Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:42])=[C:9]([CH2:11][O:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26](N(OC)C)=[O:27])=[CH:22][N:21]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:20]=3)=[CH:15][C:14]=2[O:40][CH3:41])[N:10]=1.[CH3:43][Mg]Br.Cl>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:42])=[C:9]([CH2:11][O:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26](=[O:27])[CH3:43])=[CH:22][N:21]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:20]=3)=[CH:15][C:14]=2[O:40][CH3:41])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)N(C)OC)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(C)=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-N-methoxy-N-methyl-2-propenamide (0.40 g) and tetrahydrofuran (30 mL) was added dropwise methylmagnesium bromide (1M tetrahydrofuran solution, 2.8 mL) at 0° C. and the mixture was stirred at room temperature for 2 hrs. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give (3E)-4-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-3-buten-2-one as colorless crystals (0.25 g, yield 68%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 177-178° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[NH2:10][CH:11]([CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:12]([NH:14][C:15]1([C:22]#[N:23])[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)=[O:13].C(N(CC)C(C)C)(C)C>C(#N)C>[C:22]([C:15]1([NH:14][C:12](=[O:13])[CH:11]([NH:10][C:2]2[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)[CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]1)#[N:23]
Reactant: N#Cc1ccnc(Cl)n1
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1CCC(C#N)(NC(=O)C(CC2CCCCC2)Nc2nccc(C#N)n2)CC1
Yield: 52 %

Procedure:
2-Chloro-4-pyrimidinecarbonitrile (0.3 mmol, Daves, G. D. Jr., O'Brien, D. E., Cheng, C. C. J. Het. Chem, 1964, 1, 130) and 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide (0.7 mmol) were dissolved in acetonitrile (10 mL) containing N,N-diisopropylethylamine (0.6 mmol). The solution was heated to a gentle reflux for 17 h. The volatiles were evaporated and the residue was subjected to chromatography (silica gel, eluant=EtOAc then MeOH). The methanolic fraction was concentrated to a colorless solid which was rechromatographed (10% MeOH/EtOAc) to afford the title compound as a colorless solid (52%). The material was recrystallized from dichloromethane/petroleum ether.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH2:19])[C:17]#[CH:18].C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH2:16]([NH:19][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)[C:17]#[CH:18]
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: C#CCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C#CCNCc1ccc(Oc2ccccc2)cc1
Reaction time: 18 h
Yield: 93.6 %

Procedure:
4-Phenoxybenzaldehyde (5.0 g, 25.2 mmol) and propargylamine (1.46 g, 26.5 mmol) were dissolved in 100 mL of 1% acetic acid in methanol under an atmosphere of dry nitrogen. Sodium cyanoborohydride (1.66 g, 26.5 mmol) was added, and stirring was continued for 18 hours at which time the solvent was removed under reduced pressure. The residue was suspended in ether, washed with 5% NaHCO3 and brine, and dried over Na2 SO4 to give 5.6 g (93%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10](OS(C(F)(F)F)(=O)=O)=[CH:9][C:8]([C:19]2[N:20]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:23][CH:22]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:42].C([Sn](CCCC)(CCCC)[C:48]1[O:49][CH:50]=[CH:51][CH:52]=1)CCC.[Cl-].[Li+].[F-].[NH4+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:10]([C:48]2[O:49][CH:50]=[CH:51][CH:52]=2)=[CH:9][C:8]([C:19]2[N:20]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([CH2:28][N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)=[CH:23][CH:22]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:42]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [F-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1c(-c2cc(-c3ccco3)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 90 °C
Reaction time: 6 h
Yield: 60.1 %

