Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([C:17]([N:19]3[CH2:28][CH2:27][C:26]4[N:25]=[CH:24][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:22][C:21]=4[CH2:20]3)=[O:18])[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]2)[CH2:3][CH2:2]1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[CH:1]1([CH2:4][C:5]2([C:17]([N:19]3[CH2:28][CH2:27][C:26]4[N:25]=[CH:24][C:23]([C:29]([F:30])([F:31])[F:32])=[CH:22][C:21]=4[CH2:20]3)=[O:18])[CH2:9][CH2:8][NH:7][CH2:6]2)[CH2:3][CH2:2]1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]
Reactant: CC(C)(C)OC(=O)N1CCC(CC2CC2)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N1CCc2ncc(C(F)(F)F)cc2C1)C1(CC2CC2)CCNC1
Reaction time: 4 h

Procedure:
The title compound was prepared according to general procedure D described in connection with Scheme 5. tert-Butyl 3-(cyclopropylmethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidine-1-carboxylate was dissolved in 8 mL of CH2Cl2 and 2 mL of TFA was then added to the solution at RT. The reaction mixture was stirred for 4 h and the solvent was evaporated. The desired product was obtained as TFA salt without further application for next step. 1H NMR (400 MHz, CDCl3): δ 8.78 (s, 1H), 7.82-7.78 (m, 1H), 6.86 (br s, 1H), 4.88 (dd, 2H), 3.98 (m, 3H), 3.42 (d, 1H), 3.33 (m, 1H), 3.22 (br s, 2H), 2.63 (m, 1H), 2.20 (m, 1H), 2.01-1.73 (m, 3H), 0.68 (s, 1H), 0.53 (br s, 2H), 0.066 (m, 2H); MS (ESI) m/z: Calculated for C18H22F3N3O: 353.2. found 354.1 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7](I)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1Br)([O-:14])=[O:13]>[Cu]>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: CS(=O)(=O)c1cccc(I)c1
Agent: [Cu]
Product: CS(=O)(=O)c1cccc(-c2ccccc2[N+](=O)[O-])c1
Temperature: 120 °C

Procedure:
A mixture of 3-methanesulphonyliodobenzene (26.8 g), 2-nitrobromobenzene (19.2 g) and copper powder (18.2 g) was heated at 120° C. for 27 hours to yield a residue which was purified by chromatography on a silica column eluted initially with hexane and then with mixtures of ethylacetate and hexane in which the ethylacetate content was progressively raised to 60% to give 3'-methanesulphonyl-2-nitrobiphenyl (m.p. 124°-125° C.).
Reaction SMILES: [F:1][C:2]([F:17])([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)[C:3](OC)=[O:4].[NH2:18][NH2:19]>CO>[F:1][C:2]([F:17])([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)[C:3]([NH:18][NH2:19])=[O:4]
Reactant: COC(=O)C(F)(F)c1ccc2ncccc2c1
Reactant: NN
Solvent: CO
Product: NNC(=O)C(F)(F)c1ccc2ncccc2c1

Procedure:
A solution methyl 2,2-difluoro-2-(quinolin-6-yl)acetate (400 mg, 1686 μmol) and anhydrous hydrazine (2153 μl, 67453 μmol) in MeOH (4 mL) was stirred for 1 h at 23° C. The solvents were then removed under reduced pressure to provide product as a white solid. MS (ESI pos. ion) m/z: 238 (MH+). Calc'd exact mass for C11H9F2N3O: 237.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22](O)=[O:23])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C[N:27](C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22]([NH2:27])=[O:23])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C(=O)O)ccc1OCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C(N)=O)ccc1OCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid (0.170 g, 0.000501 mol) dissolved in N,N-Dimethylformamide (7.84 mL, 0.101 mol) and treated sequentially with N,N-Diisopropylethylamine (0.524 mL, 0.00300 mol) Ammonium chloride (0.107 g, 0.00200 mol) then N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.228 g, 0.000601 mol). The reaction was stirred at r.t. overnight. The reaction was quenched with sat. sodium bicarbonate then extract with ethyl acetate (3×). The organic layers was dried (Na2SO4) and concentrated in vacuo to give 109 purified on reverse HPLC. MS: (ESI+)=339.1. 1H NMR (400 MHz, DMSO) δ 8.93 (d, J=2.2 Hz, 1H), 7.95 (s, 2H), 7.92 (s, 1H), 7.79 (dd, J=8.5, 2.2 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 5.82 (dt, J=13.2, 6.6 Hz, 1H), 4.56 (s, 4H), 1.49 (d, J=6.6 Hz, 6H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[C:3]=1[OH:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([NH:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[C:3]=1[OH:10])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Br)cc(Br)c1O
Product: CC(=O)Nc1cc(Br)cc(Br)c1O

