Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[Cl:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[S:10][C:11]=1[Cl:12]
Reactant: N[C@@H](Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1ncc(Br)c1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Br)c1-c1cc(C(=O)N[C@@H](Cc2ccc(F)cc2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid (340 mg, 1.00 mmol) [prepared according to the procedure of Example 167], 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (374 mg, 1.12 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (626 mg, 1.34 mmol) in chloroform (10 mL). DIEA (980 μL, 5.61 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (229 mg, 0.35 mmol, 31%): LC-MS (ES) m/z=603 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:38]=[CH:37][C:19]3[N:20]([CH3:36])[C:21]([C:23]4[N:31]([CH2:32][CH:33]5[CH2:35][CH2:34]5)[C:26]5=[N:27][CH:28]=[CH:29][CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.CO.C(O)C>[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:38]=[CH:37][C:19]3[N:20]([CH3:36])[C:21]([C:23]4[N:31]([CH2:32][CH:33]5[CH2:34][CH2:35]5)[C:26]5=[N:27][CH:28]=[CH:29][CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1
Reactant: Cn1c(-c2cc3cccnc3n2CC2CC2)nc2cc(C(=O)N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)ccc21
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Cn1c(-c2cc3cccnc3n2CC2CC2)nc2cc(C(=O)N3CCC[C@@H](N)C3)ccc21
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of (R)-tert-butyl(1-(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl)piperidin-3-yl)carbamate (3.402 g, 6.44 mmol) in dichloromethane (DCM) (40 ml) was added TFA (9 ml, 118 mmol) dropwise. The reaction mixture was stirred for 3 hours. The reaction mixture was concentrated under vacuum to afford a yellow oil. The oil was dissolved in methanol and loaded onto a 70 g SCX cartridge. The column was washed with MeOH (2CV) and the product collected as the free base with 2M ammonia in methanol (3CV). The product was concentrated in vacuo and dried under vacuum to afford a yellow solid. This was dissolved in hot ethanol and concentrated in vacuo. It was again dissolved in hot ethanol, concentrated in vacuo and dried under vacuum to yield the title compound as a yellow solid (2.61 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH:11]([C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])[C:12]([OH:14])=[O:13].[CH3:23]O>>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH:11]([C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])[C:12]([O:14][CH3:23])=[O:13]
Reactant: O=C(O)C(Cc1ccc(Cl)cc1Cl)c1c(Cl)cccc1Cl
Reactant: CO
Agent: Cl
Product: COC(=O)C(Cc1ccc(Cl)cc1Cl)c1c(Cl)cccc1Cl
Temperature: 0 °C

Procedure:
Gaseous hydrogen chloride is introduced through 200 parts of methanol till saturation, while cooling at 0° C. Then there are added 17 parts of 2,4-dichloro-α-(2,6-dichlorophenyl)benzenepropanoic acid and the whole is stirred and refluxed for 72 hours. The reaction mixture is poured onto water and the product is extracted twice with 1,1'-oxybisethane. The combined extracts are washed successively once with a diluted sodium bicarbonate solution and twice with water, dried, filtered and evaporated. The residue is crystallized from methanol, yielding 13.11 parts of methyl 2,4-dichloro-α-(2,6-dichlorophenyl)benzenepropanoate; mp. 115.1° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:13]([O:15]CCO)=[O:14])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[OH-].[K+].O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[NH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(OCCO)c1cc(-c2ccc(Cl)cc2)c[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1

