Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH2:13][CH2:14][C:7]3=[C:6]([CH:15]=[C:16]([N+:18]([O-])=O)[CH3:17])[C:5]=2[CH:4]=1.[C:21]([CH:24]([CH:26]([C:28]([O-:30])=[O:29])O)O)([O-:23])=[O:22].[Na+].[K+].C(O)(=O)/C=C/C(O)=O>CC(O)C>[C:28]([OH:30])(=[O:29])/[CH:26]=[CH:24]/[C:21]([OH:23])=[O:22].[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH2:13][CH2:14][C:7]3=[C:6]([CH2:15][CH:16]([NH2:18])[CH3:17])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)c(C=C(C)[N+](=O)[O-])c1n2CCC1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: O=C(O)/C=C/C(=O)O
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc2c(c1)c(CC(C)N)c1n2CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
(RS)-1-(7-Methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-propylamine fumarate was prepared from 1-(7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propene according to hthe method described in Example 1 with the following modifications: the reaction mixture was heated under reflux for 4 h, cooled to 0° C. and aqueous potassium sodium tartrate solution (50 mL) was added slowly. The mixture was stirred for 30 min, filtered through a pad of kieselguhr and the filtrate was extracted with dichloromethane (3×30 mL). The combined organic extracts were washed (water, brine), dried (sodium sulfate) and concentrated in vacuo. The concentrate was dissolved in 2-propanol (1 mL) and added to a solution of fumaric acid (0.17 g, 1.5 mmol) in 2-propanol (20 mL) at 50° C. The solution was cooled to 0° C. and filtered. The filter-cake was washed (2-propanol, ether) and dried to give the title compound as a white solid (0.22 g, 42%): mp 194-196° C.; Found: C, 63.27; H, 6.80; N, 7.69%. C19H24N2O5 requires: C, 63.32; H, 6.71; N, 7.77%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl([O-])(=O)=O.[K+].[I-:20].[K+].Cl>O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([I:20])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: [I-]
Agent: Cl
Agent: [K+]
Agent: [O-][Cl+2]([O-])[O-]
Solvent: O
Solvent: CO
Product: Nc1ccc(-c2ccc(Cl)cc2)cc1I
Temperature: 80 °C
Yield: 89208.8 %

Procedure:
To a solution of 4′-chlorobiphenyl-4-ylamine (2.03 g, 0.01 mmol) in a mixed solvent system of methanol (10 ml) and distilled water (40 ml) is added potassium chlorate (0.830 g, 6.77 mmol) and potassium iodide (3.32 g, 0.02 mol). After heating the reaction mixture to 80° C., concentrated hydrochloric acid (0.60 ml) is added, and the mixture is further heated overnight at this temperature. The solution is cooled to room temperature and the crude product is extracted with diethyl ether (×3), followed by washing of the combined organic fractions with 5% aqueous sodium thiosulfate solution and distilled water. The organic phase is dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo to give a dark solid, which is triturated with hexanes to afford 4′-chloro-3-iodobiphenyl-4-ylamine (2.94 g) as light brown solid.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:20]([CH3:29])[S:21]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)(=[O:23])=[O:22])=[N:8][CH2:7]1)C.O1CCCC1.C(O)C.[OH-].[Na+]>C(OCC)(=O)C.Cl>[CH3:29][N:20]([S:21]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)(=[O:22])=[O:23])[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11]([C:9]1[S:10][CH:6]([CH2:5][C:4]([OH:30])=[O:3])[CH2:7][N:8]=1)=[CH:19]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4nccs4)c3[nH]2)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
A mixture of ethyl(2-{7-[methyl(1,3-thiazol-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (300 mg), tetrahydrofuran (5 mL), ethanol (5 mL) and 2N aqueous sodium hydroxide solution (4 mL) was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (100 mL) and 1N hydrochloric acid (50 mL). The organic layer was dried over sodium sulfate, and filtrated, and the filtrate was concentrated. The obtained solid was washed with ethyl acetate to give the title compound (278 mg, yield 98%) as a white solid. melting point 121-123° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([C@@H:18]2[C@@H:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:22]([C@@H:31]([CH2:34][CH3:35])[CH2:32][OH:33])[C:21](=[O:36])[C@:20]([CH2:38][C:39]([OH:41])=[O:40])([CH3:37])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]([C@@H:18]2[C@@H:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:22]([C@@H:31]([CH2:34][CH3:35])[CH:32]=[O:33])[C:21](=[O:36])[C@:20]([CH2:38][C:39]([OH:41])=[O:40])([CH3:37])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: CC[C@@H](CO)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC[C@@H](C=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a −78° C. solution of oxalyl chloride (0.166 mL, 0.332 mmol) in dichloromethane (2 mL) was added dimethylsulfoxide (0.047 mL, 0.663 mmol) dropwise. After ten minutes, 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (140 mg, 0.301 mmol; Example 185) in dichloromethane (2 mL) was added dropwise. After 15 minutes, triethylamine (0.210 mL, 1.507 mmol) was added dropwise. The mixture was warmed to 0° C. for 10 minutes and then quenched with 10% aq. citric acid. The mixture was diluted with water and extracted with dichloromethane (2×). The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, and concentrated to afford the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]([CH3:13])([CH3:12])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:11])[CH2:8][CH2:9][OH:10].C(N(CC)CC)C.O.CCCCCC>CS(C)=O>[CH3:1][S:2][C:3]([CH3:12])([CH3:13])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:11])[CH2:8][CH:9]=[O:10]
Reactant: CSC(C)(C)CCCC(C)CCO
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CSC(C)(C)CCCC(C)CC=O
Reaction time: 0.08 h

