Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[BrH:12].N([O-])=O.[Na+].[Br-]>O.C(#N)C>[Br:12][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Br
Reactant: Nc1c(F)cccc1C(=O)O
Agent: O=N[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cccc(F)c1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
In a 1 L, three necked flask fitted with a dropping funnel and thermometer, were charged 2-amino-3-fluorobenzoic acid (20.0 g, 0.13 mol) and acetonitrile (160 mL). After cooling to 0° C., HBr (47%, 160 mL) was added drop wise over 10 min. To the resulting solution a solution of NaNO2 (10.0 g, 0.14 mol) in water (20.0 mL) was added drop wise over 1 h. After addition, the reaction mixture was stirred at 0° C. for 5 min, and cupper(I) bromide (22.0 g, 0.15 mol) was added portionwise over 30 min. Stirring was continued at 70° C. in a an oil bath for 1 h. After cooling to 0° C., 700 mL of water was added and the precipitate was filtered, washed with cold water and dried under vacuum to give 28.23 g (100%) of the title compound as a white solid. The crude product was used in the next step without purification.
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.C(=O)(O)[O-].[Na+]>C(O)C.O>[CH2:2]([O:12][C:1](=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1)[CH2:3][C:4]1[CH:11]=[CH:10][CH:8]=[CH:6][CH:5]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(/C=C/c1ccc(O)c(O)c1)OCCc1ccccc1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
1 g of caffeic acid was dissolved in 20 mL of ethanol and 2 mL water. 0.5 g of sodium bicarbonate was added while stirring. Stirring continued for 3 hr. Solvent and water were distilled off under vacuum. The residual solid was dissolved in 25 mL dimethylformamide and heated to 150° C. To this hot reaction mixture 0.8 mL of phenethyl bromide was added. The resulting reaction mixture was stirred for 40 hrs. Next, the reaction mixture was poured into 75 mL of cold water and extracted with ether (3×70 mL). The combined organic extract was washed with 50 mL of 5% HCl and water (60 mL). After drying over sodium sulfate, the solvent was distilled off under vacuum. The residue was crystallized from toluene by treatment with activated carbon to obtain caffeic acid phenethyl ester. The yield was 304 mg and the purity was greater than 90%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:17])[CH2:11][S:12][CH2:13][C:14]([OH:16])=O)=[CH:5][CH:4]=1)#[N:2].[CH2:18]([N:20]1[C:32]2[CH:31]=[CH:30][C:29]([NH2:33])=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:17])[CH2:11][S:12][CH2:13][C:14]([NH:33][C:29]2[CH:30]=[CH:31][C:32]3[N:20]([CH2:18][CH3:19])[C:21]4[C:26]([C:27]=3[CH:28]=2)=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:16])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(NC(=O)CSCC(=O)O)cc1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c2ccccc2c2cc(NC(=O)CSCC(=O)Nc3ccc(C#N)cc3)ccc21
Yield: 58.4 %

Procedure:
A solution of the compound obtained in Step 1 (145 mg, 0.58 mmol), 9-ethyl-9H-carbazol-3-amine (122 mg, 0.58 mmol), HATU (330 mg, 0.87 mmol) and DIEA (225 mg, 1.74 mmol) in DMF (4 mL) was stirred at room temperature for 16 hr. To the reaction solution was added dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (150 mg, 0.339 mmol, 59%) as a white powder.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:49])[NH:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=4)=[O:37])[CH2:32][CH2:31]3)[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:49])[NH:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=4)=[O:37])[CH2:32][CH2:31]3)[N:27]=2)[CH2:22]1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(C(=O)NC3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(NC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 95.1 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-{4-[1-(p-nitrobenzyloxycarbonyl)-piperidin-4-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (570 mg, 0.820 mmol) (obtained as described in Reference Example 51(5)) in anhydrous tetrahydrofuran (17 ml) were added successively acetic acid (56 μl, 0.984 mmol) and a 1.0M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (984 μl, 0.984 mmol) in an ice bath, and the mixture was stirred in the ice bath for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed successively with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:3)→ethyl acetate:methanol (95:5) as the eluant to afford 3-hydroxy-1-{4-[1-(p-nitrobenzyloxycarbonyl)-piperidin-4-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (360 mg, yield 95%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[S:4][N:3]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CN(C=O)C>O>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[S:4][N:3]=[C:2]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:6]=1
Reactant: COc1ccccc1-c1nc(Cl)ns1
Reactant: C1CNCCN1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1nc(N2CCNCC2)ns1
Temperature: 150 °C

