Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].CN(C)P(N(C)C)(N(C)C)=O.[C:24]([OH:28])(=[O:27])[CH2:25][CH3:26].BrCC#CC.Cl>O1CCCC1>[CH3:26][CH:25]([CH2:8][C:9]#[C:10][CH3:11])[C:24]([OH:28])=[O:27]
Reactant: CCC(=O)O
Reactant: [Li]CCCC
Agent: CC#CCBr
Agent: Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC#CCC(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 106 %

Procedure:
Diisopropylamine (26.0 g, 0.257 mmol, 3.1 eq) in 130 ml of tetrahydrofuran initially at -50° C. is treated dropwise with n-butyl-lithium (98.8 ml, 1.6M, 0.158 mol, 1.9 eq) over an 8 minute period while allowing the temperature to rise to -25° C. After 5 minutes longer at -20° C., the reaction mixture is treated dropwise with a mixture of hexamethylphosphoramide (17.8 g, 0.099 mol, 1.2 eq) and propionic acid (6.14 g, 0.083 mol, 1.0 eq) over a 7 minute period while the temperature rises to 0° C. Following addition the reaction mixture is warmed to room temperature and maintained there for 35 minutes. The contents are then cooled to 0° C. in an ice bath, treated dropwise over a 12 minute period with 1-bromo-2-butyne (11.0 g, 0.083 mol, 1.0 eq) in 8 ml of tetrahydrofuran. The temperature, which rises to 16° C. during addition, is allowed to warm to room temperature thereafter where it is maintained for 2 hours. The contents are carefully poured into 300 ml of 10% HCl with stirring (exothermic) followed by 500 ml of ether-pentane (1:1). The organic layer is separated and the aqueous phase extracted 2 more times with ether-pentane (1:1) giving 1800 ml of total extract volume. The combined extracts are washed with water 2×60 ml) and the combined organic extracts are dried over anhydrous sodium sulfate, magnesium sulfate and concentrated at reduced pressure to provide 11.1 g (over theory) of 2-methyl-4-hexynoic acid which is converted to the methyl ester by treatment with methyl iodide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[C:37]1([CH2:43]CO)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH2:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCc4ccccc4)cc3C)c2cc1OC
Yield: 104.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-phenyl-1-ethanol (28 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (76 mg, yield 100%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[ClH:14].[CH2:1]([NH:8][CH2:9][CH2:10][Cl:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCNCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCCNCc1ccccc1

Procedure:
A solution of N-benzyl-2-aminoethanol (12, 79.05 g, 0.523 mole) in chloroform (400 niL) was treated with thionyl chloride (80 mL, 1.09 mole) at room temperature. The resulting mixture was heated to reflux (6 h). The solvent was removed in vacuo, the residue dissloved in hot ethanol (1.3 L) and cooled overnight. The solids were collected via suction filtration and dried in vacuo at 65° C. (24 h) to afford the title compound 13 as white plates.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[CH2:16][C:15]2=[O:24])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[N:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:15](=[O:24])[CH2:16]2
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)Cc3cc(Cl)ccc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1Cc2cc(Cl)ccc2N1C1CCNCC1
Yield: 139.8 %

Procedure:
4-(5-Chloro-2-oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.4 g, 9.7 mmol) was set stirring in 1:1 TFA/CH2Cl2. After 45 min the mixture was evaporated and the golden oil brought up in Et2O. A solid formed and was filtered, washed with Et2O and air dried to give 3.4 g (97%) of a white solid. MS (electrospray): exact mass calculated for C13H15ClN2O, 250.09. m/z found, 251.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6); 7.45 (s, 2H), 7.31 (d, J=8.1 Hz, 1H), 4.55-4.45 (m, 1H), 3.68 (s, 2H), 3.50 (d, J=12.3, 2H), 3.14 (m, 2H), 2.70-2.55 (m, 2H), 1.87 (d, J=13.1 Hz, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.[CH2:29]([CH2:33][C:34](=O)[CH3:35])[C:30]([CH3:32])=O.O.[OH-].[Li+]>C1(C)C=CC=CC=1>[CH3:35][C:34]1[N:28]([C:25]2[CH:24]=[CH:23][C:22]([CH2:21][N:7]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[C:6]3[C:4]([OH:3])=[O:5])=[CH:27][CH:26]=2)[C:30]([CH3:32])=[CH:29][CH:33]=1
Reactant: CC(=O)CCC(C)=O
Reactant: CCOC(=O)c1c(-c2ccccc2)c2ccccc2n1Cc1ccc(N)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc(Cn2c(C(=O)O)c(-c3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.9 %

