Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].Cl.Cl[CH2:14][CH2:15][N:16]([CH2:18][CH2:19]Cl)[CH3:17]>ClC1C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[CH2:19][CH2:18][N:16]([CH3:17])[CH2:15][CH2:14]1
Reactant: CN(CCCl)CCCl
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Solvent: Clc1ccccc1
Solvent: ClCCl
Product: CN1CCN(c2cc([N+](=O)[O-])ccc2Cl)CC1
Yield: 66.5 %

Procedure:
A mixture of 2-chloro-5-nitrobenzenamine (7.95 g) and 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (8.86 g) in chlorobenzene (40 ml) under nitrogen was heated to reflux for 3 days before cooling and diluting with dichloromethane (60 ml). The reaction mixture was then extracted with water (2×500 ml), the aqueous layers combined and basified with 2N sodium hydroxide, then extracted with dichloromethane (4×400 ml). The combined, dried extracts were concentrated in vacuo to give a dark brown oil (7.82 g) which was purified by FCC eluting with ether to give a dark brown oil which crystallised upon standing. The material was dissolved in ethanol (40 ml) and boiled up with some charcoal (300 mg). The hot ethanolic suspension was filtered and concentrated in vacuo to give the title compound as a yellow oil which crystallised on standing (5.25 g) m.p.63°-64° C.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].Cl[CH2:7][C:8](=O)[CH2:9][C:10]([O:12]CC)=[O:11].Cl>>[NH:5]=[C:3]1[N:2]([NH2:1])[C:8]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][S:4]1
Reactant: NNC(N)=S
Reactant: CCOC(=O)CC(=O)CCl
Agent: Cl
Product: N=c1scc(CC(=O)O)n1N

Procedure:
Reaction of thiosemicarbazide and ethyl 4-chloroacetoacetate in warm concentrated hydrochloric acid yielded 2-imino-3-aminothiazoline-4-acetic acid (Compound IIIA), which is also obtained by heating the hydrochloride of Compound IA in hydrochloric acid. Refluxing Compound IIIA in ethanolic hydrochloric acid produces the hydrochloride of the corresponding acetate, Compound IIIB (ethyl 2-imino-3-aminothiazoline 4-acetate.)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([CH:30]([CH3:32])[CH3:31])[CH2:13][NH:14][C:15]([CH2:17][CH2:18][NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:16].C(N(CC)CC)C>ClCCl>[CH2:22]([O:21][C:20](=[O:29])[NH:19][CH2:18][CH2:17][C:15](=[O:16])[NH:14][CH2:13][C:12](=[O:11])[CH:30]([CH3:32])[CH3:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)C(O)CNC(=O)CCNC(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)CNC(=O)CCNC(=O)OCc1ccccc1
Temperature: -70 °C
Reaction time: 0.1 h

Procedure:
10.81 ml (126.08 mmol) oxalyl chloride are placed in 300 ml dichloromethane, cooled to −70° C. 11.94 ml (168.11 mmol) dimethylsulphoxide are slowly added dropwise. The mixture is stirred for 0.1 hours, then 32.40 g (105.07 mmol) benzyl [2-(2-hydroxy-3-methyl-butylcarbamoyl)-ethyl]-carbamate in 70 ml dichloromethane are added. The mixture is stirred for 1 hour, then 62.48 ml (450.72 mmol) triethylamine are added dropwise. The reaction mixture is stirred for 1.5 hours at −70° C., then slowly allowed to come up to ambient temperature. It is diluted with dichloromethane and washed with 1 molar hydrochloric acid, saturated sodium carbonate solution, water and saturated sodium chloride solution. The organic phase is dried and evaporated to dryness.
Reaction SMILES: [C:1]1(/[C:7](/[C:14]2[CH:19]=[CH:18][N:17]=[N:16][CH:15]=2)=[CH:8]\[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(NN)(C1C=CC(C)=CC=1)(=O)=O.CCN(CC)CC>C1(C)C=CC=CC=1>[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][N:17]=[N:16][CH:15]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)/C=C(\c1ccccc1)c1ccnnc1
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1ccccc1)c1ccnnc1
Temperature: 100 °C

