Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])=[O:4].[CH3:11][Si:12]([CH3:24])([CH3:23])[O:13][C:14]([C:16]([O:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH2:17])=[CH2:15]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH2:17][C:16]([O:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[C:14]([O:13][Si:12]([CH3:23])([CH3:11])[CH3:24])[CH2:15][C:6]=1[C:7]([O:9][CH3:10])=[O:8])=[O:4]
Reactant: COC(=O)C#CC(=O)OC
Reactant: C=C(O[Si](C)(C)C)C(=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1

Procedure:
Under argon, a solution of 7.1 g (50 mmol) of acetylenedicarboxylic acid dimethyl ester in 30 ml of toluene is added dropwise to 12.5 g (50 mmol) of 2,3-bis(trimethylsilyloxy)-1,3-butadiene (95%) and then boiled under reflux for 19 hours. The reaction mixture is cooled, the solvent is evaporated off and the residue is distilled under a high vacuum (0.1 mbar, 124°-127°), yielding the title compound in the form of a yellow, highly viscous oil, 1H-NMR (CDCl3): δ=0.18 (s, 18H), 3.09 (s, 4H), 3.78 (s, 6H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[N:15][C:16]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:17]=2[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=2)=[O:19])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[B-][N+](C)(C)C>C(O)(=O)C>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:17]=2[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=2)=[O:19])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C=Nc2ccc(F)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Agent: [B-][N+](C)(C)C
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(CNc2ccc(F)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 70 °C
Yield: 97 %

Procedure:
A solution containing 2-(1-Boc-piperidin-4-ylmethylidene)amino-N-(5-chloropyridin-2-yl)-5-fluorobenzamide from above (6.0 g, 13 mmol) and borane trimethylamine complex (2.9 g, 39 mmol) in glacial acetic acid (100 mL) was heated at 70° C. for 24 h. The solution was allowed to cool to room temperature; then the solvent was removed in vacuo, and the residue was partitioned between dichloromethane (200 mL) and water (100 mL). The biphasic mixture was treated with 2 N NaOH until neutral; then the organic layer was separated and the aqueous layer was washed again with dichloromethane (100 mL). The combined organic layers were washed with brine (100 mL), dried with MgSO4, and filtered. The filtrate was concentrated in vacuo to give 5.85 g (97%) of the title compound as an orange foam which was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([O:14][CH3:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH4+:16].[OH-].C[O:19][CH2:20][C:21](OC(=O)COC)=O>CCOCC.O>[CH3:10][O:9][C:8]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[C:11]([CH2:12][O:14][CH3:15])=[N:16][C:20]([OH:19])=[CH:21]2
Reactant: COC(=O)Cc1ccc(OC)c(OC)c1
Reactant: COCC(=O)OC(=O)COC
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: COCc1nc(O)cc2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 2 %

Procedure:
To a solution of methyl 2-(3,4-dimethoxy-phenyl)acetate SLA 28134 (3.36 g, 15.98 mmol) in methoxyacetic anhydride SMA 44010 (10.19 g, 62.85 mmol) at 0° C. in a 250 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise HClO4 (ca. 70% solution in water, 1.64 mL, 18.98 mmol). The mixture was then stirred for 45 min at RT then diluted with Et2O (151 mL). The organic solution was removed to give a viscous residue that was suspended in H2O (30 mL) at 5° C. before dropwise addition of a conc. NH4OH solution (38 mL). After complete addition, the mixture was stirred overnight at RT and extracted with CH2Cl2 (50 mL) then with CH2Cl2:MeOH=95:5 (100 mL). The organic phase was combined, washed with brine (30 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 93:7) gave 6,7-dimethoxy-1-methoxymethyl-isoquinolin-3-ol SMA 44012 as a yellow solid (96 mg, 2% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH2:5][C:6]3[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)[C:8](=[O:19])[C:7]=3[O:20][C:21]=2[CH:22]=[CH:23][CH:24]=1.[NH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[S:27]1[CH:28]=[CH:29][N:30]=[C:26]1[NH:25][C:12](=[O:14])[C@@H:11]([N:9]1[CH2:10][C:6]2[CH2:5][C:4]3[C:3]([O:2][CH3:1])=[CH:24][CH:23]=[CH:22][C:21]=3[O:20][C:7]=2[C:8]1=[O:19])[CH2:15][CH:16]([CH3:17])[CH3:18]
Reactant: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC(C)C)C(=O)O)C1
Reactant: Nc1nccs1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC(C)C)C(=O)Nc2nccs2)C1
Yield: 27.4 %

