Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]=[C:9]=[O:10])[CH:3]=1.[CH3:11][CH:12]([CH3:35])[CH:13]([NH:18][C:19]([C:21]1[S:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=2)=[CH:24][N:25]=1)=[O:20])[C:14]([O:16][CH3:17])=[O:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:10])[NH:32][C:29]2[CH:30]=[CH:31][C:26]([C:23]3[S:22][C:21]([C:19]([NH:18][C@@H:13]([CH:12]([CH3:35])[CH3:11])[C:14]([O:16][CH3:17])=[O:15])=[O:20])=[N:25][CH:24]=3)=[CH:27][CH:28]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Product: COC(=O)[C@@H](NC(=O)c1ncc(-c2ccc(NC(=O)Nc3cccc(Cl)c3)cc2)s1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 9, using 1-chloro-3-isocyanatobenzene and intermediate 2. 1HNMR (DMSO-d6, 300 MHz): δ 9.337 (s, 1H), 8.741-8.713 (d, 2H), 8.362 (s, 1H), 8.203-8.144 (t, J=8.7, 9 Hz, 1H), 7.744-7.716 (d, J=8.4 Hz, 2H), 7.581-7.552 (d, J=8.7 Hz, 2H), 7.507-7.463 (d, J=2.7, 11.1 Hz, 1H), 7.266-7.237 (d, J=3.7 Hz, 2H), 4.350-4.299 (t, J=7.5, 7.8 Hz, 1H), 3.681 (s, 3H), 2.306-2.238 (m, 1H), 0.965-0.923 (d, J=6.3 Hz, 6H); MS (ESI) m/z 485 (M−H), 487 (M+H)+.
Reaction SMILES: C([Mg]Cl)(C)C.[Li+].[Cl-].[S:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[C:13]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])[CH2:18][CH2:17]1)(=[O:15])[CH3:14]>C1COCC1>[OH:15][C:13]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])[CH2:18][CH2:17]1)([C:9]1[S:8][CH:12]=[CH:11][N:10]=1)[CH3:14]
Reactant: c1cscn1
Reactant: CCCCOC(=O)[C@H]1CC[C@H](C(C)=O)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCOC(=O)[C@H]1CC[C@H](C(C)(O)c2nccs2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cooled (0° C.) flask under nitrogen containing iPrMgCl—LiCl (1.3 M in THF, 55.2 mL, 71.8 mmol) was added thiazole (5.10 mL, 71.8 mmol) keeping the internal temperature <10° C. The resulting heterogenous mixture was warmed to RT where it was stirred for 10 min then re-cooled to −20° C. Then, a solution of butyl trans-4-acetylcyclohexanecarboxylate (12.5 g, 55.2 mmol) in THF (20+5 mL) was added via syringe. The cooling bath was then removed and the reaction mixture warmed slowly to 10° C. during which time it was observed to nearly completely homogenize. After 40 min, saturated aqueous NH4Cl followed by EtOAc were added and the layers separated, the organics dried over MgSO4, filtered and concentrated in vacuo. The crude residue was absorbed on silica and purified by flash chromatography to afford butyl trans-4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexanecarboxylate as a light yellow oil. The enantiomers were separated by chiral SFC (Chiral Technology AZ-H, 2.1×25 cm, 5 uM, 45/55 MeOH/CO2, Flow Rate: 80 mL/min, 6 min run time, WL: 220 nm) Elution was observed at 2.98 min and 4.14 min. Pooled fractions of each peak were separately concentrated under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][C:7](=O)[C:6]=2[CH:17]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].O>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][C:7](=[S:19])[C:6]=2[CH:17]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Nc1ccc2c(c1)C(=O)Nc1ccccc1S2
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc2c(c1)C(=S)Nc1ccccc1S2

