Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Br.[Br:42][CH2:43][CH2:44][NH2:45]>ClCCl.CCOC(C)=O.O>[Br:42][CH2:43][CH2:44][NH:45][C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: NCCBr
Reactant: O=C(O)c1cnccn1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NCCBr)c1cnccn1
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
2-Pyrazine carboxylic acid (1 g) in dichloromethane (30 mL) was treated with triethylamine (1.27 mL) and HATU (3.6 g) and the mixture was stirred for 10 minutes. A solution of 2-bromoethylamine hydrobromide (1.5 g) and triethylamine (1.27 mL) in dichloromethane (20 mL) was added and the reaction mixture was stirred for 3 hours. Water (50 mL) was added and the organic layer was separated and washed with water (3×50 mL). The organic layer was dried over magnesium sulphate and evaporated to give the crude product which was purified by silica gel chromatography eluting with 0-100% EtOAc/dichloromethane. The relevant fractions were combined and evaporated to give a residue which was dissolved in EtOAc (40 mL) and washed with saturated sodium hydrogen carbonate ensuring the aqueous layer was basic. The organic layer was dried over magnesium sulfate and evaporated to give the sub-titled compound (1.0 g) as a white solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH2:11][C:12]1[N:16]([CH3:17])[N:15]=[CH:14][C:13]=1[C:18]#[N:19].[N+](C1C=CC([O:29][C:30]([C:32]2[C:40]3[O:39][C:38]([CH2:41][CH3:42])=[N:37][C:36]=3[C:35]([O:43][CH:44]([F:46])[F:45])=[CH:34][CH:33]=2)=O)=CC=1)([O-])=O>CN(C)C=O>[C:18]([C:13]1[CH:14]=[N:15][N:16]([CH3:17])[C:12]=1[NH:11][C:30]([C:32]1[C:40]2[O:39][C:38]([CH2:41][CH3:42])=[N:37][C:36]=2[C:35]([O:43][CH:44]([F:45])[F:46])=[CH:34][CH:33]=1)=[O:29])#[N:19]
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)Oc3ccc([N+](=O)[O-])cc3)c2o1
Reactant: Cn1ncc(C#N)c1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Nc3c(C#N)cnn3C)c2o1
Reaction time: 1.5 h
Yield: 26.2 %

Procedure:
Sodium bis(trimethylsilyl)amide (0.53 ml) was added to a solution of 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (65 mg) in N,N-dimethylformamide (5 ml) at room temperature under an atmosphere of nitrogen. The mixture was stirred for 10 minutes before addition of 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid 4-nitrophenyl ester (100 mg), then for 90 minutes. It was quenched with water (1 ml) and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 2:1 heptane-ethyl acetate afforded the title compound as a white solid (25 mg).
Reaction SMILES: [CH3:1][O:2]C1C=C2C(C(C(O)=O)=CN2)=CC=1.[N:15]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([C:27]([NH2:29])=[O:28])[CH:19]=1)=[C:16]=[O:17]>>[N:15]([C:18]1[C:26]2[C:21](=[CH:22][C:23]([O:2][CH3:1])=[CH:24][CH:25]=2)[N:20]([C:27]([NH2:29])=[O:28])[CH:19]=1)=[C:16]=[O:17]
Reactant: COc1ccc2c(C(=O)O)c[nH]c2c1
Reactant: NC(=O)n1cc(N=C=O)c2ccccc21
Product: COc1ccc2c(N=C=O)cn(C(N)=O)c2c1

Procedure:
was prepared from 6-methoxy-indole-3-carboxylic acid using the protocol described for the preparation of 3-isocyanato-indole-1-carboxylic acid amide scheme A1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[CH:24]=1)[C:28]1[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Reactant: BrC1CCCC1