Procedure:
44.2 g. of 2-amino-4,6-dibromo-phenol were processed with 85.5 ml. of acetic anhydride keeping the temperature under 50° C. By cooling, the 2-acetylamino-4,6-dibromo-phenol separated; it was collected on a filter and crystallized from ethyl alcohol. 30 g. of pure product were obtained. M.P. = 175°-176° C.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][C:7](=[O:18])[C:8]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=3[NH:10][C:11](=O)[C:4]=2[CH:3]=1.CSC>C1COCC1>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][CH:7]([OH:18])[C:8]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=3[NH:10][CH2:11][C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(=O)Cc2ccc(Br)cc21
Solvent: CSC
Solvent: C1CCOC1
Product: OC1Cc2ccc(Br)cc2CNc2ccc(Cl)cc21
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 44 %

Procedure:
To a mixture of 8-Bromo-2-chloro-5H,11H-dibenzo[b,f]azocine-6-12-dione (2.0 g, 5.7 mmole) in THF (20 mL) was added a 2.0M solution of BH3.DMS in THF (6.9 mL, 14.3 mmole). The reaction mixture was heated to 70° C. for 6 hours. The reaction was quenched by slow addition of methanol and stirred at room temperature for 40 minutes. The residue obtained after concentration was triturated with methanol, filtered and dried in vacuo to give 8-Bromo-2-chloro-5,6,11,12-tetrahydro-dibenzo[b,f]azocine-12-ol (0.85 g, 44%). HPLC Rt=3.31 min. m/z=338 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[C:22]2[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=2[C:20]2[C:19]3[CH:18]=[C:17]([OH:28])[CH:16]=[CH:15][C:14]=3[N:13]([CH2:29][CH2:30][CH2:31][OH:32])[C:12]=2[CH:11]=1.C([O-])(=O)C.[K+].C(OCC)(=O)C>[Pd].CO>[OH:28][C:17]1[CH:16]=[CH:15][C:14]2[N:13]([CH2:29][CH2:30][CH2:31][OH:32])[C:12]3[CH:11]=[C:10]([C:3]4[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=4[O:8][CH3:9])[C:22]4[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=4[C:20]=3[C:19]=2[CH:18]=1
Reactant: COc1cccc(Cl)c1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCCO
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCCO
Yield: 51 %

