Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[C:3]=1[CH:9]=O.[F:11][C:12]([F:22])([F:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][NH2:20]>CN(C1C=CN=CC=1)C.CN1C(=O)CCC1>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]([F:11])([F:21])[F:22])[N:20]=[CH:9][C:3]=12
Reactant: O=Cc1c(I)ccnc1F
Reactant: NNc1ccccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccccc1-n1ncc2c(I)ccnc21
Temperature: 185 °C
Yield: 46 %

Procedure:
To a dry 15 mL ChemGlass pressure bottle under N2 was added 4-iodo-2-fluoro-3-formylpyridine (750 mg, 2.99 mmol), (2-(trifluoromethyl)phenyl)hydrazine (526 mg, 2.99 mmol), DMAP (200 mg, 1.637 mmol), and anhydrous NMP (4 mL). The reaction mixture was flushed with argon, securely capped and heated at 185° C. for 3.75 h. The reaction mixture was worked up according to the procedure described in Intermediate 69A to give 535 mg (44%) of the title compound (contains approximately 88% of the hydrazone intermediate) as a brown solid. LC/MS (Condition B): ret. T=4.19 min, (M+H)+ 389.90.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:19][N:18]=[C:17]([C:20]([NH:22][CH2:23][C:24]([OH:26])=O)=[O:21])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Cl:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[NH:67][CH:68]1[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1>CN(C=O)C.O>[Cl:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[NH:67][CH:68]1[CH2:73][CH2:72][N:71]([C:24](=[O:26])[CH2:23][NH:22][C:20]([C:17]2[CH:16]=[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[NH:19][N:18]=2)=[O:21])[CH2:70][CH2:69]1
Reactant: Clc1ccccc1NC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2OCc2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1cc(-c2ccccc2OCc2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a stirred solution of {[5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid (0.15 g, 0.00039 mol) in DMF (2 mL) was added DIPEA (0.224 g, 0.00174 mol), HOBt (0.065 g, 0.00048 mol) and EDCI.HCl (0.0925 g, 0.00048 mol) at ambient temperature. After 5 minutes (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride (0.1 g, 0.00041 mol) was added to the reaction mixture continued stirring at the same temperature for overnight. The reaction mixture was diluted with cold water, filtered the solid precipitated and dried to afford 0.205 g (98%) of 5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 544.2 (M+1)+, 92.2%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].CN(C)C=O.Br[CH2:21][CH2:22][OH:23]>O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:21][CH2:22][OH:23]
Reactant: Oc1ccccc1Br
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCOc1ccccc1Br
Temperature: 50 °C
Yield: 93.1 %

Procedure:
Potassium carbonate (23.8 g) and 2-bromophenol (14.9 g) were mixed with dimethylformamide (150 ml). 2-Bromoethanol (12.9 g) was added and the mixture heated to 50° C. for 18 h. The mixture was cooled and added to water (1500 ml). The product was extracted into diethyl ether (×3) and washed twice with dilute sodium hydroxide solution Evaporation gave 2-(2-bromophenoxy)ethanol (17.4 g).
Reaction SMILES: [ClH:1].Cl.Br[C:4]1[CH:5]=[C:6]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:28](=[O:29])[C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4S3(=O)=O)[CH2:16][CH2:15]2)[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1.BrCCCCN1C(=O)C2C(=CC=CC=2)[C:42]1=[O:51]>>[ClH:1].[Cl:1][C:4]1[CH:5]=[C:6]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:42](=[O:51])[C:26]4[C:27](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]3=[O:29])[CH2:16][CH2:15]2)[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCN1CCN(c2cc(Br)cc3c2OCCO3)CC1
Agent: Cl
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCN(c2cc(Cl)cc3c2OCCO3)CC1

Procedure:
This compound was prepared analogous to the method described for 2-(4-(4-(7-bromo-2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl)-butyl)-1H-isoindole-1,3(2H)-dione, dihydrochloride (Example 3) using intermediate 2a (1.30 g, 4.5 mmol) and 2-(4-bromobutyl)-1H-isoindole-1,3(2H)-dione (1.40 g, 4.9 mmol). Yield 2.20 g, m.p. 222°-4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:5]2=1.BrN1C(=[O:28])CCC1=O>C1COCC1.CC(O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11]3)[C:6](=[O:28])[NH:7][C:8]2=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3ccc(Cl)cc23)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2(C1)C(=O)Nc1ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 100.7 %

