Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:8]([CH2:9][NH:10][C:11](=[O:15])[N:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[C:23](=[O:25])=[O:24]>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]([N:12]([CH3:13])[CH3:14])=[O:15])=[C:16]([CH:17]=1)[C:23]([OH:25])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=O
Reactant: CN(C)C(=O)NCc1ccc(C(C)(C)C)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CN(C)C(=O)NCc1ccc(C(C)(C)C)cc1C(=O)O
Temperature: -70 °C
Yield: 80 %

Procedure:
A 500-mL, three-neck, round-bottomed flask equipped with a magnetic stirrer, addition funnel and thermocouple was purged with nitrogen and charged with 107a (9.36 g, 40.0 mmol) and THF (120 mL). The reaction was cooled to −70° C. and t-butyllithium (1.7 M in pentane, 56 mL, 95.2 mmol) was added dropwise. The reaction was allowed to warm to −45 to −35° C. for 0.5 h and then cooled back down to −78° C. The reaction was then cannulated into a 1-L, three-neck, round-bottomed flask which was filled with ˜100-200 g of dry ice under a flow of nitrogen. The mixture was warmed to room temperature and then concentrated under reduced pressure to dryness. Water (250 mL) and hexanes (250 mL) were added and the solution shaken. The aqueous layer was separated and extracted with methyl t-butyl ether ((150 mL). The aqueous layer was separated and then filtered through Cellpure P65 to clarify it. The aqueous filtrate was acidified with 20 mL of 12.1 M hydrochloric acid and stirred at ambient temperature overnight. After this time, the aqueous solution was decanted off, and the remaining solid was dried overnight under vacuum to afford an 80% yield of 107b (8.91 g) as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 12.97 (br s, 1H), 7.80 (d, 1H, J=2.1 Hz), 7.56 (dd, 1H, J=6.0, 2.1 Hz), 7.32 (d, 1H, J=8.1 Hz), 6.78 (t, 1H, J=5.7 Hz), 4.46 (d, 2H, J=5.7 Hz), 2.82 (s, 6H), 1.28 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:15]([F:16])=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=2[F:17])[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:17][C:10]1[CH:11]=[C:12]([CH:14]=[C:15]([F:16])[C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:22]2[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=2)[CH:7]=1)[NH2:13]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1cc(F)c(Oc2ccnc(Cl)c2)c(F)c1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2cc(Oc3c(F)cc(N)cc3F)ccn2)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
To a solution of 4-(2-chloropyridin-4-yloxy)-3,5-difluoroaniline (3.0 g, 11.7 mmol) in a mixture of N,N-dimethyl-formamide and water (v/v=3:1, 80 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (3.6 g, 17.5 mmol), potassium phosphate (4.9 g, 23.4 mmol) and tetrakis(triphenylphosphine) palladium (0.7 g, 0.6 mmol). The mixture was degassed thoroughly, heated to 100° C. and stirred under nitrogen overnight. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography to give 3,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)aniline (2.6 g, 74% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.36 (d, J=5.6 Hz, 1H), 8.28 (s, 1H), 7.98 (s, 1H), 7.24 (d, J=2.4 Hz, 1H), 6.64 (dd, J=5.6 Hz, J=2.4 Hz, 1H), 6.37 (d, J=10.8 Hz, 2H), 5.81 (s, 2H), 3.87 (s, 3H); MS (ESI): m/z 303.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][S:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:38])=[O:37])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(NS(=O)(=O)c2ccccc2)c1

