Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: N#Cc1c(N)nc2ccc(N3CCOCC3)cc2c1Cl
Solvent: O
Product: N#Cc1c(N)nc2ccc(N3CCOCC3)cc2c1NCc1ccccc1

Procedure:
3 g of 2-amino-3-cyano-4-chloro-6-(morpholin-4-yl)quinoline and 6 mL of benzylamine are stirred at 125° C. for 3 hours. The reaction mixture is poured onto 30 mL of water. The precipitated material is filtered off, washed with 20 mL of water. After drying 2.3 g of the title compound is obtained, m.p.: 202° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:4]([O:22][CH3:23])[CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:23][O:22][C:4]1[CH:3]=[C:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: COc1cc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2ccccc2)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A 100 mL round-bottom flask was purged with and maintained under an inert atmosphere of nitrogen then charged with tert-butyl 4[(4-bromo-2-methoxyphenyl)methyl]piperazine-1-carboxylate (1.00 g, 2.60 mmol, 1.00 equiv), phenylboronic acid (0.640 g, 5.25 mmol, 2.02 equiv), Tetrakis(triphenylphosphine)palladium (0.300 g, 0.260 mmol, 0.10 equiv), potassium carbonate (1.08 g, 7.81 mmol, 3.01 equiv), dioxane (24 mL), and water (4 mL). The resulting solution was stirred overnight at 80° C. and then diluted with water (10 mL) and extracted with ethyl acetate (3×5 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (3/7) to provide 0.850 g (86% yield) of tert-butyl 4-[(2-methoxy-4-phenylphenyl)methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 383 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][C:3]=1[O:10][CH3:11].[C:12]([Cu])#[N:13].[Li+].[Cl-].Cl>CN(C=O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.C(OCC)(=O)C>[F:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([C:12]#[N:13])=[C:3]([O:10][CH3:11])[CH:4]=1
Reactant: COc1cc(F)c(C)cc1Br
Reactant: N#C[Cu]
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(F)c(C)cc1C#N
Temperature: 160 °C
Yield: 86.3 %

Procedure:
A solution of 1-bromo-4-fluoro-2-methoxy-5-methyl-benzene (5.0 g, 22.8 mmol) in DMF (100 mL, 0.2 M) was treated with CuCN (4.7 g, 52.5 mmol). Equipped with a reflux condenser, the reaction was heated to 160° C. for 20 h. After cooling to room temperature, the solution was poured into a 2 L Erlenmeyer flask. ethyl acetate (400 mL), saturated aq LiCl (100 mL), 1N HCl (100 mL), 11 g of iron (III) chloride hexahydrate, and 15 mL of concd HCl was added to the solution. This green mixture was heated at 70° C. for 2 h (or until emulsion dissipated). After cooling to room temperature, the mixture was poured into a separatory funnel and extracted with ethyl acetate (600 mL total). The combined organics were washed with 1N HCl (200 mL), saturated aq LiCl (2×200 mL), and saturated aq NaCl (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting powder was dissolved in ethyl acetate (50 mL) and washed with saturated aq LiCl (3×30 mL), dried over Na2SO4, filtered, and concentrated under reduced to afford 4-fluoro-2-methoxy-5-methyl-benzonitrile (3.25 g, 86%) as a beige powder: mp 99–101° C.; Rf 0.53 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 7.39 (d, J=8.1 Hz, 1 H), 6.65 (d, J=11.1 Hz, 1 H), 3.89 (d, J=0.9 Hz, 3 H), 2.21 (s, 3 H); Anal. calcd for C9H8FNO: C, 65.45; H, 4.88. Found C, 65.17; H, 4.97.
Reaction SMILES: [C:1](/[CH:9]=[CH:10]\[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[C:1](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C\C(=O)c1ccccc1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)/C=C/C(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 87.5 %

Procedure:
A mixture of 200 mg of ethyl cis-β-benzoylacrylate, 200 mg of boron trifluoride etherate (about 47 %) and 10 ml of toluene was stirred at 80° C. for 45 minutes and then cooled, followed by the procedure as in Example 1 to give 175 mg of ethyl trans-β-benzoylacrylate as a yellow oil.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].CN([CH:21]=[C:22]([C:30](OCC)=[O:31])[CH:23]=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])C.BrC1C=CC=CC=1>>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]3[C:30](=[O:31])[C:22](/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][N:17]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(CCc2ccnc(N)c2)n1
Reactant: CCOC(=O)C=CC(=CN(C)C)C(=O)OCC
Solvent: Brc1ccccc1
Product: CCOC(=O)/C=C/c1cnc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O
Temperature: 160 °C
Yield: 6.2 %