Procedure:
A solution of tert-butyl 6-chloro-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (0.500 g, 1.63 mmol) in 1:1:1 THF/AcOH/H2O (45 mL) at about 0° C. was treated with N-Bromosuccinimide (0.319 g, 1.79 mmol) portionwise over about 20 minutes. The resulting mixture was stirred for about 90 minutes at about 0° C. The mixture was then quenched by the addition of saturated Na2CO3 (100 mL) and extracted with DCM. The combined organics were washed with saturated NaHCO3 (2×) and brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by column chromatography (20% EtOAc/Hexane) to yield tert-butyl 5-chloro-2-oxospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (0.530 g, 100%). LCMS (APCI+) m/z 223, 225 [M+H−Boc]+; Rt=3.26 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[CH3:2].[Br:22]N1C(=O)CCC1=O.Br>C(Cl)(Cl)(Cl)Cl>[Br:22][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:21]
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C#N)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)c1ccc(Oc2ccc(C#N)cc2)cc1

Procedure:
To a solution of 1.17 g of ethyl[p-(p-cyanophenoxy)phenyl]acetate in 20 ml of carbon tetrachloride is added 0.75 g of N-bromosuccinimide and a drop of 48% HBr. The mixture is stirred and refluxed for 42 hours. The solvent is removed under vacuum to give the product.
Reaction SMILES: [CH2:1]([C:4]1[N:5]=[N:6][N:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:8]=1)[CH2:2][CH3:3].[CH3:15][I:16]>C(#N)C>[I-:16].[CH3:15][N+:5]1[C:4]([CH2:1][CH2:2][CH3:3])=[CH:8][N:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:6]=1
Reactant: CI
Reactant: CCCc1cn(-c2ccncc2)nn1
Solvent: CC#N
Product: CCCc1cn(-c2ccncc2)n[n+]1C
Product: [I-]

Procedure:
4-(4-propyl-1H-1,2,3-triazol-1-yl)pyridine (3.23 g, 17.15 mmol), methyl iodide (15 ml, 240 mmol), and acetonitrile (Volume: 20 ml) were added to a 100 mL round-bottom flask and refluxed for about 19 hours. The reaction was concentrated. The resulting solid was recrystallized from ethyl acetate (100 mL) and methanol (50 mL). The precipitate was filtered and dried in vacuo at 60° C. The following 3-methyl-4-propyl-1-(pyridin-4-yl)-1H-1,2,3-triazol-3-ium iodide structure was confirmed:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)([CH3:6])[CH3:5])[CH3:2].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH2:41][CH2:42][O:43][CH3:44])[N:36]=[CH:35][N:34]=[C:33]2[S:45][C:46]1[CH:47]=[C:48]([CH:50]=[CH:51][CH:52]=1)[NH2:49].C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:1]([O:3][C:4]([C:7]1[CH:11]=[C:10]([NH:12][C:13]([NH:49][C:48]2[CH:50]=[CH:51][CH:52]=[C:46]([S:45][C:33]3[C:32]4[C:37](=[CH:38][C:39]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[C:30]([O:29][CH3:28])[CH:31]=4)[N:36]=[CH:35][N:34]=3)[CH:47]=2)=[O:21])[N:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:8]=1)([CH3:5])[CH3:6])[CH3:2]
Reactant: CCOC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(C)(C)c1cc(NC(=O)Nc2cccc(Sc3ncnc4cc(OCCOC)c(OC)cc34)c2)n(-c2ccccc2)n1
Yield: 54 %

