Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[N:5]=[C:6]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:8][C:9]=1[C:10]#[C:11][Si](C)(C)C.Cl>C(#N)C.C1COCC1>[NH2:3][C:4]1[N:5]=[C:6]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:7]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:8][C:9]=1[C:10]#[CH:11]
Reactant: CC(C)n1nc(-c2nc(C#C[Si](C)(C)C)c(N)nc2-c2ccccc2)ccc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1CCOC1
Product: C#Cc1nc(-c2ccc(=O)n(C(C)C)n2)c(-c2ccccc2)nc1N
Temperature: 27.5 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
Under ice-cooling, 12N aq. NaOH (0.9 ml) was added dropwise to a solution of 6-{5-amino-3-phenyl-6-[(trimethylsilyl)ethynyl]-2-pyrazinyl}-2-isopropyl-3(2H)-pyridazinone (908 mg) in a mixture of acetonitrile (0.9 ml) and THF (1.8 ml). The mixture was stirred at 25-30° C. for one hour, neutralized with 6N HCl, extracted with CHCl3, dried over MgSO4 and concentrated under reduced pressure to give a syrup. The syrup was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (30:70 v/v) to give 6-(5-amino-6-ethynyl-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone as a solid (196 mg).
Reaction SMILES: Cl[Si](C)(C)C.[Li+].[BH4-].[Br:8][C:9]1[S:10][C:11]([CH:14]=[CH:15][N+:16]([O-])=O)=[CH:12][CH:13]=1.CO>C1COCC1.C(Cl)(Cl)Cl>[Br:8][C:9]1[S:10][C:11]([CH2:14][CH2:15][NH2:16])=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])C=Cc1ccc(Br)s1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: NCCc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 234.6 %

Procedure:
Dry THF (30 mL) and chloro trimethyl silane (12.42 mL, 98.24 mmol) were added dropwise to LiBH4 (1.128 g, 51.28 mmol) over a period of 10 minutes under nitrogen atmosphere. This was followed by dropwise addition of 2-bromo-5-(2-nitro-vinyl)-thiophene (I-14a: 3 g, 12.82 mmol) in dry THF (30 mL) over a period of 20 minutes and the resulting mixture was stirred at room temperature for 48 hours. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mixture was quenched with methanol and concentrated to afford 6.2 g of the crude product which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:31]=[CH:32][S:28][CH:29]=4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: OB(O)c1ccsc1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccsc2)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (E106) (200 mg, 0.44 mmol) and 3-thienylboronic acid (113 mg, 0.88 mmol) in DME (3 ml) was added potassium tert-butoxide (445 mg, 3.97 mmol) and tetrakis(triphenylphosphine)palladium(0) (30.5 mg, 0.03 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. 2-3 ml of toluene added and solvent evaporated, the residue dissolved in methanol and added to a preconditioned (methanol) SCX cartridge eluting with methanol (×3), ammonia (1M in methanol (×2)) and then ammonia (2M in methanol (×3)), followed by by mass directed autoprep HPLC followed by trituration with diethyl ether to afford the title compound (E119). MS (AP+) m/e 458 [M+H]+.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[H-].[Na+].Br[CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15]>CC#N>[CH3:15][O:14][CH:13]([O:16][CH3:17])[CH2:12][S:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8]
Reactant: COC(CBr)OC
Reactant: OCCCCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: COC(CSCCCCCCO)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-mercapto-hexan-1-ol (2.5 mL) in MeCN (30 mL) at 0° C. was added sodium hydride (60% suspension in mineral oil, 0.81 g). The mixture was stirred at 0° C. for 1 h then 2-bromo-1,1-dimethoxy-ethane (2.4 mL) was added. The resulting mixture was stirred at RT for 20 h, then was quenched by addition of saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (×3), then the combined organics were washed with saturated sodium bicarbonate solution, then with brine, dried over sodium sulfate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 25% ethyl acetate in cyclohexane to give the subtitled compound as a colourless liquid. Yield 1.85 g.
Reaction SMILES: [NH:1]1[C:45](=[O:46])[C@H:40]([CH2:41][CH:42]([CH3:44])[CH3:43])[NH:39][C:37](=[O:38])[C@@H:33]([CH:34]([CH3:36])[CH3:35])[NH:32][C:30](=[O:31])[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[NH:23][C:21](=[O:22])[C@@H:16]([CH2:17][C:18](=[O:20])[OH:19])[NH:15][C:13](=[O:14])[C@H:2]1[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:47](OC=O)(=[O:52])C(C)(C)C>CN(C=O)C>[NH:1]1[C:45](=[O:46])[C@H:40]([CH2:41][CH:42]([CH3:44])[CH3:43])[NH:39][C:37](=[O:38])[C@@H:33]([CH:34]([CH3:36])[CH3:35])[NH:32][C:30](=[O:31])[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][CH:47]=[O:52])[NH:23][C:21](=[O:22])[C@@H:16]([CH2:17][C:18](=[O:19])[OH:20])[NH:15][C:13](=[O:14])[C@H:2]1[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)(C)C(=O)OC=O
Reactant: CC(C)C[C@@H]1NC(=O)[C@@H](C(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC(=O)O)NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC1=O
Solvent: CN(C)C=O
Product: CC(C)C[C@@H]1NC(=O)[C@@H](C(C)C)NC(=O)[C@H](CCCCNC=O)NC(=O)[C@@H](CC(=O)O)NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cyclo(-DTrp-DAsp-Lys-DVal-Leu-) (10.5 mg) which was prepared in Example 4, and formic pivalic anhydride(10 ml) in DMF(0. 5ml) was added TEA(10 μl). The reaction mixture was stirred at room temperature for 1 h and concentrated in vacuo. The residue was triturated with water (2 ml) to give the title compound(7.8 mg) as an off-white powder.
Reaction SMILES: [ClH:1].Cl.[C:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][C:32]([C:38](=[NH:40])[NH2:39])=[CH:33][CH:34]=4)[CH:29]=3)[C:20](=[O:26])[C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)(=[NH:5])[CH3:4]>Cl>[ClH:1].[ClH:1].[C:3]([N:6]1[CH2:7][CH2:8][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][C:32]([C:38](=[NH:39])[NH2:40])=[CH:33][CH:34]=4)[CH:29]=3)[C:20](=[O:26])[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)[CH2:10][CH2:11]1)(=[NH:5])[CH3:4]
Reactant: CCOC(=O)C(=O)N(Cc1ccc2ccc(C(=N)N)cc2c1)c1ccc(OC2CCN(C(C)=N)CC2)cc1
Agent: Cl
Product: CC(=N)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C(=N)N)cc4c3)C(=O)C(=O)O)cc2)CC1
Reaction time: 216 h
Yield: 48.3 %

