Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][CH:11]([CH3:15])[C:12](=[O:14])[CH3:13]>[OH-].[Na+].C(O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:13][C:12](=[O:14])[CH:11]([CH3:15])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)C(C)C
Reactant: O=Cc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(=O)C=Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
4-Bromo-benzaldehyde (available from Aldrich, 10.0 g, 54.3 mmol) was added to a solution of 3-methyl-butan-2-one (available from Aldrich, 4.7 g, 54.7 mmol) in 10 mL of 10% NaOH(aq) and 20 mL of ethanol. After stirring at room temperature for 3 h, the reaction mixture was diluted with water (50 mL) and extracted with diethyl ether (3×20 mL). The organic layer was then washed with brine (1×5 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (95:5 hexane/ethyl acetate) yielded the title compound (7.98 g, 58% yield) as a light yellow oil:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:33])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[CH3:19].Cl.[NH:35]1[CH2:38][CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[N:35]1([C:14]([C:13]2[CH:17]=[CH:18][C:10]([O:9][C:8]3[CH:20]=[C:21]([C:23]4[NH:24][C:25]([C:28]5[S:29][CH:30]=[CH:31][N:32]=5)=[CH:26][CH:27]=4)[CH:22]=[C:6]([O:5][C@@H:4]([CH3:33])[CH2:3][O:2][CH3:1])[CH:7]=3)=[C:11]([CH3:19])[CH:12]=2)=[O:16])[CH2:38][CH2:37][CH2:36]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)O)cc2C)cc(-c2ccc(-c3nccs3)[nH]2)c1
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2C)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
4-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-3-methylbenzoic acid (58 mg, 0.125 mmol) synthesized in Example (53a) and azetidine hydrochloride (29 mg, 0.310 mmol) were dissolved in dichloromethane (10.0 mL), and HATU (95 mg, 0.250 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.861 mmol) were added, followed by stirring at room temperature overnight under nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=75%-90%) to afford the desired compound (58 mg, yield 92%) as a yellow solid.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([F:7])=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(NS(=O)(=O)c2ccc(F)cc2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
Pyridine (500 μL, 6.19 mmol) was added to a solution of 4-fluoro-3-nitro-phenylamine (1 g, 6.41 mmol) and 4-fluoro-benzenesulfonyl chloride (1.2 g, 6.19 mmol) in DCM (20 mL) and the reaction was stirred at room temperature overnight. The reaction was then partitioned between water and DCM. The organic layer was washed several times with water and concentrated. Recrystalization from ethanol/water gave 1.57 g of the sub-title compound as tan crystals.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20]2)=[C:7]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=O)[CH:8]=1.N1C2C=CC=CC=2C=CC=N1>>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:19]3[CH2:20][CH2:21][C:22]4[C:27]3=[C:26]([CH:25]=[CH:24][CH:23]=4)[C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[N:9][C:7]=2[CH:8]=1
Reactant: CSc1ccc(N2CCc3ccccc32)c(NC(=O)N2CCN(C)CC2)c1
Agent: C1=Cc2ccccc2NN=C1
Product: CSc1ccc2c(c1)N=C(N1CCN(C)CC1)c1cccc3c1N2CC3

Procedure:
It is predicted that if the N-[5-methylthio-2-(2,3-dihydro-1H-indol-1-yl)phenyl]-4-methyl-1-piperazinecarboxamide of Example 10c is treated in the manner of Example 4c that 9-methylthio-6-(4-methyl-1-piperazinyl)1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk]-1,4]benzodiazepine will be obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[NH:17][CH:18]=[C:19]([CH:21]=O)[N:20]=1>CO>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11](/[N:14]=[CH:21]/[C:19]2[N:20]=[C:16]([CH3:15])[NH:17][CH:18]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C=O)c[nH]1
Reactant: NN1CCN(Cc2ccccc2)CC1
Solvent: CO
Product: Cc1nc(/C=N/N2CCN(Cc3ccccc3)CC2)c[nH]1
Temperature: 25 °C
Yield: 87.7 %

