Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10](=[O:27])[C@@H:11]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12][CH:13]([S:16][S:17][CH3:18])[CH2:14]Br)([CH3:8])([CH3:7])[CH3:6]>CN(C)C=O>[C:5]([O:9][C:10](=[O:27])[C@@H:11]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12][CH:13]([S:16][S:17][CH3:18])[CH2:14][N:1]=[N+:2]=[N-:3])([CH3:8])([CH3:6])[CH3:7]
Reactant: CSSC(CBr)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSSC(CN=[N+]=[N-])C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 64 %

Procedure:
Sodium azide (2.44 g, 37.6 mmol) was added to a solution of the crude (S)-5-bromo-2-tert-butoxycarbonylamino-4-methyldisulfanyl-pentanoic acid tert-butyl ester (Compound 32) obtained in the foregoing in N,N-dimethylformamide (100 ml), and the reaction mixture was stirred at room temperature for 6 hours. After completion of the reaction, the insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-5-azido-2-tert-butoxycarbonylamino-4-methyldisulfanyl-pentanoic acid tert-butyl ester (Compound 33) (1.87 g, 64%).
Reaction SMILES: [C-:1]1([C:6]#[C:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10](C#C[C-]3C=CC=C3)[CH:9]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26].[CH-]1C=CC=C1.[Fe+2].C([C-]1C=CC=C1)#C.[CH-]1C=CC=C1.[Fe+2].[I:46]C1C=CC=C(I)C=1>>[C-:1]1([C:6]#[C:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([I:46])[CH:9]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26]
Reactant: C(#C[c-]1cccc1)c1cccc(C#C[c-]2cccc2)c1
Reactant: Ic1cccc(I)c1
Agent: [Fe+2]
Agent: C#C[c-]1cccc1
Agent: c1cc[cH-]c1
Product: Ic1cccc(C#C[c-]2cccc2)c1

Procedure:
Example 11 describes the procedure for producing 1,3-bis(ferrocenylethynyl)benzene 516. Ethynylferrocene 500 was reacted with 1,3-diiodobenzene 502 to form 1-(ferrocenylethynyl)-3-iodobenzene 504. Sufficient ethynylferrocene 500 was present such that the second step of the reaction immediately proceeded. 1-(Ferrocenylethynyl)-3-iodobenzene 504 reacted with ethynylferrocene 514 to form 1,3-bis(ferrocenylethynyl)benzene 516. The reaction procedure is shown in FIG. 5.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8](OS(C)(=O)=O)[CH2:7][N:6]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:4].[N-:22]=[N+:23]=[N-:24].[Na+].O.CCCCCC.C(OCC)(=O)C>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([N:22]=[N+:23]=[N-:24])[CH2:7][N:6]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)C1CC(OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1CC(N=[N+]=[N-])CN1C(=O)OC(C)(C)C

Procedure:
4-Methanesulfonyloxy-pyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (406.92 mg, 1.26 mmol) was taken up in dry DMF under argon and sodium azide (409.50 mg, 6.30 mmol) was added. The reaction was then heated to 60EC for 48 h. The reaction was poured into water and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with sat NaHCO3 and brine then dried over MgSO4. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (3:1 hexane-ethyl acetate) Yield 303.10 mg. C11H18N4O4 MS m/e 271.2 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C=O)C.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: C1CCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CO
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCCCC3)n2n1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 52 mg, 0.151 mmol) and piperidine (52 mg, 0.603 mmol) in DMF (0.5 mL) was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (35-45% MeCN/H2O+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (31.2 mg, 52%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6H), 1.70 (br. s., 6H), 2.37 (s, 3H), 3.73 (br. s., 4H), 6.16 (s, 1H), 7.28 (s, 1H), 7.60 (d, J=8.59 Hz, 2H), 7.99 (d, J=8.59 Hz, 2H), 10.84 (s, 1H); ESI-MS: m/z 394.3 (M+H)+.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[CH2:24]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH2:25][CH2:26][CH2:27][C:28]#[CH:29]>>[CH3:34][S:31]([NH:30][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[N:3]=[N:2][N:1]([CH:4]2[CH2:23][N:8]3[C:9]4[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]3[CH2:6][CH2:5]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:29]=1)(=[O:33])=[O:32]
Reactant: C#CCCCCNS(C)(=O)=O
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Product: CS(=O)(=O)NCCCCc1cn(C2CCc3c(CC(=O)O)c4ccccc4n3C2)nn1

