Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24](O)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[NH:35][C:34]2=[O:41].O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:30][C:31]4[CH:32]=[C:33]5[C:37](=[CH:38][CH:39]=4)[C:36](=[O:40])[NH:35][C:34]5=[O:41])=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Reactant: Nc1ccc2c(c1)C(=O)NC2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)Nc4ccc5c(c4)C(=O)NC5=O)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.2 %

Procedure:
To a solution of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (50 mg, 0.12 mmol) and 5-aminoisoindoline-1,3-dione (19 mg, 0.12 mmol) in pyridine (8 mL) was added POCl3 (0.3 mL, 3.23 mmol) at 0° C., the reaction mixture was stirred at room temperature for 4 hours, a sat. NaHCO3 solution was added slowly, the solvent was removed in vacuo, water (5 mL) and methanol (2 mL) were added. The precipitate was collected by filtration and washed with water (5 mL) and methanol (5 mL) to afford 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(1,3-dioxoisoindolin-5-yl)piperidine-3-carboxamide (27 mg, 40.0%) as an orange solid. 1H NMR (300 MHz, DMSO): δ 11.20 (s, 1H), 10.59 (s, 1H), 9.64 (s, 1H), 8.83 (s, 1H), 8.13 (s, 1H), 7.86-7.73 (m, 2H), 7.63 (s, 1H), 7.38-7.29 (m, 1H), 6.78 (s, 1H), 4.77 (d, 1H, J=12.0 Hz), 4.62 (d, 1H, J=12.3 Hz), 3.66 (s, 3H), 3.61 (s, 3H), 3.16-2.94 (m, 2H), 2.60-2.55 (m, 1H), 2.04-2.01 (m, 1H), 1.76-1.72 (m, 2H), 1.52-1.41 (m, 1H). LC-MS: 560 [M+H]+, tR=1.49 min. HPLC: 99.49% at 214 nm, 99.47% at 254 nm, tR=5.33 min.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12](=[O:21])[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[CH3:10].[Br:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.CN1C(=O)N(C)CCC1>C1COCC1>[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][C:13]([CH3:14])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12]([O:11][CH2:9][CH3:10])=[O:21]
Reactant: CCOC(=O)C(C)c1ccccc1
Reactant: BrCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)C(C)(CCCCBr)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of LDA (14 mL, 28 mmol, 2.0 M in heptane) was added dropwise to a stirred solution of 202 (5.0 g, 28.06 mmol) in anhydrous THF (50 mL) at −78° C. After 1 h, the reaction mixture was added to a −78° C. cold solution of 1,4-dibromobutane (10.06 g, 23.1 mmol) in THF. After the addition of DMPU (5 mL), the reaction mixture was stirred for 1 h, then warmed to room temperature and stirred overnight. The mixture was poured into saturated aqueous NH4C1 solution (500 mL) and extracted with ethyl acetate (4×100 mL). The combined organic phases were washed with brine (100 mL), 1 M HCl (50 mL), saturated aqueous NaHCO3 solution (50 mL), and brine (100 mL). The solution was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was distilled to give 205d as an oil (7.16 g, 99%). Bp 130-131° C./0.2 mm Hg. 1H NMR (CDCl3), δ (ppm): 7.40-7.15 (m, 5H), 4.13 (q, 2H, J=6.7), 3.36 (t, 2H, J=6.7), 2.02 (m, 2H), 1.86 (m, 2H), 1.56 (s, 3H), 1.34 (m, 2H), 1.18 (t, 3H, J=6.7). 13C NMR (CDCl3), δ (ppm): 176.13, 143.91, 128.51, 126.81, 126.03, 60.93, 50.22, 38.53, 33.56, 33.30, 23.58, 22.77, 14.22. HRMS (FAB): Calcd for C15H2179BrO2 (MH+): 313.0803. found 313.0786.
Reaction SMILES: [NH2:1][CH:2]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH:3]([OH:9])[CH:4]([CH:6]1[CH2:8][CH2:7]1)[F:5].[C:17]([O:21][C:22]([N:24]1[CH:28]=[C:27]([CH2:29][C@H:30]([NH:34][C:35](=[O:52])[C@@H:36]([CH2:44][S:45]([C:48]([CH3:51])([CH3:50])[CH3:49])(=[O:47])=[O:46])[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:31](O)=[O:32])[N:26]=[CH:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.C1C=C2C(N(O)N=NC2=CC=1)=O>CN(C)C=O>[C:48]([S:45]([CH2:44][C@@H:36]([CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:35]([NH:34][C@@H:30]([CH2:29][C:27]1[N:26]=[CH:25][N:24]([C:22]([O:21][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:23])[CH:28]=1)[C:31]([NH:1][C@@H:2]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:3]([OH:9])[C@H:4]([CH:6]1[CH2:8][CH2:7]1)[F:5])=[O:32])=[O:52])(=[O:47])=[O:46])([CH3:49])([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)n1cnc(C[C@H](NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)C(=O)O)c1
Reactant: NC(CC1CCCCC1)C(O)C(F)C1CC1
Agent: O=c1c2ccccc2nnn1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1cnc(C[C@H](NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)C(=O)N[C@@H](CC2CCCCC2)[C@@H](O)[C@@H](F)C2CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 147 mg (0.64 mmol) of (1S or R,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1-fluoro-2-butanol, 365 mg (0.7 mmol) of (S)-1-(tert-butoxycarbonyl)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]imidazole-4-propionic acid, 71 mg (0.7 mmol) of triethylamine, 114 mg (0.7 mmol) of HOOBT and 285 mg (0.7 mmol) of HOBTU in 15 ml of dimethylformamide is stirred at room temperature overnight under argon. Thereafter, the dimethylformamide is evaporated in a high vacuum and the residue is taken up in 50 ml of ethyl acetate. The ethyl acetate phase is washed with 20 ml of saturated sodium bicarbonate solution and 20 ml of saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. There is obtained (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-3-fluoro-2-hydroxypropyl]-1-Boc-imidazole-4-propionamide as a yellowish foam.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][C:10]([NH:29][C:30]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[C:42](=[O:49])([O:46][CH2:47]I)[S:43][CH2:44][CH3:45]>O.C(Cl)Cl>[C:42](=[O:49])([S:43][CH2:44][CH3:45])[O:46][CH2:47][O:35][C:34](=[O:36])[CH2:33][CH2:32][C:30](=[O:31])[NH:29][C:10]([CH2:9][CH2:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14]
Reactant: CC(C)(C)OC(=O)CCC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)NC(=O)CCC(=O)O
Reactant: CCSC(=O)OCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCSC(=O)OCOC(=O)CCC(=O)NC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)CCC(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 71.9 %

