Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O)(=[O:3])[CH3:2].[NH:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1>C(O)(=O)CC>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:8]2[C:17]3[NH:13][C:14]([C:8]([C:7]4[CH:10]=[CH:11][CH:12]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=4)=[C:14]4[N:13]=[C:17]([C:8]([C:7]5[CH:10]=[CH:11][CH:12]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=5)=[C:14]5[NH:13][C:17](=[C:8]([C:7]6[CH:10]=[CH:11][CH:12]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=6)[C:14]6[CH:15]=[CH:16][C:17]=2[N:13]=6)[CH:16]=[CH:15]5)[CH:16]=[CH:15]4)=[CH:15][CH:16]=3)[CH:10]=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(C=O)c1
Reactant: c1cc[nH]c1
Solvent: CCC(=O)O
Product: CC(=O)Nc1cccc(-c2c3nc(c(-c4cccc(NC(C)=O)c4)c4ccc([nH]4)c(-c4cccc(NC(C)=O)c4)c4nc(c(-c5cccc(NC(C)=O)c5)c5ccc2[nH]5)C=C4)C=C3)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
16.32 g (0.10 mol) of 3-acetylaminobenzaldehyde (EMS-Dottikon AG) is dissolved in 300 ml of propionic acid and the solution is heated to 60° C. 6.71 g (0.10 mol) of pyrrole is instilled slowly and the dark solution is stirred for one hour at 110° C. After cooling, it is completely concentrated by evaporation in a vacuum, and the residue is recrystallized from pyridine/diethyl ether.
Reaction SMILES: Cl.[F:2][C:3]([F:19])([F:18])[CH2:4][O:5][N:6]=[C:7]([C:10]1[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][N:11]=1)[CH2:8][NH2:9].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].C(=O)([O-])[O-].[K+].[K+]>O.ClCCl>[Cl:16][C:15]1[C:10]([C:7](=[N:6][O:5][CH2:4][C:3]([F:18])([F:2])[F:19])[CH2:8][NH:9][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[C:21]([F:20])([F:31])[F:32])=[N:11][CH:12]=[C:13]([Cl:17])[CH:14]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: NCC(=NOCC(F)(F)F)c1ncc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(NCC(=NOCC(F)(F)F)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Yield: 92.8 %

Procedure:
To 2.0 g of 2-amino-1-(3,5-dichloropyridin-2-yl)ethanone-O-(2,2,2-trifluoroethyl)oxime hydrochloride in 12.0 ml of water, 1.4 g of 2-(trifluoromethyl)benzoyl chloride in 12.0 ml of dichloromethane and 2.4 g of potassium carbonate were added at room temperature with stirring, and the mixture was stirred at the same temperature for 2 hours. After completion of the reaction, the resulting organic layer was collected and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 2.6 g of the desired product as a pale yellow resinous substance.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][C:31]=1[C:42]1[NH:46][C:45]2[CH:47]=[CH:48][CH:49]=[CH:50][C:44]=2[N:43]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][CH:23]([C:26]([N:39]2[CH2:40][CH2:41][N:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[C:31]([C:42]4[NH:43][C:44]5[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=5[N:46]=4)[CH:32]=3)[CH2:37][CH2:38]2)=[O:28])[CH2:24][CH2:25]1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Fc1ccc(N2CCNCC2)cc1-c1nc2ccccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(c3ccc(F)c(-c4nc5ccccc5[nH]4)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.4 %

Procedure:
CDI (0.047 g, 0.29 mmol) was added to a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (0.07 g, 0.29 mmol) in acetonitrile (2.50 mL). The resulting solution was stirred at room temperature for 5 hours. 2-(2-Fluoro-5-piperazin-1-yl-phenyl)-1H-benzoimidazole (0.10 g, 0.27 mmol) and DIPEA (0.05 mL, 0.26 mmol) were added and reaction was heated at 65° C. overnight. Reaction was cooled to room temperature and solvent was removed under reduced pressure. DCM (2 mL) was added to the crude, organic solution was washed with water (2×4 mL) and with saturated Na2CO3 solution (2×4 mL) and concentrated. The crude reaction mixture was purified by flash chromatography (eluent: cyclohexane:AcOEt gradient from 100% of cyclohexane to 100% AcOEt) to afford 0.08 g of the title compound (60%).
