Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[C:12]([C:17]#[N:18])=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.O.O.[Sn](Cl)Cl>C(O)C.O1CCCC1>[NH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([C:11]2[C:12]([C:17]#[N:18])=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=1
Reactant: N#Cc1ccccc1-c1cc(F)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1ccccc1-c1cc(N)cc(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.3 %

Procedure:
A cooled (0° C.) suspension of 3′-fluoro-5′-nitrobiphenyl-2-carbonitrile (8.9 g, 37 mmol) in ethanol (70 ml) and tetrahydrofuran (70 ml) was treated with tin(II) chloride dihydrate (29 g, 129 mmol) and the mixture was stirred at ambient temperature for 4 h. The solvent was removed in vacuo and the residue treated with ice-cold 2N sodium hydroxide (400 ml). The resulting slurry was stirred for 30 min then extracted with dichloromethane (2×400 ml). The organics were combined, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by dry flash chromatography on silica, eluting with dichloromethane containing 0.5% triethylamine, afforded 5′-amino-3′-fluorobiphenyl-2-carbonitrile as a white solid (4.5 g, 58%): δH (400 MHz, CDCl3) 3.90 (2H, br), 6.45 (1H, ddd, J 8, 2 and 2), 6.58-6.63 (2H, m), 7.44 (1H, ddd, J 8, 8 and 2), 7.48 (1H, dd, J 8 and 2), 7.62 (1H, ddd, J 8, 8 and 2), 7.74 (1H, dd, J 8 and 2).
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[C:6](O)=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:4]1(=[O:17])=[O:16])[CH3:2].CN(C=O)C.C(Cl)(=O)C([Cl:26])=O>C(Cl)Cl>[Cl:26][C:6]1[C:7](=[O:8])[N:3]([CH2:1][CH3:2])[S:4](=[O:17])(=[O:16])[C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCN1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Temperature: 0 °C
Yield: 292.4 %

Procedure:
2-Ethyl-4-hydroxy-5-phenylisothiazol-3(2H)-one 1,1-dioxide (5 g, 19.76 mmol) was dissolved in dry DCM (250 mL) and cooled to 0° C. under N2. Dry DMF (15 mL) was added, followed by oxalyl chloride (3 mL, 34.4 mmol). The ice-bath was removed and the mixture was refluxed at 50° C. under N2 for 4 h. The reaction mixture was evaporated and the residue was diluted with EtOAc, washed with water (3×25 mL) and brine, dried over Na2SO4 and evaporated. Another (16 g, 63.24 mmol) of 2-ethyl-4-hydroxy-5-phenylisothiazol-3(2H)-one 1,1-dioxide was dissolved in dry DCM (500 mL) and cooled to 0° C. under N2. Dry DMF (20 mL) was added followed by oxalyl chloride (9 mL, 103.2 mmol). The ice-bath was removed and the mixture was refluxed at 50° C. under N2 for 4 h. The reaction mixture was evaporated and the residue was diluted with EtOAc, washed with water (3×50 mL) and brine, dried over Na2SO4 and evaporated where by red solid was obtained. The crude material from both batches were combined and purified by column chromatography on silica gel using 2.5-3% ethyl acetate in petroleum ether as eluant, and recrystallised from methanol to give the title compound (15.7 g, 70%) as a white solid; 1H NMR (400 MHz, CD3OD) δ 1.42 (t, 3H, J=7.3 Hz), 3.84 (q, 2H, J=7.3 Hz), 7.6-7.7 (m, 3H), 7.9-8.0 (m, 2H); Mass Spectrum: M+H+ 272.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Cl:15])[CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:7]1=[O:27])C.C(OC(=O)CN1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O)C>>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[C:8]1([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]1=3)[CH2:24][CH2:23][O:22]4)[C:7](=[O:27])[N:6]2[CH2:5][C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2c(Cl)cccc21
Agent: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Product: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2c(Cl)cccc21
Yield: 92 %

