Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14](=[O:28])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][Mg]Cl>C1COCC1>[OH:28][C@@:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:34][CH2:33][CH2:32][CH2:31][O:30][CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccccc2Oc2ccccc2)C1
Reactant: COCCCC[Mg]Cl
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1ccccc1Oc1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 26 %

Procedure:
To a solution of (3R)-1-(tert-butoxycarbonyl)-3-(2-phenoxybenzoyl)piperidine (6.17 g, 16.2 mmol) in THF (30 mL) at −10° C. was added dropwise 2.54 M 4-methoxybutylmagnesium chloride in THF (15 mL, 38 mmol). The resulting solution was warmed to rt slowly, and stirred over night. The reaction was quenched with sat'd NH4Cl (10 mL) and extracted with Et2O (4×10 mL). The combined organic layers were washed with water and brine. The solvent was removed and the residue was purified by flash chromatography to give (R)-tert-butyl 3-((S)-1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)piperidine-1-carboxylate (1.97 g, 26% from (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate).
Reaction SMILES: Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1.BrCCC1C=CC=CC=1.[Cl:26][C:27]1[CH:28]=[C:29]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:30]=[CH:31][C:32]=1[O:33][CH2:34][O:35][CH3:36].Br[CH2:44][C:45]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:46]>>[Cl:26][C:27]1[CH:28]=[C:29]([N:37]2[CH2:38][CH2:39][N:40]([CH2:44][C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:46])[CH2:41][CH2:42]2)[CH:30]=[CH:31][C:32]=1[O:33][CH2:34][O:35][CH3:36]
Reactant: O=C(CBr)c1ccccc1
Reactant: COCOc1ccc(N2CCNCC2)cc1Cl
Agent: BrCCc1ccccc1
Agent: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: COCOc1ccc(N2CCN(CC(=O)c3ccccc3)CC2)cc1Cl
Yield: 16.7 %

Procedure:
Production Example 1 was repeated except that 1-(4-methoxyphenyl)piperazine dihydrochloride and (2-bromoethyl)-benzene were replaced with 1-(3-chloro-4-methoxymethoxyphenyl)-piperazine (924 mg) and 2-bromoacetophenone (789 mg), respectively. Thus obtained crude product was purified on silica gel column chromatography (eluent, chloroform: acetone=20:1), to provide 2-[4-(3-chloro-4-methoxymethoxyphenyl)piperazin-1-yl]-1-phenylethan-1-one (225 mg).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:10][CH:9]([CH3:11])[CH:8]2C[CH:4]1[C:5](C)=[CH:6][CH2:7]2.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:11])[CH3:10]
Reactant: [H][H]
Reactant: COC1CC(C)C2CC=C(C)C1C2
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCC(C)OC
Reaction time: 6 h
Yield: 107.2 %

Procedure:
To a solution of 1 g (5.6 mmol) of 4,8-dimethylbicyclo[3.3.1]nona-7-en-2-yl methyl ether [IB] in 10 ml of ethanol was added 0.1 g of 5% of Pd/C and the resulting mixture was heated with stirring at a hydrogen pressure of 20 atm and a reaction temperature of 70° C. for 6 hours. After cooling, the Pd/C was filtered off and the ethanol was distilled off under reduced pressure. The residue was subjected to column chromatography and eluate with toluene gave 0.95 g of the title compound, which had a camphor-like smell.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH2:14][N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]#[N:25])=[CH:21][CH:22]=2)[CH:17]=[CH:16]1>C(OCC)C>[CH3:7][N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH2:14][N:15]1[C:23]2[C:18](=[CH:19][C:20]([CH2:24][NH2:25])=[CH:21][CH:22]=2)[CH:17]=[CH:16]1
Reactant: CN1CCCC1CCn1ccc2cc(C#N)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CN1CCCC1CCn1ccc2cc(CN)ccc21
Yield: 40.7 %

