Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:20]=[C:19]([C:21]#[C:22][CH2:23][CH2:24][OH:25])[S:18][C:13]=3[N:14]([CH2:16][CH3:17])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1>[Pd].C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[S:18][C:13]=3[N:14]([CH2:16][CH3:17])[CH:15]=2)=[O:9])=[CH:27][CH:28]=1
Reactant: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCCO)sc21
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCCCO)sc21
Yield: 81 %

Procedure:
A solution of N-(4-chlorobenzyl)-7-ethyl-2-(4-hydroxy-1-butynyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Example No. 15) (0.257 g) in 1/1 CH2Cl2/CH3OH (50 mL) is hydrogenated over 10% Pd/C (75 mg) at 35 psi for 2 h. The reaction mixture is filtered through a Celite pad, and the filtrate is concentrated in vacuo. The resulting pale yellow solid is purified via column chromatography (CH2Cl2:CH3OH; 98:2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield 0.209 g (81%) of the title compound as a white solid.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][CH:4]=[C:5]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:7].CN(C)C=O.Cl[CH2:34][C:35]#[CH:36].[H-].[Na+]>O>[F:1][CH:2]([F:27])[O:3][CH:4]=[C:5]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:36][C:35]#[CH:34])=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:7]
Reactant: COc1cc(CCNC(=O)C(=COC(F)F)c2ccc(C)cc2)ccc1O
Reactant: C#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1ccc(CCNC(=O)C(=COC(F)F)c2ccc(C)cc2)cc1OC
Yield: 43.8 %

Procedure:
Five hundred milligrams (500 mg) of 3-difluoromethoxy-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-(4-methylphenyl)acrylamide (1.33 mmol), 5 ml of anhydrous N,N-dimethylformamide, 196 mg (2.65 mmol) of 3-chloropropyne and 60 mg (1.46 mmol) of 60% sodium hydride were stirred at room temperature for 2 hours. Water was added to to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid, saturated aqueous sodium bicarbonate solution and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 242 mg of 3-difluoromethoxy-N-[2-{3-methoxy-4-(2-propynyloxy)phenyl}ethyl]-2-(4-methylphenyl)acrylamide (the present compound 1353).
Reaction SMILES: N[C:2]1[C:3]([C:16]#[N:17])=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[I:18]CI.N(OCCC(C)C)=O>C1COCC1.[Cu]I>[C:16]([C:3]1[C:2]([I:18])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1)#[N:17]
Reactant: ICI
Reactant: COC(=O)c1cc(N)c(C#N)cc1C(F)(F)F
Agent: [Cu]I
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(I)c(C#N)cc1C(F)(F)F
Temperature: 25 °C
Yield: 48 %

Procedure:
Methyl 5-amino-4-cyano-2-(trifluoromethyl)benzoate (250 mg, 1.02 mmol) was dissolved in THF (6 mL), and the mixture was sparged with nitrogen for 15 minutes. Copper (I) iodide (195 mg, 1.02 mmol) and diiodomethane (0.4 mL, 4.95 mmol) were added followed by isoamyl nitrite (0.4 mL, 3.01 mmol), and the mixture was stirred at reflux for 2.5 h. The mixture was cooled to ambient temperature and then was partitioned between ethyl acetate and 1N hydrochloric acid. The aqueous portion was extracted with ethyl acetate (2×). The combined organic portion was washed sequentially with 1:1 saturated sodium bicarbonate solution: 1 M sodium thiosulfate (2×) and brine, was dried over sodium sulfate, then filtered and concentrated to provide a semi-solid which was purified by column chromatography (silica gel, 20-50% dichloromethane in hexanes) to afford methyl 4-cyano-5-iodo-2-(trifluoromethyl)benzoate (174 mg, 0.49 mmol, 48% yield). 1H NMR (400 MHz, CDCl3): δ 8.33 (s, 1H), 7.93 (s, 1H), 3.98 (s, 3H); GCMS for C10H5F3INO2: 355 (M+).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[Br:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[Br:17])[CH:12]=[C:5]1[S:1][C:2](=[O:7])[NH:3][C:4]1=[O:6]
Reactant: O=Cc1ccc(Br)c(Br)c1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C1NC(=O)C(=Cc2ccc(Br)c(Br)c2)S1

