Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][C@H:9]([NH:12][S:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=1[O:25][CH2:26][CH2:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH:30]=[CH:31][CH:32]=[N:33]2)(=[O:15])=[O:14])[C:10]#[N:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:40]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH4+].[OH-]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[CH2:8][C@H:9]([NH:12][S:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH2:40])=[CH:18][C:17]=1[O:25][CH2:26][CH2:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH:30]=[CH:31][CH:32]=[N:33]2)(=[O:14])=[O:15])[C:10]#[N:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@@H](C#N)NS(=O)(=O)c1ccc(C(=O)O)cc1OCCc1cccc2ncccc12
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)C[C@@H](C#N)NS(=O)(=O)c1ccc(C(N)=O)cc1OCCc1cccc2ncccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
To a solution of acid 4-((S)-2-tert-butoxycarbonyl-1-cyano-ethylsulfamoyl)-3-(2-quinolin-5-yl-ethoxy)-benzoic acid (0.60 g, 1.10 mmol) in THF (20 mL) was added EDCI (0.33 g, 1.70 mmol), HOBt (0.23 g, 1.70 mmol), and N-methylmorpholine (1.70 mmol, 0.20 mL). The reaction was allowed to stirred at room temperature for 1 h then followed by addition of NH4OH (10 mL). The mixture was stirred for another 12 h. To reaction was added EtOAc (100 mL) and washed with the 5% citric acid and then saturated NaHCO3. The organic phase was dried (MgSO4), and then the solvent was removed under vacuum. The resulting crude product was purified using silica gel flash chromatography (70% EtOAc in hexanes). (S)-3-[4-Carbamoyl-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-3-cyano-propionic acid tert-butyl ester was obtained in 22% yield (0.130 g) as an off white foam. MS (APCI) m/z 525.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH3:35][NH2:36].C1COCC1>>[F:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[S:23]([NH:22][C:20]1[CH:21]=[C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:36][CH3:35])[N:7]=2)[CH:17]=[CH:18][C:19]=1[F:34])(=[O:25])=[O:24]
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cc(F)ccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nccc(-c2sc(C(C)C)nc2-c2ccc(F)c(NS(=O)(=O)c3cc(F)ccc3F)c2)n1
Yield: 83 %

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.10 g, 0.190 mmol) and methylamine in THF (1.0 mL, 2.0 mmol) the title compound was obtained (0.082 g, 0.16 mmol, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.75 (1H, s), 8.08-8.00 (m, 1H), 7.59-7.40 (m, 3H), 7.39-7.30 (m, 2H), 7.27-7.11 (m, 2H), 6.16 (br. s., 1H), 3.30-3.21 (m, 1H), 2.71 (br, 3H), 1.31 (d, J=7.0 Hz, 6H). MS (ESI): 520 [M+H]+.
Reaction SMILES: S1C2C(=NC=CC=2OC2C=CC(N)=CC=2)C=C1.F[C:19]1[CH:20]=[C:21]([NH:45][C:46]([NH:48][C:49](=[O:57])[CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[S:47])[CH:22]=[CH:23][C:24]=1[O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]2[CH:32]=[C:33](C3C=CC(S(C)(=O)=O)=CC=3)[S:34][C:27]=12>>[C:51]1([CH2:50][C:49]([NH:48][C:46](=[S:47])[NH:45][C:21]2[CH:20]=[CH:19][C:24]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]4[CH:32]=[CH:33][S:34][C:27]=34)=[CH:23][CH:22]=2)=[O:57])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1
Agent: Nc1ccc(Oc2ccnc3ccsc23)cc1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3ccsc23)cc1
Yield: 34 %

Procedure:
Staring from the amine 213, following the procedure described above for the synthesis of compound 50 (scheme 10, example 55), title compound 170c was obtained in 34% yield. 1H NMR (400 MHz, DMSO-d6 pp 12.35 (1H, s), 11.69 (1H, s), 8.47 (1H, d, J=5.28 Hz), 8.10 (1H, d, J=5.28 Hz), 7.70 (1H, s), 7.68 (1H, s), 7.54 (1H, d, J=5.28 Hz), 7.30-7.22 (7H, m), 6.61 (1H, d, J=5.28 Hz), 3.78 (2H, s). MS (m/z) 420.0 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:3][O:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6].[CH:21]1(C(OC)=O)[CH2:26]CCC[CH2:22]1>>[CH2:16]([C:2]1([CH2:3][O:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:10])([CH3:11])[CH3:12])=[O:6])[CH2:20][CH2:26][CH2:21][CH2:22][CH2:1]1)[CH2:17][CH:18]=[CH2:19]
