Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:27][O:26][CH2:25]4)[CH2:20][CH2:19]3)=[CH:14][N:13]=2)[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.C([O:31][CH2:32][C:33]1[C:34]([N:48]2[CH2:60][CH2:59][N:51]3[C:52]4[CH2:53][CH2:54][CH2:55][CH2:56][C:57]=4[CH:58]=[C:50]3[C:49]2=[O:61])=[N:35][CH:36]=[CH:37][C:38]=1B1OC(C)(C)C(C)(C)O1)(=O)C.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O1CCOCC1.O>[OH:31][CH2:32][C:33]1[C:34]([N:48]2[CH2:60][CH2:59][N:51]3[C:52]4[CH2:53][CH2:54][CH2:55][CH2:56][C:57]=4[CH:58]=[C:50]3[C:49]2=[O:61])=[N:35][CH:36]=[CH:37][C:38]=1[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:25][O:26][CH2:27]4)[CH2:20][CH2:19]3)=[CH:14][N:13]=2)[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1
Reactant: Clc1cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c2nc[nH]c2c1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=C1c2cc3c(n2CCN1c1nccc(-c2cc(Nc4ccc(N5CCN(C6COC6)CC5)cn4)c4nc[nH]c4c2)c1CO)CCCC3
Temperature: 25 °C
Yield: 14.9 %

Procedure:
A microwave vial equipped with a magnetic stirrer was charged with 118b (200 mg, 0.52 mmol), 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 114e (545 mg, 0.78 mmol), potassium carbonate (216 mg, 1.56 mmol), tris(dibenzylideneacetone) dipalladium(0) (48 mg, 0.052 mmol), tricyclohexylphosphine (146 mg, 0.52 mmol), water (0.2 mL), and dioxane (10 mL). After bubbling nitrogen through the suspension for 10 minutes, the sealed vial was irradiated under microwave at 110° C. for 1 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 118 as a white solid (50 mg, 15%). MS-ESI: [M+H]+ 646.3. 1H NMR (500 MHz, DMSO) δ 8.69 (d, J=2.0 Hz, 1H), 8.49 (d, J=5.0 Hz, 1H), 8.32-8.28 (m, 2H), 8.13 (s, 1H), 7.85-7.83 (m, 1H), 7.39-7.33 (m, 2H), 7.36 (s, 1H), 7.29 (s, 1H), 6.59 (s, 1H), 5.89 (s, 1H), 4.56 (t, J=6.5 Hz, 2H), 4.46 (t, J=6.5 Hz, 2H), 4.23-4.16 (m, 2H), 4.15-4.12 (m, 4H), 3.89-3.53 (m, 1H), 3.13-3.07 (m, 5H), 2.64-2.54 (m, 2H), 2.51-2.43 (m, 5H), 1.79-1.70 (m, 4H)
Reaction SMILES: [CH:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:12]([N:14]=[C:15]=[S:16])[CH3:13]>CC(C)=O>[CH2:12]([NH:14][C:15]([NH:11][CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[S:16])[CH3:13]
Reactant: CCN=C=S
Reactant: NC1CCCc2ccccc21
Solvent: CC(C)=O
Product: CCNC(=S)NC1CCCc2ccccc21
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To a stirred solution of 8.84 grams (0.060 mole) of 1,2,3,4-tetrahydro-1-naphthylamine in 100 ml of acetone, under a blanket of nitrogen, is added a solution of 6.27 grams (0.072 mole) of ethyl isothiocyanate in 50 ml of acetone. The reaction mixture is stirred overnight, and the solvent then evaporated at reduced pressure. Toluene is added to the residue, and the mixture is then evaporated at reduced pressure. The residue is crystallized from nitromethane to give 7.08 grams of the product, melting point 120°C. to 122°C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1)[CH3:20]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:13]([N:12]([CH2:16][CH2:17][CH3:18])[C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:26]3[CH:27]=[CH:28][C:23]([C:22]([O:21][CH2:19][CH3:20])=[O:30])=[CH:24][CH:25]=3)=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)[CH2:14][CH3:15]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C2(N(CCC)CCC)CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCN(CCC)C1(c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure F; [1-(4-ethynylphenyl)-cyclopropyl]-dipropylamine (Intermediate 123, 34.0 mg, 0.16 mmol) and ethyl-4-iodo benzoate (Reagent A, 59.0 mg, 0.21 mmol) in triethyl amine (6 mL) was treated with copper(I)iodide (13.0 mg, 0.07 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (49 mg, 0.07 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:12])=[S:11])=[CH:5][CH:4]=1.Br[CH2:14][C:15](=O)[C:16]([OH:18])=[O:17]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[S:11][CH:14]=[C:15]([C:16]([OH:18])=[O:17])[N:12]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)C(=O)CBr
Reactant: COc1ccc(NC(N)=S)cc1
Solvent: CO
Product: COc1ccc(Nc2nc(C(=O)O)cs2)cc1
Yield: 94.8 %

