Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[CH:42]1([N:45]2[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]2)[CH2:44][CH2:43]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:51][CH:48]5[CH2:49][CH2:50][N:45]([CH:42]6[CH2:44][CH2:43]6)[CH2:46][CH2:47]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NC1CCN(C2CC2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C3CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To a mixture of 0.10 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.2 mL (1.1 mmole) of ethyldiisopropyl amine and 0.038 g (0.25 mmole) of 1-cyclopropyl-piperidin-4-ylamine in 4.0 mL of dimethylformamide was added 0.11 g (0.25 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted with three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate and three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-95:5) gave 0.081 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-cyclopropyl-piperidin-4-yl)-3-methoxy-benzamide (I-66) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16](Cl)=[N:15][C:14]=3[C:13]=2[CH3:28])[CH2:7][CH2:6]1)=[O:4].CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=2)O1>>[NH2:44][C:41]1[N:42]=[CH:43][C:38]([C:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:19]3[S:20][C:12]([CH2:11][N:8]4[CH2:9][CH2:10][N:5]([C:3]([N:2]([CH3:29])[CH3:1])=[O:4])[CH2:6][CH2:7]4)=[C:13]([CH3:28])[C:14]=3[N:15]=2)=[CH:39][N:40]=1
Reactant: Cc1c(CN2CCN(C(=O)N(C)C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1c(CN2CCN(C(=O)N(C)C)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12

Procedure:
4-(2-Chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid dimethylamide was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine in General Procedure A. Purification on silica yielded 126. NMR (CDCl3): 2.44 (s, 3H, CH3), 2.56-2.60 (m, 4H, 2×CH2), 2.85 (s, 6H, 2×CH3), 3.31-3.33 (m, 4H, 2×CH2), 3.83 (s, 2H, CH2), 3.88-3.91 (m, 4H, 2×CH2), 4.03-4.05 (m, 4H, 2×CH2), 5.22 (sbr, 2H, NH2), 9.35 (s, 2H, 2×ArH). MS: (ESI+): MH+=498.32
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[SH:10].[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1)([O-:13])=[O:12].Cl>N1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=1
Reactant: Cc1cc(O)c(S)c(=O)o1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(O)c(SCc2ccc([N+](=O)[O-])cc2)c(=O)o1
Temperature: 90 °C

Procedure:
To a solution of 8.00 g. (0.0510 mole) of 4-hydroxy-3-mercapto-6-methyl-2-pyrone in 50 ml. of pyridine was added 11.0 g. (0.0510 mole) of p-nitrobenzyl bromide portionwise, keeping the temperature of the reaction mixture below 35°C. by means of an ice bath. After the addition was complete the reaction mixture was heated at 90°C. on the steam bath for two hours and 15 minutes. The mixture was then poured into ice and 100 ml. of concentrated hydrochloric acid. The cream colored solid precipitate was collected on a filter, washed with water and dried; m.p. 156°-160°C. (dec.), weight 12.2 g. (81 percent). Recrystallization from ethanol gave the pure 4-hydroxy-6-methyl-3-(4-nitrobenzylthio)-2-pyrone as tan crystals, m.p. 178°C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][CH3:13])=[CH:8][C:7]([N+:14]([O-:16])=[O:15])=[CH:6][CH:5]=2.[BH4-].[Na+].O.[F:20][C:21]([F:26])([F:25])[C:22](O)=O>>[CH3:1][CH:2]1[CH:10]([CH2:11][CH2:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=2)[N:3]1[CH2:22][C:21]([F:26])([F:25])[F:20]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCc1c(C)[nH]c2ccc([N+](=O)[O-])cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCCC1c2cc([N+](=O)[O-])ccc2N(CC(F)(F)F)C1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 200 ml 2-neck round bottom flask, equipped with a magnetic stirrer and a cold water condenser, 4-nitrophenylhydrazine was dissolved in 75 mL concentrated hydrochloric acid and stirred at room temperature for 15 minutes. A solution of 2-hexanone (5 mL) in ethanol (25 mL) was added slowly and the reaction flask was heated in an oil bath at 105° C. for 18 h. The mixture was cooled to room temperature and water (100 mL) was added. The mixture was extracted with EtOAc. The organic layer washed with saturated sodium bicarbonate solution, water, and brine solutions and evaporated to dryness. The oily residue was absorbed on silica gel and purified by silica gel chromatography with 20% EtOAc in Hexane solution to give 2-methyl-5-nitro-3-propyl-1H-indole. This indole product was dissolved in trifluoroacetic acid (10 mL) and 1 pellet sodium borohydride (0.7 g) was added and the reaction was stirred at room temperature for 18 h. Water (10 mL) was carefully added and the reaction mixture was extracted twice with EtOAc (15 mL) The organic layer washed with brine and dried over MgSO4, and purified by flash column chromatography on silica gel eluted with 20% EtOAc in hexanes to give 280 mg of 2-methyl-5-nitro-3-propyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-indole.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:12][C:11]1[C:2]([CH3:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cccc(N)c1C
Temperature: 80 °C
Yield: 75.1 %

