Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C(=O)C1C=CC=NC=1.Cl.[CH3:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CCOCC>[CH:1]1[C:16]2[C:17](=[CH:18][CH:19]=[CH:20][CH:15]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: CCCCCC
Agent: Cl
Agent: O=Cc1cccnc1
Solvent: CCOCC
Product: c1ccc2ccccc2c1
Reaction time: 1 h

Procedure:
36.1 ml (57.75 mmol) of 1.6 M n-butyllithium in hexane are added dropwise, under argon, to a stirred solution of 16.1 g (55 mmol) of 2-bromo-6-napthyl methyl ketone ethylene acetal in 120 ml of absolute ether at -70° C. The mixture is then allowed to reach 0° C. and is stirred for one hour. Then, at -30° C., 6.19 g (57.75 mmol, 5.45 ml) of nicotinaldehyde in 15 ml of absolute ether are added dropwise. The mixture is subsequently allowed to reach room temperature within one hour, and is stirred for a further hour. After acidification to pH 1 with 2 N HCl the mixture is stirred overnight. After separation of the phases, the aqueous phase is extracted once with ether, the ether phase is discarded, and the aqueous phase is neutralized with sodium bicarbonate solution, which is then extracted with ethyl acetate. After drying and evaporation, the residue is recrystallized from isopropanol. 9.2 g (60%) of 2-acetyl-6-(1-hydroxy-1-(3-pyridyl) methyl(naphthalene are obtained. Melting point 157°-9° C.
Reaction SMILES: [CH3:1][I:2].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][C:12](=[S:15])[NH:11][CH:10]2[CH3:16]>CC(C)=O>[IH:2].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([S:15][CH3:1])[NH:11][CH:10]2[CH3:16]
Reactant: CI
Reactant: COc1cccc2c1NC(=S)NC2C
Solvent: CC(C)=O
Product: COc1cccc2c1N=C(SC)NC2C
Product: I
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl iodide (1.92 g, 14 mmol) was added to a solution of 8-methoxy-4-methyl-3,4-dihydro-1H-quinazoline-2-thione (940 mg, 5 mmol) in acetone (6 ml), and the mixture was stirred for 3 h at r.t. The precipitated title compound (1.2 g, 76%) was filtered off and was used without further purification in the next step.
Reaction SMILES: N[C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[BrH:13].N([O-])=O.[Na+]>O>[Br:13][C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: Br
Reactant: COC(=O)[C@H](N)c1ccccc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)[C@@H](Br)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 40.5 %

Procedure:
(R)-methyl 2-amino-2-phenylacetate (5 g, 24.8 mmol, 1 equiv) was dissolved in a mixture of 48% Hydrogen bromide (13 ml, 198 mmol, 8 equiv) and water (19 ml). An aqueous solution of sodium nitrite (5.48 g, 79.36 mmol, 3.2 equiv) was added slowly and the mixture stirred at 0° C. for 1.5 h. The reaction was degassed in vaccuo and extracted with ether. The organic layer was further washed with water and brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified using the Biotage flash chromatography system (SNAP 100 g cartridge, Rf=0.5, 10% ethyl acetate/hexanes) to afford the (S)-methyl 2-bromo-2-phenylacetate as a light yellow oil (2.3 g, 40% yield). 1H NMR (400 MHz, DMSO-d6): δ 3.72 (s, 3H); 5.95 (s, 1H); 7.36-7.42 (m, 3H); 7.532 (d, 2H, J=1.2 Hz); 7.56 (d, 1H, J=2 Hz). MS for C9H9BrO2 m/z 229.98 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]3[CH2:16][C@H:15]([C:17]([O:19]CCCC)=O)[O:14][C:13]3=[O:24])=[CH:11][C:6]=2[S:5][C:4]1=[O:25])[CH3:2].[CH3:26][NH2:27]>CO.CCOCC>[CH3:26][NH:27][C:17]([C@@H:15]1[O:14][C:13](=[O:24])[N:12]([C:10]2[CH:9]=[CH:8][C:7]3[N:3]([CH2:1][CH3:2])[C:4](=[O:25])[S:5][C:6]=3[CH:11]=2)[CH2:16]1)=[O:19]
Reactant: CCCCOC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3CC)C(=O)O1
Reactant: CN
Solvent: CO
Solvent: CCOCC
Product: CCn1c(=O)sc2cc(N3C[C@H](C(=O)NC)OC3=O)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The butyl(5R)-3-(2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 30, Step 3, 300 mg, 0.823 mmol) is treated with 2N methylamine in MeOH (8.2 mL), and the mixture is stirred at ambient temperature for 1 h. The resulting slurry is diluted with Et2O (10 mL) and filtered to give the title compound, mp 227-229° C.; MS (ESI+) for C14H15N3O4S m/z 322 (M+H)+; [α]25D−43 (c 0.93, DMSO).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11](I)[C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].[C:15](=O)([O-])[O-].[K+].[K+].[CH:21]1(B(O)O)[CH2:23][CH2:22]1>O1CCOCC1.C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH:21]2[CH2:23][CH2:22]2)[C:12]=1[O:13][CH3:15])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: OB(O)C1CC1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(I)c(O)c(C#N)c1
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd](Cl)(Cl)c1ncccc1Cl
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(C#N)c(OC)c(C2CC2)c1
Temperature: 95 °C
Reaction time: 22 h
Yield: 45.6 %

