Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O)[CH3:2].[NH2:21]/[C:22](/[CH2:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[CH:23]\[C:24]([O:26][CH2:27][CH3:28])=[O:25].[CH:35]([C:37]1[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=1)=O.N1CCCCC1>C1(C)C=CC=CC=1>[C:16]([O:15][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[C:6]1[NH:21][C:22]([CH2:29][CH2:30][C:31]([F:32])([F:33])[F:34])=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:35]([C:37]2[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=2)[C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:20])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)/C=C(\N)CCC(F)(F)F
Reactant: CCOC(=O)CC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(CCC(F)(F)F)NC([C@@H]2CCCN2C(=O)OC(C)(C)C)=C(C(=O)OCC)C1c1ccc(C(=O)O)cc1

Procedure:
To a stirred solution of tert-Butyl (2S)-2-(3-ethoxy-3-oxopropanoyl)-1-pyrrolidinecarboxylate (1.35 g, 4.74 mmol) in 30 mL of toluene, ethyl (2Z)-3-amino-6,6,6-trifluoro-2-hexenoate (1.0 g, 4.74 mmol) was added followed by 4-formylbenzoic acid (0.711 g, 4.74 mmol) and piperidine (0.202 g, 2.37 mmol). The reaction was allowed to reflux for 3 h. The crude mixture was concentrated and carried on without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.[CH:13]1([CH2:16][NH2:17])[CH2:15][CH2:14]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:17][CH2:16][CH:13]2[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1
Reactant: NCC1CC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Solvent: ClCCl
Product: O=S(=O)(NCC1CC1)c1ccc(Br)cc1F
Yield: 40 %

Procedure:
According to general procedure C, 4-Bromo-2-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and cyclopropylmethylamine (0.31 mL, 3.65 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-(cyclopropylmethyl)-2-fluorobenzenesulfonamide (0.18 g, 40%) was provided after purification. MS (ESI) m/z 308. HPLC purity 97.7% at 210-370 nm, 10.7 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammonium Bicarb Buff. pH=9.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]2([CH3:36])[CH2:35][O:34][CH2:33]2)[NH:9]1)=[O:7])(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]3([CH3:36])[CH2:33][O:34][CH2:35]3)[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC1(CC2NC(C(=O)OC(C)(C)C)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)COC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(CC2NC(C(=O)O)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)COC1
Yield: 91 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 112b (1.0 g, 1.9 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1 g, 91%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[C:8]2([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]2)[C:9](=[O:16])[N:10]3[CH3:15])=[CH:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:15][N:10]1[C:11]2[C:7](=[C:6]([CH:3]3[CH2:4][CH2:5][O:1][CH2:2]3)[CH:14]=[CH:13][CH:12]=2)[C:8]2([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]2)[C:9]1=[O:16]
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(-c3ccoc3)cccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(C3CCOC3)cccc21
Yield: 72.5 %

