Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.[CH3:12][O:13][C:14]([NH:16][C:17](=NC(OC)=O)SC)=[O:15]>C(O)(=O)C.[Fe]>[Br:1][C:2]1[N:3]=[CH:4][C:5]2[N:9]=[C:17]([NH:16][C:14](=[O:15])[O:13][CH3:12])[NH:8][C:6]=2[CH:7]=1
Reactant: Nc1cc(Br)ncc1[N+](=O)[O-]
Reactant: COC(=O)N=C(NC(=O)OC)SC
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cnc(Br)cc2[nH]1
Temperature: 75 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
A solution of 2-bromo-5-nitropyridin-4-amine (1.5 g, 6.9 mmol) in acetic acid (20 mL) was added in portions into a 75° C. suspension of iron powder (1.5 g, 27 mmol) in acetic acid (20 mL). The reaction mixture was stirred at 75° C. for 2 h, cooled to room temperature, and filtered through celite. To the filtrate was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (1.4 g, 6.9 mmol), and the mixture was stirred at 65° C. for 60 h. The reaction mixture was cooled to room temperature and concentrated. The solid residue was triturated with dichloromethane and dried to give the title Compound (1.8 g, quantitative yield) as an orange solid. MS (EI) for C8H7BrN4O2: 271/273 (MH+).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:9]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[NH:10][C:11](=[O:20])[CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH:6]=[CH:7][CH:8]=1.[CH3:29][O:30][C:31]1[C:32](=O)[C:33](=[O:37])[C:34]=1[O:35]C>>[CH3:29][O:30][C:31]1[C:34](=[O:35])[C:33](=[O:37])[C:32]=1[NH:2][C:3]1[CH:4]=[C:5]([CH:9]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[NH:10][C:11](=[O:20])[CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1c(OC)c(=O)c1=O
Reactant: COc1ccc(C(NC(=O)C(C)c2ccccc2)c2cccc(N)c2)cc1
Agent: Cl
Product: COc1ccc(C(NC(=O)C(C)c2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Yield: 64.6 %

Procedure:
In a similar manner to that described in Example (46e) N-[(3-aminophenyl)-(4-methoxyphenyl)methyl]-2-phenylpropionamide hydrochloride (555 mg) [prepared as described in step (b) above] and 3,4-dimethoxy-3-cyclobutene-1,2-dione (398 mg) were reacted, to afford the title compound (425 mg) as a yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:28]=[CH:27][C:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:20]=4[CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11].[C:29]([O:33]C(C)(C)C)(=[O:32])[CH:30]=[CH2:31].C(N(C(C)C)CC)(C)C>CO>[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:28]=[CH:27][C:21]4[CH2:22][CH2:23][N:24]([CH2:31][CH2:30][C:29]([OH:33])=[O:32])[CH2:25][CH2:26][C:20]=4[CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCNCC4)no2)cc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCN(CCC(=O)O)CC4)no2)cc1Cl
Temperature: 90 °C
Reaction time: 5 h
Yield: 46.2 %

Procedure:
A mixture of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (Example 17) (200 mg, 0.52 mmol), 1,1-dimethylethyl 2-propenoate (151 μL, 1.04 mmol) and diisopropylethylamine (453 μL, 2.60 mmol) in methanol (5 ml) was heated in the microwave at 90° C. for 30 minutes before the solvent was removed in vacuo. The residue was dissolved in 4M HCl (2 ml) in dioxane and the mixture stirred at room temperature for 5 h. The solvent was removed in vacuo and the residue purified by MDAP. To the product containing fractions was added 2M HCl and the solution concentrated in vacuo to give the title compound as a white solid (116 mg, 0.24 mmol). δH (d6DMSO, 400 MHz): 12.73 (1H, br.s), 10.76 (1H, br.s), 8.19 (1H, d), 8.11 (1H, dd), 7.98 (1H, d), 7.93 (1H, dd), 7.46 (1H, d), 7.45 (1H, d), 4.89 (1H, septet), 3.76-3.64 (2H, m), 3.44-3.31 (4H, hidden under H2O peak), 3.25-3.03 (4H, m), 2.89 (2H, t), 1.37 (6H, d). MS (ES): C24H2635ClN3O4 requires 455; found 456 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]=[C:7]([NH:9][CH3:10])[S:8][C:4]=2[CH:3]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[Cl:1][C:2]1[CH:3]=[C:4]2[S:8][C:7]([NH:9][CH3:10])=[N:6][C:5]2=[C:11]([S:14]([Cl:13])(=[O:16])=[O:15])[CH:12]=1
Reactant: CNc1nc2ccc(Cl)cc2s1
Reactant: O=S(=O)(O)Cl
Product: CNc1nc2c(S(=O)(=O)Cl)cc(Cl)cc2s1