Procedure:
A solution of (S)-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (100 mg, 0.30 mmol), commercially available 2-amino-thiazole (37 mg, 0.36 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (66 mg, 0.33 mmol), and N-hydroxybenzotriazole (HOBt) (44 mg, 0.33 mmol) in methylene chloride (10 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded (S)-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid thiazol-2-ylamide (34 mg, 27.2%), as an off white solid. 1H NMR (DMSO-d6) δ: 12.58 (br. s., 1H), 7.50 (d, J=3.4 Hz, 1H), 7.12-7.34 (m, 2H), 6.76 (d, J=7.8 Hz, 1H), 6.68 (d, J=8.3 Hz, 1H), 5.04 (d, J=5.9 Hz, 1H), 4.36 (d, J=19.1 Hz, 1H), 4.05 (d, J=18.6 Hz, 1H), 3.82 (s, 3H), 3.55 (br. s., 2H), 1.83 (d, J=9.3 Hz, 1H), 1.68 (br. s., 1H), 1.45 (br. s., 1H), 0.93 (t, J=7.3 Hz, 6H).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:5]2[CH:13]=[C:14]([Cl:19])[C:15]([Cl:18])=[C:16]([Cl:17])[C:4]=2[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:26]([O:28][C:29]([C:31]1[CH:32]=[N:33][NH:34][CH:35]=1)=[O:30])[CH3:27].CN(C=O)C>CCOC(C)=O>[CH2:26]([O:28][C:29]([C:31]1[CH:32]=[N:33][N:34]([C:2]2[N:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:5]3[CH:13]=[C:14]([Cl:19])[C:15]([Cl:18])=[C:16]([Cl:17])[C:4]=3[N:3]=2)[CH:35]=1)=[O:30])[CH3:27]
Reactant: COCCOCn1c(Cl)nc2c(Cl)c(Cl)c(Cl)cc21
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(-c2nc3c(Cl)c(Cl)c(Cl)cc3n2COCCOC)c1
Temperature: 80 °C

