Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])=[O:30])[CH:11]=1)=[O:9].FC(F)(F)C1C=C(C=CC=1)CNC(C1C=CN=C(C2C=C(N3CCCCC3)C=CC=2NC(=O)C2C=CC=C(C(N(CCC(NCCOC)=O)C)=O)C=2)C=1)=O.[CH3:99][NH:100][CH2:101][CH2:102][N:103]1[CH2:108][CH2:107][N:106]([C:109]([O:111][C:112]([CH3:115])([CH3:114])[CH3:113])=[O:110])[CH2:105][CH2:104]1>>[CH3:99][N:100]([CH2:101][CH2:102][N:103]1[CH2:108][CH2:107][N:106]([C:109]([O:111][C:112]([CH3:115])([CH3:114])[CH3:113])=[O:110])[CH2:105][CH2:104]1)[C:34](=[O:35])[C:33]1[CH:37]=[CH:38][CH:39]=[C:31]([C:29](=[O:30])[NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]3[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:1])([F:43])[F:44])[CH:4]=3)[CH:15]=[CH:14][N:13]=2)[CH:32]=1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CNCCN1CCN(C(=O)OC(C)(C)C)CC1
Agent: COCCNC(=O)CCN(C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Product: CN(CCN1CCN(C(=O)OC(C)(C)C)CC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared from 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzoic acid 4.1e using the procedure described for the preparation of N1-(2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)-N3-(3-(2-methoxyethylamino)-3-oxopropyl)-N3-methylisophthalamide 4.2. Tert-Butyl 4-(2-(methylamino)ethyl)piperazine-1-carboxylate was used as the amine component in this coupling. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.98 (d, J=5.1 Hz, 1H), 8.75 (d, J=9.0 Hz, 1H), 8.46 (s, 1H), 8.18˜8.11 (m, 3H), 7.89˜7.53 (m, 8H), 4.72 (s, 2H), 4.00˜3.11 (m, 16H), 3.08 (s, 3H), 2.04 (d, J=4.8 Hz, 4H), 1.83 (d, J=5.7 Hz, 2H), 1.49 (s, 9H). MS (ES, m/z): 828 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]5[C:24](=[O:29])[NH:25][CH:26]=[CH:27][CH:28]=5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]5[C:24](=[O:29])[N:25]([CH2:32][CH2:33][N:34]6[CH2:39][CH2:38][O:37][CH2:36][CH2:35]6)[CH:26]=[CH:27][CH:28]=5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3ccc[nH]c3=O)cc1-2
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cccn(CCN4CCOCC4)c3=O)cc1-2
Yield: 2 %

Procedure:
Following the procedure for 477, compound 330 and 4-(2-chloroethyl)morpholine hydrochloride were reacted to give 498 (0.005 g, 2%). 1H NMR (500 MHz, DMSO) δ 9.09 (d, J=2.3, 1H), 8.09 (s, 1H), 7.72-7.66 (m, 2H), 7.61 (dd, J=8.4, 2.3, 1H), 7.08 (d, J=8.4, 1H), 6.35 (t, J=6.9, 1H), 5.95 (dt, J=13.1, 6.5, 1H), 4.40 (t, J=5.0, 2H), 4.10 (t, J=6.5, 2H), 3.60-3.53 (m, 4H), 3.46 (t, J=5.0, 2H), 2.64 (t, J=6.5, 2H), 2.46 (d, J=4.4, 4H), 1.55 (d, J=6.6, 6H). MS (ESI(+)): m/z 519.2 (M+H)
Reaction SMILES: C(O[C:4](=[O:21])[CH2:5][N:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.O.[NH2:23][NH2:24]>C(O)C>[CH3:20][N:18]1[CH:19]=[C:15]([C:12]2[CH:13]=[C:14]3[N:6]([CH2:5][C:4]([NH:23][NH2:24])=[O:21])[CH:7]=[CH:8][C:9]3=[N:10][CH:11]=2)[CH:16]=[N:17]1
Reactant: NN
Reactant: CCOC(=O)Cn1ccc2ncc(-c3cnn(C)c3)cc21
Solvent: CCO
Solvent: O
Product: Cn1cc(-c2cnc3ccn(CC(=O)NN)c3c2)cn1
Yield: 99 %

