Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:8].[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:16][C:17]([CH3:21])([CH3:20])[CH:18]=O>C(Cl)Cl>[CH3:16][C:17]([CH3:21])([CH3:20])[CH:18]=[N:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]=[CH:16][C:17]([CH3:21])([CH3:20])[CH3:18]
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: CC(C)(C)C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C=NC1CCCCC1N=CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112 %

Procedure:
(+)-1,2-trans-Diaminocyclohexane (250 mg, 2.18 mmol) in CH2Cl2 (20 mL) was treated with Na2SO4 (923 mg, 6.50 mmol) and trimethylacetaldehyde (473 μL, 4.35 mmol). The mixture was stirred at ambient temperature under an atmosphere of N2 for 0.5 h then filtered. The filter was washed with CH2Cl2 (5 mL) and the combined organics were evaporated to give N,N′-bis-(2,2-dimethylpropylidene)-cyclohexane-1,2-diamine (610 mg, 98%) as an off-white semi solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][O:8][C@@H:9]2[C@@H:17]([CH2:18][O:19][Si](C(C)(C)C)(C)C)[O:16][CH:15]3[CH:11]([N:12]=[C:13]([N:27]([CH2:35][CH2:36][CH3:37])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[S:14]3)[C@H:10]2[O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)=[CH:5][CH:4]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.[Cl-].[Na+].O>[OH:19][CH2:18][C@H:17]1[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:27]([CH2:35][CH2:36][CH3:37])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])[S:14]2)[C@@H:10]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=2)[C@@H:9]1[O:8][CH2:7][C:6]1[CH:48]=[CH:49][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CCCN(C(=O)OC(C)(C)C)C1=NC2C(O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc3ccc(OC)cc3)[C@@H]2OCc2ccc(OC)cc2)S1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OCc3ccc(OC)cc3)[C@H](OCc3ccc(OC)cc3)[C@@H](CO)O[C@@H]2S1
Yield: 90.8 %

Procedure:
To a solution of tert-butyl (5R,6S,7R)-6,7-bis(4-methoxybenzyloxy)-5-((tert-butyldimethylsilyloxy)methyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(propyl)carbamate (19 g, 26.50 mmol) in tetrahydrofuran (100 mL) was treated with TBAF (13.8 g, 53 mmol) overnight at room temperature. The resulting solution was diluted with brine (200 mL), extracted with ethyl acetate (2×200 mL), and dried over anhydrous magnesium sulfate. After removal of solvents, the residue was purified by silica gel column, eluted with 10-30% ethyl acetate in petroleum ether to give compound 19 as a yellow oil (14.5 g, 91%). (ES, m/z): [M+H]+ 603.0; 1H NMR (300 MHz, CDCl3) 7.32-7.35 (d, J=8.7 Hz, 2H), 7.17-7.20 (d, J=8.7 Hz, 2H), 6.83-6.92 (m. 4H), 6.04-6.06 (d, J=6.9 Hz, 1H), 4.64-4.66 (m, 2H), 4.40-4.48 (m, 1H), 4.17-4.38 (m, 3H), 3.72-3.83 (m, 9H), 3.45-3.60 (m, 2H), 3.43-3.45 (m, 1H), 1.58-1.63 (m, 2H), 1.53 (s, 9H), 0.78-0.83 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[C:16]#[N:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:19][OH:20]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2/[C:16](=[N:19]/[OH:20])/[NH2:17])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: N#C[C@@H]1CCCN1S(=O)(=O)c1ccc(F)cc1
Reactant: NO
Agent: Cl
Product: N/C(=N\O)[C@@H]1CCCN1S(=O)(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared by the method of Preparation 4 from (2S)-1-[(4-fluorophenyl)sulfonyl]-2-pyrrolidinecarbonitrile [see Preparation 51] and hydroxylamine hydrochloride to afford the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[N:11][NH:10][C:7]2=[N:8][CH:9]=1)([O-])=O.Cl[Sn]Cl>CCO.CC1C=CC=CC=1>[NH:10]1[C:7]2=[N:8][CH:9]=[C:4]([NH2:1])[CH:5]=[C:6]2[CH:12]=[N:11]1
Reactant: O=[N+]([O-])c1cnc2[nH]ncc2c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1cnc2[nH]ncc2c1
Temperature: 70 °C

