Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:40])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:47]([O:49][C:50]([C:52]1(Br)[CH2:55][CH2:54][CH2:53]1)=[O:51])[CH3:48]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:40])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C:52]3([C:50]([O:49][CH2:47][CH3:48])=[O:51])[CH2:55][CH2:54][CH2:53]3)[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3cccc(OC)c3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3cccc(OC)c3)n2)CC1
Temperature: 100 °C

Procedure:
To a solution of 100 mg of 4-((S)-4-tert-Butoxycarbonyl-2-{[5-hydroxy-1-(3-methoxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 4 ml of DMF, 116 mg of cesium carbonate and 74 mg of 1-Bromo-cyclobutanecarboxylic acid ethyl ester was added and heated to 100° C. for 3 h. Then, the reaction mixture was diluted with water and filtered through a Chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure. The crude product was used in the subsequent reaction. Yield: 90 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>>[OH:26][CH2:25][CH2:27][NH:28][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:22]
Reactant: NCCO
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NCCO)n(C)n1
Yield: 61 %

Procedure:
As described for example 55, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.3 mmol) was converted, using ethanolamine instead of 2-amino-2-methyl-1-propanol, to the title compound (70 mg, 61%) which was obtained as a white solid. MS: m/e=375.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]2[N:8]([CH2:9][CH2:10][CH2:11]2)[C:7](=[O:13])[CH2:6][CH2:5]1)([O-])=O>C1COCC1.[Ni]>[NH2:1][C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]2[N:8]([CH2:9][CH2:10][CH2:11]2)[C:7](=[O:13])[CH2:6][CH2:5]1
Reactant: O=C1CCC(c2ccccc2)([N+](=O)[O-])C2CCCN12
Agent: [Ni]
Solvent: C1CCOC1
Product: NC1(c2ccccc2)CCC(=O)N2CCCC21
Temperature: 25 °C
Reaction time: 90 h

Procedure:
To a solution of 60 mg (0.231 mmol) (8R,S; 8aS,R)-8-nitro-8-phenyl-hexahydro-indolizin-5-one in 1 ml THF were added 100 ul of Raney Nickel (55% in water). The mixture was stirred at room temperature under a hydrogen atmosphere for 90 hours. The apparatus was purged with argon. The catalyst was filtered (under argon), washed with THF and the filtrate was concentrated in vacuo to provide 38 mg (y: 72%) of title compound as a colorless oil. (M+H+: 231.3).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][O:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH3:31])[CH:25]=1)=[O:23].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:16][C:17]([O:19][CH2:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH3:31])[CH:25]=2)=[O:23])=[O:18])[CH2:13][O:14][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)CBr)ccc1Cl
Reactant: O=C(O)CC1(NC(=O)OCc2ccccc2)COC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1cc(C(=O)COC(=O)CC2(NC(=O)OCc3ccccc3)COC2)ccc1Cl

Procedure:
(3-{[(Benzyloxy)carbonyl]amino}oxetan-3-yl)acetic acid (Preparation 25, 0.3 g, 1.13 mmol), 2-bromo-1-(4-chloro-3-methylphenyl)ethanone (0.294 g, 1.19 mmol) and cesium carbonate (0.553 g, 1.70 mmol) were stirred in acetonitrile (10 mL) at room temperature for 2 hours. The reaction was concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound which was used without purification in the next step.
Reaction SMILES: C(O[C:4](=[O:15])[CH2:5][N:6]1[C:10]([I:11])=[C:9]([I:12])[C:8]([I:13])=[C:7]1[I:14])C.[CH2:16]([NH2:38])[CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37]>>[CH2:16]([NH:38][C:4](=[O:15])[CH2:5][N:6]1[C:7]([I:14])=[C:8]([I:13])[C:9]([I:12])=[C:10]1[I:11])[CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37]
Reactant: COCCOCCOCCOCCOCCOCCOCCN
Reactant: CCOC(=O)Cn1c(I)c(I)c(I)c1I
Product: COCCOCCOCCOCCOCCOCCOCCNC(=O)Cn1c(I)c(I)c(I)c1I
Yield: 114.2 %

