Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:36]=[CH:35][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=O.Cl.[CH3:38][O:39][CH2:40][CH2:41][O:42][CH:43]1[CH2:46][NH:45][CH2:44]1>>[CH3:38][O:39][CH2:40][CH2:41][O:42][CH:43]1[CH2:46][N:45]([CH2:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]#[C:10][C:11]3[CH:12]=[CH:13][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][O:28]4)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:35][CH:36]=3)=[CH:7][CH:8]=2)[CH2:44]1
Reactant: COCCOC1CNC1
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Agent: Cl
Product: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(CN3CC(OCCOC)C3)cc2)cc1

Procedure:
From (2S)-2-[{4-[(4-formylphenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (0.12 g) as obtained in Example 16-(1) and 3-(2-methoxyethoxy)azetidine hydrochloride (60 mg), (2S)-2-[{4-[(4-{[3-(2-methoxyethoxy)azetidin-1-yl]methyl}phenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (yellow oil) was obtained (0.10 g, 69%) in the same manner as in Example 16-1-(3).
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[CH:23](OC(N1C=CN=C1)=S)[CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1>C1C=CC=CC=1>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(OC(=S)n2ccnc2)c2nc3ccccc3s2)C1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC(Cc2nc3ccccc3s2)C1
Reaction time: 0.03 h
Yield: 80 %

Procedure:
1.15 g (4.36 mmol) of tributyltin hydride, 53.71 mg (0.33 mmol) of α,α′-azoisobutyronitrile and 1.0 g (2.18 mmol) of tert-butyl 3-[benzothiazol-2-yl(imidazole-1-carbothioyloxy)methyl]-piperidine-1-carboxylate were dissolved successively in 10 ml of benzene at room temperature. After 2 min with stirring, a vacuum was applied, and the mixture was degassed for 2 min. This operation was repeated. The reaction mixture was subsequently stirred under reflux for 45 min. Conventional work-up gave 0.58 g of tert-butyl 3-benzothiazol-2-ylmethylpiperidine-1-carboxylate; HPLC/MS (M+H)+=333 as oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([OH:15])[C@@H:5]([N:12]=[N+]=[N-])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:16])[C@H:4]([OH:15])[C@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH2:12]
Reactant: COC(=O)[C@H](O)[C@@H](N=[N+]=[N-])c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@H](O)[C@@H](N)c1ccccc1

Procedure:
The (2R,3S)-3-azido-2-hydroxy-3-phenylpropionic acid methyl ester (1, 0.5 g) is hydrogenated over 10% palladium on carbon (0.1 g) in ethanol at atmospheric pressure for 1 hour. The reaction is filtered and evaporated to yield the desired amine. Mp 106-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17].P(Cl)(Cl)Cl.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=[C:14]([C:13]([F:12])([F:25])[F:26])[CH:15]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Temperature: 25 °C
Yield: 85.5 %

Procedure:
A mixture of 5-chlorosalicylic acid(6.90 g, 40 mmol), 3,5-bis(trifluoromethyl)aniline(9.16 g, 40 mmol), phosphorus trichloride(1.74 mL, 20 mmol) and toluene(80 mL) was refluxed for 3 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate (240 mL). After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (13.12 g, 85.5%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([OH:13])=[O:12].[N+](=[CH2:17])=[N-]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:13][CH3:17])=[O:12]
Reactant: COC(=O)/C=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: C=[N+]=[N-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)/C=C/[C@H]1[C@@H](C(=O)OC)C1(C)C

