Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[S:17][C:16]=3[C:15]([S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:30])[C:3]=1[OH:31].[C:32]([O:37]C)(=[O:36])[C@H:33]([CH3:35])O.BrBr>C(Cl)(Cl)Cl>[Br:30][C:4]1[CH:5]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[S:17][C:16]=3[C:15]([S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:31][C@H:33]([CH3:35])[C:32]([OH:37])=[O:36]
Reactant: Cc1sc2c(Sc3ccccc3)c3ccccc3c(-c3cc(Br)c(O)c(Br)c3)c2c1C
Reactant: COC(=O)[C@H](C)O
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: Cc1sc2c(Sc3ccccc3)c3ccccc3c(-c3cc(Br)c(O[C@H](C)C(=O)O)c(Br)c3)c2c1C

Procedure:
Prepared from 2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenol (Example 13) and and commercially available methyl (S)-(−)-lactate according to the procedure of Example 30. White solid: mp 237-239° C.; [a]25/D=−1.99° (10.051 mg/mL, CHCl3); NMR (DMSO-d6); δ13.2 (broad s, 1H, COOH), 8.43 (d, J=8 Hz, 1H), 7.80 (s, 2H), 7.62-7.58 (m, 1H), 7.56-7.50 (m, 2H), 7.23-7.13 (m, 3H), 7.04-7.01 (m, 2H), 5.03 (quartet, J=7 Hz, 1H), 2.40 (s, 3H), 1.63 (s, 3H), 1.57 (d, J=8 Hz, 3H); MS (EI): [M+], 2 bromine isotope pattern, 640 (47%), 642 (100%), 644 (56%); Anal. calc. for C29H22Br2O3S2: C, 54.22; H, 3.45; N, 0.00. Found: C, 53.64; H, 3.33; N, 0.05.
Reaction SMILES: [OH-].[Na+].[OH-].[NH4+:4].[Cl-].[NH4+].[CH3:7][C:8]1[CH:12]=[CH:11][NH:10][C:9]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14].Cl[O-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(OCC)C.C(OCC)(=O)C.C(OC)(C)(C)C>[NH2:4][N:10]1[CH:11]=[CH:12][C:8]([CH3:7])=[C:9]1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]
Reactant: Cc1cc[nH]c1C(=O)Nc1ccccc1
Reactant: [NH4+]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: Cc1ccn(N)c1C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 105.5 %

Procedure:
In a three-necked flask it was placed aqueous solution of sodium hydroxide (32%, 95 mL, 665 mmol), ammonium hydroxide solution (8M, 31 mL, 250 mmol), ammonium chloride (10.7 g, 200 mmol) and Aliquat 336 (1.34 g, 3.3 mmol). Afterwards, a solution of 3-methyl-N-phenyl-1H-pyrrole-2-carboxamide (6.6 g, 33.2 mmol) dissolved in 140 mL diethyl ether and 70 mL methyl tert-butyl ether was added and the mixture was cooled at 0° C. affording a suspension. Over this suspension, a 10% aqueous solution of sodium hypochlorite (10%, 224 mL, 300 mmol) was added dropwise over 60 min with vigorous stirring. The reaction mixture was stirred at room temperature overnight. The reaction crude was diluted with ethyl acetate until no suspended material was observed. The layers were separated and the organic phase was washed with water and brine, dried over sodium sulphate and concentrated under reduce pressure to give 7.54 g (90% yield) of the title compound that was used in the next step without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2([CH3:23])[CH2:22][O:21]2)=[O:19])=[CH:13][C:12]=1[CH3:24])#[N:10]>>[C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:19])[C:20]([OH:21])([CH3:22])[CH2:23][O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:13][C:12]=1[CH3:24])#[N:10]
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1C#N
Reactant: Oc1ccc(F)cc1
Product: Cc1cc(NC(=O)C(C)(O)COc2ccc(F)cc2)ccc1C#N

Procedure:
N-(4-Cyano-3-methylphenyl)-3-(4-fluorophenoxy)-2-hydroxy-2-methylpropionamide was prepared as described in Example 1 starting from 4-fluorophenol and 2-methyl-oxirane-2-carboxylic acid (4-cyano-3-methylphenyl)amide. 1H NMR (DMSO-d6): 1.42 (3H, s), 2.44 (3H, s), 3.94 (1H, d, J=9.6 Hz), 4.18 (1H, d, J=9.6 Hz), 6.18 (1H, bs), 6.93 (2H, m), 7.08 (2H, m), 7.69 (1H, d, J=9.0 Hz), 7.78 (1H, dd, J=9.0 Hz and 2.1 Hz), 7.93 (1H, d, J=2.1 Hz), 10.02 (1H, s).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10]([CH3:12])C)#[N:2].Cl.[Cl:24][C:25]1[CH:26]=C([CH:29]=[CH:30][CH:31]=1)N>C(O)C>[ClH:24].[Cl:24][C:25]1[CH:26]=[C:12]([N:10]2[C:1](=[NH:2])[C:3]3[C:4]([NH:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=4)=[N:5][NH:6][C:7]=3[N:8]=[CH:9]2)[CH:29]=[CH:30][CH:31]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COc1cccc(CNc2n[nH]c(N=CN(C)C)c2C#N)c1
Agent: Cl
Solvent: CCO