Procedure:
5-Nitro-1H-pyrazolo[3,4-b]pyridine (prepared according to the procedure in Can. J. Chem. 1988, 66(3), 420) (133 mg, 0.81 mmol) was mixed with SnCl2 (1.09) in EtOH/CH3Ph (4 mL/2 mL) and heated at 70° C. for 3 hrs. The reaction was cooled to rt and concentrated to dryness. The residue was participated between 1.0 N NaOH (10 mL) and ethyl acetate (50 mL). The organic layer was washed with brine once, dried (MgSO4) and filtered. The filtrate was concentrated and the resulting crude was purified by prep. TLC using 10:2 CH2Cl2/Methanol (2 N NH3). The title compound (15.0 mg) was isolated as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH:16]([OH:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(OCC3CC3)cc2C(O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)c2cc(OCC3CC3)ccc2C1
Temperature: 25 °C

Procedure:
To 600 mg (1.88 mmol) 6-cyclopropylmethoxy-4-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (example XLIII.1) in 6 mL DCM are added 825 mg (1.88 mmol) Dess-Martin periodinane and the resulting mixture is stirred at r.t. over night. The reaction mixture is diluted with water and extracted with DCM. The organic layer is concentrated by evaporation and the residue is purified by HPLC (ACN/H2O/HCOOH).
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:5]=[C:6]2[N:13]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:12]([O:22][C@H:23]3[C@H:27]4[O:28][CH2:29][C@@H:30]([OH:31])[C@H:26]4[O:25][CH2:24]3)=[N:11][C:7]2=[N:8][C:9]=1I.CC1(C)C(C)(C)OB([C:40]2[CH:47]=[CH:46][C:43]([C:44]#[N:45])=[CH:42][CH:41]=2)O1.CCOC(C)=O.CCCCCC>O1CCOCC1.O>[OH:31][C@@H:30]1[CH2:29][O:28][C@@H:27]2[C@H:23]([O:22][C:12]3[N:13]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]4[C:7]([N:11]=3)=[N:8][C:9]([C:40]3[CH:47]=[CH:46][C:43]([C:44]#[N:45])=[CH:42][CH:41]=3)=[C:4]([Cl:3])[CH:5]=4)[CH2:24][O:25][C@H:26]12
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(I)c(Cl)cc21
Reactant: CC1(C)OB(c2ccc(C#N)cc2)OC1(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(C#N)cc3)c(Cl)cc21
Temperature: 80 °C

Procedure:
LiOH (0.43 ml, 1.290 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (43.2 mg, 0.053 mmol) were added to a stirred solution of (3R,3aR,6R,6aR)-6-[6-chloro-5-iodo-1-(2-trimethylsilylethoxy-methyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (284.9 mg, 0.514 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (143.1 mg, 0.625 mmol) in dioxane (4.2 ml) and water (0.60 ml). The reaction mixture was degassed (3×) and placed under nitrogen before being heated to 80° C. for 1.5 hours. Then the reaction mixture was cooled and partitioned between EtOAc (50 ml) and water (50 mL). The aqueous layer was extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×50 ml), dried over Na2SO4′ filtered, and evaporated under reduced pressure to give an amber residue. Flash chromatography of the residue utilizing a 12 g silica RediSep Rf® column and employing a 0-60% EtOAc/hexane gradient followed by 60% EtOAc/hexane afforded the title compound as a yellow residue. LC-MS: calculated for C25H29ClN4O5Si 528.16 observed m/e: 529.22 (M+H)+ (Rt 2.34/4 min).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[CH:3]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:36][O:37][NH:38][CH3:39].CCN(CC)CC>C(Cl)Cl.O>[CH3:36][O:37][N:38]([CH3:39])[C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[CH:3]=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: CNOC
Reactant: Cn1cnc2cc(C(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2c(c1)ncn2C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.7 %

