Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([NH2:35])=[N:5][C:6]2([C:21]1[CH:26]=[CH:25][C:24]([O:27]C)=[C:23]([C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)[CH:22]=1)[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1.B(Br)(Br)Br.O.N>C(Cl)Cl>[NH2:35][C:4]1[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])[C:6]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)[CH:22]=2)([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[N:5]=1
Reactant: COc1ccc(C2(c3ccnc(C(F)(F)F)c3)N=C(N)c3c(F)cccc32)cc1-c1cnccn1
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Solvent: O
Product: NC1=NC(c2ccnc(C(F)(F)F)c2)(c2ccc(O)c(-c3cnccn3)c2)c2cccc(F)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
To a solution of 4-fluoro-1-(4-methoxy-3-(pyrazin-2-yl)phenyl)-1-(2-(trifluoromethyl) pyridin-4-yl)-1H-isoindol-3-amine (0.65 g, 1.36 mmol) in DCM (12.5 ml), boron tribromide (0.718 ml, 4.20 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 1 hour and then allowed to reach room temperature. Water (5 ml) was added and the pH was adjusted to approx 8 with aqeuous conc. NH3. The organic phase was separated and aqueous phase was extracted with DCM (20 mL). The combined organic phases were passed through a phase separator (Sorbent) and concentrated under reduced pressure. The residue was purified twice by preparative chromatography to give the title compound (210 mg, 32%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[NH:7])[CH3:6])[CH2:3][CH2:2]1.Br[C:9](=[CH:13]OC)[C:10](=[O:12])[CH3:11].C(N(CC)CC)C.S(=O)(=O)(O)O>C(O)(C)C>[C:10]([C:9]1[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]([CH3:6])=[N:7][CH:13]=1)(=[O:12])[CH3:11]
Reactant: COC=C(Br)C(C)=O
Reactant: CC(=N)NC1CC1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(=O)c1cnc(C)n1C1CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
In a 300 mL-volume glass vessel equipped with a stirrer, a thermometer and a dropping funnel, the isopropyl alcohol solution containing 15.9 g (0.162 mol) of N-cyclopropylacetamidine (which was prepared in the above-mentioned Reference Example 4), 19.3 g (0.108 mol) of 3-bromo-4-methoxy-3-buten-2-one and 16.4 g (0.162 mol) of triethylamine were placed. The mixture was heated to 80° C. under stirring for 8 hours for carrying out reaction. After the reaction was complete, 80 mL of sulfuric acid (2 mol/L) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The concentrate was washed with methyl isobutyl ketone, and the aqueous portion was taken out. The aqueous portion was made basic by adding an aqueous 48% sodium hydroxide, while the mixture was kept at a temperature of not higher than 40° C. The aqueous basic portion was subjected to extraction with methyl isobutyl ketone, and the extracted portion was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=2/1) to give 11.8 g (yield: 67%) of 5-acetyl-1-cyclopropyl-2-methylimidazole as pale yellow liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[C:5]([CH3:14])=[C:4]([Cl:15])[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[OH:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:15][C:4]1[C:5]([CH3:14])=[C:6]([NH:8][C@@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[N:7]=[C:2]([C:27]2[CH:28]=[C:23]([OH:22])[CH:24]=[CH:25][CH:26]=2)[N:3]=1
Reactant: Cc1c(Cl)nc(Cl)nc1N[C@@H]1CCOC1
Reactant: OB(O)c1cccc(O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(Cl)nc(-c2cccc(O)c2)nc1N[C@@H]1CCOC1
Temperature: 100 °C
Reaction time: 14 h
Yield: 107.5 %

Procedure:
To a solution of (R)-2,6-dichloro-5-methyl-N-(tetrahydrofuran-3-yl)pyrimidin-4-amine (1.8 g, 7.3 mmol) in degassed dioxane and H2O (4/1, 21 mL) was added Na2CO3 (1.5 g, 14.5 mmol); Pd(PPh3)4 (296 mg, 0.36 mmol) and 3-hydroxy-phenylboronic acid (1.21 g, 8.8 mmol). The system was purged with nitrogen stream and then stirred at 100° C. for 14 h., cooled down to room temperature, diluted with water (30 mL) and the resulting mixture extracted with EtOAc (30 mL×2). The combined organic layer were dried over Na2SO4, filtered and concentrated. The residue was purified by chromatographic column on silica gel (EtOAc/petroleum ether, gradient elution, from 1/10 to 2:1) to give (R)-3-(4-chloro-5-methyl-6-(tetrahydrofuran-3-ylamino)pyrimidin-2-yl)phenol (2.4 g, 33%) as a white solid. ESI-LCMS (m/z): 306.1 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][OH:12].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1cccc(Br)c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCCSc1cccc(Br)c1
Temperature: 50 °C
Yield: 81.1 %

