Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:15])[CH:4](Br)[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[CH3:16][NH:17][CH2:18][CH2:19][NH:20][CH3:21]>C(O)C>[CH3:16][N:17]1[CH2:18][CH2:19][N:20]([CH3:21])[CH:4]([C:5]2[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)[C:3]1=[O:15]
Reactant: CNCCNC
Reactant: COC(=O)C(Br)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: CN1CCN(C)C(c2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
Bromo-(4-nitro-phenyl)-acetic acid methyl ester (547 mg, 2.00 mmol) was dissolved in ethanol (5.50 mL) and N,N′-dimethyl-ethane-1,2-diamine (1.07 mL, 9.98 mmol) was added. The reaction was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-10% MeOH/DCM as the eluting solvent to obtain 1,4-dimethyl-3-(4-nitro-phenyl)-piperazin-2-one as an orange solid (450 mg, 90%). m.p.=99-102° C.; LCMS (m/e) 250 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.19 (d, 2H, J=8.6 Hz), 7.61 (d, 2H, J=8.6 Hz), 3.83 (s, 1H), 3.81-3.70 (m, 1H), 3.26-3.18 (m, 1H), 3.08-3.00 (m, 1H), 2.97 (s, 3H), 2.78-2.68 (m, 1H), 2.18 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Br[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1.[OH-].[Na+]>CN(C=O)C.O>[Br:19][C:17]1[CH:16]=[N:15][CH:14]=[C:13]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH:18]=1
Reactant: Brc1cncc(Br)c1
Reactant: COc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.3 %

Procedure:
To a stirred suspension sodium hydride (3.0 g of 80% in mineral oil, 100 mmol) in DMF (95 mL) in an ice water bath, 4-methoxyphenol (12.2 g, 96 mmol) was added slowly under a nitrogen atmosphere. The resulting mixture was warmed to ambient temperature and stirred for 1 h. 3,5-Dibromopyridine (15.6 g of 98%, 65 mmol) was added and the mixture was then heated at 85° C. (bath temperature) for 32 h. The mixture was cooled, diluted with water (120 mL), poured into 5N sodium hydroxide (15 mL), and extracted with ether (3×150 mL). The combined ether extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation, to give a light yellow oil (21.9 g). The oil was diluted with ethanol and rotary evaporated (twice) to remove residual DMF and then diluted with ether (50 mL) and suction filtered to remove un-reacted 3,5-dibromopyridine. Rotary evaporation and high vacuum treatment left a lard-like product weighing 12.8 g. The product was 94% pure by GC-MS analysis, (66% yield) and was sometimes used, without further purification, in subsequent reactions. When desired, further purification (to 99.4%) was accomplished by column chromatography on Merck silica gel 60 (70-230 mesh) with 85:5:5:0.5 hexane/chloroform/ethyl acetate/methanol/aqueous ammonia.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[H-].[Na+].[CH2:11]([O:13][C:14]([C:16]1[C:20](CBr)=[C:19]([S:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)[N:18]([CH:32]([CH3:34])[CH3:33])[N:17]=1)=[O:15])[CH3:12].O>CN(C=O)C>[CH2:11]([O:13][C:14]([C:16]1[C:20]([CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[C:19]([S:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)[N:18]([CH:32]([CH3:33])[CH3:34])[N:17]=1)=[O:15])[CH3:12]
Reactant: OCc1ccncc1
Reactant: CCOC(=O)c1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1Cc1ccncc1
Yield: 35.2 %

Procedure:
To a solution of 55 mg of 4-(hydroxymethyl)pyridine in DMF at 0° C. was added 20 mg sodium hydride (60% in oil). To the mixture was added dropwise a solution of 229 mg of 4-bromomethyl-5-(3,5-dichlorophenylthio)-1-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester in 2 ml of N,N-dimethylformamide. After 15 min water was added and the mixture was extracted with dichloromethane (×3). The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography using ethyl acetate/iso-hexane for the elution to give 80 mg of 5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methyl]-1H-pyrazole-3carboxylic acid ethyl ester as a colourless gum. Mass spectrum (ESI) m/z 480 [M]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][NH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](Cl)(=[O:31])[CH2:26][CH2:27][C:28](Cl)=[O:29]>N1C=CC=CC=1.ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][NH:13][C:25](=[O:31])[CH2:26][CH2:27][C:28]([NH:13][CH2:12][C:11]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCC(=O)Cl
Reactant: NCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCC(=O)NCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 0 °C

