Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1.[OH-].[Li+]>CO.C1COCC1.O.O>[Cl:20][C:16]1[CH:15]=[C:14](/[CH:13]=[CH:12]/[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=2[C:3]([OH:21])=[O:2])[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc(OC)ccc1/C=C/c1cccc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(/C=C/c2cccc(Cl)c2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 74 %

Procedure:
Crude 2-[(E)-2-(3-chlorophenyl)vinyl]-5-methoxybenzoic acid methyl ester was suspended in methanol:THF:water (3:1:1 [v/v], 400 mL) and lithium hydroxide (12.10 g, 289 mmol) added. The mixture was stirred for 22 h at ambient temperature and concentrated in vacuo to give a pale brown solid. The crude product was re-dissolved in water (400 mL), the solution washed with diethyl ether (3×250 mL) and acidified to pH 2 with 1 N HCl (aq.). The aqueous was extracted with ethyl acetate (3×200 mL), the organic phase dried (MgSO4) and concentrated in vacuo to give a tan solid which was triturated with methanol and filtered to give (E)-2-[2-(3-chlorophenyl)vinyl]-5-methoxybenzoic acid (15.43 g, 53.44 mmol, 74% for 2 steps from 2-bromo-5-methoxybenzoic acid methyl ester) as an off-white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28]Br)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:28][CH2:27][CH2:26][NH:25][C:23]([O:22][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:24]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Yield: 97.3 %

Procedure:
A solution of 2.69 grams (0.010 mole) of 2,6-dichloro-4-phenylmethoxyphenol (known compound), 2.38 grams (0.010 mole) of (tert-butoxy)-N-(3-bromopropyl)carboxamide (commercially available) and 1.52 grams (0.011 mole) of potassium carbonate in 40 mL of DMF was stirred at ambient temperature during a four-day period. After this time the reaction mixture was shaken in diethyl ether and water, and the separated organic layer was washed with one portion of water and with one portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 4.15 grams of the subject compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Br:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37](O)=[O:38]>>[Br:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)=[O:38]
Reactant: O=C(O)c1ccc2ccccc2c1Br
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc5ccccc5c4Br)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 1-bromonaphthalene-2-carboxylic acid as starting compounds. The crude product is purified by crystallization from diethyl ether to yield the title compound.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[CH3:22][O:23][C:24]1[CH:48]=[CH:47][C:27]([CH2:28][N:29]2[CH:33]=[C:32]([C:34]3[N:35]=[C:36]([NH:39][C:40]4[CH:45]=[CH:44][C:43]([F:46])=[CH:42][N:41]=4)[S:37][CH:38]=3)[CH:31]=[N:30]2)=[CH:26][CH:25]=1.CC1C=CC=C(C)N=1>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:29]2[CH:33]=[C:32]([C:34]3[N:35]=[C:36]([NH:39][C:40]4[CH:45]=[CH:44][C:43]([F:46])=[CH:42][N:41]=4)[S:37][C:38]=3[F:21])[CH:31]=[N:30]2)=[CH:47][CH:48]=1
Reactant: COc1ccc(Cn2cc(-c3csc(Nc4ccc(F)cn4)n3)cn2)cc1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: COc1ccc(Cn2cc(-c3nc(Nc4ccc(F)cn4)sc3F)cn2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.9 %

Procedure:
According to Scheme 7 Step 1: Selectfluor (3.28 mmol, 1.16 g) was added portionwise to a solution of N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-2-yl)-5-fluoropyridin-2-amine (2.18 mmol, 833 mg) and of 2,6-dimethylpyridine (2.18 mmol, 0.25 mL) in DMF (25 mL) at 0° C. The reaction mixture was stirred at room temperature for 12 hours. The reaction was quenched with water (70 mL). A precipitate was formed, was filtered and was dried to yield N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-fluorothiazol-2-yl)-5-fluoropyridin-2-amine (1.85 mmol, 739 mg, 85%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])CCC.CCCCCC.C(O[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1)(C)C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:11])[CH3:10])[CH:5]=[C:6]([F:8])[C:7]=1[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1
Reactant: CC(O)c1cc(F)cc(F)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(3,5-difluorophenyl)ethanol (10.2 mmol, 1660 mg, commercial) in tetrahydrofuran (100 mL) at −78° C. was added n-butyllithium (2.5 mol/L) in hexane (2.4 equiv., 24.4 mmol, 9.8 mL) dropwise. The mixture was stirred at −78° C. for 2 hours. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.50 equiv., 25.4 mmol, 5.29 mL) was added, and the reaction mixture was stirred over night allowing to warm to room temperature. The reaction mixture was quenched with saturated NaHCO3(aq.) And extracted with etoac. The organic layer was washed with brine, dried with Na2SO4, filtered, and the filtrated was concentrated to afford the desired product which was used without further purification.
