Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[OH:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:22]([O:21][C:19]([C:18]1[CH:27]=[CH:28][C:15]([O:14][C:4]2[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=2)[C:8]#[N:9])=[CH:16][CH:17]=1)=[O:20])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: CCCCCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCOC(=O)c1ccc(Oc2ccc(C#N)c(C#N)c2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture of 4-nitrophthalonitrile (1.00 g, 7 mmol), pentyl 4-hydroxybenzoate (1.45 g, 7 mmol) and dried potassium carbonate (6.38 g, 46.2 mmol) in anhydrous DMF (50 mL) was stirred overnight at 85° C. under argon. After cooling to room temperature, the mixture was diluted with ethyl acetate (60 mL) and water (40 mL). The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated solution of NaHCO3 (40 mL), brine (40 mL) and dried over anhydrous sodium sulfate. The solvents were removed in vacuo, and the crude product was purified by column chromatography on silica gel using a dichloromethane/acetonitrile mixture (20:1) as an eluent to give the product in 85% yield. [1H NMR (δ, ppm, CDCl3): 8.15 (d, 2H, J=8.7 Hz), 7.77 (d, 1H, J=8.7 Hz), 7.35 (d, 1H, J=2.3 Hz), 7.30 (d, 1H, J=8.7 Hz), 7.12 (d, 2H, J=8.7 Hz), 4.34 (2H, t, OCH2, J=6.7 Hz), 1.79 (m, 2H, CH2), 1.42 (m, 4H, CH2CH2), 0.94 (t, 3H, J=7 Hz, CH3).]
Reaction SMILES: [F:1][C:2]1[C:12]([CH3:13])=[C:11](F)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N-:15]=[N+:16]=[N-:17].[Na+].C1(C)C=CC=CC=1.O>CS(C)=O>[N:15]([C:11]1[CH:10]=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([F:1])[C:12]=1[CH3:13])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1ccc(F)c(C)c1F
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N=[N+]=[N-])c(C)c1F
Temperature: 25 °C
Yield: 42.4 %

Procedure:
In 47 ml of dimethyl sulfoxide was dissolved 4.65 g of ethyl 2,4-difluoro-3-methylbenzoate, followed by adding thereto 3.32 g of sodium azide, and the resulting mixture was stirred at 70° C. for 20 hours. The reaction mixture was cooled to room temperature and then added to a mixed solvent of 150 ml of toluene and 150 ml of water, and the organic layer was separated. The organic layer obtained was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The resulting residue was purified by a column chromatography (eluent: toluene) to obtain 2.20 g of ethyl 4-azido-2-fluoro-3-methylbenzoate as a light-yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)cc1

Procedure:
32.6 g of 4-bromophenol, 34.2 g of benzyl bromide and 42 g of potassium carbonate in 150 ml of dimethylformamide are stirred at 40° C. for 2 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:23][CH2:22]2)=[O:20])=[CH:12]3)=[N:6][CH:7]=1.[Cl:34][C:35]1[CH:36]=[C:37]2[C:42](=[O:43])[O:41][C:39](=[O:40])[C:38]2=[CH:44][C:45]=1[Cl:46]>ClCCCl>[CH2:27]([N:24]1[CH2:25][CH2:26][N:21]([C:19]([C:13]2[N:14]([CH3:18])[C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([O:8][C:5]2[N:6]=[CH:7][C:2]([NH:1][C:39](=[O:40])[C:38]4[C:37](=[CH:36][C:35]([Cl:34])=[C:45]([Cl:46])[CH:44]=4)[C:42]([OH:43])=[O:41])=[CH:3][CH:4]=2)=[CH:17][CH:16]=3)=[O:20])[CH2:22][CH2:23]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Reactant: Cn1c(C(=O)N2CCN(Cc3ccccc3)CC2)cc2cc(Oc3ccc(N)cn3)ccc21
Solvent: ClCCCl
Product: Cn1c(C(=O)N2CCN(Cc3ccccc3)CC2)cc2cc(Oc3ccc(NC(=O)c4cc(Cl)c(Cl)cc4C(=O)O)cn3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.8 %