Procedure:
A solution of 6-chloro-N-methylbenzo[d]thiazol-2-amine (500 mg, 2.53 mmol) in chlorosulfonic acid (5 mL) was stirred at 130° c. overnight. The solution was allowed to cool and slowly added to a large excess of ice. The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chorography (silica gel) eluting with PE/EA=1:1 to get the title compound. 1H NMR (CHLOROFORM-d) δ: 7.95 (d, J=1.9 Hz, 1H), 7.89 (d, J=2.1 Hz, 1H), 6.70 (br. s., 1H), 3.16 (d, J=4.3 Hz, 3H). LC-MS: m/z 297 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.Cl[C:29]1[N:34]=[C:33]([Cl:35])[N:32]=[C:31]([Cl:36])[C:30]=1[Cl:37]>C1COCC1>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:29]2[C:30]([Cl:37])=[C:31]([Cl:36])[N:32]=[C:33]([Cl:35])[N:34]=2)[CH2:4][CH2:5]1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCC(CNc2nc(Cl)nc(Cl)c2Cl)CC1
Reaction time: 0.75 h

Procedure:
To a solution of benzyl 4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1) and N,N-diisopropylethylamine (2.6 g, 20 mmol) in THF (40 mL) at −78° C. was added a solution of tetrachloropyrimidine (4.4 g, 20 mmol). The cooling bath was removed and the solution was stirred for 45 min. The solution was concentrated and purified by filtering through a pad of silica gel using ether.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:18]([O:20]C)=[O:19])[CH:11]=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14]>CCO>[CH3:16][O:15][C:13]([C:12]1[CH:11]=[C:10]([CH:9]=[C:8]([O:7][CH2:6][CH2:5][O:4][CH3:3])[CH:17]=1)[C:18]([OH:20])=[O:19])=[O:14]
Reactant: COCCOc1cc(C(=O)OC)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCOc1cc(C(=O)O)cc(C(=O)OC)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 87.3 %

Procedure:
NaOH (45 mmol) was added to the solution of dimethyl 5-(2-methoxyethoxy)isophthalate (30 mmol) in 50 ml EtOH and stirred for 4 h at 40° C. Excess of solvent was removed in vacuo and the residue was treated with 1N HCl (aqueous) and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated to afford 3-(methoxycarbonyl)-5-(2-methoxyethoxy)benzoic acid (87.3%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:13][CH3:14])[CH:6]=[CH:7][C:8]=2[CH3:12])[N:3]=1>C(O)CC.[Ni]>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([O:13][CH3:14])[CH:6]=[CH:7][C:8]=2[CH3:12])[NH:3]1
Reactant: COc1ccc(C)c2ccc(C)nc12
Agent: [Ni]
Solvent: CCCO
Product: COc1ccc(C)c2c1NC(C)CC2
Yield: 60 %

Procedure:
Then 243 parts of 2,5-dimethyl-8-methoxyquinoline in 0.6 l propanol and 20 parts Raney nickel were hydrogenated at 80° C. under 6.9 MPa for 4 hours. This was filtered and solvent stripped under reduced pressure and distilled in vacuum to yield 60% of 2,5-dimethyl-8-methoxy-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:15].[H][H]>O1CCCC1.[Pd]>[NH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][C:3](=[O:15])[N:2]2[CH3:1]
Reactant: Cn1c(=O)ccc2c([N+](=O)[O-])cccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cn1c(=O)ccc2c(N)cccc21
Yield: 75.8 %