Procedure:
To a dry argon purged flask fitted with a magnetic stirbar, condenser and dropping funnel is charged lithium aluminum hydride (80.9 mg, 2.131 mmol), anhydrous diethyl ether (10 mL) and stirring begun. A solution of compound 34 (360 mg, 1.421 mmol) in anhydrous diethyl ether (10 mL) is charged to the dropping funnel and added drop wise to the LiAlH4 suspension and mixture stirred at ambient temperature for 30 minutes. The reaction was quenched by the sequential addition of 100 ul H2O, 125 ul 3M sodium hydroxide and 300 ul H2O. After filtration to remove insolubles, the solution was concentrated and the residue purified twice via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 5:95 to 1:9) to afford pale yellow oil 36 (149 mg, 40.7%); 1H NMR (DMSO-d6) δ 7.45 (s, 1H), 7.37-7.33 (2×m, 2H), 7.10 (d, 1H, J=8.2 Hz), 6.35 (d, 1H, J=3.1 Hz), 4.15 (t, 2H, J=7.4 Hz), 3.76 (s, 2H), 2.93-2.87 (m, 1H), 2.15 (s, 3H), 2.12-2.03 (m, 1H), 2.00-1.93 (m, 2H), 1.88-1.79 (m, 1H), 1.68-1.52 (m, 3H), 1.44-1.35 (m, 1H); ESI-MS (m/z, %): 258 (M+1, 100%).
Reaction SMILES: N[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[C:4]([O:14][CH3:15])[N:3]=1.[N+]([O-])([O-])=O.[Na+].OC1C(N2CCOCC2)=NC=C(OC)N=1.P(Cl)(Cl)([Cl:38])=O>>[Cl:38][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[C:4]([O:14][CH3:15])[N:3]=1
Reactant: COc1cnc(N2CCOCC2)c(N)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: COc1cnc(N2CCOCC2)c(O)n1
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Product: COc1cnc(N2CCOCC2)c(Cl)n1

Procedure:
The 2-amino substituent of Step A product when treated with sodium nitrate as described in Step E of Preparation 81 is converted to the 2-hydroxy group. Treatment of the 2-hydroxy-3-morpholino-6-methoxypyrazine with phosphorus oxychloride by Preparation 13, Step B method, gives 2-chloro-3-morpholino-6-methoxypyrazine.
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([C:13]([O:15][CH:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:17]([F:20])([F:19])[F:18])=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd].[C]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:17]([F:18])([F:19])[F:20])=[O:14])=[CH:27][CH:28]=1
Reactant: CCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(OC(=O)c1ccc(O)cc1)C(F)(F)F
Temperature: 25 °C
Yield: 100.8 %

Procedure:
In 15 ml of ethanol, 1.8 g of 1,1,1-trifluoro-2-octyl 4-benzyloxybenzoate prepared in the reaction step [3] mentioned above was dissolved and 0.3 g of Pd-carbon was further added. The mixture was stirred at an ambient temperature for a whole day and night under a hydrogen gas atmosphere. After the Pd-carbon was filtered off, the solvent was distilled off at a reduced pressure to obtain 1.4 g of the objective compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.N1C=CC=CC=1.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([NH:1][S:41]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)(=[O:43])=[O:42])[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(N)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C)c(CNC(=O)c2cc(NS(=O)(=O)c3ccccc3)cc3c2cnn3C2CCCC2)c(=O)[nH]1

Procedure:
6-amino-1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (30 mg, 0.079 mmol) was suspended in DCM (3 mL) followed by pyridine (0.032 mL, 0.395 mmol). The contents were vigorously stirred and then benzenesulfonyl chloride (0.011 mL, 0.087 mmol) was added and the contents stirred at RT for 1 h. The volatiles were removed in vacuo and dried on hi-vac for 1 h. The crude product was purified by reverse phase HPLC (Gradient B: 15-70%. A: Water+0.1% TFA. B: CH3CN+0.1% TFA). The product was neutralized with water and sat. NaHCO3, and extracted with 10% THF/EtOAC (hot) in duplicate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The solid was concentrated from DCM and dried in vacuum oven for 4 h at 45° C. The title compound was collected as 30 mg (72%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.68 (td, J=5.49, 3.41 Hz, 2H), 1.75-1.94 (m, 4H), 1.99-2.10 (m, 2H), 2.12 (s, 3H), 2.20 (s, 3H), 4.30 (d, J=5.05 Hz, 2H), 4.89-5.04 (m, 1H), 5.89 (s, 1H), 7.22 (d, J=1.52 Hz, 1H), 7.36 (s, 1H), 7.48-7.63 (m, 3H), 7.77-7.84 (m, 2H), 8.11 (s, 1H), 8.36 (t, J=5.05 Hz, 1H), 10.56 (s, 1H), 11.55 (s, 1H); LC-MS (ES) m/z=519.2 [M+H]
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20].[C:24]([O:28][C:29]([NH:31][C@@H:32]([CH3:36])[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:24]([O:28][C:29](=[O:30])[NH:31][C@H:32]([C:33](=[O:34])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:18]([C:19]#[N:20])[CH:17]=1)[CH3:36])([CH3:25])([CH3:26])[CH3:27]
Reactant: N#Cc1cccc(Nc2ccccc2N)c1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1Nc1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.7 %

