Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([F:15])[CH:14]=1)[NH:11][C:10]1[CH:9]([CH2:16][C:17]([OH:19])=[O:18])[CH2:8][CH2:7][CH2:6][C:5]2=1.[H-].[Na+].[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br>CN(C=O)C.O>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][N:11]1[C:10]2[CH:9]([CH2:16][C:17]([OH:19])=[O:18])[CH2:8][CH2:7][CH2:6][C:5]=2[C:4]2[C:12]1=[C:13]([F:15])[CH:14]=[C:2]([F:1])[CH:3]=2
Reactant: O=C(O)CC1CCCc2c1[nH]c1c(F)cc(F)cc21
Reactant: Clc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CC1CCCc2c1n(Cc1ccccc1Cl)c1c(F)cc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.3 %

Procedure:
A solution of 200 mg of 6,8-difluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid from Example 30 Step II in 8 cc of DMF was added portionwise 40 mg of sodium hydride. The resulting mixture was stirred for 30 min. at room temperature and 185 mg of o-chlorobenzyl bromide was then added. After stirring overnight at room temperature, the resulting mixture was diluted with water and washed with ether. The aqueous layer was acidified with (1N) HCl and extracted with ether. The ethereal layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified on preparative plates (silica gel) eluting with CHCl3 :MeOH:NH4OH (8:4:1) to yield 98 mg of 9-o-chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid, m.p. 197°-198° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.[Br:19]Br>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Br:19][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][C:2]=1[CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(Cc2cc3ccccc3o2)cc1
Reactant: BrBr
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(Cc2oc3ccccc3c2Br)cc1
Temperature: 2 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1.2 g (5 mmol) of 4-(benzofuran-2-yl)methyl-benzonitrile in 25 ml methylene chloride, a solution of 0.8 g (5 mmol) of bromine in 5 ml carbon tetrachloride is added dropwise at 2° C. The solution is stirred for 90 minutes at 2° C., the precipitate formed is suction filtered, washed with a little methylene chloride and dried.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][CH:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9][CH2:8]1.C1COCC1.CO.[ClH:28]>O1CCOCC1>[ClH:28].[ClH:28].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][CH:10]([NH2:13])[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccccn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: NC1CCN(c2ccccn2)CC1
Yield: 85 %

Procedure:
A solution of tert-butyl (1-pyridin-2-ylpiperidin-4-yl)carbamate (0.64 g, 2.31 mmol) in HCl in Dioxane (4M, 3.5 ml), THF (2.5 ml) and MeOH (2 ml) was stirred at rt for 17 h. The reaction mixture was filtered, the residue washed with EtOAc and dried to give the title compound (0.49 mg, 85%) as a solid. 1H NMR (500 MHz, D2O): 7.91 (dd, 1H), 7.78 (d, 1H), 7.22 (d, 1H), 6.88 (t, 1H), 4.12 (d, 2H), 3.56-3.48 (m, 1H), 3.26 (t, 2H), 2.15 (d, 2H), 1.67 (dq, 2H); 13C NMR (D2O): 152.1, 144.7, 135.9, 113.3, 47.6, 44.7, 28.8; Mass Spectrum: M+H 178
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:42]=[CH:41][C:7]([C:8]([NH:10][C:11]2[C:12]([NH:24][C:25](=[O:40])[C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH2:38][CH2:37][CH2:36][N:35]([CH3:39])[CH2:34][CH2:33]4)=[CH:28][CH:27]=3)=[C:13]([CH:21]=[CH:22][CH:23]=2)[O:14][CH2:15][C:16]([O:18]CC)=[O:17])=[O:9])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>CO>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2[C:12]([NH:24][C:25](=[O:40])[C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH2:38][CH2:37][CH2:36][N:35]([CH3:39])[CH2:34][CH2:33]4)=[CH:28][CH:27]=3)=[C:13]([CH:21]=[CH:22][CH:23]=2)[O:14][CH2:15][C:16]([OH:18])=[O:17])=[O:9])=[CH:41][CH:42]=1
Reactant: CCOC(=O)COc1cccc(NC(=O)c2ccc(OC)cc2)c1NC(=O)c1ccc(N2CCCN(C)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)Nc2cccc(OCC(=O)O)c2NC(=O)c2ccc(N3CCCN(C)CC3)cc2)cc1
Reaction time: 2 h
Yield: 76.1 %

