Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:13]=[N:14][C:15]([CH:18]=O)=[N:16][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].Cl.[NH2:21]O.C1(S(Cl)(=O)=O)C=CC=CC=1.Cl>N1C=CC=CC=1>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:13]=[N:14][C:15]([C:18]#[N:21])=[N:16][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](c2cnc(C=O)nc2)CC1
Reactant: NO
Agent: Cl
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCCCC[C@H]1CC[C@H](c2cnc(C#N)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
9.0 g of trans-5-(4-pentylcyclohexyl)-2-pyrimidinecarboxaldehyde are dissolved in 150 ml of pyridine under a nitrogen atmosphere, treated with 3.9 g of hydroxylamine hydrochloride and stirred at room temperature for 2 hours. Thereafter, the mixture is treated with 18.3 g of benzenesulphonyl chloride, the temperature rising to about 50° C. Subsequently, the mixture is stirred at a bath temperature of 70° C. for 6 hours, then cooled, poured into 500 ml of ice/water and 100 ml of concentrated hydrochloric acid and extracted with ether. The extract is washed with dilute hydrochloric acid, washed neutral with water, dried over sodium sulphate and evaporated. The crude product obtained is chromatographed on a column of 275 g of silica gel with hexane/20% ether. The almost pure fractions (in accordance with thin-layer chromatography) are combined and recrystallized three times from hexane. There is obtained pure trans-5-(4-pentylcyclohexyl)-2-pyrimidinecarbonitrile; m.p. 83.5° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH2:18]=[C:19]1O[C:21](=[O:22])[CH2:20]1>C(Cl)Cl>[CH2:1]([N:3]1[C:19]([CH3:18])=[CH:20][C:21](=[O:22])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]1[C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[CH3:2]
Reactant: CCNC(=CC(=O)OCC)c1ccc(Cl)cc1
Reactant: C=C1CC(=O)O1
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)n(CC)c(C)cc1=O
Temperature: 25 °C

Procedure:
4.64 g of ethyl beta-ethylamino-4-chlorocinnamate, 4.61 g of technical grade diketene and 15 ml of methylene chloride are mixed in a flask fitted with a calcium chloride drying tube. The mixture is maintained at room temperature for 137 hours. The methylene chloride is removed in vacuo and the residue triturated with ether to yield 3.2 g of crude ethyl 1-ethyl-6-methyl-2-(4'-chlorophenyl)-4-oxonicotinate. mp (215°-217° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:6]([O:8]C)=O.[CH3:17][NH:18][O:19][CH3:20].C([Mg]Cl)(C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:6]([N:18]([O:19][CH3:20])[CH3:17])=[O:8]
Reactant: CNOC
Reactant: COC(=O)c1cc(OC)cc(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc(C(=O)N(C)OC)cc(C(F)(F)F)c1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 41.4 %

Procedure:
Methyl 3-methoxy-5-trifluoromethylbenzoate (O4.014, 1 g) and N,O-dimethylhydroxylamine (416 mg) were initially charged in THF (30 ml). Thereafter, the mixture was cooled to −15° C., and isopropylmagnesium chloride (3.2 ml; 2 M in THF) was added dropwise within 10 min. The mixture was stirred at −15° C. for another 20 min before the cooling bath was removed. After 3 h, the mixture was cooled again to −15° C. and further isopropylmagnesium chloride (3.2 ml) was added. After the cooling bath had been removed, the mixture was stirred at RT for another hour, then admixed with 20% ammonium chloride solution and extracted three times with EA. The combined EA phases were dried over sodium sulfate, filtered and concentrated. The residue was purified using silica gel (50 g cartridge, DCM as eluent). 465 mg of the title compound were obtained, as well as 427 mg of reactant.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=2)[NH:10][C:11]([CH3:19])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])=[CH:5][CH:4]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([NH:10][C:11]([CH3:19])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:20]2[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(NC(C)(C)c2ccccc2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(NC(C)(C)c2ccccc2)c2cccc(N)c2)cc1
Yield: 94.6 %

