Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.Cl.[NH2:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20].[BH4-].[Na+]>ClC(Cl)C.CO>[CH3:23][C:18]([NH:17][CH2:14][C:11]1[CH:10]=[CH:9][N:8]=[CH:13][CH:12]=1)([CH3:24])[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=Cc1ccncc1
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Solvent: CO
Product: COC(=O)C(C)(C)NCc1ccncc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
1.04 ml of triethylamine and then 0.659 g of pyridine-4-carbaldehyde are successively added to a solution of 0.945 g of methyl α-aminoisobutyrate hydrochloride in 28 ml of dichloroethane. The reaction mixture is stirred overnight at a temperature in the region of 20° C. The mixture is purified by filtration on Merck Lichroprep aminopropyl-grafted silica. The filtrate is concentrated under reduced pressure and the residue thus obtained is taken up in 25 ml of methanol, 0.372 g of sodium borohydride is added. The reaction mixture is stirred for 48 hours at a temperature in the region of 20° C. and then poured into a mixture of a normal solution of sodium hydroxide/ice. The mixture obtained is extracted three times with ethyl acetate. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. 0.726 g of methyl 2-methyl-2-[(pyrid-4-ylmethyl)amino]propanoate is thus obtained in the form of an oil, the characteristics of which are as follows:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:11]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[CH2:12][CH2:13][CH3:14].C([O:26][C:27]([CH2:29][C:30](O)=[O:31])=O)C.C(=O)(OC)OC(C)(C)C[N+]#[C-].CC(C)([O-])C.[Na+]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:20]([C:19]4[CH:22]=[CH:23][C:16]([O:15][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:17][CH:18]=4)[C:27](=[O:26])[CH2:29][C:30]3=[O:31])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: CCOC(=O)CC(=O)O
Reactant: CCCCOc1ccc(C=O)cc1
Agent: CC(C)(C)[O-]
Agent: [C-]#[N+]CC(C)(C)OC(=O)OC
Agent: [Na+]
Product: CCCCOc1ccc(C2C(=O)CC(=O)N2c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from 1H-benzo[d]imidazol-5-amine (0.798 g, 6 mmol), 4-butoxybenzaldehyde (1.0 g, 6 mmol), 2-(ethoxycarbonyl)acetic acid (0.79 g, 6 mmol), 1-isocyano-2-methylpropan-2-yl methyl carbonate (0.943 g, 6 mmol) and sodium tert.-butoxide (0.572 g, 5 mmol) according to method 3.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH:28][C:29](=[O:38])[C@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:31])[C@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH:28][C:29](=[O:38])[C@H:30]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:31])[C@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:11][CH:10]=1
Reactant: C[C@H](C(=O)N[C@H](c1ccc(OCc2ccccc2)cc1)[C@H]1CCCN1C(=O)OC(C)(C)C)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H](C(=O)N[C@H](c1ccc(O)cc1)[C@H]1CCCN1C(=O)OC(C)(C)C)c1ccccc1
Yield: 45.4 %

Procedure:
(R)-tert-Butyl 2-((R)-(4-(benzyloxy)phenyl)((S)-2-phenylpropanamido)methyl)pyrrolidine-1-carboxylate (78 mg, 0.152 mmol) and palladium on carbon (10% wt) (36 mg, 0.034 mmol) in methanol (3.031 mL) was hydrogenated under 60 psi hydrogen gas for 4 h. The mixture was filtered through diatomaceous earth (Celite®) eluting with EtOAc and the filtrate concentrated in vacuo. Obtained (R)-tert-butyl 2-((R)-(4-hydroxyphenyl)((S)-2-phenylpropanamido)methyl)pyrrolidine-1-carboxylate (29.1 mg, 0.069 mmol, 98% yield) as a colorless oil which was carried forward without further purification. 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J=5.79 Hz, 1H), 7.25-7.31 (m, 1H), 7.13-7.23 (m, 4H), 6.91 (d, J=8.31 Hz, 2H), 6.52 (d, J=8.56 Hz, 2H), 4.45 (dd, J=10.83, 6.04 Hz, 1H), 3.99-4.14 (m, 1H), 3.27-3.57 (m, 3H), 1.72-2.07 (m, 2H), 1.59 (t, J=11.46 Hz, 2H), 1.51 (s, 9H), 1.42 (d, J=7.30 Hz, 3H); LRMS (ESI) m/e 447.20 [(M+Na)+, calcd for C25H32N2NaO4 447.23].