Procedure:
To a solution of [5-(5-aminopyridin-2-yloxy)-1-methyl-1H-indol-2-yl](4-benzylpiperazin-1-yl)methanone (1.00 g, 2.26 mmol) in 1,2-dichloroethane (22 mL) was added 4,5-dichlorophthalic anhydride (0.57 g, 2.62 mmol), and the mixture was stirred at room temperature for 4 hours. The resulting precipitate was collected by filtration and dried to give 1.5 g of the title compound as a white powder.
Reaction SMILES: N1(C2CCCCCCCCCC2)CCCN=CCCCCC1.[C:23]([C:25]1[CH:26]=[CH:27][C:28]([F:56])=[C:29]([C@:31]23[CH2:40][O:39][C@@H:38]([C:41]4[CH:42]=[N:43][N:44]([CH3:46])[CH:45]=4)[CH2:37][C@H:36]2[CH2:35][S:34][C:33]([NH:47]C(=O)C2C=CC=CC=2)=[N:32]3)[CH:30]=1)#[N:24]>CO>[NH2:47][C:33]1[S:34][CH2:35][C@@H:36]2[CH2:37][C@H:38]([C:41]3[CH:42]=[N:43][N:44]([CH3:46])[CH:45]=3)[O:39][CH2:40][C@:31]2([C:29]2[CH:30]=[C:25]([CH:26]=[CH:27][C:28]=2[F:56])[C:23]#[N:24])[N:32]=1
Reactant: Cn1cc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cc(C#N)ccc3F)CO2)cn1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Solvent: CO
Product: Cn1cc([C@H]2C[C@H]3CSC(N)=N[C@@]3(c3cc(C#N)ccc3F)CO2)cn1
Temperature: 50 °C

Procedure:
1,8-Diazabicycloundec-7-ene (0.298 mL, 1.89 mmol) was added to a solution of N-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C47) (1.11 g, 2.71 mmol) in methanol (100 mL). The resulting solution was heated to 50° C. for 16 hours. The reaction mixture was concentrated under reduced pressure. Purification via silica gel chromatography (Gradient: 0% to 20% methanol in dichloromethane) afforded the product as an off-white solid. Yield: 79 mg, 38%. LCMS m/z 372.2 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 7.77 (ddd, J=8.5, 4.5, 2.2 Hz, 1H), 7.69 (dd, J=7.2, 2.2 Hz, 1H), 7.60 (s, 1H), 7.47 (s, 1H), 7.36 (dd, J=12.1, 8.6 Hz, 1H), 4.71 (dd, J=11.6, 2.2 Hz, 1H), 4.24 (dd, J=11.2, 2.3 Hz, 1H), 3.87 (s, 3H), 3.76 (d, J=11.2 Hz, 1H), 3.06-3.11 (m, 1H), 2.89 (dd, J=12.5, 4.1 Hz, 1H), 2.76 (dd, J=12.7, 2.7 Hz, 1H), 2.04-2.14 (m, 1H), 1.82-1.87 (m, 1H).
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[C:13]([CH3:21])[CH:12]=2)=[N:5][N:6]([CH3:10])[C:7]=1[O:8][CH3:9])=O.C[SiH](C)C>FC(F)(F)C(O)=O>[CH3:10][N:6]1[C:7]([O:8][CH3:9])=[C:3]([CH3:1])[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:19])[CH3:20])=[C:13]([CH3:21])[CH:12]=2)=[N:5]1
Reactant: COc1c(C=O)c(-c2ccc(OC(C)C)c(C)c2)nn1C
Agent: C[SiH](C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C)c(-c2ccc(OC(C)C)c(C)c2)nn1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.1 %

Procedure:
At 0° C., a mixture of 4-formyl-3-(4-isopropoxy-3-methyl-phenyl)-5-methoxy-1-methyl-1H-pyrazole (described in Reference Preparation example 97) 4.2 g and trifluoroacetic acid 20 ml was added trimethylsilane 4.2 g. The resulting mixture was stirred at room temperature for six hours, and the solvent was distilled off under reduced pressure, and thereto was added water 10 ml. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1,4-dimethyl-3-(4-isopropoxy-3-methyl-phenyl)-5-methoxy-1H-pyrazole 3.8 g.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][N:22]2[CH:26]=[C:25]([CH2:27][C:28]([O:30]CC)=[O:29])[C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:23]2)=[CH:17][CH:16]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][N:22]2[CH:26]=[C:25]([CH2:27][C:28]([OH:30])=[O:29])[C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:23]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CC(=O)O)c(-c3ccccc3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
After a mixture of ethyl [1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetate (509 mg), 1N sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml), and ethanol (4 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (2 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain [1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetic acid (408 mg, yield: 85%). This was recrystallized from acetone-hexane. Melting point: 144–145° C.
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1.FC1(F)OC2C=C(C)C(C3N=C[C:25]([NH:28][C:29](=O)[C:30]4[CH:35]=[CH:34]C=CC=4F)=[N:26]C=3)=CC=2O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O1CCOCC1.O>[CH3:11][C:10]1[C:2]([C:30]2[CH:35]=[CH:34][C:25]([NH2:26])=[N:28][CH:29]=2)=[CH:3][C:4]2[CH2:8][CH2:7][O:6][C:5]=2[CH:9]=1
Reactant: Cc1cc2c(cc1Br)CCO2
Reactant: Cc1cc2c(cc1-c1cnc(NC(=O)c3ccccc3F)cn1)OC(F)(F)O2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc2c(cc1-c1ccc(N)nc1)CCO2
Temperature: 85 °C
Yield: 62.9 %

