Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[CH:5]=[CH:4][C:3](=[O:6])[CH2:2]1.[C:8]([O-])([O-])([O:12][CH2:13]C)[CH2:9][CH2:10]C>C(OC(=O)C)(=O)C.[Cl-].[Cl-].[Zn+2]>[CH3:13][O:12][C:8](=[C:2]1[C:3](=[O:6])[CH:4]=[CH:5][C:1]1=[O:7])[CH2:9][CH3:10]
Reactant: O=C1C=CC(=O)C1
Reactant: CCCC([O-])([O-])OCC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Product: CCC(OC)=C1C(=O)C=CC1=O

Procedure:
To a suspension of cyclopent-4-ene-1,3-dione (1.22 g, 12.6 mmol) in acetic anhydride (4 ml) were added ethyl orthobutyrate (3.74 g, 25.3 mmol) and anhydrous ZnCl2. The reaction was heated at 80° for 24 h, solid removed by filtration, the filtrate concentrated in vacuo and the residues purified by chromatography (SiO2; 70:30 hexane/EtOAc) to give 2-(α-methoxypropylidene)cyclopent-4-ene-1,3-dione as a brown oil. δ H (CDCl3) 6.88 (2H, s), 4.07 (3H, s), 3.00 (2H, t), 1.63 (2H, m), 1.08 (3H, t). m/z (ESI, 70V) 181 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:23])[C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)[C:6]=2[CH:22]=1.[F:24][CH2:25][C:26](Br)=O.C([O-])(=O)C.[Na+]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:23])[C:5]2[N:11]3[C:26]([CH2:25][F:24])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:15]=[CH:16][C:17]([S:20][CH3:21])=[CH:18][CH:19]=3)[C:6]=2[CH:22]=1
Reactant: O=C(Br)CF
Reactant: CSc1ccc(C2=NCC(NN)=Nc3c(C)cc(C)cc32)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CSc1ccc(C2=NCc3nnc(CF)n3-c3c(C)cc(C)cc32)cc1

Procedure:
In the manner given in Example 1, 7,9-dimethyl-5-[p-(methylthio)phenyl]-3H-1,4-benzodiazepin-2-yl hydrazine was reacted with fluoroacetyl bromide and after 1.5 hours with sodium acetate, then the mixture was refluxed to give 8,10-dimethyl-1-(fluoromethyl)-6-[p-(methylthio)phenyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[N:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])=[CH:15][CH:14]=1
Reactant: CCOP(=O)(CN)OCC
Reactant: COc1ccc(C=O)cc1
Product: CCOP(=O)(CN=Cc1ccc(OC)cc1)OCC
Yield: 100 %