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Cl[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][N:14]=1>CN(C)C=O>[Cl:19][C:18]1[C:13]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: Clc1cccnc1Cl
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Oc2ncccc2Cl)c1
Temperature: 120 °C

Procedure:
7.68 g of sodium hydride dispersion (ca. 50 percent in mineral oil) was washed with pentane under nitrogen and 100 ml of N)N-dimethylformamide was then added. 21.92 g (135 mmol) of 3-(trifluoromethyl)phenol was added dropwise over 30 minutes at room temperature. The resulting phenate solution was added dropwise over 2 hours, under nitrogen, to a solution of 20.1 g (136 mmol) of 2,3-dichloropyridine in 80 ml of N,N-dimethylformamide, heated to 120° C. After 3 hours of reaction time, the mixture was cooled to room temperature, the sodium chloride which had precipitated out was filtered off and the filtrate was concentrated. The residue was extracted with toluene and 0.1 N hydrochloric acid and the organic phase was washed with saturated sodium chloride solution and concentrated. The oily residue was distilled under vacuum. The yield was 24.75 g (67 percent) of a colorless oil, content (GC): 99.7 percent. Other data concerning the product was:
Reaction SMILES: [C:1]([C:9]1[CH:25]=[CH:24][C:12]([C:13]([N:15]2[CH2:20][CH2:19][C:18]3[O:21][CH:22]=[CH:23][C:17]=3[CH2:16]2)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][NH:27][CH3:28].[CH2:29]=O>C(O)(=O)C>[CH3:26][N:27]([CH2:29][C:22]1[O:21][C:18]2[CH2:19][CH2:20][N:15]([C:13](=[O:14])[C:12]3[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:25][CH:24]=3)[CH2:16][C:17]=2[CH:23]=1)[CH3:28]
Reactant: C=O
Reactant: CNC
Reactant: O=C(c1ccccc1)c1ccc(C(=O)N2CCc3occc3C2)cc1
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(C(=O)c1ccc(C(=O)c3ccccc3)cc1)C2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.230 g (0.694 mmol) of 5-(4-benzoylbenzoyl)-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 20 ml of acetic acid, 0.094 ml (1.04 mmol) of 50% aqueous dimethylamine and 0.085 ml (1.04 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 1 hour. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform to chloroform/methanol=50/1); the resulting solid was washed with hexane to yield the desired product.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:6]2[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[N:3]=1.Cl.Cl.[NH2:28][C:29]1[C:34]([C:35]#[N:36])=[CH:33][CH:32]=[C:31]([NH:37][CH2:38][CH2:39][NH2:40])[N:30]=1.CCN(C(C)C)C(C)C>CS(C)=O>[NH2:28][C:29]1[N:30]=[C:31]([NH:37][CH2:38][CH2:39][NH:40][C:2]2[N:7]3[N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:6]3[CH:5]=[C:4]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[N:3]=2)[CH:32]=[CH:33][C:34]=1[C:35]#[N:36]
Reactant: N#Cc1ccc(NCCN)nc1N
Reactant: CCOC(=O)c1nc2cc(-c3ccc(C(F)(F)F)cc3)nc(Cl)n2n1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc2cc(-c3ccc(C(F)(F)F)cc3)nc(NCCNc3ccc(C#N)c(N)n3)n2n1

Procedure:
200 mg (0.52 mmol) of ethyl 5-chloro-7-(4-trifluoromethylphenyl)[1,2,4]triazolo[1,5-c]pyrimidine-2-carboxylate (Example 149A) and 133 mg (0.62 mmol) of 2-amino-6-[(2-aminoethyl)amino]pyridine-3-carbonitrile dihydrochloride (Example 111A) are introduced into DMSO (2 ml), 0.54 ml (3.1 mmol) of DIEA is added, and the reaction solution is irradiated in a microwave reactor at 90° C. for 30 min. The reaction mixture is purified by preparative HPLC. 98 mg (38% of theory) of the product are obtained as a solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:33])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[N:9]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:19]=2[C:28]([F:31])([F:30])[F:29])[C:8]=1[CH3:32]>C1COCC1.CO>[Cl:16][C:12]1[N:11]=[C:10]2[N:9]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:19]=3[C:28]([F:29])([F:31])[F:30])[C:8]([CH3:32])=[C:7]([CH2:6][C:5]([OH:33])=[O:4])[C:15]2=[CH:14][CH:13]=1
