Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][N:14]([N:18]=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O.C(O)(=O)C.[Zn]>[NH2:18][N:14]1[CH2:15][CH2:16][CH2:17][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1
Reactant: O=NN1CCCN(C(=O)OCc2ccccc2)CC1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: NN1CCCN(C(=O)OCc2ccccc2)CC1
Temperature: 55 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a mixture of 1-benzyloxycarbonyl-4-nitrosohomopiperazine (1.0 g) in water (2.0 ml) and acetic acid (1.09 ml) was added zinc powder (745 mg) at 8-13° C. (exothermic reaction) with ice-water cooling bath. After removal of the bath, the temperature was raised till 55° C. and the reaction mixture was additionally stirred at 30-40° C. for 1 hour. Acetic acid (1.09 ml) and zinc powder (745 mg) was added to the reaction mixture and stirred at 40° for 1 hour. After cooling, zinc residue was filtered off and washed with methanol (5 ml) on the Celite. The combined filtrate was added into dichloromethane (10 ml) and sodium hydroxide (1.6 g) in water (5 ml) below 35° C. The resulting precipitate was filtered off with Celite and the residue was washed with dichloromethane (20 ml). The combined filtrate was dried over magnesium sulfate and filtered. The filtrate was condensed in vacuo to give 1-amino-4-benzyloxycarbonylhomopiperazine (690 mg). This product was used for next step without further purification.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([N:21]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[N:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]([C:5]1[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=1)[C:15]1[CH:16]=[CH:17][C:18]([N:21]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[CH:19][CH:20]=1
Reactant: c1ccc(Nc2ccccn2)nc1
Reactant: Brc1ccc(N(c2ccncc2)c2ccncc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(N(c2ccc(N(c3ccncc3)c3ccncc3)cc2)c2ccccn2)nc1
Temperature: 145 °C
Reaction time: 30 h
Yield: 41.2 %

Procedure:
A mixture of 2,2′-dipyridylamine (5.27 g, 30.76 mmol), (4-bromophenyl)-di(4-pyridyl)amine (2.50 g, 7.69 mmol), anhydrous potassium carbonate (2.66 g, 19.23 mmol), bronze powder (4.93 g, 77.64 mmol), 18-crown-6 (200 mg, 0.76 mmol), and DMF (125 mL) was heated at 145 degrees C. under nitrogen for 30 hours. The reaction was cooled and worked up by a procedure similar to that for L1. A yellowish solid was collected from a silica gel column, and was further purified by recrystallization from dichloromethane and petroleum ether, to afford a white solid of N,N-di(2-pyridyl)-N′,N′-di(4-pyridyl)-1,4-phenylenediamine (L2, 1.32 g, yield: 41%). 1H NMR (CDCl3, Bruker 400 MHz): 8.43 (d, J=4.4 Hz, 4H, pyridyl-H), 8.37 (d, J=3.6 Hz, 2H, pyridyl-H), 7.60-7.65 (m, 2H, pyridyl-H), 7.21 (d, J=8.8 Hz, 2H, phenylene-H), 7.14 (d, J=8.8 Hz, 2H, phenylene-H), 6.98-7.09 (m, 8H, pyridyl-H). Anal. Calcd (%) for C26H20N6: C, 74.98; H, 4.84; N, 20.18. Found: C, 74.53; H, 4.72; N, 19.89. IR (KBr pellet, cm−1): 1575(vs), 1505(s), 1490(s), 1467(s), 1431(vs), 1324(s), 1305.13 (s), 1276(s), 1218(m), 1163(w), 1103(w), 991(m), 811(m), 777(m), 737(w), 654(w), 622(m), 530(m).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:16])[C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[CH2:9].CO[CH:19](OC)[N:20](C)[CH3:21]>CN(C)C=O.O>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:16])[C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[CH:9][N:20]([CH3:21])[CH3:19]
Reactant: C=C(C(=O)c1sccc1Cl)c1ccncc1
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C=C(C(=O)c1sccc1Cl)c1ccncc1
Yield: 74.6 %