Procedure:
Ethyl (3-[(4-methoxybenzoyl)amino]-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}phenoxy)acetate hydrochloride (350 mg) was dissolved in 6 ml of methanol, then 1.8 ml of a 1N aqueous solution of sodium hydroxide was added at room temperature and the mixture was stirred for 2 hours. 1N hydrochloric acid (1.8 ml) was further added and the mixture was concentrated in vacuo. The resulting residue was purified by ODS column chromatography using 0.001N hydrochloric acid-acetonitrile (1:1) as an eluting solvent to give 254 mg of (3-[(4-methoxybenzoyl)amino]-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}phenoxy)acetic acid hydrochloride.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1.[CH3:31][NH2:32].[BH4-].[Na+]>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:32][CH3:31])=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1
Reactant: CN
Reactant: O=Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
Using General Procedure B: To a solution of 4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde (AMD9882) (120 mg, 0.30 mmol) in MeOH (2 mL) was added methylamine (2.0 M solution in methanol, 1 mL, 2.00 mmol) and the resultant solution was stirred at room temperature for 5 hours. Solid NaBH4 (18 mg, 0.48 mmol) was added to the solution and the mixture was stirred at room temperature for an additional 30 minutes. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2/CH3OH/NH4OH) provided the free base of the title compound (74 mg, 59%) as a white solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7](S)[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:15]>>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:15])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CC(C)Oc1cccc(S)c1
Product: COc1ccc(C(=O)Cc2cccc(OC(C)C)c2)cc1

Procedure:
3-Isopropoxythiophenol and 2-bromo-4′-methoxyacetophenone were converted to the title compound by the procedure of Preparation 1.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:23][N:24]4[CH2:27][CH:26]([N:28]5[CH2:33][CH2:32][NH:31][C:30](=[O:34])[CH2:29]5)[CH2:25]4)[N:14]3C3CCCCO3)=[C:10]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:9]=2)[C:6]2[CH:41]=[CH:42][CH:43]=[CH:44][C:5]=2[N:4]=1)[CH3:2].Cl>O1CCOCC1>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:23][N:24]4[CH2:25][CH:26]([N:28]5[CH2:33][CH2:32][NH:31][C:30](=[O:34])[CH2:29]5)[CH2:27]4)[NH:14]3)=[C:10]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:9]=2)[C:6]2[CH:41]=[CH:42][CH:43]=[CH:44][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCNC(=O)C4)C3)n(C3CCCCO3)c2n1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCNC(=O)C4)C3)[nH]c2n1
Reaction time: 24 h

