Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:30][CH3:31])=[C:9]([O:12][C@@H:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[C@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:32][C:33]1[C:34]([F:40])=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36].Cl>CC#N.O1CCOCC1>[Cl:32][C:33]1[C:34]([F:40])=[C:35]([NH:36][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:30][CH3:31])=[C:9]([O:12][C@@H:13]4[CH2:18][CH2:17][NH:16][C@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]4)[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: COC(=O)[C@@H]1C[C@H](Oc2cc3c(Cl)ncnc3cc2OC)CCN1C(=O)OC(C)(C)C
Reactant: Nc1cccc(Cl)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: COC(=O)[C@@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1
Temperature: 60 °C
Yield: 68.6 %

Procedure:
1-tert-butyl 2-methyl (2S,4R)-4-[(4-chloro-7-methoxyquinazolin-6-yl)oxy]piperidine-1,2-dicarboxylate (12) (0.45 g, 1.0 mmol) was dissolved in MeCN (11 ml) under nitrogen. 3-Chloro-2-fluoroaniline (153 mg, 1.05 mmol) was then added followed by 4M HCl in dioxane (1.2 ml). The resulting mixture was heated overnight at 60° C. The reaction mixture was cooled to −8° C. and the resulting solids collected by filtration and washed with diethylether. The solids were dissolved in methanol, loaded onto an SCX column and eluted with methanol followed by 7N NH3 in MeOH. Appropriate fractions were combined and evaporated. The residues were purified by column chromatography on SiO2 eluting with increasingly polar mixtures of DCM/methanol (100/0-95/5). The fractions containing the desired product were combined and evaporated to give methyl (2S,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxylate (13) as a clear gum (316 mg, 69%): 1H NMR Spectrum: (DMSO-d6) δ1.45-1.58 (2H, m), 2.02-2.11 (1H, m), 2.32-2.40 (1H, m), 2.57-2.67 (1H, m), 3.08-3.13 (1H, m), 3.42-3.48 (1H, m), 3.64 (3H, s), 3.95 (3H, s), 4.54-4.64 (1H, m), 7.05-7.10 (1H, m), 7.23 (1H, s), 7.28-7.33 (1H, m), 7.48-7.57 (2H, m), 7.85 (1H, s), 8.38 (1H, s), 9.56 (1H, s); Mass Spectrum: (M+H)+ 461.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)=[CH:6][C:5]=1[OH:26].N12CCCN=C1C[CH2:32][CH2:31][CH2:30][CH2:29]2.BrCCC=C.O>C(O)C.C(OCC)(=O)C>[CH2:32]([O:26][C:5]1[CH:6]=[C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:8]=[CH:9][C:4]=1[O:3][CH:2]([F:1])[F:27])[CH2:31][CH:30]=[CH2:29]
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1cccnc1C(=O)CCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Agent: C=CCCBr
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: C=CCCOc1cc(-c2nc(CCC(=O)c3ncccc3C)co2)ccc1OC(F)F
Reaction time: 8 h

Procedure:
An 80 mg quantity of the compound obtained in Example 327 and 0.09 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 2 ml of ethanol, and 80 mg of 4-bromo-1-butene was then added to the obtained solution, and heating and refluxing were conducted overnight. After cooling, water was added to the obtained reaction mixture, and ethyl acetate extraction was performed. The organic layer was washed twice with water, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1). The obtained crystals were recrystallized from aqueous 80% ethanol, thereby yielding 22 mg of white powdery 3-[2-(3-but-3-enyloxy-4-difluoromethoxyphenyl)-oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[NH:13][C:14](=[O:22])[C:15]([F:21])=[CH:16][C:17]=2[C:18]([OH:20])=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CC[N:25]=C=NCCCN(C)C.Cl.[CH:35]1[CH:36]=[CH:37][C:38]2[N:43](O)[N:42]=[N:41][C:39]=2[CH:40]=1.O.N>C(OCC)(=O)C.CN(C=O)C.O>[N:41]1([O:22][C:14]2[C:15]([F:21])=[CH:16][C:17]([C:18]([NH2:25])=[O:20])=[C:12]([NH:11][C:5]3[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:13]=2)[C:39]2[CH:40]=[CH:35][CH:36]=[CH:37][C:38]=2[N:43]=[N:42]1
Reactant: On1nnc2ccccc21
Reactant: COc1cc(Nc2[nH]c(=O)c(F)cc2C(=O)O)cc(OC)c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(Nc2nc(On3nnc4ccccc43)c(F)cc2C(N)=O)cc(OC)c1
Reaction time: 2 h