Procedure:
A solution of Example 50A (2.16 g, 10.6 mmol) in tetrahydrofuran (50 mL) was added to 5% Pd—C, wet (0.432 g, 4.06 mmol) in a 250 mL stainless steel pressure bottle. After 3 hours at about room temperature under 30 psi of hydrogen pressure, the mixture was filtered through a nylon membrane and concentrated. EtOH (22 mL) was added, and the yellow slurry was sonicated for 5 minutes and filtered, washing with EtOH (10 mL). The yellow solid was dried in a vacuum oven at 50° C. to provide the title compound (1.40 g, 8.04 mmol, 75% yield). MS (DCI) m/z 175 (M+N)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([SH:8])[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.CC(O[CH2:16][C:17]1[CH2:26][S:25][C@@H:20]2[C@H:21]([NH2:24])[C:22](=[O:23])[N:19]2[C:18]=1[C:27]([OH:29])=[O:28])=O.B(F)(F)F>C(#N)C>[NH2:24][C@@H:21]1[C:22](=[O:23])[N:19]2[C@@H:20]1[S:25][CH2:26][C:17]([CH2:16][S:8][C:6]1[N:5]3[N:9]=[CH:10][CH:11]=[C:4]3[N:3]=[C:2]([CH3:1])[CH:7]=1)=[C:18]2[C:27]([OH:29])=[O:28]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1cc(S)n2nccc2n1
Agent: FB(F)F
Solvent: CC#N
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)n2nccc2n1

Procedure:
1.1 g of 5-methylpyrazolo[1,5-a]pyrimidine-7-thiol and 1.80 g of (7R)-7-aminocephalosporanic acid were stirred for 1 hour in 18 ml of a 20 percent solution of boron trifluoride in acetonitrile. The reaction mixture was concentrated, the residue was taken up in 15 ml of water, and the pH was adjusted to 2.5 with 2N sodium hydroxide solution. The precipitated product was filtered off under suction and dried. There was obtained (6R,7R)-7-amino-3-[[(5-methylpyrazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Reaction SMILES: Cl.Cl.[N:3]1([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:14])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:15][C:16]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[CH3:15][C:16]1[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:17]=1[C:18]([NH:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]1[N:3]1[CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:19]
Reactant: Cc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: N[C@@H]1CCCC[C@@H]1N1CCCC1
Agent: Cl
Product: Cc1cc(C(F)(F)F)ccc1C(=O)NC1CCCCC1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=355.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclohexylamine dihydrochloride (intermediate F) and 2-methyl-4-trifluoromethyl-benzoic acid (CAS 23984-82-9).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)O)[CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:19]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([Cl:19])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:7]=1
Reactant: OC(c1ccc(F)cc1)c1cccc(Br)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Fc1ccc(C(Cl)c2cccc(Br)n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of (6-bromopyridin-2-yl)(4-fluorophenyl)methanol in CH2Cl2 (120 mL) @ 0° C. was added SOCl2 (5.870 g, 49.34 mmol). The mixture was allowed to slowly warm to rt and stirred for 16 hr. The mixture was cooled back to 0° C. and quenched with saturated aqueous NaHCO3. The resulting mixture was extracted 3× with CH2Cl2. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The resulting residue was purified by silica gel chromatography (20-30% CH2Cl2 in Hexanes) to give 2-bromo-6-[chloro(4-fluorophenyl)methyl]pyridine. 1H NMR (500 MHz, CDCl3) δ 7.58 (t, 1H, J=7.7), 7.51 (d, 1H, J=7.6), 7.47-7.39 (m, 3H), 7.04 (t, 2H, J=8.7), 6.08 (s, 1H), LRMS m/z (M+H) Calcd.: 300.0, found: 300.0.
Reaction SMILES: C([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=13)[CH:13]=[N:12][CH:11]=[CH:10]2)(OCC)=O.[OH-].[K+]>C(O)C.O>[NH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=13)[CH:13]=[N:12][CH:11]=[CH:10]2
Reactant: CCOC(=O)Nc1cc2ccncc2c2sc3ccccc3c12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc2ccncc2c2sc3ccccc3c12
Yield: 103 %