Procedure:
A mixture of 3-chloro-5-(2-methoxyphenyl)-1,2,4-thiadiazole (0.21 g, 0.93 mmol), piperazine (400 mg, 4.65 mmol), and DMF (3 mL) was sealed in a microwave vessel and heated by microwave irradiation at 150° C. for 5 minutes. The reaction was cooled to room temperature, diluted with water, and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to yield 1-(5-(2-methoxyphenyl)-1,2,4-thiadiazol-3-yl)piperazine. LC/MS: m/z 277.1 (M+H)+ at 2.19 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[C:48](Cl)(=[O:52])[CH:49]([CH3:51])[CH3:50]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:48](=[O:52])[CH:49]([CH3:51])[CH3:50])[CH2:42][CH2:41]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CC(C)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 41 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and isobutyryl chloride as starting materials in 41% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.45 (s, 1H), 9.38 (s, 1H), 9.31 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.73 (s, 1H), 7.21 (d, 1H), 7.04 (m, 2H), 6.87 (d, 1H), 6.78 (d, 1H), 4.40 (m, 2H), 3.95 (m, 2H), 3.03 (m, 1H), 2.83 (m, 4H), 2.27 (m, 2H), 2.01 (m, 1H), 1.76 (m, 2H), 1.10 (m, 2H), 1.00 (m, 6H). LCMS for C29H34ClN6O2 (M+H)+: m/z=533.2.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.O=P(Cl)(Cl)Cl.CN([CH:22]=[O:23])C.CC([O-])=O.[Na+].[OH-].[Na+]>ClC(Cl)C>[CH:22]([C:3]1[C:4]2[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=[CH:8][C:9]=2[NH:1][CH:2]=1)=[O:23]
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2[nH]cc(C=O)c12
Temperature: 50 °C

Procedure:
A solution of methyl indole-4-carboxylate (250 mg, 1.43 mmol) in dichloroethane (2 mL) was treated with a solution of POCl3-DMF (1.5 equivalent (eq)) at room temperature (rt). The orange solution was heated at 50° C. for 1 hour. The reaction solution was poured into ice-cold aqueous (aq.) NaOAc (1 g in 2 mL), the aqueous solution was adjusted to pH=8 with 1M NaOH, and extracted with EtOAc (10 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated to give methyl 3-formyl-indole-4-carboxylate as an oil, 271 mg (93%). 1H NMR (300 MHz, d6-DMSO) δ 3.68 (s, 3H), 7.16 (t, 1H, J=7.8 Hz), 7.40 (dd, 1H, J=7.8, 0.8 Hz), 7.56 (d, 1H, J=7.8, 0.8 Hz), 8.16 (d, 1H, J=3.2 Hz), 10.00 (s, 1H), 12.30 (br s, 1H).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH:23](=[C:5]1/[C:4](=[O:6])[NH:3][C:2](=[O:7])[S:1]/1)\[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: CCCCCCCCCCCCCCCC=O
Reactant: O=C1CSC(=O)N1
Product: CCCCCCCCCCCCCCC/C=C1\SC(=O)NC1=O

Procedure:
TZD16 was prepared according to General Procedure A presented hereinabove using 2,4-thiazolidinedione and palmitaldehyde as reactants.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH:2]=[CH2:3].F[C:7](F)(F)[C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1>C1COCC1>[CH2:1]([C:7]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)([CH2:13][CH:11]=[CH2:10])[CH2:9][CH:8]=[CH2:7])[CH:2]=[CH2:3]
Reactant: C=CC[Mg]Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: C=CCC(CC=C)(CC=C)c1ccc(N)cc1
Reaction time: 3.5 h
Yield: 87 %

