Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:36])[NH:12][CH:13]2[CH2:25][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:26]#[N:27])[CH:22]=4)[N:17]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=4)[C:16]=3[CH2:15][CH2:14]2)=CC=1)([O-])=O.Cl.CN.[CH2:40]([N:42](CC)CC)C.C1COCC1>O>[C:26]([C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)[C:16]1[CH2:15][CH2:14][CH:13]([NH:12][C:11]([NH:42][CH3:40])=[O:36])[CH2:25][C:24]2=1)#[N:27]
Reactant: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CCC(NC(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.5 %

Procedure:
Combine [6-cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-carbamic acid 4-nitrophenyl ester (Preparation 55) (306 mg, 0.63 mmol), methylamine hydrochloride (426 mg, 6.30 mmol), triethylamine (1.40 g, 1.93 mL, 13.9 mmol), and THF (30 mL). Stir the reaction mixture at room temperature for 18 h, then dilute with water (100 mL). Extract into EtOAc (3×65 mL), dry the combined organic portions (MgSO4), filter, and concentrate to give the crude product (310 mg) as a yellow oil. Purify the crude product on 40 g silica gel (50-100% (4% (2M NH3/MeOH)/CH2Cl2)/hexanes) to give 58 mg (24%) of the title compound as a yellow solid. MS (ES): m/z 377 (M+1); HPLC (Method B): Rt=3.22 min (98%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:16]=[C:15]([OH:23])[C:8]=2[S:9][C:10]=1[NH:11]C(=O)C)=[O:5])[CH3:2].OS(O)(=O)=O>CO.CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:16]=[C:15]([OH:23])[C:8]=2[S:9][C:10]=1[NH2:11])=[O:5])[CH3:2]
Reactant: CCCCc1cc(O)c2sc(NC(C)=O)c(C(=O)OCC)c2c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CC#N
Product: CCCCc1cc(O)c2sc(N)c(C(=O)OCC)c2c1
Reaction time: 168 h

Procedure:
Compound 03-6 (3.64 g, 10.9 mmol) was suspended in a mixture of MeOH (450 mL) and MeCN (100 mL). H2SO4 (1.5 mL) was added and the mixture was stirred under a N2-atmosphere, while monitoring the reaction by HPLC. After 7 days the conversion was complete and the mixture was concentrated to half of the original volume. Water was added and the pH was cautiously adjusted to 8 with conc. NH4OH. The aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with H2O (100 mL), brine (100 mL) and dried over Na2SO4. The solvent was removed in vacuo to give the crude product as a green sticky oil, which was purified by column chromatography (SiO2, EtOAc/Hept=1/4+1% Et3N). The product fractions were pooled and the solvent was removed in vacuo. The residue was dissolved in Et2O (50 mL) and the solution was washed with conc. aq. NH4Cl (2×50 mL) and brine (50 mL) to remove residual NEt3. After drying over Na2SO4, the solvent was removed in vacuo to give a-3 (2.6 g, 8.9 mmol, 82%) as a greenish grey solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH:27]=C)=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[C:4]2[CH:3]=[CH:2]1.C1C[O:36]CC1>O.[Os](=O)(=O)(=O)=O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH:27]=[O:36])=[C:23]([C:29]([F:32])([F:30])[F:31])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[C:4]2[CH:3]=[CH:2]1
Reactant: C1CCOC1
Reactant: C=Cc1ccc(NC(=O)Nc2ccc(Oc3ccnc4[nH]ccc34)cc2)cc1C(F)(F)F
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: O=Cc1ccc(NC(=O)Nc2ccc(Oc3ccnc4[nH]ccc34)cc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h
Yield: 76 %