Procedure:
2-(4-Methoxy-phenylamino)-thiazole-4-carboxylic acid (237 mg) was prepared according to General Procedure B using (4-methoxy-phenyl)-thiourea (182 mg) and 3-bromo-2-oxo-propionic acid (200 mg) in methanol (2 mL). The crude product was used in a subsequent step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][C:13](=[O:16])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CCC(O)CC2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 84.8 %

Procedure:
To a solution of 1-(4-Nitro-phenyl)-piperidin-4-ol (100 mg, 0.45 mmol) in CH2Cl2 (2 mL) is added Dess-Martin periodinane (286 mg, 0.675 mmol) at for 2.5 hours. The reaction is quenched with 1N NaOH aqueous solution. The aqueous layer is extracted with CH2Cl2, and the organic extracts are dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography (SiO2, EtOAc:Hexane=12:88 to 100:0) to give 84 mg of the title compound as a white solid.
Reaction SMILES: [NH2:1][O:2][CH2:3]CCC(O)=O.[C:9]1(=[O:14])[O:13][CH2:12][CH2:11][CH2:10]1>>[NH2:1][O:2][CH2:3][CH2:12][CH2:11][CH2:10][C:9]([OH:13])=[O:14]
Reactant: O=C1CCCO1
Reactant: NOCCCC(=O)O
Product: NOCCCCC(=O)O

Procedure:
5-Aminooxyvaleric acid is prepared in the same manner using the procedure of Preparation 6 for 4-aminooxybutyric acid except that the γ-butyrolactone is replaced by σ-valerolactone.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:3]=1[CH:4]=[O:5].[CH:11](O)([OH:14])[CH2:12][CH3:13].C(OC(OCC)OCC)C.[OH-].[Na+]>C(Cl)Cl.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:3]=1[CH:4]1[O:14][CH2:11][CH2:12][CH2:13][O:5]1
Reactant: CCC(O)O
Reactant: O=Cc1c(Br)cccc1Br
Agent: [Zr+4]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(OCC)OCC
Product: Brc1cccc(Br)c1C1OCCCO1
Reaction time: 8 h
Yield: 98 %

Procedure:
2,6-Dibromobenzaldehyde (49) (10.0 g, 37.9 mmol) was dissolved in 160 ml dry CH2Cl2. Propanediol (6.4 ml, 88.5 ml), triethylorthoformate (6.83 ml, 41 mmol) and anhydrous ZrCl4 (1.0 g) were added at ambient temperature and stirred overnight. Then NaOH (50 ml of a 10% solution) was added and stirred for an additional hour. The organic phase was separated, the aqueous phase was extracted with Et2O (2×40 ml). The combined organic phases were washed with water (3×60 ml), dried over MgSO4 and the volatiles were removed in vacuo to afford 12 g (98%) 2-(2,6-Dibromophenyl)-1,3-dioxane (acetal) as a slightly yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]([O:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])[CH3:9])[CH2:3]1.[CH3:17][O:18][C:19](=O)[CH2:20][O:21]C.C[O-].[Na+]>CO>[CH3:16][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]([O:10][C:11]([CH3:15])([CH3:14])[CH2:12][O:13][C:20](=[O:21])[CH2:19][O:18][CH3:17])[CH3:9])[CH2:3]1
Reactant: CC(OC(C)(C)CO)C1CCCC(C)(C)C1
Reactant: COCC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCC(=O)OCC(C)(C)OC(C)C1CCCC(C)(C)C1

