Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(#N)C>[N:11]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: C1COCCN1
Solvent: CC#N
Product: O=C(O)c1ccc(N2CCOCC2)nc1

Procedure:
3.00 g 6-chloronicotinic acid in 24 ml dry acetonitrile were mixed with 16.6 ml morpholine and heated to reflux for 48 hrs. The mixture was evaporated under vacuum and the residue dissolved in water. The crude product was precipitated by addition of 10% aqueous acetic acid, isolated by filtration and washed with water and methanol to give 1.83 g of the title compound.
Reaction SMILES: C(NC(C)C)(C)C.[Li].[C:9](=[O:11])=O.[CH3:12][C@H:13]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:15](=[CH:16][CH2:17][C@@H:18]3[C@@H:27]2[CH2:26][CH2:25][C@@:23]2([CH3:24])[C@H:19]3[CH2:20][CH2:21][C:22]2=O)[CH2:14]1.CI>O1CCCC1.CCCCCC.C(Cl)(Cl)(Cl)Cl>[CH3:12][C@H:13]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:15](=[CH:16][CH2:17][C@@H:18]3[C@@H:27]2[CH2:26][CH2:25][C@@:23]2([CH3:24])[C@H:19]3[CH2:20][C@@H:21]([CH3:22])[C:9]2=[O:11])[CH2:14]1
Reactant: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Reactant: O=C=O
Agent: [Li]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@H](C)C[C@@H]32)C1
Reaction time: 0.25 h
Yield: 74 %

Procedure:
Diisopropyl amine (1.165 g, 11.5 mmol) was dissolved in dry tetrahydrofuran (30 mL) at -78° C. under N2. n-Btyl lithium (4.44 mL of a 2.6M solution in hexane, 11.5 mmol) was added via syringe and the solution warmed to -23° C. (CO2, CCl4) for 0.25 h. 3β-Methylandrost-5-en-17-one (3.0 g, 10.4 mmol) in dry tetrahydrofuran (30 ml) was added via syringe and the solution stirred for 0.25 h. Methyl iodide (7.0 g, 49.33 mmol) in dry tetrahydrofuran (30 mL) was added dropwise and the mixture stirred at room temperature for 1.5 h. The solution was quenched with saturated ammonium chloride and the organic layer separated, dried over magnesiumn sulfate, filtered, and evaporated. The residual solid was chromatographed on flash silica gel (120 g) and eluted with 1/99 (v/v) ether hexane to give 3β,16α-dimethylandrost-5-en-17-one (2.32 g, 74%). up 109°-110° C. (recrystallized from methanol); NMR (CDCl3) δ5.29 (br s, J=5 Hz, 1H, H-6), 2.52 (m, 1-H, H-16), 1.07 (d J=8 Hz, 3H, C-16 Me), 0.99 (s, 3H, C-19 Me), 0.91 (s, 3H, C-18 Me); IR (KBr) 2900, 1730, 1450, 1430, 1370; MS 300 (M+, 100), 285(62), 282(2), 272(12), 267(17), 229(20), 217(30), 159(17); Anal. Calcd for C21H32O: C, 83.93; H, 10.73. Found: C, 83.79; H. 10.52.
Reaction SMILES: [Na].[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH2:3][CH2:4][CH3:5].Cl.[CH:15]([N:18]([CH2:22][CH2:23]Cl)[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>C(O)C>[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:23][CH2:22][N:18]([CH:19]([CH3:21])[CH3:20])[CH:15]([CH3:17])[CH3:16])[CH2:3][CH2:4][CH3:5]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: CCCCOc1ccccc1O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCCCOc1ccccc1OCCN(C(C)C)C(C)C
Temperature: 0 °C