Procedure:
1-[4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-3-(3-trifluoromethyl-4-vinylphenyl)urea (300 mg, 0.68 mmol) was dissolved in a solution mixture of THF (100 mL) and water (50 mL), and an osmium tetraoxide aqueous solution (0.1 M, 300 μL) and sodium periodide (590 mg, 2.76 mmol) were added thereto. The resulting mixture was stirred at room temperature for 17 hours. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine and concentrated under reduced pressure to give a crude product of 1-[4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-3-(3-trifluoromethyl-4-formylphenyl)urea (229 mg, 76%). Then, this crude formyl compound (59.4 mg, 0.14 mmol) was dissolved in methanol (3 mL), and sodium borohydride (15.5 mg, 0.41 mmol) was added thereto. The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine and concentrated under reduced pressure to give a crude product of 1-[4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-3-(3-trifluoromethyl-4-hydroxymethylphenyl)urea (50.9 mg, 85%).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([CH:6]1[CH2:11][CH2:10][N:9](C(OCC2C=CC=CC=2)=O)[CH2:8][CH2:7]1)(=[O:5])=[O:4].[H][H]>CO.[Pd]>[CH3:1][N:2]([CH3:22])[S:3]([CH:6]1[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)S(=O)(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
A solution of phenylmethyl 4-[(dimethylamino)sulfonyl]-1-piperidinecarboxylate (1.19 mmol) and 10% wt palladium/carbon (0.09 mmol) in methanol (10 ml) was vacuum pumped and back-filled with nitrogen three times. The nitrogen atmosphere was then replaced with hydrogen via a balloon and the reaction stirred for 1 hour at ambient temperature. The reaction was then filtered through a pad of celite and concentrated to give the title compound (200 mg, 87% yield), which was used directly in the next reaction without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.33 (bs, 1H) 3.30-3.22 (m, 1H) 2.96 (d, J=12.13, 2H) 2.84 (s, 6H) 2.46 (td, J=2.53, 12.38, 2H) 1.80 (d, J=12.13, 2H) 1.46 (qt, J=4.17, 12.34, 2H)
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26]([OH:28])=O)[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:52][CH2:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=1>C(OCC)(=O)C.CN(C)C=O>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)([CH3:29])[C:26](=[O:28])[NH:52][CH2:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=2)=[CH:18]1
Reactant: NCCc1ccccn1
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)NCCc1ccccn1
Reaction time: 2 h
Yield: 72186 %

Procedure:
To a solution of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan (0.400 g, 1.01 mmol) in ethyl acetate (6 mL) and N,N-dimethylformamide (4 mL) under nitrogen atmosphere was added 1-hydroxybenzotriazole (0.138 g, 1.02 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.198 g, 1.03 mmol). This mixture was stirred 2 hours and 2 (2-aminoethyl)pyridine (0.16 mL, 1.3 mmol) was added. After stirring an additional 18 hours, the resulting mixture was diluted with ethyl acetate (20 mL), and washed with aqueous 1N citric acid, aqueous saturated sodium bicarbonate, and brine solutions. The organic phase was dried over MgSO4, concentrated, and purified by flash chromatography (SiO2, 230-400 mesh, ethyl acetate eluant). After concentration, the residue was dried under vacuum at 60° C. for 48 hours to provide 0,365 g (72%) of product; 1H NMR (CDCl3) δ1.40-1.60 (2H, m), 1.56 (3H, s), 1.65-1.95 (12H, m), 2.88 (2H, t, J 6 Hz), 3.39 (2H, d, J 5 Hz), 3.50-3.70 (2H, m), 4.75 (1H, br s), 5.35 (1H, br s), 6.40 (1H, d, J 2 Hz), 7.00-7.20 (4H, m), 7.22-7.35 (2H, m), 7.52-7.60 (2H, m), 8.20 (1H, br s), 8.40-8.45 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:35])[N:4]([C:18]2[C:32]([F:33])=[CH:31][C:21]([CH2:22][NH:23]C(=O)OC(C)(C)C)=[CH:20][C:19]=2[F:34])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].Cl>O1CCCC1>[ClH:1].[NH2:23][CH2:22][C:21]1[CH:20]=[C:19]([F:34])[C:18]([N:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:2]([Cl:1])[C:3]2=[O:35])=[C:32]([F:33])[CH:31]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(F)c(-n2ccc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(F)c1
Agent: Cl
Solvent: C1CCOC1
Product: NCc1cc(F)c(-n2ccc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(F)c1

