Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)=O)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>C1COCC1>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)=[CH:9][C:10]#[N:11])[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cccc(C(=O)c2cc(OC)cc(OC)c2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Temperature: 0 °C
Yield: 95.7 %

Procedure:
To a stirred solution of cyanomethylphosphonic acid diethyl ester (1.18 ml, 7.49 mmol) in anhydrous THF (10 ml) in an ice bath was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 7.49 ml, 7.49 mmol) slowly. The mixture was stirred in rt for 40 min, before a solution of (3,5-dimethoxyphenyl)-(3-methoxyphenyl)methanone (1.02 g, 3.75 mmol) in anhydrous THF (20 ml) was added. The mixture was refluxed overnight. The solution was poured into ice water (20 ml) and the two phases were separated. The THF phase was evaporated and combined with the aqueous phase, which were then extracted with CH2Cl2 (2×40 ml), washed with water (50 ml), dried over MgSO4, filtered and concentrated in vacuo to an oil, which was purified via flash column chromatography to give 3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile as an off-white solid (1.06 g, 96%): mp, 81-83° C.; 1HNMR (DMSO-d6) δ 7.46-7.30 (m, 2H, Ar), 7.11-6.85 (m, 6H, Ar), 6.66-6.62 (m, 2H, Ar), 6.47 (t, J=1 Hz, 4H, Ar), 6.39 (s, 1H, double bond proton of one isomer), 6.38 (s, 1H, double bond proton of the other isomer), 3.78-3.73 (multiple singlets, 18H, 6OCH3), isomer ratio based on 1HNMR close to 48%:52%; 13C NMR (CDCl3) δ 163.0, 163.0, 160.9, 160.8, 159.8, 159.6, 141.0, 140.1, 138.8, 138.2, 129.8, 129.7, 122.1, 121.0, 117.8, 117.8, 116.1, 115.9, 115.0, 114.3, 107.8, 107.0, 102.3, 122.1, 122.1, 121.0, 117.8, 117.8, 116.1, 115.9, 115.0, 114.3, 107.8, 107.0, 102.3, 102.2, 95.4, 95.4, 55.6, 55.6, 55.5; Anal. Calcd. For C18H17NO3: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.10; H, 5.72; N, 4.68.
Reaction SMILES: [BrH:1].[CH3:2][O:3][CH2:4][C@H:5]([NH:30][C:31]([C:33]1[S:37][C:36]([CH3:38])=[N:35][CH:34]=1)=[O:32])[C:6]([NH:8][C@@H:9]([CH2:27][O:28][CH3:29])[C:10]([NH:12][C@@H:13]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14]([C@@:16]1([CH3:19])[CH2:18][O:17]1)=[O:15])=[O:11])=[O:7]>O1CCOCC1.C(Cl)Cl>[Br:1][CH2:18][C@:16]([OH:17])([CH3:19])[C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[C@@H:5]([NH:30][C:31]([C:33]1[S:37][C:36]([CH3:38])=[N:35][CH:34]=1)=[O:32])[CH2:4][O:3][CH3:2])[CH2:27][O:28][CH3:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Br
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@]1(C)CO1
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
Hydrobromic acid (2 eq., 0.314 mL) was added to N—((S)-3-methoxy-1-(((S)-3-methoxy-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide (1.0 g, 1.88 mmol) in dioxane (20 mL) at 0° C., the reaction allowed to warm to room temperature and stirred overnight. The mixture was diluted with DCM, washed with aqueous saturated sodium bicarbonate, brine, dried (Na2SO4) and evaporated. The residue was purified by Biotage flash column chromatography to give product as a white solid (0.722 g, 48%); 1H NMR (CDCl3): δ 8.06(s, 1H), 7.28-7.18 (m, 6H), 7.02 (d, J=7.6 Hz, 1H), 6.85 (d, J=6.4 Hz, 1H), 5.45-5.40 (m, 1H), 4.71-4.66(m, 1H), 4.53-4.48 (m, 1H), 4.20 (s, 1H), 3.85-3.75 (m, 3H), 3.57-3.52 (m, 2H), 3.44-3.39 (m, 4H), 3.31 (s, 3H), 3.23-3.18 (m, 1H), 2.94-2.89 (m, 1H), 2.75 (s, 3H), 1.18 (s, 3H); MS for C25H33BrN4O7S m/z 614 (M+H)+.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].FC(F)(F)S(O[C:35]1[CH:40]=[C:39]([CH3:41])[N:38]=[C:37]([CH3:42])[CH:36]=1)(=O)=O>>[CH3:42][C:37]1[CH:36]=[C:35]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([CH:18]=2)[CH2:16][NH:15][CH:12]2[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]2)[CH:40]=[C:39]([CH3:41])[N:38]=1
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C)n1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2cc(C)nc(C)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (400 mg, 1.02 mmol) is coupled to pyridyl triflate 91 (260 mg, 1.02 mmol) using Method B to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:15](Br)[CH3:16]>CN(C=O)C>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1)[CH3:16]