Reaction SMILES: [C:1]1([N:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:8]([O:10][CH2:11][CH:12]2[CH2:18][CH2:17][CH2:16][C:15]3[C:19]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:21]=[CH:22][C:14]=3[CH:13]2[OH:30])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[C:1]1([N:7]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:8]([O:10][CH2:11][CH:12]2[CH2:18][CH2:17][CH2:16][C:15]3[C:19]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:21]=[CH:22][C:14]=3[C:13]2=[O:30])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)COc1cccc2c1CCCC(COC(=O)N(c1ccccc1)c1ccccc1)C2O
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1cccc2c1CCCC(COC(=O)N(c1ccccc1)c1ccccc1)C2=O
Yield: 84.8 %

Procedure:
To a solution of ethyl {[(5RS,6RS)-6-(N,N -diphenylcarbamoyloxy)methyl-5-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten- 1-yl]oxy}acetate (179 mg) in CHCl3 (15 ml) was added activated MnO2 (636 mg). The mixture was refluxed for 30 minutes. Then after addition of activated MnO2 (636 mg), the mixture was refluxed for 1.5 hours. Furthermore, the mixture was added with activated MnO2 (636 mg) and then refluxed for 1 hour. After cooling, the mixture was filtered. The filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 2:1) to give ethyl {[6-(N,N-diphenylcarbamoyloxy) methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl]oxy}acetate (151.1 mg) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.[O:20]1[CH2:25][CH2:24][CH:23]([C:26](O)=[O:27])[CH2:22][CH2:21]1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.Cl>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[C:7]([NH:8][C:26]([CH:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)=[O:27])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1
Reactant: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: O=C(O)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1NC(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
To a solution of 2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl amine (0.1 g, 0.385 mmol) in DCM (3 mL) and DMF (1 mL), was added sequentially tetrahydro-2H-pyran-4-carboxlic acid (0.06 g, 0.461 mmol), N-methylmorpholine (0.127 mL, 1.16 mmol), 1-hydroxylbenzotriazole (HOBT) (0.068 g, 0.504 mmol), and EDCl.HCl (0.096 g, 0.504 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate (3 mL) and 15 mL of dichloromethane. The aqueous layer was extracted with dichloromethane (15 mL, 2×). The combined organic layers were washed with sodium bicarbonate (15 mL), brine (15 mL), dried over Na2SO4, and concentrated under vacuum. Purification by column chromatography on silica gel (0-10%) methanol in dichloromethane afforded 0.103 g (73%) of the title compound.
Reaction SMILES: COC1C=CC([C@@H]2O[C@H]2C(N)=O)=CC=1.NC1C=CC=CC=1S.N[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30][CH:31]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[CH:32]([OH:36])[C:33]([NH2:35])=[O:34].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.ClC1C=CC=CC=1>[OH:36][C@H:32]1[C:33](=[O:34])[NH:35][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30][C@H:31]1[C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1
Reactant: COc1ccc(C(Sc2ccccc2N)C(O)C(N)=O)cc1
Agent: COc1ccc([C@@H]2O[C@H]2C(N)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Nc1ccccc1S
Solvent: Clc1ccccc1
Solvent: CO
Solvent: O
Product: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Yield: 82.6 %

Procedure:
A mixture of (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxypropionamide (3.86 g) and chlorobenzene (77 ml) is refluxed with heating under nitrogen atmosphere. When the reflux is started, a solution of 2-aminothiophenol (2.75 g) and ferric chloride hexahydrate (0.54 mg) in methanol (0.1 ml) is added immediately into the reaction mixture, and the mixture is reacted at the same temperature for 5 minutes. The reaction mixture is subjected to HPLC analysis* to confirm the production of 3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)propionamide (6.09 g) [(2S,3S)/(2S,3R)=91.5/8.5]. To the reaction mixture is added p-toluenesulfonic acid monohydrate (0.76 g), and the mixture is refluxed for 32 hours, and concentrated under reduced pressure to remove the chlorobenzene. To the residue is added methanol (25 ml), and the mixture is refluxed for one hour, and cooled with ice overnight. The precipitated crystals are collected by filtration, washed with methanol, and dried at 50° C. to give (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (4.76 g).