Procedure:
The title compound was prepared from [4-(3-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and benzenesulfonyl chloride following the procedure of Example 61 as an off-white solid: MS (EI) m/z 533.2 (M+H)+; 1H NMR (DMSO-d6): δ 6.95 (d, J=7.7 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H), 7.05 (s, 1H), 7.20 (t, J=7.9 Hz, 1H), 7.35 (t, J=7.5 Hz, 2H), 7.50-7.70 (m, 9H), 7.76 (t, J=8.2 Hz, 1H), 8.33 (d, J=7.1 Hz, 1H), 9.11 (s, 1H), 10.38 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][C:12]([CH3:14])=O.Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[NH2:8][C:7]1[C:11]([C:10]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:14])[N:1]=[C:2]2[S:3][CH:4]=[C:5]([CH3:9])[C:6]=12
Reactant: Cc1csc(N)c1C#N
Reactant: CCOC(=O)CC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2scc(C)c2c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
A mixture of 2-amino-4-methyl-3-thiophenecarbonitrile (300 mg, 2.171 mmol), ethyl acetoacetate (0.275 mL, 2.171 mmol) and SnCl4 (0.510 mL, 434 mmol) in toluene (15 mL) was stirred at RT for 30 min and then reflux for 3.5 h. After cooling to RT, the mixture was quenched with 6M NaOH (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organics were washed with brine (30 mL), dried and concentrated. Purification by chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in cyclohexane, afforded the title compound (210 mg). LCMS (A) m/z: 251 [M+1]+, Rt 0.77 min (acidic).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.B(O)(O)[C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)cc1
Yield: 74.5 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), p-tolylboronic acid (0.025 g; 0.176 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) furnished 0.051 g (74%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7](O)=O)[CH:3]=1.[NH2:10][C:11]1[C:23]([NH2:24])=[CH:22][C:14]2[N:15]([CH:19]([CH3:21])[CH3:20])[C:16](=[O:18])[NH:17][C:13]=2[CH:12]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH:19]([N:15]1[C:14]2[CH:22]=[C:23]3[C:11](=[CH:12][C:13]=2[NH:17][C:16]1=[O:18])[NH:10][C:7]([C:4]1[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=1)=[N:24]3)([CH3:21])[CH3:20]
Reactant: Cc1cc(C(=O)O)n[nH]1
Reactant: CC(C)n1c(=O)[nH]c2cc(N)c(N)cc21
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: Cc1cc(-c2nc3cc4c(cc3[nH]2)[nH]c(=O)n4C(C)C)n[nH]1

Procedure:
5-Methyl-1H-pyrazole-3-carboxylic acid (126 mg, 1 mmol) and 5,6-diamino-1-isopropyl-1,3-dihydro-benzoimidazol-2-one (206 mg, 1 mmol) were heated to 160° C. in a mixture of polyphosphoric acid (5 g) and phosphorus pentoxide (500 mg, 3.5 mmol) for 6 h. This mixture was poured on water (20 ml) and stirring continued until a precipitate formed. After filtration the crude product was suspended in water and neutralized by the addition of aqueous ammonia (25%). The precipitate was collected, washed with water and dried in vacuo. Purification was achieved by chromatography on silica (dichloromethane/methanol 95:5) yielding 1-isopropyl-6-(5-methyl-1H-pyrazol-3-yl)-3,5-dihydro-1H-benzo[1,2-d;4,5-d′]diimidazol-2-one as slightly yellow solid. Yield 36 mg (12%)
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)=[N:4][C:5]([NH:8][CH2:9][C:10]2ON=[C:12]([CH3:15])[CH:11]=2)=[N:6][CH:7]=1.NCC[C:26]1[O:27]C=CC=1>C(O)CCC>[Br:1][C:2]1[C:3]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][C:11]2[O:27][CH:26]=[CH:15][CH:12]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(CNc2ncc(Br)c(Nc3cc(C)[nH]n3)n2)on1
Reactant: NCCc1ccco1
Solvent: CCCCO
Product: Cc1cc(Nc2nc(NCCc3ccco3)ncc2Br)n[nH]1
Temperature: 120 °C
Yield: 7.3 %

