Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Br)cn2)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
To a 500 mL round-bottomed flask was added 2-amino-5-bromopyridine (15.0 g, 86.7 mmol, Aldrich, St. Louis, Mo.), pyridine (150 mL, 1858 mmol) and finally para-toluenesulfonyl chloride (24.8 g, 130 mmol, Aldrich, St. Louis, Mo.) at rt. The mixture was stirred at 90° C. After 24 h, the mixture was allowed to cool to rt and then poured into water (600 mL). A precipitate formed and the mixture was stirred for 15 min and then filtered. The filtercake was washed with water and hexane and then dried under vacuum to afford the title compound as an off-white solid (27.8 g, 98%) that was carried on without further purification.
Reaction SMILES: [CH2:1]([NH:19][C:20]([O:22][CH2:23][C:24](=[C:27]([CH3:29])[CH3:28])[CH2:25][OH:26])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].BrCCCCCC(O)=O.[Br:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47](O)=[O:48]>>[CH2:1]([NH:19][C:20]([O:22][CH2:23][C:24](=[C:27]([CH3:28])[CH3:29])[CH2:25][O:26][C:47](=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][Br:39])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)=C(C)C
Reactant: O=C(O)CCCCCCCBr
Agent: O=C(O)CCCCCBr
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(COC(=O)CCCCCCCBr)=C(C)C

Procedure:
Following the procedure described in Preparation 9, but replacing 3-octadecylaminocarbonyloxy-2-methylenepropan-1-ol with 3-octadecylaminocarbonyloxy-2-isopropylidenepropan-1-ol (from Preparation 26) and 6-bromohexanoic acid with 8-bromooctanoic acid, the desired product was obtained.
Reaction SMILES: [Na].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].Cl[CH2:12][C:13]1[C:14]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:15]=2[O:16][C:17]=1[CH3:18].Cl>C(O)C.O>[CH2:9]([O:8][C:2]([CH:3]([C:4](=[O:5])[CH3:6])[CH2:12][C:13]1[C:14]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:15]=2[O:16][C:17]=1[CH3:18])=[O:7])[CH3:10]
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1CCl
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(Cc1c(C)oc2c([N+](=O)[O-])cccc12)C(C)=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 42.7 %

Procedure:
To a solution of sodium (52 mg) in ethanol (5 ml) was added ethyl acetoacetate (293 mg) and 3-chloromethyl-2-methyl-7-nitrobenzo[b]furan (339 mg). The mixture was stirred at 60° C. for 3 hours, cooled and poured into cold water. The pH of the aqueous solution was adjusted to 3 with 1N-hydrochloric acid and the separated oil was extracted with dichloromethane. The extract was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from n-hexane to give 3-(2-ethoxycarbonyl-3-oxobutyl)-2-methyl-7-nitrobenzo[b]furan (205 mg).
Reaction SMILES: C1C2C(COC(=O)N[C@H](C([N:25]3[C:29]4=[N:30][CH:31]=[C:32](Br)[CH:33]=[C:28]4[C:27]([C@@H:35]([C:37]4[C:42]([Cl:43])=[CH:41][CH:40]=[C:39]([F:44])[C:38]=4[Cl:45])[CH3:36])=[CH:26]3)=O)CC(C)C)C3C(=CC=CC=3)C=2C=CC=1.Cl.CC1(C)C(C)(C)OB([C:56]2[CH:57]=[N:58][N:59]([CH:61]3[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]3)[CH:60]=2)O1.ClC1C=CC=C(Cl)C=1C(C1C2C(=NC=C(C3C=NN(C4CCNCC4)C=3)C=2)NC=1)C>>[Cl:45][C:38]1[C:39]([F:44])=[CH:40][CH:41]=[C:42]([Cl:43])[C:37]=1[C@H:35]([C:27]1[C:28]2[C:29](=[N:30][CH:31]=[C:32]([C:56]3[CH:57]=[N:58][N:59]([CH:61]4[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]4)[CH:60]=3)[CH:33]=2)[NH:25][CH:26]=1)[CH3:36]
Reactant: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)n1cc([C@H](C)c2c(Cl)ccc(F)c2Cl)c2cc(Br)cnc21
Agent: CC(c1c(Cl)cccc1Cl)c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Agent: Cl
Product: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12