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:19][O:20]3)=[CH:15][C:14]=2Cl)=[C:10]([N+:31]([O-:33])=[O:32])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P([CH:55]2[CH2:60][CH2:59]CCC2)C2CCCCC2)CCCCC1.C1(B(O)O)CC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:1]([O:5][C:6]([C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:19][O:20]3)=[CH:15][C:14]=2[CH:59]2[CH2:60][CH2:55]2)=[C:10]([N+:31]([O-:33])=[O:32])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)OC(C)(C)C)cc3[N+](=O)[O-])c(Cl)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)OC(C)(C)C)cc3[N+](=O)[O-])c(C3CC3)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
To a stirred solution of ethyl 7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-chlorochroman-4-carboxylate (1.38 g, 2.89 mmol) in toluene (15 mL) was added successively water (0.75 mL), potassium phosphate (3.06 g, 14.4 mmol), tricyclohexylphosphine (0.32 g, 1.16 mmol), and cyclopropylboronic acid (0.74 g, 8.7 mm3ol). The resulting mixture was stirred and a balloon of nitrogen with a three-way purge valve was attached, and the flask was evacuated and refilled five times with nitrogen. Palladium(II) acetate (0.13 g, 0.58 mmol) was added, and again the flask was evacuated and refilled five times with nitrogen. The mixture was stirred in an oil bath set to 110° C. under the nitrogen balloon for 16 hours. The mixture was cooled to ambient temperature, and diluted with ethyl acetate (100 mL) and water (50 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 95/5 hexanes/ethyl acetate, to afford ethyl 7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-cyclopropylchroman-4-carboxylate as a yellow oil (0.39 g, 28%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.Cl[CH2:11][O:12][CH3:13]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([O:8][CH2:11][O:12][CH3:13])[CH:7]=1
Reactant: Oc1cc(Br)ccc1F
Reactant: COCCl
Product: COCOc1cc(Br)ccc1F

Procedure:
Starting from commercially available 5-bromo-2-fluoro-phenol and 1-chloro-1-methoxy-methane prepared according to literature (Stadlwieser, J. Synthesis 1985, 490) the title compound is obtained as colorless oil.
Reaction SMILES: FC(F)CN1CC(C2C=CNN=2)OC2(CCNCC2)C1.[CH:21]([O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][C:26]=1[CH3:34])([CH3:23])[CH3:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[H-].[Na+].ICC>C([O-])(O)=O.[Na+].CO.CN(C)C=O>[CH:21]([O:24][C:25]1[CH:33]=[CH:32][C:28]([CH:29]=[O:30])=[CH:27][C:26]=1[CH3:34])([CH3:23])[CH3:22]
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: FC(F)CN1CC(c2cc[nH]n2)OC2(CCNCC2)C1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCI
Solvent: CN(C)C=O
Product: Cc1cc(C=O)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 24 %

Procedure:
To 8-(2,2-difluoroethyl)-10-(1H-pyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecane (193 mg, 0.54 mmol), 4-isopropoxy-3-methyl-benzoic acid (110 mg, 0.56 mmol) and HATU (215 mg, 0.56 mmol) was added N,N-dimethylformamide (1.3 mL). The reaction mixture was stirred for 5 minutes at room temperature, then diisopropylethylamine (374 μL, 2.15 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was then diluted with sat. NaHCO3 (5 mL) and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layer was washed with water (5 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was passed through a silica gel plug, eluting with 30% EtOAc/DCM. The solvent was concentrated in vacuo and the residue was dissolved in N,N-dimethylformamide (1.3 mL) under an atmosphere of nitrogen, cooled to 0° C., then treated with NaH (21 mg, 0.54 mmol). The reaction mixture was stirred at 0° C. for 10 minutes, then at room temperature for 5 minutes, then iodoethane (50 μL, 0.63 mmol) was added and the reaction mixture stirred for 1 hour. The reaction mixture was diluted with methanol, microfiltered and purified by preparative LCMS (10-99% ACN/Water, 5 mM HCl modifier) to give 8-(2,2-difluoroethyl)-10-(1-ethylpyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (26 mg, 14%) and 8-(2,2-difluoroethyl)-10-(2-ethylpyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (24 mg, 13%).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][CH:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:3]1=[O:18].CO.N1C=CC=CC=1.[I:27]Cl>C(Cl)Cl>[I:27][C:10]1[CH:11]=[CH:12][C:6]2[NH:5][CH:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:3](=[O:18])[N:2]([CH3:1])[CH2:8][C:7]=2[CH:9]=1
