Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.[N:17]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:27]([O:26][C:24]([N:17]1[CH2:23][CH2:22][CH2:21][N:20]([C:2]2[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=2)[CH2:19][CH2:18]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CN(c1cc(F)ccc1[N+](=O)[O-])S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])S(C)(=O)=O

Procedure:
N-(5-Fluoro-2-nitrophenyl)-N-methylmethanesulfonamide (3.1 g, 12.5 mmol), tert-butyl 1-homopiperazinecarboxylate (2.5 g) and potassium carbonate (2 g) were heated together in DMSO (50 mL) at 80° C. overnight. The solution was allowed to cool and poured into 500 mL of water. The solid product was collected by filtration, washed with water and dried. Yield 4.6 g (86%); 1H NMR (400 MHz, CDCl3) δ 1.41 (s, 9H), 2.0 (br s, 2H), 3.01 (s, 3H), 3.28 (s, 3H), 3.3-3.8 (br, 8H), 6.64 (d, J=8.1 Hz, 1H), 6.74 (d, J=4.8 Hz, 1H), 8.09 (d, J=8.1 Hz, 1H); MS (ESI+) for C18H28N4O6S m/z 428.1709 (M+) (calc. 428.1730).
Reaction SMILES: [C:1]([O:5][C:6](=[O:52])[N:7]([CH2:17][CH:18]([OH:51])[CH:19]([NH:36][C:37](=[O:50])[CH2:38][NH:39]C(OCC1C=CC=CC=1)=O)[CH2:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([O:28]CC2C=CC=CC=2)[CH:22]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:52])[N:7]([CH2:17][CH:18]([OH:51])[CH:19]([NH:36][C:37](=[O:50])[CH2:38][NH2:39])[CH2:20][C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[C:25]([F:27])[CH:26]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cccc(CN(CC(O)C(Cc2cc(F)cc(OCc3ccccc3)c2)NC(=O)CNC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CO
Product: CCc1cccc(CN(CC(O)C(Cc2cc(O)cc(F)c2)NC(=O)CN)C(=O)OC(C)(C)C)c1
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of the product from Step 4 (130 mg, 0.18 mmol, 1.00 eq.) in methanol (0.5 mL) is added 10% Pd/C (20 mg, 0.02 mmol, 0.10 eq.). The reaction vessel is purged with H2 and then maintained under H2 via a balloon. The reaction is stirred under H2 overnight and then filtered and concentrated in vacuo yielding the product as a white solid (63 mg, 71% crude yield). Calculate mass for C26H36FN3O5: 489.26. Mass found for C26H36FN3O5: (OAMS) ES+: 489.8 (M+1), ES− 487.8 (M−1).
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH2:20](N)[CH2:21][CH2:22][CH3:23]>CN(C=O)C>[CH2:20]([NH:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CCCCNc1cccc2c1C(=O)c1ccccc1C2=O

Procedure:
1-Nitroanthraquinone was reacted in DMF at 20° C. with 5 moles n-butylamine for 5 hours. The reaction produced 1-butylamino anthraquinone which was a deep red solid having a melting point of 78° to 79° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[O:10]1[CH2:15][CH2:14][CH2:13][CH:12](O)[CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[O:9][CH:12]1[CH2:13][CH2:14][CH2:15][O:10][CH2:11]1
Reactant: OC1CCCOC1
Reactant: Oc1cc(F)cc(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cc(F)cc(OC2CCCOC2)c1
Yield: 75.8 %

