Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([O:12]C)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]>Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: COC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: O=C(O)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
A mixture of methyl (4-nitrophenoxy)acetate 31 (100 g, 474 mmol) and concentrated HCl (1000 ml) was refluxed for 8 hours. The reaction mass was cooled to room temp. Crude 40 was filtered, dried and recrystallised from a mixture of ethyl acetate:hexane (1:5) to give pure 40 (86 g, 92.1%) as a white shining powder. M.p: 186-188.5° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:27][CH3:28])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[Br:29]Br.S([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:29][C:10]1[CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[O:4][CH2:3][CH:2]([CH3:1])[CH2:27][CH3:28]
Reactant: CCC(C)COc1ccc(-c2ccc(S(=O)(=O)c3ccc(C)cc3)cc2)cc1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(C)COc1ccc(-c2ccc(S(=O)(=O)c3ccc(C)cc3)cc2)cc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 113.2 %

Procedure:
4'-(2-methylbutyloxy)-4-p-toluenesulfonylbiphenyl (41 g) prepared in the above step (ii) was dissolved in CCl4 (400 ml). To the resulting solution was dropwise added bromine (25 g) dissolved in CCl4 (100 ml), at room temperature over one hour, followed by stirring at room temperature for 5 hours, adding an aqueous solution of sodium hydrogen sulfite till the color of bromine disappeared, separating the organic layer, washing with 6N hydrochloric acid, washing with an aqueous solution of 2N NaOH, washing with water to make the solution neutral, drying and distilling off CCl4 to obtain oily 3'-bromo-4'-(2-methylbutyloxy)-4-p-toluenesulfonylbiphenyl (55.7 g).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[Br:28]N1C(=O)CCC1=O>CC#N>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:28])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1ncc2ccc(Oc3ccc(OC)cc3)cc2c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccc(OC)cc3)cc2c1O
Reaction time: 0.33 h
Yield: 60.3 %

Procedure:
To mixture of 4-Hydroxy-6-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester (1.837 g, 5 mmol; for preparation, see example 28b) and N-bromosuccinimide (1.079 g, 6 mmol) was added anhydrous MeCN with stirring. After ca. 10 min another portion of MeCN (3 mL) was added and stirring continued for 20 min. The mixture was then partitioned between water (100 mL) and CCl4 (100 mL). The organic phase was separated, dried over MgSO4 and concentrated in vacuo. The residue was recrystallized from EtOAc to give the title compound as white needles (1.345 g); MS-(+)-ion: M+1, 79Br/81Br=445.8 and 447.8.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.N1C=CN=C1.[C:23]([Si:27]([CH3:30])([CH3:29])Cl)([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[Si:27]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:30])[CH3:29]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
To a solution of (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (5.12 g, 20.8 mmol) in DMF (40 mL), imidazole (2.84 g, 41.7 mmol) and tert-butyldimethylchlorosilane (3.46 g, 22.9 mmol) were added sequentially and the mixture was stirred at ambient temperature for about 2 hours. The DMF was removed under reduced pressure and the residue partitioned between water (150 mL) and ether (150 mL). The organic phase was washed with 1N aqueous phosphoric acid (3×100 mL), water (2×100 mL), sodium bicarbonate saturated solution (2×100 mL) and brine (100 mL). The organic phase was dried with magnesium sulfate and concentrated to yield (2S,4R)-1-tert-butyl 2-methyl 4-(tert-butyldimethylsilyloxy)pyrrolidine-1,2-dicarboxylate (5.44 g, 15.1 mmol) as a colorless oil. RP-HPLC (Table 1, Method f) Rt 6.49 min.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1(=O)[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]1>>[C:4]([C:3]1[C:2]([Cl:1])=[C:11]([CH:10]=[CH:9][CH:8]=1)[NH:12][C:13]1[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH:14]=1)([O:6][CH3:7])=[O:5]
Reactant: O=C1CCCC(=O)C1
Reactant: COC(=O)c1cccc(N)c1Cl
Product: COC(=O)c1cccc(NC2=CC(=O)CCC2)c1Cl
Temperature: 120 °C
Yield: 83.9 %