Procedure:
Methyl 3-cyano-4-hydroxy-5-iodobenzoate (1.00 g) was dissolved in 1,4-dioxane (15 mL), and potassium carbonate (1.31 g), cyclopropylboronic acid (325 mg) and [1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium dichloride (108 mg) were added to the solution, and then the mixture was stirred under an argon gas flow at 95° C. for 22 hours. The reaction solution was filtered and the solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to obtain the title compound (348 mg) as a pale yellow crystal.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[NH:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15](=O)[CH3:16])=[CH:7]1.C[C:19]([O-:21])=O.[Na+]>CN(C=O)C>[Cl:3]/[C:15](/[C:8]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:6][CH:7]=1)=[CH:16]/[CH:19]=[O:21]
Reactant: CC(=O)[O-]
Reactant: CC(=O)c1c[nH]c2ncccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C/C=C(/Cl)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22 %

Procedure:
Phosphorous oxychloride (3.7 mL, 40 mmol) was added dropwise to DMF (6.2 mL, 80 mmol) at 0° C. The reaction mixture was let warm to room temperature and stirred for 15 minutes. 1-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-ethanone was added in DMF (20 mL) and the reaction heated to 60° C. for 4 hours, cooled to 0° C. and 150 mL of saturated NaOAc solution added. The reaction mixture was heated briefly to 50° C. and then extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to an oil which contains impure product. Upon standing a solid precipitated from the aqueous layer to give 0.9 g of a brown solid, 4.3 mmol, 22% yield.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH:16]([CH3:18])[O:15][CH:14]([CH3:19])[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:13][CH:14]([CH3:19])[O:15][CH:16]([CH3:18])[CH2:17]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:20])=[O:30])=[CH:24][CH:23]=1
Reactant: CC1CN(c2nn(N)c(=O)c3ccccc23)CC(C)O1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Product: CC1CN(c2nn(NC(=O)Cc3ccc(Cl)cc3)c(=O)c3ccccc23)CC(C)O1

Procedure:
The product from Example 60A and 2-(4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.48-11.49 (bs, 1H), 8.29 (ddd, J=7.9, 1.4, 0.6 Hz, 1H), 8.01 (ddd, J=8.1, 1.5, 0.7 Hz, 1H), 7.98 (ddd, J=8.2, 6.9, 1.3 Hz, 1H), 7.89 (ddd, J=7.9, 6.9, 1.5 Hz, 1H), 7.40-7.41 (m, 4H), 3.81-3.94 (m, 2H), 3.67 (s, 2H), 3.29-3.36 (m, 2H), 2.43 (dd, J=12.3, 10.3 Hz, 2H), 1.12 (d, J=6.2 Hz, 6H); MS (APCI+) M/Z 427 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]2=[C:13]3[C:3]=1[O:4][CH2:5][CH2:6][N:7]3[C:8]([CH:14]([NH2:16])[CH3:15])=[N:9]2.[NH2:17][C:18]1[C:23]([C:24]#[N:25])=[C:22](Cl)[N:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:17][C:18]1[C:23]([C:24]#[N:25])=[C:22]([NH:16][CH:14]([C:8]2[N:7]3[C:13]4[C:3]([O:4][CH2:5][CH2:6]3)=[C:2]([F:1])[CH:12]=[CH:11][C:10]=4[N:9]=2)[CH3:15])[N:21]=[CH:20][N:19]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CC(N)c1nc2ccc(F)c3c2n1CCO3
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(Nc1ncnc(N)c1C#N)c1nc2ccc(F)c3c2n1CCO3
Temperature: 100 °C
Yield: 75.2 %