Procedure:
4-[2-(4-Isopropyl-1,3-thiazol-2-yl)ethyl]-2-aminopyridine(200 mg), diethyl 4-dimethylaminomethyleneglutaconate (265 mg) was added with bromobenzene (2 ml) and heated at 120° C. for 1 hour and at 160° C. for 4 hours with stirring. The residue was purified by silica gel column chromatography to obtain the title compound (20 mg) as white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[N+:23]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F

Procedure:
The title compound was prepared from [5-(methyl-propyl-amino)-2-nitro-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example C5) (3.78 g, 10.0 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a red oil (3.40 g, 98%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13]Br.[Cl-].[NH4+]>O1CCCC1>[Br:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:12]([CH2:13][O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[CH:11]=1
Reactant: OCC(F)(F)F
Reactant: BrCc1cccc(Br)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: FC(F)(F)COCc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Under nitrogen atmosphere, a suspension of sodium hydride (352 mg, 60 wt. % oil dispersion) in tetrahydrofuran (10 ml) was cooled to 0° C., 2,2,2-trifluoroethanol (0.63 ml) was added thereto, and the mixture was stirred for 5 minutes. Then, 3-bromobenzyl bromide (2.00 g) was added thereto, and then the mixture was stirred at reflux for 1 hour. This reaction mixture was cooled to room temperature, a saturated aqueous solution of ammonium chloride was added thereto, and the mixture was extracted with ethyl acetate. This organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 10/1) to give the titled compound (2.05 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([CH2:18][C:19]#[N:20])[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])=[C:4]([CH3:21])[N:3]=1.O=P(Cl)(Cl)[Cl:24]>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:24])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([CH2:18][C:19]#[N:20])[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])=[C:4]([CH3:21])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(CC#N)cc1Cc1c(C)nc(N)nc1O
Product: COc1ccc(CC#N)cc1Cc1c(C)nc(N)nc1Cl
Temperature: 90 °C

Procedure:
The product from step (ii) (2.8 g) was added to POCl3 (25 ml) and heated at 90° C. for 15 h and then evaporated under reduced pressure. The residue was diluted with ice/water (20 mL) and the mixture adjusted to pH ˜7 with sodium bicarbonate. The mixture was heated at 50° C. for 1 h and the precipitate collected by filtration. The solid was dried under vacuum to give the subtitle compound as a brown solid, 2.88 g.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=[N+]=[N-].C1(S(O)(=O)=O)C=CC=CC=1.CCOC(C)=O>CO>[NH2:15][C:13]1[CH:12]=[C:7]([CH:6]=[C:5]([CH2:4][NH2:1])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(CN=[N+]=[N-])cc([N+](=O)[O-])c1
Agent: O=S(=O)(O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(N)cc(CN)c1
Temperature: -5 °C
Reaction time: 18 h