Procedure:
Using the procedure of Example 7, 1.26 g of (1R,cis) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylic acid and 12.7 ml of 0.5 M/l of diazomethane in methylene chloride were reacted to obtain 0.678 g of methyl (1R,cis) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =-4°±2° (c=0.6% in chloroform).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([O:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[CH3:15])=[O:6])[CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[CH3:3][C:2]([CH3:16])([O:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:10][C:9]=1[CH3:15])=[O:6])[CH3:1]
Reactant: Cc1cc(O)ccc1NC(=O)OC(C)(C)C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(NC(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
To a 200 mL round bottomed flask with a stirring bar, and an argon inlet was added 4-(1,1-dimethylethoxycarbonyl)amino-3-methylphenol (5.00 g, 22.39 mmol), Cs2CO3 (14.59 g, 44.78 mmol), DMF (50 mL), and ethyl bromoacetate (2.61 mL, 23.51 mmol). This mixture was stirred vigorously at ambient temperature for 24 h. The mixture was filtered through a frit and the DMF was removed under high vacuum. The residue was dissolved in EtOAc (300 mL) and washed with H2O (2×) and brine (1×). Drying (MgSO4), filtration, and removal of the solvent in vacuo gave a solid. This material was triturated with 5% Et2O-hexane, the solid was collected by filtration and dried in vacuo to give 5.40 g (78%) of ethyl 4-(1,1-dimethylethoxycarbonyl)amino-3-methylphenoxyacetate as a white, crystalline solid.
Reaction SMILES: CN(C)C=O.O=[CH:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:11]([O:12][CH3:13])[C:9]=1[OH:10].Cl[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:13][O:12][C:11]1[C:9]2[O:10][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7][C:8]=2[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(C=O)c1O
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cccc(OC)c2o1
Temperature: 120 °C
Reaction time: 14 h
Yield: 48 %

Procedure:
To N,N-dimethylformamide (300 ml), o-vanillin (25.2 g), ethyl chloroacetate (23.5 ml) and potassium carbonate (45 mg) were added and the resulting mixture was stirred at 120° C. for 14 hours. The reaction mixture was filtered to remove insoluble inorganic salts, and 1N hydrochloric acid (50 ml) was added to the mixture to stop the reaction. Distilled water (250 ml) was added and the resulting mixture was extracted 4 times with totally 150 ml of ethyl acetate containing 15% of n-hexane. The organic layers were washed with distilled water (100 ml) and with saturated brine (100 ml), and dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration and the solvent was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (solvent: n-hexane/ethyl acetate=10/1 to 5/1) using silica gel to obtain the desired compound (17.4 g, yield: 48%) in the form of colorless needle-shaped crystals.
Reaction SMILES: [CH2:1]([C:8]1[CH:25]=[CH:24][CH:23]=[CH:22][C:9]=1[NH:10][C@@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C@H:12]1[NH:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>C(OCC)C>[CH2:1]([C:8]1[CH:25]=[CH:24][CH:23]=[CH:22][C:9]=1[NH:10][C@@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C@H:12]1[N:20]([CH3:21])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: CN[C@@H]1Cc2ccccc2[C@H]1Nc1ccccc1Cc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)N(C)[C@@H]1Cc2ccccc2[C@H]1Nc1ccccc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
A solution of (±) trans 1-(2-benzylanilino)-2-methylaminoindane (Example 2)(0.66 g, 2.0 mmol) in dry diethyl ether (25 ml) was treated with triethylamine (0.55 ml, 4.0 mmol) and ethyl chloroformate (0.21 ml, 2.2 mmol). After stirring at room temperature for 1 h, the reaction was concentrated in vacuo and the residue was partitioned between chloroform (25 ml) and water (25 ml). The organic layer was washed with water (3×25 ml) followed by brine (25 ml), and then concentrated in vacuo to give a brown oil (0.73 g) which crystallised on cooling and was used in the next stage without purification.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[C:17]([F:30])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:32]1[CH:33]=[N:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[CH:37][N:36]=2>>[C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:32]3[CH:33]=[N:34][C:35]4[C:40]([CH:41]=3)=[CH:39][CH:38]=[CH:37][N:36]=4)=[C:17]([F:30])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: Brc1cnc2ncccc2c1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc3ncccc3c2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 444 using N-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide and 3-bromo-1,8-naphthyridine. MS (ESI): mass calcd. for C24H22FN3O2S, 435.14; m/z found, 436.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 9.46 (s, 1H), 9.23 (s, 1H), 8.89 (s, 1H), 8.85 (d, J=7.2, 1H), 8.18-8.14 (m, 1H), 7.94-7.90 (m, 1H), 7.80 (m, 1H), 7.70-7.65 (m, 1H), 7.62-7.57 (m, 1H), 7.49-7.40 (m, 3H), 1.11 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:15][C:16]([C:17]([OH:19])=O)=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:26][C@@H:27]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.O>[CH3:31][O:30][C:28](=[O:29])[C@@H:27]([NH:26][C:17]([C:16]1[N:15]=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=12)=[O:19])[C:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCn2c(-c3ccccc3)nc(C(=O)O)c2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2)C(C)(C)C
Reaction time: 0.33 h
Yield: 99.7 %

