Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:4]([CH3:18])([CH3:17])[CH2:3]1.[C:19](OC)(=[O:24])[C:20]([O:22][CH3:23])=[O:21]>C1(C)C=CC=CC=1>[CH:11]1([O:10][N:5]2[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([NH:1][C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21])[CH2:3][C:4]2([CH3:18])[CH3:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)C(=O)OC
Reactant: CC1(C)CC(N)CC(C)(C)N1OC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C(=O)NC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Yield: 48.6 %

Procedure:
A mixture of 10.0 grams (39.3 mmol) of 4-amino-1-cyclohexyloxy-2,2,6,6-tetramethylpiperidine, 27.8 grams (236 mmol) of dimethyl oxalate and 100 ml of toluene is heated at reflux. Methanol and toluene are removed from the reaction mixture by fractional distillation. The reaction is then filtered and the filtrate is concentrated to obtain a solid. Fractional crystallization of the solid from 9: 1 isopropanol :methylene chloride followed by recrystallization from heptane affords 6.5 grams (48% yield) of the title compound as a white solid melting at 124°-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27](O)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[NH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Reactant: C1CNCCN1
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)N4CCNCC4)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and piperazine using diethyl cyanophosphonate as a coupling reagent Mass: 577.17 (M+H).
Reaction SMILES: C([N:8]1[CH2:22][CH2:21][C:20]2[C:11](=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[CH3:23])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>>[C:28]1([O:27][C:25]([N:8]2[CH2:22][CH2:21][C:20]3[C:11](=[N:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19]=3[CH3:23])[CH2:10][CH2:9]2)=[O:26])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1c2c(nc3ccccc13)CCN(Cc1ccccc1)CC2
Product: Cc1c2c(nc3ccccc13)CCN(C(=O)Oc1ccccc1)CC2
Yield: 63 %

Procedure:
1,2,4,5-Tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid phenyl ester was prepared from 3-benzyl-1,2,4,5-tetrahydro-11-methyl- 3H-azepino[4,5-b]quinoline and phenyl chloroformate analogous to Example 59.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].Br[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH:4][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1
Reactant: CC1(C)OB(c2c(CBr)ccc3ccccc23)OC1(C)C
Reactant: Cc1cc(C)c(N)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(NCc2ccc3ccccc3c2B2OC(C)(C)C(C)(C)O2)c(C)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 29.2 g (216 mmol) of 2,4,6-trimethylaniline, 50.0 g (144 mmol) of 2-[2-(bromomethyl)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 22.0 g (159 mmol) of K2CO3 in 1100 cm3 of DMF was stirred at 80° C. for 12 h. The resulting mixture was poured into 2000 cm3 of water. The product was extracted with 3×400 ml of ethyl acetate. The combined extract was dried over MgSO4 and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: dichloromethane). Yield 45.0 g (78%). Anal. Calc. For C26H32BNO2: C, 77.81; H, 8.04; N, 3.49. Found: C, 77.99; H, 8.24; N, 3.26. 1H NMR (CDCl3): 8.27 (m, 1H, 8-H in naphthyl), 7.84 (m, 1H, 5-H in naphthyl), 7.81 (d, J=8.4 Hz, 1H, 4-H in naphthyl), 7.54 (m, 1H, 7-H in naphthyl), 7.48 (m, 1H, 6-H in naphthyl), 7.37 (d, J=8:4 Hz, 1H, 3-H in naphthyl), 6.87 (s, 2H, 3,5-H in mesityl), 4.39 (s, 2H, CH2N), 3.68 (br.s, 1H, NH), 2.31 (s, 6H, 2,6-Me in mesityl), 2.30 (s, 3H, 4-H in mesityl), 1.49 (s, 12H, CMe2CMe2).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([OH:25])[C@@H:14]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:13][C@@H:10]1[O:11]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.O>[CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([OH:25])[C@@H:14]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:13][CH:10]1[OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: OC1O[C@H](COCc2ccccc2)[C@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methyl 2,3,6-tri-O-benzyl-α-D-galactopyranoside (5 g, 10.75 mmol) is dissolved at 0° C. in a 9:1 mixture of trifluoroacetic acid and water (50 mL) (N. Morishima, S. Koto, M. Oshima, A. Sugimoto and S. Zen, Bull Chem. Soc. Jpn 56, 2849 (1983)). The mixture is stirred overnight at 0° C. The solvents are evaporated under reduced pressure without heating. The residue is dissolved in ethyl acetate and washed successively with sodium bi-carbonate and brine. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure so as to afford an oil. Flash chromatography on silica gel and elution with a graded mixture of ethyl acetate and hexane will afford 2,3,6-tri-O-benzyl-D-galactopyranose as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([CH3:43])([CH3:42])[CH2:9][O:10][C:11]([N:13]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:20][CH:21]=2)[C@@H:16]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][N:29]=2)[CH2:15][C@H:14]1[CH2:40][CH3:41])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:44][C:45]([F:59])([F:58])[C:46]1[CH:47]=[C:48]([CH:51]=[C:52]([C:54]([F:57])([F:56])[F:55])[CH:53]=1)[CH2:49]Br.Cl.C(OCC)(=O)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.COC(C)(C)C>[C:1]([O:5][C:6]([C:8]([CH3:42])([CH3:43])[CH2:9][O:10][C:11]([N:13]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([F:25])([F:24])[F:26])=[CH:20][CH:21]=2)[C@@H:16]([N:27]([CH2:49][C:48]2[CH:51]=[C:52]([C:54]([F:56])([F:57])[F:55])[CH:53]=[C:46]([C:45]([F:44])([F:58])[F:59])[CH:47]=2)[C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][N:29]=2)[CH2:15][C@H:14]1[CH2:40][CH3:41])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC[C@@H]1C[C@H](Nc2ccc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)OCC(C)(C)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)OCC(C)(C)C(=O)OC(C)(C)C
Reaction time: 4.5 h