Procedure:
4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-6-(3-hydroxypropyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (VI; Ar=2-chloro-6-methoxyphenyl, R10═CH2CH2CH2OH) (106) (0.20 g, 0.44 mmol) prepared as described in example 59, potassium acetate (0.20 g) and 5% Pd/C in a solution of ethyl acetate (25 ml) and methanol 1:1 (25 mL) under a atmosphere of hydrogen at 60 psi was reacted for 7 h. The catalyst was filtered off and the filtrate concentrated to dryness. The residue was partitioned between ethyl acetate and water and the organic solution was dried, the drying agent was removed and the solution was concentrated to dryness and chromatographed on silica. Elution with ethyl acetate/petroleum ether (2:1) gave 9-Hydroxy-6-(3-hydroxypropyl)-4-(2-methoxyphenyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (VI; Ar=2-methoxyphenyl, R10═CH2CH2CH2OH) (107) in a yield of 51% as an orange powder (from THF/petroleum ether), mp 296–300° C. 1H NMR δ [(CD3)2SO] 10.93 (br s, 1H), 9.31 (br s, 1H), 8.38 (d, J=2.4 Hz, 1H), 7.69 (s, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.42 (m, 1H), 7.35 (dd, J=7.5, 1.7 Hz, 1H), 7.13–7.08 (m, 2H), 7.05 (dd, J=7.2, 7.2 Hz, 1H), 4.62 (t, J=4.8 Hz, 1H), 4.48 (t, J=6.8 Hz, 2H), 3.68 (s, 3H), 3.40 (m, 2H), 1.90 (m, 2H). Found: C, 69.29; H, 4.90; N, 6.54. C24H20N2O5 requires C, 69.22; H, 4.84; N, 6.73.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[CH2:16][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([C:17]3[CH:18]=[C:19]([NH:23][S:28]([CH2:27][CH2:26][O:25][CH3:24])(=[O:30])=[O:29])[CH:20]=[CH:21][CH:22]=3)[CH2:16][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCS(=O)(=O)Cl
Reactant: Nc1cccc(C23CCCC(C2)N(Cc2ccccc2)CC3)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COCCS(=O)(=O)Nc1cccc(C23CCCC(C2)N(Cc2ccccc2)CC3)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenylamine (2.71 g, 8.84 mmol) stirred in pyridine (25 ml) at 0° C. was charged with 2-methoxy-ethanesulfonyl chloride (2.1 g, 13.26 mmol) dropwise causing a color change from yellow to bright orange. The reaction was allowed to warm to room temperature gradually and stirred 18 h. The reaction mixture was diluted with toluene and concentrated in vacuo. The residue was dissolved in CH2Cl2 and washed with saturated aqueous NaHCO3 solution (100 mL). The aqueous layer was extracted with CH2Cl2 (2×50 ml) and the organic layer was concentrated to an oil. This was dissolved in EtOAc which caused an oil to separate. The EtOAc layer was separated and washed with saturated aqueous NaHCO3 solution (100 mL). The aqueous layer was extracted with EtOAc (2×50 ml) and the combined organic layer was washed with saturated aqueous NaCl solution (50 ml), dried over Na2SO4, filtered and concentrated to a crude orange liquid (3.77 g, ˜100%). (TLC 75% EtOAc/hexanes Rf 0.48);
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6](Cl)[N:5]=[C:4]([CH3:10])[C:3]=1[CH3:11].[H][H]>C(O)C.S(=O)(=O)(O)O.[Pd]>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH3:10])[C:3]=1[CH3:11]
Reactant: [H][H]
Reactant: Cc1nc(Cl)c(C)c(Cl)c1C
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cc1cnc(C)c(C)c1Cl
Yield: 78 %

Procedure:
200 g 4,6-dichloro-2,3,5-trimethylpyridine dissolved in 300 ml ethanol and 40 ml conc. sulphuric acid. 2 g 10% Pd/C was used as catalyst. The hydrogen pressure was 2 bar and the hydrogenation was stopped when 1 equivalent of hydrogen had been consumed. After evaporation of alcohol and dilution with water and adjustment of pH to 2.1 the water was extracted with toluene. The toluene contains all starting material and 6-chloro-2,3,5-trimethylpyridine and the water phase 4-chloro-2,3,5-trimethylpyridine and 2,3,5-trimethylpyridine. The pH of the water phase is adjusted to 4.6 and extracted with toluene (3x100 ml). All 4-chloro-2,3,5-trimethylpyridine is in the toluene layer and the 2,3,5-trimethylpyridine in the water. Evaporation of the toluene gave 4-chloro-2,3,5-trimethylpyridine in 78% yield (liquid). NMR: 2×3H, 2,3; 3H, 2,5(s); 1H, 8,25(s). (CDCl3)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[CH2:19][C:20](OC)=[O:21])=[CH:11][CH:10]=1.O.[H-]>CCOCC>[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[CH2:19][CH2:20][OH:21])=[CH:11][CH:10]=1
Reactant: COC(=O)Cc1cccc2ccc(OC)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: COc1ccc2cccc(CCO)c2c1

Procedure:
3.34 g of lithium aluminum hydride are placed in a 250-cm3 flask, and ether is added gently with stirring. Using a dropping funnel, 5 g of methyl (7-methoxy-1-naphthyl)acetate previously dissolved in 50 cm3 of ether are added slowly. The reaction medium is left stirring for 30 minutes. It is poured very slowly into a mixture of water and ice so as to hydrolyze the excess unreacted hydride. The reaction medium is filtered. The aqueous phase is extracted with 3 times 50 cm3 of ether, and the ether phases are dried over magnesium sulfate and evaporated. The white solid obtained is recrystallized.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[C:27]([O:33][CH2:34][O:35][CH3:36])[CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:27]([O:33][CH2:34][O:35][CH3:36])[CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COCOc1cc(OCc2ccccc2)ccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccc(OCc2ccccc2)cc1OCOC
Yield: 99.3 %

