Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2](OCC)=O.[CH2:11]([O:18][CH2:19][C:20]([O:22]CC)=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Br.[CH2:28]([N:35]1[CH2:39][CH2:38][N:37]=[C:36]1[NH2:40])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]1[C:36]2=[N:40][C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[C:19]([O:18][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:20](=[O:22])[N:37]2[CH2:38][CH2:39]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)COCc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Reactant: NC1=NCCN1Cc1ccccc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCN2Cc1ccccc1
Yield: 18.7 %

Procedure:
Reaction of the adduct of diethyl oxalate (7.66 g, 52.4 mmol), ethyl benzyloxyacetate (10.2 g, 52.5 mmol) and sodium hydride (2.31 g of a 60% dispersion in mineral oil, 57.9 mmol) with 1-benzyl-4,5-dihydro-1H-imidazol-2-amine hydrobromide (13.39 g, 52.5 mmol) as described for intermediate 1 gave 3.98 g (18% yield) of the title ester as white crystals; mp 93° C. (ethyl acetate-hexane).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:17]=[C:8]2[C:9]3[C:14]([CH2:15][CH2:16][N:7]2[N:6]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(COC)OC>[CH2:1]([NH:4][C:5]1[N:17]=[C:8]2[C:9]3[C:14]([CH2:15][CH2:16][N:7]2[N:6]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: CC(=O)Nc1nc2n(n1)CCc1ccccc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Product: CCNc1nc2n(n1)CCc1ccccc1-2
Yield: 53 %

Procedure:
2-Acetamido-5,6-dihydro-s-triazolo[5,1-a]isoquinoline is reduced with lithium aluminum hydride at 0°-10° C in dimethoxyethane. Yield 53%, m.p. 100°-101° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[CH3:15][S-:16].[Na+]>CS(C)=O.CN(C=O)C.O>[CH3:15][S:16][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: C[S-]
Reactant: Clc1ccnc(Oc2ccccc2)n1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CSc1ccnc(Oc2ccccc2)n1
Reaction time: 1 h

Procedure:
To a stirred solution of 4-chloro-2-phenoxypyrimidine (2.00 g, 9.68 mmol) in dry DMSO (15 ml) and DMF (10 ml) at 10° C. under nitrogen was added dropwise a solution/suspension of sodium methanethiolate (0.77 g, 9.68 mmol) in dry DMSO (15 ml) and DMF (5 ml). After approximately one hour below 15° C., the reaction mixture was diluted with water and then extracted (×3) with ether. The combined ether extracts were washed with brine and then dried. Evaporation of the solvent gave 4-methylthio-2-phenoxypyrimidine as a thick, pale yellow oil (2.00 g, 87% pure by GC) which was used in the next stage without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:6]2[C:7]([O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.[Br:23]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>C1COCC1>[Br:23][C:10]1[C:5]2[O:4][CH2:3][C:2]([CH3:1])([CH3:22])[C:6]=2[C:7]([O:11][Si:12]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:19]([CH3:21])[CH3:20])=[CH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)[Si](Oc1cccc2c1C(C)(C)CO2)(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)[Si](Oc1ccc(Br)c2c1C(C)(C)CO2)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy][tris(1-methylethyl)]silane (Intermediate 24, 7.4 g, 23.19 mmol) was dissolved in THF (70.0 mL). N-Bromosuccinimide (4.2 g, 23.88 mmol) was added dissolving in few minutes. This mixture was stirred at room temperature for 3 hrs. More NBS (0.64 g, 3.48 mmol) was added and the reaction mixture was stirred at room temperature for a further hour. CCl4 (50 mL) was added to the reaction mixture and the solution was evaporated to dryness. The residue was re-suspended in CCl4 and stirred at room temperature for 15 min. The white solid was removed by filtration and the wet cake was washed with more CCl4. The CCl4 was swapped with ethyl acetate and the organic solution was washed three times with 2.5% w/w aqueous NaHCO3 and finally with water. The organic solution was dried on anhydrous Na2SO4 and evaporated to dryness to give the title compound (8.6 g) as a brown oil.
Reaction SMILES: O=[C:2]1[C:11]2[CH2:12][CH2:13]O[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=2[NH:3]1.[CH3:20][C:21]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=1[NH2:23]>C(O)COCCO.[Cl-].[Na+].O>[CH3:20][C:21]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=1[N:23]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=3[N:3]=[C:2]([NH:3][CH2:4][CH2:5][OH:15])[C:11]=2[CH2:12][CH2:13]1
Reactant: COc1ccc(N)c(C)c1
Reactant: O=c1[nH]c2c(OC(F)(F)F)cccc2c2c1CCO2
Agent: [Cl-]
Agent: [Na+]
Solvent: OCCOCCO
Solvent: O
Product: COc1ccc(N2CCc3c(NCCO)nc4c(OC(F)(F)F)cccc4c32)c(C)c1
Temperature: 250 °C
Yield: 160.3 %

