Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH:17]=[O:18])[N:13]=[CH:12][C:11]=2[C:10]([CH3:20])([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]1[CH2:25]OC[CH2:22]1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH:17]([OH:18])[CH:21]([CH3:25])[CH3:22])[N:13]=[CH:12][C:11]=2[C:10]([CH3:20])([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(C=O)cc21
Product: CC(C)C(O)c1cc2c(cn1)C(C)(C)CN2C(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
To a stirred solution of 6-formyl-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.65 g, 2.36 mmol), in THF (20 mL) at −78° C. under nitrogen was added, dropwise over 0.1 h, a solution of isopropylmagnesium chloride-lithium chloride complex in THF (1.3 M, 2.7 mL, 3.53 mmol). Resulting solution was stirred at −78° C. then was quenched with aqueous citric acid (5%, 30 mL) and extracted with DCM (4×50 mL). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give a foam. Chromatography (SiO2; gradient elution with 0-100% EtOAc in 40-60 petroleum ether) gave the title compound (0.398 g). 1H NMR (Me-d3-OD): 8.15 (1H, s), 8.08-7.45 (1H, m), 4.41 (1H, d), 3.78 (2H, s), 2.10-1.97 (1H, m), 1.60 (9H, s), 1.40 (6H, d), 0.92 (6H, t).
Reaction SMILES: [Li][CH3:2].[Li+].[Br-].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C:12]([C:16]([OH:18])=O)([CH3:15])[O:11][C:10]=2[CH:19]=1.[NH4+].[Cl-]>C(OCC)C>[C:16]([C:12]1([CH3:15])[O:11][C:10]2[CH:19]=[C:6]([Cl:5])[CH:7]=[CH:8][C:9]=2[O:14][CH2:13]1)(=[O:18])[CH3:2]
Reactant: CC1(C(=O)O)COc2ccc(Cl)cc2O1
Reactant: [Li]C
Agent: [Br-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(=O)C1(C)COc2ccc(Cl)cc2O1

Procedure:
80 ml of a 2M MeLi-LiBr solution in ethyl ether was added dropwise, under nitrogen stream, to a solution of 17.7 g of (7-chloro-2,3-dihydro-2-methyl-1,4-benzodioxin-2-yl)carboxylic acid (prepared as described in Example 3) dissolved in 420 ml of anhydrous ethyl ether. The reaction mixture was refluxed for 1 hour, then poured into 200 ml of a NH4Cl saturated solution. The separated ether phase was washed with NaHCO3 and water, then dried. Solvent was removed under vacuum. After distillation, 2-acetyl-7-chloro-2,3-dihydro-2-methyl-1,4-benzodioxin (b.p. 168°-173° C. 0.6 mm Hg) was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([CH3:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:2]1.Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]=O>[CH2:15]([O:14][C:12]([CH2:11][CH:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:2]=1)[CH3:17])=[O:13])[CH3:16]
Reactant: CCOC(=O)CC(C)c1c[nH]c2ccccc12
Reactant: Brc1cccnc1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CCOC(=O)CC(C)c1cn(-c2cccnc2)c2ccccc12

