Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]([CH:29]=1)=[N:25][C:26](=[O:28])[N:27]=2.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(CC(C)C)=O>[C:1]1([N:11]2[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]4[C:24]([CH:29]=3)=[N:25][C:26](=[O:28])[N:27]=4)[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1N=c2ccc(CCBr)cc2=N1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C1N=c2ccc(CCN3CCN(c4cccc5ccccc45)CC3)cc2=N1
Yield: 14 %

Procedure:
To a 100 ml round-bottomed flask equipped with magnetic stirrer, condenser, and nitrogen inlet were added 2.64 grams (12.4 mmol) of N-(1-naphthyl)-piperazine, 3.0 grams (12.4 mmol) of 6-(2-bromoethyl)-benzimidazolone, 1.31 grams (12.4 mmol) sodium carbonate, 50 ml methylisobutylketone, and a catalytic amount of sodium iodide. The reaction was refluxed for 3 days, cooled, and evaporated to a brown gum. The gum was partitioned between 50 ml water and 75 ml ethyl acetate, and the ethyl acetate layer washed with brine, dried over sodium sulfate, and evaporated, then chromatographed on silica gel. Fractions containing the product were combined and evaporated, the residue taken up in tetrahydrofuran, treated with hydrochloric acid gas, and the resulting hydrochloride salt of the product filtered off to give a white solid, m.p. 260-262° C., 716 mg (14% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])([O-:3])=[O:2].[H-].[Na+].[CH3:19][O:20][CH2:21][CH2:22]Br>CN(C=O)C.C(OCC)(=O)C>[CH3:19][O:20][CH2:21][CH2:22][N:10]1[C:11]2[C:7](=[CH:6][C:5]([C:13]([F:16])([F:14])[F:15])=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[CH:9]1
Reactant: O=[N+]([O-])c1cc2[nH]ccc2cc1C(F)(F)F
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCn1ccc2cc(C(F)(F)F)c([N+](=O)[O-])cc21
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
6-nitro-5-(trifluoromethyl)-1H-indole (50 mg, 0.22 mmol) was dissolved in DMF (2 mL) and treated with sodium hydride (35 mg, 0.87 mmol) to form a dark red opaque solution. The solution was stirred for 20 minutes and then added dropwise to a solution of 2-bromoethyl methyl ether (121 mg, 82 μL, 0.87 mmol) in 1 mL DMF. The reaction mixture was heated at 50° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with 50% saturated NaHCO3 (2×10 mL) and brine. The organic layer was dried over Na2SO4, filtered and dried to obtain 1-(2-methoxyethyl)-6-nitro-5-(trifluoromethyl)-1H-indole, which was used in the next step without further purification.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.[Cl:22][CH2:23][CH2:24][C:25]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)=[O:26]>C1COCC1>[Cl:22][CH2:23][CH2:24][C@H:25]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)[OH:26]
Reactant: O=C(CCCl)c1cccs1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: C1CCOC1
Product: O[C@H](CCCl)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
Borane dimethylsulfide complex (2.75 mL, 28.6 mmol) was added at room temperature to a stirred solution of (S)-2-methyl-CBS-oxazaborolidine (2.87 mL, 1M) in dry THF (50 mL). The resulting solution was stirred at room temperature to 10 mins before a solution of 3-chloro-1-(2-thienyl)-1-propanone (2.5 g, 14.3 mmol) in dry THF (100 mL) was added dropwise over 1 hr. After complete addition the resulting solution was stirred at room temperature for a further 1 hr before the solvent was removed in vacuo. The residue was taken up in ether (200 mL) and washed with NH4Cl (sat, 100 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with hexane:ether [7:3] to yield a colourless oil (2.1 g, 84%); Optical purity determined by capillary electrophoresis to be 83% ee; δH (300 MHz, CDCl3) 7.25 (1H, d, Ar), 7.08–6.9 (2H, m, Ar), 5.28–5.20 (1H, m, CHO), 3.80–3.52 (2H, m, CH2), 2.35–2.12 (2H, m, CH2).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].Cl[C:6]1[N:15]2[CH:16]=[N:17][N:18]=[C:14]2[C:13]2[CH:12]=[C:11]([O:19][CH3:20])[C:10]([O:21][CH3:22])=[CH:9][C:8]=2[N:7]=1>>[CH2:1]([O:4][C:6]1[N:18]2[N:17]=[CH:16][N:15]=[C:14]2[C:13]2[CH:12]=[C:11]([O:19][CH3:20])[C:10]([O:21][CH3:22])=[CH:9][C:8]=2[N:7]=1)[CH:2]=[CH2:3]
Reactant: C=CCO
Reactant: COc1cc2nc(Cl)n3cnnc3c2cc1OC
Product: C=CCOc1nc2cc(OC)c(OC)cc2c2ncnn12

