Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@:9]([CH3:16])([CH:11]([O:14][CH3:15])[O:12][CH3:13])[C@@H:8]3[O:17][C@@H:7]3[C:6]=2[CH:18]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH2:27][C:28]2[N:29]=[N:30][N:31]([CH3:33])[N:32]=2)=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@:9]([CH3:16])([CH:11]([O:14][CH3:15])[O:12][CH3:13])[C@H:8]([OH:17])[C@@H:7]([N:26]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)[CH2:27][C:28]3[N:29]=[N:30][N:31]([CH3:33])[N:32]=3)[C:6]=2[CH:18]=1
Reactant: COC(OC)[C@]1(C)Oc2ccc(Br)cc2[C@H]2O[C@H]21
Reactant: Cn1nnc(CNc2ccc(F)cc2)n1
Product: COC(OC)[C@]1(C)Oc2ccc(Br)cc2[C@H](N(Cc2nnn(C)n2)c2ccc(F)cc2)[C@H]1O
Yield: 53.2 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using (2R,3R,4R)-6-bromo-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (198 mg, 0.63 mmol) and N-(4-fluorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (130 mg, 0.63 mmol). The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=4:1), to give desired compound (175 mg, yield: 53%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([OH:12])=[C:9]([Br:11])[CH:10]=1)=[O:4].[CH3:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH2:19]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)C)=O)=O)(C)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][CH2:19][C:15]2[N:14]([CH3:13])[CH:18]=[CH:17][N:16]=2)=[N:7][CH:6]=1
Reactant: COC(=O)c1cnc(O)c(Br)c1
Reactant: Cn1ccnc1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cnc(OCc2nccn2C)c(Br)c1
Reaction time: 1 h
Yield: 27.1 %

Procedure:
5-Bromo-6-hydroxy-3-pyridinecarboxylic acid methyl ester (1.0 g, 4.3 mmol) was suspended in tetrahydrofurane, 1-methyl-1H-imidazole-2-methanol (0.72 g, 6.5 mmol) and triphenylphosphine was added (1.70 g, 6.5 mmol). To this mixture was added with stirring diisopropyl-azodicarboxylate (1.35 mL, 6.5 mmol) at room temperature. Stirring was continued for 1 h at room temperature, solvent was removed and the residue was purified by chromatography with heptane/ethylacetate/methanol on silica gel to yield 0.38 g of the title compound as a colorless solid, MS (ISP) 326.0, 328.0 (M+H)−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:14])=[C:4]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]=[N:6][CH:7]=1.[CH2:15](OC(OCC)OCC)C>>[Cl:1][C:2]1[C:3]2[N:14]=[CH:15][N:8]([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[C:4]=2[N:5]=[N:6][CH:7]=1
Reactant: Nc1c(Cl)cnnc1NC1CCCC1
Reactant: CCOC(OCC)OCC
Product: Clc1cnnc2c1ncn2C1CCCC1
Temperature: 25 °C
Yield: 51 %

Procedure:
A mixture of 5-chloro-N-3-cyclopentylpyridazine-3,4-diamine (Preparation 12, 1.2 g, 5.64 mmol) and triethylorthoformate (10 mL) were heated to reflux for 1.5 hours. The reaction mixture was allowed to cool to room temperature, concentrated in vacuo and triturated with EtOAc (20 mL). The solid was filtered and the filtrate was reduced to dryness. The crude material was purified by silica gel column chromatography eluting with EtOAc to afford the title compound as a yellow solid in 51% yield, 902 mg.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][N:6]=1)([O:3][CH3:4])=[O:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[N:14]1([C:9]([C:8]2[CH:12]=[CH:13][C:5]([C:1]([O:3][CH3:4])=[O:2])=[N:6][CH:7]=2)=[O:10])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(C(=O)Cl)cn1
Product: COC(=O)c1ccc(C(=O)N2CCOCC2)cn1

Procedure:
In step b, the acid chloride 11 is amidated with morpholine 12 by techniques and procedures well known and appreciated by one of ordinary skill in the art to give the corresponding 5-(morpholine-4-carbonyl)-2-pyridinecarboxylic acid, methyl ester 13.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[N+:9]([C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[CH:14]=[CH:15][CH2:16][OH:17])([O-:11])=[O:10].N1C=CN=C1>CN(C=O)C>[Si:5]([O:17][CH:16]=[CH:15][CH2:14][C:13]1[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=1[N+:9]([O-:11])=[O:10])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1ccccc1C=CCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC=CCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Tert-butyldimethylchlorosilane (5.10 g, 33.8 mmol) was added to a solution of 2-nitrocinnamyl alcohol (5.05 g, 28.2 mmol) and imidazole (2.88 g, 42.3 mmol) in DMF (100 ml). After stirring at room temperature for 18 hours the reaction mixture was partitioned between water (200 ml) and ethyl acetate (200 ml). The organic layer was separated washed with brine (2×m 100 ml) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by flash chromatography on silica gel with ethyl acetate-hexane (1:3) as eluant. (7.82 g, 95%).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[C:25]1[N:30]=[CH:29][C:28]([Br:31])=[CH:27][N:26]=1>O>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:25]3[N:30]=[CH:29][C:28]([Br:31])=[CH:27][N:26]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cnc(N2CCC(N3CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.8 %

Procedure:
4-(Piperidin-1-yl)piperidine (342 mg, 2.03 mmols) and cesium carbonate (764 mg, 2.34 mmols) were added to DMF solution (10 ml) of 2-chloro-5-bromopyrimidine (300 mg, 1.56 mmols), and stirred at room temperature for 16 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, chloroform/methanol=100/3) to obtain the entitled compound (349 mg, 69%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:7][CH:6]=2)=[O:18])[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cccc(CC(=O)c2ccc(O)cc2)c1
Reactant: ClCCN1CCCCC1
Agent: Cl
Product: COc1cccc(CC(=O)c2ccc(OCCN3CCCCC3)cc2)c1

Procedure:
1-(4-hydroxyphenyl)-2-(3-methoxyphenyl)ethanone and 1-(2-chloroethyl)piperidine hydrochloride are used as starting materials.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[C:7]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]#[N:32])=[CH:21][CH:20]=2)=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:33]([O-])([O-])([O-])[O:34][CH2:35][CH3:36]>>[C:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:17]2[C:7]3[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][CH:15]=[CH:16][C:6]=3[N:5]=[C:33]2[O:34][CH2:35][CH3:36])=[CH:20][CH:21]=1)#[N:32]
Reactant: CCOC([O-])([O-])[O-]
Reactant: CCOC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc2nc(OCC)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Acetic acid (0.2 g) was added to a solution of ethyl 3-amino-2-[(2'-cyanobiphenyl-4-yl)methyl]aminobenzoate (1.0 g) in ethyl orthocarbonate (5 ml). The mixture was stirred at 80° C. for one hour. The reaction mixture was concentrated, and the concentrate was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogen carbonate and water. The solvent was evaporated to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals (0.79 g, 69%), m.p. 131-132° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[Br-:10].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>O.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([Br:10])[C:5]([CH3:8])=[CH:4][C:3]=1[OH:9]
Reactant: Cc1ccc(C)c(O)c1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(Br)c(C)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a stirred suspension of 2,5-dimethyl phenol (5.0 g, 40.9 mmol) in H2O (150 mL), at room temperature was added tetrabutylammonium tribromide (19.9 g, 41.39 mmol) in CHCl3 (150 mL). The reaction mixture was stirred for 2 h at rt, the organic layer was separated and dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane-ethyl acetate (1:5) to afford 2,5-dimethyl-4-bromophenol as a brown solid (6.2 g, 76%); 1H NMR (300 MHz, DMSO-d6): δ 9.47 (s, 1H), 7.24 (s, 1H), 6.74 (s, 1H), 2.21 (s, 3H), 2.07 (s, 3H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-ethyl acetate (9:1); Rf=0.52.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16]C)=[O:15])[CH3:10])[CH:5]=[N:4][CH:3]=1.[OH-].[Na+]>CO.ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([OH:16])=[O:15])[CH3:10])[CH:5]=[N:4][CH:3]=1