Reactant: C=CCCC(C)(C)COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)C1CCCCC1
Product: C=CCCC1(COC(=O)N[C@H](C(=O)O)C(C)(C)C)CCCCC1

Procedure:
N-{[(1-But-3-en-1-ylcyclohexyl)methoxy]carbonyl}-3-methyl-L-valine was prepared according to the procedure for N-{[(2,2-dimethylhex-5-enyl)oxy]carbonyl}-3-methyl-L-valine by using methyl cyclohexanecarboxylate instead of ethyl isobutyrate in Step 1. LRMS (ESI) m/z 326.3 [(M+H)+; calcd for C18H32NO4: 326.2].
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)([O-:11])=[O:10]>N1C=CC=CC=1.O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:16](=[O:17])[C:15]2[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(F)cc1)c1ccc([N+](=O)[O-])cc1

Procedure:
To a stirred solution of 4-fluoro aniline (16a, 4g, 32.7 mmol) in pyridine as solvent and base to this 4-nitrobenzoyl chloride (17, 6.69 g, 36.0 mmol) is added slowly and reflux for 2h, after completion of the reaction, reaction mixture is poured in water, filter and washed with dil HCl to afford compound N-(4-fluorophenyl)-4-nitrobenzamide (18a). To a stirred solution of amide (18a, 8g, 30.7 mmol) taken in toluene lawessons reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide) (10.18 g, 25.2 mmol) is added and refluxed at 110° C. for 7h. After completion of the reaction toluene is evaporated under vacuum and water is added and extracted into chloroform finally purification by column chromatography to afford pure compound N-(4-fluorophenyl)-4-nitrobenzothioamide (19a). Treating the thioamide product (19a, 4g, 14.49 mmol) with potassium ferricyanide (4 eq) in aqueous sodium hydroxide (8 eq) solution at 90° C. for 3h cyclization takes place to obtain the 6-fluoro-2-(4-nitrophenyl)benzo[d]thiazole (20a) solid is precipitated from the reaction mixture filtered and washed with water to get 20a. Reduction of the nitro compound (20a, 1 g, 3.64 mmol) is proceeded with SnCl2.2H2O in ethanol and reflux at 80° C. for 2h. After completion of reaction ethanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered in celite bed and purified in silica column (60-120) to afforded pure compound (21a) The compound 4-(6-fluorobenzo[d]thiazol-2-yl)benzenamine (21a, 244 mg, 1 mmol) on reaction with 4-fluoro 3-methoxy benzaldehyde (22c, 152 mg, 1 mmol) in ethanol using catalytic amount of acetic acid and refluxed for 2h after completion reaction mixture is cooled to 0° C. solid is precipitated from the reaction mixture it is filtered and washed with ethanol to gave the enamine product, and immediately proceeded for the next reaction with using (p-tolylsulfonyl) methyl isocyanide (tosmic) (1.5 eq), and potassium carbonate (2 eq) as base, in 10 mL of methanol and 5 mL of DME was heated under reflux for 12 h after completion of reaction as monitored by TLC. It was cooled to room temperature (27° C.); the solution was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc and Hexane to gave compound 4c as a light yellow solid (68%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH:26]([CH3:28])[CH3:27]>CN(C)C=O>[F:18][C:2]([F:1])([F:17])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[N:7]([CH:26]([CH3:28])[CH3:27])[CH:6]=1)=[O:4]
Reactant: CC(C)I
Reactant: O=C(c1c[nH]c2cc([N+](=O)[O-])ccc12)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(C(=O)C(F)(F)F)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
A solution of 2,2,2-trifluoro-1-(6-nitro-1H-indol-3-yl)-ethanone (1.0 g, 3.87 mmol) in N,N-dimethylformamide (10 mL) at 25° C. was treated with potassium carbonate (1.34 g, 9.68 mmol). The resulting mixture was stirred at 25° C. for 10 min and then treated with 2-iodopropane (0.58 mL, 5.81 mmol). The reaction was heated at 65° C. for 3 h. At this time, the reaction was cooled to 25° C. and was partitioned between water (50 mL) and ethyl acetate (50 mL). This mixture was treated with a 1N aqueous hydrochloric acid solution (25 mL). The organic layer was washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 2,2,2-trifluoro-1-(1-isopropyl-6-nitro-1H-indol-3-yl)-ethanone (581 mg, 98%) as a yellow solid: mp 143-145° C.; EI-HRMS m/e calcd for C14H14F3NO (M+) 269.1027, found 269.1037.
