Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[C:25]([CH2:29][CH2:30][C:31](Cl)=[O:32])([O:27][CH3:28])=[O:26].C([O-])(=O)C.[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([OH:21])[C:31](=[O:32])[CH2:30][CH2:29][C:25]([O:27][CH3:28])=[O:26])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: COC(=O)CCC(=O)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)CCC(=O)N(O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Yield: 24 %

Procedure:
According to the procedure of Example 62, 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-lH-indole-3-methanamine is reacted with 2.1 eq of 3-carbomethoxypropionyl chloride in dioxane/water (1:1) in the presence of sodium acetate (2.5 eq). The crude product is purified by column chromatography (silica gel, 1:4 ethyl acetate:methylene chloride). The resulting product is slurried in ethyl acetate and filtered to give pure 4-[[[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-lH-indol-3-yl]methyl]hydroxyamino]-4-oxo-butanoic acid, methyl ester (24%); mp 157.5°-158° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([OH:14])[CH2:8][CH2:7]2)[CH3:2].[H-].[Na+].Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][N:19]=1>C1COCC1.CCOCC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([O:14][C:18]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=1)[CH2:8][CH2:7]2)[CH3:2]
Reactant: CCOc1ccc2c(c1)CCC(O)C2
Reactant: Clc1ncnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1ccc2c(c1)CCC(Oc1ncnc3ccccc13)C2
Temperature: 25 °C

Procedure:
2.57 g (13.3 mmol) of 6-ethoxytetralin-2-ol in 5 ml of THF were added, with ice-cooling, to a suspension of 400 mg of NaH (80% pure, 13.3 mmol in 40 ml of THF). The mixture was subsequently refluxed for 1 hour and cooled to room temperature, and 2.0 g (12.2 mmol) of 4-chloroquinazoline were added. The mixture was refluxed for 24 hours and cooled and then diluted with ether and washed with saturated sodium hydrogen carbonate and saturated sodium chloride solution. After the organic phase had been dried and concentrated, the residue was chromatographed on silica gel using petroleum ether/ethyl acetate (9:1, 8:2). This gave 2.39 g (61% of theory) of colorless crystals (m.p.115-117° C.).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Reactant: OB(O)c1ccc(Cl)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: C1COCCO1
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(Cl)cc2)cc1
Yield: 3.7 %

Procedure:
The title compound (10.9 mg, 3.2%, white foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (270 mg, 0.803 mmol, prepared in example 1), 4-chlorobenzeneboronic acid (151 mg, 0.966 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol), 2 M sodium carbonate (295 mg in 1.4 mL water) and 1,4-dioxane (5.5 mL) in a manner analogous to the procedure described in Example 2. The crude material was purified utilizing a Chromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solvent system, yielding 115 mg of a co-eluting mixture of unreacted starting material and title compound. This mixture was further purified by reverse phase chromatography on a Vydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45 minutes at 200 mL/min elution rate.
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[NH2:10][OH:11]>CCO>[NH2:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1](=[N:10][OH:11])[NH2:9]
Reactant: N#Cc1ccccc1N
Reactant: NO
Solvent: CCO
Product: NC(=NO)c1ccccc1N
Yield: 90.3 %

