Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([O:15]C)=[O:14])[N:10]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:8]=2)=[CH:4][CH:3]=1.C1COCC1.[Li+].[OH-]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([OH:15])=[O:14])[N:10]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:8]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.7 %

Procedure:
A 12 liter, three-neck, round bottom flask equipped with mechanical stirrer was charged with Methyl [5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetate (235 g, 0.72 mol), THF (3.5 L), methanol (1.2 L), and 2 M LiOH (1.2 L). The resulting solution was stirred at room temperature for 1.5 hours. After LC-MS showed the absence of starting material, the majority of the THF was removed by rotary evaporation. The solution was then acidified with 2 M HCl (pH=3) and the white precipitate was filtered and washed with water. After being dried under reduced pressure, 210 g (93%) of the title compound was obtained. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.53 (d, 2 H), 7.68 (d, 2 H), 7.31 (t, 2 H), 7.14 (t, 2 H), 6.57 (s, 1 H), 5.00 (s, 2 H), 4.01 (s, 2 H); m/z (APCI+) for C17H14N3O2F 312.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH:9]([NH:19][CH3:20])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1C2C(=CC=CC=2)C=CC=1.C([O-])([O-])=O.[K+].[K+].[C:37]([O:46]N1C(=O)CCC1=O)([O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])=O>C1COCC1.O>[C:14]([O:13][C:12]([NH:11][CH2:10][CH:9]([N:19]([CH3:20])[C:37]([O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:44])[CH3:45])=[O:46])[CH2:8][C:2]1([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:18])([CH3:16])([CH3:17])[CH3:15]
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: CNC(CNC(=O)OC(C)(C)C)CC1(O)CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc2ccccc2c1
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OCC[Si](C)(C)C)C(CNC(=O)OC(C)(C)C)CC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of above mixture of tert-butyl 3-(1-hydroxycyclohexyl)-2-(methylamino)-propylcarbamate and naphthalene in 3:1 THF/H2O v/v (4 mL) was added K2CO3 (100 mg, 0.72 mmol), followed by Teoc-OSu (70 mg, 0.27 mmol). The resulting solution was stirred at rt for 30 min and the organic solvent was removed under reduced pressure. The residue was extracted with EtOAc (2×). The combined organic phases were washed with brine, dried, filtered, and concentrated under vacuum. The residue was chromatographed on silica gel to give 1-(3-(t-butoxycarbonylamino)-2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propyl)cyclohexanol (100 mg, 86% for three steps). MS m/z 453 (M+Na+).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[C:3]=1[F:10].[N:11]([O-])=O.[Na+].[OH-].[Na+]>CC(O)=O>[Br:1][C:2]1[C:3]([F:10])=[C:4]2[C:5](=[CH:7][CH:8]=1)[NH:6][N:11]=[CH:9]2
Reactant: Cc1c(N)ccc(Br)c1F
Reactant: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Fc1c(Br)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.9 %

Procedure:
To a solution of 4-bromo-3-fluoro-2-methylaniline (20 g, 98.0 mmol) in CH3CO2H (600 mL) was added NaNO2 (8.1 g, 118 mmol) at 10° C. The resulting mixture was stirred at room temperature for 4 hours. Upon completion, aqueous NaOH (50%) was added to the reaction mixture until pH was ˜7-8. The mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜40% EtOAc in petroleum ether) affording the title compound (16 g). 1H NMR (300 MHz, DMSO-d6): δ 13.58 (br, 1H), 8.22 (s, 1H), 7.53 (t, 1H), 7.38 (d, 1H).
Reaction SMILES: [S:1]1(=[O:7])(=[O:6])[CH:5]=[CH:4][CH:3]=[CH:2]1.[NH2:8][CH2:9][CH2:10][NH2:11]>>[O:6]=[S:1]1(=[O:7])[CH2:5][CH2:4][CH:3]([NH:8][CH:9]2[CH2:5][CH2:4][CH2:3][CH2:2][CH:10]2[NH:11][CH:3]2[CH2:4][CH2:5][S:1](=[O:7])(=[O:6])[CH2:2]2)[CH2:2]1
Reactant: NCCN
Reactant: O=S1(=O)C=CC=C1
Product: O=S1(=O)CCC(NC2CCCCC2NC2CCS(=O)(=O)C2)C1