Procedure:
To a solution of (E)-ethyl 3-phenyl-3-(pyridazin-4-yl)acrylate (1.8 g, 7.09 mmol) in PhMe (40 mL), TsNHNH2 (2.64 g, 14.2 mmol) and Et3N (2.15 g, 21.3 mmol) was added, the resulting mixture was heated to 100° C. overnight. The reaction was detected by TLC, TLC showed the appearance of desired product, then, the solvent was removed under reduced pressure, H2O was added and extracted with AcOEt (3×50 ml), the combined organic layers were washed by brine, dried over Na2SO4 and concentrated to get the crude product, which was purified by column chromatography on silica gel (Petroleum Ether: EtOAc=3:2) to afford ethyl 3-phenyl-3-(pyridazin-4-yl)propanoate (1.20 g, yield: 66%). 1H NMR (CDCl3 400 MHz):δ9.12 (d, J=2.0 Hz, 1H), 9.09 (d, J=6.8 Hz, 1H), 7.40-7.24 (m, 4H), 7.20 (d, J=7.2 Hz, 2H), 4.56 (t, J=8.0 Hz, 1H), 4.08 (q, J=7.2 Hz, 2H), 3.09 (d, J=8.0 Hz, 2H), 1.15 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=1)[CH2:11]C1OCCO1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:22].O>S(=O)(=O)(O)O.C(OCC)C>[CH2:1]([C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=1)[CH:11]=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cc2cccc(CC3OCCO3)c2)cc1
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: O=Cc1cccc(Cc2ccccc2)c1
Reaction time: 8 h

Procedure:
A mixture of 2-(3-benzylbenzyl)-1,3-dioxolane (8.2 g), acetone (100 cm3), water (10 cm3) and concentrated sulphuric acid (20 drops) was stirred overnight, then added to diethyl ether. The resultant mixture was washed with sodium bicarbonate solution, water and brine, and dried over anhydrous magnesium sulphate. Evaporation of the solvents under reduced pressure gave 3-benzylbenzaldehyde (6.5 g), which was used without further purification.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH2:6]([OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].C(N(CC)CC)C>C(#N)C>[CH2:9]([CH2:8][CH2:7][CH2:6][O:14][S:1]([NH2:2])(=[O:4])=[O:3])[CH2:10][CH2:11][CH2:12][O:13][S:1]([NH2:2])(=[O:4])=[O:3]
Reactant: NS(=O)(=O)Cl
Reactant: OCCCCCCCO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NS(=O)(=O)OCCCCCCCOS(N)(=O)=O
Yield: 37 %

Procedure:
The title compound was obtained using the following procedure: The sulfamoyl chloride in acetonitrile solution prepared in (a) was reacted as in Example 11 with 10.5 g (0.0755 mole) of 1,7-heptanediol (95%), 30.3 g (0.300 mole) of triethylamine in 100 ml additional acetonitrile followed by using extracting, washing and concentration procedures of Example 11 through the first evaporation. The viscous residue which solidified on standing was purified by high pressure liquid chromatography using the Waters Associates® Prep LC/System 500A with PrepPAK® 500 silica. Eluting solvent used was 10:1 mixture methylene chloride-acetone at a flow rate of 200 ml/min. Fractions containing the title compound were combined and the solvents were evaporated under reduced pressure to give a viscous oil which solidified on standing. The solid was recrystallized from wet methylene chloride to give 8.2 g (37% yield) of title compound as white solid, mp 88.5°-90.5° C.
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-:4])(=[O:3])=[S:2].[K+].Br[CH2:14][CH2:15][CH2:16][Cl:17]>CC(C)=O>[Cl:17][CH2:16][CH2:15][CH2:14][S:2][S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Cc1ccc(S(=O)([O-])=S)cc1
Reactant: ClCCCBr
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)SCCCCl)cc1

Procedure:
Potassium thiotosylate (50.0 g, 221 mmol, 1.0 eq.) and 1-bromo-3-chloropropane (38.0 g, 241 mmol, 1.09 eq.) were stirred together in acetone (1 L) at room temperature for 72 hours. The mixture was then concentrated. Next, the mixture was partitioned between dichloromethane and water. The organic solution was washed with brine (2×), dried using MgSO4, concentrated and azeotroped with toluene to produce a pale yellow oil weighing 54 g (92%).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[O:7][C:6]2[CH:8]=[C:9]([NH:12]C(=O)OCC3C=CC=CC=3)[CH:10]=[CH:11][C:5]=2[C:4](=[O:23])[O:3]1>CO.[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][C:5]2[C:4](=[O:23])[O:3][C:2]([CH3:1])([CH3:24])[O:7][C:6]=2[CH:8]=1
Reactant: CC1(C)OC(=O)c2ccc(NC(=O)OCc3ccccc3)cc2O1
Agent: [Pd]
Solvent: CO
Product: CC1(C)OC(=O)c2ccc(N)cc2O1
Reaction time: 24 h
Yield: 77.5 %