Procedure:
To a stirred solution of methyl 2-methyl-3-nitrobenzoate (10.0 g, 56.4 mmol) in 60 ml of ethanol were added ammonium chloride (18.0 g, 338 mmol) dissolved in 60 mL of water and iron powder (18.8 g, 338.2 mmol). The resulting reaction mixture was heated at 80° C. for 3 h. Water was added to the reaction mixture and then it was filtered through celite. The filtrate was extracted with ethyl acetate. The combined organic layers were washed with water, dried over Na2SO4, concentrated under reduced pressure to give the title compound (7.0 g, 83%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[C:22]1[CH:23]=[CH:24][C:25]2[N:31]3[C:32]([CH3:35])=[N:33][N:34]=[C:30]3[C@H:29]([CH2:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38])[N:28]=[C:27]([C:42]3[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=3)[C:26]=2[CH:49]=1)(=O)=O.O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:48][C:45]1[CH:44]=[CH:43][C:42]([C:27]2[C:26]3[CH:49]=[C:22]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:23]=[CH:24][C:25]=3[N:31]3[C:32]([CH3:35])=[N:33][N:34]=[C:30]3[C@H:29]([CH2:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38])[N:28]=2)=[CH:47][CH:46]=1
Reactant: OB(O)c1cccnc1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-n2c(C)nnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3cccnc3)ccc2-n2c(C)nnc21
Temperature: 120 °C

Procedure:
3-Pyridinylboronic acid (27.2 mg), sodium carbonate (43.0 mg) and bis(triphenylphosphine)palladium(II) chloride (12.95 mg) were added to a 2-5 ml microwave vial. A solution of (4S)-6-(4-chlorophenyl)-4-[2-(ethylamino)-2-oxoethyl]-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl trifluoromethanesulfonate (for a preparation see Intermediate 3) (100 mg) in DME (3 ml) and water (1 ml) was added and the reaction mixture was heated at 120° C. for 20 min (microwave). The reaction mixture was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic phase was separated, washed with water (10 ml) and brine (10 ml). The organic phase was dried and the solvent evaporated. The residue was chromatographed (0-10% methanol:DCM) product was further purified by MDAP (formate modifier) to give 2-[(4S)-6-(4-chlorophenyl)-1-methyl-8-(3-pyridinyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide as a white oil (11.9 mg).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:15])[NH:9]2)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>CN(C)C=O>[C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:15])[NH:9]2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(C(C)=O)c3ccc(=O)[nH]c23)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
5-Acetyl-8-hydroxy-1H-quinolin-2-one (29.5 g, 0.15 mol) was suspended in N,N-dimethylformamide (145 mL), potassium carbonate (22.2 g, 0.16 mol) and successively 4-methoxybenzyl chloride (22.7 g, 0.15 mol) were added thereto, and the mixture was stirred at 90° C. overnight. To the reaction mixture was added purified water (0.5 L) and the mixture was stirred at room temperature overnight. The precipitate was collected by filtration, washed with purified water, dried under reduced pressure to obtain 5-acetyl-8-[(4-methoxyphenyl)methoxy]-1,2-dihydroquinolin-2-one (26.1 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:25]2)[C:21](=[O:37])[NH:20][C:19]2([C:38]([OH:40])=O)[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:53]1([S:56]([NH2:59])(=[O:58])=[O:57])[CH2:55][CH2:54]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][Si:30]([C:33]([CH3:35])([CH3:36])[CH3:34])([CH3:31])[CH3:32])[CH2:25]2)[C:21](=[O:37])[NH:20][C:19]2([C:38]([NH:59][S:56]([CH:53]3[CH2:55][CH2:54]3)(=[O:58])=[O:57])=[O:40])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(O[Si](C)(C)C(C)(C)C)CN2C1=O
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O[Si](C)(C)C(C)(C)C)CN2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.1 %

