Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]2[S:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)=[CH:10][C:5]=2[C:6](=O)[NH:7][CH:8]=1)#[N:2].P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:6]1[C:5]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[S:12][C:4]=2[C:3]([C:1]#[N:2])=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccc(-c2cc3c(=O)[nH]cc(C#N)c3s2)cc1
Product: CC(C)(C)c1ccc(-c2cc3c(Cl)ncc(C#N)c3s2)cc1
Reaction time: 1 h

Procedure:
7-Cyano-2-(4′-t-butylphenyl)-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine was dissolved in phosphorus oxychloride (25 mL) and the resulting solution heated at reflux for 2 h. After this time the mixture was poured into ice and stirred for 1 h. The precipitated solid was filtered and washed with water, drying by suction in air at room temperature affording 1.05 g of 101. 1H NMR (300 MHz, d6-DMSO) δ 8.83 (s, 1H), 8.11 (s, 1H), 7.92 (d, 2H), 7.56 (d, 2H), 1.34 (s, 9H).
Reaction SMILES: [OH:1][C@H:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:21][C:22]1[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[C:24]([CH:30]2[CH2:32][O:31]2)[N:23]=1>>[OH:31][CH:30]([C:24]1[N:23]=[C:22]([CH3:21])[C:27]([C:28]#[N:29])=[CH:26][CH:25]=1)[CH2:32][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][C@H:2]([OH:1])[C:10]2[C:11]([CH3:20])=[C:12]3[C:13](=[CH:18][CH:19]=2)[C:14](=[O:17])[O:15][CH2:16]3)[CH2:5][CH2:6]1
Reactant: Cc1nc(C2CO2)ccc1C#N
Reactant: Cc1c([C@@H](O)CN2CCNCC2)ccc2c1COC2=O
Product: Cc1nc(C(O)CN2CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)CC2)ccc1C#N

Procedure:
6-[1-Hydroxy-2-[4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-2-methyl-pyridine-3-carbonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 58 starting from 5-[(1R)-1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one and 2-methyl-6-(oxiran-2-yl)pyridine-3-carbonitrile.
Reaction SMILES: ClCCl.[F:4][C:5]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[C:6]=1[C:7]([C:9]1[CH:10]=[C:11]([C:14]([OH:16])=[O:15])[NH:12][CH:13]=1)=[O:8].[N+](=[CH2:25])=[N-]>C(OCC)C>[F:4][C:5]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[C:6]=1[C:7]([C:9]1[CH:10]=[C:11]([C:14]([O:16][CH3:25])=[O:15])[NH:12][CH:13]=1)=[O:8]
Reactant: O=C(O)c1cc(C(=O)c2c(F)cc(F)cc2F)c[nH]1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)c2c(F)cc(F)cc2F)c[nH]1
Reaction time: 3 h

Procedure:
To a dichloromethane 70 mL suspension of 4-(2,4,6-trifluorobenzoyl)-1H-pyrrole-2-carboxylic acid (Intermediate 1) (3 g, 11.2 mmol) was added diazomethane solution in diethyl ether upon cooling in an ice-water bath. After stirring for 3 hr, the reaction mixture was concentrated and chromatographed on silica gel eluting with a gradient solvent mixture of AcOEt and hexanes to give the title compound (2.74 g).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[S:15][C:7]2=[N:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:6]2[CH2:5][CH2:4]1.[H-].[Na+].[CH:18](Br)=[CH:19][C:20](=[CH2:22])[CH3:21].O>O1CCCC1>[CH:18]([O:1][CH2:2][CH:3]1[S:15][C:7]2=[N:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:6]2[CH2:5][CH2:4]1)=[CH:19][C:20](=[CH2:21])[CH3:22]
Reactant: C=C(C)C=CBr
Reactant: OCC1CCn2c(nc3ccccc32)S1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)C=COCC1CCn2c(nc3ccccc32)S1
Reaction time: 3 h
Yield: 32.3 %