Procedure:
To a solution of 4-{1-[2-(2-ethylbenzoimidazol-1-yl)-6-morpholin-4-yl-9-(tetrahydropyran-2-yl)-9H-purin-8-ylmethyl]azetidin-3-yl}piperazin-2-one (470 mg, 0.78 mmol) in dioxane (20 mL) was added 4M HCl in dioxane (1 mL). The resulting suspension was stirred at r.t for 24 h then the precipitate collected by filtration, washing with dioxane. The resulting solid was partitioned between EtOAc and H2O and the aqueous layer basified to pH 11 with NH4OH. The aqueous phase was neutralised to pH 7 with HCl then loaded onto an Isolute® SCX-2 cartridge which was washed with H2O and MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by coulmn chromatography (C18, MeOH:H2O, 30-95%) then loaded onto an Isolute® SCX-2 cartridge which was washed with H2O and MeOH and the product eluted with 2M NH3/MeOH affording 812 (69 mg, 17%). LCMS (method I): RT 2.16 min, [M+H]+ 517.3. 1H NMR (DMSO, 400 MHz): δ 7.95-7.94 (1 H, m), 7.73 (1 H, s), 7.63-7.62 (1 H, m), 7.25-7.22 (2 H, m), 4.24 (4 H, brd s), 3.79-3.74 (6 H, m), 3.46 (2 H, s), 3.23 (3 H, q, J=7.46 Hz), 3.16-3.04 (5 H, m), 2.84 (2 H, s), 2.45-2.44 (2 H, m), 1.31 (3 H, t, J=7.45 Hz)
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([C:18]3[CH2:19][CH2:20][N:21]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:22][CH:23]=3)=[C:13]([F:31])[CH:12]=2)[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.O>[NH2:1][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([C:18]3[CH2:19][CH2:20][N:21]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:22][CH:23]=3)=[C:13]([F:31])[CH:12]=2)[CH2:6]1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2cc(F)c(C3=CCN(Cc4ccccc4)CC3)c(F)c2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: NC[C@H]1CN(c2cc(F)c(C3=CCN(Cc4ccccc4)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.5 %

Procedure:
(5R)-5-(Azidomethyl)-3-[4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-3,5-difluorophenyl]-1,3-oxazolidin-2-one (WO 0181350) (10.60 g, 24.97 mmol) was dissolved in acetonitrile (250 ml) and water (25 ml). Triphenylphosphine (7.86 g, 29.96 mmol) was added and the suspension was stirred at room temperature for approximately 16 h. The reaction mixture was concentrated under vacuum. The crude material was purified by chromatography on silica gel using 2.5-5% methanol in dichloromethane to give 7.03 g of the title product.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([OH:14])[CH2:9][CH2:10][CH2:11][C:12]#[CH:13].C(N(CC)CC)C>ClCCl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:14])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C#CCCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCCCC#Cc1cccnc1

Procedure:
A dry 250 ml B 3-neck flask was fitted with a gas inlet tube extending nearly to the bottom of the flask and was charged with 9.81 ml of 3-bromopyridine, 11.8 g of 5-hexyn-1-ol, 40 ml of distilled triethylamine and 60 ml of dichloromethane. The mixture was degassed with argon for 15 minutes and 0.70 g of bis(triphenylphosphine)palladium dichloride and 0.13 g of cuprous iodide were added. The flask was evacuated and filled three times with argon and the reaction was heated to reflux for 2 hours. The cooled mixture was diluted with dichloromethane and was washed with water and brine, dried (potassium carbonate) and concentrated to 20 g of a dark red oil which was used directly in the next step. A portion was chromatographed over 70 g of silica gel eluting with 1:1 ethyl acetate-hexane containing 1% triethylamine to yield a colorless oil which was evaporatively distilled, bp 145°-150° C./0.1 mm to give an analytical sample of 6-(3-pyridinyl)-5-hexyn-1-ol.
Reaction SMILES: Br[CH2:2][C:3]([CH2:5]Br)=[O:4].[C:7]1([P:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])[OH:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[F-].[K+].CN(C=O)C>[C:7]1([P:13]([O:14][CH2:2][C:3]([CH2:5][O:15][P:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:14])=[O:4])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(CBr)CBr
Reactant: O=P(O)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(COP(=O)(c1ccccc1)c1ccccc1)COP(=O)(c1ccccc1)c1ccccc1

