Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([C@@:29]2([OH:46])[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[CH2:31][C@@H:30]2[OH:45])[CH:26]=[CH:25][CH:24]=1>>[NH2:9][C:7]([C:6]1[CH:5]=[C:4]([C:10]2[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=2[F:16])[S:3][C:2]=1[NH:1][C:23]1[N:28]=[C:27]([C@@:29]2([OH:46])[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[CH2:31][C@@H:30]2[OH:45])[CH:26]=[CH:25][CH:24]=1)=[O:8]
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: O=C(OCc1ccccc1)N1CC[C@](O)(c2cccc(Br)n2)[C@@H](O)C1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc([C@@]4(O)CCN(C(=O)OCc5ccccc5)C[C@@H]4O)n3)s2)c(F)c1

Procedure:
The title compound was prepared using the procedure listed in Example 1 with 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.11 g, 0.34 mmol) and benzyl (3S,4S)-4-(6-bromopyridin-2-yl)-3,4-dihydroxypiperidine-1-carboxylate (0.13 g, 0.33 mmol) as the starting materials.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]2[CH2:18][CH2:19][CH2:20][C:13]=12>C(Cl)Cl>[N+:12]1([O-:9])[CH:17]=[CH:16][CH:15]=[C:14]2[CH2:18][CH2:19][CH2:20][C:13]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2c(c1)CCC2
Solvent: ClCCl
Product: [O-][n+]1cccc2c1CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
mCPBA (10.0 g, 44.6 mmol) was added slowly to a mixture of 6,7-dihydro-5H-cyclopenta[b]pyridine (from Aldrich, 5.0 g, 42 mmol) in DCM (50 mL). The reaction mixture was stirred at room temperature for 2 h. The solution was then washed with aq. Na2S2O3 (50 mL) and 1 M NaOH (50 mL). The aqueous layer was extracted with DCM (5×70 mL). The combined organic layers were dried, filtered and concentrated under reduced pressure to give the sub-title compound (4.5 g, 79%). LCMS calc. for C8H10NO (M+H)+: m/z=136.1. Found: 136.2.
Reaction SMILES: CO[C:3]([C:5]1[N:13]([CH2:14][CH2:15][O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH:27][C:28]1[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=1[F:35])=[O:4].[OH-].[Na+].[CH:38]([O:40][CH2:41][CH2:42][O:43][NH2:44])=[CH2:39].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(O)C.C1COCC1>[CH:38]([O:40][CH2:41][CH2:42][O:43][NH:44][C:3]([C:5]1[N:13]([CH2:14][CH2:15][O:16][Si:17]([CH:18]([CH3:19])[CH3:20])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:22])[CH3:23])[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH:27][C:28]1[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=1[F:35])=[O:4])=[CH2:39]
Reactant: COC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1CCO[Si](C(C)C)(C(C)C)C(C)C
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C=COCCONC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1CCO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-(2-fluoro-4-iodo-phenylamino)-1-(2-triisopropylsilanyloxy-ethyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester (90 mg, 0.15 mmol) in ethanol (2 mL) was added a 1M aqueous solution of sodium hydroxide (0.15 mL, 0.15 mmol). The reaction mixture was heated at 65° C., stirred for 1 hour, cooled to room temperature, concentrated and azeotroped with toluene. The resultant residue was suspended in THF to which O-(2-vinyloxy-ethyl)-hydroxylamine (31 mg, 0.30 mmol), EDCI (37 mg, 0.19 mmol), HOBt (30 mg, 0.22 mmol) and DIPEA (105 μl, 0.60 mmol) were added. The reaction mixture was stirred at room temperature for 16 h then concentrated to give a residue which was purified by flash chromatography (Si-PPC, cyclohexane:EtOAc, gradient 100:0 to 0:100). The title compound was obtained as a yellow solid (58 mg, 57%). LCMS (method B): RT=3.24 min, M+H+=683.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](OCC)=[O:15])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1nc(CO)cs1
Reaction time: 24 h
Yield: 89 %