Reaction SMILES: ClC1C=CC([CH:6](OC2CNC2)[C:7]2[CH:12]=[CH:11][C:10](Cl)=[CH:9][CH:8]=2)=CC=1.[N-]=[C:22]=[O:23].Cl[C:25]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:26]=1[CH:27]([O:35][CH:36]1[CH2:39][N:38]([C:40]([NH:42]C(C)(C)C)=[O:41])[CH2:37]1)[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1>>[Cl:51][C:49]1[CH:48]=[CH:47][C:26]([CH:27]([O:35][CH:36]2[CH2:39][N:38]([C:40]([NH:42][CH2:6][C:7]3[CH:8]=[CH:9][C:10]([O:23][CH3:22])=[CH:11][CH:12]=3)=[O:41])[CH2:37]2)[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[CH:25][CH:50]=1
Reactant: Clc1ccc(C(OC2CNC2)c2ccc(Cl)cc2)cc1
Reactant: [N-]=C=O
Reactant: CC(C)(C)NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccc(Cl)cc2Cl)C1
Product: COc1ccc(CNC(=O)N2CC(OC(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)cc1

Procedure:
This material was prepared from 3-(4,4′-dichlorobenzhydryloxy)azetidine (36) and the corresponding commercially available isocyanate, using the procedure described for compound (5).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([N+:16]([O-])=O)=[CH:14][C:13]([N+:19]([O-])=O)=[C:12]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[CH:24]=2)[CH:11]=1.Cl.[C:33](=N)(O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CO>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([NH2:16])=[CH:14][C:13]2[N:19]=[C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:22]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[CH:24]=3)[C:12]=2[CH:11]=1
Reactant: COC(=O)CCCCCOc1cc(Nc2ccc(C)c(C)c2)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: N=C(O)c1ccccc1
Agent: Cl
Solvent: CO
Product: COC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccc(C)c(C)c1

Procedure:
2.45 g of 6-[[3-[(3,4-dimethylphenyl)amino]-4,6-dinitrophenyl]oxy]hexanoic acid methyl ester was hydrogenated in methanol according to general operating instructions 1. 500 mg of the crude product was reacted with benzimidate hydrochloride according to general operating instructions 4. Contrary to general operating instructions 4, after being taken up in solvent, the crude product was not washed with aqueous hydrochloric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH:13]2[CH2:40][CH2:39][C:16]3[N:17](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:18]=[N:19][C:15]=3[CH2:14]2)=[O:10])=[CH:4][CH:3]=1.ClC1C=CC(CC(NCC2CCC3N=CN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)C=3C2)=O)=CC=1>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH:13]2[CH2:40][CH2:39][C:16]3[NH:17][CH:18]=[N:19][C:15]=3[CH2:14]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)NCC1CCc2c(ncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: O=C(Cc1ccc(Cl)cc1)NCC1CCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C1
Solvent: CC(=O)O
Solvent: O
Product: O=C(Cc1ccc(Cl)cc1)NCC1CCc2[nH]cnc2C1
Temperature: 90 °C

Procedure:
A solution of a mixture of 2-(4-chlorophenyl)-N-((1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl)methyl)acetamide and 2-(4-chlorophenyl)-N-((3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)methyl)acetamide (0.38 g, 0.80 mmol) in a mixture of acetic acid (5 ml) and water (0.6 ml) was heated to 90° C. for 2 hours. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using a mixture of DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 0.18 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:12])[C:10]=1[NH2:11])[C:5]([O-:7])=[O:6].[CH2:13](N(CC)CC)C.Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Br:12][C:9]1[C:10]2[NH:11][C:21](=[O:23])[NH:1][C:2]=2[CH:3]=[C:4]([C:5]([O:7][CH3:13])=[O:6])[CH:8]=1
Reactant: CCN(CC)CC
Reactant: Nc1cc(C(=O)[O-])cc(Br)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c2[nH]c(=O)[nH]c2c1
Temperature: 25 °C
Yield: 46.1 %

Procedure:
A solution of 3,4-diamino-5-bromobenzoate (1 g, 4.0 mmol) and triethylamine (0.4 g, 4.0 mmol) in dichloromethane (6 mL) was cooled to 0° C. A solution of triphosgene (1.2 g, 4.08 mmol) in dichloromethane (15 mL) was added to this solution. The reaction mixture was allowed to warm to ambient temperature and maintained for 18 hours. The reaction mass was quenched with water (3 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with aqueous saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate and concentrated to obtain methyl 7-bromo-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate as an off-white solid (500 mg, 45%). 1HNMR (CDCl3+DMSO-d6): δ 11.35 (s, 1H), 11.05 (s, 1H), 7.75 (s, 1H), 7.52 (s, 1H) and 3.85 (s, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[C@H:29]([CH3:30])[C@@H:28]2[C@@:5]([C:32]([OH:34])=[O:33])([CH2:6][CH2:7][C@@:8]3([CH3:31])[C@:13]4([CH3:27])[CH2:14][CH2:15][C@H:16]5[C:21]([CH3:23])([CH3:22])[C@@H:20]([OH:24])[C@H:19]([OH:25])[CH2:18][C@:17]5([CH3:26])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1.IC.[C:37](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C@H:2]1[C@H:29]([CH3:30])[C@@H:28]2[C@@:5]([C:32]([O:34][CH3:37])=[O:33])([CH2:6][CH2:7][C@@:8]3([CH3:31])[C@:13]4([CH3:27])[CH2:14][CH2:15][C@H:16]5[C:21]([CH3:23])([CH3:22])[C@@H:20]([OH:24])[C@H:19]([OH:25])[CH2:18][C@:17]5([CH3:26])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1
Reactant: C[C@H]1[C@H](C)CC[C@]2(C(=O)O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)C[C@@H](O)[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@H]12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)[C@]12CC[C@@H](C)[C@H](C)[C@H]1C1=CC[C@@H]3[C@@]4(C)C[C@@H](O)[C@H](O)C(C)(C)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
A mixture of corosolic acid (2.0 g, 4.34 mmol), iodomethane (1 mL, 16 mmol), potassium carbonate (4.5 g, 32.6 mmol) and acetone (60 mL) was stirred at rt for 16 h. After completion of the reaction, the solids were filtered off and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel column using chloroform-methanol (10%) as eluent to furnish methyl corosolate (1.7 g, 83%), which was recrystallised from chloroform-hexane, m.p. 208-210° C.; IR (KBr): 3432, 2946, 2872, 1728, 1455, 1230, 1197, 1049 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.75 (3H, s, CH3), 0.83 (3H, s, CH3), 0.85 (3H, d, J=6.5 Hz, CH3), 0.94 (3H, d, J=5.7 Hz, CH3), 0.99 (3H, s, CH3), 1.03 (3H, s, CH3), 1.08 (3H, s, CH3), 2.23 (1H, d, J=11.0 Hz, H-18), 3.0 (1H, d, J=8.4 Hz, H-3), 3.60 (3H, s, —COOCH3), 3.62-3.71 (1H, m, H-2), 5.25 (1H, t, J=3.4 Hz, H-12); LCMS (negative ion mode): m/z 485 (M−H)−.
