Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2([C:31]([F:34])([F:33])[F:32])[O:19][N:18]=[C:17]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([NH:26][OH:27])=[NH:25])=[C:22]([CH3:30])[CH:21]=3)[CH2:16]2)[CH:11]=[C:12]([Cl:14])[CH:13]=1.[CH2:35](Br)[C:36]#[CH:37]>CN(C)C=O.O>[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2([C:31]([F:32])([F:34])[F:33])[O:19][N:18]=[C:17]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([NH:26][O:27][CH2:37][C:36]#[CH:35])=[NH:25])=[C:22]([CH3:30])[CH:21]=3)[CH2:16]2)[CH:11]=[C:12]([Cl:14])[CH:13]=1
Reactant: C#CCBr
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=N)NO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCONC(=N)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Caesium carbonate (0.122 g) was added to a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-hydroxy-2-methyl-benzamidine (0.1 g) (Example P1) in N,N-dimethylformamide (8 ml). Propargyl bromide (80% w/v in toluene) (0.028 ml) was added. The reaction mixture was stirred at ambient temperature for 20 hours. The reaction mixture was diluted with water and the mixture extracted twice with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate, and concentrated. The residue was purified by preparative HPLC to give Compound No. A2 of Table A (0.054 g) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([Cl:19])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:20])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:14]([Cl:19])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCc1ccc(O)c(Cl)c1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(CCC(=O)OCc2ccccc2)cc1Cl
Temperature: 60 °C

Procedure:
3-(3-Chloro-4-hydroxy-phenyl)-propionic acid benzyl ester (step 1) (5.9 g, 20.3 mmol) in DMF (60 ml) was treated with potassium carbonate (5.61 g, 40.6 mmol) followed by t-butyl bromoacetate (4.49 ml, 30.4 mmol) and the mixture was heated at 60° C. overnight. The reaction mixture was diluted with water (500 ml), and the product extracted into EtOAc (450 ml). The organic portion was washed with water (200 ml), brine (200 ml), dried over MgSO4 and the solvent removed in vacuo to yield a yellow oil. Purification by chromatography on silica eluting with 0-20% EtOAc in iso-hexane afforded the title product; 1H NMR (400 MHz, DMSO-d6) δ 7.34 (6H, m), 7.11 (1H, d), 6.89 (1H, d), 5.07 (2H, s), 4.74 (2H, s), 2.81 (2H, t), 2.68 (2H, t), 1.42 (9H,s). LC-MS Rt 1.64 mins; 427.3 [M+Na]+, Method 2minLC_v002.
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[K+].[N:10]1([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][NH:28][C:29](=[O:34])[CH2:30][CH2:31][CH2:32]Cl)[CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CO>[N:10]1([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][NH:28][C:29](=[O:34])[CH2:30][CH2:31][CH2:32][S:1][C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Sc1ncccn1
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(CCCSc1ncccn1)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 92.7 %

Procedure:
2.78 g of 2-mercaptopyrimidine were added to a solution of 1.95 g of 85% potassium hydroxide and 9.03 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) in 140 ml of methanol, and the resulting mixture was heated under reflux for 15 hours. At the end of this time, the reaction mixture was cooled, and the solvent was removed by distillation under reduced pressure. The resulting residue was mixed with water, and the aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 9:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 10.1 g (yield 92%) of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N:34]2[CH:38]=[N:37][N:36]=[N:35]2)=[C:23]([CH:33]=1)[CH2:24][NH:25][C:26](=[O:32])[C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>C(Cl)CCl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C@H:9]1[C:10]([N:28]1[CH2:29][CH2:30][CH2:31][C@H:27]1[C:26]([NH:25][CH2:24][C:23]1[CH:33]=[C:19]([Cl:18])[CH:20]=[CH:21][C:22]=1[N:34]1[CH:38]=[N:37][N:36]=[N:35]1)=[O:32])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C)C1C(=O)O
Reactant: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CCCN1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(C)(C)[C@H]1C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1

