Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:7]=[N+:8]([O-:31])[CH:9]=[C:10]([Cl:30])[C:11]=1[CH2:12][C@@H:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[C:17]([O:25][CH2:26][CH:27]2[CH2:29][CH2:28]2)[CH:16]=1)[OH:14].[CH:32]1([CH2:35][O:36][C:37]2[CH:49]=[CH:48][C:40]([C:41]([O:43][CH2:44][C:45](O)=[O:46])=[O:42])=[CH:39][C:38]=2[CH2:50][N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)[CH2:34][CH2:33]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[N+:8]([O-:31])[CH:9]=[C:10]([Cl:30])[C:11]=1[CH2:12][C@H:13]([O:14][C:45](=[O:46])[CH2:44][O:43][C:41](=[O:42])[C:40]1[CH:48]=[CH:49][C:37]([O:36][CH2:35][CH:32]2[CH2:34][CH2:33]2)=[C:38]([CH2:50][N:51]2[CH2:52][CH2:53][O:54][CH2:55][CH2:56]2)[CH:39]=1)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[C:17]([O:25][CH2:26][CH:27]2[CH2:29][CH2:28]2)[CH:16]=1
Reactant: O=C(O)COC(=O)c1ccc(OCC2CC2)c(CN2CCOCC2)c1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(COC(=O)c1ccc(OCC2CC2)c(CN2CCOCC2)c1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
EDC (82 mg, 0.429 mmol) was added to a solution of compound (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (120 mg, 0.286 mmol), 2-(4-(cyclopropylmethoxy)-3-(morpholinomethyl)-benzoyloxy)acetic acid (300 mg, 0.859 mmol) and DMAP (18 mg, 0.143 mmol) in DCM (1 ml) at RT under nitrogen atmosphere. The mixture was stirred at RT overnight. The mixture was then diluted with DCM and washed with NaHCO3 sat. sol., HCl 0.1N and brine. The organic phase was dried over Na2SO4, and the solvent was evaporated. The crude was purified through Preparative HPLC to give (S)-3,5-dichloro-4-(2-(2-(4-(cyclopropylmethoxy)-3-(morpholinomethyl)-benzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-ethyl)pyridine 1-oxide (150 mg, 70% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].N1C(C)=CC=CC=1C>CC#N>[C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)[CH2:20][C:21]([O:23][CH3:24])=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCNc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)CBr
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: COC(=O)CN(CCC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Temperature: 115 °C
Yield: 71.4 %

Procedure:
A neat solution of 8.82 g (30.39 mmol) of 3-(3,4-dichloro-phenylamino)-propionic acid tert-butyl ester, 13.97 ml (151.97 mmol) of methyl bromoacetate and 17.64 ml (151.97 mmol) of 2,6-lutidine was stirred 14 h at 60° C., diluted with 20 ml of CH3CN and heated at 115° C. for 6 h. The reaction was then partitioned between aq. 10% KHSO4 solution and EtOAc (3×). The organic phases were washed with aq. 10% NaCl solution, dried over Na2SO4 evaporated and purified by flash silica gel column (n-heptane:EtOAc 95:5 to 9:1) to yield 7.86 g (71%) of the title compound as an yellow oil. MS: 362.0 (MH+, 2Cl).
Reaction SMILES: C([O:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)C.[N+:12]([C:15]1[CH:16]=[CH:17][C:18](F)=[C:19]([CH3:21])[CH:20]=1)([O-:14])=[O:13].C(N(CC)C(C)C)(C)C>CS(C)=O>[OH:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:20][C:19]=2[CH3:21])[CH2:10][CH2:11]1
Reactant: CCOCCN1CCNCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCN(CCO)CC1