Procedure:
Following the procedure as described in EXAMPLE 2, and making non-critical variations using ethyl(4′-chloro-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetate to replace ethyl(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate, the title compound was obtained in 92% yield as a colorless solid: mp 228-229° C.; 1H NMR (300 MHz, CDCl3) δ 7.26-7.21 (m, 1H), 7.03 (dd, 1H), 6.71 (dd, 1H), 6.52 (s, 1H), 6.36 (s, 1H), 4.93 (dd, 2H), 4.69-4.63 (m, 1H), 4.54-4.51 (m, 3H), 2.95 (t, 2H); 13C NMR (75 MHz, CDCl3) 6177.8, 170.9, 162.1, 162.1, 143.1, 131.7, 130.0, 128.6, 124.7, 119.6, 118.7, 117.0, 106.7, 92.8, 77.2, 72.3, 58.1, 41.2, 28.9; MS (ES−) m/z 370.4 (M−1).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][O:12][CH2:13]C)=[C:6]([CH3:15])[CH:5]=1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.FC(F)(F)S(O[C:31]1[CH:32]=[C:33]([C:41]([O:43][CH3:44])=[O:42])[C:34](=[CH:39][CH:40]=1)[C:35]([O:37][CH3:38])=[O:36])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>P[C-]1C=CC=C1.[C-]1(P)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH3:13][O:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH2:3][C:40]2[CH:39]=[C:34]([C:35]([O:37][CH3:38])=[O:36])[C:33](=[CH:32][CH:31]=2)[C:41]([O:43][CH3:44])=[O:42])=[CH:5][C:6]=1[CH3:15]
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1C(=O)OC
Reactant: C=CCc1ccc(OCOCC)c(C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Product: COCOc1ccc(CCCc2ccc(C(=O)OC)c(C(=O)OC)c2)cc1C

Procedure:
In a manner similar to Example 1e, by reacting 4.5 g (21.6 mmol) of 4-allyl-1-ethoxymethoxy-2-methylbenzene with 6.3 g (25.7 mmol) of 9-BBN, 7.4 g (21.6 mmol) of dimethyl 4-trifluoromethanesulphonyloxyphthalate, 5.9 g (42.6 mmol) of potassium carbonate and 880 mg (1.05 mmol) of dichloropalladium diphosphinoferrocene. A yellow oil is obtained (m=7 g, y=80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](O)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.B.O.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(-c2ccc(Cl)cc2)cc1
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: OCCc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 4 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Borane-methylsulphide complex (12 ml.) was added to a stirred solution of 2-[4-(4-chlorophenyl)-phenyl]acetic acid (24.7 g.) in tetrahydrofuran (100 ml.), maintained at 4° C. and under an atmosphere of nitrogen. After 1 hour at 4° C., the reaction mixture was allowed to warm up to room temperature and was then stirred for an additional 20 hours. The excess borane was then decomposed by careful addition of water (50 ml.) to the stirred reaction mixture. Ethyl acetate (200 ml.) and a saturated aqueous solution of sodium hydrogen carbonate (200 ml.) was then added to the mixture. After separation, the organic phase was washed with water, dried (MgSO4) and evaporated. The residue was recrystallised from a mixture of hexane and toluene to give 2-[4-(4-chlorophenyl)phenyl]-ethanol (21.5 g.), m.p. 113°-115° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15]O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][C@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][NH:20]1.CCN(C(C)C)C(C)C.[I-].C(C[P+](C)(C)C)#N>>[C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C@@H:19]2[CH3:18])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1CCCCN1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCCCN1CCN1CCC(NC(=O)OC(C)(C)C)CC1