Procedure:
A mixture of 5-bromo-2-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Method 1; 290 mg, 11.0 mmol), 2-(2-aminoethyl)furan (330 mg, 3.0 mmol) and 1-butanol (5 ml) was heated at 120° C. for 5 hours. The mixture was allowed to cool to ambient temperature and the volatiles removed by evaporation. The residue was dissolved in DCM and washed with water followed by brine. The organics were separated, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with ether, the solid product collected and purified by column chromatography on silica gel eluting with DCM/methanol (95:5) to give the titled compound (80 mg, 22%). 1H NMR (DMSO): δ 2.1 (s, 3H), 2.85 (m, 2H), 3.45 (m 2H), 6.10 (m, 1H), 6.35 (m, 1H), 6.4 (br s, 1H), 7.15 (br s, 1H), 7.5 (s, 1H), 8.0 (br s, 2H), 12.05 (br s, 1H); MS: m/z 363.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH:11]2[N:20]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][N:26]=3)[C:18](=[O:19])[C:13]3[N:14]=[CH:15][CH:16]=[N:17][C:12]2=3)=[O:9])[CH2:4][CH2:3]1.C(OC(=O)C(C(C(OC(=O)C1C=CC=CC=1)=O)O)O)(=O)C1C=CC=CC=1>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C@@H:11]2[N:20]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][N:26]=3)[C:18](=[O:19])[C:13]3[N:14]=[CH:15][CH:16]=[N:17][C:12]2=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CN1CCN(C(=O)OC2c3nccnc3C(=O)N2c2ccc(Cl)cn2)CC1
Agent: O=C(OC(=O)C(O)C(O)C(=O)OC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CN1CCN(C(=O)O[C@H]2c3nccnc3C(=O)N2c2ccc(Cl)cn2)CC1

Procedure:
Accordingly, racemic zopiclone is preferably reacted with a resolving agent (+)-O,O′-dibenzoyl tartaric acid in methylene dichloride at room temperature to obtain the diastereomeric salt (Scheme IV) which is crystallized from acetonitrile followed by conversion into eszopiclone by treating with an inorganic base, such as NaOH. Eszopiclone thus obtained has a purity above 99%. Eszopiclone is recrystallized from ethyl acetate to obtain the product with purity of 99.9%
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:13])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH3:12].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][C:16]=1[CH3:24]>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[C:4]([NH2:13])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:17][C:16]=1[CH3:24]
Reactant: COCCOc1ncc(N)cc1Br
Reactant: Cc1cc(B(O)O)ccc1Cl
Product: COCCOc1ncc(N)cc1-c1ccc(Cl)c(C)c1

Procedure:
The title compound was synthesized in analogy to Example E, using 5-bromo-6-(2-methoxy-ethoxy)-pyridin-3-ylamine (example 69 b) and B-(4-chloro-3-methylphenyl)-boronic acid (CAN 161950-10-3) as starting materials; GC/MS (FID/EI): 100%, 292 (M)+.
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5](C(=O)C)([F:14])[CH2:6][CH2:7][C:8]#[C:9][Si](C)(C)C)C.[O-]CC.[Na+].C(O)C.[OH-].[Na+]>C(O)C>[F:14][CH:5]([CH2:6][CH2:7][C:8]#[CH:9])[C:4]([OH:18])=[O:3]
Reactant: CCOC(=O)C(F)(CCC#C[Si](C)(C)C)C(C)=O
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C#CCCC(F)C(=O)O
Reaction time: 18 h
Yield: 101 %

Procedure:
To a solution of 2-acetyl-2-fluoro-6-(trimethylsilyl)-5-hexynoic acid ethyl ester (6.63 g) in ethanol (20 ml) was added 27 ml of 2.65M sodium ethoxide/ethanol. After 18 hours, 7 ml of 4N sodium hydroxide was added. After 6 hours, the solvent was removed by rotary evaporation and the residual materials partitioned between ethyl ether and dilute hydrochloric acid. The organic layer was dried (MgSO4) and the solvent removed by rotary evaporation to give an oil which was vacuum distilled to yield 3.2 g of 2-fluoro-5-hexynoic acid; b.p. 118°/14 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([O:12][CH3:13])=[N:7][C:8]([NH2:11])=[CH:9][CH:10]=1)=[O:4].[Cl:14]Cl>C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([O:12][CH3:13])=[N:7][C:8]([NH2:11])=[C:9]([Cl:14])[CH:10]=1)=[O:4]
Reactant: ClCl
Reactant: COC(=O)c1ccc(N)nc1OC
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)c(N)nc1OC
Yield: 67.3 %

