Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:7][CH:8]=1.C(Cl)(=O)C(Cl)=O.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([C:31]([NH:33][NH2:34])=[O:32])=[CH:28][CH:29]=2)[CH:24]=[N:23]1.C(=O)([O-])O.[Na+]>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[F:14][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([NH:34][NH:33][C:31]([C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[NH:22][N:23]=[CH:24]3)=[O:32])=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: NNC(=O)c1ccc2[nH]ncc2c1
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(CCc1cccc(C(F)(F)F)c1)NNC(=O)c1ccc2[nH]ncc2c1
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
To a solution of 3-[3-(trifluoromethyl)phenyl]propionic acid (437 mg, 2.00 mmol) and N,N-dimethylformamide (1 drop) in tetrahydrofuran (4 mL) was added oxalyl chloride (0.183 mL, 2.10 mmol) at room temperature, and the resulting mixture was stirred for 30 min. The reaction mixture was added dropwise to a mixture of 1H-indazole-5-carbohydrazide (352 mg, 2.00 mmol), tetrahydrofuran (10 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) at room temperature, and the resulting mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane/ethanol to give the title compound (383 mg, yield 51%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.Cl.[NH2:22][C@@H:23]([C:28]([NH:30][CH2:31][C:32]([NH:34][C@H:35]([C:43]([NH:45][CH:46]1[CH:53]2[CH2:54][CH:49]3[CH2:50][CH:51]([CH2:55][CH:47]1[CH2:48]3)[CH2:52]2)=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:33])=[O:29])[CH2:24][CH2:25][S:26][CH3:27]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([NH:22][C@@H:23]([C:28]([NH:30][CH2:31][C:32]([NH:34][C@H:35]([C:43]([NH:45][CH:46]1[CH:53]2[CH2:54][CH:49]3[CH2:50][CH:51]([CH2:55][CH:47]1[CH2:48]3)[CH2:52]2)=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:33])=[O:29])[CH2:24][CH2:25][S:26][CH3:27])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CSCC[C@@H](N)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NC1C2CC3CC(C2)CC1C3
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NC1C2CC3CC(C2)CC1C3

Procedure:
The title compound was prepared by the general method of Example 1 using t-butoxycarbonyl-L-phenylalanine (2.3 g, 8.6 mmole) and the title product of Example 6 (4.5 g, 8.6 mmole) in 50 ml of dichloromethane stirred with 5A molecular sieves. The crude product was purified by column chromatography on silica gel, giving 4.7 g of analytically pure title compound.
Reaction SMILES: C(O[C:4](=[O:9])[CH2:5][C:6]([CH3:8])=O)C.[CH2:10]([CH:13]([NH:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][CH3:12]>C(O)C>[CH3:8][C:6]1[NH:21][N:20]([CH:13]([CH2:10][CH2:11][CH3:12])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:4](=[O:9])[CH:5]=1
Reactant: CCCC(NN)c1ccccc1
Reactant: CCOC(=O)CC(C)=O
Solvent: CCO
Product: CCCC(c1ccccc1)n1[nH]c(C)cc1=O

Procedure:
13 g of acetoacetic acid ethyl ester were dissolved in 20 ml of absolute ethanol. 16.4 g of α-n-propylbenzylhydrazine in a little absolute ethanol were slowly added to this solution under nitrogen. After the exothermic reaction had subsided, the mixture was heated for 2 hours under reflux.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][C:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[NH2:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45].C(N(CC)CC)C>CN(C)C=O>[CH3:15][CH:2]([CH3:1])[CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])=[O:12])=[CH:13][CH:14]=1)=[O:5]
Reactant: CC(C)CC(=O)c1ccc(C(=O)O)cc1
Reactant: COC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)c1ccc(C(=O)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 74.6 %