Procedure:
It is prepared analogously to 9 starting from tert-butyl ester 8 (2 g, 8.19 mmol), (S)-2-methyl-piperidine (0.985 ml, 8.19 mmol), DIEA (1.8 ml, 10.65 mmol) and cyanomethyl-trimethyl-phosphonium iodide (2.39 g, 9.83 mmol).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:8]([OH:10])=O.[CH2:11]([O:13][C:14]([C:16]1([NH2:25])[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1)=[O:15])[CH3:12].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.O>[CH2:11]([O:13][C:14]([C:16]1([NH:25][C:8]([CH:2]2[CH2:3][CH:4]3[CH2:7][CH:1]2[CH2:6][CH2:5]3)=[O:10])[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)C1CC2CCC1C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)C2CC3CCC2C3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
To a solution of bicyclo[2.2.1]heptane-2-carboxylic acid (102 mg, 0.73 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (150 mg, 0.73 mmol), HATU (333 mg, 0.87 mmol) in anhydrous DMF (1 mL) is added DIPEA (1904, 1.10 mmol). The resulting solution is stirred at RT overnight. Water (10 mL) is poured into the reaction mixture and then extracted with EtOAc (3×5 mL). The combined organic layers are concentrated in vacuo. The residue is purified by flash column chromatography (12 g silica gel, gradient elution: 0-30% EtOAc in heptane) to give product (272) as yellow oil (148 mg, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[F-].[Cs+].C[Si](C)(C)[C:14]([F:17])([F:16])[F:15].Cl>COCCOC.C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:6]([OH:7])[C:14]([F:17])([F:16])[F:15])=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(Cl)nc1
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: OC(c1ccc(Cl)nc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.3 %

Procedure:
To a solution of 6-chloronicotinaldehyde (5.93 g, 41.9 mmol) and CsF (1.27 g, 8.38 mmol) in DME (350 mL) was added trimethyl(trifluoromethyl)silane (9.82 mL, 62.8 mmol) in THF (30 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature and the reaction was stirred at ambient temperature for 18 hours. 1 N HCl (50 mL) in water was added and the reaction was stirred at ambient temperature for 1 hour. Ethyl acetate (100 mL) was added. The organic layer was separated, washed with saturated sodium bicarbonate and brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (4:1 hexane/ethyl acetate) to give 1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethanol (8.8 g, 99.3%) as an oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:15][C:16]([C:18]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]2[CH2:27][CH2:28][N:29](C(=O)C(F)(F)F)[CH2:30][CH2:31][C:19]=12)=[O:17].[OH-].[Na+]>CN(C=O)C>[O:13]([CH2:15][C:16]([C:18]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]2[CH2:27][CH2:28][NH:29][CH2:30][CH2:31][C:19]=12)=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Oc1ccccc1
Reactant: O=C(CBr)c1c2n(c3ccccc13)CCN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(COc1ccccc1)c1c2n(c3ccccc13)CCNCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(Chart E, Step 2): To a dry round bottom charged with a heterogeneous mixture of K2CO3 (40.77 mg, 0.30 mmol) and phenol (27.8 mg, 0.30 mmol) in DMF (1.5 mL) is added a solution of 1-[11-(2-bromoacetyl)-1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,7-a]indol-3-yl]-2,2,2-trifluoro-1-ethanone in DMF (1.5 mL). After stirring at ambient temperature for 18 hours, aq. 1N NaOH (1 mL) is added at once to deprotect the indole in situ. The mixture is stirred for an hour then partitioned between water and ethyl acetate, the aqueous layer is extracted two more times with ethyl acetate. The organics are combined, dried with MgSO4, filtered and concentrated to 95 mg of a crude oil. The crude is purified by LC (230-400 silica gel) eluting with 0.5% NH4OH and 3.5% methanol in dichloromethane to afford 69 mg of 2-phenoxy-1-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-11-yl)-1-ethanone as a white solid. IR (drift) 1662, 1598, 1516, 1495, 1458, 1443, 1420, 1345, 1244, 1198, 1191, 1052, 975, 746, 688 cm−1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2)#[CH:2].[CH3:13][N:14]([CH2:16][C:17]1[N:18]([C:22]2[CH:23]=[C:24]([NH:32][C:33](=[O:42])[C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[C:36](I)[CH:35]=3)[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=2)[CH:19]=[CH:20][N:21]=1)[CH3:15]>>[CH3:15][N:14]([CH2:16][C:17]1[N:18]([C:22]2[CH:23]=[C:24]([NH:32][C:33](=[O:42])[C:34]3[CH:35]=[CH:36][C:37]([CH3:40])=[C:38]([C:2]#[C:1][C:3]4[CH:4]=[N:5][CH:6]=[C:7]5[C:12]=4[N:11]=[CH:10][CH:9]=[CH:8]5)[CH:39]=3)[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=2)[CH:19]=[CH:20][N:21]=1)[CH3:13]
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1I
Reactant: C#Cc1cncc2cccnc12
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1C#Cc1cncc2cccnc12

