Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O([C:8]1[C:13]([C:14]2[N:18]=[CH:17][NH:16][N:15]=2)=[N:12][N:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10](=[O:25])[CH:9]=1)C1C=CC=CC=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>CCO>[CH:26]([NH:29][C:8]1[C:13]([C:14]2[N:18]=[CH:17][NH:16][N:15]=2)=[N:12][N:11]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:10](=[O:25])[CH:9]=1)([CH3:28])[CH3:27]
Reactant: O=c1cc(Oc2ccccc2)c(-c2nc[nH]n2)nn1-c1ccccc1
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)Nc1cc(=O)n(-c2ccccc2)nc1-c1nc[nH]n1
Temperature: 150 °C

Procedure:
5-Phenoxy-2-phenyl-6-(1H-1,2,4-triazol-3-yl)-3(2H)-pyridazinone (see Example 8) (140 mg, 0.42 mmol), isopropylamine (355 mg, 6 mmol) and EtOH (4 mL) were placed in a 10 mL pressurized reaction vial. The mixture was heated by microwave irradiation at 150° C. for 60 min. The solvent was then evaporated off and the residue was crystallized on treatment with Et2O (15 mL). The crude product was filtered off and recrystallized from a 3:2 mixture of EtOH and Et2O (10 mL) to yield a white crystalline substance (94 mg, 76%). Mp 203-205° C., 1H NMR (400 MHz, DMSO-d6) δ 1.27 (d, 6H, J=6.3 Hz, CH3), 3.71-3.77 (m, 1H, CH(CH3)2), 5.83 (s, 1H, H-4), 7.37-7.66 (m, 5H, C6H5), 8.32 (br s, 1H), 8.46 (br s, 1H) ppm.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:32]([CH2:34][O:35]C(=O)C)=[O:33]>>[OH:35][CH2:34][C:32]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][CH:28]4[CH2:29][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:33]
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c1
Reactant: CC(=O)OCC(=O)Cl
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A171) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([PH:7](=[O:11])[O:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([CH:23]=[CH2:24])[CH:14]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:1]1([P:7]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:21])[CH3:22])=[C:15]([CH:23]=[CH2:24])[CH:14]=2)(=[O:11])[O:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO[PH](=O)c1ccccc1
Reactant: C=Cc1cc(Br)ccc1OC(C)C
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=Cc1cc(P(=O)(OCC)c2ccccc2)ccc1OC(C)C
Temperature: 68 °C
Yield: 87 %

Procedure:
To a degassed mixture of ethyl phenylphosphinate (1.87 g, 11.0 mmol) and 4-bromo-1-isopropoxy-2-vinylbenzene (2.43 g, 10.0 mmol) in acetonitrile (66 mL) were added the triethylamine (3.1 mL, 22.0 mmol), palladium acetate (112 mg, 0.5 mmol), and 1,1′-bis(diphenylphosphino)ferrocene (277 mg, 0.5 mmol). The mixture was further degassed and heated at 68° C. for 24 hrs. The volatiles were removed in vacuo, and the crude was purified by column chromatography using 50 to 80% ethyl acetate in petroleum ether to afford compound BA4 (3.74 g) in 87% yield.
Reaction SMILES: CC1[N:7]=[CH:6]C(COP(O)(O)=O)=C(C=O)C=1O.C(O[CH2:21][CH2:22][C@@H:23]([C:25]([OH:27])=[O:26])[NH2:24])(=O)C>OP([O-])([O-])=O.[K+].[K+]>[C:6]([CH2:21][CH2:22][CH:23]([NH2:24])[C:25]([OH:27])=[O:26])#[N:7]
Reactant: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Reactant: CC(=O)OCC[C@H](N)C(=O)O
Agent: O=P([O-])([O-])O
Agent: [K+]
Product: N#CCCC(N)C(=O)O

Procedure:
Then, 250 μl 200 mM K2HPO4, 10 μl 10 mM pyridoxal phosphate (PLP), 110 μl 25 mM O-acetyl-L-homoserine (OAHS) dissolved in 100 mM K2HPO4, and γ-cyano-α-aminobutyric acid synthase (GCAs) obtained in Example 5 were added to this trapped H11 CN, and the mixture was subjected to enzymatic reaction at 65° C. for 10 minutes.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([F:17])[C:9]=1F.C(=O)(O)[O-].[Na+].O>CS(C)=O>[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([F:17])[C:9]=1[N:4]1[CH:5]=[N:6][C:2]([CH3:1])=[N:3]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: Cc1nc[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ncn(-c2c(F)cc([N+](=O)[O-])cc2F)n1
Temperature: 80 °C
Yield: 18.1 %