Procedure:
14-tert-Butoxycarbonylamino-18-(tert-butyl-dimethyl-silanyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (500 mg, 0.86 mmol.) was dissolved in 25 mL of THF and treated with CDI (180 mg, 1.12 mmol.). (Care was taken to avoid moisture by using oven dried glassware and maintaining a dry N2 atmosphere). After refluxing the reaction mixture for 2 h, it was cooled to rt and treated sequentially with cyclopropylsulfonamide (135 mg, 1.12 mmol.) and DBU (170 mg, 1.12 mmol.). The reaction mixture was stirred for 4 h at rt, and the THF was removed by rotary evaporation. The residue was partitioned between ethyl acetate and pH 4 buffer. The organic phase was dried (MgSO4) and concentrated in vacuo to give the crude product. It was then purified by flash chromatography (eluting with 33% ethyl acetate in hexane) to give 300 mg (51%) of [18-(tert-butyl-dimethyl-silanyloxy)-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester as a white solid. 1H NMR (300 MHz, CD3OD) δ 1H 0.07 (s, 3H), 0.08 (s, 3H), 0.85 (s, 9H), 0.87-1.49 (m, 21H), 1.73-1.95 (m, 3H), 2.08-2.16 (m, 1H), 2.25-2.36 (m, 2H), 2.42-2.56 (m, 1H), 2.85-2.93 (m, 1H), 3.65-3.74 (dd, J=10.61, 3.66 Hz, 1H), 3.89 (d, J=10.25 Hz, 1H), 4.34 (m, J=9.70, 9.70 Hz, 1H), 4.43 (t, J=7.87 Hz, 1H), 4.57 (s, 1H), 4.94-5.01 (m, 1H), 5.10 (d, J=8.78 Hz, 1H), 5.66-5.75 (m, 1H), 6.55 (s, 1H), 10.13 (s, 1H); MS m/z 683 (M++1).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:9][CH:8]=1)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:43][C:44]([NH2:46])=[NH:45])[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1>>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:43][C:44]2[N:45]=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH:17]=[CH:16][CH:15]=[N:14]4)=[CH:9][CH:8]=3)[CH:4]=[C:3]([C:2]([F:20])([F:19])[F:1])[N:46]=2)[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(-n2cccn2)cc1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2nc(-c3ccc(-n4cccn4)cc3)cc(C(F)(F)F)n2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 4,4,4-trifluoro-1-(4-pyrazol-1-yl-phenyl)-butane-1,3-dione (137 mg, 0.0.49 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (180 mg, 0.49 mmol) using in analogous manner the procedure described in example 29). Obtained as a pale-yellow solid (25 mg, 10%). Mp 252-254° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]#[C:11][C:12]1[N:17]=[C:16]([CH3:18])[C:15]([C:19]([O:21][CH3:22])=[O:20])=[C:14]([NH:23][C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[N:17]=[C:16]([CH3:18])[C:15]([C:19]([O:21][CH3:22])=[O:20])=[C:14]([NH:23][C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)[N:13]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1c(C)nc(C#CCNC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1c(C)nc(CCCNC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-(3-(tert-butoxycarbonylamino)prop-1-ynyl)-4-methyl-6-(m-tolylamino)pyrimidine-5-carboxylate (0.190 g, 0.463 mmol) was dissolved in EtOH (4 mL). To this solution was added palladium on carbon (0.049 g, 0.046 mmol) and the resulting mixture was stirred overnight at RT under H2 atmosphere. The mixture was filtered through a pad of Celite, and the filtrate was evaporated to give the title compound as a brown oil, which was used in next step without further purification. [M+H] calc'd for C22H30N4O4, 415; found, 415.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])=[O:2].[CH3:18][C@H:19]([NH:28][CH3:29])[C@H:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C1C=CC=CC=1>[CH3:29][N:28]1[CH:19]([CH3:18])[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:2][CH:1]1[C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]
Reactant: CCOP(=O)(Cc1ccccc1C=O)OCC
Reactant: CN[C@@H](C)[C@H](O)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: CCOP(=O)(Cc1ccccc1C1OC(c2ccccc2)C(C)N1C)OCC
Reaction time: 24 h

