Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([N:9]([CH:14]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[CH2:16][CH2:15]1)[CH2:10][C:11]([OH:13])=[O:12])C1C=CC=CC=1>C(O)C.[C].[Pd]>[CH3:26][O:25][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][C:20]=1[O:23][CH3:24])[CH:14]([NH:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:15][CH2:16]2
Reactant: COc1cc2c(cc1OC)C(N(CC(=O)O)Cc1ccccc1)CC2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1OC)C(NCC(=O)O)CC2
Yield: 85.9 %

Procedure:
N-Benzyl-N-(5,6-dimethoxy-1-indanyl)glycine hydrochloride (14 g) is dissolved in 300 ml of ethanol, 3.0 g of 5% palladium-carbon is added and catalytic reduction is carried out at ordinary temperature and pressure. After absorption of the calculated amount of hydrogen, the catalyst is filtered off, and the ethanol is distilled off under reduced pressure. The residue is dissolved in 10 ml of water and adjusted to pH 7.0 with aqueous ammonia. The crystalline precipitates are collected by filtration, washed with a small amount of water, and dried, to give 8.0 g of N-(5,6-dimethoxy-1-indanyl)glycine as colorless needles. Melting point: 213°-216° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=2)[CH:19]=1)[C:5]([NH:7][C@@H:8]([C:10]1[CH:11]=[N:12][C:13]([CH3:16])=[N:14][CH:15]=1)[CH3:9])=[O:6].[NH:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[CH:17]=[C:4]([CH:3]=[C:2]([N:27]3[CH2:31][CH2:30][CH2:29][C:28]3=[O:32])[CH:19]=2)[C:5]([NH:7][C@@H:8]([C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[N:14][CH:15]=2)[CH3:9])=[O:6])=[N:21][CH:22]=1
Reactant: Cc1ccc(-c2cc(Br)cc(C(=O)N[C@H](C)c3cnc(C)nc3)c2)nc1
Reactant: O=C1CCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3cnc(C)nc3)cc(N3CCCC3=O)c2)nc1

Procedure:
Into a 5 mL microwave vial was charged (R)-3-bromo-5-(5-methylpyridin-2-yl)-N-(1-(2-methylpyrimidin-5-yl)ethyl)benzamide (20 mg, 0.05 mmol), 2-pyrrolidinone (7 mg, 0.08 mmol) xantphos (3 mg, 0.005 mmol), tris(dibenzylideneacetone)dipalladium(0) (2 mg, 0.002 mmol), cesium carbonate (50 mg, 0.1 mmol), and 1,4-dioxane (0.8 mL). The mixture was subjected to microwave irradiation at 130° C. for 10 min. The cooled mixture was diluted with 3 mL of methanol and purified by reverse phase HPLC to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3([CH3:17])[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.Br[CH2:19][CH:20]1[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CS(C)=O.O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:7](=[O:12])[C:6]3([CH3:17])[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: BrCC1CC1
Reactant: CC12COCCN1c1nc(Cl)ncc1NC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC12COCCN1c1nc(Cl)ncc1N(CC1CC1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 131.7 %

Procedure:
2-Chloro-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (0.846 g, 3.32 mmol) and (bromomethyl)cyclopropane (0.672 g, 4.98 mmol) were mixed in DMSO (5 ml). Potassium carbonate (0.918 g, 6.64 mmol) was added. The mixture was stirred for 30 minutes at room temperature and then for 2 hours at 35° C. EtOAc (40 ml) was added followed by addition of water (30 ml). Aqueous phase was separated and extracted with EtOAc (2×30 ml). The combined organic phase was washed with water (2×20 ml). The organic solution was concentrated to near dryness at which point a solid had precipitated out. EtOAc (5 ml) and hexanes (20 ml) were added and the mixture was stirred for 20 minutes. The solid was collected by filtration to afford 1.35 g product as a white solid. Concentration and crystallization of mother liquor afforded another 0.28 g of compound as second crop. 1H NMR (400 MHz, CDCl3) δ=0.34 (m, 2H), 0.46 (m, 2H), 1.13 (m, 1H), 1.39 (s, 3H), 3.21 (m, 1H), 3.55 (m, 1H), 3.66 (d, 1H), 3.77 (m, 1H), 3.85-4.02 (m, 4H), 8.20 (s, 1H)
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:31])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:30]=[CH:29][C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=3)[CH:20]=2)[C:16]=1Cl)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[C:36]([CH3:43])=[C:37]2[C:42]=1[O:41][CH2:40][CH2:39][CH2:38]2.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:31])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:30]=[CH:29][C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=3)[CH:20]=2)[C:16]=1[C:35]1[C:36]([CH3:43])=[C:37]2[C:42](=[C:33]([F:32])[CH:34]=1)[O:41][CH2:40][CH2:39][CH2:38]2)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1Cl
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cc(F)c2c1CCCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1-c1cc(F)c2c(c1C)CCCO2
Temperature: 120 °C
Yield: 41.6 %

