Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([CH2:16][CH2:15][S:14][C:13]([NH:17]C(=O)OC(C)(C)C)=[N:12]3)[CH2:10][CH:9]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[C:31]([C:33]1C=C(B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:25]1([CH:9]2[CH2:10][C:11]3([CH2:16][CH2:15][S:14][C:13]([NH2:17])=[N:12]3)[C:4]3[C:5](=[CH:6][CH:7]=[C:2]([C:37]4[CH:36]=[N:32][CH:31]=[CH:33][CH:38]=4)[CH:3]=3)[O:8]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)NC1=NC2(CCS1)CC(c1ccccc1)Oc1ccc(Br)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: NC1=NC2(CCS1)CC(c1ccccc1)Oc1ccc(-c3cccnc3)cc12
Temperature: 110 °C
Yield: 5.5 %

Procedure:
To a solution of t-butyl 6-bromo-2-phenyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]thiazine]-2′-ylcarbamate (39 mg, 0.08 mmol), 3-cyanophenylboronic acid (19.7 mg, 0.16 mmol), and Cs2CO3 (120 mg) in 1,4-dioxane (4 mL) and H2O (0.5 mL) charged in a 10 mL CEM microwave test tube is added PdCl2(PPh3)2 (20 mg). The system is degassed by sweeping with N2. The tube is capped and heated to 110° C. for 30 min in a CEM microwave reactor. Solvent is removed in vacuo and the residue is purified by preparative HPLC to give 2-phenyl-6-(pyridin-3-yl)-5′,6′-dihydrospiro[chroman-4,4′-[1,3]thiazin]-2′-amine (1.7 mg) as a TFA salt. MS ESI +ve m/z 389 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH2:17][C:18]2([CH3:22])[CH3:21])=[CH:13][CH:12]=1>ClCCl>[CH3:9][O:10][C:11]1[C:12]([C:5](=[O:7])[CH3:6])=[CH:13][C:14]2[CH2:15][CH2:16][CH2:17][C:18]([CH3:22])([CH3:21])[C:19]=2[CH:20]=1
Reactant: COc1ccc2c(c1)C(C)(C)CCC2
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2c(cc1C(C)=O)CCCC2(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a suspension of aluminum chloride (1-2 g, 90 mmol) in dichloromethane (300 mL) at 0° C. was added acetyl chloride (6.8 ml, 90 mmol). After stirring at 0° C. for 20 min the mixture turned into clear solution. The mixture was then cooled to −78° C. and 7-methoxy-1,1-dimethyl-1,2,3,4-tetrahydro-naphthalene (Compound A-85, 13.2 g, 69 mmol) in dichloromethane (20 mL) was added. After stirring at 78° C. for 2 h the mixture was poured onto ice and extracted with diethyl ether. The combined organic layers were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 10% ethyl acetate in hexane) to give the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].S([CH:33](O)[CH2:34][Cl:35])(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:33][CH2:34][Cl:35])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)C(O)CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCCCl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
14 g of (S)-N-tert-butoxycarbonyltyrosine, dissolved in 140 ml of DMF, are placed in a three-necked flask under a nitrogen atmosphere. 4.8 g of 50% sodium hydride in oil are added slowly using a spatula. 16.87 g of 1-tosyl-2-chloroethanol are added after the mixture has been stirred for 2 h at room temperature. 2.4 g of 50% sodium hydride in oil, and a further 8.4 ml of 1-tosyl-2-chloroethanol, are added after the mixture has been stirred for 2 days. The same procedure is carried out after 24 h and the stirring is continued for a further 24 h. The reaction is stopped by adding 100 ml of distilled water, and the reaction mixture is concentrated to dryness under reduced pressure. The residue which is obtained is taken up in 100 ml of distilled water and then extracted with 3 times 100 ml of ethyl acetate. The aqueous phase is separated off after settling and acidified to pH3 with 50 ml of 1N HCl, and the product is extracted with 3 times 100 ml of ethyl acetate. The organic phases are combined, washed with 2 times 50 ml of water, separated off, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure in order to yield 13.51 g of (S)-N-tert-butoxycarbonyl-4-O-(2-chloroethyl)tyrosine in the form of a chestnut oil (Rf=0.5, toluene 70%/methanol 20%/diethylamine 10%), which is used as such in the following step.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([S:16][C:17]3[N:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[CH:13]=[CH:14][CH:15]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[N-:31]=[N+:32]=[N-:33].[Na+].Cl.C(N(CC)CC)C>>[OH:30][C:5]1[C:6]([CH2:27][CH2:28][CH3:29])=[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:17]3[C:18]([C:19]4[N:31]=[N:32][NH:33][N:20]=4)=[CH:21][CH:22]=[CH:23][N:24]=3)[CH:11]=2)[CH:25]=[CH:26][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(OCc2cccc(Sc3ncccc3C#N)c2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCCc1c(OCc2cccc(Sc3ncccc3-c3nn[nH]n3)c2)ccc(C(C)=O)c1O
Yield: 47.9 %

