Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1.[OH-].[NH4+:12]>C(O)CCC>[I:8][C:6]1[CH:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH2:12])[CH:7]=1
Reactant: [NH4+]
Reactant: COc1cc(I)cc(F)n1
Agent: [OH-]
Solvent: CCCCO
Product: COc1cc(I)cc(N)n1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a solution of 2-fluoro-4-iodo-6-methoxypyridine (7.1 g, 28 mmol) in n-butanol (64 ml) was added 28% solution of ammonium hydroxide (20 ml, 140 mmol). The reaction mixture was heated to 120° C. After 16 hours LRMS indicated incomplete conversion to product. Additional 28% solution of ammonium hydroxide (20 ml, 140 mmol) was added and the reaction mixture was reheated to 120° C. After 16 h LRMS indicated incomplete conversion to product. Additional 28% solution of ammonium hydroxide (8.0 ml, 56 mmol) was added and the reaction mixture was reheated to 120° C. After 24 h the reaction mixture was cooled, partially concentrated, diluted with ethyl ether, washed with water, then dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (ethyl ether/isohexane gradient) to give 4-iodo-6-methoxypyridin-2-amine LRMS (ESI) calculated for C6H8IN2O [M+H]+, 251.0 found 250.9.
Reaction SMILES: C([O:5][C:6](=[O:24])[CH2:7][N:8]([C:15](=[O:23])[CH:16]([CH3:22])[CH2:17][S:18][C:19](=[O:21])[CH3:20])[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(C)(C)C.C[Si](I)(C)C.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:19]([S:18][CH2:17][CH:16]([CH3:22])[C:15]([N:8]([CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)[CH2:7][C:6]([OH:24])=[O:5])=[O:23])(=[O:21])[CH3:20]
Reactant: CC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C1CCCCC1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)SCC(C)C(=O)N(CC(=O)O)C1CCCCC1
Yield: 84.1 %

Procedure:
To a solution of N-(3-acetylthio-2-methylpropanoyl)-N-cyclohexylglycine t-butyl ester (36.4 g, 0.101 mol) in 300 ml of methylene chloride was added trimethylsilyl iodide (20.4 g, 0.102 mol). After stirring at room temperature for 1.75 hours 50 ml of water was added, followed in 10 min. by 500 ml of saturated sodium bicarbonate solution. An emulsion formed which was separated by centrifuging. The aqueous solution was separated, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The extracts were dried, filtered, and concentrated to yield 25.6 g (83.4%) of N-(3-acetylthio-2-methylpropanoyl)-N-cyclohexylglycine as a pale yellow oil. The compound was characterized as its DCHA salt, prepared by dissolving the acid in ether and adding DCHA to pH 8-9. The salt was isolated as a white crystalline solid, m.p. 142°-144°.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:14])[N:7](C(OCC)=O)[C:6]=1[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2].[K+].[Br-]>C(OCC)(=O)C.CCCCCC>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:14])[NH:7][C:6]=1[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2c(Cl)cccc21
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cccc(Cl)c12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 2 (Method A) from 3-acetylamino-2-benzoyl-4-chloro-1-(ethoxycarbonyl)indole (step 3). m.p.: 221-222° C. (ethyl acetate/hexane) 1H-NMR (CDCl3) δ: 9.12 (1H, br s), 7.82 (2H, d, J=7 Hz), 7.60-7.20 (6H, m), 7.12 (1H, d, J=7 Hz), 1.79 (3H, s) IR (KBr) ν: 3400, 3150, 1670, 1630, 1507, 1270, 780, 730 cm−1
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C:10]2[CH:15]=[CH:14][C:13]3[O:16][CH2:17][O:18][C:12]=3[CH:11]=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.N[C:20](N)=[O:21]>>[Cl:8][C:5]1[N:4]=[C:3]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]4[O:16][CH2:17][O:18][C:12]=4[CH:11]=3)[C:20](=[O:21])[NH:1][C:2]2=[CH:7][CH:6]=1
Reactant: Nc1ccc(Cl)nc1Nc1ccc2c(c1)OCO2
Reactant: NC(N)=O
Product: O=c1[nH]c2ccc(Cl)nc2n1-c1ccc2c(c1)OCO2
Reaction time: 0.17 h

