Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[N:14][CH:13]=[CH:12][CH:11]=2)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Cl:2][CH2:3][C:4]1[N:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=1
Reactant: CC(C)CNc1c(NC(=O)CCl)cnc2cccnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)Cn1c(CCl)nc2cnc3cccnc3c21
Temperature: 25 °C
Yield: 101.4 %

Procedure:
To a solution of 2-chloro-N-{4-[(2-methylpropyl)amino][1,5]naphthyridin-3-yl}acetamide hydrochloride (from Part C, approximately 70 mmol) in 3:1 ethanol/water (280 mL) was added 6 M aqueous potassium carbonate (17.5 mL). The reaction mixture was stirred at room temperature over the weekend. The volatiles were removed under reduced pressure and the residue was partitioned between dichloromethane (200 mL) and brine (100 mL). The aqueous layer was extracted with dichloromethane (2×50 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 19.5 g of 2-(chloromethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine, which contained a small amount of dichloromethane and was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:51])[C:16]([N:18]2[CH2:42][CH2:41][C@:21]3([N:25](C(OCC4C=CC=CC=4)=O)[C:24](=[O:36])[CH:23]([C:37]([O:39][CH3:40])=[O:38])[CH2:22]3)[CH2:20][C@@H:19]2[C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=2[CH3:50])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>CO.[Pd]>[F:53][C:2]([F:1])([F:52])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:51])[C:16]([N:18]2[CH2:42][CH2:41][C@:21]3([NH:25][C:24](=[O:36])[CH:23]([C:37]([O:39][CH3:40])=[O:38])[CH2:22]3)[CH2:20][C@@H:19]2[C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=2[CH3:50])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: COC(=O)C1C[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N(C(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1C[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
3-methyl 1-(phenylmethyl) (5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-2-oxo-1,8-diazaspiro[4.5]decane-1,3-dicarboxylate (Intermediate 34, 78 mg) was dissolved in Methanol (3 ml), Pd/C (8.83 mg, 8.30 μmol) was added and the suspension was left stirring at rt, under a H2 atmosphere (1 atm), for 1 hr. The Pd was filtered out and the solvent was removed obtaining the title compound (60 mg); UPLC: Rt=0.82 mins, m/z=618 [M+H]+.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.[H-].[Na+].[I:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([CH3:26])=[C:22]([CH:24]=O)[N:23]=2)[CH:20]=1>C1COCC1>[I:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([CH3:26])=[C:22](/[CH:24]=[CH:9]/[C:10]#[N:11])[N:23]=2)[CH:20]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cc1c(C=O)nc2ccc(I)cn12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(/C=C/C#N)nc2ccc(I)cn12
Reaction time: 16 h
Yield: 44.4 %

Procedure:
To a stirred suspension of cyanomethylphosphonic acid diethyl ester (619 mg) in THF (2 ml) was added NaH (60% in oil, 144 mg) at 0° C., and the mixture was stirred at same temperature for 16 h. A solution of 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carbaldehyde (250 mg) in THF (2 ml) was added, and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with saturated NH4Cl solution, and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, concentrate, and purified by column chromatography (hexane/EtOAc) to afford the title compound (120 mg) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[CH:4][C:3]=1[N:22]1[C:30](=[O:31])[NH:29][C:28]2[C:23]1=[N:24][C:25]([CH2:34]Cl)=[N:26][C:27]=2[O:32][CH3:33].[N-:36]=[N+:37]=[N-:38].[Na+].Cl>CN(C)C=O>[N:36]([CH2:34][C:25]1[N:24]=[C:23]2[C:28]([NH:29][C:30](=[O:31])[N:22]2[C:3]2[CH:4]=[C:5]([O:10][CH2:11][C:12]3[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=3[F:21])[C:6]([O:8][CH3:9])=[CH:7][C:2]=2[Cl:1])=[C:27]([O:32][CH3:33])[N:26]=1)=[N+:37]=[N-:38]
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CCl)nc32)cc1OCc1c(OC)ccc(F)c1F
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CN=[N+]=[N-])nc32)cc1OCc1c(OC)ccc(F)c1F
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
A mixture of 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2-chloromethyl-6-methoxy-7,9-dihydro-8H-purin-8-one (0.1 g) and sodium azide (15 mg) in N,N-dimethylformamide (2 mL) was stirred at 100° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/4). The obtained product was suspended in a mixed solvent (n-hexane/ethyl acetate=1/1), and collected by filtration. The collected material was dried under reduced pressure to give 2-azidomethyl-9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (74 mg). To this material were added tetrahydrofuran (5 mL), ethanol (1 mL) and 10% platinum-carbon powder (20 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/methanol=9/1−methanol) to give 2-aminomethyl-9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (44 mg). To this material were added tetrahydrofuran (3 mL), triethylamine (0.1 mL) and di(tert-butyl)dicarbonate (28 mg), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/4) to give the title compound (36 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:24])=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15]2)(=[O:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:31](I)[CH3:32]>CN(C)C=O.C(OCC)(=O)C>[CH2:31]([N:9]([S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])[C:10]1[CH:11]=[CH:12][C:13]([CH3:24])=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15]2)[CH3:32]
Reactant: CCOC(=O)c1cc2c(C)ccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(C)ccc(N(CC)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
To a mixture of ethyl 7-[(2-thienylsulfonyl)amino]-4-methyl-1H-indole-2-carboxylate (2.89 g), potassium carbonate (1.2 g) and N,N-dimethylformamide (25 ml) was added dropwise a solution of ethyl iodide (0.67 ml) in N,N-dimethylformamide (2 ml) under ice-cooling. The mixture was stirred at room temperature for 2 days. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained yellow oil was crystallized from ethyl acetate-hexane, and the obtained crystals were washed with ethyl acetate-hexane to give the title compound (2.16 g, yield 70%) as colorless prism crystals. melting point 148-149° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([Cl:10])[CH:3]=1.[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:17]\[S@@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])=[C:4]([Cl:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1Cl
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C\c1ccc(Br)cc1Cl
Temperature: 37 °C
Reaction time: 78 h

