Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:13][C:12]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[CH:22]=[C:21]([CH3:32])[N:20]=3)[CH:18]=2)=[N:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[CH:22]=[C:21]([CH3:32])[N:20]=[C:19]([N:17]3[CH:18]=[C:14]([C:12]4[S:13][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:10][N:11]=4)[N:15]=[CH:16]3)[N:24]=2)=[CH:26][CH:27]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3ncc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3ncc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 18.1 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-2-{1-[4-(4-chloro-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.1 g) in dichloromethane (2 mL) was added TFA (2 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane) to yielded the title compound as a light brown solid (0.016 g, 5%). MS (ISP) 433.2 [(M+H)+]; mp 255.5° C.
Reaction SMILES: [CH2:1]([P:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)[O:4]CC)[CH3:2].C(Cl)(=O)C([Cl:17])=O>C1C=CC=CC=1>[CH2:1]([P:3]([Cl:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4])[CH3:2]
Reactant: CCOP(=O)(CC)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: CCP(=O)(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl ethylphenylphosphinate (2 g, 10 mmol) in benzene (200 mL) is added oxalyl chloride (1.3 mL, 15 mmol). The mixture is stirred for 3 hours at room temperature. The volatiles are removed on a rotary evaporater and the product is dried under vacuum for 12 hours to give ethylphenylphosphinic chloride as an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[N:27][NH:28]3)=[CH:24][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[S:31]([NH2:41])(=[O:40])([C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)=[O:32].C[Si](Cl)(C)C>C(O)CCC>[NH:28]1[C:29]2[C:25](=[CH:24][CH:23]=[C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([NH:39][C:36]4[CH:37]=[CH:38][C:33]([S:31]([NH2:41])(=[O:32])=[O:40])=[CH:34][CH:35]=4)[N:3]=3)[CH:30]=2)[CH:26]=[N:27]1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cn[nH]c5c4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cn[nH]c5c4)nc(Nc4ccc(S(N)(=O)=O)cc4)nc32)cc1
Temperature: 116 °C
Yield: 56.3 %

Procedure:
A mixture of 2-chloro-N-(1H-indazol-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (150 mg, 0.34 mmol), sulfanilamide (125 mg, 0.73 mmol) and trimethylsilyl chloride (TMSCl) (0.100 mL, 0.79 mmol) inn-butyl alcohol (4 mL) was heated at 116° C. for 96 h. The mixture was then purified by HPLC to give 4-(4-(1H-indazol-6-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzenesulfonamide (110 mg).
Reaction SMILES: C([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])C.[F:16][C:17]([F:21])([F:20])[CH2:18]I>C1COCC1>[CH2:12]([O:11][C:9]([C:7]1([CH2:18][C:17]([F:21])([F:20])[F:16])[CH2:8][CH2:3][N:4]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:5][CH2:6]1)=[O:10])[CH3:13]
Reactant: CCC1CCCCN1C(=O)OC(C)(C)C
Reactant: FC(F)(F)CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC(F)(F)F)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Under a argon atmosphere a vacuum dried 750 mL four necked flask (with mechanical stirrer) was charged with 6.6 mL diisopropylamine and 100 mL THF. The solution was cooled to −5° C./−10° C. 29.1 mL of 1.6M n-butyllithium in hexane was added over a period of 20 min. The light yellow solution was stirred for 30 min at −5°/−10° C. and afterwards cooled to −75° C. A solution of 10 g (38.8 mmol) ethyl 1-tert-butoxycarbonylpiperidine in 75 mL THF was added over a period of 50 min. The yellow solution was stirred at −75° C. for 2 h. A solution of 9.8 g (46.7 mmol) 2,2,2-trifluoroethyl iodide in 25 mL THF was added dropwise over a period of 45 min. The reaction was stirred for 1 h at −75° C. and allowed to warm up over night to ambient temperature. The reaction was cooled down to 0° C., quenched with 250 mL 10% citric acid aq. solution The aqueous layer was separated and extracted twice with 200 mL ethyl acetate. The organic layers were washed once with 200 mL brine, dried over Na2SO4, filtered and evaporated.
Reaction SMILES: Cl[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[C:12]([Cl:14])=[CH:13][C:4]=2[N:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:14][C:12]1[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:5]2[N:6]([CH:7]([CH3:9])[CH3:8])[C:2]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[N:3][C:4]=2[CH:13]=1
Reactant: CN1CCNCC1
Reactant: CC(C)n1c(Cl)nc2cc(Cl)c([N+](=O)[O-])cc21
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)n1c(N2CCN(C)CC2)nc2cc(Cl)c([N+](=O)[O-])cc21
Yield: 84.7 %

