Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:2].Cl.Cl[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].C(OC(=O)NC1CCC(NCC2C=C(C3C=NC=CC=3)C=CC=2OC)CC1)(C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2].C(COC)OC>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[CH:1]=[O:2]
Reactant: COc1ccc(B(O)O)cc1C=O
Reactant: Clc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(-c2cccnc2)cc1CNC1CCC(NC(=O)OC(C)(C)C)CC1
Solvent: COCCOC
Product: COc1ccc(-c2ccncc2)cc1C=O
Temperature: 65 °C
Reaction time: 24 h

Procedure:
To a 2-L 3-neck RB flask equipped with a mechanical stirrer, condenser with N2 inlet and temperature probe is added 3-formyl-4-methoxyphenylboronic acid P15 (49.83 g, 276.90 mmol), 4-chloropyridine hydrochloride (46.63 g, 310.84 mmol), triphenylphosphine (7.42 g, 28.28 mmol) and dimethoxyethane (280 mL). To the resulting white slurry is added 2M aqueous K2CO3 (290 mL). The resulting mixture is degassed for 20 minutes with N2 and Pd(OAc)2 (1.65 g, 7.36 mmol) is added. Under N2 atmosphere the mixture is heated to 65° C. After 47 h additional 4-chloropyridine hydrochloride (12.82 g, 85.50 mmol), triphenylphosphine (3.63 g, 13.83 mmol) and Pd(OAc)2 (632.3 mg, 2.82 mmol) is added and heating is resumed for an additional 24 h. The reaction mixture is partitioned between EtOAc (300 mL) and H2O (300 mL). The aqueous layer is extracted with EtOAc (4×400 mL) and the combined organic extracts are concentrated to a yellow-orange viscous oil. The crude reaction product is purified by filter chromatography on SiO2 eluting with EtOAc/hexanes (30 to 100%) followed by 3% MeOH/EtOAc. The yellow solid is triturated with 10% Et2O/hexanes and filtered to give 2-methoxy-5-(pyridin-4-yl)benzaldehyde P9 (53.0 g, 90%) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.39 (s, 1H), 8.61 (d, J=6.10 Hz, 2H), 8.11 (d, J=8.54 Hz, 1H), 8.06 (d, J=2.20 Hz, 1H), 7.70 (d, J=5.12 Hz, 2H), 7.38 (d, J=8.78 Hz, 1H), 3.98 (s, 3H) 13C NMR (101 MHz, DMSO-d6) δ ppm 189.63, 162.77, 150.92, 146.15, 135.17, 130.03, 126.71, 125.13, 121.34, 114.37, 57.01; LRMS (ESI) Calcd for C13H11NO2 [M]: 213.079. Found [M+H]: 214.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].N1CCCCC1.C(O)(=O)C>CC(O)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:13]([C:14](=[O:15])[CH3:16])[C:12]([O:18][CH3:19])=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: COC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-nitrobenzaldehyde (15.1 g, 0.1 mol), methyl acetoacetate (12.773 g, 0.11 mol), piperidine (0.41 g, 476 mL, 4.8 mmol), and acetic acid (0.288 g, 274 mL, 4.8 mmol) in 2-propanol (400 mL) was stirred at room temperature for 48 hours. The white solid, methyl 2-{(4-nitrophenyl)methylene}-3-oxobutyrate, formed was filtered, washed with 2-propanol (2×50 mL) and dried (21.80 g, 93%).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17](O)=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]([N:23]3[CH2:24][CH2:25][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:22]3)=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=C1c2ccccc2C=Cc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C=C2c3ccccc3C=Cc3ccccc32)CC1