Procedure:
The title compound was prepared as a mixture of diastereomers from 1-(tert-butoxycarbonyl)-3,3-dimethyl-dl-proline (61 mg, 0.25 mmol) and N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]-L-prolinamide (Example 26, Step B, 95 mg, 0.25 mmol) essentially according to the EDC coupling procedure described in Example 39, Step D. The diastereomeric products were separated by reverse phase HPLC and were carried on directly to deprotection.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]=[C:11]=[S:12])=[O:9])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[C:29]=1[CH3:36].C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]([NH:32][C:31]2[CH:33]=[CH:34][C:28]([O:27][C:18]3[C:17]4[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=4)[N:21]=[CH:20][CH:19]=3)=[C:29]([CH3:36])[C:30]=2[CH3:35])=[S:12])=[O:9])=[CH:6][CH:7]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(N=C=S)c1ccc(Cl)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
Commercially available 4-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4quinolyl)oxy]-2,3-dimethylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (55 mg, yield 68%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:22]#[N:23])[C:15](=[O:21])C(OCC)=O)=[CH:10][CH:9]=1.C=O>O.C(Cl)Cl>[OH:21][CH2:15][CH:14]([C:11]1[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=1)[C:22]#[N:23]
Reactant: CCOC(=O)C(=O)C(C#N)c1ccc(Cl)cc1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#CC(CO)c1ccc(Cl)cc1
Reaction time: 0.03 h

Procedure:
Sodium carbonate (204 mg, 1.9 mmol) dissolved in water (1.2 mL) was added dropwise over 10,min to a vigorously stirred mixture of the above ethyl 3-(4-chlorophenyl)-3-cyano-2-oxopropanoate (400 mg 1.59 mmol), 37% HCHO (131 μL 1.75 mmol) and methylene chloride (2 mL). After an additional 2 min, the mixture was diluted with ˜one mL each of water and methylene chloride and phase separated. Acidification of the aqueous phase and filtration of the precipitated solid recovered 68 mg (17%) of the starting material. The organic phase was washed twice with water, dried and stripped to give a colorless oil. Flash chromatography on 10 g of silica gel eluting with 5→50% ethyl acetate in hexane recovered 43 mg of a higher Rf product assumed to be 4-chloroatroponitrile, and 210 mg (75%) of the desired alcohol, Rf 0.09 (silica gel, ethyl acetate:hexane=1:4).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(C(C)C)C(C)C)C>CS(C)=O>[CH:7]([C:5]1[S:6][C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)=[CH:3][CH:4]=1)=[O:8]
Reactant: O=Cc1ccc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)s2)CC1
Temperature: 130 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
A mixture of 5-bromothiophene-2-carboxaldehyde (3.82 g, 20.0 mmol), tert-butyl piperazine-1-carboxylate (4.1 g, 22.0 mmol), N-ethyl-N,N-diisopropylamine (7.0 ml, 40.0 mmol) and dimethylsulphoxide (5.0 ml) were stirred at 130° C. under an atmosphere of nitrogen for 18 h. The cooled mixture was partitioned between ethyl acetate and water. The organics were washed with water, brine, dried over magnesium sulphate and evaporated. The resultant dark red solid was purified by silica column chromatography, eluting with dichloromethane followed by ethyl acetate/dichloromethane (15%) to give tert-butyl 4-(5-formylthien-2-yl)piperazine-1-carboxylate (4.3 g, 73%).
Reaction SMILES: [CH3:1][C:2]1([CH:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[CH3:21][NH2:22]>O1CCCC1.[Cl-].[Na+].O>[CH3:21][NH:22][C:16](=[O:20])[CH:15]([CH2:19][CH2:18][OH:17])[C:2]1([CH3:1])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CC1(C2CCOC2=O)OCCc2c1[nH]c1ccccc21
Reactant: CN
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C(CCO)C1(C)OCCc2c1[nH]c1ccccc21

