Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2C=1.Br[CH2:15][C:16](=O)[C:17]([CH3:20])([CH3:19])[CH3:18].C(O)C>[Pt](=O)=O.CO>[CH3:18][C:17]([C:16]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:15]=1)([CH3:20])[CH3:19]
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Reactant: CC(C)(C)C(=O)CBr
Agent: O=[Pt]=O
Solvent: CO
Solvent: CCO
Product: CC(C)(C)c1cn2c(n1)CNCC2

Procedure:
2-(1,1-Dimethylethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine was prepared in an analogous manner to that described above for 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (Intermediate 4) but starting from 1-bromo-3,3-dimethyl-2-butanone instead of 3-bromo-1,1,1-trifluoro-2-propanone and using platinum (IV) oxide and ethanol in the place of 10% palladium on carbon paste and methanol for the hydrogenation step.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:6]([CH2:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:7]=[CH:8][CH:9]=1)=[O:4].[OH-:21].[Na+].O.Cl>O1CCOCC1>[O:18]=[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:10][N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3]([OH:4])=[O:21]
Reactant: O=C(Cn1cccc1C(=O)C(Cl)(Cl)Cl)c1ccccn1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Cn1cccc1C(=O)O)c1ccccn1
Temperature: 25 °C

Procedure:
To a solution of 2,2,2-trichloro-1-{1-[2-oxo-2-(pyridin-2-yl)ethyl]-1H-pyrrol-2-yl}ethanone (600 mg, 1.8 mmol) in 1,4-dioxane (20 ml) was added a solution of a aqueous solution of sodium hydroxide (1 M) (3.6 mL, 3.6 mmol) at 0° C. The mixture was allowed to warm to room temperature. After completion (30 minutes; reaction monitored by LCMS) water was added (40 mL). The mixture was then acidified with aqueous HCl (1 M) and extracted with EtOAc (3×40 mL). The organic layers were dried (Na2SO4), filtrated and concentrated in vacuo to give 1-[2-oxo-2-(pyridin-2-yl)ethyl]-1H-pyrrole-2-carboxylic acid as a pale brown solid that was used such as in the next step without purification (500 mg). ESI-MI m/z [M+H]+ 245.0.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32]([O-:34])=[O:33].[Na+]>>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32]([C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1)(=[O:33])=[O:34]
Reactant: O=S([O-])c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4ccc5ccccc5c4)cc3c2C1
Yield: 85 %

Procedure:
The product of Example 29, step B and sodium 2-naphthylsulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 80:20 hexane/ethyl acetate) provided tert-butyl 8-(2-naphthylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (450 mg, 85%) as an orange solid: 1H NMR (CDCl3, 300 MHz) δ 8.58 (s, 1H), 8.14 (s, 1H), 8.02-7.82 (m, 5H), 7.66-7.56 (m, 2H), 7.50 (d, J=8.7 Hz, 1H), 4.57 (s, 2H), 3.82 (t, J=5.4 Hz, 2H), 2.90-2.80 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].CCN(CC)CC.[Br:14][C:15]1[CH:16]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[N:19][CH:20]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[OH:4][CH2:3][C:2]([NH:1][S:21]([C:17]1[CH:18]=[N:19][CH:20]=[C:15]([Br:14])[CH:16]=1)(=[O:23])=[O:22])([CH3:6])[CH3:5]
Reactant: CC(C)(N)CO
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(CO)NS(=O)(=O)c1cncc(Br)c1
Temperature: 23 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a solution of commercially available 2-amino-2-methyl-1-propanol (478 mg, 5 mmol) and Et3N (0.75 mL, 5 mmol) in THF (50 mL) at 0° C. was added portionwise added 5-bromo-pyridine-3-sulfonyl chloride [CAS-No. 65001-21-0] (according to J. Org. Chem. 1989, 54(2), 389) (1.28 g, 5 mmol) and the mixture was stirred at 23° C. for 1 h. The reaction is worked up by neutralization with 5% citric acid, extracted with EtOAc, washed with sat. NaHCO3-sol. and brine, dried over Na2SO4, filtered and concentrated to give a light brown solid, which was purified by trituration with heptane/diethyl ether gave the title compound as a white solid (1.25 g, 82%). MS (ISP) 309.2 [(M+H)+], 311.1 [(M+2+H)+]; mp 112° C.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1(S([N:28]2[C:36]3[C:31](=[CH:32][C:33]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=4)=[CH:34][CH:35]=3)[C:30]3[CH:45]=[C:46]([Cl:49])[CH:47]=[N:48][C:29]2=3)(=O)=O)C=CC=CC=1.CO>C1COCC1>[Cl:49][C:46]1[CH:47]=[N:48][C:29]2[NH:28][C:36]3[C:31]([C:30]=2[CH:45]=1)=[CH:32][C:33]([C:37]1[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=1)=[CH:34][CH:35]=3
Reactant: COc1ccc(-c2ccc3c(c2)c2cc(Cl)cnc2n3S(=O)(=O)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3[nH]c4ncc(Cl)cc4c3c2)cc1
Yield: 85 %