Procedure:
(2S)-4-(tert-butoxy)-2-({[(5R)-5-isopropyl-3-(1-isoquinolinyl)-4,5-dihydro-5-isoxazolyl]carbonyl}amino)-4-oxobutanoic acid [obtained by coupling reaction of Compound (VIIf) with Asp(O-t-Bu)-OMe and hydrolysis] was reacted according to the same procedure as Preparation 5 to give bromomethyl ketone derivative (tert-butyl (3S)-5-bromo-3-({[(5R)-5-isopropyl-3-(1-isoquinolinyl)-4,5-dihydro-5-isoxazolyl]carbonyl}amino)-4-oxopentanoate). This bromomethyl ketone derivative was reacted with diphenylphosphinic acid in KF/DMF (see Preparation 5) to give diphenylphosphoryloxymethyl ketone derivative, which was then reacted according to the same procedure as Example 2 to give the title compound (Compound of Example 60).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[C:17]3[CH:18]=[C:19]([C:22]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=4)=[O:23])[CH:20]=[CH:21][C:16]=3[O:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.F[C:37](F)(F)[C:38]1C=C(S(Cl)(=O)=O)C=CC=1>>[CH2:37]([O:30][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:25]([NH:24][C:22]([C:19]2[CH:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]([S:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:34])([F:1])[F:35])[CH:4]=4)(=[O:10])=[O:11])[C:17]=3[CH:18]=2)=[O:23])=[CH:26][CH:27]=1)[CH3:38]
Reactant: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(C(F)(F)F)c2)CCO3)cc1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(C(F)(F)F)c2)CCO3)cc1

Procedure:
4-{[4-(3-Trifluoromethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=505.1 (M−H), was prepared as described for example 14, steps 1 to 8. Step 7 was performed using 3-trifluoromethyl-benzenesulfonyl chloride and yielded 4-{[4-(3-trifluoromethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][CH2:18][NH:19][C:20](OC(C)(C)C)=[O:21])[N:13]=[C:12]([NH2:27])[N:11]=2)[C:7]([CH3:28])=[CH:6][C:5]=1[O:29][CH3:30].FC(F)(F)C(O)=O.[C:39]([O:43][C:44]([CH2:46][NH:47][CH2:48][CH2:49][CH2:50]C(O)=O)=[O:45])([CH3:42])([CH3:41])[CH3:40].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>ClCCl>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][CH2:18][NH:19][C:20](=[O:21])[CH2:50][CH2:49][CH2:48][NH:47][CH2:46][C:44]([O:43][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:45])[N:13]=[C:12]([NH2:27])[N:11]=2)[C:7]([CH3:28])=[CH:6][C:5]=1[O:29][CH3:30]
Reactant: COC(=O)c1cc(-c2cc(SCCNC(=O)OC(C)(C)C)nc(N)n2)c(C)cc1OC
Reactant: CC(C)(C)OC(=O)CNCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(-c2cc(SCCNC(=O)CCCNCC(=O)OC(C)(C)C)nc(N)n2)c(C)cc1OC
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 90.4 %

Procedure:
5-[2-Amino-6-(2-tert-butoxycarbonylaminoethylsulfanyl)pyrimidin-4-yl]-2-methoxy-4-methylbenzoic acid methyl ester (88 mg, 0.20 mmol) obtained in Step 1 of Example 3-1 was dissolved with dichloromethane (2.5 ml) in a reaction vessel, and cooled to 0° C. Trifluoroacetic acid (0.7 ml) was added to the solution, and stirred for 2.5 hours while gradually warming from 0° C. to room temperature. The reaction solution was concentrated under reduced pressure, and then benzene (1.5 ml) was added to the resulting residue. The solution was again concentrated under reduced pressure. This treatment was repeated three times, and the obtained pale yellow oily material was dissolved in N,N-dimethylformamide (3.0 ml). 4-tert-Butoxycarbonylmethylaminobutanoic acid (65 mg, 0.3 mmol) and N-hydroxybenzotriazole (54 mg, 0.4 mmol) were added to the solution. Diisopropylethylamine (0.5 ml, 2.8 mmol) was added to the solution, and then 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (115 mg, 0.6 mmol) was added. The resulting mixture was stirred at room temperature for 13 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and extracted with ethyl acetate (100 ml). The ethyl acetate solution was sequentially washed with 1N hydrochloric acid (50 ml), water (50 ml), a saturated aqueous sodium bicarbonate solution (50 ml), water (50 ml), and a saturated aqueous sodium chloride solution (50 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate (10 g). After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate to ethyl acetate:methanol=25:1) to yield 5-(2-amino-6-{2-[4-(tert-butoxycarbonylmethylamino)butyrylamino]ethylsulfanyl}pyrimidin-4-yl)-2-methoxy-4-methylbenzoic acid methyl ester (99 mg) as a colorless syrup-like material.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([NH2:11])=[O:10])[CH:6]=[CH:5][CH:4]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[C:12]([O:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([NH2:11])=[O:10])[CH:6]=[CH:5][CH:4]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1cccc(CO)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCc1cccc(C(N)=O)n1