Procedure:
A mixture of 7.9 g. of the aminopyridine product of Step B and 25 g. of urea was heated in an oil bath at 185°-190° C. The reaction was kept at this temperature for 10 minutes then cooled and extracted with water. The crude product was extracted with 75 ml. of 2.5 N sodium hydroxide. The alkaline solution was treated with charcoal and excess acetic acid then was added to precipitate the product. The precipitate was purified by crystallization from dimethylformamide-ether.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:16]([O:18]C)=[O:17])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.CO.[Li+].[OH-]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:16]([OH:18])=[O:17])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: COCCCc1cc(C(=O)OC)c2ccccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCCCc1cc(C(=O)O)c2ccccc2c1

Procedure:
Methyl 3-[3-(methyloxy)propyl]-1-naphthalenecarboxylate (1 eq.) from the previous step was taken up in a 2:1 (v/v) mixture of MeOH:THF (0.08 M). To this solution was then added LiOH (2.0 M aq. solution, 3 eq.) and the resulting cloudy solution was vigorously stirred at RT for 24 h. The volatiles were then removed in vacuo and the pH of the residue was carefully adjusted to ˜2 with 1 N aq. HCl before it was extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][CH:20]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:20][CH2:19][CH2:18][C:9]2[CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:31][CH2:30]1
Reactant: O=CCCc1cc(-c2ccccc2)n(-c2ccccc2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccccc1N1CCN(CCCc2cc(-c3ccccc3)n(-c3ccccc3)n2)CC1

Procedure:
74 mg (83%) of target compound was obtained by using a method same as in Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (55 mg, 0.199 mmol), 1-(2-fluorophenyl)piperazine (0.026 mL, 0.166 mmol), DIPEA (35 mL, 0.199 mmol) and NaBH(OAc)3 (148 mg, 0.697 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[H-].[Na+].[CH3:13][C:14]([CH3:27])([CH3:26])[C:15]([O:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16]>>[CH3:13][C:14]([CH3:27])([CH3:26])[C:15]([O:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[S:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:9])=[O:8])=[O:16]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)NOC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(OC(=O)C(C)(C)C)S(=O)(=O)c1cccnc1

Procedure:
N-[(tert-Butoxy)carbonyl]pyridine-3-sulfonamido 2,2-dimethylpropanoate (110) is synthesised from 3-pyridine sulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino 2,2-dimethylpropanoate according to Scheme 2. δH (500 MHz, CHLOROFORM-d) 9.16-9.26 (1H, m), 8.89 (1H, d, 4.4 Hz), 8.36 (1H, d, 8.2 Hz), 7.54 (1H, dd, 8.2, 4.9 Hz), 1.42 (9H, s), 1.37 (9H, s)
Reaction SMILES: [C:1]([C:9]1[O:13][C:12]2[C:14](=[O:24])[C:15]3[C:20]([C:21](=[O:22])[C:11]=2[CH:10]=1)=[CH:19][CH:18]=[C:17](Br)[CH:16]=3)(=[O:8])[C:2]1C=CC=CC=1.C(C1OC2C(=O)C3C(C(=O)C=2C=1)=CC=C([Cl:41])C=3)C>>[C:1]([C:9]1[O:13][C:12]2[C:14](=[O:24])[C:15]3[C:20]([C:21](=[O:22])[C:11]=2[CH:10]=1)=[CH:19][CH:18]=[C:17]([Cl:41])[CH:16]=3)(=[O:8])[CH3:2]
Reactant: CCc1cc2c(o1)C(=O)c1cc(Cl)ccc1C2=O
Reactant: O=C(c1ccccc1)c1cc2c(o1)C(=O)c1cc(Br)ccc1C2=O
Product: CC(=O)c1cc2c(o1)C(=O)c1cc(Cl)ccc1C2=O
Yield: 30 %

Procedure:
The 2-acetyl-7-chloro-4H,9H-naphtho [2,3-b]furan-4,9-dione 3-2 (R1=Cl, R3=CH3, R7=H) was obtained according to the procedure described in example 13 by using 2-ethyl-7-chloro-4H,9H-naphtho[2,3-b]furan-4,9-dione 1-3 (R1=C1, R4=CH3) as starting materials with yield of 30%. 1H NMR (in CDCl3) δ 2.67 (s, 3H), 7.61 (s, 1H), 7.74-7.78 (m, 1H), 8.17-8.23 (m, 2H).
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].N.P(Cl)(Cl)([Cl:22])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:22])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1c[nH]c2ccc(OC)cc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: CCCC(=O)c1cnc2ccc(OC)cc2c1Cl
Yield: 62 %