Procedure:
To 65 ml. of allyl alcohol cooled to room temperature is added 2.8 g. of sodiuom followed by addition of an additional 120 ml. of allyl alcohol. To the resulting mixture at room temperature is added 15.0 g. of 5-chloro-8,9-dimethoxy-1,2,4-triazolo[4,3-c]quinazoline. The resulting precipitate is filtered off, washed with diethyl ether, dissolved in methylene chloride, washed with water, dried and evaporated in vacuo to dryness. The residue is twice crystallized from ethanol after treatment with charcoal to obtain 5-allyloxy-8,9-dimethoxy-1,2,4-triazolo[1,5-c]quinazoline, m.p. 189°-191° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([Li])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[OH:12])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]c1ccccc1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cccc(Oc2ccccc2)c1
Temperature: -78 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
To a stirred solution of 3-phenoxybenzaldehyde (2 g, 10.09 mmol) in THF (15 mL) at −78° C. was added phenyllithium (6.73 mL, 1.8M solution in cyclohexane-ether) dropwise. After stirring under argon at −78° C. for 4 hrs, the reaction was quenched with water and extracted with diethyl ether. The organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude mixture was purified via flash SiO2 chromatography (ethyl acetate/hexanes (10%/90%) to (20%/80%)) to give 128 (2.79 g, 86% yield): 1H-NMR (400 MHz, chloroform-d) δ 6.87-7.38 (m, 10H), 7.09 (m, 1H), 6.99 (app d, J=7.3 Hz, 1H), 6.88 (m, J=8.6, 2.2 Hz, 1H), 5.81 (s, 4H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[OH:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[OH:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(O)cc1
Reactant: Cc1nc(Cl)c2ccccc2n1
Product: Cc1nc(Nc2ccc(O)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (818 mg, 4.58 mmol), 4-hydroxy-aniline (500 mg, 4.58 mmol) by a procedure similar to Example 1b to give 498 mg (43%) of off white solids. 1H NMR (DMSO-d6): 9.51 (s, 1H), 9.34 (s, 1H), 8.44 (d, J=7.8 Hz, 1H), 7.77 (t, J=8.4 Hz, 1H), 7.67-7.48 (m, 4H), 6.79 (d, J=7.8 Hz, 2H), 2.45 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:18][CH2:17][C:16](=O)[CH2:15][CH:14]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(O)=O.Cl.[CH2:25]([NH2:27])C.[OH-].[Na+]>ClCCCl>[CH3:25][NH:27][CH:16]1[CH2:17][CH2:18][C:13]([C:8]2[C:7]3[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[NH:10][CH:9]=2)=[CH:14][CH2:15]1
Reactant: CCN
Reactant: O=C1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CNC1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Reaction time: 16 h
Yield: 103.9 %

Procedure:
A solution of compound 119 (0.5 g, 1.951 mmol) in 1,2-dichloroethane (10 mL) was treated with AcOH (0.11 mL, 1.951 mmol), ethylamine hydrochloride (0.159 g, 1.951 mmol), NaBH(OAC)3 (0.62 g, 2.926 mmol) at room temperature and stirred for over night (16 h). The reaction was basified with 2N NaOH (25 mL) and product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layer washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M NH3 in MeOH:CH2Cl2, 1:9) to obtain compound 126 (0.55 g, 99%) as a semi-solid. 1H NMR (DMSO-d6) δ 1.07 (t, 3H, J=7.2 Hz), 1.47-1.58 (m, 1H), 1.99-2.08 (m, 2H), 2.42-2.59 (m, 3H), 2.67-2.73 (m, 2H), 2.82-2.90 (m, 1H), 6.14 (brs, 1H), 7.81 (s, 1H), 7.86-7.97 (m, 2H), 8.31 (d, 1H, J=2.1 Hz); ESI-MS (m/z, %): 286 (MH+, 100), 241 (33).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH:10](=O)/[CH:11]=[CH:12]/[CH3:13].[OH-].[NH4+]>Cl>[CH3:13][C:12]1[CH:11]=[CH:10][C:7]2[C:2](=[C:3]([CH3:9])[C:4]([OH:8])=[CH:5][CH:6]=2)[N:1]=1
Reactant: C/C=C/C=O
Reactant: Cc1c(N)cccc1O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1ccc2ccc(O)c(C)c2n1
Yield: 126.7 %

