Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4](=N)[O:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1)=[CH:10][CH:9]=[C:8]1[N:20]([CH3:23])[CH:21]=[CH:22][C:7]=21)#[N:2].[OH-:25].[Na+]>Cl.CS(C)=O.O>[C:1]([C:3]1[C:4](=[O:25])[O:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1)=[CH:10][CH:9]=[C:8]1[N:20]([CH3:23])[CH:21]=[CH:22][C:7]=21)#[N:2]
Reactant: [OH-]
Reactant: Cc1cncc(-c2c(C#N)c(=N)oc3c2ccc2c3ccn2C)c1
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cncc(-c2c(C#N)c(=O)oc3c2ccc2c3ccn2C)c1
Yield: 68 %

Procedure:
A solution of 3-cyano-2-imino-4-(5-methyl-pyridin-3-yl)-7-methyl-2H-pyrrolo[2,3-h]chromene (50 mg, 0.14 mmol) in 10% HCl (2 mL) and DMSO (0.5 mL) was stirred at room temperature for approximately 4 h. The yellow suspension was diluted with water (5 mL), neutralized to approximate pH=9 using 10% NaOH, and extracted with EtOAc (3×20 mL). The EtOAc extracts were washed with brine (10 mL), dried over MgSO4, and evaporated to yield a yellow solid. The solid was purified by flash column chromatography (silica gel, EtOAc:hexanes, 50-80% EtOAc) to yield a yellow solid (31 mg, 68%). 1H NMR (DMSO-d6): 8.71 (d, J=1.8 Hz, 1H), 8.58 (d, J=2.1 Hz, 1H), 7.88 (m, 1H), 7.61 (d, J=3.0 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H) 6.93 (d, J=8.7 Hz, 1H), 6.91 (d, J=3.3 Hz, 1H), 3.88 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: CN1CCOCC1.[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[CH:18]1([C:21]2[CH:25]=[C:24]([NH2:26])[NH:23][N:22]=2)[CH2:20][CH2:19]1.C(OCC)C>ClC>[CH:18]1([C:21]2[CH:25]=[C:24]([NH:26][C:13](=[O:14])[C:12]3[CH:16]=[CH:17][C:9]([Br:8])=[CH:10][CH:11]=3)[NH:23][N:22]=2)[CH2:20][CH2:19]1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Nc1cc(C2CC2)n[nH]1
Agent: CCl
Solvent: CCOCC
Solvent: CN1CCOCC1
Product: O=C(Nc1cc(C2CC2)n[nH]1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.9 %

Procedure:
122 mg (loading 1.91 mmol/g, 0.233 mmol) of polystyrene supported N-methylmorpholine were suspended in 4 ml of chloromethane and then treated with 25.6 mg (0.117 mmol) of 4-bromobenzoyl chloride followed by 4.8 mg (0.039 mmol) of 3-cyclopropyl-5-amino-pyrazole. After 48 hours under stirring at room temperature the resin was separated by filtration and washed with 2 ml of dichloromethane. The filtrate was evaporated to dryness, the residue re-dissolved in 4 ml of dichloromethane and 100 mg of polystyrene supported trisamine were added. After 48 hours or stirring at room temperature the resin was filtered, washed with 2 ml of dichloromethane and concentrated to give, after triturating with diethylether, 9.3 mg (78% yield) of the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([F:27])[C:25]=1[F:26]>>[CH3:16][C:7]1[C:6]2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:22]3[CH:21]=[C:20]([F:19])[C:25]([F:26])=[C:24]([F:27])[CH:23]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=12
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Product: Cc1c2n(c3c(-c4cc(F)c(F)c(F)c4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, grey solid (45 mg, 51%), MS (ISP) m/z=356.6 [(M+H)+], mp 253° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 3,4,5-trifluoro-phenylboronic acid (57.2 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[C:31]3[C:26](=[C:27]([Cl:33])[CH:28]=[C:29]([Cl:32])[CH:30]=3)[CH2:25][N:24]([CH3:34])[CH2:23]2)[CH:17]=1)=[O:14].[OH:35][C@H:36]([C@@H:47]([OH:58])[C:48]([O:50]N1C(=O)CCC1=O)=O)[C:37]([O:39]N1C(=O)CCC1=O)=O.[CH2:59]([N:61]([CH2:64][CH3:65])[CH2:62][CH3:63])C>CN(C=O)C>[Cl:32][C:29]1[CH:30]=[C:31]2[C:26](=[C:27]([Cl:33])[CH:28]=1)[CH2:25][N:24]([CH3:34])[CH2:23][CH:22]2[C:18]1[CH:17]=[C:16]([NH:15][C:13](=[O:14])[CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:37](=[O:39])[C@H:36]([OH:35])[C@@H:47]([OH:58])[C:48]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13](=[O:14])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:63]3[C:31]4[C:65](=[C:27]([Cl:33])[CH:28]=[C:29]([Cl:32])[CH:30]=4)[CH2:64][N:61]([CH3:59])[CH2:62]3)[CH:17]=2)=[O:50])[CH:21]=[CH:20][CH:19]=1
