Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[C:7]([CH:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH2:10]1)=[O:8].[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br>CN(C)C=O>[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18](=[O:19])[C:9]([C:7](=[O:8])[C:6]2[CH:20]=[CH:21][CH:22]=[C:4]([CH3:3])[CH:5]=2)=[CH:10]1
Reactant: Cc1cccc(C(=O)C2CNc3ccccc3C2=O)c1
Reactant: Fc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)c2cn(Cc3ccccc3F)c3ccccc3c2=O)c1
Yield: 45.8 %

Procedure:
Compound 4x was prepared following the procedure outlined in Step 3 of Example 1 using 26 mg (0.65 mmol) of sodium hydride (60%), 132 mg (0.50 mmol) of 3-(3-methyl-benzoyl)-2,3-dihydro-1H-quinolin-4-one, 3 mL of anhydrous dimethylformamide, and 123 mg (0.65 mmol) of 2-fluorobenzylbromide. The crude product was purified by flash chromatography to yield 85 mg of a colorless solid 4x: LC-MSD, m/z for C24H18FNO2, [M+H]+=372.4, [M+2H]+=373.4; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=2.687 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.40 (s, 3H), 5.42 (s, 2H), 7.02-7.18 (m, 3H), 7.28-7.36 (m, 3H), 7.36-7.42 (m, 2H), 7.58-7.66 (m, 3H), 8.31 (s, 1H), 8.43-8.47 (m, 1H).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[F:12][C:13]1[N:14]=[CH:15][C:16]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)=[CH:17][CH:18]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: COC(=O)c1cc(Br)oc1C
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(F)nc2)oc1C
Yield: 89.5 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.6 g), 2-fluoropyridine-5-boronic acid (2.1 g), tetrakis(triphenylphosphine)palladium(0) (0.7 g), 2N aqueous sodium carbonate solution (15 mL) and 1,2-dimethoxyethane (20 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.5 g, 87%) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[N:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[CH:17]=O)=[N+:9]=[N-:10].[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:21]=1[NH2:22]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1/[CH:17]=[N:22]/[C:21]1[C:23]([F:27])=[CH:24][CH:25]=[CH:26][C:20]=1[Cl:19])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=Nc1ccncc1C=O
Reactant: Nc1c(F)cccc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=Nc1ccncc1/C=N/c1c(F)cccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (7.1 mL, 51 mmol) was added to a cooled (0° C.) mixture of 4-azidopyridine-3-carbaldehyde (2.52 g, 17 mmol) and 2-chloro-6-fluoroaniline (2.47 g, 17 mmol) in DCM (60 mL) under nitrogen. Titanium tetrachloride (1 M, 10.2 mL, 10.2 mmol) was then added and the resulting mixture was stirred for 1 hour at 0° C. before warming to room temperature and stirring for a further 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was suspended in toluene and filtered through a pad of Celite®. The filtrate was concentrated to dryness under reduced pressure to afford the title compound as a yellow solid. This crude material was employed in the next step without further purification or analysis.
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7](=[O:13])[CH:8]=[C:9]([C:11]#[N:12])[O:10][C:5]=2[CH:4]=1.[Na].[OH:17][C:18]1[CH:19]=[C:20]([CH:33]=[CH:34][CH:35]=1)[O:21][CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.O>CS(C)=O>[C:11]([C:9]1[O:10][C:5]2[CH:4]=[C:3]([CH2:2][O:17][C:18]3[CH:35]=[CH:34][CH:33]=[C:20]([O:21][CH2:22][C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=4)[CH:19]=3)[CH:15]=[CH:14][C:6]=2[C:7](=[O:13])[CH:8]=1)#[N:12]
Reactant: Oc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: N#Cc1cc(=O)c2ccc(CBr)cc2o1
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc(=O)c2ccc(COc3cccc(OCc4ccc5ccccc5n4)c3)cc2o1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.5 g of 7-bromomethyl-2-cyano-4-oxo-4H-1-benzopyran and 1.5 g of the sodium salt of 2-(3-hydroxyphenoxy)methylquinoline are combined in 10 ml of dimethylsulfoxide and stirred at room temperature for 5 hours. The mixture is poured into water and extracted with methylene chloride. The organic solution is dried and evaporated. The residue is recrystallized from ethyl acetate/dimethylformamide to give 0.72 g of 2-cyano-7-(3-(quinolin-2- ylmethoxy)phenoxymethyl)-4-oxo-4H-1-benzopyran.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH2:13]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][N:30]([CH3:35])[C:31](=[O:34])[CH:32]=[CH2:33])=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:13]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][N:30]([CH3:35])[C:31](=[O:34])/[CH:32]=[CH:33]/[C:2]2[CH:11]=[N:10][C:9]3[NH:8][C:7](=[O:12])[CH2:6][CH2:5][C:4]=3[CH:3]=2)=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCc2cc(Br)cnc2N1
Reactant: C=CC(=O)N(C)Cc1cn(Cc2ccccc2)c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 33.8 %

