Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:5])[C:2]#[C:3][CH3:4].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CCOCC>[CH2:1]([O:5][S:14]([CH3:13])(=[O:16])=[O:15])[C:2]#[C:3][CH3:4]
Reactant: CC#CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC#CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
2-Butyne-1-ol (1.4 g, 20 mmol) is dissolved in ether (50 mL) and cooled to 0° C. Triethylamine (3.3 mL, 24 mmol) is added to the solution. Methanesulfonyl chloride (1.6 mL, 22 mmol) is dissolved in ether (5 mL) and added dropwise to the reaction solution. The mixture is stirred for 30 minutes at 0° C., then filtered and concentrated to give crude methanesulfonic acid but-2-ynyl ester 20 (2.96 g, 20 mmol, quant.) as a colorless liquid: 1H-NMR (400 MHz, CDCl3) δ=4.79 (q, J=2.4 Hz, 2H), 3.08 (s, 3H), 1.87 (t, J=2.4 Hz, 3H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[CH:10]=[C:9]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:24].[CH:25]([C:27]1[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=1)[O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:12]1([CH:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:9]2[CH:8]=[CH:7][C:6](=[O:24])[N:5]([CH2:4][CH2:3][NH:2][CH2:25][C:27]3[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=3)[O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:10]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NCCn1cc(C(c2ccccc2)c2ccccc2)ccc1=O
Reactant: CCOC(=O)COc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)COc1cccc(CNCCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.9 %

Procedure:
To a solution of 1-(2-aminoethyl)-5-(diphenylmethyl)pyridin-2(1H)-one hydrochloride (350 mg), ethyl (3-formylphenoxy)acetate (214 mg) and TEA (114 mg) in DCM (10 mL) was added sodium triacetoxyborohydride (326 mg) on ice bath temperature and the resulting mixture was stirred for 4 hours at ambient temperature. And then the reaction mixture was partitioned between DCM and saturated NaHCO3 aqueous solution The organic layer was washed with brine, dried over sodium sulfate and filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:MeOH=99:1-90:10) to give ethyl {3-[({2-[5-(diphenylmethyl)-2-oxopyridin-1(2H)-yl]ethyl}amino)methyl]phenoxy}acetate (321 mg).
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[NH2:19][C@H:20]([C:33]([NH:35][CH2:36][CH3:37])=[O:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][CH:23]=1.Cl>>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([NH:19][C@H:20]([C:33]([NH:35][CH2:36][CH3:37])=[O:34])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[CH:26][CH:27]=1)=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCNC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Agent: Cl
Product: CCNC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 4 °C

Procedure:
6.27 g (25 mmoles) of Z-Val-OH and 7.52 g (25 mmoles) of H-Tyr(But)-NH-C2H5.HCl are subjected to a condensation reaction analogously to Example 30 C. After being precipitated by means of water, the substance is dissolved in 70 ml of 95 percent strength alcohol and the solution is filtered hot and cooled (3 hours at 4° C.). The precipitate is filtered off. Yield 9.01 g (72.5%), melting point 181°, [α]D23 =-39.8° (c=1, dimethylformamide).
Reaction SMILES: [I-].[K+].[Cu][C:4]#[N:5].FC1C=CC([CH:13]2[C:21]3[C:16](=[CH:17][C:18](Br)=[CH:19][CH:20]=3)[CH2:15][O:14]2)=CC=1.C1(C)C=CC=CC=1>CN(C)C=O.N>[CH2:13]1[C:21]2[C:16](=[CH:17][C:18]([C:4]#[N:5])=[CH:19][CH:20]=2)[CH2:15][O:14]1
Reactant: Fc1ccc(C2OCc3cc(Br)ccc32)cc1
Reactant: N#C[Cu]
Agent: N
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)COC2
Temperature: 100 °C
Reaction time: 2 h
Yield: 133.3 %

Procedure:
Potassium iodide (25 g), Copper (I) cyanide (11.8 g) were added to a solution of the [1-(3-dimethylamino)propyl)]-1-(4-fluorophenyl)-1,3-dihydro-5-bromoisobenzofuran (25 g) in dimethylformamide (25 ml). The reaction mixture was heated to 135–145° C. and maintained for 28 hours. The reaction mixture was cooled to 100° C. and poured in ammonia solution containing toluene and stirred for 2 hours to get a clear separation of layers. Then the organic layer after acid base treatment was separated and washed with water twice (2×100 ml), dried with anhydrous sodium sulfate and finally the toluene layer was distilled to get the crude 1-[3-(dimethylamino) propyl]-14-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile base 16.5 g, with the following HPLC profile.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44].Cl>CO>[ClH:27].[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CCN(C)C)CC1
Agent: Cl
Solvent: CO
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CCN(C)C)CC1