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cccc(CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
Methyl 3-hydroxyphenylacetate (132.5 g, 0.80 mole) was added dropwise to a suspension of 50% NaH (43.2 g, 0.90 mole) in DMF (i.e.) at 0° C. under N2. The solution was stirred 1 hour at room temperature, cooled in an ice bath, and ethyl bromide (120 ml, 1.6 mole) added. The reaction mixture was stirred overnight at room temperature, filtered, and concentrated in vacuo. A solution of the residue in diethyl ether was washed with dilute NaOH solution and saturated NaCl, dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate:hexane (1:3→1:9) to give methyl 3-ethoxyphenylacetate (94.9 g). 1H NMR (DMSO-d6, 200 MHz) δ: 1.30 (t, J=7 Hz, 3H, ethyl CH3), 3.59 (s, 3H, ester CH3), 3.61 (s, 2H, ArCH2), 3.98 (q, J=7 Hz, 2H, ethyl CH2), 6.28-6.81 (m, 3H), 7.16-7.24 (m, 1H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1([F:10])[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5]1.Cl[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=1.Cl>C1COCC1>[Cl:18][C:17]1[C:12]([O:9][CH2:8][CH:6]2[CH2:7][C:4]([F:10])([F:3])[CH2:5]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: OCC1CC(F)(F)C1
Reactant: Clc1cccnc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC1(F)CC(COc2ncccc2Cl)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 1.017 g, 70.6 mmol) was suspended in THF (30.0 mL) and the reaction was cooled to 0° C. under nitrogen with an ice bath. (3,3-Difluorocyclobutyl)methanol (Preparation 36, 2.95 g, 24.2 mmol) in THF (30 mL) was added dropwise to the mixture maintaining the temperature at 0° C. After stirring for 30 minutes, 2,3-dichloropyridine (3.25 g, 22.0 mmol) was added and the suspension was heated to reflux for 16 hours. An aqueous solution of HCl (1 M, 20 mL) was added and the reaction was extracted with EtOAc (2×100 mL). The combined organics were then dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage®, gradient of 0-50% EtOAc in heptane,) to afford the title compound (4.82 g, 85%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[CH3:41][C:42]1[C:47]([S:48](Cl)(=[O:50])=[O:49])=[CH:46][CH:45]=[CH:44][N:43]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:48]([C:47]2[C:42]([CH3:41])=[N:43][CH:44]=[CH:45][CH:46]=2)(=[O:50])=[O:49])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: Cc1ncccc1S(=O)(=O)Cl
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncccc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)c(F)c1-c1cccnc1F
Yield: 86.1 %

Procedure:
To a suspension of sodium hydride (60% in oil, 34 mg) in tetrahydrofuran (2 mL) were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (226 mg), 15-crown-5 (185 mg) and a solution of 2-methylpyridine-3-sulfonyl chloride (174 mg) in tetrahydrofuran (1 mL) at room temperature, and the mixture was stirred for 18 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=17:3→1:1) to give the title compound as a yellow oil (yield 288 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10][NH:11][C:12]([NH2:14])=[S:13])=[CH:4][CH:3]=1.Br[CH:24]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=1)[C:25](OCC)=[O:26]>C(O)C.C(N(C(C)C)CC)(C)C>[C:18]([O:17][C:16](=[O:22])[NH:15][C@@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:10][NH:11][C:12]1[S:13][C:24]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=2)=[C:25]([OH:26])[N:14]=1)([CH3:19])([CH3:21])[CH3:20]
Reactant: CCOC(=O)C(Br)c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N[C@H](CNC(N)=S)Cc1ccc(Cl)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](CNc1nc(O)c(-c2ccc(F)c(F)c2)s1)Cc1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
