Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27](=[O:31])[NH:28][O:29][CH3:30])([CH3:26])[CH3:25])[CH2:14][C:13](=O)[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:51])=CC=1>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27](=[O:31])[NH:28][O:29][CH3:30])([CH3:26])[CH3:25])[CH2:14][C:13](=[S:51])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CONC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CONC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=S)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
A mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbamoyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (25 mg, 0.042 mmol) and Lawesson's reagent (33 mg, 0.084 mmol) in THF (1 mL) was stirred at room temperature for 1 h, and then diluted with toluene (10 mL). The mixture was concentrated and the residue was washed with DCM twice. The DCM solutions were combined and concentrated. The residue was purified by flash column to give the title compound as white solid (10 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:20][CH:22]2[O:24][CH2:23]2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: ClCC1CO1
Reactant: O=C1CCc2c(O)ccc(Cl)c2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C1CCc2c(OCC3CO3)ccc(Cl)c2N1
Reaction time: 6 h

Procedure:
20.0 grams of 8-chloro-5-hydroxy-3,4-dihydrocarbostyril and 18 g of potassium carbonate are suspended in 160 ml of isopropyl alcohol, then 40 ml of epichlorohydrin are added and the reaction is carried out at 70°-80° C. for 6 hours. The reaction mixture is concentrated under reduced pressure and the thus-obtained residue is stirred with 100 ml of 2N-sodium hydroxide under cooling conditions. The insoluble matter is separated by filtration, washed with water and dried. The crude crystals are recrystallized from isopropanol to obtain 18.5 g of 8-chloro-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 161°-165° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[C:33]([O:35][CH3:36])=[O:34]>>[CH3:36][O:35][C:33]([C:32]1[CH:31]=[CH:30][C:29]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18](=[O:22])[N:19]([CH3:21])[CH:20]=3)[C:10]([F:12])([F:11])[F:13])=[C:4]([Cl:24])[CH:3]=2)=[CH:28][C:27]=1[O:26][CH3:25])=[O:34]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1OC
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2)cc1OC

Procedure:
In analogy to Example 150, step 2, 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 165, step 3) was reacted with 3-methoxy-4-methoxycarbonylphenylboronic acid to give the title compound as an off-white solid. MS (m/e)=510.2 [M+H+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[H][H]>O.N.[Ru]>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1ccncc1
Agent: [Ru]
Agent: N
Solvent: O
Product: O=C(O)CCC1CCNCC1
Yield: 97.7 %

Procedure:
A solution of 3-pyridin4-yl-acrylic acid (4.20 g, 28.0 mmol) in water (50 mL) and ammonia (aq, 25%, 4 mL) was hydrogenated at 60 bar in a high pressure steel autoclave in presence of ruthenium (5% on alumina, 439 mg). When hydrogen pressure remained constant (3 days) the catalyst was removed from the reaction mixture by filtration. The catalyst was washed with ethanol and water, and the ethanol was removed from the solution on a rotavapor and the aqueous solution was freeze dried to give 3-piperidin4-yl-propionic acid (4.30 g, 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C@@:11]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]2[C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][N:28]([S:40]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[C:25]2=[N:26][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[Cl:21][C:22]1[CH:23]=[C:24]2[C:30]([C:2]3[N:7]=[C:6]([NH:8][C@H:9]4[CH2:14][CH2:13][CH2:12][C@@:11]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:10]4)[C:5]([F:20])=[CH:4][N:3]=3)=[CH:29][N:28]([S:40]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=3)(=[O:41])=[O:42])[C:25]2=[N:26][CH:27]=1
Reactant: COC(=O)[C@]1(C)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@]1(C)CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1

Procedure:
In a 25 mL round-bottomed flask were combined (1R,3S)-methyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate, 52h, (0.061 g, 0.202 mmol), 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.096 g, 0.222 mmol), disodium carbonate (0.064 g, 0.607 mmol) in 5 mL of THF and 1 ml of water. The reaction mixture was degassed via a stream of nitrogen. To the reaction was added tetrakis triphenyl phosphine palladium (0) (0.021 g, 0.202 mmol) and the reaction was stirred at reflux overnight. The reaction was concentrated in vacuo and purified by silica gel chromatography (4:1 Hexanes:EtOAc), yielding 85 mg of desired product, 52i.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH3:9].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[NH:12][NH2:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:16]([O:15][C:11]([NH:12][N:13]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:9])=[O:14])[CH3:17]
Reactant: CCOC(=O)NN
Reactant: CC(=O)c1ccccc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)NN=C(C)c1ccccc1C

