Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N=C=N.[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([C:34]([F:37])([F:36])[F:35])[O:16][N:15]=[C:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:27]([NH:29][CH2:30][C:31](O)=[O:32])=[O:28])=[CH:19][CH:18]=3)[CH2:13]2)[CH:8]=[C:9]([Cl:11])[CH:10]=1.[F:38][C:39]([F:43])([F:42])[CH2:40][NH2:41]>ClCCl>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([C:34]([F:36])([F:37])[F:35])[O:16][N:15]=[C:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:27]([NH:29][CH2:30][C:31](=[O:32])[NH:41][CH2:40][C:39]([F:43])([F:42])[F:38])=[O:28])=[CH:19][CH:18]=3)[CH2:13]2)[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: NCC(F)(F)F
Reactant: O=C(O)CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: N=C=N
Solvent: ClCCl
Product: O=C(CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
PS-Carbodiimide (0.53 g, 123 mmol/g, Argonaut Technologies, Inc.) was added to a stirred mixture of N-[[4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenyl]carbonyl]glycine (i.e. the product of Step D, 510 mg) and 2,2,2-trifluoroethylamine (0.072 mL) in dichloromethane (3 mL) at room temperature. The mixture was stirred at room temperature for 5 h, then filtered and concentrated under reduced pressure. The residue was purified by column chromatography to provide the title compound (99 mg), a compound of this invention, as a white solid. 1H NMR (CDCl3): δ 8.82 (d, 1H), 8.26 (d, 1H), 7.46-7.67 (m, 7H), 7.09 (m, 2H), 4.28 (d, 2H), 4.25 (d, 1H), 3.96 (m, 2H), 3.88 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[C:17]([CH2:19]O)[CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([N:21]4[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]4)=[C:17]([CH2:19][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN1CCN(c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2CO)CC1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CN1CCN(c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2CN2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To {5-[(7-chloroquinolin-4-yl)amino]-2-(4-methylpiperazin-1-yl)phenyl}methanol (0.300 g, 0.78 mmol) in 6 mL of DMF at 0° C. was added thionyl chloride (0.28 mL, 5 eq). The reaction mixture was warmed up to room temperature and stirred for 2 h. The solvent was evaporated. The residue was suspended in 6 mL of DMF and morpholine (1.39 mL, 20 eq) was added at 0° C. The solution was stirred overnight at room temperature, evaporated and the residue was purified by flash chromatography (DCM/MeOH/NH4OH//9/1/0.1) to yield expected compound as a pale yellow solid (238 mg, 67% yield). m/z (ESI) 452.2 [M+H]+;
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[Br:10].[CH3:11][O:12][CH:13]([O:16]C)[CH:14]=[CH2:15].C(N(CC)CC)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[Br:10][C:3]1[C:4]([F:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[CH2:15][CH2:14][C:13]([O:12][CH3:11])=[O:16]
Reactant: Fc1cc(F)c(Br)c(Br)c1
Reactant: C=CC(OC)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cc(F)cc(F)c1Br
Temperature: 90 °C

Procedure:
A mixture of 1,2-dibromo-3,5-difluorobenzene (4.5 g), 3,3-dimethoxyprop-1-ene (5.1 mL), tetrabutylammonium chloride (4.6 g) and triethylamine (3.5 mL) in N,N-dimethylformamide (50 mL) is purged with nitrogen for 20 minutes. Palladium-(II)-acetate (111 mg) is added and the mixture heated for 16 hours at 90° C. After cooling the mixture is partitioned between aqueous HCl (1 M) and diethyl ether, the organic layer dried (Na2SO4), volatiles evaporated under reduced pressure and the residue purified by column chromatography (silica gel; hexane:ethyl acetate 98:2→80:20) to give the title compound (Yield 3.6 g).
Reaction SMILES: Br[C:2]1[CH:15]=[N:14][C:5]2[NH:6][C:7](=[O:13])[C:8]([CH3:12])([CH3:11])[NH:9][CH2:10][C:4]=2[CH:3]=1.[CH3:16][O:17][C:18]1[C:19]([O:31][CH2:32][CH2:33][CH3:34])=[C:20]([CH:28]=[CH:29][CH:30]=1)[CH2:21][N:22]([CH3:27])[C:23](=[O:26])[CH:24]=[CH2:25].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CCOCC.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:11][C:8]1([CH3:12])[C:7](=[O:13])[NH:6][C:5]2[N:14]=[CH:15][C:2](/[CH:25]=[CH:24]/[C:23]([N:22]([CH2:21][C:20]3[CH:28]=[CH:29][CH:30]=[C:18]([O:17][CH3:16])[C:19]=3[O:31][CH2:32][CH2:33][CH3:34])[CH3:27])=[O:26])=[CH:3][C:4]=2[CH2:10][NH:9]1
Reactant: CC1(C)NCc2cc(Br)cnc2NC1=O
Reactant: C=CC(=O)N(C)Cc1cccc(OC)c1OCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCC#N
Product: CCCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNC(C)(C)C(=O)N3)cccc1OC
Reaction time: 0.08 h
Yield: 60.3 %