Procedure:
Following a similar procedure to that described in Example (94b), 1.39 g of N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-N-(1-methyl-1-phenylethyl)amine [prepared as described in step (a) above], 1.76 g of nickel chloride hexahydrate, 559 mg of sodium borohydride and 100 ml of methanol were reacted, to obtain 1.21 g of the title compound as a yellow oil.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH2:15][CH2:16][C@@H:17]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([Cl:35])[CH:28]=1)[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[CH3:36][C:37]([CH3:41])([CH3:40])[CH:38]=O>C(Cl)Cl>[Cl:35][C:29]1[CH:28]=[C:27]([NH:26][C@H:17]([CH2:16][NH:15][CH2:36][C:37]([CH3:41])([CH3:40])[CH3:38])[CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH:32]=[CH:31][C:30]=1[C:33]#[N:34]
Reactant: CC(C)(C)C=O
Reactant: CC(C)(C)OC(=O)C[C@@H](CN)Nc1ccc(C#N)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)CNC[C@H](CC(=O)OC(C)(C)C)Nc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
NaBH(OAc)3 (0.5 g, 2.32 mmol) was added to a solution of 1,1-dimethylethyl (3S)-4-amino-3-[(3-chloro-4-cyanophenyl)amino]butanoate (0.48 g, 1.55 mol), and trimethylacetaldehyde (0.14 g, 1.60 mmol) in CH2Cl2 (35 mL). After stirring at room temperature for 2 h, the reaction was diluted with CH2Cl2 (35 mL), washed with saturated NaHCO3, dried over Na2SO4, filtered, and concentrated to yield the titled product (0.575 g, 98%) as an oil. LC-MS (ES) m/e 380.6 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][N:5]([CH2:19][C:20]([OH:22])=[O:21])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)([OH:3])=O.C(=O)(O)[O-].[Na+]>C(OC(=O)C)(=O)C>[O:12]([C:8]1[CH:7]=[C:6]([N:5]2[CH2:19][C:20](=[O:21])[O:22][C:1](=[O:3])[CH2:4]2)[CH:11]=[CH:10][CH:9]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)CN(CC(=O)O)c1cccc(Oc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1CN(c2cccc(Oc3ccccc3)c2)CC(=O)O1
Yield: 100 %

Procedure:
[Carboxymethyl-(3-phenoxyphenyl)amino]acetic acid 25 (5 g) was heated at reflux in acetic anhydride (30 mL) for 1 h. The cooled reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed several times with saturated aqueous sodium bicarbonate (until no further effervescence was observed) and twice with brine. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the title compound as a golden oil (4.7 g, 100%). 1HNMR (300 MHz) (CDCl3) δ 6.10 (1H, m), 6.67 (2H, br d), 7.03 (2H, d), 7.17 (1H, t), 7.30 (1H, t) and 7.39 (2H, t).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH2:30]([SH:34])[CH2:31][CH2:32][CH3:33]>O1CCOCC1.CN(C=O)C>[CH2:30]([S:34][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCS
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCCCSc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and butanethiol in dioxane and DMF. ES-MS m/e (%): 459 (M+H+, 100).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[O:24][CH2:25][CH2:26]Cl>CS(C)=O.O>[CH:7]1([NH:13][CH2:26][CH2:25][O:24][C:15]2[CH:16]=[CH:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: ClCCOc1ccc2ccccc2c1
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc2cc(OCCNC3CCCCC3)ccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and cyclohexylamine (0.32 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 2-(2-naphthyloxy)-1-chloro ethane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-cyclohexyl-[2-(naphthalen-2-yloxy)-ethyl]amine, solid, m.p. 89° C., (yield 0.56 gm, 85.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([OH:17])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=O)[CH:7]=1.[NH2:19][CH2:20][CH:21]=[CH:22][C:23]([OH:25])=[O:24].C(=O)([O-])O.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([OH:17])=[C:6]([C:8](=[N:19][CH:20]=[CH:21][CH2:22][C:23]([OH:25])=[O:24])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: NCC=CC(=O)O
Reactant: Cc1cc(Cl)cc(C(=O)c2ccc(Cl)cc2)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Cl)cc(C(=NC=CCC(=O)O)c2ccc(Cl)cc2)c1O