Procedure:
Crude 2-hydroxyethyl 4-(4-chlorophenyl)pyrrole-2-carboxylate (3 g.) was heated on a steam bath with potassium hydroxide (2 g.) in 25 ml. of water and 25 ml. of ethanol for 30 minutes. The balance of the ethanol was evaporated in vacuo, chloroform (25 ml.) was added and 4-(4-chlorophenyl)pyrrole-2-carboxylic acid (723 mg., m.p. 219°-222° C., ir(KBr): 3390, 3077 and 1695 cm.-1, m/e 221/223) recovered by filtration.
Reaction SMILES: C([NH:4][C:5]([CH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[C:20]([NH2:27])=[C:19]([Cl:28])[CH:18]=1)(C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=O)C.Cl>CC(O)=O.O>[ClH:28].[NH2:4][CH:5]([CH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[C:20]([NH2:27])=[C:19]([Cl:28])[CH:18]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(Cc1cc(Cl)c(N)c(C(F)(F)F)c1)(NC(C)=O)C(=O)OCC
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(Cl)cc(CC(N)C(=O)O)cc1C(F)(F)F
Temperature: 140 °C
Reaction time: 0.25 h

Procedure:
To a solution of 40.0 g (94.16 mmol) diethyl 2-acetylamino-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-malonate (Intermediate product 56) in 110 mL AcOH and 150 mL water was added 50 mL conc. aqueous HCl and the reaction mixture was heated to 140° C. for 4 hours. The precipitate formed was filtered off and discarded. The filtrate was evaporated i. vac., combined with 100 mL EtOH and stirred for 15 minutes at RT. The precipitate formed was filtered off, washed with EtOH and dried i. vac. The crude product was used in the next reaction step without any further purification.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([OH:9])[C:6]([NH:10][C:11](=[O:25])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][N:4]=1)=O.CC([O-])=O.[Na+].Cl.[OH:32][NH2:33]>O>[OH:9][C:7]1[C:6]([NH:10][C:11](=[O:25])[CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:5][N:4]=[C:3]([CH:1]=[N:33][OH:32])[N:8]=1
Reactant: NO
Reactant: O=Cc1ncc(NC(=O)C(c2ccccc2)c2ccccc2)c(O)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(Nc1cnc(C=NO)nc1O)C(c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of compound 3-h (1 g, 3.0 mmol), NaOAc (0.5 g, 6.0 mmol) and hydroxyamine hydrochloride (0.31 g, 4.5 mmol) in H2O (25 mL) was stirred at 100° C. for 2 h. The precipitated was isolated by filtration to afford the product, 3-2-a, as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 12.31 (s, 1H), 9.89 (s, 1H), 8.85 (s, 1H), 7.74 (s, 1H), 7.33-7.23 (m, 1H), 5.71 (s, 1H). LC-MS: (M+H)+ 349.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16](C)([CH3:19])[CH2:17][OH:18]>>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:15][CH:16]([CH3:19])[CH2:17][OH:18])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(N)CO
Product: CC(CO)Nc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
Using the method of Example 1, 4-chloro-3-nitroquinoline was reacted with 2-amino-2-methyl-1-propanol to afford 2-[(3-nitro-4-quinolinyl)amino]-1-propanol, m.p. 207°-211° C. Analysis: Calculated for C12H13N3O3 : %C, 58.3; %H, 5.3; %N,17; Found: %C, 58.6; %H, 5.3; %N, 17.2.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[N:3]1.[CH2:12]([Si:14]([CH2:24][CH3:25])([CH2:22][CH3:23])[O:15][C:16](/[C:18](/[CH3:21])=[CH:19]/[CH3:20])=[CH2:17])[CH3:13]>>[CH3:21][C:18]1[CH:19]([CH3:20])[O:8][CH:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=2[N+:9]([O-:11])=[O:10])[CH2:17][C:16]=1[O:15][Si:14]([CH2:22][CH3:23])([CH2:12][CH3:13])[CH2:24][CH3:25]
Reactant: Cn1ncc([N+](=O)[O-])c1C=O
Reactant: C=C(O[Si](CC)(CC)CC)/C(C)=C/C
Product: CC[Si](CC)(CC)OC1=C(C)C(C)OC(c2c([N+](=O)[O-])cnn2C)C1
Temperature: 65 °C