Procedure:
172 mg (0.69 mmol) of 5H-dibenzo[a,d][7]annulen-5-ylideneacetic acid, 144 mg (0.78 mmol) of t-butyl 1-piperazinecarboxylate, 148 mg (0.77 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride and 0.11 ml (0.79 mmol) of triethylamine were stirred in 5 ml of dichloromethane at room temperature overnight. The reaction mixture was washed with 0.5 N aqueous sodium hydroxide solution and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[C:10]#N)=[CH:5][CH:4]=1.O=[CH:24][C:25](=C)[CH3:26]>>[CH3:26][C:25]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[CH:24]=1
Reactant: C=C(C)C=O
Reactant: CSc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1
Product: CSc1ccc(-c2cc(C)cn2-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-methylthiophenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as pale brown scaly crystals (yield 31%), melting at 172-173° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH3:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:16]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:17]
Reactant: CCBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 102.1 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (V-1) (3 g, 15 mmol) in DMF (6 mL) were added bromoethane (3.24 g, 30 mmol) and K2CO3 (4.26 g, 30 mmol). The reaction mixture was stirred at 60° C. overnight, then diluted with EtOAc, washed with water and then brine. The organic layer was separated, then dried over Na2SO4, and concentrated to afford the title compound (3.40 g). MS (m/z): 223 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][C:13]([F:16])([F:15])[F:14])[C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C>[Pd].C(O)C>[F:16][C:13]([F:14])([F:15])[O:12][C:10]1[C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=[CH:2][CH:11]=1
Reactant: Nc1nc2c(OC(F)(F)F)cc(Br)cc2s1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nc2c(OC(F)(F)F)cccc2s1
Yield: 72.4 %

Procedure:
6-Bromo-4-trifluoromethoxy-benzothiazol-2-ylamine (157 mg, 0.50 mg), triethylamine (0.21 ml, 1.5 mmol) and palladium on carbon (10%, 15 mg) are suspended in ethanol (12 ml) and hydrogenated at atmospheric pressure for 96 h. The catalyst was filtered off and the solution evaporated to dryness. The residue was dissolved in ethyl acetate, washed three times with water, dried and the solvent removed in vacuo. The product is obtained as brown solid (85 mg, 73%). MS: m/e=235 (M+H+).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH2:15][C:16]([OH:18])=[O:17])=[CH:9][NH:10]2.[C:19](=O)([O-])O.[Na+]>CO>[CH3:19][CH:15]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[Br:5])[NH:10][CH:9]=1)[C:16]([OH:18])=[O:17]
Reactant: O=C(O)Cc1c[nH]c2cccc(Br)c12
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: CC(C(=O)O)c1c[nH]c2cccc(Br)c12
Reaction time: 0.5 h

Procedure:
To methanol (10 mL), thionyl chloride (0.76 mL) was added dropwise at −15 to −10° C., followed by stirring for 30 minutes. To the mixture, (4-bromo-1H-indol-3-yl)acetic acid (Chemical and Pharmaceutical Bulletin, 33(9), 3696-3708 (1985), 1.32 g) was added, followed by stifling at room temperature for 2 hours. To the reaction mixture, an aqueous saturated sodium hydrogen carbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed in turn with water and saturated saline, dried and then concentrated. The residue was washed with diisopropyl ether/n-hexane (1:2) to obtain the titled compound having the following physical properties (1.26 g).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([C:14]2[O:18][NH:17][C:16](=[O:19])[CH:15]=2)[CH2:11][CH2:10][N:9]1C(OC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Br>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([C:14]2[O:18][NH:17][C:16](=[O:19])[CH:15]=2)[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1Cc1ccccc1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@H](Cc3ccccc3)C2)o[nH]1
Reaction time: 8 h

