Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1.[CH3:6][O:7][C:8]([C:10]1([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[C:14]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:12][CH2:11]1)=[O:9].[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>C1COCC1.[Cl-].[Na+].O>[CH3:6][O:7][C:8]([C:10]1([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])=[CH:20][CH:19]=3)[C:14]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:11][CH2:12]1)=[O:9]
Reactant: COC(=O)C1(c2onc(-c3ccc(O)cc3)c2-c2ccccc2)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(c2onc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)c2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
Imidazole (2.1 g) is added to a solution consisting of the 1-[3-(4-hydroxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropanecarboxylic acid methyl ester (9.6 g) and tert-butyldimethylsilyl chloride (4.7 g) in THF (100 mL). The reaction mixture is stirred at room temperature overnight. Brine solution is added and the reaction mixture is twice extracted with ethyl acetate. The combined extracts are dried and concentrated. Repeated concentration from hexane and then pentane gave 1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropanecarboxylic acid methyl ester (12.8 g.)
Reaction SMILES: [OH:1][C:2]([CH3:28])([CH3:27])[CH2:3][C@@:4]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl.[NH2:30][OH:31].CCN(CC)CC>CO>[OH:31][NH:30][C:17](=[NH:18])[C:16]1[CH:19]=[CH:20][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:27])[CH3:28])([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:14][CH:15]=1
Reactant: C[C@@H](c1ccc(C#N)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@@H](c1ccc(C(=N)NO)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C

Procedure:
A mixture of 4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]ethyl}-benzonitrile (0.50 g), hydroxylamine hydrochloride (0.18 g), and NEt3 (0.43 mL), and methanol (10 mL) was stirred at reflux temperature for 5 h. After cooling to room temperature, the solvent was evaporated, mixture was concentrated, ethyl acetate was added to the residue, and the resulting mixture was washed with water and brine. The organic solution was dried Na2SO4) and concentrated and the residue was purified by chromatography on silica gel (CH2Cl2/MeOH 98:2->93:7) to afford the title compound as a foam-like solid.
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][N:9]([CH3:30])[CH:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[O:25][C:26](Br)=[CH:27][CH:28]=3)=[O:23])=[CH:17][CH:16]=2)[CH2:11]1.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)#[CH:32]>CN(C=O)C>[CH3:8][N:9]([CH3:30])[CH:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[O:25][C:26]([C:32]#[C:31][C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)=[CH:27][CH:28]=3)=[O:23])=[CH:17][CH:16]=2)[CH2:11]1
Reactant: C#Cc1ccc(C)cc1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(Br)o3)cc2)C1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: Cc1ccc(C#Cc2ccc(C(=O)Nc3ccc(N4CCC(N(C)C)C4)cc3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.042 ml of diisopropylamine was added under argon to 3.8 mg of Pd(tBu)2Cl2 and 0.95 mg of Cul in 0.2 ml of DMF. A solution of 94.6 mg of 5-bromofuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-amide in 0.3 ml of DMF and a solution of 4-ethynyltoluene in 0.3 ml of DMF were then added dropwise. The solution was stirred at room temperature overnight. The precipitate which had separated out was filtered off with suction and the filtrate purified by preparative HPLC. The desired product with the molecular weight of 413.52; MS (ESI): 414 was obtained as hydrotrifluoroacetate.
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C@H:4]1[C@H:6]([C:7](Cl)=[O:8])[C:5]1([CH3:11])[CH3:10].[C:13]1([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH:22]([OH:28])[CH2:23]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:12])=[CH:3][C@H:4]1[C@H:6]([C:7]([O:28][CH:22]2[CH2:21][C:20]3[C:24](=[CH:25][CH:26]=[CH:27][C:19]=3[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:23]2)=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Reactant: OC1Cc2cccc(-c3ccccc3)c2C1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)OC1Cc2cccc(-c3ccccc3)c2C1