Procedure:
To a solution of ethyl 2-[(tert-butoxycarbonyl)amino]thiazole-4-carboxylate (27.3 g, 100 mmol) prepared by the method of Kim and Kahn (Synlett, 1999, 8, 1239-1240) in 500 mL of THF at 0 C was added a solution of Red-A1 in toluene (80 mL of 65 wt % solution) dropwise. The reaction mixture was stirred for 1 d and then quenched with water and 1N HCl. Extracted 2×EtOAc and the EtOAc extracts were dried over MgSO4. The solution was filtered, concentrated by rotary evaporator, and chromatographed on SiO2 using 33% hexanes in EtOAC to give 20.5 g (89%) of 2-[(tert-butoxycarbonyl)amino]-4-hydroxymethylthiazole 42a. 1H-NMR (400 MHz, CDCl3): δ 6.98 (s, 1H), 4.81 (s, 2H), 1.81 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7](=[O:15])[CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[CH3:18][N:19]([CH3:21])[CH:20]=[C:8]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:7]([C:6]1[CH:5]=[CH:4][O:3][C:2]=1[CH3:1])=[O:15]
Reactant: COC(OC)N(C)C
Reactant: Cc1occc1C(=O)Cc1ccncc1
Product: Cc1occc1C(=O)C(=CN(C)C)c1ccncc1
Temperature: 100 °C
Yield: 85.8 %

Procedure:
A mixture of 1-(2-methyl-3-furanyl)-2-(4-pyridinyl)ethanone (1.006 g, 5 mmol) in N,N-dimethylformamide dimethyl acetal (0.664 ml, 5 mmol) was heated at 100° C. for 2 hours. The mixture was cooled to room temperature and the solvent was evaporated. The residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with water and brine, dried and evaporated to give the title compound as an oil (1.1 g, 86%). LC/MS [M+H]+=257.
Reaction SMILES: [NH2:1][CH:2]1[C:13]2[CH:5]([N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH2:4][CH2:3]1.O[C@H](CC1C=CC=CC=1)C(O)=O>>[NH2:1][C@@H:2]1[C:13]2[CH:5]([N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH2:4][CH2:3]1
Reactant: NC1CCC2N=c3ccccc3=C12
Agent: O=C(O)[C@H](O)Cc1ccccc1
Product: N[C@H]1CCC2N=c3ccccc3=C21

Procedure:
In Step B, the racemic aminotetrahydrocyclopenta[b]indole of formula (3) is resolved using (R)-2-hydroxy-3-phenylpropionic acid to obtain the salt of the (S)-aminotetrahydrocyclopenta[b]indole of formula (8). The salt formation is preferably done in isopropanol, with heating for about 1 to 6 hours, followed by cooling to obtain the desired enantiomer.
Reaction SMILES: [Cu][C:2]#[N:3].C(ON=O)(C)(C)C.[Br:11][C:12]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:13]=1N.Cl>CS(C)=O>[Br:11][C:12]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:13]=1[C:2]#[N:3]
Reactant: Nc1ccc(Br)cc1Br
Reactant: N#C[Cu]
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CS(C)=O
Product: N#Cc1ccc(Br)cc1Br
Temperature: 45 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
A solution of copper(I) cyanide (2.32 g, 25.9 mmol) in anhydrous dimethylsulfoxide (50 mL) is stirred at 60° C., and to this solution is added tert-butylnitrite (7.1 mL, 59.7 mmol) all at once. A solution of 2,4-dibromoaniline (5.0 g, 19.9 mmol) in anhydrous dimethylsulfoxide (30 mL) is added dropwise, via cannula, to the mixture. After the addition is complete the reaction mixture is stirred for 1 hr, cooled to 45° C., and then treated slowly with 5N HCl (50 mL). Five minutes later, the reaction mixture is cooled to ambient temperature and extracted with 1:1 ethyl acetate:hexane (2×300 mL). The combined organic layers are washed with water (100 mL) and saturated aqueous sodium chloride (100 mL), dried, concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with hexane containing from 0–5% ethyl acetate. Fractions containing product are combined and concentrated under reduced pressure to provide the title compound (1.61 g, 31% yield).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([OH:14])=O.[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([NH:21][C:20]1[CH:22]=[CH:23][C:17]([O:16][CH3:15])=[C:18]([N:24]2[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]2)[CH:19]=1)=[O:14]
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: O=C(O)c1cccc2c(Br)cccc12
Product: COc1ccc(NC(=O)c2cccc3c(Br)cccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from 5-bromo-1-naphthoic acid (J. Chem. Soc., 1950, 991) and 4-methoxy-3-(4-methylpiperazin-1-yl)aniline (EP0533268A1) using a similar procedure to Example 1.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:10]([C:11](Cl)=[O:12])=[CH:9][N:8]=[C:7]([S:14][CH3:15])[N:6]=1)([CH3:3])[CH3:2].[CH2:16]([NH2:19])[CH:17]=[CH2:18]>O1CCCC1.C(OCC)(=O)C>[CH2:16]([NH:19][C:11]([C:10]1[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:6][C:7]([S:14][CH3:15])=[N:8][CH:9]=1)=[O:12])[CH:17]=[CH2:18]
Reactant: CSc1ncc(C(=O)Cl)c(NC(C)C)n1
Reactant: C=CCN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCNC(=O)c1cnc(SC)nc1NC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a 0° C. suspension of 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylic acid chloride in 10 mL of tetrahydrofuran is added 3.5 mL (46.2 mmol) of allylamine and 20 mL of tetrahydrofuran. The reaction suspension is allowed to warm briefly to room temperature, then stored at 0° C. overnight. The reaction mixture is diluted with ethyl acetate, washed with 1N HCl, a saturated solution of sodium bicarbonate, and brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated to give 2.1 g (51%) of the title compound:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([C:12]([O:14]C)=[O:13])=[CH:10][S:11][C:5]=2[C:4]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[N:3]1>CCO.[OH-].[Na+]>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([C:12]([OH:14])=[O:13])=[CH:10][S:11][C:5]=2[C:4]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[N:3]1
Reactant: COC(=O)c1csc2c(-c3ccncc3)nn(C)c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(-c2ccncc2)c2scc(C(=O)O)c2c1=O

