Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26].[CH:30](O)([CH3:32])[CH3:31]>>[CH3:31][CH:30]([O:27][C:25]([C:24]([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:9])=[CH:15][CH:14]=1)([CH3:29])[CH3:28])=[O:26])[CH3:32]
Reactant: CC(C)O
Reactant: CC(C)(Br)C(=O)O
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)OC(=O)C(C)(C)Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Yield: 38.8 %

Procedure:
1 liter of isopropyl alcohol, 232.5 g (1 mol) of (4-chlorophenyl)(4-hydroxyphenyl)methanone, 138 g (1 mol) of potassium carbonate and 355 g (1.7 mol) of the 1-methylethyl ester of 2-bromo-2-methylpropanoic acid are introduced into a 4 liter reactor equipped with a stirrer and a condenser. The reaction medium is heated gently, with vigorous stirring, and then kept under reflux for 8 hours. About 400 ml of isopropyl alcohol are then distilled off, after which the medium is cooled, with stirring. The precipitate formed is filtered off and then washed with water in the heterogeneous phase, with shaking. It is filtered off and then washed again with 2% sodium hydroxide solution and then with water until the washings are neutral. The product is filtered off and purified by recrystallization from isopropyl alcohol to give 140 g of fenofibrate (yield=38.8%).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][O:8][CH:9]([CH2:19][O:20]CC2C=CC=CC=2)[CH2:10][O:11]CC2C=CC=CC=2)[C:5]2[C:28]([Cl:35])=[C:29]([Cl:34])[C:30]([Cl:33])=[C:31]([Cl:32])[C:4]=2[N:3]=1.B(Cl)(Cl)Cl.C(Cl)Cl>CO>[Cl:1][C:2]1[N:6]([CH2:7][O:8][CH:9]([CH2:19][OH:20])[CH2:10][OH:11])[C:5]2[C:28]([Cl:35])=[C:29]([Cl:34])[C:30]([Cl:33])=[C:31]([Cl:32])[C:4]=2[N:3]=1
Reactant: Clc1c(Cl)c(Cl)c2c(nc(Cl)n2COC(COCc2ccccc2)COCc2ccccc2)c1Cl
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: OCC(CO)OCn1c(Cl)nc2c(Cl)c(Cl)c(Cl)c(Cl)c21
Yield: 50.7 %