Procedure:
To a solution of 4′-furan-3-yl-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.60 g, 1.66 mmol) in ethyl acetate (30 mL) was added palladium on carbon (10% w/w, 0.40 g). The reaction mixture was shaken under a pressure of hydrogen gas (60 psi) in a Parr hydrogenation apparatus at ambient temperature for 16 h and filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo and the residue recrystallized from dichloromethane/diethyl ether to afford methyl-4′-(tetrahydrofuran-3-yl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.44 g, 73%) as a colorless solid: mp 182-184° C. (dichloromethane/ether); 1H NMR (300 MHz, CDCl3) δ 7.31-7.35 (m, 1H), 7.08-7.01 (m, 1H), 6.77 (d, J=7.7 Hz, 1H), 6.52-6.48 (m, 1H), 6.15 (d, J=13.3 Hz, 1H), 5.90-5.84 (m, 2H), 4.96 (dd, J=9.26, 1.0 Hz, 1H), 4.78-4.67 (m, 1H), 4.11-3.59 (m, 3H), 3.39-3.18 (m, 2H), 2.40-1.94 (m, 1H), 1.63-1.36 (m, 1H); MS (ES+) m/z 365.9 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C:4]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3]1.[CH3:28][I:29]>C(Cl)Cl>[I-:29].[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:4]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:5][CH2:6][N+:2]([CH3:28])([CH3:1])[CH2:3]1)[CH3:27]
Reactant: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OCC)CCN(C)C2)cc1
Reactant: CI
Solvent: ClCCl
Product: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OCC)CC[N+](C)(C)C2)cc1
Product: [I-]
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(1-methyl-3-(4-pentylphenylsulfonamido)pyrrolidin-3-yl)acetate (25 mg, 0.063 mmol) in methylene chloride (1 mL) was added methyl iodide (100 μL). The solution was stirred overnight and concentrated to give the title compound as a white solid (33 mg, quantitative). ESI 411.3 [M]+, calcd for [C21H35N2O4S]+ 411.23.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.C(OB([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)O)=O.[C:20](=O)([O-])[O-:21].[K+].[K+].O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([C:18]2[CH:19]=[C:14]([CH:15]=[CH:16][CH:17]=2)[CH:20]=[O:21])[CH:5]=[CH:4][N:3]=1
Reactant: O=COB(O)c1ccccc1
Reactant: O=C([O-])[O-]
Reactant: Fc1cc(I)ccn1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cccc(-c2ccnc(F)c2)c1

Procedure:
2 fluoro-4-iodo pyridine (5 g), 3 formylphenylboronic acid (4 g), and palladium tetrakis triphenylphosphine were suspended in 500 mL of THF. Potassium carbonate (7.42 g) was added along with 50 mL of water. The flask was purged with nitrogen and the mixture heated to 65 C for 4 hours. The solvent was removed by rotary evaporation and the residue partitioned between ethyl acetate and water. Removal of the ethyl acetate gave a residue which was chromatographed on silica gel (1:1 ethyl acetate hexanes) to give the desired product. Yield: 1.42 g. LC-MS showed the product had the expected M+H+ of 202.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([N:7]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9]1)[CH:5]=C.CSC>ClCCl.CO>[C:27]([O:26][C:24]([N:7]([CH2:4][CH:5]=[O:1])[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[CH2:10][CH2:9]1)=[O:25])([CH3:29])([CH3:30])[CH3:28]
Reactant: O=[O+][O-]
Reactant: C=CCN(C(=O)OC(C)(C)C)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CO
Solvent: CSC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CC=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ozone (g) was bubbled into a solution of benzyl 4-[allyl(tert-butoxycarbonyl)amino]piperidine-1-carboxylate (2.75 g, 7.34 mmol) in dichloromethane (30 mL) and methanol (15 mL) at −78° C. for 17 min. Nitrogen (g) was then bubbled into the mixture for 30 min followed by the addition of dimethylsulfide (2.70 mL, 36.72 mmol). The reaction warmed to ambient temperature and stirred for 3 h. The mixture was concentrated and redissolved in ethyl acetate. The ethyl acetate layer was washed with water (2×), brine (2×), dried over sodium sulfate, filtered, and concentrated to give the title compound (2.5 g). MS 277.09 (M+1-boc group)
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]1([CH3:17])[CH:11]=[CH:10][C:9]([S:12]([O:15]C)(=[O:14])=[O:13])=[CH:8][CH:7]=1>>[C:6]1([CH3:17])[CH:7]=[CH:8][C:9]([S:12]([O-:15])(=[O:13])=[O:14])=[CH:10][CH:11]=1.[CH3:6][S+:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCSC1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: C[S+]1CCCC1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 72 h

