Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:12][C:11]1[C:2]([Cl:1])=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][C:10]=1[Cl:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1
Product: COC(=O)c1cc(Cl)c(OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 120.2 %

Procedure:
Crude methyl 4-(benzyloxy)-3,5-dichlorobenzoate (2) (16.9 g) was prepared from methyl 3,5-dichloro-4-hydroxybenzoate (1) (10 g, 45.2 mmol) and benzyl bromide (15.5 g, 90 mmol) using a procedure essentially the same as in Step (i) for AAA-001, except that the mixture was stirred at RT for 18 h. The crude product was partially purified by silica gel chromatography (330 g, 0-10% EtOAc/isohexane) to afford a white solid. The material was used in the next step without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O-:15])(=O)=[O:13])=[CH:8][CH:7]=1.[Na+]>CN(C)C=O>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([Cl:3])(=[O:15])=[O:13])=[CH:8][CH:7]=1
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(O)cc1
Temperature: 60 °C
Yield: 61.7 %

Procedure:
Thionyl chloride (44.3 mL, 604 mmol, and 6.91 Eq) and N,N-dimethylformamide (DMF)(1 mL) were added to sodium 4-hydroxybenzenesulfonate (20.3 g, 87.2 mmol, and 1.00 Eq) under an argon atmosphere, and the mixture was stirred under reflux at 60° C. for 4 hours. The resultant mixture was cooled to room temperature and ice (160 g) was added thereto. The mixture was stirred and the water layer was extracted with dichloromethane (1×60 mL, 2×40 mL). The obtained organic layer was washed with ice water (40 mL) and dried with sodium sulfate. The solvent was removed by an evaporator and 4-hydroxybenzene sulfonyl chloride (10.4 g, 53.8 mmol, 62%) was obtained as oil.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](I)=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1>C(O)C.[OH-].[Pd+2].[OH-].[C]>[Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1nc(Cl)[nH]c1I
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])c1c[nH]c(Cl)n1
Reaction time: 5 h
Yield: 83.5 %

Procedure:
2-Chloro-5-iodo-4-nitroimidazole (273 mg) was dissolved in ethanol (5 ml), then triethylamine(420 μl) and 20% palladium hydroxide-carbon (27 mg) were added, the reaction mixture was subjected to hydrogenation at a room temperature under normal pressure for 5 hours, there was obtained 2-chloro-4-nitroimidazole (123 mg, yield: 83.4%) as colorless solid product.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][OH:12])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1>O1CCCC1.[O-2].[O-2].[Mn+4]>[O:1]1[C:10]2[CH:9]=[C:8]([CH:11]=[O:12])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: OCc1cc2c(cn1)OCCO2
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1cc2c(cn1)OCCO2
Temperature: 70 °C
Reaction time: 5 h
Yield: 48.8 %

Procedure:
To a solution of 111 g of (2,3-dihydro-(1,4)dioxino(2,3-c)pyridin-7-yl)methanol in 1110 mL of tetrahydrofuran, 164 g of manganese dioxide was added, the mixture was stirred for 5 hours at 70° C. and stirred overnight at room temperature. The reaction mixture was subjected to celite filtration and the filter residue was washed with 500 mL of tetrahydrofuran. The filtrate and the wash liquid were combined to evaporate the solvent under reduced pressure. The obtained residue was recrystallized from 750 mL of 2-propanol to give 53.5 g of 2,3-dihydro-(1,4)dioxino(2,3-c)pyridin-7-carbaldehyde as a light yellow solid.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][OH:12])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1>ClCCl.[O-2].[O-2].[Mn+4]>[O:1]1[C:10]2[CH:9]=[C:8]([CH:11]=[O:12])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: OCc1cc2c(cn1)OCCO2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cc2c(cn1)OCCO2
Yield: 60.6 %