Procedure:
Compound 155 (0.52 g, 51%) was prepared from 154 (1.5 g, 2.6 mmole), BCl3 (5M solution in CH2Cl2, 14 mL), CH2Cl2 (30 mL) and MeOH (20 mL) by the method described for 166 which on recrystallization from EtOAC gave 155: m.p. 155°; 1H NMR (DMSO-d6): d 5.76 (s, 2 H, C-1'), 4.63 (t, 2 H, exchanges with D2O, 2×OH), 3.54-3.48 (m, 1 H, C-3'), 3.43-3.25 (m, 4 H, C-4' and 5'H). Anal. Calcd. for C11H9N2Cl5O3 : C, 33.46; H, 2.28; N, 7.09. Found: C, 33.60; H, 2;15; N, 6.91.
Reaction SMILES: [C:1](=[O:4])(O)[O-].[Na+].[NH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.[CH:35]1([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)(OOC1C=CC([N+]([O-])=O)=CC=1)N>C(#N)C>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH2:9][CH2:8][CH:7]([NH:6][C:1]([N:43]3[CH2:44][CH2:45][N:40]([CH:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)[CH2:41][CH2:42]3)=[O:4])[CH2:12][CH2:11]2)=[CH:14][CH:15]=1)(=[O:21])[CH3:20]
Reactant: C1CCC(N2CCNCC2)C1
Reactant: O=C([O-])O
Reactant: CC(=O)c1ccc(N2CCC(N)CC2)cc1
Agent: NC(=O)OOc1ccc([N+](=O)[O-])cc1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)c1ccc(N2CCC(NC(=O)N3CCN(C4CCCC4)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium bicarbonate (40 mmol) in acetonitrile (50 mL) is added hydrochloride salt of 1-[4-(4-amino-piperidin-1-yl)-phenyl]-ethanone (10 mmol) and p-nitrophenyl chloroformate (10 mmol) at 0° C. The mixture is stirred at rt for 1 hour. A solution of 1-cyclopentylpiperazine (10.5 mmol) and TEA (25 mmol) in acetonitrile (15 mL) is added to the mixture at rt. The resulting mixture is stirred until no p-nitrophenoxyl carbamate remained by TLC. The mixture is then concentrated, diluted with EtOAc (100 mL) and washed with aqueous potassium carbonate (2×80 mL), and dried over MgSO4. Removal of the solvent, followed by PTLC purification gives the title compound. 1H NMR (300 MHz, CDCl3) δ 7.85 (d, 2H), 6.84 (d, 2H), 4.41 (d, 1H), 3.81-3.98 (m, 3H), 3.52-3.40 (m, 4H), 3.02 (t, 2H), 2.2.66-2.43 (m, 8H), 2.15-2.01 (m, 2H), 1.97-1.82 (m, 2H), 1.78-1.64 (m, 2H), 1.60-1.41 (m, 6H); LC-MS (M+1) 399.5.
Reaction SMILES: C[Si]([C:5]1[NH:10][C:9](=[O:11])[N:8]([Si](C)(C)C)[C:7](=[O:16])[C:6]=1[F:17])(C)C.F[C:19]1[C:20](=[O:26])NC(=O)NC=1.[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:29]=1[CH:30]=[O:31].C(O)CO>C(Cl)(Cl)Cl>[OH:26][CH2:20][CH2:19][O:31][CH:30]([N:10]1[CH:5]=[C:6]([F:17])[C:7](=[O:16])[NH:8][C:9]1=[O:11])[C:29]1[C:28]([Cl:27])=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:36]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: C[Si](C)(C)c1[nH]c(=O)n([Si](C)(C)C)c(=O)c1F
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: OCCO
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c(=O)n(C(OCCO)c2c(Cl)cccc2Cl)cc1F

Procedure:
Bis(trimethylsilyl)-5-fluorouracil prepared from 5-fluorouracil (10 g), and 2-2,6-dichlorophenyl-1,3-dioxolan (32.0 g) which had been prepared from 2,6-dichlorobenzaldehyde and ethylene glycol were subjected to reaction as in Example 10. Following adding chloroform (100 ml), the reaction mixture was washed twice with a cold saturated NaCl aqueous solution, and then aqueous sodium bicarbonate, and water, and dried over anhydrous magnesium sulfate. The solvent was evaporated off and the residue was purified by column chromatography using silica gel and acetone-chloroform (1:4) as an eluant to give 6.9 g of crystalline 1-[α-(2-hydroxyethoxy)-2,6-dichlorobenzyl]-5-fluorouracil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:8]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=3[CH3:25])[CH:9]=[C:10]([C:15](=[O:17])[CH:16]=2)[C:11]([O:13]C)=[O:12])[CH2:3][CH2:2]1.[CH:26](Br)([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+].[ClH:36]>CN(C)C=O>[ClH:36].[OH:24][C:21]1[CH:22]=[CH:23][C:18]([N:8]2[C:7]([CH:4]3[CH2:5][CH2:6][N:1]([CH:26]([CH3:28])[CH3:27])[CH2:2][CH2:3]3)=[CH:16][C:15](=[O:17])[C:10]([C:11]([OH:13])=[O:12])=[CH:9]2)=[C:19]([CH3:25])[CH:20]=1
Reactant: COC(=O)c1cn(-c2ccc(O)cc2C)c(C2CCNCC2)cc1=O
Reactant: CC(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)ccc1-n1cc(C(=O)O)c(=O)cc1C1CCN(C(C)C)CC1