Procedure:
A mixture of 1.76 g of tetrahydrothiophene and 3.72 g of methyl p-toluenesulfonate was allowed to stand for 3 days at room temperature. The crystals which were deposited were collected by filtration, washed with diethyl ether, and dried. By this procedure crystals of S-methyltetrahydrothiophenium p-toluenesulfonate were obtained. After the product was recrystallized, it had a melting point of 145.0° to 148.0°C.
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:12])[C:9]=1[CH2:10]2.Cl(O)(=O)(=O)=[O:14]>O1CCCC1>[C:8]1([OH:12])[C:9]2[CH2:10][C@@H:11]([OH:1])[C@H:2]([OH:14])[CH2:3][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: Oc1cccc2c1CC1OC1C2
Solvent: C1CCOC1
Product: Oc1cccc2c1C[C@@H](O)[C@H](O)C2

Procedure:
Alternatively, the 2,3-trans-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(substituted-amino)propoxy]-2,3-naphthalenediol isomer XXVII can be prepared from a 5,8-dihydro-1-naphthol of the structure ##STR34## prepared as described hereinbefore, by mixing a cooled solution (temperature less than about 30° C.) of 5,8-dihydro-1-naphthol in ethyl acetate with m-chloroperbenzoic acid and mixing the resulting slurry with a mixture of ethyl ether and aqueous sodium bicarbonate, to form 5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol ##STR35## and reacting the 5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol in tetrahydrofuran with aqueous perchloric acid at a temperature within the range of from about 0° to about 60° C., to form trans-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol XXV which can be converted to the 2,3-trans-1,2,3,4-tetrahydro-5-[2,3-(epoxy)-propoxy]-2,3-naphthalenediol XXVI which in turn can be converted to the 2,3-trans-1,2,3,4-tetrahydro-5-[2-hydroxy-3-substituted amino)propoxy]-2,3-naphthalenediol XXVII in a manner similar to that described hereinbefore.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:17]#[N:18])=[CH:12][N:13]=[C:14]([NH:15][CH3:16])[C:5]=3[C:4]=2[CH:3]=1.C([O-])([O-])=[O:20].[K+].[K+].OO>CS(C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:17]([NH2:18])=[O:20])=[CH:12][N:13]=[C:14]([NH:15][CH3:16])[C:5]=3[C:4]=2[CH:3]=1
Reactant: CNc1ncc(C#N)c2[nH]c3ccc(F)cc3c12
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CNc1ncc(C(N)=O)c2[nH]c3ccc(F)cc3c12
Temperature: 50 °C

Procedure:
8-Fluoro-1-(methylamino)-5H-pyrido[4,3-b]indole-4-carbonitrile (36 mg, 0.150 mmol) was combined with K2CO3 (55.9 mg, 0.405 mmol) and dissolved in DMSO (3 ml) followed by the addition of hydrogen peroxide (0.066 ml, 0.749 mmol). The solution was heated at 50° C. for three hr. The solution was cooled to ambient temperature directly purified by HPLC (eluted with MeCN/H2O with 1% TFA).
Reaction SMILES: C([NH:4][C@H:5]([C:7]([O:9]C(=O)[C@H](C)NC(O)=O)=[O:8])[CH3:6])(O)=[O:2].C([NH:21][C@@H:22]1[C:28](=[O:29])[O:27][C:25](=[O:26])[CH:24]([CH3:30])[CH2:23]1)(O)=O>C1C=CC=CC=1>[CH3:6][C@H:5]([NH2:4])[C:7]([OH:9])=[O:8].[CH3:30][CH:24]([C:25]([OH:26])=[O:2])[CH2:23][C@@H:22]([C:28]([OH:27])=[O:29])[NH2:21]
Reactant: C[C@H](NC(=O)O)C(=O)OC(=O)[C@H](C)NC(=O)O
Reactant: CC1C[C@H](NC(=O)O)C(=O)OC1=O
Solvent: c1ccccc1
Product: CC(C[C@H](N)C(=O)O)C(=O)O
Product: C[C@H](N)C(=O)O
Reaction time: 84 h