Procedure:
Starting from 16.7 g. (0.1 mol) diethyl aminomethylphosphonate and 13.6 g. (0.1 mol) p-methoxybenzaldehyde and following the procedure described in Example 1, 28.5 g. (yield: 100%) of the desired product are obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.ClC1C=CC=C(C(OO)=[O:37])C=1.O>C(Cl)Cl>[CH3:22][S:21]([C:18]1[CH:17]=[CH:16][C:15]([N:4]2[C:5]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:6][C:7](=[O:8])[C:2]([CH3:1])=[C:3]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:20][CH:19]=1)=[O:37]
Reactant: CSc1ccc(-n2c(-c3ccccc3)cc(=O)c(C)c2-c2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: Cc1c(-c2ccccc2)n(-c2ccc(S(C)=O)cc2)c(-c2ccccc2)cc1=O
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
Dissolved in 30 ml of methylene chloride was 1.1 g (0.0029 mole) of 3-methyl-1-(4-methylthiophenyl)-2,6-diphenyl-4(1H)-pyridinone, followed by addition of 0.6 g (0.0034 mole) of m-chloroperbenzoic acid (as oxidizing agent). After stirring the reaction mixture for 15 minutes, it was poured into water, followed by extraction with methylene chloride. The organic layer (the extract) was washed with 20 ml of a saturated aqueous solution of sodium hydrogen carbonate and then with water. The organic layer was thereafter dried over anhydrous sodium sulfate. The solvent was distilled off and the resulting crystals were recrystallized form a 2:1 mixed solvent of acetone and hexane, affording 1.1 g of 1-(4-methanesulfinylphenyl)-3-methyl-2,6-diphenyl-4(1H)-pyridinone having a melting point of 242°-244° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH:22]([CH3:28])[CH2:23][N:24]([CH2:26][CH3:27])[CH3:25])[C:10]=2[CH:9]=1)=S.[ClH:30].C(O)(=O)/C=C/C(O)=[O:35]>C(O)C.C(OC(C)C)(C)C>[ClH:30].[CH3:1][CH:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH:22]([CH3:28])[CH2:23][N:24]([CH2:26][CH3:27])[CH3:25])[C:10]=2[CH:9]=1)=[O:35]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: CCN(C)CC(C)N1c2ccccc2Sc2ccc(C(=S)NCCC(C)C)cc21
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: CCN(C)CC(C)N1c2ccccc2Sc2ccc(C(=O)NCCC(C)C)cc21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
N-(3-Methylbutyl)-10-[(2RS)-1-(N-ethyl-N-methyl-amino)-2-propyl]-2-phenothiazinecarbothioamide (0.3 g) is dissolved in a solution of fumaric acid (81 mg) in absolute ethanol (5 cc) and the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual orange product of meringue-like consistency is dissolved in acetic acid (5 cc) and mercuric acetate (0.23 g) is added. The orange suspension obtained is stirred for 16 hours at a temperature in the region of 20° C. The reaction mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 60° C. The residue is taken up with distilled water (10 cc) and filtered and the filtrate is alkalinized with caustic soda (d=1.33) to pH 13 and extracted with ethyl acetate (2×10 cc). The combined organic phases are washed with saturated aqueous sodium chloride solution (10 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow oil (0.15 g) is dissolved in ethyl acetate (2 cc), and isopropyl ether (20 cc) is added. The solution obtained is cooled to a temperature in the region of 5° C. and a solution (5.1 cc) of 0.065N hydrochloric acid in isopropyl ether is added dropwise and with stirring. The precipitate formed is drained, washed with isopropyl ether (3×5 cc) and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 40° C. N-(3-Methylbutyl)-10-[(2RS)-1-(N-ethyl-N-methylamino)-2-propyl]-2-phenothiazinecarboxamide hydrochloride (0.13 g) is thereby obtained in the form of an off-white solid, m.p. 110-120° C. (melts forming a paste).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(Cl)Cl.C(N(CC)CC)C>>[CH3:18][C@@:12]1([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:31])([F:30])[F:19])[CH:26]=4)[CH:3]=3)[CH:8]=2)[CH2:16][O:15][C:14](=[O:17])[NH:13]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@]1(c2ccc3cc(Oc4cccc(C(F)(F)F)c4)ccc3c2)COC(=O)N1
Reaction time: 10 h
Yield: 21 %

Procedure:
(R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (Example 4, 65 mg, 0.27 mmol), 3-(trifluoromethyl)phenylboronic acid (101 mg, 0.54 mmol) and cupric acetate (48.5 mg, 0.000267 mol) were placed in a vial, purged with N2, following by methylene chloride (2 mL, 0.03 mol) and triethylamine (0.186 mL, 0.00134 mol) at 23° C. The reaction was allowed to stir for about for 10 hours, and filtrated. The crude material was then purified via chromatography (SiO2, 4 g, 0-35%) to give a pure product (22 mg, 31%). 1H NMR (CHLOROFORM-d) δ: 7.87 (d, J=9.0 Hz, 1H), 7.83 (s, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.45-7.52 (m, 2H), 7.37-7.43 (m, 1H), 7.35 (d, J=2.0 Hz, 1H), 7.27-7.31 (m, 2H), 7.22 (d, J=8.3 Hz, 1H), 6.01 (s, 1H), 4.39-4.49 (m, 2H), 1.87 (s, 3H). MS (M+1): 388.20.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]([F:11])[C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+]([O-])([O-])=O.[Na+].[ClH:18]>O.O1CCOCC1.[Cu](Cl)Cl>[Br:12][C:8]1[C:9]([F:11])=[CH:10][C:2]([Cl:18])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Nc1cc(F)c(Br)cc1C(=O)O
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(Br)c(F)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of 2-amino-5-bromo-4-fluorobenzoic acid (14.5 g, 62.2 mmol) in concentrated hydrochloric acid (30 mL) at 0° C. was added dropwise a solution of sodium nitrate (4.72 g, 68.4 mmol) in water (15 mL). The mixture was stirred at 0° C. for 2 hours, then diluted with 1,4-dioxane (40 mL) and added dropwise to a solution of copper chloride (7.4 g, 74.4 mmol) in concentrated hydrochloric acid (25 mL) under mechanical stirring while the reaction temperature was kept below 7° C. (ice-salt bath). After the addition was complete, the mixture was stirred at 0° C. for another 1 hour. Water was added, and the precipitate was filtered. The filter cake was washed with water and dissolved in ethyl acetate. The filtrate was extracted with ethyl acetate once and washed with water and then with brine. The combined organic layers were dried over sodium sulfate and concentrated to give the crude product 28 (14.5 g, 92%), which was used for the next step without further purification. MS ESI (m/z): 251 (M−H)−.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:17][CH3:18])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[NH:8][C:7]1=[O:16].[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:17][CH3:18])[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=4)[NH:8][C:7]3=[O:16])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccc(C)cc21
Reactant: Clc1cccc(N2CCNCC2)c1
Product: CCC1(CCCCN2CCN(c3cccc(Cl)c3)CC2)C(=O)Nc2ccc(C)cc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one and 1-(3-chloro-phenyl)-piperazine.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[CH3:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[CH2:27][NH:28][CH3:29]>>[CH3:29][N:28]([CH2:27][C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([CH3:23])[CH:25]=1)[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: CNCc1cccc(C)c1
Product: Cc1cccc(CN(C)CCn2cnc(-c3cc(C(=O)O)ccn3)c2)c1
Yield: 57 %