Procedure:
In a 1-l round-bottomed flask, 15.3 g (0.054 mole) of (5-chloro-2-hydroxy-3-methylphenyl)(4-chlorophenyl)methanone, 5 g (0.049 mole) of 4-amino-2-butenoic acid and 4.5 g (0.054 mole) of sodium hydrogencarbonate are introduced in 700 ml of methanol. The mixture is evaporated to dryness on a water bath at 100° C. under reduced pressure. The operation is repeated seven times, evaporating 500 ml of methanol at a time. The dry residue is taken up with 200 ml of methylene chloride and 300 ml of water, acidified to pH 4 with 3.7 g of citric acid and then extracted with l of methylene chloride. The organic phase is washed with water, decanted, dried over MgSO4, filtered and evaporated to dryness. The compound is crystallised in 100 ml of hexane, filtered, drained and dissolved in 100 ml of ethyl acetate. The product crystallises slowly. It is filtered, drained and washed with 10 ml of ether.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][CH2:12][CH3:13])=[N:8]2)=[C:4]([CH3:14])[N:3]=1.[CH3:15][NH:16][CH3:17]>C(O)C>[CH3:15][N:16]([CH3:17])[C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][CH2:12][CH3:13])=[N:8]2)=[C:4]([CH3:14])[N:3]=1
Reactant: CCCc1nc2nc(Cl)nc(C)c2[nH]1
Reactant: CNC
Solvent: CCO
Product: CCCc1nc2nc(N(C)C)nc(C)c2[nH]1
Temperature: 110 °C

Procedure:
To a solution of 2-Chloro-6-methyl-8-propylpurine (from Step 1 of Example 32) (0.1 g, 0.47 mmol) in ethanol (2 ml) was added condensed dimethylamine (1 ml) at 0° C. The mixture was then placed in a steel-bomb and heated at 110° C. for 7 hours. The reactions was cooled and the mixture was concentrated in vacuo. The residue was partitioned between CHCl3 and water, and the organic was separated and dried over MgSO4. The crude product obtained after removal of the solvent was purified by flash-chromatography on silica-gel using 5% MeOH in CHCl3 giving the titled compound as an amorphous solid (0.065 g, 64%). NMR (CDCl3): δ1.01 (t, J=8 Hz, 3H), 1.8 (q, J=8 Hz, 2H), 2.65 (s, 3H), 2.8 (t, J=8 Hz, 2H), 3.2 (s, 6H). FAB-MS: m/e 220 (M+H).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[CH2:9][CH2:8]2)=[O:4].[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:23])[C:5]([C:3]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:4])=[N:14][CH:13]=2)[CH2:8][CH2:9][C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1ncc2c(c1O)CCC(=O)N2Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1ncc2c(c1O)CCC(=O)N2Cc1ccccc1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-1,2,3,4-tetrahydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (76 mg, 0.24 mmol), glycine (1.74 g, 23.1 mmol) and NaOMe solution (34 mL, 17.1 mmol, 0.5M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 1 with 4M HCl, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 67 mg of the title compound as a white solid. MS: (+) m/z 356.11 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[NH:10][C:9]=2[CH:18]=O)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[NH:30][C:31](=[O:34])[CH2:32][OH:33])[NH:26][C:25](=[O:35])[CH2:24]2>>[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[NH:30][C:31](=[O:34])[CH2:32][OH:33])[NH:26][C:25](=[O:35])[C:24]2=[CH:18][C:9]1[NH:10][C:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C:12]=2[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Reactant: O=C(CO)Nc1cc2c(cc1F)CC(=O)N2
Product: O=C(CO)Nc1cc2c(cc1F)C(=Cc1[nH]c3c(c1-c1ccc(F)cc1)C(=O)NCC3)C(=O)N2
Yield: 80.6 %

Procedure:
The title compound was prepared under the same conditions as described in Example 46 with 3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-acetamide as starting materials to give N-{5-fluoro-3-[3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-acetamide (72 mg, 80.6%), as a red solid.
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:18][C@H:19]([CH3:24])[O:20][C@H:21]([CH3:23])[CH:22]=3)[CH:14]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>>[CH3:23][C@H:21]1[CH2:22][CH:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)[CH2:18][C@@H:19]([CH3:24])[O:20]1
Reactant: [H][H]
Reactant: C[C@@H]1C=C(c2ccc3c(c2)CN(Cc2ccccc2)C3)C[C@H](C)O1
Product: C[C@@H]1CC(c2ccc3c(c2)CNC3)C[C@H](C)O1

