Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O)#[N:2].[F:12][C:13]1([F:31])[CH2:18][CH2:17][C:16]([CH2:29][NH2:30])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH:30][CH2:29][C:16]1([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:31])[CH2:14][CH2:15]1)=[O:7])#[N:2]
Reactant: N#Cc1ccccc1C(=O)O
Reactant: NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1
Product: N#Cc1ccccc1C(=O)NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1

Procedure:
From 2-cyanobenzoic acid and C-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=424.2, tR (minutes, Method D)=0.66
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([C:16]#[C:17][Si](C)(C)C)=[CH:14][N:13]=[C:12]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1>CO.[OH-].[Na+]>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([C:16]#[CH:17])=[CH:14][N:13]=[C:12]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C#Cc1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
To the solution of crude N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-phenyl-5-((trimethylsilyl)ethynyl) pyrimidin-4-amine in MeOH (3 mL), 20% NaOH was added until the pH was adjusted to 12. After stirring at rt for 15 min, the reaction mixture was evaporated to dryness and purified by silica gel chromatography (hexane/EtOAc=3:1-1:1 as eluent) to afford N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-ethynyl-2-phenylpyrimidin-4-amine (Compound 14) (71 mg, 48%). LC-MS (m/z): 302.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6): δ 0.71-0.76 (m, 2H), 0.94-1.01 (m, 2H), 1.90-1.99 (m, 1H), 6.18-6.28 (bs, 1H), 7.06-7.10 (bs, 1H), 7.51-7.53 (m, 3H), 8.34-8.39 (m, 3H), 9.86 (s, 1H), 12.10 (s, 1H).
Reaction SMILES: [CH:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]3[N:34]=[CH:35][N:36]=[C:10]23)[CH2:5][CH2:4]1)=[O:2].Br[Mg][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1.Cl>O1CCCC1>[OH:2][CH:1]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)[C@H:3]1[CH2:4][CH2:5][C@H:6]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]3[N:34]=[CH:35][N:36]=[C:10]23)[CH2:7][CH2:8]1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C=O)CC2)c2ncnn12
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(O)c3ccc(OC)cc3)CC2)c2ncnn12
Temperature: -78 °C
Reaction time: 2 h

Procedure:
4′-{[4-(trans-4-Formylcyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (2.6 g) was dissolved in tetrahydrofuran (50 mL), and bromo(4-methoxyphenyl)magnesium (0.5M tetrahydrofuran solution, 16 mL) was added at −78° C. The reaction mixture was stirred at −78° C. for 2 hr, 1 N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (2.2 g, 70%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]([C:12]3[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:14][CH:13]=3)[N:10]=[CH:9][N:8]=2)=[CH:3][CH:2]=1.[CH3:30]OC(OC)(N(C)C)C>>[CH3:30][C:9]1[N:8]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[N:11]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:28][CH:29]=2)[N:10]=1
Reactant: COC(C)(OC)N(C)C
Reactant: c1ccc2nc(COc3ccc(-n4ncnc4-c4ccncc4)cc3)ccc2c1
Product: Cc1nc(-c2ccncc2)n(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(5-Pyridin-4-yl-[1,2,4]triazol-1-yl)-phenoxymethyl]-quinoline but substituting N,N-dimethylacetamide dimethyl acetal provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=6.2 Hz, 2 H), 8.22 (d, J=8.3 Hz, 1 H), 8.08 (d, J=8.3 Hz, 1H), 7.84 (d, J=7.7 Hz, 1H), 7.74 (m, 1 H), 7.65 (d, J=8.3 Hz, 1 H), 7.56 (m, 1 H), 7.36 (d, J=6.2 Hz, 2 H), 7.25 (d, J=9.1 Hz, 2H), 7.09 (d, J=8.7 Hz, 2H), 5.41 (s, 2H), 2.48 (s, 3H); MS: (M+H m/z=394.4).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:25][CH3:26])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH2:23]O)[CH:20]=[CH:21][CH:22]=1.P(Br)(Br)[Br:28]>ClCCl>[Br:28][CH2:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:6]1[C:5]([O:25][CH3:26])=[N:4][C:3]2[C:7]1=[N:8][C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[N:10][C:2]=2[NH2:1]
Reactant: COCCOc1nc(N)c2nc(OC)n(Cc3cccc(CO)c3)c2n1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: COCCOc1nc(N)c2nc(OC)n(Cc3cccc(CBr)c3)c2n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of Compound 7 (65 mg, 0.18 mmol) in dichloromethane (2 mL) was cooled to 0° C. and phosphorus tribromide (17 μL, 48.9 mg, 0.18 mmol) was added by syringe. The reaction mixture was stirred at 0° C. and the progress of the reaction was monitored by TLC (silica gel, eluting 10% methanol in ethyl acetate). After 20 minutes, the reaction mixture was quenched with saturated sodium bicarbonate solution, washed with water, and the combined organic layers were dried over sodium sulfate and evaporated to dryness. The crude mixture containing Compound (11) was used in the next step without further purification. LCMS: m/z for C17H20BrN5O3++H observed 423 and 424.1 at 1.42 minutes of a 3.0 minute run, eluting 5-95% CH3CN in H2O (C18 column).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.CC([O-])(C)C.[K+].[N:18](OC(C)(C)C)=[O:19]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[N:18][OH:19])[C:10]=2[CH:11]=1
Reactant: Clc1cc2c(cn1)CCCC2
Reactant: CC(C)(C)ON=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: ON=C1CCCc2cnc(Cl)cc21
Reaction time: 12 h

