Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:3](=[O:29])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([CH:22]=CC(OCC)=O)=[CH:6]1.CN(CCC1C=CC=CC=1)C(=O)CC1C=C2C(=CC=1)N(OCC1C=CC=CC=1)C=[C:45]2[CH:59]=[C:60]([C:62]([O:64]CC)=[O:63])C.CN(CCC1C=CC=CC=1)C(=O)CN1C2C(=CC(OCC3C=CC=CC=3)=CC=2)C(C=C(C(O)=O)C=C)=C1>CC(C)=O.CCOCC>[CH3:1][N:2]([CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:3](=[O:29])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([CH:22]=[CH:45][CH:59]=[CH:60][C:62]([OH:64])=[O:63])=[CH:6]1
Reactant: CCOC(=O)C=Cc1cn(CC(=O)N(C)CCc2ccccc2)c2ccc(OCc3ccccc3)cc12
Reactant: CCOC(=O)C(C)=Cc1cn(OCc2ccccc2)c2ccc(CC(=O)N(C)CCc3ccccc3)cc12
Agent: C=CC(=Cc1cn(CC(=O)N(C)CCc2ccccc2)c2ccc(OCc3ccccc3)cc12)C(=O)O
Solvent: CCOCC
Solvent: CC(C)=O
Product: CN(CCc1ccccc1)C(=O)Cn1cc(C=CC=CC(=O)O)c2cc(OCc3ccccc3)ccc21

Procedure:
When N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboethoxyvinyl)-indol-1-yl]acetamide in the procedure of Example 23 is replaced with N-methyl-N-phenethyl-2-[1-benzyloxy-3-(2-carbethoxy-2-methylvinyl)indol-5-yl]acetamide then the product prepared is N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboxy-1,3-butadienyl)indol-1-yl]acetamide. (solvent system (acetone/ether) m.p. 189°-190° C.)
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.[Li]CCCC>C1COCC1.Cl>[C:7]1([C:3]2[O:4][CH:5]=[CH:6][C:2]=2[B:13]([OH:18])[OH:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1ccoc1-c1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccoc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
To a mixture of 3-bromo-2-phenylfuran (6.70 g, 30.0 mmol) and B(Oi-Pr)3 (10.4 mL, 45.0 mmol) in THF (67 mL) was added n-BuLi (1.65 M in hexane, 36.4 mL, 60 mmol) at −78° C. The mixture was stirred at −78° C. for 30 min and at 0° C. for 30 min. The mixture was diluted with 1 M HCl aqueous solution at 0° C., extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and triturated with EtOAc/hexane to yield the title compound (2.23 g, 40% yield) as a green solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 6.64 (1H, d, J=1.4 Hz), 7.21-7.45 (3H, m), 7.69 (1H, d, J=1.6 Hz), 8.00-8.08 (2H, m).
Reaction SMILES: Cl.Cl.Cl[CH:4]([CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[NH:9].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[N:17]1([CH2:16][CH:4]2[CH2:5][O:6][N:7]=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:9]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: N=C(NOCC(Cl)CN1CCCCC1)c1cccnc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: c1cncc(C2=NOCC(CN3CCCCC3)N2)c1
Reaction time: 6 h

Procedure:
13.2 g (35.7 mmol) of N-[2-chloro-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidamide dihydrochloride was added to a solution of 16.5 g (143.5 mmole) of potassium tert-butoxide dissolved in 150 ml of tert-butanol. The mixture was boiled for 6 hours, then evaporated in vacuum. 100 ml of 5% sodium hydroxide solution was added and the mixture was extracted three times with 300 ml portions of ethyl acetate.
Reaction SMILES: [Cl:1]CCC[N:5](C)C(=O)C(C1C=CC(Cl)=CC=1CC1C=CC=CC=1)=O.[I-].[Na+].N1CCOCC1.Cl.[O:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][N:43]([CH3:63])[C:44](=[O:62])[C:45]([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][C:48]=2[C:54](=O)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=O)[CH2:36][CH2:35]1>CC(CC)=O>[ClH:1].[O:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][N:43]([CH3:63])[C:44]([C:45]2[NH:5][C:54]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[C:48]3[C:47]=2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49]3)=[O:62])[CH2:36][CH2:35]1
Reactant: CN(CCCN1CCOCC1)C(=O)C(=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CN(CCCCl)C(=O)C(=O)c1ccc(Cl)cc1Cc1ccccc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCN1
Solvent: CCC(C)=O
Product: CN(CCCN1CCOCC1)C(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12

