Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[OH:24])=[CH:12][CH:11]=[CH:10][N:9]=1.CI.[C:30](OCC)(=O)C>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[O:24][CH3:30])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: CCOC(C)=O
Reactant: Oc1cnccc1CCCOc1cccnc1Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cnccc1CCCOc1cccnc1Oc1cccc(Br)c1
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 0.26 g, 6.5 mmol) is suspended in DMF (30 ml), and thereto is added 2-(3-bromophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine (2.0 g, 5,0 mmol) obtained in Example 32 at room temperature, and the mixture is stirred for 30 minutes. To the mixture is added methyl iodide (0.78 g, 0.34 mmol) under ice-cooling, and the mixture is further stirred for 30 minutes. To the reaction solution is added ethyl acetate (250 ml), and the organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by basic silica gel column chromatography (eluent: chloroform/ethyl acetate), and recrystallized from diethyl ether to give the title compound (0.75 g) as colorless crystals, m.p. 134-136° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[C:13]3[C:7]([CH2:8][CH:9]([C:14]([OH:16])=O)[S:10][C:11]=3[N:12]=1)=[N:6][N:5]2[CH2:17][C:18]1[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=1.Cl.[Cl:29][CH2:30][CH2:31][NH2:32].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[NH2:1][C:2]1[N:3]=[C:4]2[C:13]3[C:7]([CH2:8][CH:9]([C:14]([NH:32][CH2:31][CH2:30][Cl:29])=[O:16])[S:10][C:11]=3[N:12]=1)=[N:6][N:5]2[CH2:17][C:18]1[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=1
Reactant: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C(=O)O)C3)c1C
Reactant: NCCCl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C(=O)NCCCl)C3)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.6 %

Procedure:
A mixture composed of 4-amino-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7,8-dihydro-2H-6-thia-1,2,3,5-tetraazaacenaphthylene-7-carboxylic acid of Example 8 (40 mg), 2-chloroethylamine hydrochloride (24 mg), 1-hydroxybenzotriazole monohydrate (24 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40 mg), triethylamine (44 μL) and dehydrated N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate and sequentially washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (dichloromethane-ethyl acetate) to obtain the title compound (10 mg, 22%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[C:4]([CH:28]2[CH2:30][O:29]2)[C:5]([O:26][CH3:27])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH3:9])[CH:7]=1.[CH:32]([NH2:35])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C.CO>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:31])=[C:4]([CH:28]([OH:29])[CH2:30][NH:35][CH:32]([CH3:34])[CH3:33])[C:5]([O:26][CH3:27])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH3:9])[CH:7]=1
Reactant: CC(C)N
Reactant: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1C1CO1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1C(O)CNC(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
N-[1-(5-chloro-2-methoxy-4-methyl-3-oxiran-2-ylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (140.0 mg, 0.32 mmol) was stirred in methylene chloride (1.1 mL). Isopropylamine (124 μL, 1.6 mmol) and DIPEA (282 pt, 1.62 mmol) were added. The mixture was stirred at 80° C. overnight. Methanol was added and purification by preparative LC/MS (pH 10) gave the desired compound (12.9 mg, 8%). LCMS calculated for C25H36ClN6O3 (M+H)+: m/z=503.3. found: 503.1.
