46 (br d, J=8 Hz, 1H), 7.66 (br s, 1H).
Reaction SMILES: O.[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[C:6]([OH:8])=[O:7].Cl[C:14]1C=C(C=CC=1O)C(O)=O>CO>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([OH:12])=[C:3]([Cl:2])[CH:4]=1
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(O)c(Cl)c1
Temperature: 55 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
To a solution of 3-chloro-4-hydroxy-benzoic acid hemihydrate (9.08 g, 50 mmol) in methanol (150 mL) is added slowly (conc)sulfuric acid (22.5 mL). The resulting solution is heated to 55° C. and stirred 2 hours then cooled to 20° C. Poured solution into ice and extracted with ether. The organic is washed with brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 30% ethyl acetate in hexanes) to give 9.5 g of title compound as a white crystalline solid. 1H NMR (CDCl3) δ 3.90 (s, 3H), 7.06 (d, J=9 Hz, 1H), 7.88 (dd, J=9, 2 Hz, 1H), 8.05 (d, J=2 Hz, 1H). MS (EI) m/z 186/188 (M+, Cl).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(O)(C(F)(F)F)=O>>[CH3:27][C:25]1[CH:24]=[CH:23][C:5]2=[C:6]3[C:11](=[C:2]([NH2:1])[N:3]=[C:4]2[CH:26]=1)[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH3:21])=[CH:18][CH:19]=1)=[CH:7]3
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Reactant: C1CNCCN1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)N4CCNCC4)cc3)cc12

Procedure:
8-Methyl-2-(4-(1-(piperazin-1-yl)ethyl)phenethyl)benzo[f][1,7]naphthyridin-5-amine was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and piperazine (commercially available) following the procedures described for Example 182. 1H NMR (Methanol-d4) TFA Salt: δ 8.83 (s, 1H), 8.75 (s, 1H), 8.39 (d, 1H), 7.51 (s, 1H), 7.46 (d, 1H), 7.26 (m, 4H), 3.62 (m, 1H), 3.25 (t, 2H), 3.12 (t, 2H), 2.80 (m, 4H), 2.69 (m, 4H), 2.56 (s, 3H), 1.42 (d, 3H). LRMS [M+H]=426.2
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:37]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:14]([N:16]([CH2:26][C:27]2[C:31]3=[N:32][C:33]([Cl:36])=[CH:34][CH:35]=[C:30]3[S:29][CH:28]=2)[C@@H:17]([CH3:25])[CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[O:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>>[NH2:37][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:7][CH:8]=1)[C:14]([N:16]([CH2:26][C:27]1[C:31]2=[N:32][C:33]([Cl:36])=[CH:34][CH:35]=[C:30]2[S:29][CH:28]=1)[C@@H:17]([CH3:25])[CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[O:15]
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccc(Cl)nc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccc(Cl)nc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Yield: 118.6 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (9H-fluoren-9-yl)methyl(S)-3-(4-tert-butoxyphenyl)-1-(((5-chlorothieno[3,2-b]pyridin-3-yl)methyl)((S)-1,1-diethoxypropan-2-yl)amino)-1-oxopropan-2-ylcarbamate (Compound III-11) (512 mg, 0.66 mmol) was treated with piperidine and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound (429 mg, 119%).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][N:50]1[C:58]2[C:53](=[CH:54][C:55]([C:59]3[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=3)=[CH:56][CH:57]=2)[CH:52]=[CH:51]1>CN(C=O)C>[CH3:49][N:50]1[C:58]2[C:53](=[CH:54][C:55]([C:59]3[CH:60]=[C:61]([NH:65][C:22]([C:17]4[C:18](=[O:21])[O:19][C:20]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][C:11]=5[OH:10])=[O:24])[CH:62]=[CH:63][CH:64]=3)=[CH:56][CH:57]=2)[CH:52]=[CH:51]1
Reactant: Cn1ccc2cc(-c3cccc(N)c3)ccc21
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
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
Product: Cn1ccc2cc(-c3cccc(NC(=O)c4cc5cccc(O)c5oc4=O)c3)ccc21
Temperature: 25 °C
Yield: 45 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1-methyl-1H-indol-5-yl)-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.012 g of product in 48% yield: LCMS (ESI) m/z 411 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.Cl[C:9]1[CH:14]=[C:13]([S:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:23])[CH:12]=[CH:11][N:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:23])[C:16]=1[S:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:7][C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[CH:14]=1
Reactant: Cc1cccc(C)c1Sc1ccnc(Cl)c1
Reactant: Cc1csc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1csc(Nc2cc(Sc3c(C)cccc3C)ccn2)n1
Yield: 47.7 %

