Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:8][Si:9]([C:12]#[C:13][C:14]1[NH:18][C:17]([C@@H:19]2[CH2:24][C@@H:23]3[C@@H:21]([CH2:22]3)[N:20]2C(OC(C)(C)C)=O)=[N:16][CH:15]=1)([CH3:11])[CH3:10]>ClCCCl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:8][Si:9]([C:12]#[C:13][C:14]1[N:18]=[C:17]([C@@H:19]2[CH2:24][C@@H:23]3[C@@H:21]([CH2:22]3)[NH:20]2)[NH:16][CH:15]=1)([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(C#C[Si](C)(C)C)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: C[Si](C)(C)C#Cc1c[nH]c([C@@H]2C[C@H]3C[C@H]3N2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TFA (500 μl, 6.49 mmol) was added to a solution of (1R,3S,5R)-tert-butyl 3-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (299 mg, 0.865 mmol) in DCE (5 mL) and the reaction was stirred at rt for 30 min. The reaction was concentrated to dryness and then resubmitted to the reaction conditions for 5 h. The reaction was concentrated to yield a TFA salt of (1R,3S,5R)-3-(4-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane as a viscous brown oil which was used without further purification. LC-MS retention time 2.755 min; m/z 246.25 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:15]2[C:24]([CH3:26])([CH3:25])[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:27]([OH:29])=O)[CH:21]=3)[NH:16]2)[CH:6]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:8]=1)#[N:2].Cl.CN(C)CCCN=C=NCC.[CH3:42][S:43]([NH2:46])(=[O:45])=[O:44]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:15]2[C:24]([CH3:26])([CH3:25])[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:27]([NH:46][S:43]([CH3:42])(=[O:45])=[O:44])=[O:29])[CH:21]=3)[NH:16]2)[CH:6]=[C:7]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[CH:8]=1)#[N:2]
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(C#N)cc(N2CCOCC2)c1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cc(C#N)cc(N2CCOCC2)c1
Temperature: 65 °C
Yield: 29.9 %

Procedure:
A mixture of 2-(3-cyano-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (60 mg, 0.15 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44 mg, 0.23 mmol), 4-dimethylaminopyridine (28 mg, 0.23 mmol), methane sulfonamide (43 mg, 0.45 mmol) in dichloromethane (10 mL) was heated at 65° C. for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[2-(3-cyano-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (21 mg, 30%) as a light yellow solid: LC/MS m/e calcd for C24H28N4O4S (M+H)+: 469.6, observed: 469.2.
Reaction SMILES: [Cl:1][C:2]([Cl:13])=[CH:3][CH:4]([CH:10]([CH3:12])[CH3:11])[C:5]([O:7]CC)=[O:6].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]([Cl:13])=[CH:3][CH:4]([CH:10]([CH3:11])[CH3:12])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(C=C(Cl)Cl)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(C=C(Cl)Cl)C(=O)O
Yield: 84.9 %