Procedure:
Using the procedure described in Example 159B, phenyl 3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate described in Example 168B (0.115 g, 0.33 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (0.118 g, 0.33 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) at 50° C. for 5 hours, to afford 1-[3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}urea as solid (0.111 g, 54%). 1H NMR (300 MHz, DMSO-d6) δ 9.25 (br, 1H), 8.68 (s, 1H), 8.54 (s, 1H), 7.79 (s, 1H), 7.54 (m, 4H), 7.37 (m, 5H), 7.25 (d, 1H), 6.42 (s, 1H), 4.33 (m, 2H), 3.99 (s, 3H), 3.76 (m, 2H), 3.34 (s, 3H), 3.25 (q, 2H), 1.46 (s, 6H), 1.04 (t, 3H); LC-MS (ESI) m/z 583 (M−OEt)+.
Reaction SMILES: [C:1]1(=[O:12])[O:7][C:5](=O)[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[CH3:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:15]=1[NH2:16]>C(OCC)(=O)C>[CH3:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:15]=1[N:16]1[C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2][C:1]1=[O:12]
Reactant: Cc1cccc(C)c1N
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1N1C(=O)Cc2ccccc2C1=O
Reaction time: 1 h
Yield: 68 %

Procedure:
0.67 g (4.13 mmol) of homophthalic anhydride and 0.4 g (3.30 mmol) of 2,6-dimethylaniline were mixed, and melted at a temperature of 200° C. for 1 hour. The reactant was dissolved in ethyl acetate, washed with aqueous NaHCO3 solution, with water and then with saturated aqueous sodium chloride, dried over anhydrous MgSO4, and subjected to filtration with a folded filter paper. The filtrate was concentrated and evaporated to dryness. The residue was recrystallized by using a mixture of CH2Cl2 and hexane, to obtain 0.565 g (yield 68%) of the specified substance as light yellow granulated crystals. It showed the following physical properties and analyzed values.
Reaction SMILES: [NH2:1][C:2]1[N:31]=[C:5]2[N:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:7]([CH3:20])=[C:8]([C:18]#[N:19])[C@@H:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>N1C=CC=CC=1>[C:18]([C:8]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[N:4]2[N:3]=[C:2]([NH:1][C:33](=[O:34])[O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:31]=[C:5]2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=2)[C:7]=1[CH3:20])#[N:19]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (400 mg, 874 μmol) was initially charged in abs. pyridine (15 ml). At 0° C., benzyl chloroformate was added in a plurality of portions (3×460 mg, 3×2621 μmol; 9 eq.), and the mixture was then stirred for 12 h with warming to RT. Once HPLC analysis showed substantial conversion, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (500 mg, quant.).
Reaction SMILES: ClC1C=CC=C[N:3]=1.S(=O)(=O)(O)O.Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1.C([O-])(=O)C.[NH4+]>COCCOCCOC>[NH2:3][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Clc1ccccn1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: COCCOCCOC
Product: Nc1ncccc1[N+](=O)[O-]

Procedure:
A general synthesis route begins with 2-chloropyridine which is nitrated in the presence of sulfuric acid to make 2-chloro-3-nitropyridine. This material is reacted with ammonium acetate in the presence of diglyme at about 160° C. to form 2-amino-3-nitropyridine which is reduced to form 2,3-diaminopyridine. The 2,3-diaminopyridine is reacted with 2-thiophenecarboxylic acid in the presence of polyphosphoric acid at about 125° C. to prepare 2-(2-thienyl)imidazolo [4,5]pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:22]#[N:23])[CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:7]2.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1.C(Cl)Cl>[C:24]([N:10]1[C:11]2[C:6](=[CH:5][C:4]([C:22]#[N:23])=[CH:3][C:2]=2[Cl:1])[CH2:7][CH:8]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1cc(Cl)c2c(c1)CC(NS(=O)(=O)c1ccccc1)CN2
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1cc(Cl)c2c(c1)CC(NS(=O)(=O)c1ccccc1)CN2C(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 28.1 %