Procedure:
A solution of 2.5 g ethyl 3-(3-indolyl)-butyrate and 1.15 ml of 3-bromopyridine in 25 ml of pyridine is refluxed with 1.25 g of copper oxide and 1.25 g of potassium carbonate for 72 hours, filtered and evaporated to a brown oil which is chromatographed on 64 g of silica with 8:1 toluene-ethyl acetate to yield 3-(3-ethoxycarbonyl-2-propyl)-N-(3-pyridyl)indole; Rf (15% EtOAc, 85% toluene/silica gel)=0.35; IR (CH2Cl2) 1725 cm-1.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[C:3]([O:5]CC)=[O:4].[OH-].[Na+].Cl>CO>[CH3:1][C:2]([CH3:19])([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Cc1ccc(C(F)(F)F)cc1)C(=O)O
Temperature: 80 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
Dissolve ethyl 2,2-dimethyl-3-[4-(trifluoromethyl)phenyl]propanoate (400 mg, 1.46 mmol) in MeOH (2 mL) and add aqueous NaOH solution (3 mL of 3 N). Heat to 80° C. and stir for 3 h. Cool to ambient temperature and acidify with 1 N HCl until pH 4. Extract with EtOAc. Combine organic extracts, wash with brine, dry over sodium sulfate, filter, and concentrate to give the title compound (272 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH:10]([OH:12])[CH3:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17]C(=O)C.[CH3:22]CN(CC)CC.CS(Cl)(=O)=O>C(Cl)Cl.CO>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH:10]([O:12][CH3:22])[CH3:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH2:17]
Reactant: COC(=O)c1cc(C(C)O)c(C(F)(F)F)cc1NC(C)=O
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(C(C)OC)c(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
A solution of 2-acetylamino-5-(1-hydroxy-ethyl)-4-trifluoromethyl-benzoic acid methyl ester (600 mg, 1.97 mmol) and Et3N (412 μL, 3.0 mmol) in DCM (6 mL) was cooled to 0° C. and treated with methanesulfonyl chloride (194 μL, 2.46 mmol) dropwise. The mixture was allowed to warm to r.t. and stirred for 2 h. The mixture was then diluted with DCM, and washed once with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil which was taken up in MeOH. This solution was allowed to stand for 60 h at r.t. The mixture was then concentrated in vacuo and the crude product was purified by column chromatography (silica gel 60, hexanes/EtOAc 5:1) to give 2-amino-5-(1-methoxy-ethyl)-4-trifluoromethyl-benzoic acid methyl ester (196 mg, 0.71 mmol, 36%) as a white powder, m.p. 112-114° C., ESI-MS: m/z 278 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[CH:12][N:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[ClH:31]>CCOC(C)=O>[ClH:31].[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][N:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cn1)OCC
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1ccc(N)cn1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl({5-[bis(tert-butoxycarbonyl)amino]pyridin-2-yl}methyl)phosphonate (Compound 260B, 2.5 g, 5.6 mmol) in dry EtOAc (150 mL) was added HCl in EtOAc solution dropwise. The reaction mixture was stirred at room temperature for 1 h. The solids were collected by filtration, dried to give 2.1 g of the desired product as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ=1.16 (t, J=7.2 Hz, 6H), 3.64 (d, J=22.0 Hz 2H), 3.97-4.04 (m, 4H), 7.50 (dd, J=2.0, 8.8 Hz, 1H), 7.64 (dd, J=2.0, 8.8 Hz, 1H), 7.95 (d, J=2.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][CH:9]2C#N)=O)=[CH:4][CH:3]=1.F[B-](F)(F)F.[H+].[C:27]([C:33]([O:35][CH3:36])=[O:34])#[C:28][C:29]([O:31][CH3:32])=[O:30]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[N:8]3[C:9]([S:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=43)=[C:28]([C:29]([O:31][CH3:32])=[O:30])[C:27]=2[C:33]([O:35][CH3:36])=[O:34])=[CH:19][CH:20]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: N#CC1Sc2ccccc2N1C(=O)c1ccc(Cl)cc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1c(C(=O)OC)c2sc3ccccc3n2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(4-chlorobenzoyl)-2,3-dihydrobenzo[d]thiazole-2-carbonitrile (9.12 g, 30.0 mmol) in dichloromethane (50 mL) was added dropwise 9 mL of tetrafluoroboric acid (HBF4). The solution was stirred for 3 h at room temperature. The brown precipitates appeared were collected by filtration and the filter cake was washed with ether. The solid salt was added to a solution of dimethyl acetylenedicarboxylate (12.7 g, 90.0 mmol) in DMF (40 mL) and then warmed at 35° C. for 14 h. The reaction mixture was concentrated in vacuo and the residue was crystallized from methanol to give dimethyl 1-(4-chlorophenyl)benzo[d]pyrrolo[2,1-b]thiazole-2,3-dicarboxylate, 2.5 g (21%); mp 172-173° C. 1H NMR (DMSO-d6) δ 3.64 (3H, s, COOMe), 3.83 (3H, s, COOMe), 6.85-6.87 (1H, m, ArH), 7.30-7.42 (2H, m, ArH), 7.60-7.66 (4H, m, 4×ArH), 8.04-8.06 (1H, m, ArH). Anal. Calcd. for (C20H14ClNO4S.0.5H2O): C, 58.75; H, 3.70; N, 3.43; S, 7.84. Found: C, 58.76; H, 3.45; N, 3.59; S, 7.73.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:10]=1.Br[C:36]1[CH:37]=[CH:38][C:39]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[C:40]([CH:44]=1)[C:41]([OH:43])=[O:42].C(=O)(O)[O-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C(OCC)(=O)C.C(#N)C>[C:49]([O:48][C:46]([NH:45][C:39]1[CH:38]=[CH:37][C:36]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[C:12]3=[N:13][CH:14]=2)=[CH:44][C:40]=1[C:41]([OH:43])=[O:42])=[O:47])([CH3:52])([CH3:50])[CH3:51]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1C(=O)O
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC#N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(NC(=O)OC(C)(C)C)c(C(=O)O)c3)cc12
Temperature: 75 °C
Yield: 35 %