Reactant: ClI
Reactant: COC(=O)CC1Nc2ccccc2CN(C)C1=O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: COC(=O)CC1Nc2ccc(I)cc2CN(C)C1=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
Methyl 2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate (100 g, 0.4 moles) was added to CH2Cl2 (500 ml) plus MeOH (500 ml) and heated at 40° C. for 0.5 hr. The solution was cooled to 26° C. and pyridine (64 g, 0.8 mole) added. Iodine monochloride (71.3 g, 0.44 mole) dissolved in CH2Cl2 (500 ml) was added dropwise over 30 minutes and the reaction stirred for a further 1.0 hr. The product was filtered off, washed with 60/80 petrol and dried in vacuo to yield the title compound (113 g, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:4]=2[N:3]=1.Cl.[CH3:21][C:22]1[NH:23]C=CN=1.O.NN.C([O-])([O-])(OCC)C>C(O)C.CO>[Cl:19][C:16]1[CH:17]=[CH:18][C:4]2[N:3]3[C:22]([CH3:21])=[N:23][N:1]=[C:2]3[CH2:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]=2[CH:15]=1
Reactant: Cc1ncc[nH]1
Reactant: NC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Agent: CCOC(C)([O-])[O-]
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Solvent: CO
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 1.35 parts of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine in 25 parts by volume of methanol are added 0.6 part of 2-methylimidazole hydrochloride and 6 parts by volume of 1 mole methanol solution of hydrazine hydrate. The mixture is stirred at room temperature for 1.5 hours, followed by addition of 4.8 parts of ethyl orthoacetate and 10 parts by volume of ethanol containing 10% hydrogen chloride. The mixture is refluxed for 30 minutes, followed by evaporation of the solvent. The residue is neutralized with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The methylene chloride extract is washed with water and dried over sodium sulfate, followed by evaporation of the solvent. The residue is purified by means of silica gel column-chromatography to give 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-a][1,4] benzodiazepine. Recrystallization from a mixture of acetone and n-hexane affords colorless needles. Melting point: 225° C to 226° C.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Li]CCCC.[C:33]([N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH:41]1C=O)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].CCOC(C)=O.CCCCCC>C1COCC1.O>[C:33]([N:40]1[CH2:41][CH2:42][CH2:43][CH2:44][CH:45]1/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]
Reactant: CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C=O
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC/C=C\C1CCCCN1C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
A suspension of heptyltriphenylphosphonium bromide (13.0 g, 30.41 mmol) in 60 mL of THF was cooled to −30° C. and treated with n-BuLi (12.2 mL, 30.41 mmol) dropwise. The deep red solution was slowly warmed to 0° C., stirred for 30 min, and then cooled to −78° C. The ylide was treated with a solution of N-Boc-piperidine-2-carboxaldehyde (4.0 g, 20.27 mmol) in 7 mL of THF, and the mixture was slowly warmed to room temperature. The mixture was diluted with water, and the organic layer was separated. The aqueous layer was extracted with ether and the combined extracts were dried over K2CO3 and then concentrated to give a crude product as an oil. Chromatography on silica with 5% EtOAc/hexane afforded 5.7 g (70%) of the product that was homogeneous by TLC analysis. 1H NMR (250 MHz) δ 5.72-5.49 (pair of m, 2H), 5.02-4.96 (br s, 1H), 3.97-3.89 (br d, 1H), 2.89-2.76 (dt, 1H), 2.14-1.99 (m, 2H), 1.61-1.24 (m, 21H), 0.88-0.83 (t, 3H); 13C NMR (62.7 MHz) 154.6 (s), 133.3 (s), 127.8 (s), 78.9 (s), 48.8 (s), 39.5 (s), 32.3 (s), 30.9 (s), 30.6 (s), 27.6 (s), 25.9 (s), 23.9 (s), 22.5 (s), 21.1 (s), 19.4 (s), 16.9 (s), 14.8 (s), 13.2 (s) ppm.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]([C:28]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])[CH2:15][CH:16]=[CH:17][C:18]3[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([C:25](=[NH:27])[NH2:26])[CH:19]=3)=[CH:10][C:9]=2[C:35]([F:38])([F:37])[F:36])[CH2:3][CH2:2]1.[C:39](=[NH:44])(OCC)[CH3:40].C(N(CC)CC)C.FC(F)(F)C(O)=O>C(O)C>[NH:44]=[C:39]([N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]([C:28]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])[CH2:15][CH:16]=[CH:17][C:18]3[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([C:25](=[NH:26])[NH2:27])[CH:19]=3)=[CH:10][C:9]=2[C:35]([F:36])([F:37])[F:38])[CH2:3][CH2:2]1)[CH3:40]