Procedure:
In 20 g of chloroform were dissolved 6.0 g of the ethyl α-bromo-α-(2,2,2-trichloroethyl)isovalerate and, after the addition of 3.5 g of 1,5-diazabicyclo[5,4,0]undecene-5(DBU), the solution was stirred at room temperature for 2 hours. The reaction mixture was then diluted with diethyl ether, washed with water and dilute aqueous hydrogen chloride and dried over anhydrous magnesium sulfate. The low-boiling fraction was removed by distillation, whereupon 4.6 g of oily product were obtained. Based on its NMR spectrum and GC-mass spectrum, this product was identified to be ethyl α-isopropyl-β-trichloromethylacrylate containing a certain amount of ethyl α-bromo-α-(2,2-dichlorovinyl) isovalerate. In 50 ml of ethanol were dissolved 4.6 g of the oily product obtained above and, following the addition of 0.4 g of 5% palladium-on-carbon, the solution was stirred in an atmosphere of hydrogen gas at 55° C. for 6 hours. Thereafter, the reaction mixture was filtered to remove the catalyst and the ethanol was distilled off. By the above procedure there were obtained 3.9 g of ethyl α-(2,2-dichlorovinyl)isovalerate as an oil. Then, 3.9 g of this ethyl α-(2,2-dichlorovinyl)isovalerate were dissolved in 20 ml of ethanol and a solution of 2.0 g of sodium hydroxide in 10 ml of water was added to the above ethanol solution. The mixture was stirred at room temperature for 10 hours, at the end of which time the ethanol was distilled off. The residue was neutralized with aqueous hydrogen chloride and extracted with diethyl ether. The ethereal solution yielded 2.9 g of α-(2,2-dichlorovinyl)isovaleric acid having the following NMR spectrum [yield: 84% based on ethyl α-bromo-α-(2,2,2-trichloroethyl)isovalerate].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH:30]=[O:31])[CH:16]=[CH:17][C:18]=1[N:19]1[CH:23]=[N:22][C:21]([CH3:24])=[N:20]1.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]([OH:31])[CH2:29][CH2:28][CH2:27][C:26]#[C:25][C:15]2[CH:16]=[CH:17][C:18]([N:19]3[CH:23]=[N:22][C:21]([CH3:24])=[N:20]3)=[C:13]([O:12][CH3:11])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc([Mg]Br)cc1Cl
Reactant: COc1cc(C#CCCCC=O)ccc1-n1cnc(C)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C#CCCCC(O)c2ccc(Cl)c(Cl)c2)ccc1-n1cnc(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,4-Dichlorophenylmagnesium bromide (0.5 M THF solution, 13 mL) was added dropwise to a mixture of 6-[3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]hex-5-ynal (900 mg) in THF (32 mL) at −78° C., and the mixture was stirred for 1 hr under ice-cooling and at room temperature for 14 hr. 3,4-Dichlorophenylmagnesium bromide (0.5M THF solution, 13 mL) was added to the reaction mixture under ice-cooling, and the mixture was stirred for 1 hr under ice-cooling. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (349 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][CH2:7][C:8]2[CH:21]=[CH:20][C:11]([O:12][CH:13]([CH3:19])[C:14](OCC)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>CCOCC>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][CH2:7][C:8]2[CH:21]=[CH:20][C:11]([O:12][CH:13]([CH3:19])[CH2:14][OH:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)Oc1ccc(CNc2ccc(Cl)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: CC(CO)Oc1ccc(CNc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.2 %

Procedure:
A solution of 2.0 g of ethyl 2-[4-(4-chloroanilinomethyl)phenoxy]propionate in 20 ml of ether is dropwise added to a suspension of 324 mg of lithium aluminum hydride in 20 ml of anhydrous ether over a period of 10 minutes under 10° C. The mixture is stirred for 20 minutes at room temperature and cooled under 10° C., and to the mixture is dropwise added 25 ml of 10% ammonium chloride aqueous solution. An insoluble material is filtered off and the ether layer is separated. The aqueous layer is extracted with ether and both of the ether layers are combined. The extract is washed with a saturated sodium chloride aqueous solution and dried, after which the solvent is distilled off. The residue is collected by filtration, washed with a mixture of n-hexane and diisopropyl ether and dried to give 1.42 g of 2-[4-(4-chloroanilinomethyl)phenoxy]propanol, mp 81° to 83° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+]>ClCCl.FC(F)(F)C(O)=O.O>[O:1]1[C:5]2[CH:6]=[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3ccoc3c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2ccc(C3CCNCC3)cc2o1
Temperature: 15 °C
Reaction time: 1 h
Yield: 112.9 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of tert-butyl 4-(1-benzofuran-6-yl)piperidine-1-carboxylate (compound 63.4, 200 mg, 0.66 mmol) in dichloromethane (3 mL) and trifluoroacetic acid (1 mL). The resulting solution was stirred at 15° C. for 1 hour, then the pH was carefully adjusted to =9 with aqueous sodium hydroxide (2 M). The mixture was diluted with H2O (20 mL) and the layers were separated. The aqueous phase was extracted with dichloromethane (4×20 mL) and the combined organic layers were washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield the title compound as a brown oil (150 mg, crude).
Reaction SMILES: [CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17]([CH:19]=C)[CH:16]=[C:15]([Cl:21])[C:14]=2[Cl:22])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.[O:23]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17]([CH:19]=[O:23])[CH:16]=[C:15]([Cl:21])[C:14]=2[Cl:22])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1
Reactant: O=[O+][O-]
Reactant: C=Cc1cc(Cl)c(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1cc(C=O)cc(Cl)c1Cl)C1CC1

