Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7]C=[CH:5][C:3]=1N.[CH3:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[NH2:19])=[CH:13][CH:12]=1.BrC(Br)(CC)CC>C(N(CC)CC)C>[CH3:9][S:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]2[CH2:7][CH2:8][CH2:2][CH2:3][CH2:5]2)=[CH:15][CH:16]=1
Reactant: CSc1ccc(-c2ccccc2N)cc1
Reactant: Nc1ccccc1Br
Agent: CCC(Br)(Br)CC
Solvent: CCN(CC)CC
Product: CSc1ccc(-c2ccccc2N2CCCCC2)cc1

Procedure:
Compounds of Formula I wherein X is a single bond and R1 is 1-piperidinyl or 1-pyrrolyl can be prepared from 2-bromoaniline as shown in Scheme 15. Suzuki coupling of 2-bromoaniline with 4-thiomethylphenylboronic acid using the method described above followed by condensation of the resulting 2-(4-methylthiophenyl)aniline with dibromopentane in the presence of an amine base, such as triethylamine, affords the corresponding 1-[2-(4-methylthiophenyl)phenyl]piperidine. Oxidation if the methylthio to the methylsulfonyl using methods described above provides compounds of Formula I wherein R1 is 1-piperidinyl. Alternately the starting 2-bromoaniline can be converted to the 1-[(2-bromophenyl)phenyl]pyrrole by treatment with 2,5-dimethoxytetrahydrofuran in glacial acetic acid. Suzuki coupling of the resulting intermediate with 4-methylthiophenylboronic acid followed by oxidation, as described above, gives the 1-[2-(4-methylsulfonylphenyl)phenyl]pyrrole. ##STR26##
Reaction SMILES: [F:1][C:2]([F:32])([C:28]([F:31])([F:30])[F:29])[C:3]([F:27])([F:26])[C:4]([F:25])([F:24])[O:5][C:6]([F:23])([F:22])[C:7]([F:21])([F:20])[O:8][C:9]([F:19])([F:18])[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16]Br.[CH2:33]([O:39][C:40]1[CH:41]=[N:42][C:43]([C:46]2[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=2)=[N:44][CH:45]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>O>[CH2:33]([O:39][C:40]1[CH:45]=[N:44][C:43]([C:46]2[CH:47]=[CH:48][C:49]([O:52][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][C:9]([O:8][C:7]([F:21])([F:20])[C:6]([F:23])([F:22])[O:5][C:4]([F:25])([F:24])[C:3]([F:27])([F:26])[C:2]([F:32])([F:1])[C:28]([F:31])([F:30])[F:29])([F:19])[F:18])=[CH:50][CH:51]=2)=[N:42][CH:41]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: FC(F)(COCCOCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Solvent: O
Product: CCCCCCOc1cnc(-c2ccc(OCCOCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 2-(2-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)ethoxy)ethyl bromide (7.7 g of 90% purity by gas chromatography 11.8 mmol) with 5-hexyloxy-2-(4-hydroxyphenyl)pyrimidine (3.0 g, 11.0 mmol). The resulting product was isolated by addition of water (50 mL) to the reaction mixture, followed by filtration and recrystallization from ethanol. The recrystallized precipitate was dried at about 130° C., and the resulting product was further purified by distillation using a Kugelrohr apparatus (b.p. 185-210° C. at 0.01 torr; yield 5.6 g).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH2:22][O:23][CH3:24])=[C:16]([CH3:25])[CH:15]=2)[CH:11]=1)[C:6]([OH:8])=[O:7].C1CCC(N=C=NC2CCCCC2)CC1.[F:42][C:43]1[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:26][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[C:16]([CH3:25])[C:17]([O:21][CH2:22][O:23][CH3:24])=[C:18]([CH3:20])[CH:19]=2)[CH:11]=1)[C:6]([O:8][C:46]1[CH:47]=[CH:48][C:43]([F:42])=[CH:44][CH:45]=1)=[O:7]
Reactant: COCOc1c(C)cc(/C=C/c2cc(C(=O)O)cc(N(C)C)c2)cc1C
Reactant: Oc1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCOc1c(C)cc(/C=C/c2cc(C(=O)Oc3ccc(F)cc3)cc(N(C)C)c2)cc1C
Reaction time: 18 h

