Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[S:5][C:6]=1[NH:7][CH3:8].N1C=CC=CC=1.[CH3:21][CH:22]([CH2:26][S:27][CH3:28])[C:23](Cl)=[O:24]>ClC(Cl)C.O>[Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[S:5][C:6]=1[N:7]([CH3:8])[C:23](=[O:24])[CH:22]([CH3:21])[CH2:26][S:27][CH3:28]
Reactant: CSCC(C)C(=O)Cl
Reactant: CNc1sc(-c2cccnc2)nc1Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Solvent: O
Product: CSCC(C)C(=O)N(C)c1sc(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.1 %

Procedure:
To a solution of (4-chloro-2-pyridin-3-yl-thiazol-5-yl)-methylamine (200 mg, 0.88 mmol) in dichloroethane (2 mL) was added pyridine (83 mg, 1.05 mmol), N,N-dimethylaminopyridine (54 mg, 0.44 mmol) followed by 2-methyl-3-methylsulfanyl-propionyl chloride (160 mg, 1.05 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction was diluted with water and the mixture was extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to afford a light yellow solid (250 mg, 84%): mp 70-73° C.; 1H NMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 8.75 (d, J=3.8 Hz, 1H), 8.28-8.15 (m, 1H), 7.45 (dd, J=8.0, 4.9 Hz, 1H), 3.32 (s, 3H), 2.99-2.72 (m, 2H), 2.50 (d, J=7.5 Hz, 1H), 2.06 (d, J=2.5 Hz, 3H), 1.31-1.14 (m, 3H); ESIMS m/z 342 (M+1).
Reaction SMILES: [CH2:1]([N:4]([CH:10]([CH3:13])[CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].O.[CH2:15]([NH:22][CH2:23]C(O)=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:15]([N:22]1[CH2:23][CH2:3][CH:2]2[CH:11]1[CH:10]([CH3:13])[N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)CNCc1ccccc1
Reactant: C=CCN(C(=O)OCC)C(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1CC2CCN(Cc3ccccc3)C2C1C

Procedure:
37 g (0.2 mol) of ethyl N-allyl-N-(1-oxo-2-propyl)-carbamate are heated under reflux overnight in a water separator with 33 g (0.2 mol) of N-benzylglycine in 500 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].C(#N)C.Br[CH2:14][CH:15]1[O:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][CH2:16]1>C(OCC)C>[O:20]1[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][CH2:16][CH:15]1[CH2:14][N:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]=[CH:4]1
Reactant: BrCC1COc2ccccc2O1
Reactant: Clc1nc[nH]c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC#N
Product: Clc1ncn(CC2COc3ccccc3O2)c1Cl
Temperature: 25 °C
Yield: 51.2 %

Procedure:
4,5-Dichloroimidazole (0.68 g, 5 mmol) and potassium hydroxide (0.28 g, 5 mmol) were added to a round bottom flask. Acetonitrile (2 mL) was added and the mixture was brought to reflux and stirred 30 min until all KOH was consumed. 2-(Bromomethyl)-1,4-benzodioxane (1.5 mL, 10 mmol) was added and the solution was returned to reflux overnight, during which time a white precipitate formed. The mixture was cooled to ambient temperature and filtered to remove the precipitate. The filtrate was concentrated via rotary evaporation at 75° C. until a yellow liquid remained. Upon cooling, the solution yielded a yellow solid. The solid was stirred in diethyl ether and filtered to yield a pale yellow solid (0.73 g, 52% yield).
Reaction SMILES: [C:1]1([CH:7]2[NH:11][C:10](=[O:12])[CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:13]1[CH2:23][CH:14]1[CH2:15][C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17]>O.CC(C)=O>[CH3:19][CH:20]([CH3:22])[CH2:21][N:8]1[CH2:9][C:10](=[O:12])[NH:11][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[OH:13][CH:14]([CH3:23])[CH2:15][C:16]([O-:18])=[O:17]
Reactant: CC(C)COC(=O)CC1CO1
Reactant: O=C1CNC(c2ccccc2)N1
Solvent: CC(C)=O
Solvent: O
Product: CC(C)CN1CC(=O)NC1c1ccccc1
Product: CC(O)CC(=O)[O-]

