Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH3:17][O:18][C:19](=[O:31])[CH2:20][C@H:21]1[C:25]2[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]=2[O:23][CH2:22]1.[Br:32][C:33]1[C:41]([C:42]#[N:43])=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][C@@H:37]2O.C(P(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:17][O:18][C:19](=[O:31])[CH2:20][C@H:21]1[C:25]2[CH:26]=[CH:27][C:28]([O:30][C@H:37]3[C:38]4[C:34](=[C:33]([Br:32])[C:41]([C:42]#[N:43])=[CH:40][CH:39]=4)[CH2:35][CH2:36]3)=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: N#Cc1ccc2c(c1Br)CC[C@@H]2O
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Reaction time: 0.5 h

Procedure:
A solution of di-tert-butyl azodicarboxylate (3.30 g) in tetrahydrofuran (5 mL) is added dropwise over 45 min to a solution of (S)-(6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (for preparation see WO 2008001931; 2.10 g), (S)-4-bromo-1-hydroxy-indan-5-carbonitrile (2.40 g) and tri-n-butyl-phosphine (3.8 mL) in tetrahydrofuran (25 mL) at −10° C. The resulting solution is stirred for 30 min and then diluted with ethyl acetate. The resulting solution is washed with water and brine and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:30) to give the title compound. LC (method 2): tR=1.15 min; Mass spectrum (ESI+): m/z=428/430 (Br) [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([C:30]([S:33]([CH3:36])(=[O:35])=[O:34])([CH3:32])[CH3:31])[CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)=[CH:16][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1.C(Cl)Cl.CCO[C:43]([CH3:45])=[O:44]>>[F:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([C:30]([S:33]([CH3:36])(=[O:34])=[O:35])([CH3:32])[CH3:31])[CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)=[CH:16][C:3]=1[CH2:4][N:5]([C:6]1[CH:7]=[CH:8][C:9]([S:12]([CH3:15])(=[O:13])=[O:14])=[CH:10][CH:11]=1)[C:43](=[O:44])[C:45]1[CH:18]=[CH:19][CH:2]=[CH:3][CH:4]=1
Reactant: CC(C)(c1cc(-c2ccc(F)c(CNc3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(c1cc(-c2ccc(F)c(CN(C(=O)c3ccccc3)c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O

Procedure:
Prepared in two steps according to the procedures described in EXAMPLE 44 (Steps 2 and 3) but using {2-fluoro-5-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-benzyl}-(4-methanesulfonyl-phenyl)-amine from EXAMPLE 61 (Step 4) as the starting material. Flash chromatography (CH2Cl2:EtOAc; 3:7) afforded the title compound as a foam.
Reaction SMILES: [SH:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:22][O:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34](O)=[O:35])=[CH:28][C:27]=1[O:37][CH3:38]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:22][O:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([N:6]2[CH2:5][CH2:4][S:3][C:2]2=[S:1])=[O:35])=[CH:28][C:27]=1[O:37][CH3:38]
Reactant: SC1=NCCS1
Reactant: COCOc1ccc(CCC(=O)O)cc1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCOc1ccc(CCC(=O)N2CCSC2=S)cc1OC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In an atmosphere of argon 4.03 g of 3-(4-methoxymethoxy-3-methoxyphenyl)propionic acid and 1.79 g of 2-mercaptothiazoline were dissolved in 80 ml of dichloromethane followed by the addition of 3.10 g of dicyclohexylcarbodiimide and 0.21 g of 4-dimethylaminopyridine. The mixture was stirred at room temperature for 15 hours, and the reaction mixture was filtered. The filtrate was washed with a 1N aqueous sodium hydroxide, water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue subjected to column chromatography on silica gel. From the fraction eluted with methylene chloride was obtained 5.07 g of N-[3-(4-methoxymethoxy-3-methoxyphenyl)propanoyl]-thiazolidine-2thione.
Reaction SMILES: [Na].[CH:2]1[CH2:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:8][C:9]([O:11][CH3:12])=[O:10]>O1CCCC1>[CH3:12][O:11][C:9](=[O:10])[CH2:8][CH:3]1[CH:2]=[CH:6][CH:5]=[CH:4]1
Reactant: COC(=O)CBr
Reactant: C1=CCC=C1
Agent: [Na]
Solvent: C1CCOC1
Product: COC(=O)CC1C=CC=C1