Procedure:
Ethyl N-[4-[(1-acetoimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2-naphthyl)methyl]oxamate obtained in Example 23 (100 mg) was dissolved in 20 ml of concentrated hydrochloric acid and the solution was allowed to stand at 5° C. for 9 days. The reaction solution was evaporated, and the resulting residue was purified by an ODS (YMC-GEL ODS-A 120-230/70) column chromatography using methanol:water (3:97) as the eluent, followed by addition of a small amount of 1N hydrochloric acid and freeze-drying to give 23 mg of N-[4-[(1-acetoimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2-naphthyl)methyl]oxamic acid dihydrochloride.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[C:4](OC)=[O:5].[BH4-].[Na+].O.C(OCC)(=O)C>C(O)C>[F:1][C:2]([F:18])([F:19])[CH:3]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[CH2:4][OH:5]
Reactant: COC(=O)C(Nc1cccc([N+](=O)[O-])c1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(NC(CO)C(F)(F)F)c1
Reaction time: 4 h
Yield: 73.8 %

Procedure:
To a solution of methyl 3,3,3-trifluoro-2-((3-nitrophenyl)amino)propanoate (C13, 297 mg) in ethanol (10 mL), sodium borohydride (121 mg) was added at room temperature, and the mixture was stirred at the same temperature for 4 hours. To the reaction mixture, water and ethyl acetate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 50% hexane in ethyl acetate) to obtain 3,3,3-trifluoro-2-((3-nitrophenyl)amino)propan-1-ol (C14, 197 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2[N:15]([CH3:22])[C:16](=[O:21])[C:17]([CH3:20])=[C:18]([OH:19])[C:13]=2[C:12](=[O:23])[N:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:10]1=[O:33].C(N(CC)CC)C.Cl.CN(C)C.[C:46]1([CH3:56])[CH:51]=[CH:50][C:49]([S:52](Cl)(=[O:54])=[O:53])=[CH:48][CH:47]=1>C(#N)C.CO>[CH3:56][C:46]1[CH:51]=[CH:50][C:49]([S:52]([O:19][C:18]2[C:13]3[C:12](=[O:23])[N:11]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)[C:10](=[O:33])[N:9]([C:3]4[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=4[F:1])[C:14]=3[N:15]([CH3:22])[C:16](=[O:21])[C:17]=2[CH3:20])(=[O:54])=[O:53])=[CH:48][CH:47]=1
Reactant: COc1ccc(Cn2c(=O)c3c(O)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(Cn2c(=O)c3c(OS(=O)(=O)c4ccc(C)cc4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Reaction time: 1 h
Yield: 77.5 %

