Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[C:12]3[CH:19]=[CH:18][N:17]([C@H:20]4[C@@H:24]5[O:25]C(C)(C)[O:27][C@@H:23]5[C@H:22]([CH2:30][OH:31])[CH2:21]4)[C:13]=3[N:14]=[CH:15][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[S:39]([NH2:42])(=[O:41])=[O:40]>C(C#N)(C)=O.C(Cl)Cl>[S:39](=[O:41])(=[O:40])([O:31][CH2:30][C@@H:22]1[CH2:21][C@@H:20]([N:17]2[C:13]3[N:14]=[CH:15][N:16]=[C:11]([NH:10][C@@H:1]4[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[CH2:3][CH2:2]4)[C:12]=3[CH:19]=[CH:18]2)[C@H:24]([OH:25])[C@@H:23]1[OH:27])[NH2:42]
Reactant: NS(=O)(=O)Cl
Reactant: CC1(C)O[C@@H]2[C@H](CO)C[C@@H](n3ccc4c(N[C@H]5CCc6ccccc65)ncnc43)[C@@H]2O1
Agent: CC(=O)C#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: NS(=O)(=O)OC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 2 h
Yield: 46 %

Procedure:
To a suspension of ((3aR,4S,6R,6aS)-6-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]-dioxol-4-yl)methanol (45.9 mg, 0.109 mmol) and pyridine (0.0180 mL, 0.222 mmol) in AcCN (1.10 mL) and DCM (0.500 mL) at 0° C. under an atmosphere of nitrogen was added dropwise a 2.00 M solution of chlorosulfonamide in AcCN (0.110 mL, 0.220 mmol, as prepared in 1j). The suspension was stirred for 2 h and more 2.00 M of chlorosulfonamide in AcCN solution (0.150 mL, 3.00 mmol) was added. After 5 min the reaction was quenched with MeOH (1.00 mL) and the solvent was removed in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to afford the title compound as a white solid (23.1 mg, 46%). 1H NMR (400 MHz, CD3OD, δ): 8.36 (s, 1H), 7.62 (d, J=3.1 Hz, 1H), 7.43-7.33 (m, 4H), 7.04 (d, J=3.0 Hz, 1H), 5.67 (br s, 1H), 5.25-5.20 (m, 1H), 4.61 (dd, J=3.8, 9.3 Hz, 1H), 4.48 (dd, J=2.0, 9.9 Hz, 1H), 4.27-4.22 (m, 2H), 3.74 (s, 1H), 3.27-3.20 (m, 1H), 3.13-3.05 (m, 1H), 3.02-2.90 (m, 1H), 2.87-2.77 (m, 1H), 2.35-2.19 (m, 3H) ppm. LC/MS: Rt=0.94 min, ES+ 460. (FA standard).
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:32]=[CH:31][C:18]([O:19][CH2:20][CH:21]([OH:30])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1.[Cl:33][C:34]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=1B(O)O>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.C(O)C>[Cl:33][C:34]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=1[C:15]1[CH:32]=[CH:31][C:18]([O:19][CH2:20][CH:21]([OH:30])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1
Reactant: OC(CCc1cccnc1)COc1ccc(Br)cc1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: OC(CCc1cccnc1)COc1ccc(-c2ccc(Cl)cc2Cl)cc1
Temperature: 120 °C
Yield: 78.1 %