Procedure:
3-Chloro-5,6,7,8-tetrahydro-isoquinoline (Chemische Berichte 1948, 81, 279) (8.82 g; 52.6 mmol) dissolved in THF (65 ml) is added under stirring at room temperature to a solution of KOtBu (11.78 g; 105.2 mmol) in THF (100 ml). The red turbid solution is stirred for 12 hours and then cooled to 0° C. tert-Butyl nitrite (18.7 ml; 157.8 mmol) is added dropwise, the reaction mixture is stirred at room temperature for 4 hours and poured on brine. The reaction mixture is extracted with ethyl acetate three times, the organic phases are combined, dried over Na2SO4 and evaporated to dryness, yielding the desired product as brownish crystals. 1H-NMR (400 MHz; DMSO-d6): 11.83 (s, 1H); 8.28 (s, 1H); 7.66 (s, 1H); 2.72 (m, 2H); 2.66 (m, 2H); 1.77 (m, 2H). MS (m/z) ES+: (197, MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:12][CH:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[NH2:26][NH2:27]>>[CH:20]1([N:11]([CH2:12][CH:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)[S:8]([C:5]2[CH:6]=[N:7][C:2]([NH:26][NH2:27])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NN
Reactant: CC1(C)OCC(CN(C2CCCC2)S(=O)(=O)c2ccc(Cl)nc2)O1
Solvent: O
Product: CC1(C)OCC(CN(C2CCCC2)S(=O)(=O)c2ccc(NN)nc2)O1
Yield: 99 %

Procedure:
According to Process 4.2, starting with 0.92 g of 6-chloro-N-cyclopentyl-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]pyridine-3-sulfonamide and 0.24 mL of hydrazine hydrate, 0.85 g of N-cyclopentyl-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-6-hydrazinylpyridine-3-sulfonamide is obtained in the form of a yellow oil.
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][CH2:4][C:3]2[CH:10]=[CH:11][C:12]3[C:17]([C:2]1=2)=[CH:16][CH:15]=[CH:14][CH:13]=3.S(=O)(=O)(O)O.[CH2:23](O)[CH3:24]>>[O:1]1[CH:6]([C:7]([O:9][CH2:23][CH3:24])=[O:8])[CH2:5][CH2:4][C:3]2[CH:10]=[CH:11][C:12]3[C:17]([C:2]1=2)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: O=C(O)C1CCc2ccc3ccccc3c2O1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCc2ccc3ccccc3c2O1
Yield: 63.5 %

