Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14].[H-].[Na+].Cl>CN(C)C(=O)C>[F:11][C:12]([F:16])([F:15])[CH2:13][O:14][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: OCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc(OCC(F)(F)F)nc1
Temperature: 90 °C
Reaction time: 21 h
Yield: 77.8 %

Procedure:
A mixture of 6-chloronicotinic acid (7.0 g, 44.4 mmol), 2,2,2-trifluoroethanol (6.40 mL, 89.0 mmol) and sodium hydride (5.33 g, 133.0 mmol, 60% in oil) in N,N-dimethylacetamide (400 mL) is stirred at 90° C. for 21 hours. After cooling to room temperature, the reaction mixture is poured slowly into 2M hydrochloric acid (300 mL) and extracted with n-hexane/ethyl acetate (1:10, 500 mL). The organic layer is washed with 2M hydrochloric acid (300 mL×2) and dried over sodium sulfate. The organic solvent is concentrated under reduced pressure to give 7.64 g (78% yield) of the title compound as colorless oil. This material is used for the next reaction (Step-2) without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][CH2:11]Cl)=[C:6]([CH:9]=1)[CH2:7]Cl.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:9]=[C:6]2[C:5]([CH2:10][CH2:11][N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:7]2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: ClCCc1ccc(Cl)cc1CCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Clc1ccc2c(c1)CN(c1ccccc1)CC2
Yield: 18.5 %

Procedure:
5-Chloro-2-(2-chloroethyl)benzyl chloride (8 g), was dissolved in chloroform (50 ml), then aniline (2.79 g,) and triethylamine (8.01 g,) were added to the solution. The mixture was refluxed for 18 hr. then cooled and washed with 2M sodium hydroxide solution (2×100 ml). The chloroform layer was dried (magnesium sulphate) and evaporated in vacuo. The residue was distilled in vacuo to afford 7-chloro-2-phenyl-1,2,3,4-tetrahydroisoquinoline (1.35 g), b.pt. 170°-180°/0.6-0.8 mmHg) characterised by its nmr spectrum.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:28](O)=[O:29])=[CH:4][N:3]=1.[CH2:31]([N:33]([CH2:38][CH3:39])[CH2:34][CH2:35][CH2:36][NH2:37])[CH3:32].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CO.O1CCCC1>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:19])[NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=4)=[CH:15][CH:16]=3)=[CH:9][S:10][C:6]=2[C:5]([C:28]([NH:37][CH2:36][CH2:35][CH2:34][N:33]([CH2:38][CH3:39])[CH2:31][CH3:32])=[O:29])=[CH:4][N:3]=1
Reactant: CCN(CC)CCCN
Reactant: Nc1ncc(C(=O)O)c2scc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)CCCNC(=O)c1cnc(N)c2c(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)csc12

Procedure:
As shown in the Scheme above, 1-(4-(4-aminothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea ((1), prepared as described in WO2005/10009), in a mixture of pyridine and tetrahydrofuran can be treated with iodine at room temperature, followed by treatment with potassium hydroxide at elevated temperature to provide 1-(4-(4-amino-7-iodothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea (2). Methyl 4-amino-3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridine-7-carboxylate (3) can be prepared by reacting 1-(4-(4-amino-7-iodothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea (2) with carbon monoxide gas in the presence of a catalyst such as but not limited to [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane, and a base such as but not limited to triethylamine. The reaction is typically performed under pressure and at an elevated temperature. Methyl 4-amino-3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridine-7-carboxylate (3) can be reacted with aqueous lithium hydroxide to provide 4-amino-3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridine-7-carboxylic acid (4). The reaction is typically performed at elevated temperature in a solvent such as but not limited to tetrahydrofuran and methanol. 4-Amino-3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridine-7-carboxylic acid (4) can be reacted with N,N-diethyl-1,3-propanediamine in the presence of a coupling agent such as but not limited to 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, an auxiliary coupling reagent such as but not limited to 1-hydroxybenzotriazole hydrate, and a base such as but not limited to N-methylmorpholine to provide 4-amino-N-[3-(diethylamino)propyl]-3-(4-{[(3-fluorophenyl)carbamoyl]amino}phenyl)thieno[3,2-c]pyridine-7-carboxamide (5). The reaction is typically performed in a solvent such as but limited to N,N-dimethylformamide.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[C:14]([N+:15]([O-])=O)=[CH:13][NH:12][N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.[Sn](Cl)Cl>C(O)C>[C:1]1([NH:7][C:8]([C:10]2[C:14]([NH2:15])=[CH:13][NH:12][N:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccccc1)c1n[nH]cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1c[nH]nc1C(=O)Nc1ccccc1
Yield: 17.3 %

