Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](O)=O)=[CH:11][C:10]=1[CH2:18][O:19][CH3:20])[CH3:2].[NH2:21][C:22](=[N:41][OH:42])[C:23]1[CH:32]=[C:31]2[C:26]([CH2:27][CH2:28][N:29]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]2)=[CH:25][CH:24]=1>CCOC(C)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:42][N:41]=[C:22]([C:23]3[CH:32]=[C:31]4[C:26]([CH2:27][CH2:28][N:29]([CH2:33][C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:30]4)=[CH:25][CH:24]=3)[N:21]=2)=[CH:11][C:10]=1[CH2:18][O:19][CH3:20])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN1CCc2ccc(C(N)=NO)cc2C1
Reactant: CCc1ccccc1-c1ccc(C(=O)O)cc1COC
Solvent: CCOC(C)=O
Product: CCc1ccccc1-c1ccc(-c2nc(-c3ccc4c(c3)CN(CC(=O)OC(C)(C)C)CC4)no2)cc1COC

Procedure:
Title compound was prepared following general procedure 2 starting from Intermediate 23 (162 mg; 0.6 mmol) and Intermediate 5 (174 mg; 0.6 mmol). The reaction mixture was diluted with EtOAc, washed with water and brine and evaporated under vacuum. Purification by silica column chromatography (c-Hex/(DCM/EtOAc 1:1), 90/10 to 50/50) afforded the title compound as a yellowish oil. LC/MS (method B): 541.4 (M+H)+. HPLC (Method A) Rt 4.90 min (Purity: 96.1%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C([Li])CCC.[O:26]1[CH2:29][C:28](=[O:30])[CH2:27]1>C1COCC1>[CH3:7][C:4]1[N:3]([C:8]2[CH:12]=[C:11]([C:28]3([OH:30])[CH2:29][O:26][CH2:27]3)[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19])[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: O=C1COC1
Reactant: Cc1ccc(C)n1-c1ccn(COCC[Si](C)(C)C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(C2(O)COC2)n(COCC[Si](C)(C)C)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 86.3 %

Procedure:
Into a 5 L 4-necked round-bottom flask under nitrogen was placed 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole (132.0 g, 452.89 mmol, 1.00 equiv.) in THF (2 L), followed by the addition of butyl lithium (208 mL, 2.4 M, 1.10 equiv) dropwise with stirring at −78° C. over 15 min. The resulting solution was stirred at −50° C. for 40 min. To this was added a solution of oxetan-3-one (40.0 g, 555.07 mmol, 1.20 equiv) in THF (500 mL), dropwise with stirring at −78° C. over 30 min. The resulting solution was stirred at −78° C. for 30 min then quenched by the addition of 2 L of satd. aq. NH4Cl. The mixture was concentrated in vacuo and extracted with 3×1 L of EtOAc. The combined organic layers were washed with 2×1 L of water and 1×500 mL of brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with EtOAc/petroleum ether (1:20-1:5) to afford 3-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-5-yl]oxetan-3-ol (142.0 g, 82% yield) as a light yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[CH3:17].S(=O)(=O)(O)O.[CH3:23]O>>[CH3:23][O:15][C:14]([CH:10]1[CH2:11][C:12](=[O:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([CH3:17])[CH:4]=2)[CH2:9]1)=[O:16]
Reactant: Cc1cc(N2CC(C(=O)O)CC2=O)ccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1CC(=O)N(c2ccc(O)c(C)c2)C1

Procedure:
In analogy to the esterification described in Example 2b), the (RS)-1-(4-hydroxy-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid is reacted with methanol in presence of sulfuric acid to yield the (RS)-1-(4-hydroxy-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a light brown solid; MS: m/e=250 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.[C:11]([O:15][C:16](=[O:34])[N:17]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:11]([O:15][C:16](=[O:34])[N:17]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:2]2[CH:7]=[N:6][C:5]([C:8](=[O:9])[NH2:10])=[CH:4][N:3]=2)=[CH:29][CH:28]=1)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: NC(=O)c1cnc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N(CCc1ccccc1)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCc1ccccc1)Cc1ccc(Oc2cnc(C(N)=O)cn2)cc1
Temperature: 140 °C
Yield: 12.7 %

