Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=5)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>CCO>[F:38][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][NH:30][C:26]1[N:25]=[C:24]([C:23]2[C:18]3[C:19](=[N:20][C:15]([NH:14][CH:11]4[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]4)=[N:16][CH:17]=3)[NH:21][N:22]=2)[CH:29]=[CH:28][N:27]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4ccnc(NCc5cccc(F)c5)n4)n[nH]c3n2)CC1
Agent: Cl
Solvent: CCO
Product: NC1CCC(Nc2ncc3c(-c4ccnc(NCc5cccc(F)c5)n4)n[nH]c3n2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (4-{3-[2-(3-fluoro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester (110 mg, 0.23 mmol) in EtOH (4 mL) was added conc. HCl (4 mL). The reaction mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to afford N-{3-[2-(3-fluoro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-cyclohexane-1,4-diamine; hydrochloride. (Yield 50 mg, 39.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[N:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[N:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCn1ncc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(cnn4CCC(=O)O)c3)no2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.8 %

Procedure:
Ethyl 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]propanoate (D5) (240 mg) was dissolved in MeOH (5 ml), treated with 2 M aqueous NaOH (5 ml) and stirred at RT overnight and vacuumed to remove the MeOH. The reaction mixture was then diluted with 1M aqueous NaOH, washed with EtOAc (×2) and acidified to pH=3. This solution was extracted with EtOAc (×3) and the combined extracts washed with brine and evaporated to give the crude product. This was purified using the MDAP system to give the title compound (13 mg) as a white solid. δH (CDCl3, 400 MHz): 1.44 (6H, d), 3.03 (2H, t), 4.68-4.75 (3H, m), 7.05 (1H, d), 7.60 (1H, d), 8.06 (1H, d), 8.11 (1H, s), 8.15 (1H, d), 8.24 (1H, s), 8.56 (1H, s). MS (ES): C21H1935ClN4O4 requires 426; found 427 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:15]=[C:10]3[CH:9]=[C:8]2[C:20]2[C:25]([F:26])=[C:24](Cl)[N:23]=[CH:22][N:21]=2)=[CH:4][CH:3]=1.C(O)C>[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([S:16]([CH3:19])(=[O:17])=[O:18])[CH:15]=[C:10]3[CH:9]=[C:8]2[C:20]2[C:25]([F:26])=[CH:24][N:23]=[CH:22][N:21]=2)=[CH:28][CH:29]=1
Reactant: CS(=O)(=O)c1cnc2c(c1)cc(-c1ncnc(Cl)c1F)n2Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CS(=O)(=O)c1cnc2c(c1)cc(-c1ncncc1F)n2Cc1ccc(F)cc1
Temperature: 22.5 °C
Reaction time: 1.5 h
Yield: 81.5 %

Procedure:
A mixture of 1-(4-fluorobenzyl)-5-methanesulfonyl-2-(6-chloro-5-fluoropyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine obtained in Example 36 (5) (12 mg), ethanol (1 ml), ethyl acetate (1 ml) and 10% palladium on carbon (10 mg) was stirred under hydrogen stream at 15 to 30° C. for 1.5 hour. The catalyst was filtered through Celite. The filtrate was concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (methanol:dichloromethane=1:99) to obtain the desired product (9 mg) as a white powder.
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=CC=2)=CC=1.[CH3:35][CH:36]([CH3:72])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][C:46]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:66]=[CH:65][CH:64]=[C:63]([C:67]([F:70])([F:69])[F:68])[CH:62]=4)=[O:59])=[CH:53][CH:52]=3)=[CH:47][CH:48]=2)[C:43]1=[O:71])[C:38]([O:40]C)=[O:39]>>[CH3:35][CH:36]([CH3:72])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][C:46]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:66]=[CH:65][CH:64]=[C:63]([C:67]([F:70])([F:68])[F:69])[CH:62]=4)=[O:59])=[CH:53][CH:52]=3)=[CH:47][CH:48]=2)[C:43]1=[O:71])[C:38]([OH:40])=[O:39]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Yield: 97 %

