Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:24])[C@H:6]([CH3:23])[CH2:7][C@H:8]([NH2:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH3:3].[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([F:37])[C:34]=1[O:35][CH3:36])[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:2]([O:4][C:5](=[O:24])[C@H:6]([CH3:23])[CH2:7][C@H:8]([NH:22][C:29](=[O:30])[C:28]1[CH:32]=[C:33]([F:37])[C:34]([O:35][CH3:36])=[C:26]([F:25])[CH:27]=1)[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)[CH3:3]
Reactant: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: COc1c(F)cc(C(=O)O)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(F)c(OC)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
To a solution of (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride salt (200 mg, 0.58 mmol) in CH2Cl2 (2 mL) and DMF (2 mL) at rt is added 3,5difluoro-4-methoxy benzoic acid (108 mg, 0.58 mmol) followed by an addition of TEA (0.32 mL, 2.3 mmol) and HATU (262 mg, 0.69 mmol). The mixture is stirred at rt for 4 hours and quenched with saturated NaHCO3 and diluted in ethyl acetate. The organic layer is washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained material is purified by preparative silica gel thin-layer chromatography plates (eluent:EtOAc/hepane=3/2) to give 265 mg of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-methoxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]=2[NH:7][C:6]1=[O:18].S(Cl)([Cl:21])=O>ClC(Cl)Cl>[Cl:21][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]=2[NH:7][C:6]1=[O:18]
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2n1CCCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n1CCCCl
Reaction time: 1 h
Yield: 56 %

Procedure:
To a stirred mixture of 23 parts of 1,3-dihydro-1-(3-hydroxypropyl)-5-(trifluoromethyl)-2H-benzimidazol-2-one in 150 parts of trichloromethane are added dropwise 32 parts of sulfinyl chloride. Upon completion, the whole is heated to reflux and stirring is continued for 1 hour at reflux temperature. After cooling, the reaction mixture is evaporated and the residue is crystallized from 2,2'-oxybispropane, yielding 14 parts (56%) of 1-(3-chloropropyl)-1,3-dihydro-5-(trifluoromethyl)-2H-benzimidazol-2-one.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([C@H:22]1[CH2:26][O:25][C:24](=[O:27])[NH:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH2:15]([C@H:22]1[CH2:26][O:25][C:24](=[O:27])[N:23]1[C:12](=[O:14])[CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)CCCOCc1ccccc1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C(CCCOCc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
4-Benzyloxybutyric acid (238 g), (S)-4-benzyl-2-oxazolidinone (217 g) and chloroform (1300 mL) were mixed. After an addition of 4-dimethylaminopyridine (45 g) and WSC.HCl (282 g) to the mixture at ice temperature, the resulting mixture was stirred at RT overnight. The reaction mixture was concentrated in vacuo and toluene (2 L) was poured into the residue. The mixture was washed with 1 N hydrochloric acid (1.5 L), saturated aqueous sodium bicarbonate (2 L) and brine (1.5 L), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (424.8 g) as a crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([O-])=[O:25])=[CH:22][CH:21]=1>>[CH3:18][N:19]([CH3:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([NH:1][C:24](=[O:25])[C:23]5[CH:27]=[CH:28][C:20]([N:19]([CH3:29])[CH3:18])=[CH:21][CH:22]=5)=[CH:3][CH:4]=4)[NH:8][CH:7]=3)=[CH:12][CH:13]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: CN(C)c1ccc(C(=O)[O-])cc1
Reactant: Nc1ccc(-c2c[nH]c3cc(N)ccc23)cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc(-c3c[nH]c4cc(NC(=O)c5ccc(N(C)C)cc5)ccc34)cc2)cc1

Procedure:
Compound 626 was prepared according to the procedure described in Scheme IV from 6-amino-3-(4-aminophenyl)-1H-indole and 4-dimethylaminobenzoate. [M+H]+ calcd for C32H31N5O2: 518.15; found: 518.09.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:29]1[CH2:31][CH:30]1[CH2:32][O:33][C:34]([C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[N:42]=[CH:41][CH:40]=[CH:39]2)=[O:35]>C(O)(C)C>[OH:29][CH:30]([CH2:31][N:25]1[CH2:26][CH2:27][CH2:28][CH:23]([C:21](=[O:22])[NH:20][CH:10]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:24]1)[CH2:32][O:33][C:34]([C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[N:42]=[CH:41][CH:40]=[CH:39]2)=[O:35]
Reactant: O=C(OCC1CO1)c1ccc2ncccc2c1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCNC1
Solvent: CC(C)O
Product: O=C(OCC(O)CN1CCCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)C1)c1ccc2ncccc2c1
Temperature: 70 °C
Yield: 83.7 %

