Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[N:6][C:7](Cl)=[CH:8][CH:9]=1)(=[O:3])[NH2:2].[NH:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:35]1.CCN(C(C)C)C(C)C>CN1CCCC1=O>[C:43]([O:42][C:41]([NH:40][C@@H:36]1[CH2:37][CH2:38][CH2:39][N:34]([C:7]2[N:6]=[C:5]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:25])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[C:4]([C:1](=[O:3])[NH2:2])=[CH:9][CH:8]=2)[CH2:35]1)=[O:47])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: NC(=O)c1ccc(Cl)nc1Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(C(N)=O)c(Nc3ccc(N4CCN(C(=O)OCc5ccccc5)CC4)cc3)n2)C1
Temperature: 100 °C
Yield: 87.2 %

Procedure:
A mixture of benzyl 4-(4-(3-carbamoyl-6-chloropyridin-2-ylamino)phenyl)piperazine-1-carboxylate (4 g, 8.58 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (2.58 g, 12.88 mmol), and DIEA (3.00 mL, 17.17 mmol) in N-methyl-2-pyrrolidinone (6 mL) was placed in two capped scintillation vials and heated at 100° C. overnight. The reaction mixtures were quenched with water and filtered. The solid was purified by MPLC chromatography (ISCO, 6% NH4OH/MeOH/CH2Cl2, two 40 g stacked silica gel columns) to give 4.71 g of ((R)-benzyl 4-(4-(6-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-carbamoylpyridin-2-ylamino)phenyl)piperazine-1-carboxylate).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[O:31][CH:32]([CH3:34])[CH3:33].[F:35][C:36]([F:47])([F:46])[C:37]([C:42]([F:45])([F:44])[F:43])=[CH:38][C:39](O)=[O:40]>C(#N)C>[F:35][C:36]([F:46])([F:47])[C:37]([C:42]([F:43])([F:44])[F:45])=[CH:38][C:39]([NH:16][C@:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:31][CH:32]([CH3:34])[CH3:33])[CH:4]=1)([C:17]1[CH:22]=[C:21]([O:23][C:24]([F:28])([F:29])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=1)[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:40]
Reactant: CC(C)Oc1cc([C@](N)(Cc2ccccc2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reactant: O=C(O)C=C(C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: CC(C)Oc1cc([C@@](Cc2ccccc2)(NC(=O)C=C(C(F)(F)F)C(F)(F)F)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
A round bottom flask was charged with IIDQ polystyrene resin (493 mg, 1.5 mmol/g, 0.74 mmol) and acetonitrile (5 mL) and sealed with a rubber septum. The suspension was vacuumed and reflushed with argon three times. To the resulting slurry was added a solution of (R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine, prepared as described in Procedures 109, 110, 111, 112, 113, 114, (180 mg, 0.37 mmol) and 4,4,4-trifluoro-3-(trifluoromethyl)crotonic acid (93 mg, 0.45 mmol) in acetonitrile (5 mL) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and purified by ISCO chromatography (40 g column) using hexane/EtOAc (0-15% over 30 min) to give (R)-4,4,4-trifluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)but-2-enamide (Example 291) as a white solid at a retention time of 20 min (199 mg, 74% yield). LCMS: RT=2.18 min [M+H] 674.33 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=4.25 min, Purity 98% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) 7.19 ppm, 3H, m; 7.02 ppm, 1H, dd, J=10.55, 8.79 Hz; 6.95 ppm, 3H, m; 6.85 ppm, 1H, s; 6.67 ppm, 3H, d, J=7.03 Hz; 6.62 ppm, 1H, m; 6.13 ppm, 1H, s; 5.88 ppm, 1H, tt, J=53.00, 2.86, 2.75 Hz; 4.36 ppm, 1H, ddd, J=11.97, 6.15, 6.04 Hz; 3.99 ppm, 1H, d, J=13.18 Hz; 3.71 ppm, 1H, d, J=13.18 Hz; 1.26 ppm, 6H, m.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8](OCC)=[O:9])[C:5](=[O:13])[C:4]2[N:14]=[C:15]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:16][C:3]1=2.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:8]([C:6]2[C:5](=[O:13])[C:4]3[N:14]=[C:15]([CH2:17][N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:16][C:3]=3[N:2]([CH3:1])[CH:7]=2)=[O:9])=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1cn(C)c2sc(CN3CCOCC3)nc2c1=O
Reactant: NCc1ccc(Cl)cc1
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2nc(CN3CCOCC3)sc21
Temperature: 190 °C