Procedure:
To a solution of compound 163A (164 mg, 0.472 mmol) in pyridine (1 mL) and CH2Cl2 (1 my) at RT was added benzoyl chloride (82 μL, 0.71 mmol), and the mixture was then stirred at 50° C. for 16 h. After cooling to RT, the reaction was concentrated in vacuo and the resultant residue was taken into MeOH (4 mL), and Et3N (1 mL) added. The reaction was stirred at 70° C. for 1 h. After cooling to RT, the reaction was concentrated. The residue was diluted with 10% aqueous citric acid, then extracted with EtOAc (3×15 mL). The combined EtOAc extracts were concentrated. The resulting residue was purified using preparative HPLC (YMC S5 ODS 20×100 mm) eluting with MeOH (50-80%) in H2O for 8 min, and then 80% MeOH in H2O for 7 min to give the title compound (60 mg, 28%) as a white solid. HPLC: 99% at 6.2 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A 90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 452 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.C(NC(C)C)(C)C.[Li].[CH3:17][C:18]([CH3:20])=[O:19]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:8])[C:7]=1[C:18]([OH:19])([CH3:20])[CH3:17]
Reactant: CC(C)=O
Reactant: Fc1cncc(Br)c1
Agent: [Li]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(O)c1c(F)cncc1Br
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a round bottom flask is added 3-bromo-5-fluoropyridine (475 mg, 2.7 mmol) in 4 ml of dry THF at −78° C., followed by the addition of lithium diisopropylamine (1.6 ml, 3.2 mmol). The reaction mixture is stirred at −78° C. for 1 hour, followed by the addition of acetone (0.6 ml). The reaction mixture is warmed up and stirred at room temperature for 30 minutes. The reaction mixture is diluted with EtOAc, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 190 mg of 2-(3-bromo-5-fluoro-pyridin-4-yl)-propan-2-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[Br:10]Br.ClCCl.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:10][C:6]1[C:5]([F:8])=[CH:4][C:3]([OH:9])=[C:2]([Cl:1])[CH:7]=1
Reactant: BrBr
Reactant: Oc1cc(F)ccc1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Oc1cc(F)c(Br)cc1Cl
Temperature: 75 °C
Reaction time: 2 h

Procedure:
2-Chloro-5-fluorophenol (24.1 g, 165 mmol) was dissolved in anhydrous chloroform (200 mL), heated to 75° C. and treated with a solution of bromine (8.5 mL, 165 mmol) in anhydrous chloroform (40 mL) added dropwise over 5 minutes. After 3 hours the reaction was treated with additional bromine (1.7 mL, 33 mmol) in anhydrous chloroform (15 mL) and stirred at 75° C. After 2 hours, the reaction was cooled to room temperature and treated with dichloromethane (300 mL) and Na2S2O3 (100 mL, saturated aqueous solution). After mixing vigorously, the layers were separated and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting yellow liquid was purified by vacuum distillation. Compound C.1 (22.3 g, 60%) was obtained as a colorless liquid. LC-MS ESI (neg.) m/e: 224.9 (M−H). 1H NMR (400 MHz) (CDCl3) □ 7.51 (d, J=6.9 Hz, 1H); 6.85 (d, J=9.2 Hz, 1H); 5.69 (s, 1H).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.Cl.[NH2:14][C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=1)[C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19].C(N(CC)CC)C.Cl.[CH3:35][O:36][C:37](=[O:40])[CH2:38][NH2:39]>ClCCl.O>[CH3:35][O:36][C:37]([CH2:38][NH:39][C:2](=[O:4])[NH:14][C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=1)[C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])=[O:40]
Reactant: COC(=O)CN
Reactant: C=CCOC(=O)c1cccc(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)c1cccc(NC(=O)NCC(=O)OC)c1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 214.1 %

Procedure:
A suspension of triphosgene (2.5 g, 8.42 mmol) and allyl 3-aminobenzoate hydrochloride (4.0 g, 18.7 mmol) in dichloromethane (80 ml) is cooled to -20° C. and triethylamine (9.64 ml, 69.2 mmol) is added dropwise thereto. The mixture is strirred for 30 minutes. To the mixture is added glycine methyl ester hydrochloride (2.82 g, 22.44 mmol). Then, triethylamine (3.75 ml, 18.7 mmol) is added dropwise, followed by stirring at -20° C. for 2.5 hours. Ice-cooled water is added to the reaction solution and, after stirring, the aqueous layer is extracted twice with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to obtain the objective compound (5.27 g). Yield 96%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([CH3:30])[CH:25]=CC(S(O)(=O)=O)=C[CH:21]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(OC(C)(C)C)(=O)C.O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:17]([O:19][C:20]([CH3:30])([CH3:25])[CH3:21])=[O:18])[NH2:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)(C)C
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H](N)CCCNC(=O)OCc1ccccc1
Temperature: 10 °C