Product: COc1cccc(CNc2n[nH]c3ncn(-c4cccc(Cl)c4)c(=N)c23)c1
Temperature: 10 °C

Procedure:
A mixture of 5.97 g (20 mmol) of 4-cyano-5-(dimethylamino-methyleneamino)-3-(3-methoxy-benzylamino)-pyrazole, 3.77 g (23 mmol) of 3-chloro-aniline hydrochloride and 100 ml of ethanol is heated under reflux for 36 hours. Cooling to approx. 10° C., filtering and washing the filter residue with ethanol yield title compound II; m.p. 251-253° C. (decomp.). The filtrate is concentrated by evaporation in vacuo, the oily residue is partitioned between ethyl acetate and water and the organic phase is washed with brine, dried over sodium sulfate and concentrated to a volume of approx. 25 ml using an RV, a crystalline precipitate being formed. Filtering and washing the filter residue with a small amount of ethyl acetate and diethyl ether yield title compound I (see Example 52); m.p. 194-195° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[Mg]Br.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.Br[C:26]1[CH2:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2>C1COCC1.[Cl-].[Na+].O.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]>[C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:26]1[CH2:34][C:33]2[C:28]([CH:27]=1)=[CH:29][CH:30]=[CH:31][CH:32]=2
Reactant: BrC1=Cc2ccccc2C1
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c(C2=Cc3ccccc3C2)c(C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 50.0 ml (20.0 mmol) of 0.4 M mesitylmagnesium bromide in THF, 230 mg (0.40 mmol) of Pd(dba)2, 162 mg (0.80 mmol) of PtBu3, and 3.90 g (20.0 mmol) of 2-bromo-1H-indene was stirred for 48 h at ambient temperature. Then, to the resulting mixture 200 ml of brine was added. The organic layer was separated, and the aqueous layer was extracted with 3×100 ml of ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The product was isolated by flash chromatography on Silica Gel 60 (40-63 um, d 30 mm, l 300 mm, eluent: hexanes-dichloromethane, 20:1, vol.). Yield 3.19 g (68%) of white solid.
Reaction SMILES: C(=O)(O)[O-].[Na+].O.[S:7]1[C:11]2=[CH:12][N:13]=[C:14]([C:16](=[O:18])[CH3:17])[CH:15]=[C:10]2[CH:9]=[CH:8]1.[Br:19]Br>C(Cl)(Cl)(Cl)Cl>[Br:19][C:9]1[C:10]2[C:11](=[CH:12][N:13]=[C:14]([C:16](=[O:18])[CH3:17])[CH:15]=2)[S:7][CH:8]=1
Reactant: CC(=O)c1cc2ccsc2cn1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1cc2c(Br)csc2cn1
Reaction time: 8 h
Yield: 35.9 %

Procedure:
An aqueous saturated sodium bicarbonate solution (10 ml) and water (10 ml) was added to a solution of 1-thieno[2,3-c]pyridin-5-yl-ethanone (600 mg, 3.39 mmol) in carbon tetrachloride (5 ml). Bromine (0.523 ml, 10.2 mmol) was added and the reaction was stirred overnight. The biphasic mixture was allowed to separate and the organic layer was diluted with dichloromethane (25 ml) and washed with 10% sodium sulfide (in ammonium hydroxide) (1×20 mL), and brine (1×20 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was then purified by chromatography (chromatotron, 4μ plate, 0-200% ethyl acetate in hexanes) to yield 1-(3-bromo-thieno[2,3-c]pyridin-5-yl)-ethanone as a white solid (311.3 mg, 36%). 1H NMR (250 MHz, CDCl3): δ 9.20 (s, 1H), 8.54 (s, 1H), 7.30 (s, 1H), 7.30 (s, 1H), 2.85 (s, 3H). MS [E+] 255 & 257 (M+H)+.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20](C(O)=O)[CH2:19][CH2:18]4)=[N:15][CH:16]=3)[CH2:7][CH2:6]2)[O:4]CC1.S(=O)(=O)(O)O.[OH-].[Na+]>O1CCCC1.O.CC(C)=O>[N:17]1([C:14]2[N:15]=[CH:16][C:11]([N:8]3[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]3)=[CH:12][CH:13]=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH2:19][CH2:18]1