Procedure:
To a solution of Compound 5 (80 mg, 0.225 mmol) in DCM (3 mL) were added DCC (70 mg, 0.338 mmol), DMAP (5.5 mg, 0.045 mmol), and 4-fluorophenol (61.5 mg, 0.450 mmol) at room temperature. The reaction mixture was stirred overnight (about 18 hours) and filtered through Celite. The filtrate was washed with brine, and dried with Na2SO4. The solution was filtered and concentrated. The residue was subjected to chromatography over silica gel (Hexanes/EtOAc=8/1) to give (E)-4-fluorophenyl 3-(dimethylamino)-5-(4-(methoxymethoxy)-3,5-dimethyl-styryl)benzoate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[C:20]([C:22]1[CH:23]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:26][CH:27]=1)#[N:21]>CCCCCC.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:26]3[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=3)[C:20]#[N:21])[N:3]=2)[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cccc(C#N)c2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1cccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)c1
Yield: 57 %

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 3-cyanophenylboronic acid pinacol ester with reaction time of 15 h. Column chromatography (hexane/ethyl acetate 1:1) gave 57% of the title compound as an colorless solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C@H:8]2[CH2:12][C@@:11]([CH:16]([CH3:18])[CH3:17])([C:13]([OH:15])=O)[CH:10]=[CH:9]2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:22]=[N:23][C:24]2[CH2:25][CH2:26][NH:27][CH2:28][C:29]=2[CH:30]=1>>[CH3:7][C:4]1[N:3]([C@H:8]2[CH2:12][C@:11]([C:13]([N:27]3[CH2:26][CH2:25][C:24]4[N:23]=[CH:22][C:21]([C:20]([F:19])([F:31])[F:32])=[CH:30][C:29]=4[CH2:28]3)=[O:15])([CH:16]([CH3:18])[CH3:17])[CH:10]=[CH:9]2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: Cc1ccc(C)n1[C@@H]1C=C[C@@](C(=O)O)(C(C)C)C1
Reactant: FC(F)(F)c1cnc2c(c1)CNCC2
Product: Cc1ccc(C)n1[C@@H]1C=C[C@@](C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)(C(C)C)C1

Procedure:
reacting (1S,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropylcyclopent-2-ene-1-carboxylic acid with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine to form 6-{[(1S,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropylcyclopent-2-en-1-yl]carbonyl}-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine;
Reaction SMILES: [N+]([O-])(O)=O.CC(O)=O.[CH2:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)[CH3:10].[Br:20]Br>O.[N+]([O-])([O-])=O.[Ag+]>[Br:20][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:11]=1[CH2:9][CH3:10])[C:15]([OH:17])=[O:16]
Reactant: BrBr
Reactant: CCc1ccc(C(=O)O)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CCc1ccc(C(=O)O)cc1Br

Procedure:
To a mixture of conc. HNO3 (66 mL), glacial AcOH (300 mL) and water (50 mL), 4-ethyl-benzoic acid (15 g) was added, stirring vigorously, before treating with bromine (5.67 mL). Finally a solution of AgNO3 (16.97 g) in water (50 mL) was added dropwise and the mixture was stirred vigorously for 2 h. The precipitate was collected by filtration, washed well with water, before being extracted with hot, saturated K2CO3 solution, and then treated with charcoal. The hot solution was filtered through kieselguhr and the solution was acidified to pH1 using conc. HCl. The resulting white precipitate was collected by filtration and dried in the vacuum oven overnight at 60° C. to afford the title compound (19.46 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9](=[C:16]2SCS2)[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH:24]([CH3:28])[NH:23]1.[NH2:29][NH2:30]>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:30][N:29]=[C:16]([N:26]3[CH2:25][CH:24]([CH3:28])[NH:23][CH:22]([CH3:21])[CH2:27]3)[C:9]=2[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(C(=C1SCS1)c1ccncc1)c1ccc(Cl)cc1
Reactant: CC1CNCC(C)N1
Reactant: NN
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1CN(c2n[nH]c(-c3ccc(Cl)cc3)c2-c2ccncc2)CC(C)N1
Reaction time: 1 h

