Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1[C:11]2([O:19][C:18]3[C:13](=[C:14](O)[CH:15]=[C:16](C=O)[C:17]=3C(O)=O)C2)C2(C)C(C(C)(C)C(O)C(O)C2)CC1.[N:31]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[C:34]([NH:41][CH2:42]C2C=CC(OC)=CC=2)=[N:33][N:32]=1.C(=O)=O>CS(C)=O>[N:31]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[C:34]([N:41]([C:15]2[CH:14]=[CH:13][C:18]([O:19][CH3:11])=[CH:17][CH:16]=2)[CH3:42])=[N:33][N:32]=1
Reactant: CC1CCC2C(C)(C)C(O)C(O)CC2(C)C12Cc1c(O)cc(C=O)c(C(=O)O)c1O2
Reactant: COc1ccc(CNc2nnnc3ccccc23)cc1
Agent: O=C=O
Solvent: CS(C)=O
Product: COc1ccc(N(C)c2nnnc3ccccc23)cc1
Reaction time: 0.21 h

Procedure:
T-47D, HT29, H1299, MX-1 and MDAMB435 cells were grown and harvested as in Example 29. An aliquot of 90 μL of cells (4.4×104 cells/mL) was added to a well of a 96-well microtiter plate containing 5 μL of a 10% DMSO in RPMI-1640 media solution containing 10 nM to 100 μM of benzo[d][1,2,3]triazin-4-yl-(4-methoxy-phenyl)methyl-amine (1 nM to 10 μM final). An aliquot of 45 μL of cells was added to a well of a 96-well microtiter plate containing 5 μL of a 10% DMSO in RPMI-1640 media solution without compound as the control sample for maximal cell proliferation (LMax). The samples were mixed by agitation and then incubated at 37° C. for 48 h in a 5% CO2-95% humidity incubator. After incubation, the samples were removed from the incubator and 25 μL of CellTiter-Glo™ reagent (Promega) was added. The samples were mixed by agitation and incubated at room temperature for 10-15 min. Plates were then read using a luminescent plate reader (Model SPECTRAfluor Plus, Tecan) to give Ltest values.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C([Mg]Cl)(C)C.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.CCOCC>[CH2:17]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=Cc1ccccc1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To an ether solution (7.5 ml) containing tetraisopropoxytitanium (0.284 g, 1.0 mmol) and diethyl malonate (0.145 g, 0.5 mmol) was added dropwise at −50° C. 1.53 ml of 1.31M ether solution containing isopropylmagnesium chloride (2 mmol). Upon stirring at −40° C. for 1 hour, the reaction liquid turned from yellow into brown. The reaction liquid was stirred together with benzaldehyde (0.080 g, 0.75 mmol) at 0° C. for 1 hour. With 1N hydrochloric acid added, the reaction liquid was stirred at room temperature for 15 minutes. After treatment and purification as in Referential Example 1, there was obtained diethyl benzylmalonate in deallylated form (yields: 97%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH:26]([C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].Cl>CC(N(C)C)=O.O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH:26]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NC(CC(=O)O)c1cccnc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1nc(C(=O)NC(CC(=O)O)c2cccnc2)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 41.3 %

Procedure:
To a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.16 mmol) and 3-amino-3-pyridin-3-yl-propionic acid (52 mg, 0.31 mmol) (commercially available from Combi-Blocks SS-4195) in DMA (2 mL) was added sodium methoxide (17 mg, 0.31 mmol). The resultant suspension mixture was heated in a 150° C. oil bath for 2 h. After cooled, reaction mixture was diluted with water (75 mL) and acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried in vacuo to provide the title compound 30 mg (0.066 mmol) in 42% yield. LC-MS ESI−: 453 (M−1)−.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1.C1C(=O)N([Br:23])C(=O)C1>C(#N)C>[Br:23][C:5]1[CH:6]=[C:7]2[C:12](=[N:13][C:4]=1[CH:3]([O:2][CH3:1])[O:14][CH3:15])[NH:11][CH2:10][CH2:9][CH2:8]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(OC)c1ccc2c(n1)NCCC2
Solvent: CC#N
Product: COC(OC)c1nc2c(cc1Br)CCCN2
Temperature: 25 °C

