Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([NH2:10])[C:7]([C:11]2[N:12]=[N:13][NH:14][N:15]=2)=[CH:6][CH:5]=1.[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[I-].[Na+].[H-].[Na+]>C(OCC)(=O)C.CCCCCC.O.CN(C=O)C>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:14]2[N:13]=[N:12][C:11]([C:7]3[C:8]([NH2:10])=[N:9][C:4]([CH2:3][O:2][CH3:1])=[CH:5][CH:6]=3)=[N:15]2)=[CH:30][CH:31]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COCc1ccc(-c2nn[nH]n2)c(N)n1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: COCc1ccc(-c2nnn(Cc3ccc(OCc4ccccc4)cc3)n2)c(N)n1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 12.3 %

Procedure:
6-Methoxymethyl-3-(2H-tetrazol-5-yl)-pyridin-2-ylamine (50 mg) described in Manufacturing Example 6-3, 4-benzyloxybenzyl chloride (57 mg), sodium iodide (36 mg), NaH (9.7 mg/60% in oil), and DMF (3 mL) were stirred for 15 minutes at 60° C. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was concentrated and purified by NH silica gel column chromatography (hexane:ethyl acetate=2:1). The residue thus obtained was solidified with ethyl acetate-hexane to obtain the titled compound (12 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1>O>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:11](=[O:13])[CH2:10][CH2:9][CH2:8]2
Reactant: O=C(O)CCCc1cccc(F)c1
Solvent: O
Product: O=C1CCCc2cc(F)ccc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
A mixture of 4-(3-fluorophenyl)butanoic acid (10 g) and polyphosphoric acid (100 g) was heated to 70° C. with stirring for 2 h. The reaction mixture was cooled and water was carefully added (400 cm3). The aqueous mixture was extracted with diethyl ether (3×75 cm3) and the combined extracts were washed sequentially with aqueous potassium hydroxide solution (1 M, 75 cm3), water (75 cm3) and saturated aqueous sodium chloride solution (75 cm3). The combined organic extracts were dried (Na2SO4), and the solvent was distilled off under reduced pressure. The crude product (6.58 g) was purified by column chromatography [silica, eluting with petroleum ether (b. p. 40-60° C.)-ethyl acetate (20:1)] to afford the title compound (6.36 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:12]2[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C:13]=12>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:12]2[CH2:16][NH:15][CH2:14][C:13]=12
Reactant: CC(C)(C)OC(=O)N1Cc2c(Br)sc(-c3ccccc3)c2C1
Solvent: O=C(O)C(F)(F)F
Product: Brc1sc(-c2ccccc2)c2c1CNC2
Reaction time: 0.17 h
Yield: 91 %

Procedure:
1.5 ml of trifluoroacetic acid are added to 0.98 g (1.32 mmol) of 1-bromo-3-phenyl-5-(1,1-dimethylethoxy)carbonyl-5,6-dihydro-4H-thieno[3,4-c]pyrrole. After 10 minutes at room temperature, the solvent is evaporated to dryness. 5 ml of toluene are added and the mixture is evaporated to dryness. The residue is triturated with 5 ml of diethyl ether, filtered and dried. There is obtained 0.95 g of a yellowish solid. Yield 91%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]1([OH:18])[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[CH3:11][C:12]1([OH:18])[CH2:17][CH2:16][CH2:15][N:14]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:13]1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC1(O)CCCNC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(O)CCCN(c2ccncc2[N+](=O)[O-])C1

Procedure:
Method 1 of Example 1 was followed using 1 equivalent each of 4-chloro-3-nitropyridine, 3-methylpiperidin-3-ol and triethyl amine in DMF yielding 3-methyl-1-(3-nitropyridin-4-yl)piperidin-3-ol. LCMS (m/z): 238.1 (MH+); LC Rt=1.39 min.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:6][CH:7]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[N:3]=[N:4][C:5]([N:8]3[CH:12]=[CH:11][N:10]=[CH:9]3)=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: Clc1ccc(-n2ccnc2)nn1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Brc1ccc(Oc2ccc(-n3ccnc3)nn2)cc1