Procedure:
A mixture of intermediate (9-a) (7 g), ethanol (160 ml) and sulfuric acid was stirred and refluxed for 1 hour. The reaction mixture was evaporated and the oily residue was taken up in water. After treating with sodium hydroxide, the product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 5 g (63.5%) of ethyl 3,4-dihydro-2H-naphto[1,2-b]pyran-2-carboxylate (interm. 10-a).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[Cl:13]Cl.Cl>>[Cl:13][C:9]([CH3:10])([CH3:11])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:12]
Reactant: CC(C)C(=O)c1ccc(Cl)cc1
Reactant: ClCl
Agent: Cl
Product: CC(C)(Cl)C(=O)c1ccc(Cl)cc1

Procedure:
182.7 g (1.0 mol) of 1-(4-chlorophenyl)-2-methylpropan-1-one are warmed to 40° and chlorinated with 71 g (1.0 mol) of chlorine gas at 40°-65° in the course of 5 hours. The dissolved HCl gas is then driven off by blowing with nitrogen. The liquid crude product is then reacted further.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:19]([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46]Br>C1COCC1>[Br:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46][C@@:19]1([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17][C@H:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:15][CH:14]=2)[N:20]1[C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22]
Reactant: BrC/C=C\CBr
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@]1(C/C=C\CBr)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 38.2 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1,2-pyrrolidinedicarboxylate (D34, 0.2 g, 0.47 mmol) in dry THF (2 mL) at −78° C. was added LiHMDS (0.51 mL of a 1M solution in THF, 0.51 mmol). The mixture was allowed to warm to −30° C. and stirred for 30 min at this temperature. The yellow slurry was cooled to −78° C. and (2Z)-1,4-dibromo-2-butene (0.30 mL, 2.81 mmol) was added. The reaction mixture was left under stirring for 40 min and then quenched with a saturated ammonium chloride solution. The aqueous layer was extracted with ethyl acetate, dried (Na2SO4) and evaporated. The crude material was purified by chromatography on silica gel using cyclohexane/ethyl acetate (9:1) affording the title compound (101 mg, 38%); Rt (HPLC) 7.42 min. MS: (ES/+) m/z: 462 and 464 [MH+-Boc]; C28H33BrFNO5 requires 562.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>O1CCCC1>[CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][N:27]([CH2:36][C:32]4[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=4)[CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:5]
Reactant: Cn1ccnc1C=O
Reactant: CN(c1cccc2cc(C3=NCC4(CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC4(CCN(Cc5nccn5C)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.6 %

Procedure:
To a solution of N-methyl-N-[2-(1-thia-3,8-diazaspiro[4.5]dec-2-en-2-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (100 mg) and 1-methyl-1H-imidazole-2-carbaldehyde (33 mg) in tetrahydrofuran (3 mL) was added sodium triacetoxyborohydride (125 mg), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (14 mg, yield 12%) as white crystals from a fraction eluted with ethyl acetate. melting point 103° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:43])[O:26][CH2:27][O:28][C:29](=[O:42])[CH2:30][CH2:31][C:32]([O:34]CC2C=CC=CC=2)=[O:33])[CH:5]=[CH:6][C:7]=1[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15]>[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:43])[O:26][CH2:27][O:28][C:29](=[O:42])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:5]=[CH:6][C:7]=1[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)OCOC(=O)CCC(=O)OCc2ccccc2)cc1Cl
Agent: [Pd]
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)OCOC(=O)CCC(=O)O)cc1Cl

Procedure:
1-(3-(Benzyloxycarbonyl)propanoyloxy)methyl N-[2-[3-chloro-4-(2-methylbenzoyl)-phenylamino]phenyl]carbamate (Compound 204) (2.2 g, 3.6 mmol) was dissolved in EtOAcetate (500 ml), 10% Pd on carbon (750 mg) was added, and the reaction mixture was hydrogenated (1 atm) under vigorously shaken until no more starting material remained, as seen on TLC. The reaction mixture was purified by chromatography using a mixture of methanol/chloroform 1:9 to give the title compound.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:16][C:17]1[CH:18]=[C:19]([CH:25]2[CH2:27][CH:26]2[C:28](Cl)=[O:29])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].[NH4+].[Cl-]>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:28]([CH:26]1[CH2:27][CH:25]1[C:19]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([F:16])[CH:18]=1)=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: COc1ccc(C2CC2C(=O)Cl)cc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2CC2C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1F
Reaction time: 0.5 h

