Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[O:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[CH:16][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Oc3ccccc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1=C(c2ccc(Oc3ccccc3)cc2)CCNC1
Yield: 47 %

Procedure:
To a 3 ml of methylene chloride solution of 772 mg of N-tert-butoxycarbonyl-4-(4-phenoxyphenyl)-4-piperidinol synthesized in Step A, a 3 ml of trifluoroacetic acid was dropwise added under ice cooling. The resultant mixture was stirred at room temperature for 2 hours, then adjusted by 10% aqueous sodium hydroxide solution to pH=9 to 10 and extracted with ether. The extract was dried, filtered, then concentrated under reduced pressure to give a residue, which was then recrystallized from ether/methylene chloride to give 4-(4-phenoxyphenyl)-1,2,3,6-tetrahydropyridine in an amount of 250 mg (yield 47%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:6]([O:8][CH3:9])=[O:7].[O-:14][C:15]#[N:16].[K+].CO.CN(C)[CH:22]=[O:23]>C(OCC)(=O)C.O>[Cl:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:2][NH:16][C:15]([O:23][CH3:22])=[O:14]
Reactant: N#C[O-]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(Cl)c(CBr)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)NCc1cc(C(=O)OC)ccc1Cl
Temperature: 90 °C
Reaction time: 4 h

Procedure:
16.0 g of the obtained methyl 3-bromomethyl-4-chlorobenzoate, 15.0 g of potassium cyanate and 35 ml of methanol were added to 200 ml of N,N-dimethylformamide, followed by stirring at 90° C. for 4 hours. After completion of the reaction, water was added to the reaction mixture, extraction with ethyl acetate was carried out, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were washed with isopropanol to obtain 25.2 g of methyl 4-chloro-3-(methoxycarbonylaminomethyl)benzoate as white crystals.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C=O)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([O:5][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1

Procedure:
While cooling on ice, Boc-L-Pro-OH (1.08 g, 5.0 mmol) and benzyl bromide (0.893 ml, 75 mmol) were reacted in DMF (10 ml) in the presence of triethylamine (10.5 ml, 75 mmol) to obtain Boc-L-Pro-OBzl as an oily product. This product was reacted under ice-cooling with 2 N HCl/dioxane (5 eq.) for three hours to obtain H-L-Pro-OBzl-HCl.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:42]=[C:43]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)[CH2:44][NH:45][C:46]([C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:50][CH:49]=1)=[O:47]>CN(C=O)C.O>[OH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([N:63]1[CH2:62][CH2:61][N:60]([C:43](=[O:42])[CH2:44][NH:45][C:46]([C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:50][CH:49]=2)=[O:47])[CH2:65][CH2:64]1)=[O:15]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2O)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 2-hydroxy-benzoic acid (35.5 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 60% EtOAc in hexane as eluent). Further purification by preparative HPLC afforded 58 mg (50.9% yield) of biphenyl-4-carboxylicacid {2-[4-(2-hydroxy-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 93.06%, 1H NMR: (DMSO) δ 8.6 (t, 1H), 8.0-7.92 (d, 2H), 7.84-7.7 (q, 4H), 7.56-7.46 (t, 2H), 7.44-7.38 (t, 1H), 7.3-7.2 (t, 1H), 7.2-7.12 (d, 1H), 6.94-6.8 (m, 2H), 4.2 (s, 2H), 3.7-3.5 (s, 5H), 3.3-3.1 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[C:9](=O)([O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[O:10]N1C(=O)CCC1=O.C(N(CC)CC)C.S([O-])(O)(=O)=O.[Na+]>O1CCOCC1.O>[CH3:7][CH:6]([CH3:8])[C@@H:2]([NH:1][C:9]([O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[O:10])[C:3]([OH:5])=[O:4]
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: CC(C)[C@@H](N)C(=O)O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CC(C)[C@@H](NC(=O)OCC[Si](C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
A mixture of (R)-2-amino-3-methylbutanoic acid (2.01 g, 17.16 mmol) and 2,5-dioxopyrrolidin-1-yl 2-(trimethylsilyl)ethyl carbonate (4.89 g, 18.87 mmol) in 1:1 dioxane/water (40 mL) was treated with triethylamine (3.59 mL, 25.7 mmol), and the mixture was stirred for two days at room temperature. The mixture was acidified with saturated sodium hydrogen sulfate and extracted 3× with ethyl acetate. The combined organic phases were washed with saturated sodium hydrogen sulfate, water, and brine, then dried over sodium sulfate and concentrated in-vacuo to yield the title compound (4.17 g, 15.96 mmol, 93% yield) as an amber oil.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C([CH:10]1[CH2:15][CH:14]2[O:16]C1C=C2)(OC)=O.Cl.C(Cl)Cl>O>[CH2:1]([N:3]([CH2:4][CH3:5])[C:14](=[O:16])[CH:15]=[CH2:10])[CH3:2]
Reactant: COC(=O)C1CC2C=CC1O2
Reactant: CCNCC
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)N(CC)CC
Temperature: 140 °C
Reaction time: 15 h