Procedure:
To 2.04 g. (10 mmol.) of 7-methylthio-3,7-dimethyloctan-1-ol in 25 ml. of freshly distilled dimethylsulfoxide, under nitrogen at 20°, is added via syringe 11.2 ml. (80 mmol.) of triethylamine while stirring vigorously. Sulfur trioxide-2 pyridine complex (10.28 g., 64 mmol.) in dimethylsulfoxide (50 ml.) is added slowly to the mixture via dropping funnel under the same conditions. After addition is complete, the reaction mixture is stirred for 5 minutes and poured into cold water. Hexane is added and the organic layer separated, washed well with water and dried over calcium sulfate. Evaporation of the solvent at reduced pressure affords 7-methylthio-3,7-dimethyloctan-1-al.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1.[H-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].FC(F)(F)C(O)=O>O1CCCC1.CC#N.O>[O:13]=[C:10]1[N:9]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:8]2[CH:14]=[C:4]([O:3][C:2]([F:1])([F:15])[F:16])[CH:5]=[CH:6][C:7]=2[O:12][CH2:11]1
Reactant: CCOC(=O)CBr
Reactant: O=C1COc2ccc(OC(F)(F)F)cc2N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN1C(=O)COc2ccc(OC(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.4 %

Procedure:
A solution of 6-[(trifluoromethyl)oxy]-2H-1,4-benzoxazin-3(4H)-one (2.86 g, 12.3 mmol) dissolved in 13 mL of anhydrous tetrahydrofuran was added drop-wise to a mixture of sodium hydride (60% by weight in mineral oil, 0.54 g, 13.5 mmol) suspended in 26 mL of anhydrous tetrahydrofuran under argon. The mixture was allowed to stir at room temperature for 10 minutes and then ethyl bromoacetate (1.63 mL, 14.7 mmol) was added to the mixture and stirred vigorously for 1.5 hours before it was determined to be complete by LCMS (two Aquasil C18, 20×1 mm columns were run in sequence, 4 minutes at 0.1 mL/min, 1-99% CH3CN/H2O with 0.018% trifluoroacetic acid, ES) Rt=2.77 min and m/e 320 [M+1]+. The reaction was quenched by adding 5 mL of a 4 M solution of hydrochloric acid in dioxane. After allowing the mixture to stir for one hour, all of the volatiles were removed by rotary evaporation, and the crude residue was purified by silica gel chromatography (120 g Redisep column, silica, 40 um, 60 Å, 50 mL/min, A: methylene chloride, B: methanol, B: 0% to 35% over 30 min; detection at 214 nm) to give ethyl {3-oxo-6-[(trifluoromethyl)oxy]-2,3-dihydro-4H-1,4-benzoxazin-4-yl}acetate (2.85 g, 8.9 mmol, 73%) as an orange oil. MS (ES) m/e 320 [M+1]+.
Reaction SMILES: Cl.[Br:2][C:3]1[N:8]=[C:7]([CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:18]1(=O)[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.[OH-].[Na+].[Cl-].[Na+].O>[Br:2][C:3]1[N:8]=[C:7]([CH2:9][NH:10][C:18]2[CH2:22][CH2:21][C:20](=[O:23])[CH:19]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: NCc1cccc(Br)n1
Reactant: O=C1CCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1C=C(NCc2cccc(Br)n2)CC1
Temperature: 95 °C