Procedure:
At room temperature and under inert atmosphere, 1.0 M TBAF in THF (1.9 mL, 5 equiv.) was added a solution of 9-benzenesulfonyl-3-chloro-6-(4-methoxyphenyl)-9H-pyrido[2,3-b]indole (26) (169 mg, 0.376 mmol) in anhydrous THF (17 mL). The solution was refluxed for 2 h. The resulting mixture was then cautiously quenched at 0° C. with H2O. The mixture was extracted with EtOAc (3×10 mL). The resulting organic layers were dried over MgSO4, filtered, and solvents were removed under reduced pressure. The crude product was purified by flash chromatography (CH2Cl2/EtOAc 9:1) to afford R277 in 85% yield as a yellow solid; mp>220° C. (MeOH); IR: 3109, 3035, 2935, 2848, 1630, 1603, 1578, 1483, 1232, 1090, 1033, 800, 778, 700 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ 12.02 (bs, 1H), 8.74 (d, 1H, J=2.4 Hz), 8.49 (d, 1H, J=1.8 Hz), 8.42 (d, 1H, J=2.4 Hz), 7.76 (dd, 1H, J=1.8, 8.6 Hz), 7.55 (d, 1H, J=8.5 Hz), 7.06 (d, 1H, J=8.7 Hz), 3.81 (s, 3H); 13C-NMR (75 MHz, DMSO-d6): δ 158.4 (C), 150.7 (C), 144.1 (CH), 138.8 (C), 133.2 (C), 132.1 (C), 128.3 (CH), 127.7 (2 CH), 126.2 (CH), 121.7 (C), 120.2 (C), 119.3 (CH), 126.6 (C), 114.4 (2 CH), 111.8 (CH), 55.2 (CH3); MS (ESI) m/z 309.1 [M+H]+; HRMS (EI): Calcd for C18H13ClN2O: 308.0716. Found: 308.0714.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[N:10]([C:11](=[O:33])[C@@H:12]([NH:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:9][CH2:8][N:7]([CH2:34][C:35]([OH:37])=[O:36])[C:6]1=[O:38].C([O-])(O)=O.[Na+].[ClH:44].O=C1N([O:55][C:56](=O)[C:57]2[CH:62]=[CH:61][C:60]([NH:63][C:64]([NH2:66])=[NH:65])=[CH:59][CH:58]=2)C(=O)C2C1C1CC2C=C1.Cl>O1CCOCC1>[ClH:44].[CH2:26]([O:25][C:23]([NH:22][C@@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:11]([N:10]1[CH2:9][CH2:8][N:7]([CH2:34][C:35]([OH:37])=[O:36])[C:6](=[O:38])[C@@H:5]1[CH2:4][CH2:3][CH2:2][NH:1][C:56](=[O:55])[C:57]1[CH:58]=[CH:59][C:60]([NH:63][C:64]([NH2:66])=[NH:65])=[CH:61][CH:62]=1)=[O:33])=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N2CCN(CC(=O)O)C(=O)[C@@H]2CCCN)cc1
Reactant: N=C(N)Nc1ccc(C(=O)ON2C(=O)C3C4C=CC(C4)C3C2=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N2CCN(CC(=O)O)C(=O)[C@@H]2CCCNC(=O)c2ccc(NC(=N)N)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
In 50 ml of a 50% aqueous solution of dioxane was dissolved 0.5 g of (S,S)-3-(3-aminopropyl)-4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl1-2-oxopiperazine-1-acetic acid produced in Reference Example 35. To the solution was added 0.24 g of NaHCO3, to which was then added 0.377 g of 4-guanidinobenzoic acid 3,5-dioxo-4-azatricyclo[5,2,1,0 2,6)deca-8-en-4-yl ester hydrochloride. The mixture was stirred for two hours at room temperature. The pH of the reaction mixture was adjusted to 3 with 1N-HCl, followed by distilling off dioxane. The residue was purified by means of a column chromatography (eluting with H2O→10% aqueous solution of CH3CN→a 20% aqueous solution of CH3CN→a 50% aqueous solution of CH3CN) to afford 0.43 g of the title compound.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)(=O)=O.C([Li])CCC.[CH2:38]([OH:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>>[CH3:40][C:39]([CH3:42])([CH3:41])[CH2:38][O:43][C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1
Reactant: CC(C)(C)CO
Reactant: CS(=O)(=O)c1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: [Li]CCCC
Product: CC(C)(C)COc1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
2-Methylsulfonyl-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 86 (30 mg, 0.06 mmol) was reacted with 2 equivalents each of n-butyl lithium and neopentyl alcohol by the procedure described in Reference Examples 6 and 7 to afford 2-(2,2-dimethylpropyloxy)-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine: HPLC/MS: m/e=514 (M++1); Rt4.48 min. 1H-NMR400 MHz (CDCl3): δ 1.20-1.30 (s, 9H), 3.88 (s, 2H), 7.15-7.28 (m, 7H), 7.40-7.43 (m, 1H), 7.58-7.61 (m, 1H), 8.52-8.56 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1([CH3:41])[C:31]2[CH:30]=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:28]=[CH:27][C:26]=2[CH2:25][CH2:24][CH2:23]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([C:29]3[CH:28]=[CH:27][C:26]4[CH2:25][CH2:24][CH2:23][C:22]([CH3:41])([CH3:21])[C:31]=4[CH:30]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)CCCc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)n2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(-c3ccc4c(c3)C(C)(C)CCC4)n2)CC1