Reaction SMILES: Br.[Br:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][N:7]=1)=O.Cl.[O:15]([NH2:17])[CH3:16]>CCO>[CH3:16][O:15][N:17]=[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][N:7]=1)[CH2:3][Br:2]
Reactant: CON
Reactant: CCc1ccc(C(=O)CBr)nc1
Agent: Br
Agent: Cl
Solvent: CCO
Product: CCc1ccc(C(CBr)=NOC)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 2-bromo-1-(5-ethylpyridin-2-yl)ethanone hydrobromide (1.024 g, 3.314 mmol; Supplier=Kalexsyn; Lot=1003-TTP-185) in EtOH (10 ml) was added methoxylamine hydrochloride (553.5 mg, 6.628 mmol). Left to stir at RT overnight. The reaction mixture was evaporated in vacuo. The residue was dissolved in DCM and an equal volume of saturated NaHCO3 was added and the biphasic mixture stirred for 30 minutes. The phases were separated and the aqueous phase was extracted with DCM. The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to afford a pale yellow oil which crystallized upon standing. 1H-NMR (CDCl3): δ 8.50 (s, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.59 (m, 1H), 4.79 (s, 1H), 4.64 (s, 1H), 4.13 (d, J=4.4 Hz, 3H), 2.70 (q, J=7.7 Hz, 2H), 1.28 (t, J=7.7 Hz, 3H). HPLC: 3.429 min., 30 area % and 3.621 min., 31 area % @ 210 nm; 3.414 min., 36 area % and 3.618 min., 36 area % @ 210 nm. MS (ESI—) for C10H13BrN2O m/z 258.2 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9](=[O:21])[C:10]3[CH:20]=[C:19]4[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]4)=[CH:13][C:11]=3[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]1([CH3:30])[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1.O1CCCC1>ClCCl>[CH3:30][C:22]1[CH:27]=[CH:26][C:25]([C:9]([C:10]2[C:11]([NH:12][C:7](=[O:8])[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[CH:20]=2)=[O:21])=[CH:24][CH:23]=1
Reactant: O=c1oc(-c2ccccc2)nc2cc3c(cc12)CCCC3
Reactant: Cc1ccc([Mg]Br)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cc3c(cc2NC(=O)c2ccccc2)CCCC3)cc1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
N-[3-(4-Methyl-benzoyl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-benzamide was prepared by a modification of the route described in Okabe, M. and Sun, R. C.; Tetrahedron 1995, 51(7), 1861-1866). To a 100 mL flask containing a solution 2-phenyl-6,7,8,9-tetrahydro-naphtho[2,3-d][1,3]oxazin-4-one (220 mg, 0.793 mmol) in dichloromethane (20 mL) under nitrogen and cooled to −78 C was added dropwise by syringe p-tolylmagnesium bromide solution in tetrahydrofuran (1.0 M, 0.87 mL, 0.87 mmol) and the yellow solution was allowed to warm to room temperature overnight with stirring. Reaction had not proceeded to completion and was re-cooled to −78 C and added more p-tolylmagnesium bromide solution (0.30 mL, 0.38 eq) and transferred the reaction to an acetonitrile-CO2 bath (−42 C) and stirred for 1 hour. Quenched by addition of saturated ammonium chloride solution (2 mL) and allowed to warm to ambient temperature. Diluted further with water (10 mL) and the organic fraction was removed using a hydrophobic frit, evaporated onto silica gel, and chromatographed using ISCO Companion with a Redisep silica gel 40 g cartridge and a gradient of heptane and ethyl acetate (0% to 20%). Evaporation gave N-[3-(4-methyl-benzoyl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-benzamide as a pale yellow solid 191.4 mg (65.3% Yield). LCMS (5 min acidic) 3.52 min 100% pure by ELSD and UV ES+ 370. HNMR (CDCl3) >95% pure 11.69 (s, 1H), 8.08-8.06 (m, 2H), 7.65-7.63 (m, 2H), 7.55-7.48 (m, 3H), 7.33-7.29 (m, 3H), 2.92-2.89 (m, 2H), 2.71-2.68 (m, 2H), 2.46 (s, 3H), 1.87-1.79 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([F:9])=[CH:11][CH:12]=2)[CH:3]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: Cc1ccc(O)cc1
