Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].Cl[S:9]([OH:12])(=[O:11])=[O:10]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[S:9](=[O:12])(=[O:11])=[O:10]
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Solvent: Cc1ccccn1
Product: O=S(=O)=O
Reaction time: 0.5 h

Procedure:
In a 50 ml 3-neck RBF equipped with a magnetic stir bar, thermocouple probe, addition funnel, nitrogen inlet adapter, and a rubber septum, charged dichloromethane (anh) (2.5 ml) and 2-picoline (1.46 ml, 14.7 mmol). This 2-picoline solution was chilled in an ice/NaCl bath to −2° C. Then a solution of chlorosulfonic acid (0.478 ml, 7.14 mmol) in dichloromethane (anh) (2.5 ml) was added over 30 minutes, with the temperature being maintained below 5° C. The resulting orange solution was stirred for 30 minutes before being added to the sulfation reaction at room temperature as described in this Example, step 2.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:29][C:30]1[C:31]([CH3:39])=[CH:32][C:33]2[N:34]([N:36]=[CH:37][N:38]=2)[N:35]=1>O1CCCC1>[ClH:29].[ClH:29].[C:3]1([CH:9]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:30]3[C:31]([CH3:39])=[CH:32][C:33]4[N:34]([N:36]=[CH:37][N:38]=4)[N:35]=3)[CH2:14][CH2:15]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cc2ncnn2nc1Cl
Reactant: OCCCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2ncnn2nc1OCCCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Product: Cl
Temperature: 0 °C

Procedure:
210 mg of 60% sodium hydride in oil was suspended in 15 ml of tetrahydrofuran; 0.91 g of 4-(diphenylmethyl)-1-piperazinehexanol was added, followed by heating and refluxing for 1 hour. After cooling, 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine was added, followed by heating and refluxing for 3 hours. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with dichloromethane-ethyl acetate-methanol (1.0:10:1). The desired fraction was collected and dissolved in 5 ml of ethyl acetate; 1.44 ml of a 4 N hydrogen chloride solution in ethyl acetate was added; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 1.06 g of the title compound, which was then recrystallized from ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[CH3:26])=[C:10]([C:13]1[N:17]([CH3:18])[N:16]=[N:15][N:14]=1)C=O.C1(P(=[CH:46][CH:47]=[O:48])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:49]1C=CC=CC=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[CH3:26])=[C:10]([C:13]1[N:17]([CH3:18])[N:16]=[N:15][N:14]=1)[CH:49]=[CH:46][CH:47]=[O:48]
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C(=C(C=O)c2nnnn2C)c2ccc(C)cc2C)c(C)c1
Reactant: c1ccccc1
Product: Cc1ccc(C(=C(C=CC=O)c2nnnn2C)c2ccc(C)cc2C)c(C)c1

