Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][C:13](=[O:21])[CH:12]([N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])[N:11]=1.Br[CH2:34][C:35]1[S:36][C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[N:39]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O.C(OCC)(=O)C.C(O)(=O)C>[S:36]1[C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[N:39]=[C:35]1[CH2:34][N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[F:3])=[N:11][CH:12]([N:22]2[C:23](=[O:32])[C:24]3=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]3[C:26]2=[O:27])[C:13]1=[O:21]
Reactant: O=C1Nc2ccccc2C(c2ccccc2F)=NC1N1C(=O)c2ccccc2C1=O
Reactant: BrCc1nc2ccccc2s1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2F)c2ccccc2N1Cc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (0.11 g of a 60% dispersion in mineral oil) in N,N-dimethylformamide (20 ml) was added gradually (3RS)-2,3-dihydro-5-(2-fluorophenyl)-3-phthalimido-1H-1,4-benzodiazepin-2-one (1.00 g) under nitrogen atmosphere at cooling in an ice-bath. The mixture was stirred under the same condition for 0.5 hour and at ambient temperature for 1 hour. The mixture was cooled in an ice-bath and a solution of 2-bromomethyl-benzothiazole (0.63 g) in N,N-dimethylformamide (5 ml) was added dropwise thereto. The mixture was stirred for 1 hour at the same temperature and at ambient temperature overnight. To the reaction mixture was added acetic acid (0.5 g) under cooling in an ice-bath. The resultant mixture was poured into a mixture of ethyl acetate (100 ml) and water (50 ml) under stirring. The mixture was adjusted to pH 7.5-8.0 with sodium bicarbonate. The organic layer was separated. The aqueous layer was extracted with ethyl acetate (50 ml). The combined organic layer was washed with a brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to afford (3RS)-1-(benzothiazol-2 -yl)methyl-2,3-dihydro-5-(2-fluorophenyl)-3-phthalimido-1H-1,4-benzodiazepin-2-one. This product was allowed to use in a next reaction step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[C:25]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35]Cl)(=[O:27])[CH3:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:25]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][N:15]1[C:14](=[O:17])[N:11]2[N:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:10]2=[N:16]1)(=[O:27])[CH3:26]
Reactant: CC(=O)Oc1ccccc1CCl
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccccc1Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Temperature: 60 °C
Yield: 99.8 %

Procedure:
To a solution of the 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (800 mg, 2.24 mmol), prepared as described in Example 1, in 30 mL of DMF was added 2-(chloromethyl)phenyl acetate (497 mg, 2.69 mmol), followed by K2CO3 (619 mg, 4.48 mmol). The reaction was heated at 60° C. for overnight. After this time, the reaction was allowed to cool to RT and then was diluted with 250 mL of EtOAc. The resultant solution was washed with saturated aqueous NaCl (100 mL×3). The organic layer was dried over MgSO4, filtered, evaporated under reduced pressure to provide the title compound, 2-((7,8-bis(4-chlorophenyl)-3-oxo-[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl)methyl)phenyl acetate, (1.13 gm) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][C@@H:21]([CH3:23])[N:11]2[C:12]3[CH:13]=[C:14]([CH3:20])[C:15](Br)=[CH:16][C:17]=3[CH:18]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:22][C@@H:21]([CH3:23])[N:11]2[C:12]3[CH:13]=[C:14]([CH3:20])[CH:15]=[CH:16][C:17]=3[CH:18]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2c(cc1Br)cc1n2[C@H](C)CN(C(=O)OC(C)(C)C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2cc3n(c2c1)[C@H](C)CN(C(=O)OC(C)(C)C)C3
Reaction time: 6 h
Yield: 49 %

Procedure:
To a solution of 1.52 g (R)-8-bromo-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester in 15 ml ethanol was added 0.15 g 10% palladium on charcoal and the mixture was stirred under a hydrogen atmosphere for 6 h. A further 0.15 g 10% palladium on charcoal was added and the mixture was stirred a further 6hunder a hydrogen atmosphere. Again 0.15 g 10% palladium on charcoal was added and the mixture was stirred a further 6 h under a hydrogen atmosphere. The catalyst was removed by filtration over dicalite and the filtrate was evaporated. The residue was purified by chromatography on silica gel with hexane:ethyl acetate=4:1 to yield 0.59 g (R)-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester as a white foam. MS: (M+H)=301.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12].[C:13]([O:20][CH3:21])(=[O:19])[CH2:14][CH2:15][C:16]([O-])=[O:17]>>[CH3:21][O:20][C:13](=[O:19])[CH2:14][CH2:15][C:16](=[O:17])[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:11][CH3:12])[C:5]=1[O:9][CH3:10]
Reactant: COc1cccc(OC)c1OC
Reactant: COC(=O)CCC(=O)[O-]
Product: COC(=O)CCC(=O)c1ccc(OC)c(OC)c1OC
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 72.7 %