Product: Cc1ccc(O)c(Cc2ccc(F)cc2)c1

Procedure:
Alkylation of 4-methylphenol with 4-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methyl-2-(4′-fluorobenzyl)phenol). This material was converted to compound 84 and compound 85 by the procedure similar to that in Example 18 method B.
Reaction SMILES: [C:1]([O:9][CH:10]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:30].[NH4+].[OH-]>C(O)(=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:30]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:9][C:10]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:14][CH:15]=1
Reactant: O=C(OC(C(=O)c1ccc(F)cc1)c1ccncc1)c1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CC(=O)O
Product: Fc1ccc(-c2nc(-c3ccccc3)oc2-c2ccncc2)cc1
Yield: 7.3 %

Procedure:
A solution of 2-benzoyloxy-1-(4-fluorophenyl)-2-(4-pyridyl)ethanone (0.131 g, 0.391 mmol) and ammonium acetate (0.28 g, 3.63 mmol) in glacial acetic acid (3 mL) was heated at reflux for 1.5 h. After cooling, the mixture was neutralized with conc. NH4OH and the solvent was removed in vacuo to give a yellow oil. Purification by flash chromatography (15-25% EtOAc/Hex) afforded the title compound as a white solid (9.0 mg): ESMS (m/z): 317 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:4][CH:3]=1.Cl.[CH2:38]([NH2:40])[CH3:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH:40][CH2:38][CH3:39])[CH:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCN
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3cccc(C=O)c3)ccc2-n2c(C)nnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCNCc1cccc(-c2ccc3c(c2)C(c2ccc(Cl)cc2)=N[C@@H](CC(=O)NCC)c2nnc(C)n2-3)c1
Reaction time: 0.08 h

Procedure:
(S)-2-(6-(4-Chlorophenyl)-8-(3-formylphenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (for a preparation see Intermediate 5) (75 mg) was dissolved in DCM (5 ml). Ethylamine hydrochloride (18.42 mg) and acetic acid (8.62 μl) were added and the reaction mixture was stirred for 5 min. Sodium triacetoxyborohydride (160 mg) was added and the reaction mixture was stirred at room temperature, under nitrogen, overnight. Saturated sodium hydrogen carbonate solution (5 ml) was added and the reaction mixture was stirred for 10 min. The organic phase was separated and the saturated sodium hydrogen carbonate solution was extracted with DCM (10 ml). The DCM extracts were combined, dried and the solvent was evaporated. The residue was chromatographed (0-15% methanol:DCM) and triturated with diethyl ether. The solid was dried in a vacuum dessicator at 40° C. over the weekend to give (S)-2-(6-(4-chlorophenyl)-8-(3-((ethylamino)methyl)phenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (52.4 mg) as a white solid. LCMS (formate): MH+ 527, RT 0.75 min
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[N:12]3[C:15]([CH3:18])=[CH:16][S:17][C:11]3=[N:10][C:9]=2[C@@H:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20])[CH:5]=[CH:6][CH:7]=1.O1CCOCC1.O.[OH-].[Na+]>Cl>[NH2:21][C@H:19]([C:9]1[N:10]=[C:11]2[S:17][CH:16]=[C:15]([CH3:18])[N:12]2[C:13](=[O:14])[C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:20]
