Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[C:13]([C:16]1[CH:56]=[CH:55][C:19]([O:20][C@@H:21]2[CH2:26][CH2:25][C@H:24]([N:27]3[C:32](=[O:33])[C:31]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]5[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=5)=[CH:37][CH:36]=4)=[C:30]([CH2:49][CH2:50][CH3:51])[N:29]4[N:52]=[CH:53][N:54]=[C:28]34)[CH2:23][CH2:22]2)=[CH:18][CH:17]=1)(=[O:15])[CH3:14]>O.C(OCC)(=O)C>[C:13]([C:16]1[CH:17]=[CH:18][C:19]([O:20][C@@H:21]2[CH2:26][CH2:25][C@H:24]([N:27]3[C:32](=[O:33])[C:31]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=5[C:47]5[NH:3][C:4](=[O:7])[O:5][N:48]=5)=[CH:37][CH:36]=4)=[C:30]([CH2:49][CH2:50][CH3:51])[N:29]4[N:52]=[CH:53][N:54]=[C:28]34)[CH2:23][CH2:22]2)=[CH:55][CH:56]=1)(=[O:15])[CH3:14]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@@H](Oc3ccc(C(C)=O)cc3)CC2)c2ncnn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@@H](Oc3ccc(C(C)=O)cc3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.88 g), sodium hydrogen carbonate (1.4 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C. for 30 min, 4′-({4-[cis-4-(4-acetylphenoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.50 g) was added, and the mixture was stirred at 90° C. for 40 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (4 mL). N,N′-Carbonyldiimidazole (0.16 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, and the mixture was stirred at room temperature for 50 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was heated under reflux in ethanol (10 mL)-20% sulfuric acid (5 mL) for 16 hr. The solvent was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.097 g, 17%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.F[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.[F-].[K+]>CN1CCCC1=O>[CH:21]1[C:22]2[C:9]3([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH2:3][CH2:4]4)[CH2:23][CH:16]([C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: Fc1ccccn1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: c1ccc(NC2CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)nc1
Yield: 50 %

Procedure:
4-amino-1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-piperidine (0.305 g, 1.0 mmol, prepared as described in Example 8b), 2-fluoropyridine (0.117 g, 1.2 mmol), and anhydrous potassium fluoride (0.174 g, 3.0 mmol) were heated to 150° C. in 3 mL N-methylpyrrolidinone for 52 hours. The warm reaction mixture was added slowly to a rapidly stirring mixture of aqueous NaOH/ice/methanol to give a tan precipitate. The solid was collected and washed with water. The solid was dissolved in methanolic hydrogen chloride and concentrated to dryness several times from methanol to give the hydrochloride salt of the title compound as a white solid (0.239 g, 0.5 mmol, 50%), mp 270° C. (decomp); MS(CI): 382 (M+H); NMR (300MHz, DMSO-d6): 10.27(br s, 1H), 7.95-7.85(m, 2H), 7.39-7.33(m, 5H), 7.04-6.96(m, 5H), 6.85(br m, 1H), 4.47(s, 1H), 4.41(s, 2H), 4.20-4.00(br m, 1H), 3.66-3.30(m, 4H), 2.76(s, 2H), 2.20-2.04(m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]([NH:14]C(=O)COC)[CH3:13])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N(CCO)(CCO)CCO.[OH-].[Na+]>O>[C:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C@H:12]([NH2:14])[CH3:13])=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC(=O)N[C@H](C)c1ccc(OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCN(CCO)CCO
Product: C[C@@H](N)c1ccc(OC(C)(C)C)cc1
Yield: 73 %