Procedure:
The compound of example 38 was prepared analogous to compound of example 8 by hydrolysis of compound of example 37.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([CH:21]=3)N)[CH2:11][CH2:10]2)[CH:3]=1.N([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].[ClH:35]>O.[Cu]Cl>[Cl:35][C:19]1[CH:21]=[C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=3)[CH2:10][CH2:11]2)[CH:16]=[CH:17][C:18]=1[N+:22]([O-:24])=[O:23].[Cl:35][C:19]1[CH:21]=[C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=3)[CH2:10][CH2:11]2)[CH:16]=[CH:17][C:18]=1[N+:22]([O-:24])=[O:23]
Reactant: Cc1cc(C)nc(N2CCN(c3ccc([N+](=O)[O-])c(N)c3)CC2)c1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: Cc1cc(C)nc(N2CCN(c3ccc([N+](=O)[O-])c(Cl)c3)CC2)c1
Reaction time: 0.25 h
Yield: 54 %

Procedure:
50% Aqueous hydrochloric acid (30 mL) was cooled to −20° C., 5-[4-(4,6-dimethyl-2-pyridyl)piperazin-1-yl]-2-nitro-aniline (1.4 g, 4.28 mmol) was added and the reaction mixture stirred for 15 min. A solution of sodium nitrite (350 mg, 5.14 mmol) in water (8 mL) was added and the reaction mixture stirred for 15 min. This solution was added dropwise to a cooled solution of copper (I) chloride (635 mg, 6.42 mmol) in 50% hydrochloric acid (20 mL) over a period of 20 min and stirred for a further 10 min before basifying with saturated sodium carbonate solution. The mixture was extracted with ethyl acetate and the organic phase was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give a crude residue. Purification by column chromatography over silica gel (100-200 mesh) using 8% ethyl acetate in petroleum ether as eluent afforded 1-(3-chloro-4-nitro-phenyl)-4-(4,6-dimethyl-pyridin-2-yl)-piperazine 1-(3-chloro-4-nitro-phenyl)-4-(4,6-dimethyl-2-pyridyl)piperazine (800 mg, 54%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([N:13]=[N+]=[N-])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[H][H]>CO.[Re]>[CH3:1][O:2][C:3](=[O:16])[CH:4]([NH2:13])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C(CSc1ccccc1)N=[N+]=[N-]
Reactant: [H][H]
Agent: [Re]
Agent: Cl
Solvent: CO
Product: COC(=O)C(N)CSc1ccccc1
Yield: 80.1 %

Procedure:
0.91 gram (3.84 mmoles) of the 2-azido-3-phenylmercapto-propionic acid methyl ester obtained in Example 2 in 8 ml of methanol was treated with 0.28 gram (7.68 mmoles) of hydrogen chloride, 1 mole % of rhenium VII sulfide based on the azido compound employed was added and the mixture hydrogenated in an autoclave at a hydrogen pressure of 60 bar at 25° C. for 3.5 hours. After the end of the reaction the catalyst was filtered off with suction, the solvent remained under reduced pressure and the residue treated with 20 ml of acetone. After addition of 20 ml of diethyl ether for complete precipitation, the precipitate was filtered off with suction, then washed with diethyl ether and dried at 40° C. for 12 hours under reduced pressure. There were obtained 0.65 gram (68% of theory) of 2-amino-3-phenylmercapto-propionic acid methyl ester.HCl with a melting point of 123° to 125° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.Cl.[NH2:10][C@H:11]([CH3:20])[C:12]([NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[O:13].C(=O)([O-])[O-].[K+].[K+]>[Cu]I.CS(C)=O>[Br:8][C:6]1[CH:7]=[C:2]([NH:10][C@H:11]([CH3:20])[C:12]([NH:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[O:13])[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: C[C@@H](N)C(=O)NCC(F)(F)F
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: C[C@@H](Nc1cncc(Br)c1)C(=O)NCC(F)(F)F
Temperature: 120 °C
Yield: 74.8 %

