Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10](O)=[O:11])[CH:8]=[CH:9][C:2]=12.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[BH4-].[Na+]>O1CCCC1>[N:1]1[S:5][N:4]=[C:3]2[CH:6]=[C:7]([CH2:10][OH:11])[CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc2nsnc2c1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCc1ccc2nsnc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Benzo[1,2,5]thiadiazole-5-carboxylic acid (2.00 g, 11.11 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to 0° C. To this was added triethylamine (1.80 mL, 12.87 mmol) followed by isobutylchloroformate (1.62 mL, 12.40 mmol) in a dropwise manner. The resulting slurry was stirred for a further 30 minutes at 0° C. and then filtered into a mixture of sodium borohydride (0.83 g, 21.84 mol) in ice water (20 mL). The resulting mixture was stirred at 0° C. for 30 minutes, evaporated to one quarter of its volume and then extracted with dichloromethane (3×50 mL). The organic phases were combined and then dried over sodium sulfate. This was followed by concentration under reduced pressure to provide the desired product as a white solid which was used without further purification (1.50 g, 81%).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:12])/[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH2:11])=[CH:6][CH:5]=1.[C:13]1([C:19]2[C:23]([C:24]([F:27])([F:26])[F:25])=[C:22]([C:28](F)=O)[O:21][N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:13]1([C:19]2[C:23]([C:24]([F:26])([F:27])[F:25])=[C:22]([C:28]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([CH:10]=[CH2:11])=[CH:6][CH:5]=4)[N:12]=3)[O:21][N:20]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C=Cc1ccc(/C(N)=N/O)cc1
Reactant: O=C(F)c1onc(-c2ccccc2)c1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=Cc1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Temperature: 62 °C
Reaction time: 3 h
Yield: 61.8 %

Procedure:
To a mixture of (Z)—N′-hydroxy-4-vinylbenzimidamide (1.439 g, 8.87 mmol) and 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride (2.300 g, 8.87 mmol) in acetonitrile was added DIEA (1.860 mL, 10.65 mmol). The reaction mixture was heated to 62° C. After 3 hours, the reaction mixture was cooled and a white solid precipitate formed. The solid was filtered and washed with ethyl acetate, then dried to give about 2.1 g of 5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-3-(4-vinylphenyl)-1,2,4-oxadiazole. MS (m+1)=384. HPLC Peak RT=1.24 minutes (Analytical Method B).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]3)[N:9]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)CCC>>[N:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]4[CH2:16][C:17]([CH3:24])([CH3:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH2:20]4)[N:9]=3)=[CH:4][CH:3]=2)[CH:31]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(Br)cc3)n2)CC(C)(C)N1
Product: CC1(C)CC(Nc2nccc(-c3ccc(-c4cccnc4)cc3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared analogous to Step D of Example 172, starting from [4-(4-bromophenyl)-pyrimidin-2-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 3-tributylstannanyl-pyridine. Yield: 45 mg (24%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=2)[C:13]#[N:14])[CH:8]=1.[CH3:20][O:21][C:22]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].CCN(C(C)C)C(C)C>C(#N)C>[Cl:19][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:22]=2[O:21][CH3:20])=[CH:8][C:7]=1[O:9][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2)c(OC)c1
Reaction time: 8 h
Yield: 57.9 %

Procedure:
3-{[5-(Aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.05 g, 0.17 mmol), 2,4-bis(methyloxy)benzoyl chloride (0.046 g, 0.25 mmol) and DIPEA (0.05 mL, 0.25 mmol) were dissolved in acetonitrile (3 mL) and stirred overnight. The solvent was evaporated. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were lyophilized then EtOAc (25 mL) and saturated NaHCO3 (10 mL) were added. The layers were separated and the aqueous layer extracted with EtOAc (2×10 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound (0.045 g, 57%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.57 (t, 1H), 7.79 (s, 1H), 7.67-7.77 (m, 1H), 7.58 (d, 1H), 7.44 (s, 1H), 7.36 (s, 1H), 7.22-7.26 (m, 1H), 7.12-7.22 (m, 1H), 6.59 (d, 1H), 6.62 (s, 1H), 4.46 (d, 2H), 3.83 (s, 3H), 3.80 (s, 3H). MS: m/z 457.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=2)=[N:8][CH:9]=1)([O-])=O.[H][H]>CO.ClCCl.[Pd]>[NH2:1][C:4]1[C:5]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=2)=[N:8][CH:9]=1
Reactant: CC(=O)Nc1cccc(Oc2cc(Nc3ccccc3)c([N+](=O)[O-])cn2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)Nc1cccc(Oc2cc(Nc3ccccc3)c(N)cn2)c1

Procedure:
The product of Step 5 (37.7 g, 103.5 mmol) in MeOH (350 mL) and dichloromethane (350 mL) was hydrogenated for overnight with a balloon of hydrogen gas in the presence of 10% palladium on carbon (3.5 g). After filtration of the catalyst through a pad of Celite, the filtrate was concentrated in vacuo to afford the title compound as a crude foam (˜35 g, quantitative). 1H NMR (400 MHz, MeOD) δ ppm 7.56 (s, 1H), 7.39-7.40 (m, 1H), 7.19-7.34 (m, 5H), 7.07-7.11 (m, 1H), 6.73 (dt, 1H, 1.8 Hz, 7.1 Hz), 6.48 (s, 1H), 3.32-3.34 (m, 3H), 2.12 (s, 3H). MS (ES+) m/e 335 [M+H]+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]([O:14][CH2:15][CH3:16])(=[O:13])[CH3:12].Cl[C:18]1[S:19][C:20]2[CH:26]=[C:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:24]=[CH:23][C:21]=2[N:22]=1.Cl>C1COCC1.C1(C)C=CC=CC=1>[CH2:15]([O:14][C:11](=[O:13])[CH2:12][C:18]1[S:19][C:20]2[CH:26]=[C:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:24]=[CH:23][C:21]=2[N:22]=1)[CH3:16]
Reactant: CC(C)(C)OC(=O)c1ccc2nc(Cl)sc2c1
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1nc2ccc(C(=O)OC(C)(C)C)cc2s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a solution of sodium bis(trimethylsilyl)amide (4.9 mL of a 1M solution in THF, 4.90 mmol) in toluene (10 mL) at −78° C. was added dropwise ethyl acetate (0.26 mL, 2.7 mmol) and the mixture stirred for 1 h then a solution of Compound 188a (0.60 g, 2.2 mmol) in toluene (5 mL) was added over a 7 minute period. The resulting mixture was maintained at −78° C. for 1 h then slowly warmed to 0° C. over a period of 1.5 h. The reaction mixture was poured into a 1 N HCl solution and extracted with EtOAc. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-50% EtOAc/hexanes to give Compound 188b (480 mg, 67% yield) as a white solid. LCMS=2.13 min using analytical method (B), 322.0 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.57-8.52 (m, 1H), 8.11 (dd, J=8.6, 1.5 Hz, 1H), 8.04-7.98 (m, 1H), 4.32-4.25 (m, 2H), 4.20 (s, 2H), 1.63 (s, 9H), 1.32 (t, J=7.2 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH:7]2[N:9]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]([C:20]#[N:21])=[CH:12][CH:11]=3)[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[CH3:22][CH:8]1[C:2](=[O:1])[CH2:3][CH:4]2[N:9]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]([C:20]#[N:21])=[CH:12][CH:11]=3)[CH:7]1[CH2:6][CH2:5]2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#Cc1ccc(N2C3CCC2CC(=O)C3)c2ccccc12
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1C(=O)CC2CCC1N2c1ccc(C#N)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