Procedure:
A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (1.05 g, 4.60 mmole), N-(1-benzyl-1H-indol-3-ylmethyl)-N-methyl-acrylamide (1.40 g, 4.60 mmole), Pd(OAc)2 (0.10 g, 0.46 mmole), tri-ortho-tolylphosphine (0.28 g, 0.92 mmole) and diisopropylethylamine (1.20 mL 6.90 mmole) in propionitrile (75 mL) was deoxygenated, then was and heated to reflux under a N2 overnight. The dark mixture was filtered through a pad of Celite®, and the filter pad was rinsed with acetonitrile (300 mL). The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (5% MeOH/CHCl3). The title compound (0.70 g. 35%) was obtained as a light yellow solid after drying in vacuo: MS (ES) m/e 451 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])[CH3:2].C([O-])(=O)C.[Na+].[Br:18]Br>C(O)(=O)C.O>[Br:18][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:12])[CH:3]2[CH2:1][CH3:2]
Reactant: BrBr
Reactant: CCC1C(=O)Nc2ccccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCC1C(=O)Nc2ccc(Br)cc21

Procedure:
A solution of 3-ethyloxindole (6.0 g, 40 mmol) and sodium acetate (4 g, 48 mmol) in acetic acid (100 ml) was treated with bromine (6.4 g, 40 mmol). After 30 min. the mixture was diluted with water and extracted with EtOAc (2×); the combined organic layers were washed with water, sat. sodium hydrogen carbonate solution, and brine, dried (MgSO4) and evaporated to afford the crude product (9.2 g, 96%). A sample was recrystallized from EtOAc/hexane to obtain the subtitled compound, m.p. 130-132° C.; 1H-NMR (DMSO-d6) δ 0.74 (t, 3H, J=7.5 Hz), 1.8-2.0 (m, 2H), 3.45 (t, 1H, J=5.5 Hz,), 6.76 (d, 1H, J=8.35 Hz), 7.42 (m, 1H), 10.43 (s, 1H); MS (−ESI) m/z 238/240 (M−H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:24]C)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16]C(=O)OC(C)(C)C)[CH:10]=2)[CH:8]=1)#[N:2].[N:26]([Sn](CCCC)(CCCC)CCCC)=[N+:27]=[N-:28].C(OCC)(=O)C.Cl>C1(C)C=CC=CC=1>[NH2:16][CH2:15][C:11]1[CH:10]=[C:9]([C:7]2[C:6]([OH:24])=[CH:5][CH:4]=[C:3]([C:1]3[NH:2][N:28]=[N:27][N:26]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: COc1ccc(C#N)cc1-c1cccc(CNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: NCc1cccc(-c2cc(-c3nnn[nH]3)ccc2O)c1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
tert-Butyl (5′-cyano-2′-methoxy-biphenyl-3-yl-methyl)-carbamate (0.73 g, 2.16 mmol), prepared as in Reference 19, and azidotributyltin (0.9 mL, 3.2 mmol) was dissolved in toluene (5 mL) and the solution was refluxed for 14 hours. The mixture cooled to room temperature and then workup with ethyl acetate and 1N HCl gave a slurry. The slurry was dried by rotovap and then triturated with hexanes. The solids were collected by filtration and treated with hydrobromic acid (48% aqueous, 15 mL). The mixture was refluxed for 14 hours at 120° C. and then diluted with water (50 mL). The dilution was dried by lyophilization to give 3′-aminomethyl-5-(1H-tetrazol-5-yl)-biphenyl-2-ol (0.4 g).
Reaction SMILES: [C:1]1([C:7]2([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>ClCCl>[C:1]1([C:7]2([CH2:12][O:13][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC1(c2ccccc2)CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(c2ccccc2)CCCC1
Reaction time: 16 h
Yield: 83.16 %