Procedure:
To a mixture of acid 73 (519 mg, 1.01 mmol) in H2O (3 mL) and CH2Cl2 (3 mL) was added NaHCO3 (176 mg, 2.09 mmol) and TBAHSO4 (342 mg, 1.01 mmol). After stirring for 20 min, S-ethyl O-iodomethyl carbonothioate (192 mg, 0.77 mmol) in CH2Cl2 (1 mL) was added. The biphasic reaction was stirred vigorously for 3 h and was diluted with water and CH2Cl2. The layers were separated and the organic layer was washed with H2O, 0.5 N HCl solution, saturated NaHCO3 solution, saturated NaCl solution, dried over MgSO4, filtered and concentrated to dryness. The crude product was triturated with Et2O and the solids were removed by filtration and rinsed with small portions of Et2O. After concentration, the combined filtrates were purified by flash chromatography on a Biotage™ flash chromatography system, using a gradient of 20-60% EtOAc in CH2Cl2 as eluent, to furnish compound 74 (351 mg, 72%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.33 (t, J=7.4 Hz, 3H), 1.44 (s, 27H), 1.94-1.98 (m, 6H), 2.20-2.24 (m, 6H), 2.43 (t, J=6.9 Hz, 2H), 2.70 (t, J=6.9 Hz, 2H), 2.89 (q, J=7.4 Hz, 2H), 5.81 (s, 2H), 5.98 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1.C([O-])(=O)C.[Na+].CN(C=O)C>O>[CH:3]([C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1)=[CH2:2]
Reactant: NS(=O)(=O)c1cc2cc(CCBr)ccc2s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1ccc2sc(S(N)(=O)=O)cc2c1
Yield: 101 %

Procedure:
A solution of 4.0 g (0.012 mol) of 5-(2-bromoethyl)-2-sulfamoylbenzo[b]thiophene, 2.0 g (0.024 mol) of sodium acetate and 40 ml of DMF was heated at 100° C. under nitrogen. After 15 hours the mixture was poured into water and the aqueous phase was extracted 3X with ethyl acetate. The extracts were dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel by elution with 20% (V/V) ethyl acetate-hexane to yield 2.9 g (30%) of 5-ethenyl-2-sulfamoylbenzo[b]thiophene, m.p. 168°-170° C. (1,2-dichloroethane). Further elution with 40% (V/V) ethyl acetate-hexane yielded 3.74 g (59%) of 5-(2-acetoxyethyl)2-sulfamoylbenzo[b]thiophene, m.p. 120°-122° C. (1,2-dichloroethane).
Reaction SMILES: [CH2:1]([C@:3]1([OH:11])[CH2:7][CH2:6][NH:5][C@H:4]1[CH:8]([CH3:10])[CH3:9])[CH3:2].[F:12][C:13]1[CH:20]=[C:19](F)[CH:18]=[C:17]([F:22])[C:14]=1[C:15]#[N:16].C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:1]([C@:3]1([OH:11])[CH2:7][CH2:6][N:5]([C:19]2[CH:20]=[C:13]([F:12])[C:14]([C:15]#[N:16])=[C:17]([F:22])[CH:18]=2)[C@H:4]1[CH:8]([CH3:10])[CH3:9])[CH3:2]
Reactant: CC[C@]1(O)CCN[C@H]1C(C)C
Reactant: N#Cc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@]1(O)CCN(c2cc(F)c(C#N)c(F)c2)[C@H]1C(C)C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-3-ethyl-2-isopropylpyrrolidin-3-ol 0.5 oxalate (203 mg), 2,4,6-trifluorobenzonitrile (157 mg) and lithium carbonate (163 mg), the title compound was obtained as colorless oil (yield: 143 mg, yield: 49%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5](=[O:18])[CH:6]=[C:7]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][CH3:9].C1(C)C=CC(S([N:29]=[N+:30]=[N-])(=O)=O)=CC=1.C(N(CC)CC)C>>[CH3:1][O:2][C:3](=[O:19])[C:4](=[N+:29]=[N-:30])[C:5](=[O:18])[CH2:6][CH:7]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:8]=[CH2:9]
Reactant: CCC(=CC(=O)CC(=O)OC)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Product: C=CC(CC(=O)C(=[N+]=[N-])C(=O)OC)OCc1ccccc1
Yield: 98.1 %

Procedure:
In accordance with the process of Preparation 1, 5-benzyloxy-3-oxo-heptenoic acid methyl ester (1.07 g; 4.1 mmol), p-toluene-sulfonyl azide (810 mg; 4.1 mmol) and triethylamine (450 mg; 4.5 mmol) were used as starting materials to obtain 1.16 g of 5-benzyloxy-2-diazo-3-oxo-6-heptenoic acid methyl ester as a yellow oily product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](Cl)(=[O:12])=[O:11])=[O:4].[CH2:14]([O:16][C:17](=[O:21])[CH2:18][NH:19][CH3:20])[CH3:15].O.Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:12])(=[O:11])[N:19]([CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:21])[CH3:20])=[O:4]
Reactant: CCOC(=O)CNC
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)CN(C)S(=O)(=O)c1ccsc1C(=O)OC
Reaction time: 0.33 h