Procedure:
4-Nitro-1H-pyrazole-3-carboxylic acid phenylamide (100 mg; 0.43 mmol) was dissolved in ethanol (5 ml), treated with tin (II) chloride dihydrate (500 mg; 2.15 mmol) then heated at reflux overnight. The reaction mixture was cooled and evaporated. The residue was partitioned between ethyl acetate and brine, and the ethyl acetate layer was separated, dried (MgSO4), filtered and evaporated. The crude product was purified by flash column chromatography eluting with 1:1 ethyl acetate/petroleum ether then 5% methanol/dichloromethane. Evaporation of product containing fractions followed by preparative LC/MS gave 15 mg of the product as an off white solid. (LC/MS: Rt 1.40, [M+H]+ 202.95).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)[C:52]([O:54]C)=[O:53])C3=O)=CC=2)=CC=1.O1C2C=CC(C(Cl)=O)=CC=2OC1>>[O:53]1[C:5]2[CH:6]=[CH:7][C:2]([C:1]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]4[CH:24]=[C:23]5[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]5=[O:25])=[CH:18][CH:17]=4)=[CH:14][CH:15]=3)=[O:8])=[CH:3][C:4]=2[O:54][CH2:52]1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Agent: O=C(Cl)c1ccc2c(c1)OCO2
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc5c(c4)OCO5)cc3)cc2C1=O
Yield: 83.7 %

Procedure:
The compound of example 127 was prepared analogous to compound of example 97 by reaction of compound of example 6 with benzo[d][1,3]dioxole-5-carbonyl chloride.
Reaction SMILES: CS(O[CH:6]1[CH2:10][CH2:9][S:8][CH2:7]1)(=O)=O.[C:11]([O-:14])(=[S:13])[CH3:12].[K+]>CC(C)=O>[CH3:12][C:11]([S:13][CH:6]1[CH2:10][CH2:9][S:8][CH2:7]1)=[O:14]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CCSC1
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)SC1CCSC1
Yield: 52 %