Procedure:
((S)-1-{5-Bromo-3[(S)-1-(2,6-dichloro-3-fluorophenyl)ethyl]-pyrrolo[2,3-b]pyridine-1-carbonyl}-3-methylbutyl)carbamic acid 9H-fluoren-9-ylmethyl ester was treated with 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyrazol-1-yl]piperidine hydrochloride according to typical Suzuki coupling procedure described for synthesis of 3-[1-(2,6-Dichlorophenyl)ethyl]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine in example 1, to give the title compound. 1H NMR (400 MHz, DMSO-d6): δ=1.70-1.80 (m, 2H), 1.83 (d, J=7.1 Hz, 3H), 1.94 (dd, J=11.6, 2.0 Hz, 2H), 2.08 (br s, 1H), 2.57 (td, J=12.3, 2.3 Hz, 2H), 3.03 (ddd, J=12.6, 2.9, 2.7 Hz, 2H), 4.17 (tt, J=11.6, 4.1 Hz, 1H), 5.16 (q, J=7.2 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 7.36-7.44 (m, 2H), 7.48-7.65 (m, 1H), 7.56 (d, J=0.5 Hz, 1H), 8.03 (s, 1H), 8.39 (d, J=2.0 Hz, 1H), 11.51 (d, J=1.8 Hz, 1H). MS (ES+): m/z 458.07/460.05 (100/70) [MH+]. HPLC: tR=2.53 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Br.[Cl:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:29][C:27](=[O:28])[CH2:26][O:25][C:24]1[CH:30]=[CH:31][C:21]([Cl:20])=[CH:22][CH:23]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(COc1ccc(Cl)cc1)OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
In a reaction vessel were placed 0.20 g of 3,5-dichloro-4-(3-bromopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 0.11 g of 4-chlorophenoxyacetic acid, 0.08 g of potassium carbonate and 5 ml of N,N-dimethylformamide, followed by stirring at room temperature for 12 hours. The reaction mixture was poured into water, and extracted twice with 30 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.23 g of 3,5-dichloro-4-(3-(4-chlorophenoxyacetyloxy)propyloxy)-1-(3,3-dichloro-2-propenyloxy) benzene (91% yield), nD22.0 1.5709.
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[OH:5][CH:6]([CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1>C1(C)C=CC=CC=1.[OH-].[K+]>[ClH:3].[ClH:3].[OH:5][CH:6]([CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:15][CH2:16][N:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:1]2=[O:2])[CH2:10][CH2:9]1
Reactant: COc1ccccc1OCC(O)CN1CCC(NCCNc2ccncc2)CC1
Reactant: O=C(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccccc1OCC(O)CN1CCC(N2CCN(c3ccncc3)C2=O)CC1
Product: Cl