Procedure:
To 750 ml of absolute ethanol was added gradually 13.8 g (0.60 mole) of metallic sodium cut into pieces. After all the sodium had reacted 49.8 g (0.30 mole) of o-butoxyphenol was added. The solution was cooled down in ice-water whereupon a solution of 60.0 g (0.30 mole) of diisopropylaminoethylchloride hydrochloride in 150 ml of absolute ethanol was added rapidly with stirring. The reaction mixture was then boiled under reflux for 5 hours.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])=[N:10][C:6]=2[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]([CH2:28][OH:29])[CH:23]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:19][C:18]1[C:11]([C:9]2[S:8][C:7]3[C:2]([NH:21][C:22]4[CH:23]=[C:24]([CH2:28][OH:29])[N:25]=[CH:26][N:27]=4)=[N:3][CH:4]=[C:5]([F:20])[C:6]=3[N:10]=2)=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14]
Reactant: N#Cc1cccc(Cl)c1-c1nc2c(F)cnc(Br)c2s1
Reactant: Nc1cc(CO)ncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1cccc(Cl)c1-c1nc2c(F)cnc(Nc3cc(CO)ncn3)c2s1
Temperature: 80 °C
Yield: 51.8 %

Procedure:
A mixture of 2-(4-bromo-7-fluorothiazolo[5,4-c]pyridin-2-yl)-3-chlorobenzonitrile (0.35 g, 0.95 mmol), (6-aminopyrimidin-4-yl)methanol (125 mg, 1.0 mmol), XantPhos (0.055 g, 0.095 mmol) and Cs2CO3 (780 mg, 2.38 mmol) in dioxane (11 mL) was degassed with a stream of argon. Pd2(dba)3 (0.048 g, 0.047 mmol) was added and the reaction mixture was heated at 80° C. for 6 hours in a sealed vial. After cooling to room temperature, the crude reaction mixture was diluted with EtOAc (100 mL) and water (20 mL) and the resultant mixture was filtered through Celite® washing with EtOAc (50 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated under reduced pressure The resultant residue was purified by column chromatography on silica gel eluting with 0-10% MeOH in DCM, then triturated with diethyl ether (×2), to afford the title compound as a pale yellow solid (203 mg, 52% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.79 (br s, 1H), 8.61 (d, J=1.2 Hz, 1H), 8.52 (d, J=1.8 Hz, 1H), 8.16-8.08 (m, 2H), 7.86 (t, J=8.0 Hz, 1H), 7.58 (s, 1H), 5.57 (t, J=5.7 Hz, 1H), 4.48 (d, J=5.7 Hz, 2H). LCMS (Method C): RT=3.29 min, m/z: 413 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[NH2:14])=[CH:6][CH:5]=1)[CH3:2].C(O)(C)(C)C.[Li].N>O1CCCC1.O.CO>[CH2:1]([O:3][C:4]1[CH2:13][C:12]2[C:11]([NH2:14])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2cccc(N)c2c1
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOC1=CCc2cccc(N)c2C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
Next, to a mixture of (7-ethoxy-1-naphthyl)amine (1.80 g, 9.61 mmol) and tert-butanol (2.13 g, 28.8 mmol) in tetrahydrofuran (20 mL) was collected liquid ammonia (300 mL) at −78° C. To the mixture was added lithium (0.200 g, 28.8 mmol) over 30 minutes and stirred at −78° C. for 1 hour. Methanol and water was added, and the mixture was stirred at room temperature for 16 hours to allow ammonia to evaporate. To the obtained residue was added ethyl acetate. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (7-ethoxy-5,8-dihydronaphthalen-1-yl)amine (1.37 g, 76% yield).
Reaction SMILES: [CH2:1]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:20](OC(=O)C)(=[O:22])[CH3:21]>C1(C)C=CC=CC=1>[C:20]([NH:17][C:16]1[CH:15]=[CH:14][C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:19][CH:18]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCc1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCc1ccc(NC(C)=O)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
In a 1-liter flask fitted with a stirrer and reflux condenser is added 137.5 grams (0.525 mole) of p-n-dodecylaniline, dissolved in 138 ml of toluene. To this is added over a 15-minute period 57.5 ml of acetic anhydride. The temperature rises from 40° to 80° C. After all the acetic anhydride is added, the reaction mixture is stirred at 40° C. for 3 hours. The reaction mixture is then cooled to yield the crude product which is recrystallized from 800 ml of methanol to give 151.1 grams of the above-named material as a solid melting at 100°-102° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:13](=O)([O-:16])[O:14]C.[Mg+2].COC(=O)[O-].Cl>>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:13]([OH:16])=[O:14]
Reactant: COC(=O)[O-]
Reactant: Oc1cccc2c(O)cccc12
Agent: Cl
Agent: [Mg+2]
Product: O=C(O)c1ccc2c(O)cccc2c1O
Temperature: 0 °C

