Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:33])/[C:19](=[N:25]\[O:26][CH2:27][C:28](=[O:32])[NH:29][O:30][CH3:31])/[C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:34])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:41]([O:44][CH2:45]I)(=[O:43])[CH3:42].Cl>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:33])/[C:19](=[N:25]\[O:26][CH2:27][C:28](=[O:32])[NH:29][O:30][CH3:31])/[C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:34])[N:10]2[C:11]=1[C:12]([O:14][CH2:45][O:44][C:41](=[O:43])[CH3:42])=[O:13])(=[O:3])[CH3:2]
Reactant: CONC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1ccco1
Reactant: CC(=O)OCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CONC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(C)=O)=C(COC(C)=O)CS[C@H]12)c1ccco1
Reaction time: 1 h

Procedure:
(6R,7R)-3-Acetoxymethyl-7-[Z-2-methoxycarbamoylmethoxyimino-2-(fur-2-yl)acetamido]-ceph-3-em-4-carboxylic acid (992 mg) was dissolved in dry N,N-dimethylformamide (8 ml). Dried potassium carbonate (138 mg) was added and the mixture was stirred at 0°. Iodomethyl acetate (1.1 g) in a little dimethylformamide was added, stirring was continued at 0° for 1 hr, and the mixture was poured into hydrochloric acid (N, 50 ml) and extracted with ethyl acetate (3×50 ml). The ethyl acetate extracts were washed with N-hydrochloric acid (2×50 ml), water (100 ml) and saturated sodium hydrogen carbonate solution (2×30 ml), dried (Na2SO4) and evaporated. The residue in a little ethyl acetate was added dropwise to well-stirred light petroleum (b.p. 40°-60°), when the ester separated as an off-white powder, 513 mg, λmax (EtOH) 277.5 nm, νmax (Nujol) 3240 (--NH), 1786 (β-lactam), 1765, 1742 (acetate+--CO2CH2OCOCH3), 1680, 1540 cm-1 (--CONH--), τ(DMSOd6) 6.25 (--OCH3, 2--CH2 --), 5.38 (--O--CH2 --CO--), 2.01, 3.11, 3.22 (fur-2-yl), 0.18 (--CONH--), 4.05 (7H), 4.69 (6H), 4.99, 5.25 (3--CH2 --), 7.86, 7.96 (--COCH3), 4.09 (--OCH2O--).
Reaction SMILES: [NH2:1][C@@H:2](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[CH2:3][OH:4].C(N(CC)C(C)C)(C)C.C1COCC1.[C:28](=O)([O:34]C(C)(C)C)[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>CCOC(C)=O>[C:30]([O:29][C:28](=[O:34])[NH:1][C@H:2]([CH2:3][OH:4])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: N[C@@H](/C=C/c1ccc(Br)cc1)CO
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](/C=C/c1ccc(Br)cc1)CO
Temperature: 0 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
(E)-(S)-2-amino-4-(4-bromo-phenyl)-but-3-en-1-ol (7.8 g) and N,N-diisopropylethylamine (11.1 ml) were combined with THF (150 ml) to give a colourless solution. The reaction mixture was cooled to 0° C. and di-tert-butyl carbonate (7.17 g) was added. The reaction mixture was stirred at room temperature overnight to afford a yellow solution. The reaction mixture was then poured into EtOAc and washed sequentially with 1 M aq. HCl, 1 M aq. NaOH and saturated brine. The organic layer was dried over Na2SO4, filtered, and the filtrate was then stirred over charcoal (2 g) for 30 min. The mixture was then filtered through celite and the filtrate was concentrated in vacuo to afford [(E)-(S)-3-(4-bromo-phenyl)-1-hydroxymethyl-allyl]-carbamic acid tert-butyl ester as an off-white solid (10.8 g, 98%). MS (ISP): 344.0 ([{81Br}M+H]+), 342.0 ([{79Br} M+H]+), 287.9 ([{81Br}M+H—C4H8]+), 286.0 ([{79Br} M+H—C4H8]+).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:21])[CH2:16][CH2:17][C:18](O)=O)[CH2:6]1)(=[O:3])[CH3:2].S(Cl)([Cl:33])=O>C1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:21])[CH2:16][CH2:17][CH2:18][Cl:33])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]32)C1
Solvent: c1ccccc1
Product: CC(=O)O[C@@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCCCl)CC[C@@H]32)C1

