Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]=1[C:19]1[N:20]=[CH:21][N:22]([C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26](O)=[O:27])[CH:23]=1>>[CH:1]1([NH:6][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[N:22]2[CH:23]=[C:19]([C:9]3[C:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:11][O:12][C:8]=3[CH3:7])[N:20]=[CH:21]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccccc2C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccccc2C(=O)NC2CCCC2)cn1
Yield: 40 %

Procedure:
As described for Example 71, cyclopentylamine was converted, using 2-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (48 mg, 40%) which was obtained as an off-white solid. MS: m/e=413.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=O)[CH2:10][N:11]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[N:12]2)=[N:6][CH:7]=1.Cl>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[N:12]2)=[N:6][CH:7]=1
Reactant: O=C(Cn1cc([N+](=O)[O-])cn1)Nc1ccc(F)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnn(CCNc2ccc(F)cn2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To N-(5-fluoropyridin-2-yl)-2-(4-nitro-1H-pyrazol-1-yl)acetamide (493 mg) in THF (2.0 mL), BH3 THF-complex solution (1 M in THF, 7.3 mL, 7.3 mmol) was added dropwise. After stirring at rt for 3 h, the reaction mixture was quenched with 1 N aq. HCl-solution (3 mL, 3 mmol). The mixture was stirred for 15 min at rt, and heated to 60° C. for 1.5 h. The reaction mixture was diluted with EtOAc, washed with sat. aq. Na2CO3-solution. The aq. layer was reextracted with EtOAc and the comb. org. layers were evaporated, dissolved in DCM and washed with brine. The org. layer was dried (MgSO4), filtered and the solvent was removed by reduced pressure to yield 5-fluoro-N-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridin-2-amine as a yellow solid. LC-MS conditions A: tR=0.53 min, [M+H]+=252.36.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@H:6]1[CH2:10][C@H:9]([OH:11])[C@@H:8]([NH2:12])[CH2:7]1)=[O:5].C(N(C(C)C)C(C)C)C.[Cl:22][C:23]1[S:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C1COCC1>[CH3:2][O:3][C:4]([C@H:6]1[CH2:10][C@H:9]([OH:11])[C@@H:8]([NH:12][C:28]([C:26]2[S:27][C:23]([Cl:22])=[CH:24][CH:25]=2)=[O:29])[CH2:7]1)=[O:5]
Reactant: COC(=O)[C@@H]1C[C@H](N)[C@@H](O)C1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1
Reaction time: 18 h

Procedure:
A solution of (1R,3S,4S)-3-amino-4-hydroxy-cyclopentanecarboxylic acid methyl ester hydrochloride (160 mg) in THF (5 ml) was treated under an argon atmosphere with N-ethyldiisopropylamine (0.56 ml), 5-chloro-2-thiophenecarboxylic acid (160 mg) and BOP (434 mg). The mixture soon turned to a clear light yellow solution and was then stirred for 18 h. The reaction mixture was concentrated. The crude product was purified by chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 3:7) to give (1R,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-cyclopentane-carboxylic acid methyl ester as colorless gum. MS: 304.0 ([M+H]+).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[C:7]([C:13]([OH:15])=[O:14])=[N:8][CH:9]=[C:10]([F:12])[CH:11]=1.[CH3:16]O>>[F:5][C:6]1[C:7]([C:13]([O:15][CH3:16])=[O:14])=[N:8][CH:9]=[C:10]([F:12])[CH:11]=1
Reactant: CO
Reactant: O=C(O)c1ncc(F)cc1F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ncc(F)cc1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 10 mL of methanol was added dropwise 2.5 mL of thionylchloride under cooling in an ice bath over 30 minutes. To the reaction mixture was added 500 mg of 3,5-difluoropyridine-2-carboxylic acid, and warmed to room temperature, followed by stirring for 3 days. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. After filtration, it was concentrated under reduced pressure to obtain 496 mg of methyl 3,5-difluoropyridine-2-carboxylate.
Reaction SMILES: CN(S(F)(F)[F:5])C.O[CH:9]([C:17]1[CH:26]=[N:25][C:24]2[N:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:22](=[O:36])[N:21]3[N:37]=[CH:38][N:39]=[C:20]3[C:19]=2[CH:18]=1)[CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(#N)C.C(=O)(O)[O-].[Na+]>[F:5][CH:9]([C:17]1[CH:26]=[N:25][C:24]2[N:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:22](=[O:36])[N:21]3[N:37]=[CH:38][N:39]=[C:20]3[C:19]=2[CH:18]=1)[CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C(O)CN4CCOCC4)cnc32)cc1
Reactant: CN(C)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C(F)CN4CCOCC4)cnc32)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 22.8 %