Procedure:
The title compound can be synthesized from 8-ethynyl-1,6-naphthyridine and N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 1. 8-ethynyl-1,6-naphthyridine is prepared from 8-bromo-1,6-naphthyridine and ethynyltrimethylsilane according to the 2 steps procedure described in Example 1.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=3[C:14](=[O:22])[N:13]3[CH2:23][CH2:24][CH2:25][C@H:12]3[C:11]=12)=[O:6])[C:2]#[CH:3].IN1C(=O)CCC1=O.[CH2:34]([NH:37][CH2:38][CH:39]=[CH2:40])[CH:35]=[CH2:36]>C(O)(=O)C>[Cl:21][C:20]1[C:15]2[C:14](=[O:22])[N:13]3[CH2:23][CH2:24][CH2:25][C@H:12]3[C:11]3[N:10]([CH:9]=[N:8][C:7]=3[C:5]3[O:6][C:2]([CH2:3][N:37]([CH2:38][CH:39]=[CH2:40])[CH2:34][CH:35]=[CH2:36])=[CH:1][N:4]=3)[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: C=CCNCC=C
Reactant: C#CCNC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: C=CCN(CC=C)Cc1cnc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)o1
Temperature: 25 °C
Reaction time: 19 h
Yield: 28.7 %

Procedure:
A solution of 7.95 g (0.0224 mol) of (S)-8-chloro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid prop-2-ynylamide in 200 ml of acetic acid was treated with 7.56 g (0.0336 mol) of N-iodosuccinimide while gassing with argon. After stirring at room temperature for 19 hrs. and at 50° for 4 hrs. the dark brown suspension obtained was completely freed from the solvents and dried azeotropically several times with toluene. The red-brown solid residue was dissolved in 100 ml of THF, treated with 23.9 ml (0.194 mol) of diallylamine and stirred at room temperature for 48 hrs. The solution obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated, the dark brown product was chromatographed over basic Alox (grade III) with dichloromethane/ethyl acetate 4:1 as the eluent and recrystallized from hot isopropyl ether. There were obtained 2.89 g (29%) of (S)-8-chloro-1-(5-diallylaminomethyl-oxazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one as a yellow foam; [α]D20 =+11.3° (MeOH, c=1%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].[Br:12]C(Cl)(Cl)C(Cl)(Cl)Br.O>O1CCCC1>[Br:12][C:3]1[C:2]([Cl:1])=[C:10]([F:11])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(F)c(Cl)c1Br
Temperature: -75 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
n-Butyl lithium (25M solution, 76 ml) was added to a stirred solution of diisopropylamine (28 ml) in dry tetrahydrofuran (THF) at −75° C., and maintained at −30° C. for a further 1 hour, to produce lithium diisopropylamide (LDA). After re-cooling to −75° C., a solution of 3 -chloro-4-fluorobenzoic acid (14.4 g) in dry THF was added over 1 hour, and stirring was continued overnight at −75° C. A solution of 1,2-dibromotetrachloroethane (42.77 g) in dry THF was then added over 20 minutes, stirring was continued for 2 hours at −70° C. then at room temperature for 4 hours. Water was added, the organic and aqueous phases were separated and the aqueous phase was washed with ether, then acidified with hydrochloric acid solution and extracted with dichloromethane. The dichloromethane extract was dried (anhydrous magnesium sulphate) and the solvent evaporated to give 2-bromo-3-chloro-4-fluorobenzoic acid (19.54 g) as a beige solid, NMR (DMSO-D6) 7.55(t,1H), 7.75(dd,1H), 13.8(brs,1H).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([OH:11])=O)[N:4]=[CH:3]1.[P:12]([OH:15])([OH:14])[OH:13].P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[OH:11][C:9]([P:12]([OH:15])(=[O:13])[OH:14])([P:12]([OH:15])(=[O:14])[OH:13])[CH2:8][CH2:7][C:5]1[N:4]=[CH:3][NH:2][CH:6]=1
Reactant: OP(O)O
Reactant: O=C(O)CCc1c[nH]cn1
Agent: Cl
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1
Product: O=P(O)(O)C(O)(CCc1c[nH]cn1)P(=O)(O)O
Reaction time: 4 h