Procedure:
4-Chloro-5-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (100 mg, 0.159 mmol) was dissolved in 1,4-dioxane (3.0 mL), and the solution was added with 2-(tributylstannyl)furan (0.150 mL, 0.477 mmol), tetrakis(triphenylphosphine)palladium (15.0 mg, 0.0130 mmol) and lithium chloride (60.6 mg, 1.43 mmol), followed by stirring at 90° C. for 6.0 hours under argon atmosphere. The reaction mixture was added with 10% aqueous ammonium fluoride solution and filtered using Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=6/1) to obtain 4-chloro-5-(2-furyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (52.2 mg, yield 60%).
Reaction SMILES: CN1CCOCC1.[Na+].[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH:20]([CH2:24][CH2:25][CH3:26])[C:21]([O-:23])=O)[CH:17]=2)[CH:12]=[CH:11][N:10]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][C:35]2=[O:40])=[CH:30][CH:29]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[O:40]=[C:35]1[CH2:36][CH2:37][CH2:38][CH2:39][N:34]1[C:31]1[CH:30]=[CH:29][C:28]([NH:27][C:21](=[O:23])[CH:20]([O:19][C:16]2[CH:17]=[C:18]3[C:13]([CH:12]=[CH:11][N:10]=[CH:9]3)=[CH:14][CH:15]=2)[CH2:24][CH2:25][CH3:26])=[CH:33][CH:32]=1
Reactant: Nc1ccc(N2CCCCC2=O)cc1
Reactant: CCCC(Oc1ccc2ccncc2c1)C(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCC(Oc1ccc2ccncc2c1)C(=O)Nc1ccc(N2CCCCC2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
390 ml (3.55 mmol) of 4-methylmorpholine are added to a solution of 940 mg (3.52 mmol) of 2-(isoquinolin-7-yloxy)pentanoic acid sodium salt, 670 mg (3.52 mmol) of 1-(4-aminophenyl)piperidin-2-one, 670 mg (3.52 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (DAPECI) and 480 mg (3.56 mmol) of 1-hydroxybenzotriazole (HOBt) in 2 ml of DMF, and the mixture is stirred at room temperature for 18 hours. The reaction mixture is introduced into water, and the precipitate is filtered off, giving N-[4-(2-oxopiperidin-1-yl)phenyl]-2-(isoquinolin-7-yloxy)pentanamide as a colourless solid; ESI 418.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=1.Cl.[CH3:17][C@@H:18]1[CH2:23][O:22][CH2:21][CH2:20][NH:19]1.C(N(CC)CC)C>O1CCCC1>[CH3:8][N:7]1[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=[C:2]1[N:19]1[CH2:20][CH2:21][O:22][CH2:23][C@H:18]1[CH3:17]
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: C[C@@H]1COCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1COCCN1c1nc(-c2ccncn2)cc(=O)n1C
Yield: 75 %

Procedure:
A solution of 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.32 g, 1.44 mmol), (3R)-3-methylmorpholine hydrochloride (0.4 g, 2.9 mmol) and triethylamine (0.9 g, 8.9 mmol) in tetrahydrofuran (20 ml) was stirred for 10 hours at 100° C. The solution was partitioned between water and chloroform, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford 3-methyl-2-((3R)-3-methylmorpholin-4-yl)-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.31 g, 1.08 mmol, 75%) as white crystals.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]4CC4)=[CH:20][C:16]([C:17]([OH:19])=O)=[C:15]([F:25])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C12(COC3C(C)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.CS(N)(=O)=O.[N:54]1([S:58]([NH2:61])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55]1>>[C:1]12([CH2:11][O:12][C:13]3[C:21]([CH3:22])=[CH:20][C:16]([C:17]([NH:61][S:58]([N:54]4[CH2:57][CH2:56][CH2:55]4)(=[O:60])=[O:59])=[O:19])=[C:15]([F:25])[CH:14]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: NS(=O)(=O)N1CCC1
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: CS(N)(=O)=O
Agent: Cc1cc(C(=O)O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Product: Cc1cc(C(=O)NS(=O)(=O)N2CCC2)c(F)cc1OCC12CC3CC(CC(C3)C1)C2