Procedure:
To a stirred solution of (1-phenyl-cyclopentyl)-methanol] (278) (10 g, 56.73 mmol) in dichloromethane (110 mL) was added triethyl amine (16 mL, 113.47 mmol) followed by mesyl chloride (5.3 mL, 68.08 mmol) at 0° C. Stirring was continued at room temperature for 16 h. After completion of the reaction, the reaction mixture was diluted with dichloromethane (50 mL) and washed with water (100 mL) and saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL). The separated organic fraction was dried and concentrated. The crude product was purified by Combi-Flash column (eluted at 10-20% ethyl acetate in hexane) to get methanesulfonic acid 1-phenyl-cyclopentylmethyl ester (279) (12 g, 83.16%) as a yellow semi-solid.
Reaction SMILES: CC1C=C(CN)C=CC=1OC(F)(F)F.FC1C=C(C=CC=1[N+]([O-])=O)OCC1C=CC(C)=CN=1.[CH3:34][C:35]1[CH:36]=[C:37]([CH:56]=[CH:57][C:58]=1[O:59][C:60]([F:63])([F:62])[F:61])[CH2:38][NH:39][C:40]1[C:41]([NH2:55])=[CH:42][CH:43]=[C:44]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][N:49]=2)[CH:45]=1.[C:64]1(=[O:74])[C@@H:72]2[C@@H:67]([CH2:68][CH2:69][CH2:70][CH2:71]2)[C:66](=O)[O:65]1>>[CH3:54][C:51]1[CH:52]=[CH:53][C:48]([CH2:47][O:46][C:44]2[CH:43]=[CH:42][C:41]3[N:55]=[C:66]([C@H:67]4[CH2:68][CH2:69][CH2:70][CH2:71][C@H:72]4[C:64]([OH:74])=[O:65])[N:39]([CH2:38][C:37]4[CH:56]=[CH:57][C:58]([O:59][C:60]([F:62])([F:63])[F:61])=[C:35]([CH3:34])[CH:36]=4)[C:40]=3[CH:45]=2)=[N:49][CH:50]=1
Reactant: Cc1ccc(COc2ccc(N)c(NCc3ccc(OC(F)(F)F)c(C)c3)c2)nc1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: Cc1cc(CN)ccc1OC(F)(F)F
Agent: Cc1ccc(COc2ccc([N+](=O)[O-])c(F)c2)nc1
Product: Cc1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(OC(F)(F)F)c(C)c4)c3c2)nc1

Procedure:
The title compound was prepared using analogous conditions described in Example 92 using (3-methyl-4-(trifluoromethoxy)phenyl)methanamine and 2-((3-fluoro-4-nitrophenoxy)methyl)-5-methylpyridine in Step B and N1-(3-methyl-4-(trifluoromethoxy)benzyl)-5-((5-methylpyridin-2-yl)methoxy)benzene-1,2-diamine and cis-hexahydroisobenzofuran-1,3-dione in Step D. MS (ESI): mass calcd. for C30H30F3N3O4, 553.22; m/z found, 554.0 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 12.04 (s, 1H), 8.34 (d, J=1.9, 1H), 7.56 (dd, J=7.8, 2.0, 1H), 7.45 (d, J=8.7, 1H), 7.33 (d, J=7.9, 1H), 7.21-7.19 (m, 2H), 7.08-6.97 (m, 2H), 6.83 (dd, J=8.7, 2.3, 1H), 5.49-5.33 (m, 2H), 5.08 (s, 2H), 3.73-3.64 (m, 1H), 2.75-2.64 (m, 1H), 2.27 (s, 3H), 2.19 (s, 3H), 1.90-1.41 (m, 6H), 1.33 (s, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13](OCC)=[O:14])[CH3:2].C1(C)C=CC=CC=1.O.[NH2:27][NH2:28]>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([NH:27][NH2:28])=[O:14])[CH3:2]
Reactant: CCOC(=O)C(=O)c1c(CC)cc(C)cc1CC
Reactant: NN
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN
Temperature: 70 °C
Reaction time: 7 h

Procedure:
To a 100 mL volume three-necked flask, ethyl 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetate ((9-a) (10.0 g)) and toluene (35 ml) were added. Hydrazine hydrate (2.13 ml) was added dropwise thereto at 60° C. and the obtained mixture was stirred at 70° C. for 7 hours. The reaction mixture was cooled to room temperature, water was added thereto and the organic layer was removed. The aqueous layer was extracted with toluene. The organic layers were combined and concentrated under reduced pressure to give 9.40 g of 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetohydrazide ((12-1)-(11)-39).
Reaction SMILES: [C:1]([OH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:13]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=[CH2:12].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[CH:15]1[C:14]2[N:13]([CH2:10][CH2:11][CH2:12][S:8][C:1](=[O:9])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: OC(=S)c1ccccc1
Reactant: C=CCn1c2ccccc2c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(SCCCn1c2ccccc2c2ccccc21)c1ccccc1

