Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C@@H:12]1[CH2:16][CH2:15][C@@H:14]([C:17]([N:19]2[CH2:26][CH2:25][C@:24]3([CH3:30])[C:27]([CH3:29])([CH3:28])[C@H:20]2[CH2:21][C:22]2[C:34]([OH:35])=[CH:33][CH:32]=[CH:31][C:23]=23)=[O:18])[CH2:13]1.C(N(CC)CC)C>ClCCl>[OH:35][C:34]1[C:22]2[CH2:21][C@@H:20]3[C:27]([CH3:29])([CH3:28])[C@:24]([CH3:30])([C:23]=2[CH:31]=[CH:32][CH:33]=1)[CH2:25][CH2:26][N:19]3[C:17]([C@@H:14]1[CH2:15][CH2:16][C@@H:12]([NH:11][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH2:13]1)=[O:18]
Reactant: CC1(C)[C@H]2Cc3c(O)cccc3[C@]1(C)CCN2C(=O)[C@@H]1CC[C@@H](N)C1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)[C@H]2Cc3c(O)cccc3[C@]1(C)CCN2C(=O)[C@@H]1CC[C@@H](NS(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzenesulfonyl chloride (41 mg) is added to a solution of [(1R,3R)-3-amino-cyclopentyl]-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone (80 mg) and triethylamine (120 μL) in dichloromethane (1 mL). The resulting solution is stirred at room temperature overnight and then concentrated under reduced pressure. The residue is purified by HPLC on reversed phase (MeCN/H2O/F3CCO2H) to give the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[CH3:22])[C:12]2[C:11](=[O:23])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:24])(=[O:3])[CH3:2].ClCCl.F[B-](F)(F)F.[CH2:33]([O+](CC)CC)[CH3:34].CO>O>[C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[CH3:22])[C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2[O:23][CH2:33][CH3:34])[NH:6][C:5]=1[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccc(C#N)cc1C
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1C)C(C(C)=O)=C(C)N2
Reaction time: 2 h

Procedure:
150 mg (0.470 mmol) of 4-(3-acetyl-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridin-4-yl)-3-methylbenzonitrile are dissolved under an argon atmosphere in 10 ml of abs. dichloromethane, and 178 mg (0.939 mmol) of triethyloxonium tetrafluoroborate are added. After a reaction time of two hours at room temperature (reaction checked by HPLC), the mixture is mixed with 5 ml of methanol and 0.5 ml of water and again stirred for 2 h. It is then diluted with 20 ml of water and extracted three times with dichloromethane. The combined organic phases are dried with sodium sulfate, and the solvent is removed in a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 110 mg (67.4% of theory) of the title compound are obtained.
Reaction SMILES: F[C:2]1[C:11]([CH:12]=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[OH:14][CH2:15][CH2:16][NH:17][NH2:18]>CO>[OH:14][CH2:15][CH2:16][N:17]1[C:2]2[C:11](=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:12]=[N:18]1
Reactant: COC(=O)c1cccc(C=O)c1F
Reactant: NNCCO
Solvent: CO
Product: COC(=O)c1cccc2cnn(CCO)c12
Yield: 64.6 %

Procedure:
A mixture of methyl 2-fluoro-3-formylbenzoate (3.6 g, 19.9 mmol) from Step C above and hydroxy ethyl hydrazine (1.5 g, 19.9 mmol) in MeOH (16 mL) was irradiated with microwaves at 150° C. for 1.5 h. The reaction mixture was cooled and partitioned between H2O and ethyl acetate. The aqueous phase was extracted with additional ethyl acetate and then the combined organic extracts were dried (Na2SO4) filtered, concentrated and purified by column chromatography (silica gel, 70:30 hexanes/ethyl acetate) to afford methyl 1-(2-hydroxyethyl)-1H-indazole-7-carboxylate as a yellow solid (2.83 g, 65%): 1H NMR (500 MHz, CDCl3) δ 8.13 (s, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H); 7.18 (t, J=8.5 Hz, 1H), 4.84 (t, J=5.0 Hz, 2H), 4.13-4.07 (m, 2H), 3.99 (s, 3H), 3.20-3.10 (m, 1H).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[H-].[Na+].Cl[C:8]1[C:12]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:11][S:10][N:9]=1.O>O1CCCC1>[CH2:1]([O:4][C:8]1[C:12]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:11][S:10][N:9]=1)[CH:2]=[CH2:3]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of allyl alcohol (650 mg, 9 mmol) and sodium hydride (310 mg,9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)=[O:7].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:20][CH:19]=1.C(N(CC)CC)C.C(O)C>CCOCC>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=3)=[O:7])[CH2:31][CH2:32]2)=[CH:20][CH:19]=1
Reactant: N#Cc1ccc(NC(=O)NCCCCl)cc1
Reactant: Clc1ccc(CCCN2CCNCC2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: N#Cc1ccc(NC(=O)NCCCN2CCN(CCCc3ccc(Cl)cc3)CC2)cc1
Yield: 42 %