Procedure:
A mixture of (S)-methyl 2-(tert-butoxy)-2-(7-chloro-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (50 mg, 0.113 mmol), 2-(8-fluoro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (36.4 mg, 0.124 mmol) and 2M Na2CO3 (0.113 mL, 0.226 mmol) in DMF (1.5 mL) was added tetrakis(triphenylphosphine)pallafium(0) (13.07 mg, 0.011 mmol) and the mixture was subjected to microwave heating at 120° C. for 1 h. The mixture was then filtered and purified by prep HPLC to afford atrope isomer 1 (major, first eluting): (2S)-methyl 2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (27 mg, 0.047 mmol, 41.7% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ: 7.56 (d, J=7.9 Hz, 1H), 7.52 (s, 1H), 7.09 (d, J=7.9 Hz, 1H), 6.92 (d, J=10.7 Hz, 1H), 6.84 (s, 1H), 5.03 (s, 1H), 4.41-4.32 (m, 2H), 3.66 (s, 3H), 2.88-2.78 (m, 6H), 2.77 (s, 3H), 2.26-2.17 (m, 2H), 1.86 (s, 3H), 1.85-1.79 (m, 4H), 1.19 (s, 9H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:6]2)=O.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@:25]([OH:40])([C@H:32]([S:34][CH:35]([CH2:38][OH:39])[CH2:36][OH:37])[CH3:33])[CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@@:25]([OH:40])([CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)[C@H:32]([S:34][C@@H:35]1[CH2:36][O:37][C@@H:1]([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:6]3)[O:39][CH2:38]1)[CH3:33]
Reactant: COC(=O)c1ccc2cc(C=O)ccc2c1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2cc([C@H]3OC[C@H](S[C@H](C)[C@](O)(Cn4cncn4)c4ccc(F)cc4F)CO3)ccc2c1
Temperature: 0 °C

Procedure:
A solution of methyl 6-formyl-2-naphthalenecarboxylate (227 mg, 1.06 mmol) obtained in example 3 (2), (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (381 mg, 1.06 mmol) and p-toluenesulfonic acid monohydrate (363 mg, 1.91 mmol) in anhydrous tetrahydrofuran (50 ml) was concentrated at room temperature using a rotary evaporator under reduced pressure and then using a vacuum pump. A solution of the residue in anhydrous tetrahydrofuran (40 ml) was concentrated according to the procedure described above. The same procedure was repeated twice. A solution of the resulting residue in tetrahydrofuran (50 ml) was poured into a saturated aqueous sodium hydrogencarbonate solution cooled to 0° C. with stirring. The mixture was extracted with ethyl acetate and the organic layer was washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The oily residue was chromatographed on a silica gel column using ethyl acetate-hexane (1:2) as the eluant to afford methyl 6-[trans-5-[((1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-2-naphthalenecarboxylate (trans isomer, 331 mg, yield 56%) as a white solid, and then using ethyl acetate-hexane (3:1) as the eluant to afford methyl 6-[cis-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-2-naphthalenecarboxylate (cis isomer, 77 mg, yield 14%) as a colorless oil. The trans isomer was recrystallized from ethyl acetate-hexane to give white fluffy crystals.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.COCCOC>[C:16]1([C:2]2[C:3]3[C:8]([CH:9]=[C:10]4[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1c2ccccc2cc2ccccc12
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 98.3 %