Procedure:
57 g (0.25 mol) of 2-[1-(3,3-dimethyl-cyclohexyl)-ethoxy]-2-methyl-propan-1-ol, 41.6 g (0.4 mol) of methoxyacetic acid methyl ester and 0.3 g of sodium methylate in 50 g methanol were placed in a 250-ml stirred vessel and were boiled under reflux. During this, methanol was distilled off via a still head. Then 100 ml water and 100 ml toluene were added to the reaction solution at room temperature, the aqueous phase was separated, the organic phase was washed with water until neutral and concentrated by evaporation. The raw product (81 g) was fractionated on a 30-cm Vigreux column in vacuum.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=4)=[CH:15][CH:16]=3)[N:11]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[CH:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>>[N+:24]([C:20]1[CH:19]=[C:18]([C:14]2[CH:13]=[C:12]3[C:17]([C:9]([C:6]4[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=4)=[CH:10][N:11]3[C:27]3[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=3)=[CH:16][CH:15]=2)[CH:23]=[CH:22][CH:21]=1)([O-:26])=[O:25]
Reactant: COc1ccc(-c2cn(-c3ccncc3)c3cc(-c4cccc([N+](=O)[O-])c4)ccc23)cc1
Agent: BrB(Br)Br
Product: O=[N+]([O-])c1cccc(-c2ccc3c(-c4ccc(O)cc4)cn(-c4ccncc4)c3c2)c1

Procedure:
The target compound was prepared as in Example 15 using 3-(4-methoxyphenyl)-6-(3-nitrophenyl)-1-(pyridin-4-yl)-1H-indole (58 mg, 0.138 mmol) and boron tribromide (BBr3, 65 μL, 0.691 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Br[C:22]1[CH:23]=[C:24]([C:27]([OH:29])=[O:28])[S:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:9]([C:8]1[C:3]([O:2][CH3:1])=[C:4]([C:22]2[CH:23]=[C:24]([C:27]([OH:29])=[O:28])[S:25][CH:26]=2)[CH:5]=[CH:6][CH:7]=1)([O-:11])=[O:10]
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
Reactant: O=C(O)c1cc(Br)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(-c2csc(C(=O)O)c2)cccc1[N+](=O)[O-]
Yield: 133.4 %

Procedure:
2-(2-Methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4d (0.81 g, 2.9 mmol), 4-bromo-thiophene-2-carboxylic acid (0.3 g, 1.45 mmol), tetrakis(triphenylphosphine)palladium (80 mg, 0.073 mmol) and sodium carbonate (0.31 g, 2.9 mmol) were dissolved in a solvent mixture of 20 mL of 1,4-dioxane and 10 mL of water. The reaction was heated to reflux for 0.5 hours. The mixture was adjusted to pH 3 with 1 N hydrochloric acid and extracted with ethyl acetate (20 mL×3). The combined organic extracts were concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound 4-(3-nitro-2-methoxy-phenyl)-thiophene-2-carboxylic acid 19a (0.54 g) as a brown oil, which was directly used in the next step.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)=[CH:22][C:21]3=[O:36])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.CO>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=3)=[CH:22][C:21]2=[O:36])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc(C(F)(F)F)c2)=CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(C(F)(F)F)c2)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A solution of (S)-4-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,2-dimethyl[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.54 g, 1.00 mmol) in dichloromethane (10 mL) and methanol (10 mL) at 25° C. was treated with p-toluenesulfonic acid monohydrate (0.04 g, 0.21 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The residue was diluted with dichloromethane (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-10% methanol/dichloromethane gradient) afforded (S)-4-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.38 g, 78%) as a light, yellow solid: HR-ES-MS m/z calculated for C23H27N4O5F3 [M+H]+ 497.2007, observed 497.2007; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.5 Hz, 3H), 0.95 (d, J=6.5 Hz, 3H), 1.36-1.54 (m, 1H), 1.54-1.64 (m, 1H), 1.70-1.84 (m, 1H), 3.22-3.32 (m, 2H), 3.72-3.81 (m, 1H), 3.87 (dd, J=13.6, 7.7 Hz, 1H), 4.09 (dd, J=13.6, 4.0 Hz, 1H), 4.21 (d, J=18.3 Hz, 1H), 4.60 (d, J=18.3 Hz, 1H), 4.70 (t, J=5.6 Hz, 1H), 4.86-4.96 (m, 3H), 6.42 (d, J=2.1 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.65-7.74 (m, 3H), 7.75 (s, 1H), 10.76 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:13]I>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[N:7]([CH3:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=c1[nH]cnc2cc(Br)ccc12
Solvent: CN(C)C=O
Product: Cn1cnc2cc(Br)ccc2c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
400 mg 7-Bromoquinazolin-4(3H)-one was dissolved in DMF and 720 mg of CsCO3 and 130 μL of methyliodide were added and the mixture stirred for 3 h at 25° C. Additional 50 μL methyliodide were added and stirred overnight at 25° C. The mixture was filtered off and the mother liquor diluted with DCM and extracted with water. The solvent was removed to yield 490 mg of 7-bromo-3-methylquinazolin-4(3H)-one as solid.
Reaction SMILES: [Li+].[OH-].[CH2:3]([N:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]([O:18]C)=[O:17])[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.O>C1COCC1.CO>[CH2:3]([N:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]([OH:18])=[O:17])[C:11]1=[O:20])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1nccn(Cc2ccccc2)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1nccn(Cc2ccccc2)c1=O
Yield: 81.6 %