Procedure:
A mixture of 1-(3-chloropropyl)-3-(4-cyanophenyl)urea (3.57 g; 15 mmole), 1-[3-(4-chlorophenyl)propyl]piperazine (3.58 g; 15 mmole), triethylamine (1.52 g; 15 mmole), and ethanol (100 ml) was refluxed for 35 hours. The solvent was removed in vacuo and water added to the residue. The product was extracted with ether, dried, and concentrated in vacuo. The resulting reddish-yellow oil was purified on a silica gel column (methylene chloride/methanol 9:1) to give the product as a free base (2.8 g; 42% yield). The product was dissolved in ether and precipitated with ethereal hydrochloric acid to provide, after recrystallization from water, the title compound as colorless crystals, m.p. 219°-221° C.
Reaction SMILES: [Br:1][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][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1>>[Br-:1].[CH3:27][C:23]1[CH:22]=[N+:21]([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][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cccnc1
Reactant: BrCCCCCCCCCCCCCc1cccnc1
Product: Cc1ccc[n+](CCCCCCCCCCCCCc2cccnc2)c1
Product: [Br-]
Yield: 65 %

Procedure:
3-(13-Bromo-tridecyl)-pyridine (1 mmol) was added to 3-picoline (5 ml), and the mixture was heated at 50 C overnight. The excess picoline was removed in vacuum, and the resulting residue was partitioned between water and ether. The aqueous layer was washed extensively with ether until no picoline left in the aqueous layer, and then the aqueous layer was extracted with chloroform. The chloroform was removed to afford the product (65%). 1HNMR (300 MHz, CDCl3, ppm), 9.36 (s, 1H), 9.22 (d, J=5.4, 1H), 8.44 (br, 2H), 8.21 (d, J=7.5, 1H), 7.97 (m, 1H), 7.54 (d, 7.2, 1H), 7.24-7.24 m, 1H), 4.96 (t, J=7.2, 2H), 2.58-2.65 M, 5H), 2.00-2.07 (m, 4H), 1.58-1.60 (m, 2H), 1.20-1.36 (m, 16H); 13CNMR, 148.76, 146.10, 145.58, 144.77, 142.38, 139.83, 137.29, 127.80, 123.98, 62.28, 58.71, 33.31, 32.36, 31.32, 29.80, 29.74, 29.64, 29.38, 29.35, 26.45, 19.15, 18.81.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[N+]([C:18]1[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=1)([O-])=O>O1CCCC1>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][C:18]3[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=3)=[N:3][C:4]=2[CH:10]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(Sc3ccc(C=O)o3)nc2c1
Temperature: 25 °C
Yield: 27.3 %