Procedure:
(R)—N-1-(4-tert-Butoxyphenyl)ethylmethoxyacetamide from example 1.3 (180 g with a purity of 94%; corresponds to 0.64 mol of pure substance) was mixed with triethanolamine (20 ml) with stirring and then admixed with 50% NaOH (70.8 g, 0.89 mol). The mixture was then stirred at a bath temperature of 140° C. for another seven hours, after which all of the amide had been converted according to GC. The mixture was diluted with water (100 ml), cooled and extracted with tert-butyl methyl ether (3×100 ml). The combined extracts were washed with saturated sodium chloride solution (50 ml) and dried over Na2SO4. After the solvent had been removed on a rotary evaporator, 123.7 g (73%) of (R)-1-(4-tert-butoxyphenyl)ethylamine were obtained in the form of a pale brownish oil. The chemical purity was 99.4%, the optical purity 98.9% ee.
Reaction SMILES: [SH:1][CH2:2][CH:3]([SH:6])[CH2:4][SH:5].[C:7]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])=O.B(F)(F)F.CCOCC>C(Cl)Cl>[SH:1][CH2:2][CH:3]1[CH2:4][S:5][C:10]([CH3:12])([CH2:9][CH2:8][C:7]([O:14][CH2:15][CH3:16])=[O:13])[S:6]1
Reactant: CCOC(=O)CCC(C)=O
Reactant: SCC(S)CS
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CCC1(C)SCC(CS)S1

Procedure:
The title compound was prepared according to the procedure of Example 1 using 1,2,3-trimercaptopropane (5.6 g, 0.04 mol), ethyl levulinate (5.8 g, 0.04 mol) and boron trifluoride etherate (1.25 ml) in methylene chloride (150 ml). The crude product was chromatographed on silica gel using 5% ethyl acetate/hexane as eluent to give 3.35 g (31%) of product.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[NH:4][C:5](=[S:9])[NH:6][C:7]=1[CH3:8].[OH-].[Na+].CI.[C:15](O)(=O)C>O>[CH3:1][C:2]1[C:3](=[O:10])[NH:4][C:5]([S:9][CH3:15])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1[nH]c(=S)[nH]c(=O)c1C
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CSc1nc(C)c(C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a stirred solution of 5,6-dimethyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (10.0 g, 64.0 mmol, Example 1, Step A) and sodium hydroxide (10.0 g, 260.0 mmol) in water (150 mL) at ambient temperature was added methyl iodide (15.0 g, 320.0 mmol), and the reaction mixture was stirred at ambient temperature overnight. Then the reaction mixture was acidified with acetic acid (50 mL), and the solid was collected by filtration and dried to afford 7.0 g (64%) of the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.87 (s, 3H), 2.18 (s, 3H), 2.45 (s, 3H), 12.38 (bs, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH:24]1[CH2:26][CH2:25]1.C(=O)([O-])[O-]>C(O)C>[CH:24]1([CH2:23][N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=[CH:8]3)[CH2:3][CH2:2]2)[CH2:26][CH2:25]1
Reactant: c1ccc2c(c1)ccn2C1CCNCC1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: c1ccc2c(c1)ccn2C1CCN(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.9 %

Procedure:
To a solution of 1-N-(piperidin-4-yl)-indole (0.6 g, 3 mmol) in dry ethanol (4 mL) was added anhydrous potassium carbonate (680 mg, 4.9 mmol). After stirring for 15 minutes at ambient temperature, bromomethylcyclopropane (0.29 mL,4.5 mmol) was added. Stirring was continued overnight. An additional amount of carbonate (0.22 g) and bromomethylcyclopropane (0.14 mL) was added. After 3 hours, the reaction mixture was quenched with water and extracted with ethyl acetate (3×). The combined organic phase was washed with water, dried, evaporated, and purified by column chromatography on silica gel eluting with methylene chloride/ethanol (98:2). Evaporation of the eluting solvent gave the title compound as an oil (480 mg, 63% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].C(N(CC)CC)C.[OH:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O>ClCCl.O>[Br:21][C:20]([Br:24])=[CH:35][C:34]1[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=1[OH:32]
Reactant: O=Cc1ccccc1O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Oc1ccccc1C=C(Br)Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of triphenylphosphine (10.5 g, 40 mmol), carbon tetrabromide (6.6 g, 20 mmol) and triethylamine (3.0 g, 30 mmol) in dichloromethane (10 mL) was added 2-hydroxy-benzaldehyde (1.62 g, 13 mmol), and the mixture temperature was maintained at around 0° C. during the addition. After the addition was completed, the reaction mixture was stirred at room temperature for 1 hour. After the reaction, the mixture was poured into water (200 mL). And then the mixture was extracted with ethyl acetate (200 mL), washed with water (200 mL). The organic phase was dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, ethyl acetate/petroleum ether=1:5) to give the pure product 2-(2,2-dibromovinyl)phenol as a pink solid (2.8 g, 76%). LRMS (M−H)−: calcd 275.9. found 275.
Reaction SMILES: OS(O)(=O)=O.[CH2:6]=[O:7].[CH3:8][C:9]1[C:18]2([CH2:20][CH2:19]2)[C@:17]([OH:22])([CH3:21])[C:15](=[O:16])[C:14]2[C:10]=1[C@@H:11](O)[C@@:12](CO)([CH3:23])[CH:13]=2>CC(C)=O>[CH3:23][C:12]1[CH:13]=[C:14]2[C:10](=[C:9]([CH3:8])[C:18]3([C@:17]([OH:22])([CH3:21])[C:15]2=[O:16])[CH2:20][CH2:19]3)[C:11]=1[CH2:6][OH:7]
Reactant: CC1=C2C(=C[C@@](C)(CO)[C@@H]2O)C(=O)[C@](C)(O)C12CC2
Reactant: C=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC1=C(CO)C2=C(C)C3(CC3)[C@@](C)(O)C(=O)C2=C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.2 %

