Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:23])[N:18]([CH2:19][C:20]#[CH:21])[C:17](=[O:22])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:25]1[CH:26]=[C:27]2[C:40](=[CH:41][CH:42]=1)[CH2:39][C@:29]1([C:37]3[C:32](=[N:33][CH:34]=[CH:35][CH:36]=3)[NH:31][C:30]1=[O:38])[CH2:28]2.C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:23])[N:18]([CH2:19][C:20]#[C:21][C:25]3[CH:26]=[C:27]4[C:40](=[CH:41][CH:42]=3)[CH2:39][C@:29]3([C:37]5[C:32](=[N:33][CH:34]=[CH:35][CH:36]=5)[NH:31][C:30]3=[O:38])[CH2:28]4)[C:17](=[O:22])[C:12]3([CH2:13][CH2:14][CH2:15][CH2:16]3)[NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C#CCN1C(=O)C2(CCCC2)NC[C@@]1(C)c1cc(F)cc(F)c1
Reactant: O=C1Nc2ncccc2[C@]12Cc1ccc(Br)cc1C2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@]1(c2cc(F)cc(F)c2)CNC2(CCCC2)C(=O)N1CC#Cc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 80 °C

Procedure:
A suspension of (8R)-8-(3,5-difluorophenyl)-8-methyl-9-prop-2-yn-1-yl-6,9-diazaspiro[4.5]decan-10-one from Step A (25 mg, 0.079 mmol), (R)-5-bromo-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (25 mg, 0.079 mmol described in intermediate 12 tetrakis(triphenylphosphine)palladium(0) (4.5 mg, 0.0039 mmol), copper(I)iodide (3.0 mg, 0.016 mmol), and triethylamine (0.022 mL, 0.16 mmol) in degassed DMF (0.5 ml) was heated at 80° C. for 16 hour. The mixture was filtered and purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The desired fractions were concentrated in vacuo to yield the title compound. MS: m/z=553 (M+1). HRMS: m/z=553.2400; calculated m/z=553.2410 for C33H31F2N4O2.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:24]=[CH:25][C:26]=3[OH:27])[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CN(C=O)C.[H-].[Na+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38]>O>[C:1]12([C:11]3[CH:12]=[C:13]([CH:24]=[CH:25][C:26]=3[O:27][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(OCc1ccccc1)c1ccc(O)c(C23CC4CC(CC(C4)C2)C3)c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
2.1 g (5.79 mmol) of benzyl 3-(1-adamantyl)-4-hydroxybenzoate and 20 ml of DMF were introduced into a three-necked flask and 191 mg (6.34 mmol) of sodium hydride (80% in oil) were added portionwise. The mixture was stirred until the evolution of gas had ceased, then 565 μl (5.79 mmol) of methyl bromoacetate were added and the mixture was stirred at room temperature for twelve hours. The reaction medium was poured into water and extracted with ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The solid was triturated from hexane, filtered off and dried. 2.36 g (94%) of the expected compound, having a melting point of 134°-5° C., were recovered.
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]12[CH2:29][O:28][C@@H:27]([CH3:30])[CH2:26][C@H:25]1[CH2:24][S:23][C:22]([NH:31]C(=O)C1C=CC=CC=1)=[N:21]2>CO>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]12[CH2:29][O:28][C@@H:27]([CH3:30])[CH2:26][C@H:25]1[CH2:24][S:23][C:22]([NH2:31])=[N:21]2
Reactant: C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: C[C@H]1C[C@H]2CSC(N)=N[C@@]2(c2ccc(F)cc2F)CO1
Temperature: 80 °C