Procedure:
7.2 parts 30% methanolic Na-methylate solution are added to 36.5 parts diethylamine. 77 parts 2-carbomethoxy-7-oxabicyclo(2,2,1)hept-5-ene are added drop-wise at 40° C. The reaction medium is then stirred for 15 hours at this temperature and neutralised with 4 parts concentrated hydrochloric acid. 100 parts methylene chloride and 50 parts water are added, the organic phase separated off, and the aqueous phase extracted 3 times with 25 parts methylene chloride in each instance. The combined organic phases are reduced in a rotary evaporator at a bath temperature of 90° C. and under a vacuum of 20 Torr. The residue is heated under a vacuum of 20 Torr to 110° to 120° C. (bath temperature 140° C.). On conclusion of the furane separation, the sedimentation temperature increases and the product distills over at the now lowered pressure. 21 parts N,N-diethylacrylamide with a boiling point of 55° C. at 1 Torr are obtained.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Cl:32][C:33]1[CH:40]=[CH:39][C:38]([N:41]2[CH:45]=[CH:44][CH:43]=[N:42]2)=[CH:37][C:34]=1[CH:35]=[O:36]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([CH:35]([C:34]3[CH:37]=[C:38]([N:41]4[CH:45]=[CH:44][CH:43]=[N:42]4)[CH:39]=[CH:40][C:33]=3[Cl:32])[OH:36])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: O=Cc1cc(-n2cccn2)ccc1Cl
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(O)c1cc(-n2cccn2)ccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (356 mg, 0.68 mmol) in THF was added isopropylmagnesium chloride (0.75 mL, 1.5 mmol) slowly at 0° C. One hour later 2-chloro-5-pyrazol-1-yl-benzaldehyde (140 mg, 0.68 mmol) was added and warmed up the reaction mixture to RT for 2 hours, quenched with water, extracted with ethyl acetate, concentrated and purified by flash column to give 4-chloro-N-{5-chloro-2-[(2-chloro-5-pyrazol-1-yl-phenyl)-hydroxy-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].O=C1[CH2:13][C@H:12]2[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H]([CH2:10][CH2:11]2)C1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:5]=[C:4]1[CH2:13][CH:12]2[N:14]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH:2]([CH2:10][CH2:11]2)[CH2:3]1
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CC(=O)C2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (2.38 g, 6.6 mmol) in dry THF at 0° C. was added n-BuLi (2.7 mL, 2.5 M) dropwise. After stirring at 0° C. for 30 min, (1R,5S)-tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (500 mg, 2.2 mmol) was added and the mixture was stirred at 0° C. for additional 16 hrs. The reaction was quenched by sat. NH4Cl and extracted with EtOAc (50 mL×3) and purified by SGC (eluting with petroleum ether/ethyl acetate=20/1) to give target compound (130 mg, 27%). 1H NMR (500 MHz, CDCl3) δ 4.77 (t, J=4.0 Hz, 2H), 4.21 (br s, 1H), 4.11 (br s, 1H), 2.43-2.33 (m, 2H), 2.01 (s, 1H), 1.98 (s, 1H), 1.79 (d, J=3.0 Hz, 2H), 1.53-1.49 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[N:27]1[C:31](=[O:32])[CH2:30][CH2:29][C:28]1=[O:33]>CN(C=O)C.C(OCC)(=O)C>[C:28]1(=[O:33])[N:27]([O:10][C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[C:31](=[O:32])[CH2:30][CH2:29]1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: O=C1CCC(=O)N1O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(O)cc1)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a solution of 4-hydroxyphenylacetic acid (3.0 g, 20 mmol) in DMF was added HOBT (3.7 g, 24 mmol) followed by EDC (4.2 g, 22 mmol) and the mixture was stirred at room temperature for 30 min. N-hydroxysuccinimide (2.3 g, 20 mmol) was added and stirred at room temperature overnight. The resulting mixture was diluted with ethyl acetate (150 ml), extracted with 5% citric acid (2×), saturated NaHCO3 (2×) and brine (1×) and was dried over anhydrous Na2SO4. Following removal of the solvent in vacuo the product was dissolved in CH2Cl2 and precipitated with hexanes to afford 4-hydroxyphenylacetic acid succinimidyl ester (3.9 g, 78%). 1H NMR (300 MHz, DMSO-d6): 2.79 (s, 4H), 3.93 (s, 2H), 6.72 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.5 Hz, 2H), 9.41 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3[CH2:13][CH2:12]3)[CH:10]=[C:6]2[N:5]=[C:4]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.CN1C(=O)CCC1>CN(C=O)C>[CH:11]1([C:9]2[CH:10]=[C:6]3[N:5]=[C:4]([NH:14][C:15](=[O:26])[C:16]4[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=4)[CH:3]=[C:2]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[N:7]3[N:8]=2)[CH2:13][CH2:12]1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nc(C4CC4)cc3n2)cc1
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCOCC3)n3nc(C4CC4)cc3n2)cc1
Temperature: 25 °C

