Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1.C(Cl)Cl.CO>[OH-].[Na+]>[N:4]1[NH:3][N:2]=[N:1][C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(OCc2nn[nH]n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: O=C(O)c1ccc(OCc2nn[nH]n2)cc1

Procedure:
Methyl 4-(2H-Tetrazol-5-ylmethoxy)-benzoate was refluxed in 3N sodium hydroxide. The reaction was followed by TLC (DCM:MeOH=9:1). The reaction mixture was cooled, acidified and the product filtered off. The impure product was washed with DCM, dissolved in MeOH, filtered and purified by column chromatography on silica gel (DCM:MeOH=9:1). The resulting product was recrystallised from DCM:MeOH=95:5. This was repeated until the product was pure. This afforded 13.82 g (30%) of the title compound.
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:8]2[C@@H:11]([S:12]([CH3:15])(=[O:14])=[O:13])[NH:10][C:9]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]1(S([O-])=O)[CH:34]=[CH:33]C=[CH:31][CH:30]=1.[Na+].ClCCCl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:23]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:8]2[CH:11]([S:12]([C:15]3[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=3)(=[O:14])=[O:13])[NH:10][C:9]2=[O:16])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=S([O-])c1ccccc1
Reactant: CS(=O)(=O)[C@H]1NC(=O)[C@H]1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: O=C1NC(S(=O)(=O)c2ccccc2)[C@@H]1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 72.8 %

Procedure:
A mixture of 30 g of (3R-cis)-3-triphenylmethyl-4-methylsulfonyl-2-azetidinone, 40 g of sodium benzenesulfinate, 25 g of tetra-n-butylammonium bromide, 400 ml of 1,2-dichloroethane, and 100 ml of water were refluxed under nitrogen for 30 minutes. The dichloroethane was removed in vacuo and the residue was extracted with 700 ml of ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate solution, then water, then saturated aqueous sodium chloride solution. The extract was dried over sodium sulfate and evaporated. The residue was chromatographed on a 50×280 mm silica gel column eluted with 1000 ml 1:4 ethyl acetate:hexane, then 1000 ml 1:1 ethyl acetate:hexane. (3R)-3-triphenylmethyl-4-phenylsulfonyl-2-azetidinone (25.3 g) was obtained as a mixture of cis and trans isomers.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH:38]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=4)/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1ccc(CN2CCCC2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(CN3CCCC3)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-(pyrrolidin-1-yl-methyl)-aniline
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:6]2=[C:7]([OH:12])[CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[O:4][CH2:3]1.Cl[C:15]1[N:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.C(OCC)(=O)C>[N+:21]([C:18]1[CH:17]=[N:16][C:15]([O:12][C:7]2[C:6]3[C:2]([CH3:13])([CH3:1])[CH2:3][O:4][C:5]=3[C:10]([CH3:11])=[CH:9][CH:8]=2)=[N:20][CH:19]=1)([O-:23])=[O:22]
Reactant: Cc1ccc(O)c2c1OCC2(C)C
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc(Oc2ncc([N+](=O)[O-])cn2)c2c1OCC2(C)C
Temperature: 40 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
3,3,7-Trimethyl-2,3-dihydro-1-benzofuran-4-ol (Intermediate 27, 178 mg, 1.0 mmol) and 2-chloro-5-nitropyrimidine (191.5 mg, 1.2 mmol) were dissolved in CH3CN (3.0 mL) and K2CO3 (345.5 mg, 2.5 mmol) was added. The resulting suspension was heated to 40° C. and stirred for 1 hour. The reaction mixture was then diluted with water (50 mL) and ethyl acetate (50 mL), The organic phase was collected, washed with brine (50 mL) and dried over Na2SO4. The residue was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate 97:3 as eluents affording the title compound (243 mg).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[N:12]=[C:11]([C:13]#N)[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH-:17].[Na+].[OH2:19]>>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[N:12]=[C:11]([C:13]([OH:19])=[O:17])[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O
Reactant: N#Cc1cccc(Cc2ccc(F)cc2)n1
Agent: [Na+]
Product: O=C(O)c1cccc(Cc2ccc(F)cc2)n1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
6-(4-Fluorobenzyl)picolinonitrile (24 mg, 113 μmol; CAN 1237431-32-1) and powdered sodium hydroxide (18.1 mg, 452 μmol) were dissolved in water (3 mL). The reaction mixture was heated to 90° C. for 2.5 h. Additional powdered sodium hydroxide (18.1 mg, 452 μmol) was added and heating was continued for another 2.5 h. The reaction mixture was poured onto 25 mL ice/0.1N HCl and extracted with EtOAc (2×20 mL). The combined organic layers were washed with ice water/brine (25 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound (21 mg, 80%) as light yellow oil which was used in the next step without further purification. MS (EI): m/e=230.1 [M−H]−.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[H][H].C(C1C=CC=CC=1)(=O)C.[C:29](=O)([O:33]CC)[O:30][CH2:31][CH3:32]>CCCCCC>[CH2:31]([O:30][C:29](=[O:33])[CH2:16][C:15]([C:12]1[CH:11]=[CH:10][C:9]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)=[CH:14][CH:13]=1)=[O:17])[CH3:32]
Reactant: CC(=O)c1ccc(C2CCCCC2)cc1
Reactant: [H][H]
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(=O)c1ccccc1
Product: CCOC(=O)CC(=O)c1ccc(C2CCCCC2)cc1
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
Into a three-neck 2 L round-bottom flask equipped with an addition funnel, nitrogen inlet, magnetic stirrer, heating mantle, thermocouple and condenser, was placed 21.7 g (0.543 moles) of a 60%-in-oil dispersion of sodium hydride. To this was added dry hexane (1 L). The resulting suspension was stirred for 15 minutes, stirring was halted and the solids were allowed to settle. The clear supernatant containing the hexane and dissolved oil was then removed via a cannula. Diethyl carbonate(1 L) was added and the suspension was heated to 120° C. To this suspension was cautiously added dropwise, over 40 minutes, a solution of 100 g (0.494 moles) of 4′-cyclohexyl actephenone dissolved in 250 mL of diethyl carbonate. As addition proceeded a reaction initiated, hydrogen was evolved and the color changed to tan. After the acetophenone derivative addition was complete, the reaction was heated for 1 additional hour. The reaction mixture was cooled and was poured into a 2 L separatory funnel. The diethyl carbonate layer was twice washed with 10% acetic acid solution and then dried over MgSO4. The solution was then filtered and concentrated on a rotary evaporator followed by pumping with high vacuum at 70° C. for 18 hr. The concentrated solution crystallised on cooling over 24 hrs to give a colorless solid. The product obtained was then used without further purification, yield 133 g (98%). 1H NMR reveals that the β-keto ester product actually exists as a keto-enol tautomer mixture in solution, with the keto form predominant in the solid.
Reaction SMILES: [F-].[K+].CN(C=O)C.C[Si](C)(C)[C:10]([F:13])([F:12])[F:11].[F:16][C:17]1[N:22]=[C:21](I)[C:20]([O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:19][CH:18]=1>CN1C(=O)CCC1.[Cu]I.ClCCCl>[F:16][C:17]1[N:22]=[C:21]([C:10]([F:13])([F:12])[F:11])[C:20]([O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:19][CH:18]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COCCOCOc1ccc(F)nc1I
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCCC1=O
Product: COCCOCOc1ccc(F)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.9 %