Procedure:
Following general procedure F, 1-(6-bromo-4-(trans-4-(2-(dimethylamino)ethyl)cyclohexyl amino)quinolin-3-yl)ethanone (4.8 g, 11.5 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (3.8 g, 13.1 mmol) to obtain the free base. The purified product was suspended in methanol (100 mL) after which HCl (125 mL, 1.25 M in methanol) was added to form a solution. The solution was concentrated to ˜50 mL and the resultant solid was filtered, washed with methanol, and dried to obtain desired product (3.8 g, 58% over two steps) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.10 (s, 1H), 8.50 (s, 1H), 8.27 (dd, J=8.8, 1.8 Hz, 1H), 7.97 (d, J=8.8 Hz, 1H), 7.73 (s, 2H), 4.55-4.48 (m, 1H), 3.27-3.15 (m, 2H), 2.90 (s, 6H), 2.74 (s, 3H), 2.42 (br d, J=12.3 Hz, 2H), 2.04 (br d, J=12.9 Hz, 2H), 1.84-1.65 (m, 4H), 1.63-1.56 (m, 1H), 1.34 (q, J=12.3 Hz, 2H); ESI MS m/z 500 [C27H31Cl2N3O2+H]+; HPLC>99% (AUC), tR=6.87 min.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:13]1([N:12]2[CH2:2][CH2:3][C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: ClCCc1ccccc1CCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: c1ccc(N2CCc3ccccc3C2)cc1
Yield: 29.7 %

Procedure:
A mixture of 2-(2-chloroethyl)benzyl chloride (19 g), aniline (9.3 g), and triethylamine (22.22 g,) in chloroform (80 ml) was heated at reflux for 6 hrs. The reaction mixture was cooled and washed with 2M sodium hydroxide solution (3×100 ml). The chloroform layer was dried (magnesium sulphate) and evaporated in vacuo. The residue was distilled in vacuo to afford 2-phenyl-1,2,3,4-tetrahydroisoquinoline (6.2 g. b.pt. 112°-113°/0.08-0.1 mmHg) characterised by its nmr spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CO[CH2:11][CH2:12][C:13](OC)(OC)[CH3:14]>[Cl-].[Zn+2].[Cl-].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:6]([C:13]([CH3:14])=[CH:12][CH:11]=[N:5]2)=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COCCC(C)(OC)OC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Product: Cc1ccnc2cc(Cl)ccc12
Reaction time: 8 h

Procedure:
To a mixture containing 3-chloroaniline (1.59 g), ferric chloride hexahydrate (5.4 g), zinc chloride (0.2 g), ethanol (20 ml of 95% aqueous solution) preheated to 60° C. was added 1,3,3-trimethoxybutane (1.48 g). The resulting mixture was refluxed for two hours and allowed to stand overnight. The volatile materials were then removed in vacuo and the residue rendered basic with 10% aqueous sodium hydroxide. The resulting mixture was partitioned between water and diethyl ether (3 times). The combined ether layer was dried over magnesium sulfate. Rotary evaporation of the ether solution gave a dark liquid. The liquid was added to a silica gel column and eluted with hexane/ethyl acetate (3:1) to give the desired product as tan crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]([CH:5]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH2:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20](O)=[O:21])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1)=[O:4].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.Cl.[CH2:66]([O:73][NH2:74])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>CN(C=O)C>[CH2:66]([O:73][NH:74][C:20]([CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH:5]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:27])=[O:28])[C:3]([N:2]([CH3:36])[CH3:1])=[O:4])=[CH:24][CH:23]=2)=[CH:13][CH:14]=1)=[O:21])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: Cc1ccc(S(=O)(=O)NC(Cc2ccc(Oc3ccc(CCC(=O)O)cc3)cc2)C(=O)N(C)C)cc1
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC(Cc2ccc(Oc3ccc(CCC(=O)NOCc4ccccc4)cc3)cc2)C(=O)N(C)C)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
The acid compound 25 (0.85 g, 1.66 mmol) was dissolved in dry DMF (20 mL) and cooled to 0-5° C. 1-Hydroxybenzotriazole (0.25 g, 1.82 mmol), EDCI (0.32 g, 1.66 mmol), and triethylamine (0.7 mL, 5.0 mmol) were added to the above mixture followed by stirring for 15 min. O-Benzylhydroxylamine hydrochloride (0.3 g, 1.83 mmol) was added and the mixture was allowed to come to room temperature and stirred for 18 h. The solvent was evaporated under reduced pressure and the residual oil was taken up in EtOAc (50 mL). The organic layer was extracted with 2.0 M HCl (1×10 mL), saturated NaHCO3 (1×10 mL), and brine (1×25 mL). The resulting EtOAc layer was dried and concentrated to yield the crude product. Flash chromatography on silica gel (hexanes:ethyl acetate—1:1 containing 1% acetic acid) yielded the desired benzyl hydroxamate 26 (0.8 g, 78%). 1H NMR (400 MHz, DMSO-d6): 8.06 (d, J=9.6 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.30-7.36 (m, 5H), 7.29 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 6.81 (d, J=8.8 Hz, 2H), 4.72 (s, 2H), 4.26-4.32 (m, 1H), 2.75-2.82 (m, 3H), 2.68 (s, 3H), 2.57-2.63 (dd, J=13.6 and 7.6 Hz, 1H), 2.35 (s, 3H), 2.25 (t, J=7.2 Hz, 2H).
Reaction SMILES: [CH3:1][C:2](=[CH2:14])[CH2:3][C:4]([O:10]CCC)(OCCC)[CH3:5].[CH3:15][C:16]([CH3:20])=[CH:17][CH2:18]O.C1CCCCC1>C(O)=O>[CH3:5][C:4]([CH2:10][CH2:18][CH:17]=[C:16]([CH3:20])[CH3:15])=[CH:3][C:2](=[O:14])[CH3:1]
Reactant: C=C(C)CC(C)(OCCC)OCCC
Reactant: CC(C)=CCO
Solvent: C1CCCCC1
Solvent: O=CO
Product: CC(=O)C=C(C)CCC=C(C)C
Yield: 89 %