Procedure:
Step R (1): A mixture of 3-methyl-1H-1,2,4-triazole (8.12 g, 98 mmol), 1,2,3-trifluoro-5-nitrobenzene (17.3 g, 98 mmol), and sodium bicarbonate (8.21 g, 98 mmol) in DMSO (100 mL) was heated at 80° C. for 24 h. The reaction mixture was allowed to cool to rt and was poured into water (800 mL). The aqueous mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were sequentially washed with water (500 mL) and brine solution (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel chromatography (30-80% EtOAc/hexane, linear gradient) to afford a 1.7:1.0 mixture of two regioisomeric products as an orange solid. The orange solid was recrystallized from EtOAc (hot-cold) to provide 4.25 g of 1-(2,6-difluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole as a white solid. The mother liquor was recrystallized from EtOAc/Hex (hot-rt) to afford 1.89 g of 1-(2,6-difluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole as a light yellow solid. The mother liquor was repeatly chromatographed under the previously stated conditions to provide two samples. One sample was partially enriched in the slightly less polar isomer, 1-(2,6-difluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole. The other sample was partially enriched in the slightly more polar isomer, 1-(2,6-difluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole. Both samples were independently recrystallized from EtOAc/Hex to provide an additional 1.9 g of 1-(2,6-difluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole and 1.37 g of 1-(2,6-difluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole. A combined total of 6.15 g (26% yield) of 1-(2,6-difluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole and 3.2 g (13% yield) of 1-(2,6-difluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[Br:15][CH2:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1sc2ccccc2c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COC(=O)c1sc2ccccc2c1CBr
Temperature: 25 °C
Yield: 82 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and reflux condenser was purged with nitrogen and charged with methyl 3-methylbenzo[b]thiophene-2-carboxylate (2.00 g, 9.70 mmol) and benzene (20 mL). N-bromosuccinimide (1.72 g, 9.70 mmol) and 2,2′-azobisisobutyronitrile (160 mg, 1.00 mmol) were added, and the mixture was refluxed for 2 h. After this time, the mixture was cooled to room temperature and filtered. The filter cake was rinsed with carbon tetrachloride (20 mL) and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford 103a in 82% yield (2.27 g) as a white solid: mp 101-102° C.; 1H NMR (500 MHz, CDCl3) d 7.97 (m, 1H), 7.86 (m, 1H), 7.51 (m, 2H), 5.22 (s, 2H), 3.97 (s, 3H).
Reaction SMILES: C[Al](C)C.[C:5]([C:9]1[CH:29]=[CH:28][C:12]([CH2:13][NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:18]=2)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].C[O:31][C:32]([C:34]1[N:35]=[CH:36][CH:37]=[C:38]2[CH:42]=[CH:41][NH:40][C:39]=12)=O>ClCCl>[C:5]([C:9]1[CH:29]=[CH:28][C:12]([CH2:13][N:14]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]([F:26])([F:27])[F:25])[CH:18]=2)[C:32]([C:34]2[N:35]=[CH:36][CH:37]=[C:38]3[CH:42]=[CH:41][NH:40][C:39]=23)=[O:31])=[CH:11][CH:10]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: COC(=O)c1nccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)c(C(F)(F)F)c2)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)c(C(F)(F)F)c2)C(=O)c2nccc3cc[nH]c23)cc1
Yield: 100.5 %

Procedure:
Trimethylaluminum solution (2 M in heptane, 0.14 mL, 0.28 mmol) was added at RT to a solution of (4-tert-butyl-benzyl)-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-amine (100 mg, 0.28 mmol) in dichloromethane (0.7 mL), then after 15 min a solution of 1H-pyrrolo[2,3-c]pyridine-7-carboxylic acid methyl ester (50 mg, 0.14 mmol) in dichloromethane was added. After 2 h the reaction mixture was partitioned between ethyl acetate and 2 M aq. hydrochloric acid solution. The organic layer was washed with brine, dried (MgSO4), evaporated, and chromatographed (SiO2, heptane/ethyl acetate gradient), to afford the title compound (70 mg, 50%). White foam, MS (ISP) 498.3 (M+H)+.
Reaction SMILES: BrC1C=CC(Cl)=C(S(Cl)(=O)=O)C=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:24]([F:27])([F:26])[F:25])=[C:18]([S:20](Cl)(=[O:22])=[O:21])[CH:19]=1.[CH2:28]1[O:37][C:36]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=2[O:29]1>>[O:37]1[C:36]2[CH:35]=[CH:34][C:32]([NH:33][S:20]([C:18]3[CH:19]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=3[C:24]([F:27])([F:26])[F:25])(=[O:22])=[O:21])=[CH:31][C:30]=2[O:29][CH2:28]1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1C(F)(F)F
Reactant: Nc1ccc2c(c1)OCO2
Agent: O=S(=O)(Cl)c1cc(Br)ccc1Cl
Product: O=S(=O)(Nc1ccc2c(c1)OCO2)c1cc(Cl)ccc1C(F)(F)F