Procedure:
The mixture of methyl 5-methyl-4-oxo-7-(pyridin-4-yl)thieno[2,3-d]pyridazine-3-carboxylate (1.70 g, 5.9 mmol) in EtOH (20 mL) and aq. NaOH solution (8%) was heated to reflux for 2 h. After completion of the reaction, the reaction mixture was concentrated in vacuum and the aqueous phase was washed with ether (50 mL). The aqueous layer was neutralized with aq. HCl (5%) to pH 6˜7 and filtered. The residual was recrystallized from EtOH to give the title compound as a yellow solid.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH:6]=[CH:7]1)[CH2:4][CH:3]([C:9]1[NH:17][C:16]3[C:15](=[O:18])[N:14]([CH2:19][CH2:20][CH3:21])[C:13](=[O:22])[N:12]([CH2:23][CH2:24][CH3:25])[C:11]=3[N:10]=1)[CH2:2]2>CO.[Pd]>[CH:5]12[O:8][CH:1]([CH2:7][CH2:6]1)[CH2:2][CH:3]([C:9]1[NH:17][C:16]3[C:15](=[O:18])[N:14]([CH2:19][CH2:20][CH3:21])[C:13](=[O:22])[N:12]([CH2:23][CH2:24][CH3:25])[C:11]=3[N:10]=1)[CH2:4]2
Reactant: CCCn1c(=O)c2[nH]c(C3CC4C=CC(C3)O4)nc2n(CCC)c1=O
Agent: [Pd]
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C3CC4CCC(C3)O4)nc2n(CCC)c1=O
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a solution of 8-(8-Oxa-bicyclo[3.2.1]oct-6-en-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (Example 50) (0.029 mmol, 0.010 g) in MeOH (5 ml) was added 10% Pd/C (50% H2O) and the resulting suspension stirred briskly under H2 (1 atm) for 2 h. The mixture was filtered through Celite and the cake rinsed with MeOH. Filtration and evaporation followed by purification by PLC, eluting with 1:1 EtOAc/CH2Cl2, provided the title compound (0.010 g, 100%). 1H NMR (100 MHz, CDCl3): 0.93-0.99 (m, 6H), 1.68-1.89 (m, 8H), 2.04-2.07 (m, 2H), 2.16-2.25 (m, 2H), 3.34-3.42 (m, 1H), 4.05-4.12 (m, 4H), 4.50 (br s, 2H), 8.9 (br s, 1H).
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][Zn+])[CH3:3].Br[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=1>C1COCC1.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]>[F:20][C:19]([F:21])([F:22])[O:18][C:14]1[CH:13]=[C:12]([CH2:8][CH2:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:10])[CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)Oc1cccc(Br)c1
Reactant: CCOC(=O)CCC[Zn+]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)CCCc1cccc(OC(F)(F)F)c1
Yield: 40.9 %