Procedure:
To a solution of 1-(3-chlorothiophen-2-yl)-2-(pyridin-4-yl)prop-2-en-1-one (1 eq, 27 mmol) in anhydrous N,N-dimethylformamide (40 mL) was added N,N-dimethylformamide dimethyl acetal (4 eq, 108 mmol). The reaction mixture was stirred under reflux for 1.5 h. The mixture was diluted with water (600 mL) and extracted with dichloromethane (4×200 mL) and ethylacetate (4×200 mL). The combined extracts were washed with water, brine, dried over Na2SO4 and concentrated. The obtained residue was purified by column chromatography on silica gel (DCM:MeOH, 40:1 to 20:1) to afford intermediate 5.9 g of 1-(3-chlorothiophen-2-yl)-3-(dimethylamino)-2-(pyridin-4-yl)prop-2-en-1-one (74% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br.Br[CH2:18][C:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:20]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:18]=1[C:19](=[O:20])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Product: CCOC(=O)n1c(C(=O)c2cccnc2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 3-(bromoacetyl)pyridine hydrobromide (H. McKennis et al., J. Org. Chem., 1963, 387). 1H-NMR (CDCl3) δ: 8.95 (1H, dd, J=0.7, 2.2 Hz), 8.70 (1H, dd, J=1.8, 4.8 Hz), 8.23 (1H, d, J=1.5 Hz), 8.03-7.99 (1H, m), 7.57 (1H, d, J=8.4 Hz), 7.41-7.28 (2H, m), 6.08 (2H, br s), 3.87 (2H, q, J=7.0 Hz), 0.92 (3H, t, J=7.0 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC>>[CH:24]1([CH2:23][N:13]2[N:12]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14]2=[O:21])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: BrCC1CCCCC1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(CC3CCCCC3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and bromomethylcyclohexane as described for compound 8. Purified by chromatography (dichloromethane). Crystallized from petroleum ether (60-95° C.). M.p. 137-139° C.
Reaction SMILES: [F:1][C@H:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][NH:4]S(C1C=CC(C)=CC=1)(=O)=O.N.[Na]>CO>[F:1][C@H:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][NH2:4]
Reactant: Cc1ccc(S(=O)(=O)NC[C@H](F)Cc2ccccc2)cc1
Agent: N
Agent: [Na]
Solvent: CO
Product: NC[C@H](F)Cc1ccccc1
Reaction time: 0.08 h
Yield: 28.1 %

Procedure:
To a two necked flask equipped with a dry ice condenser was added (R)-N-(2-Fluoro-3-phenylpropyl)-4-methylbenzenesulfonamide (1.0 g) and ammonia gas to condense about 25 mL of liquid. Small pieces of sodium were added to the stirred solution until a dark orange color persisted for 5 min. Methanol was added to quench the reaction. After evaporation of the ammonia the product was dissolved in MeOH, filtered, and concentrated. The residue was extracted into chloroform and chromatographed over silica gel with an ammoniated mixture of MeOH/ether (1:19) to give 0.14 g of the title compound as an oil. MS ES (M++H-NH3)=136.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O>CN1C(=O)CCC1>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NCc1ccccc1
Reactant: CN1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
A solution of N-benzyl-5-bromo-2-nitrobenzenamine (100 mg, 0.32 mmol) and 1-methylpiperazine (65 mg, 0.65 mmol) in NMP (1 mL) was heated to 110° C. for 16 h. The solution was cooled to room temperature to which was slowly added H2O (5 mL). The resulting yellow precipitate was filtered, washed with 2 mL of water, dried (high vacuum, 14 h) to furnish N-benzyl-5-(4-methylpiperazin-1-yl)-2-nitrobenzenamine (73 mg, 0.22 mmol), 69% yield. 1H NMR (500 MHz, DMSO-D6) d (ppm) 8.81 (m, 1H), 7.90 (d, J=9.5 Hz, 1H), 7.44-7.34 (m, 4H), 7.30-7.25 (m, 1H), 6.41 (dd, J=2.5 Hz, 10 Hz, 1H), 5.97 (d, J=2.5 Hz, 1H), 4.58 (d, J=6 Hz, 2H) 3.4-3.2 (m, 4H), 2.34 (m, 4H), 2.19 (s, 3H).+ESI HRMS (calcd for C18H23N4O2, M+1) 327.1821, found 327.1816
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.C1C(=O)N([Br:23])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClC(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][Br:23])=[CH:13][CH:14]=1
Reactant: COc1ccccc1-c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccccc1-c1ccc(CBr)cc1