Procedure:
LiOH (0.82 mL, 0.82 mmol, 1.0 M in H2O) was added to a solution of methyl 4-benzyl-3-oxo-3,4-dihydropyrazine-2-carboxylate (100 mg, 0.41 mmol) in a mixture of THF (4.5 mL) and MeOH (1.5 mL) at ambient temperature for 4 hours. The reaction mixture was acidified to pH 1 with aqueous 1 N HCl solution and treated with water (5 mL), extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated to afford 77 mg (82%) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:16][N:17]4C(=O)C5=CC=CC=C5C4=O)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:6]=2[CH:34]=1.O.NN>C(O)C>[NH2:17][CH2:16][CH2:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:34][C:6]=3[C:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:8][CH2:9][C:10]2=[N:14][N:13]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 21, a solution of 8-fluoro-6-phenyl-1-(2-phthalimidoethyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine in ethanol is heated with hydrazine hydrate to give 1-(2-aminoethyl)-8-fluoro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>O.CN(C)P(N(C)C)(N(C)C)=O>[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: CSc1ccc(O)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CSc1ccc(Oc2ccc(C#N)cc2)cc1
Temperature: 100 °C
Yield: 46.8 %

Procedure:
A mixture of 12.1 g (0.100 mole) of 4-fluorobenzonitrile, 21.0 g (0.150 mole) of 4-(methylthio)phenol, 20.7 g (0.150 mole) of anhydrous potassium carbonate (K2CO3) and 150 ml of hexamethyl phosphoramide was heated at 100° C. for 4 hrs. The reaction mixture was cooled and poured into a solution of 200 ml of 20% aqueous NaOH and 500 ml of water. The crystalline product was collected by filtration and washed well with water. The product was dissolved in CH2Cl2 and dried (Na2SO4). Removal of solvent in vacuo afforded 11.3 g (46.9% yield) of product. Recrystallization from hexane gave purified 4-(4-(methylthio)phenoxy)benzonitrile, mp 65°-66° C.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[C:7]3[CH:29]=[C:30]([C:34]4[N:35]=[C:36]5[CH2:41][CH2:40][CH2:39][CH2:38][N:37]5[CH:42]=4)[CH:31]=[C:32]([CH3:33])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[C:7]3[CH:29]=[C:30]([C:34]4[N:35]=[C:36]5[CH2:41][CH2:40][CH2:39][CH2:38][N:37]5[CH:42]=4)[CH:31]=[C:32]([CH3:33])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(-c2cn3c(n2)CCCC3)cc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cn3c(n2)CCCC3)cc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 208 from tert.butyl 4'-[(2-cyclopropyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [Cl-].C([Al+]CC)C.[C:7]([C:9]1[N:10]=[C:11]2[CH:17]=[CH:16][NH:15][C:12]2=[N:13][CH:14]=1)#[CH:8].[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].C([O-])(O)=O.[Na+]>ClCCl.C(OCC)(=O)C>[C:7]([C:9]1[N:10]=[C:11]2[C:17]([C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:16][NH:15][C:12]2=[N:13][CH:14]=1)#[CH:8]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C#Cc1cnc2[nH]ccc2n1
Agent: CC[Al+]CC
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C#Cc1cnc2[nH]cc(C(=O)C(C)(C)C)c2n1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 12.5 %

