Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](I)[CH:7]=1.[N:9]1([CH2:14][CH2:15][N:16]2[CH:20]=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:18]=[N:17]2)[CH2:13][CH2:12][CH2:11][CH2:10]1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:19]2[CH:18]=[N:17][N:16]([CH2:15][CH2:14][N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[CH:20]=2)[CH:7]=1
Reactant: CC1(C)OB(c2cnn(CCN3CCCC3)c2)OC1(C)C
Reactant: Brc1cncc(I)c1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Brc1cncc(-c2cnn(CCN3CCCC3)c2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A solution of 5.43 g (19.1 mmol) 3-bromo-5-iodo-pyridine and 6.12 g (21.0 mmol) 1-(2-pyrrolidin-1-yl-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazol in 17 ml 1,2-dimethoxyethan was treated with 8.12 g (38.2 mmol) tri-potassium-phosphate-trihydrate and was heated to 80° C. under nitrogen. Then 403 mg (0.57 mmol) bis(triphenyl-phosphine)palladium(II)-chloride were added. The reaction mixture was stirred for 18 hours at 80° C. The reaction mixture was partitioned between water and dichloromethane. The organic phase was extracted several times with 1 N HCl and was washed with water. The aqueous phases were combined, basified with 50% aqueous NaOH. Brine and THF were added. The organic phase was separated and the aqueous phase was extracted several times with THF. The combined organic phases were dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column with dichloromethane/methanol as eluent yielding 3-bromo-5-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-pyridine as brown oil; HPLC-MS: 1.29 min, [M+H] 321/323.
Reaction SMILES: [N:1]([CH2:8][CH2:9][OH:10])([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:11]12[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH:16]C(=O)[O:14][C:12]2=[O:13].N12CCN(CC1)CC2.CN(C)C=O>O.CO>[C:12]([OH:14])(=[O:13])[C:11]1[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH2:16].[C:12]([OH:14])(=[O:13])[C:11]1[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH2:16].[C:12]([OH:14])(=[O:13])[C:11]1[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH2:16].[N:1]([CH2:8][CH2:9][OH:10])([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: C1CN2CCN1CC2
Solvent: OCCN(CCO)CCO
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccccc1C(=O)O
Temperature: 120 °C
Yield: 90.3 %

Procedure:
Into a 1 liter round bottom flask equipped with mechanical stirrer, dropping funnel, and thermometer was charged triethanolamine (149.2 grams, 1.0 mol; obtained from Sigma-Aldrich), isatoic anhydride (520.0 grams, 3.5 mol), 1,4-diazabicyclo[2.2.2]octane (DABCO) (45.0 grams, 0.4 mol), and dimethylformamide (1,500 milliliters). The mixture was stirred and heated to 120° C. for a period of about 2 hours. The mixture was then cooled to room temperature, and methanol (2 liters) was added. Deionized water (1 liter) was added, causing the solution to turn cloudy. This solution was stirred for 2 hours, and then filtered, washed with 5×250 milliliters of methanol, and oven dried at 60° C. to yield 506 grams of a beige solid.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8]2)=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[C:13]1([CH:9]2[CH2:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:19]=[CH:20][C:2]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22]([F:33])([F:32])[F:21])=[CH:3][CH:4]=3)[CH2:8]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Brc1ccc(CN2CCCC(c3ccccc3)C2)cc1
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: CCO
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccccc1-c1ccc(CN2CCCC(c3ccccc3)C2)cc1
Temperature: 120 °C
Yield: 100 %

Procedure:
100 mg of 1-(4-Bromo-benzyl)-3-phenyl-piperidine was combined with 862 mg of 2-(Trifluoromethyl)phenyl boronic acid, 35 mg of tetrakis(triphenylphosphine)palladium(0), 1.015 mL of 2M sodium carbonate solution, 2.7 mL toluene and 1.4 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was purified by reverse phase HPLC. ES MS (+) m/z 396, 100% yield
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=O)=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.2 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (52 mg, 45%).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C:3]([O:5][CH2:6][N:7]1[C:15]2[N:14]=[CH:13][NH:12][C:11]=2[C:10](=[O:16])[N:9]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:8]1=[O:25])=[O:4].[CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)=[O:29].N1C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:22][C:20]([CH3:21])([CH3:23])[C:19]([O:18][CH2:17][N:9]1[C:10](=[O:16])[C:11]2[N:12]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH:28]=[O:29])[CH:13]=[N:14][C:15]=2[N:7]([CH2:6][O:5][C:3](=[O:4])[C:2]([CH3:27])([CH3:26])[CH3:1])[C:8]1=[O:25])=[O:24]
Reactant: CC(C)(C)C(=O)OCn1c(=O)c2[nH]cnc2n(COC(=O)C(C)(C)C)c1=O
Reactant: O=Cc1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCn1c(=O)c2c(ncn2-c2ccccc2C=O)n(COC(=O)C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 37 h
Yield: 31.7 %