Procedure:
To a solution of 4-(3-methylbutanoyl)benzoic acid (9.5 g, 46 mmol) in N,N-dimethylformamide (80 mL) was added O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (26.3 g, 69.1 mmol) at 0° C. The mixture was stirred for 40 minutes. Methyl 3-aminopropanoate hydrochloride (7.72 g, 55.3 mmol) and triethylamine (23.3 g, 230 mmol) were added and the reaction was allowed to warm to room temperature and stir for 16 hours. The reaction mixture was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography gave methyl 3-(4-(3-methylbutanoyl)benzamido)propanoate (10 g, 77%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, δ): 7.98 (d, J=8.0 Hz, 2H), 7.83 (d, J=8.4 Hz, 2H), 6.91 (s, 1H), 3.72-3.76 (m, 5H), 2.84 (d, J=6.0 Hz, 2H), 2.66-2.69 (t, J=6.0 Hz, 2H), 2.23-2.33 (m, 1H), 0.99 (d, J=6.4 Hz, 6H).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCCCC.Br[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[C:18]([CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[N:17][N:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>O1CCCC1.[Cl-].[Cl-].[Zn+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:28][O:27][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][C:22]=1[O:25][CH3:26])[C:15]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[N:16][N:17]=[C:18]2[CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1
Reactant: [Li]c1ccccc1
Reactant: COc1cc2c(Br)nnc(Cc3ccncc3)c2cc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc2c(Cc3ccncc3)nnc(-c3ccccc3)c2cc1OC

Procedure:
In dry environment, ZnCl2 (379 mg, 2.78 mmoles) was dissolved in tetrahydrofuran (20 ml), then the temperature was brought to 0° C. and a 2M solution of phenyl lithium in hexane (1.4 ml, 2.8 mmoles) was dropped therein. The temperature was left to rise to room value and 1-bromo-6,7-dimethoxy-4-pyridin-4-ylmethyl-phthalazine (500 mg, 1.39 mmoles), obtained as described in example 65, palladium acetate (15 mg, 0.0695 mmole) and triphenylphosphine (36 mg, 0.139 mmole) were added and the whole was refluxed for 1.5 hour. The reaction was stopped with some drops of NaOH, then the mixture was dried and the residue taken up in water and CH2Cl2. The organic phase was dried to yield a residue which was chromatographed (eluent:methylene chloride, then methylene chloride/2% methanol, then methylene chloride/5% methanol). The eluate was dissolved in methylene chloride, treated with TONSIL® and filtered over celite. The mother liquor was dried yielding 172 mg of the title product.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][N:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1>C(O)(=O)C.[Pt](=O)=O>[F:21][C:2]([F:1])([F:22])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]2[CH2:10][CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:16][CH2:17][NH:18]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccnc(Cc2ccc(OC(F)(F)F)cc2)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(Cc2ccc(OC(F)(F)F)cc2)C1
Reaction time: 5 h
Yield: 99.9 %

Procedure:
To a solution of methyl 2-(4-(trifluoromethoxy)benzyl)isonicotinate (8.04 g, 25.83 mmol) in acetic acid (40 mL) was added platinum(IV) oxide (0.343 g, 1.51 mmol) and the resulting mixture hydrogenated at 5 bar in a Büchi hydrogenator for 5 h. The reaction mixture was filtered through a diatomeous earth filter carton and the catalyst washed with methanol. The solvents were evaporated, the residue dissolved in DCM and washed with 10% Na2CO3. After phase separation the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4 and evaporated. Methyl 2-(4-(trifluoromethoxy)benzyl)piperidine-4-carboxylate (8.19 g, 100%) was isolated as a dark brown oil. MS m/z 318 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)=[N:5][C:4]([N:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:3]1.[BH4-].[Na+]>CO>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:20])[CH3:21])[CH:13]=2)=[N:5][C:4]([NH:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:3]1
Reactant: CN(C)Cc1cccc(OCCCNc2nc(N=Cc3ccccc3)nn2C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1cccc(OCCCNc2nc(NCc3ccccc3)nn2C)c1
Reaction time: 12 h
Yield: 69.6 %