Procedure:
A solution of (2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-methanol (250 mg, 1.5 mmol) in dichloromethane (5 mL) was treated with manganese dioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered and evaporated affording a white solid (150 mg, 61%); MS (APCI+) m/z 166 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4].Cl[CH2:14][C:15]([N:17]([CH3:19])[CH3:18])=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH:4][CH2:14][C:15]([N:17]([CH3:19])[CH3:18])=[O:16]
Reactant: Cc1cc(C)c(N)c([N+](=O)[O-])c1
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(NCC(=O)N(C)C)c([N+](=O)[O-])c1
Temperature: 120 °C
Reaction time: 14 h

Procedure:
A mixture of 2,4-dimethyl-6-nitroaniline (5.00 g, 30.1 mmol), 2-chloro-N,N-dimethylacetamide (18.3 g, 150 mmol), K2CO3 (6.24 g, 45.2 mmol), and KI (499 mg, 3.01 mmol) in DMF (100 mL) was heated at 120° C. for 7 h, then at 130° C. for 14 h. The cooled mixture was quenched with H2O (200 mL) and extracted with CH2Cl2 (3×150 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=252 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.Cl[Sn]Cl>Cl.CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: COc1ccc([N+](=O)[O-])c2ncccc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Product: COc1ccc(N)c2ncccc12
Yield: 91.8 %

Procedure:
In a similar fashion using route 2 general procedure 4, 5-methoxy-8-nitroquinoline 585 (550 mg, 2.69 mmol), SnCl2 (1.53 g, 8.08 mmol), 6N HCl (3 drops) and MeOH (15 ml) for 1.3 h at 70° C. for 4 h gave the title compound (430 mg, 91%) which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])[N:8]=1)=[O:5].[CH:27](=O)[CH2:28][CH3:29].[Na].C(O)(=O)C>CO.ClCCl>[F:26][C:21]1[CH:22]=[C:23]([F:25])[CH:24]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH:15]2[CH2:16][CH2:17][N:18]([CH2:27][CH2:28][CH3:29])[CH2:19][CH2:20]2)=[O:14])[N:8]=1)=[O:5]
Reactant: CCC=O
Reactant: O=C(Nc1cccc(C(=O)C2CCNCC2)n1)c1c(F)cc(F)cc1F
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCCN1CCC(C(=O)c2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Reaction time: 1.5 h

Procedure:
Mix 2,4,6-trifluoro-N-[6-(piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide (50 mg), propionaldehyde (80 mg), sodium triacetoxyborobydride (38 mg) and acetic acid (21 mg) with dichloromethane (5 mL) and stir for 1.5 hrs. Dilute with methanol and load on a SCX column (10 g), wash with methanol, elute the product with 2M NH3-methanol. Purify the product on a silica gel column (10 g, dichloromethane/2M NH3 in methanol, gradient) to obtain the title compound as a free base (26 mg). Mass spectrum (electrospray) m/z=406 (M+1); 1H NMR (CDCl3): 8.52 (d, 1H), 8.38 (br, 1H), 7.92 (t, 1H), 7.82 (dd, 1H), 6.82 (m, 2H), 3.61 (br, 1H), 3.00 (m, 2H), 2.34 (m, 2H), 2.11 (m, 2H), 1.87 (m, 3H), 1.60 (m, 5H), 0.90 (t, J=7.3 Hz, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:19]>ClCCl>[ClH:19].[CH3:18][C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)([CH3:17])[CH2:15][OH:16]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C)(C)CO)CC1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(CO)N1CCNCC1
Reaction time: 12 h

Procedure:
To a solution of 4-(2-hydroxy-1,1-dimethyl-ethyl)-piperazin-1-carboxylic acid tert-butyl ester (0.42 g) in anhydrous dichloromethane (10 mL) was added 2M hydrogen chloride (8.4 ml) and the mixture stirred for 12 hours. The solvent was evaporated to give 2-methyl-2-piperazin-1-yl-propan-1-ol hydrochloride salt as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CC(O)=O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1
Reactant: N#CCc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: N#CCc1cccc(N)c1
Reaction time: 2 h

