Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[C:14]([O:18][C:19]([NH:21][C:22]1([C:37](O)=[O:38])[CH2:27][CH2:26][N:25]([C:28]2[C:29]3[CH:36]=[CH:35][NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:24][CH2:23]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CC(N(C)C)=O>[C:10]([C:9]1[CH:8]=[CH:7][C:6]([C@@H:2]([NH:1][C:37]([C:22]2([NH:21][C:19](=[O:20])[O:18][C:14]([CH3:16])([CH3:15])[CH3:17])[CH2:23][CH2:24][N:25]([C:28]3[C:29]4[CH:36]=[CH:35][NH:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH2:26][CH2:27]2)=[O:38])[CH2:3][CH2:4][OH:5])=[CH:13][CH:12]=1)#[N:11]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: N#Cc1ccc([C@@H](N)CCO)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CCO)c2ccc(C#N)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 46.3 %

Procedure:
(S)-4-(1-amino-3-hydroxypropyl)benzonitrile (Intermediate 46) (195 mg, 1.11 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (400 mg, 1.11 mmol) and DIPEA (0.580 mL, 3.32 mmol) in DMA (5 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (463 mg, 1.22 mmol) was added and the resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness then diluted with EtOAc (300 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% MeOH with ammonia in DCM. Pure fractions were evaporated to dryness to afford (S)-tert-butyl 4-(1-(4-cyanophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (267 mg, 46.4%) as a white solid. (S)-tert-butyl 4-(1-(4-cyanophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (267 mg, 0.51 mmol) was suspended in dioxane (5.00 mL) and 4M hydrogen chloride in dioxane (0.769 mL, 22.14 mmol) added. The reaction was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5N ammonia/MeOH and pure fractions were evaporated to dryness. The product was then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (S)-4-amino-N-(1-(4-cyanophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (70.0 mg, 15.1%) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].CO.[OH-].[Na+]>C1COCC1.[OH-].[Na+]>[NH2:19][S:16]([C:13]1[CH:12]=[CH:11][C:10]([C:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[S:6][C:7]=2[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)(=[O:17])=[O:18]
Reactant: COC(=O)c1cc(-c2ccc(S(N)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NS(=O)(=O)c1ccc(-c2cc(C(=O)O)sc2-c2ccc(F)cc2)cc1
Temperature: 45 °C
Yield: 98.8 %

Procedure:
To a solution of 4-(4-(aminosulfonyl)phenyl)-5-(4-fluorophenyl)thiophene-2-carboxylic acid methyl ester (Example 1, Step 5) (0.210 g) in THF (2.0 mL) were added MeOH (1.0 mL), NaOH 1N (1.0 mL) and a few drops of NaOH 10N. The resulting mixture was heated at 45° C. for 2 h and the reaction was then partitioned between EtOAc and HCl (3N) to provide the title product as a white solid (0.200 g).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]([CH3:19])([CH:16]([CH3:18])[CH3:17])[C:14]#[N:15]>C(Cl)Cl>[C:14]([C:13]([NH:12][C:4](=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:1]([OH:6])=[O:11])([CH3:19])[CH:16]([CH3:18])[CH3:17])#[N:15]
Reactant: CC(C)C(C)(N)C#N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)C(C)(C#N)NC(=O)c1ccccc1C(=O)O
Reaction time: 3 h
Yield: 89.8 %