Procedure:
Take up 5-chloropyrazine-2-carboxamide (0.0527 g, 0.334 mmol), (4-hydroxybenzyl)phenethylcarbamic acid tert-butyl ester (Example 380, Part B) (0.110 g, 0.334 mmol) and K2CO3 (0.116 g, 0.836 mmol) in DMF (0.80 mL). Heat at 140° C. for 21.5 hours. Concentrate the reaction mixture then purify by flash chromatography, eluting with 50% ethyl acetate in hexanes to give the title compound (0.019 g, 12.7%):
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)[CH:2]=[CH2:3].[H-].[Na+].Br[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>CN(C)C=O>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:10](=[O:15])[CH2:9][CH2:8]2)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc2c(c1)CCC(=O)N2
Reactant: COc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(c1)CCC(=O)N2c1ccc(OC)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 42 %

Procedure:
2 Grams of 6-allyloxy-3,4-dihydro-2(1H)-quinolinone was dissolved in 50 ml of dimethyl-formamide, then 0.5 g of 60% oily sodium hydride and 5 ml of p-bromoanisole were added thereto by the procedures similar to those employed in Reference example 7, further 4 g of cuprous chloride was added, and stirred at 120° C. for 24 hours. The inorganic materials were removed by filtration, and the filtrate was concentrated under reduced pressure. Thus obtained residual product was subjected to extraction with 200 ml of methylene chloride, the extract was washed with water and an aqueous solution saturated with sodium chloride. Then the extract was concentrated and subjected to purification by passing through a silica gel column, there was obtained 1.3 g (42%) of 6-allyloxy-3,4-dihydro-1-(4-methoxyphenyl)-2(1H)-quinolinone.
Reaction SMILES: C([O:5][C:6](=[O:24])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH:16]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[NH2:17])(C)(C)C.[C:25]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:30]=[CH:29][C:28]([C:31]2[CH:35]=[C:34]([CH3:36])[N:33]([CH2:37][CH2:38]O)[N:32]=2)=[CH:27][CH:26]=1>>[C:25]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:30]=[CH:29][C:28]([C:31]2[CH:35]=[C:34]([CH3:36])[N:33]([CH2:37][CH2:38][O:15][C:12]3[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][C:6]([OH:5])=[O:24])=[C:10]([CH:16]([C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])[NH2:17])[CH:11]=3)[N:32]=2)=[CH:27][CH:26]=1
Reactant: Cc1cc(-c2ccc(-c3ccccc3)cc2)nn1CCO
Reactant: CC(C)OC(=O)C(N)c1cc(O)ccc1CCC(=O)OC(C)(C)C
Product: Cc1cc(-c2ccc(-c3ccccc3)cc2)nn1CCOc1ccc(CCC(=O)O)c(C(N)C(=O)OC(C)C)c1

Procedure:
The title compound was prepared from 3-[4-hydroxy-2-(isopropoxycarbonyl-amino-methyl)-phenyl]-propionic acid tert-butyl ester (Prep 16) and 2-(3-biphenyl-4-yl-5-methyl-pyrazol-1-yl)-ethanol (Prep 11) using Standard coupling procedure B followed by Standard hydrolysis procedure C. MS [ES] m/e 542 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:29][CH2:30][CH:31]=[C:32]1[C:38]2[CH:39]=[CH:40][CH:41]=[N:42][C:37]=2[CH2:36][O:35][C:34]2[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:29][CH2:30][CH:31]=[C:32]3[C:38]4[CH:39]=[CH:40][CH:41]=[N:42][C:37]=4[CH2:36][O:35][C:34]4[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]3=4)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cc(C2(O)CCNCC2)ccc1Cl
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)c([N+](=O)[O-])c3)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 14 h
Yield: 30.3 %

Procedure:
To a solution of the 4-(4-Chloro-3-nitro-phenyl)-piperidin-4-ol (0.295 g, 1.2 mmol) in isopropanol was added 2,6-lutidine (0.225 mL, 2.1 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.224 g, 0.6 mmol), added in portions over 1 h. The solution was then stirred at 80° C. for an additional 14 h. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (15% methanol/85% methylene chloride) to yield the title compound (0.100 g, 30%). 1H-NMR (CDCl3): δ 1.53 (s, 6H), 1.70 (d, 2H), 1.81-2.18 (m, 4H), 2.3-2.44 (m, 4H), 2.56 (t, 2H), 2.69 (d, 2H), 5.32 (bs, 2H), 6.16 (t, 1H), 6.81 (d, 1H), 7.28 (t, 2H), 7.48 (t, 2H), 7.58 (t, 2H), 8.06 (s, 1H). ESI-MS m/z: 550 (M+1), retention time 1.51
Reaction SMILES: OC[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=NOC)[C:10]([NH:12]C)=[O:11].[H-].[Na+].CC(C)CC1(C2C=NC(S(C)(=O)=O)=C(C)C=2)OCCO1.O>CS(C)=O>[C:4]1([CH2:9][C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][CH:7]=[CH:8][CH:3]=1
Reactant: CNC(=O)C(=NOC)c1ccccc1CO
Agent: Cc1cc(C2(CC(C)C)OCCO2)cnc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 132.2 %

