Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH:20]([F:22])[F:21])=[CH:17][CH:16]=[C:15]([F:23])[C:14]=3[Cl:24])[CH3:12])=[CH:9][N:8](C(OC(C)(C)C)=O)[C:5]2=[N:6][CH:7]=1.[CH3:32][C:33]1[N:37]([C@H:38]2[CH2:43][CH2:42][C@H:41]([OH:44])[CH2:40][CH2:39]2)[N:36]=[CH:35][C:34]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].O.[ClH:61].CCOCC>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.O1CCOCC1>[Cl:24][C:14]1[C:15]([F:23])=[CH:16][CH:17]=[C:18]([O:19][CH:20]([F:21])[F:22])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:34]3[CH:35]=[N:36][N:37]([C@H:38]4[CH2:43][CH2:42][C@H:41]([OH:44])[CH2:40][CH2:39]4)[C:33]=3[CH3:32])[CH:3]=2)[NH:8][CH:9]=1)[CH3:12].[ClH:61]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1[C@H]1CC[C@H](O)CC1
Reactant: C[C@H](c1c(OC(F)F)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: Cc1c(-c2cnc3[nH]cc([C@H](C)c4c(OC(F)F)ccc(F)c4Cl)c3c2)cnn1[C@H]1CC[C@H](O)CC1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 5-bromo-3-{(1S)-1-[2-chloro-6-(difluoromethoxy)-3-fluorophenyl]-ethyl}-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (70.0 mg, 0.135 mmol), trans-4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]cyclohexanol (53.6 mg, 0.175 mmol), Pd(PPh3)4 (7.78 mg, 0.00673 mmol), K2CO3 (0.0558 g, 0.404 mmol) and 4:1 dioxane:H2O (5 mL, 50 mmol) was heated to 95° C. for 2 h. The solution was cooled to 45° C., and 12 M of HCl in H2O (0.2 mL, 2 mmol) was added, stirring for an additional 2 h. The solution was concentrated in vacuo and transferred to a separation funnel. The material was extracted with DCM and sat. NaHCO3. The organic layer was loaded onto silica gel for column chromatography, eluting with 2-4% (7N NH3 in MeOH)/DCM. The fractions containing the pure product were concentrated in vacuo, redissolved in MeOH, and 2.0 M of HCl in Et2O (1 mL, 2 mmol) was added at rt. The solution was stirred for 1 h, and concentrated in vacuo to afford the title compound as an HCl salt. 1H NMR (free base; 400 MHz, CD3OD): δ=1.45-1.57 (mc, 2H), 1.84 (d, J=7.0 Hz, 3H), 1.91-2.12 (m, 6H), 2.22 (s, 3H), 3.67 (tt, J=10.8, 4.4 Hz, 1H), 4.18 (tt, J=11.0, 4.4 Hz, 1H), 5.11 (q, J=7.2 Hz, 1H), 6.44 (brt, J=73.8 Hz, 1H), 7.13 (dd, J=8.8, 4.4 Hz, 1H), 7.19 (dd, J=8.8, 8.4 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.39 (d, J=1.2 Hz, 1H), 7.46 (s, 1H), 8.12 (d, J=2.0 Hz, 1H). 1H NMR(HCl salt; 400 MHz, CD3OD): δ=1.45-1.57 (mc, 2H), 1.89 (d, J=7.0 Hz, 3H), 1.91-2.12 (m, 6H), 2.23 (s, 3H), 3.67 (tt, J=11.2, 4.2 Hz, 1H), 4.24 (tt, J=11.0, 4.4 Hz, 1H), 5.20 (q, J=7.2 Hz, 1H), 6.71 (brt, J=73.6 Hz, 1H), 7.19 (dd, J=8.8, 4.4 Hz, 1H), 7.26 (dd, J=8.8, 8.0 Hz, 1H), 7.64 (s, 1H), 7.73 (d, J=1.2 Hz, 1H), 7.98 (d, J=1.6 Hz, 1H), 8.38 (d, J=1.6 Hz, 1H). MS (ES+): m/z=519.16/521.18 (100/50) [MH+]. HPLC: tR=1.45 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH2:7][CH:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]=2[N:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH:37]=[N:38][N:39]3C(=O)C)O1>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:39]1[C:40]2[C:36](=[C:35]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH2:12][C:13]5[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=5)[CH2:7][CH:6]5[CH2:23][O:24][CH2:25][CH2:26][N:5]5[C:4]=4[N:3]=3)[CH:43]=[CH:42][CH:41]=2)[CH:37]=[N:38]1
