Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[O:15])=[C:12]([CH3:29])[O:11][N:10]=1.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([NH:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:15])=[C:12]([CH3:29])[O:11][N:10]=1
Reactant: COC(=O)CCC1CCCCC1NC(=O)c1c(-c2c(F)cccc2Cl)noc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)N[C@@H]1CCCC[C@H]1CCC(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of methyl 3-(2-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclohexyl)propanoate (0.127 g, 0.3 mmol) in THF (5 mL) was treated with a 0.5 M sol'n of LiOH in water (3 mL). The sol'n was stirred at r.t. for 5 hr. The reaction was diluted with water (3 mL) and washed with EtOAc (2×5 mL). The pH of the aqueous was adjusted to ˜3 with 0.1 M HCl and extracted with EtOAc (4×5 mL). The organic extractions were then washed with brine (2×5 mL), dried over sodium sulfate and the solvent removed to afford 0.095 g (80%) as a white solid. MS (ES+) m/z 409.0 (M+H)+, (ES−) m/z 407.0 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1.[Br:27]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:27][C:9]1[CH:8]=[C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:26])[C:16]2[O:15][CH2:14][C@H:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:12]3[C:23](=[O:25])[NH:24][C:10]=1[C:11]=23
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OC[C@@H]3c1ccccn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc(Br)c2[nH]c(=O)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A solution of (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (2.50 g, 7.18 mmol) in tetrahydrofuran (47 mL) was treated with N-bromosuccinimide (1.40 g, 7.89 mmol) and stirred at room temperature for 1 h, at which time the reaction mixture was treated with additional N-bromosuccinimide (0.70 g, 3.93 mmol) and stirred at 45° C. for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (50% ethyl acetate/hexanes to 100% ethyl acetate) gave the desired product (3.0 g, 98%) as a single enantiomer. LCMS calculated for C19H16BrN4O3 (M+H)+: m/z=427.1, 429.1. found: 426.8, 428.8.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].C([O:7][C:8](=O)[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N:15]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[C:16]1=[O:30])C.C(OCC)(=O)C>C(OCC)C.CCCCCC.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[OH:7][C:8]1([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=3)[C:16]2=[O:30])[CH2:2][CH2:1]1
Reactant: CC[Mg+]
Reactant: CCOC(=O)c1ccncc1N1CCN(c2cccc(C(F)(F)F)c2)C1=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Br-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1N(c2cccc(C(F)(F)F)c2)CCN1c1cnccc1C1(O)CC1
Reaction time: 1.5 h
Yield: 6.7 %

Procedure:
2.5 M Solution of EtMgBr (0.8 mL, 1.974 mmol) was added drop wise to a solution of titanium(IV)isopropoxide (187.3 mg, 0.659 mmol) in diethyl ether (10 mL) for a period of 15 minutes at −78° C. under nitrogen atmosphere. The resulting mixture was stirred for 90 minutes. This was followed by the addition of 3-[2-oxo-3-(3-trifluoromethyl-phenyl)-imidazolidin-1-yl]-isonicotinic acid ethyl ester (I-36c: 125 mg, 0.329 mmol) in diethyl ether (3 mL) at −78° C. and continued stirring at room temperature overnight. The reaction was monitored by TLC (80% ethyl acetate in hexane). The reaction mixture was cooled and partitioned between ethyl acetate and 1N HCl. The organic layer was concentrated to yield crude product which was purified by preparative HPLC to afford 8 mg of the product (6% yield).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29]C(=O)OC(C)(C)C)[CH2:24]4)=[N:21][CH:22]=2)=[N:13][C:12]([C:37]2[CH:42]=[C:41]([Cl:43])[C:40]([OH:44])=[C:39]([Cl:45])[CH:38]=2)=[CH:11][CH:10]=3)=[O:5])C[CH2:2]1.C(O)(C(F)(F)F)=O>>[ClH:43].[ClH:43].[ClH:43].[NH2:29][C@@H:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:20]2[N:21]=[CH:22][C:17]([NH:16][C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:37]5[CH:38]=[C:39]([Cl:45])[C:40]([OH:44])=[C:41]([Cl:43])[CH:42]=5)[N:13]=4)[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[CH2:1][CH3:2])=[CH:18][CH:19]=2)[CH2:24]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)nc34)cn2)C1
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@@H](N)C2)nc1
Product: Cl
Yield: 247.4 %