Procedure:
With stirring, 392 ml of an approx. 20% solution of phosgene in toluene are added dropwise at a reaction temperature of 5° to 10° C in the course of 1 hour to a mixture of 31.5 g of 1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-[2-(4-pyridylamino)-ethylamino]-piperidine in 300 ml of toluene and 126 ml of 3N aqueous potassium hydroxide solution. Thereafter 120 ml of a 6N aqueous potassium hydroxide solution are added dropwise at the same temperature in the course of 30 minutes. The reaction mixture is further stirred for 30 minutes at 10° C and for 20 hours at room temperature. The aqueous acid phase is separated, concentrated to a volume of approx. 50 ml and made alkaline with a concentrated aqueous solution of ammonia. The emulsion is extracted with four 75 ml portions of methylene chloride. The combined methylene chloride phases are dried over sodium sulphate and concentrated. The residue is chromatographed through a column of 800 g of silica gel using a 9:1 mixture of methylene chloride and methanol as eluant. The purified 1-{1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-piperidyl}-3-(4-pyridyl)-imidazolidin-2-one is taken up in methanol and the solution is acidified with methanolic hydrochloric acid. The acid solution is concentrated under reduced pressure. The residue is treated with toluene and recrystallised from a mixture of methanol and diethyl ether to yield the 1-{1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-piperidyl}-3-(4-pyridyl)-imidazolidin-2-one-dihydrochloride in the form of the hemihydrate; m.p. 230°-234° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH:42]([CH2:47][F:48])[CH2:41]3)=[CH:36][N:35]=2)[C:30](=[O:49])[N:29]([CH3:50])[CH:28]=1)(=O)C.O[Li].O>CC(O)C.C1COCC1.O>[F:26][C:9]1[CH:8]=[C:7]([C:27]2[CH:32]=[C:31]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([N:40]4[CH2:45][CH2:44][N:43]([CH3:46])[CH:42]([CH2:47][F:48])[CH2:41]4)=[CH:36][N:35]=3)[C:30](=[O:49])[N:29]([CH3:50])[CH:28]=2)[C:6]([CH2:5][OH:4])=[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])[CH:10]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)C(CF)C4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li]O
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)nc2)CC1CF
Temperature: 30 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A mixture of 111h (750 mg, 1.09 mmol) and LiOH hydrate (2.3 g, 55 mmol) in iPrOH (10 mL), THF (10 mL) and H2O (10 mL) was stirred at 30° C. for 1 h. The mixture was evaporated in vacuo, and the residue was extracted with DCM (3×30 mL). The combined extracts were concentrated under reduced pressure. And the residue was purified on silica gel column (DCM: MeOH=50:1) to give 111 as a yellow solid (700 mg, 93%). MS: [M+H]+ 644. 1H NMR (500 MHz, MeOD) δ 8.54 (d, J=2.0 Hz, 1H), 7.93 (d, J=1.5 Hz, 1H), 7.41 (m, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.21 (d, J=9.0 Hz, 2H), 7.02 (d, J=9.0 Hz, 1H), 6.72 (s, 1H), 4.67-4.46 (m, 4H), 4.19 (s, 3H), 4.02 (m, 1H), 3.70 (s, 3H), 3.51 (d, J=11.5 Hz, 1H), 3.42 (d, J=11. Hz, 1H), 3.36 (s, 1H), 2.96 (d, J=11.5 Hz, 1H), 2.85 (m, 1H), 2.73-2.50 (m, 7H), 2.48 (s, 3H), 1.88 (m, 2H), 1.78 (m, 2H)
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Cl:9][CH2:10][CH2:11][C:12](O)=[O:13].FC(F)(F)S(O)(=O)=O.ClCCl>O>[Cl:9][CH2:10][CH2:11][C:12]([C:6]1[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=1[OH:5])=[O:13]
Reactant: O=C(O)CCCl
Reactant: Oc1cccc(O)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(CCCl)c1ccc(O)cc1O
Temperature: 80 °C
Yield: 74.6 %

Procedure:
To a stirred mixture of resorcinol (10 g, 91 mmol) and 3-chloropropanoic acid (9.95 g, 92 mmol) was added trifluoromethanesulfonic acid (50 g, 333 mmol) in one portion. The solution was warmed to 80° C. for 30 min, cooled to room temperature over 15 min, and poured into dichloromethane (200 mL). The resulting solution was slowly poured into water (200 mL), and the layers were separated. The aqueous layer was extracted with dichloromethane (2×100 mL), dried over anhydrous sodium sulfate, and filtered. Concentration under reduced pressure afforded 3-chloro-1-(2,4-dihydroxyphenyl)propan-1-one (13.62 g, 67.9 mmol, 74.8% yield) as an orange semi-solid. The compound was used without any further purification. LC/MS M+1=200; 1H NMR (400 MHz, CDCl3) δ ppm 12.39 (1H, s), 7.56 (1H, d, J=8.58 Hz), 7.19 (1H, s), 6.17-6.49 (1H, m), 5.23 (1H, s), 3.78-4.01 (2H, m), and 3.34 (2H, t, J=6.71 Hz).
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=S)[CH3:6])C.O.[NH2:21][NH2:22]>CCO>[Br:17][C:14]1[CH:13]=[C:12]2[C:11](=[CH:16][CH:15]=1)[O:10][CH2:9][C:8]1[N:7]2[CH:5]([CH3:6])[C:4](=[O:3])[NH:21][N:22]=1
Reactant: CCOC(=O)[C@@H](C)N1C(=S)COc2ccc(Br)cc21
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC1C(=O)NN=C2COc3ccc(Br)cc3N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.3 %