Procedure:
Example 1 was repeated using the thiophene dioxide of Example 1 but substituting 1,2-diaminocyclohexane for 1,2-diaminoethane. The resultant product, N,N'-bis(1,1-dioxotetrahydro-3-thienyl)-1,2-diaminocyclohexane obtained was a viscous liquid that became a semi-solid. The infrared spectrum showed absorptions at 3300 cm-1 (NH), at 1300 cm-1 and 1130 cm-1 (SO2).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[C:8]([CH2:10][CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1.C1(C)C=CC=CC=1>[OH:17][CH2:16][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][C:8]2[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(CCc2nc(NC(C)=O)sc2Cc2ccc(S(C)(=O)=O)cc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(CO)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.4 %

Procedure:
To a stirred solution of methyl 4-(2-{2-(acetylamino)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)benzoate (2 g) in dry THF (40 ml) was added dropwise 1.0M diisobutylaluminium hydride solution in toluene (14.8 ml) at −78° C. under N2 atmosphere. The reaction mixture was stirred at r.t. for 4 hours, and then quenched with MeOH. AcOEt and 1N—HCl were added to the mixture, and extracted. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with CHCl3/MeOH (20:1) as an eluent to give N-{4-{2-[4-(hydroxymethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (552.3 mg) as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:30]=[CH:29][C:8]([O:9][CH:10]([CH3:28])[C:11](=[O:27])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:16][CH:15]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:38][S:39]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:28])[C:11](=[O:27])[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])=[CH:18][CH:19]=2)=[CH:29][CH:30]=1)(=[O:41])=[O:40]
Reactant: CC(Oc1ccc(CCCO)cc1)C(=O)COc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(CCCOS(C)(=O)=O)cc1)C(=O)COc1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 0.75 h
Yield: 83.1 %

Procedure:
A solution of (3R and 3S)-3-[4-(3-hydroxypropyl)phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone (0.092 g, 0.22 mmol) in dry dichloromethane (5 ml) was cooled to 0° C. and treated with triethylamine (0.07 ml, 0.5 mmol) followed by methanesulfonyl chloride (0.03 ml, 0.39 mmol). After 45 minutes at 0° C., the reaction mixture was quenched by addition of ethyl acetate (100 ml) and water. The organic phase was washed with saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation and chromatography of the residue on silica gel (elution toluene and ethyl acetate, 9:1) gave 0.090 g (82%) of the title material as an oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[N:11]1([CH2:17][CH2:18][NH2:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[N:11]1([CH2:17][CH2:18][NH:19][C:6]2[CH:5]=[CH:4][C:3]([N+:8]([O-:10])=[O:9])=[CH:2][CH:7]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: NCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(NCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.2 %

Procedure:
A 50 mL round bottom flask was dried in an oven overnight and cooled to room temperature under Ar(g). The flask was charged with fluoronitrobenzene (0.187 mL, 1.77 mmol), 2-Morpholin-4-yl-ethylamine (0.299 g, 2.30 mmol) and dioxane (9.0 mL). To the solution, diisopropyl ethyl amine (0.463 mL, 2.66 mmol) was added dropwise and allowed to stir at 105° C. for 48 h. The mixture was extracted with EtOAc (3×30 mL), and with brine (2×30 mL). The combined organic layers were then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude mixture was then purified over silica (10% MeOH/90% CHCl3) affording (2-Morpholin-4-yl-ethyl)-(4-nitro-phenyl)-amine as a yellow solid (0.315 g, 1.26 mmol, 71% yield).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[C:15]2[O:14][CH:13]([CH2:12][NH:34][CH:31]3[CH2:33][CH2:32]3)[CH2:17][C:16]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Reactant: NC1CC1
Product: Cc1cccc(C)c1-c1cc(Cl)cc2c1OC(CNC1CC1)C2