Procedure:
A mixture of methyl 2-chloro-3-aminobenzoate (11.11 g, 59.86 mM) and 1,3-cyclohexanedione (9.05 g, 80.8 mM) was heated at 120° C. under a stream of nitrogen for 4 hours. The resultant solid was triturated with hot ethyl acetate, then dried in vacuo to afford 14.05 g (84%) of 3-(3-carbomethoxy-2-chloroanilino)cyclohex-2-en-1-one as a yellow orange solid. 1H NMR (CDCl3) δ 7.6 (dt, 1H, J=1 and 8 Hz), 7.3 (t, 1H, J=8 Hz), 6.6 (br s, 1H), 5.62 (s, 1H), 3.95 (s, 3H), 2.6 (t, 2H, J=6 Hz), 2.4 (t, 2H, J=6 Hz), and 2.1 (m, 2H). IR (CHCl3, cm−1) 3050, 2950, 1729, 1536, 1351, 1299, 1290, 1267, and 1135. MS (ES) m/e 278, 280, 282.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:31])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)=[C:10]([CH2:17][CH3:18])[NH:11]2.Cl[CH:34]([F:36])[F:35]>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:31][CH:34]([F:36])[F:35])=[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:24][CH:25]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(OC(F)(F)F)cc1
Reactant: FC(F)Cl
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared by the method of Preparation 10c using [2-ethyl-8-fluoro-4-oxo-3-(4-trifluoromethoxybenzyl)-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester and chlorodifluoromethane.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:14])[O:9][C:8]2[CH:10]=[CH:11][S:12][C:7]=2[C:6](=O)[CH2:5]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:3][C:4]1([CH3:14])[O:9][C:8]2[CH:10]=[CH:11][S:12][C:7]=2[CH:6]=[CH:5]1
Reactant: CC1(C)CC(=O)c2sccc2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(C)C=Cc2sccc2O1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Sodium borohydride (3.27 g, 86.3 mmol) was added to a solution of 5,6-dihydro-5,5-dimethyl-7H-thieno[3,2-b]-pyran-7-one (12.1 g, 66.4 mmol) in ethanol (100 mL) and the resultant mixture was stirred at rt for 17 h. The mixture was poured into water (400 mL) and extracted with dichloromethane (2×100 mL). The dichloromethane solution was washed with water (5×), dried over sodium sulfate, and filtered. Molecular sieves (12 g) and p-toluenesulfonic acid (1.2 g, 6.3 mmol) was added to the resultant solution and stirred at 0° C. for 1.5 h. The reaction mixture was filtered, washed with saturated aqueous sodium bicarbonate and dried over sodium sulfate. The solvent was evaporated in vacuo to give the product, 11.0 g (99%), as a red oil which was identical in all respects to the product described in Method A.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:20])[CH3:21])[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=2[O:9][CH3:10])=[O:31])=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CO)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1COC(=O)Nc1ccc(Cl)cc1

Procedure:
Using ethyl 3-[3-(hydroxymethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 4-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:10]1[C:2]([F:1])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C(=O)O)c1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1cccc(CBr)c1F
Yield: 17.5 %

Procedure:
A mixture of 2-fluoro-3-methylbenzoic acid (0.462 g, 3 mmol), N-bromosuccinimide (0.560 g, 3.15 mmol), azobisisobutyronitrile (AIBN) (0.024 g, 0.15 mmol) and CCl4 (10 ml) was heated at reflux for 18 h. The reaction mixture was then reduced in vacuo and partitioned between ethyl acetate and aqueous K2CO3. The aqueous layer was acidified (2M HCl) and cooled in ice. The precipitate obtained was collected by filtration and dried in vacuo to give 3-bromomethyl-2-fluoro-benzoic acid (0.1225 g, 13%) as a colourless solid. (LC/MS: Rt 3.18, [M−H]− 232.91).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[F:24][C:25]1[C:26]([CH3:32])=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[C:26]=2[CH3:32])=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Cc1c(O)cccc1F
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cccc(F)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3-fluoro-2-methylphenol: 1H-NMR (CDCl3) δ 8.57 (1H, d, J=2.3 Hz), 8.14 (1H, d, J=7.5 Hz), 8.10 (1H, d, J=2.3 Hz), 8.00 (2H, d, J=8.3 Hz), 7.43 (2H, d, J=8.3 Hz), 7.25 (1H, m), 7.03 (1H, t, J=8.3 Hz), 6.91 (1H, d, J=8.1 Hz), 5.40 (1H, m), 3.90 (3H, s), 2.06 (3H, s), 1.60 (3H, d, J=7.5 Hz).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[C:14]([CH3:18])[S:15][C:16]=2Br)=[O:11])[CH:6]=[CH:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[F:61][C:62]1[CH:63]=[C:64]([CH:66]=[C:67]([F:69])[CH:68]=1)[NH2:65].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O1CCOCC1>[OH:1][CH2:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[C:14]([CH3:18])[S:15][C:16]=2[NH:65][C:64]2[CH:63]=[C:62]([F:61])[CH:68]=[C:67]([F:69])[CH:66]=2)=[O:11])[CH:6]=[CH:5][N:4]=1
Reactant: Cc1nc(C(=O)Nc2ccnc(CO)c2)c(Br)s1
Reactant: Nc1cc(F)cc(F)c1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1nc(C(=O)Nc2ccnc(CO)c2)c(Nc2cc(F)cc(F)c2)s1
Yield: 8.4 %