Reactant: Cc1csc2nc([C@H](C)NC(=O)OC(C)(C)C)c(-c3cccc(F)c3)c(=O)n12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1csc2nc([C@H](C)N)c(-c3cccc(F)c3)c(=O)n12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 105.6 %

Procedure:
(S)-tert-Butyl 1-(6-(3-fluorophenyl)-3-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)ethylcarbamate (4.15 g, 10.3 mmol) was dissolved in a 4.0 M solution of hydrogen chloride in 1,4-dioxane (25.7 mL, 102.8 mmol) and the solution was stirred at room temperature for 45 minutes. HPLC indicated that the reaction was complete. To the solution was added water (10 mL) followed by 3 N aqueous sodium hydroxide solution at 0-5° C. to adjust the pH to 10. The aqueous mixture was extracted with ethyl acetate (2×30 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-7-(1-Aminoethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (3.30 g, 10.88 mmol, 103% yield). LCMS calculated for C15H15FN3OS (M+H)+: m/z 304.08; Found 303.9. 1H NMR (400 MHz, DMSO-d6) δ 8 7.45 (ddd, J=8.1, 7.9, 5.9 Hz, 1H), 7.19 (m, 1H), 7.12 (m, 2H) 7.04 (q, J=1.1 Hz, 1H), 3.57 (q, J=6.6 Hz, 1H), 2.64 (d, J=1.3 Hz, 3H), 1.10 (d, J=6.7 Hz, 3H)
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[C:19]([N+:20]([O-])=O)=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=1)=O.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>ClCCl.[NH4+].[O-][V](=O)=O.[Pt]>[O:2]=[C:3]1[NH:20][C:19]2[CH:18]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=[N:11][C:10]=2[N:6]2[CH2:7][CH2:8][CH2:9][C@@H:5]12
Reactant: COC(=O)c1cnc(N2CCC[C@H]2C(=O)OC)c([N+](=O)[O-])c1
Agent: O=[V](=O)[O-]
Agent: [Pt]
Agent: [NH4+]
Solvent: ClCCl
Product: COC(=O)c1cnc2c(c1)NC(=O)[C@@H]1CCCN21
Reaction time: 5 h
Yield: 8 %

Procedure:
(S)-Methyl 6-(2-(methoxycarbonyl)pyrrolidin-1-yl)-5-nitronicotinate (1.45 g, 46.9 mmol) and triphenyl phosphite (5.00 mg, 0.0161 mmol) were dissolved in dichloromethane (12 mL). Ammonium metavanadate (50 mg, 0.427 mmol) and Pt/C (5% wt., 200 mg) were added and the reaction mixture was stirred under hydrogen (80 psi) for 5 h. The reaction mixture was filtered through a small plug of celite and the precipitate was washed multiple times with hot dichloromethane until it was free from white precipitate. The filtrate was concentrated in vacuo and crystallized with ethyl ether (15 mL). The resulting solid was filtered off and dried in vacuum to afford the title compound as an off-white solid (0.930 g, 80%). [M+H] calc'd for C12H13N3O3, 248; found, 248.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH2:10][NH2:11])=[N:6][CH:7]=[CH:8][N:9]=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[CH:33](O)=[O:34]>CN(C=O)C>[Cl:3][C:4]1[C:5]([CH2:10][NH:11][CH:33]=[O:34])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: NCc1nccnc1Cl
Reactant: O=CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=CNCc1nccnc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of C-(3-chloro-pyrazin-2-yl)-methylamine bis-hydrochloride (6.0 g, 0.027 mol) in DMF (50 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (7.9 g, 0.041 mol), diisopropyl ethylamine (24.2 mL, 0.139 mol), hydrate (400.0 mg, 0.003 mol) and formic acid (1.57 mL, 0.041 mol). The reaction was left to stir at rt for 16 h under an atmosphere of nitrogen. The solvent was then removed under reduced pressure and the residue was purified by chromatography (5% DCM in hexane. 1H NMR (400 MHz, CD3OD) δ ppm 4.72 (s, 2H), 8.26 (s, 1H), 8.39 (d, J=1.77 Hz, 1H), 8.57 (d, J=2.53 Hz, 1H). MS (ES+): m/z 172.11, 174.09 [MH+]; HPLC: tR=1.57 min (OpenLynx, polar—7 min).