Procedure:
3,4-dibenzyloxybenzylamine (1.1 g, 3.45 mmol) was dissolved in anhydrous pyridine (8 ml) and cooled to 0° C. with stirring under nitrogen. To this solution, succinyl chloride (0.23 g, 1.42 mmol) was added dropwise over 30 minutes as a solution in dichloromethane (50 ml), while maintaining the reaction mixture at 0° C. The reaction was allowed to warm to room temperature and stirred for an additional 45 minutes. The reaction was poured onto crushed ice (70 g) and the dichloromethane layer was separated. The organic extract was washed with dilute aqueous hydrochloric acid (2×20 ml of 0.1M solution), water (20 ml), and dried (NON. Removal of the solvent at reduced pressure afforded a crude solid, which was triturated with methanol (5 ml) to afford after filtration the protected diamide, yield 300 mg.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=O)=[C:4](F)[CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:4]3[C:5](=[CH:8][C:9]([O:10][CH3:11])=[C:2]([Cl:1])[CH:3]=3)[CH:6]=[N:21]2)=[CH:16][CH:15]=1
Reactant: NNc1ccc(F)cc1
Reactant: COc1cc(C=O)c(F)cc1Cl
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cc2cnn(-c3ccc(F)cc3)c2cc1Cl
Temperature: 150 °C

Procedure:
4-Chloro-2-fluoro-5-methoxy benzaldehyde (204 mg, 1.1 mmol) and 4-fluorophenylhydrazine (176 mg, 1.1 mmol) were dissolved in N-methylpyrrolidine (5 mL). After addition of cesium carbonate (1.15 g, 3.3 mmol) the mixture was heated in a microwave reactor (CEM Discovery, 150 Watt) to 150° C. for 20 min. After dilution with DCM the mixture was washed with sat. NaHCO3, brine and the organic phase was evaporated. After purification of the crude by flash chromatography on silica gel 253 mg (84%) of the subtitle compound were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]([C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])[CH:9]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].C([O-])(=O)C.O=[C:38]([CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:39]([O:41][CH2:42][CH3:43])=[O:40]>C(O)C.[Ni]>[C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]([C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][CH:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[CH:9]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1cc2c(cc1OC)C(N(CC(=O)OC(C)(C)C)C(=O)[C@H](C)N)CC2
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: [Ni]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1CCc2cc(OC)c(OC)cc21
Yield: 33.3 %

Procedure:
L-Alanyl-N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester (4.0 g) is dissolved in 80 ml of ethanol, and 0.77 g of sodium acetate, 4.0 g of acetate acid, 4.0 g of ethyl 2-oxo-4-phenyl-butyrate, 12 g of molecular sieve 3A and 6.0 g of Raney nickel are added. Thereafter, the reaction and treatment are carried out as in Example 2 to give 2.0 g of N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester as slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([CH3:14])[C:5]2[NH:6]C(=O)O[C:9](=[O:10])[C:4]=2[CH:3]=1.[C:15]([O:19][CH3:20])(=[O:18])[NH:16][NH2:17].CO>O>[NH2:6][C:5]1[C:12]([CH3:14])=[CH:13][C:2]([Cl:1])=[CH:3][C:4]=1[C:9]([NH:17][NH:16][C:15]([O:19][CH3:20])=[O:18])=[O:10]
Reactant: COC(=O)NN
Reactant: Cc1cc(Cl)cc2c(=O)oc(=O)[nH]c12
Solvent: CO
Solvent: O
Product: COC(=O)NNC(=O)c1cc(Cl)cc(C)c1N
Yield: 60.2 %