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.5 mL, 3 mmol) was added to a suspension of N-[(4aR,6S,8aS)-8a-(2,4-difluorophenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C22) (1.40 g, 3.48 mmol) in methanol (100 mL), and the resulting mixture was heated at 80° C. for 18 hours. After removal of solvent in vacuo, the residue was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate; the aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography (Eluent: ethyl acetate) afforded the product as a white solid. Yield: 840 mg, 2.82 mmol, 81%. LCMS m/z 299.2 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 7.30-7.38 (m, 1H), 6.92-7.00 (m, 2H), 4.08 (dd, J=11.1, 2.2 Hz, 1H), 3.69-3.78 (m, 1H), 3.65 (d, J=11.1 Hz, 1H), 2.83-2.93 (m, 2H), 2.62-2.68 (m, 1H), 1.65-1.76 (m, 1H), 1.54 (ddd, J=13.1, 4.1, 2.4 Hz, 1H), 1.22 (d, J=6.2 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[C:8]([OH:14])=[C:7]([CH:15]([CH3:17])[CH3:16])[CH:6]=1)=[O:4].[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][C:20]=1[O:27][CH3:28].C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>O>[CH:15]([C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][C:20]=2[O:27][CH3:28])[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[C:8]=1[OH:14])([CH3:17])[CH3:16]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(C)c1cc(C(=O)CBr)cc(C(C)C)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C=O)ccc1OCC(=O)c1cc(C(C)C)c(O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6.00 g (18.3 mmol) of 2-bromo-1-(4-hydroxy-3,5-di-isopropylphenyl)-ethanone and 2.78 g (18.3 mmol) of 4-hydroxy-3-methoxy-benzaldehyde in 20 ml of ethyl acetate 5.00 g (36.7 mmol) of potassium carbonate is added and the mixture is stirred for 18 hours at room temperature. After addition of water and adjusting the pH to 5-6 by adding 32% HCl, the mixture is extracted with ethyl acetate. The combined extracts are washed with water, dried and evaporated to give compound 102. 1H-NMR (300 MHz, CDCl3), δ (ppm): 7.79 (s, 2H), 7.46-7.45 (d, 1H), 7.41-7.38 (dd, 1H), 6.90-6.87 (d, 1H), 5.43 (s, 2H), 3.97 (s, 3H), 3.24-3.15 (sept., 2H), 1.32-1.29 (d, 12H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[N:11]=[C:12]2[C:17](=[C:18]3[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]3)[CH:16]=[CH:15][CH:14]=[CH:13]2>C1C=CC=CC=1>[Br:1][CH2:9][C:10]1[N:11]=[C:12]2[C:17](=[C:18]3[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]3)[CH:16]=[CH:15][CH:14]=[CH:13]2
Reactant: Cc1nc2ccccc2c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Product: BrCc1nc2ccccc2c2ccccc12
Reaction time: 0.75 h
Yield: 87 %

Procedure:
N-bromosuccinimide (557 mg, 3.13 mmol) was added to a solution of the phenanthridine 5 (403 mg, 2.09 mmol) in benzene (20 mL) and the reaction mixture was stirred while lit with a tungsten lamp (150 W) for 45 minutes. The reaction crude, including precipitated succinimide, was deposited onto silica and purified by flash chromatography eluting with CH2Cl2. Evaporation of the solvent under reduced pressure yielded the bromo 6 as a white solid (495 mg, 87.1%).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH:4]([OH:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CCCCCC.O>CC(C)=O>[CH:1]#[C:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C#CCC(O)CCCCC
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: O
Solvent: CC(C)=O
Product: C#CCC(=O)CCCCC

