Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C1C=CC(N[N:12]=[C:13]([C:16]#[N:17])[C:14]#[N:15])=CC=1)C.[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1.C(#N)CC#N.O.[NH2:37][NH2:38]>>[CH2:27]([O:26][C:24](=[O:25])[C:23]1[CH:22]=[CH:21][C:20]([NH:19][N:12]=[C:13]2[C:14]([NH2:15])=[N:38][N:37]=[C:16]2[NH2:17])=[CH:30][CH:29]=1)[CH3:28]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCOC(=O)c1ccc(NN=C(C#N)C#N)cc1
Reactant: NN
Solvent: N#CCC#N
Solvent: O
Product: CCOC(=O)c1ccc(NN=C2C(N)=NN=C2N)cc1

Procedure:
4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzoic acid ethyl ester was prepared using 121 mg (0.5 mmol) of 4-(N′-dicyanomethylenehydrazino)benzoic acid ethyl ester, which was derived from ethyl 4-aminobenzoate (165 mg, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. The hydrazine hydrate was added to the solution at a temperature of 75° C. The solution cleared briefly and then a precipitate formed. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 45 mg (33%) of the compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[CH:3]=1.[CH2:11]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH2:19])=[CH:16][CH:15]=1)[CH3:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>[Pd].C([O-])(=O)C.C(#N)C>[CH2:11]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH:19][C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[CH:3]=2)=[CH:16][CH:15]=1)[CH3:12]
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: C=Cc1ccc(OCC)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOc1ccc(C=Cc2cc(F)c(F)c(F)c2)cc1

Procedure:
A mixture of 10.5 g of 1-bromo-3,4,5-trifluorobenzene, 7.4 g of p-ethoxystyrene, 0.25 g of Pd acetate, 0.6 g of tri-o-tolylphosphine, 7 g of triethylamine and 125 ml of acetonitrile is heated at reflux until completion of the reaction. Customary working-up gives 1-(p-ethoxyphenyl)-2-(3,4,5-trifluorophenyl)ethene (C 76 I), which is hydrogenated on Pd-C (5%) in THF to give 1-(p-ethoxyphenyl)-2-(3,4,5-trifluorophenyl)-ethane, C 45 I.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1.[H][H]>CO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)Cc1ccc(N)cc1
Yield: 98.7 %

Procedure:
(4-Nitro-phenyl)-acetic acid methyl ester (1.08 g, 5.52 mmol) was dissolved in methanol (50 mL) and EtOAc (50 mL), then added to a Parr bottle containing 10% Pd/C (0.42 g), the vessel was subjected to hydrogen atmosphere (40 psi) for 2 h under the Parr Shaker Apparatus conditions. Workup with filtration via a glass membrane filter paper, solvent was removed under reduced pressure to afford (4-amino-phenyl)-acetic acid methyl ester as an oil (0.9 g, 98.7%). 1H NMR (CDCl3) δ 7.05 (d, 1H), 6.62 (d, 1H), 3.63 (s, 3H), 3.6 (bs, 2H) 3.5 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([NH:16][S:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:10])=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Reactant: CC(C)(C)N
Product: CC(C)(C)NS(=O)(=O)c1cncc(Br)c1
Yield: 105.7 %

Procedure:
Prepared by general procedure III from 5-bromo-pyridine-3-sulfonyl chloride (Example B.2 step 2) (500 mg, 2 mmol) and tert-butylamine (1.03 mL, 10 mmol) to give the title compound as a white solid (620 mg, 108%). MS (ISP) 293.0 [(M+H)+], 295.2 [(M+2+H)+]. mp 110° C.
Reaction SMILES: C(N(CCC)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)CC.[CH3:31][N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH:37]=O.[C:39]([BH3-])#[N:40].[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:6]([N:40]([CH2:39][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH2:21][C:22]3[NH:26][CH:25]=[CH:24][N:23]=3)[CH2:37][C:33]3[N:32]([CH3:31])[CH:36]=[CH:35][N:34]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:7][CH2:8][CH3:9])[CH2:5][CH3:10]
Reactant: Cn1ccnc1C=O
Reactant: [BH3-]C#N
Reactant: CCCN(CCC)c1ccc(NC(=O)c2ccc(CNCc3ncc[nH]3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3nccn3C)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (52.0 mg) obtained in Example 47-3 was dissolved in methanol (1.6 ml) and then added with 1-methylimidazol-2-aldehyde (16.4 mg), and sodium cyanoborohydride (15.6 mg). The solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 14 hours. After completion of the reaction, the reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then separated and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (15.2 mg) of the subject compound as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:6]=1[NH2:7].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:3]([CH3:15])=[N:4][N:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH3:14])[C:6]=2[NH2:7])=[CH:19][CH:18]=1
Reactant: Cc1ccccc1-n1nc(C)c(Br)c1N
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1nc(C)c(-c2ccc(F)cc2)c1N
Temperature: 110 °C

