Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:6][C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]([O:14]CC)=[O:13])[C:8]=2[CH3:17])=[CH:4][CH2:3]1.[OH-].[Na+].Cl>C(O)C.O>[CH3:1][C:2]1([CH3:18])[CH2:6][C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[C:8]=2[CH3:17])=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1noc(C2=CCC(C)(C)C2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)noc1C1=CCC(C)(C)C1
Temperature: 25 °C

Procedure:
To a stirred solution of ethyl 5-(4,4-dimethylcyclopent-1-en-1-yl)-4-methylisoxazole-3-carboxylate (243 mg, 0.975 mmol) in ethanol (5 mL), 2M NaOH (aq) (0.975 mL, 1.949 mmol) was added and the solution was stirred at room temperature. Upon completion the reaction mixture was diluted with water (30 mL) and acidified to pH 5-6 by the addition of 2M HCl (aq). The aqueous phase was extracted with EtOAc (2×20 mL) and the combined organic extracts were washed with brine (20 mL), dried over MgSO4 and filtered. The solvent was removed under reduced pressure to afford the title compound;
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.Br[C:8]1[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=1.C(N(C(C)C)CC)(C)C>>[NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)[CH2:3]1
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: N[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2CC[C@@H](N)C2)nc1C
Yield: 86.5 %

Procedure:
The same operation as in Example (237a) was performed using (3R)-3-aminopyrrolidine (0.16 mL, 1.80 mmol), ethyl 2-bromo-4-methylthiazole-5-carboxylate (300 mg, 1.20 mmol) and diisopropylethylamine (0.42 mL, 2.40 mmol), to obtain 265 mg of the title compound as a pale yellow solid (87%).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:3]=1[NH:4][CH:5]1[CH2:10][O:9][C:7](=[O:8])[CH2:6]1.[CH3:16][O:17][CH2:18][C:19](Cl)=[O:20]>>[CH3:16][O:17][CH2:18][C:19]([N:4]([CH:5]1[CH2:10][O:9][C:7](=[O:8])[CH2:6]1)[C:3]1[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:2]=1[CH3:1])=[O:20]
Reactant: COCC(=O)Cl
Reactant: Cc1cccc(C)c1NC1COC(=O)C1
Product: COCC(=O)N(c1c(C)cccc1C)C1COC(=O)C1

Procedure:
3-(2,6-dimethylanilino)-gamma-butyrolactone was acylated with methoxyacetyl chloride according to the procedure described in Example 2C above to yield N-methoxyacetyl-3-(2,6-dimethylanilino)-gamma-butyrolactone.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:24]C3CCCCO3)[CH:14]=[C:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]1=2)[CH3:2].Cl>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:24])[CH:14]=[C:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(OCc3ccccc3)c21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(O)cc(OCc3ccccc3)c21
Yield: 88.3 %

Procedure:
A solution of [4-benzyloxy-1-hydroxy-6-(tetrahydro-pyran-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (1.00 g, 2.35 mmol) in THF (10 mL) was treated with 6N HCl (0.3 mL) at 0° C. for 2 h. The mixture was diluted with ethyl acetate and washed with brine. The organic phase was separated, dried (Na2SO4), and concentrated. The residue was purified by the flash column chromatography (silica, hexanes/ethyl acetate=2:3) to afford the title compound (710 mg, 89%). 1H NMR (300 MHz, CD3OD) δ 7.51-7.38 (m, 5H), 6.64 (s, 1H), 6.61 (s, 1H), 5.58-5.53 (m, 1H), 5.14 (s, 2H), 4.12 (q, 2H), 3.28-3.20 (m, 1H), 2.47-2.43 (m, 1H), 1.22 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[NH2:17][CH2:18][C:19]([OH:21])=[O:20].CCN(C(C)C)C(C)C>Cl>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:17][CH2:18][C:19]([OH:21])=[O:20])[CH:3]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: NCC(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2cc(NCC(=O)O)ncn2)cc1
Temperature: 200 °C
Yield: 60 %