Procedure:
A solution of 1-(6-bromopyridin-2-yl)methanamine hydrochloride (500 mg, 2.24 mmol) in toluene (10 ml) was charged with triethylamine (0.31 ml, 2.24 mmol). The reaction was stirred for 5 minutes after which cyclopentane-1,3-dione (330 mg, 3.36 mmol) and p-toluenesulfonic acid monohydrate (43 mg, 0.022 mmol) were added. The reaction mixture was heated to reflux at 95° C. for 45 minutes. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (15 ml), 2N sodium hydroxide (10 ml) and brine (10 ml). The layers were separated and the organic layer was then dried over sodium sulfate, filtered and concentrated to yield the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([S:11][CH2:12][C:13](=O)[CH3:14])[CH:8]=[C:7]([F:16])[CH:6]=1)[CH3:2].Cl.[Cl:19][C:20]1[CH:21]=[C:22]([NH:26]N)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:6]=[C:7]([F:16])[CH:8]=[C:9]([S:11][C:12]2[C:23]3[C:22](=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[NH:26][C:13]=2[CH3:14])[CH:10]=1)[CH3:2]
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)c1cc(F)cc(SCC(C)=O)c1
Agent: Cl
Product: CCOC(=O)c1cc(F)cc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 3-fluoro-5-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:14]([Li])CCC.CI.[Cl-].[NH4+]>CCOCC>[CH3:13][O:12][C:3]1[C:2]([CH3:14])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1
Reactant: [Li]CCCC
Reactant: COc1ncc(C(F)(F)F)cc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Product: COc1ncc(C(F)(F)F)cc1C
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of 5.12 g (0.020 mol) of 3-bromo-2-methoxy-5-(trifluoromethyl)pyridine in 60 ml of ether was cooled to -70° C. and blanketed with nitrogen. A solution containing 0.021 mole of butyl lithium (8.4 ml of 2.5 M) was added slowly with stirring keeping the temperature below about -65° C. and the mixture allowed to react for another 30 min. Methyl iodide (0.62 ml, 0.01 mol) was added to the mixture and stirring continued at -70° C. for about 30 min. The mixture was allowed to warm to about 20° C. and was then poured onto a mixture of ice and saturated aqueous ammonium chloride. The organic layer that formed was recovered. The aqueous layer was extracted with ether and the extract added to the organic layer. The combined organic materials were dried over sodium sulfate and concentrated by evaporation under reduced pressure. The residue was distilled to obtain 2.1 g (54 percent of theory) of the title compound as a colorless oil boiling at 67°-69° C. at 24 mm pressure. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([O:13][CH2:14][CH2:15][OH:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.Cl[CH:18]1[CH:23]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[NH:22][CH2:21][CH2:20][NH:19]1>>[CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([O:13][CH2:14][CH2:15][O:16][C:18]3[C:23]([N:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]4)=[N:22][CH:21]=[CH:20][N:19]=3)[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: ClC1NCCNC1N1CCNCC1
Reactant: CNc1ccc2cccc(OCCO)c2n1
Product: CNc1ccc2cccc(OCCOc3nccnc3N3CCNCC3)c2n1
Yield: 31 %