Procedure:
A mixture of 0.7 g 2-phenylimidazolidine-4-one and 1 g 2-methylpropyl 3,4-epoxybutanoate are heated for 12 h at 70° (external temperature) in 2 ml water and 2 ml acetone. After evaporating, the residue is taken up with ether and the white solid obtained is filtered, and recrystallised from ethyl/acetate, 2-Methylpropyl-2-phenyl-4-oxoimidazolidine-β-hydroxybutanoate is obtained as a white powder, m.p. 126°-128° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH:5]([CH3:9])[C:6]([OH:8])=O.C(Cl)Cl.[C:13]([O:17][C:18]([N:20]1[C:24]([NH2:25])=[CH:23][C:22]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[N:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.Cl>>[C:13]([O:17][C:18]([N:20]1[C:24]([NH:25][C:6](=[O:8])[CH:5]([CH3:9])[CH2:4][CH2:3][CH2:2][Br:1])=[CH:23][C:22]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[N:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)n1nc(-c2ccc(Cl)cc2)cc1N
Reactant: CC(CCCBr)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CCCBr)C(=O)Nc1cc(-c2ccc(Cl)cc2)nn1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
To a solution of 5-bromo-2-methyl-pentanoic acid (1.79 g, 9.2 mmol, 1 eq) in anhydrous DCM (8 mL) oxalyl chloride (1.0 mL, 12.0 mmol, 1.3 eq) was added dropwise and the mixture was stirred at room temperature for 16 hours. After evaporation of the solvent and the excess oxalyl chloride, the residue was dissolved in anhydrous DCM (8 mL) and a solution of 5-amino-3-(4-chloro-phenyl)-pyrazole-1-carboxylic acid tert-butyl ester (2.7 g, 9.2 mmol, 1.0 eq) and triethylamine (1.7 mL, 12 mmol, 1.3 eq) was added dropwise at 0° C. The mixture was allowed to reach room temperature and stirred at room temperature for 24 hours, after which another 0.5 eq of activated 5-bromo-2-methyl-pentanoic acid was added. HCl 1M was added; the crude was extracted with DCM and purified through SiO2 column (eluent DCM) to give 3.3 g (yield 97%) of the title product.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.N1CCCC[CH2:14]1.CC(O)=O>CO>[C:1]1([C:7](=[CH2:14])[C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cc1ccccc1
Reactant: C1CCNCC1
Agent: C=O
Solvent: CO
Solvent: CC(=O)O
Product: C=C(C(C)=O)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
1-Phenyl-propan-2-one (40.8 g) was dissolved in 200 ml of MeOH. Formaline (37%) (79 mL), piperidine (4 ml) and HOAc (4 ml) where added and de reaction was stirred for 3 h at 60° C. The reaction mixture was evaporated to dryness under reduced pressure. The residue was taken up in diethyl ether, and extracted with water. The organic layer was washed with 1M HCl, dried over MgSO4 and evaporated under reduced pressure to yield 36.3 g of a yellow liquid. 1H NMR (400 MHz, CDCl3) δ 2.41 (s, 3H), 5.87 (s, 1H), 6.18 (s, 1H), 7.24-7.40 (m, 5H).
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1.O>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[CH:18]=[CH:19][C:14]([O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][NH2:3])=[CH:7][CH:8]=2)=[N:15][CH:16]=1
Reactant: NCCc1ccc(O)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
Sodium hydride/60 percent oil dispersion (0.72 mg, 18 mmol) was added in portions to a slurry of tyramine (2.1 g, 15 mmol) in anh. DMF (25 mL). After 15 minutes, 2-chloro-5-(trifluoromethyl)pyridine (2.9 g, 16 mmol) was added neat and the reaction heated to 50° C. for 3 hours. After cooling, the reaction was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The organic portions were combined and washed with brine (50 mL) and dried (Na2SO4). Filtration and removal of solvent left a brown residue that partially solidified. This was triturated in minimal ethyl acetate and collected by filtration, leaving product as a white solid, 3.0 g, 10.6 mmol, 71 percent yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].Cl[C:11]([C:13]([O:20][CH3:21])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12].C(N(CC)CC)C>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:11](=[O:12])[C:13]([O:20][CH3:21])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)C(C)(OC)C(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(OC)C(=O)Nc1cc(Cl)cc(Cl)c1
Yield: 50 %