Procedure:
According to the procedure described in Ex. 2, 2.3 g of 2,3,4,5-tetraiodopyrrol-1-acetic acid ethyl ester (prepared according to the procedure described in Ex. 1) (0.00457 mol) and 23.27 g of compound B, 3,6,9,12,15,18,21-heptaoxadocosylamine, (0.0685 mol) are reacted. 3.82 g of N-[3,6,9,12,15,18,21-heptaoxadocos-1-y1]-2,3,4,5-tetraiodopyrrol-1-acetamide (0.0040 mol) are obtained.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:36][C:37]([O-:40])([CH3:39])[CH3:38].[K+]>>[C:37]([O:40][C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][CH:11]([N:14]3[CH2:15][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[O:20])[CH2:17]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)([CH3:39])([CH3:38])[CH3:36]
Reactant: CC(C)(C)[O-]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(F)nc3)CC2)C1
Agent: [K+]
Product: CC(C)(C)Oc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from N-({1-[4-(6-fluoro-pyridin-3-yl)-4-hydroxy-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide 6a and t-BuOK using the procedure described in Example 8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[NH:8][O:9][C:5]=2[CH:4]=1.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C1COCC1>[CH3:18][O:17][C:15](=[O:16])[CH2:14][N:8]1[C:7](=[O:10])[C:6]2[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:9]1
Reactant: COc1ccc2c(=O)[nH]oc2c1
Reactant: COC(=O)CBr
Solvent: C1CCOC1
Product: COC(=O)Cn1oc2cc(OC)ccc2c1=O
Yield: 43.5 %

Procedure:
The KN(TMS)2 (7.2 g) was added to a solution of compound 22B (4 g) in 150 mL of THF at 0° C. by portion, another one hour at 0° C. with stirring. Methyl bromoacetate (7 g) was added, stirred at RT overnight. The reaction mixture was quenched with 150 mL of ethyl acetate and 100 mL of 2N HCl. The organic layer was separated, washed with water, brine, dried (MgSO4), concentrated to afford an off-white solid compound 22C (2.5 g). mp 185-188° C.; MS: 238 (M+1)+. Preparation of 5-Chlorosulfonyl-6-methoxy-3-oxo-3H-benzo[d]isoxazol-2-yl-acetic acid methyl ester (Compound 22D)
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[NH:6][N:5]=[N:4]1)[CH3:2].Br[CH2:10][CH2:11][Cl:12].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[Cl:12][CH2:11][CH2:10][N:6]1[C:7](=[O:8])[N:3]([CH2:1][CH3:2])[N:4]=[N:5]1
Reactant: CCn1nn[nH]c1=O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CCn1nnn(CCCl)c1=O
Yield: 80 %

Procedure:
A mixture of 22 parts of 1-ethyl-1,4-dihydro-5H-tetrazol-5-one, 45 parts of 1-bromo-2-chloroethane, 26 parts of sodium carbonate, 0.3 parts of potassium iodide and 240 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The aqueous phase is extracted three times with dichloromethane. The combined organic phases are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated, yielding 28.4 parts (80%) of 1-(2-chloroethyl)-4-ethyl-1,4-dihydro-5H-tetrazol-5-one as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([F:36])=[C:14]([C@:16]4([CH3:35])[CH2:21][C@@H:20]([C:22]([F:25])([F:24])[F:23])[O:19][C:18]([NH:26]C(=O)C5C=CC=CC=5)=[N:17]4)[CH:15]=3)[O:8][C:4]=2[CH:3]=1.C1CCN2C(=NCCC2)CC1.CO>[NH4+].[Cl-].CCOC(C)=O>[NH2:26][C:18]1[O:19][C@H:20]([C:22]([F:25])([F:24])[F:23])[CH2:21][C@:16]([C:14]2[CH:15]=[C:10]([NH:9][C:7]3[O:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:38]=[CH:37][C:5]=4[N:6]=3)[CH:11]=[CH:12][C:13]=2[F:36])([CH3:35])[N:17]=1
Reactant: C[C@@]1(c2cc(Nc3nc4ccc(Cl)cc4o3)ccc2F)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccccc2)=N1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: C[C@@]1(c2cc(Nc3nc4ccc(Cl)cc4o3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 65 °C
Reaction time: 4 h
Yield: 7.8 %