Procedure:
A mixture of 75 g of polyphosphoric acid (Acros), 1,2,3-trimethoxybenzene (5.0 g, 29.73 mmol), and mono-methyl succinate (5.9 g, 44.59 mmol) were mechanically stirred at 45° C. for 2.5 h. The reaction mixture was then poured into a 1000 mL beaker containing round 250 mL of ice, and stirred well until all the product was precipitated out. The tan colored product was then filtered and washed with water and dried under vacuum. 6.1 g (72%) of 55 was obtained, which was pure by NMR.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[O:20][C:21]([C:24]3[S:25][C:26]([CH:30]=O)=[C:27]([CH3:29])[CH:28]=3)=[N:22][N:23]=2)[CH:16]=[C:15]([CH3:32])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])[CH3:2].[CH3:33][NH:34][CH3:35]>>[CH3:33][N:34]([CH2:30][C:26]1[S:25][C:24]([C:21]2[O:20][C:19]([C:17]3[CH:16]=[C:15]([CH3:32])[C:4]([O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])=[C:3]([CH2:1][CH3:2])[CH:18]=3)=[N:23][N:22]=2)=[CH:28][C:27]=1[CH3:29])[CH3:35]
Reactant: CCc1cc(-c2nnc(-c3cc(C)c(C=O)s3)o2)cc(C)c1OC[C@@H](O)CNC(=O)CO
Reactant: CNC
Product: CCc1cc(-c2nnc(-c3cc(C)c(CN(C)C)s3)o2)cc(C)c1OC[C@@H](O)CNC(=O)CO
Yield: 31.5 %

Procedure:
The title compound (4 mg) is prepared starting from N-((2S)-3-{2-ethyl-4-[5-(5-formyl-4-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide (12 mg, 26 μmol) and dimethylamine (14 mg, 105 μmol) according to Method C; LC-MS*: tR=0.80 min; [M+1]+=488.95; 1H NMR (D6-DMSO): δ1.23 (t, J=7.5 Hz, 3H), 2.23 (s, 3H), 2.26 (s, 6H), 2.35 (s, 3H), 2.73 (q, J=7.5 Hz, 2H), 3.21-3.29 (m, 1H), 3.39-3.47 (m, 1H), 3.61 (s, 2H), 3.71-3.81 (m, 2H), 3.84 (d, J=3.3 Hz, 2H), 3.93-4.00 (m, 1H), 5.31 (d, J=5.3 Hz, 1H), 5.55 (t, J=5.5 Hz, 1H), 7.68-7.72 (m, 2H), 7.77 (s, 2H).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][N:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:4]1([C:9]2[CH:14]=[C:13]([CH2:15][O:16][S:24]([CH3:27])(=[O:26])=[O:25])[CH:12]=[CH:11][N:10]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2cc(CO)ccn2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2cc(COS(C)(=O)=O)ccn2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-4-yl]-methanol (530 mg, 2.72 mmol) in dry CH2Cl2 (5 mL) was treated at 0° C. with Et3N (0.50 mL, 3.56 mmol) followed by DMAP (34 mg, 0.27 mmol) and Ms-Cl (0.27 mL, 3.46 mmol). After stirring at rt for 2 h, the reaction was quenched with water (5 mL). The org. layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (5:1 to 2:1 hept-EA) gave the title compound as a light brown oil. TLC:rf (1:2 hept-EA)=0.36.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C@H:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=O.[CH3:18][NH:19][CH3:20].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C1COCC1>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C@@H:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:19]([CH3:20])[CH3:18]
Reactant: O=C[C@H]1CCC[C@@H]1c1c[nH]c2ccc(I)cc12
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)C[C@@H]1CCC[C@H]1c1c[nH]c2ccc(I)cc12
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a room temperature solution of (1S,2S)-2-(5-iodo-1H-indol-3-yl)-cyclo-pentanecarbaldehyde (17.5 g, 51.6 mMol) in 200 mL of methanol was added with stirring dimethylamine (64 mL of a 2.0 M solution in THF, 128 mMol) followed by acetic acid (0.5 mL). After 15 min, NaBH(OAc)3 (12 g, 57 mMol) was added slowly. The resulting mixture was stirred 18 h and was then concentrated under vacuum. The residue was partitioned between ethyl acetate (400 mL) and aqueous NaHCO3 (300 mL). The organic layer was washed twice with aqueous NaHCO3 (250 mL). Every aqueous layer was extracted with ethyl acetate (50 mL) to make sure no product was left in aqueous. The combined organic extracts were then dried over MgSO4. Solvent was removed under vacuum and the residue was pump dried overnight to give crude trans [2-(5-iodo-1H-indol-3-yl)-cyclopentylmethyl]-dimethylamine (19.4 g, 100%) which was used directly for the next reaction without further purification. An analytical sample was prepared by crystallization from ethyl acetate. 1H NMR (400 MHz, methanol-d4) δ 7.86 (s, 1H), 7.30 (d, 1H), 7.14 (d, 1H), 7.02 (s, 1H), 2.80 (m, 1H), 2.27 (m, 3H), 2.12 (s, 6H), 2.10 (m, 2H), 1.79 (m, 3H), 1.46 (m, 1H); 13C NMR (400 MHz, methanol-d4), δ 137.6, 131.1, 130.5, 128.9, 123.2, 119.0, 114.6, 82.3, 66.2, 46.0, 45.6, 43.4, 35.0, 33.0, 25.2; HRMS (EI), exact mass calc'd for C16H21IN2 (M+H) 369.0828, found 369.0836.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2)=[O:4].Cl.O1CCOCC1.[NH2:25][CH2:26][CH2:27][OH:28].N>C1COCC1.O.CCOC(C)=O.C(=O)(O)[O-].[Na+].CO.C(Cl)Cl>[OH:28][CH2:27][CH2:26][NH:25][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2)=[O:4]
Reactant: O=C(CCl)N1CCSc2cc([N+](=O)[O-])ccc21
Reactant: NCCO
Agent: Cl
Agent: N
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(CNCCO)N1CCSc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.3 %