Reactant: CCN(CC)CC
Reactant: O=C(ON1C(=O)CCC1=O)[C@H](O)[C@@H](O)C(=O)ON1C(=O)CCC1=O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)CCOCCOCCOCCN)c2)C1
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)CCOCCOCCOCCNC(=O)[C@H](O)[C@@H](O)C(=O)NCCOCCOCCOCCC(=O)Nc3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1
Temperature: 35 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-N-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)propanamide (intermediate 179.7) (270 mg, 0.53 mmol, 2.00 equiv) in anhydrous DMF (5.0 mL) was added (2R,3R)-bis(2,5-dioxopyrrolidin-1-yl) 2,3-dihydroxysuccinate (prepared from (2R,3R)-tartaric acid as described in example 168) (91.0 mg, 0.26 mmol, 1.00 equiv) and triethylamine (0.3 mL) and the resulting solution was stirred for 2 h at 35° C. The resulting mixture was then concentrated under vacuum. The residue was purified by Prep-HPLC, to give 170 mg (56%) of a TFA salt of (2R,3R)—N1,N4-bis(2-(2-(2-(3-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamino)-3-oxopropoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide as an off-white solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 7.92 (s, 1H), 7.65 (s, 2H), 7.54 (d, J=1.5 Hz, 2H), 7.36-7.46 (m, 4H), 7.02 (dd, J=7.5, 1.2 Hz, 2H), 6.90 (s, 2H), 4.83-4.75 (m, 2H), 4.65-4.60 (m, 2H), 4.53 (s, 1H), 4.46 (m, 3H), 3.88-3.80 (m, 6H), 3.64-3.51 (m, 22H), 3.41-3.35 (m, 4H), 3.16 (s, 6H), 2.64 (t, J=6.0 Hz, 4H). MS (m/z): 1136 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.COC(OC)OC.[C:18]1([CH3:28])C=CC(S(O)(=O)=O)=CC=1.[CH3:29][NH:30][CH2:31]C>C(OCC)(=O)C.C1CCCCC1>[CH2:18]([N:30]([CH3:31])[CH:29]=[N:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([OH:9])=[CH:6][C:7]=1[CH3:8])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCNC
Reactant: Cc1cc(O)c(C)cc1N
Solvent: COC(OC)OC
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCN(C)C=Nc1cc(C)c(O)cc1C
Temperature: 50 °C
Yield: 55 %

Procedure:
To a mixture of 10.0 g (73 mmol) of 4-amino-2,5-dimethylphenol and 73 ml (0.84 mol) of trimethoxymethane 0.73 g (4.2 mmol) of p-toluene sulfonic acid were added and the mixture was heated to reflux for 2 hours. Then the volatiles were removed in vacuo and the residue was dissolved in 73 ml of toluene and 12.9 g (217 mmol) N-methylethanamine were added. The reaction mixture was heated to 50° C. for 20 hrs and concentrated in vacuo. Column chromatographie (gradient: cyclohexane->ethyl acetate) yielded 9.17 g (44 mmol) 55% of N-ethyl-N′-(4-hydroxy-2,5-dimethylphenyl)-N-methylimidoformamide; log P (pH 2.3)=0.41.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].[C:18](Cl)(=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22]>O>[C:18]([NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: COC(=O)c1cccc(N)c1