Procedure:
Prepared according to the method described in Example 33a) from toluene (3 ml), aqueous sodium carbonate (2 M, 1.4 ml), (±)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.51 g), ethanol (0.8 ml), 2,4-dichlorobenzeneboronic acid (0.32 g) and tetrakis(triphenylphosphine)palladium(0) (75 mg) with heating at 120° C. for 4 hours. The residue obtained after work up was purified by column chromatography over silica eluting with dichloromethane then ether then ethyl acetate to give (±)-1-(2',4'-dichlorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (0.48 g). A sample that had been purified by reverse phase HPLC was converted to the oxalate salt by treatment of the parent compound in ether with a saturated ethereal solution of oxalic acid. The precipitated salt was filtered to give the title compound (0.23 g).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[S:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][N:16]2[CH:19]=[C:20]([CH2:22][CH2:23]O)[N:21]=[C:15]2[CH:14]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:23][CH2:22][C:20]3[N:21]=[C:15]4[CH:14]=[C:13]([F:12])[CH:18]=[CH:17][N:16]4[CH:19]=3)[N:7]=[CH:6][C:5]=2[S:4][CH:3]=1
Reactant: O=c1[nH]ncc2scc(Br)c12
Reactant: OCCc1cn2ccc(F)cc2n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1c2c(Br)csc2cnn1CCc1cn2ccc(F)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
A mixture of 3-bromothieno[2,3-d]pyridazin-4(5H)-one from Example 3.4 (231 mg, 1 mmol), 2-(7-fluoroimidazo[1,2-a]pyridin-2-yl)ethanol from Example a5 (180 mg, 1.00 mmol) and Ph3P (525 mg, 2.00 mmol) was dissolved in THF (6 mL). Then DEAD (0.317 mL, 2.00 mmol) in THF (1 mL) was added. The resulting mixture was stirred at room temperature under nitrogen overnight. The mixture was concentrated and purified on the ISCO Combiflash system using a 40 g C-18 column using the following gradient: A: Water (0.1% NH4HCO3); B: Methanol; 30% B to 80% B over 20 min (160 mg, yield: 17.7%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[C:11][Si](C)(C)C)[C:3]=1[CH:4]=O.CO.[NH3:18]>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:3]=1[CH:4]=[N:18][CH:11]=[CH:10]2
Reactant: C[Si](C)(C)C#Cc1cccc(F)c1C=O
Reactant: N
Solvent: CO
Product: Fc1cccc2ccncc12
Temperature: 80 °C
Yield: 58 %

Procedure:
2-Fluoro-6-[(trimethylsilyl)ethynyl]benzaldehyde Description 40; 10.38 g, 47.1 mmol) was dissolved in 2M ammonia in methanol (235 ml, 471 mmol) in a Parr flask and the resulting mixture heated at 80° C. with shaking on a Parr apparatus (ca. 35 psi achieved). The reaction was cooled and the solvents evaporated. The residue was purified by column chromatography on silica eluting with a gradient from neat dichloromethane to 2% methanol in dichloromethane to give the title compound (4.0 g, 58%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Li])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[P:19]([Cl:21])Cl>>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([P:19]([C:13]3[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:11][CH:12]=3)[Cl:21])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COP(Cl)Cl
Reactant: [Li]c1ccc(CCCc2ccccc2)cc1
Product: ClP(c1ccc(CCCc2ccccc2)cc1)c1ccc(CCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
p-(3-phenylpropyl)phenyllithium (8.1 g, 40 mmol) in 150 ml solvent (Et2O/THF 1/1) was added dropwise to CH3OPCl2 (2.66 g, 20 mmol) in 70 ml solvent (Et2O/THF 1/1) at -70° C. The addition was completed in 2 h. The reaction mixture was stirred overnight at room temperature and then brought to reflux for 2 h. The precipitate was filtered and the solvent of the solution was removed by applying vacuum. PCl3 (15 ml) was added to the resulting viscous oil and stirred for 24 h. Then the mixture was kept at 70° C. and 1 mm Hg for 2 h to remove excess PCl3 and byproduct. The product, di[p-(3-phenylpropyl)phenyl]chlorophosphine, was obtained as a pale yellow viscous oil with 90% yield. The product was characterized by 31P NMR. 83.6.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10]C)=[O:9])=[CH:4][N:3]=1.[CH:12]([OH:15])([CH3:14])[CH3:13]>>[CH:12]([O:15][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][N:7]=1)([CH3:14])[CH3:13]
Reactant: COC(=O)c1cnc(Cl)nc1
Reactant: CC(C)O
Product: CC(C)Oc1ncc(C(=O)O)cn1
Yield: 14 %