Procedure:
A solution of 2′-methylacetophenone (0.98 ml, 7.4 mmol), ethyl carbazate (0.81 g, 7.8 mmol) and p-toluenesulfonic acid monohydrate (70 mg, 0.37 mmol) in toluene (30 ml) was heated at reflux temperature with a Dean-Stark apparatus for 2 h. Solvent evaporation and flash chromatography (silica gel, hexane-ethyl acetate, 80:20) gave N′-(1-o-tolyl-ethylidene)-hydrazinecarboxylic acid ethyl ester; 1H NMR (CDCl3, 400 MHz) δ 7.72 (bs, 1H), 7.21 (m, 4H), 4.31 (q, 2H, J=7.1 Hz), 2.37 (s, 3H), 2.17 (s, 3H), 1.34 (t, 3H, J=7.1 Hz).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].C1N2CN3CN(C2)C[N:13]1C3.Cl>C1(C)C=CC=CC=1.C(O)C>[NH2:13][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: NCC(=O)c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 92.8 %

Procedure:
To a stirred solution of 2-bromo-1-(4-bromophenyl)ethanone (130 g 0.478 mol) in toluene (2500 mL) was added hexamethylenetetramine (65.6 g 0.478 mol). The mixture was stirred at 40° C. for 16 hrs. The resulting solid was filtered off and washed with toluene and ether to give a white solid. To a stirred suspension of this white solid in ethanol (800 mL) was added concentrated hydrochloride acid (300 mL). The mixture was stirred at ambient temperature for 20 hrs. The solid was collected by filtration and washed with ethanol and water and dried in vacuo to give 2-amino-1-(4-bromophenyl)ethanone (4) (95 g, yield: 92%) as a white solid, which was used without purification for the next step. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.58 (s, br, 2H), 7.96 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.7 Hz, 2H), 4.48-4.52 (m, 2H). ES LC-MS m/z=214, 216 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15]O)=[CH:8][C:7]=1[O:21][CH3:22].N1C=CC=CC=1>O>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15][Cl:3])=[CH:8][C:7]=1[O:21][CH3:22]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(Sc2ccccc2CO)ccc1Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(Sc2ccccc2CCl)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
Thionyl chloride (6.5 g) is added dropwise to a stirred mixture of the alcohol from the preceding preparation (11.2 g) and pyridine (4.0 g) at 10°-20° C. The mixture is stirred at room temperature for 3 hours and, after standing overnight, for one additional hour at 30°-40° C. The cooled mixture is decomposed by dropwise addition of water (20 ml) and the product extracted with benzene. The work-up of the extract, followed by crystallization of the crude residue from a small volume of hexane, yields 10.2 g (85%) of 2-(4-chloro-3-methoxyphenylthio)benzyl chloride which in the pure state melts at 57°-59° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:21]=[CH:20][C:8]([C:9](=[O:19])[CH2:10][CH:11]([C:16]([CH3:18])=[O:17])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H-].[Na+].[CH3:24]I.O>O1CCCC1>[CH3:24][C:11]([CH2:10][C:9]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:21][CH:20]=1)=[O:19])([C:16]([CH3:18])=[O:17])[C:12]([O:14][CH3:15])=[O:13]
Reactant: CI
Reactant: COC(=O)C(CC(=O)c1ccc(S(C)(=O)=O)cc1)C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)(CC(=O)c1ccc(S(C)(=O)=O)cc1)C(C)=O
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
0.65 g (2.1 mmol) of methyl 2-(4-methylsulfonylphenacyl)acetoacetate [prepared as described in Example 43(ii)] was dissolved in 20 ml of anhydrous tetrahydrofuran, and 92 mg (2.3 mmol) of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to the resulting solution, whilst ice-cooling and under a nitrogen atmosphere. The mixture was stirred for 10 minutes, after which 1.1 ml (2.5 mmol) of methyl iodide were added, whilst ice-cooling, and the mixture was stirred for 2 hours. At the end of this time, water was added to the mixture, which was then extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was applied to a silica gel chromatography column and eluted with a 2:3 by volume mixture of ethyl acetate and hexane, to give 0.54 g (yield 80%) of the title compound as a slightly yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][C:31]=1[C:39]#[N:40]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])[CH:4]=2)=[CH:32][C:31]=1[C:39]#[N:40]
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: N#Cc1cc(B(O)O)ccc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CC(c1cc(Oc2ccc(Cl)c(C#N)c2)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 5, 6-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 1, step 4) was reacted with 4-chloro-3-cyanophenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless foam. MS (m/e)=551.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[N:4][CH:5]=[C:6]([O:11][CH3:12])[C:7]=1[N+:8]([O-:10])=[O:9].P(Cl)(Cl)[Cl:18]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[N:4][C:5]([Cl:18])=[C:6]([O:11][CH3:12])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: ClP(Cl)Cl
Reactant: COC(=O)c1ncc(OC)c([N+](=O)[O-])c1Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(Cl)c(OC)c([N+](=O)[O-])c1Cl