Procedure:
Into a 3 l 4-necked round-bottom flask was placed 7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 4, 114.6 g, 550.3 mmol) in acetonitrile (2 l). This was followed by the addition of NBS (103 g, 578 mol) in portions with stirring at 25° C. The resulting solution was stirred for 30 min at 25° C. The resulting mixture was concentrated under vacuum and the residue was diluted with 1000 ml of diethylether. The mixture was washed with 3×100 ml of ice/water. The aqueous phase was extracted with 2×100 ml of diethylether and the organic layers were combined. The resulting mixture was washed with 1×100 ml of brine, dried over sodium sulfate and concentrated under vacuum to give the title compound as a light yellow solid. LC-MS: (ES, m/z):
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[Cl:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H][H]>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][NH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[Cl:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cl)c(NC(=O)COCc2ccccc2)c1
Reactant: [H][H]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(NCCOCc2ccccc2)c1
Yield: 101.7 %

Procedure:
2-Benzyloxy-N-(2-chloro-5-methoxy-phenyl)acetamide (2) (18.9 g, 62.0 mmol) in THF (100 mL) was stirred and lithium aluminum hydride (4.9 g, 130.0 mmol) was added slowly over 15 min. There was a rapid evolution of hydrogen gas as the first of the lithium aluminium hydride was added. The reaction was then heated to reflux for 4 h and allowed to stand at RT over the weekend. The reaction was then quenched by the dropwise addition of water (50 mL) to the stirred solution. There was a violent evolution of hydrogen causing the reaction mixture to reflux. The reaction was then concentrated in vacuum to a slurry. Water (200 mL) and ethyl acetate (200 mL) were added and the mixture vigorously shaken. The reaction was then filtered through celite to remove the precipitated aluminium hydroxide and the ethyl acetate solution was separated, dried over magnesium sulfate and concentrated in vacuo to afford 18.4 g (quantitative) of (2-Benzyloxy-ethyl)-(2-chloro-5-methoxyphenyl) amine (3) as a gum. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 43.3, 55.3, 68.2, 73.0, 98.1, 1018, 111.6, 127.6, 127.7, 128.4, 129.3, 137.9, 144.8, and 159.5.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:12](=[O:13])[C:11]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[NH:10][C:9]2=[O:19])=[CH:5][CH:4]=1.[C:22]1([CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH2:30]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[ClH:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12](=[O:13])[C:11]3([CH2:14][CH2:15][N:16]([CH2:30][CH2:29][CH:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:17][CH2:18]3)[NH:10][C:9]2=[O:19])=[CH:20][CH:21]=1
Reactant: BrCCC(c1ccccc1)c1ccccc1
Reactant: O=C1NC2(CCNCC2)C(=O)N1Cc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC2(CCN(CCC(c3ccccc3)c3ccccc3)CC2)C(=O)N1Cc1ccc(Br)cc1
Temperature: 60 °C
Yield: 32.1 %

Procedure:
A mixture of 26.2 mg (70 μmol) of 3-(4-bromo-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride, 21.4 mg (70 μmol) of 3,3-diphenylpropyl bromide and 29 mg (210 μmol) of potassium carbonate in 1 mL of anhydrous DMF was heated overnight at 60° C. After cooling to room temperature, 0.5 mL of water was added and the solution was extracted with DCM (2×2 mL). The crude material was purified by semi-preparative HPLC (method A) yielding 12.8 mg (32.1%) of Compound 3 as a white solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2C(=O)C3=CC=CC=C3C2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([CH2:7][O:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NOCc1ccccc1

