Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.O[CH:28]([C:58]1[O:59][CH:60]=[CH:61][N:62]=1)[CH2:29][C@H:30]1[CH2:41][CH2:40][C:39]2[S:38][C:37]3[N:36]=[CH:35][N:34]=[C:33]([O:42][CH:43]4[CH2:48][CH2:47][CH:46]([N:49]([CH3:57])[C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[CH2:45][CH2:44]4)[C:32]=3[C:31]1=2>ClCCl>[I:1][CH:28]([C:58]1[O:59][CH:60]=[CH:61][N:62]=1)[CH2:29][C@H:30]1[CH2:41][CH2:40][C:39]2[S:38][C:37]3[N:36]=[CH:35][N:34]=[C:33]([O:42][CH:43]4[CH2:48][CH2:47][CH:46]([N:49]([CH3:57])[C:50](=[O:56])[O:51][C:52]([CH3:53])([CH3:54])[CH3:55])[CH2:45][CH2:44]4)[C:32]=3[C:31]1=2
Reactant: II
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(O)c2ncco2)CC4)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(I)c2ncco2)CC4)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 61.4 %

Procedure:
For the preparation of the starting material compound 47.1, see Example 47. A solution of iodine (244 mg), Ph3P (252 mg) and imidazole (143 mg, 2.10 mmol, 3.49 equiv) in dry dichloromethane (20 mL) was stirred at 0° C. for 30 min under nitrogen. Then a solution of tert-butyl N-(4-[[(3R)-3-[2-hydroxy-2-(1,3-oxazol-2-yl)ethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (310 mg, 0.60 mmol, 1.00 equiv) was added dropwise to the reaction mixture and the resulting solution was stirred for 2.5 h at room temperature. The reaction was then quenched with saturated aqueous NaHSO3 and extracted with 2×30 mL of dichloromethane. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate. After concentrated in vacuo, the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to give tert-butyl N-(4-[[(3R)-3-[2-iodo-2-(1,3-oxazol-2-yl)ethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (230 mg, 61%) as a yellow solid. MS (ES): m/z 625 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:37](N2CCCCC2)=[O:38])[C:8]([O:35][CH3:36])=[C:9]([NH:11]C(=O)C(C2C3C(=CC=CC=3)C(OCCN3CCOCC3)=CC=2)=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=[O:47].CCN(C(C)C)C(C)C.N1CCCCC1>C(Cl)Cl.CN(C=O)C>[NH2:11][C:9]1[C:8]([O:35][CH3:36])=[C:7]([CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:10]=1)[C:37]([OH:38])=[O:47]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1c(NC(=O)C(=O)c2ccc(OCCN3CCOCC3)c3ccccc23)cc(C(C)(C)C)cc1C(=O)N1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COc1c(N)cc(C(C)(C)C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
N-[5-tert-Butyl-2-methoxy-3-(piperidine-1-carbonyl)-phenyl]-2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-2-oxo-acetamide (31) 26 mg (0.049 mmol) of the compound obtained above was converted to the acid chloride by reaction with oxalyl chloride (54 μl, 0.5 mmol) in 0.5 mL DCM in the presence of a catalytic amount of DMF (rt, 2 h). After removal of the solvent, the crude acid chloride was dissolved in 1 mL DCM. DIEA (0.2 mmol) was added, followed by the addition of piperidine (0.1 mmol). The resulting mixture was stirred at rt overnight. Aqueous work-up and purification by LC-MS resulted in 7.6 mg pure product. Calculated mass=602. Observed mass=602
Reaction SMILES: [NH2:1][CH:2]([CH:6]1[CH2:11][CH:10]2[CH:8]([C:9]2([F:13])[F:12])[CH2:7]1)[C:3]([OH:5])=[O:4].[Si](C=[N+]=[N-])(C)(C)[CH3:15]>C(Cl)Cl.CO>[NH2:1][CH:2]([CH:6]1[CH2:7][CH:8]2[CH:10]([C:9]2([F:12])[F:13])[CH2:11]1)[C:3]([O:5][CH3:15])=[O:4]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: NC(C(=O)O)C1CC2C(C1)C2(F)F
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(N)C1CC2C(C1)C2(F)F
Temperature: 25 °C
Yield: 84.11 %