Procedure:
A solution of 3,3-bis(2,4-dimethylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal (4.5 g, 13.0 mmoles) and triphenylphosphoranylidene acetaldehyde (4.1 g, 13.0 mmoles) in benzene was heated at reflux temperature for 6 hours. The reaction mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with 10% (v/v) ethyl acetate in hexane to give 5.9 g of the title compound as an oil. MS (CI): m/e=373 for (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]([O:11]CC)=[O:10])[S:7][CH:8]=1)([CH3:3])[CH3:2].[OH-].[Li+]>CO.C1COCC1.O>[CH:1]([C:4]1[N:5]=[C:6]([C:9]([OH:11])=[O:10])[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1nc(C(C)C)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)c1csc(C(=O)O)n1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
A solution of ethyl 4-isopropylthiazole-2-carboxylate (example 53, step a) (2.2 g) in a mixture of methanol (10 mL) and THF (20 mL) was treated with a solution of lithium hydroxide (0.264 g) in water (20 mL). The reaction mixture was stirred at 20° C. for 24 hours. The organic solvent was removed under reduced pressure and the remaining aqueous mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 2M hydrochloric acid and extracted twice with ethyl acetate, the combined organics were washed with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was triturated with cyclohexane to afford the subtitled compound. Yield 0.93 g.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][C:8]([CH2:10][CH:3]1[CH2:4][CH2:5]2)=[O:9].ClC(O[CH2:15][CH2:16]Cl)=O.O>C(Cl)(Cl)Cl>[CH2:1]([N:2]1[CH:6]2[CH2:5][CH2:4][CH:3]1[CH2:10][C:8](=[O:9])[CH2:7]2)[C:16]1[CH:15]=[CH:5][CH:4]=[CH:3][CH:10]=1
Reactant: CN1C2CCC1CC(=O)C2
Reactant: O=C(Cl)OCCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1CC2CCC(C1)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
25 g of tropinone was dissolved in 100 mL of chloroform, and 50 mL of chloroethyl chloroformate was added thereto and stirred at room temperature for 6 hours. The reaction liquid was concentrated, 100 mL of methanol was added thereto, and heated overnight under reflux. The reaction liquid was cooled to room temperature and concentrated, and the resulting crude product was dissolved in 80 mL of N-methylpyrrolidone. 43 mL of benzyl bromide and 99 g of potassium carbonate were added thereto and stirred overnight at room temperature. The reaction liquid was poured into water, and extracted three times with ethyl acetate. The organic layer was washed with water and saturated saline water, dried with anhydrous magnesium sulfate, and the solvent was evaporated off under reduced pressure to obtain 29.5 g of the entitled compound as a pale yellow liquid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([OH:35])=O)=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]=23)[CH2:3][CH2:2]1.[NH2:36][C@@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([NH:36][C@@H:37]4[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:39][CH2:38]4)=[O:35])=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:16]=23)[CH2:2][CH2:3]1
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)cc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c8) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([N:13]1[CH2:29][CH2:28][C:16]3([N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][NH:18][C:17]3=[O:27])[CH2:15][CH2:14]1)[CH2:7]2.[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[ClH:1].[CH2:30]([N:18]1[C:17](=[O:27])[C:16]2([CH2:28][CH2:29][N:13]([CH:6]3[CH2:5][CH2:4][C:3]4[C:8](=[C:9]([Cl:12])[CH:10]=[CH:11][C:2]=4[Cl:1])[CH2:7]3)[CH2:14][CH2:15]2)[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCc3c(Cl)ccc(Cl)c3C1)CC2
Reactant: BrCc1ccccc1
Product: Cl
Product: O=C1N(Cc2ccccc2)CN(c2ccccc2)C12CCN(C1CCc3c(Cl)ccc(Cl)c3C1)CC2

Procedure:
The title compound, m.p.>250° C. and MS: m/e=520.3, 522.3 (M+H+) was prepared in accordance with the general method of example 4 from 8-(5,8-dichloro-1,2,3,4-tetrahydro-2-naphthyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and benzyl bromide.
Reaction SMILES: [C:1]1([C:9]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([O:16][CH3:17])=[CH:14][CH:13]=2)=O)[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.C(OC(=O)[NH:24][NH2:25])C.O=[S:28](Cl)Cl>>[CH3:6][O:5][C:4]1[CH:7]=[CH:8][C:1]([C:9]2[N:25]=[N:24][S:28][C:11]=2[C:12]2[CH:19]=[CH:18][C:15]([O:16][CH3:17])=[CH:14][CH:13]=2)=[CH:2][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)NN
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2nnsc2-c2ccc(OC)cc2)cc1
Temperature: 60 °C

Procedure:
The hydrazone (7.0 g, 20 mmol) derived from desoxyanisoin (Aldrich) and ethylcarbazate was added to 20 ml of SOCl2 ;which had been cooled in an ice bath. The reaction was heated at 60° C. for 1 hour, cooled and then the solvent was removed under vacuum. The crude residue was triturated with ether affording 7.5 g of crude material, m.p. 80°-82° C. This was recrystallized from ether affording 3.59 g (60%) of 7, m.p. 84°-86° C. as red crystals. A simple column filtration through silica afforded white, analytically pure crystals of 7, m.p. 84°-86° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[Cl:59]C1C=C(C=CC=1)C(Cl)=O>>[Cl:59][C:6]1[CH:7]=[C:2]([CH:3]=[CH:4][CH:5]=1)[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)=[O:8]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cccc(Cl)c4)cc3)cc2C1=O

