Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])=[CH:22][C:21]3=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])=[CH:22][C:21]2=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccc(F)cc2F)=CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2ccc(F)cc2F)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A solution of (S)-2-[4-(2,4-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.62 g, 1.24 mmol) in methanol (12.4 mL) at 25° C. was treated with p-toluenesulfonic acid monohydrate (35 mg, 0.18 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction was diluted with ethyl acetate (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 2-5% methanol/dichloromethane gradient) afforded (S)-2-[4-(2,4-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.46 g, 80%) as an off-white solid: HR-ES-MS m/z calculated for C22H26N4O5F2 [M+H]+ 465.1944, observed 465.1944; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H), 1.34-1.50 (m, 1H), 1.50-1.67 (m, 1H), 1.67-1.89 (m, 1H), 3.21-3.32 (m, 2H), 3.78 (br. s., 1H), 3.87 (dd, J=13.6, 7.5 Hz, 1H), 4.09 (dd, J=13.6, 3.6 Hz, 1H), 4.22 (d, J=18.4 Hz, 1H), 4.60 (d, J=18.4 Hz, 1H), 4.71 (t, J=5.4 Hz, 1H), 4.81-4.99 (m, 3H), 6.41 (d, J=2.1 Hz, 1H), 7.12-7.26 (m, 1H), 7.48-7.66 (m, 3H), 10.78 (s, 1H).
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)#[N:3].[C:26]1(=O)[CH2:29][CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(Cl)Cl>[ClH:1].[CH:26]1([N:21]2[C@@H:20]([CH3:25])[CH2:19][N:18]([C:16]([CH:13]3[CH2:14][CH2:15][N:10]([C:7]4[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:9][CH:8]=4)[CH2:11][CH2:12]3)=[O:17])[CH2:23][C@H:22]2[CH3:24])[CH2:29][CH2:28][CH2:27]1
Reactant: O=C1CCC1
Reactant: C[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cc3)CC2)C[C@H](C)N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cc3)CC2)C[C@H](C)N1C1CCC1
Yield: 15.4 %

Procedure:
(2R,6S)-4-[1-(4-Cyanophenyl)-piperidine-4-carbonyl]-2,6-dimethylpiperazine hydrochloride (D13)(0.30 g), TEA (0.4 ml), cyclobutanone (0.13 g) and sodium triacetoxyborohydride (0.40 g) in DCM (5 ml) were heated to 100° C. in a microwave reactor for 5 min. The reaction mixture was then washed with saturated potassium carbonate solution (2×30 ml), and brine (30 ml). The organic layer was then dried (MgSO4) and evaporated give the crude product which was purified by column chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing the required product were evaporated to give the free base compound which was converted to the HCl salt by redissolving in DCM and then treating with excess hydrogen chloride (1 M solution in diethyl ether), evaporating and then crystallising from acetone to give the title compound (E33) as a pale grey solid (0.053 g). MS electrospray (+ve) 381 (MH+). 1H NMR δ [DMSO-d6]: 11.28 plus 10.10 (1H, m, rotomers), 7.59 (2H, d, J=8.4 Hz), 7.00 (2H, d, J=8.OHz), 4.31-3.73 (6H, m), 3.60-3.22 (3H, m), 2.97 (3H, m), 2.50-2.08 (4H, m), 1.78-1.61 (6H, m), 1.50-1.10 (6H, m).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]([C:33]([OH:35])=[O:34])[C:24]=1[C:36](O)=[O:37].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:36]([C:24]3[C:25]([C:33]([OH:35])=[O:34])=[CH:26][C:27]4[C:32]([CH:23]=3)=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:37])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: O=C(O)c1cc2ccccc2cc1C(=O)O
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc2ccccc2cc1C(=O)O