Procedure:
To (2S,4S)-methyl 2-benzyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.99 g) was added HBr (33% in HOAc, 20 mL) and the solution was stirred for 8 h. The volatiles were concentrated and the residues purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-40% acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 15 minutes with a flow of 100 mL/minutes. The title compound was isolated (0.62 g, 30%). 1H NMR (600 MHz, dmso) δ 1.47 (m, 1H), 1.67-1.83 (m, 3H), 2.51-2.67 (m, 3H), 2.74-2.89 (m, 2H), 3.04-3.15 (m, 1H), 5.67 (s, 1H), 7.21 (m, 5H); [α]20D +47.0 (MeOH/H2O 1:1, c=1); HRMS Calculated for [C15H19N2O2]+: 259.1447. Found: 259.1449.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:32](I)[CH3:33]>CN(C)C=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH2:32][CH3:33])[C:25]([F:26])([F:28])[F:27])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C(F)(F)F)c23)c(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a solution of 1-[9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (100.5 mg, 0.235 mmol) in N,N-dimethylformamide (1.5 mL) was added sodium hydride (14.1 mg, 0.353 mmol) at 0° C. After 30 min, to the mixture was added ethyl iodide (94 μL, 1.175 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3.5 hrs. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless powder (80.7 mg, 0.177 mmol, 76%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C@:9]([CH3:37])([C:33]([F:36])([F:35])[F:34])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[C:29]([NH2:30])=[CH:28][C:27]([C:31]#[N:32])=[CH:26][N:25]=3)=[O:23])[N:16]=2)([CH3:14])[N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:7][C:8]1[C@:9]([CH3:37])([C:33]([F:36])([F:34])[F:35])[O:10][CH2:11][C@:12]([C:15]2[N:16]=[C:17]([NH:21][C:22]([C:24]3[C:29]([NH2:30])=[CH:28][C:27]([C:31]#[N:32])=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:19][CH:20]=2)([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(NC(=O)c3ncc(C#N)cc3N)n2)CO[C@@]1(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@]1(c2cccc(NC(=O)c3ncc(C#N)cc3N)n2)CO[C@@](C)(C(F)(F)F)C(N)=N1
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
To a solution of ((2R,5R)-5-{6-[(3-amino-5-cyano-pyridine-2-carbonyl)-amino]-pyridin-2-yl}-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester (71 mg, 0.133 mmol) in DCM (3 ml) was added TFA (1 ml). After stirring for 1.5 h the mixture was poured onto 10% aq. Na2CO3 and extracted three times with DCM. The combined organic layers were dried with K2CO3, filtered and evaporated. The title compound (46 mg) was obtained after chromatography on silica gel (hexanes/15-25% (EtOAc/EtOH 9:1)) as a yellow solid. HPLC: RtH3=3.027 min; ESIMS: 434 [(M+H)+]; 1H-NMR (600 MHz, DMSO-d6): 10.23 (s, 1H), 8.25 (s, 1H), 8.06 (d, 1H), 7.85 (t, 1H), 7.69 (s, 1H), 7.36-7.27 (m, broad, 3H), 6.12-6.00, (s, broad, 2H), 3.94 (d, 1H), 3.76 (d, 1H), 1.42 (s, 3H), 1.34 (s, 3H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=1)[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH3:22])=[CH:16][CH:15]=1)=[O:12].B(O)(O)[C:33]1[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=1>C1(C)C=CC=CC=1.C(O)C.O>[CH:23]1([N:21]([CH2:20][C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:11]([C:10]3[CH:9]=[C:8]([C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)[CH:31]=[CH:30][CH:29]=3)=[O:12])=[CH:15][CH:16]=2)[CH3:22])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CN(Cc1ccc(NC(=O)c2cccc(Br)c2)cc1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2cccc(C(=O)Nc3ccc(CN(C)C4CCCCC4)cc3)c2)cc1

Procedure:
K2CO3 (0.2 mmol, 0.03 g) and a Pd(dppf)2 catalyst:DCM complex (1:1) (0.03 mmol, 0.02 g) was added to a mixture of 3-bromo-N-{4-[(cyclohexyl-methyl-amino)-methyl]-phenyl}-benzamide Compound 10f (0.1 mmol, 0.04 g) and p-tolylboronic acid Compound 11a (0.12 mmol, 0.02 g) in a mixed solution of toluene/ethanol/water (7 mL/1 mL/1 mL). The resulting suspension was heated to reflux for 5 hrs, concentrated and purified with preparative TLC (10% MeOH/2% Et3N/88% EtOAc) to yield 4′-methyl-biphenyl-3-carboxylic acid {4-[(cyclohexyl-methyl-amino)-methyl]-phenyl}amide Compound 11b (0.02 g, 48%). MS m/e 413 (M+1).
Reaction SMILES: O1CCCO[CH:2]1[C:7]1[CH:11]=[CH:10][S:9][C:8]=1[S:12]([NH:15][NH2:16])(=[O:14])=[O:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.C(OCC)(=O)C>[S:12]1(=[O:14])(=[O:13])[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:2]=[N:16][NH:15]1
Reactant: NNS(=O)(=O)c1sccc1C1OCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=S1(=O)NN=Cc2ccsc21
Temperature: 56 °C
Yield: 17.9 %