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[OH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH2:29][CH:30]([CH2:35][CH2:36][CH3:37])[C:31]([O:33][CH3:34])=[O:32])=[CH:23]2.O[CH2:39][CH2:40][CH2:41][NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=1.C(P(CCCC)CCCC)CCC>O1CCCC1>[N:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[NH:42][CH2:41][CH2:40][CH2:39][O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH2:29][CH:30]([CH2:35][CH2:36][CH3:37])[C:31]([O:33][CH3:34])=[O:32])=[CH:23]2
Reactant: OCCCNc1ccccn1
Reactant: CCCC(Cc1cc2cc(O)ccc2[nH]1)C(=O)OC
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCC(Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (0.12 g, 0.48 mmol) was added to the solution of methyl 2-[(5-hydroxyindolyl)methyl]pentanoate (0.03 g, 0.12 mmol), as prepared in the preceding step, 2-(3-hydroxypropyl)aminopyridine (0.026 g, 0.17 mmol), as prepared in step b of Example 1, and tri-n-butylphosphine (0.09 g, 0.46 mmol) in tetrahydrofuran (6.0 mL). After stirring at ambient temperature overnight (16 h), the reaction was concentrated and the residue was purified by flash chromatography on silica gel (10%–50% ethyl acetate in hexane) to give the title compound as a yellow oil (0.016 g, 36%). 1H-NMR (400 MHz, CDCl3) δ 8.08 (m, 1H), 7.39 (m, 1H), 7.20 (d, J=8.9 Hz, 1H), 7.07 (d, J=2.4 Hz, 1H), 7.02 (d, J=3.3 Hz, 1H), 6.88 (dd, J=8.9, 2.4 Hz, 1H), 6.53 (m, 1H), 6.40 (m, 2H), 4.32 (br s, 1H), 4.42 (m, 1H), 4.25 (m, 3H), 3.52 (m, 5H), 2.91 (m, 1H), 2.20 (m, 2H), 1.72 (m, 2H), 1.43 (m, 3H), 0.95 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[NH:5][CH:6]=[N:7]2.[CH3:16][NH2:17]>CO>[CH3:16][NH:17][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[NH:5][CH:6]=[N:7]2
Reactant: CN
Reactant: O=c1[nH]cnc2ccc([N+](=O)[O-])c(Cl)c12
Solvent: CO
Product: CNc1c([N+](=O)[O-])ccc2nc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5-Chloro-6-nitroquinazolin-4-one, from Example 3 (0.26 g, 1.15 mmol) was suspended in MeOH (3 mL) at −20° C. Methylamine gas was passed into the mixture for a few minutes, resulting in a clear solution. The solution was stirred at room temperature for 5 h and evaporated to give 5-methylamino-6-nitroquinazolin-4-one in quantitative yield. The above amine (350 mg, 1.6 mmol) was hydrogenated over platinum oxide (30 mg) in MeOH (200 mL) at 60 psi for 4 h. The mixture was filtered through diatomaceous earth and the solvent evaporated, to give 6-amino-5-methylaminoquinazolin-4-one, which was immediately suspended in EtOAc (20 mL) and THF (10 mL). A solution of 2,6-dichlorophenylisothiocyanate (340 mg, 1.67 mmol) in EtOAc (5 mL) was added, and the mixture stirred for 16 h. The reaction mixture was concentrated to half the volume, filtered, and the solid washed with EtOAc to yield the thiourea (400 mg, 64% over 2 steps.)