Procedure:
2,2-Dimethylpropionic acid [3-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydropurin-1-yl]methyl ester (10.2 g), 2-formylphenylboronic acid (8.04 g), and copper(II) acetate (7.30 g) were suspended in N,N-dimethylformamide (50 ml), pyridine (4.34 ml) was added thereto, and the mixture was stirred at room temperature for 37 hours. The reaction mixture was diluted with ethyl acetate; and washed with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 4.12 g of the title compound from the elution fraction of hexane-ethyl acetate (1:2).
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6](=[S:9])SC)([OH:3])=[O:2].[N-:10]=[N+:11]=[N-:12].[Na+]>O>[C:1]([CH2:4][N:5]1[C:6]([SH:9])=[N:12][N:11]=[N:10]1)([OH:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CSC(=S)NCC(=O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)Cn1nnnc1S

Procedure:
A mixture of 16.5 g. (0.1 mol.) of methyl carboxymethyldithiocarbamate and 14.3 g. (0.22 mol.) of sodium azide in 150 ml. of water was heated at 56° for 12 hours. The reaction mixture was extracted with ether, then acidified to pH 1.5 with dilute hydrochloric acid and extracted with ethyl acetate. The extract was dried (MgSO4) and evaporated to dryness to give 1-carboxymethyl-tetrazole-5-thiol, m.p. 178°-179°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH2:24])=[N:9]3)=[N:6][CH:7]=1.C(O)C>C(=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH2:24])=[N:9]3)=[N:6][CH:7]=1
Reactant: NC1=NC2(c3ccc(F)cn3)CN(c3ncc(F)cn3)CC2CS1
Agent: O=C=O
Solvent: CCO
Product: NC1=N[C@@]2(c3ccc(F)cn3)CN(c3ncc(F)cn3)C[C@H]2CS1
Yield: 39.7 %

Procedure:
Racemic 7a-(5-fluoro-2-pyridyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine (60 mg, 0.172 mmol) is separated into its constituent enantiomers by chiral SFC (Column: Chiralpak AD-H (5μ), 21.2×250 mm; eluent: 40% ethanol (0.2% diethylmethylamine) in CO2; flow: 70 mL/min at UV 260 nm). The second eluting isomer is the title compound (23.8 mg). ES/MS (m/e): 349 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]C)=[C:9]([F:15])[CH:8]=1)C.B(Br)(Br)Br.CO>C(Cl)Cl>[CH3:1][O:3][C:4](=[O:17])[CH:5]([CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:15])[CH:8]=1
Reactant: CCOC(=O)C(C)Cc1ccc(OC)c(F)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(C)Cc1ccc(O)c(F)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
After 3-(3-fluoro-4-methoxy-phenyl)-2-methyl-propionic acid ethyl ester (0.728 g, 3.03 mmol) obtained in Step B was dissolved in anhydrous DCM (10 mL), 1M BBr3 solution (4.5 mL, 4.5 mmol) was added thereto at −78° C., and the mixture was stirred at room temperature for 3 hours. After the termination of the reaction, the reactant was added with MeOH, concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex=1/2) to obtain the title compound (0.64 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)=[CH:4][CH:3]=1.[CH:14](=[O:18])[CH:15]([CH3:17])[CH3:16]>>[CH3:16][CH:15]([CH3:17])[CH:14]([C:11]1[N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:13][CH:12]=2)[N:8]=[CH:9][N:10]=1)[OH:18]
Reactant: CC(C)C=O
Reactant: Cc1ccc(Cn2cncn2)cc1
Product: Cc1ccc(Cn2ncnc2C(O)C(C)C)cc1
Yield: 66 %

Procedure:
2-Methyl-1-[1-(4-methylbenzyl)-1H-1,2,4-triazol-5-yl]propan-1-ol was synthesized in a manner similar to that of procedure 21 B but using 1-(4-methylbenzyl)-1H-1,2,4-triazole and isobutyraldehyde as the starting materials. The product was isolated as a white solid in 66% yield.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[Br:19][C:20]1[C:21]([NH2:25])=[N:22][NH:23][CH:24]=1>O1CCCC1>[Br:19][C:20]1[C:21]([NH:25][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])=[N:22][NH:23][CH:24]=1
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: Nc1n[nH]cc1Br
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=CNc1n[nH]cc1Br