Procedure:
A mixture of 1-methyl-N3 -phenylmethylene-N5 -[3-[3-[(dimethylamino)methyl]phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (2.0 g) and sodium borohydride (0.95 g) in methanol was stirred at 25° for 12 hr. The mixture was poured onto water and extracted with ethyl acetate. The organic extract was washed with brine and distilled to give the title compound as a pale yellow oil (1.4 g) b.p. 180° (0.04 mm). TLC silica; methanol:ammonia (80:1) Rf 0.7.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.[Br-].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Zn+].C1COCC1>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=4)=[CH:3][C:4]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Reactant: [Zn+]c1ccccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ccccn4)cc3C)c(C)nc12
Temperature: 65 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a mixture of 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.50 g, 1.27 mmol) and PdCl2(dppf) (0.047 g, 0.064 mmol) is added a 0.5 M solution of 2-pyridylzinc bromide in THF (5.1 mL, 2.55 mmol). The mixture is stirred at 65° C. overnight, diluted with EtOAc (50 mL), washed with 10% citric acid (50 mL), water (40 mL), brine (40 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (20%-40% EtOAc/hexane gradient) furnish the title compound (0.45 g, 1.15 mmol, 89%). 1H NMR (CDCl3), δ 0.88 (t, J=7.5 Hz, 6H), 1.75-1.93 (m, 4H), 2.17 (s, 3H), 2.52 (s, 6H), 3.30-3.39 (m, 1H), 6.67 (s, 1H), 7.12-7.16 (m, 1H), 7.53 (s, 1H), 7.63-7.71 (m, 2H), 8.57 (dt, J=1.3, 4.8 Hz, 1H). LC/MS (m/z): calcd. for C23H26N4S (M+H)+: 391.6; found: 391.2.
Reaction SMILES: Cl.[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6]([NH2:17])[C:5]=2[CH:4]=1.[CH2:18]([C@H:26]1[CH2:31]N[CH2:29][CH2:28][NH:27]1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O.C1(C)C=CC=CC=1>[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6]([N:17]3[CH2:29][CH2:28][NH:27][C@@H:26]([CH2:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:31]3)[C:5]=2[CH:4]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Reactant: c1ccc(CC[C@H]2CNCCN2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccccc2)C1
Yield: 67.9 %

Procedure:
Heat a suspension of 2-methyl-4H-3-thia4,9-diaza-benzo[f]-azulen-10-ylamine hydrochloride (466 mg, 1.75 mmol) and 2-(S)-phenethyl-piperazine (1.0 g, 5.3 mmol) in DMSO (2.5 mL) and toluene (10 mL) at reflux for 48 hours. Evaporate the toluene under vacuo and pour the resulting solution into water (10 mL). Purify the resulting brown solid by flash chromatography eluting with methylene chloride/methanol (95:5) to give 2-methyl-10-(3-(S)-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene as a yellow solid (478 mg, 65%): mp 75–84° C.; 1H NMR(CDCl3): δ1.76 (m, 2H), 2.31 (s, 3H), 2.60 (dd, 1H), 2.71 (m, 2H), 2.80 (m, 1H), 2.92 (m, 2H), 3.04 (m, 1H), 3.96 (m, 1H), 4.12 (m, 1H), 4.91 (s, 1H), 6.29 (s, 1H), 6.60 (d, 1H), 6.89 (t, 1H), 6.96 (t, 1H), 7.03 (d, 1H), 7.15–7.30 (m, 5H); MS (APCI) m/z (rel intensity) 403 (100).
Reaction SMILES: [C:1]([N:8]([CH3:19])[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>CC(C)=O>[C:1]([N:8]([CH3:19])[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:27][C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[CH:14][CH:13]=1)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CN(CC(=O)c1ccc(O)cc1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(CC(=O)c1ccc(OCC(=O)OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 92.7 %

Procedure:
A mixture of 4-[2-(BOC-methylamino)acetyl]phenol (5.04 g, 19.0 mmol) and K2CO3 (2.63 g, 19.0 mmol) in acetone (100 mL) was stirred at reflux under argon for 1 h. The mixture was cooled to RT and benzyl bromoacetate (5.23 g, 22.8 mmol) was added. The reaction was heated at reflux for 18 h, then was cooled and filtered. The filter cake was washed with acetone, and the filtrate was concentrated on the rotavap. The residue was dissolved in CH2Cl2 (300 mL) and washed sequentially with H2O (50 mL) and brine (50 mL). Drying (Na2SO4), concentration, and silica gel flash chromatography (1:3 EtOAc/hexanes) yielded the title compound (7.28 g, 93%): 1H NMR (250 MHz, CDCl3) δ 6.85-7.95 (m, 9 H), 5.23 (s, 2H), 4.71 (s, 2H), 4.55 (d, 2H), 2.95 (d, 3H), 1.45 (d, 9H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[O:2].[OH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH2:16][CH2:15]1
Reactant: O=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1ccc(S(=O)(=O)N2CCC(O)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4-formyl-benzenesulfonyl chloride (1.0 g) in DCM (10 mL) was added 4-hydroxypiperidine (0.984 g), followed by NaHCO3 (10 mL, aq sat'd) and the mixture stirred for 2 h at RT. The aqueous layer was washed with DCM (2×25 mL), and the combined organic portions washed with brine, dried over Na2SO4, filtered, and the solvent removed under reduced pressure to provide 4-(4-hydroxypiperidine-1-sulfonyl)benzaldehyde. The product was purified on anhydrous silica (10% MeOH/DCM). M+H 269.9
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.[Cl:17][C:18]1[S:22][N:21]=[C:20]([CH2:23]Cl)[N:19]=1>>[Cl:17][C:18]1[S:22][N:21]=[C:20]([CH2:23][N:3]2[C:4]3[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[N:19]=1
Reactant: ClCc1nsc(Cl)n1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nsc(Cl)n1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 5-chloro-3-(chloromethyl)-1,2,4-thiadiazole: MS (ES) m/z 357 (M+1) and 359 (M+1, isotope).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:8]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:9]=3[S:10](=O)(=O)[CH:11]=2)=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.CCOC(C)=O.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:8]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:9]=3[S:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)S(=O)(=O)C=C2Oc1ccc(Br)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2c(Oc3ccc(Br)cc3)csc2c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 71.4 %