Procedure:
3-Butyryl-6-methoxy-4(1H)-quinolone (20 g) was heated under reflux in phosphorus oxychloride for 1 hour. The mixture was cooled, poured onto ice and carefully neutralized with ammonia solution. The mixture was extracted with dichloromethane and the combined extracts washed with sodium hydrogen carbonate solution (×2) and brine. The organic solution was dried, filtered and evaporated to give 3-butyryl-4-chloro-6-methoxy-quinoline (13.3 g, 62%) as an oil which crystallized from ether/petrol; m.p. 73°-75°.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C([Mg]Cl)(C)C.[CH:21]([C:23]1[CH:35]=[CH:34][C:26]([C:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1)=[O:22]>O1CCCC1>[Si:6]([O:5][C:4]1[CH:3]=[C:2]([CH:21]([OH:22])[C:23]2[CH:24]=[CH:25][C:26]([C:27]([N:29]([CH2:30][CH3:31])[CH2:32][CH3:33])=[O:28])=[CH:34][CH:35]=2)[CH:15]=[CH:14][CH:13]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CCN(CC)C(=O)c1ccc(C=O)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(I)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(C(O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Iodophenoxy-tert-butyldimethylsilane (48.85 g, 146 mmol) was placed in a 250 mL flask with 180 mL of dry tetrahydrofuran at room temperature under nitrogen, Isopropylmagnesium chloride (73 mL, 146 mmol, 2.0 M solution in tetrahydrofuran) was added through an addition funnel to form a light yellow solution. The reaction was stirred at room temperature for 1 hour. In the meantime, 30 g of 4-formyl-N,N-diethylbenzamide was dissolved in 300 mL of dry tetrahydrofuran in another 1000 mL flask and cooled to −72° C. under nitrogen. The freshly prepared 3-phenoxy-tert-butyl-dimethylsilane magnesium chloride was slowly added into the 1000 mL flask. The transfer rate was monitored to maintain reaction temperature below −70° C. The reaction was allowed to warm to room temperature while stirring overnight. The mixture was quenched with 24 mL of saturated aqueous ammonium chloride, diluted with 600 mL of diethyl ether, and washed with 600 mL of water followed by 150 mL of saturated sodium chloride. The ethereal solution was dried over sodium sulfate and the solvent was removed to give crude 4-{[3-(tert-butyl-dimethylsilanyloxy)phenyl]hydroxymethyl}-N,N-diethylbenzamide as a yellow oil. Crude yield was˜100%. The crude product was slurried in a solution of 20% ethyl acetate in pentane. The resulting white precipitate was collected by filtration, washed with pentane, and dried overnight (30 mmHg, 40° C.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[N:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[CH2:20][CH2:21]Br>>[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[CH2:20][CH2:21][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[N:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:6]1
Reactant: Clc1ccc2c(n1)N(C1CCNCC1)CC2
Reactant: Fc1ccc(CCBr)c(F)c1
Product: Fc1ccc(CCN2CCC(N3CCc4ccc(Cl)nc43)CC2)c(F)c1
Yield: 7.8 %

Procedure:
1-(Piperidin-4-yl)-6-chloro-7-azaindoline (0.5 g) and 2,4-difluorophenethyl bromide (0.43 g) were treated as in Example 2 to give the hydrochloride (74 mg) of the title compound as a brown powder (yield: 7.8%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH:13]1[O:18][CH2:17][CH2:16]C[O:14]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C(#N)C>[O:18]1[CH2:17][CH2:16][O:14][CH:13]1[CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCCC1OCCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1ccc(OCCC2OCCO2)cc1
Yield: 104.5 %

Procedure:
In a 500 ml flask, 120 ml of acetonitrile, 13.8 g of 4-hydroxybenzaldehyde, 19.9 g of 2-(2-bromoethyl)-1,3-dioxane, 1.8 g of potassium iodide, and 35.8 g of potassium carbonate were placed and then, reacted at 80° C. for 5 hr. Thereafter, to the reaction mixture was added 200 ml of ethyl acetate and washed once with a saturated aqueous potassium carbonate solution, distilled water and saturated saline. The washed organic phase was dried over anhydrous magnesium sulfate and the solvent was removed, to give 23.7 g of 4-(2-[1,3]-dioxolan-2-yl-ethoxy)benzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:14](=[O:25])[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][N:38]=1)=[O:35].O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:33][C:34](=[O:35])[NH:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][N:38]=1)[N:9]=[C:8]2[C:14](=[O:25])[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:17]1)=[O:4]
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: COC(=O)c1ccc2[nH]nc(C(=O)NC3CCN(C(C)C)CC3)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)c(C(=O)NC1CCN(C(C)C)CC1)nn2CC(=O)Nc1ccc(Cl)cn1
Reaction time: 48 h