Procedure:
3,5-Dichloroaniline (3.33 grams, 0.02 mole), ethyl 2-(chlorocarbonyl)-2-methoxypropionate (4.0 grams, 0.02 mole), prepared in Example LXII Part C, and triethylamine (2.08 grams, 0.02 mole) were reacted in a manner similar to the procedure described in Example I to give 4.40 grams (0.01 mole) of ethyl 3-[(3,5-dichlorophenyl)amino]-2-methoxy-2-methyl-3-oxopropanoate having a melting point of 72° C.-75° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [CH3:1][CH:2]([C:9]1[CH:17]=[C:13]([C:14]([OH:16])=[O:15])[C:12]([OH:18])=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=1[CH3:26].[CH2:27]=[O:28].S(=O)(=O)(O)O>C(O)(=O)C>[CH3:1][CH:2]([C:9]1[CH:17]=[C:13]([C:14]([OH:16])=[O:15])[C:12]([OH:18])=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:20]1([CH3:19])[CH:21]=[CH:22][CH:23]=[C:24]([CH:27]=[O:28])[C:25]=1[CH3:26]
Reactant: Cc1ccccc1C
Reactant: C=O
Agent: CC(c1ccccc1)c1ccc(O)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cccc(C=O)c1C

Procedure:
To a mixture of 24.2 parts of 5-α-methylbenzylsalicylic acid, 21.2 parts of o-xylene, 8.9 parts of 37% formalin and 25 parts of acetic acid was added 4.0 parts of 95% sulfuric acid (catalyst). After being heated under reflux for 5 hours, the reaction mixture was washed with water, and unreacted o-xylene and water were removed by vacuum distillation to give 35 parts of 5-α-methylbenzylsalicylic acid-o-xylene-formaldehyde co-condensation product. 10 parts of the co-condensation product was converted into its tin salt in a similar manner as in Synthesis Example 3. There was obtained 13 parts of tin salt of 5-α-methylbenzylsalicylic acid-o-xylene-formaldehyde co-condensation product.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.O[C@H:13]([CH3:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(P(CCCC)CCCC)CCC.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Br:1][C:2]1[C:3]([O:11][C@@H:13]([CH3:23])[CH2:14][NH:15][C:16]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1
Reactant: C[C@@H](O)CNC(=O)OC(C)(C)C
Reactant: COC(=O)c1scc(Br)c1O
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: COC(=O)c1scc(Br)c1O[C@@H](C)CNC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
To a solution of methyl 4-bromo-3-hydroxythiophene-2-carboxylate (237 mg), tert-butyl [(2R)-2-hydroxypropyl]carbamate (175 mg), tri-n-butylphosphine (0.75 mL) and THF (10 mL) was added dropwise diethyl azodicarboxylate (40% toluene solution, 1.4 mL) at room temperature, and the mixture was stirred for 2 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent gradient; 0→15% ethyl acetate/hexane) to give the title compound (239 mg, 65%) as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[O:13])=[CH:21][CH:20]=1
Reactant: O=Cc1cccc(O)c1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(Oc2cccc(C=O)c2)cc1
Reaction time: 27.5 h
Yield: 18.5 %

Procedure:
Triethylamine (7.1 ml, 51 mmol) was added dropwise at room temperature to a suspension of 3-hydroxybenzaldehyde (1.72 g, 14.1 mmol), 4-methoxyphenylboronic acid (3.16 g, 20.8 mmol), molecular sieves 4A powder (1.95 g) and copper (II) acetate (2.96 g, 16.3 mmol) in methylene chloride (100 ml), and the mixture was stirred for 27.5 hrs. The reaction mixture was diluted with ethyl acetate (200 ml), and the insoluble materials were filtered off and washed with ethyl acetate. The filtrate and washings were combined, washed with 10% hydrochloric acid and brine in turn and dried. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=7) to give 3-[(4-methoxy)phenoxy]benzaldehyde (596 mg, 19%) as a pale brown oil.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=1.Cl[C:23]1[C:28]([C:29]([OH:31])=[O:30])=[CH:27][N:26]=[C:25]([Cl:32])[C:24]=1[F:33]>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:23]2[C:28]([C:29]([OH:31])=[O:30])=[CH:27][N:26]=[C:25]([Cl:32])[C:24]=2[F:33])=[C:16]([F:21])[CH:15]=1
Reactant: O=C(O)c1cnc(Cl)c(F)c1Cl
Reactant: Nc1ccc(Br)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cnc(Cl)c(F)c1Nc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
nBuLi (14.7 mL, 36.7 mmol, 2.5 M solution in hexanes) was added to a stirred solution of diisopropylamine (5.15 mL, 36.7 mmol) in THF (20 mL) at 0° C. After 20 minutes, the reaction mixture was cooled to −78° C. and a solution of 4-bromo-2-fluorophenylamine (4.65 g, 24.5 mmol) in THF (10 mL) was added. After 20 minutes, a solution of 4,6-dichloro-5-fluoro-nicotinic acid (Sanchez et al J Heterocylc. Chem. 1993, 30 (4), 855-9) (2.57 g, 12.25 mmol) in THF (10 mL) was added. After 10 minutes, the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. After quenching the reaction mixture with 10% HCl (20 mL), it was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Trituration with methylene chloride yielded 3.21 g (72%) of clean desired product.
Reaction SMILES: [F:1]C1C(OC)=CC=C(F)C=1C1C=CN=CC=1NC.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](OC)[C:21]=1[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[N:34]([CH2:51]C(F)(F)F)[C:35](=[O:50])[C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([S:46]([CH3:49])(=[O:48])=[O:47])[CH:37]=1.[C:56]([O-:59])(=O)C.[NH4+].C(#N)C>>[F:19][C:20]1[C:25]([O:59][CH3:56])=[CH:24][CH:23]=[C:22]([F:1])[C:21]=1[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[N:34]([CH3:51])[C:35](=[O:50])[C:36]1[CH:41]=[C:40]([C:42]([F:44])([F:43])[F:45])[CH:39]=[C:38]([S:46]([CH3:49])(=[O:47])=[O:48])[CH:37]=1
Reactant: CNc1cnccc1-c1c(F)ccc(OC)c1F
Reactant: CC(=O)[O-]
Reactant: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Agent: [NH4+]
Solvent: CC#N
Product: COc1ccc(F)c(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(S(C)(=O)=O)c2)c1F

