Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:56]([CH3:59])[CH2:57][CH3:58])[C@H:26]([O:54][CH3:55])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:52][CH3:53])[C@@H:36]([CH3:51])[C:37]([NH:39][CH2:40][CH2:41][C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:44][CH:43]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:61][CH2:62][CH2:63][C:64]([OH:66])=[O:65].C([BH3-])#N.[Na+]>>[C:64]([CH2:63][CH2:62][CH2:61][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:56]([CH3:59])[CH2:57][CH3:58])[C@H:26]([O:54][CH3:55])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:52][CH3:53])[C@@H:36]([CH3:51])[C:37]([NH:39][CH2:40][CH2:41][C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:44][CH:43]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12])([OH:66])=[O:65]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1c[nH]c2ccccc12)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reactant: O=CCCC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1c[nH]c2ccccc12)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
The title compound was synthesized by analogy with the synthesis process of Example 1 by reacting 100 mg (119 μmol) N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[2-(1H-indol-3-yl)ethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetic acid salt (intermediate 24) with a 15% aqueous solution of 4-oxobutanoic acid in the presence of sodium cyanoborohydride.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]([NH:44]C(=O)OC(C)(C)C)[CH2:7][NH:8][C:9]1[CH:10]=[N:11][C:12]([C:24](=[O:43])[NH:25]C(C2C=CC(OC)=CC=2)C2C=CC(OC)=CC=2)=[C:13]([NH:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[N:17]=2)[CH:14]=1)(=[O:3])[CH3:2].[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53].C([SiH](CC)CC)C>C(Cl)Cl>[OH:58][C:52]([C:54]([F:57])([F:56])[F:55])=[O:53].[C:1]([NH:4][CH2:5][CH:6]([NH2:44])[CH2:7][NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[N:17]=2)[C:12]([C:24]([NH2:25])=[O:43])=[N:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C(NC(=O)c2ncc(NCC(CNC(C)=O)NC(=O)OC(C)(C)C)cc2Nc2cc(C)cc(C)n2)c2ccc(OC)cc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NCC(N)CNc1cnc(C(N)=O)c(Nc2cc(C)cc(C)n2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl {1-(acetylamino)-3-[(6-{[bis(4-methoxyphenyl)methyl]carbamoyl}-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl)amino]propan-2-yl}carbamate in DCM (1 mL) were added TFA (0.2 mL) and triethylsilane (0.146 mL, 0.917 mmol). The reaction mixture was stirred at room temperature for 4 hours, and then concentrated under reduced pressure. The residue was purified via reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to give 5-{[3-(acetylamino)-2-aminopropyl]amino}-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide TFA salt. MS ESI calc'd for C18H26N7O2 [M+H]+ 372. found 372. 1H NMR (500 MHz, CD3OD) δ 7.84 (d, J=2 Hz, 1H), 7.41 (s, 1H), 7.21 (s, 1H), 6.95 (s, 1H), 3.60-3.42 (m, 5H), 2.54 (s, 3H), 2.43 (s, 3H), 1.99 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: FC(F)(F)c1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Product: FC(F)(F)c1cc2c(NCc3ccccc3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-trifluoromethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-trifluoromethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Br:6].C(O[CH:12]1[NH:15][C:14](=[O:16])[CH2:13]1)(=O)C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC=CC=1>[Br:1][CH2:2][CH:3]([O:7][CH:12]1[NH:15][C:14](=[O:16])[CH2:13]1)[CH2:4][CH2:5][Br:6]
Reactant: CC(=O)OC1CC(=O)N1
Reactant: OC(CBr)CCBr
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C1CC(OC(CBr)CCBr)N1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of 1,4-dibromo-2-butanol (5.8 ml), 4-Acetoxyazetidinone (6.46 g), Palladium acetate (450 mg), Triethylamine (7 ml) and dry Benzene (75 ml) was stirred at room temperature under nitrogen for 23 hrs. Resulting solid was filtered off and filtrate was washed with water, brine and then dried over Magnesium sulfate. The residual oil, after evaporation, was purified by column chromatography using Hexane and Ethyl acetate (2:1) and the title compound was obtained. Yield: 5.88 g (78%). NMR (CDCl3): 2.05-2.17 (2H, m), 2.87-3.27 (2H, m), 3.42-3.60 (4H, m), 3.90-4.02 (1H, m), 5.23-5.33 (1H, m), 6.53 (1H, br, s). IR (Neat), cm-1 : 3260, 1771.