Procedure:
The title compound was prepared in 57% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 3-methyl-N-methylbenzylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 2.20 (3H, s), 2.29 (3H, s), 2.68 (2H, t, J=6 Hz), 3.85 (2H, s), 4.02 (1H, t, J=5.9 Hz), 4.15 (1H, t, J=6.0 Hz), 6.96 (1H, m), 7.11 (2H, t, J=9.0 Hz), 7.18-7.27 (2H, m), 7.51 (1H, d, J=3.6 Hz), 7.74 (1H, s), 8.28 (1H, s), 8.47 (1H, d, J=4.8 Hz). [M+H] Calc'd for C20H22N4O2, 351. Found, 351.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[N:42]([CH3:46])[CH:43]=[CH:44][N:45]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[N:42]([CH3:46])[CH:43]=[CH:44][N:45]=2)=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: CON(C)C(=O)c1nccn1C
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3nccn3C)c(F)c2F)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3) and N-methoxy-N,1-dimethyl-1H-imidazole-2-carboxamide
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Br:26])[CH:24]=3)[N:19]([S:27]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33]([O:40][CH3:41])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH:18]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[Br:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]([S:27]([C:30]1[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]([O:40][CH3:41])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH:18]=[C:17]2[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1)=[O:16]
Reactant: COc1ccc(S(=O)(=O)n2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)c3cc(Br)ccc32)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)n2cc(C(=O)N3CCCNCC3)c3cc(Br)ccc32)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
To a solution of 4-[5-Bromo-1-(4-methoxy-naphthalene-1-sulfonyl)-1H-indole-3-carbonyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (A) (45 mg, 0.07 mmol) in dichloromethane (5 cm3) was added trifluoroacetic acid (2 cm3). The solution was shaken at room temperature for 1 h before the solvent was removed under reduced pressure. The residue was dissolved in N,N-dimethylformamide (DMF) (1 cm3) and purified using reverse phase HPLC (Agilent Technologies, CombiHT SB-C18, Preparative cartridge 21.2×100 mm, 5-micron) using a linear gradient of water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid). The desired peak was then evaporated under reduced pressure to afford the title compound (83) (45.9 mg, 27%). Positive ion APCI (M+H)+ 543.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][CH2:19][OH:20])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][CH2:19][O:20][S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(CCO)ccc2C1
Product: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)cc1