Procedure:
To 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (0.1 mmol) and 2,3-naphthalenedicarboxylic acid (0.1 mmol) was dissolved in DCM (3 mL) was added HOBt (1.0 eq, 14.0 mg) and EDC (1.0 eq, 19.0 mg). The resultant solution was stirred overnight. The solution was purified by preparative hplc (Gilson) to yield 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-naphthalenecarboxylic acid. This compound was dissolved in 3 mL of DCM with 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (41.3 mg, 0.1 mmol) to which was added HOBt (1.0 eq, 14.0 mg) and EDC (1.0 eq, 19.0 mg). The resultant solution was stirred overnight and purified by preparative hplc (Gilson) to give 1,1-dimethylethyl (2S)-4-[(5′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-naphthalenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate. This compound was then dissolved in 2 mL of dioxane:MeOH (3:1). Three drops of HCl (concentrated) were added to the resultant solution and it was heated at 60° C. for 1 h. The solution was applied to an amine column which was rinsed with 10 mL of dioxane:MeOH (3:1) to afford 2.7 mg (3.4%) of the above named product. LC-MS m/z 798 (M+H)+, 1.42 min (ret time).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17]2)([CH2:11][C:12]([F:15])([F:14])[F:13])[C:9]#[CH:10])=[CH:4][CH:3]=1>C(O)C.O=[Pt]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17]2)([CH2:9][CH3:10])[CH2:11][C:12]([F:14])([F:15])[F:13])=[CH:4][CH:3]=1
Reactant: C#CC(CC(F)(F)F)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Agent: O=[Pt]=O
Solvent: CCO
Product: CCC(CC(F)(F)F)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21

Procedure:
To a solution of the product of Step D (100 mg, 0.21 mmol) in ethanol (3 mL) was added PtO2 (10 mg, 0.044 mmol) at room temperature under H2 atmosphere for 2 h. The solid was filtered off and filtrate was concentrated in vacuo to obtain the title compound as colorless oil. LC/MS m/z=468.1[M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].C([O:14][C:15](=O)[CH:16]([CH3:20])[C:17]([CH3:19])=O)C>>[CH3:11][O:10][C:8]1[CH:7]=[C:6]2[C:4](=[C:3]([O:2][CH3:1])[CH:9]=1)[N:5]=[C:17]([CH3:19])[C:16]([CH3:20])=[C:15]2[OH:14]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: COc1ccc(N)c(OC)c1
Product: COc1cc(OC)c2nc(C)c(C)c(O)c2c1

Procedure:
Prepared according to procedure R using 2,4-dimethoxy aniline (1.99 g, 13.0 mmol), ethyl-2-methyl-acetoacetate (3.7 mL, 26.2 mmol), and PPA (6.78 g, 67.8 mmol) to afford 6,8-dimethoxy-2,3-dimethylquinolin-4-ol. Mass Spectrum (ESI) m/e=234.1 (M+1).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:9]=1[C:10](Cl)=[O:11]>C(Cl)Cl.O>[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:9]=1[C:10]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[O:11]
Reactant: CC(C)(N)CO
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: ClCCl
Solvent: O
Product: CC(C)(CO)NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a 0° C. solution of 2-amino-2-methylpropanol (10.1 g, 113.3 mmol) in CH2Cl2 (75 mL) under nitrogen was added dropwise a solution of 2,6-difluorobenzoyl chloride (10.0 g, 56.6 mmol) in CH2Cl2 (50 mL). The reaction mixture was then warmed to room temperature and stirred overnight. The reaction mixture was diluted with H2O, and the aqueous phase was extracted with CH2Cl2, dried (MgSO4) and concentrated. Purification via trituration with hexanes afforded 12.05 g (93%) of the amide, a white solid. 1H NMR (400 MHz, CDCl3) δ 1.41 (s, 6 H), 3.66-3.75 (m, 2 H), 3.77-3.87 (m, 1 H), 5.94 (s, 1 H), 6.90-6.99 (m, 2 H), 7.31-7.41 (m, 1 H).
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:16]([CH:19]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:21][CH:20]1O)=[N+:17]=[N-:18]>C(Cl)Cl>[N:16]([CH:19]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:21][CH:20]1[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:17]=[N-:18]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: [N-]=[N+]=NC1CCCN(C(=O)OCc2ccccc2)CC1O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CN(C(=O)OCc2ccccc2)CCCC1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.3 %

Procedure:
TBDMSOTf (0.010 g, 0.038 mmol) was added drop-wise to the mixture of benzyl 4-azido-3-hydroxyazepane-1-carboxylate (0.010 g, 0.034 mmol, WO 2010/114971, Example 90.5) and TEA (0.0096 mL, 0.069 mmol) in DCM (50 mL). The mixture was stirred at about 25° C. for about 3 h. The mixture was concentrated under reduced pressure and the residue was purified by Prep-TLC (EtOAc/pet ether ¼) to give benzyl 4-azido-3-(tert-butyldimethylsilyloxy)azepane-1-carboxylate (0.005 g, 36%). The material was used without characterization.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.Cl.[Cl:11][C:12]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:13]=1[NH2:14]>>[Cl:11][C:12]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:13]=1[NH:14][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: COc1ccc(Cl)c(N)c1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: Cl
Product: COc1ccc(Cl)c(Nc2cc(C)nc(N)n2)c1