Procedure:
A suspension of 7-bromo-3,3-dimethyl-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.30 g, 1.1 mmol) and N-(3-methoxy-2-propoxybenzyl)-N-methylacrylamide (0.35 g, 1.3 mmol) in propionitrile (5 mL) and DMF (1.3 mL) was de-oxygenated with Ar for 5 min. The mixture was treated with (i-Pr)2EtN (0.41 mL, 2.4 mmol) and was de-oxygenated with Ar for 10 min. Pd(OAc)2 (25 mg, 0.11 mmol) and P(o-tol)3 (69 mg, 0.23 mmol) were added simultaneously, and the mixture was de-oxygenated a third time for 5 min. The mixture was heated to reflux overnight, then allowed to cool. The mixture was diluted with Et2O (50 mL) and EtOAc (25 mL), washed with H2O (25 mL), dried over Na2SO4, filtered and concentrated to an orange residue. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 98:2 to 97:3) gave the title compound (0.30 g, 60%) as an off-white solid: MS (ESI) m/e 453 (M+H)+.
Reaction SMILES: [CH2:1]([C:8](=[CH2:12])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:28](O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCOCC.CN(C)C1C=CN=CC=1>[CH2:1]([C:8](=[CH2:12])[C:9]([O:11][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(Cc1ccccc1)C(=O)O
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: C=C(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 44 h

Procedure:
2-Benzylacrylic acid (2.20 g, 13.6 mmol) in dry ether (40 mL) was treated with dicyclohexylcarbodiimide (2.60 g, 12.6 mmol), benzyl alcohol (1.30 mL, 12.6 mmol) and 4-dimethylaminopyridine (0.310 g, 2.54 mmol). After stirring at room temperature for 44 h, the mixture was filtered and evaporated. Chromatography of the residue on silica with 5% oil: b.p. 150° C. (0.2 mm); TLC (20% ethyl acetate/80% hexane) Rf =0.31; 1H-NMR (CDCl3) 7.15-7.40 (m, 10H), 6.28 (m, 1H), 5.49 (m, 1H), 5.17 (2H,s), 3.67 (s, 2H).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][CH:4]=[C:3]([CH:9]=O)[CH:2]=1.[C:11]([CH2:13][CH2:14][NH:15][NH2:16])#[N:12]>CO>[C:11]([CH2:13][CH2:14][NH:15][N:16]=[CH:9][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[N:16][NH:15][CH2:14][CH2:13][C:11]#[N:12])=[CH:1][CH:2]=1)#[N:12]
Reactant: O=Cc1ccc(C=O)cc1
Reactant: N#CCCNN
Solvent: CO
Product: N#CCCNN=Cc1ccc(C=NNCCC#N)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 102 g terephthaldehyde in 700 ml methanol 129.4 g of 2-cyanoethylhydrazine are added drop-wise within 20 minutes. The temperature increases to about 50° C., and an orange-red solution generally arises. After about 10 minutes further crystallization occurs. Stirring continues for 30 minutes and a precipitate that appears is filtered with suction. After washing with a little cold methanol the precipitate is dried under vacuum. 187 g of beige colored product are produced.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)[C:11]2=[O:21])=[CH:6][CH:5]=1.[CH2:24](I)[C:25]([CH3:28])([CH3:27])[CH3:26]>>[CH3:24][C:25]([CH3:28])([CH3:27])[CH2:26][N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:21])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:15][C:16]1=[O:20]
Reactant: O=C1CC2(CCN1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Reactant: CC(C)(C)CI
Product: CC(C)(C)CN1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1=O