Procedure:
A mixture of 2-(3,5-dimethoxyphenylamino)-5-fluoro-6-oxo-1,6-dihydropyridin-3-carboxylic acid (200 mg), WSC.HCl (312 mg), HOBt.H2O (249 mg), and DMF (2 ml) was stirred at room temperature for 45 minutes. 25% ammonia water (1 ml) was added, followed by stirring at the same temperature for 2 hours. Ethyl acetate was added to the reaction mixture. The resultant was washed with saturated saline and dried over anhydrous magnesium sulfate, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=7:3 to 1:1), and a yellow solid of 6-(1H-1,2,3-benzotriazol-1-yloxy)-2-(3,5-dimethoxyphenylamino)-5-fluoronicotinamide (109 mg) was thus obtained.
Reaction SMILES: [ClH:1].[CH:2]([CH:4]1[CH2:6][C:5]1([C:11]([O:13][CH3:14])=[O:12])[C:7]([O:9][CH3:10])=[O:8])=[CH2:3].[Cl-].[Al+3].[Cl-].[Cl-]>COCCOC>[Cl:1][CH:4]([CH2:6][CH:5]([C:11]([O:13][CH3:14])=[O:12])[C:7]([O:9][CH3:10])=[O:8])[CH:2]=[CH2:3]
Reactant: Cl
Reactant: C=CC1CC1(C(=O)OC)C(=O)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: COCCOC
Product: C=CC(Cl)CC(C(=O)OC)C(=O)OC
Reaction time: 8 h

Procedure:
400 g of 1,2-dimethoxy ethane were introduced into a 1 liter glass flask equipped with a stirrer and a thermometer and admixed with 69 g of gaseous hydrogen chloride. 184.1 g of 1-vinyl-2,2-dicarbomethoxy cyclopropane (93.7% pure, 0.937 mol) and 0.65 g of aluminum chloride were then added to the contents, and the mixture was stirred. The temperature of the mixture rose to 40° C. The reaction was allowed to go to completion by letting the mixture stand overnight. After filtering off a slight turbidity, the reaction mixture was distilled in a 70 cm column. After collecting the 1,2-dimethoxy ethane which distilled over first and became available for reuse as a solvent in subsequent batches, the target product distilled over in pure form at 87° C./0.8 mbar.
Reaction SMILES: C([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]([CH3:14])[CH2:5]1)(=O)C.C(O[CH:18]=[C:19]([C:25]([O:27]CC)=O)[C:20]([O:22]CC)=[O:21])C.O.[OH-].[Na+]>C(O)(=O)C>[CH3:14][CH:6]1[N:7]2[CH:18]=[C:19]([C:20]([OH:22])=[O:21])[C:25](=[O:27])[C:9]3[C:8]2=[C:13]([CH:12]=[CH:11][CH:10]=3)[NH:4][CH2:5]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(=O)N1CC(C)Nc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC1CNc2cccc3c(=O)c(C(=O)O)cn1c23
Temperature: 120 °C

Procedure:
A mixture of 0.0894 mole (1.7 g) of optically purified (+) 1-acetyl-3-methyl-1,2,3,4-tetrahydroquinoxaline and 0.009 mole (1.9 g) diethyl ethoxymethylenemalonate is heated over one hour to 200° C. and maintained at that temperature for 1.5 hours. After cooling, 5 g of polyphosphoric acid are added and the mixture is heated at 120° C. until foaming stops. The mixture is stirred into water and the solution is made strongly basic with 25 percent sodium hydroxide. The solution is stirred and heated on a steam bath for one hour, then neutralized with acetic acid. Cooling, followed by filtration provides an olive green solid R(+) 2,3-dihydro-3-methyl-7-oxopyrido[1,2,3-de]quinoxaline-6-carboxylic acid, m.p.>250° C. Analysis: Calculated for C13H12N2O3 : %C, 63.9; %H, 5.0; %N, 11.5; Found: %C, 63.4; %H, 5.0; %N, 11.6. Optical rotation [α]21D =93±3+(C= 0.594, N,N-dimethylformamide: ethanol, 1/1).
Reaction SMILES: C([N:4]1[C:8]2=[N:9][C:10]([O:13]C(=O)C)=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH:4]1[C:8]2=[N:9][C:10]([OH:13])=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1
Reactant: CC(=O)Oc1ccc2ccn(C(C)=O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Oc1ccc2cc[nH]c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.9 %