Procedure:
A mixture of 1.6 g. (8.8 mmole) of crude 3-methylsulfonyloxy-thiolane and 1.5 g. (8.8 mmole) potassium thioacetate in 40 ml. acetone was refluxed under nitrogen for 20 hr. The mixture was then concentrated in vacuo and the residue was partitioned between 40 ml. ethyl acetate and 40 ml. water. The ethyl acetate layer was separated and washed with 30 ml. water and 30 ml. saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromographed on silica gel eluting with methylene chloride to yield 740 mg. (52%) of the title compound.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[CH:15]1[CH:20]=[CH:19][C:18]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][C:24]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:17][CH:16]=1.Cl.C(N(CC)CC)C>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:31][CH2:30][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][C:18]2[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=2)=[C:24]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:25]=1)#[N:2]
Reactant: NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: N#CNC(=NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 23.1 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.25 g, 1.3 mmol) was dissolved in methanol (10 ml), and 3,4-(dibenzyloxy)phenethylamine hydrochloride (0.54 g, 1.5 mmol) and triethylamine (0.15 g, 1.5 mmol) were added. The mixture was stirred at room temperature for 45 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate thus obtained was extracted with ethyl acetate (100 ml×3). The ethyl acetate layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 50 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure to give N-cyano-N'-[2-(3,4-dibenzyloxyphenyl)ethyl]-3-pyridinecarboximidamide (0.13 g, 0.3 mmol, yield: 21%) as colorless syrup. Next, to this syrup was added a 5% hydrogen chloride in methanol (2 ml). The solution was crystallized from methanol diethyl ether to give N-cyano-N'-[ 2-(3,4-dibenzyloxyphenyl)ethyl]-3-pyridinecarboximidamide hydrochloride as colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][N:13]=[C:12]3[NH2:19])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:20](Cl)(=[O:22])[CH3:21]>ClCCl>[NH2:19][C:12]1[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([C:4]3[CH:3]=[C:2]([NH:1][C:20](=[O:22])[CH3:21])[CH:7]=[C:6]([F:8])[CH:5]=3)[CH:10]=2)[N:15]=[CH:14][N:13]=1
Reactant: Nc1cc(F)cc(-c2ccc3ncnc(N)c3c2)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Nc1cc(F)cc(-c2ccc3ncnc(N)c3c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 4 mL screw-cap vial was added 6-(3-amino-5-fluoro-phenyl)quinazolin-4-amine, 25 mg; 0.10 mmol) followed by DCM (0.5 mL), TEA (2 equiv., 0.20 mmol, 0.0277 mL), and acetyl chloride (2 equiv., 0.20 mmol, 15.43 mg). The reaction was capped and shaken at room temperature for 2 h. Reaction was then diluted with 2 mL dichloromethane, and washed with water. Resultant precipitate was collected by filtration, then purified by reverse phase HPLC. Purification recovered 6 mg of desired product. 1H NMR (400 MHz, DMSO) δ 10.35-10.24 (s, 1H), 8.61-8.49 (d, J=1.7 Hz, 1H), 8.43-8.36 (s, 1H), 8.05-7.97 (dd, J=8.7, 1.8 Hz, 1H), 7.98-7.82 (bs, 1H), 7.77-7.73 (d, J=8.7 Hz, 1H), 7.71-7.67 (s, 1H), 7.65-7.56 (d, J=11.2 Hz, 1H), 7.42-7.30 (d, J=10.0 Hz, 1H), 2.11-2.08 (s, 3H). LCMS M/Z (M+H) 297.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[C:16]1[C:17](CCCC2C=CC=CC=2)=[C:18](S([O-])(=O)=O)C=CC=1C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36]([NH:39][CH2:40][CH2:41][CH:42]([C:49]1[CH:54]=[C:53]([CH3:55])[CH:52]=[CH:51][C:50]=1[O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([CH3:38])[CH3:37].O>CS(C)=O>[CH2:57]([O:56][C:50]1[CH:51]=[CH:52][C:53]([CH3:55])=[CH:54][C:49]=1[CH:42]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:41][CH2:40][N:39]([CH2:18][CH2:17][CH:16]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:36]([CH3:38])[CH3:37])[C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: Cc1ccc(OCc2ccccc2)c(C(CCNC(C)C)c2ccccc2)c1
Reactant: Cc1ccc(OCc2ccccc2)c(-c2c(C)ccc(S(=O)(=O)[O-])c2CCCc2ccccc2)c1
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(OCc2ccccc2)c(C(CCN(CCC(c2ccccc2)c2cc(C)ccc2OCc2ccccc2)C(C)C)c2ccccc2)c1
Temperature: 65 °C

Procedure:
A mixture of 3-(2-(benzyloxy)-5-methylphenyl)-3-phenylpropyl-4-methylbenzenesulfonate of Formula IVa (120 g) and N-isopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenylpropylamine (92 g) in dimethylsulfoxide (600 ml) was heated at 60-70° C. for 18-20 hours. The reaction mass was cooled to 25-35° C., decomposed with water (600 ml), and extracted with toluene (600 ml). The toluene layer was washed with a mixture of concentrated hydrochloric acid (60 ml) and water (606 ml). The organic layer was then washed with 10% sodium hydroxide solution (240 ml), followed by water (600 ml). The organic layer was distilled completely to obtain the title compound as a syrup. Yield: 128 g (75.4%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([CH:8]1[CH2:12][C:11](=[O:13])[N:10]([CH:14]2[CH2:19][CH:18]([CH3:20])[CH2:17][CH2:16][CH:15]2[CH:21]([CH3:23])[CH3:22])[CH2:9]1)=[O:7]>O1CCCC1>[CH:21]([CH:15]1[CH2:16][CH2:17][CH:18]([CH3:20])[CH2:19][CH:14]1[N:10]1[C:11](=[O:13])[CH2:12][CH:8]([C:6]([OH:7])=[O:5])[CH2:9]1)([CH3:22])[CH3:23]
Reactant: COC(=O)C1CC(=O)N(C2CC(C)CCC2C(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1CCC(C(C)C)C(N2CC(C(=O)O)CC2=O)C1
Reaction time: 1.5 h
Yield: 89.1 %

