Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26]>>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)=[CH:20][C:19]=1[C:25]([F:26])([F:27])[F:28]
Reactant: Cc1ccc(N)cc1C(F)(F)F
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: Cc1ccc(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1C(F)(F)F
Yield: 17.2 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (50 mg, 0.22 mmol) and 4-methyl-3-trifluoromethyl-phenylamine (0.03 mL, 0.33 mmol) to provide 236 (14 mg, 17% yield) as a brown solid. LC-MS (M+H=370, obsd.=370). 1H NMR (400 MHz, d6-DMSO): δ 11.73 (s, 1H), 9.11 (s, 1H), 8.52 (dd, 1H), 8.47 (dd, 1H), 8.18 (d, 1H), 7.90 (d, 1H), 7.54 (dd, 1H), 7.43 (m, 2H), 7.28 (m, 2H), 2.41 (s, 3).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:19][C:20]1([CH3:28])[CH2:25][C:24](=[O:26])[CH2:23][C:22](=O)[CH2:21]1>C1C=CC=CC=1>[CH3:19][C:20]1([CH3:28])[CH2:25][C:24](=[O:26])[CH:23]=[C:22]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:21]1
Reactant: C1CCNCC1
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)CC(=O)C=C(N2CCCCC2)C1
Temperature: 25 °C

Procedure:
Piperdine (7.0 mL; 0.0713 mol) and a catalytic quantity of p-toluenesulfonic acid monohydrate was added to a solution of 5,5-dimethylcyclohexane-1,3-dione (10.0 g; 0.0713 mol) in benzene (100 mL) and the resultant solution was heated at reflux. After 3 hours further piperidine (0.71 mL; 7.13 mmol) was added and the solution was allowed to reflux for a further 16 hours. The reaction mixture was cooled to room temperature and washed with 10% NaCHO3 solution (20 mL), dried over anhydrous sodium sulfate and the solvent evaporated (in vacuo) to leave an orange crystalline solid. (14.23 g, 96%). 1H-nmr (CDCl3) d: 5.3, (s 1H, H-2), 3.4-3.2 (m, 4H, H-2′, H-6′), 2.2 (s, 2H, H-6), 2.1 (s, 2H, H-4), 1.75-1.4 (m, 6H, H-3′, H-4′, H-5′), 1.00 (s, 6H, 2×CH3).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH:11]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=3)[OH:12])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH:37]=[N:38][NH:39]3)O1>>[NH:39]1[C:40]2[C:36](=[C:35]([C:2]3[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]4[S:10][C:9]([CH:11]([C:13]5[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=5)[OH:12])=[CH:8][C:6]=4[N:7]=3)[CH:43]=[CH:42][CH:41]=2)[CH:37]=[N:38]1
Reactant: CSc1ccc(C(O)c2cc3nc(Cl)nc(N4CCOCC4)c3s2)cc1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CSc1ccc(C(O)c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)cc1