Procedure:
To a solution of one gram of 3,4-dihydro-2-hydroxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole in dry tetrahydrofuran (20 ml) was treated with 0.5 g of 50% sodium hydride containing mineral oil at 0° C. under stirring. The mixture was stirred for 1 hr, then one gram of isoprenylbromide was added, and the stirring was continued for three hours at room temperature. The reaction mixture was condensed under reduced pressure. The residue was added with water and then extracted with chloroform, and dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure. The residue was chromatographed on silica gel and eluted with chloroform to obtain 0.42 g (yield: 30%) of the intended product, m.p. 56°-60° C.;
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.C([Li])(C)(C)C.[C:17](=[O:19])=[O:18]>>[CH3:11][C:3]1[C:2]([C:17]([OH:19])=[O:18])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][NH:7]2
Reactant: O=C=O
Reactant: Cc1c(Br)ccc2[nH]ncc12
Agent: [Li]C(C)(C)C
Product: Cc1c(C(=O)O)ccc2[nH]ncc12

Procedure:
This compound was prepared in a manner similar to the preparation of 88 using commercially available 4-bromo-2,3-dimethylaniline as starting material. After an acylation step, N-(4-bromo-2,3-dimethylphenyl)acetamide was treated with isoamyl nitrite, then 10% aqueous HCl to yield 5-bromo-4-methyl-1H-indazole. 5-bromo-4-methyl-1H-indazole was treated with t-butyl lithium and carbon dioxide to yield 4-methyl-1H-indazole-5-carboxylic acid, which in turn was treated with thiosemicarbazide and polyphorsphoric acid to form 5-(4-methyl-1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine. MS (API-ES) m/z (%): 232 (100%, M++1).
Reaction SMILES: Br[C:2]1[N:3]([CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([Cl:12])[N:5]=2.[OH-:20].[Na+].[CH3:22]O>CO.CS(C)=O>[Cl:12][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([O:20][CH3:22])[N:3]2[CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:8]([NH2:11])[N:7]=1
Reactant: [OH-]
Reactant: Nc1nc(Cl)nc2c1nc(Br)n2CC1CCOCC1
Reactant: CO
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1nc2c(N)nc(Cl)nc2n1CC1CCOCC1
Temperature: 25 °C

Procedure:
To a solution of 8-bromo-2-chloro-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (1.36 g) in dry MeOH (27.5 mL) was added 1M sodium hydroxide solution (27.5 mL) and the mixture was stirred at reflux for 30 mins. The reaction was cooled to room temperature and concentrated in vacuo. The residue obtained was triturated with water (60 mL) and extracted with EtOAc (120 mL). The organic layer was washed with brine (60 mL), dried over MgSO4, filtered and concentrated in vacuo to give a pink/white solid. The material was taken up in MeOH/DMSO (1:1) and a precipitate crashed out of solution. The solid was filtered off and the filtrate was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (10-45%). The filtered solid was combined with the material obtained from the purification to give the title compound (192 mg).
Reaction SMILES: O1C2C=CC(O)=CC=2OC1.[O:11]1[C:15]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12]1.C1(CCN2C3C(=CC=CC=3)C(=O)C2=O)CC1.[C:37]1([CH:43]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[N:44]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46](=[O:53])[C:45]2=[O:54])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:55]1([CH:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:44]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]([OH:53])([C:18]3[C:17]([OH:20])=[CH:16][C:15]4[O:11][CH2:12][CH2:13][C:14]=4[CH:19]=3)[C:45]2=[O:54])[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: Oc1ccc2c(c1)OCC2
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)OCC2

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1,3-benzodioxol-5-ol with 2,3-dihydrobenzofuran-6-ol (Foster et al., J. Chem. Soc. 1948:2254-2258) and 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with 1-(diphenylmethyl)-1H-indole-2,3-dione, the title compound was obtained (68%) as a white solid: MS (ES+) m/z 450.4 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]2([CH3:24])[CH3:23].[Br-:25].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[Br:25][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]3([CH3:24])[CH3:23])[C:5]=1[O:9][CH3:10]
Reactant: [Br-]
Reactant: COc1cccc(OC)c1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(Br)c(OC)c1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of 6-(2,6-dimethoxyphenyl)-1,1,4,4-tetramethy-1,2,3,4-tetrahydronaphthlene (340 mg, 1.05 mmol) in dichloromethane (10 mL) was added pyridinium tribromide (335 mg, 1.05 mmol) and the reaction mixture stirred at room temperature overnight. The solution was diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (eluent: ethyl acetate/hexane, 0.5:9.5) to give 0.24 g (57%) of 6-(5-bromo-2,6-dimethoxyphenyl)-1,1,4,4-tetramethy-1,2,3,4-tetrahydronaphthlene. 1H NMR (500 MHz; CDCl3): δ1.28 (s, 6 H); 1.31 (s, 6 H); 1.70 (s, 4 H); 3.35 (s, 3 H); 3.73 (s, 3 H); 7.14 (dd, J1=1.5 Hz, J2=8.5 Hz, 1 H); 7.15 (dd, J1=2.0 Hz, J2=8.5 Hz, 1H); 7.30 (d, J=8.0 Hz, 1H); 7.36 (d, J=1.5 Hz, 1H); 7.45 (d, J=8.0 Hz, 1 H), 7.95 (br, 1 H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH:18]=[CH:17][C:16]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:15][C:14]=1[CH2:13][C@H:12]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35]C(=O)C)(=[O:3])[CH3:2].[OH-].[Na+]>CO.C(OCC)C>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH:18]=[CH:17][C:16]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:15][C:14]=1[CH2:13][C@H:12]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCCCO)Cc4cc(OC5CCCCO5)ccc4[C@H]3CC[C@]12C