Procedure:
4-Ethoxy-4-oxobutylzinc bromide solution (25 mL, 0.5 M in THF, 12.5 mmol) was added to a solution of 1-bromo-3-(trifluoromethoxy)benzene (2.6 g, 10.8 mmol) in THF (10 mL) under N2. Pd(dppf)Cl2 (1.18 g, 1.62 mmol) was added, and the reaction was heated at reflux for 3 h. The solution was concentrated and purified by silica gel chromatography (0-20% EtOAc/hexanes) to give 1.22 g (41%) of the title compound as a clear oil. 1H NMR (400 MHz, DMSO-d6): δ 1.26 (3H, t, J=7.2 Hz), 1.91-2.00 (2H, m), 2.32 (2H, t, J=7.4 Hz), 2.67 (2H, t, J=7.4 Hz), 4.13 (2H, q, J=7.2 Hz), 7.03-7.07 (2H, m), 7.11 (1H, d, J=7.7 Hz), 7.30 (1H, t, J=7.7 Hz).
Reaction SMILES: C[Mg]Br.[CH2:4]1COCC1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=2)[N:13]=[C:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30][CH2:31][CH3:32])[N:11]=1.CN1C(=O)CCC1>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3].O.C(OCC)(=O)C>[CH2:31]([S:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:12]1[N:11]=[C:10]([CH3:4])[C:19]2[C:14](=[CH:15][C:16]([C:20]([F:22])([F:21])[F:23])=[CH:17][CH:18]=2)[N:13]=1)[CH3:32]
Reactant: CCSc1ccccc1-c1nc(Cl)c2ccc(C(F)(F)F)cc2n1
Reactant: C1CCOC1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: C[Mg]Br
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCSc1ccccc1-c1nc(C)c2ccc(C(F)(F)F)cc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.1 ml of methylmagnesium bromide (a 1 M THF solution) was added to a mixture of 380 mg of 4-chloro-2-(2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline, 72 mg of iron(III) acetylacetonate, 8 ml of THF and 0.8 ml of NMP, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture, and the mixture was filtered. The aqueous layer of the filtrate was extracted with ethyl acetate, combined with the organic layer of the filtrate, sequentially washed with 0.5 N hydrochloric acid, water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The mixture was concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 123 mg of 2-(2-ethylsulfanylphenyl)-4-methyl-7-trifluoromethylquinazoline (Compound of Present Invention 13).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][N:10]=[C:9]([NH:12]C(=O)C)[CH:8]=2)=[CH:3][CH:2]=1>Cl>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[NH:11][N:10]=[C:9]([NH2:12])[CH:8]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1cc(-c2ccncc2)[nH]n1
Agent: Cl
Product: Nc1cc(-c2ccncc2)[nH]n1
Yield: 117.5 %