Procedure:
20 G. of 3-chlorosulfonylthiophene-2-carboxylic acid methyl ester are dissolved in absolute chloroform, whereupon 21 g. of sarcosine ethyl ester are added dropwise during 10 minutes. In so doing, the mixture warms up to 50° C. After 20 minutes, the mixture is cooled, shaken once each time with water, 0.5-N hydrochloric acid and a sodium bicarbonate solution, dried and evaporated. The remaining oil is brought to crystallization with ethanol. There is obtained 3-(N-carbethoxymethyl-N-methyl-sulfamoyl)-thiophene-2-carboxylic acid methyl ester of melting point 84°-85° C.
Reaction SMILES: C(N1CCCC(C(OCC)=O)C1)(=O)C1C=CC=CC=1.Cl.[O:21]=[C:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH:23]1[C:28]([O:30][CH3:31])=[O:29].Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>>[CH2:36]([O:35][C:33]([N:25]1[CH2:26][CH2:27][C:22](=[O:21])[CH:23]([C:28]([O:30][CH3:31])=[O:29])[CH2:24]1)=[O:34])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C1CNCCC1=O
Agent: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Agent: Cl
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CCC1=O

Procedure:
This compound may be prepared in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with commercially available methyl 4-oxo-3-piperidinecarboxylate hydrochloride, diisopropylethylaamine and commercially available benzyl chloroformate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20][NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:34](I)[CH3:35].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20][N:21]([CH2:34][CH3:35])[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:23])=[O:24])[CH2:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)C[C@@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(C#N)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C[C@H](CC(=O)OC(C)(C)C)Nc1ccc(C#N)c(Cl)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the crude 1,1-dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-{[(2-nitrophenyl)sulfonyl]amino}butanoate from the previous step, ethyl iodide (2.59 mL, 32.4 mmol) and K2CO3 (325 mesh, 6.71 g, 48.6 mmol) in DMF (93 mL) was stirred at room temperature for 60 min. The reaction was diluted with H2O (200 mL) and extracted with Et2O (3×). The organic extracts were washed with H2O (2×), dried over Na2SO4, filtered, and concentrated. The crude product was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:31]=1[NH:45][C:46]([NH:48][C:49]1[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=1)=[O:47].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:34]2[CH:33]=[CH:32][C:31]([NH:45][C:46]([NH:48][C:49]3[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=3)=[O:47])=[C:30]([F:29])[CH:35]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3ccncc3)c(F)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccc(NC(=O)Nc4ccncc4)c(F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (40 mg, 0.09 mmol) in dioxane (2 ml) were added 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(pyridin-4-yl)urea (62 mg, 0.14 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(11)dichloride dichloromethane complex (7.5 mg, 0.01 mmol) and 136 μl of a 2M aqueous solution of cesium carbonate. The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by reverse phase using SP1® Purification System to give 25 mg (45% yield) as a white solid. Purity 97%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:14])[O:12][CH3:13])[CH:5]=[C:6]([Br:9])[C:7]=1[F:8].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:11](=[O:14])[O:12][CH3:13])[CH:5]=[C:6]([Br:9])[C:7]=1[F:8]
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)Nc1cc(Br)c(F)c(Br)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)N(Cc1ccc(OC)cc1)c1cc(Br)c(F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
A stirred solution of methyl (3,5-dibromo-4-fluorophenyl)carbamate (0.82 g, 2.508 mmol) in DMF (20 mL) was treated with sodium bis(trimethylsilyl)amide (3.01 mL, 3.01 mmol), stirred at room temperature for 30 minutes, then 1-(chloromethyl)-4-methoxybenzene (0.410 mL, 3.01 mmol) was added, stirred at 70° C. for two hours. The reaction mixture was partitioned between NH4Cl solution and EtOAc. The organic layer was washed with NaHCO3 solution (2×), then brine, then dried over MgSO4, filtered and evaporated to dryness to give 1.40 g colorless film, which was purified by column chromatography on silica (120 g silica, gradient from 100% hexanes to 20% EtOAc in hexanes) to give methyl (3,5-dibromo-4-fluorophenyl)(4-methoxybenzyl)carbamate (1.01 g)
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:7]2[CH:20]=[C:19]([OH:21])[C:10]3[C:11]4[CH2:18][CH2:17][S:16][C:12]=4[C:13](=O)[O:14][C:9]=3[CH:8]=2)[CH3:6])[CH2:3][CH2:2]1.[CH2:22]([Mg]Br)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH:1]1([CH2:4][CH:5]([C:7]2[CH:20]=[C:19]([OH:21])[C:10]3[C:11]4[CH2:18][CH2:17][S:16][C:12]=4[C:13]([CH2:3][CH2:2][CH2:1][CH2:4][CH2:5][CH3:6])([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[O:14][C:9]=3[CH:8]=2)[CH3:6])[CH2:3][CH2:2]1
Reactant: CC(CC1CC1)c1cc(O)c2c3c(c(=O)oc2c1)SCC3
Reactant: CCCCCC[Mg]Br
Product: CCCCCCC1(CCCCCC)Oc2cc(C(C)CC3CC3)cc(O)c2C2=C1SCC2