Reactant: CCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCC(=O)Nc1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To anhydrous pyridine (120 ml), methyl 3-aminobenzoate (5.00 g) was dissolved, and valeryl chloride (4.13 ml) was added while cooling on ice. The mixture was stirred at room temperature for 4 hours. Distilled water was added to the solution. The whole was extracted with ethyl acetate, washed with 5% sodium hydrogencarbonate aqueous solution and water, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (Kieselgel 60=170 g, hexane/ethyl acetate=3/1) to obtain the above-captioned compound ([6]-(62)-90) (7.70 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:14]([CH:15]=O)[CH:13]2[CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(=O)NC(=O)C=C1.ClC1C=C(C=CC=1Cl)N.N1C=CC=CC=1.Cl.[CH3:47][O:48][NH2:49]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:14]([CH:15]=[N:49][O:48][CH3:47])[CH:13]2[CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CC2C(C=O)C2(c2ccc(Cl)c(Cl)c2)C1
Reactant: CON
Agent: Cl
Agent: Nc1ccc(Cl)c(Cl)c1
Agent: O=C1C=CC(=O)N1
Solvent: c1ccncc1
Solvent: CCO
Product: CON=CC1C2CN(C(=O)OC(C)(C)C)CC12c1ccc(Cl)c(Cl)c1
Yield: 90 %

Procedure:
To a solution of tert-butyl 1-(3,4-dichlorophenyl)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.50 g, 7.02 mmol, prepared from maleimide and 3,4-dichloroaniline according to the methods described in WO 2009141412 and WO 2008074716), in ethanol (40 mL) under nitrogen atmosphere, were added pyridine (2.82 mL, 35.04 mmol) and O-methylhydroxylamine hydrochloride (1.17 g, 14.01 mmol). The reaction mixture was refluxed for 5 h. After completion of the reaction as confirmed by TLC, the solvent was evaporated. The crude compound was extracted with ethyl acetate (20 mL). The organic layer was separated, washed with 5% HCl (5 mL), water (10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1:9 EtOAc:Pet Ether) to afford pure tert-butyl 1-(3,4-dichlorophenyl)-6-((methoxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.45 g, 90%) as a viscous oil as a mixture of isomers.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([O:8]C2C=CC(C#N)=CC=2)=O)=[CH:4][CH:3]=1.[CH3:19][C:20]1([CH3:28])[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][C:21]1=[O:27].C(N(CC)CC)C.CC(C)(O)C#N>C(#N)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:22]2[C:21](=[O:27])[C:20]([CH3:28])([CH3:19])[CH2:25][CH2:24][C:23]2=[O:26])=[O:8])=[CH:17][CH:18]=1
Reactant: Cc1ccc(C(=O)Oc2ccc(C#N)cc2)cc1
Reactant: CC1(C)CCC(=O)CC1=O
Agent: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(C(=O)C2C(=O)CCC(C)(C)C2=O)cc1

Procedure:
A 50-mL single neck round bottom flask was charged with 4-cyanophenyl 4-methylbenzoate (2.65 g, 11.2 mmol), 4,4-dimethyl-1,3-cyclohexanedione (2.10 g, 15 mmol) and acetonitrile (15 mL). Then triethylamine (2.5 g, 25 mmol) and acetone cyanohydrin (0.14 mL, 1.5 mmol) were added and the mixture was refluxed for 6 hours. Volatiles were stripped from the reaction mixture and the residue was partitioned between diethyl ether (100 mL) and water (50 mL). The organic layer was extracted with saturated aqueous sodium bicarbonate (30 mL), then water (10 mL), then brine (10 mL). All aqueous layers were combined and 1N hydrochloric acid was added to pH 1. The resulting oil was extracted into dichloromethane (30 mL, 2×15 mL). The dichloromethane layers were combined, dried over magnesium sulfate, filtered and stripped to a brown oil (3.57 g). The crude product was chromatographed on silica gel (200 g), eluting with hexanes-ethyl acetate (4:1). Fractions containing pure product were concentrated to a yellow oil (2.08 g), which was crystallized from hexanes to afford the title compound as off-white crystals, 1.35 g (46.8%), m.p. 78-79° C. 1H NMR (DMSO-d6): δ 1.08 (s, 6), 1.84 (m, 2), 2.36 (s, 3), 2.61 (m, 2), 7.26 (d, 2), 7.60 (d, 2).