Procedure:
Thiobenzoic acid (30 g, 0.20 mol) was added to 9-allylcarbazole (11.9 g, 0.057 mol) in 100 mL toluene, and the reaction was carried out at 90° C. with argon purge via radical mechanism using AIBN as the initiator (1.8 g, 11 mmol, in 300 mg increments at 1 hr intervals). After 6 hrs the reaction mixture was poured into a 1 L separatory funnel containing 20 g sodium bicarbonate (NaHCO3, 0.24 mol) in 250 mL water, extracted with 100 mL chloroform, and the organic phase was washed twice with 200 mL water before solvent removal under reduced pressure. The crude product was subsequently washed in 100 mL hot hexane, 150 mL ethanol, and finally 150 mL of 15:1 ethanol:chloroform. Evaporation of leftover solvent at 80° C. under reduced pressure yielded compound 16 in ca. 90% purity as a dark brown, viscous syrup which solidified upon cooling (9.35 g, 0.024 mol, 42% yield, ˜10% wt dibenzoyl disulfide). 1H NMR (300 MHz, CDCl3): δ=8.10 (d, 2 carbazole H, J=8.1 Hz), 8.00-7.95 (m, 2 aromatic H ortho to COS), 7.62-7.41 (m, 3 aromatic H meta and para to COS plus 4 carbazole H), 7.27-7.19 (m, 2 carbazole H), 4.43 (t, NCH2, J=6.9 Hz), 3.06 (t, SCH2, J=6.9 Hz), 2.26 (tt, NCH2CH2CH2S, J=6.9, 6.9 Hz). 13C NMR (300 MHz, CDCl3): δ=191.56, 140.25, 136.88, 133.50, 128.65, 127.23, 125.75, 122.91, 120.41, 119.00, 108.55, 41.65, 28.95, 26.41.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:10]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:9]1=[O:30])(=O)=O.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>ClCCl>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([N:10]2[C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[CH:14]=3)[CH2:12][N:8]([CH2:7][CH2:6][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:9]2=[O:30])=[CH:24][CH:25]=1
Reactant: CS(=O)(=O)OCCN1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Cl)cc2)C1=O
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=C1N(CCN2CCOCC2)C[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
To a solution of (S)-2-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethyl methanesulfonate (30 mg, 0.065 mmol) in anhydrous dichloromethane (3 mL) is added morpholine (16.9 mg, 0.194 mmol). After 3 h at room temperature, the residue is purified by preparatory LC/MS to provide the title compound; 1H NMR (CD3OD, 400 MHz) δ 7.71 (s, 1H), 7.62-7.53 (m, 3H), 7.43 (d, J=9.2 Hz, 2H), 7.25 (d, J=9.2 Hz, 2H), 5.58 (dd, J=9.2, 6.2 Hz, 1H), 4.04 (t, J=9.2 Hz, 1H), 3.95-4.59 (m, 6H), 3.49-3.26 (m, 4H), 3.24 (dd, J=9.0, 6.2 Hz, 1H), 3.19-3.01 (m, 2H); HPLC-MS calculated for C22H24ClF3N3O2 (M+H+) 454.1, found 454.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1.C(Cl)(=O)C(Cl)=O.C[N:37](C=O)C>ClCCCl.CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH2:37])=[O:28])=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(C(=O)O)nc3)n2)n1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCCl
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(C(N)=O)nc3)n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
To a solution of 5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridine-2-carboxylic acid (Intermediate 124, 50 mg, 128 μmol) in DCE (10 mL) and DMF (100 μL) was added oxalyl chloride (22 μL, 256 μmol). The resulting solution was stirred at room temperature for 2 h, evaporated to dryness and re-suspended in a solution of ammonia in dioxane (7N, 10 mL). The reaction mixture was stirred overnight at room temperature and then poured into water (50 mL). The mixture was extracted with DCM (3×50 mL) and the combined organics were dried and concentrated under vacuum to afford a crude yellow solid. The crude material was suspended in MeOH, filtered and washed with further MeOH. The resulting solid was recrystallised in dioxane and water to afford the title compound as a white solid (15 mg, 30%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:9]=1[O:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=O.[Cl-].[Al+3].[Cl-].[Cl-]>CN(C=O)C.C1COCC1>[CH3:15][C:11]1([CH3:16])[C:12](=[O:14])[C:17]2[CH:18]=[CH:19][C:20]([CH3:21])=[C:8]([CH3:7])[C:9]=2[O:10]1
Reactant: Cc1cccc(OC(C)(C)C(=O)O)c1C
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1C)OC(C)(C)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
Oxalyl dichloride (21 mL, 221 mmol) and DMF (3 drops) were sequentially added to a solution of THF (300 mL) containing 2-(2,3-dimethylphenoxy)-2-methylpropanoic acid (38.3 g, 184 mmol) synthesized in Reference Example 16 under ice-cooling condition, and the mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and then the residue was dissolved in methylene chloride (250 mL). To this solution, aluminium chloride (36.2 g, 276 mmol) was added at −78° C., and the mixture was warmed to room temperature and stirred for 15 hours. The reaction solution was concentrated under reduced pressure, and then water was added to the residue and extraction was performed using ethyl acetate. The extract was washed with saturated saline, and then dried using anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane-ethyl acetate 95:5 to 5/1) to give 26.4 g of the title compound (yield: 75%).
Reaction SMILES: O[CH:2]=[CH:3][C:4]([C:6]1([CH3:13])[CH2:9][C:8]2([CH2:12][CH2:11][CH2:10]2)[CH2:7]1)=[O:5].S(Cl)([Cl:16])=O>C1C=CC=CC=1>[Cl:16]/[CH:2]=[CH:3]/[C:4]([C:6]1([CH3:13])[CH2:9][C:8]2([CH2:12][CH2:11][CH2:10]2)[CH2:7]1)=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CC1(C(=O)C=CO)CC2(CCC2)C1
Solvent: c1ccccc1
Product: CC1(C(=O)/C=C/Cl)CC2(CCC2)C1
Reaction time: 18 h
Yield: 60.3 %

