Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N)cc2)COC1(C)C
Reactant: Clc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(Nc3ccc(Cl)cc3)cc2)COC1(C)C
Temperature: 110 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
In a pressure tube, (S)-4-[2-(4-amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.3 g), 1-bromo-4-chlorobenzene (215 mg) and cesium carbonate (458 mg) were combined with dioxane (3 ml) to give a yellow suspension. The mixture was degassed by bubbling through argon for several minutes. Xantphos (32.5 mg) and tris(dibenzylideneacetone)dipalladium chloroform complex (29.1 mg) were then added and the tube was sealed. The reaction mixture was stirred at 110° C. overnight. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (SiO2; gradient: 0% to 100% EtOAc in hexane) to afford (S)-4-{2-[4-(4-chloro-phenylamino)-phenyl]-ethyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (228 mg, 57%) as a yellow oil. MS (EI): 432 ({37Cl}M+), 430 ({35Cl}M+H—OH+), 376 ({37Cl}[M−C4H8]+), 374 ({35Cl}[M−C4H8]), 231 ({37Cl}[ClC6H4NHC6H4CH═CH2]+), 229 ({35Cl}[ClC6H4NHC6H4CH═CH2]+), 57 ([C4H9]+).
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C:21]4([CH2:25][C:26]#[N:27])[CH2:24][NH:23][CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.C(N(CC)C(C)C)(C)C.[CH2:39]([S:41](Cl)(=[O:43])=[O:42])[CH3:40].Cl>O1CCCC1>[CH2:39]([S:41]([N:23]1[CH2:22][C:21]([CH2:25][C:26]#[N:27])([N:19]2[CH:20]=[C:16]([C:15]3[C:10]4[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:28])([CH3:1])[CH3:29])[C:11]=4[N:12]=[CH:13][N:14]=3)[CH:17]=[N:18]2)[CH2:24]1)(=[O:43])=[O:42])[CH3:40]
Reactant: CCS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Reaction time: 1.5 h

Procedure:
To a solution of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-ylacetonitrile (0.100 g, 0.244 mmol) in tetrahydrofuran (2 mL) containing N,N-diisopropylethylamine (0.085 mL, 0.49 mmol) was added ethanesulfonyl chloride (0.023 mL, 0.24 mmol). After stirring for 1.5 hours, the reaction mixture was poured into dilute HCl and extracted with three portions of ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, decanted and concentrated to afford product, used without further purification in Step 5 (111 mg, 91%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[CH2:6]([O:8][C:9](=[O:13])/[CH:10]=[CH:11]/[CH3:12])[CH3:7].[H-].[Na+]>>[CH2:6]([O:8][C:9](=[O:13])[CH2:10][CH:11]([CH3:12])[O:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH3:7]
Reactant: OCCCCl
Reactant: C/C=C/C(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(C)OCCCCl

Procedure:
The 7-iodo-3-methyl-4-exaheptanoic acid ethyl ester was obtained in the following manner: The 3-chloropropanol was added to the crotonic acid ethyl ester in the presence of sodium hydride to obtain the 7-chloro-3-methyl-4-oxaheptanoic acid ethyl ester (boiling point1 : 74° - 82° C). Then the 7-iodo-3-methyl-4-oxaheptanoic acid ethyl ester (boiling point0.05 : 62° - 65° C) was obtained in acetone with sodium iodide according to Finkelstein.
Reaction SMILES: [CH3:1][C:2]1[O:26][C:5]2=[CH:6][C:7]3[S:8][C:9]4[C:14]([C:15]=3[C:16]([C:17]3[CH:22]=[C:21]([I:23])[C:20]([OH:24])=[C:19]([I:25])[CH:18]=3)=[C:4]2[C:3]=1[CH3:27])=[CH:13][CH:12]=[CH:11][CH:10]=4.O[C@@H:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([O:32]C)=[O:31]>>[CH3:1][C:2]1[O:26][C:5]2=[CH:6][C:7]3[S:8][C:9]4[C:14]([C:15]=3[C:16]([C:17]3[CH:18]=[C:19]([I:25])[C:20]([O:24][C@H:29]([CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:30]([OH:32])=[O:31])=[C:21]([I:23])[CH:22]=3)=[C:4]2[C:3]=1[CH3:27])=[CH:13][CH:12]=[CH:11][CH:10]=4
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: Cc1oc2cc3sc4ccccc4c3c(-c3cc(I)c(O)c(I)c3)c2c1C
Product: Cc1oc2cc3sc4ccccc4c3c(-c3cc(I)c(O[C@H](Cc4ccccc4)C(=O)O)c(I)c3)c2c1C