Procedure:
A mixture of 6-hydroxymethyl-2-pyridinecarboxamide (80 g) and acetic anhydride (198.8 ml) in tetrahydrofuran (800 ml) was heated under reflux for 24 hours. The reaction mixture was added to a mixture of ethyl acetate and water and the mixture was adjusted to pH 8 with potassium carbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated to give 6-acetoxymethyl-2-pyridinecarboxamide (93.34 g).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[NH:19][CH:20]1[C:35](=[O:36])[N:22]2[C:23]([C:28]([O:30]C(C)(C)C)=[O:29])=[C:24]([CH3:27])[CH2:25][S:26][C@H:21]12>>[CH3:8][O:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[NH:19][CH:20]1[C:35](=[O:36])[N:22]2[C:23]([C:28]([OH:30])=[O:29])=[C:24]([CH3:27])[CH2:25][S:26][C@H:21]12
Reactant: COn1c(NC2C(=O)N3C(C(=O)OC(C)(C)C)=C(C)CS[C@H]23)nc2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: COn1c(NC2C(=O)N3C(C(=O)O)=C(C)CS[C@H]23)nc2ccccc21

Procedure:
The process described in Example 7, but using only TFA at 0°, was repeated using t-butyl 7-(1-methoxybenzimidazol-2-yl)amino-3-methylceph-3-em-4-carboxylate as starting material to give 7-(1-methoxybenzimidazol-2-yl)amino-3-methylceph-3-em-4-carboxylic acid as the hydrated trifluoroacetate salt (69%) having the following n.m.r. in d6DMSO:2.10 (s, 3H); 3.40 (d, 1H); 3.60 (d, 1H); 3.72 (s, 3H); 5.23 (d, 1H); 5.67 (d, 1H); 7.18-7.58 (m, 4H).
Reaction SMILES: [OH-].[K+].Cl.[CH2:4]([NH2:6])[CH3:5].[C:7]([N:12]1[CH2:17][CH:16]([CH3:18])[C:15](=O)[CH:14]([CH3:20])[CH2:13]1)([O:9][CH2:10][CH3:11])=[O:8].C([BH3-])#N.[Na+]>CO>[CH2:4]([NH:6][CH:15]1[CH:16]([CH3:18])[CH2:17][N:12]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:13][CH:14]1[CH3:20])[CH3:5]
Reactant: CCN
Reactant: CCOC(=O)N1CC(C)C(=O)C(C)C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CO
Product: CCNC1C(C)CN(C(=O)OCC)CC1C
Reaction time: 6 h