Procedure:
A mixture of N-((4S,6S)-4-(5-((6-chlorobenzo[d]oxazol-2-yl)amino)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (0.200 g, 0.366 mmol), DBU (0.072 mL, 0.475 mmol) and MeOH (3 mL) was stirred at 65° C. After 4 h, the mixture was diluted with saturated NH4Cl and EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The crude was purified by silica gel chromatography: 0-100% in 15 min, then 100% EtOAc-hexane. The product was obtained as a white solid (67.4 mg, 91% pure). The crude was further purified by reverse phase HPLC: 10-100% in 16 min, MeCN in water with 0.1% TFA. The combined fractions were neutralized with solid Na2CO3, and extracted with DCM three times. The organic phase was dried over Na2SO4 and concentrated in vacuo. The product was obtained as a white solid (12.7 mg, 8% yield). MS m/z=443 [M+H]+. Calculated for C19H15ClF4N4O2: 442.8.
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[O:12]([NH2:14])[CH3:13].C([O-])([O-])=O.[K+].[K+].O>CCOCC>[O:7]([C:8]([CH2:13][O:12][NH2:14])=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: NOCC(=O)Oc1ccccc1
Reaction time: 64 h
Yield: 89.9 %

Procedure:
Phenylchloroformate (14.78 g, 94.4 mmol) was dissolved in Et2O (375 mL) and methoxylamine hydrochloride (7.88 g, 94.4 mmol), K2CO3 (15.66 g, 113.3 mmol), and water (18 mL) were added and the solution stirred over 64 hours. Solids were filtered, the phases separated, and the organic component concentrated under reduced pressure. The crude liquid was purified by column chromatography with silica gel (1:4 EtOAc/hexanes) to afford N-(phenoxycarbonyl)methoxylamine as a white solid (14.18 g, 90%).
Reaction SMILES: [O:1]1[C:5]([C:6]2[S:10][C:9]([S:11](Cl)(=[O:13])=[O:12])=[CH:8][CH:7]=2)=[CH:4][CH:3]=[N:2]1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)[CH:19]=[CH:20][CH:21]=1>>[O:1]1[C:5]([C:6]2[S:10][C:9]([S:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[NH:26][N:25]=[N:24][N:23]=4)[CH:17]=3)(=[O:13])=[O:12])=[CH:8][CH:7]=2)=[CH:4][CH:3]=[N:2]1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccno2)s1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2ccno2)s1

Procedure:
The title compound was prepared according to General Procedure 1, described in Example 1, with 5-isoxazol-5-ylthiophene-2-sulfonyl chloride (13.7 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). MS (ESI+) calcd mass for C14H10N6O3S2 374.025580, found 374.025420.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:15])=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[C:5]([F:8])=[CH:6][CH:7]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(O)C>[C:16]([NH:1][C:2]1[C:3]([F:15])=[C:4]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[C:5]([F:8])=[CH:6][CH:7]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(F)c(-c2ccncc2)c1F
Solvent: CCO
Product: CC(=O)Nc1ccc(F)c(-c2ccncc2)c1F
Reaction time: 1 h
Yield: 86 %

Procedure:
A mixture of 4-(3-amino-2,6-difluorophenyl)-pyridine (6.5 g), acetic anhydride (4.9 g) and ethanol (200 ml) was heated at reflux. After 1 hour, a further 3.3 ml acetic anhydride was added and a third portion (1.5 ml) after another 3.5 hours. Reflux was continued for a total of 6 hours after which time the solution was cooled and evaporated and the residue was partitioned between aqueous sodium bicarbonate and chloroform. The organic layer was washed with water, dried and evaporated to give the solid product of m.p. 148°-150° C. (6.8 g, 86% yield). NMR (CDCl3, 60 MHz): 8.8 (m, 2H), 8.05 (m, 2H), 7.4 (m, 2H), 6.9 (m, 1H), 2.2 (s, 3H).
Reaction SMILES: [F:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:10][S:11]([O:9][CH2:8][C:2]1([F:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(F)CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(F)CCOCC1