Procedure:
To a solution of 4 g 3-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1H-indazole-5-carboxylic acid methyl ester in 35 mL DMF, 3.8 g Cs2CO3 and 2.9 g 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide were added at RT and the reaction mixture was stirred for 2 d. After addition of 50 mL water the mixture was extracted with ethyl acetate (3×150 mL), the combined organic layers were dried over MgSO4 and filtered. The solvents were removed under reduced pressure and the residue was recrystallized from diisopropylether. Yield: 3.8 g MS (ES+): m/e=513, chloro pattern.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH2:31][C:32]([N:34]([CH3:42])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)=[O:33])[CH3:30]>>[CH3:30][N:29]([CH2:31][C:32]([N:34]([C:35]1[CH:36]=[CH:37][C:38]([NH:41]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:39][CH:40]=1)[CH3:42])=[O:33])[CH3:28]
Reactant: CN(C)CC(=O)N(C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(N(C)C(=O)CN(C)C)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenylenediamine
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[CH2:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17].CCN(C(C)C)C(C)C>ClCCl>[CH2:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[C:12]([F:15])([F:14])[F:13])[CH2:20][CH2:19]1)[CH3:17]
Reactant: CCN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CBr)c(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN1CCN(Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
1-(Bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (34 g, 120 mmol) obtained in Step (1) above was stirred in a solvent of dichloromethane (300 mL). The reaction solution was added with 1-ethylpiperazine (15.97 mL, 126 mmol) and DIPEA (27.2 mL, 156 mmol), followed by stirring for about 3 hours at room temperature. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (21.7 g, 57%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([OH:18])=O)=[N:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[CH:6][N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:52]([O:55][CH:56]1[C:60]2=[N:61][CH:62]=[C:63]([NH2:79])[C:64]([N:65]3[CH2:70][CH2:69][CH2:68][C@H:67]([NH:71][C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[CH2:66]3)=[C:59]2[CH2:58][CH2:57]1)(=[O:54])[CH3:53]>ClCCCl>[C:52]([O:55][CH:56]1[C:60]2=[N:61][CH:62]=[C:63]([NH:79][C:16]([C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]4[C:9]([F:15])=[CH:10][CH:11]=[CH:12][C:13]=4[F:14])[N:4]=3)=[O:18])[C:64]([N:65]3[CH2:70][CH2:69][CH2:68][C@H:67]([NH:71][C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[CH2:66]3)=[C:59]2[CH2:58][CH2:57]1)(=[O:54])[CH3:53]
Reactant: Nc1ncc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1nc(-c3c(F)cccc3F)cnc1N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.2 %

Procedure:
To a pre-stirred solution of 3-amino-6-(2,6-difluorophenyl)pyrazine-2-carboxylic acid (18 mg, 0.070 mmol), HATU (32 mg, 0.084 mmol), and DIPEA (36 μL, 0.21 mmol) in 1,2-dichloroethane (0.3 mL) was added a solution of 3-amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (38 mg, 0.097 mmol) in 1,2-dichloroethane (0.5 mL). The resulting solution was stirred at ambient temperature for 3 h. The crude reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (20 g silica gel column, eluting with 0-10% MeOH in DCM) to afford the sub-title compound (18 mg, 41%). LC/MS (ESI) calc. for C31H36F2N2O5(M+H)+: m/z=624.3. found: 624.1.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][C:6](=O)[C:5]=12.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17]>N1C=CC=CC=1>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][C:6](=[S:17])[C:5]=12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1Nc2ccccc2Cn2cccc21
Solvent: c1ccncc1
Product: S=C1Nc2ccccc2Cn2cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6.0 g. of 5,10-dihydro-11H-pyrrolo[2,1-c]-[1,4]benzodiazepin-11-one (Example 1), 2.64 g. of phosphorus pentasulfide and 50 ml. of pyridine is stirred and heated at the reflux temperature for 4 hours, and concentrated to remove the pyridine. The residue is treated with 75 ml. of 5% aqueous sodium bicarbonate solution and 5 ml. of methanol and stirred at room temperature overnight. The product crystallizes gradually and is collected, washed with water and dried. This crude product is dissolved in chloroform, passed through a bed of Magnesol® silica gel, and the solvent evaporated to give yellow crystals of 5,10-dihydro-11H-pyrrolo[2,1-c][1,4]benzodiazepin-11-thione, m.p. 228°-231°.
Reaction SMILES: [CH3:1][S-:2].[Na+].[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1>C1COCC1>[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][S:2][CH3:1])=[CH:7][CH:6]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSCc1ccc(Br)cc1
Temperature: 60 °C