Procedure:
To a solution of amino(6,6-difluorobicyclo[3.1.0]hex-3-yl)acetic acid (1.0 g, 5.23 mmol) in CH2Cl2:MeOH (4:1) was added dropwise TMSCHN2 (10.5 mL) over 10 min at 0° C. until a neon yellow color persisted. The reaction mixture was allowed to warm to 25° C. over 19 h. The solvent was removed in vacuo to obtain methyl amino(6,6-difluorobicyclo[3.1.0]hex-3-yl)acetate as a light yellow oil (0.9 g, 84.11%). Mass Spectrum (−ESI): 206 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:11]1[CH2:21][CH2:20][CH:14]([C:15](OCC)=[O:16])[CH2:13][CH2:12]1)[CH2:8][CH2:9][CH3:10].C(N1CCC(C(O)=O)CC1)CCC.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1.O>[CH2:7]([N:11]1[CH2:21][CH2:20][CH:14]([CH2:15][OH:16])[CH2:13][CH2:12]1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCN1CCC(C(=O)OCC)CC1
Agent: CCCCN1CCC(C(=O)O)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: O
Product: CCCCN1CCC(CO)CC1
Reaction time: 0.5 h
Yield: 115.2 %

Procedure:
A suspension of lithium aluminum hydride (1.39 g) in THF (100 ml) was ice-cooled, to which was added dropwise a solution of a mixture (4.15 g) of ethyl 1-n-butylisonipecotate and 1-n-butylisonipecotic acid obtained in Preparation Example 19 in THF (100 ml) over a period of 15 minutes with stirring. The mixture was stirred under ice-cooling for 10 minutes, and then at room temperature for 30 minutes. To the reaction solution were successively added water (2 ml), a 15% aqueous solution of sodium hydroxide (2 ml), water (6 ml) and anhydrous magnesium sulfate, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was filtered off with Celite, and the solvent was distilled off under reduced pressure to give the title compound (3.84 g). This compound was used for the subsequent reaction without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20](OCC)=[O:21])[N:19]=2)[CH:16]=1>>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20]([NH:4][C:3]3[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=3[CH3:1])=[O:21])[N:19]=2)[CH:16]=1
Reactant: Cc1cccc(C)c1N
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: Cc1cccc(C)c1NC(=O)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using 2,6-dimethylaniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:26])[C@H:19]([CH:20]=[C:21]=[CH2:22])[C@H:18]1[C:23]([OH:25])=[O:24].[C:27]([C@@H:29](O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:31]=1)#[N:28]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:16][C:17]1([CH3:26])[C@H:19]([CH:20]=[C:21]=[CH2:22])[C@H:18]1[C:23]([O:25][C@H:29]([C:27]#[N:28])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:31]=1)=[O:24]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: C=C=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C=C[C@@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 35.5 %

Procedure:
1.22 g of dicyclohexylcarbodiimide and a few crystals of 4-dimethylamino-pyridine were added at 0° C. to a solution of 900 mg of (1R,trans) 2,2-dimethyl-3-(1,2-propadienyl)cyclopropane-carboxylic acid in 20 ml of methylene chloride and the mixture was stirred at 0° C. for 15 minutes. A solution of 1.46 g of (S)α-cyano-3-phenoxy-benzyl alcohol in 7 ml of methylene chloride was added to the mixture which was stirred for 5 hours at 20° C. and then filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 6-4 and then a 7-3 benzene-petroleum ether (b.p.=35° to 70° C.) mixture yielded 754 mg of (S)α-cyano-3-phenoxy-benzyl (1R,trans) 2,2-dimethyl-3-(1,2-propadienyl)-cyclopropane-carboxylate with a specific rotation of [α]D20 =-25° (c=0.7% in chloroform).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:17]([F:19])([F:18])[CH2:16][O:15][CH2:14][C:13]([NH2:20])=[N:12]3)[CH2:10][CH2:9][O:8][C:5]2=[CH:6][CH:7]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[N:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([C:2]2[CH:3]=[C:4]3[C@@:11]4([C:17]([F:19])([F:18])[CH2:16][O:15][CH2:14][C:13]([NH2:20])=[N:12]4)[CH2:10][CH2:9][O:8][C:5]3=[CH:6][CH:7]=2)[CH:25]=[N:26][CH:27]=1
Reactant: NC1=N[C@@]2(CCOc3ccc(Br)cc32)C(F)(F)COC1
Reactant: OB(O)c1cncc(Cl)c1
Product: NC1=N[C@@]2(CCOc3ccc(-c4cncc(Cl)c4)cc32)C(F)(F)COC1
Yield: 35 %

