Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[N:17]=[CH:16][C:15]3[N:18]=[CH:19][N:20]([C:21]4[S:25][C:24]([C:26]([O:28]C)=O)=[C:23]([O:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[C:38]([F:41])([F:40])[F:39])[CH:22]=4)[C:14]=3[CH:13]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH3:42]>CO>[C:26]([C:24]1[S:25][C:21]([N:20]2[C:14]3[CH:13]=[C:12]([C:10]([NH:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:11])[N:17]=[CH:16][C:15]=3[N:18]=[CH:19]2)=[CH:22][C:23]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:39])[F:40])(=[O:28])[NH2:42]
Reactant: COC(=O)c1sc(-n2cnc3cnc(C(=O)NCCN4CCOCC4)cc32)cc1OCc1ccccc1C(F)(F)F
Reactant: N
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3cnc(C(=O)NCCN4CCOCC4)cc32)cc1OCc1ccccc1C(F)(F)F
Temperature: 125 °C
Reaction time: 4 h

Procedure:
A mixture of 150 mg of methyl 5-{6-[(2-morpholin-4-ylethyl)carbamoyl]-1H-imidazo[4,5-c]pyridin-1-yl}-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (compound B9) and 20 ml of a saturated solution of ammonia in methanol was stirred in a microwave vial at 125° C. for 4 h in the microwave cavity. The reaction mixture was concentrated to dryness, the resulting residue was dissolved in 5 ml of methanol and purified by preparative HPLC (water/acetonitrile, elution gradient 9/1 to 1/9 (v/v)). After lyophilization the title compound was obtained.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[C:10](Cl)=[N:11][CH:12]=[CH:13][C:8]=2[N:7]([CH3:15])[C:6]1=[O:16])[C:2]#[C:3][CH3:4].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(OCC)(=O)C.O>CN1CCCC1=O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:10]2[C:9]3[N:5]([CH2:1][C:2]#[C:3][CH3:4])[C:6](=[O:16])[N:7]([CH3:15])[C:8]=3[CH:13]=[CH:12][N:11]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC#CCn1c(=O)n(C)c2ccnc(Cl)c21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CC#CCn1c(=O)n(C)c2ccnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 180 °C
Yield: 31.6 %

Procedure:
A solution of 3-(2-butynyl)-4-chloro-1-methyl-1,3-dihydroimidazo[4.5-c]pyridin-2-one (compound 82d) (0.865 g) and piperazine-1-carboxylic acid t-butyl ester (4.57 g) in 1-methyl-2-pyrrolidone (2 mL) was heated at 180° C. for two hours under a nitrogen atmosphere. Piperazine-1-carboxylic acid t-butyl ester (5.00 g) was then added again, and this was heated at 180° C. for five hours. Ethyl acetate (400 mL) and water (200 mL) were added, and the organic layer was washed twice with 200 mL of water and then once with 200 mL of saturated aqueous sodium chloride solution, and then was dried over anhydrous magnesium sulfate. The organic layer was filtered and concentrated under reduced pressure, and the residue was purified by silica gel chromatography. The ethyl acetate:hexane 3:2 fraction gave the title compound (0.447 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:27][CH2:28][CH2:29][N:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:27][CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][NH:32][C:31]4=[O:35])=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCCN1CCNC1=O
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Product: Cn1c(=O)c(C(=O)NCCN2CCNC2=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 97.5 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (10 mg, 0.028 mmol) described in example 92 and 1-(2-aminoethyl)-2-imidazolidinone (47 mg, 0.364 mmol), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-N-[2-(2-oxo-1-imidazolidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxamide (12 mg, 98% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.33 (br s, 1 H), 8.54 (s, 1 H), 7.37 (s, 1 H), 7.16-7.13 (m, 2 H), 7.03-6.99 (m, 2 H), 4.38 (s, 1 H), 4.12 (s, 2 H), 3.62 (m, 2 H), 3.56-3.53 (m, 5 H), 3.45-3.39 (m, 4 H); HRMS m/z calcd for C22H23N5O4F: 440.1734 Found: 440.1732.
Reaction SMILES: [OH:1][CH:2]([CH3:22])[CH2:3][CH:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH3:21]>[Pd].O>[OH:1][CH:2]([CH3:22])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH3:21]
Reactant: CC(O)CC=Cc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Agent: [Pd]
Solvent: O
Product: CC(O)CCCc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1