Procedure:
A mixture of 2,4,5,6-tetrachloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazole (0.275 g, 0.80 mmol), Cs2CO3 (0.524 g, 1.61 mmol), 1H-pyrazole-4-carboxylic acid ethyl ester (0.124 g, 0.89 mmol), and DMF (4 mL) was heated to 80° C. for 2 h. The mixture was cooled to 23° C. EtOAc was added and the mixture was washed with brine. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified (FCC) to yield the titled compound as a mixture of regioisomers (0.166 g, 46%). MS (ESI/CI): mass calcd. for C17H17Cl3N4O4, 446.0; m/z found, 447.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 9.01-8.97 (m, 2H), 8.40 (t, J=2.3 Hz, 1H), 8.37 (s, 1H), 8.21 (s, 1H), 8.13 (s, 1H), 6.09 (s, 2H), 6.01 (s, 2H), 4.30 (qd, J=7.1 Hz, 2.9, 8H), 3.58-3.51 (m, 2H), 3.44 (d, J=4.9 Hz, 2H), 3.11 (s, 3H), 3.08 (s, 3H), 1.32 (tt, J=7.1 Hz, 1.7 Hz, 6H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=[O:8])=CC=1.[OH:12][CH:13]([N:26]1[C:32](=[O:33])[C@@H:31]2[C@H:27]1[S:28][C:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[N:30]2)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:15].CC1(C)S[C@@H]2[C@H](NC(CC3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.CC1(C)S[C@@H]2[C@H](NC(COC3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O>O.ClCCl.CC(C)=O>[OH:12][CH:13]([N:26]1[C@H:27]([SH:28])[C@H:31]([NH:30][C:29](=[O:8])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32]1=[O:33])[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:15]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(COC(=O)C(O)N2C(=O)[C@H]3N=C(Cc4ccccc4)S[C@H]32)cc1
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Toluene-4-sulphonic acid (6.0g, 31.5mmol) in water (15ml) was added to a solution of 4-methoxybenzyl (2RS)-2-hydroxy-2-[(1R,5R)-3-benzyl-4-thia-2,6-diazabicyclo [3.2.0]hept-2-en-7-on-6-yl]acetate (7.42g, 18.0mmol) prepared from Penicillin G as described for the benzhydryl ester derived from Penicillin V, S. Yamamoto, N. Haga, T. Aoki, S. Hayashi, H. Tanida, and W. Nagata, Heterocycles, 1977, 8, 283) in dichloromethane (30ml) and acetone (30ml) . After stirring for 2.5 h at room temperature, the reaction mixture was diluted with dichloromethane, washed with water (x2), dried and concentrated in vacuo to yield crude 4-methoxybenzyl (2RS)-2-hydroxy-2-[(3R,4R)-4-mercapto-3-phenylacetamidoazetidin-2-on-1-yl]acetate as a yellow foam.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])=[CH2:2].[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH:1]([C:3]1[CH:4]=[C:5]([CH:6]2[O:13][CH2:12][CH2:11][O:7]2)[CH:8]=[CH:9][CH:10]=1)=[CH2:2]
Reactant: C=Cc1cccc(C=O)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C=Cc1cccc(C2OCCO2)c1
Temperature: 25 °C

Procedure:
To a solution of 3-ethenylbenzaldehyde from Step 1 (3.77 g) and ethylene glycol (1.8 mL) in benzene (40 mL ) was added p-toluenesulfonic acid monohydrate (100 mg). The reaction mixture was heated to reflux for 6 hours. The water produced by the reaction was collected in a Dean-Stark trap. The reaction was allowed to cool to room temperature. The reaction was diluted with NH4OAc buffer and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated. Flash chromatography of the residue using 15% diethyl ether in hexane afforded the title compound.
Reaction SMILES: COC1C=CC2CC3C(=O)C(C)(C=2C=1)CCCC3.Cl[CH2:20][CH2:21][CH2:22][CH2:23][C:24]1([CH2:37][CH3:38])[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=2)[CH2:27][CH2:26][C:25]1=[O:36]>>[CH2:37]([C:24]12[C:25](=[O:36])[CH:26]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][C:33]=31)[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH3:38]
Reactant: CCC1(CCCCCl)C(=O)CCc2ccc(OC)cc21
Agent: COc1ccc2c(c1)C1(C)CCCCC(C2)C1=O
Product: CCC12CCCCC(Cc3ccc(OC)cc31)C2=O

Procedure:
Using a procedure analogous to that described in Example X for the preparation of 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one there is obtained from 37.4 g. of 1-(4-chlorobutyl)-1-ethyl-7-methoxy-2-tetralone, 22.2 g. of the title product, b.p. 138° to 142° C. (0.35 mm.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:18][NH2:19].[O-]S([O-])(=O)=O.[Mg+2]>C(O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[N:19]/[CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2ccc(C=O)cc2)cc1Br
Reactant: CN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Solvent: ClCCl
Product: C/N=C/c1ccc(-c2ccc(OC)c(Br)c2)cc1
Yield: 98 %