Procedure:
To a suspension of 55% sodium hydride dispersion in mineral oil (1.57 g, 36.0 mmol) in tetrahydrofuran (100 ml) was added ethyl diethylphosphonoacetate (7.17 g, 32.0 mmol) at 0° C. with stirring, and the resulting mixture was stirred for 30 minutes at 0° C. under a nitrogen atmosphere. Subsequently, a solution of 4-benzyloxy-2-methoxymethoxy-benzaldehyde (7.46 g, 27.4 mmol) obtained in step (b) of Example 197 in tetrahydrofuran was added at 0° C. with stirring, and the resulting mixture was stirred for 2 hours at 0° C. under a nitrogen atmosphere. After stirring, water (200 ml) was added, and the resulting mixture was extracted with ethyl acetate (200 ml×2). The organic layer was washed successively with water (100 ml×1) and saturated aqueous sodium chloride solution (100 ml×1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:1-1:1) as the eluent to afford the title compound (9.32 g, yield: 99%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][C:56]1[C:60]([C:61](Cl)=[O:62])=[C:59]([CH3:64])[O:58][N:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:61]([C:60]2[C:56]([CH3:55])=[N:57][O:58][C:59]=2[CH3:64])=[O:62])[CH2:49][CH2:48]1
Reactant: Cc1noc(C)c1C(=O)Cl
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(C)c1C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 3,5-dimethylisoxazole-4-carbonyl chloride as starting materials (43% yield). LCMS for C30H32ClN8O3 (M+H)+: m/z=587.2.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:29][CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCCC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 88.2 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (10 g, 29.6 mmol), cyclohexyl amine (3.4 ml, 30.0 mmol), diisopropylethylamine (11 ml, 65.0 mmol) in propan-2-ol (150 ml) was heated at 80° C. for 14 h. The mixture was then cooled to 25° C. and stirred for 6 h. The resulting yellow solid was collected by vacuum filtration, washed with propan-2-ol (1×30 ml), and was air-dried to afford (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-cyclohexyl-amine (10.45 g, 90%). LCMS (Method G, ESI): RT=1.33 min, m+H=401.2; 1H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.91 (s, 1H), 8.13 (d, J=7.6 Hz, 2H), 7.82 (d, J=4.1 Hz, 1H), 7.77 (t, J=7.4 Hz, 1H), 7.66 (t, J=7.8 Hz, 2H), 6.99 (d, J=4.2 Hz, 1H), 4.12-4.01 (m, 1H), 2.02-1.93 (m, 2H), 1.76-1.54 (m, 3H), 1.55-1.38 (m, 4H), 1.33-1.20 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[C:15](\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:16][CH3:17])/[C:12]([OH:14])=O)=[CH:7][CH:6]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:48][N:49]([CH3:60])[CH2:50][CH2:51][O:52][C:53]1[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][CH:54]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:48][N:49]([CH3:60])[CH2:50][CH2:51][O:52][C:53]1[CH:58]=[CH:57][C:56]([NH:59][C:12](=[O:14])/[C:11](/[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=2)=[C:15](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[CH2:16][CH3:17])=[CH:55][CH:54]=1
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: CC/C(=C(\C(=O)O)c1ccc(OCOC)cc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(OCOC)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43 %