Procedure:
Following general procedure IV-2, (R)-tert-butyl [1-(5-{[3-(cyclopropanecarbonyl)-6-(3,5-dichloro-4-hydroxyphenyl)-1,5-naphthyridin-4-yl]amino}pyridin-2-yl)piperidin-3-yl]carbamate (80 mg, 0.12 mmol) was reacted with TFA (2 mL) followed by formation of the trihydrochloride salt to afford the desired product (48 mg, 62%) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 9.39 (s, 1H), 8.49 (d, J=9.5 Hz, 1H), 8.42 (d, J=9.0 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 7.92 (dd, J=9.5, 2.0 Hz, 1H), 7.58 (s, 2H), 7.28 (d, J=9.5 Hz, 1H), 4.42-4.32 (m, 1H), 4.16-3.96 (m, 1H), 3.52-3.22 (m, 5H), 2.29-2.18 (m, 1H), 2.08-1.98 (m, 1H), 1.88-1.75 (m, 2H), 1.37-1.20 (m, 3H); ESI MS m/z 537 [M+H]+; HPLC 98.0% (AUC), tR=9.92 min
Reaction SMILES: [NH2:1][C:2]1([CH3:16])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11](C#N)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.Cl[CH2:18][C:19]([N:21]1[C@@H:25]([C:26]#[CH:27])[CH2:24][CH2:23][C@H:22]1[C:28]#[N:29])=[O:20].[C:30](#[N:32])C>>[C:26]([C@@H:25]1[N:21]([C:19](=[O:20])[CH2:18][NH:1][C:2]2([CH3:16])[CH2:3][CH2:4][N:5]([C:8]3[C:13]([C:30]#[N:32])=[CH:12][CH:11]=[CH:10][N:9]=3)[CH2:6][CH2:7]2)[C@H:22]([C:28]#[N:29])[CH2:23][CH2:24]1)#[CH:27]
Reactant: CC#N
Reactant: CC1(N)CCN(c2ccc(C#N)cn2)CC1
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1(C)CCN(c2ncccc2C#N)CC1

Procedure:
A mixture of Example 30D (60 mg, 0.31 mmol) and (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (105 mg, 0.49 mmol, Example 8D) in acetonitrile (2 mL) was stirred at 23° C. for 72 hours. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by chromatography (silica gel, eluting with 96% dichloromethane/4% methanol/0.1% ammonium hydroxide) to provide the titled compound as a white foam. MS (CI) m/z 377 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.38 (s, 1H), 7.58 (dd, 1H), 6.59 (d, 1H), 4.74 (t, 1H), 4.63-4.57 (m, 1H), 3.78-3.68 (m, 6H), 2.53 (s, 1H), 2.43-2.34 (m, 2H), 1.69-1.50 (m, 4H), 1.19 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=[C:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:19]=3)=[N:15][CH:16]=2)[CH2:10][CH2:9]1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38](=O)[O:39]C2C=CC=CC=2)[CH:32]=1.C(N(CC)CC)C>CS(C)=O>[CH:8]1([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=3)[CH:24]=[C:25]3[CH2:30][CH2:29][N:28]([C:38]([NH:37][C:33]4[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=4)=[O:39])[CH2:27][CH2:26]3)=[N:15][CH:16]=2)[CH2:10][CH2:9]1
Reactant: C(=C1CCNCC1)c1cccc(Oc2ccc(C3CC3)cn2)c1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccnc1)N1CCC(=Cc2cccc(Oc3ccc(C4CC4)cn3)c2)CC1
Temperature: 60 °C
Yield: 58 %