Procedure:
A mixture of 1-(6-fluoro-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)ethylamine (108 mg, 0.49 mmol), 4-amino-6-chloro-5-cyanopyrimidine (75 mg, 0.49 mmol) and DIPEA (171 μL, 0.98 mmol) in IPA (1 mL) was heated for 18 h at 100° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was taken up in MeOH and acidified with TFA, at which point the solution became homogenous. The reaction mixture was passed through a 2 g Isolute® SCX-2 cartridge, eluting with 2M NH3/MeOH. The basic fraction was concentrated in vacuo and the resulting brown residue was purified by column chromatography (Si—PPC, gradient 0-8% 2M NH3/MeOH in DCM) to afford 434 as a pale yellow solid (125 mg, 75%). LCMS (Method K): RT 2.49 min [M+H]+ 340.1. 1H NMR (DMSO, 400 MHz): δ 8.02 (1H, s), 7.74 (1H, d, J=7.4 Hz), 7.27 (2H, br s), 7.09 (1H, dd, J=8.7, 3.3 Hz), 6.95 (1H, dd, J=12.3, 8.8 Hz), 5.60 (1H, dq, J=7.4, 6.8 Hz), 4.50-4.41 (2H, m), 4.36-4.27 (2H, m), 1.58 (3H, d, J=6.8 Hz)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].[CH2:8]([N:15]1[CH2:22][C:19]2([CH2:21][CH2:20]2)[NH:18][CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:8]([N:15]1[CH2:22][C:19]2([CH2:21][CH2:20]2)[N:18]([C:3](=[O:4])[C:2]([F:7])([F:6])[F:1])[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: c1ccc(CN2CCNC3(CC3)C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(N1CCN(Cc2ccccc2)CC12CC2)C(F)(F)F
Reaction time: 1 h
Yield: 102.1 %

Procedure:
Anhydrous trifluoroacetic acid (8.50 ml, 61.1 mmol) was added dropwise to a methylene chloride (200 ml) solution of the compound (10.3 g, 50.9 mmol) obtained in Step 3 above and triethylamine (17 ml, 122 mmol) with ice cooling and the resulting mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, the resulting mixture was diluted with chloroform, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (15.5 g, 100%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2](Cl)(Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClCCCl.[OH2:15]>>[C:2]([Cl:1])(=[O:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O
Reactant: ClC(Cl)(Cl)c1ccccc1
Solvent: ClCCCl
Product: O=C(Cl)c1ccccc1

Procedure:
α, α,α-Trichlorotoluene (19.6 g; 0.1M), ferric chloride (4.1 g; 0.02M) and 1,2-dichloroethane (500 ml) were stirred under reflux under heavier than water Dean and Stark apparatus. Water (1.8 g) was then added to the Dean and Stark apparatus and the mixture was refluxed for 4 hours. By this time, all of the water had been consumed. The mixture was then filtered through Hyflo (Trade Mark) to remove the ferric chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1.[CH:34]1([C:40]2[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:37]3[CH:36]=[CH:35][C:34]([CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)=[CH:39][CH:38]=3)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccc(C4CCCCC4)cc3)cc2)cc1

Procedure:
{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester (1.5 g, 2.7 mmol) was coupled with 4-cyclohexyl phenyl-boronic acid (700 m g, 3.4 mmol) according to general procedure G to give {4-[2-(4′-cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}acetic acid methyl ester.
Reaction SMILES: [Cl:1][CH:2]([CH2:15][CH3:16])[C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:17]([N:9]1[C:8]2[CH:13]=[CH:14][C:5]([C:3](=[O:4])[CH:2]([Cl:1])[CH2:15][CH3:16])=[CH:6][C:7]=2[O:11][C:10]1=[O:12])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CCC(Cl)C(=O)c1ccc2[nH]c(=O)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(Cl)C(=O)c1ccc2c(c1)oc(=O)n2Cc1ccccc1