Procedure:
(Dimethylamino)sulfur trifluoride (0.010 ml, 0.18 mmol) was added to a stirred solution of 9-(1-hydroxy-2-morpholinoethyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (49 mg, 0.090 mmol) in acetonitrile (1 ml). After 4 hours, additional (dimethylamino)sulfur trifluoride (0.035 ml, 0.36 mmol) was added and the mixture was stirred at 60° C. for 20 hours, cooled to room temperature, diluted with aqueous sodium bicarbonate (3 mL) and extracted with DCM (2×3 mL). The combined extracts were concentrated under a stream of nitrogen and the residue was taken up in methanol, filtered and purified by preparative HPLC. The resulting material retained some impurities so it was diluted with aqueous sodium bicarbonate (3 mL) and extracted with DCM (2×3 mL). The combined extracts were concentrated under a stream of nitrogen and the residue was purified by flash chromatography (elution with 0-40% IPA in ethyl acetate) to afford 9 mg (21%) of 269 as a white powder.
Reaction SMILES: CO.[OH:3][CH2:4][CH2:5][NH:6][C:7]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:10][C:8]=1[NH2:9].Cl.[C:24](=N)(OC)[CH3:25]>O>[O:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[C:11]1[CH:12]=[CH:13][C:7]2[N:6]([CH2:5][CH2:4][OH:3])[C:24]([CH3:25])=[N:9][C:8]=2[CH:10]=1
Reactant: COC(C)=N
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NCCO
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CCO
Yield: 42.6 %

Procedure:
To a methanol (5 mL) solution of 2-(2-(2-hydroxyethyl)aminoanilin-5-yl)benzoxazole (see Working Example 88-1) (0.10 g, 0.4 mmol) was added methyl acetimidate hydrochloride (0.08 g, 0.7 mmol), and this was heated to reflux for 3 hours. After the reaction was complete, water was added, and the precipitated crystals were filtered, and after being washed with water were dried to yield the title compound (0.05 g, 49% yield) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH:13]=C.C[OH:16]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH:13]=[O:16]
Reactant: CO
Reactant: C=Cc1cc(OC(F)(F)F)ccc1Cl
Solvent: ClCCl
Product: O=Cc1cc(OC(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Chloro-2-vinyl-4-(trifluoromethoxy)benzene (Description 26; 274 mg, 1.2 mmol) was dissolved in dichloromethane (15 mL) and methanol (5 mL) and the solution cooled to −78° C. Ozone was then bubbled through until the solution turned blue. Dimethyl sulfide (1 mL) was added and the solution allowed to stir to ambient temperature for 16 hours. Concentration yielded an oil which was purified by silica chromatography to give the title compound (120 mg, 0.53 mmol).
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([N:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[C@H:13]([C:23]([O:25]C)=[O:24])[O:12][C:11]1([CH3:28])[CH3:27])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.CO>[C:3]([O:7][C:8]([N:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[C@H:13]([C:23]([OH:25])=[O:24])[O:12][C:11]1([CH3:28])[CH3:27])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1c1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(F)cc2F)[C@H](C(=O)O)OC1(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.5 %