Reaction SMILES: [F-].[Cs+].[OH:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:15][CH3:16])[C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8].Br[CH2:18]Br.CCOCC>CN(C=O)C>[CH2:16]1[O:14][C:13]2[C:4]([O:3][CH3:18])=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][C:12]=2[O:15]1
Reactant: BrCBr
Reactant: COC(=O)c1cc(O)c(O)c(OC)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cc(OC)c2c(c1)OCO2
Temperature: 110 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
Cesium fluoride (26.5 g, 174 mmol) was added quickly to a stirred solution of diol 4 (7.7 g, 39 mmol) in DMF (80 ml) at rt under Ar. After stirring for 1 h, dibromomethane (5.4 ml, 78 mmol) was added dropwise at rt and the mixture heated to 110° C. for 12 h. Upon cooling to rt, ether (300 ml) was added and the mixture washed with cold water (3×50 ml). The combined aqueous phase was then extracted with ether (2×100 ml), dried and concentrated in vacuo. The resultant crude residue was absorbed onto silica gel (gravity) and purified via silica gel chromatography (gravity, 1:5; EtOAc in n-hexane), affording methylenedioxy derivative 5 (8.1 g, 99%) as a colorless powder; m.p. 89–91° C. (mp 89–91° C., Pettit and Singh, 1987); 1H-NMR (300 MHz):3.89 (3H, s, —OCH3), 3.94 (3H, s, —OCH3), 6.05 (2H, s, —OCH2O—), 7.21 (1H, d,J=1.8 Hz, ArH), 7.33 (I H, d, J=1.8 Hz, ArH).
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Cl:15][C:16]1[N:24]=[C:23]2[C:19]([NH:20][CH:21]=[N:22]2)=[C:18](Cl)[N:17]=1>C(O)CCC>[CH:1]1([NH:5][C:18]2[N:17]=[C:16]([Cl:15])[N:24]=[C:23]3[C:19]=2[NH:20][CH:21]=[N:22]3)[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCC1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc(NC2CCC2)c2[nH]cnc2n1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
Cyclobutylamine (20 g, 0.28M) and N,N-diisopropylethylamine (50.4 ml, 0.28M) is added to a suspension of 2,6-dichloropurine (48.4 g, 0.25M) in n-butanol (480 ml). The mixture is stirred at 60° C. for 20 hours. The mnixture is cooled and the precipitate isolated by filtration, washed with n-butanol and dried under vacuum to give 6cyclobutylamino-2-chloropurine;ES+ (M−1) 222.5; mp 237.8° C. dec.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:15][C:14](=[O:16])[C:13]3=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]3[N:11]=2)=[CH:8][C:7]([S:24](Cl)(=[O:26])=[O:25])=[C:6]([O:28][CH3:29])[CH:5]=1)[CH3:2].CN(C1C=CC=CN=1)C.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>ClCCl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:28][CH3:29])[C:7]([S:24]([N:43]2[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]2)(=[O:26])=[O:25])=[CH:8][C:9]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]2[N:11]=1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)c(OC)cc3OCC)nn12
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)c(OC)cc3OCC)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
20 mg (0.045 mmol) of 4-ethoxy-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo-[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride are dissolved in 0.5 ml of dichloromethane and admixed with a spatula tip of dimethylaminopyridine and 14 mg (0.136 mmol) of N-methylpiperazine, and the reaction mixture is stirred at room temperature overnight. Purification over silica gel gives 12.8 mg (55%) of 2-[2-ethoxy-4-methoxy-5-(4-methylpiperazine-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]([C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24](=[O:45])[NH:25][C@H:26]([CH2:35][N:36]([CH3:44])C(OC(C)(C)C)=O)[C@H:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[OH:28])[CH2:19]1)([OH:17])[CH2:10][CH2:11][CH2:12][NH:13]C(=O)[O-].[C:46]([OH:52])(C(F)(F)F)=[O:47].[CH2:53](Cl)Cl>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]([C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24](=[O:45])[NH:25][C@H:26]([CH2:35][NH:36][CH3:44])[C@H:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[OH:28])[CH2:19]1)([OH:17])[CH2:10][CH2:11][CH2:12][NH:13][C:46](=[O:47])[O:52][CH3:53]