Procedure:
2,5-Dichloro-1-isopropyl-6-nitrobenzimidazole (4.6 g) was suspended in toluene (31 ml) and to the suspension was added dropwise N-methylpiperazine (8.4 g) and then the mixture was refluxed for 30 minutes. To the reaction solution was added ethyl acetate and the mixture was washed with water and then extracted with 2N hydrochloric acid. The water layer was separated and made basic with an aqueous sodium hydroxide solution and then extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure to give 5-chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)-6-nitrobenzimidazole (4.8 g). A part of the obtained product was recrystallized from acetonitrile, which showed the physical properties consistent with those in Preparation 8.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH3:31])([CH3:30])[CH2:5][S:6][CH2:7][C:8]1[C:13]([CH3:14])=[C:12]([O:15][CH3:16])[CH:11]=[CH:10][N+:9]=1[C:17]1[NH:18][C:19]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:20]=2[N:21]=1)[CH3:2].[CH3:32][S:33]([OH:36])(=[O:35])=[O:34]>CO>[CH3:32][S:33]([O-:36])(=[O:35])=[O:34].[CH2:1]([O:3][C:4]([CH3:30])([CH3:31])[CH2:5][S:6][CH2:7][C:8]1[C:13]([CH3:14])=[C:12]([O:15][CH3:16])[CH:11]=[CH:10][N+:9]=1[C:17]1[NH:18][C:19]2[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[CH:23]=[CH:22][C:20]=2[N:21]=1)[CH3:2]
Reactant: CS(=O)(=O)O
Agent: CCOC(C)(C)CSCc1c(C)c(OC)cc[n+]1-c1nc2ccc(C(F)(F)F)cc2[nH]1
Solvent: CO
Product: CS(=O)(=O)[O-]

Procedure:
450 mg of intramolecularly deprotonized 2-[((2-ethoxy-2-methylpropyl)thio]methyl]-4-methoxy-3-methyl-1-[5-(trifluoromethyl)-2-benzimidazolyl]pyridinium cation were dissolved in methanol and treated with 110 mg of methanesulfonic acid. The solution was concentrated several times while adding n-hexane each time. The residue was crystallized from tert. butyl methyl ether. The 2-[[(2-ethoxy-2-methylpropyl)thio]methyl]-4-methoxy-3-methyl-1-[5-(trifluoromethyl)-2-benzimidazolyl]pyridinium methanesulfonate obtained exhibited a melting point of 49°-54°.
Reaction SMILES: [C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:19][C:20]1[CH:32]=[CH:31][C:23]2[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=2[CH:21]=1>>[C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:19][C:20]2[CH:32]=[CH:31][C:23]3[O:24][C:25]([CH3:29])([CH3:30])[O:26][C:27](=[O:28])[C:22]=3[CH:21]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC1(C)OC(=O)c2cc(N)ccc2O1
Reactant: CCCCCCCCC#Cc1ccc(C=O)cc1
Product: CCCCCCCCC#Cc1ccc(CNc2ccc3c(c2)C(=O)OC(C)(C)O3)cc1

Procedure:
The title compound was prepared following the procedure A using 4-dec-1-ynylbenzaldehyde and 6-amino-2,2-dimethyl-4H-1,3-benzodioxin-4-one (purification by flash chromatography on SiO2, EtOAc/c-Hex 10/90 up to 40/60 in 45 min.) as a colorless oil (55%). HPLC, Rt: 5.9 min (purity: 99.4%). 1H NMR (CDCl3) δ 7.29 (d, J=8.3 Hz, 2H), 7.19 (d, J=8.3 Hz, 2H), 7.09 (d, J=2.6 Hz, 1H), 6.79-6.67 (m, 2H), 4.21 (s, 2H), 4.18 (brs, 1H), 2.31 (t, J=7.2 Hz, 2H), 1.62 (s, 6H), 1.57-1.45 (m, 2H), 1.43-1.31 (m, 3H), 1.30-1.12 (m, 7H), 0.80 (t, J=7.2 Hz, 3H)
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27]Cl)=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1.C(OCC)(=O)C>O1CCCC1.CCO.CCCCCC>[CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27][N:45]2[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Nc2c(NC(=O)CCl)ccc3c2C(=O)c2ccccc2C3=O)cc1
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(C(=O)Nc2c(NC(=O)CN3CCN(C)CC3)ccc3c2C(=O)c2ccccc2C3=O)cc1
Reaction time: 0.12 h
Yield: 55 %