Procedure:
To a stirred boiling mixture of 28.1 g (0.189 mole) of phthalic anhydride in 28 ml methylene chloride is added dropwise 23.6 g (0.21 mole) of 2-amino-2,3-dimethylbutyronitrile in 57 ml methylene chloride. After the addition, heating is constinued for 3 hours. The mixture is cooled and the precipitate removed by filtration, washed with methylene chloride and air-dried to give 44.2 g (90%) of N-(cyano-1,2-dimethylpropyl)phthalamic acid, melting point 154-155° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2.C(OC([NH:34][C@H:35]([C:39](O)=[O:40])[C@@H:36]([CH3:38])[OH:37])=O)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>C1COCC1>[NH2:34][C@@H:35]([CH:36]([OH:37])[CH3:38])[C:39]([N:23]1[CH2:22][CH2:21][N:20]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:6]3[CH:5]=[CH:4][C:3]4[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=4[CH:7]=3)[N:19]=2)[CH2:25][CH2:24]1)=[O:40]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCNCC4)n3)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(O)[C@H](N)C(=O)N1CCN(c2cccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
200 mg (0.57 mmol) of 1-[6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-pyridin-2-yl]piperazine, 138 mg (0.629 mmol) of N-(tert-butoxycarbonyl)-L-threonine, 105 mg (0.69 mmol) of HOBt, 132 mg (0.69 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 291 μl (1.72 mmol) of DIPEA are dissolved in 5 ml of THF and stirred at room temperature for 18 h. The crude product was purified by column chromatography and silica gel, dissolved in dioxane, and an excess of 4N HCl in dioxane was added. The reaction mixture is stirred at room temperature for 12 h, evaporated and purified by means of preparative HPLC. The product is converted into the hydrochloride using methanolic HCl.
Reaction SMILES: [ClH:1].[N:2]1([NH2:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[C:13]1(=O)[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]1>CC(O)=O.O>[ClH:1].[N:2]1([N:12]=[C:13]2[CH2:18][CH2:17][CH2:16][C:15]([OH:19])=[CH:14]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: NN1CCCc2ccccc21
Reactant: O=C1CCCC(=O)C1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: OC1=CC(=NN2CCCc3ccccc32)CCC1
Temperature: 40 °C
Yield: 69.1 %

Procedure:
3,4-Dihydro-1(2H)-quinolinamine hydrochloride (5.0 g, 27 mmol) and 1,3-cyclohexanedione (3.1 g, 27 mmol) was mixed in AcOH (4.3 mL) and H2O (4.3 mL). The mixture was heated at 40° C. for 10 min until dissolved completely. The mixture was then concentrated to dryness. The residue was washed with acetonitrile then filtered to yield 3-(3,4-dihydro-1(2H)-quinolinylimino)-1-cyclohexen-1-ol hydrochloride (5.2 g, 69%) as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]=2[S:8][C:7]=1[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>>[CH3:16][N:12]1[C:13](=[O:15])[C:14]2[C:6]([S:5][CH2:4][CH2:3][CH2:2][NH:1][C:35]([N:34]([CH3:38])[CH3:33])=[O:36])=[C:7]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[S:8][C:9]=2[N:10]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:11]1=[O:17]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCN)c(Cc3cccc4ccccc34)sc21
Reactant: CN(C)C(=O)Cl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCNC(=O)N(C)C)c(Cc3cccc4ccccc34)sc21
Yield: 69.4 %

Procedure:
Prepared from 5-[(3-aminopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenyl-methyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (10 mg) and dimethylcarbamoyl chloride (24.8 mg) following the method of Example 41 to give the title compound (8 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:15]([N:18]1[C:26](=[O:27])[C:25]2[C:20](=[N:21][C:22](SC)=[N:23][CH:24]=2)[N:19]1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH2:40][CH2:39][N:38]([CH3:41])[C:37]2=[O:42])[N:31]=1)[CH:16]=[CH2:17]>>[CH2:15]([N:18]1[C:26](=[O:27])[C:25]2[C:20](=[N:21][C:22]([NH:12][C:11]3[CH:13]=[CH:14][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:9][CH:10]=3)=[N:23][CH:24]=2)[N:19]1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH2:40][CH2:39][N:38]([CH3:41])[C:37]2=[O:42])[N:31]=1)[CH:16]=[CH2:17]
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(N2CCN(C)C2=O)n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Product: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc2n1-c1cccc(N2CCN(C)C2=O)n1

Procedure:
In the same manner as in Example 29-2, but using 4-(4-methylpiperazin-1-yl)aniline in place of [5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Example 29-2 and using 2-allyl-1-[6-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-2-yl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one in place of 2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one, 115.6 mg of the entitled compound was obtained as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12](=[O:23])[NH:13][C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH3:15].[CH:24]([O-])([O-])OCC.O>CN(C=O)C>[O:23]=[C:12]1[C:3]2[C:2](=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)[N:1]=[CH:24][N:13]1[C:14]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc(N)c(C(=O)NC(C)(C)c2ccccc2)c1
Reactant: CCOC([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ncn(C(C)(C)c3ccccc3)c(=O)c2c1
Temperature: 150 °C
Reaction time: 24 h
Yield: 81.2 %