Procedure:
A solution of 2-chloro-1-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethanone (1.0 g, 3.67 mmol) in THF (20 mL) was treated with 4M HCl in 1,4-dioxane (4.58 mL, 18.33 mmol), followed by the slow addition of a solution of 2-aminoethanol (2.207 mL, 36.7 mmol) in water (4 mL). The dark solution was stirred at room temperature for 24 hours. The mixture was diluted with EtOAc (50 mL) and saturated sodium bicarbonate (100 mL), then stirred for 20 minutes. The contents were poured into a separatory funnel, and the organic layer was separated, dried (Na2SO4), filtered, and concentrated to give a dark yellow residue. This residue was subjected to flash chromatography on silica gel using 5:95 MeOH:CH2Cl2 followed by 5:95 (2M NH3 in MeOH):CH2Cl2 to give a yellow residue (320 mg, 29.4%). 1H-NMR (CDCl3) δ 8.14 (d, J=2.7 Hz, 1H), 7.95 (dd, J=2.7, 9.0 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H), 4.02 (t, J=5.1 Hz, 2H), 3.61 (t, J=5.1 Hz, 2H), 3.57 (s, 2H), 3.28 (t, J=5.4 Hz, 2H), 2.77 (t, J=4.8 Hz, 2H); ESI-MS (m/z, %): 298 (MH+, 100%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19].ClCCl>C(#N)C>[F:15][C:16]1[CH:23]=[C:22]([O:24][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: N#Cc1ccc(O)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1ccc(OCc2ccccc2)cc1F
Yield: 84.3 %

Procedure:
15.2 ml (0.127 mol) of benzyl bromide and 29.3 g (0.212 mol) of potassium carbonate are added to a solution of 13.3 g (0.106 mol) of 2-fluoro-4-hydroxybenzonitrile in 150 ml of acetonitrile. The mixture is stirred at reflux for 1 hour 30 minutes and then filtered, the filtrate is concentrated under reduced pressure, and the oil obtained is diluted in the minimum amount of dichloromethane. After crystallization by addition of diisopropyl ether, filtration and drying, 20.3 g of product are obtained. Melting point : 87° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Cl>>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][N:17]1[CH2:16][CH2:15][N:14]([C@H:11]2[CH2:10][CH2:9][C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:13][CH2:12]2)[CH2:19][CH2:18]1
Reactant: ClCc1ccccc1Cl
Reactant: Fc1ccc([C@H]2CC[C@H](N3CCNCC3)CC2)cc1
Product: Fc1ccc([C@H]2CC[C@H](N3CCN(Cc4ccccc4Cl)CC3)CC2)cc1