Procedure:
2-methoxy-4′-methylbiphenyl, 160 mg (0.81 mmol), NBS, 158 mg (0.91 mmol), and AIBN, 1 mg (0.006 mmol) were suspended in 7 mL tetrachloromethane, and refluxed for 24 hours. The product was filtered, and the solvent removed from the filtrate by rotary evaporation. Equal amounts of diethyl ether and water were added and the product extracted. The ether layer was separated and dried over MgSO4, filtered, and the solvent removed. 4-(2-Methoxyphenyl)benzyl bromide, 128 mg, was obtained as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[C@H:9]3[CH2:10][C:11]4[C:12]([C:16]([O:18]CC)=[O:17])=[N:13][NH:14][C:15]=4[C@@H:8]23)=[CH:3][CH:2]=1.[Li+].[OH-]>C1COCC1.O>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[C@H:9]3[CH2:10][C:11]4[C:12]([C:16]([OH:18])=[O:17])=[N:13][NH:14][C:15]=4[C@@H:8]23)=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1n[nH]c2c1C[C@@H]1C(c3ccncc3)[C@H]21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1n[nH]c2c1C[C@@H]1C(c3ccncc3)[C@H]21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 147.9 %

Procedure:
Ethyl (1aR,5aR)-1-(pyridin-4-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylate (357 mg, 1.326 mmol) was taken up in THF (4.00 mL) and H2O (4.00 mL). LiOH (95 mg, 3.98 mmol) was added and the reaction was stirred at room temperature for 1.5 h. The organic solvent was removed under reduced pressure to give the title compound (473 mg) as a brown solid. LCMS m/z=242.3 [M+H]+.
Reaction SMILES: Cl[SiH:2]([CH2:5][CH3:6])[CH2:3][CH3:4].[CH2:7]([NH:10][CH2:11][CH2:12][CH3:13])[CH2:8][CH3:9]>>[CH2:7]([N:10]([SiH:2]([CH2:5][CH3:6])[CH2:3][CH3:4])[CH2:11][CH2:12][CH3:13])[CH2:8][CH3:9]
Reactant: CCCNCCC
Reactant: CC[SiH](Cl)CC
Product: CCCN(CCC)[SiH](CC)CC
Temperature: 25 °C
Yield: 78.5 %

