Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[S:8][C:7]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.Cl[C:14]1[C:18]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:17][S:16][N:15]=1>C1COCC1>[CH3:3][C:4]1[S:8][C:7]([CH2:9][CH2:10][CH2:11][O:12][C:14]2[C:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:17][S:16][N:15]=2)=[CH:6][CH:5]=1
Reactant: Clc1nsnc1-c1cccnc1
Reactant: Cc1ccc(CCCO)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(CCCOc2nsnc2-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (10.2 mmol) was added to a solution of 3-(5-methyl-2-thienyl)-1-propanol (4.0 g, 25.5 mmol) in THF (40 ml). The mixture was stirred for 1 h at room temperature, whereupon a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (1.0 g, 5.1 mmol) in THF (10 ml) was added dropwise to the reaction mixture. After stirring overnight at room temperature, the reaction was quenched with water then extracted with diethyl ether. The organic phase was dried over NaCl/Na2 SO4 then evaporated to yield crude 3-(3-(5-methyl-2-thienyl)propoxy-1,2,5-thiadiazol-4-yl)pyridine. A solution of 3-(3-(5-methyl-2-thienyl)propoxy-1,2,5-thiadiazol-4-yl)pyridine (1.0 g, 3.2 mmol) and iodomethane (2.3 g, 16.0 mmol) in 60 ml of acetone was refluxed overnight. The solution was evaporated to yield 1.5 g of the quaternized product. Sodium borohydride (0.6 g, 16.0 mmol) was carefully added to a solution of the quaternized product (1.5 g) in ethanol (30 ml).The reaction was evaporated and the resulting residue was taken up in waterand extracted with methylene chloride (3×100 ml). The organic phase was dried over NaCl/Na2SO4 then evaporated. The residue was purified by radial chromatography eluting with 0.5% NH4OH/5.0% EtOH in CHCl3. The oxalate salt was made to yield 337 mg of the title compound. M.p. 134°-137° C. (Compound 129).
Reaction SMILES: C(OC([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:28])[CH:14]([NH:16][C:17](=[O:27])[C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=1)[CH3:15])=O)(C)(C)C.[O:29]=[C:30]1[O:34][CH:33]([O:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40]C=2)[CH:32]([NH:44][C:45](C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=[O:46])[CH2:31]1>>[CH2:36]([O:35][CH:33]1[CH:32]([NH:44][C:45]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:28])[CH:14]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([N:24]([CH3:25])[CH3:26])=[CH:20][CH:19]=2)[CH3:15])=[O:46])[CH2:31][C:30](=[O:29])[O:34]1)[C:37]1[CH:38]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(NC(=O)c1ccc(N(C)C)cc1)C(=O)N1CCCC1C(=O)OC(C)(C)C
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CC(NC(=O)c1ccc(N(C)C)cc1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Yield: 45 %

Procedure:
Prepared from 1-(2-(4-dimethylamino-benzoylamino)-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester and syn-(2-benzyloxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester according to the procedure used to prepare 98a to afford 60 mg (45% yield). 1H-NMR (500 MHz, CDCl3): δ 1.04 (d, 0.75H), 1.35 (d, 2.25H), 1.80-2.50 (m, 5H), 2.75-3.20 (m, 8H), 3.45-3.75 (m, 2H), 4.05-4.20 (m, 0.5H), 4.30-4.80 (m, 3.5H), 4.80-4.95 (m, 1.5H), 5.52 (d, H), 5.75-6.00 (m, 0.5H), 6.60-6.90 (m, 3H), 7.10-7.50 (m, 4H), 7.50-7.80 (m, 2H); retention time on analytical HPLC: 10.46 min; LC-MS: m/z=523 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([OH:23])=O.S(Cl)(Cl)=O.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:23]
Reactant: C1COCCN1
Reactant: COc1cccc(-c2ccc3c(C(=O)O)c(OC)ccc3c2)c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COc1cccc(-c2ccc3c(C(=O)N4CCOCC4)c(OC)ccc3c2)c1
Temperature: 0 °C

Procedure:
2-Methoxy-6-(3-methoxyphenyl)-1-naphthoic acid (200 mg, 0.65 mmol, 1 eq) is boiled under reflux with 5 ml of thionyl chloride under a nitrogen atmosphere for 30 min according to method E. The residue is dissolved in dry THF and added to 1 ml of morpholine cooled at 0° C. The reaction mixture is boiled under reflux over night. After the solvent has been removed on a rotary evaporator, purification is effected by column chromatography with dichloromethane/methanol 95/5 as the eluent. Characterization of the compound was not effected. The raw product was directly employed for ether cleavage.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8](OS(C)(=O)=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[N:16]([CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)=[N+:17]=[N-:18]
Reactant: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC1CCC2(CC1)OCCO2
Temperature: 100 °C
Reaction time: 20 h
Yield: 100.9 %