Procedure:
A solution of 4,5-dihydro-3-(1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indole-1-yl)-2(3H)-furanone (described in Example 1, 20 g, 0.074 mole) in tetrahydrofuran (200 ml) and 40% aqueous methylamine-(200 ml)-is refluxed for 24 hr. The reaction mixture is diluted with brine and extracted with diethyl ether. The organic extracts are washed with brine, dried over magnesium sulfate and evaporated. The residue is subjected to chromatography on silica gel using acetone-benzene (1:2). The eluates are evaporated and crystallized from diethyl ether-hexane to obtain isomer A (6.9 g) of the title compound, mp 169°-171° C. The eluant for the column is changed to acetone-benzene (1:1) and the eluates are evaporated followed by trituration of the residue to obtain isomer B (7.5 g) of the title compound, mp 194°-196° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][S:16][C:10]=2[CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8]1.CN(C)[CH:25]=[O:26]>>[CH3:6][N:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[C:15]([CH:25]=[O:26])[S:16][C:10]=2[CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8]1
Reactant: CN1CCc2ccsc2C(c2ccccc2)C1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCc2cc(C=O)sc2C(c2ccccc2)C1

Procedure:
Phosphorous oxychloride (4.6 ml) was added dropwise to a stirred solution of 6-methyl-8-phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (3.98 g) in dimethylformamide (17 ml) cooled in an ice bath. The mixture was heated to 60° for 18 hours and then evaporated. The residue was dissolved in iced water (50 ml), basified with 2M sodium hydroxide to pH~12 and extracted with dichloromethane (2×100 ml). The extracts were dried, filtered and evaporated to a brown oil. Crystallisation from hexane gave the title product as yellow crystals (m.p. 88°).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[Cl:9].[CH2:10]([N:12]([CH2:34][CH3:35])[CH:13]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[C:24]([CH3:25])=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[CH:33])[CH:27]=3)[NH:22][N:21]=2)=[O:19])[CH2:14]1)[CH3:11]>>[Cl:9][C:3]1[CH:4]=[C:5]([C:33]#[C:32][C:28]2[CH:27]=[C:26]([C:23]3[NH:22][N:21]=[C:20]([C:18]([N:15]4[CH2:16][CH2:17][CH:13]([N:12]([CH2:34][CH3:35])[CH2:10][CH3:11])[CH2:14]4)=[O:19])[C:24]=3[CH3:25])[CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: C#Cc1cccc(-c2[nH]nc(C(=O)N3CCC(N(CC)CC)C3)c2C)c1
Reactant: Clc1ccc(I)cc1Cl
Product: CCN(CC)C1CCN(C(=O)c2n[nH]c(-c3cccc(C#Cc4ccc(Cl)c(Cl)c4)c3)c2C)C1

Procedure:
In analogy to the procedure described in Example 31F], 1,2-dichloro-4-iodobenzene and (3-diethylamino-pyrrolidin-1-yl)-[5-(3-ethynyl-phenyl)-4-methyl-1H-pyrazol-3-yl]-methanone (Example 31E]) gave the title compound in 71% yield yellow foam. MS: 495.2 (MH+, 2 Cl).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[CH:7]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH2:6][CH:5]1[CH3:22])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH:29]([C:31]1[CH:32]=[C:33](B(O)O)[O:34][CH:35]=1)=[O:30].C1(C)C=CC=CC=1>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][CH:18]([O:17][C:16](=[O:21])[NH:15][C@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:33]3[O:34][CH:35]=[C:31]([CH:29]=[O:30])[CH:32]=3)[CH:9]=2)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:22])[CH2:6]1)[CH3:20]
Reactant: CC(=O)N1c2ccc(Br)cc2C(NC(=O)OC(C)C)CC1C
Reactant: O=Cc1coc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3cc(C=O)co3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C