Procedure:
Prepared from 4-(2,3-dimethyl-1-oxa-9-thia-cyclopenta[b]fluoren-4-yl)-2,6 -diiodo-phenol and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester according to the procedure in Example 8 to provide the title compound as a white solid: mp 215-217: NMR (DMSO-d6): δ8.17 (s, 1H), 7.94 (d, J=8 Hz, 1H), 7.85 (d, J=4 Hz, 2H), 7.39-7.30 (m, 5H), 7.22 (dd, J=7 Hz, 1H), 7.16 (dd, J=7, 1 Hz, 1H), 6.87 (d, J=8 Hz, 1H), 5.41 (s, 1H), 3.43 (dd, J=6, 1 Hz, 2H), 2.36 (s, 3H), 1.56 (s, 3H); MS (+FAB): [M+H]+, 745; Anal. Calc. for C31H22I2O4S: C, 50.02; H, 2.98; N, 0.00. Found: C, 47.59; H, 2.98; N, 0.13.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([CH3:17])[CH:9]=1.CN(C=O)C.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>ClCCl>[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:14])=[C:10]([CH3:17])[CH:9]=1
Reactant: C1COCCN1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 10.6 ml (47 mmol) oxalyl chloride in 30 ml dichloromethane is added dropwise to a iced-cooled solution of 5.21 g (23.5 mmol) 4-bromo-2-methyl-benzoic acid and 0.0087 ml DMF in 100 ml CH2Cl2. After complete addition, the cooling bath is removed and stirring maintained for 2 h at RT. The solvent is evaporated to dryness and the residue is dried in vacuo and dissolved in 100 ml dichloromethane and 8.21 ml N-ethyl-diisopropylamine is added. To this solution 2.5 ml (28 mmol) morpholine is added slowly. Stirring is continued for 0.5 h, then the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo to afford the title compound which is used in the next step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH:20]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=3)[C:21]([O:23]CC3C=CC=CC=3)=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1>C1COCC1.[Pd]>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH:20]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=3)[C:21]([OH:23])=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: COc1ccc(C(Oc2ccc3c(N)nccc3c2)C(=O)OCc2ccccc2)cc1OC
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(C(Oc2ccc3c(N)nccc3c2)C(=O)O)cc1OC
Reaction time: 16 h
Yield: 110 %