Procedure:
A solution of 3-nitrophenyl acetonitrile (500 mg, 3.1 mmol) in 5% AcOH (10 ml) was heated to 80° C. Iron powder (1.5 g, 27 mmol) was then added and the resulting mixture stirred for 2 h. The reaction mixture was filtered through celite and the filter cake washed with MeCN (4×50 ml). The combined MeCN layers were evaporated in vacuo and the residue was re-dissolved in EtOAc (30 ml) followed by 2M HCl (30 ml). The aqueous layer was separated, basified to pH 10 with 6M NaOH, and extracted with EtOAc (3×80 ml). The combined organic layers were dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([Br:16])=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li]CCCC.CN([CH:25]=[O:26])C>>[Br:16][C:9]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:2]([CH:25]=[O:26])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[CH:14]2
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: O=Cc1c2ccccc2c(Br)c2ccccc12
Temperature: 25 °C
Yield: 76 %

Procedure:
This material was made from 9,10-dibromoanthracene (Eastman, 20 g, 60 mmol) by the procedure of R. Kuhn and H. Fischer, Chem. Ber. 94 3060 (1961) with some modifications. In this procedure, the reaction mixture was cooled to -78° before the n-BuLi (Aldrich) was added. The resulting mixture was warmed to RT over 1 h and then refluxed until the crystalline starting material disappeared. The mixture was then cooled to -78° again before the DMF was added (in one portion). The flask was warmed to RT and then quenched with 1M HBr (200 mL). The two-phase system was then extracted with CH2Cl2 (3×500 mL). The extracts were combined, dried (MgSO4), filtered, and the solvent removed to give the crude material. This was purified by preparative HPLC using PhCH3 as the eluting solvent to give 13.06 g (76%) of 10-bromo-9-anthracenecarbaldehyde mp 215°-216.5°, (lit. mp 218°, P. Kuhn and H. Fischer, Chem. Ber. 94 3060 (1961)), (C, H, Br).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:5]2.O.[CH3:20][N:21](C)C=O>C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].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].[C-]#N.[Zn+2].[C-]#N>[C:20]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:5]2)#[N:21]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(Br)cc2C1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)NC1Cc2ccc(C#N)cc2C1
Temperature: 110 °C
Reaction time: 21 h
Yield: 78 %

Procedure:
A flask containing 1,1-dimethylethyl (5-bromo-2,3-dihydro-1H-inden-2-yl)carbamate (3.0 g, 9.26 mmol) from the preceding step, diphenylphosphinoferrocene (645 mg, 1.16 mmol), Pd2 dba3 (532 mg, 0.58 mmol), zinc cyanide (1.50 g, 12.8 mmol) and water in 50 mL dimethylformamide was degassed four times under nitrogen and allowed to stir at 110° C. for 21 hours. Upon cooling the reaction was quenched with saturated NH4Cl and the organics were taken up in ethyl acetate. The organic layer was washed with water (3×), sat. NaCl and dried over MgSO4. The solvent was removed in vacuo and the residual orange-yellow oil was purified by silica gel column chromatography (15-40% ethyl acetate/hexanes) yielding 1.85 g (7.18 mmol, 78% yield) of the 1,1-dimethylethyl (5-cyano-2,3-dihydro-1H-inden-2-yl)carbamate as an off-white solid. 1H NMR (400 MHz, CDCl3) delta 7.47 (s, 1H), 7.45 (d, 1H, J=7.9 Hz), 7.28 (d, 1H, J=7.7 Hz), 4.69 (br.s), 1H), 4.47 (s(br), 1H), 3.33-3.25 (m, 2H), 2.86-2.80 (m, 2H), 2.79 (s, 9H) ppm. (M+1) 259.1, 2.46 min (LC/MS method A).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1F.[NH2:15][NH2:16]>C(O)C>[N+:10]([C:7]1[CH:6]=[C:5]2[C:4]([C:3](=[O:2])[NH:15][NH:16]2)=[CH:9][CH:8]=1)([O-:12])=[O:11]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1F
Reactant: NN
Solvent: CCO
Product: O=c1[nH][nH]c2cc([N+](=O)[O-])ccc12