Procedure:
Following a literature procedure (Lin et al. (1997) Synth. Commun., 27: 1975-1980), a 2 M solution of allyl magnesium chloride in THF (0.400 L, 0.800 mol) was diluted with additional THF (1.00 L) and then treated dropwise with a solution of 4-(trifluoromethyl)aniline (19.9 mL, 0.160 mol) in THF (210 mL) at −50° C. under argon. After complete addition the sides of the reaction flask were rinsed with additional THF (150 mL). The resulting solution was heated at reflux. The reaction was monitored by TLC for the complete consumption of 4-(trifluoromethyl)aniline. After 3.5 h, the mixture was concentrated and then CH2Cl2 was added. The organic solution was washed with water, dried (Na2SO4), and filtered. The filtrate was concentrated and chromatographed [silica, CH2Cl2/hexanes (2:1)], affording a pale yellow solid (31.7 g, 87%): 1H NMR δ 2.36-2.43 (m, 6H), 3.48-3.66 (br, 2H), 4.94-5.06 (m, 6H), 5.50-5.64 (m, 3H), 6.62-6.70 (m, 2H), 7.06-7.12 (m, 2H); 13C NMR δ 42.1, 42.6, 115.0, 117.5, 127.6, 135.0, 135.8, 144.1; FABMS obsd 228.1757, calcd 228.1752 [(M+H)+, M=C16H21N].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.Cl[CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>>[O:19]=[S:18]1(=[O:20])[CH2:17][CH2:16][CH2:15][N:1]1[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CCN)cc1
Reactant: O=S(=O)(Cl)CCCCl
Product: COC(=O)c1ccc(CCN2CCCS2(=O)=O)cc1

Procedure:
Using methyl 4-(2-aminoethyl)benzoate (0.78 g) and 3-chloropropane-1-sulfonyl chloride (0.69 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (1.00 g) was obtained.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]1[C:19]([CH3:20])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:21])[CH:11]=1.[C:22](Cl)(=[O:24])[CH3:23].C(=O)([O-])O.[Na+]>ClCCl>[C:22]([NH:9][C:10]1[C:19]([CH3:20])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:21])[CH:11]=1)(=[O:24])[CH3:23]
Reactant: COC(=O)c1cc(C)c(N)cc1C
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(C)c(NC(C)=O)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 111.4 %

Procedure:
Triethylamine (1.16 ml, 8.32 mmol) was added to a suspension of methyl 4-amino-2,5-dimethylbenzoate monohydrochloride (0.600 g, 2.78 mmol) in dichloromethane (8 ml), and the resulting mixture was cooled with ice water, followed by adding dropwise thereto a solution of acetyl chloride (0.263 g, 3.35 mmol) in dichloromethane (2 ml). The resulting mixture was heated to room temperature and stirred for 3 hours, and then acetyl chloride (0.262 g, 3.34 mmol) was further added thereto and stirred for 1.5 hours. The resulting mixture was added to a saturated aqueous sodium hydrogencarbonate solution and extracted three times with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain methyl 4-(acetylamino)-2,5-dimethylbenzoate (0.685 g, 99%).
Reaction SMILES: [F:1][C:2]1([F:25])[C:15]([F:17])([F:16])[C:14]2[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:6][CH:7]=2.[CH2:26]([O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][N:32]=1)[CH2:27][CH2:28][CH3:29]>>[CH2:26]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C:12]2[CH:11]=[CH:10][C:9]3[C:8]4[C:3](=[CH:4][C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:6][CH:7]=4)[C:2]([F:25])([F:1])[C:15]([F:17])([F:16])[C:14]=3[CH:13]=2)=[CH:33][N:32]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCOc1ccc(B(O)O)cn1
Reactant: CCCCCCc1ccc2c(c1)C(F)(F)C(F)(F)c1cc(Br)ccc1-2
Product: CCCCCCc1ccc2c(c1)C(F)(F)C(F)(F)c1cc(-c3ccc(OCCCC)nc3)ccc1-2

