Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:3]=1[CH:4]=[O:5].[CH:11]1([C:14]2[CH:15]=[CH:16][C:17]3[C:23](=[O:24])[NH:22][CH2:21][CH2:20][NH:19][C:18]=3[CH:25]=2)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Br:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([N:22]2[C:23](=[O:24])[C:17]3[CH:16]=[CH:15][C:14]([CH:11]4[CH2:13][CH2:12]4)=[CH:25][C:18]=3[NH:19][CH2:20][CH2:21]2)[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Br)cccc1Br
Reactant: O=C1NCCNc2cc(C3CC3)ccc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=Cc1c(Br)cccc1N1CCNc2cc(C3CC3)ccc2C1=O
Yield: 88.3 %

Procedure:
A mixture of 2,6-Dibromo-benzaldehyde (1.06 g, 4 mmol, 4 eq), 8-Cyclopropyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (202 mg, 1 mmol, 1 eq), Xantphos (12 mg, 0.02 mmol, 0.02 eq), Pd(dba)2 (18 mg, 0.03 mmol, 0.03 eq), cesium carbonate (652 mg, 2 mmol, 2 eq.) in 40 mL dioxane was degassed with argon for 1 min, and heated to 100 C for 14 hours under an argon atmosphere. The reaction was cooled, and the filtered through a sintered glass funnel, concentrated to dryness and triturated with CH2Cl2. The filtrated was purified on a silica gel column using a gradient of 30 to 40% ethyl acetate in hexanes to give 340 mg 2-Bromo-6-(8-cyclopropyl-5-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-benzaldehyde, 88% which was suitable for use in the next step.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[N+:7]([CH2:9]S(C1C=CC(C)=CC=1)(=O)=O)#[C-:8].[CH:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26])=[O:21]>CO>[O:21]1[C:20]([C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])=[CH:9][N:7]=[CH:8]1
Reactant: N#Cc1cccc(C=O)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#Cc1cccc(-c2cnco2)c1
Yield: 40.5 %

Procedure:
MeOH (28 mL) was added to a round bottom flask containing K2CO3 (4.22 gm, 30.50 mmol), 1-(isocyanomethylsulfonyl)-4-methylbenzene (3.28 gm, 16.78 mmol), and 3-formylbenzonitrile (2.00 gm, 15.25 mmol). The reaction mixture was refluxed for 2 h. After this time, the mixture was concentrated under reduced pressure. The remaining residue was dissolved in water (50 ml). The aqueous solution was extract with EtOAc (50 ml). The EtOAc layer was washed with saturated aqueous NaCl (30 ml), dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography eluting with a gradient of 0-100% EtOAc/Hexanes to give the product, 3-(oxazol-5-yl)benzonitrile, (1.05 gm, 6.17 mmol, 41% yield) as a yellow solid. Anal. Calcd. for C10H6N2O m/z 170.1, found: 171.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cccc(Br)c1
Solvent: CCO
Product: CCOC(=O)C(=CNc1cccc(Br)c1)C(=O)OCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
3-Bromoaniline (10.0 g, 47 mmol) was dissolved in abs. ethanol (100 mL). Diethyl ethoxymethylenemalonate (10.2 g, 47 mmol) was added. The solution stirred at 80° C. overnight. The solution was slowly cooled and a precipitant formed. The product was filtered and dried to give 12.6 g (70%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]([O:7][C:8]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]2[C:9]=1[C:10]([CH3:31])=[C:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:12]([O:19][CH:20]([F:22])[F:21])=[N:13]2)([CH3:6])[CH3:5].[OH-].[Li+]>O1CCCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:8]([O:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:32])=[O:2])=[C:9]2[C:14]=1[N:13]=[C:12]([O:19][CH:20]([F:21])[F:22])[C:11]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)=[C:10]2[CH3:31]
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)c2nc(OC(F)F)c(Cc3ccc(Cl)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(Cl)cc2)c(OC(F)F)nc2c(Cl)ccc(OC(C)(C)C(=O)O)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-[8-chloro-3-(4-chlorobenzyl)-2-difluoromethoxy-4-methylquinolin-5-yloxy]-2-methylpropionic acid methyl ester (0.030 g), tetrahydrofuran (2.0 mL) and 1.0 M aqueous lithium hydroxide solution (2.0 mL) was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure, diluted with water and the pH adjusted to 4 by the addition of sodium dihydrogenphosphate. The mixture was extracted with ethyl acetate and the combined extracts dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound, 0.027 g.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([C:12]1[C:13]([NH2:25])=[C:14]([C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1)[C:15]([OH:17])=O)C>N1C=CC=CC=1.[OH-].[Na+]>[CH3:24][O:23][C:18]1[C:19]([O:21][CH3:22])=[CH:20][CH:12]=[C:13]2[C:14]=1[C:15](=[O:17])[N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8](=[O:9])[NH:25]2
Reactant: O=C=Nc1ccccc1
Reactant: CCc1cc(OC)c(OC)c(C(=O)O)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1ccc2[nH]c(=O)n(-c3ccccc3)c(=O)c2c1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To phenyl isocyanate (2.26 ml, 2.48 g, 20.8 mM) in pyridine (9.2 ml) at 0° C. was added a cold solution of ethyl 2-amino-5,6-dimethoxybenzoic acid (3.0 g, 13.3 mM) in pyridine (16.7 ml). The solution was stirred at 0° C. for thirty minutes, then kept at room temperature for one hour. The solution was then concentrated to dryness to give a white solid. This was dissolved in 69.9 ml of 1N NaOH (4:1 MeOH-H2O) and heated at reflux for two hours. The solvent was removed in vacuo and the gummy residue partially dissolved in H2O (100 ml). The mixture was taken to pH 6 with acetic acid and the resulting white solid filtered, washed well with H2O (50 ml) and dried to afford crude product as a white solid; 4.13 g, mp 215°-225° C. (softens 190° C.). Recrystallization from isopropanol (250 ml) afforded the title compound as a white solid; 2.65 g (65.8%); mp 241°-243° C. CF3COOH(TMS) 7.10-7.80 (m, 7H, 7-H, 8-H, 9-H, 10-H, 11-H, 12-H, 13-H), 4.05 (s, 3H, 5 or 6-OCH3), 10 (s, 3H, 5 or 6-OCH3). M+ 298.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C@@:8]23[O:15][C@@:12]([CH:16]([OH:18])[CH3:17])([CH2:13][O:14]2)[C@@H:11]([OH:19])[C@H:10]([OH:20])[C@H:9]3[OH:21])=[CH:4][C:3]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=1.C(N(CC)CC)C>CO.[Pd]>[CH2:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C:3]2[CH:4]=[C:5]([C@@:8]34[O:15][C@@:12]([CH:16]([OH:18])[CH3:17])([CH2:13][O:14]3)[C@@H:11]([OH:19])[C@H:10]([OH:20])[C@H:9]4[OH:21])[CH:6]=[CH:7][CH:2]=2)=[CH:28][CH:27]=1)[CH3:31]
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOc1ccc(Cc2cccc([C@]34OC[C@](C(C)O)(O3)[C@@H](O)[C@H](O)[C@H]4O)c2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 102.3 %