Procedure:
In a manner similar to Example 12A, the reaction of 0.41 g (0.0018 mole) of (±)-trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride with 0.37 g (0.0018 mole) of (+)-4-phenyl-2-indanol (EE 50%), 0.16 g (0.002 mole) of pyridine and toluene gave (+)-4-phenyl-2-indanyl (±)-trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate, EE 50% (alcohol moiety). The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2]
Reactant: CCCCCC(C(=O)OCC)c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCC(C(=O)OCC)c1cccc(N)c1
Yield: 97.5 %

Procedure:
A solution of 2-(3-nitro-phenyl)-heptanoic acid ethyl ester (4.451 g, 15.9 mmole) in 150 mL of ethyl acetate containing 1.69 g of 10% palladium on carbon was subjected to atmospheric pressure of hydrogen for 15 hours. The mixture was filtered through a Celite/SiO2 pad and the volatiles were removed in vacuo to yield 3.866 g of 2-(3-amino-phenyl)-heptanoic acid ethyl ester as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([Cl:33])=[CH:14][C:15]([F:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=3)[CH:17]=1)[N:5]=2.[Cl:34][CH2:35][C:36](Cl)=[O:37]>CN(C)C(=O)C.C(OCC)(=O)C>[Cl:33][C:13]1[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:36](=[O:37])[CH2:35][Cl:34])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:17][C:16]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=2)=[C:15]([F:32])[CH:14]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4n3)c(Cl)cc2F)c1
Reactant: O=C(Cl)CCl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CCl)sc4n3)c(Cl)cc2F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.415 mmol) in N,N-dimethylacetamide (3.0 mL) was added chloroacetyl chloride (52.8 μL, 0.664 mmol), and the mixture was stirred at room temperature for 4 hr. Chloroacetyl chloride (26.4 μL, 0.332 mmol) was further added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (15 mL), 5% aqueous sodium hydrogen carbonate solution (15 mL) and saturated brine (15 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give N-[4-chloro-5-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-2-fluorophenyl]-3-(1-cyano-1-methylethyl)benzamide as an oily residue.
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[NH:19][C:20]3=[O:23])=[CH:15][CH:14]=2)[CH2:8]1)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+].O>CN(C)C=O>[N:34]([CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:31])([F:32])[F:33])[NH:19][C:20]3=[O:23])=[CH:15][CH:14]=2)[CH2:8]1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 65 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
The 2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethyl methanesulfonate (169.1 mg, 0.351 mmol) obtained in step C was dissolved in N,N-dimethylformamide (1.3 ml). Thereafter, sodium azide (96.2 mg, 1.33 mmol) was added to the obtained solution, and the mixture was then stirred at 65° C. for 4 hours. Thereafter, water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with a saturated saline solution, and was then dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1 to 3:1), so as to obtain 7-(5-azidomethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (139.6 mg; yield: 93%) in the form of a colorless solid.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH:22][CH:23]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH2:27][O:26][C:25]2[CH:34]=[CH:35][C:36]([CH2:38][CH2:39][OH:40])=[CH:37][C:24]1=2>N1C=CC=CC=1>[OH:22][CH:23]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH2:27][O:26][C:25]2[CH:34]=[CH:35][C:36]([CH2:38][CH2:39][O:40][C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:37][C:24]1=2
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCc1ccc2c(c1)C(O)c1ccccc1CO2
Solvent: c1ccncc1
Solvent: O
Product: OC1c2ccccc2COc2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc21
Temperature: 50 °C
Reaction time: 5 h
Yield: 64.9 %