Procedure:
A dry 25 mL was charged with potassium fluoride (1.0 g, 18 mmol), copper(I) iodide (3.4 g, 18 mmol) and a stirbar. The flask was evacuated to <1 mm Hg and the solid was heated using a 170° C. oil bath for 2 h. The flask was cooled to room temperature and the vacuum was released with nitrogen. The flask was fitted with a septa/inert atmosphere inlet. The solids were treated with 5 mL freshly distilled DMF, trimethyl(trifluoromethyl)silane (2.7 ml, 18 mmol), and a solution of 6-fluoro-2-iodo-3-((2-methoxyethoxy)methoxy)pyridine (3.90 g, 12 mmol) in 5 mL dry NMP. The reaction was stirred at room temperature for 16 h, and then poured onto 150 mL dry DCE. The slurry was stirred for 1 h, and then filtered through a 0.22 μm PTFE membrane. The solids were washed with DCE (2×50 mL), and the combined DCE filtrates were concentrated in vacuo. The residue was taken up in 250 mL dry EtOH, and cooled using an ice-water bath. The slurry was filtered through a pad of Celite® (diatomaceous earth), and concentrated in vacuo to afford ˜7 mL of sample (in NMP). The sample was loaded onto a Waters Xterra Prep C18 MS Packed by Vydac/The Separations Group (50 mm×300 mm, PN PA0000-050730, 10 μm particle size, spherical shape; gradient: 0→4 min@20 mL/min, 40% B; 4→5 min, 20→100 mL/min@ 40% B; 5→25 min@100 mL/min, linear gradient to 70% B; 25→35 min@100 mL/min, isocratic at 70% B; 35 min, step to 100% B @100 mL/min; 35→50 min@100 mL/min, 100% B; 50 min, step to 40% B @ 100 mL/min; 60 min end. A fraction that eluted from 19.3 to 21.7 minutes was isolated. The solvent was removed in vacuo to afford 6-fluoro-3-((2-methoxyethoxy)methoxy)-2-(trifluoromethyl)pyridine (2.0964 g, 65% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 3.36 (s, 3H) 3.52-3.59 (m, 2H) 3.84-3.90 (m, 2H) 5.35 (s, 2H) 7.10 (ddd, J=8.95, 3.77, 0.59 Hz, 1H) 7.86 (ddd, J=9.00, 6.06, 0.59 Hz, 1H). 19F NMR (376 MHz, chloroform-d) δ ppm −75.45 (dd, J=6.50, 3.90 Hz, 1 F) −66.65 (s, 3 F). 13C NMR (101 MHz, chloroform-d) δ ppm 58.91 (s, 1 C) 68.32 (s, 1 C) 71.30 (s, 1 C) 113.61 (q, J=1.01 Hz, 1 C) 114.00 (d, J=0.87 Hz, 1 C) 120.73 (qd, J=274.47, 1.52 Hz, 1 C) 133.80 (dq, J=35.26, 13.00 Hz, 1 C) 149.84 (d, J=5.20 Hz, 1 C) 156.28 (dq, J=238.58, 1.00, 0.87 Hz, 1 C). HPLC-MS: 2.04 min (>99%@215 nm; >99% @254 nm; m/z=270.0, calculated for C10H11F4NO3+H+=270.1).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[CH:8][O:9][C:4]=2[C:3]=1O.[C:21](=[O:24])([O-])[O-].[K+].[K+].S([O-])(O[CH3:31])(=O)=O>CC(C)=O>[CH3:31][O:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[CH:8][O:9][C:4]=2[C:3]=1[O:24][CH3:21]
Reactant: O=C([O-])[O-]
Reactant: COS(=O)(=O)[O-]
Reactant: Cc1ccc(-c2coc3c(O)c(O)ccc3c2=O)cc1
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc2c(=O)c(-c3ccc(C)cc3)coc2c1OC