Procedure:
Method A; To a mixture of 3 (2.50 g, 8.00 mmol), EDC.HCl (1.84 g, 9.60 mmol) and HOBt (1.30 g, 9.62 mmol) in DMF (50 ml) was added a solution of 4-(2-(dimethylamino)ethoxy)benzene-amine dihydrochloride (2.23 g, 8.81 mmol) and N,N-Diisopropylethylamine (4.13 g, 32.0 mmol) under ice cooling, and the mixture was stirred at room temperature for 18 h. The reaction was quenched with saturated aqueous NaHCO3 under ice cooling, and the whole was extracted with AcOEt, the organic layer was washed with H2O×2, brine, dried over Na2SO4, then concentrated. Purification by silica gel flash column chromatography (eluent: AcOEt then CHCl3/MeOH, 10:1) and recystallization from AcOEt-hexanes gave 4 (43%). 4: colorless powder; 1H-NMR (CDCl3) δ 1.05 (3H, t, J=7.4), 2.33 (6H, s), 2.71 (2H, t, J=5.7 Hz), 2.77 (2H, q, J=7.4 Hz), 3.43 (3H, s), 4.04 (2H, t, J=5.7 Hz), 5.09 (2H, s), 6.78 (2H, d, J=8.8 Hz), 6.88 (2H, d, J=9.0 Hz), 7.00 (2H, d, J=8.8 Hz), 7.00 (1H, brs) 7.06 (2H, m), 7.12-7.23 (3H, m), 7.41 (2H, d, J=9.0 Hz).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[S:10][C:9]2=[N:11][C:12]([C:14]([OH:16])=O)=[CH:13][N:8]2[CH:7]=1.[N-:17]=[N+:18]=[N-:19].[Na+]>O>[Br:5][C:6]1[S:10][C:9]2=[N:11][C:12]([C:14]([N:17]=[N+:18]=[N-:19])=[O:16])=[CH:13][N:8]2[CH:7]=1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: [N-]=[N+]=NC(=O)c1cn2cc(Br)sc2n1
Temperature: 85 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
Thionyl chloride (0.33 mol) was added to 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid (13.1 mmol). The reaction mixture was stirred at 85° C. during 3 hrs. The mixture was then concentrated under vacuum and the residue was taken in acetone (40 mL). The sodium azide (14.4 mmol) in water (5.2 mL) was added in one portion at 0° C. and the mixture was stirred at 0-10° C. for 45 min. Water was added, and the solid filtered off and washed with water and then with a mixture of water/acetone (50/50). The solid was dried in vacuo to give compound 9 as a beige solid in 80% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 8.27 (s, 1H), 8.49 (s, 1H); and MS (ESI, EI+) m/z=272.05-274.07 (MH+).
Reaction SMILES: [H-].[Na+].[Br-].[CH:4]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O>CS(C)=O.O>[C:4]1(=[CH:32][C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[O:29][CH3:28])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COc1ccccc1C=O
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CCCC2)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1C=C1CCCC1
Temperature: 60 °C
Yield: 67 %

Procedure:
A suspension of sodium hydride (608 mmol, 24.3 g; 60% dispersion in oil) in dry DMSO (3L) was heated to 60° C. for one hour and cooled to an internal temperature of 42° C. Cyclopentyltriphenylphosphonium bromide (608 mmol, 250 g) was added in one portion and to the resulting red solution was added 2-methoxybenzaldehyde (669 mmol, 91.0 g; 80.7 mL) dropwise over a few minutes. The dark reaction mixture was heated to 60° C. for 18 hours and cooled to room temperature. The reaction was diluted with water (4L), extracted with CH2Cl2 (2×3L) and concentrated in vacuo. The residue was partitioned between 15:1 hexane/EtOAc (1.3L) and water (1.6L), the organics washed with water (3×600 mL), dried (Na2SO4) and concentrated in vacuo. Upon concentration, triphenylphosphine oxide crystallized out of solution. The suspension was diluted with hexane, the solids removed by filtration, and the filtrate concentrated in vacuo to afford a dark oil. This material was vacuum distilled to afford the title compound as a light yellow oil (76.7 g, 67%). The desired material comes over at 90°-97° C. at 0.05 mm Hg and is used as such in the subsequent transformation.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:25])[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[Cl:24])[CH3:16])C1C=CC=CC=1.[Li].[Li+].[O-:28][O-]>C1COCC1.O>[Cl:24][C:18]1[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=1[C@@H:15]([CH3:16])[C:14]([OH:25])=[O:28]
Reactant: [O-][O-]
Reactant: CC(C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1cccc(Cl)c1Cl
Agent: [Li+]
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](C(=O)O)c1cccc(Cl)c1Cl
Yield: 86.9 %

Procedure:
To a solution of compound 20 (160 mg, 0.42 mmol) in THF (5 mL) and water at 0° C., was added a solution of lithium peroxide (prepared by adding 30% hydrogen peroxide (2.9 mL, 2.10 mmol) to lithium hydroxide (17.6 mg, 0.41 mmol) in water (0.679 mL)) dropwise. The mixture was stirred for 0° C. for 1h, quenched with sat.Na2SO3 (1.28 mL), solvent was removed in vacuo. The mixture was diluted with water and aqueous solution was extracted with DCM twice. The aq.layer was acidified with Conc.HCl and extracted with EtOAc twice. Combined organic layers were washed with brine and dried over MgSO4, concentrated. Purified by column chromatography (EtOAc/n-Hexane 40:60) to afforded compound 21 (80 mg, 86.9%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 1.51 (d, J=7.2 Hz, 3H), 4.27 (q, J=6.8 Hz, 1H), 7.16-7.24 (m, 2H), 7.37 (d, J=7.6 Hz, 1H)).