Procedure:
2-Amino-10,11-dihydrodibenzo[b,f][1,4]thiazepin-11-one (0.12 g was dissolved in toluene (20 ml). Phosphorus pentasulphide (0.11 g) was added to the solution and the whole was stirred under reflux for 16 hours and then cooled. Addition of water (40 ml) and separation of the phases gave, after evaporation of the dried organic layer, a yellow solid which was purified by column chromatography on silica gel and recrystallisation from ethanol to give the product as yellow needles (0.22 g, m/s. M- =258).
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:24][CH2:25][CH2:26][CH2:27]Cl)=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35]([NH:37][CH2:38][CH3:39])[CH3:36].[I-].[Na+]>CN(C=O)C>[CH2:35]([N:37]([CH2:38][CH3:39])[CH2:27][CH2:26][CH2:25][CH2:24][O:23][C:16]1[C:15]2[C:14]3[C:22]4=[C:10]([O:9][CH2:8][CH:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:21]4[C:20]=2[CH:19]=[CH:18][CH:17]=1)[CH:11]=[CH:12][CH:13]=3)[CH3:36]
Reactant: CCNCC
Reactant: ClCCCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 50 °C
Yield: 32.9 %

Procedure:
To a mixture of 4-chlorobutyl 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl ether (0.36 g, 0.9 mmol) in dry DMF (10 mL) is added potassium carbonate (0.63 g, 4.6 mmol), diethylamine (0.48 mL, 4.6 mmol), and sodium iodide (0.135 g, 0.9 mmol). The mixture is heated at 50° C. for 20 h. The mixture is then cooled to room temperature and partitioned between water and ether. The ether layer is washed twice with water (50 mL) then dried over anhydrous sodium sulfate and concentrated. Column chromatography (60 mL silica) using 5% methanol in methylene chloride as eluent gave 0.127 g (33%) of the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([NH:19][CH:20]=[N:21]2)=[C:17](Cl)[N:16]=1>CS(C)=O>[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][NH:21]2)=[C:17]([O:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:16]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1nc(Oc2ccccc2)c2nc[nH]c2n1
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
Potassium t-butoxide (J. T. Baker, 7.3 g, 64.8 mmol) was added to a solution of phenol (Mallinckrodt, 15.2 g, 162 mmol) in 50 mL anhydrous DMSO. After stirring for 30 minutes, 2-amino-6-chloropurine (Sigma, lot #69F4064. 5.5 g, 32.4 mmol) was added and the mixture stirred for 6 days at 100° C. The reaction was poured onto ice and extracted with EtOAc. The solvents were removed in vacuo and the resultant oil applied to a silica gel column. Elution with CHCl3 /MeOH (95:5, v/v) followed by combination and evaporation of appropriate fractions gave 1.6 g (7.0 mmol, 22%) of product. mp=228° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]([CH3:18])[C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1.[CH3:19][C:20]1[N:25]=[C:24]([NH2:26])[CH:23]=[CH:22][CH:21]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:26][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:19])[N:25]=2)=[O:8])=[CH:4][C:3]=1[N:11]([CH3:18])[C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1
Reactant: Cc1cccc(N)n1
Reactant: CN(c1cncnc1)c1cc(C(=O)O)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(NC(=O)c2ccc(F)c(N(C)c3cncnc3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
Compound 20 (300 mg, 1.15 mmol, 1.00 eq) was dissolved in Dioxane (5.0 mL), and 1N LiOH (5.0 mL) was added. The reaction was stirred at rt for 45 minutes. The reaction was quenched with 1N HCl (5.0 mL) and extracted (3×) with ether. The combined organics were dried (MgSO4), filtered, and concentrated in vacuo to afford 200 mg (70%) of crude 4-fluoro-3-(methyl(pyrimidin-5-yl)amino)benzoic acid as a yellow solid. The product was confirmed by LCMS (>90% @ 220 nm and 254 nm) and carried forward without purification. 4-fluoro-3-(methyl(pyrimidin-5-yl)amino)benzoic acid (30 mg, 0.12 mmol, 1.0 eq), 6-methylpyridin-2-amine (15 mg, 0.14 mmol, 1.2 eq), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (91 mg, 0.24 mmol, 2.0 eq), and N,N-Diisopropylethylamine (85 mg, 0.66 mmol, 5.5 eq) were dissolved in DMF (0.98 mL) and stirred at rt overnight. The reaction was quenched with water, and the layers were separated via phase separation. The organic layer was dried on air concentrator and purified by mass directed preparatory HPLC to afford 15 mg (36%) of the title compound as a mono-TFA salt: 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.65 (s, 1H), 8.28 (s, 2H), 8.14 (dd, J=7.7, 2.2 Hz, 1H), 8.00-7.94 (m, 2H), 7.75 (t, J=7.9 Hz, 1H), 7.48 (dd, J=10.7, 8.7 Hz, 1H), 7.05 (dd, J=7.4, 1H), 3.39 (s, 3H), 2.45 (s, 3H); ES-MS [M+1]+:338.1.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH3:24]I.[Cl-].[NH4+]>CN(C)C=O>[CH3:1][S:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:9]=1)([CH3:24])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(SC)c1cccc(C(=O)c2ccccc2)c1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(SC)c1cccc(C(=O)c2ccccc2)c1
Reaction time: 0.5 h