Procedure:
2-Mercapto-5-methoxybenzimidazole (1.8 g, 10.0 mmol) is suspended into 25 mL of tetrahydrofuran (THF) under argon. Then, 575 mg (12.0 mmol) of sodium hydride are added. The reaction mixture is stirred at room temperature until gas evolution has ceased. A solution of 5-nitro-2-furaldehyde (1.4 g, 10.0 mmol) in 30 mL of THF is then added dropwise and the reaction mixture is stirred at room temperature for 2 h, upon which it is poured on ice and extracted 3 times with 50 mL of ethyl acetate. The organic extracts are combined, washed with brine, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The residue is triturated in diisopropyl ether and the resulting suspension is stirred for 1 h. The solid is filtered, washed twice with diisopropyl ether and dried. 0.75 g of 5-(5-methoxy-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde is obtained as a pale yellow powder. The filtrate is concentrated under reduced pressure and the residue is purified by chromatography on a prepacked 90 g 15-40 μm silica gel cartridge (eluting solvent: ethyl acetate). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. 0.92 g of additional 5-(5-methoxy-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde is obtained as a pale yellow powder. mp: 94-99° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[CH2:15][N:14]([CH3:16])[CH2:13][CH2:12][C:5]=3[NH:6][C:7]=2[C:8]([F:11])=[CH:9][CH:10]=1.[H-].[Na+].CC1C=CC(S(O[CH2:30][CH2:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=O)=O)=CC=1>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:4]3[CH2:15][N:14]([CH3:16])[CH2:13][CH2:12][C:5]=3[N:6]([CH2:30][CH2:31][C:32]3[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=3)[C:7]=2[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Reactant: CN1CCc2[nH]c3c(F)ccc(Cl)c3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CCn2c3c(c4c(Cl)ccc(F)c42)CN(C)CC3)cn1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 9-chloro-6-fluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (500 mg, 2.1 mmol) in DMF (5 mL), sodium hydride (252 mg, 6.3 mmol) was added. After stirring at 60° C. for 30 min., 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (1.5 g, 5.25 mmol) was added to the reaction mixture and stirred at the same temperature for 1 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase HPLC to obtain the 9-chloro-6-fluoro-2,3,4,5-tetrahydro-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA) δ (ppm): 8.37 (s, 1H), 8.12 (d, 1H), 7.73 (d, 1H), 7.02 (dd, 1H), 6.86 (t, 1H), 5.1 (m, 1H), 4.57 (t, 2H), 4.56 (m, 1H), 3.85 (m, 1H), 3.6 (m, 1H), 3.27 (m, 3H), 3.2 m (2, H), 3.1 (s, 3H), 2.69 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15](C=O)=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].N1CCCC[CH2:28]1>C(O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12](=[C:24]2[S:20][C:21](=[O:26])[NH:22][C:23]2=[O:25])[C:19]2[CH:18]=[CH:15][CH:14]=[CH:13][CH:28]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: O=C1CSC(=O)N1
Reactant: CCc1ccc(CCOc2ccc(C=O)cc2)nc1
Reactant: C1CCNCC1
Solvent: CCO
Product: CCc1ccc(CCOC(=C2SC(=O)NC2=O)c2ccccc2)nc1
Yield: 64 %

Procedure:
A mixture of 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde (2.40 g), 2,4-thiazolidinedione (1.66 g), ethanol (40 ml) and piperidine (0.2 ml) was heated under reflux for 8 hours. The resulting crystals were recrystallized form ethyl acetate to give 2.14 g (64%) of 5-{[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene}-2,4-thiazolidinedione as colorless crystals. m.p.: 165.5°-167° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8](Cl)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>[CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1Cl
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1-c1ccccc1
Yield: 80 %

Procedure:
Microwave vial was charged with 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid ethyl ester (100 mg, 0.376 mmol), phenylboronic acid (2 eq), Cs2CO3 (3 eq), Pd(PPh3)2Cl2 (0.08 eq), DME (1 ml), and ethanol (0.25 ml). The vial was irradiated in microwave synthesizer at 140° C. for 20 min. The contents of the vial were filtered through a celite pad, which was washed out thoroughly with methanol. The filtrate was evaporated, and the residue was purified by column chromatography to give 3-(2-phenyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid ethyl ester (96 mg, 80%).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][CH2:26][OH:27])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>C(Cl)Cl>[Si:33]([O:27][CH2:26][CH2:25][C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C