Procedure:
A mixture of EXAMPLE 37C (1.4 g), methanesulfonyl chloride (1.054 mL), triethylamine (2.99 mL), and 4-dimethylaminopyridine (0.051 g) in CH2Cl2 (20 mL) was stirred at 0° C. for 2 hours, concentrated and chromatographed on silica gel eluting with 30% ethyl acetate in hexanes to give the product.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH:30]1([N:33]=[C:34]=[O:35])[CH2:32][CH2:31]1>>[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[CH2:18][CH:17]([NH:29][C:34]([NH:33][CH:30]3[CH2:32][CH2:31]3)=[O:35])[CH2:16]2)=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Reactant: O=C=NC1CC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)NC3CC3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
108 mg (0.22 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 7A) and 22 mg (0.26 mmol, 1.2 eq.) of cyclopropyl isocyanate were reacted according to General Method 4. Yield: 64 mg (76% of theory)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([F:11])=[C:8]([CH:10]=1)[NH2:9])([O-:3])=[O:2].CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1>C(O)(=O)C>[F:11][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:10][C:8]=1[N:9]1[CH:14]=[CH:18][CH:17]=[CH:16]1
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(F)c(-n2cccc2)c1
Temperature: 110 °C
Yield: 78 %

Procedure:
5-Nitro-2-fluoroaniline (7.0 g, 44.8 mmol) was taken up in acetic acid (60 mL) in a 250 mL round bottomed flask and treated with 2,5-dimethoxytetrahydrofuran (6.3 mL, 49.8 mmol). The resulting mixture was heated to 110° C. for 4 hours. TLC analysis indicated complete conversion of starting material to product after 4 hours. Thus, the reaction mixture was cooled to ambient temperature, transferred to a separatory funnel and partitioned (CH2Cl2//H2O). The organic phase was washed with H2O (3×50 mL), brine (3×50 mL), dried over Na2SO4 and evaporated in vacuo to give a light brown residue. The residue was purified by flash chromatography (hexanes→1:9 EtOAc/hexanes) to afford the title compound as a light yellow solid (7.2 g, 78%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[CH3:25].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.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>[CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[CH3:25]
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Reactant: CCC(=O)c1ccc(B(O)O)c(C)c1
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: [K+]
Solvent: COCCOC
Product: CCC(=O)c1ccc(-c2cc([N+](=O)[O-])ccc2C)c(C)c1
Temperature: 90 °C
Reaction time: 14 h
Yield: 81.2 %

Procedure:
2.5 g (13 mmol) of 2-methyl-4-propionylbenzeneboronic acid are placed in 100 ml of dimethoxyethane in a round-bottomed flask, and 2.2 g (10 mmol) of 2-bromo-4-nitrotoluene and 13 ml of aqueous 2M potassium carbonate solution are added. The medium is degassed for 10 minutes with a flow of nitrogen, and 580 mg (0.5 mmol) of tetrakis(triphenylphosphine)palladium are then added. The medium is stirred for 14 hours at 90° C. and then worked up as usual. The residue is obtained after chromatography on a column of silica (eluent: 1 ethyl acetate/9 heptane) to give 2.3 g (81%) of the expected product in the form of a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:24]1([C:30]2[CH:31]=[CH:32][C:33]3[NH:34][C:35]4[C:40]([C:41]=3[CH:42]=2)=[CH:39][C:38]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:37][CH:36]=4)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O.C1(C)C(C)=CC=CC=1>[C:24]1([C:30]2[CH:31]=[CH:32][C:33]3[N:34]([C:2]4[CH:7]=[CH:6][C:5]([C:8]5[C:17]([C:18]6[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=6)=[N:16][C:15]6[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=6)[N:9]=5)=[CH:4][CH:3]=4)[C:35]4[C:40]([C:41]=3[CH:42]=2)=[CH:39][C:38]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:37][CH:36]=4)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Brc1ccc(-c2nc3ccccc3nc2-c2ccccc2)cc1
Reactant: c1ccc(-c2ccc3[nH]c4ccc(-c5ccccc5)cc4c3c2)cc1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: c1ccc(-c2ccc3c(c2)c2cc(-c4ccccc4)ccc2n3-c2ccc(-c3nc4ccccc4nc3-c3ccccc3)cc2)cc1
Yield: 81 %