Procedure:
A mixture of acetic acid 1-acetyl-1H-pyrrolo[2,3-b]pyridin-6-yl ester (4.0 g, 18.3 mmol) and potassium carbonate (10.45 g, 75.7 mmol) in methanol/water (50%, 260 mL) was stirred at room temperature for 12 h. The reaction mixture was concentrated to half its volume and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 10% methanol/dichloromethane) afforded 1H-pyrrolo[2,3-b]pyridin-6-ol (1.52 g, 62%): LC/MS m/e calcd for C7H6N2O [M+H]+ 135.14, observed 135.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:50][C@H:51]1[C@@H:55]([OH:56])[CH2:54][N:53]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:52]1>CN(C=O)C>[C:60]([O:59][C:57]([N:53]1[CH2:54][C@H:55]([OH:56])[C@H:51]([NH:50][C:12]([C:11]2[CH:10]=[N:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[CH:16][CH:15]=2)=[O:14])[CH2:52]1)=[O:58])([CH3:63])([CH3:61])[CH3:62]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@@H](O)C1
Reactant: O=C(O)c1ccc(-c2cccc(F)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)[C@H](NC(=O)c2ccc(-c3cccc(F)c3)nc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
To a solution of 6-(3-fluorophenyl)nicotinic acid (391 mg, 1.8 mmol ) in DMF (10 mL) at 0° C. was added HATU (753 mg, 1.98 mmol) and DIPEA (0.47 mL, 2.07 mmol ). After 15 min, cis-tert-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate was added and the reaction stirred at room temperature for 5 hrs. The solvent was removed in vacuo and the residue diluted with ethyl acetate and water. The layers were separated and the organic layer washed with brine, dried (MgSO4) and the solvent removed to give an oil, which after chromatography (silica, 65% ethyl acetate:hex) to give the desired product, cis-tert-butyl-3-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)-4-hydroxypyrrolidine-1-carboxylate (420 mg, 58%). LC/MS (M+H)=401.9 observed, 402.18 expected.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[CH2:37]([NH2:41])[CH2:38][CH2:39][CH3:40]>>[CH2:37]([NH:41][C:23](=[O:24])[CH:22]([N:8]1[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[CH:7]1[CH2:6][C:5]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCN
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: CCCCNC(=O)C(c1ccccc1)N1CCCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with n-butylamine.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14](F)[CH:13]=[C:12](F)[N:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[O-:18][CH2:19][CH3:20].[Na+].[CH2:22]([OH:24])[CH3:23]>>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([O:18][CH2:19][CH3:20])[CH:13]=[C:12]([O:24][CH2:22][CH3:23])[N:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC[O-]
Reactant: CCO
Reactant: CC(=O)N1CCN(c2nc(F)cc(F)n2)CC1
Agent: [Na+]
Product: CCOc1cc(OCC)nc(N2CCN(C(C)=O)CC2)n1
Temperature: 0 °C

Procedure:
A solution of 1-acetyl-4-(4,6-difluoropyrimidin-2-yl)piperazine (1.5 g) and sodium ethoxide (1.3 g) in ethanol (15 ml) was refluxed under heating for 1 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give the title compound (1.8 g) as a pale-brown solid.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][C:10]=2[Cl:12])[NH:5][C:4]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:2].[H-].[Na+].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[C:21]1([S:27]([N:5]2[C:6]3[C:11](=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[CH:7]=3)[C:3]([CH:1]=[O:2])=[C:4]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1C=O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C=O)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of ethyl 3-formyl-4,6-dichloroindole-2-carboxylate (5.0 g) in dry DMF (30 ml) was added to a suspension of sodium hydride (0.629 g; 80% suspension in mineral oil) in dry DMF (10 ml) under nitrogen at 0°. The reaction was stirred at this temperature for 45 min then phenylsulfonyl chloride (2.5 ml) was added giving a yellow precipitate. The reaction was allowed to warm slowly to room temperature, stirred for a further 14 h then poured into water (250 ml). The solid was filtered, washed with water and then with ethyl acetate to give the title compound (4.493 g,) as a white solid, m.p. 225.8°-226.3°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]([CH3:24])([C:21](O)=[O:22])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:54][C:55]1[C:63]([NH2:64])=[CH:62][CH:61]=[CH:60][C:56]=1[C:57]([NH2:59])=[O:58]>CN(C=O)C>[NH2:54][C:55]1[C:56]([C:57](=[O:58])[NH2:59])=[CH:60][CH:61]=[CH:62][C:63]=1[NH:64][C:21]([C:20]1([CH3:24])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:22]
Reactant: NC(=O)c1cccc(N)c1N
Reactant: CC1(C(=O)O)Cc2ccccc2CN1C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C(=O)Nc2cccc(C(N)=O)c2N)Cc2ccccc2CN1C(=O)OCc1ccccc1
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
Step-4: To a solution of 2-((benzyloxy)carbonyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (620 mg, 1.91 mmol) in anhydrous DMF (5 ml) was added EDC.HCl (1.098 mg, 5.73 mmol), HOAt (390 mg, 2.87 mmol) and triethylamine (0.4 ml, 2.87 mmol) at RT and the mixture was stirred for 10 min. To this reaction mixture, 2,3-diaminobenzamide (346 mg, 2.29 mmol) was added and heated to 55° C. for 3 days. The reaction mixture was poured into ice cold water and stirred for 30 min. The precipitate formed was filtered and dried under vacuum and purified by preparative TLC using ethyl acetate as eluent to afford benzyl 3-((2-amino-3-carbamoylphenyl)carbamoyl)-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate. MS (ES+): m/z 481.2 [M+Na]+
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([CH3:19])[CH:18]=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[C:10]3[N+:20]([O-])=O)[C:6]1=[O:23])[CH:2]=[CH2:3].N1[CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:4][N:5]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([CH3:19])[CH:18]=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[C:10]3[N:20]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[C:6]1=[O:23])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)c2ccc([N+](=O)[O-])c3cc(C)cc(c23)C1=O
Reactant: C1CCNC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCON1C(=O)c2ccc(N3CCCC3)c3cc(C)cc(c23)C1=O
Yield: 96.2 %