Procedure:
To a solution of 250 ml of 1M H2SO4 and 200 ml acetone was added 40 g paraformaldehyde (MW 30, 1.33 mol). The solution was heated to clear and was then allowed to cool to room temperature. 1 g illudin S (MW 264, 3.79 mmol) was added to the above solution. The mixture was stirred at room temperature for 72 h and was partitioned between ethyl acetate and water. The organic extracts were washed by saturated NaHCO3 and saline respectively to neutral. After being dried by MgSO4, the solution was concentrated and chromatographed to give 245 mg 14 (23.4%) and 226 mg HMAF (24.3%). 14 is a white crystal: mp 100.5-102.5; IR (KBr) 3469, 2966, 2858, 1703, 1656, 1596, 1172 cm−1; 1H NMR (CDCl3) δ 0.48 (m, 1H), 0.84 (m, 1H), 0.99 (m, 1H), 1.10 (s, 3H), 1.17 (m, 1H), 1.32 (s, 3H), 1.67 (s, 3H), 3.61 (s, 1H), 3.73 (d, J=11.7 Hz, 1H), 3.96 (d, J =11.7 Hz, 1H), 4.56 (s, 1H), 4.75 (d, J=5.4 Hz, 1H), 4.91 (d, J=5.4 Hz, 1H). 6.52 (s, 1H); 13C NMR (CDCl3) δ 199.7, 141.4, 136.5, 135.9, 134.7, 90.0, 80.3 75.9, 70.8, 46.8, 32.3, 24.7, 22.5, 13.8, 8.9, 5.6; MS m/z 276 (M+), 217, 201, 173; HRMS for C16H20O4 calcd 276.1362, found 276.1364; UV λmax 305 nm (ε3148).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].CN(C)C(=N)N(C)C.[CH2:12]([C@@H:19]1[CH2:23][O:22][C:21](=[O:24])[N:20]1[C:25](=[O:37])[C@H:26](Br)[CH:27]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCOC(C)=O.CCCCCC>C(#N)C>[N:1]([C@@H:26]([CH:27]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[C:25]([N:20]1[C@H:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:23][O:22][C:21]1=[O:24])=[O:37])=[N+:2]=[N-:3]
Reactant: CCCCC(CCCC)[C@@H](Br)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: CN(C)C(=N)N(C)C
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCC(CCCC)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reaction time: 96 h