Procedure:
The cross coupling reaction of (R)-6-bromo-6′,6′-difluoro-6′,7′-dihydro-2′H-spiro[chroman-4,5′-[1,4]oxazepin]-3′-amine (intermediate C3.2) with 5-chloropyridin-3-ylboronic acid yielded the title compound (35% yield) as a light brown, amorphous material. MS (ISP): m/z=380.2 [M+H]+.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[O:26][C:27]([CH3:30])=[N:28][N:29]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:24][C:25]4[O:26][C:27]([CH3:30])=[N:28][N:29]=4)=[O:2])([CH2:5][CH2:6]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Cc1nnc(N)o1
Product: Cc1nnc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)o1
Yield: 23.2 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-amino-5-methyl-1,3,4-oxadiazole (33.7 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(5-methyl-1,3,4-oxadiazol-2-yl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (14.5 mg).
Reaction SMILES: O.NN.C([N:7]1[CH2:12][C:11](=[O:13])[NH:10][CH:9]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=2)[C:8]1=[O:28])(=O)C>CN(C=O)C.O>[O:21]([C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][CH:9]1[NH:10][C:11](=[O:13])[CH2:12][NH:7][C:8]1=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(=O)N1CC(=O)NC(Cc2cccc(Oc3ccccc3)c2)C1=O
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CNC(=O)C(Cc2cccc(Oc3ccccc3)c2)N1
Reaction time: 2 h
Yield: 66.5 %

Procedure:
Add hydrazine hydrate (0.7 mL, 14.2 mmol) to a solution of 1-acetyl-3-(3-phenoxy-benzyl)-piperazine-2,5-dione (4.8 g, 14.2 mmol) in DMF (10 mL). Stir 2 h, dilute with water (50 mL) and stir an additional 30 minutes. Filter, wash with water, then cold methanol to obtain the title compound as a white powder (2.8 g, 67%): 1H NMR (CDCl3) δ 2.84 (dd, 1H), 2.96 (d, 1H), 3.05 (dd, 1H), 3.42 (d, 1H), 4.03 (m, 1H), 6.83–6.97 (m, 5H), 7.09 (t, 1H), 7.27 (t, 1H), 7.34 (t, 2H), 7.92 (bs, 1H), 8.12 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:17][C@@H:18]([CH2:21][CH3:22])[CH2:19]O.S(=O)(=O)(O)O>C1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH:18]([CH3:19])[CH2:21][CH3:22])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC[C@H](C)CO
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCC(C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Yield: 97.9 %

Procedure:
93 m mol (20 g) of 4'-hydroxybiphenyl-4-carboxylic acid and 467 m mol (41 g) of (S)-(-)-2-methylbutanol were refluxed for 25 hours in 150 ml of benzene in the presence of 2 ml of Conc. sulfuric acid while removing water. The resulting reaction solution was concentrated and was recrystallized from a toluene-hexane solvent mixture to obtain 26.0 g of the objective ester (m.p. 116-117.8° C., [α]D23 =+4.35° (CHCl3)). (Yield: 98 %).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH2:27][NH2:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH2:27][NH:28][C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=2[F:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: Cc1ccc(CN)cc1Cl
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Product: Cc1ccc(CNC(=O)c2nc(-c3c(F)cccc3F)n(C)c(=O)c2O)cc1Cl

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 3-chloro-4-methylbenzylamine (78 mg, 0.5 mmol). The title product was obtained as an off-white solid (35.3 mg, 84% yield). 1HNMR (500 MHz, CDCl3) δ: 12.27 (1H, s), 7.78 (1H, br s), 7.53–7.45 (1H, m), 7.31–7.03 (5H, m), 4.52 (2H, d, J=3.96 Hz), 3.41 (3H, s), 2.33 (3H, s). HRMS (ESI) calcd for C20H17ClF2N3O3 (M+H): 420.0926; found: 420.0929.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N:7][C:8]([NH2:12])=[N:9][C:10]=1[CH3:11].[CH:19]([C:21]1[CH:22]=[C:23]([CH:30]=[CH:31][CH:32]=1)[O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=O>C1COCC1.[BH4-].[Na+]>[NH2:12][C:8]1[N:9]=[C:10]([CH3:11])[C:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:19][C:21]2[CH:22]=[C:23]([CH:30]=[CH:31][CH:32]=2)[O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:6]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:7]=1
Reactant: COC(=O)COc1cccc(C=O)c1
Reactant: CCCCCNc1nc(N)nc(C)c1CCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCNc1nc(N)nc(C)c1CCCNCc1cccc(OCC(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.2 %