Procedure:
[6-(1-Methyl-1H-pyrazol-4-yl)-pyrrolo[3,2-b]pyridin-1-yl]-acetic acid ethyl ester (122 mg, 0.42 mmol) was dissolved in ethanol (1 mL) and hydrazine hydrate (500 uL). The solution was heated to reflux for 1 hour. Next the solution was concentrated down under vacuum and redissolved in a minimal amount of hot methanol. The product crystallized and was a collected by filtration to afford the title compound (114.8 mg, 99% yield). MS m/z=271 [M+H+]+
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[F:14][C:15]([S:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])([F:17])[F:16]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([S:18][C:15]([F:17])([F:14])[F:16])[CH:20]=1)(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: Nc1cccc(SC(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc(SC(F)(F)F)c1
Yield: 66 %

Procedure:
The title compound (1.26 g, 3.3 mmol) was prepared from 2-nitrobenzenesulfonyl chloride (1.1 g, 5.0 mmol) and 3-[(trifluoromethyl)sulfanyl]aniline (1.06 g, 5.5 mmol) using the methods of (IntA1), step 1.
Reaction SMILES: [OH:1][C:2]12[CH2:15][CH:14]([CH3:16])[CH2:13][C:12](=[O:17])[CH:11]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2.[CH:18]([O:20][CH2:21][CH3:22])=[CH2:19].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CCCCC.C(OCC)C>[CH2:18]([O:20][CH:21]([O:1][C:2]12[CH2:15][CH:14]([CH3:16])[CH2:13][C:12](=[O:17])[CH:11]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH3:22])[CH3:19]
Reactant: C=COCC
Reactant: CC1CC(=O)C2CCCCCCCCC2(O)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCCCC
Solvent: CCOCC
Product: CCOC(C)OC12CCCCCCCCC1C(=O)CC(C)C2
Yield: 67.6 %

Procedure:
A mixture of 119 mg (0.5 mmol) of (30) and 384 μl (4 mmol) ethyl vinyl ether was stirred at 25° C. in the presence of 25 mg (0.1 mmol) pyridinium p-toluenesulfonate (PPTS) for 2 hours (94% conversion). Flash chromatography of the reaction mixture, using SiO2 (14 g) and n-pentane/diethyl ether=95:5 as eluent, afforded 105 mg (61%) of (31) as a ˜1:1 mixture of diastereomers.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH3:9])[O:4][C@H:3]1[O:10][C@H:11]([CH3:24])[CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[N:25]([CH2:28][C@@H:29]([CH3:33])[C:30](O)=[O:31])=[N+:26]=[N-:27].CCN=C=NCCCN(C)C.Cl.C(O)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[N:25]([CH2:28][C@@H:29]([CH3:33])[C:30]([O:8][C@H:6]1[C@H:5]([CH3:9])[O:4][C@@H:3]([O:10][C@H:11]([CH3:24])[CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@H:2]([OH:1])[CH2:7]1)=[O:31])=[N+:26]=[N-:27]
Reactant: C[C@H](CCC(=O)OCc1ccccc1)O[C@@H]1O[C@@H](C)[C@H](O)C[C@H]1O
Reactant: C[C@H](CN=[N+]=[N-])C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: C[C@H](CCC(=O)OCc1ccccc1)O[C@@H]1O[C@@H](C)[C@H](OC(=O)[C@H](C)CN=[N+]=[N-])C[C@H]1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 17 %

Procedure:
To prepare 8, a solution of 38 (22.6 mg, 66.8 μmol) and 3-azido-(2R)-methylpropanoic acid (Rej et al., J. Org. Chem. 61:6289-95 (1996), which is hereby incorporated by reference in its entirety) (37, 8.6 mg, 66.8 μmol) in 2 mL dichloromethane was treated with 4-dimethylaminopyridine (16.3 mg, 133.6 μmol) and EDC hydrochloride (25.7 mg, 133.6 μmol). After stirring at room temperature for 12 hours the reaction was quenched by addition of 5% aqueous acetic acid (100 μl), dried over Na2SO4, and concentrated in vacuo. Flash column chromatography on silica using a gradient of 0-10% isopropanol in dichloromethane afforded (R)-benzyl 4-(((2R,3R,5R,6S)-5-(((R)-3-azido-2-methylpropanoyl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)pentanoate (8) (5.2 mg, 11.6 μmol, 17%) as a colorless oil. 1H NMR (400 MHz, chloroform-d): δ (ppm) 7.40-7.31 (m, 5H), 5.15 (d, J=13.6 Hz, 1H), 5.11 (d, J=13.6 Hz, 1H), 4.86 (ddd, J=10.9 Hz, 9.4 Hz, 4.6 Hz, 1H), 4.73-4.70 (m, 1H), 3.90-3.76 (m, 3H), 3.52 (dd, J=12.2 Hz, 7.5 Hz, 1H), 3.38 (dd, J=12.2 Hz, 5.6 Hz, 1H), 2.71-2.60 (m, 1H), 2.57-2.42 (m, 2H), 2.13-2.05 (m, 2H), 1.93-1.83 (m, 3H), 1.20 (d, J=7.0 Hz, 3H), 1.17 (d, J=6.3 Hz, 3H), 1.16 (d, J=6.2 Hz, 3H). See FIG. 105.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[O:10]1C[CH2:13][CH2:12][CH2:11]1.BrC(F)(F)C(OCC)=O.C(=O)CC.O1CCCC1.C(=O)CC>[Zn].O1CCCC1>[CH2:6]([O:5][C:3](=[O:4])[C:2]([F:9])([F:8])[CH:11]([OH:10])[CH2:12][CH3:13])[CH3:7]
Reactant: C1CCOC1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Zn]
Solvent: CCC=O
Product: CCOC(=O)C(F)(F)C(O)CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
Into a 2-L glass flask with a dropping funnel and a condenser, 70.6 g (1.08 mol/1.1 eq) of activated zinc metal and 300 mL of tetrahydrofuran (THF, dehydrated) were added. An ethyl bromodifluoroacetate/THF solution (prepared by dissolving 200 g (0.985 mol) of ethyl bromodifluoroacetate into 80 mL of THF (dehydrated)) and a propionaldehyde/THF solution (prepared by dissolving 58.7 g (1.01 mol/1.0 eq) of propionaldehyde in 80 mL of THF (dehydrated)) were simultaneously dropped into the glass flask. The resulting solution was stirred for 2 hours at room temperature. The completion of the reaction was confirmed by gas chromatography. After that, the solution was separated into an organic layer and an aqueous layer with the addition of water and diisopropyl ether. The thus-obtained organic layer was washed with diluted hydrochloric acid and with water, dried, concentrated under a reduced pressure, and then, distillated under a reduced pressure. With this, 110 g of 2,2-difluoro-3-hydroxy-pentanoic acid ethyl ester was obtained as a light-brown oily substance (yield: 60%, purity: 98%).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].C1(C=CC(O)=CC=1)O.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[CH:3]([CH2:4][N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])=[O:2]
Reactant: COC(CN(C(=O)C1CCCCC1)c1ccccn1)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: Oc1ccc(O)cc1
Product: O=CCN(C(=O)C1CCCCC1)c1ccccn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A solution consisting of 0.6 g of Compound 1A, 0.02 g of hydroquinone in 10 mL of 2 N HCl was stirred, under a nitrogen atmosphere, for 0.5 h at a temperature of 80° C. The resultant mixture was then cooled with a water bath and ice, followed by alkalinization with a 5% aqueous sodium carbonate solution (pH=9), and then by extraction with dichloromethane (2×10 mL). The obtained organic phase was dried over anhydrous sodium sulphate and evaporated to dryness. The obtained end-product material (Compound 1B; yield 68%) was suitable for use in subsequent reactions, with no additional purification processing.
Reaction SMILES: N1C=CC=CC=1.[N:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)#[N:20]>ClCCl.C(N(CC)CC)C>[N:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:14][CH2:15][N:16]([S:27]([C:24]3[CH:23]=[CH:22][C:21]([C:19]#[N:20])=[CH:26][CH:25]=3)(=[O:29])=[O:28])[CH2:17][CH2:18]2)=[CH:9][CH:8]=1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(S(=O)(=O)N2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.6 %

Procedure:
Pyridine (1 ml) was added to a solution of 1-(4-pyridyl)piperazine (0.33 g) in dry dichloromethane (20 ml) and triethylamine (1 ml) at 5° C. The reaction mixture was treated with 4-cyanobenzenesulphonyl chloride (0.40 g). The reaction mixture was then stirred under argon for 4 hours allowing to warm to room temperature. The dichloromethane solvent was removed by evaporation and the residual pyridine solution poured into aqueous sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic extracts were then washed with aqueous sodium hydrogen carbonate solution, water, brine, dried (MgSO4) and evaporated to yield a pale cream solid which was then recrystallised from ethyl acetate isohexane to give 1-(4-pyridyl)-4-(4-cyanophenylsulphonyl)piperazine (0.31 g) as a solid. m.p. 212-213° C.; microanalysis, found: C, 58.8; H, 4.9; N, 17.1%; C16H16N4O2S requires: C, 8.5: H, 4.91; N, 17.1%; NMR: (CDCl3) 3.18(t,4H), 3.44(t,4H), 6.62(dd,2H), 7.88(q,4H), 8.30(dd,2H); MS: m/z 329 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:6]([CH:10]=1)[C:7]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1COc1ccccc1Cl
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 81.8 %

Procedure:
A mixture of 5-chloro-2-[(2-chlorophenoxy)methyl]benzoic acid (step 2, 85 mg, 0.28 mmol), methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5, 73 mg, 0.34 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (107 mg, 0.56 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (76 mg, 0.56 mmol) and triethylamine (117 μL, 0.84 mmol) in dichloromethane (3 mL) was stirred at room temperature for 19 hours. Water (5 mL) was added and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (10 mL×2) and the combined organic extracts were dried (sodium sulfate). After removal of solvent, the residue was purified by pTLC eluting with hexane/ethyl acetate (2/1) to afford 105 mg (82%) of the title compound:
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:5](Cl)=[O:6])[CH3:3].CC(C)CC(Cl)=[O:19]>>[CH3:1][CH:2]([C@H:4]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:5]([OH:19])=[O:6])[CH3:3]
Reactant: CC(C)CC(=O)Cl
Reactant: CC(C)[C@H](CC1CCCCC1)C(=O)Cl
Product: CC(C)[C@H](CC1CCCCC1)C(=O)O

Procedure:
α(S)-(1-Methylethyl)cyclohexanepropionic acid chloride: By following procedure (a) of this example but replacing propionyl chloride with 3-methylbutanoyl chloride, α(S)-(1-methylethyl)-cyclohexane propionic acid is obtained. 1H NMR (CDCl3) δ 2.27 (ddd, J=10.5, 7, 3.5 Hz, 1H), 1.91-1.80 (m, 2H), 1.73-1.55 (m, 5H), 1.35-1.08 (m, 5H), 0.98-0.77 (m, 2H), 0.97 (d, J=7 Hz, 3H), 0.96 (d, J=7 Hz, 3H). Thereafter, the latter compound was converted to its corresponding acid chloride in the same manner as described in section (a) of this example.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](=[O:14])([O:12]C)[O:10][CH3:11].CN(C)C=O.C(OCC)C>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.O>[C:9](=[O:12])([O:10][CH3:11])[O:14][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)OC
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)OCc1ccccc1
Yield: 65 %

Procedure:
Benzyl chloride (31.65 g, 0.25 mole), dimethyl carbonate (90.0 g, 1.0 mole), tetra-n-butylphosphonium bromide (3.39 g, 0.01 mole) and N,N-dimethylformamide (200 ml) are heated to 117° C.-118° C. for 6 hours. After heating is discontinued the reaction mixture is added to 300 ml of diethyl ether and 300 ml of water. The organic layer is washed with 3×100-ml allotments of water followed by 2×100 ml-portions of 10 percent aqueous HCl, 100 ml of saturated aqueous NaHCO3 and 100 ml of a saturated aqueous NaCl solution, and dried over MgSO4. After solvent removal, distillation gives 27.02 g (65 percent yield based on benzyl chloride) of benzyl methyl carbonate, b.p. 110° C.-111° C. (11 torr).
Reaction SMILES: [CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:46])[CH3:45])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([OH:29])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:51][S:52][CH3:53].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:45])[CH3:46])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([O:29][CH2:51][S:52][CH3:53])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Reactant: CSC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CSCO[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of the compound of Example 1 (5.0 g, 6.9 mmol) and methyl sulfide (4.1 mL) in acetonitrile (35 mL) at 0° C. was added benzoyl peroxide (6.7 g) in four portions over 20 minutes, and the mixture was stirred at 0° C. for 1 hour and then at room temperature for 1 hour. The reaction was diluted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient of 33-100% ethyl acetate in chloroform to give the title compound (4.56 g, 84% yield).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[CH:6][CH:7]=[C:8]2[C:12]([CH3:13])=[C:11]([CH3:14])[NH:10][C:9]=12.I[CH2:16][CH:17]([CH3:19])[CH3:18].O>O1CCCC1>[Cl:3][C:4]1[N:5]=[CH:6][CH:7]=[C:8]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:9]=12
Reactant: CC(C)CI
Reactant: Cc1[nH]c2c(Cl)nccc2c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C)n(CC(C)C)c2c(Cl)nccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
Sodium hydride (60%, 33 mg, 0.83 mmol) was added to a solution of 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine (100 mg, 0.53 mmol) prepared in Step 1 in anhydrous tetrahydrofuran (2.8 ml). The reaction mixture was stirred for 30 minutes at room temperature. 1-Iodo-2-methylpropane (64 μl, 0.67 mmol) was added to the reaction mixture, which was then stirred overnight at room temperature. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/9, v/v) to give 108 mg of the titled compound as a white solid. (Yield: 86%)
Reaction SMILES: [CH3:1][O:2][CH:3]([O:22][CH3:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[C:6]([N+:19]([O-])=O)[CH:5]=1>C(O)C.[Pt]=O>[CH3:1][O:2][CH:3]([O:22][CH3:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[C:6]([CH:5]=1)[NH2:19]
Reactant: COC(OC)c1ccc(OCCN2CCOCC2)c([N+](=O)[O-])c1
Agent: O=[Pt]
Solvent: CCO
Product: COC(OC)c1ccc(OCCN2CCOCC2)c(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
A solution of 4-dimethoxymethyl-1-(2-morpholinoethoxy)-2-nitrobenzene obtained in Step 2 (2.97 g, 9.10 mmol) in ethanol (30.0 mL) was added with platinum oxide (0.02 g, 0.10 mmol), followed by stirring at room temperature under hydrogen atmosphere for 2 hours. The reaction mixture was filtered, the solvent of filtrate was evaporated under reduced pressure, the resulting crude product was crystallized from mixed solvent of ethyl acetate/hexane (1/1) to obtain 5-dimethoxymethyl-2-(2-morpholinoethoxy)aniline (0.70 g, 26%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1COCC1.[Na]>CO>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:1][C:2]2[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Nc1ncccc1CO
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncccc2CO)CC1

Procedure:
The product from Step 1 and 1-(tert-butyloxycarbonyl)piperidin-4-one are heated together in a solvent such as THF or methanol. The cooled mixture is treated with sodium cyanpborohydride to give 1-(tert-butyloxycarbonyl)-4-(3-hydroxymethyl-2-pyridylamino) piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[CH3:12].O.O.[Sn](Cl)Cl>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:11])[C:3]=1[CH3:12])[NH2:8]
Reactant: Cc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cl)cc(N)cc1Cl
Yield: 79.9 %

Procedure:
Dissolve 1,3-dichloro-2-methyl-5-nitrobenzene (0.50 g, 2.43 mmol) in DMF and treat with tin (II) chloride dihydrate (2.74 g, 12.1 mmol) in a single portion. Stir the reaction for 1 hour and dilute with ethyl acetate and filter through celite. Wash the filtrate four times with water and twice with brine, dry over MgSO4, filter and concentrate to a dark oil. Purify the residue by silica gel chromatography eluting with a gradient of 5% to 10% ethyl acetate in hexanes to give 342 mg (80%) of the titled product as white flakes.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=O)[CH2:3]1.[CH:18]1([N:23]2[C:27]([NH2:28])=[C:26]([C:29]([NH2:31])=[O:30])[C:25]([CH2:32][CH3:33])=[N:24]2)[CH2:22][CH2:21][CH2:20][CH2:19]1.CS(O)(=O)=O>C(Cl)Cl>[CH:18]1([N:23]2[C:27]3=[N:28][C:13]([C:12]4[CH:15]=[CH:16][CH:17]=[C:10]([O:9][CH:4]5[CH2:5][CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3]5)[CH:11]=4)=[N:31][C:29](=[O:30])[C:26]3=[C:25]([CH2:32][CH3:33])[NH:24]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CN1CCCCC(Oc2cccc(C=O)c2)C1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3cccc(OC4CCCCN(C)C4)c3)nc(=O)c1-2
Yield: 44.9 %

Procedure:
A mixture of 3-(1-methyl-3-hexahydroazepinyloxy)benzaldehyde (0.79 g, 3.4 mol), 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (0.5 g, 2.2 mmol), methanesulfonic acid (0.25 ml) and xylenes (25 ml) was refluxed overnight. The solvent was stripped, the residue was dissolved in CH2Cl2 and purified by column chromatography on silica gel eluting with ether, then acetone, then 0.5% Et3N/acetone to afford 0.43 g (45%) of 1-cyclopentyl-3-ethyl-6-[3-(1-methyl-3-hexahydroazepinyloxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 195-196° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:7]([CH3:8])[N:6]=[C:5]([OH:9])[CH:4]=1.[Cl:12]N1C(C)(C)C(=O)N(Cl)C1=O>CCOCC>[F:11][C:2]([F:1])([F:10])[C:3]1[N:7]([CH3:8])[N:6]=[C:5]([OH:9])[C:4]=1[Cl:12]
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: Cn1nc(O)cc1C(F)(F)F
Solvent: CCOCC
Product: Cn1nc(O)c(Cl)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h
Yield: 171.4 %

Procedure:
1907 g (11.48 mol) of 5-trifluoromethyl-3-hydroxy-1-methylpyrazole was stirred with 8 kg of ether and cooled to 0° C. 1222 g (6.2 mol) of 1,3-dichloro-5,5-dimethylhydantoin was added in three equal portions and the mixture was allowed to cool to 0° C. after each addition. The mixture was stirred for 4 hours, washed with water, brine and water. All washes were extracted with ether and the combined ether solutions were dried with MgSO4 filtered, evaporated on a rotary evaporator and recrystallized from methylcyclohexane to give 2131 g of a tan solid, m.p. 136°-140° C.