Procedure:
To a solution of (E)-3-methylpent-3-en-2-one (2.69 mL, 24.1 mmol) in DCM (200 mL) cooled to 0° C. was added Et3N (10.5 mL, 79.5 mmol) followed by TESOTf (6.0 mL, 26.5 mmol). The mixture was warmed to room temperature and stirred for 18 hr. Saturated aqueous NaHCO3 solution (100 mL) and DCM (200 mL) were added. The aqueous layer was extracted with DCM (3×200 mL) and the combined organic layers were washed with brine (100 mL), separated, dried over MgSO4 and concentrated under reduced pressure to give (E)-triethyl((3-methylpenta-1,3-dien-2-yl)oxy)silane. To a solution of 2-methyl-4-nitro-pyrazole-3-carbaldehyde (1.0 g, 8 mmol, intermediate 3) in CDCl3 (28 mL) was added (E)-triethyl((3-methylpenta-1,3-dien-2-yl)oxy)silane (1.6 g, 7.55 mmol) followed by EuFOD (220 mg, 0.50 mmol). The reaction mixture was heated at 65° C. behind a blast shield for 18 hr in a pressure tube. The mixture was cooled to room temperature and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 5-(5,6-dimethyl-4-((triethylsilyl)oxy)-3,6-dihydro-2H-pyran-2-yl)-1-methyl-4-nitro-1H-pyrazole as a colourless oil (2.92 g, quantitative). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 5.64 (dd, J=10.9, 3.6 Hz, 1H), 4.33-4.28 (m, 1H), 4.25-3.94 (m, 3H), 2.50-2.41 (m, 1H), 2.31 (m, 1H), 1.61 (s, 3H), 1.31 (d, J=6.4 Hz, 3H), 1.05-0.97 (m, 6H), 0.73-0.61 (m, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:2]=12.OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[CH2:24](O)[CH3:25]>>[N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([C:10]([O:12][CH2:24][CH3:25])=[O:11])=[CH:9][C:2]=12
Reactant: CCO
Reactant: O=C(O)c1cc2nccnc2s1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cc2nccnc2s1
Temperature: 80 °C
Yield: 80 %

Procedure:
Thieno[3,2-b]pyrazine-6-carboxylic acid (2 g, 11.10 mmol) was dissolved in ethanol (30 mL). Concentrate H2SO4 (5.92 mL, 111 mmol) was slowly added. The resulting mixture was heated at 80° C. overnight. The reaction mixture was cooled en neutralized with saturated Na2CO3 solution. The resulting precipitate was collected to give ethyl thieno[3,2-b]pyrazine-6-carboxylate 86 (1.85 g, 80%) as a brown solid. (m/z)=209 (M+H)+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH:14]1[CH2:19][CH2:18][N:17](C(=O)C2C=CC=CC=2)[CH2:16][CH2:15]1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[CH:8][CH:7]=1>C(O)C>[CH3:2][N:3]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([S:12][CH3:13])=[CH:10][CH:11]=1
Reactant: CSc1ccc(CCN(C)C2CCN(C(=O)c3ccccc3)CC2)cc1
Agent: Cl
Solvent: CCO
Product: CSc1ccc(CCN(C)C2CCNCC2)cc1
Yield: 88.9 %

Procedure:
60 ml of 5N hydrochloric acid was added to a solution of 5.8 g of 4-{N-methyl-N-[2-(4-methylthiophenyl)ethyl]amino}-1-benzoylpiperidine in 20 ml of ethanol. The mixture was refluxed by heating, for 12 hours. To the reaction mixture was added 100 ml of ethanol, followed by concentration under reduced pressure. To the residue was added ice water. The mixture was made basic with a 25% aqueous sodium hydroxide solution and then extracted with chloroform. The extract was water-washed, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3.7 g of 4-{N-methyl-N-[2-(4-methylthiophenyl)ethyl]amino}piperidine as a light yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:3]=12.[Br:14]N1C(=O)CCC1=O.O>C(O)(=O)C>[Br:14][C:7]1[C:2]([Cl:1])=[C:3]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][C:4]2=[N:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1c[nH]c2nccc(Cl)c12
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1c[nH]c2ncc(Br)c(Cl)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.2 %