Procedure:
2-(1-Trityl-1H-imidazol-4-yl)ethanol (20 g, 56.5 mmol) is dissolved in CH2Cl2 (500 mL). To this is added imidazole (11.5 g, 169 mmol) and tert-butyldimethylsilylchloride (10.2 g, 67.8 mmol). The solution is stirred at room temperature until LCMS indicated the reaction is complete. The solution is partitioned between CH2Cl2 and aqueous saturated NaHCO3. The organic layer is washed further with aqueous saturated NaHCO3 and brine.
Reaction SMILES: [C:1]([C:3]([CH3:11])([CH3:10])[CH:4]([OH:9])[CH2:5][C:6]([OH:8])=[O:7])#[N:2].[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.Cl>CN(C=O)C.C1(C)C=CC=CC=1>[C:1]([C:3]([CH3:11])([CH3:10])[CH:4]([OH:9])[CH2:5][C:6]([O:8][CH3:12])=[O:7])#[N:2]
Reactant: CC(C)(C#N)C(O)CC(=O)O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)CC(O)C(C)(C)C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
4-Cyano-3-hydroxy-4-methylpentanoic acid (7.7 g, 49 mmol) was dissolved in DMF (50 mL) and potassium carbonate (10.16 g, 73.5 mmol) was added. Dimethyl sulfate (8.03 g, 63.7 mmol) was dropwise added with vigorous stirring. The mixture was stirred at room temperature for 2 hr and toluene (50 mL) was added. 2N Aqueous hydrochloric acid solution (40 mL, 80 mmol) was dropwise added with vigorous stirring. After partitioning, a toluene layer was separated and an aqueous layer was extracted again with toluene (25 mL). The toluene layers were combined and concentrated under reduced pressure to give methyl 4-cyano-3-hydroxy-4-methylpentanoate (7.13 g, 41.6 mmol). The yield was 85% relative to 4-cyano-3-hydroxy-4-methylpentanoic acid.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[C:10]1(B2OC(C)(C)C(C)(C)O2)[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[Br:9][C:5]1[CH:6]=[C:7]([NH2:8])[C:2]([C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=2)=[N:3][CH:4]=1
Reactant: Nc1cc(Br)cnc1Br
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
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: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Nc1cc(Br)cnc1C1=CCCCC1
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
A stirred mixture of 2,5-dibromopyridin-3-amine (0.2135 g, 0.848 mmol), 1-cyclohexen-1-yl-boronic acid pinacol ester (0.30 mL, 1.40 mmol), tetrakis(triphenylphosphine)palladium (0.098 g, 0.084 mmol), and 2.0M sodium carbonate (2.0 mL, 4.00 mmol) in toluene (1.5 mL) and ethanol (0.5 mL) was heated to 90° C. After 2.5 h, the reaction was cooled to rt then diluted with water. After extraction with EtOAc, the organic extraction was dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified on silica gel (0-35% EtOAc in hexanes) to afford a white solid as 5-bromo-2-cyclohexenylpyridin-3-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.01 (1H, d, J=2.0 Hz), 7.10 (1H, d, J=2.3 Hz), 6.00 (1H, tt, J=3.7, 2.0 Hz), 3.96 (2H, br. s.), 2.45 (2H, m), 2.26 (2H, m), 1.87 (4H, m). 2,5-Dicyclohexenylpyridin-3-amine was also isolated. 1H NMR (400 MHz, CDCl3) δ ppm 8.07 (1H, d, J=2.0 Hz), 6.95 (1H, d, J=2.0 Hz), 6.16 (1H, m), 6.05 (1H, m), 3.81 (2H, br. s.), 2.48 (4H, m), 2.27 (4H, m), 1.87 (8H, m).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=2)[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1.[CH3:32][O:33][C:34](=[O:37])[CH2:35]Br.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:32][O:33][C:34](=[O:37])[CH2:35][NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=2)[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1
Reactant: Cc1cnc(CN(Cc2ccc(CN)cc2CO)C2CCCc3cccnc32)c(C)c1
Reactant: COC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CNCc1ccc(CN(Cc2ncc(C)cc2C)C2CCCc3cccnc32)c(CO)c1