Procedure:
4-Oxo-6-trifluoromethoxy-2,3,4,5-tetrahydrofuro[3,2-c]quinoline(5.0 g, 19 mmol) was dissolved in diethylene glycol(30 ml) and 2-methyl-4-methoxyaniline(6.1 ml, 46 mmol) was added. The reaction mixture was refluxed at 250° C. for 15 hours, diluted in brine(20 ml), and the aqueous layer was extracted with dichloromethane(15 ml) for 3 times. The organic layer was washed with water(15 ml) for 3 times, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 6.6 g of desired compound as solid in 91% of yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH2:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[Br:17][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH2:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C(N)=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: NC(=O)c1ccccc1-c1ccc(CBr)cc1
Reaction time: 20 h

Procedure:
A mixture of 4'-methylbiphenyl-2-carboxamide (2.1 g), N-bromo-succinimide (2.5 g) and azobisisobutyronitrate (AIBN;82 mg) in benzene (20 ml) was stirred for 20 hours at 60° to 70° C. Resulting crystalline precipitates were collected by filtration, washed with isopropylether and suspended in water. The suspension was stirred for 30 minutes, and insoluble materials were collected by filtration and dried to give crude crystals. Recrystallization from ethyl acetate--methanol afforded colorless needles (1.6 g, 55%), m.p. 220°-221° C.(decomp.).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:20]=3[CH:30]=2)[C@@H:11]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][O:38][CH2:39][C@H:40]([O:42][CH2:43][CH3:44])[CH3:41])=[CH:33][CH:32]=2)[C@H:10]([CH2:45][NH2:46])[CH2:9]1)=O)(C)(C)C.[C:47](Cl)(=[O:49])[CH3:48]>>[CH2:43]([O:42][C@H:40]([CH3:41])[CH2:39][O:38][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([C@@H:11]2[C@@H:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:20]=4[CH:30]=3)[CH2:13][NH:8][CH2:9][C@H:10]2[CH2:45][NH:46][C:47](=[O:49])[CH3:48])=[CH:32][CH:33]=1)[CH3:44]
Reactant: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CN)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reactant: CC(=O)Cl
Product: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CNC(C)=O)CNC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1

Procedure:
Analogously to example 2a, (3R,4R,5R)-3-aminomethyl-4-[4-((R)-2-ethoxypropoxy-methyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester (example 6a) and acetyl chloride are used to afford the title compound as a yellow oil oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.12 (EtOAc); Rt=4.87 (gradient I).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:6]([NH2:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[F:15][C:16]([F:21])([F:20])[C:17](=N)N>C(O)C>[F:15][C:16]([F:21])([F:20])[C:17]1[NH:1][CH:2]2[CH2:3][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH:6]2[N:7]=1
Reactant: N=C(N)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@@H](N)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2N=C(C(F)(F)F)NC2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the product from Step C (250 mg) in ethanol (5 mL) was added 2,2,2-trifluoroethanimidamide (180 mg) and the reaction mixture heated to reflux. After 2 h, the mixture was cooled to ambient temperature and the solvent evaporated in vacuo and used without further purification. LC/MS 224.2 (14+1-56).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH2:16]([NH2:22])[C@@H:17]1[O:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>>[CH2:16]([NH:22][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13])[C@@H:17]1[O:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC[C@H]1CCCO1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC[C@H]2CCCO2)c1Cl
Yield: 96.6 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (993 mg, 3.41 mmol), (2R)-tetrahydrofurfurylamine (0.36 mL, 3.49 mmol) and triethylamine(0.72 mL, 5.17 mmol) were reacted to form the desired product (1.17 g, 97%). EI-MS m/z 353(M-H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[CH:7]=1.[C:17]1([CH2:23][CH2:24][Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[CH:7]=1
Reactant: COc1ccc(Br)cc1C1=NC(C)(C)CO1
Reactant: Br[Mg]CCc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)COC(c2cc(Br)ccc2CCc2ccccc2)=N1
Reaction time: 18 h
Yield: 103.1 %

