Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=O)[CH:9]=2)[NH:4][CH:3]1[C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[C:17]([CH3:27])[CH:16]=1.[CH:29]1([S:32]([NH2:35])(=[O:34])=[O:33])[CH2:31][CH2:30]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1([CH3:28])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([NH:35][S:32]([CH:29]3[CH2:31][CH2:30]3)(=[O:34])=[O:33])=[O:14])[CH:9]=2)[NH:4][CH:3]1[C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[C:17]([CH3:27])[CH:16]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1cc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)cc(N2CCOCC2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C2Nc3ccc(C(=O)NS(=O)(=O)C4CC4)cc3CC2(C)C)cc(N2CCOCC2)c1
Temperature: 65 °C
Yield: 23.9 %

Procedure:
A mixture of 3,3-dimethyl-2-(3-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (150 mg, 0.39 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (110 mg, 0.59 mmol), 4-dimethylaminopyridine (72 mg, 0.59 mmol), cyclopropane sulfonamide (140 mg, 1.17 mmol) in dichloromethane (5 mL) was heated for at 65° C. for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid [3,3-dimethyl-2-(3-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (45 mg, 25%) as a light yellow solid: LC/MS m/e calcd for C26H33N3O4S (M+H)+: 484.6, observed: 484.2.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1>CO.O=[Pt]=O>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2cccnc2c1
Agent: O=[Pt]=O
Solvent: CO
Product: COC(=O)c1ccc2c(c1)NCCC2
Yield: 98.8 %

Procedure:
A solution of methyl quinoline-7-carboxylate (185 mg, 1.0 mmol) and PtO2 (20 mg) in methanol (10 mL) was shaken under an atmosphere of hydrogen for 2 h. The reaction mixture was filtered through diatomaceous earth, and concentrated under reduced pressure to provide methyl 1,2,3,4-tetrahydroquinoline-7-carboxylate (189 mg): ESI MS m/z 192 [M+H]+.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[CH:3]=1.Cl.[NH2:15][CH:16]([CH2:19][CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:17][OH:18].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH2:22]([O:21][CH2:20][CH2:19][CH:16]([NH:15][C:5]([C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=1)[C:1]([O:12][CH3:13])=[O:11])=[O:7])[CH2:17][OH:18])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NC(CO)CCOCc1ccccc1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(C(=O)NC(CO)CCOCc2ccccc2)c1

Procedure:
Methyl hydrogen isophthalate (1.5 g, 8.2 mmol), 2-amino-4-(benzyloxy)butan-1-ol hydrochloride (2 g, 8.6 mmol), diisopropylethylamine (4.2 mL, 24.7 mmol), and HATU (3.8 mg, 9.9 mmol), in DMF (15 mL) are stirred at room temperature 1 h. The reaction is diluted in ethyl acetate and washed with water, 1N hydrochloric acid (aq), saturated sodium bicarbonate, brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 4% methanol/chloroform) provides the title compound. 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 8.18 (d, 1H, J=7.9 Hz), 7.86 (d, 1H, J=7.9 Hz), 7.43 (t, 1H, J=7.6 Hz), 7.42–7.35 (m, 5H), 4.59 (s, 2H), 4.33 (m, 1H), 3.96 (s, 3H), 3.88–3.72 (m, 4H), 3.53 (s, 1H), 2.08 (m, 2H).
Reaction SMILES: O[C:2]1([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21]>C(OCC)(=O)C.CCCCCC>[CH:30]([C:27]1[CH:26]=[CH:25][C:24]([CH2:23][CH:2]2[C:6]3[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:18])([CH3:17])[CH3:19])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=3[O:4][C:3]2([CH3:22])[CH3:21])=[CH:29][CH:28]=1)([CH3:32])[CH3:31]
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)Cc1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2Cc1ccc(C(C)C)cc1
Yield: 63 %