Procedure:
Obtained from the title compound of Example 15 by a procedure similar to that described in Example 2, but using 10% palladium on charcoal as catalyst, as a foam. Rf 0.16 (SS 7). Found: C,75.18; H,8.91; N,9.07. C19H28N2O; 0.17 H2O requires C,75.19; H,9.41; N,9.22%.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([O:10][CH3:11])=[O:9].COCC(OC(C)C)=O>CC(OC)(C)C>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)[C@@H]1CCCC[C@H]1N
Agent: COCC(=O)OC(C)C
Solvent: COC(C)(C)C
Product: COC(=O)[C@H]1CCCC[C@@H]1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
50 g (0.32 mol) of methyl trans-2-aminocyclohexanecarboxylate were dissolved in 200 ml of MTBE and, after addition of 0.16 mol of isopropyl methoxyacetate and 0.5 g of Novozym 435 (Novo Nordisk), shaken at room temperature for 8 h. The enzyme was filtered off and then the solvent was removed and the residue was distilled under reduced pressure. 23.5 g of methyl (1S,2S)-2-aminocyclohexanecarboxylate and 35.2 g of methyl (1R,2R)-2-(2-methoxyacetylamino) cyclohexanecarboxylate were obtained, each with an ee of 99.8%. The ee of the amine was determined after N-acylation with acetic anhydride by gas chromatography on a B-PH GC column (supplied by Astec, N.J., USA), while the N-2-methoxyacetamide was put on this column without derivatization.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:33]([OH:35])[CH3:34])[CH:30]=[CH:31][CH:32]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([OH:35])[CH3:34])[CH:28]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(O)c1cccc(N)c1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(O)c1cccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c1
Temperature: 150 °C
Yield: 42.2 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 μmol), 1-(3-aminophenyl)ethanol (72.2 mg, 526 μmol), xantphos (60.9 mg, 105 μmol), Pd2(dba)3 (32.1 mg, 35.1 μmol) and cesium carbonate (229 mg, 702 μmol) in dioxane (2 mL) was heated in a microwave at 150° C. for 20 min. The mixture was cooled then filtered through a pad of celite. The filtrate was concentrated in vacuo then purified by chromatography (silica, 40-70% ethyl acetate in hexanes) to give N-tert-butyl-2-(3-(1-hydroxyethyl)phenylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (143 mg, 148 μmol, 42%) as a yellow solid. (EI/CI) m/z: 519.3 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][C:10]([NH:13][C:14](=[O:19])C(F)(F)F)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(O)=O.ClC1C=C(N2CC(C)C(NC=O)=N2)C=CC=1Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][C:10]([NH:13][CH:14]=[O:19])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1=NN(c2cccc(Cl)c2)CC1)C(F)(F)F
Agent: CC1CN(c2ccc(Cl)c(Cl)c2)N=C1NC=O
Solvent: O=CO
Solvent: ClCCl
Product: O=CNC1=NN(c2cccc(Cl)c2)CC1
Reaction time: 0.5 h

Procedure:
A mixture of 2.0 g. of 3-amino-1-(m-chlorophenyl)-2-pyrazoline (prepared in Example 10) and 10 ml. of a mixture of formic acid and acetic anhydride (Example 15) is allowed to stand at room temperature for 30 minutes. Then the solvent is evaporated in vacuo to give an oil. The oil is dissolved in dichloromethane and is columnized and recrystallized as described in Example 5 to give 1.32 g. of the desired product as pale yellow needles, m.p. 143°-145° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([F:19])[CH:10]=2)=[N:4][C:5](Br)=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH2:37][CH2:36][C:31]3([O:35][CH2:34][CH2:33][O:32]3)[CH2:30][CH:29]=2)O1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[NH2:1][C:2]1[C:3]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([F:19])[CH:10]=2)=[N:4][C:5]([C:28]2[CH2:37][CH2:36][C:31]3([O:35][CH2:34][CH2:33][O:32]3)[CH2:30][CH:29]=2)=[CH:6][N:7]=1
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Reactant: COC(=O)c1ccc(-c2nc(Br)cnc2N)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc(C3=CCC4(CC3)OCCO4)cnc2N)cc1F
Temperature: 100 °C
Yield: 75 %