Procedure:
A solution of 14 g of 1-nonyn-4-ol in 100 ml of acetone is cooled to 0° and treated dropwise with 70 ml of 2.67 molar Jones reagent with stirring. The reaction mixture is poured into a mixture of hexane and water, the organic layer is separated and washed with water, dried over sodium sulfate, stripped of solvent, and the residue distilled to give the title product.
Reaction SMILES: Cl.[NH2:2][C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[CH2:4][OH:5].[CH2:13]([O:20][C:21](ON1C(=O)CCC1=O)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C1COCC1>[OH:5][CH2:4][C:3]([NH:2][C:21](=[O:22])[O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6]
Reactant: CC(N)(CO)c1ccccc1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(CO)(NC(=O)OCc1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
2-Amino-2-phenylpropan-1-ol hydrochloride (0.5 g, 2.7 mmol) was reacted with N-(benzyloxycarbonyloxy)-succinimide (0.73 g, 2.9 mmol) and triethylamine (0.82 mL, 5.9 mmol) in THF (25 mL) at 0° C. for 1.0 hours and then at room temperature for 1 hour. The reaction was concentrated and extracted with ethyl acetate (25 mL). The extract was washed with water (2×) and brine, dried over MgSO4, and concentrated to give the crude title compound and used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][C:13](=[O:15])[CH3:14])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:7]([O:12][C:13](=[O:15])[CH3:14])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(O)c(OC(C)=O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCc2ccccc2)c(OC(C)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
The compound of step 1 of example 252 (20 g, 89.2 mmol) was dissolved in DMF (100 ml) and cooled in an ice bath. Potassium carbonate (18.4 g, 134 mmol) and, immediately thereafter, benzyl bromide (15.2 g, 89.2 mmol) were added. The mixture was stirred for 30 min at room temperature, filtered into a mixture of 2 N hydrochloric acid and diethyl ether. The solid was washed repeatedly with diethyl ether. The combined ethereal phases were washed with water, dried over sodium chloride, decanted and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to yield 21 g of the title compound.
Reaction SMILES: [CH2:1]([P:12](=[O:21])([O:17][CH:18]([CH3:20])[CH3:19])[O:13][CH:14]([CH3:16])[CH3:15])[P:2](=[O:11])([O:7][CH:8]([CH3:10])[CH3:9])[O:3][CH:4]([CH3:6])[CH3:5].C=O.[CH2:24](NCC)C>CO>[C:1]([P:2](=[O:11])([O:7][CH:8]([CH3:9])[CH3:10])[O:3][CH:4]([CH3:6])[CH3:5])([P:12](=[O:21])([O:13][CH:14]([CH3:16])[CH3:15])[O:17][CH:18]([CH3:20])[CH3:19])=[CH2:24]
Reactant: CCNCC
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Agent: C=O
Solvent: CO
Product: C=C(P(=O)(OC(C)C)OC(C)C)P(=O)(OC(C)C)OC(C)C
Yield: 24.3 %

Procedure:
11.95 g (34.7 mmol) of tetraisopropyl methylenebisphosphonate, 5.2 g (173.5 mmol) of paraformaldehyde and 2.54 g (34.7 mmol) of diethylamine are combined with the same reactants and at the same conditions as described above in Example I. This mixture is then refluxed for 117 hours. After the methanol has been eliminated as described above in Example I, 3.0 g of tetraisopropyl ethenylidenebisphosphonate is produced as a clear liquid.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:13]([CH2:16][S:17]([OH:20])(=[O:19])=[O:18])[CH2:14][NH2:15].[CH2:21]([OH:23])C>O1CCOCC1.[OH-].[Na+].O>[NH2:15][C@H:14]([C:21]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:23])[CH2:13][C:16]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:10]=1.[CH2:13]([CH2:16][S:17]([OH:20])(=[O:19])=[O:18])[CH2:14][NH2:15]
Reactant: CCO
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: NCCCS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N—BOC-L-phenylalanine-N-hydroxusuccinimide ester (400 mg, 1.1 mmol) in a mixture of ethanol (6 mL) and 1,4-dioxane (4 mL) was added to a solution of L-Phe-Homotaurine (273 mg, 1.0 mmol) in 1N NaOH (1.05 mL), water (3 mL) and ethanol (4 mL). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the solid (601.9 mg) was suspended in a mixture of acetone (8 mL) and isopropanol (0.2 mL) and stirred overnight at room temperature. The mixture was heated under refluxed for 30 minutes and then was cooled to room temperature. The white solid was collected by filtration, washed with ether, then dried in the vacuum oven for 45 minutes. The resulting solid (423.1 mg) was dissolved in a mixture of water/tert-butanol (7:3, 5 mL) and treated with Amberlite IR-120 plus (washed, 15 g dry weight) for 2 minutes at room temperature. The resin was removed by filtration and washed 3 times with the mixed solvents of water and tert-butanol (10 mL). Concentrated HCl (4 mL) was added. The solvents were removed under reduced pressure, and the resulting solid was dried in vacuum. The compound was purified by recrystallization from a mixed solvent of THF and MeOH. The resulting solid was heated under reflux in methanol (about 3 mL) to remove the yellowish color. The solid was dried in vacuo. Compound X was obtained as white solid (84.4 mg, 20%). The 1H and 13C NMR were consistent with the structure.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:9]2[C:10](=[O:17])[CH:11]([NH2:16])[CH2:12][CH:13]=[CH:14][CH2:15][CH:8]2[CH2:7][CH2:6]1)=[O:4].[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[N:9]2[C:10](=[O:17])[CH:11]([NH:16][C:25]([NH:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:26])[CH2:12][CH:13]=[CH:14][CH2:15][CH:8]2[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCC2CC=CCC(N)C(=O)N21
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCC2CC=CCC(NC(=O)Nc3ccccc3)C(=O)N21