Procedure:
3.53 g. (20 mMol) 3-(4-imidazolyl)-propionic acid hydrochloride are heated with 2.26 g. phosphorous acid in 10 ml. chlorobenzene to 110° C., while stirring. 4.12 g. (30 mMol) phosphorus trichloride are slowly added dropwise thereto and heating continued for 4 hours at 110° C. After cooling, the chlorobenzene is decanted off and the residue boiled under reflux for 5 hours with 15 ml. 6N hydrochloric aci. The reaction mixture is allowed to cool, mixed with active charcoal, filtered and the filtrate evaporated. The residue is taken up in 10 ml. water, the solution is adjusted with an aqueous solution of sodium bicarbonate to a pH value of 5.5 and mixed with methanol until no further precipitate is formed. The precipitate is filtered off with suction, washed with methanol and dried. There are obtained 3.23 g. (48% of theory) of the title compound. The product is obtained as the monosodium salt with 1 mole of water of crystallisation.
Reaction SMILES: F[C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[Cl:20].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CN(C)P(=O)(N(C)C)N(C)C>[O:24]1[CH2:25][CH2:26][N:21]([C:2]2[CH:14]=[C:12]3[C:13]4[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]3=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=4[C:3]=2[Cl:20])[CH2:22][CH2:23]1
Reactant: C1COCCN1
Reactant: CC1CCc2c(Cl)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1CCc2c(Cl)c(N3CCOCC3)cc3c(=O)c(C(=O)O)cn1c23
Reaction time: 5 h
Yield: 20.9 %

Procedure:
An autoclave containing a mixture of 3 g of 9-fluoro-8-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 8 g of morpholine and 30 ml of hexamethylphosphoric triamide was immersed in an oil bath at 190° C. and reaction was continued for 5 hours. After completion of reaction, the reaction mixture was cooled to precipitate crystals which then were collected by filtration. The crystals thus obtained were recrystallized from dimethylformamide to give 0.77 g of 9-morpholino-8-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. m.p. 271° to 274° C., white rhombic crystals.
Reaction SMILES: [I-:1].[Zn+2:2].[I-].[F:4][C:5]1([F:12])[CH2:10][CH2:9][CH:8](O)[CH2:7][CH2:6]1>C1COCC1>[I-:1].[F:4][C:5]1([F:12])[CH2:10][CH2:9][CH:8]([Zn+:2])[CH2:7][CH2:6]1
Reactant: [Zn+2]
Reactant: OC1CCC(F)(F)CC1
Agent: [I-]
Solvent: C1CCOC1
Product: FC1(F)CCC([Zn+])CC1