Procedure:
Tetramethylguanidine azide (TMGA) (5.398 g, 37.70 mmol) was added dropwise (5 min) to a 25° C. solution of (4R)-4-benzyl-3-[(2R)-2-bromo-3-butylheptanoyl]-1,3-oxazolidin-2-one (4.0 g, 9.42 mmol) in acetonitrile (50 mL). The reaction was stirred for 4 days. An aliquot was taken and TLC (1:4 EtOAc-hexane) indicated that reaction was complete. The solvent was removed in vacuo. The resulting black semi-solid was dissolved in CH2Cl2 (200 mL) and quenched with 1N HCl (30 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to obtain (4R)-3-[(2S)-2-azido-3-butylheptanoyl]-4-benzyl-1,3-oxazolidin-2-one as a crude yellow oil (3.61 g, 99.1%). Mass Spectrum (−ESI): 385 (M−H)−.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=O)[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10]2)=[CH:4][CH:3]=1.O1CCOCC1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[S:40])[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1nn(Cc2ccc(I)cc2)c2ncccc2c1=O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(Cc2ccc(I)cc2)c2ncccc2c1=S
Temperature: 25 °C

Procedure:
Ethyl 1-[(4-iodophenyl)methyl]-4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxylate (800 mg, 1.84 mmol) was suspended in toluene (5 mL) and dioxane (5 mL) and placed into a preheated oil bath to 110° C. Lawesson's Reagent (409 mg, 1.01 mmol, 0.55 equiv) was added portionwise over 45 minutes and after an additional 30 minutes at 110° C., the mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 95:5; dichloromethane:methanol), providing the titled compound.
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=O.[N:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1.[C:19](=O)(O)[O-].[Na+]>O1CCCC1>[C:3]1([CH3:19])[CH:2]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5](=[O:7])[CH2:18][C:15]1[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=1
Reactant: COC(=O)c1cccc(C)c1
Reactant: Cc1ccncc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Cc1ccncc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
Methyl 3-methylbenzoate (6.0 g, 40 mmol), tetrahydrofuran (50 mL), and 4-picoline (4.1 g, 44 mmol) were stirred at −78° C. under an atmosphere of nitrogen. Sodium (bis)trimethylsilylamide 1.0 M in tetrahydrofuran (88 mL, 88 mmol) was added dropwise. The mixture was allowed to warm to room temperature, stirred for 16 hours and then was poured into saturated aqueous sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (3×50 mL). The combined organics were washed with brine (2×50 mL), dried over magnesium sulfate, and concentrated. The product was recrystallized from ethyl acetate/hexane to yield a light yellow solid (5.7 g, 67%), mp 118.0-119.0° C.; 1H NMR (acetone-d6/300 MHz) 8.50 (m, 2H), 7.90 (m, 2H), 7.44 (m, 2H), 7.29 (m, 2H), 4.45 (s, 2H), 2.41 (s, 3H); ESHRMS m/z 212.1067 (M+H, C14H13NO requires 212.1075); Anal. Calc'd for C14H13NO; C, 79.59; H, 6.20; N, 6.63. Found; C, 79.54; H, 6.30; N, 6.56.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.[CH3:28]O>>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)[C:7]([CH2:11][O:12][CH3:28])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CO
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Product: CCCCc1nc(Cl)c(COC)n1Cc1ccc([N+](=O)[O-])cc1

Procedure:
2-n-butyl-4-chloro-5-hydroxymethyl-1-(4-nitrobenzyl)imidazole (10.5 g, 32.4 mmol, 1 eq), conc. sulfuric acid (26 mL) and methanol (300 mL) were mixed and refluxed overnight. The solvent was removed in vacuo and the residue taken up in water (about 300 mL). The pH was adjusted to 5 with 1N NaOH and then this aqueous portion extracted with ethyl acetate (3×250 mL). The organic layers were collected, dried (MgSO4) and the solvent removed in vacuo to yield 11.57 g of an amber oil. NMR (200 MHz, CDCl3) δ 8.22 (d, 2H, J=8 Hz); 7.15 (d, 2H, J=8 Hz); 5.26 (s, 2H); 4.25 (s, 2H); 3.23 (s, 3H); 2.52 (t, 2H, J=7 Hz); 1.64 (t of t, 2H, J=7,7 Hz); 1.28 (t of q, 2H, J=7,7 Hz); 0.81 (t, 3H, J=7 Hz). Anal. Calcd. for C16H20ClN3O3.(H2O)0.5 : C, 55.41; H, 6.10; Cl, 10.22. Found: C, 55.21; H, 6.22; Cl, 9.92.
Reaction SMILES: [I-].ClC1C=CC=C[N+:4]=1C.CCN(C(C)C)C(C)C.[Br:19][C:20]1[CH:28]=[CH:27][C:23](C(O)=O)=[CH:22][N:21]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:40]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[N:39]=[C:38]([C:47]([OH:49])=O)[CH:37]=2)=[CH:32][CH:31]=1>C(Cl)Cl.CN(C=O)C>[Br:19][C:20]1[N:21]=[C:22]([NH:4][C:47]([C:38]2[CH:37]=[C:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[N:40]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[N:39]=2)=[O:49])[CH:23]=[CH:27][CH:28]=1
Reactant: C[n+]1ccccc1Cl
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)n(C2CCCCO2)n1
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Br)n1)c1cc(-c2ccc(F)cc2)n(C2CCCCO2)n1
Reaction time: 1 h
Yield: 50 %