Procedure:
2,4-Cyclopentadienyl acetic acid methyl ester was prepared from the sodium salt of cyclopentadiene and methyl bromoacetate in tetrahydrofuran by the method of J. J. Partridge [J. Am. Chem. Soc., 95, 7171 (1973)].
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[N:19]=[C:18]([CH:20]([NH2:22])[CH3:21])[O:17][N:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[C:31]([O:34][CH2:35]Br)(=[O:33])[CH3:32].O>CC#N.C(OCC)(=O)C>[CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[N:19]=[C:18]([CH:20]([NH:22][CH2:32][C:31]([O:34][CH3:35])=[O:33])[CH3:21])[O:17][N:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(=O)OCBr
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3noc(C(C)N)n3)s2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)CNC(C)c1nc(-c2cnc(Oc3ccc(OC(C)C)cc3)s2)no1
Reaction time: 2 h
Yield: 24.5 %

Procedure:
To a solution of Example 40D (100 mg, 0.22 mmol) in CH3CN (1.0 mL) was added K2CO3 (150 mg, 1.1 mmol) and bromomethyl acetate (20 μL, 0.22 mmol). The reaction solution was heated to reflux with stirring for 2 hours, cooled, diluted with ethyl acetate and poured into water. The organics were separated, dried (Na2SO4), filtered and concentrated by rotary evaporation. The residue was purified by reverse phase HPLC (water:acetonitrile; gradient of 5% to 90% acetonitrile) to provide the title compound (23 mg, 0.054 mmol, 24%). MS (ESI APCI) m/z 419.19 (M+H+); 1H NMR (300 MHz, DMSO-d6) δ 8.01 (s, 1H) 7.37 (d, J=8.82 Hz, 2H) 7.04 (d, J=9.19 Hz, 2H) 4.57-4.72 (m, 2H) 3.83 (bs, 2H) 3.66 (s, 3H) 1.57 (d, J=6.99 Hz, 3H) 1.29 (d, J=6.25 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=C[C:5]2[NH:6][C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([Br:16])=[CH:9][CH:8]=3.S(Cl)([Cl:20])(=O)=O.[CH:22]([Cl:25])(Cl)Cl>>[Br:1][C:2]1[CH:3]=[C:22]([Cl:25])[C:5]2[NH:6][C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([Br:16])=[CH:9][C:8]=3[Cl:20]
Reactant: O=S(=O)(Cl)Cl
Reactant: Brc1ccc2c(c1)Sc1cc(Br)ccc1N2
Reactant: ClC(Cl)Cl
Product: Clc1cc(Br)cc2c1Nc1c(Cl)cc(Br)cc1S2
Temperature: 25 °C
Reaction time: 36 h

Procedure:
The 3,7-dibromophenothiazine (6.25 g, 17.5 mmol) was dissolved in 200 mL of chloroform (CHCl3). Sulfuryl chloride (SO2Cl2, 3.13 mL, 38.5 mmol) was added dropwise over 15 min. The dark mixture was stirred at RT for 36 h. The mixture was then filtered and the solid washed with CHCl3. The solid was collected and stirred in Et2O and the resulting green solid was filtered off and dried under vacuum to give a quantitative yield of the desired product.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6]C(Cl)Cl.[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][C:17](=O)[NH:18]2)=[CH:13][C:12]=1[F:22].[C:23]([O-:26])(=O)C.[Na+]>O.CN(C)C=O>[Cl:6][C:17]1[NH:18][C:19]2[C:14]([CH2:15][C:16]=1[CH:23]=[O:26])=[CH:13][C:12]([F:22])=[C:11]([Cl:10])[CH:20]=2
Reactant: CC(=O)[O-]
Reactant: O=C1CCc2cc(F)c(Cl)cc2N1
Reactant: ClC(Cl)Cl
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=CC1=C(Cl)Nc2cc(Cl)c(F)cc2C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
55.6 cm3 of phosphoryl chloride are added in the course of 30 minutes, with stirring, at between 10° and 15° C., to a mixture of 250 cm3 of trichloromethane and 54 cm3 of dimethylformamide and the mixture is stirred for 1 hour at a temperature close to 20° C. 52 g of 7-chloro-6-fluoro-3,4-dihydrocarbostyril are added progressively, with vigorous stirring, in the course of 10 minutes, at about 20° C. to the solution obtained. The suspension obtained is heated to a temperature close to 60° C. and is kept at this temperature for a further 2 hours, with stirring. The reaction mixture is concentrated under reduced pressure (20 kPa) at 50° C. until a pasty mixture is obtained. A mixture of 250 cm3 of water and 250 g of crushed ice is added, with vigorous stirring. The solid obtained is drained at about 5° C. and washed with 4 times 125 cm3 of water at 5° C. The moist product obtained and 58 g of sodium acetate are added simultaneously, in the course of 1 hour, to 500 cm3 of water at 90° C. in such a way as to maintain the pH at about 6. The mixture is stirred for a further 15 minutes at 90° C., the temperature is allowed to fall to about 50° C. and the product is drained at this temperature and washed with 3 times 250 cm3 of water at about 20° C. 54.3 g of 2,7-dichloro-6-fluoro-3-formyl-1,4-dihydroquinoline are obtained in the form of a yellow solid melting at 260° C. which is used in this form for the subsequent steps.
Reaction SMILES: [C:1]1([CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([CH2:19][NH:20][C:21]([NH:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:22])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:38]([O:41][C@H:42]1[C@@H:46]([O:47][C:48](=[O:50])[CH3:49])[C@H:45](OC(=O)C)[O:44][C@@H:43]1[CH2:55][O:56][C:57](=[O:59])[CH3:58])(=[O:40])[CH3:39].C[Si](OS(C(F)(F)F)(=O)=O)(C)C>ClC(Cl)(Cl)C.C(OCC)(=O)C>[NH3:9].[C:38]([O:41][C@H:42]1[C@@H:46]([O:47][C:48](=[O:50])[CH3:49])[C@H:45]([N:14]2[CH:13]=[N:12][C:11]3[C:15]2=[N:16][C:17]([CH2:19][NH:20][C:21]([NH:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:22])=[N:18][C:10]=3[NH:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:44][C@@H:43]1[CH2:55][O:56][C:57](=[O:59])[CH3:58])(=[O:40])[CH3:39]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(NCCN1CCCCC1)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(=O)NCCN4CCCCC4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 132.1 %