Procedure:
To a solution of 7-(tert-butoxycarbonyl)-3-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid (Intermediate 3B) (2.0 g, 5.82 mmol) in DMF was added (S)-methyl 2-amino-3,3-dimethylbutanoate (1.18 g, 8.15 mmol), followed by DIEA (2.26 g, 17.47 mmol). The resulting mixture was stirred for 20 min and TBTU (2.43 g, 7.57 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted with water and extracted with EtOAc, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate/hexanes 10-50% gradient to give Intermediate 22A 2.73 g (98%). LCMS (+ESI) m/z 470.0 [M+H]+.
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:14]3[C:18]=2[N:17]=[C:16]2[CH2:19][CH2:20][CH2:21][CH2:22][C:15]=32)C=CC=CC=1.[CH3:43][O:44][C:45]([C:47]1[O:48][C:49]([C:52](=O)[CH3:53])=[CH:50][CH:51]=1)=[O:46]>>[CH3:43][O:44][C:45]([C:47]1[O:48][C:49](/[C:52](/[CH3:53])=[CH:9]/[C:10]2[CH:11]=[CH:12][CH:13]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:14]3[C:18]=2[N:17]=[C:16]2[CH2:19][CH2:20][CH2:21][CH2:22][C:15]=32)=[CH:50][CH:51]=1)=[O:46]
Reactant: CCCCCCCCC1C=CC(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)=C2N=C3CCCCC3=C21
Reactant: COC(=O)c1ccc(C(C)=O)o1
Agent: [Br-]
Product: CCCCCCCCC1C=CC(/C=C(\C)c2ccc(C(=O)OC)o2)=C2N=C3CCCCC3=C21
Yield: 51 %

Procedure:
Using the conditions described in Example 37, the Wittig condensation reaction of 2.8 g of the phosphonium salt from Example 26 with 0.76 g of 5-acetyl-2-furancarboxylic acid methyl ester from Example 45 produced 1.0 g (52.5%) of (E)-5-[1-methyl-2-(1,2,3,4- tetrahydro-9-octyl-9H-dibenzo[b,d]pyrrol-6-yl)ethenyl]-2-furan carboxylic acid methyl ester as a yellow oil after chromatographic purification.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:11]Br.Br>C(Cl)Cl>[Br:11][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(I)cc1
Reactant: BrBr
Agent: Br
Solvent: ClCCl
Product: O=C(CBr)c1ccc(I)cc1
Yield: 80 %