Procedure:
By reacting 7-(3-cyclopropyl-2-propyl)-1,2-dihydro9-hydroxy-4-oxo-4H-thieno[2,3-c][1]benzopyran with n-hexyl magnesium bromide, using the procedure described above in Example 8, there is obtained 7-(3-cyclopropyl-2-propyl)-4,4-di(1-hexyl)-1,2-dihydro-9-hydroxy-4H-thieno[2,3-c][1]benzopyran. The benzopyran is then reacted with morpholinoacetic acid and dicyclohexylcarbodiimide according to the method of Example 9 to yield the desired ester.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[C:30]([O:43][CH3:44])[CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].O.C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:11][CH:12]([CH3:15])[CH3:13])[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[C:30]([O:43][CH3:44])[CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:45]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(OC)c2)CCN3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(OC)c2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 183.1 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-methoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.3 g) and isobutylaldehyde (0.22 ml) were dissolved in 1,2-dichloroethane (15 ml), and to the solution, triacetoxy sodium borohydride (0.31 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The mixture was poured into water, neutralized with solution of sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then, dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-methoxyphenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 4) (0.3 g) as yellow amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:28])[CH:3]=1.Br[CH2:30][CH2:31][OH:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:30][CH2:31][OH:32])=[C:22]([F:27])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:28])[CH:3]=1
Reactant: OCCBr
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(OCCO)c(F)c1

Procedure:
In analogy to example 221, step 6, 5-[3-(4-chloro-2-methyl-phenyl)-3-(3-fluoro-4-hydroxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 324, step 1) was reacted with 2-bromoethanol in N,N-dimethylacetamide in the presence of cesium carbonate to give the title compound as a colourless foam, MS (ESI+): m/z=444.2 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([CH3:24])=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])=[CH:10][CH:9]=1)[NH2:6].[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:30]=1[C:31](Cl)=[O:32].CCN(C(C)C)C(C)C>ClCCl>[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([CH3:24])=[CH:18][C:19]=2[C:20]([F:21])([F:22])[F:23])=[CH:12][CH:13]=1)[NH:6][C:31]([C:30]1[C:29]([Cl:28])=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:38])=[O:32]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 0.08 h
Yield: 94.9 %

Procedure:
To a suspension of 4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester hydrochloride salt (150 mg, 0.37 mmol) and 2,6-dichlorobenzoyl chloride (85 mg, 0.4 mmol) in dichloromethane (6 mL) was added DIEA (257 μL, 1.48 mmol) at room temperature. After 5 min, a clear solution was obtained which was stirred for 48 h. Then, the mixture was concentrated and the residue was dissolved in ethyl acetate (50 mL). The ethyl acetate solution was washed with 0.5 N HCl (50 mL), saturated NaHCO3 solution (50 mL) and brine solution (50 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave crude product, which was purified by silica gel chromatography on a Biotage (40 m) column to give 190 mg (95% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C25H21Cl2F3N2O4 (M+Na) 563.0724, found 563.0726.