Procedure:
The title compound was prepared in an analogous manner to tetrahydro-2H-pyran-4-yl)zinc(II) iodide except that 4,4-difluorocyclohexanol (Affinity Chemicals) was used instead of tetrahydro-2H-pyran-4-ol in Step 1 to afford a 0.26 M solution of (4,4-difluorocyclohexyl)zinc(II) iodide in THF.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH3:14])=[CH:8][N+:7]=1[O-:15].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[Cl:5][C:6]1[C:11]([CH3:12])=[C:10]([N+:1]([O-:4])=[O:2])[C:9]([O:13][CH3:14])=[CH:8][N+:7]=1[O-:15]
Reactant: COc1cc(C)c(Cl)[n+]([O-])c1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1c[n+]([O-])c(Cl)c(C)c1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
Concentrated nitric acid (2.5 mL) was added drop-wise to a 0° C. solution of C2 (350 mg, 2.02 mmol) in concentrated sulfuric acid (2.5 mL). The reaction mixture was heated at 90° C. for 1 hour, then cooled to room temperature and poured onto crushed ice. The resulting mixture was neutralized to pH 6-7 with saturated aqueous sodium carbonate solution, and extracted with ethyl acetate. The combined organic layers were washed with water, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to provide the product as a light yellow solid. Yield: 370 mg, 1.69 mmol, 84%. LCMS m/z 219.0, 221.1 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 3.94 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[CH3:15][O:16][C:17](=[O:50])[CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][C@H:24]1[C:28](=[O:29])[CH2:27][C@@H:26]([OH:30])[C@@H:25]1[C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[CH:36]([O:40]CC1C=CC(OC)=CC=1)[CH2:35][CH2:34]2.ClC(Cl)C.C([O-])(O)=O.[Na+]>ClCCl.O>[CH3:15][O:16][C:17](=[O:50])[CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][C@H:24]1[C:28](=[O:29])[CH2:27][C@@H:26]([OH:30])[C@@H:25]1[C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[CH2:35][CH2:34]2
Reactant: COC(=O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O)[C@@H]1c1ccc2c(c1)CCC2OCc1ccc(OC)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: COC(=O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O)[C@@H]1c1ccc2c(c1)CCC2=O
Reaction time: 1 h
Yield: 64.3 %

Procedure:
DDQ (10 mg, 0.041 mmol) was added to a mixture of 15-5 (11 mg, 0.021 mmol) in dichloromethane (0.5 mL)/water (25 μL). After 1 h, dichloroethane (0.5 mL) was added and the reaction was stirred overnight. Saturated NaHCO3 solution was added and the resulting mixture was extracted with dichloromethane (3×20 mL). The combined dichloromethane solution was washed with brine and then was dried (Na2SO4), filtered and evaporated. Purification of the residue by flash chromatography on silica gel (60% ethyl acetate/hexanes) gave 15-8 (5 mg, 59%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([CH:9]=1)[CH2:7]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:36]NC(=O)CCC(N)=O>C1COCC1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([CH:9]=1)[CH2:7][Br:36]
Reactant: NC(=O)CCC(=O)NBr
Reactant: COCCOCOc1ccc(I)cc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOCOc1ccc(I)cc1CBr
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-iodo-2-(2-methoxy-ethoxymethoxy)-benzyl alcohol (7.5 g, 22 mmol) in 60 mL of THF at 15° C. is added triphenylphospine (6.35 g, 24 mmol) followed by N-bromosuccinamide (4.3 g, 24 mmol). The solution is stirred for 5 min. The solution is allowed to warm to ambient temperature. After 20 min, the solution is concentrated. The crude product is purified by column chromatography eluting with EtOAc:CH2Cl2 :hexane (3:1:6).
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([CH:15]=[CH2:16])[CH:9]=[CH:10][CH:11]=2)[N:6]=1)(=O)C.O>CO>[OH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([CH:15]=[CH2:16])[CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: C=Cc1cccc2ccc(OC(C)=O)nc12
Solvent: O
Solvent: CO
Product: C=Cc1cccc2ccc(O)nc12
Temperature: 55 °C
Yield: 100.4 %

Procedure:
18.6 g (87.3 mmol) of 2-acetoxy-8-vinylquinoline, 290 ml of water and 290 ml of methanol are placed in a 1 l round-bottomed flask. The reaction mixture is heated at 55° C. for 2 h and then the methanol is evaporated under vacuum. Extraction is carried out with ethyl acetate (2×200 ml). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under vacuum to provide 15.0 g of 2-hydroxy-8-vinylquinoline in the form of a yellow solid; M.p.=96° C. (Quantitative yield)