Procedure:
Methyl α-methylthio(m-benzoylphenyl)acetate (713 mg) was dissolved in 6 ml of anhydrous dimethylformamide, and with ice cooling, 100 mg (65% content) of sodium hydride was added. The mixture was stirred for 30 minutes. The reaction mixture turned black violet. When 0.3 ml of methyl iodide was added with ice cooling, the color vanished immediately. The mixture was stirred for 10 minutes at room temperature, and then an aqueous solution of ammonium chloride (500 mg/30 ml) was added. The mixture was extracted three times with 20 ml of diethyl ether. The organic layer was washed three times with 10 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using benzene and methylene chloride as eluents to give 111 mg of methyl α-methylthio-α-(m-benzoylphenyl)propionate and 461 mg of a mixture which was shown by NMR analysis to consist of methyl α-methylthio(m-benzoylphenyl)acetate and methyl α-methylthio-α-(m-benzoylphenyl)propionate (the mole ratio=7:11).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]#[N:22])[C:11]=3[N:10]=[C:9]2[C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.[NH2:41][C:42]1[CH:43]=[CH:44][C:45](Br)=[N:46][CH:47]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.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]>[NH2:41][C:42]1[CH:43]=[CH:44][C:45]([C:29]2[CH:30]=[CH:31][C:26]([C:9]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:13](=[O:14])[C:12]4[CH:15]=[N:16][N:17]([C:18]5[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=5)[C:21]#[N:22])[C:11]=4[N:10]=3)=[CH:27][CH:28]=2)=[N:46][CH:47]=1
Reactant: Nc1ccc(Br)nc1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cnn4-c4cccc(C#N)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)cn5)cc4)nc32)c1
Temperature: 100 °C

Procedure:
A solution of 3-{5-(4-chloro-phenyl)-4-oxo-6-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenyl]-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl}-benzonitrile (prepared as described in example 40, 1.00 g, 1.81 mmol) in N,N-dimethylformamide (25 mL) is added and the resulted mixture is degassed with argon for 0.5 h. Then 5-amino-2-bromopyridine (0.472 g, 2.72 mmol), cesium carbonate (1.18 g, 3.62 mmol), Pd(dppf)2Cl2 (0.147 g, 0.181 mmol) and is degassed with argon for 0.5 h. The reaction mixture is then heated at 100° C. for 2 h. The reaction mixture is cooled to rt and diluted with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by preparative HPLC to afford 3-[6-[4-(5-amino-pyridin-2-yl)-phenyl]-5-(4-chloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzonitrile. LC-MS calculated for C29H18ClN7O (M+H+) 516.1, found 516.1.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:5]([C:21]([O:23]C)=[O:22])=[N:6][C:7]([N:14]([CH3:20])[S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2.Cl>O1CCOCC1.O>[OH:3][C:4]1[C:5]([C:21]([OH:23])=[O:22])=[N:6][C:7]([N:14]([CH3:20])[S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: CCS(=O)(=O)N(C)c1nc(C(=O)OC)c(O)c2ncccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N(C)c1nc(C(=O)O)c(O)c2ncccc12
Temperature: 55 °C