Procedure:
The crude material, 2-fluoro-4-nitro-benzoic acid methyl ester, from above was treated with hydrazine (1.6 mL, 51 mmol) in ethanol under reflux for 14 hrs. After removal of solvent by evaporation, the residue was washed with water. The precipitate product was filtered and dried on the vacuum pump to give the title compound which was used without further purification(4.0 g, 85% for two steps). MS (ES+): m/e=180.1 (M+H), 178.0 (M−H); LC/Method A/1.83 min.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]#[CH:10])=[CH:3]1.N1C=CN=C1.[CH2:16]([Si:18](Cl)([CH2:21][CH3:22])[CH2:19][CH3:20])[CH3:17]>CN(C)C=O.CCOCC>[CH2:8]([C:4]1[C:5](=[O:7])[CH2:6][CH:2]([O:1][Si:18]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:16][CH3:17])[CH:3]=1)[C:9]#[CH:10]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C#CCC1=CC(O)CC1=O
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CCC1=CC(O[Si](CC)(CC)CC)CC1=O
Yield: 80.3 %

Procedure:
A solution of 250 mg (1.84 mmole) of the title compound of Example 2 in 4 ml of dimethylformamide was treated successively with 200 mg (3 mmole) of imidazole and 300 mg (2 mmole) of triethylsilyl chloride. After stirring for thirty minutes, the reaction mixture was diluted with ether, washed with water, dried over sodium sulfate, filtered, and concentrated to dryness. The crude material was chromatographed on silica gel to give 0.37 g of the title compound as an oil. Structure assignment was confirmed by the proton nmr spectrum: 2.13 (t, J=2 Hz, ≡C--H), 3.08 (mult, --CH2 --C≡), 4.90 (mult, C-11), 7.35 ppm ##STR7##
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH3:6][NH:7][C:8]1[C:9](=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:10]([O:12][CH3:13])=[O:11].[OH-].[Na+]>ClCCl.O>[Br:1][CH2:2][C:3]([N:7]([C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])[CH3:6])=[O:4]
Reactant: CNc1ccccc1C(=O)OC
Reactant: O=C(Br)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccccc1N(C)C(=O)CBr
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.6 %

Procedure:
A solution of bromoacetyl bromide (209 g) in dichloromethane (200 ml) was added dropwise to a cooled (ice bath) solution of methyl N-methylanthranilate (168 g) in dichloromethane (1.41). A solution of sodium hydroxide (59 g) in water (400 ml) was added dropwise and the reaction mixture was stirred at room temperature for 20 h. The organic phase was separated and washed with 1M hydrochloric acid (500 ml), brine (300 ml), saturated sodium hydrogen carbonate solution (400 ml), dried (Na2SO4) then evaporated to afford the required product (255 g). 1H NMR (360 MHz, CDCl3) δ3.23 (3H, s), 3.54 (1H, d, J=11 Hz), 3.60 (1H, d, J=11 Hz), 3.90 (3H, s), 7.40 (1H, d, J=8 Hz), 7.51 (1H, dd, J1 =J2 =8 Hz), 7.65 (1H, dd, J1 =J2 =8 Hz), 8.04 (1H, d, J=8 Hz).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].O[C:7]1[CH:12]=[C:11]([CH3:13])[NH:10][C:9](=[O:14])[C:8]=1[C:15]#[N:16].[NH4+].[OH-]>C(Cl)(Cl)Cl>[Cl:3][C:7]1[CH:12]=[C:11]([CH3:13])[NH:10][C:9](=[O:14])[C:8]=1[C:15]#[N:16]
Reactant: Cc1cc(O)c(C#N)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)c(C#N)c(=O)[nH]1
Reaction time: 0.08 h
Yield: 36 %

