Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:4][CH:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[S:28]([N:31]1[CH2:38][CH2:37][CH2:36][C@H:32]1[C:33](Cl)=[O:34])(=[O:30])=[O:29].C(OCC)(=O)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:13][N:12]([C:33](=[O:34])[C@@H:32]3[CH2:36][CH2:37][CH2:38][N:31]3[S:28]([C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=3)(=[O:30])=[O:29])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)[C@@H]1CCCN1S(=O)(=O)c1ccc2ccccc2c1
Reactant: Clc1ccc(C2CNc3ccccc3S2)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C([C@@H]1CCCN1S(=O)(=O)c1ccc2ccccc2c1)N1C[C@@H](c2ccc(Cl)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.5 %

Procedure:
To a solution of (±)-2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (10.01 g, 0.038 mole) in pyridine (150 ml) is added (S)-N-(2-naphthalenesulfonyl)prolyl chloride (18.57 g, 0.057 mole), and the mixture is stirred at room temperature for 4 hours. To the reaction mixture is added ethyl acetate, and the mixture is washed with 5% hydrochloric acid, water, aqueous sodium hydrogen carbonate solution, water and saline in this order, and the ethyl acetate layer is separated, dried over sodium sulfate and distilled to remove the solvent. The resulting caramel is subjected to silica gel column chromatography (hexane: ethyl acetate=5:1-3:1). From the fraction eluted first there is obtained (R)-2-(4-chlorophenyl)-4-[(S)-N-(2-naphthalenesulfonyl)prolyl]-3,4-dihydro-2H-1,4-benzothiazine (10.75 g, 51%) as crystals. M.p. 147°-151° C.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[O:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:15]1COC[CH2:16]1.[C-]#[C-].[Na+].[Na+].Cl>C1(C)C(C)=CC=CC=1>[C:15]([C:12]1([OH:14])[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)#[CH:16]
Reactant: C1CCOC1
Reactant: O=C1c2ccccc2-c2ccccc21
Agent: Cl
Agent: [C-]#[C-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: C#CC1(O)c2ccccc2-c2ccccc21
Reaction time: 8 h

Procedure:
9 g (0.05 mol) of 9-fluorenone and 100 ml of anhydrous THF are charged into a dry flask of 250 ml. To the resulting solution a suspension of sodium acetylide [17.8 g (0.0525 mol) in mineral oil/xylene, 18% by weight based on the suspension; solid purity 95%] is added under nitrogen, by means of a syringe. The resulting suspension is kept overnight under nitrogen and with stirring before being poured into 75 ml of 10% HCl. The phases are separated and the aqueous phase is extracted twice with 100 ml of ethyl ether. The organic extracts are combined and thoroughly dried over sodium sulfate. By eliminating the solvent, 10.1 g of product is obtained, which is used without any further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([C:16]([OH:18])=O)[N:7]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH3:32][NH:33][CH:34]([CH2:36][CH3:37])[CH3:35]>C(Cl)(Cl)Cl>[CH3:32][N:33]([CH:34]([CH3:35])[CH2:36][CH3:37])[C:16]([C:8]1[N:7]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:15]2[C:10]([CH:9]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:18]
Reactant: O=C(O)c1cc2ccccc2c(-c2cccs2)n1
Reactant: CCC(C)NC
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(C)N(C)C(=O)c1cc2ccccc2c(-c2cccs2)n1
Yield: 65.6 %

Procedure:
Operations are carried out as for Example 7, starting from 3 g of 1-(2-thienyl) isoquinoline 3-carboxylic acid, 1.73 g of triethylamine, 1.86 g of ethyl chloroformate and 1.69 g of N-methyl 2-butanamine in 150 ml of chloroform. 2.5 g of N-methyl N-(1-methyl propyl) 1-(2-thienyl) isoquinoline 3-carboxamide, melting at 146° C. are obtained.
Reaction SMILES: C(OC(CCCCC)CCCC(CCCCCCC(OCC)=O)(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)(=O)C.[C:40]([O:43][CH:44]([CH2:74][CH2:75][CH2:76][CH2:77][CH3:78])[CH2:45][CH2:46][CH2:47][C:48]([CH2:63][CH2:64][CH2:65][CH2:66][O:67][CH2:68][C:69]([O:71][CH2:72][CH3:73])=[O:70])(C(OC(C)(C)C)=O)[C:49]([O:51]C(C)(C)C)=[O:50])(=[O:42])[CH3:41]>>[C:49]([CH:48]([CH2:47][CH2:46][CH2:45][CH:44]([O:43][C:40](=[O:42])[CH3:41])[CH2:74][CH2:75][CH2:76][CH2:77][CH3:78])[CH2:63][CH2:64][CH2:65][CH2:66][O:67][CH2:68][C:69]([O:71][CH2:72][CH3:73])=[O:70])([OH:51])=[O:50]
Reactant: CCCCCC(CCCC(CCCCOCC(=O)OCC)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC(C)=O
Agent: CCCCCC(CCCC(CCCCCCC(=O)OCC)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC(C)=O
Product: CCCCCC(CCCC(CCCCOCC(=O)OCC)C(=O)O)OC(C)=O

Procedure:
This compound is prepared essentially by the method described in Example 1, Step D except that the di-tert.-butyl 2-(4-acetoxynonyl)-2-(6-ethoxycarbonylhexyl)-malonate of the example is replaced by di-tert.-butyl 2-(4-acetoxynonyl)-2-[4-(ethoxycarbonylmethoxy)-butyl]-malonate. The title compound is purified by column chromatography on silica gel.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.Cl.[CH3:29][C:30]1([OH:34])[CH2:33][NH:32][CH2:31]1.Cl>O1CCCC1>[OH:34][C:30]1([CH3:29])[CH2:33][N:32]([S:2]([C:5]2[CH:14]=[C:13]3[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][NH:11][C:12]3=[O:15])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH2:31]1
Reactant: CC1(O)CNC1
Reactant: O=C(O)c1c[nH]c(=O)c2cc(S(=O)(=O)Cl)ccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(O)CN(S(=O)(=O)c2ccc3c(C(=O)O)c[nH]c(=O)c3c2)C1

Procedure:
7-(Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (1 g), diisopropylethylamine (3 ml) and 3-methylazetidin-3-ol hydrochloride (0.8 g) in tetrahydrofuran (8 ml) were heated at 55° C. for 3 days. The mixture was acidified with hydrochloric acid and then filtered to yield 7-[(3-hydroxy-3-methylazetidin-1-yl)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid as a pale pink solid.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][O:6]/[N:7]=[C:8](/[C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([CH2:19][C:20]3[C:21]([F:31])=[C:22]4[C:27](=[CH:28][C:29]=3[F:30])[N:26]=[CH:25][CH:24]=[CH:23]4)=[N:17][N:18]=2)[N:15]=1)\[CH3:9].COCCN(S(F)(F)[F:42])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:42][CH2:2][CH2:3][CH2:4][CH2:5][O:6]/[N:7]=[C:8](/[C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([CH2:19][C:20]3[C:21]([F:31])=[C:22]4[C:27](=[CH:28][C:29]=3[F:30])[N:26]=[CH:25][CH:24]=[CH:23]4)=[N:17][N:18]=2)[N:15]=1)\[CH3:9]
Reactant: C/C(=N\OCCCCO)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C/C(=N\OCCCCF)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Reaction time: 1 h

Procedure:
To a solution of (E)-1-(3-((5,7-difluoroquinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone O-4-hydroxybutyl oxime (30 mg, 0.070 mmol) (example 65) in 4 mL of DCM at −78° C. was added bis(2-methoxyethyl)aminosulfur trifluoride (180 mg, 0.813 mmol). The mixture was stirred at this temperature for 1 h, and stirred at it overnight. The mixture was poured into saturated aqueous NaHCO3, extracted with DCM, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with DCM/methanol afforded the title compound. 1H-NMR (400 MHz, CDCl3) δ ppm 8.94 (s, 1H), 8.37 (d, 1H), 7.98 (d, 1H), 7.81 (d, 1H), 7.63 (d, 1H), 7.44 (dd, 1H), 4.81 (s, 2H), 4.58-4.57 (m, 1H), 4.45 (t, 1H), 4.32 (t, 2H), 2.26 (s, 3H), 1.90-1.78 (m, 4H). LCMS (method A): [MH]+=429, tR=5.239 min.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[CH:11]=[C:10]([C:18](O)=[O:19])[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:25])=O.CN(C)C=O>ClCCl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[CH:11]=[C:10]([C:18]([Cl:25])=[O:19])[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2cccnc2n(Cc2ccccc2)c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2cccnc2n(Cc2ccccc2)c1=O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
1.61 g (5.7 mmol) of 1-benzyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid was dissolved in dichloromethane (60 mL), and 3.5 mL (42 mmol) of oxalyl chloride was added thereto. One droplet of N,N-dimethylformamide was added to the above mixture, and the resulting mixture was stirred for one hour at 40° C. The reaction solution was concentrated under reduced pressure, and thus 1-benzyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in dichloromethane (60 mL), and 0.71 g (6.3 mmol) of 1,3-cyclohexanedione and 0.97 mL (6.9 mmol) of triethylamine were added to the above solution. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into an aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with dichloromethane. The organic phase was dried and concentrated. The residue was washed with diisopropyl ether, and thus 2.13 g of the title compound was obtained as a light yellow solid (yield: quantitative).
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[C:8]([O:24][CH3:25])=[C:9]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]([C:15]#[N:16])=[C:11]([CH3:14])[C:12]=1I.[CH:26](/B(O)O)=[CH:27]\[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[Br:6][C:7]1[C:8]([O:24][CH3:25])=[C:9]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]([C:15]#[N:16])=[C:11]([CH3:14])[C:12]=1[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1c(Br)c(I)c(C)c(C#N)c1NC(=O)C(C)(C)C
Reactant: OB(O)/C=C/c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(Br)c(C=Cc2ccccc2)c(C)c(C#N)c1NC(=O)C(C)(C)C
Temperature: 95 °C
Reaction time: 8 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (6.4 mg, 5.5 μmol) was added to an N,N-dimethylformamide (1.0 ml) suspension of N-(3-bromo-6-cyano-4-iodo-2-methoxy-5-methylphenyl)-2,2-dimethylpropionamide (I-6) (50 mg, 111 μmol), trans-β-styreneboronic acid (17.2 mg, 116 μmol), potassium phosphate n-hydrate (74-78%, 64 mg, 222 μmol), followed by stirred overnight at 95° C. The reaction liquid was cooled, then ethyl acetate (30 ml) was added, followed by washing with saturated brine (30 ml×2), drying over anhydrous magnesium sulfate, concentrating under reduced pressure.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[CH:9][CH:8]=1.[CH2:22]=O>C(O)(=O)C>[Cl:6][C:7]1[CH:8]=[C:9]2[C:10]([CH2:13][CH2:14][N:15]([C:16](=[O:21])[C:17]([F:19])([F:20])[F:18])[CH2:22]2)=[CH:11][CH:12]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)C(F)(F)F
Reactant: C=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(N1CCc2ccc(Cl)cc2C1)C(F)(F)F
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a mixture of concentrated sulfuric acid (40 mL) and acetic acid (60 mL), N-[2-(4-chlorophenyl)ethyl]-2,2,2-trifluoroacetamide (14.2 g) and paraformaldehyde (2.79 g) were added sequentially and stirred overnight under an argon atmosphere. The reaction mixture was added to ice-cold water, extracted with ethyl acetate, and then washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 7-chloro-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline (13.7 g) as a light-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([N:26]([S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:34](=[O:41])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCS(=O)(=O)N(C(=O)c1ccccc1)c1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a suspension of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfonamide (0.2 g, 0.41 mmol) in dioxane (15 mL) were added benzoyl chloride (57 mg, 0.41 mmol) and triethylamine (0.14 g, 1.38 mmol). The reaction was stirred at rt for 1 h, then concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/EtOAc (v/v)=4/1) to afford the title compound as a white solid (0.14 g, 55%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]([CH3:21])[C:16]([O:18]CC)=O)[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:28][C:16](=[O:18])[CH:15]([C:7]2[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([OH:4])[CH:6]=2)[CH3:21])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)C(C)c1ccc(OC(C)=O)c(OC(C)=O)c1
Product: CC(C(=O)NC1CCCCC1)c1ccc(O)c(O)c1

Procedure:
Ethyl 3,4-diacetoxyphenylpropionate and cyclohexylamine were used to obtain N-Cyclohexyl-3,4-dihydroxyphenylpropionamide by carrying out the same procedures as described in Example 1 as an fatty product.
Reaction SMILES: C([O:8][C:9]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=1[C:11]#[N:12])C1C=CC=CC=1.C(O)C.Cl[Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27].N1C=CN=C1>[Pd].C(OCC)C>[F:20][C:17]([F:18])([F:19])[C:14]1[CH:15]=[CH:16][C:9]([O:8][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])=[C:10]([CH:13]=1)[C:11]#[N:12]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: N#Cc1cc(C(F)(F)F)ccc1OCc1ccccc1
Agent: [Pd]
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CCO
Product: CC(C)[Si](Oc1ccc(C(F)(F)F)cc1C#N)(C(C)C)C(C)C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
Intermediate B, Step 2: A 250-mL round bottom flask containing a magnetic stir bar was charged successively with 2-(benzyloxy)-5-(trifluoromethyl)benzonitrile (7.30 g, 26.3 mmol), ethanol (76 mL) and 10 wt % palladium on carbon (560 mg, 5.27 mmol). The resulting solution was put under a hydrogen atmosphere and stirred for 3 h. The solution was then filtered and evaporated until all ethanol was removed. The residue was redissolved in DMF (38 mL), and chlorotriisopropylsilane (9.02 mL, 42.1 mmol) and imidazole (2.87 g, 42.1 mmol) were added and stirred for 4 h. At this time the solution was diluted with diethyl ether (300 mL) and washed with brine (5×100 mL). The organic layer was dried (MgSO4) and concentrated on a rotary evaporator. The residue was purified using a 120 g silica gel cartridge and 20:1 Hex/EtOAc to 4:1 Hex/EtOAc to elute 5-(trifluoromethyl)-2-(triisopropylsilyloxy)benzonitrile (8.80 g, 25.6 mmol, 97% yield) as a colorless oil. LC/MS [M+H]-=344.19. 1H-NMR (400 MHz, CDCl3) δ=7.83 (s, 1H), 7.70 (dd, J=8.0, 3.6 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 1.15-1.0 (m, 21H).
Reaction SMILES: [CH2:1]1[O:24][CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:11][CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)[O:3][CH2:2]1.[N-:25]=[N+:26]=[N-:27].[Na+]>CS(C)=O.O>[CH2:1]1[O:24][CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:11][CH2:12][N:25]=[N+:26]=[N-:27])[O:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccccc2C2OCCO2)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCc1ccccc1C1OCCO1
Yield: 95.7 %

Procedure:
A solution of 2-(2-(4-methylphenylsulphonyloxy)ethyl)benzaldehyde ethylene acetal (1.43 g, 4.10 mmol) and sodium azide (0.53 g, 8.2 mmol) in DMSO (20 ml) was stirred for 16 h, diluted with water, extracted three times with ether, washed with brine, dried over sodium sulphate and evaporated to afford the product as a yellow oil (0.86 g), MS (+EI) 190 [(M-NH2)+], 1H NMR (d6 -DMSO) 7.53-7.25 (4H, m), 5.92 (1H, s), 4.19-3.95 (4H, m), 3.53 (2H, t, J7.2 Hz), 2.98 (2H, t, J7.2 Hz).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][N:22]=1.O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:14][C:12]2[S:13][C:9]([C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[O:8])=[C:10]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[N:11]=2)=[O:26])=[CH:23][N:22]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)c1ccc(Cl)nc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
Compound 454 (125 mg, 0.450 mmol) and DMAP (3.0 mg, 0.022 mmol) were suspended in pyridine (2 mL), and 6-chloronicotinoyl chloride (158 mg, 0.897 mmol) was added thereto, followed by stirring at 80° C. for 1 hour. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was reslurried with ethanol to afford the entitled Compound 502 (138 mg, 73%) as a pale brown solid.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[N:5]([CH2:16][CH3:17])[C:4]=2[CH:3]=1.[CH3:18][C:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][N:21](C(OC(C)(C)C)=O)[N:20]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH2:16]([N:5]1[C:4]2[CH:3]=[C:2]([C:23]3[CH:22]=[N:21][NH:20][C:19]=3[CH3:18])[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]21[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH3:17]
Reactant: CCN1c2cc(Br)sc2C(=O)NC12CCCC2
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCN1c2cc(-c3cn[nH]c3C)sc2C(=O)NC12CCCC2
Temperature: 100 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
A flask was charged with 6′-bromo-1′-ethyl-1′H-spiro [cyclopentane-1,2′-thieno[3,2-d]pyrimidin]-4′(3′H)-one (158 mg, 0.50 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (463 mg, 1.5 mmol), sodium carbonate (150 mg, 2.5 mmol), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL). The flask was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (41 mg, 0.050 mmol) was added to the mixture. The flask was purged with argon again. After stirring at 100° C. for 1 h, 8 M aqueous NaOH (0.5 mL) was added. After stirring at 100° C. for 1 h, organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 50:50 hexane/EtOAc to EtOAc), then crystallized from MeOH/EtOAc/hexane to give the title compound (86 mg, 54%) as a yellow solid:
Reaction SMILES: [C:1]([C:4]1[C:5]([I:21])=[C:6]([C:15]([I:20])=[C:16]([NH2:19])[C:17]=1[I:18])[NH:7][C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])([OH:3])=[O:2].[C:22](OC(=O)C)(=[O:24])[CH3:23]>Cl(O)(=O)(=O)=O>[C:1]([C:4]1[C:5]([I:21])=[C:6]([C:15]([I:20])=[C:16]([NH:19][C:22](=[O:24])[CH3:23])[C:17]=1[I:18])[NH:7][C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])([OH:3])=[O:2]
Reactant: Nc1c(I)c(NC(=O)CCC(=O)O)c(I)c(C(=O)O)c1I
Reactant: CC(=O)OC(C)=O
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(=O)Nc1c(I)c(NC(=O)CCC(=O)O)c(I)c(C(=O)O)c1I

Procedure:
Potassium iododichloride (335 ml. 2.23N in water), was added over a period of forty minutes to a stirred suspension of 57.3 g. of 3'-carboxy-5'-aminosuccinanilic acid in 435 ml. of water. The solid product was collected by filtration and recrystallized from water and from aqueous dimethylformamide. The product was purified by converting it to the diammonium salt and then to the disodium salt, m.p. 222°-225° C. (dec.). The latter was acidified to produce the free acid form of 3'-carboxy-5'-amino-2',4',6'-triiodosuccinanilic acid, cream colored solid, m.p. 156.2°-172.2° C. (dec.). 3'-Carboxy-5'-amino-2',4',6'-triiodosuccinanilic acid can be acylated with acetic anhydride, using a few drops of perchloric acid as a catalyst to obtain 3'-carboxy-5'-acetamido-2',4',6'-triiodosuccinanilic acid [B; R is CH3CONH, R' and R" are H, Y' is CH2CH2, Z is OH].
Reaction SMILES: Cl.C(NCC(C(C1C=CC(O)=C(O)C=1)=O)C)(C)(C)C.C([Cl:26])(=O)C(C)(C)C.FC(F)(F)C(O)=O.Cl.Cl.[C:36]([NH:40][CH2:41][C:42]([C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])=[C:46]([O:57][C:58](=[O:63])[C:59]([CH3:62])([CH3:61])[CH3:60])[CH:45]=1)=[O:43])([CH3:39])([CH3:38])[CH3:37]>[Pd]>[ClH:26].[C:58]([O:57][C:46]1[CH:45]=[C:44]([CH:49]=[CH:48][C:47]=1[O:50][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])[CH:42]([OH:43])[CH2:41][NH:40][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:63])[C:59]([CH3:62])([CH3:60])[CH3:61]
Reactant: CC(C)(C)NCC(=O)c1ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Pd]
Agent: CC(CNC(C)(C)C)C(=O)c1ccc(O)c(O)c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NCC(O)c1ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1

Procedure:
3,4-Dihydroxyphenyl 1-(tert-butylaminomethyl)ethyl ketone hydrochloride (8 g.) was reacted with 18 ml. of pivalyl chloride in 35 ml. of trifluoroacetic acid, the resulting ester-amine salt was converted to the ester-amine, and the ester-amine was treated with hydrochloric acid to yield 10.5 g. of 3,4-bis-(pivalyloxy)phenyl tert-butylaminomethyl ketone hydrochloride, m.p. 200°-202° C. (uncorr.). This ketone was catalytically hydrogenated in the presence of palladium-on-charcoal catalyst to yield 3,4-bis(pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride as a white crystalline solid which melted at 205°-207° C. (uncorr.).
Reaction SMILES: O=[C:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]([N:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)[C:6]1[CH:7]=[N:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)=[O:4].Cl.[NH2:35][OH:36].N1C(C)=CC=CC=1C>CCO>[OH:36][N:35]=[C:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]([N:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=1)[C:6]1[CH:7]=[N:8][C:9]([C:12]([F:15])([F:13])[F:14])=[CH:10][CH:11]=1)=[O:4]
Reactant: O=C(C(=O)N(CCc1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)nc1)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: Cc1cccc(C)n1
Product: O=C(C(=NO)c1ccccc1)N(CCc1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 45.7 %

Procedure:
To a solution of 2-oxo-2-phenyl-N-[2-(4-trifluoromethyl-phenyl)-ethyl]-N-(6-trifluoromethyl-pyridin-3-yl)-acetamide (46 mg, 0.1 mmol) in EtOH (2 mL) was added hydroxylamine hydrochloride (14 mg, 0.2 mmol) and 2,6-lutidine (32 mg, 0.3 mmol) and the mixture stirred at ambient temperature for 36 h then concentrated and redissolved in EtOAc (5 mL), washed with 10% aqueous citric acid (3×5 mL), dried over Na2SO4, filtered, then purified by chromatography (SiO2, heptane:ethyl acetate=95:5 to 50:50) to afford the title compound (22 mg, 46%) as a white solid. MS m/e: 480.3 [M+H]+.