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.ClCCl.[Si:13]([O:30][CH2:31][C:32]1[N:33]=[C:34]([N:44]2[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]2)[N:35]([CH2:40][C:41]#[C:42][CH3:43])[C:36]=1[C:37](=[S:39])[NH2:38])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[Si:13]([O:30][CH2:31][C:32]1[N:33]=[C:34]([N:44]2[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]2)[N:35]([CH2:40][C:41]#[C:42][CH3:43])[C:36]=1[C:37]([S:39][CH3:6])=[NH:38])([C:26]([CH3:28])([CH3:27])[CH3:29])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C(N)=S
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C(=N)SC
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.8 %

Procedure:
1.23 g of trimethyloxonium tetrafluoroborate was added to a 100 ml dichloromethane solution of 4.351 g of t-butyl 4-[4-(t-butyldiphenylsilanyloxymethyl)-1-(2-butynyl)-5-thiocarbamoyl-1H-imidazol-2-yl]piperazine-1-carboxylate, and the mixture was stirred at room temperature for 15 hours. 300 ml of ethyl acetate was added to the solution, and the organic layer was washed successively with 100 ml of a saturated sodium bicarbonate solution and 100 ml a saturated ammonium chloride solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure to give 4.439 g of the title compound.
Reaction SMILES: [OH-].[K+].[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:25])[C:17]2[C:22]([CH2:23][OH:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:26]I>CS(C)=O.O>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:25])[C:17]2[C:22]([CH2:23][O:24][CH3:26])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN(c1ncccc1CO)C1CCN(Cc2ccccc2)CC1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COCc1cccnc1N(C)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
To a mixture of powdered potassium hydroxide (356 mg) in dry dimethylsulfoxide (2 ml) under nitrogen is added a solution of 1-benzyl-4-(N-methyl-N-(3-hydroxymethyl-2-pyridyl)amino)piperidine (XXX, EXAMPLE 35, 494 mg) in dry dimethylsulfoxide (1.2 ml) followed by methyl iodide (118 μl). The resulting mixture is stirred at 20°-25° for 30 min and is then diluted with water (15 ml) and extracted with methylene chloride (2×20 ml). The combined organic phases are washed with water (2×10 ml) and saline (10 ml), dried over sodium sulfate and concentrated under reduced pressure to give a concentrate which is then chromatographed (silica gel, a gradient of ethyl acetate/hexane (20/80→40/60)) to give the title compound, NMR (CDCl3, 400 MHz) 8.22, 7.67, 7.31, 7.25, 6.89, 4.40, 3.50, 3.41, 3.28, 2.94, 2.77, 2.01, 1.86 and 1.70δ.