Procedure:
The title compound was prepared (0.056 g, 34%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and cyclopropylamine (0.39 g, 6.77 mmol). mp 214-216° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O.C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>ClCCl>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:10]
Reactant: Nc1ccccc1
Reactant: O=C(O)CCCOc1ccc(Cl)cc1Cl
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCOc1ccc(Cl)cc1Cl)Nc1ccccc1
Temperature: -30 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
To a solution of the 4-(2,4-dichloro-phenoxy)-butyric acid (9.8 g, 40 mmol) and triethylamine (6.0 ml, 40 mmol) in dichloromethane (150 mL) was added dropwise isobutyl chlorocarbonate (6 mL, 40 mol) at −30° C. After stirring at −30° C. for 3 h, aniline (4 mL 40 mol) was added dropwise. The reaction mixture was stirred for 3 h at −30° C. and then allowed to warm up to RT. Aqueous HCl (5%, 100 mL) was added and stirring was continued for 0.5 h. The phases were separated, the aqueous layer was extracted with dichloromethane (2×200 mL). The combined organic extracts were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the product (10 g, 77.5%). 1H-NMR (CDCl3): δ 7.49 (d, 2H, J=8.0 Hz), 7.38 (d, 1H, J=2.4 Hz), 7.31 (t, 2H, J=8.0 Hz), 7.18 (dd, 1H, J1=8.8 Hz, J2=2.4 Hz) 7.12 (t, 1H, J=8.0), 6.87 (d, 1H, J=8.8 Hz), 4.12 (t, 2H, J=6.4 Hz), 2.64 (t, 2H, J=6.4 Hz), 2.25 (p, 2H, J=6.4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C@@H:14]([CH3:17])[CH2:15][OH:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:18]=O.[BH4-].[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:18])[C@@H:14]([CH3:17])[CH2:15][OH:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C=O
Reactant: COc1ccc(CCN[C@@H](C)CO)cc1OC
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CCN(C)[C@@H](C)CO)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.1 %

Procedure:
To a solution of 6.25 g of (0.026 mole) (S)-2-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-1-propanol in 50 ml of MeOH under argon was added 3.9 ml (0.052 mole) of 37% aqueous formaldehyde and 4.7 g of sodiumborohydride pellets added one at a time. The solution was stirred at RT for 24 hr. an additional 1.0 ml of 37% aqueous formaldehyde and 1.0 g of sodium borohydride were added and the solution stirred for an additional 2.5 hr. Enough glacial acetic acid was added to react with the sodium borohydride. The reaction was made basic by addition of 3N sodium hydroxide. The methanol was evaporated in vacuo and the residue was extracted three times with ether. The organics were washed with brine an dried (K2CO3). Evaporation of the solvent in vacuo gave 5.74 g of (S)-2-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]-1-propanol as an oil (87% yield).
Reaction SMILES: C(OC([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=O)CCC.[H-].[Na+].IC.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>CN(C=O)C.ClCCl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[CH2:11]([NH:12][CH3:18])[CH2:10][CH2:9][CH3:8]
Reactant: CCCCOC(=O)CCCCN
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CI
Solvent: CN(C)C=O
Product: CCCCNC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-butyloxycarbonylbutylamine (140 mg, 0.80 mmole) was dissolved in DMF (8 ml), and sodium hydride (NaH, 20 mg, 1 eq. wt.) and iodomethane (0.10 ml, 2 eq. wt.) were added thereto. The reaction mixture was stirred for 30 minutes at room temperature and filtered through celite bed and then concentrated under reduced pressure to remove the solvent. The residue was diluted with ethyl acetate, washed with 0.5N aqueous hydrochloric acid solution, dried over anhydrous magnesium sulfate and filtered. The organic layer was concentrated under reduced pressure and dried by means of a vaccum pump to obtain a white solid, which was then dissolved in dichloromethane and cooled down to 0° C. To this mixture was added 1 ml of trifluoroacetic acid (TFA). The reaction solution was stirred for 30 minutes at room temperature, concentrated under reduced pressure and then dried by means of a vaccum pump to obtain the title compound (0.16 g) in a quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[C@H:4]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])C(C)C.Br[C:40]1[CH:48]=C2C(CN(C3(C(OC)=O)CCCC3)C2=O)=[CH:42][CH:41]=1.CC1(C)C(C)(C)OB(C2C=CC(NC(NC3C=CC=C(C(F)(F)F)C=3)=O)=CC=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[O:37]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:34])[F:36])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)[CH:11]=2)[CH2:16][N:8]1[C:4]1([C:3]([O:2][CH3:1])=[O:38])[CH2:42][CH2:41][CH2:40][CH2:48]1
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Reactant: COC(=O)C1(N2Cc3ccc(Br)cc3C2=O)CCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)OC1(C)C
Solvent: ClCCl
Product: COC(=O)C1(N2Cc3ccc(-c4ccc(NC(=O)Nc5cccc(C(F)(F)F)c5)cc4)cc3C2=O)CCCC1