Procedure:
4-Bromo-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (2 g, 7.52 mmol), 4-fluorophenylboronic acid (2.10 g, 11.3 mmol), and Pd(PPh3)4 (434 mg, 0.38 mmol) were dissolved in DMF (20 mL), and Na2CO3 (saturated aq solution, 18 mL) was added. The mixture was degassed for 10 min and then heated at 110° C. for 2 h. The reaction mixture was diluted, and the solid was filtered off. The solvent was concentrated under reduced pressure, and the residue purified by silica gel flash chromatography using 10 to 40% ethyl acetate in hexanes to give 1.2 g (90% pure, 51%) of the title compound. 1H NMR (300 MHz, CD2Cl2) δ 7.25-7.34 (m, 6H), 7.08 (t, 2H), 3.62 (s, 2H), 2.20 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=O.[C:19](OC(=O)C)(=[O:21])[CH3:20].C(N(CC)CC)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]([OH:43])=O)=[CH:36][CH:35]=1>C(OCC)(=O)C.O>[C:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:3]3[C:2](=[CH:7][C:6]([O:8][CH3:9])=[CH:5][CH:4]=3)[O:1][C:41](=[O:43])[C:40]=2[C:37]2[CH:36]=[CH:35][C:34]([F:33])=[CH:39][CH:38]=2)=[CH:13][CH:14]=1)(=[O:21])[CH3:20]
Reactant: COc1ccc(C(=O)c2ccc(O)cc2)c(O)c1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc2c(-c3ccc(OC(C)=O)cc3)c(-c3ccc(F)cc3)c(=O)oc2c1
Temperature: 135 °C
Reaction time: 18 h

Procedure:
A mixture of (2-hydroxy-4-methoxyphenyl)-(4-hydroxyphenyl)-methanone (7.33 g, 30.0 mmol), acetic anhydride (15 ml), triethylamine (5.5 ml, 39.5 mmol), and 4-fluorophenyl acetic acid (4.63 g, 30.0 mmol) was stirred at 135° C. for 18 h, and the resulting orange coloured solution poured into water (120 ml) and stirred for 3 h. The resulting mixture of aqueous solution plus sticky solid was diluted with ethyl acetate (300 ml) to dissolve the solid, and the organic layer separated. The aqueous phase was further extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed with water, and saturated sodium chloride solution, then dried over sodium sulfate and evaporated to give a yellow/orange solid, which was recrystallised from 2:1 ethanol/water (600ml) to give the product as an off-white solid, which was vacuum dried.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[C:16]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[CH:15]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[N:37](=[CH:45][CH2:46]Cl)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]Cl.O>CN(C=O)C.C(OCC)C>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:46][CH2:45][N:37]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:24][CH:23]=1)=[C:16]([C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)[CH:15]=[CH:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: ClCC=NCCCCCCCl
Reactant: Oc1ccc(Oc2c(-c3ccc(F)cc3)ccc3cc(OCc4ccccc4)ccc23)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: Fc1ccc(-c2ccc3cc(OCc4ccccc4)ccc3c2Oc2ccc(OCCN3CCCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 65.9 %

