Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:13]=[N:12][C:5]=3[CH:6]=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1.[CH2:19]([O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)[CH2:20][CH3:21]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:17][CH:16]([CH3:18])[CH2:15][N:14]1[C:4]2[C:3]3[C:2]([C:26]4[CH:27]=[CH:28][C:23]([O:22][CH2:19][CH2:20][CH3:21])=[CH:24][CH:25]=4)=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:12]=[CH:13]1
Reactant: CC(C)Cn1cnc2cnc3cccc(Br)c3c21
Reactant: CCCOc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCOc1ccc(-c2cccc3ncc4ncn(CC(C)C)c4c23)cc1
Yield: 90 %

Procedure:
9-Bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (1.0 g, 3.4 mmol) and 4-propoxyphenylboronic acid (1.0 g, 5.5 mmol) were coupled according to Part J of Example 1. The palladium (II) acetate (2.5 mg, 0.011 mmol) was added as a 5 mg/mL solution in toluene. The work-up procedure described in Parts 125–135 was followed. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) to provide 1.1 g of 1-(2-methylpropyl)-9-(4-propoxyphenyl)-1H-imidazo[4,5-c]quinoline as a dark brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].O.Br[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=1[F:31]>C(COC)OC>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:12]=[CH:11][CH:10]=2)=[C:25]([F:31])[CH:26]=1
Reactant: Nc1ccc(Br)c(F)c1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)n1cccc1-c1ccc(N)cc1F
Temperature: 70 °C
Reaction time: 3 h

Procedure:
1.6 g of 1-(t-butoxycarbonyl)pyrrole-2-boronic acid, 200 mg of tetrakistriphenylphosphine palladium, 5 ml of aqueous saturated sodium carbonate solution and 5 ml of water were added in order to a dimethoxyethane (10 ml) solution of 1 g of 4-bromo-3-fluoro-phenylamine, and the reaction liquid was stirred in a nitrogen atmosphere at 70° C. for 3 hours. After cooled, the reaction liquid was filtered through Celite, and the filtrate was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=2/1) to obtain the entitled compound as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:15][CH2:16][C:17]2([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH2:12][CH2:13][OH:14])[C:8]2[C:4](=[CH:5][N:6]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[N:7]=2)[CH:3]=1.C(N(CC)CC)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:15][CH2:16][C:17]2([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH2:12][CH2:13][O:14][S:53]([CH3:52])(=[O:55])=[O:54])[C:8]2[C:4](=[CH:5][N:6]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:43])[CH3:44])[N:7]=2)[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(COC(CCO)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(COC(CCOS(C)(=O)=O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reaction time: 1 h
Yield: 110.5 %