Procedure:
Using N-(3-hydroxy-3-(4-isopropylbenzyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 250, the title compound was synthesized in the same manner as in Example 271. Yield: 63%. Melting point: 130-132° C. (ethyl acetate-hexane).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][CH:12]([CH3:22])[CH2:13][CH:14]([C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1)[OH:15].C(N(CC)CC)C>ClCCl.O>[CH3:11][CH:12]([CH3:22])[CH2:13][C:14]([C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1)=[O:15]
Reactant: CC(C)CC(O)c1cnccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)c1cnccn1
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
A solution of oxalylchloride (2.65 mL, 3.92 g, 30.9 mmol) in dichloromethane (50 mL) was cooled to −60° C. and DMSO (4.4 mL, 4.82 g, 4.4 mL) was added while maintaining the temperature between −50 and −60° C. A solution of 3-methyl-1-(pyrazin-2-yl)butan-1-ol (4.66 g, 28.0 mmol) in dichloromethane (10 mL) was added and the mixture was stirred for 15 min at −60° C. Triethylamine (19.45 mL, 14.17 g, 140 mmol) was added (T≈−55° C.) and the mixture was allowed to reach room temperature. Water was added and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Column chromatography (silica, EtOAc/Heptane 1/9) afforded 3-methyl-1-(pyrazin-2-yl)butan-1-one as a dark yellow oil (4.3 g; 94%).
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].C1(SC)C=CC=CC=1.CC(C1C=CC(OCC(O)COC(C=C)=O)=CC=1)(C1C=CC(OCC(O)COC(C=C)=O)=CC=1)C.ClS(O)(=O)=O.[Br:62]Br>C(Cl)Cl>[Br:62][C:2]([CH3:13])([CH3:1])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([S:11][CH3:12])=[CH:9][CH:10]=1)=[O:4]
Reactant: CSc1ccc(C(=O)C(C)C)cc1
Reactant: BrBr
Agent: C=CC(=O)OCC(O)COc1ccc(C(C)(C)c2ccc(OCC(O)COC(=O)C=C)cc2)cc1
Agent: O=S(=O)(O)Cl
Solvent: CSc1ccccc1
Solvent: ClCCl
Product: CSc1ccc(C(=O)C(C)(C)Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
149.2 g (0.77 mol) of 2-methyl-1-[4-(methylthio)-phenyl]-propan-1-one, prepared by acylating thioanisol (as is described in EP-A-3002), are dissolved in 770 ml of methylene chloride. 0.2 ml of chlorosulfonic acid and 123.0 g (0.77 mol) of bromine are added dropwise slowly to this solution, with cooling, at room temperature. After stirring overnight, the solution is concentrated and is then reacted further as described below.
Reaction SMILES: [C:1]1([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl>CO>[C:1]1([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=2)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(NC(=O)c2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)c2ccccc2)cc1
Reaction time: 3 h
Yield: 79.9 %

Procedure:
Subsequently, 34.7 g of methyl 4-(phenylcarbonylamino)benzoate was dissolved in 500 mg of methanol and thereto 50 mg of 10% KOH was added. After stirring for 3 hours, the mixture was neutralized with hydrochloric acid and then filtered, to give an acid compound, 4-(phenylcarbonylamino) benzoic acid (26.2 g, 80% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][NH:25]C(=O)OCC)[CH2:19][CH2:18]2)=[N:14][C:13]2[C:8]1=[N:9][CH:10]=[N:11][CH:12]=2.[OH-].[K+]>CC(O)C>[NH2:25][CH2:24][CH2:23][N:20]1[CH2:19][CH2:18][CH:17]([NH:16][C:15]2[N:7]([CH2:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[C:8]3[C:13]([N:14]=2)=[CH:12][N:11]=[CH:10][N:9]=3)[CH2:22][CH2:21]1
Reactant: CCOC(=O)NCCN1CCC(Nc2nc3cncnc3n2Cc2cccs2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: NCCN1CCC(Nc2nc3cncnc3n2Cc2cccs2)CC1
Reaction time: 8 h
Yield: 56 %

Procedure:
A mixture of 10 parts of ethyl [2-[4-[[9-(2-thienylmethyl)-9H-purin-8-yl]amino]-1-piperidinyl]ethyl]carbamate, 10 parts of potassium hydroxide and 240 parts of 2-propanol was stirred overnight at reflux temperature. The reaction mixture was evaporated. Water was added. After stirring, the product was filtered off and dried, yielding 3.6 parts (56%) of N-[1-(2-aminoethyl)-4-piperidinyl]-9-(2-thienylmethyl)-9H-purin-8-amine (compound 163).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][NH:7][C:8](=[O:37])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:36])[O:21][CH2:22][CH:23]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)C.Cl>O1CCCC1>[CH:25]1[C:24]2[CH:23]([CH2:22][O:21][C:20](=[O:36])[NH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8](=[O:37])[NH:7][CH2:6][CH2:5][CH:4]=[O:3])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]=2[CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(CCNC(=O)CCCCCCCCCCNC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Agent: Cl
Solvent: C1CCOC1
Product: O=CCCNC(=O)CCCCCCCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 83.6 %