Procedure:
Add sodium hydride (324 mg, 8.0 mmol) into a solution of 4-[6-benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-yloxy]-phenol (1.18 g, 2.7 mmol) in DMF (10 mL) and stir for 20 minutes at room temperature. Add 2-(hexamethyleneimino)ethyl chloride hydrogen chloride (1.07 g, 5.4 mmol) and stir at room temperature for 12 hours. Add H2O (10 mL) and diethyl ether (100 mL). Separate layers and wash the aqueous layer with diethyl ether (2×50 mL). Combine organic layers, dry with magnesium sulfate and concentrate in vacuo. Purify the residue over silica gel, eluting the material with a step gradient of methanol/dichloromethane (0% to 10%), to obtain 1.0 g of the title compound (66%): mass spectrum (ion spray) m/z=562.3 (M+H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.S(Cl)([Cl:13])=O.[CH3:15]O>>[ClH:13].[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:15])=[O:9])[CH2:4][CH2:3]1
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Product: COC(=O)[C@H]1CC[C@H](N)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
25.6 g of trans-4-aminocyclohexane carboxylic acid was suspended in 150 mL of methanol, and 15.7 mL of thionyl chloride was added dropwise thereto under ice-cooling. After stirring at room temperature for 5 hours, the reaction mixture was concentrated under reduced pressure and the residue was suspended in diisopropyl ether. The precipitate was collected by filtration to obtain 34.0 g of methyl trans-4-aminocyclohexane carboxylate hydrochloride as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][C@H:9]1/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=O)(C)(C)C.Cl.[CH3:33]O>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([NH:13][C@H:11]2[CH2:12][NH:8][C@H:9](/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:33])=[O:30])[CH2:10]2)(=[O:15])=[O:16])=[CH:22][CH:21]=1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1C[C@H](NS(=O)(=O)c2ccc(Cl)cc2)C[C@H]1/C=C\CCCC(=O)O
Agent: Cl
Product: COC(=O)CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1

Procedure:
A solution of (2S,4R)-1-t-butoxycarbonyl-2-[(Z)-5-carboxy-1-pentenyl]-4-(4-chlorophenylsulfonylamino)pyrrolidine (2.90 g) in methanol (50 ml) saturated with hydrogen chloride was stirred at room temperature overnight and the solvent was evaporated in vacuo. The residue was dissolved in chloroform (50 ml) and the solution was washed successively with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo to give (2S,4R)-4-(4-chlorophenylsulfonylamino)-2-[(Z)-5-methoxycarbonyl-1-pentenyl]pyrrolidine (2.28 g) as a pale brown oil.
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N)CCCCCCCCCCC.[C:33]1(=O)[O:37][CH2:36][CH2:35][CH2:34]1>O>[CH2:1]([N:19]1[CH2:33][CH2:34][CH2:35][C:36]1=[O:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: O=C1CCCO1
Agent: CCCCCCCCCCCCN
Solvent: O
Product: CCCCCCCCCCCCCCCCCCN1CCCC1=O
Yield: 96 %

Procedure:
The procedure described in Example I was repeated except that octadecylamine (Armeen 18D) was substituted for n-dodecylamine and the product was stripped of water and excess butyrolactone and was discharged at about 75° C. to provide 96% pure N-octadecyl-2-pyrrolidone solid in a yield of 96%.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[C:1](=[O:2])([O:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[O:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Cl
Reactant: Oc1ccccc1
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
In a planar-section pot with flow-spoilers, a blower/stirrer and reflux condenser, 0.75 mol/h of phosgene was continuously bubbled into 141 g (1.50 mol) of phenol in the presence of 14.1 g (10 wt. % with reference to phenol) of a powdered aluminium oxide 507-C-I (neutral) from CAMAG. After about 2 h reaction time, the phenol conversion was 41%, wherein 66 g of diphenyl carbonate were formed. The selectivity to give carbonate was >99%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:20]=[CH:19][C:18]2[O:17][C:16]3[C:11](=[CH:12][C:13]([C:21](=[O:26])[CH2:22][CH2:23][CH2:24]Cl)=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)=[O:6].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[I-].[K+]>CC(=O)CC>[N:27]1([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:20]=[CH:19][C:18]3[O:17][C:16]4[C:11](=[CH:12][C:13]([C:21](=[O:26])[CH2:22][CH2:23][CH2:24][N:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:14][CH:15]=4)[CH2:10][C:9]=3[CH:8]=2)=[O:6])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C(CCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCl)ccc1O2
Reactant: C1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(CCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCN3CCCCC3)ccc1O2
Reaction time: 48 h