Procedure:
6-[2-(Toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester is prepared as example 7d from 1.60 g (5.77 mmol) 6-(2-hydroxy-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 10b) and 1.21 g (6.35 mmol) 4-methyl-benzenesulfonyl chloride.
Reaction SMILES: [C:1]([N:4]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:31]=[CH:30][C:20]([O:21][CH2:22][CH2:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=O)=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:32])[CH2:6]1)(=[O:3])[CH3:2].CN(C=O)C.[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47]>C(Cl)Cl.C(Cl)(=O)C(Cl)=O>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([N:4]([C@H:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([C:15](=[O:16])[C:17]3[CH:31]=[CH:30][C:20]([O:21][CH2:22][CH2:23][C:24]([CH3:28])([CH3:29])[C:25]([NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[O:27])=[CH:19][CH:18]=3)[C@@H:7]([CH3:32])[CH2:6]2)[C:1](=[O:3])[CH3:2])=[CH:34][CH:35]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(C)(C)C(=O)O)cc2)c2ccccc21
Reactant: CS(N)(=O)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(C)(C)C(=O)NS(C)(=O)=O)cc2)c2ccccc21
Temperature: 25 °C

Procedure:
(2S,4R)-4-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-2,2-dimethyl-butyric acid (200 mg, 0.37 mmol) was dissolved in methylene chloride (5 mL) and oxalyl chloride (2 mL). A single drop of DMF was added, and the mixture was stirred at room temperature until gas evolution ceased. All volatiles were removed. The slurry was dissolved in methylene chloride (10 mL) and triethylamine (2 mL). Methanesulfonamide (200 mg, 2.10 mmol) was added and the reaction mixture was stirred for 3 hours. The mixture was partitioned between methylene chloride and water; the organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by preparatory HPLC.
Reaction SMILES: ClS([N:5]=[C:6]=O)(=O)=O.CC(OC([N:15](C(OC(C)(C)C)=O)[C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:22]2[N:23]([CH3:32])[C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[C:26]([Cl:31])[CH:25]=3)[CH:21]=1)=O)(C)C.CN(C=O)C>C(#N)C>[NH2:15][C:16]1[CH:21]=[C:20]([C:22]2[N:23]([CH3:32])[C:24]3[C:29]([C:30]=2[C:6]#[N:5])=[CH:28][CH:27]=[C:26]([Cl:31])[CH:25]=3)[CH:19]=[N:18][CH:17]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cn1c(-c2cncc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2)cc2ccc(Cl)cc21
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cn1c(-c2cncc(N)c2)c(C#N)c2ccc(Cl)cc21
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
Chlorosulfonyl isocyanate (1.63 g, 11.5 mmol) is added to a solution of 3-[bis[[(1,1-dimethylethyl)oxy]carbonyl]amino]-5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridine (0.91 g, 1.99 mmol) in acetonitrile (200 mL) and the reaction mixture is stirred for 10 min. DMF (3 mL) is added and the reaction mixture is stirred for 3 h. 20 g silica gel is added to the mixture and the solvent is removed in vacuo. The resulting solid is heated to 65° C. under high vacuum for 2 h. The mixture is cooled to room temperature and then purified by silica gel flash chromatography (dichloromethane-methanol-triethylamine, 83:8:9) to afford 2-(5-amino-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.76 (s, 3H), 5.72 (s, 2H), 7.15 (t, J=2.3 Hz, 1H), 7.35 (dd, J=8.5, 1.9 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H), 8.12 (d, J=2.5 Hz, 1H). MS (ESI) m/z 283.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4](N)=[O:5].C(OC(=O)C)(=[O:15])C.C(O)(=O)C.N([O-])=O.[Na+]>C(OCC)C>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:15])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(Cl)nc(Cl)c1C(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1cc(Cl)nc(Cl)c1C(=O)O
Reaction time: 18 h

Procedure:
A solution of 2,6-dichloro-4-methyl-nicotinamide (6.40 g) in 2:1 acetic anhydride/acetic acid (156 mL) was treated with sodium nitrite (21.5 g), stirred for 18 hours, poured into diethyl ether (600 mL) and filtered. The filtrate was concentrated with a toluene azeotrope, and the concentrate was treated with brine and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated; and this concentrate was suspended in hexane, sonicated and filtered.
Reaction SMILES: [N:1]([CH2:4][CH2:5][OH:6])=[N+:2]=[N-:3].CCN(CC)CC.[Br:14][C:15]([CH3:20])([CH3:19])[C:16](Br)=[O:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:1]([CH2:4][CH2:5][O:6][C:16](=[O:17])[C:15]([Br:14])([CH3:20])[CH3:19])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCO
Reactant: CC(C)(Br)C(=O)Br
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(Br)C(=O)OCCN=[N+]=[N-]