Procedure:
To a solution of benzyl 2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-ylcarbamate (3.5 g) in methanol (250 mL) was added Pd/C (350 mg) and hydrogenated under 2 Kg of pressure for 24 h. The reaction mixture was filtered through a bed of celite and concentrated to give the title compound (1.6 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][CH:21]2[CH2:28][CH:24]3[CH2:25][NH:26][CH2:27][CH:23]3[CH2:22]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:16]([CH:17]=2)=[N:15][N:14]([CH3:18])[C:13]=3[CH3:19])=[N:6][CH:7]=1.[C:29]([CH2:31][C:32](O)=[O:33])#[N:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:20][CH:21]2[CH2:22][CH:23]3[CH2:27][N:26]([C:32](=[O:33])[CH2:31][C:29]#[N:30])[CH2:25][CH:24]3[CH2:28]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:16]([CH:17]=2)=[N:15][N:14]([CH3:18])[C:13]=3[CH3:19])=[N:6][CH:7]=1
Reactant: N#CCC(=O)O
Reactant: Cc1c2ccc(Nc3ncc(Cl)c(NC4CC5CNCC5C4)n3)cc2nn1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c2ccc(Nc3ncc(Cl)c(NC4CC5CN(C(=O)CC#N)CC5C4)n3)cc2nn1C
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 86.4 %

Procedure:
To a solution of 5-chloro-N2-(2,3-dimethyl-2H-indazol-6-yl)-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (484.7 mg, 1.22 mmol) and 2-cyanoacetic acid (155.0 mg, 1.82 mmol) in a mixture of DCM (40 mL) and DMF (10 mL) were added HATU (673.2 mg, 1.77 mmol) and Et3N (0.60 g, 5.90 mmol). The reaction mixture was stirred at rt for 5.5 h, then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=40/1) to give the title compound as a beige solid (0.49 g, 87%).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:35])[N:11]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:12]([CH3:26])=[CH:13][C:14]=1[C:15]([N:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[C:10](=[O:35])[N:11]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[C:12]([CH3:26])=[CH:13][C:14]=1[C:15]([N:17]([CH2:22][CH:23]([CH3:24])[CH3:25])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]
Reactant: Cc1cc(C(=O)N(CC(C)C)CC(C)C)c(OCc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C(=O)N(CC(C)C)CC(C)C)c(O)c(=O)n1CC(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
A mixture of 3-benzyloxy-4-diisobutylaminocarbonyl-6-methyl-1-tert-butyloxycarbonylmethyl-2-pyridinone from step 4 above (0.80 g) and 10% Pd on carbon (180 mg) in ethanol (40 mL) was shaken on a Parr apparatus under an atmosphere of hydrogen (50 psi) for 18 h. The catalyst was removed by filtration and the filtrate solvents were removed in vacuo to give the title compound (0.608 g;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([NH:12][C:13]([S:15][CH3:16])=[NH:14])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24]([O:27][CH2:28][C:29](Cl)=[O:30])(=[O:26])[CH3:25]>ClCCl>[C:24]([O:27][CH2:28][C:29]([N:14]=[C:13]([NH:12][C:10]([NH:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:11])[S:15][CH3:16])=[O:30])(=[O:26])[CH3:25]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CSC(=N)NC(=O)NCc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC(=NC(=O)COC(C)=O)NC(=O)NCc1ccc(Cl)cc1
Yield: 61.8 %

Procedure:
To a dichloromethane solution (2.0 mL) of methyl N-({[(4-chlorobenzen-1-yl)methyl]amino}carbonyl)-carbamimidothioate (257 mg, 1.00 mmol) synthesized in Reference Synthesis Example 326, triethylamine (279 μL, 2.00 mmol) and 2-chloro-2-oxoethyl acetate (162 μL, 1.50 mmol) were added and the resultant mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (221 mg, yield 62%).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([S:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]C)[CH:9]=1)[CH3:6].N(CCO)CCO>ClCCl>[CH2:5]([S:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[CH3:6]
Reactant: CCSc1cccc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: OCCNCCO
Product: CCSc1cccc(O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.9 %

Procedure:
Boron tribromide (1M in dichloromethane, 70 ml, 70 mmol) was added dropwise to a solution of 1-(ethylsulfanyl)-3-methoxybenzene (5.9 g, 35 mmol) in dichloromethane (150 ml) at 0° C. The mixture was allowed to warm to room temperature, stirred for 18 h then cooled to 0° C. A solution of diethanolamine (20 ml) in dichloromethane (40 ml) was added dropwise (Caution—strong exotherm!) and the mixture was stirred at ambient temperature for 15 min once addition was complete, then poured onto ice water. The mixture was extracted with dichloromethane and the organic phase was washed with 2N hydrochloric acid, water, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (20:80 to 30:70) as eluant to give 3-(ethylsulfanyl)phenol (4.53 g) as a colourless oil.
Reaction SMILES: C(OC(N1CC[N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)CC1)=O)(C)(C)C.[C:31]1([C:37]2([OH:43])[CH2:42][CH2:41]N[CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[O:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[O:30][C@@H:21]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][N:11]3[CH2:39][CH2:38][C:37]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)([OH:43])[CH2:42][CH2:41]3)=[CH:20][CH:19]=2)[CH2:22]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Product: OC1(c2ccccc2)CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1