Procedure:
The named compound is prepared by substituting 4-bromo-1H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2141 gms. of 4-bromo-1H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: CSC.B.[Br:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:14][C:15](O)=[O:16])[CH:10]=[C:11]([F:13])[CH:12]=1>C1COCC1>[Br:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:14][CH2:15][OH:16])[CH:10]=[C:11]([F:13])[CH:12]=1
Reactant: O=C(O)Cc1cc(F)cc(CBr)c1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCCc1cc(F)cc(CBr)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Borane dimethyl sulfide complex (2M in THF, 26.3 mL) was added dropwise over 10 minutes to a solution of 2-(3-(bromomethyl)-5-fluorophenyl)acetic acid [Aromatic Intermediate 4, step a] (6.5 g) in THF (120 mL) at 0° C. The mixture was stirred at 0° C. for 10 minutes and then at 20° C. for 1 hour. The reaction mixture was quenched by dropwise addition of methanol and the solvents were removed under reduced pressure. The crude product was purified by flash silica chromatography using 30% ethyl acetate in isohexane. Fractions containing the product were concentrated to dryness to afford the titled compound. Yield 4.70 g.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[C:32]([CH3:31])[CH:33]=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: Cc1cccc(B(O)O)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc32)c1
Yield: 45 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 3-methylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (45%).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=[O:5].Cl>[OH-].[Na+]>[OH:12][C:9]1[CH:8]=[C:7]2[C:6]([C:4](=[O:5])[CH2:3][CH2:2][O:13]2)=[CH:11][CH:10]=1
Reactant: O=C(CCCl)c1ccc(O)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCOc2cc(O)ccc21
Reaction time: 2 h

Procedure:
The crude 3-chloro-1-(2,4-dihydroxy-phenyl)-propan-1-one (6.9 g) is dissolved in sodium hydroxide (2N, 100 mL) at 0° C. The solution is stirred for 2 h and acidified with HCl (5N) to pH=3. The mixture is extracted with ethyl acetate (3×50 mL). The combined organic phase is washed with brine and dried over sodium sulfate. After evaporation of solvent, 7-hydroxy-chroman-4-one is obtained as yellow solid: 1H NMR (400 MHz, MeOD) δ 7.70 (d, 1H, J=8.8 Hz), 6.47 (dd, 1H, J=2.4, 8.8 Hz), 6.30 (d, 1H, J=2.0 Hz), 4.47 (t, 2H, J=6.4 Hz), 2.70 (t, 2H, J=6.4 Hz).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:22])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+]>CO>[CH3:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:19])([F:20])[F:21])=[C:8]([CH3:22])[NH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1[nH]c(C)c(-c2ccccc2C(F)(F)F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1[nH]c(C(=O)O)c(C)c1-c1ccccc1C(F)(F)F
Reaction time: 8 h
Yield: 34.3 %

Procedure:
To a solution of 3,5-dimethyl-4-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carboxylic acid ethyl ester (0.96 g) in methanol was added 4 N NaOH (6 mL). The reaction mixture was then heated to reflux with stirring overnight. After cooling, solvent was removed and the crude material was diluted with water. Solids were removed by filtration and washed with water. The aqueous filtrate was acidified with formic acid to precipitate the product. The precipitates were collected by filtration and washed with water, and then dried under high vacuum to afford 3,5-dimethyl-4-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carboxylic acid (0.30 g). MS (ES): 284 (MH+).
Reaction SMILES: CC1[N:3]([C:8]2[CH:17]=[C:11]3[CH:12]([CH3:16])[O:13][CH2:14][CH2:15][N:10]3[N:9]=2)C(C)=CC=1.Cl.NO>C(O)C>[CH3:16][CH:12]1[C:11]2=[CH:17][C:8]([NH2:3])=[N:9][N:10]2[CH2:15][CH2:14][O:13]1
Reactant: Cc1ccc(C)n1-c1cc2n(n1)CCOC2C
Agent: Cl
Agent: NO
Solvent: CCO
Product: CC1OCCn2nc(N)cc21
Temperature: 25 °C
Yield: 8.2 %