Procedure:
N-carboxy-L-alanine anhydride and N-carboxy-γ-methyl-L-glutamic acid anhydride were added to benzene at a molar ratio of 9:1 and 1.8 wt % in total, and the mixture was stirred at 55° C.-65° C. for 3-4 days to give a poly-L-alanine/γ-methyl-L-glutamic acid copolymer (molar ratio 9:1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[N+:29]([O-])=O)[CH:3]=1.[CH3:32]CO.CCOC(C)=O>[Pd]>[CH2:1]([C:2]1[N:7]=[C:6]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[NH2:29])[CH:3]=1)[CH3:32]
Reactant: Cc1cc(-c2ccncc2[N+](=O)[O-])cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Reactant: CCO
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cc(-c2ccncc2N)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Reaction time: 18 h
Yield: 95 %

Procedure:
To a solution of 6-methyl-N,N-di-BOC-3′-nitro-4,4′-bipyridin-2-amine in EtOH/EtOAc (1:1, 0.2M) was added Pd/C (10% by weight) and the reaction was stirred under a H2 balloon for 18 hrs. Filtered through Celite, washed with EtOAc and concentrated the filtrate to afford 6-ethyl-N2,N2-di-BOC-4,4′-bipyridine-2,3′-diamine in >95% yield. LCMS (m/z): 401.0 (MH+); LC Rt=2.81 min.
Reaction SMILES: Cl[CH2:2][S:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[N:12][CH:11]=[CH:10]2)(=[O:5])=[O:4].[NH2:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([NH:23][CH3:24])=[O:22]>CO>[NH3:6].[CH:13]1[C:14]2[C:9](=[CH:8][C:7]([NH:6][S:3]([CH2:2][NH:17][C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21]([NH:23][CH3:24])=[O:22])(=[O:5])=[O:4])=[CH:16][CH:15]=2)[CH:10]=[CH:11][N:12]=1
Reactant: CNC(=O)c1cccc(N)c1
Reactant: O=S(=O)(CCl)Nc1ccc2cnccc2c1
Solvent: CO
Product: CNC(=O)c1cccc(NCS(=O)(=O)Nc2ccc3cnccc3c2)c1
Product: N
Temperature: 60 °C
Reaction time: 3 h
Yield: 2 %

Procedure:
To 1-chloro-N-(isoquinolin-6-yl) methanesulfonamide in MeOH is added KI and the solution is heated to 60° C. for 40 minutes. The mixture is cooled to 45° C. and 3-amino-N-methylbenzamide is added and stirred at 45° C. After 2-4 hours or when TLC indicated completion of the reaction, the solvents are evaporated and the residue is taken up in EtOAc and extracted with NaHCO3 (sat). The organics are dried (Na2SO4), filtered and evaporated. Flash chromatography (SiO2, 2% NH3(2M) in MeOH/3% MeOH/CH2Cl2) gives 3-((N-isoquinolin-6-ylsulfamoyl)methylamino)-N-methylbenzamide.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[NH2:16][C@@H:17]([C:19]([OH:21])=[O:20])[CH3:18].C([O-])([O-])=O.[Na+].[Na+].[N+](C1C=CC=C([N+]([O-])=O)C=1C(O)=O)([O-])=O>>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=1[C:6]([NH:16][C@H:17]([CH3:18])[C:19]([OH:21])=[O:20])=[O:7])([O-:3])=[O:2]
Reactant: C[C@@H](N)C(=O)O
Reactant: O=C(Cl)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@@H](NC(=O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-])C(=O)O

