Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[F:10][C:4]1[CH:3]=[C:2]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[C:18]([O:19][CH3:20])[CH:17]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Nc1c(F)cc(Br)cc1F
Product: COc1ccc(-c2cc(F)c(N)c(F)c2)cc1OC
Yield: 30.6 %

Procedure:
The title compound (39 mg) was prepared from 4-bromo-2,6-difluoroaniline (100 mg, 0.48 mmol) and 3,4-dimethoxyphenylboronic acid (113 mg, 0.62 mmol) as a pale-yellow solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.25 (dd, J 2, 8.3, 2H), 7.18-7.10 (m, 2H), 6.94 (d, J 8.4, 1H), 5.21 (s, 2H), 3.81 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.Cl[C:9]1[CH:10]=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[C:13]([O:15][CH3:16])[CH:14]=1>>[CH3:7][C:5]1[NH:4][N:3]=[C:2]([O:1][C:9]2[CH:10]=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[C:13]([O:15][CH3:16])[CH:14]=2)[CH:6]=1
Reactant: Cc1cc(O)n[nH]1
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Product: COc1cc(Oc2cc(C)[nH]n2)ccc1[N+](=O)[O-]
Yield: 13.2 %

Procedure:
Reaction of 3-hydroxy-5-methylpyrazole with 5-chloro-2-nitroanisole was carried out in the same manner as Example 3, to give a yellow viscous substance of 5-methyl-3-(3-methoxy-4-nitrophenyloxy)pyrazole (yield: 13.2%). 1H-NMR (CDCl3, TMS, ppm): δ 2.34 (s, 3H), 3.93 (s, 3H), 5.74 (s, 1H), 6.70 (dd, J=2.4 and 9.1 Hz, 1H), 6.85 (d, J=2.4 Hz, 1H), 7.95 (d, J=9.1 Hz, 1H), 9.45 (br s, 1H).
Reaction SMILES: [S:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)(=[O:4])(=[O:3])[NH2:2].Cl[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([S:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=2[F:36])[N:20]=1>>[F:36][C:30]1[C:31]([F:35])=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][S:27][C:21]1[N:20]=[C:19]([NH:2][S:1]([N:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]2)(=[O:3])=[O:4])[CH:24]=[C:23]([O:25][CH3:26])[N:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(N)(=O)=O)CC1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Product: COc1cc(NS(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared from 1,1-dimethylethyl 4-sulfamoylpiperazine-1-carboxylate (the product of example 15, step i), 0.22 g) and 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of Example 35, step i) (0.25 g) according to the procedure outlined in Example 1, step iv). The crude material was purified by column chromatography on silica gel using EtOAc/isohexane (2:8) as eluent. Yield: 0.36 g
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[O:14][CH:11]1[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([Mg]Cl)[CH:16]=[CH2:17]>O1CCCC1>[CH2:17]([C:10]([OH:14])([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:11][CH2:12][OH:13])[CH:16]=[CH2:15]
Reactant: C=CC[Mg]Cl
Reactant: OCC1OC1COCc1ccccc1
Solvent: C1CCOC1
Product: C=CCC(O)(CCO)COCc1ccccc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A solution of 4-benzyloxy-2,3-epoxy-1-butanol (6.28 g, 32.37 mmol) in anhydrous tetrahydrofuran (75 mL) was added dropwise at -40° C. over a period of 45 minutes, to a 2M solution of allyl magnesium chloride (48.5 mL, 97 mmol) and tetrahydrofuran (50 mL). The solution was stirred at -40° C. for 1 hour, warmed to 0° C. and quenched by addition of aqueous ammonium chloride solution. The tetrahydrofuran layer was separated and the aqueous layer was extracted with ethyl acetate (three times). The combined organic extract was dried (magnesium sulfate), filtered and concentrated to obtain a mixture of compounds A and B.
Reaction SMILES: [CH2:1]([C:8]1([CH2:19][N:20]([CH3:22])[CH3:21])[CH2:13][CH2:12][C:11]([N:16]([CH3:18])[CH3:17])([C:14]#N)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([Mg]Cl)[CH:28]=[CH:27]C=[CH:25][CH:24]=1.[NH4+].[Cl-].O>C1COCC1>[CH2:1]([C:8]1([CH2:19][N:20]([CH3:21])[CH3:22])[CH2:13][CH2:12][C:11]([N:16]([CH3:17])[CH3:18])([C:14]2[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: CN(C)CC1(Cc2ccccc2)CCC(C#N)(N(C)C)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CC1(Cc2ccccc2)CCC(c2ccccc2)(N(C)C)CC1
Reaction time: 8 h