Procedure:
tert-butyl 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzylcarbamate (from step 3) (1.39 g, 2.71 mmol) was dissolved in 20 ml tetrahydrofuran and treated with 4 ml concentrated hydrochloric acid. The solution was evaporated and dried in vacuo to a fine white solid (1.20 g, 99%). 1H-NMR (400 MHz, DMSO-d6) δ 8.54 (m, 2H), 7.86 (d, J=7.57 Hz, 1H), 7.65 (quartet, J=7.62, 1H), 7.50 (d, J=9.25 Hz, 2H), 7.34 (dt, J=10.50, 2.45 Hz, 1H), 7.16 (dt, J=8.38, 2.55 Hz, 1H), 6.78 (d, J=7.86 Hz, 1H), 5.37 (s, 2H), 4.10 (br s, 2H), 4.97-3.14 (v br s, 3H). 19F-NMR (400 MHz, DMSO-d6) δ−109.21 (quintet, J=7.77 Hz, 1F), −113.51 (quartet, j=8.95 Hz, 1F), −119.56 (d, J=9.44 Hz, 2F). LC/MS tr=4.33 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50° C.) ES-MS m/z 413 (M+H). ES-HRMS m/z 413.0712 (M+H calcd for C19H14ClF4N2O2 requires 413.0674).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4]1.[OH-].[Li+].O>C1COCC1>[NH2:1][CH2:2][C:3]1([CH2:22][C:23]([OH:25])=[O:24])[CH2:4][C@@H:5]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[N:6]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:7]1
Reactant: CCOC(=O)CC1(CN)C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1CC(CN)(CC(=O)O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Ester (2S)-di-tert-butyl 4-(aminomethyl)-4-(2-ethoxy-2-oxoethyl)pyrrolidine-1,2-dicarboxylate (C6) (560 mg, 1.45 mmol) was dissolved in THF (12 ml). To this was added 1N lithium hydroxide in water (2.9 ml, 2.9 mmol, 2.0 eq). The mixture was stirred at room temperature overnight. The reaction was cooled to 0° C. and quenched with 1N hydrochloric acid in water. The mixture was blown to dryness with N2 gas and stripped from acetonitrile several times to give 2-((5S)-3-(aminomethyl)-1,5-bis(tert-butoxycarbonyl)pyrrolidin-3-yl)acetic acid (D6) (1.45 mmol) as a glassy solid. 1H NMR (DMSO) δ 1.35 (m, 18H), 2.00 (m, 2H), 2.35 (m, 2H), 2.80 (m, 1H), 3.65 (m, 1H), 4.00 (m, 1H); LCMS for C17H30N2O6 358.21 [M], found ES+ 359.21 [M+H]+ and ES− 357.21 [M−H]− at 1.8 minutes retention time, using 10-90% acetonitrile/water (with 0.1% formic acid buffer) gradient over 5 minutes.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][C:27]([C:35]#[N:36])=[C:26]2[NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Br:44])[CH:39]=1>O1CCCC1>[Br:44][C:40]1[CH:39]=[C:38]([NH:37][C:26]2[C:25]3[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])[CH:24]=3)[N:29]=[CH:28][C:27]=2[C:35]#[N:36])[CH:43]=[CH:42][CH:41]=1
Reactant: COc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1N
Reactant: CC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC#CC(=O)Nc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cc1OC
Yield: 53.3 %

Procedure:
To a solution of 1.44 g (17.14 mmol) of 2-butynoic acid and 2.26 g (16.5 mmol) of isobutyl chloroformate in 30 ml of tetrahydrofuran at 0° C., with stirring, was added 3.1 g (3.4 mmol) of N-methyl morpholine. This solution of the mixed anhydride was added to a stirred solution of 1.13 g (3.06 mmol) of 6-amino-4-[(3-bromophenyl)amino]-7-methoxy-3-quinolinecarbonitrile in 30 ml tetrahydrofuran in three portions over a 24 hour period. The solvent was removed. The residue was stirred with dilute sodium bicarbonate solution. Solid was collected and washed with water and ether. This was recrystallized from 1-butanol. The resulting solid was taken up in hot tetrahydrofuran and filtered through silica gel. The filtrate was concentrated and diluted with hexanes to give 0.71 g of N-[4-[(3-bromophenyl)amino]-3-cyano-7-methoxy-6-quinolinyl]-2-butynamide as a yellow powder: mass spectrum (electrospray, m/e): M+H 437.1,438.1.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=4[F:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[F:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][N:30]=[N+:31]=[N-:32])[CH2:17][C:16]=2[CH:18]=[CH:19][CH:20]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(F)cc4F)c3O2)cc1
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2cccc(-c3ccc(F)cc3F)c2O1
Yield: 97.7 %