Procedure:
The title compound was prepared from a mixture of 2-amino-4-chloro-6-methyl-pyrimidine (100 mg, 0.696 mmol) and 2-chloro-5-methoxyaniline hydrochloride (203 mg, 1.05 mmol) similar to Example 117 and isolated as a white solid (132 mg, 72%). 1H NMR (CDCl3): 7.77 (d, J=2.7 Hz, 1H), 7.28 (d, J=9.0 Hz, 6.74 (s, 1H), 6.57 (dd, J=3.0, 8.7 Hz, 1H), 6.04 (s, 1H), 4.81 (s, 2H), 3.82 (s, 3H), 2.26 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]([C:11]1[C:12](=[O:20])[NH:13][CH:14]=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:29]>CN(C)C=O.O>[CH2:21]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([C:11]1[C:12]([O:20][CH3:29])=[N:13][CH:14]=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=1)=[O:10])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CI
Reactant: O=C(O)c1c[nH]c(=O)c(C(=O)N(Cc2ccccc2)Cc2ccccc2)c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(C(=O)O)cc1C(=O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
To a solution of 0.5 g (1.4 mmol) 2-Oxo-1,2-dihydro-pyridine-3,5-dicarboxylic acid bis-benzylamide in 10 mL of N,N-dimethylformamide (DMF) was added 0.25 g (1.9 mmol) diisopropylethylamine amine followed by 0.19 g (1.4 mmol) iodomethane. The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with saturated aqueous NaCl solution, and dried over MgSO4. The product was crystallized from ethyl acetate, providing 0.24 g (46% yield) of the title compound. MS: m/z (APCI, AP+) 376.3 [M−]+. CHN Analysis: Calcd: C, 70.38; H, 5.64; N, 11.19. Found: C, 70.05; H, 5.49; N, 10.89.
Reaction SMILES: [NH:1]=[C:2]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([NH:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:20])=[O:19])[CH:13]=2)[CH:9]=[CH:10][CH:11]=1)SC.[CH2:35]([O:37][CH:38]([O:41][CH2:42][CH3:43])[CH2:39][NH2:40])[CH3:36].ClCCl.CCOC(C)=O>C(O)CC>[CH2:35]([O:37][CH:38]([O:41][CH2:42][CH3:43])[CH2:39][NH:40][C:2]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([NH:21][CH:22]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:20])=[O:19])[CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=[NH:1])[CH3:36]
Reactant: CCOC(=O)CC(NS(=O)(=O)c1cccc(-c2cccc(NC(=N)SC)c2)c1)c1ccccc1
Reactant: CCOC(CN)OCC
Solvent: CCOC(C)=O
Solvent: CCCO
Solvent: ClCCl
Product: CCOC(=O)CC(NS(=O)(=O)c1cccc(-c2cccc(NC(=N)NCC(OCC)OCC)c2)c1)c1ccccc1

Procedure:
1.25 g Ethyl 3-{[(3′-{[imino(methylsulfanyl)methyl]amino}[1,1′-biphenyl]-3-yl)-sulfonyl]amino}-3-phenyl-propanoate 14.1.2 were dissolved in 20 ml n-propanol and 0.32 g aminoacetaldehyde-diethylacetal were added dropwise to the boiling solution within 6 h. flash chromatography (dichloromethane/acetic acid ethyl ester4+1) yielded 1.1 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[CH:19]=[CH:20]/[CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][N:24]2[CH2:25][CH2:26][CH:21](/[CH:20]=[CH:19]/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[F:12])[CH2:22][CH2:23]2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: Fc1ccccc1/C=C/C1CCNCC1
Reactant: COc1ncc(Cl)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ncc(Cl)cc1CN1CCC(/C=C/c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 58.2 %