Procedure:
To a mixture of (R)-2-(6-bromo-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (75.2 g, 219 mmol) in EtOH (800 mL) was added hydrazine hydrate (98%, 21.9 g, 438 mmol) and the mixture was stirred at ambient temperature overnight. The precipitate was collected by filtration and washed with cold EtOH (3×80 mL) to give 6-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (6 g, 9%) as a yellow solid. The filtrate was concentrated to give 70 g of crude product, which was purified by chromatography on silica gel (eluting with 10-25% EtOAc in petroleum ether) to give a second batch of (R)-6-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (45.9 g, 71%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.53 (brs, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.03 (s, 1H), 6.89 (d, J=8.4 Hz, 1H), 4.69-4.52 (m, 3H), 1.52 (d, J=6.8 Hz, 3H). SFC (Table 1, Method 32) Rt=6.075 min.; [α]D20=−314.92 (C=0.002 g/mL in methanol).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[C:18]([Cl:33])[CH:17]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7]1.[OH:34][CH2:35][C:36]([CH3:41])([CH3:40])[C:37](O)=[O:38].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[ClH:33].[Cl:33][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:14]3[N:6]([CH2:5][CH2:4][NH:3][C:35](=[O:34])[C:36]([CH3:41])([CH3:40])[CH2:37][OH:38])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Reactant: CC(C)(CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(CO)C(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 15 h
Yield: 141.4 %

Procedure:
A solution of 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg), 3-hydroxy-2,2-dimethylpropanoic acid (68 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (166 mg), 1-hydroxybenzotriazole monohydrate (132 mg) and triethylamine (0.40 mL) in N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 20 hrs. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate→methanol:ethyl acetate=15:85). After concentration under reduced pressure, ethyl acetate (2.0 mL) and 4N hydrochloric acid/ethyl acetate (0.5 mL) were added, and the mixture was stirred at room temperature for 15 hrs. After concentration under reduced pressure, the precipitated crystals were collected by filtration. To a solution of the collected crystals in ethanol (2.0 mL) was added 1N aqueous sodium hydroxide solution at room temperature, and the mixture was stirred for 2 days. The mixture was concentrated under reduced pressure and a solution of the residue in ethyl acetate was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, 4N hydrochloric acid/ethyl acetate (0.5 mL) was added to a solution of the residue in ethyl acetate (1.0 mL). After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to give the title compound (119 mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:25]=[CH:24]3)=[CH:21][CH:22]=2)[C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3]1.Cl.[NH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:1][C:2]1([F:32])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[N:25]=[CH:24]3)=[CH:21][CH:22]=2)[C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:13])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: O=C(O)c1ccc(C(Nc2ccc(-n3cnc(C(F)(F)F)c3)nc2)C2CC(F)(F)C2)cc1
Reactant: CCOC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1ccc(C(Nc2ccc(-n3cnc(C(F)(F)F)c3)nc2)C2CC(F)(F)C2)cc1
Reaction time: 16 h
Yield: 11.5 %

Procedure:
Dimethylformamide (0.270 mL) was added to a vial containing crude 4-((3,3-difluorocyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)methyl)benzoic acid (24.0 mg, approximately 0.120 mmol pure), ethyl 3-aminopropanoate hydrochloride (16.3 mg, 0.110 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (40.3 mg, 0.110 mmol). Diisopropylethylamine (0.046 mL, 0.270 mmol) was then added. The reaction was stirred for 16 h, and was then concentrated. Purification by column chromatography (0-60% ethyl acetate in heptane) afforded ethyl 3-(4-((3,3-difluorocyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)methyl)benzamido)propanoate (7.00 mg) as an oil. MS (M+1): 552.3.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>ClC1C=CC=CC=1.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:5]1([N:11]=[C:1]=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)Cl
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: O=C=NC1CCCCC1
Temperature: 79 °C
Yield: 142.5 %

Procedure:
500 g of chlorobenzene and 7 g of triphenylphosphine oxide (0.025 mol) were placed in the glass vessel and 47 g of gaseous phosgene was introduced at room temperature. The reaction mixture was subsequently heated to 78° C., with vigorous phosgene reflux being established. While stirring vigorously at 78-80° C., a total of 99.2 g of cyclohexylamine (1 mol) dissolved in 200 g of chlorobenzene and at the same time a further 116 g of phosgene were introduced over a period of 3 hours. After addition was complete, the system was maintained at 78-80° C. for a further one hour without introduction of phosgene to allow further reaction to occur and the residual unreacted phosgene was subsequently stripped out at 40° C. by means of nitrogen. The reaction mixture obtained was a fluid suspension from which the solid obtained was separated by filtration. 1.9 g of solid were able to be isolated in this way. The filtered crude product was worked up by distillation. Removal of the solvent and fractional distillation gave 84.6 g of cyclohexyl isocyanate (0.677 mol). This corresponds to 67.7% of the theoretical yield.
Reaction SMILES: CO[C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[CH2:6]1)=[O:4].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][C:28]2=[O:33])=[CH:23][CH:22]=1>>[OH:10][C@H:8]1[CH2:9][C@H:5]([C:3](=[O:4])[NH:20][C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][C:28]3=[O:33])=[CH:25][CH:26]=2)[CH2:6][C@@H:7]1[NH:11][C:12]([C:14]1[S:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[O:13]
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1
Product: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(N3CCOCC3=O)cc2)C[C@@H]1O)c1ccc(Cl)s1