Procedure:
1-methylethyl (1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation see Example 61) (150 mg, 0.406 mmol) was mixed with potassium carbonate (112 mg, 0.812 mmol), tetrakis(triphenylphosphine)palladium(0) (23.47 mg, 0.020 mmol) and (4-formyl-2-furanyl)boronic acid (68.2 mg, 0.487 mmol, available from Frontier scientific), dissolved in ethanol (1 mL) and toluene (1 mL) and stirred under nitrogen at 90° C. for 2.5 days. The reaction A was partitioned between distilled water (20 mL) and EtOAc (60 mL). The aqueous layer was extracted with EtOAc (2×60 mL) and the organic fractions were combined, washed (brine (50 mL)), dried (sodium sulfate) and evaporated to dryness to give a dark brown solid (184 mg) which was purified using MDAP. Product-containing fractions were evaporated to dryness to give a yellow/brown solid (32 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:20]=[C:21]2[NH:25][CH2:24][CH2:23][S:22]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:25]2[CH2:24][CH2:23][S:22][C:21]2=[N:20][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=2)(=[O:19])=[O:18])=[CH:6][N:7]=1
Reactant: Cc1ccc(S(=O)(=O)N=C2NCCS2)cc1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N=C2SCCN2Cc2ccc(Cl)nc2)cc1
Yield: 92 %

Procedure:
A mixture of 1.62 g of 6-chloro-3-chloromethyl pyridine (CCMP), 2.56 g of 2-[(4-methylphenyl) sulfonylimino]thiazolidine, 3.0 g of potassium carbonate, and 50 ml acetonitrile was heated under reflux for 3 hours. After the reaction, the product in the reaction mixture was purified by known crystallization techniques to yield pale yellowish crystals of 3.51 g 3-(2-chloro-5-pyridylmethyl)-2-[(4-methylphenyl)sulfonylimino]thiazolidine. The thus formed crystals have a melting point in a range of from 162.1 to 162.8° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[CH2:18](I)[CH3:19].[H-].[Na+].O1CCCC1>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([N:12]([CH2:18][CH3:19])[CH2:13][C:14]([F:16])([F:17])[F:15])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1cc(NCC(F)(F)F)ncn1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC#CCOc1cc(N(CC)CC(F)(F)F)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
In 2 ml of N,N-dimethylformamide were dissolved 40 mg of 4-(2-butynyloxy)-6-(2,2,2-trifluoroethylamino)pyrimidine and 31 mg of ethyl iodide, to which 8 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 1 hour. Then, 6 ml of tetrahydrofuran was added, and the mixture was further stirred at room temperature for 4.5 hours. Then, ice water was added to the reaction mixture, from which the tetrahydrofuran was distilled out under reduced pressure. The residue was extracted with tert-butyl methyl ether. The organic layer was washed twice with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel thin layer chromatography to give 37 mg of 4-(2-butynyloxy)-6-(N-ethyl-N-2,2,2-trifluoroethylamino)pyrimidine (the present compound (115)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:10]2[CH2:11][C:12]3[C:17]([CH:9]12)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([O:28][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:26][CH:27]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1C2Cc3ccccc3C21
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccc(C(C)(C)C)cc1
Yield: 16.9 %

Procedure:
A solution of (±) N-tert-butoxycarbonyl-1,2-iminoindane (5 g, 22 mmol), 4-tert-butylphenol (3.34 g, 22 mmol) and pyridinium p-toluenesulfonate (109 mg) in chloroform (150 ml) was heated at reflux for 2 h. On cooling, the solution was washed sequentially with 10% aq. NaOH, water and then brine. After drying over MgSO4, solvents were removed in vacuo and the resultant brown oil subjected to column chromatography on silica gel eluting with 20% diethyl ether in hexanes to afford the title compound (1.42 g).
Reaction SMILES: [OH-].[Na+].[CH:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=3)[C:20]=1[S:21][CH2:22][CH3:23])=[O:15])[CH2:10]2>CO>[CH:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)[C:20]=1[S:21][CH2:22][CH3:23])=[O:15])[CH2:10]2
Reactant: CCSc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCSc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 91.8 %