Procedure:
Two hundred mg (0.62 mM) of 6-carbethoxyaminobenzothieno[3,2-h]isoquinoline (9), prepared in the preceding Example, was added to a solution of 2 g KOH in 5 ml ethanol and 2 ml water. Two layers formed. The mixture was stirred and heated at reflux for approximately 2-3 hr. A yellow solid separated after about an hour, and was collected via filtration and air dried to give 160 mg product, m.p. 220° C.-225° C. This initial product was recrystallized twice from a mixture of DMF and water to provide 120 mg final product, m.p. 223.5° C.-224.5° C., which was then characterized via I.R. and mass spectrometry as compound 10.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=3)[CH:10]=[CH:9][CH:8]=2)=[CH:5][N:6]=1.C([Sn](CCCC)(CCCC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)CCC>C1(C)C=CC=CC=1.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>[CH3:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:4]3[O:3][C:2]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[N:6][CH:5]=3)[N:12]=2)[CH:19]=1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(Cl)o3)n2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccnc(Nc2cccc(-c3cnc(-c4ccccn4)o3)n2)c1
Yield: 31.8 %

Procedure:
A mixture of [6-(2-chloro-oxazol-5-yl)-pyridin-2-yl]-(4-methyl-pyridin-2-yl)-amine (44 mg, 0.153 mmol), 2-tri-n-butylstannyl pyridine (68 mg, 0.184 mmol) and Pd(PPh3)4 (18 mg, 0.016 mmol) in toluene (4 ml) was heated to reflux for 18 h and then concentrated in vacuo. The residue was purified by column chromatography on SiO2 eluting with 5% EtOH in DCM to afford the title compound as a pale orange solid (16 mg, 31%). 1H NMR (300 MHz, DMSO-d6): δ=9.85 (s, 1H), 8.76 (d, J=5.0 Hz, 1H), 8.21 (d, J=7.8 Hz, 1H), 8.12 (d, J=5.0 Hz, 1H), 8.03 (t, J=7.8 Hz, 1H), 7.94 (s, 1H), 7.91 (s, 1H), 7.80 (t, J=7.8 Hz, 1H), 7.67 (d, J=8.5, 1H), 7.58 (m, 1H), 7.39 (d, J=7.2 Hz, 1H), 6.78 (d, J=5.0 Hz, 1H), 2.38 (s, 3H). (ESI+) m/z 330 (M+H)+. Retention time=2.29 mins (method 1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10]2)=[CH:4][N:3]=1.ClC1N=CC(OC2CCN(C)CC2)=CN=1.[F:30][C:31]1([F:77])[CH2:36][CH2:35][CH:34]([C:37]2[C:46]3[CH:45]([O:47]CC4C=CC(OC)=CC=4)[CH2:44][C:43]([CH3:58])([CH3:57])[CH2:42][C:41]=3[N:40]=[C:39]([CH:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)[C:38]=2[CH:65]([F:76])[C:66]2[CH:71]=[CH:70][C:69]([C:72]([F:75])([F:74])[F:73])=[CH:68][CH:67]=2)[CH2:33][CH2:32]1>>[F:77][C:31]1([F:30])[CH2:36][CH2:35][CH:34]([C:37]2[C:46]3[CH:45]([OH:47])[CH2:44][C:43]([CH3:57])([CH3:58])[CH2:42][C:41]=3[N:40]=[C:39]([CH:59]3[CH2:64][CH2:63][N:62]([C:2]4[N:7]=[CH:6][C:5]([O:8][C@@H:9]5[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10]5)=[CH:4][N:3]=4)[CH2:61][CH2:60]3)[C:38]=2[CH:65]([F:76])[C:66]2[CH:71]=[CH:70][C:69]([C:72]([F:74])([F:75])[F:73])=[CH:68][CH:67]=2)[CH2:33][CH2:32]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: CN1CC[C@@H](Oc2cnc(Cl)nc2)C1
Agent: CN1CCC(Oc2cnc(Cl)nc2)CC1
Product: CN1CC[C@@H](Oc2cnc(N3CCC(c4nc5c(c(C6CCC(F)(F)CC6)c4C(F)c4ccc(C(F)(F)F)cc4)C(O)CC(C)(C)C5)CC3)nc2)C1

