Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1>>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Product: O=C(O)c1ccc(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)cc1
Yield: 85.9 %

Procedure:
3-nitrophthalic anhydride (0.79 g, 0.0041 mol) and p-aminobenzoic acid (0.56 g, 0.0041 mol) were refluxed as above overnight. Concentration of the solution under vacuum by rotary evaporator and crystallisation of the product from EtOH/H2O yielded 1.1 g (68%) of 125 as a vibrant light yellow powder: mp=338–340° C.; Rf 0.76 (A): Rf 0.89 (C): Rf 0.66 (D): R (cm−1): 2750–3125 (OH), 3091 (C═CH), 2671 (C—H), 1782 (C═O), 1736 (C═O), 1693 (C═O), 1610 (C═C), 1585 (C═C), 1529 (N═O), 1513 (C═C), 1433 (C═C), 1378 (C—O), 1360 (N═O), 1291 (C—O), 766 (C═CH); MS m/z (rel intensity) 311 (100), 267 (25), 191 (15).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>C(O)(C)C>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][N:5]=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:29])=[O:30])=[CH:24][CH:23]=2)[N:3]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(Cl)nc1N
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(Nc2ccc(S(N)(=O)=O)cc2)nc1N

Procedure:
A solution of (4-amino-2-chloro-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone (120 mg, 0.40 mmol, Example 289) and 4-amino-benzenesulfonamide (260 mg, 1.51 mmol, Aldrich) in isopropyl alcohol (30 mL) was stirred for 2 hours at 150° C. in a sealed pressure bottle. The reaction was cooled and poured into water (˜60 mL) and the resulting precipitate was filtered and air dried. This residue was purified by silica gel chromatography (2% triethylamine/ethyl acetate) to give 4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-benzenesulfonamide as a white solid. MS: M+H; 436
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pt].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(Cl)cc2)CC1
Agent: [Pt]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(Cl)cc2)CC1
Yield: 99.3 %

Procedure:
A solution of 2 g of 4-(4-chloro-benzylidene)-piperidine-1-carboxylic acid tert-butyl ester and 0.5 g of 5% platinum on carbon in 10 mL of ethanol was allowed to stir overnight under 1 atm of hydrogen. The catalyst was filtered off and, the solution concentrated to give 2 g of 4-(4-chloro-benzyl)-piperidine-1-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5](O)=[O:6].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[NH:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([NH2:46])[CH:44]=2)[N:39]([CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)[N:38]=1>CN(C=O)C>[NH:30]1[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N:28]=[C:29]1[C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([NH:46][C:5]([CH:3]3[CH2:4][C:2]3([F:8])[F:1])=[O:6])[CH:44]=2)[N:39]([CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)[N:38]=1
Reactant: O=C(O)C1CC1(F)F
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)C1CC1(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
2,2-Difluorocyclopropanecarboxylic acid (8 mg, 0.065 mmol), HOBt (12 mg, 0.089 mmol), EDC (17 mg, 0.089 mmol) and sodium bicarbonate (56 mg, 0.059 mmol) were added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (20 mg, 0.059 mmol) in DMF (6 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound as a solid in a 50% yield. 1H NMR (400 MHz, CD3OD): δ 8.51 (s, 1H), 7.77 (m, 1H), 7.67 (m, 3H), 7.27 (m, 2H), 5.86 (d, 1H, J=7.6 Hz), 4.00 (m, 1H), 3.81 (m, 1H), 2.74-2.61 (m, 2H), 2.13 (m, 3H), 1.84 (m, 2H), 1.69 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([CH2:19][OH:20])=[CH:7][N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[C:30](N)[N:29]=1>C1COCC1>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:9]1[C:8]([CH2:19][OH:20])=[CH:7][N:6]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][N:29]=2)[N:10]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: NCCNc1ncc(CO)c(-c2ccc(Cl)cc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(NCCNc2ncc(CO)c(-c3ccc(Cl)cc3Cl)n2)nc1
Temperature: 70 °C

Procedure:
{2-[(2-aminoethyl)amino]-4-(2,4-dichlorophenyl)pyrimidin-5-yl}methan-1-ol was dissolved in 3 mL of anhydrous THF and 1.47 g (4.50 mmol) of anhydrous cesium carbonate was added. 2-chloro-5-nitro-6-aminopyridine (143 mg, 0.9 mmol) was added in one portion and the yellow suspension heated at 70° C. for 18 h. The reaction mixture was filtered, concentrated and the residue chromatographed (silica gel, 5% methanol/methylene chloride) to give [4-(2,4-dichlorophenyl)-2-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)pyrimidin-5-yl]methan-1-ol, 216 mg (53%), as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([O:10][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1cc(O)cc(C(=O)OC)c1
Yield: 39.4 %

Procedure:
A mixture of 10.0 g (0.06 mol) of 3,5-dihydroxybenzoic acid methyl ester, 12.3 ml (0.06 mol) of 1-bromodecane and 8.2 g (0.06 mol) of potassium carbonate in 200 ml of acetone and 20 ml of DMF was stirred at reflux under argon for 24 hours. After the usual workup, purification by HPLC using 15% ethyl acetate-hexane gave 7.3 g (34% yield, mp 92°-94°) of 3-(decyloxy)-5-hydroxybenzoic acid methyl ester. The nmr spectra was consistent with the structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1.[CH:21]([O:23][CH3:24])=O.[H-].[Na+].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2/[C:16](=[CH:21]\[O:23][CH3:24])/[C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccccc1CCc1ccc(F)cc1
Reactant: COC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO/C=C(/C(=O)OC)c1ccccc1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 81 %

Procedure:
A solution of methyl 2-(2-[4-fluorophenyl]ethyl)phenylacetate (2.83g) and methyl formate (12.8ml) in dry DMF (20ml) was added dropwise over 20 minutes to a stirred suspension of sodium hydride (0.50g) in dry DMF (30ml) cooled in an ice bath. Effervescence and foaming built up slowly, and, when it had subsided, the mixture was allowed to warm to room temperature and stir for 3.5 hours. The mixture was diluted with water, acidified with concentrated hydrochloric acid and extracted with ether. The extracts were washed with water, dried and concentrated. A stirred solution of the resulting viscous yellow oil (3.34g) in DMF (30ml) was treated successively with potassium carbonate (3.05g) and dimethyl sulphate (1.54g). After 2 hours, the reaction mixture was poured into water and extracted with ether. The extracts were washed with water, dried, concentrated and chromatographed using 30% ether in petrol to give (E)-methyl 2-(2-[2-(4-fluorophenyl)ethyl]phenyl)-3-methoxypropenoate (2.64g, 81% yield) as a colourless solid m.p. 411/2°-421/2° C., lH NMR (CDCl3); delta 2.76 (4H,br s), 3.70 (3H,s), 3.82 (3H,s), 7.58 (1H,s), ppm.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:4](=[CH:5][C:6]([F:24])=[C:7]([Cl:23])[CH:8]=2)[N:3]=1.Cl.[F:26][C:27]1([F:33])[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1>C(N(CC)CC)C>[Cl:23][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[F:24])[N:3]=[C:2]([N:29]1[CH2:30][CH2:31][CH2:32][C:27]([F:33])([F:26])[CH2:28]1)[C:11]([C:12]1[N:16]=[N:15][NH:14][N:13]=1)=[C:10]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: FC1(F)CCCNC1
Reactant: Fc1cc2nc(Cl)c(-c3nnn[nH]3)c(-c3ccccc3)c2cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: Fc1cc2nc(N3CCCC(F)(F)C3)c(-c3nn[nH]n3)c(-c3ccccc3)c2cc1Cl

Procedure:
The title compound was prepared in analogy to example 102 step C from 2,6-dichloro-7-fluoro-4-phenyl-3-(1H-tetrazol-5-yl)-quinoline (prepared as described in example 107 step B), 3,3-difluoro-piperidine hydrochloride and triethylamine. Off-white solid. MS (ESI): 445.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24](O)=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[C:43]([NH2:47])([CH3:46])([CH3:45])[CH3:44]>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]1[C:24]([NH:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C(=O)O)C1
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
0.285 g of 1-(benzyloxycarbonyl)-4-(tert.butoxycarbonyl)-2-piperazinecarboxylic acid was dissolved in 10 ml of dry tetrahydrofuran and cooled to -15° C. while stirring. There was then added 0.09 g of N-ethylmorpholine followed immediately by 0.107 g of isobutyl chloroformate. The mixture was stirred for 5 minutes and then 0.2 g of tert.butylamine was added dropwise. Stirring was continued overnight, during which time the mixture was allowed to reach room temperature. The solvent was removed by evaporation and there was obtained a buff coloured oil which was partitioned between ethyl acetate and water. The organic phase was washed in sequence with 10% citric acid solution, sodium bicarbonate solution and saturated sodium chloride solution and dried over anhydrous sodium sulphate. The solvent was removed by evaporation to give 0.185 g of 1-(benzyloxycarbonyl)-4-(tert.butoxycarbonyl)-N-tert.butyl-2-piperazinecarboxamide as a light brown oil; MS: m/e 420 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][C:6]=1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1.[Cl-].[Cl-].[Ca+2]>C(O)C.O.[Fe]>[F:1][C:2]1[CH:26]=[C:25]([CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][C:6]=1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)[NH2:27]
Reactant: Cn1nccc1-c1cc(-c2ccccc2)ccc1Oc1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Cn1nccc1-c1cc(-c2ccccc2)ccc1Oc1ccc(N)cc1F
Yield: 83.6 %

Procedure:
5-[4-(2-Fluoro-4-nitrophenoxy)biphenyl-3-yl]-1-methyl-1H-pyrazole (Preparation 29, 870 mg, 2.33 mmol) was dissolved in ethanol (8 mL) and water (2 mL). Iron powder (624 mg, 11.17 mmol) and CaCl2 (248 mg, 2.33 mmol) were then added and the reaction mixture was refluxed for 3 hours. After filtration through Celite™, the filtrate was concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 15% ethyl acetate in hexane) to afford the title compound (700 mg, 84%).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11]>C1N2CCN(CC2)C1>[CH2:14]([O:13][C:9](=[O:12])[C:10]([CH:1]([OH:8])[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[CH2:11])[CH3:15]
Reactant: O=Cc1cccnc1
Reactant: C=CC(=O)OCC
Agent: C1CN2CCN1CC2
Product: C=C(C(=O)OCC)C(O)c1cccnc1
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a solution of nicotinaldehyde (10.0 g, 93.4 mmol) in ethyl acrylate (20 mL, ˜200 mmol) at room temperature was added DABCO (0.5 g, 4.5 mmol) and the mixture was stirred overnight. Excess ethyl acrylate was removed in vacuo to give a crude solid. This was washed with hexane to give 2-[(hydroxy)(pyridin-3-yl)methyl]acrylic acid ethyl ester (18.5 g, 95%) as an off white solid. δH (CDCl3) 8.62 (d, J 1.7 Hz, 1H), 8.53 (dd, J 4.8, 1.3 Hz, 1H), 7.81 (d, J 7.9 Hz, 1H), 7.28 (s, 1H), 6.42 (s, 1H), 5.93 (s, 1H), 5.63 (s, 1H), 4.18 (m, 2H), 3.20 (br, 1H), 1.27 (t, J 7.1 Hz, 3H). LCMS (ES+) 208.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Cl:13][C:14]1[CH:15]=[C:16]([SH:21])[CH:17]=[C:18]([Cl:20])[CH:19]=1>>[Cl:13][C:14]1[CH:15]=[C:16]([S:21][C:2]2[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Sc1cc(Cl)cc(Cl)c1
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2cc(Cl)cc(Cl)c2)s1

Procedure:
Prepared according to the procedure described as in Step B for example 1 from 1-(5-Chloro-4-nitro-2-thienyl)ethanone (0.502 g, 2.45 mmol) and 3,5-dichlorobenzenethiol (0.438 g, 2.45 mmol). The title compound was obtained as a yellow solid (0.403 g, 47.5% yield). 1H NMR (300 MHz, CDCl3) δ: 8.08 (1H, s), 7.57 (3H, m), 2.51 (3H, s).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[F:23][C:24]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:25]=1[C:26](=O)[CH2:27]Br>>[F:23][C:24]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:25]=1[C:26]1[N:12]=[C:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=2)[S:13][CH:27]=1
Reactant: COc1ccc(C(=O)CBr)c(F)c1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Product: COc1ccc(-c2csc(-c3ccc(-c4ccccc4[N+](=O)[O-])c(C(=O)O)c3)n2)c(F)c1
Yield: 89 %

Procedure:
4-[4-(2-Fluoro-4-methoxy-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (253 mg, 89%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-fluoro-4-methoxyphenacyl bromide (available from ASDI Incorporated) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (d, J=1.8 Hz, 1H), 8.10-8.21 (m, 3H), 7.94 (d, J=2.4 Hz, 1H), 7.59-7.78 (m, 2H), 7.39 (d, J=8.0 Hz, 2H), 6.93-7.02 (m, 2H), 3.83 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[NH:10][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[N:10]([S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1cccc(Cc2c[nH]c3ncc(-c4cccnc4)cc23)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(Cc3cccc([N+](=O)[O-])c3)c3cc(-c4cccnc4)cnc32)cc1
Reaction time: 3 h

Procedure:
To 3-(3-nitro-benzyl)-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (P-1402, 141 mg, 0.43 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (60% dispersion in mineral oil, 21 mg, 0.512 mmol) under an atmosphere of nitrogen. After thirty minutes, p-toluenesulfonyl chloride (114 mg, 0.60 mmol) in N,N-dimethyl-formamide was added and the reaction was stirred for three hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. All solids were filtered and purified by silica gel column chromatography eluting with 40% ethyl acetate in hexane to give the compound (552, 120 mg, 58%). MS(ESI)[M+H+]+=485.25.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:4][N:3]1[P:5](Br)([N:7]1[CH2:9][C:8]1([CH3:11])[CH3:10])=[S:6].[CH3:14][N:15]([CH3:20])[CH2:16][CH2:17][CH2:18][NH2:19]>C1COCC1>[CH3:1][C:2]1([CH3:13])[CH2:4][N:3]1[P:5]([N:7]1[CH2:9][C:8]1([CH3:11])[CH3:10])(=[S:6])[NH:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:20])[CH3:14]
Reactant: CN(C)CCCN
Reactant: CC1(C)CN1P(=S)(Br)N1CC1(C)C
Solvent: C1CCOC1
Product: CN(C)CCCNP(=S)(N1CC1(C)C)N1CC1(C)C
Temperature: 25 °C
Yield: 35 %

Procedure:
In a similar manner 0.025 moles of P,P-bis(2,2-dimethyl-1-aziridinyl)thiophosphinic bromide and about 170 ml of THF are treated by dropwise addition with 0.02 moles of 3-dimethylaminopropyl amine in 25 millimeters of THF stirred for several hours at ambient temperature, filtered, concentrated by rotary evaporation, and vacuum distilled to produce about 35% yield of P,P-bis(2,2-dimethyl-1-aziridinyl)-N-(3-dimethylaminopropyl)thiophosphinic amide.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[Cl:5][C:6]1[CH:11]=[C:10](Cl)[N:9]=[C:8]([S:13]([CH3:16])(=[O:15])=[O:14])[N:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:5][C:6]1[CH:11]=[C:10]([NH:4][O:3][CH3:2])[N:9]=[C:8]([S:13]([CH3:16])(=[O:15])=[O:14])[N:7]=1
Reactant: CON
Reactant: CS(=O)(=O)c1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CONc1cc(Cl)nc(S(C)(=O)=O)n1
Temperature: 90 °C

Procedure:
40 g (0.48 mol) of O-methylhydroxylamine hydrochloride is added to a solution of 100 g (0.44 mol) of 4,6-dichloro-2-methylsulfonylpyrimidine in 400 ml of N,N-dimethylformamide. 66 g (0.48 mol) of potassium carbonate is added and the whole is heated at 90° C. for 10 hours. The mixture is allowed to cool, is evaporated down, the residue is taken up in 10% strength aqueous hydrochloric acid and dichloromethane, the phases are separated, dried and concentrated in a rotary evaporator. The 4-chloro-6-methoxyamino-2-methylsulfonylpyrimidine obtained as byproduct may be separated by chromatography on silica gel (developer: cyclohexane/ethyl acetate). There is obtained 39 g (45%) of the title compound as a white crystalline mass of m.p. 135° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:16]=[C:17]([C:19](OCC)=[O:20])[N:18]=2)[CH:15]=1>>[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:16]=[C:17]([C:19]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[CH3:8])=[O:20])[N:18]=2)[CH:15]=1
Reactant: Cc1ccccc1N
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: Cc1ccccc1NC(=O)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using o-toluidine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[O:15]([C:22]1[CH:23]=[C:24]([CH2:28]O)[CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[O:15]([C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: COC(=O)C1CC1c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)C1CC1c1ccc(OCc2cccc(Oc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 79 %

Procedure:
A solution of methyl 2-(4-hydroxyphenyl)cyclopropanecarboxylate (0.158 g, 0.822 mmol), (3-phenoxyphenyl)methanol (0.150 g, 0.747 mmol) and tributylphosphine (0.301 g, 1.49 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.375 g, 1.49 mmol) was added, and the mixture was stirred at room temperature for 60 hr. Hexane (15 mL) was added to the reaction mixture, and the precipitated insoluble material was filtrated. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-30:70) to give the title compound (0.221 g, yield 72%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.FC1C=C([C:41]2[CH:46]=[CH:45][C:44]([C:47]([C@@H:49]3[CH2:53][CH2:52][CH2:51][C@H:50]3[C:54]([OH:56])=[O:55])=[O:48])=[CH:43][CH:42]=2)C=CC=1NC1SC2C=C(OC(F)(F)F)C=CC=2N=1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:11]2[O:10][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([C:41]4[CH:42]=[CH:43][C:44]([C:47]([C@@H:49]5[CH2:53][CH2:52][CH2:51][C@H:50]5[C:54]([OH:56])=[O:55])=[O:48])=[CH:45][CH:46]=4)=[CH:3][CH:4]=3)=[N:13][C:12]=2[CH:14]=1
Reactant: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(OC(F)(F)F)cc4s3)c(F)c2)cc1
Reactant: Cc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Product: Cc1ccc2oc(Nc3ccc(-c4ccc(C(=O)[C@@H]5CCC[C@H]5C(=O)O)cc4)cc3)nc2c1
Yield: 17 %

Procedure:
This compound was prepared from N-(4-bromophenyl)-N-(5-methyl-1,3-benzoxazol-2-yl)amine (0.50 g, 1.65 mmol), methyl (1R,2R)-2-(4-bromobenzoyl) cyclopentanecarboxylate (0.57 g, 1.83 mmol, 94.5% ee) in a similar manner to the method described for (1R,2R)-2-({3′-fluoro-4′-[(6-trifluoromethoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid. Yield: 17%. 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1 H), 8.05 (d, 2 H), 7.75–7.90 (m, 6 H), 7.35 (d, 1 H), 7.25 (s, 1 H), 6.95 (d, 1 H), 4.05 (q, 1 H), 3.20 (s, 1 H), 2.40 (s, 3 H), 2.15 (m, 1 H), 2.00 (m, 1 H), 1.55–1.80 (m, 4 H). LC-MS m/z 441.3 (MH+), ret. time 3.48 min.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-])=O)[C:5]=1[CH2:14][N:15]=[N+]=[N-].C(O)(=O)C>C(O)C.[Pd]>[NH2:11][C:6]1[CH:7]=[C:8]([F:10])[CH:9]=[C:4]2[C:5]=1[CH2:14][NH:15][C:3]2=[O:2]
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc(F)cc2c1CNC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.86 g (7.32 mmol) of 2-(azidomethyl)-5-fluoro-3-nitrobenzoic acid methyl ester is added in 46 ml of ethanol and 3.4 ml of glacial acetic acid and mixed with 256.6 mg of Pd/C. After stirring overnight at room temperature under hydrogen atmosphere, the catalyst is suctioned off via a glass-fiber filter, and the filtrate is evaporated to the dry state. The residue, 1.18 mg (97.5%) of the desired compound, is further incorporated in crude form.