Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:11][CH2:12][CH2:13][CH3:14])[NH:7][C:8]=1[C:9]#[N:10])(=[O:3])[CH3:2].[CH2:15]([Mg]Br)C>>[CH2:11]([C:6]1[NH:7][C:8]([C:9]#[N:10])=[C:4]([C:1](=[O:3])[CH2:2][CH3:15])[N:5]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CC[Mg]Br
Reactant: CCCCc1nc(C(C)=O)c(C#N)[nH]1
Product: CCCCc1nc(C(=O)CC)c(C#N)[nH]1
Yield: 51.9 %

Procedure:
Following a procedure similar to that described in Preparation 24(i), but using ethylmagnesium bromide instead of methylmagnesium bromide, the title compound, melting at 84°-85° C, was obtained in a 51.9% yield.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH2:19][CH2:20][CH:21]2[O:26][CH2:25][CH2:24][CH2:23][O:22]2)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[OH-].[NH4+:28]>CC(O)C>[O:22]1[CH2:23][CH2:24][CH2:25][O:26][CH:21]1[CH2:20][CH2:19][C:4]1[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=[C:2]([NH2:28])[N:3]=1
Reactant: [NH4+]
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(CCC4OCCCO4)c3n2)cc1
Agent: [OH-]
Solvent: CC(C)O
Product: Nc1nc(CCC2OCCCO2)c2nc(-c3ccc(F)cc3)ccc2n1
Temperature: 100 °C
Yield: 70 %

Procedure:
A suspension of 2-chloro-4-(2-[1,3]dioxan-2-yl-ethyl)-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine (9 mg, 0.024 mmol) in iPrOH (0.5 mL) and 30% ammonium hydroxide (4 mL) was heated at 100° C. for 30 minutes. Solvents were concentrated in vacuo and the residue was purified by RP HPLC using a C18 column with a gradient of H2O and 0.1% TFA-acetonitrile, to provide the title compound as a white solid (6 mg, yield: 70%). The resulting title compound was characterised as follows: MS (m/z) 355.0 [M+H]+; HPLC Rt=3.34 minutes (Method A).
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[CH2:22]([O:24][C:25]([C:27]1[CH:28]=[CH:29][C:30]([C:37]2[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]([O:45][CH3:46])[CH:38]=2)=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2)=[O:26])[CH3:23]>CC#N>[CH2:22]([O:24][C:25]([C:27]1[CH:28]=[CH:29][C:30]([C:37]2[CH:38]=[C:39]([O:45][CH3:46])[CH:40]=[C:41]([O:43][CH3:44])[C:42]=2[F:21])=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2)=[O:26])[CH3:23]
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Reactant: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2)c2cccnc12
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2F)c2cccnc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 34.4 %

Procedure:
SelectFluor (2.04 g, 5.8 mmol, 2 equiv) was added to a cold (−5° C.) solution of 5-(3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid ethyl ester (Step 174.2) (970 mg, 2.9 mmol) in CH3CN (40 mL), under an argon atmosphere. The reaction mixture was allowed to warm to rt, stirred at that temperature for 6 h, quenched by addition of a saturated aqueous solution of NaHCO3, and concentrated. The residue was diluted in EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc, 3:2) followed by trituration in Et2O to provide 355 mg of the title compound: ESI-MS: 356.2 [M+H]+; tR=3.80 min (System 1); TLC: Rf=0.18 (Hex/EtOAc, 3:2).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([N:15]2[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:17](=[O:25])[NH:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[Cl:8][C:9]1[C:10]([N:15]2[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:17]([O:25][S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])=[N:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CC(OS(=O)(=O)c2ccccc2)=NN1c1ncccc1Cl
Reaction time: 2 h
Yield: 94 %