Reactant: COC(=O)c1cccc(C(C)Nc2cncc(Cl)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(Nc1cncc(Cl)n1)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
A mixture of methyl 3-{1-[(6-chloropyrazin-2-yl)amino]ethyl}benzoate (30 mg, 0.1 mmol) in dilute aqueous sodium hydroxide (0.5 mL, 2M, 1 mmol), methanol (2 mL) and dichloromethane (1 mL) was stirred at room temperature for 16 hours. After this time the mixture was concentrated under reduced pressure and the residue was dissolved in water (5 mL) which was then acidified to pH 6 with dilute aqueous hydrochloric acid (1M). The aqueous solution was extracted with ethyl acetate (3×10 mL) and the extracts were washed with brine (10 mL), dried (MgSO4) and concentrated under reduced pressure to give 3-{1-[(6-chloropyrazin-2-yl)amino]ethyl}benzoic acid (11 mg, 41%) as a beige coloured oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=2)=[CH:4][CH:3]=1.[S:24]1[CH2:30][C:28](=[O:29])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:25]1=[S:26].[Cl-].[NH4+].N>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16](=[C:30]3[S:24][C:25](=[S:26])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:28]3=[O:29])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc(Br)cc2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2ccc(Br)cc2)n1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 4 g of ethyl 2-(3-p-bromophenylureido)thiazol-4-ylglyoxylate, 2 g of rhodanine-3-acetic acid, 1 g of ammonium chloride, 1 ml of 28% v/v aqueous ammonia and 50 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Cl)[N:16]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])[CH3:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[C:17]1[N:16]=[C:15]([N:9]2[C:10]([C:11]([F:14])([F:13])[F:12])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(C)cc1B(O)O
Reactant: CCOC(=O)c1cnn(-c2cccc(Cl)n2)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)ccc3OC)n2)c1C(F)(F)F
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a flask containing the title compound from Example 1 Step A (1.50 g, 4.69 mmol) were added 2-methoxy-5-methylphenyl boronic acid (0.779 g, 4.69 mmol) and trans-dichlorobis(triphenylphosphine) palladium (II) (329 mg, 0.469 mmol). Acetonitrile (12 mL) and sodium carbonate (11.7 mL, 1.0 M aqueous, 11.7 mmol) were added, and the resulting mixture was degassed via nitrogen sparge. The reaction mixture was stirred at 70° C. for 18 h, then was allowed to cool to room temperature and was poured into water. The mixture was extracted with EtOAc, and the organic phase was concentrated in vacuo. Purification by chromatography on silica gel (0 to 20% EtOAc in hexanes, then 20 to 100% EtOAc in hexanes) provided compound the title compound: LCMS m/z 406.4 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.12 (s, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.91 (t, J=8.0 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.19 (dd, J=8.0, 2.0 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 4.39 (q, J=7.0 Hz, 2H), 3.87 (s, 3H), 2.35 (s, 3H), 1.40 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([OH:24])=[N:12][CH:13]=[CH:14]2)=[N:9]1.FC(F)(F)S(O[CH2:31][C:32]([F:35])([F:34])[F:33])(=O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11](=[O:24])[N:12]([CH2:31][C:32]([F:35])([F:34])[F:33])[CH:13]=[CH:14]2)=[N:9]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Oc1nccc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc12
Solvent: CN(C)C=O