Procedure:
To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-3-hydroxypropoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (56 mg, 0.086 mmol) and TRIETHYLAMINE (0.036 ml, 0.259 mmol) in DCM (1.5 ml) at 0 C was added METHANESULFONYL CHLORIDE (0.013 ml, 0.173 mmol). The ice bath was removed and stirring continued for 1 h. The reaction was cooled to 0 C and quenched by addition of sat'd sodium bicarbonate. The reaction was diluted with ether and the layers separated. The ethereal was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 69 mg title compound (quantitative yield). LC/MS (HPLC method 1): tR=4.42 min, 726.2(MH)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:24][CH2:23][C:5]2=[C:6]([C:9]3[O:13][N:12]=[C:11]([C:14]4[CH:19]=[C:18]([CH3:20])[C:17]([OH:21])=[C:16]([CH3:22])[CH:15]=4)[N:10]=3)[S:7][CH:8]=[C:4]2[CH2:3]1.[OH-].[Na+].[CH2:28]([CH:30]1[O:32][CH2:31]1)Cl>C(O)(C)C.O>[CH3:22][C:16]1[CH:15]=[C:14]([C:11]2[N:10]=[C:9]([C:6]3[S:7][CH:8]=[C:4]4[CH2:3][C:2]([CH3:25])([CH3:1])[CH2:24][CH2:23][C:5]=34)[O:13][N:12]=2)[CH:19]=[C:18]([CH3:20])[C:17]=1[O:21][CH2:28][CH:30]1[CH2:31][O:32]1
Reactant: ClCC1CO1
Reactant: Cc1cc(-c2noc(-c3scc4c3CCC(C)(C)C4)n2)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(-c2noc(-c3scc4c3CCC(C)(C)C4)n2)cc(C)c1OCC1CO1
Temperature: 50 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
A solution of 4-[5-(5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenol (35 mg, 1.18 mmol) in isopropanol (17 mL) is treated with 2 N aq. NaOH (8.6 mL) followed by epichlorohydrine (660 mg, 7.14 mmol). The mixture is stirred at 50° C. for 18 h before it is diluted with water and extracted twice with EA. The combined organic extracts are dried over Na2SO4, filtered, evaporated and dried to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-5-(5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-[1,2,4]oxadiazole (480 mg) as a pale yellow oil; LC-MS: tR=1.24 min, [M+1]+=411.31.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[C:26]([N:35]2[CH2:40][C@H:39]([CH3:41])[C@@H:38]([OH:42])[C@H:37]([NH:43]C(=O)OC(C)(C)C)[CH2:36]2)=[C:27]2[CH2:33][CH2:32][CH:31]([OH:34])[C:28]2=[N:29][CH:30]=1)=[O:23])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[C:26]([N:35]2[CH2:40][C@H:39]([CH3:41])[C@@H:38]([OH:42])[C@H:37]([NH2:43])[CH2:36]2)=[C:27]2[CH2:33][CH2:32][CH:31]([OH:34])[C:28]2=[N:29][CH:30]=1)=[O:23]
Reactant: C[C@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnc3c2CCC3O)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnc3c2CCC3O)C[C@@H](N)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl {(3R,4R,5S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-4-hydroxy-5-methylpiperidin-3-yl}carbamate (7.0 mg, 0.01 mmol) and 4.0 M TFA in DCM (2.0 mL) was stirred at room temperature for 1 h. After removal of the solvent under reduced pressure, the residue was diluted with MeOH, filtered and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give both diastereoisomers of the title compound as white powders. On analytical HPLC (Waters SunFire™ C18, 2.1×50 mm, 5 μm; flow rate 3 mL/min.; injection volume 2 μL; gradient from 2 to 80% B in 3 minutes (A=water with 0.025% TFA, B=MeCN)), the diastereoisomers had the following properties:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCN(C2C=CC(O[CH2:41][CH2:42][CH2:43][Cl:44])=CC=2)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:41][CH2:42][CH2:43][Cl:44])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(O)c2)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OCCCCl)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(OCCCCl)c2)CC1

Procedure:
Prepared from 4-(3-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (D12) using the same method described in Description 9 (D9).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[C:6](OC)=[N:7][CH:8]=1.O=P(Cl)(Cl)[Cl:17]>CN(C=O)C>[Cl:17][C:6]1[C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]([CH2:2][Cl:1])=[CH:8][N:7]=1
Reactant: COc1ncc(CCl)cc1C(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(CCl)cnc1Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
To a cold solution of 5-(chloromethyl)-2-methoxy-3-(trifluoromethyl)pyridine (0.3 g, 1.33 mmol) in DMF (0.6 mL) was added dropwise POCl3 (1.02 g, 6.65 mmol). The reaction was stirred for 1 h at 100° C. in a sealed tube. The reaction was cooled to room temperature, and poured onto ice water (10 mL). The reaction was extracted with DCM (thrice) and the combined organic layer was washed with water and brine, dried with MgSO4 and concentrated. The residue was purified by silica gel column chromatography to provide the title compound (0.20 g). LCMS m/z=230.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 4.62 (s, 2H), 8.06 (d, J=2.3 Hz, 1H), 8.57 (d, J=2.3 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:15]([C:25]([F:28])([F:27])[F:26])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[F:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42].ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([CH2:18][N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:15]([C:25]([F:28])([F:27])[F:26])=[CH:14][C:10]=1[C:11]([NH:42][C:41]1[CH:43]=[CH:44][CH:45]=[C:39]([F:38])[CH:40]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1OCc1ccccc1
Reactant: Nc1cccc(F)c1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(Nc1cccc(F)c1)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1OCc1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 2-(benzyloxy)-4-(morpholinomethyl)-5-(trifluoromethyl)benzoic acid (270 mg, 0.683 mmol) in N,N-Dimethylformamide (DMF) (5 mL) was added DIPEA (0.239 mL, 1.366 mmol), 3-fluoroaniline (0.086 mL, 0.888 mmol), 1-hydroxy-7-azabenzotriazole (112 mg, 0.819 mmol) and EDC (262 mg, 1.366 mmol). The solution was stirred for 3 hours then partitioned between EtOAc (20 ml) and water (15 ml). The organic layer was separated, washed further with water (2×20 ml), dried (MgSO4) and the solvent removed. Purification by column (SiO2, Isolute 3:1-1:1 Cyclohexane/EtOAc) gave the product as a white solid. 133 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:8]2([CH2:13][CH2:12][N:11]([C:14](=[O:33])[CH:15]([NH:25]C(OC(C)(C)C)=O)[CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH2:9]2)[CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.[C:47]([NH:54][C:55]([CH3:60])([C:57](O)=[O:58])[CH3:56])([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>>[CH2:1]([O:3][C:4]([CH:6]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:8]2([CH2:13][CH2:12][N:11]([C:14](=[O:33])[CH:15]([NH:25][C:57](=[O:58])[C:55]([NH:54][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])([CH3:60])[CH3:56])[CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH2:9]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CCOC(=O)C1CC2(CCN(C(=O)C(CCCc3ccccc3)NC(=O)OC(C)(C)C)CC2)c2ccccc21
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CC2(CCN(C(=O)C(CCCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)CC2)c2ccccc21
Yield: 62.1 %