Procedure:
In the same manner as in Production Example 5-1, but using 4-(2-ethoxyethyl)piperazine in place of N-ethylpiperazine used in Production Example 5-1, using 5-nitro-2-fluorotoluene in place of 2-fluoro-5-nitrobenzyl alcohol, using N,N-diisopropylethylamine in place of potassium carbonate, and using dimethylsulfoxide in place of N-methylpyrrolidone, the entitled compound was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([S:10][C:11]3[N:16]=[N:15][CH:14]=[CH:13][CH:12]=3)=[C:7]([CH3:17])[C:6]=2[CH:18]=1.Cl.[O:20]1CCOCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([S:10][C:11]3[CH:12]=[CH:13][C:14](=[O:20])[NH:15][N:16]=3)=[C:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: C1COCCO1
Reactant: Cc1c(Sc2cccnn2)oc2ccc(Cl)cc12
Agent: Cl
Product: Cc1c(Sc2ccc(=O)[nH]n2)oc2ccc(Cl)cc12
Yield: 73 %

Procedure:
A mixture of 6-(5-chloro-3-methyl-benzofuran-2-sulfenyl)-pyridazine (1.6 mmol, 500 mg), conc. HCl (1 mL), and dioxane (5 mL) was heated at 1000C for 2 hours. The reaction mixture was cooled and evaporated to dryness. Water (10 mL) was added to the residue, and the resulting white precipitate was collected and crystallized from ethanol to obtain the desired product, 6-(5-chloro-3-methyl-benzofuran-2-sulfenyl)-2-H-pyridazin-3-one (73%, 113 mg); mp>240° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH:24]([NH:27][CH2:28][CH2:29][NH2:30])([CH3:26])[CH3:25]>>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:30][CH2:29][CH2:28][NH:27][CH:24]([CH3:26])[CH3:25])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][CH:10]([CH2:16]3)[CH2:9]1)[CH2:17]2)=[O:5]
Reactant: CC(C)NCCN
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Product: CC(C)NCCNCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 16.7 %

Procedure:
Synthesized as in Example 26 using 2-chloro-5-formyl-N-(tricyclo [3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.500 g, Example 25b) and N-isopropylethylenediamine (0.186 g) to give the title compound as a solid (0.105 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([C:17]1[NH:18][CH:19]=[C:20]([N+:22]([O-])=O)[N:21]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl.CN(C)CCCN=C=NCC.[C:37]([O:41][C:42]([NH:44][C:45]([CH3:64])([CH3:63])[C:46]([NH:48][C@H:49]([CH2:53][C:54]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[NH:56][CH:55]=1)[C:50](O)=[O:51])=[O:47])=[O:43])([CH3:40])([CH3:39])[CH3:38]>[Pd].O1CCCC1>[C:37]([O:41][C:42]([NH:44][C:45]([CH3:64])([CH3:63])[C:46]([NH:48][C@H:49]([CH2:53][C:54]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[NH:56][CH:55]=1)[C:50]([NH:22][C:20]1[N:21]=[C:17]([CH:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:18][CH:19]=1)=[O:51])=[O:47])=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CCOC(=O)C(c1ccc2ccccc2c1)c1nc([N+](=O)[O-])c[nH]1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(c1ccc2ccccc2c1)c1nc(NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)c[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.1 %

