Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:10]=1)[C:5]([OH:7])=[O:6].C(Cl)(=O)C(Cl)=O.[CH2:25](O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl.CN(C)C=O.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14])[CH:10]=1)[C:5]([O:7][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:6]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(C(=O)O)c1
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of the acid 14 (3.80 g, 13.3 mmol) and oxalyl chloride (5.8 mL, 66 mmol) in methylene chloride (60 mL) was added ca. 0.05 mL of N,N-dimethylformamide as a catalyst. After stirring 1 hr at ambient temperature, the reaction was evaporated in vacuo, diluted with methylene chloride, and reacted with benzyl alcohol (1.38 mL, 13.3 mmol) and 4-(N,N-dimethylamino)pyridine (1.60 g, 13.3 mmol). After stirring 16 hrs at ambient temperature, the solution was washed with dilute aqueous HCl, dilute aqueous NaHCO3, and brine, dried over Na2SO4, and filtered. The filtrate was then evaporated in vacuo giving a quantitative yield of gold oil. 1H NMR (300 MHz, CDCl3) δ 7.64 (t, 1H, J=1.5 Hz), 7.45-7.28 (m, 6H), 7.02 (m, 1H), 5.35 (s, 2H), 0.98 (s, 9H), 0.22 (s, 6H).
Reaction SMILES: [CH2:1]([C:8]1([C:14](OC)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C(OCC)=O)CCC1>>[CH2:1]([C:8]1([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1(Cc2ccccc2)CCCCC1
Agent: CCOC(=O)C1CCC1
Product: OCC1(Cc2ccccc2)CCCCC1

Procedure:
(1-Benzylcyclohexyl)methanol was prepared as in example 5f except that methyl 1-benzylcyclohexanecarboxylate was substituted for ethyl cyclobutanecarboxylate. 1H NMR (300 MHz, DMSO-d6) δ 7.12-7.28 (m, 5H), 4.46 (t, J=5 Hz, 1H), 3.06 (d, J=5 Hz, 2H), 2.55 (s, 2H), 1.10-1.55 (m, 10H).
Reaction SMILES: [NH2:1][CH:2]1[C:30](=[O:31])[N:4]2[C:5]([C:14]([O:16][CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:6]([CH:10]=[N:11][O:12][CH3:13])[C@@H:7]([CH3:9])[S:8][C@H:3]12.CCN(CC)CC.[Cl:39][CH2:40][C:41]([NH:43][C:44]1[S:45][CH:46]=[C:47](/[C:49](=[N:53]/[O:54][CH3:55])/[C:50](Cl)=[O:51])[N:48]=1)=[O:42]>C(Cl)Cl>[Cl:39][CH2:40][C:41]([NH:43][C:44]1[S:45][CH:46]=[C:47](/[C:49](=[N:53]/[O:54][CH3:55])/[C:50]([NH:1][CH:2]2[C:30](=[O:31])[N:4]3[C:5]([C:14]([O:16][CH:17]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:15])=[C:6]([CH:10]=[N:11][O:12][CH3:13])[C@@H:7]([CH3:9])[S:8][C@H:3]23)=[O:51])[N:48]=1)=[O:42]
Reactant: CO/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1
Reactant: CON=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2S[C@@H]1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(NC(=O)CCl)n3)[C@H]2S[C@@H]1C
Yield: 81.7 %