Procedure:
Using a 100 ml round bottom with reflux condenser, PCI5 (6.7 g, 32 mmol), POCl3 (3.0 mL, 32 mmol) and 30 ml CHCl3 (dry) were stirred for 5 min (see: Heterocycles, vol. 60, No. 6, 2003, 1461-1468). Added 4-hydroxy-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (4 g, 26.6 mmol) and stirred for 2 h at 80° C. Quenched reaction while hot and poured into 1 L beaker with 100 “g” ice, 24 mL NH4OH, pH by paper was 8-9. Stirred 5 min and filtered. Washed solid with water. Suspended solid in ethanol and filtered and washed with ethanol. Gave: 4-chloro-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (1.7 g, 9.58 mmol, 40% yield)1H NMR (400 MHz, DMSO-d6) δ ppm 12.85 (br. s., 1H) 6.53 (s, 1H) 2.28 (s, 3H) MS(ES) [M+H]+ 168.9.
Reaction SMILES: [OH:1][C:2]1[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][C:5]([CH2:6][NH:7][N:8]2[CH:12]=[CH:11][N:10]=[C:9]2SC)=[CH:4][C:3]=1[C:21]([CH3:24])([CH3:23])[CH3:22].[BH4-].[Na+].N>C(O)C.[Ni](Cl)Cl>[OH:1][C:2]1[C:16]([C:17]([CH3:19])([CH3:18])[CH3:20])=[CH:15][C:5]([CH2:6][NH:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][C:3]=1[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CSc1nccn1NCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl[Ni]Cl
Agent: N
Agent: [BH4-]
Solvent: CCO
Product: CC(C)(C)c1cc(CNn2ccnc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Variant (a): 200 mg of 1-(4-hydroxy-3,5-di-tert.-butylbenzylamino)-2-methylmercaptoimidazole are dissolved in 8 ml of ethanol together with 0.41 g of nickel(II) chloride.6H2O. This solution is cooled in an ice-bath and 0.7 g of sodium borohydride is added portionwise within 1 hour. After completion of the addition, the ice-bath is removed and the black reaction mixture is stirred at room temperature for an additional 4 hours. For the work-up, the mixture is again cooled and sufficient 2N hydrochloric acid is added so that the reaction mixture has an acidic reaction. The resulting mixture is stirred for a few minutes and treated with conc. ammonia up to an alkaline reaction. Subsequently, the mixture is filtered through a bed of siliceous earth and the filter cake is washed five times with methylene chloride. The organic phase of the filtrate is separated, washed twice with water, dried over sodium sulfate and evaporated. The crystalline residue is reprecipitated from methanol/water and there is obtained 1-(4-hydroxy-3,5-di-tert.-butylbenzylamino)imidazole in the form of colorless crystals of m.p. 171°-174°.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH:11](=[O:18])C1C=CC=CC=1.N1CCCC1>CO>[O:18]1[C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3](=[O:4])[CH2:2][CH2:11]1
Reactant: O=Cc1ccccc1
Reactant: O=C(CO)c1ccccc1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1CCOc2ccccc21
Temperature: 50 °C

Procedure:
2-Hydroxyacetophenone compounds of structure XXXXI are treated with benzaldehyde compounds of structure XXXXII under suitable conditions to provide chroman-4-one compounds of structure XXXXIII. In some embodiments, 2-hydroxyacetophenone compounds of structure XXXXI are treated with benzaldehyde compounds of structure XXXXII, pyrrolidine, and methanol, with heating to about 50° C. for about 2 days to provide chroman-4-one compounds of structure XXXXIII. Chroman-4-one compounds of structure XXXXIII are then reacted tris(dibenzylideneacetone)dipalladium(0), tri-tert-butylphosphonium tetrafluoroborate, potassium bicarbonate, a suitable arylbromide, and 1,4-dioxane/water (4:1,) at about 110° C. to provide chroman-4-one compounds of structure XXXXIV. Chroman-4-one compounds of structure XXXXIV are then treated with methyl magnesium chloride in tetrahydrofuran at about 0° C., followed by 80% AcOH/H2O with warming to about 90° C. to provide compounds of structure XXXXV.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:14][CH:13]=3)(O)[CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O)(=O)=O.CO>ClCCCl.[Pd]>[N:1]1([CH2:6][CH:7]2[CH2:8][CH:9]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:16][CH:17]=3)[CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1(c2ccc(CN3CCCC3)cc2)CC(CN2CCCC2)C1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: ClCCCl
Solvent: CO
Product: c1cc(C2CC(CN3CCCC3)C2)ccc1CN1CCCC1
Temperature: 25 °C