Procedure:
2-Chloro-1-methylpyridinium iodide (950 mg, 3.7 mmol) and DIPEA (0.7 mL) were added to a solution of 6-bromopicolinic acid 2 (500 mg, 2.47 mmol) in dry DCM/DMF (30/5 mL). The reaction mixture was stirred for 1 hr. tert-Butyl 3-amino-5-(4-fluorophenyl)-1H-pyrazole-1-carboxylate 1 was added (650 mg, 2.47 mmol). The resulting yellow reaction mixture was stirred for 3 days. Then the reaction mixture was concentrated under reduced pressure, the residue was diluted in chloroform and washed with water and brine, and then dried over Na2SO4. The resulting crude mixture was purified on silica gel (EtOAc: pet-ether, 1:3) to give 6-bromo-N-(5-(4-fluorophenyl)-1H-pyrazol-3-yl) picolinamide 3 (450 mg, 50%) as a white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1.[BH3-][C:32]#[N:33].[Na+]>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:3][C:2]2[NH:1][CH:5]=[CH:32][N:33]=2)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1
Reactant: [BH3-]C#N
Reactant: O=Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: [Na+]
Solvent: CO
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CNc2ncc[nH]2)cc1)Cc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 120 h
Yield: 19.4 %

Procedure:
Using General Procedure A: To a stirred solution of 4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde (200 mg, 0.49 mmol) and the amine (41 mg, 0.49 mmol) from above in MeOH (5 mL) was added NaBH3CN (94.3 mg, 1.5 mmol) and the mixture was stirred at room temperature for 5 days. Purification of the crude yellow foam by column chromatography on silica gel (100:1:1—CH2Cl2:MeOH:NH4OH) afforded AMD9741 (26 mg, 15%) as a brown solid (22 mg, 10%). 1H NMR (CDCl3) δ 1.61–1.76 (m, 1H), 1.92–2.09 (m, 2H), 2.17–2.27 (m, 1H), 2.68–2.76 (m, 1H), 2.80–2.90 (m, 1H), 3.64 (s, 2H), 3.89 (d, 1H, J=16.5 Hz), 4.05–4.14 (m, 2H), 4.22 (s, 2H), 4.39 (br s, 1H), 6.54 (s, 2H), 7.06 (d, 2H, J=7.8 Hz), 7.15–7.20 (m, 3H), 7.25 (d, 2H, J=6.9 Hz), 7.43 (d, 1H, J=7.8 Hz), 7.54 (br s, 2H), 8.67 (d, 1H, J=4.5 Hz); 13C NMR (CDCl3) δ 19.22, 21.83, 27.12, 45.73, 46.41, 51.49, 58.49, 111.83, 112.90, 115.59, 119.64, 120.29, 125.33, 126.71, 132.76, 135.33, 135.86, 136.22, 144.75, 148.75, 154.19, 155.23. ES-MS m/z 464.3 (M+H). Anal. Calcd. for C28H29N7.1.4CH2Cl2: C, 60.62; H, 5.50; N, 16.83. Found: C, 60.53; H, 5.48; N, 16.94.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([F:23])[C:15]=1[O:24][CH3:25]>C(COC)OC.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([O:24][CH3:25])[C:16]=2[F:23])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(N)nc(Cl)n1
Reactant: COc1c(Cl)ccc(B(O)O)c1F
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(N)nc(-c2ccc(Cl)c(OC)c2F)n1
Temperature: 80 °C
Yield: 53.5 %