Procedure:
A suspension of 4-bromo-2-chlorobenzaldehyde (1150 mg, 5240 μmol), (r)-(+)-2-methyl-2-propanesulfinamide (1588 mg, 13100 μmol), copper(ii) sulfate (696.4 μl, 15720 μmol) in DCM (10 mL) was stirred at 37° C. for 78 h. Reaction filtered through Celite, and solid washed repeatedly with DCM. Filtrate concentrated then purified on silica (80 g) eluting product with 0>30% of EtOAc/Hex. MS (ESI pos. ion) m/z: 322/324 (MH+). Calc'd exact mass for C11H13BrClNOS: 321/323.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[C:15]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:16][C:17]([CH3:19])=[O:18]>>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:16]([C:17](=[O:18])[CH3:19])[C:15]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Product: CCOC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O

Procedure:
The title compound is prepared in analogy to example 25 (stage 25a) starting from 2-methyl-4-oxo-4H-chromene-8-carbaldehyde (200 mg, 1.062 mmol) and ethyl acetoacetate (138 mg, 1.062 mmol). 309 mg (97% of theory) of the title compound are obtained as an E/Z isomer mixture.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][C@H:19]([C:27]([NH:29][C@H:30]([C:35]([O:37][CH3:38])=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[ClH:46].C1(OC)C=CC=CC=1>>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][C@H:19]([C:27]([NH:29][C@H:30]([C:35]([O:37][CH3:38])=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[ClH:46]
Reactant: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: COc1ccccc1
Product: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)[C@@H](N)Cc1ccc(O)cc1

Procedure:
As in step A of Example 1A, 2.0 g of Boc-Tyr-DAla-Phe-Met-OCH3 was treated with HCl, anisole, EtOAC to give H-Tyr-DAla-Phe-Met-OCH3.HCl which was dissolved in 40 ml of water, methanol, acetic acid (94:5:1) and applied to a column (2.5×100 cm) of C18Hi+Flosil (80-100 mesh, Applied Science Laboratories, Inc.). The sample was eluted at 3 ml/min with a convex gradient formed from 2 liters of water, methanol, acetic acid (94:5:1) into which was fed methanol, water, acetic acid (50:49:1). The solid resulting from the evaporation of the product peak was dissolved in 10 ml of isopropanol and diluted with 100 ml of hexane to give 1.27 g (68%) of H-Tyr-DAla-Phe-Met-OCH3.HOAc, m.p. 64°-65° C., [α]D26 =10.57°, (c, 1.01 in methanol).
Reaction SMILES: B.[Na].[CH3:3][OH:4].[Cl-].[NH4+].[O:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1>>[OH:4][CH2:3][C@H:8]1[C:9](=[CH2:8])[CH2:10][CH2:11][C@@H:9]1[CH2:10][CH2:11][OH:7]
Reactant: C1CCOC1
Reactant: CO
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Product: C=C1CC[C@H](CCO)[C@H]1CO
Temperature: 80 °C
Yield: 30.2 %