Procedure:
To a solution of 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (230 g, 626 mmol) in THF (3450 mL) was added DIBAL-H (1.0 M in DCM, 3132 mL, 3132 mmol). The mixture was heated to 60° C. for 18 hours. The mixture was cooled down to 40° C. DIBAL-H (1.0 M in DCM or Toluene, 500 mL, 500 mmol) was added. The mixture was refluxed for 6 hours. DIBAL-H (1.0 M in DCM, 300 mL, 300 mmol) was added. The mixture was refluxed for 8 hours, after which time the reaction was cooled to 0° C. over 2 hours. EtOAc (1226 mL) was added very slowly. Rochelle salt solution (884 g, 626 mmol in 6000 mL water) was slowly added (over 3 hours). The resulting solution was aged at room temperature for 18 hours. The organic layer was separated from the aqueous layer. The aqueous layer was extracted with EtOAc (1000 mL). The combined organic layer was washed with brined, dried with anhydrous Na2SO4 and concentrated in vacuo to afford 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene (149.8 g, 446.9 mmol, 71% yield) as a white solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ ppm=3.81 (s, 3 H), 6.46 (s, 1 H), 6.90 (d, J=9.09 Hz, 3 H), 7.16-7.22 (m, 1 H), 7.31-7.40 (m, 2H), 7.46 (d, J=9.09 Hz, 1 H), LC/MS (m/l, MH+): 336.8.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[N:7][O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:27]=[C:26](F)[C:25]([F:29])=[CH:24][C:23]=1[C:30](=[O:32])[CH3:31].CCN(C(C)C)C(C)C>CS(C)=O>[CH:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][N:7]=[C:4]2[CH2:3][CH2:2][N:1]([C:26]3[CH:27]=[C:22]([F:21])[C:23]([C:30](=[O:32])[CH3:31])=[CH:24][C:25]=3[F:29])[CH2:6][CH2:5]2)[CH2:14][CH2:13]1)=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Reactant: CC(=O)c1cc(F)c(F)cc1F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(F)c(N2CCC(=NOC3CCN(C(=O)OC(C)C)CC3)CC2)cc1F
Temperature: 130 °C
Yield: 62 %