Procedure:
Into a suspension of 4-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine (50.0 g) in acetic acid (300 mL) were added N-bromosuccinimide (NBS, 70.9 g, 1.60 equiv) in small portions at 25° C. The reaction mixture was stirred at 25° C. for 18 h. Water (3.0 mL) was added slowly over 30 min to get a light yellow slurry. The resulting solid was collected by filtration and washed with a 2:2:1 (v/v/v) mixture of saturated sodium sulfite solution, water, and methanol, followed by water and a 1:1 (v/v) mixture of methanol and water. The cake was dried in a vacuum at 50° C. oven overnight to give the 44.9 g (65% yield) of 5-bromo-4-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine as an light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.7 (s, 1H), 8.93 (s, 1H), 8.66 (s, 1H). 13C NMR (75 MHz, DMSO-d6) δ 146.9, 146.4, 133.9, 133.2, 127.0, 116.7, 111.3. HRMS calcd. For C7H2BrC1N3O2 [M-H]−: 273.9024, found 273.9031.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12](N)=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[I-:16].[K+].N(OC(C)(C)C)=O>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[N:13][C:12]([I:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: [I-]
Agent: CC(C)(C)ON=O
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Clc1cc(Oc2ccc(I)nc2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
A mixture of 5-((2-chloropyridin-4-yl)oxy)pyridin-2-amine (1.00 g, 4.51 mmol) and potassium iodide (3.74 g, 22.5 mmol) in DCM (15 mL) was treated dropwise with t-butyl nitrite (4.65 g, 45.1 mmol) and the mixture was stirred overnight at RT. The mixture was diluted with EtOAc (75 mL) and washed with 10% Na2CO3 (50 mL), then water (50 mL) and finally brine (50 mL) and dried over sodium sulfate. The solvents were evaporated at reduced pressure to give a thick oily solution. EtOAc (100 mL) was added and the solution was washed with 0.1M sodium thiosulfate (75 mL), brine (50 mL) and dried over sodium sulfate. The solvents were evaporated at reduced pressure, and the residual oil was purified by silica gel chromatography to provide 2-chloro-4-((6-iodopyridin-3-yl)oxy)pyridine (695 mg, 46%). 1H NMR (400 MHz, DMSO-d6): δ 8.80 (d, J=3.0 Hz, 1H), 8.73 (d, J=5.8 Hz, 1H), 8.35 (d, J=8.6 Hz, 1H), 7.91 (dd, J=8.6, 3.1 Hz, 1H), 7.61 (d, J=2.3 Hz, 1H), 7.48 (dd, J=5.8, 2.3 Hz, 1H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.N1C=CC=CC=1.[CH3:19][N:20]1[C:25](=[O:26])[CH:24]=[C:23]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:22]=[C:21]1[CH2:33][C:34]([O-:36])=O.[Na+].[F:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:40]=1[CH2:41][CH:42]([CH3:48])[NH:43]2>CN(C)C=O.C(OCC)(=O)C.O>[F:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:40]=1[CH2:41][CH:42]([CH3:48])[N:43]2[C:34](=[O:36])[CH2:33][C:21]1[N:20]([CH3:19])[C:25](=[O:26])[CH:24]=[C:23]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[N:22]=1
Reactant: CC1Cc2c(F)cccc2N1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC1Cc2c(F)cccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)n1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.2 %