Procedure:
45 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 14 mg of 2-aminoacetic acid and 56 mg of DIPEA were dissolved in 1 mL of n- and charged into a microwave vial and the vial obtained was heated to 200° C. for 45 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc: NEt3=50:1 solvent mixture. 2-(6-(4-Methoxyphenylamino)pyrimidin-4-ylamino)acetic acid in the form of a colorless solid was obtained.
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:8]([C:18]2[CH:23]=[CH:22][C:21](C(=O)C(F)(F)F)=[CH:20][CH:19]=2)[N:7]=1)=[O:4].[C:32](OC(=O)CC)(=O)CC>CN(C)C1C=CN=CC=1.O>[C:18]1([N:8]2[CH:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[CH2:10][C:6]([NH:5][C:3](=[O:4])[CH2:2][CH3:32])=[N:7]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCC(=O)OC(=O)CC
Reactant: Cc1ccc(C2CC(NC(=O)C(F)(F)F)=NN2c2ccc(C(=O)C(F)(F)F)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Product: CCC(=O)NC1=NN(c2ccccc2)C(c2ccc(C)cc2)C1
Temperature: 25 °C

Procedure:
A mixture of 4.5 g. of 3-amino-1-phenyl-5-p-tolyl-2-pyrazoline (prepared in Example 3), 20.0 ml. of propionic anhydride and 200 mg. of 4-dimethylaminopyridine is heated on a steam bath for 2 hours. The reaction mixture is cooled to room temperature then water is added to separate a solid. The solid is collected then is dissolved in dichloromethane. The solution is passed through a short column of a hydrous magnesium silicate. The effluent is heated to reflux and hexane is added until turbidity appears. The mixture is cooled and filtered to collect a solid. The solid is recrystallized again from 80% ethanol. This material is dissolved in 100 ml. of methanol, then 200 mg. of potassium carbonate is added and the mixture is refluxed for 15 minutes. Water is added until turbidity appears. The mixture is cooled and filtered to collect the solid. The solid is dissolved in dichloromethane. This solution is columnized and recrystallized as described above to yield 2.4 g. of the desired product as colorless needles, m.p. 123.5°-125° C.
Reaction SMILES: C(OC1N=C2C(N=C(OC)N2CCCCCl)=C(N)N=1)CCC.FC(F)(F)C(O)=O.[CH3:30][O:31][C:32]1[N:33]=[C:34]2[C:39]([N:40]=1)=[C:38]([NH2:41])[NH:37][C:36]([O:42][C@@H:43]([CH3:46])[CH2:44][CH3:45])=[N:35]2.Br[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][Cl:53]>>[Cl:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][N:33]1[C:32]([O:31][CH3:30])=[N:40][C:39]2[C:34]1=[N:35][C:36]([O:42][C@@H:43]([CH3:46])[CH2:44][CH3:45])=[N:37][C:38]=2[NH2:41]
Reactant: CC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: ClCCCCCBr
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCCl)c2n1

Procedure:
Prepared similarly to Intermediate 14 from 8-(methyloxy)-2-{[(1S)-1-methylpropyl]oxy}-1H-purin-6-amine trifluoroacetate and 1-bromo-5-chloropentane.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:19])[NH:15][CH2:16][CH2:17][CH3:18])(C)(C)C.C(Cl)Cl.FC(F)(F)C(O)=O>>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([NH:15][CH2:16][CH2:17][CH3:18])=[O:19]
Reactant: CCCNC(=O)c1ccccc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCNC(=O)c1ccccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-Propylcarbamoyl-phenyl)-carbamic acid tert-butyl ester (0.570 g, 0.00205 mol) was dissolved in Methylene chloride (5.0 mL, 0.078 mol) and Trifluoroacetic Acid (3.0 mL, 0.039 mol) was added to the mixture. The reaction was allowed to stir overnight at room temperature. The reaction mixture was reduced under nitrogen and the crude product (360 mg, 99%) was used in subsequent chemistry without further purification. The excess TFA will be neutralized in the next synthetic step. LC/MS (ESI): 179.24.
Reaction SMILES: C([O:5][C:6](=[O:24])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=2)(=[O:16])=[O:15])[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Br:23][C:19]1[CH:18]=[C:17]([S:14]([N:11]2[CH:12]=[CH:13][C:9](/[CH:8]=[CH:7]/[C:6]([OH:24])=[O:5])=[CH:10]2)(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2cccc(Br)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccn(S(=O)(=O)c2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.6 %