Procedure:
A mixture of 3-bromobenzenethiol (1.5 g, 7.93 mmol), 2-bromoethanol (1.19 g, 9.52 mmol) and Cs2CO3 (5.16 g, 15.8 mmol) in DMF (10 ml) was heated to 50° C. overnight. The reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and dried. The crude product was purified by column chromatography to afford the titled compound (1.5 g, 81%). 1HNMR (400 MHz, CDCl3): δ 3.12 (t, J=6.0 Hz, 2H), 3.77 (t, J=6.4 Hz, 2H), 7.14 (t, J=8.0 Hz, 1H), 7.26-7.34 (m, 2H), 7.51 (s, 1H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1.CN(C)[CH:16]=[O:17].[BH4-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:16][OH:17])=[N:8][CH:9]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(Br)nc1
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: OCc1ccc(F)cn1
Temperature: 25 °C

Procedure:
Add butyllithium (10.9 mL, 27.22 mmol, 2.5 M solution in hexanes) to a −78° C. solution of 2-bromo-5-fluoro-pyridine (3.99 g, 22.68 mmol) in toluene (200 mL). Stir the reaction at −78° C. for 90 min and then add N,N-dimethylformamide (2.3 mL, 29.71 mmol) via syringe. Stir the reaction for an additional 2 h at −78° C. and then add sodium borohydride (1.72 g, 45.36 mmol) and allow the reaction to warm to room temperature over a 12 h period. Quench the reaction with saturated aqueous sodium bicarbonate (20 mL) and dilute with ethyl acetate (100 mL). Separate the organic phase and dry (magnesium sulfate), filter and concentrate in vacuo to give a yellow oil. Purify the oil by column chromatography (silica gel; 10% to 50% ethyl acetate in hexanes) to give 1.30 g (45%) as a clear colorless oil. 1H NMR (300 MHz, CDCl3): δ 8.41s, 1H), 7.46-7.37 (m, 1H), 7.32-7.27 (m, 1H), 4.75 (s, 2H), 3.64 (br s, 1H).
Reaction SMILES: O1C[CH2:5][N:4]([CH:7]=[O:8])[CH2:3]C1.CNC.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]([C:25]3[CH:26]=[C:27]4[C:31](=[C:32](C(O)=O)[CH:33]=3)[NH:30][N:29]=[CH:28]4)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][C:14]=1[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(#N)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]([C:25]3[CH:26]=[C:27]4[C:31](=[C:32]([C:7]([N:4]([CH3:5])[CH3:3])=[O:8])[CH:33]=3)[NH:30][N:29]=[CH:28]4)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][C:14]=1[CH3:37]
Reactant: Cc1cc(-c2ncccc2-c2cc(C(=O)O)c3[nH]ncc3c2)ccc1F
Reactant: O=CN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ncccc2-c2cc(C(=O)N(C)C)c3[nH]ncc3c2)ccc1F