Procedure:
This material was prepared as a off-white semi-solid in analogy to example 1 step E) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-1,7-dione and neopentyl iodide. MS (ESI): 399.1 (MH+).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].CN(C(ON1N=[N:40][C:35]2C=[CH:37][CH:38]=[CH:39][C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N1CCCCC1>CN(C=O)C>[N:40]1([C:19]([C:18]2[CH:17]=[CH:16][C:15]([C:14]#[C:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:24])=[CH:12][CH:11]=3)=[CH:23][CH:22]=2)=[O:21])[CH2:37][CH2:38][CH2:39][CH2:34][CH2:35]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(=O)NC(C)Cc1ccc(C#Cc2ccc(C(=O)O)cc2)cc1
Agent: F[B-](F)(F)F
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(=O)NC(C)Cc1ccc(C#Cc2ccc(C(=O)N3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 30 mg (0.10 mmol) 4-((4-(2-acetamidopropyl)phenyl)ethynyl)benzoic acid (I72.2) in 1 mL DMF are added 20.0 μl (0.10 mmol) TEA and 50 mg (0.15 mmol) TBTU. The mixture is stirred at r.t. for 5 min before it is added to 10 mg (0.12 mmol) piperidine in 500 μl DMF. After stirring at r.t. for 72 h the mixture is purified by HPLC (MeOH/H2O/NH3).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CN1C(=O)CCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(Oc2ccc(C#N)cc2)c(C)c1
Temperature: 140 °C
Yield: 96.5 %

Procedure:
Into a 250 mL three-necked, round-bottomed flask equipped with a magnetic stir-bar, nitrogen inlet, and a condenser, 2,4,6-trimethylphenol (6.00 g, 44.1 mmol), 4-fluorobenzonitrile (5.34 g, 44.1 mmol), potassium carbonate (7.30 g, 52.8 mmol), and a mixture of NMP (100 mL) and toluene (60 mL) were placed. The reaction mixture was then heated and maintained around 140° C. for 8 hours with vigorous nitrogen flow. The dark solution was filtered while it was warm and the filtrate was poured into distilled water containing 5% hydrochloric acid. The solution was separated into organic layer and aqueous layer. The organic layer was diluted with dichloromethane and separated. The solvent was removed completely from the organic extract. Light brown oily residue was freeze-dried to afford 10.1 g (97% yield) of the desired product. Anal. Calcd. for C16H15NO: C, 80.98%; H, 6.37%; N, 5.90%; O, 6.74%. Found: C, 80.31%; H, 6.37%; N, 5.75%; O, 6.46%. FT-IR (KBr, cm−1): 2226 (C≡N stretch). Mass spectrum (m/e): 237 (M+, 100% relative abundance), 222, 204, 194. 1H NMR (CDCl3, ppm) δ 2.05 (s, 6H, CH3), 2.30 (s, 3H, CH3), 6.81–6.84 (d, 2H, Ar), 6.91 (s, 2H, Ar), 7.53–7.56 (d, 2H, Ar). 13C NMR (CDCl3, ppm) δ 16.10, 20.79, 115.48, 129.07, 129.15, 129.88, 130.48, 134.25, 147.84, 150.03, 161.44.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH2:28][CH2:29][CH2:30][CH2:31][OH:32]>>[OH:32][CH2:31][CH2:30][CH2:29][NH:28][C:23]([C:22]1[CH:21]=[CH:20][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:18])=[CH:27][CH:26]=1)=[O:24]
Reactant: NCCCO
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCCO)cc2)CC1
Yield: 76 %

Procedure:
By the same procedure as described in the example 1, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid and using 3-amino-1-propanol. Then, the product was recrystallized using ethyl acetate and ether to give the desired compound.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:30]C(=O)OC(C)(C)C)=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:7]=1>C(O)(C(F)(F)F)=O>[F:1][C:2]1[C:3]([NH2:30])=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)cc1F
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)cc1F
Yield: 20.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl (3-fluoro-5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)carbamate (90 mg, 0.179 mmol) was deprotected in TFA (10 mL) to afford 15 mg (16.3% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.47 (s, 1H), 8.42-8.41 (d, 1H), 8.26-8.21 (m, 2H), 8.11-0.810 (d, 1H), 7.98 (s, 1H), 7.69 (s, 1H), 7.41-7.33 (m, 1H), 7.12-6.99 (m, 3H), 5.44 (s, 2H). MS: m/z=403.4 (M+1), HPLC: 97.56% in method A.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[NH:10][CH:9]=2)[CH:5]=[C:4]([Cl:19])[N:3]=1.[CH2:20]([CH:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)[CH:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1>O>[NH2:27][CH:24]1[CH2:23][CH2:22][CH:21]([CH2:20][CH:28]2[CH2:33][CH2:32][CH:31]([NH:34][C:2]3[CH:7]=[C:6]([C:8]4[C:16]5[C:11](=[N:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=5)[NH:10][CH:9]=4)[CH:5]=[C:4]([Cl:19])[N:3]=3)[CH2:30][CH2:29]2)[CH2:26][CH2:25]1
Reactant: NC1CCC(CC2CCC(N)CC2)CC1
Reactant: COc1cnc2[nH]cc(-c3cc(Cl)nc(Cl)c3)c2c1
Solvent: O
Product: COc1cnc2[nH]cc(-c3cc(Cl)nc(NC4CCC(CC5CCC(N)CC5)CC4)c3)c2c1
Yield: 58.7 %