Procedure:
In 4 ml of N,N-dimethylformamide was dissolved 0.24 g of methyl 6-(4-piperidinyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinate, and 0.17 g of isopropyl bromide and 0.06 g of potassium carbonate were added to the solution, after which they were reacted at 60° C. for 6 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was dissolved in a mixture of 20 ml of chloroform and 20 ml of water. The organic layer was separated, washed twice with 20-ml portions of water, and dried with anhydrous sodium sulfate. Then, the solvent was removed by distillation under reduced pressure, and the oily substance thus obtained was purified by a column chromatography (Wako Silica Gel C-200; eluent: chloroform/ethanol (20:1 by volume) mixture). The fraction containing the objective substance was concentrated, and to the oily substance thus obtained was added 5 ml of 6N hydrochloric acid, and they were refluxed for 2 hours. The solvent was removed by distillation under reduced pressure to obtain 0.11 g of 1-(4-hydroxy-2-methylphenyl)-6-(1-isopropyl-4-piperidinyl)-4-oxo-1,4-dihydronicotinic acid hydrochloride having a melting point of 195.5°-200.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH3:21])=[CH:16][N:15]=1>>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][CH2:6][C:7]1[S:8][C:9]([C:16]2[C:17]([CH3:21])=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=2)=[CH:10][CH:11]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: COC(=O)CCCc1cccs1
Product: COC(=O)CCCc1ccc(-c2nc(Cl)ncc2C)s1
Yield: 12 %

Procedure:
4-[5-(2-Chloro-5-methyl-pyrimidin-4-yl)-thiophen-2-yl]-butyric acid methyl ester was prepared analogous to Step B of Method A, starting from 4-thiophen-2-yl-butyric acid methyl ester and 2,4-dichloro-5-methyl-pyrimidine. Yield: 12%.
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([CH2:31][OH:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:3].CC(C)=[O:35].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.C1C=CC=CC=1.CO>[CH3:3][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:31]([OH:35])=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C:16](=[O:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:1]
Reactant: CC(C)=O
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: c1ccccc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 5 h

Procedure:
Starting off with Betulin (10 g) in acetone (300 mL), add freshly prepared Jones Reagent added dropwise at 0° C. Stir for 5 hours, quench with methanol (100 mL), then stir for 5 minutes and add H2O (200 mL). Remove organic solvent under vacuum, and then separate the precipitate by filtration. Wash precipitate on the filter with cooled water, and dry to obtain crude material. This dry material is to be dissolved in 30 mL benzene. The solution is then filtered through a layer of aluminum oxide and the eluate is treated with an aqueous 10% KOH solution until complete precipitation. The precipitate is then separated by filtration, washed with 10 mL cooled benzene, and dried to obtain white solid. The salt is dissolved in 30 mL methanol and the solution is poured into 100 mL 15% aqueous HCL solution. The betulonic acid (2.7 g) is obtained after the precipitate is filtered, washed with water, and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])=[O:15])[C:12](=[O:23])[NH:11][C:10]([CH3:24])=[C:9]2[C:25]([O:27][CH3:28])=[O:26])=[CH:4][CH:3]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([NH2:48])[CH:43]=2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].Cl.CN(C)CCCN=C=NCC.C(Cl)Cl>CN(C)C1C=CN=CC=1.CN(C=O)C.O>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:43]=[C:44]([CH:45]=[CH:46][CH:47]=2)[NH:48][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][NH:16][C:14]([N:13]2[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:9]([C:25]([O:27][CH3:28])=[O:26])=[C:10]([CH3:24])[NH:11][C:12]2=[O:23])=[O:15])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Reactant: COC(=O)C1=C(C)NC(=O)N(C(=O)NCCCC(=O)O)C1c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1=C(C)NC(=O)N(C(=O)NCCCC(=O)Nc2cccc(C3CCN(C(=O)OC(C)(C)C)CC3)c2)C1c1ccc(F)cc1
Reaction time: 12 h
Yield: 33.2 %