Procedure:
Using the procedure essentially as described for Example 1 using 2-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylsulfanyl]-nicotinonitrile (350 mg, 0.836 mmol), sodium azide (544 mg, 8.36 mmol), and triethylamine hydrochloride (1.15 g, 8.36 mmol) to yield the title compound as a tan solid (185 mg, 48%): 1H NMR (DMSO-d6) δ 0.796 (t, 3H), 1.45 (sextuplet, 2H), 2.56 (t, 2H), 2.58 (s, 3H), 5.29 (s, 2H), 6.73 (d, 1H), 7.38 (dd, 1H), 7.48 (m, 3H), 7.57 (s, 1H), 7.82 (d, 1H), 8.16 (d, 1H), 8.44 (dd, 1H), 12.84 (s, 1H); MS (esi negative) m/z 460 (m−1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:12][O:13][CH2:14][CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1>>[OH:1][C:2]1[CH:3]=[C:4]([C:8](=[N:12][O:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:29][CH:30]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1cccc(O)c1
Yield: 84.2 %

Procedure:
Following a procedure similar to that described in Example 40(f), but using 0.33 g of 3'-hydroxyacetophenone and 0.70 g of 5-[4-(2-aminooxyethoxy)benzyl]-thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)], 0.74 g of the title compound, melting at 133°-135° C., was obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.O.[C:15]([OH:19])(=[O:18])[CH:16]=O>C(O)(=O)C.O>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])/[CH:12]=[CH:16]/[C:15]([OH:19])=[O:18])=[CH:5][CH:4]=1
Reactant: O=CC(=O)O
Reactant: CSc1ccc(/C=C/C(C)=O)cc1
Solvent: O
Solvent: CC(=O)O
Product: CSc1ccc(/C=C/C(=O)/C=C/C(=O)O)cc1