Procedure:
A mixture of thiazolidine-2,4-dione (90%, 65 mg, 0.5 mmol), 3,4-dibromobenzaldehyde (132 mg, 0.5 mmol), and piperidine (247 μL, 2.5 mmol) was shaken in acetic acid (2 mL) at 110° C. for 16 hours. After cooling, the mixture was concentrated to dryness in vacuo. The resulting crude product was shaken with water, centrifuged, and the supernatant was discarded. Subsequently the residue was shaken with ethanol, centrifuged, the supernatant was discarded and the residue was further evaporated to dryness to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16](=O)[CH3:17])[CH2:11][C:10]=3[C:19](=[O:21])[O:20][C:5]=2[CH:4]=1.[CH3:22][NH2:23]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([NH:23][CH3:22])[CH3:17])[CH2:11][C:10]=3[C:19](=[O:21])[O:20][C:5]=2[CH:4]=1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CN(CC(C)=O)CC3
Reactant: CN
Product: CNC(C)CN1CCc2c(c(=O)oc3cc(OC)ccc23)C1
Yield: 69.6 %

Procedure:
Prepared by the method described for Example 51 from 1,2,3,4-tetrahydro-8-methoxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one (16.5 g, 0.057 moles) and methylamine (8 ml, 0.18 moles). Recrystallization from ethyl acetate gave the product (12.0 g), mp 109°-111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]([CH2:16][CH2:17][CH2:18]O)[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]([CH2:16][CH2:17][CH2:18][Cl:24])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: OCCCN(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Product: ClCCCN(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1

Procedure:
3-[N,N-bis-(4-chlorobenzyl)amino]propyl chloride was prepared by halogenating 3-[N,N-bis-(4-chlorobenzyl)amino]propanol using thionyl chloride.
Reaction SMILES: [C:1]1([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:18][N:19]=[C:20]=[O:21]>C1(C)C=CC=CC=1.P([O-])(OCCCC)(OCCCC)=O>[CH3:18][NH:19][C:20]([N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:21]
Reactant: CN=C=O
Reactant: c1ccc(Nc2cccc3ccccc23)cc1
Agent: CCCCOP(=O)([O-])OCCCC
Solvent: Cc1ccccc1
Product: CNC(=O)N(c1ccccc1)c1cccc2ccccc12
Temperature: 100 °C
Yield: 80 %

Procedure:
0.5 mole of α-naphthyl-phenylamine was taken together with 0.53 mole of methyl isocyanate and 0.6 g of di-n-butyl phosphate in 150 ml of toluene. The mixture was warmed at 100° C. for 24 hours, with stirring, and then cooled to 10° C. After the product had been filtered off, washed with 150 ml of cold toluene and dried, 0.4 mole of N-methyl-N'-phenyl-N'-α-naphthyl-urea was obtained. Melting point: 146° C./yield: 80% of theory,
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.[CH3:52][N:53]1[C:57]([CH3:58])=[C:56]([CH2:59][N:60]2[CH2:65][CH2:64][N:63]([C:66]3[C:71]([C:72]4[CH:79]=[CH:78][C:75]([CH2:76][NH2:77])=[CH:74][CH:73]=4)=[N:70][CH:69]=[CH:68][N:67]=3)[CH2:62][CH2:61]2)[CH:55]=[N:54]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:52][N:53]1[C:57]([CH3:58])=[C:56]([CH2:59][N:60]2[CH2:61][CH2:62][N:63]([C:66]3[C:71]([C:72]4[CH:73]=[CH:74][C:75]([CH2:76][NH:77][C:6]([CH:3]5[CH2:4][CH2:5][O:1][CH2:2]5)=[O:8])=[CH:78][CH:79]=4)=[N:70][CH:69]=[CH:68][N:67]=3)[CH2:64][CH2:65]2)[CH:55]=[N:54]1
Reactant: O=C(O)C1CCOC1
Reactant: Cc1c(CN2CCN(c3nccnc3-c3ccc(CN)cc3)CC2)cnn1C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(CN2CCN(c3nccnc3-c3ccc(CNC(=O)C4CCOC4)cc3)CC2)cnn1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38.8 %