Procedure:
25.7 g (100 mmol) of 9-bromoanthracene, 12.8 g (105 mmol) of phenylboronic acid, 233 mg (1.0 mmol) of palladium acetate(II), and 913 mg (3.0 mmol) of tri(o-tolyl)phospine were put into a 500-mL three-neck flask and nitrogen substitution was carried out. Then, 100 mL of ethylene glycol dimethyl ether and 75 mL (190 mmol) of a sodium carbonate aqueous solution (2.0 mol/L) were added thereto, and the reaction mixture was stirred at 90° C. for 5 hours. After the reaction, the reaction mixture was subjected to suction filtration to collect a precipitated solid. The obtained solid was dissolved into toluene, and the resulting solution was subjected to suction filtration through Florisil, celite, and then alumina. The filtrate was washed with water and saturated saline, and then an organic layer was dried with magnesium sulfate. This mixture is naturally filtrated, and the filtrate was condensed to obtain 25.0 g of a light-brown solid that was a target matter with the yield of 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[OH:23])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([OH:34])=[O:33].C[O-].[Na+:37]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH:22]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[OH:23])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O-:34])=[O:33].[Na+:37]
Reactant: O=C(NCC(O)c1ccc(Cl)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(NCC(O)c1ccc(Cl)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of 6-chloro-7-(4-(2-(4-chlorophenyl)-2-hydroxyethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.046 g, 0.092 mmol) in methanol (1 ml) was added 0.5M sodium methanolate in methanol (0.18 ml, 0.092 mmol), and the reaction was stirred at ambient temperature for 16 hours. It was concentrated, taken up in dichloromethane and hexanes, and concentrated again to yield 46 mg of the title compound (96% yield). MS (apci) m/z=501.8 (M−Na+2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][N:28]1[C:36]2[C:31](=[C:32]([CH3:40])[C:33](B(O)O)=[CH:34][CH:35]=2)[CH:30]=[N:29]1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:33]5[C:32]([CH3:40])=[C:31]6[C:36](=[CH:35][CH:34]=5)[N:28]([CH3:27])[N:29]=[CH:30]6)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1c(B(O)O)ccc2c1cnn2C
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc6c(cnn6C)c5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 1,4-dimethyl-indazole-5-boronic acid following a procedure analogous to that described for Intermediate 6. LC (method 10): tR=0.88 min; Mass spectrum (ESI+): m/z=503 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:15])[CH2:11][CH2:12][C:13]#[CH:14].[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:10](=[O:15])[CH2:11][CH2:12][C:13]#[CH:14])[C:17](=[O:16])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C#CCCC(=O)Nc1ccc(F)cc1F
Product: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1ccc(F)cc1F
Yield: 99.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 34(B), from N-(2,4-difluorophenyl)pent-4-ynamide (630 mg, 3.01 mmol) and (BOC)2O (789 mg, 3.61 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, 100% DCM as eluent) to afford 924 mg of tert-butyl 2,4-difluorophenyl(pent-4-ynoyl)carbamate as a colorless oil (Yield: 99%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C:11]2[CH:37]=[CH:36][C:14]([CH2:15][C@H:16]3[CH2:20][CH2:19][C@H:18]([C@H:21]([OH:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]3C(OC(C)(C)C)=O)=[CH:13][C:12]=2[Br:38])=[O:9])[N:6]=1.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl.C(#N)C.O.CO>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C:11]2[CH:37]=[CH:36][C:14]([CH2:15][C@H:16]3[CH2:20][CH2:19][C@H:18]([C@H:21]([OH:28])[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:17]3)=[CH:13][C:12]=2[Br:38])=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(NC(=O)Cc3csc(N)n3)c(Br)c2)CC[C@@H]1[C@H](O)c1ccccc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Nc1nc(CC(=O)Nc2ccc(C[C@H]3CC[C@H]([C@H](O)c4ccccc4)N3)cc2Br)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of 75 mg (0.124 mmol) of tert-butyl (2R,5R)-2-(4-{[(2-amino-1,3-thiazol-4-yl)acetyl]amino}-3-bromobenzyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-1-carboxylate (from Step A, Example 313) in 2.0 mL DCM was added 1.0 mL TFA and the reaction mixture stirred at room temperature for 2 h. Azeotrop with toluene (2×) to excess acid. The residue was then taken up in acetonitrile/water/MeOH (9:1:1) and purified on the Gilson HPLC eluting with a 10-90% gradient of acetonitrile/water with 0.05% TFA buffer. The fractions containing the product were combined, frozen, and lyophilized to give a white foam (56 mg, 90%). m/z (ES) 501 (M)+ and 503 (M+2)+, also 523 (MNa)+ and 525 (MNa+2)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CN=CC=2)C=C[C:22]=1C(O)=O.O.ON1C2C=CC=CC=2N=N1.C(N)C1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC>CCOC(C)=O.CN(C=O)C.C1COCC1>[CH3:22][C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:1][NH:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1)=[O:10]
Reactant: O=C(NCc1ccccc1)c1ccc2cnccc2n1
Reactant: O=C(O)c1ccc2cnccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: NCc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccccc1CNC(=O)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
compound #2 N-benzyl-2-[1,6]naphthyridinecarboxamide To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol), 1-hydroxybenzo-triazole hydrate (42.7 mg, 0.316 mmol), benzylamine (45 mg, 0.42 mmol) in anhy. THF (5 ml) at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60.6 mg, 0.316 mmol). The resulting mixture was allowed to stir at RT. After 20 min, DMF (2 ml) was added to the reaction mixture and the mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum and the resulting residue was redissolved in CH2Cl2 (100 ml). The organic layer was washed with aq. NaHCO3, dried over anhy. MgSO4, and concentrated to give the crude mixture. Chromatography of the crude (Hex: EtOAc=1:1 to pure EtOAc) afforded desired product as white solid (97 mg, 99%): m.p. 113-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][CH2:6][CH:7]1[CH2:12][N:11]([CH:13]([CH3:19])[C:14](OCC)=[O:15])[C:10](=O)[CH2:9][O:8]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][CH2:6][CH:7]1[CH2:12][N:11]([CH:13]([CH3:19])[CH2:14][OH:15])[CH2:10][CH2:9][O:8]1
Reactant: CCOC(=O)C(C)N1CC(COc2cccc(Cl)c2)OCC1=O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC(CO)N1CCOC(COc2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.3 %