Procedure:
Piperidine-3-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (13) (150 mg; 0.4 mmol) is dissolved in isopropanol (10 mL) at ambient temperature. Quinoline-6-carboxylic acid oxiranylmethyl ester (17) (90.8 mg; 0.4 mmol) is added, then the mixture is heated to 70° C. and maintained for 18 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (1%→20% methanol in methylene chloride) affording the desired product (203.4 mg) as an oil. ESMS: MH+ 608.4 (base).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[N:15]1([CH2:21][CH:22]([N:26]2[CH:30]=[C:29]([C:31]3[C:32]4[CH:39]=[CH:38][N:37](COCC[Si](C)(C)C)[C:33]=4[N:34]=[CH:35][N:36]=3)[CH:28]=[N:27]2)[CH2:23][C:24]#[N:25])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(#N)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([N:18]3[CH2:17][CH2:16][N:15]([CH2:21][CH:22]([N:26]4[CH:30]=[C:29]([C:31]5[C:32]6[CH:39]=[CH:38][NH:37][C:33]=6[N:34]=[CH:35][N:36]=5)[CH:28]=[N:27]4)[CH2:23][C:24]#[N:25])[CH2:20][CH2:19]3)(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21
Reactant: O=S(=O)(Cl)c1ccc2[nH]ncc2c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#CCC(CN1CCN(S(=O)(=O)c2ccc3[nH]ncc3c2)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 16 h