Procedure:
5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-N,N-dimethyl-1H-indazole-7-carboxamide was prepared analogous to the preparation of 5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazol-7-yl)(morpholino)methanone by the reaction of dimethyl amine (0.55 mL, 1.1 mmol, 2M in THF) with 5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-7-carboxylic acid (100 mg, 0.28 mmol), HBTU (140 mg, 0.36 mmol), NEt3 (57 mg, 0.08 mL, 0.57 mmol) in acetonitrile (4 mL). Extractive work-up followed by preparative HPLC purification and neutralization procedure as discussed previously provided desired 5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-N,N-dimethyl-1H-indazole-7-carboxamide as a white solid. 1H NMR (DMSO-d6): δ 13.05 (s, 1H), 8.63 (dd, 1H, J=1.7 and 4.7 Hz), 8.13 (s, 1H), 7.87 (dd, 1H, J=1.4 and 7.6 Hz), 7.81 (s, 1H), 7.46 (dd, 1H, J=4.7 and 7.6 Hz), 7.32 (d, 1H, J=7.3 Hz), 7.02-6.98 (m, 1H), 6.95-6.89 (app m. 2H), 2.93 (br s, 3H), 2.57 (br s, 3H), 2.09 (s, 3H).19F NMR (DMSO-d6): δ −118.91. LCMS: rt 4.63 min (A), purity 97%, MS (m/e) 375 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:16])[C@:4]1([CH2:32][C:31]2[CH:34]=[CH:35][C:28]([Br:27])=[CH:29][CH:30]=2)[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: BrCc1ccc(Br)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@]1(Cc2ccc(Br)cc2)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 21 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)proline methyl ester (1.30 g) in THF (20 mL) at −78° C. was added a solution of KHMDS (1.25 g) in THF (20 mL). After 45 minutes, a solution of 4-bromobenzyl bromide (1.59 g) in THF (20 mL) was added at −78° C. The reaction mixture was warmed to room temperature over 3 hours and stirred for an additional 3 hours. The mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), filtered and concentrated. Purification by flash column chromatography (silica gel; EtOAc/hexane 1:2) afforded N-(tert-butoxycarbonyl)-2-(4-bromobenzyl)proline methyl ester (0.474 g). MS (m/z) 398 (MH+). (2) To a solution of the compound obtained above (0.474 g) in CH2Cl2 (5 mL) was added TFA (1.5 mL). After 1 hour, the reaction mixture was diluted with CH2Cl2, washed with aqueous NaHCO3 and brine, dried (Na2SO4) and concentrated to give 2-(4-bromobenzyl)proline methyl ester. MS (m/z) 298 (MH+). (3) 3,5-Dichlorophenylisocyanate (0.50 g) was added to a solution of the compound obtained above in THF (10 mL) and DIEA (2.0 mL). After 4 hours stirring at room temperature, the reaction mixture was concentrated. The residue was redissolved in EtOAc, washed with aqueous NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. Purification by chromatography (silica gel: EtOAc/hexane: 1/4, Chromatotron (Harrison Research)) afforded 0.33 g of N-[(3,5-dichlorophenyl)carbamoyl]-2-(4-bromobenzyl)proline methyl ester. MS (m/z) 485 (MH+). mp 170.9° C. (4) The compound obtained above (0.153 g) was dissolved in hot EtOH (10 mL) and cooled to 0° C. To the solution at 0° C. was added NaOEt (0.010 g). After 45 minutes of stirring, the mixture was concentrated. Purification by chromatography (silica gel: 15% EtOAc/hexane, Chromatotron) afforded the titled compound (0.129 g). MS (m/z) 453 (MH+). mp 69.4° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1B(O)O>COCCOC.O>[Cl:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]1[C:12]([O:16][CH3:17])=[CH:13][CH:14]=[CH:15][C:10]=1[F:9]
Reactant: Clc1ccccc1Br
Reactant: COc1cccc(F)c1B(O)O
Solvent: O
Solvent: COCCOC
Product: COc1cccc(F)c1-c1ccccc1Cl
Yield: 122.2 %

Procedure:
Treatment of 2-bromochlorobenzene (9 mL, 77.6 mmol) with 2-fluoro-6-methoxybenzene boronic acid (10.0 g, 58.8 mmol) in DME-water (5:1, 250 mL) according to the procedure described for Example 69, Step 1 provided 17.0 g of 2′-chloro-2-fluoro-6-methoxybiphenyl as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[Li+].[OH-]>CO.O>[CH:16]1([CH2:15][N:9]2[C:10]([C:11]([F:12])([F:13])[F:14])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[CH2:18][CH2:17]1
Reactant: CCOC(=O)c1cnn(CC2CC2)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnn(CC2CC2)c1C(F)(F)F
Yield: 92.8 %

Procedure:
To a solution of 1-cyclopropylmethyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (120 mg, 0.46 mmol) in methanol (5 mL) and water (5 mL) was added LiOH (13 mg, 0.54 mmol). The reaction mixture was stirred at reflux overnight, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was diluted with water and the solution was acidified to pH=2 with concentrated HCL. The resulting mixture was then extracted with ethyl acetate three times. The combined organic layers were concentrated in vacuo to give 1-cyclopropylmethyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (100 mg, 93%), which was used without further purification.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(OCC)(=O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:3]([CH:6]=1)[CH:4]=[O:5])([O-:12])=[O:11]
Reactant: Oc1ccccc1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=Cc1cc([N+](=O)[O-])ccc1Oc1ccccc1
Temperature: 70 °C
Yield: 99.5 %