Procedure:
A mixture of 1-(4-chlorophenyl)-2-(1,3-dithietan-2-ylidene)-2-(4-pyridinyl)ethanone (3.2 g, 0.01 mol; prepared as set forth in Step 1 of Example A-341) and 2,6-dimethylpiperazine (3.43 g, 0.03 mol) in 35 mL of toluene was heated at reflux for 12 hours. Toluene and excess 2,6-dimethylpiperazine were then removed under vacuum and the crude thiamide produced was used without purification. A solution of the crude thiamide and anhydrous hydrazine (0.65 g, 0.02 mol) in 40 mL of dry tetrahydrofuran was stirred at room temperature overnight. After the removal of tetrahydrofuran, the residue was stirred with a mixture of ethyl acetate and ammonium hydroxide for one hour. The precipitate was filtered and air dried to give 1.6 g of 1-[5-(4-chlorophenyl)-4-(4pyridinyl)-1H-pyrazol-3-yl]-3,5-dimethylpiperazine as a white solid (43% overall yield), mp: 236-238° C. Anal. Calc'd. for C20H22ClN5.0.25H2O: C, 64.51; H, 6.09; N, 18.81; Cl, 9.52. Found: C, 64.28; H, 5.85; N, 18.70; Cl, 9.67.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:3]=1.ClC1C=C(O)C=CC=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[OH:40]>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[O:40][C:2]1[C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:3]=1
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: O=C(c1ccc(C(F)(F)F)nc1Cl)N1CCCc2ccccc21
Agent: Oc1cccc(Cl)c1
Product: O=C(c1ccc(C(F)(F)F)nc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21

Procedure:
The title compound was prepared in analogy to Example 25, Step 2, replacing (2-chloro-5-fluoro-pyridin-3-yl)-(3,4-dihydro-2H-quinolin-1-yl)-methanone with (2-chloro-6-trifluoromethyl-pyridin-3-yl)-(3,4-dihydro-2H-quinolin-1-yl)-methanone and 3-chloro-phenol with 2,5-dichloro-phenol ([CAS RN 583-78-8]). MS (ISP): 467.1 [M+H]+.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[CH2:25][CH:26]=[O:27])[C:5]1=[O:30])[CH:2]=[CH2:3].[CH:32]1([Mg]Br)[CH2:34][CH2:33]1>C1COCC1>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[CH2:25][CH:26]([CH:32]2[CH2:34][CH2:33]2)[OH:27])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: Br[Mg]C1CC1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC=O)C1=O
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC(O)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of (S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)pentanal (160 mg, 0.349 mmol; Example 130, Step A) in THF (3.5 mL) was added 0.5 M cyclopropylmagnesium bromide in THF (2.09 mL, 1.05 mmol) at 0° C. Then the reaction was allowed to warm to rt and stirred for 3.5 h. The reaction was quenched (sat NH4Cl solution), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a mixture of two diastereomers. The crude product was used in the next step without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C)C=O.[OH:20][C:21]1[C:22]([CH:31]=[O:32])=[CH:23][C:24]2[O:29][CH2:28][CH2:27][O:26][C:25]=2[CH:30]=1>C(OCC)(=O)C.O>[CH2:7]([O:20][C:21]1[C:22]([CH:31]=[O:32])=[CH:23][C:24]2[O:29][CH2:28][CH2:27][O:26][C:25]=2[CH:30]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1cc2c(cc1O)OCCO2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1cc2c(cc1OCc1ccccc1)OCCO2
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Potassium carbonate (0.27 g) and benzyl bromide (0.17 mL) were sequentially added to an N,N-dimethylformamide (2 mL) solution of 7-hydroxy-2,3-dihydrobenzo[1,4]dioxine-6-carbaldehyde (0.23 g), followed by stirring at 65° C. for 2 hours. Benzyl bromide (0.077 mL) was added to the reaction mixture, followed by stirring at 65° C. for 30 minutes. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 75-60% hexane/ethyl acetate] to obtain 0.32 g of 7-(benzyloxy)-2,3-dihydrobenzo[1,4]dioxine-6-carbaldehyde as a light yellow solid.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[NH:10][C:9]([S:11][CH2:12][C:13]3[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=3)=[N:8][C:5]2=[N:6][CH:7]=1.S(=O)(=O)(O)[OH:24].N([O-])=O.[Na+].[OH-].[Na+]>O>[OH:24][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([S:11][CH2:12][C:13]3[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: COc1c(C)cnc(CSc2nc3ncc(N)cc3[nH]2)c1C
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(C)cnc(CSc2nc3ncc(O)cc3[nH]2)c1C
Temperature: 0 °C