Procedure:
Triethylamine (1.85 g, 18.5 mmol) was added dropwise over 1 h to a mixture of ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. the product of Example 1, Step A) (5.0 g, 18.5 mmol) and benzenesulfonyl chloride (3.27 g, 18.5 mmol) in dichloromethane (20 mL) at 0° C. The temperature was not allowed to exceed 1° C. After stirring the reaction mixture for an additional 2 h, a further portion of benzenesulfonyl chloride (0.5 g, 1.85 mmol) was added. Then a further portion of triethylamine (0.187 g, 1.85 mmol) was added dropwise to the mixture. After stirring for 0.5 h more, the mixture was partitioned between water (100 mL) and dichloromethane (100 mL). The organic layer was dried (MgSO4) and evaporated to provide the title product as an orange solid (7.18 g, 94% yield). Product recrystallized from ethyl acetate/hexanes melted at 84-85° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH2:16])=[O:15])[CH2:6][CH2:5]2.CC[O:21]C(C)=O>C(C#N)(C)=O.O>[OH:21][C:7]([CH3:17])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:18])[C:14]([NH2:16])=[O:15]
Reactant: CCOC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(N)=O)O2
Agent: CC(=O)C#N
Solvent: O
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(N)=O)=C(C)C1=O

Procedure:
A solution of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (1.0 equiv.) in 3 mL AcCN (0.28 M) and a drop of water was cooled to 0° C. A solution of ceric ammonium nitrate (CAN) (2.2 equiv) in water (0.5 M) cooled to 0° C. was added dropwise over 2-3 minutes. The solution was then immediately treated with 10 mL EtOAc and the layers separated. The organic layer was washed 3×5 mL H2O and the combined aqueous phases back extracted with 3×5 mL EtOAc. The combined organics were washed with 10 mL saturated NaCl and dried over Na2SO4. Flash chromatography yielded the desired 2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide derivative.
Reaction SMILES: Cl[CH:2]([C:13](=O)[CH3:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:4].[CH2:16]([SH:19])[CH2:17][SH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3]([C:2]2[S:18][CH2:17][CH2:16][S:19][C:13]=2[CH3:14])=[O:4])=[CH:7][CH:8]=1
Reactant: SCCS
Reactant: CC(=O)C(Cl)C(=O)Nc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1=C(C(=O)Nc2ccc(Cl)cc2)SCCS1
Yield: 84 %

Procedure:
2-Chloro-N-(4-chlorophenyl)-3-oxobutanamide (24.7 g, 0.1 mole), 1,2-ethanedithiol (9.4 g, 0.1 mole) and a small amount of p-toluenesulfonic acid were heated under reflux in benzene (150 ml), using a Dean-Stark trap to remove water (1.9 ml collected). The reaction mixture was filtered, treated with triethylamine (8 ml), and refluxed for a further 30 minutes. The mixture was then washed with water, dilute hydrochloric acid, and water. Evaporation of the benzene gave a white solid, which was recrystallized from absolute ethanol. The product melted at 115°-117° C. (24 g, 84% yield).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1>>[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[C:17]([C:2]2[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:16]=[CH:15][CH:14]=1
Reactant: CCc1ccc(N)c(Br)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: CCc1ccc(N)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
2-bromo-4-ethylaniline and 3-trifluoromethylbenzene boronic acid can be combined to form 2-(3-trifluoromethylphenyl)-4-ethylaniline,
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@H:5]3[C@@H:21]([C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:2]124)[CH2:20][CH2:19][C@@:18]1([CH3:29])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[CH2:30]([CH2:32][NH2:33])[OH:31].C(O)CCC>COC(C)(C)C>[OH:1][C@:2]12[CH2:26][C@@H:25]([OH:27])[CH2:24][CH2:23][C@:22]1([CH3:28])[C@@H:21]1[C@H:5]([C@H:6]3[C@:18]([CH3:29])([CH2:19][CH2:20]1)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:8][CH2:7]3)[CH2:4][C@H:3]2[NH:33][CH2:32][CH2:30][OH:31]
Reactant: NCCO
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Solvent: COC(C)(C)C
Solvent: CCCCO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@@H](NCCO)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 91.7 %