Procedure:
A microwave vial was charged with 5-bromo-2-methyl-thiazole-4-carboxylic acid (2-hydroxymethyl-pyridin-4-yl)-amide (0.135 g, 0.411 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.81 g, 0.140 mmol) and palladium dibenzylideneacetone (Pd2dba3)-chloroform complex (0.044 g, 0.043 mmol). Degassed dioxane (10 ml) was added, followed by 3,5-difluoroaniline (0.064 g, 0.496 mmol) and cesium carbonate (0.271 g, 0.831 mmol) The vial was then irradiated in a microwave oven at 150° C. for 40 min. The mixture was diluted with THF and the solids filtered, washing with THF. The filtrate was evaporated and the residue purified by flash chromatography on silica gel with dichloromethane/methanol 100:0→90:10 gradient to yield the title compound (0.013 g, 8%) as an off-white solid, MS (ISP): m/e=377.4 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].[C:24](Cl)(=O)[CH2:25][CH2:26][CH2:27][CH3:28]>CN1C(=O)CCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=[C:24]1[CH2:25][CH2:26][CH2:27][CH3:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCNc1c(N)cnc2ccccc12
Reactant: CCCCC(=O)Cl
Solvent: CN1CCCC1=O
Product: CCCCc1nc2cnc3ccccc3c2n1CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The product from step (iii) (1.23 g) was dissolved in NMP (25 mL) and valeryl chloride (0.46 mL) was added dropwise. The reaction mixture was stirred for 1.5 h at rt, heated to 50° C. for 24 h then heated to 80° C. for 2 days. The solvent was evaporated and the reaction mixture poured into DCM. The solid precipitate was filtered off and the filtrate was purified on silica eluting with 10% MeOH in DCM to give subtitle compound (0.9 g).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:20])([F:19])[CH2:9][O:10][P:11]([O-:18])[O:12][CH2:13][C:14]([F:17])([F:16])[F:15].Br[CH2:22][C:23]([N:25]([CH3:27])[CH3:26])=[O:24]>C1COCC1>[CH3:26][N:25]([CH3:27])[C:23](=[O:24])[CH2:22][P:11](=[O:18])([O:12][CH2:13][C:14]([F:17])([F:15])[F:16])[O:10][CH2:9][C:8]([F:7])([F:19])[F:20]
Reactant: [O-]P(OCC(F)(F)F)OCC(F)(F)F
Reactant: CN(C)C(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)C(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reaction time: 1 h
Yield: 41 %