Procedure:
Compound CC-12 (0.86 g, 2 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and to the solution was added successively with DIPEA (1 ml, 6 mmole) and N-methylpiperazine (0.88 ml, 8 mmole) under stirring for 5 to 10 minutes. This mixture was heated under reflux for 16 hours. After the completion of the reaction, the mixture was filtered, and the filtrate was concentrated by reduced pressure concentrator (such as Vacuum Evaporator). The residue was extracted with ethyl acetate for several times. The extract was dried on magnesium sulfate, and concentrated under reduced pressure. The crude product was washed with ethyl acetate/hexane. Finally, the crude product was recrystallized in hot ethanol to obtain a kelly green compound CC-43. Mol. Wt.: 496.5570 (C29H28N4O4); Rf: 0.28 (ethyl acetate:n-hexane=1:2); Yield: 55%; Mp.: 214-215° C. (EtOH); HRMS (EI) m/z: calcd [M]+, 496.2111 (C29H28N4O4+); found, 496.2115; 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 1.76 (s, 3H, —CH3), 1.96 (br, 4H, —CH2—), 2.38 (br, 4H, —CH2—), 2.43 (s, 3H, —CH3), 3.13 (s, 2H, —CH2N—), 7.45 (d, J=7.8 Hz, 2H, Ar—H), 7.87-7.93 (m, 2H, Ar—H), 8.08-8.16 (m, 4H, Ar—H), 8.27 (d, J=9.0 Hz, 1H, Ar—H), 8.81 (d, J=8.7 Hz, 1H, Ar—H), 10.01 (s, 1H, Ar—NH—), 10.50 (s, 1H, Ar—NH—); 13C-NMR (75 MHz, DMSO-d6) δ (ppm): 20.89, 26.48, 53.13, 54.62, 61.92, 65.54, 127.72, 126.30, 126.40, 126.92, 127.69, 127.92, 127.98, 129.22, 129.43, 130.53, 132.30, 134.12, 134.41, 134.45, 140.21, 142.61, 166.27 (NCO), 168.89, 169.15 (NCO), 181.42 (CO), 183.84 (CO).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([N+:21]([O-])=O)[CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([NH2:21])[CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(O)c([N+](=O)[O-])c1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(O)c(N)c1)NC(=O)OC(C)(C)C
Yield: 82.2 %

Procedure:
A mixture of N-(tert-butoxycarbonyl)-3-nitro-L-tyrosine methyl ester (2.0 g) and 10% Pd-C (1.0 g) in MeOH (10 ml) was subjected to catalytic hydrogenolysis at atmospheric pressure. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was triturated with ether to give 3-amino-N-(tert-butoxycarbonyl)-L-tyrosine methyl ester (1.5 g) as a solid. To a solution of the obtained compound (1.0 g) in CH2Cl2 (10 ml) was added 2,6-dichlorobenzoyl chloride (0.74 g) and DIEA (1.1 g) and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluent; 2:1, Hexane/AcOEt) to give N-(tert-butoxycarbonyl)-3-(2,6-dichlorobenzamido)-L-tyrosine methyl ester (1.2 g). The obtained compound was treated in a similar manner as described in R. Example 4 to give 3-[(2,6-Dichlorobenzoyl)amino]-L-tyrosine methyl ester, hydrochloride salt.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]2[C:14](=[C:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.F[C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1>O>[N+:37]([C:34]1[CH:35]=[CH:36][C:31]([N:10]2[CH2:11][CH2:12][CH2:13][C:14](=[C:15]([CH3:17])[CH3:16])[CH:9]2[CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:19][CH:18]=2)=[CH:32][CH:33]=1)([O-:39])=[O:38]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1ccc(CC2NCCCC2=C(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CC2C(=C(C)C)CCCN2c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A mixture of 1.0 g. of 2-(p-methoxybenzyl)-3-isopropylidenepiperidine hydrochloride, 1.1 g. of powdered potassium carbonate, 10 ml. of dimethyl sulfoxide, and 0.4 ml. of p-fluoronitrobenzene was stirred and heated on a steam bath for 1 hour. The reaction mixture was then poured into water and the water was decanted from the precipitated gum. The gum was washed with several portions of water and then taken up in diethyl ether, and the ether was washed with several portions of water. The ether was dried and filtered, and the filtrate was evaporated to dryness under reduced pressure to yield 1-(p-nitrophenyl)-2-(p-methoxybenzyl)-3-isopropylidenepiperidine as a residue. Neither the residue nor its hydrochloride could be induced to crystallize, although only one component could be observed on thin layer chromatographic analysis using several developing systems on both silica gel and alumina. The nuclear magnetic resonance spectrum (CDCl3) of the crude residue showed: 439 (A2B2), 410, (A2B2), 295 (t,1,J=7 cps), 222 (a,3), 172 (d,2, J=7 cps), 95, (s,3), 76 (d,3,J=1-2 cps). The ultraviolet spectrum (95% ethanol) showed: 272s (ε4100), 286s (ε3500), 400 m (ε16300); lit, p-methylanisole 277 (ε2100), 284 (ε1800); N,N-dimethyl-p-nitroaniline 395 (ε20000).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:10]([C:11]([F:14])([F:13])[F:12])[CH2:9][N:8]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:7]1)=O)C.O1CCCC1.[OH-].[Na+]>S([O-])([O-])(=O)=O.[Na+].[Na+].CCCCCC.C(OCC)(=O)C>[CH2:15]([N:8]1[CH2:9][C@@H:10]([C:11]([F:14])([F:12])[F:13])[C@H:6]([CH2:4][OH:3])[CH2:7]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C(F)(F)F
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: OC[C@@H]1CN(Cc2ccccc2)C[C@H]1C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 91.4 %

