Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][C:3]=1[CH:10]1[S:14](=[O:16])(=[O:15])[NH:13][C:12](=[O:17])[CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>O1CCOCC1.C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][Br:38])[CH:5]=[CH:4][C:3]=1[CH:10]1[S:14](=[O:16])(=[O:15])[NH:13][C:12](=[O:17])[CH2:11]1
Reactant: O=C1CC(c2ccc(CO)cc2Br)S(=O)(=O)N1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CC#N
Product: O=C1CC(c2ccc(CBr)cc2Br)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-[2-bromo-4-(hydroxymethyl)phenyl]isothiazolidin-3-one 1,1-dioxide (54.0 mg, 0.169 mmol) in 1,4-dioxane (5 mL) was added triphenylphosphine (49 mg, 0.18 mmol) and carbon tetrabromide (62 mg, 0.18 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was diluted with acetonitrile and purified by preparative LCMS to give the product as a white solid.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8](C)=[C:7]([NH2:12])[CH:6]=1)[C:2](C)=[O:3].[NH2:13]C1C=CC=CC=1OC>>[NH2:12][C:7]1[CH:6]=[C:5]([NH:1][C:2]([NH2:13])=[O:3])[CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)Nc1ccc(C)c(N)c1
Reactant: COc1ccccc1N
Product: NC(=O)Nc1cccc(N)c1

Procedure:
4-acetamino-2-aminotoluene or -2-aminoanisole;
Reaction SMILES: [OH-:1].[Na+].[O:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1>O>[CH:6]12[CH2:7][CH:4]([CH:4]=[CH:5]1)[CH2:5][CH:6]2[C:7]([OH:3])=[O:1]
Reactant: C1CCOC1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C1CC2C=CC1C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
19.0 g (58.5 mmol) of the Diels-Alder adduct was dissolved in 115 ml of tetrahydrofuran, 12.9 g (300 mmol) of sodium hydroxide in 140 ml of water was added on ice cooling, the mixture was stirred at room temperature for 24 hours. After distilling off tetrahydrofuran, the product was neutralized with 27 ml of concentrated hydrochloric acid and extracted with a mixture solvent of hexane-methylene chloride (98:2) (100 ml×4). The extract was dried over anhydrous magnesium sulfate, the solution was filtered, and the solvent was distilled off to obtain 8.3 g of crude 5-norbornene-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26](OCC)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:34][CH:35]([CH2:38][OH:39])[CH2:36][OH:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:34][CH:35]([CH2:38][OH:39])[CH2:36][OH:37])=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: NC(CO)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Product: O=C(NC(CO)CO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-amino-1,3-propanediol using conditions similar to those employed in Example 563 to provide a white solid: ES+ MS: 499 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[C:5]([N+:26]([O-:28])=[O:27])[CH:4]=1.[C:29]1([CH:35]2[CH2:44][C:43]3[C:38](=[CH:39][C:40]([OH:45])=[CH:41][CH:42]=3)[O:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([O:45][C:40]2[CH:39]=[C:38]3[C:43]([CH2:44][CH:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:36][O:37]3)=[CH:42][CH:41]=2)=[C:5]([N+:26]([O-:28])=[O:27])[CH:4]=1
Reactant: COc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)c([N+](=O)[O-])c1
Reactant: Oc1ccc2c(c1)OCC(c1ccccc1)C2
Product: COc1ccc(Oc2ccc3c(c2)OCC(c2ccccc2)C3)c([N+](=O)[O-])c1