Procedure:
1,5-dihydroxy-naphthalene (5.04 g, 31.4 mmol) and magnesium methyl carbonate (2 M in DMF, 34.0 mL), 273 g of ice, 2M HCl (85.0 mL)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C1(=O)O[CH2:15][CH2:14][O:13]1.C(=O)=O>N1C=CN=C1.C(OCC)C>[OH:13][CH2:14][CH2:15][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10]
Reactant: O=C1OCCO1
Reactant: NS(=O)(=O)c1ccccc1O
Agent: O=C=O
Agent: c1c[nH]cn1
Solvent: CCOCC
Product: NS(=O)(=O)c1ccccc1OCCO
Reaction time: 18 h
Yield: 52.5 %

Procedure:
A mixture of 74.6 g (0.43 mol) of 2-hydroxybenzenesulfonamide, 45.3 g (0.51 mole) of ethylene carbonate and 0.9 g of imidazole was heated to 160° with vigorous stirring. After about four hours the carbon dioxide evolution had subsided and no unreacted 2-hydroxybenzenesulfonamide was present in the reaction mixture. The mixture was allowed to cool and about 400 ml of diethyl ether was added to the thick oil. The two-phase mixture was stirred vigorously and was heated to reflux for about one hour. The diethyl ether was decanted off and a fresh portion of diethyl ether was added. The mixture was again stirred and heated to reflux. After the diethyl ether was decanted off a fresh portion of diethyl ether was added and the mixture was allowed to stand at ambient temperature for about 18 hours. The resulting light brown solid was isolated by filtration and was recrystallized from nitromethane to afford 49 g (53%) of the title compound; m.p. 94°-99° C. The infrared spectrum exhibited a broad peak at approximately 3400 cm-1 consistent with the primary alcohol of the product and peaks at 3370 cm-1 and 3270 cm-1 consistent with the NH2 of a primary sulfonamide.
Reaction SMILES: [N:1]1([C:6]2[CH:19]=[CH:18][C:9]([CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]3=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(C(C)C)CC)(C)C.Cl[S:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])(=[O:32])=[O:31]>ClCCl>[N:1]1([C:6]2[CH:19]=[CH:18][C:9]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([S:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])(=[O:32])=[O:31])[CH2:13][C:12]3=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)CS(=O)(=O)Cl
Reactant: O=C1CNCCN1Cc1ccc(-n2ccnc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CS(=O)(=O)N1CCN(Cc2ccc(-n3ccnc3)cc2)C(=O)C1
Yield: 19.7 %