Reactant: CC(=O)n1ncc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Reactant: CS(=O)(=O)c1ccc(CN2CC3COCCN3c3nc(Cl)ncc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(CN2CC3COCCN3c3nc(-c4cccc5[nH]ncc45)ncc32)cc1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 3 using 2-chloro-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x9, 75 mg, 0.190 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)ethanone (109 mg, 0.381 mmol) and PdCl2(dppf) (6.97 mg, 9.52 μmol) in dioxane (2 mL) and aqueous saturated NaHCO3 (0.4 mL). 1H NMR (400 MHz, DMSO-d6) δ 3.18-3.38 (m, 5H), 3.88-4.05 (m, 3H), 4.09-4.19 (m, 2H), 4.73 (m, 4H), 7.49 (s, 1H), 7.56 (s, 1H), 7.65 (d, J=8.34 Hz, 2H), 7.72 (s, 1H), 7.84 (d, J=7.33 Hz, 1H), 7.94 (d, J=8.34 Hz, 2H), 8.61 (s, 1H), 13.00-13.68 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C24H24N6O3S, 477.16. found 477.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][NH2:42])=[CH:36][CH:35]=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:19])[NH:42][CH2:41][CH2:40][C:37]3[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=3)=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: NCCc1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 105.1 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (100 g, 265.40 mmol) was dissolved in dry dichloromethane (750 ml) and few drops of DMF. Oxalyl Chloride (24.310 ml, 278.67 mmol) was slowly added to the mixture under nitrogen stream over a period of 0.5 hours at ambient temperature. Gas evolution was observed. The mixture was stirred for 5 hours at ambient temperature and cooled in an ice bath. 2-(4-Chlorophenyl)ethanamine (40.602 ml, 291.94 mmol) and diisopropylethylamine (55.624 ml, 318.48 mmol) were added. The mixture was warmed to ambient temperature and stirred for 16 hours. The crude mixture was transferred to a separatory funnel and washed with 1N HCl, water, and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude solid was further dried under high vacuum to provide 143.5 g of a pink solid. This solid was recrystallized from hot EtOAc/hexanes to provide 130.0 g of the title compound as a light purple solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:14]([OH:16])=O>>[Br:10][C:11]1[CH:12]=[C:13]([C:14]([C:4]2[C:3]3[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=3[S:1][C:5]=2[C:13]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[CH:11][CH:12]=2)=[O:16])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: c1ccc2sccc2c1
Reactant: COc1ccc(C(=O)O)cc1Br
Product: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(OC)c(Br)c2)cc1
Yield: 76 %

Procedure:
The title compound was prepared in 76% yield from 2-(4-methoxyphenyl)]benzo[b]thiophene (Example 3, Part A) and 3-bromo-4-methoxybenzoic acid by essentially following the procedures detailed in Example 2, Part C.