Procedure:
Using the method of Example 3, Step B, 4-methylthiazol-2-amine (0.274 g, 2.40 mmol), 2-chloro-4-(2,6-dimethylphenylthio)pyridine (0.600 g, 2.40 mmol), potassium phosphate (0.561 g, 2.64 mmol), Pd2(dba)3 (0.110 g, 0.120 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.070 g, 0.120 mmol) were reacted to provide N-(4-(2,6-dimethylphenylthio)pyridin-2-yl)-4-methylthiazol-2-amine (0.375 g, 48% yield). 1H NMR (d6-DMSO) δ 11.01 (s, 1H), 8.03 (d, 1H), 7.31-7.40 (m, 3H), 6.57 (s, 1H), 6.50 (s, 1H), 6.41 (d, 1H), 2.40 (s, 6H), 2.20 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=3)[N:7]=[C:6]([C:30]#[N:31])[C:5]=2[N:4]=[N:3]1.[CH3:32][S:33]([CH:36]=[CH2:37])(=[O:35])=[O:34]>C(#N)C>[CH3:1][N:2]1[C:10]2=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH:20]4[CH2:21][CH2:22][N:23]([CH2:37][CH2:36][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:24][CH2:25]4)=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=3)=[N:7][C:6]([C:30]#[N:31])=[C:5]2[N:4]=[N:3]1
Reactant: C=CS(C)(=O)=O
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)cc21
Solvent: CC#N
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCN(CCS(C)(=O)=O)CC4)c(C(F)(F)F)c3)cc21

Procedure:
1-Methyl-6-(4-(2-(piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]-triazolo[4,5-c]pyridine-4-carbonitrile (50 mg) and methylsulfonylethene (0.051 ml) were combined in acetonitrile (3 ml) and the reaction mixture microwaved at 120° C. for 20 minutes. The reaction mixture was concentrated under vacuum and the resulting solid suspended in methanol and filtered off to afford the title compound (43.8 mg).
Reaction SMILES: C1(C)C=CC(C(Cl)=O)=CC=1.[NH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19](=[O:27])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH2:13][CH2:12]1>>[N:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19](=[O:27])[C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)=[CH:13][CH:12]=1
Reactant: Cc1ccc(C(=O)NCC2CCNCC2)cc1
Agent: Cc1ccc(C(=O)Cl)cc1
Product: Cc1ccc(C(=O)NCc2ccncc2)cc1
Yield: 87.7 %