Procedure:
A mixture of 1-(4-amino-benzyl)-3-phenyl-1H-indolecarboxylic acid ethyl ester (0.20 g, 0.54 mmol), acetonylacetone (0.16 mL, 1.35 mmol), and toluene (15 mL) was heated at reflux under nitrogen using a Dean-Stark trap for 6 h. The reaction was cooled and concentrated. The residue was re-dissolved in 10 mL of 2:1:1 THF/MeOH/water. Lithium hydroxide monohydrate (0.09 g, 2.1 mmol) was added and the mixture was stirred at room temperature overnight. Most of the organic solvents was removed and the reaction mixture was made acidic (pH 6) with glacial acetic acid, and the solid was collected and purified by HPLC to afford the title compound (0.027 g, 6%) as a brown solid: 1H NMR (DMSO-d6) δ 1.91 (s, 6H), 5.75 (s, 2H), 7.01-7.30 (m, 6H), 7.32-7.38 (m, 2H), 7.40-7.50 (m, 6H), 7.68 (d, J=8.54 Hz, 1H), 12.80 (br s, 1H); MS (ESI) m/z 421 (MH+); MS (ESI) m/z 419 ([M−H]−); HRMS calcd for C28H26N2O2: 421.1905; found (ESI+): 421.1915.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.F[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.C1COCC1.CCOCC>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: N#Cc1ccccc1F
Reactant: Cc1csc(Nc2cc(O)ccn2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CS(C)=O
Product: Cc1csc(Nc2cc(Oc3ccccc3C#N)ccn2)n1
Temperature: 90 °C
Yield: 8.7 %

Procedure:
2-(4-Methylthiazol-2-ylamino)pyridin-4-ol (0.100 g, 0.483 mmol), 2-fluorobenzonitrile (0.064 g, 0.531-mmol) and potassium carbonate (0.167 g, 1.21 mmol) were combined in DMSO and heated at 90° C. overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried, and concentrated. The residue was purified by MPLC, eluting with 3:1 hexane:ethyl acetate to afford the free base. The free base was dissolved in THF (3 mL) and 1M HCl in ether (6 mL) was added. The solution was diluted with ether (15 mL), triturated for 10 minutes, and filtered to afford 2-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzonitrile (0.013 g, 8.65% yield) as white solid. 1H NMR (CDCl3) δ 8.26 (d, 1H), 7.72 (dd, 1H), 7.60 (m, 1H), 7.32 (dt, 1H), 7.14 (d, 1H), 6.53 (dd, 1H), 6.42 (d, 1H), 6.33 (d, 1H), 2.23 (d, 3H); HPLC Rt=2.67 min; Mass spectrum (esi) m/z=309 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:23][CH2:22]1)(=[O:17])[CH2:13][C:14]([CH3:16])=O.[NH2:35]/[C:36](/[CH3:42])=[CH:37]\[C:38]([O:40][CH3:41])=[O:39]>C(O)(C)C>[CH3:16][C:14]1[NH:35][C:36]([CH3:42])=[C:37]([C:38]([O:40][CH3:41])=[O:39])[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:13]=1[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:23][CH2:22]1)=[O:17]
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OCCN1CCN(c2cccc(Cl)c2Cl)CC1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(c3cccc(Cl)c3Cl)CC2)C1c1cccc([N+](=O)[O-])c1
Yield: 75.7 %

Procedure:
A mixture of m-nitrobenzaldehyde, 2-[4-(2,3-dichlorophenyl)-1-piperazinyl]ethyl acetoacetate and methyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give 2-[4-(2,3-dichlorophenyl)-1-piperazinyl]ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate as yellow crystals, m.p. 189°-190° C. Yield 75.7%.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]=[O:16]>C(O)CCCCCCC>[C:1]1([C@@H:7]([N:9]([CH2:10][Si:11]([CH3:13])([CH3:12])[CH3:14])[CH2:15][O:16][CH2:8][CH2:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](NC[Si](C)(C)C)c1ccccc1
Reactant: C=O
Solvent: CCCCCCCCO
Product: CCCCCCCCOCN(C[Si](C)(C)C)[C@@H](C)c1ccccc1