Procedure:
To a solution of methyl 4-(3-amino-6-bromopyrazin-2-yl)-2-fluorobenzoate (10 g, 30.7 mmol) in DME (77 mL) was added 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (9.79 g, 36.8 mmol), PdCl2(dppf).CH2Cl2 adduct (1.252 g, 1.533 mmol), H2O (25.6 mL) and then last sodium carbonate (9.75 g, 92 mmol). The reaction was heat at 100° C. in oil bath for 2 h. Cooled down. The reaction mixture was extracted by EtOAc 3 times, the organic was washed with water and brine, dried and concentrated. The crude material was recrystallized in DCM and heptane (1:1) to give product methyl 4-(3-amino-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrazin-2-yl)-2-fluorobenzoate in 75% yield. LCMS (m/z): 382.2 (MH+), 0.82 min.
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH+:14]=[CH:13]1)([OH:10])=O.[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[F:29])[NH2:25]>>[N:12]1([CH2:11][C:8]([NH:25][C:24]2[CH:26]=[CH:27][C:28]([F:29])=[C:22]([F:21])[CH:23]=2)=[O:10])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: Nc1ccc(F)c(F)c1
Reactant: O=C(O)Cn1c[nH+]c2ccccc21
Agent: O=C([O-])C(F)(F)F
Product: O=C(Cn1cnc2ccccc21)Nc1ccc(F)c(F)c1

Procedure:
The title compound was synthesised according to the procedure described in Example 92, from 3-carboxymethyl-3H-benzoimidazol-1-ium trifluoro-acetate and 3,4-difluoroaniline Yield 9.1 mg (26%). Calculated for C15H11F2N3O m/z: 287.2, found 288.3 [M+H]+. 1H NMR (400 MD, MeOD) δ ppm 5.2 (s, 2H), 7.3 (m, 4 H), 7.5 (d, J=7.1 Hz, 1H), 7.7 (m, 2H),8.2(s, 1H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[S:13][N:12]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[N:10]=1>C(O)=O>[CH:1]([NH:8][C:9]1[S:13][N:12]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[N:10]=1)=[O:3]
Reactant: COC(=O)c1nsc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: COC(=O)c1nsc(NC=O)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.8 %

Procedure:
To a mixture of formic acid (33 g) and acetic anhydride (22 g) was added methyl 5-amino-1,2,4-thiadiazole-3-carboxylate (6.2 g), and then the mixture was stirred for 2 days at ambient temperature. The reaction mixture was concentrated under reduced pressure and the residue was triturated with a mixture of diethyl ether and n-hexane to give the title compound (7.2 g), mp. 210° to 215° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](OCCCCCCC)=[C:6]([CH:38]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2OC2C=CC(C(F)(F)F)=CC=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[CH3:47][O:48][C:49]1[CH:54]=[CH:53][C:52](B(O)O)=[CH:51][CH:50]=1>>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:10]([NH:9][C:7]([C:6]2[CH:38]=[C:2]([C:52]3[CH:53]=[CH:54][C:49]([O:48][CH3:47])=[CH:50][CH:51]=3)[CH:3]=[CH:4][CH:5]=2)=[O:8])[C:11]([OH:13])=[O:12])=[CH:20][CH:19]=1
Reactant: CCCCCCCOc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cccc(C(=O)N[C@@H](Cc3ccc(-c4ccccc4)cc3)C(=O)O)c2)cc1
Yield: 81.9 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(3-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-methoxy-phenyl boronic acid (0.106 mg, 0.69 mmol) by following general procedure D yielding the title compound (85 mg, 80%) as a white solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:10]([NH:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=1)=[O:11].CO.[OH-].[Li+]>O1CCCC1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=1)=[O:11]
Reactant: COC(=O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Temperature: 25 °C

Procedure:
Methyl 4-(isoindoline-2-carboxamido)benzoate (1.65 g, 5.57 mmol) was dissolved in tetrahydrofuran (30 ml) and methanol (15.00 ml) followed by the addition of lithium hydroxide (11.14 ml, 22.27 mmol) and the mixture was allowed to stir at ambient temperature over the weekend. The organic solvent was removed under vacuum, the aqueous layer was adjusted to pH ˜3 with 2N aqueous HCl, and the resulting solid was filtered with water washes to provide the title compound after drying.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH:7]1([O:10][C:11]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][C:12]=2[CH:13]=O)[CH2:9][CH2:8]1.P(=O)(OC=[N+]=[N-])OC(=O)C>CO>[CH:7]1([O:10][C:11]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][C:12]=2[C:13]#[CH:1])[CH2:9][CH2:8]1
Reactant: O=Cc1cc(OC(F)(F)F)ccc1OC1CC1
Reactant: O=C([O-])[O-]
Agent: CC(=O)O[PH](=O)OC=[N+]=[N-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(OC(F)(F)F)ccc1OC1CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.4 %

Procedure:
Potassium carbonate (6.15 g, 44 mmol) was added to a stirred solution of 2-cyclopropyloxy-5-trifluoromethoxybenzaldehyde (Description 3; 4.4 g, 17.8 mmol), and acetyl diazomethyl phosphonate (6.15 g, 32 mmol) in dry methanol (50 ml) at +5° C. The reaction mixture was stirred at +5° C. for 30 minutes and at room temperature for 3.5 hours. The mixture was quenched with saturated aqueous ammonium chloride and extracted into hexane (3×30 ml). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-45%) to give the title compound (4.2 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]1[CH2:10][S:11][C:12]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:13]=2[CH2:14][N:15]=1>C(O)C>[Cl:20][C:16]1[C:13]2[CH2:14][NH:15][C:9](=[N:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:10][S:11][C:12]=2[CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: ClC1=NCc2c(Cl)cccc2SC1
Solvent: CCO
Product: Clc1cccc2c1CNC(=Nc1ccccc1)CS2
Temperature: 25 °C

Procedure:
A solution of aniline (4.8 ml) in dry ethanol (10 ml) was added dropwise at room temperature to a stirred solution of 3,6-dichloro-2,5-dihydro-1,4-benzothiazepine (2.5 g) in dry ethanol (65 ml). The reaction mixture was heated under reflux for 91/2 hours, cooled to room temperature, filtered and the solvent was removed from the filtrate by evaporation at reduced pressure. The oily residue was separated into fractions by chromatography on a silica gel support using chloroform/ethanol (50:1) as eluent. Purification of those fractions containing the product by flash chromatography using ethyl acetate/hexane (2:3) as eluent gave 6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from ethyl acetate/hexane. Yield 0.27 g (m.p. 150°-152° C.).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[C:10]([C:19]([O:21]CC)=O)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].Cl>C(Cl)(Cl)Cl>[CH2:32]([N:31]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:19]([C:10]1[C:9](=[O:24])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]2[C:12]([C:11]=1[OH:18])=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:21])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCOC(=O)c1c(O)c2ccccc2n(Cc2ccccc2)c1=O
Reactant: CCCCCCNCCCCCC
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCN(CCCCCC)C(=O)c1c(O)c2ccccc2n(Cc2ccccc2)c1=O
Temperature: 130 °C

Procedure:
A mixture of 0.30 g of ethyl 1-benzyl-4-hydroxy-1,2-dihydro-2-oxoquinoline-3-carboxylate and 2 ml of dihexylamine was stirred under heating at 130° C. for 2 hours. After cooling to room temperature, to the reaction solution were added chloroform and 1 N hydrochloric acid, and the separated organic phase was washed with 1 N hydrochloric acid and water. The organic phase was dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography ((silica gel; Merk silica gel 230-4000 mesh (Merk Co.), developing solvent; chloroform) and allowed to stand for crystallization to give 0.36 g of N,N-dihexyl-1-benzyl-4-hydroxy-1,2-dihydro-2-oxoquinoline-3-carboxamide.
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:19]([NH:29][S@](C(C)(C)C)=O)[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)=[N:4][CH:5]=[C:6]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH:7]=1.[ClH:36].O1CCOCC1>CO>[ClH:36].[NH2:29][C@H:19]([C:3]1[N:4]=[CH:5][C:6]([N:8]2[C:9](=[O:18])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])=[CH:7][C:2]=1[Br:1])[CH2:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=1
Reactant: CC(C)(C)[S@](=O)N[C@@H](Cc1cc(F)cc(F)c1)c1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@@H](Cc1cc(F)cc(F)c1)c1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(S)—N—((S)-1-(3-bromo-5-(1,3-dioxoisoindolin-2-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (30D, 2.6 G, 4.6 mmol) was dissolved in 40 mL of methanol and cooled to 0° C. To it was added 4N HCl/1,4-dioxane (4.6 ml). The reaction mixture was allowed to stir at room temperature for 10 minutes and concentrated to afford product (S)-2-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-bromopyridin-3-yl)isoindoline-1,3-dione hydrochloride. To the mixture of the above HCl salt (˜4.6 mmol) and di-tert-butyl dicarbonate (1 g, 4.6 mmol) in 50 mL of CH2Cl2 was added triethylamine (1.28 mL, 9.2 mmol) at 0° C. The reaction mixture was stirred for overnight and concentrated in vacuo. The residue was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Then it was purified on silica gel chromatography eluting with EtOAc/hexanes to yield the title compound. MS (m/z) 559.71 [M+H]+.
Reaction SMILES: [C:1](=O)(OC(Cl)(Cl)Cl)[O:2]C(Cl)(Cl)Cl.[NH2:13][C:14]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].[OH-].[Na+].C1(C)C=CC=CC=1>O>[F:23][C:21]1[CH:20]=[CH:19][C:15]2[C:16](=[O:18])[O:17][C:1](=[O:2])[NH:13][C:14]=2[CH:22]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1[nH]c2cc(F)ccc2c(=O)o1
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
Bis(trichloromethyl) carbonate (3.73 g, 12.57 mmol) was added to a solution of 2-amino-4-fluorobenzoic acid (1.3 g, 8.38 mmol) in sodium hydroxide (2N in water) (8.80 mL, 17.60 mmol) and water (9 mL) at room temperature. The resulting suspension was stirred for 15 minutes then toluene (9.00 mL) was added. The mixture was stirred at room temperature for 18 hours. The resulting precipitate was collected by filtration, washed with water, followed by 20% acetronitrile in Et2O (10 mL) and dried under vacuum at 40° C. to afford 7-fluoro-1H-3,1-benzoxazine-2,4-dione (0.852 g, 56.1%) as a off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]([N:11]([CH2:18][CH3:19])[CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:9][C:8]([Cl:20])=[CH:7][C:3]=1[C:4]([OH:6])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:63][CH2:64][C:65]1[C:66](=[O:73])[NH:67][C:68]([CH3:72])=[CH:69][C:70]=1[CH3:71]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:10]([N:11]([CH2:18][CH3:19])[CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:9][C:8]([Cl:20])=[CH:7][C:3]=1[C:4]([NH:63][CH2:64][C:65]1[C:66](=[O:73])[NH:67][C:68]([CH3:72])=[CH:69][C:70]=1[CH3:71])=[O:6]
Reactant: CCN(c1cc(Cl)cc(C(=O)O)c1Br)C1CCOCC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(c1cc(Cl)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1Br)C1CCOCC1
Yield: 69.1 %