Procedure:
In analogy to example 1C, (1R,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-cyclopentanecarboxylic acid methyl ester (example 1B) was reacted with 4-(4-amino-phenyl)-morpholin-3-one (CAS 438056-69-0) to give 5-chloro-thiophene-2-carboxylic acid {(1S,2S,4R)-2-hydroxy-4-[4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-cyclopentyl}-amide. Yellow solid. MS: 464.4 ([M+H]+)
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[C:24]([F:25])=[C:23]([CH2:26][O:27][C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[C:22]([F:34])=[C:21]([NH:35][C:36](=[O:39])[CH2:37]Cl)[C:17]=3[C:18](=[O:20])[CH:19]=2)=[CH:10][C:9]=1[F:40])=[O:6])[CH:2]=[CH2:3].Cl.[CH3:42][NH:43][CH3:44].C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[CH2:1]([O:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[C:24]([F:25])=[C:23]([CH2:26][O:27][C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[C:22]([F:34])=[C:21]([NH:35][C:36](=[O:39])[CH2:37][N:43]([CH3:44])[CH3:42])[C:17]=3[C:18](=[O:20])[CH:19]=2)=[CH:10][C:9]=1[F:40])=[O:6])[CH:2]=[CH2:3]
Reactant: CNC
Reactant: C=CCOC(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)CCl)c(F)c(COC(=O)OCC=C)c(F)c3o2)cc1F
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)CN(C)C)c(F)c(COC(=O)OCC=C)c(F)c3o2)cc1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
To a solution of 2-[4-(allyloxycarbonyl)amino-3-fluorophenyl]-7-[(allyloxycarbonyl)oxy]methyl-5-(chloroacetamido)-6,8-difluoro-4H-1-benzopyran-4-one (2.12 g, 3.65 mmol) in dimethylformamide (40 mL) were added dimethylamine hydrochloride (1.49 g, 18.3 mmol) and diisopropylethylamine (3.2 mL, 18 mmol), and the mixture was stirred at 50° C. for 2 hours. Water was added thereto, and the mixture was extracted with ethyl acetate to afford 2-[4-(allyloxycarbonyl)amino-3-fluorophenyl]-7-[(allyloxycarbonyl)oxy]methyl-5-(dimethylamino)acetamido-6,8-difluoro-4H-1-benzopyran-4-one (2.12 g, 99%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]([C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:16])[C:13]([O:27]C)=[N:12][C:11]([CH3:29])=[C:10]2[C:30]([O:32][CH3:33])=[O:31])[CH:5]=[CH:6][C:7]=1[F:8].[Br:34]Br>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]([C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:16])[C:13](=[O:27])[NH:12][C:11]([CH2:29][Br:34])=[C:10]2[C:30]([O:32][CH3:33])=[O:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: BrBr
Reactant: COC(=O)C1=C(C)N=C(OC)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)c(F)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1=C(CBr)NC(=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)c(F)c1
Reaction time: 1.5 h
Yield: 102.6 %

Procedure:
To a well stirred solution of (+)-6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (1.5 mmol, 0.66 g) in 5 mL of chloroform was added a solution of bromine (1.5 mmol, 0.09 mL) in 3 mL of chloroform at 0° C. and the solution was allowed to attain room temperature over 1.5 h. The solvent was removed in vacuo and the residue was again dissolved in CHCl3, (20 mL) and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and the solvent was removed in vacuo to get 0.81 g of (+)-6-(3,4-difluorophenyl)-1,6-dihydro-2-oxo-5-methoxycarbonyl-4-bromomethyl-1-[(4-nitrophenyloxy)carbonyl]pyrimidine as a yellow foam. It was used in the next step without any purification. 1H NMR δ3.75 (s, 3 H), 4.67 (ABq, dA=4.56, dB=4.78, J=10.8 Hz, 2 H), 6.35 (s, 1 H), 7.09-7.19 (m, 4 H), 7.37 (d, J=9.0 Hz, 2 H), 8.27 (d, J=9.0 Hz, 2 H).