Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:14]=[C:15]([C@H:20]([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([N:40]3[CH2:45][CH2:44][CH2:43][NH:42][C:41]3=[O:46])[CH2:36][CH2:35]2)[CH2:21][N:22]([CH3:31])[C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]=[CH:17][C:18]=1[Cl:19]>ClCCl>[C:23]([N:22]([CH3:31])[CH2:21][C@H:20]([C:15]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([Cl:12])[CH:14]=1)[CH2:32][CH2:33][N+:34]1([O-:6])[CH2:35][CH2:36][CH:37]([N:40]2[CH2:45][CH2:44][CH2:43][NH:42][C:41]2=[O:46])[CH2:38][CH2:39]1)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(C[C@@H](CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Solvent: ClCCl
Product: CN(C[C@@H](CC[N+]1([O-])CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reaction time: 1 h
Yield: 61 %

Procedure:
3-Chloroperoxybenzoic acid (0.700 g) in dichloromethane (16 mL) was added dropwise to a solution of (S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2-oxoperhydropyrimidin-1-yl)piperidino]butyl]-N-methylbenzamide (1.31 g) in dichloromethane (12 mL) at 0° C. After being stirred for 1 hour, the reaction mixture was diluted with dichloromethane, washed with aqueous sodium bicarbonate, dried, and evaporated. The crude product was chromatographed, with dichloromethane:methanol (gradient 98:2, 70:30) as eluent. The purified product (0.592 g) and p-toluenesulfonic acid monohydrate (0.232 g) were dissolved in dichloromethane:methanol and evaporated to give the title compound as a white solid (0.824 g); MS: m/z=533(M+1); Analysis for C27H 34Cl2N4O3.1.10 C7H8O3S.1.10 H2O: Calculated: C, 56.11; H, 6.10; N, 7.54; Found: C, 55.85; H, 5.96; N, 7.33.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[CH2:10]([O:12][C:13](=[O:16])[NH:14][NH2:15])[CH3:11]>C(O)C>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:1](=[N:15][NH:14][C:13]([O:12][CH2:10][CH3:11])=[O:16])[CH3:2]
Reactant: CCOC(=O)NN
Reactant: CC(=O)c1ccccn1
Solvent: CCO
Product: CCOC(=O)NN=C(C)c1ccccn1
Temperature: 25 °C
Yield: 36.7 %

Procedure:
A mixture of 6.06 gm (0.05 mole) of 2-acetylpyridine, 5.21 gm (0.05 mole) of ethylcarbazate and 100 ml of absolute ethanol is refluxed 2 hr. The hot solution is filtered. The filtrate is cooled to room temperature and then chilled in the refrigerator. The product is collected, washed with Skellysolve B and dried to yield 3.8 gm (37%) of the title compound having a melting point of 113.2° C.
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][N:17](C3CCCCO3)[C:14]2=[CH:15][N:16]=1>>[C:20]1([C:19]2[C:13]3[C:14](=[CH:15][N:16]=[C:11]([C:5]4[CH:6]=[N:1][CH:2]=[N:3][CH:4]=4)[CH:12]=3)[NH:17][N:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OB(O)c1cncnc1
Reactant: Brc1cc2c(-c3ccccc3)nn(C3CCCCO3)c2cn1
Product: c1ccc(-c2n[nH]c3cnc(-c4cncnc4)cc23)cc1
Yield: 25 %