Reactant: O=C(O)C(F)(F)F
Reactant: CN(C[C@@H](NC(=O)N1CCC[C@@H]([C@@](O)(CCCNC(=O)[O-])c2cccc(F)c2Cl)C1)[C@@H](O)C1CCCCC1)C(=O)OC(C)(C)C
Reactant: ClCCl
Product: CNC[C@@H](NC(=O)N1CCC[C@@H]([C@@](O)(CCCNC(=O)OC)c2cccc(F)c2Cl)C1)[C@@H](O)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 84 %

Procedure:
(S)-4-(2-chloro-3-fluorophenyl)-4-((R)-1-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(N-methyl-N-(t-butoxycarbonyl)amino)propan-2-ylcarbamoyl)piperidin-3-yl)-4-hydroxybutylcarbamate (70 mg, 0.104 mmol) was cooled to 0° C. and a 20% solution of TFA in CH2Cl2 (5 mL) was added. The mixture was stirred at 0° C. for about 20 min and quenched with satd aq NaHCO3. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, then concentrated in vacuo to give crude product, which was purified by preparative HPLC to afford methyl (S)-4-(2-chloro-3-fluorophenyl)-4-((R)-1-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-ylcarbamoyl)piperidin-3-yl)-4-hydroxybutylcarbamate (50 mg, yield 84%). 1H NMR (400 MHz, MeOD): 0.90-1.87 (m, 18H), 1.87-2.08 (m, 2H), 2.10-2.22 (s, 1H), 2.60-2.72 (t, 1H), 2.72 (s, 3H), 2.75-2.85 (t, 1H), 2.90-3.10 (m, 3H), 3.40-3.47 (m, 1H), 3.60 (s, 3H), 3.90-4.05 (d, 1H), 4.05-4.15 (m, 1H), 4.25-4.40 (d, 1H), 7.10-7.20 (s, 1H), 7.32-7.41 (t, 1H), 7.50-7.60 (t, 1H). MS (E/Z): 571.35 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C([N:12](CC)CC)C.[C:17]1([N:23]2[CH2:28][CH2:27]C[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CCOCC>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([N:12]2[CH2:27][CH2:28][N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24][CH2:25]2)[N:3]=1
Reactant: CCN(CC)CC
Reactant: c1ccc(N2CCCCC2)cc1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: O
Solvent: CCOCC
Product: Clc1cc(Cl)nc(N2CCN(c3ccccc3)CC2)n1
Reaction time: 1 h
Yield: 34 %

Procedure:
The synthesis method shall be explained concretely following the order below. 2,4,6-trichloropyrimidine (20 ml, 165 mmol) and triethylamine (27.7 ml) were dissolved in ether (200 ml), and phenylpiperadine (25.2 ml, 165 mmol) was added under ice cooling. After approximately 1 hour of agitation at room temperature, water was added, and extraction was carried out 2 times with ether. After washing the ether layer with saturated saline, drying was done with MgSO4, and the solvent was distilled away under reduced pressure. Purification was done by silica gel chromatography (hexane:ethyl acetate=19:1), and 17.6 g (34% yield) of 4,6-dichloro-2-(4-phenylpiperazin-1-yl)pyrimidine was obtained. NMR data for the obtained 4,6-dichloro-2-(4-phenylpiperazin-1-yl)pyrimidine is shown below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]([OH:20])[C:15](=[NH:19])OCC)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10].[C:21]1(N)[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]([C:15]2[NH:19][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:27]=2)[OH:20])[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]
Reactant: Nc1ccccc1N
Reactant: CCOC(=N)C(O)c1cc(OC)c(OC)c([N+](=O)[O-])c1
Solvent: CCO