A mixture of (S)-tert-butyl 3-(4-chlorophenyl)-1-thioureidopropan-2-ylcarbamate (0.585 g, 1.70 mmol) and ethyl 2-bromo-2-(3,4-difluorophenyl)acetate (0.500 g, 1.79 mmol) in ethyl alcohol (2 mL) and diisopropylethylamine (0.3 mL) in a sealed vial (Biotage microwave vial, 5 mL) with a magnetic stirring bar was heated in a microwave oven (Initiator, Biotage) at 120° C. for 15 minutes. After cooling to ambient temperature, the volatiles were removed in vacuum. The residue was partitioned between EtOAc and water. The combined organic portions were washed with brine. The crude product was purified by flash column chromatography (20% of EtOAc in hexanes for 5 minutes, 20% to 100% of EtOAc in hexanes over 23 minutes). The product was obtained as a white solid, 0.201 g, 24%. 1H NMR (300 MHz, CD3OD) δ 1.22-1.39 (m, 9H), 2.52-2.97 (m, 2H), 3.35-3.60 (m, 1H), 3.64-3.85 (m, 1H), 3.92-4.24 (m, 1H), 7.11-7.46 (m, 7H). LCMS (API-ES): 496.1/498.1 (M++H), chloro pattern.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:21]3[N:22]=[C:23](S(C)(=O)=O)[N:24]=[C:25]([CH3:26])[C:20]=3[CH:19]=[CH:18][C:17]2=[O:31])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[NH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C1COCC1>[CH2:1]([NH:8][C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:21]3[N:22]=[C:23]([N:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)[N:24]=[C:25]([CH3:26])[C:20]=3[CH:19]=[CH:18][C:17]2=[O:31])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccc(C(=O)NCc2ccccc2)cc1
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(N2CCNCC2)nc2c1ccc(=O)n2-c1ccc(C(=O)NCc2ccccc2)cc1
Reaction time: 18 h

Procedure:
The resin (A3), 0.0214 mmol) was suspended in THF (1 ml) and NEt3 (14 mg, 0.14 mmol). To this mixture was added piperazine (21 mg, 0.128 mmol) and shaking continued for 18 h. The resin was washed with THF (2×1 min), DMF (3×1 min, 60° C.) and with DCM (3×1 min) at rt.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([C:12]#[N:13])[C:9]2[N:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[S:16][C:8]=2[C:7]=1[OH:21])=[O:5])C.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].Cl>C[O-].[Na+].CO.O>[C:17]([C:15]1[S:16][C:8]2[C:7]([OH:21])=[C:6]([C:4]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:5])[N:11]=[C:10]([C:12]#[N:13])[C:9]=2[N:14]=1)([CH3:18])([CH3:19])[CH3:20]
Reactant: CCOC(=O)c1nc(C#N)c2nc(C(C)(C)C)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1nc2c(C#N)nc(C(=O)NCC(=O)O)c(O)c2s1
Yield: 53.4 %

Procedure:
A suspension of 2-tert-butyl-4-cyano-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (85 mg, 0.28 mmol) and glycine (188 mg, 2.5 mmol) in 4.4 mL of 0.5 N NaOMe in methanol was heated at reflux temperature for 25 h. The reaction mixture was diluted with water, acidified with 1 N HCl, and extracted with ethyl acetate. The organic fraction was concentrated to a residue and purified by reverse phase chromatography on a C-18 column, eluting the desired product with a gradient of 10-90% acetonitrile in water+0.1% formic acid. The lyophilized material fractions provided 50 mg of white solid. MS (ESI−): m/z 333.0 (M−1).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16](Cl)(=[O:18])[CH3:17].Cl>C(Cl)Cl>[CH3:5][O:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1
Reactant: COCCCc1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COCCCc1ccc(C(C)=O)cc1

Procedure:
Next, 195 g of AlCl3 and 100 g of 3-methoxypropylbenzene were poured into 1.5 liters of CH2Cl2, and the resulting mixture was cooled with ice under stirring. Thereto was gradually added dropwise 79 g of acetyl chloride (CH3COCl), and the thus obtained mixture was stirred under ice-cooling continuously for 6 hours. After the termination of the evolution of hydrogen chloride (HCl) gas was ascertained, the reaction solution was poured into 1 liter of dilute hydrochloric acid, and the CH2Cl2 layer was separated, after which the CH2Cl2 was distilled off, and the residue was distilled under reduced pressure to obtain p-(3-methoxypropyl)acetophenone. The boiling point of this compound was 94-95° C./0.3 mmHg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@H:13]2[CH2:15][O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S-:17].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@H:13]([OH:14])[CH2:15][S:17][CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]([C@H]2CO2)C1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC[C@@H](O)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