Procedure:
To a solution of 656 mg of diphenylmethyl 7-amino-2α-methyl-3-methoxyiminomethylceph-3-em-4-carboxylate in 30 ml of CH2Cl2 were added, at -20° C., 0.2 ml of Et3N and 407 mg of 2-(2-chloroacetylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetylchloride, and the mixture was stirred at from -20° C. to -15° C. for 1.5 hours. The reaction solution was washed with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl solution, successively, and dried over MgSO4, followed by distilling off the CH2Cl2 under reduced pressure. The residue was added on a column of silica gel, and the fractions eluted with CH2Cl2.AcOEt (15:1) were collected to distill off the solvent under reduced pressure, thus yielding 783 mg (75%) of diphenylmethyl 7-[2-(2-chloroacetylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-2α-methyl-3-methoxyiminomethylceph-3-em-4-carboxylate.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6](=[O:13])[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[N:9]=2)[CH2:3][CH2:2]1.[ClH:14].Cl[O-].[Na+].S(=O)(O)[O-].[Na+].[OH-].[Na+]>O>[Cl:14][C:7]1[C:6](=[O:13])[NH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[N:9][C:8]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1cc(=O)[nH]c(C2CC2)n1
Reactant: Cl
Agent: O=S([O-])O
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: O=C(O)c1nc(C2CC2)[nH]c(=O)c1Cl
Temperature: 17.5 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-cyclopropyl-1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acid (i.e. the product of Step A1 or A2) (9.2 g, 52 mmol) in water (30 mL) and concentrated hydrochloric acid (22 g, 220 mmol) at 15° C. was added dropwise aqueous sodium hypochlorite solution (11%, 40 g, 59 mmol) over 15 minutes so that with cooling the reaction mixture was maintained at 15-20° C. The mixture was then held at 20-25° C. for 1 h. Solid sodium bisulfite (ca. 2 g) was added, and then aqueous sodium hydroxide solution (50%, 8 g, 0.10 mol) was added dropwise so that with cooling the reaction mixture was maintained at about 25° C. The mixture was cooled to 10° C., and the suspended product was isolated by filtration and washed with a minimum amount of cold water. The product was then dried to constant weight in vacuum-oven at 50° C. to afford the title compound (7.5 g).
Reaction SMILES: N12CCCN=C1CCCCC2.Br[CH2:13][CH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:17][C:16]=1[OH:28]>C(Cl)Cl>[Cl:21][C:19]1[C:18]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:17][C:16]2[O:28][CH2:13][CH2:14][C:15]=2[CH:20]=1
Reactant: Oc1cc(N2CCCCC2)c(Cl)cc1CCBr
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Clc1cc2c(cc1N1CCCCC1)OCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.2 ml (8.0 mmole) of 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) are added at 0° to a solution of 2.50 g (7.8 mmole) of 1-bromo-2-[5-chloro-2-hydroxy-4-(piperidin-1-yl)-phenyl]-ethane in 50 ml of absolute methylene chloride and the whole is then stirred for 3 hours at room temperature. The reaction mixture is washed with saturated sodium chloride solution and the organic phases are combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. The residue is chromatographed over silica gel using methylene chloride as eluant. Recrystallisation from petroleum ether yields 5-chloro-6-(piperidin-1-yl)-2,3-dihydrobenzofuran having a melting point of 38°-40°.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][N:6]([CH3:24])[C:7](=[S:23])[O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([CH2:16][CH2:17][CH3:18])=[C:11]([OH:19])[C:10]=1[C:20](=[O:22])[CH3:21].C(N(CC)CC)C>O1CCCC1.O.C(OCC)C>[CH3:24][N:6]([CH3:5])[C:7](=[S:23])[O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([CH2:16][CH2:17][CH3:18])=[C:11]([O:19][C:1](=[O:3])[CH3:2])[C:10]=1[C:20](=[O:22])[CH3:21]
Reactant: CCCc1cc(Cl)c(OC(=S)N(C)C)c(C(C)=O)c1O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCc1cc(Cl)c(OC(=S)N(C)C)c(C(C)=O)c1OC(C)=O
Temperature: 0 °C

Procedure:
Acetyl chloride (1.9 g, 25 mmol) was added dropwise to an ice-cold stirring mixture of O-(2-acetyl-3-hydroxy-4-propyl-6-chlorophenyl) dimethylthiocarbamate (6.3 g, 20 mmol) (Step a) and triethylamine (3.0 g, 30 mmol) in tetrahydrofuran (50 mL) The mixture was stirred for 2 hours and then diluted with water and diethyl ether. The organic layer was separated, dried (MgSO4), filtered and concentrated to obtain the title compound as an oil which crystallized on standing. The crystals were slurried with hexane, filtered and dried to give the title compound, m.p. 86°-88° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:9]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:44][CH2:45][C@@H:46]([OH:51])[C:47]([O:49][CH3:50])=[O:48].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:21])([F:20])[F:22])=[CH:16][CH:17]=3)[N:9]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([NH:44][CH2:45][C@@H:46]([OH:51])[C:47]([O:49][CH3:50])=[O:48])=[O:29])=[CH:26][CH:25]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)[C@H](O)CN
Reactant: O=C(O)c1ccc(Cn2nc(C3CCCCC3)cc2-c2ccc(OC(F)(F)F)cc2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](O)CNC(=O)c1ccc(Cn2nc(C3CCCCC3)cc2-c2ccc(OC(F)(F)F)cc2)cc1