Procedure:
A mixture of ethyl 2-(2-naphthyl)-2-(4-nitroimidazolyl)acetate (2.04 grams, 6.27 mmol), tetrahydrofuran (20 mL), and 10% palladium on carbon (2.04 gram) was hydrogenated at ambient temperature and pressure until complete as determined by hplc (20 hours). The catalyst was removed by filtration and rinsed with tetrahydrofuran (10 mL). The filtrate was added to a slurry consisting of 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (1.20 grams, 6.27 mmol), tetrahydrofuran (10 mL), and (2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indol-3-ylpropanoic acid (2.44 grams, 6.27 mmol) and stirred 16 hours at ambient temperature. The reaction mixture was partitioned between water (150 mL) and ethyl acetate (3×50 mL). The organic extracts were combined, washed with saturated sodium chloride solution, dried using sodium sulfate, and evaporated. The resulting crude oil was purified by column chromatography on silica gel with hexane:ethyl acetate:methanol (10:10:1) as an eluent giving 1.72 grams (41%) of ethyl 2-(4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indol-3-ylpropanoyl amino)imidazolyl]-2-(2-naphthyl)acetate. A 0.2 gram sample was further purified using preparative reverse phase hplc to give 0.16 grams of ethyl 2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino)-3-indol-3-ylpropanoyl amino)imidazolyl]-2-(2-naphthyl)acetate for analytical study. MS (FIA) m/z 667.4 [(M+H)+]. Anal. calcd. exact mass for C37H43N6O6 [(M+H)+]=667.3244. Exact mass found by mass spectrometry: C37H43N6O6 [(M+H)+]=667.3254. 1H nmr (CDCl3): 1.25-1.42 (m, 19H), 3.24-3.33 (m, 2H), 4.28-4.33 (m, 2H), 4.98-5.01 (m, 1H), 5.94 (s, 1H), 6.85-7.01(m, 3H), 7.18-7.21 (m, 2H), 7.35-7.39 (m, 2H), 7.49-7.58 (m, 4H), 7.78-7.84 (m, 4H), 8.69 (s, 1H), 10.65 (s, broad, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]3)[C:9]2=[NH:12])=[CH:4][CH:3]=1.O=[C:21]([CH3:25])[C:22](=[S:24])[NH2:23]>CO>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([C:9]42[NH:23][C:22](=[S:24])[C:21]([CH3:25])=[N:12]4)[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]3)=[CH:4][CH:3]=1
Reactant: COC1CCC2(CCc3ccc(Br)cc3C2=N)CC1
Reactant: CC(=O)C(N)=S
Solvent: CO
Product: COC1CCC2(CCc3ccc(Br)cc3C23N=C(C)C(=S)N3)CC1
Temperature: 60 °C
Yield: 43.2 %

Procedure:
7′-Bromo-4-methoxy-3′,4′-dihydro-1′H-spiro[cyclohexane-1,2′-naphthalen]-1′-imine (Intermediate 14, 0.350 g, 1.09 mmol) and 2-oxopropanethioamide (Intermediate 1, 0.336 g, 3.26 mmol) were dissolved in dry MeOH (5 mL) and the resulting orange solution was heated at 60° C. under N2 (g) overnight. The mixture was concentrated and purified by flash column chromatography using a gradient of 0-10% EtOAc in heptane to give the title compound (0.192 g, 43% yield): MS (ES+) m/z 407.12 [M+H]+.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=O)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].C(=O)(O)[O-].[Na+].[NH2:19][O:20][CH2:21][C:22]([NH2:24])=[O:23].Cl>O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:19][O:20][CH2:21][C:22](=[O:23])[NH2:24])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: NOCC(N)=O
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.2 %