Procedure:
A 10-mL RB-flask was charged with 4-{[(6-(4-fluorophenyl)-5-(methoxycarbonyl)-4-methyl-2-oxo-3,6-dihydro-1(2H)-pyrimidinyl)carbonyl]amino}butanoic acid (77.0 mg, 0.189 mmol), tert-butyl-4-[3-(amino)phenyl]-1-piperidinecarboxylate (52.2 mg, 0.189 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride (0.567 mmol, 87.8 mg), 4-dimethylaminopyridine (11.5 mg, 0.0945 mmol) in DMF:DCM (0.2:2.0 mL) at room temperature. The reaction mixture was stirred for 12 h and water (10.0 mL) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with CHCl3 (3×10 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed (silica, hexanes:EtOAc 9:1) to afford the desired product (40.9 mg, 33.2%): 1H NMR (400 MHz, CDCl3) δ 8.03 (m, 3H), 7.57 (s, 1H), 7.36-7.28 (m, 3H), 7.27-7.22 (m, 1H), 6.97-6.89 (m, 3H), 6.72 (s, 1H), 3.72 (s, 3H), 3.47-3.37 (m, 2H), 2.42 (s, 3H), 2.37-2.29 (m, 2H), 1.98-1.91 (m, 2H), 1.86-1.75 (m, 2H), 1.72-1.54 (m, 7H), 1.48 (s, 9H); ESMS m/e: 652.2 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]1[CH2:40][CH2:39][C:12]2[N:13]=[C:14]([NH:16][C:17](=[O:38])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]4[CH:29]=[C:28]([C:30]5[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=5)[N:27]=[N:26]4)[CH:19]=3)[S:15][C:11]=2[CH2:10]1.[CH3:41][O:42][CH2:43][CH2:44]Br.C(N(CC)CC)C.[I-].[Na+]>CCO>[C:36]([C:33]1[CH:32]=[CH:31][C:30]([C:28]2[N:27]=[N:26][N:25]([CH2:24][C:20]3[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=3)[C:17]([NH:16][C:14]3[S:15][C:11]4[CH2:10][C@H:9]([NH:8][CH2:44][CH2:43][O:42][CH3:41])[CH2:40][CH2:39][C:12]=4[N:13]=3)=[O:38])[CH:29]=2)=[CH:35][CH:34]=1)#[N:37]
Reactant: N#Cc1ccc(-c2cn(Cc3cccc(C(=O)Nc4nc5c(s4)C[C@H](N)CC5)c3)nn2)cc1
Reactant: COCCBr
Agent: [I-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CCN(CC)CC
Product: COCCN[C@@H]1CCc2nc(NC(=O)c3cccc(Cn4cc(-c5ccc(C#N)cc5)nn4)c3)sc2C1
Temperature: 110 °C
Yield: 38.7 %

Procedure:
Add to a solution of N—((R)-6-amino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-3-[4-(4-cyano-phenyl)-1,2,3-triazol-1-ylmethyl]-benzamide trifluoroacetate (0.92 g, 1.61 mmol), bromoethyl methyl ether (0.22 g, 1.61 mmol), triethylamine (0.33 g, 3.22 mmol) and sodium iodide (0.02 mg, 0.16 mmol) in 8 mL of EtOH. Heat the reaction mixture at 110° C. under microwave irradiation for 5 h. Filter the mixture, concentrate and purify via preparative HPLC to give 0.32 g, 39% yield of 3-[4-(4-cyano-phenyl)-[1,2,3]triazol-1-ylmethyl]-N—[(R)-6-(2-methoxy-ethylamino)-4,5,6,7-tetrahydro-benzothiazol-2-yl]-benzamide as white foam. MS, ES+ 514.45 (M+H), rt 5.27 min
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1C.[C:12](=[O:15])([O-])[O-:13].[Na+].[Na+].[Mn]([O-])(=O)(=O)=O.[K+]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[C:12]([OH:13])=[O:15]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1c(Br)cccc1[N+](=O)[O-]
Yield: 30.5 %