Procedure:
A solution of 10.2 g of 17β-acetoxy-7α-(5-acetoxypentyl)-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-triene in 205 ml of methanol is stirred with 33.7 ml of sodium hydroxide solution for 45 minutes at 15° C. Then, it is diluted with diethyl ether, washed with water, dried on sodium sulfate and concentrated by evaporation in a vacuum. 5.6 of 17β-acetoxy-7α-(5-hydroxypentyl)-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-triene is obtained. [αD22=+32.2° (c=0.505% in chloroform)
Reaction SMILES: C(OC([NH:8][C:9]([C:11]1[CH:52]=[CH:51][C:14]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH:25]([C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)[CH2:26][C:27]([O:29]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:28])[C:21](=[O:49])[C:20]2=[O:50])=[CH:13][CH:12]=1)=[NH:10])=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH:25]([C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)[CH2:26][C:27]([OH:29])=[O:28])[C:21](=[O:49])[C:20]2=[O:50])=[CH:51][CH:52]=1)(=[NH:8])[NH2:10]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(OCCCN2CCN(C(CC(=O)OC(c3ccccc3)c3ccccc3)c3cccnc3)C(=O)C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N=C(N)c1ccc(OCCCN2CCN(C(CC(=O)O)c3cccnc3)C(=O)C2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
A mixture of 2.3 g of diphenylmethyl 3-[4-[3-(4-tert-butoxycarbonylamidinophenoxy)propyl]-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)propionate, 18.5 ml of anisole and 37 ml of trifluoroacetic acid was stirred at room temperature for 3 hours and then distilled under reduced pressure to remove the solvent. The resulting residue was suspended in a mixed solvent of 15 ml of ethyl acetate and 13 ml of water, followed by adding thereto 0.55 g of sodium hydrogencarbonate, and the resulting mixture was stirred at room temperature for 30 minutes. The aqueous layer was separated, adjusted to pH 3.5 with a saturated aqueous sodium hydrogencarbonate solution, and then concentrated to a volume of about 10 ml under reduced pressure. The resulting concentrate was purified by a reversed phase column chromatography (eluent: 25% aqueous acetonitrile solution) to obtain 0.82 g of 3-[4-[3-(4-amidinophenoxy)propyl]-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)propionic acid as colorless crystals.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5]C=CC=1.CC(C)([O-])C.[Na+].[C:14]([O:19][CH2:20]CCC)(=[O:18])[C:15]([CH3:17])=[CH2:16]>C1C=CC=CC=1>[CH3:7][CH:1]([O:19][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])[CH2:6][CH3:5].[C:14]([O:19][CH3:20])(=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: Cc1ccccc1
Reactant: C=C(C)C(=O)OCCCC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C=C(C)C(=O)OC
Product: C=C(C)C(=O)OC(C)CC
Reaction time: 0.07 h
Yield: 71 %

Procedure:
Similarly as in Example 1, the charge consisted of 48.2 ml of toluene and 0.0343 mol of MMA. The initiator prepared from 0.000286 mol of LiA, 0.00172 mol of sodium tert-butoxide, and 2.8 ml of benzene was added at 20° C. under stirring. After 4 minutes, 0.0343 mol of n-butyl methacrylate was added and the mixture was allowed to react for 1 hour. The block copolymer poly/methyl methacrylate -b- n-butyl methacrylate) was then isolated in the yield of 71%.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:11]=[C:10]([CH2:12][CH:13]=O)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][N:26]([CH2:13][CH2:12][C:10]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:3][CH:2]([F:15])[F:1])[CH:11]=2)[CH2:25][CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1ccc(CC=O)cc1OC(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CCc2ccc(C#N)c(OC(F)F)c2)CC1
Yield: 27.3 %