Procedure:
To a clear dark solution of 1-(4-iodophenyl)ethanone (1.046 kg, 4.251 mol, 1 equiv.) in DCM (8 L) was charged (dropwise) bromine (228 ml, 4.45 mol, 1.047 equiv.) over the period of 30 to 45 min at the ambient temperature. The reaction was slightly exothermic (temperature increased to about 20˜25° C.) and released a lot of hydrogen bromide gas as the by-product. The reaction was considered as complete after 3 to 4 hrs as indicated by HPLC (typically ˜7% starting material, ˜10% di-bromo by-product, and ˜83% desired mono-bromo product, all in area % by HPLC). It was then quenched and neutralized by aqueous NaHCO3 solution wash (4 L), followed by brine wash (3 L). Upon drying over Na2SO4, it is rotavapped and solvent swapped to THF and the desired product was crystallized from THF (final volume about 2 L) at from 50° C. to 20° C. to afford the 1st crop: 340 g (98% HPLC purity); by concentrating the mother liquor to about half-volume to afford the 2nd crop: 426 g (98% HPLC purity); by further concentrating and addition of hexanes (i.e., THF/hexanes, 1:1) to afford the 3rd crop: 339 g (97+% HPLC purity). The combined crystal title compound was 1.105 kg (80% yield). 1H NMR (500 MHz, CDCl3): 7.88 (d, 2H), 7.70 (d, 2H), 4.42 (s, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]([C:21]([F:24])([F:23])[F:22])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2[C:17]#[C:18][CH2:19][CH3:20])=[O:5])C.C1COCC1.CCO.O.O[Li].O.Cl>O>[C:17]([C:10]1[CH:11]=[C:12]([Cl:16])[CH:13]=[C:14]2[C:9]=1[O:8][CH:7]([C:21]([F:22])([F:23])[F:24])[C:6]([C:4]([OH:5])=[O:3])=[CH:15]2)#[C:18][CH2:19][CH3:20]
Reactant: CCC#Cc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)OCC)=C2
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCC#Cc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 60 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To 0.768 g (2.14 mmole) of ethyl-8-but-1-ynyl-6-chloro-2-(trifluoromethyl)-2H-chromene-3- carboxylate was added 11 mL of a solvent mixture of THF/EtOH/H2O (7:2: 1) followed by 135 mg (3.22 mmole) of LiOH—H2O. The mixture was stirred at 60° C. for two hours. The mixture was concd, treated with water, and acidified with 0.5N HCl. The crude solid was purified by reverse phase chromatography to afford 0.575 g (81%) of a yellow crystalline solid: 1H NMR (CDCl3/400 MHz) 1.24 (t, 3H, J=7.2 Hz), 2.46 (q, 2H, J=7.6 Hz), 5.74 (q, 1H J=6.8 Hz), 7.16 (d, 1H, J=2.8 Hz), 7.39 (d, 1H, J=2.4 Hz), 7.81 (s, 1H); MS (ES+) 331 (M+1, 100); HRMS (ES−) m/z calcd for (C15H10O3ClF3) 329.0187, found 329.0202.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:40]5[CH:39]=[CH:38][CH:37]=[C:36]([F:35])[C:41]=5[F:42])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: OB(O)c1cccc(F)c1F
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(F)c5F)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2,3-difluoro-phenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[NH:7][C:6](=O)[NH:5][C:4]=2[CH:3]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:6]1[NH:5][C:4]2[CH:3]=[C:2]([Cl:1])[S:10][C:9]=2[S:8](=[O:12])(=[O:11])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Nc2cc(Cl)sc2S(=O)(=O)N1
Solvent: c1ccncc1
Product: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A suspension of 6-chloro-2,3-dihydro-3-oxo-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (10.75 g, 0.045 mol) in phosphorus oxychloride (100 ml) was cooled on an ice bath and dry pyridine (7.3 ml, 0.09 mol) was added dropwise at such a rate that the temperature did not exceed 10° C. The mixture was then heated at 95°-100° C. for 16 h, and cooled to room temperature. A yellow precipitate was removed by filtration, and the filtrate was concentrated in vacuo. To the residue was added 200 g of ice, and the resulting mixture was stirred for 1 h, and filtered. The isolated solid was dissolved in saturated aqueous sodium hydrogen carbonate (100 ml), and filtered to remove a small amount of insoluble material. After treatment with decolorising charcoal the filtrate was adjusted to pH 2 with 4M hydrochloric acid and the precipitate that formed was filtered, washed with water and dried to yield 5.55 g (48%) of the title compound; mp >240° C. decomp.
Reaction SMILES: [Mg].BrC(Br)C.[CH2:6]([CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:15]Br)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[C:27](=O)([O:30]C)[O:28][CH3:29]>O1CCCC1>[CH2:6]([CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:15][C:27]([O:28][CH3:29])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: COC(=O)OC
Reactant: CCCCCCCCCCC(CBr)CCCCCCCC
Agent: CC(Br)Br
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCCC(CCCCCCCC)CC(=O)OC
Reaction time: 2 h
Yield: 66.5 %