Procedure:
N,O-Bistrimethylsilylacetamide (0.34 ml, 1.4 mmol) was added to a stirred suspension of N-({6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-N′-[2-(1-piperidinyl)ethyl]urea (100 mg, 0.2 mmol) (Preparation 5) in 1,1,1-trichloroethane (20 ml) at 50° C. The reaction mixture was stirred at this temperature for 30 minutes, allowed to cool to room temperature and then evaporated under reduced pressure. Toluene (5 ml) was added and the solvent was removed under reduced pressure. The residue was redissolved in toluene (20 ml) and (2R,3R,4R,5S)-4,5-bis(acetyloxy)-2-[(acetyloxy)methyl]tetrahydro-3-furanyl acetate (0.064 g, 0.2 mmol) and then trimethylsilyltrifluoromethanesulphonate (0.1 ml, 0.35 mmol) were added. The reaction mixture was then heated under reflux for 2 hours. The reaction was allowed to cool to room temperature and diluted with ethyl acetate (100 ml). The solution was washed with saturated aqueous sodium hydrogen carbonate solution (50 ml) and saturated aqueous sodium chloride solution (50 ml) and then dried over anhydrous magnesium sulphate. The solvent was removed to give a residue that was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:1 by volume) to give the title compound as an oil (100 mg).
Reaction SMILES: [Mg].C(Br)C.[CH:5]1([C:8]#[CH:9])[CH2:7][CH2:6]1.CC.[CH3:12][O:13][CH:14](OC)[O:15][CH3:16]>O1CCCC1.C1(C)C=CC=CC=1>[CH3:12][O:13][CH:14]([O:15][CH3:16])[C:9]#[C:8][CH:5]1[CH2:7][CH2:6]1
Reactant: C#CC1CC1
Reactant: COC(OC)OC
Agent: CC
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCBr
Product: COC(C#CC1CC1)OC
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Magnesium (26.7 g, 1.1 mol) was suspended in 350 ml tetrahydrofurane and ethylbromide (74.6 ml, 1 mol) was added at such a rate, that the tetrahydrofurane continued to reflux. After completion of the addition the mixture was stirred one hour at 50-60° C. to complete the reaction. After cooling to room temperature ethynyl-cyclopropane 7 (80.6 ml, 70% in toluene, 0.95 mol) was added slowly during 30 minutes (evolution of ethane!) to the Grignard-reagent. After the addition the mixture was stirred one more hour at RT before trimethylorthoformate (120.3 ml, 1.1 mol) and toluene (400 ml) were added. The mixture was heated up (oil-bath temperature 100°-120° C.) and the tetrahydrofurane was removed by distillation during 4 hours. After cooling to RT and stirring over night the reaction mixture was diluted by addition of TBME (500 ml) and water was slowly added (50 ml). The clear organic solution was decanted from the highly viscous magnesium hydroxide phase. The magnesium hydroxide phase was extracted two more times with TBME (2 times 100 ml) and the combined organic solutions were dried over magnesium sulfate, filtered and concentrated. Compound 8 was isolated through vacuum-distillation (10 mbar, bp: 55°-60° C., 99 g, 0.7 mol).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([S:16]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:31])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: ClCCl
Product: COC(=O)CCS(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The title compound of Example 5 (0.5 g, 0.0015 mole), meta-chloroper-benzoic acid (0.32 g, 0.0015 mole) and methylene chloride (25 ml) were stirred under argon for 12 hours. The excess peroxide was destroyed with a saturated potassium carbonate solution, the phases separated, washed with hexane and water, and dried over magnesium sulfate. The solid was filtered, recrystallized from ethyl ether and methylene chloride and dried in vacuo, m.p. ca. 106-108° C.