Reaction SMILES: FC1C(NC2C=C(C)NN=2)=NC([NH:8][C@H:9]([C:11]2[N:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH3:10])=NC=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:37]=[N+:38]=[N-].[Na+]>C(Cl)Cl>[N:8]([CH:9]([C:11]1[N:12]=[CH:13][C:14]([F:17])=[CH:15][N:16]=1)[CH3:10])=[N+:37]=[N-:38]
Reactant: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2F)n[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(N=[N+]=[N-])c1ncc(F)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
A round-bottom flask containing 1-(5-fluoropyrimidin-2-yl)ethanol (Method 4, 0.79 g, 5.55 mmol) was charged with triethylamine (0.67 g, 6.66 mmol) and anhydrous DCM (10 ml). The solution was cooled to 0° C., and methanesulfonyl chloride (0.70 g, 4.1 mmol) was added dropwise. The resulting mixture was allowed to stir at room temperature for 2 hours, at which point the volatile components were removed using a rotary evaporator. The residue was dissolved in DMF (15 ml) and treated with sodium azide (0.72 g, 11.1 mmol). The resulting mixture was stirred at room temperature for 60 hours. It was then partitioned between EtOAc and brine. The organic layer was obtained, dried (Na2SO4), and evaporated to dryness. The crude material was purified by silica gel chromatography (by ISCO Combiflash with gradient EtOAc and hexanes) to afford the title compound as a colourless oil (0.60 g, 65% yield over two steps). GC-MS, 167 (M), 138 (M-N2), 125 (M-N3); 1H NMR (CDCl3) δ 8.60 (s, 2H), 4.60 (m, 1H), 1.65 (d, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:6][C:7](=[O:19])/[CH:8]=[CH:9]/[C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[CH:15][NH:16]2)=[CH:12][CH:11]=1)[CH2:4][CH3:5].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33]>CN(C)C=O>[CH2:3]([NH:6][C:7](/[CH:8]=[CH:9]/[C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[CH:15][N:16]2[CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=2[O:32][CH3:33])=[CH:12][CH:11]=1)=[O:19])[CH2:4][CH3:5]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: CCCNC(=O)/C=C/c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCNC(=O)/C=C/c1ccc2ccn(Cc3ccc(C(=O)OC)cc3OC)c2c1
Reaction time: 1 h
Yield: 62.9 %

Procedure:
Sodium hydride (0.12 g of a 60% dispersion in mineral oil) was added to a stirred solution of E-N-propylindole-6-acrylamide (0.7 g) in N,N-dimethylformamide (35 ml) cooled by an ice bath. After approximately 1 hr, a solution of methyl 4-bromomethyl-3-methoxybenzoate (0.79 g) (see Example 1, part 1) in N,N-dimethylformamide (2 ml) was added, the cooling bath removed and the mixture stirred for 1 hr. The mixture was poured into ice and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and evaporated. The residue was crystallized from a mixture of ethyl acetate and hexane to give methyl E-4-[6-[2-(propylcarbamoyl)vinyl]indol-1-ylmethyl]-3-methoxybenzoate (0.78 g) as a white solid. The mother liquor was evaporated and the residue was purified by flash chromatography, eluting with 1:1 ethyl acetate:hexane, to give a further quantity of the product (0.23 g, 84% combined yield); partial NMR (250 MHz, DMSO-d6): 0.87(t, 3H, CH2CH2CH3), 1.45(m, 2H, CH2CH2CH3), 3.12(m, 2H, CH2CH2CH3) 3.83(s, 3H, OCH3), 3.96(s, 3H, OCH3), 5.46(s, 2H, NCH2Ar), 7.98(br t, 1H, NHCO).
Reaction SMILES: [CH3:1][CH2:2][C:3]([NH:5][CH:6]1[C:25](=[O:26])[N:8]2[C:9]([C:22]([OH:24])=[O:23])=[C:10]([CH2:13][S:14][C:15]3[S:16][C:17]([CH2:20][NH2:21])=[N:18][N:19]=3)[CH2:11][S:12][C@H:7]12)=[S:4].C(N(CC)CC)C.[CH3:34][N:35]=[C:36]=[O:37]>O.O1CCCC1>[CH3:1][CH2:2][C:3]([NH:5][CH:6]1[C:25](=[O:26])[N:8]2[C:9]([C:22]([OH:24])=[O:23])=[C:10]([CH2:13][S:14][C:15]3[S:16][C:17]([CH2:20][NH:21][C:36]([NH:35][CH3:34])=[O:37])=[N:18][N:19]=3)[CH2:11][S:12][C@H:7]12)=[S:4]
Reactant: CCC(=S)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CN)s3)CS[C@H]12
Reactant: CN=C=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(=S)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CNC(=O)NC)s3)CS[C@H]12
Reaction time: 2 h
Yield: 96.2 %

Procedure:
7-Methylthioacetamido-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.8 g.) and triethylamine (0.8 g.) was dissolved in a mixture of water (40 ml.) and tetrahydrofuran (40 ml.). A solution of methyl isocyanate (0.46 g.) in tetrahydrofuran (10 ml.) was added dropwise to the solution at 0°-5° C., and the mixture was stirred at the same temperature for 2 hrs. The tetrahydrofuran was distilled off under reduced pressure from the reaction mixture. The residue was washed with ethyl acetate and then adjusted to pH1.0 with 10% hydrochloric acid. The precipitating crystals were collected by filtration and then washed with water to give 7-methylthioacetamido-3-[5-(3-methylureidomethyl)-1,3,4-thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylic acid (1.96 g.). The product was suspended in water (50 ml.), and sodium bicarbonate (0.66 g.) was added to the suspension under ice-cooling to give a solution. The insoluble substance was filtered off from the solution, and the solution was adjusted to pH1.0 with 10% hydrochloric acid. The precipitating crystals were collected by filtration, washed with water to give the pure object compound. m.p. 177°-179° C. (dec.).
Reaction SMILES: Br[C:2]1[NH:3][C:4](=[O:11])[C:5]2[NH:6][CH:7]=[N:8][C:9]=2[N:10]=1.[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=1)[CH3:13].COCCO>O>[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:2]2[NH:3][C:4](=[O:11])[C:5]3[NH:6][CH:7]=[N:8][C:9]=3[N:10]=2)=[CH:17][N:16]=1)[CH3:13]
Reactant: O=c1[nH]c(Br)nc2nc[nH]c12
Reactant: CCOc1ccc(N)cn1
Solvent: O
Solvent: COCCO
Product: CCOc1ccc(Nc2nc3nc[nH]c3c(=O)[nH]2)cn1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A mixture of 2-bromohypoxanthine (6.3 g; 29.3 mmol), 2-ethoxy-5-aminopyridine (12.1 g; 87.9 mmol), 2-methoxyethanol (90 mL), and water (15 mL) is heated under reflux for 3 h. The reaction mixture is cooled to room temperature, the precipitate collected by filtration and washed with water and methanol to afford N2-(2-Ethoxypyridin-5-yl)guanine (6.4 g), m.p. >350° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][CH:8]2[CH2:24][N:12]3[CH2:13][CH2:14][N:15]([C:17]4[N:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=4)[CH2:16][CH:11]3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][CH:8]2[CH2:24][N:12]3[CH2:13][CH2:14][N:15]([C:17]4[N:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH2:16][CH:11]3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Fc1ccc(OCC2CCC3CN(c4ccc(Cl)nn4)CCN3C2)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Fc1ccc(OCC2CCC3CN(c4cccnn4)CCN3C2)cc1

Procedure:
A mixture of 0.150 g (0.363 mmol) of (7RS,9aSR)-7-(4-fluorophenoxy)methyl-2-(6-chloropyridazin-3-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Example 32). 0.10 mL (0.72 mmol) of triethylamine, and 20 mg of 10% Pd/C in 10 mL of ethanol were shaken under 50 psi of hydrogen for 18 h. The mixture was filtered through Celite and the filtrate was evaporated. The residue was dissolved in chloroform, washed with water, dried (magenesium sulfate), filtered and evaporated. mp (.HCl) 246–250° C. HRMS calcd for C19H23FN4O: 342.1851, found: 342.1826.
Reaction SMILES: [C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:11][C:10]=1[CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(I)CCCCC>>[CH2:15]([C:12]1[N:13]([CH3:14])[C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([CH3:21])[CH:11]=1)[CH3:16].[CH2:12]([CH2:15][C:16]([O-:18])=[O:17])[CH2:11][CH2:10][CH2:9][CH2:1][CH3:2]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccccc2)n1C
Solvent: CCCCCCI
Product: CCCCCCCC(=O)[O-]
Product: CCc1cc(C)c(C(=O)c2ccccc2)n1C

Procedure:
The alkylation procedure of Example 77A is performed upon ethyl 5-benzoyl-1,4-dimethylpyrrole-2-acetate (from Example 86), using an equivalent quantity of n-hexyl iodide instead of methyl iodide used in Example 77A to yield ethyl 5-benzoyl-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate.