Procedure:
Triethylamine (0.35 mL, 2.59 mmol) was added to a mixture of 3-(2-aminophenylamino)benzonitrile (177 mg, 0.85 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (190 mg, 1.02 mmol), HOAt (140 mg, 1.02 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (190 mg, 1.02 mmol) in anhydrous DCM (10 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 10 min then slowly warmed to RT. Stirring at RT was continued for 16 h. The reaction mixture was then partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with DCM (×3) and the combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-2% 2M NH3/MeOH in DCM) to afford the title compound as a yellow oil (290 mg, 90%). Material still impure, taken forward in the next step without further purification. LCMS (Method J): RT 3.54 min [M+H]+ 380.8
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:10][OH:11])[CH:7]=[N:8][CH:9]=1.[CH2:12](I)[CH3:13]>CS(C)=O.O>[Br:3][C:4]1[CH:9]=[N:8][CH:7]=[C:6]([CH2:10][O:11][CH2:12][CH3:13])[CH:5]=1
Reactant: CCI
Reactant: OCc1cncc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a mixture of powdered KOH (5.96 g, 106.4 mmol) in anhydrous DMSO (20 mL) was added under argon a solution of (5-bromopyridin-3-yl)methanol (example 26c) (5 g, 26.6 mmol) in anhydrous DMSO (20 mL), followed by EtI (2.6 mL, 31.9 mmol). The reaction mixture was stirred at room temperature for 1 hour then diluted with water and extracted with EtOAc. The organic phase was washed with water and brine, dried over MgSO4, filtered and evaporated to give 5.6 g of 3-bromo-5-(ethoxymethyl)pyridine as a dark brown oil in 97% yield. 1H NMR (400 MHz, CDCl3): 1.27 (t, 3H), 3.57-3.59 (q, 2H), 4.50 (s, 2H,), 8.48 (s, 1H), 8.60 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:13]([CH3:14])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C@@H:8]([NH2:10])[CH3:9].CC(C)([O-])C.[K+].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>COCCOC>[CH3:14][N:13]1[C:4]2[C:5](=[N:6][C:7]([C@@H:8]([NH2:10])[CH3:9])=[C:2]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:3]=2)[CH:11]=[CH:12]1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Reactant: C1COCCN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: C[C@H](N)c1nc2ccn(C)c2cc1N1CCOCC1

Procedure:
(S)-1-(6-Bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (1.6 g, 6.30 mmol) was stirred with potassium tert-butoxide (2.83 g, 25.2 mmol) and morpholine (6.58 g, 76 mmol) in DME (50 mL) at 88° C. for 4 hours. The mixture was then concentrated in vacuo. The residue was taken up in acetonitrile and water, and was lyophilized to give the title compound, which was used without further purification. ESI-MS m/z [M+H]+ calc'd for C14H20N4O, 261; found 261.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[C:5]2[CH2:6][CH2:7][C:8](=[O:11])[C:9]=2[CH:10]=1.O.ON1C2C=CC=CC=2N=N1.[NH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[C:4]([C:12]([NH:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:14])[CH:3]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)c1cc(Br)cc2c1CCC2=O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CNC(=O)c1cc(Br)cc2c1CCC2=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of Example 6 (250 mg, 0.98 mmol) in N,N-dimethylformamide (5 mL) was added N-cyclohexylcarbodiimide-N′-methyl polystyrene (761 mg, 1.5 mmol) and 1-hydroxybenzotriazole hydrate (255 mg, 1.7 mmol). The mixture was agitated at room temperature for about 5 minutes, treated with t-butyl glycinate (150 mg, 1.2 mmol), shaken for about 15 hours, and filtered. The filtrate was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate (1:1) as the moblie phase to provide the desired product. MS (APCI): m/z 311, 313 (M+H-tBu)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][O:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][C@@H:14]23)[CH:19]=1>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:10][C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][O:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][NH:26][CH2:27][C@@H:14]23)[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Reactant: O=Cc1ccccc1F
Product: Fc1ccccc1CNc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCOC2

