Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.[C:43]([NH:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[NH2:57])([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>CN(C=O)C>[C:46]([O:45][C:43]([NH:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[NH:57][C:17]([C:15]1[NH:14][C:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C:10]=2[CH:16]=1)=[O:19])=[O:44])([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c(C(=O)O)cc2C1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2c([nH]1)CCN(C(=O)OC(C)(C)C)C2
Reaction time: 1 h

Procedure:
To a solution of compound 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (1.0 eq) in DMF was added triethyl amine (2.2 eq), Bis (2-oxo-3-oxazolidinyl) phosphonic chloride (BOP, 1.2 eq.) and stirred for 1 hr. Monoboc phenylene diamine was added and reaction was stirred for 24 hrs. Reaction mixture was then quenched with water and extracted with ethyl acetate, dried over sodium sulphate and concentrated to dryness. Crude mass was then purified by silica gel column chromatography to afford tert-butyl 2-({2-[(tert-butoxycarbonyl)amino]phenyl}carbamoyl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, which was then reacted with hydrochloric acid saturated diethyl ether to get N-(2-aminophenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2]pyridine-2-carboxamide
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[Cl:12])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(C(C)=O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:7][C:6]=1[Cl:12])[CH3:2]
Reactant: CCOC(=O)c1ccc(O)cc1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc(OCc2ccccc2)cc1Cl
Yield: 86.9 %

Procedure:
16.76 g (83.5 mmol) of 2-chloro-4-hydroxy-benzoic acid ethyl ester and 23.1 g (167 mmol) of potassium carbonate were added to 100 mL of methyl ethyl ketone followed by the addition of 17.1 g (100 mmol) of bromomethylbenzene while stirring. After refluxing for 28 hours, the mixture was cooled and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography to obtain 21.1 g of a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([NH2:19])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[CH:12]=[C:11]([NH:19][C:21](=[O:23])[CH3:22])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(N)cc(C(C)(C)C)cc1OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(C(C)(C)C)cc(OCc2ccccc2)c1C

Procedure:
This is obtained, by acetylating 2-methyl-3-amino-5-tert.-butylphenyl benzyl ether with acetic anhydride in toluene, in the form of colorless crystals; m.p. 170°-172° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.S(Cl)(Cl)=O.[CH2:18]([C@@H:25]1[CH2:30][C@@H:29]([N:31]([CH2:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]=[CH:41][CH:40]=2)[C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH2:28][CH2:27][NH:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N>C(Cl)Cl.CO>[CH2:18]([C@@H:25]1[CH2:30][C@@H:29]([N:31]([CH2:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]=[CH:41][CH:40]=2)[C:32](=[O:37])[C:33]([F:35])([F:36])[F:34])[CH2:28][CH2:27][N:26]1[C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: O=S(Cl)Cl
Product: O=C(c1cccc(C(F)(F)F)c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
106 mg (0.56 mmol) of 3-trifluoromethylbenzoic acid are reacted in analogy to Example 2j first with 58 μl (0.795 mmol) of thionyl chloride and subsequently with 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine to give the product. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.56, FD-MS: M+ =599.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11](Cl)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:15][NH:16][CH2:17][C:18]#[CH:19].C(N(CC)CC)C>O1CCCC1>[CH2:17]([N:16]([CH3:15])[S:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:13])=[O:12])[C:18]#[CH:19]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: C#CCNC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCN(C)S(=O)(=O)c1ccc(OC)c(OC)c1
Yield: 64.8 %