Procedure:
A solution of 3,5-difluorophenol (1.15 g, 8.81 mmol), tetrahydro-2H-pyran-3-ol (0.900 g, 8.81 mmol), triphenylphosphine (2.31 g, 8.81 mmol) and DIAD (1.74 mL, 8.81 mmol) in THF (10 mL) was stirred overnight. The solution was then concentrated under reduced pressure and the residue was purified by purified by column chromatography on silica gel using CombiFlash® apparatus eluting with EtOAc/hexanes (0-30%). The purification afforded 1.43 g (75.8%) of the sub-title compound as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[OH:29][C:30]1[CH:35]=[C:34]([CH3:36])[O:33][C:32](=[O:37])[CH:31]=1>CN(C)C1C=CN=CC=1.ClCCCl>[OH:29][C:30]1[CH:35]=[C:34]([CH3:36])[O:33][C:32](=[O:37])[C:31]=1[C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: Cc1cc(O)cc(=O)o1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: Cc1cc(O)c(C(=O)Cc2cccc([N+](=O)[O-])c2)c(=O)o1
Reaction time: 1 h
Yield: 57.6 %

Procedure:
3-Nitrophenylacetic acid (7.20 g, 39.6 mmol) and then dicyclohexylcarbodiimide (8.6 g, 42 mmol) were added to a 1,2-dichloroethane (100 ml) suspension of 4-hydroxy-6-methyl-2-pyrone (5.00 g, 39.6 mmol) at room temperature, then 4-dimethylaminopyridine (0.24 g, 2.0 mmol) added and stirring carried out for 1 hour at 60° C., after which further 4-dimethylaminopyridine (0.48 g, 4.0 mmol) was added and stirring performed for 6 hours at 60° C. While the solution was still warm, the dicyclohexylurea was filtered off, and the reaction solution washed with dilute hydrochloric acid (50 ml), after which the aqueous layer was extracted with dichloromethane. After drying with anhydrous sodium sulphate, the solvent was distilled off and separation and purification carried out column chromatography. When recrystallization was performed from ethanol, 4-hydroxy-6-methyl-3-(3-nitrophenylacetyl)-2-pyrone (6.60 g, 58%) was obtained as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][CH2:20][N:21]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:16][N:15]([CH2:30][C:31]3[C:36]([CH3:37])=[C:35]([O:38][CH3:39])[C:34]([CH3:40])=[CH:33][N:32]=3)[C:4]=2[N:5]=[C:6]([NH:8]C(=O)C(C)(C)C)[N:7]=1>[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][CH2:20][N:21]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:16][N:15]([CH2:30][C:31]3[C:36]([CH3:37])=[C:35]([O:38][CH3:39])[C:34]([CH3:40])=[CH:33][N:32]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: COc1c(C)cnc(Cn2cc(C#CCN(CC(C)C)CC(C)C)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Agent: [Cl-]
Agent: [Zn+2]
Product: COc1c(C)cnc(Cn2cc(C#CCN(CC(C)C)CC(C)C)c3c(Cl)nc(N)nc32)c1C

Procedure:
The title compound was prepared by cleaving the pivaloyl protecting group of N-[4-chloro-5-(3-diisobutylamino-prop-1-ynyl)-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide with ZnCl2 according to the General Procedure B. tR: 5.23 min. 1H-NMR (CDCl3) δ 8.23 (s, 1H), 7.08 (s, 1H), 5.31 (s, 2H), 4.99 (s, 1H), 3.76 (s, 3H), 3.56 (s, 2H), 2.29 (s, 3H), 2.27 (d, 4H), 2.21 (s, 3H), 1.74 (m, 2H), 0.90 (d, 12H).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:18])=[O:5].Cl[C:24]1C=CC(C(C2N(C)C(CC(OCC)=O)=CC=2C)=O)=CC=1>>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH:12]([CH3:24])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:18])=[O:5]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccccc2C)n1C
Product: CCOC(=O)C(C)c1cc(C)c(C(=O)c2ccccc2C)n1C

Procedure:
The methylation procedure of Example 77A is repeated, except that an equivalent quantity of ethyl 5-(2'-methylbenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 92) is methylated instead of the ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A, to yield ethyl 5-(2'-methylbenzoyl)-1,4,α-trimethylpyrrole-2-acetate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O-:9])=[O:8].[Na+].[C:11]([O:17][CH2:18]Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>C(N(CC)CC)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9][CH2:18][O:17][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:8]
Reactant: O=C([O-])c1cnccn1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCOC(=O)c1cnccn1