Procedure:
Using 2-fluorobenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 134. LRMS (ES)+: 354.3 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.CO[CH:11]([NH:15][C:16]([NH2:18])=[O:17])[C:12](O)=[O:13]>Cl>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[C:1]([CH:11]2[NH:15][C:16](=[O:17])[NH:18][C:12]2=[O:13])[CH:2]=1
Reactant: COC(NC(N)=O)C(=O)O
Reactant: Oc1ccc(Br)cc1
Agent: Cl
Product: O=C1NC(=O)C(c2cc(Br)ccc2O)N1

Procedure:
To a 500-ml round-bottom flask equipped with a means for stirring and temperature control is added 0.55 mole (95.16 g) of p-bromophenol, 0.30 mole (44.44 g) of α-methoxyhydantoic acid, and 50 ml of concentrated HCl. The mixture is stirred at 50° C. for 17 hours. The water layer is then decanted, and the gum is washed with water several times. The resulting solid material is then crystallized from an ethanol-water solution to give the title compound having a melting point of 274° C. The structure is confirmed using C13 nuclear magnetic resonance spectroscopy.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[SH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[OH-].[Na+]>C(Cl)Cl>[C:1](=[O:7])([S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Sc1ccccn1
Reactant: CCCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCC(=O)Sc1ccccn1
Reaction time: 1 h
Yield: 88.3 %

Procedure:
Following a general procedure (Rao et al., J. Org. Chem. 2000, 65: 1084), to a solution of n-hexanoyl chloride (6.73 g, 50.0 mmol) in CH2Cl2 (200 mL) was added 2-mercaptopyridine (5.55 g, 50.0 mmol) in portions as a solid during 5 min. The resulting mixture was stirred for 1 h, then 2 N NaOH (50 mL) was added. The organic phase was isolated, washed (water), dried (Na2SO4) and concentrated to afford a yellow oil. The oil was distilled bulb-to-bulb (110-120° C./0.03 mmHg) to afford a pale yellow oil (9.24 g, 88%): 1H NMR δ 0.89 (m, 3H), 1.35 (m, 4H), 1.73 (m, 2H), 2.69 (m, 2H), 7.29 (m, 1H), 7.60-7.76 (m, 2H), 8.62 (m, 1H); 13C NMR δ 13.7, 22.1, 24.9, 30.9, 44.0, 123.3, 129.9, 136.9, 150.2, 151.5, 196.4. Anal. Calcd for C11H15NOS: C, 63.12; H, 7.22; N, 6.69. Found: C, 63.02; H, 7.24; N, 6.74.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:24][OH:25])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:26](Cl)([CH3:29])(=[O:28])=[O:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:24][O:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCCNC(=O)C(CO)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Product: COC(=O)CCCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(4-methoxycarbonylbutyl)propanamide (507 mg) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(4-methoxycarbonylbutyl)propanamide (409.7 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:16]C(=O)C)[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:9].[OH-].[Na+]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:9])[NH2:16]
Reactant: CC(=O)Nc1ccc(C(=O)N2CCOCC2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(N)ccc1C(=O)N1CCOCC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
700.0 mg (2.67 mmol) N-[3-methyl-4-(morpholin-4-yl-carbonyl)-phenyl]-acetamide are combined with 7 ml 4-molar sodium hydroxide solution and stirred overnight at 65° C. The reaction mixture is poured onto ice water and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and evaporated down i. vac.
Reaction SMILES: ClCCl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:31]=[CH:32][C:33]=1[O:34][CH2:35][C:36]([OH:38])=O)[C:9]([CH:11]=[P:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[NH2:39][C:40]1[S:41][C:42]2[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=2[N:44]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(N(CC)CC)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:31]=[CH:32][C:33]=1[O:34][CH2:35][C:36]([NH:39][C:40]1[S:41][C:42]2[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=2[N:44]=1)=[O:38])[C:9]([CH:11]=[P:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: COc1cc(C(=O)C=P(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1OCC(=O)O
Reactant: Nc1nc2ccccc2s1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)C=P(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1OCC(=O)Nc1nc2ccccc2s1
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To dichloromethane (50 ml) are added (3-methoxy-4-carboxymethoxybenzoyl)methylenetriphenylphosphorane (5 g), 2-aminobenzothiazole (1.9 g), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (2.93 g) and triethylamine (3.3 ml), and the mixture is stirred overnight. After the reaction is complete, the mixture is washed with an aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate to remove the solvent, and further recrystallized from toluene to give [3-methoxy-4-(2-benzothiazolylaminocarbonylmethoxy)benzoyl]methylenetriphenylphosphorane (5.17 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([CH3:19])[CH:13]=[CH:14][C:15]=2[O:17]C)[C:10](=[O:20])[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([CH3:19])[CH:13]=[CH:14][C:15]=2[OH:17])[C:10](=[O:20])[C:9]1=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C)c2c1N(Cc1ccccc1)C(=O)C2=O
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(O)c2c1C(=O)C(=O)N2Cc1ccccc1
Yield: 25.5 %