Procedure:
A mixture of 4.5 parts of 3-chloro-6-(1H-imidazol-1-yl)pyridazine, 3.2 parts of 4-bromophenol, 4.2 parts of sodium carbonate and 80 parts of 2-propanone was stirred and refluxed over weekend. The reaction mixture was evaporated and the residue was taken up in water and 2.2'-oxybispropane. The layers were separated. The organic phase was dried, filtered and evapoated. The residue was crystallized from 2-propanol, yielding 3.5 parts of 3-(4-bromophenoxy)-6-(1H-imidazol-1-yl)pyridazine; mp. 168.4° C. (compound 6).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:47]=[C:48]([CH2:50][CH2:51][CH2:52][O:53][CH3:54])[CH:49]=1)[CH2:10][N:11]([CH:44]1[CH2:46][CH2:45]1)[C:12](=[O:43])[CH:13]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][C:34]2[C:39]([Cl:40])=[CH:38][C:37]([CH3:41])=[CH:36][C:35]=2[Cl:42])=[CH:26][CH:25]=1)[CH2:14][NH:15]C(=O)OC(C)(C)C)#[N:2].[N:55]([Sn](CCCC)(CCCC)CCCC)=[N+:56]=[N-:57].C(O)(=O)C.N>C1C(Cl)=CC=C(Cl)C=1.CO.C(Cl)Cl>[NH2:15][CH2:14][CH:13]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][C:34]2[C:35]([Cl:42])=[CH:36][C:37]([CH3:41])=[CH:38][C:39]=2[Cl:40])=[CH:26][CH:25]=1)[C:12]([N:11]([CH:44]1[CH2:45][CH2:46]1)[CH2:10][C:9]1[CH:8]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][C:1]2[NH:57][N:56]=[N:55][N:2]=2)[CH:49]=[C:48]([CH2:50][CH2:51][CH2:52][O:53][CH3:54])[CH:47]=1)=[O:43]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCC#N)c1
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COCCCc1cc(CN(C(=O)C(CN)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCc2nnn[nH]2)c1
Temperature: 150 °C

Procedure:
To a solution of tert-butyl (3-[[3-(3-cyanopropoxy)-5-(3-methoxypropyl)benzyl](cyclopropyl)amino]-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 74 in dichlorobenzene (0.08 M) was added azidotributyltin (2 eq.). The resulting mixture was heated to 150° C. for 22 h. The reaction was quenched with glacial acetic acid (6 eq.) and directly loaded onto a silica gel column packed with 85:15 (v/v) CH2Cl2: 2.0 M NH3 in MeOH. Elution with the same solvent system afforded the title compound as a yellow oil. MS (ESI+): 725.4.
Reaction SMILES: FC(F)(F)C1C=C(S(Cl)(=O)=O)C=CC=1.N1CC[C@H](O[N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])C1.FC(F)(F)C(O)=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:22]1(=[O:31])[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29](=[O:30])[NH:21]1
Reactant: O=C1c2ccccc2C(=O)N1O[C@H]1CCNC1
Agent: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
3-Trifluoromethylphenylsulfonyl chloride (1.96 g, 8.00 mmol) was added to a solution of (S)-2-(pyrrolidin-3-yloxy)isoindoline-1,3-dione) trifluoroacetic acid salt (2.77 g, 8.00 mmol) and N,N-diisopropylethylamine (3.10 g, 24.0 mmol) in CH2Cl2 (50 ml) and stirred at room temperature for 4 hours. The reaction mixture was washed with aqueous 1 N HCl solution (50 ml×2), H2O (50 ml×3) and brine (50 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether: 12.5/87.5 to 50/50) to give (S)-2-(1-(3-trifluoromethyl)phenylsulfonyl)pyrrolidin-3-yloxy)isoindoline-1,3-dione (1.87 g, 53%) as a white solid.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].[F:13][C:14]([F:27])([F:26])[C:15]1[CH:25]=[CH:24][C:18]([O:19]C2CNC2)=[CH:17][CH:16]=1>O1CCCC1.O.C1C=CC=CC=1>[F:13][C:14]([F:26])([F:27])[C:15]1[CH:25]=[CH:24][C:18]([O:19][CH:11]2[CH2:9][N:8]([C:1]([N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)=[O:2])[CH2:12]2)=[CH:17][CH:16]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccccc1
Product: O=C(N1CC(Oc2ccc(C(F)(F)F)cc2)C1)n1ccnc1
Reaction time: 6 h
Yield: 45 %