Procedure:
A solution of crude compound 2-(difluoromethoxy)-4-(2-oxoethyl)benzonitrile (100 mg, 0.48 mmol), N-Boc Piperazine (100 mg, 0.54 mmol) and NaBH(OAc)3 (0.4 g, 2 mmol) in 20 mL of anhydrous DCM was stirred at ambient temperature overnight. The reaction mixture was added 50 mL of DCM, washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified with prep-TLC to afford tert-butyl-4-{2-[4-cyano-3-(difluoromethoxy)phenyl]ethyl}piperazine-1-carboxylate (50 mg, 27% yield). The material was further treated with TFA to remove the Boc group. The crude product was used directly in the next step. MS: m/e 282 (M+1)+.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].Cl.[NH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:12])=[CH:13][CH:14]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(O)c1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC(O)c1ccc(C(=O)NCCC(=O)OCC)cc1
Reaction time: 16 h
Yield: 92.5 %

Procedure:
N,N-dimethylformamide (8.60 mL) was added to a vial containing 4-(1-hydroxybutyl)benzoic acid (250 mg, 1.29 mmol), ethyl 3-aminopropanoate hydrochloride (395 mg, 2.57 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (979 mg, 2.57 mmol). Diisopropylethylamine (1.12 mL, 6.44 mmol) was then added. The reaction was stirred for 16 h, and was then concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) afforded ethyl 3-(4-(1-hydroxybutyl)benzamido)propanoate (350 mg, 93% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=8.2 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 6.84 (br.s., 1H), 4.74 (t, J=6.5 Hz, 1H), 4.23-4.07 (m, 2H), 3.72 (q, J=5.9 Hz, 2H), 2.64 (t, J=5.9 Hz, 2H), 1.85-1.72 (m, 1H), 1.72-1.58 (m, 1H), 1.52-1.37 (m, 1H), 1.37-1.30 (m, 1H), 1.28 (t, J=7.2 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H). MS (M+1) 294.3.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:7][C:8]1[C:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][S:11][N:12]=1)[CH:4]([CH3:6])[CH3:5]>CC(C)=O>[I-:2].[CH2:3]([O:7][C:8]1[C:9]([C:13]2[CH:14]=[N+:15]([CH3:1])[CH:16]=[CH:17][CH:18]=2)=[N:10][S:11][N:12]=1)[CH:4]([CH3:6])[CH3:5]
Reactant: CI
Reactant: CC(C)COc1nsnc1-c1cccnc1
Solvent: CC(C)=O
Product: CC(C)COc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.6 ml, 10 mmol) and 3-(4-iso-butoxy-1,2,5-thiadiazol-3-yl)pyridine (588 mg, 2.5 mmol) in acetone (5 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 0.88 g (87%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9]C)=[O:8])[N:6]=1.Cl[C:12]([O:14][CH3:15])=[O:13].[OH-].[Li+]>N1C=CC=CC=1.C1COCC1.CO>[CH3:15][O:14][C:12]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1)=[O:13]
Reactant: COC(=O)Cl
Reactant: COC(=O)c1csc(N)n1
Agent: [Li+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)Nc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
Methyl 2-aminothiazole-4-carboxylate (1.0 g, 6.32 mmol) was dissolved in dry pyridine and methyl chloroformate (0.733 ml, 9.48 mmol) was added slowly in RT. The reaction mixture was stirred at RT overnight and evaporated to dryness. The evaporation residue was dissolved in dry THF/methanol (9:1) mixture, 1M lithium hydroxide (3.50 ml, 3.50 mmol) was added and the reaction mixture was stirred for 4 h in RT. 1M litium hydroxide (2.33 ml, 2.33 mmol) was added and the mixture was stirred overnight and evaporated to dryness. DCM was added and pH was adjusted to 3. The product was filtered and dried in vacuum. Yield 76%. 1H-NMR (400 MHz; DMSO-d6): δ 3.75 (s, 3H), 7.95 (s, 1H), 12.05 (s, 1H), 12.76 (bs, 1H).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:11].Cl.Cl.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[ClH:31].[ClH:11].[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][CH2:15][NH:14][C:9]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:23][CH2:22]2)=[CH:26][CH:27]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C=NCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCN1CCN(Cc2ccc(Cl)cc2)CC1)NCc1ccccc1
Yield: 154.1 %