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-(4-methylsulfanyl-phenyl)-methanol was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in general procedure A. Purification by column chromatography yielded 404. (400 MHz, CDCl3): 2.52 (3H, s, CH3), 2.60 (1H, m, CH), 3.91-3.93 (4H, m, CH2), 4.09-4.11 (4H, m, CH2), 6.15 (1H, b, OH), 7.30 (1H, m, ar), 7.33 (1H, m, ar), 7.35 (1H, m, ar), 7.43 (1H, m, ar), 7.46 (1H, m, ar), 7.51 (1H, m, ar), 7.59 (1H, m, ar), 8.38 (1H, d, ar), 9.02 (1H, s, ar), 10.10 (1H, b, NH). (M+H)+ 490.27
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][C:5]([O:7]CC)=[O:6].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26](Cl)(=[O:28])=[O:27].CCN(CC)CC>C(Cl)Cl>[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26]([NH:2][C@@H:3]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:4][C:5]([OH:7])=[O:6])(=[O:27])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)C[C@@H](N)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C[C@@H](NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
To a solution of (R)-ethyl 3-amino-3-phenylpropanoate hydrochloride (5.04 g, 21.9 mmol) and naphthalene-2-sulfonyl chloride (4.97 g, 21.9 mmol) in CH2Cl2 (60 mL) was added a solution of Et3N (7.65 mL, 54.9 mmol) in CH2Cl2 (60 mL) at 0° C. over a period of 45 min. The reaction mixture was stirred at room temperature for 42 h and then washed with aqueous 1 M HCl (300 mL). The organic layer was dried (Na2SO4) and evaporated to dryness, which gave 8.05 g (96%) of S9-1 as a light pink solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[C:11]([CH3:13])[N:12]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(O)(=O)C>[C:20]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[C:11]([CH3:13])[N:12]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(-c2ccccc2N)[nH]c1-c1cccnc1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccccc1-c1nc(C)c(-c2cccnc2)[nH]1

Procedure:
A solution of 2-(2-aminophenyl)-4-methyl-5-(3-pyridyl)imidazole (0.5 g) and acetic anhydride (0.38 ml) in acetic acid (5 ml) was stirred at ambient temperature for 1.5 hours. The resulting precipitate was collected by filtration, and recrystallized from ethanol to give 2-(2-acetamidophenyl)-4-methyl-5-(3-pyridyl)imidazole (0.55 g).
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C(O[CH:9]1[NH:12][C:11](=[O:13])[CH:10]1[CH3:14])(=O)C>[OH-].[Na+].O.CC(C)=O>[C:1]([S:3][CH:9]1[NH:12][C:11](=[O:13])[CH:10]1[CH3:14])(=[O:4])[CH3:2]
Reactant: CC(=O)OC1NC(=O)C1C
Reactant: CC(O)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)SC1NC(=O)C1C

Procedure:
A solution of 1.5 ml of thioacetic acid in 20.5 ml of 1N sodium hydroxide solution is added dropwise at room temperature, under nitrogen, to a solution of 2 g of 4-acetoxy-3-methyl-azetidin-2-one (produced according to K. Clauss et. al., Lieb. Ann. Chem., 1974, 539; racemic mixture of cis- and trans-isomer in a ratio of 3:1, Mp. 53°-65°) in 5.16 ml of water and 1.25 ml of acetone, and the mixture is stirred at the same temperature for 3 hours. The reaction mixture is exhaustively extracted with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed over 150 g of silica gel with toluene/ethyl acetate (9:1) and yields the almost pure trans-isomer of the title compound with the following physico-chemical properties:
Reaction SMILES: [CH2:1]([C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].S(Cl)([Cl:29])=O>>[CH2:1]([C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([Cl:29])=[O:23])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(C(=O)O)cc2)nc1
Product: CCCCCCCCCCCc1cnc(-c2ccc(C(=O)Cl)cc2)nc1

Procedure:
4-(5-n-Undecylpyrimidine-2-yl)benzoic acid (1.70 g) was heated together with excess thionyl chloride for 8 hours under reflux and thereafter, unaltered thionyl chloride was distilled off to obtain 4-(5-n-undecylpyrimidine-2-yl)benzoic acid chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[C:29]([C:30](Cl)=[O:31])=[C:28]([CH3:33])[O:27][N:26]=1>>[CH3:16][N:15]([CH3:17])[C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:13][CH2:12][CH:11]([NH:14][C:30]([C:29]2[C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[Cl:18])=[N:26][O:27][C:28]=2[CH3:33])=[O:31])[CH2:10][CH2:9]1
Reactant: CN(C)C1(c2cccc(F)c2)CCC(N)CC1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)Cl
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)NC1CCC(c2cccc(F)c2)(N(C)C)CC1