Procedure:
The compound of example 342 was prepared analogous to compound of example 330 by reaction of the compound of example 341, compound of example 327 and Pd(dppf)Cl2: CH2Cl2.
Reaction SMILES: C(OC([N:8]1[CH2:39][CH2:38][C:12]2=[C:13]([N:20]3[CH2:23][CH:22]([C:24](=[O:37])[NH:25][CH:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])[CH2:28][CH2:27]4)[CH2:21]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:35][C:34]([CH3:36])=[CH:33][CH2:32][N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:24]([CH:22]2[CH2:23][N:20]([C:13]3[N:14]4[C:18]([N:19]=[C:11]5[CH2:10][CH2:9][NH:8][CH2:39][CH2:38][C:12]=35)=[CH:17][CH:16]=[N:15]4)[CH2:21]2)=[O:37])[CH2:27][CH2:28]1
Reactant: CC(C)=CCN1CCC(NC(=O)C2CN(c3c4c(nc5ccnn35)CCN(C(=O)OC(C)(C)C)CC4)C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)=CCN1CCC(NC(=O)C2CN(c3c4c(nc5ccnn35)CCNCC4)C2)CC1
Reaction time: 2.5 h

Procedure:
To 70 mg (0.13 mmol) 10-{3-[1-(3-Methyl-but-2-enyl)-piperidin-4-ylcarbamoyl]-azetidin-1-yl}-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester in 2 mL of DCM was added 0.13 mL TFA and stirring was continued for 2.5 h at room temperature. The reaction mixture was concentrated and the residue, after addition of small amounts of 1N NaOH and MeOH, purified by HPLC.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]([C:9]([OH:12])([CH3:11])[CH3:10])[N:8]=1)[CH3:2]>C(O)(=O)C>[CH2:1]([S:3][C:4]1[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]([C:9]([OH:12])([CH3:10])[CH3:11])[N:8]=1)[CH3:2]
Reactant: CCOC(=O)c1c(C(C)(C)O)nc(SCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C(C)(C)O)nc(SCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
2.22 g of ethyl 2-ethylthio-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] were added to 20 ml of a 25% v/v aqueous solution of acetic acid, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was crystallized by the addition of ethyl acetate, to give 1.22 g of the title compound as crystals, melting at 185°-188° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1)=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO.CN(C=O)C.C(Cl)Cl.N>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([N:33]4[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]4)=[CH:31][CH:32]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Reactant: Cc1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cs1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(N6CCN(C(=O)OC(C)(C)C)CC6)cc5)nc34)CC2)cs1
Temperature: 85 °C
Yield: 43.9 %

Procedure:
To a mixture of 5-bromo-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.062 g, 0.15 mmol) in EtOH (2.6 mL) and DMF (0.35 mL), tert-butyl 4-(4-formylphenyl)piperazine-1-carboxylate (0.044 g, 0.165 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.45 mL, 0.45 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v 96:4) to give the title compound as a off-white solid (0.043 g, 47%); 1H-NMR (500 Mz, DMSO-d6): δ 1.43 (s, 9H, C(CH3)3), 2.61-2.70 (m, 7H), 3.22-3.31 (m, 4H), 3.43-3.52 (m, 4H), 3.60-3.68 (m, 6H), 7.07 (d, J=9.0 Hz, 2H, ArH, C6H4), 7.32 (s, 1H, thiazole 5-H), 8.04 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.22 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 4.01 min—653/655 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 653.2022, calculated for C30H38BrN8O2S (M+H)+: 653.2019.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]1[C:19](=[O:28])[NH:20][C:21]3[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:12]2.[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][N:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:37][C:34]1[CH:33]=[N:32][C:31]([O:30][CH3:29])=[N:36][CH:35]=1)[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]1[C:19](=[O:28])[NH:20][C:21]3[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:12]2
Reactant: COCCNCCOc1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc2c1
Reactant: COc1ncc(C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COCCN(CCOc1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc2c1)Cc1cnc(OC)nc1