Procedure:
Bis(2,2,2 trifluoroethyl)phosphite (5.0 mmol, 0.79 mL) was added to a solution of sodium hydride (0.420 g, 0.018 mol) and HMPA (8.6 mmol, 1.5 mL) at 10° C. in THF (20 mL). Immediately after addition, 2-bromo-N,N-dimethylacetamide (3.9 mmol) was added dropwise. The reaction temperature was maintained at 10° C. for 4.5 hours. The reaction was then quenched with saturated aqueous ammonium chloride (2 mL) and standard aqueous work-up was performed. Final purification by flash column chromatography (silica gel, 80% hexane, 20% ethyl acetate) yielded the desired compound (34%) as a colorless oil. c). To a solution of potassium tert-butoxide (705 mg, 6.33 mmol) in anhydrous THF (25 mL) at 0° C., bis(2,2,2-trifluoroethyl)phosphite (1.00 mL, 6.33 mmol) was added. 2-bromo-N,N-dimethylacetamide (12.66 mmol) was then added by syringe. Upon completion of the addition step, the reaction was allowed to proceed for one hour with monitoring by TLC. The reaction was then quenched with a saturated solution of aqueous ammonium chloride (20 mL). The aqueous phase was extracted with diethyl ether (3×20 mL). The combined organic extracts were washed with water (3×20 mL) and with a saturated sodium chloride solution (1×20 mL). The solvent was removed by rotary evaporation and the crude material was further concentrated under oil pump vacuum. The final product was purified by column chromatography (silica gel, 2:1 hexanes/ethyl acetate) yielding the desired compound (41%). (ii) From bis-(2,2,2-trifluoroethyl)phosphonoacetic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C@@H:17]4[O:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]4)=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[ClH:30].CCOCC>O1CCOCC1>[ClH:30].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C@@H:17]4[O:22][CH2:21][CH2:20][NH:19][CH2:18]4)=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc3[nH]c(-c4ccc(F)cc4)nc3c2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Fc1ccc(-c2nc3cc([C@H]4CNCCO4)ccc3[nH]2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
(S)-tert-Butyl 2-(2-(4-fluorophenyl)-1H-benzo[d]imidazol-5-yl)morpholine-4-carboxylate (88 mg, 0.22 mmol) was dissolved in dioxane (1 ml) and a solution of HCl in dioxane (4M, 0.66 ml, 2.66 mmol) was added. The reaction mixture was stirred for 3 h at 60° C. After cooling ether (2 ml) was added and the solid was filtered off. It was washed with ether and dried in vacuo to afford (S)-2-(2-(4-fluorophenyl)-1H-benzo[d]imidazol-5-yl)morpholine hydrochloride (56 mg, 76%) as an off-white solid. MS (ISP): 298.2 ([M+H]+).
Reaction SMILES: C[O:2][C:3](F)([F:10])[C:4]([F:9])([F:8])[C:5]([F:7])=[O:6].S(=O)(=O)=O>>[F:8][C:4]([F:9])([C:5]([F:7])=[O:6])[C:3]([F:10])=[O:2]
Reactant: COC(F)(F)C(F)(F)C(=O)F
Agent: O=S(=O)=O
Product: O=C(F)C(F)(F)C(=O)F

Procedure:
3-Methoxytetrafluoropropionyl fluoride (F. S. Fawcett, C. W. Tullock and D. D. Coffman, J. Amer. Chem. Soc., 84, 4275 (1962)) (81 g, 0.45 mol) was slowly added to sulfur trioxide (80 g, 1.0 mol) at 40° C., and the product difluoromalonyl difluoride, bp -9° C., was continuously removed by distillation through a low temperature still, yield 58 g (0.40 mol, 90%). The product structure was confirmed by: λmax 1860 cm-1 (COF), 19F NMR (no solvent), +17.1 ppm (t J=10 Hz), 2F, COF and -114.2 ppm (t J=10 Hz) 2F, CF2.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([CH:13]=[CH:12][CH:11]=[C:9]([OH:10])[CH:8]=1)[OH:7].C([O:16][C:17](=O)[CH:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[C:24]=1[F:32])[C:19](=O)[CH3:20])C>O>[F:32][C:24]1[C:25]([N+:29]([O-:31])=[O:30])=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][C:18]1[C:17](=[O:16])[O:7][C:6]2[CH:8]=[C:9]([OH:10])[CH:11]=[CH:12][C:13]=2[C:19]=1[CH3:20]
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)C(Cc1cccc([N+](=O)[O-])c1F)C(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(Cc2cccc([N+](=O)[O-])c2F)c(=O)oc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
Concentrated sulfuric acid (21.5 mL) was added at 0° C. to a mixture of resorcinol (14.8 g, 135 mmol) and 2-(2-fluoro-3-nitrobenzyl)-3-oxobutanoic acid ethyl ester (38.2 g, 135 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into water, and the solid was filtered off. It was washed with water and methanol to yield the title compound (28.3 g, 64%) as a pale yellow powder.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]([C:5]1[N:14]=[C:13](O)[C:12]2[CH2:11][C:10]([CH3:17])([CH3:16])[CH2:9][CH2:8][C:7]=2[N:6]=1)[CH3:4].C(Cl)(Cl)[Cl:20]>P(Cl)(Cl)(Cl)=O>[Cl:20][C:13]1[C:12]2[CH2:11][C:10]([CH3:17])([CH3:16])[CH2:9][CH2:8][C:7]=2[N:6]=[C:5]([CH:3]([N:2]([CH3:18])[CH3:1])[CH3:4])[N:14]=1
Reactant: CC(c1nc(O)c2c(n1)CCC(C)(C)C2)N(C)C
Reactant: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CC(c1nc(Cl)c2c(n1)CCC(C)(C)C2)N(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
A solution of 2-[1-(dimethylamino)ethyl]-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-ol (50 mg, 0.20 mmol) in a mixture of chloroform (1.5 mL) and phosphorous oxychloride (0.5 mL) was heated to reflux for 90 minutes. After cooling to room temperature the reaction mixture was concentrated and the residue was partitioned between saturated aqueous sodium bicarbonate (20 mL) and ethyl acetate (20 mL). The mixture was stirred for 15 minutes and pH was maintained above 7 by the addition of solid sodium bicarbonate. The organic layer was separated and washed with water (10 mL) and brine, dried over sodium sulfate, filtered and concentrated to give 1-(4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)-N,N-dimethylethanamine (46 mg, 85%). MS (EI) for C14H22ClN3: 268 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])[CH3:13]>C(O)(C)C>[N+:9]([C:3]1[CH:4]=[CH:5][C:6]([N:20]2[CH2:19][CH2:18][N:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH2:22][CH2:21]2)=[N:7][C:2]=1[NH2:1])([O-:11])=[O:10]
Reactant: CCOC(=O)N1CCNCC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CC(C)O
Product: CCOC(=O)N1CCN(c2ccc([N+](=O)[O-])c(N)n2)CC1