Procedure:
A mixture of 3′-bromo-4′-methoxy-1,1′-biphenyl-4-carbaldehyde (7.56g, 26.0 mmol), prepared in the previous step, methylamine (16.2 mL of an 8.03 M solution in ethanol; 130 mmol) and 20.0 g of anhydrous MgSO4 in 150 mL of methylene chloride was stirred under nitrogen at room temperature for 22 h. The reaction was filtered and the filtrate concentrated under reduced pressure to give N-[(E)-(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methylidene]-N-methylamine (7.77 g, 98%) as a brown solid, mp 115-117° C. Elemental Analysis for C15H14BrNO. Calc'd: C, 59.23; H; 4.64; N, 4.60. Found: C, 58.99; H, 4.38; N, 4.63
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1.[F:13][C:14]1[CH:37]=[CH:36][C:17]([CH2:18][NH:19][C:20]([C:22]2[S:26][C:25]([N:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]3=[O:34])=[N:24][C:23]=2[CH3:35])=[O:21])=[CH:16][CH:15]=1>>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:33][C:30]2[CH:31]=[CH:32][N:27]([C:25]3[S:26][C:22]([C:20]([NH:19][CH2:18][C:17]4[CH:16]=[CH:15][C:14]([F:13])=[CH:37][CH:36]=4)=[O:21])=[C:23]([CH3:35])[N:24]=3)[C:28](=[O:34])[CH:29]=2)=[CH:6][CH:5]=1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccc(F)cc1
Reactant: FC(F)Oc1ccc(CBr)cc1
Product: Cc1nc(-n2ccc(OCc3ccc(OC(F)F)cc3)cc2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 25 %

Procedure:
Following the procedure as described in Example 9, making variation only as required to use 4-(difluoromethoxy)benzyl bromide in place of 2-cyclopropylethyl 4-methylbenzenesulfonate to react with N-(4-fluorobenzyl)-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 25% yield: mp 242-244° C. (dichloromethane/methanol); 1H NMR (300 MHz, DMSO-d6) δ 8.78 (t, J=5.8 Hz, 1H), 8.60 (dd, J=8.1, 3.0 Hz, 1H), 7.56-7.47 (m, 2H), 7.34-7.08 (m, 7H), 6.43-6.32 (m, 1H), 6.22 (s, 1H), 5.15 (s, 2H), 4.34 (d, J=5.8 Hz, 2H), 2.52 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.4, 163.2, 161.9, 160.0, 151.4, 150.4, 136.1, 133.7, 132.7, 130.5, 129.8, 123.6, 120.1, 119.2, 116.7, 115.6, 113.3, 104.3, 97.5, 70.1, 44.6, 17.5; MS (ES+) m/z 516.4 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[NH:20]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][O:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][O:40][CH2:39]1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH3:8][CH:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][O:40][CH2:39]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][O:11][CH3:12]
Reactant: CS(=O)(=O)OCC1CCCOC1
Reactant: COCC(C)Oc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCC(C)Oc1nc(N)c2nc(OC)n(CC3CCCOC3)c2n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 62.7 %

Procedure:
To a solution of 2-{[1-methyl-2-(methoxy)ethyl]oxy}-8-(methoxy)-9H-purin-6-amine trifluoroacetic acid salt (500 mg) in dry N,N-dimethylformamide (6.0 ml) at room temperature and under nitrogen was added potassium carbonate (0.75 g) in one go. The reaction was stirred at 60° C. for 1.5 hours. A solution of tetrahydro-2H-pyran-3-ylmethyl methanesulfonate (0.29 g) in dry N,N-dimethylformamide (1.0 ml) was added in one go and the reaction heated at 90° C. for 2 hours. The reaction was cooled to room temperature and then diluted with ethyl acetate (20 ml) and washed with water (10 ml). The organic layer was concentrated in vacuo. The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (10-60%) to afford the title compound as a clear viscous oil (300 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.CCN(C(C)C)C(C)C.[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:25][N:26]=[C:27]=[O:28].[N-]=C=O>CN1C(=O)CCC1.CN(C1C=CN=CC=1)C>[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:25][NH:26][C:27](=[O:28])[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1csc(N)n1
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: [N-]=C=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Temperature: 160 °C