Procedure:
A suspension of 1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (9.7 g, 1.0 eq), EDCI (10.5 g, 1.2 eq), and HOBt (7.4 g, 1.2 eq) in 150 mL CH2Cl2 was stirred at rt for 5 min, and then N-methoxymethanamine hydrochloride (6.7 g, 1.5 eq) and Et3N (18.5 g, 4.0 eq) were added. The reaction mixture was stirred at rt overnight. Water was added and extracted with CH2Cl2. The extract was dried, concentrated, and purified by column chromatography to give the desired product (9.5 g, 80%). 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=1.2 Hz, 1H), 7.93 (s, 1H), 7.72 (dd, J=8.8 Hz, 1.6 Hz, 1H), 7.40 (dd, J=8.4 Hz, 0.8 Hz, 1H), 3.87 (s, 3H), 3.57 (s, 3H), 3.40 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][C:19]([F:23])=[CH:20][CH:21]=2)[N:16](C(=O)C)[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][C:19]([F:23])=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)n1cc(CC2CCCN2C(=O)OC(C)(C)C)c2ccc(F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC1Cc1c[nH]c2cc(F)ccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
A solution containing crude 19 (48 g) in reagent grade MeOH (480 mL) was cooled to 0° C. Aqueous NaOH (1 M, 144 mL) was added in one portion. After 30 min, TLC analysis revealed complete consumption of starting material [TLC analysis, 3:2 hexane/EtOAc, Rf(19)=0.7; Rf(20)=0.8]. The reaction mixture was neutralized with 1 N HCl and the product was extracted with DCM. The DCM extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was absorbed onto 200 mL of silica gel and chromatographed (80% to 65% hexane/EtOAc) to afford 31.7 g of 20 as a thick oil. 1H NMR (CDCl3, 300 MHz) δ8.11 (br s, 1H), 7.65-7.57 (m, 1H), 7.04 (m, 1H), 6.96 (s, 1H), 6.87 (t, J=2.8 Hz, 1H), 4.16-4.09 (m, 1H), 3.45-3.14 (m, 3H), 2.76-2.63 (m, 1H), 1.75 (br s, 4H), 1.58 (s, 9H) ppm.
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[CH:6][CH:5]=1)([O-])=O.[CH2:9]1[CH:11]([CH2:12][C:13]([NH2:15])=[O:14])[CH2:10]1>CO.C(O)(=O)C.[Pd]>[NH2:1][C:4]1[NH:8][N:7]=[CH:6][CH:5]=1.[CH2:10]1[CH:11]([CH2:12][C:13]([NH2:15])=[O:14])[CH2:9]1
Reactant: O=[N+]([O-])c1ccn[nH]1
Agent: [Pd]
Agent: NC(=O)CC1CC1
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccn[nH]1

Procedure:
1 g of 5-nitro-1H-pyrazole-3-cyclopropylmethylcarboxamide is dissolved in 30 ml of methanol and 2 ml of acetic acid. This mixture is hydrogenated in the presence of 110 mg of Pd/C under 5 bar until reaction is complete. The mixture is filtered through celite, evaporated to dryness and purified by column chromatography (silica gel, methanol:DCM=1:30).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1O)=[N:13][C:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)=[CH:11][CH:10]=2)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:29]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:29])=[N:13][C:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2ccc(-c3ccc(OC)c(OC)c3)nc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2ccc(-c3ccc(OC)c(OC)c3)nc2c1Cl
Temperature: 125 °C
Reaction time: 1.5 h