Procedure:
2.0 g (8 mmol) of the compound A and 1.32 g (8 mmol) of (-)-ephedrine were dissolved in 100 ml of benzene and heated under reflux in a water separator for 24 h. The solvent was then removed by rotary evaporation and the residue was chromatographed on silica gel (eluent CH2Cl2 /ethanol 9.5/0.5; Rf=0.55). The product F was obtained as an oil.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[S:15][C:16]([C:19]#[N:20])=[CH:17][N:18]=3)[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Br[CH2:31][C:32]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[O:33]>CN(C=O)C>[N:34]1([C:32](=[O:33])[CH2:31][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]4[S:15][C:16]([C:19]#[N:20])=[CH:17][N:18]=4)[CH:8]=3)[CH2:2][CH2:3]2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: N#Cc1cnc(Nc2cc(N3CCNCC3)ncn2)s1
Reactant: O=C(CBr)N1CCOCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnc(Nc2cc(N3CCN(CC(=O)N4CCOCC4)CC3)ncn2)s1
Temperature: 0 °C

Procedure:
2-[(6-Piperazin-1-ylpyrimidin-4-yl)amino]-1,3-thiazole-5-carbonitrile 12-3 (0.10 g, 0.35 mmol) and diisopropylethylamine (0.049 g, 0.38 mmol) were dissolved in DMF. After cooling to 0° C., a DMF solution of 4-(bromoacetyl)morpholine 12-4 (0.08 g, 0.38 mmol) was added slowly via addition funnel. The product was purified on a C18 preparative LC column and isolated via lyophilization. Hi-Res MS: calc: 415.1655 found: 415.1663. 1H-NMR (CD3OD): 8.49 ppm (s, 1H); 8.03 ppm (s, 1H); 6.27 ppm (s, 1H); 4.34 ppm (s, 2H); 3.70 ppm (m, 4H); 3.65 ppm (m, 4H); 3.42 ppm (t, 2H); 3.33 ppm (m, 6H).
Reaction SMILES: [S:1]1[CH:5]=[C:4]2[C:6](O[C:9](=[O:10])[C:3]2=[CH:2]1)=[O:7].[CH2:11]([CH:13]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:14][CH2:15][C:16]1[C:22]([F:23])=[C:21]([F:24])[C:19]([NH2:20])=[C:18]([F:25])[C:17]=1[F:26])[CH3:12]>C1(C)C=CC=CC=1>[CH2:11]([CH:13]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:14][CH2:15][C:16]1[C:17]([F:26])=[C:18]([F:25])[C:19]([N:20]2[C:9](=[O:10])[C:3]3=[CH:2][S:1][CH:5]=[C:4]3[C:6]2=[O:7])=[C:21]([F:24])[C:22]=1[F:23])[CH3:12]
Reactant: O=C1OC(=O)c2cscc21
Reactant: CCCCC(CC)CCc1c(F)c(F)c(N)c(F)c1F
Solvent: Cc1ccccc1
Product: CCCCC(CC)CCc1c(F)c(F)c(N2C(=O)c3cscc3C2=O)c(F)c1F

Procedure:
A solution of thiophene-3,4-dicarboxylic anhydride (8.0 mmol) and 4-(3-ethylheptyl)-2,3,5,6-tetrafluoroaniline (8.5 mmol) in 125 ml of toluene is refluxed for 24 h. The crude product is collected by filtration of the cold reaction mixture. Another portion of product can be recovered by washing the filtrate with 5% hydrochloric acid and then evaporating the solvent. The target molecule is purified by recrystallization from toluene, dissolved in 150 ml of thionyl chloride and refluxed for 3 hrs. The reaction mixture is concentrated down, dried, and purified.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:6]=2[N:7]=1.[CH2:14]1[N:19]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[CH2:18][CH2:17][O:16][CH2:15]1.NC1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:26][C:23]2[CH:22]=[CH:21][C:20]([N:19]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[CH:25][CH:24]=2)[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:6]=2[N:7]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1C
Solvent: CCO
Solvent: Nc1ccccc1
Product: Cc1sc2nc(Cl)nc(Nc3ccc(N4CCOCC4)cc3)c2c1C
Yield: 112.5 %