Procedure:
The title compound of step 1 (0.88 g, 2.94 mmol) was dissolved in THF (35 mL) and mixed in drops with 2M phenylmagnesium chloride solution (5.1 mL, 10.2 mmol) with ice cooling. The reaction solution was heated to boiling for 8 h. For work up the solution was mixed with 20% NH4Cl solution (0.6 mL) and water (0.4 mL) with ice cooling, extracted with ether (3×25 mL), the ether solution was washed with water, dried (Na2SO4) and concentrated to low volume in a vacuum. The residue was purified by column chromatography with EtOH/EE (1:20). 2 fractions were obtained, wherein according to LCMS, inter alia, the more polar fraction (300 mg) contained the desired substance.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[CH:21][CH:22]=3)[N:17]([C:32]3[N:37]=[CH:36][N:35]=[C:34]([NH:38][CH3:39])[CH:33]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:20]2[CH:19]=[C:18]3[C:23]([C:15]([C:11]4[CH:10]=[C:9]([NH:8][C:1](=[O:3])[CH3:2])[CH:14]=[CH:13][CH:12]=4)=[CH:16][N:17]3[C:32]3[CH:33]=[C:34]([NH:38][CH3:39])[N:35]=[CH:36][N:37]=3)=[CH:22][CH:21]=2)=[CH:29][CH:28]=1
Reactant: CNc1cc(-n2cc(-c3cccc(N)c3)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNc1cc(-n2cc(-c3cccc(NC(C)=O)c3)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
Acetic anhydride (20.3 μL, 0.214 mmol) was added to a mixture solution of 6-(3-(3-aminophenyl)-6-(4-methoxyphenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine (30 mg, 0.071 mmol) and pyridine (28.7 μL, 0.355 mmol) in methylene chloride (2 mL) at room temperature. After stirring for 1 hour at room temperature, the reaction solution was added to saturated sodium bicarbonate aqueous solution and then extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The residue was purified by chromatography (preparative HPLC). The target compound (15 mg) was obtained as white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[CH:5]=1.[CH3:17][O:18][C:19](=[O:54])[NH:20][C@H:21]([C:25]([N:27]1[CH2:31][C@@H:30]([S:32][CH3:33])[CH2:29][C@H:28]1[C:34]1[NH:35][CH:36]=[C:37]([C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:41][CH:40]=2)[N:38]=1)=[O:26])[CH:22]([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:42]2[CH:43]=[CH:44][C:39]([C:37]3[N:38]=[C:34]([C@@H:28]4[CH2:29][C@H:30]([S:32][CH3:33])[CH2:31][N:27]4[C:25](=[O:26])[C@@H:21]([NH:20][C:19]([O:18][CH3:17])=[O:54])[CH:22]([CH3:24])[CH3:23])[NH:35][CH:36]=3)=[CH:40][CH:41]=2)=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[CH:5]=1)=[O:16]
Reactant: COC(=O)c1ccc(Br)c(OC(F)(F)F)c1
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](SC)C[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](SC)C[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)OC)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 100 °C

Procedure:
To a mixture of 4-bromo-3-trifluoromethoxy-benzoic acid methyl ester (184 mg, 0.62 mmol), [(S)-2-methyl-1-((2S,4S)-4-methylsulfanyl-2-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (300 mg, 0.55 mmol) and potassium carbonate (344 mg, 2.49 mmol) at RT was added toluene (1.35 mL) followed by water (0.69 mL). The reaction mixture was purged with nitrogen, Pd(dppf)Cl2CH2Cl2 (27.4 mg, 0.034 mmol) was added under an atmosphere of nitrogen. The reaction vial was capped and heated at 100° C. overnight, cooled to RT and partitioned between EtOAc (10 mL) and water (2 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give a brownish oil which was purified by silica gel chromatography (12 g silica gel, 0-100% EtOAc/Hexanes). Desired fractions were combined and concentrated to give the title intermediate as an orange oil. (m/z): [M+H]+ calcd for C30H33F3N4O6S 635.21. found 635.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[CH:6]=1.[N+]([O-])([O-])=[O:12].[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(O)(=O)C.O.O>[Cl:1][C:2]1[S:3][C:4]2[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:5]=2[CH:6]=1
Reactant: Clc1cc2c(s1)CCCC2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCCc2cc(Cl)sc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
10.0 g (57.9 mmol) of 2-chloro-4,5,6,7-tetrahydro-1-benzothiophene are dissolved in acetic acid/water (247 ml/82 ml), 127 g (231 mmol) of ammonium cerium (IV) nitrate in water (50 ml) are added and the mixture is stirred at room temperature for 5 h. The reaction mixture is added to ice-water and extracted with dichloromethane. After washing with water, the organic phase is dried over sodium sulphate and concentrated under reduced pressure. This gives 5.60 g of 2-chloro-5,6-dihydro-1-benzothiophen-7(4H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:7][CH:6]=[CH:5][C:4]=1[N+:16]([O-])=O.O.NN>[Ni].C(O)C>[CH3:1][O:2][C:3]1[C:8]([N:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:16]
Reactant: COc1c(N2CCN(C)CC2)cccc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1c(N)cccc1N1CCN(C)CC1
Yield: 67 %