Procedure:
A mixture of 2.0 g (E)-3-[1-(3-bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid tert-butyl ester with 60 ml dichloromethane and 6.0 ml TFA is stirred at ambient temperature for 24 h. The dichloromethane and TFA is evaporated and the residue is coevaporated with toluene for a few times. By this method 0.77 g brown solid is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]2=[N:9][C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:25]([F:28])([F:27])[F:26])=[C:16]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:17]=3)=[CH:11][N:5]2[N:4]=1)#[N:2].CC[OH:31].CS(C)=O.[OH-].[Na+].OO>O>[CH3:21][C:20]([CH3:23])([CH3:22])[C:19]([NH:18][C:16]1[CH:17]=[C:12]([C:10]2[N:9]=[C:6]3[N:5]([CH:11]=2)[N:4]=[C:3]([C:1]([NH2:2])=[O:31])[CH:8]=[CH:7]3)[CH:13]=[CH:14][C:15]=1[C:25]([F:28])([F:26])[F:27])=[O:24]
Reactant: CCO
Reactant: CC(C)(C)C(=O)Nc1cc(-c2cn3nc(C#N)ccc3n2)ccc1C(F)(F)F
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)C(=O)Nc1cc(-c2cn3nc(C(N)=O)ccc3n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
An 8 mL vial is charged with N-[5-(6-cyanoimidazo[2,1-f]pyridazin-2-yl)-2-(trifluoromethyl)phenyl]-2,2-dimethyl-propanamide (0.019 g, 0.05 mmol), EtOH-DMSO (1.2 mL, 5:1), NaOH (0.1 mL, 1M in water), and H2O2 (0.1 mL, 30% in water). The mixture is stirred for 2 hr at room temp, diluted with water (4 mL), extracted EtOAc (2×) and CH2Cl2 (1 x). Organics are dried, concentrated onto celite and purified on silica (0-100% EtOAc in CH2Cl2) to give the title compound (12 mg, 60% yield). LCMS m/z=406.5 [M+H]+, tR=2.12 min. (compound same as Example 180)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[NH:5][CH:6]([CH3:11])[CH2:7][C:8]([OH:10])=O.[OH-].[Na+]>O>[Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:4]2[C:3]=1[C:8](=[O:10])[CH2:7][CH:6]([CH3:11])[NH:5]2
Reactant: CC(CC(=O)O)Nc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1CC(=O)c2c(ccc(Cl)c2Cl)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.8 %

Procedure:
300 g of polyphosphoric acid was added to 99.24 g (0.40 mole) of the 3-(3,4-dichloroanilino)butyric acid and this mixture was stirred at 90°-100° C. for 4 hours. After being allowed to cool to room temperature, the resulting reaction solution was diluted with 3 liters of water and then adjusted to pH 4-5 with an aqueous sodium hydroxide solution. Then, the solid matter which separated out was extracted with chloroform and this extract was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (using chloroform as the developing solvent). The fraction containing the desired product was evaporated to dryness under reduced pressure and the resulting residue was recrystallized from benzene to obtain 9.94 g (10.8% yield) of 5,6-dichloro-2-methyl-4-oxo-1,2,3,4-tetra-hydroquinoline in the form of yellow crystals. On the other hand, another fraction was worked up in the same manner as above to obtain 13.53 g (14.7% yield) of a structural isomer thereof, or 6,7-dichloro-2-methyl- 4-oxo-1,2,3,4-tetrahydroquinoline, in the form of yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].[F:27][C:28]([F:39])([F:38])[C:29]1[N:33]2[CH2:34][CH2:35][NH:36][CH2:37][C:32]2=[N:31][N:30]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([N:36]4[CH2:35][CH2:34][N:33]5[C:29]([C:28]([F:39])([F:27])[F:38])=[N:30][N:31]=[C:32]5[CH2:37]4)=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(Br)cc2)C1
Reactant: FC(F)(F)c1nnc2n1CCNC2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(N3CCn4c(nnc4C(F)(F)F)C3)cc2)C1
Yield: 62 %