Procedure:
4-Benzyl-1-piperazinamine (K. L. Rinehart Jr et al. Bioorg. Chem., 6, 341 (1977); 10 g) and 2-methylimidazole-4-carbaldehyde (5.8 g) were suspended in methanol (200 ml), and the reaction mixture was heated under reflux for 3 hours. The reaction solution was cooled to room temperature, and then the solvent was distilled off under reduced pressure. To the residue was added diethyl ether, and the deposited precipitate was collected by filtration to obtain the title compound as a pale brown solid (13 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[CH:17][N:18]4[CH2:23][C:24]([NH2:26])=[O:25])[N:10]=2)[CH:5]=[N:6][C:7]=1Cl.[CH:27]([NH2:30])([CH3:29])[CH3:28]>O1CCOCC1.CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[CH:17][N:18]4[CH2:23][C:24]([NH2:26])=[O:25])[N:10]=2)[CH:5]=[N:6][C:7]=1[NH:30][CH:27]([CH3:29])[CH3:28]
Reactant: NC(=O)Cn1ccc2c(-c3noc(-c4cnc(Cl)c(Cl)c4)n3)cccc21
Reactant: CC(C)N
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: CC(C)Nc1ncc(-c2nc(-c3cccc4c3ccn4CC(N)=O)no2)cc1Cl
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a mixed solution of 2-{4-[5-(5,6-dichloropyridin-3-yl)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl}acetamide (100 mg) in dioxane (2 ml) and NMP (2 ml) was added isopropylamine (2200, followed by stirring at 150° C. for 1 hour in a microwave reaction vessel. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by silica gel chromatography (n-hexane:EtOAc=40:60 to 0:100), and the obtained residue was suspended in diisopropyl ether under heating, and collected by filtration to obtain 2-(4-{5-[5-chloro-6-(isopropylamino)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)acetamide (62 mg) as white powders.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH:14]12[O:20][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19]2>O>[OH:20][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1CCNCC1
Reactant: C1CCC2OC2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: OC1CCCCC1N1CCCCC1
Temperature: 90 °C
Yield: 102.3 %

Procedure:
Piperidine hydrochloride (3.648 g, 30 mmol) was stirred in a mixture of 4.0 mL of water and 4.146 g of ground potassium carbonate. This mixture was heated to 90° C. and cyclohexene oxide (1.01 mL, 10 mmol) was added. The resulting mixture was heated at 100° C. for 18 hours. The reaction was cooled then filtered to remove carbonate salts. The filter cake was washed with 25 mL of diethyl ether and 50 mL of ethyl acetate. The filtrate and washings were combined and washed with brine (2×20 mL), dried over magnesium sulfate, filtered, and evaporated to give 1.875 g (>100%) of the title compound which was used without further purification. 1H NMR consistent with desired product.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:5][CH:4]=1.[S:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33]>>[CH3:20][C:19]1[O:18][C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:16][C:15]=1[CH2:14][CH2:13][O:12][C:6]1[C:7]2[CH:11]=[CH:10][S:9][C:8]=2[C:3]([CH2:2][CH:31]2[S:27][C:28](=[O:33])[NH:29][C:30]2=[O:32])=[CH:4][CH:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CBr)c2sccc12
Reactant: O=C1CSC(=O)N1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC2SC(=O)NC2=O)c2sccc12

Procedure:
reacting 4-[2-(7-Bromomethyl-benzo[b]thiophen-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole with 2,4-thiazolidinedione to give 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedione,
Reaction SMILES: [Na].Br[C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([N+:15]([O-:17])=[O:16])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.N1C=CC=CC=1.[F:24][C:25]([F:29])([F:28])[CH2:26][OH:27]>>[CH3:14][O:13][C:12]1[C:3]([O:27][CH2:26][C:25]([F:29])([F:28])[F:24])=[C:4]2[C:9](=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: COc1cc([N+](=O)[O-])c2ncccc2c1Br
Reactant: OCC(F)(F)F
Agent: [Na]
Solvent: c1ccncc1
Product: COc1cc([N+](=O)[O-])c2ncccc2c1OCC(F)(F)F