Product: COc1cc(C(O)c2nc3ccccc3[nH]2)cc([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19.7 g of ethyl (3,4-dimethoxy-5-nitrophenyl)hydroxyacetimidate are dissolved in 500 ml of ethanol, 6.73 g of o-phenylenediamine are added, the mixture is stirred at room temperature for 2 hours and subsequently held at the reflux temperature overnight. After distillation of the solvent, the residue is treated with 50 ml of water, made alkaline with sodium carbonate solution and extracted twice with 250 ml of methylene chloride each time. The organic phase is washed with water, dried over sodium sulfate and evaporated. The orange residue obtained is chromatographed on 400 g of silica gel with methylene chloride/ethyl acetate (1:1). From ether/hexane there is obtained α-(3,4-dimethoxy-5-nitrophenyl)-2-benzimidazolemethanol in the form of yellowish crystals of m.p. 50° (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](F)[C:3]=1[C:10](=[O:22])[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:13]>CS(C)=O.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[C:10](=[O:22])[CH:11]=[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[O:13]2
Reactant: COc1ccc(C(=O)CC(=O)c2c(F)cc(F)cc2F)cc1
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(-c2cc(=O)c3c(F)cc(F)cc3o2)cc1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
In a 100 mL 3-neck round-bottomed flask fitted with condenser and magnetic stirrer were placed dry THF (20 mL) and p-methoxy acetophenone (0.386 g, 2.57 mmol) under nitrogen. To this solution, LHMDS (2.69 mL as a 1M solution in THF, 2.57 mmol) was added drop wise at 25° C. After completion of addition, the mixture was stirred for 30 min at rt, then 2,4,6-trifluoro-benzoyl chloride (0.5 g, 2.57 mmol) in THF (5 mL) was added slowly at rt via syringe. The reaction mixture was stirred overnight at rt. The reaction was quenched with saturated NH4Cl solution (10 mL). The organic layer was separated and aqueous layer was extracted with EtOAc. The combined organic layer was dries over Na2SO4, concentrated to give crude product, which was purified by column chromatography using 20% EtOAc in hexane, to give 215 mg of 1-(2,4,6-trifluoro-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (27%). 1-(2,4,6-trifluoro-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (100 mg) in DMSO (2 mL) was heated at 100-110° C. for 1 h. Then the reaction mixture was cooled to rt and diluted with water. The product was filtered and dried to give 62 mg of 5,7-difluoro-2-(4-methoxy-phenyl)-chromen-4-one (68%). MS (ES) m/z: 289.07 (M+1); 19F-NMR (DMSO-d6): δ −101.9, −109.2.
Reaction SMILES: Cl[CH2:2][C:3]([F:10])([F:9])[CH2:4][CH2:5][C:6]([OH:8])=[O:7].Cl.[BrH:12]>O1CCOCC1.C(O)(=O)C>[Br:12][CH2:2][C:3]([F:10])([F:9])[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C(O)CCC(F)(F)CCl
Reactant: Br
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C(O)CCC(F)(F)CBr

Procedure:
A solution of the product from Step 2 (14.2 g, 57.9 mmol) in a 5:1 methanol/H2O solvent mixture (240 mL) was stirred as lithium hydroxide mono-hydrate (7.29 g, 174 mmol) was added. After stirring at room temperature for 2 h, the reaction volume was concentrated and the remainder was partitioned between dichloromethane (300 mL) and 4N HCl (100 mL). The organic phase was separated, dried over sodium sulfate and concentrated to afford 8.60 g (68%) of the product as a white solid. This product contains 33% of the 5-chloro adduct. 1H NMR (400 MHz, Chloroform-d) δ 3.67 (t, 0.6H), 3.53 (t, 1.4H), 2.62 (t, 2H), 2.43-2.28 (m, 2H). 5-Chloro-4,4-difluoro-pentanoic acid can be prepared in an analogous fashion by substituting HCl in dioxane for the HBr in acetic acid in Step 1.