Procedure:
A solution of 10.5 g (54.6 mmol) of (E)-4-[4-(methylthio)phenyl]but-3-en-2-one and 5.02 g (54.6 mmol) of glyoxylic acid monohydrate in 15 ml of acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with methylene chloride. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with methylene chloride. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from methylene chloride/ether yielded (E,E)-6-[4-(methylthio)-phenyl]-4-oxo-2,5-hexadienoic acid of melting point 160°-163°.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[N:25]1>>[N:24]1([CH2:23][N:8]2[C:9]([C:10](=[O:19])[C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]2=[O:20])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[N:25]1
Reactant: ClCn1nnc2ccccc21
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cn2nnc3ccccc32)c1
Yield: 36.4 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 1-chloromethyl-1H-benzotriazole were reacted by the same way with the example 1 to obtain the titled compound (152 mg, yield: 36.4%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][C:14]=1[F:21]>C1COCC1>[Si:1]([O:8][CH2:9][CH:10]([C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[C:14]([F:21])[CH:15]=1)[OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: Fc1cc([Mg]Br)ccc1Cl
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(O)c1ccc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of 2-(tert-butyldimethylsilyloxy)acetaldehyde (2.00 g, 10.3 mmol) in dry THF (40 mL) was placed in an ice bath, and (4-chloro-3-fluorophenyl)magnesium bromide (24.8 mL, 12.4 mmol) was added dropwise via a syringe. The reaction mixture was stirred at 0° C. for 1 hour and then carefully quenched by dropwise addition of water. The reaction mixture was concentrated, and the residue was partitioned between EtOAc and saturated aqueous NH4Cl. The organics were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/EtOAc (20:1) to give 2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanol (2.92 g, 9.58 mmol, 92.8% yield) as an oil.
Reaction SMILES: O[C:2]([C:14]1[CH:15]=[C:16]([CH3:46])[C:17]([O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39]C2CCCCO2)=[C:18]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26]C2CCCCO2)[CH:19]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[H][H]>C(O)C.[Pd]>[C:8]1([CH:2]([C:14]2[CH:15]=[C:16]([CH3:46])[C:17]([O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][OH:39])=[C:18]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])[CH:19]=2)[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cc(C(O)(CC(C)(C)C)c2ccccc2)cc(OCCOCCOC2CCCCO2)c1OCCOCCOC1CCCCO1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C(CC(C)(C)C)c2ccccc2)cc(OCCOCCO)c1OCCOCCO
Reaction time: 2 h
Yield: 94.2 %

Procedure:
5-(1-Hydroxy-1-phenyl-3,3-dimethyl-1-butyl)-3-methyl-1,2-di(2-[2-(2-tetrahydropyranyloxy)ethoxy]ethoxy)benzene (3.0 g, 0.005 mole) was dissolved in absolute ethanol (100 ml) with 10% Pd/C catalyst (0.4 g). This mixture was shaken in a Parr hydrogenator at 50 psi hydrogen pressure for 18 hours. The solution was filtered and 1N HCl (10 ml) was added to the filtrate. After 2 hours, the alcohol was evaporated in vacuo, the residual oil was dissolved in methylene chloride (50 ml) and washed with water (25 ml), brine (25 ml) and dried over MgSO4. Evaporation gave the title compound as a colorless oil (2.17 g, 95% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.Br[CH:16]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH:16]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:7][CH:6]=1)(=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCC(Br)C(=O)OCC
Reactant: CCCCCC(=O)c1ccc(O)cc1
Product: CCCCCCCCC(Oc1ccc(C(=O)CCCCC)cc1)C(=O)OCC
Yield: 80.4 %