Procedure:
In this process, 17.2 g of 11-hydroxy-2-(2-hydroxyethyl)-6,11-dihydrodibenz[b,e]oxepin is dissolved in 50 ml of pyridine. To the solution is added 30 g of triphenylchloromethane and the mixture is stirred at 50° C. for 5 hours. After adding water and stirring the mixture for 2 hours, the solvent is distilled away under reduced pressure. The mixture is extracted with 1000 ml of ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent is distilled away under reduced pressure and the resultant residue is purified by column chromatography on silica gel (eluent: hexane:ethyl acetate=3:1 ) to obtain 21.7 g of the desired product as a colorless amorphous.
Reaction SMILES: FC(F)(F)C(O)=O.C[O:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:18][C:19]([NH2:22])=[N:20][N:21]=2)=[CH:13][CH:12]=1.[OH-].[Na+]>O>[NH2:22][C:19]1[S:18][C:17]([C:14]2[CH:13]=[CH:12][C:11]([C:10]([OH:23])=[O:9])=[CH:16][CH:15]=2)=[N:21][N:20]=1
Reactant: COC(=O)c1ccc(-c2nnc(N)s2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1nnc(-c2ccc(C(=O)O)cc2)s1
Yield: 99.7 %

Procedure:
To a solution of 4-(5-amino-1,3,4-thiadiazol-2-yl)benzoic acid methyl ester trifluoroacetic acid salt (8 g) in water was added 1N sodium hydroxide and the mixture was adjusted to pH 8. The precipitate was collected by filtration to give 4-(5-amino-1,3,4-thiadiazol-2-yl)benzoic acid (5.05 g).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[O:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[O:16])=[CH:10][CH:9]=1)C>O.C(O)C>[C:22]1([C:19]2[O:18][C:17]([C:15]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([CH2:7][C:6]([OH:28])=[O:5])=[CH:13][CH:12]=3)=[O:16])=[CH:21][CH:20]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2ccc(-c3ccccc3)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1ccc(NC(=O)c2ccc(-c3ccccc3)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A solution of sodium hydroxide (100 mg) in water (5 ml) was added to a stirred solution of {4-[(5-phenyl-furan-2-carbonyl)-amino]-phenyl}-acetic acid ethyl ester (1) (75 mg, 0.214 mmoles) in ethanol (10 ml) and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was diluted with water (10 ml) and acidified to pH=2 with 1 M aqueous hydrochloric acid. The precipitate was collected, washed with water and the residue was triturated with cyclohexane to afford (2) (61.5 mg) as a white solid. LC/MS System D; Rt=3.01 mins, m/z (ES−)=320 (M−H for C19H15NO4).
Reaction SMILES: [C:1]([N:8]1[CH2:31][CH2:30][C@@:15]23[C:16]4[CH:17]=[C:18]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)(OC(C)(C)C)=O.O1CCO[CH2:34][CH2:33]1.Cl.C(Br)C#C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:31][CH2:30][C@@:15]23[C:16]4[CH:17]=[C:18]([O:23][C:24](=[O:29])[C:25]([CH3:27])([CH3:28])[CH3:26])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)[C:33]#[CH:34]
Reactant: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OC(=O)C(C)(C)C)cc13
Reactant: C1COCCO1
Agent: C#CCBr
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C#CCN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OC(=O)C(C)(C)C)cc13
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of compound 31 (5 mg, 0.012 mmol) in dry CH2Cl2 (0.2 mL) was added 4 M HCl dioxane solution (0.5 mL) and the mixture stirred for 2 h at 0° C. Solvent was evaporated under reduced pressure. The crude amine salt 32 was dissolved in CH2Cl2 (0.5 mL) and to the mixture was slowly added 80 wt % propargyl bromide solution in toluene (2 μL, 0.020 mmol) and TEA (9 μL, 0.064 mmol) at 0° C. After 4 h stirring, the reaction mixture was concentrated under reduced pressure. The crude product was purified on a silica gel column chromatography (1:1 n-Hexane/EtOAc) to give a colorless oil (3 mg, 68% yield): 1H NMR (300 MHz, CDCl3) 1.15˜1.87 (m, 20H); 2.14˜2.31 (m, 2H); 2.67˜2.74 (m, 2H); 3.02 (d, J=18.6 Hz, 1H); 3.12˜3.14 (m, 1H); 3.36˜3.39 (m, 2H); 6.81˜6.93 (m, 2H); 7.16 (d, J=8.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.C[O:14][CH:15](OC)[CH2:16][CH2:17][CH2:18][CH:19]=O>CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]/[C:9](/[N+:10]([O-:12])=[O:11])=[CH:19]\[CH2:18][CH2:17][CH2:16][CH:15]=[O:14])=[CH:6][CH:7]=1
Reactant: COC(CCCC=O)OC
Reactant: O=[N+]([O-])CCc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=CCCC/C=C(\Cc1ccc(Cl)cc1)[N+](=O)[O-]
Yield: 45.1 %