Reaction SMILES: [CH2:1]([O:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[NH:30][C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32])[C:21]=1[OH:38])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:39]N1C(C)(C)C(=O)N(Cl)C1=O.C(OCC)(=O)C>CC(C)=O>[CH2:1]([O:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([C:20]1[CH:29]=[C:28]([Cl:39])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[NH:30][C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32])[C:21]=1[OH:38])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: CCCCCCCCCCCCOCCCNC(=O)c1ccc2c(NC(=O)OCC(C)C)cccc2c1O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCOCCCNC(=O)c1cc(Cl)c2c(NC(=O)OCC(C)C)cccc2c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
In 30 ml of acetone, 5.28 g (0.01 mol) of 2-(3-dodecoxypropylcarbamoyl)-5-isobutoxycarbonylamino-1-naphthol synthesized in accordance with the method described in JP-A No. 123158/1987 was dissolved and 2.00 g (0.01 mol) of 1,3-dichloro-5,5-dimethylhydantoin was added to the solution, followed by stirring for 2 hours at room temperature. Then 50 ml of ethyl acetate was added to the reaction mixture, followed by washing with a 5% aqueous sodium hydroxide solution and then washing with water. The solvent was distilled off and crystallization from acetonitrile was carried out, to give 5.17 g (yield: 92%) of 2-(3-dodecoxypropylcarbamoyl)-4-chloro-5-isobutoxycarbonylamino-1-naphthol
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[CH:19][C:18]=1[C:29]([F:32])([F:31])[F:30].Cl>COCCOCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:17]2[C:18]([C:29]([F:31])([F:32])[F:30])=[CH:19][C:20]([N+:26]([O-:28])=[O:27])=[CH:21][C:22]=2[N+:23]([O-:25])=[O:24])[C:9](=[O:13])[O:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Nc1cccc(Cl)c1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: CCOC(=O)N(c1cccc(Cl)c1)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.3 %

Procedure:
Ethyl 3-chlorophenylcarbamate (1.0256 g) was dissolved in diglyme (3 ml), and to the solution were added sodium hydride (205.5 mg) and 2-chloro-3,5-dinitrobenzotrifluoride (1.1583 g). The reaction mixture was stirred at room temperature for 4 hours. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by silica gel column (75 g, hexane:ethyl acetate=5:1) and recrystallized from hexane-ethyl acetate to give the title compound (0.7854 g, 42%).