Procedure:
From 9,9,10,10-tetrafluoro-2-bromo-7-hexyl-9,10-dihydrophenanthrene and 2-butoxypyridine-5-boronic acid in analogy to Example 7.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[C:10]([S:13][CH2:14][CH:15]([CH3:19])[C:16](Cl)=[O:17])(=[O:12])[CH3:11]>>[C:10]([S:13][CH2:14][CH:15]([CH3:19])[C:16]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:17])(=[O:12])[CH3:11]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CC(=O)SCC(C)C(=O)Cl
Product: CC(=O)SCC(C)C(=O)N[C@@H](CC(C)C)C(=O)O

Procedure:
Following the procedure of Example 16, L-leucine is reacted with 3-acetylthio-2-methylpropanoyl chloride to give (±)-N-[3-(acetylthio)-2-methyl -1-oxopropyl]-L-leucine.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=3)=[CH:35][CH:34]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1.Cl>CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=3)=[CH:35][CH:34]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(F)c(F)c3)cc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(F)c(F)c3)cc2)cn1
Temperature: 55 °C

Procedure:
A 1M aqueous solution of NaOH (2.0 mL, 2.0 mmol) was added to a THF (1 mL) and MeOH (5 mL) solution of ethyl 3-(5-(5-chloro-2-(((3′,4′-difluoro-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)picolinamido)propanoate (50 mg, 0.09 mmol) and the resulting mixture was heated to 55° C. After 10 min the resulting mixture was neutralized with 2M aqueous HCl, concentrated and extracted with EtOAc. The combined extracts were concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:20].[F:21][C:22]([F:34])([F:33])[C:23]1[CH:24]=[C:25]([N:30]=[C:31]=[O:32])[CH:26]=[CH:27][C:28]=1[Cl:29]>>[Cl:29][C:28]1[CH:27]=[CH:26][C:25]([NH:30][C:31]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[C:16]4[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[F:20])=[O:32])=[CH:24][C:23]=1[C:22]([F:21])([F:33])[F:34]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F
Yield: 88 %

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one and 3-trifluoromethyl-4-chloro-phenylisocyanate to afford the title compound, yield: 88%. 1H-NMR (DMSO-d6), δ (ppm), J (Hz): 6.67 ppm (d, 1H, J=5.5 Hz, HPy), 7.06 (d, 1H, Harom), 7.30 (d, 1H, Harom), 7.66 (m, 2H, Harom), 8.12 (m, 2H, Harom), 8.17 (s, 1H, Harom), 8.38 (d, J=5.5 Hz, HPy), 8.88 (s, 1H, NH), 9.92 (s, 1H, NH), 12.91 (br s, 1H, NHAr); 19F NMR (470 MHz, DMSO-d6): δ=−61.5, −124.2 ppm; LC-MS (m/z): 494.1 (M+H, 100), rt=5.24 min; HRMS (6.17 min): m/z calcd. for C21H13ClF4N6O3 [M+H+]: 494.06376. found: 494.06335.
Reaction SMILES: Br[CH:2]([C:4]1[S:8][C:7]([S:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[C:6]([N+:18]([O-:20])=[O:19])[CH:5]=1)[CH3:3].[NH3:21]>CO>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[S:9][C:7]1[S:8][C:4]([CH:2]([NH2:21])[CH3:3])=[CH:5][C:6]=1[N+:18]([O-:20])=[O:19]
Reactant: CC(Br)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Reactant: N
Solvent: CO
Product: CC(N)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Temperature: 100 °C
Yield: 10 %