Reactant: O=C(O)N1CCN(c2ccc(N3CCC4(CC3)OCCO4)cn2)c2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=C1CCN(c2ccc(N3CCNc4ccccc43)nc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 150-ml flask, 5.51 g of tert-butyl ester of 4-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid (intermediate 7.1) is put in 21 ml of tetrahydrofuran, 21 ml of water and 20 ml of acetone. It is cooled on an ice bath and 8.24 ml of 95% sulfuric acid is added gently. It is stirred at room temperature for 18 h. The solution is then poured into water. 5N sodium hydroxide is added to basic pH and it is extracted twice with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The raw product obtained is chromatographed on silica gel, eluting with a gradient of ternary solvents, on the one hand heptane and on the other hand heptane/ethyl acetate/methanol 4/5/1 varying from 10% to 100%. 2.39 g of 6′-(3,4-dihydro-2H-quinoxalin-1-yl)-2,3,5,6-tetrahydro-[1,3′]bipyridinyl-4-one is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH2:14][CH2:15][CH3:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:40][C:41]1[N:45]2[C:46](=[O:55])[N:47]([CH:49]3[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]3)[CH2:48][C:44]2=[CH:43][N:42]=1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:40][C:41]1[N:45]2[C:46](=[O:55])[N:47]([CH:49]3[CH2:54][CH2:53][N:52]([C:10]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:12])[CH2:51][CH2:50]3)[CH2:48][C:44]2=[CH:43][N:42]=1
Reactant: CCCCC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ncc2n1C(=O)N(C1CCNCC1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCC(NC(=O)OC(C)(C)C)C(=O)N1CCC(N2Cc3cnc(C)n3C2=O)CC1
Yield: 81.2 %

Procedure:
To a solution of 2-((tert-butoxycarbonyl)amino)hexanoic acid (0.46 g) obtained in Example 80a), HOBt (0.46 g) and WSC (0.58 g) in acetonitrile (20 ml) was added a solution of 5-methyl-2-(4-piperidinyl)-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (0.6 g), DBU (0.6 ml) and triethylamine (0.61 ml) in acetonitrile (20 ml), and mixed for 15 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in dichloromethane. The dichloromethane solution was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with basic silica gel column (ethyl acetate/methanol=10/1) to obtain the title compound as colorless powder (0.7 g, 75%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20](Br)[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:20]/[CH:21]=[CH:22]/[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Reactant: BrCC=Cc1ccccc1
Product: C(=C/c1ccccc1)\CN1CCC(c2ccc(Oc3ccccc3)cc2)CC1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and cinnamyl bromide to produce the above.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[CH:8]2)=[O:4].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16].O1CCOCC1>CCOCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:22][C:21]1[CH:24]=[CH:25][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=1)=[O:4]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc2c(ccn2C)c1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)c(Cc1ccc([N+](=O)[O-])cc1)cn2C
Temperature: 25 °C
Yield: 58.6 %

Procedure:
A solution of 1-methyl-1H-indole-5-carboxylic acid methyl ester (0.38 g, 2.0 mmol), prepared using procedures as described in Example 1, Ag2O (0.51 g, 2.2 mmol), 4-nitro-benzyl bromide (0.48 g, 2.2 mmol) and dioxane (6 mL) was heated to reflux for 25 hr, then more 4-nitro-benzyl bromide (0.48 g, 2.2 mmol) was added and the solution was heated at reflux an additional 4 days. After cooling to room temperature, the reaction mixture was diluted with ether (50 mL) and ethyl acetate (50 mL), washed with aq. NH4Cl (50 mL) and then brine (50 mL). The organic layer was dried over MgSO4, filtered and concentrated. The remaining residue was subjected to flash chromatography (ethyl acetate/hexane, 1:4) to provide of 1-methyl-3-(4-nitro-phenylmethyl)-1H-indole-5-carboxylic acid methyl ester (0.38 g, 58% yield). 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 8.16 (d, 2H, J=8.3 Hz), 7.98 (d, 1H, J=8.3 Hz), 7.45 (d, 2H, J=8.3 Hz), 7.35 (d, 1H, J=8.3 Hz), 6.90 (s, 1H), 4.25 (s, 2H), 3.94 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[N:16]=[CH:17]3)[N:21]=2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)cn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)cn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 28 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[6-(4-fluoro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.52 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (dichloromethane/MeOH) and crystallization (ethyl acetate/heptane) yielded the title compound as an off-white solid (0.13 g, 48%). MS (ISN) 462.0 [(M−H)−]; mp 260° C.