Procedure:
0.19 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 120 μl of pyridine are added to a solution of 0.22 g of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (prepared in step 2c of example 4c) in 3 ml of N,N-dimethylformamide. The resulting suspension is stirred at ambient temperature for 15 minutes and then 0.11 g of (+)-4-fluoro-2-methyl-2,3-dihydro-1H-indole [reference example 8c, step 6c] is rapidly added. The reaction mixture is stirred at ambient temperature for 64 hours and is then treated with a mixture of 20 ml of water and 2 ml of ethyl acetate, and then stirred at ambient temperature for 2 hours. The precipitate formed is filtered off, and then rinsed successively with 3 ml of water and 3×6 ml of diethyl ether. The solid obtained is dried with suction, then dried under reduced pressure at 40° C. 82 mg of (−)-2-{2-[4-fluoro-2-methyl-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are thus obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH2:8].[OH-].[Na+].[Cl:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>C(Cl)Cl>[Cl:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([NH:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:18]
Reactant: O=C(Cl)CCOCCCl
Reactant: NCc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCOCCCl)NCc1ccccn1
Yield: 65 %

Procedure:
A cooled solution of (2-pyridyl)methanamine (0.55 g, 5.1 mmol) in CH2Cl2 was stirred vigorously with 2% aqueous NaOH (12.2 mL, 6.1 mmol) while 3-(2-chloroethoxy)propanoyl chloride (6.1 mmol, prepared by refluxing 3-(2-chloroethoxy)propanoic acid with SOCl2) in CH2Cl2 was added dropwise. The same NaOH solution was then used to maintain pH at 9, and at costant pH the layers were separated. The organic phase was washed with 3 N HCl, with H2O, and then dried over Na2SO4 and evaporated under reduced pressure. The crude residue was chromatographed (CHCl3/AcOEt, 1:1, as eluent) to afford pure compound in 65% yield. 1H NMR (CDCl3): δ 2.38-2.41 (m, 2H), 2.60-2.63 (m, 2H), 3.54-3.60 (m, 2H), 3.66-3.69 (m, 2H), 4.45 (d, 2H, J=6.1 Hz), 6.12 (br t, 1H, D2O exchanged), 7.09-7.11 (m, 2H), 8.40-8.42 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[C:19]([C:23]1[CH:24]=[C:25]2[C:30](=O)[O:29][C:27](=[O:28])[C:26]2=[CH:32][CH:33]=1)([CH3:22])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[C:30](=[O:29])[C:25]3[C:26](=[CH:32][CH:33]=[C:23]([C:19]([CH3:21])([CH3:20])[CH3:22])[CH:24]=3)[C:27]2=[O:28])=[O:8])=[CH:17][CH:18]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)OC2=O
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Nc2ccccc2N2C(=O)c3ccc(C(C)(C)C)cc3C2=O)cc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 84.2 %

Procedure:
A slurry of N1-(4-methoxybenzoyl)-1,2-benzenediamine (100 mg, 0.413 mmol) and 4-tert-butylphthalic anhydride (84.3 mg, 0.413 mmol) in toluene (1.5 mL) was placed in a bath heated to 110° C. After 16 h, the mixture was concentrated in vacuo and the residue purified by flash chromatography (silica gel, hexanes/ethyl acetate) to afford 149 mg (85%) of the title compound. The material was further purified by recrystallization from hexanes/ethyl acetate.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]([O:17][CH3:18])=[CH:10][C:9]=2[N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)=[O:5])C.CO.[ClH:28]>>[ClH:28].[CH3:18][O:17][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH:10]=1)[O:7][C:6]([C:4]([OH:5])=[O:3])=[CH:15][C:14]2=[O:16]
Reactant: CCOC(=O)c1cc(=O)c2cc(OC)cc(N3CCN(C)CC3)c2o1
Agent: Cl
Solvent: CO
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)O)cc(=O)c2c1