Procedure:
The process for producing pivaloyloxymethyl pyrazinecarboxylate is now described taking the use of the sodium salt as an example of said alkali metal pyrazinecarboxylate. Thus, pyrazinecarboxylic acid is dissolved in an aqueous solution containing an equimoler amount, with respect to the acid, of sodium hydroxide, water is then distilled off, and the residue is dried to give sodium pyrazinecarboxylate. To this sodium pyrazinecarboxylate is added 1-2 molar equivalents, with respect to sodium pyrazinecarboxylate, of chloromethyl pivalate, and, as the catalyst, 0.1-0.3 molar equivalent, with respect to sodium pyrazinecarboxylate, of a tertiary amine, e.g. triethylamine, and the reaction is conducted at 90°-120° C. for 3-10 hours, whereby pivaloyloxymethyl pyrazinecarboxylate is produced. As an alternative, pivaloyloxymethyl pyrazinecarboxylate can also be obtained without the aid of a catalyst by conducting the reaction in a solvent in which sodium pyrazinecarboxylate is at least partially soluble and which is inert to the reaction, for example dimethylformamide or N-methyl-2-pyrrolidone.
Reaction SMILES: [BH4-].[Na+].[Br:3][CH2:4][C:5]([C:7]1[S:11][CH:10]=[N:9][CH:8]=1)=[O:6].O>CO>[Br:3][CH2:4][CH:5]([C:7]1[S:11][CH:10]=[N:9][CH:8]=1)[OH:6]
Reactant: O=C(CBr)c1cncs1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(CBr)c1cncs1
Reaction time: 0.75 h
Yield: 62.5 %

Procedure:
Sodium borohydride (38 mg, 1.0 mmol) was added in one portion to a solution of 207 mg (1.0 mmol) of the product from Example 3 in 2 mL of methanol at 0° C. After stirring for 0.75 h, water was added and the mixture extracted three times with diethyl ether. The combined organic phase was washed with brine, dried(MgSO4) and the solvent removed in vacuo. Flash chromatography (silica gel, 30-40% ethyl acetate-hexanes) afforded 130 mg (62%) of the title compound as a colorless oil: 1H NMR (400 MHz, CDCl3) δ8.78 (s, 1H), 7.83 (s, 1H), 5.28-5.24 (m, 1H), 3.70 (dd, 1H, J=10.6, 3.9 Hz), 3.61 (dd, 1H, J=10.6, 7.9 Hz), 2.95 (d, 1H, J=4.3 Hz).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Br:13][C:14]1[CH:19]=[C:18]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([Br:37])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:17]=[C:16]([Br:38])[C:15]=1[OH:39].O[C@H:41]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:42]([O:44][CH3:45])=[O:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC.C1C=CC=CC=1>[Br:38][C:16]1[CH:17]=[C:18]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([Br:37])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:19]=[C:14]([Br:13])[C:15]=1[O:39][C@@H:41]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:42]([O:44][CH3:45])=[O:43]
Reactant: COC(=O)[C@H](O)Cc1ccccc1
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: COC(=O)[C@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Temperature: 80 °C
Yield: 96.3 %