Procedure:
In an autoclave, a mixture of 120 parts of 4-methyl-2,2-di-n-propoxy-4-pentene, 50 parts of prenol and 170 parts of cyclohexane is heated with 3.4 parts of formic acid for 4 hours at 160°C. Fractional distillation gives 57.5 parts of 4,8-dimethyl-3,7-nonadien-2-one, equivalent to a yield of 89% and a conversion of 67% based on prenol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]=NCC2C=CC=CC=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C(O)=[O:26]>O.C1COCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]=[O:26])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=NCc2ccccc2)CC1
Reactant: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1

Procedure:
A solution of trans-[4-(benzylimino-methyl)-cyclohexyl]-carbamic acid tert-butyl ester (2.50 g, 8.00 mmol) and oxalic acid (0.80 g) in water/THF (50 mL, 1:1) was stirred for 10 h at room temperature. The reaction mixture was concentrated under reduced pressure and methylene chloride (50 mL) was added to the residue. The organic phase was dried and concentrated under reduced pressure to give trans-(4-Formyl-cyclohexyl)-carbamic acid tert-butyl ester (1.3 g, 80%).
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@@H:9]1[CH2:13][CH2:12][CH:11]([C:14](N(OC)C)=[O:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[CH2:20]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]1[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CON(C)C(=O)C1CC[C@@H](N(Cc2ccccc2)Cc2ccccc2)C1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: O=CC1CC[C@@H](N(Cc2ccccc2)Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A solution of (3R)-3-(dibenzylamino)-N-methoxy-N-methylcyclopentanecarboxamide (3.34 g, 9.48 mmol) in THF (70 mL) was cooled to about −78° C., followed by the drop-wise addition of DIBAL-H (1.0 M in hexanes, 9.48 mL, 9.48 mmol). The reaction mixture was stirred at about −78° C. for about 1 h, and was quenched by drop-wise addition of saturated aqueous sodium potassium tartrate. The resulting mixture was stirred at room temperature for about 1 h. The solvent was removed under reduced pressure and the aqueous layer was extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by chromatography on neutral alumina eluting with a gradient of 0-20% EtOAc in heptane to yield (3R)-3-(dibenzylamino)cyclopentanecarbaldehyde (1.63 g, 75%) as a colorless oil: LC/MS (Table 2, Method a) Rt=2.03 min; MS m/z: 294 (M+H)+.
Reaction SMILES: [OH-].[OH:2][C:3]1[N+:7]2[CH2:8][CH2:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]=2S[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21]1(S(C=C)=O)C=CC=C[CH:22]=1>C1(C)C(C)=CC=CC=1>[C:15]1([C:4]2[C:3](=[O:2])[N:7]3[C:6](=[CH:21][CH:22]=2)[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[CH2:9][CH2:8]3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=CS(=O)c1ccccc1
Reactant: Oc1c(-c2ccccc2)sc2[n+]1CCc1ccsc1-2
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: O=c1c(-c2ccccc2)ccc2n1CCc1ccsc1-2