Procedure:
To a dichloromethane (0.03 M) solution of 1,1-dimethylethyl cyclopropyl[(2,3-dichloro-5-ethenylphenyl)methyl]carbamate (1 eq.) from Step 2, Amine 6 was bubbled at −78° C. freshly generated ozone until a persistent blue color was obtained. To this was then added triphenylphosphine (1.2 eq.) in one rapid portion and the resulting mixture was slowly warmed to RT over 3 h. The volatiles were removed in vacuo and the remaining residue was triturated with 2:1 (v/v) Hex:Et2O. The insolubles were removed via filtration and the filtrate was concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26](O)=[O:27])[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([NH:31][CH2:32][CH2:33][OH:34])[CH3:30]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)[CH2:25][C:26]([N:31]([CH2:29][CH3:30])[CH2:32][CH2:33][OH:34])=[O:27])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCNCCO
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3ncccc3c2)cc1
Product: CCN(CCO)C(=O)CN(c1ccc2ncccc2c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-acetic acid with 2-ethylamino-ethanol
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH2:8][CH2:9][CH3:10])[NH:5][C:6]=1[I:7].[H-].[Na+].[C:13]([NH:20][CH2:21][CH2:22]Br)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O>CN(C=O)C>[C:16]([O:15][C:13](=[O:14])[NH:20][CH2:21][CH2:22][N:3]1[C:2]([I:1])=[C:6]([I:7])[N:5]=[C:4]1[CH2:8][CH2:9][CH3:10])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCCc1nc(I)c(I)[nH]1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1nc(I)c(I)n1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4,5-diiodo-2-propyl-1H-imidazole (15.000 g; 41.443 mmol) in anhydrous DMF (260 ml) was added portionwise, at rt, 55-65% sodium hydride moistened with oil (1.989 g; 49.732 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 20 min. The mixture was then heated to 100° C., and a colorless homogeneous solution of 2-(Boc-amino)-ethylbromide (10.216 g; 45.587 mmol) in anhydrous DMF (100 ml) was added dropwise, over 1 h, with an addition funnel. After completion of the addition, the resulting dark-orange homogeneous mixture was further heated at 100° C. for 1 h30. The reaction mixture was cooled to rt, and water (300 ml) was added slowly. This mixture was extracted with ether (3×200 ml). The combined organic layers were washed with brine (2×100 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure to give a yellow oil. The crude was purified by FC (heptane/EA=1/1) to give the pure product [2-(4,5-diiodo-2-propyl-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester as a yellow solid which was further dried under HV (8.690 g; 42%). LC-MS: tR=0.88 min.; [M+H]+=505.77 g/mol.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:30]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[C:22]([NH2:31])[C:21]=2[N:20]=[C:19]1[CH2:32][CH3:33])[CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)(C)(C)C>FC(F)(F)C(O)=O>[CH2:32]([C:19]1[N:18]([CH2:17][CH2:16][CH2:15][CH2:14][NH:7][CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:30]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[C:22]([NH2:31])[C:21]=2[N:20]=1)[CH3:33]
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCN(C(=O)OC(C)(C)C)C1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCNC1CCOCC1