Procedure:
To 3-amino-2-methylphenol (5.0 g, 41 mmol) in refluxing 6N HCl (100 mL) was added dropwise (E)-but-2-enal (5.7 g, 81 mmol) and the reaction was heated to reflux for 2 hours. After cooling, the reaction was neutralized with ammonium hydroxide and extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to yield 2,8-dimethylquinolin-7-ol (9.0 g, 51% yield) as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([Cu])#[N:25].C(N)CN>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:24]#[N:25])=[CH:11][C:10]=1[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: Brc1ccc(OCc2ccccc2)c(CCc2ccccc2)c1
Solvent: CN(C)C=O
Solvent: NCCN
Product: N#Cc1ccc(OCc2ccccc2)c(CCc2ccccc2)c1
Temperature: 25 °C
Yield: 42.5 %

Procedure:
To a stirred solution of the 4-benzyloxy-3-(phenethyl)phenylbromide, (5.5 g, 15 mmol) in DMF (200 ml, dried) was added CuCN (3.32 g, 37 mmol). The reaction was heated to reflux and held at reflux for 20 hours, under argon. The reaction mixture was allowed to cool to ambient temperature, poured into ice water, treated with ethylene diamine (200 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with brine (2×60 ml), dried (MgSO4) and evaporated. The crude material was purified by chromatography to give 4-benzyloxy-3-phenethylbenzonitrile as a white solid (2.0 g, 43%).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][CH:25]([C:27]#[N:28])[CH3:26])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].S(=O)(=O)(O)[OH:32]>O>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH:25]([C:27](=[O:32])[NH2:28])[CH3:26])=[O:23])=[CH:29][CH:30]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(C)C#N)cc1
Reactant: O=S(=O)(O)O
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(C)C(N)=O)cc1

Procedure:
A mixture of 5 g. (12.1 m moles) 1-cyanoethyl 4-(hexadecylamino)benzoate in 100 ml. 75% sulfuric acid is heated at 50° C. for 20 hours. The cooled solution is diluted with water, filtered, and the residue is dried to yield the amide as a white amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=O)=[N:11][N:10]([CH:18]([CH3:20])[CH3:19])[C:9]2=[O:21])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][CH:28]=[C:27]2[O:36][C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][C:38]=1[F:44].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][CH:28]=[C:27]2[O:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:15]([C:12]2[C:13](=[O:14])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9](=[O:21])[N:10]([CH:18]([CH3:20])[CH3:19])[N:11]=2)=[O:17])=[CH:39][C:38]=1[F:44]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: CC(C)n1nc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4nn(C(C)C)c(=O)n(-c5ccc(F)cc5)c4=O)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(4-fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid (500 mg, 2 mmol), 4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenylamine (535 mg, 1.70 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (639 mg, 1.68 mmol) and N,N-diisopropylethylamine (279 uL, 1.60 mmol) in N,N-dimethylformamide (8 mL) was stirred at rt for 3 h. The solvent was removed and the residue dissolved in EtOAc and washed with saturated NaHCO3 solution water and brine. After drying over magnesium sulfate, solvent was evaporated and the product was purified by ISCO silica gel chromatography (hexane: EtOAc 1:4) to give 835 mg (83%), which triturated with ether and dried. mp=225-226° C.; LCMS m/z=590 (M+1); 1H NMR DMSO) δ: 10.87 (s, 1H), 8.49 (d, 1H, J=5.2 Hz), 7.97 (dd, 1H, J=12.6, 2.2 Hz), 7.59-7.36 (m, 8H), 6.50 (d, 1H, J=4.9 Hz), 4.90 (m, 1H), 3.95 (s, 6H), 3.32 (s, 3H), 1.38 (d, 6H, J=6.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([OH:12])=O.S(=O)(=O)(O)O.O.[NH2:19][NH2:20]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([NH:19][NH2:20])=[O:12]
Reactant: NN
Reactant: O=C(O)Cc1c(F)cccc1F
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: NNC(=O)Cc1c(F)cccc1F