Procedure:
A solution of Methyl 3-Azidomethyl-5-nitrobenzoate (15.50 g, 65.7 mmol) and benzene sulfonic acid (22.14 g, 140 mmol) in warm methanol (320 ml) was placed in a Parr shaker bottle and purged with nitrogen for 15 minutes. Palladium on carbon catalyst (10% Pd/C, 4.0 g) was added and the shaker bottle was further purged with 7 pressurization-evacuation cycles, repressurized, and allowed to shake 18 hours, during which time the required amount of hydrogen was consumed. The catalyst was removed by filtration through a bed of Celite and the filtrate was concentrated under reduced pressure yielding a tan oil. Trituration with refluxing EtOAc (2×150 ml) followed by cooling 12 hours at -5° C. gave a tan solid which was collected by filtration, washed with EtOAc (2×50 ml) and dried under vacuum (25.82 g, 80%). 1H NMR (CD3OD): 8.25-8.23 (m, 1H), 8.07-8.06 (m, 1H), 7.86-7.80 (m, 5H), 7.49-7.42 (m, 6H), 4.29 (s, 2H), 3.97 (s, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:15]2[N:16]=[CH:17][N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:19]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.[CH:26](O)([CH3:28])[CH3:27]>>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:15]2[N:16]=[CH:17][N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:19]=2)[C:12]([O:14][CH:26]([CH3:28])[CH3:27])=[O:13])=[CH:6][CH:5]=1
Reactant: Nc1ccc(CC(C(=O)O)c2cn(C3CCCCC3)cn2)cn1
Reactant: CC(C)O
Agent: Cl
Product: CC(C)OC(=O)C(Cc1ccc(N)nc1)c1cn(C2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2 ml of an HCl-saturated ether solution were added to a solution of 38.0 mg (0.12 mmol) of the compound from example 1i in 5 ml of isopropanol and stirred at RT for 4 h. The solution was then concentrated to dryness, and the resulting residue was dried under high vacuum. 25 mg of the title compound resulted as bishydrochloride in the form of an amorphous solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[CH:5]=[CH:4]1.N1C=CC=CC=1.[C:15]1([C:21](Cl)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:15]1([C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:1][CH2:2][C@@H:3]2[O:7][C:6](=[O:8])[CH:5]=[CH:4]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1C=C[C@H](CO)O1
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1C=C[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Reaction time: 6 h
Yield: 90.3 %

Procedure:
(R)-(+)-5-Hydroxymethyl-2 (5H)-furanone (1.94 g, 17.0 mmol) was dissolved in anhydrous pyridine (60 mol), triphenylmethyl chloride (14.3 g, 51.2 mmol) was added to the solution at room temperature, and the mixture was stirred for 6 hr. Ethanol was added to the reaction solution at 0° C., and the mixture was stirred for one hr. The reaction solution was concentrated under reduced pressure, and the concentrate was subjected to azeotropic distillation twice with toluene and purified by column chromatographic separation on silica gel (hexane:ethyl acetate=3:1 to 2:1) to give (R)-(+)-5-triphenylmethyloxymethyl-2 (5H)-furanone (5.47 g, 90%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:15](N)([NH2:18])(=[O:17])=[O:16]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15](=[O:17])(=[O:16])[NH2:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCN(S(N)(=O)=O)CC1

Procedure:
To a solution of 1,4-Diazepane-1-carboxylic acid tert-butyl ester (3.16 g) in dioxane (40 ml) was added sulfamide (4.0 g) and the reaction mixture was then heated at reflux for 18 h. The reaction mixture was then reduced in vacuo and the residue partitioned between EtOAc (100 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×100 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a white solid. Yield: 4.27 g
Reaction SMILES: [CH2:1]([S:7][S:8][CH2:9][C@H:10]([NH2:14])[C:11]([OH:13])=O)[C@H:2]([NH2:6])[C:3]([OH:5])=O.[CH3:15][N:16]=[C:17]=[O:18]>[OH-].[Na+]>[CH3:15][N:16]1[C:11](=[O:13])[C@H:10]([CH2:9][S:8][S:7][CH2:1][C@@H:2]2[C:3](=[O:5])[N:16]([CH3:15])[C:17](=[O:18])[NH:6]2)[NH:14][C:17]1=[O:18]
Reactant: N[C@@H](CSSC[C@H](N)C(=O)O)C(=O)O
Reactant: CN=C=O
Agent: [Na+]
Agent: [OH-]
Product: CN1C(=O)N[C@@H](CSSC[C@H]2NC(=O)N(C)C2=O)C1=O
Reaction time: 2 h