Procedure:
A solution of tert-butyl[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]tetrahydro-2H-pyran-4-ylcarbamate in trifluroacetic acid was stirred at 40° C. for 4 hrs. Reaction mixture was then poured on ice-water mixture and extracted with chloroform. Organic layer was dried over sodium sulphate and concentrated under deduced pressure to afford the title compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[CH:31]1([N:36]=[C:37]=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:17][CH2:16]3)=[O:14])[N:36]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[C:37]2=[O:38])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=NC1CCCC1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3C3CCCC3)CC2)c1

Procedure:
In analogy to example 2, (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 2, step 3) was reacted with sodium iodide and cyclopentyl isocyanate to give the title compound as a colorless solid. MS: 511.1 ([M+H]+)
Reaction SMILES: C[O:2][C@@H:3]([C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:27]=[C:15]3[C:16]4[C:21]([CH2:22][CH2:23][N:14]3[C:13](=[O:28])[CH2:12][N:11]=2)=[C:20]([C:24]([CH3:26])=[CH2:25])[CH:19]=[CH:18][CH:17]=4)[CH:9]=1)[CH3:4].[BH4-].[Na+]>CO.C(Cl)Cl.O>[CH:24]1([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:21]=2[CH2:22][CH2:23][N:14]2[C:13](=[O:28])[CH2:12][N:11]=[C:10]([N:8]4[CH:9]=[C:5]([CH:3]([OH:2])[CH3:4])[N:6]=[CH:7]4)[CH:27]=[C:15]23)[CH2:26][CH2:25]1
Reactant: C=C(C)c1cccc2c1CCN1C(=O)CN=C(n3cnc([C@@H](C)OC)c3)C=C21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(O)c1cn(C2=NCC(=O)N3CCc4c(cccc4C4CC4)C3=C2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.3 %

Procedure:
A solution of 2-(4-acetyl-1H-imidazol-1-yl)-9-cyclopropyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (202 mg, 0.35 mmol, it can be obtained by analogy to example 118) in MeOH (8 mL) was treated with NaBH4 (27 mg, 0.71 mmol) and the mixture was stirred at RT for 10 min. The mixture was then diluted with DCM and H2O, and the aqueous phase was extracte with DCM. The combined org. layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by SFC (column: PPU 5 m, 250×30 mm, 60A, Princeton; eluent: 12-17% MeOH/CO2 over 14 min; flow 100 mL/min; UV detection at 220 nm) and crystallization in Et2O gave the title compound as a solid (41 mg). UPLC-MS: MS 363.2 (M+H+); UPLC rt 0.86 min. 1H NMR (600 MHz, DMSO-d6): δ ppm 0.55-0.71 (m, 2H); 0.88-1.02 (m, 2H); 1.35 (d, J=6.40 Hz, 3H); 1.87-2.05 (m, 1H); 2.99-3.17 (m, 2H); 3.79-3.97 (m, 2H); 4.17-4.31 (m, 2H); 4.55-4.71 (m, 1H); 5.01 (d, J=4.89 Hz, 1H); 7.09-7.25 (m, 2H); 7.25-7.39 (m, 1H); 7.46 (s, 1H); 7.84-7.98 (m, 1H); 8.16 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][NH2:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH:16]([O-])([O-])OCC>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:16]=[N:15][N:14]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: CCOC([O-])[O-]
Product: Clc1ccc(-c2ccc3nncn3c2)cc1