Procedure:
Prepared according to the general procedure B from 1-chloro-4-(2-nitroethyl)benzene 112g (24 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (1.93 g, 45% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: [CH2:1]([S:3][C:4](=[O:11])[CH2:5][C:6]([S:8][CH2:9][CH3:10])=[O:7])[CH3:2].N12CCN(CC1)CC2.[C:20]1(=[O:25])[CH2:24][CH2:23][CH:22]=[CH:21]1>COCCOC>[CH2:1]([S:3][C:4](=[O:11])[CH:5]([CH:22]1[CH2:23][CH2:24][C:20](=[O:25])[CH2:21]1)[C:6]([S:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: O=C1C=CCC1
Reactant: CCSC(=O)CC(=O)SCC
Agent: C1CN2CCN1CC2
Solvent: COCCOC
Product: CCSC(=O)C(C(=O)SCC)C1CCC(=O)C1
Yield: 86.8 %

Procedure:
A solution of dithiomalonic acid di-S-ethyl ester (42.3 g, 0.22 mol) and 1,4-diazabicyclo[2,2,2]octane (24.7 g, 0.22 mol), cyclopent-2-enone (17.6 g, 0.21 mol) in 1,2-dimethoxyethane (300 mL) was stirred at room temperature under nitrogen for 48 h. The mixture was concentrated in vacuo to give a residue which was purified by flash column chromatography (QingDao silica gel, 200-300 mesh, 5% ethyl acetate/pentane) afforded 2-(3-oxo-cyclopentyl)-dithiomalonic acid di-S-ethyl ester as a white solid (50.0 g, 82%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:10]([CH2:11][OH:12])=[CH:9][CH:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:6]=1)[CH3:3].[CH2:23]([O:25][C:26](=[O:39])[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][C:32]=1[CH3:38])([CH3:29])[CH3:28])[CH3:24].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>C1COCC1>[CH2:23]([O:25][C:26](=[O:39])[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([O:12][CH2:11][C:10]2[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[N:6][C:7]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)=[CH:8][CH:9]=2)=[CH:33][C:32]=1[CH3:38])([CH3:28])[CH3:29])[CH3:24]
Reactant: CN(C)Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2CN(C)C)cc1C
Reaction time: 6 h

Procedure:
0.170 g (0.548 mmol) of the above prepared [2-dimethylaminomethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol and 0.122 g (0.512 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) were dissolved in 6 ml of abs. THF and treated successively at 0° C. with 0.133 g (0.658 mmol) of tributylphosphine and 0.114 g (0.659 mmol) of N,N,N′,N′-tetramethylazodicarboxamide. The cooling bath was then removed and stirring continued for additional 6 h. The reaction mixture was then poured onto crashed ice, extracted twice with AcOEt, washed with water and brine, and dried over magnesium sulfate. Evaporation of the solvents i. V., followed by flash chromatography (SiO2, hexane/AcOEt=25/75) yielded 0.016 g of the title product as yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:11][C:12]#[CH:13])=O)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[BrH:14].C(OCC)(=O)C>C(OCCC)(=O)C>[Br:14][CH2:13][C:12]1[C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=2[S:9][CH:11]=1
Reactant: C#CCS(=O)c1cc(C)cc(C)c1
Reactant: Br
Solvent: CCOC(C)=O
Solvent: CCCOC(C)=O
Product: Cc1cc(C)c2c(CBr)csc2c1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
In 40 mL of propyl acetate, was dissolved 2.26 g (11.7 mmol) of the compound obtained in Example 13. The refluxing was carried out for 30 minutes. The solution was then cooled, and 1.59 mL (14 mmol) of a 48% hydrobromic acid was added. The resulting mixture was allowed to stand at room temperature for 30 minutes. Ethyl acetate was subsequently added, and the obtained mixture was washed with water, dried with magnesium sulfate and vacuum concentrated to obtain 2.49 g of 3-(bromomethyl)-4,6-dimethylbenzo[b]thiophene. The yield was 84%.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12])[CH:5]=[O:6].[CH3:15][N:16](C=O)C>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.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>[C:15]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12])[CH:5]=[O:6])#[N:16]
Reactant: O=Cc1ccc(OC(F)(F)F)c(I)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: N#Cc1cc(C=O)ccc1OC(F)(F)F
Temperature: 100 °C

