Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[I:25][C:26]1[C:31]2[O:32][CH2:33][O:34][C:30]=2[C:29]([NH2:35])=[CH:28][CH:27]=1>O1CCOCC1.CC(N(C)C)=O>[I:25][C:26]1[C:31]2[O:32][CH2:33][O:34][C:30]=2[C:29]([NH:35][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[CH:28][CH:27]=1
Reactant: Nc1ccc(I)c2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: COc1cc2c(Nc3ccc(I)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: 80 °C
Yield: 70.6 %

Procedure:
4.0M HCl in Dioxane (0.37 ml) was added to a stirred suspension of 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (500 mg) and 7-iodo-1,3-benzodioxol-4-amine (0.39 g) in DMA (1 ml). The resultant mixture was stirred and heated to 80° C. for 10 mins. A grey precipitate was formed which was filtered and washed with further DMA followed by diethyl ether and dried to give N-(7-iodo-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine as a beige solid (0.59 g); NMR Spectrum: (DMSOd6) 2.29-2.37 (m, 2H); 3.03-3.14 (m, 2H); 3.22-3.30 (m, 2H), 3.40-3.51 (m, 2H), 3.78-3.88 (m, 2H), 3.94-4.00 (m, 5H), 4.31 (t, 2H), 6.11 (s, 2H), 6.80 (d, 1H), 7.27 (d, 1H), 7.41 (s, 1H), 8.29 (s, 1H), 8.78 (s, 1H); Mass Spectrum: M+H+ 562.9.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[CH:10]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:19][C@H:20]([CH3:34])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:25][CH:24]=1.C([BH3-])#N.[Na+]>CO>[CH3:33][O:32][C:30]([CH2:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][C@H:20]([NH:19][CH2:10][C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH3:34])=[CH:24][CH:25]=1)=[O:31]
Reactant: COC(=O)Cc1ccc(OC[C@@H](C)N)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](C=O)c1cccc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(OC[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2cccc(Cl)c2)cc1

Procedure:
Following a procedure similar to that described in Preparation 29, but using 5.2 g of (R)-α-t-butyldimethylsilyloxy-α-(3-chlorophenyl)acetaldehyde (prepared as described in Preparation 49), 4.24 g of methyl 4-[2(R)-amino-1-propoxy]phenylacetate (prepared as described in Preparation 27), 50 ml of absolute methanol and 3.4 g of sodium cyanoborohydride, the title compound was obtained having an Rf=0.20 (thin layer chromatography over silica gel, using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent). [α]D23 -34.7° (c=1.024, chloroform).
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.Cl[C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:42][C:41](=[O:43])[C:40]([CH3:45])([CH3:44])[CH2:39]2)=[C:34]([F:46])[CH:33]=1.[CH3:47][N:48]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N>[CH3:44][C:40]1([CH3:45])[C:41](=[O:43])[CH2:42][CH:38]([C:35]2[CH:36]=[CH:37][C:32]([C:47]#[N:48])=[CH:33][C:34]=2[F:46])[CH2:39]1
Reactant: CN1CCCC1=O
Reactant: CC1(C)CC(c2ccc(Cl)cc2F)CC1=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC1(C)CC(c2ccc(C#N)cc2F)CC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
Di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (1.75 g, 4.11 mmol) is added to a solution of 4-(4-chloro-2-fluoro-phenyl)-2,2-dimethyl-cyclopentanone (33 g, 137.10 mmol), zinc cyanide (9.66 g, 82.26 mmol), and N-methylpyrrolidone (148.50 mL) at 125° C. and the mixture is stirred for 15 minutes. π-Allylpalladium(II) chloride dimer (0.76 g, 4.11 mmol) is added to the solution and the mixture is stirred for 30 minutes. Diatomaceous earth (15 g) is added and the mixture is cooled to rt. The mixture is filtered through diatomaceous earth and washed with MTBE (450 mL). Water (450 mL) is added and the mixture is extracted with MTBE (150 mL). The mixture is washed with brine, dried over MgSO4, filtered, and concentrated to dryness to give the title compound (34 g, 97%). 1H NMR (300.16 MHz, CDCl3) δ 7.47-7.33 (m, 3H), 3.76-3.63 (m, 1H), 2.83-2.76 (m, 1H), 2.43-2.33 (m, 1H), 2.25 (dd, J=6.3, 12.6 Hz, 1H), 1.91 (t, J=12.3 Hz, 1H), 1.168 (s, 3H), 1.147 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[CH3:10].[H-].[Na+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>CN(C=O)C>[CH3:1][N:2]([CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[CH3:10]
Reactant: COc1ccc(CCl)cc1
Reactant: CNc1ccc(Br)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(C)c2ccc(Br)cc2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.7 g (13.57 mmol) of N-methyl-4-bromo-2-methylaniline in 20 ml of DMF at room temperature was added 608 mg (15.2 mmol) of NaH and the mixture was stirred at room temperature for 0.5 h. After this time, 2.05 ml (15.1 mmol) of 4-methoxybenzyl chloride was added and the reaction mixture was heated to 60° C. for 12 hours. After this time, the reaction mixture was allowed to cool to room temperature and was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:EtOAc, 20:1) to give the title compound. 1H-NMR (CDCl3) δ 2.41 (s, 3H), 2.58 (s, 3H), 3.84 (s, 3H), 3.98 (s, 2H), 6.89–6.94 (m, 3H), 7.29–7.36 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][CH:18]([CH3:20])[CH3:19])[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].[N:21]1([C:25]([C:27]2[N:32]=[CH:31][C:30](Br)=[CH:29][N:28]=2)=[O:26])[CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CC(N(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]Br.O>[N:21]1([C:25]([C:27]2[N:28]=[CH:29][C:30]([O:1][C:2]3[CH:3]=[C:4]([CH:14]=[C:15]([O:17][CH:18]([CH3:20])[CH3:19])[CH:16]=3)[C:5]([NH:7][C:8]3[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=3)=[O:6])=[CH:31][N:32]=2)=[O:26])[CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: O=C(c1ncc(Br)cn1)N1CCC1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)Oc1cc(Oc2cnc(C(=O)N3CCC3)nc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Reaction time: 4 h
Yield: 50.1 %