Procedure:
To a solution of 0.5 g (0.02 g atom) of sodium in 30 ml of 2,2,2-trifluoroethanol were added 5.6 g (0.02 mole) of 5-bromo-6-methoxy-8-nitroquinoline and 7 ml of pyridine. The mixture was heated under reflux for 158 hr and filtered to remove 1.3 g of starting material. The filtrate was concentrated to 50 ml, diluted with diethyl ether, washed with water and dried (potassium carbonate). Solvent removal left a tan crystalline powder, mp 109°-115° which was extracted with benzene. (A trace of insoluble red crystals was discarded.) The benzene solution was concentrated and the resulting residue was crystallized from diethyl ether-petroleum ether (20°-40°) (5:1) to give 0.4 g of pale tan crystals of 6-methoxy-8-nitro-5-(2,2,2-trifluoroethoxy)quinoline, mp 117°-119°. Concentration of the mother liquor provided an additional 2 g of product, mp 100°-111°. Crystallization of the first fraction from diethyl ether and vacuum drying, overnight, at 60°, gave the analytical sample, mp 120°-121°.
Reaction SMILES: II.Br[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:12][CH:13]([CH3:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[O:26].Cl>O1CCCC1.[Zn]>[OH:26][CH:25]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([CH3:27])[CH3:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)CCCCCCCCCCCC=O
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(C)CCCCCCCCCCCC(O)CC(=O)OC(C)(C)C
Yield: 52.6 %

Procedure:
Activated zinc (118 mg), a small crystal of iodine, and tetrahydrofuran (3 ml) were stirred and heated under reflux. To the mixture was added a solution of tert-butyl bromoacetate (312 mg) and 13-methyltetradecanal (226 mg) in tetrahydrofuran (3 ml), and the reactants were stirred and heated under reflux for 1 hour. Anhydrous conditions were maintained throughout the experiment. The cooled solution was poured into 0.1 N hydrochloric acid (5.6 ml) and the pH was adjusted to 2.0 with 2 N hydrochloric acid. The excess of zinc was filtered off and the crude products were extracted with ethyl acetate. The ethyl acetate solution was washed with aqueous sodium hydrogen carbonate and brine, and then dried over magnesium sulfate. The ethyl acetate was evaporated off under reduced pressure to give the crude ester, which was purified by column chromatography on silica gel (Merck) and eluted with a mixture of cyclohexane and ethyl acetate (19:1). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was dried by high vacuum pump to afford an oil of tert-butyl 3-hydroxy-15-methylhexadecanoate (180 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH:12]1([CH2:15][OH:16])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:3]([O:16][CH2:15][CH:12]2[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: OCC1CC1
Product: O=C(O)c1cnc(OCC2CC2)c(Cl)c1
Yield: 98 %

Procedure:
The title compound is prepared in 98% yield (4.65 g, white solid) from 5,6-dichloronicotinic acid (4.00 g, 20.8 mmol) and cyclopropylmethanol (2.25 g, 31.3 mmol) in a similar manner to Step-1 of Amine-1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[I:15])=[CH:5][CH:4]=1.[CH2:16]([C:20]1[NH:21][C:22]([CH:26]=[O:27])=[C:23]([Cl:25])[N:24]=1)[CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:16]([C:20]1[N:21]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[I:15])=[CH:5][CH:4]=2)[C:22]([CH:26]=[O:27])=[C:23]([Cl:25])[N:24]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: BrCc1ccc(-c2ccccc2I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2I)cc1
Reaction time: 24 h

Procedure:
A solution of 4-(bromomethyl)-2'-iodobiphenyl (9.23 g; preparable as described in Example 2(b)) in dry dimethylformamide (50 ml) was added to a stirring mixture of 2-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (preparable as described in Drugs of the Future (1991), Vol. 16, p 305), anhydrous potassium carbonate (6.9 g) and dry dimethylformamide (100 ml), at ambient temperature. Stirring was continued at ambient temperature for 24 hours. Water (200 ml) was added and the resulting mixture was extracted with diethyl ether (500 ml then 200 ml). The combined extracts were washed with water (2×100 ml) and dried over magnesium sulphate. The organic solvent was evaporated and the residual orange oil was purified by flash chromatography on silica gel (eluting with 5% then 30% ethyl acetate in petroleum ether (b.p. 60°-80° C.)) to give the intermediate compound 2-butyl-4-chloro-1-(2'-iodobiphenyl-4-ylmethyl)-1H-imidazol-5-carboxaldehyde as a yellow oil (8.06 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH:10]([C:25]#[N:26])[CH2:11][CH2:12][C@H:13]([O:23][CH3:24])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[NH2:28][OH:29]>CCO>[C:1]([O:5][C:6](=[O:27])[N:7]([CH:10]([C:25]([NH:28][OH:29])=[NH:26])[CH2:11][CH2:12][C@H:13]([O:23][CH3:24])[CH2:14][O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(C(=O)OC(C)(C)C)C(C#N)CC[C@@H](COCc1ccccc1)OC
Reactant: NO
Solvent: CCO
Product: CCN(C(=O)OC(C)(C)C)C(CC[C@@H](COCc1ccccc1)OC)C(=N)NO
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl[(4S)-5-(benzyloxy)-1-cyano-4-methoxypentyl]ethylcarbamate (74 g, 197 mmol) in EtOH (1000 mL) was added TEA (54.8 mL, 393 mmol) and NH2OH (50% in water, 14.45 mL, 236 mmol). The resulting solution was stirred at 40° C. overnight and then concentrated in vacuo. The residue was dissolved in MeOH and the solvent was removed under reduced pressure (3×) to remove water. The crude residue was used in the next reaction without further purification. LC-MS: 410.5 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1)=[O:24]
Reactant: CN1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(Cl)c1ccco1
Product: CN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccco4)cc23)CC1
Yield: 8 %