Procedure:
In a microwave vial equipped with a magnetic stirrer, 3,5-Dibromopyridine (Aldrich Chemical) (1 g, 4.22 mmol), (R)-2-amino-N-(2,2,2-trifluoroethyl)propanamide hydrochloride (0.872 g, 4.22 mmol), Potassium carbonate (2.334 g, 16.89 mmol) were added followed by DMSO (6.03 ml, 0.7M). The reaction mixture was stirred and purged under nitrogen for 10 minutes, then Copper (I) Iodide (0.08 g, 0.422 mmol) was added and the reaction mixture was heated in an oil bath at 120° C. for 2 hours. The cooled reaction mixture was then partitioned between Isopropanol (IPA): Chloroform (1:3) and Water, the aqueous layer was extracted with twice with IPA:Chloroform mixture. The combined organic layers were extracted with water, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude sample. Purification on silica (100 g SNAP Biotage column) using 0-5% Methanol/Dichloromethane gave (R)-2-(5-bromopyridin-3-ylamino)-N-(2,2,2-trifluoroethyl)propanamide, I-1, (1.03 g, 74.8% yield) LRMS (ESI) m/z 325.9 [(M+H)+; calcd for C10H11BrF3N3O: 326.01]
Reaction SMILES: [OH:1][C@H:2]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:3][NH:4][C@H:5]([CH3:20])[CH2:6][C:7]1[C:15]2[C:10](=[C:11]([C:16]([O:18]C)=[O:17])[CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1.[OH-].[K+].CO>O>[OH:1][C@H:2]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:3][NH:4][C@H:5]([CH3:20])[CH2:6][C:7]1[C:15]2[C:10](=[C:11]([C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1
Reactant: COC(=O)c1cccc2c(C[C@@H](C)NC[C@H](O)c3cccnc3)c[nH]c12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H](Cc1c[nH]c2c(C(=O)O)cccc12)NC[C@H](O)c1cccnc1

Procedure:
A solution of methyl 3-[(2R)-2-((2R)-2-hydroxy-2-pyridin-3-yl-ethylamino)propyl]-1H-indole-7-carboxylate (440 mg, 1.24 mmol) and potassium hydroxide (1.14 g, 20 mmol) in water (2 mL)/methanol (10 mL) is stirred at room temperature for 19 hours. After concentrated, the resultant is purified by reversed phase column chromatography (octadecylsilyl, trifluoroacetic acid/water/methanol) to give the desired 3-[(2R)-2-((2R)-2-hydroxy-2-pyridin-3-ylethylamino)propyl]-1H-indole-7-carboxylic acid.2 trifluoroacetate (560 mg, yield: 80%).
Reaction SMILES: [CH2:1]([CH:4]([CH2:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7]Br)[CH2:2][CH3:3].CC([O-])(C)C.[K+].O>C1C=CC=CC=1>[CH2:5]([CH:4]([CH2:9][CH2:10][CH3:11])[CH2:1][CH:2]=[CH2:3])[CH2:6][CH3:7]
Reactant: CCCC(CCC)CCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: C=CCC(CCC)CCC
Reaction time: 2 h

Procedure:
To 100 g of 4-propylheptyl bromide in 400 ml of benzene was added 90 g of t-BuOK in 300 ml of DM$0. The temperature was kept below 50° C. during the addition. The mixture was stirred for 2 hrs and 600 ml of water was added. The organic phase was separated and the aqueous phase extracted with petroleumether (b.p. 40°-60°). The combined organic phases were washed with water and brine. After drying with Na2SO4 and evaporation the residue was distilled. Yield: 23.2 g (b.p. 56°-59° C./75 Torr). 1H-NMR(CDCl3): δ0.9(6H,CH3), 1.2(9H,CH2,CH), 2.0(2H,CH2C=C), 4.8-5.1(2H,CH2 =C), 5.5-6.0(1H,CH=C)
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[NH2:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:47][CH2:46][CH2:45][C:44]1=[O:48].OS([O-])(=O)=O.[Na+]>CCO>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][C:21]2[CH:22]=[C:23]3[C:18]([C:17]([OH:32])=[C:16]([C:33]([NH:39][CH2:40][CH2:41][CH2:42][N:43]4[CH2:47][CH2:46][CH2:45][C:44]4=[O:48])=[O:34])[C:15](=[O:38])[N:14]3[CH2:13][CH2:12][NH:3][C:2]([C:10]3[C:5]([C:4]([NH:39][CH2:40][CH2:41][CH2:42][N:43]4[CH2:47][CH2:46][CH2:45][C:44]4=[O:48])=[O:11])=[CH:6][CH:7]=[CH:8][CH:9]=3)=[O:1])=[N:19][CH:20]=2)=[CH:30][CH:29]=1
Reactant: NCCCN1CCCC1=O
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(NCCCN1CCCC1=O)c1ccccc1C(=O)NCCn1c(=O)c(C(=O)NCCCN2CCCC2=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.025 g, 0.049 mmol) in EtOH (1 mL) under nitrogen was treated with 1-(3-aminopropyl)-2-pyrrolidinone (0.0085 mL, 0.061 mmol) for 30 min. 150° C. The reaction was further microwaved for 30 min.@150° C. after the addition of an additional equivalent (0.0085 mL) of the amine, cooled to ambient temperature, and treated with 1N NaHSO4. The resulting suspension was filtered, washed with EtOH and the filtrate was concentrated in vacuo. The filtrate residue was purified by reversed phase HPLC. Pure fractions were combined and concentrated to afford the title compound as a pale yellow glass: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.74 (ddd, J=12.42, 6.11, 5.90 Hz, 2 H), 1.84-1.95 (m, 2 H), 1.99-2.12 (m, 4 H), 2.41 (td, J=8.14, 2.25 Hz, 4 H), 3.21-3.32 (m, 2 H), 3.35-3.50 (m, 10 H), 3.61-3.73 (m, 2 H), 4.07 (s, 2 H), 4.48 (t, J=6.74 Hz, 2 H), 6.91-7.01 (m, 2 H), 7.17-7.23 (m, 2 H), 7.47-7.62 (m, 4 H), 7.71 (dd, J=5.26, 3.44 Hz, 1 H), 7.77 (t, J=5.90 Hz, 1 H), 8.18 (s, 1 H), 8.49 (s, 1 H), 10.31 (t, J=5.76 Hz, 1 H); ES+ MS: 754 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1)=[O:2].[H-].[Na+].[Cl:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21](/[CH:25]=[CH:26]/[C:27]3[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=3)[CH2:30]Cl)=[N:22]2)=[CH:17][CH:16]=1>CN(C=O)C>[Cl:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21](/[CH:25]=[CH:26]/[C:27]3[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=3)[CH2:30][N:9]3[C:10]4[C:6](=[CH:5][CH:4]=[C:3]([CH:1]=[O:2])[CH:11]=4)[CH:7]=[CH:8]3)=[N:22]2)=[CH:17][CH:16]=1
Reactant: O=Cc1ccc2cc[nH]c2c1
Reactant: ClCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc2ccn(Cc3cccc(/C=C/c4ccc5ccc(Cl)cc5n4)c3)c2c1