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2C(F)(F)F)c2nc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c2ccc(Cl)nc2n1Cc1ccc(S(C)(=O)=O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1M Aqueous NaOH (0.25 ml) is added to a stirring suspension of [6-chloro-1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester: (0.01 g, 0.021 mmol) in 1:1 THF/MeOH (0.5 ml). The resulting suspension is sonicated and allowed to stir at room temperature overnight. The solvent is removed in vacuo and the crude solid is dissolved in water (0.5 ml) and acidified to pH 2-3 using 1 N HCl. The suspension which forms is filtered, washed with water (0.5 ml) and dried under high vacuum to yield the titled compound. (MH+ 461)
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH2:6]([N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O1C[CH2:23][CH2:22][CH2:21]1>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1>[CH2:6]([N:13]1[CH2:18][CH2:17][C:16](=[CH:4][C:3]2[CH:23]=[CH:22][CH:21]=[CH:1][CH:2]=2)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [Li]CCCC
Reactant: C1CCOC1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C(=C1CCN(Cc2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a stream of argon, 49.0 g (126 mmol) of benzyltriphenylphosphonium chloride was suspended in 100 ml of anhydrous tetrahydrofurane, and thereto 86 ml of butyllithium was added dropwise under cooling with ice. After stirring the mixture at room temperature for 1 hour, thereto was added dropwise a solution of 1-benzyl-4-piperidone in anhydrous tetrahydrofurane under cooling with ice and the obtained mixture was refluxed with heating for 15 hours. The reaction solution was filtrated, and diethyl ether and water were added to the filtrate, and the organic phase was taken out. The organic phase was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the resulting oily matter was subjected to a column chromatography using 1 kg of silica gel and eluted with ethyl acetate-hexane (1:100 to 3:100) to obtain 22.6 g of 1-benzyl-4-benzylidenepiperidine.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[NH2:35][CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][C:39]1=[O:43]>>[O:43]=[C:39]1[CH2:40][CH2:41][CH2:42][N:38]1[CH2:37][CH2:36][NH:35][C:29](=[O:30])[CH:28]([N:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:34])([F:33])[F:1])=[O:6])[CH:9]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)[CH:24]=[N:25]1)[CH3:32]
Reactant: NCCN1CCCC1=O
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Product: CC(C(=O)NCCN1CCCC1=O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoro ethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and 1-(2-aminoethyl)pyrrolidin-2-one (Matrix and Cat. No. 016683). LCMS (M+H)+: m/z=584.2.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18](O)=[O:19])[CH:8]=1)=[O:5].C(N(CC)C(C)C)(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.[NH2:62][CH2:63][C:64]([CH3:67])([OH:66])[CH3:65]>CN(C=O)C.C(#N)C>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:62][CH2:63][C:64]([OH:66])([CH3:67])[CH3:65])=[O:19])[CH:8]=1)=[O:5]
Reactant: CC(C)(O)CN
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ncccc3F)c(Cl)cc2Cl)n(-c2ccccc2)n1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CNC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)c(Cl)cc2Cl)n(-c2ccccc2)n1
Temperature: 10 °C
Reaction time: 0.33 h
Yield: 66.6 %

Procedure:
5-(2,4-dichloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 107, 78 g, 166 mmol) was sonicated in DMF (300 mL) with N,N-diisopropylethylamine (58 mL, 332 mmol) to give a clear solution, which was cooled to 10° C. TPTU (74 g, 249 mmol) was added portionwise and the mixture stirred at 10° C. for 20 minutes. A solution of 1-amino-2-methylpropan-2-ol (22.1 g, 249 mmol) in DMF (50 mL) was added dropwise at 10° C. and the mixture then allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was partitioned between EtOAc (600 mL) and water (600 mL). The aqueous layer was separated and extracted with additional EtOAc (3×200 mL). The combined organic layers were washed with saturated aqueous