Procedure:
The solid obtained in step A (2.4 g, 48 mmol) was dissolved in acetone (70 mL). p-Toluenesulfonic acid (0.20 g, 1 mmol) was added and the mixture was stirred at refluxing temperature (56° C.) for 2h. The solvent was evaporated, the residue obtained was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate (20 mL) and brine. The ethyl acetate layer was dried over MgSO4 and evaporated to a green solid which was flash chromatographed (silica, hexane-ethyl acetate gradient) to provide a white solid (1.62 g, 90%). mp:125°-127° C. Cl-MS m/e 189 (M+H)+. 1HNMR (DMSO-d6):δ:7.44 (1H, 1s, CH); 7.44 (1H, d, J=5.0 Hz); 8.05 (1H, d, J=5.0 Hz); 8.24 (1H, 1s, CH=N). 13C NMR (DMSO-d6): δ:2125.96, 132.00, 133.64, 136.96, 137.12.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[N:18]([CH2:19][CH2:20][CH3:21])[N:17]=[C:16]([C:22]#[N:23])[CH:15]=1.C([O-])(=O)C.[K+].[Br:29]Br.S([O-])(O)=O.[Na+]>C(O)(=O)C.ClCCl.O>[Br:29][C:15]1[C:16]([C:22]#[N:23])=[N:17][N:18]([CH2:19][CH2:20][CH3:21])[C:14]=1[CH2:13][CH2:12][N:3]1[C:2](=[O:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:11]
Reactant: CCCn1nc(C#N)cc1CCN1C(=O)c2ccccc2C1=O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CCCn1nc(C#N)c(Br)c1CCN1C(=O)c2ccccc2C1=O
Reaction time: 24 h
Yield: 97.4 %

Procedure:
To a solution of 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carbonitrile (14.1 g, 45.7 mmol) and potassium acetate (6.73 g, 68.6 mmol) in acetic acid (91 mL) and dichloromethane (46 mL) was slowly added bromine (3.28 g, 64.0 mmol). The mixture was stirred for one day. Saturated aqueous sodium hydrogensulfite was added until the mixture became colorless, then the mixture was concentrated under reduced pressure to form a slurry. Water (450 mL) was added to the slurry and a white solid was isolated by filtration, washed with water, and dried to afford 17.24 g of 4-bromo-5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carbonitrile as a white solid.
Reaction SMILES: [CH3:1][N+:2]#[C-:3].[Li]CCCC.CCCCCC.[CH3:15][C:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:20])[C:17](Cl)=[O:18].[Na+].[Cl-]>C1COCC1>[CH3:20][C:16]([C:17]1[O:18][CH:1]=[N:2][CH:3]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:15]
Reactant: [C-]#[N+]C
Reactant: CC(C)(C(=O)Cl)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)c1cnco1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 53.9 %

Procedure:
To a solution of methyl isocyanide (1.3 mmol, 1.3 eq.) in THF (5 mL) at −78° C. was added dropwise a solution of n-BuLi in Hexane (2.5 M, 1.3 mmol, 1.3 eq.). The resulting yellowish solution was stirred at −78° C. for an additional 45 min and 2-Methyl-2-phenylpropionyl chloride (1.0 mmol, 1.0 eq.) was slowly added. The mixture was stirred at −78° C. for an additional 1 h and allowed to warm to room temperature followed by the addition of saturated aqueous NaCl solution (5 mL). The mixture was extracted by EtOAc (3×5 mL) and the combined organic extracts were washed by saturated aqueous NaCl solution, dried by Na2SO4, filtered and evaporated in vacuo. The residue was further purified by flash chromatography (silica gel, 10% EtOAc/Hexanes) to afford 5-(1-Methyl-1-phenylethyl)oxazole as a colorless oil (101 mg, 54%). 1H NMR: δ (400 MHz, CDCl3) 7.74 (s,1H), 7.30 (m, 2H), 7.23 (m, 3H), 6.85 (s,1H), 1.69 (s, 6H). MS (M+H+): 188.1
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:20])[CH2:4][CH:5]([CH3:19])[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)(O)[CH:7]([CH3:9])[CH3:8]>C(O)=O>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:6](=[C:7]([CH3:8])[CH3:9])[CH:5]([CH3:19])[CH2:4][N:3]([CH3:20])[CH3:2])[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(C(O)(C(C)C)C(C)CN(C)C)c1
Agent: Cl
Solvent: O=CO
Product: COc1cccc(C(=C(C)C)C(C)CN(C)C)c1
Yield: 76.8 %