Procedure:
To a solution of 2-(2-formamidothiazol-4-yl)glyoxylic acid (4.63 g.) and sodium bicarbonate (1.95 g.) in water (230 ml.) was added 2-aminooxyacetamide (2.5 g.) and the mixture was stirred at room temperature for 6 hours while keeping at pH 5. After adjusting the solution to pH 1.5 with 10% hydrochloric acid, the precipitates were collected by filtration, washed with water and dried to give 2-(2-formamidothiazol-4-yl)-2-carbamoylmethoxyiminoacetic acid (syn isomer, 3.6 g.), mp 195° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([CH3:26])[C:23]([OH:25])=[O:24])=[CH:17][C:16]=2[C:27]([F:30])([F:29])[F:28])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:62]([NH:65][CH2:66][CH2:67]O)(=[O:64])[CH3:63]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([CH3:26])[C:23]([O:25][CH2:67][CH2:66][NH:65][C:62](=[O:64])[CH3:63])=[O:24])=[CH:17][C:16]=2[C:27]([F:30])([F:28])[F:29])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1
Reactant: CC(Cc1ccc(OCc2cc(Cl)cc3c2OC(C)(C)C3)c(C(F)(F)F)c1)C(=O)O
Reactant: CC(=O)NCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)NCCOC(=O)C(C)Cc1ccc(OCc2cc(Cl)cc3c2OC(C)(C)C3)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A solution of 3-(4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)-2-methylpropanoic acid (38) (50 mg, 0.113 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (54.3 mg, 0.169 mmol), and diisopropylethylamine (39.3 μL, 0.225 mmol) in DMF (1.5 mL) was stirred at room temperature for 30 min, then N-acetylethanolamine (23 mg, 0.226 mmol) was added. The reaction mixture was stirred at room temperature overnight. After evaporation of solvent in vacuo, the residue was purified by preparative HPLC to afford 2-acetamidoethyl 3-(4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)-2-methylpropanoate (155) (45 mg, 70%). 1H NMR (400 MHz, CDCl3) δ: 7.39 (s, 1H), 7.04 (m, 2H), 7.05-7.00 (m, 2H), 5.47 (br, 1H), 5.06 (s, 2H), 4.10 (m, 2H), 3.44-3.37 (m, 2H), 3.05 (s, 2H), 2.96-2.91 (m, 1H), 2.76-2.66 (m, 2H), 1.93 (s, 3H), 1.49 (s, 6H), 1.19 (d, J=6.8 Hz, 3H). LC-MS ESI m/z: found 528.0 [M−H]−.
Reaction SMILES: CC(OC([N:8]([C:16]1[NH:17][C:18]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([O:33][C:34]3[CH:39]=[C:38]([CH:40]4[CH2:42][CH2:41]4)[CH:37]=[C:36]([C:43]#[N:44])[CH:35]=3)[C:27]=2[F:45])=[O:23])=[C:19]([Cl:21])[N:20]=1)C(OC(C)(C)C)=O)=O)(C)C.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>C(Cl)Cl>[F:49][C:48]([F:51])([F:50])[C:46]([OH:52])=[O:47].[NH2:8][C:16]1[NH:17][C:18]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([O:33][C:34]3[CH:39]=[C:38]([CH:40]4[CH2:42][CH2:41]4)[CH:37]=[C:36]([C:43]#[N:44])[CH:35]=3)[C:27]=2[F:45])=[O:23])=[C:19]([Cl:21])[N:20]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(C#N)cc(C4CC4)c3)c2F)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(N)nc3Cl)c2F)cc(C2CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
To a solution of bis(1,1-dimethylethyl)(4-chloro-5-{[({4-chloro-3-[(3-cyano-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-imidazol-2-yl)imidodicarbonate (161 mg, 0.244 mmol) in DCM (5 ml) was added TFA (2.5 ml) and the reaction mixture was stirred at RT for 3 hours. The solvent was removed and the crude material was purified via reverse phase HPLC to give 2-amino-4-chloro-N-({4-chloro-3-[(3-cyano-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide trifluoroacetate (59 mg, 0.103 mmol, 42% yield).
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1>C1COCC1>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:20]2([OH:23])[CH2:21][CH2:22][O:17][CH2:18][CH2:19]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: O=C1CCOCC1
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc(OCc3ccccc3)cc2)CCOCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
In a 100 ml round-bottomed flask was placed magnesium turnings (1.85 g, 76.1 mmol), which was stirred under vacuum without solvent overnight. To it were slowly added anhydrous THF 40 ml and 4-benzyloxy bromobenzene (10 g, 38 mmol) over 15 min with occasional heating by a heat gun to keep the Grignard reagent formation going. After the addition was complete, the resulting gray slurry was stirred for 1 hr at 60° C. To it was added tetrahydro-4H-pyran-4-one (3.5 ml, 38 mmol) upon cooling in an ice-water bath. After stirring for 30 min, the solvent was removed under reduced pressure and diluted with AcOEt and sat. NH4Cl aq. The organic phase was separated, concentrated, and chromatographed on silica gel eluting with 40% AcOEt/hexanes to give 4-(4-benzyloxyphenyl)tetrahydro-2H-pyran-4-ol 5.95 g (55%).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2Cl)(=[O:5])=[O:4].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23][NH2:24]>CO>[CH3:1][N:2]([CH3:18])[S:3]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2[NH:24][CH2:23][C:22]1[CH:25]=[CH:26][C:27]([Cl:28])=[C:20]([Cl:19])[CH:21]=1)(=[O:5])=[O:4]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(Cl)c2cccc(S(=O)(=O)N(C)C)c2n1
Solvent: CO
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(S(=O)(=O)N(C)C)c2n1
Yield: 12.6 %