To 156AF03-217 (552 mg, 2 mmol) in THF (20 mL) under argon atmosphere at −78° C. was added dropwise lithium bis(trimethylsilyl)amide (2.6 mL, 2.6 mmol, 1 M in THF). After 30 min at −78° C., iodomethane (2.0 mL) was added over 1 min and the reaction was allowed to warm to rt overnight. Partitioning of the reaction mixture between ethyl acetate (2×500 mL) and water (500 mL), drying of the combined organic phases over Na2SO4, filtration, removing of volatiles in vacuo and purification by preparative TLC (ethyl acetate/n-heptane 1:4, 5× eluted) afforded the title compound (115 mg, 20%) as a thick oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].C([N-]C(C)C)(C)C.[Li+].CN([CH:21]=[O:22])C.Cl>O1CCCC1.O>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([F:8])=[C:6]([CH:7]=1)[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: Cc1cc(F)ccc1Br
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(F)c(C=O)cc1Br
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-5-fluorotoluene (20 g) in dry tetrahydrofuran (200 ml) was added dropwise lithium diisopropylamide (2.0 M, heptan-tetrohydrofuran-ethylbenzene solution, 52.9 ml) under argon atmosphere at −78° C. After stirring as such for 2 hours, a solution of DMF (41 ml) in dry tetrahydrofuran (50 ml) was added dropwise. The mixture was returned to room temperature and stirred for 1 hour. Then, water was added and the mixture was neutralized with 1N hydrochloric acid. After extraction with ethyl acetate, the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=24:1) and re-crystallized from hexane-ethyl acetate to give 5-bromo-2-fluoro-4-methylbenzaldehyde (9.39 g).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]([O:12][CH:13]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6])#[N:2].Cl.[CH3:30][NH:31][CH3:32]>CC(C)=O.C1(C)C=CC=CC=1>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]([O:12][CH:13]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:14]1[CH:15]=[CH:16][C:17]([C:18]([N:31]([CH3:32])[CH3:30])=[O:19])=[CH:21][CH:22]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6])#[N:2]
Reactant: CC(C)C[C@H](OC(c1ccccc1)c1ccc(C(=O)O)cc1)C(=O)NCC#N
Reactant: CNC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CC(C)C[C@H](OC(c1ccccc1)c1ccc(C(=O)N(C)C)cc1)C(=O)NCC#N

Procedure:
Using the same coupling procedure as described for example 47, 4-[[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]benzoic acid (51 mg, 0.134 mmol) was reacted with dimethylamine hydrochloride (11 mg, 0.134 mmol, 1 eg) to give the title compound as an oil after chromatography with 25% acetone/toluene.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[CH3:25][O:26][C:27]1[CH:41]=[CH:40][C:30]([O:31][C:32]2[CH:33]=[C:34]([CH2:38][NH2:39])[CH:35]=[CH:36][CH:37]=2)=[CH:29][CH:28]=1.[NH2:42][C:43]1[N:52]=[C:51]([N:53]2[CH2:58][CH2:57][N:56]([CH3:59])[CH2:55][CH2:54]2)[C:50]2[C:45](=[CH:46][C:47]([C:60](O)=[O:61])=[CH:48][CH:49]=2)[N:44]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:42][C:43]1[N:52]=[C:51]([N:53]2[CH2:54][CH2:55][N:56]([CH3:59])[CH2:57][CH2:58]2)[C:50]2[C:45](=[CH:46][C:47]([C:60]([NH:39][CH2:38][C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([O:31][C:30]4[CH:40]=[CH:41][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[CH:33]=3)=[O:61])=[CH:48][CH:49]=2)[N:44]=1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Reactant: COc1ccc(Oc2cccc(CN)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Oc2cccc(CNC(=O)c3ccc4c(N5CCN(C)CC5)nc(N)nc4c3)c2)cc1
Reaction time: 1 h