Procedure:
To a solution of methyl 4-amino-3-[(2-phenylpropan-2-yl)carbamoyl]benzoate (0.13 g, 0.42 mmol) in DMF (2.5 mL) was added ethyl orthoformate (3.0 mL, 18 mmol) followed by one scoop of 3 Å molecular sieves. The reaction mixture was heated to 150° C. and stirred for 1 d. The mixture was cooled to rt, water was added and the mixture was extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (50% to 100% EtOAc/hexanes) to afford methyl 4-oxo-3-(2-phenylpropan-2-yl)-3,4-dihydroquinazoline-6-carboxylate (0.11 g, 84%). LC-MS: (FA) ES+ 323.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH:3]=[N:4][OH:5].CC(C)([O-])C.[K+].[F:13][C:14]1[CH:32]=[CH:31][CH:30]=[CH:29][C:15]=1[CH2:16][NH:17][C:18]1[C:23]([F:24])=[CH:22][N:21]=[C:20](S(C)(=O)=O)[N:19]=1>C1COCC1>[F:24][C:23]1[C:18]([NH:17][CH2:16][C:15]2[CH:29]=[CH:30][CH:31]=[CH:32][C:14]=2[F:13])=[N:19][C:20]([O:5][N:4]=[CH:3][CH:2]([CH3:6])[CH3:1])=[N:21][CH:22]=1
Reactant: CC(C)C=NO
Reactant: CS(=O)(=O)c1ncc(F)c(NCc2ccccc2F)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)C=NOc1ncc(F)c(NCc2ccccc2F)n1
Reaction time: 0.25 h
Yield: 551.9 %

Procedure:
To a solution of 2-methylpropionaldehyde oxime (0.047 g, 0.54 mmol) in anhydrous THF (3 mL) was added a solution of potassium tert-butoxide (KOtBu, 1 M in THF; 0.50 mL, 0.50 mmol) at room temperature, and the resulting pale-yellow mixture was stirred for 15 min. To the resulting solution was added 2-fluorobenzyl-(5-fluoro-2-methanesulfonylpyrimidin-4-yl)amine (0.125 g, 0.42 mmol), and the resulting tan mixture was stirred at room temperature for 16 h. The entire reaction mixture was adsorbed to Celite (2.5 g) and the adsorbed material was purified by flash chromatography (40 g SiO2; 0→100% EtOAc/hexanes) to give 2-methylpropionaldehyde O-[5-fluoro-4-(2-fluorobenzylamino)-pyrimidin-2-yl]oxime (0.71 g, 56%) as a colorless oil: IR (thin film) 3261, 3179, 3049, 2973, 2936, 2872, 1676, 1622, 1568, 1531, 1491, 1457, 1409, 1372 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J=2.5 Hz, 1H), 7.71 (d, J=7.5 Hz, 1H), 7.43 (t, J=6.9 Hz, 1H), 7.29 (m, J=7.6 Hz, 1H), 7.09 (m, 2H), 5.42 (s, 1H), 4.76 (d, J=5.8 Hz, 2H), 2.79 (dq, J=13.9, 6.9 Hz, 1H), 1.18 (d, J=6.8 Hz, 6H); ESIMS m/z 307 ([M+H]+), 305 ([M−H]−).
Reaction SMILES: [N:1]([C:4]1[C:5]2[N:6]([C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:21][N:22]=2)[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]=1[C:10]#[N:11])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>CO.O>[NH2:1][C:4]1[C:5]2[N:6]([C:20]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[CH:21][N:22]=2)[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]=1[C:10]#[N:11]
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2c(N3CCOCC3)cnc2c1N=[N+]=[N-]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: O
Product: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2c(N3CCOCC3)cnc2c1N
Temperature: 25 °C
Yield: 87.9 %