Procedure:
0.2 Gram of 6-amino-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylthio]imidazo[4,5-b]pyridine was dissolved in a mixture consisting of 3 ml of water and 0.1 ml of concentrated sulfuric acid. This mixture was stirred at 0° C., and 59 mg of sodium nitrite was added, then the mixture was further stirred at the same temperature for 1 hour. The reaction solution was neutralized by adding 4N-sodium hydroxide aqueous solution, and the crystals formed were collected by filtration. Recrystallized from ethanol to obtain 0.2 g of 6-hydroxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylthio]imidazo[4,5-b]pyridine in the form of yellow powdery crystals. Melting point: 178°-179.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)C)=[CH:5][CH:4]=1.[C:12]([O-])(=O)C.[NH4+].[C:17]([BH3-])#[N:18].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:17]([NH2:18])[CH3:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CC(=O)[O-]
Reactant: [BH3-]C#N
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CC(C)N)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 32 g (0.21 mol) of 4'-methoxyacetophenone and 165 g (2.1 mol) of ammonium acetate in 450 ml of methanol is combined with 13.5 g (0.21 mol) of sodium cyanoborohydride, which is added in batches thereto at ambient temperature, with stirring. After a further 20 hours, ice is added and the mixture is acidified with hydrochloric acid (conc. HCl H2O=1/1) until the pH is 2. The acidic solution is extracted with dichloromethane. The aqueous phase is then mixed with conc. ammonia, with cooling, until a clearly alkaline reaction occurs and then extracted exhaustively with dichloromethane. The combined dichloromethane extracts are dried over sodium sulphate and evaporated to dryness in vacuo. The crude 2-(4-methoxyphenyl)-1-methylethylamine thus obtained is purified by column chromatography over silica gel (eluant: dichloro-methane/methanol=20/1) to remove any by-products. A colorless oil is obtained which can be used for reaction without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: CCc1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: CCc1cc2c(NCc3ccc(F)cc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(4-fluorobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([NH2:16])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:4].C([N-]C(C)C)(C)C.[Li+].[CH3:25][Si:26]([CH2:29][CH2:30]OCCl)([CH3:28])[CH3:27].C1C[O:37][CH2:36]C1>>[CH3:1][O:2][C:3](=[O:4])[CH:5]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH:16][CH2:36][O:37][CH:29]([Si:26]([CH3:25])([CH3:27])[CH3:28])[CH3:30]
Reactant: COC(=O)C(N)Cc1c[nH]c2ccccc12
Reactant: C1CCOC1
Reactant: C[Si](C)(C)CCOCCl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COC(=O)C(Cc1c[nH]c2ccccc12)NCOC(C)[Si](C)(C)C
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 44 %

Procedure:
A solution of DL-tryptophan methyl esterbenzaldimine (4.0 g, 13 mmol) in 30 mL THF was added over 15 minutes to a mixture of 20.2 mL lithiumdiisopropylamide (10% suspension in hexan) and 70 mL dry THF, cooled to -10° C. under nitrogen atmosphere. The stirring was continued for an additional 45 minutes, keeping the temperature at -10° C. A solution of trimethylsilylethoxymethylchloride (2.2 g, 13.2 mmol) in 5 mL THF was added and the mixture stirred overnight at room temperature. The reaction mixture was decomposed with 100 mL distilled water, extracted with ethyl acetate (3×100 mL), and the organic solvent was removed in vacuo. The resulting oily residue was treated with 30 mL 1N hydrochloric acid for 1 hour at room temperature after which the reaction mixture was made basic with sodium bicarbonate and extracted with ethyl acetate (3×100 mL). The organic layer was dried over Na2SO4, evaporated to give the crude product which was separated by flash chromatography on silica gel using a mixture of toluene/ethanol 500:30 (v/v) as elution solvent. The fractions, containing the main product (TLC on silica gel, toluene/ethanol 10:2 (v/v), Rf 0.38) were combined and evaporated to dryness in vacuo. Trituration of the oily residue with diethyl ether gave 2.0 g (44%) of α-trimethylsilylethoxymethyl- DL-tryptophan methyl ester, mp 113°-115° C.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([Cl:9])[N:6]=[C:5](Cl)[C:4]=1[Cl:11])#[N:2].[NH:12]1[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]1>>[C:1]([C:3]1[N:8]=[C:7]([Cl:9])[N:6]=[C:5]([N:12]2[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]2)[C:4]=1[Cl:11])#[N:2]
Reactant: O=S1CCNCC1
Reactant: N#Cc1nc(Cl)nc(Cl)c1Cl
Product: N#Cc1nc(Cl)nc(N2CCS(=O)CC2)c1Cl