Procedure:
Diethylazodicarboxylate (0.839 mL, 5.50 mmol) was added dropwise to a stirred, room temperature suspension of 2,6-dibromo-4-(6-bromo-benzo [b]naphtho[2,3-d]thiophen-11-yl)-phenol (2.00 g, 3.55 mmol), (R)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.96 g, 5.50 mmol), triphenylphosphine (1.40 g, 5.50 mmol) and benzene (15 mL) under a dry nitrogen atmosphere. Dissolution occurred and the solution was heated in an 80° C. oil bath for 19 h. Upon cooling to room temperature, the reaction mixture was diluted with ether and silica gel (60 mL) was added. The reaction mixture was concentrated and the silica adsorbate was flash chromatographed (95:5 petroleum ether:ethyl acetate) to provide the title compound as a white solid (2.48 g, 94 %): mp 140-143° C.: [a]D25=-56.87° (10.02 mg/mL CHCl3); NMR (CDCl3); δ8.36 (ddd, J=8, 1, 1 Hz, 1 H), 7.83 (ddd, J=8, 1, 1 Hz, 1 H), 7.68 (ddd, J=8, 7, 1 Hz, 1 H), 7.60 (dd, J=5, 2 Hz, 2 H), 7.60-7.49 (m, 2 H), 7.46-7.27 (m, 6 H), 7.18 (ddd, J=8, 7, 1 Hz, 1 H), 6.74 (ddd, J=8, 1, 1 Hz, 1 H), 5.26 (dd, J =8, 6 Hz, 1 H), 3.76 (s, 3 H), 3.59 (dd, J=8, 5 Hz, 2 H); MS (FAB+): [M+], 3 bromine isotope pattern, 722 (31%), 724 (94%) 726 (100%) 728 (40%); Anal. Calc. for C32H21Br3O3S: C, 52.99, H, 2.99, N, 0.00. Found: C, 52.99, H, 2.85, N, 0.03.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[N:10]=[N:9][C:8]=1[C:19]([N:21]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:22]1[CH2:27][C@@H:26]([C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]1)=[O:20].C(OCC)(=O)C.[ClH:53]>C(OCC)(=O)C>[ClH:53].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[N:10]=[N:9][C:8]=1[C:19]([N:21]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:22]1[CH2:27][C@@H:26]([C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])[CH2:25][NH:24][CH2:23]1)=[O:20]
Reactant: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1C
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)nnn1-c1ccccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3S,5R)-3-[{[5-(4-methoxybutyl)-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (255 mg) was dissolved in ethyl acetate (0.5 ml), 4N hydrogen chloride-ethyl acetate solution (0.5 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was dried under reduced pressure to give the object product (220 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH2:9])[CH:7]=1.[C:20]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35](O)=[O:36])=[N:33][CH:34]=2)[CH2:25][CH2:24]1)(=[O:22])[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:20]([N:23]1[CH2:24][CH2:25][N:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([NH:9][CH2:8][C:6]3[CH:7]=[C:2]([F:1])[C:3]([C:10]4[CH:15]=[CH:14][N:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=4)=[N:4][CH:5]=3)=[O:36])=[N:33][CH:34]=2)[CH2:27][CH2:28]1)(=[O:22])[CH3:21]
Reactant: CC(=O)N1CCN(c2ccc(C(=O)O)nc2)CC1
Reactant: NCc1cnc(-c2ccnc(C(F)(F)F)c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc(C(=O)NCc3cnc(-c4ccnc(C(F)(F)F)c4)c(F)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (3-fluoro-2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methanamine 84-2 (54 mg, 0.20 mmol), 5-(4-acetylpiperazin-1-yl)picolinic acid 48-2 (50 mg, 0.20 mmol) and HATU (76 mg, 0.20 mmol) in DMF (0.9 mL) was added DIEA (0.16 mL, 1.00 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 5-(4-acetylpiperazin-1-yl)-N-((3-fluoro-2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methyl)picolinamide 84 as a white powder. MS m/z 503.20 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 9.28 (t, 1H, J=6.4 Hz), 8.92 (d, 1H, J=5.2 Hz), 8.62 (m, 1H), 8.32 (m, 2H), 8.20 (d, 1H, J=4.8 Hz), 7.88-7.82 (m, 2H), 7.43 (dd, 1H, J1=9.0 Hz, J2=3.2 Hz), 4.59 (d, 2H, J=6.4 Hz), 3.61-3.58 (m, 4H), 3.41-3.39 (m, 4H), 2.05 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12](F)[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].[CH2:18]([NH2:20])[CH3:19]>C1COCC1>[Cl:1][C:2]1[CH:13]=[C:12]([NH:20][CH2:18][CH3:19])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(NC1CC1)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: CCN
Solvent: C1CCOC1
Product: CCNc1cc(Cl)c(C(=O)NC2CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.17 g (8.40 mmol) of 2-chloro-N-cyclopropyl-4-fluoro-5-nitrobenzamide were initially charged in 100 ml of THF, 12 ml of a 2 molar solution of ethylamine in THF (16.79 mmol) were added and the mixture was stirred in a closed ampoule at room temperature for 18 hours. The reaction mixture was poured onto water, the organic solvents were distilled off and the residue obtained was filtered off with suction. Yield: 2.10 g (81% of theory)
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[C:15]([CH3:23])[CH:14]=1.Br[CH2:25]C(O)=O.Cl>O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:25])(=[O:21])=[O:20])=[C:15]([CH3:23])[CH:14]=1
Reactant: O=C(O)CBr
Reactant: Cc1cc(Br)ccc1S(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: O
Product: Cc1cc(Br)ccc1S(C)(=O)=O
Temperature: 75 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
235 mg Sodium sulfite and 470 mg NaHCO3 were dissolved in 1.75 mL of water and heated to 75° C. 500 mg of 4-Bromo-2-methyl-benzenesulfonyl chloride were added in portions within 10 min (gas formation) and the mixture stirred for 1 h at 75° C. 387 mg of Bromoacetic acid and 150 μL of water was added in small portions and the mixture stirred at 105° C. overnight. After cooling to 25° C. the mixture was acidified to pH 1 using 4N HCl. The resulting precipitate was collected and washed with water to yield 205 mg solid.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][SH:7].Cl[C:9]1[CH:14]=[C:13]([CH3:15])[N+:12]([O-:16])=[C:11]([CH3:17])[CH:10]=1>CN1CCCC1=O>[CH3:17][C:11]1[CH:10]=[C:9]([S:7][CH2:6][CH2:5][CH2:4][OH:3])[CH:14]=[C:13]([CH3:15])[N+:12]=1[O-:16]
Reactant: OCCCS
Reactant: Cc1cc(Cl)cc(C)[n+]1[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cc(SCCCO)cc(C)[n+]1[O-]
Reaction time: 0.17 h

