Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]1[NH2:12].[N:13]1[C:20]([Cl:21])=[N:19][C:17](Cl)=[N:16][C:14]=1[Cl:15].CCN(C(C)C)C(C)C.O>C1COCC1>[Cl:15][C:14]1[N:13]=[C:20]([Cl:21])[N:19]=[C:17]([NH:12][C@@H:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:11][C@@H:3]2[O:2][CH3:1])[N:16]=1
Reactant: CO[C@H]1Cc2ccccc2[C@H]1N
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 49.5 %

Procedure:
To a solution of (1R,2S)-2-methoxyindan-1-amine (242.8 mg, 0.001488 mol) in THF (1 mL) was added cyanuric chloride (313 mg, 0.00170 mol) at 0° C., followed by DIPEA (300 μL, 0.002 mol) and the reaction was stirred at 0° C. for 1.5 hours. The reaction was poured into water and extracted with CH2Cl2. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 15% EtOAc/hexanes) to obtain 229.1 mg (49%) of the title compound. LC/MS: Rt=2.03 min, ES+ 311 (FA standard).
Reaction SMILES: [CH:1]1([C:7]([N:9]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:34]([F:37])([F:36])[F:35])[CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[O:25][CH3:26])[CH2:14][CH2:13]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NC1C=CC=CC=1N(C(C1CCCCC1)=O)CCN1CCN([C:54]2C=CC=C[C:55]=2[O:60]C)CC1>>[CH:1]1([C:7]([N:9]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:34]([F:36])([F:37])[F:35])[CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:55](=[O:60])[CH3:54])=[CH:20][C:19]=3[O:25][CH3:26])[CH2:16][CH2:17]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2N)CC1
Reactant: COc1cc(N)ccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2OC(F)(F)F)CC1
Product: COc1cc(NC(C)=O)ccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2OC(F)(F)F)CC1
Reaction time: 20 h

Procedure:
The title compound was synthesized according to the procedure reported in example 28 but substituting the compound of example 56 for the compound of example 27 and stirring for 20 h. The residue was purified by flash chromatography (CHCl3-2 N methanolic NH3 100:3) affording the title compound as a vitreous pink solid. Yield: 77%.
Reaction SMILES: I[C:2]1[C:3]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:4][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:6]=1[CH3:7].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>C1COCC1>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]([OH:28])[C:2]2[C:3]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:4][N:5]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[C:6]=2[CH3:7])=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1nn(Cc2ccc(OC)cc2)c(C)c1I
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(Cc2ccc(OC)cc2)c(C)c1C(O)c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
To a stirred solution of ethyl 4-iodo-1-(4-methoxybenzyl)-5-methyl-1H-pyrazole-3-carboxylate (Step 1.2) (6.23 g, 15.57 mmol) in THF (100 mL) under Ar was added TurboGrignard (15.57 mL, 20.24 mmol) at −10° C. After 15 min, 4-chlorobenzaldehyde (2.188 g, 15.57 mmol) was added. The reaction mixture was stirred for 30 min at this temperature, quenched with a saturated aqueous solution of NH4Cl (50 mL), extracted with EtOAc (2×50 mL). The combined organic layers were washed with a saturated aqueous solution of NH4Cl (75 mL), dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (hexane/EtOAc 20-50%) to afford the title product (4.50 g, 10.85 mmol, 70% yield) as a colorless oil. tR: 5.34 min (HPLC 1); tR: 1.15 min (LC-MS 2); ESI-MS: 415 [M+H]+ (LC-MS 2); Rf=0.40 (hexane/EtOAc 1:1).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3](=[O:13])[C:4]([S:11][CH3:12])=[N:5][O:6][C:7]([NH:9][CH3:10])=[O:8].[S:15](Cl)(Cl)=[O:16].[CH:19]([NH:22][P:23](=[S:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])([CH3:21])[CH3:20]>N1C=CC=CC=1>[CH3:14][N:2]([CH3:1])[C:3](=[O:13])[C:4]([S:11][CH3:12])=[N:5][O:6][C:7]([NH:9][CH2:10][S:15]([N:22]([P:23]([O:24][CH2:25][CH3:26])([O:27][CH2:28][CH3:29])=[S:30])[CH:19]([CH3:21])[CH3:20])=[O:16])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CCOP(=S)(NC(C)C)OCC
Reactant: CNC(=O)ON=C(SC)C(=O)N(C)C
Solvent: c1ccncc1
Product: CCOP(=S)(OCC)N(C(C)C)S(=O)CNC(=O)ON=C(SC)C(=O)N(C)C