Procedure:
By using an analogous procedure to that described for Reference Example 14, 9H-fluoren-9-ylmethyl 11-[(3,3-diethoxypropyl)amino]-1-oxoundecylcarbamate (480 mg, 0.87 mmol, obtained from Reference Example 29) in tetrahydrofuran (5 ml) was reacted with 0.5 N hydrochloric acid (4 ml) at room temperature for 5 hours. Purification by chromatography (flash column, silica gel, 75% ethyl acetate in hexanes) provided 9H-fluoren-9-ylmethyl-11-oxo-11-[(3-oxopropyl)amino]undecyl-carbamate (348 mg, 84%) as a white waxy solid.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].N=C1CC(C)CCN1.[OH:13][C:14]1[C:15]([N+:21]([O-])=O)=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1>>[C:1]([OH:4])(=[O:3])[CH3:2].[OH:13][CH:14]1[CH2:19][CH2:18][CH:17]([CH3:20])[NH:16][C:15]1=[NH:21]
Reactant: Cc1ccc(O)c([N+](=O)[O-])n1
Agent: CC1CCNC(=N)C1
Solvent: CC(=O)O
Product: CC1CCC(O)C(=N)N1

Procedure:
The method of preparation of 2-imino-4-methylpiperidine acetate was used to convert 3-hydroxy-6-methyl-2-nitropyridine to the title compound except the reaction was run at 55° C. Product was obtained as a dark solid which was recrystallized from EtOH/EtOAc to give light amber crystals. The analysis of the product was found to be consistent with the proposed structure. m.p. 158-160° C. MH+=129; 1H NMR (D2O): δ4.40-4.30 (m, 1H); 3.60-3.40 (m, 1H); 2.00-1.40 (m, 4H); 1.72 (s, 3H); 1.10 (d, J=7 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[O:26]=[S:27]1(=[O:33])[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28]1>>[O:26]=[S:27]1(=[O:33])[CH2:31][CH2:30][CH:29]([NH:32][C:22]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:25])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:17])[C:10]=3[CH:18]=2)=[O:24])[CH2:28]1
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: NC1CCS(=O)(=O)C1
Product: CC1(C)c2cc(C(=O)NC3CCS(=O)(=O)C3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and (1,1-dioxotetrahydrothiophen-3-yl)amine
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Br)[CH:22]=1>CN(C)C=O.O>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[N:4]([CH2:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][N:3]3[C:2]([Br:1])=[C:6]([N+:7]([O-:9])=[O:8])[C:5]([Br:10])=[N:4]3)[CH:22]=2)[N:3]=1
Reactant: O=[N+]([O-])c1c(Br)n[nH]c1Br
Reactant: BrCc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(Br)nn(Cc2cccc(Cn3nc(Br)c([N+](=O)[O-])c3Br)c2)c1Br
Reaction time: 0.83 h

Procedure:
13.54 g of 3,5-dibromo-4-nitropyrazole, 11.1 g potassium carbonate, 0.8 g of potassium iodide and 6.6 g α, α′-dibromo-m-xylene are heated to 100° C. in 40 ml of dimethyl formamide. After 50 minutes the reaction mixture is allowed to cool and poured into 400 ml water. The precipitate is filtered, washed with water and dried in vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1.C(N1N=C(C2C=CC(OC)=C(OC)C=2)[C@H]2[C@H](CCCC2)C1=O)C1C=CC=CC=1.[H-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C2=NN(Cc3ccc(C(=O)O)cc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 4-chloromethylbenzoic acid as described for compound 78 using 12 mmol of sodium hydride instead of 6 mmol. After evaporating the reaction mixture, the residue was partitioned between aqueous sodium carbonate and ethyl acetate. The aqueous solution was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The compound was purified by chromatography (ethyl acetate) and crystallized from diethyl ether. M.p. 135°-139° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([CH2:16][C:17]3[NH:18][CH:19]=[CH:20][N:21]=3)[CH:12]=[C:13]([O:14]C)[C:7]=2[CH:6]=1)=[O:4].Br>C(O)(=O)C>[OH:14][C:13]1[C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[S:9][C:8]=2[CH:10]=[C:11]([CH2:16][C:17]2[NH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1
Reactant: COC(=O)c1cc2c(OC)cc(Cc3ncc[nH]3)cc2s1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1cc2c(O)cc(Cc3ncc[nH]3)cc2s1
Yield: 57.3 %