Procedure:
A mixture of ethyl 4-methyl-2-(morpholin-4-ylmethyl)-7-oxo-4,7-dihydro[1,3]-thiazolo[5,4-b]pyridine-6-carboxylate (Preparation 30, 105 mg) and 4-chlorobenzyl-amine (1 mL) is heated to 190° C. for 40 min. and then allowed to cool to ambient temperature. The solvent is removed in vacuo. The mixture is diluted with ether to precipitate 89 mg (66%) of the title compound as a tan solid. Physical characteristics: 1H NMR (DMSO-d6) δ 2.59, 3.64, 3.91, 4.00, 4.56, 7.33-7.36, 8.75, 10.59; IR (diffuse reflectance) 2857, 2809, 1662, 1599, 1569, 1550, 1531, 1526, 1517, 1492, 1346, 1296, 1116, 797, 732 cm−1. Anal. Found: C, 55.50; H, 4.98; N, 12.00.
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][CH:22]1[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (0.141 g, 0.509 mmol) (note: this intermediate is disclosed in U.S. Pat. No. 7,112,592 Example 32b) in dry dichloromethane (3 mL) was added 4-amino-1-BOC-piperidine (0.1532 g, 0.765 mmol), triethylamine (0.16 mL, 1.148 mmol), HOBT (0.1145 g, 0.748 mmol), and EDC (0.1455 g, 0.759 mmol) sequentially at room temperature under nitrogen. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the residue was purified by HPLC (30×100 mm Waters Sunfire column; 5 micron; 35 mL/minute; 210 nM; 15% to 100% CH3CN+0.05% TFA/water+0.05% TFA over 15 minutes; desired product elutes at 50% CH3CN+0.05% TFA/water+0.05% TFA) to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9]C)=[O:8])=[C:5]([C:11]([O:13][CH3:14])=[O:12])[N:4]=[C:3]1[CH3:15].[Li+].[OH-]>C1COCC1.CO>[CH3:14][O:13][C:11]([C:5]1[N:4]=[C:3]([CH3:15])[N:2]([CH3:1])[C:6]=1[C:7]([OH:9])=[O:8])=[O:12]
Reactant: COC(=O)c1nc(C)n(C)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1nc(C)n(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 7 h
Yield: 73.1 %

Procedure:
To a solution of dimethyl 1,2-dimethyl-1H-imidazole-4,5-dicarboxylate (1.89 g, 8.91 mmol) in THF (35 mL) and MeOH (15 mL) was added at 0-5° C. LiOH (1M; 9.35 mL, 9.35 mmol). The reaction mixture was stirred at RT for 7 h and the solvents were evaporated in vacuo. The residue was poured into water (20 mL) and ethyl acetate (30 mL). The ethyl acetate phase was washed with water (10 mL). The combined aqueous phases were acidified with hydrochloric acid (1M, 10 mL) and extracted with dichloromethane/MeOH (95:5, 8×60 mL). The dichloromethane/MeOH phases were dried over MgSO4, filtered and evaporated to give the product as colorless solid (1.29 g, 6.51 mmol, 73.1%). MS: M=199.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:6][NH:7][C:8](=[O:24])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21].Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:6][NH:7][C:8](=[O:24])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][CH:19]1[CH2:22][O:23][C:31](=[O:33])[O:21][CH2:20]1
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC(CO)CO)cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC2COC(=O)OC2)cc1OC
Temperature: 25 °C
Yield: 180.7 %

Procedure:
To a solution of N-(3,4-dimethoxybenzyl)-2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-5-nitrobenzamide (134 mg) in a mixture of dichloromethane (1 mL) and pyridine (1 mL) was added triphosgene (49.1 mg) at −78° C. Then, the resulting mixture was stirred for an hour at ambient temperature. The mixture was diluted with ethyl acetate and washed successively with diluted ammonium chloride, water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and ethyl acetate (7:3) to give N-(3,4-dimethoxybenzyl)-5-nitro-2-(2-oxo-1,3-dioxan-5-ylamino)benzamide (129 mg) as a solid substance.
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([N+:11]([O-])=O)[C:3]=1[NH2:4].O.O.Cl[Sn]Cl.C(O)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[C:3]([NH2:4])=[C:5]([NH2:11])[CH:6]=[C:7]([F:10])[C:8]=1[F:9]
Reactant: Nc1c([N+](=O)[O-])cc(F)c(F)c1Br
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(F)c(F)c(Br)c1N
Temperature: 25 °C

Procedure:
3-Bromo-4,5-difluoro-1,2-diaminobenzene was prepared using an adaptation of the method of Bellamy et al. (Bellamy, F. D. et al., Tetrahedron Lett. 25: 839 (1984)). A mixture of 2-bromo-3,4-difluoro-6-nitroaniline (700 mg, 2.78 mmol) and SnCl2.2H2O (3.14 g, 13.9 mmol) dissolved in 7 mL ethyl acetate and 3 mL absolute ethanol under N2 was heated at 75 ° C. for 2 h. All the starting material had reacted as evidenced by TLC (silica gel, 2:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 20 mL crushed ice. Sufficient sat'd NaHCO3 solution was added (foaming!) to bring the pH to 5. The thick yellow white emulsion was then extracted with 3×25 mL ethyl acetate and the combined organic extracts washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a dark brown oil which crystallized on standing to yield 410 mg (66%). 1H NMR (CDCl3) δ 3.59 (br s, 4H, 2(NH2)); 6.52 (m, 1H, H-6).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=[O:18].[Na+]>S(=O)(=O)(O)O.O>[OH:18][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=N[O-]
Reactant: Nc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Temperature: -5 °C
Reaction time: 0.67 h
Yield: 67.5 %

Procedure:
3-Amino-5-pentafluorosulfanylbenzoic acid (1.5 g, example 2a)) was dissolved in 35% sulfuric acid (45 ml) and cooled to −5° C., and a solution of sodium nitrite (387 mg) in water (40 ml) was added dropwise within 10 min. After 40 min, the cooling bath was removed and the mixture was heated to 100° C. After 4 h, the mixture was cooled and the solution was decanted. The clear acidic solution was extracted five times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. The crude product was crystallized from ethyl acetate/heptane. 1 g of the desired compound was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[NH:7][C:6]1=[O:16].Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][N:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8](=[O:15])[NH:7][C:6]3=[O:16])[CH2:29][CH2:28]2)=[O:26])=[CH:23][CH:24]=1
Reactant: O=c1[nH]c(=O)n(CCCCl)c2ccccc12
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=C(c1ccc(F)cc1)C1CCN(CCCn2c(=O)[nH]c(=O)c3ccccc32)CC1
Yield: 18.5 %

Procedure:
A mixture of 3.6 parts of 1-(3-chloropropyl)-2,4(1H,3H)-quinazolinedione, 3.02 parts of (4-fluorophenyl)(4-piperidinyl)methanone hydrochloride, 3.7 parts of sodium carbonate, 0.1 parts of potassium iodide and 120 parts of 4-methyl-2-pentanone is stirred and refluxed overnight using a water-separator. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and concentrated to a small volume. After cooling the concentrate, the precipitated product is filtered off and crystallized from 2-propanol, yielding 1.3 parts (18.5%) of 1-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]-2,4(1H,3H)-quinazolinedione; mp. 192.9° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:16])=[CH:5][C:6]([C:11](OCC)=[O:12])=[N:7][C:8]=1[O:9][CH3:10])#[N:2].[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].CCOC(C)=O>O1CCCC1.C(O)C>[OH:12][CH2:11][C:6]1[CH:5]=[C:4]([CH3:16])[C:3]([C:1]#[N:2])=[C:8]([O:9][CH3:10])[N:7]=1
Reactant: CCOC(=O)c1cc(C)c(C#N)c(OC)n1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1nc(CO)cc(C)c1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.7 %

Procedure:
To a stirred suspension of ethyl 5-cyano-6-methoxy-4-methylpicolinate (5.0 g, 22.70 mmol) and calcium chloride (10 g, 90 mmol) in tetrahydrofuran (50 mL) and ethanol (50.0 mL) at 0° C. in an ice bath was added sodium borohydride (2.5 g, 66.1 mmol). The reaction was slowly allowed to warm to RT and stirred for 18 hr. A large amount of ppt. formed and LCMS showed that the reaction was complete. An equal volume of EtOAc was added and the reaction stirred for 1 hr. The suspension was filtered through a pad of Celite and washed with EtOAc. The filtrate was transferred to a separatory funnel, washed with aq. NH4Cl, brine, dried (Na2SO4), filtered and concentrated under vacuum. Purification by silica gel chromatography (Analogix, SF40-120g, 0 to 30% EtOAc in CH2Cl2) gave the product 6-(hydroxymethyl)-2-methoxy-4-methylnicotinonitrile (3.75 g, 21.05 mmol, 93% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.16 (s, 1H), 5.61 (t, J=5.8 Hz, 1H), 4.51 (d, J=5.8 Hz, 2H), 3.94 (s, 3H), 2.47 (s, 3H). MS(ES)+ m/e 179.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][C:16]([C:17]([OH:19])=[O:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24]N(C)CCN(C)C.C([Li])CCC.IC.[Cl-].[NH4+].Cl>C1(C)C=CC=CC=1.O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:20]([F:21])([F:22])[F:23])=[N:15][C:16]([C:17]([OH:19])=[O:18])=[C:10]2[CH:9]1[CH3:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1
Reactant: CN(C)CCN(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Solvent: CI
Product: CC1c2c(C(=O)O)nc(C(F)(F)F)n2CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 24.2 %

Procedure:
3-Trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-1,7-dicarboxylic acid 7-tert-butyl ester 27d (0.85 g, 2.54 mmol) was dissolved in a mixture of 25 mL of anhydrous toluene and 8 mL of anhydrous tetrahydrofuran. The reaction flask was placed in a dry ice-acetone bath and cooled to −78° C., and then tetramethyl-ethylenediamine (1.32 mL, 8087 mmol) was added to the flask. n-Butyllithium (5.55 mL, 8.87 mmol) was added dropwise in 5 minutes. After reacting at −78° C. for 15 minutes, iodomethane (0.4 mL, 6.34 mmol) was added dropwise. The reaction mixture was reacted at −78° C. for 10 minutes, then was allowed to warm up to room temperature and reacted for 2 hours until thin lay chromatography showed the starting material disappeared. 15 mL of saturated ammonium chloride and 20 mL of water were added to the reaction mixture successively. The mixture was adjusted to pH 3-4 with 2 N hydrochloric acid, and extracted with ethyl acetate (30 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 8-methyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-1,7-dicarboxylic acid 7-tert-butyl ester 39a (0.215 g, yield 24.3%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[NH:31][C:32]([NH:34][C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=1[F:42])=[O:33])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])=[O:18])[CH:13]=2)[CH:7]=1.[OH-].[Na+].O.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[NH:31][C:32]([NH:34][C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=1[F:42])=[O:33])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: CCOC(=O)CCCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCC(=O)O)c[nH]4)c3)cc2F)c1
Temperature: 60 °C

Procedure:
To a stirred solution of ethyl 4-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoate (45 mg, 0.078 mmol) in 10 ml of THF was added 3 ml of 1M NaOH (3.0 mmol). The mixture was heated at 60° C. for 3 hours, cooled to room temperature and poured into 100 ml of water. 2M HCl was added until pH=5. The precipitates were filtered, washed with water, and dried to give 4-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoic acid as grey solid. Yield: 40 mg, 93%.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:5](=[CH:10][C:11]([F:15])=[C:12]([I:14])[CH:13]=1)[C:6](OC)=[O:7].[Cl-].[Ca+2].[Cl-].[BH4-].[Na+]>C(O)C>[F:15][C:11]1[C:12]([I:14])=[CH:13][C:4]([CH2:3][OH:2])=[C:5]([CH2:6][OH:7])[CH:10]=1
Reactant: COC(=O)c1cc(F)c(I)cc1C(=O)OC
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: OCc1cc(F)c(I)cc1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
To 9.38 mmol 4-fluoro-5-iodo-phthalic acid dimethyl ester in 25 ml absolute ethanol was added 9.38 mmol calcium chloride. 18.8 mmol sodium borohydride was then added in small portions and the reaction mixture was stirred for 4 h at room temperature, then at reflux for 2 h and then at room temperature overnight. The mixture was quenched by addition of 20 ml 1 M aq. hydrochloric acid and diluted with water and ethyl acetate. The phases were separated and the organic phase was extracted four times with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a yellow oil (98% yield). MS (m/e): 283.1 ([M+H]+, 100%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=O)(C)(C)C.[ClH:15].O1CCOC[CH2:17]1>>[ClH:15].[CH3:17][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: C1COCCO1
Agent: Cl
Product: CN1CCNCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4N HCl-dioxane (20 mL) was added to 3-oxopiperazine-1-carboxylic acid tert-butyl ester (2.06 g) obtained from Referential Example 90, followed by stirring at room temperature for 1 hour. The reaction solvent was removed under reduced pressure, to thereby give the title compound as an oily product (1.44 g, 99%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:10]([O:12]CC3C=CC=CC=3)=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12.C1(OC)C=CC=CC=1.Cl>C(Cl)Cl.[N+](C)([O-])=O.[Ti](Cl)(Cl)(Cl)Cl>[NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12
Reactant: CC1=C(C(=O)OCc2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 32 %

Procedure:
To a solution of benzyl 7β-amino-3-methyl-3-cephem-4-carboxylate (1.2 g) and anisole (5.2 ml) in methylene chloride (100 ml) is added a solution of titanium tetrachloride (2.6 g) in nitromethane under ice cooling, and the mixture stirred for 9.5 hours at room temperature. The reaction mixture is adjusted to pH 1 or less with diluted hydrochloric acid (70 ml), washed with ethyl acetate, and neutralized with 6 N-sodium hydroxide. The resulting titanium hydroxide is removed by filtration, and the filtrate concentrated under reduced pressure at a temperature below 50° C. The resulting crystals are collected by filtration to give 7β-amino-3-methyl-3-cephem-4-carboxylic acid (270 mg). Yield: 32%. This product was identical with an authentic specimen in NMR and IR spectra.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[Cu][C:14]#[N:15]>CN1CCCC1=O.C(OCC)(=O)C.O>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:14]#[N:15])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1nc(Cl)cc(N)c1[N+](=O)[O-]
Reaction time: 0.2 h
Yield: 23.9 %

Procedure:
A stirred suspension of 4-amino-2,6-dichloro-3-nitro-pyridine (17.5 g, 841 mmol) and copper (i) cyanide (15.1 g, 168.3 mmol) in 170 ml of 1-methyl-2-pyrrolidinone was lowered into an oil bath preheated to 180° C. and stirring continued for 12 minutes. The mixture was allowed to cool and diluted with ethyl acetate (700 ml) and water (700 ml) and the resultant suspension filtered. The organic layer was separated and further washed with water (500 ml) and 0.1N HCl (500 ml). The organic layer was then dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown solid which was washed with diethylether and dichloromethane to afford 4-amino-6-chloro-3-nitro-pyridine-2-carbonitrile (8 g).