Procedure:
First, into a 200-mL three-neck flask were placed 2.2 g (6.0 mmol) of 2-(4-bromophenyl)-3-phenylquinoxaline, 1.9 g (6.0 mmol) of 3,6-diphenyl-9H-carbazole, and 1.1 g (12.0 mmol) of sodium tert-butoxide. The air in the flask was replaced with nitrogen, and 60 mL of xylene was placed into this flask. The mixture was degassed by stirring under reduced pressure. To this mixture were added 0.2 mL of tri(tert-butyl)phosphine and 71 mg (0.12 mmol) of bis(benzylideneacetone)palladium(0). This mixture was stirred under a nitrogen stream at 140° C. for 6 hours. After the predetermined time had elapsed, water was added to the obtained mixture, and the mixture was separated into an organic layer and an aqueous layer. Organic substances were extracted with toluene from the aqueous layer. The solution of the obtained extract was combined with the organic layer, and the mixture was washed with saturated brine and dried with magnesium sulfate. The obtained mixture was gravity filtered, and the filtrate was concentrated to give an oily substance. This oily substance was purified by silica gel column chromatography (with a developing solvent of toluene), followed by recrystallization from toluene, whereby 3.0 g of a yellow powder of Cz1PQ-III, which is the substance to be produced, was obtained in 81% yield.
Reaction SMILES: [CH:1]1([N:7]([CH3:36])[C:8](=[O:35])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([NH:23][C:24](=[O:26])[CH3:25])[N:17]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[CH2:16]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:37]>C(OCC)(=O)C>[ClH:37].[CH:1]1([N:7]([CH3:36])[C:8](=[O:35])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([NH:23][C:24](=[O:26])[CH3:25])[N:17]([CH2:27][C:28]([OH:30])=[O:29])[CH2:16]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)NC1=Nc2ccc(OCCCC(=O)N(C)C3CCCCC3)cc2CN1CC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)NC1=Nc2ccc(OCCCC(=O)N(C)C3CCCCC3)cc2CN1CC(=O)O

Procedure:
A solution of N-cyclohexyl-N-methyl-4-[2-acetamido-3-tert-butoxycarbonylmethyl-3,4-dihydroquinazolin-6-yl]oxybutyramide in ethyl acetate saturated with hydrogen chloride was stirred for 1 hour at room temperature. The resulting precipate was collected by filtration and dried to afford the title compound as a hygroscopic solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:29])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][C:14]=2[Cl:16])[N:9]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[C:8]=1[CH3:28]>C1COCC1.CO>[Cl:16][C:14]1[CH:13]=[CH:12][N:11]=[C:10]2[N:9]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[C:8]([CH3:28])=[C:7]([CH2:6][C:5]([OH:29])=[O:4])[C:15]=12
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2)c2nccc(Cl)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c2c(Cl)ccnc2n1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1M Aqueous NaOH (0.5 ml) is added to a stirring solution of [4-chloro-1-(4-methanesulfonyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (38 mg, 0.093 mmol) in 1:1 THF/MeOH (1 ml). After stirring at room temperature for 4 hours, the reaction mixture is filtered to remove any undissolved material and is evaporated to dryness. The resulting oil is dissolved in water (1 ml) and acidified to pH 2. The resulting precipitate collected by filtration and dried in vacuo to afford [4-chloro-1-(4-methanesulfonyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid. (MH+ 393)
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH2:16].C([O-])([O-])=O.[K+].[K+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]1([C:7]2[O:11][C:10]([C:12]([NH:16][NH:15][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
To a stirred suspension of 5-phenylfuran-2-carboxylic acid (200 mg, 1.06 mmol), tert-butyl hydrazinecarboxylate (140 mg, 1.06 mmol) and K2CO3 (440 mg, 3.19 mmol) in DCM (20 mL), HATU (404 mg, 1.06 mmol) was added. The mixture was stirred at RT for 3 h, then filtered to give the crude tert-butyl 2-(5-phenylfuran-2-carbonyl)hydrazinecarboxylate as a white solid (300 mg, 93%), which was directly used for next step without further purification. MS (ES+) C16H18N2O4 requires: 302. found: 247 [M+H−56]+.