Reaction SMILES: [CH3:1][N:2]([NH:4][C:5]([C:7]1[N:8]([CH3:13])[CH:9]=[C:10]([NH2:12])[N:11]=1)=[O:6])[CH3:3].[CH3:14][N:15]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[N:17]=[C:16]1[C:23](Cl)=[O:24]>C1COCC1.C(Cl)Cl>[CH3:3][N:2]([NH:4][C:5]([C:7]1[N:8]([CH3:13])[CH:9]=[C:10]([NH:12][C:23]([C:16]2[N:15]([CH3:14])[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[N:17]=2)=[O:24])[N:11]=1)=[O:6])[CH3:1]
Reactant: Cn1cc([N+](=O)[O-])nc1C(=O)Cl
Reactant: CN(C)NC(=O)c1nc(N)cn1C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)NC(=O)c1nc(NC(=O)c2nc([N+](=O)[O-])cn2C)cn1C
Temperature: -20 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
The amine from above was dissolved in dry THF (20 mL) and cooled to -20° C. The stirring reaction mixture was placed under argon and a solution of 1-methyl-4-nitroimidazole-2-carbonyl chloride (2.18 g, 11.5 mmol) in dry CH2Cl2 (10 mL) was added dropwise. The reaction was allowed to warm to room temperature and stirred overnight then concentrated to dryness and water was added. The suspension was filtered and the solid was washed with carbon tetrachloride and water, then dried in-vacuo (80° C.) to provide N-(N',N'-dimethylamino)-1-methyl-4-[1-methyl-4-nitroimidazole-2-carboxamido]imidazole-2-carboxamide as a pale yellow crystalline solid, 2.18 g (68.8% yield). A sample for analysis was obtained by recrystallization from water: mp 239° C. (dec.). TLC (5% MeOH/CHCl3) Rf 0.66. 1H--NMR (CDCl3); δ2.69 (s, 6H, N(CH3)2), 4.07 (s, 3H, N--CH3), 4.21 (s, 3H, N--CH3), 7.43 (s, 1H, NH). IR (nujol: υ3397 and 1678 cm-1. MS(El) m/z (rel. intensity) 336 (M+, 100), 293 (M+1-N(CH3)2, 85).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[NH:10][CH:11]([CH2:14][O:15][CH3:16])[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]I.[H-].[Na+]>C1COCC1.CN(C=O)C>[CH2:1]([O:8][C:9](=[O:17])[N:10]([CH:11]([CH2:14][O:15][CH3:16])[CH2:12][CH3:13])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(COC)NC(=O)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCC(COC)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
To a solution of (1-methoxymethyl-propyl)-carbamic acid benzyl ester (4.4 g, 18.5 mmol, 1.0 eq.) and MeI (6.9 mL, 111 mmol, 6 eq.) in THF/DMF (4:1, 50 mL) at 0° C. was slowly added NaH (1.35 g, 55.5 mmol, 3 eq.). The resulting mixture was warmed to room temperature and stirred over night. The reaction was quenched carefully by slow addition of water until no bubbling (H2) was observed. The reaction mixture was poured over ice water and extracted with 3×EtOAc. The combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (30% to 50% EtOAc-hexanes) to give (1-methoxymethyl-propyl)-methyl-carbamic acid benzyl ester (4.4 g, 94%).
Reaction SMILES: [F:1][C:2]([F:33])([CH2:9][CH2:10][C@H:11]([C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[C:20]([CH2:21][C@@H:22]([OH:32])[CH2:23][CH2:24]2)=[CH:19][CH:18]=3)[CH2:15][CH2:14]1)[CH3:12])[C:3]([OH:8])([CH2:6][CH3:7])[CH2:4][CH3:5]>C1C=CC=CC=1.C(O)C>[CH3:5][CH2:4][C:3]([OH:8])([C:2]([F:33])([F:1])[CH2:9][CH2:10][C@H:11]([C@@H:13]1[C@@:30]2([CH3:31])[CH2:29][CH2:28][CH2:27]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22]([OH:32])[CH2:23][CH2:24][C:25]\3=[CH2:26])/[C@@H:16]2[CH2:15][CH2:14]1)[CH3:12])[CH2:6][CH3:7]
Reactant: CCC(O)(CC)C(F)(F)CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCO
Solvent: c1ccccc1
Product: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCC(F)(F)C(O)(CC)CC)CC[C@@H]12
Yield: 28 %