Procedure:
Following the procedure of Example W1, 2-allyloxy-5-methyl-7-nitro-benzo[de]isoquinoline-1,3-dione (0.52 g, 1.7 mmol, from Example I2), pyrrolidine (0.23 g, 3.2 mmol), triethyl amine (0.65 g, 6.4 mmol) in DMF (5 mL) were reacted to give 0.55 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([CH3:27])=[C:17]([O:20][C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)[CH:18]=2)[NH:13][CH:12]=1)[CH2:9][NH2:10].O=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl.O1CCOCC1>O1CCOCC1.C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:11]2[C:19]3[C:14](=[CH:15][C:16]([CH3:27])=[C:17]([O:20][C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)[CH:18]=3)[NH:13][C:12]=2[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:10][CH:9]=1
Reactant: Cc1cc2[nH]cc(C(CN)c3ccccc3F)c2cc1Oc1cncnc1
Reactant: CCOC(=O)C=O
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(C)c(Oc3cncnc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a solution of 2-(2-fluorophenyl)-2-(6-methyl-5-(pyrimidin-5-yloxy)-1H-indol-3-yl)ethanamine (0.262 g, 0.724 mmol) and 50% ethyl 2-oxoacetate in toluene (0.316 mL, 1.593 mmol) in 1,4-dioxane (18.10 mL) under nitrogen was added 4 N HCl/1,4-dioxane (0.543 mL, 2.172 mmol). After stirring overnight, the reaction was concentrated in vacuo and dissolved in water. Saturated aqueous NaHCO3 was added until pH ˜12 by litmus paper. The solution was extracted with EtOAc (2×). After separation of the layers, the organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give crude product which was used in subsequent step. This was added to 10% Pd/C (0.770 g, 0.724 mmol) in toluene (10.34 mL), and the reaction was refluxed for 45 min. After cooling to room temperature, the reaction was filtered through a pad of CELITE® and rinsed with EtOAc. The filtrate was concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 40 g column eluting with 0-2% MeOH/CH2Cl2. Appropriate fractions were collected and concentrated in vacuo to give the desired product (0.0716 g, 0.162 mmol, 22.4% yield) as a tan solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[CH:18]1([O:21][CH2:22][CH2:23][O:24][C:25]2[CH:37]=[CH:36][C:28]([O:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>>[CH:18]1([O:21][CH2:22][CH2:23][O:24][C:25]2[CH:26]=[CH:27][C:28]([O:29][CH:30]3[CH2:35][CH2:34][N:33]([CH2:2][C:3]([NH:5][C@@H:6]4[CH2:11][O:10][C:9]5=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]5[CH2:7]4)=[O:4])[CH2:32][CH2:31]3)=[CH:36][CH:37]=2)[CH2:20][CH2:19]1
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Reactant: c1cc(OC2CCNCC2)ccc1OCCOC1CC1
Product: O=C(CN1CCC(Oc2ccc(OCCOC3CC3)cc2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 38.7 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(4-(2-(cyclopropoxy)ethoxy)phenoxy)piperidine (277 mg, 1.0 mmol) as crude materials, 97 mg title compound was generated and yield was 39%.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]([CH2:13][C:14]([F:17])([F:16])[F:15])([C:9]([F:12])([F:11])[F:10])[O:8][C:4]=2[CH:3]=1.[Cu][C:21]#[N:22].NCCN>CN(C)C=O>[C:21]([C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]([CH2:13][C:14]([F:17])([F:16])[F:15])([C:9]([F:12])([F:11])[F:10])[O:8][C:4]=2[CH:3]=1)#[N:22]
Reactant: N#C[Cu]
Reactant: FC(F)(F)CC1(C(F)(F)F)Oc2ccc(Br)cc2O1
Solvent: CN(C)C=O
Solvent: NCCN
Product: N#Cc1ccc2c(c1)OC(CC(F)(F)F)(C(F)(F)F)O2
Temperature: 160 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
35 g of the product of Example 24 were dissolved in 75 ml of dimethylformamide, and 10.5 g of copper(I) cyanide were added. The mixture was stirred for 8 hours at 160° C. The hot mixture was then discharged into 100 ml of ice-water, and 30 g of 1,2-diaminoethane were added. After stirring for 30 minutes, the organic phase was separated off and the aqueous phase was extracted with methylene chloride. The combined organic phases were washed with a solution of 30 g of 1,2-diaminoethane in 75 ml of water, dried over magnesium sulphate and distilled under high vacuum to give 20.5 g of product (=69% of theory). The. boiling point was 110° C. at 0.02 mbar. =19F NMR: -58.1 and -84.6 ppm. 1H NMR: 3.08 ppm.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:29])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22]([OH:28])[CH2:23][C@H:24]([OH:27])[C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].O[C@@H:31]1[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2[C@H](C)CCCC(C)C)C[C@@H](O)C1>>[CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:29])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22]([OH:28])[CH2:23][C@H:24]([OH:27])[C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)/[CH:3]=[CH:4]/[C@@H:5]([CH:6]([CH3:7])[CH3:8])[CH3:31]
Reactant: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Product: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)/C=C/[C@H](C)C(C)C)CC[C@@H]23)C[C@@H](O)C[C@@H]1O