Procedure:
Under nitrogen atmosphere, to a solution of 1-(2-fluoro-4-iodophenyl)-5-hydroxy-3-(4-methoxybenzyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione (41 g, 72.8 mmol) (Prepared as per reference WO2005121142) in acetonitrile (300 ml), triethylamine (30.4 ml, 218 mmol) and trimethylamine hydrochloride (3.48 g, 36.4 mmol) were added slowly followed by addition of p-toluensulfonylchloride (27.8 g, 146 mmol) in acetonitrile (300 ml) at 0° C., and the mixture was stirred under ice cooling for 1 hr, and then at room temperature for 24 h. To the reaction mixture was added methanol (220 ml), and the mixture was stirred at room temperature for 1 h. The precipitated crystals were collected by filtration, dried under vacuum to afford the titled compound (40.5 g, 78%)
Reaction SMILES: C1(C[N:8](CC2C=CC=CC=2)[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][C:15]2[N:19]=[C:20]4[CH2:25][CH2:24][CH2:23][CH2:22][N:21]4[C:14]3=2)C=CC=CC=1.[OH-].[Na+]>C(O)=O.C(Cl)Cl.[OH-].[OH-].[Pd+2]>[CH:12]1[CH:11]=[CH:10][C:9]([NH2:8])=[C:18]2[C:13]=1[C:14]1[N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C:20]3=[N:19][C:15]=1[CH:16]=[N:17]2
Reactant: c1ccc(CN(Cc2ccccc2)c2cccc3c2ncc2nc4n(c23)CCCC4)cc1
Agent: [Pd+2]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=CO
Product: Nc1cccc2c1ncc1nc3n(c12)CCCC3
Yield: 32.6 %

Procedure:
Palladium hydroxide on carbon (0.35 g) was added to a solution of N,N-bis(phenylmethyl)-8,9,10,11 tetrahydropyrido[1',2':1,2]imidazo[4,5-c]quinolin-4-amine (0.38 g, 0.9 mmole) in formic acid (about 15 mL). The reaction mixture was heated at reflux for 3 days then diluted with methylene chloride and made basic (about pH 9) with 10% sodium hydroxide. The methylene chloride layer was separated, dried over magnesium sulfate and then concentrated under vacuum to provide a white solid. The material was purified by column chromatography (silica gel eluting with 4-10% methanol in methylene chloride v/v) to provide a solid. The solid was suspended in methylene chloride (20 mL) then isolated by filtration and dried to provide 70 mg of 8,9,10,11 tetrahydropyrido[1',2':1,2]imidazo[4,5-c]quinolin-4-amine as a solid, m.p. 275°-278° C. Calculated for C14H14N4 +0.2 CH2Cl2 : %C, 66.81; %H, 5.69; %N, 21.95; Found: %C, 67.06; %H, 5.60; %N, 22.18.
Reaction SMILES: FC1C=C(CC(N[C@H](C(O)=O)C(C)C)=O)C=C(F)C=1.[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([NH:31][C@H:32]([C:43]([O:45]C)=[O:44])[CH2:33][C:34]2[NH:35][C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1>>[F:27][C:25]1[CH:24]=[C:23]([CH2:28][C:29]([NH:31][C@H:32]([C:43]([OH:45])=[O:44])[CH2:33][C:34]2[NH:35][C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:30])[CH:22]=[C:21]([F:20])[CH:26]=1
Reactant: COC(=O)[C@H](Cc1cc2ccccc2[nH]1)NC(=O)Cc1cc(F)cc(F)c1
Agent: CC(C)[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: O=C(Cc1cc(F)cc(F)c1)N[C@@H](Cc1cc2ccccc2[nH]1)C(=O)O
Yield: 118.1 %