Procedure:
A mixture of crude 8-azido-6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-imidazo[1,2-a]pyridine-7-carbonitrile (144 mg, 0.33 mmol) and triphenylphosphine (133 mg, 0.51 mmol) in MeOH (4 mL) was stirred and refluxed for 1 h. 2M HCl in water (1 mL) was added and the reaction mixture was further refluxed for 1 h. The reaction mixture was cooled to RT, concentrated under vacuum and the remaining residue was dissolved in water. The aqueous solution was basified to pH 12 by the addition of a 2M NaOH solution in water. The resulting slurry was extracted with DCM (3×) and the combined organic fractions were dried over Na2SO4, filtered and evaporated. The remaining residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, DCM/MeOH 99:1→92:8) to yield the title compound (112 mg, 0.29 mmol, 87%). MS: 388 [M+1]+; HPLC: AtRet=1.91; TLC: RF 0.56 (DCM/MeOH 95:5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14](O)=[O:15])=[C:12]([CH2:17][O:18][CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[NH:11][C:10]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:33]1([CH:39]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:40][CH2:41][NH2:42])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14](=[O:15])[NH:42][CH2:41][CH2:40][CH:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[C:12]([CH2:17][O:18][CH2:19][CH2:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)[NH:11][C:10]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: O=C(O)C1=C(COCCC2CCCCC2)NC(c2ccccc2)=NC1c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NCCC(c1ccccc1)c1ccccc1)C1=C(COCCC2CCCCC2)NC(c2ccccc2)=NC1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60.0 mg (0.110 mmol) of 4-(3-chlorophenyl)-6-[(2-cyclohexylethoxy)methyl]-2-phenyl-1,4-dihydropyrimidine-5-carboxylic acid and 34.9 mg (0.165 mmol) of 3,3-diphenylpropylamine were dissolved in 10 ml of dichloromethane. 31.6 mg (0.165 mmol) of WSC hydrochloride and 16.8 mg (0.110 mmol) of 1-hydroxybenzotriazole (hereinafter referred to as “HOBT”) were added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and then washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=3/1 to 1/1) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])=[CH:6][C:5]([C:18]2[C:19](=[O:38])[N:20]([CH:35]([CH3:37])[CH3:36])[C:21]3[C:26]([CH:27]=2)=[CH:25][N:24]=[C:23]([NH:28][C:29](=O)[O:30]C(C)=C)[CH:22]=3)=[C:4]([CH3:39])[CH:3]=1.Cl.[NH:41]1[CH2:44][CH2:43][CH2:42]1.CN1CCCC1>O1CCOCC1>[F:1][C:2]1[C:7]([NH:8][C:9]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:6][C:5]([C:18]2[C:19](=[O:38])[N:20]([CH:35]([CH3:36])[CH3:37])[C:21]3[C:26]([CH:27]=2)=[CH:25][N:24]=[C:23]([NH:28][C:29]([N:41]2[CH2:44][CH2:43][CH2:42]2)=[O:30])[CH:22]=3)=[C:4]([CH3:39])[CH:3]=1
Reactant: C1CNC1
Reactant: C=C(C)OC(=O)Nc1cc2c(cn1)cc(-c1cc(NC(=O)Nc3ccccc3)c(F)cc1C)c(=O)n2C(C)C
Agent: CN1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(F)c(NC(=O)Nc2ccccc2)cc1-c1cc2cnc(NC(=O)N3CCC3)cc2n(C(C)C)c1=O
Temperature: 70 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
A suspension of prop-1-en-2-yl (3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)carbamate (0.1 g, 0.189 mmol) in dioxane (3 mL) was treated with azetidine hydrochloride (0.071 g, 0.755 mmol) and 1-methylpyrrolidine (0.129 g, 1.511 mmol) and heated at 70° C. for 16 h, then cooled to RT and stirred for 24 h. The mixture was concentrated to dryness and purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The fractions were neutralized with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford N-(3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)azetidine-1-carboxamide (43 mg, 43% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.34 (s, 1H), 9.01 (s, 1H), 8.60 (s, 1H), 8.49 (s, 1H), 8.38 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.25 (t, J=7.8 Hz, 2H), 7.14 (d, J=12.2 Hz, 1H), 6.95 (t, J=7.4 Hz, 1H), 5.35 (m, 1H), 4.02 (t, J=7.5 Hz, 4H), 2.17 (t, J=7.7 Hz, 2H), 2.07 (s, 3H), 1.55 (d, J=7.0 Hz, 6H); MS (ESI) m/z: 529.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Cl[CH:8]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:8]2[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9]2)[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: COC(=O)C1CC(Cl)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)C1CC(n2cc(Br)cn2)C1
Temperature: 70 °C