Procedure:
A mixed solution of 2.86 g (9.50 mmol) of trans-1-benzyl-4-trifluoromethylpyrrolidine-3-carboxylic acid ethyl ester and 15 ml of absolute tetrahydrofuran is added dropwise to the above suspension over 40 minutes on cooling with ice. After stirring at 0° C. for 1.5 hours, the excess reagent is decomposed by adding several drops of sodium sulfate (decahydrate) and 2N sodium hydroxide. Insoluble matter is removed by filtration under reduced pressure. The filtrate is concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (elusion solvent; n-hexane/ethyl acetate (5/1→5/2 (by volume, hereinafter the same))) to give 2.25 g of the objective substance as a colorless powder (yield 91.4%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:15]=[C:14]2[CH2:24][CH2:25][C:26](O)=[O:27])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1N=C[N:32](C(N2C=NC=C2)=O)C=1.C([O-])(=O)C.[NH4+]>C1COCC1>[C:1]([O:5][C:6](=[O:29])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:15]=[C:14]2[CH2:24][CH2:25][C:26](=[O:27])[NH2:32])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c(CCC(=O)O)ccc2-c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(-n2c(CCC(N)=O)ccc2-c2ccccc2)cc1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-[2-(2-carboxy-ethyl)-5-phenyl-pyrrol-1yl]-benzoic acid tert-butyl ester (1.33 mmol, 1.0 eq.) in THF (10 ml) was added CDI (1,1′carbonyldiimidazole, 1.60 mmol, 1.2 eq). The mixture was stirred at 45° C. for 2 h. To the reaction mixture was then added ammonium acetate (1.72 mmol, 1.3 eq.). The mixture was stirred at 45° C. for 16 hours.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH2:18]([N:20](CC)[CH2:21][CH3:22])[CH3:19].C(NCC)C>C(Cl)Cl.O.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:20]([CH2:21][CH3:22])[CH2:18][CH3:19])=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromo-2-methylbenzoic acid (25.0 g, 116 mmol) in DCM (400 mL) was treated with oxalyl chloride (11.7 mL, 134 mmol) and a catalytic amount of dry DMF (0.1 mL). The reaction was allowed to stir under nitrogen for 2 hours at room temperature. Removal of excess solvent gave crude acid chloride which was redissolved in DCM (400 mL). The mixture was then cooled to 0° C. and triethyl amine (40.5 mL, 291 mmol) was added followed by the slow addition of diethyl amine (24.3 mL, 233 mmol). The reaction was then allowed to warm to room temperature overnight. The crude mixture was then diluted with 400 mL of water and extracted with DCM (3×500 mL). The combined organic layers were then washed with brine (200 mL), dried over magnesium sulfate, filtered and then concentrated. The crude material was purified via MPLC (10% EtOAc/Hex) to afford 4-bromo-N,N-diethyl-2-methylbenzamide.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C@H:10]([C:22]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=[CH:31]3)[CH2:27][CH2:26][CH2:25][N:24]4[CH:23]=2)[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.CCN(C(C)C)C(C)C.[CH:50]1(C(Cl)=O)[CH2:53][CH2:52][CH2:51]1>C(Cl)Cl>[CH:50]1([C:6]([N:8]2[CH2:12][C@@H:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)[C@H:10]([C:22]3[C:32]4=[C:33]5[C:28](=[CH:29][CH:30]=[CH:31]4)[CH2:27][CH2:26][CH2:25][N:24]5[CH:23]=3)[CH2:9]2)=[O:5])[CH2:53][CH2:52][CH2:51]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C1
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(C1CCC1)N1C[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35852.2 %