Procedure:
A solution of 1.50 g of ethyl 2-[6-(3-chlorophenoxymethyl)-3-oxomorpholin-4-yl]propionate in 10 ml of anhydrous tetrahydrofuran was added dropwise to a suspension of 0.51 g of lithium aluminum hydride in 20 ml of anhydrous tetrahydrofuran, whilst ice-cooling. The mixture was stirred at room temperature for 2.5 hours, after which excess lithium aluminum hydride was decomposed by adding sodium sulfate decahydrate to the mixture. Insolubles were then removed from the reaction mixture by filtration with the help of a Celite (trade name) filter aid, and the solvent was removed from the filtrate by evaporation under reduced pressure, to give 0.97 g of the title compound having an Rf value of 0.19 (on silica gel thin layer chromatography, using a 3:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[OH-].[Na+].[Br:11][CH2:12][C:13](Cl)=[O:14]>ClCCl>[Br:11][CH2:12][C:13]([NH:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1)=[O:14]
Reactant: O=C(Cl)CBr
Reactant: Cc1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cccc(NC(=O)CBr)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a slurry of m-toluidine (15.5 mL, 140 mmol) in a 2N aqueous solution of sodium hydroxide (75 mL) was added dropwise a solution of bromoacetyl chloride (11.6 mL, 140 mmol) in dichloromethane (50 mL) and the reaction mixture was stirred at room temperature for about 30 min. The layers were separated and the organic layer was washed with 1N aqueous hydrochloric acid, dried (MgSO4), filtered and concentrated under vacuum. The residue was triturated twice from dichloromethane/hexane (1:4) to provide 2-bromo-N-m-tolyl-acetamide. MS (DCI-NH3): m/z 245, 247 (M+NH3)+.
Reaction SMILES: [OH:1][CH:2]([C@@H:14]([NH:19][C:20](=[O:36])[O:21][CH2:22][C:23]1([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25][CH2:24]1)[CH2:15][CH2:16][CH2:17][CH3:18])[C:3](=[O:13])[NH:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].OC([C@@H](NC(=O)OCC1(CCC2C=CC=CC=2)CCC1)CCCC)C(=O)N[C@@H](C1C=CC=CC=1)C>>[O:13]=[C:3]([NH:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])[C:2]([C@@H:14]([NH:19][C:20](=[O:36])[O:21][CH2:22][C:23]1([CH2:27][CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:24][CH2:25][CH2:26]1)[CH2:15][CH2:16][CH2:17][CH3:18])=[O:1]
Reactant: CCCC[C@H](NC(=O)OCC1(CCCc2ccccc2)CCC1)C(O)C(=O)N[C@H](C)c1ccccc1
Agent: CCCC[C@H](NC(=O)OCC1(CCc2ccccc2)CCC1)C(O)C(=O)N[C@H](C)c1ccccc1
Product: CCCC[C@H](NC(=O)OCC1(CCCc2ccccc2)CCC1)C(=O)C(=O)N[C@H](C)c1ccccc1