Procedure:
The product from example 1 step (v) (0.2 g) was dissolved in THF (10 mL) then methyl 2-(3-formylphenoxy)acetate (0.154 g) was added and stirred at rt overnight. Sodium borohydride (0.0301 mg) was added and stirred for 3 hr. The reaction was quenched with water and extracted with EtOAc, dried and solvent removed under reduced pressure. The residue was purified by RPHPLC to afford the title compound 0.038 g.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[N:27]1([C@H:32]2[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:34]3[CH2:35][CH2:36][CH2:37][C@H:32]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)[CH2:33]3)=[O:20])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: C1CNC[C@@H](N2CCCC2)C1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCC[C@H](N4CCCC4)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-3-(pyrrolidin-1-yl)piperidine dihydrochloride. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.42-1.55 (m, 1 H) 1.61 (d, J=9.76 Hz, 1 H) 1.77 (br. s., 5 H) 2.06 (d, J=8.79 Hz, 1 H) 2.42 (s, 3 H) 2.77 (br. s., 2H) 2.87-3.09 (m, 2 H) 3.12-3.24 (m, 2 H) 3.33 (br. s., 1 H) 3.47-3.92 (m, 1 H) 3.93-4.48 (m, 1 H) 7.53 (dd, J=8.30, 1.95 Hz, 1 H) 7.58 (s, 1 H) 7.90-7.95 (m, 2 H) 8.08 (d, J=7.81 Hz, 1 H) 8.46-8.51 (m, 2 H); ESI-MS m/z [M+H]+ 457.3.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14]1(=O)[CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:12][C:10]1[CH:11]=[C:2]([NH:1][CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)cc(N)c1C
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)c1cc(Cl)cc(NC2CCC2)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
To a stirred solution of methyl 3-amino-5-chloro-2-methylbenzoate (2.0 g, 10 mmol) and cyclobutanone (1.4 g, 20 mmol) in dichloroethane (20 mL), acetic acid (3.6 g, 60 mmol) was added and reaction stirred at room temperature for 10 minutes. Then sodium triacetoxyborohydride (6.3 g, 30 mmol) was added at 0° C. and the reaction stirred for 3 h at room temperature. On completion, the solvent was removed under reduced pressure and the crude material was purified by column chromatography to afford the title compound (1.4 g, 56%).
Reaction SMILES: [Cl-].Cl.[CH2:3]([N:10]([CH2:14][C:15]1[N:16]=[CH:17][NH:18][C:19]=1[C:20]([O:22][CH3:23])=[O:21])[CH2:11][CH2:12]Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(#N)C>[CH2:3]([N:10]1[CH2:11][CH2:12][N:16]2[CH:17]=[N:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:15]2[CH2:14]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1[nH]cnc1CN(CCCl)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CC#N
Product: COC(=O)c1ncn2c1CN(Cc1ccccc1)CC2
Temperature: 80 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
The chloride, Intermediate 1E (0.97 g, 3.15 mmol) was dissolved in acetonitrile (30 mL) and TEA (1.77 mL, 12.62 mmol) was added drop wise. The resulting mixture was stirred at 80° C. under nitrogen overnight. The mixture was allowed to cool, was filtered and the filtrate was concentrated. The residue was partitioned between DCM and saturated NaHCO3 solution and the phases were separated. The aqueous phase was further extracted with DCM and combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated. The crude residue was purified using normal phase chromatography, eluting with a 0-40% methanol/DCM gradient to provide product Intermediate 1F (0.58 g, 66%) as a brown solid.
Reaction SMILES: [NH2:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33].C(N(C(C)C)CC)(C)C.[CH2:49]([O:51][C:52](=[O:57])[CH2:53][CH2:54][CH2:55]Br)[CH3:50].C(OC(C)C)(=O)C>O.CN(C)C=O>[CH2:49]([O:51][C:52](=[O:57])[CH2:53][CH2:54][CH2:55][NH:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33])[CH3:50]
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1F
Reactant: CCOC(=O)CCCBr
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)C
Solvent: O
Product: CCOC(=O)CCCN[C@@H](Cn1c(=O)c(-c2cccc(OC)c2F)c(C)n(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Temperature: 82.5 °C