Procedure:
Diethylaluminum chloride (1.0 M in hexanes, 19.1 mL, 19.1 mmol) was added to a suspension of impure 2-ethynyl-5H-pyrrolo[2,3-b]pyrazine (0.911 g, 6.36 mmol) in 25 mL of dichloromethane at 0-5° C. The mixture was stirred at 0-5° C. for 30 min., then pivaloyl chloride (7.8 mL, 63.6 mmol) was slowly added. The mixture was heated to reflux and stirred for 6 h then cooled to 0-5° C. Sat. Aq. NaHCO3 (50 mL) was carefully added, and the resulting mixture was diluted with 100 mL of ethyl acetate and filtered through a plug of Celite, rinsing with ethyl acetate and water. The filtrate layers were separated, and the aqueous layer extracted with 250 mL of ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated to a residue. Silica gel chromatography (20->60% EtOAc/hexanes) afforded 0.180 g (12%) of 1-(2-ethynyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)=[O:4].[CH2:23]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(Cl)CCl.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[CH2:30]([N:29]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:16](=[O:18])[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:14][CH:13]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCCCCCNCc1ccccc1
Reactant: COC(=O)c1ccccc1COc1ccc(CC(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: CCCCCCN(Cc1ccccc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4-{[2-(Methoxycarbonyl)benzyl]oxy}phenyl)acetic acid (50 mg, 0.166 mmol) was dissolved in DCM (2 ml), N-hexylbenzylamine (38.2 mg, 0.2 mmol) was added, then EDC (38.3 mg, 0.2 mmol) was added and then DMAP (24.4 mg, 0.2 mmol) was added. The mixture was stirred at room temperature overnight. 1% HCl (1 ml) and water (1 ml) were added into the mixture. The two phases were separated by using a Whatman Filter Tube. The obtained organic solution was evaporated in vacuum and the oil product (71 mg) was left. It was then used directly in next step.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]1[CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH3:14])#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:26][C:27](CC)=[O:28]>>[C:1]([CH2:3][CH:4]1[CH2:8][CH2:7][C:6]2([O:28][CH2:27][CH2:26][O:9]2)[CH:5]1[CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH3:14])#[N:2]
Reactant: CC/C=C\CC1C(=O)CCC1CC#N
Reactant: CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC/C=C\CC1C(CC#N)CCC12OCCO2
Reaction time: 9 h

Procedure:
Into a 2 liter flask fitted with a 1 meter adiabatic column provided with a metallic lining, are placed: 212 g of 3-cyanomethyl-2-(cis-2-n-pentenyl)-1-cyclopentanone, 512 g of the glycoketal of methylethyl ketone and 2.1 g of para-toluenesulphonic acid. The mass is progressively heated in order to slowly distil the methyl ethyl ketone from the head of the column (temperature of the mass 120°-140°C; temperature of the vapour 77°-79°C). The operation lasts about 9 hours. The mass is then cooled, 10 g of dry sodium carbonate added thereto, stirred for a half-hour and the mass washed to neutrality after diluting with 200 ml of ethyl ether. After distillation of the solvent and rectification of the crude product, there is obtained 229.2 g of 3-cyanomethyl-1,1-ethylenedioxy-2-(cis-2-n-pentenyl)-cyclopentane. The product exhibits the following constants: b.p.0.5 = 130°C, nD15 = 1.4862. The infra-red spectrum had principal bands at: 2240, 1650, 730, 1150, 1115 and 1040 cm-1. NMR Spectrum: 0.95, 4.82, 5.36.