Procedure:
[1-(3-phenylpropyl)cyclobutyl]methyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate was prepared as in example 6c except that [1-(3-phenylpropyl)cyclobutyl]methyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate was substituted for [1-(2-phenylethyl)cyclobutyl]methyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate. M.P.=91-93° C. Elemental analysis: Theory; C=73.14%, H=8.18%, N=5.69%. Found; C=72.81%, H=8.22%, N=5.82%. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J=8 Hz, 1H), 7.45 (d, J=8 Hz, 1H), 7.11-7.26 (m, 10H), 4.91 (qnt, J=8 Hz, 1H), 4.70 (m, 1H), 3.85 (s, 2H), 2.50 (m, 2H), 1.55-1.74 (m, 6H), 1.13-1.45 (m, 13H), 0.74 (t, J=7 Hz, 13H). ES-LCMS m/z 515 (M+Na). HRMS C30H40N2O4 m/z 515.2886 (M+Na)Cal; 515.2891 (M+Na)Obs.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][CH:27]=2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)[C:22]1[CH:23]=[N:24][C:25]([C:28]([F:30])([F:31])[F:29])=[N:26][CH:27]=1)=[O:6]
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: NCC(c1ccc(F)cc1)c1cnc(C(F)(F)F)nc1
Product: O=C(NCC(c1ccc(F)cc1)c1cnc(C(F)(F)F)nc1)c1c(F)cccc1Cl

Procedure:
From 2-chloro-6-fluorobenzoic acid and 2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=442.0, tR (minutes, Method F)=2.99
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](Cl)(=O)C(Cl)=O.CN(C=O)C.Cl.CNOC>ClCCl.C(N(CC)CC)C>[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:9])[CH3:10]
Reactant: O=C(O)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: CNOC
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccccc1

Procedure:
Scheme 8 depicts synthesis of 2-amino-4-aryl thiazoles of the formula (46) (wherein R4, R5, R6, R7, R8 and R9 are as defined above) which is prepared from acetophenones of the formula (45) using known approaches. Certain di- and tri-substituted acetophenones were not commercially available and they were prepared from the corresponding benzoic acid derivative of formula (41) in three steps. Thus, acid of formula (41) was converted to the corresponding acid chloride of formula (42) using oxalyl chloride in the presence of catalytic amounts of DMF in dry dichloromethane. The acid chloride of formula (42) was converted to corresponding Weinerb amide of formula (44) by treating with N,O-dimethylhydroxylamine hydrochloride of formula (43) in the presence of a suitable base such as triethylamine. The addition of alkyl magnesium iodide to Weinreb amide of formula (44) afforded acetophenone derivative of formula (45).