Procedure:
Following the procedure as described in Example 50 step 5 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(adamantan-1-ylmethoxy)-2-fluoro-5-methylbenzoic acid and methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained as colorless solid (0.06 g, 27%): 1H NMR (300 MHz, DMSO-d6) δ 11.59 (s, 1H), 7.48 (d, J=8.3 Hz, 1H), 6.93 (d, J=12.9 Hz, 1H), 4.04 (t, J=7.7 Hz, 4H), 3.62 (s, 2H), 2.19-2.14 (m, 5H), 1.99 (s, 3H), 1.75-1.66 (m, 12H); MS (ES+) m/z 437.2 (M+1); MS (ES−) m/z 435.2 (M−1).
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=1)=O.[CH3:23][NH2:24].CO>O1CCCC1.CO>[CH3:23][NH:24][CH2:1][C:3]1[CH:7]=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=1
Reactant: CN
Reactant: O=Cc1cc(NC(=O)c2ccccc2)n(-c2ccccc2)n1
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1cc(NC(=O)c2ccccc2)n(-c2ccccc2)n1
Reaction time: 18 h

Procedure:
N-(3-Formyl-1-phenyl-1H-pyrazol-5-yl)benzamide (303 mg) was dissolved in tetrahydrofuran (5 mL) and methanol (3 mL), and 40% methylamine-methanol solution (1.1 mL) was added at room temperature. After stirring for 18 hr, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (3 mL), sodium borohydride (118 mg) was added under ice-cooling and the mixture was further stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=1:1→ethyl acetate) to give a free base of the title compound as a pale-yellow amorphous form (yield 248 mg). The obtained free base was dissolved in tetrahydrofuran (5 mL), and the mixture was added to a solution of fumaric acid (94 mg) in ethanol (10 mL). The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 137 mg, yield 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=2)[C:20]([OH:22])=O)[N:10]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:57][C:58]([F:70])([F:69])[C:59]1[CH:64]=[CH:63][C:62]([C:65]2([NH2:68])[CH2:67][CH2:66]2)=[CH:61][CH:60]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=2)[C:20]([NH:68][C:65]2([C:62]3[CH:63]=[CH:64][C:59]([C:58]([F:57])([F:69])[F:70])=[CH:60][CH:61]=3)[CH2:67][CH2:66]2)=[O:22])[N:10]=1
Reactant: NC1(c2ccc(C(F)(F)F)cc2)CC1
Reactant: COc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1C(=O)NC1(c2ccc(C(F)(F)F)cc2)CC1
Yield: 16.9 %

Procedure:
The title compound was prepared according to the procedure described in Example-17 by using 5-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-methoxybenzoic acid (Intermediate-11, 0.100 g, 0.270 mmol), THF (10 mL), di-isopropyl ethyl amine (10.0 mL), TBTU (0.177 g, 0.540 mmol) and 1-[4-(trifluoromethyl)phenyl]cyclopropanamine (intermediate-13, 0.066 g, 0.320 mmol) to afford 0.025 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.23 (s, 4H), 3.94 (s, 3H), 7.26 (d, J=9.0 Hz, 1H), 7.42 (d, J=8.4 Hz, 3H), 7.30-7.48 (m, 4H), 7.99 (d, J=9.3 Hz, 1H), 8.05 (s, 1H), 8.96 (s, 1H), 12.51 (br s, 1H); MS (m/z): 547.15 (M+).
Reaction SMILES: [C:1]([CH:4]([C:10]1[N:18]2[C:13]([C:14](=[O:27])[NH:15][C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[N:17]2)=[C:12]([CH3:28])[N:11]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:3])[CH3:2].[BH4-].[Na+]>>[OH:3][CH:1]([CH:4]([C:10]1[N:18]2[C:13]([C:14](=[O:27])[NH:15][C:16]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)=[N:17]2)=[C:12]([CH3:28])[N:11]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCCCC(C(C)=O)c1nc(C)c2c(=O)[nH]c(Cc3ccc(C)cc3)nn12
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCC(c1nc(C)c2c(=O)[nH]c(Cc3ccc(C)cc3)nn12)C(C)O