Procedure:
A solution of 4.0 g of (2-methylspiro[3.3]hept-2-yl) (2-hydroxyvinyl) ketone in 25.0 ml of benzene was added dropwise with stirring to 3.95 g of thionyl chloride. The reaction mixture was allowed to stand for 18 hr at 25° C. The product was isolated by distillation (high vacuum) to afford 2.66 g 1-chloro-3-(2-methylspiro[3.3]hept-2-yl)-1E-propen-3-one as a yellow oil (40%).
Reaction SMILES: [F:1][CH:2]([F:33])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1[C:13]2[N:14]([N:18]=[C:19]([NH:21][C:22]3[CH:32]=[CH:31][C:25]4[CH2:26][CH2:27][NH:28][CH2:29][CH2:30][C:24]=4[CH:23]=3)[N:20]=2)[CH:15]=[CH:16][CH:17]=1.Cl[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37]>>[F:33][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1[C:13]2[N:14]([N:18]=[C:19]([NH:21][C:22]3[CH:32]=[CH:31][C:25]4[CH2:26][CH2:27][N:28]([CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:29][CH2:30][C:24]=4[CH:23]=3)[N:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)C(=O)CCl
Reactant: Fc1ccc(OCC(F)F)c(-c2cccn3nc(Nc4ccc5c(c4)CCNCC5)nc23)c1
Product: CN(C)C(=O)CN1CCc2ccc(Nc3nc4c(-c5cc(F)ccc5OCC(F)F)cccn4n3)cc2CC1

Procedure:
2-(7-{8-[2-(2,2-Difluoro-ethoxy)-5-fluoro-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-N,N-dimethyl-acetamide was prepared from {8-[2-(2,2-difluoro-ethoxy)-5-fluoro-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7yl)-amine (0.097 g, 0.210 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.033 mL, 0.321 mmol) in a manner analogous to Example 313 to give product (0.045 g, 39%). MP=218° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.53 (s, 1H), 8.78 (d, 1H), 7.62 (m, 2H), 7.40 (m, 2H), 7.29 (m, 2H), 7.00 (m, 2H), 6.23 (br m, 1H), 4.35 (m, 2H), 3.22 (s, 2H), 3.05 (s, 3H), 2.80 (br m, 7H), 2.60 (m, 4H). MS=539 (MH)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:2].[CH3:15][CH2:16][CH2:17][CH:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:22][CH:18]([CH2:19][CH2:20][CH3:21])[CH2:17][CH2:16][CH3:15])=[O:10])=[CH:11][CH:12]=1)[CH3:14]
Reactant: CCN(CC)c1ccc(C(=O)O)cc1
Reactant: CCCC(N)CCC
Product: CCCC(CCC)NC(=O)c1ccc(N(CC)CC)cc1

Procedure:
Prepared in a similar manner to example 4 using 4-diethylamino benzoic acid and 4-heptylamine. (31% %). 1H NMR (500 MHz, CDCl3): δ 0.92(t, 6H, J=7.17 Hz), 1.18 (t, 6H, J=7.04 Hz), 1.41(m, 4H), 1.55(m, 4H), 3.39 (m, 4H), 4.15 (m, 1H), 5.62 (m, 1H), 6.64 (d, 2H, J=10.26 Hz), 7.64 (d, 2H, J=10.26 Hz). MS (M+H, 291).