Procedure:
To a solution of 2-(5-bromo-2-methoxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole (31.21 g) in THF (40 ml) was added PhCH2CH2MgBr (0.22 mol) as a solution in diethyl ether (240 ml). The mixture was stirred for 18 hours, the solvents evaporated and the residue partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was separated, evaporated and the resulting residue purified by MPLC eluting with dichloromethane to give 2-(5-bromo-2-(phenethyl)phenyl)-4,4-dimethyl-4,5-dihydrooxazole (40.56 g).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH3:22][C:23]1[NH:24][CH:25]=[CH:26][N:27]=1>>[CH3:22][C:23]1[N:24]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH:25]=[CH:26][N:27]=1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Yield: 49 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (25 mg, 0.0786 mmol) is reacted with 2-methyl-1H-imidazole according to the GPA affording 14.5 mg (49%) of a yellowish powder. Rt=1.98 min.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:16]=3[N:17]=[C:18]([CH3:20])[N:19]=2)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:38](=[O:37])[CH2:39][OH:40])[CH2:32][CH2:33]4)=[O:26])[C:16]=3[N:17]=[C:18]([CH3:20])[N:19]=2)[CH2:3][CH2:4]1
Reactant: Cc1ccc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f57) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: S(N1CC1)(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O.[NH2:16][C@@H:17]([C@H:20]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)/[CH:21]=[CH:22]/[CH3:23])[CH2:18][NH2:19].Br[C:35]1[S:36][CH:37]=[CH:38][N:39]=1.[CH:40]1[C:49]2[C:44](=[CH:45][C:46](B(O)O)=[CH:47][CH:48]=2)[CH:43]=[CH:42][N:41]=1.N[C@@H]([C@H](C1C=CC(C(F)(F)F)=CC=1)/C=C/C)CO>>[NH2:16][C@@H:17]([C@H:20]([C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=1)/[CH:21]=[CH:22]/[CH3:23])[CH2:18][NH:19][C:35]1[S:36][C:37]([C:46]2[CH:45]=[C:44]3[C:49](=[CH:48][CH:47]=2)[CH:40]=[N:41][CH:42]=[CH:43]3)=[CH:38][N:39]=1
Reactant: C/C=C/[C@@H](c1ccc(C(F)(F)F)cc1)[C@H](N)CN
Reactant: OB(O)c1ccc2cnccc2c1
Reactant: Brc1nccs1
Agent: C/C=C/[C@@H](c1ccc(C(F)(F)F)cc1)[C@H](N)CO
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)N2CC2)cc1
Product: C/C=C/[C@@H](c1ccc(C(F)(F)F)cc1)[C@H](N)CNc1ncc(-c2ccc3cnccc3c2)s1

Procedure:
The title compound was synthesized in a manner similar to that described for Example 35 using a nosyl aziridine intermediate to introduce the (2S,3S,E)-2-amino-3-(4-(trifluoromethyl)phenyl)hex-4-enylamine side chain to make the bromothiazole intermediate that was coupled with isoquinolin-6-ylboronic acid. The nosyl aziridne was prepared in a similar manner to that described for Example 17 starting with (2S,3S,E)-2-amino-3-(4-(trifluoromethyl)phenyl)hex-4-en-1-ol which was prepared as shown in Scheme 35. MS m/z: 469 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm 9.12 (s, 1H) 8.38 (d, J=5.87 Hz, 1H) 8.03 (d, J=8.80 Hz, 1H) 7.86 (dd, J=8.61, 1.76 Hz, 1H) 7.70-7.80 (m, 2H) 7.65 (t, J=4.01 Hz, 3H) 7.50 (d, J=8.22 Hz, 2H) 5.63-5.83 (m, 2H) 3.65 (dd, J=13.11, 2.74 Hz, 1H) 3.37-3.44 (m, 2H) 3.21-3.30 (m, 1H) 1.73 (dd, J=6.26, 1.37 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]>C(OCC)(=O)C>[Cl-:7].[CH3:12][O:11][C:9]([CH2:8][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:10]
Reactant: c1ccncc1
Reactant: COC(=O)CCl
Solvent: CCOC(C)=O
Product: COC(=O)C[n+]1ccccc1
Product: [Cl-]
Temperature: 25 °C