Procedure:
A mixture of methanesulfonic acid 1,4-dioxa-spiro[4.5]dec-8-yl ester (2.80 g, 11.9 mmol) and sodium azide (3.86 g, 59.3 mmol) in 50 mL of dry DMF was stirred for 20 h at 100° C. under nitrogen. The final mixture was cooled to room temperature dilute with brine and extracted with three portions of ether. The organic portions were combined, dried over Na2SO4 and concentrated to give 8-azido-1,4-dioxa-spiro[4.5]decane (2.2 g, 100%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:15].[CH:16]([C:18]([CH2:20][CH3:21])=[O:19])=[CH2:17].C[O-].[Na+]>CO.CCOC(C)=O>[OH:1][CH2:2][CH2:3][C:4]1([CH2:17][CH2:16][C:18](=[O:19])[CH2:20][CH3:21])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:15]
Reactant: C=CC(=O)CC
Reactant: COc1ccc2c(c1)CC(CCO)C2=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(=O)CCC1(CCO)Cc2cc(OC)ccc2C1=O
Temperature: 60 °C
Yield: 93 %

Procedure:
A solution of 2-(2-hydroxyethyl)-5-methoxy-1-indanone (105 mg, 0.51 mmol) in methanol (2.0 mL) at room temperature was treated with ethyl vinyl ketone (EVK, 0.102 mL) and 0.5M sodium methoxide in methanol (0.204 mL, 0.1 mmol). The mixture was stirred in a capped flask and heated in an oil bath at 60° C. for 8 hours. After cooling, the reaction mixture was diluted with EtOAc (25 mL), washed with 0.2N HCl (15 mL), water (15 mL), and brine (15 mL), dried over MgSO4, filtered, and evaporated under vacuum to afford 2-(2-hydroxyethyl)-5-methoxy-2-(3-oxopentyl)-1-indanone (138 mg, 93% yield) as an oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:7][N:6]=[C:5]([C:8]([Cl:11])([Cl:10])[Cl:9])[N:4]=1.C(N(CC)CC)C.[Cl:19][C:20]([Cl:24])([Cl:23])[S:21]Cl>C1C=CC=CC=1>[CH3:1][N:2]([S:21][C:20]([Cl:24])([Cl:23])[Cl:19])[C:3]1[S:7][N:6]=[C:5]([C:8]([Cl:11])([Cl:9])[Cl:10])[N:4]=1
Reactant: CNc1nc(C(Cl)(Cl)Cl)ns1
Reactant: ClSC(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(SC(Cl)(Cl)Cl)c1nc(C(Cl)(Cl)Cl)ns1
Yield: 23 %

Procedure:
To a 3-neck flask equpped with condenser, thermometer and stirring bar was added 11.6 g (0.05 mole) 5-methylamino-3-trichloromethyl-1,2,4- thiadiazole, 5.1 g (0.05 mole) triethylamine and 150 milliliters of benzene. After 9.3 g (0.05 mole) trichloromethane-sulfenyl chloride was added, the reaction mixture was heated at reflux for 20 hours and filtered hot. The filtrate was evaporated under vacuum to give a beige solid which was refluxed in 400 milliliters of ligroin and filtered. The ligroin was cooled, filtered and the filtrate evaporated to 20 milliliters and filtered. The resulting solid was recrystallized again from ligroin to obtain 4.4 g (23% yield) of product; mp=106° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:21][NH:22][C:23]([CH3:36])([CH3:35])[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)[CH2:3][O:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1C=CC(C#N)=CC=1)[CH3:6].[OH-].[K+].O.[C:40](O)(=O)[CH2:41][C:42]([CH2:47][C:48](O)=O)([C:44]([OH:46])=[O:45])O>C(O)CO>[OH:1][C@H:2]([CH2:21][NH:22][C:23]([CH3:35])([CH3:36])[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)[CH2:3][O:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:40]=[CH:41][C:42]([C:44]([OH:46])=[O:45])=[CH:47][CH:48]=1)[CH3:6]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC(OC[C@H](O)CNC(C)(C)Cc1ccc2ccccc2c1)c1ccccc1-c1ccc(C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CC(OC[C@H](O)CNC(C)(C)Cc1ccc2ccccc2c1)c1ccccc1-c1ccc(C(=O)O)cc1
Temperature: 160 °C
Reaction time: 8 h