Procedure:
100 mg (0.26 mmol) of 7-(1-acetylhexyl)-5-methyl-2-(4-methylbenzyl)-imidazo[5,1-f][1,2,4]triazin-4(3H)-one (Example 2) are reacted analogously to Example 8 with 15 mg (0.39 mmol) of sodium borohydride to give 7-[1-(1-hydroxyethyl)hexyl]-5-methyl-2-(4-methylbenzyl)-imidazo[5,1-f][1,2,4]triazin-4(3H)-one.
Reaction SMILES: Cl.[F:2][C:3]([F:13])([F:12])[CH:4]([CH3:11])[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].[OH-].[Na+].[C:16](OC(=O)C)(=[O:18])[CH3:17]>O>[C:16]([NH:7][C@H:6]([C:8]([OH:10])=[O:9])[CH2:5][CH:4]([C:3]([F:12])([F:13])[F:2])[CH3:11])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C[C@H](N)C(=O)O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N[C@@H](CC(C)C(F)(F)F)C(=O)O
Temperature: 25 °C

Procedure:
To a cold (0° C.) solution of the 5,5,5-trifluoroleucine HCl salt (from Step 1 above) in H2O (30 mL) was added 1M aqueous NaOH (60 mL, 60 mmol) followed by acetic anhydride (3.5 mL, 36.7 mmol). The mixture was stirred at room temperature for 30 min to 1 h. After acidification with 6M aqueous HCl (6 mL), the mixture was extracted with EtOAc (6×). The combined EtOAc extracts were washed with brine, dried (MgSO4) and concentrated. The residue was swished with hexanes:Et2O (1:1) to afford N-acetyl-5,5,5-trifluoroleucine as a white solid.
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][S:7][CH2:6]1)([O:3][CH3:4])=[O:2].[CH3:12][O:13][CH2:14][CH2:15]Br.O>CS(C)=O>[C:1]([C:5]1([CH2:15][CH2:14][O:13][CH3:12])[C:10](=[O:11])[CH2:9][CH2:8][S:7][CH2:6]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1CSCCC1=O
Reactant: COCCBr
Solvent: CS(C)=O
Solvent: O
Product: COCCC1(C(=O)OC)CSCCC1=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 5.3 g (25 mmol) of potassium enolate of 4H-2,3,5,6-tetrahydro-3-carbomethoxythiopyran-4-one in 50 ml DMSO, was added 3.47 g (25 mmol) of 2-bromoethyl methyl ether. The solution was stirred under N2 at room temperature for 4 days. The reaction mixture was poured into 500 ml H2O and extracted three times with ethyl acetate. The combined ethyl acetate solution was washed with water; 5% NaOH; H2O and brine; dried over magnesium sulfate, filtered and concentrated in vacuo to give about 5 g crude product. Chromatographed through a pressure column eluting with 10% ethyl acetate-n-hexane to give 2.49 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][N:8]([S:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)(=[O:13])=[O:12])[C@@H:7]([C:25]([O:27]C(C)(C)C)=[O:26])[CH2:6]1)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][N:8]([S:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)(=[O:13])=[O:12])[C@@H:7]([C:25]([OH:27])=[O:26])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CCN(S(=O)(=O)CCCOc2ccc(F)cc2)[C@@H](C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCN(S(=O)(=O)CCCOc2ccc(F)cc2)[C@@H](C(=O)O)C1
Temperature: 22 °C
Yield: 96.2 %