Procedure:
The title compound was prepared in analogy to example 284, from [4-(2,6-difluoro-3-methoxy-phenyl)-pyridin-3-yl]-methyl-amine and 3-methanesulfonyl-5-trifluoromethyl-benzoyl chloride (example 223, intermediate d) and using preparative HPLC (ammonium acetate/acetonitrile) for the purification. Off-white solid (25%). MS (ESI): m/z=501.2 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.C(O)(=O)CCCCCCCCCCC.C(Cl)(=O)CCCCCCCCCCC.[C:33]([N:46]=[C:47]=[S:48])(=[O:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].[CH3:49][O:50][C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][C:60]=1[O:61][CH3:62])[N:57]=[CH:56][CH:55]=[C:54]2[O:63][C:64]1[CH:70]=[CH:69][C:67]([NH2:68])=[C:66]([F:71])[CH:65]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:49][O:50][C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][C:60]=1[O:61][CH3:62])[N:57]=[CH:56][CH:55]=[C:54]2[O:63][C:64]1[CH:70]=[CH:69][C:67]([NH:68][C:47]([NH:46][C:33](=[O:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[S:48])=[C:66]([F:71])[CH:65]=1
Reactant: CCCCCCCCCCCC(=O)N=C=S
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: CCCCCCCCCCCC(=O)Cl
Agent: CCCCCCCCCCCC(=O)O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCCCCCCCC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available dodecanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and dodecanoyl isothiocyanate was prepared using the resultant dodecanoyl chloride as a starting compound according to the description of the literature. Dodecanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (60 mg, yield 68%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:41][OH:42])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:30][CH:31]=[C:26]4[C:25]([C:39]#[N:40])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:45])C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:41][OH:42])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([N:32]5[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]5)=[CH:30][CH:31]=[C:26]4[C:25]([C:39]([NH2:40])=[O:45])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCN(c2ccc3c(C#N)cn(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)c3n2)CC1
Reactant: CCO
Solvent: O
Product: CN1CCN(c2ccc3c(C(N)=O)cn(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)c3n2)CC1
Temperature: 45 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
In a 25 mL round-bottomed flask, 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-6-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (43 mg, 76.0 μmol) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (2.00 mg, 4.66 μmol, Eq: 0.0613) were combined with ethanol (1.00 ml) and water (1.00 ml) to give a colorless solution. The reaction mixture was heated to 45° C. and stirred for 1 h. The crude reaction mixture was concentrated in vacuo. Mixture was diluted with acetonitrile and water and filtered. The resultant filtrate was lyophilized to give 1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-6-(4-methyl-piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (35 mg, 97%, [M+H]+ 584).
Reaction SMILES: OC1(C2C=CC=CC=2)CCN(C2N=C[C:11]([NH:14][C:15]([C:17]3[O:21][C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:19][C:18]=3[C:28]([F:31])([F:30])[F:29])=[O:16])=[CH:10][CH:9]=2)CC1.NC1[CH:40]=[C:41]2[C:46](=CC=1)[CH2:45][N:44]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:43][CH2:42]2>>[N:22]1([C:20]2[O:21][C:17]([C:15]([NH:14][C:11]3[CH:40]=[C:41]4[C:42](=[CH:9][CH:10]=3)[CH2:43][N:44]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:46]4)=[O:16])=[C:18]([C:28]([F:31])([F:30])[F:29])[N:19]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(Nc1ccc(N2CCC(O)(c3ccccc3)CC2)nc1)c1oc(N2CCCCC2)nc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Product: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)c3oc(N4CCCCC4)nc3C(F)(F)F)ccc2C1