Procedure:
Using General Procedure A: Reaction of (5-Aminomethyl-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol, methylbromoacetate and DIPEA in CH2Cl2 gave (4-{[(3,5-Dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzylamino)-acetic acid methyl ester as a white foamy solid. 1H NMR (CDCl3) δ 1.60 (m, 1H), 1.80 (br s, 1H), 1.98 (m, 1H), 2.19 (m, 2H), 2.22 (s 3H), 2.25 (s, 3H), 2.64 (m, 1H), 2.79 (m, 1H), 3.40 (s, 2H), 3.63-3.77 (m, 8H), 3.91 (t, 1H, J=7.5 Hz), 4.15 (m, 2H), 4.36 (d, 1H, J=12.0 Hz), 7.01 (dd, 1H, J=7.5, 3.0 Hz), 7.16 (d, 1H, J=7.5 Hz), 7.21-7.31 (m, 4H), 8.16 (s, 1H), 8.37 (d, 1H, J=3.0 Hz). 3C NMR (CDCl3) δ 18.3, 18.6, 21.1, 22.1, 29.8, 50.4, 52.1, 53.3, 54.4, 54.6, 57.9, 63.0, 121.9, 127.4, 131.4, 131.8, 132.2, 133.8, 134.9, 136.3, 136.9, 139.3, 139.7, 142.6, 146.5, 146.9, 153.7, 157.3, 173.2. HPLC: 98%. ES-MS m/z 489 [M+H]+, 511 [M+Na]+. Anal. Calcd. for C29H36N4O3.0.1 CH2Cl2: C, 70.31; H, 7.34; N, 11.27. Found: C, 70.54; H, 7.48; N, 11.17.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[NH:14]1[CH2:15][CH2:16][CH:11]([CH2:10][N:9]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:13]1
Reactant: NCC1CCNCC1
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: C(=NCC1CCNCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzaldehyde (4.6 g; 0.044 mol) was added dropwise to a solution of 4-aminomethylpiperidine (5.0 g; 0.044 mol) in toluene (20 ml). The solution thus obtained was stirred for 3 h at room temperature. Then the solvent was removed by evaporation at reduced pressure and the residue was taken up twice with toluene to give the desired product that was used as such without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH2:16])=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:17][CH2:18][CH2:19][Cl:20].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.C(OCC)(=O)C>[Cl:20][CH2:19][CH2:18][O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH2:16])=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:17][CH2:18][CH2:19][O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH2:16])=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccc(-c2cccc(O)c2)cc1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC(=O)c1ccc(-c2cccc(OCCBr)c2)cc1
Product: NC(=O)c1ccc(-c2cccc(OCCCl)c2)cc1

Procedure:
Into three separate microwave vials was distributed equally a mixture of 3′-hydroxy-4-biphenylcarboxamide (Intermediate A-1-1) (1.0 g, 0.005 mol), 1-bromo-2-chloroethane (2.8 g, 0.02 mol) and potassium carbonate (2.8 g, 0.02 mol) in ethanol (2.2 mL) and water (1.8 mL) was placed in a microwave at 150° C. until the reaction was complete as determined by LC/MS. The contents of the vials were combined and diluted with ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo to give 3′-[(2-chloroethyl)oxy]-4-biphenylcarboxamide and 3′-[(2-bromoethyl)oxy]-4-biphenylcarboxamide as an off-white solid. LC/MS indicates that this product is a mixture of the chloroethoxy (M+H) 276, 2.34 min. (LC/MS method A) and the bromoethoxy (M+H) 320, tR 2.42 min. in a ratio of ˜81/19% respectively. This product was used without further purification.
Reaction SMILES: [Br:1][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][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[C:28]([OH:33])(=[O:32])[CH:29]([CH3:31])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[Br:1][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][NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH:29]([C:28]([OH:33])=[O:32])[CH3:31])=[O:24])=[CH:26][CH:27]=1
Reactant: CC(O)C(=O)O
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(OC(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1)C(=O)O

Procedure:
A flask containing 10.0 g. 4-(16-bromohexadecylamino)benzoic acid, 3.3 g. lactic acid, 500 mg. toluenesulfonic acid and 500 ml. toluene is equipped with a Soxhlet extractor charged with activated 4 A Linde molecular sieves. The solution is refluxed for 24 hours, during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and left to cool, whereupon the product separates as off-white crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].F[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COCCN
Solvent: CCO
Product: COCCNc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-methoxyethaneamine (3 mL) is added to a solution of 1-fluoro-2-nitrobenzene (400 mg, 2.84 mmol) in ethanol. The reaction may be stirred at room temperature for an appropriate time period (such as overnight) and concentrated. The residue may be purified by any appropriate method including Biotage column chromatography to give N-(2-methoxyethyl)-2-nitroaniline (477 mg).