Procedure:
A mixture of 1.7 g (0.01 mole) 1,1'-carbonyldiimidazole in 50 ml of tetrahydrofuran and 3 g (0.015 mole) of 3-[4-(trifluoromethyl)phenoxy]azetidine was stirred for 6 hr. The reaction mixture was diluted with water and extracted with 3×50 ml of methylene chloride. The extracts upon concentrating in vacuo gave an amber residue which was dissolved in 20 ml of benzene and washed with dilute hydrochloric acid, then washed with water. The benzene portion was concentrated to give a semi-solid residue which when triturated with isopropyl ether gave 1.4 g of gray material. Recrystallization from acetonitrile gave 1.3 g (41.8%) of fine gray crystals, m.p. 139°-140° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([F:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:17]([O:19]CC)=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1.O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:1][C:2]1[C:11]([F:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:15][CH2:16]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(Cl)c(F)c(Cl)c2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)c(Cl)c2c1=O
Temperature: 0 °C
Yield: 100.5 %

Procedure:
5.2 g of ethyl 5,7-dichloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate are heated under reflux in a mixture of 38 ml of acetic acid, 30 ml of water and 4.3 ml of concentrated sulphuric acid for 2.5 hours. After cooling, the mixture is poured into 250 ml of ice-water and the precipitate is filtered off with suction, washed with water and dried. 4.8 g of 5,7-dichloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 277°-278° C. are obtained.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][N:9]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](OB(O)O)=[CH:18][CH:17]=1>O1CCOCC1.CO.CCOC(C)=O.O>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:11]2[CH:12]=[CH:13][C:8]([NH2:7])=[N:9][CH:10]=2)=[CH:18][CH:17]=1
Reactant: Nc1ccc(Br)cn1
Reactant: OB(O)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2ccc(Cl)cc2)cn1
Temperature: 110 °C
Reaction time: 2.5 h

Procedure:
300 mL (600 mmol) of a 2 M Na2CO3 solution and 3.45 g (3.0 mmol) tetrakis-triphenylphosphane-palladium are added successively to a solution of 53.5 g (300 mmol) 2-amino-5-bromopyridine and 50.0 g (313 mmol) 4-chlorophenylboric acid in 1.0 L 1,4-dioxane and 250 mL methanol under argon. The reaction mixture is stirred for 2.5 h at 110° C. The solvent is eliminated i.vac., the residue is taken up in EtOAc and water. The organic phase is dried over Na2SO4 and the solvent is eliminated i.vac. Further purification is carried out by column chromatography on silica gel (gradient: DCM to DCM/MeOH 20:1).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:26])[C:13]([C:23](O)=[O:24])=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C=O)C>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:26])[C:13]([CH2:23][OH:24])=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=c1c(CO)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Temperature: 80 °C
Reaction time: 24 h
Yield: 95.6 %

Procedure:
To a 90 ml DMF solution of 15.0 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was added 9.9 g of 1,1′-carbonyldiimidazole, followed by stirring at 80° C. for 24 hours. After cooling, the reaction mixture was poured into ice water, and the solid precipitated was collected by filtration. Next, 1.9 g of sodium borohydride was added at 0° C. to a mixed solution of 200 ml THF and 100 ml water of the resulting solid, followed by stirring at the same temperature for 2 hours. Water was added, the solvent was evaporated under a reduced pressure, and the insoluble materials were collected by filtration to obtain 13.8 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-(hydroxymethyl)quinolin-4(1H)-one.
Reaction SMILES: N[C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([N:25]([CH3:27])[CH3:26])[CH:5]=2.C(ON=O)(C)(C)C.[BH4-].[Na+]>C1COCC1>[Br:24][C:16]1[CH:15]=[C:14]([CH:10]2[C:9]3[C:4](=[CH:5][C:6]([N:25]([CH3:27])[CH3:26])=[CH:7][CH:8]=3)[O:3][CH:2]=[C:11]2[C:12]#[N:13])[CH:19]=[C:18]([O:20][CH3:21])[C:17]=1[O:22][CH3:23]
Reactant: COc1cc(C2C(C#N)=C(N)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Agent: CC(C)(C)ON=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C2C(C#N)=COc3cc(N(C)C)ccc32)cc(Br)c1OC
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 9.1 %