Procedure:
Suspend N5 -benzyloxycarbonyl-ornithine (80 g, 0.3 mol) in t-butyl acetate (250 mL) and cool to 10° C. Add p-toluenesulfonic acid (57 g, 0.3 mol) and add, by dropwise addition, concentrated sulfuric acid (80 mL). Stir at 10° C. until the reaction is complete, basify to pH 8 by adding a suspension of sodium bicarbonate in water. Extract with ethyl acetate, dry (MgSO4), and evaporate to give N5 -benzyloxycarbonyl-ornithine, t-butyl ester.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][C:6]([C:14]([O:16]C)=[O:15])=[C:7]([C:10]([O:12]C)=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+].Cl>O>[S:1]1[C:9]2[C:4](=[N:5][C:6]([C:14]([OH:16])=[O:15])=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1cc2sccc2nc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc2sccc2nc1C(=O)O
Temperature: 60 °C

Procedure:
Dimethyl thieno[3,2-b]pyridine-5,6-dicarboxylate (3.75 g, 0.0149 mol) is added to a solution of sodium hydroxide (1.8 g, 0.045 mol) in water (20 mL) and the mixture is warmed at 60° C. for 20 hours. The reaction mixture is diluted with water, cooled in an ice bath, and acidified by the addition of concentrated hydrochloric acid. A precipitate of thieno[3,2-b]pyridine-5,6-dicarboxylic acid is filtered off and dried overnight to give 3.1 g (93%) mp>380° C.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[NH:33]1[CH2:38][CH2:37][CH:36]([C:39]2[S:40][C:41]3[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=3[N:43]=2)[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[S:40]1[C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=[C:39]1[CH:36]1[CH2:35][CH2:34][N:33]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][N:5]([C@H:14]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[O:16])[CH2:4]2)[CH2:38][CH2:37]1
Reactant: c1ccc2sc(C3CCNCC3)nc2c1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(c4nc5ccccc5s4)CC3)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
To a solution of 52 mg of α-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxybenzyl ester (prepared above as Aldehyde 5) and 50 mg of 2-(piperidin-4-yl)benzothiazole (from Step B) in 2.5 mL of THF was added two spatula tips of 3 Å molecular sieves. After stirring at room temperature for 20 mim., 50 mg of sodium triacetoxyborohydride was added and the reaction was stirred at room temperature for 18 hours. The reaction was quenched with MeOH and diluted with EtOAc. After filtering molecular sieves, the filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous MgSO4. Concentration under reduced pressure followed by flash chromatography eluting with 20% EtOAc in hexane followed by 50% EtOAc in hexane afforded 56 mg of the title compound as a white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[C:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:7]=2)[CH2:3][CH2:2]1.CN(CCN(C)C)C.C([Li])(C)(C)C.[Br:36]C(F)(F)C(F)(F)Br>C1COCC1>[Br:36][C:7]1[C:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:9][C:10]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:11][C:6]=1[C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:22]
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: COCCCc1cc(CCCOC)cc(C(=O)NC2CC2)c1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COCCCc1cc(CCCOC)c(Br)c(C(=O)NC2CC2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a THF (0.1 M) solution of N-cyclopropyl-3,5-bis(3-methoxypropyl)benzamide (1 eq.) from the previous step and freshly distilled TMEDA (1 eq.) was added at −78° C. t-butyl lithium (1.7 M in pentanes, 1 eq.) dropwise over 10 min. The resulting reaction mixture was then slowly warmed to 0° C. over 1 h and stirred at 0° C. for 1 h. With the now orange reaction solution re-cooled to −78° C., 1,2-dibromotetrafluoroethane was added neat, dropwise over 10 min. The cooling bath was removed and the reaction mixture was stirred at RT for 18 h. The reaction was then quenched with 1 N aq. NaOH and extracted with EtOAc. The combined organic extracts were washed further with 10% aq. HCl, water and brine, dried over Na2SO4, filtered, and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a pale yellow oil.