Reaction SMILES: Cl[CH:2]([CH3:23])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[CH:12]=[CH:13]/[C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.[CH2:24]([NH:27][CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26]>>[CH2:24]([N:27]([CH2:28][CH2:29][CH3:30])[CH:2]([CH3:23])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[CH:12]=[CH:13]/[C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)[CH2:25][CH3:26]
Reactant: CCCNCCC
Reactant: CC(Cl)CCOc1ccccc1/C=C/c1nc2ccccc2o1
Product: CCCN(CCC)C(C)CCOc1ccccc1/C=C/c1nc2ccccc2o1

Procedure:
The title compound was prepared as described in Example 1 starting with (B) of this Example (3.0 g, 9.2 mmol) and using dipropylamine in place of dibutylamine to produce 0.61 g (17% yield) of the free base of the title compound which was converted to the HCl salt, mp 152°-153° C. IR(KBr): 1600 cm-1. MS: 393(MH+). 1H NMR (CDCl3): δ 8.24-6.97 (m, 10H), 4.08 (t, J=5.2 Hz, 2H), 3.18 (m, 6H), 1.98 (m, 8H), 0.99 (m, 6H).
Reaction SMILES: O.[F:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([O:12][C:13]2[C:14]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:5][C:4]=1[NH:25][C:26](=[O:28])[CH3:27]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:9][C:7]1[C:6]([O:12][C:13]2[C:14]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:5][C:4]([NH:25][C:26](=[O:28])[CH3:27])=[C:3]([F:2])[CH:8]=1
Reactant: COC(=O)COc1ncccc1Oc1cc(NC(C)=O)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)COc1ncccc1Oc1cc(NC(C)=O)c(F)cc1N
Temperature: 45 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a mixture of 3.6 g of an iron powder, 10 ml of acetic acid and 1 ml of water was added a solution of 3.67 g of N-[2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}-4-nitrophenyl]acetamide in 12 ml of acetic acid and 2 ml of ethyl acetate, dropwise while maintaining the temperature of the reaction solution at 45° C. or lower. After completion of the addition, the mixture was stirred for 1 hour at 40° C., then, the reaction mixture was filtrated through Celite, and concentrated. The residue was diluted with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated. Then, the resulted residue was washed with diisopropyl ether to obtain 3.09 g of N-[4-amino-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyl oxy}phenyl]acetamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=4)[CH:26]=[C:25]([CH2:34][C:35]([O:37]CC)=[O:36])[CH:24]=3)=[O:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].O.[OH-].[Li+]>O1CCCC1.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=4)[CH:26]=[C:25]([CH2:34][C:35]([OH:37])=[O:36])[CH:24]=3)=[O:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc(S(=O)(=O)N3CCN(C(=O)OCC)CC3)cc2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(S(=O)(=O)c2ccc(C(=O)c3cc(CC(=O)O)cc4ccc(F)cc34)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 4-[4-(3-ethoxycarbonylmethyl-7-fluoro-naphthalene-1-carbonyl)-benzenesulfonyl]-piperazine-1-carboxylic acid ethyl ester (0.110 g, 0.20 mmol) in tetrahydrofuran (12 mL) was added a solution of lithium hydroxide monohydrate (0.042 g, 0.99 mmol) in water (3 mL) and the reaction mixture was stirred for 14 hours at room temperature. The reaction mixture was concentrated under reduced pressure, diluted with water (6 mL) and washed with ethyl acetate (2×5 mL). The aqueous layer was acidified with an aqueous solution of hydrochloric acid (1 N), then extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 0.058 (56%) of 4-[4-(3-carboxymethyl-7-fluoro-naphthalene-1-carbonyl)-benzenesulfonyl]-piperazine-1-carboxylic acid ethyl ester as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.51 (br. s, 1 H), 8.10-8.20 (m, 2H), 8.00 (d, J=8.3 Hz, 2 H), 7.90 (d, J=8.3 Hz, 2 H), 7.82-7.88 (m, 1 H), 7.72 (s, 1 H), 7.57 (td, J=8.7, 2.2 Hz, 1 H), 3.99 (q, J=6.9 Hz, 2 H), 3.82 (s, 2 H), 3.46 (br. s, 4 H), 2.96 (br. s, 4 H), 1.13 (t, J=6.9 Hz, 3 H). MS cald. for C26H25FN2O7S ([M+H]+) 529, obsd. 529.3.