Procedure:
Treatment of (±)-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (4.3 g, 10.37 mmol) with sodium azide (3.03 g, 46.68 mmol) generally according to the procedure described for Intermediate 98 gave 2.91 g (98%) of (±)-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide. Treatment of the azide with palladium on carbon (0.29 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 2.3 g (76%) of (±)-1-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 222-224° C.; Anal calcd. for C15H13F2NOHCl: C, 60.51; H, 4.74; N, 4.7. Found C, 60.65; H, 4.76; N, 4.51.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].C(NCC)C>CN(C)C=O>[CH2:24]([O:23][C:21]([CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(-c2ccc(C(=O)OCC)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A mixture of ethyl 4′-hydroxybiphenyl-4-carboxylate (2.262 g), ethyl bromoacetate (1.871 g) and potassium carbonate (1.940 g) in N,N-dimethylformamide (50 mL) was stirred at 60° C. for 1 hr. Diethylamine (6.820 g) was added to the reaction mixture. After being stirred at room temperature for 30 minutes, the mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford ethyl 4′-ethoxycarbonylmethoxybiphenyl-4-carboxylate (3.06 g) as a crude product. A mixture of the crude ethyl 4′-ethoxycarbonylmethoxybiphenyl-4-carboxylate, sodium borohydride (0.706 g), tetrahydrofuran (40 mL) and ethanol (10 mL) was stirred at 60° C. for 1 hr. Methanol (10 mL) was added to the reaction mixture, and stirred at room temperature for additional 30 minutes. The solvent was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate and 1 mol/L hydrochloric acid. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (3.000 g)
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH:14]=[CH:15][C:16]([C:18]3[S:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)=[O:17])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C.C(O)C.O=[Pt]=O>[S:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=[C:18]1[C:16](=[O:17])[CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][CH2:10]1
Reactant: O=C(C=CC1CCN(Cc2ccccc2)CC1)c1nc2ccccc2s1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(CCC1CCN(Cc2ccccc2)CC1)c1nc2ccccc2s1
Yield: 105.6 %

Procedure:
A solution of 2-benzothiazolyl 2-[1-(phenylmethyl)-4-piperidinyl]vinyl ketone (146 mg, 0.4 mmol) in a mixture of ethyl acetate/ethanol (10 ml/10 ml) was treated with PtO2 (20 mg) and hydrogenated at 50 psi for 3 hours. The mixture was filtered through Celite® and the filtrate was concentrated to dryness to give 0.154 g of a dark oil. The oil was purified through silica gel column chromatography using chloroform as eluent to give 37 mg of the title compound as a brown oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:12]=1)[O:9][C:8]([CH3:17])([CH3:16])[CH2:7][C:6]2([CH3:19])[CH3:18])#[CH:2].[CH2:20]([O:22][C:23](=[O:33])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](I)[CH:27]=1)[CH3:21]>[Cu]I.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(CC)CC)C>[CH2:20]([O:22][C:23](=[O:33])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[C:11]([CH:13]([CH3:14])[CH3:15])[CH:12]=2)[O:9][C:8]([CH3:17])([CH3:16])[CH2:7][C:6]3([CH3:18])[CH3:19])[CH:27]=1)[CH3:21]
Reactant: CCOC(=O)C=Cc1cccc(I)c1
Reactant: C#Cc1cc(C(C)C)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1cccc(C#Cc2cc(C(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)c1

Procedure:
Following General Procedure B and using 6-ethynyl-8-isopropyl-2,2,4,4-tetramethylchroman (Intermediate 32, 0.05 g, 0.2 mmol), ethyl-3-iodo cinnamate (Reagent 6, 0.118 g, 0.39 mmol), triethyl amine (2 mL), copper(I)iodide (0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.107 mmol) followed by flash column chromatography over silica gel (230–400 mesh), the title compound was obtained (0.058 g, 69%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C([Cl:15])=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([Cl:15])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)Cc1cccc(Br)c1
Temperature: 0 °C
Yield: 100 %