Procedure:
7-(4-Methoxy-2-nitrophenoxy)-3-phenylchroman was prepared as described for 6-(4-methoxy-2-nitrophenoxy)-2-phenylchroman in Example 3(a) using 0.5 g of 3-phenylchroman-7-ol. 1H NMR (400 MHz, d6-DMSO) δ: 7.60 (d, 1H, J 3.1 Hz), 7.35 (m, 4H), 7.32 (dd, 1H, J 9.1, 3.1 Hz), 7.27-7.29 (m, 1H), 7.21 (d, 1H, J 9.1 Hz), 7.12 (d, 1H, J 8.3 Hz), 6.48 (dd, 1H, J 8.3, 2.5 Hz), 6.38 (d, 1H, J 2.5 Hz), 4.26 (dd, 1H, J 10.4, 3.5 Hz), 4.08 (t, 1H, J 10.4 Hz), 3.85 (s, 3H), 3.20 (m, 1H), 2.90-3.04 (m, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].I[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]2[N:22]([CH3:23])[CH2:21][CH2:20][N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:18]=2[N:31]=1>CN(C=O)C>[C:3]([CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]2[N:22]([CH3:23])[CH2:21][CH2:20][N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:18]=2[N:31]=1)#[N:4]
Reactant: CCOC(=O)CC#N
Reactant: CN1CCN(C(=O)OC(C)(C)C)c2nc(CCI)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C#N)CCc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCN2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
NaH (620 mg, 24.55 mmol) was suspended in DMF (203 mL) at 0° C. under N2. Ethyl cyanoacetate (2.6 mL, 24.55 mmol) was added and the resulting mixture stirred for 30 min at 0° C. Tert-butyl 6-(2-iodoethyl)-1-methyl-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate (6.6 g, 16.37 mmol) in DMF (10 mL) was introduced to the reaction mixture and stirred for 2 hours at room temperature. The mixture was cooled to 0 and quenched with water and extracted with EtOAc (3×). The organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica, 90% EtOAC/Hex) to afford colorless oil (5.78 g, 91% yield). H NMR (CDCl3) δ 1.35 (q, 3H), 1.55 (s, 9H), 2.38 (m, 2H), 2.89 (t, 2H), 2.93 (s, 3H), 3.32 (t, 2H), 3.85 (t, 2H), 3.90(m, 1H), 4.30 (q, 2H), 6.85(d, 2H). LC-MS (M+H) 389.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([OH:22])[CH:16]=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][O-:27].[Na+]>O1CCCC1.O>[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][O:27][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([OH:22])[CH:16]=1
Reactant: CN(C)CC[O-]
Reactant: Cc1ccc(Nc2c(C#N)cnc3cnc(F)cc23)cc1O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Nc2c(C#N)cnc3cnc(OCCN(C)C)cc23)cc1O

Procedure:
To 160 mg of 6-fluoro-4-(3-hydroxy-4-methyl-phenylamino)-[1,7]naphthyridine-3-carbonitrile under an inert atmosphere was added 3 mL of 1 M sodium (2-dimethylamino-ethoxide) in tetrahydrofuran. After refluxing for 3 hours, the reaction was diluted with Water and the product extracted five times with chloroform. The crude product was purified by flash chromatography with 1% triethyl amine and 10% methanol/chloroform followed by recrystallized from chloroform/ether to give 106 mg of 6-(2-dimethylamino-ethoxy)-4-(3-hydroxy-4-methyl-phenylamino)-[1,7]naphthyridine-3-carbonitrile as a yellowish solid: melting point 100-180° C. (decomposed, effervescence); mass spectrum (m/e): M+H 419.9.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:28]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[C:28]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:33]=[CH:32][CH:31]=[C:30]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7]2)[CH:29]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Product: O=C1OC2(CCN(C(=O)c3cn(-c4cccc(-c5ccccc5)c4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure VI as described above, the arylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 3-biphenylboronic acid gave the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.B([C:16]1[S:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)(O)O>>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:16]1[S:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH:11]=[CH:10]2
Reactant: Oc1ccc2nc(Cl)ccc2c1
Reactant: O=C(O)c1ccc(B(O)O)s1
Product: O=C(O)c1ccc(-c2ccc3cc(O)ccc3n2)s1

Procedure:
Followed Scheme 3: Starting Materials: 2-chloroquinolin-6-ol and 5-boronothiophene-2-carboxylic acid. 1H NMR (CD3OD, 400 MHz): δ 8.25 (d, J=8.8 Hz, 1H), 7.97 (dd, J=9.2, 3.2 Hz, 2H), 7.88-7.82 (m, 2H), 7.41 (dd, J=9.2, 2.8 Hz, 1H), 7.19 (d, J=2.4 Hz, 1H). MS (ESI): m/z 271.6 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15].C([O-])(=O)C.[Na+]>CC(N(C)C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2](/[CH:15]=[CH:14]/[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:3]([CH3:12])[CH:4]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(/C=C/C(=O)OC(C)(C)C)c(C)c1
Temperature: 140 °C
Yield: 40.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (5.0 g, 4.33 mmol) was added to a stirred solution of methyl 4-bromo-3-methylbenzoate (9.93 g, 43.3 mmol), tert-butyl acrylate (50 ml, 341.3 mmol) and sodium acetate (35.8 g, 436.4 mmol) in DMA (350 ml). The mixture was heated at 140° C. for 5 h, filtered through Celite® filter agent and the filtrate was concentrated in vacuo. The residue was redissolved in EtOAc, washed with 0.3M KHSO4 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 15% EtOAc:85% hexane to 20% EtOAc:80% hexane) to yield the title compound (4.81 g, 40%).
Reaction SMILES: [CH3:1][N:2]1[CH:17]=[C:5]2[N:6](C(OC(C)(C)C)=O)[CH2:7][CH2:8][CH2:9][C:4]2=[N:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH:17]=[C:5]2[NH:6][CH2:7][CH2:8][CH2:9][C:4]2=[N:3]1
Reactant: Cn1cc2c(n1)CCCN2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc2c(n1)CCCN2
Reaction time: 18 h
Yield: 0 %

Procedure:
To a stirred solution of tert-butyl 2-methyl-6,7-dihydro-2H-pyrazolo[4,3-b]pyridine-4(5H)-carboxylate (56 mg, 236 mol) in CH2Cl2 (4.00 mL) was added TFA (740 mg, 500 μL, 6.49 mmol) at room temperature. After 18 h, the reaction mixture was concentrated in vacuo and the residue obtained was purified by chromatography (40 g column, 50 m silica-gel from Analogix, 0 to 5% 9:1 methanol:ammonium hydroxide in CH2Cl2, 20 min) to give 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridine (25 mg, 77%). 1H NMR (CHLOROFORM-d) δ: 6.81 (s, 1H), 3.75 (s, 3H), 3.11-3.18 (m, 2H), 3.04 (s, 1H), 2.73 (t, J=6.4 Hz, 2H), 1.86-2.00 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C:5]=2[C:4]([CH3:18])=[N:3]1.[ClH:19]>CO.CCOC(C)=O>[ClH:19].[CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[C:4]([CH3:18])=[N:3]1
Reactant: Cc1nn(C)c2c1CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nn(C)c2c1CNCC2
Yield: 90.9 %

Procedure:
To a solution of tert-butyl 1,3-dimethyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (3.00 g) in MeOH was added a solution of HCl in EtOAc (3.0 M). White solid was precipitated out after 3.0 h reaction. The resulted mixture was filtered and the residue was dried to give the title compound as a white solid (2.00 g, 90.90%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 152.21 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][NH:8][CH:7]2[CH2:10][CH2:11][N:12]([C:13](=[O:29])[CH:14]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:6]12)=[O:4].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([S:40]([CH3:39])(=[O:42])=[O:41])[CH:7]2[CH2:10][CH2:11][N:12]([C:13](=[O:29])[CH:14]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:6]12)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1CNC2CCN(C(=O)C(NC(=O)OC(C)(C)C)C3CCCCC3)C21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(S(C)(=O)=O)C2CCN(C(=O)C(NC(=O)OC(C)(C)C)C3CCCCC3)C12
Reaction time: 1.5 h
Yield: 102.5 %

Procedure:
A solution of 27 (0.9 g, 2.2 mmol) in DCM (20 mL) was cooled to 0° C. and treated with DIPEA (0.75 mL, 4.3 mmol) and DMAP (31 mg, 0.25 mmol). Methanesulfonyl chloride (0.3 mL, 3.9 mmol) was then added. After 1.5 h, the solution was diluted with DCM, washed successively with 1M HCl, brine, dried over anhydrous Na2SO4, filtered and concentrated to afford sulfonamide 28 as an off-white foam (1.1 g) which was used without further purification. 1H NMR (CDCl3, 300 MHz): δ5.23 (d, J=9.0 Hz, 1H), 4.74 (d, J=5.1 Hz, 1H), 4.31-4.28 (m, 2H), 4.03 (app t, J=9.3 Hz, 1H), 3.83-3.76 (m, 1H), 3.76 (s, 3H), 3.59-3.47 (m, 2H), 3.42-3.4 (m, 1H), 2.91 (s, 3H), 2.51 (dd, J=5.7, 13.8 Hz, 1H), 2.09-2.05 (m, 1H), 1.75-1.53 (m, 6H), 1.43 (s, 9H), 1.26-1.04 (m, 6H) ppm; 13C NMR (CDCl3, 75 MHz): δ172.7, 171.6, 155.9, 79.8, 66.1, 63.1, 56.9, 52.8, 50.7, 47.2, 46.2, 41.2, 35.6, 33.3, 29.8, 28.5, 28.4, 26.2, 26.1, 26.0 ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N:27]2[CH2:32][CH2:31][CH:30]([CH3:33])[CH2:29][CH2:28]2)[CH:26]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][C:20]([NH:22][NH2:23])=O)=[CH:10][CH:9]=1)=[O:6].[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>>[CH2:34]([N:36]1[C:37](=[O:38])[NH:23][N:22]=[C:20]1[CH2:19][O:18][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][CH:30]([CH3:33])[CH2:29][CH2:28]3)[CH:26]=[C:2]([F:1])[CH:3]=2)=[CH:9][CH:10]=1)[CH3:35]
Reactant: CCN=C=O
Reactant: CC1CCN(c2cc(F)cc(C(=O)Nc3ccc(OCC(=O)NN)c4ccccc34)c2)CC1
Product: CCn1c(COc2ccc(NC(=O)c3cc(F)cc(N4CCC(C)CC4)c3)c3ccccc23)n[nH]c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.7 %

Procedure:
To a solution of 3-fluoro-N-(4-hydrazinocarbonylmethoxy-naphthalen-1-yl)-5-(4-methyl-piperidin-1-yl)-benzamide (0.35 g, 0.77 mmol) tetrahydrofuran (10 ml) is added ethylisocyanate (60 mg, 1.1 eq). The mixture is stirred at room temperature for 15 hours before being evaporated to dryness to give the urea intermediate as a solid (0.34 g). MS: 522 (M+1). Urea intermediate (0.1 g, 0.19 mmol) in 5% NaOH (2 ml) is heated at 100° C. for five hours. The mixture is then extracted with ethyl acetate, washed with water, dried over Na2SO4 and evaporated to dryness. The residue is purified by column chromatography on silica gel eluted with ethyl acetate then ethyl acetate containing a few drops of ammonium hydroxide to give N-[4-(4-ethyl-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-ylmethoxy)-naphthalen-1-yl]-3-fluoro-5-(4-methyl-piperidin-1-yl)-benzamide as a white solid (21 mg). Mp: 240-241° C. 1H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 10.27 (s, 1H), 8.16 (d, J=5.1 Hz, 1H), 7.88 (d, J=4.5 Hz, 1H), 7.57-6.95 (m, 7H), 5.27 (s, 2H), 3.78 (m, 4H), 2.77 (t, J=11.4 Hz, 2H) 1.68 (m, 3H), 1.20 (brs, 6H), 0.95 (brs, 3H). MS: 504 (M+1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[C:26]([O:30][C:31](=[O:49])[N:32]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[F:48])[C:33]1[CH:38]=[CH:37][C:36]([CH:39]=[O:40])=[CH:35][N:34]=1)([CH3:29])([CH3:28])[CH3:27].[Cl-].[NH4+]>O1CCCC1>[C:26]([O:30][C:31](=[O:49])[N:32]([C:33]1[CH:38]=[CH:37][C:36]([CH:39]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=3)[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:11]=2)[OH:40])=[CH:35][N:34]=1)[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[F:48])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1F)c1ccc(C=O)cn1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(Cl)cnc21
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1F)c1ccc(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Temperature: 5 °C
Yield: 41 %

Procedure:
To a solution of 1-benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (581, 0.420 g, 1.00 mmol) in tetrahydrofuran (15.0 mL) at −40° C. under nitrogen, isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.49 mL) was added slowly. The reaction was allowed to warm to 5° C. over 70 minutes, then cooled to −40° C., followed by adding (2-fluoro-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester 579 in tetrahydrofuran (6.0 mL). The reaction was allowed to warm to room temperature over 1 hour, then poured into aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (582, 0.25 g, 41%). MS (ESI) [M+H+]+=623.1.
Reaction SMILES: [N:1]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:8])=[CH:3][C:2]=1[CH3:9].C([Li])(C)(C)C.[CH:15]1([CH2:21][C:22](=[O:36])[CH2:23][C:24]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C1COCC1>[CH:15]1([CH2:21][C:22]([CH2:9][C:2]2[CH:3]=[C:4]([CH3:8])[CH:5]=[C:6]([CH3:7])[N:1]=2)([OH:36])[CH2:23][C:24]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])([CH3:26])[CH3:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)CC1CCCCC1
Reactant: Cc1cc(C)nc(C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc(C)cc(C)n1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.1 %

Procedure:
To a solution of collidine (0.113 g) in THF (1 mL) cooled to −70° C. was added dropwise over 3 minutes tert-butyl lithium (1.7 M in pentane, 0.55 mL). The mixture was stirred for 5 minutes and then 1-cyclohexyl-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (Example 15) (0.095 g) in THF (0.5 mL) was added dropwise. After 10 minutes at −70° C., the reaction was quenched by addition of EtOH (0.2 mL) and warmed to room temperature. The mixture was diluted with EtOAc, washed with water, dried over sodium sulfate, filtered, and evaporated. The residue was fractionated by preparative layer chromatography (developer: methylene chloride-EtOAc (99:1)) followed by preparative layer chromatography (developer:hexanes-methylene chloride-EtOH (1:1:0.01)) to give the title compound as an oil (73 mg).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:3].C(N(CC)CC)C.[C:17]([Si:21](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])([CH3:19])[CH3:18]>C(#N)C>[Si:21]([NH:3][CH:2]([CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(N[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of racemic α-methyl-benzenemethanamine (24.2 g, 0.2 mol) and triethylamine (42 mL, 0.30 mol) in acetonitrile (400 mL) in a flame-dried flask under nitrogen was added dropwise t-butylchlorodiphenylsilane (47 mL, 0.18 mol). The mixture was stirred at room temperature for 3 hours and then filtered to remove the insoluble white precipitate (triethylamine hydrochloride). After removal of the solvent in vacuo, the crude product was taken up in ether and washed sequentially with H2O, saturated NaHCO3 solution and brine. The solution was dried (Na2SO4 /K2CO3) and concentrated to leave a clear oil which was distilled under high vacuum. The major fraction consisting of the pure title compound (30.5 g, 47%) distilled from 160° to 165° C. at about 0.4 mm Hg.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:13]3C(=O)C4=CC=CC=C4C3=O)=[CH:8][C:7]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([F:32])[CH:25]=3)=[N:6]2)[CH2:3][CH2:2]1.O.NN>CO>[NH2:13][CH2:12][C:9]1[C:10](=[O:11])[N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:6]=[C:7]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([F:32])[CH:25]=2)[CH:8]=1
Reactant: COc1ccc(-c2cc(CN3C(=O)c4ccccc4C3=O)c(=O)n(CC3CC3)n2)cc1F
Agent: NN
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cc(CN)c(=O)n(CC3CC3)n2)cc1F
Yield: 99.7 %

Procedure:
To a solution of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxypheyl)-4-phthalimidomethyl-2H-pyridazin-3-one (190 mg, 0.43 mmol) in methanol (5 mL) was added hydrazine monohydrate (110 mg, 2.20 mmol), and the mixture was heated under reflux for 2 hours. Methanol was distilled off, and chloroform (20 mL) was added to the residue. The mixture was successively washed with water (10 mL) and brine (10 mL) in this order, and was then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by preparative thin-layer chromatography on silica gel [developing solvent: chloroform/10% w/v solution of methanol in ammonia (20/1)] to yield the title compound as yellow crystals (130 mg, 97.8%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][CH3:23].[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][CH2:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:31]([NH:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:32])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)Nc1ccccc1
Yield: 54.4 %

Procedure:
Using the general method of Example 145, except that the reaction was run at ambient temperature, 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.2 mmol) was reacted with phenyl isocyanate (0.35 mL, 3.2 mmol) to provide 0.75 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea as white needles, m.p. 185-187° C. Analysis: Calculated for C25H30N6O. H2O: %C, 66.94; %H, 7.19; %N, 18.74; Found: %C, 67.31; %H, 7.20; %N, 18.70.