Procedure:
Sodium hydroxide (6.73 mL, 6.73 mmol, 1N solution) was added to a suspension of methyl 8-hydroxy-5-[methyl(ethylsulfonyl)amino]-1,6-naphthyridine-7-carboxylate (730 mg, 2.24 mmol) in a 2:1 solution of dioxane/water (20 mL) and the resulting mixture was heated overnight at 55° C. overnight. The opaque solution was acidified to a pH=7 using 1N HCl solution. The reaction was cooled and the solids that had precipitated out of solution were collected by vacuum filtration to give the desired product as an off-white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:43])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[C:33]([CH2:34][O:35]C3CCCCO3)=[CH:32][N:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]([N:14]([CH3:15])[C:12]1[C:11]([CH3:18])=[CH:10][C:9]2[NH:19][C:20](=[O:43])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[C:33]([CH2:34][OH:35])=[CH:32][N:31]=[N:30]4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:17]
Reactant: CCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(C)c1cc2c(cc1C)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-(ethyl-methyl-amino)-4-methyl-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M81) (0.39 g, 0.64 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a off-white solid (159 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl-].[CH3:12][C:13]1[CH:22]=[CH:21][C:16]([CH:17]=[N+:18]([CH3:20])[CH3:19])=[CH:15][CH:14]=1.CC1C=CC(C=O)=CC=1.CNC>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:17]([N:18]([CH3:19])[CH3:20])[C:16]1[CH:21]=[CH:22][C:13]([CH3:12])=[CH:14][CH:15]=1
Reactant: Cc1ccc(C=[N+](C)C)cc1
Reactant: Clc1ccc2[nH]ccc2c1
Agent: CNC
Agent: Cc1ccc(C=O)cc1
Agent: [Cl-]
Product: Cc1ccc(C(c2c[nH]c3ccc(Cl)cc23)N(C)C)cc1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-chloro-1H-indole and (4-methyl-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 4-methyl-benzaldehyde and dimethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5[CH2:33][CH2:32][CH2:31][CH:30]=5)[N:24]=4)=[O:22])[CH2:17][C:16]3([CH3:35])[CH3:34])=[O:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1>[Pd].CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[N:24]=4)=[O:22])[CH2:17][C:16]3([CH3:35])[CH3:34])=[O:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CN(C(=O)c2cccc(C3=CCCC3)n2)CCN1C(=O)c1ncn(-c2cccc(Cl)c2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CN(C(=O)c2cccc(C3CCCC3)n2)CCN1C(=O)c1ncn(-c2cccc(Cl)c2)n1
Reaction time: 3.5 h

Procedure:
A mixture of 15 mg (31 μmol) [1-(3-chloro-phenyl)-1H-[1,2,4]-triazol-3-yl]-[4-(6-cyclopent-1-enyl-pyridine-2-carbonyl]-2,2-dimethyl-piperazin-1-yl]-methanone and 4 mg palladium on carbon in 5.0 mL EtOAc was hydrogenated at RT for 3.5 h. The catalyst was removed by filtration and the solvent was evaporated in vacuo. The resulting residue was purified by HPLC.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[C:7]=1[OH:14]>CO.[C].[Pd]>[CH3:13][C:8]1[CH:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[C:7]=1[OH:14]
Reactant: Cc1cc(C)c(O)c(-c2ccco2)c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(O)c(C2CCCO2)c1
Reaction time: 12 h
Yield: 98.1 %

Procedure:
2-(furan-2-yl)-4,6-dimethylphenol (Compound 6-18) (200 mg, 1.06 mmol) were dissolved in methanol 3 mL. Palladium carbon (30 mg) was added thereto, followed by stirring under hydrogen balloon for 12 hours. After the completion of the reaction, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to obtain 2,4-dimethyl-6-(tetrahydrofuran-2-yl)phenol (200 mg, 98%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=O.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(O)(=O)C.O>CCO>[N:31]1[CH:32]=[CH:33][C:28]([CH2:27][NH:26][C:3]([C:5]2[N:6]=[C:7]([C:24]#[N:25])[C:8]3[C:9](=[O:23])[N:10]([CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:11]=[CH:12][C:13]=3[C:14]=2[OH:15])=[O:2])=[CH:29][CH:30]=1
Reactant: NCc1ccncc1
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: N#Cc1nc(C(=O)NCc2ccncc2)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Yield: 35.1 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (35 mg, 0.104 mmol) and 4-(aminomethyl)-pyridine (0.040 mL, 0.366 mmol) in 2 mL of EtOH was refluxed for 16 h. Acetic acid (0.1 mL) and water (3 mL) were added, and the mixture was allowed to come to r.t. The resulting precipitate was filtered, washed with 5 mL of water/MeOH (1:1), and dried under high vacuum to afford 15 mg of the title compound as a gray solid. MS: (+) m/z 412.20 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:28])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[O:13][C:14]=1[CH2:15][OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C>>[CH2:1]([O:8][C:9]1[C:10](=[O:28])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:21])=[O:20])[O:13][C:14]=1[CH:15]=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1OCc1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1oc(CNS(=O)(=O)c2ccccc2)cc(=O)c1OCc1ccccc1
Temperature: 60 °C
Yield: 71.7 %