Reactant: N=C(N)c1ccc(O)c(C=CCN(C(=O)CCC(=O)O)c2ccc(OC3CCNCC3)c(C(F)(F)F)c2)c1
Reactant: CCOC(C)=N
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(=N)N1CCC(Oc2ccc(N(CC=Cc3cc(C(=N)N)ccc3O)C(=O)CCC(=O)O)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-(hydroxy)-3-amidinophenyl)prop-2-en-1-yl)benzenamine (2.5 g) and ethyl acetimidate (2 g) in ethanol (100 mL) was added triethylamine and the solution was stirred at ambient temperature for 4 hours. The solution was acidified with trifluoroacetic acid, concentrated, separated on HPLC (CH3CN/H2O, gradient) and freeze-dried to afford 4-(N′-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-(hydroxy)-3-amidinophenyl)prop-2-en-1-yl)benzenamine.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.Cl.[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>C(O)CCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:8]([CH:9]=1)=[N:19][N:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]=2[NH2:7]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Nc1c2ccc(Br)cc2nn1-c1ccccc1
Temperature: 140 °C
Reaction time: 72 h
Yield: 25.6 %

Procedure:
To a dried flask charged with 4-bromo-2-fluorobenzonitrile (4.0 g, 18.0 mmol) in n-butanol (60 mL) was added a solution of phenylhydrazine hydrochloride (10.4 g, 72.0 mmol, 4.0 eq) and diisopropylethylamine (13.2 mL, 75.6 mmol, 4.2 eq) in n-butanol (35 mL). The reaction mixture was stirred at 140° C. under N2 for 3 days. The mixture was cooled to rt and partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified using an ISCO® instrument (gradient 10 to 65% EtOAc/hexane) and the product containing fractions were concentrated. Crystallization from DCM-hexane afforded 1.33 g (26%) of the title compound as beige solid. 1H NMR (300 MHz, DMSO-d6) δ 7.71 (d, 1H), 7.69 to 7.66 (m, 2H), 7.58 to 7.54 (m, 2H), 7.47 to 7.44 (m, 2H), 6.78 (dd, 1H), 6.50 (s, 2H); ES-MS m/z 288.1/290.1 [M+H]+, RT (min) 2.28.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:17])[C:5]([C:8]2[NH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:12]=2)=[N:6][CH:7]=1.[H-].[Na+].[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:17])[C:5]([C:8]2[N:12]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:28])([CH3:27])[CH3:20])[CH:11]=[C:10]([C:13]([F:14])([F:15])[F:16])[N:9]=2)=[N:6][CH:7]=1
Reactant: FC(F)(F)c1cnc(-c2ncc(Br)cc2Cl)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ncc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In N,N-dimethylformamide (13 mL) was dissolved 5-bromo-3-chloro-2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (1.27 g), 60% sodium hydride (187 mg) was added to the solution under ice-cooling, and after raising the mixture to room temperature, the mixture was stirred for 1 hour. The reaction mixture was ice-cooled, 2-(trimethylsilyl)ethoxymethyl chloride (1.03 mL) was added to the mixture, and after raising the mixture to room temperature, the mixture was stirred for 1 hour. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated brine, and dried over anhydrous magnesium sulfate. After concentrating the mixture under reduced pressure, the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 95:5) to obtain 5-bromo-3-chloro-2-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (1.56 g).
Reaction SMILES: C(C1C=CC=C(C(C)C)C=1N=[C:14]=[O:15])(C)C.[CH2:16]([O:18][C:19](=[O:36])[C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2([C:33](=[O:35])[NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1)[CH3:17]>C1(C)C=CC=CC=1>[CH2:16]([O:18][C:19](=[O:36])[C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:27]3([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:33](=[O:35])[NH:34][C:14]2=[O:15])=[CH:24][CH:25]=1)[CH3:17]
Reactant: CCOC(=O)c1ccc(NC2(C(N)=O)CCCCC2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N2C(=O)NC(=O)C23CCCCC3)cc1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
380 μl (1.85 mmol, 1.2 eq.) of 2,6-diisopropylphenyl isocyanate are added to a solution of 450 mg (1.55 mmol, 1 eq.) of 4-(1-carbamoyl-cyclohexylamino)benzoic acid ethyl ester in 15 ml of toluene. The reaction medium is stirred at 180° C. for 2 hours with microwave irradiation. The toluene is evaporated off and the residue is purified on silica gel (heptane/ethyl acetate). The product 4-(2,4-dioxo-1,3-diazaspiro[4.5]dec-1-yl)benzoic acid ethyl ester is obtained in the form of a white solid.