Product: CC(C)c1ccc(N(Cc2cnn(C3CCCC3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.50 mg) and bromocyclopentane (0.12 mL) as starting materials, 5-benzyloxy-N-[(1-cyclopentylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.54 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 17, N-[(1-cyclopentylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.27 g) was obtained. melting point: 173° C.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:26]4[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and 4-bromo-benzenesulfonamide (59 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (60 mg, 50%). MS (ISN) 480.9 [(M−H)−]; mp 228-230° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[S:13][C:12]([NH2:14])=[N:11][N:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1C=CC([NH:20][C:21](N)=[S:22])=N1>>[N:1]1([CH2:7][CH2:8][C:9]2[S:13][C:12]([NH:14][C:21]([NH2:20])=[S:22])=[N:11][N:10]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: NC(=S)Nc1cc[nH]n1
Reactant: Nc1nnc(CCN2CCOCC2)s1
Product: NC(=S)Nc1nnc(CCN2CCOCC2)s1

Procedure:
The titled compound is prepared from 5-(2-Morpholin-4-yl-ethyl)-[1,3,4]thiadiazol-2-ylamine (54b) following the procedure described for (1H-pyrazol-3-yl)-thiourea (35a)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH3:51])=[CH:45][CH:44]=1)[C:9]1[N:14]2[N:15]=[CH:16][CH:17]=[C:13]2[N:12]=[C:11]([NH:18][C@H:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]2)[C:10]=1[CH2:32][CH2:33][CH2:34][O:35][Si](C(C)(C)C)(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6]([N:8]([C:43]1[CH:44]=[CH:45][C:46]([O:49][CH2:50][CH3:51])=[CH:47][CH:48]=1)[C:9]1[N:14]2[N:15]=[CH:16][CH:17]=[C:13]2[N:12]=[C:11]([NH:18][C@H:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:20]2)[C:10]=1[CH2:32][CH2:33][CH2:34][OH:35])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCCO[Si](C)(C)C(C)(C)C)c(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)nc3ccnn23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCCO)c(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)nc3ccnn23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
To a tetrahydrofuran (1.3 mL) solution containing tert-butyl (S)-3-[7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6-(3-tert-butyldimethylsiloxypropyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate (13.3 mg), was added tetrabutylammonium fluoride (1 mol/L tetrahydrofuran solution, 26 μL), and the mixture was stirred at room temperature for 3 hr. After the reaction, the mixture was purified with PTLC (50% ethyl acetate-hexane) to obtain the title compound (7.7 mg).
Reaction SMILES: [OH:1][C@@H:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])/[CH:3]=[CH:4]/[C@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[CH2:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.C(Cl)CCl.C1C=CC2N(O)N=[N:37]C=2C=1.[Cl-].N.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:1][C@@H:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])/[CH:3]=[CH:4]/[C@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[CH2:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:37])=[O:18])=[CH:15][CH:14]=1
Reactant: On1nnc2ccccc21
Reactant: CCCCC[C@H](O)/C=C/[C@H]1CCC(=O)N1CCc1ccc(C(=O)O)cc1
Agent: N
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC[C@H](O)/C=C/[C@H]1CCC(=O)N1CCc1ccc(C(N)=O)cc1
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a solution of 4-[2-{(2R)-2-[(1E,3S)-3-hydroxy-oct-1-enyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid (71.90 mg, 0.2 mmol) in DMF (1 mL) was added EDC (57.51 mg, 0.3 mmol), HOBt (40.54 mg, 0.3 mmol), ammonia chloride (21.40 mg, 0.4 mmoL) and DIPEA. The mixture was stirred for overnight. After evaporation of the solvent, the residue was purified through RP-HPLC using ACN and H2O/0.1% TFA to afford the desired product (70 mg) as a white solid. 