Procedure:
Tetrabutylammonium iodide (53 mg) was added to a solution of the compound obtained in Example 9 (2) above (217 mg) in tert-butyl methyl ether (4 ml) under nitrogen atmosphere at 0° C. 3,5-Bis(trifluoromethyl)benzyl bromide (164 mg) was added dropwise and the solution was stirred for 4.5 hours while the temperature was gradually raised from 0° C. to room temperature. To the reaction mixture, were added with 1N hydrochloric acid and ethyl acetate, and the organic layer was separated, washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel; hexane:ethyl acetate=19:1→4:1) to give the titled compound (182 mg). MS (m/z): 833 [M+H]+.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C@@:10]23[CH2:25][C@H:24]2[CH2:23][C:22]([F:27])([F:26])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]([NH:28]C(=O)OC(C)(C)C)[C:15](=[O:36])[N:14]2[CH2:37][C@H:38]([O:40][C:41]4[N:42]=[C:43]5[C:48](=[C:49]6[C:54]=4[CH:53]=[CH:52][CH:51]=[CH:50]6)[CH:47]=[CH:46][CH:45]=[CH:44]5)[CH2:39][C@H:13]2[C:12](=[O:55])[NH:11]3)=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[ClH:56]>C(OCC)(=O)C.O1CCOCC1>[NH2:28][C@@H:16]1[C:15](=[O:36])[N:14]2[CH2:37][C@H:38]([O:40][C:41]3[N:42]=[C:43]4[C:48](=[C:49]5[C:54]=3[CH:53]=[CH:52][CH:51]=[CH:50]5)[CH:47]=[CH:46][CH:45]=[CH:44]4)[CH2:39][C@H:13]2[C:12](=[O:55])[NH:11][C@:10]2([C:8]([NH:7][S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])=[O:9])[CH2:25][C@H:24]2[CH2:23][C:22]([F:26])([F:27])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[ClH:56]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4c4ccccc34)CN2C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4c4ccccc34)CN2C1=O
Reaction time: 4 h