Procedure:
Following the procedures in Example 136, pyrimidin-5-ylboronic acid and 5-bromo-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine were reacted and the product was deprotected to give 150 as a yellow solid (25 mg, 25%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.59 (s, 1H), 9.26 (s, 1H), 9.21 (s, 1H), 8.79 (s, 1H), 8.40 (s, 1H), 8.18 (d, 2H), 7.57 (t, 2H), 7.47 (t, 1H). ESI MS m/z=274 (M+1)
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2C(=O)O[CH:17]([C:21]([F:24])([F:23])[F:22])[N:16]=2)=[CH:11][CH:10]=1.Cl[C:26](=[CH2:31])[C:27]([O:29][CH3:30])=[O:28]>C(#N)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[NH:16][C:17]([C:21]([F:22])([F:23])[F:24])=[CH:31][C:26]=2[C:27]([O:29][CH3:30])=[O:28])=[CH:13][CH:14]=1
Reactant: C=C(Cl)C(=O)OC
Reactant: O=C1OC(C(F)(F)F)N=C1c1ccc(Cl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
Triethylamine (5.58 g, 0.055 mol) is added dropwise to a mixture of 4-(p-chlorophenyl)-2-(tri-fluoromethyl)-5(2H)-oxazolone (15.6 g, 0.054 mol), methyl α-chloroacrylate (6.52. g, 0.054 mol) and acetonitrile (50 mL). The reaction mixture heats up to 55° C. during the addition. After the addition is complete, the reaction mixture is heated at reflux temperature for one hour, cooled to room temperature and filtered. The filtrate is poured into an ether/water mixture and extracted with ether. The combined organic extracts are dried over anhydrous magnesium sulfate and concentrated in vacuo to give a black residue. Recrystallization of the residue from hexane gives the title compound as an orange solid (8.25 g, 50.2%). Indentified by NMR spectral analyses.
Reaction SMILES: ClC1C=C([N:8]2[CH2:13][C@H:12]([CH3:14])[NH:11][C@H:10]([CH3:15])[CH2:9]2)C=CN=1.Br[C:17]1[CH:18]=[C:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:20]([O:23][CH3:24])=[N:21][CH:22]=1>>[CH3:15][C@H:10]1[NH:11][C@@H:12]([CH3:14])[CH2:13][N:8]([C:17]2[CH:18]=[C:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:20]([O:23][CH3:24])=[N:21][CH:22]=2)[CH2:9]1
Reactant: C[C@@H]1CN(c2ccnc(Cl)c2)C[C@H](C)N1
Reactant: COc1ncc(Br)cc1C(=O)OC(C)(C)C
Product: COc1ncc(N2C[C@@H](C)N[C@@H](C)C2)cc1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared in a similar manner to cis-1-(2-chloro-4-pyridinyl)-3,5-dimethylpiperazine (D19) using 1,1-dimethylethyl 5-bromo-2-(methyloxy)-3-pyridinecarboxylate (D23) and cis-2,2-dimethylpiperazine as the starting materials.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH3:26][O:27][CH2:28][CH2:29]Br>COCCBr.O>[CH3:26][O:27][CH2:28][CH2:29][O:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc([N+](=O)[O-])ccc1NC(C)=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
The mixture of N-(2-hydroxy-4-nitrophenyl)acetamide (93 g, 0.47 mol, 1.00 equiv), potassium carbonate (184 g, 1.33 mol, 2.81 equiv) and dimethylformamide (465 ml) was stirred at 60° C. as 2-bromoethyl methyl ether (90 g, 0.647 mol, 1.36 equiv) was added over 15 minutes. After 1 hour, additional 2-bromoethyl methyl ether (4 g, 0.028 mol, 0.059 equiv) was added and the mixture was stirred at 60° C. for another hour. The mixture was cooled to room temperature and poured into 1 L of water. After 30 minutes, the product was formed and collected by filtration and washed with water and heptane. The product was dried in a vacuum oven at 60° C. to give the title compound 97 g. MS (ESI) m/z: 255 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][N:15]=3)[NH:10][C:5]2=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([N:10]1[C:5]2[C:6](=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:8]=[C:9]1[C:11]1[O:12][CH:13]=[CH:14][N:15]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Clc1ccc2[nH]c(-c3ncco3)cc2n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(cc(-c3ncco3)n2Cc2ccccc2)n1