Procedure:
To a stirring solution of 3-pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutanol (Example 210, General procedure B, Step D) (0.10 g, 0.32 mmol) in 1,2-dichloroethane (3.2 mL) was added methanesulfonic acid (0.31 g, 3.2 mmol). The reaction was then heated to 65 □C (oil bath) for 30 minutes. The reaction was then cooled to room temperature and transferred to a Parr bottle. To this crude solution was added 5 mL of MeOH, 10% Pd/C (100 mg), and then the reaction vessel was pressurized to 45 psi with H2. After 30 min the reaction was purged with N2, filtered through a pad of celite, and concentrated under reduced pressure. Purification of this material was accomplished flash column chromatography using a 15 g ISCO column, pre-packing material on silica, eluting with a gradient of 20%–45% MeOH/CH2Cl2 with 0.1% NH4OH. The product containing fractions were collected and concentrated to give the title compound as the (0.97 mg) as the bis-methanesulfonic acid salt.
Reaction SMILES: B#B.[C:3]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)(=[O:8])[CH2:4][CH2:5][CH2:6][CH3:7].CO.Cl>C1COCC1.CCOCC>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C@@H:3]([OH:8])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(=O)c1ccco1
Agent: B#B
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: CCCC[C@H](O)c1ccco1
Temperature: 10 °C
Yield: 70 %

Procedure:
10.4 mmol (10.4 mL) of diborane (1M solution in THF) was added dropwise in a period of 10 m at room temperature to a solution of 2-valeryl furan (2.62 g, 17.2 mmol) and 1.68 mmol (4.2 mL) of (3aR)-1,3,3-triphenyl pyrrolidino [1,2-c) [1,3,2) oxazaborole (see E. J. Corey et al. J. Am. Chem. Soc. 1987, 109, 7925-26, 0.4M solution in THF) in 25 mL THF. The reaction mixture was stirred for 20 m and was cooled to 10° C. 6 mL methanol was cautiously added and followed by adding 62 mg HCl (by weight) in ether. Stirred for 0.5 h, white solid was precipitated out. The cloudy mixture was poured into 100 mL ether and 100 mL water. The organic layer was separated, washed with saturated sodium bicarbonate, water, brine, dried and filtered. The filtrate was evaporated to an yellowish oil which was chromatographed eluting with 10% ethyl acetate in hexane to obtain 70% of the product. [α]25D =-13°, 60% ee by Mosher' ester analysis.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([CH3:16])[CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(O)(=O)C.[Cl-].[Na+].O>[C:1]([O:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([CH3:16])[C:12]=1[Br:17])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(COC(=O)c2ccccc2)on1
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1noc(COC(=O)c2ccccc2)c1Br
Temperature: 90 °C
Yield: 78.9 %

Procedure:
A solution of (3-methylisoxazol-5-yl)methyl benzoate (20.1 g, 92.4 mmol) in acetic acid (77.3 mL) was treated with N-bromosuccinimide (19.7 g, 111 mmol) and heated in a sealed tube at 90° C. for 4 h. The reaction mixture was diluted with brine and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (100% hexanes to 20% ethyl acetate/hexanes) gave the desired product (21.6 g, 79%). LCMS calculated for C12H11BrNO3 (M+H)+: m/z=296.0, 298.0. found: 296.0, 298.0.