Procedure:
To a solution of tert-butyl (2R,6S,13aS,14aR,16aS)-14a-(cyclopropylsulfonylcarbamoyl)-12,12-difluoro-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate (Example 19, 195 mg, 0.249 mmol) in ethyl acetate (1 mL) stiffing at room temperature was added 4 N hydrogen chloride (1.24 mL, 5.0 mmol) in dioxane. The reaction mixture was stirred for 4 h, and then the solvent was evaporated under reduced pressure. The residue was triturated with ethyl acetate and the product was filtered as a white solid. The solid was dissolved in methanol and the solvent was evaporated to provide the title compound (2R,6S,13aS,14aR,16aS)-6-amino-N-(cyclopropylsulfonyl)-12,12-difluoro-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide, Hydrochloric Acid (178 mg, 0.247 mmol, 99% yield).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.Cl.[NH:13]1[CH2:16][CH2:15][CH2:14]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl>ClCCl>[N:13]1([C:6]([C:5]2[CH:9]=[C:10]([CH3:11])[C:2]([Cl:1])=[N:3][CH:4]=2)=[O:8])[CH2:16][CH2:15][CH2:14]1
Reactant: Cc1cc(C(=O)O)cnc1Cl
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2CCC2)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
Commercially available 6-chloro-5-methylnicotinic acid (200 mg, 1.29 mmol) was dissolved in dichloromethane (7.0 mL), and azetidine hydrochloride (160 mg, 1.71 mmol), HATU (1000 mg, 2.63 mmol) and N,N-diisopropylethylamine (0.69 mL, 3.96 mmol) were added, followed by stirring at room temperature overnight under nitrogen atmosphere. 0.5N hydrochloric acid (30 mL) was added, and extraction was carried out with dichloromethane (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-75%) to afford the desired compound (160 mg, yield 64%) as a colorless liquid.
Reaction SMILES: [CH2:1]([C:15]1[CH:45]=[CH:44][C:18]([O:19][CH2:20][CH:21]([OH:43])[CH2:22][O:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CCO[CH2:49][CH3:50]>CN(C)C=O>[C:49]1([CH2:50][O:43][CH:21]([CH2:22][O:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:20][O:19][C:18]2[CH:17]=[CH:16][C:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:45][CH:44]=2)[CH:16]=[CH:15][CH:1]=[CH:2][CH:3]=1
Reactant: CCCCCCCCCCCCCCc1ccc(OCC(O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCc1ccc(OCC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)OCc2ccccc2)cc1
Reaction time: 3 h
Yield: 198.4 %

Procedure:
To a solution of about 13.78 g of 1-(4-tetradecyl phenoxy)-3-(triphenylmethoxy)-2-propanol in about 45 ml of dimethylformamide was added a suspension of about 1.426 g of ether pre-washed sodium hydride in about 10 ml of dimethylformamide, followed by a solution of about 4.06 g of benzylbromide in about 5 ml of dimethylformamide. The mixture was stirred under argon for about 3 hours, quenched very slowly with water and extracted twice with about 50% ether in hexane. The organic layer was dried, filtered and the solvents removed, giving about 15.7 g of the desired title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:23]=1.O>CN(C)C=O>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][O:17][C:4]3[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[N:13]4)=[C:2]([CH3:1])[CH:3]=3)[N:23]=2)=[CH:33][CH:32]=1
Reactant: ClCc1cccc(-c2ccc(Cl)cc2)n1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2cccc(-c3ccc(Cl)cc3)n2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
A solution of 97 mg (0.42 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 17 mg (0.42 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 100 mg (0.42 mmol) 2-Chloromethyl-6-(4-chloro-phenyl)-pyridine [ZA 6706809] were added and stirred continued at r.t. over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water and n-heptane. The residue was dried at 40° C. to give 143 mg (78%) of the title compound as white powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][C@@H:13]2[CH2:17][C@H:16]([O:18][CH2:19][C:20]([O-:22])=[O:21])[C@@H:15]([OH:23])[C@H:14]2[OH:24])[C:3]=1[N+:25]([O-])=O.CO.[C:30](O)(=O)[CH3:31]>>[NH2:25][C:3]1[C:4]([NH:12][C@@H:13]2[CH2:17][C@H:16]([O:18][CH2:19][C:20]([O:22][CH2:30][CH3:31])=[O:21])[C@@H:15]([OH:23])[C@H:14]2[OH:24])=[N:5][C:6]([S:8][CH2:9][CH2:10][CH3:11])=[N:7][C:2]=1[Cl:1]
Reactant: CC(=O)O
Reactant: CCCSc1nc(Cl)c([N+](=O)[O-])c(N[C@@H]2C[C@H](OCC(=O)[O-])[C@@H](O)[C@H]2O)n1
Solvent: CO
Product: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCC(=O)OCC)[C@@H](O)[C@H]2O)n1
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Compound 7a (5 g, 0.011 mol) was added to methanol (25 mL) at 25-30° C. Acetic acid (15 mL) was added slowly to the reaction mixture over 30 min. The reaction mixture was stirred at 25-30° C. for 2 h. After 2 hrs, the reaction was monitored by TLC and showed completion. The reaction mixture was passed through a diatomaceous earth (Celite) pad and the pad was washed with methanol (25 mL). The filtrate was concentrated under reduced pressure at 50° C. The thus obtained residue was mixed with water (50 mL) and basified with aqueous NaHCO3 to pH 9.0. The aqueous layer was extracted with ethyl acetate (3×25 mL). The combined extract was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide the crude product (89%), which was used for next step without further purification.
Reaction SMILES: [CH2:1]([NH:7][C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([SH:15])[S:14][C:10]=2[CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([N:28]=[C:29]=[O:30])[CH:23]=[C:24]([O:26][CH3:27])[CH:25]=1>ClCCl>[CH3:27][O:26][C:24]1[CH:23]=[C:22]([NH:28][C:29](=[O:30])[N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([SH:15])[S:14][C:10]=3[CH:9]=2)[CH:21]=[C:20]([O:19][CH3:18])[CH:25]=1
Reactant: COc1cc(N=C=O)cc(OC)c1
Reactant: CCCCCCNc1ccc2nc(S)sc2c1
Solvent: ClCCl
Product: CCCCCCN(C(=O)Nc1cc(OC)cc(OC)c1)c1ccc2nc(S)sc2c1
Reaction time: 8 h
Yield: 42.8 %