Procedure:
This compound is prepared analogously to Intermediate E (step 2) by replacing S-bromo-2-chloro-benzenesulfonyl chloride with 5-chloro-2-trifluoromethyl-benzenesulfonyl chloride and by replacing aniline with 3,4-(methylenedioxy)aniline to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([OH:24])=O)=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([N:33]([CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:29][CH2:28]1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([NH:26][C@H:27]3[CH2:28][CH2:29][C@H:30]([N:33]([CH2:38][C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:31][CH2:32]3)=[O:24])=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCN(CC(=O)OC(C)(C)C)[C@H]1CC[C@H](N)CC1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc2oc(C(=O)O)cc2c1
Product: CCCCN(CC(=O)OC(C)(C)C)[C@H]1CC[C@H](NC(=O)c2cc3cc(C(=N)NC(=O)OCc4ccccc4)ccc3o2)CC1

Procedure:
In the same manner as in Example 15 (3), 5-(benzyloxycarbonylamidino)-2-benzofurancarboxylic acid (785 mg, 2.32 mmol) and t-butyl trans-(4-aminocyclohexyl-N-n-butylamino)acetate (680 mg, 2.32 mmol) were condensed and purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1-1/4) to give 1.06 g of t-butyl trans-[4-[[5-(benzyloxycarbonylamidino)-2-benzofuranyl)carbonylamino)cyclohexyl-N-n-butylamino]acetate as a colorless solid (75%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH2:25][CH3:26])=[C:18](/[F:24])\[C:19](OCC)=[O:20])[C:3]=1[O:27][CH2:28][CH3:29].[H-].C([Al+]CC(C)C)C(C)C>>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:15])[CH3:16])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH2:25][CH3:26])=[C:18](/[F:24])\[CH2:19][OH:20])[C:3]=1[O:27][CH2:28][CH3:29]
Reactant: CCOC(=O)/C(F)=C(/CC)c1cc2c(c(Br)c1OCC)C(C)(C)CC=C2C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CCOc1c(/C(CC)=C(/F)CO)cc2c(c1Br)C(C)(C)CC=C2C(C)C

Procedure:
Following General Procedure G-1, ethyl (2E)-3-(4-bromo-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-pent-2-enoate (Compound A-126, 1.07 g, 2.29 mmol) and diisobutylaluminum hydride (1M in methylene chloride, 5.5 mL, 5.5 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 10% ethyl acetate in hexanes).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2(OC)[C@H:15]([OH:16])[C@@H:14]([OH:17])[C@H:13]([OH:18])[C@@H:12]([CH2:19][OH:20])[O:11]2)=[CH:4][C:3]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][CH:25]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl.CC#N>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:10]2[C@H:15]([OH:16])[C@@H:14]([OH:17])[C@H:13]([OH:18])[C@@H:12]([CH2:19][OH:20])[O:11]2)=[CH:4][C:3]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][CH:25]=1
Reactant: CCOc1ccc(Cc2cc(C3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc(OC)c2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOCC
Product: CCOc1ccc(Cc2cc(C3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc(OC)c2Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of triol 74-3 (6.6 g, 14.14 mmol) in CH2Cl2/CH3CN (70 mL/70 mL) were added triethylsilane (4.5 mL, 28.28 mmol) and boron trifluoride diethyl etherate (3.6 mL, 28.28 mmol) at −50° C. The mixture was warmed up to 0° C. slowly and stirred at 0° C. for 2 hours. To the mixture was added aq. saturated NaHCO3 solution (50 mL) slowly and extracted with EtOAc (100 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was carried on to the next step without purification.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[CH2:6][NH:5][C:4]1=[O:14].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]2.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25]([NH:2][C@H:3]1[CH2:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[CH2:6][NH:5][C:4]1=[O:14])=[O:26])=[CH:19]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: N[C@H]1Cc2ccccc2CNC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1Cc2ccccc2CNC1=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C