(R)-(S)-3-Oxiranylpyrrolidine-1-carboxylic acid t-butyl ester (1.0 g, 4.7 mmol, 1.0 eq.) in DMF (10 mL) was combined with sodium methyl mercaptide (2.5 g, 14.1 mmol, 3.0 eq.), and the resulting mixture was stirred at 50° C. for 3 hours under nitrogen. Upon completion of the reaction, the mixture was concentrated under vacuum, extracted with EtOAc, washed with saturated aqueous NaCl and water, dried, and concentrated. The crude product was purified by preparative HPLC (MeCN:EtOH=4:6) to yield the title compound (700 mg).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([OH:16])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:17][CH3:18])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:19])[CH:5]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:17][CH3:18])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:19])[CH:5]=1
Reactant: CCC12CCC(=O)C=C1c1c(cc(O)c(Cl)c1Cl)C2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(CC)C2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 5,6-dichloro-9a-ethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (6.0 gm., 0.02 mole), ethyl bromoacetate (4.0 gm., 0.025 mole) and potassium carbonate (8.3 gm., 0.06 mole) in dimethylformamide (35 ml.) is heated at 50° C. and stirred for one hour. The mixture is cooled and poured into water (300 ml.). The solid product that separates is removed by filtration, then washed with water followed by benzene (10 ml.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:5]([C:4]1[CH:3]=[C:2]([CH:12]=[CH:11][C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:9]=[CH:8][CH:7]=1)=[O:6]
Reactant: O=Cc1cccc(Br)c1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C=Cc1cccc(C=O)c1
Temperature: 100 °C

Procedure:
To a stirred mixture of 3-bromobenzaldehyde (20 g), tert butyl acrylate (40 mL), triethylamine (44 mL) and tris(2-methylphenyl)phosphine (3.4 g) in dry dimethylformamide (300 mL) is added palladium (II) acetate in one portion. The resulting dark brown mixture is heated at 100° C. for 18 hours then evaporated in vacuo. The residual semi-solid is partitioned between ethyl acetate (250 mL) and 2 N hydrochloric acid (250 mL). the organic phase is washed three times with water (250 mL), dried over magnesium sulphate and evaporated. The resulting dark brown oil (28.1 g) is purified by flash chromatography on silica eluting initially with a mixture of cyclohexane and dichloromethane (4:1 v/v) then with a mixture of cyclohexane and dichloromethane (1:1 v/v). Fractions homogeneous in the required product are combined and evaporated to give tert-butyl 3-(3-formylphenyl)acrylate as a yellow oil (14.08 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([NH:5][C@H:6]([CH3:10])[C:7](O)=[O:8])=[O:4].N1C=CC=CC=1.C(Cl)(=O)C([Cl:22])=O>ClCCl>[F:1][C:2]([F:12])([F:11])[C:3]([NH:5][C@H:6]([CH3:10])[C:7]([Cl:22])=[O:8])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@@H](NC(=O)C(F)(F)F)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H](NC(=O)C(F)(F)F)C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound obtained in step 1) (17.2 g, 0.0845 mol) was dissolved in 300 ml of dichloromethane, and 1 ml of pyridine was added. The reaction mixture was cooled in ice-water bath to 0˜3, and oxalyl chloride (25.8 g, 0.203 mol) was added dropwise. After the completion of the addition, the temperature was slowly raised to room temperature, and a reaction was allowed to proceed for 3 hours. Evaporation was carried out under reduced pressure to remove the solvent, and 50 ml×2 benzene was added to remove residual solvent by azeotropism. The obtained (R)—N-trifluoroacetyl-2-amino propionyl chloride can be directly used for the subsequent reaction.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][C:9](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH3:25])[C:4]1=[O:5])[CH3:2].[C:26](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:26])[C:9](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH3:25])[C:4]1=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCn1c(=O)c2[nH]c(/C=C/c3cccc(OC)c3)nc2n(CC)c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCn1c(=O)c2c(nc(/C=C/c3cccc(OC)c3)n2C)n(CC)c1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