Procedure:
To a solution of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-7-dimethylamino-4H-chromene (101 mg, 0.239 mmol) in anhydrous THF (5 mL) at 0° C., was added tert-butylnitrite (0.1 mL, 0.76 mmol) via a syringe under argon. The brown solution was stirred at 0° C. for 2.5 h. Sodium borohydride (20 mg, 0.52 mmol) was added in one portion. The reaction mixture was warmed up to room temperature slowly and stirred overnight. It was quenched with addition of water (5 mL), and extracted with EtOAc (2×15 mL). The EtOAc solution was washed with brine (5 mL), dried over MgSO4, and evaporated to yield a brown residue. The residue was purified by flash column chromatography (silica gel, EtOAc:hexanes, 1:4) to yield 9 mg (9%) of the product as an off-white solid 1H NMR (CDCl3): 8.30 (d, J=1.2 Hz, 1H), 6.93 (d, J=2.1 Hz, 1H), 7.76 (dd, J=0.6, 8.7 Hz, 1H), 6.72 (d, J=1.8 Hz, 1H), 6.45 (dd, J=2.4, 8.7 Hz, 1H), 6.30 (d, J=2.7 Hz, 1H), 4.60 (s, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 2.95 (s, 6H).
Reaction SMILES: C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C.[C:19]([N:26]1[CH2:33][CH2:32][CH2:31][C@@H:27]1[C:28]([OH:30])=O)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[Cl:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1>C1(C)C=CC=CC=1>[Cl:34][C:35]1[CH:41]=[CH:40][C:38]([NH:39][C:28]([C@H:27]2[CH2:31][CH2:32][CH2:33][N:26]2[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:30])=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: Nc1ccc(Cl)cc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4.82 g (19.5 mmol) of ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate (EEDQ) are added to a suspension of 2.80 g (13.0 mmol) of N-Boc-D-proline and 1.66 g (13.0 mmol) of 4-chloroaniline in 50 ml of toluene, and the mixture is stirred at room temperature for 3 hours. The reaction mixture is filtered, and petroleum ether is added to the filtrate. The precipitate formed is filtered off and dried, giving tert-butyl (R)-2-(4-chlorophenyl-carbamoyl)pyrrolidine-1-carboxylate as colourless crystals; ESI 325.
Reaction SMILES: Br[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Br:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].[OH-].[Na+].CCOCC>C1(C)C=CC=CC=1>[Br:14][C:8]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[Cl:15])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: NCc1ccccc1Cl
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1NCc1ccccc1Cl
Yield: 61.5 %

Procedure:
A suspension of 2,5-dibromo-3-nitrobenzoic acid (10.76 g, 0.0331 mol) in toluene (100 mL) was placed under argon, treated with 2-chlorobenzylamine (14.06 g, 0.0993 mol) and the mixture was brought to reflux. A clear, red solution resulted and the solution was refluxed for 24 hours, cooled, poured into 5% sodium hydroxide solution (600 mL) and ether (100 mL). The insoluble material was filtered off, the layers separated and the aqueous phase was added to the insoluble material and acidified with 10% hydrochloric acid solution. The separated crystalline product was collected, washed with water and the solid was crystallized from a large volume of methanol to provide 7.85 g (61.5%) of the yellow crystalline 5-bromo-2-[(2-chlorophenyl)methyl]amino-3-nitrobenzoic acid; mp 159-161° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:18])[CH2:16][OH:17])[CH2:6]1)(=[O:3])[CH3:2].[C:28](OC)(=[O:34])[CH2:29][C:30]([O:32][CH3:33])=[O:31].[Cl-].[Ca+2].[Cl-]>C1(C)C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:18])[CH2:16][O:17][C:28](=[O:34])[CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)CC(=O)OC
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](C(=O)CO)[C@@]4(C)CC[C@@H]32)C1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COC(=O)CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 160 °C

Procedure:
A mixture of 200 mg of 3β-acetoxy-21-hydroxypregn-5-en-20-one, 10 ml of dimethyl malonate and 2.0 g of calcium chloride was heated in an oil-bath having a temperature of 84° C. for 4 days under nitrogen whereupon 20 ml of toluene was added. The reaction was then arranged for distillation at atmospheric pressure and the bath temperature was raised to 160° C. during 1.5 hours. Subsequently the temperature of the bath temperature was lowered to 84° and the mixture was subjected to distillation at high vacuum for 1.5 hours. The resulting solid residue was dissolved in 15 ml of ether, 2.5 ml of hexane and some charcoal was added. Filtration through diatomaceous earth, followed by concentration of the filtrate with intermittent addition of hexane and ether gave a suspension which after filtration gave 3β-acetoxy-21-[methoxycarbonyl]acetoxy-pregn-5-en-20-one.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:35][CH2:36][CH2:37][CH2:38][OH:39])(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[C:40](O)(=[O:58])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]/[CH:48]=[CH:49]\[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCCCCC>[C:16]([O:35][CH2:36][CH2:37][CH2:38][O:39][C:40](=[O:58])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]/[CH:48]=[CH:49]\[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCOC(=O)CCCCCCC/C=C\CCCCCCCC