Procedure:
The title compound was prepared from (S)-(-)-N-1-phenylethyl-N-trimethylsilylmethylamine by reaction with n-octanol and aqueous formaldehyde following the procedure of Example 2 to give the crude acetal (90% pure) as a colourless oil (9.1 g, 91%)δC (CD2Cl2)--1.28 (SiMe3), 14.29, 23.08, 30.31, 29.74, 29.89, 26.82, 33.32, 63.13 (O Octyl), 19.37 (CMe), 40.11 (NCH2Si), 62.10 (CH), 84.69 (NCH2O), 126.82, 127.96, 128.31, 145.95 (Ph).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:18]([C:20]2[CH:21]=[N:22][C:23](Cl)=[N:24][CH:25]=2)=[O:19])[CH:15]2[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:27]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)#[N:28]>>[CH:15]1([N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:18]([C:20]2[CH:21]=[N:22][C:23]([C:33]3[CH:34]=[CH:35][C:30]([CH2:29][C:27]#[N:28])=[CH:31][CH:32]=3)=[N:24][CH:25]=2)=[O:19])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cnc(Cl)nc2)C2CC2)CC1
Reactant: N#CCc1ccc(B(O)O)cc1
Product: N#CCc1ccc(-c2ncc(C(=O)N(C3CCNCC3)C3CC3)cn2)cc1

Procedure:
The title compound is prepared from 4-[(2-chloro-pyrimidine-5-carbonyl)-cyclopropyl-amino]-piperidine-1-carboxylic acid tert-butyl ester and (4-cyanomethylphenyl)boronic acid following a procedure analogous to that described in Intermediate 6. LC (method 4): tR=0.85 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH3:11])([CH3:3])[CH3:2].[Br:13]Br>>[Br:13][CH2:11][C:10]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])=[O:12]
Reactant: CC(=O)c1cnccc1C(C)C
Reactant: BrBr
Product: CC(C)c1ccncc1C(=O)CBr

Procedure:
By the reaction in the same manner as in Example 53-ii) using 1-(4-isopropylpyridin-3-yl)ethanone (0.90 g) and bromine (0.63 g), crude 2-bromo-1-(4-isopropylpyridin-3-yl)ethanone hydrobromate (1.70 g) was obtained as a pale-brown amorphous compound. Then, by the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-isopropylpyridin-3-yl)ethanone hydrobromate (340 mg) and 3-(aminocarbonothionyl)benzamide (240 mg), the title compound (59 mg) was obtained as colorless powder crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([NH2:15])=[C:4]([F:16])[CH:3]=1.C(N(CC)CC)C.[C:24](Cl)(Cl)=[S:25]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([N:15]=[C:24]=[S:25])=[CH:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][CH:12]=[CH:13][N:14]=1
Reactant: Nc1cc(Oc2ncccn2)c(Cl)cc1F
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Fc1cc(Cl)c(Oc2ncccn2)cc1N=C=S

Procedure:
4-Chloro-2-fluoro-5-(2-pyrimidinyloxy)-benzenamine (50 g) and triethyl amine (42.2 g) were dissolved in anhydrous ethyl acetate (400 ml) and stirred under ice cooling. Thiophosgene (74.3 g) dissolved in ethyl acetate (400 ml) was slowly added to the stirred solution. The mixture was heated at reflux for 2 hr and filtered. Evaporation of the solvent afforded 2-(2-chloro-4-fluoro-5-isothiocyanatophenoxy)-pyrimidine which was used for the next step without purification. 1H NMR, CDCl3, 7.12 (1H, t, J=4.7 Hz), 7.13 (1H, d, J=7.0 Hz), 7.32 (1H, d, J=8.9 Hz), 8.58 (2H, t, J=4.7 Hz).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:3][CH:2]([CH3:4])[C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:12]=1)=[O:5]
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCNCC1
Reaction time: 2 h
Yield: 78.5 %