Procedure:
A mixture of 1.05 g of 6-chloro-8-methyl-1H-benzo[d]-1,3-oxazine-2,4-dione, 0.46 g of methyl carbazate and 20 ml of methanol was heated to reflux for 3 hours. After the reaction mixture was allowed to cool to around room temperature, water was poured thereto and the mixture was extracted with ethyl acetate three times. The resulting organic layer was concentrated under reduced pressure, and the residue was washed with toluene to obtain 0.77 g of N-(2-amino-5-chloro-3-methylbenzoyl)-N′-methoxycarbonylhydrazine of the formula:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:39][CH2:38][C:11]2[N:12]=[C:13]([NH:15][C:16](=[O:37])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]4[CH:28]=[C:27]([C:29]5[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=5)[CH:26]=[N:25]4)[CH:18]=3)[S:14][C:10]=2[CH2:9]1)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][C@H:8]1[CH2:39][CH2:38][C:11]2[N:12]=[C:13]([NH:15][C:16](=[O:37])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]4[CH:28]=[C:27]([C:29]5[CH:30]=[CH:31][C:32]([C:35]#[N:36])=[CH:33][CH:34]=5)[CH:26]=[N:25]4)[CH:18]=3)[S:14][C:10]=2[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2nc(NC(=O)c3cccc(Cn4cc(-c5ccc(C#N)cc5)cn4)c3)sc2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(-c2cnn(Cc3cccc(C(=O)Nc4nc5c(s4)C[C@@H](N)CC5)c3)c2)cc1
Yield: 73.3 %

Procedure:
Stir ((S)-2-{3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-benzoylamino}-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester (0.38 g, 0.69 mmol) in 2 mL CH2Cl2 and 2 mL TFA for 3 h in a capped flask. Concentrate the reaction and bring to alkaline pH with aq. Na2CO3. Triturate the residue with CH2Cl2 and filter the product to give 0.23 g 75% yield of N—((S)-6-amino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-benzamide as a beige solid. MS, ES+ 455.73 (M+H), rt 1.39 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:16]([OH:18])=O)=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[NH4+:28].[OH-]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:16]([NH2:28])=[O:18])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4]
Reactant: [NH4+]
Reactant: CCn1cc(C(=O)O)c2ccc(C(=O)OC)cc21
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCn1cc(C(N)=O)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
1-Ethyl-1H-indole-3,6-dicarboxylic acid 6-methyl ester (600 mg, 2.43 mmol) was suspended in a solution of CH2Cl2 (27 ml) and DMF (20 μL). Oxalyl chloride (470 μL, 5.38 mmol) was added, and the reaction mixture was stirred for 1 hour at room temperature. This mixture was then slowly poured into a rapidly stirring solution of concentrated NH4OH (10 mL). This was then partitioned in H2O and EtOAc. The residue from the ethyl acetate layer was triturated with acetone to yield 6-methoxycarbonyl-1-ethyl-1H-indole-3-carboxamide (511 mg, 85%) as a white solid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:12]3([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[N:11]([C:25]3[CH:30]=[CH:29][C:28]([I:31])=[CH:27][CH:26]=3)[C:10](=[O:32])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCOCC1.[ClH:39].C(Cl)[Cl:41]>CO>[ClH:41].[ClH:39].[CH:1]1([NH:7][C:8]2[C:12]3([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[N:11]([C:25]3[CH:26]=[CH:27][C:28]([I:31])=[CH:29][CH:30]=3)[C:10](=[O:32])[N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(NC1CCCCC1)=NC(=O)N2c1ccc(I)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C1N=C(NC2CCCCC2)C2(CCNCC2)N1c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of tert-butyl 4-(cyclohexylamino)-1-(4-iodophenyl)-2-oxo-1,3,8-triazaspiro[4.5]dec-3-ene-8-carboxylate (10.9 g, 19.7 mmol) in 4N HCl dioxane (99 mL, 395 mmol) was added small amounts of DCM and MeOH to obtain a solution. After stirring at rt for 1 h, the reaction mixture was concentrated in vacuo, the residue was triturated with diethyl ether and the product was isolated as a white solid by filtration. LRMS (M+1)=453. LC analysis and 1H NMR indicate the presence of an unknown (20%), the titled compound was used as is in subsequent steps, allowing for purification at a later stage.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.C(N(CC)CC)C.[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(O)C>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][N:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: C1CNCCNC1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: c1ccc2nc(CN3CCCNCC3)ccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.3 %