Reaction SMILES: [C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>ClCCl>[C:16]([O:9][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])(=[O:18])[CH3:17]
Reactant: C[C@H](O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
In a 25 ml nitrogen-purged flask, with exclusion of air and moisture, 8.28 mmol (1.01 g, 1.00 ml) of (S)-1-phenylethanol (Fluka, 99% ee), 12.4 mmol (1.50 equ., 983 mg, 1.00 ml) of pyridine and 15 ml of dichloromethane are charged and cooled down to 0° C. (ice bath). With stirring, 10.8 mmol (1.30 equ., 1.10 g, 1.02 ml) of acetic anhydride is added dropwise over 10 min. Within a period of 12 h, the mixture is warmed up to room temperature and successively extracted twice each with 20 ml of 1 M aqueous hydrochloric acid solution, saturated sodium hydrogencarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, separated from the desiccant by filtration and freed from solvent in a rotary evaporator. The crude product was purified by chromatography over silica gel (mobile solvent: hexane:ethyl acetate=9:1). The product fractions are combined and freed from solvent in a rotary evaporator. After drying in an oil-pump vacuum, a clear liquid remains (1.25 g, 7.62 mmol, 92%). Analytics: 1H-NMR (CDCl3, 200 MHz): δ=1.52 (d) 3J=6.6 Hz [3H], 2.06 (s) [3H], 5.94 (q) 3J=6.6 Hz [1H], 7.24-7.38 (m) [5H]; 13C-{1H}-NMR (CDCl3, 50 MHz): δ=21.4 (s), 22.2 (s), 72.3 (s), 126.1 (s), 127.9 (s), 128.5 (s), 141.7 (s), 170.3 (s); MS (EI, 70 eV, pos. ions): m/z (% rel. int.): 164 (25) [M+], 122 (77), 107 (36), 105 (69), 104 (100), 103 (24), 79 (27), 78 (27), 77 (43), 51 (24), 43 (90); EA: C: 72.95% (calc. 73.15%), H: 7.28% (calc. 7.37%); GC (Hewlett Packard 5890, 25 m fused silica, 0.25 inner diameter, 2,6-dimethyl-3-pentyl-β-CD (95% methyl-/5% phenylpolysiloxane), FID, 80° C., 4° C. min−1, 120° C. 0.2 min iso, 0.63 bar hydrogen): 99.8% ee.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][C:21](O)=[O:22])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:4]=1.[CH3:26][NH:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:26][N:27]([C:21](=[O:22])[CH2:20][C@H:17]1[CH2:18][CH2:19][C@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[NH:6][N:7]=[C:3]([C:2]([F:24])([F:25])[F:1])[CH:4]=3)=[CH:13][CH:12]=2)[CH2:15][CH2:16]1)[CH2:28][C:29]([O:31][CH3:32])=[O:30]
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Reactant: CNCC(=O)OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CN(C)C(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)n[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 20 mL scintillation vial was added the product from Example 26C (30 mg, 0.085 mmol), methyl 2-(methylamino)acetate (10.0 mg, 0.097 mmol), and N,N-dimethylformamide (0.85 mL) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (39.0 mg, 0.102 mmol) and diisopropylethylamine (30.0 μL, 0.176 mmol). Following 4 hours of stirring at room temperature, the solvent was evaporated and the residue purified over RP-HPLC to afford the title product. The NMR spectrum includes a mixture of rotamers, with the major rotamer being reported. 1H NMR (500 (MHz, DMSO-d6) δ ppm 0.98-1.20 (m, 2 H), 1.38-1.55 (m, 2 H), 1.70-1.93 (m, 5 H), 2.20-2.33 (m, 2 H), 2.78-2.88 (m, 1 H), 3.01-3.10 (m, 3 H), 3.64 (s, 3 H), 4.08 (s, 2 H), 7.03-7.19 (m, 1 H), 7.28-7.41 (m, 2 H), 7.66-7.76 (m, 2 H), 13.80-14.09 (m, 1 H); MS (ESI) m/z 438 [M+H]+.