Procedure:
A 100-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 150g (550 mg, 1.0 eq., 2.38 mmol), hydroxylamine hydrochloride (827 mg, 5.0 eq., 11.9 mmol), and ethanol (30 mL). The mixture was refluxed for 2 days. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 150h (30 mg, 8%) as a yellow oil. MS-ESI: [M+H]+ 154.1. 1H NMR (500 MHz, CDCl3) δ 5.37 (s, 1H), 4.73 (q, J=7.0 Hz, 1H), 4.26-4.23 (m, 1H), 4.08-4.03 (m, 1H), 3.91-3.90 (m, 1H), 3.90-3.87 (m, 1H), 1.65 (d, J=7.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[C:14](=[O:35])[N:15]([C@@H:31]([CH3:34])[CH2:32][OH:33])[C:16](=[O:30])[N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)[C:18]=3[CH3:19])=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:36][N:37](C)C=O>[C-]#N.[Zn+2].[C-]#N.[Zn].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>[OH:33][CH2:32][C@@H:31]([N:15]1[C:14](=[O:35])[C:13]([C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:36]#[N:37])=[CH:3][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[C:18]([CH3:19])[N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[C:16]1=[O:30])[CH3:34]
Reactant: Cc1c(-c2ccnn2-c2ccc(Br)cc2)c(=O)n([C@@H](C)CO)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n([C@@H](C)CO)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-5-(1-(4-bromophenyl)-1H-pyrazol-5-yl)-3-(1-hydroxypropan-2-yl)-6-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Example 122) (5.0 mg) in N,N-dimethy formamide (1.0 ml) were added zinc cyanide (10.3 mg), zinc dust (1.2 mg) and tetrakis(triphenylphosphine)palladium (5.3 mg) and the resulting mixture was stirred at 120° C. for four hours. The reaction mixture was filtered and thereto was added ethyl acetate (50 ml) and the mixture was washed with water (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (S)-4-(5-(3-(1-hydroxypropan-2-yl)-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (1.9 mg) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C(#N)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-chloroaniline (10.0 g) and triethylamine (16.4 ml) in acetonitrile (80 ml) was added dropwise pivaloyl chloride (14.5 ml) under ice-cooling. The mixture was allowed to warm to room temperature and stirred for 5 hrs. The obtained reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (1500 ml) and water (1500 ml). The organic layer was washed successively with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diethyl ether and hexane to give N-(4-chlorophenyl)-2,2-dimethylpropionamide (15.0 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25]([OH:27])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH2:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][NH:29]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:25]([N:29]3[CH2:30][CH2:31][C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:28]3)=[O:27])[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[O:24])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Reactant: c1ccc2c(c1)CCNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N3CCc4ccccc4C3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)-biphenyl-3-carboxylic acid (50 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) were added 1,2,3,4-tetrahydroisoquinoline (50 mg, 0.38 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (120 μL, 0.69 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction solution was purified by preparative HPLC to afford the final product as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])#[CH:18]>>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]#[C:18][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: C#Cc1ccccc1F
Product: O=c1[nH]c2nccc(C#Cc3ccccc3F)c2c2ccccc12
Yield: 74.7 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using 83 (100 mg, 0.43 mmol) and 1-ethynyl-2-fluorobenzene (0.07 mL, 0.65 mmol) to provide 259 (101 mg, 75% yield) as a tan solid. LC-MS (M+H=315 obsd.=315).
Reaction SMILES: F[B-](F)(F)F.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:15])=[C:11]([N+:13]#[N:14])[CH:12]=1.C([O-])(=O)C.[K+]>C(Cl)(Cl)Cl.C1OCCOCCOCCOCCOCCOC1>[Br:6][C:7]1[CH:12]=[C:11]2[C:10]([CH:15]=[N:14][NH:13]2)=[CH:9][CH:8]=1
Reactant: Cc1ccc(Br)cc1[N+]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: ClC(Cl)Cl
Product: Brc1ccc2cn[nH]c2c1
Reaction time: 2 h
Yield: 86.7 %

Procedure:
5-Bromo-2-methylphenyldiazonium tetrafluoroborate (1.50 g) was added to a mixture of potassium acetate (1.0 g) and 18-crown-6 (70 mg) in chloroform (50 mL) at room temperature in portions and then the reaction was stirred for 2 h. The resulting mixture was filtered and washed with chloroform. The filtrate was concentrated, and the residue was dissolved in diethyl ether, which was then washed with water, brine, dried, and the solvent was removed to give the product 6-bromoindazole (0.9 g). The product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:8]1[CH:12]=[CH:11][NH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]=[O:14]>C(=O)([O-])[O-].[K+].[K+].O1CCCC1>[CH2:1]([C:8]1[CH:12]=[CH:11][NH:10][C:9]=1[CH2:13][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: c1ccc(Cc2cc[nH]c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: OCc1[nH]ccc1Cc1ccccc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 97.2 %

Procedure:
2.18 g (13.9 mmole) of 3-benzylpyrrole, 0.42 g (13.9 mmole) of paraformaldehyde and 0.07 g (0.5 mmole) of anhydrous potassium carbonate are mixed and stirred at 50° C. for 4 hours in the an atmosphere of nitrogen. Dry tetrahydrofuran is added to the reaction solution and filtered. The filtrate is concentrated to obtain 2.53 g of 3-benzyl-1-pyrrolylmethanol as a pale yellow liquid. Yield 97.3%. nD31.5 1.5837.