Procedure:
After a mixture consisting of 2-chloromethyl-quinoline hydrochloride (63.16 g, 295 mmol), triethyl-amine (29.85 g, 295 mmol), homopiperazine (50.08 g, 591 mmol) and ethanol (600 ml) was stirred at room temperature for 2 days, the solvent was distilled off under reduced pressure. Water was added to the residue. After the resulting mixture was washed three times with ethyl ether, sodium chloride was added to the water layer, followed by extraction four times with chloroform-methanol (2:1). The extract was washed with an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, whereby 28.00 g of the title compound were obtained as a yellow oil (yield: 39.3%).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][C:13]1[N:14]=[CH:15][C:16]([CH2:19][NH2:20])=[N:17][CH:18]=1.C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:20][CH2:19][C:16]3[CH:15]=[N:14][C:13]([CH3:12])=[CH:18][N:17]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: Cc1cnc(CN)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cc1cnc(CNc2ccc3ncc(Br)n3n2)cn1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and (5-methylpyrazin-2-yl)methanamine according to general procedure 1 providing the intermediate (64 mg, 34%) as a yellow solid: Rf=0.67 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 8.69 (s, 1H), 8.47 (s, 1H), 7.60 (d, J=9.7 Hz, 1H), 7.39 (s, 1H), 6.79 (d, J=9.7 Hz, 1H), 4.66 (s, 2H), 2.53 (s, 3H); ES-MS: (M+H)=319, 321 m/z.
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=O.[Cl-].[CH3:16][O:17][CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[CH3:16][O:17][CH:18]=[CH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
(for Example 11): Potassium t-butoxide (8.40 g) was added under argon to a stirred, ice-cooled, mixture of 2-pyridinecarboxaldehyde (5.36 g) and (methoxymethyl)triphenylphosphonium chloride (25.65 g) in dry THF (100 ml). The mixture was stirred for 1 hour and was then poured into ice-water (100 ml). The mixture was extracted with ether (3×50 ml) and the organic solution extracted with 2M hydrochloric acid (3×25 ml). These acid extracts were washed with ether (25 ml), basified to pH 11 with 2M sodium hydroxide and extracted with ether (1×100 ml). These combined extracts were washed with water (25 ml), saturated brine (2×25 ml), dried (MgSO4) and evaporated. Flash chromatography, eluting with ether, gave 1-methoxy-2-(2-pyridyl)ethene as a yellow oil (4.03 g). A solution of this oil (810 mg) and methyl 4(Z)-6-(4-o-methylsulphonyloxyphenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl)hexenoate (1.65 g) in acetonitrile (10 ml) was treated with p-toluenesulphonic acid monohydrate (1.25 g) and the mixture stirred at 80° C. for 18 hours. Ether (100 ml) was added to the cooled solution and the mixture washed with 5% w/v sodium bicarbonate (1×40 ml), saturated brine (2×25 ml), dried (MgSO4) and evaporated. Purification of the residue by MPLC, eluting with ethyl acetate/hexane (75:25) gave methyl 4(Z)-6-([2,4,5-cis]-4-o-methylsulphonyloxphenyl-2-[2-pyridylmethyl]-1,3-dioxan-5-yl)hexenoate as a pale yellow oil (1.50 g); NMR (CDCl3): 1.51 (1H, m), 1.88 (1H, m), 2.25 (4H, m), 2.41 (1H, m), 3.22 (3H, s), 3.29 (2H, d J=5 Hz), 3.68 (3H, s), 3.91 (1H, dm J=11 Hz), 4.06 (1H, bd J=11 Hz), 5.26 (4H, m), 7.15 (1H, m), 7.32 (4H, m), 7.60 (2H, m), 8.56 (1H, dd J=5, 0.5 Hz); m/e 476 (M+H)+.
Reaction SMILES: Cl.C([O:4][C:5](=[O:29])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]2[C:18]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[N:19][CH2:20][CH2:21][C:8]=12)C.[OH-].[K+]>O.CO>[ClH:28].[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]1[C:18]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)=[N:19][CH2:20][CH2:21][C:8]1=[C:7]2[CH2:6][C:5]([OH:29])=[O:4]
Reactant: CCOC(=O)Cc1c2n(c3ccc(OC)cc13)C(c1ccc(Cl)cc1)=NCC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)c(CC(=O)O)c1n2C(c2ccc(Cl)cc2)=NCC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
117.2 g (0.27 mol) of 7-methoxy-1-(p-chlorophenyl)-3,4-dihydro-pyrimido[1,6-a]indole-5-acetic acid ethyl ester hydrochloride are introduced, while stirring, into a solution of 550 g of potassium hydroxide in 200 ml of water and 1500 ml of methanol. The mixture is stirred for 10 hours at room temperature, the methanol is distilled off in vacuo, the residue is dissolved in 1500 ml of ice-water, and 700 ml of concentrated hydrochloric acid are added to the solution while cooling with ice. The separated hydrochloride is filtered with suction and recrystallised from 2300 ml of 50% ethanol to yield 7-methoxy-1-(p-chlorophenyl)-3,4-dihydro-pyrimido[1,6-a]indole-5-acetic acid hydrochloride in the form of yellowish crystals having a melting point of 225°-228° (with decomposition).
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1>N1C=CC=CC=1>[OH:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[CH:13][C:14]([OH:16])=[O:15])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1cc(C=CC(=O)O)ccc1O
Temperature: 90 °C
Yield: 92 %

