Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH2:11]([C:13]([CH2:18][OH:19])([CH2:16][OH:17])[CH2:14][CH3:15])[OH:12]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:2]([C:15]([C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[O:4])([C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[O:4])[CH2:14][C:13]([CH2:18][OH:19])([CH2:16][OH:17])[CH2:11][OH:12])([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[O:4]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC(CO)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)C(=O)C(CC(CO)(CO)CO)(C(=O)C(=O)OCC)C(=O)C(=O)OCC
Yield: 106.2 %

Procedure:
A reaction vessel equipped with a stirrer, a condenser and a decanter was charged with 500 g (3.42 mol) of diethyl oxalate, 31.3 g (0.23 mol) of trimethylolpropane and 1 g (0.0053 mol) of p-toluenesulfonic acid one hydrate, and mixed at 130° C. for 5 hours. After removing 32.3 g of ethanol, it was then cooled and excess amount of diethyl oxalate was evaporated to obtain 106.1 g of crude triethoxalyltrimethylolpropane (yield 85%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][C:41]=2[CH3:42])[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][C:41]=2[CH3:42])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccncc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1ccncc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(C)cc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K30) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a white solid (301 mg, 76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:22]=[N:21][CH:20]=[CH:19][C:11]=1[C:12]([NH:14][NH:15][C:16](=[S:18])[NH2:17])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrC(Br)(Br)Br.C(Br)(Br)(Br)Br.C(N(CC)CC)C>CN(C=O)C>[NH2:17][C:16]1[S:18][C:12]([C:11]2[CH:19]=[CH:20][N:21]=[CH:22][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[N:14][N:15]=1
Reactant: NC(=S)NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nnc(-c2ccncc2Nc2ccc(I)cc2F)s1
Temperature: 50 °C
Yield: 4.7 %

Procedure:
To a solution of 2-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}hydrazine carbothioamide (220 mg; 0.51 mmol) in DMF (5.00 mL) were added resin bound triphenylphosphine (401 mg; 1.53 mmol), carbon tetrabromide tetrabromomethane (508 mg; 1.53 mmol), and triethyl amine (180 mg; 1.53 mmol). The mixture was heated at 50° C. for 5 h. Filtered and purified on Agilent Prep. HPLC system to get 10 mg of [4-(5-Amino-[1,3,4]thiadiazol-2-yl)-pyridin-3-yl]-(2-fluoro-4-iodo-phenyl)-amine. MS m/z: 414 M+1
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[CH2:5][C:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[CH:9]=1)=[O:7]>CO>[Cl:15][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][S:2][CH3:1])[CH:13]=[C:12]([Cl:14])[CH:11]=1
Reactant: C[S-]
Reactant: O=C(CBr)c1cc(Cl)cc(Cl)c1
Agent: [Na+]
Solvent: CO
Product: CSCC(=O)c1cc(Cl)cc(Cl)c1
Yield: 93.8 %

Procedure:
3.7 g (0.015 mol) of 1-(3,5-dichlorophenyl)-2-methylthio-1-ethanone are prepared by addition at 0° C. of 1.23 g (0.017 mol) of sodium methanethiolate in solution in 10 ml of methanol to 4.28 g (0.016 mol) of 2-bromo-1-(3,5-dichlorophenyl)-1-ethanone obtained above.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][S:36][C:37]1[N:38]=[CH:39][N:40]2[CH:44]=[C:43]([Sn](CCCC)(CCCC)CCCC)[S:42][C:41]=12)=[N+:28]=[N-:29]>>[N:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][S:36][C:37]1[N:38]=[CH:39][N:40]2[CH:44]=[C:43]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])[S:42][C:41]=12)=[N+:28]=[N-:29]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCCCCCCN=[N+]=[N-])c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCCCCCN=[N+]=[N-])c4s3)[C@H](C)[C@H]12
Yield: 46.7 %

Procedure:
The procedure of Example 1a) was repeated, except that 611 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.01 g of 7-(6-azidohexyl)thio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 493 mg of 4-nitrobenzyl (1S,5R,6S)-2-[7-(6-azidohexyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[CH2:10]=O>O.[Pd]>[CH3:10][N:5]1[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: C=O
Agent: [Pd]
Solvent: O
Product: CN1C[C@H](O)C[C@H]1C(=O)O
Reaction time: 24 h
Yield: 98.3 %