Procedure:
Beginning with 1.13 gm (5.0 mMol) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 0.52 mL (5.0 mMol) 2-furoyl chloride, 0.129 gm (8.1%) of the title compound were recovered as a tan solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.O[C:7]1[N:8]=[C:9]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][CH2:30][C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])[N:21]=2)[N:10]=[N:11][C:12]=1[C:13]([CH3:19])([CH3:18])[C:14]([O:16]C)=O.[NH3:38]>C(#N)C>[CH3:19][C:13]1([CH3:18])[C:12]2[N:11]=[N:10][C:9]([C:20]3[C:28]4[C:23](=[N:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH2:29][CH2:30][C:31]([F:37])([F:36])[C:32]([F:34])([F:35])[F:33])[N:21]=3)=[N:8][C:7]=2[NH:38][C:14]1=[O:16]
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(CCC(F)(F)C(F)(F)F)c3ncccc23)nc1O
Reactant: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4 ml of phosphoryl chloride were added to 263 mg (0.571 mmol) of the compound from Example 16A, and the mixture was stirred at RT overnight. The reaction mixture was dissolved in 38 ml of acetonitrile and, with ice-cooling, stirred into 24 ml of concentrated aqueous ammonia solution (33% strength). The mixture was stirred at RT for 2 days. The reaction mixture was then concentrated. The residue was taken up in water and ethanol and stirred at RT for 1 h. The precipitate formed was filtered off with suction and washed with water and ethanol. This residue was purified by preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). This gave 119 mg of the title compound (49% of theory).
Reaction SMILES: [C:1]1([CH:7]([OH:10])[C:8]#[CH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl/[C:12](=[N:18]\[OH:19])/[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[OH:10][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]1[O:19][N:18]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=1
Reactant: C#CC(O)c1ccccc1
Reactant: CCOC(=O)/C(Cl)=N/O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(C(O)c2ccccc2)on1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
1-phenylprop-2-yn-1-ol (0.802 mL, 6.60 mmol) was added to a mixture of (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (0.50 g; 3.30 mmol) and sodium hydrogen carbonate (0.554 g; 6.60 mmol) in ethyl acetate (15 mL) and water (0.2 mL) and stirred at room temperature for 24 hours. The resulting mixture was filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 40% ethyl acetate in heptane) to yield 0.571 g (70%) of ethyl 5-(hydroxy(phenyl)methyl)isoxazole-3-carboxylate as a colorless oil.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]([NH:13][C@@H:14]([CH3:31])[CH2:15][N:16]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([Cl:29])[C:22]=3[CH3:30])=[N:17]2)=[O:12])[N:10]=1)(=[O:5])[CH3:4]>O.C(O)C>[Cl:29][C:23]1[C:22]([CH3:30])=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:11]([C:9]3[N:10]=[C:6]([CH:3]([OH:5])[CH3:4])[S:7][CH:8]=3)=[O:12])[CH3:31])[N:17]=2)[CH:26]=[CH:25][C:24]=1[C:27]#[N:28]
Reactant: CC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3C)n2)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(C(C)O)n3)n2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