Procedure:
A solution of 24.6 mg product from Step A Example 6, 15.9 mg EDC, 11.2 mg HOBt, 17.2 mg methyl (2R)-3-amino-2-hydroxypropanoate hydrochloride from Step C Example 4 and 39 μL DIEA in 0.5 mL DMF was stirred at room temperature over night. The title compound was isolated by preparative HPLC using 55˜75% MeCN gradient over 10 minutes at 8.0 mL per minute with 0.1% TFA on a 9.4×250 mm SB-C18 Zorbax column as a white solid after lyophilization. LC-MS: 2.55 min. (M+H=546.3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][CH2:16][N:15]([C:19](OC(C)(C)C)=O)[CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1.[F:30][C:31]1[CH:38]=[CH:37][C:34](C=O)=[CH:33][CH:32]=1.[BH3-]C#N.[Na+]>>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:34]4[CH:37]=[CH:38][C:31]([F:30])=[CH:32][CH:33]=4)[CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Reactant: O=Cc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(Cc3ccc(F)cc3)C1)O2

Procedure:
(±)-(E)-3-{1′-(4-Fluoro-benzyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid methyl ester was synthesized starting from Intermediate 5 (339 mg, 1.00 mmol), according to the procedure described in Example 40, Step A, using 4-fluorobenzaldehyde (0.13 ml, 1.2 mmol) and NaBH3CN (76 mg, 1.2 mmol). The product was obtained as a white solid (320 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:12]=[C:13]([F:23])[C:14]3[O:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[C:15]=3[CH:22]=2)=[O:10])=[C:4]([Cl:24])[CH:3]=1.[H-].[Na+].[CH3:27]I>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:11]2[CH:12]=[C:13]([F:23])[C:14]3[O:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[C:15]=3[CH:22]=2)=[O:10])=[C:4]([Cl:24])[CH:3]=1
Reactant: CN1C(=O)COc2c(F)cc(C(=O)Cc3ccc(Br)cc3Cl)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CC(C(=O)c1cc(F)c2c(c1)N(C)C(=O)CO2)c1ccc(Br)cc1Cl

Procedure:
In analogy to Example 1, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-acetyl]-8-fluoro-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with sodium hydride and methyl iodide to give the title compound as a light yellow foam. MS (m/e, ISP neg. ion)=423.9 [M−H+].
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[O:8][C:9]([CH3:14])([CH3:13])[O:10][C:11](=[O:12])[C:6]=2[CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]2[O:8][C:9]([CH3:13])([CH3:14])[O:10][C:11](=[O:12])[C:6]=2[CH:5]=1
Reactant: CC1(C)OC(=O)c2cc([N+](=O)[O-])ccc2O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OC(=O)c2cc(N)ccc2O1
Reaction time: 12 h
Yield: 98.6 %

Procedure:
To a solution of 6-nitro-2,2-dimethyl-4H-1,3-benzodioxin-4-one (4.1 g) in EtOH (30 mL) was added Pd/C (1.947 g) under nitrogen atmosphere and then hydrogenated for 12 h at rt. The reaction mixture was filtered through a bed of celite, washed with EtOH and THF. The filtrates were concentrated under vacuum to give the title compound as pale yellow solid (3.5 g, 98%). 1H NMR (CDCl3) δ 7.71 (d, J=8.7 Hz, 1H), 7.15 (d, J=2.6 Hz, 1H), 6.83 (dd, J=8.7 Hz, 2.6 Hz, 1H), 3.44 (brs, 2H), 2.63 (s, 6H).
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=2)[N:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)=[CH:54][CH:53]=1>CN(C=O)C.C(OCC)C>[F:71][C:68]1[CH:67]=[CH:66][C:65]([CH:58]([C:55]2[CH:56]=[CH:57][C:52]([F:51])=[CH:53][CH:54]=2)[N:59]2[CH2:60][CH2:61][N:62]([C:12]([C@@H:11]([NH:10][C:8]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[O:9])[CH:15]([CH3:17])[CH3:16])=[O:14])[CH2:63][CH2:64]2)=[CH:70][CH:69]=1
Reactant: CC(C)[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)[C@H](NC(=O)N1CCCCCC1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]-3-methyl-butyric acid (0.26 g, 1.1 mmol, Example 26, Step B) was dissolved in dry DMF (5 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.37 mL, 2.1 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.40 g, 1.1 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.31 g, 1.1 mmol) was then added. After additional 90 minutes stirring at 0° C., reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (2×50 mL), and dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (60% EtOAc in hexane) to provide 0.45 g (82%) of the pure titled compound as a white foam; mp 72-82° C. APCI-MS m/z 513.2 (MH+).
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13]Cl)[CH:11]=[CH:12][C:4]=2[O:3]1.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>CS(C)=O>[CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CC1Oc2ccc(CCl)cc2NC1=O
Reactant: c1c[nH]cn1
Solvent: CS(C)=O
Product: CC1Oc2ccc(Cn3ccnc3)cc2NC1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
1.25 g (5.9 mmol) of (±)-2-methyl-3-oxo-6-chloromethyl-3,4-dihydro-2H-1,4-benzoxazine is dissolved in 12.5 ml of dimethyl sulfoxide, mixed with 0.804 g (11.8 mmol) of imidazole and stirred for 8 hours at 70° C. After stirring overnight at room temperature, the reaction mixture is spun on an oil pump until dry, and the residue is chromatographed on silica gel (mobile solvent: methylene chloride/ethanol). 940 mg (65.7%) of the desired imidazole compound is obtained, melting point 219-222° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:32][CH3:33])[C:10]([NH:12][CH2:13]/[CH:14]=[CH:15]/[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:17]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:28]([O:27][C:25]([N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([CH2:15][CH2:14][CH2:13][NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:32][CH3:33])=[CH:17]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)NC/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Agent: [Pd]
Solvent: CCO
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCc1cn(C(=O)OC(C)(C)C)c2ccccc12
Reaction time: 24 h