Procedure:
Methyl 2-(dimethylamino)-N-[[[[[(diethoxyphosphinothioyl)isopropylamino]sulfinyl]methylamino]carbonyl]oxy]-2-oxoethanimidothioate was prepared by the procedure employed in Example 21, by reacting methyl 2-(dimethylamino)-N-[[(methylamino)carbonyl]oxy]-2-oxoethanimidothioate (3.29 g, 0.015 mole), thionyl chloride (1.79 g, 0.015 mole), and O,O-diethyl isopropylphosphoramidothioate (3.17 g, 0.015 mole) in pyridine (10 ml). Column chromatography afforded 2.6 g of an oil of the formula below, nD24 1.5211 ##STR42##
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][C@@H:11]2[CH2:16][CH2:15][C@H:14]([C:17](OCC)=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:5]=[N:6][C:7]=1[CH2:8][CH3:9].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][C@@H:14]([CH2:17][OH:18])[CH2:13][CH2:12]2)=[N:4][CH:5]=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCOC(=O)[C@H]1CC[C@@H](Nc2ncnc(CC)c2Cl)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ncnc(N[C@H]2CC[C@@H](CO)CC2)c1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of 12.47 g (0.040 mol) of ethyl cis-4-(5-chloro-6-ethylpyrimidin-4-ylamino)-cyclohexanecarboxylate (preparation: DE-A-44 17 163) in 25 ml of dry tetrahydrofuran was added dropwise at from 20° to 30° C. to a suspension of 1.52 g (0.04 mol) of lithium aluminum hydride in 150 ml of dry tetrahydrofuran. The mixture was subsequently stirred at 50° C. for 1 hour and cooled to room temperature, and 10 ml of water were carefully added dropwise. After removal of inorganic material by filtration with suction, the organic phase was dried and concentrated. For purification, the crude product was chromatographed on silica gel (using ethyl acetate as eluent). 5.2 g (48.2% of theory) were obtained of a yellow oil which solidified on standing. m.p.: 71° to 72° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([OH:12])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C.Cl>CN(C)C=O>[CH3:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([NH:33][C:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[O:12])[CH2:29][CH2:28]1
Reactant: C[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)c1nc2ccccc2s1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CC[C@H](NC(=O)c2nc3ccccc3s2)CC1
Temperature: 50 °C

Procedure:
A solution of benzothiazole-2-carboxylic acid (359 mg, 2 mmol), and 1,1′-carbonyldiimidazole (325 mg, 2 mmol) in dimethylformamide (4 mL) was heated at 50° C. for 1 hour. After this time, trans-4-methylcyclohexylamine hydrochloride (300 mg, 2 mmol), and N,N-diisopropylethylamine (0.525 mL, 3 mmol) were added and the mixture heated at 50° C. for 3 hours. The reaction mixture was cooled, and treated with 10% HCl (15 mL). The solution was extracted with ethyl acetate (15 mL). The ethyl acetate extract was then washed with 10% HCl (15 mL), water (15 mL), and brine (15 mL). Dilution of the remaining solution with ethyl acetate (50 mL) and cooling to −20° C. afforded 25 mg (5%) 412:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C:12]([C:17]1[CH:27]=[CH:26][CH:25]=[C:19]2C(N[C:23](=[O:24])[C:18]=12)=O)(OCC)=[O:13].C(N(CC)CC)C>O1CCCC1>[C:23]1(=[O:24])[N:1]([CH2:2][C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[C:12](=[O:13])[C:17]2=[CH:27][CH:26]=[CH:25][CH:19]=[C:18]12
Reactant: CCOC(=O)c1cccc2c1C(=O)NC2=O
Reactant: NCc1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Yield: 77.9 %