Procedure:
To 40 g (305 mmol) of trans-4-hydroxy-L-proline in 80 ml of water was added 80 ml of 30% aqueous formaldehyde solution and 7.0 g of 5% palladium on carbon catalyst (50% wet), and the mixture was hydrogenated at 50 psig using a Parr Shaker. After 24 hours, the catalyst was recovered by filtration over diatomaceous earth and the filtrate evaporated under reduced pressure to provide 43.5 g (98.3%) of title product; mp 140°-142° C. (decomposition); 1H-NMR (D2O): 4.65 (m, 1H), 4.20 (dd, 1H), 3.97 (dd, 1H), 3.2 (dm, 1H), 2.50 (m, 1H), 2.25 (m, 1H); [alpha]D =-54.8° (c=1.18, H2O).
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[C:8]([OH:24])=[C:9]([C:21](=[O:23])[CH3:22])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:21]([C:9]1[C:8]2[O:24][CH2:2][C:3](=[O:4])[NH:6][C:7]=2[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=[O:23])[CH3:22]
Reactant: O=C(Cl)CCl
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(N)c1O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)c2c1OCC(=O)N2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-Chloroacetyl chloride (1.8 mL) was added dropwise to a stirred mixture of 1-(3-amino-4-(benzyloxy)-2-hydroxyphenyl)ethanone (example 11, step c) (5.2 g) and sodium hydrogen carbonate (3.74 g) in DMF (30 mL) and then stirred for 2 h. Cesium carbonate (7.90 g) was added and the mixture heated at 100° C. for 20 h. The mixture was cooled to ambient temperature, quenched with water (500 mL), extracted with ethyl acetate (2×200 mL), washed with water (3×300 mL) and brine, dried over anhydrous sodium sulphate, filtered and evaporated under vacuum. The solid residue was treated with diethyl ether, filtered and dried to afford the subtitled compound as a beige solid. Yield 5.7 g.
Reaction SMILES: [O:1]=[C:2]1[NH:16][C:5]2=[CH:6][C:7]3[CH:8]=[C:9]([C:13]([OH:15])=O)[NH:10][C:11]=3[CH:12]=[C:4]2[NH:3]1.[CH2:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH2:17]([CH:24]1[CH2:29][CH2:28][N:27]([C:13]([C:9]2[NH:10][C:11]3[CH:12]=[C:4]4[NH:3][C:2](=[O:1])[NH:16][C:5]4=[CH:6][C:7]=3[CH:8]=2)=[O:15])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)c1cc2cc3[nH]c(=O)[nH]c3cc2[nH]1
Solvent: CC#N
Product: O=C(c1cc2cc3[nH]c(=O)[nH]c3cc2[nH]1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 2-oxo-1,2,3,5-tetrahydro-imidazo[4,5-f)indole-6-carboxylic acid and 4-benzylpiperidine according to the method described in Example 1/c. Mp.: >270° C. (acetonitrile).
Reaction SMILES: [C:1]([C:5]1[C:10]([OH:11])=[C:9]([CH3:12])[C:8]([CH2:13]Cl)=[C:7]([CH3:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[P:16]([O:21]C)([O:19][CH3:20])[O:17][CH3:18]>CCCCCCC>[C:1]([C:5]1[CH:6]=[C:7]([CH3:15])[C:8]([CH2:13][P:16](=[O:21])([O:19][CH3:20])[O:17][CH3:18])=[C:9]([CH3:12])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CCl
Reactant: COP(OC)OC
Solvent: CCCCCCC
Product: COP(=O)(Cc1c(C)cc(C(C)(C)C)c(O)c1C)OC

Procedure:
To 16.1 grams of 6-tert.-butyl-3-chloromethyl-2,4-dimethylphenol dissolved in 40 ml. of dry n-heptane was added 9.55 grams of trimethyl phosphite. One-third of the trimethyl phosphite was initially added dropwise at room temperature, the remainder being added dropwise at 70°. The reaction mixture was then heated at reflux (97°) for ten hours and the residual white solid isolated by stripping off the volatiles by distillation at 50° to 60° at reduced pressure. The residue was triturated twice with petroleum ether and recrystallized, after clarification, from a solvent mixture of n-hexane and isopropanol yielding the desired product as white crystals melting at 146° to 148°. (compound 1)
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]1([CH3:14])[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C.C(OCC)C>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:13][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:14])[CH3:22])[CH3:21]
Reactant: Cc1ccccc1O
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C(C)Oc1ccccc1C
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 102.3 %