Procedure:
To a well stirred mixture of 5-chloro-2-(1,3-oxazol-2-yl)-1H-pyrrolo[3,2-b]pyridine (0.39 g, 1.8 mmol, from Step 2) in DMF (8 mL) was added Cs2CO3 (1.7 g, 5.3 mmol) and benzyl bromide (0.21 mL, 1.8 mmol, Aldrich). After stirring overnight, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with an additional two portions of EtOAc. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The resulting light yellow crystalline solid was used directly in Step 4. LCMS (M+H)+: 310.1/312.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[N:18]([CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:17]([CH2:26][CH3:27])=[N:16][C:10]=3[C:11]([NH2:15])=[N:12][C:13]=2[CH:14]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:15][C:11]1[C:10]2[N:16]=[C:17]([CH2:26][CH3:27])[N:18]([CH2:19][CH:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[C:9]=2[C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:35](=[O:37])[CH3:36])=[CH:14][C:13]=2[N:12]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCc1nc2c(N)nc3cc(CCCN)ccc3c2n1CC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(N)nc3cc(CCCNC(C)=O)ccc3c2n1CC1CCOCC1
Reaction time: 18 h
Yield: 24.8 %

Procedure:
7-(3-Aminopropyl)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (500 mg, 1.4 mmol), triethylamine (410 mg, 4.1 mmol), and acetic anhydride (153 mg, 1.5 mmol) were combined in dichloromethane (50 mL) at 0° C. and the reaction was stirred for approximately 18 hours. Aqueous sodium carbonate (1%, 50 mL) was added and the reaction mixture was stirred for one additional hour. The fractions were separated and the aqueous fraction was extracted with chloroform (3×20 mL). The combined organic fractions were sequentially dried (MgSO4), filtered and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient, 0-15% CMA over 2000 mL followed by 15-20% CMA over 500 mL). The desired product was further purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a 0-8% gradient of methanol in dichloromethane). A final recrystallization from acetonitrile provided 142 mg of N-{3-[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propyl}acetamide as a white solid, mp 209-211° C.
Reaction SMILES: [CH2:1]([S:8][C:9]([CH3:35])([CH:33]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:32])[S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:37][OH:38].C(=O)([O-])[O-].[K+].[K+].CO>O>[CH2:1]([S:8][C:9]([CH3:35])([CH:33]=[N:37][OH:38])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:32])[S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CN(c1cccc2cc(C(=O)NCC(C)(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(c1cccc2cc(C(=O)NCC(C)(C=NO)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.3 %

Procedure:
A mixture of N-[2-(benzylthio)-2-methyl-3-oxopropyl]-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.00 g), hydroxylamine hydrochloride (0.26 g), potassium carbonate (0.52 g) and methanol (8 ml) was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated to give the title compound (0.25 g, yield 55%) as colorless amorphous crystals. MS: 543 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[CH3:18][O:19][CH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[CH2:12]([NH:11][C:9](=[O:10])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:20][O:19][CH3:18])[CH:26]=2)=[CH:3][CH:4]=1)([CH3:17])[CH3:16])[CH:13]([CH3:15])[CH3:14]
Reactant: COCc1cccc(B(O)O)c1
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Product: COCc1cccc(-c2ccc(C(C)(C)C(=O)NCC(C)C)cc2)c1
Yield: 91 %