Procedure:
The procedure described in Example 21 was followed, using benzyl isocyanate (1.33 g; 10 mmole), 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole), methylene chloride (250 ml) and triethylamine (4.3 ml; 31 mmole) to provide the title compound (3.65 g; 77% yield) as colorless crystals, m.p. 203°-206° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[O:10]C[N:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][C:6]=2[CH:15]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.O>[C:11]([NH:8][CH2:7][C:6]1[CH:15]=[C:2]([C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]=1[OH:10])([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N1COc2c(cc(Br)cc2-c2ccccc2)C1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)NCc1cc(-c2cccnc2)cc(-c2ccccc2)c1O
Temperature: 60.5 °C
Yield: 49.7 %

Procedure:
A mixture of 6-bromo-3-(tert-butyl)-8-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazine (from Example 42, Step 2) (0.485 g, 1.41 mmol), pyridin-3-ylboronic acid (0.346 g, 2.0 equiv), and potassium carbonate (0.777 g, 4 equiv) in isopropanol (30 mL) and water (6 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)Pd (0) (90 mg, 5.5 mol %) was added and the resulting mixture was heated at 55-66° C. for 3 hours. The cooled reaction mixture was concentrated and the resulting residue was purified by column chromatograph to give 3-((tert-butylamino)methyl)-5-(pyridine-3-yl)-[1,1′-biphenyl]-2-ol (0.233 g).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:27][CH2:26]2)[CH2:21][CH2:20]1)=[O:18].O>CN(C)C=O>[CH3:3][C:2](=[CH2:4])[C:1]([O:6][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]([CH:19]1[CH2:20][CH2:21][CH:22]([CH:25]2[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:27][CH2:26]2)[CH2:23][CH2:24]1)=[O:18])=[O:5]
Reactant: C=C(C)C(=O)O
Reactant: CCCCCC1CCC(C2CCC(C(=O)OCCCCCCBr)CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)C(=O)OCCCCCCOC(=O)C1CCC(C2CCC(CCCCC)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methacrylic acid (3.6 g, 41.8 mmol) in dimethylformamide (30 ml) is added dropwise to an ice cooled slurry of sodium hydride (60% suspension in paraffin oil) (1.5 g, 37.5 mmol) in dimethylformamide (50 ml). Once addition is complete, the mixture is allowed to warm to room temperature and is stirred for 1 h, the intermediate 4′-pentyl-bicyclohexyl-4-carboxylic acid 6-bromo-hexyl ester (15.0 g, 33.8 mmol) in dimethylformamide (100 ml) is added dropwise. The mixture is stirred at 50° C. over night. The mixture is cooled to room temperature, poured into icy water, and this is extracted three times with DCM. The DCM solution is washed with brine, water and then dried over sodium sulphate. The solution is evaporated to dryness and recrystallised from acetonitrile to afford a white waxy solid. Further purification is achieved by preparative HPLC using water/acetonitrile as eluant.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]([C@@H:8]2[CH2:12][C@H:11]([S:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:10][N:9]2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])=[O:7])[CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][CH:51]=1)=[O:47]>C(Cl)Cl.C(OCC)(=O)C>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][S:13][C@@H:11]2[CH2:10][N:9]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])[C@H:8]([C:6]([N:4]3[CH2:5][CH:2]([NH:1][C:46]([O:48][CH2:49][C:50]4[CH:51]=[CH:52][C:53]([N+:56]([O-:58])=[O:57])=[CH:54][CH:55]=4)=[O:47])[CH2:3]3)=[O:7])[CH2:12]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(N)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reaction time: 0.67 h
Yield: 58.2 %

Procedure:
0.81 g of (2S, 4S)-2-(3-aminoazetidin-1-ylcarbonyl)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (a) above] was dissolved in 20 ml of methylene chloride, and 0.32 g of diisopropylethylamine and 0.40 g of p-nitrobenzyl chloroformate were added to the resulting solution, whilst ice-cooling. The resulting mixture was then stirred at the same temperature for 40 minutes. At the end of this time, the reaction mixture was diluted with ethyl acetate and washed with water and with an aqueous solution of sodium chloride, in that order. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography (silica gel 60 9385, manufactured by Merck, 40 g) to give 0.64 g of the title compound, in the form of an amorphous powder, from the fraction obtained by elution with a 99:1 by volume mixture of ethyl acetate and methanol.