Procedure:
A portion (58.3 mg) of the product from Example 1 is transferred to a 3-necked, 200 ml, round-bottomed flask equipped with a gas dispersion tube, gas exit bubbler and a thermometer. A charge of 150 mg of anthracene in 150 ml of benzene is added and the resulting solution irradiated at 10° C. (cold room) under a steady stream of nitrogen gas using 3-22 watt, circular fluorescent light bulbs. After 42 h of irradiation, TLC indicates the complete disappearance of a spot co-migrating with 5,6-trans-1α-hydroxyvitamin D3 and the appearance of a new spot co-migrating with 1α-hydroxyvitamin D3. After 45 h of irradiation the reaction is worked up by evaporation of the solvent. The residue is taken up in 15 ml of ether and filtered. The precipitate is washed with ether (3 ml, 3×). The combined filtrate and washings are evaporated and the residue applied in benzene to a 1×55 cm silica gel column. The column is eluted with benzene then with ethyl acetate/hexane mixtures, to yield 45 mg of a white powder shown to be identical with 1α-hydroxyvitamin D3 by comparison of nmr, uv, mass spectra and chromatographic properties with those of an authentic sample of this compound (prepared from 1α-hydroxycholesterol). Utilizing procedures essentially similar to that described above, but substituting other appropriate 5,6-trans-vitamin D compounds for 5,6-trans-1α-hydroxyvitamin D3, there is obtained 1α-hydroxyvitamin D2 from 5,6-trans-1α-hydroxyvitamin D2 ; 1α,25-dihydroxyvitamin D3 from 5,6-trans-1α,25-dihydroxyvitamin D3 ; 1α,24,25-trihydroxyvitamin D3 from 5,6-trans-1α,24,25-trihydroxyvitamin D3 ; 1α,25,26-trihydroxyvitamin D3 from 5,6-trans-1α,25,26-trihydroxyvitamin D3 ; 1α,24-dihydroxyvitamin D2 from 5,6-trans-1α,24-dihydroxyvitamin D2 ; 1α,25-dihydroxyvitamin D2 from 5,6-trans-1α,25-dihydroxyvitamin D2 ; 1α,24,25-trihydroxyvitamin D2 from 5,6-trans-1α,24,25-trihydroxyvitamin D2.