Procedure:
The title compound from Step A (155 mg, 0.29 mmol) was treated with TFA as in Step A and the residue was reacted with BOC-α-methyl alanine (73.5 mg, 0.377 mmol), EDC (72.0 mg, 0.377 mmol), HOBT (53 mg, 0.377 mmol), NMM (0.032 ml, 0.290 mmol) according to the procedure used for Example 1, Step A. Flash chromatography provided the title compound (112 mg, 0.18 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[C:10]1=[O:19].N([O-])=[O:21].[Na+].S(=O)(=O)(O)O.Cl>O.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:21])=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[C:10]1=[O:19]
Reactant: Nc1ccc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1
Reactant: O=N[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)ccc1F

Procedure:
The compound (VI) is prepared by reacting the compound (VIII) with a 1 to 2 equivalent amount of sodium nitrite in a solvent (e.g. sulfuric acid, hydrochloric acid, acetic acid, water) at a temperature of 0° to 20° C. for a period of 5 minutes to 5 hours to obtain its diazonium salt, followed by hydrolysis of the diazonium salt in dilute sulfuric acid at a temperature of 20° to 100° C. In the hydrolysis, a copper compound such as cuprous oxide or cupric nitrate may be used in place of dilute sulfuric acid.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22](OC)=[O:23])[N:4]=1)#[N:2].[NH2:26][CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CCO>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([NH:26][CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:23])[N:4]=1)#[N:2]
Reactant: CCOC(=O)C(C)(C)CN
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3cccc(F)c3)ccc2c1O
Solvent: CCO
Product: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3cccc(F)c3)ccc2c1O

Procedure:
Methyl 1-cyano-7-(3-fluorophenoxy)-4-hydroxyisoquinoline-3-carboxylate (18 mg, 0.05 mmol) and ethyl 3-amino-2,2-dimethylpropanoate (31 mg, 0.21 mmol) in EtOH (3 mL) were heated at 150° C. in a microwave for 1.5 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 22 mg. MS: (−) m/z 450.30 (M−1).
Reaction SMILES: C1COCC1.I[C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9].C(N(CC)CC)C.[CH:21]#[C:22][CH2:23][CH2:24][CH3:25]>C(OCC)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)I>[C:21]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9])#[C:22][CH2:23][CH2:24][CH3:25]
Reactant: Nc1ccccc1I
Reactant: C#CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20 mL THF were placed in the flask and degassed with argon. Then 2.3 g (10 mmol) 2-iodo-aniline, 0.72 g (1.0 mmol) PdCl2(PPh3)2 and 0.20 g (1.0 mmol) copper iodide were added and the flask was rinsed with argon. Then 4.2 mL (30 mmol) triethylamine and 1.5 mL (15 mmol) 1-pentyne were added. The reaction mixture was stirred for 3 h at RT, diluted with diethyl ether, filtered through kieselguhr and evaporated down.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([NH2:23])=[O:22]>>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:23]=[C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)[O:22][CH:2]=2)=[CH:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: NC(=O)c1ccccn1
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Product: CS(=O)(=O)c1ccc(-c2coc(-c3ccccn3)n2)cc1
Temperature: 150 °C
Yield: 3.9 %