Procedure:
A solution of methyl-6-amino-2-methoxypyridine-3-carboxylate (0.4 g) in acetic acid (10 ml) was treated with a solution of Cl2 (0.19 g) in HOAc (4 ml) at room temperature for 3 h. The AcOH was removed by rotary evaporation and the residue treated with aqueous NaHCO3 (50 mL) and the product extracted into EtOAc (100 mL). Evaporation afforded methyl-6-amino-5-chloro-2-methoxypyridine-3-carboxylate (0.32 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[C:13]=3[CH:22]=2)[CH:5]=[C:4]([F:23])[C:3]=1[C:24]([F:27])([F:26])[F:25].[O-][Mn](=O)(=O)=O.[K+].[N+](=C)=[N-].[C:37](O)(=[O:39])C>O.CO.O1CCCC1.C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([C:17]([CH3:21])([CH3:20])[C:18]([O:39][CH3:37])=[O:19])[C:13]=3[CH:22]=2)[CH:5]=[C:4]([F:23])[C:3]=1[C:24]([F:27])([F:26])[F:25]
Reactant: CC(C)(CO)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Reactant: CC(=O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: C=[N+]=[N-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C(C)(C)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21

Procedure:
A solution of 6-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl) oxy]-β,β-dimethyl-1H-benzotriazole-1-ethanol (2.2 g, 0.00545 mole) in acetic acid and water is stirred at 56°-80° C., treated portionwise with solid KMnO4 (8.5 g, 0.054 mole) over a 3 hour period, cooled and filtered. The filtrate is concentrated in vacuo to give a gum residue. The residue is chromatographed on silica gel with 15% tetrahydrofuran in chloroform to afford a white solid, 1.2 g. The solid is dissolved in methanol, treated with a solution of diazomethane in tetrahydrofuran, heated on a steam bath and concentrated in vacuo to give a solid residue. Chromatography of the residue using silica gel and 5% tetrahydrofuran in carbon tetrachloride as eluant affords the title product as a white solid, 0.65 g, mp 76.8°-80° C., identified by elemental and NMR analyses.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]C)=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[OH-].[Na+].Cl>O.CO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: COC(=O)Cc1ccc(O)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
Methyl 4-hydroxy-3-nitrophenylacetate (21.1 g, 0.1 mol) was suspended in a mixture of water (55 ml) and methanol (105 ml). The suspension was stirred at room temperature while a solution of sodium hydroxide (8.8 g, 0.22 mol) in water (50 ml) was added dropwise over 20 minutes, maintaining the reaction temperature between 20 and 25° C. by water bath cooling. The resultant dark red solution was stirred at room temperature for 15 minutes, diluted with water and acidified to pH1-2 by addition of 2M hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with brine (200 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to give 4-hydroxy-3-nitrophenylacetic acid (19.6 g) as a yellow solid.
Reaction SMILES: COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:10]2)=CC=1.[Si:23]([O:40][CH:41]([CH3:45])[C:42]([NH2:44])=O)([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[Si:23]([O:40][CH:41]([CH3:45])[C:42](=[S:10])[NH2:44])([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(N)=O
Solvent: C1CCOC1
Product: CC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(N)=S
Temperature: 60 °C

Procedure:
A flask containing 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (387 mg, 0.957 mmol) was put under nitrogen atmosphere. 2-(tert-butyldiphenylsilyloxy)propanamide (622 mg, 1.899 mmol) dissolved in dry THF (10 ml) was added, temperature was raised to 60° C. and the mixture was allowed to react for 3 h. The solvent was evaporated and the product was extracted from DCM/water. The product was used in the next step without further purification. LC-MS: [M+1]=344.56.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([O:27][PH:28]([OH:30])=[O:29])[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(Cl)(=O)C(C)(C)C.[Cl-].[NH4+]>C(#N)C.N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([O:27][PH:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C(NCCCCC(O[PH](=O)O)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(NCCCCC(O[PH](=O)OCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
An acetonitrile (29.7 ml) solution of the benzyl 6-benzyloxycarbonylamino-2-((hydroxyphosphinoyl)oxy)hexanoate (2.97 g) obtained in the above step (a) was added with benzyl alcohol (3.53 ml) and a pyridine (11.9 ml)-acetonitrile (11.9 ml) mixed solution of pivaloyl chloride (4.20 ml), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction system, and the organic substances were extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and pyridine was removed by azeotropic distillation using toluene. The residue was roughly purified by silica gel (Kanto Kagaku Co., 60 N, spherical, neutral) chromatography (300 g, hexane:ethyl acetate=3:2) to obtain crude benzyl 6-benzyloxycarbonylamino-2-((benzyloxyphosphinoyl)oxy)hexanoate (2.45 g, 68%). This compound was subjected to the measurement of molecular weight and then used in the following reaction without further purification.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16](O)[CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)=[N:14][CH:15]=1)[CH3:9].[S:28](Cl)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>ClCCl.O>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]([S:28]([C:31]2[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)=[N:14][CH:15]=1)[CH3:9]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCc1ccc(C(COc2ccc(C=O)cc2)S(=O)(=O)c2ccc(C)cc2)nc1
Temperature: 2.5 °C
Reaction time: 4 h