Procedure:
200 mg of 5-chloro-2-methoxy-3-pyridinecarboxaldehyde and 263 mg of 4-[(E)-2-(2-fluorophenyl)-1-ethenyl]piperidine were dissolved in 5 ml of 1,2-dichloroethane. To the mixture were added 0.09 ml of acetic acid and 339 mg of sodium triacetoxyborohydride, followed by stirring at room temperature for 2.5 hours. The reaction solution was filtered through NH-form silica gel, and the filtrate was evaporated. Ethyl acetate was added to the residue, and the mixture was filtered through alumina, and the filtrate was evaporated. The crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to give 245 mg of the title compound as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][CH2:16][C:17](=O)[N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[CH:10][CH:9]=2)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[N:18]1([CH2:17][CH2:16][CH2:15][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([CH2:4][OH:3])=[CH:14]3)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)c1cc2cc(CCC(=O)N3CCCC3)ccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc2cc(CCCN3CCCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
To a solution of 5-(3-oxo-3-pyrrolidin-1-yl-propyl)-1H-indole-2-carboxylic acid ethyl ester (1.5 g, 4.8 mmol) in 100 mL of tetrahydrofuran, lithium aluminum hydride powder (728 mg, 19.2 mmol) was added. The mixture was stirred under nitrogen at room temperature for 2 hour. To the reaction mixture was added water (0.75 mL), 15% sodium hydroxide (0.75 mL) and water (0.75 mL). It was then filtered through a pad of celite and the filtrate was concentrated. The residue was washed with ethyl acetate to give 960 mg (78%) of [5-(3-pyrrolidin-1-yl-propyl)-1H-indol-2-yl]-methanol.
Reaction SMILES: C(C1C=C(C(C)(C)C)C=C(CNC2C(Br)=CC=CC=2Br)C=1O)(C)(C)C.[BH4-].[Na+].[C:28]([C:32]1[CH:37]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:35]=[C:34]([CH:42]=[N:43][C:44]2[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][C:45]=2[Cl:51])[C:33]=1[OH:52])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([C:32]1[CH:37]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:35]=[C:34]([CH2:42][NH:43][C:44]2[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][C:45]=2[Cl:51])[C:33]=1[OH:52])([CH3:29])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1cc(C=Nc2c(Cl)cccc2Cl)c(O)c(C(C)(C)C)c1
Agent: CC(C)(C)c1cc(CNc2c(Br)cccc2Br)c(O)c(C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)c1cc(CNc2c(Cl)cccc2Cl)c(O)c(C(C)(C)C)c1

Procedure:
Using an analogous procedure to the synthesis of 2,4-bis(tert-butyl)-6-[[(2,6-dibromophenyl)amino]methyl]phenol described above, NaBH4 (0.8 g) was added to a solution of 2,4-bis(tert-butyl)-6-[[(2,6-dichlorophenyl)imino]methyl]phenol (0.91 g, 2.41 mmol). The product was purified from hot hexane and isolated as colourless crystals. Yield 0.61 g, 67%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)[CH2:13]1.CCN(CC)CC>C(Cl)Cl>[O:11]=[C:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)[CH2:13]1
Reactant: CCOC(=O)c1ccc(N2CCC(O)C2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCC(=O)C2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
To a round bottom flask was added CH2Cl2 (30 ml), 2M oxalyl chloride (4.31 mL, 8.63 mmol). The resulting solution was cooled to −78° C. DMSO (1.225 mL, 17.26 mmol) was then slowly added to the solution over 10 min. The reaction was then stirred at −78° C. for 15 min. The ethyl 4-(3-hydroxypyrrolidin-1-yl)benzoate (1.45 g, 6.16 mmol) pre-dissolved in CH2Cl2 (15 ml) was added to the reaction mixture over 10 min. The resulting solution was stirred at −78° C. for 2 hrs. After this time, Et3N (3.78 mL, 27.1 mmol) was added to the reaction mixture and the resulting solution was slowly warmed to 0° C. over 20 min. The reaction mixture was then diluted with CH2Cl2 (100 ml). The reaction mixture was wash with saturated aqueous NaHCO3 (100 ml), water (100 ml) and saturated aqueous NaCl (100 ml). The organic layer was separated, dried over MgSO4, filtered and concentrated to give crude product. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-30% EtOAc/Hex) to give the product ethyl 4-(3-oxopyrrolidin-1-yl)benzoate (1.31 g, 5.62 mmol, 91% yield) as yellow solid. Anal. Calcd. for C13H15NO3 m/z 233.2, found: 234.0 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:44]1[N:45]=[C:46]([NH2:49])[S:47][CH:48]=1)[C:19]([NH:21][CH:22]1[C:42](=[O:43])[N:24]2[C:25]([C:39]([OH:41])=[O:40])=[C:26]([CH2:29][S:30][C:31]3[N:35]([CH2:36][CH:37]=[CH2:38])[N:34]=[N:33][N:32]=3)[CH2:27][S:28][C@H:23]12)=[O:20])=[O:14])(C)(C)C>C1(OC)C=CC=CC=1>[C:13]([CH2:15][O:16][N:17]=[C:18]([C:44]1[N:45]=[C:46]([NH2:49])[S:47][CH:48]=1)[C:19]([NH:21][CH:22]1[C:42](=[O:43])[N:24]2[C:25]([C:39]([OH:41])=[O:40])=[C:26]([CH2:29][S:30][C:31]3[N:35]([CH2:36][CH:37]=[CH2:38])[N:34]=[N:33][N:32]=3)[CH2:27][S:28][C@H:23]12)=[O:20])([OH:14])=[O:12]
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Yield: 42.8 %