Procedure:
The raw material meta-bromophenylacetic acid (100 g, 0.47 mol, 1.0 eq) was dissolved in dichloromethane (500 ml), then was cooled to 0° C. in ice-salt bath. Oxalyl chloride (120 g, 0.95 mol, 2.0 eq) was added dropwise to the reaction mixture with temperature maintaining 0° C. After the dropping was finished, the reaction temperature was changed to room temperature and reacted for two hours. The reaction mixture was concentrated under reduced pressure to obtain meta-bromophenylacetyl chloride (110 g, 0.47 mol) after the reaction completed. The obtained meta-bromophenylacetyl chloride was dissolved in dichloromethane (200 ml) for further use.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([OH:12])=[CH:7]2.[CH3:13][O-:14].[Na+]>CN(C=O)C.CO>[CH3:13][O:14][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([OH:12])=[CH:7]2
Reactant: C[O-]
Reactant: Oc1cc2cccc(F)c2cn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cccc2cc(O)ncc12
Temperature: 90 °C
Yield: 23.3 %

Procedure:
8-Fluoroisoquinolin-3-ol (561 mg, 3.43 mmol) was dissolved in DMF (3 mL) and sodium methoxide (828 mg, 15.33 mmol) added. The reaction mixture was heated at 90° C. for 14 hours, then diluted with methanol and absorbed onto an SPE (TsOH) cartridge. The column was rinsed with methanol and the compound was then eluted with 7 M ammonia in methanol to afford the title compound (140 mg, 0.798 mmol, 23.2%). LC-MS (2) Rt=1.23 min; m/z (ESI+) 176 (M+H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])=[CH:5][CH:4]=1.[NH:21]([C:23]([NH:25][C:26]1[S:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][CH:27]=1)=[S:24])[NH2:22]>>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:22][NH:21][C:23]([NH:25][C:26]3[S:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][CH:27]=3)=[S:24])[CH3:16])[C:10]=2[OH:18])=[CH:5][CH:4]=1
Reactant: NNC(=S)Nc1ccc(C(=O)O)s1
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)s1)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O

Procedure:
From 1-[5-(4-trifluoromethylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (40.0 mg, 0.14 mmol) and 5-hydrazinocabonothioylamino-2-thiophenecarboxylic acid (34.0 mg, 0.14 mmol), the desired product was obtained in the same manner as in Synthetic Example 114 as a pale yellow solid (55.8 mg, yield 82%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C1C(=O)N([Cl:27])C(=O)C1>CN(C=O)C>[Cl:27][C:7]1[CH:6]=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[C:8]=1[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[O:18][CH3:19]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccnn1C(C)C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1-c1c(Cl)cnn1C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.1 %

Procedure:
To a stirred, ice-cooled solution of 1-isopropyl-5-(2-methoxy-5-nitro-phenyl)-1H-pyrazole from Example 1.81, Step C (1.0 g, 3.83 mmol) in DMF (10 mL) was added NCS (0.56 g, 4.22 mmol) over a period of 10 minutes. The reaction mixture was warmed to ambient temperature and stirred at 55° C. for 6 h. The reaction mixture was cooled and poured into an ice-water mixture with vigorous stirring to form a white solid, which was filtered and washed with cold water until free of DMF. The solid was dried in vacuo to yield 4-chloro-1-isopropyl-5-(2-methoxy-5-nitro-phenyl)-1H-pyrazole (1.1 g, 97%). LCMS m/z (%)=296 M+H+, (35Cl, 100), 298 (37Cl, 28.5). 1H NMR (400 MHz, CDC3) δ: 8.4 (dd, J1=9.09 Hz, J2=2.78 Hz, 1H), 8.19 (d, J=2.8 Hz), 7.6 (s, 1H), 7.14 (d, J=9.18 Hz, 1H), 4.10 (m, 1H), 3.94 (s, 3H), 1.49 (d, J=6.62 Hz, 3H), 1.36 (d, J=6.62 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[S:12][CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[N:15]=1.[CH:19](O)([CH3:21])[CH3:20].C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH:19]([O:17][C:16]([C@@H:14]1[CH2:13][S:12][C:11]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])=[N:15]1)=[O:18])([CH3:21])[CH3:20]
Reactant: COc1ccc(C2=N[C@H](C(=O)O)CS2)c(OC)c1
Reactant: CC(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(C2=N[C@H](C(=O)OC(C)C)CS2)c(OC)c1

Procedure:
Next, 2-(2,4-dimethoxyphenyl)-4,5-dihydro-thiazole-4-(R)-carboxylic acid is reacted with isopropanol; DCC; and 4-(dimethylamino)pyridine (DMAP) in tetrahydrofuran (THF) at room temperature to form isopropyl-2-(2,4-dimethoxyphenyl)-4,5-dihydro-thiazole-4-(R)-carboxylate.