Procedure:
The commercial starting material ethyl 2-aminothiazole-4-carboxylate (2 mmol) was dissolved in NMP and DIEA (1 equivalent) was added followed by addition of the 3,4-dichloro-benzyl isocyanate (1 equivalent). Add 5% DMAP. Heat at 160° C. under microwave irradiation for 30 min Added additional isocyanate reagent (1.0 eq) and microwave for another 30 minutes at 160° C. to obtain ethyl 2-(3-(3,4-dichlorobenzyl)ureido)thiazole-4-carboxylate in >90% conversion.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[F:19][C:20]([F:31])([F:32])[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=2)=[CH:24][CH:23]=1
Reactant: CN(C(=O)Oc1ccc(I)cc1)c1ccccc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: CN(C(=O)Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from methyl-phenyl-carbamic acid 4-iodo-phenyl ester and 4-trifluoromethoxyphenylboronic acid. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane 1:9) (17%, brown oil).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28].N1C=CC=CC=1>C(OCC)C>[C:27](=[O:28])([O:29][CH2:30][CH3:31])[O:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])[C:4]([F:25])=[CH:3][C:2]=1[Cl:1]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCCO)c(Cl)cc2F)c1=O
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)OCCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using 3-[4-chloro-2-fluoro-5-(2-hydroxyethoxy)-phenyl]-1-methyl-6 -trifluoromethyl-2,4(1H,3H)-pyrimidinedione and ethyl chloroformate with pyridine in diethyl ether there is obtained 2-[2-chloro-5-(3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorophenoxy]-ethyl ethyl carbonate, 1H-NMR (CDCl3, 400 MHz): 7.32 ppm (d,1H), 6.81 ppm (d,1H), 6.36 ppm (s,1H), 4.47°-4.54 ppm (m,2H), 4.16°-4.27 ppm (m,4H), 3.56 ppm (d,3H), 1.32 ppm (t,3H);
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][N:12]([CH2:28][C@@H:29]2[CH2:33][CH2:32][CH2:31][NH:30]2)[C:13]([C:15]2[CH:25]=[C:24]([O:26][CH3:27])[C:18]3[O:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[CH:16]=2)=[O:14])[N:2]=1.[C:34]1(=O)[CH2:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:34]1([N:30]2[CH2:31][CH2:32][CH2:33][C@H:29]2[CH2:28][N:12]([CH2:11][C:3]2[N:2]=[CH:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:13]([C:15]2[CH:25]=[C:24]([O:26][CH3:27])[C:18]3[O:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[CH:16]=2)=[O:14])[CH2:37][CH2:36][CH2:35]1
Reactant: COc1cc(C(=O)N(Cc2cc3ccccc3cn2)C[C@@H]2CCCN2)cc2c1OC(C)(C)O2
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C(=O)N(Cc2cc3ccccc3cn2)C[C@@H]2CCCN2C2CCC2)cc2c1OC(C)(C)O2
Yield: 60.5 %