Procedure:
A method similar to that used for the preparation of (107b) was used except that methyl N-[(3,5-difluorophenyl)acetyl]-L-methioninate (110a) (300 mg) was used instead of methyl N-[(3,5-difluorophenyl)acetyl]-L-valinate to afford the desired product (341 mg). This material was not further characterized but used in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](OS(C1C=CC=CC=1)(=O)=O)[CH:7]=[CH:6]2)#[N:2].[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)#[CH:24]>CCCCCCC.CCOC(C)=O>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]#[C:24][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[C:3]([C:1]#[N:2])[CH:12]=[CH:11]3)=[CH:26][CH:27]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: N#Cc1ccc2cc(OS(=O)(=O)c3ccccc3)ccc2c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ccc(C#Cc2ccc3cc(C#N)ccc3c2)cc1

Procedure:
This product was prepared from benzenesulfonic acid 6-cyano-naphthalen-2-yl ester and 1-ethynyl-4-methoxy-benzene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 95:5; yield (140 mg, 98%); 1H NMR δ (CDCl3): 8.20 (s, 1H), 8.06 (s, 1H), 7.88 (t, J=7.81 Hz, 2H), 7.71-7.59 (dm, 2H), 6.92 (m, 2H), 3.83 (s, 3H); LCMS m/z: 283.
Reaction SMILES: Br[N:2]1[C:6](=O)[CH2:5][CH2:4][C:3]1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=O)[CH2:27]C2>C(Cl)(Cl)(Cl)Cl>[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:29]2[CH:28]([CH3:27])[CH:5]3[CH2:6][NH:2][CH2:3][CH:4]3[C:25]=2[CH:24]=1
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(c1)C1CNCC1C2C
Temperature: 85 °C
Reaction time: 3 h

Procedure:
N-bromosuccinimide (12.1 g, 67.9 mmol) and 2,2′-azobisisobutyronitrile (0.1 g, 0.6 mmol) were added to a solution of 5-methoxy-1-indanone (10.0 g, 61.7 mmol) in carbon tetrachloride (104 mL). The reaction mixture was stirred for 3 hours at 85° C. and then allowed to cool to room temperature. The reaction mixture was filtered through Celite, which was then washed with CH2Cl2 (100 mL). The filtrate was washed with brine (50 mL), dried over MgSO4, and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C10H9BrO2+H: 241, observed: 241.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9]#[N:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:23]1([CH2:29][O:30][CH2:31][CH2:32][Br:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Br-:33].[C:9]([C:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:7][N+:1]([CH2:32][CH2:31][O:30][CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2)#[N:10]
Reactant: BrCCOCc1ccccc1
Reactant: N#CC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Product: N#CC(c1ccccc1)(c1ccccc1)C12CC[N+](CCOCc3ccccc3)(CC1)C2
Product: [Br-]
Yield: 36.7 %

Procedure:
Following the general procedure outlined in Example 24, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)acetonitrile (0.044 g, 0.152 mmol) and 2-bromoethyl phenylmethyl ether (0.040 mL, 0.253 mmol) in 2CH3CN/3CHCl3 (3.5 mL) were reacted to give the desired product (0.0281 g, 37.0%). EI-MS m/z 423 (M+) Rt (2.02 min).
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][C:17]([CH:18]=[C:19]4[CH2:23][CH2:22][O:21][C:20]4=[O:24])=[CH:16][C:15]=3[C:31]([F:34])([F:33])[F:32])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2]>CO.[H][H].[Pd]>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:15]([C:31]([F:32])([F:34])[F:33])=[CH:16][C:17]([CH2:18][CH:19]4[CH2:23][CH2:22][O:21][C:20]4=[O:24])=[CH:25][C:26]=3[C:27]([F:29])([F:30])[F:28])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(C=C4CCOC4=O)cc3C(F)(F)F)cc12
Agent: [Pd]
Solvent: CO
Product: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CC4CCOC4=O)cc3C(F)(F)F)cc12

Procedure:
0.2 g (0.38 mmol) of benzylidene compound from Example 24 are dissolved in 100 ml of methanol and hydrogenated with hydrogen for 18 hours in the presence of palladium on active carbon. The catalyst is filtered off through kieselguhr and the filtrate is concentrated in vacuo. The crude product is purified by chromatography on silica gel 60 in the isocratic gradient mode using toluene/ethyl acetate (10:1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=2)[OH:9])[CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>O.[O-2].[O-2].[O-2].[Cr+6]>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1cccc(Oc2ccccc2)c1)c1cccc(Br)n1
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1cccc(Oc2ccccc2)c1)c1cccc(Br)n1
Reaction time: 1 h