Procedure:
3 g (123.3 mmol) of magnesium was suspended in 30 ml of a dehydrated tetrahydrofuran solution under nitrogen atmosphere to activate the magnesium with dibromoethane. 120 ml of a dehydrated tetrahydrofuran solution comprising 8.0 g (22.1 mmol) of the synthesized 2-octyl-1-bromododecane was added to this solution by dropping. After dropping, the solution was stirred for two hours. The reaction mixture was cooled with ice, 2.0 ml (23.7 mmol) of dimethyl carbonate was added, and the mixture was stirred overnight at room temperature (25° C.). After filtering the reaction solution, adding diluted hydrochloric acid to the filtrate, and extracting using hexane, the solvent was evaporated under reduced pressure. The residue was distilled under the conditions of 0.15 mmHg and an oil bath temperature of 180 to 190° C. to obtain 5.0 g (14.7 mmol) of methyl 3-octyl-tridecanoate as a colorless oil. The fluidity of this compound did not decrease even when cooled to −20° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[C:18]([Cl:20])[N:17]=[C:16](Cl)[N:15]=1)[CH3:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:30]=[CH:29][C:28]([C@@H:31]([NH2:33])[CH3:32])=[CH:27][CH:26]=1.CS(C)=O.CCN(C(C)C)C(C)C>[Cl-].[Na+].O>[C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[C:18]([Cl:20])[N:17]=[C:16]([NH:33][C@H:31]([C:28]2[CH:27]=[CH:26][C:25]([O:24][C:23]([F:22])([F:34])[F:35])=[CH:30][CH:29]=2)[CH3:32])[N:15]=1)[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](N)c1ccc(OC(F)(F)F)cc1
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1cc(Cl)nc(Cl)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(Cl)cc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1ccc(OC(F)(F)F)cc1
Temperature: 85 °C

Procedure:
To a microwave vial with a stir bar was added (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one (75.0 mg, 0.224 mmol) and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine (59.7 mg, 0.247 mmol), followed by DMSO (0.9 mL) and DIEA (118 ul, 0.673 mmol). The vial was capped and the reaction mixture heated in a preheated oil bath at 85° C. for 2 hr. The mixture was diluted with brine and extracted with EtOAc two times. The combined organic phases were dried over sodium sulfate, filtered, concentrated and dried on house vacuum to afford crude (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a brown solid film, (yield assumed quantitative). LCMS m/z 503.2 (M+H)+, Rt 1.24 min.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][NH:3]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:33][O:34][NH:35][CH3:36].CCN(CC)CC>C(Cl)Cl>[CH3:33][O:34][N:35]([CH3:36])[C:8]([C:6]1[CH:5]=[CH:4][NH:3][C:2](=[O:1])[CH:7]=1)=[O:10]
Reactant: O=C(O)c1cc[nH]c(=O)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc[nH]c(=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a suspension of 2-oxo-1,2-dihydropyridine-4-carboxylic acid (8.0 g, 1.0 eq), EDCI (13.2 g, 1.2 eq) and HOBt (9.3 g, 1.2 eq) in 150 mL CH2Cl2 were added N-methoxymethanamine hydrochloride (6.8 g, 1.2 eq) and Et3N (26.2 g, 4.5 eq). The reaction mixture was stirred at rt overnight, concentrated, and purified by column chromatography to give the desired product (6.3, 60% yield). 1H NMR (400 MHz, CDCl3) δ 12.79 (s, 1H), 7.40 (d, J=6.8 Hz, 1H), 6.77 (s, 1H), 6.43 (dd, J=6.8 Hz, 1.6 Hz, 1H), 3.62 (s, 3H), 3.34 (s, 3H).