Procedure:
62.50 g (260.79 mmol) 6-(2-chloro-butyryl)-3H-benzoxazol-2-one, 31 mL (261.00 mmol) benzylbromide, 160.00 g (1157.74 mmol) potassium carbonate and 3000 mL acetone are stirred for 24 h at RT. The reaction mixture is concentrated by rotary evaporation i. V. and the residue is separated on silica gel (eluant cyclohexane/EA). The suitable fractions are concentrated by rotary evaporation i. V. and the residue is crystallised with EtOH.
Reaction SMILES: C(C1C(F)=CC(O)=C(C=1)C(NCC1C=CC=C([N+]([O-])=O)C=1)=O)#N.C([O:26][C:27](=[O:52])[CH2:28][O:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([C:37]#[N:38])=[CH:32][C:31]=1[C:39](=[O:51])[NH:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([N+:48]([O-:50])=[O:49])[CH:43]=1)C.CO>O1CCOCC1.ClCCl>[C:37]([C:33]1[C:34]([F:36])=[CH:35][C:30]([O:29][CH2:28][C:27]([OH:52])=[O:26])=[C:31]([C:39](=[O:51])[NH:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([N+:48]([O-:50])=[O:49])[CH:43]=2)[CH:32]=1)#[N:38]
Reactant: CCOC(=O)COc1cc(F)c(C#N)cc1C(=O)NCc1cccc([N+](=O)[O-])c1
Agent: N#Cc1cc(C(=O)NCc2cccc([N+](=O)[O-])c2)c(O)cc1F
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: N#Cc1cc(C(=O)NCc2cccc([N+](=O)[O-])c2)c(OCC(=O)O)cc1F

Procedure:
[4-Cyano-5-fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid was prepared in an analogous manner to that set forth in Example 45 (Steps 8-9) except that in Step 8, 5-cyano-4-fluoro-2-hydroxy-N-(3-nitro-benzyl)-benzamide was used in place of N-(4-bromo-2-fluorobenzyl)-4-fluoro-2-hydroxy-5-methyl-benzamide. In Step 9, special care was taken in the hydrolysis of [4-cyano-5-fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid ethyl ester. The hydrolysis was performed in dioxane instead of ethanol and quenched after 15 minutes to prevent hydrolysis of the cyano functionality: mp 179-180° C.; Rf 0.22 (20 6 methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 9.12 (t, J=6.0 Hz, 1H), 8.21 (d, J=7.8 Hz, 1H), 8.19 (s, 1H), 8.10 (dd, J1=8.4 Hz, J2=2.6 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.61 (t, J=8.0 Hz, 1H), 7.45 (d, J=11.4 Hz, 1H), 4.99 (s, 2H), 4.61 (d, J=6.0 Hz, 2H); ESI-LC/MS m/z calcd for C17H12FN3O6: 373.1; Found 472.0 (M−1)−. Anal. calcd for C17H12FN3O6: C, 54.70; N, 11.26; H, 3.24. Found C, 54.43; N, 11.07; H, 3.32.
Reaction SMILES: I.I[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[C:12]([CH3:24])[CH:11]=2)[C:4]=1[NH2:25].[C:26]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)#[CH:27]>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:32][C:31]1[CH:33]=[CH:34][C:28]([C:26]#[C:27][C:3]2[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]4[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=4)=[C:12]([CH3:24])[CH:11]=3)[C:4]=2[NH2:25])=[CH:29][CH:30]=1
Reactant: C#Cc1ccc(N)cc1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc(I)c3N)cc2C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(Oc2ccc(Nc3ncnc(C#Cc4ccc(N)cc4)c3N)cc2C)cn1
Yield: 65.9 %

Procedure:
6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine hydriodide (270 mg) was dissolved in a mixed solvent of acetonitrile (10.3 mL)/triethylamine (7.72 mL), and 4-ethynylaniline (80.3 mg), trans-dichlorobis(triphenylphosphine)palladium(II) (20.8 mg) and copper(I) iodide (7.16 mg) were sequentially added. The title compound (134 mg) was obtained as a powder by the reaction in the same manner as in Example 9 (iv).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[C:12]([C:16]1[CH:17]=[CH:18][C:19]([O:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])=[C:20](B(O)O)[CH:21]=1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.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>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([O:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])=[C:20]([C:2]2[N:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=2)[CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: COCCOCOc1ccc(C(C)(C)C)cc1B(O)O
Reactant: FC(F)(F)c1ccc(Cl)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COCCOCOc1ccc(C(C)(C)C)cc1-c1ccc(C(F)(F)F)nn1
Temperature: 80 °C
Yield: 87.7 %