Procedure:
2M aqueous sodium hydroxide (2.446 mL, 4.89 mmol) was added in one portion to methyl 4-[4-(2-adamantylcarbamoyl)-5-ethylsulfanyl-pyrazol-1-yl]benzoate (Intermediate#99) (430 mg, 0.98 mmol) in methanol (20 mL). The resulting mixture was stirred at 20° C. for 18 hours. The reaction mixture was concentrated, diluted with water (50 mL) and adjusted to pH 3 with 2M HCl. The precipitate was collected by filtration, washed with water (20 mL) and dried under vacuum to afford 4-[4-(2-adamantylcarbamoyl)-5-ethylsulfanyl-pyrazol-1-yl]benzoic acid (383 mg, 92%) as a white solid.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3].[CH3:20][N:21]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[CH2:30][CH2:31][NH2:32])[CH3:22].C(OC(C)C)(C)C>>[CH3:22][N:21]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[CH2:30][CH2:31][NH:32][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3])[CH3:20]
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ccccc21
Reactant: CN(C)CC1CCCCN1CCN
Solvent: CC(C)OC(C)C
Product: CN(C)CC1CCCCN1CCNC(=O)N1c2ccccc2NC(=O)c2ccccc21
Yield: 73 %

Procedure:
Prepared analogously to Example 2 from 5-(chlorocarbonyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 2-[2-[(dimethylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 73% of theory. Colourless crystals, m.p. 152°-154° C. (diisopropylether).
Reaction SMILES: O([C:8]1[CH:9]=[C:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[CH:12][CH:13]=1)C1C=CC=CC=1.[C:20](C1C=C(CC(O)=O)C=CC=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.S(=O)(=O)(O)O>C(O)C>[C:20]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[CH:12][CH:13]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2)c1
Reactant: O=C(O)Cc1cccc(C(=O)c2ccccc2)c1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)Cc1cccc(C(=O)c2ccccc2)c1

Procedure:
The procedure is as in Example 33 for the preparation of ethyl (3-phenoxyphenyl)acetate, starting with (3-benzoylphenyl)acetic acid (16.6 g) and 36N aqueous sulphuric acid solution (2 cc) in ethanol (200 cc). Ethyl (3-benzoylphenyl)acetate (16.8 g) is obtained in the form of a brown oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: Cl[C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:4][C:5]2[CH:6]=[C:7]3[CH2:14][CH2:13][CH2:12][C:8]3=[CH:9][C:10]=2[N:11]=1.[CH3:21][N:22]([CH3:30])[CH:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[CH3:21][N:22]([CH3:30])[CH:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:2]2[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:4][C:5]3[CH:6]=[C:7]4[CH2:14][CH2:13][CH2:12][C:8]4=[CH:9][C:10]=3[N:11]=2)[CH2:25][CH2:24]1
Reactant: CN(C)C1CCC(N)CC1
Reactant: Clc1nc2cc3c(cc2nc1-c1ccccn1)CCC3
Solvent: Cc1ccccc1
Product: CN(C)C1CCC(Nc2nc3cc4c(cc3nc2-c2ccccn2)CCC4)CC1
Yield: 43.6 %

Procedure:
A solution of 2-chloro-3-pyridin-2-yl-7,8-dihydro-6H-cyclopenta[g]quinoxaline (0.5 g) and N,N-dimethyl-cyclohexane-1,4-diamine (0.51 g) in toluene (30 mL) was refluxed under nitrogen atmosphere for 16 hours. The reaction was cooled, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 1:19 methanol/dichloromethane) to give a yellow solid. Recrystallization from methanol and water gave the product as yellow crystals ( 0.3 g); mp 158-161° C.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.CN1CCOCC1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([Cl:36])[CH:27]=1>ClCCl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:33])=[O:34])=[C:28]([Cl:36])[CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Cl
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (1.20 g, 5.09 mmol) in dichloromethane (35 ml) was treated with morpholinomethyl-polystyrene HL resin (2.43 g, 4.2 mmol/g loading, 10.21 mmol) and then the 4-bromo-2-chlorobenzenesulfonyl chloride (2.96 g, 10.21 mmol). The resulting solution was stirred at room temperature overnight. The resin and was filtered, washed with methanol, and the solvent evaporated in vacuo. The residue was then passed through an SCX column eluting first with methanol followed by 2M ammonia in methanol. The basic fractions were collectedand solvent evaporated in vacuo to afford a crude product which was purified further by chromatography using a Flashmaster using an elution gradient of 0 to 5% methanol in dichloromethane. The relevant fractions were collected, combined and the solvent evaporated in vacuo to afford the title compound (E104). MS (ES+) m/e 488/490/492 [M+H]+.