Procedure:
As described for Example 118, the polar diastereoisomer of 1-(3-fluorophenyl)-N,N-dimethylcyclohexane-1,4-diamine (350 mg) was reacted with 400 mg 3-(2-chlorophenyl)-5-methylisoxazole-4-carbonylchloride and worked up in a similar manner. The resultant crude product (590 mg) was chromatographed on silica gel (4.0×15 cm) with ethyl acetate/n-hexane/methanol (V:V=1:1:1). 440 mg of the polar diastereoisomer of 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxylic acid [4-dimethylamino-4-(3-fluorophenyl)cyclohexyl]amide were obtained which, dissolved in 90 ml 2-butanone, were converted overnight into the corresponding hydrochloride by adding 17 μl water and 120 μl chlorotrimethylsilane (460 mg of white solid, Mp. 209-211° C.).
Reaction SMILES: [C:1]1([C@H:11]([NH:13][CH2:14][C@@H:15]2[C@@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][N:17]([C:26]([C:28]3[CH:40]=[CH:39][C:31]([O:32][CH2:33][C:34]([O:36]CC)=[O:35])=[CH:30][CH:29]=3)=[O:27])[CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].[ClH:43]>C1COCC1.O>[ClH:43].[C:1]1([C@H:11]([NH:13][CH2:14][C@@H:15]2[C@@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][N:17]([C:26]([C:28]3[CH:29]=[CH:30][C:31]([O:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:39][CH:40]=3)=[O:27])[CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)COc1ccc(C(=O)N2C[C@H](CN[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](NC[C@H]1CN(C(=O)c2ccc(OCC(=O)O)cc2)C[C@@H]1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 174 mg of ethyl (4-{[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}phenoxy)acetate and 3.0 ml of a THF-water (2:1) mixed solvent was mixed with 22 mg of lithium hydroxide and stirred at room temperature. After completion of the reaction, this was neutralized by adding 1 M hydrochloric acid. This was extracted with chloroform, dried with anhydrous sodium sulfate and then concentrated under a reduced pressure. The thus obtained residue was purified by a fractional high performance liquid chromatography (acetonitrile-water) and then treated with hydrochloric acid to obtain 31 mg of (4-{[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}phenoxy)acetic acid hydrochloride as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[S:19][C:20]([CH2:28][CH2:29][CH2:30]Cl)=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:22]=3)[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na+].[I-:33]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[S:19][C:20]([CH2:28][CH2:29][CH2:30][I:33])=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:22]=3)[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCC3)sc1CCCCl
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCC3)sc1CCCI
Temperature: 80 °C
Reaction time: 48 h
Yield: 32.9 %