Procedure:
A mixture of 10 g of 4-aminomethylbenzoic acid, 14.5 g of carbethoxyphthalimide, 9.2 ml of triethylamine and 140 ml of tetrahydrofuran is maintained for 72 hours at reflux temperature. The precipitate formed is isolated at room temperature; after washing with an aqueous acidic solution and drying, 14.5 g of product are obtained. M.p.=264° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:8]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29]O)=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:57]>CN(C=O)C.O>[Br:57][CH2:29][C:19]1[CH:20]=[C:21]([C:24]2[O:25][CH:26]=[CH:27][N:28]=2)[CH:22]=[CH:23][C:18]=1[C:13]1[C:12]([S:9]([N:8]([C:3]2[C:2]([CH3:1])=[C:6]([CH3:7])[O:5][N:4]=2)[CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])(=[O:11])=[O:10])=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrC(Br)(Br)Br
Reactant: COCCOCN(c1noc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCN(c1noc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CBr
Reaction time: 5 h
Yield: 68.6 %

Procedure:
To a solution of the title compound of step E (0.37 g, 072 mmol) in 5 mL of DMF at 5° C., triphenylphosphine (0.283 g, 1.08 mmol) and carbon tetrabromide (0.358 g, 1.08 mmol) were added and the mixture stirred for 5 hours. The solution was then diluted with 100 mL of water and the aqueous solution was extracted with 3×100 mL of EtOAc. The combined organic extracts were then washed once with water and dried and evaporated. The residue thus obtained was chromatographed on 20 g of silica gel using 2:1 hexane:EtOAc to afford 0.285 g (69%) of the title compound of this step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(O)(=O)CCCCC(O)=O.[NH:27]1[C:35]2[C:30](=[CH:31][C:32]([CH:36]([NH2:38])[CH3:37])=[CH:33][CH:34]=2)[CH:29]=[CH:28]1.CCN(C(C)C)C(C)C.CCCCO>CCOC(C)=O>[NH:27]1[C:35]2[C:30](=[CH:31][C:32]([CH:36]([NH:38][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:10]=[C:11]([CH:14]5[CH2:16][CH2:15]5)[NH:12][N:13]=4)[CH:5]=[CH:4][N:3]=3)[CH3:37])=[CH:33][CH:34]=2)[CH:29]=[CH:28]1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: CC(N)c1ccc2[nH]ccc2c1
Agent: O=C(O)CCCCC(=O)O
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1nccc(Nc2cc(C3CC3)[nH]n2)n1)c1ccc2[nH]ccc2c1
Temperature: 120 °C
Yield: 24.7 %

Procedure:
A vessel was charged with 53 (665 mg, 2.82 mmol), 1-(1H-indol-5-yl)ethanamine adipic acid salt (1.45 g mg, 6.20 mmol, CASRN 1282097-87-3), DIPEA (7.4 mL) and n-BuOH (57 mL), sealed and heated at 120° C. for 12 d. The reaction mixture was cooled and diluted with EtOAc. The organic layer was washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified by reverse-phase HPLC purification to afford 250.0 mg (24.7%) of racemic N2-(1-(1H-indol-5-yl)ethyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (180) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[C:3]=1[C:15]#[N:16].C(N(CC)CC)C.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:15]([C:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6][C:5]=2[CH:13]=[CH:14][C:2]=1[NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])#[N:16]
Reactant: CC(C)(C)C(=O)Cl
Reactant: N#Cc1c(N)ccc2sc3ccccc3c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc2sc3ccccc3c2c1C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-amino-1-cyanodibenzothiophene (J. Heterocyclyl. Chem., 1977, 14(7), 1209-1214; 0.043 g, 0.19 mmol), triethylamine (0.04 g, 0.4 mmol) and pivaloyl chloride (0.05 g, 0.4 mmol) in DCM (2 ml) was stirred at ambient temperature for 24 hours. The resultant mixture was extracted with water and the organic phase reduced to a residue which was triturated with ether/iso-hexane to give the title compound. NMR: 9.78 (s, 1H), 8.81 (m, 1H), 8.38 (d, 1H), 8.16 (m, 1H), 7.58 (m, 2H), 7.48 (d, 1H), 1.18 (s, 9H); m/z 307 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:19](Cl)(Cl)=[S:20]>O1CCCC1>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:9]=2)=[CH:4][CH:3]=1)=[C:19]=[S:20]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(-c2nc(-c3cccnc3)no2)cc1
Solvent: C1CCOC1
Product: S=C=Nc1ccc(-c2nc(-c3cccnc3)no2)cc1
Yield: 30 %