1HNMR (CD3OD, ppm) δ 0.879 (m, 3H), 2.297 (br, 6H), 1.49 (m, 2H), 1.75 (m, 1H), 2.19 (m, 1H), 2.34 (m, 2H), 2.89 (m, 2H), 3.17 (m, 1H), 3.73 (t, J=7.0 Hz, 1H), 4.04 (t, J=6.2 Hz, 2H), 5.45 (dd, J=8.8 and 15.1 Hz, 1H), 5.66 (dd, J=6.6 and 15.1 Hz, 1H), 7.30 (d, J=7.7 Hz, 2H), 7.82 (d, J=7.7 Hz, 2H), (m/z): 381.4 (+Na+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:38])=[C:4]([CH:35]=[CH:36][CH:37]=1)[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[CH:24][N:23](COCC[Si](C)(C)C)[N:22]=3)[CH:17]=[C:16]([CH3:34])[N:15]=2)[CH2:9][CH2:8]1)=[O:6].O.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[Cl:1][C:2]1[C:3]([F:38])=[C:4]([CH:35]=[CH:36][CH:37]=1)[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[CH:24][NH:23][N:22]=3)[CH:17]=[C:16]([CH3:34])[N:15]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: Cc1cc(Nc2ccn(COCC[Si](C)(C)C)n2)nc(CC2CCN(C(=O)c3cccc(Cl)c3F)CC2)n1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2cc[nH]n2)nc(CC2CCN(C(=O)c3cccc(Cl)c3F)CC2)n1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
24.9 mg of 2-((1-(3-chloro-2-fluorobenzoyl)piperidin-4-yl)methyl)-6-methyl-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrimidin-4-amine was dissolved in 0.9 ml of trifluoroacetic acid and 0.1 ml of water at room temperature, followed by stirring the reaction mixture at 60° C. for 30 minutes. The reaction mixture was cooled to room temperature, and concentrated in vacuo. The reaction mixture was purified by a reversed phase preparative liquid chromatography, followed by concentrating the obtained fraction in vacuo to give the title compound as a white solid.
Reaction SMILES: [Na].[Cl-:2].[CH2:3]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][CH2:10][NH+:11]([CH3:13])[CH3:12])[CH3:4].[CH2:15](O)[CH2:16]CC>>[Cl-:2].[CH2:3]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][CH2:10][NH+:11]([CH3:12])[CH3:13])[CH2:4][CH2:15][CH3:16]
Reactant: CCCCO
Reactant: CCOC(=O)NCCC[NH+](C)C
Agent: [Cl-]
Agent: [Na]
Product: CCCCOC(=O)NCCC[NH+](C)C

Procedure:
4.6 g (0.2 g-atom) of sodium are dissolved in 200 ml of n-butanol. To this add 21.0 g (0.1 mole) of N-(3-dimethylammoniopropyl)-carbamic acid ethyl ester chloride and boil the mixture for 6 hours with reflux. Concentrate, admix with water, ether out, dry the ether phase over MgSO4, introduce dry HCl gas while stirring and cooling, decant the ether solution, and drag the remaining oil in vacuum. One obtains 13.1 g of nD20 = 1.4735.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[O:11][CH2:12][C@@H:13]2[CH2:17][C@@H:16]([NH2:18])[CH2:15][N:14]2[C:19](=[O:29])[NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[CH:5][CH:4]=1)[CH3:2].[NH:31](C(OC(C)(C)C)=O)[CH2:32][C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[O:11][CH2:12][C@@H:13]2[CH2:17][C@@H:16]([NH:18][C:33](=[O:34])[CH2:32][NH2:31])[CH2:15][N:14]2[C:19](=[O:29])[NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(NC(=O)OC[C@@H]2C[C@@H](N)CN2C(=O)NCc2ccccc2Cl)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCc1ccc(NC(=O)OC[C@@H]2C[C@@H](NC(=O)CN)CN2C(=O)NCc2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a solution of ((2S,4R)-4-amino-1-(2-chlorobenzylcarbamoyl)pyrrolidin-2-yl)methyl 4-ethylphenylcarbamate (60 mg, 0.14 mmol) in DMF were added Boc-Gly-OH (37 mg, 0.21 mmol) and HBTU (80 mg, 0.21 mmol). The reaction mixture was stirred at rt overnight and purified on RP-HPLC using a mixture of acetonitrile and H2O. The fraction containing the product was combined and concentrated. The residue was dissolved in MeOH and 4N HCl in dioxane. The reaction mixture was stirred at rt for 1 h and concentrated to give ((2S,4R)-4-(2-aminoacetamido)-1-(2-chlorobenzylcarbamoyl)pyrrolidin-2-yl)methyl 4-ethylphenylcarbamate (37 mg, 51%). LRMS (M+H+) m/z 488.1.