Procedure:
6-Amino-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid methyl ester, 8, (120 mg, 0.5 mmol), phenyl isocyanate (110 μL, 1 mmol) and triethyl amine (200 μL) are stirred in CH2Cl2 (10 mL) at room temperature. After complete consumption of starting material, the reaction is poured into 1 N HCl; washed with brine; and dried of sodium sulfate. The organics are evaporated and the residue is purified over silica (40% ethyl acetate: hexane). The desired product is obtained as a clear oil. 1H NMR (CDCl3): δ 7.81 (s, 1H), 7.35 (m, 2H), 7.23 (t, J=7.3 Hz, 2H), 6.98 (t, J=7.4 Hz, 1H), 6.85 (bs, 1H), 5.81 (m, 2H), 5.28 (m, 1H), 4.52 (dd, J=8.9, 2.5 Hz, 1H),4.27 (m, 1H), 3.58 (s, 3H), 2.95–2.82 (m, 2H), 2.45 (m, 1H), 2.29 (m, 1H), 2.16–1.96 (m, 4H). 13C NMR (CDCl3): δ 173.0, 172.4, 155.8, 139.4, 129.1, 129.0, 126.2, 122.8, 119.9, 60.6, 58.9, 52.1, 51.3, 34.9, 33.1, 33.0, 27.5. ESI MS: 358.15 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:14]1[S:18][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]2)=[N:16][CH:15]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[S:18][C:17]([N:19]3[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:16][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CCOC(=O)C1CCN(c2ncc(Br)s2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)C1CCN(c2ncc(-c3cccc([N+](=O)[O-])c3)s2)CC1
Temperature: 100 °C
Yield: 23.4 %