Procedure:
Reactions similar to those of Reference Example 29 and Example 38 were performed except for using 2-chloro-5-{[(3R)-1-methylpyrrolidin-3-yl]oxy}pyrimidine, which was prepared by a method similar to that of Reference Example 30, instead of 2-chloro-5-[(1-methylpiperidin-4-yl)oxy]pyrimidine, and from 100 mg (0.155 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 58 mg of the title compound was obtained as a white solid (yield: 44%).
Reaction SMILES: [CH3:1][C:2]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:3]=1[C:4]([O:6][CH:7]([CH3:23])[CH2:8][N:9]([C:16](OC(C)(C)C)=O)[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:5].C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>Cl.O1CCOCC1.C(Cl)Cl>[CH3:1][C:2]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:3]=1[C:4]([O:6][CH:7]([CH3:23])[CH2:8][N:9]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[CH3:16])=[O:5]
Reactant: Cc1cc(C)c(C(=O)OC(C)CN(C(=O)OC(C)(C)C)C2CCCCC2)c(C)c1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C)c(C(=O)OC(C)CN(C)C2CCCCC2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-((tert-butoxycarbonyl)(cyclohexyl)amino)propan-2-yl 2,4,6-trimethyl-benzoate (1.0 g, 2.48 mmol) was dissolved in dioxane-HCl (15 mL). The reaction mixture was stirred at rt for 2 hours. Solvent was evaporated. Crude solid was dissolved in DCE (10 ml) and formaldehyde (0.34 mL, 3.96 mmol), and sodium triacetoxyborohydride (1.67 g, 7.92 mmol) and acetic acid (0.5 mL) were added at 0° C. The resultant reaction mixture was stirred at rt for 16 hours. The reaction mixture was diluted in DCM and washed with 1N NaOH, water and brine. The organic layer was dried over sodium sulphate and concentrated to dryness. The crude compound was purified by column chromatography to obtain 1-(cyclohexyl(methyl)amino)propan-2-yl 2,4,6-trimethylbenzoate. Yield: 0.6 (76%); 1H NMR (400 MHz, CDCl3) δ 6.82 (s, 2H), 5.27-5.25 (m, 1H), 2.64-2.62 (m, 1H), 2.51-2.46 (m, 1H), 2.29 (s, 9H), 2.25 (s, 3H), 1.75-1.74 (m, 4H), 1.33-1.31 (d, J=6 Hz, 3H), 1.18-1.13 (m, 4H), 1.09-1.03 (m, 1H); LCMS: m/z=317.8 [M+H], RT=2.98 min (Column: X, Program: P1).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C@@H:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=3)[OH:25])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:37]1[CH2:42][CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH2:39][CH2:38]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[Cs+]>O.O1CCCC1.C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C@@H:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=3)[OH:25])=[C:11]([C:40]3[CH2:41][CH2:42][O:37][CH2:38][CH:39]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc([C@@H](O)c2c(C(C)C)nc3c(c2I)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C3)cc1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc([C@@H](O)c2c(C(C)C)nc3c(c2C2=CCOCC2)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C3)cc1

Procedure:
Obtained by starting from (R)—((S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl)(4-isopropoxyphenyl)methanol and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A 2 M solution of caesium carbonate in water is used instead caesium fluoride. The reaction is run in tetrahydrofurane/toluene 5:1.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4](I)[CH:3]=1.[CH3:18][C:19]1([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:24][CH2:23][N:22]([C:25]2[N:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][N:26]=2)[CH2:21][CH2:20]1.CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(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>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:28]2[CH:27]=[N:26][C:25]([N:22]3[CH2:23][CH2:24][C:19]([CH3:18])([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:20][CH2:21]3)=[N:30][CH:29]=2)[CH:3]=1
Reactant: CCOC(=O)C1(C)CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CCNC(=O)Nc1nc2cc(I)cc(Br)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Temperature: 80 °C
Yield: 41.2 %