Procedure:
Dissolve racemic tetrahydro-furan-3-carboxylic acid (0.067 g, 0.58 mmol) in methylene chloride (5 mL). Add benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (PyBOP) (0.453 g, 0.87 mmol). Add 1-hydroxybenzotriazole (0.118 g, 0.87 mmol). Add 4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzylamine (0.24 g, 0.63 mmol) dissolved in methylene chloride (5 mL). Stir at rt for 5 min. Add diisopropylethylamine (0.113 g, 0.87 mmol). Stir at rt for 4 hr. Purify by normal phase chromatography (4% 7 N ammonia-methonal/ethyl acetate) to give racemic tetrahydro-furan-3-carboxylic acid 4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzylamide (0.107 g, 39%). MS (ES): m/z=476.3[M+H]. Dissolve this racemate (0.107 g, 0.23 mmol) in acetonitrile (1 mL) and water (4 mL). Add aq. 1 N HCl (1 eq., 0.23 mmol, 0.23 mL). Freeze the solution to −78° C. in a dry-ice/acetone bath. Place the solution in the lyophilizer for 48 hr. to give the title compound (0.110 g, 94%). MS (ES): m/z=476.3 [M+H].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][N:11]=[C:10]([NH2:17])[CH:9]=2)[CH2:4][CH2:3]1>CCOC(C)=O.CCO.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([NH2:14])=[CH:12][N:11]=[C:10]([NH2:17])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2cc(N)ncc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN1CCN(c2cc(N)ncc2N)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.8 %

Procedure:
Pd on C, (10%, wet, Degussa) (140 mg, 0.1316 mmol) was added to a stirred solution of 4-(4-methylpiperazin-1-yl)-5-nitro-pyridin-2-amine (355 mg, 1.496 mmol) in a mixture of EtOAc (5 mL) and EtOH (50 mL). The reaction was placed under an atmosphere of hydrogen and stirred at ambient temperature for 16 hours. The catalyst was removed by filtration through a pad of celite and the filtrate concentrated in vacuo to give 4-(4-methylpiperazin-1-yl)pyridine-2,5-diamine as a brown solid (291 mg, 94% Yield). MS (ES+) 208.1.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([CH:14]([OH:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)=O.Cl.[NH2:24][C:25]([NH2:27])=[NH:26].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:26][C:25]1[N:27]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[C:9]([CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[OH:21])[CH:8]=2)[CH:4]=[CH:3][N:24]=1
Reactant: CN(C)/C=C/C(=O)c1ccc(F)c(C(O)c2ccccc2)c1
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1nccc(-c2ccc(F)c(C(O)c3ccccc3)c2)n1
Temperature: 150 °C

Procedure:
A 5 mL microwave tube was charged with (2E)-3-(dimethylamino)-1-{4-fluoro-3-[hydroxy(phenyl)methyl]phenyl}-2-propen-1-one (0.2 mmol), guanidine hydrochloride (0.4 mmol), potassium carbonate (0.6 mmol) and ethanol (3.5 mL). The reaction was heated to 150° C. for 600 s using microwave irradiation. The reaction was concentrated to dryness and the residue was taken up in water and extracted with ethyl acetate. The organics were dried over magnesium sulfate, filtered and concentrated to dryness. Reconcentration from diethyl ether provided [5-(2-amino-4-pyrimidinyl)-2-fluorophenyl]-(phenyl)methanol as a white foam. H1 NMR (d6-dmso): 8.34 (dd, 1H), 8.26 (d, 1H), 7.93 (m, 1H), 7.31 (m, 4H), 7.21 (m, 2H), 7.05 (d, 1H), 6.67 (br s, 2H), 6.10 (d, 1H), 5.94 (d, 1H). Mass (ES+)=296.1 (100%).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[CH:7]1([C:13]2[CH:14]=[CH:15][C:16]([O:39][CH3:40])=[C:17]([C:19]3[N:20]=[C:21]([NH:24][C:25]([N:27]4[CH2:32][CH2:31][N:30]([CH:33]5[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]5)[CH2:29][CH2:28]4)=[O:26])[S:22][CH:23]=3)[CH:18]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.O>C(Cl)Cl>[CH:7]1([C:13]2[CH:14]=[CH:15][C:16]([O:39][CH3:40])=[C:17]([C:19]3[N:20]=[C:21]([NH:24][C:25]([N:27]4[CH2:28][CH2:29][N:30]([CH:33]5[CH2:38][CH2:37][CH2:36][N:35]([C:5](=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])[CH2:34]5)[CH2:31][CH2:32]4)=[O:26])[S:22][CH:23]=3)[CH:18]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COc1ccc(C2CCCCC2)cc1-c1csc(NC(=O)N2CCN(C3CCCNC3)CC2)n1
Reactant: CC(C)N=C=O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C2CCCCC2)cc1-c1csc(NC(=O)N2CCN(C3CCCN(C(=O)NC(C)C)C3)CC2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.06 ml of isopropyl isocyanate was added to a solution of 0.2 g of the compound obtained in step 2.4 in 1.2 ml of DCM, at 0° C. The medium was stirred for 2 h at 0° C. then hydrolysed with 5 ml of water and diluted with 10 ml of DCM. The organic phase was washed twice with a saturated NaHCO3 solution then with a saturated NaCl solution. After drying over MgSO4, the organic phase was concentrated then purified by flash chromatography to produce 0.16 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1.COC(C1C(C)=CC(C2C=CC=C(C(F)(F)F)C=2)=C(Cl)N=1)=O.CC1C(C(O)=O)=NC=C(C2C=CC=C(C(F)(F)F)C=2)C=1.[N:64]1([CH:69]2[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]2)[CH2:68][CH2:67][CH2:66][CH2:65]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([N:72]2[CH2:73][CH2:74][CH:69]([N:64]3[CH2:68][CH2:67][CH2:66][CH2:65]3)[CH2:70][CH2:71]2)=[O:10])[C:5]([CH3:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Agent: COC(=O)c1nc(Cl)c(-c2cccc(C(F)(F)F)c2)cc1C
Agent: Cc1cc(-c2cccc(C(F)(F)F)c2)cnc1C(=O)O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 1, 6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid [prepared from 6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester (intermediate 2) by saponification in analogy to the procedure described for intermediate 1B] was reacted with 4-pyrrolidin-1-yl-piperidine to give the title compound as light brown solid. MS: 452.1 (MH+, 1Cl).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[Cl:11]Cl>C(O)(=O)C>[Cl:11][C:4]1[C:5]([OH:10])=[C:6]([CH:9]=[C:2]([Br:1])[CH:3]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: ClCl
Solvent: CC(=O)O
Product: O=Cc1cc(Br)cc(Cl)c1O