Procedure:
Ethyl-6-methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylate (1.0 g. 2.89 mmol), as prepared in Reference Example 2d above, was suspended in 6 M HCl (60 ml) and methanol (10 mL) and warmed to reflux for 3.0 h. The reaction was allowed to cool. The solution was concentrated in vacuo and anhydrous toluene was added (×3) and the solution was again concentrated in vacuo. The residue was dried under vacuum (17 h) to yield 6-methoxy-8-(4-methyl-1-piperazinyl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride as a yellow powder (1.0 g, quantitative yield).
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=C1)=O.[CH3:13][C:14]([O:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[CH:28][C:29]([O:31][C:32]3[N:33]=[CH:34][C:35]([C:38]([OH:40])=O)=[N:36][CH:37]=3)=[CH:30][C:23]=2[CH2:22][CH2:21]1)=[O:19])([CH3:16])[CH3:15].CN>ClCCl>[CH3:1][NH:3][C:38]([C:35]1[N:36]=[CH:37][C:32]([O:31][C:29]2[CH:28]=[CH:27][C:24]3[CH2:25][CH2:26][N:20]([C:18]([O:17][C:14]([CH3:13])([CH3:16])[CH3:15])=[O:19])[CH2:21][CH2:22][C:23]=3[CH:30]=2)=[N:33][CH:34]=1)=[O:40]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Oc3cnc(C(=O)O)cn3)cc2CC1
Agent: CN
Solvent: ClCCl
Product: CNC(=O)c1cnc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.8 %

Procedure:
1,1′-Carbonyldiimidazole (16.6 g, 102 mmol) was added to a solution of 5-[(3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrazinecarboxylic acid (D49, Step 2) (37.5 g, 97 mmol) in dry dichloromethane (400 ml) and the resulting mixture was stirred at room temperature for 18 hours. Methylamine (2M solution in tetrahydrofuran) (100 ml) was added and the mixture stirred for 2 hours. The solvent was removed in vacuo and the residue was purified by column chromatography eluting with a mixture of ethyl acetate:chloroform (1:1) to afford the title compound (25.8 g); MS (ES+) m/e 399 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][N:12]3[C:16]([C:17]([F:20])([F:19])[F:18])=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:14]=[N:13]3)[CH:8]=2)[CH2:3]1.C1CCN2C(=NCCC2)CC1.[CH3:37][CH:38]([S:40](Cl)(=[O:42])=[O:41])[CH3:39].S(Cl)(Cl)(=O)=O>C(Cl)Cl>[CH3:37][CH:38]([S:40]([NH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][N:12]3[C:16]([C:17]([F:18])([F:19])[F:20])=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:14]=[N:13]3)[CH:8]=2)[CH2:3]1)(=[O:42])=[O:41])[CH3:39]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CCOC(=O)c1cnn(Cc2ccc3c(c2)C[C@@H](N)C3)c1C(F)(F)F
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O=S(=O)(Cl)Cl
Product: CCOC(=O)c1cnn(Cc2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-Ethyl 1-((2-amino-2,3-dihydro-1H-inden-5-yl)methyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.102 mmol, 36 mg) was suspended in DCM (2 mL) and DBU (0.306 mmol, 0.046 mL, 46.5 mg) added which caused all solids to go into solution. Propane-2-sulfonyl chloride (0.204 mmol, 0.023 mL, 29.1 mg) was added dropwise and the reaction stirred at room temperature for 1 h. An additional 1 eq of sulfonyl chloride was added and the mixture stirred for a further 3 h before leaving to stand overnight and after this time an additional 2 eq. sulfonyl chloride and 3 eq. DBU added. The mixture was concentrated and purified on reverse phase HPLC to give the desired compound as a clear film (12 mg, 0.026 mmol, 25.6%). 1H NMR (400 MHz, CDCl3) δ 1.36 (m, 9H) 2.85 (m, 2H) 3.15 (m, 1H) 3.30 (m, 2H) 4.20 (m, 1H) 4.31 (m, 3H) 5.49 (s, 1H) 7.02 (m, 2H) 7.20 (d, 1H) 7.99 (s, 1H).