Procedure:
The preparation is carried out analogously to FS 102 starting from 4-(4-chloro-1,3,5-triazin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (US 2005/59668) and 2-(8,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: Cl.NO.[Na].C[O:6][C:7](=[O:23])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].C[O-].[Na+]>CO>[O:22]=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([OH:23])=[O:6]
Reactant: COC(=O)CCCCC1CCc2ccccc2C1=O
Agent: C[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: O=C(O)CCCCC1CCc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.7 %

Procedure:
To a solution of 5.0 g (22.9 mmol) 1-oxo-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid ethyl ester (1a) (Pradeep, K., and Saravanan, K., Tetrahedron 54 (1998) 2161-2168) and 5.79 g ethyl-5-bromo-pentanoate (27.7 mmol) in 10 mL ethanol at reflux is added a freshly prepared solution of 0.53 g sodium in 15 mL ethanol. After 10 h at reflux enough water is added for the precipitate to dissolve. The solvent is evaporated, the residue is dissolved in a solution of 3.85 g KOH in 7 mL MeOH and 5 mL H2O and refluxed for another 10 h. After cooling the solution is poured into 25 mL ice-cold 4N HCl and extracted with CH2Cl2. Evaporation of the solvent leaves a residue of crude 5-(1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl)-pentanoic acid (1b) which is dissolved in 100 mL MeOH. A few drops of H2SO4 are added and the solution is refluxed over night. After addition of some sodiumbicarbonate-solution the solvent is evaporated and the residue is subjected to column-chromatography yielding 1.9 g methyl-(5-(1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl)-pentanoate) (1c). To a solution of 1.6 g (23 mmol) hydroxylamine hydrochloride in 40 mL MeOH is added 15 mL of a solution of 0.8 g (35 mmol) of sodium in 30 mL of MeOH. To this, a solution of 3.0 g (11.5 mmol) methyl-(5-(1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl)-pentanoate) (1c) in 20 mL MeOH is added, followed by the remaining 15 mL of the sodium methylate solution. After stirring for 6 h at rt the solvent is evaporated, acidified with 2N HCl and extracted with CH2Cl2. After evaporation the residue is purified by column-chromatography yielding 2.2 g of the title compound as an oil, MS (APCI): 260.1 (M−1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[NH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Reactant: NCCc1ccc(O)cc1
Solvent: COCCOC
Product: N#Cc1c(NCCc2ccc(O)cc2)nc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and tyramine in DME. ES-MS m/e (%): 376 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.[S:23](Cl)([Cl:26])(=[O:25])=[O:24].N1C=CC=CC=1>C(Cl)Cl>[S:23]([Cl:26])([O:8][C:7]1[CH:6]=[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])[C:4]([F:22])=[CH:3][C:2]=1[Cl:1])(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OS(=O)(=O)Cl)c(Cl)cc2F)c1=O