Procedure:
To a solution of 1-(7-bromo-5-iodobenzo[d]thiazol-2-yl)-3-ethylurea (22.7 g, 53.20 mmol) and ethyl 4-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperidine-4-carboxylate (20 g, 53.2 mmol) in 1,4-dioxane:MeOH (300:180 mL) was added potassium phosphate (17 g, 79 mmol) at rt. The resulting mixture was degassed for 15-20 min by purging N2 followed by addition of tetrakis(triphenylphosphine)palladium(0) (6.1 g, 5.32 mmol). The reaction mixture was again degassed for another 15-20 min then heated up to 80° C. or 5 h. After completion of reaction (by TLC), the reaction was cooled to rt, diluted with EtOAc (500 mL) and passed through celite. The filtrate was evaporated and the crude residue purified over 100-200 M silica-gel by using 1.50% MeOH: DCM to obtain the desired product as an off-white solid (12 g, 41%). 1H NMR (DMSO-d6): δ 1.09 (t, J=7.20 Hz, 3H), 1.20 (m, 6H), 1.45 (m, 2H), 2.03 (m, 2H), 3.16 (m, 2H), 3.30 (q, J=7.20, 2H), 4.12 (q, J=6.80 Hz, 2H), 4.25 (m, 2H), 6.75 (br s, 1H), 7.69 (s, 1H), 7.86 (s, 1H); 8.75 (s, 2H) and 10.91 (br s, 1H). MS: 547.11 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][CH:7]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:30])[CH:4]([C:20]1[CH:21]=[CH:22][C:23]([C:26]([CH3:28])([CH3:27])[CH3:29])=[CH:24][CH:25]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1)c1ccc(C(C)(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(Cc1ccc(O)cc1)c1ccc(C(C)(C)C)cc1
Reaction time: 8 h

Procedure:
The mixture of crude 3-(4-Benzyloxyphenyl)-2-(4-tert-butylphenyl)-propionic acid methyl ester from step A and 10% Pd/C (200 mg) in methanol (75 mL) was stirred under an atmosphere of H2 overnight. The mixture was filtered through celite and concentrated under vacuum to afford 2-(4-tert-Butylphenyl)-3-(4-hydroxyphenyl)-propionic acid methyl ester as a light yellow oil. TLC: Rf=0.15 hexane/ethyl acetate (7:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].S(Cl)(Cl)=O.COC1C=CC(C(Cl)=O)=CC=1[N+]([O-])=O.[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.CCN(C(C)C)C(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[O:9])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1ccccn1
Agent: COc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccn2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
4-methoxy-3-nitrobenzoic acid (10.0 g, 0.051 mol), and thionyl chloride (25 g, 0.212 mol), were refluxed together for 24 hours. The reaction mixture was cooled to room temperature and concentrated. The off-white solid was carried onto the next step. Step 2: 4-methoxy-3-nitrobenzoyl chloride (1.08 g, 0.005 mol), 2-aminopyridine (0.94 g, 0.01 mol) and DIPEA (1.8 mL, 0.01 mol) were allowed to stir in dichloromethane (10 mL) for 48 hours to form 4-methoxy-3-nitro-N-(pyridin-2-yl)benzamide. Intermediate was purified via silica column chromatography using 0 to 100% ethyl acetate in hexane. Step 3: Into a 100 mL round bottom flask was placed 4-methoxy-3-nitro-N-(pyridin-2-yl)benzamide (0.735 g, 2.69 mmol), 10% Palladium on carbon (250 mg), ethanol (50 mL), and acetic acid (10 mL) under inert atmosphere. Atmosphere then exchanged with hydrogen (via balloon) and allowed to stir 24 hours at room temperature. Reaction mixture was filtered through celite, concentrated under reduced pressure, then purified via silica column chromatography using 0 to 100% ethyl acetate in hexane. MS m/z=244 [M+H]+. Calc'd for C13H13N3O2: 243.3.