Procedure:
3α-Acetoxy-5β-cholanic acid (4.18 g; 10 mmoles) was added to 60 ml of anhydrous benzene. The solution was cooled with ice, and with stirring, 4.5 ml of thionyl chloride was gradually added dropwise. After the addition, the mixture was reacted at room temperature for 2.5 hours with stirring. The reaction mixture was concentrated under reduced pressure, and 20 ml of anhydrous benzene was added to the residue. The mixture was repeatedly concentrated under reduced pressure to remove the thionyl chloride contained in the residue. The resulting solid crude product, 3α-acetoxy-5β-cholanyl chloride, was used as a starting compound in the subsequent step without purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[OH:9].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C=O)C>[CH2:10]([O:9][C:3]1[CH:4]=[C:5]([NH2:6])[CH:7]=[CH:8][C:2]=1[F:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccccc1
Reactant: Nc1ccc(F)c(O)c1
Solvent: CN(C)C=O
Product: Nc1ccc(F)c(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.8 %

Procedure:
79 g (0.62 mol) of 4-fluoro-3-hydroxy-aniline in DMF (1.3 l) were treated under argon portion wise over a period of 15 minutes with 76.7 g (0.68 mol) of potassium t-butylate whereas the temperature of the reaction solution was kept between RT and 28° C. Stirring was continued for 15 minutes then 79 ml (0.68 mol) of benzyl chloride were added dropwise while keeping the temperature of the reaction solution between RT and 30° C. After stirring for 2 h at RT the reaction solution was poured into ice water (6 l) which was then extracted 3-fold with ether (about 3 l each). The combined organic layers were washed with brine (1.5 l) and dried over magnesium sulfate and the solvent removed in vacuo. The residue was purified by chromatography over a short silica gel column with methylene chloride as eluent. Combination of the purified fractions and concentration in vacuo gave 92.7 g (68.6%) of the desired 3-benzyloxy-4-fluoro-phenylamine as light yellow crystalline solid. ISP mass spectrum, m/e: 218.2 (M+1 calculated for C13H12FNO: 218.2).
Reaction SMILES: O([BH-](OC(C)=O)OC(C)=O)C(C)=O.[Na+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH:32]=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.ClCCCl>CC(O)=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:32][C:31]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:29]([O:28][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:30]=2)=[CH:18][CH:17]=1
Reactant: Nc1ccc(Br)cc1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(CNc2ccc(Br)cc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.6 %

Procedure:
Sodium triacetoxyl-borohydride (470 mg, 2.21 mmol) was added to a solution of 4-bromo-phenylamine (252 mg, 1.47 mmol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (324 mg, 1.47 mmol) in 10 ml of 1,2-dichloroethtane (DCE), 0.5 ml of HOAc was added. The mixture was stirred overnight at room temperature, followed by addition of 15 ml of DCE. The organic phase was washed with water and dried over sodium sulfate. The solvent was removed by rotovap to give 656 mg of crude (4-bromo-phenyl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine. It was used for next step without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[N:8]([CH3:16])[CH:7]=[C:6]2[CH3:17].B(Br)(Br)Br>C(Cl)Cl>[CH3:16][N:8]1[C:9]2[C:5](=[CH:4][C:3]([OH:2])=[C:11]([C:12]([F:13])([F:14])[F:15])[CH:10]=2)[C:6]([CH3:17])=[CH:7]1
Reactant: COc1cc2c(C)cn(C)c2cc1C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cn(C)c2cc(C(F)(F)F)c(O)cc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 34.2 %

Procedure:
5-Methoxy-1,3-dimethyl-6-trifluoromethyl-1H-indole (725 mg, 3 mmol) in methylene chloride (15 ml) was cooled to zero degrees C., and BBr3 (14.9 ml of a 1 N solution in methylene chloride) was slowly added via syringe. The reaction mixture was stirred 15 minutes at zero degrees C., then allowed to warm to room temperature with stirring for one hour. The reaction mixture was quenched slowly with 75 mL 1 N NaOH. The mixture was acidified to pH 5 with 1 N HCl, extracted with methylene chloride, and the combined organic layers were washed with water, brine, and dried over magnesium sulfate. Solvent was removed under reduced pressure, and the residue was chromatographed (20% EtOAc/Hexanes) to give 235 mg (75%) 1,3-Dimethyl-6-trifluoromethyl-1H-indol-5-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[CH:11]1([C:16](O)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([C:16]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:9][CH3:10])[CH:5]=2)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(O)C1CCCC1
Reactant: COc1ccccc1OC
Product: COc1ccc(C(=O)C2CCCC2)cc1OC
Temperature: 60 °C
Reaction time: 24 h
Yield: 116.1 %