Procedure:
A solution of 10.16 g of 3-(4-chloro-2-fluoro-5 -hydroxyphenyl)-1-methyl-6 -trifluoromethyl-2,4 (1H,3H)-pyrimidinedione and 20.20 g of sulphuryl chloride in 100 ml of methylene chloride is treated with a solution of 3.56 g of pyridine in 10 ml of methylene chloride while stirring and cooling during 5 minutes. The temperature rises to 20° C. The reaction mixture is stirred at 20°-25° C. for 15 minutes, subsequently poured on to ice and stirred vigorously. The organic phase is washed throughly with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from diethyl ether/n-hexane. There is obtained 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorophenyl chlorosulphate m.p. 133°-135° C.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH:7]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1)[CH2:8][NH:9][C:10]([C:12]1([CH2:17][C:18]([OH:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:18]([CH2:17][C:12]1([C:10]([NH:9][CH2:8][CH:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C:6]([OH:30])=[O:5])=[O:11])[CH2:16][CH2:15][CH2:14][CH2:13]1)([OH:20])=[O:19]
Reactant: CC(C)(C)OC(=O)C(CNC(=O)C1(CC(=O)O)CCCC1)Cc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1(C(=O)NCC(Cc2ccc(Cl)c(Cl)c2)C(=O)O)CCCC1
Reaction time: 2 h
Yield: 39 %

Procedure:
To a solution of 2-(1-(3-tert-butoxy-2-(3,4-dichlorobenzyl)-3-oxopropylcarbamoyl)cyclopentyl)acetic acid (30.6 mg, 0.067 mmol) in DCM (0.7 ml), TFA (0.257 ml, 3.34 mmol) was added. The reaction mixture was allowed to stir for 2 hr and then concentrated under reduced pressure. The obtained residue was purified by RP-HPLC (SunFire, H2O (0.1% TFA) I CH3CN), and then lyophilized to give 3-(1-(carboxymethyl)cyclopentanecarboxamido)-2-(3,4-dichlorobenzyl)propanoic acid (10.5 mg); Retention time=0.67 minutes (condition B); MS (m+1)=402.0; 1H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.47-1.58 (m, 6H) 1.97-2.04 (m, 2H) 2.54-2.63 (m, 2H) 2.68-2.84 (m, 3H) 3.13-3.28 (m, 2H) 7.17-7.19 (m, 1H) 7.43 (d, J=2.0 Hz, 1H) 7.52-7.54 (m, 1H) 7.61-7.63 (app t, 1H) 12.14 (br s, 2H); HRMS (ES+) m/z for C18H22Cl2NO5 [M+H]+ calcd 402.0875. found 402.0855.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH:14]=[N:15][NH:16][C:17]([O:19]C)=O>ClC1C=CC=CC=1Cl>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)[N:4]2[C:3]=1[CH:14]=[N:15][NH:16][C:17]2=[O:19]
Reactant: COC(=O)NN=Cc1nc(-c2cccc(C)c2)[nH]c1C
Solvent: Clc1ccccc1Cl
Product: Cc1cccc(-c2nc(C)c3cn[nH]c(=O)n23)c1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 84.2 %

Procedure:
A mixture of 3-[(5-methyl-2-m-tolyl-4-imidazolyl)-methylene]carbazic acid, methyl ester (5.1 gm., 0.019 mole) and o-dichlorobenzene (75 ml.) is heated slowly (45 minutes) to reflux, refluxed for 1.5 hours, then stirred at room temperature overnight (appr. 15-16 hours). The reaction mixture is filtered to afford 3.9 gm. (0.016 mole) title product. Recrystallization from o-dichlorobenzene yields partially solvated product, m.p. 188°-198° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH2:15]>C(O)(C)C>[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: CN(C)CCN
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CC(C)O
Product: CN(C)CCNc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 92 %