Procedure:
1H-Indazole-5-sulfonyl chloride (26 mg, 0.12 mmol; from Step 1) was added to a solution of 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (24 mg, 0.041 mmol; from Example 12, Step 2) and triethylamine (57 uL, 0.40 mmol) in acetonitrile (0.30 mL). The mixture was stirred for 16 hours, then solvent was removed in vacuo. The residue was stirred in a 1:1 mixture of DCM:TFA for 1 hour, concentrated, and stirred in a solution of methanol (1 mL) containing ethylenediamine (0.2 mL) for one hour. Purification via preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH afforded product as the free base (5 mg, 24%). 1H NMR (300 MHz, d6-dmso): δ 12.08 (br s, 1H), 8.70 (s, 1H), 8.60 (s, 1H), 8.31-8.30 (m, 2H), 8.26-8.23 (m, 1H), 7.72 (d, 1H), 7.61 (dd, 1H), 7.52 (d, 1H), 6.87 (d, 1H), 4.93-4.81 (m, 1H), 3.39-2.41 (m, 12H); LCMS (M+H)+: 517.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:14])[CH:3]=2)=[CH:18][CH:17]=1
Reactant: COc1cccc2c(Cl)cc(C)nc12
Reactant: NCc1ccc(Cl)cc1
Product: COc1cccc2c(NCc3ccc(Cl)cc3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-2-methyl-8-methoxyquinoline and 4-chlorobenzylamine.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[C:10]([CH3:14])([CH3:13])[CH2:11][OH:12].Cl.N1C=CC=CC=1.Cl>CCOCC>[Br:9][C:6]1[CH:7]=[CH:8][C:3]2[O:2][CH:11]([OH:12])[C:10]([CH3:14])([CH3:13])[C:4]=2[CH:5]=1
Reactant: COc1ccc(Br)cc1C(C)(C)CO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC1(C)c2cc(Br)ccc2OC1O
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
2-(2-(Methoxy-5-bromophenyl)-2-methyl-1-propanol (30 g, 0.115 mole) was added to molten pyridine hydrochloride (60 g) and the mixture heated with stirring at 190°-200° C. for 50 minutes. Addition to ice-water containing a little hydrochloric acid and isolated through ether gave, after recrystallisation from petroleum ether (b.p. 80°-100° C.) 11.7 g (42%) title product m.p. 114°-5° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:30])[N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:12]=[C:13]([C:15]2[NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=3[N:23]=2)[CH:14]=1)#[N:2].[CH3:31]I>CC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:30])[N:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:12]=[C:13]([C:15]2[N:16]=[C:19]3[N:20]([CH3:31])[CH:21]=[CH:22][CH:17]=[C:18]3[N:23]=2)[CH:14]=1)#[N:2]
Reactant: CI
Reactant: N#Cc1ccccc1-c1cc(-c2nc3cnccc3[nH]2)cn(-c2ccccc2)c1=O
Solvent: CC(C)=O
Product: Cn1cccc2nc(-c3cc(-c4ccccc4C#N)c(=O)n(-c4ccccc4)c3)nc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3 mg of 3-(2-cyanophenyl)-5-(1H-imidazo[4,5-c]pyridin-2-yl)-1-phenyl-1,2-dihydropyridin-2-one was dissolved in 3 ml of acetone. To the mixture was added 2 ml of methyl iodide, followed by stirring at room temperature overnight. The mixture was evaporated, and the residue was diluted with 1 ml of water. To the mixture was added 20 mg of sodium hydroxide, followed by stirring at room temperature for 4 hours. The reaction solution was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated, and the residue was purified by silica gel chromatography (NH silica) (hexane/ethyl acetate system), to give 2 mg of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4](=[S:6])=[S:5].O=O>C(O)(C)C>[CH3:1][N:2]([C:4]([S:6][S:6][C:4]([N:2]([CH3:3])[CH3:1])=[S:5])=[S:5])[CH3:3]
Reactant: CNC
Reactant: S=C=S
Agent: O=O
Solvent: CC(C)O
Product: CN(C)C(=S)SSC(=S)N(C)C
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
13.5 g (0.3 mol) of dimethylamine and 24.4 mg (0.1×10-3 mol) of Mn(CH3COO)2.4H2O were dissolved in 100 g of isopropanol in the reaction equipment described in Example 1. 22.8 g (0.3 mol) of carbon disulfide were added to this solution. The resulting clear, dark brown solution was heated to 50° C., stirred vigorously, and subjected to 1.7 bar of oxygen. Under these conditions, the reaction came to an end after 90 minutes. TMTD was obtained with a yield of 98.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][NH:8][C:7](=[S:16])[C:6]=2[CH:17]=1.[OH-].[Na+].[CH3:20]I>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([S:16][CH3:20])[C:6]=2[CH:17]=1
Reactant: CI
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1C(=S)NC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSC1=NCc2nnc(C)n2-c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
An ice cold, stirred mixture of 8-chloro-4,5-dihydro-1-methyl-6H-s-triazolo[4,3-a][1,4]benzodiazepine-6-thione (VIIIa) (13.2 g., 0.05 mole) in methanol (75 ml.) was treated with 55 ml. of 0.945 N aqueous sodium hydroxide solution. The ice bath was removed and after 10 minutes methyl iodide (3.11 ml., 0.05 mole) was added to the solution. About 5 minutes after this addition the mixture solidified. It was kept at ambient temperature for one hour, mixed with ice water and stirred for 10 minutes. The solid was collected by filtration, washed with water and dried to give 12.0 g. of the title compound, IXa, melting point 244°-249°. The analytical sample was recrystallized from methylene chloride/ethyl acetate and had melting point 247.5°-249°.
Reaction SMILES: [ClH:1].Cl.[CH:3]1([C:7]2[N:8]=[N:9][C:10]([O:26][CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=2)[CH2:6][CH2:5][CH2:4]1.Cl.[CH2:34](OCC)C>C(Cl)Cl>[ClH:1].[ClH:1].[CH:3]1([C:7]2[N:8]=[N:9][C:10]([O:26][CH:27]3[CH2:28][CH2:29][N:30]([CH3:34])[CH2:31][CH2:32]3)=[CH:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:17][CH:18]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: c1cc(-c2cc(OC3CCNCC3)nnc2C2CCC2)ccc1OC1CCCCC1
Reactant: CCOCC
Agent: Cl
Solvent: ClCCl
Product: CN1CCC(Oc2cc(-c3ccc(OC4CCCCC4)cc3)c(C3CCC3)nn2)CC1