Yield: 54 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.030 g, 0.078 mmol) was added to a solution of crude 1-[3-(4-methoxyphenoxy)phenyl]methanamine (0.045 g) and 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (0.015 g, 0.052 mmol) in N,N-dimethylformamide (2.0 mL) with N,N-diisopropylethylamine (0.027 mL, 0.16 mmol) at r.t. The reaction was stirred for 1 h. The product was purified without workup by RP-HPLC (pH=10) to give the desired product (0.014 g, 44%) as a white amorphous solid. Analytical LCMS (M+H)+: m/z=499.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:51][C:52]1[N:56]([CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=2)[N:55]=[C:54]([NH2:64])[CH:53]=1>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[CH:17]=1)[C:12]([NH:64][C:54]1[CH:53]=[C:52]([CH3:51])[N:56]([CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=2)[N:55]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: Cc1cc(N)nn1Cc1ccccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)c2cc(OCc3ccccc3)cc(OC(C)C)c2)nn1Cc1ccccn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 31 %

Procedure:
3-Benzyloxy-5-isopropoxy-benzoic acid (0.35 mmol) is dissolved in acetonitrile, di-isopropyl ethyl amine (3 eq.), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium (1.2 eq.) and 5-methyl-1-pyridine-2-ylmethyl-1H-pyrazole-3-ylamine (1.0 eq., prepared similar to 1-pyridine-2-ylmethyl-1H-pyrazole-3-ylamine) is added and stirred at RT for 14 hours. The solvent is removed in vacuo. 3-Benzyloxy-5-isopropoxy-N-(5-methyl-1-pyridine-2-ylmethyl-1H-pyrazole-3-yl)-benzamide is obtained after column chromatography (chloroform (methanol) as a colourless powder in a yield of 31%; HPLC (Method B): 3.25 min; LC-MS: 2.350 min, 457.15 (M÷H+);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[CH:13][C:12](=O)[NH:11][N:10]=1.O=P(Cl)(Cl)[Cl:18].C(N(CC)CC)C>O1CCOCC1>[Cl:18][C:12]1[N:11]=[N:10][C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])=[N:14][CH:13]=1
Reactant: O=c1cnc(-c2c(F)cccc2F)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Fc1cccc(F)c1-c1ncc(Cl)nn1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1 g of 3-(2,6-difluorophenyl)-[1,2,4]triazin-6(1H)-one is placed in 20 ml of dioxane and at room temperature 0.73 g of POCl3 is added. Then, within a period of 5 min, 0.48 g of triethylamine in 3 ml of dioxane is added dropwise and stirring is carried out at room temperature for 30 min. The reaction mixture is then poured into ice-water and extracted with ethyl acetate, and the organic phase is separated off and concentrated. In this way 6-chloro-3-(2,6-difluorophenyl)-[1,2,4]triazine is obtained in the form of a yellow oil. The crude product is reacted further without purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:35])[C:15](=[O:34])[CH2:16][O:17][C:18]2[N:23]=[C:22]([CH3:24])[C:21]([NH:25]C(=O)OC(C)(C)C)=[C:20]([CH3:33])[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(NC1C(C)=NC(OCC(O)=O)=NC=1C)=O)(C)(C)C.Cl>C(Cl)(Cl)Cl>[NH2:25][C:21]1[C:22]([CH3:24])=[N:23][C:18]([O:17][CH2:16][C:15]([N:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)[CH3:35])=[O:34])=[N:19][C:20]=1[CH3:33]
Reactant: Cc1nc(OCC(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1NC(=O)OC(C)(C)C
Agent: Cc1nc(OCC(=O)O)nc(C)c1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Cc1nc(OCC(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 103.9 %

Procedure:
Compound 30 (calculated assuming that Compound 9 in the previous process was 74.74 g and the yield of amidation was 80%) was dissolved in chloroform (140 mL). The solution was added to a 6N aqueous HCl solution (530 mL) at room temperature (20 to 30° C.). The equipment used to add compound 30 was thoroughly washed with chloroform (240 mL) and was then stirred at room temperature (20 to 30° C.) for 2.5 hours. After the chloroform layer was separated, chloroform (300 mL) was added to the aqueous layer. While ice (740.7 g in total) was added as necessary, a 4N aqueous sodium hydroxide solution (805 mL) was added portionwise. An additional amount of 4N aqueous sodium hydroxide solution (25 mL to adjust the pH of the aqueous layer to 8.5) was added, followed by the addition of chloroform (80 mL), and separation was performed. After the chloroform layer was separated, chloroform (200 mL) was added to the aqueous layer and separation was performed again. The chloroform layer collected in the two extraction processes was dried over magnesium sulfate and suction-filtered. The filtrate was then evaporated under reduced pressure to give 100.15 g (103.9% yield, in 2 steps) of the crude desired product as a pale yellow solid.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3][CH2:2]1.O1C2C(=CC=CC=2)CCC1.[Li]CCCC.[C:27](=[O:29])=[O:28]>C(O)(=O)C.[Zn]>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:27]([OH:29])=[O:28])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C=O
Reactant: O=C1CCOc2ccccc21
Agent: [Li]CCCC
Agent: [Zn]
Agent: c1ccc2c(c1)CCCO2
Solvent: CC(=O)O
Product: O=C(O)c1cccc2c1OCCC2

Procedure:
The synthesis of chroman-5-carboxylic acid derivatives started with the alkylation of 3-hydroxy-benzoic acid methyl ester (36; commercially available) with propargyl bromide in the presence of K2CO3 to give phenylether (37) which was cyclised to the chromen derivative (38) by heating to reflux in N,N-diethylaniline. The carboxylic ester was saponified by treatment of (38) mith NaOH in MeOH and water and the obtained chromen derivative (39) was hydrogenated to give the desired acid (40). The corresponding chroman-8-carboxylic acid derivatives were synthesized by reduction of 4-chromanone (41; commercially available) with zinc in acetic acid and subsequent ortho-metalation of the intermediate chroman derivative (42) with n-BuLi and trapping with carbon dioxide to give the desired acid (43).
Reaction SMILES: NC1C=CC(F)=CC=1C(NC)=O.Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][C:26]=2[O:40][CH3:41])[N:15]=1.[NH2:42][C:43]1[CH:52]=[CH:51][C:50]([C@H:53]2[CH2:58][CH2:57][C@H:56]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:55][CH2:54]2)=[C:49]2[C:44]=1[C:45](=[O:65])[C:46]([CH3:64])=[CH:47][NH:48]2>>[CH2:32]([O:31][P:30]([CH2:29][C:28]1[CH:38]=[CH:39][C:25]([NH:24][C:16]2[N:15]=[C:14]([NH:42][C:43]3[CH:52]=[CH:51][C:50]([C@H:53]4[CH2:54][CH2:55][C@H:56]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:57][CH2:58]4)=[C:49]4[C:44]=3[C:45](=[O:65])[C:46]([CH3:64])=[CH:47][NH:48]4)[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=2)=[C:26]([O:40][CH3:41])[CH:27]=1)([O:34][CH2:35][CH3:36])=[O:37])[CH3:33]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CCOC(=O)[C@H]1CC[C@H](c2ccc(N)c3c(=O)c(C)c[nH]c32)CC1
Agent: CNC(=O)c1cc(F)ccc1N
Product: CCOC(=O)[C@H]1CC[C@H](c2ccc(Nc3nc(Nc4ccc(CP(=O)(OCC)OCC)cc4OC)ncc3C(F)(F)F)c3c(=O)c(C)c[nH]c32)CC1

Procedure:
The title compound was prepared according to Compound 102A using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (233.0 mg, 0.44 mmol) and ethyl trans-4-(5-amino-3-methyl-4-oxo-1,4-dihydroquinolin-8-yl)cyclohexanecarboxylate (Compound 304A, 172.0 mg, 0.52 mmol). 1H NMR (400 MHz, MeOD) δ ppm 1.26-1.35 (m, 9H) 1.69-1.94 (m, 6 H) 2.14 (s, 3 H) 2.31 (d, J=13.64 Hz, 2 H) 2.83 (br. s., 1 H) 2.97-3.06 (m, 1 H) 3.33 (s, 1 H) 3.39 (s, 1 H) 3.91 (s, 3 H) 4.10 (quin, J=7.26 Hz, 4 H) 4.24 (q, J=7.24 Hz, 2 H) 6.93 (m, J=6.06 Hz, 1 H) 7.11 (t, J=2.02 Hz, 1 H) 7.35 (d, J=7.83 Hz, 1 H) 7.81 (d, J=7.83 Hz, 1 H) 7.87 (s, 1 H) 8.31 (s, 1 H) 8.49 (br. s., 1 H). MS (ES+): m/z: 746.20/747.19 (100/40) [MH+]. HPLC: tR=4.42 min (Micromass ZQ3: polar—5 min).