Procedure:
4-Chloro-2-methylquinoline-8-sulfonic dimethylamide (80 mg, 0.281 mmole) and 3,4-dichlorobenzylamine (100 mg, 0.568 mmole) were stirred at 155° C. for 10 min in a microwave oven. Methanol was added and the mixture was concentrated, mixed with dichloromethane and then filtered. The residue was purified using silica gel chromatography, eluting with dichloromethane:methanol 95:5. Precipitation in ethyl acetate gave a pink solid (15 mg, 13%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:24]1[S:28][C:27]([C:29]2[CH:30]=[CH:31][C:32]3[CH2:39][CH:38]4[C:40]5([CH2:44][N:43]([CH2:45][C:46]([F:49])([F:48])[F:47])[S:42](=[O:51])(=[O:50])[NH:41]5)[CH:35]([CH2:36][CH2:37]4)[CH2:34][C:33]=3[CH:52]=2)=[N:26][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:24]2[S:28][C:27]([C:29]3[CH:30]=[CH:31][C:32]4[CH2:39][CH:38]5[C:40]6([CH2:44][N:43]([CH2:45][C:46]([F:47])([F:48])[F:49])[S:42](=[O:51])(=[O:50])[NH:41]6)[CH:35]([CH2:36][CH2:37]5)[CH2:34][C:33]=4[CH:52]=3)=[N:26][CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(Br)s3)ccc2C1
Product: CC(C)(C)OC(=O)N1CC=C(c2cnc(-c3ccc4c(c3)CC3CCC(C4)C34CN(CC(F)(F)F)S(=O)(=O)N4)s2)CC1

Procedure:
Prepared from the boronate from Step 2 and the bromide from Example 36, Step 2 by the method described for Example 36, Step 3. Contains ˜10% unsubstituted thiazole.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([OH:10])[CH2:9][CH:3]1[CH2:4][CH2:5]2.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][N:2]1[CH:6]2[CH2:5][CH2:4][CH:3]1[CH2:9][CH:8]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:7]2
Reactant: CS(=O)(=O)Cl
Reactant: CN1C2CCC1CC(O)C2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C2CCC1CC(OS(C)(=O)=O)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of tropine (10.0 g, 70.8 mmol), 4-dimethylaminopyridine (80 mg, 0.60 mmol), and triethylamine (11.0 mL, 78.9 mmol) in DCM (125 mL) was cooled to 0° C., charged with methanesulfonyl chloride (5.50 mL, 71.0 mmol), slowly allowed to warm to rt, and stirred for an additional 16 h at rt. The reaction mixture was partitioned between CHCl3 and sat. NaHCO3, and the layers were separated. The aqueous layer was extracted with CHCl3 (3×) and the combined organic fractions were washed with sat. NaHCO3 (2×), brine (2×), dried over Na2SO4, filtered, and concentrated in vacuo resulting in the title compound as a pale brown solid. This material was taken on to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ=1.94-2.09 (m, 6H), 2.20 (dt, J=15.4, 4.2 Hz, 2H), 2.28 (s, 3H), 2.99 (s, 3H), 3.10-3.17 (m, 2H), 4.94 (t, J=5.1 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:14]([O:18][C:19]([N:21]1[C@@H:25]([C@H:26]([OH:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:23][C@H:22]1[CH2:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[OH:33][C@H:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@H:25]1[CH2:24][CH2:23][C@@H:22]([CH2:34][C:35]2[CH:43]=[CH:42][C:38]([C:39]([N:11]3[CH2:12][CH2:13][N:8]([CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:9][CH2:10]3)=[O:40])=[CH:37][CH:36]=2)[N:21]1[C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20]
Reactant: c1ccc(CN2CCNCC2)nc1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)N3CCN(Cc4ccccn4)CC3)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 0.018 g (0.102 mmol) of (1-(pyridine-2-ylmethyl)piperazine and 0.035 g (0.085 mmol) of 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid in 2 mL of N,N-dimethylformamide was added 0.074 mL (0.425 mmol) of N,N-diisopropylethylamine and 0.065 g (0.170 mmol) of HATU. The resulting mixture was stirred under an atmosphere of nitrogen for 3 h and then purified directly by reverse-phase HPLC (TMC Pro-Pac C18; 10-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). LC/MS: m/z (ES) 571.2 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[CH:18]([O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)([CH3:20])[CH3:19]>>[CH2:12]([NH:11][C:9](=[O:10])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([O:21][CH:18]([CH3:20])[CH3:19])[CH:27]=2)=[CH:3][CH:4]=1)([CH3:17])[CH3:16])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)Oc1cccc(B(O)O)c1
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2cccc(OC(C)C)c2)cc1
Yield: 60 %