Procedure:
Vanillin (40 g, 263 mmol) was dissolved in pyridine (120 ml), and malonic acid (41 g, 395 mm ol) was added, followed by piperidine (4 ml). The mixture was heated at 90° C. for 6 hs under N2. After removal of pridine, the residue was poured into water (500 ml), acidified to PH=3 by aq.HCl. The precipitate was collected, washed by water (150 ml×3), and dried to give product (47 g, 91.8%). LC-MS: m/e 193 (M−1)
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[S:20]1[CH:24]=[CH:23][C:22]2[C:25]([NH2:29])=[CH:26][CH:27]=[CH:28][C:21]1=2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[S:20]1[C:21]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:16](=[O:18])[CH2:15][C:3]3[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]4[CH2:10][CH2:11][O:12][CH2:13][CH2:14]4)[N:4]=3)[C:22]=2[CH:23]=[CH:24]1
Reactant: Nc1cccc2sccc12
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)Nc2cccc3sccc23)nc(N2CCOCC2)cc1=O
Yield: 14.3 %

Procedure:
The product is prepared according to the procedure described in example 86, using 551 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 328 mg of benzo[b]thiophen-4-ylamine and 498 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 324 μl of pyridine and 8.0 ml of N,N-dimethylformamide. 110 mg of N-(1-benzothiophen-4-yl)-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([S:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)([CH3:11])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])C>CO.[OH-].[Na+]>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([S:12][C:5]([CH3:11])([CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[C:4]([OH:21])=[O:3])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(C)(CC=C(C)C)Sc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(SC(C)(CC=C(C)C)C(=O)O)cc1

Procedure:
2-(4Methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid was prepared starting from 2-(4-methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid ethyl ester (2.0 g, 6.4 mmol) dissolved in methanol (50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in Example 1. Yield is 1.9 g, 99% of low melting solid. MS: 280 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.[Cl:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.N1C=CC=CC=1>ClCCl>[Cl:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[S:3][C:4]3[C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=3[N:6]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Yield: 54 %

Procedure:
and 2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol (1.0 g, 3.8 mmol), 4-(chloromethyl) benzoyl chloride (810 mg, 4.2 mmol) and pyridine (0.36 ml, 4.5 mmol) are reacted in dichloromethane (20 ml) for 18 h. The reaction is quenched with water (25 ml) and brought to pH 8.0 with sodium carbonate. The mixture is extracted with dichloromethane and the combined organic layers are dried and evapoarted to dryness. Flash chromatography (silica, eluent methylene chloride containing 2.5% methanol) affords the product as white crystalls in 54% yield. MS: m/e=418 (M+H+).