Procedure:
A solution of 7.6 g. of o-benzyl-p-chlorophenylglyoxylic acid (3-chloropropyl)methylamide in 40 ml. of ethyl methyl ketone is treated with 3.0 g. of sodium iodide and 3.5 g. of morpholine and the mixture is boiled at reflux for 30 hours. After concentration under reduced pressure, the residue is partitioned between water and methylene chloride, the organic phase washed with water, dried over sodium sulfate and concentrated to dryness. The residual oily base is purified on 500 g. of aluminum oxide using methylene chloride/ethyl acetate (4:1) for the elution, dissolved in diethyl ether and treated with excess ethereal hydrochloric acid. The hydrochloride which crystallizes out is recrystallized from isopropanol/diethyl ether, and there is obtained 4.9 g. of o-benzoyl-p-chlorophenylglyoxylic acid [3-(morpholino)propyl]methylamide hydrochloride in the form of light yellow crystals having a melting point of 169°-172° C. (decomposition).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Ba+2].[OH-]>C1COCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd](Cl)Cl>[C:15]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=3)[N:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(-c3ccccc3)ccc2c1

Procedure:
2-Chloro-6-nitroquinoline (10.5 g, 50.4 mmol) (Byoung S. L. et al. Heterocycles. 1998, 48.12, 65), phenylboronic acid (7.4 g, 60.4 mmol), palladium dichloride bis(triphenylphosphine) (0.70 g, 1.01 mmol) and barium hydroxide (38.1 g, 0.121 mol) in 200 ml of anhydrous THF are stirred at 65° C. for 20 hours. The mixture is diluted with water, extracted with CH2Cl2 and evaporated, and the residue is chromatographed on silica gel (1/1 hexane/ethyl acetate). Yield: 7.8 g (62%); IR (KBr): 3475, 3357, 1592, 1479 cm−1.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:19]=[C:18]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:31])OC(C)(C)C)[CH3:23])[N:17]=[CH:16][C:15]=4[N:32]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl.[CH3:34]O>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:19]=[C:18]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:31])[CH3:34])[CH3:23])[N:17]=[CH:16][C:15]=4[N:32]=3)=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: CO
Reactant: C[C@@H](COc1cc2oc(-c3ccc(OCC4CC4)cc3)nc2cn1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCC4CC4)cc3)nc2cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl ((2S)-1-((2-(4-(cyclopropylmethoxy)phenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)carbamate (210 mg) was added 2 M hydrogen chloride/methanol (5 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (5 mL) and acetic anhydride (5 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (46.5 mg). 1H NMR (300 MHz, CDCl3) δ 0.29-0.46 (2H, m), 0.63-0.78 (2H, m), 1.22-1.40 (4H, m), 1.97 (3H, s), 3.90 (2H, d, J=7.2 Hz), 4.28-4.48 (3H, m), 6.07 (1H, brs), 6.90 (1H, s), 7.03 (2H, d, J==9.0 Hz), 8.14 (2H, d, J=9.0 Hz), 8.52 (1H, s).
Reaction SMILES: Br[C:2]1[C:3]([CH3:19])=[N:4][N:5]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])=[C:8]([CH3:18])[O:7][C:6]=12.C([Li])CCC.[N:25]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[N:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C1COCC1>[C:37]([O:36][C:34]([NH:25][N:26]([C:2]1[C:3]([CH3:19])=[N:4][N:5]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])=[C:8]([CH3:18])[O:7][C:6]=12)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 7-bromo-3-(2,4-dichloro-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazole (710 mg, 1.972 mmol) in THF (15.5 ml) under N2 at −78° C. is added n-butyllithium (0.789 ml, 1.972 mmol) dropwise; the temperature is maintained below −70° C. for the addition and then the reaction mixture is stirred for 5 mins at −78° C. before the addition of di-tert-butyl azodicarboxylate (545 mg, 2.366 mmol) in THF (1.5 ml); the temperature is maintained below −60° C. for the period of the addition. After stirring at −78° C. for 30 mins, the reaction is quenched with sat. ammonium chloride solution and allowed to warm to RT. Ammonium chloride solution (sat.) is added and the mixture is extracted with EtOAc (2×100 ml). The combined organics extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product is purified ISCO chromatography eluting (0 to 100%) EtOAci iso-hexane on a 40 g SiO2 cartridge to give the title compound as an orange solid; MS: m/z 511.22 [M+H]+
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[CH:14]=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32](O)=[O:33])=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([NH:20][C:15]2[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]3[O:3][C:2]([CH3:21])([CH3:1])[CH:6]([C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=4)[C:5]=3[CH:14]=2)=[O:33])=[CH:26][CH:25]=1
Reactant: COc1ccc(CCC(=O)O)cc1
Reactant: Cc1ccc(C2c3cc(N)c(C)c(C)c3OC2(C)C)cc1
Product: COc1ccc(CCC(=O)Nc2cc3c(c(C)c2C)OC(C)(C)C3c2ccc(C)cc2)cc1
Yield: 64 %