Procedure:
The compound of example 107 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 3-chlorobenzoyl chloride. The compound of example 107 was used directly without isolation for the preparation of compound of example 108.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]=1.[C:12]1(=O)[O:17][C:15](=[O:16])[CH:14]=[CH:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[C:15](=[O:16])[CH:14]=[CH:13][C:12]2=[O:17])[CH:2]=1
Reactant: O=C1C=CC(=O)O1
Reactant: NCCCOc1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=C1C=CC(=O)N1CCCOc1cccnc1

Procedure:
From 2 to 3 mmol of the appropriate 3-(pyridin-3-yloxy)propylamine in 5 ml of THF are admixed in succession with 500 mg of maleic anhydride (molecular mass: 98.06; 5.1 mmol) and 200 mg of p-toluenesulphonic acid hydrate (molecular mass: 190.22; 1.0 mmol). The solution is refluxed for 24 hours and concentrated to dryness. The residue is chromatographed on silica gel to give the desired 1-[3-(pyridin-3-yloxy)propyl]-pyrrole-2,5-dione derivative.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:19]#[N:20])[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[C:9]=2[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[C:7]1=[O:32])[CH3:2].[OH-:35].[K+].Cl.C([OH:42])(C)(C)C>>[F:16][C:15]([F:18])([F:17])[C:14]([OH:42])=[O:35].[CH2:33]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:19]([NH2:20])=[O:42])[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[C:9]=2[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:30])([F:31])[F:29])[C:7]1=[O:32])[CH3:34]
Reactant: CCN(CC)CCn1c(=O)n(Cc2ccccc2C(F)(F)F)c2c(C(F)(F)F)cc(C#N)cc21
Reactant: CC(C)(C)O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: CCN(CC)CCn1c(=O)n(Cc2ccccc2C(F)(F)F)c2c(C(F)(F)F)cc(C(N)=O)cc21
Product: O=C(O)C(F)(F)F
Temperature: 60 °C

Procedure:
A solution of 3-[2-(diethylamino)ethyl]-2-oxo-7-(trifluoromethyl)-1-[2-(trifluoromethyl)benzyl]-2,3-dihydro-1H-benzimidazole-5-carbonitrile (2.8 mg) in t-butanol (2 ml) was stirred with heating at 60° C. To the solution was added powdered potassium hydroxide crashed in mortar (24.3 mg), and the mixture was stirred with heating at 60° C. for 30 minutes. To the reaction mixture was added 1N hydrochloric acid, and the mixture was concentrated in vacuo. The resultant residue was purified by HPLC using condition 2 to give the title compound (4.0 mg, quantitative yield).
Reaction SMILES: S(OC)(OC)(=O)=O.[N:8]1S[N:11]=[C:10]2[CH:13]=[C:14](CC#N)[CH:15]=[CH:16][C:9]=12.C(N([CH2:25][CH3:26])CC)C.[CH2:27](O)[CH3:28]>O>[CH:27]([C:25]1[CH:26]=[N:8][C:9]2[C:10](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1)=[CH2:28]
Reactant: CCN(CC)CC
Reactant: CCO
Reactant: N#CCc1ccc2nsnc2c1
Solvent: COS(=O)(=O)OC
Solvent: O
Product: C=Cc1cnc2ccccc2n1
Yield: 66 %

Procedure:
Dimethyl sulfate (1.07 ml, 11.3 mmol) was added dropwise, while maintaining the mixture temperature below 40° C., to a solution of amine (a) (2.6 g 11.3 mmol) in ethanol (3 ml). The thick mixture was diluted with water (15 ml) then triethylamine (1.13 ml) was added and the mixture heated for 2 hours on a water bath. After cooling the mixture was extracted with diethyl ether. The organic phase was dried over magnesium sulfate, concentrated to dryness and the residue was chromatographed on silica eluting with heptane-ethyl acetate (3-1) to give the product (1.16 g, 66%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]2[N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:16]=[CH:17][C:3]=12.Cl.[CH:25]12[NH:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][O:27][CH2:26]2.C(N(CC)CC)C>C(O)C>[CH:29]12[N:32]([C:2]3[N:7]=[C:6]([C:8]4[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=4)[N:5]=[C:4]4[N:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[N:16]=[CH:17][C:3]=34)[CH:25]([CH2:31][CH2:30]1)[CH2:26][O:27][CH2:28]2
Reactant: Oc1cccc(-c2nc(Br)c3cnn(-c4ccccc4)c3n2)c1
Reactant: C1CC2COCC1N2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Oc1cccc(-c2nc(N3C4CCC3COC4)c3cnn(-c4ccccc4)c3n2)c1
Temperature: 130 °C