Procedure:
6-Amino-2-chloro-5-nitropyridine (Acros, 3.66 g 21 mmol) and 1-ethoxycarbonylpiperazine (6.36 g 42 mmol) in isopropanol (85 ml) are refluxed for 3 h. The reaction mixture with a yellow precipitate is poured on water/Na2CO3 and extracted twice with methylene chloride. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to yield the title compound as yellow crystals, which are purified by recrystallisation from tert.-butyl methyl ether (5.5 g 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][N:10]([CH3:12])[CH3:11])[C:5]([Cl:13])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:31]CNC[CH2:27]2)=[N:18]1.C(O)(C)C>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][N:10]2[CH2:12][CH2:27][N:26]([C:19]3[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[S:17][N:18]=3)[CH2:31][CH2:11]2)[C:5]([Cl:13])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: CN(C)C=Cc1cc(Cl)c([N+](=O)[O-])cc1Cl
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc(Cl)c(C=CN2CCN(c3nsc4ccccc34)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,5-Dichloro-4-(2-dimethylaminoethenyl)-nitrobenzene (15 g, 0.057 mol) and 4-(1,2-benzisothiazol-3-yl)-piperazine (18.9 g, 0.086 mol) were combined in acetic acid (150 ml) and stirred overnight at room temperature under a nitrogen atmosphere. The slurry was poured slowly into a mixture of hexanes (300 ml) and isopropanol (300 ml) with stirring. The product was isolated by filtration as a brick red solid and washed with hexanes. The yield was 23.4 g, 93%; mp 194°-5° C. NMR (CDCl3) δ 8.05 (s, 1), 7.95-7.80 (m, 2), 7.56-7.35 (m, 3), 7.01 (d, 1), 5.60 (d, 1), 3.95-3.46 (m, 8). Analysis Calculated for C19H16N4O2Cl2S: C, 52.41; H, 3.70; N, 12.87. Found: C, 52.05; H, 3.36; N, 12.58.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[NH:18][CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:32][O:33][CH2:34][CH2:35]Br>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[N:18]([CH2:35][CH2:34][O:33][CH3:32])[CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCBr
Reactant: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3[nH]ccc23)ccc2c1CCCO2
Solvent: O
Solvent: CC#N
Product: COCCn1ccc2c(-c3ccc4c(c3C)CCCO4)c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c21

Procedure:
The title compound was prepared in a manner similar to that described in example 41 from 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetic acid and 2-bromoethyl methyl ether and was isolated by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) on an achiral column. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.29-7.36 (m, 1H) 6.97-7.12 (m, 1H) 6.69-6.82 (m, 1H) 5.71-5.81 (m, 1H) 5.18-5.49 (m, 1H) 4.82-4.90 (m, 1H) 4.72-4.79 (m, 1H) 4.57-4.67 (m, 1H) 4.16-4.28 (m, 2H) 3.75-3.85 (m, 2H) 3.69-3.72 (m, 3H) 3.51 (s, 2H) 3.34 (s, 3H) 2.63-2.76 (m, 2H) 2.06-2.16 (m, 2H) 1.93-2.06 (m, 3H) 1.01-1.21 (m, 9H); LCMS (m/z) ES+=483 (M+1).