Procedure:
The mixture of the 2-bromo-1-[4-(methylsulfonyl)phenyl]ethanone (500 mg, 1.8 mmol) and pyridine 2-carboxamide (551 mg, 4.51 mmol) was heated to 150° C. for 1 hour. Then the reaction mixture was cooled, and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate twice, and the combined organic layers were washed with water and brine, dried over MgSO4. After concentration, the solid residue was dissolved in methanol and subject to mass-directed HPLC purification to give 21 mg of 2-{4-[4-(methylsulfonyl)phenyl]-1,3-oxazol-2-yl}pyridine. LCMS: m/z 301.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>C(O)C.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(OCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
A suspension of methyl 3-(4-benzyloxyphenyl)propanoate in ethanol (200 ml) and THF (100 ml) was treated with an aqueous solution of potassium hydroxide (6.7 g, 1.5 N, 101.2 mmol). The mixture was stirred at 60° C. for 1.5 hours, cooled to room temperature, adjusted to pH 3-4 with 1N HCl. The solvent was removed in vacuo to give the title material (12.8 g, 98%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[O:5][CH2:4][CH2:3]1.[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=1.C(N(CC)CC)C>O1CCCC1>[Cl:13][C:14]1[N:15]=[N:16][C:17]([N:10]2[CH2:11][CH2:12][C:6]3([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH2:7]3)[CH2:8][CH2:9]2)=[CH:18][CH:19]=1
Reactant: CN1CCOC2(CCNCC2)C1
Reactant: Clc1ccc(Cl)nn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCOC2(CCN(c3ccc(Cl)nn3)CC2)C1
Yield: 44.8 %

Procedure:
To a solution of compound 405 (406.0 mg, 2.39 mmol) in tetrahydrofuran (17 mL) was added 3,6-dichloropyridazine (361.7 mg, 2.43 mmol), followed by triethylamine (0.680 mL, 4.89 mmol). The resulting solution was stirred at reflux for 38 hours. The reaction mixture was then concentrated and the residue was purified by reverse phase HPLC (acetonitrile/H2O containing 0.1% TFA each, 25 min from 10 to 40%) to give compound 406 as a sticky yellow solid (303 mg, 45%). LCMS-ESI (POS), M/Z, M+1: Found 283.1, Calculated 283.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:22][CH2:21][C@H:20]([O:23][C:24]4[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][C:25]=4[F:34])[C:19]3=[O:35])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Li+].[OH-]>C1COCC1>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:22][CH2:21][C@H:20]([O:23][C:24]4[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[F:34])[C:19]3=[O:35])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: COC(=O)c1ccc(O[C@H]2CCN(C3CCN(c4ncc(C(F)(F)F)cc4Cl)CC3)C2=O)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(O[C@H]2CCN(C3CCN(c4ncc(C(F)(F)F)cc4Cl)CC3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
To a solution of (S)-methyl 4-(1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-3-fluorobenzoate (0.1 g, 0.19 mmol) in THF (2 mL) was added LiOH (3 M, 2 mL) and the reaction was stirred overnight at ambient temperature. The THF was removed with a stream of nitrogen. The aqueous layer was acidified with 1 N HCl to about pH 1 and the solid that formed was filtered and washed with water. The solid was dried under vacuum to yield (S)-4-(1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-3-fluorobenzoic acid (0.040 g, 0.081 mmol, 42% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[H][H]>CO.[Pd]>[NH2:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(O)cc1N
Yield: 95.3 %