Procedure:
When the bridging group n is =NOCH2 --, an appropriately substituted or unsubstituted phenylmethyl chloride, for example, 3-trifluoromethylphenylmethyl chloride, is reacted under basic conditions with N-hydroxyphthalimide in dimethyl sulfoxide, yielding the corresponding N-(phenylmethoxy)phthalimide. The so-prepared phthalimide is in turn reacted with hydrazine monohydrate in ethanol, affording an O-(phenylmethyl)hydroxylamine, for example, O-(3-trifluorophenylmethyl)hydroxylamine. The O-(phenylmethyl)hydroxylamine is then reacted with 2,4-di[(1,1 -dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone, as described above, yielding the targeted 2,4-diamino-6-phenylmethoxyimino-5,6,7,8-tetrahydroquinazoline. Example 13 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([Mg]Br)=[CH:34][CH:33]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:20]3[CH:21]=[CH:22][C:23]([O:26][C:27]([F:30])([F:28])[F:29])=[CH:24][CH:25]=3)([C:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=3)[OH:19])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CCCOc1ccc(CN2CCC(C(=O)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCOc1ccc(CN2CCC(C(O)(c3ccc(Cl)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 65 °C
Reaction time: 3.5 h

Procedure:
A solution of 0.6 gram (0.0014 mole) of N-(4-propoxyphenylmethyl)-4-(4-trifluoromethoxyphenyicarbonyl)piperidine in 15 mL of tetrahydrofuran was stirred, and to the stirred solution was slowly added 1.8 mL of 4-chlorophenylmagnesium bromide (0.0018 mole-1M in diethyl ether). Upon completion of the addition, the reaction mixture was warmed to 65° C., where it was stirred for 3.5 hours. After this time the reaction mixture was allowed to cool to ambient temperature, where it stirred for about 18 hours. The reaction mixture was then poured into a mixture of 50 mL of ice and 75 mL of an aqueous solution saturated with ammonium chloride. The mixture was stirred until the ice melted and then extracted with ethyl acetate. The extract was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue, which was dissolved in boiling petroleum ether and treated with decolorizing carbon. Diatomaceous earth was stirred in, and the mixture was filtered through a pad of activated magnesium silicate. The magnesium silicate pad was washed with 30% acetone in methylene chloride. The filtrate and wash were combined and concentrated under reduced pressure, yielding 0.4 gram of N-(4-propoxyphenylmethyl)-4-[(4-trifluoromethoxyphenyl)(4-chlorophenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([N:8]1[CH2:27][CH2:26][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:14]=[C:15]([OH:16])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]([F:39])([F:38])[C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1>>[CH2:1]([N:8]1[CH2:27][CH2:26][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:14]=[C:15]([O:16][CH2:34][C:33]3[CH:32]=[CH:31][C:30]([C:29]([F:28])([F:38])[F:39])=[CH:37][CH:36]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc(O)c3c(n2)CCN(Cc2ccccc2)C3)c1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: O=[N+]([O-])c1cccc(-c2nc3c(c(OCc4ccc(C(F)(F)F)cc4)n2)CN(Cc2ccccc2)CC3)c1

Procedure:
The title compound was prepared from 6-benzyl-2-(3-nitro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ol (which was obtained in Intermediate 9) and 4-(trifluoromethyl)benzyl bromide according to Method A; LC retention time 2.95 min; MS: m/z (ESI) 521 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:10]=2)=[CH:5][CH:4]=1.[N:27]([C:38]([C:45]#[N:46])([CH3:44])[CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[N:28][C:29]([C:36]#[N:37])([CH3:35])[CH2:30][CH2:31][C:32]([OH:34])=[O:33].C([O-])([O-])=O.[Cs+].[Cs+].O>CC(C)=O>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][O:42][C:41](=[O:43])[CH2:40][CH2:39][C:38]([N:27]=[N:28][C:29]([C:36]#[N:37])([CH3:35])[CH2:30][CH2:31][C:32]([O:34][CH2:2][C:3]3[CH:4]=[CH:5][C:6]([C:9]4[CH:10]=[C:11]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=5)[N:12]=[C:13]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=5)[CH:14]=4)=[CH:7][CH:8]=3)=[O:33])([C:45]#[N:46])[CH3:44])=[CH:4][CH:5]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:12]=1
Reactant: CC(C#N)(CCC(=O)O)N=NC(C)(C#N)CCC(=O)O
Reactant: BrCc1ccc(-c2cc(-c3ccccn3)nc(-c3ccccn3)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C#N)(CCC(=O)OCc1ccc(-c2cc(-c3ccccn3)nc(-c3ccccn3)c2)cc1)N=NC(C)(C#N)CCC(=O)OCc1ccc(-c2cc(-c3ccccn3)nc(-c3ccccn3)c2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 46.3 %