Procedure:
3,4-Dimethoxybenzene sulfonyl chloride (11.8 g) in tetrahydrofuran (100 mL) is added slowly with stirring to a mixture of N-methylpropargylamine (3.5 g), triethylamine (5.05 g), and tetrahydrofuran (100 mL). The resulting mixture is refluxed 1 hour, cooled, filtered, and evaporated to dryness. The residue is treated with water, filtered, washed with water, and dried. Recrystallization from ethanol gave 8.7 g of the title product.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[OH:19][C:20]1[CH:21]=[C:22]([C:27]2[C:28](=[S:33])[NH:29][CH:30]=[N:31][CH:32]=2)[CH:23]=[CH:24][C:25]=1[OH:26].B(F)(F)F.CCOCC>S1(CCCC1)(=O)=O.ClCCl>[NH2:13][C@@H:10]1[C:11](=[O:12])[N:8]2[C@@H:9]1[S:14][CH2:15][C:6]([CH2:5][S:33][C:28]1[C:27]([C:22]3[CH:23]=[CH:24][C:25]([OH:26])=[C:20]([OH:19])[CH:21]=3)=[CH:32][N:31]=[CH:30][N:29]=1)=[C:7]2[C:16]([OH:18])=[O:17]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Oc1ccc(-c2cnc[nH]c2=S)cc1O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=S1(=O)CCCC1
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3ncncc3-c3ccc(O)c(O)c3)CS[C@H]12
Yield: 88.8 %

Procedure:
7-Aminocephalosporanic acid (220 mg) (0.81 mmol) and 250 mg (1.04 mmol) of 5-(3,4-dihydroxyphenyl)-4(3H)-pyrimidinethione are suspended in 8 ml of sulpholane/dichloromethane (1:1 v/v) and treated with 5 ml of boron trifluoride diethyl etherate while stirring. After 18 hours the mixture is concentrated in a vacuum and the residue is washed with diethyl ether. Then, 2 ml of ethanol and 4 ml of water are added thereto and sodium hydrogen carbonate is added until pH 5 has been reached. The product is filtered off under suction, washed with water and diethyl ether and dried in a high vacuum at room temperature. There are obtained 311 mg of (6R,7R)-7-amino-3-[[[5-(3,4-dihydroxyphenyl)-4-pyrimidinyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=2)[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].OC(C(F)(F)F)=O.[NH2:38][CH2:39][C:40]([CH3:45])([CH3:44])[C:41]([OH:43])=[O:42].C[O-].[Na+]>CCO>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=3)=[N:6][C:5]([C:3]([NH:38][CH2:39][C:40]([CH3:45])([CH3:44])[C:41]([OH:43])=[O:42])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1nc(-c2cncc(F)c2)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: CC(C)(CN)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)(CNC(=O)c1nc(-c2cncc(F)c2)c2c(=O)n(Cc3ccccc3)ccc2c1O)C(=O)O
Temperature: 140 °C
Yield: 34 %