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N:12]([O-])=O.[Na+].[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])(=[O:19])[CH2:17][CH3:18].C([O-])(=O)C.[Na+]>Cl.O.C(O)C>[O:19]=[C:16]([CH2:17][CH3:18])[C:20](=[N:12][NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCC(=O)CC(=O)OC
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC(=O)C(=NNc1cccc(C(F)(F)F)c1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
A slurry of 3-(trifluoromethyl)aniline (8.03 g, 50 mmol) in 6 N HCl (50 mL) was cooled to 0° C. and treated dropwise with a solution of sodium nitrite (4.10 g, 60 mmol) in water (10 mL). The resulting pale yellow solution was poured into a suspension of methyl propionylacetate (6.50 g, 50 mmol) and sodium acetate (24.00 g, 292 mmol) in ethanol (80 mL), pre-cooled to 0° C. The resulting yellow/orange slurry was stirred for 30 min. The product was collected by filtration and washed with water (100 mL). The crude material was dissolved in ethyl acetate (100 mL) and dried (Na2SO4). The product crystallized upon concentration of the ethyl acetate to give (14.00 g, 93%) of methyl 3-oxo-2-{[3-(trifluoromethyl)phenyl]hydrazono}pentanoate as a yellow/orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:33]([OH:35])=[O:34])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([C:27]([F:30])([F:29])[F:28])=[CH:24][C:25]=2[CH3:26])=[CH:16][CH:15]=1)=[O:10].Cl.[CH2:37]([N:39]([CH2:42][CH2:43]Cl)[CH2:40][CH3:41])[CH3:38]>>[CH2:37]([N:39]([CH2:42][CH2:43][O:34][C:33](=[O:35])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([C:27]([F:29])([F:30])[F:28])=[CH:24][C:25]=2[CH3:26])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:10])[CH2:40][CH3:41])[CH3:38]
Reactant: CCN(CC)CCCl
Reactant: Cc1cc(C(F)(F)F)n(C)c(=O)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1
Agent: Cl
Product: CCN(CC)CCOC(=O)[C@H](Cc1ccc(-c2c(C)cc(C(F)(F)F)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
N-[(2,6-dichlorophenyl)carbonyl]-4-[1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-20 pyridinyl]-L-phenylalanine 2-[(N,N-diethyl)amino]ethyl ester can be prepared from N-[(2,6-dichlorophenyl)carbonyl]-4-[1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine and 2-[(N,N-diethyl)amino]ethyl chloride hydrochloride using the general procedure described in example 39.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:6]=2[N:7]=1.O.[CH3:20][N:21]1C(=O)CCC1>>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH3:20])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:6]=2[N:7]=1
Reactant: CN1CCCC1=O
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1Cl)CC2
Solvent: O