Procedure:
To a mixture of L-cystine (12 g) and 2 molar sodium hydroxide solution (50 ml), cooled to 0°-5° C. in an ice bath, was added, dropwise, methyl isocyanate (8.55 g). The clear solution was stirred at 0° for 2 hours, and then at room temperature over night.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]([CH:24]([CH3:26])[CH3:25])[CH3:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:3][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH2:20][CH2:21][N:22]([CH:24]([CH3:26])[CH3:25])[CH3:23])=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)[CH3:1]
Reactant: CC(C)N(C)CCCCl
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N(C)CCCOc1ccc(C2(CN(C)C)CCOCC2)cc1
Yield: 26.9 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500 mg, 2.13 mmol), (3-chloro-propyl)-isopropyl-methyl-amine (318 mg, 2,13 mmol), DMF (10 ml) and K2CO3 (1.18 g, 8.52 mmol) were reacted together according to general procedure B. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (96:3:1) provided the title compound (200 mg, 43%) as a white solid. 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.87 (d, 2H), 4.00 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.83 (sep, 1H), 2.55 (t, 2H), 2.40 (s, 2H), 2.22 (s, 3H), 2.14-2.05 (m, 2H), 1.96 (s, 6H), 2.00-1.82 (m, 4H), 1.00 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][NH:5][C:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:7][CH3:8].N1C=CC=CC=1.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CCOCC>[CH2:30]([O:29][C:27]([NH:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][NH:5][C:6]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([OH:9])[CH2:7][CH3:8])=[O:28])[CH3:31]
Reactant: CCOC(=O)Cl
Reactant: CCC(O)(NCc1ccccc1N)c1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Nc1ccccc1CNC(O)(CC)c1ccccc1

Procedure:
2.6 g (0.01 mole) of N-2-amino-benzyl-1-phenyl-2-methyl-amino-1-ethanol are dissolved in 30 ml of ether. To the solution 0.79 g (0.01 mole) of anhydrous pyridine are added, whereupon 1.3 g (0.012 mole) of ethyl chloroformate are added under vigorous stirring and cooling and the reaction is carried out at 15° C. The reaction mixture which contains a white precipitate is stirred at room temperature for 330 minutes, poured into 30 ml of icecold water, the aqueous phase is extracted three times with 100 ml of ether each, the united ether extracts are dried over anhydrous sodium sulfate and evaporated in vacuo. Thus 2.8 g of N-[2-ethoxycarbonylamino-benzyl]-1-phenyl-2-methyl-amino-1-ethanol are obtained in the form of a yellowish-white oil which can be subjected to further reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=S)=[CH:17][CH:16]=1.C(N(CC)CC)C>O1CCCC1.S([O-])([O-])(=O)=O.[Cu+2]>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[O:13][C:3]3[CH:4]=[CH:5][C:6]([O:8][C:9]([F:10])([F:11])[F:12])=[CH:7][C:2]=3[N:1]=2)=[CH:17][CH:16]=1
Reactant: Nc1cc(OC(F)(F)F)ccc1O
Reactant: S=C=Nc1ccc(Br)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: FC(F)(F)Oc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.1 %

Procedure:
To a mixture of 2-amino-4-(trifluoromethoxy)phenol (0.9 g, 0.0047 mol) in tetrahydrofuran (60 mL) was added 4-bromophenyl isothiocyanate (1 g, 0.0047 mol) at room temperature. The mixture was stirred for 16 hours at room temperature. Anhydrous copper sulfate (7.1 g, 0.0443 mol, 9.43 eq.), triethylamine (0.67 mL, 0.0047 mol, 1 eq.), and silica gel (8.5 g) were added to the reaction mixture. The mixture was stirred for 4 hours at room temperature. The solvent was removed under reduced pressure. The mixture was filtered through silica gel pad using 25% ethyl acetate/n-heptane as a mobile phase to give orange colored solid. The solid was purified by flash column chromatography on silica using 0%-25% ethyl acetate/n-heptane as a mobile phase. The solvent was removed, and the residue was triturated with n-heptane to give N2-(4-bromophenyl)-5-(trifluoromethoxy)-1,3-benzoxazol-2-amine (0.9 g, 0.0024 mol).
Reaction SMILES: [B:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([F:13])[CH:5]=1)([OH:3])[OH:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[F:48][C:49]1([F:54])[CH2:53][CH2:52][NH:51][CH2:50]1.Cl>CN(C=O)C.O>[F:48][C:49]1([F:54])[CH2:53][CH2:52][N:51]([C:8]([C:7]2[CH:11]=[CH:12][C:4]([B:1]([OH:2])[OH:3])=[CH:5][C:6]=2[F:13])=[O:10])[CH2:50]1
Reactant: O=C(O)c1ccc(B(O)O)cc1F
Reactant: FC1(F)CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc(B(O)O)cc1F)N1CCC(F)(F)C1
Yield: 52.6 %