Procedure:
A mixture of 5-bromo-6-methyl-2,3-dihydrobenzo[b]furan (160) (350 mg, purity ca 40%, 0.66 mmol), 2-aminopyridine-5-boronic acid pinacol ester (11) (360 mg, 1.6 mmol), bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (113 mg, 5% mol), and K3PO4 (348 mg, 1.6 mmol) in 2 ml ACN, 2 ml dioxane, 1 ml H2O was bubbled with argon before heated at 85° C. for 4 h. After cooling down to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine. Org. phase was dried over Na2SO4, concentrated and then subjected to prep HPLC purification to give 94 mg 5-(6-methyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)-2-pyridylamine (161) (yield: 63%, purity>95%) as light yellow solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:19])[CH2:6][NH:7][C:8](=[O:18])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17]>O.C(O)C>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1/[CH:10]=[CH:9]/[C:8]([NH:7][CH2:6][C:5]([OH:19])=[O:4])=[O:18]
Reactant: COC(=O)CNC(=O)/C=C/c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CNC(=O)/C=C/c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (400 mg, 10.0 mmol) of sodium hydroxide in water (2 ml) was added to a solution of (2.34 g, 9.9 mmol) of (E)-2-(3-(2-fluorophenyl)acrylamido)acetic acid methyl ester in ethanol (50 ml). The reaction solution was stirred for 1 h at RT and then concentrated in vacuo. The residue was taken up in water and washed twice with ethyl acetate. The aqueous phase was then adjusted carefully to pH 4 with 3% hydrochloric acid, and extraction with ethyl acetate was carried out. The organic phase was concentrated in vacuo, 1.22 g (5.5 mmol, 55%) of (E)-2-(3-(2-fluorophenyl)acryl-amido)acetic acid (S7) being obtained as residue.
Reaction SMILES: Cl.C([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1.C([N:34]1[CH2:41][CH2:40][CH2:39][C@H:35]1[C:36](O)=[O:37])(OCC1C=CC=CC=1)=O>>[CH:13]1([CH2:12][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH:22][C:36]([C@@H:35]2[CH2:39][CH2:40][CH2:41][NH:34]2)=[O:37])(=[O:11])[OH:9])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Product: O=C(NC[C@@H](O)CP(=O)(O)CC1CCCCC1)[C@@H]1CCCN1

Procedure:
Step 4, Method B of Example 1 was substantially repeated in this Example 7 except for employing ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride and N-Cbz-L-proline as the starting materials. Subsequent hydrogenation of the resulting benzyl ester in accordance with the procedures of Step 5, Method A of Example 1 and RP-HPLC purification yielded the title compound. 1H NMR (CD3OD, 300 MHz): δ 4.32-4.18 (m, 1H), 4.13-3.95 (m, 1H), 3.55-3.20 (m, 4H), 2.52-2.35 (m, 1H), 2.15-1.99 (m, 3H), 1.95 (br. d, 2H), 1.80-1.58 (m, 6H), 1.52 (dd, 2H), 1.40-1.15 (m, 3H), 1.13-0.95 (m, 2H). 31P NMR (CD3OD, 300 MHz): δ 42.01. LCMS m/z: [M+H]+=333.2.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[NH2:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.C(O)C.[OH-].[K+:20].[K+].NC1[C:31]2[C:26](=C[CH:28]=[CH:29][CH:30]=2)[NH:25]C=1C([O-])=O>O.C(#N)C>[K+:20].[N:25]1[CH:26]=[CH:31][C:30]([NH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:4]([O-:3])=[O:5])=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1N
Reactant: Nc1c(C(=O)[O-])[nH]c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: CCO
Product: O=C([O-])c1[nH]c2ccccc2c1Nc1ccncc1
Temperature: 75 °C
Reaction time: 3 h
Yield: 140 %