Procedure:
To a solution of 6-formyl indole (Example 29a) (0.63 g, 4.3 mmol) in dry DMF (20 ml) was added sodium hydride (60% dispersion in oil) (0.22 g, 5.5 mmol) portionwise over 5 minutes with stirring. The reaction mixture was stirred for a further 20 minutes, then solid 3-[2(E)-(7-chloroquinolin-2-yl)ethenyl]benzyl chloride (Example 14b) (1.7 g, 5.4 mmol) was added portionwise over 5 minutes, and the reaction mixture left to stir for 18 hours. The reaction was quenched with water, extracted into ethyl acetate, the combined organic extracts washed with water, then brine, dried, filtered and evaporated in vacuo. The crude solid was purified by flash chromatography on silica, eluting with 30% diethyl ether in hexane to give a pale yellow solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][C:6](=O)[C:5]=12.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17]>N1C=CC=CC=1>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][C:6](=[S:17])[C:5]=12
Reactant: O=C1Nc2ccccc2Cn2cccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: S=C1Nc2ccccc2Cn2cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6.0 g. of 5,10-dihydro-11H-pyrrolo[2,1-c]-[1,4]benzodiazepin-11-one (Example 1), 2.64 g. of phosphorus pentasulfide and 50 ml. of pyridine is stirred and heated at the reflux temperature for 4 hours, and concentrated to remove the pyridine. The residue is treated with 75 ml. of 5% aqueous sodium bicarbonate solution and 5 ml. of methanol and stirred at room temperature overnight. The product crystallizes gradually and is collected, washed with water and dried. This crude product is dissolved in chloroform, passed through a bed of Magnesol® silica gel, and the solvent evaporated to give yellow crystals of 5,10-dihydro-11H-pyrrolo[2,1-c][1,4]benzodiazepin-11-thione, m.p. 228°-231°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([CH:15]=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.[BH4-].[Na+].[ClH:28]>CO>[ClH:28].[ClH:28].[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([CH2:15][NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NCCc1ccccn1
Reactant: O=Cc1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(-c2ccc(CNCCc3ccccn3)o2)cc1
Yield: 87 %