Reaction SMILES: [F:1][C:2]1([F:15])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:4]=2[O:3]1.[Li]C(CC)C.C(O[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)(C)C.[NH4+].[Cl-].Cl>O1CCCC1.O>[F:15][C:2]1([F:1])[O:6][C:5]2[C:7]([B:25]3[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]3)=[CH:8][CH:9]=[C:10]([Si:11]([CH3:12])([CH3:14])[CH3:13])[C:4]=2[O:3]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: C[Si](C)(C)c1cccc2c1OC(F)(F)O2
Agent: Cl
Agent: [Cl-]
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc([Si](C)(C)C)c3c2OC(F)(F)O3)OC1(C)C
Temperature: -75 °C
Reaction time: 2 h

Procedure:
(2,2-Difluorobenzo[d][1,3]dioxol-4-yl)trimethylsilane (5.0 g, 22 mmol, prepared as described in Gorecka, Joanna; Leroux, Frederic; Schlosser, Manfred, European Journal of Organic Chemistry 2004, 1, 64-68) was added to a stirred solution of sec-BuLi (1.4 M; 10 mL, 14 mmol) in dry tetrahydrofuran (28 mL) cooled to −75° C. After 2 h at −75° C., 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.2 g, 23 mmol) was added, and the mixture was stirred for 90 min at −75° C. The mixture was treated with saturated NH4Cl (5 mL) and warmed to 20° C. The mixture was combined with water (75 mL), acidified with 6 M HCl and extracted with diethyl ether (100 mL). The organic phase was washed with saturated NaCl (15 mL), dried (Na2SO4) and evaporated to give the title compound (estimated purity of 60%) which was used without further purification: 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J=7.5 Hz, 1H), 7.07 (d, J=7.5 Hz, 1H), 1.36 (s, 12H), 0.33 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −49.33; EIMS m/z 356.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C1COCC1.Cl.[CH2:19]([S:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25])[CH3:20].C(=O)([O-])O.[Na+]>O>[CH2:19]([S:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([NH:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1)=[O:25])[CH3:20]
Reactant: Nc1cc(C(F)(F)F)cnc1O
Reactant: CCSc1ccccc1C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCSc1ccccc1C(=O)Nc1cc(C(F)(F)F)cnc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a mixture of 3-amino-5-trifluoromethylpyridin-2-ol (0.75 g) and THF (5 ml), 2-ethylsulfanylbenzoic acid hydrochloride (0.93 g) was added under ice-cooling, heated to room temperature, and stirred for 2 hours. After the mixture was allowed to stand overnight, the mixture was heated to 50° C., and stirred with heating for 6 hours. To the mixture, sodium hydrogen carbonate (0.35 g) was added, and stirred with heating for further 2.5 hours. After the mixture was allowed to stand, water was poured thereinto, and the precipitated solid was collected by filtration. The obtained solid was washed with water, and dried to give 1.37 g of 2-ethylsulfanyl-N-(2-hydroxy-5-trifluoromethylpyridin-3-yl)-benzamide (Compound (1B)-506).
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].CN(C)C=O.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl>[Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([Cl:23])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C(=O)O)cc(OC)c1Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-3,5-dimethoxybenzoic acid (Acta Chem. Scand., 2, 34-41, (1948)) (22.6 g, 86.6 mmol) in methylene chloride (400 mL) was added dimethylformamide (1.5 mL, 19.4 mmol). Oxalyl chloride (13.0 g, 102.0 mmol) was gradually added to the ice-cold solution, and the mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was concentrated under reduced pressure to yield crude crystals of 4-bromo-3,5-dimethoxybenzoyl chloride. To an ice-cold solution of 2-amino-2-methylpropanol (8.40 g, 94.2 mmol) in methylene chloride (100 mL) were added N,N-diisopropylethylamine (16.6 mL, 95.3 mmol) and a solution of the crude 4-bromo-3,5-dimethoxybenzoyl chloride in methylene chloride (200 mL). After the mixture was stirred at room temperature for 10 minutes, the mixture was washed successively with water, 8.0 M hydrochloric acid, a saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Thionyl chloride (47.5 mL, 651.0 mmol) was added to the residue, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture were added ice water and a 2.5 M aqueous sodium hydroxide (600 mL, 1500 mmol), and the mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized form diethyl ether-hexane to yield 2-(4-bromo-3,5-dimethoxyphenyl)-4,4-dimethyl-2-oxazoline as colorless fine needles (melting point: 172.5-174.5° C.) (20.9 g, yield: 77%).