Procedure:
The title compound was prepared according to the procedure of Example 90, Step 2, starting from the product obtained in Step 2 above and 2-chloro-3-(1-piperazinyl)piperazine (from Example 90, Step 1). The crude product was purified by column chromatography (gradient: 1% NH4OH in EtOAc/MeOH (90:10) to 1% NH4OH in EtOAc/MeOH (80:20) in first purification step and gradient 0.5% NH4OH in CHCl3/MeOH (95:5) to 1% NH4OH in CHCl3/MeOH (90:10) in second purification). Yield 31%; mp 54.0-56.5° C.; MS m/z 381 (M+H)+. Anal. (C20H24N6O2.0.5 H2O) C, H, N.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9](O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].S(=O)(=O)(O)O.O.[Cr](O)(O)(=O)=O>CC(C)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: O=[Cr](=O)(O)O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C1CCCCC1
Temperature: 5 °C
Yield: 81.3 %

Procedure:
In 1 liter of acetone was dissolved 110 g (0.64 mole) of the resulting 4-ethoxycarbonylcyclohexanol, and the resulting solution was cooled to 5° C. or lower on an ice bath. To this solution was added dropwise a solution containing 69 ml of sulfuric acid, 80 g (0.8 mole) of chromic anhydride and 220 ml of water while the reaction temperature was controlled so as to be 15° C. or lower. The addition was stopped at the time when three quarters of the aforesaid chromic acid solution had been added. Then, in order to remove the surplus oxidant, 5 ml of isopropyl alcohol was added, and the resulting mixture was subjected to reaction at room temperature for 30 minutes. The supernatant was separated by decantation, after which the remaining solid was washed with two 300-ml portions of acetone, and the washings were combined with the supernatant. Next, the resulting solution was neutralized by use of a saturated aqueous solution of sodium hydrogencarbonate. The acetone solution was concentrated by means of a rotary evaporator and then distilled under reduced pressure to obtain 89 g (0.52 mole, yield: 81%) of 4-ethoxycarbonylcyclohexane having a boiling point of 95° to 97° C./2 mmHg.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[O:48][CH3:49])[CH2:42][CH2:43][NH2:44]>>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH2:42][CH2:43][NH:44][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([CH3:34])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])[CH:45]=[CH:46][C:47]=1[O:48][CH3:49]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: COc1ccc(CCN)cc1OC
Product: COc1ccc(CCNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(-c4ccccc4C)c(C)c2)C3)cc1OC

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 3,4-dimethoxyphenethylamine, m.p. 130-136° C. MS [(+)ESI, m/z]: 600 [M+H]+
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:36])[CH2:17][CH2:18][C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@@H:22]1[C:26]([O:28]CC1C=CC=CC=1)=[O:27])=[O:20])=[O:10])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:26]([C@H:22]1[CH2:23][CH2:24][CH2:25][N:21]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:36])([OH:28])=[O:27]
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)CCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@H]1CCCN1C(=O)CCC(=O)N1CCC[C@@H]1C(=O)O
Yield: 108.9 %

Procedure:
A solution of 256 mg (0.5 mmol) (R)-1-[4-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-4-oxo-butyryl]-pyrrolidine-2-carboxylic acid benzyl ester in 5 ml ethanol was stirred with 13 mg 10% Palladium on carbon under 1 atm of hydrogen for 16 h at room temperature. After filtration to remove the catalyst, concentration in vacuo afforded 170 mg (100%) of the title compound (R)-1-[4-[(R)-2-carboxy-pyrrolidin-1-yl]-4-oxo-butyryl]-pyrrolidine-2-carboxylic acid as a colorless viscous oil.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][CH2:59][C@@H:60]([OH:62])[CH3:61]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][CH2:59][C@H:60]([OH:62])[CH3:61])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H](O)CN
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC[C@@H](C)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (S)-1-aminopropan-2-ol. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, J=6.1 Hz, 3 H) 1.12-1.41 (m, 3 H) 1.55-1.87 (m, 8 H) 1.70-1.88 (m, 4 H) 3.21 (q, J=6.3 Hz, 1 H) 3.32 (s, 3 H) 3.77 (m, 1 H) 3.94 (s, 3 H) 4.16 (t, J=13.0 Hz, 2 H) 4.49 (quin., J=12.1 Hz, 1 H) 7.53 (d, J=8.6 Hz, 1 H) 7.58 (s, 1 H) 8.14 (d, J=8.3 Hz, 1 H) 8.23 (s, 1 H) 8.41-8.47 (m, 1 H) 8.51-8.57 (m, 1 H). [M+H] calc'd for C25H32F2N6O4 519; found 519.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[O:7][C:8]2[CH:17]=[C:16]([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][C:9]=2[C:10]=1[C:11]([NH2:13])=O)=[O:5].O=S(Cl)Cl>>[Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[O:7][C:8]2[CH:17]=[C:16]([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][C:9]=2[C:10]=1[C:11]#[N:13])=[O:5]
Reactant: Cc1cccc(-c2ccc3c(C(N)=O)c(C(=O)c4ccc(Cl)cc4Cl)oc3c2)c1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(-c2ccc3c(C#N)c(C(=O)c4ccc(Cl)cc4Cl)oc3c2)c1
Temperature: 80 °C
Yield: 13.2 %