Procedure:
To a stirred suspension of Compound 19 (6.85 g, 21.7 mmol) and zinc cyanide (4.07 g, 34.7 mmol) in dry DMF (35 ml) was added tetrakis(triphenylphosphine)palladium(0) (3.00 g, 2.60 mmol) portionwise at room temperature. The reaction mixture was heated at 100° C. for 9 h. The reaction mixture was diluted with toluene (100 ml)-2M NH3 aq. (100 ml). The organic layer was separated. The aqueous layer was diluted with toluene (100 ml), filtered through a pad of celite and the filter cake was washed with toluene. The organic layer was separated and the aqueous layer was extracted with toluene. The combined solution was washed with 2M NH3 aq. (50 ml) and brine, dried (MgSO4), and concentrated in vacuo to give crude product as a dark tan oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].Cl.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:27]2[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([C:38]3[CH:43]=[CH:42][C:41]([C:44](N4CCN(C5C=CC=CC=5)CC4)=[O:45])=[CH:40][CH:39]=3)[N:28]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[CH3:16]>C(OCC)C>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:27]2[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([C:38]3[CH:39]=[CH:40][C:41]([C:44]([N:11]4[CH2:10][CH2:9][N:8]([C:6]([C:2]5[O:1][CH:5]=[CH:4][CH:3]=5)=[O:7])[CH2:13][CH2:12]4)=[O:45])=[CH:42][CH:43]=3)[N:28]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[CH3:16]
Reactant: O=C(c1ccco1)N1CCNCC1
Reactant: CCOc1ccc(C2=NN(c3ccc(C(=O)N4CCN(c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Agent: Cl
Solvent: CCOCC
Product: CCOc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C(=O)c5ccco5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC

Procedure:
Prepared from intermediate product A1 and 1-(furan-2-yl-methanoyl)piperazine as described for compound 1. Cystallised from diethyl ether as the free base. M.p. 114–115° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH:12](O)=[O:13]>>[CH:12]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[CH3:1])=[O:13]
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Reactant: O=CO
Product: Cc1cc([N+](=O)[O-])ccc1NC=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
1000 g of formic acid were introduced into a flask fitted with a stirrer and a reflux condenser. 151 g (1 mol) of 2-methyl-4-nitroaniline were added, and the resultant mixture was slowly heated to the reflux point. After four hours, the reaction mixture was poured into 5 l of ice water. The resultant precipitate was filtered off with suction, washed with water until neutral and then dried at 60° C. under reduced pressure. Recrystallization of the resultant crude product from 2.5 l of methanol or ethanol gave 171 g of N-formyl-2-methyl-4-nitroaniline (yield: 95%) as yellow crystals, which melted at 162° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:27])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2].[CH2:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:29]>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:33]2[CH2:34][CH2:35][N:30]([CH2:28][CH3:29])[CH2:31][CH2:32]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:27])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2]
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12
Reactant: CCN1CCNCC1
Solvent: ClCCl
Product: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(CC)CC4)ccc3OCC)nn12
Temperature: 0 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
470 mg (1.14 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride are dissolved in 20 ml of dichloromethane and cooled to 0° C. 390 mg (3.42 mmol) of N-ethylpiperazine are added, and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic phase is washed twice with water and dried over sodium sulphate and the solvent is removed under reduced pressure. Crystallization from ether gives 370 mg (66%) of a colourless solid.