Procedure:
7.82 g of 4-amino-3-nitrophenol in 460 ml of methanol were hydrogenated with catalytic amount of palladium on carbon (800 mg, 10% Pd/C). After hydrogen uptake was complete, the catalyst was filtered off, washed with methanol and the filtrate was concentred under reduced pressure to give 6 g of crude 3,4-diaminophenol.
Reaction SMILES: [NH2:1][C:2]1[O:3][C@H:4]([C:28]([F:31])([F:30])[F:29])[CH2:5][C@:6]([C:10]2[CH:11]=[C:12]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][N:21]=3)[CH:13]=[C:14]([F:17])[C:15]=2[F:16])([CH2:8][F:9])[N:7]=1.[CH:32]1([C:35]#[CH:36])[CH2:34][CH2:33]1.C1(C)C=CC=CC=1.C(NCC)C>[Cu]I.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.CN(C=O)C>[NH2:1][C:2]1[O:3][C@H:4]([C:28]([F:31])([F:30])[F:29])[CH2:5][C@:6]([C:10]2[CH:11]=[C:12]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([C:36]#[C:35][CH:32]4[CH2:34][CH2:33]4)=[CH:22][N:21]=3)[CH:13]=[C:14]([F:17])[C:15]=2[F:16])([CH2:8][F:9])[N:7]=1
Reactant: NC1=N[C@](CF)(c2cc(NC(=O)c3ccc(Br)cn3)cc(F)c2F)C[C@@H](C(F)(F)F)O1
Reactant: C#CC1CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: NC1=N[C@](CF)(c2cc(NC(=O)c3ccc(C#CC4CC4)cn3)cc(F)c2F)C[C@@H](C(F)(F)F)O1
Yield: 66.5 %

Procedure:
To a microwave vial were charged with N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4,5-difluorophenyl)-5-bromopicolinamide (0.144 g, 0.282 mmol, Example 157), cyclopropylacetylene, 70 wt. % solution in toluene (0.061 mL, 0.507 mmol), copper(I) iodide (8.05 mg, 0.042 mmol), tetrakis(triphenylphosphine)palladium (0.016 g, 0.014 mmol), diethylamine (0.175 mL, 1.690 mmol) and DMF (2.0 mL). The vial was purged with N2 for 5 min, and then microwaved at 90° C. for 50 min. LCMS indicated full conversion to the desired product with MS+=497 (M+1). The reaction mixture was partitioned between EtOAc and water. The separated organic layer was concentrated and the resulted residue was purified by Shimadzu HPLC to afford N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4,5-difluorophenyl)-5-(cyclopropylethynyl)picolinamide (0.093 g, 0.187 mmol, 66.5% yield) as light yellow solid. MS m/z=497.1 [M+H]+. Calculated for C23H18F6N4O2: 496.4
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][CH:11]=[C:10]3[N:14]([CH3:18])[N:15]=[C:16]([NH2:17])[C:9]=23)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([N:26]=[C:27]=[O:28])[CH:23]=[CH:22][C:21]=1[F:29].FC1C=CC(C)=CC=1N=C=O>>[NH2:17][C:16]1[C:9]2[C:10](=[CH:11][N:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:24]3[CH:23]=[CH:22][C:21]([F:29])=[C:20]([Cl:19])[CH:25]=3)=[O:28])=[CH:7][CH:6]=2)[N:14]([CH3:18])[N:15]=1
Reactant: Cn1nc(N)c2c(-c3ccc(N)cc3)cncc21
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Agent: Cc1ccc(F)c(N=C=O)c1
Product: Cn1nc(N)c2c(-c3ccc(NC(=O)Nc4ccc(F)c(Cl)c4)cc3)cncc21

Procedure:
The title compound was prepared using the procedure described in Example 1E using the product from Example 6A and 2-chloro-1-fluoro-4-isocyanato-benzene instead of the product from Example 1D and 1-fluoro-2-isocyanato-4-methyl-benzene. MS (ESI(+)) m/e 411 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 3.92 (s, 3H) 4.61-4.72 (m, 2H) 7.32-7.37 (m, 2H) 7.47 (d, J=8.82 Hz, 2H) 7.63 (d, J=8.82 Hz, 2H) 7.79-7.84 (m, 1H) 7.94 (s, 1H) 8.87 (s, 1H) 8.95 (s, 1H) 8.96 (s, 1H).