ammonium chloride solution (300 mL), water (5×200 mL), dried (magnesium sulphate) and concentrated in vacuo to give an orange oil. The oil was treated with acetonitrile (300 mL) and the resulting solid collected by filtration, washed with acetonitrile and dried under vacuum to afford the title compound as a colourless solid (60 g, 66%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:35])[C:4]([N:6]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:8]2([CH2:13][CH2:12][N:11]([CH:14]3[CH2:20][CH:19]4[N:21](C(OC(C)(C)C)=O)[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[CH2:10][CH2:9]2)[CH2:7]1)=[O:5].O1CCOCC1.Cl>CO.CCOCC>[CH:19]12[NH:21][CH:16]([CH2:17][CH2:18]1)[CH2:15][CH:14]([N:11]1[CH2:10][CH2:9][C:8]3([C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:6]([C:4]([N:3]([CH3:35])[CH3:2])=[O:5])[CH2:7]3)[CH2:13][CH2:12]1)[CH2:20]2
Reactant: CN(C)C(=O)N1CC2(CCN(C3CC4CCC(C3)N4C(=O)OC(C)(C)C)CC2)c2ccccc21
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CO
Product: CN(C)C(=O)N1CC2(CCN(C3CC4CCC(C3)N4)CC2)c2ccccc21
Reaction time: 8 h

Procedure:
Tert-butyl 3-(1-(dimethylcarbamoyl)spiro[indoline-3,4′-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate hydrochloride 6ac (0.850 g, 1.683 mmol) was dissolved in MeOH (5 mL) followed by dioxane (40 mL) and treated with 4N HCl in dioxane (4.21 mL, 16.83 mmol). The reaction was allowed to stir overnight (complete conversion). The mixture was diluted with Et2O (150 mL) and filtered. The precipitate was washed with EtOAc (3×30 mL) and dried to provide 1′-(8-azabicyclo[3.2.1]octan-3-yl)-N,N-dimethylspiro[indoline-3,4′-piperidine]-1-carboxamide 6ad bis-hydrochloride as an off white solid (95% purity by LC/MS). This material was used for the next step without further purification. LC/MS m/z 369.0 [M+H]+ retention time 1.04 minutes (10-99% CH3CN—H2O gradient with 0.03% TFA, 5 min)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]([OH:19])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C@H:21]([C:23]([NH:25][C@H:26]([CH:39]=[O:40])[CH2:27][C:28](=[N:34][NH:35][C:36]([NH2:38])=[O:37])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:24])[CH3:22].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]([NH:20][C@H:21]([C:23]([NH:25][C@H:26]([CH:39]=[O:40])[CH2:27][C:28](=[N:34][NH:35][C:36]([NH2:38])=[O:37])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:24])[CH3:22])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc2ccccc2n1Cc1ccccc1
Reactant: C[C@H](N)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](NC(=O)c1cc2ccccc2n1Cc1ccccc1)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Yield: 56.1 %

Procedure:
1-Benzylindole-2-carboxylic acid (477 mg, 1.9 mmol) and 3(S)-(alaninyl)amino-4-oxobutanoic acid, t-butyl ester semicarbazone (581 mg, 1.9 mmol) were dissolved in methylene chloride (8 mL) and both DMAP (232 mg, 1.9 mmol) and EDAC (498 mg, 2.6 mmol) were added to the solution under a nitrogen atmosphere at 0° C. The resultant solution was stirred for 1 hour at 0° C. and an additional 2 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed successively with saturated sodium bicarbonate solution and brine, dried over sodium sulfate, and concentrated to give a yellow foam. Flash column chromatographic purification of the foam (silica gel, methanol/methylene chloride 2-5%) afforded the title product as a white powder (570 mg, 56%). TLC (methanol/methylene chloride: 1/9, silica gel): Rf=0.38; 1H-NMR (CDCl3): δ8.60 (bs, 1H), 7.67 (dd, J=8.0, 1.1, 1H), 7.50 (d, J=8.0, 1H). 7.33-7.01 (m, 8H), 6.79 (d, J=7.4, 1H), 5.78 (s, 2H), 4.87-4.83 (m, 1H), 4.67-4.62 (m, 1H), 2.73-2.43 (m, 2H), 1.46 (d, J=7.1, 3H), 1.39 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]2[C:6]2=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=[CH:14][N:5]2[C:4]2[CH:20]=[CH:21][S:22][C:3]1=2.[C-]#N.[K+].C(O)C[OH:28]>>[O:1]=[C:2]1[N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]2[C:6]2=[C:12]([C:15]([O:17][CH2:18][CH2:19][OH:28])=[O:16])[N:13]=[CH:14][N:5]2[C:4]2[CH:20]=[CH:21][S:22][C:3]1=2