Product: CNc1nc(Cl)nc2c1CCC2c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of Preparation AR [2,4-dichloro-7-(2-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine] (900 mg, 3.00 mmol) in NMP (Volume: 3.00E+04 μl) was added 2 M monomethanamine (7525 μl, 15.05 mmol). The resulting reaction mixture was stirred at RT for 1 h. Water was added (120 ml) to the mixture and stirred for 30 min. The mixture was filtered to get light green solid which was dried to get 2-chloro-7-(2-chlorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (713 mg, 2.424 mmol, 81% yield). LC-MS (M+H)+=295.9. 1H NMR (400 MHz, CD3OD) δ 7.50-7.39 (m, 1H), 7.34-7.19 (m, 2H), 7.04-6.90 (m, 1H), 4.86-4.72 (m, 1H), 3.07 (s, 3H), 2.90-2.67 (m, 3H), 2.11-1.91 (m, 1H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:7][C:8](=[CH:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16]O)[CH3:14])[CH3:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([O:6][CH2:16][CH2:15][CH:13]([CH2:12][CH2:11][CH:10]=[C:8]([CH3:9])[CH3:7])[CH3:14])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: CC(C)=CCCC(C)CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCCC(C)CCC=C(C)C
Temperature: 150 °C

Procedure:
24 g of methacrylic acid, 31 g of citronellol and 1.5 g of p-toluenesulfonic acid in 500 mL of toluene were heated to reflux at a oil temperature of 150° C. for 19 h. Subsequently, the reaction mixture was quenched by the addition of salt saturated sodium bicarbonate solution. The mixed solution was extracted with ether. The organic layers were combined and washed with salt saturated sodium bicarbonate solution, an aqueous solution of sodium hydride, and then salt saturated ammonium chloride solution, and then dried over salt saturated brine and sodium sulfate anhydrous. Finally, the resultant oily product was evaporated under reduced pressure to obtain citronellyl methacrylate.
Reaction SMILES: I[C:2]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:14]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19])([CH3:16])[CH3:15]>>[CH:14]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([CH3:16])[CH3:15]
Reactant: CC(C)c1ccccc1N
Reactant: O=C(O)c1cccc(C(=O)O)c1I
Product: CC(C)c1ccccc1Nc1c(C(=O)O)cccc1C(=O)O
Yield: 38 %

Procedure:
Similar reaction of 2-iodoisophthalic acid and 2-isopropylaniline gave 2-[(2-isopropyl)phenylamino]-isophthalic acid (38%), mp (EtOAc/petroleum ether) 217-219° C. 1H NMR [(CD3)2SO] δ 1.25 (d, J=6.8 Hz, 6 H, 2×CH3), 3.22-3.29 (m, 1 H, CH), 6.81 (dd, J=7.4, 1.8 Hz, 1 H, H-3' or H-6'), 6.93 (t, J=7.7 Hz, 1 H, H-2), 6.92-7.02 (m, 2 H, H-4' and H-5'), 7.26 (dd, J=7.1, 2.2 Hz, 1 H, H-6' or H-3'), 7.90 (d, J=7.7 Hz, 2 H, H-4 and H-6), 9.69 (s, 1 H, NH), 12.93 (br s, 2 H, 2×COOH). Anal. (C17H17NO4) C, H, N.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:13]([OH:14])=[C:12]([CH:15]([OH:17])[CH3:16])[C:11]([CH:18]=[CH2:19])=[CH:10][N:9]=1>[O-2].[O-2].[O-2].[Cr+6].C(Cl)Cl>[CH3:7][C:8]1[C:13]([OH:14])=[C:12]([C:15](=[O:17])[CH3:16])[C:11]([CH:18]=[CH2:19])=[CH:10][N:9]=1
Reactant: C=Cc1cnc(C)c(O)c1C(C)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=Cc1cnc(C)c(O)c1C(C)=O
Reaction time: 0.33 h

Procedure:
To 750 ml. of dry methylene chloride containing 47.5 ml. of dry pyridine was added with stirring and cooling 29.6 g. of chromium trioxide. The mixture was aged 20 minutes at room temperature and then treated with a solution of 10.96 g. of the product from Example 10, Step B, in 250 ml. of dry methylene chloride over 15 minutes. After one hour at room temperature, the reaction mixture was filtered and the residue was washed with 2×100 ml. of methylene chloride. The methylene chloride filtrates were extracted with 3×500 ml. of 5% (w/w) aqueous sodium hydroxide solution, dried over magnesium sulfate and evaporated to dryness. The residue was crystallized from hexane to give 2-methyl-3-hydroxy-4-acetyl-5-vinylpyridine.