Procedure:
Powdered KOH (2.8 g, 50 mmol) was added in portions to the stirred solution of ethylamine hydrochloride (4.0 g, 50 mmol) in methanol (50 ml) and 1-carbethoxy-3,5-dimethyl-4-piperidinone (5.0 g, 25.12 mmol) obtained by a procedure as described in Example 25 (Step-1), was added to it. The resulting reaction mixture was stirred for 6 hr. A solution of sodium cyanoborohydride (1.6 g, 25.12 mmol) in methanol (10 ml) was added dropwise to it and stirring was continued for 16 hr. The reaction mixture was concentrated to dryness. The obtained residue was dissolved in water and extracted with chloroform. Chloroform layer was extracted with 50% HCl and acid layer was basified with KOH (20%) solution. The oil thus separated was extracted with chloroform, dried (Na2SO4) and concentrated to give Mixtures A+B of 4-ethylamino-1-carbethoxy-3,5-dimethylpiperidine as an oil. Yield 5.6 g (97.7%), C12H24N2O2, m/z 229 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[C:4]([CH:10]=[CH:11][C:12]([CH3:16])([OH:15])[CH:13]=[CH2:14])=[C:3]1[CH3:17].[Cl-].[OH-].[K+].S(OC)(O[CH3:25])(=O)=O>CCCCCC.C(OCC)C.CCCCCCCC(OCC(OC(CCCCCCC)=O)COC(CCCCCCC)=O)=O>[O:1]=[C:2]1[CH2:7][CH2:6][C:5]([CH3:8])([CH3:9])[C:4]([CH:10]=[CH:11][C:12]([O:15][CH3:25])([CH3:16])[CH:13]=[CH2:14])=[C:3]1[CH3:17]
Reactant: COS(=O)(=O)OC
Reactant: C=CC(C)(O)C=CC1=C(C)C(=O)CCC1(C)C
Agent: CCCCCCCC(=O)OCC(COC(=O)CCCCCCC)OC(=O)CCCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOCC
Product: C=CC(C)(C=CC1=C(C)C(=O)CCC1(C)C)OC
Yield: 99.6 %

Procedure:
2.34 g of 1-(3-oxo-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methyl-1,4-pentadien-3-ol were dissolved in 15 ml of hexane and 5 ml of diethyl ether, treated with 2 drops of tricaprylm thylammonium chloride and 4.54 ml of aqueous potassium hydroxide solution (prepared from 70 g of powdered potassium hydroxide and 50 ml of water) and stirred well. 1.98 g of dimethyl sulphate were subsequently added to the mixture and the course of the reaction was followed by gas chromatography. After stirring at room temperature for 4 hours (product/educt ratio 99.7:0.3), the mixture was poured on to ice. The organic phase was separated, washed neutral with water, dried over sodium sulphate and concentrated under a water-jet vacuum. There were obtained 2.47 g of 1-(3-oxo-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methoxy-3-methyl-1,4-pentadiene as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[CH:41][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([N:26]3[CH2:30][CH:29]4[CH2:31][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH:28]4[CH2:27]3)=[N:9]2)=[CH:5][CH:4]=1.[F:43][C:44]1[CH:49]=[CH:48][C:47]([N:50]2[C:55](=[O:56])[C:54]([C:57](O)=[O:58])=[CH:53][CH:52]=[N:51]2)=[CH:46][CH:45]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:57]([C:54]2[C:55](=[O:56])[N:50]([C:47]3[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=3)[N:51]=[CH:52][CH:53]=2)=[O:58])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:42][CH:41]=3)[N:9]=[C:10]([N:26]3[CH2:30][CH:29]4[CH2:31][N:32]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:33][CH:28]4[CH2:27]3)[C:11]=12
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(N3CC4CN(C(=O)OC(C)(C)C)CC4C3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(N3CC4CN(C(=O)OC(C)(C)C)CC4C3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
A round-bottomed flask was charged with tert-butyl 5-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (44.8 mg, 0.0780 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (54.8 mg, 0.234 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (74.7 mg, 0.390 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (52.7 mg, 0.390 mmol), N-ethyl-N-isopropylpropan-2-amine (101 mg, 0.780 mmol) and DMF (10 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction was partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude material was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (42.5 mg, 68.9%). LRMS (APCI pos): m/e 691 (M−99).