Procedure:
485 mg (1.00 mmol) of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine, 379 mg (1.20 mmol) of 5-bromo-2-tert-butoxycarbonylamino-benzoic acid and 40 mg (49 μmol) of dichloro[1,1′-bis(diphenylphoshino)ferrocene]palladium(II) dichloromethane adduct were placed in a vial. 8 mL of acetonitrile and 8 mL of a saturated aqueous solution of sodium bicarbonate were added. The vial was closed and the mixture heated to 75° C. for 17 h. The crude mixture was distributed between ethyl acetate and 10% aqueous citric acid. The aqueous layer was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated. The crude was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford 204 mg (0.35 mmol, 35%) of 2-tert-butoxycarbonylamino-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 13.80 (s, br. 1H), 10.56 (s, 1H), 8.90 (d, 1H), 8.42 (d, 1H), 8.35 (d, 1H), 8.28 (d, 1H), 8.01 (dd, 1H), 7.65 (dd, 1H), 7.50 (ddd, 1H), 7.26 (ddd, 1H), 7.25 (d(d), 1H), 7.11 (ddd, 1H), 5.86 (s, 2H), 8.87 (s, 3H), 3.70 (t, 2H), 1.50 (s, 9H), 0.87 (t, 2H), −0.09 (s, 9H) MS: m/z 591.2 (M+H+), 613.2 (M+Na+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[CH3:28])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[NH:29]1[C:33]([C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)=[N:32][N:31]=[N:30]1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.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].ClCCl.C(OCC)(=O)C.O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([C:37]3[CH:36]=[CH:35][C:34]([C:33]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:39][CH:38]=3)=[CH:7][CH:6]=2)[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[C:22]([CH3:28])[CH:23]=1
Reactant: OB(O)c1ccc(-c2nnn[nH]2)cc1
Reactant: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(-c3nnn[nH]3)cc2)cc1
Temperature: 80 °C

Procedure:
To a solution of (E)-5-(3-(4-bromophenyl)-3-(4-fluoro-2-methylphenyl)-1-(hydroxyimino)propyl)-1-methylpyridin-2(1H)-one (0.1 g, example 224) in dioxane (1 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane adduct (CAS RN: [95464-05-4]) (9.21 mg), 4-(1H-tetrazol-5-yl)phenylboronic acid (64.3 mg, CAS RN: [179942-55-3]), water (0.65 mL) and aqueous 2M sodium carbonate solution (338 μL) and the reaction mixture was heated for 23 hours at 80° C. The reaction mixture was poured on 10% aqueous citric acid solution and ethyl acetate and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography using a MPLC system (20 g silica gel column, CombiFlash Companion, Isco Inc.) eluting with a gradient of dichloromethane:methanol (100:0 to 75:25). The product was purified a second time by preparative HPLC (phenomenex gemini column) with a gradient of acetonitrile:water (containing 0.5% formic acid) (10:90 to 98:2) to yield the title compound containing 10% of the corresponding Z isomer as as a white foam, MS (ESI+): m/z=509.21 [M+H]+.
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[CH3:7][CH:8]([C:13]1[CH:19]=[C:18]([C:20](F)([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:14]=1[NH2:15])[CH2:9][CH:10]([CH3:12])[CH3:11].O.S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1>[CH3:7][CH:8]([C:13]1[CH:19]=[C:18]([CH:20]([C:21]([F:22])([F:23])[F:24])[C:25]([F:27])([F:28])[F:26])[CH:17]=[CH:16][C:14]=1[NH2:15])[CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)CC(C)c1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1N
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(C)c1cc(C(C(F)(F)F)C(F)(F)F)ccc1N
Reaction time: 0.17 h
Yield: 98.1 %

Procedure:
Aluminum lithium hydride (2 g, 52.7 mmol) was suspended in tetrahydrofuran (60 ml), followed by adding dropwise thereto 2-(1,3-dimethylbutyl)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (14 g, 40.5 mmol), and the resulting mixture was stirred at reflux temperature for 3 hours. Water was added to the reaction mixture in small portions under ice-cooling, followed by stirring for 10 minutes. Magnesium sulfate was added thereto and then stirred for 10 minutes. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to obtain 13 g of the desired compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)=[O:24])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2ccccc2)CCN3)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(Cc3ccccc3)CCN4)cc2)CC1
Yield: 32 %