Procedure:
The title compound was prepared using procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate and N-hex-5-yn-1-ylmethanesulfonamide. MS (+ESI) m/z: 446.2.
Reaction SMILES: [C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:18]O>CCOCC.CN(C)C=O>[C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([O:10][CH3:18])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(C(=O)O)c1ccccc1
Reactant: CO
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: COC(=O)C(C(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
Phenylmalonic acid (13.5 g, 0.07 mol) in dry ether (40 mL) was treated with thionyl chloride (8.92 g, 5.4 mL, 0.071 mol) and one drop of N,N-dimethylformamide. The mixture was heated at 40°-50° C. for 3 hours. The clear solution was evaporated under reduced pressure to remove any residual thionyl chloride. The oily residue was redissolved in dry ether (40 mL) and the solution was treated with methyl alcohol (0.075 mol, 3 mL) and refluxed for 2 hours. The reaction mixture was cooled to room temperature and washed with water. The organic layer was extracted with saturated solution of sodium bicarbonate until alkaline. The combined extracts were washed with ether and the aqueous layer acidified with 5N NCl to pH 1. The precipitated oil was extracted with CH2Cl2 (50 mL×3). The combined extracts were washed with water (50 mL×4) and dried over anhydrous MgSO4. The oily product crystallized on standing.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:6]2=[N:5][N:4]=1.[NH:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH:23]=[CH:22]1>>[NH:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[C:23]([C:15]2[CH2:14][CH2:13][N:12]([C:9]3[CH2:10][CH2:11][C:6]4[N:7]([C:3]([C:2]([F:20])([F:19])[F:1])=[N:4][N:5]=4)[N:8]=3)[CH2:17][CH:16]=2)=[CH:22]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C1CCN(C2=Nn3c(nnc3C(F)(F)F)CC2)CC1
Product: FC(F)(F)c1nnc2n1N=C(N1CC=C(c3c[nH]c4ncccc34)CC1)CC2
Yield: 27 %

Procedure:
Obtained in 27% yield by an analogous method to Example 2, starting from 1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-one and 1H-pyrrolo[2,3-b]pyridine.
Reaction SMILES: CS(C)=O.[Cl-].[CH2:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:7]=[CH2:8].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:6]([O:9][CH2:10][CH2:11][CH2:12][CH:13]=[O:14])[CH:7]=[CH2:8]
Reactant: C=CCOCCCCO
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCOCCCC=O
Temperature: -80 °C
Reaction time: 0.05 h

Procedure:
13 mL of DMSO (246 mmol) was gradually added to a solution prepared by dissolving oxaryl chloride (5.8 mL, 66 mmol) in 123 mL of CHCl3, which solution had been cooled to −80° C., and the mixture was stirred for three minutes. 6.8 g of 4-allyloxy-1-butanol (52 mmol) was then added to the mixture. After the solution was stirred for 15 minutes, 43 mL of triethylamine (594 mmol) was added thereto and the reaction solution was stirred for 10 hours, while the temperature of the reaction solution was allowed to return to room temperature. The reaction was quenched by adding distilled water and the CHCl3 layer was separated. The separated layer was washed with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and saturated brine and dried with anhydrous Na2SO4. The solvent was distilled away under reduced pressure, whereby pale yellow liquid was obtained (6.0 g, 90%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[C:6]([F:14])[CH:5]=1.CC(C[AlH]CC(C)C)C.CCCCCC.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[K+]>C1COCC1>[F:10][C:8]1[CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=[C:6]([F:14])[C:7]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(=O)c1cc(F)c([N+](=O)[O-])c(F)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=[N+]([O-])c1c(F)cc(CO)cc1F
Temperature: 2.5 °C
Reaction time: 2.5 h