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f28) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][CH:2]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][C:27](=[O:29])[O:26][N:25]=3)=[CH:14][CH:13]=2)=[C:7]([CH2:30][CH2:31][CH3:32])[N:6]2[N:33]=[C:34]([CH3:36])[N:35]=[C:5]12.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C.C(#N)C>[CH3:39][C:37]([CH3:38])([CH3:40])[C:2](=[O:1])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][C:27](=[O:29])[O:26][N:25]=3)=[CH:16][CH:17]=2)=[C:7]([CH2:30][CH2:31][CH3:32])[N:6]2[N:33]=[C:34]([CH3:36])[N:35]=[C:5]12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(O)C(C)(C)C)c2nc(C)nn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(=O)C(C)(C)C)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A mixture of 4-(2-hydroxy-3,3-dimethylbutyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.52 g), Dess-Martin reagent (0.81 g) and acetonitrile (15 mL) was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate and sodium thiosulfate-pentahydrate were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.43 g, 85%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C:11]([CH3:18])([CH2:16]O)[C:12]([O:14][CH3:15])=[O:13].[CH3:19][S:20](Cl)(=O)=O.[Na].CS>ClCCl.Cl.O1CCOCC1.C(OCC)(=O)C>[CH3:15][O:14][C:12](=[O:13])[C:11]([CH3:10])([CH3:18])[CH2:16][S:20][CH3:19]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(C)(C)CO
Agent: CS
Agent: Cl
Agent: [Na]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)CSC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 24 %

Procedure:
N,N-Diisopropylethylamine (15.5 g, 0.12 mol) was added to a solution of methyl 2,2-dimethyl-3-hydroxypropionate (13.2 g, 0.1 mol) in dichloromethane (150 mL) and the solution was cooled to 0° C. Methane sulfonyl chloride (12.6 g, 0.11 mol) was then added dropwise and the mixture was stirred at 0° C. for 90 minutes. The reaction mixture was then diluted with 0.5M hydrochloric acid (100 mL) and the layers were separated. The aqueous was extracted with dichloromethane (2×50 mL) and the combined organic solution was dried over magnesium sulfate and concentrated in vacuo. Methanethiol sodium salt (7.7 g, 0.11 mol) was added to a solution of the residue in dioxan (100 mL) and the mixture was heated under reflux for 24 hours. The mixture was then diluted with ethyl acetate (250 mL), washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography on silica gel, eluting with dichloromethane:pentane 50:50 to 100:0, afforded the title compound as a pale yellow oil in 24% yield, 3.85 g.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH:22](F)[C:23]2[C:24]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[C:25]3[C:30](=[CH:31][C:32]=2[CH:33]([CH3:35])[CH3:34])[O:29][C:28]([CH3:37])([CH3:36])[CH2:27][C:26]3=[O:38])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].CO>O1CCCC1.C(OCC)(=O)C>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([CH2:22][C:23]2[C:24]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)=[C:25]3[C:30](=[CH:31][C:32]=2[CH:33]([CH3:35])[CH3:34])[O:29][C:28]([CH3:36])([CH3:37])[CH2:27][C@@H:26]3[OH:38])=[CH:20][CH:21]=1)([CH3:14])([CH3:15])[CH3:13]
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(C(C)(C)C)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1Cc1ccc(C(C)(C)C)cc1)[C@@H](O)CC(C)(C)O2
Reaction time: 0.5 h

Procedure:
150 μl (840 μmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 4.70 mg (30 μmol) of (1R,2S)-1-aminoindan-2-ol in 5 ml of tetrahydrofuran, and the mixture is stirred for 30 min. A solution of 100 mg (210 μmol) of rac-6-[(4-tert-butylphenyl)(fluoro)methyl]-5-(4-fluorophenyl)-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 28A) in 5 ml of tetrahydrofuran is then slowly added dropwise. After 3 h of stirring at room temperature, methanol is added and the solvent is reduced under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 10:1→5:1) gives the target product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:6](=O)[O:7]C1C=CC=CC=1.[NH2:20][NH2:21].O>C(O)C>[NH2:20][N:21]1[CH2:2][CH2:3][CH2:4][N:5]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:6]1=[O:7]
Reactant: NN
Reactant: O=C(Oc1ccccc1)N(CCCCl)CC(F)(F)F
Solvent: O
Solvent: CCO
Product: NN1CCCN(CC(F)(F)F)C1=O
Temperature: 90 °C
Reaction time: 5 h

Procedure:
Into a 100-mL round-bottom flask, was placed phenyl N-(3-chloropropyl)-N-(2,2,2-trifluoroethyl)carbamate (1.4 g, 4.73 mmol, 1.00 equiv), NH2NH2.H2O (6 mL), ethanol (40 mL). The resulting solution was stirred for 5 h at 90° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 50 mL of H2O. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×30 mL of brine. The mixture was dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. This resulted in 200 mg (crude) of 1-amino-3-(2,2,2-trifluoroethyl)-1,3-diazinan-2-one as a light yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[NH2:34][C:35]1[S:39][N:38]=[C:37](/[C:40](=[N:44]/[O:45][CH2:46][CH3:47])/[C:41](Cl)=[O:42])[N:36]=1.CC(N(C)C)=O>ClCCl>[NH2:34][C:35]1[S:39][N:38]=[C:37](/[C:40](=[N:44]/[O:45][CH2:46][CH3:47])/[C:41]([NH:1][C@@H:2]2[C:20](=[O:21])[N:4]3[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]23)=[O:42])[N:36]=1
Reactant: CCO/N=C(\C(=O)Cl)c1nsc(N)n1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CC(C)=O)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
In 200 ml of dichloromethane is suspended 11 g of 7β-amino-3(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid. To the suspension is added 14 g of bistrimethylsilylacetamide and the mixture is stirred at room temperature until complete dissolution and cooled in an ice-water bath. To this solution, 14 g of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-ethoxyiminoacetyl chloride is added and the mixture is stirred for a while, to which 6 g of dimethylacetamide is added. The whole mixture is stirred with ice-cooling for 60 minutes. The dichloromethane is evaporated off and the residue is dissolved in methyl ethyl ketone. The solution is washed with water and dried. The solvent is then evaporated off and diethyl ether is added to the residue to give a fine precipitate, which is collected by filtration, giving 12.5 g of the above-identified compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[CH2:13]([S:17](Cl)(=[O:19])=[O:18])[CH2:14][CH2:15][CH3:16]>C(Cl)Cl>[CH2:13]([S:17]([NH:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:19])=[O:18])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCS(=O)(=O)Cl
Reactant: COCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCS(=O)(=O)NCCOC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.4 ml of 2-methoxyethylamine (5.5 g, 73.7 mmol) and 10.2 ml of triethylamine (7.4 g, 73.7 mmol) were dissolved at room temperature in 72 ml of methylene chloride. Likewise at room temperature 9.6 ml of n-butanesulfonyl chloride (11.5 g, 73.7 mmol) were added dropwise to this solution over the course of one hour. After 1 h of stirring at room temperature the reaction mixture was washed twice with 100 ml of water. The organic phase was dried over magnesium sulphate, the methylene chloride was distilled off and the oily residue which remained was dried in vacuo. This gave 12.4 g of the target compound, whose constitution was verified by NMR spectroscopy.