Procedure:
A mixture of 4-bromo-1H-pyrazole (500 mg, 3.40 mmol), methyl 3-chlorocyclobutanecarboxylate (607 mg, 4.08 mmol), and potassium carbonate (1.18 g, 8.50 mmol) in DMF (5 mL) was heated to 70° C. for 24 hours. The reaction mixture was cooled to ambient temperature and diluted with diethyl ether (200 mL). The mixture was washed with water (2×50 mL) and then brine (25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by column chromatography on silica (0-100% diethyl ether/hexanes) to afford methyl 3-(4-bromo-1H-pyrazol-1-yl)cyclobutanecarboxylate (Isomer 1) and methyl 3-(4-bromo-1H-pyrazol-1-yl)cyclobutanecarboxylate (Isomer 2). Methyl 3-(4-bromo-1H-pyrazol-1-yl)cyclobutanecarboxylate (Isomer 1): MS ESI calc'd. for C9H12BrN2O2 [M+H]+ 259 and 261. found 259 and 261. 1H NMR (500 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.59 (s, 1H), 5.02-4.95 (m, 1H), 3.65 (s, 3H), 3.20-3.14 (m, 1H), 2.75-2.66 (m, 2H), 2.64-2.56 (m, 2H).
Reaction SMILES: S(C)C.[CH3:4][Li].[C:6]([NH:25][C@@H:26]([CH2:29][CH3:30])[CH:27]=[O:28])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH4+].[Cl-]>CCOCC>[C:6]([NH:25][C@@H:26]([CH2:29][CH3:30])[C@H:27]([OH:28])[CH3:4])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[C@@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CSC
Solvent: CCOCC
Product: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)O
Temperature: 25 °C

Procedure:
To a stirred suspension of CuBr.SMe2 (3 g, 14.6 mmol) in anhydrous ether (100 ml) under an argon atmosphere at −78° C., was added methyl lithium (1.6M in ether, 16.5 ml, 4.0 eq, 26.5 mmol) dropwise and the solution allowed to warm to room temperature over 1 h. The mixture was recooled to −78° C., and a solution of (S)-2-(trityl-amino)-butyraldehyde (2.2 g, 6.62 mmol) in ether (25 ml) was added dropwise with stirring. The reaction mixture was stirred at this temperature for 2 h then allowed to warm to room temperature over 1 h. A saturated aqueous solution of NH4Cl (50 ml) was added and the two layers separated. The organic phase was washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by flash silica gel column chromatography, eluted with hexane:ethyl acetate (80:20) to afford (2R,3S)-3-(trityl-amino)-pentan-2-ol as a light yellow oil; Yield: 1.5 g (66%). (75% de 2R, 3S: 25% de 2S, 3S). 1H-NMR (d6-DMSO, 250 MHz): δ 0.0.47+0.55 (2×t, J=7.50+7.26 Hz —NHCH(CH2CH3)CH(CH3)OH), 0.99-1.12 (m, 5 H, —NHCH(CH2CH3)CH(CH3)OH), 2.01 (1 H, m, —NHCH(CH2CH3)CH(CH3)OH), 3.22-3.43 (m, 1H, —NHCH(CH2CH3)CH(CH3)OH), 4.41 [1 H, d, J=3.3, NHCH(CH2CH3)CH(CH3)OH], 7.14-7.56 (15 H, m, ArH). δC (250 MHz, CDCl3) 146.88 (C), 128.97 (6×CH), 127.83 (6×CH), 126.43 (3×CH), 71.03 (C), 68.13 (CH), 58.77 (CH), 23.09 (CH2), 17.88 (CH3), 10.47 (CH3)
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]([C@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(#N)C.CN(C=O)C>[CH2:29]([N:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]([C@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1cccc(-c2cn[nH]c2)c1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OC(C)(C)C)c1cccc(-c2cnn(CCc3ccccc3)c2)c1
Temperature: 50 °C
Yield: 77.3 %

Procedure:
To a vial was added Intermediate 11B (110 mg, 0.383 mmol) in acetonitrile (0.7 mL) and DMF (0.7 mL) and potassium carbonate (159.0 mg, 1.148 mmol). The reaction was stirred for 10 min before (2-bromoethyl)benzene (106 mg, 0.574 mmol) was added. The resulting mixture was heated at 50° C. for 16 h. The reaction was quenched with water and extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated. The crude was purified by flash chromatography to give Intermediate 11C (116 mg, 0.296 mmol, 77.0% yield) as a white solid. LCMS=2.20 min [M+1]=392.3 (Method B).