Procedure:
5,6α-epoxicholestan-3β-ol (8.9 g, 22.1 mmol, 1 eq) and ethanolamine (2.7 ml, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give 5α-Hydroxy-6β-[2-hydroxyethylamino]-cholestan-3β-ol as a white solid (9.4 g, 98%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 17% yield.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[CH2:12]([N:19]1[C:27]([OH:28])=[N:26][C:25]2[C:20]1=[N:21][C:22]([CH2:30]Cl)=[N:23][C:24]=2[NH2:29])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH2:12]([N:19]1[C:27]([OH:28])=[N:26][C:25]2[C:20]1=[N:21][C:22]([CH2:30][CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[N:23][C:24]=2[NH2:29])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)CC(=O)OC
Reactant: Nc1nc(CCl)nc2c1nc(O)n2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To dimethyl malonate (493 mg, 3.73 mmol) in DMF (8 ml) was added in an ice bath sodium hydride (75 mg, 3.13 mmol). Then the mixture was stirred at room temperature for 30 minutes. Thereto was added 9-benzyl-2-chloromethyl-8-hydroxyadenine (0.10 g, 0.37 mmol), and the mixture was stirred at room temperature for 21 hours. After removing the solvent, the residue was poured into water, concentrated, and neutralized with hydrochloric acid. The resulting solid was filtered, washed with water and dried in vacuo under heating to give 9-benzyl-2-(2,2-dimethoxycarbonylethyl)-8-hydroxyadenine (92 mg, 0.24 mmol) as a white solid. Thus obtained 9-benzyl-2-(2,2-dimethoxycarbonylethyl)-8-hydroxyadenine (79 mg, 0.20 mmol) was added to a mixed solvent of concentrated hydrochloric acid (2 ml) and 1,4-dioxane (6 ml), and the mixture was refluxed for 6 hours. After the reaction mixture was neutralized in an ice bath with saturated sodium hydrogencarbonate solution, the resulting solid was filtered, washed with water and dried in vacuo under heating to give the captioned compound (55 mg, 0.18 mmol) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2cc(-c3ccccn3)ccc21
Product: CC1c2ccc(-c3ccccn3)cc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-pyridin-2-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1.[NH2:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12].CN(C)CCO.Cl>O>[Cl:9][C:4]1[CH:3]=[C:2]([NH:10][CH:11]([CH3:12])[C:13]([OH:15])=[O:14])[CH:7]=[CH:6][C:5]=1[Cl:8]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: C[C@H](N)C(=O)O
Agent: CN(C)CCO
Agent: Cl
Solvent: O
Product: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Temperature: 90 °C
Yield: 52.4 %

Procedure:
A mixture of 1-bromo-3,4-dichlorobenzene (5.10 g, 22.1 mmol), L-alanine (2.96 g, 33.2 mmol) copper(I) iodide (421 mg, 2.21 mmol), tri-potassium phosphate n-hydrate (15.3 g, 66.4 mmol), 2-(dimethylamino)ethanol (5.92 g, 66.4 mmol), and water (22 mL) was heated at 90° C. for 40 h, then poured onto ice water. The pH was set to 6 with 25% aq. HCl solution, and the mixture was extracted with EtOAc. The aqueous phase was acidified to pH 4.5 and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; EtOAc) afforded the title compound (2.71 g, 53%) as a 60:40 mixture of the (S) and (R) stereoisomers. Light brown solid, MS: 232.1 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][SH:16])=[CH:13][CH:12]=1.[Na]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:15]([S:16][CH:15](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Br)cc1
Reactant: SCc1ccc(Cl)cc1
Agent: [Na]
Product: Clc1ccc(C(/C=C\c2ccc(Br)cc2)SC(/C=C\c2ccc(Br)cc2)c2ccc(Cl)cc2)cc1

Procedure:
A solution of 4-bromophenylacetylene (0.02 mol) and 4-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-bromostyryl 4-chlorobenzylsulfide. The title compound was obtained in 87% yield following oxidation. 1HNMR (CDC13) δ 4.58 (2H, s), 6.72 (1H, d, JH,H=12.08), 7.15-7.68 (8H aromatic+1H ethylenic).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][C:4]=1[OH:13].[C:14]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[OH:25])([CH3:17])([CH3:16])[CH3:15].[OH-].[Na+].Cl>O>[OH:25][C:19]1[C:18]([C:14]([CH3:16])([CH3:15])[CH3:17])=[CH:23][C:22]([CH3:24])=[CH:21][C:20]=1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][C:4]=1[OH:13]
Reactant: CC(C)(C)c1ccc(CO)c(O)c1
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(Cc2ccc(C(C)(C)C)cc2O)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 36 %