Reaction SMILES: ClC(OCC)=O.[CH:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=1[S:19]([CH3:22])(=[O:21])=[O:20])([CH3:9])[CH3:8].C(N(CC)CC)C>C1COCC1>[CH:7]([C:10]1[CH:18]=[CH:17][C:13]([CH2:14][OH:15])=[CH:12][C:11]=1[S:19]([CH3:22])(=[O:20])=[O:21])([CH3:9])[CH3:8]
Reactant: CC(C)c1ccc(C(=O)O)cc1S(C)(=O)=O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1ccc(CO)cc1S(C)(=O)=O
Reaction time: 1 h
Yield: 68.5 %

Procedure:
2.3 g of ethyl chloroformate dissolved in 5 ml of THF were added dropwise at -10° C. to a solution of 4.8 g of 4-isopropyl-3-methylsulfonylbenzoic acid and 2.1 g of triethylamine in 40 ml of THF. After stirring for 1 hour, the precipitate which was deposited was filtered off with suction, and the filtrate was added dropwise to a solution of 2.3 g of sodium borohydride in 25 ml of water. The reaction mixture was subsequently stirred for 5 h, acidified with hydrochloric acid and extracted with ether, and the organic phase was washed with 10 percent sodium hydroxide solution. After concentrating, 3.1 g of 4-isopropyl-3-methylsulfonylbenzyl alcohol were obtained.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:19]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[C:22]([C:23]([O:25]C)=[O:24])=[CH:21][N:20]=1>C1COCC1.CCOC(C)=O>[F:32][C:29]([F:30])([F:31])[C:27]1[C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=[C:19]([O:5][CH:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])[CH:28]=1
Reactant: CC(O)C(F)(F)F
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(Oc1cc(C(F)(F)F)c(C(=O)O)cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
To a solution of 180 mg (1.56 mmol) of 1,1,1-trifluoro-2-propanol in 10 mL of THF at −78° C. was added 1.56 mL (1.56 mmol) of sodium bis(trimethylsilyl)amide (1.0M in THF). After 30 min at −78° C., 250 mg (1.04 mmol) of methyl 6-chloro-4-(trifluoromethyl)nicotinate was added. The reaction mixture was gradually warmed up to rt and stirred over night. The mixture was diluted with 10 mL of EtOAc and washed with brine. The organic layer was dried over MgSO4 and concentrated. Purification using HPLC B gave 160 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.57 (d, J=6.6, 3H), 5.91 (m, 1H), 7.26 (s, 1H), 8.98 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[CH:7]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][O:18][C:10]1[CH:9]=[C:8]([N:6]2[CH:7]=[C:3]([CH2:2][N:20]3[CH2:25][CH2:24][N:23]([CH2:2][C:3]4[N:4]=[CH:5][N:6]([C:8]5[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=5)[CH:7]=4)[CH2:22][CH2:21]3)[N:4]=[CH:5]2)[CH:13]=[C:12]([O:14][CH3:15])[C:11]=1[O:16][CH3:17]
Reactant: C1CNCCN1
Reactant: COc1cc(-n2cnc(CCl)c2)cc(OC)c1OC
Product: COc1cc(-n2cnc(CN3CCN(Cc4cn(-c5cc(OC)c(OC)c(OC)c5)cn4)CC3)c2)cc(OC)c1OC

Procedure:
4-Chloromethyl-1-(3,4,5-trimethoxyphenyl)imidazole (87 mg) and piperazine (13 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:21]#[N:22])[CH:9]=[C:10]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[N:6]2[N:5]=[CH:4][N:3]=1.N.[OH:24]O>C(O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:21]([NH2:22])=[O:24])[CH:9]=[C:10]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1c1cc(C#N)c2c(N)ncnn12
Reactant: OO
Agent: N
Solvent: CCO
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1c1cc(C(N)=O)c2c(N)ncnn12
Temperature: 25 °C
Reaction time: 19 h

Procedure:
to a solution of Compound 14 (12 mg) in ethanol (4.8 mL) was added 0.7 mL 28% aqueous ammonia and 0.18 mL 30% hydrogen peroxide. The mixture was stirred in a sealed vial at RT for 19 h. The solvent was removed in vacuo, and the crude product was purified on flash silica gel eluting with 10% MeOH in EtOAc to afford the product as pale yellow solid (9.1 mg). This material was recrystallised from EtOAc/MeOH to afford Compound 15 (6.5 mg) as a colourless solid: ESI-MS m/z 324 ([M+H]+); 1H NMR (500 MHz, d6-DMSO): δ 10.38 (d, J 3.1 Hz, 1H), 8.07 (br s, 1H), 8.04 (d, J 3.1 Hz, 1H), 7.91 (s, 1H), 7.52 (br s, 1H), 7.23 (s, 1H), 5.39 (s, 1H), 4.98 (d, J 7.4 Hz, 1H), 4.74 (s, 1H), 4.64 (t, J 5.8 Hz, 1H), 3.82-3.73 (m, 2H), 3.71-3.66 (m, 1H), 3.55 (dd, J 7.1 Hz, 8.3 Hz, 1H), 0.82 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:17][CH2:16][CH2:15][C@@H:14]3[N:9]2[C:10](=[O:18])[CH2:11][CH:12]=[CH:13]3)=[CH:4][CH:3]=1.[H][H]>CO.[Pt]=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:17][CH2:16][CH2:15][C@@H:14]3[N:9]2[C:10](=[O:18])[CH2:11][CH2:12][CH2:13]3)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C1CC=C[C@@H]2CCC[C@H](c3ccc(F)cc3)N12
Agent: O=[Pt]
Solvent: CO
Product: O=C1CCC[C@@H]2CCC[C@H](c3ccc(F)cc3)N12
Yield: 99.2 %

Procedure:
Platinum oxide (10 mg) was added to a solution of (6R*,9aS*)-6-(4-fluorophenyl)-3,6,7,8,9,9a-hexahydroquinolizin-4-one (550 mg) in methanol (5 mL), and the reaction solution was stirred in a hydrogen stream at room temperature for three hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 550 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[CH3:6][O:7][C:8]1[N:13]=[C:12](/[CH:14]=[CH:15]/[C:16]2[N:34]=[C:19]3[C@H:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH2:21][CH2:22][CH2:23][N:18]3[N:17]=2)[CH:11]=[CH:10][C:9]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1.C(OCC)(=O)C>C(O)C>[S:1]([O:3][S:1]([OH:4])(=[O:3])=[O:2])([OH:2])(=[O:5])=[O:4].[CH3:6][O:7][C:8]1[N:13]=[C:12](/[CH:14]=[CH:15]/[C:16]2[N:34]=[C:19]3[C@H:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH2:21][CH2:22][CH2:23][N:18]3[N:17]=2)[CH:11]=[CH:10][C:9]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1
Reactant: O=S(=O)(O)O
Agent: COc1nc(/C=C/c2nc3n(n2)CCC[C@H]3c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=S(=O)(O)OS(=O)(=O)O
Temperature: 25 °C

Procedure:
Concentrated sulfuric acid (11.5 μL) was added to a solution of (8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine (98.09 mg) in ethanol (1 mL), and 1 mL of ethyl acetate was added with stirring at room temperature. Since the oily portion was confirmed on the bottom of the recovery flask, the oily substance was dissolved by ultrasonic treatment. Stirring at room temperature under shading for about 30 minutes resulted in precipitation of a solid. The solid was collected by filtration through a glass filter and dried under reduced pressure at room temperature to obtain 127.94 mg of the title compound as white solid crystals.