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][C@H:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:35]=[CH:34][C:33]([C:36]([OH:38])=O)=[C:32]([F:39])[CH:31]=1)[CH3:22])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.[Br:47][C:48]1[CH:66]=[N:65][C:51]2[O:52][C:53]([CH3:64])([CH3:63])[C:54](=[O:62])[N:55]([CH:56]3[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]3)[C:50]=2[CH:49]=1>>[Br:47][C:48]1[CH:66]=[N:65][C:51]2[O:52][C:53]([CH3:63])([CH3:64])[C:54](=[O:62])[N:55]([CH:56]3[CH2:57][CH2:58][N:59]([C:36]([C:33]4[CH:34]=[CH:35][C:30]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[O:23][C@H:21]([CH3:22])[CH2:20][CH2:19][OH:18])=[CH:31][C:32]=4[F:39])=[O:38])[CH2:60][CH2:61]3)[C:50]=2[CH:49]=1
Reactant: CC1(C)Oc2ncc(Br)cc2N(C2CCNCC2)C1=O
Reactant: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ccccc1-c1ccc(C(=O)O)c(F)c1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CCO)Oc1ccccc1-c1ccc(C(=O)N2CCC(N3C(=O)C(C)(C)Oc4ncc(Br)cc43)CC2)c(F)c1

Procedure:
In accordance with the methods of Examples 13-4 and 5-5, the compound of Example 5-3 was used instead of the compound of Example 13-3, and the compound of Example 52-2 was used instead of the compound of Reference Example 3 to afford 7-bromo-1-{1-[(3-fluoro-2′-{[(1R)-3-hydroxy-1-methylpropyl]oxy}biphenyl-4-yl)carbonyl]piperidin-4-yl}-3,3-dimethyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].F[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.O>CN(C=O)C>[CH:23]([C:22]1[CH:25]=[CH:26][C:19]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)=[CH:20][CH:21]=1)=[O:24]
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(CC(=O)O)cc2)cc1
Temperature: 78 °C
Reaction time: 18 h
Yield: 25.5 %

Procedure:
To a suspension of 4-hydroxyphenylacetic acid (5.8 g, 38.2 mmoles) in dry DMF (50 mL) under argon, was added K2CO3 (15.8 g, 114.5 mmoles), and 4-fluorobenzaldehyde (23.7 g, 190.8 mmoles), and the reaction mixture was stirred at 78±2° C. for 18 hours under argon (Note: the reaction mixture becomes very viscous soon after the addition of 4-fluorobenzaldehyde, which slowly liquefies again). Subsequently the reaction mixture was cooled to room temperature, then poured into water (250 mL) and stirred for 15 minutes. The aqueous layer was extracted with ethyl acetate (2×75 mL); the organic layer was discarded and the resulting aqueous layer was acidified with HCl (˜6M) to pH 2.0. The aqueous layer was extracted with ethyl acetate (2×100 mL), the combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate and evaporated under reduced pressure to afford a mixture which was purified by silica gel chromatography using hexane-ethyl acetate (7:3) containing 1% acetic acid as eluent to yield a pale yellow solid (2.5 g, 25.6%). 1H NMR (400 MHz, DMSO-d6): δ ppm: 12.34 (br, 1H), 9.92 (s, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.8 Hz, 2H), 7.11 (overlapped d, J=8.8 Hz, 2H), 7.10 (overlapped d, J=8.8 Hz, 2H), 3.61 (s, 2H).
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].[NH2:7][C:8]1[CH:27]=[CH:26][C:11]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH3:1][NH:2][S:3]([NH:7][C:8]1[CH:27]=[CH:26][C:11]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:18][CH2:19]2)=[CH:10][CH:9]=1)(=[O:5])=[O:4]
Reactant: Nc1ccc(OCC2CCN(c3ccncc3)CC2)cc1
Reactant: CNS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CNS(=O)(=O)Nc1ccc(OCC2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 39.6 %

Procedure:
Methylsulphamoyl chloride (0.39 g) was added dropwise to a stirred solution of 4-[(4-aminophenoxy)methyl]-1-[4-pyridyl]-piperidine (see Preparation 4) (0.57 g) in pyridine (15 ml) and the mixture was stirred at room temperature for 6 hours. An additional 0.39 g of methylsulphamoyl chloride was then added and the mixture was stirred for a further 18 hours and then evaporated. The residue was partitioned between sodium bicarbonate solution and ethyl acetate. The organic layer was separated and the aqueous layer was extracted several times with ethyl acetate. The combined organic layers were washed with water, dried (Na2SO4) and evaporated. The solid residue was crystallised from ethanol to give the title compound, (0.30 g), m.p. 170.5°-172.5°.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[NH:14][C@@H:15]([C:17]1[N:21]([CH2:22][CH3:23])[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])=[N:19][N:18]=1)[CH3:16])(C)(C)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:22]([N:21]1[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])=[N:19][N:18]=[C:17]1[C@H:15]([NH2:14])[CH3:16])[CH3:23]