Procedure:
In a 300 ml eggplant-type flask equipped with a Dimroth condenser, 10.3 g (0.057 mol) of intermediate 2-(hydroxymethyl)-5-t-butylphenol and 10.2 g (0.062 mol) of 2-t-butyl-4-methylphenol were suspended in 60 ml of water. To this suspension, an aqueous solution having 10.2 g (0.26 mol) of sodium hydroxide dissolved in 50 ml of water, was added, and the mixture was stirred by a magnetic stirrer. This mixture was heated to a temperature of from 100° to 110° C. and stirred at that temperature for 17.5 hours. The reaction mixture was cooled to room temperature, acidified by concentrated hydrochloric acid and then extracted with ethyl acetate. The obtained ethyl acetate solution was washed with water and then dried over anhydrous magnesium sulfate. From the solution having the anhydrous magnesium sulfate removed, ethyl acetate was distilled off, and the obtained residue was roughly separated by silica gel column chromatography. To the obtained brown highly viscous oil, n-hexane was added and left to stand still to obtain 6.7 g (0.021 mol, yield: 36.0%) of (2-hydroxy-3-t-butyl-5-methylphenyl)-(2-hydroxy-4-t-butylphenyl)methane as a white solid. By 1HNMR, this solid was confirmed to be the desired product.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C([Li])CCC.[I:25]I.S([O-])([O-])(=O)=S.[Na+].[Na+].N>O1CCCC1>[CH3:7][C:4]1[N:3]([C:8]2[CH:12]=[C:11]([I:25])[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: II
Reactant: Cc1ccc(C)n1-c1ccn(-c2cccc(F)c2)n1
Agent: N
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(I)n(-c2cccc(F)c2)n1
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a solution of 3-(2,5-dimethylpyrrol-1-yl)-1-(3-fluorophenyl)-1H-pyrazole (10.4 g) in tetrahydrofuran (100 ml) cooled to −78° C. was added n-butyllithium (1.6M solution in n-hexane, 31 ml) over 10 minutes, and then the mixture was stirred for 30 minutes. To the mixture was added dropwise a solution of iodine (12.4 g) in tetrahydrofuran (20 ml) over 10 minutes, and the mixture was stirred for additional 30 minutes. To the mixture were sequentially added a 20 wt % aqueous solution of sodium thiosulfate and a saturated aqueous ammonia, and then the mixture was warmed to room temperature, and extracted with ethyl acetate. The separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the resulting residue was added a mixed solvent of n-hexane/ethyl acetate (2/1), and the mixture was stirred. The insoluble substance was collected by filtration, and dried under reduced pressure to give the titled compound (4.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:21][CH3:22])[C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH2:19][OH:20])[N:13]=1.[H-].[Na+].I[CH3:26].O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:21][CH3:22])[C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH2:19][O:20][CH3:26])[N:13]=1
Reactant: CI
Reactant: CCN(c1nc(C)cc(CO)n1)c1ccc(C(C)C)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(c1nc(C)cc(COC)n1)c1ccc(C(C)C)cc1Br

Procedure:
To the product of Example 24 and sodium hydride (1.1 eq.) in dry THF under nitrogen was added iodomethane (1.1 eq.) and after four hours the reaction was poured into H2O and extracted three times with CHCl3. The combined extracts were dried over MgSO4, filtered, and evaporated under vacuum. The material was purified by chromatography on silica gel using 10% EtOAc in hexanes to give a light yellow oil. (Rf =0.37)
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[NH:6][CH2:5][CH2:4][O:3]1.C1C=CC=CC=1.C(N(CC)CC)C.[Cl:21][CH:22]([Cl:26])[C:23](Cl)=[O:24]>O>[CH3:1][C:2]1([CH3:7])[N:6]([C:23](=[O:24])[CH:22]([Cl:26])[Cl:21])[CH2:5][CH2:4][O:3]1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC1(C)NCCO1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)OCCN1C(=O)C(Cl)Cl