Procedure:
A mixture of 6-(3,4-dimethoxy-phenyl)-4-hydroxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester (Stage 249.1.3, 493 mg, 1.391 mmol) in POCl3 was stirred at 125° C. for 1.5 h. Then the RM was evaporated to dryness. The residue was quenched with saturated aqueous NaHCO3. The suspension was filtered, the cake was washed with water and dried in the vacuum oven to give the title compound as a brown solid. Used for next step without further purification. (HPLC: tR 3.80 min (Method A); M+H=373 MS-ES)
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[C:17](O)(=O)CCCCC(O)=O>>[C:12]([O:14][CH3:17])(=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: O=C(O)CCCCCCCCCCC(=O)O
Reactant: O=C(O)CCCCC(=O)O
Product: CCCCCCCCCCCC(=O)OC

Procedure:
Fermentation of dodecane with strain H534 under the standard fermentation conditions (Example 20) produced approximately 139 g/l within 233 hrs with a substrate conversion efficiency of 32.1%. The final production rate was 0.58 g/l/hr. The product was 82.7% dodecanedioic acid. The remaining product was predominantly adipic acid. With methyl laurate as the substrate, H534 produced 115.3 g/l dicarboxylic acid within 223 hrs with a substrate conversion efficiency of 34.6%. The production rate was 0.49 g/l/hr. The product was 89.1% dodecanedioic acid. The remaining product was predominantly adipic acid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C@@H:12]2[O:14][CH2:13]2)=[CH:10][CH:9]=1)([O-:7])=[O:6].N(C[C@@H](C1C=CC([N+]([O-])=O)=CC=1)O)=[N+]=[N-]>C1N(CCCS(O)(=O)=O)CCOC1.C(OCC)C>[N:1]([CH:12]([C:11]1[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:16][CH:15]=1)[CH2:13][OH:14])=[N+:2]=[N-:3]
Reactant: O=[N+]([O-])c1ccc([C@H]2CO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)CCCN1CCOCC1
Agent: [N-]=[N+]=NC[C@H](O)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Solvent: CCOCC
Product: [N-]=[N+]=NC(CO)c1ccc([N+](=O)[O-])cc1

Procedure:
To 60 ml of MOPS buffer (50 mM, pH=7.0), 0.47 gram (3.2 mmol) of racemic para-nitro styrene oxide was added and the suspension was stirred for 60 min. The halohydrin dehalogenase, obtained as described in Example 1, (29 mg in 6 ml buffer) was added. A prepared stock solution of 0.12 gram (1.6 mmol) NaN3 in 5 ml MOPS buffer was slowly added over a period of 24 hours. The reaction was stopped and the suspension was three times extracted with diethylether. After separating, the organic phase was dried with MgSO4, and removed by rotary evaporator yielding an orange oil. This mixture was redissolved in diethylether and the composition and e.e. of the products were determined by chiral HPLC. The mixture mainly consisted of (S)-para-nitro styrene oxide in 46% yield (98% e.e.) and (R)-2-azido-1-(para-nitrophenyl)ethanol in 47% yield (97% e.e.). The chemical side product 2-azido-2-(para-nitrophenyl)ethanol was formed to a total of 4% of the reaction mixture. The product of chemical hydrolysis of the epoxide, para-nitrophenyl ethanediol was formed in 3%. All the mentioned yields are calculated yields. Flash chromatography on silica 60H using heptane/ethylacetate (ratio 7:3) as eluent yielded pure epoxide and azido alcohols. The NMR data were identical with synthesized racemic reference compounds.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:20][CH:21]2[CH2:23][CH2:22]2)=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=1.Cl[C:25]([O:27][CH3:28])=[O:26]>N1C=CC=CC=1>[CH:21]1([S:20][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:25]([O:27][CH3:28])=[O:26])=[CH:7][C:6]=2[C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:22][CH2:23]1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cc(N)ccc1SC1CC1
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc(SC2CC2)c([C@H]2CCCN2C(=O)OC(C)(C)C)c1
Reaction time: 0.5 h
Yield: 109 %