Compound r (1.70 g, 5.0 mmol) obtained in Reference Example 17 was dissolved in 40 ml of dimethylformamide. To the solution were added 1.73 g (12.5 mmol) of potassium carbonate and subsequently 0.62 ml (10.0 mmol) of methyl iodide, and the resulting mixture was stirred at 50° C. for 30 minutes. After cooling, insoluble matters were filtered off, and 100 ml of water was added to the filtrate. The mixture was extracted three times with 50 ml of chloroform. The extract was washed twice with water and once with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The obtained crude crystals were purified by silica gel column chromatography (eluent: 40% ethyl acetate/hexane), followed by recrystallization from cyclohexane/toluene to give 1.10 g (yield 62%) of Compound s as pale yellow needles.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Br:10][C:11]1[C:12]([F:20])=[C:13]([CH2:18]O)[C:14]([Cl:17])=[CH:15][CH:16]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH2:18][F:7])[C:12]=1[F:20]
Reactant: CCN(CC)S(F)(F)F
Reactant: OCc1c(Cl)ccc(Br)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FCc1c(Cl)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
A solution of diethylamino sulfur trifluoride (7.6 g, 0.047 mol) in methylene chloride (25 mL) was slowly added to (3-bromo-6-chloro-2-fluorophenyl) methanol (10.3 g, 0.043 mol) in methylene chloride (150 mL) at 0° C. The solution was stirred at ambient temperature for 1 hour. A saturated solution of sodium bicarbonate (100 mL) was cautiously added and the mixture extracted with methylene chloride (2×100 mL). The combined organic phases were dried (sodium sulfate) and concentrated. The dark residual oil was purified by chromatography (5% ethyl acetate in hexanes) to give 1-bromo-4-chloro-3-fluoromethyl-2-fluorobenzene (6.20 g, 0.024 mol): 1H NMR (CDCl3): δ 7.55(m, 1H) 7.18 (dd, 1H) 5.6 (d, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH2:14][CH3:15])[C:11]=1F)[CH:7]=[O:8])[CH3:2].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH2:14][CH3:15])[C:11]=1[N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[CH:7]=[O:8])[CH3:2]
Reactant: c1nc[nH]n1
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOc1cc(C=O)cc(OCC)c1-n1cncn1
Temperature: 110 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
5.00 g (23.6 mMol) of 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), 3.25 g (=2.0 eq.) of 1,2,4-triazole and 6.51 g (=2.0 eq.) of potassium carbonate was dissolved under argon in 50 mL of DMSO; the reaction mixture was stirred for 1 hour at 110° C. Then, it was cooled down to ambient temperature, poured into crashed ice and extracted twice with ethyl acetate. The organic phases were washed with water, dried over MgSO4, filtered and evaporated i.V. The crude product was purified by chromatography (silicagel, eluent:gradient of n-heptane/ethyl acetate) to yield 5.28 g of the title compound as colorless solid. MS: 261.9 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18]C)=[CH:4][C:3]=1[NH:20][C:21](=[O:23])[CH3:22].C(Cl)Cl.B(Br)(Br)Br.Cl>O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])=[CH:4][C:3]=1[NH:20][C:21](=[O:23])[CH3:22]
Reactant: COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1[N+](=O)[O-]
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1cc(Oc2ccccc2O)c([N+](=O)[O-])cc1F
Yield: 62 %

Procedure:
5.4 g of N-[2-fluoro-5-(2-methoxyphenoxy)-4-nitrophenyl]acetamide was dissolved in 50 mol of methylene chloride, then, 4.7 g of boron tribromide was added under ice cooling. The mixture was stirred for 2 hours under the same temperature, conc. hydrochloric acid was added to the solution and the resulted mixture was poured into water, extracted with ethyl acetate, the organic layer was washed with water, dried over magnesium sulfate, concentrated, and the resulted crystal was washed with t-butyl methyl ether to obtain 3.2 g of N-[2-fluoro-5-(2-hydroxyphenoxy)-4-nitrophenyl]acetamide.