Procedure:
2-(Hydroxymethyl)-α-(methoxyimino)-N-methyl-benzeneacetamide (0.46 g, 2.07 mmol) was dissolved with stirring in anhydrous dimethyl sulphoxide (20 mL) and 60% sodium hydride (0.10 g, 2.5 mmol) added. The reaction mixture was stirred at room temperature for 20 minutes and a solution of 2-(2,2-dimethylethyl)-2-(5-methyl-6-methylsulphonyl-3-pyridinyl)-1,3-dioxolane (0.62 g, 2.07 mmol) in anhydrous dimethyl sulphoxide (5 mL) added. The reaction mixture was heated to 45° C. and stirred overnight. It was then cooled to room temperature and poured into water. This was extracted with ethyl acetate (2×40 mL), the organic extracts combined and washed with water and brine, and dried (Na2SO4). Evaporation of the solvent under reduced pressure and purification of the residue by chromatography over silica (10-50% ethyl acetate:pentane) gave the desired product (0.37 g, 40%) as a clear gum.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Cl:5][C:6]1[C:7]([N:12]2[C:16]([C:17]3[O:22][C:21](=[O:23])[C:20]4[CH:24]=[C:25]([N+:29]([O-:31])=[O:30])[CH:26]=[C:27]([CH3:28])[C:19]=4[N:18]=3)=[CH:15][C:14]([C:32]([F:35])([F:34])[F:33])=[N:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1>O1CCOCC1>[Cl:5][C:6]1[C:7]([N:12]2[C:16]([C:17]([NH:18][C:19]3[C:20]([C:21]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:23])=[CH:24][C:25]([N+:29]([O-:31])=[O:30])=[CH:26][C:27]=3[CH3:28])=[O:22])=[CH:15][C:14]([C:32]([F:35])([F:34])[F:33])=[N:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cc([N+](=O)[O-])cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: CC(C)N
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])cc(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 8 h
Yield: 14.3 %

Procedure:
Isopropyl amine (0.35 mL, 4.11 mmol) was added to a solution of 619 mg (1.37 mmol) of the product of Step B in dioxane (8 mL) at 25° C. After being stirred overnight, the resulting heterogenous mixture was concentrated and the residue was triturated with methanol (10 mL). Filtration gave 100 mg of the title product. The filtrate was concentrated and the resulting residue was triturated with diethyl ether. Filtration of the resulting solid provided an additional 320 mg of the title product, m.p. 170-172° C.
Reaction SMILES: C1C=CC(O[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][C:10]#[N:11])=CC=1.[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>C(O)(C)C>[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:8](=[N:9][C:10]#[N:11])[O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:23][CH:22]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: COc1ccc(N)cc1
Solvent: CC(C)O
Product: COc1ccc(NC(=NC#N)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.3 %

Procedure:
A slurry of diphenyl cyancarbonimidate (1 g) in isopropanol (10 mL) was treated with 4-methoxyaniline (517 mg). After stirring at room temperature for a further 2.5 hours the reaction mixture was filtered. The insoluble material was washed with isopropanol to give the title compound (778 mg) as a white solid, which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:18].[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24](B(O)O)[CH:25]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:22]3[CH:21]=[C:20]([CH3:19])[CH:25]=[CH:24][C:23]=3[O:29][CH3:30])=[C:3]([F:18])[CH:4]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: COc1ccc(C)cc1B(O)O
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(Br)c(F)c1
Product: COc1ccc(C)cc1-c1ccc(S(=O)(=O)c2ccc(F)cc2)cc1F

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of example 9 step (i) and 5-methyl-2-methoxybenzene boronic acid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9]I)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:11]#[C-:12].[Na+].[Na+]>>[C:1]1([CH2:7][CH2:8][CH2:9][C:11]#[CH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [C-]#[C-]
Reactant: ICCCc1ccccc1
Agent: [Na+]
Product: C#CCCCc1ccccc1

Procedure:
The title compound was synthesized using 3-phenyl-1-iodopropane and sodium acetylide by conducting the reactions similar to those mentioned in Reference example 29.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[N:10][N:11]3[C:16](O)=[C:15]([CH3:18])[CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)[Cl:37].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:37][C:16]1[N:11]2[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:12]2[N:13]=[CH:14][C:15]=1[CH3:18]
Reactant: Cc1cnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1cnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn2c1Cl
Temperature: 100 °C
Yield: 96.2 %