Procedure:
A mixture of 19.6 g (0.05 mole) of 2,7-bis(4-chlorobutyryl)-xanthene, 34.0 g (0.4 mole) of piperidine, 16.6 g (0.1 mole) of potassium iodide and 200 ml. of butanone was refluxed with stirring for 21/2 days. The reaction mixture was poured into 1000 ml. of water, and the solid which precipitated was filtered and recrystallized from methylene chloride-acetone then from acetone to give the desired product. M.P. 115°-117°C.
Reaction SMILES: [C:1]([NH:4][C@H:5]([CH2:9][O:10][CH3:11])[C:6]([OH:8])=O)(=[O:3])[CH3:2].ClC(OCC(C)C)=O.CN1CCOCC1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1.C(OCC)(=O)C>[C:1]([NH:4][C@H:5]([CH2:9][O:10][CH3:11])[C:6]([NH:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: COC[C@@H](NC(C)=O)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 17.8 %

Procedure:
To a suspension of (R)-2-acetylamino-3-methoxypropionic acid (5 g, 31.05 mmol) in tetrahydrofuran (50 mL), under a nitrogen atmosphere at −20° C., was added isobutyl chloroformate (4.04 mL, 31.05 mmol) over a period of 10 minutes. The temperature was maintained at −20° C. for 10 minutes. 4-Methylmorpholine (3.42 mL, 31.05 mmol) was added over a period of 10 minutes, and the temperature was maintained for a further 10 minutes. Benzylamine (3.39 mL, 31.05 mmol) was added directly into the reaction mixture via a syringe at −20° C. over a period of 10 minutes. The temperature of the reaction mixture was maintained at −20° C. for a further 20 minutes. The reaction mixture was quenched with aqueous HCl (1M; 21.88 mL). Solvent was removed by evaporation at 45-50° C., and crude material (16 g) was isolated. Ethyl acetate (50 mL) was added, and the reaction mixture was washed with water (2×2.5 mL). The organic layer was dried over sodium sulphate and the solvent was completely removed by evaporation to give crude material (5.77 g). A portion (5.5 g) of this material was dissolved in ethyl acetate (50 mL) at 50-55° C. The temperature was maintained for 10 minutes, before cooling to 25° C. After stirring at this temperature for 2 hours the reaction mixture was filtered. The wet filter cake was washed with ethyl acetate (2.5 mL). The residue was dried under suction for 20 minutes, then dried under vacuum at 40° C. to constant weight, to give the title compound (1.38 g, 18.5%). Chiral purity: 99.2%. Chemical HPLC: 96.8%.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.C([O-])(=O)C.[Na+].O>C(O)C>[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][CH:10]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CNc1ccc(F)cc1
Temperature: 80 °C

Procedure:
Ethyl bromoacetate (8.09 g, 48.4 mmol) was slowly added to a solution of 4-fluoroaniline (5.38 g, 48.4 mmol) and sodium acetate (5.16 g, 62.9 mmol) in ethanol (62 mL) and the mixture was heated at 80° C. for 2 h. Water was added and the reaction was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-20% EtOAc in hexanes) to afford ethyl 2-((4-fluorophenyl)amino)acetate (1).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH2:22])[CH2:13][C:12]2=1)C1C=CC=CC=1.[H][H]>C(O)C.[Ni]>[OH:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH2:22])[CH2:13][C:12]2=1
Reactant: NC1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: NC1CCc2[nH]c3ccc(O)cc3c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
To a solution of 0.871 gm (2.98 mMol) 6-benzyloxy-3-amino-1,2,3,4-tetrahydro-9H-carbazole in 200 mL ethanol were added about 2.0 gm Raney Nickel and hydrogen introduced to the reaction mixture under balloon pressure. After stirring for 18 hours at room temperature the balloon was refilled with hydrogen and the reaction stirred an additional 3 days at room temperature. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give a colorless solid. The residual solid was subjected to silica gel chromatography, eluting with 80:15:5 dichloromethane:menthanol:ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure to give 0.335 gm (56%) of the title compound.
Reaction SMILES: [N:1]1([CH2:7][C:8]#[C:9][C:10]2[C:15]3[N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:17]=[N:18][C:14]=3[CH:13]=[C:12]([C:25]([F:28])([F:27])[F:26])[CH:11]=2)[CH2:6][CH2:5]O[CH2:3][CH2:2]1.N1CCCC[CH2:30]1>>[C:19]1([N:16]2[C:15]3[C:10]([C:9]#[C:8][CH2:7][N:1]4[CH2:6][CH2:5][CH2:30][CH2:3][CH2:2]4)=[CH:11][C:12]([C:25]([F:28])([F:27])[F:26])=[CH:13][C:14]=3[N:18]=[CH:17]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: FC(F)(F)c1cc(C#CCN2CCOCC2)c2c(c1)ncn2-c1ccccc1
Reactant: C1CCNCC1
Product: FC(F)(F)c1cc(C#CCN2CCCCC2)c2c(c1)ncn2-c1ccccc1
Yield: 17 %