Procedure:
Anthranilonitrile (1 g, 8.5 mmol) and hydroxylamine (50% in water, 0.57 cm3, 9.3 mmol, 1.1 eq) in EtOH (42.5 cm3) were stirred under reflux for 24 hours, after which the volatiles were removed under reduced pressure and residue was partitioned between water (5 cm3) and CH2Cl2 (100 cm3). The organic phase was evaporated to dryness in the rotary evaporator followed by high vacuum line to give the product 2-amino-N′-hydroxybenzimidamide (1.16 g, 90.3%) as a solid, mp 85-86° C.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8]P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)([O-])=O>O1CCCC1>[CH:33]1[CH:40]=[CH:39][C:36](/[CH:37]=[CH:8]/[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:29][CH:28]=2)=[CH:35][CH:34]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(C[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In an embodiment of the invention, a method for preparing the aforesaid alignment film in a laboratory level is illustrated as an example. 10 g of 4-nitrobenzyl bromide is mixed with 12 g of triphenylphosphine and dissolved in 150 ml of a dry tetrahydrofuran solution, heated to 75° C. and agitated under reflux for 48 hours, to obtain 8.2 g of a dry white p-nitrobenzyl triphenylphosphine. The p-nitrobenzyl triphenylphosphine is mixed with 2.6 g of p-nitrobenzaldehyde in a 150 ml tetrahydrofuran solution, and agitated under room temperature for about 24 hours to obtain 4.2 g of p-nitrostilbene. The resultant p-nitrostilbene is mixed with 14.7 g of tin dichloride, dissolved in a mixed solution of 30 ml/40% hydrochloride acid and 100 ml acetone, agitated under the room temperature for about 2 hours and refluxed for 8 hours to obtain p-aminostilbene. The p-aminostilbene is mixed with 9,9′-bianthracyl tetracarboxylic dianhydride in a dry NMP (N-methyl-pyrrolidone) solution under agitation for 24 hours, under protection of nitrogen gas, to obtain the precursor of the polyimide alignment film involved in the embodiment. The precursor is heated to 230° C. to obtain the final alignment film, which is a light sensitive alignment film.
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]([CH2:31]Cl)=[CH2:30])[C@@H:9]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[I-:34]>CC(C)=O>[CH2:1]([N:8]([CH2:28][C:29]([CH2:31][I:34])=[CH2:30])[C@@H:9]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: C=C(CCl)CN(Cc1ccccc1)[C@@H](CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C(CI)CN(Cc1ccccc1)[C@@H](CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
A mixture of 1-benzyl 4-tert-butyl(2S)-2-{benzyl[2-(chloromethyl)prop-2-en-1-yl]amino}succinate from step 1b (8.7 g) and NaI (8.0 g) in acetone (100 mL) was stirred at RT overnight. The solid was filtered off and the filtrate concentrated. The residue was treated with methylene chloride and filtered through a pad of silica gel to give 1-benzyl 4-tert-butyl(2S)-2-{benzyl[2-(iodomethyl)prop-2-en-1-yl]amino}succinate (9.2 g). MS (ESI): 550.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][C@:7]([OH:18])([C:15]([OH:17])=O)[CH2:8]2.[CH3:19][Li].Cl>CCOCC.C(Cl)(Cl)Cl>[C:15]([C@@:7]1([OH:18])[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH2:8]1)(=[O:17])[CH3:19]
Reactant: COc1ccc(OC)c2c1CC[C@](O)(C(=O)O)C2
Reactant: [Li]C
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COc1ccc(OC)c2c1CC[C@](O)(C(C)=O)C2