Procedure:
To a solution of 5-cyclopropyl-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine trifluoroacetate (125 mg, 0.408 mmol) in DMSO (5 mL) was added phenyl pyridin-3-ylcarbamate (87.4 mg, 0.408 mmol) followed by triethylamine (0.12 mL, 0.82 mmol). The reaction was heated to 60° C. overnight and then allowed to cool to RT. The reaction mixture was partitioned between EtOAc and water. The organic layer was dried and concentrated. Purification by silica gel column chromatography (0-5% MeOH/CH2Cl2) afforded the title compound as a white foam (101 mg, 58% yield). MS (APCI 10V) AP+2 427.07; 1H NMR (400 MHz, CDCl3) δ ppm 0.61-0.66 (m, 2H) 0.93-0.99 (m, 2H) 1.55 (s, 1H) 1.81-1.89 (m, 1H) 2.45 (t, 2H) 2.58 (t, 2H) 3.50 (t, 2H) 3.60 (t, 2H) 6.38 (s, 1H) 6.44 (s, 1H) 6.80 (d, 1H) 6.94 (br. s., 1H) 6.96-7.01 (m, 2H) 7.20-7.23 (m, 1H) 7.29-7.35 (m, 2H) 7.99-8.01 (m, 1H) 8.26 (d, 1H) 8.42 (d, 1H).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Br[CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCCC1>[O:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]1[O:26][CH2:25][CH2:24][CH2:23][CH2:22][O:19][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: BrCCCCOC1CCCCO1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To a stirring solution of 2.0 g (7.0 mmol) of oleic acid and 1.6 g (7.0 mmol) of 2-(4-bromobutoxy)tetrahydro-2H-pyran in 20 mL of tetrahydrofuran is added 2.3 g (7.1 mmol) of cesium carbonate and the reaction mixture is stirred overnight at room temperature. The reaction mixture is poured into water and extracted with three 100 mL portions of ether. The combined organic layers are dried over MgSO4 and concentrated in vacuo affording 2.9 g (100%) of (Z)-9-octadecenoic acid 4-[(tetrahydro-2H-pyran-2-yl)oxy]butyl ester. Next, 500 mg of Dowex 50W 8X resin is added to a stirring solution of 2.9 g (7.0 mmol) of (Z)-9-octadecenoic acid 4-[(tetrahydro-2H-pyran-2-yl)oxy]butyl ester in 100 mL of 1:1 tetrahydrofuran/methanol and the reaction mixture is stirred overnight at room temperature. The reaction mixture is filtered and concentrated in vacuo affording 2.4 g (100%) of alcohol. Next, 11 mL of 2.0M Jones reagent is added at 0° C. to a stirring solution of 2.4 g (7.0 mmol) of alcohol in 75 mL of acetone and the reaction mixture is stirred for 2 hours. The reaction mixture is poured into water and extracted with three 50 mL portions of ether. The combined organic layers are dried over MgSO4 and concentrated in vacuo affording 2.1 g (81%) of title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:6]2=[CH:7][C:8]3[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][C:13]=3[N:5]2[CH2:4][CH2:3]1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28](O)=[O:29])[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([NH:14][C:10]4[CH:11]=[CH:12][C:13]5[N:5]6[CH2:4][CH2:3][C:2]([CH3:15])([CH3:1])[C:6]6=[CH:7][C:8]=5[CH:9]=4)=[O:29])[CH2:26][CH2:27]3)=[CH:24][C:19]=2[O:18][CH2:17]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CC1(C)CCn2c1cc1cc(N)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)CCn2c1cc1cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1,1-Dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-amine (40.0 mg, 0.200 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (41.2 mg, 0.200 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (84.2 μL, 0.600 mmol) and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added to the mixture and the resulting solution was allowed to stir for 5 minutes at room temperature. The crude product was then purified by preparative HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(1,1-dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]-indol-7-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 388.2. found 389.2 (M+1)+. Retention time of 2.02 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 7.06-7.02 (m, 2H), 6.96-6.90 (m, 2H), 6.03 (s, 2H), 5.98 (d, J=0.7 Hz, 1H), 4.06 (t, J=6.8 Hz, 2H), 2.35 (t, J=6.8 Hz, 2H), 1.42-1.38 (m, 2H), 1.34 (s, 6H), 1.05-1.01 (m, 2H).
Reaction SMILES: [NH:1]([C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[C@H:2]([C:20]([NH:22][C@H:23]([C:26]([NH:28][C@H:29]([C:32]([O:34]C)=[O:33])[CH2:30][OH:31])=[O:27])[CH2:24][OH:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[OH-].[Na+].Cl>CO.O>[NH:1]([C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:37])[C@H:2]([C:20]([NH:22][C@H:23]([C:26]([NH:28][C@H:29]([C:32]([OH:34])=[O:33])[CH2:30][OH:31])=[O:27])[CH2:24][OH:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=1)(=[O:11])=[O:10]
Reactant: COC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3.5 Grams of Z-Arg(Tos)-Ser-Ser-OMe was dissolved in 50 ml of methanol and 10 ml of water, and 8.06 ml of 1N-sodium hydroxide was added thereto, the mixture was stirred at a room temperature for 45 minutes, next 7.24 ml of 1N-HCl was added to neutralize the reaction mixture, then methanol was removed by distillation, and the residue was extracted with n-butanol. The extract was washed with water, and n-butanol and water were removed by distillation, the residue was crystallized by adding ether, reprecipitated from methanol-ethyl acetate to obtain 2.60 g of Z-Arg(Tos)-Ser-Ser-OH.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)=[NH:4].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[C:20]([C:28](O)=O)[N:19]=2)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[N:21]=[C:20]([C:28]3[O:1][N:2]=[C:3]([C:5]4[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=4)[N:4]=3)[N:19]=2)=[CH:16][CH:17]=1
Reactant: N=C(NO)c1cccnc1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2nc(-c3cccnc3)no2)n1

Procedure:
The title compound was prepared from available N-hydroxy-3-pyridinecarboxamidine [CAS-No. 1594-58-7] (0.103 g, 0.75 mmol) and 4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.1) (0.15 g, 0.5 mmol) according to the general procedure V. Obtained as a yellow solid (0.092 g, 46%). MS (ISP) 404.4 [(M+H)+]; mp 168.5° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:19][CH2:20][CH:21]1[O:25][CH2:24][CH2:23][O:22]1>C(#N)C.C(OCC)(=O)C>[CH2:1]([NH:8][CH2:19][CH2:20][CH:21]1[O:25][CH2:24][CH2:23][O:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCC1OCCO1
Reactant: NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: c1ccc(CNCCC2OCCO2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.3 %

Procedure:
To a mixture of benzylamine (2.18 mL, 20.0 mmol) and di-iso-propylethylamine (2.61 mL, 15.0 mmol) in acetonitrile (30 mL) was added 2-(2-bromoethyl)-1,3-dioxolane (1.17 mL, 10.0 mmol). The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was purified by flash column chromatography eluting with 0 to 4% methanol/dichloromethane to afford the title compound (0.836 g, 40%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[C:26]([O:31][CH2:32]I)(=[O:30])[CH:27]([CH3:29])[CH3:28]>C(N(CC)CC)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH2:32][O:31][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Reactant: CC(C)C(=O)OCI
Solvent: CCN(CC)CC
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)C)=CCS[C@H]12)c1csc(N)n1

Procedure:
In the same manner as Example 8, 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer) was reacted with iodomethyl isobutyrate in the presence of triethylamine to give isobutyryloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer), mp 95°-100° C. (decompn.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH:7]=1.[CH3:29][S:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+].CCCC>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.C(O)C>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:6]2[CH:7]=[C:2]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([S:30][CH3:29])[CH:36]=3)[CH:3]=[CH:4][C:5]=2[F:28])[CH2:9][C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:23])[F:24])=[N:11]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(Br)ccc2F)c(F)c1
Reactant: CSc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCC
Product: CSc1cccc(-c2ccc(F)c(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)c1
Temperature: 88 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
5-(5-Bromo-2-fluoro-phenyl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (50.0 mg, 0.11 mmol) prepared in Step 5 of Preparation 8, 3-(methylthio)phenylboronic acid (26.7 mg, 0.16 mmol), Pd(PPh3)4 (12.3 mg, cat.) and a 2N sodium carbonate solution (500.0 uL) were added to a mixed solvent of ethanol (500.0 uL) and 1,2-dimethylethane (2.0 mL). The reaction mixture was stirred at 88° C. for 2 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/15) to give 35.0 mg of the titled compound as a white liquid.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1(=[C:14]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25]C(C)(C)C)=[O:24])=[CH:17][C:16]=2[F:30])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[C:8]1(=[C:14]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:17][C:16]=2[F:30])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.1 %

Procedure:
Trifluoroacetic acid (2.0 mL) was added dropwise to 78 (210 mg, 0.514 mmol) dissolved in CH2Cl2 (2 mL) at 0° C. The reaction mixture was stirred at RT for 3 h and the volatiles were removed under reduced pressure. The residue was recrystallized (EtOAc:hexanes) to afford 98.0 mg (54%) of 79 as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.52 (br s, 6H), 1.98 (br s, 2H), 2.19 (br s, 2H), 6.52 (d, J=16.0 Hz, 1H), 6.66 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 7.11 (t, J=7.9 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.52 (m, 2H), 9.33 (s, 1H), 12.40 (br s, 1H). LRMS (ESI): m/z 353 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1>>[ClH:1].[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2nccc(Cl)c2c1
Reactant: c1ccc2c(c1)CCNC2
Product: Cl
Product: Oc1ccc2nccc(N3CCc4ccccc4C3)c2c1

Procedure:
The title compound, MS: m/e=277.2 (M+H+), was prepared 4-chloro-quinolin-6-ol and 1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[N:16]4[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:15]4[N:14]=[CH:13][C:12]=3[C:23]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)=[O:24])[CH:8]=2)[CH:3]=[CH:2]1.[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[N:16]4[N:17]=[CH:18][C:19]([C:20]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:21])=[C:15]4[N:14]=[CH:13][C:12]=3[C:23]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)=[O:24])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1cnn2c(Nc3ccc4cc[nH]c4c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc4cc[nH]c4c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 35 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(6-indolylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.10 mmol) obtained in step 2 and ethanesulfonamide (0.092 g, 0.84 mmol), the title compound (0.020 g, 36%) was obtained.
Reaction SMILES: [C:1]1(=O)[O:7][C:5](=O)[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[NH2:13]OC1CCCCCC=1.[C:22]1(C)C=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH:11]1[CH:10]=[CH:9][CH:8]=[C:4]2[C:3]=1[CH:2]=[C:1]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:13]1[C:5]2=[O:7]
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: Cc1ccccc1
Reactant: NOC1=CCCCCC1
Solvent: ClC(Cl)Cl
Product: O=c1c2ccccc2cc2n1CCCCC2
Temperature: 25 °C

Procedure:
Homophthalic anhydride (4.86 g, 30 mmol) was added portionwise over 10 minutes to a refluxing solution of 1-aza-2-methoxycycloheptene (4.20 g, 33 mmol) in toluene. After addition was complete, the reaction mixture was heated an additional 1 h before cooling to ambient temperature. The reaction mixture was diluted with chloroform, the resulting solution was washed twice with sodium hydroxide, and the dried (magnesium sulfate) organic layer was concentrated in vacuo. The residue was chromatographed on silica gel using chloroform, followed by 4% methanol in chloroform, as eluent to give the desired compound. This was triturated with 20% ether in hexanes (40 ml) to yield the title compound as an off-white solid (2.21 g, 42%), m.p. 99-101° C.