Procedure:
Into 50 ml round bottomed flask were added 6-(hexylamino)-1,3-benzothiazole-2-thiol (58.5 mg, 0.22 mmol), dichloromethane (10 ml) and 3,5-dimethoxyphenyl isocyanate (39.5 mg, 0.22 mmol). The reaction mixture was stirred 8 h, filtered, and the solid that was obtained was triturated with chloroform, followed with chloroform/methanol (9:1 mixture) to give 42 mg (43%) of the title compound. 1H NMR (DMSO-d6) δ=0.79 (t, 3H), 1.19 (br s, 5H), 1.40 (t, 2H), 3.28 (br s, 2H), 3.57 (t, 2H), 3.61 (s, 5H), 6.65 (d, 1H), 7.20 (d, 2H), 7.28 (d, 1H), 7.61 (d, 1H), 7.67 (s, 1H); ESIMS: m/z 444 (M−H).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C:7]([OH:9])=O)(=[O:3])[CH3:2].[CH2:18]([O:25][C:26](=[O:38])[C@H:27]([CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26](=[O:38])[C@H:27]([CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:28][C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(=O)SCC(C(=O)O)C(C)c1ccccc1
Product: CC(=O)SCC(C(=O)N[C@@H](COCc1ccccc1)C(=O)OCc1ccccc1)C(C)c1ccccc1
Yield: 62 %

Procedure:
Using the procedure described in Example 60, starting with 2-acetylthiomethyl-3-phenylbutanoic acid and O-benzylserine benzyl ester, and after purification by chromatography, eluting with a hexane/ethyl acetate (8:2 by volume) mixture, N-(2-acetylthiomethyl-1-oxo-3-phenylbutyl)-O-benzylserine benzyl ester is obtained in a 62% yield, the characteristics of which are as follows: Rf =0.16 [hexane/ethyl acetate (8:2 by volume)].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][N:10]3[CH:13]=[CH:14][N:15]=[C:9]3[CH:8]=2)=[CH:3][CH:2]=1.Br[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([NH:26][C:27]2[S:28][C:29]([CH:33]([CH3:35])[CH3:34])=[C:30]([CH3:32])[N:31]=2)=[O:25])=[C:19]([F:36])[CH:18]=1.C([O-])(=O)C.[K+]>CS(C)=O>[F:36][C:19]1[CH:18]=[C:17]([C:13]2[N:10]3[CH:11]=[CH:12][C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[CH:8][C:9]3=[N:15][CH:14]=2)[CH:22]=[CH:21][C:20]=1[CH2:23][C:24]([NH:26][C:27]1[S:28][C:29]([CH:33]([CH3:35])[CH3:34])=[C:30]([CH3:32])[N:31]=1)=[O:25]
Reactant: Cc1nc(NC(=O)Cc2ccc(Br)cc2F)sc1C(C)C
Reactant: c1cc(-c2ccn3ccnc3c2)ccn1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1nc(NC(=O)Cc2ccc(-c3cnc4cc(-c5ccncc5)ccn34)cc2F)sc1C(C)C
Yield: 11.3 %

