Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([O:14][CH3:15])=[CH:4][N:3]=1.[N+:16]([C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][C:20]=1[NH2:34])([O-:18])=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[CH3:15][O:14][C:5]1[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:7][C:2]([C:23]2[CH:22]=[CH:21][C:20]([NH2:34])=[C:19]([N+:16]([O-:18])=[O:17])[CH:24]=2)=[N:3][CH:4]=1
Reactant: COc1cnc(Cl)nc1N1CCOCC1
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
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: C1COCCO1
Product: COc1cnc(-c2ccc(N)c([N+](=O)[O-])c2)nc1N1CCOCC1
Yield: 144.2 %

Procedure:
A mixture of 4-(2-chloro-5-methoxy-pyrimidin-4-yl)-morpholine (1.0 g, 1 eq.), 2-nitro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (1.26 g, 1.1 eq.), dioxane (20 ml), Pd(PPh3)4 (0.05 g, 0.1 eq.) and 2M sodium carbonate (6.53 ml, 3.0 eq.) was heated to reflux overnight. The solvent was removed in vacuo, the residue extracted with EA, and the organic layer washed with brine and dried. The crude was purified by chromatography to give a brown solid (2.08 g, 47.83%).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]([OH:20])[C:13]3[N:14]([N:16]=[C:17]([CH3:19])[CH:18]=3)[CH:15]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CS(O[C@H:26]([C@@H:28]1[CH2:32][C:31](=[O:33])[N:30]([C@@H:34]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[CH3:35])[CH2:29]1)[CH3:27])(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C.C1COCC1>[C:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]([O:20][C@@H:26]([C@H:28]3[CH2:29][N:30]([C@@H:34]([C:36]4[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=4)[CH3:35])[C:31](=[O:33])[CH2:32]3)[CH3:27])[C:13]3[N:14]([N:16]=[C:17]([CH3:19])[CH:18]=3)[CH:15]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)OS(C)(=O)=O)CC2=O)cc1
Reactant: Cc1cc2c(O)cc(-c3cnn(C(C)(C)C)c3)cn2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4cnn(C(C)(C)C)c4)cn4nc(C)cc34)CC2=O)cc1
Yield: 31.5 %

Procedure:
To a solution of 6-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-methylpyrazolo[1,5-a]pyridin-4-ol (5 mg) in DMF (3 mL) was added (S)-1-((R)-5-oxo-1-((R)-1-phenylethyl)pyrrolidin-3-yl)ethyl methanesulfonate 1.30 (9 mg) and 1 M solution of NaHMDS in THF (0.15 mL) at rt. After 2 h. the reaction mixture was extracted with ethyl acetate. Combined organics were washed with brine, dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to provide to provide 3 mg of (R)-4-((R)-1-((6-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-methylpyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one. LCMS [M+H]+: 517.18.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][O:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([CH2:36][C:37](O)=[O:38])[CH2:32][CH2:31]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:37](=[O:38])[CH2:36][C@H:33]5[CH2:34][CH2:35][C@H:30]([O:29][CH3:28])[CH2:31][CH2:32]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CO[C@H]1CC[C@H](CC(=O)O)CC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CO[C@H]1CC[C@H](CC(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4OCC5)CC3)CC2)CC1

Procedure:
The title compound, white solid (106 mg, 88%), MS (ISP) m/z=485.5 [(M+H)+], mp 188.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and trans-2-(4-methoxy-cyclohexyl)-acetic acid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>>[CH3:1][N:2]([CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([CH3:13])=[CH:15][CH:16]=1
Reactant: CNCCC#Cc1ccccn1
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: Cc1ccc(C(=O)N(C)CCC#Cc2ccccn2)cc1
Yield: 35.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 4-methylbenzoyl chloride (58 mg, 0.37 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 31 mg of N,4-dimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brown oil (Yield: 36%).
Reaction SMILES: C[N:2]([CH3:14])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=1)=O.N[C:16]1[C:20]([C:21]#[N:22])=C[NH:18][N:17]=1>C(O)(=O)C>[CH3:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:5]2[N:18]3[N:17]=[CH:16][C:20]([C:21]#[N:22])=[C:14]3[N:2]=[CH:3][CH:4]=2)[CH:12]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: Cc1ccnc(C(=O)C=CN(C)C)c1
Solvent: CC(=O)O
Product: Cc1ccnc(-c2ccnc3c(C#N)cnn23)c1

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-1-(4-methyl-2-pyridyl)-2-propen-1-one and 0.01 mole of 3-aminopyrazole-4-carbonitrile in glacial acetic acid is refluxed for 8 hours and worked up as for Example 53 to give the product of the example.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[O:11][C:10]([CH3:34])([CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=1)[CH2:9][C:8]2=[O:35])(=[O:3])[CH3:2].[H][H]>CO.C1C=CC=CC=1.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:18])[CH3:19])[O:11][C:10]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)([CH3:34])[CH2:9][C:8]2=[O:35])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)CC(C)(C)C)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O
Agent: [Pd]
Solvent: c1ccccc1
Solvent: CO
Product: CC(=O)Oc1cc2c(cc1C(C)(C)CC(C)(C)C)OC(C)(COc1ccc(N)cc1)CC2=O

Procedure:
12.3 g of 6-acetoxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetramethylbutyl)chroman-4-one (prepared as described in Preparation 19) were dissolved in a mixture of 200 ml of methanol and 20 ml of benzene, and then catalytically reduced for 6 hours at room temperature, in the presence of 2.4 g of 10% w/w palladium-on-carbon, under 1 atmosphere (about 1 bar) pressure of hydrogen. The catalyst was filtered off, and the filtrate was condensed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography, eluted with a 4:1 by volume mixture of benzene and ethyl acetate, to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([N+:12]#[C-:13])([CH3:11])([CH3:10])[CH3:9].[C:14]1([CH:24]=O)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>Cl(O)(=O)(=O)=O>[C:8]([NH:12][C:13]1[N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[N:1][C:24]=1[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Nc1ccccn1
Reactant: O=Cc1cccc2ccccc12
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)Nc1c(-c2cccc3ccccc23)nc2ccccn12

Procedure:
Compound (31) was prepared in accordance with general instructions 1 from 1.0 ml 2-aminopyridine solution (0.1 M, MC), 0.575 ml tert-butyl isocyanide solution (0.2 M, MC), 0.500 ml naphthalene-1-carbaldehyde solution (0.3 M, MC), and 10 μl perchloric acid (w=20%). Calculated mass 315.4; found mass 316.3 (ESI-MS)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([S:8][C:9](=O)[CH3:10])([CH3:7])[CH3:6])[CH3:2].[F:13][C:14]([F:29])([F:28])CCOS(C1C=CC(C)=CC=1)(=O)=O.C[O-].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]([CH3:7])([S:8][CH2:9][CH2:10][C:14]([F:29])([F:28])[F:13])[CH3:6])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCC(F)(F)F)cc1
Reactant: CCOC(=O)C(C)(C)SC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SCCC(F)(F)F
Temperature: 25 °C
Yield: 82.6 %

Procedure:
A solution of 2-acetylsulfanyl-2-methyl-propionic acid ethyl ester (1.7 g, 8.72 mmol), toluene-4-sulfonic acid 3,3,3-trifluoro-propyl ester (2.3 g, 8.72 mmol) and sodium methoxide (1.9 g, 34.9 mmol) in ethanol (13 mL) are heated to 130° C. in a sealed tube for 4 h. The reaction is cooled to room temperature and concentrated under reduced pressure. The residue is diluted with DCM and washed with saturated aqueous NaHCO3 solution and brine. The organic layer is dried (Na2SO4), filtered and the filtrate concentrated under reduced pressure to afford 1.76 g of title compound as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (3H, t, J=7 Hz), 1.51 (3H, s), 2.26-2.42 (2H, m), 2.76-2.85 (2H, m), 4.18 (2H, q, J=6.96 Hz)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OP([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)(=O)OCC)C.CN(C)C=O.C(O)C>O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[CH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(Cc1ccc(C#N)cc1)OCC
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C=C2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
Under argon, to a stirred mixture of N-benzyl-4-piperidone (Aldrich) (26.0 g, 0.137 mol) and (4-cyano-benzyl)-phosphonic acid diethyl ester (36.6 g, 0.1445 mol) in dimethylformamide (260 mL) sodium hydride (60%, 7.8 g, 0.195 mol) was added at 0° C. The reaction mixture was stirred at room temperature overnight, then ethanol (10 mL) was added dropwise, the so obtained mixture was poured into water (300 mL), and extracted with diethyl ether (3×300 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography using Kieselgel 60 (0.040-0.063 mm) (Merck) as adsorbent, and n-hexane:ethyl acetate=2:1 as eluent to yield 34.65 g (87%) of the title compound as an oil.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4]CC.[CH2:7]([Li])CCC.C(O[CH:15]([C:17](C)([OH:23])[C:18](N(C)C)=[O:19])[CH3:16])C.[Cl-].[NH4+]>C1COCC1.O.CCCCCC>[OH:19][CH:18]([C:17](=[O:23])[C:15]#[C:16][CH2:1][CH2:2][CH2:3][CH3:4])[CH3:7]
Reactant: [Li]CCCC
Reactant: C#CCCCC
Reactant: CCOC(C)C(C)(O)C(=O)N(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCCCC#CC(=O)C(C)O
Temperature: -50 °C
Reaction time: 0.25 h

Procedure:
A solution of 22 g of hexyne in 300 ml of THF was placed in a flask, and cooled to -50° C. Then, 170 ml of a 1.55M n-hexane solution of n-butyllithium was dropped thereto. The resulting mixture was stirred at -50° C. for 15 minutes, and then a solution of 50 g of (S) 1-ethoxyethyl-N,N-dimethyllactamide as obtained in Example 1 (2) in 150 ml of THF was dropped thereto. The resulting mixture was stirred at the same temperature as above for two hours, and then an aqueous solution of 28.3 g of ammonium chloride in 200 ml of water was dropped to terminate the reaction.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]([C:15]([O:17]CC)=[O:16])[CH:6]=1.O.[OH-].[Li+]>C(Cl)Cl.O>[CH3:1][NH:2][CH2:4][C:5]1[N:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[N:8]=[C:7]([C:15]([OH:17])=[O:16])[CH:6]=1
Reactant: CN
Reactant: CCOC(=O)c1cc(CBr)nc(C(F)(F)F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CNCc1cc(C(=O)O)nc(C(F)(F)F)n1

Procedure:
A solution of methylamine (33 wt % in Ethanol, 1.12 mmol, Aldrich) was added portionwise to a solution of ethyl 6-(bromomethyl)-2-(trifluoromethyl)pyrimidine-4-carboxylate (0.150 g, 0.321 mmol, Example 5, Step A) in methylene chloride (3.0 mL), until reaction was complete. Solvent was removed in vacuo. The residue was dissolved in tetrahydrofuran (7.0 mL) and water (2.0 mL), and lithium hydroxide monohydrate (0.135 g, 3.21 mmol) was added. After a 5 minute reaction time, the mixture was treated with 1N HCl to adjust the pH to 7, then was purified using preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). LC-MS: 236.1 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:10][OH:11])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Br[C:13]1[S:14][CH:15]=[CH:16][N:17]=1>O1CCOCC1>[S:14]1[CH:15]=[CH:16][N:17]=[C:13]1[N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][OH:11])[CH2:5][CH2:6]1
Reactant: OCC(O)CN1CCNCC1
Reactant: Brc1nccs1
Solvent: C1COCCO1
Product: OCC(O)CN1CCN(c2nccs2)CC1

Procedure:
Grams 6.4 of 1-(2,3-dihydroxypropyl)piperazine and 3.3 g of 2-bromo-1,3-thiazole in 50 ml dioxane were refluxed for 24 hours. The reaction mixture was evaporated to dryness and the so obtained residue was purified on column eluting with chloroform:methanol (9:1). Grams 1.5 of 3-[4-(1,3-thiazol-2-yl)piperazin-1-yl] propane-1,2-diol which, by recrystallization from acetone, melted at 138°-139° C., were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)=[O:4].O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH2:24][C:25]1[CH:34]=[CH:33][C:32]([C:35]([C:37]2[N:45]3[C:40]([CH:41]=[CH:42][CH:43]=[CH:44]3)=[C:39](Br)[C:38]=2[CH3:47])=[O:36])=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28]>COCCOC.O.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>[NH2:24][C:25]1[CH:34]=[CH:33][C:32]([C:35]([C:37]2[N:45]3[C:40]([CH:41]=[CH:42][CH:43]=[CH:44]3)=[C:39]([C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=3)[C:38]=2[CH3:47])=[O:36])=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(Br)c3ccccn23)ccc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cccc(-c2c(C)c(C(=O)c3ccc(N)c(C(=O)OC)c3)n3ccccc23)c1
Temperature: 90 °C
Yield: 65.9 %

Procedure:
0.229 g (1.27 mmol) of [3-(methoxycarbonyl)phenyl]boronic acid, 0.492 g (2.12 mmol) of potassium phosphate dihydrate and 0.024 g (0.02 mmol) of tetrakis(triphenylphosphine)palladium are added, under an argon atmosphere at ambient temperature, to 0.410 g (1.06 mmol) of methyl 2-amino-5-[(1-bromo-2-methylindolizin-3-yl)carbonyl]benzoate in 8 ml of a DME/H2O (5/1) mixture. The reaction medium is heated at 90° C. for 18 hours. The reaction medium is extracted with dichloromethane, washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, filtered, and then concentrated under reduced pressure. The solid obtained is purified by silica gel column chromatography, elution being carried out with dichloromethane. 309 mg of a yellow solid are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([OH:16])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:17][CH3:18])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:19])[CH:5]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:17][CH3:18])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:19])[CH:5]=1
Reactant: CCC12CCC(=O)C=C1c1c(cc(O)c(Cl)c1Cl)C2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(CC)C2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 5,6-dichloro-9a-ethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (6.0 gm., 0.02 mole), ethyl bromoacetate (4.0 gm., 0.025 mole) and potassium carbonate (8.3 gm., 0.06 mole) in dimethyl-formamide (35 ml.) is heated at 50° C. and stirred for one hour. The mixture is cooled and poured into water (300 ml.). The solid product that separates is removed by filtration, then washed with water followed by benzene (10 ml.).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[SH:14][CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:17][CH2:16][CH2:15][S:14][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: OCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(SCCO)c([N+](=O)[O-])c1
Yield: 97.7 %

Procedure:
To a solution of 4-fluoro-3-nitrobenzoic acid (15 g, 81 mmol) in DMF (250 ml) was added 2-mercaptoethanol (6.27 ml, 89 mmol), and potassium carbonate (28.0 g, 203 mmol). The reaction was allowed to stir over night. The reaction mixture had turned solid and yellow. TLC analysis indicated consumption of starting material. The reaction mixture was treated with H2O (300 mL) and extracted with DCM (2×100 mL). The aqueous layer was then treated with concentrated HCl until a pH of 1 was attained. The organic layer was extracted with EtOAc (4×150 mL). The combined EtOAc extracts were dried over Na2SO4 and concentrated in vacuo to provide 4-(2-hydroxyethylthio)-3-nitrobenzoic acid (19.24 g, 79. mmol) in 98% yield, which was used without further purification.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH:18]1([CH2:21][C:22]([NH2:30])([CH3:29])[C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH2:20][CH2:19]1.CO>CCCCCCC>[CH:18]1([CH2:21][C:22]([NH:30][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])([CH3:29])[C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH2:20][CH2:19]1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Solvent: CO
Solvent: CCCCCCC
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2ccc(C3CC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 357e) as starting materials. The product was isolated by chiral chromatography on Reprosil Chiral NR using heptane/10% 2-propanol as eluent. The (+)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 397.2230 (M+H)+, αD20 (MeOH)=+25.7°.
Reaction SMILES: [NH2:1][CH:2]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH:3]([NH:9][CH:10]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])[CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:26]([NH:1][CH:2]([CH2:22][CH:23]([CH3:24])[CH3:25])[CH:3]([NH:9][CH:10]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])[CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C(NC(C)C(=O)N1CCC[C@H]1C(=O)O)C(N)CC(C)C
Product: CCOC(=O)C(NC(C)C(=O)N1CCC[C@H]1C(=O)O)C(CC(C)C)NC(=O)c1ccccc1