Procedure:
In 1 mL dichloromethane was dissolved 40 mg (0.089 mmol) of 7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carboxylic acid isoquinolin-3-ylmethyl-(S)-1-pyrrolidin-2-ylmethyl-amide, to this solution was added 20 mg (0.25 mmol) of cyclobutanone and 53 mg (0.25 mmol) of sodium triacetoxyborohydride. After overnight the reaction was quenched with aqueous sodium bicarbonate and purified using reverse phase HPLC, mobile phase with a gradient 10-70% acetonitrile in 40 min. Fractions containing pure product were evaporated, the residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate, dried with anhydrous magnesium sulfate and evaporated in vacuum to yield 27 mg of the product as the free base as a pale yellow solid. LC-MSD, m/z for C30H35N3O4 [M+H]+: 502.7. 1H NMR (400 MHz, CDCl3): δ 1.4-2.0 (m, 9 H), 1.7 (s, 6 H), 2.3-2.4 (m, 1 H), 2.8-3.5 (m, 5 H), 3.7 (bs, 3 H), 3.8-4.0 (m, 1 H), 4.9-5.1 (m, 2 H), 6.6 (s, 1 H), 6.7-6.9 (m, 1 H), 7.5 (bs, 1 H), 7.5-7.6 (m, 1 H), 7.6-7.7 (m, 1 H), 7.8-7.9 (m, 1 H), 7.9-8.0 (m, 1 H), 9.2 (s, 1 H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25](OCC)=[O:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Li+].[BH4-]>C1COCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([CH2:25][OH:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc2[nH]c(CO)cc2c1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
Ethyl 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indole-2-carboxylate (1.18 g, 3.0 mmol) was added to a solution of LiBH4 (132 mg, 6.0 mmol) in THF (10 mL) and water (0.1 mL). The mixture was allowed to stir for 16 h at 25° C. before it was quenched with water (10 mL) and slowly made acidic by addition of 1 N HCl. The mixture was extracted with three 50-mL portions of ethyl acetate. The organic extracts were dried over Na2SO4 and evaporated to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(hydroxymethyl)-1H-indol-5-yl)cyclopropanecarboxamide (770 mg, 73%). A small amount was further purified by reverse phase HPLC. ESI-MS m/z calc. 350.4. found 351.3 (M+1)+; retention time 2.59 minutes.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C:24](=O)[C:25]#[C:26][CH:27]1[CH2:29][CH2:28]1)C.C(C1CC1)#C.ClC(OCC)=O>C(O)C>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:24](=[O:23])[CH:25]=[C:26]([CH:27]5[CH2:29][CH2:28]5)[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C#CC1CC1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Agent: C#CC1CC1
Agent: CCOC(=O)Cl
Solvent: CCO
Product: O=c1cc(C2CC2)n2c(n1)O[C@H](COc1ccc(C3CCCCC3)cc1)C2
Temperature: 170 °C
Yield: 95.2 %

Procedure:
To a solution of (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.5 g, 1.82 mmol), (see Example 28), in ethanol (5 mL) was added cyclopropyl-propynoic acid ethyl ester (0.377 g, 2.73 mmol) (prepared from ethynyl-cyclopropane and ethyl chloroformate in accordance with the procedures of G. Cai et al., Tetrahedron, 2006, 5697-5708). The reaction mixture was heated in a microwave oven at 170° C. for 30 min. The solvent was removed under vacuum, and the residue purified by flash column chromatography (silica gel, 2% 7N NH3 in MeOH/CH2Cl2) to afford 0.635 g of (S)-2-(4-cyclohexyl-phenoxymethyl)-5-cyclopropyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one as a white solid. [α]D25 −13.40 (c 0.5, CHCl3)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[O:5][C:6]=1[CH3:7].[CH3:11][O:12][C:13](=[O:20])[C@@H:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH2:15]>>[CH3:7][C:6]1[O:5][C:4]([C:8]([NH:15][C@H:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([O:12][CH3:11])=[O:20])=[O:10])=[CH:3][C:2]=1[CH3:1]
Reactant: COC(=O)[C@H](N)CC(C)C
Reactant: Cc1cc(C(=O)O)oc1C
Product: COC(=O)[C@@H](CC(C)C)NC(=O)c1cc(C)c(C)o1
Yield: 27 %

Procedure:
Prepared in a similar manner to example 4 using 4,5-dimethyl-furan-2-carboxylic acid and D-leucine methyl ester. Yield: 27%. 1H NMR (500 MHz, CDCl3): δ 0.96 (t, 6H), 1.66 (m, 3H), 1.96 (s, 3H), 2.26 (s, 3H), 3.75 (s, 3H), 4.78 (m, 1H), 6.51 (d, 1H), 6.89 (s, 1H). MS (M+H, 268).