Procedure:
To 85G (1.25 g, 3.74 mmol) in pyridine (8.0 mL) at 0° C. was added methyl chloroformate (0.4 mL, 5.23 mmol). After 30 min, the reaction was quenched by MeOH (2.0 mL). Pyridine was removed under high vacuum. The crude was suspended in EtOAc and washed by 1.0 N HCl (2×20 mL), sat. NaHCO3 and brine. The organic layer was dried over Na2SO4. After evaporation of solvent, 85H (1.6 g, 95% yield) was obtained as a solid used for next step without purification. 1H NMR (400 MHz, DMSO-d6, 100° C.) δ ppm 0.52-0.64 (m, 2H) 0.94-1.05 (m, 2H) 1.17-1.28 (s, 9H) 1.54-1.63 (m, 1H) 1.77-1.86 (m, 2H) 2.18-2.29 (m, 2H) 3.46-3.57 (m, 2H) 3.62-3.68 (s, 3H) 5.05 (dd, J=7.70, 3.85 Hz, 1H) 7.23 (s, 1H) 7.32-7.40 (m, 1H) 7.40-7.47 (m, 1H) 9.26 (s, 1H), LC-MS 293 (M-Boc).
Reaction SMILES: IC.CN([CH:6]=[O:7])C.[Br:8][C:9]1[CH:10]=[C:11]([CH2:14]O)[O:12][CH:13]=1.[H-].[Na+]>O.C(OCC)(=O)C>[Br:8][C:9]1[CH:10]=[C:11]([CH2:14][O:7][CH3:6])[O:12][CH:13]=1
Reactant: OCc1cc(Br)co1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: O
Product: COCc1cc(Br)co1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Iodomethane (1.6 mL) was added to a DMF (15 mL) solution of (4-bromofuran-2-yl)methanol (3.0 g) as obtained in Example 18-(1). Under ice cooling, 60% sodium hydride (0.82 g) was added in divided portions, and the mixture was stirred for 1 hour and 40 minutes at room temperature. Ethyl acetate and water were added, and the organic layer was isolated. The extract was washed with water and brine sequentially, and dried over anhydrous magnesium sulfate. Then, the desiccant was filtered out, and the solvent was distilled off under reduced pressure to obtain partially purified 4-bromo-2-(methoxymethyl)furan (yellow oil) (3.9 g).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[N:37]=[CH:38][S:39][C:40]=1[CH2:41][CH2:42]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:42][CH2:41][C:40]3[S:39][CH:38]=[N:37][C:36]=3[CH3:35])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Reactant: Cc1ncsc1CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ncsc1CCOc1ccc(-c2c(C)nc(C)c([C@H](OC(C)(C)C)C(=O)O)c2N2CCC(C)(C)CC2)cc1
Reaction time: 18 h
Yield: 17.3 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (20 mg, 0.043 mmol), 2-(4-methylthiazol-5-yl)ethanol (30.6 mg, 0.213 mmol) and Ph3P-resin (55.8 mg, 0.213 mmol) in THF (2 mL) was added DEAD (0.020 mL, 0.128 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (0.854 mL, 0.854 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-(2-(4-methylthiazol-5-yl)ethoxy)phenyl)pyridin-3-yl)acetic acid (4.2 mg, 7.42 μmol, 17.39% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.87 (s, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.17 (s, 1H), 7.13-7.08 (m, 2H), 5.54 (s, 1H), 4.54-4.41 (m, 6H), 4.26-4.15 (m, 2H), 2.68 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H), 1.28 (br. s., 4H), 1.15 (s, 9H), 0.80 (br. s., 6H). LCMS (M+H)=566.5.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.FC(F)(F)C(O)=O.[C@H:35]12[CH2:41][C@H:38]([NH:39][CH2:40]1)[CH2:37][O:36]2.C(N(CC)C(C)C)(C)C>ClC(Cl)C.O1CCCC1>[CH3:20][O:19][C:16]1[C:17]2[N:18]=[C:10]([NH:9][C:8]([N:39]3[CH2:40][C@@H:35]4[CH2:41][C@H:38]3[CH2:37][O:36]4)=[O:27])[S:11][C:12]=2[C:13]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[N:14][CH:15]=1
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)N3C[C@@H]4C[C@H]3CO4)nc12