Procedure:
A reaction mixture of 4′-(4-bromomethylphenyl)-2,2′:6′,2″-terpyridine (1.500 g, 3.729 mmol), 4,4′-azobis(4-cyanopentanoic acid) (500 mg, 1.7839 mmol), Cs2CO3 (750 mg, 2.302 mmol), 1.0 ml of water and 100 ml of acetone was stirred vigorously at room temperature for 5 days. The solvents were removed under vacuum, and CH2Cl2 was added. The precipitate was filtered off. The filtrate was evaporated to dryness under vacuum, and then 300 ml of CH2Cl2-hexane mixture solvents (1:12, v/v) was added. The precipitate was filtered, and dried, and further purified by column chromatography (Al2O3) using ethyl acetate-hexane (3:2, v/v) as eluent to give pure product (0.763 g, 46%). 1H-NMR (CDCl3): δ=8.64 (m, 12H), 7.85 (m, 8H), 7.47 (m, 4H), 7.30 (m, 4H), 5.20 (s, 4H, —CH2—O—C(O)—), 2.65-2.48(m,8H, —OOC—CH2CH2—), 1.69(m, 6H, =N—C(CN)—CH3). HRMS (TOF): calculated for C56H47N10O4[(M+H)+] m/z=923.3782, found m/z=923.3759 Fluorescent Spectral Properties: λex=320 nm, λem=380 nm.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:14][S:15][CH2:16][C:3]1=2.[N-:17]=[N+:18]=[N-:19].[Na+].[Cl-].[NH4+]>CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]3[NH:19][N:18]=[N:17][N:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:14][S:15][CH2:16][C:3]1=2
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2nc3c(c(=O)n2c1)CSC3
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2c(nc3ccc(-c4nnn[nH]4)cn13)CSC2

Procedure:
A mixture of 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carbonitrile (1.0 g., 0.004 mol), sodium azide (0.81 g., 0.012 mol) and ammonium chloride (0.69 g., 0.013 mol) in dimethylformamide (150 ml) is heated at 100°-105° C. for 18 hours. The solvent is removed at reduced pressure. The residue is triturated with 1 N hydrochloric acid, filtered, washed with water, dissolved in 10% aqueous potassium carbonate, filtered and reprecipitated with 1 N hydrochloric acid. The solid is filtered off and recrystallized from dimethylformamide-methanol to give a crystalline product (0.96 g.), mp 285° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8].CO[CH:13](OC)[CH2:14][C:15](=O)[CH3:16]>CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:14][C:15]([CH3:16])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(CC(C)=O)OC
Reactant: NNc1ccc(Cl)c(Cl)c1
Solvent: CCO
Solvent: O
Product: Cc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Yield: 66.3 %