Procedure:
Cesium carbonate (53.86 g, 165.3 mmol) was added to a solution of 2-cresol (10.0 g, 92.5 mmol) in anhydrous DMF (500 mL) at room temperature under an atmosphere of nitrogen. After five minutes, ethyl 2-bromopropionate (16.7 mL, 92.5 mmol, d=1.394) was added rapidly dropwise and the resultant mixture was allowed to stir at 90° C. for 18 h. The reaction mixture was diluted with diethyl ether, then extracted twice with 1N HCl and twice with water. The organic layer was dried over MgSO4 and concentrated in vacuo to provide the title compound (19.7 g, 100%). 1H NMR (400 MHz, CDCl3) δ 7.16 (d, 1H, J=7.43 Hz), 7.11 (t, 1H, J=7.43 Hz), 6.89 (t, 1H, J=7.48 Hz), 6.70 (d, 1H, J=7.43 Hz), 4.75 (q, 1H, J=6.65 Hz), 4.23 (q, 2H, J=6.65 Hz), 2.30 (s, 3H), 1.64 (dd, 3H, J=7.04 Hz, 0.78 Hz), 1.26 (td, 3H, J=7.04 Hz, 0.78 Hz). Rf=0.37 in 25% ether in hexanes.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:9]=[CH:8]1)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O>C1COCC1>[NH2:1][CH2:4][CH2:5][CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:9]=[CH:8]1
Reactant: [N-]=[N+]=NCCCn1cnc(-c2ccc(F)cc2)c1-c1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NCCCn1cnc(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The compound of example 3, described above (254 mg, 0.79 mmol), was dissolved in THF (2 mL) an added dropwise to a 0° solution of 1N LiAlH4 in THF (1.2 mL, 1.2 mmol), stirred at 0° for 15 min, EtOAc (4 mL) was carefully added and the mixture was added to ice cold 10% NaOH (15 mL) and the product was extracted with EtOAc (4×25 mL), dried (K2CO3) and concentrated to a waxy solid, (175 mg, 5%). mp=81°-82°.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]>C(O)(C)C>[C:9]([C:8]1[CH:12]=[CH:13][C:5]([CH2:1][C:2](=[O:3])[CH3:4])=[CH:6][CH:7]=1)([O:3][CH:2]([CH3:4])[CH3:1])=[O:10]
Reactant: CC(=O)Cc1ccc(C(=O)Cl)cc1
Solvent: CC(C)O
Product: CC(=O)Cc1ccc(C(=O)OC(C)C)cc1
Reaction time: 72 h

Procedure:
Isopropanol (30 ml) was added to 4-acetonylbenzoyl chloride (2.61 g) and the solution left at room temperature 3 days. Removal of the solvent gave the title compound as an oil. γ (CDCl3) 8.66 (3H, d, J=7 Hz), 7.88 (3H, s), 6.28 (2H, s), 4.78 (1H, h, J=7 Hz), 2.80 (2H, d, J=9 Hz) 2.04 (2H, d, J=9 Hz).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21]C(OC(C)(C)C)=O)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:29].CCOCC>O1CCOCC1>[ClH:29].[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH2:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinecarboxylate (0.78 g, 2.0 mmol) in dioxane (10 mL) was added 4M HCl in dioxane (5 mL) at 0° C. The reaction mixture was stirred at rt for 1 h, then, Et2O (10 mL) was added. The solid precipitation was collected by filtration, washed with Et2O (2×), and dried under vacuum to provide (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbohydrazide hydrochloride (0.65 g, 99%), which was used directly in the next step. ESI-MS (EI+, m/z): 291.19 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:20][CH:19]4[O:21][CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[N:11]=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH3:32])=[O:30])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:33]([C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43](=O)[O:44]C2C=CC=CC=2)=[CH:38][CH:37]=1)(=[O:35])[NH2:34]>>[CH3:32][NH:31][C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([C:10]2[N:11]=[C:12]([N:14]3[CH2:20][CH:19]4[O:21][CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:43]([NH:42][C:39]4[CH:40]=[CH:41][C:36]([C:33]([NH2:34])=[O:35])=[CH:37][CH:38]=4)=[O:44])=[CH:7][CH:6]=3)[N:9]=2)=[CH:23][CH:24]=1)=[O:30]
Reactant: NC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3CC4CCC(C3)O4)n2)cc1
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(NC(=O)Nc4ccc(C(N)=O)cc4)cc3)nc(N3CC4CCC(C3)O4)n2)cc1
Yield: 13 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl 4-carbamoylphenylcarbamate. Yield 90 mg, 13% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][C@H:16]([CH3:18])[N:15]([CH3:19])[C@H:14]([CH3:20])[CH2:13]1)[NH:8][CH2:7][CH2:6]2.C[Al](C)C.[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]([C:42](OC)=[O:43])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:13][C@H:14]([CH3:20])[N:15]([CH3:19])[C@H:16]([CH3:18])[CH2:17]1)[N:8]([C:42]([C:35]1[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:32]([CH:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[CH:33][CH:34]=1)=[O:43])[CH2:7][CH2:6]2
Reactant: COC(=O)c1ccc(C2CCN(C)CC2)c2ccccc12
Reactant: COc1cc2c(cc1N1C[C@@H](C)N(C)[C@@H](C)C1)NCC2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1C[C@@H](C)N(C)[C@@H](C)C1)N(C(=O)c1ccc(C3CCN(C)CC3)c3ccccc13)CC2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 35.3 %

Procedure:
A stirred solution of D3 (58 mg, 0.21 mmole) in toluene (5 ml) under argon was treated with 2M trimethylaluminium in toluene (0.13 ml, 0.25 mmole), then stirred at room temperature for 0.75 h. A solution of D9 (60 mg, 0.21 mmole) in toluene (5 ml) was added and the mixture was heated under reflux for 3.5 h, then allowed to cool to room temperature. The mixture was added to a 5 g silica gel column and eluted with 0-10% MeOH/DCM to afford a yellow oil. This was further purified by preparative plate TLC on silica gel eluting with 9:1:0.1 DCM/MeOH/0.88 NH3 to afford the title compound as a white solid (39 mg, 35%). MH+ 527.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:13]1([CH2:16][CH:17]([C:20]2[CH:21]=[N:22][C:23]([CH:26]([F:28])[F:27])=[CH:24][CH:25]=2)[CH2:18][NH2:19])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:20]1[CH:21]=[N:22][C:23]([CH:26]([F:28])[F:27])=[CH:24][CH:25]=1)[CH2:16][CH:13]1[CH2:14][CH2:15]1)=[O:6]
Reactant: NCC(CC1CC1)c1ccc(C(F)F)nc1
Reactant: COc1cccc(C(=O)O)c1Cl
Product: COc1cccc(C(=O)NCC(CC2CC2)c2ccc(C(F)F)nc2)c1Cl

Procedure:
From 2-chloro-3-methoxybenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine. LCMS (MH+): m/z=395.1, tR (minutes, Method F)=2.96
Reaction SMILES: CO[CH:3](O)[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([F:15])[CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:16].CC(N([C@H]1CCNC[C@H]1O)C(=O)[O-])(C)C.[C:33]([O:37][C:38](=[O:47])[NH:39][C@H:40]1[CH2:45][CH2:44][NH:43][CH2:42][C@H:41]1[OH:46])([CH3:36])([CH3:35])[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[F:15][C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][C:6](=[O:16])[N:5]2[CH2:4][CH2:3][N:43]2[CH2:44][CH2:45][C@H:40]([NH:39][C:38](=[O:47])[O:37][C:33]([CH3:34])([CH3:35])[CH3:36])[C@H:41]([OH:46])[CH2:42]2)=[N:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC[C@H]1O
Reactant: COC(O)Cn1c(=O)ccc2ncc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)N(C(=O)[O-])[C@H]1CCNC[C@H]1O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCN(CCn2c(=O)ccc3ncc(F)cc32)C[C@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(7-Fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde methyl hemiacetal (200 mg, 0.8396 mmol) and 1,1-dimethylethyl[(3R,4S)-3-hydroxy-4-piperidinyl]carbamate (for a synthesis see WO2004058144, Example 5(c), cis-(3-hydroxy-piperidin-4-yl)-carbamic acid tert-butyl ester Enantiomer 1) (182 mg, 1 eq.) were stirred in chloroform (10 ml) plus MeOH (0.5 ml) under argon for 2 hours. Sodium triacetoxyborohydride (534 mg, 3 eq.) was added in one portion and the mixture was stirred at rt overnight, then quenched by addition of saturated aqueous sodium hydrogen cabonate (20 ml) and extracted with 20% v:v MeOH in DCM (3×200 ml). The organic extractes were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica, eluted with 0-20% (2M ammonia in MeOH) in DCM. Appropriate fractions were combined and evaporated under reduced pressure to give title compound (247 mg) as an off-white foam.
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[OH:11].[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOCC.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][Cl:12]
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCCCl)cc1
Reactant: Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: ClCCCCCCCCOc1ccc2ccccc2c1
Reaction time: 4 h