Procedure:
Methyl (4aS, 7aS)-1-hydroxy-7-methylene-1, 4a, 5, 6, 7a-pentahydrocyclopenta[c]pyran-4-carboxylate (2.0 g, 0.0095 mol) obtained in Example 22 wad dissolved in 40 mι of tetrahydrofuran, and after sodium boron hydride (1.8 g, 0.047 mol) was added, the reaction mixture was heated and refluxed at 80° C. 9.5 mι of methanol wad added dropwise to this solution in the course of 1 hour, and the reaction mixture was stirred further at the same temperature. 50 mι of saturated ammonium chloride solution wad added to the reaction mixture. After an organic solvent was once distilled off, the aqueous layer was extracted by ethyl acetate (100 mι×3). The organic layer was joined, and was dried by adding magnesium sulfate, filtered, and thereafter concentrated under a reduced pressure. The residual matter was purified by chromatography using silica gel, and the solvent of the fraction obtained from ether:ethyl acetate=3:7 eluent was distilled off. A colorless oily substance was thus obtained, i.e., 2-[(1R, 2R)-2-(hydroxymethyl)-3-methylenecyclopent-1-yl]-ethane-1-ol (450 mg, yield=30.2%). This 2-[(1R, 2R)-2-(hydroxymethyl)-3-methylcyclopent-1-yl]-ethane-1-ol had the following physicochemical properties:
Reaction SMILES: CC1C=CC(C(O)=O)=CC=1.[CH2:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)C(C)C>>[CH3:11][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=3)[N:22]=2)=[CH:19][CH:20]=1
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1
Agent: Cc1ccc(C(=O)O)cc1
Product: Cc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1

Procedure:
The title compound was prepared from 4-methylbenzoic acid by procedures analogous to those described in Preparations (8A-8C) for the preparation of {4-[5-(4-isobutyl-phenyl)-[1,2,4]oxadiazol-3-yl]-phenyl}-methanol.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=3)[O:10][C:3]=12.[CH3:19][C:20]1[C:28]([NH2:29])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][NH:24]2>>[CH3:18][C:13]1[CH:12]=[C:11]([C:9]2[O:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:29][C:28]3[C:20]([CH3:19])=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[CH:22]4)[CH:8]=2)[CH:16]=[C:15]([CH3:17])[CH:14]=1
Reactant: Cc1c(N)ccc2[nH]ccc12
Reactant: Cc1cc(C)cc(-c2cc3nccc(Cl)c3o2)c1
Product: Cc1cc(C)cc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4C)c3o2)c1

Procedure:
The title compound was prepared by procedure E using 7-chloro-2-(3,5-dimethylphenyl)furo[3,2-b]pyridine (26.00 mg; 0.10 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (15.49 mg; 0.11 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one, and was obtained as a beige solid (25 mg, 67%). (HPLC (method F): 96%, RT: 4.45 min); 1H NMR (500 MHz, DMSO-d6) δ [ppm] 11.15 (s, 1H), 8.54 (s, 1H), 7.95 (d, J=5.5, 1H), 7.50 (s, 2H), 7.38 (t, J=2.7, 1H), 7.33 (s, 1H), 7.31 (d, J=8.4, 1H), 7.08-6.95 (m, 2H), 6.52 (s, 1H), 6.14 (d, J=5.5, 1H), 2.36 (s, 3H), 2.30 (s, 6H); MS (m/z) 368 [M+H]+, RT: 4.3 min.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[CH2:17][S:18]C(=O)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>CO.O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[CH2:17][SH:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)SCC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(CS)NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
2.23 g of this acetamide was dissolved in a mixed solvent of 30 ml of methanol and 3 ml of water, and cooled in an ice bath. 0.48 g of 85% potassium hydroxide was added to this solution, and stirred at 0° C. for 1.5 hours. pH of the reaction solution was adjusted to 7 by adding 2N aqueous hydrochloric acid, and extraction was carried out by adding 100 ml of dichloromethane and 50 ml of water. The dichloromethane layer was washed twice with water, and dried over anhydrous magnesium sulfate. The solvent was evapoated in vacuo to obtain the captioned colorless oily N-[3-{3-(piperidinomethyl)phenoxy}propyl]-2-mercaptoacetamide. Yield: 1.86 g.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:26]=1.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>CC([O-])=O.CC([O-])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd+2].C1(C)C=CC=CC=1>[CH3:27][Si:28]([C:31]#[C:32][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:26]=1)([CH3:30])[CH3:29]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ncn2c1CN=C(c1ccccc1)c1cc(Br)ccc1-2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncn2c1CN=C(c1ccccc1)c1cc(C#C[Si](C)(C)C)ccc1-2
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.9 %