Procedure:
To a stirred, cold (0° C.) solution of (2R,4R)-1-[3-(4-fluorophenoxy)-propane-1-sulfonyl]-piperidine-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester (1.15 g, 2.5 mmol) in 10 mL of methylene chloride was added 10 mL of trifluoracetic acid. The mixture was allowed warm to ambient temperature (22° C.) over 16 hours. The mixture was concentrated in vacuo to give 970 mg of crude (2R,4R)-1-[3-(4-fluorophenoxy)-propane-1-sulfonyl]-piperidine-2,4-dicarboxylic acid 4-methyl ester as a orange solid.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[NH2:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[Cl:22])=[CH:19][CH:18]=[CH:17][CH:16]=2>O1CCCC1>[Cl:22][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[NH:11][CH:5]=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cnc2ccccc2c1Cl
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CNc1cnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83 %

Procedure:
Acetic anhydride (16 mL, 170 mmol) was cooled to 0° C., and formic acid (7.2 mL of 97% pure material, 190 mmol) was added over a period of ten minutes. The solution was stirred for 2.5 hours at room temperature and then added to a stirred solution of 3-amino-4-chloroquinoline (10.0 g, 56.0 mmol) in tetrahydrofuran (THF) (100 mL). The reaction was stirred for one hour at room temperature and then concentrated under reduced pressure. Methanol (50 mL) was added to the residue, stirred for 30 minutes, and removed under reduced pressure. The residue was then stirred with dichloromethane (150 mL) and saturated aqueous sodium bicarbonate (50 mL) for three days. A solid was present and was isolated by filtration and dried under high vacuum. The filtrate was concentrated under reduced pressure, and the residue was dissolved in methanol (400 mL). The solution was dried over potassium carbonate, filtered, and concentrated under reduced pressure. The residue was combined with the solid isolated by filtration to provide 9.6 g of 4-chloroquinolin-3-ylformamide as a brown solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]2[CH:25]([CH2:26][O:27][CH2:28][C:29](OCC)=[O:30])[O:24][CH2:23][CH2:22][N:21]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:20]2)[CH:15]=[CH:16][C:17]=1[Cl:18].O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]2[CH:25]([CH2:26][O:27][CH2:28][CH2:29][OH:30])[O:24][CH2:23][CH2:22][N:21]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:20]2)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: CCOC(=O)COCC1OCCN(C(=O)OC(C)(C)C)CC1c1ccc(Cl)c(Cl)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(COCCO)C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 73.3 %

Procedure:
Lithium aluminum hydride (90 mg) was added to a solution of aluminum chloride (90 mg) in THF (5 mL), and the mixture was stirred at room temperature for 40 min. A solution of tert-butyl (6SR,7SR)-6-(3,4-dichlorophenyl)-7-[(2-ethoxy-2-oxoethoxy)methyl]-1,4-oxazepane-4-carboxylate (300 mg) in THF (5 ml) was added dropwise to the reaction mixture, and the mixture was stirred at 0° C. for 1 hr. Sodium sulfate 10 hydrate was added to the reaction mixture, the mixture was stirred at room temperature for 30 min, and the resultant salt was filtered off. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (200 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C([O-])([O-])=O.[K+].[K+].Cl>O.CC#N>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)[CH3:23]
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 80 °C
Yield: 79.8 %

Procedure:
A mixture of 4-(4-bromophenyl)phenol (3.74 g, 15.0 mmol), MeCN (20 ml), ethyl 4-bromobutyrate (4.42 g, 22.7 mmol), and K2CO3 (3.12 g, 22.6 mmol) was stirred at 80° C. After 16 h water (100 ml) and 1N HCl (40 ml) were added, and the product was extracted (3×AcOEt), the combined extracts were washed with brine (2×), dried (MgSO4), and concentrated. The residue was recrystallized from EtOH (40 ml) to yield 4.35 g (80%) of 4-(4′-bromobiphenyl-4-yloxy)butyric acid ethyl ester as colorless plates.
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>N1C=CC=CC=1>[F:21][C:3]1[C:2]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Product: CN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C)CC1

Procedure:
7-Fluoro-1-methyl-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under conditions analogous to Example 1 but starting from 5 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 16 g of 1-methylpiperazine in 50 cm3 of pyridine. After concentrating the reaction mixture