Procedure:
A solution of 3-5-{2-[(2-methoxyethyl)amino]ethoxy}-1H-indol-2-yl)-2(1H) -quinolinone 2-1 (150 mg, 0.4 mmol), 2-methoxypyrimidine-5-carboxaldehyde (110 mg, 0.8 mmol) and sodium triacetoxyborohydride (168 mg, 0.8 mmol) in DCE (25 mL) was stirred under ambient conditions for 18 h. The reaction mixture was concentrated, and the residue was partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was suspended in ethyl ether with the aid of sonication, then filtered and air dried to provide 3-[5-(2-{(2-methoxyethyl)[(2-methoxy-5-pyrimidinyl) methyl]amino}ethoxy)-1H-indol-2-yl]-2(1H)-quinolinone (2-2) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 11.05 (s, 1H), 9.60 (s, 1H), 8.53 (s, 2H), 8.33 (s, 1H), 7.68 (d, 1H, J=8 Hz), 7.52 (t, 1H, J=8 Hz), 7.34 (d, 1H, J=8 Hz), 7.27 (t, 1H, J=8 Hz), 7.22 (d, 1H, J=8 Hz), 7.05 (s, 1H), 6.96 (s, 1H), 6.86 (dd, 1H, J=8, 2 Hz), 4.13 (t, 2H, J=6 Hz), 4.01 (s, 3H), 3.80 (s, 2H), 3.53 (t, 2H, J=6 Hz), 3.34 (s, 3H), 3.01 (t, 2H, J=6 Hz), 2.84 (t, 2H, J=6 Hz).
Reaction SMILES: [S-:1][CH2:2][CH3:3].[Na+].[C:5]([C:9]1[C:14]2[O:15][CH2:16][C:17]([CH3:19])([CH3:18])[C:13]=2[CH:12]=[C:11]([C:20](=[O:23])[CH2:21]Cl)[CH:10]=1)([CH3:8])([CH3:7])[CH3:6]>CO>[C:5]([C:9]1[C:14]2[O:15][CH2:16][C:17]([CH3:19])([CH3:18])[C:13]=2[CH:12]=[C:11]([C:20](=[O:23])[CH2:21][S:1][CH2:2][CH3:3])[CH:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC[S-]
Reactant: CC(C)(C)c1cc(C(=O)CCl)cc2c1OCC2(C)C
Agent: [Na+]
Solvent: CO
Product: CCSCC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Reaction time: 2.5 h
Yield: 58.7 %

Procedure:
Sodium thioethoxide (0.54 g, 6.4 mmol) is added in portions to a solution of 1 -(7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl)-2-chloroethan-1-one (1.12 g, 4.0 mmol) in 30 mL of methanol at room temperature. The reaction is stirred for 2.5 h, and concentrated in vacuo. The residue is dissolved in ether, washed with water and with brine, dried over anhydrous magnesium sulfate, and concentrated to give 1.12 g of the crude product. Purification by flash column chromatography on silica gel (5% ethyl acetate-hexane) afforded 0.72 g of the title compound as a light yellow oil.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1.N([O-])=O.[Na+].[BrH:16]>O.[Cu]Br>[Br:16][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1
Reactant: Br
Reactant: Nc1nc2c(Cl)cccc2s1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1cccc2sc(Br)nc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Slurry 2-amino-4-chlorobenzothiazole (0.255 mol) in water (325 mL), heat to reflux and add 48% hydrobromic acid (130 mL). Maintain at reflux for 20 minutes, cool to 0° C. and add a solution of sodium nitrite (17.56 g, 0.255 mol) in water (90 mL), maintaining a temperature of 0° C. Stir at 0° C. for 15 minutes and add by dropwise addition (while keeping cold) to a rapidly stirring mixture of copper (I) bromide (42.03 g, 0.293 mol) in 48% hydrobromic acid (86 mL) and water (225 mL). Stir at room temperature for 20 minutes and then heat on a steam bath for an additional 20 minutes. Allow to stand overnight, extract into methylene chloride and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give 2-bromo-4-chlorobenzothiazole.