Procedure:
0.44 g (0.0044 mol) triethyl amine was added to a solution of 1 g (0.0036 mol) 4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde and 0.7 g (0.0036 mol) tosyl chloride dissolved in 25 mL dichloromethane at 0-5° C. Reaction mixture was stirred at 0-5° C. for 4 hr. Progress of the reaction was monitored by TLC and after completion of reaction, substantial work-up in excess water yielded the desired product. Yield of the product was 1 g (70%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:16][C:17]1[NH:22][C:21](=[O:23])[C:20]([CH:24]([NH:26][C:27](=[O:37])[CH:28]([CH:34]([OH:36])[CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33])[CH3:25])=[N:19][N:18]=1.C(N(CC)CC)C>ClCCl>[C:34]([CH:28]([CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33])[C:27]([NH:26][CH:24]([C:20]1[C:21](=[O:23])[NH:22][C:17]([CH2:16][C:15]2[CH:38]=[CH:39][C:40]([O:41][CH3:42])=[C:13]([O:12][CH3:11])[CH:14]=2)=[N:18][N:19]=1)[CH3:25])=[O:37])(=[O:36])[CH3:35]
Reactant: C=CCCCC(C(=O)NC(C)c1nnc(Cc2ccc(OC)c(OC)c2)[nH]c1=O)C(C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCCC(C(C)=O)C(=O)NC(C)c1nnc(Cc2ccc(OC)c(OC)c2)[nH]c1=O
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
100 mg (0.76 mmol) of oxalyl chloride in 5 ml of dichloromethane are treated dropwise at −70° C. with 130 mg (1.64 mmol) of dimethyl sulphoxide. The mixture is stirred at −70° C. for 30 min, then 280 mg (0.63 mmol) of N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-2-(1-hydroxyethyl)-6-heptenamide (Example 29A) are added. After a further 30 min, during which the temperature in the batch rises to about −60° C., 320 mg (3.15 mmol) of triethylamine are added and the cooling bath is then removed. If the batch temperature is warmed almost to room temperature, 10 ml of water are added and the phases are separated after stirring briefly. The dried organic phase is chromatographed in dichloromethane/methanol 50/1.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:24])[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1.CN(C)C1C=CC=CC=1.O1CCOCC1>C1(C)C=CC=CC=1.CCCCCCC.C(OCC)(=O)C.O>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH3:24])[C:21]([OH:23])=[O:22])=[CH:18][CH:19]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: CC(C(=O)O)c1ccc(OCCCCCCO)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC(=O)OCCCCCCOc1ccc(C(C)C(=O)O)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 88.5 %

Procedure:
Acrylic acid chloride (74.3 g) was dropped for 10 minutes to a mixture of (4-(6-hydroxyhexyloxy)phenyl)propionic acid (200 g), N,N-dimethylaniline (100 g), BHT (0.3 g), and dioxane (1,000 mL). After stirring at 60° C. for 5 hours, the reaction mixture was poured into water and stirred with addition of ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation from the ethyl acetate layer to obtain solids. The solids were dissolved in toluene and poured into plenty of heptane and re-precipitated to obtain (4-(6-acryloyloxyhexyloxy)phenyl)propionic acid (AK2: 213 g). Melting point: 64° C. to 68° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2ccccc12
Reactant: C=C(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=C(C)C(=O)c1ccc2c(C)cccc2c1
Yield: 58.1 %

Procedure:
1-methylnaphthalene (142 mg), methacryloyl chloride (110 mg), and aluminium chloride (160 mg) were reacted in dichloromethane (1.5 mL) at from −30° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (122 mg).