Procedure:
A solution of of 3,4-dichlorophenylhydrazine (4.27 g, 20.0 mmol) in EtOH (50 ml) and H2O (50 ml) was treated with 3-oxobutyraldehyde dimethyl acetal (2.64 g, 20.0 mmol) and refluxed for 1 h. The alcohol was removed in vacuo and the aqueous residue was extracted with AcOEt (2×150 ml). The organic phase was dried (Na2SO4), filtered and evaporated. The remaining oil was chromatographed [silica, elution with gradient hexane to 10% (hexane/AcOEt=1:1)] to obtain 3.01 g (66%) of 1-(3,4-dichloro-phenyl)-3-methyl-1H-pyrazole [Mp. 57-58° C. (AcOEt/hexane), MS: m/e=226 (M+)]as off-white crystals and 1.32 g (29%) of 1-(3,4-dichloro-phenyl)-5-methyl-1H-pyrazole [Mp. 46-47° C. (hexane), MS: m/e=226 (M+)]as white crystals.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:14]([C:17]1[NH:21][N:20]=[C:19]([NH:22][C:23]2[C:24]3[CH2:40][CH2:39][CH2:38][C:25]=3[N:26]=[C:27]([N:29]3[CH2:33][CH2:32][CH2:31][CH:30]3[C:34](OC)=[O:35])[N:28]=2)[CH:18]=1)([CH3:16])[CH3:15]>C1COCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:34]([C@@H:30]2[CH2:31][CH2:32][CH2:33][N:29]2[C:27]2[N:28]=[C:23]([NH:22][C:19]3[CH:18]=[C:17]([CH:14]([CH3:16])[CH3:15])[NH:21][N:20]=3)[C:24]3[CH2:40][CH2:39][CH2:38][C:25]=3[N:26]=2)=[O:35])=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCCN1c1nc2c(c(Nc3cc(C(C)C)[nH]n3)n1)CCC2
Reactant: Nc1ccc(F)nc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)c1cc(Nc2nc(N3CCC[C@H]3C(=O)Nc3ccc(F)nc3)nc3c2CCC3)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
To a solution of 6-fluoropyridin-3-amine (6.05 g, 13 mmol) in dry THF (100 mL) was added 2M solution of isopropylmagnesium chloride in THF (27 mL, 54 mmol) dropwise under nitrogen at 0° C. The resultant mixture was stirred at 0° C. for 20 min. To this solution was added a solution of methyl 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate (5 g, 13 mmol) in THF (20 mL) dropwise at 0° C. and the reaction mixture was allowed to stir at RT for 2 h. The reaction was quenched with saturated ammonium chloride solution (50 mL). The product was extracted with EtOAc (2×40 mL) and the organic layer was dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave solid residue which was purified by column chromatography on silica gel using 1-2% MeOH-DCM system as eluent followed by chiral purification to afford (S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (2.2 g). 1H NMR (CDCl3, freebase) δ (ppm): 1.22 (d, 6H), 1.90-2.21 (m, 6H), 2.60-2.70 (m, 1H), 2.72 (t, 2H), 2.88 (t, 2H), 2.81-2.96 (m, 1H), 3.60-3.80 (m, 2H), 4.77 (d, 2H), 6.40 (s, 1H), 6.74 (s, 1H), 6.82 (d, 1H), 7.90 (s, 1H), 8.13 (s, 1H). The other enantiomer was prepared using the (R) chiral starting material.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1([NH:15][C:16]2[C:17](=[O:35])[N:18]([C:22]3[CH:23]=[C:24]([CH:31]=[CH:32][C:33]=3[CH3:34])[C:25]([NH:27][CH:28]3[CH2:30][CH2:29]3)=[O:26])[CH:19]=[CH:20][N:21]=2)[CH2:14][CH2:13]1.[CH3:36][NH2:37]>O.O1CCOCC1>[CH:28]1([NH:27][C:25](=[O:26])[C:24]2[CH:31]=[CH:32][C:33]([CH3:34])=[C:22]([N:18]3[CH:19]=[CH:20][N:21]=[C:16]([NH:15][C:12]4([C:6]5[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:37][CH3:36])[CH2:14][CH2:13]4)[C:17]3=[O:35])[CH:23]=2)[CH2:30][CH2:29]1
Reactant: CN
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3cc(F)ccc3OCCCl)CC2)c1=O
Solvent: C1COCCO1
Solvent: O
Product: CNCCOc1ccc(F)cc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)ccc3C)c2=O)CC1