Procedure:
Scheme II illustrates methodology useful for preparing the ethyl N-gly-amino-3-(3,5-dihalo-2-hydroxy)phenyl propionate portion which can be coupled to the tetrahydropyrimidinobenzoic acid moiety. Briefly, 3,5-halo substituted salicylaldehydes may be prepared by direct halogenation as, for example, would be the case where 5-bromosalicylaldehyde is slurried in acetic acid and an equivalent or more of chlorine is added to yield 3-chloro-5-bromo-2-hydroxybenzaldehyde. Some product precipitates and can be recovered by filtration. The remainder may be recovered by diluting the filtrate with water and isolating the precipitate. Combining the solids and drying gives 3-chloro-5-bromo-2-hydroxybenzaldehyde. 3-iodo-5-chlorosalicylaldehyde may be prepared by reacting 5-chlorosalicylaldehyde with N-iodosuccinimide in DMF and subjecting the reaction mixture to usual work-up conditions. 3-iodo-5-bromosalicylaldehyde may be prepared by reacting 5-bromosalicylaldehyde in acetonitrile with potassium iodide and chloramine T. Work-up gives a material that when treated with hexanes gives the desired 3-iodo-5-chlorosalicylaldehyde.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:11]([CH2:13][NH2:14])[OH:12]>O1CCOCC1.CC(OC)(C)C>[Cl:1][C:2]1[C:3]([NH:14][CH2:13][CH2:11][OH:12])=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cnc(Cl)c(Cl)c1
Reactant: NCCO
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: N#Cc1cnc(NCCO)c(Cl)c1
Temperature: 80 °C
Yield: 89.3 %

Procedure:
A mixture of 5,6-dichloro-nicotinonitrile (Bionet GC-0755, 500 mg, 2.89 mmol) and ethanolamine (0.87 mL, 14.45 mmol) was prepared in anhydrous dioxane (5 mL) and heated at 80° C. for 24 hours. The reaction mixture was diluted with MTBE (50 mL) and washed with water (2×25 mL) and brine (25 ml). The aqueous layers were extracted with MTBE (50 mL). The organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a white powder (510 mg, 89%). HPLC (Method A), Rt: 1.9 min (purity: 99.9%). UPLC/MS, M−(ESI): 196.0.
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1.Br[CH:16]([CH3:22])[C:17]([O:19]CC)=[O:18]>C(Br)C.O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH3:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:16]([CH3:22])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1ccsc1-c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCBr
Product: Cc1ccsc1-c1ccc(C(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.9 %