Procedure:
To an ether solution (15 ml) of 12b having an optical purity of 100% (M.P. 117°-120° C.; [α]D20 -37.9° (c=1.01, chloroform)) (670 mg, 2.66 mmole), an ether solution of methyl lithium (0.84 mmole/ml, 33 ml, 28.3 mmole) is gradually added in 1 hour and 20 minutes in an argon stream. The resultant mixture is stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture is slowly poured into dilute hydrochloric acid (conc. hydrochloric acid: water=4:30) (270 ml) under stirring, and after saturation with sodium chloride, extracted with ether (150 ml×2). The ether extracts are combined, washed with a saturated aqueous solution of sodium hydrogen carbonate (20 ml), a 10% aqueous solution of sodium thiosulfate (10 ml) and a saturated aqueous solution of sodium chloride (20 ml) in order and dried over anhydrous magnesium sulfate. After filtration and evaporation, pale yellow needles (615 mg) are obtained. Purification by column chromatography (silica gel, 60 g; ether-hexane (4:1)) affords the objective 13b having an optical purity of 100% as pale yellow needles (420 mg, 63%). M.P. 119°-126° C. [α]D20 -47.4° (c=1.06, chloroform). The product is recrystallized from chloroform-ether to obtain an analytical sample as colorless needles. M.P. 128°-129° C. [α]D20 -48.2° (c=0.982, chloroform). IRνmaxNujol cm-1 : 3480 (OH), 1700 (COCH3). NMR (in CDCl3): 1.87 (2H, broad t, J=6.5 Hz, CH2CH2CCH2), 2.29 (3H, s, COCH3), 2.52-3.02 (4H, m, CH2CH2CCH2), 3.52 (1H, s, OH), 3.76 (3H, s, OCH3), 3.78 (3H, s, OCH3), 6.62 (2H, s, aromatic proton).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH:22][C@@H:23]([CH2:36][NH2:37])[CH2:24][O:25][C:26]1[C:34]2[NH:33][C:32](=[O:35])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1>>[OH:22][C@H:23]([CH2:24][O:25][C:26]1[C:34]2[NH:33][C:32](=[O:35])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1)[CH2:36][NH:37][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Product: CCCCS(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from butane-1-sulfonic acid [4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example 228) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 255 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.83(t, J=7.2 Hz, 3 H), 1.20–1.70 (m, 6 H), 1.95–2.10 (m, 2 H), 2.67 (brt, J=11.7 Hz, 2 H), 2.70–3.20 (m, 7 H), 3.62–3.75 (m, 2 H), 3.95–4.10 (m, 3 H), 6.59 (d, J=7.5 Hz, 1 H), 6.63 (d, J=8.0 Hz, 1 H), 6.80–7.00 (m, 3 H), 7.06 (d, J=9.0 Hz, 2 H), 9.32 (brs, 1 H), 10.61 (brs, 1 H), 10.73 (brs, 1 H); MS (ES) m/z: 518.1 (MH+); HRMS Calcd. for C25H36N5O5S (MH+): 518.2437. Found: 518.2452.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[C:13]([C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:18]=1)([CH3:16])([CH3:15])[CH3:14].[NH2:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([O:41][C:42]2[CH:47]=[CH:46][N:45]=[C:44]([NH:48][C:49](=[O:53])[CH2:50][O:51][CH3:52])[CH:43]=2)=[CH:33][CH:32]=1.CO>C(Cl)Cl>[C:13]([C:17]1[CH:21]=[C:20]([NH:22][C:6](=[O:7])[NH:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]([O:41][C:42]3[CH:47]=[CH:46][N:45]=[C:44]([NH:48][C:49](=[O:53])[CH2:50][O:51][CH3:52])[CH:43]=3)=[CH:33][CH:32]=2)[N:19]([C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[N:18]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: COCC(=O)Nc1cc(Oc2ccc(N)c3ccccc23)ccn1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CO
Product: COCC(=O)Nc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Reaction time: 16 h
Yield: 44.5 %