Procedure:
9.3 mg of 24,24-difluoro-3β,25-dihydroxy-26,27-dimethylcholesta-5,7-diene was dissolved in a mixture of 90 ml of benzene and 40 ml of ethanol, and in anargon stream at 0° C., the solution was irradiated with ultra-violetlight for 7 minutes using a medium-pressure mercury lamp through a Vycor filter. Subsequently, the reaction mixture was heated under reflux for 1 hour in at atmosphere of argon. The solvent was evaporated under reduced pressure, and the resulting crude product was purified by thin-layer silica gel chromatography (developing solvent: benzene/ethyl acetate=10:1;developed four times) to give 2.6 mg of the captioned vitamin D3 derivative [the compound of formula (I) in which X is H].
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[C:12]([CH3:32])=[CH:13][C:14]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]3([CH3:31])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH2:21][CH2:20]2)=[C:15]([OH:17])[CH:16]=1.[Cl:33][C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[ClH:33].[F:10][C:11]1[C:12]([CH3:32])=[CH:13][C:14]2[N:18]([CH:19]3[CH2:20][CH2:21][N:22]([C:25]4([CH3:31])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH2:23][CH2:24]3)[C:34](=[O:36])[O:17][C:15]=2[CH:16]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(NC2CCN(C3(C)CCOCC3)CC2)c(O)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc2c(cc1F)oc(=O)n2C1CCN(C2(C)CCOCC2)CC1
Product: Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Hünig's base (0.07 mL, 0.401 mmol) was added to a solution of 5-fluoro-4-methyl-2-{[1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinyl]amino}phenol (D5, 47 mg, 0.146 mmol) in dichloromethane (5 mL) at rt under argon. The reaction was cooled to 0° C., the triphosgene (22.8 mg, 0.077 mmol) was added and the mixture was stirred for 1 h at 0° C. The reaction was quenched with saturated aqueous NaHCO3 (5 mL) and partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×) and the combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give a brown oil. The crude residue was purified via chromatography (amino-doped silica, iso-hexane-ethyl acetate) to give the free base of the title compound as a white solid. HCl (0.05 mL, 0.05 mmol, 1 M in diethyl ether) was added to a solution of the free base in dichloromethane (0.5 mL). The solvent was removed by rotary evaporation and the resulting residue was triturated with diethyl ether (2×) to give 6-fluoro-5-methyl-3-[1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one hydrochloride (E1, 13.1 mg, 22% yield) as a white solid.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Ca+2].[OH-].[C:12](Cl)(=O)CC.N>C(Cl)Cl.C(C(C)=O)C>[C:3]([CH2:2][C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH2:5][CH3:12]
Reactant: COC(=O)CC(C)=O
Reactant: CCC(=O)Cl
Agent: N
Agent: [Ca+2]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CCC(=O)CC(=O)OC
Yield: 89.9 %

Procedure:
Under the same conditions as in Example 1, 116 g (1.0 mol) of methyl acetoacetate in a mixture of 520 ml of methylene chloride and 30 ml of methyl ethyl ketone were reacted with 77.8 g (1.05 mol) of calcium hydroxide and 106.5 g (1.15 mol) of propionyl chloride. The pH in the subsequent reaction with ammonia was adjusted to 9.1. This gave 117 g (GC purity 79.0%) of methyl propionylacetate (yield 71.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[N+:15]([O-])=O>[C].[Pd].C1COCC1.CCO>[NH2:15][C:3]1[CH:4]=[C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CCOC(=O)C(C)c1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(N)c(N)c1
Reaction time: 3 h

Procedure:
To the flask was added THF/EtOH (1:1, 50 mL) followed by Ethyl 2-(4-amino-3-nitrophenyl)propanoate (2.12 g, 8.90 mmol) and 10% palladium carbon (220 mg) at room temperature. The reaction mixture was hydrogenated and stirred for 3 hrs at 45 psi then filtered through celite bed, and washed with EtOH. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:4-1:2) as eluant.