Procedure:
To a mixture of 1.2 g (0.05 mole) of magnesium turnings and 50 ml of anhydrous tetrahydrofuran was added under a nitrogen stream one drop of ethyl bromide, followed by adding 10 g (0.0395 mole) of 4-(3-methyl-2-thienyl)-1-bromobenzene (boiling point 171°-175° C./16-17 mmHg). After refluxing for 30 minutes, the mixture was cooled. To the mixture was added a solution of 2.8 g (0.0205 mole) of anhydrous zinc chloride in 50 ml of anhydrous tetrahydrofuran, and the mixture was stirred at room temperature for 3 hours. To the mixture was added 7.2 g (0.0398 mole) of ethyl 2-bromopropionate. After having been stirred at 50° to 60° C. for one hour, the mixture was freed from the solvent by distillation under reduced pressure. The residue was mixed with 50 ml of 2 N hydrochloric acid and 50 ml of benzene. The organic layer was separated, washed with water, and freed from the solvent by distillation under reduced pressure. The residue was mixed with 50 ml of an ethanol solution containing 2.3 g of sodium hydroxide, heated under reflux for 3 hours, and then freed from the ethanol by distillation. The residue was mixed with 100 ml of water and 50 ml of benzene. The aqueous layer was separated, neutralized with hydrochloric acid, and the liberated oily substance was extracted with cyclohexane. The extract solution was dried over anhydrous magnesium sulfate and freed from the solvent by distillation under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: cyclohexane) to obtain 3.2 g (32.9% yield) of intended 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:25]=[C:26]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([N:40]4[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]4)=[CH:36][N:35]=3)[C:27]3[N:28]([CH:30]=[CH:31][N:32]=3)[N:29]=2)[C:5]([CH2:22][OH:23])=[C:6]([N:8]2[CH2:20][CH2:19][N:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[CH:18]=[C:10]3[C:9]2=[O:21])[CH:7]=1.ClC1C=C(NC2C=CC(N3CCN(C4[CH2:73][O:72][CH2:71]4)CC3)=CN=2)C2N(C=CN=2)N=1.C(OCC1C(B2OC(C)(C)C(C)(C)O2)=CC(F)=CC=1N1CCN2C3CCCCC=3C=C2C1=O)(=O)C>>[F:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:25]=[C:26]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([N:40]4[CH2:45][CH2:44][N:43]([CH:46]5[CH2:73][O:72][CH2:71]5)[CH2:42][CH2:41]4)=[CH:36][N:35]=3)[C:27]3[N:28]([CH:30]=[CH:31][N:32]=3)[N:29]=2)[C:5]([CH2:22][OH:23])=[C:6]([N:8]2[CH2:20][CH2:19][N:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[CH:18]=[C:10]3[C:9]2=[O:21])[CH:7]=1
Reactant: CN1CCN(c2ccc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)nn4ccnc34)nc2)CC1
Reactant: Clc1cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c2nccn2n1
Agent: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Product: O=C1c2cc3c(n2CCN1c1cc(F)cc(-c2cc(Nc4ccc(N5CCN(C6COC6)CC5)cn4)c4nccn4n2)c1CO)CCCC3
Yield: 9 %

Procedure:
Following the procedures as described for compound 104, Suzuki reaction of 105a (385 mg, 1.0 mmol) and 4-Fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 101l gave 105 as a yellow solid (60 mg, 9%). LCMS: [M+H]+ 664. 1H NMR (500 MHz, DMSO) δ 10.04 (d, J=4.0, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 8.10-8.13 (m, 1H), 7.70 (s, 1H), 7.44-7.55 (m, 3H), 7.34-7.36 (m, 1H), 6.52 (s, 1H), 4.84 (s, 1H), 4.66-4.72 (m, 3H), 4.33-4.43 (m, 2H), 4.11-4.19 (m, 3H), 3.86-3.89 (m, 2H), 3.49-3.51 (m, 2H), 3.03-3.14 (m, 4H), 2.57-2.63 (m, 3H), 2.45-2.47 (m, 4H), 1.77-1.80 (m, 2H), 1.68-1.69 (m, 2H)
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@H:16]3[NH:20][CH2:19][C@H:18]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[N:34]1([CH2:39][C:40](O)=[O:41])[CH:38]=[N:37][CH:36]=[N:35]1>>[N:34]1([CH2:39][C:40]([N:20]2[C@H:16]([C:14](=[O:15])[NH:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:33][CH:32]=4)=[CH:8][CH:9]=3)[CH2:17][C@@H:18]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:19]2)=[O:41])[CH:38]=[N:37][CH:36]=[N:35]1
Reactant: O=C(N[C@H]1CN[C@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1)OCc1ccccc1
Reactant: O=C(O)Cn1cncn1
Product: O=C(N[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1)OCc1ccccc1
Yield: 72 %

Procedure:
Proceeding as in Example 1, but substituting benzyl (3R,5S)-5-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidin-3-ylcarbamate and 2-(1H-1,2,4-triazol-1-yl)acetic acid, gave benzyl (3R,5S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-5-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidin-3-ylcarbamate (1.57 g, 2.81 mmol, 72% yield).