Procedure:
N-(5-Pyridin-4-yl-1H-pyrazol-3-yl)-acetamide (4.1 g, 20.3 mmol) was heated in 6N HCl (30 mL) overnight. Solution was concentrated in vacuum to afford the title compound (3.82 g , 96% yield) as a white hydrochloride salt. 1H NMR (d6-DMSO): 8.92-8.91 (2H, d), 8.43-8.42 (2H, d), 7.38-6.81 (1H, br s). FIA MS: MH+161.2, M−159.1.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[C@H:6]([CH3:8])[NH2:7])[CH3:3].C(N(CC)CC)C.Br[CH2:18][C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:28]>C(O)C>[CH2:2]([O:4][C:5](=[O:9])[C@H:6]([CH3:8])[NH:7][CH2:18][C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:28])[CH3:3]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=[N+]([O-])c1cccc(Cl)c1CBr
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)NCc1c(Cl)cccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
18.24 g of L-alanine ethyl ester hydrochloride in 60 ml of ethanol was added dropwise to a mixture of 25 ml of triethylamine in 60 ml of ethanol and the mixture was heated to 80° C. The resulting solution was added dropwise at this temperature to a solution of 15 g of α-bromo-2-chloro-6-nitrotoluene in 60 ml of ethanol. The mixture was stirred at 80° C. overnight and then evaporated to dryness. The residue was treated with 150 ml of deionised water and extracted twice with 100 ml of methylene chloride. The methylene chloride extracts were washed with water, dried and evaporated. The resulting product was purified by chromatography on silica gel with methylene chloride/5% methanol. There were obtained 15.75 g (91% of theory) of N-(2-chloro-6-nitrobenzyl)-L-alanine ethyl ester; nD20 =1.5267.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([CH:6]=[CH:7][CH2:8]1)[CH2:4][CH:3]([NH2:10])[CH2:2]2.[H][H]>C(O)C.[C].[Pd]>[CH:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH:3]([NH2:10])[CH2:2]2
Reactant: NC1CC2C=CCC(C1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NC1CC2CCCC(C1)C2

Procedure:
To bicyclo[3.3.1]non-6-en-3-amine (100 mg, 0.729 mmol) in ethanol (3 mL), 10% palladium-carbon (10 mg) was added in a nitrogen stream, and the reaction solution was stirred in a hydrogen stream at room temperature for 1 day. After completion of the reaction, the reaction solution was filtered through celite and the filtrate was evaporated under reduced pressure. The resulting crude reaction product was used for the next step without to further purification (98.5 mg).
Reaction SMILES: O=CC([NH-])=O.[N+:6]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)([O-])=O>[NH4+].[Cl-].CCO.[Fe]>[NH2:6][C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: O=[N+]([O-])c1cc2ccccc2[nH]1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH-]C(=O)C=O
Solvent: CCO
Product: Nc1cc2ccccc2[nH]1

Procedure:
Reduction of nitro group to amine group used one of the following methods. Method A: Nitro indole 2-oxoacetyl amide and catalytic amount of palladium on carbon (Pd—C) was mixed in EtOH. The mixture was hydrogenated using Parr reactor under hydrogen pressure of 40-50 psi at room temperature for 24 hours. Then, solid was removed via filtration and filtrate was concentrated under vacuum to give crude amino indole 2-oxoacetyl amide which could be used as was or purified by silica gel chromatography. Method B: An excess of Fe (10-50 eq.) was added into the solution of nitro indole 2-oxoacetyl amide in saturated aqueous NH4Cl-EtOH (volume 1:1). The mixture was stirred at room temperature to 115° C. for 24 hours to 3 days. Solid was removed via filtration and solvents were removed under vacuum. Then, the residue was partitioned between water and EtOAc (equal volume to solvents used in reaction). The aqueous phase was extracted with EtOAc (3×e equal volume to solvents used in reaction). The combined organic phase was dried over MgSO4, filtered and concentrated under vacuum to give a crude amino indole 2-oxoacetyl amide which could be used as was or purified by silica gel chromatography.
Reaction SMILES: C(OC([O:11][C:12]1([CH2:51][CH3:52])[C:17]2[CH:18]=[C:19]3[N:27]([C:28](=[O:29])[C:16]=2[CH2:15][O:14][C:13]1=[O:50])[CH2:26][C:25]1[C:24]([CH2:30][CH2:31][Si:32]([CH3:45])([CH3:44])[CH2:33][CH2:34][CH2:35][O:36][C:37]([C:39]2[O:43][N:42]=[CH:41][CH:40]=2)=[O:38])=[C:23]2[CH:46]=[CH:47][CH:48]=[CH:49][C:22]2=[N:21][C:20]3=1)=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH2:51]([C:12]1([OH:11])[C:17]2[CH:18]=[C:19]3[N:27]([C:28](=[O:29])[C:16]=2[CH2:15][O:14][C:13]1=[O:50])[CH2:26][C:25]1[C:24]([CH2:30][CH2:31][Si:32]([CH3:45])([CH3:44])[CH2:33][CH2:34][CH2:35][O:36][C:37]([C:39]2[O:43][NH:42][CH2:41][CH:40]=2)=[O:38])=[C:23]2[CH:46]=[CH:47][CH:48]=[CH:49][C:22]2=[N:21][C:20]3=1)[CH3:52]
Reactant: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(=O)c1ccno1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(=O)C1=CCNO1