Procedure:
2.85 g of 5,6-dihydro-3-hydroxy-2-phenylthiazolo[3,2-a]thieno[2,3-c]pyridinium hydroxide (internal salt) was heated under reflux overnight in 100 ml of xylene together with 1.45 ml of phenylvinyl sulfoxide, whereupon the reaction mixture was evaporated in vacuo and the residue obtained was chromatographed on silica gel with toluene/ethyl acetate (9:1). There was obtained 4,5-dihydro-8-phenyl-7H-thieno[2,3-a]quinolizin-7-one of m.p. 133°-134° (from ethyl acetate).
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([C:28]2[S:29][CH:30]=[CH:31][N:32]=2)=[C:23]([CH:27]=1)[C:24](O)=[O:25])(=[O:18])=[O:17]>>[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([C:28]2[S:29][CH:30]=[CH:31][N:32]=2)=[C:23]([CH:27]=1)[C:24]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=2)[CH2:2][CH2:3]1)=[O:25])(=[O:17])=[O:18]
Reactant: CS(=O)(=O)c1ccc(-c2nccs2)c(C(=O)O)c1
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Product: CS(=O)(=O)c1ccc(-c2nccs2)c(C(=O)N2CCN(c3ccc(C#N)cc3)CC2)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from 4-piperazin-1-yl-benzonitrile [68104-63-2] and 5-Methanesulfonyl-2-thiazol-2-yl-benzoic acid (Example O). MS (ISP): 453.5 MH+.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10](=[O:17])[O:11][C:12]([CH3:16])=[CH:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.C(O)(=[O:22])C>C1(C)C=CC=CC=1.C(O)C>[CH2:1]([S:8]([C:9]1[C:10](=[O:17])[O:11][C:12]([CH3:16])=[CH:13][C:14]=1[OH:15])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Cc1cc(O)c(SCc2ccccc2)c(=O)o1
Agent: OO
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(O)c(S(=O)Cc2ccccc2)c(=O)o1
Yield: 69 %

Procedure:
3-Benzylthio-4-hydroxy-6-methyl-2-pyrone (7.45 g., 0.0282 mol) and 30% hydrogen peroxide (3.7 g., 0.033 mol) were combined in 30 ml. glacial acetic acid and stirred at room temperature for 20 hours. The solution was then diluted with a mixture of toluene and ethanol (5:1) and warmed in vacuo to codistil the acetic acid. The recovered tan solid was recrystallized from toluene (DARCO) to give 5.4 g. (69 percent) of the desired product: m.p. 150°-153°C. One additional recrystallization from toluene gave the pure compound: m.p. 155°-156°C.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:15][C:16]([C:18]1[N:19]=[C:20]([N:23]2[CH2:26][CH:25]([S:27][C:28]3[C@H:29]([CH3:52])[C@@H:30]4[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]4[C:32]=3[C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)=[O:34])[CH2:24]2)[S:21][CH:22]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][C@@H:10]([NH:15][C:16]([C:18]1[N:19]=[C:20]([N:23]2[CH2:24][CH:25]([S:27][C:28]3[C@H:29]([CH3:52])[C@@H:30]4[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]4[C:32]=3[C:33]([O:35][CH2:36][C:37]3[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=3)=[O:34])[CH2:26]2)[S:21][CH:22]=1)=[O:17])[CH2:11][CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)C[C@@H](CO)NC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Yield: 55.3 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-3-methylbutylcarbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (640 mg, 0.827 mmol) (obtained as described in Example 42(1)) in tetrahydrofuran (32 ml) were added acetic acid (142 μl, 2.48mmol) and a solution of 1 M tetrabutylammonium fluoride in tetrahydrofuran (2.48 ml, 2.48 mmol) in an ice bath and the mixture was stirred for 2 days at room temperature. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate and ethyl acetate:methanol (9:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-((1S)-1-hydroxymethyl-3-methylbutylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (302 mg, yield 55%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([NH:24][C:25]4[CH:34]=[C:33]5[C:28]([CH2:29][CH2:30][N:31]([CH3:35])[CH2:32]5)=[CH:27][CH:26]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:38]=1[C:39](Cl)=[O:40]>C1COCC1.CO>[F:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:38]=1[C:39]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:16]([C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([NH:24][C:25]4[CH:34]=[C:33]5[C:28]([CH2:29][CH2:30][N:31]([CH3:35])[CH2:32]5)=[CH:27][CH:26]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:3]=1)=[O:40]
Reactant: CN1CCc2ccc(Nc3ncc(F)c(-c4c(-c5cccc(N)c5)nn5ccccc45)n3)cc2C1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCc2ccc(Nc3ncc(F)c(-c4c(-c5cccc(NC(=O)c6c(F)cccc6F)c5)nn5ccccc45)n3)cc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.1 %