Procedure:
The title compound was synthesized as described for Intermediate example I-81 in 14% yield starting from methyl 2-chloropyrimidine-5-carboxylate and isopropanol.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]#[C:10][C@@H:11]([OH:13])[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([O:13][C@H:11]([C:10]#[C:9]/[CH:8]=[CH:7]/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:12])(=[O:16])[CH3:15]
Reactant: C[C@H](O)C#C/C=C/c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](C)C#C/C=C/c1ccccc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
To a solution of alcohol 7 (400 mg, 2.32 mmol) in pyridine (pyridine was distilled over CaH2 and stored over KOH; 4.6 mL) at 23° C. was added acetic anhydride (1.10 mL, 11.6 mmol). The resulting mixture was stirred for 2 h at 23° C. The reaction was quenched by 1 N aqueous HCl (10 mL) at 0° C. and diluted with EtOAc (5 mL). The mixture was poured into a separatory funnel. The layers were separated and the aqueous layer was extracted with EtOAc (3×3 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue via flash chromatography (silica gel 40 mL; 5→30% EtOAc in hexanes) afforded acetate 8 (486 mg, 98%, 95% ee; the ee value was determined by HPLC ((S,S) Whelk; 25 cm, 1.0 mL/min, hexanes/iPrOH=95/5).) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9]C)=[O:8])=[C:5]([Br:11])[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[N:3]1.[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[C:5]([Br:11])[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)=[N:3]1
Reactant: COC(=O)c1c(Br)c(-c2cccc(C(F)(F)F)c2)nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(-c2cccc(C(F)(F)F)c2)c(Br)c1C(=O)O

Procedure:
Following the above procedure, the same methyl ester was brominated in refluxing acetic acid. Methyl 1-methyl-3-(3-trifluoromethylphenyl)-4-bromopyrazole-5-carboxylate thus formed was purified by chromatography over silica gel using methylene dichloride as the eluant. 3.0 g. of 1-methyl-3-(3-trifluoromethylphenyl)-4-bromopyrazole-5-carboxylic acid were obtained (from 8.0 g. of unbrominated ester starting material). The ester was hydrolyzed by the procedure of Example 1 using dilute aqueous sodium hydroxide in aqueous ethanol and the free acid isolated by acidification of the hydrolysis mixture. Recrystallization of the free acid ethanol yielded 1-methyl-3-(3-trifluoromethylphenyl)-4-bromopyrazole-5-carboxylic acid melting at 182°-4° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:32][C:31]([C:33]2[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=2)[C:36]#[N:37])=[CH:30][C:29](=O)[O:28]1>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:24][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:40]=[CH:39][CH:38]=[C:35]([C:36]#[N:37])[CH:34]=1)=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccc3ccccc23)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccc3ccccc23)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (2-amino-4-naphthalen-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example G14) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. Obtained as an off-white solid (92 mg) and used crude in the next step (Example 20).
Reaction SMILES: Cl.[CH:2]1([C:5]2[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=2)[CH2:4][CH2:3]1.[C:14]([C:16]([C:19]1[CH:20]=[C:21]([CH:37]=[CH:38][CH:39]=1)[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([C:32](O)=[O:33])=[CH:29][CH:30]=2)[C:25]([CH3:35])=[C:24]1[CH3:36])([CH3:18])[CH3:17])#[N:15]>>[C:14]([C:16]([C:19]1[CH:20]=[C:21]([CH:37]=[CH:38][CH:39]=1)[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([C:32]([NH:13][C@H:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]4[CH2:4][CH2:3]4)[CH:6]=3)[CH3:12])=[O:33])=[CH:29][CH:30]=2)[C:25]([CH3:35])=[C:24]1[CH3:36])([CH3:18])[CH3:17])#[N:15]
Reactant: Cc1c(C)n(Cc2cccc(C(C)(C)C#N)c2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1cccc(C2CC2)c1
Agent: Cl
Product: Cc1c(C)n(Cc2cccc(C(C)(C)C#N)c2)c2ccc(C(=O)N[C@@H](C)c3cccc(C4CC4)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 4, Example 1, using (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and 1-(3-(2-cyanopropan-2-yl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 490 [M+H]+.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]>CN1CCCC1=O>[CH3:1][S:2][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(C(F)(F)F)cc1SC
Yield: 94.5 %

Procedure:
Dry sodium thiomethoxide (0.385 g. 0.0055M) was added to a stirred solution of methyl 2-chloro-4-trifluoromethylbenzoate (1.19 g, 0.005M) in anhydrous N-methylpyrrolidinone (10 ml) at 5° C. The mixture was acidified and extracted (t-butyl methyl ether), washed (water) and evaporated to give methyl 2-methylthio-4-trifluoromethylbenzoate (1.18 g, 94% yield). 1H-nmr 2.44(s,3H). 3.89(s,3H). 7.33(1H), 7.41(1H), 8.02(1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:18][C@H:19]2[CH2:23][O:22][C:21]([NH2:24])=[N:20]2)CC2C=CC(OC)=CC=2)[CH:5]=[CH:6][CH:7]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:18][C@H:19]2[CH2:23][O:22][C:21]([NH2:24])=[N:20]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN(C[C@H]2COC(N)=N2)c2cccc(Cl)c2)cc1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@H](CNc2cccc(Cl)c2)CO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.8 %