Procedure:
Prepared in a similar manner to Example 1 from 2-(4-bromophenyl)-N-isobutyl-2-methylpropanamide (example 1a) and 3-(methoxymethyl)phenylboronic acid. Yield: 91%. 1H NMR (400 MHz, DMSO): δ 0.72-0.74 (d, 6H), 1.46 (s, 6H), 1.68 (m, 1H), 2.83 (t, 2H), 3.29 (s, 3H), 4.45 (s, 2H), 7.27-7.29 (d, 1H), 7.33 (t, 1H), 7.36-7.38 (d, 2H), 7.41 (t, 1H), 7.53-7.55 (d, 2H), 7.58-7.60 (d, 2H). MS (M+H, 340).
Reaction SMILES: [F:1][C:2]1[C:8](F)=[C:7]([F:10])[CH:6]=[C:5]([N+:11]([O-:13])=[O:12])[C:3]=1[NH2:4].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.CCN(CC)CC>CS(C)=O.II>[F:1][C:2]1[C:3]([NH2:4])=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=[C:7]([F:10])[C:8]=1[NH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=1
Reactant: NCc1ccc(F)cc1
Reactant: Nc1c([N+](=O)[O-])cc(F)c(F)c1F
Agent: II
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1c([N+](=O)[O-])cc(F)c(NCc2ccc(F)cc2)c1F
Temperature: 120 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
To a stirred suspension of compound 2 (0.060 g, 0.31 mmol, 1.0 equiv) in dry DMSO (0.3 mL) was added 4-fluorobenzylamine (0.117 g, 0.940 mmol, 3.00 equiv) followed by Et3N (54.0 μL, 0.370 mmol, 1.20 equiv) and I2 (catalytic, 1.0 mg). The reaction mixture was heated to 120° C. and stirred at 120° C. for 16 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to RT, diluted with water (25 mL) and extracted with EtOAc (2×50 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude; which was purified by silica gel column chromatography (EtOAc/Hexane 2:23) to afford compound 3 (0.064 g, 69%) as yellow solid. TLC: 25% EtOAc/Hexane (Rf: 0.20); 1H NMR (400 MHz, CDCl3): δ 7.67 (dd, J=2.0, 12.8 Hz, 1H), 7.31-7.28 (m, 2H), 7.05 (t, J=6.8 Hz, 2H), 6.05 (br s, 2H, Exc), 4.63 (d, J=6.0 Hz, 2H), 4.53 (br s, 1H, Exc); LC-MS: m/z=296 (M+-1) at RT 3.64 (98.8% purity)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:18]1(B(O)O)[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1>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:18]1([C:2]2[CH:3]=[C:4]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(Br)c2)CC1
Reactant: OB(O)C1=CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CN1CCN(c2ccc([N+](=O)[O-])c(C3=CCCCC3)c2)CC1
Temperature: 100 °C
Yield: 123 %

Procedure:
A mixture of 102 mg (0.340 mmol) 1-(3-bromo-4-nitro-phenyl)-4-methyl-piperazine (as prepared in Example 9, step (a)), 59.7 mg (0.474 mmol) cyclohexen-1-ylboronic acid, 43.8 mg (0.0379 mmol) of tetrakis(triphenylphosphine)palladium (0) under Ar was treated with 206 μL (0.412 mmol) of 2.0 M degassed aq Na2CO3, 0.6 mL degassed anh toluene and 0.2 mL degassed anh EtOH and the mixture was heated at 100° C. for 21 h. After cooling to RT, the mixture was poured into EtOAc (10 mL), washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo. Chromatography on a 5-g silica SPE column with 1-3% EtOH in dichloromethane afforded 126 mg of the title compound (74% purity by RP-HPLC (C18 column) as a mixture with triphenylphosphine) as a yellow oil that was used in the following reaction without further purification. Mass spectrum (ESI, m/z): Calcd. for C17H23N3O3, 302.2 (M+H), found 302.2.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12]Br.Cl.[CH2:15]([NH2:17])[CH3:16].CCN(CC)CC>CN(C=O)C>[CH2:15]([N:17]1[CH2:12][C:4]2[C:3](=[CH:8][CH:7]=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=2)[CH2:2]1)[CH3:16]
Reactant: O=[N+]([O-])c1ccc(CBr)c(CBr)c1
Reactant: CCN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 55.7 %