Procedure:
Using 2,2,6,7-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine obtained Reference Example 139 and 3-(4-methoxyphenyl)propionic acid, the title compound was obtained in the same manner as in Reference Example 359.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([Cl:16])=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2ccccc2[nH]1
Reaction time: 18 h

Procedure:
A suspension of indole-2-carboxylic acid (0.742 g, 4.6 mmol) in dichloromethane (3 mL) was treated with oxalyl chloride (0.700 g, 5.52 mmol) and one drop of dimethyl formamide. The reaction mixture was shaken for 18 h. The solvent was removed under reduced pressure and dried under high vacuum to afford a quantitative amount of 1H-2-indolecarbonyl chloride. The oil was directly used in the following reaction.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH:7]1[CH2:22][CH:11]2[CH2:12][O:13][C:14]3[C:19]([C:10]2([S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:9][CH2:8]1)=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[F:21])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([C:10]23[CH2:9][CH2:8][CH:7]([O:6][CH2:5][CH2:4][NH2:1])[CH2:22][CH:11]2[CH2:12][O:13][C:14]2[C:19]3=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])(=[O:24])=[O:25])=[CH:31][CH:30]=1
Reactant: [N-]=[N+]=NCCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Temperature: 60 °C
Reaction time: 16 h
Yield: 46.9 %

Procedure:
A solution of 8-(2-azido-ethoxy)-10a-(4-chloro-benzenesulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene (110 mg, 0.242 mmol) in 4:1 THF/H2O (5 mL) was treated with Ph3P (127 mg, 0.484 mmol) and the reaction was heated to 60° C. After 16 h, the reaction mixture was cooled to ambient temperature and concentrated in vacuo to remove the THF. The reaction mixture was diluted with saturated aqueous NH4Cl and extracted with CH2Cl2 (3×). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Flash chromatography (10% MeOH/CH2Cl2) provided the title compound (52 mg, 52%): 1H NMR (CDCl3 400 MHz) δ 7.62 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.06 (m, 1H), 6.43 (m, 1H), 5.22 (dd, J=10.9, 2.9 Hz, 1H), 4.11 (d, J=11.7 Hz, 1H), 3.51 (m, 1H), 3.41 (m, 2H), 2.98 (m, 1H), 2.88 (br s, 2H,), 2.39 (m, 2H), 1.94 (m, 2H), 1.49 (m, 3H), 1.13 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][C:3]=1[CH:4]=O.[NH2:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[NH2:28])[C:22]([OH:24])=[O:23].CCOC(C)=O>CC(N(C)C)=O>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][C:3]=1[C:4]1[NH:18][C:19]2[CH:20]=[C:21]([C:22]([OH:24])=[O:23])[CH:25]=[CH:26][C:27]=2[N:28]=1
Reactant: COc1ncccc1-c1ccc(O)c(C=O)c1
Reactant: Nc1ccc(C(=O)O)cc1N
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold flask with a rubber stopper were added 2-hydroxy-5-(2-methoxy-pyridin-3-yl)-benzaldehyde (22.35 g, 0.0975 mol) and 3,4-diamino-benzoic acid (17.2 g, 0.113 mol) and the solid mixture was stirred at 0° C. for 15 min. Then DMA (120 mL) was added into the mixture via a syringe and the resulting solution was stirred at 0° C. for 2 h, and at the room temperature for 3 h. The rubber stopper was removed and the reaction mixture was stirred at 110° C. for 14 h open to the air. The DMA was removed under reduced pressure and the residue was mixed with 200 mL EtOAc, and sonicated for 15 min. The mixture was filtered to get the solid precipitate, which was mixture with 150 mL EtOAc, and sonicated for 5 min. The resulting mixture was filtered to get the solid crude that was dried at 40° C. for 6 h under reduced pressure to afford a mixture of the title compound and DMA (ratio 1:1) (16.15 g, 38%). 1H NMR (DMSO-d4) δ 3.92 (s, 3H), 7.14 (m, 1H), 7.15 (s, 1H), 7.64 (d, J=6 Hz, 1H), 7.74 (d, J=6 Hz, 1H), 7.84 (d, J=6 Hz, 1H), 7.91 (d, J=6 Hz, 1H), 8.19 (d, J=6 Hz, 1H), 8.21 (d, J=6 Hz, 1H), 8.29 (s, 1H). DMA also shows as 61.96 (s, 3H), 2.79 (s, 3H) and 2.94 (s, 3H). ESI-MS m/z 362.5 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[F:13])([O-])=O.C(O)C.C(O)(=O)C.[H][H]>[Pd].[Fe].O>[F:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Fe]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Nc1cc([N+](=O)[O-])ccc1F
Yield: 85.6 %