Procedure:
To a solution of 1-(4-bromo-phenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Intermediate I, 400 mg, 1.18 mmol) in anhydrous toluene (5 mL) were added Pd2(dba)3 (5.4 mg, 0.006 mmol), BINAP (11.0 mg, 0.018 mmol), sodium tert-butoxide (227 mg, 2.34 mmol) and 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (prepared by the procedure as described in reference J. Med. Chem., 2005, 48, 141-151) (340 mg, 1.77 mmol) at r.t. and reaction mixture was refluxed for 6 h. Reaction mixture was then concentrated and the crude product was purified by column chromatography (silica gel, 6:4 EtOAc:Pet. ether) to afford the title compound as white solid (330 mg, 62%).
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([C:22]#[C:23][CH2:24][N:25]([CH2:33][CH2:34][CH2:35][O:36][CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][O:38]4)[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:16]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H][H]>[Rh]>[C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([CH2:22][CH2:23][CH2:24][N:25]([CH2:33][CH2:34][CH2:35][O:36][CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][O:38]4)[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:16]=3)=[O:14])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CC(C)(C)OC(=O)N(CC#Cc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1)CCCOC1CCCCO1
Reactant: [H][H]
Agent: [Rh]
Product: CC(C)(C)OC(=O)N(CCCOC1CCCCO1)CCCc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Yield: 68.1 %

Procedure:
A stirred suspension of tert-butyl 3-(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)prop-2-ynyl[3-(tetrahydro-2H-pyran-2-yloxy)propyl]carbamate (Example 2(iii)) (0.35 g) and 5% rhodium on carbon (0.020 g) was stirred under a positive pressure (2 barr) of hydrogen until no further uptake was observed. The mixture was filtered and concentrated. The residue was purified by chromatography on silica gel eluting with dichloromethane:acetone (19:1 to 9:1) to afford the sub-titled compound (0.24 g) as a colourless gum.
Reaction SMILES: [O:1]=[C:2]1[O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:12](=O)[CH2:13][CH2:14][N:3]1[C:4]=23.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>C(O)C.O>[O:1]=[C:2]1[O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:12](=[N:17][OH:18])[CH2:13][CH2:14][N:3]1[C:4]=23
Reactant: O=C1CCN2C(=O)OCc3cccc1c32
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1OCc2cccc3c2N1CCC3=NO

Procedure:
6,7-Dihydro-3,7-dioxo-1H,3H,5H-pyrido[3,2,1-ij][3,1]benzoxazine (5 g), hydroxylamine hydrochloride (2.1 g) and sodium acetate (7.5 g) were dissolved in a mixed solvent of ethanol-water (5:1) (90 ml) and the mixture was refluxed for 2 hours. After completion of the reaction, the solvent was distilled off and the resulting residue was poured into water. Crystals which precipitated were collected by filtration and dried to give 6,7-dihydro-3-oxo-7-hydroxyimino-1H,3H,5H-pyrido[3,2,1-ij][3,1]benzoxazine. The compound was dissolved in acetic acid (150 ml) and platinum oxide (250 mg) was added thereto. The mixture was subjected to catalytic reduction at 50° C. and 4 atmospheres. After completion of the catalytic reduction, catalyst was filtered off and the filtrate was concentrated to give 6,7-dihydro-3-oxo-7-amino-1H,3H,5H-pyrido [3,2,1-ij][3,1]benzoxazine (5 g).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:8][CH2:9][CH:10]([NH:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:11][O:12][C:13](=[O:15])[CH3:14])(=[O:7])[CH3:6].C(N(CC)CC)C>>[C:5]([O:8][CH2:9][CH:10]([N:16]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:1](=[O:3])[CH3:2])[CH2:11][O:12][C:13](=[O:15])[CH3:14])(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CC(=O)OCC(COC(C)=O)NCC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Product: CC(=O)OCC(COC(C)=O)N(CC(=O)OC(C)(C)C)C(C)=O
Yield: 50.3 %