Procedure:
A mixture of bromide 5 (0.3 g, 0.73 mmol), trimethylsilylacetylene (0.143 g, 1.46 mmol) and bis(triphenylphosphine)-palladium-(II) acetate (55 mg, 0.073 mmol) in a mixed solvent system of toluene (20 mL) and anhydrous TEA (50 mL) was heated to reflux under argon. See, Liu, et al., 1996; Austin, et al., 1981; Heck, 1985. After stirring for 12 hours at reflux, the mixture was cooled to room temperature and the precipitate which formed was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was treated with a saturated aqueous solution of NaHCO3 (20 mL), and extracted with CHCl3 (3×25 mL). The combined extracts were washed with brine and dried (Na2SO4). After removal of solvent under reduced pressure, the residue was purified by flash chromatography (silica gel, EtOAc) to afford 6 (XLiXHeII-048) as a white solid (0.29 g, 93%). This benzodiazepine can also be obtained from 2 in 45% yield by following the same procedure 6 (XLiXHeII-048): mp: 170-172° C.; IR (KBr) 2958, 2152, 1718 cm−1; 1H NMR (CDCl3) δ 0.23 (s, 9H), 1.42 (t, 3H, J=7.2 Hz), 4.04 (d, 1H, J=12.6 Hz), 4.41 (m, 2H, J=7.2 Hz), 6.23 (d, 1H, J=12.6 Hz), 7.35-7.55 (m, 7H), 7.73 (dd, 1H, J=8.3 Hz and 1.9 Hz), 7.93 (s, 1H); MS (EI) m/e (relative intensity) 427 (M+, 76), 412 (5), 381 (55), 353 (100) 303 (10), 287 (7). Anal. Calcd. for C25H25N3O2Si.⅓EtOAc: C, 69.22; H, 6.01; N, 9.20. Found: C, 68.87; H, 5.81; N, 9.37.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)N)=[CH:4][N:3]=1.[CH3:19][NH+:20]1[C@@H:25]2[CH2:26][C:27]([CH2:29][C@H:21]1[CH2:22][CH2:23][CH2:24]2)=O.S(=O)(=O)(O)O>O1CCOCC1>[CH3:18][C:15]1[CH:14]=[C:13]2[C:12](=[CH:17][CH:16]=1)[N:10]([CH2:9][CH2:8][C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:23]1[CH2:24][CH:25]3[N:20]([CH3:19])[CH:21]([C:22]2=1)[CH2:29][CH2:27][CH2:26]3
Reactant: Cc1ccc(N(N)CCc2ccc(Cl)nc2)cc1
Reactant: C[NH+]1[C@@H]2CCC[C@H]1CC(=O)C2
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(Cl)nc2)CC2CCCC1N2C
Temperature: 80 °C

Procedure:
In a 25 ml, round-bottomed flask were combined 2-chloro-5-(2-(1-p-tolylhydrazinyl)-ethyl)pyridine (50 mg, 0.19 mmol; Example 117D), pseudopelletierine hydrochloride (40 g, 0.21 mmol; Acros), and concentrated sulfuric acid (31 μL) in dioxane (8 mL). The reaction mixture was heated to 80° C. for 6 hours, then cooled to room temperature. The solvent was removed under vacuum and residue was purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in buffer (0.1% trifluoroacetic acid) over 15 minutes] to afford the title compound as the bistrifluoroacetic acid salt: 1H NMR (300 MHz, methanol-d4) δ ppm 0.94-1.13 (m, 1H), 1.39-1.51 (m, 1H), 1.71-1.80 (m, 1H), 1.91-2.17 (m, 3H), 2.43 (s, 3H), 2.50 (d, J=18 Hz, 1H), 2.66 (s, 3H), 2.96 (dd, J=18, 7 Hz, 1H), 3.14-3.23 (m, 2H), 3.83 (t, J=5 Hz, 1H), 4.41 (t, J=6 Hz, 2H), 4.90 (d, J=2 Hz, 1H), 7.09 (d, J=8 Hz, 1H), 7.24 (s, 1H), 7.32 (d, J=8 Hz, 1H), 7.37 (d, J=8 Hz, 1H), 7.50 (dd, J=8, 2 Hz, 1H), 7.77 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 380 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:16])[N:6]([CH2:14]Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)([CH3:3])[CH3:2].[C:17]([O-:20])(=[O:19])[CH3:18].[Na+]>C(#N)C>[CH:1]([O:4][C:5](=[O:16])[N:6]([CH2:14][O:20][C:17](=[O:19])[CH3:18])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CC(C)OC(=O)N(CCl)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)OCN(C(=O)OC(C)C)c1cccc(Cl)c1
Reaction time: 4 h
Yield: 59.8 %