Procedure:
Prepared in a similar manner to Example 8 from 2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) and 3-isopropoxyphenylboronic acid. Yield: 60%. 1H NMR (400 MHz, CDCl3): δ 0.8 (d, 6H), 1.35 (d, 6H), 1.65 (s, 6H), 1.67-1.70 (m,1H), 3 (m, 2H), 4.6 (m, 1H), 6.9 (dd, 1H), 7.1 (t, 1H), 7.15 (d, 1H), 7.35 (t, 1H), 7.45 (d, 2H), 7.6 (d, 2H). MS (M+H, 354).
Reaction SMILES: [OH:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:17][C:16]([CH3:18])=[C:15]3[C:11]=2[CH2:12][C@H:13]2[C:19]([CH3:21])([CH3:20])[C@H:14]23)=[O:9])=[CH:4][C:3]=1[CH3:25].[OH-].[Na+].[Na+].[I-].Cl[CH2:31][C@@H:32]([OH:35])[CH2:33][OH:34]>C(O)(C)C.C(O)=O>[OH:35][C@@H:32]([CH2:33][OH:34])[CH2:31][O:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:17][C:16]([CH3:18])=[C:15]3[C:11]=2[CH2:12][C@H:13]2[C:19]([CH3:21])([CH3:20])[C@H:14]23)=[O:9])=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(CNC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1O
Reactant: OC[C@H](O)CCl
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CC(C)O
Product: Cc1cc(CNC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OC[C@@H](O)CO
Temperature: 90 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
To a solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3,5-dimethyl-benzylamide (8.9 mg, 0.025 mmol) in isopropanol (1 mL) is added 2 N aq. NaOH (100 μL), NaI (1 mg, 0.007 mmol) and (S)-3-chloro-propane-1,2-diol (11.1 mg, 0.1 mmol). The reaction mixture is heated to 90° C. and shaken for 8 h before it is cooled to rt. Formic acid (0.2 mL) is added and the reaction mixture is separated by prep. HPLC to give (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)-3,5-dimethyl-benzylamide (3.7 mg) as a colourless lyophilisate. LC-MS: tR=0.94 min, [M+1]+=430.27.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C@@H:6]([NH:13][C:14]1[C:19]([NH2:20])=[CH:18][N:17]=[C:16]([CH3:21])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C@@H:6]([N:13]1[C:14]2[CH:15]=[C:16]([CH3:21])[N:17]=[CH:18][C:19]=2[NH:20][C:28]1=[O:29])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](Nc1cc(C)ncc1N)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)[nH]c2cnc(C)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.1 %

Procedure:
To a solution of (R)-3-(5-amino-2-methyl-pyridin-4-ylamino)-3-phenyl-propionic acid ethyl ester (594 mg, 1.98 mmol) in THF (20 mL) was added CDI (483 mg, 2.98 mmol). The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH as an eluent to afford 484 mg (75%) of the title compound as light brown solid. LCMS, M++1, m/z: 326.85.