Procedure:
A Smith process vial was charged with a suspension of 3-(4-bromo-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol (0.18 g, 0.49 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (approximately 100 mg, 0.67 mmol) in ethanol (4 mL). The suspension was treated with triethylamine (750 μL, 5.7 mmol) and was then heated in the microwave reactor for 10 minutes at 130° C. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 20% acetonitrile/80% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide 3-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol. MS (ES+): 400.3 (M+H)+
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([O:15][CH3:16])[C:8]([O:13][CH3:14])=[C:9]([O:11][CH3:12])[CH:10]=1.[C:17]1([P:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Br-:1].[C:30]1([P+:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:2][CH2:3][CH2:4][C:5]2[CH:6]=[C:7]([O:15][CH3:16])[C:8]([O:13][CH3:14])=[C:9]([O:11][CH3:12])[CH:10]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1cc(CCCBr)cc(OC)c1OC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1OC
Product: [Br-]
Temperature: 25 °C
Yield: 51 %

Procedure:
Dissolved in 50 ml of toluene were 7.65 g (26.5 mmol) of 5-(3-bromopropyl)-1,2,3-trimethoxybenzene and 6.9 g (26.5 mmol) of triphenylphosphine, followed by heating under reflux for 23 hours. The reaction mixture was allowed to cool down to room temperature. The supernatant was thereafter removed by decantation, whereby 7.46 g of crude triphenyl[3-(3,4,5-trimethoxyphenyl)propyl]phosphonium bromide were obtained as colorless oil (yield: 51%). The crude oil was used in the next reaction without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][OH:26]>C(#N)C>[OH:26][CH2:25][C@@H:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:10]1[N:11]=[C:6]([CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[C:2]([CH3:1])[CH:3]=2)[NH:7][C:8](=[O:16])[C:9]=1[C:14]#[N:15]
Reactant: CSc1nc(Cc2cccc(C)c2)[nH]c(=O)c1C#N
Reactant: OC[C@@H]1CCCN1
Solvent: CC#N
Product: Cc1cccc(Cc2nc(N3CCC[C@H]3CO)c(C#N)c(=O)[nH]2)c1
Temperature: 25 °C

Procedure:
0.1 g (0.37 mmol) of 2-(3-methylbenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile is heated with 0.11 g (1.1 mmol) of (S)-(+)-2-pyrrolidinemethanol in 3 ml of acetonitrile at 90° C. under argon for five days. After cooling to room temperature, the crude product is purified by preparative HPLC. 0.035 g (29% of theory) of the title compound is obtained as a colourless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[C:10](\[CH3:14])/[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[CH2:16]([Li])[CH2:17]CC.CN(C)C1C=CC(C=O)=CC=1.O>CCCCCC>[CH3:15][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[C:10](\[CH3:14])/[C:11]([O:13][CH2:16][CH3:17])=[O:12])=[CH:7][CH:8]=1
Reactant: [Li]CCCC
Reactant: C/C(=C\c1ccc(N(C)C)cc1)C(=O)O
Agent: CN(C)c1ccc(C=O)cc1
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)/C(C)=C/c1ccc(N(C)C)cc1