Procedure:
To a solution of 3,5-difluoro-4-nitro-benzoic acid methyl ester (10.95 g, 50 mmol) in THF (250 mL) was added at 0-5° C. under argon a 1M DIBAL solution in hexane (165 mL, 165 mmol) within 1.5 h. The reaction mixture was stirred for 2.5 h at 0-5° C. before it was added to 200 mL cold 1M aq. potassium tartrate solution under ice-cooling. After stirring the reaction mixture for 0.5 h at 25° C. the aqueous phase was extracted with EtOAc. Combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated to provide the title compound as a yellow solid: TLC (hexane-EtOAc 1.1) Rf=0.35; HPLC RtA=1.31 min; 1H NMR (400 MHz, CDCl3): δ 7.12 (d, 2H), 4.77 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.[Br:13]Br>C(O)(=O)C>[NH2:1][C:2]1[S:3][C:4]2[C:11](=[O:12])[CH:10]([Br:13])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: BrBr
Reactant: Nc1nc2c(s1)C(=O)CCCC2
Solvent: CC(=O)O
Product: Nc1nc2c(s1)C(=O)C(Br)CCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 26z (1.96 g, 7.45 mmol; HBr salt form) in glacial acetic acid (70 mL) was treated dropwise with Br2 (421 uL, 8.2 mmol). The reaction mixture was stirred at room temperature for 30 min. The crude product was collected by filtration, washed with cold acetone, and dried to yield 27z which was used in the next step without purification (1.98 g, 78%). 1H NMR (600 MHz, 2 DMSO-d6): δ 8.71 (br s, 2H), 5.11 (dd, J=6.9 Hz, 3.3 Hz, 1H), 3.08-2.90 (m, 2H), 2.473 2.39 (m, 1H), 2.28-2.20 (m, 1H), 2.14 (dd, J=10.1 Hz, 2.3 Hz, 1H), 1.98-1.90 (m, 1H). MS (ESI) m/z [M+H]+ 260.92; [(M+2)+H]+ 262.88. 5 6
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>ClC=C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:20])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Solvent: ClC=C(Cl)Cl
Product: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reaction time: 3 h

Procedure:
A solution of 164.7 g 4-benzyloxybenzoic acid obtained in step (a) and 80 ml of thionyl chloride in 750 ml of trichloroethylene was refluxed with stirring for 3 hrs. The crystalline residue obtained after evaporation was recrystallized from petroleum ether b.p. 80°-110° C.
Reaction SMILES: Br[CH:2]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4][C:5]([N:7]1[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9]([OH:11])=[O:10])=[O:6].[C:23]([O-:26])(=[S:25])[CH3:24].[K+]>C(O)C>[C:23]([S:25][CH:2]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4][C:5]([N:7]1[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9]([OH:11])=[O:10])=[O:6])(=[O:26])[CH3:24]
Reactant: CC([O-])=S
Reactant: O=C(c1ccccc1)C(Br)CCC(=O)N1CCC[C@H]1C(=O)O
Agent: [K+]
Solvent: CCO
Product: CC(=O)SC(CCC(=O)N1CCC[C@H]1C(=O)O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2.0 g. of 1-(4-bromo-4-benzoylbutyryl)-L-proline (Example 42) in 20 ml. of ethanol is added 752 mg. of potassium thioacetate. The mixture is stirred at room temperature for 18 hours, evaporated to dryness and the residue is partitioned between dichloromethane and water. The dichloromethane layer is separated, washed with saline, dried over magnesium sulfate, treated with charcoal and evaporated to a gum. This gum is dissolved in ethyl acetate-hexane-acetic acid (75:25:2) and chromatographed on a 1"×15" silica gel column (100 ml. hold back volume) taking 50 ml. cuts. Cuts 3-6 are combined to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:10][C:11]2[NH:15][C:14]3=[CH:16][S:17][CH:18]=[C:13]3[N:12]=2)[CH:4]=1.[H-].[Na+].Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[CH2:25]([O:24][C:22]([N:12]1[C:13]2=[CH:18][S:17][CH:16]=[C:14]2[N:15]=[C:11]1[S:10][CH2:9][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)Cl
Reactant: COc1ccnc(CSc2nc3cscc3[nH]2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)n1c(SCc2cc(OC)ccn2)nc2cscc21
Temperature: 36 °C