Procedure:
Under ice cooling, a solution of 31 mg of lithium hydroxide dissolved in 5 ml of water was added dropwise to a solution of 402 mg of methyl (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-(2,4-difluorophenyl)-5-oxazolidinecarboxylate dissolved in 10 ml of methanol. After the mixture was stirred at room temperature for 45 minutes, the reaction mixture was concentrated under reduced pressure. Water and diethyl ether were added to the residue, and the aqueous layer was collected by separation. The aqueous layer was adjusted to about pH 2 by adding 10% aqueous hydrochloric acid thereto under ice cooling and then extracted with chloroform. After the chloroform layer was washed with water and dried, the solvent was removed to obtain 385 mg of (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-(2,4-difluorophenyl)-5-oxazolidinecarboxylic acid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([C:2]2[S:6][C:5]([S:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:12]=3)(=[O:9])=[O:8])=[CH:4][CH:3]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1ccccc1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2ccccc2)s1
Yield: 19.3 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, starting from 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.05 mmol) and phenylboronic acid (7.3 mg, 0.06 mmol) affording 3.7 mg (19%) of the title compound. MS (ESI+) calcd for C17H13N5O2S2 383.051066, found 383.050986.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1/[CH:23]=[CH:24]\[C:25]([O:27][CH2:28]C)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Mg]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:10][C@H:9]1[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C\[C@@H]1C[C@@H](SCc2ccc(OC)cc2)CN1C(=O)OC(C)(C)C
Agent: [Mg]
Solvent: CO
Product: COC(=O)CC[C@@H]1C[C@@H](SCc2ccc(OC)cc2)CN1C(=O)OC(C)(C)C

Procedure:
3.78 g (9 mmol, 1eq) (E)- and/or (Z)-(2S,4R)-2-(2-Ethoxycarbonyl-vinyl)-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 42 ml MeOH were treated with 1.32 g (54 mmol, 6 eq) magnesium at RT for 5 h. The solvent was evaporated, the crude product dissolved in EtOAc and filtered from the solid particles. This process was repeated, the solvent evaporated yielding 3.67 g (quant) (2R,4R)-4-(4-Methoxy-benzylsulfanyl)-2-(2-methoxycarbonyl-ethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as colorless oil, MS: 410 (MH+).
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][C@H:15]([C@H:18]1[C@@H:21]([C:22]#[CH:23])[N:20]([C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])[C:19]1=[O:32])[CH2:16][CH3:17]>CN(C)C=O.C(OCC)(=O)C>[Si:6]([O:14][C@H:15]([C@H:18]1[C@@H:21]([C:22]#[CH:23])[N:20]([C@@H:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH3:25])[C:19]1=[O:32])[CH2:16][CH3:17])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: C#C[C@@H]1[C@H]([C@@H](O)CC)C(=O)N1[C@H](C)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#C[C@@H]1[C@H]([C@H](CC)O[Si](C)(C)C(C)(C)C)C(=O)N1[C@H](C)c1ccccc1
Reaction time: 8 h
Yield: 92.7 %

Procedure:
Imidazole (554 mg, 8.14 mmol) and tert-butyldimethylsilyl chloride (1.13 g, 7.52 mmol) were added to a solution of the compound (1.61 g, 6.26 mmol) prepared in Example 3 in N,N-dimethylformamide (7 ml) at room temperature in an argon atmosphere. After stirring overnight at this temperature, the mixture was diluted with ethyl acetate. The organic layer was washed with saturated aqueous solution of potassium hydrogensulfate and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel chromatography (hexane/ethyl acetate=20/1) to obtain 2.157 g (yield 93%) of the title compound as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[Cl:31][C:32]1[N:37]=[CH:36][N:35]=[C:34]([C:38](O)=[O:39])[CH:33]=1>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:38]([C:34]3[CH:33]=[C:32]([Cl:31])[N:37]=[CH:36][N:35]=3)=[O:39])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Reactant: O=C(O)c1cc(Cl)ncn1
Product: Nc1nccn2c([C@@H]3CCCN3C(=O)c3cc(Cl)ncn3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Yield: 6.2 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from the compound described in intermediate 2b and 6-chloropyrimidine-4-carboxylic acid, to afford the title compound (2.5 mg, 6.2%). Data: UPLC (C) Rt: 1.64 min; m/z 540.3 (M+H)+.
Reaction SMILES: O[C:2]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[OH:13])([CH3:4])[CH3:3].C([O-])=O.[NH4+]>CC(O)=O.O.[Pd]>[CH:2]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[OH:13])([CH3:4])[CH3:3]
Reactant: COc1ccc(O)c(C(C)(C)O)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(O)c(C(C)C)c1
Temperature: 100 °C
Yield: 96.8 %