Procedure:
In a 2 mL microwave vial was placed N-(7-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2J, 100 mg, 0.27 mmol) and morpholine (47.0 mg, 0.54 mmol). To the sealed vial was then added NMP (2 ml) and the mixture was then heated in the microwave at 120° C. for 15 minutes. After cooling to room temperature, DMF (1 ml) was added. The crude product mixture was filtered by syringe filter and purified by preparatory HPLC (35-45% ACN/water, TFA mode). Lyophilization of the collected fractions gave the titled compound product (42 mg, 37% yield) as an off-white powder. 1H NMR (400 MHz, DMSO-d6) δ=10.84 (s, 1 H), 7.99 (d, J=8.1 Hz, 2 H), 7.59 (d, J=7.8 Hz, 2 H), 7.34 (s, 1 H), 6.06 (s, 1 H), 5.18 (s, 1 H), 3.97-3.58 (m, 8 H), 2.15-1.96 (m, 1 H), 1.45 (s, 5 H), 1.08-0.92 (m, 2 H), 0.88-0.74 (m, 2 H); ESI-MS: m/z 422.2 (M+H)+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CO.[OH-].[Na+]>CN(C=O)C.O>[NH:24](/[C:13](=[C:6]1\[C:5](=[O:23])[NH:4][C:12]2[C:7]\1=[CH:8][CH:9]=[CH:10][CH:11]=2)/[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccccc2/C1=C(/Nc1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
450 mg (1.5 mmol) of 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 0.41 ml of (4.5 mmol) of aniline are stirred in 7 ml of DMF for 90 minutes at 120° C. After cooling to ambient temperature 7 ml of methanol and 3 ml of 1N sodium hydroxide solution are added. The mixture is stirred for 20 minutes, then diluted with water, the crystalline reaction product is suction filtered and dried.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([OH:33])[CH:27]=1)[C:10]([O:12][CH2:13][C@H:14]([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18])[CH3:15])=[O:11])=O)(C)(C)C.[ClH:34]>O1CCOCC1>[ClH:34].[NH2:8][C@@H:9]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([OH:33])[CH:27]=1)[C:10]([O:12][CH2:13][C@H:14]([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18])[CH3:15])=[O:11]
Reactant: C[C@H](COC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C)OC(=O)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](COC(=O)[C@@H](N)Cc1ccc(O)c(O)c1)OC(=O)c1ccccc1
Yield: 87 %