Procedure:
To a 500 ml Parr hydrogenation reactor were charged 8.1 g (0.0438 mole) of 2,4-dinitrofluorobenzene, 0.5 g of 5% palladium on carbon catalyst, 1.0 g (0.018 mole) of powdered iron, 150 ml of ethanol, 50 ml of glacial acetic acid, and 5 ml of water. The reaction was stopped after 152 psi of hydrogen had been absorbed. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure leaving a red solid. This solid was passed through a pad of silica gel, eluting with methylene chloride. The solvent was evaporated from the eluate, producing 5.85 g of crude 2-fluoro-5-nitroaniline, m.p. 94°-96° C. Analysis of the nmr spectrum of this material showed it to be >90% pure 2-fluoro-5-nitroaniline.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][CH:10]2[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13][N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:11]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na]>CCO>[C:1]1([C@@H:7]([NH:9][C@H:10]2[C@H:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13][N:12]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:11]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1N[C@@H](C)c1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1N[C@@H](C)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
The 1-tert-butyl 4-ethyl 3-(((S)-1-phenylethyl)amino)piperidine-1,4-dicarboxylate 5 (8.0 g, 21.2 mmol, 1.0 equiv) was dissolved in dry EtOH (20 mL) under N2. In a separate flame-dried Schlenk flask was placed dry EtOH (150 mL), and sodium (0.450 g, 63.6 mmol, 3.0 equiv) was added portion-wise under N2. The mixture was kept under N2 and vented to remove evolved gases until all of the sodium had dissolved. The clear solution of 1-tert-butyl 4-ethyl 3-(((S)-1-phenylethyl)amino)piperidine-1,4-dicarboxylate was then transferred to the NaOEt solution, and the mixture was stirred at 80° C. under N2 for 16 h. The solvent was removed under in vacuo, and brine (150 mL) was added and the mixture was brought to pH=10 with 1 N NaOH and extracted with EtOAc (100 mL×3). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (silica, petroleum ether/EtOAc=5:1) to give (trans)-1-tert-butyl 4-ethyl 3-(((S)-1-phenylethyl)amino)piperidine-1,4-dicarboxylate 6 as a slight yellow solid (3.7 g, yield: 46%). ESI-MS (M+H)+: 377.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([SH:14])[CH:5]=1.C(N(CC)C(C)C)(C)C.Br[CH2:26][CH2:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(OCC)(=O)C>C(#N)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:7]=[C:6]([S:14][CH2:26][CH2:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:5]=1
Reactant: CC(C)(C)OC(=O)CCCBr
Reactant: COC(=O)c1cc(S)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cc(SCCCC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 3-mercapto-5-trifluoromethyl-benzoic acid methyl ester (990 mg, 4.19 mmol) in acetonitrile (25 mL) were added N,N-diisopropylethylamine (1.08 g, 1.46 mL, 8.38 mmol) and tert-butyl 4-bromobutanoate (935 mg, 4.19 mmol, CAS RN 110611-91-1). The clear yellow solution was stirred at room temperature for 2.5 hours and then poured on water and ethyl acetate and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 50 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30). Light yellow liquid (1.27 g, 80%). MS (ESI+): m/z=379 ([M+]).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH2:4][N:5](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6]2.FC(F)(F)C(O)=O>>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][CH2:6]2
Reactant: Fc1cc(C(F)(F)F)cc2c1CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(C(F)(F)F)cc2c1CNC2