Procedure:
To a solution of (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 450 μmol) in DCM (5 mL) under a nitrogen atmosphere was added 4M HCl in dioxane (1.7 mL, 6.8 mmol). The mixture was stirred at room temperature for 2 h. The solvent was then removed under vacuum and the residue dissolved in DCM (5 mL). DIPEA (320 μL, 1.8 mmol) and cyclobutylcarbonyl chloride (64 mg, 0.54 μmol) were added and the mixture stirred at room temperature for 16 h. The solvent was removed under vacuum and the residue dissolved in DCM, washed with saturated sodium carbonate solution and water and evaporated. The residue was purified by column chromatography (SiO2, EtOAc/hexanes) and recrystallised from methanol to yield cyclobutyl-[(3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidin-1-yl]-methanone as a white solid 82 mg, 43%). M.p.=253-255° C.; 1H NMR (400 MHz, DMSO-d6) δ: 10.80 (dd, J=8.0 and 2.0 Hz, 1H), 7.54 (dd, J=17.6 and 8.0 Hz, 1H), 7.36 (dd, J=18.0, 8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.20-7.16 (m, 2H), 7.01 (t, J=7.6 Hz, 1H), 6.93-6.88 (m, 1H), 6.86-6.81 (m, 1H), 6.76 (m, 1H), 4.10-3.87 (m, 6H), 3.52-3.29 (m, 3H), 2.82 (t, J=6.0 Hz, 2H), 2.24-2.00 (m, 6H), 1.87 (m, 1H), 1.75 (m, 1H). LCMS: m/e 424.16 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]1([CH3:18])[C@@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@:5]1([CH3:18])[C@@H:9]([O:10][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@@]1(C)[C@@H](O)CCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@@]1(C)[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a solution of compound 3A (0.591 g, 2.27 mmol) in CH2Cl2 (6.5 mL) at rt was added imidazole (0.464 g, 6.81 mmol) followed by tert-butydimethylsilyl chloride (1.71 g, 11.4 mmol). After stirring overnight, the reaction mixture was partitioned between H2O and CH2Cl2. The CH2Cl2 layer was washed with 1 M H3PO4 and water, then dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 30% EtOAc/hexane to yield compound 3B (0.519 g). LC/MS m/z 396 [M+Na]+.
Reaction SMILES: [CH3:1][NH2:2].Br.[CH3:4][C:5]1[C:9]([C:10]([O:12][CH2:13][CH2:14][CH3:15])=[O:11])=[C:8]([NH:16][C:17]([O:19]C2C=CC=CC=2)=O)[S:7][N:6]=1>C(O)C>[CH3:1][NH:2][C:17](=[O:19])[NH:16][C:8]1[S:7][N:6]=[C:5]([CH3:4])[C:9]=1[C:10]([O:12][CH2:13][CH2:14][CH3:15])=[O:11]
Reactant: CCCOC(=O)c1c(C)nsc1NC(=O)Oc1ccccc1
Reactant: CN
Agent: Br
Solvent: CCO
Product: CCCOC(=O)c1c(C)nsc1NC(=O)NC

Procedure:
A solution of methylamine in ethanol (33% w/v; 50 ml.) was added, cautiously with swirling, to 3-methyl-5-phenoxycarbonylamino-4-n-propoxycarbonylisothiazole hydrobromide (16 g.). When the initial exothermic reaction had subsided, the mixture was heated to reflux for 15 minutes, cooled and filtered. The solid was washed with water, and dried to give 3-methyl-1-(3-methyl-4-n-propoxycarbonylisothiazol-5-yl)urea (7.3 g.), m.p. 191° C.