Procedure:
A mixture of (3-nitrophenyl)boronic acid (188 mg, 1.13 mmol), ethyl 1-(5-bromo-1,3-thiazol-2-yl)piperidine-4-carboxylate (300 mg, 0.94 mmol), palladium(II) acetate (10.5 mg, 0.047 mmol), and tris(2-methylphenyl)phosphane (286 mg, 0.94 mmol) in 1,2-dimethoxyethane (1.9 mL) and 2M aqueous sodium carbonate (0.7 mL, 1.4 mmol) was heated to 100° C. in the microwave for 30 minutes. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL) and washed with 1:1 water:brine (50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. Purification by CombiFlash (0-40% ethyl acetate/hexanes) provided 79 mg (0.22 mmol, 23% yield) of ethyl 1-[5-(3-nitrophenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylate as a yellow solid.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]([CH2:12][CH3:13])[C:10](=[O:11])[C:5]2=[N:4][CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][C:16]=1[O:24][CH2:25][C:26]1[N:27]([CH3:31])[N:28]=[CH:29][N:30]=1>>[CH2:12]([N:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:18]3[CH:19]=[CH:20][C:15]([F:14])=[C:16]([O:24][CH2:25][C:26]4[N:27]([CH3:31])[N:28]=[CH:29][N:30]=4)[CH:17]=3)=[CH:3][N:4]=[C:5]2[C:10]1=[O:11])[CH3:13]
Reactant: Cn1ncnc1COc1cc(B(O)O)ccc1F
Reactant: CCn1ccn2c(Br)cnc2c1=O
Product: CCn1ccn2c(-c3ccc(F)c(OCc4ncnn4C)c3)cnc2c1=O
Yield: 23 %

Procedure:
3-Bromo-7-ethyl-7H-imidazo[1,2-a]pyrazin-8-one and 4-fluoro-3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)benzeneboronic acid were coupled to give the title compound as a white solid (43 mg, 23%): δH (400 MHz, d6-DMSO) 1.26 (3H, t, J 7), 3.94 (3H, s), 3.96 (2H, s), 5.52 (2H, s), 7.22-7.26 (2H, m), 7.44 (1H, dd, J 11 and 8), 7.65 (1H, d, J 6), 7.64 (1H, dd, J 8 and 2), 7.66 (1H, s), 7.98 (1H, s); m/z (ES+) 369 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](=O)[NH:4][C:5]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[N:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.S(Cl)([Cl:21])=O>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:21])=[N:4][C:5]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[N:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: O=c1[nH]c(-n2cccn2)nc(-n2cccn2)c1Br
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1nc(-n2cccn2)nc(-n2cccn2)c1Br
Yield: 61.2 %

Procedure:
To a solution of 1 g (3.26 mmol) of 5-bromo-2,6-di(1H-pyrazol-1-yl)pyrimidin-4(3H)-one (intermediate 8) in 10 ml of DMF and 40 ml of DCM was added dropwise a solution of 0.71 ml (9.8 mmol) of thionyl chloride in 10 ml DCM. The reaction mixture was refluxed for two hours, at which time no starting material was observed by TLC. The solution was extracted two times with 10 ml of saturated solution of NaHCO3 and Brine. The organic layer was separated, dried with MgSO4 and concentrated to give 0.65 g (61.5%) of the 4-chloro-pyrimidine derivative.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:21]=[CH:20][C:14]([C:15](OCC)=[O:16])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[NH2:22][C:23]1[N:27](C(OC(C)(C)C)=O)[N:26]=[C:25]([CH2:35][CH2:36][C:37]2[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]([O:45][CH3:46])[CH:38]=2)[CH:24]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:21]=[CH:20][C:14]([C:15]([NH:22][C:23]4[CH:24]=[C:25]([CH2:35][CH2:36][C:37]5[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]([O:45][CH3:46])[CH:38]=5)[NH:26][N:27]=4)=[O:16])=[CH:13][CH:12]=3)[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)c1ccc(N2CCN(C3CCC3)CC2)cc1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN(C5CCC5)CC4)cc3)n[nH]2)cc(OC)c1
Yield: 6.1 %