Procedure:
To a solution of 1-[4-(1-imidazolyl)benzyl]piperazin-2-one (586 mg) and diisopropylethylamine (388 mg) in dichloromethane (10 ml) was added dropwise, under ice-cooling, a solution of methyl chlorosulfonylacetate (380 mg) in dichloromethane (10 ml), and the mixture was stirred at room temperature overnight. The reaction solution was washed with 0.5N hydrochloric acid and saturated brine, dried and concentrated, and the residue was purified with silica gel column chromatography (eluent: methanol/dichloromethane=1/10) to give colorless oil of 1-[4-(1-imidazolyl)benzyl]-4-methoxycarbonylmethylsulfonyl-2-oxopiperazine (0.170 g).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1.F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C=O)C>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2ccccn2)c2ccccc12
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (45.7 mg, 1.142 mmol, 60% dispersion in mineral oil) was added to a solution of methyl 1H-indole-3-carboxylate (200 mg, 1.142 mmol) in DMF (2283 μl) at RT. After 30 min, 2-fluoropyridine (99 μl, 1.142 mmol) was added to the mixture and the resulting suspension was heated at 120° C. for 14 h. The reaction mixture was diluted with DMF, filtered, and purified by HPLC to afford the title compound as a white solid.
Reaction SMILES: O=[C:2]1[CH:20]=[C:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[C:13]=3[CH2:14][CH2:15][N:6]2[C:5](=[O:21])[CH2:4][NH:3]1.O=P(Cl)(Cl)Cl.[CH:27]1([C:30]2[N:31]=[CH:32][NH:33][CH:34]=2)[CH2:29][CH2:28]1>ClCCCl.C(Cl)Cl>[CH:27]1([C:30]2[N:31]=[CH:32][N:33]([C:2]3[CH:20]=[C:7]4[C:8]5[CH:9]=[CH:10][CH:11]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[C:13]=5[CH2:14][CH2:15][N:6]4[C:5](=[O:21])[CH2:4][N:3]=3)[CH:34]=2)[CH2:29][CH2:28]1
Reactant: c1nc(C2CC2)c[nH]1
Reactant: COC(=O)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2c1CCN1C(=O)CN=C(n3cnc(C4CC4)c3)C=C21
Temperature: 100 °C
Yield: 39 %

Procedure:
Example 132. A solution of methyl 2,5-dioxo-2,3,4,5,7,8-hexahydro-[1,4]diazepino[7,1-a]isoquinoline-9-carboxylate (225 mg, 0.79 mmol) in DCE (20 mL) was treated with POCl3 (0.37 mL, 3.93 mmol) and the mixture was heated to 100° C. for 1 h. The mixture was then allowed to cool to RT, and then concentrated in vacuo, and dried azeotropically with toluene. The residue obtained was taken up in DCE (40 mL) and 4-cyclopropyl-1H-imidazole (261 mg, 2.41 mmol) were added. The mixture was heated to to 100° C. for 1 h and then allowed to cool to RT, diluted with DCM and washed with a saturated aq, solution of NaHCO3. The org. layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, AcOEt/MeOH 100:0 to 90:10) and crystallization in Et2O/petroleum ether gave the title compound (116 mg). UPLC-MS: MS 377.2 (M+H+); UPLC rt 0.88 min. 1H NMR (600 MHz, DMSO-d6): δ ppm 0.54-0.73 (m, 2H); 0.73-0.88 (m, 2H); 1.74-1.89 (m, 1H); 3.25 (br s, 2H); 3.67-3.82 (m, 2H); 3.88 (s, 3H); 4.25 (br s, 2H); 7.13 (s, 1H); 7.44 (s, 1H); 7.48-7.57 (m, 1H); 7.96 (d, J=7.65 Hz, 1H); 8.09 (s, 1H); 8.19 (d, J=7.91, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([OH:12])=[C:7]([Cl:13])[CH:6]=1)C.[Na+].[I-].C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH:25]1[CH2:27][CH2:26]1>CC(C)=O>[CH3:1][O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][CH2:24][CH:25]2[CH2:27][CH2:26]2)=[C:7]([Cl:13])[CH:6]=1
Reactant: CCOC(=O)c1cc(Cl)c(O)c(Cl)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cl)c(OCC2CC2)c(Cl)c1
Yield: 86.9 %

Procedure:
3,5-Dichloro-4-hydroxy-benzoic acid ethyl ester (1.0 g, 4.5 mmol, 1.0 eq) was dissolved in acetone (14 mL), NaI (0.5 eq) and K2CO3 (0.98 g, 9.0 mmol, 2.0 eq) were added ad the mixture was stirred at room temperature for 30 min. (Bromomethyl)cyclopropane (0.39 mL, 4.1 mmol, 0.9 eq) was added, and the mixture was refluxed for 2 days. The solvent was concentrated under reduced pressure, NaOH 10% was added, and it was extracted with DCM and dried. The title product (0.98 g, yield 79%) was recovered and used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:38])[C@@H:18]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH2:19][N:20]([CH:28]([CH3:30])[CH3:29])C(=O)OC(C)(C)C)[CH2:13][CH2:12]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:38])[C@@H:18]([C:31]3[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=3)[CH2:19][NH:20][CH:28]([CH3:30])[CH3:29])[CH2:15][CH2:16]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC[C@@H](C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
(S)-tert-Butyl 3-(4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate (0.040 g, 0.066 mmol) was placed in DCM (3 mL). TFA (0.3 mL) was then added. The reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, dissolved in minimal DCM, and added dropwise to a stirring solution of 1M HCl in ether. The solid product was filtered, washed with ether, and dried to give (S)-1-(4-(5-bromo-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-3-(isopropylamino)propan-1-one (0.03 g, 90% yield) as the dihydrochloride salt. MS ESI (+) m/z 505 detected.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]2[CH:14]=[N:15][CH:16]=[C:10]2[CH:9]=1)=[O:4].[OH-].[Na+]>CO>[C:3]([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]2[CH:14]=[N:15][CH:16]=[C:10]2[CH:9]=1)([OH:4])=[O:2]
Reactant: COC(=O)CCCc1ccn2cncc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCc1ccn2cncc2c1
Reaction time: 5 h

Procedure:
7-(3-methoxycarbonylpropyl)-imidazo[1,5-a]pyridine (Example 24, 8.0 mg) is dissolved in 0.3 ml of methanol and 0.1 ml of 1N NaOH is added. The mixture is stirred at 25° for 5 hours, evaporated, and the residue is redissolved in 5 ml of water. The aqueous solution is washed with 2 ml of ethyl acetate, brought to pH=6 with 2N sulfuric acid and extracted with methylene chloride (3×5 ml). The organic extracts are dried over sodium sulfate/magnesium sulfate and evaporated to yield 7-(3-carboxypropyl)-imidazo[1,5-a]pyridine, IR (CHCl3) 1720 cm-1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH2:9][CH:10]([CH2:16][CH2:17][CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH2:9][CH:10]([CH2:16][CH2:17][CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CCCC(CC(=O)c1ccc(Br)cc1)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCCC(CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)C(=O)OCC
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 46.9 %

Procedure:
To a 150 mL 3-neck flask fitted with a reflux condenser was added ethyl 2-[2-(4-bromophenyl)-2-oxoethyl]pentanoate (1.33 g, 4.10 mmol) and 4-nitro phenyl boronic acid (0.81 g, 4.9 mmol), dissolved in toluene (37 mL) and dioxane (10 mL), followed by addition of saturated aqueous sodium carbonate (11 mL). A thin-gauge needle was inserted into the bi-phasic mixture and the mixture was degassed with argon over 30 minutes, at which point 1,2-bis[(diphenylphosphino) ferrocene] dichloropalladium(II) (0.17 g, 0.20 mmol) was added, followed by 15 minutes of degassing. The mixture was heated to 85° C. for 16 h. The very darkly colored reaction mixture was allowed to cool, and diluted with ethyl acetate (100 mL) and saturated aqueous sodium chloride solution (100 mL). The layers were separated, the aqueous layer extracted twice with ethyl acetate (50 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (75 mL), dried over anhydrous magnesium sulfate, and filtered in vacuo through 2 cm Celite®/2 cm silica. The filtrate was concentrated under reduced pressure, leaving a dark red-brown oil, that was purified by flash chromatography (10:1 hexane:ethyl acetate, then 7:1 hexane:ethyl acetate, then 4:1 hexane:ethyl acetate) to afford ethyl 2-[2-(4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]pentanoate (0.71 g, 48%). LC-MS ret. time 3.88 min, m/z 369.8 (MH+); 1H NMR (300 MHz, CDCl3) δ 0.95 (t, 3H), 1.30 (t, 3H), 1.35–1.50 (m, 2H), 1.60–1.83 (m, 2H), 3.0–3.18 (m, 2H), 3.5 (dd, 1H), 4.20 (q, 2H), 7.65–7.88 (overlapping d, 4H), 8.10 (d, 2H), 8.35 (d, 2H).
Reaction SMILES: S(=O)(=O)(O)O.C(O)(=[O:8])C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]#[N:19])=[CH:13][CH:12]=1.[OH-].[NH4+]>CCCCCC>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]([NH2:19])=[O:8])=[CH:13][CH:12]=1
Reactant: CC(=O)O
Reactant: N#CC(c1ccccc1)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CCCCCC
Product: NC(=O)C(c1ccccc1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 130 °C
Yield: 87 %