Procedure:
A 250 mL Parr hydrogenation vessel was charged with (S,E)-tert-butyl 3-(3-(2-(tert-butoxycarbonylamino)butanamido)prop-1-enyl)-1H-indole-1-carboxylate (280 mg, 0.42 mmol), 10% palladium on carbon (34 mg), and ethanol (6.0 mL). The vessel was evacuated and filled with hydrogen. This was repeated two more times. The vessel was then filled with 50 psi hydrogen. After 24 h, the resulting solution was filtered through CELITE and the filtrate concentrated in vacuo to yield 3-[3-(2-(S)-tert-butoxycarbonylamino-butyrylamino)-propyl]indole-1-carboxylic acid tert-butyl ester. 1H NMR (300 MHz, CDCl3) δ 7.21-7.24 (m, 1H), 7.07-7.12 (m, 1H), 6.64-6.71 (m, 1H), 6.42-6.46 (m, 1H), 4.38-4.45 (m, 1H), 3.39-3.53 (m, 2H), 2.53 (t, J=6.8 Hz, 2H), 1.67-1.96 (m, 4H), and 0.88-0.93 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[CH:6]=[O:7].[BH4-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[CH:13]=1
Reactant: COc1cc(C=O)ccc1Oc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(CO)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a solution of 3-(methyloxy)-4-{[3-(trifluoromethyl)phenyl]oxy}benzaldehyde (720 mg, 2.430 mmol) in ethanol (20 mL) was added slowly NaBH4(110 mg, 2.92 mmol) at 0° C. The mixture was then allowed to warm to room temperature and stirring continued for 2 h. The reaction was quenched with NH4Cl sat. solution and extracted with EA. The organic layer was separated and concentrated to afford the title compound (715 mg, 2.397 mmol, 99% yield). LCMS: rt=3.12 min, [M+H+−H2O]=281
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([NH2:9])[NH:6][N:5]=1)([CH3:3])[CH3:2].[C:10]([C:12]([C:22](=O)[CH3:23])=[CH:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)#[N:11].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([CH:13]2[N:6]3[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=[C:7]3[NH:9][C:22]([CH3:23])=[C:12]2[C:10]#[N:11])=[CH:15][CH:16]=1)#[N:19]
Reactant: CC(C)c1n[nH]c(N)n1
Reactant: CC(=O)C(C#N)=Cc1ccc(C#N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(C(C)C)nc2N1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Under an atmosphere of argon, 3-isopropyl-1H-1,2,4-triazole-5-amine (241 mg, 1.9 mmol) and 4-(2-cyano-3-oxobut-1-en-1-yl)benzonitrile (300 mg, 1.5 mmol, 0.8 eq.) were dissolved in DMF (3 ml), and solid sodium bicarbonate (803 mg, 9.6 mmol, 5 eq.) was added. The mixture was stirred at 55° C. overnight. The mixture was then filtered and the DMF was distilled off from the filtrate under reduced pressure. The residue was suspended in methanol (2 ml), and the solid was then filtered off and dried under high vacuum (34 mg, 7% of theory). The filtrate was acidified with 1 N hydrochloric acid and purified by preparative HPLC (Kromasil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA), which gave a second product fraction (67 mg, 13% of theory) as a solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].OS(O)(=O)=O.[ClH:12].[CH3:13][N:14]1[CH2:19][CH2:18][C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:20]#[N:21])[CH2:16][CH2:15]1>C1COCC1>[ClH:12].[ClH:12].[CH3:13][N:14]1[CH2:19][CH2:18][C:17]([CH2:20][NH2:21])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15]1
Reactant: CN1CCC(C#N)(c2ccccc2)CC1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Al+3]
Solvent: C1CCOC1
Product: CN1CCC(CN)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of LAH (7.5 mmol) in THF (10 mL) is added dropwise conc. H2SO4 (3.8 mmol) at 0° C. After stirred at 0° C. for 0.5 h, 1-methyl-4-phenylpiperidine-4-carbonitrile hydrochloride (2.5 mmol) is added at 0° C. The reaction mixture is stirred at 60° C. for 6 h. After cooled down to 0° C., the reaction is quenched by the addition of Na2SO4-10H2O. The resulting mixture is filtered through celite, and the filtrate is concentrated in vacuo. The residue is suspended in ether and treated with HCl in 1,4-dioxane. The resulting white solid is collected by filtration to give the title compound, which is directly used for the next reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl.O>O1CCOCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:13](=[O:15])[O:8][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: Nc1ccc(O)cc1C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c2ccc(O)cc2c(=O)o1