Procedure:
To a solution of (1R,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(1-hydroxyethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol 1 (10.0 g, 21.6 mmol, HPLC: 97.5%) in methanol (80 mL) were added Pd/C (1.5 g, 0.705 mmol, 5%) and triethylamine (5 mL, 32.4 mmol) at room temperature in turn. The mixture was stirred at room temperature under H2 for 20 hours and filtered. The filtrate was concentrated in vacuo. To the residue were added ethyl acetate (80 mL) and water (50 mL) and the resulting mixture was stirred at room temperature for 5 min, then stood for a few minutes and partitioned. The organic layer was washed with saturated aqueous sodium chloride (50 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 30 as a white solid (9.2 g, 99.6%, HPLC: 97.1%). The compound was characterized by the following spectroscopic data: 1H NMR (600 MHz, CD3OD) δ (ppm): 7.43 (s, 1H), 7.38 (d, 1H), 7.26 (t, 1H), 7.15 (d, 1H), 7.11 (d, 2H), 6.82 (d, 2H), 4.18 (d, 1H), 4.01 (m, 3H), 3.95-3.91 (m, 3H), 3.80 (dd, 1H), 3.68 (t, 1H), 3.60 (d, 1H), 1.37 (t, 3H), 1.33 (d, 3H); and MS (ESI, pos. ion) m/z: 417.1[M+H]+.
Reaction SMILES: CO.[CH2:3]([C:7]1[N:8]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47]3[N:51](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:50]=[N:49][N:48]=3)=[CH:37][CH:36]=2)[C:9]([C:13]([O:15][CH:16]([O:18][C:19](=[O:33])[CH2:20][CH2:21][CH2:22][C@@H:23]([O:29][N+:30]([O-:32])=[O:31])[CH2:24][O:25][N+:26]([O-:28])=[O:27])[CH3:17])=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6]>ClCCl>[CH2:3]([C:7]1[N:8]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47]3[NH:51][N:50]=[N:49][N:48]=3)=[CH:39][CH:40]=2)[C:9]([C:13]([O:15][CH:16]([O:18][C:19](=[O:33])[CH2:20][CH2:21][CH2:22][C@@H:23]([O:29][N+:30]([O-:32])=[O:31])[CH2:24][O:25][N+:26]([O-:28])=[O:27])[CH3:17])=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc(Cl)c(C(=O)OC(C)OC(=O)CCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CCCCc1nc(Cl)c(C(=O)OC(C)OC(=O)CCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A methanol (5 mL)/dichloromethane (5 mL) solution of 1-{[(5R)-5,6-bis(nitrooxy)hexanoyl]oxy}ethyl 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate (713 mg, 0.756 mmol) was heated by microwave irradiation (120° C., 10 minutes). Purification of the reaction mixture by reversed-phase mass-directed high-performance liquid chromatography afforded the title compound. Chromatography of the diastereomeric mixture over Chiralpak AD-H, eluting with methanol/carbon dioxide, afforded the separate diastereomers.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:33]=[CH:32][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:30]=[CH:29][C:19]([C:20]([N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[O:21])=[C:18]([OH:31])[CH:17]=2)=[CH:7][CH:6]=1.[C:34](OC1C=CC=CC=1)(=[O:36])[CH3:35].C(N(CC)CC)C>C(Cl)Cl>[C:34]([N:2]=[N:3][CH2:4][C:5]1[CH:33]=[CH:32][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:30]=[CH:29][C:19]([C:20]([N:22]([CH:26]([CH3:27])[CH3:28])[CH:23]([CH3:25])[CH3:24])=[O:21])=[C:18]([OH:31])[CH:17]=2)=[CH:7][CH:6]=1)(=[O:36])[CH3:35]
Reactant: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C=NN)cc2)cc1O)C(C)C
Reactant: CC(=O)Oc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N=NCc1ccc(OCCCCCOc2ccc(C(=O)N(C(C)C)C(C)C)c(O)c2)cc1
Reaction time: 8 h