Procedure:
3-[3-[[1-[2-(2-chloroethoxy)-5-fluorophenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide (Example 278e, 0.25 g) and 40% methylamine in water (1 mL) were stirred together at 100° C. in dioxane (8 mL) in a sealed tube for 24 h. Purification of the cooled solution by preparative HPLC (Xbridge column—acetonitrile/0.2% ammonia mobile phase) gave the title compound (110 mg).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[S:18][C:17]([C:19]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[C:24](=[O:32])[NH:25][C:26]3=[O:31])=[O:20])=[CH:16][CH:15]=1.O[CH:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:13][C:14]1[S:18][C:17]([C:19]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[C:24](=[O:32])[N:25]([CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)[C:26]3=[O:31])=[O:20])=[CH:16][CH:15]=1
Reactant: O=C(Nc1cccc2c1C(=O)NC2=O)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)CC1
Reaction time: 2 h

Procedure:
At room temperature, 0.12 ml (0.76 mmol) of diethyl azodicarboxylate (DEAD) is added dropwise to a suspension of 150 mg (0.49 mmol) of 5-chloro-N-(1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl)-2-thiophenecarboxamide, 148 mg (0.73 mmol) of tert-butyl 4-hydroxytetrahydro-1(2H)-pyridinecarboxylate and 199 mg (0.76 mmol) of triphenylphosphine in 1.95 ml of absolute THF. After 2 h at room temperature, the mixture is concentrated and the residue is separated by chromatography on silica gel (dichloromethane/methanol mixture) and the product is isolated.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=O)[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:4]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:2]([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(-c2ccccc2)c(=O)[nH]c2ccccc12
Product: Cc1c(-c2ccccc2)c(Cl)nc2ccccc12
Temperature: 0 °C

Procedure:
A mixture of 4-methyl-3-phenylquinolin-2-one (1.18 g.) and phosphorus oxychloride (60 ml.) was heated under reflux for 2 hr. The mixture was cooled and poured into ice-water (200 ml.), and the resulting mixture was extracted with ethyl acetate (3×50 ml.). The ethyl acetate extract was washed successively with saturated sodium carbonate solution (3×50 ml.) and water (50 ml.), dried (Na2SO4), and evaporated in vacuo to dryness. The residue was crystallised from cyclohexane to give 2-chloro-4-methyl-3-phenylquinoline, m.p. 88°-90°.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][N:10]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:11]([NH:14][C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)(=[O:13])=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:45](Cl)(=[O:50])[CH2:46][CH2:47][CH2:48][CH3:49]>ClCCl>[CH2:31]([N:10]([CH2:9][CH:6]1[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:45](=[O:50])[CH2:46][CH2:47][CH2:48][CH3:49])[CH2:8][CH2:7]1)[S:11]([NH:14][C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1)(=[O:12])=[O:13])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reactant: CCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)NCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reaction time: 0.5 h

Procedure:
Amine (22) (23.5 mg, 40 μmole, 1.0 eq) was suspended in dichloromethane, then triethylamine (16.7 μL, 120 μmole, 3.0 eq) and valeryl chloride (5 μL, 42 μmole, 1.05 eq) were added and the reaction stirred 30 minutes. Silica gel chromatography provided the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.45 (s, 2H), 8.21 (s, 1H), 7.62 (t, 1H), 7.36 (d, 2H), 7.25 (t, 2H), 7.18 (t, 1H), 4.42 (s, 2H), 3.30 (water), 3.00 (s, 2H), 2.74 (t, 2H), 2.48 (DMSO), 1.99 (t, 2H), 1.56 (m, 4H), 1.41 (m, 2H), 1.26 (m, 1H), 1.20 (m, 3H), 0.81 (t, 3H), 0.60 (m, 4H).