Procedure:
Compound 269 is synthesized from Intermediate C and 4-phenyl-piperidin-4-ol according to General Method K. (LC/MS method 16: ES+ m/z 403.4 [M+H]+, Rt=2.68 min)
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1([C@H:19]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH3:20])[CH2:18][O:17]1>CN(C=O)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]([OH:17])([C@H:19]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH3:20])[CH2:18][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1
Reactant: c1nc[nH]n1
Reactant: C[C@@H](OC1CCCCO1)C1(c2cc(F)ccc2F)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](OC1CCCCO1)C(O)(Cn1cncn1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
To a stirred suspension of NaH (60% in oil, 21.0 g, 0.525 mol) in DMF (300 ml) was added portionwise 1,2,4-triazole (43.3 g, 0.627 mol) at the inner temperature from 2° C. to 11° C. over 30 min. The resulting mixture was stirred at r.t. for 1.5 hrs. To this mixture was added a solution of 2-(2,5-Difluorophenyl)-2-[(1R)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl]oxirane (48.3 g, 0.170 mol) in DMF (50 ml). The mixture was stirred at 60° C. for 1 hr. and then at 65° C. for 14 hrs. The reaction mixture was cooled down to 10° C. and then poured into ice-water (800 mL ). The resulting mixture was extracted with EtOAc (400 ml+200 ml×2 ). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silicagel (n-hexane: EtOAc=4:1˜1:5) to give (3R)-2-(2,5difluorophenyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (43.9 g, 73% ) and recovered starting material (13.2 g, 27%). Physical form: colorless syrup; FAB-MS: m/z 354 (M+H)+; 1H-NMR(CDCl3): 1.00(3H×½,d,J=6.6Hz),1.13(3H×½,d,J=6.6Hz), 1.42˜1.88(6H,m)3.38˜3.60(1H,m),3.80˜4.00(1H,m),4.32˜5.02(5H,m),6.83˜6.99 (2H,m),7.14˜7.21(1H,m),7.73(1H×½,s),7.74(1H×½,s),7.92(1H×½,s)7.95(1H×½,s),
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[C:27][CH:28]4[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O=[CH:35][CH2:36][NH:37]C(=O)OC(C)(C)C.[BH3-]C#N.[Na+].Cl>CO.O.CO.CC(O)=O>[NH2:37][CH2:36][CH2:35][N:30]1[CH2:31][CH2:32][CH2:33][CH:28]([C:27]#[C:26][C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][N:17]=[C:16]3[NH:15][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:2]([CH3:1])[CH:3]=2)[CH2:29]1
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: Cc1cc(Nc2ncnc3ccc(C#CC4CCCNC4)cc23)ccc1Oc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(Nc2ncnc3ccc(C#CC4CCCN(CCN)C4)cc23)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
(3-Methyl-4-phenoxy-phenyl)-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine (114 mg, 0.2 mmol) and tert-butyl N-(2-oxoethyl)carbamate (320 mg, 2.0 mmol) were dissolved in MeOH/H2O (5/0.5 mL) and the pH was adjusted to 5 with AcOH. The reaction was stirred at room temperature overnight and followed by the addition of NaBH3CN (13 mg, 0.2 mmol) over a period of 1 hour. After stirring for another hour, the reaction was concentrated and the residue was partitioned between CH2Cl2 (30 mL) and saturated Na2CO3 (20 mL). The separated organic layer was dried over sodium sulfate and concentrated. Purification by silica gel column using 5% MeOH in EtOAc gave the free base which was dissolved in MeOH. HCl gas was passed through the solution for 5 min and the deprotected product precipitated as HCl salt The mixture was diluted with EtOAc and the solid was collected by suction filtraton, rinsed with EtOAc, and further dried to afford 83 mg (71%) of yellow solid: 1H NMR (CD3OD) δ 1.71-1.82 (br, 2H), 2.0-2.12 (br, 2H), 2.27 (s, 3H), 3.00 (t, 1H), 3.03-3.19 (br, 2H), 3.40 (br, 1H), 3.50 (s, 2H), 3.62 (br d, 1H), 3.70 (m, 1H), 3.89 (br d, 1H), 6.93 (m, 3H), 7.08 (t, 1H), 7.33 (t, 2H), 7.52 (d, 1H), 7.64 (s, 1H), 7.79 (d, 1H), 8.05 (d, 1H), 8.75 (s, 1H), 8.77 (s, 1H); MS m/z (MH+) 476.1.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[F:33][C:34]([F:44])([F:43])[C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1>O>[C:16]([O:15][C:13]([N:10]1[CH2:9][CH2:8][CH:7]([CH2:6][C:5]2[CH:20]=[CH:21][C:2]([O:1][CH2:39][C:38]3[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:43])[F:44])=[CH:42][CH:41]=3)=[CH:3][CH:4]=2)[CH2:12][CH2:11]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(O)cc2)CC1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