Procedure:
From (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-carbamic acid phenyl ester with (1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]heptane trifluoroacetate and N,N-diisopropylethylamine in dichloroethane and tetrahydrofuran. ES-MS m/e (%): 392 (M+H+, 100).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([O:20]C)=[O:19])[CH2:14][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@H]1CC[C@H](CN[C@@H]2C[C@H]2c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@H]1CC[C@H](CN[C@@H]2C[C@H]2c2ccccc2)CC1

Procedure:
The trans-methyl 4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexanecarboxylate (80 mg, 0.278 mmol) was stirred in a mixture of methanol (3 mL) and sodium hydroxide (3 ml, 3.00 mmol) for 1 hour at room temperature. The solution was then concentrated and purified by preparatory HPLC (5 to 50% AcCN:H2O with 0.1% formic acid modifier). The fractions were combined, 0.5 mL of 6 M HCl was added into each fraction and the product was evaporated. trans-4-(((trans-2-Phenylcyclopropyl)amino)methyl)cyclohexanecarboxylic acid (30 mg, 0.082 mmol, 29.6% yield) was isolated as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.29-7.38 (m, 2H), 7.22-7.28 (m, 1H), 7.08-7.22 (m, 2H), 3.09 (d, J=7.07 Hz, 2H), 3.00 (dt, J=4.07, 7.77 Hz, 1H), 2.53 (ddd, J=3.79, 6.57, 10.36 Hz, 1H), 2.29 (tt, J=3.54, 12.25 Hz, 1H), 2.08 (dd, J=3.28, 13.39 Hz, 2H), 1.94 (dd, J=3.03, 13.14 Hz, 2H), 1.76 (ddd, J=4.29, 7.71, 11.24 Hz, 1H), 1.55 (ddd, J=4.55, 6.57, 10.61 Hz, 1H), 1.43-1.52 (m, 2H), 1.35-1.42 (m, 1H), 1.15 (qd, J=3.54, 12.72 Hz, 2H); LC-MS Rt=0.62 min; MS (ESI): 274.2 [M+H]+.
Reaction SMILES: C([NH:4][C:5]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)(C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=O)C.[ClH:26]>>[ClH:26].[N+:23]([C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][C@@H:5]([C:6]([OH:8])=[O:7])[NH2:4])([O-:25])=[O:24]
Reactant: CCOC(=O)C(Cc1cccc([N+](=O)[O-])c1)(NC(C)=O)C(=O)OCC
Agent: Cl
Product: N[C@@H](Cc1cccc([N+](=O)[O-])c1)C(=O)O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A suspension of 34 g of diethyl 2-(acetylamino)-2-(3-nitrobenzyl)malonate in 510 cm3 of concentrated hydrochloric acid is heated at a temperature in the region of 100° C. for 18 hours: a vigorous evolution of gas takes place and the suspension dissolves when hot. The reaction mixture is then cooled to a temperature in the region of 0° C., after which it is stirred for 1 hour at 0° C. and finally filtered through a sinter funnel. The filter cake is washed with twice 50 cm3 of filtrate and dried in a fume cupboard and then in an oven under vacuum (10 Pa) at a temperature in the region of 60° C. 23.4 g of 3-nitrophenylalanine hydrochloride are obtained in the form of white crystals melting at 222° C.