Procedure:
Compound 54A is prepared according to the procedure described for compound 33C, using the following reactants: 2-methoxy-3-(4-methylpiperazin-1-yl)-1-nitrobenzene (3.6 g); hydrazine hydrate (4 ml); ethanol (50 ml); Raney nickel (one spatula-ful). The crude product is purified by flash chromatography with a mixture (90/9/1) of dichloromethane/methanol/aqueous ammonia).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:21])=[C:6]([CH:10]=[C:11]2[C:15](=[O:16])[NH:14][N:13]=[C:12]2[O:17][CH:18]([CH3:20])[CH3:19])[NH:7][C:8]=1[CH3:9])([OH:3])=[O:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH3:33][N:34]([CH2:36][CH2:37]O)[CH3:35]>ClCCl>[CH3:33][N:34]([CH3:35])[CH2:36][CH2:37][O:2][C:1]([C:4]1[C:5]([CH3:21])=[C:6]([CH:10]=[C:11]2[C:15](=[O:16])[NH:14][N:13]=[C:12]2[O:17][CH:18]([CH3:19])[CH3:20])[NH:7][C:8]=1[CH3:9])=[O:3]
Reactant: CN(C)CCO
Reactant: Cc1[nH]c(C=C2C(=O)NN=C2OC(C)C)c(C)c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1[nH]c(C=C2C(=O)NN=C2OC(C)C)c(C)c1C(=O)OCCN(C)C
Reaction time: 24 h

Procedure:
A mixture of 4-[(4-carboxy-3,5-dimethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one (200 mg, 0.68 mmol) in dichloromethane (20 ml) and a drop of DMF, was treated with oxalyldichloride (0.2 ml). The stirring was continued for 24 h and a solution of dimethylaminoethanol (0.6 g, 6.7 mmol) in dichloromethane (5 ml) was added. The stirring was continued for 24 h. The solvent was evaporated to dryness, the solid residue was treated with NaHCO3 (5%) and extracted with dichloromethane. The solid obtained after elimination of the solvent was recrystallized from n-heptane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C@@H:12]2[O:16][CH2:15][C@@H:14]([S:17]C(=O)C)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[O-].[Na+].CO>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C@@H:12]2[O:16][CH2:15][C@@H:14]([SH:17])[CH2:13]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(=O)S[C@@H]1CO[C@@H](CS(=O)(=O)c2ccc(F)cc2)C1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(C[C@H]1C[C@H](S)CO1)c1ccc(F)cc1
Yield: 63.1 %