Procedure:
To a solution of 3-cyclobutyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.17 mmol, 0.08 g) and aqueous formaldehyde (37%, 0.83 mmol, 0.07 mL) in dry DCM (1 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 1.0 mmol, 0.42 g). The mixture was shaken for 12 hours. The reaction was placed directly onto a 4 g SiO2 cartridge and the column was eluted with 0-6% (2N NH3 in MeOH) in DCM to give 3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-6-(1-methyl-piperidin-4-yloxy)-pyridazine. The neutral amine was treated with 2N HCl in diethyl ether (1 mL) and DCM (1 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.05 g). LCMS: m/z 423 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.26-7.47 (3H, m), 7.02-7.11 (2H, m), 5.35-5.60 (1H, m), 4.37-4.48 (1H, m), 3.97-4.13 (1H, m), 3.67 (1H, d), 3.23-3.53 (2H, m), 2.92 (3H, s), 1.95-2.62 (12H, m), 1.75-1.92 (3H, m), 1.29-1.68 (6H, m).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:2]1.Br[CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C(=O)(O)[O-].[Na+]>C(#N)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][N:19]3[C:23](=[O:24])[C:22]4=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]4[C:20]3=[O:29])[CH2:14][CH2:15]2)=[N:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: c1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2n[nH]c3ccccc23)CC1
Temperature: 25 °C

Procedure:
A suspension of 4-(1H-indazol-3-yl)piperazine (1.6 g, 7.9 mmol), N-(2-bromoethyl)phthalimide (2.1 g, 7.9 mmol), and sodium bicarbonate (0.7 g, 8.3 mmol) in acetonitrile (160 ml) was warmed to reflux for 24 hours. Upon cooling to room temperature, the reaction mixture was filtered through a pad of celite and the solids were washed with DCM. The combined filtrates were concentrated to give the N-[2-[4-(1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide which was used without further purification.
Reaction SMILES: Cl[S:2]([C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[N:7]2[N:6]=1)(=[O:4])=[O:3].C(#N)C.C[Si](C)(C)[NH:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29]>N1C=CC=CC=1>[Cl:28][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:29])[C:22]=1[NH:21][S:2]([C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[N:7]2[N:6]=1)(=[O:4])=[O:3]
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Cl)nc2n1
Reactant: C[Si](C)(C)Nc1c(Cl)cccc1Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1cc(C)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 77.2 %

Procedure:
A solution consisting of 102.4 mg (0.415 mmole) of 2-chlorosulfonyl-5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine, 2.0 ml of acetonitrile, and 33.6 μl (0.415 mmole) of pyridine was stirred 5 minutes. N-trimethylsilyl-2,6-dichloroaniline, 86.9 μl (0.456 mmole) was added. The solution was stirred at room temperature for 16 hours and the reaction monitored by thin layer chromatography and by reverse phase HPLC. The 2-chlorosulfonyl compound gradually disappeared and a new peak appeared. The reaction was about 10-30 percent complete after 16 hours. An additional 33.6 μl of pyridine was added and the solution heated at 65° C. for 4 hours and at reflux for 16 hours. The solvent was removed under nitrogen and the residue treated with 4 ml of 0.5N NaOH and stirred for 0.5 hour. The solution was extracted with CH2Cl2, acidified with concentrated HCl and filtered. The precipitate was washed with water and dissolved in CH3CN. The resulting solution was heated to reflux, filtered through silica gel and the solvent removed in vacuo to obtain 119 mg (0.321 mmole, 77.2 percent yield) of N-(2,6-dichlorophenyl)-5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide as a light yellow solid. The product was further purified by washing with acetone, and recrystallizing from refluxing CH3CN to obtain 91.5 mg (0.246 mmole) of product as a white powder, m.p. 263°-265° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2.[CH3:26][N:27](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]([C:2]1[N:3]=[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2)#[N:27]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Cl)cc3ccc(F)cc23)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3ccc(F)cc23)C1
Temperature: 160 °C
Yield: 72 %