Procedure:
To a slurry of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-6-methylpyrazolo[1,5-a]pyrimidin-7-ol (I-3A-1c; 119 mg, 0.321 mmol) and diisopropylethylamine (0.084 ml, 0.48 mmol) in toluene (2.2 ml) at room temperature was added POCl3 (0.15 ml, 1.61 mmol), dropwise. The mixture was heated at 100° C. for 22 hours, cooled to room temperature, then slowly added to a stirred mixture of ice, saturated aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was separated and extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), and then concentrated, in vacuo, to afford the crude product (120 mg). Purification on a Biotage™ Flash 12M column using 0–8% ethyl acetate in hexanes as eluant afforded I-3A-1d (102 mg, 82%) as a yellow solid: +ESI MS (M+1) 388.1; 1H NMR (400 MHz, CD2Cl2) δ 8.44 (s, 1H), 7.55–7.37 (m, 6H), 7.27 (d, J=8.7 Hz, 2H), 2.51 (s, 3H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:16][CH:15]([CH2:17][OH:18])[CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl.CN(C)C1C=CN=CC=1>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:14][CH:15]([CH2:17][O:18][S:32]([C:29]4[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=4)(=[O:34])=[O:33])[CH2:16]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CC(c2ccc(CN3CCCC3)cc2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CC(c3ccc(CN4CCCC4)cc3)C2)cc1
Yield: 89.2 %

Procedure:
To a stirring solution of [3-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutyl]-methanol (0.56 g, 2.3 mmol) prepared above in 5 mL of dichlormethane was added triethyl amine (1.6 mL, 2.7 mmol) followed by 4-(dimethyl amino)pyridine (2.8 mg, 0.23 mmol) and p-toluene sulfonyl chloride (0.52 g, 2.7 mmol). After 1 hr the reaction was quenched with a saturated aqueous solution of NaHCO3. The reaction was diluted and extracted with dichloromethane. The organic layers were dried over magnesium sulfate, filtered through a fritted funnel, and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography, using a 40 g ISCO column, eluting with a gradient of 4%, 6%, and 10% MeOH/CH2Cl2. The product containing fractions were collected and concentrate under reduced pressure to give the title compound (0.82 g, 93% yield) as a colorless oil and a mixture of cis:trans isomers.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:10][N:11]([CH3:20])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[OH-].[Na+]>CO.[Al]>[C:4]1([C:1](=[O:3])[CH:2]=[CH:16][C:15]2[CH:18]=[CH:19][C:12]([N:11]([CH3:20])[CH3:10])=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CC(=O)c1ccccc1
Agent: [Al]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)c1ccc(C=CC(=O)c2ccccc2)cc1
Reaction time: 48 h