Procedure:
6F (130 mg, 0.29 mmol) was dissolved in THF (8 mL). To this solution was added 10% Pd/C (cat.), and the mixture was hydrogenated at 50 psi for 16 h. The reaction was filtered and concentrated to provide 6G (113 mg, 10%). LC-MS: 355.19 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[Cl:37][C:38]1[CH:46]=[C:45]2[C:41]([CH2:42][CH2:43][NH:44]2)=[CH:40][CH:39]=1>ClCCCl>[Cl:37][C:38]1[CH:46]=[C:45]2[C:41]([CH2:42][CH2:43][N:44]2[C:9]2[C:4]3[CH:3]=[C:2]([CH3:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)=[CH:40][CH:39]=1
Reactant: Cc1cc2c(=O)[nH]cnc2cn1
Reactant: Clc1ccc2c(c1)NCC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc2c(N3CCc4ccc(Cl)cc43)ncnc2cn1
Temperature: 60 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
6Methyl-pyrido[3,4-d]pyrimid-4one (200 mg, 1.24 mmol), polymer-supported triphenylphosphine (2.06 g of 3.0 mmol Pig resin, 6.20 mmol) and anhydrous carbon tetrachloride (1.20 mL, 12.40 mmol) were combined in 1,2-dichloroethane (6 mL). The mixture was heated to 60° C. under an atmosphere of dry N2(g) for 18 hours. 6-Chloroindoline (1.1 eq.) was added and heating was continued at 60° C. for another 18 hours. The triphenyphosphine-bearing resin was filtered off and washed several times with chloroform. The filtrate and washings were concentrated in vacuo and preparative reversed-phase (C18) chromatography utilizing a gradient of 15% to 70% MeCN/pH4.5, 50 mM NH4OAc followed by lyophilization of the appropriate fractions afforded the title product (30%) as its free-base: MP: 232-234° C.; LC-MS: 297 (MH+); anal. RP-HPLC: 4.33 minutes.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6]([CH3:20])([CH3:19])[C:7]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:8]>ClCCl.CCCCCCC>[CH3:19][CH:6]1[C:7](=[O:8])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:12]=[CH:11][C:10]=2[CH2:20]1
Reactant: CC(C)(Cl)C(=O)c1cccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: ClCCl
Product: CC1Cc2ccc3ccccc3c2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
Aluminium chloride (35 g, 0.26 mole) was suspended in 200 ml of anhydrous dichioromethane. 2-Chloro-2-methyl-1-(1-naphthalenyl)-1-propanone (30.0 g, 0.13 mole) in 30 ml of heptane was slowly added to this suspension. During the addition (30 min) the temperature was kept at room temperature. After the addition was completed, the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was poured onto 400 g of ice water, and the organic layer was separated. The organic layer was successively washed twice with a 5 wt % aqueous hydrochloric acid solution (150 ml) and once with a 2 wt % aqueous sodium bicarbonate solution (150 ml). After drying over anhydrous magnesium sulfate the solution was concentrated under reduced pressure. The yield of crude 2,3-dihydro-2-methyl-1H-benz[e]inden-1-one was 23.4 g or 93%. Distillation of the crude product under reduced pressure (b.p. 130° C., 0.5 mbar) gave 18.7 g (75%) of 2,3-dihydro-2-methyl-1H-benz[e]inden-1-one, which crystallized upon standing at room temperature.
Reaction SMILES: C(OC([N:8]1[C@H:12]([C:13](O)=O)[C@@H:11]([CH:16]([CH3:18])[CH3:17])[O:10]C1(C)C)=O)(C)(C)C.[CH3:21][CH:22]([C:24]1[CH:25]=[C:26]([NH2:31])[C:27]([NH2:30])=[CH:28][CH:29]=1)[CH3:23]>>[NH2:8][C@H:12]([C:13]1[NH:30][C:27]2[CH:28]=[CH:29][C:24]([CH:22]([CH3:21])[CH3:23])=[CH:25][C:26]=2[N:31]=1)[C@H:11]([OH:10])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)c1ccc(N)c(N)c1
Reactant: CC(C)[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1C(=O)O
Product: CC(C)c1ccc2[nH]c([C@@H](N)[C@H](O)C(C)C)nc2c1