Procedure:
The title compound was prepared from trans 1-[4-(4-fluorophenyl)-1-cyclohexyl]piperazine and 2-chlorobenzyl chloride by the method described in example 15 to give the product (44%, mp: 83°-85° C.). Calc'd for C23H28ClFN2.0.4H2O: C, 70.09%; H, 7.37%; N, 7.11%. Found: C, 69.99%; H, 7.38%; N, 7.07%.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][O:10][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:13].ClCCl.CO>C(O)C>[C:1]1([C@@H:7]([CH2:12][CH2:11][OH:10])[C:8]([NH2:13])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=C1OCC[C@@H]1c1ccccc1
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: NC(=O)[C@H](CCO)c1ccccc1
Yield: 63.3 %

Procedure:
(R)-2-phenylbutyrolactone (1 gram) was dissolved in 5 ml of absolute ethanol, followed by the addition of 0.5 gram of gaseous ammonia. The solution was kept in a stoppered flask, and the progress of the reaction was followed by thin layer chromatography (eluent dichloromethane/methanol 20:1). After the reaction was judged complete, the ethanol was evaporated and the resulting residue redissolved in ethyl acetate. Ammonia was removed by extraction with 1% HCl, and the ethyl acetate solution was dried over MgSO4, filtered, and rotary evaporated to leave 0.7 grams of (R)-2-phenyl-4hydroxybutyramide.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[O:7][C@@H:8]([C:11]([OH:13])=O)[CH2:9][O:10][C:5]=2[CH:4]=1.C(Cl)(=O)C(Cl)=O.Cl.[NH:25]1[C:33]2[C:28](=[CH:29][C:30]([C@H:34]([NH2:36])[CH3:35])=[CH:31][CH:32]=2)[CH:27]=[N:26]1.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.C(#N)C>[NH:25]1[C:33]2[C:28](=[CH:29][C:30]([C@H:34]([NH:36][C:11]([C@@H:8]3[O:7][C:6]4[CH:14]=[CH:15][C:3]([C:2]([F:1])([F:17])[F:16])=[CH:4][C:5]=4[O:10][CH2:9]3)=[O:13])[CH3:35])=[CH:31][CH:32]=2)[CH:27]=[N:26]1
Reactant: C[C@@H](N)c1ccc2[nH]ncc2c1
Reactant: O=C(O)[C@H]1COc2cc(C(F)(F)F)ccc2O1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](NC(=O)[C@H]1COc2cc(C(F)(F)F)ccc2O1)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
A stirred solution of (R)-6-(trifluoromethyl)-2,3-dihydrobenzo[b][1,4]dioxine-2-carboxylic acid (55 mg, 0.22 mmol) in anhydrous DCM (6 mL) was cooled to 0° C. DMF (1 drop) was added, followed by oxalyl chloride (26 μL, 0.3 mmol). The reaction was allowed to warm to room temperature and stirred for 30 minutes, then evaporated to dryness. A solution of (R)-1-(1H-Indazol-5-yl)ethylamine hydrochloride (40 mg, 0.2 mmol) in acetonitrile (6 mL) was added, followed by N,N-diisopropylethylamine (53 μL, 0.3 mmol), and the reaction was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated NaHCO3 solution (5 mL) and extracted with EtOAc (3×5 mL). The combined organics were washed with brine (2×5 mL), dried (MgSO4), filtered and evaporated to dryness. Flash chromatography (0 to 4% MeOH in DCM over 30 minutes) gave the product (35 mg) as a solid. 1H NMR (400 MHz; DMSO-d6) 13.0 (1H, s), 8.63 (1H, dd), 8.04 (1H, s), 7.69 (1H, s), 7.50 (1H, d), 7.37-7.33 (2H, m), 7.23-7.18 (2H, m), 7.07 (1H, d), 5.09-5.05 (1H, m), 4.93-4.90 (1H, m), 4.47-4.43 (1H, m), 4.35-4.32 (1H, m), 1.43 (3H, d).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[C:21](=N)(OCC)[CH2:22][CH3:23].CCN(CC)CC>CCO>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]2[O:15][C:21]([CH2:22][CH3:23])=[N:17][N:16]=2)=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=N)CC
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1nnc(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)benzohydrazide (6.0 g, 21.4 mmol; reported in Tanaka, A. et al. J. Med. Chem. 1998, 41, 2390) and ethyl propionimidate hydrochloride (3.5 g, 25.7 mmol; preparation reported in WO2007/73299 A1) in EtOH (120 mL) was added Et3N (2.59 g, 25.7 mmol). The mixture was stirred at room temperature for 1 hr then concentrated in vacuo. The residue was partitioned into EtOAc and H2O and the organics were washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (EtOAc-hexanes) gave 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-ethyl-1,3,4-oxadiazole as a brown oil (3.0 g, 44% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1>CN(C)C=O.CCN(CN(CC)CC)CC.C(Cl)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:12][N:11]([CH2:5][CH3:4])[CH2:10][CH3:9])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: CCN(CC)CN(CC)CC
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Product: CCN(CC)CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 1, a solution of 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide, N,N,N',N'-tetraethyldiaminomethane and acetyl chloride (in 0.25 molar excess compared to the N,N,N',N'-tetraethyldiaminomethane) are reacted together to give 8-chloro-1-[2-(diethylamino)ethyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@H:7]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@@H:9]([CH2:19][OH:20])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:26]>CN(C=O)C>[C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@H:7]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[C@@H:9]([CH2:19][O:20][CH3:26])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 20 °C