Procedure:
To a solution of 2-(1-hydroxy-1-methyl-ethyl)-4-methoxy-phenol (50.57 g, 278 mmol) in 550 ml AcOH was added 10% Pd/C (as a slurry in 20 ml H2O) Ammonium formate (87.52 g, 1388 mmol) was added in portions. The mixture was warmed to 100° C. for 1 hour, cooled and filtered through a pad of celite. The celite pad was washed with ethyl acetate. The mother liquor was mixed with H2O and extracted with ethyl acetate. The combined organics were washed with H2O, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 2-isopropyl-4-methoxy-phenol (44.74 g, 97%) as a pale yellow oil.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH:13]1([S:18][C:19]2[N:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=3)[N:22]=[CH:21][C:20]=2[C:34](O)=[O:35])[CH2:17][CH2:16][CH2:15][CH2:14]1.Cl.[CH:38]12[CH2:47][CH:42]3[CH2:43][CH:44]([CH2:46][CH:40]([CH2:41]3)[CH:39]1[NH2:48])[CH2:45]2.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH:38]12[CH2:47][CH:42]3[CH2:43][CH:44]([CH2:46][CH:40]([CH2:41]3)[CH:39]1[NH:48][C:34]([C:20]1[CH:21]=[N:22][N:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=3)[C:19]=1[S:18][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1)=[O:35])[CH2:45]2
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)O)c2SC2CCCC2)cc1
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-n2ncc(C(=O)NC3C4CC5CC(C4)CC3C5)c2SC2CCCC2)cc1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (199 mg, 1.04 mmol) was added in one portion to 5-(cyclopentylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylic acid (Intermediate #93) (300 mg, 0.87 mmol), 2-Adamantanamine hydrochloride (179 mg, 0.95 mmol), 1-Hydroxybenzotriazole (140 mg, 1.04 mmol) and N-Ethyldiisopropylamine (0.450 mL, 2.60 mmol) in DMF (7 mL) at 20° C. under nitrogen. The resulting mixture was stirred at 20° C. for 18 hours.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].C(O)(=O)C.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([C:33](=O)[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:23]([C:28](OCC)=[O:29])[N:24]2[CH3:27])=[CH:20][CH:19]=1>O>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[N:10][N:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=4)[C:28](=[O:29])[C:23]=3[N:24]([CH3:27])[C:25]=2[CH:26]=1
Reactant: CCOC(=O)C(=O)c1c(C(=O)OCC)n(C)c2cc(Cl)ccc12
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1nn(-c2cccc(Cl)c2)c(=O)c2c1c1ccc(Cl)cc1n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
7.0 g (39.1 mmol) of 3-chlorophenylhydrazine hydrochloride are dissolved in 50 ml of water and 5 ml of a 35% sodium hydroxide solution. Extraction is carried out with diethyl ether. The organic phase is dried over sodium sulphate, filtered and concentrated under reduced pressure. An oil is obtained, to which are added 100 ml of acetic acid and 4.0 g (12.35 mmol) of ethyl 6-chloro-2-(ethoxycarbonyl)-1-methyl-α-oxo-1H-indole-3-acetate. The reaction mixture is stirred for 30 min at room temperature and then for 6 h at reflux. The mixture is cooled, 100 ml of water are added and an insoluble material is collected by filtration, washed with water and purified by chromatography on a silica column (eluant: dichloromethane/ethyl acetate: 98/2). 4.59 g (11 mmol) of compound are isolated in the form of a white solid.
Reaction SMILES: [OH:1][CH:2]1[C@@H:6]2[CH2:7][C:8](=[O:9])[N:5]2[C:4]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])=[C:3]1[CH3:18].N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C([O-])(=O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:25]([O:1][CH:2]1[C@@H:6]2[CH2:7][C:8](=[O:9])[N:5]2[C:4]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:15])[Cl:16])=[O:11])=[C:3]1[CH3:18])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C[C@H]2C1O
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC1C(C)=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C[C@@H]12