Procedure:
12 g of (60% strength) NaH are added in portions to 50 ml of dry N-methylpyrrolidone (NMP). The mixture is stirred for 10 min. 19 g (0.22 mol) of 3-hydroxypropyl mercaptan are metered in the course of 30 min and the mixture is stirred for a further 30 min until evolution of gas has ended. A solution of 28.8 g (0.2 mol) of 4-chloro-2,6-dimethylpyridine-N-oxide in 150 ml of NMP is then added dropwise in the course of 30 min, and the reaction mixture is stirred for 1 h at RT, then for 1 h at 70° C. and after this for a further 1 h at 100° C.
Reaction SMILES: [O:1]1[CH2:6][C:5](=[O:7])[NH:4][C:3]2[CH:8]=[N:9][CH:10]=[CH:11][C:2]1=2.[H-].[Na+].Br[CH2:15][C:16]([C:18]1[CH:23]=[C:22]([Br:24])[C:21]([OH:25])=[C:20]([Br:26])[CH:19]=1)=[O:17]>CN(C)C=O>[Br:24][C:22]1[CH:23]=[C:18]([C:16](=[O:17])[CH2:15][N:4]2[C:5](=[O:7])[CH2:6][O:1][C:2]3[CH:11]=[CH:10][N:9]=[CH:8][C:3]2=3)[CH:19]=[C:20]([Br:26])[C:21]=1[OH:25]
Reactant: O=C(CBr)c1cc(Br)c(O)c(Br)c1
Reactant: O=C1COc2ccncc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)COc2ccncc21)c1cc(Br)c(O)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 10 ml flask, 4H-pyrido[4,3-b][1,4]oxazin-3-one (50 mg, 0.33 mmol) was dissolved in N,N-dimethyl formamide (2.0 ml) and then cooled to 0□. Sodium hydride (15 mg, 0.37 mmol) was added thereto at 0□ and then stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0□, 2-bromo-1-(3,5-dibromo-4-hydroxy-phenyl)-ethanone (124 mg, 0.33 mmol) was added thereto dropwise and stirred at 0□ for 30 minutes, and then the mixture was stirred at room temperature for 1 hour. The precipitates formed were filtered and washed with acetonitrile. The resulting solid was recrystallized from methanol to obtain the target compound 56, i.e., 4-[2-(3,5-dibromo-4-hydroxy-phenyl)-2-oxo-ethyl]-4H-pyrido[4,3-b][1,4]oxazin-3-one, as white solid (48 mg, 33%).
Reaction SMILES: [C:1]1([CH2:7][CH:8]([NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1C2C(=CC=CC=2)CCC1>[CH3:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:7]=[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:15]=1
Reactant: Cc1ccccc1C(=O)NC(Cc1ccccc1)c1ccncc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: c1ccc2c(c1)CCCC2
Product: Cc1ccccc1-c1nc(-c2ccncc2)cc2ccccc12
Temperature: 230 °C
Reaction time: 5 h
Yield: 72.1 %