Procedure:
To a solution of (S)-tert-butyl 3-((3-chloro-7-fluoroisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (0.5 g, 1.37 mmol) in DMF (15 mL) was added Zn(CN)2 (0.48 g, 4.1 mmol), and Pd(PPh3)4(0.16 g, 0.14 mmol) under a nitrogen atmosphere. The mixture was heated to 160° C. for 30 minutes in a microwave reactor. The mixture was partition between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The organic layers were combined, washed with saturated aqueous NaCl (3×50 mL) and concentrated in vacuo. The crude product was purified by column chromatography eluting with petroleum ether and ethyl acetate (PE/EtOAc=10:1-5:1 gradient) to give the title compound (0.36 g, 72%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38-8.35 (d, J=10.8 Hz, 1H), 8.01-7.97 (m, 1H), 7.77-7.72 (m, 3H), 4.66-4.58 (m, 1H), 3.69-3.67 (m, 1H), 3.48-3.46 (m, 1H), 3.39-3.37 (m, 1H), 3.28-3.27 (m, 1H), 2.2 (s, 1H), 1.97-1.91 (m, 1H), 1.40 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:23])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])([CH3:14])[CH2:6][CH2:5]2.CC([O:28]C)(C)C>O>[OH:28][C:7]([CH3:14])([C:15](=[O:16])[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:23]
Reactant: COC(C)(C)C
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)N1CCCCC1)O2
Solvent: O
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)N2CCCCC2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 319 mg of (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperidin-1-yl)methanone (1.02 mmol) in 5 mL MTBE which was treated with 1.077 g FeCl3.6H2O in 6 mL H2O. The reaction mixture rapidly turned black which faded to a yellow color over the course of the reaction. An additional 2 mL MTBE was added and stirred vigorously for 3 h at room temp. The reaction was quenched with 10 mL H2O and 10 mL MTBE, the layers separated and the organics washed with H2O until colorless. The combined aqueous phases were extracted 2×10 mL MTBE and the combined organics washed with saturated NaCl and dried over Na2SO4. Flash chromatography yielded 335 mg of 2-(3-hydroxy-3-methyl-4-oxo-4-(piperidin-1-yl)butyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione as a dark yellow oil.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[C:9]([C:10]2[C:19]3[O:18][CH2:17][C@H:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:15]4[C:26]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[N:27][C:13]([C:14]=34)=[CH:12][CH:11]=2)=[C:8]([CH3:34])[O:7][N:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:42][C:43]([N:45]([CH3:47])[CH3:46])=[O:44]>C(Cl)Cl.CO>[CH3:4][C:5]1[C:9]([C:10]2[C:19]3[O:18][CH2:17][C@H:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:15]4[C:26]([N:28]5[CH2:33][CH2:32][N:31]([CH2:42][C:43]([N:45]([CH3:47])[CH3:46])=[O:44])[CH2:30][CH2:29]5)=[N:27][C:13]([C:14]=34)=[CH:12][CH:11]=2)=[C:8]([CH3:34])[O:7][N:6]=1
Reactant: CN(C)C(=O)CCl
Reactant: Cc1noc(C)c1-c1ccc2nc(N3CCNCC3)n3c2c1OC[C@@H]3c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: Cc1noc(C)c1-c1ccc2nc(N3CCN(CC(=O)N(C)C)CC3)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 28.4 %

Procedure:
To a solution of (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-piperazin-1-yl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine trihydrochloride (10 mg, 0.03 mmol) in methylene chloride (1.0 mL), potassium carbonate (18 mg, 0.13 mmol) was added, followed by 2-chloro-N,N-dimethylacetamide (2.7 μL, 0.026 mmol) and the mixture was stirred for 5 min. The mixture was then heated at 60° C. overnight. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to give the title compound, (3.7 mg, 30%). LCMS calc. for C27H32N7O3 (M+H)+: m/z=502.2. found: 502.3.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3]1.[CH:10](=O)[CH2:11][CH2:12][CH3:13].S1C=CC=C1>CO.[Pd]>[CH2:10]([N:4]1[CH2:5][CH2:6][C@@H:7]([CH2:8][OH:9])[C@H:2]([OH:1])[CH2:3]1)[CH2:11][CH2:12][CH3:13]
Reactant: OC[C@@H]1CCNC[C@H]1O
Reactant: CCCC=O
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: CCCCN1CC[C@@H](CO)[C@H](O)C1
Yield: 99.5 %

Procedure:
A mixture of intermediate (1-a) (0.022 mol) and butanal (0.025 mol) in methanol (150 ml) was hydrogenated with palladium on activated carbon (10%) (1 g) as a catalyst in the presence of a solution of thiophene (4% in THF) (1 ml). After uptake of H2 (1 equiv.), the catalyst was filtered off and the filtrate was evaporated, yielding 4.1 g of (±)-trans-1-butyl-3-hydroxy-4-piperidinemethanol (interm. 1-b) (99.5%, used in next reaction step without further purification).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=[O:5])[CH3:4].[CH2:7]([O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Ba+2].[OH-]>CCO>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([CH:19]=[CH:4][C:3](=[O:5])[CH:2]([CH3:6])[CH3:1])=[CH:21][CH:22]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)C(C)C
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)C(=O)C=Cc1ccc(OCc2ccccc2)cc1

Procedure:
The title compound was prepared as described in the General Method 2 using 81.1 g (942 mmol) of 3-methyl-butan-2-one, 100 g (474 mmol) of 4-benzyloxy benzaldehyde, 10 g of anhydrous barium hydroxide and 500 mL of EtOH.