Procedure:
A mixture of 3-hydroxy-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (250 mg, 0.91 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyrimidine (242 mg, 1.0 mmol), cesium carbonate (886 mg, 2.72 mmol) and bromotris(triphenylphosphine)copper(I) (423 mg, 0.45 mmol) in DMA (5 mL) was stirred in a ‘Biotage initiator Microwave’ at 160° C. for 4 hours. The mixture was added to ethyl acetate (50 mL) and water (50 mL), the organic layer washed with brine (50 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a brown oil. The residue was chromatographed on silica, eluting with a gradient of 0-10% methanol in ethyl acetate, to give the desired compound (199 mg).
Reaction SMILES: COC(=O)[CH:4]([C:17]#[N:18])[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15].Cl>CO>[CH3:13][O:12][C:8]1[C:9]([CH3:11])=[CH:10][C:5]([CH2:4][C:17]#[N:18])=[C:6]([N+:14]([O-:16])=[O:15])[CH:7]=1
Reactant: COC(=O)C(C#N)c1cc(C)c(OC)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Product: COc1cc([N+](=O)[O-])c(CC#N)cc1C
Temperature: 25 °C

Procedure:
To a solution of cyano-(4-methoxy-5-methyl-2-nitrophenyl)acetic acid methyl ester in methanol (1.7 mL) was added 6 mol/L hydrochloric acid (1.7 mL), and this mixture was heated under reflux for 9 hours. After cooling to ambient temperature, this organic solvent was removed under reduced pressure and resulting mixture was extracted with ethyl acetate. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.25 g).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:32][CH2:33][C:34]([O:36]C)=[O:35])([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])[CH2:3]1.[OH-].[Na+]>O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:3]1
Reactant: CCCc1c(OCCCOc2ccccc2)ccc2c1OC(CCC(=O)OC)(CCC(=O)OC)CC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCc1c(OCCCOc2ccccc2)ccc2c1OC(CCC(=O)O)(CCC(=O)O)CC2=O
Reaction time: 1 h
Yield: 86.9 %

Procedure:
A mixture of 611 mg (1.19 mmol) of the title product of Example 16, 0.72 ml of 50% aqueous sodium hydroxide, and 11.7 ml of water was stirred at reflux. After one hour, another 2 ml of water was added and the reaction mixture was heated for an additional 2 hours. The mixture was allowed to cool and then partitioned between 75 ml of ethyl acetate and 50 ml of 3N hydrochloric acid. The aqueous layer was further extracted twice with 25 ml aliquots of ethyl acetate. The combined organic extracts were washed with water, with brine, dried over magnesium sulfate, filtered, and solvent removed on a rotary evaporator to give 501 mg of title product, m.p. 161.5°-162° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[CH:9]=2)[CH:4]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[O:3]1.[OH-:23].[Na+].Cl>CS(C)=O.CN(C=O)C>[OH:23][C:4]1([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:5]2[C:10](=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2)[CH2:11][CH:2]([CH3:1])[O:3]1
Reactant: [OH-]
Reactant: COc1ccc2c(c1)CC(C)OC2c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CC(C)OC2(O)c1ccc([N+](=O)[O-])cc1
Reaction time: 5 h

Procedure:
A solution of 3 (1.3 g) in 4 ml of DMSO and 24 ml of DMF was cooled to 8-12° C. and air was passed through the mixture. To the solution was added 1.2 ml of 50% aqueous sodium hydroxide in one portion and the resulting mixture was stirred for 5 hours. HCl (1 N) was added, and extracted with ethyl acetate three times. The combined organic phase was washed with water in order to remove DMF, dried over Na2SO4. Removal of the solvent afforded syrup crude product (1.6 g), which was used directly for the next step.
Reaction SMILES: FC1C=CC([C:8]2([CH2:12][NH2:13])[CH2:11][CH2:10][CH2:9]2)=CC=1.F[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[N:16]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1(C)C=CC=CC=1>[F:21][C:17]1[N:16]=[C:15]([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)[CH:20]=[CH:19][CH:18]=1
Reactant: Fc1cccc(F)n1
Reactant: NCC1(c2ccc(F)cc2)CCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC1(c2cccc(F)n2)CCC1
Yield: 64 %

Procedure:
Following the same procedure as described for 2-(3-fluoropyridin-2-yl)acetonitrile (Example 18), 2,6-difluoropyridine (5.0 g, 43 mmol, 1.0 equiv), cyclobutylcarbonitrile (3.5 g, 43 mmol, 1.0 equiv) and NaHMDS (2.0 M in THF, 24 mL, 47 mmol, 1.1 equiv) in toluene (100 mL) gave the desired product (4.9 g, 64%) as a colorless oil following purification over silica gel using 25% EtOAc/hexanes as eluent.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]=[O:18].[OH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[OH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:6]1[N:5]=[CH:4][C:3]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:17]=[O:18])=[CH:2][CH:7]=1
Reactant: O=Cc1c[nH]c2ccc(-c3cnccc3Br)cc12
Reactant: OB(O)c1ccccc1O
Product: O=Cc1c[nH]c2ccc(-c3ccc(-c4ccccc4O)nc3)cc12

Procedure:
The title compound was prepared in analogous manner as described for 2. Thus, starting from 3 (0.1 g, 0.33 mmol) and 2-hydroxy benzeneboronic acid instead of 6-bromo-3-iodopyridineboronic acid following the above described procedure gave 50 mg of pure 4.
Reaction SMILES: C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[NH:16]([C:23]1[O:24][CH2:25][C:26](=O)[C:27]=1[C:28]([OH:30])=[O:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.[NH2:39][C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1.Cl>C(Cl)Cl>[C:17]1([NH:16][C:23]([C:27]2[C:28](=[O:30])[O:29][CH2:25][C:26]=2[NH:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C(O)C1=C(Nc2ccccc2)OCC1=O
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC2=C(C(=O)Nc3ccccc3)C(=O)OC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, BOP-Cl (5.09 grams, 0.02 mol) was added in one portion to a well-stirred solution of 2-anilino-4-oxo-3-furoic acid (4.38 grams, 0.02 mol) and triethylamine (2.8 ml, 20 mmol) in 34 ml methylene chloride, at 0° C. The reaction mixture was stirred at 0° C. for 45 min after which time 2.35 grams (0.022 mol) of p-toluidine in 17 ml methylene chloride were added over a period of 15 min. followed by the dropwise addition of triethylamine (2.8 ml, 20 mmol). The reaction mixture was stirred at 5°-10° C. for 30 min and at room temperature for 2 hours, poured into ice-water, acidified with 2N hydrochloric acid (pH 1), and then extracted with methylene chloride. The organic extract was washed with 5% aqueous sodium bicarbonate solution, dried over sodium sulfate, and the solvent evaporated under reduced pressure leaving the crude product which was recrystallized from ethanol. Yield: 3.37 grams, mp 181°-183° C. (R=C6H4CH3 --p).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])=[O:24])[C:5]1=[O:31].[N:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][C:26]([CH3:29])([CH3:30])[CH2:27][OH:28])=[O:24])[C:5](=[O:31])[N:4]3[CH2:3][CH2:2][NH:1][C:38]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:39])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: CC(C)(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Reactant: O=C(Cl)N1CCOCC1
Product: CC(C)(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(=O)N2CCOCC2)c1=O