Procedure:
Trifluoroacetic acid (20 ml) was added under ice-cooling to a stirred suspension of 7-[2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(2.05 g) in anisole (2 ml), and the resultant mixture was stirred for 2 hours at ambient temperature. The reaction mixture was concentrated under reduced pressure and diethyl ether was added thereto. Precipitates were collected by filtration, washed with diethyl ether, dried and dissolved in an aqueous solution of sodium bicarbonate. An insoluble material was filtered off and the filtrate was adjusted to pH 3.2 with conc.hydrochloride acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.8 g).
Reaction SMILES: Br[C:2]1[C:3]([CH3:16])=[C:4]([CH3:15])[C:5]2[O:9][C:8]([CH2:11][OH:12])([CH3:10])[CH2:7][C:6]=2[C:13]=1[CH3:14].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[CH3:10][C:8]1([CH2:11][OH:12])[CH2:7][C:6]2[C:13]([CH3:14])=[C:2]([N:27]3[CH2:28][CH2:29][N:24]([C:21]4[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=4)[CH2:25][CH2:26]3)[C:3]([CH3:16])=[C:4]([CH3:15])[C:5]=2[O:9]1
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(CO)O2
Reactant: Cc1ccc(N2CCNCC2)cc1
Product: Cc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(CO)O4)CC2)cc1
Yield: 6.8 %

Procedure:
By using (5-bromo-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-2-yl)methanol (360 mg, 1.16 mmol) synthesized in Reference example 123 and 1-(4-methylphenyl)piperazine (668 mg, 3.79 mmol), the reaction was carried out in the same manner as Example 1 to obtain the title compound 30 mg (yield 6%). Melting point was 152 to 155° C. (ethyl acetate-hexane).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][N:17]3[C:10](=[CH:11][C:12]4[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=43)[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[O:49])=[CH:44][N:43]=2)[C:27]1=[O:56].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[CH3:20][C:14]1([CH3:21])[CH2:13][C:12]2[CH:11]=[C:10]3[N:17]([CH2:18][CH2:19][N:8]([C:4]4[C:3]([CH:23]=[O:24])=[C:2]([C:30]5[CH:29]=[C:28]([NH:41][C:42]6[CH:47]=[CH:46][C:45]([C:48]([N:50]7[CH2:55][CH2:54][O:53][CH2:52][CH2:51]7)=[O:49])=[CH:44][N:43]=6)[C:27](=[O:56])[N:26]([CH3:25])[CH:31]=5)[CH:7]=[CH:6][N:5]=4)[C:9]3=[O:22])[C:16]=2[CH2:15]1
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2C=O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 100 °C
Yield: 83.2 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 4-chloro-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridine-3-carbaldehyde 108a (100 mg, 0.29 mmol), 1-methyl-3-(5-(morpholine-4-carbonyl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-di-oxaborolan-2-yl)pyridin-2(1H)-one 111c (192 mg, 0.44 mmol), Pd(dppf)Cl2 (12 mg, 0.015 mmol), K3PO4 (123 mg, 0.58 mmol), sodium acetate (47 mg, 0.58 mmol), acetonitrile (10 mL), and water (5 drops). After three cycles of vacuum/N2 flush, the mixture was heated at 100° C. for 1 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. It was cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography (dichloromethane/methanol 40:1) to afford 269a (150 mg, 83%) as a brown solid. MS-ESI: [M+H]+ 621.8