Procedure:
5.8 gm (0.02 mol) of 6-cyano-2,5-dichloro-4-(1-oxido-thiomorpholino)-pyrimidine (m.p. 145°-147°C), obtained from 6-cyano-2,4,5-trichloro-pyrimidine and thiomorpholine-1-oxide, were slowly added to a solution of 19.4 gm (0.1 mol) of piperazine hexahydrate in 100 ml of dioxane, whereby a mild endothermic reaction was released and a solution was rapidly formed. After standing for a short time, the reaction mixture was evaporated almost to dryness in vacuo, and the residue was taken up in about 100 ml of water. The reaction product, which separated out as pale yellow precipitate, was suction-filtered off, washed with water and dried. Yield: 6.4 gm (94% of theory); m.p. 203°-205°C.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:16].[K+].[K+]>C(#N)C.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH:1]([C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1)=[O:16]
Reactant: COC(=O)CCOc1ccc(C)cc1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)CCOc1ccc(C=O)cc1
Reaction time: 3.5 h
Yield: 92.5 %

Procedure:
A solution of methyl 3-(4-methylphenoxy)-propanoate, (15.0 g, 0.077 moles) in acetonitrile, (270 ml), was added to a solution of potassium peroxydisulphate, (41.60 g, 0.154 moles) and copper (II) sulphate (3.85 g, 0.015 moles) in water, (270 ml). The resulting mixture was stirred at 65°-70° C. for 3.5 h, then cooled and extracted with diethyl ether. The organic extract was washed with water, saturated brine and dried, (MgSO4). Evaporation of the solvent gave 14.83 g of an orange oil which was distilled at 0.1 mm/Hg to yield 7.40 g (47%) of the title compound as an oil which crystallized, mp 48°-50° C., υmax (mull) 1735, 1680, (shoulder at 1685), 1605, 1580, 1515 cm-1 δ(CDCl3) 2.81 (2H, t, J 6 Hz, CH2CO2) 3.72 (3H, S, CH3) 4.30 (2H, t, J6 Hz OCH2) 7.39 (4H, ABq, Δυ75 Hz, J9 Hz C6H4) 9.90 (1H, s, CHO).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:15]C[C:17](Cl)=[O:18].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[ClH:15].[ClH:15].[N:8]1([CH2:6][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:18])[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=C(Cl)CCl
Reactant: C1COCCN1
Product: Cl
Product: O=C(CN1CCCNCC1)N1CCOCC1

Procedure:
prepared from [1,4]diazepane-1-carboxylic acid tert-butyl ester, chloroacetylchloride and morpholine in an analogous manner as described in example 15.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:29]([NH2:34])[CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)(Cl)Cl>[CH2:29]([NH:34][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCN
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCNC(=O)c1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 55.8 %

Procedure:
A mixture containing 8.16 g (0.04 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 6.2 ml (0.44 mol) of triethylamine in 240 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 4 ml (0.042 mol) of ethyl chloroformate in 20 ml of chloroform is dropped to the above mixture at -15° C. during 20 minutes. After stirring for 5 minutes, 3.835 g (0.044 mol) of n-pentylamine dissolved in 40 ml of chloroform are dropped to the above solution at -15° C. during 20 minutes. The reaction mixture is stirred below -10° C. for 1 hour and then let to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 100 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 100 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 6.1 g (55.8%) of the named product as orange yellow crystals after recrystallization from ethanol, m.p.: 112°-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH2:30][CH2:31][OH:32])(=[NH:29])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.N1C=CC=CC=1.[C:39](Cl)(=[O:41])[CH3:40]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH2:30][CH2:31][OH:32])(=[N:29][C:39](=[O:41])[CH3:40])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: N=S(=O)(CCO)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N=S(=O)(CCO)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 27.5 °C
Reaction time: 3 h
Yield: 16.8 %

Procedure:
To a stirring solution of S-[4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-S-(2-hydroxy ethyl)-sulfoximide (0.550 g, 0.00111 mol) in DCM(10 mL) was added pyridine (0.131 g, 0.001665 mol) at 5-10° C. under nitrogen atmosphere followed acetyl chloride (0.105 g, 0.00134 mol). Reaction mixture was stirred for 3 hr at 25-30° C. Subsequent work up and column purification (55% ethyl acetate in hexane and 100-200 mesh silica gel) gave 100 mg of desired product in 17% yield.