Procedure:
A mixture of 6-(1-imidazolylmethyl)-4-methoxybenzo[b]thiophene-2-carboxylic acid methyl ester (100 mg.), 48% aqueous hydrobromic acid (2.0 ml.) and acetic acid (1.0 ml.) was heated under reflux for 4 hours and then evaporated. The residue was dissolved in water and the solution was basified with sodium hydroxide solution and filtered. The filtrate was acidified with acetic acid and the solid was filtered off, washed with water and dried to give 4-hydroxy-6-(1-imidazolylmethyl)benzo[b]thiophene-2-carboxylic acid (52 mg.), m.p. 297°-299° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH3:17])[C:4]=1[NH:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[Cl:18][CH2:19][C:20](Cl)=[O:21].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:18][CH2:19][C:20]([N:5]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4]1[C:12]([CH2:16][CH3:17])=[CH:13][CH:14]=[CH:15][C:3]=1[CH2:1][CH3:2])=[O:21]
Reactant: CCOC(=O)CNc1c(CC)cccc1CC
Reactant: O=C(Cl)CCl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C(=O)CCl)c1c(CC)cccc1CC
Reaction time: 2 h

Procedure:
23.5 Grams (0.1 mol) of ethyl 2,6-diethylanilinoacetate and 11.3 g (0.1 mol) of monochloroacetic acid chloride were dissolved in 100 ml of benzene, 11.0 g of triethylamine was then added dropwise thereto with stirring maintaining the reaction temperature at 10°-20° C. and, thereafter, stirring was continued for further 2 hours at a room temperature. The reaction solution was washed with successive, 5% sodium hydroxide aqueous solution, 5% hydrochloric acid aqueous solution, and water. Then, the benzene layer was dried over anhydrous sodium sulfate. Thereafter, benzene was removed under reduced pressure to obtain the end product, ethyl N-chloroacetyl-2,6-diethylanilinoacetate. nD26 : 1.5225.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[F:27][C:28]1[CH:29]=[C:30]([N:35]2[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]2)[CH:31]=[CH:32][C:33]=1[F:34].N1C2C(=NC=CC=2)N(O)N=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:19])[NH:40][C:37]3[CH:38]=[CH:39][N:35]([C:30]4[CH:31]=[CH:32][C:33]([F:34])=[C:28]([F:27])[CH:29]=4)[N:36]=3)=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: Nc1ccn(-c2ccc(F)c(F)c2)n1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccn(-c5ccc(F)c(F)c5)n4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 60 h
Yield: 92.3 %

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.050 g, 0.13 mmol), 1-(3,4-difluorophenyl)-1H-pyrazol-3-amine (0.028 g, 0.15 mmol), and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.018 g, 0.13 mmol) in DMF (0.7 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.028 g, 0.15 mmol), and the reaction was allowed to stir at ambient temperature for 60 hours. The reaction was diluted with EtOAc and washed with 10% citric acid, saturated sodium bicarbonate, and saturated sodium chloride. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a linear gradient of 5-70% EtOAc/hexanes to yield the desired product (0.067 g, 0.12 mmol, 91% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([OH:10])=[C:8]([C:11]#[N:12])[O:7][C:6]=2[CH:13]=1.[CH3:14][NH:15][NH2:16]>C1C=CC=CC=1>[CH3:14][NH:15][NH:16][C:11]([C:8]1[O:7][C:6]2[CH:13]=[CH:2][CH:3]=[CH:4][C:5]=2[C:9]=1[OH:10])=[NH:12]
Reactant: CNN
Reactant: N#Cc1oc2cc(Cl)ccc2c1O
Solvent: c1ccccc1
Product: CNNC(=N)c1oc2ccccc2c1O
Yield: 43.7 %