Procedure:
N-(4-pyridylmethyl)-p-methylbenzamide was synthesized from p-toluoyl chloride and 4-pryidylmethylamine in the same manner as employed in Example 1 above. The pure product has a melting point 142.7° C., yield of 87.7%. The intermediate product was converted to pure N-(4-piperidinylmethyl)-p-methylbenzamide as previously described (Example 1); melting point 226.6° C., yield 70.7%, and evaluated according to Tables I, II, and III.
Reaction SMILES: CSC.B.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:15])[CH2:13][Cl:14])=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.CC1OCCC1>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]([OH:15])[CH2:13][Cl:14])=[CH:10][CH:11]=1
Reactant: O=C(CCl)c1ccc(Br)cc1
Agent: B
Solvent: CSC
Solvent: CC1CCCO1
Solvent: Cc1ccccc1
Product: O[C@@H](CCl)c1ccc(Br)cc1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Borane dimethylsulfide (2.0 kg, 24.8 moles, 94% w/w) was mixed in toluene (8 L) at tjacket=20° C. (R)-(+)-Methyl-CBS-oxazaborolidine (2.6 kg, 2.74 moles, 1M) as a toluene solution was added. The charging vessel was rinsed with toluene (0.5 L) and tjacket was set to 45° C. 1-(4-Bromo-phenyl)-2-chloro-ethanone (7.84 kg, 33.6 moles), which is commercially available from Jiangyan Keyan Fine Chemical Co. Ltd, was dissolved in 2-MeTHF (75 L) in a separate vessel and when tinner was above 40° C. in the first vessel, the 2-MeTHF solution was added during 3 h. The latter vessel was rinsed with 2-MeTHF (2 L) and added to the reaction mixture, which was left stirring at tjacket=45° C. for 1 h. Analysis of a sample on HPLC indicated full conversion at this point using the following gradient method (mobile phase 20-95% B; A: 5% CH3CN in H2O with 0.1% TFA, B: 95% CH3CN in H2O with 0.085% TFA, 10 min run) on Chromolith Performance RP-18e, 4.6×100 mm. The reaction mixture was cooled to tjacket=10° C. before slow quench with MeOH (36 L). The first liter of MeOH was added during 30 min. and the rest during additional 30 min. MeOH was distilled off under vacuum at tjacket=50° C. The organic solution left was cooled to tjacket=20° C., washed with 1M HCl in H2O (7 L conc HCl+73 L H2O) and concentrated under vacuum at tjacket=50° C. to approximately 40 L. Example 1 obtained in a 2-MeTHF solution can be stored at 10° C. for 20 h or used directly in the next synthetic step.
Reaction SMILES: [C:1](OC(C)C)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].[H][H]>[Cr].[Cu]>[CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)CCCCCCCCCCCCCCC(=O)OC(C)C
Reactant: [H][H]
Agent: [Cr]
Agent: [Cu]
Product: CC(C)CCCCCCCCCCCCCCCO
Temperature: 275 °C
Reaction time: 7 h

Procedure:
Into a 20 liters autoclave were charged 4770 g of isopropyl isostearate [Emery 2310, isopropyl isostearate, available from the Emery Co., Ltd. of U.S.A.) and 239 g of a copper-chromium catalyst (Nikki Co., Ltd.). Thereafter, hydrogen gas was charged into the autoclave at a pressure of 150 kg/cm2, followed by heating the reaction mixture to 275° C. After the hydrogenation under conditions of 150 m kg/cm2 and 275° C. for about 7 hours, the resulting reaction product was cooled, from which the solid catalyst was removed thereby obtaining 3500 g of a crude product. The crude product was distilled under reduced pressure to obtain 3300 g of colorless, transparent isostearyl alcohol as a distillate of 80° to 167° C./0.6 mmHg. The thus obtained isostearyl alcohol (monomethyl-branched isostearyl alcohol) had an acid value of 0.05, a saponification value of 5.5, and a hydroxyl group value of 181.4. The alcohol had absorption peaks at 3340 and 1055 cm-1 in the IR analysis and at delta 3.50 (broad triplet, --CH2 --OH) in the NMR analysis (CCl4 solvent). It was found from the gas chromatography that the alcohol was a mixture of alcohols which had about 75% of an alkyl group containing 18 carbon atoms in total with the remainder having 14 to 16 carbon atoms in total and whose branched methyl groups were positioned almost at the central portion of the alkyl main chain.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:30][CH3:31])([C:27](O)=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.N.C1COCC1.C[N:49](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27](=[O:28])[NH2:49])([CH2:25][CH3:26])[CH2:30][CH3:31])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(N)=O
Reaction time: 4 h
Yield: 70 %

Procedure:
At the room temperature, a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethyl-1-hydroxycarbonyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (100 mg, 0.167 mmol), NH3 in THF (8.5 mg, 0.5 mmol), HATU (100 mg, 0.25 mmol) and DMAP (60 mg, 0.50 mmol) in DMF (3 mL) was stirred for 4 h. Then the mixture was poured into water and extracted with EtOAc thrice. The combined organic phase was washed with saturated NaCl solution twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a white solid (70 mg).
Reaction SMILES: Cl.Cl.[CH3:3][CH:4]1[O:8][C:7]2[CH:9]=[C:10]([NH2:14])[C:11]([NH2:13])=[CH:12][C:6]=2[O:5]1.[OH-].[K+].C(O[C:20]([S-])=[S:21])C.[K+].C(O)(=O)C>C(O)(C)C.O>[CH3:3][CH:4]1[O:5][C:6]2=[CH:12][C:11]3[NH:13][C:20]([SH:21])=[N:14][C:10]=3[CH:9]=[C:7]2[O:8]1
Reactant: CCOC(=S)[S-]
Reactant: CC1Oc2cc(N)c(N)cc2O1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(C)O
Product: CC1Oc2cc3nc(S)[nH]c3cc2O1
Yield: 87 %