Procedure:
1-[4-Hydroxyphenyl]-1-hexanone (384 mg, 2.0 mmol) and ethyl (RS)-2-bromodecanoate (614 mg, 2.2 mmol) were reacted according to the procedure used for the preparation of I to give Ethyl (RS)-2-[4-Hexanoylphenoxy]decanoate (628 mg, 80%). 1H NMR (400 MHz, CDCl3): δ 7.86 (d, J=9.0 Hz, 2H), 6.84 (d, J=9.0 Hz, 2H), 4.60-4.65 (m, 1H), 4.15 (q, J=7.0 Hz, 2H), 2.83 (t, J=7.3 Hz, 2H), 1.86-1.97 (m, 2H), 1.61-1.70 (m, 2H), 1.38-1.52 (m, 2H), 1.20-1.34 (m, 14H), 1.18 (t, J=7.2 Hz, 3H), 0.78-0.87 (m, 6H); 13C NMR (101 MHz, CDCl3): δ 199.17, 171.36, 161.78, 130.95, 130.46 (2C), 114.72 (2C), 76.66, 61.51, 38.41, 32.84, 32.00, 31.76, 29.52, 29.35 (2C), 25.31, 24.41, 22.83, 22.74, 14.33, 14.26, 14.14. The resulting ester (628 mg, 1.6 mmol) was saponified with lithium hydroxide (193 mg, 8.0 mmol) according to the procedure used for the preparation of I to give (RS)-2-[4-Hexanoylphenoxy]decanoic Acid (468 mg, 80%). 1H NMR (400 MHz, CDCl3): δ 7.93 (d, J=9.0 Hz, 2H), 6.91 (d, J=9.0 Hz, 2H), 5.77 (br s, 1H), 4.70 (dd, J=5.8, 6.6 Hz, 1H), 2.89 (t, J=7.4 Hz, 2H), 1.97-2.03 (m, 2H), 1.67-1.74 (m, 2H), 1.44-1.60 (m, 2H), 1.23-1.37 (m, 14H), 0.90 (t, J=6.8 Hz, 3H), 0.87 (t, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 199.76, 176.29, 161.56, 131.20, 130.70 (2C), 114.81 (2C), 76.12, 38.56, 32.78, 32.03, 31.80, 29.53, 29.40, 29.36, 25.36, 24.51, 22.87, 22.76, 14.33, 14.20. The acid (468 mg, 1.3 mmol) was then converted to the sodium salt according to the procedure used for the preparation of I to give Sodium (RS)-2-[4-Hexanoylphenoxy]decanoate (459 mg, 93%) as a white solid. mp 275-280° C.; 1H NMR (400 MHz, CD3OD): δ 7.91 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 4.44-4.48 (m, 1H), 2.89-2.96 (m, 2H), 1.88-1.96 (m, 2H), 1.63-1.71 (m, 2H), 1.44-1.61 (m, 2H), 1.24-1.38 (m, 14H), 0.84-0.93 (m, 6H); 13C NMR (101 MHz, CD3OD): δ 200.89, 177.86, 163.36, 130.27 (2C), 129.60, 114.75 (2C), 79.54, 37.94, 33.18, 31.86, 31.49, 29.44, 29.38, 29.21, 25.73, 24.55, 22.58, 22.45, 13.36, 13.23; LRMS (ESI): m/z 769.8 (M2H+), 747.8 (2M-Na++2H+), 363.2 (M-Na++2H+); HPLC: 3.min.
Reaction SMILES: [H-].[Na+].C(OP([CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])(OCC)=O)C.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH3:15][O:14][C:12](=[O:13])[C:11](=[C:27]1[CH2:28][CH2:29][N:24]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:25][CH2:26]1)[CH3:16]
Reactant: CCOP(=O)(OCC)C(C)C(=O)OC
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)=C1CCN(Cc2ccccc2)CC1
Reaction time: 0.67 h

Procedure:
To a suspension of NaH (60% in mineral oil, 6 g, 0.15 mol) in dry THF (300 mL), under N2 atmosphere, was added a solution of methyl 2-(diethoxyphosphoryl)-propionate (33.6 g, 0.15 mol) in dry THF (150 mL) at such a rate to keep the temperature below 30° C. After being stirred at r.t for 40 min, a solution of N-benzyl-4-piperidone (28.35 g, 0.15 mol) in dry THF (100 mL) was added dropwise keeping the temperature below 30° C. After the addition was completed, the mixture was stirred at r.t for 30 min. The reaction was quenched with NH4Cl (sat. aq., 400 mL). The mixture was extracted with Et2O (300 mL×2) and the combined extracts were washed with brine, dried and concentrated to give the crude product as a red oil, which was used directly in the next step.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH:15]=[O:16])[CH:13]=3)[C:8]([CH2:17][CH3:18])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][Mg]Cl>O1CCCC1>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH:15]([OH:16])[CH3:19])[CH:13]=3)[C:8]([CH2:17][CH3:18])=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[Mg]Cl
Reactant: CCc1nn(C2CCCC2)c2cc(C=O)ccc12
Solvent: C1CCOC1
Product: CCc1nn(C2CCCC2)c2cc(C(C)O)ccc12
Temperature: 25 °C