Product: O=c1c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2ccn1CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(2-chlorophenyl)-3-(4-chlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-ol (I-9A-1b: 150 mg, 0.421 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (107 mg, 0.463 mmol) and CS2CO3 (151 mg, 0.463 mmol) in DMF (2.1 ml) were stirred overnight at room temperature. The reaction mixture was extracted from saturated aqueous NaHCO3 with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), concentrated in vacuo, and then purified on a Biotage™ Flash 12M column using 0–40% ethyl acetate in hexanes as eluant to give the title compound 9A-1 (145 mg, 79%) as a colorless solid: +ES MS (M+1) 438.3; 1H NMR (CD2Cl2) δ 7.70 (d, J=6.2 Hz, 1H), 7.59–7.56 (m, 1H), 7.52–7.43 (m, 3H), 7.38–7.34 (m, 2H), 7.29–7.25 (m, 3H), 5.03 (br s, 2H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([OH:6])=[O:5])[CH3:2].S(=O)(=O)(O)O.[CH3:16]O>>[CH3:16][O:5][C:4](=[O:6])[CH:3]([CH2:1][CH3:2])[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CO
Reactant: CCCCC(CC)C(=O)O
Agent: O=S(=O)(O)O
Product: CCCCC(CC)C(=O)OC
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
173.0 g of a feed mixture consisting of 598.4 g of 2-ethyl-hexanoic acid, 397.8 g of methanol, and 3.8 g of concentrated sulfuric acid is placed in a 1-liter flask equipped with a bottom valve, a stirrer, an internal thermometer, and a Claisen bridge including a receiver. The flask contents are stirred for 30 minutes at 120° C. and the distilled amounts are collected in the receiver. While a temperature of 120° C. is maintained, the feed mixture is added continuously to the flask in an amount sufficient to maintain a constant reactor volume of 300 to 320 ml, allowing for the distilled amounts and amounts drawn off through the bottom valve. After the system has been adjusted to equilibrium, the following balance is obtained with a test period of 6 hours:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]NC(=O)C2C=CC(N3CCCC3)=CC=2)=[CH:9][CH:8]=1)[CH3:2].[C:29]1([S:35](CC2C=CC(CO)=CC=2)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH:5]=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(CNC(=O)c2ccc(N3CCCC3)cc2)cc1
Reactant: O=S(=O)(Cc1ccc(CO)cc1)c1ccccc1
Product: CCOC(=O)C=Cc1ccc(CS(=O)(=O)c2ccccc2)cc1
Yield: 82 %

Procedure:
The titled compound was prepared as described in the process (5-2) using the compound from the process (10-3).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.[N:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[C:38]([C:43]3[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=3)[CH:39]=[CH:40][C:41]=2[OH:42])=[CH:32][N:31]=1>>[Cl:1][C:2]1[C:3]([O:42][C:41]2[CH:40]=[CH:39][C:38]([C:43]3[CH:44]=[CH:45][C:46]([C:49]([F:50])([F:51])[F:52])=[CH:47][CH:48]=3)=[CH:37][C:36]=2[C:33]2[CH:34]=[CH:35][N:30]=[N:31][CH:32]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1-c1ccnnc1
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnnc3)cc2F)c(OC)c1
Yield: 74.1 %

Procedure:
Prepared according to Preparation 22 using 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 16, 175 mg, 0.379 mmol) and 3-pyridazin-4-yl-4′-(trifluoromethyl)biphenyl-4-ol (Preparation 8, 120 mg, 0.379 mmol) to afford the title compound as a solid (213 mg, 74%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:4])=[O:3].[NH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[Br:26]>>[Br:26][C:21]1[C:22]([CH3:25])=[N:23][O:24][C:20]=1[NH:19][S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: Cc1ccc(OCc2sccc2S(=O)(=O)Cl)cc1
Product: Cc1ccc(OCc2sccc2S(=O)(=O)Nc2onc(C)c2Br)cc1
Yield: 64 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl]-thiophene-3-sulfonamide was prepared, as described in Example 2, by reacting 3-chlorosulfonyl-2-[(4-methylphenoxy)methyl]thiophene with 5-amino-4-bromo-3-methylisoxazole, resulting in a 64% yield, m.p. 128-130° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([Br:24])=[CH:7][C:8]([F:23])=[C:9]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[NH:13][C:12]2=[O:22])[CH:10]=1)[CH:2]=[CH2:3].CI.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:4][C:5]1[C:6]([Br:24])=[CH:7][C:8]([F:23])=[C:9]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[N:13]([CH3:27])[C:12]2=[O:22])[CH:10]=1)[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCOc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Br