Procedure:
Prepared in analogy to Example A2(c) from 4-Fluoro-6-trifluoromethyl-2-trityl-2,3-dihydro-1H-isoindole and trifluoroacetic acid. Yellow oil. MS (m/e): 206.1 ([M+H+, 100%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=[C:2]1[C:11](OCC)=[O:12].[BH4-].[Na+].[Cl-].[Ca+2].[Cl-].CC(C)=O>C(O)C>[OH:12][CH2:11][C:2]1[S:1][CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=1
Reactant: CCOC(=O)c1csc(C(=O)OCC)n1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(CO)n1
Reaction time: 2 h
Yield: 63.7 %

Procedure:
Diethyl thiazole-2,4-dicarboxylate (1.5 g) was suspended in 15 ml of ethanol, and at -10° C., 3 ml of an ethanol solution of 0.16 g of sodium borohydride and 0.58 g of calcium chloride was added. The mixture was stirred at this temperature for 2 hours. Acetone was added to decompose the excess of the reducing agent, and then the solvent was evaporated under reduced pressure. Dilute sulfuric acid was added to the residue, and insoluble calcium sulfate was separated by filtration. The filtrate was adjusted to pH 10 with an aqueous solution of potassium carbonate, and then extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, and then further concentrated under reduced pressure. The residue was treated with isopropyl ether to give 0.78 g (yield 64%) of ethyl 2-hydroxymethylthiazole-4-carboxylate as a colorless crystalline powder.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:25][CH2:26][OH:27])[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[N:3]1.C(O)(=O)C.[CH:38](=O)[CH2:39][CH3:40].C([BH3-])#N.[Na+]>CO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:25][CH2:26][OH:27])[C:17]4[CH2:23][N:22]([CH2:38][CH2:39][CH3:40])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:11][CH:12]=2)[CH:4]=[N:3]1
Reactant: CCC=O
Reactant: Cn1cc(-c2ccc(Nc3nc4c(c(N(CCO)c5ccccc5)n3)CNCC4)cc2)cn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN1CCc2nc(Nc3ccc(-c4cnn(C)c4)cc3)nc(N(CCO)c3ccccc3)c2C1
Yield: 17.5 %

Procedure:
2-((2-(4-(1-Methyl-1H-pyrazol-4-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (40 mg, 0.09 mmol, Example 38a) was dissolved in methanol (2 mL). Acetic acid (1.037 μL, 0.02 mmol) was added followed by propionaldehyde (0.013 mL, 0.18 mmol). The reaction mixture was stirred for 30 minutes at room temperature before sodium cyanoborohydride (11.39 mg, 0.18 mmol) was added. The solvent was evaporated under reduced pressure, the crude dissolved in few drops of dimethylformamide and acetonitrile, filtered and purified by preparative HPLC yielding 2-((2-(4-(1-methyl-1H-pyrazol-4-yl)phenylamino)-6-propyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (7.6 mg, 15.4%) as acetic acid salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:27])[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21]O)=[CH:19][N:18]=[C:17]1[CH2:23][N:24]([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:47]1(=[O:57])[NH:51][C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12.N(C(OCC)=O)=NC(OCC)=O>>[F:15][C:13]1[CH:12]=[CH:11][C:10]([N:16]2[C:20]([CH2:21][N:51]3[C:47](=[O:57])[C:48]4=[CH:56][CH:55]=[CH:54][CH:53]=[C:49]4[C:50]3=[O:52])=[CH:19][N:18]=[C:17]2[CH2:23][N:24]([CH3:25])[CH3:26])=[C:9]([C:8](=[O:27])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:14]=1
Reactant: CN(C)Cc1ncc(CO)n1-c1ccc(F)cc1C(=O)c1ccccc1F
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN(C)Cc1ncc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(F)cc1C(=O)c1ccccc1F

Procedure:
In the manner given in Example 3, 2',5-difluoro-2-[2-[(dimethylamino)methyl]-5-hydroxymethylimidazol-1-yl]-benzophenone, triphenylphosphine, phthalimide and thereafter diethyl azodicarboxylate are reacted together to give N-[[1-[4-fluoro-2-(o-fluorobenzoyl)phenyl]-2-[(dimethylamino)methyl]imidazol-5-yl]methyl]phthalimide.