Procedure:
This compound was prepared from 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxy-1,1-dimethylethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide and 4-morpholinecarbonyl chloride employing methods similar to those described in Example 450 and was obtained as an orange solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.36 (s, 6 H), 2.03 (s, 1 H), 3.13-3.20 (m, 4 H), 3.27-3.30 (m, 2 H), 3.48 (dt, J=4.56, 2.35 Hz, 6 H), 4.13 (s, 2 H), 4.27 (t, J=6.04 Hz, 2 H), 5.09-5.15 (m, 1 H), 6.75 (t, J=5.76 Hz, 1 H), 7.10-7.18 (m, 2.04 Hz, 2 H), 7.39-7.44 (m, 2 H), 8.23 (d, J=1.54 Hz, 1 H), 8.53 (d, J=1.26 Hz, 1 H), 10.53 (s, 1 H); ES+ MS: 542 (M+H+).
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[CH2:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]1=O)C.O.[NH2:14]N>C(O)C>[CH3:10][C:7]1([CH3:11])[C:6]2[C:5](=[CH:4][NH:2][N:14]=2)[CH2:9][CH2:8]1
Reactant: CN(C)C=C1CCC(C)(C)C1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC1(C)CCc2c[nH]nc21
Temperature: 25 °C
Yield: 102.8 %

Procedure:
To a solution of 2-[(dimethylamino)methylene]-5,5-dimethylcyclopentanone (12.5 g, 75 mmol) in ethanol (100 mL) at room temperature was added hydrazine hydrate (4 mL, 82.3 mmol). The reaction mixture was heated at reflux overnight. It was then cooled to room temperature and concentrated. Water (700 mL) was added to the residue, and the resulting solution was extracted twice with diethyl ether (2×250 mL). The organic extracts were combined, dried over MgSO4 and concentrated to give the title compound as an oil (10.5 g). 1H NMR indicated the oil to be ˜60% pure. It was used directly for Step C.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]([F:43])([F:42])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39][CH2:40]Br)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]>>[F:18][C:19]([F:42])([F:43])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39][CH2:40][N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3nc(-c4ccccc4)ns3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(3-phenyl-[1,2,4]thiadiazol-5-yl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[O:8][CH:9]=[CH:10][CH:11]=1.[O:12]1[CH2:17][CH2:16][CH:15]([CH:18]=[O:19])[CH2:14][CH2:13]1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:6][C:7]1[O:8][C:9]([CH:18]([CH:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)[OH:19])=[CH:10][CH:11]=1
Reactant: O=CC1CCOCC1
Reactant: Cc1ccco1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)C2CCOCC2)o1
Temperature: -70 °C
Reaction time: 2 h
Yield: 112.9 %

Procedure:
12.0 ml (30 mmol, 1.5 eq) of a 2.5 M solution of n-butyllithium in hexane were added dropwise to a solution of 2.46 g (30 mmol, 1.5 eq) of 2-methylfuran in 50 ml of tetrahydrofuran cooled to −70° C. The reaction medium was stirred and allowed to return to ambient temperature for 2 hours. The reaction medium was cooled to −70° C. and then 2.28 g (20 mmol, 1 eq) of tetrahydro-2H-pyran-4-carbaldehyde were added. The reaction medium was stirred at ambient temperature for 2 hours. The reaction medium was treated with a saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, washed with a saturated sodium chloride solution and evaporated. 4.43 g of (5-methylfuran-2-yl)-(tetrahydropyran-4-yl)methanol were obtained. Yield=100%.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH:8]([CH2:13][C:14]([O:16]C)=[O:15])[C:9]([O:11]C)=[O:10])[CH:6]=1.[OH-].[Li+]>C1COCC1.O.O>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH:8]([CH2:13][C:14]([OH:16])=[O:15])[C:9]([OH:11])=[O:10])[CH:6]=1
Reactant: COC(=O)CC(Cn1cc(I)cn1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC(Cn1cc(I)cn1)C(=O)O
Temperature: 25 °C