Procedure:
Compound 153 was prepared by the general procedure for compound 1, by using compound A-4 and tert-butyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate as the starting materials. 1H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 7.54 (s, 1H), 7.47 (d, 1H, J=8.4 Hz), 7.15 (d, 1H, J=8.4 Hz), 4.47 (s, 2H), 3.61 (m, 4H), 3.55 (t, 2H, J=5.9 Hz), 2.77 (t, 2H, J=5.9 Hz), 1.61 (m, 6H), 1.43 (s, 9H); LCMS (ESI) Rt=5.47 min, [M+1]+ 495.3.
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[C@H:13]([OH:26])[CH2:14][C@:15]4([CH3:25])[C@@:19]([OH:24])([C:20]([CH2:22][OH:23])=[O:21])[CH2:18][CH2:17][C@H:16]4[C@@H:11]3[CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2.[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28]1>N1C=CC=CC=1>[C:30]([CH2:29][CH2:28][C:27](=[O:33])[O:23][CH2:22][C:20](=[O:21])[C@:19]1([OH:24])[C@:15]2([CH3:25])[C@H:16]([C@H:11]3[C@H:12]([C@H:13]([OH:26])[CH2:14]2)[C@:2]2([CH3:1])[C:8](=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2)[CH2:9][CH2:10]3)[CH2:17][CH2:18]1)([OH:32])=[O:31]
Reactant: O=C1CCC(=O)O1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Solvent: c1ccncc1
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)COC(=O)CCC(=O)O

Procedure:
A solution of 3.60 g of 11-epi-cortisol and 1.00 g of succinic anhydride in 45 ml of pyridine was stirred for 4 days at room temperatures The reaction was concentrated. The residue was partitioned between methylene chloride and water. The organic phase was partitioned with sodium bicarbonate. The aqueous layer was washed with methylene chloride. The aqueous layer was acidified with 10% aqueous U HCl and was extracted with chloroform. The organic phase was concentrated. The residue was chromatographed on RP2 silica gel (20% ethyl acetate/methylene chloride) to yield the product which was crystallized from hot ethyl acetate to yield 2.00 g of the white, solid product, mp 208-209. Anal. Calcd for C25H34O8. Calcd/Found: C, 64.92/64.24; H, 7.41/7.08
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=1.[C:19]1([P:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[Br-:1].[CH3:10][O:9][C:7]([C:6]1[CH:11]=[CH:12][C:3]([CH2:2][P+:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:4][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:8]
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccccc1
Product: [Br-]

Procedure:
A solution of product from step D) (9.43 g; 31 mmol) and triphenylphosphine (10.07 mg; 38 mmol) in toluene (100 ml) was refluxed for 1 hour 30 min. The resulting precipitate was filtered, and washed with ether to give 4-methyloxycarbonyl-3-phenyl-benzyltriphenylphosphonium bromide as a white solid (15.85 g; 90%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]([NH:13][CH2:14][CH:15]3[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.[Br:28]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([Br:28])[CH:9]=[C:10]([C:11]([NH:13][CH2:14][CH:15]3[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCOC(CNC(=O)c2ccc3c(N)ncnn23)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(CNC(=O)c2cc(Br)c3c(N)ncnn23)C1
Temperature: 25 °C

Procedure:
A solution of tert-butyl 2-({[(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)carbonyl]amino}methyl)morpholine-4-carboxylate (100 mg, 0.27 mmol) in THF (5 mL) was cooled to −50° C. and treated with 1,3-dibromo-5,5-dimethylhydantoin (37 mg, 0.13 mmol) in portions over 30 min. The reaction was then quenched with satd. Na2SO3 and warmed to rt. The product was extracted with EtOAc, dried (MgSO4), and concentrated. The crude product was triturated with EtOAc and filtered. A white solid was collected (60 mg, 50%). MS [M+H]+=545.96, 456.86; LCMS RT=2.90 min.