Procedure:
To a mixture of 2-bromo-6-nitrotoluene (8 g), sodium carbonate (18.1 g) and water (500 mL) was added potassium permanganate (23.4 g), and the mixture was heated for reflux overnight. The insoluble material was removed by filtration, and the filtrate was washed with diethyl ether. The aqueous layer was acidified by addition of concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate (three times). The extract was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 2-bromo-6-nitrobenzoic acid (2.78 g). Tin (II) chloride dihydrate (9.18 g) was dissolved in concentrated hydrochloric acid (30 mL). To the solution was added 2-bromo-6-nitrobenzoic acid (2.78 g), and the mixture was stirred at 80° C. for 1.5 hours. The insoluble material was collected by filtration, washed with 2 mol/L hydrochloric acid and dried under reduced pressure. The obtained crystal (2.05 g) was suspended in concentrated hydrochloric acid (35 mL). To the suspension was added a solution of sodium nitrite (0.79 g) in water (6 mL) under ice-cooling, and the mixture was stirred for 20 minutes. To the reaction mixture was added a solution of tin (II) chloride dihydrate (5.78 g) in concentrated hydrochloric acid (10 mL), and the mixture was stirred at room temperature for 1 hour. Then the mixture was stirred at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give the title compound (1.27 g)
Reaction SMILES: O[C:2]1([CH2:13][C:14](=[O:16])[CH3:15])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[NH:4][C:3]1=O.C(OCC)(=O)C.O>C1COCC1>[CH3:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][CH:3]=[C:2]2[CH2:13][CH:14]([OH:16])[CH3:15]
Reactant: CC(=O)CC1(O)C(=O)Nc2ccc(C)cc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2[nH]cc(CC(C)O)c2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78 %

Procedure:
The aldol product 47 (10 mmol) was dissolved in absolute THF (20 ml) under an Ar atmosphere. BH3xTHF (30 ml, 1 M solution, 30 mmol) was then added to the mixture, while cooling with a water bath, and the mixture was stirred at room temperature for 15 hours. The course of the reaction was monitored by TLC. When the reaction had ended, the reaction solution was added to a mixture of ethyl acetate (50 ml) and H2O (50 ml). After separation of the phases, the aqueous phase was extracted twice with 30 ml portions of ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was filtered over silica gel with ethyl acetate. The crude product obtained after removal of the solvent was purified by column chromatography on silica gel (eluent:ethyl acetate/cyclohexane: 1:2).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].C1(CN)CCCCC1.[O:16]=[C:17]1[C:25]2([CH2:29][O:28][C:27]3[CH:30]=[C:31]4[C:35](=[CH:36][C:26]2=3)[CH2:34][CH2:33][O:32]4)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]1[CH2:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][CH:39]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[O:16]=[C:17]1[C:25]2([CH2:29][O:28][C:27]3[CH:30]=[C:31]4[C:35](=[CH:36][C:26]2=3)[CH2:34][CH2:33][O:32]4)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]1[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([C:42]([NH:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:43])=[CH:45][CH:46]=1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Reactant: NCc1cccs1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(NCc1cccs1)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-thiophenemethylamine to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-(thiophen-2-ylmethyl)benzamide was obtained (48%) as a colorless solid: mp 167-168° C.; 1H NMR (300 MHz, CDCl3) δ7.81-7.73 (m, 2H), 7.43-7.37 (m, 2H), 7.27-7.16 (m, 3H), 7.07-7.00 (m, 2H), 6.99-6.95 (m, 1H), 6.75-6.70 (m, 1H), 6.48-6.40 (m, 3H), 4.99 (ABq, 2H), 4.84 (ABq, 2H), 4.83-4.78 (m, 2H), 4.59-4.50 (m, 2H), 3.09-2.90 (m, 2H); 13C NMR (75 MHz, CDCl3) δ178.0, 166.5, 161.9, 161.3, 141.7, 140.6, 139.4, 133.7, 132.6, 128.7, 127.7, 127.5, 126.9, 126.2, 125.3, 124.0, 123.6, 120.0 (2C), 118.8, 109.1, 93.3, 80.6, 72.4, 57.7, 43.8, 38.8, 29.0; MS (ES+) m/z 509.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[N:16]([O-])=O.[Na+].[C:20](#[N:24])[CH2:21][C:22]#[N:23]>>[CH3:15][C@H:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][N:16]=[C:21]([C:20]#[N:24])[C:22]#[N:23])=[CH:3][CH:4]=2)=[N:13][NH:12][C:11](=[O:14])[CH2:10]1
Reactant: O=N[O-]
Reactant: N#CCC#N
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Agent: [Na+]
Product: C[C@@H]1CC(=O)NN=C1c1ccc(NN=C(C#N)C#N)cc1