Procedure:
To a freshly prepared solution of 2,2,2-trichloroethyl 1-hydroxy-2-methylcarbapen-2-em-3-carboxylate in methylene chloride, prepared from 100 mg. (0.317 mmole) of the 1-beta-oxide by Examples 11 and 12) was added 24 microl. (0.317 mmole) of pyridine, 29 microl. (0.317 mmole) of acetic anhydride and 4 mg. of 4-dimethylaminopyridine. Infrared spectral analysis indicated clean conversion to the desired acetate. Following water wash and drying, evaporation to dryness gave 2,2,2-trichloroethyl 1-acetoxy-2-methylcarbapen-2-em-3-carboxylate [ir (CH2Cl2) 1780, 1725, 1700 cm-1 ; Rf 0.7-0.75 (4:1 chloroform:ethyl acetate].
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[C:10]([CH3:24])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([O:22][CH3:23])([CH3:21])[CH2:13][CH2:12]2>N1C=CC=CC=1>[C:1]([O:8][C:9]1[C:10]([CH3:24])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([O:22][CH3:23])([CH3:21])[CH2:13][CH2:12]2)(=[O:3])[CH3:2]
Reactant: COC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC1(C)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Acetic anhydride (135 mL) was added dropwise to a solution of 6-hydroxy-2-methoxy-2,5,7,8-tetramethylchroman (71.8 g, 303.85 mmol) in pyridine (90 mL) which was cooled by an ice/water bath. After the addition was complete, the reaction mixture was allowed to warm to ambient temperature. After stirring at ambient temperature for 18 h, the reaction mixture was added to 1 L of ice water. This mixture was allowed to stir for 2 h and was then extracted with diethyl ether (3×200 mL). The combined organics were washed with 2N HCl (200 mL), brine (200 mL), saturated sodium bicarbonate (200 mL) and brine (200 mL). The organic solution was dried (sodium sulfate) and concentrated in vacuo to give 74.11 g (87% crude yield) of a yellow solid which was used crude in the next reaction.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH:3]1[CH:9]([CH3:12])[C:10]#N.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=[O:25])C.O>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH:3]1[CH:9]([CH3:12])[CH:10]=[O:25]
Reactant: CC(C#N)C1CC(C)(C)CC1C
Reactant: CC(=O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C=O)C1CC(C)(C)CC1C
Temperature: 25 °C

Procedure:
2-(2,4,4-Trimethylcyclopentyl)propanenitrile 6 is placed in toluene at 10° C. under an inert atmosphere. 1.2 eq. of Dibal (diisobutylaluminum hydride) are added thereto dropwise. The reaction medium is stirred at ambient temperature for a few hours and is then poured onto a 20:40:40 mixture of acetic acid, water and ice. The aqueous phase is extracted once with toluene. The combined organic phases are washed with a sodium bicarbonate solution and then with an aqueous sodium chloride solution. After drying over magnesium sulfate, filtering through paper and evaporating the solvent, the crude product, obtained in the form of three diastereomers observed by GC in proportions of 73:16:11, is distilled under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:31]([C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:49])OC2C=CC=CC=2)=[CH:36][CH:35]=1)(=[O:33])[NH2:32]>CN(C=O)C>[CH3:30][NH:29][C:27]([NH:26][C:23]1[CH:22]=[CH:21][C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:41]([NH:40][C:37]4[CH:36]=[CH:35][C:34]([C:31]([NH2:32])=[O:33])=[CH:39][CH:38]=4)=[O:49])=[CH:7][CH:6]=3)[N:9]=2)=[CH:25][CH:24]=1)=[O:28]
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3CCOCC3)n2)cc1
Reactant: NC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(NC(=O)Nc4ccc(C(N)=O)cc4)cc3)nc(N3CCOCC3)n2)cc1
Temperature: 90 °C
Yield: 5.3 %

Procedure:
To a solution of 1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea (0.6 g, 1.5 mmol) and triethylamine(4-5 mL) in dry DMF (10 mL), phenyl 4-carbamoylphenylcarbamate (1.15 g, 4.5 mmol).) was added at room temperature and mixture was heated to 90° C. for 10 hours under nitrogen atmosphere. After cooling to room temperature reaction mixture was quenched with ice water and resulting solid was filtered to get crude product. Crude product was purified by Preparative HPLC to give 4-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide (45 mg, 5.3% yield).