Procedure:
A mixture of (S)-4-amino-2,3,4,5-tetrahydro-2-benzazepin-3(1H)-one hydrochloride (all of that prepared above), tetrahydrofuran (25 mL), 5-chloroindole-2-carboxylic acid (198 mg), 1-hydroxy-7-azabenzotriazole (150 mg), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (210 mg) was stirred at room temperature. Diisopropylethylamine (202 mg) was added, and after 16 h the resulting yellow solution was evaporated under vacuum. The residue was dissolved in ethyl acetate (150 mL), and this was washed sequentially with 1.0 M aqueous hydrochloric acid (50 mL twice), 1.0 M aqueous sodium hydroxide (50 mL), water (50 mL), and brine (25 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum to provide crude product. The product was crystallized by dissolving in warm methanol (40 mL) and adding diethyl ether (100 mL). The crystals were filtered, washed with diethyl ether (30 mL twice), and dried under vacuum to provide the title compound (181 mg). HPLC/MS [M+H]+, 354.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:10]=1[CH2:11][N:12]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)[CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:10]=1[CH2:11][N:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]2[NH:30][N:29]=[N:28][N:20]=2)=[CH:21][CH:22]=1)[CH2:13][CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(-c2nnn[nH]2)cc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A mixture of 4-[N-(2-benzyloxy-5-bromobenzyl)-N-ethyl-amino]benzonitrile (3.79 g), sodium azide (0.9 g) and ammonium chloride (1.4 g) in N,N-dimethylformamide (30 mL) was heated and stirred at 120° C. for 18 hours. The reaction mixture was allowed to cool and was poured into water (100 mL). The precipitate was filtered and dried. On crystallization from acetic acid there was obtained 5-[4-[N-(2- benzyloxy-5-bromobenzyl)-N-ethylamino)phenyl]tetrazole, yield 1.2 g, mp 206°-208° C.
Reaction SMILES: C([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2COC(=O)C1C=CC=CC=1)(=O)C(C)C.CC1C=CC=CC=1N>O1CCOCC1>[N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)c1cnc2c(COC(=O)c3ccccc3)cccc2c1Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1N
Product: c1ccc2ncccc2c1
Reaction time: 1 h
Yield: 113 %

Procedure:
A solution of 3-isobutyryl-4-chloro-8-benzoyloxymethylquinoline (3.68 g, 10 mmol) and 2-methylaniline (2.13 ml, 20 mmol) in dioxan (50 ml) was heated at reflux for 2 hours, then evaporated, taken up in dichloromethane, washed with aqueous sodium bicarbonate, water and brine, dried and evaporated to an oil. This was taken up in 1% methanolic sodium hydroxide solution (100 ml) and stirred vigorously for 1 hour. The methanol was evaporated, water and dichloromethane added, the aqueous phase adjusted to pH 10 and extracted with dichloromethane. The organic extracts were dried, evaporated and chromatographed (silica, gel, 1%-2% methanol in dichloromethane). Trituration of the product fractions with ether followed by recrystallization from aqueous methanol gave 3-isobutyryl-4-(2-methylphenylamino)-8-hydroxymethyl)quinoline (1.46 g, 44%), m.p. 116°-118°.
Reaction SMILES: [CH3:1][S:2]([CH2:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][N:8]=1)=[O:6])=O.C(OCC)(=O)C.Cl.C([Br:28])(=O)C>ClCCl>[CH3:1][S:2][CH:4]([Br:28])[C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][N:8]=1)=[O:6]
Reactant: CC(=O)Br
Reactant: CS(=O)CC(=O)c1cc(-c2ccccc2)on1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CSC(Br)C(=O)c1cc(-c2ccccc2)on1
Yield: 103.5 %

Procedure:
A reaction identical with that of Example 3 is performed on the 3-methylsulfinylacetyl-5-phenylisoxazole (1.25 g) prepared in a manner similar to that described in Example 1 or 2 with the exception that the ethyl acetate solution of hydrogen chloride is replaced by a solution of acetyl bromide (741 mg, 6.025 milimoles) in dichloromethane (10 ml) to give 3-(2-methylthio-2-bromoacetyl)-5-phenylisoxazole (1.62 g, 103.5 %) as a crude crystalline residue.
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[C:8](=[O:26])[NH:7][C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]1=2)(=[O:3])[CH3:2].Br[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]([C:42]2[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=2[C:44]#[N:45])[N:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[C:8](=[O:26])[N:7]([CH2:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]([C:42]3[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=3[C:44]#[N:45])[N:34]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]1=2)(=[O:3])[CH3:2]
Reactant: N#Cc1ccccc1-n1nc(CBr)c2ccccc21
Reactant: CC(=O)N1c2ccccc2NC(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccccc2N(Cc2nn(-c3ccccc3C#N)c3ccccc23)C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.2 %