Reactant: CCn1c([C@@H](C)NC(=O)OC(C)(C)C)nnc1S(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: CCn1c([C@@H](C)N)nnc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (121 ml) was added to the [(R)-1-(4-ethyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)ethyl]-carbamic acid t-butyl ester (100.0 g) obtained in Example 8-(5), and the mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure to obtain (R)-1-(4-ethyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)ethylamine trifluoroacetate as a white powder (103.8 g).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C@@H:16]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1>>[CH:1]1([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][NH:26][C@@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc(OC2C=CCCC2)c1
Product: C1=CC(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)CCC1

Procedure:
The product from Example 59A and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)O)=[CH:31][CH:30]=1>C1COCC1>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([O:12][CH:35]([C:32]1[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:11])[CH2:3]2
Reactant: O=C(O)C1CN2CCC1CC2
Reactant: COc1ccc(C(O)c2ccccc2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: COc1ccc(C(OC(=O)C2CN3CCC2CC3)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 13.5 %

Procedure:
Quinuclidine-3-carboxylic acid hydrochloride (150 mg, 0.78 mmol), EDC (225 mg, 1.17 mmol), and HOBT (180 mg, 1.17 mmol) were dissolved in dry THF (7.5 ml). (4-Methoxyphenyl)(phenyl)methanol (184 mg, 0.86 mmol) and TEA (382 μl, 2.74 mmol) were added, and the resulting reaction was stirred at room temperature for four days. THF was removed under vacuum, and the crude residue was partitioned between EtOAc and water. The organic phase was washed with a sat. NaHCO3, dried over Na2SO4, filtered, and evaporated. The crude was purified by flash chromatography (EtOAc/MeOH=8/2 to EtOAc/MeOH=7:3+1% NH4OH) to give (4-methoxyphenyl)(phenyl)methyl quinuclidine-3-carboxylate (37 mg, mixture of diastereoisomers). The compound was used as such in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][NH:5][C:4](=[O:7])[CH:3]1[O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:32]([O:34][C:35](=[O:38])[CH2:36]Br)[CH3:33].O>C1COCC1>[CH2:32]([O:34][C:35](=[O:38])[CH2:36][N:5]1[CH2:6][C:2]([CH3:21])([CH3:1])[CH:3]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:18])([F:20])[F:19])[CH:10]=2)[C:4]1=[O:7])[CH3:33]
Reactant: CC1(C)CNC(=O)C1Oc1ccc(C#N)c(C(F)(F)F)c1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CN1CC(C)(C)C(Oc2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 25 °C

Procedure:
To a −78° C. stirring solution of 4-(4,4-Dimethyl-2-oxo-pyrrolidin-3-yloxy)-2-trifluoromethyl-benzonitrile (Compound (1), product of Example 3, Step E, 5.00 g, 16.8 mmoles) in 100 mL THF under a nitrogen atmosphere was added lithium bis(trimethylsilyl)amide (1 M in THF, 18.4 mL, 18.4 mmoles) and bromoacetic acid ethyl ester (2) (2.0 mL, 18.4 mmoles). The cooling bath was allowed to warm up to ambient temperature overnight. Water (25 mL) was added and the reaction mixture was concentrated in vacuo. Methylene chloride (100 mL) and water (50 mL) was added, the mixture is agitated and the layers are separated. The organic layer was concentrated in vacuo. The product (3) is used as is for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](N3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:33][O:34][C:35]1[CH:41]=[CH:40][C:38]([OH:39])=[CH:37][CH:36]=1.CN(C)C=O>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:39][C:38]3[CH:40]=[CH:41][C:35]([O:34][CH3:33])=[CH:36][CH:37]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(O)cc1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(OC(=O)c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3.0 g (8.2 mmol) of (S)-1-[(8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl)carbonyl]imidazole, 1.59 g (11.5 mmol) of powdered potassium carbonate, 1.43 g (11.5 