Procedure:
The title compound is prepared by the procedure of Example 16 using 0.955 g of product from Example 31, 0.72 ml of 25% sodium methoxide/methyl alcohol and 10 ml of tetrahydrofuran to give 0.523 g of the desired product.
Reaction SMILES: Cl.[F:2][C:3]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]=2[C:8]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])=[N:7]1.[CH3:28][N:29]1[C:33]([C:34](Cl)=[O:35])=[CH:32][N:31]=[CH:30]1.C(N(CC)CC)C>C(Cl)Cl>[F:2][C:3]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:34]([C:33]3[N:29]([CH3:28])[CH:30]=[N:31][CH:32]=3)=[O:35])[CH2:10][C:9]=2[C:8]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])=[N:7]1
Reactant: Cn1cncc1C(=O)Cl
Reactant: N#Cc1cccc(-c2nn(Cc3ccc(F)cc3F)c3c2CNCC3)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cncc1C(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2Cc2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
A mixture of 3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (7c) (0.04 g, 0.114 mmol), 3-Methyl-3H-imidazole-4-carbonyl chloride (0.083 g, 0.457 mmol) and triethylamine (138 mg, 1.37 mmol) in CH2Cl2 was stirred at 25° C. for 16 h. The crude product was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 43 mg of 3-[1-(2,4-Difluoro-benzyl)-5-(3-methyl-3H-imidazole-4-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (8w).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](OCC)=[O:17])=[CH:10][N:9]=1>C1COCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][N:9]=1
Reactant: CCOC(=O)CCc1ccc(Cl)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCc1ccc(Cl)nc1
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a suspension of 0.2 g of LAH in 25 ml of dry THF at 0° C. under nitrogen was added a solution of 1.11 g (5.2 mmol) of ethyl 3-(2-chloropyridin-5-yl)-propionate in 5 ml of THF. The reaction mixture was kept at 3° C.-5° C. for 1 h and quenched with 0.2 ml of water, 0.2 ml of 10% NaOH, and 0.6 ml of water successively. The mixture was filtered through celite (washing with ether) and the filtrate was concentrated in vacuo to yield 0.87 g (theory) of 2-chloro-5-(3-hydroxypropyl)-pyridine as a yellow viscous oil (crude).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([CH3:12])[C:8]2=[O:11])=[CH:4][C:3]=1[O:13][CH3:14].Cl[C:16]1[N:21]=[C:20]([NH:22][CH3:23])[C:19]([C:24]([F:27])([F:26])[F:25])=[CH:18][N:17]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1.C(Cl)Cl>[CH3:14][O:13][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:16]1[N:21]=[C:20]([NH:22][CH3:23])[C:19]([C:24]([F:27])([F:25])[F:26])=[CH:18][N:17]=1)[C:8](=[O:11])[N:7]([CH3:12])[CH2:6]2
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Reactant: COc1cc2c(cc1N)C(=O)N(C)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNc1nc(Nc2cc3c(cc2OC)CN(C)C3=O)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 13 %

Procedure:
A mixture of impure 6-amino-5-methoxy-2-methylisoindolin-1-one (<0.57 mmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (66 mg, 0.31 mmol) and pTSA (59 mg, 0.31 mmol) in dioxane (4 mL) was heated to 100° C. for 4 h. DCM (10 mL) and saturated aqueous NaHCO3 (10 mL) were added and the organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via reversed phase preparative HPLC gave 5-methoxy-2-methyl-6-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)isoindolin-1-one (15 mg, 13%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=368 at 2.89 min. 1H NMR (400 MHz, CDCl3): δ 9.04 (s, 1H), 8.17 (s, 1H), 7.80 (s, 1H), 6.93 (s, 1H), 5.26 (br s, 1H), 4.31 (s, 2H), 3.97 (s, 3H), 3.20 (d, J 4.7, 3H), 3.18 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH3:21][O:22][C:23]1[N:28]=[C:27]([CH2:29]O)[CH:26]=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC>C1COCC1.[Cl-].[Na+].O>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:29][C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[N:28]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: COc1cccc(CO)n1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Agent: CCCCP(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 3.2 %

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (100 mg, 0.4 mmol), (6-methoxy-pyridin-2-yl)-methanol (example 10-75a) (101 mg, 0.7 mmol), tributylphosphine (147 mg, 0.7 mmol), and 1,1″″-azobis(N,N-dimethylformamide) (125 mg, 0.7 mmol) were dissolved in THF (5 mL) and stirred at room temperature for 15 hours. The reaction was diluted with brine (100 mL) and extracted with ethyl acetate (2×, 100 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated on the rotovap. The residue was taken up in methanol (5 mL) and purified by reversed phase HPLC (5 to 95% acetonitrile in H2O: 25 minute gradient). The pure fractions were combined, concentrated then re-dissolved in ethyl acetate/hexane (1:9). The solution was cooled at 5° C. for 15 hrs, where a white solid formed. The precipitate was collected to afford 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-((6-methoxypyridin-2-yl)methyl)imidazolidine-2,4-dione (5 mg, 4%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ2.11 (s, 3H), 2.37 (s, 3H), 3.74 (s, 3H), 4.17 (s, 2H), 4.54 (s, 2H), 5.17 (s, 2H), 6.69 (d, J=7.6 Hz, 1H), 6.96 (d, J=6.8 Hz, 1H), 7.67 (d, J=6.8 Hz, 1H), 7.76 (s, 1H), 8.17 (s, 1H). MS M+H calculated 397.2; found 397.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.23 μM.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.Cl[C:13]1[CH:18]=[N:17][CH:16]=[CH:15][N:14]=1>C1(C)C=CC=CC=1>[N:14]1[CH:15]=[CH:16][N:17]=[CH:18][C:13]=1[NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][CH:3]=1
Reactant: Clc1cnccn1
Reactant: Nc1ccc(C(F)(F)F)nc1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(Nc2cnccn2)cn1
Temperature: 95 °C