Procedure:
To polyphosphoric acid (76 g) was added 1,2-dimethoxybenzene (7.9 g, 0.057 mol) followed by cyclopentanecarboxylic acid (9.8 g, 0.086 mol). The mixture was stirred at 60° C. during 24 hours then cooled down to −5° C. and quenched by the addition of 200 ml ice/water followed by 100 ml of ether. After stirring at room temperature for 3 hours, the two layers were separated and the aqueous phase extracted with three 100 nil portions of ether. The two ethereal phases were combined, washed with 50 ml of NaOH and 50 ml of brine and dried over MgSO4. Filtration and concentration gave 15.5 g of dark brown oil. This oil was purified by vacuum distillation (180-190° C., 0.03 mbar) through a short path to give 11.8 g (88%) of a white solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[F:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[C:36]([CH3:41])[CH:35]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:38][C:37]3[CH:39]=[CH:40][C:34]([F:33])=[CH:35][C:36]=3[CH3:41])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][C:21]4([C:27]5[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:26]=5[O:25][CH2:24]4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1cc(F)ccc1N
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)COc3cccc(F)c34)cnc12
Product: CCOC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC4(CC3)COc3cccc(F)c34)cnc12
Yield: 17.2 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.171 g, 0.372 mmol) obtained in step 2 and 4-fluoro-2-methylaniline (0.050 mL, 0.446 mmol), the title compound (0.035 g, 17%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9]2)=[CH:4][CH:3]=1.CO[N-]C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([C:13](=[O:15])[CH2:4][CH2:3][CH:2]=[CH2:7])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCN(c2ccc(Cl)cc2)C1
Agent: C[N-]OC
Solvent: C1CCOC1
Product: C=CCCC(=O)C1CCN(c2ccc(Cl)cc2)C1
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution of 1-(4-chlorophenyl)-pyrrolidine-3-carboxylic acid and methoxy-methyl amide (1.1 g, 4.1 mmol) in tetrahydrofuran (20 mL) was cooled to 0° C. while maintaining the solution under an at mosphere of nitrogen. To the cold solution was added a THF solution of 4-butenylmagnesium bromide (0.5M in THF, 16.4 mL, 8.2 mmol) in a dropwise manner. After stirring for 1 hour the bath was removed and stirring was continued overnight. The resulting solution was poured into water, acidified to pH 3-4 with 1 N hydrochloric acid and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification of the crude by flash column chromatography (silica gel, 0-25% ethyl acetate in heptane) gave the title compound as a colorless oil (940 mg, 87%); 1H NMR (CDCl3, 300 MHz) δ 7.15 (d, J=9 Hz, 2H), 6.46 (d, J=9 Hz, 2H), 5.81 (m, 1H), 5.12 (m, 2H), 3.54 (m, 2H), 3.26-3.39 (m, 3H), 2.62 (m, 2H), 2.36 (m, 2H) and 2.12-2.26 (m, 2H).
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[OH:14])[CH:9]=[O:10])[CH3:4]>O.[N+]([O-])([O-])=O.[Ag+]>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[OH:14])[C:9]([OH:1])=[O:10])[CH3:4]
Reactant: [OH-]
Reactant: CCOc1cc(C=O)ccc1O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOc1cc(C(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26.4 %

Procedure:
A solution of silver nitrate (45.0 g, 265.0 mmol, 1.0 equiv) in water (230 mL) was treated with NaOH (10.6 g, 265 mmol, 1.0 equiv) and stirred for 20 min at rt. The formed precipitate was filtered off, washed with water (3×200 mL) and directly suspended in water (260 mL). To this suspension was added 3-ethoxy-4-hydroxy-benzaldehyde (20.0 g, 120.4 mmol, 0.45 equiv) and NaOH (26.5 g, 662.5 mmol, 2.5 equiv) the reaction mixture heated to reflux for 2 h. The reaction mixture was filtered, acidified to pH 2 by addition of sulfuric acid and the solution extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, the solvent removed by evaporation under reduced pressure and the crude material purified over a plug of silica eluting with dichloromethane/methanol/acetic acid (97:2:1) to give 5.8 g (27%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.32 (t, J=7.0 Hz, 3H), 4.04 (q, J=7.0 Hz, 2H), 6.88 (d, J=8.0 Hz, 1H), 7.46 (s, 1H), 7.48 (d, J=8.0 Hz, 1H), 9.67 (br s, 1H), 12.42 (br s, 1H). 13C NMR (75 MHz, DMSO): δ 14.52, 63.93, 114.09, 115.11, 121.68, 123.49, 146.29, 151.32, 167.22. MS (ISN): 181.0 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[Cl:15].Br[CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:21]1(=[O:30])[N:20]([CH2:19][CH2:18][CH2:17][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][C:3]=2[Cl:15])[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: O=C1CCC(c2ccc(O)c(Cl)c2)=NN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCC(c2ccc(OCCCN3C(=O)c4ccccc4C3=O)c(Cl)c2)=NN1
Reaction time: 0.17 h
Yield: 87.6 %