Procedure:
A solution of 5 g chromium trioxide in 10 ml water is added to a mixture of 20 g 6-bromo-α-(3-phenoxyphenyl)-2-pyridinemethanol (see Ex. 18) and 70 ml glacial acetic acid. After stirring for 1 hr. at room temperature, the reaction mixture is added to ice:water and extracted with chloroform. The organic layer is washed with 2.5N NaOH, then with water, dried (Na2SO4) and solvent removed. Yield: 15.4 g of the title product, m.p. 65°-6° C. (from methanol); Br 22.87 (22.56).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:22]3[S:21][CH:25]=[CH:24][N:23]=3)[CH:27]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1cccc(-c2nccs2)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2nccs2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 3-(thiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 409.16 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[C:21]([O-])([O-])(OCC)[CH2:22][CH3:23].S(=O)(=O)(O)O>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:21]([CH2:22][CH3:23])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: CCOC([O-])([O-])CC
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1.4 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine prepared in Example 1, 50 parts by volume of ethanol and 4 parts by volume of ethyl orthopropionate is added 0.5 part by volume of concentrated sulfuric acid. The mixture is stirred for 30 minutes at room temperature and then treated in a similar manner to Example 14, whereby 8-chloro-1-ethyl-6-phenyl-4H-s-triazolo- [4,3-a] [1,4] benzodiazepine is yielded as crystals. Recrystallization from acetone yields colorless prisms melting at 229° C to 230° C.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[N:15][C:14]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[C:23](=[O:27])[C:22]([CH2:33][C:34]([O:36]C)=[O:35])([CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:21][CH2:20]4)=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1>C(O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[N:15][C:14]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[C:23](=[O:27])[C:22]([CH2:33][C:34]([OH:36])=[O:35])([CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:21][CH2:20]4)=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)CC1(CC(F)(F)F)CCc2cc(-c3ccc(Nc4cccc(Cl)c4)nn3)ccc2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CC1(CC(F)(F)F)CCc2cc(-c3ccc(Nc4cccc(Cl)c4)nn3)ccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
Lithium hydroxide (0.063 g, 1.49 mmol) was added to a solution of 21E1 (0.15 g, 0.298 mmol) in 6 mL of ethanol-water (3:1) mixture, and the reaction mixture was stirred at room temperature for 4 h. After the solvent was removed in vacuo, the residue was diluted with water. The aqueous layer was acidified by addition of saturated citric acid solution until pH 2 was attained. The resulting solution was cooled to 0° C., and solids obtained were filtered off and dried under vacuum to afford the title compound 21 (0.118 g, 78%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.6 (bs, 1H), 9.78 (s, 1H), 8.19 (s, 1H), 8.13 (d, J=9.6 Hz, 1H), 8.07-7.95 (m, 3H), 7.58 (d, J=8.0 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.28 (d, J=9.2 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H), 3.24-2.87 (m, 5H), 2.68 (d, J=15.2 Hz, 1H), 2.34 (d, J=14.4 Hz, 1H), 2.14 (m, 1H). ESI-MS m/z: 490 (M+H)+; HPLC purity: 97%.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][NH:3]1.[H-].[Na+].I[CH2:28][CH3:29]>C1COCC1>[CH2:28]([N:3]1[CH2:4][CH:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:6]2([CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[C:2]1=[O:1])[CH3:29]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NCC2c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CC(c2ccccc2)C2(CCCN(C(=O)OC(C)(C)C)C2)C1=O
Reaction time: 0.17 h

Procedure:
tert-Butyl 1-oxo-4-phenyl-2,7-diazaspiro[4,5]decane-7-carboxylate (ASW MedChem) (1 g, 3.03 mmol) was dissolved in THF (20 ml) under an atmosphere of nitrogen. The solution was cooled (ice/brine bath) and treated with sodium hydride (60% in oil) (0.133 g, 3.33 mmol). The reaction mixture was stirred for 10 minutes and iodoethane (0.269 ml, 3.33 mmol) was added dropwise. The ice bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound. The resulting diastereomeric mixture was used in the next step without further purification.