Procedure:
By treating a solution of N-(2-amino-1-ethoxycarbonyl-4-methylpentyl)-D,L-alanyl-L-proline (prepared as described in Example 79) in organic solvent with benzoyl chloride, one can obtain N-(2-benzamido-1-ethoxycarbonyl-4-methylpentyl)-D,L-alanyl-L-proline.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([C:13]3[CH:22]=[C:21]4[C:16]([C:17](=[O:28])[C:18]([C:25]([OH:27])=[O:26])=[CH:19][N:20]4[CH2:23][CH3:24])=[CH:15][C:14]=3[F:29])[CH2:8]2)=[CH:4][CH:3]=1.[CH2:30]=O>C(O)(=O)C>[Br:1][C:2]1[S:6][C:5]([CH:7]2[N:12]([CH3:30])[CH2:11][CH2:10][N:9]([C:13]3[CH:22]=[C:21]4[C:16]([C:17](=[O:28])[C:18]([C:25]([OH:27])=[O:26])=[CH:19][N:20]4[CH2:23][CH3:24])=[CH:15][C:14]=3[F:29])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: C=O
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4ccc(Br)s4)C3)cc21
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(c4ccc(Br)s4)C3)cc21

Procedure:
A 150 mg portion of 7-[3-(5-bromo-2-thienyl)-1piperazinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was dissolved in a mixture of 0.6 ml of 37% formaldehyde and 0.75 ml of glacial acetic acid, heated on a steam bath for 2 hours and then evaporated. The residue was diluted with 3 ml of water, adjusted to pH 7 with 1N sodium hydroxide and the solid collected, giving 120 mg of the desired product, mp 243°-245° C. (dec.).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)(=[O:5])=[O:4].C1C(=O)N([Br:22])C(=O)C1>C(Cl)Cl>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[C:12]([Br:22])[CH:13]=1)(=[O:4])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: CNS(=O)(=O)CCc1ccc(N)cc1
Solvent: ClCCl
Product: CNS(=O)(=O)CCc1ccc(N)c(Br)c1
Temperature: 0 °C
Yield: 85.6 %

Procedure:
A solution of 318 mg (1.48 mmol) of 2-(4-aminophenyl)-ethanesulfonic acid methylamide (as prepared in the previous step) in CH2Cl2 (20 mL) was cooled to 0° C. and treated with 251 mg (1.41 mmol) of NBS at that temperature for 1 h. The mixture was diluted with CH2Cl2 (30 mL) and washed with saturated aqueous NaHCO3 (1×30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 25-g Varian MegaBond Elut SPE column with 50% EtOAc-hexane afforded 354 mg (81%) of the title compound as a white solid: 1H-NMR (CD3CN; 400 MHz): δ 7.34 (d, 1H, J=2.0 Hz), 7.03 (dd, 1H, J=8.0, 2.0 Hz), 6.77 (d, 1H, J=8.0 Hz), 5.06-4.97 (m, 1H), 4.48-4.40 (br s, 2H), 3.25-3.18 (m, 2H), 2.93-2.86 (m, 2H), 2.67 (d, 3H, J=5.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C9H13N2O2SBr, 293.0/295.0 (M+H). found 293.0/295.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[C@H:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=1.O=[C:19]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]1.C([BH3-])#N.[Na+]>C(O)(=O)C>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][CH:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][CH:15]=2)[O:12][CH2:11][C:10]2[N:5]3[C@H:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=2)[CH2:20]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: C[C@@H]1C(=O)NN=C2COc3ccc(N)cc3N21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@@H]1C(=O)NN=C2COc3ccc(NC4CCN(C(=O)OC(C)(C)C)C4)cc3N21
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A solution of (R)-6-amino-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Example #148, Step D, 2.4 g, 10.32 mmol) and tert-butyl 3-oxopyrrolidine-1-carboxylate (Aldrich, 2.0 g, 6.23 mmol) was stirred at 15° C. for 10 min and then acetic acid (7 mL) was added. The reaction mixture was stirred for 30 min and sodium cyanoborohydride (0.68 g, 11 mmol) was added. The reaction mixture was stirred at ambient temperature overnight then concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 100% EtOAc) to give 3-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.3 g, 53%) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6): δ 10.71 (s, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.42 (s, 1H), 6.20 (d, J=8.4 Hz, 1H), 5.63-5.53 (m, 1H), 4.73 (m, 1H), 4.52-4.41 (m, 2H), 4.06-3.99 (m, 1H), 3.62-3.37 (m, 2H), 3.15-2.92 (m, 1H), 2.10 (m, 1H), 1.64 (m, 1H), 1.38 (s, 9H), 1.30 (m, 3H). LCMS (Table 1, Method 2) Rt=1.059 min.; MS m/z: 424 [M+Na]+.