Procedure:
A solution of tert-butyl (2R,4R) 4-(tert-butyl-dimethyl-silyl)oxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (9.32 g) in DMF (15 ml) was added to a stirred suspension of sodium hydride (60% dispersion) (1.37 g) in DMF 100 ml) at −10° C. Iodomethane (2.13 ml) was added and the reaction allowed to warm to 20° C. The reaction mixture was quenched carefully with water and evaporated to dryness. The crude material was partitioned between ethyl acetate (250 ml) and water (100 ml). The organic layer was washed with brine (100 ml), dried over Magnesium sulphate, filtered and evaporated to give tert-butyl (2R,4R) 4-(tert-butyl-dimethyl-silyl)oxy-2-(methoxymethyl)pyrrolidine-1-carboxylate (6.68 g) as a colourless oil. NMR Spectrum: (DMSOd6) 0.02 (6H, s); 0.83-0.84 (9H, s); 1.36 (9H, s); 1.78 (1H, d); 1.99 (1H, s); 2.99 (1H, d); 3.19 (3H, d); 3.23-3.48 (3H, m); 3.80 (1H, s); 4.33 (1H, s).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@H:9]([CH2:20][O:21][CH3:22])[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(CC)CC)C>C(Cl)Cl>[CH3:2][C:1]([NH:8][C@@H:9]([C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:20][O:21][CH3:22])=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: COC[C@@H](N)C(=O)NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
A solution of acetic anhydride (262 mg, 2.56 mmol) and (R)-2-amino-N-benzyl-3-methoxypropanamide 1.6 TFA (1000 mg, 2.56 mmol) in 10 mL of DCM and triethylamine (3.6 mL, 25.6 mmol) was added. The resulting solution was stirred at room temperature for three hours. DCM (200 mL) was added to the reaction mixture. The resulting solution was washed with H2O (200 mL), 0.2 N HCl (100 mL), 5% NaHCO3 (100 mL), and then H2O (100 mL) and dried over Na2SO4. A white solid was obtained after the solvent was removed under reduced pressure. The crude product was purified by crystallization from ethyl acetate/hexane (1:1). The desired product was obtained with a purity of 99% (220 mg, yield: 33.0%). 1H NMR (500 MHz, CDCl3) δ 2.05 (s, 3H). 3.39 (s, 3H), 3.45 (t, 1H), 3.84 (m, 1H), 4.48 (s, 2H), 4.56 (m, 1H), 6.44 (br., 1H). 6.74 (br., 1H), 7.28 (m, 3H), 7.36 (m, 2H). LC-MS (m/z) calculated 250.1. Found 251.1 [M+H]+, 273.1 [M+Na]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.[C:14](=[O:16])=[O:15]>C(OCC)C.CCCCCC>[Br:8][C:4]1[N:3]=[C:2]([C:14]([OH:16])=[O:15])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C=O
Reactant: Brc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(O)c1cccc(Br)n1
Temperature: -50 °C
Reaction time: 0.17 h

Procedure:
A suspension of 2,6-dibromopyridine (19 g) in diethylether (200 ml) was added to a mixture of n-butyl lithium (130 ml of a 1.6M solution in hexane) and diethylether (200 ml) cooled to -50° C. The resulting solution was stirred at -50° C. for 10 minutes before pouring onto a slurry of diethyl ether(100 ml) and dry-ice. The mixture was allowed to warm to room temperature and filtered. The resulting solid was dissolved in 2N sodium hydroxide (350 ml) and extracted with diethyl ether (2×300 ml). The aqueous layer was separated and acidified with 2N hydrochloric acid. The resulting precipitate was filtered and washed with water to give 6-bromo-2-pyridine carboxylic acid (7.25 g): NMR (d6DMSO) δ7.69(d,1H), 7.95(d,1H), 8.05(dd,1H); m/e 202(M+H)+.