Procedure:
6-Amino-2-chloro-pyrimidine-4-carboxylic acid methyl ester (2.25 g, 12 mmol), 4-chloro-2-fluoro-3-methoxyphenylboronic acid (3.27 g, 16 mmol), and bis(triphenylphosphine)palladium(II) dichoride (842 mg, 1.2 mmol) were combined in 12 mL of dimethoxyethane and 12 mL of water. The reaction mixture was heated at 80° C. for 2 hours and the cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried, and concentrated under vacuum. The product was purified by column chromatography to yield 6-amino-2-(4-chloro-2-fluoro-3-methoxy-phenyl)pyrimidine-4-carboxylic acid methyl ester (2.0 g, 53.5% yield): mp 188-190° C.: 1H NMR (CDCl3): δ 7.66 (dd, 1H), 7.22 (dd, 1H), 7.14 (s, 1H), 5.25 (br s, 2H), 4.0 (s, 3H), 3.99 (s, 3H).
Reaction SMILES: CO[CH2:3][NH:4][CH2:5][CH2:6][C@@H:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[OH:8].[H-].[Na+].F[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.CN(C)[CH:29]=[O:30]>>[CH3:3][N:4]([CH2:5][CH2:6][CH:7]([O:8][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[O:30][CH3:29]
Reactant: COCNCC[C@H](O)c1cccs1
Reactant: CN(C)C=O
Reactant: Fc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Product: CON(C)CCC(Oc1cccc2ccccc12)c1cccs1
Temperature: 70 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
10.0 g of (S)-3-methoxymethylamino-1-(2-thienyl)propan-1-ol from example 2 was dissolved in 30 mL of N,N-dimethylformamide at ambient temperature, to which was added sodium hydride (3.9 g, 60%) with vigorous stirring. Then, 9.4 g of 1-fluoronaphthalene was added and the mixture was stirred at 70° C. for 8 hours. Upon completion of naphthalenation, the reaction mixture was quenched with water (90 mL). After extraction with toluene (30 mL×3), the organic layer was combined and concentrated. Subsequently, the crude product was purified by silica gel column chromatography to give objective compound as an amber oil (13.5 g, 82.8%). 1H NMR (400 MHz, CDCl3) δ (ppm)=2.3 (m, 1H), 2.5 (m, 1H), 2.6 (s, 3H), 2.9 (t, 2H), 3.5 (s, 3H), 5.8 (m, 1H), 6.8 (m, 1H), 6.9 (d, 1H), 7.0 (s, 1H), 7.2 (d, 1H), 7.3 (m, 1H), 7.4 (d, 1H), 7.5 (m, 2H), 7.8 (d, 1H), 8.3 (d, 1H).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[NH:7][CH:6]=1.C(O[CH:18](O)[C:19]([F:22])([F:21])[F:20])C.C(O)(=O)C>C(O)C>[ClH:1].[F:20][C:19]([F:22])([F:21])[CH:18]1[C:6]2[NH:7][C:8]3[C:13](=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1
Reactant: NCCc1c[nH]c2ccc(O)cc12
Reactant: CCOC(O)C(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: Oc1ccc2[nH]c3c(c2c1)CCNC3C(F)(F)F

Procedure:
A mixture of 3-(2-amino-ethyl)-1H-indol-5-ol hydrochloride (0.5 g), trifluoroacetaldehyde ethyl hemiacetal (0.35 mL), acetic acid (0.32 mL) and ethanol (22.5 mL) was heated at reflux for 16 h. The solvent and excess reagents were evaporated to dryness under vacuum. The residue was washed with diethyl ether to afford 1-trifluoromethyl-2,3,4,9-tetrahydro-1H-β-carbolin-6-ol hydrochloride (0.5 g).