Procedure:
A solution of 4-borono-2-fluorobenzoic acid (1.00 g, 5.44 mmol), N,N-diisopropylethylamine (2.85 mL, 16.31 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.163 g, 5.69 mmol) and 3,3-difluoropyrrolidine hydrochloride (1.00 g, 6.97 mmol) in DMF (6 mL) was stirred at room temperature for 22 h. Following addition of 1 N HCl (16 mL), the mixture was extracted with ethyl acetate (40 mL). HPLC analysis showed that the aqueous phase still contained product. The aqueous phase was neutralized to pH 7 with solid NaOH and K2CO3 and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and concentrated to give a thick brown oil. This residue was treated with equal volume of water. The white crystalline solid formed from the mixture was collected by filtration and washed with small amount of ether to give the desired product (0.7811 g). The filtrate was purified by reverse phase HPLC (Sunfire S10 30×250 mm column, 30-50% solvent B gradient) to give additional product (0.5632 g). The combined yield of the product was 1.344 g (91% yield). MS (ES+) m/z: 274 (M+H); LC retention time: 2.68 min (analytical HPLC Method A).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[C:20]([CH3:21])=[C:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:34])[CH:17]=2)[CH:12]=1)=O.C(OCC)(=O)C>O1CCCC1>[CH2:32]([S:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:22][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([F:34])[CH:17]=3)[CH:12]=[C:11]([CH2:9][OH:8])[C:20]=2[CH3:21])=[CH:24][CH:25]=1)(=[O:30])=[O:31])[CH3:33]
Reactant: CCS(=O)(=O)c1ccc(Cc2c(C)c(C(=O)OC)cc3ccc(F)cc23)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(Cc2c(C)c(CO)cc3ccc(F)cc23)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
A suspension of lithium aluminum hydride (399 mg, 10.5 mmol) in tetrahydrofuran (25 mL) was cooled to 0° C. under a stream of argon. A solution of 4-(4-ethanesulfonyl-benzyl)-6-fluoro-3-methyl-naphthalene-2-carboxylic acid methyl ester (870 mg, 2.18 mmol) in tetrahydrofuran (30 mL) was added slowly drop-wise to the 0° C. suspension. The reaction mixture was stirred at 0° C. for 15 minutes. The reaction mixture was warmed to room temperature and it was stirred at room temperature for 15 minutes. The reaction mixture was cooled again to 0° C. Ethyl acetate was added drop-wise to quench the unreacted lithium aluminum hydride. A saturated aqueous solution of potassium sodium tartrate was added. The organic phase was separated, dried over MgSO4, filtered, and concentrated to afford 780 mg (96%) of [4-(4-ethanesulfonyl-benzyl)-6-fluoro-3-methyl-naphthalen-2-yl]-methanol as an oily white solid. This product was used in subsequent reactions without further purification. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.98 (dd, J=8.9, 6.2 Hz, 1 H), 7.90 (s, 1 H), 7.73 (d, J=8.2 Hz, 2 H), 7.67 (d, J=12.4 Hz, 1 H), 7.34 (dd, J=8.9, 2.1 Hz, 1 H), 7.29 (d, J=8.2 Hz, 2 H), 5.27 (t, J=5.1 Hz, 1 H), 4.66 (d, J=5.1 Hz, 2 H), 4.58 (s, 2 H), 3.20 (q, J=7.2 Hz, 2 H), 2.31 (s, 3 H), 1.04 (t, J=7.2 Hz, 3 H). HRMS (ES+) cald. for C21H21FO3S [(M+Na)+] 395.1087, obsd. 395.1088.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16](=O)[NH:17][C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2.P(Cl)(Cl)([Cl:23])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16]([Cl:23])=[N:17][C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)-c1cc(=O)[nH]c(=O)n1CC2
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2c(cc1OC)-c1cc(Cl)nc(=O)n1CC2

Procedure:
A mixture of 30.0 g of 9,10-dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido(6,1-a)isoquinolin-2,4-dione and 300 ml of phosphorus oxychloride is heated on a steam bath for 4 hours. The excess of phosphorus oxychloride is distilled under reduced pressure. The residue is poured into a cold solution of sodium hydroxide. A yellow solid precipitates which is collected by filtration. The product is purified by passage through a silica gel column using chloroform as eluent. Yield 28.0 g, m.p. 235°-236° C.