Sodium borohydride (0.056 g, 1.477 mmol) was added into a flask and the atmosphere was replaced with nitrogen. Dry ethanol was added and the reaction mixture was cooled to 0° C. (S)-2-acetyl-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide (0.316 g, 0.738 mmol) was added and the reaction mixture was warmed slowly to RT while stirring overnight. The crude product was cooled to 0° C., a few drops of water was added, the pH was adjusted below 7 and the mixture was evaporated. 5% of DCM/MeOH was added and the crude product was washed with 1M NaHCO3, water and dried. Yield 68.1%. 1H-NMR (400 MHz; DMSO-d6): δ 1.13 (d, 3H), 1.40 (dd, 3H), 2.52 (s, 3H), 4.37 (m, 2H), 4.48 (m, 1H), 4.92 (m, 1H), 6.24 (t, 1H), 6.62 (d, 1H), 7.63 (d, 1H), 7.82 (d, 1H), 7.87 (dd, 1H), 8.10 (s, 1H), 8.37 (dd, 1H).
Reaction SMILES: ClC(OCC(C)C)=[O:3].[C:9]([N:16]([CH2:18][C:19]([OH:21])=[O:20])[CH3:17])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].CN1CCOCC1.[CH2:29]([NH2:39])[C:30]1[CH:38]=[CH:37][C:36]2[O:35][CH2:34][O:33][C:32]=2[CH:31]=1>C1COCC1>[C:29]([NH2:39])(=[O:3])[C:30]1[CH:38]=[CH:37][C:36]2[O:35][CH2:34][O:33][C:32]=2[CH:31]=1.[C:9]([N:16]([CH2:18][C:19]([OH:21])=[O:20])[CH3:17])([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10]
Reactant: CC(C)COC(=O)Cl
Reactant: NCc1ccc2c(c1)OCO2
Agent: CN(CC(=O)O)C(=O)OC(C)(C)C
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: NC(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
Isobutyl chloroformate (226 μL, 1.73 mmol) was added to a solution of N-Boc sarcosine (1.73 mmol) and N-methylmorpholine (192 μL, 1.73 mmol) in THF. After two minutes, piperonylamine (216 mL, 1.73 mmol) was added and the mixture allowed to warm to room temperature. After thirty minutes, the reaction mixture was passed through a bed of Celite and all volatiles were removed under reduced pressure to yield N-Boc sarcosine piperonyl amide (531 mg, 95%) as a white solid. 1H NMR: (CDCl3) δ2.41 (s,3), 3.28 (s,2), 4.39 (d,2), 5.95 (s,2), 6.80 (m,3), 7.43 (bs,1), 9.04 (bs,1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])[C:5]([Cl:24])=[CH:4][N:3]=1.[NH2:25][C:26]1[CH:38]=[CH:37][C:29]2[N:30]([CH3:36])[C:31](=[O:35])[CH2:32][CH2:33][CH2:34][C:28]=2[CH:27]=1.Cl>COC(O)C.O1CCOCC1>[Cl:24][C:5]1[C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])=[N:7][C:2]([NH:25][C:26]2[CH:38]=[CH:37][C:29]3[N:30]([CH3:36])[C:31](=[O:35])[CH2:32][CH2:33][CH2:34][C:28]=3[CH:27]=2)=[N:3][CH:4]=1
Reactant: NC(=O)c1cc(N2CCCCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Agent: COC(C)O
Agent: Cl
Solvent: C1COCCO1
Product: CN1C(=O)CCCc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCCCC5)cc4C(N)=O)n3)ccc21
Temperature: 120 °C
Yield: 21.1 %

Procedure:
2-(2,5-dichloro-pyrimidin-4-ylamino)-5-piperidin-1-yl-benzamide (50.1 mg, 0.137 mmol) and 7-amino-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (28.7 mg, 0.151 mmol) were slurried in methoxyethanol (2.0 mL) prior to adding ˜0.2 mL of 4N HCl in dioxane. This mixture was heated at 120° C. for 2 h. After quenching with saturated aqueous NaHCO3 solution (2 mL), the resulting precipitate was collected by filtration, successively washed water (5×2 mL) and ether (2×1 mL) to afford product (15 mg, 21%) as a yellow powder that had the following properties: mp: 295-297° C.; LC/MS (ESI+): 520 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 11.20 (s, 1H), 9.45 (s, 1H), 8.42 (d, J=8.0, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.65 (m, 2H), 7.52 (d, J=8.9, 1H), 7.30 (s, 1H), 7.20 (d, J=8.6, 1H), 7.05 (d, J=9.4, 1H), 3.20 (s, 3H), 3.18 (m, 4H), 2.65-2.20 (series of m, 6H), 1.65 (m, 4H), 1.55 (m, 2H).