tert-Butyl 4-(4-hydroxybenzyl)piperidine-1-carboxylate (1.78 g, 6.1 mmol), potassium carbonate (1.27 g, 9.2 mmol), N,N-dimethylformamide (18 ml) and 4-(trifluoromethyl)benzylbromide (1.75 g, 7.3 mmol) were mixed and stirred at room temperature overnight. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→60:40) to afford the title compound as a colorless powder (2.64 g, 96%).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[OH:5][CH2:6][C@@H:7]([CH3:28])[C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1.S(Cl)([Cl:32])(=O)=O.Cl>N1C=CC=CC=1>[C:1]([OH:4])(=[O:3])[CH3:2].[Cl:32][C:16]1[C:17](=[O:27])[CH2:18][CH2:19][C@@:20]2([CH3:21])[C:15]=1[CH2:14][CH2:13][C@@H:12]1[C@@H:22]2[CH2:23][CH2:24][C@@:25]2([CH3:26])[C@H:11]1[CH2:10][CH2:9][C@@H:8]2[C@H:7]([CH3:28])[CH2:6][OH:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(Cl)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a stirred solution of (20S)-21-hydroxy-20-methylpregn-4-en-3-one acetate (10.2 g, 27.38 mmol) in pyridine (100 mL) cooled to 15° C. there was added sulfuryl chloride (4.4 mL, 54.76 mmol) dropwise. After 30 minutes, the reaction mixture was poured into 1N hydrochloric acid and extracted with ether. The combined organic extracts were successively washed with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate and brine. The solution was then dried over magnesium sulfate and concentrated to give an orange solid. Flash chromatography of this material [eluting with ethyl acetate-hexane (3:7)] gave (20S)-4-chloro-21-hydroxy-20-methylpregn-4-en-3 -one acetate as a white solid (8.5 g, 72%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9](=O)[CH2:10][CH3:11].[OH-].[K+]>>[CH2:1](/[N:8]=[CH:9]/[CH2:10][CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCC=O
Agent: [K+]
Agent: [OH-]
Product: CC/C=N/Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of benzylamine (20.0 g, 184 mmol) was added propionaldehyde (10.8 g, 184 mmol) over 1 hour. Potassium hydroxide (5.2 g, 92.7 mmol) was added, and the reaction was allowed to stand for 1 hour, during which time the solution separated into two layers. The organic layer was isolated and stored over potassium hydroxide pellets overnight in the refrigerator to give the product as a cloudy liquid, which was used without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([C:7]([O:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[N:5]2[C:23](=[O:25])[CH2:24][C@H:4]2[C:3]1=[O:26]>C(Cl)Cl>[OH:26][CH:3]1[C@@H:4]2[CH2:24][C:23](=[O:25])[N:5]2[CH:6]([C:7]([O:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH:2]1[CH3:1]
Reactant: CC1C(=O)[C@@H]2CC(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC1C(O)[C@@H]2CC(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
By the procedures of Example 3, benzhydryl 2-methyl-1-oxocarbapenam-3-carboxylate (53 mg. in 3 ml. of methylene chloride employing only the 10 mg. reducing agent initially charged) was converted to purified benzhydryl 1-hydroxy-2-methylcarbapenam-3-carboxylate [53 mg.; Rf 0.30 (4:1 chloroform:ethyl acetate)].
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15]C(=O)OC(C)(C)C)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1>[CH2:2]([N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([NH2:15])[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(Cc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4N HCl in dioxane (1 mL) was added to (S)-tert-butyl 1-benzylpiperidin-3-ylcarbamate (0.5 mmol). The reaction was stirred at room temperature for 30 minutes. The solvent was removed by vacuo. The crude product was progressed to the next step without purification.