Procedure:
To methyl 3-chloro-5-methoxy-4-nitro-pyridine-2-carboxylate, N-oxide (0.300 g, 1.12 mmol) in 5 mL of chloroform was added PCl3 (0.664 mL, 7.62 mmol). The reaction mixture was heated to reflux for 8 hr and then concentrated to dryness in vacuo to give 300 mg of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:21])[CH2:10][N:9]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CN=C(c2ccccc2F)c2ccccc2N1
Product: Fc1ccccc1C1=NCC(=S)Nc2ccccc21

Procedure:
A mixture of 1,3-dihydro-5-(o-fluorophenyl)-2H-1,4-benzodiazepin-2-one [Sternbach et al., J. Org. Chem. 27, 3788 (1962)] and P2S5 can be reacted in the same manner as in preparation I to produce 1,3-dihydro-5-(o-fluorophenyl)-2H-1,4-benzodiazepine-2-thione. This latter compound can then be substituted in the procedure of Exmple 1 to produce 6-(o-fluorophenyll)-1methyl-4H-s-triazolo[4,3-a] [1,4] benzodiazepine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:2]=1.[H-].[Na+].[CH2:15](Cl)[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C>CN(C)C=O>[CH2:15]([N:9]1[CH2:10][CH2:11][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:8]1=[O:12])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1NCCN1c1cccnc1
Reactant: ClCC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1N(C/C=C/c2ccccc2)CCN1c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.7 %

Procedure:
To a solution of 150 g of 1-(3-pyridyl)-2-imidazolidinone dissolved in 1500 ml of N,N-dimethylformamide was added 40 g of sodium hydride (60% oily dispersion). After the mixture was stirred at room temperature for 10 minutes, 154 g of cinnamyl chloride (trans-form) was added dropwise under ice-cooling and the mixture was stirred for 2 hours. After addition of 10 ml of acetic acid, the solvent was distilled off under reduced pressure and to the residue was added water, followed by extraction with chloroform. After washing with saturated aqueous sodium hydrogen carbonate and saturated saline water, the extract was dried. Chloroform was distilled off, and isopropyl ester was added to the residue. The precipitated crystals were collected by filtration and recrystallized from ethanol to give 238.1 g of (E)-1-cinnamyl-3-(3-pyridyl)-2-imidazolidinone as colorless prisms.
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[CH:19]2>>[NH:21]1[C:22]2[C:18](=[CH:17][C:16]([NH:15][C:12](=[O:13])[CH2:11][C:1]34[CH2:10][CH:5]5[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]5)[CH2:2]3)[CH2:8]4)=[CH:24][CH:23]=2)[CH:19]=[N:20]1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccc2[nH]ncc2c1
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1ccc2[nH]ncc2c1
Yield: 82.5 %

Procedure:
Prepared according to the method of Example 1b) from 1-adamantaneacetyl chloride (0.1 g) and 5-aminoindazole (0.067 g) to give the title compound as a white solid (0.12 g).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:2]#[CH:3].[H-].[Na+].Br[CH2:15][CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN1CCCC1=O>[Si:18]([O:17][CH2:16][CH2:15][N:4]([CH2:1][C:2]#[CH:3])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: C#CCN(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C

Procedure:
The sub-titled compound was prepared from tert-butyl prop-2-yn-1-ylcarbamate (0.8 g), 60% sodium hydride (0.227 g), (2-bromoethoxy)-tert-butyldimethylsilane (1 ml) and anhydrous N-methyl-2-pyrrolidinone (4 ml) by the method of Example 2(ii). The crude product was purified by chromatography on silica gel eluting with iso-hexane:ethyl acetate (25:1) to afford (0.8 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][C:5]=1[CH3:15])[CH3:2].[OH-].[Na+].Cl>O.CO>[CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[CH3:15])[CH3:2]
Reactant: CCOC(=O)c1ccc(OCC)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOc1ccc(C(=O)O)cc1C
Temperature: 0 °C
Yield: 64 %

Procedure:
The crude ethyl 4-ethoxy-3-methyl-benzoate was suspended in a solution of NaOH (10.5 g, 263 mmol) in water (50 mL) and methanol (25 mL). The reaction mixture was refluxed for 1 h. The reaction mixture was cooled to 0° C., acidified with 12 M HCl (24.7 mL, 296 mmol) and the resulting solid filtered. The solid was slurried with acetonitrile and filtered to provide 4-ethoxy-3-methyl-benzoic acid (760 mg, 4.22 mmol, 64%) as a light pink solid. ESI-MS m/z calc. 180.07864. Found 181.3 (M+1)+; Retention time: 1.31 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 7.77 (dd, J=8.5, 2.2 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 4.11 (q, J=7.0 Hz, 2H), 2.17 (s, 3H), 1.36 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([NH:25][C:26](=[O:28])[CH3:27])[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[NH:25][C:26](=[O:28])[CH3:27])[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC(=O)Nc1cccc2c1CCNC2C
Product: CC(=O)Nc1cccc2c1CCN(C(=O)c1cc3ncc(Cl)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with N-(1-Methyl-1,2,3,4-tetrahydro-isoquinolin-5-yl)-acetamide to provide the title compound in moderate yield.
Reaction SMILES: [I-].[K+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1.[CH3:27][NH:28][CH2:29][CH:30]1[CH2:32][CH2:31]1>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][N:28]([CH2:29][CH:30]4[CH2:32][CH2:31]4)[CH3:27])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1
Reactant: CNCC1CC1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2)CC1CC1