Procedure:
3-Hydroxybenzo[b]furo-2-carbonitrile (1.40 g, 8.8 mmol, described in Example 3) was dissolved with heating in benzene (50 mL) and methyl hydrazine (1 mL, ca. 19 mmol) was added. The solution was stirred and refluxed for 2 hr and evaporated to dryness. The pasty residue (ca. 2 g) was applied in chloroform solution to chromatography on neutral alumina. Elution with 2% MeOH in CHCl3 (v/v) gave 3-hydroxybenzo[b]furan-2-carboximidic acid, 2-methylhydrazide (0.79 g): IR (CHCl3) 3510, 3480, 3450, 3200, 1635 and 1595 cm-1 ; and NMR (CDCl3) δ2.65 (3H, s), 5.7 (3H, broad), ca. 7.4 (1H, br), 7.2 (3H, m) and 7.75 (1H, d).
Reaction SMILES: C([O:8][C@H:9]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:24][CH2:23][C@:22]3([CH2:29][CH2:28][C@H:27]([OH:30])[C@@H:26]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])[CH2:25]3)[C:21]2=[O:37])=[CH:16][CH:15]=1)[C:10]([F:13])([F:12])[F:11])C1C=CC=CC=1>CO.[Pd]>[OH:30][C@H:27]1[CH2:28][CH2:29][C@@:22]2([C:21](=[O:37])[N:20]([C:17]3[CH:16]=[CH:15][C:14]([C@@H:9]([OH:8])[C:10]([F:11])([F:12])[F:13])=[CH:19][CH:18]=3)[CH2:24][CH2:23]2)[CH2:25][C@@H:26]1[O:31][CH2:32][C:33]([F:36])([F:34])[F:35]
Reactant: O=C1N(c2ccc([C@@H](OCc3ccccc3)C(F)(F)F)cc2)CC[C@]12CC[C@H](O)[C@@H](OCC(F)(F)F)C2
Agent: [Pd]
Solvent: CO
Product: O=C1N(c2ccc([C@@H](O)C(F)(F)F)cc2)CC[C@]12CC[C@H](O)[C@@H](OCC(F)(F)F)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
(5R,7R,8R) and (5S,7S,8S)-2-(4-((R)-1-(benzyloxy)-2,2,2-trifluoroethyl)phenyl)-8-hydroxy-7-(2,2,2-trifluoroethoxy)-2-azaspiro[4.5]decan-1-one (174 mg, from Example 17) was dissolved in methanol (12 mL). Palladium on activated charcoal (10% Pd, 52 mg) was added and the mixture was purged with hydrogen (4 times). The reaction mixture was stirred under hydrogen at RT for 3 hours. The catalyst was removed by filtration over a filter aid (dicalite, Acros Organics), washed with additional ethyl acetate and the filtrate was evaporated. The crude material was purified by flash chromatography (gradient of ethyl acetate in heptane) to provide the title compound as a colorless foam (144 mg). MS (ESI): 442.3 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1.O>CN(C=O)C>[Si:18]([O:1][CH2:2][C:3]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:9][CH2:10][CH2:11][CH2:12]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: OCc1cc(Br)ccc1OCCN1CCCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 30 h
Yield: 76 %

Procedure:
To a solution of (500 mg, 1.67 mmol) 1-[2-(2-hydroxymethyl-4-bromophenoxy)ethyl]pyrrolidine (Part A) in 5.5 mL of anhydrous DMF was added 377 mg of t-butyldimethylsilyl chloride followed by addition of 113 mg of imidazole. The reaction mixture was stirred at room temperature for 30 h. To the reaction was added 6 mL of water. The mixture was extracted with EtOAc (3×60 mL). The combined organic layers were dried over MgSO4 and concentrated to dryness. The residue was azeotroped with xylenes to remove any DMF present. Purification by flash chromatography (silica gel, 3% to 4% [10% conc NH4OH in MeOH]/CH2Cl2) afforded 528 mg (1.27 mmol, 77%) of a yellow oil.
Reaction SMILES: [CH3:1][C@@H:2]1[C:8](=[O:9])[NH:7][CH2:6][C@H:5]([CH3:10])[CH2:4][N:3]1C(OCC1C=CC=CC=1)=O>C(O)C.[Pd]>[CH3:1][C@H:2]1[NH:3][CH2:4][C@@H:5]([CH3:10])[CH2:6][NH:7][C:8]1=[O:9]
Reactant: C[C@H]1CNC(=O)[C@@H](C)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1CNC(=O)[C@@H](C)NC1

Procedure:
A solution of benzyl (2R,6S)-hexahydro-2,6-dimethyl-3-oxo-1H-1,4-diazepine-1-carboxylate (220 mg, 0.8 mmol) in ethanol (10 mL) was stirred at room temperature overnight under a hydrogen balloon, using Pd/C (30 mg) as catalyst. The catalyst was filtered over Celite and washed with 10% methanol in dichloromethane. The solvent was removed to yield (3R,6R)-hexahydro-3,6-dimethyl-2H-1,4-diazepin-2-one as white crystalline solid. MS (M+1): 143.1
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[N:10]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:9]2=[N:8][C:7]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1>>[CH3:5][C:6]1[N:10]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:9]2=[N:8][C:7]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[C:18]([N+:1]([O-:4])=[O:2])[CH:17]=1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(-c2nc3cc(C)ccn3c2C)cc1
Product: CC(=O)Nc1ccc(-c2nc3cc(C)ccn3c2C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 35 ml of nitric acid (fuming, d=1.50) was added portionwise 3,7-dimethyl-2-(4-acetamidophenyl)imidazo-[1,2-a]pyridine (5.6 g) at 3°-10° C. for a period of 10 minutes and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was poured into ice-water (500 ml) and the precipitates collected by filtration, were washed with water (100 ml×4) and dried over phosphorus pentoxide under reduced pressure to give 3,7-dimethyl-2-(4-acetamido-3-nitrophenyl)-imidazo[1,2-a]pyridine (3.3 g). mp. 204°-208° C. (dec.).