Procedure:
9.9 g of 2-methyl-1,3-benzodioxole-5,6-diamine dihydrochloride were suspended in 125 ml of isopropanol. While stirring there was added dropwise thereto a solution of 4.75 g of potassium hydroxide in 40 ml of water and the mixture was stirred at room temperature for an additional 30 minutes. After adding 7.5 g of purified potassium ethylxanthate, the solution was boiled at reflux overnight, then diluted with 125 ml of water and made neutral with a small amount of glacial acetic acid. The cooled suspension was filtered under suction and the crystals were washed well with water. There were obtained 7.5 g (87.4% of theory) of 2-methyl-5H-1,3-dioxolo(4,5-f)benzimidazole-6-thiol with a melting point above 300° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]2[NH:25][CH:24]([C:26](O)=[O:27])[CH2:23][S:22]2)[CH:16]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:26]([CH:24]2[CH2:23][S:22][CH:21]([C:17]3[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=3)[NH:25]2)=[O:27])=[CH:12][CH:13]=1
Reactant: CC(C)CCOc1ccc(CN)cc1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CCOc1ccc(CNC(=O)C2CSC(c3cccnc3)N2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
A mixture of 1.13 g of p-(3 methylbutoxy)benzylamine, 1.29 g of 2-(3-pyridyl)thiazolidine-4-carboxylic acid, 1.25 g of dicyclohexylcarbodiimide and 0.82 g of 1-hydroxybenzotriazole in 20 ml of N,N-dimethylformamide was stirred overnight at room temperature. The reaction mixture was diluted with 100 ml of ethyl acetate, and the insoluble matter was filtered off. The filtrate was washed in sequence with saturated aqueous solution of sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure Purification of the thus-obtained residue by silica gel column chromatography (eluent: ethyl acetate) gave 2.20 g of N-[p-(3-methylbutoxy)benzyl]-2-(3-pyridyl)thiazolidine-4-carboxamide. To a solution of this compound in 60 ml of ethyl acetate was added 4 ml of 4N hydrogen chloride solution in dioxane. The precipitate solid was collected by filtration, washed with ethyl acetate and dried under reduced pressure to give 2.30 g of N-[p-(3-methylbutoxy)benzyl]-2-(3-pyridyl)thiazolidine-4-carboxamide dihydrochloride. Melting point 120°-128° C.
Reaction SMILES: I[C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[S:30][CH:31]=[CH:32][N:33]=1)CCC>C1(C)C=CC=CC=1.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>[S:30]1[CH:31]=[CH:32][N:33]=[C:29]1[C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(I)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-c2nccs2)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 120 °C
Yield: 62.9 %

Procedure:
To a solution of 1.1 g of 10,11-dihydro-10-(4-iodobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 1.49 g of 2-(tributylstannyl)thiazole (Reference Example 48) in 50 ml of toluene under nitrogen is added 0.2 g of tetrakis(triphenylphosphine)palladium and the mixture heated to 120° C. for 16 hours. The toluene is evaporated in vacuo to a residue which is columned on silica gel by elution with 7:1 to 1:1 ethyl acetate:hexane to give 0.62 g of the desired product as an amphorous solid; M+H=372.3; M+Na=395.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:10]=[N+:11]=[N-:12])[CH2:7][N:6]1C(OC(C)(C)C)=O)=[O:4].[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>C(Cl)Cl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:10]=[N+:11]=[N-:12])[CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1
Reaction time: 16 h

Procedure:
To a solution of (2S,4S)-4-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (7.8 g, 28.8 mmol) in methylene chloride (30 mL) was added a mixture of trifluoroacetic acid and methylene chloride (1:5, 20 mL) and the reaction mixture was stirred at room temp. for 16 h. The reaction mixture was concentrated under reduced pressure to give (2S,4S)-4-azido-pyrrolidine-2-carboxylic acid methyl ester trifluoroacetate salt (9.6 g, crude) as a light brown oil. The compound was used in the next step without further purification. MS calcd. for C6H11N4O2 [(M+H)+] 171.0, obsd. 171.2.