Procedure:
A mixture of 2-fluoro-nitrobenzene (2.8 g, 20 mmol) and N,N-dimethylethylenediamine (3.3 mL, 30 mmol) in isopropanol is heated at 90°-100° C. for 16 h, cooled to 0° C. and filtered. The filtercake is washed with cold isopropanol and air-dried to give the title compound as an orange solid, 3.83 g (92% yield), identified by HPLC and mass spectral analyses.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH:20]([F:22])[F:21])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].C(O)(=O)C.[BH4-].[Na+].Cl>O.O1CCCC1>[Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH:20]([F:22])[F:21])(=[O:18])=[O:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(CCl)c1ccc(-c2ccc(S(=O)(=O)C(F)F)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(-c2ccc(C(O)CCl)cc2)cc1)C(F)F
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
To a 500-mL sidearm flask equipped with a thermometer and nitrogen inlet was charged 47.0 g (0.130 mol) of ca. 95%-pure 2-chloro-1-[4'-[(difluoromethyl) -sulfonyl][1,1'-biphenyl]-4-yl]ethanone, 200 mL of tetrahydrofuran, 1.40 mL (23 mmol) of glacial acetic acid, and 10 mL of water. The orange solution was cooled to 5° C. and 2.4 g (31 mmol) of sodium borohydride was added in three portions over about 15 minutes. The mixture was held for 15 minutes at 10° C., diluted with 200 mL of water, and acidified to pH 2 with about 40 mL of aqueous 1N HCl. Most of the THF was removed in vacuo and the oil was extracted with 400 mL of ethyl acetate. The ethyl acetate layer was washed in succession with water, aqueous NaHCO3, and aqueous NaCl, then dried with MgSO4, filtered, and concentrated to dryness. Then residue was crystallized from 200 mL of 1:1 toluene/hexanes, filtered, and washed with 50 mL of 1:1 toluene/hexanes to afford 35.3 g (78% yield) of product as a pale orange solid, m.p. 104-107° C.; a sample purified by chromatography and crystallization from EtOAc/hexanes had m.p. 111-112° C. 1H-NMR (CDCl3) δ3.3 (br s, 1H), 3.7 (dd, 1H), 3.8 (dd, 1H), 5.0 (dd, 1H), 6.23 (t, 1H, J=60 Hz), 7.55 (d, 2H), 7.65 (d, 2H), 7.82 (d, 2H), 8.05 (d, 2H). 13C-NMR (CDCl3) δ50.5, 73.5, 114.7 (t, JCF =286 Hz), 126.9, 127.7, 128.1, 130.1, 131.1, 138.6, 141.0, 148.1 ppm. 19F-NMR(CDCl3) δ-121.8 ppm (d, JHF =53 Hz). Mass spectrum m/z=346 (M+), 297 (M+ --CH2Cl, base peak), 182 amu.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.[CH2:27]([O:34][C:35]([NH:37][C@H:38]([C:51]([NH:53][CH2:54][C:55]([C:57]1[C:58]([O:67][CH3:68])=[N:59][C:60]2[C:65]([CH:66]=1)=[CH:64][CH:63]=[CH:62][CH:61]=2)=O)=[O:52])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:27]([O:34][C:35]([NH:37][C@H:38]([C:51]1[O:52][C:55]([C:57]2[C:58]([O:67][CH3:68])=[N:59][C:60]3[C:65]([CH:66]=2)=[CH:64][CH:63]=[CH:62][CH:61]=3)=[CH:54][N:53]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])=[O:36])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1nc2ccccc2cc1C(=O)CNC(=O)[C@H](CCCCCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1nc2ccccc2cc1-c1cnc([C@H](CCCCCC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
PPh3 (2.0 eq.) and C2Cl6 (2.0 eq.) were dissolved in DCM (0.72 M) at room temperature and Et3N (4.0 eq.) was added, followed after 5 min of stirring by dropwise addition of a solution of F3 in DCM (0.36 M). The mixture was stirred at room temperature for 1 h and then was diluted with DCM, washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. Crude was purified by column chromatography (eluent: Petroleum ether/EtOAc from 94:6 to 2:3) to give the title compound as orange oil. MS (ES+) C32H37N3O6: 560 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].CN(C=O)C.N1([C:21]([CH:23]2[C:36](=[O:37])[C:35]3[C:26](=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH:31]=[CH:30][CH:29]=[N:28]4)[N:25]=[CH:24]2)=[O:22])C=CN=C1>C(O)(=O)C>[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:21]([CH:23]1[C:36](=[O:37])[C:35]2[C:26](=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH:31]=[CH:30][CH:29]=[N:28]3)[N:25]=[CH:24]1)=[O:22]
Reactant: O=C1c2ccc3cccnc3c2N=CC1C(=O)n1ccnc1
Reactant: COCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COCCOCCOC(=O)C1C=Nc2c(ccc3cccnc23)C1=O
Reaction time: 0.5 h

Procedure:
Sodium hydride (3.15 g, 60%) was added in portions to a mixture of 2-(2-methoxyethoxy)ethanol (15 ml) and DMF (200 ml). The mixture was stirred for approximately 30 minutes until effervescence ceased. 3-(Imidazol-1-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline (21.05 g) was added and the mixture stirred for 18 hours. The mixture was acidified to pH 5-6 with acetic acid, and evaporated to dryness under reduced pressure. Water (50 ml) was added and the mixture extracted with dichloromethane. The organic layer was washed with brine, dried (MgSO4) and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography on silica using dichloromethane, followed by a 24:1:0.1 mixture of dichloromethane methanol : triethylamine as eluant. The product so obtained was triturated with ethyl acetate to give 3-[2-(2-methoxyethoxy)ethoxycarbonyl]-4-oxo-3,4-dihydro-1,10-phenanthroline in 68% overall yield, mp 164-165° C.