Procedure:
After (R)-4-benzyl-oxazolidin-2-on (0.858 g, 4.84 mmol) was dissolved in anhydrous THF (15 mL), NaH (0.226 g, 5.64 mmol) was added thereto, and the mixture was stirred for 30 minutes. 2-(3-Fluoro-4-methoxy-phenyl)-cyclopropanecarbonyl chloride obtained in Step B was added thereto at −78° C., and the mixture was stirred for 15 minutes, and then stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was added with NH4Cl and extracted with ethyl acetate. The organic layer was separated, dried with anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex/MC=1/5/10) to obtain the title compounds [(more polar, 33 mg, 49%), (less polar, 33 mg, 49%)].
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][CH:6]([C:8]([OH:10])=O)[CH2:5][C:4]([CH3:12])([CH3:11])[O:3]1.[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[N:15]1.S(Cl)(Cl)=O>C(Cl)Cl>[N:14]1([C:8]([CH:6]2[CH2:5][C:4]([CH3:12])([CH3:11])[O:3][C:2]([CH3:1])([CH3:13])[CH2:7]2)=[O:10])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[N:15]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC1(C)CC(C(=O)O)CC(C)(C)O1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1(C)CC(C(=O)n2nnc3ccccc32)CC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,2,6,6-tetramethyl-tetrahydro-pyran-4-carboxylic acid (1.4 g, 6.8 mmol) and benzotriazole (2.4 g, 20.3 mmol) in 34 mL of DCM was added thionyl chloride (0.55 mL, 7.4 mmol) dropwise and the mixture was allowed to stir for 8 hrs at RT. The mixture was filtered to remove the ppt and the filtrate washed with saturated NaHCO3 (2×40 mL) and then brine (50 mL). The organic layer was dried over Na2SO4 and concentrated to give 1.9 g (97%) of a white ppt.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[N:18]=[C:17]([C:19]([N:21]4[CH2:26][CH2:25][CH:24]([N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[CH2:23][CH2:22]4)=[O:20])[C:16]([CH3:32])=[CH:15][C:14]=3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[N:10]=[N:9]2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>FC(F)(F)C(O)=O>[CH3:32][C:16]1[C:17]([C:19]([N:21]2[CH2:22][CH2:23][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:25][CH2:26]2)=[O:20])=[N:18][C:13]([C:11]2[N:10]=[N:9][NH:8][CH:12]=2)=[C:14]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)[CH:15]=1
Reactant: COc1ccc(Cn2cc(-c3nc(C(=O)N4CCC(N5CCCC5)CC4)c(C)cc3-c3cccc(C(F)(F)F)c3)nn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(-c2c[nH]nn2)nc1C(=O)N1CCC(N2CCCC2)CC1
Yield: 78.4 %

Procedure:
0.30 g (0.50 mmol) of [6-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (intermediate 13) in 3.2 ml of trifluoroacetic acid were stirred at reflux for 23 hours. The reaction mixture was then poured into crashed ice, the pH was adjusted to 8-9 with aqueous Na2CO3 and the mixture was extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 98:2 to 4:1) to give 0.19 g (77%) of the title compound as an off-white solid. MS: 485.4 (MH+).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([S:13](Cl)(=[O:15])=[O:14])=[C:7]([O:17][CH3:18])[CH:6]=1)[C:2]#[CH:3].[OH:19][CH2:20][C@:21]([OH:71])([CH3:70])[C:22](=[O:69])[C@@H:23]([NH:28][C:29](=[O:68])[C@@H:30]([NH:38][C:39](=[O:67])[C@@H:40]([NH:45][C:46](=[O:66])[C@@H:47]([NH:56][C:57](=[O:65])[CH2:58][N:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1)[CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:24][CH:25]([CH3:27])[CH3:26]>>[CH3:12][O:11][C:9]1[CH:10]=[C:5]([O:4][CH2:1][C:2]#[CH:3])[CH:6]=[C:7]([O:17][CH3:18])[C:8]=1[S:13]([O:19][CH2:20][C:21]([OH:71])([CH3:70])[C:22](=[O:69])[C@H:23]([CH2:24][CH:25]([CH3:26])[CH3:27])[NH:28][C:29](=[O:68])[C@H:30]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:38][C:39](=[O:67])[C@H:40]([CH2:41][CH:42]([CH3:44])[CH3:43])[NH:45][C:46](=[O:66])[C@H:47]([CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[NH:56][C:57](=[O:65])[CH2:58][N:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1)(=[O:15])=[O:14]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)[C@](C)(O)CO
Reactant: C#CCOc1cc(OC)c(S(=O)(=O)Cl)c(OC)c1
Product: C#CCOc1cc(OC)c(S(=O)(=O)OCC(C)(O)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc2ccccc2)NC(=O)CN2CCOCC2)c(OC)c1