Procedure:
A solution of 5-(4-aminophenyl)-3 -(3-pyridyl)-1,2,4-oxadiazole in tetrahydrofuran is reacted with thiophosgene according to Example 14 to give the title compound in 30% yield, m.p. 121°-123° .
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH2:35]Cl.[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(N(CC)CC)C>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][CH2:35][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: C1CCNCC1
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCN3CCCCC3)c2n1
Temperature: 60 °C
Reaction time: 18 h
Yield: 51.6 %

Procedure:
N2-Butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate (192 mg, 0.547 mmol) and potassium carbonate (189 mg, 1.368 mmol) were suspended in DMF (3 ml) and heated to 60° C. for 1 hour. The reaction mixture was cooled to room temperature, 1-bromo-4-chlorobutane (0.063 ml, 0.547 mmol) added and the reaction stirred for a further 18 hours. Piperidine (0.054 ml, 0.547 mmol) and triethylamine (0.076 ml, 0.547 mmol) were added and the reaction mixture heated to 60° C. for 72 hours. The solvent was removed in vacuo and the residue partitioned between DCM (2 ml) and water (2 ml). The aqueous phase was re-extracted with DCM (2 ml) and the combined organic extracts were concentrated. The residue (ca. 200 mg) was dissolved in 1:1 MeOH:DMSO (1 ml) and purified by MDAP (Method A). The product containing fractions were evaporated in vacuo to give the impure title compound as a yellow gum (106 mg) which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C@@H:7]([NH:10][S@](C(C)(C)C)=O)[CH2:8][CH3:9].[ClH:17].O>CO.O1CCOCC1>[ClH:17].[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C@@H:7]([NH2:10])[CH2:8][CH3:9]
Reactant: CC[C@H](N[S@@](=O)C(C)(C)C)c1ncccn1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CC[C@H](N)c1ncccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of (S)-2-methyl-propane-2-sulfinic acid ((S)-1-pyrimidin-2-yl-propyl)-amide (Comp. No. 14a) (1.4 g, 5.8 mmol) in methanol was added 4 M hydrogen chloride in dioxane (4.35 ml) and the mixture was stirred for 1 h at 25° C. Water (100 ml) was added and the aqueous phase was washed with methyl tert-butyl ether. The aqueous layer was freeze-dried to give 0.919 g (75%) of (S)-1-pyrimidin-2-yl-propylamine hydrochloride. LC/MS (method 5): Rt=0.69 min; m/z=138.15 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][CH2:30]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:37]1([C:43]2([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][CH2:30][N:46]3[CH2:45][CH2:44][C:43]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare according to the method of example 3.3 using 3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-propyl-methanesulfonate (5 mmol) and 4phenyl-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[O:25][C:26]([NH:29][C:30]4[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=4[F:38])=[N:27][N:28]=3)=[O:23])=[C:17]([F:39])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])C.C1COCC1.CO>O>[F:39][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[NH:21][C:22]([C:24]1[O:25][C:26]([NH:29][C:30]2[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=2[F:38])=[N:27][N:28]=1)=[O:23])[O:14][C@@H:11]1[CH2:10][CH2:9][C@H:8]([C:6]([OH:7])=[O:5])[CH2:13][CH2:12]1
Reactant: CCOC(=O)C1CCC(Oc2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)c(F)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(O[C@H]2CC[C@@H](C(=O)O)CC2)cc1F)c1nnc(Nc2cc(F)c(F)cc2F)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.6 %