Procedure:
To a stirred solution of (S)-4-{[(3-chloro-phenyl)-(4-methoxy-benzyl)-amino]-methyl}-4,5-dihydro-oxazol-2-ylamine (97 mg) at r.t. in dichloromethane (10 ml) were added anisole (0.31 ml) and trifluoroacetic acid (2.74 ml). The mixture was stirred at r.t. for 48 h and was then concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated aq. sodium bicarbonate solution, the phases were separated, and the organic phase was dried and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient:dichloromethane->dichloromethane/methanol 85:15) to give (S)-4-[(3-chloro-phenylamino)-methyl]-4,5-dihydro-oxazol-2-ylamine (22 mg, 35%) as a white gum. MS (ISP): 228.1 ([{37Cl}M+H]+), 226.2 ([{35Cl}M+H]+)
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]([C:27]([O:29][CH3:30])=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=O)[NH:12][CH:11]3[C:32]3[C:37]([F:38])=[C:36]([F:39])[CH:35]=[CH:34][C:33]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:43]>C1COCC1.C1(C)C=CC=CC=1>[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:29][CH3:30])=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[S:43])[NH:12][CH:11]3[C:32]3[C:37]([F:38])=[C:36]([F:39])[CH:35]=[CH:34][C:33]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2c(C)ccc(F)c2F)C12C(=O)Nc1cc(Cl)ccc12
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=S)NC(c2c(C)ccc(F)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 50 °C
Yield: 91.6 %

Procedure:
A mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5,6-difluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.067 mmol) and P2S5 (45 mg, 0.20 mmol) in THF (2 mL) was heated at 50° C. for 2 h, and then diluted with toluene (10 mL). The mixture was concentrated in vacuo and the residue was washed with DCM twice. The DCM layers were combined and concentrated. The residue was purified by flash chromatography to give the title compound as white solid (38 mg).
Reaction SMILES: C([N-]C1CCCCC1)(C)C.[Li+].C([Li])CCC.C(NC1CCCCC1)(C)C.[CH2:27]([O:29][C:30](=[O:36])[CH2:31][Si](C)(C)C)[CH3:28].[CH3:37][C:38]([C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)=O>>[CH2:27]([O:29][C:30](=[O:36])[CH:31]=[C:38]([C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[CH3:37])[CH3:28]
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C[Si](C)(C)C
Agent: CC(C)NC1CCCCC1
Agent: CC(C)[N-]C1CCCCC1
Agent: [Li+]
Product: CCOC(=O)C=C(C)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a solution of lithium isopropylcyclohexylamide (prepared from 12.5 ml of n-butyllithium 1.6M solution and isopropyl cyclohexylamine (3.3 ml) (ex Aldrich) in TMF was added at -60°, ethyltrimethylsilylacetate (3.6 ml) (ex Fluka). After 30 minutes at -60°, 4-chloro acetophenone (ex Aldrich) (1.55 g) was added. After 18 hours at 25° the mixture was partitioned between ether and water and worked up in the usual manner. Purification by chromatography (silica; ether/hexane) gave Ethyl-3-(4-chlorophenyl)-but-2-enoate (1.22 g), as a 1:1 mixture of E:Z olefin isomers. NMR 1H: 7.2(4H,m), 6.0 and 5.0(1H,m), 4.12(2H,m), 2.51 and 1.90(3H,s), 1.25(3H,m).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1.[CH3:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][NH:15]1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[I:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:16][CH2:17][CH2:18][C@H:14]2[CH3:13])=[CH:7][CH:8]=1
Reactant: C[C@@H]1CCCN1
Reactant: ClCCCOc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C[C@@H]1CCCN1CCCOc1ccc(I)cc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A suspension of 1-(3-chloropropoxy)-4-iodobenzene obtained in Example 1-(1) (2.79 g), (R)-2-methylpyrrolidine (0.961 g), sodium iodide (0.282 g) and potassium carbonate (2.60 g) in acetonitrile (2.8 mL) was stirred in a sealed tube at 100° C. for 5 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=10:1) to give the titled compound (3.27 g) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@H:10]1[CH2:14][C@H:13](Br)[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:23])[C@H:10]1[CH2:14][C@@H:13]([N:24]=[N+:25]=[N-:26])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Br)C[C@@H]1C(=O)OCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])C[C@@H]1C(=O)OCc1ccccc1