Procedure:
A stirred solution of 4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide monohydrochloride (220 mg, 0.46 mmol) in 10 mL anhydrous methylene chloride is treated with phenyl acetate (73 uL, 0.51 mmol) and triethylamine (73 uL, 0.51 mmol). The solution is stirred overnight, concentrated in vacuo and the resulting liquid is purified by chromatography on silica gel (15 g) with 80-100% ethyl acetate/hexane as the eluent to afford 4-[5-[4-(acetyliminoaminomethyl)phenoxy]pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide as a colorless foam; CHN calculated for C27H37N3O5 --0.5 H2O: Theory: % C: 65.83; % H: 7.78; % N: 8,53; Found: % C: 65.58; % H: 7.63; % N: 8,16.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4](Cl)=[O:5].[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[O:5]
Reactant: CCOP(OCC)OCC
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Product: CCOP(=O)(OCC)C(=O)c1c(C)cc(C)cc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
91 parts of 2,4,6-trimethylbenzoyl chloride are introduced into an apparatus as described in Example 1. 83 parts of triethyl phosphite are added in the course of 15 minutes at 60° C., after which the mixture is stirred for 8 hours at 80° C. The material discharged from the flask is distilled under a pressure of 0.4 mm and the fraction boiling at 120°-122° C. under this pressure is collected. 51 parts (36 percent of theory) of diethyl 2,4,6-trimethylbenzoylphosphonate are obtained as a pale yellowish liquid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]([O:35]C)=[O:34])[CH:31]=3)[NH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:4]>[OH-].[K+]>[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][CH:21]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]([OH:35])=[O:34])[CH:31]=3)[NH:26][CH:25]=2)[CH2:22][CH2:23]1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc2[nH]cc(CCCCN3CCC(c4c[nH]c5ccc(C(=O)OC)cc45)CC3)c2c1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1ccc2[nH]cc(CCCCN3CCC(c4c[nH]c5ccc(C(=O)O)cc45)CC3)c2c1