Procedure:
A mixture of 3.4 g (15.1 mmol) of 6-(4-hydroxy-3-chlorophenyl)-4,5-dihydro-3(2H)-pyridazinone, prepared according to the methods described in Eur. Pat. Appl. 178,189A2, 4.87 g (18.2 mmol) of N-(3-bromopropyl)phthalimide, and 2.30 g (16.6 mmol) of anhydrous K2CO3 in 80 ml of DMF is heated for 3 hrs at 100° C. The DMF is removed under vacuum and 150 ml of 1:1 EtOAc-H2O is added to the residue and stirred vigorously for 10 min. The solid precipitate is collected by suction filtration, washed with water (2×150 ml), washed with EtOAc (2. 50 ml), and dried under vacuum at 80° C. to give 5.45 g of 6-[4-(3-phthalimidopropyloxy)-3-chlorophenyl]-4,5-dihydro-3(2H)-pyridazinone as a white solid, m.p. 230°-232° C.
Reaction SMILES: [OH:1][CH:2]1[CH:6]([OH:7])[CH:5]([N:8]2[C:12]3[N:13]=[C:14]([S:27][CH3:28])[N:15]=[C:16]([NH:17][CH:18]4[CH2:20][CH:19]4[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:11]=3[N:10]=[N:9]2)[CH2:4][CH:3]1[C:29]([NH:31][C:32]1C=CC=[CH:34][CH:33]=1)=[O:30].C(N)CC>>[OH:1][CH:2]1[CH:6]([OH:7])[CH:5]([N:8]2[C:12]3[N:13]=[C:14]([S:27][CH3:28])[N:15]=[C:16]([NH:17][CH:18]4[CH2:20][CH:19]4[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:11]=3[N:10]=[N:9]2)[CH2:4][CH:3]1[C:29]([NH:31][CH2:32][CH2:33][CH3:34])=[O:30]
Reactant: CSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)Nc4ccccc4)C(O)C3O)c2n1
Solvent: CCCN
Product: CCCNC(=O)C1CC(n2nnc3c(NC4CC4c4ccccc4)nc(SC)nc32)C(O)C1O

Procedure:
The subtitle compound was prepared according to the method of example 39, step a) using the product of example 20, step b) and propylamine.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]=[C:9]=[S:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:11][C:12]1[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=1>CN(C=O)C>[Br:11][C:12]1[C:13]([NH:18][C:9]2[S:10][C:2]3[C:7]([N:8]=2)=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ncccc1Br
Reactant: S=C=Nc1cccnc1Cl
Solvent: CN(C)C=O
Product: Brc1cccnc1Nc1nc2cccnc2s1
Temperature: 120 °C
Yield: 36.8 %

Procedure:
Heated a mixture of 2-chloro-3-isothiocyanatopyridine (0.986 g, 5.78 mmol) and 3-bromopyridin-2-amine (1.00 g, 5.78 mmol) in DMF (4 mL) at 80° C. for 3 hours. Heated at 120° C. overnight. Cooled, partitioned between ethyl acetate and water, washed with 2N NaOH, water, brine, dried, and concentrated. Crystallized from dichloromethane:hexanes (1:10, 110 mL) and filtered. The filtered material was further purified by dissolving in dichloromethane (10 mL), and subjecting to MPLC (Biotage) eluting with 3:2 hexane:ethyl acetate. The higher Rf component was concentrated to afford the title compound (0.654 g, 36.8% yield) as a white powder.
Reaction SMILES: Br[CH2:2][CH:3]1[O:19][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:18])([CH3:17])[CH2:8]3.[N-:20]=[N+:21]=[N-:22].[Na+]>>[N:20]([CH2:2][CH:3]1[O:19][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:18])([CH3:17])[CH2:8]3)=[N+:21]=[N-:22]
Reactant: Cc1cc2c(c3c1NC(=O)C(C)(C)C3)OC(CBr)C2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: Cc1cc2c(c3c1NC(=O)C(C)(C)C3)OC(CN=[N+]=[N-])C2
Yield: 86.1 %