Procedure:
4-(4-cyclobutylpiperazin-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide was prepared as for Example 94, but starting from ethyl 4-(4-cyclobutylpiperazin-1-yl)benzoate (202 mg, 0.7 mmol), tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (292 mg, 0.84 mmol) and 1M NaHMDS (1.23 ml, 1.23 mmol) in THF (5 ml). The crude product was purified by reverse phase prep. HPLC (basic) using a 39-59% gradient of acetonitrile in water containing 1% 0.880 ammonia. The clean fractions were combined and evaporated to afford the title compound (21 mg, 6%); 1H NMR (399.9 MHz, DMSO-d6) δ 1.61-1.71 (2H, m), 1.81-1.86 (2H, m), 1.99-2.02 (2H, m), 2.38 (4H, t), 2.75 (1H, s), 2.85-2.87 (4H, m), 3.26-3.27 (4H, m), 3.72 (6H, d), 6.33 (1H, t), 6.42-6.43 (2H, m), 6.45 (1H, s), 6.95 (2H, d), 7.90 (2H, d), 10.29 (1H, s), 12.07 (1H, s). MS=m/z 490 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:21])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([Cl:19])[CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1.[C:22]([O-])([O-])=O.[Cs+].[Cs+].IC.CCOC(C)=O>CN(C=O)C.O>[Br:1][C:2]1[C:3]([CH3:21])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([Cl:19])[CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:22])[C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Br)cccc1-n1c(=O)[nH]c2c(Cl)cccc2c1=O
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1c(Br)cccc1-n1c(=O)c2cccc(Cl)c2n(C)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.3 %

Procedure:
A solution of 3-(3-bromo-2-methylphenyl)-8-chloroquinazoline-2,4(1H,3H)-dione (1.45 g, 3.97 mmol) in DMF (15 mL) was treated with Cs2CO3 (3.88 g, 11.9 mmol) and iodomethane (2.48 mL, 39.7 mmol) and stirred at room temperature for 1.5 h. The mixture was diluted with water and a mixture of EtOAc and hexanes. The organic phase was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (gradient from 5-40%), to give 3-(3-bromo-2-methylphenyl)-8-chloro-1-methylquinazoline-2,4(1H,3H)-dione as a white solid (1.3 g, 81% yield). Mass spectrum m/z 379, 391 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=[CH:11][C:10]([CH2:25]Cl)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=[CH:11][C:10]([CH2:25][N:27]2[CH2:32][CH2:31][N:30]([CH2:25][C:10]3[CH:11]=[C:12]([C:13]4[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=4)[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:9]=3)[CH2:29][CH2:28]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: COc1cc(-c2cc(CCl)nn2Cc2ccccc2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)n(Cc5ccccc5)n4)CC3)nn2Cc2ccccc2)cc(OC)c1OC

Procedure:
1-Benzyl-3-chloromethyl-5-(3,4,5-trimethoxy-phenyl)pyrazole (559 mg) and piperazine (59 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]4[C:19]5[N:33](C6CCCCO6)[N:32]=[CH:31][C:20]=5[C:21](=[O:30])[N:22]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:23]=4[CH:24]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1(C(C2C(C3C=CC4C5NN(C6CCCCO6)CC=5C(=O)N(CC(F)(F)F)C=4C=3)=CC=CN=2)=O)CCOCC1.[ClH:79]>O>[ClH:79].[N:1]1([C:7]([C:9]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]4[C:19]5[NH:33][N:32]=[CH:31][C:20]=5[C:21](=[O:30])[N:22]([CH2:25][C:26]([F:27])([F:29])[F:28])[C:23]=4[CH:24]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(c1ncccc1-c1ccc2c3c(cnn3C3CCCCO3)c(=O)n(CC(F)(F)F)c2c1)N1CCOCC1
Agent: Cl
Agent: O=C(c1ncccc1-c1ccc2c3c(c(=O)n(CC(F)(F)F)c2c1)CN(C1CCCCO1)N3)N1CCOCC1
Solvent: O
Product: O=C(c1ncccc1-c1ccc2c3[nH]ncc3c(=O)n(CC(F)(F)F)c2c1)N1CCOCC1
Yield: 78 %

Procedure:
The product is obtained according to the procedure described in Step 1.7. starting with 7-[2-(morpholin-4-ylcarbonyl)pyrid-3-yl]-1-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 7-[2-(morpholin-4-ylcarbonyl)pyrid-3-yl]-2-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one, in the form of a white powder (hydrochloride, 0.7 H2O; yield 78%).