Procedure:
A solution of 1,3-dicyclohexylcarbodiimide (23.7 g) and 4-(N,N-dimethylamino)pyridine (15.9 g) in methylene chloride (200 ml) was added to a solution of 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (33.6 g) and z-octadeca-9-enoic acid (30 g) in methylene chloride (400 ml) under nitrogen at room temperature. On completion of reaction as evidenced by tic analysis the solution was diluted with hexane, filtered, concentrated and purified by dry column chromatography to yield 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-(z-octadeca-9-enoyloxy)propane as a free flowing pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38]([O:40]C)=[O:39])=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:48][CH:47]([F:49])[CH2:46]4)[N:21]=3)[C@H:14]2[CH3:50])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Li+]>O1CCOCC1>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38]([OH:40])=[O:39])=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:48][CH:47]([F:49])[CH2:46]4)[N:21]=3)[C@H:14]2[CH3:50])[CH:4]=[C:3]([C:2]([F:52])([F:51])[F:1])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2cnc(OC)c(-c3cnc(N4CC(F)C4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ncc(-c2ccc(C(=O)O)cc2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(3-fluoroazetidin-1-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (Step A, 200 mg, 0.273 mmol) was dissolved in 1,4-dioxane (5 mL). Added 0.5N lithium hydroxide (2.5 mL, 1.25 mmol) and stirred at room temperature for 3 hours at which time LCMS showed complete hydrolysis. The reaction was quenched by adding 1.25 mL of 1N HCl, followed by water. The reaction was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, filtered and evaporated. The crude isolate was purified on a BIOTAGE SNAP 30 g C18 column, eluting with 40-100% CH3CN/water (0.05% TFA). The purified fractions were partitioned between pH 7 phosphate buffer and ethyl acetate. The aqueous was extracted a second time with ethyl acetate, then washed with pH 7.0 buffer and brine. The organic was dried over sodium sulfate, filtered and evaporated to give the title compound. LCMS (M+H)+: 720.4. 1H NMR (CDCl3, 500 MHz): δ 8.22 (d, 1H), 8.20 (s, 1H), 8.04 (s, 1H), 7.98 (d, 1H), 7.89 (s, 1H), 7.74 (s, 2H), 7.49 (d, 1H), 7.35 (d, 1H) 5.68 (d, 1H), 5.51 (m, 0.5H), 5.40 (m, 0.5H), 4.74 (d, 1H), 4.47 (m, 3H), 4.32 (m, 2H), 4.00 (d, s, 4H), 2.39 (s, 3H), 0.75 (d, 3H). RTA IC50: 12 nM.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])[N:13]=[C:12]2[N:26]1[C:34]2[CH:33]=[CH:32][N:31]=[CH:30][C:29]=2[CH:28]=[CH:27]1)C)(C)(C)C.Cl>O1CCOCC1>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:14]1[N:13]=[C:12]([N:26]2[C:34]3[CH:33]=[CH:32][N:31]=[CH:30][C:29]=3[CH:28]=[CH:27]2)[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([NH:7][CH3:6])[CH:10]=2)[N:15]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc2nc(-c3ccccc3F)nc(-n3ccc4cnccc43)c2c1
Agent: Cl
Solvent: C1COCCO1
Product: CNc1ccc2nc(-c3ccccc3F)nc(-n3ccc4cnccc43)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[2-(2-Fluoro-phenyl)-4-pyrrolo[3,2-c]pyridin-1-yl-quinazolin-6-yl]-methylcarbamic acid tert-butyl ester from Step F (0.066 g, 0.14 mmol) was taken in a 25 ml round bottomed flask and to this was added 4N hydrochloric acid in dioxane (0.5 ml) and the mixture magnetically stirred at room temperature for 0.5 hr. The solvent was removed and title compound was obtained pure after column purification on a HPLC reverse phase column, using a water and acetonitrile gradient containing 0.1% trifluoroacetic acid to yield (0.016 g, 30%). MS (ES) 370.1 (M+H)+