Procedure:
Acetophenone (28.0 g, 0.15 mole) and 4-dimethylaminobenzaldehyde (22.35 g, 0.15 mole) were dissolved in methanol (150 ml) in a 500 ml, 3-necked round bottom flask. The flask was wrapped in aluminium foil to exclude light and was fitted with a mechanical stirrer and a water cooled condenser. The third neck was stoppered and used to obtain samples for monitoring during the reaction. Aqueous sodium hydroxide solution (50 ml of 30% w/v) was added dropwise to the vigorously stirred clear methanolic solution. A yellow/orange solid started separating from the reaction solution (which had turned orange) after about 24 hours. Stirring was continued for about 48 hours at ambient temperature and the intermediate title compound was isolated by vacuum filtration, washed successively with water, methanol and petroleum ether (40-60° C.) and dried in vacuo to give 23.3 g (62% of theory) of 1-phenyl-3-(4-dimethylaminophenyl)-1-oxo-prop-2-ene with a melting point of 112-114° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5](Cl)[C:6]([CH3:12])=[N:7]2.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.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>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([CH3:12])=[N:7]2
Reactant: Cc1nc2cccc(Br)c2nc1Cl
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1nc2cccc(Br)c2nc1-c1ccccc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
A suspension of 5-bromo-3-chloro-2-methylquinoxaline (126e; 327 mg, 1.270 mmol), phenylboronic acid (Aldrich; 155 mg, 1.270 mmol), Na2CO3 (673 mg, 6.35 mmol), and Pd(PPh3)4 (Strem Chemicals, Inc.; 73.4 mg, 0.063 mmol) in a mixture of CH3CN (9.00 mL) and water (3 mL) was stirred under argon at 80° C. for 16 h. The reaction was cooled to RT and concentrated onto silica gel. Chromatographic purification (silica gel, 0-40% EtOAc/hexanes) furnished 5-bromo-2-methyl-3-phenylquinoxaline (340.0 mg, 1.136 mmol, 89% yield) as a peach-colored solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.03 (2H, d, J=7.8 Hz), 7.77 (2H, dd, J=7.9, 1.7 Hz), 7.60 (1H, d, J=7.8 Hz), 7.48-7.57 (3H, m), 2.85 (3H, s). m/z (ESI, +ve) 298.9/300.8 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]3[C:13]([O:15][C:16](=O)[C:9]=3[CH:8]=2)=[O:14])=[CH:5][C:4]2[C:18]([O:20][C:21](=O)[C:3]=2[CH:2]=1)=[O:19].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].O>C1COCC1>[OH:15][CH2:16][C:9]1[CH:8]=[C:7]([C:6]2[CH:1]=[CH:2][C:3]([CH2:21][OH:20])=[C:4]([CH2:18][OH:19])[CH:5]=2)[CH:12]=[CH:11][C:10]=1[CH2:13][OH:14]
Reactant: O=C1OC(=O)c2cc(-c3ccc4c(c3)C(=O)OC4=O)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc(CO)c(CO)c2)cc1CO
Temperature: 100 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
To a solution of 3,3′,4,4′-biphenyltetracarboxylic dianhydride (6.0 g, 20.4 mmol, 1.0 molar equivalent) in THF (600 mL) heated to 100° C. is added carefully a solution of LiAlH4 (1M in tetrahydrofuran) (81 mL, 81.6 mmol, 2.0 molar equivalents). The reaction mixture is stirred overnight at 100° C. To this resulting solution cooled at 0° C. is added a 2M sodium hydroxide solution (50 mL) followed by cold water (25 mL) and THF (50 mL). The reaction mixture is then filtered and concentrated under vacuum. The crude product is then washed with THF (20 mL), water (10 mL) and dried over vacuum to give a white powder (3.1 g, 55%). If necessary, the compound can be further purified by recrystallisation in water to give the expected compound as a white powder (3.3 g, 79%). 1H NMR (300.13 MHz, DMSO) δ (ppm) 4.57 (d, J=4.5 Hz, 4H) 4.61 (d, J=4.5 Hz, 4H) 5.09 (t, J=5.2 Hz, 2H) 5.15 (t, J=5.2 Hz, 2H) 7.46 (d, J=8.1 Hz, 2H) 7.52 (dd, J1=8.1, J2=1.8 Hz, 2H) 7.70 (d, J=1.8 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]([CH3:14])[S:10]([CH3:13])(=[O:12])=[O:11])[N:4]=1)#[N:2].[OH-].N>CO.[Ni]>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]([CH3:14])[S:10]([CH3:13])(=[O:12])=[O:11])[N:4]=1
Reactant: CN(c1nccc(C#N)n1)S(C)(=O)=O
Agent: [Ni]
Agent: N
Agent: [OH-]
Solvent: CO
Product: CN(c1nccc(CN)n1)S(C)(=O)=O
Reaction time: 2 h

Procedure:
A solution of N-(4-cyano-pyrimidin-2-yl)-N-methyl-methanesulfonamide (0.15 g, 0.71 mmol) in MeOH and 28% aqueous ammonia hydroxide (1.2 mL, 0.70 mmol) was hydrogenated over Raney-Ni catalyst using a continuous flow hydrogenation apparatus (conditions: 1 mL/minute, 25° C., 10 bar). After 2 hours, the solvent was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 5% MeOH in CH2Cl2. The major fractions were combined and the solvent was concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26]OS(C)(=O)=O)=[CH:20][CH:19]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:26][CH2:25][CH2:24][C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: CS(=O)(=O)OCCCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SCCCc2ccncc2)cc1
Temperature: 100 °C
Yield: 22 %

Procedure:
To a stirring solution of 4-mercapto-benzoic acid methyl ester (506 mg, 3.01 mmol) and potassium carbonate (1.245 g, 9.01 mmol) in dimethylformamide (10 mL), is added methanesulfonic acid 3-pyridin-4-yl-propyl ester (See Intermediate 14) in dicholoromethane (11 mL, 2.73 mmol). The dichloromethane is removed in vacuo and then the reaction is heated to 100° C. for 4 h. The reaction is allowed to cool to room temperature and washed with water while extracting with ethyl acetate. The organic portion is concentrated in vacuo. The resulting residue is purified using radial chromatography, eluting with methanol and dichloromethane to obtain 174 mg (22%) of the title compound. MS (ES+) m/e 288.1 (M+1)+.