Procedure:
A mixture of 3-chloro-6-trifluoromethylpyridazine [purchased from Combi-Blocks] (250 mg, 1.37 mmol), (5-(tert-butyl)-2-((2-methoxyethoxy)methoxy)phenyl)boronic acid [Intermediate 7] (463.8 mg, 1.64 mmol) and potassium carbonate (284.5 mg, 2.06 mmol) in dimethoxyethane (7.5 mL) and water (2.5 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (79.1 mg, 0.068 mmol) was added and the reaction mixture heated to 80° C. in a sealed vial for 22 hours. The cooled reaction mixture was partitioned between ethyl acetate (50 mL) and 10% aqueous sodium carbonate solution (50 mL), the organic phase separated, washed with water (50 mL) and saturated brine (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a brown syrup. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 30% ethyl acetate in hexanes to give 3-(5-(tert-butyl)-2-((2-methoxyethoxy)methoxy)phenyl)-6-(trifluoromethyl)pyridazine (0.462 g, 88% yield) as a colorless syrup.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:8]([F:14])([F:13])[CH:7]([C:15]3[CH:16]=[N:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][CH:20]=3)[CH2:6][CH2:5][C:4]=2[C:3]=1[OH:28].[F:29][C@@H:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:31]O>>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][C:11]([F:12])=[C:2]([F:1])[C:3]=3[O:28][CH2:31][CH:30]([F:29])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:8]2([F:14])[F:13])=[CH:16][N:17]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCC[C@H](F)CO
Reactant: CCCCCCOc1ccc(C2CCc3c(cc(F)c(F)c3O)C2(F)F)cn1
Product: CCCCCCCCC(F)COc1c(F)c(F)cc2c1CCC(c1ccc(OCCCCCC)nc1)C2(F)F

Procedure:
From 2,3,5,5-tetrafluoro-6-(6-hexyloxypyridin-3-yl)-5,6,7,8-tetrahydronaphthalen-1-ol and 2-(S)-fluorodecan-1-ol by means of the Mitsunobu reaction.
Reaction SMILES: CO[CH2:3][C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1.B(Br)(Br)[Br:18].O>C(Cl)Cl>[Br:18][CH2:3][C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1
Reactant: COCc1ccc2sc(S(N)(=O)=O)cc2c1
Reactant: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)c1cc2cc(CBr)ccc2s1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-methoxymethyl-2sulfamoylbenzo[b]thiophene (7.4 g, 0.029 mol) in 300 ml of dry methylene chloride cooled to -30° C. was added boron tribromide (30 ml of a lM solution in methylene chloride, 0.03 mol) over a 20 minute period. The resulting solution was stirred for 11/2 hours as the temperature rose to ambient. The solution was cooled to 0° C. and there was added dropwise 150 ml of water keeping the temperature below 20° C. The methylene chloride layer was separated and the aqueous suspension was extracted with three portions (200 ml) of methanol-chloroform (50/50). The combined extracts were washed with ice water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 8.8 g of tan solid (quantitative yield of crude product) which after recrystallization from 1,2-dichloroethane had m.p. 171°-173° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[CH3:13][O:14][S:15]([O:18]C)(=[O:17])=[O:16]>>[CH3:13][O:14][S:15]([O-:18])(=[O:17])=[O:16].[CH3:13][N+:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:12]
Reactant: Cc1ccc2cc(Cl)ccc2n1
Reactant: COS(=O)(=O)OC
Product: COS(=O)(=O)[O-]
Product: Cc1ccc2cc(Cl)ccc2[n+]1C
Yield: 95 %

Procedure:
6-Chloro-2-methyl quinoline, 3 (3 g, 16.9 mmol) was alkylated with dimethylsulphate (2.13 g, 16.9 mmol) as above to give the title compound (4.88 g, 16.1 mmol, 95%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.[CH2:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[CH3:1][C:2]1[C:10]([O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH:30][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCc1ccccc1
Reactant: Cc1c(Oc2ccc(C(N)=O)cn2)ccc2c1CCC2=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: Cc1c(Oc2ccc(C(N)=O)cn2)ccc2c1CCC2NCCc1ccccc1
Yield: 81.7 %

Procedure:
Using a method similar to Example 14, using 6-(4-methyl-1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 12, 100 mg, 0.354 mmol), phenethylamine (52 mg, 0.425 mmol), Ti(iPrO)4 (201 mg, 0.708 mmol), TiCl4 (11.0M/DCM, 0.708 ml, 0.708 mmol), and NaBH3CN (44 mg, 0.708 mmol) gives the title compound (112 mg) as a white solid. Mass spectrum (ion spray): m/z=388 (M+1); 1HNMR (CDCl3): 8.57 (s, 1H), 8.14 (d, 1H), 7.32-7.19 (m, 5H), 7.14 (d, 1H), 6.91-6.87 (m, 2H), 6.03 (br. s, 2H), 428 (t, 1H), 3.01 (t, 2H), 2.94 (m, 1H), 2.85 (m, 2H), 2.74 (m, 1H), 2.44 (m, 1H), 2.02 (s, 3H), 1.86 (m, 1H).