Procedure:
Traditional method to make organoaminocarbosilane: Chlorodiethysilane (18.5 g, 151 mmol) was added dropwise to a stirred solution of di-n-propylamine (32.1 g, 317 mmol) in hexanes (250 mL) at −15° C. The resulting white slurry was allowed to warm to room temperature while stirring. The white solids were removed by filtration and the colorless filtrate was purified by vacuum distillation to obtain 22.2 g of N,N-di-n-propylaminodiethylsilane. GC-MS showed the following peaks: 187 (M+), 172 (M-15), 158, 144, 130, 116, 100, 87, 72. This product was determined after hydrolysis to contain 537 ppm chloride.
Reaction SMILES: O1CCOCC1.Cl.[NH2:8][C:9]([NH2:11])=[NH:10].[OH-].[Na+].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[C:22]([NH:10][C:9]([NH2:11])=[NH:8])([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:23]
Reactant: N=C(N)N
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N=C(N)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1,4-Dioxane (20 ml) is added to a solution of guanidine hydrochloride (0.96 g, 10 mmol) and sodium hydroxide (0.8 g, 20 mmol) in water (10 ml) and the resulting mixture is cooled to 0° C. Benzyloxycarbonyl chloride (1.1 ml, 7.7 mmol) is added dropwise with vigorous stirring over a period of 10 min. After the addition is completed, the ice-bath is removed and stirring is continued for 1 h at room temperature. The mixture is concentrated in vacuo to one third of its original volume and extracted three times with ethyl acetate (20 ml each). The combined extracts are washed with brine (20 ml) and dried with anhydrous sodium sulfate. After filtering and removal of the solvent under reduced pressure N-Cbz-guanidine (1.31 g, 88%) is obtained as a white powder: mp: 120-122° C.; 1H NMR (360 MHz, DMSO-d6) δ 7.35-7.25 (m, 5H), 6.88 (br s, 4H), 4.95 (s, 2H); Electrospray-MS m/e 194 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:33])[C:23]3[CH:28]=[C:27]([F:29])[C:26]([O:30]C)=[C:25]([F:32])[CH:24]=3)[C@@H:14]([CH3:34])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:33])[C:23]3[CH:28]=[C:27]([F:29])[C:26]([OH:30])=[C:25]([F:32])[CH:24]=3)[C@@H:14]([CH3:34])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: COc1c(F)cc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2cc(F)c(O)c(F)c2)c2ccccc21
Temperature: 25 °C
Yield: 78.7 %

Procedure:
N-(4-chlorophenyl)-N-[(2S,4R)-1-(3,5-difluoro-4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (200 mg, 0.41 mmol) was dissolved in dichloromethane and a solution of BBr3 (1.0 M in dichloromethane, 3.0 mL) was added; the reaction mixture was stirred at room temperature for until no starting material remained. The reaction mixture was washed with sat. NaHCO3 and brine carefully. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography using Hexanes-EtOAc system to give N-(4-chlorophenyl)-N-[(2S,4R)-1-(3,5-difluoro-4-hydroxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (152 mg, 78%).
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[C:7]([C:12]([O:14]CC)=[O:13])=[CH:6][N:5]([CH3:17])[C:4]=2[CH:3]=1.Cl>[OH-].[Na+]>[Cl:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[C:7]([C:12]([OH:14])=[O:13])=[CH:6][N:5]([CH3:17])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cn(C)c2cc(Cl)sc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1cc(C(=O)O)c(=O)c2sc(Cl)cc21
Reaction time: 3 h

Procedure:
A mixture of ethyl 2-chloro-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate (1.6 g) and 0.35M aqueous sodium hydroxide solution (50 ml) was stirred at 95° for 3 hours. The mixture was cooled to 0° and acidified with 5M hydrochloric acid to pH 4. After 15 minutes the solid was collected, washed with water and stirred with a mixture of diethyl ether (60 ml) and industrial methylated spirit (10 ml) for 2 hours. The solid was collected and dried to give the novel compound 2-chloro-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[CH2:19][NH2:20])=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:15]1[CH:16]=[N:17][C:12]([CH3:11])=[N:13][CH:14]=1)[CH2:21][CH:22]1[CH2:24][CH2:23]1)=[O:6]
Reactant: Cc1ncc(C(CN)CC2CC2)cn1
Reactant: O=C(O)c1ccccc1Cl
Product: Cc1ncc(C(CNC(=O)c2ccccc2Cl)CC2CC2)cn1

