Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C@@H:22]([CH2:26][OH:27])[CH2:23][CH2:24][CH3:25]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C@H:22]([CH2:23][CH2:24][CH3:25])[CH2:26][OH:27])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CCC[C@@H](N)CO
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCC[C@H](CO)Nc1nc(Cl)nc2c1SCC2
Temperature: 120 °C

Procedure:
1.4 g 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (II) are placed in 9 ml dioxane, then first 3.5 ml diisopropylethylamine, then 0.9 g D-norvalinol are added. The reaction mixture is heated in the microwave at 120° C., until there is no further reaction, and cooled, then evaporated down. The residue is treated with petroleum ether/ethyl acetate 9:1 in the ultrasound bath, the solid is suction filtered and dried. 1.5 g (III-3) are obtained as a solid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH2:25][CH2:26][CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>CN(C=O)C.O>[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])([C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:25][CH2:26][CH3:27]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCC(Br)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(C(=O)OCC)C(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
To a solution of diethyl malonate (8.01 g; 50 mmol) in dry DMF (25 mL) under nitrogen atmosphere was added potassium carbonate (7.6 g; 55 mmol), which has been dried at 120° C. for 12 h before using. After stirring for 15 min at room temperature, ethyl 2-bromovalerate (8.53 mL; 50 mmol) was slowly added under nitrogen and the mixture was vigorously stirred at room temperature for 24 h. The reaction mixture was poured in water (240 mL) and neutralized by adding a solution of hydrochloric acid 6N. The product was extracted with diethyl ether (2x240 mL) and the combined organic layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by distillation under reduced pressure furnished 12.8 g (99%) of the title compound as a colorless liquid (bp. 117° C., 2 mbar, temperature of the oil bath 165° C.).
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:23])=[C:16]([CH:22]=2)[C:17]([O:19]CC)=[O:18])[CH:7]=[CH:8][CH:9]=1>O1CCOCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:23])=[C:16]([CH:22]=2)[C:17]([OH:19])=[O:18])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cc(OCc2cccc(Cl)c2)ccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(OCc2cccc(Cl)c2)cc1C(=O)O
Temperature: 65 °C
Reaction time: 5 h
Yield: 92.6 %

Procedure:
Lithium hydroxide (16.3 g, 389 mmol) was added to a solution of ethyl 5-{[(3-chlorophenyl)methyl]oxy}-2-methylbenzoate (79 g, 259 mmol) in 1,4-dioxane (1 L) and water (0.5 L). The reaction mixture was stirred at 65° C. for 5 hours, allowed to cool and stood at room temperature for 14 hours. The reaction was concentrated to remove the 1,4-dioxane, and the resulting brown aqueous solution was washed with diethyl ether (3×1 L). The aqueous layer was then acidified with 2N HCl (approximately 200 ml) and the resulting precipitate filtered and washed with water to give a yellow solid. This was dried overnight at 40° C. in a vacuum oven to give the title compound as a yellow solid (66.38 g). MS (ES−) [C15H1335ClO3—H]− 275. 1H-NMR (400 MHz, d6-DMSO) δ 2.43 (3H, s), 5.14 (2H, s), 7.10-7.13 (1H, m), 7.21-7.23 (1H, m), 7.38-7.47 (4H, m), 7.52 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]#[N:32])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH3:9].C([Sn](=O)CCCC)CCC.[N:45]([Si](C)(C)C)=[N+:46]=[N-:47]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][C:31]3[N:45]=[N:46][NH:47][N:32]=3)=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)[CH3:9]
Reactant: Cc1noc(-c2ccc(-c3ccc(CC#N)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1F
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Cc1noc(-c2ccc(-c3ccc(Cc4nn[nH]n4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1F
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of [5-(4′-cyanomethyl-biphenyl-4-yl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-fluoro-phenyl)-ethyl ester (0.200 g, 0.44 mmol) in toluene (5 mL) was added dibutyltin oxide (0.011 g, 0.04 mmol), followed by azidotrimethylsilane (0.07 mL, 0.53 mmol), and the reaction was stirred at 100° C. for 5 hours, and then stirred at room temperature overnight. The mixture was concentrated, and the residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried and concentrated, and the crude material was purified by preparative HPLC to give the title compound.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([CH:6]=[CH2:7])=[CH2:5].[C:10]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])(=[O:14])[C:11]([CH3:13])=[CH2:12].F[P-](F)(F)(F)(F)F.C([N+]1C=CN(C)C=1)CCC>C(C1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1)C1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1>[CH3:12][C:11]1([C:10]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14])[CH2:7][CH2:6][C:4](=[O:5])[CH2:3][CH2:13]1
Reactant: C=C(C)C(=O)OCC(C)C
Reactant: C=CC(=C)O[Si](C)(C)C
Agent: CC(C)(C)c1cc(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Agent: CCCC[n+]1ccn(C)c1
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)COC(=O)C1(C)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 21.4 %