Procedure:
A solution of dimethyl 2-((4-iodo-1H-pyrazol-1-yl)methyl)succinate (200 mg, 0.61 mmol) and lithium hydroxide (40 mg, 1.80 mmol) in THF/water (4 mL/1 mL) was stirred at 60° C. for 12 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 2-((4-iodo-1H-pyrazol-1-yl)methyl)succinic acid. MS ESI calc'd. for C8H10IN2O4 [M+H]+ 325. found 325. 1H NMR (400 MHz, CD3OD) δ 7.76 (s, 1H), 7.50 (s, 1H), 4.60-4.48 (m, 2H), 3.46-3.38 (m, 1H), 2.83-2.73 (m, 1H), 2.60-2.51 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](B(O)O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:14]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:17][N:16]2[CH2:25][CH2:26][CH2:27][C:15]=12>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]1[C:14]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)=[C:15]2[CH2:27][CH2:26][CH2:25][N:16]2[N:17]=1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Brc1c(-c2ccccn2)nn2c1CCC2
Product: c1ccc(-c2nn3c(c2-c2ccc4[nH]ccc4c2)CCC3)nc1
Yield: 3.5 %

Procedure:
In a similar fashion to Example 1, react 1H-indole-5-boronic acid (Fluka; 150 mg, 0.95 mmol) with 3-bromo-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (Preparation 4; 250 mg, 0.95 mmol) to provide the title compound (10 mg, 4%) as an off-white solid. MS ESI+ m/e 301 (M+1). 1H NMR (CDCl3) δ 8.67-8.58 (m, 1H), 7.61 (s, 1H), 7.52-7.45 (m, 1H), 7.39-7.29 (m, 2H), 7.21-7.16 (m, 1H), 7.14-7.04 (m, 2H), 6.52-6.48 (m, 1H), 4.31-4.21 (m, 2H), 3.06-2.98 (m, 2H), 2.73-2.60 (m, 2H). TLC (SiO2): Rf 0.4 (1:3 [80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]/dichloromethane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([OH:23])=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:24]([C:27]2[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[CH:35]1([CH2:39]Br)[CH2:38][CH2:37][CH2:36]1>>[CH:35]1([CH2:39][O:22][C:21]([C@@:19]23[CH2:18][N:17]([S:24]([C:27]4[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)(=[O:25])=[O:26])[CH2:16][CH2:15][C:14]2=[CH:13][C:12]2[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[CH:10][C:11]=2[CH2:20]3)=[O:23])[CH2:38][CH2:37][CH2:36]1
Reactant: COc1ccc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(C(=O)O)C2)cn1
Reactant: BrCC1CCC1
Product: COc1ccc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(C(=O)OCC3CCC3)C2)cn1

Procedure:
The title compound was prepared by the method of Preparation 54b using (R)-1-(4-fluorophenyl)-6-(6-methoxy pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic acid and cyclobutylmethyl bromide. 1H NMR (400 MHz, CHCl3-d): δ 8.59 (d, 1H), 7.89 (dd, 1H), 7.45-7.37 (m, 3H), 7.16 (t, 2H), 6.84 (d, 1H), 6.42 (d, 1H), 4.40 (dd, 1H), 4.06 (dd, 2H), 4.01 (s, 3H), 3.89-3.81 (m, 1H), 3.28 (d, 1H), 2.88-2.81 (m, 1H), 2.58-2.51 (m, 4H), 2.03-1.92 (m, 2H), 1.79-1.70 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH2:25]([Mg]Br)[CH3:26]>>[F:24][C:2]([F:1])([F:23])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]([OH:20])[CH2:25][CH3:26])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Product: CCC(O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared as described in Example 24 from 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde and ethylmagnesium bromide and isolated as a yellow oil (5.00 g, 100%): 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.20-8.12 (m, 2H), 7.85-7.76 (m, 2H), 7.50-7.44 (m, 2H), 7.39 (dq, J=8.0, 1.0 Hz, 2H), 4.68 (t, J=6.5 Hz, 1H), 1.93-1.75 (m, 2H), 1.59 (s, 1H), 0.95 (t, J=7.4 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 364 ([M+H]+).