Procedure:
A solution of lithium hydroxide (965 mg, 23.0 mmol) in water (5 mL) was added in one portion to a solution of 4-(3-fluoro-4-{[5-(2,4,5-trifluoro-phenylamino)-[1,3,4]oxadiazole-2-carbonyl]-amino}-phenoxy)-cyclohexanecarboxylic acid ethyl ester (Intermediate 1, 1.2 g, 2.3 mmol) in a 1:1 mixture of THF and methanol (50 mL) and the mixture was stirred at ambient temperature for 4 h. The mixture was concentrated in vacuo, acidified with a 1M aqueous solution of citric acid and then filtered to leave a solid. The solid was washed with water, dried and recrystallised from ethanol (30 mL) to give the title compound as a white solid (700 mg, 64%).
Reaction SMILES: [CH2:1]([Br:10])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[S:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.O.C(OCC)C>[N+](C)([O-])=O>[Br-:10].[CH2:1]([S+:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: C1CCSC1
Reactant: O=C(CBr)c1ccccc1
Solvent: C[N+](=O)[O-]
Solvent: CCOCC
Solvent: O
Product: O=C(C[S+]1CCCC1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
88.2 g (0.44 mole) of phenacyl bromide and 39.1 g (0.44 mole) of tetrahydrothiophene were dissolved in 220 g of nitromethane, which was stirred for 4 hours at room temperature. 800 g of water and 400 g of diethyl ether were added to the reaction solution whereupon the mixture separated into two layers. The aqueous layer was taken out, which was an aqueous solution of the target compound, phenacyltetrahydrothiophenium bromide.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH:25]([CH3:27])[CH3:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:25]([O:24][C:18]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
The mixture of 2-(2-isopropoxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (6) (265 mg, 0.69 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (6 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and the solution acidified with conc. HCl until no more white precipitate came out of the water. The precipitate is filtered to give a pure product (7) as white solid (244 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]=[CH:9][NH:8][C:7](=[O:12])[C:6]=2[CH:13]=1.[H-].[Na+].Br[CH2:17][CH2:18][Cl:19].C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]=[CH:9][N:8]([CH2:17][CH2:18][Cl:19])[C:7](=[O:12])[C:6]=2[CH:13]=1
Reactant: O=C1NC=COc2ccc(Cl)cc21
Reactant: ClCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2cc(Cl)ccc2OC=CN1CCCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
50 mg of 7-chloro-4,5-dihydro-1,4-benzoxazepin-5-one was dissolved in dimethylformamide (1 ml), then 12 mg (1.2 equivalents) of 60% sodium hydride was added under ice cooling. This was agitated for 30 minutes, then 54 mg (1.5 equivalents) of 1-bromo-2-chloroethane was added and the result was agitated at room temperature for 10 hours. Ice water was added to the reaction solution, and extraction was performed by ethyl acetate. This ethyl acetate extract was washed by saline and was dried with anhydrous magnesium sulfate. The solvent was distilled off and the resultant crude product was refined with silica gel column chromatography (hexane: ethyl acetate=4:1) to obtain the above-referenced compound in an amount of 28 mg (yield of 42%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([SH:22])[N:3]=1.[C:23](=O)(O)[O-].[Na+].Cl.[CH3:29][C:30]1[N:31]=[C:32](Cl)[S:33][CH:34]=1>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:29][C:30]2[N:31]=[C:32]([CH3:23])[S:33][CH:34]=2)[N:3]=1
Reactant: O=C([O-])O
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: Cc1csc(Cl)n1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(CSc2nc(N)c(C#N)c(-c3ccc(OCCO)cc3)c2C#N)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
31.2 mg (0.1 mmol) of 2-amino-4-[4-(2-hydroxyethoxy)phenyl]-6-sulphanyl-pyridine-3,5-dicarbonitrile are dissolved in 0.3 ml of DMF. 33.6 mg (0.4 mmol) of sodium bicarbonate and 26.7 mg (0.15 mmol) of 4-methyl-2-chloro-1,3-thiazole hydrochloride are then added. The suspension is shaken at RT overnight, filtered, and purified by preparative HPLC [column: Macherey-Nagel VP 50/21 Nucleosil 100-5 C18 Nautilus, 20×50 mm; flow rate: 25 ml/min; gradient (A=acetonitrile, B=water+0.3% trifluoroacetic acid): 0 min 10% A; 2.0 min 10% A; 6.0 min 90% A; 7.0 min 90% A; 7.1 min 10% A; 8.0 min 10% A; detection: 220 nm]. Concentration of the appropriate fraction gives 20.2 mg (47.7% of theory) of product.