Procedure:
Compound 2d (0.22 g, 0.78 mmol), 1-(2,4,5-trifluoro-phenyl)-ethanone (0.22 mL), DIEA (0.22 mL, 1.33 mmol), and DMSO (2 mL) were combined and heated at 130° C. for 20 h. The mixture was cooled to room temperature and purified by flash chromatography (eluent: 10 to 40% EtOAc+0.1% triethylamine in hexane) to afford 211 mg (62% yield) of 4-[1-(4-acetyl-2,5-difluoro-phenyl)-piperidin-4-ylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester 50a: LC-MS 438.0 (MH+).
Reaction SMILES: [CH:1](C1C=CC(CC2C(=O)NC3C=CC(Cl)=CC=3C(C3C=CC(O)=CC=3)=N2)=CC=1)([CH3:3])[CH3:2].C([C:34]1[CH:61]=[CH:60][C:37]([CH2:38][CH:39]2[C:45](=[O:46])[N:44]([CH3:47])[C:43]3[CH:48]=[CH:49][C:50]([Cl:52])=[CH:51][C:42]=3[C:41]([C:53]3[CH:58]=[CH:57][C:56]([OH:59])=[CH:55][CH:54]=3)=[N:40]2)=[CH:36][CH:35]=1)(C)C>>[CH:1]([C:35]1[CH:36]=[C:37]([CH:60]=[CH:61][CH:34]=1)[CH2:38][CH:39]1[C:45](=[O:46])[N:44]([CH3:47])[C:43]2[CH:48]=[CH:49][C:50]([Cl:52])=[CH:51][C:42]=2[C:41]([C:53]2[CH:54]=[CH:55][C:56]([OH:59])=[CH:57][CH:58]=2)=[N:40]1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CC2N=C(c3ccc(O)cc3)c3cc(Cl)ccc3N(C)C2=O)cc1
Reactant: CC(C)c1ccc(CC2N=C(c3ccc(O)cc3)c3cc(Cl)ccc3NC2=O)cc1
Product: CC(C)c1cccc(CC2N=C(c3ccc(O)cc3)c3cc(Cl)ccc3N(C)C2=O)c1

Procedure:
1H NMR (300 MHz, DMSO-d6) δ 1.18 and 1.21 (two d, 6H), 2.84 (heptet, 1H), 3.3-3.4 (m, 5H; contains NMe singlet at 3.34), 3.82 (t, 1H), 6.85 (d, 2H), 7.0-7.3 (m, 5H), 7.38 (d, 2H), 7.64 (d, 1H), 7.77 (dd, 1H), 9-11 (br s, 1H). MS, m/z 433.2 [M+1]. (Z)-3-(4-Isopropylbenzyl)-7-chloro-5-(4-hydroxyphenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one. 1H NMR (300 MHz, DMSO-d6) 1.15 (d, 6H), 2.82 (septet, 1H), 3.24-3.38 (m, 2H), 3.63 (m, 1H), 6.79 (m, 2H), 7.10-7.30 (m, 8H), 7.59 (dd, 1H), 9.45 (s, 1H), 10.61 (s, 1H). MS, m/z 419.3 [M+1]. (Z)-3-(4-Isopropylbenzyl)-7-chloro-5-(4-hydroxyphenyl)-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one. 1HNMR (300 MHz, DMSO-d6) δ 1.15 (d, 6H), 2.84 (septet, 1H), 3.26-3.41 (m, 5H), 3.77 (m, 1H), 6.84 (m, 2H), 7.10-7.40 (m, 7H), 7.63 (d, 1H), 7.73 (dd, 1H), 10.2 (br s, 1H). MS, m/z 433.3 [M+1]. Method B:
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[OH:22][CH2:23][CH2:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][C:28](=[O:34])[NH:29]2>>[CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14](/[CH:17]=[C:27]3\[C:28](=[O:34])[NH:29][C:30]4[C:26]\3=[C:25]([CH2:24][CH2:23][OH:22])[CH:33]=[CH:32][CH:31]=4)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2]
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2c(CCO)cccc2N1
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4cccc(CCO)c43)c(C)c2C1=O
Yield: 29.5 %

Procedure:
The title compound was prepared under the same conditions as described in step 10 of Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j obtained from step 9 of Example 1 and 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-5-(2-diethylamino-ethyl)-2-[4-(2-hydroxy-ethyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 17 (18 mg, yield 29.5%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH3:11])=[CH:6][CH:5]=1.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>CO>[OH:16][N:15]=[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:13])=[CH:5][CH:6]=1)[CH3:11]
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C(C)=NO)cc1
Temperature: 40 °C
Yield: 96.1 %

Procedure:
A mixture of 4-acetylbenzoic acid methyl ester (1.0 g, 5.6 mmol), hydroxylamine hydrochloride (3.1 g, 45 mmol) and sodium acetate (3.7 g, 45 mmol) in methanol (50 mL) was heated at 40° C. for 2 hours. The mixture was evaporated to dryness and the residue partitioned between EtOAc (40 mL) and water (40 mL). The organic layer was washed with brine (40 mL), dried over anhydrous MgSO4 and evaporated to dryness to afford the title compound as a white solid (1.04 g, 96%). LC-MS: (FA) ES+ 194; 1H NMR (400 MHz, MeOD) δ 8.02-7.98 (m, 2H), 7.78-7.75 (m, 2H), 3.90 (s, 3H), 2.24 (s, 3H).