Procedure:
A mixture of 7-benzyl-1-(5-fluoro-pyridin-3-yl)-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (17 mg, 0.042 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (39 mg, 0.17 mmol), and NaOMe (18 mg, 0.34 mmol) in EtOH (2 mL) was heated at 140° C. for 6 h in a microwave reactor. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-40% EtOAc/CH2Cl2+1% AcOH). The product was then dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2, and the resulting precipitate was isolated by filtration to give 7 mg of the title compound. MS: (+) m/z 491.37 (M+1).
Reaction SMILES: [OH:1]O.[NH2:3][C:4]1[N:8]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:7]=[CH:6][C:5]=1[C:14]#[N:15]>C(O)C.N>[NH2:3][C:4]1[N:8]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:7]=[CH:6][C:5]=1[C:14]([NH2:15])=[O:1]
Reactant: OO
Reactant: N#Cc1cnn(C2CCCC2)c1N
Agent: N
Solvent: CCO
Product: NC(=O)c1cnn(C2CCCC2)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
85 ml of 30% strength hydrogen peroxide solution are added to a solution of 5-amino-1-cyclopentyl-1H-pyrazole-4-carbonitrile (6.74 g, 38.3 mmol) in a mixture of 300 ml of ethanol and 371 ml of concentrated aqueous ammonia solution at room temperature and stirred at room temperature overnight. The nonaqueous solvents are then stripped off in a rotary evaporator. The product precipitates as solid from the remaining mixture and is filtered off with suction, washed with diethyl ether and dried under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Cl:14])[N:13]=1)[C:5](N(OC)C)=[O:6].[CH3:15][Li]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH3:15])[CH:11]=[C:12]([Cl:14])[N:13]=1
Reactant: [Li]C
Reactant: CON(C)C(=O)c1cc(Cl)nc(Cl)c1
Solvent: CCOCC
Product: CC(=O)c1cc(Cl)nc(Cl)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2,6-Dichloro-N-methoxy-N-methylisonicotinamide (Intermediate 47, 780 mg, 3.3 mmol) in anhydrous diethylether (13 ml) was cooled to −78° C. Methyllithium (1.6 M solution in diethyl ether (5.2 ml, 8.3 mmol) was added dropwise. The mixture was stirred at −78° C. for 1 h and quenched with ammonium chloride solution, followed by warming to room temperature. The reaction mixture was diluted with water (20 ml) and extracted with diethyl ether (2×30 ml), dried over sodium sulphate and concentrated in vacuo to give the title compound (575 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[C:10]2[C:11]3[C:12](=[N:24][N:25]([CH2:27][C:28]4[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[CH:30][N:29]=4)[N:26]=2)[CH:13]=[C:14]([C:19]([O:21]CC)=[O:20])[C:15]=3[CH2:16][S:17][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]2[C:11]3[C:12](=[N:24][N:25]([CH2:27][C:28]4[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[CH:30][N:29]=4)[N:26]=2)[CH:13]=[C:14]([C:19]([OH:21])=[O:20])[C:15]=3[CH2:16][S:17][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2nn(Cc3ncc(C)c(OC)c3C)nc3c-2c1CSN=C3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(C)cnc(Cn2nc3cc(C(=O)O)c4c-3c(n2)C(NC(=O)OC(C)(C)C)=NSC4)c1C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
Ethyl 4-[bis(tert-butoxycarbonyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulene-8-carboxylate (0.92 g) was dissolved in methanol (10 ml) under cooling in an ice bath. A 1 N sodium hydroxide solution (10 ml) was added, and the mixture was stirred for 16 hours while gradually returning to room temperature. The reaction solution was neutralized with a 0.5 N hydrochloric acid solution, and then the solvent was concentrated. The resulting residue was diluted with chloroform and washed with a 10% citric acid solution, and the organic layer was dried over sodium sulfate. The solvent was evaporated, and the resulting residue was recrystallized from hexane and ethyl acetate to obtain the title compound as a solid (0.68 g, 91%).
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:7][C:8]([NH:10][C@@H:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:12]([OH:16])[C:13]([OH:15])=[O:14])=[O:9])[CH3:6].S(=O)(O)O.Cl.[CH3:29]O>C1(C)C=CC=CC=1>[CH3:29][O:14][C:13](=[O:15])[C@@H:12]([OH:16])[C@@H:11]([NH:10][C:8]([O:7][CH2:5][CH3:6])=[O:9])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Reactant: CO
Agent: Cl
Agent: O=S(O)O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)OC
Temperature: 25 °C

Procedure:
Thionyl chloride (596 mg) was added to methanol (1.39 g) over 10 minutes under ice-cooling, and the mixture was reacted at the same temperature for 1 hour. The resultant solution was added to a solution of (2S,3S)-3-(ethoxycarbonyl)amino-2-hydroxy-4-phenylbutyric acid (HPLC area ratio of erythro-isomer/threo-isomer=99/1) (1.04 g) and toluene (10 ml) over 10 minutes under ice-cooling. The mixture was reacted at the same temperature for 2 hours and then warmed to room temperature. From the resultant reaction solution, methanol and thionyl chloride as well as components secondarily produced from these reagents and having a low boiling point such as sulfurous acid, hydrogen chloride or the like were distilled off under reduced pressure. Tetrahydrofuran was added to the resultant residue to obtain a tetrahydrofuran solution (10.12 g) of (2S,3S)-3-(ethoxycarbonyl)amino-2-hydroxy-4-phenylbutyric acid methyl ester. The HPLC area ratio of erythro-isomer/threo-isomer was 99/1, and the diastereomer excess was 99% d.e.
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][N+:30]([O-])=O)[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]>CCOC(C)=O.CO.[Fe]>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][NH2:30])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC[N+](=O)[O-])c[nH]c34)no2)cc1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCN)c[nH]c34)no2)cc1Cl
Yield: 71.7 %

Procedure:
Water (20 mL) and concentrated HCl solution (10 mL) were added to a solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-3-(2-nitroethyl)-1H-indole (D83) (2.1 g) in EtOAc (70 mL) and methanol (150 mL). The mixture was heated to reflux and stirred efficiently. Fe (6.0 g) was added in portions. After the addition was complete, the reaction mixture was refluxed for 8 hours. The solid was filtered off and the filtrate was concentrated and then basified with saturated NaHCO3 solution. The solid was filtered off and the filtrate was extracted with dichloromethane (200 mL). The organic layer was washed with water and brine, and then dried over MgSO4. Removal of the solvent gave the product 2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]ethanamine (D84) (1.4 g) as a yellow foam solid. No further purification was carried out. MS (ES): C21H21ClN4O2 requires 396; found 397.2 (M+H+).
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.[Cl:25][C:26]1[CH:27]=[C:28]([NH:32][NH2:33])[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:27]=[C:28]([N:32]2[C:2]3[C:3](=[CH:14][CH:15]=[C:16]([OH:18])[CH:17]=3)[C:4]([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=3[OH:13])=[N:33]2)[CH:29]=[CH:30][CH:31]=1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Reactant: NNc1cccc(Cl)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: Oc1ccc(-c2nn(-c3cccc(Cl)c3)c3cc(O)ccc23)c(O)c1
Yield: 87.9 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (2.46 g, 10 mmol), sodium acetate (0.82 g, 10 mmol) and 3-chlorophenylhydrazine hydrochloride (1.97 g, 11 mmol) to give 3.1 g of product as a tan solid Crystallized from EtOAc/hexane to give 1.4 g of an off-white solid (mp 228–230° C.).
Reaction SMILES: C(O)(=O)C.C1COCC1.[Br:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([CH:18]([O:20][Si](C(C)(C)C)(C)C)[CH3:19])=[CH:13][C:12]=1[NH:28][C:29]([N:31]1[CH:36]=[CH:35][C:34](=[O:37])[CH2:33][CH:32]1[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)=[O:30]>O>[Br:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([CH:18]([OH:20])[CH3:19])=[CH:13][C:12]=1[NH:28][C:29]([N:31]1[CH:36]=[CH:35][C:34](=[O:37])[CH2:33][CH:32]1[C:38]1[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=1)=[O:30]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1cc(NC(=O)N2C=CC(=O)CC2c2ccc(F)cc2)c(Br)cc1Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1cc(NC(=O)N2C=CC(=O)CC2c2ccc(F)cc2)c(Br)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
A mixture of acetic acid (4.5 ml), water (1.5 ml) and THF (1.5 ml) was added to a flask containing 2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid {2-bromo-5-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-4-chloro-phenyl}-amide (0.144 g, 0.247 mmol). The mixture was stirred at room temperature for 16 hours. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification by flash chromatography (EtOAc) gave 2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid [2-bromo-4-chloro-5-(1-hydroxy-ethyl)-phenyl]-amide (0.082 g, 71%) as a white foam. MS (M+H) 468.
Reaction SMILES: [CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][NH:14][NH:13]1)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH2:25]([O:32][C:33]([N:14]1[CH2:15][CH2:16][CH2:17][C@@H:12]([C:10](=[O:11])[NH:9][CH2:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:13]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(NCCc1ccccc1)[C@@H]1CCCNN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1ccccc1)[C@@H]1CCCN(C(=O)OCc2ccccc2)N1
Temperature: -5 °C
Reaction time: 1.5 h
Yield: 99.3 %