Procedure:
0.8 g of methyl 3-[1-(4-(5-methoxycarbonylindol-3-yl)butyl)-4-piperidyl]indole-5-carboxylate [obtainable according to Example 1] is boiled for 0.5 h with 100 ml of 2N ethanolic KOH, worked up in a conventional manner and 3-[1-(4-(5-carboxyindol-3-yl)butyl)-4-piperidyl]-indole-5-carboxylic acid is obtained.
Reaction SMILES: [H-].[Na+].[CH:3]([NH:6][C:7]1[C:12]([C:13](=O)[CH3:14])=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1)([CH3:5])[CH3:4].[Cl-].[Na+].[O:20]1[CH2:25][CH2:24]OCC1>>[CH:3]([N:6]1[C:7]2[N:8]=[C:9]([S:16][CH3:17])[N:10]=[CH:11][C:12]=2[C:13]([CH3:14])=[CH:24][C:25]1=[O:20])([CH3:4])[CH3:5]
Reactant: C1COCCO1
Reactant: CSc1ncc(C(C)=O)c(NC(C)C)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Product: CSc1ncc2c(C)cc(=O)n(C(C)C)c2n1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Sodium hydride (16.75 g, 0.042 mol) is placed in 200 mL dioxane and combined with triethylphosphonoacetate (83.8 mL, 0.419 mmol), so that the temperature does not exceed 5° C. After the addition is complete, the mixture is heated to 20° C. and 1-(4-isopropylamino-2-methylsulphanyl-pyrimidin-5-yl)-ethanone (11.1 g, 0.049 mol) dissolved in 100 mL dioxane is added thereto. The mixture is stirred for 16 h at 90° C., then combined with 10% sodium chloride solution and extracted with ethyl acetate. The organic phase is dried, the solvent is eliminated in vacuo and the crude product is purified by normal phase chromatography (cyclohexane/ethyl acetate 90:10→50:50 in 45 min; flow 200 mL/min) and 8-isopropyl-5-methyl-2-methylsulphanyl-8H-pyrido[2,3-d]pyrimidin-7-one (HPLC-MS: tRet.=1.74 min; MS(M+H)+=250; method FECS1) is obtained.
Reaction SMILES: [OH:1][CH:2]([CH2:19][OH:20])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[K+].[C:23]([O:40]C)(=O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[OH:1][CH:2]([CH2:19][OH:20])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:23](=[O:40])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCNCC(O)CO
Reactant: CCCCCCCCCCCCCCCC(=O)OC
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)CC(O)CO

Procedure:
N-(2,3-dihydroxypropyl)-N-tetradecylamine (1.0 g, 0.0035 moles) and potassium hydroxide (0.01 g, 0.18 mmole) were heated to 85° C. under vacuum. Methyl palmitate (1.036 g, 0.0038 mole) was heated to melt and added dropwise to the reaction. The reaction was heated under vacuum for 6 hours. A waxy off-white solid was obtained (crude yield=1.77 g). The waxy solid was recrystalized from hot hexane (yield=0.33 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].C1N=C[N:28](C(N2C=NC=C2)=O)C=1.N>O1CCCC1.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:12][CH2:13][CH:14]([O:17][CH2:18][C:19]([NH2:28])=[O:20])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[C:22]([F:23])([F:24])[F:25])([O-:3])=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a heated solution (60° C.) of 2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]acetic acid (300 mg, 0.83 mmol) in tetrahydrofuran (25 ml) was added CDI (300 mg, 1.85 mmol, 2.2 eq) at reflux and then stirred for 1 hour at 60° C. (oil bath temperature). The resulting solution was poured into ammonia (25 ml) at room temperature and stirred for an additional 1 hour. The contents were diluted with water (100 ml) and the resulting mixture was extracted with ethyl acetate (3×100 ml). The organic layers were combined, washed with saturated aqueous sodium chloride (100 ml), dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum to afford 2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]acetamide as yellow solid (220 mg, 74%). (ES, m/z) [M+H]+ 362; 1H NMR (300 MHz, DMSO): δ 8.06 (d, J=9.0 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.27 (d, J=4.2 Hz, 1H), 7.07 (s, 2H), 6.85 (dd, J=2.4 Hz, 9.3 Hz, 1H), 3.82 (s, 2H), 3.40-3.55 (m, 2H), 1.90-2.10 (m, 4H), 1.10-1.50 (m, 4H)
Reaction SMILES: [H-].[Na+].C(S)C.C[O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH:12]([N:18]([CH2:22][CH2:23][CH2:24][S:25][CH3:26])[CH2:19][CH2:20][CH3:21])[CH2:13]2>CN(C)C=O>[OH:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH:12]([N:18]([CH2:22][CH2:23][CH2:24][S:25][CH3:26])[CH2:19][CH2:20][CH3:21])[CH2:13]2
Reactant: CCCN(CCCSC)C1CCc2c(cccc2OC)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: CCCN(CCCSC)C1CCc2c(O)cccc2C1
Reaction time: 20 h