Procedure:
A mixture of dibromide 118 (9.27 g, 30.0 mmol), ethylamine hydrochloride (2.45 g, 30.0 mmol) and Et3N (21 mL, 150 mmol) in DMF (100 mL) was stirred at 20° C. for 90 min. The mixture was partitioned between EtOAc and aqueous Na2CO3 solution. The organic fraction was washed with water, dried and the solvent evaporated to give isoindole 245 (3.21 g, 56%) as a dark oil: 1H NMR δ 8.11 (dd, J=8.1, 2.1 Hz, 1H, H-6), 8.05 (d, J=2.1 Hz, 1H, H-4), 7.34 (d, J=8.1 Hz, 1H, H-7), 3.99 (s, 4H, H-1, H-3), 2.82 (q, J=7.2 Hz, 2H, CH2), 1.22 (t, J=7.2 Hz, 3H, CH3); HRMS (FAB+) calcd for C10H13N2O2 (MH+) m/z 193.0977, found 193.0983.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]=[C:11]=[S:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:13]([NH:16][CH2:17][C:18](O)=[O:19])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:18](=[O:19])[CH2:17][N:16]([CH:13]([CH3:15])[CH3:14])[C:11]3=[S:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)NCC(=O)O
Reactant: S=C=Nc1ccc2c(c1)CCC2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)N1CC(=O)N(c2ccc3c(c2)CCC3)C1=S
Yield: 36.1 %

Procedure:
The title compound was prepared by the procedure described in Example 45 using 17.5 g of indan-5-yl-isothiocyanate, 21.2 g of N-isopropyl glycine, 21.0 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethanol afforded the title compound (9.9 g) as a white solid, m.p. 178°-180° C. Anal. Calcd. for. C15H18N2O S: C, 56.66; H, 6.61; N, 10.21. Found: C, 56.70; H, 6.67; N, 10.22. Mass spectrum (EI, M.+) m/z 274.
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])[CH2:2][CH3:3].OCC[C:14]#[N:15]>C(O)C>[C:1]([CH2:5][C:6]([O:8][CH2:9][CH2:10][C:14]#[N:15])=[O:7])(=[O:4])[CH2:2][CH3:3]
Reactant: CCOC(=O)CC(=O)CC
Reactant: N#CCCO
Solvent: CCO
Product: CCC(=O)CC(=O)OCCC#N
Temperature: 202.5 °C
Yield: 73.5 %

Procedure:
A mixture of ethyl propionylacetate (25 g, 0.173 mol) and 3-hydroxypropionitrile (18.48 g, 0.26 mol) was stirred and heated at 200-205° C. for 2 hours and the ethanol formed was removed by distillation. The residue was subjected to high vacuum distillation and the fraction distilling at 120-125° C. at 0.4 mm Hg was collected to get 2-cyanoethyl propionylacetate (21.5 g, 73.4%). A mixture of 4-nitrobenzaldehyde (14.46 g, 0.957 mol), 2-cyanoethyl propionylacetate (17.0 g, 0.1005 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 24 h. The white solid, 2-cyanoethyl 3-{(4-nitrophenyl)methylene}-4-oxopentanoate, was filtered, washed with 2-propanol (2×50 mL) dried and used without further purification (Yield: 28.34 g, 97%); m.p. 98-100° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:19]1[CH:36]=[C:35]2[C:22]([CH2:23][CH2:24][C:25]3([C:28]42[N:32]=[C:31]([NH2:33])[C:30]([CH3:34])=[N:29]4)[CH2:27][CH2:26]3)=[CH:21][CH:20]=1>>[F:8][C:6]1[CH:5]=[C:4]([C:19]2[CH:36]=[C:35]3[C:22]([CH2:23][CH2:24][C:25]4([C:28]53[N:32]=[C:31]([NH2:33])[C:30]([CH3:34])=[N:29]5)[CH2:26][CH2:27]4)=[CH:21][CH:20]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CCC21CC1
Reactant: CC1(C)OB(c2cc(F)cc(F)c2)OC1(C)C
Product: CC1=NC2(N=C1N)c1cc(-c3cc(F)cc(F)c3)ccc1CCC21CC1
Yield: 61.5 %

Procedure:
The title compound was prepared following the procedure described for Example 2, starting from (3,5-difluorophenyl)boronic acid pinacol ester (113 mg, 0.47 mmol) and 7′-bromo-5″-methyl-3′,4′-dihydrodispiro[cyclopropane-1,2′-naphthalene-1′,2″-imidazol]-4″-amine (Example 1, 100 mg, 0.31 mmol). Purification by flash silica gel chromatography using a step wise gradient of CHCl3/MeOH (40:1-30:1-20:1) and preparative HPLC gave the title compound (67 mg, 61% yield).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1)([O-:17])=[O:16]>ClCCl>[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][C:9]2([OH:8])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: OC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CC2(O)CCNCC2)cc1
Reaction time: 12 h