Procedure:
The title compound was prepared according to Method 4 using (4S,5R)-3-(tert-butoxycarbonyl)-5-isopropyl-2,2-dimethyl-1,3-oxazolidine-4-carboxylic acid (Preparation 60) and 4-(1-methylethyl)-1,2-benzenediamine.
Reaction SMILES: [CH2:1]([C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:23]S(C)=O.[OH-].[Na+].CI>O>[CH2:1]([C:16]1[CH:17]=[C:18]([O:22][CH3:23])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCc1cccc(O)c1
Reactant: CS(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a two necked round bottomed flask with a reflux condenser is added 3-pentadecyl phenol, DMSO, sodium hydroxide followed by dropwise addition of alkylating agent such as methyl iodide with constant stirring at room temperature. The stirring is continued for about 6-8 hrs. The reaction mixture is then poured into deionized water and the organic matter is extracted in diethyl ether, separated the organic layer, washed with water and dried, purified to obtain 3-pentadecyl anisole.
Reaction SMILES: F[C:2]1[C:3]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([S:15][CH3:16])[N:9]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.[Cu]I>[CH3:25][O:24][C:21]1[N:22]=[CH:23][C:18]([NH:17][C:2]2[C:3]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([S:15][CH3:16])[N:9]=3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(N)cn1
Reactant: CSc1nc(C)nc(-c2nccnc2F)n1
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2nccnc2-c2nc(C)nc(SC)n2)cn1
Temperature: 100 °C
Yield: 76.3 %

Procedure:
A glass microwave reaction vessel was charged with 2-(3-fluoropyrazin-2-yl)-4-methyl-6-(methylthio)-1,3,5-triazine (61 mg, 0.257 mmol), 5-amino-2-methoxypyridine (0.038 mL, 0.309 mmol), copper(I) iodide (5 mg, 0.026 mmol) and N,N-diisopropylethylamine (0.089 mL, 0.514 mmol) in dioxane (1 mL). The reaction mixture was stirred and heated at 100° C. for 24 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 20% EtOAc/CH2Cl2 to give N-(6-methoxypyridin-3-yl)-3-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrazin-2-amine (67 mg, 0.196 mmol, 76% yield) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 11.34 (s, 1H); 8.36 (d, J=1.90 Hz, 1H); 8.26 (s, 2H); 8.00 (dd, J=8.99, 2.56 Hz, 1H); 6.80 (d, J=8.77 Hz, 1H); 3.96 (s, 3H); 2.77 (s, 3H); 2.68 (s, 3H). m/z (ESI, +ve ion) 342.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([O:17][CH3:18])[C:13](NC)=[O:14].CC1C=CC(C)=C[C:26]=1[O:27]CC1C=CC=CC=1C(O)C(OC)=O.CI>>[CH3:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([O:17][CH3:18])[C:13]([O:27][CH3:26])=[O:14]
Reactant: CNC(=O)C(OC)c1ccccc1COc1cc(C)ccc1C
Reactant: COC(=O)C(O)c1ccccc1COc1cc(C)ccc1C
Solvent: CI
Product: COC(=O)C(OC)c1ccccc1COc1cc(C)ccc1C

Procedure:
WO 95/27693 discloses that a 2-substituted phenyl-N-alkylacetamide compound having an alkoxy group at the 2-position typified by 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxy-N-methylacetamide is useful as an agricultural fungicide, and also discloses, as a method for producing the compound; a method in which methyl 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-hydroxyacetate is reacted with methyl iodide to obtain methyl 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyacetate, and then the methyl 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyacetate is reacted with methylamine to obtain 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxy-N-methylacetamide.
Reaction SMILES: [O:1]=[C:2]([NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.[C:22]1([NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].FC(F)(F)C(O)=O>O1CCCC1>[NH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:29][C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2](=[O:1])[NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:13][CH:12]=1
Reactant: O=C(COc1ccc(C(=O)O)cc1)NCc1cccnc1
Reactant: Nc1ccccc1N
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccccc1NC(=O)c1ccc(OCC(=O)NCc2cccnc2)cc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
0.34 g (2.1 mmole) of N,N′-carbonyldiimidazole was added to a tetrahydrofuran (10 ml) suspension including 0.6 g (2.1 mmole) of 4-{2-oxo-2-[(pyridin-3-ylmethyl)amino]ethoxy}benzoic acid, followed by stirring at 45° C. for 1 hour. After cooling to room temperature, 2.1 g (19.4 mmole, 8 equivalents) of 1,2-phenylenediamine and 0.4 ml of trifluoroacetic acid were added, and reaction was further carried out for 15 hours. After completion of the reaction, a post-treatment was performed in the same manner as in Example 6 to obtain 0.67 g (yield: 53%) of N-(2-aminophenyl)-4-{2-oxo-2-[(pyridin-3-ylmethyl)amino]ethoxy}-benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:13]1[C:14]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)[CH2:21][CH2:20]2)=[N:15][CH:16]=[CH:17][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[C:14]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)[CH2:21][CH2:20]3)=[N:15][CH:16]=[CH:17][N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: Cn1cc(CN2CCN(c3nccnc3Cl)CC2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1cc(CN2CCN(c3nccnc3-c3ccc(F)c(Cl)c3)CC2)cn1
Temperature: 110 °C
Yield: 57.8 %

Procedure:
Add 3-chloro-4-fluorobenzeneboronic acid (71 mg, 0.41 mmol) to a mixture of 3′-chloro-4-(1-methyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (104 mg, 0.34 mmol), potassium carbonate (113 mg, 0.82 mmol) and tetrakis(triphenyl-phosphine)palladium(0) (0.002 g, 0.002 mmol) in N,N-dimethylacetamide (2 mL) and water (1 mL). Purge with nitrogen and heat overnight at 110° C. Cool to room temperature, add water (10 mL), extract with DCM (3×20 mL), combine and purify using high pH reverse phase HPLC to give title compound (76 mg, 57.7%). MS (ES): m/z=387 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:7]=1.[C:19]([O-])(=O)[CH3:20].[Na+]>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][C:19]([CH3:20])=[C:9]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:8]2=[O:17]
Reactant: O=C(Cc1ccc(F)cc1)c1cc(Br)ccc1O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1oc2ccc(Br)cc2c(=O)c1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
Intermediate 6 (6.1 g, 19.73 mmoles) was taken in a RB flask and to this acetic anhydride (40 ml) and sodium acetate (11.3 g, 137.75 mmoles) were added and the mixture was refluxed for 12 h. After cooling to RT, the reaction mixture was quenched by the addition of ice cold water. The solid formed was filtered and washed with water. The product was dried under vacuum to afford the title compound as white solid (4.1 g, 63% yield). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 8.35(d, J=1.9Hz, 1H), 7.77(dd, J=8.8, 1.9Hz, 1H), 7.37(d, J=8.9Hz, 1H), 7.27(t, J=5.7Hz, 2H), 7.17(t, J=8.6Hz, 2H), 2.33(s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][S:9]1(=[O:18])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30]Br>>[Br:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[S:9]1(=[O:18])=[O:17]
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1F
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1ccccc1F
Yield: 66.7 %

Procedure:
In an analogous manner as described in general procedure IV, 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.22 g, 0.83 mmol) was treated with cesium carbonate (0.27 g, 0.83 mmol) and 1-Bromo-2-(2-bromo-ethoxy)-ethane (0.03 mL, 3.3 mmol) to provide 0.23 g (67%) of 1-[2-(2-bromoethoxy)ethyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide. HRMS: calculated for C16H16BrFN2O3S+H+, 415.01218; found (ESI, [M+H]+), 415.0127; HPLC purity 100.0% at 210-370 nm, 10.1 minutes; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([O:13][C:14](=[O:16])[CH3:15])[C:7](=[N+]=[N-])[C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].CC(C)=[O:19].CC1(C)OO1>CC(C)=O>[C:1]([O:4][CH2:5][CH:6]([O:13][C:14](=[O:16])[CH3:15])[C:7](=[O:19])[C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(OC(C)=O)C(=[N+]=[N-])C(C)=O
Reactant: CC(C)=O
Agent: CC1(C)OO1
Product: CC(=O)OCC(OC(C)=O)C(=O)C(C)=O
Reaction time: 1 h