Procedure:
Charge a mixture of 7.50 kg (26.66 mol) of 3-amino-1H-indole-2-carboxylic acid ethyl ester, 37.5L of ethanol and 37.5 L of 4M KOH to a 30-gal reactor and heat to 75° C. over 30 min. Monitor the progress of the reaction by HPLC (Column—150×3.9 mm Waters Symmetry C18, 5 micron; mobile phase—20% acetonitrile/80% 0.1% TFA in water; flow rate—1.0 mL/min; wavelength—225 nm; RT: 3-amino-1H-indole-2-carboxylic acid potassium salt—3.3 min; 3-amino-1H-indole-2-carboxylic acid ethyl ester—6.0 min). Typically achieve, a 100% conversion within 3 h. Cool the mixture to 25° C. over 2 h and concentrate at 50–60° C./50 torr to a residue. Add a total of 37.5 L of water and heat the mixture to and hold at 85° C. for 30 min. Cool the mixture to 10° C. over 2 hours, and then further cool to and hold at 5° C. for 2 hours. Filter off the solid that forms, wash with a total of 10 L of 4M KOH solution and air dry. Further dry the solid at 35° C. in a forced air oven for 72 h to give 10.9 kg, 140% yield of the title compound: HPLC analysis 70.7% pure.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:16])[CH2:14]Br)[CH3:11]>C1COCC1>[CH2:10]([O:12][C:13](=[O:16])[CH2:14][NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:11]
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)CBr
Solvent: C1CCOC1
Product: CCOC(=O)CNCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
4-Fluorobenzylamine (13.86 g, 110 mmol) was dissolved in 25 ml THF and the solution was cooled to 0° C. Bromo-acetic acid ethyl ester (8.35 g, 50 mmol) dissolved in 25 ml THF was added dropwise at 0° C. After stirring for 2 hours at room temperature the solid was filtered off and the fitrate was evaporated. The title compound was purified by chromatography (SiO2, c-hexane/ethyl acetate, 2/1) and was isolated as yellow oil (10.35 g, 98%).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]3[C:18](=[C:19](Cl)[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:25][S:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.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>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]3[C:18](=[C:19]([C:30]4[CH:31]=[CH:32][C:27]([S:26][CH3:25])=[CH:28][CH:29]=4)[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(Oc2ccnc3c(Cl)cccc23)CC1
Reactant: CSc1ccc(B(O)O)cc1
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: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2cccc3c(OC4CCN(C(=O)OC(C)C)CC4)ccnc23)cc1

Procedure:
In a 25 mL round-bottomed flask equipped with a reflux condenser and N2 inlet septum was placed a stir bar, 4-(8-chloro-quinolin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (198 mg, 0.57 mmol), 4-methylthiophenylboronic acid (287 mg, 1.7 mmol), tetrakis(triphenylphosphine)palladium (98 mg, 0.085 mmol), 2M sodium carbonate (0.6 mL) and toluene (4 mL). The mixture was refluxed 36 h under N2. The resulting mixture was diluted with ethyl acetate and extracted with H2O. The organic extract was dried and concentrated to give the crude product. The crude product was purified by column chromatography to using 50% EtOAc/Hexane and preparative HPLC to give the desired product. 1H NMR (CDCl3, 400 MHz) δ 1.27 (d, 6H), 2.04 (m, 2H), 2.17 (m, 2H), 2.55 (s, 3H), 3.59 (m, 2H), 3.83 (m, 2H), 4.97 (m, 1H), 5.09 (m, 1H), 7.14 (s, 1H), 7.41 (m, 4H), 7.81 (t, 1H), 7.90 (d, 1H), 8.38 (d, 1H), 9.11 (s, 1H). Exact mass calculated for C25H28N2O3S 436.18, found 437.2 (MH+).
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1)=[O:4].[Bi]=O>C(O)(=O)C>[CH3:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[C:2]([C:12]2[CH:13]=[CH:14][C:15]([S:18][CH3:19])=[CH:16][CH:17]=2)=[O:1])[CH:10]=[CH:9][CH:8]=1
Reactant: CSc1ccc(C(O)C(=O)c2cccc(C)c2)cc1
Agent: O=[Bi]
Solvent: CC(=O)O
Product: CSc1ccc(C(=O)C(=O)c2cccc(C)c2)cc1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 43.2 %

Procedure:
The ketone from step 2 (30.5 mmol, 8.31 g) was diluted with acetic acid (90 ml) and heated to ˜90° C. Bi2O3 (30.5 mmol, 14.2 g) was added. After stirring 15 minutes, additional bismuth oxide (15 mmol, 7 g) was added. After 30 additional minutes, the mixture was filtered through silica and Celite®, then lyophilized. The residue was subjected to chromatography (3:1 hexane: ethyl acetate), affording the title compound as a yellow solid (3.56 g, 43%), which was used in the next step.
Reaction SMILES: [CH3:1][C:2]([NH:17]C(=O)OC(C)(C)C)([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[N:6][N:5]=1)[CH3:3].[ClH:25].C(OCC)(=O)C>C(O)C>[ClH:25].[ClH:25].[CH3:9][N:8]1[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[N:6][N:5]=[C:4]1[C:2]([NH2:17])([CH3:1])[CH3:3]
Reactant: Cc1ccccc1-c1nnc(C(C)(C)NC(=O)OC(C)(C)C)n1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccccc1-c1nnc(C(C)(C)N)n1C

Procedure:
tert-Butyl {1-methyl-1-[4-methyl-5-(2-methylphenyl)-1,2,4-triazol-3-yl]ethyl}carbamate was reacted with a 4M hydrochloric acid-ethyl acetate solution in ethanol under heating to obtain 2-[4-methyl-5-(2-methylphenyl)-1,2,4-triazol-3-yl]propan-2-amine dihydrochloride.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]=O)=[CH:32][C:17]=1[C:18]([NH:20][CH2:21][C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2)=[O:19].[NH2:40][CH2:41][CH2:42][CH2:43][OH:44]>ClCCl>[Cl:15][C:16]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][NH:40][CH2:41][CH2:42][CH2:43][OH:44])=[CH:32][C:17]=1[C:18]([NH:20][CH2:21][C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2)=[O:19]
Reactant: NCCCO
Reactant: O=CCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCNCCCO)ccc1Cl

Procedure:
Sodium triacetoxyborohydride (1.86 g) was added to a solution of 2-chloro-5-(3-oxopropyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (1.57 g, Example 29b) and 3-amino-1-propanol(0.8 ml) in dichloromethane (150 ml). After 24 h the crude reaction mixture was purified by chromatography (eluting with 5–20% methanol in dichloromethane+1% ammonia) to give the subtitled compound as a white solid (1.05 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:24][CH2:25][O:26][CH3:27])=[C:10]([C:12]2[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]=[CH:15][CH:16]=2)[CH:11]=1)=[O:5])[CH3:2].[H][H]>[Pt].[C].C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:24][CH2:25][O:26][CH3:27])=[C:10]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]=1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(OCOC)c(-c2cccn2C(=O)OC(C)(C)C)c1
Agent: [Pt]
Solvent: CCO
Product: CCOC(=O)c1ccc(OCOC)c(C2CCCN2C(=O)OC(C)(C)C)c1

Procedure:
8.2 g of 5% platinum-carbon catalyst was added to an ethanol (400 ml) solution of 28.4 g of t-butyl 2-(5-ethoxycarbonyl-2-methoxymethoxy-phenyl)-pyrrole-1-carboxylate, and the reaction liquid was stirred for 3 days in a hydrogen atmosphere. The catalyst was removed through filtration through Celite, and the solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/6.5 to 1/6) to obtain the entitled compound as a colorless oily substance.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10](CC3C=CC=CC=3)[C:9]=2[C:8](=[O:21])[N:7]([CH2:22][CH3:23])[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:21])[N:7]([CH2:22][CH3:23])[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CC)c(=O)c2c1ncn2Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCCCn1c(=O)n(CC)c(=O)c2[nH]cnc21
Reaction time: 8 h
Yield: 89 %

Procedure:
3-butyl-1-ethyl-7-(phenylmethyl)-3,7-dihydro-1H-purine-2,6-dione (0.353 g, 1.08 mmol) was dissolved in acetic acid (30 mL), 20% palladium hydroxide on carbon (0.238 g) was added, and the mixture was shaken under hydrogen (at 50 psi) overnight. The catalyst was removed by filtration through Celite® and washed with acetic acid. The filtrate was concentrated under reduced pressure to yield the title compound (0.227 g, 89%); 1H NMR (400 MHz; CDCl3) δ: 0.97 (3H, t), 1.28 (3H, t), 1.38-1.47 (2H, m), 1.74-1.82 (2H, m), 4.12-4.17 (4H, m), 7.80 (1H, s); m/z 237 [MH+].
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[C:18]1([CH3:28])[C:19]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=1>>[CH3:16][C:13]1([CH3:17])[N:12]([S:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH3:28])(=[O:26])=[O:25])[N: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)[C:14]1=[O:15]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: Cc1ccccc1S(=O)(=O)N1N(C2C3CC4CC(C3)CC2C4)C(=O)C1(C)C

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and o-toluenesulfonyl chloride were used for a similar reaction and treatment as Example 169, and the title compound was obtained as a white crystalline powder.