Procedure:
Under nitrogen, 1.4 g (5.0 mmol) of 2-(4-methoxy-2-picolylmercapto)-1H-thieno[3,4-d]imidazole were dissolved in 15 ml of anhydrous dimethylformamide, and 270 mg (6 mmol) of a 60% suspension of NaH in oil were added in portions, and the mixture was heated at 30°-40° C. for 10 minutes. Now, at 25° C., 0.5 ml (5 mmol) of ethyl chloroformate (95%) was added, during which the temperature increases to about 36° C. 30 minutes later the crystalline product was filtered off with suction and washed twice with diethyl ether. Melting point 154°-156° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[N:19][NH:20]2)=[CH:16][CH:15]=1>>[NH:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]([N:13]=[C:6]3[C:5]4[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH:22]=2)[CH:18]=[N:19]1
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Reactant: Nc1ccc2cn[nH]c2c1
Product: O=C1Nc2cc(Br)ccc2C1=Nc1ccc2cn[nH]c2c1
Yield: 48.1 %

Procedure:
The title compound (82 mg, 48%) was synthesized as a orange red solid according to the method described for Example A74 using 6-bromoisatin (113 mg, 0.5 mmol), 6-aminoindazole (73 mg, 0.55 mmol). 1H NMR indicated a 83:17 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H, NH), 10.93 (brs, 1H, NH), 8.09 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.08 (s, 1H), 7.05 (d, J=1.6 Hz, 1H), 6.92 (dd, J=8.0 Hz, 1.6 Hz, 1H), 6.77 (dd, J=8.4 Hz, 1.2 Hz, 1H), 6.27 (d, J=8.0 Hz, 1H); MS ESI 341.1 [M+H]+, calcd for [C15H9BrN4O+H]+ 341.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:35])[O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([C:30]([F:33])([F:32])[F:31])=[CH:25][C:24]=3[NH2:34])=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:36][N:37]1[C:41]([CH3:42])=[CH:40][C:39]([C:43](O)=[O:44])=[N:38]1.C(N(CC)C(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12](=[O:35])[O:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([C:30]([F:33])([F:31])[F:32])=[CH:25][C:24]=3[NH:34][C:43]([C:39]3[CH:40]=[C:41]([CH3:42])[N:37]([CH3:36])[N:38]=3)=[O:44])=[CH:20][CH:21]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)nn1C
Reactant: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(Nc3cc(Cl)c(C(F)(F)F)cc3N)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(Nc3cc(Cl)c(C(F)(F)F)cc3NC(=O)c3cc(C)n(C)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.9 %

Procedure:
To a stirred solution of 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl (4-methylphenyl)sulfonylcarbamate (step 2, 200 mg, 0.379 mmol) in dichloromethane (1.7 ml) was added a solution of 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (63.8 mg, 0.455 mmol) and N,N-diisopropylethylamine (118 mg, 0.909 mmol) in dichloromethane (1.7 ml), then to the mixture was added a solution of HOBt (61.5 mg, 0.455 mmol) and HBTU (431 mg, 1.14 mmol) in DMF (2.5 ml), and the mixture was stirred at room temperature for 20 h. The mixture was quenched with water (100 ml). The whole was extracted with ethyl acetate (100 ml×3). The combined organic layer was washed with water (100 ml×3), brine (50 ml), dried (MgSO4), and concentrated. Purification by PTLC eluting with hexane/ethyl acetate (1:1) to afford 145 mg (59%) of the title compound as a red solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:17][CH2:16][C:8]2[C:9]3[CH:10]=[CH:11][NH:12][C:13]=3[CH:14]=[CH:15][C:7]=2[CH2:6]1)[CH2:2][CH3:3].ClS([N:25]=[C:26]=O)(=O)=O.CN(C)C=O.O>C(#N)C>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:17][CH2:16][C:8]2[C:9]3[C:10]([C:26]#[N:25])=[CH:11][NH:12][C:13]=3[CH:14]=[CH:15][C:7]=2[CH2:6]1)[CH2:19][CH3:20]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCCN(CCC)C1CCc2c(ccc3[nH]ccc23)C1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: CCCN(CCC)C1CCc2c(ccc3[nH]cc(C#N)c23)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
To an ice-cold solution of di-n-propyl-(6,7,8,9-tetrahydro-3H-benzo[e]indol-7yl)amine, 9a (Chart 2) (180 mg, 0.67 mmol) in acetonitrile (5 mL) was added dropwise with a solution of chlorosufonyl isocyanate (60 mL, 0.68 mmol) in acetonitrile (1 mL) over 10 minutes. After stirring for 1 hour, dimethyl formamide (100 mL) was added and the reaction was stirred for an additional 2 hours. Water was added and extraction (dichloromethane) followed by evaporation of the combined organic extracts afforded 170 mg (86%) of the crude product. Purification on a silica column (hexane/ethyl acetate/methanol) afforded 45 mg (23%) of the pure material.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1)[CH3:2].CCN(CC)CC.[O:22]=[C:23]1[NH:32][C:31]2[N:30]=[C:29]([O:33][CH2:34][CH2:35][CH2:36][CH:37]=O)[CH:28]=[CH:27][C:26]=2[CH2:25][CH2:24]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH2:1]([C:3]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([CH2:37][CH2:36][CH2:35][CH2:34][O:33][C:29]3[N:30]=[C:31]4[C:26]([CH2:25][CH2:24][C:23](=[O:22])[NH:32]4)=[CH:27][CH:28]=3)[CH2:13][CH2:14]2)[CH:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Reactant: CCc1cccc(N2CCNCC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1cccc(N2CCN(CCCCOc3ccc4c(n3)NC(=O)CC4)CC2)n1
Reaction time: 0.08 h
Yield: 47.4 %