Procedure:
1 g sodium hydride in 40 g dimethylformamide is treated at 0° with 3.3 ml ethylmercaptan. 4.5 g 1,2,3,4-tetrahydro-5-methoxy-2-[N-(3-methylthiopropyl)-N-propylamino]-naphthalene in 30 ml dimethylformamide are added. The reaction mixture is stirred for 20 hours at 120°, cooled, concentrated and partitioned between ether and 2 N hydrochloric acid. The aqueous phase is adjusted to pH 11 at 5° and extracted with methylene chloride. The organic phase is dried, filtered and concentrated to give the crude title compound, which is converted into the hydrogen fumarate in isopropanol/pentane. M.pt. sintering from 70° (from ethanol/ether). The starting material may be obtained as follows:
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]=1)[NH2:2].[CH3:13][C:14](=NNC1C2C(=CC=CC=2)C=NN=1)[CH:15]=C(C)C.N(C1C2C(=CC=CC=2)C(NN)=NN=1)N.C(OC(NNC1C2C(=CC=CC=2)C=NN=1)=O)C>>[NH:1]([C:3]1[N:4]=[N:5][C:6]2[CH2:13][CH2:14][CH2:15][CH2:10][CH2:9][CH2:8][C:7]=2[C:12]=1[CH3:11])[NH2:2]
Reactant: NNc1nncc2ccccc12
Reactant: CC(C)=CC(C)=NNc1nncc2ccccc12
Agent: CCOC(=O)NNc1nncc2ccccc12
Agent: NNc1nnc(NN)c2ccccc12
Product: Cc1c(NN)nnc2c1CCCCCC2

Procedure:
1-hydrazinophthalazine derivatives, e.g., 1-hydrazinophthalazine, 1-[2-(1,3-dimethyl-2-butenylidene)-hydrazino]phthalazine, 1,4-dihydrazinophthalazine or 1-(N'-ethoxycarbonylhydrazino)phthalazine.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].CO.[OH-].[Na+:35]>CC(O)C>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:35]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Yield: 30.1 %

Procedure:
In a 100 ml flask were placed Fluvastatin methyl ester (3.0 g), MeOH (20 ml) and NaOH (0.29 g). After a clear solution was obtained propan-2-ol (80 ml) was added and the solution was stirred at room temperature over night. A little precipitation occurred, propan-2-ol (40 ml) was added and the solution was stirred at room temperature for another night. The product was isolated by filtration under nitrogen, washed with acetone (35 ml) and dried at 50EC in a vacuum oven for 22.5 h to obtain 0.92 g of fluvastatin sodium crystal Form LXV.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[CH2:10](Br)[CH2:11][CH:12]([CH3:14])[CH3:13]>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH3:2]
Reactant: CC(C)CCBr
Reactant: CCOC(CN)OCC
Product: CCOC(CNCCC(C)C)OCC
Reaction time: 8 h
Yield: 77.2 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-5 with the modification that the reaction was carried out overnight, 2,2-diethoxyethanamine (2.91 ml, 20 mmol) was reacted with isoamylbromide (1.26 ml, 10 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: n-hexane:ethyl acetate=90:10 to 80:20) to obtain the title compound (1.57 g, 77%).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:23][C:24](=[O:26])[CH3:25]>>[CH2:23]([N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20])[C:24]([CH3:25])=[O:26]
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: CC(=O)CCl
Product: CC(=O)Cn1c(C(=O)c2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Yield: 45 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and chloroacetone were reacted by the same way with the example 1 to obtain the titled compound (155 mg, yield: 45%).
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](/[CH:24]=[CH:25]/[C:26]2[CH:39]=[CH:38][C:29]([C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[O:31])=[CH:28][CH:27]=2)=[N:16]1.C(N)C.[C:43](N1C=CN=C1)([N:45]1[CH:49]=[CH:48][N:47]=[CH:46]1)=[O:44]>C1COCC1.O>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](/[CH:24]=[CH:25]/[C:26]2[CH:27]=[CH:28][C:29]([C:30]([N:32]3[CH2:37][CH2:36][N:35]([C:43]([N:45]4[CH:49]=[CH:48][N:47]=[CH:46]4)=[O:44])[CH2:34][CH2:33]3)=[O:31])=[CH:38][CH:39]=2)=[N:16]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Agent: CCN
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCN(C(=O)n2ccnc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.3 %

Procedure:
A solution of dihydrochloride of Compound 18 (400 mg, 1.09 mmol) in THF (20 mL) was added with ethylamine (177 mg, 2.18 mmol) and 1,1′-carbonyldiimidazole (352 mg, 2.18 mmol), followed by stirring at room temperature for 1.5 hours. The reaction mixture was added with water and was extracted with ethyl acetate. The organic layer was washed with saturated brine, and was dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by preparative thin-layer chromatography (chloroform/acetone=1/1) to obtain Compound 48 (350 mg, 44%).