Procedure:
7,8-Dihydroxy-3-(4-methylphenyl)-4H-1-benzopyran-4-one (2.7 g), described in example 9, is dissolved in dry acetone (50 ml). Pyrolyzed potassium carbonate (4.14 g) is added and the mixture is heated to reflux. A solution of methyl sulphate (3.78 g) in acetone (10 ml) is then added dropwise and heating is maintained for three more hours. After cooling, the solid is filtered and the solution is evaporated to dryness under vacuum. Water is added to the residue which is filtered, washed with an aqueous sodium hydroxide solution (1N) then with water and dried. After crystallization in methanol, 7,8-dimethoxy-3-(4-methylphenyl)-4H-1-benzopyran-4-one is obtained, m.p. 135°.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.F[C:40](F)(F)[C:41]([OH:43])=[O:42].CSC>C(S)(S)C>[NH2:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:40][C:41]([OH:43])=[O:42]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(N)=O
Reactant: O=C(O)C(F)(F)F
Agent: CC(S)S
Solvent: CSC
Product: CC(=O)O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12)C(N)=O
Temperature: 0 °C
Yield: 60 %

Procedure:
BocDTrp-Leu-MetNH2 (47.5 mmole) was added to a solution of trifluoroacetic acid (230 ml.), dimethylsulfide (260 ml.) and ethanedithiol (20 ml.) with cooling to 0° C. The mixture was allowed to warm to room temperature during one and one half hours, then stripped of volatiles. Attempted crystallization of the residue from ethyl acetate-hexane was unsuccessful, and the mixture was stripped again. The residue was dissolved in methanol-ether. Removal of a small amount (about 300 mg.) of solid and addition of acetic acid to the filtrate afforded HDTrp-Leu-MetNH2 acetate salt in 60% yield (12.6 g., m.r. 154°-160° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH:11]2[CH2:13][CH2:12]2)[CH2:9][OH:10])=[CH:4][CH:3]=1.[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].C(N(CC)CC)C>ClCCl>[CH3:21][C:20]1[CH:22]=[CH:23][C:17]([S:14]([O:10][CH2:9][C@@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:11]2[CH2:13][CH2:12]2)(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: OC[C@@H](c1ccc(Cl)cc1)C1CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@@H](c2ccc(Cl)cc2)C2CC2)cc1
Reaction time: 72 h
Yield: 95.9 %