Reactant: OCCO
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1sccc1-2
Agent: [C-]#N
Agent: [K+]
Product: O=C(OCCO)c1ncn2c1[C@@H]1CCCN1C(=O)c1sccc1-2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 3.12 g (10 mmol) of ethyl (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxylate, 80 mg of powdered potassium cyanide and 30 ml of ethyleneglycol is stirred at 100° C. overnight. After removal of the ethyleneglycol, the residue is purified by column chromatography. There is obtained 2-hydroxyethyl (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxylate of melting point 182°-184° C.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([N:12]3[C:16](=[O:17])[CH:15]=[CH:14][C:13]3=[O:18])[CH:10]=[CH:11][C:5]=2[N:4]=1.N[C:20]1C=CC2N=C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)N(C(OC(C)(C)C)=O)C=2C=1.C1(=O)OC(=O)CCC1>>[ClH:1].[NH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([N:12]3[C:13](=[O:18])[CH2:20][CH2:14][CH2:15][C:16]3=[O:17])[CH:10]=[CH:11][C:5]=2[N:4]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2ccc(N)cc2n1C(=O)OC(C)(C)C
Reactant: Nc1nc2ccc(N3C(=O)C=CC3=O)cc2[nH]1
Agent: Cl
Agent: O=C1CCCC(=O)O1
Product: Nc1nc2ccc(N3C(=O)CCCC3=O)cc2[nH]1
Yield: 93 %

Procedure:
Following the same procedure to synthesize 1-(2-amino-1H-benzo[d]imidazol-6-yl)-1H-pyrrole-2,5-dione hydrochloride, tert-butyl 6-amino-2-(bis(tert-butoxycarbonyl)amino)-1H-benzo[d]imidazole-1-carboxylate (0.113 g, 0.252 mmol) was reacted with glutaric anhydride (0.029 g, 0.252 mmol) to give the title compound (0.066 g, 93% yield) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.85 (s, 1H), δ 7.28 (s, 2H), δ 2.42 (m, 4H), δ 1.97 (m, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 174.1, 172.6, 135.2, 129.8, 125.9, 103.6, 35.6, 32.9, 20.9 ppm; HRMS (ESI) Calcd for C12H12N4O2 (M+) 244.0960. Found 244.0969.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].[CH3:16][N:17]([CH3:32])[C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[C:23]2[S:28](Cl)(=[O:30])=[O:29].C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:28]([C:23]3[C:24]4[C:19](=[C:18]([N:17]([CH3:32])[CH3:16])[CH:27]=[CH:26][CH:25]=4)[CH:20]=[CH:21][CH:22]=3)(=[O:30])=[O:29])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: COC(=O)c1cnc(N2CCNCC2)s1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3cccc4c(N(C)C)cccc34)CC2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.1 %

Procedure:
To a solution of compound 11 (200 mg, 0.886 mmol) in dichloromethane (7.5 mL) were added 5-dimethylamino-naphthalene-1-sulfonyl chloride (356 mg, 1.320 mmol) and triethylamine (220 mg, 2.169 mmol) under N2 atmosphere. The reaction mixture was stirred at room temperature for 4 h. Water (10 mL) followed by dichloromethane (10 mL) were added to the reaction mixture and the organic layer was separated, dried on sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 12k as a solid (233 mg, 57.50%). HPLC: 99.04% (Rt=12.33 min).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:28]([O:27][C:25]([CH:24]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)C(Br)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccsc2)SCC(N)C1=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccsc2)CN(CC(=O)OC(C)(C)C)C1=O
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a solution of 0.47 g of t-butyl α-[6-amino-5-oxo-2-(3-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (d) above] and 0.8 g of ethyl 2-bromo-4-phenylbutyrate in 7 ml of dimethylformamide was added 1.0 g of sodium carbonate. The reaction mixture was stirred at 70° C. for 18 hours and then dissolved in ethyl acetate and an aqueous solution of sodium chloride. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated off. The residue was subjected to silica gel column chromatography using a 1:20 by volume mixture of ethyl acetate and methylene chloride to give two isomers, A and B (ascribed to the asymmetric carbon atom to which the phenethyl group is attached). The first eluted isomer A was an oily compound in a yield of 0.27 g.