Procedure:
A mixture of Example 149e (0.634 g, 2.16 mmol) and 4,4′-methylenedicyclohexanamine (2.267 g, 10.78 mmol) was heated at 155° C. for 90 minutes and cooled. While still warm, the slurry was treated with water and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered, concentrated, and purified on a 28 g Biotage KP-NH column using the ISCO Companion flash system eluting with MeOH/EtOAc (3:97 to 5:95) to give 593 mg of the title compound. 55 mg of this material was further purified by reverse-phase HPLC as described in Example 56 to give 17 mg of the title compound as trifluoroacetic acid salts. 1H NMR (400 MHz, CD3OD) ppm 1.02-1.45 (m, 9H), 1.57-1.92 (m, 9H), 1.99-2.18 (m, 2H), 3.02 (m, 1H), 3.70 (m, 1H), 3.95 (s, 3H), 6.72-6.92 (m, 2H), 7.80-7.91 (m, 2H), 8.06 (s, 1H). MS (DCI+) m/z 468.3 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:14]=2)[CH:9]=[N:8]1>CO.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: CCOC(=O)/C=C/c1ccc2c(cnn2C2CCCCO2)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ccc2c(cnn2C2CCCCO2)c1
Yield: 75 %

Procedure:
A stirred solution of (E)-ethyl 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)acrylate (0.78 g, 2.60 mmol) in MeOH (30 mL) and Pd/C (100 mg, 0.094 mmol) was stirred under hydrogen atmosphere overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated and dried to give ethyl 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propanoate (0.59 g, 75%), used without further purification. 1HNMR: 400 MHz, DMSO-d6: δ 1.13-1.15 (m, 3H), 1.56-1.57 (m, 2H), 1.58-1.59 (m, 1H), 1.93-2.05 (m, 2H), 2.39-2.50 (m, 1H), 2.63-2.69 (m, 2H), 2.94-2.96 (m, 2H), 3.58 (s, 1H), 3.71-3.76 (m, 1H), 3.86-3.89 (m, 1H), 4.04 (q, J=6.80 Hz, 2H), 5.79-5.80 (m, 1H), 7.29-7.31 (m, 1H), 7.57-7.62 (m, 2H), 8.18 (s, 1H). LCMS: RT 0.99 min; LCMS (ES-API), m/z 219 (M-THP).
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:12]=[C:11]([OH:13])[C:10](=[O:14])[CH:9]=[C:8]2[CH3:15])[CH:2]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:12]=[C:11]([O:13][CH2:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[C:10](=[O:14])[CH:9]=[C:8]2[CH3:15])[CH:2]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1cc(=O)c(O)cn1-c1cccc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2cn(-c3cccc(-c4ccccc4)c3)c(C)cc2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4.8 g (17.4 mmol) 1-biphenyl-3-yl-5-hydroxy-2-methylpyridin-4(1H)-one in 150 ml of DMF was added 4.1 g (26.1 mmol) PMBCl, and 12.0 g (87.0 mmol) K2CO3. The reaction was stirred at rt for 2 h, after which time water was added and a precipitate formed. The solid was collected by filtration and purified by flash chromatography (100 g silica gel, 0-20% MeOH:EtOAc) to afford 1-biphenyl-3-yl-5-[(4-methoxybenzyl)oxy]-2-methylpyridin-4(1H)-one. 1H NMR δ (ppm) (DMSO-d6): 7.84 (1 H, d, J=7.86 Hz), 7.77 (2 H, d, J=7.71 Hz), 7.73 (1 H, s), 7.64 (1 H, t, J=7.84 Hz), 7.53-7.47 (3 H, m), 7.46-7.39 (2 H, m), 7.38-7.30 (3 H, m), 6.93 (2 H, d, J=8.32 Hz), 6.23 (1 H, s), 4.89 (2 H, s), 3.77-3.70 (3 H, m), 2.03 (3 H, s). LCMS (M+H)+=398.3.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:31][C:32]([NH:34][C@@H:35]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36]([OH:38])=O)=[O:33])[CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30].CCN(C(C)C)C(C)C.[CH3:52][O:53][C@:54]1([C:63]2[CH:68]=[CH:67][C:66]([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=3[CH:75]=[CH2:76])=[CH:65][CH:64]=2)[CH2:58][NH:57][C@H:56]([C:59]([O:61][CH3:62])=[O:60])[CH2:55]1>C(Cl)Cl>[CH2:25]([O:31][C:32]([NH:34][C@@H:35]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36]([N:57]1[CH2:58][C@:54]([O:53][CH3:52])([C:63]2[CH:64]=[CH:65][C:66]([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=3[CH:75]=[CH2:76])=[CH:67][CH:68]=2)[CH2:55][C@H:56]1[C:59]([O:61][CH3:62])=[O:60])=[O:38])=[O:33])[CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30]
Reactant: C=CCCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: C=Cc1ccccc1-c1ccc([C@@]2(OC)CN[C@H](C(=O)OC)C2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCOC(=O)N[C@H](C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3C=C)cc2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
HATU (139 mg, 0.365 mmol) was added to a solution of (S)-2-((hex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoic acid (128 mg, 0.498 mmol), DIEA (0.174 mL, 0.996 mmol) and (2S,4R)-methyl 4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (112 mg, 0.332 mmol) in DCM (5 mL). The reaction was stirred at r.t. overnight. The reaction was evaporated and purified on the Biotage (10-40% EtOAc in hexanes) to give (2S,4R)-methyl 1-((S)-2-((hex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (151 mg, 79% yield) as a clear oil. LCMS: rt=2.05 min. [M+Na]30 =599; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1[C:18]([Sn](CCCC)(CCCC)CCCC)=[N:19][CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:18]2[C:17]([CH3:16])=[CH:22][CH:21]=[CH:20][N:19]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccc1C
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1cccnc1-c1nc2cc(F)cc(F)c2c(Cl)c1C
Temperature: 100 °C
Reaction time: 68 h