Procedure:
Into a solution of tert-butyl 4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidinecarboxylate (335 mg, 0.930 mmol) in CH2Cl2 (10.0 mL) was added TFA (10.0 mL) at room temperature. The reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was dissolved in 20 mL of CHCl3/i-PrOH (3:1) and was basified with 5% KOH solution (10 mL). The aqueous layer was extracted with CHCl3/i-PrOH (3:1, 3×10 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 2-methyl-N-[4-methyl-3-(4-piperidinyl)phenyl]propanamide (190 mg, 78%): ESMS m/e: 261.0 (M+H)+.
Reaction SMILES: [OH-].[Na+:2].[F:3][CH:4]([F:42])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]1[N:17]2[CH:18]=[C:19]([C:23]3[CH:24]=[N:25][C:26]([N:29]4[CH2:35][CH2:34][CH:33]5[C:31]([C:36]([O:38]CC)=[O:37])([CH2:32]5)[CH2:30]4)=[N:27][CH:28]=3)[C:20]([F:22])=[CH:21][C:16]2=[N:15][C:14]=1[CH3:41]>C1COCC1.CO.O>[F:42][CH:4]([F:3])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]1[N:17]2[CH:18]=[C:19]([C:23]3[CH:24]=[N:25][C:26]([N:29]4[CH2:35][CH2:34][CH:33]5[C:31]([C:36]([O-:38])=[O:37])([CH2:32]5)[CH2:30]4)=[N:27][CH:28]=3)[C:20]([F:22])=[CH:21][C:16]2=[N:15][C:14]=1[CH3:41].[Na+:2]
Reactant: CCOC(=O)C12CC1CCN(c1ncc(-c3cn4c(Cc5ccccc5OC(F)F)c(C)nc4cc3F)cn1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1nc2cc(F)c(-c3cnc(N4CCC5CC5(C(=O)[O-])C4)nc3)cn2c1Cc1ccccc1OC(F)F
Temperature: 70 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
Sodium hydroxide (7.5 mg, 0.188 mmol) was added to a solution of Example 177 (0.104 g, 0.188 mmol) in THF-MeOH-water, 1:1:1 (4 mL). The mixture was stirred at 70° C. for 3 h. The reaction mixture was concentrated, diluted with water and washed with diethyl ether, then the aqueous layer was freeze-dried, to give the title compound (100 mg, 100%) as a white lyophilised solid. δH (400 MHz, DMSO-d6) 8.21 (d, J 1.3 Hz, 2H), 8.12 (d, J 7.5 Hz, 1H), 7.22 (m, 1H), 7.08 (m, 1H), 7.05 (t, J 72, 76 Hz, 1H), 6.97 (m, 1H), 6.92 (m, 1H), 6.81 (dd, J 7.5, 1.1 Hz, 1H), 4.12 (s, 2H), 4.04 (m, 1H), 3.96 (m, 1H), 3.43 (m, 1H), 3.07 (m, 1H), 2.07 (s, 3H), 1.76 (m, 1H), 1.50 (m, 1H), 1.15 (m, 1H), 0.72 (dd, J 8.7, 2.9 Hz, 1H), 0.00 (dd, J 5.4, 3.2 Hz, 1H). LCMS (pH 10): MH+ 524, RT 1.56 minutes.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5](B(O)O)=[CH:4][N:3]=1.Br[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=1.[NH2:23][C:24]1[N:25]=[C:26]([CH3:29])[S:27][CH:28]=1>>[CH3:11][C:9]1[S:10][C:6]2[C:5]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=3)=[CH:4][N:3]=[C:2]([NH:23][C:24]3[N:25]=[C:26]([CH3:29])[S:27][CH:28]=3)[C:7]=2[N:8]=1
Reactant: Cc1nc2c(Cl)ncc(B(O)O)c2s1
Reactant: Cc1nc(N)cs1
Reactant: Cc1cc(Br)ccn1
Product: Cc1cc(-c2cnc(Nc3csc(C)n3)c3nc(C)sc23)ccn1