Procedure:
A solution of (2R)-2-phenylcarbonyloxypropyl (2S)-2-(tert-butoxycarbonyl)amino-3-(3,4-dihydroxyphenyl)propanoate 2 (6.3 g, 13.7 mmol) in 50 mL of 4N HCl in dioxane was stirred at room temperature for 30 min. The reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in about 20 mL of anhydrous acetonitrile and 4 mL of ether. The solution was refrigerated, and the resulting white precipitate was filtered, washed with ether, and dried under vacuum to afford 4.7 g (87% yield) of the hydrochloride salt 3 as a white solid. NMR (400 MHz, CD3OD): δ 1.40 (d, J=6.4 Hz, 3H), 2.99 (dd, J=7.6, 14.4 Hz, 1H), 3.10 (dd, J=5.6, 14.4 Hz, 1H), 4.24 (dd, J=6, 8 Hz, 1H), 4.38 (dd, J=6.8, 11.6 Hz, 1H), 4.52 (dd, J=3.2, 11.6 Hz, 1H), 5.40 (m, 1H), 6.52 (dd, J=2.2, 8.4 Hz, 1H), 6.66 (d, J=2.2 Hz, 1H), 6.69 (d, J=8.2 Hz, 1H), 7.47 (t, J=7.6 Hz, 2H), 7.60 (t, J=7.6 Hz, 1H), 8.02 (d, J=7.6 Hz, 2H). MS (ESI) m/z 360.15 (M+H)+ and 358.09 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][C:24]([NH2:27])([CH3:26])[CH3:25]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:25][C:24]([NH2:27])([CH3:26])[CH2:23][NH:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)(N)CN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(N)CNc1c([N+](=O)[O-])cnc2ccccc12
Reaction time: 48 h
Yield: 94.1 %

Procedure:
A stirred solution of 4-chloro-3-nitroquinoline (2.08 g, 10.0 mmol) in 20 mL of anhydrous CH2Cl2, under N2, was treated with triethylamine (2.79 mL, 20.0 mol) and 1,2-diamino-2-methylpropane (1.15 mL, 11.0 mmol). After stirring for 2 d, the reaction mixture was diluted with 100 mL of CHCl3 washed with H2O (3×50 mL) and brine (50 mL). The organic portion was dried over Na2SO4 and concentrated to give 2-methyl-N1-(3-nitroquinolin-4-yl)propane-1,2-diamine (2.45 g) as a bright yellow solid.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[C:14]([CH3:19])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[C:14]([CH3:19])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])([OH:7])=[O:5]
Reactant: CCOC(=O)c1cc2c(C)cccc2n1CCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(C)cccc2n1CCC(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.4 %

Procedure:
A mixture of ethyl 1-(2-tert-butoxycarbonylethyl)-4-methyl-1H-indole-2-carboxylate (3.76 g, 11.4 mmol), trifluoroacetic acid (14.8 g, 130 mmol) and dichloromethane (50 ml) was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue, followed by extraction with diethyl ether (three times). The extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain ethyl 1-(2-carboxyethyl)-4-methyl-1H-indole-2-carboxylate (3.12 g).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24]C=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC3OCCOC=3C=2)C(F)=CN=1.CC1C(N)=C(C)[O:49][N:48]=1>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[C:21]([CH3:22])=[N:48][O:49][C:25]=4[CH3:24])[N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: Cc1noc(C)c1N
Agent: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Cc1noc(C)c1Nc1ncc(F)c(Nc2ccc3c(c2)OCCO3)n1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3,5-dimethyl-4-isoxazolamine were reacted to yield N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3,5-dimethylisoxazol-4-yl)-2,4-pyrimidinediamine. LCMS: ret. time: 18.89 min.; purity: 98%; MS (m/e): 358 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH:33]([CH3:35])[CH3:34])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:36])=[CH:16][C:15]=2[F:37])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][NH2:39]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH:33]([CH3:35])[CH3:34])[C:23]4[N:24]=[C:25]([NH:39][CH3:38])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:36])=[CH:16][C:15]=2[F:37])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)no4)c(F)cc3C)c(=O)n(C(C)C)c2n1
Reactant: CN
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)no4)c(F)cc3C)c(=O)n(C(C)C)c2n1
Yield: 50 %