Procedure:
137 mL (0.983 mol) of triethylamine is added to a solution of 41.5 g (0.410 mol) of 4-hydroxypiperidine in 500 mL of dichloromethane. Then 56.28 g (0.328 mol) of 4-nitrobenzylchloride is slowly added. The reaction mixture is boiled for 12 hours. The solid formed is suction filtered, the filtrate is washed twice with water and dried over magnesium sulfate. The solvent is evaporated down. Yield: 66.45 g (86% of theory); C12H16N2O3 (M=236.27); calc.: molecular ion peak (M+H)+: 237; found: molecular ion peak (M+H)+: 237.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]2[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][CH:26]=2)/[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:14]=[CH:13]3)=[CH:4][CH:3]=1.[O:40]1[CH2:44][CH2:43]OC1=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[OH:40][CH2:44][CH2:43][O:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]2[CH:26]=[CH:27][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][CH:30]=2)/[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:14]=[CH:13]3)=[CH:6][CH:7]=1
Reactant: O=C1OCCO1
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(O)cc2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(OCCO)cc2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Temperature: 90 °C
Yield: 47.9 %

Procedure:
A mixture of (E)-ethyl 3-(4-((E)-2-(4-hydroxyphenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate (352 mg, 0.67 mmol; Compound 339, Step 1), 1,3-dioxolan-2-one (296 mg, 3.37 mmol), and potassium carbonate (185 mg, 1.34 mmol) in DMF (7 mL) was heated to 90° C. overnight. The mixture was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with brine (3×), dried over sodium sulfate, and purified by flash chromatography on silica gel eluting with 0 to 100% ethyl acetate/hexanes to afford 182 mg of the title compound as a yellow foam. NMR (400 MHz, DMSO-d6): δ 8.11 (s, 1H), 7.72 (d, 1H), 7.62 (s, 1H), 7.47 (d, 1H), 7.40 (d, 2H), 7.21 (dd, 1H), 7.08 (d, 2H), 6.88 (d, 2H), 6.78 (d, 2H), 6.48 (d, 1H), 5.85 (dd, 1H), 4.83 (t, 1H), 4.14 (qt, 2H), 4.17-3.88 (m, 3H), 3.76 (m, 1H), 3.69 (m, 2H), 2.44-2.37 (m, 3H), 2.00 (m, 2H), 1.75 (m, 1H), 1.60 (m, 2H), 1.21 (t, 3H), 0.89 (t, 3H). LCMS: 483 [(M-THP+H)+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:12][C:13]1[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[CH:16]=[N:15][CH:14]=1)[CH2:7]2.[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1B(O)O>COCCOC.O.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>[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:12][C:13]1[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[CH:16]=[N:15][CH:14]=1)[CH2:7]2
Reactant: N#Cc1ccc(Cn2cncc2CN2CCc3c(Br)cccc3C2)cc1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccc(Cn2cncc2CN2CCc3c(cccc3-c3ccc(Cl)cc3Cl)C2)cc1

Procedure:
A solution of 5-bromo-2-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-1,2,3,4-tetrahydroisoquinoline (Example 10; 100 mg, 250 0.25 mmol), 2,4-dichlorophenyl boronic acid (53 mg, 0.275 mmol) and tetrakis(triphenylphosphine)palladium(0) in DME (2 mL) and water (0.5 mL) was heated to 80° C. for 20 h. The mixture was partitioned between water and EtOAc, washed with aqueous NaHCO3, water (2×), dried and evaporated. Column chromatography of the residue (silica gel; CHCl3 /MeOH 80:1) afforded the title compound as a white solid. FAB ms (m+1) 473.2