Procedure:
Starting from (RS)-1-dimethylamino-2,4-dimethyl-pentan-3-one and 1-bromo-3-methoxy-benzene, (2RS,3RS)-1-dimethylamino-3-(3-methoxy-phenyl)-2,4-dimethyl-pentan-3-ol hydrochloride (26) was obtained, under the conditions given in Example 1 (1st step), in a yield of 44% and with a melting point of 180°-181° C. 30 g (0.1 mole) of compound (26) were reacted with 450 ml of concentrated formic acid as in Example 5. The crude base obtained was introduced on to a column packed with silica gel. Elution with 7:1 diisopropyl ether/methanol gave 19 g base (77% theoretical) as a light yellow, viscous oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:28]=[CH:27][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH:55]2[CH2:57][O:56]2)=[CH:49][CH:48]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH3:26][O:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][NH:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:57][C@H:55]([OH:56])[CH2:54][O:53][C:50]3[CH:51]=[CH:52][C:47]([OH:46])=[CH:48][CH:49]=3)=[CH:28][CH:27]=2)[CH2:14][CH2:13]1)=[O:16]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc(CNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)c1
Product: COc1cccc(CNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)c1

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(3-methoxybenzyl)-1-piperidinecarboxamide (0.73 g, 2.0 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane according to Procedure G to give the title compound (0.53 g, 0.67 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[H-].[Na+].[CH2:12]([O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24](Cl)=[CH:25][CH:26]=[N:27]2)=[CH:22][C:21]=1[C:31]([O:33][CH3:34])=[O:32])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C>CS(C)=O.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:24]2[C:23]3[C:28](=[CH:29][C:20]([O:19][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[C:21]([C:31]([O:33][CH3:34])=[O:32])[CH:22]=3)[N:27]=[CH:26][CH:25]=2)=[CH:4][C:3]=1[Cl:9]
Reactant: Nc1ccc(O)cc1Cl
Reactant: COC(=O)c1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
After dissolving 4-amino-3-chlorophenol (2.22 g, 15.45 mmol) in dimethylsulfoxide (40 ml), sodium hydride (618 mg, 15.45 mmol) was gradually added at room temperature and the mixture was stirred for 30 minutes. Methyl 7-(benzyloxy)-4-chloro-6-quinolinecarboxylate (4.05 g, 12.36 mmol) was added, and the mixture was heated at 100° C. for 2 hours while stirring. Upon cooling to room temperature, the reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off and subjected to silica gel column chromatography (eluent—ethyl acetate), the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (3.938 g, 9.06 mmol, 73.3%) as light brown crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[K+].[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[S:32](Cl)(=[O:34])=[O:33])[CH:25]=[CH:24][CH:23]=1>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([S:32]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:31]=3[N:22]=[CH:23][CH:24]=[CH:25]4)(=[O:33])=[O:34])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: COc1ccc(-c2c[nH]c3ncccc23)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(-c2cn(S(=O)(=O)c3cccc4cccnc34)c3ncccc23)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16 %

Procedure:
3-(3,4-Dimethoxy-phenyl)-1H-pyrrolo-[2,3-b]pyridine, 1, (50 mg, 0.20 mmol) was dissolved in methylene chloride (4 mL). Aqueous potassium hydroxide (50% wt/vol, 300 μL) and tetrabutylammonium hydrogen sulfate (2 mg, 0.007 mmol) were added. The reaction mixture was stirred for 10 minutes at room temperature. Into the reaction was added 8-quinoline-sulfonyl chloride (48 mg, 0.21 mmol) and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated and the residue was washed with brine and ethyl acetate. The organic portion was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by preparative TLC (75% ethyl acetate:hexanes). The product was eluted from the silica with ethyl acetate and filtration. The filtrate was concentrated to provide 7 (14 mg, 16%). MS(ESI) [M+H+]+=445.9.