Procedure:
A mixture of 54 g (0.25 mole) of 5-(4-nitrophenyl)-2-furaldehyde and 30.5 g (0.25 mole) of 2-(2-aminoethyl)pyridine in 300 ml of methanol was heated under reflux for 21/2 hours. The resulting solution was cooled to 25°, and 9.5 g (0.25 mole) of sodium borohydride was added in portions over 1 hour at 25°-30°. The solution was heated under reflux for 15 min, and the solvent was removed on a rotary evaporator. The residual solid was partitioned between water and chloroform. The chloroform layer (400 ml) was separated, dried over MgSO4, and concentrated on a rotary evaporator to give 81 g of a reddish brown, oily residue which solidified on standing. The residual solid was dissolved in 400 ml of absolute methanol and treated with 200 ml of absolute methanol saturated with hydrogen chloride with cooling in ice. The yellow solid which was deposited was collected by filtration using a rubber dam and dried in a vacuum oven at oil pump pressure at 100° C. for 8 hr to give 86 g (87%) of product. Two additional recrystallizations from absolute methanol gave an analytical sample, m.p. 173°-177°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](B(O)O)=[CH:7][CH:6]=[CH:5][N:4]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=2)=[C:15]([F:26])[CH:14]=1>>[F:26][C:15]1[CH:14]=[C:13]([C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:18]=[CH:17][C:16]=1[C:19]1[N:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Reactant: COc1ncccc1B(O)O
Product: COc1ncccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using (2-(methoxy)pyridin-3-yl)boronic acid and 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): mass calcd. for C16H13FN4O, 296.11; m/z found, 297.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.62-8.56 (m, 1H), 8.19 (dd, J=1.9, 5.0, 1H), 8.12 (d, J=1.5, 1H), 8.01-7.94 (m, 1H), 7.70-7.65 (m, 1H), 7.48-7.41 (m, 2H), 7.00 (dd, J=5.0, 7.31, 1H), 4.66 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: I[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1.[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)[CH3:21].C(#N)C>C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1)[CH3:21]
Reactant: CCc1ccccc1B(O)O
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(I)nc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCc1ccccc1-c1cn2c(n1)-c1ccc(C(=O)OC)cc1OCC2
Yield: 14.6 %

Procedure:
Methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (80 mg, 1 eq), 2-ethylphenylboronic acid (60 mg, 1.75 eq), and tetrakis(triphenylphosphine)palladium (10 mg, 0.05 eq), in 1.0 M aqueous sodium carbonate (1.0 mL) and acetonitrile (1.0 mL) were heated to 140° C. for 10 min in a sealed microwave reactor. The crude reaction mixture was concentrated and purified using reverse phase HPLC to yield 297 (11 mg). ESI-MS: 349.1 (M)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH2:8].O[C:10]1[C:11]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH2:22])=[O:21])[C:12]=2[N:13]=[N:14][N:15]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:10]1[C:11]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH2:22])=[O:21])[C:12]=2[N:13]=[N:14][N:15]=1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Reactant: NCc1ccccn1
Product: NC(=O)c1cccc2c(NCc3ccccn3)nnnc12

Procedure:
Compound 5 was prepared following general synthetic scheme 7 wherein pyridin-2-ylmethanamine was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [281 (M+1)], 1H NMR (400 MHz, DMSO-d): δ 9.40 (s, 2H), 8.56-8.51 (m, 3H), 8.04 (s, 1H), 8.00 (t, 1H), 7.76-7.72 (m, 1H), 7.40 (d, 1H), 7.29-7.26 (m, 1H), 4.99 (d, 2H).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[CH2:25][OH:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[Cl:27][C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][N:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>ClCCl.O1CCCC1>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:16])[CH2:11][C@H:10]2[CH2:25][O:26][C:31]2[CH:30]=[N:29][C:28]([Cl:27])=[CH:33][CH:32]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: Oc1ccc(Cl)nc1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2CO)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2COc2ccc(Cl)nc2)CC1
Reaction time: 8 h
Yield: 38.4 %

Procedure:
To a cold mixture (ice bath) of (1R,2R,4S)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-hydroxymethyl-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 155, 28.5 mg), 2-chloro-5-hydroxypyridine (19 mg) and triphenyl phosphine (28 mg) in dichloromethane (1 mL) was added a solution of di-tert-butyl-azodicarboxylate (25 mg) in tetrahydrofuran (1 mL). The reaction mixture was stirred overnight then adsorbed unto silica and was purified by flash chromatography on silica gel with a gradient of cyclohexane:ethyl acetate (4:1 to 1:1 v/v) as eluant to afford the title compound (14 mg, 36%) as a colorless solid. MS (EI): 512.0 (M+H)+.