Procedure:
(2R)-2-(4-Chlorophenyl)-2-cyclopropylethanol (6.50 g, 33.0 mmol), tosyl chloride (7.86 g, 41.0 mmol) and 6.0 ml of triethylamine (6.0 ml) are dissolved in dichloromethane (150 ml) and allowed to stir for 3 days. The reaction mixture is washed successively with 1 N HCl (100 ml), water (100 ml) and saturated brine solution (100 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel eluting with ether:hexane (10:90 to 25:75) to afford the title compound as a colorless oil (11.1 g, 96%) which is characterized by 1HNMR, 13CNMR and mass spectral analysis.
Reaction SMILES: C(C1C=C(N[CH:11]([C:15]2[CH:20]=[CH:19][C:18](OC)=[C:17]([O:23][CH3:24])[CH:16]=2)[C:12]([OH:14])=[O:13])C=CC=1)(=O)N.[NH2:25][C:26]1[CH:27]=[C:28]([C:32]([F:36])=[CH:33][C:34]=1[F:35])[C:29]([NH2:31])=[O:30].COC1C=C(B(O)O)C=CC=1[F:45].O.C(O)(=O)C=O>>[C:29]([C:28]1[C:32]([F:36])=[CH:33][C:34]([F:35])=[C:26]([NH:25][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([F:45])=[C:17]([O:23][CH3:24])[CH:16]=2)[C:12]([OH:14])=[O:13])[CH:27]=1)(=[O:30])[NH2:31]
Reactant: COc1ccc(C(Nc2cccc(C(N)=O)c2)C(=O)O)cc1OC
Reactant: COc1cc(B(O)O)ccc1F
Reactant: NC(=O)c1cc(N)c(F)cc1F
Agent: O=CC(=O)O
Solvent: O
Product: COc1cc(C(Nc2cc(C(N)=O)c(F)cc2F)C(=O)O)ccc1F
Yield: 87 %

Procedure:
41A was prepared in a procedure similar to that of 1A using 3-amino-4,6-difluorobenzamide, 7C, and glyoxylic acid monohydrate. Yield: 87%. 1H NMR (400 MHz, Methanol-d4) δ ppm 3.87 (s, 3H) 5.11 (s, 1H) 6.97-7.11 (m, 4H) 7.26 (d, J=8.79 Hz, 1H), LCMS: 355 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[CH3:9][C:10]1([CH3:27])[O:14][C@H:13]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:12][O:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:9][C:10]1([CH3:27])[O:14][C@H:13]([CH2:15][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)[CH2:12][O:11]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@@H](Cn2ccc([N+](=O)[O-])n2)O1
Temperature: 90 °C
Reaction time: 6 h
Yield: 71.7 %

Procedure:
A solution of 3-nitro-1H-pyrazole (prepared as in Example 5, 12.0 g, 106 mmol) in N,N-dimethylformamide (150 mL) was treated with toluene-4-sulfonic acid (S)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl ester (25.5 g, 89.0 mmol), and potassium carbonate (24.5 g, 178 mmol). The reaction mixture was stirred for 6 h at 90° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with water twice, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 330 g, 5% to 30% ethyl acetate/hexanes) to afford 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-3-nitro-1H-pyrazole (14.5 g, 72%) as light yellow oil: LR-ES-MS m/z calculated for C9H13N3O4 [M]+ 227, observed [M+H]+ 228. 1H NMR (300 MHz, CDCl3) δ ppm 1.35 (s, 3H), 1.40 (s, 3H), 3.77 (dd, J=8.8, 5.7 Hz, 1H), 4.13 (dd, J=8.8, 6.6 Hz, 1H), 4.27 (dd, J=14.0, 6.6 Hz, 1H), 4.39 (dd, J=14.0, 3.6 Hz, 1H), 4.45-4.59 (m, 1H), 6.92 (d, J=2.4 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]=[C:8]2[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: COc1cccc2c1CCCC2=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cccc2c1CCC=C2N1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Titanium tetrachloride (31.1 ml) in dry toluene (210 ml) is added slowly to a stirred solution of 5-methoxy-1-tetralone (100 g) and pyrrolidine (263 g) in anhydrous toluene (2 l) cooled in a methanol ice bath under N2 while maintaining a temperature of less than 7° C. When the addition is complete, the reaction mixture is allowed to stir at RT for 31/2 hrs. The reaction mixture is filtered, the solid washed with anhydrous toluene, and the filtrate evaporated in vacuo, resulting in a gold viscous liquid, which is dissolved in 1.8 l of dry tetrahydrofuran and filtered. The filtrate is used as is in the next step.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[N:2]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][NH2:26])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C.[CH3:48][O:49][C:50]1[C:55]2[O:56][C:57]([CH3:60])([CH3:59])[O:58][C:54]=2[CH:53]=[C:52]([C:61](Cl)=[O:62])[CH:51]=1>ClCCl>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][N:26]([CH2:11][C:3]1[N:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:61]([C:52]1[CH:51]=[C:50]([O:49][CH3:48])[C:55]2[O:56][C:57]([CH3:60])([CH3:59])[O:58][C:54]=2[CH:53]=1)=[O:62])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Reactant: O=Cc1cc2ccccc2nn1
Reactant: COc1cc(C(=O)Cl)cc2c1OC(C)(C)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N(Cc2cc3ccccc3nn2)C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc2c1OC(C)(C)O2