Procedure:
reacting (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone of formula V with sodium nitrite and malononitrile under acidic conditions to obtain levosimendan of formula I.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:43])([F:42])[C:10]1[CH:11]=[C:12]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[C:13]([N:15]([CH:17]([CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:18][C:19]([OH:21])=O)[CH3:16])=[O:14].[CH:44]1([C:50]2[CH:56]=[CH:55][C:53]([NH2:54])=[CH:52][CH:51]=2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>C(Cl)Cl>[CH:44]1([C:50]2[CH:51]=[CH:52][C:53]([NH:54][C:19](=[O:21])[CH2:18][CH:17]([N:15]([C:13](=[O:14])[C:12]3[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=[C:10]([C:9]([F:42])([F:8])[F:43])[CH:11]=3)[CH3:16])[CH:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:55][CH:56]=2)[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CC(=O)O)C(c1ccccc1)c1ccccc1
Reactant: Nc1ccc(C2CCCCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CC(=O)Nc1ccc(C2CCCCC2)cc1)C(c1ccccc1)c1ccccc1
Reaction time: 24 h

Procedure:
A solution of 0.05 ml (0.362 mmol) of triethylamine and 37 mg (0.0726 mmol) of 3-[N-(3,5-bistrifluoromethyl-benzoyl)-N-methyl-amino]-4,4-diphenyl-butanoic acid in 0.5 ml of methylene chloride and a solution of 30.6 mg (0.289 mmol) of 1-propanephosphonic acid anhydride in 0.5 ml of methylene chloride are added in succession to 15.2 mg (0.087 mmol) of 4-cyclohexylaniline and the mixture is left to stand at room temperature for 24 hours. The reaction mixture is then washed with 0.5 ml of a 1N aqueous potassium carbonate solution. The organic phase is concentrated by evaporation in a vacuum centrifuge. The title compound is obtained in the form of a white foam. TLC: methylene chloride/methanol (95:5) Rf =0.44
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[C:8]([OH:17])[C:6]=2[CH:7]=1)[CH3:2].[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=1)(=[O:21])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[C:8]([O:17][C:25]3[CH:26]=[CH:27][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:23][CH:24]=3)[C:6]=2[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(O)c2cc(CC)oc2c1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(CC)oc2c1
Temperature: 100 °C
Yield: 60.6 %

Procedure:
A mixture of ethyl 2-ethyl-4-hydroxy-1-benzofuran-6-carboxylate (0.80 g, 3.4 mmol), 4-fluorophenyl methyl sulfone (0.60 g, 3.4 mmol) and Cs2CO3 (1.12 g, 3.4 mmol) in DMF (40 mL) was heated to 100° C. overnight. The reaction was monitored by TLC (petroleum ether/EtOAc 4:1). The mixture was poured into water (50 mL) and extracted with EtOAc (90 mL×3). The organic layer was washed with brine (50 mL×2), dried over Na2SO4 and concentrated. The product was purified via column chromatography on silica gel eluted with petroleum ether/EtOAc (20:1) to afford the desired compound (0.80 g, 60%) as a colorless oil.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[CH:11][CH:10]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=3)[NH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.ClCCOC(Cl)=O.CO>ClC(Cl)C>[F:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:14][CH:10]1[CH:11]=[CH:12][CH2:13][NH:8][CH2:9]1
Reactant: Fc1ccc2[nH]cc(CC3C=CCN(Cc4ccccc4)C3)c2c1
Agent: O=C(Cl)OCCCl
Solvent: CC(Cl)Cl
Solvent: CO
Product: Fc1ccc2[nH]cc(CC3C=CCNC3)c2c1
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
A solution of 3-[(1-benzyl-1,2,3,6-tetrahydro-3-pyridinyl)methyl]-5-fluoro-1H-indole (500 mg, 1.57 mmol) in dichloroethane is treated with chloroethylchloro-formate (0.51 mL, 4.7 mmol), stirred at 80° C. for 4.5 hr, cooled and concentrated in vacuo to give a residue. The residue is treated with methanol, heated at reflux temperature overnight, cooled and concentrated in vacuo. The resultant residue is purified by column chromatography (10% MeOH/CH2Cl2+NH4OH) to give the title compound as a pale yellow solid, 240 mg (66%) mp 145° C. (dec.), identified by NMR and mass spectral analyses.