Procedure:
Lithium hydroxide, monohydrate (LiOH, H2O) (13.22 g, 0.315 mol) was added to a solution of 1-(2-isopropyl-5-methyl-cyclohexyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (obtained as in EXAMPLE I, 59 g, 0.21 mol,) in a mixture of tetrahydrofuran (THF:H2O:CH3OH) (1:1:1) (300 mL) at room temperature and was stirred for 1-2 hours. THF and CH3OH were then removed via evaporation. HCl was added and the reaction mixture was extracted three times with ethyl acetate. The organic fractions were combined, washed with brine, dried, and concentrated to provide 1-(2-isopropyl-5-methyl-cyclohexyl)-5-oxo-pyrrolidine-3-carboxylic acid (50 g), which was further evaporated with benzene twice to remove traces of water.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:34]=[CH:33][C:16]([CH2:17][N:18]4[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[C:20]([O:30][CH2:31][CH3:32])=[N:19]4)=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[Cl:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:34]=[CH:33][C:16]([CH2:17][N:18]4[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:20]([O:30][CH2:31][CH3:32])=[N:19]4)=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cn4c(Cl)cccc4n3)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCc3cn4c(Cl)cccc4n3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
After a mixture of ethyl 3-[1-[4-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzyl]-3-ethoxy-1H-pyrazol-4-yl]propionate (507 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (2 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[4-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzyl]-3-ethoxy-1H-pyrazol-4-yl]propionic acid (448 mg, yield 94%). This was recrystallized from ethanol. Melting point: 153–154° C.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:25]=[CH:26][CH:27]=1)[CH2:9][CH:10]([CH:16]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[OH:17])[C:11]([O:13]CC)=[O:12])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].S([O-])(O)(=O)=O.[K+]>CO>[C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:25]=[CH:26][CH:27]=1)[CH2:9][CH:10]([CH:16]([C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)[OH:17])[C:11]([OH:13])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(Cc1cccc(OC(C)(C)C)c1)C(O)c1ccc(F)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)Oc1cccc(CC(C(=O)O)C(O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl (2RS,3RS)-2-[3-(tert-butyloxy)benzyl]-3-(4-fluorophenyl)-3-hydroxypropanoate (8.8 g, 23.5 mmol) in methanol (100 ml) was added 2N aqueous sodium hydroxide solution (23.5 ml, 47 mmol), and the mixture was stirred at room temperature for 3 hrs. The reaction solution was acidified with 5% aqueous potassium hydrogen sulfate solution (100 ml). The mixture was extracted with ethyl acetate (200 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was crystallized from hexane to give (2RS,3RS)-2-[3-(tert-butyloxy)benzyl]-3-(4-fluorophenyl)-3-hydroxypropanoic acid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:51][C:52]1[CH:53]=[C:54]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=2)[CH:55]=[CH:56][C:57]=1[CH3:58].C(N(CC)CC)C>ClCCCl>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18](=[O:20])[NH:65][C:61]3[CH:60]=[C:59]([C:54]4[CH:55]=[CH:56][C:57]([CH3:58])=[C:52]([CH3:51])[CH:53]=4)[CH:64]=[CH:63][CH:62]=3)=[CH:21][CH:22]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Reactant: Cc1ccc(-c2cccc(N)c2)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCCl
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(C)c(C)c5)c4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
A mixture of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 2) (50 mg, 0.1415 mmol), 1-(3-(dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (32.55 mg, 0.170 mmol), 1-hydroxybenzotriazole monohydrate (26.01 mg, 0.170 mmol), and 1,2-dichloroethane (2 ml) was stirred at ambient temperature for 30 minutes. To the mixture was added 3′,4′-dimethylbiphenyl-3-amine hydrochloride (39.69 mg, 0.170 mmol) and triethylamine (98.62 μl, 0.707 mmol) and the mixture was stirred for 2 days at ambient temperature. The crude mixture was purified on silica gel (EtOAc in hexanes gradient) to provide 36 mg of the title compound as a thin film (48%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[O:18]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([O:3][CH:4]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:26]=2)=[CH:15][CH:16]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(OCC)c1ccc(OCc2cccc(Oc3ccccc3)c2)cc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) was dissolved in dimethylformamide (2.0 mL), and 3-phenoxybenzyl chloride (116 μL, 0.63 mmol), potassium carbonate (174 mg, 1.26 mmol), and potassium iodide (catalytic amount, about 5 mg) were sequentially added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 40° C. for 4 hours. To the reaction solution, a saturated aqueous solution of ammonium chloride was added, and the organic matter was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, then dried over anhydrous sodium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 80:20 (v/v)), whereby the objective title compound was obtained (165 mg, yield: 93%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][CH2:12][N:13]=2)=[CH:5][CH:4]=1.[C:14](NC1C=CC=CC=1)(=[O:19])[CH2:15][C:16]([CH3:18])=[O:17]>>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][CH2:11][CH2:12][N:13]=2)=[CH:7][CH:8]=1)[C:14](=[O:19])[CH2:15][C:16]([CH3:18])=[O:17]
Reactant: CNc1ccc(C2=NCCO2)cc1
Reactant: CC(=O)CC(=O)Nc1ccccc1
Product: CC(=O)CC(=O)N(C)c1ccc(C2=NCCO2)cc1