Procedure:
2′-[1-[(2R)-2-Hydroxy-3-[[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino]propoxy]ethyl]biphenyl-4-carbonitrile (1.0 g) obtained in Example 7, Step 2 was dissolved in ethylene glycol (15 ml). Potassium hydroxide (2.76 g) was added and the mixture was stirred overnight at 160° C. The reaction mixture was allowed to return to room temperature, a small amount of water was added and 10% aqueous citric acid was added to adjust the mixture to pH 4-5. The precipitated solid was collected by filtration to give the title compound (924 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH2:24][CH3:25])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:26][N:27]1[C:31]([C:32](Cl)=[O:33])=[CH:30][C:29]([CH3:35])=[N:28]1.[OH-].[Na+]>CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([CH2:24][CH3:25])=[C:2]([NH:1][C:32]([C:31]5[N:27]([CH3:26])[N:28]=[C:29]([CH3:35])[CH:30]=5)=[O:33])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: CCc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1cc(C)nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a solution of N-[6-(3-amino-4-ethylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (202 mg, 0.60 mmol) in N-methylpyrrolidone (3 mL) was added 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (143 mg, 0.90 mmol), and the mixture was stirred at room temperature for 8 hr. A 1N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→80/20) and recrystallized from a mixed solvent of ethyl acetate/diisopropyl ether to give the title compound (167 mg, yield 61%) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8]([O:12][C:13](=[O:16])[NH:14][NH2:15])([CH3:11])([CH3:10])[CH3:9]>O>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][NH:15][NH:14][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:16])[CH3:7]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)CBr
Solvent: O
Product: CCOC(=O)CNNC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Ethyl bromoacetate 3 (6.97 mL, 62.8 mmol) was added to a stirred solution of tert-butylcarbazate 2 (24.9 g, 188.6 mmol) in water (25 mL) at room temperature. The mixture was stirred for 30 min. Water layer was then extracted with ethyl acetate (3×). Ethyl acetate extracts were pooled together and washed with brine. Ethyl acetate was evaporated under vacuum to get crude product which was purified by flash column chromatography using hexane:ethyl acetate (70:30) as an eluent (yield 70%). 1H NMR (500 MHz, CDCl3) 1.28 (3H, CH2—CH3, t), 1.45 (9H, C—CH3, s), 3.64 (2H, NH—CH2—CO, s), 4.20 (2H, CH2CH3, q); MS Anal. Mol. Wt. 218.25 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:32].Br[C:34]1[CH:35]=[C:36]([N:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[C:45]([N:50]([CH3:52])[CH3:51])[CH:46]=3)[C:41]2=[O:53])[CH:37]=[CH:38][CH:39]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:51][N:50]([CH3:52])[C:45]1[CH:46]=[C:47]2[C:42](=[CH:43][CH:44]=1)[C:41](=[O:53])[N:40]([C:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[O:25])=[CH:20][N:19]=4)[C:3](=[O:32])[N:2]([CH3:1])[CH:7]=3)[CH:35]=1)[CH:49]=[CH:48]2
Reactant: CN(C)c1ccc2c(=O)n(-c3cccc(Br)c3)ccc2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CN(C)c1ccc2c(=O)n(-c3cccc(-c4cc(Nc5ccc(C(=O)N6CCOCC6)cn5)c(=O)n(C)c4)c3)ccc2c1
Temperature: 100 °C
Yield: 60 %

Procedure:
To 1-Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (58 mg, 0.13 mmol), 2-(3-Bromo-phenyl)-6-dimethylamino-2H-isoquinolin-1-one (45 mg, 0.13 mmol), potassium phosphate (56 mg, 0.26 mmol), 2-(dicyclohexylphoshphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (3.7 mg, 0.0078 mmol), and bis(dibenzylidineacetone)palladium(0) (2.2 mg, 0.0038 mmol) was added 4 mL of degassed 1:3 water/n-butanol. The headspace of the vessel was evacuated and backfilled with argon 4 times. This was heated at 100° C. for 2 hours. This was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by preparative TLC (5% methanol/dichloromethane) to yield 6-Dimethylamino-2-(3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one (45 mg, 0.078 mmol). MS (ESI) 577.1 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH:6]([CH3:10])[C:7](Br)=[O:8].[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][C:12]1=[O:20]>C(=S)=S>[Br:5][CH:6]([CH3:10])[C:7]([C:18]1[CH:17]=[CH:16][C:15]2[S:11][C:12](=[O:20])[NH:13][C:14]=2[CH:19]=1)=[O:8]
Reactant: O=c1[nH]c2ccccc2s1
Reactant: CC(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(Br)C(=O)c1ccc2sc(=O)[nH]c2c1
Temperature: 0 °C
Yield: 85.3 %