Procedure:
A mixture of Compound 63 (70 mg, 0.1 mmol), 10% palladium on carbon (20 mg, 20%) in 20 mL of ethanol was hydrogenated for 18 hours at a balloon pressure of hydrogen at 21° C. The catalyst was removed by filtration over celite and the filtrate was evaporated to give a crude product, which was chromatographed to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:28])[C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23]C)=[C:19]([CH:25]([CH3:27])[CH3:26])[CH:18]=1)[CH2:5][CH:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].B(Br)(Br)Br>ClCCl>[Cl:28][C:14]1[CH:13]=[C:4]([CH:3]=[C:2]([Cl:1])[C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH:25]([CH3:26])[CH3:27])[CH:18]=1)[CH2:5][CH:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12]
Reactant: COc1ccc(Oc2c(Cl)cc(CC3SC(=O)NC3=O)cc2Cl)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Cl)cc(CC3SC(=O)NC3=O)cc2Cl)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of the title compound from Step E (26 mg, 0.058 mmol) in dichloromethane (1 ml) at room temperature was added boron tribromide (1M in dichloromethane 0.12 ml, 0.12 mmol). A tan precipitation was immediately formed. After stirring at room temperature for about 30 minutes, the mixture was quenched with water (5 ml), and extracted with dichloromethane (3×10 ml). The combined extracts were dried, filtered, and concentrated. The residue was purified by preparative TLC (7% methanol in dichloromethane) to afford the title compound (19 mg) as a solid. MS (APCI−) Calc: 425.0, Found: 424.0 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][C:15](=[N:18][O:19][CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[CH2:14][CH2:13]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:23]1[CH2:24][CH2:25][CH:20]([O:19][N:18]=[C:15]2[CH2:16][CH2:17][N:12]([C:3]3[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:7][C:2]=3[F:1])[CH2:13][CH2:14]2)[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(ON=C2CCN(c3ccc(S(C)(=O)=O)cc3F)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(N2CCC(=NOC3CCNCC3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of 1-1 (1.88 g, 4 mmol) in 30 mL of DCM, was added TFA (3 mL, 40 mmol) and the reaction mixture was stirred at room temperature for 3 h. It was quenched with saturated NaHCO3, extracted with DCM 3 times, dried and concentrated to give 1.37 g (3.7 mmol) of 63a.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[C:11]1[S:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:20])[C:18]=2[N:19]=1>CC(O)=O.[Fe]>[Cl:1][C:2]1[C:3]([C:11]2[S:12][C:13]3[CH:14]=[N:15][CH:16]=[C:17]([F:20])[C:18]=3[N:19]=2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1-c1nc2c(F)cncc2s1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cccc(Cl)c1-c1nc2c(F)cncc2s1
Temperature: 100 °C
Yield: 92 %

Procedure:
Iron powder (7.95 g, 141 mmol) was added to a solution of 2-(2-chloro-6-nitrophenyl)-7-fluorothiazolo[5,4-c]pyridine (4.35 g, 14.1 mmol) in AcOH (130 mL). The reaction mixture was heated at 100° C. for 30 minutes and then allowed to cool to room temperature. The volatiles were removed under reduced pressure and the resultant residue was dissolved in DCM/MeOH and filtered through Celite® washing the filter pad thoroughly with further DCM/MeOH. The filtrate was concentrated under reduced pressure and the resultant residue was purified by column chromatography on silica gel eluting with 0-5% MeOH in DCM to afford the title compound as a yellow solid (3.63 g, 92% yield). 1H NMR (300 MHz, CDCl3): δ 9.03 (s, 1H), 8.52 (d, J=2.4 Hz, 1H), 7.16 (t, J=8.2 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.75 (d, J=8.3 Hz, 1H), 6.28 (br s, 2H). LCMS (Method D): RT=3.51 min, m/z: 280 [M+H+].