Procedure:
70.4 g (0.41 mol) of 2,6-difluorophenylacetic acid, 700 ml of ethanol and 35 ml of concentrated sulphuric acid are heated under reflux for 3 hours. The reaction mixture is then concentrated by evaporation, taken up in dichloromethane and the solution is extracted by shaking in succession with water, 2N sodium carbonate solution and again with water. After drying over magnesium sulphate, the organic phase is concentrated by evaporation. The residue is dissolved in 560 ml of ethanol. After the addition of 30 ml (31 g; 0.62 mol) of hydrazine hydrate, the whole is heated under reflux for 4 days. After cooling, the resulting crystals are filtered off to yield 56.4 g (74% of the theoretical yield) of 2,6-difluorophenylacetic acid hydrazide which melts at 177-178°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH:6]=[C:5]2O.P(Cl)(Cl)([Cl:22])=O>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH:6]=[C:5]2[Cl:22]
Reactant: Oc1cc(-c2cccc(F)c2)nc2ccc(Br)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: Fc1cccc(-c2cc(Cl)c3cc(Br)ccc3n2)c1
Temperature: 110 °C
Yield: 83.8 %

Procedure:
Into a 500 mL three-neck round-bottom flask equipped with a condenser, magnetic stirrer and nitrogen inlet was placed 5.2 g (16.3 mmoles) of 6-bromo-2-(3-fluorophenyl)-quinolin-4-ol. To this was added 15.2 mL (25.0 g, 163 mmoles, 10 equiv.) of phosphorus oxychloride with stirring. The mixture was then heated to 110° C. for 4 hr. At the end of this time the reaction was cooled to room temperature and water cautiously added dropwise until all of the POCl3 was consumed. The product crystallised from the water and the solids were collected by filtration. The solids were washed with water and placed in a 250 mL Erlenmeyer where they were then triturated with water. After collection by filtration, washing with water, and drying in a vacuum oven, 4.6 g (84%) of the pure product was obtained.
Reaction SMILES: C([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][C:14]([CH3:20])([C:16]([O:18]C)=[O:17])[CH3:15])=[CH:11][CH:12]=1)=O)(C)(C)C.Cl.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[OH:32])[C:26]([NH2:28])=[NH:27].CCN=C=NCCCN(C)C.Cl.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[C:26]([C:25]1[CH:29]=[CH:30][C:31]([O:32][C:6]([C:8]2[S:9][C:10]([CH2:13][C:14]([CH3:20])([CH3:15])[C:16]([OH:18])=[O:17])=[CH:11][CH:12]=2)=[O:5])=[C:23]([F:22])[CH:24]=1)(=[NH:28])[NH2:27]
Reactant: N=C(N)c1ccc(O)c(F)c1
Reactant: COC(=O)C(C)(C)Cc1ccc(C(=O)OC(C)(C)C)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Cc1ccc(C(=O)Oc2ccc(C(=N)N)cc2F)s1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To 5-(2-Methyl-2-methoxycarbonylpropyl)thiophene-2-carboxylic acid tert-butyl ester (5.0 g, 16.8 mmol) was added trifluoroacetic acid (20 mL), and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated, and the residue was dissolved in pyridine (30 mL), 3-fluoro-4-hydroxybenzamidine hydrochloride (3.2 g, 16.8 mmol) and WSC hydrochloride (3.8 g, 19.8 mmol) were added, and the mixture was stirred at 50° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, 4N-hydrochloric acid solution (10 mL) and 4N-Hydrogen chloride in 1,4-Dioxane (10 mL) were added to the obtained residue, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to give the title compound (2.8 g, 5.86 mmol, 35%).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[N:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:19]3[CH:34]=[CH:33][C:22]([C:23]([NH:25][CH:26]=[CH:27][C:28]([O:30]CC)=[O:29])=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=2)[CH:7]=1.O1CCCC1.[OH-].[Li+]>CO>[F:35][C:2]([F:1])([F:36])[C:3]1[CH:4]=[N:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:24])=[CH:33][CH:34]=3)[CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: CCCC(Nc1ccc(-n2cc(C(F)(F)F)cn2)cc1)c1ccc(C(=O)NC=CC(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC(Nc1ccc(-n2cc(C(F)(F)F)cn2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.7 %