Procedure:
A solution of 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxaldehyde (1.00 g, 4.13 mmol) in 40 mL of tetrahydrofuran under argon was cooled to −78° C. and with stirring treated with 3 mL of 3 M methylmagnesium chloride in tetrahydrofuran. The reaction was stirred at −78° C. for 1 hour, slowly warmed to room temperature overnight and then quenched by addition of 100 mL of saturated aqueous NH4Cl. The mixture was extracted with 3×50 mL of ethyl acetate and the combined organic fractions were dried over sodium sulfate and concentrated to give 1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)ethanol as a yellow solid. The crude residue was not purified but used as such in the next step.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)[NH2:2].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20](=[CH:26]N(C)C)[C:21](OCC)=[O:22])=[CH:16][CH:15]=1)#[N:13].Cl.CCN(C(C)C)C(C)C>CC(O)C>[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:26]=[N:2][N:1]([C:3]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=3)[C:21]=2[OH:22])=[CH:16][CH:15]=1)#[N:13]
Reactant: NNc1ccc(C(=O)O)cn1
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
Combined 6-hydrazinylnicotinic acid (6.00 g, 39.2 mmol) and ethyl 2-(4-cyanophenyl)-3-(dimethylamino)acrylate (10.05 g, 41.1 mmol) and 2-propanol (80 mL) and treated with 1.85% hydrochloric acid (77 mL, 39.2 mmol). The reaction was stirred at room temperature for 16 h, then Hunig's base (34.1 mL, 196 mmol) was add to the suspension which became homogeneous. The mixture was stirred for 3 h. The reaction mixture was washed with isopropyl acetate (2×150 mL). The combined organic layers were extracted with water (40 mL) and the combined aqueous layers were concentrated in vacuo to give a solid. The solid was triturated with 1N HCl (300 mL), filtered and washed with water (20 mL), then slurried in ethanol (350 mL) and granulated overnight. The solid was collected by filtration and dried in vacuum to give the title compound (9.20 g, 77% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.79 (d, J=8.34 Hz, 2H) 8.14 (br. s., 2H) 8.47 (d, J=7.07 Hz, 1H) 8.71 (br. s., 2H) 8.97 (s, 1H) 13.44 (br. s., 1H) 13.60 (br. s., 1H). MS [M+H]307.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H][H]>C1COCC1.[Pd]>[NH2:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:10]=1
Reactant: [H][H]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)O)c(F)c1

Procedure:
A solution of 2-fluoro-4-nitro-benzoic acid (2.8 g, 15.1 mmol) in 100 mL THF was combined with palladium/charcoal 10% (250 mg) and hydrogenated for 6.5 h in a Parr apparatus at ambient temperature at 3 bar hydrogen pressure. Then the mixture is filtered.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8](Cl)[N:9]=[C:10]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[C:5]=2[S:4][CH:3]=1.[CH2:17]([CH2:19][NH2:20])[OH:18].O>CN1CCCC1=O>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([NH:20][CH2:19][CH2:17][OH:18])[N:9]=[C:10]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[C:5]=2[S:4][CH:3]=1
Reactant: Clc1nc(-c2ccco2)c2scc(Br)c2n1
Reactant: NCCO
Solvent: O
Solvent: CN1CCCC1=O
Product: OCCNc1nc(-c2ccco2)c2scc(Br)c2n1
Temperature: 90 °C
Yield: 37.8 %