Procedure:
Experimental conditions analogous to Example 1, from 0.26 g (1.65 mmol) of cinnoline-3-carbaldehyde, 0.49 g (2.47 mmol) of (S)-2-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester, 10 mL dichloromethane, and 0.52 mg (2.47 mmol) of sodium triacetoxyborohydride. The reaction was quenched with aqueous sodium bicarbonate. The residue from the organic layer was purified using flash chromatography (0-20% methanol in dichloromethane). The organic layer was concentrated under vacuum and dissolved in 5 mL dichloromethane. To this solution were added 0.34 mL (2.47 mmol) of triethylamine and 0.4 g (1.65 mmol) of 7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carbonyl chloride. After 1 hour the reaction mixture was purified using flash chromatography (10-100% ethyl acetate in hexane), gave 182 mg as a yellow solid. LC-MSD, m/z for C30H36N4O6 [M+H]+: 549.7
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][N:3]=1.[C:15]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[F:1][C:2]1[C:7]([C:8]([O:10][CH3:15])=[O:9])=[C:6]([C:11]([F:12])([F:13])[F:14])[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1c(C(F)(F)F)ccnc1F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1c(C(F)(F)F)ccnc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a mixture of 2-fluoro-4-(trifluoromethyl)pyridine-3-carboxylic acid (1.06 g) and K2CO3 (0.701 g) in DMF (dry) (10 mL) was added MeI (0.317 mL). The mixture was stirred at room temperature for 3 h. The mixture was directly purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (1.13 g, containing EtOAc and hexane, ca. 75% purity).
Reaction SMILES: C(=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.CCO[C:14]([CH3:16])=[O:15].[CH3:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[O:15]1[CH2:14][C@H:16]1[CH2:9][O:8][C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][C:6]=1[C:19]1[CH:18]=[CH:17][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(C)=O
Reactant: CCCCCC
Reactant: COc1ccc(C=O)cc1
Product: c1ccc(-c2ccccc2OC[C@@H]2CO2)cc1

Procedure:
13C NMR (CDCl3): δ155, 148, 132, 129, 128, 127, 126, 121,113, 69, 50, 44. TLC: Rf =0.5 in 25% EtOAc/hexane, p-anisaldehyde stain, UV.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:20])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[C:29]([Cl:30])=[CH:28][C:25]([CH:26]=O)=[C:24]([OH:31])[CH:23]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[NH2:20][C:9]1[N:10]=[CH:11][N:12]=[C:13]([N:14]2[CH2:19][CH2:18][N:17]([CH2:26][C:25]3[CH:28]=[C:29]([Cl:30])[C:22]([Cl:21])=[CH:23][C:24]=3[OH:31])[CH2:16][CH2:15]2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Nc1ncnc(N2CCNCC2)c1-c1ccc(F)cc1
Reactant: O=Cc1cc(Cl)c(Cl)cc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: Nc1ncnc(N2CCN(Cc3cc(Cl)c(Cl)cc3O)CC2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
A reaction mixture of 5-(4-fluoro-phenyl)-6-piperazin-1-yl-pyrimidin-4-ylamine (400.0 mg; 1.46 mmol; 1.00 eq.), 4,5-dichloro-2-hydroxy-benzaldehyde (279.5 mg; 1.46 mmol; 1.00 eq.), Acetic acid (87.8 mg; 1.46 mmol; 1.00 eq.) and sodium triacetoxy borohydride (926.1 mg; 4.39 mmol; 3.00 eq.) in DCE (10 ml) was stirred overnight at RT. The reaction solution was diluted with DCM and washed with brine. The organic layer was dried and concentrated, which was added 10 ml of ether and stirred for 5 mins. The precipitate was filtered to afford the title as white off solid (528 mg, yield 80.5%). LC-MS: (M+1=448, obsd.=448/450).