Reaction SMILES: N[CH2:2][CH2:3][C:4]1[N:8]2[C:9]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:10]=3[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])=[N:12][CH2:13][C:7]2=[N:6][N:5]=1.C=O.[C:28]([BH3-])#[N:29].[Na+].[CH2:32](N)CN>C(#N)C.C(O)(=O)C>[CH3:32][N:29]([CH3:28])[CH2:2][CH2:3][C:4]1[N:8]2[C:9]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:10]=3[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])=[N:12][CH2:13][C:7]2=[N:6][N:5]=1
Reactant: NCCN
Reactant: [BH3-]C#N
Reactant: NCCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(C)CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 22, a mixture of 1-(2-aminoethyl)-8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, 37% aqueous formaldehyde and acetic acid in acetonitrile is treated with sodium cyanoborohydride and the resulting boron complex is warmed with aqueous ethylenediamine to give 1-[2-(dimethylamino)ethyl]-8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[CH:10]=[CH:11][C:12]3[NH:18][C:17](=[O:19])[CH2:16][N:15]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:13]=3[CH:26]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:30])=O>C(Cl)Cl>[Cl:30][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:9]1[CH:10]=[CH:11][C:12]2[NH:18][C:17](=[O:19])[CH2:16][N:15]=[C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH:26]=1
Reactant: O=C1CN=C(c2ccccc2)c2cc(C(O)c3ccc(Cl)cc3)ccc2N1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1CN=C(c2ccccc2)c2cc(C(Cl)c3ccc(Cl)cc3)ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of intermediate (28) (0.0125 mol) in thionyl chloride (5 ml) and DCM (100 ml) was stirred at room temperature overnight. The mixture was evaporated till dryness. The product was used without further purification, yielding 4.93 g (100%) of (±)-7-[chloro(4-chlorophenyl)methyl]-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (intermediate 29).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:32](Cl)(=O)[O:33]C1C=CC([N+]([O-])=O)=CC=1.[CH:45]1([CH2:48][NH2:49])[CH2:47][CH2:46]1.C(N(CC)CC)C>ClCCl.C(=O)(O)[O-].[Na+]>[CH:45]1([CH2:48][NH:49][C:32]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][CH:7]3[CH2:12][CH2:11][N:10]([CH2:13][C:14]4[CH:15]=[CH:16][C:17]([C:20]([OH:29])([C:21]([F:22])([F:23])[F:24])[C:25]([F:28])([F:26])[F:27])=[CH:18][CH:19]=4)[CH2:9][CH2:8]3)=[CH:30][CH:31]=2)=[O:33])[CH2:47][CH2:46]1
Reactant: NCC1CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CC1)Nc1ccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
A solution of 2-(4-((4-(4-aminophenoxy)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.446 mmol, 200 mg) and 4-nitrophenyl carbonochloridate (0.446 mmol, 90 mg) in dichloromethane (1 mL) were stirred at room temperature for 30 minutes. Cyclopropylmethanamine (0.892 mmol, 0.091 mL, 63.4 mg) was added, followed by triethylamine (1.338 mmol, 0.187 mL, 135 mg) and the reaction stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and saturated sodium bicarbonate solution was added. The organic layer was separated and concentrated under vacuum. The residue was purified by silica column chromatography (eluent 2-8% methanol in dichloromethane) to give the title compound (55.3 mg). MS (ESI) m/z 546.2 [M+H]+
Reaction SMILES: CC1C=N[C:5]2[C:6]3[O:15][C@@H:14]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[CH2:13][O:12][C:7]=3[CH:8]=[CH:9][C:10]=2C=1.[NH:28]1[CH2:31][CH:30]([CH2:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([F:42])[CH:40]=3)[NH:35][CH:34]=2)[CH2:29]1.C([N:45]([CH2:48][CH3:49])[CH2:46][CH3:47])C>CS(C)=O>[F:42][C:39]1[CH:40]=[C:41]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[C:33]2[CH2:32][CH:30]1[CH2:31][N:28]([CH2:16][CH:14]2[O:15][C:6]3=[C:5]4[C:46](=[CH:47][CH:8]=[C:7]3[O:12][CH2:13]2)[N:45]=[C:48]([CH3:49])[CH:9]=[CH:10]4)[CH2:29]1
Reactant: Fc1ccc2[nH]cc(CC3CNC3)c2c1
Reactant: CCN(CC)CC