Procedure:
The bromo benzyl ester 35 (4.67 g, 12.1 mmol) and NaN3 (4.7 g, 72.3 mmol) were suspended in 175 mL DMF. This mixture was subjected to the procedure for the synthesis of 20 ethyl ester, to give 3.73 g (89% crude yield) of a colorless oil which was used directly in subsequent reactions. 1H NMR (CDCl3) δ1.33/1.45 (2s, 9H), 2.18 (m, 1H), 2.48 (m, 1H), 3.48 (m, 1H), 3.71 (m, 1H), 4.14 (m, 1H), 4.35/4.49 (2dd, J=8.7/3.0 Hz, 1H), 5.16 (m, 2H), 7.34 (s, 5H). FAB MS; MH+ calc. for C17H23N4O4 =347.1719, found 347.1726.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([CH2:15]O)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].CN(C)C=O.S(Cl)([Cl:33])=O>ClCCl>[Cl:33][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH:8]=[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:6]2[CH2:5][C:4]1[CH:22]=[CH:23][C:24]([Cl:25])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cc2c(CO)cccc2n1Cc1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(CCl)cccc2n1Cc1ccc(Cl)c(Cl)c1
Yield: 67 %

Procedure:
Ethyl N-(3,4-dichlorobenzyl)-4-hydroxymethylindole-2-carboxylate (0.89 g), dimethylformamide (0.5 ml) and thionyl chloride (189 μl) in dichloromethane (40 ml) were stirred at ambient temperature overnight and the resulting precipitate as filtered and dried in vacuo to give the product as a white solid (0.62 g, 67%); NMR δ(CD3SOCD3) 1.30 (t, 3H), 4.30 (q, 2H), 5.10 (s, 2H), 5.85 (s, 2H), 6.90 (m, 1H), 7.30 (m, 3H) 7.55 (m, 3H), M/z (+) 396.2 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC[N+]1C=CC(C2C=C[N+](CC)=CC=2)=CC=1.[Br-].[Br-]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CCOC(=O)CCCCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: CC[n+]1ccc(-c2cc[n+](CC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Product: CCOC(=O)CCCCCNc1c(N)cnc2ccccc12
Reaction time: 8 h
Yield: 97.4 %

Procedure:
Ethyl 6-(3-nitroquinolin-4-ylamino)hexanoate (27.1 g, 81.8 mmol, prepared as described in Parts A and B of Example 6) was treated with sodium hydrosulfite (49.8 g, 286 mmol), potassium carbonate (44.6 g, 323 mmol), and ethyl viologen dibromide (0.306 g, 0.818 mmol) according to a modification of the method described in Part A of Example 8. After the reaction was stirred overnight, additional sodium hydrosulfite (5.0 g, 29 mmol) was added, and the reaction was stirred for one additional hour. The organic layer was separated, washed three times with water, and concentrated under reduced pressure to provide 24 g of ethyl 6-(3-aminoquinolin-4-ylamino)hexanoate.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:6]
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(c1ccc([N+](=O)[O-])cc1Br)N1CCCC1

Procedure:
Prepared analogously to Example 1a from 2-bromo-4-nitro-benzoic acid and pyrrolidine with TBTU and NMM in DMF.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([O:14][CH2:15]C)=[O:13])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:17][O-:18].[Na+].[NH4+].[Cl-]>CO>[CH3:17][O:18][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[O-]
Reactant: CCOC(=O)c1cc2cccnc2nc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2cccnc2nc1OC

Procedure:
Ethyl 2-chloro-1,8-naphthyridine-3-carboxylate (104.0 mg, 0.44 mmol) was dissolved in anhydrous MeOH under N2. NaOMe (33.2 mg, 0.62 mmol) was added as a solution in MeOH. The mixture was refluxed for 15 h, and then it was allowed to cool. NH4Cl (sat) was added and the product extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered and concentrated to yield 102.0 mg (quant) of the title compound.