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A crude product (16.67 g) of 3-(5-allyloxy-4-bromo-2-fluorophenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, methyl iodide (7.18 g) and potassium carbonate (7.03 g) were suspended in DMF (80 ml), and the mixture was stirred at room temperature for 8 hours. After the reaction, DMF was distilled off under reduced pressure, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off, and the resulting oily substance was purified by chromatography on silica gel (ethyl acetate:n-hexane=1:3 v/v), and the resulting oily substance was crystallized from ethyl acetate-n-hexane to obtain the objective 3-(5-allyloxy-4-bromo-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (5.42 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.[C:19](=[O:26])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[NH2:20].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[CH3:16][Si:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][O:12][CH2:11][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([NH:20][C:19](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=[C:4]2[CH:10]=[N:9]1
Reactant: C[Si](C)(C)CCOCn1ncc2cc(Br)cnc21
Reactant: CC(C)(C)OC(N)=O
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnc2c(cnn2COCC[Si](C)(C)C)c1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
Pd2(dibenzylidene acetone)3 (“Pd2dba3”; 0.031 g, 0.033 mmol) was added to a suspension of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine (0.110 g, 0.335 mmol), tert-butyl carbamate (0.118 g, 1.00 mmol), Xantphos (0.039 g, 0.067 mmol), Cs2CO3 (0.163 g, 0.503 mmol) in THF (10 mL). The reaction mixture was purged with argon for 10 minutes and heated to reflux under argon overnight. The reaction mixture was cooled to room temperature and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (9:1) to give tert-butyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-ylcarbamate (0.100 g, 82%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[N:14][CH:13]=[CH:12][N:11]3[C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:19]=2)=[CH:4][CH:3]=1.C1COCC1.Cl[C:37]([CH2:39][O:40]C(=O)C)=[O:38]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[N:14][CH:13]=[CH:12][N:11]3[C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([C:37](=[O:38])[CH2:39][OH:40])[CH2:27][CH2:26]3)[N:19]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1nccn2c(-c3ccnc(NC4CCNCC4)n3)c(-c3ccc(F)cc3)nc12
Solvent: C1CCOC1
Product: Cc1nccn2c(-c3ccnc(NC4CCN(C(=O)CO)CC4)n3)c(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-[2-(4-Fluorophenyl)-8-methylimidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylpiperidin-4-ylamine (Example #H.1.1; 0.2 g, 0.5 mmol) in THF (1.1 mL, 1.4 mmol) was cooled to about 0° C. Then TEA (0.13 mL, 0.94 mmol) was added followed by acetic acid chlorocarbonylmethyl ester (0.077 g, 0.56 mmol). After about 16 h, the mixture was allowed to warm to ambient temperature and filtered, washing with MeOH. The filtrate was treated with 2.50 M aqueous sodium hydroxide (0.20 mL) at ambient temperature. After about 16 h, the mixture was treated with additional 2.50 M aqueous sodium hydroxide (0.16 mL). After about 6 h, the mixture was acidified to pH 5 using 1 N HCl. The mixture was treated with DCM and water, and the layers were separated. The aqueous layer was washed with DCM (3×20 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude material was taken up in DCM/MeOH and purified via FCC using DCM/2.5% NH4OH in MeOH (95:5) to yield the title compound as a white solid after drying (0.115 g, 50%): LC/MS (Table 1, Method b) Rt=1.6 min; MS m/z: 462.3 (M+H)+.