Procedure:
A solution of concentrated sulfuric acid (50 mL) and glacial acetic acid (50 mL) was added to bis(4-fluorophenyl)phenylacetonitrile (18.9 g, 0.06 mol) at rt. The resulting orange solution was stirred and heated at 130° C. for 3 h. The reaction was cooled to 0° C., poured into ice water (150 mL) and neutralized with ammonium hydroxide. The organics were extracted with chloroform (3×100 mL), combined and washed with brine (2×50 mL). The organics were dried (Na2SO4) and concentrated under reduced pressure to afford a yellow-orange solid. The solid was stirred with hot hexane (100 ml) for 30 min and filtered. Crystallization from dichloromethane/hexane gave bis(4-fluorophenyl)phenylacetamide (3) as a white crystalline solid (16.9 g, 0.052 mol, 87%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([OH:14])=O)[NH:9]2)=[CH:5][C:4]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1.[C:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])[CH3:26]>>[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([N:31]3[CH2:32][CH2:33][N:28]([C:25](=[O:27])[CH3:26])[CH2:29][CH2:30]3)=[O:14])[NH:9]2)=[CH:5][C:4]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:17]1
Reactant: CC(=O)N1CCNCC1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)O)[nH]c3cc2Br)CC1
Agent: Cl
Product: CC(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)c(Br)cc3[nH]2)CC1
Yield: 52 %

Procedure:
The title compound was synthesized in analogy to example 1, from 6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate a) and 1-acetylpiperazine to afford the title compound as a light-yellow foam (52%).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)(O)[CH2:8][O:9]C)[CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)=O>[C:14]1([CH3:18])[CH:15]=[CH:16][CH:17]=[C:12]([CH:7]([C:3]2[CH:2]=[C:1]([CH3:19])[CH:6]=[CH:5][CH:4]=2)[CH:8]=[O:9])[CH:13]=1
Reactant: COCC(O)(c1cccc(C)c1)c1cccc(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=CO
Product: Cc1cccc(C(C=O)c2cccc(C)c2)c1
Yield: 94.8 %

Procedure:
A solution of 1,1-bis-(3-tolyl)-2-methoxyethanol (24.66 g) (obtained by reaction of (3-tolyl)magnesium bromide on methyl 2-methoxyacetate in tetrahydrofuran) in formic acid (30 cc) is refluxed for 12 hours, cooled and poured into a mixture of saturated sodium carbonate solution (400 cc) and ethyl acetate (400 cc). The organic phase is washed with water (3×300 cc) and with saturated sodium chloride solution (300 cc), then dried and concentrated to dryness under reduced pressure (2.7 kPa) to give bis-(3-tolyl)acetaldehyde (20.45 g) in the form of a yellow oil.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[O:15]1[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16]1>>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:21][CH2:20][C:17]2[CH:18]=[CH:19][O:15][CH:16]=2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: OCc1ccoc1
Product: N#Cc1c(OCc2ccoc2)cccc1[N+](=O)[O-]
Yield: 100 %

Procedure:
Prepared as in Example 158c from 2,6-dinitrobenzonitrile and 3-furanmethanol in 100% yield. 1H NMR (400 MHz, d-DMSO) δ 5.27 (s, 2H), 6.59 (s, 1H), 7.69 (s, 1H), 7.91-7.84 (m, 4H).