Procedure:
In a procedure analogous to Example A1, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-isopropyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)urea (0.1 g, 0.2 mmol) and methylamine were combined to provide 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-isopropyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)urea (45 mg, 50% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.78 (brs, 1H), 8.57 (brs, 1H), 7.85 (d, J=9 Hz, 1H), 7.75 (brs, 1H), 7.62 (s, 1H), 7.15 (d, J=12 Hz, 1H), 6.00 (s, 1H), 5.74 (m, 1H), 2.89 (d, J=5 Hz, 3H), 2.07 (s, 3H), 1.56 (d, J=6 Hz, 6H), 1.21 (s, 9H); MS (ESI) m/z: 508.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][CH:18]=[CH:17]2)=[O:13].Cl.Cl.[CH3:26][N:27]([CH3:35])[C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:28]([N:27]([CH3:35])[CH3:26])[CH:29]=2)=[O:7])=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][CH:18]=[CH:17]2)=[O:13]
Reactant: O=C(Cl)c1ccc(Cl)c(NC(=O)c2ccc3ncccc3c2)c1
Reactant: CN(C)c1cccc(N)c1
Agent: Cl
Product: CN(C)c1cccc(NC(=O)c2ccc(Cl)c(NC(=O)c3ccc4ncccc4c3)c2)c1

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-3-(6-quinolylcarbonylamino)benzoyl chloride was reacted with 3-dimethylaminoaniline dihydrochloride to give the title compound; NMR Spectrum: (DMSOd6) 3.04 (s, 6H), 6.5 (d, 1H), 7.08-7.20 (m, 3H), 7.61-7.64 (m, 1H), 7.74 (d, 1H), 7.92 (d, 1H) 8.1-8.2 (m, 2H), 7.31 (d, 1H), 8.58 (d, 1H), 8.72 (s, 1H), 9.02 (s, 1H) 10.13 (s, 1H), 10.5 (s, 1H); Mass Spectrum: Mass Spectrum: M+H+ 445 and 447.
Reaction SMILES: O.[NH2:2][NH2:3].[O:4]1[C:8]2([CH2:13][CH2:12][CH:11]([C:14]3[N:19]=[CH:18][C:17]([C:20](=O)[CH2:21][C:22]([O:24]C(C)(C)C)=O)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[O:7][CH2:6][CH2:5]1>O1CCOCC1>[O:4]1[C:8]2([CH2:13][CH2:12][CH:11]([C:14]3[N:19]=[CH:18][C:17]([C:20]4[CH:21]=[C:22]([OH:24])[NH:3][N:2]=4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[O:7][CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccc(C2CCC3(CC2)OCCO3)nc1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: Oc1cc(-c2ccc(C3CCC4(CC3)OCCO4)nc2)n[nH]1

Procedure:
Hydrazine hydrate (5 mL) was added to a solution of Example 93C (1.07 g, 2.96 mmol) in dioxane (10 mL). The resulting solution was refluxed for 3 hours before it was cooled and partitioned with tetrahydrofuran and brine. The aqueous phase was acidified with 6 N hydrochloric acid to pH 2 and extracted repeatedly with a tetrahydrofuran/ethyl acetate mixture. The combined organic phases were dried (magnesium sulfate), filtered, and concentrated. The crude product was recrystallized from ethyl acetate and hexane to provide a light brown solid.
Reaction SMILES: O[CH2:2][CH:3]1[N:9]2[C:10](=[O:13])[O:11][N:12]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:15][CH2:2][CH:3]1[N:9]2[C:10](=[O:13])[O:11][N:12]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: BrC(Br)(Br)Br
Reactant: O=c1onc2n1C(CO)CCCC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=c1onc2n1C(CBr)CCCC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of the product of Example 5 in dichloromethane was added carbon tetrabromide (460 mg, 1.3 mmol). This solution was cooled in an ice bath and stirred for 5 minutes. Triphenylphosphine (437 mg, 1.6 mmol) was added to the solution and stirring was continued for 5 minutes at 0° C. before allowing it to warm slowly to room temperature. The solvent was removed under reduced pressure. The residue was placed on a filter and washed three times with ether. The filtrate solvent was then removed under reduced pressure to yield the title compound. Mass Spectra for C8H11N2O2Br: M+H=246.