Procedure:
The reaction of 2,6-dinitrobenzoyl chloride (prepared from 2,6-dinitrobenzoic acid, 1.4 g and SOCl2, 15 mL) with D-alanine (0.7 g, 7.92 mmol) in the presence of Na2CO3 (0.83 g, 7.92 mmol) as described in intermediate 2 gave the title compound as a pale brown color solid (1.58 g, 85%), mp 202-204° C. 1H NMR (400 MHz, DMSO-d6): δ 12.79 (1H, br s), 9.24 (1H, d, J=7.6 Hz), 8.45 (2H, d, J=8.4 Hz), 7.93 (1H, t, J=8.4 Hz), 4.48 (1H, pentet, J=7.3 Hz), 1.33 (3H, d, J=7.2 Hz); LC-MS (negative ion mode): m/z 282 (M−H)−.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[N:21]=[C:20]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH3:28])[CH:27]=3)[C:19]3[C:14](=[CH:15][C:16]([OH:29])=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[N:21]=[C:20]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH3:28])[CH:27]=3)[C:19]3[C:14](=[CH:15][C:16]([O:29][CH2:37][CH2:38][CH2:39][N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[CH:17][CH:18]=3)[N:13]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)c3ccc(O)cc3n2)cc1
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)c3ccc(OCCCN4CCOCC4)cc3n2)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of [2-(4-acetamidophenylsulfanyl)-7-hydroxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (32 mg, 7.87.10−5 mol) in DMF (1 mL) is added potassium carbonate (65 mg, 4.72.10−4 mol) and the reaction mixture is heated to 80° C. N-(3-chloropropyl)morpholine (39 mg, 2.36.10−4 mol) is then added, and the mixture is stirred at 80° C. for 4 hours, cooled to room temperature and the solvent is evaporated. The resulting residue is purified by flash chromatography to afford the desired [2-(4-acetamidophenylsulfanyl)-7-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: C([BH-](CC)CC)C.[Li+].C(N(CC)[C:12]1[N:17]=[C:16]([NH:18][C:19]([NH:21][C:22]2[N:23]=[C:24]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[S:25][CH:26]=2)=[O:20])[C:15](C)=[CH:14][CH:13]=1)C.[CH3:36][CH2:37][N:38]([CH:42](C)C)[CH:39](C)[CH3:40]>C1COCC1>[CH2:37]([N:38]([CH2:42][C:12]1[N:17]=[C:16]([NH:18][C:19]([NH:21][C:22]2[N:23]=[C:24]([CH:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)[S:25][CH:26]=2)=[O:20])[CH:15]=[CH:14][CH:13]=1)[CH2:39][CH3:40])[CH3:36]
Reactant: CCN(CC)c1ccc(C)c(NC(=O)Nc2csc(-c3ccncc3)n2)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)Cc1cccc(NC(=O)Nc2csc(C3CCNCC3)n2)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Lithium triethylborohydride (0.84 mL, 0.84 mmol, 1.0 M in THF) was added to a solution of 1-(6-diethylamino-methyl-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)urea (100 mg, 0.24 mmol, Example 117) and DIEA (63 μL, 0.36 mmol) in THF (5 mL) and the resulting mixture was stirred 6 h at RT. The reaction was quenched via dropwise addition of MeOH and concentrated in vacuo. Purification by preparative HPLC (5-60% CH3CN/H2O) gave a white solid. MS m/z: 389.2 (M+H). Calc'd for C19H28N6OS-388.53.
Reaction SMILES: [CH:1]1([N:7]([CH3:18])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC(C(OCC)=O)=CC=1.C1C(=O)N([Br:38])C(=O)C1>>[CH:1]1([N:7]([CH3:18])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][Br:38])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)N(C)C2CCCCC2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CCOC(=O)c1ccc(C)cc1
Product: CN(C1CCCCC1)S(=O)(=O)c1ccc(CBr)cc1
Yield: 90.1 %

Procedure:
Utilising the procedure described in Example 1(a) employing N-cyclohexyl-N-methyl 4-methylbenzenesulphonamide (20.0 g, 0.075 mol) in lieu of ethyl 4-methylbenzoate and two equivalents of NBS (27.0 g, 0.15 mol) yielded a crude product of N-cyclohexyl-N-methyl 4-bromomethylbenzenesulphonamide (23.4 g, 90%) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Br:12][CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].C(Cl)CCl>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([CH2:13][Br:12])=[C:15]([N+:23]([O-:25])=[O:24])[CH:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: NNC(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NNC(=O)c1ccc(CBr)c([N+](=O)[O-])c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 100 mL round-bottom flask was added 2.1 g (12.3 mmol) of 4-chlorobenzoic acid hydrazide, 3.20 g (12.3 mmol) of 4-bromomethyl-3-nitro benzoic acid, 3.54 g (18.5 mmol) of EDC, and 200 mL of DCM. Allowed to stir at room temperature for 18 h. Removed ⅔ of DCM, added water and filtered off white solid and washed with Et2O to give 3-nitro-4-bromomethyl-benzoic acid N′-(4-chloro-benzoyl)-hydrazide as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.99 (s, 1 H) 5.12 (s, 1 H) 7.59-7.64 (m, 2 H) 7.91-7.95 (m, 2 H) 7.96 (d, J=8.21 Hz, 1 H) 8.22-8.29 (m,1 H) 8.57 (dd, J=6.57, 1.77 Hz, 1 H) 10.76 (s, 1 H) 10.94 (dd, J=5.18, 0.88 Hz, 1 H). MS (m/z) 413.9 M (+1), tR=1.28, Meth 10. To a 500 mL round-bottom flask was added 4.95 g (12.0 mmol) of 3-nitro-4-bromomethyl-benzoic acid N′-(4-chloro-benzoyl)-hydrazide, 6.09 g (36.0 mmol) DMC, and 100 mL of DCE. To this pale yellow solution was added 6.70 mL (48.0 mmol) of Et3N, slowly over 5 min. The dark green solution was allowed to stir at 40° C. for 30 min. then cooled to room temperature stirred for 18 h. Removed solvent and purified over a silica plug 10-30% EtOAc/Hep to give the title compound as yellow solid. MS (m/z) 350.0 M (+1), retention time=1.51, Method 10.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH2:11][C@H:12]([OH:18])[CH2:13][C@H:14]([OH:17])[CH:15]=[CH2:16].CN(C=O)C.N1[CH:28]=[CH:27]N=C1.[C:29]([Si:33](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:32])([CH3:31])[CH3:30]>CCCCCC.CCOC(C)=O>[C:29]([Si:33]([C:28]1[CH:27]=[CH:45][CH:40]=[CH:41][CH:42]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:18][C@H:12]([CH2:13][C@H:14]([O:17][Si:33]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:15]=[CH2:16])[CH2:11][C:10]#[C:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C=C[C@@H](O)C[C@@H](O)CC#CCOC1CCCCO1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=C[C@H](C[C@H](CC#CCOC1CCCCO1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 20 h

Procedure:
10.40 g (40.9 mmol) of (3S,5S)-9-(tetrahydro-pyran-2-yloxy)-non-1-en-7-yne-3,5-diol was dissolved in 30 ml of abs. DMF and treated successively with 18.9 g (6.8 eq.) of imidazole and 35.5 ml (3.4 eq.) of tert-butyl-chlorodiphenylsilane. After stirring for 20 h at 40°, the reaction mixture was poured onto crushed ice/EtOEt. Usual workup followed by flash chromatography (SiO2, hexane/AcOEt=96/6) gave 25.16 g of (5S,7S)-2-[5,7-bis-(tert-butyl-diphenyl-silanyloxy)-non-8-en-2-ynyloxy]-tetrahydropyran as colorless oil (1:1 epimeric mixture).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11].O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[C:4]([F:8])[C:3]=1[OH:9]
Reactant: O=[N+]([O-])O
Reactant: Oc1c(F)cccc1F
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(F)c(O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 2,6-difluorophenol (2.00 g) in acetic acid (20 ml) was added dropwise 60% nitric acid (1.20 ml) in an ice bath and the mixture was stirred at room temperature for 1 hour. After pouring into iced water, the reaction mixture was extracted with ethyl acetate. The extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=3/1→2/1 as an eluant to give the desired compound (1.37 g, yield 51%) as a pale yellow solid.