Procedure:
To 240 mg (1.02 mmol of 2,4-dichloro-5,6-dimethyl-thieno[2,3-d]pyrimidine in 50 ml of ethyl alcohol were added 220.20 mg (1.23 mmol) of 4-(4-morpholino)aniline and 130.90 mg (1.23 mmol) of aniline, and then the mixture was stirred under reflux. After completion of the reaction, the reaction solvent, ethyl alcohol, was evaporated under reduced pressure, and the residue was crystallized from ethyl alcohol and filtered, yielding 430 mg (quantitative) of 2-chloro-5,6-dimethyl-thieno[2,3-d]pyrimidin-4-yl-4-morpholin-4-yl-phenylamine. 220 mg (0.53 mmol) of the obtained product was dissolved in 20 ml of 1-butanol in a sealed tube, and 223 μl (1.59 mmol) of triethylamine and 45.9 mg of piperazine were added thereto, and the mixture was stirred at 120° C. After completion of the reaction, the resulting solid was filtered and the filtrate was concentrated under reduced pressure and then crystallized from ethyl acetate, yielding 30 mg (15% yield) of 5,6-dimethyl-2-piperazin-1-yl-thieno[2,3-d]pyrimidin-4-yl-4-morpholin-4-yl-phenylamine. To 9 mg (0.02 mmol) of the obtained compound and 5,6-dimethyl-2-piperazin-1-yl-thieno[2,3-d]pyrimidin-4-yl-4-morpholin-4-yl-phenylamine in 5 ml of dimethyl chloride were added 3.5 μl (0.02 mmol) of triethylamine and 4.1 mg (0.02 mmol) of picolinoyl chloride hydrochloride, and then the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solvent, dimethyl chloride, was evaporated under reduced pressure, and the residue was crystallized from dimethyl chloride, thus obtaining 6 mg (30% yield) of the title product.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5][O:6][CH2:7][C:8]([OH:10])=O)[CH3:2].[NH2:12][C@@H:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:40][CH:39]=1)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15]>>[C:45]([O:44][C:41]1[CH:40]=[CH:39][C:38]([CH2:37][C@H:13]([NH:12][C:8](=[O:10])[CH2:7][O:6][NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:43][CH:42]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CCNC(=O)NOCC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: CCNC(=O)NOCC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 48 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([OH:14])[C:10]([F:13])([F:12])[F:11].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C@@H:9]([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:2]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1
Reactant: O[C@H](c1ccc(Cl)cc1Br)C(F)(F)F
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O[C@H](c1ccc(Cl)cc1-c1ccccc1)C(F)(F)F
Temperature: 90 °C

Procedure:
To a solution of (R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanol (300 mg, 1.1 mmol) in dioxane (12 mL) was added phenyl boronic acid (185 mg, 1.5 mmol), Pd2(dppf)Cl2 (35 mg, 0.07 mmol) and Na2CO3 (3 mL, 2.0 M, aq). The reaction was heated to 90° C. for 2 h, then cooled to RT, and concentrated in vacuo. The residue was taken up in CH2Cl2, washed with brine, and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4. Purification by normal phase silica gel column (EtOAc/hexanes) to provide a white solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])([CH3:7])[CH3:6]>S(=O)(=O)(O)O>[CH:5]([C:8]1[CH:14]=[CH:13][C:12]([N+:1]([O-:4])=[O:2])=[CH:11][C:9]=1[NH2:10])([CH3:7])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CC(C)c1ccccc1N
Agent: O=S(=O)(O)O
Product: CC(C)c1ccc([N+](=O)[O-])cc1N
Reaction time: 0.5 h
Yield: 15.7 %

Procedure:
70% HNO3 (5.1 mL, 84.76 mmol, 1.2 equiv) was added dropwise to a mixture of 2-isopropylaniline (10 mL, 9.55 g, 70.63 mmol, 1 equiv) in 70 mL of conc. sulfuric acid at 0° C. The reaction mixture was stirred at this temperature for 30 minutes and then poured onto ice. The aqueous mixture was extracted with EtOAc (2×150 mL). The organic layers were combined and washed with sat'd NaHCO3. After evaporation, the residue was purified by column chromatography on silica gel using EtOAc/hexanes (3/7) to give 2 g of product (16%) as a dark red oil.