Procedure:
2-Azidoethanol (17.40 g, 0.2 mol), freshly distilled methylene chloride (150 mL), and Et3N (21.21 g, 0.21 mol) were added into a three-neck round-bottom flask equipped with a condenser and a dropping funnel. Under nitrogen atmosphere and magnetic stirring, freshly distilled anhydrous methylene chloride (150 mL), DMAP (1.7 g, 14 mmol), and freshly distilled anhydrous Et3N (46.5 g, 0.46 mol) were sequentially added. After the flask was immersed into an ice-water bath, 2-bromoisobutyryl bromide (48.28 g, 0.21 mol) was added dropwise into the previous solution. Twenty-four hours later, the reaction mixture was washed successively with 1M HCl (3×200 mL) solution and deionized water (1×200 mL). The organic phase was dried over anhydrous MgSO4 overnight. After filter and removal of methylene chloride on a rotary evaporator, the obtained residues were distilled under reduced pressure to give a colorless viscous liquid. The yield was: 33.4 g, 70%. 1H NMR (CDCl3, δ, ppm): 4.24 (t, 2H, N3CH2CH2), 3.52 (t, 2H, N3CH2), 1.96 (s, 6H, (CH3)2Br).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][N:7]=[C:6]([N:10]2[C:14]([NH:15][C:16]3[CH:17]=[C:18]([NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[CH:19]=[CH:20][C:21]=3[CH3:22])=[CH:13][C:12]([CH3:36])=[N:11]2)[CH:5]=1)=O.[N:37]1([CH2:43][CH2:44][NH2:45])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.CS(C)=O>CC(O)C>[CH3:22][C:21]1[CH:20]=[CH:19][C:18]([NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[CH:17][C:16]=1[NH:15][C:14]1[N:10]([C:6]2[CH:5]=[C:4]([NH:45][CH2:44][CH2:43][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[N:9]=[CH:8][N:7]=2)[N:11]=[C:12]([CH3:36])[CH:13]=1
Reactant: Cc1cc(Nc2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc2C)n(-c2cc(S(C)=O)ncn2)n1
Reactant: NCCN1CCOCC1
Solvent: CS(C)=O
Solvent: CC(C)O
Product: Cc1cc(Nc2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc2C)n(-c2cc(NCCN3CCOCC3)ncn2)n1
Temperature: 80 °C

Procedure:
The mixture of N-{3-[2-(6-Methanesulfinyl-pyrimidin-4-yl)-5-methyl-2H-pyrazol-3-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide (20 mg, 0.04 mmol) and 2-Morpholin-4-yl-ethylamine (100 uL) in 2-propanol is heated to 80° C. for 3 hours. The reaction mixture is cooled to room temperature and condensed. The crude product is then treated with 1 mL DMSO and purified by LC/MS to afford N-(4-Methyl-3-{5-methyl-2-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-2H-pyrazol-3-ylamino}-phenyl)-3-trifluoromethyl-benzamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][S:9]2(=[O:18])=[O:17])=[C:4]([CH3:19])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:39][CH2:40][CH2:41]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[Br:39][CH2:40][CH2:41][N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[CH3:19])[S:9]1(=[O:17])=[O:18]
Reactant: Cc1cc(F)ccc1N1c2ccccc2NS1(=O)=O
Reactant: OCCBr
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(F)ccc1N1c2ccccc2N(CCBr)S1(=O)=O

Procedure:
1-(4-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (prepared analogously as described in general procedure I, 0.35 g, 1.3 mmol) was treated with triphenylphosphine (0.46 g, 1.5 mmol), 2-bromoethanol (0.21 g, 1.4 mmol) and diisopropylazodicarboxylate (0.35 g, 1.7 mmol) to provide 0.32 g of 1-(2-bromoethyl)-3-(4-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide. HRMS: calculated for C15H14BrFN2O2S, 383.99434; found (EI, M+), 383.9958
Reaction SMILES: Br[CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(Cl)Cl>CO>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([N:19]1[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:7]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)C(Br)Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccccc1)N1CCN(C)CC1
Yield: 14.3 %

Procedure:
EThyl 2-bromo-3-phenylpropionate (1.95 g) was treated with 3.05 g N-methylpiperazine as described in Example 95 to afford 0.30 g pure product after chromatography (9:1 CH2Cl2 :MeOH). NMR (300 MHz, CDCl3) delta 1.10 (d, J=7 Hz, 3H), 2.26 (s, 3H), 3.37 (m, 1H), 4.00 (m, 2H).