Procedure:
To a suspension of aluminum chloride (91.8 g) in carbon disulfide (200 ml) was added 2-bromopropionyl bromide (50 g) and 2-benzothiazolinone (20 g) and the resulting solution was refluxed for 6 hours with stirring. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo to give a residue, which was washed with diisopropyl ether and recrystallized from a mixture of ethyl acetate and diethyl ether to give 5-(2-bromopropionyl)-2-benzothiazolinone (32.3 g).
Reaction SMILES: [CH:1]1([N:4]2[C:8]([O:9][CH:10]([C:12]3[N:13]=[N:14][N:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19](I)[CH:18]=4)[N:16]=3)[CH3:11])=[N:7][N:6]=[C:5]2[C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH2:3][CH2:2]1.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH:1]1([N:4]2[C:5]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[N:6][N:7]=[C:8]2[O:9][CH:10]([C:12]2[N:13]=[N:14][N:15]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[C:30]#[N:31])[N:16]=2)[CH3:11])[CH2:3][CH2:2]1
Reactant: CC(Oc1nnc(-c2ccncc2)n1C1CC1)c1nnn(-c2cccc(I)c2)n1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(Oc1nnc(-c2ccncc2)n1C1CC1)c1nnn(-c2cccc(C#N)c2)n1

Procedure:
The title compound is prepared from 4-(4-cyclopropyl-5-{1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4H-[1,2,4]triazol-3-yl)-pyridine (1 mmol), zinc cyanide (1.1 mmol), palladium (0) tetrakis-triphenylphosphine (0.05 mmol) in DMF (5 mL) at 80° C. overnight.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=1.[OH-].[K+]>C(O)C.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=1
Reactant: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
To a stirred solution of ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (38.0 g, 106.741 mmol) in ethanol (200 mL) and water (100 mL) was added KOH (23.9 g, 426.964 mmol) at room temperature. The mixture was stirred at RT for 4 h and after complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (50 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×150 mL) and thecombined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and evaporated in vacuo to afford 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (30.0 g, 95%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[CH3:12].[NH4+].[Cl-]>O.C(O)(C)C.[Fe]>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([NH2:9])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: Cc1c(N)cc(F)cc1Br
Temperature: 110 °C

Procedure:
To iron powder (325 mesh, 2.25 g, 40.3 mmol) in 30 ml water and 80 ml isopropanol was added commercially available 1-bromo-5-fluoro-2-methyl-3-nitro-benzene (3.04 g, 13 mmol) in 45 ml isopropanol and NH4Cl (1.46 g, 27.3 mmol). The resulting mixture was heated at 110° C. for 2 h. After evaporation of most of the isopropanol the aq solution was extracted with ethyl acetate three times. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and evaporated. The crude product was used without further purification in the next step.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]([N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=2)[C:33]([C:42]([OH:44])=O)=[CH:32]1)([CH3:30])[CH3:29].[NH2:45][C:46]1[S:47][CH:48]=[CH:49][N:50]=1>C(Cl)Cl>[S:47]1[CH:48]=[CH:49][N:50]=[C:46]1[NH:45][C:42]([C:33]1[C:34]2[C:39](=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[N:31]([CH:28]([CH3:29])[CH3:30])[CH:32]=1)=[O:44]
Reactant: Nc1nccs1
Reactant: COc1ccc2c(C(=O)O)cn(C(C)C)c2c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2c(C(=O)Nc3nccs3)cn(C(C)C)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
A solution of triphenylphosphine (219 mg, 0.84 mmol) in methylene chloride (3 mL) cooled to 0° C. was treated with N-bromosuccinimide (149 mg, 0.84 mmol). The reaction was stirred at 0° C. for 15 min. At this time, the reaction was treated with 1-isopropyl-6-methoxy-1H-indole-3-carboxylic acid (150 mg, 0.64 mmol). The reaction was stirred at 0° C. for 5 min and then was allowed to warm to 25° C. where it was stirred for 30 min. The reaction was then treated with 2-aminothiazole (148 mg, 1.48 mmol) and stirred at 25° C. for 24 h. At this time, the mixture was partitioned between water (50 mL) and ethyl acetate (50 mL) and treated with a 1N aqueous hydrochloric acid solution (25 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×25 mL) and a saturated aqueous sodium chloride solution (1×25 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 1-isopropyl-6-methoxy-1H-indole-3-carboxylic acid thiazol-2-ylamide (101 mg, 50%) as tan solid: mp 182-185° C.; EI-HRMS m/e calcd for C16H17N3O2S (M+) 315.1041, found 315.1039.
Reaction SMILES: [CH3:1][C:2](=[O:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH:15][CH2:16][CH:17]([CH2:19]O)[OH:18]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[O:18][CH:17]([CH2:16][OH:15])[CH2:19][O:14]1
Reactant: OCC(O)CO
Reactant: CCCCCCCCCCCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC1(C)OCC(CO)O1
Reaction time: 24 h