Procedure:
4-(1-Benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (20 mg) was reacted with 1-methyl piperazine as in General Procedure 8 to give the title compound as a yellow solid (32% yield). M.p. 180-181° C., LCMS: m/z=428.30 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.31 (s, 3H), 2.33-2.52 (m, 4H), 3.38-3.43 (m, 2H), 3.45-3.55 (m, 2H), 3.46-3.50 (m, 2H), 3.58-3.62 (m, 2H), 3.64-3.82 (m, 2H), 4.48 (s, 2H), 5.29 (s, 1H), 6.83 (s, 1H), 7.27-7.39 (m, 9H), 7.69 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:9][CH:10]=1)([CH3:5])[CH2:3][NH2:4].[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=2)[C:29](O)=[O:30])[N:20]=1>>[CH3:5][C:2]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:9][CH:10]=1)([CH3:1])[CH2:3][NH:4][C:29](=[O:30])[C:28]1[CH:32]=[C:24]([C:21]2[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=2)[CH:25]=[N:26][CH:27]=1
Reactant: CC(C)(CN)c1coc(-c2ccccc2)n1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: CC(C)(CNC(=O)c1cncc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccccc2)n1
Yield: 13 %

Procedure:
This compound was synthesized from 2-methyl-2-(2-phenyloxazol-4-yl)propan-1-amine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (19 mgs, 13% yield). 1H NMR (CDCl3) δ 9.45 (t, J=9.0 Hz, 1H), 9.35 (s, 1H), 8.42 (s, 1H), 8.03 (s, 2H), 7.51-7.40 (m, 4H), 3.62 (bs, 2H), 1.42 (s, 6H). MS (ESI) m/z: Calculated for C22H18F3N5O3: 457.14. found: 458.1 (M+H)+.
Reaction SMILES: [CH2:1]1[O:34][C:33]2[CH:32]=[CH:31][C:5]([CH2:6][N:7]([S:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([O:28][CH3:29])=[CH:23][C:22]=3[CH3:30])(=[O:20])=[O:19])[C@H:8]([CH2:16][NH2:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=2[O:2]1.C[Si](C#N)(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].C(OCC)(=O)C>C(#N)C>[CH2:1]1[O:34][C:33]2[CH:32]=[CH:31][C:5]([CH2:6][N:7]([S:18]([C:21]3[C:22]([CH3:30])=[CH:23][C:24]([O:28][CH3:29])=[CH:25][C:26]=3[CH3:27])(=[O:20])=[O:19])[C@H:8]([CH2:16][NH:17][S:42]([CH3:41])(=[O:44])=[O:43])[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[CH:4][C:3]=2[O:2]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CN)C(=O)OC(C)(C)C)c(C)c1
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNS(C)(=O)=O)C(=O)OC(C)(C)C)c(C)c1
Reaction time: 8 h
Yield: 122.7 %

Procedure:
To a mixture of tert-butyl 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-amino-propionate (1.02 g, 2.0 mmol), with trimethylsilyl cyanide (0.7 ml, 5.2 mmol) in dry acetonitrile (15 ml) was added methanesulfonyl chloride (0.18 ml, 2.3 mmol) and the material was stirred overnight. Ethyl acetate (80 ml) was added and the material was partitioned with aqueous hydrochloric acid (1.5%, 80 ml). The organic phase was collected and washed with an equal volume of brine; The aqueous phases were back extracted with ethyl acetate (2×80 ml) and the organic phases combined, dried (MgSO4), filtered and condensed to provide tert-butyl 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-methanesulfonylamino-propionate as a pale yellow semi-viscous oil (1.4 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=1)=O>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=3)[N:8]=2)[N:7]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: CCc1ccc(C(=O)CBr)cc1[N+](=O)[O-]
Solvent: O
Solvent: CC#N
Product: CCc1ccc(-c2cn3nc(Cl)ccc3n2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
A solution of 6-chloropyridazin-3-amine (4.76 g, 0.037 mol) and 2-bromo-1-(4-ethyl-3-nitrophenyl)ethanone (10.0 g, 0.037 mol) in acetonitrile (100 mL) is heated at reflux for 18 hr. The reaction mixture is diluted with water (500 mL), stirred at room temperature for 1 hour and solids are collected by filtration to give the title compound (6.9 g, 62% yield). LCMS m/z=303.3, 305.4 [M+H]+, tR=2.90 min.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:7][C:6]1[CH:8]=[CH:9][C:10]([O:12][CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(O)ccc1O
Reactant: CCCCCCCCCCCCC(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCC(Oc1ccc(O)c(C(C)(C)C)c1)C(=O)OCC
Yield: 37.5 %