Procedure:
From 2-chlorobenzoic acid and 2-(2-methyl-pyrimidin-5-yl)-3-cyclopropyl-propylamine. LCMS (MH+): m/z=330.1, tR (minutes, Method F)=2.32
Reaction SMILES: CO[C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:7][O:8][C:9]=1[CH3:10])=[O:4].CCN=C=NCCCN(C)C.[NH2:29][C:30]1[CH:31]=[C:32]([CH2:36][C:37]([NH:39][C:40]2[CH:45]=[C:44]([O:46][CH3:47])[C:43]([O:48][CH3:49])=[C:42]([O:50][CH3:51])[CH:41]=2)=[O:38])[CH:33]=[CH:34][CH:35]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:47][O:46][C:44]1[CH:45]=[C:40]([NH:39][C:37](=[O:38])[CH2:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([NH:29][C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[F:17])=[N:7][O:8][C:9]=3[CH3:10])=[O:4])[CH:31]=2)[CH:41]=[C:42]([O:50][CH3:51])[C:43]=1[O:48][CH3:49]
Reactant: COC(=O)c1c(-c2ccccc2F)noc1C
Reactant: COc1cc(NC(=O)Cc2cccc(N)c2)cc(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(NC(=O)Cc2cccc(NC(=O)c3c(-c4ccccc4F)noc3C)c2)cc(OC)c1OC
Reaction time: 6 h
Yield: 61.3 %

Procedure:
To a solution of 4-methoxycarbonyl-5-methyl-3-(2-fluorophenyl)isoxazole (1.00 g, 4.52 mmol) in CH2Cl2 (30 ml) was added EDCI (1.51 g, 9.04 mmol), DMAP (0.11 g, 0.90 mmol), and 2-(3-aminophenyl)-N-(3,4,5-trimethoxyphenyl)acetamide (1.70 g, 5.42 mmol). The reaction was allowed to stir for 6 h then applied to a silica gal column eluting first CH2Cl2 with followed by 10% acetone in CH2Cl2 to give the title compound (1.44 g, 62%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]([C:13]3[C:18]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=3[CH:22]([CH3:24])[CH3:23])[CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH:25]1[C:37]2[NH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]=2[CH:28]=[CH:27][C:26]=1[C:38]#[N:39].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:22]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([CH:19]([CH3:21])[CH3:20])[C:13]=1[N:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:4]1[CH:3]=[C:2]([N:36]2[C:37]3[CH:25]=[C:26]([C:38]#[N:39])[CH:27]=[CH:28][C:29]=3[C:30]3[C:35]2=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:7]=[CH:6][CH:5]=1)([CH3:24])[CH3:23]
Reactant: N#Cc1ccc2c(c1)[nH]c1ccccc12
Reactant: CC(C)c1cccc(C(C)C)c1-n1ccnc1-c1cccc(Br)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)c1cccc(C(C)C)c1-n1ccnc1-c1cccc(-n2c3ccccc3c3ccc(C#N)cc32)c1
Yield: 93.4 %