Procedure:
Using the compound obtained in Example 299 (1.93 g 5.96 mmol) and sodium azide (2.8 g, 43.1 mmol), the procedure of Example 278 was followed (reaction, post-treatment, and recrystallization from chloroform-ether). 1.47 g of the title compound was obtained as colorless crystals (86.2%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31](F)=[CH:30]C=CC=3F)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(C=CC=2)N)C=CN=1.C1(S(Cl)(=O)=O)CC1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:14])[CH3:15])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([CH:26]3[CH2:31][CH2:30]3)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Agent: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Agent: O=S(=O)(Cl)C1CC1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)C3CC3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 94.4 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (1.0 g, 3.03 mmol) and cyclopropanesulfonyl chloride (465 mg, 3.32 mmol) the title compound of Step A was obtained (1.24 g, 94.4% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.30 (d, J=5.3 Hz, 1H), 7.36-7.42 (m, 2H), 7.29-7.36 (m, 2H), 7.01 (d, J=5.3 Hz, 1H), 6.91-6.93 (br, 1H), 3.29-3.40 (m, 1H), 2.46-2.53 (m, 1H), 1.44 (d, J=7.0 Hz, 6H), 1.12-1.18 (m, 2H), 093-1.01 (m, 2H). MS (ES+): 435 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C([O-])(O)=O.[Na+].[Br:17][CH2:18][C:19](Br)=[O:20]>C(Cl)Cl>[Br:17][CH2:18][C:19]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1])=[O:20]
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(NC(=O)CBr)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 64 h

Procedure:
To a solution of 2-methyl-3-nitroaniline (5.0 g, 32.9 mmol) in 120 ml of CH2Cl2 was added 120 ml of saturated NaHCO3 and bromoacetyl bromide (2.85 ml, 6.6 g, 32.9 mmol). The reaction was stirred at room temperature for 64 hours. The layers were separated, and the organic layer was washed with water, brine and then dried over MgSO4. Solvent evaporation afforded 2-bromo-N-(2-methyl-3-nitrophenyl)acetamide as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[NH:18]C(=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.CCCCCC.C(OCC)(=O)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[NH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cc([N+](=O)[O-])ccc1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: Nc1cc([N+](=O)[O-])ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.7 %

Procedure:
To a solution of tert-butyl (2-(benzyloxy)-5-nitrophenyl)carbamate (1.0 g) in DCM (10 mL), cooled to 0° C., was added trifluoroacetic acid (5.0 mL). The reaction mixture was stirred at 0° C. for 15 minutes and then at room temperature for 30 minutes. The reaction was monitored by TLC using hexane:ethyl acetate (3:7) as mobile phase. After completion, the reaction mixture was quenched in water and neutralized with sodium bicarbonate. Product was extracted into DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated completely under reduce pressure at 40° C. Crude material was purified by trituration with diethyl ether to give 0.7 g of 2-(benzyloxy)-5-nitroaniline. 1H NMR: DMSO-d6 (400 MHz): 5.26 (s, 2H), 5.44 (s, 2H), 7.04 (d, 1H, J=8.8), 7.34 (m, 1H), 7.45 (m, 3H), 7.50 (s, 1H), 7.520 (d, 2H, J=2.8).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[N:9][N:8]2[CH2:18][CH2:19][CH2:20][C:7]=12)=[O:5])C.[OH-].[Na+]>C(O)C>[CH3:17][C:13]1[N:12]=[C:11]([C:10]2[C:6]([C:4]([OH:5])=[O:3])=[C:7]3[CH2:20][CH2:19][CH2:18][N:8]3[N:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1c(-c2cccc(C)n2)nn2c1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(-c2nn3c(c2C(=O)O)CCC3)n1
Temperature: 25 °C

Procedure:
A solution of 2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid ethyl ester (1.6 g, 5.9 mmol) and 2 N sodium hydroxide (6 mL, 29 mmol) in absolute ethanol (50 mL) is refluxed for 5 h. The mixture is cooled to room temperature and concentrated in vacuo. The residue is suspended in water and acidified to pH 5 with 1 N hydrochloric acid. The aqueous solution is extracted three times with dichloromethane. The organic extracts are combined, dried (sodium sulfate), filtered, and concentrated in vacuo to yield the title compound, 1.4 g (97%), as a white solid.