Procedure:
A mixture of 52.4 g (0.2 mole) of Isopropyl-N-chloromethyl-N-(3-chlorophenyl)-carbamate and 24.6 g (0.3 mole) of anhydrous sodium acetate in 700 ml of anhydrous acetonitrile was boiled for four hours under reflux. After cooling, the salts were filtered off, the filtrate was evaporated, the residue was dissolved in 300 ml of ether and the ether solution was washed with water and dried over freshly calcined sodium sulfate. Thereafter, the solvent was distilled off and the resulting oil was distilled in vacuo. 34.2 g (95% of theory) of Isopropyl-N-acetoxymethyl-N-(3-chlorophenyl)-carbamate of boiling point 134° C/0.3 mm Hg and refractive index nD20 1.5074 were obtained.
Reaction SMILES: N[C:2]1[N:6]([CH2:7][C:8]([OH:11])([CH3:10])[CH3:9])[C:5]([CH2:12][CH2:13][CH2:14][CH3:15])=[N:4][C:3]=1[C:16]#[N:17].C(I)[I:19].C(ON=O)CC(C)C>C(Cl)(Cl)Cl>[CH2:12]([C:5]1[N:6]([CH2:7][C:8]([OH:11])([CH3:10])[CH3:9])[C:2]([I:19])=[C:3]([C:16]#[N:17])[N:4]=1)[CH2:13][CH2:14][CH3:15]
Reactant: ICI
Reactant: CCCCc1nc(C#N)c(N)n1CC(C)(C)O
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: CCCCc1nc(C#N)c(I)n1CC(C)(C)O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a solution of 5-amino-2-butyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazole-4-carbonitrile S4 (600 mg, 2.54 mmol, 1.0 equiv) and CH2I2 (2.0 mL) in CHCl3 (25 mL) at 80° C. was added a solution of isoamylnitrite (1.36 mL, 10.2 mmol, 4.0 equiv) in CHCl3 (5 mL) over 20 min. The reaction was stirred for additional 30 min at 80° C. then cooled to 25° C. The reaction was concentrated in vacuo and purification by silica gel column chromatography (1/9 EtOAc/hexanes-7/3 EtOAc/hexanes, gradient) afforded the title compound (687 mg, 78%) as a yellow solid: 1H NMR (CDCl3, 600 Hz) δ 0.88 (t, J=6.0 Hz, 3H), 1.29 (s, 6H), 1.33 (hex, J=7.8 Hz, 2H), 1.66 (pent, J=7.8 Hz, 2H), 2.88 (t, J=7.8 Hz, 2H), 3.95 (s, 2H); 13C NMR (CDCl3, 150 Hz) δ 13.7, 22.2, 28.3, 28.4, 29.6, 56.6, 71.6, 83.6, 115.1, 120.6, 155.4; MS (APCI+): calcd C12H19IN3O [M+H]+348.2. found 348.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7]([NH:9][CH:10]1[CH2:12][CH2:11]1)=O.B>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[CH2:7][NH:9][CH:10]1[CH2:11][CH2:12]1
Reactant: O=C(NC1CC1)c1cc(Br)ccc1Cl
Agent: B
Solvent: C1CCOC1
Product: Clc1ccc(Br)cc1CNC1CC1
Temperature: 25 °C

Procedure:
At 0° C., a suspension of 5-bromo-2-chloro-N-cyclopropylbenzamide from the previous step (1 eq.) in THF (0.4 M) was added borane (1 M THF solution, 3 eq.). The resulting suspension was warmed to RT over 1 h and then heated at reflux for 1 h. The now pale yellow solution was re-cooled to 0° C. and carefully quenched with 1 N aq. HCl. The resulting mixture was heated at reflux for 1 h to ensure complete breakdown of the amine-borane complex. Following careful neutralization with 1 N aq. NaOH, the aqueous layer was separated and back extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product thus obtained was purified further by way of column chromatography (SiO2, Hex→80:20 (v/v) Hex:Et2O) to reveal the title compound as a colorless oil.