Procedure:
This compound was prepared by treating 4-aminobenzonitrile with a slight excess, on a molar equivalents basis, of methyl iodide in tetrahydrofuran solvent for 4 hrs at room temperature. Removal of the THF and other volatiles, followed by recrystallization, gave a 76% yield of 4-(N-methyl)aminobenzonitrile, mp 85-87° C. Using Example 1 procedure, the aforesaid substituted nitrile was treated with ethanolamine to obtain a 70% yield of 2-[4-(N-methyl) aminophenyl]oxazoline, mp 145-147° C. Following the Example 6 procedure, the aforesaid compound was treated with TDO to form the oxazoline shown below, having a methyl group attached to the nitrogen in the acetoacetanilide segment. The product was recrystallized from ethyl acetate, mp 102-105° C. Elemental analysis, FT-IR, exhibiting 1726 (C—O) and 1635 (—C═N—) cm−1 absorptions, and with 1H NMR confirmed the below drawn structure.
Reaction SMILES: [CH3:1][O:2]/[C:3](=[CH:7]\[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][CH2:18][C:19]1[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=1[CH3:24])[CH:12]=[CH:11]2)/[C:4]([OH:6])=[O:5].[H][H]>CO.ClCCl.[Pd]>[CH3:1][O:2][CH:3]([CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][CH2:18][C:19]1[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=1[CH3:24])[CH:12]=[CH:11]2)[C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: CO/C(=C\c1ccc2c(ccn2CCc2nc(-c3ccccc3)oc2C)c1)C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COC(Cc1ccc2c(ccn2CCc2nc(-c3ccccc3)oc2C)c1)C(=O)O
Yield: 77.4 %

Procedure:
A suspension of 9 mg of (Z)-2-Methoxy-3-{1-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl]-1H-indol-5-yl}-acrylic acid in 2 ml of methanol and 1 ml of dichloromethane and 6 mg of Pd/C 10%) was hydrogenated at 22° C. and 1 bar until hydrogen uptake ceased (2 h). The mixture was filtered, the filtrate evaporated and the residue was purified by HPLC (RP-18, CH3CN/H2O, gradient) to give 7 mg of the title compound as a colorless oil. MS: (M−H)− 403.3.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([F:23])=[C:18](B(O)O)[CH:19]=1.O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:12][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:16]2[CH:15]=[C:14]([Cl:13])[CH:19]=[CH:18][C:17]=2[F:23])[CH:11]=1
Reactant: OB(O)c1cc(Cl)ccc1F
Reactant: Clc1cc(Cl)c2cccnc2n1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Cl)cc1-c1cc(Cl)c2cccnc2n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of 9.95 g (50.0 mmol) 2,4-dichloro-[1,8]naphthyridine (described by Koller, Chemische Berichte 60: 407 (1927)), 8.72 g (50.0 mmol) 5-chloro-2-fluorophenylboronic acid und 5.04 g (60.0 mmol) sodium hydrogencarbonate in 100 ml DMF und 50 ml water was heated to 80° C. under nitrogen. 701 mg (1.0 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added and the mixture was stirred for 16 hrs at 80° C. Water was added to the reaction mixture and the precipitate was filtered off, dried in vacuum and recrystallized from 2-propanol. This yielded 4-chloro-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine as yellowish crystals; HPLC-MS: 2.49 min, [M+H] 293.