Procedure:
Ethyl 2-(1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-5-(3-chloropropyl)thiazole-4-carboxylate (23F) (0.943 g, 2.02 mmol) was dissolved in Acetonitrile (10 mL). To this reaction mixture was added NaI (0.309 g, 2.06 mmol) and heated to 80° C. The reaction was stirred for 48 hours. The reaction was filtered and concentrated under reduced pressure. The crude material was dissolved in EtOAc, washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure to provide 0.370 g (97%) of the desired product ethyl 2-(1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-5-(3-iodopropyl)thiazole-4-carboxylate (23G): LC/MS (APCI): m/z 557.2 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:7][C:8]([C:10]3[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=3)[CH:13]=[O:14])=[CH:9][C:2]=12.[BH4-].[Na+].O>C(O)C>[N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:7][C:8]([C:10]3[CH:11]=[C:12]([CH2:13][OH:14])[CH:15]=[CH:16][CH:17]=3)=[CH:9][C:2]=12
Reactant: O=Cc1cccc(-c2cc3nccnc3[nH]2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1cccc(-c2cc3nccnc3[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
A suspension of 3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-benzaldehyde [0.4 g, Example 9(a)] in ethanol (50 mL) was treated with sodium borohydride (200 mg). The mixture was allowed to stir at ambient temperature for 1 hour then treated with water (10 mL) and then evaporated. The residual solid was triturated with water (50 mL) to give a pale yellow solid which was washed with water and then recrystallised from methanol to yield the title compound (0.35 g) as a yellow crystalline solid, m.p. 225-226° C. [Elemental analysis: C, 68.72; H, 4.73; N,18.44%. Calculated for C13H11N3O: C, 69.32; H, 4.92; N, 18.65%].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=O)=[CH:3][CH:2]=1.[Li+].CC([N-]C(C)C)C.[N:24]1[S:25][N:26]=[C:27]2[CH:32]=[C:31]([NH:33][C:34]3[N:41]=[CH:40][CH:39]=[CH:38][C:35]=3[CH:36]=O)[CH:30]=[CH:29][C:28]=12.O>C1COCC1>[N:24]1[S:25][N:26]=[C:27]2[CH:32]=[C:31]([N:33]3[C:34]4[C:35](=[CH:38][CH:39]=[CH:40][N:41]=4)[CH:36]=[C:10]([CH2:9][CH2:8][CH2:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[C:11]3=[O:13])[CH:30]=[CH:29][C:28]=12
Reactant: O=Cc1cccnc1Nc1ccc2nsnc2c1
Reactant: CCOC(=O)CCCCc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(CCCc2ccncc2)cc2cccnc2n1-c1ccc2nsnc2c1
Yield: 43 %

Procedure:
Ethyl 5-(pyridin-4-yl)pentanoate (1.5 eq., prepared in Synthetic Example 2) was dissolved in dry THF. To the solution was added LDA (2M solution, 1.5 eq.) at −78° C. or below in a dry ice-methanol bath under nitrogen atmosphere while stirring and the mixture was stirred for 1 hour. Next, to the reaction mixture was added dropwise a solution of 2-(2,1,3-benzothiadiazol-5-ylamino)-nicotinaldehyde (1.0 eq., prepared in Synthetic Example 1a)) in THF and the resultant mixture was stirred for 2 hours at −78° C. and then continued to stir for 24 hours until it reached room temperature. The reaction mixture was treated with water, and extracted with methylene chloride. The extract was dried, and evaporated. To the residue was added ethyl acetate to form crystals. Thus, 1-(2,1,3-benzothiadiazol-5-yl) -3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one was obtained. The product was purified through flash column chromatography and recrystallization (yield: 43%, mp 193.5–195.5° C./DMF).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[CH2:12][C:11]=2[CH:18]=1.C(N(CC)CC)C.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:16]=[CH:15][N:14]([C:32](=[O:33])[CH2:31][O:30][CH3:29])[C:13](=[O:17])[CH2:12][C:11]=2[CH:18]=1
Reactant: O=C1Cc2cc(OCc3cccc(F)c3)ccc2C=CN1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)N1C=Cc2ccc(OCc3cccc(F)c3)cc2CC1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 23.5 %