Procedure:
37 g of N-[2-phenyl-1-(4-pyridyl)ethyl]-2-methylbenzamide in 800 ml of tetralin are heated with 240 g of phosphorus pentoxide and 60 g of Celite filtration aid, to improve distribution, at 180°-200° C. for 5 hours. After cooling to 120°-140° C., a further 120 g of phosphorus pentoxide are added and the mixture is heated at 230° C. (reflux) for 16 hours. After cooling, the tetralin is decanted off and the residue is washed several times with toluene. The washed residue is suspended in toluene and water is slowly added with stirring. The aqueous phase is separated off and made highly alkaline with potassium hydroxide. The product is extracted with toluene and, after distilling out the toluene, is chromatographed on silica gel using chloroform/ethyl acetate (8:2). 25 g of oily base are isolated, which provides a hydrochloride of melting point 255°-259° C. with ethanolic hydrochloric acid.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[CH2:10][CH2:11]2)(=[O:22])=[O:23])=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(OC)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CN2CCC(C(=O)O)(S(=O)(=O)c3ccc(OC)cc3)CC2)cc1

Procedure:
4-(4Methoxy-benzenesulfonyl)1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4Methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperidine-4carboxylic acid ethyl ester (4.2 g, 10 mmol) dissolve in methanol (30 mL), 10 N sodium hydroxide (10 mL), tetrahydrohydrofuran (20 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g (71%). white solid mp 190° C., MS: 420.4 (M+H)+.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:28][CH3:29])=[C:23](B(O)O)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:28][CH3:29])=[C:23]([Pb+3:17])[CH:24]=1
Reactant: [Pb+4]
Reactant: CCc1ccc(Br)cc1B(O)O
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(Br)cc1[Pb+3]
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 67.2 %

Procedure:
To a mixture of lead tetraacetate (13.7 g, 31.00 mmol) and mercuric diacetate (0.47 g, 1.50 mmol), thoroughly flushed with nitrogen, is added anhydrous chloroform (42 ml). This mixture is warmed to 40° C., and 5-bromo-2-ethylphenylboronic acid (6.50 g, 28.00 mmol) is added in one portion and the suspension is heated at this temperature for 5 hours. The mixture is then allowed to cool to room temperature, followed by further cooling to 0° C. then addition of powdered anhydrous potassium carbonate (3.22 g) with rapid stirring for 5 minutes then filtration. The filtrate is concentrated to half its volume, followed by the addition of hexanes to induce precipitation. This mixture is further concentrated, the solvent decanted, and the solid washed with hexanes to afford 5-bromo-2-ethylphenyllead triacetate (10.69 g) as a sandy coloured solid.