Procedure:
To a stirred solution of N-(5-benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzene sulfonamide (10-01) (2.8 g, 6.98 mmol) in ethyl acetate (100 mL) IBX (2-iodoxy benzoic acid) (5.86 gm, 20.95 mmol) was added and the reaction mixture was heated up to 60° C. for 6 h. After completion of the reaction, the reaction mixture was filtered and concentrated to get the crude compound. It was then purified using normal column chromatography to get N-(5-benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-benzene sulfonamide (11-01) (2.0 g, 71.71%) as a gummy liquid.
Reaction SMILES: CO.[NH2:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:44])[C@@H:16]([CH2:30][CH2:31][CH2:32][NH:33]C(OCC2C=CC=CC=2)=O)[NH:17][C:18]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[O:19])=[CH:9][CH:8]=1)=[O:5]>C(O)(=O)C.CO.[Pd]>[NH2:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:44])[C@@H:16]([CH2:30][CH2:31][CH2:32][NH2:33])[NH:17][C:18]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[O:19])=[CH:9][CH:8]=1)=[O:5]
Reactant: NC(=O)Cc1ccc(CNC(=O)[C@@H](CCCNC(=O)OCc2ccccc2)NC(=O)c2ccc3ccccc3c2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: NCCC[C@@H](NC(=O)c1ccc2ccccc2c1)C(=O)NCc1ccc(CC(N)=O)cc1
Yield: 86 %

Procedure:
Prepared analogously to Example 1d) but using glacial acetic acid/methanol=1/1 (v/v) as solvent instead of methanol, from (R)-N-[[4-(aminocarbonylmethyl)phenyl]methyl]-N2 -[(2-naphthyl)carbonyl]-N5 -(phenylmethoxycarbonyl)-ornithinamide by catalytic hydrogenation in the presence of palladium on activated charcoal in a yield of 86% of theory. Colourless, highly viscous oil which was used without any further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1.C(N(CC)CC)C.[CH3:15][N:16]1[CH:20]=[C:19]([S:21](Cl)(=[O:23])=[O:22])[N:18]=[C:17]1[CH3:25]>C(Cl)Cl>[CH3:15][N:16]1[CH:20]=[C:19]([S:21]([N:1]2[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]2)(=[O:23])=[O:22])[N:18]=[C:17]1[CH3:25]
Reactant: O=Cc1cn[nH]c1
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(S(=O)(=O)n2cc(C=O)cn2)cn1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve 1H-pyrazole-4-carboxaldehyde (0.150 g, 1.56 mmol) in DCM (5 mL). Add triethylamine (240 μL, 1.72 mmol) and 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (0.334 g, 1.72 mmol). Stir at ambient temperature for 18 hr. Concentrate, and purify via silica gel chromatography, eluting with 50:50 to 100:0 ethyl acetate:hexanes to give the title preparation (317 mg, 80%). GC-MS: m/z=254 [M+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[F:17][C:18]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:21]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1cc(F)ccc1F
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cc(F)ccc3F)c2)CC1
Yield: 108.5 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 2,5-difluorobenzoyl chloride (28 μL, 0.229 mmol), 44.7 mg (>100%) of the title compound were recovered.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][CH2:7][C:6](=O)[NH:5][C:4]2[CH:10]=[CH:11][CH:12]=[CH:13][C:3]1=2.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>O.C1COCC1>[CH3:1][C:2]1([CH3:14])[CH2:8][CH2:7][CH2:6][NH:5][C:4]2[CH:10]=[CH:11][CH:12]=[CH:13][C:3]1=2
Reactant: CC1(C)CCC(=O)Nc2ccccc21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCCNc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5,5-Dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (1.5 g, 8.0 mmol) was dissolved into THF (20 ml) and cooled down to 0° C. LAH (0.5 g 60% in oil, 13 mmol) was added in portions. The reaction was heated to reflux for 2 h. TLC showed a new spot alongside staring lactam. Another 360 mg of LAH was added and the mixture was heated for 2 h. H2O was added until sizzling stopped followed by 2N NaOH. Stirred for 15 min at RT. Na2SO4 (3.8 g) was added and the mixture was stirred for 15 min followed by filtration over Celite®. Diluted with EtOAc and washed with H2O, dried (MgSO4), filtered and concentrated to give 5,5-Dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine.