Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])[C:5]([CH:23]=O)=[C:4]([S:25][CH3:26])[N:3]=1.O.[NH2:28][NH2:29]>C(O)(C)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])[C:5]([CH:23]=[N:28][NH2:29])=[C:4]([S:25][CH3:26])[N:3]=1
Reactant: NN
Reactant: CSc1nc(N)nc(NCC(=O)Nc2cccc(C(F)(F)F)c2)c1C=O
Solvent: CC(C)O
Solvent: O
Product: CSc1nc(N)nc(NCC(=O)Nc2cccc(C(F)(F)F)c2)c1C=NN
Temperature: 80 °C
Yield: 45.1 %

Procedure:
To a disposable sealed tube was added 2-(2-amino-5-formyl-6-methylsulfanyl-pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide (100 mg, 0.25 mmol, 1.0 eq.), isopropanol (4.0 mL), and hydrazine monohydrate (0.048 mL, 0.96 mmol, 3.8 eq.). The tube was sealed and heated to 80° C. overnight. The reaction was then quenched with H2O (10 mL) and EtOAc (50 mL). The EtOAc layer washed with brine, dried with Na2SO4, and concentrated to give crude 2-(2-amino-5-hydrazonomethyl-6-methylsulfanyl-pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide as an oil. The crude product was then precipitated out with 3 mL water and 0.5 mL of ACN, filtered and rinsed with 2 mL of H2O to give pure 2-(2-amino-5-hydrazonomethyl-6-methylsulfanyl-pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide as a yellow solid (45.0 mg, 45%). LC/MSD (HP Series 1100 MSD): Expected MW: 399, Observed M+H, 400.1, Retention time: 1.43 min. ANALYTICAL HPLC: >90%, Retention time: 3.89 min (8 minute run). 1H-NMR (d6-DMSO): 10.42 (s, 1H), 9.15 (t, 1H), 8.15 (s, 1H), 8.05 (s, 1H), 7.80 (d, 1H), 7.58 (t, 1H), 7.42 (d, 1H), 6.45 (s, 2H), 5.25 (br s, 2H), 4.30 (d, 2H), 2.40 (s, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:21])[C:10]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])([CH3:12])[CH3:11])=[C:4]([F:22])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31](=[O:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33].Cl>C1(C)C=CC=CC=1.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:30][C:31]([OH:37])([C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:21]=[C:9]2[C:10]([C:13]2[C:14]([Cl:20])=[CH:15][CH:16]=[CH:17][C:18]=2[Cl:19])([CH3:11])[CH3:12])=[C:4]([F:22])[CH:3]=1
Reactant: CC(C)(C(=N)Nc1ccc(Br)cc1F)c1c(Cl)cccc1Cl
Reactant: CCOC(=O)C(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(O)CN(c2ccc(Br)cc2F)C(C(C)(C)c2c(Cl)cccc2Cl)=N1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
To a mixture of N-(4-bromo-2-fluorophenyl)-2-(2,6-dichlorophenyl)-2-methylpropanimidamide (48.0 g, 119 mmol), K2CO3 (41.0 g, 297 mmol) in toluene (180 mL) and THF (180 mL) at 55° C. was added slowly a solution of ethyl 3-bromo-2-oxopropanoate (23.3 mL, 166 mmol) in 24 mL of THF over 50 minutes. The reaction mixture was kept at 55° C. for 1.5 hours. A white slurry was observed. The reaction mixture was cooled to 5° C. HCl (0.5N, 450 mL) was added drop-wise (end point pH=9˜10). After addition, the suspension was cooled to 0° C. The solid was collected by filtration, washed with water (2×50 mL), and then dried in a vacuum oven at 60° C. overnight. Ethyl 1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylate (59 g, 114 mmol, 96% yield) was obtained as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 7.11 (m, 3H), 6.96 (m, 2H), 6.72 (t, 1H, J=8.28 Hz), 4.35 (m, 2H), 4.25 (d, 1H, J=10.5 Hz), 3.80 (d, 1H, J=10.8 Hz), 1.98 (s, 3H), 1.93 (s, 3H), 1.38 (t, 3H, J=7.03 Hz); 13C-NMR (CDCl3, 126 MHz) δ 173.0, 171.5, 159.8, 157.8, 137.3, 135.7, 132.1, 131.1, 128.1, 127.4, 125.6, 122.2, 120.1, 93.5, 62.5, 45.5, 30.2, 14.0; MS m/e 517.05 (M+H+); HPLC (XBridge 5μ C18 4.6×50 mm, 4 mL/min, Solvent A: 10% MeOH/water with 0.2% H3PO4, Solvent B: 90% MeOH/water with 0.2% H3PO4, gradient with 0-100% B over 4 minutes): 2.74 minutes.
Reaction SMILES: C([C@@H:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@@H:5]1[OH:13])(O)=O.[N:14](C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[NH2:14][C@H:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[OH:13]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: O=C(O)[C@@H]1c2ccccc2C[C@@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N[C@H]1c2ccccc2C[C@H]1O

Procedure:
One gram of the hydroxamic acid of (1R,2S)-1-carboxy-2-hydroxyindane is reacted with equimolar amounts of diethyl azodicarboxylate and triphenylphosphine in tetrahydrofuran at room temperature using the procedure of Bittner, Grinberg and Kartoon (Tet. Lett. 23, 1965-8 (1974)). The product is isolated by acidification and extraction of the reaction mixture with ethyl acetate, followed by basification of the resulting aqueous solution with NaOH, extraction with methyl t-butyl ether, drying of the extracts over MgSO4, filtration, and the removal of solvent by rotary evaporation. The product (1S,2R)-1-amino-2-indanol is isolated as a light yellow oil.
Reaction SMILES: C[O:2][C:3]1[N:4]=[N:5][C:6]([S:9]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:11])=[O:10])=[CH:7][CH:8]=1.Cl>O1CCOCC1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[C:12]1[S:9]([C:6]1[CH:7]=[CH:8][C:3](=[O:2])[NH:4][N:5]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)c2cc3ccccc3[nH]2)nn1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc(S(=O)(=O)c2cc3ccccc3[nH]2)n[nH]1
Temperature: 100 °C

Procedure:
A mixture of 3-methoxy-6-(indole-2-sulfonyl)-pyridazine (0.58 mmol, 290 mg), conc. HCl (0.5 mL), and dioxane (3 mL) was heated at 100° C. for 2 hours. The reaction mixture was cooled and evaporated to dryness. Water (10 mL) was added to the residue, and the resulting solid, 6-(indole-2-sulfonyl)-pyridazin-3-one was collected and dried (83%, 133 mg); mp 248° C.-249° C.
Reaction SMILES: [C:1]([CH2:3]C(CC1C2C(=CC=CC=2)C=CC=1)C(O)=O)#[N:2].[CH2:19]([O:21][C:22](=[O:40])[CH:23]([CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:20].ClCC#N.[H-].[Na+]>CN(C=O)C>[CH2:27]([O:26][C:24](=[O:25])[C:23]([CH2:3][C:1]#[N:2])([CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1)[C:22]([O:21][CH2:19][CH3:20])=[O:40])[CH3:28]
Reactant: CCOC(=O)C(Cc1cccc2ccccc12)C(=O)OCC
Reactant: N#CCC(Cc1cccc2ccccc12)C(=O)O
Agent: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC#N)(Cc1cccc2ccccc12)C(=O)OCC
Reaction time: 1 h

Procedure:
2(R,S)-Cyanomethyl-3-α-naphthylpropionic acid: 3.0 g of α-naphthylmethylmalonic acid diethyl ester and, after 30 minutes, 0.6 ml of chloroacetonitrile are added to a stirred suspension of 0.44 g of sodium hydride dispersion in 50 ml of DMF. The reaction mixture is stirred for 1 hour at 50° and then concentrated by evaporation in a high vacuum. The residue is dissolved in ethyl acetate, washed with 0.1N hydrochloric acid and water, dried over sodium sulphate, concentrated by evaporation and purified by chromatography on silica gel with toluene, yielding cyanomethyl-(α-naphthylmethyl)-malonic acid diethyl ester.
Reaction SMILES: CI.[C:3](=[O:6])([O-])[O-].[K+].[K+].[Br:9][C:10]1[C:15]([F:16])=[CH:14][NH:13][C:12](=O)[CH:11]=1.O>CN(C)C=O>[Br:9][C:10]1[C:15]([F:16])=[CH:14][N:13]([CH3:12])[C:3](=[O:6])[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(Br)c(F)c[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1cc(F)c(Br)cc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (0.9 mL) was added to a mixture of potassium carbonate (2.34 g) and 4-bromo-5-fluoro-1H-pyridin-2-one (2.50 g) in dimethylformamide (25 mL) at room temperature. The mixture was stirred at room temperature overnight and then water was added. The resulting mixture was extracted with ethyl acetate and the combined extracts were washed with brine and dried (MgSO4). The solvent was evaporated to afford the crude title compound that was recrystallized from Et2O. Yield: 1.22 g (45% of theory); Mass spectrum (ESI+): m/z=206/208 (Br) [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9](=[NH:12])[NH:10][OH:11])[CH:6]=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C:16]([OH:18])=[O:17])C.CC1C=C(C=C(C)C=1O)C=O>>[OH:11][NH:10][C:9]([C:7]1[CH:6]=[C:5]([CH3:13])[C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:3]([CH3:1])[CH:8]=1)=[NH:12]
Reactant: CCc1cc(C(=N)NO)cc(C)c1CCC(=O)O
Agent: Cc1cc(C=O)cc(C)c1O
Product: Cc1cc(C(=N)NO)cc(C)c1CCC(=O)O

Procedure:
The title compound is prepared in analogy to 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid starting from 3,5-dimethyl-4-hydroxybenzaldehyde; LC-MS: tR=0.57 min, [M+1]+=237.02; 1H NMR (D6-DMSO): δ2.29 (s, 6H), 2.30-2.36 (m, 2H), 2.80-2.87 (m, 2H), 5.66 (s, 2H), 7.30 (s, 2H), 9.46 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.Cl.Cl[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:17][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: ClCc1cccnc1
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Agent: Cl
Product: Cc1cc(N2CCCC2)c2ccc(OCc3cccnc3)cc2n1

Procedure:
In analogy to example 6 there was prepared: on reaction of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 3-(chloromethyl)pyridine hydrochloride, whereby the product was isolated as free base, 2-methyl-7-(pyridin-3-ylmethoxy)-4-pyrrolidin-1-yl-quinoline as a red solid. ISP mass spectrum, m/e: 320.4 (M+1 calculated for C22H21N3O: 320).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[F:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36].[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:35](=[O:36])[C:34]2[CH:38]=[CH:39][CH:40]=[C:32]([F:31])[CH:33]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: O=C1Nc2ccccc2C2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)O1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C2(CCN(C(=O)c3cn(C(=O)c4cccc(F)c4)c4cc(Cl)ccc34)CC2)O1
Reaction time: 0.25 h

Procedure:
To a solution of 100 mg (0.252 mmol) 1′-[(6-chloro-1H-indol-3-yl)carbonyl]spiro[3,1-benzoxazine-4,4′-piperidin]-2(1H)-one (described in example 1) in dry DMF (5 ml) was added 10 mg NaH (0.25 mmol, 60% in oil). After 15 minutes at RT, 43.9 mg (0.277 mmol) of 3-fluoro-benzoyl chloride was added and stirring continued overnight. The reaction mixture was poured onto an aqueous solution of ammonium chloride, and the product extracted twice with ethyl acetate. The combined organic phases were dried on Na2SO4 and the solvent evaporated under reduced pressure. Purification by preparative HPLC yielded 1′-{[6-chloro-1-(3-fluorobenzoyl)-1H-indol-3-yl]carbonyl}spiro[3,1-benzoxazine-4,4′-piperidin]-2(1H)-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[N:12][CH2:13][CH2:14][O:15][N+:16]([O-:18])=[O:17])[NH:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.[C:19](Cl)(=[O:21])[CH3:20].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:19]([NH:1][C:2]1[CH:3]=[C:4]([C:8](=[N:12][CH2:13][CH2:14][O:15][N+:16]([O-:18])=[O:17])[NH:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: N#CNC(=NCCO[N+](=O)[O-])c1cncc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1cncc(C(=NCCO[N+](=O)[O-])NC#N)c1
Yield: 94.5 %

Procedure:
To a solution of 5-amino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide (105 mg, 0.42 mmol) (see Example 1) in pyridine (1 ml) was added acetyl chloride (45 μl, 0.63 mmol), and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, a cold aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography with a mixed solvent of methanol and chloroform as an eluent to give the title compound (116 mg, yield 95%) as hygroscopic powder.
Reaction SMILES: Br[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CN(C=O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:2]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH3:3])=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: C1COCCN1
Reactant: CC(Br)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(c1ccc([N+](=O)[O-])cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
A mixture of 1-(1-bromo-ethyl)-4-nitro-benzene (1.24 g, 5.43 mmol), potassium carbonate (2.25 g, 16.3 mmol) and morpholine (1.2 mL, 13.6 mmol) in DMF (10 mL) was stirred at room temperature for 16 h, then evaporated. The residue was suspended in ethyl acetate, washed with water and brine, dried (sodium sulfate) and evaporated to provide 4-[1-(4-nitro-phenyl)-ethyl]-morpholine (1.225 g, 95% yield) as a yellow oil. 1H-NMR (DMSO-d6, 500 MHz) 8.19 (d, 2H), 7.16 (d, 2H), 3.56 (m, 5H), 2.41 (m, 2H), 2.26 (m, 2H), 1.29 (d, 3H) ppm; MS (FIA) 237.2 (M+H); HPLC (Method A) 2.248 min.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:3][CH:2]=1.Cl[C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1.[H-].[Na+]>CN(C=O)C>[N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)=[CH:16][CH:15]=2)=[N:3][CH:2]=1
Reactant: Clc1cnccn1
Reactant: Oc1ccc(CCNc2ncnc3nccnc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cnc(Oc2ccc(CCNc3ncnc4nccnc34)cc2)cn1
Temperature: 55 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a solution of 4-[2-(pteridin-4-ylamino)ethyl]phenol (0.267 g, 1.0 mmol) and 2-chloropyrazine (0.114 g, 1.0 mmol) in anhydrous DMF (7 mL) was added 60% sodium hydride (NaH) in mineral oil (0.060 g, 1.5 mmol) portionwise. The mixture was stirred at 55° C. overnight and then at 70° C. for a total reaction time of 32 h. The solvent was removed in vacuo and the residue was suspended in H2O. The solid was collected by suction filtration, washed with H2O and Et2O, dried in a vacuum oven at 55° C. overnight to afford pteridin-4-yl-{2-[4-(pyrazin-2-yloxy)-phenyl]-ethyl}-amine (0.291 g, 84%) as a light brown solid: 1H NMR (300 MHz, CDCl3) δ 9.02 (d, J=1.9 Hz, 1H), 8.82 (s, 1H), 8.63 (d, J=1.9 Hz, 1H), 8.43 (d, J=1.5 Hz, 1H), 8.26 (d, J=2.4 Hz, 1H), 8.10 (dd, J=2.4, 1.5 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 3.99 (dd, J=13.6, 6.9 Hz, 2H), 3.08 (t, J=6.9 Hz, 2H); ESIMS m/z 346.24 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](N(OC)C)=[O:10].[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CON(C)C(=O)Cc1ccccc1Cl
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1Cl)c1ccccc1
Reaction time: 5 h
Yield: 14.8 %

Procedure:
To a solution of 2-(2-chlorophenyl)-N-methoxy-N-methylacetamide (0.51 g, 2.4 mmol) in anhydrous THF (10 mL) cooled to −78° C., a solution of phenylmagnesium bromide (1 mol/L, 3.5 mL) in THF was added. The reaction mixture was stirred at this temperature for five hours. TLC (PE:EtOAc=10:1) indicated that 50% of the starting materials were consumed. H2O (10 mL) was added to quench the reaction, and the aqueous layer extracted with EtOAc (10 mL×3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc=50:1) to afford Intermediate 10 as a colorless oil (80 mg, yield: 14.8%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.Cl.Cl.[CH3:31][N:32]([CH3:35])[NH:33][CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:31][N:32]([CH3:35])[N:33]([CH3:34])[C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CNN(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)N(C)C(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 70.8 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid trimethylhydrazide (33 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), N,N,N′-trimethylhydrazine dihydrochloride (49 mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 466.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@@H:4]([NH:9][C:10]([C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:25])=[CH:19][CH:18]=2)[CH:13]=1)=[O:11])[CH:5]([CH3:8])[CH2:6][CH3:7].[K+].[Br-]>>[CH3:8][CH:5]([CH2:6][CH3:7])[C@H:4]([NH:9][C:10]([C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:25])=[CH:19][CH:18]=2)[CH:13]=1)=[O:11])[C:3]([OH:33])=[O:2]
Reactant: CCC(C)[C@H](NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3)cc2)no1)C(=O)OC
Agent: [Br-]
Agent: [K+]
Product: CCC(C)[C@H](NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3)cc2)no1)C(=O)O
Yield: 66.5 %

Procedure:
The title compound was prepared from (S)-3-methyl-2-({3-[4-(3-phenyl-ureido)-phenyl]-isoxazole-5-carbonyl}-amino)-pentanoic acid methyl ester as set forth in Example 8 and was obtained in 66.5% yield. Mass (ES+): 437 (M++1); IR (KBr): 3336, 3280, 1717, 1667 (br), 1599, 1542 (br); 1H NMR (DMSO-d6) δ: 0.84, 0.88 (2×d, 6H), 1.51-1.68 (m, 2H), 1.71-1.79 (m, 1H), 4.36 (m, 1H), 6.94 (t, 1H), 7.25 (t, 2H), 7.42 (d, 2H), 7.57 (d, 2H), 7.58 (s, 1H), 7.80 (d, 2H), 8.77 (br, 1H), 8.97 (br, 1H), 9.13 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[C:4]([Cl:17])[N:3]=1.[BH4-].[Na+]>CCO>[Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]([N:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)=[O:11])[CH:5]=[C:4]([Cl:17])[N:3]=1
Reactant: O=Cc1c(C(=O)N2CCCC2)cc(Cl)nc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(c1cc(Cl)nc(Cl)c1CO)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the above aldehyde and sodium borohydride (400 mg, 10 mmol) in EtOH (50 mL) is stirred at room temperature for 1 hour. After evaporation of EtOH, EtOAc (40 mL) and water (40 mL) are added to the residue. The organic layer is separated, washed once with 1 N NaOH, 1N HCl and brine, dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (1:1 hexane:EtOAc) to give (2,6-dichloro-3-hydroxymethyl-pyridin-4-yl)-pyrrolidin-1-yl-methanone.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4](Cl)=[O:5])[CH3:2].[NH2:11][C:12]([NH2:14])=[O:13]>C(#N)C>[CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([NH:11][C:12]([NH2:14])=[O:13])=[O:5])[CH3:2]
Reactant: CCCCC(CC)C(=O)Cl
Reactant: NC(N)=O
Solvent: CC#N
Product: CCCCC(CC)C(=O)NC(N)=O

Procedure:
2-Ethyl-hexanoylchloride (0.057 mol, Sigma-Aldrich Israel Ltd.), dissolved in dry acetonitrile (50 ml), was slowly added to a dry, boiling solution of urea (0.14 mole) in acetonitrile (100 ml) and allowed to reflux for 2 hours. Thereafter the organic solvent was evaporated under reduced pressure and the product was dissolved in ethyl acetate (100 ml) and washed three times with 20 ml of distilled water. The organic fraction was dried over MgSO4, filtered and evaporated under reduced pressure. The product was purified by crystallization from ethyl acetate.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:29])[CH2:15][CH2:16][CH2:17]/[C:18](=[CH:19]\[CH:20]=[C:21]3\[CH2:22][C@@H:23]([OH:28])[CH2:24][CH2:25][C:26]\3=[CH2:27])/[C@@H:13]2[CH2:12][CH2:11]1)[CH2:3][CH2:4][CH2:5][C:6]([OH:9])([CH3:8])[CH3:7].C[Mg]Br.[Cl-].[NH4+]>C1C=CC=CC=1>[CH3:8][C:6]([OH:9])([CH2:5][CH2:4][CH2:3][C@H:2]([C@@H:10]1[C@:14]2([CH3:29])[C@H:13]([C:18]3[C@H:17]([CH2:16][CH2:15]2)[C@:26]2([CH3:27])[C:21]([CH2:22][C@@H:23]([OH:28])[CH2:24][CH2:25]2)=[CH:20][CH:19]=3)[CH2:12][CH2:11]1)[CH3:1])[CH3:7]
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)(C)O)CC[C@@H]12
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
As noted above, the 3β-hydroxy-27-norcholest-5,7-dien-25-one prepared in accordance with the process of the instant invention is readily converted by techniques well-known in the art into 25-hydroxyvitamin D3. Thus, as described in the previously cited RECUEIL reference, 3β-hydroxy-27-norcholest-5,7-dien-25-one in dry benzene may be treated with methyl magnesium bromide at about 5° C. The reaction mixture is stirred for 8 - 18 hours and then is worked up by the addition of an aqueous solution of ammonium chloride. The cholest-5,7-diene-3β,25-diol so produced is crystallized from successively tetrahydrofuran-diisopropyl ether and tetrahydrofuran-ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][C:5]2[C:7]([CH3:13])=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[C:4]=2[O:3]1.[CH3:15][O:16]C(Cl)Cl>ClCCl.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[CH3:1][C:2]1([CH3:14])[CH2:6][C:5]2[C:7]([CH3:13])=[C:8]([CH3:12])[C:9]([CH:15]=[O:16])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: COC(Cl)Cl
Reactant: Cc1cc(C)c2c(c1C)CC(C)(C)O2
Agent: [Ti+4]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1C=O)OC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 34.5 g of the 2,3-dihydro-2,2,4,5,7-pentamethylbenzofuran in 200 ml of absolute dichloromethane was added 200 ml of titanium chloride (IV) and 18 ml of α,α-dichloromethyl methyl ether at 0° C. With stirring at room temperature for 45 minutes and refluxing for 15 minutes, the reaction mixture was quenched with 300 ml of water and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford a crude product. Final purification was carried by recrystallization to afford 37.2 g of 2,3-dihydro-2,2,4,5,7-pentamethyl-benzofuran-6-carboxaldehyde as a white solid.
Reaction SMILES: [CH2:1]1[O:23][C:4]2([CH2:9][CH2:8][C:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17](OC)[CH:16]=3)([C:10](OC)=[O:11])[CH2:6][CH2:5]2)[O:3][CH2:2]1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH2:2]1[O:3][C:4]2([CH2:9][CH2:8][C:7]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)([CH2:10][OH:11])[CH2:6][CH2:5]2)[O:23][CH2:1]1
Reactant: COC(=O)C1(Cc2cccc(OC)c2)CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1(Cc2ccccc2)CCC2(CC1)OCCO2
Yield: 93 %

Procedure:
A solution of 22.3 g. (0.77 M) of 4-benzyl-4-carbomethoxy-1-cyclohexaneone ethylene ketal [5] (prepared as in Example 4B) in 220 ml. of tetrahydrofuran is added to 3 g. of lithium aluminum hydride in 30 ml. of tetrahydrofuran. The mixture is stirred at reflux temperature for about 5.5 hours and then cooled in ice. There is added successively 3 ml. of water, 3 ml. of aqueous 15% sodium hydroxide solution and 9 ml. of water. The inorganic gel is collected on a filter and the filtrate evaporated to dryness. The residue is recrystallized from methylene chloride: Skellysolve B to give 18.8 g. (93% yield) of 4-benzyl-4-hydroxymethylcyclohexan-1-one ethylene ketal (1), having a melting point of 76° to 78° C.