Procedure:
To a stirred solution of 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.17 g, 0.685 mmol) in toluene (1.40 mL) was added 3-methyl-2-(tributylstannyl)pyridine (0.29 g, 0.75 mmol), and palladium tetrakistriphenylphosphine (0.079 g, 0.069 mmol). The reaction was stirred at 100° C. and stirring continued for 68 h. The reaction mixture was cooled to rt and concentrated in vacuo. The crude material was purified by column chromatography on silica gel, eluting with (0-50% EtOAc in hexanes) to provide 4-chloro-5,7-difluoro-3-methyl-2-(3-methylpyridin-2-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=305.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[F:11].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)[C:5]=1[F:11]
Reactant: COC(=O)c1cccc(N)c1F
Reactant: O=Cc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(N=Cc2cccc(Br)c2)c1F
Temperature: 25 °C
Yield: 100 %

Procedure:
To a stirred solution of 3-amino-2-fluoro-benzoic acid (25 g, 161 mmol) in methanol (300 mL) was added thionyl chloride (30 mL, 403 mmol) dropewise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-amino-2-fluoro-benzoic acid methyl ester (27.5 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8FNO2 (M+H)+: 170.16, observed: 169.9. A mixture solution of 3-amino-2-fluoro-benzoic acid methyl ester (26 g, 153.8 mmol), 3-bromo-benzaldehyde (28.5 g, 153.8 mmol) and p-toluenesulfonic acid (590 mg, 3.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 3-[(3-bromo-benzylidene)-amino]-2-fluoro-benzoic acid methyl ester (51.7 g, quant.) as a pale-white solid: MS calcd. for C15H11BrFlNO2 337.16, obsd. (ESI+) [(M+H)+] 336.0 & 338.0.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[C:18]2[O:17][CH2:16][CH2:15][C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6].[H-].[Na+]>CN(C)C=O>[O:6]=[C:5]1[CH2:4][CH2:3][CH2:2][N:7]1[C:8]1[C:18]2[O:17][CH2:16][CH2:15][C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C1=Cc2cccc(NC(=O)CCCCl)c2OCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cccc(N3CCCC3=O)c2OCC1
Reaction time: 1.5 h
Yield: 53.5 %

Procedure:
To a solution of ethyl 9-(4-chloro-1-oxobutylamino)-2,3-dihydro-1-benzoxepin-4-carboxylate (0.44 g) in N,N-dimethylformamide (4.4 ml) was added sodium hydride (0.17 g, 60%) at ambient temperature. The reaction mixture was stirred for 1.5 hours at the same temperature and partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by medium pressure liquid chromatography (silica gel) using a mixture of ethyl acetate and n-hexane (1:4˜1:1) to give a solid of ethyl 2,3-dihydro-9-(2-oxo-1-pyrrolidinyl)-1-benzoxepin-4-carboxylate (0.21 g).