Procedure:
To a rt solution of tert-butyl(S)-1-((2S,3S)-1-acetyl-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (84.6 mg, 202 μmol) in DMF (505 μl) was added 2-(3-(bromomethyl)-1H-indazol-1-yl)benzonitrile (75.7 mg, 243 μmol), cesium carbonate (85.6 mg, 263 μmol), and sodium iodide (39.4 mg, 263 μmol). The reaction was stirred at rt for 16 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((2S,3S)-1-acetyl-5-((1-(2-cyanophenyl)-1H-indazol-3-yl)methyl)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (79 mg, 60%) as a white solid. MS m/z 672 (MNa)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]2[NH:7][C:8](=[O:27])[N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH:30]1[C:40]2[C:41]3[CH:32]([CH2:33][C:34](=[O:42])[NH:35][C:36]=3[CH:37]=[CH:38][CH:39]=2)[CH2:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]2[NH:7][C:8](=[O:27])[N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([C:24]([N:30]5[C:40]6[C:41]7[CH:32]([CH2:33][C:34](=[O:42])[NH:35][C:36]=7[CH:37]=[CH:38][CH:39]=6)[CH2:31]5)=[O:25])[CH:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ccn3)CC1)C(=O)N2
Reactant: O=C1CC2CNc3cccc(c32)N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CC5CC(=O)Nc6cccc4c65)ccn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
67 mg (0.17 mmol) 4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylic acid and 30 mg (0.17 mmol) 1,2,2a,5-tetrahydro-3H-pyrrolo[4,3,2-de]quinolin-4-one in 56 μL (0.40 mmol) TEA and 1.8 mL DMF were combined with 58 mg (0.18 mmol) TBTU and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [C:1]([C:4]1[C:5]([F:16])=[C:6](N)[C:7]([O:13][CH3:14])=[CH:8][C:9]=1OCC)(=[O:3])[CH3:2].[CH3:17][C:18](C1C=CC(OC)=CC=1F)=[O:19].C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:16][C:5]1[CH:6]=[C:7]([O:13][CH3:14])[CH:8]=[CH:9][C:4]=1[C:1]1([CH3:2])[O:3][CH2:17][CH2:18][O:19]1
Reactant: COc1ccc(C(C)=O)c(F)c1
Reactant: CCOc1cc(OC)c(N)c(F)c1C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: OCCO
Product: COc1ccc(C2(C)OCCO2)c(F)c1

Procedure:
Starting material 3-acetyl-2-fluoro-6-methoxyphenetyl-amine, was prepared in following manner: A mixture of 2-Fluoro-4-methoxyacetophenone (5 g) (Fluorochem), ethylene glycol (4 ml), and p-toluensulfonic acid (50 mg) in toluene was refluxed 10 hours to give 5.7 g of 2-(2-fluoro-4-methoxyphenyl)-2-methyl-1,3-dioxolane. This was converted to 2-fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)-benzaldehyde according to Example 362 of WO 93/03022. This compound was converted to 2-fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)-cinnamic acid ethylester according to the methods described in Example 353 of WO 93/03022. 2-Fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)cinnamic acid ethylester was then treated with KOH in dioxane and water to yield 2-fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)cinnamic acid. Hydrolysis with aqueous HCl in dioxane gave 3-acetyl-2-fluoro-6-methoxycinnamic acid. N-(3-Acetyl-2-fluoro-6-methoxyphenetyl)-N'-(5-chloropyrid-2-yl)-urea was then prepared in a manner analogous to the method in Example 7. 1H NMR (250 MHz, CDCl3) δ 9.18 (br s, 1H), 8.97 (br s, 1H), 7.85 (d, 1H), 7.83 (t, 1H), 7.51 (dd, 1H), 6.83 (d, 1H), 6.70 (d, 1H), 3.82 (s, 3H), 3.57 (g, 2H), 3.08-2.92 (m, 2H), 2.51 (d, 3H).