Procedure:
A reactor equipped with a stirrer, reflux-condenser, thermometer and nitrogen gas inlet pipe was charged with 297 g of 2-tridecanone, 166 g of glycerol and a solvent amount of toluene, and following addition of p-toluenesulfonic acid as a catalyst, the dehydrative condensation reaction was carried out at the reflux temperature for 24 hours. The resulting crude product was washed with an aqueous solution of potassium carbonate and further with 3 portions of distilled water and finally purified by distillation under reduced pressure to provide 2-methyl-2-undecyl-4-hydroxymethyl-1,3-dioxolane.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[C:19]=1[CH3:26]>ClCCl>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[C:19]=3[CH3:26])=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Reactant: Cc1c(N)ccc(O)c1C
Solvent: ClCCl
Product: Cc1c(O)ccc(NC(=O)c2cc(NC3CCCCC3)ncn2)c1C

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-amino-2,3-xylenol (TCI), the title compound was obtained as a white solid after trituration in dichloromethane. 1H NMR (300MHz, DMSO-d6) δ [ppm] 9.91 (1H, s), 9.20 (1H, s), 8.50 (1H, s), 7.73 (1H, d, J=8.0 Hz), 7.18 (1H, d, J=8.5 Hz), 7.12 (1H, s), 6.65 (1H, d, J=8.5 Hz), 3.87 (1H, m), 2.07 (3H, s), 2.06 (3H, s), 1.91-1.61 (5H, m), 1.56-1.15 (5H, m). MS (ESI): 341.1. HPLC (Condition A): Rt 3.02 min (HPLC purity 77.8%).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].[CH3:10][N:11]([CH3:16])[C:12](=[NH:15])[CH2:13]Cl>C(O)C>[CH3:10][N:11]([CH3:16])[C:12]([CH2:13][S:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1)=[NH:15]
Reactant: Sc1nnc(S)s1
Reactant: CN(C)C(=N)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)C(=N)CSc1nnc(S)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
In 30 ml of ethanol was suspended 2.25 g of 2,5-dimercapto-1,3,4-thiadiazole, and 30 ml of 1N-sodium hydroxide solution was added to the suspension. The mixture was stirred at room temperature for 30 minutes. To the mixture was added 2.36 g of N,N-dimethylchloroacetamidine. The mixture was stirred at room temperature for an hour and concentrated under reduced pressure. The precipitating crystals were collected by filtration and washed with cold water and then a (1:1) mixture of methanol and ethyl ether to obtain 1.87 g of 2-(N,N-dimethylamidinomethylthio)-5-mercapto-1,3,4-thiadiazole as colorless crystals (mp 95°-97° C.).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])=[CH:12][CH:11]=1
Reactant: COc1ccc(C=O)cc1
Reactant: N[C@@H](CO)C(=O)O
Product: COc1ccc(CN[C@@H](CO)C(=O)O)cc1

Procedure:
The title compound was prepared from serine (29.6 g, 0.3 mmol) and p-methoxybenzaldehyde (68.0 mL, 0.6 mmol) according to Method W and was obtained as a white solid (36.2 g, 59%) that was used crude. δH (DMSO-d6) 7.37 (2H, dd, J 8.7 and 1.9 Hz), 6.93 (2H, dd, J 8.7 and 1.9 Hz), 3.99 (2H, s), 3.55 (3H, s), 3.73 (3H, m), 3.15 (1H, t, J 4.7 Hz). Not all exchangeable protons were observed.