Procedure:
Isomer 1 of ethyl 3-(4-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenylamino)butyl)benzamido)propenoate (0.300 g, 0.597 mmol) was dissolved in methanol (8.0 mL) and tetrahydrofuran (4.2 mL) and treated with 2N aqueous lithium hydroxide (4.2 mL, 8.4 mmol). The mixture was stirred at ambient temperature for 4 hours. The crude reaction mixture was concentrated and the residual solid was dissolved in water and acidified to pH=4 with 1.0M aqueous hydrochloric acid. A brown precipitate formed. The precipitate was collected by filtration, washed with water, and dried in vacuo to afford 3-(4-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenylamino)butyl)benzamido)propanoic acid, Isomer 1 (0.220 g, 78%) as a solid. 1H NMR (400 MHz, CDCl3, δ): 7.91 (s, 1H), 7.78 (s, 1H), 7.67 (d, J=7.6 Hz, 2H), 7.35 (d, J=6.8 Hz, 2H), 7.27 (d, J=7.2 Hz, 2H), 7.03-6.88 (m, 1H), 6.60-6.42 (m, 2H), 4.33 (t, J=6.3 Hz, 1H), 3.64 (s, 2H), 2.72-2.54 (m, 2H), 1.87-1.65 (m, 2H), 1.51-1.22 (m, 2H), 0.90 (t, J=7.0 Hz, 3H). MS (M+1): 475.2.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[SH:20][C:21]1[S:22][C:23]([C:26]([OH:30])([CH2:28][CH3:29])[CH3:27])=[CH:24][N:25]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([S:20][C:21]4[S:22][C:23]([C:26]([OH:30])([CH3:27])[CH2:28][CH3:29])=[CH:24][N:25]=4)=[CH:3][CH:4]=3)[O:9][C:8](=[O:12])[CH:7]=2)=[CH:14][CH:15]=1
Reactant: O=c1cc(-c2ccc(F)cc2)c2ccc(Br)cc2o1
Reactant: CCC(C)(O)c1cnc(S)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCC(C)(O)c1cnc(Sc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)s1

Procedure:
Employing the procedure described in Example 1, Step 3, using 7-bromo-4-(4-fluorophenyl)-2H-chromen-2-one, 2-(2-mercapto-1,3-thiazole-5-yl)butan-2-ol and K2CO3 in NMP, the title compound was obtained. 1H NMR (400 MHz, acetone-d6): δ 7.72 (s, 1H), 7.63-7.68 (m, 2H), 7.51 (d, 1H), 7.43 (d, 1H), 7.33-7.41 (m, 3H), 6.38 (s, 1H), 1.93-1.80 (m, 2H), 1.61 (s, 3H), 0.90 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=O)[NH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([Cl:17])=[N:4][CH:3]=1
Reactant: COc1ccc2c(=O)[nH]cc(Br)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)ncc(Br)c2c1
Yield: 65 %

Procedure:
A solution of 4-bromo-6-methoxyisoquinolin-1(2H)-one (1.5 g, 5.90 mmol) in POCl3 (15 ml) was refluxed for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The combine organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (10% ethyl acetate in pet ether) to get desired compound (1.1 g, 65%) as white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.53(s, 1H), 8.27-8.24 (d, J=12 Hz, 1H), 7.56-7.53 (d, J=12 Hz, 1H), 7.41 (s, 1H), 4.02 (s, 3H); MS: MS m/z 273.99 (M++1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23](Cl)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[C:15]1=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][C:17]=2[N:16]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)[C:15]1=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(Cl)nc32)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCCC4)nc32)cc1
Yield: 90.7 %

Procedure:
Using the method of Example N-4, pyrrolidine (0.04 mL, 0.52 mmol), 3-benzyloxy-7-chloro-6-fluoro-1-(4-methylphenyl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example T-2, 0.17 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) were combined in 20 mL of acetonitrile to give 0.17 g of the title compound as a solid, mp 192-194° C.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[CH2:10](I)[CH:11]=[CH2:12].O>CN1C(=O)N(C)CC1>[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]([OH:8])[CH2:12][CH:11]=[CH2:10])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: C=CCI
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: C=CCC(O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
5.90 ml (50 mmol) p-tolualdehyde was dissolved in 150 ml of DMI, and 5.5 ml (60 mmol, 1.2 eq.) allyl iodide and 10.34 g (66 mmol, 1.3 eq.) SnF2 were added. The reaction became warm to the touch and much precipitate formed as the reaction progressed. After stirring for 1 hour at room temperature, 200 ml of H2O was added, the mixture was extracted with Et2O (1×250 ml, 2 ×100 ml), the combined Et2O layers were washed with sat. NH4Cl (3×50 ml, to remove excess DMI), dried over MgSO4, and evaporated in vacuo to an oil. Flash chromatography (1:4 EtOAc:hexanes, Rf 0.56) yielded 7.5 g (93%) of product as a clear oil. 1H NMR (CDCl3): 7.25 and 7.15 (4H, phenyl), 5.8 and 5.15 (3H, vinyl), 4.65 (1H, CHOH), 2.5 (2H, CH2), 2.35 (2H, CH2), 2.35 (3H, CH3), and 2.15 (1H, OH) ppm.