Procedure:
The title compound, MS: m/e=354.1 (M+H+), was prepared in accordance with the general method of example 2, step 1 and step 2 from 4-chloro-2-methyl-thiazolo[4,5-c]pyridine-7-boronic acid (Example D), 4-bromo-2-methylpyridine and 4-amino-2-methylthiazole (Example C).
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Si:19]([O:36][CH2:37][CH2:38][C@@H:39]([CH3:42])[CH2:40]O)([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH:43]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45].C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCCCCC>[Si:19]([O:36][CH2:37][CH2:38][C@@H:39]([CH3:42])[CH2:40][N:43]([C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])([C:32]([CH3:33])([CH3:34])[CH3:35])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@@H](CO)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 56.8 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (6.33 g) was added to a solution of (2R)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-methylbutan-1-ol (Synthesis, 2002, p. 1993) (4.30 g), di-tert-butyl iminodicarboxylate (5.45 g), and tributylphosphine (4.65 mL) in toluene (130 mL) with stirring at 0° C. The mixture was heated to room temperature and stirred overnight. Then, the reaction solution was diluted with hexane, and insoluble matter was filtered off through celite. The filtrate was concentrated under reduced pressure, and the obtained crude product was then purified by silica gel column chromatography to obtain the title compound (3.86 g).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)=[O:4].[NH3:20].O>CO>[C:10]1([C:8]2[C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=3[NH:5][C:3](=[O:4])[CH2:2][N:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N
Reactant: O=C(CBr)Nc1ccccc1C(=O)c1ccccc1
Solvent: CO
Solvent: O
Product: O=C1CN=C(c2ccccc2)c2ccccc2N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
A suspension of 2-bromoacetamidobenzophenone (275 g, 0.86 mol) in methanol (1 L) was treated with a solution of saturated ammonia in methanol (3 L), and the resulting solution was stirred at ambient temperature for 6 h, then was heated at reflux for an additional 4 h. After cooling, water (500 mL) was added, and the solution was concentrated by evaporation to about 1 L in volume, yielding crystalline 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one (20) (200.7 g, 98%).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[Si:10](Cl)([CH3:13])([CH3:12])[CH3:11]>ClCCl>[Si:10]([C:7]1[NH:6][C:5](=[O:8])[N:4]([Si:10]([CH3:13])([CH3:12])[CH3:11])[C:3](=[O:9])[C:2]=1[F:1])([CH3:13])([CH3:12])[CH3:11]
Reactant: C[Si](C)(C)Cl
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: ClCCl
Product: C[Si](C)(C)c1[nH]c(=O)n([Si](C)(C)C)c(=O)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-fluorouracil (130 mg, 1.0 mmol) in dichloromethane (5 mL), N,O-Bis-TMS-Acetamide (0.86 mL, 3.5 mmol) and TMS-Cl (0.1 mL) were added. After 2 h stirring at room temperature (clear solution) the reaction mixture was concentrated under reduced pressure to afford bis-TMS-5-fluorouracil.
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[CH:5]([C:10]([OH:12])=[O:11])[CH:6]([OH:9])[CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.[CH3:23][O:24][N:25]=[C:26]([C:30]([O:36][CH2:37][CH3:38])([O:33][CH2:34][CH3:35])[CH2:31][Br:32])[C:27](O)=[O:28].P(Cl)(Cl)(Cl)=O>C(Cl)Cl.CN(C)C=O>[CH3:23][O:24][N:25]=[C:26]([C:30]([O:36][CH2:37][CH3:38])([O:33][CH2:34][CH3:35])[CH2:31][Br:32])[C:27]([NH:1][CH:2]1[C:13](=[O:14])[N:4]2[CH:5]([C:10]([OH:12])=[O:11])[CH:6]([OH:9])[CH2:7][S:8][C@H:3]12)=[O:28]
Reactant: CCOC(CBr)(OCC)C(=NOC)C(=O)O
Reactant: NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(CBr)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Yield: 44.2 %

Procedure:
7-Amino-3-hydroxycepham-4-carboxylic acid (1.09 g., purity 84.8%), trimethylsilylacetamide (5.3 g.), 2-methoxyimino-3,3-diethoxy-4-bromobutyric acid (syn isomer, 1.8 g.), phosphorus oxychloride (0.68 ml.), N,N-dimethylformamide (0.55 ml.) and methylene chloride (25 ml.) were treated in a similar manner to that of Example 25 (1) to give 7-(2-methoxyimino-3,3-diethoxy-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 1.1 g.).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@H:11]2[C@H:19]3[N:14]([C:15]4[CH:23]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[S:30]([NH:33]C(C)(C)C)(=[O:32])=[O:31])=[CH:20][C:16]=4[O:17][CH2:18]3)[C:13](=[O:38])[O:12]2)=[O:8])=[CH:4][CH:3]=1.CC(=O)OCC>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@H:11]2[C@H:19]3[N:14]([C:15]4[CH:23]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[S:30]([NH2:33])(=[O:31])=[O:32])=[CH:20][C:16]=4[O:17][CH2:18]3)[C:13](=[O:38])[O:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc2c(c1)OC[C@H]1[C@H](CNC(=O)c3ccc(Cl)s3)OC(=O)N21
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccccc1-c1ccc2c(c1)OC[C@H]1[C@H](CNC(=O)c3ccc(Cl)s3)OC(=O)N21
Temperature: 40 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
Compound 5-chloro-N-(((3S,3aS)-1-oxo-7-(2-t-butylaminosulfonylphenyl)-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-3-yl)methyl)thiophene-2-carboxamide (124 mg, 0.215 mmol) was dissolved in 2 ml of TFA. The resulting mixture was heated to 40° C. and agitated for 2 h. TLC (PE/EA=1/1) was employed to monitor the reaction. After the reaction completed, TFA was evaporated, and the remainder was diluted by 20 ml of EA, washed with 8 ml of water and 8 ml of saturated saline solution for one time each, dried over anhydrous sodium sulfate, and the solvent was evaporated. Column chromatography (PE/EA=2/1) afforded 91 mg of white solid, yield: 81.22%.