Procedure:
Prepared in analogy to Example A62(c) from 2-benzyl-5-((2S,6R)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-2,3-dihydro-1H-isoindole and hydrogen. Brown oil. MS (m/e): 232.1 ([M+H]+, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:32](=[O:34])[NH2:33])([CH2:18][C:19]([O:21][CH:22]1[CH:27]([CH:28]([CH3:30])[CH3:29])[CH2:26][CH2:25][CH:24]([CH3:31])[CH2:23]1)=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@@:12]([C:32](=[O:34])[NH2:33])([CH2:18][C:19]([O:21][CH:22]1[CH:27]([CH:28]([CH3:30])[CH3:29])[CH2:26][CH2:25][CH:24]([CH3:31])[CH2:23]1)=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CC(=O)OC1CC(C)CCC1C(C)C)(NC(=O)OCc1ccccc1)C(N)=O
Solvent: CC(C)=O
Product: CCOC(=O)[C@](CC(=O)OC1CC(C)CCC1C(C)C)(NC(=O)OCc1ccccc1)C(N)=O
Temperature: 40 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
Acetone (750 g) was added to ethyl 2-benzyloxycarbonylamino-2-carbamoyl-3-[(−)-menthyloxycarbonyl]propionate (150 g, 0.315 mol) and the mixture was heated to 40° C., the solid was dissolved and then the solution was gradually cooled. It was placed to be matured at 10° C. overnight and then stirred at 5° C. for about an hour. The crystals were filtered, washed with sprayed cold acetone (50 ml×2) and dried in airflow at 60° C. to give ethyl (2R)-2-benzyloxycarbonylamino-2-carbamoyl-3-[(−)-menthyloxycarbonyl]propionate (57.9 g). mp. 124° C., yield 38.6%: optical purity (HPLC) 98.8% d.e.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([CH2:14][NH2:15])[OH:13]>>[OH:13][CH2:12][CH2:14][NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1c(Cl)cccc1Cl
Reactant: NCCO
Product: O=[N+]([O-])c1c(Cl)cccc1NCCO

Procedure:
0.04 mole (7.7 g) of 2,6-dichloronitrobenzene in 30 ml of ethanolamine is heated for 8 hours at 70° C. The reaction mixture is poured onto ice, and then extracted with ethyl acetate. After washing and drying, the ethyl acetate phase is evaporated to dryness under vacuum. The dry extract is recrystallized from ethanol. The product obtained melts at 78° C. (literature value 78.5° C.).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[CH:9][C:10]2[C:15]([CH:16]=1)=[C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]1=[C:12]1[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=21)(=O)=O.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]2=[C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=32)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)(Oc1cc2c3ccccc3c3ccccc3c2cn1)C(F)(F)F
Reactant: OB(O)c1ccccc1
Product: c1ccc(-c2cc3c4ccccc4c4ccccc4c3cn2)cc1

Procedure:
Dibenzo[f,h]isoquinolin-3-yl trifluoromethanesulfonate compound as synthesized in above Step 4 of Compound 1 synthesis reacts with phenylboronic acid under Suzuki reaction condition as described in Step 7 of Compound 1 synthesis to give the ligand 3-phenyldibenzo[f,h]isoquinoline.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([C:9]#[CH:10])[CH2:3][O:4][Si:5]([CH3:8])([CH3:7])[CH3:6].Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH2:16]([O:15][C:13](=[O:14])[C:10]#[C:9][C:2]([CH3:11])([CH3:1])[CH2:3][O:4][Si:5]([CH3:6])([CH3:8])[CH3:7])[CH3:17]
Reactant: CCOC(=O)Cl
Reactant: C#CC(C)(C)CO[Si](C)(C)C
Product: CCOC(=O)C#CC(C)(C)CO[Si](C)(C)C

Procedure:
The title compound was prepared from (2,2-dimethyl-but-3-ynyloxy)-trimethyl-silane and ethyl chloroformate in accordance with the procedures of G. Cai et al., Tetrahedron, 2006, (5697-5708).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[N:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[Cl:5][C:6]1[N:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]=[C:1]=[O:2])=[CH:15][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(Oc2cccc(Cl)n2)cc1
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(Oc2cccc(Cl)n2)cc1
Reaction time: 0.33 h

Procedure:
A stream of phosgene was passed into 120 ml. of dry toluene maintained at a temperature of about 0 to about 5° C. until a weight of 13.4 grams (0.135 mole) had been absorbed. 4-((6-Chloro-2-pyridinyl)oxy)benzenamine (10.0 grams; 0.045 mole) in 100 ml. of dry toluene was then added to the stirred phosgene solution over a period of about 15 minutes while maintaining the reaction temperature within a range of about 2° to about 5° C. Following the completion of the addition, the reaction mixture was stirred for about 20 minutes and the reaction temperature then gradually raised as excess phosgene was purged with a stream of nitrogen. When a reaction temperature of about 85° C. was attained, the reaction mixture became clear. The toluene solvent was then substantially removed under reduced pressure and hexane added to the residue to give the desired 4-((6-chloro-2-pyridinyl)oxy)phenyl isocyanate product as a white crystalline product having a melting point of 96° -97° C.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][N:15]([CH3:29])[C:16]([C:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]=1[CH2:27][CH3:28])=[O:17])[CH:8]=[CH:7]2>C(O)(=O)C>[Br:1][C:5]1[C:4]([OH:3])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([CH2:14][N:15]([CH3:29])[C:16]([C:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]=1[CH2:27][CH3:28])=[O:17])=[CH:10]2
Reactant: CCc1oc2ccccc2c1C(=O)N(C)Cc1ccc2cc(O)ccc2c1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCc1oc2ccccc2c1C(=O)N(C)Cc1ccc2c(Br)c(O)ccc2c1
Reaction time: 8 h
Yield: 95 %