Procedure:
A solution of 7-bromo-2-chloro-4-(2-furyl)thieno[3,2-d]pyrimidine (110 mg, 0.35 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was treated with ethanolamine (32 μL, 0.52 mmol), heated at 90° C. for 16 h, cooled, poured into water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by chromatography (SiO2: EtOAc:Heptane, 1:1) to give the title compound (45 mg, 38%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([NH:11][CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)=[O:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][C:43]1[C:48]([CH2:49]O)=[CH:47][CH:46]=[CH:45][N:44]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:49][C:48]2[C:43]([CH3:42])=[N:44][CH:45]=[CH:46][CH:47]=2)=[CH:4][C:3]=1[C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=1)=[O:10]
Reactant: Cc1ncccc1CO
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(O)ccc2Cl)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(CNC(=O)c2cc(OCc3cccnc3C)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of methyl 4-({[(2-chloro-5-hydroxyphenyl)carbonyl]amino}methyl)benzoate (100 mg, 0.31 mmol) in THF (5 ml) was treated with triphenylphosphine (1.2 eq, 98 mg, 0.37 mmol), (2-methyl-3-pyridinyl)methanol (38 mg, 0.31 mmol) and diisopropylazodicarboxylate (1.2 eq, 110 ul, 0.56 mmol) and stirred at room temperature for 4 hours. Mixture diluted with methanol and purified by SCX cartridge eluting with methanol first then 2M ammonia in methanol. Basic fractions combined and evaporated to give the title compound as an off-white solid. MS (ES+) m/z 425 [M+H]+ (C23H2135ClN2O4). 1H-NMR (400 MHz, d6-DMSO) δ 3.85 (3H, s), 4.51 (2H, d, J 6), 5.18 (2H, s), 7.10-7.96 (9H, m), 8.42 (1H, dd, J 1.6, J 4.8), 9.07 (1H, t, J 6).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH2:14][C:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[NH:27]CC(OC(C)(C)C)=O)=[O:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:36]([OH:42])([C:38](F)(F)F)=[O:37].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH2:14][C:15]([C:17]2[C:26]([CH2:38][C:36]([OH:42])=[O:37])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[NH2:27])=[O:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)N1CCN(C(=O)CC(=O)c2ccc3ccccc3c2NCC(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)CC(=O)c2c(CC(=O)O)cc3ccccc3c2N)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[((4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl)carbonyl][(1,1-dimethylethoxycarbonyl)methyl]aminonaphthalene (147 mg, 0.30 mmol) in CH2Cl2 (2.0 mL) was added TFA (3.0 mL). The resulting reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was evaporated in vacuo to afford an oil, which was diluted with water (15 mL), adjusted to pH 4.5 by saturated NaHCO3, then extracted by ethyl acetate (3×15 mL). The organic layer was evaporated in vacuo to afford 2-[((4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl)carbonyl][carboxymethyl]-aminonaphthalene (90 mg) as a solid; NMR (CDCl3) 1.26 (t, 3), 3.24-3.30 (m, 2), 3.35-3.42 (m, 6), 3.57 (m, 2), 4.14 (q, 2), 4.52 (s, 2), 7.48 (d, 1), 7.58 (m, 2), 7.84-7.94 (m, 4) ppm.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:8][C:9](=[O:21])[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][C:18]([O-:20])=[O:19])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl.C(O)(=O)C>CO>[CH3:1][C:2]1[C:3]([NH:8][C:9](=[O:21])[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][C:18]([OH:20])=[O:19])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1NC(=O)Nc1ccccc1CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cccnc1NC(=O)Nc1ccccc1CC(=O)O
Reaction time: 16 h

Procedure:
A solution of methyl 4-(2-(3-methylpyridylureido)phenylacetate (1 eq.) in methanol was treated with 1 N NaOH (2 eq.). The reaction was stirred for 16 h, then acidified carefully with 1 N HCl to pH 7 then with acetic acid to pH 3. The product was filtered and washed with methanol then ether to give 4-(2-(3-methylpyridylureido)phenylacetic acid: 1H NMR (CD3SOCD3, 300 MHz, ppm) 11.97 (s, 1H), 8.64 (brs, 1H), 8.31 (s, 1H), 7.69 (m, 1H), 7.62 (d, 8.4 Hz, 2H), 7.33 (d, 8.4 Hz, 2H), 7.09 (m, 1H), 3.62 (s, 2H), 2.38 (s, 3H); m/z 286.