Procedure:
In the manner given in Preparation 29, potassium iodide and 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in tetrahydrofuran are treated with methyl(cyclopropylmethyl)amine to give 8-chloro-1-[[(cyclopropylmethyl)methylamino]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine. Preparation 31 8-Bromo-1-[[(cyclopropylemethyl)ethylamino]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[F:24]>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[F:24])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(C=O)c(Cl)cc1O
Reactant: Fc1cc(Cl)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(Cl)cc1OCc1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-Chloro-4-hydroxy-5-methoxy-benzaldehyde (136, 0.548 g, 2.94 mmol, prepared as described in Example 46, Scheme 45, step 1) was dissolved in N,N-dimethylformamide (40 mL) and sodium hydride (60% dispersion in mineral oil, 0.200 g, 5.00 mmol) was added. After 20 minutes, 1-bromomethyl-4-chloro-2-fluoro-benzene (139, 685 μL, 5.00 mmol) was added to the reaction mixture. The reaction was stirred at room temperature under an atmosphere of nitrogen for 5.5 hours. The reaction was concentrated to dryness in vacuo. The reaction was resuspended in water/saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography, eluting with 5-35% ethyl acetate in hexane give a white solid (140, 0.942 g, 97%), consistent with the desired compound by 1H-NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[O:19]=[C:20]1[C:25]2=[CH:26][NH:27][C:28]([CH:29]=O)=[C:24]2[CH2:23][CH2:22][O:21]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13](=[CH:29][C:28]4[NH:27][CH:26]=[C:25]5[C:20](=[O:19])[O:21][CH2:22][CH2:23][C:24]=45)[C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc3c(c2)NC(=O)C3)cc1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: COc1ccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]cc3c2CCOC3=O)cc1

Procedure:
6-(4-Methoxy-phenyl)-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH:7]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[CH2:15]([O:3][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCCc1ccc2sccc2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COCCc2ccc3sccc3c2)cc1
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a solution of NaH (60% oil dispersion, 2.4 g, 0.06 mol) in DMF (50 ml) heated at 60° C. with stirring under N2 was added dropwise a solution of 5-(2-hydroxyethyl)benzo[b]thiophene (8.9 g, 0.05 mol) in DMF (50 ml). After 1/2 hour, a solution of benzyl bromide (10.3 g, 7.2 ml, d=1.438, 0.06 mol) in DMF (50 ml) was added dropwise. After 15 hours, the solution was poured into H2O and the aqueous phase extracted with ethyl acetate (3X). The organic layers were backwashed with H2O, saturated NaCl, dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel and the product was eluted with 10% (V/V) ethyl acetatehexane to yield 9.7 g (72%) of product. The material was used directly in the next step without further purification.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([CH3:21])=[N:11][C:12]([O:16][CH2:17][C:18]([OH:20])=O)=[N:13][C:14]=1[CH3:15])=O)(C)(C)C.[CH:22]1([C:26]([N:28]2[CH2:33][CH2:32][CH:31]([NH:34][CH3:35])[CH2:30][CH2:29]2)=[O:27])[CH2:25][CH2:24][CH2:23]1>>[NH2:8][C:9]1[C:14]([CH3:15])=[N:13][C:12]([O:16][CH2:17][C:18]([N:34]([CH:31]2[CH2:32][CH2:33][N:28]([C:26]([CH:22]3[CH2:25][CH2:24][CH2:23]3)=[O:27])[CH2:29][CH2:30]2)[CH3:35])=[O:20])=[N:11][C:10]=1[CH3:21]
Reactant: CNC1CCN(C(=O)C2CCC2)CC1
Reactant: Cc1nc(OCC(=O)O)nc(C)c1NC(=O)OC(C)(C)C
Product: Cc1nc(OCC(=O)N(C)C2CCN(C(=O)C3CCC3)CC2)nc(C)c1N

Procedure:
The title compound was synthesized from Compound 9 and cyclobutyl (4-(methylamino)piperidine-1-yl)methanone in the same manner as in Example 64.