Procedure:
A mixture of 2-fluoro-5-nitrobenzaldehyde (1.0 g, 5.91 mmol), phenol (0.557 g, 5.91 mmol), and K2CO3 (1.635 g, 11.83 mmol) in dioxane (6 mL) was heated at 70° C. overnight. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (60 mL). The solution was washed with water (2×30 mL) and saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give the title compound (1.43 g, 99% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=O)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:40]1[CH2:45][CH2:44][CH:43]([C:46]2[CH:53]=[CH:52][C:49]([C:50]#[N:51])=[CH:48][CH:47]=2)[CH2:42][CH2:41]1>CN(C)C=O.CCN(C(C)C)C(C)C>[CH2:1]([C:3]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=[O:14])=[CH:8][C:4]=1[C:5]([N:40]1[CH2:45][CH2:44][CH:43]([C:46]2[CH:53]=[CH:52][C:49]([C:50]#[N:51])=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)=[O:7])[CH3:2]
Reactant: CCc1cc(C)c(C=O)cc1C(=O)O
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(C)c(C=O)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a round-bottom flask was added a solution of 2-ethyl-5-formyl-4-methylbenzoic acid (compound 211.4, 450 mg, 2.34 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL). DIEA (907 mg, 7.02 mmol, 3.00 equiv) and HBTU (1.30 g, 3.43 mmol, 1.50 equiv) were added to the reaction mixture. The resulting solution was stirred for 30 min at 25° C. A solution of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 624 mg, 2.80 mmol, 1.20 equiv) in DIEA (2 mL) was added dropwise. The resulting solution was stirred for 30 min at 25° C., then quenched with 20 mL of water. The aqueous phase was extracted with 3×30 mL of ethyl acetate. The combined organic layers were washed with 1×50 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (5:1) as eluent to furnish 720 mg (85%) of the title compound as a yellow solid.
Reaction SMILES: P(Br)(Br)Br.[BrH:5].[CH2:6]([C@H:11]1[CH2:16][CH2:15][C@H:14](O)[CH2:13][CH2:12]1)[CH2:7][CH2:8][CH2:9][CH3:10]>O>[CH2:6]([C@H:11]1[CH2:16][CH2:15][C@H:14]([Br:5])[CH2:13][CH2:12]1)[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCC[C@H]1CC[C@H](O)CC1
Reactant: Br
Agent: BrP(Br)Br
Solvent: O
Product: CCCCC[C@H]1CC[C@H](Br)CC1
Reaction time: 1 h

Procedure:
To a mixture of 104 g of phosphorus tribromide and 5 drops of a 48% aqueous solution of hydrogen bromide, 138 g of trans-4-pentylcyclohexanol were added dropwise under stirring while the temperature was controlled below 10° C. After the completion of the dropwise addition, the reaction mixture was reacted for one hour at the same temperature and then at room temperature for additional 1 hour. After the completion of the reaction, the reaction mixture was added with 200 ml of water, followed by extraction with diethyl ether. After the extract was washed with saturated NaCl, anhydrous sodium sulfate was added to dry the extract. The resultant mixture was filtered and the solvent was distilled off from the filtrate under reduced pressure, whereby trans-4-pentylcyclohexyl bromide was obtained.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[C:29]2[CH:30]=[CH:31][CH:32]=[C:33]([C:34](O)=[O:35])[C:28]=2[O:27][CH2:26][CH2:25]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:33]2[C:28]3[O:27][CH2:26][CH2:25][O:24][C:29]=3[CH:30]=[CH:31][CH:32]=2)=[O:35])=[O:10])[N:12]=1
Reactant: O=C(O)c1cccc2c1OCCO2
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OCCO3)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,3-Dihydro-benzo[1,4]dioxine-5-carboxylic acid. LC-MS (basic): tR=0.88 min; [M+H]+=490.1.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][S:44][CH:43]([C:47]([OH:49])=O)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].[NH2:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[NH:56][N:55]=[C:54]2[C:60]([O:62][CH3:63])=[O:61]>CN(C=O)C>[CH3:63][O:62][C:60]([C:54]1[C:53]2[C:57](=[CH:58][CH:59]=[C:51]([NH:50][C:47]([CH:43]3[S:44][CH2:45][CH2:46][N:41]([C:39]([O:38][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:40])[CH2:42]3)=[O:49])[CH:52]=2)[NH:56][N:55]=1)=[O:61]
Reactant: CC(C)(C)OC(=O)N1CCSC(C(=O)O)C1
Reactant: COC(=O)c1n[nH]c2ccc(N)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1n[nH]c2ccc(NC(=O)C3CN(C(=O)OC(C)(C)C)CCS3)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (1.9 g, 5 mmol) and diisopropyl ethyl amine (DIEA) (2.7 mL) was added to a suspension of 4-(tert-butoxycarbonyl)thiomorpholine-2-carboxylic acid (1.3 g, 5 mmol) in DMF (10 mL) and was stirred at room temperature for 15 minutes. Methyl 5-amino-1H-indazole-3-carboxylate (0.95 g, 5 mmol)) was added to the reaction and was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×20 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product (2.1 g) was progressed to the next step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=2)[O:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:4][C:3]=1[CH3:23].[NH2:24][C:25]([NH2:27])=[O:26]>Cl.O1CCOCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]3[CH:12]=[C:13]([O:14][CH2:15][C:16]([OH:18])=[O:17])[CH:19]=[CH:20][CH:21]=3)[NH:24][C:25](=[O:26])[N:27]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: NC(N)=O
Reactant: Cc1cc(C(=O)/C=C/c2cccc(OCC(=O)O)c2)ccc1O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(-c3cccc(OCC(=O)O)c3)[nH]c(=O)n2)ccc1O
Temperature: 25 °C
Yield: 54.4 %