Procedure:
E-3-(4-Dimethylaminophenyl)-2-methyl-propenoic acid guanidide hydrochloride ##STR6## 1 a) 1 eq. of triethyl phosphonopropionate was deprotonated with 1 eq. of n-butyllithium in hexane at 0° C., and 1 eq. of 4-dimethylaminobenzaldehyd was then added at RT. After the aldehyde had reacted completely, the mixture was worked up with water and extracted three times by shaking with toluene. After the combined organic phases had been dried over magnesium sulfate, the solvent was removed in vacuo and the crude product which remained was separated by chromatography over silica gel using EA/HEP mixtures as the eluent. Ethyl E-3-(4-dimethylamino-phenyl)-2-methyl-acrylate was isolated. orange-yellowish oil MS 233 (M+)
Reaction SMILES: C1(O[C:8]([N:14]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([CH:28]4[C:34]5=[N:35][CH:36]=[C:37]([Br:39])[CH:38]=[C:33]5[CH2:32][CH2:31][C:30]5[CH:40]=[C:41]([Cl:45])[CH:42]=[C:43]([Cl:44])[C:29]4=5)[CH2:24][CH2:23]3)=[O:21])[CH2:15]2)=[N:9][S:10]([CH3:13])(=[O:12])=[O:11])C=CC=CC=1.[NH4+:46].[OH-]>CC(O)C>[Br:39][C:37]1[CH:38]=[C:33]2[CH2:32][CH2:31][C:30]3[CH:40]=[C:41]([Cl:45])[CH:42]=[C:43]([Cl:44])[C:29]=3[CH:28]([CH:25]3[CH2:24][CH2:23][N:22]([C:20](=[O:21])[CH2:19][CH:16]4[CH2:17][CH2:18][N:14]([C:8](=[NH:46])[NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH2:15]4)[CH2:27][CH2:26]3)[C:34]2=[N:35][CH:36]=1
Reactant: [NH4+]
Reactant: CS(=O)(=O)N=C(Oc1ccccc1)N1CCC(CC(=O)N2CCC(C3c4ncc(Br)cc4CCc4cc(Cl)cc(Cl)c43)CC2)C1
Agent: [OH-]
Solvent: CC(C)O
Product: CS(=O)(=O)NC(=N)N1CCC(CC(=O)N2CCC(C3c4ncc(Br)cc4CCc4cc(Cl)cc(Cl)c43)CC2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product of Example 26 is dissolved in 2-propanol and concentrated NH4OH is added. The mixture is stirred at 25° C. for 24 h and then evaporated to dryness. The residue is triturated with Et2O (2×250 ml) and the ether discarded. The resulting product is chromatographed on a silica gel column to give the title compound.
Reaction SMILES: [CH2:1]([S:15][CH2:16][CH2:17][OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C=CC=CC=1.[C:25](Cl)(=[O:27])[CH3:26].[NH4+].[Cl-]>C1COCC1.C(OCC)C>[CH2:1]([S:15][CH2:16][CH2:17][O:18][C:25](=[O:27])[CH3:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCCCCCCCSCCO
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCSCCOC(C)=O
Temperature: 25 °C
Reaction time: 23 h
Yield: 72.2 %

Procedure:
2-Tetradecylsulfanyl-ethanol (0.54 g, 1.97 mmol) was dissolved in dry THF (10 ml) and pyridine (0.16 ml, 1.97 mmol) was added followed by acetyl chloride (0.15 m, 2.16 mmol). The resulting mixture was allowed to stir at ambient temperature for 23 hours, then another portion of acetyl chloride (0.075 ml, 1.08 mmol) and pyridine (0.080 ml, 0.95 mmol) was added. The mixture was stirred at ambient temperature for a further 90 minutes and then portioned between diethyl ether (30 ml) and 10% NH4Cl (30 ml). The organic layer was washed with brine (40 ml), dried (Na2SO4) and concentrated in vacuo. Toluene (10 mL) was added to the residue. The solvents were evaporated in vacuo and the crude product was purified by flash chromatography on silica gel (heptane:EtOAc 9:1) to afford 0.45 g (72%) of the title compound as a colorless solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH2:16][C:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[S:19][CH:18]=1.[C:26]([O:30][C:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27]>ClCCl>[C:26]([O:30][C:31](=[O:32])[NH:33][CH2:34][C:35]([NH:16][C:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[S:19][CH:18]=1)=[O:36])([CH3:29])([CH3:27])[CH3:28]
Reactant: Nc1csc2ncccc12
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nc1csc2ncccc12
Yield: 85.5 %

Procedure:
1,3-Dicyclohexylcarbodiimide (11 g) was added with stirring to a solution of 3-aminothieno[2,3-b]pyridine (8 g) and N-(tert-butoxycarbonyl)glycine (10 g) in 200 mL of dichloromethane. After one hour the reaction mixture was filtered to remove the separated 1,3-dicyclohexylurea and evaporated to an oil. Crystallization from ethyl ether afforded 14 g of a solid, m.p. 190°-192° C. Recrystallization of 3 g from acetonitrile afforded 2.4 g of crystals, m.p. 192°-194° C. Final recrystallization from acetonitrile afforded 2.0 g of crystals, m.p. 194°-196° C.