Procedure:
5-(1-bromoethyl)-2-(2,4-dichlorophenyl)sulfanyl-3-nitro-thiophene (0.2 g, 0.49 mmol) was dissolved in ammonia in MeOH (2 M, 8 mL). The resulting mixture was sealed in a steel bomb and was heated at 100° C. for 2 hours. The reaction mixture was concentrated and the crude solid was purified by silica gel chromatography using a 98:2 mixture of dichloromethane and methanol as eluent to afford the title product (16 mg, 10% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.38 (1H, m), 8.08 (1H, m), 7.99 (1H, m), 7.82 (1H, s), 7.71 (1H, m), 4.61(1H, m), 1.45 (3H, d). MS m/z: 331.8 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:12](N)=[O:13].S(=O)(=O)(O)O.[OH-].[Na+].[C:22]([O-])(O)=[O:23].[Na+]>CO.O>[CH3:22][O:23][C:12]([C:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[N:8][C:9]=2[CH:10]=[CH:11][C:2]=1[NH2:1])=[O:13]
Reactant: O=C([O-])O
Reactant: NC(=O)c1c(N)ccc2ncccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1c(N)ccc2ncccc12
Temperature: 140 °C
Reaction time: 0.22 h
Yield: 26 %

Procedure:
To a solution of 2 g (10.68 mmol) of the above 6-amino-quinoline-5-carboxylic acid amide in 10.76 mL of absolute methanol is added 2.34 mL (42.73 mmol) of concentrated sulphuric acid. The reaction is stirred in a microwave during 13 minutes at 140° C. The reaction is repeated 6 times with flask opening after each run because of gas formation. The mixture is then cooled at 0° C. and water is added. The pH of the mixture is increased slowly to 6 with addition of an aqueous 6N NaOH solution. The pH is adjusted to 8 with a saturated aqueous solution of NaHCO3. The product is extracted with ethyl acetate (4 times) and the combined organic layers are dried on Na2SO4, filtrated and evaporated. After flash chromatography purification with heptane and ethyl acetate as eluants, 555 mg (26%) of a yellowish solid are obtained; LC/MS: 203/204 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([F:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([F:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f42) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:24])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]1[CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]1)[CH2:7]2.CI.[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([F:24])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]1[CH2:13][CH2:14][N:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:16][CH2:17]1)[CH:7]2[CH3:27]
Reactant: O=C1c2c(Br)cc(F)cc2CN1C1CCN(C2CCCCC2)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1c2cc(F)cc(Br)c2C(=O)N1C1CCN(C2CCCCC2)CC1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 7-bromo-2-(1-cyclohexylpiperidin-4-yl)-5-fluoro-2,3-dihydro-1H-isoindol-1-one (70 mg, 0.177 mmol) and methyliodide (1.1 equiv., 0.195 mmol, 0.012 mL) in anhydrous tetrahydrofuran (3.5 mL) under nitrogen at −78° C., 1M sodium bis(trimethylsilyl)amide in tetrahydrofuran (1.2 equiv., 0.212 mL) was slowly added. The reaction mixture was stirred for 90 min and quenched by adding dropwise a 10% ammonium hydroxide solution. Dichloromethane was added, the layers were separated, and the aqueous layer was extracted twice dichloromethane. Organic layers were collected, dried and evaporated. Crude (58 mg) was used without further purification.
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([O:11]CC)=[O:10])[C:6](=[O:14])[C:5]2[CH:15]=[C:16]([CH3:18])[S:17][C:4]1=2)[CH3:2].[OH-].[Na+]>C(O)(=O)C>[CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[C:6](=[O:14])[C:5]2[CH:15]=[C:16]([CH3:18])[S:17][C:4]1=2)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2sc(C)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(C)sc21
Temperature: 90 °C

Procedure:
A mixture of 0.24 part of ethyl 7-ethyl-4,7-dihydro-2-methyl-4-oxothieno(2,3-b)pyridine-5-carboxylate and 3 parts by volume of 2N sodium hydroxide is heated at 90° C for 5 minutes. After cooling the solution is neutralized with acetic acid to give a precipitate which is collected by filtration, whereby 7-ethyl-4,7-dihydro-2-methyl-4-oxothieno(2,3-b)pyridine-5-carboxylic acid is obtained as crystals. Recrystallization from chloroform-ethanol gives colorless prisms melting at 232°-233° C. This product is identical with the product in Example 13.