Procedure:
A mixture of 17.5 g 2-naphthol, 32.0 g of 1-chloro-8-(p-toluenesulphonyloxy)octane, 32.0 g of anhydrous potassium carbonate and 200 ml of DMF was stirred at 60° for 4 hours. Water and ether were then added, the ethereal solution was separated, and washed with water and dilute aqueous potassium hydroxide, then dried and evaporated. The residue was chromatographed on silica gel, eluting with 3:2 hexane: dichloromethane, to afford the title compound as a solid, mp 35°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]1(O)[CH2:19][CH2:18][CH2:17][CH2:16]1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11]([O:13][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: OC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 19 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-2-methylalanine (1.00 g, 4.92 mmol) in DCM (10 ml) at 0° C. was added cyclopentanol (0.83 ml, 9.84 mmol), EDCI (1.06 g, 5.42 mmol) and finally DMAP (60 mg, 0.49 mmol). The reaction mixture was warmed to RT and stirred for 18 hours. The DCM was removed in vacuo to give a clear oil. The crude residue was dissolved in EtOAc (100 ml) and washed with water, 1 M NaHCO3 and brine. The organic phase was dried (MgSO4) and concentrated in vacuo. The crude extract was purified by column chromatography (10% EtOAc in heptane) to yield the desired product as a clear oil (0.254 g, 20% yield).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])[N:12]=[C:11]([N:24]2[C:28]([C:29]([F:32])([F:31])[F:30])=[C:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:26]=[N:25]2)[CH:10]=1.[I:38]I>C(Cl)(Cl)Cl>[I:38][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])[N:12]=[C:11]([N:24]2[C:28]([C:29]([F:32])([F:31])[F:30])=[C:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:26]=[N:25]2)[CH:10]=1
Reactant: II
Reactant: CCOC(=O)c1cnn(-c2cc(N)cc(-c3cc(C)ccc3OC)n2)c1C(F)(F)F
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnn(-c2cc(I)cc(-c3cc(C)ccc3OC)n2)c1C(F)(F)F
Temperature: 60 °C

Procedure:
Tert-butyl nitrite (0.68 mL, 0.59 mmol) was added to a solution of the title compound from Example 19 Step E (1.2 g, 2.9 mmol) and iodine (0.87 g, 3.4 mmol) in chloroform (20 mL). The resulting mixture was heated at 60° C. for 30 min, cooled and quenched with aqueous sodium sulfite. Extraction with hexane-EtOAc, followed by silica gel flash chromatography using Hexane-EtOAc (20/1 to 7/1) provided the title compound: LCMS m/z 532.6 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.54 (d, J=1.1 Hz, 1H), 8.15 (s, 1H), 7.98 (d, J=1.1 Hz, 1H), 7.79 (d, J=2.1 Hz, 1H), 7.25 (dd, J=8.5 Hz, 2.1 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H), 3.93 (s, 3H), 2.39 (s, 3H), 1.42 (t, J=7.1 Hz, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[C@H:15]4[CH2:16][C@H:12]([CH2:13][CH2:14]4)[C@H:11]3[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Br:22]Br>C(O)(=O)C.C(Cl)Cl.C(=O)([O-])O>[Br:22][C:3]1[C:4]2[CH:9]=[C:8]([C@H:10]3[C@H:15]4[CH2:16][C@H:12]([CH2:13][CH2:14]4)[C@H:11]3[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[CH:7]=[CH:6][C:5]=2[S:1][CH:2]=1
Reactant: BrBr
Reactant: CN(C)C(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1c1ccc2sccc2c1
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C)C(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1c1ccc2scc(Br)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.8 %

Procedure:
To a solution of (1S,2R,3S,4R)-3-(1-benzothien-5-yl)-N,N-dimethylbicyclo[2,2,1]heptane-2-carboxamide (30 mg, 0.1 mmol) in acetic acid (2 mL) was added bromine (5.5 μL, 0.1 mmol) and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with methylene chloride (5 mL) and neutralised by careful addition of a saturated hydrogen carbonate solution. The layers were separated and the aqueous was extracted with methylene chloride (2×5 mL). The organic extracts were washed with water, dried over magnesium sulfate and evaporated in vacuo to give (1S,2R,3S,4R)-3-(3-bromo-1-benzothien-5-yl)-N,N-dimethylbicyclo[2,2,1]heptane-2-carboxamide as a glass (37 mg, 97%). M/e 378/380 (MH+).