Procedure:
To a solution of methyl diazo diacetate 7 (20 mg, 0.088 mmol) in acetone (1 mL) was added dimethyldioxirane acetone solution (2.5 mL, ca. 0.07-0.09 M). The resulting mixture was stirred for 1 h and solvent and excess reagents were removed under reduced pressure to obtain 19 as bright yellow oil (yield=19 mg, quantitative).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]>O>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][NH:1][CH2:2][CH2:3][CH2:4][OH:5])[CH3:12]
Reactant: NCCCO
Reactant: CCOC(=O)CBr
Solvent: O
Product: CCOC(=O)CNCCCO
Temperature: 7.5 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
3-Aminopropan-1-ol (154 g; 2.05 mol) is cooled to −5° C. Ethyl bromoacetate (143.6 g: 817 mmol) is added dropwise over a period of 1.5 hours maintaining the temperature around 5-10° C. The stirring is continued for 10 minutes. LC-MS showed that all ethyl bromoactetate has reacted. Then water (570 ml) is added to the reaction mixture. The aqueous mixture is washed three times with ethylacetate (3 times 140 ml). The combined organic phases are back extracted with water (2 times 140 ml). The aqueous phases are combined and saturated with sodium chloride (255 g). The aqueous solution is extracted with methylene chloride (6 times 750 ml). The combined organic phases are dried over sodium sulfate and the solvent is removed under reduced pressure. A yellow oil is obtained (83 g; yield 63%)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:35])([CH3:34])[C@@H:11]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:12]([O:14][CH2:15][O:16][C:17](=[O:25])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:13])(=[O:7])=[O:6].[N-:36]=[N+:37]=[N-:38].[Na+]>CS(C)=O>[N:36]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:35])([CH3:34])[C@@H:11]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:12]([O:14][CH2:15][O:16][C:17](=[O:25])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:13])(=[O:7])=[O:6])=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)OCOC(=O)Cc1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(COS(=O)(=O)CCCN=[N+]=[N-])[C@@H](OCc1ccccc1)C(=O)OCOC(=O)Cc1ccccc1

Procedure:
Following the general procedure for the preparation of azides of Description 16, (2-phenylacetyloxy)methyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (28a) (0.44 g, 0.84 mmol) dissolved in 5 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 140 mg (2.1 mmol) of sodium azide (NaN3). After work-up, the crude title compound (28b) was used in the next step without further purification. MS (ESI) m/z 556.12 (M+Na)+.
Reaction SMILES: N(C(C)C)C(C)C.C([Li])CCC.[CH3:13][CH2:14][O:15][C:16]([CH3:18])=[O:17].[F:19][C:20]([F:30])([F:29])[C:21]([C:23]1[S:27][C:26]([SH:28])=[N:25][CH:24]=1)=[O:22]>C1COCC1>[CH2:14]([O:15][C:16](=[O:17])[CH2:18][C:21]([OH:22])([C:23]1[S:27][C:26]([SH:28])=[N:25][CH:24]=1)[C:20]([F:29])([F:19])[F:30])[CH3:13]
Reactant: O=C(c1cnc(S)s1)C(F)(F)F
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)(c1cnc(S)s1)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
iPr2NH (205 mg, 2.0 mmol) was dissolved in THF (3.5 mL) and cooled to −10° C. n-Butyllithium (2.5M, 0.81 mL, 2.0 mmol) was added dropwise, and the reaction was cooled to −78° C. EtOAc (179 mg, 2.0 μmmol) in THF (0.5 mL) was added, followed by 10a (188 mg, 0.9 mmol) in THF (10.5 mL), and the reaction was stirred at −78° C. for 1 hour. The reaction was warmed to −10° C. and quenched with 5% aqueous NH4Cl (10 mL). The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with 1N HCl and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (50% Et2O in hexanes) to give the desired product, 10b.