Reaction SMILES: [OH:1][C:2]1[CH2:6][O:5][C:4](=[O:7])[C:3]=1[C:8](=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[CH2:6][O:5][C:4](=[O:7])[C:3]=1[C:8](=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: O=C(CCCCCCCC=Cc1ccc(Cl)cc1)C1=C(O)COC1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(CCCCCCCCCc1ccc(Cl)cc1)C1=C(O)COC1=O
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
To a solution of 1.58 g (4.35 mmol) of 4-hydroxy-3-[10-(4-chlorophenyl)-1-oxodec-9-enyl]-2(5H)-furanone in 100 mL of ethyl acetate is added 250 mg of 5% palladium on carbon and subjected to atmospheric hydrogenation using a balloon to deliver the hydrogen. After 1.5 hours, the reaction is worked up by filtering through Solka Flok. The filtrate is washed with copious amounts of ethyl acetate and concentrated in vacuo to give 1.05 g (66%) of pure 4-hydroxy-3-[10-(4-chlorophenyl)1-oxodecyl]-2(5H)-furanone.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1.[CH:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[Br:13][C:14]1[C:19]([CH2:20][CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[OH:28])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Cc1cccnc1Br
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OC(Cc1cccnc1Br)c1ccccc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of n-butyllithium in hexanes (2.5 M, 27.9 mL, 0.0698 mol) was added dropwise over a period of 30 min to a solution of N,N-diisopropylamine (9.9 mL, 0.069 mol, 1.2 equiv) in anhydrous THF (40 mL) at −78° C. The resulting mixture was slowly warmed to 5° C. over 30 min, then cooled to −78° C., and a solution of 2-bromo-3-methylpyridine (6.5 mL, 0.058 mol) in anhydrous THF (20 mL) was added dropwise over 45 min and stirred for 1 h. A solution of benzaldehyde (7.1 mL, 0.069 mol) in THF (20 mL) was then added dropwise over 15 min. The resulting solution was gradually warmed to 23° C. The reaction mixture was quenched with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 25% ethyl acetate in petroleum ether to give the title compound. MS: m/z=280.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:5]=[O:6].I[CH3:15]>[Ag]=O.C(#N)C>[Br:1][C:2]1[C:3]([O:13][CH3:15])=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:5]=[O:6]
Reactant: CI
Reactant: O=Cc1cc([N+](=O)[O-])cc(Br)c1O
Agent: O=[Ag]
Solvent: CC#N
Product: COc1c(Br)cc([N+](=O)[O-])cc1C=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 46.1 %

Procedure:
Into an appropriately sized pressure bottle was placed commercially available 3-bromo-2-hydroxy-5-nitrobenzaldehyde (2.46 gm, 10.00 mmol), iodomethane (6.23 mL, 100 mmol), silver oxide (2.317 g, 10.00 mmol) and acetonitrile (50 mL). The bottle was sealed and heated with stirring at 50° C. for 2 h. The reaction mixture was filtered through celite and the filtrate concentrated to give a solid residue that was triturated with hexane, collected by filtration and dried. The resulting solid was purified by silica gel chromatography (hexane-ethylacetate) to give the title compound (1.2 g, 46%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1[N:14]1[CH:18]=[N:17][C:16]([CH3:19])=[N:15]1)[CH:2]=[CH2:3].CO.[Cl-].[NH4+]>[Fe].O>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([CH:8]=[CH:7][C:6]=1[N:14]1[CH:18]=[N:17][C:16]([CH3:19])=[N:15]1)[NH2:11])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc([N+](=O)[O-])ccc1-n1cnc(C)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: C=CCOc1cc(N)ccc1-n1cnc(C)n1
Temperature: 65 °C
Reaction time: 0.83 h
Yield: 61 %

Procedure:
Iron powder-325 mesh (565 mg, 9.6 mmol), was taken in a round bottom flask charged with a mixture of 1-(2-(allyloxy)-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (500 mg, 1.921 mmol), absolute methanol (5 ml), water (1 mL) and ammonium chloride (517 mg, 9.61 mmol). A water-cooled reflux condenser was attached to the flask and the heterogeneous mixture was heated to 65° C. with vigorous stirring for 50 min. The reaction mixture was filtered and washed with methanol. The solvent was removed in vacuo. EtOAc was added to the residue, and washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated to afford 3-(allyloxy)-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline. (270 mg, 61% yield). LC-MS (M+H)+=231.2 1H NMR (400 MHz, DMSO-d6) δ ppm 8.434 (s, 1H), 7.11 (d, 1H, J=8.8 Hz), 6.34 (s, 1H), 6.21 (d, 1H, J=8.4 Hz), 5.99-5.93 (m, 1H), 5.42 (s, 2H), 5.29-5.18 (m, 2H), 4.50-4.48 (m, 2H), 2.28 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15]([OH:25])(=[O:24])[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH2:17]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([OH:25])=[O:24])[CH2:11][CH2:10]1
Reactant: C=C(C(=O)O)c1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCO
Product: COc1ccccc1N1CCN(CC(C(=O)O)c2ccccc2)CC1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
1-(2-Methoxyphenyl)piperazine (22.6 g, 0.118 mol) and atropic acid (174 g, 0.118 mol) in ethanol (300 ml) were heated under reflux for 18 hours, cooled to room temperature, and evaporated in vacuo. The solid was triturated with acetone (3×100 ml) to give a first crop of product (13.8 g) as white crystals. The filtrate was evaporated in vacuo to give an oil which slowly crystallised over 1 month. The solid was triturated with acetone (200 ml) to give a second crop of the hemihydrate of the product (9.01 g) as white crystals, m.p. 160°-163°. (Found: C, 68.4; H, 7.2; N, 7.9. C20H24N2O3.0.5H2O requires C, 68.8; H, 7.21 N, 8.0%.)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH:31]=[CH2:32]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:32][CH2:31][CH:30]=[CH2:29])=[CH:16][CH:15]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-BOC-tyrosine methyl ester (10.0 g, 33.9 mmol) was dissolved in DMF (40 mL) and potassium carbonate (5.62 g, 40.7 mmol) and 4-bromo-1-butene (4.13 mL, 40.7 mmol) were added. The mixture was stirred at rt for 18 h before being diluted with EtOAc (120 mL) and partitioned with 1M hydrochloric acid. The organic phase was washed with hydrochloric acid and then with brine before being dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica using a gradient of EtOAc and (50/70) petroleum ether to yield a white solid, 3.20 g, 27%. Rf=0.82 (1/2 EtOAc/(50/70) petroleum ether).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[C:13]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:14]=[N:15][CH:16]=1.[H-].[Na+].[CH3:25]I>CN(C=O)C>[CH3:25][N:17]([C:13]1[CH:14]=[N:15][CH:16]=[C:11]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:12]=1)[S:18]([CH2:21][CH3:22])(=[O:20])=[O:19]
Reactant: CCS(=O)(=O)Nc1cncc(-c2cc3ccccc3n2C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N(C)c1cncc(-c2cc3ccccc3n2C)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A flask is charged with ethanesulfonic acid [5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide (Example 226, 100 mg, 0.317 mmol) and DMF (4 mL). The reaction is cooled to 0° C. and sodium hydride (15.85 mg, 0.396 mmol) is added. The reaction is stirred at 0° C. for 10 min, then methyl iodide (56.3 mg, 0.396 mmol) is added. The reaction is stirred for 1 hour at room temperature. The reaction is quenched with water (0.5 mL) and filtered. The filtrate is purified using Xbridge C18 eluting with a 10 to 100% acetonitrile-water gradient to afford ethanesulfonic acid methyl-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide. 1H NMR (400 MHz, MeOD) δ ppm 1.39 (t, J=7.5 Hz, 3H), 3.28 (q, J=7.5 Hz, 2H), 3.49 (s, 3H), 3.84 (s, 3H), 6.74 (s, 1H), 7.14 (t, J=7.6 Hz, 1H), 7.28 (ddd, J=7.6, 1.1 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 8.13 (t, J=2.1 Hz, 1H), 8.70 (d, J=2.0 Hz, 1H), 8.70 (d, J=2.5 Hz, 1H). HRMS (ESI) m/z 330.1281 [(M+H)+ Calcd for C17H19N3O2S 330.1270].