Procedure:
To a solution of 2-bromo-5-chloro-3-[ethyl(oxan-4-yl)amino]benzoic acid (109 mg, 0.3 mmol) in DMF (3 ml) at room temperature under nitrogen was added PyBOP (187 mg, 0.36 mmol) followed by N-ethyl-N-(propan-2-yl)propan-2-amine (78 μl, 0.45 mmol) and 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 56 mg, 0.33 mmol). After stirring for 1 hour at room EtOAc (30 ml) was added to the reaction mixture and this was then washed with deionized water (2×10 ml) followed by saturated NaHCO3(aq) (2×10 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified twice by FCC (5 g silica, Isolute cartridge, gradient of eluents; 100% DCM to 98:2 DCM:MeOH). The sample was dried in a vacuum oven for 18 hours to give 103 mg (65%) of the title compound as a pale yellow solid. LC-MS 94%, m/z=496.0/498.0/500.0, 1H NMR (500 MHz, Chloroform-d) δ 11.00 (s, 1H), 7.20-7.10 (m, 1H), 7.10-7.05 (m, 2H), 5.94 (s, 1H), 4.54 (d, J=5.9 Hz, 2H), 3.96 (d, J=11.4 Hz, 2H), 3.42-3.26 (m, 2H), 3.28-3.12 (m, 1H), 3.09 (q, J=7.0 Hz, 2H), 2.39 (s, 3H), 2.23 (s, 3H), 1.72 (td, J=8.5, 3.8 Hz, 4H), 0.90 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6]O)[CH3:2].S(Cl)([Cl:12])=O>C(Cl)Cl>[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][Cl:12])[CH3:2]
Reactant: CCN(CC)CCCO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)CCCCl
Yield: 36.9 %

Procedure:
A solution of 3-diethylamino-1-propanol (Aldrich) (10 g, 76 mmol) in DCM was stirred at 0° C. A solution of thionyl chloride (DCM 30 mL) was then added drop-wise such that the reaction temperature remained at 0° C. Once addition is complete, the reaction was refluxed for one hour. The reaction was allowed to cool and the excess DCM and thionyl chloride were removed under vacuum. The residue was basified (pH8–9) using 2N NaOH and the aqueous mixture extracted with DCM (3×100 mL). The organic extracts were combined, dried (MgSO4) and evaporated to give a brown oil. The oil was distilled (160°–165° C.) to give the product as a clear oil (4.2 g 36.9%).