Procedure:
2-(3-bromophenyl)-1-(2,6-diisopropylphenyl)-1H-imidazole (4.39 g, 11.45 mmol), 9H-carbazole-2-carbonitrile (2 g, 10.40 mmol), Pd2dba3 (0.333 g, 0.364 mmol) and 2-dicyclohexylphosphino-2′,6′ dimethoxybiphenyl (S-Phos) (0.597 g, 1.457 mmol) were charged into the reaction flask with 300 mL of m-xylenes. Potassium phosphate tribasic anhydrous (3.86 g, 18.21 mmol) was ground into a fine powder using a mortar and pestle then was added to the reaction mixture. The reaction mixture was degassed with nitrogen then was heated at reflux for 5½ days. This biphasic mixture was passed through a plug of Celite® to remove some insoluble materials. The organic layer was separated and dried over magnesium sulfate. The organics were filtered and concentrated under vacuum. The crude residue was passed through a silica gel column using 25% ethyl acetate/10% DCM/hexanes. The product fractions yielded 9-(3-(1-(2,6-diisopropylphenyl)-1H-imidazol-2-yl)phenyl)-9H-carbazole-2-carbonitrile (93.4% yield) as a tan solid.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH:33]([CH3:35])[CH3:34].[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=3[O:32][CH:33]([CH3:35])[CH3:34])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Reactant: COC(=O)c1ccc(CBr)c(OC(C)C)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cn2nc(-c3ccccc3)cc2-c2ccccc2)c(OC(C)C)c1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To a solution of 3,5-diphenyl-1H-pyrazole (0.36 g, 1.65 mmol) in N,N-dimethylformamide (8.6 mL) was added sodium hydride (60% in oil, 66 mg, 1.65 mmol) with stirring at room temperature, and the mixture was stirred at the same temperature for 30 min. A solution of methyl 4-(bromomethyl)-3-isopropoxybenzoate (0.43 g, 1.50 mmol) in N,N-dimethylformamide (4.3 mL) and sodium iodide (22 mg, 0.15 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and the mixture washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=4/1) to give the title compound (0.59 g, yield 92%) as a colorless oil. MS (ESI+): 427 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:6]1[N:10]=[N:9][C:8]([CH3:11])=[N:7]1)([CH3:5])[CH3:4].C([Li])CCC.CON(C)[C:20](=[O:39])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C@H:29]2[CH2:34][CH2:33][C@H:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:31][CH2:30]2)=[CH:23][CH:22]=1>C1COCC1>[C:35]([CH:32]1[CH2:31][CH2:30][CH:29]([NH:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:20](=[O:39])[CH2:11][C:8]3[N:9]=[N:10][N:6]([C:3]([O:2][CH3:1])([CH3:5])[CH3:4])[N:7]=3)=[CH:22][CH:23]=2)[CH2:34][CH2:33]1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CON(C)C(=O)c1ccc(CN[C@H]2CC[C@H](C(C)(C)C)CC2)cc1
Reactant: COC(C)(C)n1nnc(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(C)(C)n1nnc(CC(=O)c2ccc(CNC3CCC(C(C)(C)C)CC3)cc2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 101.7 %

Procedure:
To a solution of 2-(1-methoxy-1-methylethyl)-5-methyl-2H-tetrazole (893 mg, 5.7 mmol) in THF (10 ml) cooled to −78° C. on a dry-ice-acetone bath was added dropwise a solution of n-butyl lithium in hexanes (3.6 ml, 1.6 M, 5.7 mmol). The mixture was stirred at −78° C. for 30 min, and at 0° C. for an additional 30 min, then recooled to −78° C. This solution was then slowly transferred (by cannulation) to a solution of N-methoxy-N-methyl-trans-4-{[4-tert-butylcyclohexylamino]methyl}benzamide (760 mg, 2.3 mmol) in THF (15 ml) maintained at −78° C. The reaction mixture was stirred for 30 min at −78° C. and then quenched by the addition of methanol (2 ml). Solvent was removed by rotary evaporation, and the residue was dissolved in ethyl acetate (100 ml). The organic phase was washed once with saturated aqueous sodium hydrogen carbonate (100 ml); dried over anhydrous sodium sulphate and taken to dryness by rotary evaporation to leave 1.0 g (100%) of the title material as an clear oil.
Reaction SMILES: O1CCCCC1O[CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH:9]=[CH2:10].[BrH:25]>C(OCC)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([S:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:8]=[CH:9][CH2:10][Br:25])=[CH:19][CH:20]=1
Reactant: Br
Reactant: C=CC(OC1CCCCO1)c1ccccc1Sc1ccc(F)cc1
Solvent: CCOCC
Product: Fc1ccc(Sc2ccccc2C=CCBr)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 1-tetrahydropyranyloxy-1-[2-(4-fluorophenylthio)phenyl]prop-2-ene (2.71 g; 7.87 mmol) in 20 ml of diethyl ether under nitrogen cooled in an ice bath, was added concentrated HBr and the mixture stirred at 0° C. for one hour. The ice bath was removed and the reaction mixture stirred at room temperature overnight. The reaction mixture was poured into water and extracted twice with hexane. The organics were collected and washed with water and then brine and dried over MgSO4 and concentrated to afford the subtitle compound.