Procedure:
Combine 7-pyridin-4-yl-imidazo[1,2-a]pyridine (0.242 g, 1.24 mmol), 2-(4-Bromo-2-fluoro-phenyl)-N-(5-isopropyl-4-methyl-thiazol-2-yl)-acetamide (0.460 g, 1.24 mmol), and potassium acetate (0.243 g, 2.48 mmol) in DMSO (5 mL). De-gas the mixture with N2 for 10 minutes, then add dichlorobis(triphenylphosphine) palladium(II) (0.087 g, 0.124 mmol). Stir the reaction at 100° C. under N2 for 14 hours. Purify using an SCX cartridge (10 g VARIAN bond elut), eluting with 1:1 methanol:dichloromethane, then 1:1 2 M NH3 in methanol:dichloromethane. The latter is purified via reverse phase chromatography using a 25 cm by 50.8 mm (i.d.) column w/10 micron particles (MeCN/0.03% HCl H2O (5:95) to 100% MeCN; 30 minutes). Compound obtained is extracted with ethyl acetate versus 1 N NaOH. The organic layer is washed with aqueous saturated sodium chloride. Dry the resulting organics over magnesium sulfate, filter, and concentrate to afford product (0.068 g, 11%). MS(ES), m/z 486 (M+1).
Reaction SMILES: O.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[NH:13][N:12]=2)=[CH:6][CH:5]=1.[CH2:28]([N:32]=[C:33]=[O:34])[CH2:29][CH2:30][CH3:31]>C1COCC1>[CH2:28]([NH:32][C:33]([NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[NH:13][N:12]=2)=[CH:6][CH:5]=1)=[O:34])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCN=C=O
Reactant: NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCNC(=O)NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
A mixture of 200 mg (0.521 mmol) of 3-(4-aminomethyl-phenylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine hydrate, 0.061 ml (0.548 mmol) of butyl isocyanate and 5 ml of THF is stirred at 20° C. for 15 hours and then concentrated by evaporation in vacuo. The residue is digested in 5 ml of boiling methanol, cooled to 5° C. and filtered, yielding 3-[4-(n-butylamino-carbonylamino-methyl)-phenylamino]-4-(3-chloro-phenyl-amino)-1H-pyrazolo[3,4-d]pyrimidine; m.p. 217-218° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 85 %

Procedure:
As described for example 105, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99 mg, 0.33 mmol) was converted, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to the title compound (105 mg, 85%) which was obtained as a white solid. MS: m/e=412.5 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].[Br:13]Br.O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:13][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]=2[CH:9]=1
Reactant: O=C(O)C1Cc2ccccc2O1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)C1Cc2cc(Br)ccc2O1
Reaction time: 16 h
Yield: 107.3 %

Procedure:
To a solution of 2,3-dihydro-benzofuran-2-carboxylic acid (510 mg, 3.11 mmol) in glacial acetic acid (4 mL) is added bromine (497 mg, 3.11 mmol) dropwise. After 16 hours, the reaction is quenched with water (100 mL) and sodium bisulfite (1 g, 9.6 mmol) and extracted twice with EtOAc (100 mL). The extracts are concentrated in vacuo and dried under high vacuum to afford 5-bromo-2,3-dihydro-benzofuran-2-carboxylic acid (811 mg) as a solid. MS: 241 (M+H), 1H NMR [300 MHz, (CD3)2SO]: δ 13.05 (1H, s); 7.4 (1H, s); 7.25 (1H, d); 6.8 (1H, m); 5.25 (1H, q), 3.55 (1H, dd); 3.25 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.[C:10]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:12][CH2:13][CH3:14])=[O:11].O1CCOCC1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:15]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1cnc(Cl)cn1
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1cnc(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
To a solution of (5-chloro-2-pyrazinyl)methanol (11.0 g) in dioxane (carbethoxymethylene)triphenylphosphorane (29.2 g). After stirring for 2 hours at room temperature, a resulting precipitate was filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (11.0 g).