Procedure:
In a dried flask under an inert atmosphere, 50 mg (0.18 mmol) of 8-(3-fluoro-benzyloxy)-1,3-dihydro-benzo[d]azepin-2-one were dissolved in 3 ml of dichloromethane, and the solution cooled to 0° C. Thereupon, 21 mg (0.21 mmol) triethylamine were added and stirring continued at 0° C. Finally, 18 μl (0.2 mmol) of methoxyacetic acid chloride were added. The reaction mixture was left to warm to RT and stirring continued for 18 h. For the working-up, the reaction mixture was evaporated under reduced pressure. For purification, the crude material obtained was directly transferred on a column and chromatographed on silica gel using a 99:1-mixture of dichloromethane and methanol as the eluent. There were obtained 15 mg (24% of theory) of 8-(3-fluoro-benzyloxy)-3-methoxyacetyl-1,3-dihydro-benzo[d]azepin-2-one as a white powder; MS: m/e=356 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[C:13](OC(=O)C)(=[O:15])[CH3:14].O>C(O)(=O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:13](=[O:15])[CH3:14])=[C:3]([C:9]([F:10])([F:11])[F:12])[CH:4]=1
Reactant: Nc1ccc(O)cc1C(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(O)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
4-Amino-3-trifluoromethylphenol (0.212 g; 1.2 mmol) was dissolved in 10 ml of glacial acetic acid under nitrogen atmosphere and acetic anhydride (0.3 ml; 3.0 mmol) was added followed with stirring for an hour at room temperature. Water (0.5 ml) was added into the reaction mixture and then evaporated to dryness. Toluene (50 ml) was added and the evaporation was repeated to give a quantitative yield of pure N-(4-Hydroxy-2-trifluoromethylphenyl)acetamide. 1H NMR (400 MHz, DMSO-d6): 1.99 (3H, s), 7.01 (1H, dd, J=8.6 Hz, J=2.6 Hz), 7.02 (1H, d, J=2.5 Hz), 7.19 (1H, d, J=8.4 Hz), 9.33 (1H, s), 10.08 (1H, br s).
Reaction SMILES: [O:1]=[C:2]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([C:23]2[C:24]([NH:38][CH2:39][CH2:40][CH3:41])=[N:25][C:26]([NH:29][CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[N:27][CH:28]=2)=[O:22])[CH:15]=1)[C@@H:3]([NH:5]C(=O)OC(C)(C)C)[CH3:4]>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[NH2:5][C@@H:3]([CH3:4])[C:2]([NH:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]([C:23]2[C:24]([NH:38][CH2:39][CH2:40][CH3:41])=[N:25][C:26]([NH:29][CH2:30][CH2:31][C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)=[N:27][CH:28]=2)=[O:22])[CH:17]=[CH:18][CH:19]=1)=[O:1]
Reactant: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)N)c1
Reaction time: 3 h
Yield: 66.6 %

Procedure:
To a solution of (S)-tert-butyl (1-oxo-1-((3-(4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxamido)phenyl)amino)propan-2-yl)carbamate (A5, 137 mg) in chloroform (2 mL), trifluoroacetic acid (2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 3 hours. The solvent was evaporated under reduced pressure, and to the obtained residue, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the obtained residue, ethyl acetate was added, and the solid matter was taken by filtration, and dried under reduced pressure to obtain (S)—N-(3-(2-aminopropanamido)phenyl)-4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxamide (A6, 75 mg) as white solid.
Reaction SMILES: [C:1](=[O:19])([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:7]=1)[O:2][CH2:3][CH3:4].[H-].[Na+].Cl.Cl[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CN(C=O)C.C(Cl)Cl>[C:1](=[O:19])([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([N:14]([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[S:15]([CH3:18])(=[O:16])=[O:17])[CH:7]=1)[O:2][CH2:3][CH3:4]
Reactant: ClCCN1CCOCC1
Reactant: CCOC(=O)Oc1ccc(OC)c(NS(C)(=O)=O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(OC)c(N(CCN2CCOCC2)S(C)(=O)=O)c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 21.1 %