Procedure:
To a solution of 1-(6-ethyl-pyridin-2-yl)-piperazine (0.41 g, 2.13 mmol) in dichloroethane (15 mL) was added Et3N (0.22 g, 2.13 mmol) and the mixture was stirred for 5 min. 4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.50 g, 2.13 mmol) was added as a solution in dichloroethane (3 mL) and the mixture was stirred at room temperature for 15 min. NaBH(OAc)3 (0.63 g, 3.00 mmol) was added as a solid and the reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated. Purification by liquid chromatography (Biotage 40M, gradient elution 100% CH2Cl2 to 99% CH2Cl2/MeOH) afforded the title compound as a sticky white foam (413 mg, 1.01 mmol, 47%). The foam was dissolved in Et2O and treated with anhydrous HCl gas to give a white precipitate. The mixture was filtered and dried to give a white powder (287 mg). MS: APCI: M+1: 410.3 (Exact Mass: 409.25).
Reaction SMILES: [OH-:1].[Li+].C[O:4][C:5](=[O:30])[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[CH2:11][CH2:10]1>O1CCCC1>[C:5]([CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([OH:29])=[O:1])[CH2:11][CH2:10]1)([OH:4])=[O:30]
Reactant: [OH-]
Reactant: COC(=O)CCCN1CCN(CCCCN2C(=O)c3ccccc3C2=O)CC1
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)CCCN1CCN(CCCCNC(=O)c2ccccc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Aqueous lithium hydroxide (5 mL of a 4 M solution) was added to a solution of 11 (2.50 g, 6.50 mmol) stirring in tetrahydrofuran (40 mL). The reaction mixture was stirred at ambient temperature for 4 hours. The solvent was removed under vacuum and the residue dissolved in water (25 mL) and extracted with dichloromethane (1×25 mL). The aqueous solution was acidified to pH 6 as indicated by pH paper and extracted with ethyl acetate (3×25 mL). The acidic aqueous solution was evaporated to dryness and dried under vacuum to give the carboxylic acid 12 (3.58 g, quantitative yield) as a yellow foam: 1H NMR (300 MHz, CD3OD) δ 1.61-1.89 (m, 6H), 2.27-2.38 (m, 2H), 2.75-3.09 (m, 10H), 3.33-3.35 (m, 6H), 3.41 (t, J=6.3 Hz, 2H), 7.38-7.47 (m, 3H), 7.62-7.65 (m, 1H); ESI MS m/z 392 [C20H29N3O5+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[CH3:10].C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5][C:4]=1[CH3:10]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)cc1C
Solvent: CC(C)O
Product: CCOC(=O)C(=CNc1ccc(OC)c(C)c1)C(=O)OCC
Yield: 75.9 %

Procedure:
4-Methoxy-3-methylaniline (45.2 g) was dissolved in isopropanol (100 ml) to prepare a solution. Diethyl ethoxymethylenemalonate (71.3 g) was added to the solution, and the mixture was heated under reflux for 5 min. The reaction solution was cooled, and the solvent was then removed by distillation under the reduced pressure. The residue was washed with ether-hexane to give diethyl 2-[(4-methoxy-3-methyl-phenylamino)-methylene]-malonate (76.9 g, yield 76%).