Procedure:
To a solution of 5-amino-2-trifluoromethylpyridine (0.81 g) in 3 Ml toluene was added chloropyrazine (0.45 Ml, 1.0 equiv) via syringe. The homogeneous solution was heated to 95° C., then cooled to room temperature and concentrated in vacuo. Purification by silica gel chromatography (40% EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 7.5 (s, 1H) 7.6 (s, 1H) 8.0 (s, 1H) 8.2 (s, 1H) 8.4 (s, 2H) 8.8 (s, 1H); (M+H)+241.1.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[OH:19])[CH2:11][C@H:10]1[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CS(C)=O>[CH2:1]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[O:19][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:11][C@H:10]1[OH:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc2c1C[C@@H](NCc1ccccc1)[C@H](O)C2
Reactant: CCOC(=O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)COc1cccc2c1C[C@@H](NCc1ccccc1)[C@H](O)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
To a stirring solution of trans 3-benzylamino-2,5-dihydroxy-1,2,3,4-tetrahydronaphthalene (14 g) in dry dimethylsulfoxide (150 mL) was added sodium methoxide (3.05 g). This was stirred for 10 min at room temperature, then cooled in a 10° C. bath while ethyl bromoacetate (9.1 g) was added over 3 min, during which the temperature of the mixture remained below 25° C. The cooling bath was removed, and the reaction mixture was stirred for 4.5 h at room temperature under nitrogen. Dilution with a half-saturated aqueous sodium bicarbonate solution (800 mL) was followed by extraction with diethyl ether (250 mL four times). The combined extracts were washed sequentially with cold 5% aqueous sodium hydroxide solution, water (300 mL twice), and brine and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum to provide crude product. The crude product was recrystallized from 50% ethyl acetate in hexane (100 mL) to yield the title product (13 g) as a white solid (mp 93-97° C.).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9](I)=[C:8]([CH3:12])[C:6]=2[N:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([C:23]3[CH:22]=[N:21][C:20]([F:19])=[CH:25][CH:24]=3)=[C:8]([CH3:12])[C:6]=2[N:7]=1
Reactant: Cc1c(I)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: OB(O)c1ccc(F)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1c(-c2ccc(F)nc2)sc2c(N3CCOCC3)nc(Cl)nc12

Procedure:
2-Chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine (1 eq), 2-fluoro-5-pyridineboronic acid (1.1 eq) and bis(triphenylphosphine)palladium(II) dichloride (0.1 eq) in 1M Na2CO3 aqueous solution (3 eq) and an equal volume of acetonitrile was heated to 100° C. in a sealed microwave reactor for 30 min. Reaction mixture was concentrated, then crude product was purified by flash chromatography to give 4-(2-chloro-6-(6-fluoropyridin-3-yl)-7-methylthieno[3,2-d]pyrimidin-4-yl)morpholine. MS (Q1) 365 (M+)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[C:8]([Mg]Br)#[CH:9].[Cl-].[NH4+]>C1COCC1>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]([OH:7])[C:8]#[CH:9])=[CH:2]1
Reactant: C#C[Mg]Br
Reactant: O=Cc1ccoc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)c1ccoc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-furaldehyde (25.0 g, 0.26 mol) in THF (250 mL) at 78° C. was added ethynylmagnesium bromide (572 mL, 0.286, 0.5M THF) at the rate of 10 mL per minute. The mixture was slowly warmed to room temperature, stirred for 1 hour and then poured into a cooled ammonium chloride solution. The mixture was extracted with ethyl acetate, and the organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was distilled at 50°-55° C. and 0.24 mmHg to afford 1-(3-furyl)-1-hydroxy-2-propyne.