Procedure:
Pyridine (1 equivalent) and methyl chloroacetate (1 equivalent) in ethyl acetate were heated (80° C.) for 24 hours. The reaction mixture was cooled to room temperature and the resulting crystalline pyridinium salt filtered, washed with ethyl acetate, and dried in vacuum.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.CN.[Li].O>O1CCCC1.C(O)(C)(C)C>[CH2:1]1[C:10]2[CH:5]([CH2:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: c1ccc2c(c1)CCNC2
Agent: CN
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: C1=CCC2CCNCC2=C1
Temperature: -10 °C

Procedure:
Typically, the tetrahydroisoquinoline was suspended or dissolved in a cosolvent such as tetrahydrofuran or t-butyl alcohol. This mixture was cooled to −10° C. and methylamine was added and the temperature was maintained at −10° C. The lithium metal was charged in portions and the reaction mixture was stirred at −10° C. for another 30 minutes to about 2 hours after sufficient lithium metal was charged. The reaction mixture was warmed to room temperature and then added to water to produce the product hexahydroisoquinoline as a precipitate.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.CS(O[C@H:13]1[CH2:18][CH2:17][C@H:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]1)(=O)=O>CN(C)C=O>[N:3]1([C@@H:13]2[CH2:14][CH2:15][C@H:16]([NH:19][C:20](=[O:21])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:17][CH2:18]2)[CH:7]=[N:6][CH:5]=[N:4]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](n2cncn2)CC1
Reaction time: 0.08 h
Yield: 86.2 %

Procedure:
Sodium hydride (60%, 0.034 g, 0.86 mmol) was added portionwise to a solution of 1H-1,2,4-triazole (0.064 g, 0.92 mmol) in N,N-dimethylformamide (2 mL). After stirred for 5 min, trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl methanesulfonate (0.18 g, 0.61 mmol) was added. The resulting mixture was stirred at 65° C. over weekend. The cooled mixture was poured into ice-cold water, extracted with EtOAc. The organic layers were concentrated and purified on silica gel (eluting with 0 to 5% MeOH in EtOAc) to give tert-butyl [cis-4-(1H-1,2,4-triazol-1-yl)cyclohexyl]carbamate (0.14 g, 86%). LCMS calculated for C13H23N4O2 (M+H)+: m/z=267.2. Found: 267.1. This carbamate intermediate was treated with trifluoroacetic acid (0.28 mL, 3.7 mmol) in methylene chloride (1 mL) at room temperature for 1 h and then concentrated to give the desired product as TFA salt. LCMS calculated for C8H15N4 (M+H)+: m/z=167.1. Found: 167.2.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[Mg:4].[C:5]([O:13]CC)(=[O:12])[CH2:6][C:7]([O:9]CC)=[O:8]>C(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([CH:6]([C:7]([O-:9])=[O:8])[C:5]([O-:13])=[O:12])[CH3:2].[CH2:1]([O:3][Mg+2:4])[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)CC(=O)OCC
Reactant: [Mg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCC(C(=O)[O-])C(=O)[O-]
Product: CCO[Mg+2]
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Separately, 0.9 ml of absolute ethanol and two drops of carbon tetrachloride were added to 0.4 g of metallic magnesium. When a reaction began, a mixture of 2.6 ml of diethyl malonate, 1.6 ml of absolute ethanol and 6 ml of toluene was added dropwise to the reaction mixture at a temperature not higher than 60° C., followed by stirring at 60° C. for 1 hour to give ethoxymagnesium ethyl malonate.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:25])[C@H:18]([OH:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.ClC1[C:36]2[C:31](=[CH:32][C:33]([CH3:37])=[CH:34][CH:35]=2)[N:30]=[C:29]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[OH:44])[N:28]=1.C(N(CC)CC)C>[Pd].CO>[OH:24][C@@H:18]([C:17]([N:14]1[CH2:13][CH2:12][N:11]([C:9]2[C:36]3[C:31](=[CH:32][C:33]([CH3:37])=[CH:34][CH:35]=3)[N:30]=[C:29]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[OH:44])[N:28]=2)[CH2:16][CH2:15]1)=[O:25])[CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: COC(=O)C[C@@H](O)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
4-((R)-2-Hydroxy-3-methoxycarbonyl-propionyl)-piperazine-1-carboxylic acid benzyl ester (0.52 g, 1.5 mmol) and MeOH (15 mL) were stirred with 10% Pd/C under an H2 atmosphere at ambient pressure overnight. After filtration and evaporation of the solvent the residue was taken up in CH2Cl2, and 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.40 g, 1.50 mmol) plus triethylamine (0.41 mL, 3.00 mmol) were added. The reaction mixture was stirred at room temperature overnight, washed with water, dried over Na2SO4, and concentrated. Purification via silica gel chromatography using 0-10% MeOH/CH2Cl2 provided (R)-methyl 3-hydroxy-4-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-oxobutanoate (0.38 g, 57%). LC/MS: m/z 451.1 (M+H)+ at 2.18 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.ClC(Cl)(Cl)C(=N)O[C:31]([CH3:34])([CH3:33])[CH3:32].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1CCCCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([C:14]([O:16][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)C(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.9 %