Procedure:
Sodium thiomethoxide (1.0 g, 14.3 mmol) and 4-bromobenzyl bromide (2.65 g, 10.6 mmol) were combined with anhyd THF (50 mL) and the reaction mixture was stirred at 60° C. After 3 h the reaction mixture was concentrated in vacuo and the residue was washed into a separatory funnel with EtOAc and water. The organic layer was separated, dried (anhyd MgSO4), and concentrated in vacuo to yield 1-bromo-4-methylthiomethyl-benzene. To a solution of this crude thioether in DCM (100 mL) was added 3-chloroperoxybenzoic acid (77%, 4.0 g) portionwise. After stirring overnight the reaction mixture was poured into a separatory funnel, washed with 1N NaOH, dried (Na2SO4), and concentrated in vacuo. The residue was crystallized from EtOAc-Hex to afford 1-bromo-4-methanesulfonylmethyl-benzene (2.02 g, 76%) as light tan needles:
Reaction SMILES: [F:1][C:2]([F:12])([C:8]([F:11])([F:10])[F:9])[C:3](=O)[CH2:4][C:5]#[N:6].[C:13]1([CH3:21])[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.ClCCl>C(O)C>[F:1][C:2]([F:12])([C:3]1[CH:4]=[C:5]([NH2:6])[N:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:21])=[CH:14][CH:15]=2)[N:20]=1)[C:8]([F:9])([F:11])[F:10]
Reactant: Cc1ccc(NN)cc1
Reactant: N#CCC(=O)C(F)(F)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(F)(F)C(F)(F)F)cc2N)cc1
Temperature: 25 °C
Yield: 52 %

Procedure:
Heat a mixture of 4,4,5,5,5-pentafluoro-3-oxo-pentanenitrile (4.0 g, 21.4 mmol) and p-tolyl-hydrazine (10 g, 64.1 mmol) in ethanol (20 mL) to 95° C. in a sealed tube apparatus for 15 hours. After cooling to room temperature, remove the solvent under reduced pressure to give a yellow solid. Distribute the solid between dichloromethane (250 mL), distilled water (150 mL) and a saturated aq. sodium bicarbonate solution (50 mL). Isolate the aqueous phase and extract with dichloromethane (100 mL). Dry the combined organic phases over sodium sulfate and concentrate to give a dark gold oil. Subject oil to silica gel chromatography eluting with ethyl acetate and hexanes to give a light brown solid (3.24 g, 52% yield). MS(ES+): m/z=292.1 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[C:7]([CH:11]=1)[C:8](O)=[O:9].O.[NH2:25][NH2:26]>>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6]([C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:25][NH:26][C:8]2=[O:9])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccc(C(F)(F)F)cc2)c(C(=O)O)c1
Reactant: NN
Solvent: O
Product: COc1ccc2c(-c3ccc(C(F)(F)F)cc3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 5-methoxy-2-(4-trifluoromethylbenzoyl)benzoic acid unpurified with hydrazine hydrate.
Reaction SMILES: [OH:1]O.[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1>C(O)(=O)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N+:9]([O-:1])[CH:10]=1
Reactant: OO
Reactant: COc1ccc(C)nc1
Solvent: CC(=O)O
Product: COc1ccc(C)[n+]([O-])c1
Reaction time: 3 h
Yield: 77 %

Procedure:
120 g of 30% strength hydrogen peroxide solution are added dropwise to a solution of 60.9 g of 5-methoxy-2-methylpyridine in 300 ml of glacial acetic acid at 60° C. in the course of 1 hour and the mixture is subsequently stirred for 3 hours. After destruction of excess per-compounds by addition of active manganese dioxide, the mixture is filtered, the filtrate is concentrated, the residue is clarified hot in 500 ml of ethyl acetate, the mixture is concentrated again and the residue is distilled under 0.3 mbar. 54 g (77% of theory) of 5-methoxy-2-methylpyridine 1-oxide are obtained as a rapidly solidifying oil (b.p. 130° C.); m.p. 80°-84° C.