Reactant: Cc1cnc2c3c(ccc2c1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CC(Cc2c[nH]c4ccc(F)cc24)C1)O3

Procedure:
A solution of (2R)-4-bromobenzenesulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-]quinolin-2-ylmethyl ester (0.35 g, 0.80 mmol), 3-azetidin-3-ylmethyl-5-fluoro-1H-indole (0.19 g, 0.96 mmol) and triethylamine (0.16 mL, 1.2 mmol) in dimethylsulfoxide (20 mL) was heated at 90° C. under nitrogen overnight. The reaction mixture was quenched with 1N sodium hydroxide and extracted with methylene chloride (3×80 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The resulting crude oil was column chromatographed on silica gel (3% methanol-ethyl acetate). The product-containing fractions were concentrated in vacuum to give 0.090 g of the (S)-enantiomer of the title compound as a brown oil. The dihydrochloride salt was prepared in ethyl acetate and collected as 0.068 g of a yellow solid, m.p. 125° C. (dec).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([O:10][C:11]2[CH:12]=[C:13]([C:19]3[N:23]([CH3:24])[NH:22][C:21](=[O:25])[CH:20]=3)[CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:9][CH2:8][CH2:7][CH2:6]1.C[Si](C)(C)[NH:28][Si](C)(C)C>O1CCCC1.O1C=CC=C1.O1CCCC1>[CH:5]1([O:10][C:11]2[CH:12]=[C:13]([C:19]3[N:23]([CH3:24])[N:22]([C:1]([NH2:28])=[O:2])[C:21](=[O:25])[CH:20]=3)[CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(-c2cc(=O)[nH]n2C)cc1OC1CCCC1
Solvent: C1CCOC1
Solvent: c1ccoc1
Product: COc1ccc(-c2cc(=O)n(C(N)=O)n2C)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a 0° C. solution of phosgene (8.75 mmol, 4.61 mL; 1.9 M solution in toluene) in dry tetrahydrofuran (30 mi) is added 5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,2-dihydro-1-methyl-3H-pyrazol-3-one (7.0 mmol, 2.02 g) in dry tetrahydrofuran furan (15 mL) dropwise over 20 minutes. The resulting cloudy solution is stirred at 0° C. for 10 minutes and at room temperature for 1 hour after which a homogenous solution is obtained. The reaction mixture is cooled to 0° C. and hexamethyldisilazane (17.5 mmol, 2.82 g; 3.64 mi) in dry tetrahydrofuran (15 mL) is added in one portion. The resulting suspension is stirred at room temperature for 1 hour and then the volatiles are removed in vacuo. The residue is partitioned between 2% aqueous acetic acid (200 mi) and ethyl acetate (200 mi) and the aqueous phase is extracted with ethyl acetate (150 mL). The combined organic layers are washed with H2O (100 mL), dried (Na2SO4), and concentrated in vacuo to afford a tan solid. This material is triturated with ether and dried in vacuo for 1 hour at 60° C. to give the title compound as a white solid (1.80 g; 78%). 1H NMR (DMSO-d6 400 MHz) δ 7.23 (br s, 1H); 7.02 (m, 3H); 6.92 (br s, 1H); 6.08 (s, 1H); 4.86 (m, 1H); 3.78 (s, 3H); 3.72 (s, 3H); 1.88 (m, 2H); 1.70 (m, 4H); 1.56 (m, 2H). IR (KBr, cm-1) 3400, 3300, 3200, 2950, 1760, 1500,1330,1250,1130.
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=4)[CH:18]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[O:7])=[C:4]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:3]=1.C(B(CC)[C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1)C>>[ClH:27].[C:33]([O:32][C:30]([C:4]1[CH:3]=[C:2]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[CH:29]=[CH:28][C:5]=1[C:6]([N:8]1[CH2:9][CH2:10][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[CH:18]=2)(=[O:16])=[O:15])[CH2:12][CH2:13]1)=[O:7])=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CCB(CC)c1ccncc1
Reactant: CC(C)(C)OC(=O)c1cc(Br)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Product: CC(C)(C)OC(=O)c1cc(-c2ccncc2)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Product: Cl

Procedure:
In the same manner as in Referential Example 7, a reaction was conducted using 1-[4-bromo-2-(tert-butoxycarbonyl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine and diethyl(4-pyridyl)borane as starting materials, whereby the title compound was obtained.