Reaction SMILES: [C:1]1([C:7]2([CH2:13][CH2:14][C:15]([OH:17])=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O/[N:19]=[C:20](/[C:22]1[CH:39]=[CH:38][C:25]([CH2:26][N:27]2[CH2:30][CH:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]2)=[CH:24][CH:23]=1)\[NH2:21].C(N=C=NC(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(#N)C.CCOC(C)=O>[C:1]1([C:7]2([CH2:13][CH2:14][C:15]3[O:17][N:21]=[C:20]([C:22]4[CH:23]=[CH:24][C:25]([CH2:26][N:27]5[CH2:28][CH:29]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:30]5)=[CH:38][CH:39]=4)[N:19]=3)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Reactant: O=C(O)CCC1(c2ccccc2)CCCCC1
Agent: CC(C)N=C=NC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(CCC4(c5ccccc5)CCCCC4)n3)cc2)C1
Reaction time: 1.5 h

Procedure:
To a stirred solution of the 3-(1-phenylcyclohexyl)propanoic acid (0.118 g, 0.508 mmol) and the (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (Intermediate 1, 0.155 g, 0.508 mmol) in acetonitrile (5.0 mL) at room temperature was added the 1,3-diisopropylcarbodiimide (0.095 mL, 0.609 mmol). The stirring was continued at room temperature and followed by LC/MS. After 90 min., TBAF (0.609 mL, 0.609 mmol) was added to the reaction. The reaction was found to be over after 2 h. The reaction mixture was diluted with EtOAc and washed with water followed by brine. It was then concentrated and purified by preparative HPLC to give the tert-butyl 1-(4-(5-(2-(1-phenylcyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate as a glassy solid. LCMS of the tert-butyl 1-(4-(5-(2-(1-phenylcyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (Conditions: Start % B═O; Final % B=100; Gradient Time=2 min; Flow Rate=5 ml/min; Wavelength=220; Solvent A=10% MeOH—90% H20—0.1% TFA; Solvent B=90% MeOH—10% H2O—0.1% TFA and Column 4=Phenomenex Luna 5u C18 4.6×30 mm (2 min. grad)) (M+H)+=502.39. Retention time=1.927.
Reaction SMILES: [C:1]1([S:7]([NH:10][C@@H:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C:25](=[O:27])[NH:24][S:23]3(=[O:29])=[O:28])=[C:18]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:17]=2)[C:12]([OH:14])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=1[NH2:78]>CN(C=O)C>[NH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=1[NH:78][C:12](=[O:14])[C@@H:11]([NH:10][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:26][C:25](=[O:27])[NH:24][S:23]2(=[O:28])=[O:29])=[C:18]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:17]=1
Reactant: Nc1ccccc1N
Reactant: O=C1CN(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)[C@H](Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (S)-2-benzenesulfonylamino-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionic acid (110 mg, 0.2 mmol) in DMF (5 mL) is added diisopropylethylamine (0.038 mL, 0.22 mmol) and HATU (84 mg, 0.22 mmol). The mixture is stirred at RT for 10 min then a solution of 1,2-diaminobenzene (26 mg, 0.24 mmol) in DMF (1 mL) is added and stirring is continued for 48 h. The solvent is removed under reduced pressure to give the title compound which is used directly in the next step