Procedure:
116 g of tert-butylhydroquinone, 234 g of ethyl α-bromotetradecanoate and 170 g of potassium carbonate were mixed in 1.6 liters of acetone and reacted for 48 hours under refluxing and stirring. After the reaction, the acetone was distilled off and the residue was dissolved in one liter of ethyl acetate. The organic solvent layer was washed with water, dried with sodium sulfate and concentrated. The residue was recrystallized from 250 ml of n-hexane to obtain 110 g of a white solid. The melting point was 45° to 48° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[CH:8]1[C:18]2[C:17](=[C:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[CH2:14][O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH:8]1[C:18]2[C:17](=[C:19]3[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6])[CH2:21][CH2:20]3)[C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[CH2:14][O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc2c(c1)COc1ccccc1C2=C1CCNCC1
Reactant: CC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)CCCN1CCC(=C2c3ccccc3COc3ccccc32)CC1

Procedure:
A solution of 10 g of 5-bromo-2-pentanone in 40 cc of chloroform is added dropwise within 10 minutes to a mixture of 13.8 g of 4-(6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)piperidine and 12.7 g of sodium carbonate in 200 cc of chloroform, and the mixture is heated at reflux for 18 hours. After cooling, filtration is effected, the filtrate is washed with water, dried over magnesium sulphate, and the solvent is completely removed by distillation. The oily residue is then chromatographed on 250 g of silica gel with a mixture of chloroform/ethanol 95:5, and the so purified title compound is converted into the hydrogen fumarate form. M.P. 228°-230°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:29]=[CH:28][C:16]3[CH2:17][C@H:18]([CH2:23][C:24]([O:26]C)=[O:25])[C:19](=[O:22])[NH:20][CH2:21][C:15]=3[CH:14]=2)[CH:3]=1.N1C=CC=CC=1NCCCOC1C=CC2CC(CC(OCC)=O)C(=O)NCC=2C=1.CO.Cl>O>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:29]=[CH:28][C:16]3[CH2:17][C@H:18]([CH2:23][C:24]([OH:26])=[O:25])[C:19](=[O:22])[NH:20][CH2:21][C:15]=3[CH:14]=2)[CH:3]=1
Reactant: COC(=O)C[C@H]1Cc2ccc(OCCCNc3cc(N)ccn3)cc2CNC1=O
Agent: CCOC(=O)CC1Cc2ccc(OCCCNc3ccccn3)cc2CNC1=O
Agent: Cl
Solvent: O
Solvent: CO
Product: Nc1ccnc(NCCCOc2ccc3c(c2)CNC(=O)[C@@H](CC(=O)O)C3)c1

Procedure:
According to the procedure of Example 1(c), except substituting methyl (R)-8-[3-[(4-amino-2-pyridyl)amino]-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate for the ethyl (±)-8-[3-(2-pyridylamino)-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate, the title compound was prepared as an off-white solid: [α]D23+74.97° (c 1.45, MeOH); MS (ES) m/e 385.4 (M+H)+. Anal. Calcd for C20H24N4O4. HCl.1.5 H2O: C, 53.63; H, 6.30; N, 12.50. Found: C, 53.87; H, 6.13; N, 12.42.
Reaction SMILES: [CH:1]1([N:4]([CH2:8][CH:9]2[CH2:14]CCCO2)[C:5]([Cl:7])=[O:6])[CH2:3][CH2:2]1.C1(NC2CC[O:22][CH2:21][CH2:20]2)CC1>C(Cl)Cl.CO>[CH:1]1([N:4]([CH:8]2[CH2:9][CH2:14][O:22][CH2:21][CH2:20]2)[C:5]([Cl:7])=[O:6])[CH2:2][CH2:3]1
Reactant: C1CC(NC2CC2)CCO1
Reactant: O=C(Cl)N(CC1CCCCO1)C1CC1
Solvent: ClCCl
Solvent: CO
Product: O=C(Cl)N(C1CCOCC1)C1CC1

Procedure:
The title compound is prepared analogously as described for cyclopropyl-(tetrahydro-pyran-2-ylmethyl)-carbamoyl chloride starting from commercially available cyclopropyl-(tetrahydro-pyran-4-yl)-amine. TLC, Rf (CH2Cl2/MeOH 95:5)=0.9.