Procedure:
This was prepared in a similar manner to 7-(3-(4-morpholinyl)prop-1-ynyl)-1-phenyl-5-trifluoromethylbenzimidazole using piperidine in place of morpholine to realise the desired product (13 mg, 17%) m/z, 384.4 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([O-:10])=[O:9].[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>ClCCl>[CH3:25][CH:24]([CH3:26])[C:23]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:13]=[CH:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:16][CH:15]=2)[CH2:18][CH2:19]1)=[O:27]
Reactant: CC(C)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Triethylamine (976 mg, 9.66 mmol) was added to a solution of 1-(4-nitrophenyl)piperazine (1.00 g, 4.83 mmol) in dichloromethane (20 mL) at 0° C. and stirred for 30 min. Isobutyryl chloride (617 mg, 5.79 mmol) was then added and the mixture was warmed to ambient temperature and stirred for 4 h. the reaction mixture was quenched with ice-water and the organic layer separated. The aqueous layer was extracted with dichloromethane (5×5 mL) and the combined organic layers were washed water, saturated sodium bicarbonate solution, brine, dried over anhydrous sodium sulphate and concentrated in vacuo to afford 2-methyl-1-[4-(4-nitrophenyl)piperazin-1-yl]propan-1-one (1.20 g, 90%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:32])[N:5]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:6]([CH:12]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][NH:21]3)[CH2:13][C:14]#[CH:15])=[N:7]2.[NH2:33]C1N=C2C(NC=N2)=C(Br)N=1.BrC1N=CN=C2C=1NC=N2>>[NH2:33][C:24]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][NH:21]2)=[C:17]([NH:16][CH:12]([C:6]2[N:5]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:4](=[O:32])[C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[CH3:1])[N:7]=2)[CH2:13][C:14]#[CH:15])[N:25]=1
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Reactant: C#CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)c2c(=O)n1-c1ccccc1
Agent: Brc1ncnc2nc[nH]c12
Product: C#CCC(Nc1nc(N)nc2[nH]cnc12)c1nc2cccc(C)c2c(=O)n1-c1ccccc1

Procedure:
Compound 165 was prepared following the general procedure described above for the preparation of compound 161, but 2-amino-6-bromopurine was substituted for 6-bromopurine in step D. ESI-MS m/z=437 (MH+).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:22]#[N:23])=[CH:12]1)[CH3:10].[I:24]I>C1COCC1>[CH2:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:22]#[N:23])=[C:12]1[I:24])[CH3:10]
Reactant: CCn1cc(C#N)c2ccc(OC)cc21
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCn1c(I)c(C#N)c2ccc(OC)cc21
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
A 2M solution of lithium diisopropyl amide in THF/hexanes (Acros) (3.9 mL, 7.8 mmol) is diluted with THF (5 mL) in a flame-dried flask. After cooling the reaction to −30° C., a solution of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.30 g, 6.5 mmol) in THF (10 mL) is added dropwise during 10 min, maintaining the temperature at −30° C. After stirring for an additional 30 min at this temperature, a solution of iodine (2.31 g, 9.1 mmol) in THF (5 mL) is added during 10 min. After the addition, the reaction is warmed to ambient temperature during 1 h. The reaction is then diluted with ice-H2O and extracted with EtOAc (2×). The combined organic phases are washed with 1M sodium thiosulfate and saturated NaCl and then concentrated to a brown solid. Chromatography (CH2Cl2/hexanes, 1/1) over silica gel gives 1.31 g (62%) of 1-ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile as an off-white solid.