Procedure:
To a solution of N-{4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-5-fluoro-2-pyrimidinyl}-2-methyl-1,2,3,4-tetrahydro-7-isoquinolinamine (50 mg, 0.11 mmol) in THF (5 mL) was added 2,6-difluorobenzoyl chloride (20 mg, 0.11 mmol) and the reaction mixture stirred at rt for 20 min. The reaction was diluted with MeOH, adsorbed to silica gel, and purified by column chromatography (0-10% MeOH/DCM+1% NH4OH) to afford the title compound (15.4 mg, 24%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.52 (s, 1H), 8.86 (d, J=7.69 Hz, 1H), 8.45-8.46 (m, 1H), 8.06 (s, 1H), 7.89 (d, J=8.61 Hz, 1H), 7.71-7.73 (m, 1H), 7.54-7.58 (m, 1H), 7.30-7.47 (m, 4H), 7.20-7.24 (m, 3H), 7.08-7.12 (m, 1H), 6.86 (d, J=8.42 Hz, 1H), 3.26 (s, 2H), 2.66-2.69 (m, 2H), 2.49-2.51 (m, 2H), 2.26 (s, 3H); ESIMS (M+H)+=606.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@H:19]([OH:28])[CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH:29](=O)[CH2:30][CH3:31]>>[OH:28][C@H:19]([CH2:20][O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:18][N:10]([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:29][CH2:30][CH3:31])=[CH:3][CH:4]=1)[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(N)cc1)C[C@H](O)COc1ccccc1
Reactant: CCC=O
Product: CCCNc1ccc(CCN(C[C@H](O)COc2ccccc2)C(=O)OC(C)(C)C)cc1
Yield: 100.3 %

Procedure:
1.52 g of t-butyl (S)-N-[2-(4-aminophenyl)ethyl]-N-(2-hydroxy-3-phenoxypropyl)carbamate and 0.23 g of propionaldehyde were subjected to a reductive amination reaction to obtain 1.69 g of t-butyl (S)-N-(2-hydroxy-3-phenoxypropyl)-N-[2-(4-propylaminophenyl)ethyl]carbamate.
Reaction SMILES: [OH-].[Li+].[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][N:14]=1)[C:8]([O:10]C)=[O:9])#[N:4]>C1COCC1.O>[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][N:14]=1)[C:8]([OH:10])=[O:9])#[N:4]
Reactant: COC(=O)c1ccnc(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
Lithium hydroxide (96 mg, 4.0 mmol) was added to a solution of methyl 2-cyanoisonicotinate (0.6 g, 3.7 mmol) in THF—H2O (20 mL, 7:3 v/v) at 0° C. The reaction mixture was allowed to warm up to room temperature and further stirred for 1 h. The reaction mixture was concentrated under reduced pressure and then diluted with water. The aqueous layer was washed with EtOAc. The pH of the aqueous layer was adjusted to ˜3 using 1.5N HCl and the organic product was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 2-cyanoisonicotinic acid (490 mg, yield 89%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 14.11 (br s, 1H), 8.93-8.91 (dd, J=4.9 Hz, 0.8 Hz, 1H), 8.34 (d, J=0.9 Hz, 1H), 8.11-8.10 (m, 1H). MS (ESI) m/z: Calculated for C7H4N2O2: 148.03. found: 147.2 (M−H)−.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([NH:14][NH2:15])[C:8]1=[O:16])=[O:5])C>Cl>[C:4]([CH2:6][N:7]1[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([NH:14][NH2:15])[C:8]1=[O:16])([OH:5])=[O:3]
Reactant: CCOC(=O)Cn1c(C)cnc(NN)c1=O
Agent: Cl
Product: Cc1cnc(NN)c(=O)n1CC(=O)O
Yield: 90.1 %

Procedure:
A solution of the compound of Example 4 (6.3 g, 0.028 mol) in HCl (6N, 160 mL) was heated at 60 to 70° C. for 2 hours. The reaction mixture was concentrated under vacuum to afford the title compound (5.0 g, 91%) as a yellow solid, which used in the next step without further purification. 1H NMR (D2O) δ 2.18 (s, 3H), 4.8 (s, 2H), 6.71 (s, 1H).