Procedure:
Acetyl chloride (0.357 ml, 5.0 mmol) was added dropwise to a stirred solution of tert-butyl 2-{[1,3-bis(acetyloxy)propan-2-yl]amino}acetate (1.22 g, 4.2 mmol) and triethylamine (0.696 ml, 5.0 mmol). After 2 hours the reaction was quenched by the addition of water. The organic phase was separated and washed with further aliquots of water before being dried over MgSO4, filtered and concentrated in vacuo. The title compound was purified by silica column chromatography eluting with 25% EtOAc:Hept to yield the title compound (0.7 g, 50%). 1H NMR (250 MHz, CHLOROFORM-d) δ 4.04-4.44 (5H, m), 3.98 (1H, s), 3.88 (1H, s), 2.08 (3H, s), 2.05 (6H, s), 1.47 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH3:21])=[C:9]([O:12]CC3C=CC=CC=3)[CH:10]=2)[N:5]=[C:4]([N:22]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:30])[CH2:24][CH2:23]2)[N:3]=1>[Pd].C(O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH3:21])=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([N:22]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[O:30])[CH2:24][CH2:23]2)[N:3]=1
Reactant: COc1cc2nc(N3CCCN(C(=O)N4CCOCC4)CC3)nc(N)c2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1cc2nc(N3CCCN(C(=O)N4CCOCC4)CC3)nc(N)c2cc1O
Temperature: 50 °C
Reaction time: 72 h
Yield: 53.5 %

Procedure:
10% palladium on charcoal (3 g) was added to a suspension of 4-amino-6-benzyloxy-7-methoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinazoline (16.35 g, 0.033 mol) in ethanol (800 ml) and the reaction stirred at 50° C. under a hydrogen atmosphere of 414 kPa (60 p.s.i.) for 72 hours. On cooling, the reaction mixture was filtered through Arbocel™, washed well with further ethanol and the filtrate concentrated under reduced pressure. The crude product was purified on silica gel eluting with a solvent gradient of 0.880 aqueous ammonia:methanol:dichloromethane (0.5:3.5:96 to 1:7:92, v/v) to give the subtitle compound as a white solid (7.1 g, 53%). Rf 0.17 (0.880 aqueous ammonia:methanol:dichloromethane 1:7:92, v/v). MS m/z 403 (MH)+.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5].[F-:16].[K+]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC>[F:16][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5]
Reactant: O=C(OCC(F)(F)F)c1ccccc1Cl
Reactant: [F-]
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Product: O=C(OCC(F)(F)F)c1ccccc1F
Yield: 60.5 %

Procedure:
Into a 1 l glass reactor equipped with a condenser, 238.5 g (1 mol) of 2,2,2-trifluoroethyl 2-chlorobenzoate, 87 g (1.5 mol) of spray dried potassium fluoride, 23.9 g of tetrabutyl phosphonium bromide and 480 g of sulforane were charged and reacted at 180° C. for 20 hours under vigorous stirring. After cooling, the inorganic salt was removed by filtration, and the filtrate was distilled under reduced pressure to obtain 134.3 g (yield: 60.5%) of 2,2,2-trifluoroethyl 2-fluorobenzoate.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8]C2C=CC(Cl)=C(NC(=O)C3C=CC=C(Cl)C=3)C=2)=[O:7])=[CH:4][N:3]=1.C(N1CCNCC1)(=O)C>>[C:6]([NH2:8])(=[O:7])[C:5]1[CH:26]=[CH:27][CH:2]=[N:3][CH:4]=1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2cccc(Cl)c2)c1)c1ccc(Cl)nc1
Agent: CC(=O)N1CCNCC1
Product: NC(=O)c1cccnc1

Procedure:
6-chloro-N-(4-chloro-3-(3-chlorobenzamido)phenyl)nicotinamide (0.16 mmol) was used in general procedure 3 with 1-acetylpiperazine (0.83 mmol). The product was purified by RP-HPLC to give 6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(3-chlorobenzamido)phenyl))phenyl)nicotinamide. MS (Q1) 512.0 (M)+
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:9][C:10]([NH:12][OH:13])=[O:11])([CH3:8])([CH3:7])[CH3:6]>>[C:1]([O:13][NH:12][C:10]([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NO
Product: CC(=O)ONC(=O)OC(C)(C)C