Procedure:
A solution of bromine in 50 mL glacial acetic acid was added dropwise under nitrogen over 3 h to a solution of 2-ethyl-benzofuran-3-carboxylic acid (6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (1.5 g, 4.17 mmol), prepared in the previous step, in 150 mL glacial acetic acid at room temperature. The reaction stirred for 17 h (overnight). The solvent was removed under reduced pressure. The residue was dissolved in methylene chloride, extracted with 5% sodium bicarbonate, dried (MgSO4) and solvent removed under reduced pressure to give 2-ethyl-benzofuran-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (1.74 g, 95%) as a brown solid, mp 176-178° C.
Reaction SMILES: [Br-].[C:2]1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[C:44]([O:50][CH2:51][CH3:52])[CH:43]=2)=O)=[CH:36][C:35]=1[N+:53]([O-:55])=[O:54]>C1COCC1>[CH2:51]([O:50][C:44]1[CH:43]=[C:42]([C:40]([C:37]2[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[C:35]([N+:53]([O-:55])=[O:54])[CH:36]=2)=[CH2:2])[CH:47]=[CH:46][C:45]=1[O:48][CH3:49])[CH3:52]
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1cc(C(=O)c2ccc(OC)c([N+](=O)[O-])c2)ccc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(c1ccc(OC)c(OCC)c1)c1ccc(OC)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 65.1 %

Procedure:
To a stirred suspension of triphenylmethylphosphonium bromide (1.8 g, 5.1 mmol) in THF (30 mL) in an ice bath was added lithium bis(trimethylsilyl)amide (1.0M solution in THF, 5.1 mL, 5.1 mmol) dropwise. The mixture was stirred at room temperature for 40 min. The Wittig reagent was then added slowly to a stirred suspension of (4-methoxy-3-nitro-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanone (1.4 g, 4.2 mmol) in THF (30 mL) in an ice bath. The mixture was stirred at room temperature for 5 hr. The mixture was poured into ice water (100 mL). The aqueous layer was extracted with methyl chloride (4×30 mL). The combined organic layers were washed with water (2×50 mL), brine (50 mL) and dried (MgSO4). Removal of solvent and chromatography (silica gel) gave 1-(3-ethoxy-4-methoxy-phenyl)-1-(3-nitro-4-methoxy-phenyl)-ethene as a solid (0.9 g, 67% yield): 1H NMR (CDCl3) δ 1.44 (t, J=7.2 Hz, 3H, CH3), 3.89 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 4.10 (q, J=7.0 Hz, 2H, OCH2), 5.37 (d, J=9.7 Hz, 2H, CH2), 6.83-6.84 (m, 3H, CH), 7.06(d, J=8.9 Hz, 1H, CH), 7.49-7.54 (dd, J=2.3, 8.9 Hz, 1H, CH), 7.84 (d, J=2.1 Hz, 1H, CH); 13C NMR (CDCl3) δ 14.70, 55.94, 56.56, 64.35, 111.19, 112.74, 113.10, 113.68, 120.80, 125.11, 133.08, 133.66, 134.27, 139.42, 147.24, 148.03, 149.49, 152.30.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O)(=O)C>[Pd].CO>[NH2:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:10]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.7 %

Procedure:
To a solution of 2-fluoro-4-nitrobenzoic acid (1.0 g, 5.4 mmol) in 20 mL of a mixture of acetic acid and methanol (1:1), was added a catalytic amount of palladium on charcoal (25 mg). The reaction was stirred under an atmosphere of hydrogen gas at room temperature overnight. The mixture was then filtered through celite and the solvent was removed by evaporation to yield 0.86 g (100%) of the title compound as a cream coloured solid.