mmol) of hydroquinone monomethyl ether and 20 ml of dry dimethylformamide is stirred at room temperature for 16 hours, then poured into 60 ml of water and extracted three times with methylene chloride. The organic extracts are washed twice with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. After chromatography on silica gel while eluting with ethyl acetate and subsequent recrystallization from ethyl acetate there is obtained p-methoxyphenyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 210°-211°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][N:19]1[C:25](=[O:26])[CH:24]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=2[C:21]2[CH:35]=[CH:36][CH:37]=[CH:38][C:20]1=2>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][N:19]2[C:25](=[O:26])[CH:24]([CH2:27][CH:28]3[CH2:30][CH2:29]3)[C:23]3[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=3[C:21]3[CH:35]=[CH:36][CH:37]=[CH:38][C:20]2=3)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NN1C(=O)C(CC2CC2)c2ccccc2-c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CC2CC2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using N-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and 5-amino-7-cyclopropymethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-L), the title compound was prepared. The reaction was monitored by tlc (Rf=0.30, 5% MeOH/CHCl3) and product was purified by chromatography (silica, 3% MeOH/CHCl3).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:18][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1)[C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:9].[CH2:24]([N:27]([CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH:31]=O)[CH2:25][CH3:26].C(OC)(OC)OC.[BH4-].[Na+]>CO>[CH2:33]([N:27]([CH2:24][CH2:25][CH3:26])[CH2:28][CH2:29][CH2:30][CH2:31][N:15]1[CH2:16][CH2:17][CH:12]([CH2:11][NH:10][C:8](=[O:9])[N:7]([CH2:18][C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)[CH2:6][C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[CH2:13][CH2:14]1)[CH2:34][CH3:35]
Reactant: O=C(NCC1CCNCC1)N(Cc1ncc[nH]1)Cc1ncc[nH]1
Reactant: CCCN(CCC)CCCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCCN(CCC)CCCCN1CCC(CNC(=O)N(Cc2ncc[nH]2)Cc2ncc[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.4 %

Procedure:
Under an argon atmosphere, to a methanol (2.3 mL) solution of the compound (73 mg) obtained in Example 10, 4-(dipropylamino)butanal (39 mg) and trimethyl orthoformate (49 mg) were added at 0° C. The reaction solution was stirred at room temperature for 2 hours. To the reaction solution, sodium borohydride (17 mg) was added at 0° C., followed by stirring for one hour. The reaction solution was concentrated under reduced pressure, and then an aqueous 5N sodium hydroxide solution (10 mL) was added to the residue. The aqueous layer was extracted twice with chloroform (30 mL). The combined organic layer was dried over anhydrous magnesium sulfate. After removing the anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (dichrolomethane:methanol:28% aqueous ammonia=10:1:0→80:10:1) to obtain the title compound (37 mg) having the following physical properties.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([O:11][CH3:12])[C:3]=1[N:13]1[C:21]2[CH:20]=[CH:19][NH:18][C:17](=[O:22])[C:16]=2[C:15]([C:23]2[CH:24]=[C:25]([C:28]([NH2:30])=[O:29])[S:26][CH:27]=2)=[CH:14]1.[Cl-].[Ca+2].[Cl-].C(O)C>O>[NH2:8][C:6]1[CH:5]=[C:4]([O:11][CH3:12])[C:3]([N:13]2[C:21]3[CH:20]=[CH:19][NH:18][C:17](=[O:22])[C:16]=3[C:15]([C:23]3[CH:24]=[C:25]([C:28]([NH2:30])=[O:29])[S:26][CH:27]=3)=[CH:14]2)=[C:2]([F:1])[CH:7]=1
Reactant: COc1cc([N+](=O)[O-])cc(F)c1-n1cc(-c2csc(C(N)=O)c2)c2c(=O)[nH]ccc21
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: COc1cc(N)cc(F)c1-n1cc(-c2csc(C(N)=O)c2)c2c(=O)[nH]ccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
To a solution of 4-(1-(2-fluoro-6-methoxy-4-nitrophenyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)thiophene-2-carboxamide (45.0 mg) and calcium chloride (11.7 mg) in a mixed solvent of ethanol (5 ml) and water (1 ml) was added reduced iron (29.3 mg), and the mixture was stirred at 100° C. for 2 hr. The insoluble substance was removed by the filtration, and washed with water and ethyl acetate. The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (30.0 mg).