Procedure:
To a solution of N-[(benzyloxy)carbonyl]-2-methylalanine (1 g, 4.21 mmol) in DCM (10 ml anhydrous), cyclohexane (10 ml) at 0° C. under nitrogen was added boron trifluoride diethyl etherate (7.7 μl, catalytic). tert-Butyl 2,2,2-trichloroacetimidate (1.51 ml, 8.43 mmol) in cyclohexane (10 ml) was then added slowly over 30 minutes before allowing to warm to RT. Reaction was allowed to stir at RT for 16 hours. To the crude reaction mixture was added 190 mg of NaHCO3 and the reaction filtered. The mother liquors were concentrated in vacuo. The crude extract was purified by column chromatography (10% EtOAc in heptane) to yield the desired product (0.863 g, 70% yield).
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[C:21]([F:22])=[CH:20][C:19]([O:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[C:30]2[C:31]([N+:41]([O-:43])=[O:42])=[N:32][N:33](C3CCCCO3)[CH:34]=2)=[CH:18][C:17]=1[F:44])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O.ClCCl>CO>[F:22][C:21]1[CH:20]=[C:19]([O:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[C:30]2[C:31]([N+:41]([O-:43])=[O:42])=[N:32][NH:33][CH:34]=2)[CH:18]=[C:17]([F:44])[C:16]=1[S:13]([NH:7][C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(=[O:15])=[O:14]
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1c(F)cc(O[C@H]2CCCC[C@@H]2c2cn(C3CCCCO3)nc2[N+](=O)[O-])cc1F
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1n[nH]cc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2cscn2)c(F)c1
Yield: 54.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the tert-butyl{[2,6-difluoro-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)phenyl]sulfonyl}1,3-thiazol-4-ylcarbamate (426 mg, 0.636 mmol) prepared in Example 116b, trifluoroacetic acid (1.0 mL), dichloromethane (1.0 mL) and methanol (0.1 mL), to yield the title compound (167 mg, 54%) as a colorless solid.
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:17]([O:19]C(C)(C)C)=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.[C:26]([CH2:28][S:29]([CH2:32][C:33](O)=[O:34])(=[O:31])=[O:30])#[N:27].C1(N=C=NC2CCCCC2)CCCCC1.FC(F)(F)C(O)=O>>[C:26]([CH2:28][S:29]([CH2:32][C:33]([NH:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:13][N:14]=[N:15][N:16]=3)[CH3:10])[CH2:7][S:8][C@H:3]12)=[O:34])(=[O:31])=[O:30])#[N:27]
Reactant: N#CCS(=O)(=O)CC(=O)O
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)(=O)CC#N)[C@H]2SC1

Procedure:
t-Butyl 7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate (5.75 g, 15 mmol), cyanomethylsulfonylacetic acid (2.45 g, 15 mmol), and dicylohexylcarbodiimide (3.1 g, 15 mmol) were reacted as in Example 6. The t-butyl ester was treated with trifluoroacetic acid for 20 minutes as in Example 6, to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(Cl)c(Cl)c2)CC1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 8 h
Yield: 102.9 %

Procedure:
Platinum oxide (0.3 g) was added to a solution of 1-(tert-butoxycarbonyl)-4-(3,4-dichlorobenzylidene)piperidine (29 g, 84.7 mmol) in ethyl acetate (500 ml) and the mixture was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered through celite and the filtrate was concentrated to give 1-(tert-butoxycarbonyl)4-(3,4-dichlorobenzyl)piperidine (30 g) as a tan oil.