Procedure:
[(tert-Butoxy)carbonyl]amino acetate is prepared from acetyl chloride and N-tert-butoxycarbonyl hydroxylamine according to Scheme 1 and the method described by Carpino et al. J. Am. Chem. Soc. 1959, 955-957. (10 g, 100%), 1H NMR (500 MHz, DMSO-d6) δ ppm 10.57 (1H, br. s.), 2.10 (3H, s), 1.41 (9H, s).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]([CH2:11][CH2:12][OH:13])[C:6]([CH3:10])=[C:7]([CH3:9])[N:8]=1.Cl[CH2:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl>O1CCCC1>[CH3:3][C:4]1[N:5]([CH2:11][CH2:12][O:13][CH2:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:6]([CH3:10])=[C:7]([CH3:9])[N:8]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Cc1nc(C)n(CCO)c1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)COCCn1c(C)nc(C)c1C
Reaction time: 4 h
Yield: 36.9 %

Procedure:
Sodium hydride (80% dispersion in oil) (7.8 g) was suspended in dry tetrahydrofuran (100 ml). 2-(2,4,5-Trimethylimidazol-1-yl)ethanol (20 g) was added and the suspension sonicated until there was no further gas evolution. Ethyl 4-chloroacetoacetate (21.3 g) in dry tetrahydrofuran (25 ml) was added over 0.75 hours with sonication, and sonication continued for a further 4 hours. The suspension was poured into 2N hydrochloric acid (200 ml) and the tetrahydrofuran removed under vacuum. The aqueous solution was washed with dichloromethane (3×50 ml) and then neutralised with potassium carbonate. The aqueous phase was extracted with dichloromethane (5×100 ml), the combined organic extracts dried over magnesium sulphate and solvent removed under vacuum. The crude product was chromatographed over silica eluting with a mixture of methanol and ethyl acetate (1:3) to yield the title compound as a pale red oil 13.5 g (37%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][C:10]1[C:11]([O:36][CH3:37])=[CH:12][C:13]([O:34][CH3:35])=[C:14](/[CH:16]=[CH:17]/[C:18]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH:29][CH2:30][C:31]([OH:33])=[O:32])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[O:19])[CH:15]=1>C(#N)C.C(O)C.[Pd](Cl)Cl>[NH:1]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:8]=[C:9]1[C:10]1[C:11]([O:36][CH3:37])=[CH:12][C:13]([O:34][CH3:35])=[C:14](/[CH:16]=[CH:17]/[C:18]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH:29][CH2:30][C:31]([OH:33])=[O:32])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[O:19])[CH:15]=1
Reactant: COc1cc(OC)c(/C=C/C(=O)c2ccc(S(=O)(=O)NCC(=O)O)cc2)cc1C#Cc1ccccc1N
Agent: Cl[Pd]Cl
Solvent: CCO
Solvent: CC#N
Product: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)NCC(=O)O)cc1
Yield: 22.9 %

Procedure:
A suspension of (4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonylamino)acetic acid (Ex-51A, 153 mg, 0.294 mmol) in acetonitrile (130 mL) was purged with nitrogen gas for 10 minutes. Palladium (II) chloride (5.2 mg, 0.029 mmol) was added to the reaction vessel. The reaction mixture was refluxed for 2 h. The reaction mixture was gravity filtered and yielded a red solid. The crude was swished in ethanol to give 35 mg (23%) of the title compound as a red solid, mp 189–190° C. 1H-NMR (300 MHz, DMSO-d6) 11.18 (br s, 1H), 8.25 (m, 3H), 8.06 (d, 1H, J=15.3 Hz), 7.89 (m, 5H), 7.49 (d, 1H, J=7.8 Hz), 7.41 (d, 1H, J=8.1 Hz), 7.03 (t, 1H, J=6.6 (m, 1H), 6.83 (s, 1H), 4.04 (s, 3H), 3.99 (s, 3H). MS (ESI, for C27H24N2O7S) Found: 520 [(M+H)+].