Procedure:
2-(Trimethylsilyloxy)buta-1,3-diene (40 g, 281 mmol) was weighed into a Teflon™ microwave container. Isobutyl methacrylate (50.8 mL, 317 mmol) was added followed by 4,4′-methylenebis(2,6-di-tert-butylphenol) (0.5 g, 1.177 mmol), finally 1-butyl-3-methylimidazolium hexafluorophosphate (0.5 mL) was added, the vessel transferred to the Advancer microwave and heated for 4 hr (normal absorption, no fixed hold time, 190° C.). After 1 hr 20 min an error message was seen for the temperature probe, the error was cleared and heating was continued for a further hour. At this time the software had frozen forcing a shutdown at the mains. The reaction mixture was allowed to cool to RT. Tetrahydrofuran (THF) (200 mL) was added and the solution transferred to a round bottomed flask. 2M HCl was added and the reaction mixture left to stir overnight. DCM was added to the reaction mixture, whereupon an emulsion formed. An attempt to filter this was unsuccessful, and the mixture was left to stand overnight. The organic layer was separated, dried (Na2SO4) and evaporated to give a sticky oil. Flash column chromatography, eluting with ethyl acetate/isohexane gave 2-methylpropyl 1-methyl-4-oxocyclohexanecarboxylate as a yellow oil (12.74 g, 60.0 mmol, 21.35% yield).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19]>CN(C)C=O>[CH2:18]([O:9][C:8]([C:6]1[O:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1)=[O:10])[CH3:19]
Reactant: CCI
Reactant: O=Cc1ccc(C(=O)O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C=O)o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.3 %

Procedure:
5-Formyl-2-furancarboxylic acid (2.9 g) was dissolved in N,N-dimethylformamide (30 ml), and potassium carbonate (2.9 g) and iodoethane (3.6 g) were added. The mixture was stirred at room temperature for 12 hours, poured into ice water and extracted with diethyl ether. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-formyl- 2-furancarboxylic acid ethyl ester (1.3 g). 5-Formyl-2-furancarboxylic acid ethyl ester (1.3 g) in methylene chloride (5 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.3 g) in methylene chloride (5 ml) at room temperature. The mixture was stirred at room temprature for 30 minutes, and water was added to the mixture. The resulting mixture was extracted with diethyl ether, and the extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-difluoromethyl-2-furancarboxylic acid ethyl ester (0.7 g). 5-Difluoromethyl-2-furancarboxylic acid ethyl ester (2.3 g) synthesized in this manner was dissolved in ethanol (20 ml), and 1N aqueous sodium hydroxide (15 ml) was added. The mixture was stirred at room temperature and concentrated under reduced paressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Precipitated crystals were collected by filtration and washed with hexane-isopropyl ether to give 5-difluoromethyl-2-furancarboxylic acid (1.2 g) as crystals.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][N+:9]([O-])=[C:8]([CH3:13])[CH:7]=2)[CH2:3][CH2:2]1.[C:14]([O:17]C(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:17][CH2:13][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:11]=[CH:10][N:9]=1)(=[O:16])[CH3:15]
Reactant: Cc1cc(OCC2CC2)cc[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCc1cc(OCC2CC2)ccn1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
4-cyclopropylmethoxy-2-methylpyridine-N-oxide (3.8 g 0.021 mol) was dissolved in acetic anhydride (10 ml) and was added dropwise to acetic anhydride (20 ml) (warmed to 90° C.). After the addition the temperature was raised to 110° C. and the mixture was stirred at 110° C. for 1 h and then the solvent was distilled off and the crude product was used without purification. NMR data is given below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:15]([F:16])=[CH:14][C:12]([NH2:13])=[C:11]([F:17])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38](Cl)=[O:39])[C:33]2=[O:41])=[CH:28][CH:27]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:15]([F:16])=[CH:14][C:12]([NH:13][C:38]([C:34]3[C:33](=[O:41])[N:32]([C:29]4[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=4)[CH:37]=[CH:36][CH:35]=3)=[O:39])=[C:11]([F:17])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
A solution of Example A1 (0.147 g, 0.572 mmol) in THF (1 mL) was treated with Et3N (0.120 mL, 0.858 mmol) and a suspension of Example A3 (0.216 g, 0.858 mmol) in THF (2 mL). The mixture was layered with argon and stirred at RT overnight. The mixture was cooled to RT, the solid removed via filtration, rinsed with THF and the filtrate concentrated to dryness. The residue was triturated with MeCN, sonicated and the resulting solid collected via filtration and dried to afford N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (104 mg, 38%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.51 (s, 1H), 8.71-8.61 (m, 2H), 8.38 (d, J=5.8 Hz, 1H), 8.23 (dd, J=6.6, 2.2 Hz, 1H), 7.69 (m, 3H), 7.49 (m, 2H), 7.25 (d, J=2.3 Hz, 1H), 7.13 (dd, J=5.8, 2.3 Hz, 1H), 6.82 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:15][CH:16]=2)[CH2:11][CH:10]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:15][CH:16]=2)[CH2:11][CH:10]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(NS(=O)(=O)c2ccccc2)Cc2cc(-c3ccccc3)ncc2N1Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(NC1Cc2cc(-c3ccccc3)ncc2N(Cc2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a suspension of 3I (80 mg, 0.17 mmol) in THF (1 mL) at RT under argon was added borane-tetrahydrofuran complex (0.85 mL, 0.85 mmol) dropwise. After the addition, the reaction became a clear solution. The reaction was allowed to stir at RT under argon for 1 h. After this time, no starting material was detected by LC-MS. MeOH (1 mL) was added carefully to the reaction and the reaction was stirred at RT for overnight. The solvent was concentrated. The resultant residue was partitioned between CH2Cl2 and saturated aqueous NaHCO3 (20 mL). The layers were separated. The aqueous layer was extracted with CH2Cl2 (20 mL×3). The combined organics were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. The resultant residue was purified by silica gel (10 g) column chromatography eluting with a gradient of EtOAc (0-60%) in hexane to give the title compound as a white foam (71 mg, 88%). LC/MS (method A): retention time=2.69 min, (M+H)+=456. 1H-NMR (CDCl3, 400 MHz): δ8.00 (s, 1H), 7.75-7.85 (m, 4H), 7.47-7.55 (m, 1H), 7.10-7.48 (m, 11H), 5.44 (d, J=8.2 Hz, 1H), 4.30 (dd, J1=90 Hz, J2=16.4 Hz, 2H), 3.80-3.90 (m, 1H), 3.35-3.45 (m, 1H), 3.10 (dd, J1=4.9 Hz, J2=1.8 Hz, 1H), 2.93 (dd, J1=16.7 Hz, J2=4.5Hz, 1H), 2.65 (dd, J1=4.9 Hz, J2=1.8 Hz, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C@:5]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:37])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1.[C@@H:44]12[NH:52][C@@H:48]([CH2:49][CH2:50][CH2:51]1)[CH2:47][O:46][CH2:45]2.CCN(C(C)C)C(C)C>CS(C)=O>[C@@H:48]12[N:52]([CH2:2][CH2:3][NH:4][C@:5]34[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]3[C@@H:7]3[C@@:20]([CH3:23])([CH2:21][CH2:22]4)[C@@:19]4([CH3:24])[C@@H:10]([C@:11]5([CH3:37])[C@@H:16]([CH2:17][CH2:18]4)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]4[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=4)=[CH:13][CH2:12]5)[CH2:9][CH2:8]3)[C@@H:44]([CH2:51][CH2:50][CH2:49]1)[CH2:45][O:46][CH2:47]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCCl)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C1C[C@@H]2COC[C@H](C1)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3[C@@H]4CCC[C@H]3COC4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 120 °C

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-chloroethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (20 mg, 0.033 mmol), (1R,5S)-3-oxa-9-azabicyclo[3.3.1]nonane (16.78 mg, 0.132 mmol) and Hunig's Base (0.029 mL, 0.165 mmol) in DMSO (1 mL) was heated to 120° C. for 1 h. The reaction mixture was quenched with distilled water (2 mL), extracted with dichloromethane (2×2 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1R,5S)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate as a brown solid which was taken to the next step without further purification.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1)([O-:4])=[O:3].N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][NH:12][C:19](=[O:21])[CH3:20])=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.6 %

Procedure:
To a solution of 8.0 g (42 mmol, 1.0 eq.) of (4-nitrophenyl)methanamine hydrochloride in 40 mL of methylene chloride and 28 mL (340 mmol, 8.0 eq.) of pyridine was added 16 mL (170 mmol, 4.0 eq.) of acetic anhydride. The mixture was stirred at room temperature for 16 h and diluted with 200 mL of methylene chloride. The organic solution was washed with sat. brine and dried (Na2SO4). The solvent was removed in vacuo to provide 8.0 g (41 mmol, 98%) of N-(4-nitrobenzyl)acetamide (I-21).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:13])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=[C:23]=S>C(#N)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:23]1[NH:1][C:2]2[CH:3]=[C:4]([OH:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=2[N:12]=1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: COC(=O)c1cc(N)c(N)cc1O
Solvent: CC#N
Product: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.2 %

Procedure:
To a solution of methyl 4,5-diamino-2-hydroxybenzoate (0.500 g, 2.74 mmol) in acetonitrile (15.0 mL) was added 1,3-dichloro-2-isothiocyanatobenzene (Intermediate-5, 0.550 g, 2.72 mmol). The reaction mass was stirred at RT for 24 h and N,N-di-isopropyl carbodimide (1.0 mL) was added to it. The reaction mass stirred at RT for 4-6 h. The reaction mass was cooled and filtered to afford 0.500 g of the desired product. 1HNMR (DMSO-d6): δ 3.86 (s, 3H), 6.56 (s, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.38 (s, 1H), 7.52 (d, J=7.8 Hz, 2H), 10.49-10.64 (s, 3H); MS [M+H]+: 352.08.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[NH4+]=[S:12].C(N(CC)CC)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([C:7](=[S:12])[NH2:8])[CH:9]=1
Reactant: N#Cc1cc(Br)ccc1F
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)c1cc(Br)ccc1F
Temperature: 50 °C
Yield: 97.8 %

Procedure:
5-bromo-2-fluoro-benzonitrile (12.4 mmol, 2470 mg) in pyridine (6.5 mL) was treated with ammonium sulfide (40 mass % in water, 1.1 equiv., 13.6 mmol, 2.32 mL) and triethylamine (1.1 equiv., 13.6 mmol, 1.90 mL). The reaction mixture was heated at 50° C. for 3 hours, then cooled to room temperature. The reaction mixture was partitioned between EtOAc and water. The organic later was washed with water (3×), and brine (3×), dried with MgSO4, then concentrated. The residue was purified on silica eluted with 0 to 50% EtOAc in Heptane to provide 5-bromo-2-fluoro-benzenecarbothioamide (2.84 g, 94% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9](O)(=[O:11])[CH3:10]>S(Cl)(Cl)=O>[C:9]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])(=[O:11])[CH3:10]
Reactant: CC(=O)O
Reactant: Oc1ccccc1F
Solvent: O=S(Cl)Cl
Product: CC(=O)Oc1ccccc1F
Temperature: 150 °C

Procedure:
2-Fluorophenol (99.4 g, 886.7 mmol) was stirred in thionyl chloride (71.2 mL) and acetic acid (51 mL) added. After the initial reaction had subsided the mixture was heated to reflux for 4 hours. The solution was then heated at 150° C. overnight. The resulting dark solution was distilled under reduced pressure at an oil bath temperature of 190° C. to give the title compound as a pale yellow oil (120.9 g, 784.4 mmol).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH2:6])=[S:5].Cl[CH:8]([C:19](=O)[CH2:20][CH2:21][CH3:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C>C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[S:5][C:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)=[C:19]([CH2:20][CH2:21][CH3:22])[N:6]=1
Reactant: CCCC(=O)C(Cl)Cc1ccc([N+](=O)[O-])cc1
Reactant: COCC(N)=S
Solvent: CCOC(C)=O
Product: CCCc1nc(COC)sc1Cc1ccc([N+](=O)[O-])cc1
Yield: 25.7 %

Procedure:
A mixture of 1.2 g of methoxythioacetamide and 3 g of 2-chloro-1-(4-nitrophenyl)hexan-3-one is heated at 90°-100° C. for 4 hours and then cooled and taken up with ethyl acetate. The solution obtained is passed over animal charcoal and then evaporated. The brown oil obtained is purified on a silica column (eluent: 6/4 cyclohexane/ethyl acetate) to give 0.9 g of 2-methoxymethyl-4-propyl-5-(4-nitrobenzyl)thiazole in the form of a brown oil, which is used as such for the next step.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[CH:6][N:5]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:30])/[C:15](=[N:22]\[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C:11](=[O:31])[N:10]2[S:32]([OH:35])(=[O:34])=[O:33])[N:4]=1.Cl.[N:37]1([C:42](N)=[NH:43])C=CC=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:21][C:18]1[S:19][CH:20]=[C:16](/[C:15](=[N:22]/[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:14]([NH:13][C@@H:12]2[C:11](=[O:31])[N:10]([S:32]([OH:35])(=[O:34])=[O:33])[C@@H:9]2[CH2:8][N:5]2[CH:6]=[N:7][C:3]([CH2:2][NH:1][C:42]([NH2:43])=[NH:37])=[N:4]2)=[O:30])[N:17]=1
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cnc(CN)n1)c1csc(N)n1)C(=O)O
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cnc(CNC(=N)N)n1)c1csc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.4 %

Procedure:
To a solution 2-(((Z)-(2-(((2R,3S)-2-((3-(aminomethyl)-1H-1,2,4-triazol-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid (25 mg, 0.047 mmol) and pyrazole-1-carboxamidine hydrochloride (10.9 mg, 0.099 mmol) in DMF (470 μL) was added DIPEA (33 μL, 0.188 mmol). After stirring at rt for 12 h the solution was concentrated in vacuo. Toluene was added and it was reconcentrated (3×). The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (16 mg, 52%) as a white powder. LCMS: Rt=0.31 min, m/z=574.3 (M+1) Method 2m_acidic; 1H NMR (500 MHz, DMSO-d6) δ 9.45 (br s, 1H), 8.47 (s, 1H), 7.86 (br s, 1H), 7.31 (br s, 3H), 6.74 (br s, 1H), 6.55 (s, 1H), 5.22 (br s, 1H), 4.69-4.59 (m, 1H), 4.60-4.50 (m, 1H), 4.45-4.36 (m, 2H), 4.34-4.26 (m, 1H), 1.35 (s, 3H) 1.41 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1)(=[O:27])[CH3:26]
Reactant: Nc1ccc(CCN2CCC(NC(=O)c3ccccc3)CC2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(CCN2CCC(NC(=O)c3ccccc3)CC2)cc1
Reaction time: 24 h

Procedure:
1-[2-(p-Aminophenyl)ethyl]-4-benzamidopiperidine (2.3 g.) was refluxed for 2 hours with acetic anhydride (22 ml.) in anhydrous pyridine (100 ml.). The solution was refrigerated for 24 hours and a crystalline product was filtered off, which after washing with ether yielded the title compound, m.p. 270°-275° C. (dec.). Found: C, 72.6; N, 7.55; N, 11.6. C22H27N3O2 requires C, 72.3; H, 7.45; N, 11.5%).