Procedure:
A mixture of 2-(2,4-Dichloro-benzoyl)-6-m-tolyl-benzofuran-3-carboxylic acid amide from Example 2 step 7 (46.2 mg, 0.11 mmol) and SOCl2 (3 mL) was heated at 80° C. for 15 h. The reaction was cooled down to rt and the solvent was removed under reduced pressure. The residue was purified by pre-HPLC to afford a yellow solid (5.9 mg, 13%) as product. 1H-NMR (CDCl3): δ 7.88 (d, J=8.3 Hz, 1H), 7.79 (s, 1H), 7.73 (dd, J=1.5, 8.3 Hz, 1H), 7.54 (d, J=1.5 Hz, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.4 (dd, J=1.5, 8.3 Hz, 1H), 7.41 (m, 2H), 7.36 (t, 1H), 7.23 (d, J=8.3 Hz, 1H), 2.42 (s, 3H); LC-MS (MH+=406/408).
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:8](=[O:19])[N:7]([CH3:20])[C:6]=2[S:5][C:4]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:2][C:3]2[C:11]3[C:10](=[O:12])[N:9]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:8](=[O:19])[N:7]([CH3:20])[C:6]=3[S:5][C:4]=2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)CCn1c(=O)c2c(CBr)c(-c3ccc(Cl)cc3)sc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COC(=O)CCn1c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)sc2n(C)c1=O
Temperature: 100 °C
Yield: 40.4 %

Procedure:
To a solution of methyl 3-(5-(bromomethyl)-6-(4-chlorophenyl)-1-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (30 mg, 0.064 mmol) in toluene (2 mL) was added (4-chlorophenyl)boronic acid (9.94 mg, 0.064 mmol) and aq. Cs2CO3 solution (1 M, 0.5 mL). The reaction was degassed under nitrogen gas (3×) then Pd(PPh3)4 (3 mg) was added. The reaction was heated at 100° C. for 18 h, cooled to RT then diluted with EA (10 mL). The organic layer was washed with brine (5 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (1:1) to give methyl 3-(5-(4-chlorobenzyl)-6-(4-chlorophenyl)-1-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (13 mg, 40.6% yield) as a white solid. LCMS: MH+ 503 and TR=2.145 min.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl.Cl.[Cl:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[Cl:24]CCCN1CCNCC1.Cl.Cl.C(N(CC)CC)C>C(O)C>[ClH:14].[ClH:24].[CH2:1]([N:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][Cl:14])[CH2:19][CH2:20]1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClCCCN1CCNCC1
Reactant: BrCC=Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: ClCCCN1CCN(CC=Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 278.1 %

Procedure:
6.0 g of cinnamyl bromide were added to a mixture of 7.4 g of 1-(3-chloropropyl)piperazine dihydrochloride hemihydrate, 6.1 g of triethylamine and 100 ml of reagent ethanol. The mixture was refluxed for 4 hours and then stirred overnight. After removal of the solvent in vacuo, water was added to the residue. The product was then extracted with ether and the extract was dried (magnesium sulfate) and concentrated. The resulting oil was chromatographed on silica gel (methylene chloride/methanol: 9/1) and precipitated with ethereal hydrochloric acid to give 7.4 g (70% of theory) of 1-cinnamyl-4-(3-chloropropyl)piperazine dihydrochloride.