Procedure:
A solution of ethyl 4-methoxy-3-(methylsulfonamido)phenyl carbonate (0.850 g, 2.94 mmol) in dry DMF (15 ml) was cooled to 0° C. under nitrogen atmosphere, and sodium hydride (60% w/w, 0.300 g, 7.50 mmol) was added portion-wise. After 10 minutes, the cold bath was removed, 4-(2-chloroethyl)morpholine hydrochloride (0.680 mg, 3.65 mmol) was added, and the mixture was heated to 90° C. for 2 hours. After cooling to RT, the reaction mixture was diluted with DCM and washed with water. The organic layer was washed with brine and dried over Na2SO4; the solvent was evaporated and the crude was purified by flash chromatography on silica gel column (DCM:MeOH=10:0.1) affording ethyl 4-methoxy-3-(N-(2-morpholinoethyl)methylsulfonamido)-phenyl carbonate (0.250 g, 0.621 mmol, 21.14% yield, UPLC-MS purity: 97%, MS/ESI+ 403.1 [MH]+).
Reaction SMILES: C[Al](C)C.[CH2:5]([NH2:8])[CH2:6][NH2:7].C(O[C:12](=O)[CH2:13][S:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=1)C>C1(C)C=CC=CC=1>[Cl:22][C:17]1[CH:16]=[C:15]([S:14][CH2:13][C:12]2[NH:7][CH2:6][CH2:5][N:8]=2)[CH:20]=[C:19]([Cl:21])[CH:18]=1
Reactant: CCOC(=O)CSc1cc(Cl)cc(Cl)c1
Reactant: NCCN
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Clc1cc(Cl)cc(SCC2=NCCN2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
To dry toluene (4 ml) under an inert atmosphere at 0° C. was added a toluene solution of trimethylaluminium (2.70 ml, 5.39 mmol, 2 M solution). A solution of ethylenediamine (0.36 ml, 5.39 mmol) in toluene (1.5 ml) was then added dropwise and the reaction mixture was then allowed to warm to room temperature and stirred for 1 h at this temperature before being re-cooled to 0° C. To this mixture was added dropwise a solution of (3,5-dichloro-phenylsulfanyl)-acetic acid ethyl ester (0.72 g, 2.70 mmol) in toluene (3 ml). The reaction mixture was then heated at 95° C. for 45 min and then cooled first to room temperature and finally to 0° C. The mixture was quenched by dropwise addition of methanol (1 ml) and when all gas evolution had ceased the mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo. The residue was triturated in ether to yield a white solid (0.21 g, 30%) which was collected by filtration; MS (ISP): 265.0, 263.1, 261.1 ([M+H]+.).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].CS(C)=O.Cl[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>O>[CH2:36]([O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21]
Reactant: CCCCCCCCCCCCCCCCCl
Reactant: Oc1ccccc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCCOc1ccccc1-c1ccccc1
Temperature: 70 °C
Reaction time: 7.5 h

Procedure:
A 100 mL 3-neck flask was equipped with a magnetic stirrer, a reflux condenser, a nitrogen blanket, and a heating mantle with a temperature controller and a thermocouple. The flask was charged with o-phenylphenol (3.42 grams, 0.02 moles), with KOH pellets (1.37 grams, 0.02 moles, 85%), and with 15 mL of DMSO. The mixture was stirred at 100° C. under nitrogen until all of the KOH had dissolved (about 2 hours). The dark solution was cooled to 70° C., then the 1-chlorohexadecane (5.22 grams, 0.02 moles) was then added all at once. An exotherm to about 80° C. was observed. The reaction mixture was then stirred at 75° C. for about 7.5 hours, then it was poured into about 500 mL of water; solids separated.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[Na+].[NH2:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[S:8][C:7]=1[C:18]([NH2:20])=[O:19]>C(O)(=O)C.O>[NH2:1][C:2]([NH:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[S:8][C:7]=1[C:18]([NH2:20])=[O:19])=[O:3]
Reactant: NC(=O)c1sc(-c2ccc(F)cc2)cc1N
Reactant: [N-]=C=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1cc(-c2ccc(F)cc2)sc1C(N)=O
Reaction time: 20 h
Yield: 13.2 %

Procedure:
Sodium isocyanate (1.08 g) was added portionwise to a stirred suspension of 3-amino-5-(4-fluorophenyl)-2-thiophenecarboxamide (3.2 g) in acetic acid (150 mL) and water (90 mL). After 20 h, the solid was filtered off and washed with water, methanol and ether. Recrystallisation from methanol/dimethylsulphoxide gave the title urea (0.5 g) as a 1:1 dimethylsulphoxide solvate.