Procedure:
Five and one-tenth (5.1 g.) grams of 2,2-dimethyl oxazolidine dissolved in 50 ml. of benzene was treated with 5.5 g. of triethylamine and 7.4 g. of dichloroacetyl chloride was added dropwise with stirring and cooling in an ice bath. The mixture was poured into water, the benzene solution separated, dried over anhydrous magnesium sulfate and the solvent stripped under vacuum. The product was a waxy solid which had a melting point of 113°-115° C. on recrystallization from diethyl ether.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].Cl.[NH2:6][CH:7]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=O.C([O-])(O)=O.[Na+]>Cl>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[NH:3][C:2](=[S:1])[NH:6][C:7]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[CH:15][CH:14]=1
Reactant: COc1cc(C(N)C(=O)c2ccc(F)cc2)ccn1
Reactant: N#C[S-]
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Product: COc1cc(-c2[nH]c(=S)[nH]c2-c2ccc(F)cc2)ccn1

Procedure:
Potassium thiocyanate (2 g, 20.6 mmol) was introduced into a solution of 23d (3.2 g; 10.8 mmol) in 10% strength hydrochloric acid (50 ml). The reaction mixture was stirred under reflux for 30 min. The orange solution was cooled and neutralized using 10% strength NaHCO3 solution. The precipitate was filtered off, washed with H2O and dried under reduced pressure over CaCl2. The crude product was triturated with ethanol, and insoluble components were filtered off. On standing, 24d precipitated from the ethanolic filtrate.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([OH:21])[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.Br[C:23]1[CH:28]=[CH:27][C:26]([CH:29]([F:31])[F:30])=[CH:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][C:23]3[CH:28]=[CH:27][C:26]([CH:29]([F:31])[F:30])=[CH:25][CH:24]=3)[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1
Reactant: FC(F)c1ccc(Br)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(F)F)cc3)c3c(c2)OC(C)(C)C3)n1
Temperature: 160 °C
Yield: 12.1 %

Procedure:
A mixture of 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (102 mg, 0.36 mmol), 1-bromo-4-difluoromethyl benzene (110 mg, 0.53 mmol), Cs2CO3 (174 mg, 0.53 mmol) and CuI (1 mg) in DMF (5 mL) was heated for 2 hr at 160° C. in the microwave. The mixture was filtered and the filtrate was purified by reverse phase chromatograph to give a white solid (18 mg, 12% yield). 1H NMR (400 MHz, CDCl3) δ 9.92 (d, J=2.02 Hz, 1 H) 8.52 (s, 1 H) 7.72 (dd, J=10.36, 1.77 Hz, 1 H) 7.64 (d, J=8.34 Hz, 1 H) 7.28 (s, 1 H) 7.09 (t, J=7.96 Hz, 1 H) 7.05 (s, 1 H) 6.97 (s, 1 H) 6.77 (d, J=2.02 Hz, 1 H) 3.78 (s, 3 H) 2.98 (s, 2 H) 1.51 (s, 6 H); LCMS for C22H21F2N3O3 m/z 414.00 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:36]1[CH2:37][CH2:38][N:33]([C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:34][CH:35]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1S(=O)(=O)c1ccc(C)cc1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)ccc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
5-Bromo-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester (844 mg, 2.0 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (742 mg, 2.4 mmol), potassium phosphate (848 mg, 4.0 mmol), and tetrakis(triphenylphosphine) palladium (116 mg, 0.1 mmol) were placed into a flask. After deaeration, the air was replaced with nitrogen. Anhydrous dioxane (16 ml) and water (4 ml) were added to the flask, and this was stirred at 80° C. for 15 hours. After cooling it to room temperature, the reaction mixture was filtered through Celite, and then washed with ethyl acetate. The filtrate was concentrated, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography. Thus, 5-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester was obtained as a colorless amorphous material (1.0 g, 97.2%).