Procedure:
To a solution of (S)-hexahydro pyridazine-3-carboxylic acid phenethyl-amide (376 mg, 1.59 mmol) and Et3N (0.66 mL) in CH2Cl2 (10 mL) at 0° C., is added benzylchloroformate (270 mg, 1.59 mmol) dropwise. After stirring at −5° C. for 1.5 hours, the reaction mixture is diluted with CH2Cl2 (50 mL) and washed with 10 mL of water. The organic layer is dried over Na2SO4 and concentrated to give (S)-3-phenethylcarbamoyl-tetrahydro-pyridazine-1-carboxylic acid benzyl ester (580 mg) as pale gum without further purification for next step reaction. (NMR and MS data confirmed, U-3133-59).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:28](O)=[O:29])[N:18]([CH3:27])[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1>>[C:2]1([NH:1][C:28]([C:17]2[N:18]([CH3:27])[C:19]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([CH3:8])=[CH:14][CH:13]=3)[N:16]=2)=[O:29])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Reactant: Nc1ccccc1
Product: Cc1ccc(-c2nc(C(=O)Nc3ccccc3)n(C)c2-c2ccc(C)cc2)cc1

Procedure:
Using essentially the same procedure as Example 9, Step B, but using aniline (0.020 mL), 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Example 9, Step A was converted to the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.FC(F)(F)S(O[C:22]1[CH:35]=[C:34]2[C:25]([O:26][C:27]3[CH:28]=[CH:29][C:30]([C:41]4[C:42]([F:47])=[N:43][CH:44]=[CH:45][CH:46]=4)=[CH:31][C:32]=3[C@:33]32[CH2:39][O:38][C:37]([NH2:40])=[N:36]3)=[C:24]([F:48])[CH:23]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C=O)C>[O:1]1[CH2:2][CH:3]=[C:4]([C:22]2[CH:23]=[C:24]([F:48])[C:25]3[O:26][C:27]4[C:32](=[CH:31][C:30]([C:41]5[C:42]([F:47])=[N:43][CH:44]=[CH:45][CH:46]=5)=[CH:29][CH:28]=4)[C@@:33]4([CH2:39][O:38][C:37]([NH2:40])=[N:36]4)[C:34]=3[CH:35]=2)[CH2:5][CH2:6]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(OS(=O)(=O)C(F)(F)F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(C3=CCOCC3)cc12
Temperature: 85 °C

Procedure:
A flask was charged with tetrakis(triphenylphosphine)palladium (29.3 mg, 0.025 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (106 mg, 0.506 mmol), (S)-2-amino-5′-fluoro-2′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (130 mg, 0.253 mmol), sodium carbonate (saturated) (0.253 mL, 1.266 mmol) and DMF (2 ml). The solution was heated at 85° C. for 18 hours. The product was purified via Gilson HPLC (gradient elution 20-90% MeCN/H2O, 0.1% TFA) to afford (S)-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:20]([C:32]([F:35])([F:34])[F:33])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:37]>C(O)C>[ClH:37].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:20]([C:32]([F:33])([F:34])[F:35])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CCCCCCCOc1ccc(CCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C(F)(F)F
Agent: Cl
Solvent: CCO
Product: CCCCCCCOc1ccc(CCC(N)(CO)CO)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 1-2 (640 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (3 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (492 mg) as white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([O:12][CH3:15])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C(C)(C)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (10.03 g, 49.4 mmol) in MeOH/DCM (60 mL/140 mL) at room temperature was added drop wise (trimethylsilyl)diazomethane (37.0 mL, 74.0 mmol). The reaction mixture was stirred for 30 minutes. Acetic acid was added drop wise to quench (trimethylsilyl)diazomethane. The reaction mixture was concentrated under reduced pressure to afford the desired product as a white solid (10.56 g). LCMS m/z 240.2 (M+Na)+, Rt 0.71 min.