Procedure:
A mixture of 8.5 g. of 5-(4-chlorophenyl)-2-hydrazinopyridine and 80.0 ml. of ethyl orthoformate is refluxed for 5 hours. The mixture is filtered and the solid is washed with hexane to give 6.5 g. of the product of the Example, m.p. 259°-262° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:14]=[CH:15][N:16](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(#N)C.[Br:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=1[CH2:49]Br)[C:44]#[N:45]>C(OCC)(=O)C>[Br:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=1[CH2:49][N:16]1[CH:17]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[N:14]=[CH:15]1)[C:44]#[N:45]
Reactant: N#Cc1ccc(CBr)c(Br)c1
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCCc1cn(Cc2ccc(C#N)cc2Br)cn1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To 4-[4-(tert-butyldimethylsilanyloxy)butyl]-1-trityl-1H-imidazole (3.95 g, 7.95 mmol) is added acetonitrile (300 mL). To this solution is added 3-bromo-4-bromomethylbenzonitrile (2.14 g, 7.78 mmol). The solution is stirred at 40° C. for 18 h. The solvent is then removed in vacuo and methanol (300 ml) is added. The solution is heated to 55° C. and stirred for 1.5 h. Saturated sodium bicarbonate is then added and stirred for 10 min. The organic solvent is removed in vacuo, and the crude product extracted into ethyl acetate and washed with water. The organic solvent is removed in vacuo to give the crude product. Chromatography (silica gel, 1:0 to 1:1 to 0:1 hexanes:ethyl acetate) gives the pure product. MS (ESI) m/z 448, 450 (M+H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[C:20]([CH3:27])=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>>[F:18][C:19]1[C:20]([CH3:27])=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: Cc1c(F)cccc1CBr
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: Cc1c(F)cccc1CN1N(C2C3CC4CC(C3)CC2C4)C(=O)C1(C)C

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3-fluoro-2-methylbenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [CH:1]1([C:6]2([CH3:20])[CH2:14][C:13]3[C:8](=[C:9]([Cl:18])[C:10]([Cl:17])=[C:11]([S:15]C)[CH:12]=3)[C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].[Cl-].[NH4+]>N>[CH:1]1([C:6]2([CH3:20])[CH2:14][C:13]3[C:8](=[C:9]([Cl:18])[C:10]([Cl:17])=[C:11]([SH:15])[CH:12]=3)[C:7]2=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: CC1(C2CCCC2)Cc2cc(S)c(Cl)c(Cl)c2C1=O

Procedure:
To a stirred suspension of 2-cyclopentyl-2-methyl-5-methylthio-6,7-dichloro-1-indanone (3.59 g., 0.01 mole) in liquid ammonia (100 ml.) cooled in a dry-ice-acetone bath is added sodium (460 mg., 0.02 gr. atom) in small portions until a permanent blue color persists. Ammonium chloride (1.0 g.) is added, the excess ammonia is evaporated and the reaction mixture is dissolved in water, acidified and extracted with ether which is washed with water, dried over magnesium sulfate and evaporated at reduced pressure affording 2-cyclopentyl-2-methyl-5-mercapto-6,7-dichloro-1-indanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]#[N:28])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:25][CH2:24][O:23][CH2:22]3)[C:17](O)=[O:18])[C:10](=[O:26])[CH:9]=2)[CH:7]=1.[NH2:29][C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]#[N:28])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:25][CH2:24][O:23][CH2:22]3)[C:17]([NH:29][C:30]3[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[CH:32][CH:31]=3)=[O:18])[C:10](=[O:26])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2CCOC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: COc1cn(C(CC2CCOC2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
900 mg (purity 94%, 2.1 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydrofuran-3-yl)propanoic acid (mixture of racemic diastereomers) and 446 mg (2.3 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 682 mg (purity 97%, 54% of theory) and 113 mg (purity 92%, 9% of theory)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH:18]([CH2:20]O)[CH2:17][C:16]2=[O:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH:18]([CH2:20][Cl:25])[CH2:17][C:16]2=[O:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(CO)CN1c1ccc(OCc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C1CC(CCl)CN1c1ccc(OCc2ccccc2)cc1
Yield: 15.6 %

Procedure:
740 mg (2.49 mmol) (RS)-1-(4-benzyloxy-phenyl)-4-hydroxymethyl-pyrrolidin-2-one is dissolved in 20 ml toluene. 1.08 ml (14.9 mmol) thionyl chloride is added and the mixture refluxed for 6 hours. Evaporation and chromatography (silica gel, n-hexane/ethyl acetate 1:1) yields 123 mg (16%) of a brownish semisolid. MS: m/e=315.2 (M+).