Procedure:
Step 1): A solution of 5-hydroxyanthranilic acid (500 mg, 3.26 mmol) and triphosgene (1.45 g, 4.9 mmol) in 1,4-dioxane (20 ml) was refluxed overnight. The reaction mixture was poured into H2O (30 ml), and then the precipitates were filtered and dried to give 6-hydroxy-1,2-dihydro-4H-3,1-benzoxazin-2,4-dione, 360 mg (62%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:12]=[CH:13][C:14]3[N:20]([CH3:21])[C:19](=[O:22])[CH:18]([CH3:23])[CH2:17][N:16]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:15]=3[N:30]=2)=[C:6]([O:31][CH3:32])[CH:5]=1.I[CH3:35].[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:11]2[N:12]=[CH:13][C:14]3[N:20]([CH3:21])[C:19](=[O:22])[CH:18]([CH3:23])[CH2:17][N:16]([CH:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)[C:15]=3[N:30]=2)[CH3:35])=[C:6]([O:31][CH3:32])[CH:5]=1
Reactant: COC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCCC2)CC(C)C(=O)N3C)c(OC)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(C)c2ncc3c(n2)N(C2CCCCC2)CC(C)C(=O)N3C)c(OC)c1
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a mixture of 0.170 g (0.00037 mole) of (rac)-4-(9-cyclohexyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid methyl ester, 0.35 mL (0.00056 mole) of iodomethane and 10 mL of N,N-dimethylformamide at 0 degrees, was added 0.024 g of sodium hydride (60% dispersion in mineral oil). The mixture was stirred at 0 degrees for 2 hours and then partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography, eluting with hexanes-ethyl acetate (30:70) to give 0.170 g of (rac)-4-[(9-cyclohexyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)-methyl-amino]-3-methoxy-benzoic acid methyl ester as white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH:28][CH2:29][CH:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH3:31])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:38](Cl)(=[O:40])[CH3:39]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:28]([C:38](=[O:40])[CH3:39])[CH2:29][CH:30]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH3:31])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNCC(C)c4ccccc4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN(CC(C)c4ccccc4)C(C)=O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-(4′-{3-methyl-4-[(2-phenyl-propylamino)-methyl]-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester and acetyl chloride.
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](=[NH:5])[NH2:4].Cl.[F:8][CH:9]([C:14](OC)=[O:15])[C:10](OC)=[O:11]>>[F:1][CH:2]([F:6])[C:3]1[NH:4][C:14]([OH:15])=[C:9]([F:8])[C:10](=[O:11])[N:5]=1
Reactant: N=C(N)C(F)F
Reactant: COC(=O)C(F)C(=O)OC
Agent: Cl
Product: O=c1nc(C(F)F)[nH]c(O)c1F
Temperature: 80 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
Sodium metal (0.91 g, 40 mmol) was dissolved in MeOH (100 mL) to form sodium methoxide. 2,2-Difluoroethanimidamide.HCl (1.73 g, 13 mmol) was added followed by dimethyl fluoropropanedioate (2.0 g, 13 mmol). The resulting solution was stirred at 80° C. for 3 hours, then cooled to room temperature. Aqueous HCl (6 mL, 6M, 36 mmol) was added and the resulting mixture was concentrated in vacuo. The remaining solid was washed with cold water and filtered yielding 2-(difluoromethyl)-5-fluoro-6-hydroxy-4(1H)-pyrimidinone (1.43 g, 61%)