Procedure:
15.46 g of 1-benzyl-4-methyl-7-methoxy-2,3-indoledione and 74 g of pyridine hydrochloride were heated to 200° C. for 2.5 hours. The mixture was partitioned between methylene chloride and aqueous dimethyl sulfoxide. The organic layer was separated and evaporated to give 3.75 g of crude 1-benzyl-4-methyl-7-hydroxy-2,3-indoledione in the form of a red solid having a melting point of 255°-262° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CN.Cl.[BH3-][C:19]#[N:20].[Na+]>CO.CC(O)=O>[CH3:19][NH:20][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h
Yield: 55 %

Procedure:
tert-Butyl 4-oxopiperidine-1-carboxylate (5.0 g, 25.126 mmol, 1.0 eq.) was dissolved in MeOH (50 ml); AcOH (2 drops) and CH3NH2.HCl (2.2 g, 32.663 mmol, 1.3 eq.) were added and stirring was carried out for 2 hours at RT. NaCNBH3 (3.11 g, 50.25 mmol, 2.0 eq.) was added in portions at 0° C. and the mixture was stirred for 14 hours at RT. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (Alox, 3% MeOH in DCM). Yield: 55% (3.0 g, 14.019 mmol)
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]4)[CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:3]=1.[CH3:31][C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:31][C:32]1[N:36]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:14][CH:15]([N:17]5[CH2:18][CH2:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22]5)[CH2:16]4)[N:8]3[CH3:11])=[C:4]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:3]=2)[C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[N:33]=1
Reactant: Cn1c(CN2CC(N3CCS(=O)(=O)CC3)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Cc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCS(=O)(=O)CC4)C3)n(C)c2n1
Temperature: 145 °C
Yield: 83.9 %

Procedure:
A mixture of 2-chloro-8-[3-(1,1-Dioxo-1-thiomorpholin-4-yl)azetidin-1-ylmethyl]-9-methyl-6-morpholin-4-yl-9H-purine (125 mg, 0.27 mmol), 2-methylbenzimidazole (402 mg, 0.30 mmol), tris(dibenzylideneacetone)dipalladium (13 mg, 0.01 mmol), Xphos (13 mg, 0.02 mmol) and Cs2CO3 (179 mg, 0.55 mmol) in dioxane (4 mL) was purged with argon then heated at 145° C. for 30 min in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM then eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-15%) followed by an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH to give 355 as a cream solid (125 mg, 84%). LCMS (Method G): RT 4.73 min, [M+H]+ 552.2. 1H NMR (CDCl3, 400 MHz): δ 8.10-8.05 (m, 1 H); 7.73-7.67 (m, 1 H); 7.29-7.24 (m, 2 H); 4.35 (m, 4 H); 3.90-3.82 (m, 9 H); 3.59 (m, 2 H); 3.28 (m, 1 H); 3.11-3.04 (m, 6 H); 2.94 (s, 3 H) and 2.87-2.82 (m, 4 H)