Procedure:
To a reactor was charged a solution of 3-((R)-2-amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 1e (3000 g) and dimethylformamide (4.5 L). The mixture was stirred and diisopropylethylamine (924 g) and ethyl-4-bromobutyrate (1287 g) were charged to the reactor and the reactor contents were heated to 80-85° C. After completion of the reaction (4 hr) the contents were cooled to 25-30° C. and isopropyl acetate (15.0 L) and water (9.0 L) were added. The mixture was agitated and the layers allowed to settle. The water layer was removed and the organic layer was washed with citric acid/water (300 g/6.0 L). The layers were separated and the organic layer was treated with a solution of 85% phosphoric acid/H2O (1055 g/21.0 L). The mixture was agitated, allowed to settle, and the layers were separated. The organic layer was treated with a solution of 85% phosphoric acid/H2O (422 g/6.0 L). The mixture was agitated, allowed to settle, and the layers were separated. The aqueous phosphate layers were combined and washed with isopropyl acetate (2×6.0 L). After layer separation, isopropyl acetate (15.0 L) was added to the aqueous layer, followed by slow addition of a solution of potassium carbonate/water (3.04 kg/4.5 L) while mixing. The layers were separated and the aqueous layer was extracted with i-PrOAc (6.0 L). After layer separation, the combined organic layers were washed with sodium bicarbonate/water (1.20 kg/15.0 L). Reagent alcohol (6.0 L) was added to the organic layer and the solution concentrated by vacuum distillation until the reactor volume was ˜9.0 L. Reagent alcohol (12.0 L) was added and distillation was resumed until the volume was 9.0 L. The concentrated solution of 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid ethyl ester 4a was used in the next step. LCMS (ESI) m/z 660.2 (MH+)
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:4]=1[C:5]([O:7]CC)=O.[CH:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].C(N(CC)C(C)C)(C)C>C(O)C>[CH:17]([C:20]1[CH:26]=[CH:25][C:23]([N:24]2[CH2:2][C:3]3[C:4](=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=3)[C:5]2=[O:7])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1CBr
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccc(N2Cc3ccc([N+](=O)[O-])cc3C2=O)cc1
Temperature: 110 °C
Yield: 75.1 %

Procedure:
A mixture of ethyl 2-(bromomethyl)-5-nitrobenzoate (1.88 g, 6.52 mmol), 4-isopropylaniline (1.11 mL, 7.83 mmol) and N,N-diisopropylethylamine (1.36 mL, 7.83 mmol) in ethanol (75 mL) was heated in a sealed tube at 110° C. overnight. After this time, the mixture was cooled to room temperature and the solid collected by filtration to afford 2-(4-isopropylphenyl)-6-nitroisoindolin-1-one (1.45 g, 75%) as a yellow solid: mp 225-227° C.; 1H NMR (300 MHz, CDCl3) δ 8.77 (d, J=2.0 Hz, 1H) 8.48 (dd, J=8.3, 2.1 Hz, 1H), 7.76-7.69 (m, 3H), 7.32 (d, J=8.6 Hz, 2H), 2.94 (sept, J=6.9 Hz, 1H), 1.28 (d, J=6.9 Hz, 6H); ESI MS m/z 297 [M+H]+.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:27]2[N:28]=[C:29]([NH:32]C=O)[S:30][CH:31]=2)[C:7]([NH:9][C@@H:10]2[C:25](=[O:26])[N:12]3[C:13]([C:22]([OH:24])=[O:23])=[C:14]([CH2:17][O:18][C:19](=[O:21])[NH2:20])[CH2:15][S:16][C@H:11]23)=[O:8])[CH2:3][CH2:2]1.Cl.C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[NH2:32][C:29]1[S:30][CH:31]=[C:27]([C:6](=[N:5][O:4][CH:1]2[CH2:2][CH2:3]2)[C:7]([NH:9][C@@H:10]2[C:25](=[O:26])[N:12]3[C:13]([C:22]([OH:24])=[O:23])=[C:14]([CH2:17][O:18][C:19](=[O:21])[NH2:20])[CH2:15][S:16][C@H:11]23)=[O:8])[N:28]=1
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NOC3CC3)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NOC3CC3)c3csc(N)n3)[C@H]2SC1
Temperature: 0 °C
Yield: 45.5 %

Procedure:
A mixture of 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (2.0 g) and concentrated hydrochloric acid (1.2 ml) in a mixture of methanol (15 ml) and tetrahydrofuran (15 ml) was warmed at 33° to 35° C. for 1.5 hours. The mixture was poured into ice-water, adjusted to pH 7.5 with saturated aqueous solution of sodium bicarbonate and washed with ethyl acetate. The aqueous solution was adjusted to pH 2 with 1N hydrochloric acid and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate to give 7β-[2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.86 g).