Procedure:
Prepared in a similar manner to compound 13, except from 4-(propargyloxy)-2,6-dimethoxybenzene-1-sulfonyl chloride and (S)—N—((S)-1-(((2R,4S)-1,2-dihydroxy-2,6-dimethyl-3-oxoheptan-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1
Reaction time: 10 h
Yield: 96.8 %

Procedure:
3,4-difluoro-nitrobenzene (100 g, 0.63 mol) was added dropwise to morpholine (60 g, 0.69 mol) and triethylamine (70 g, 0.69 mol) in ethyl acetate (300 mL) within 1 hour while maintaining the temperature below 50° C. The mixture is stirred at 45˜50° C. for 10 hours until the completion of the reaction. The mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate, filtered, dried, to provide 138 g of yellow solid in 97% yield.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(C(C)C)CC)(C)C.ClCCl.Cl[C:25]1[O:26][C:27]2[C:28](=[C:30]([C:42]#[N:43])[C:31]([CH3:41])=[C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:33]=2[F:34])[N:29]=1>C(OCC)(=O)C>[C:42]([C:30]1[C:28]2[N:29]=[C:25]([NH:2][CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[O:26][C:27]=2[C:33]([F:34])=[C:32]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:31]=1[CH3:41])#[N:43]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(NCCC(=O)OC(C)(C)C)nc2c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
With cooling with ice, tert-butyl 3-aminopropionate hydrochloride (230 mg, 1.26 mmol) and diisopropylethylamine (430 μl, 2.53 mmol) were added to a dichloromethane (10 ml) solution of 2-chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (302 mg, 1.05 mmol), followed by stirring at room temperature for 1 hour. The reaction liquid was cooled to room temperature, then ethyl acetate was added, and followed by washing with saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=4:1→1:1, v/v) to obtain the entitled compound (402 mg, 97%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[I:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1ncnc2[nH]ccc12
Solvent: ClC(Cl)Cl
Product: Clc1ncnc2[nH]cc(I)c12
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (30 g/0.02 mol) dissolved in 80 mL of chloroform was added 4.5 g (0.02 mol) of N-iodosuccinimide and the resulting mixture heated at reflux for 1 h. After cooling to room temperature, the percipitate was removed by flitration and dried under reduced pressure affording 4.6 g (82%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8](=[O:9])[O:7][CH:6]([CH2:10][CH2:11][C:12]([O:14]C)=[O:13])[C:5]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:2].[OH-].[Na+].O>CO>[CH2:1]([O:3][C:4]1[C:8](=[O:9])[O:7][CH:6]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:5]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:2]
Reactant: CCOC1=C(c2ccccc2)C(CCC(=O)OC)OC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC1=C(c2ccccc2)C(CCC(=O)O)OC1=O
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
To a solution of methyl 3-(4-ethoxy-5-oxo-3-phenyl2,5-dihydro-2-furyl)propionate (0.20 g) in methanol (2 ml) was added 1N sodium hydroxide solution (0.8 ml) during a period of a few minutes at ambient temperature. The solution was stirred for 30 minutes at the same temperature and then poured into water (10 ml). The mixture was washed with diethyl ether and the aqueous layer was adjusted to pH 1 with aqueous 10% hydrochloric acid. The separated oil was extracted with ethyl acetate twice. The combined organic layers were washed with water three times, dried, and evaporated to dryness. The residue was crystallized from a mixture of diethyl ether and n-hexane to yield 3-(4-ethoxy-5-oxo-3-phenyl2,5-dihydro-2-furyl)propionic acid (121 mg) as a crystal.