Procedure:
(E)-2-(3-(3-(4-hydroxy-3-methylphenyl)-3-oxoprop-1-enyl)phenoxy)acetic acid (15.0 g, 48.0 mmol) and urea (14.4 g, 0.24 mol) were suspended in 200 mL of 4N HCl solution in dioxane, and the reaction mixture was heated to reflux overnight, then cooled to room temperature. The resulted mixture was concentrated in vacuo to remove dioxane. The residues were suspended in 150 mL of 2-propanol and heated in a 90° C. oil bath for 10 minutes, then cooled down to room temperature. The suspension was filtered and washed with 50 mL of 2-propanol and dried in the air. 9.2 g (54%) of the desired ({3-[6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl]phenyl}oxy)acetic acid were obtained. 1H NMR (400 MHz, DMSO-d6): 10.39 (s, 1H), 8.00 (s, 1H), 7.90 (m, 1H), 7.75 (m, 1H), 7.65 (s, 1H), 7.40-7.55 (m, 2H), 7.16 (m, 1H), 6.95 (m, 1H), 4.80 (s, 2H), 2.20 (s, 3H). MS (EI) for C19H16N2O5: 353 (MH+).
Reaction SMILES: O[CH2:2][C@H:3]([NH:5]C(=O)OC(C)(C)C)[CH3:4].[Cl:13][C:14]1[CH:34]=[CH:33][CH:32]=[CH:31][C:15]=1[CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29])(=[O:21])=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[NH2:5][C@H:3]([CH3:4])[CH2:2][N:18]([CH2:17][CH2:16][C:15]1[CH:31]=[CH:32][CH:33]=[CH:34][C:14]=1[Cl:13])[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29])(=[O:21])=[O:20]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCc1ccccc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](N)CN(CCc1ccccc1Cl)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 22.6 %

Procedure:
740 mg of (R)-tert-butyl 1-hydroxypropan-2-ylcarbamate was dissolved in 30 mL of tetrahydrofuran in a nitrogen atmosphere, and 1.44 g of N-(2-chlorophenethyl)-2-nitrobenzenesulfonamide and 3.3 g of triphenylphosphine were added thereto. 2.5 mL of diisopropyl azodicarboxylate was added thereto at 0° C., and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue (intermediate) was dissolved in 20 mL of dichloromethane. To the solution, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was neutralized with a saturated aqueous solution of sodium bicarbonate, followed by extraction with dichloromethane (30 mL×3). The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain 380 mg of the title compound as a pale yellow oil (23%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[N:9]=[C:8]([NH:17][C@H:18]([CH2:20][CH3:21])[CH3:19])[CH:7]=1.I[CH3:24]>CN(C=O)C>[CH3:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[C:10]([N:12]([S:13]([CH3:16])(=[O:15])=[O:14])[CH3:24])[N:9]=[C:8]([NH:17][C@H:18]([CH2:20][CH3:21])[CH3:19])[CH:7]=1
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(NS(C)(=O)=O)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(N(C)S(C)(=O)=O)n1
Reaction time: 0.17 h
Yield: 86 %

Procedure:
Add sodium hydride (47 mg, 1.18 mmol, 60% dispersion in mineral oil) to a solution of (S)-2-sec-butylamino-6-methanesulfonylamino-isonicotinic acid methyl ester (356 mg, 1.18 mmol) in DMF (5 mL) at 0° C. Stir for 10 min, add iodomethane (0.11 mL, 1.77 mmol) dropwise. Stir the mixture at room temperature for 2 h, cool and quench the reaction with an ammonium chloride solution. Extract the mixture with ethyl acetate (3×30 mL) and wash the combined extract with water, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 20:80 ethyl acetate:hexanes) to give the title compound (320 mg, 86%).