Procedure:
To a stirred suspension of CDI (28.8 g, 178 mmol) in DCM (250 mL) at RT, under nitrogen, was added 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (7) (40.7 g, 178 mmol) portion-wise over 1 hr. After 1 hr the resulting dark red solution was added dropwise, over 1 hr, to a stirred solution of N-(4-(4-aminonaphthalen-1-yloxy)pyridin-2-yl)-2-methoxyacetamide (12) (35.5 g, 99 mmol) in DCM (1 L). After 1 hr MeOH (100 mL) was added and the mixture was kept at RT for 16 hr. The reaction mixture was evaporated in vacuo and the residue was taken up into DCM (500 mL) and was washed with water and saturated aqueous NaHCO3 solution (500 mL). The organic layer was dried (MgSO4), evaporated in vacuo and the residue purified by flash column chromatography (SiO2, 800 g, 2% MeOH in DCM, isocratic elution). This product was recrystallized from ethyl acetate/heptane (800 mL of a 5:3 v/v mixture) to afford N-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-methoxyacetamide (1) (25.5 g, 45%) as a white powder. Found: C, 68.41; H, 5.93; N, 14.36; C33H34N6O4 requires: C, 68.49; H, 5.92; N, 14.52%.
Reaction SMILES: [I-].[CH2:2]([O:4][C:5]([C@@:7]1([NH:12][C:13](N2C=C[N+](C)=C2)=[O:14])[CH2:9][C@H:8]1[CH:10]=[CH2:11])=[O:6])[CH3:3].[CH2:21]([N:29]([CH3:38])[C:30]([C@@H:32]1[CH2:36][C@@H:35]([OH:37])[CH2:34][NH:33]1)=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH:27][CH3:28].C(OC([C@@]1(NC(N2C[C@H](O)C[C@H]2C(=O)N(CCCCC=C)C)=O)C[C@@H]1C=C)=O)C>>[CH2:2]([O:4][C:5]([C@@:7]1([NH:12][C:13]([N:33]2[CH2:34][C@H:35]([OH:37])[CH2:36][C@H:32]2[C:30](=[O:31])[N:29]([CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH3:28])[CH3:38])=[O:14])[CH2:9][C@@H:8]1[CH:10]=[CH2:11])=[O:6])[CH3:3]
Reactant: CC=CCCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)n1cc[n+](C)c1)C(=O)OCC
Agent: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)N[C@]1(C(=O)OCC)C[C@@H]1C=C
Agent: [I-]
Product: C=C[C@H]1C[C@]1(NC(=O)N1C[C@H](O)C[C@H]1C(=O)N(C)CCCCC=CCC)C(=O)OCC
Yield: 48 %

Procedure:
Compound 72b was synthesized from compounds 34 and 71b as a beige solid in 48% yield, following the procedure as described for compound 50.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C([O-])(O)=O.[Na+].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.O1CCOCC1.CCOC(C)=O>[CH2:13]([O:20][C:21]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Piperazin-2-one (2.00 g, 20.0 mmol) was dissolved in H2O (10 ml)-1,4-dioxane (10 ml); and NaHCO3 (1.85 g, 22.0 mmol) and benzylchloroformate (3.42 g, 20.0 mmol) was added thereto. After stirring at room temperature for 13 h, the reaction mixture was diluted with H2O and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with brine, dried over MgSO4. The desiccant was removed through filtration and the filtrate was concentrated under reduced pressure to obtain crude 3-Oxo-piperazine-1-carboxylic acid benzyl ester as pale brown oil. This oil was used for the next step without further purification. The crude 3-Oxo-piperazine-1-carboxylic acid benzyl ester was dissolved in DMF (40 ml) and NaH (55% in oil, 1.05 g, 24.0 mmol) and SEMCl (5.01 g, 30.0 mmol) was added thereto at room temperature. After stirring at 50° C. for 18 h, the reaction mixture was diluted with EtOAc. The mixture was washed with H2O and brine, dried over MgSO4. The desiccant was removed through filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc=8/2 to 5/5, to obtain the intended compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.CO[C:15](OC)([CH3:17])[CH3:16].B(F)(F)F.CCOCC.C(N(CC)CC)C>CC(C)=O>[OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]2[O:10][C:15]([CH3:17])([CH3:16])[O:8][C:7]2=[O:9])=[CH:4][CH:3]=1
Reactant: COC(C)(C)OC
Reactant: O=C(O)C(O)c1ccc(O)cc1
Agent: FB(F)F
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC1(C)OC(=O)C(c2ccc(O)cc2)O1
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution of commercial 4-hydroxy-mandelic acid (10.0 gr, 0.05 mol) in acetone (160 ml), 2,2-dimethoxypropane (56 mL, 0.45 mol) and BF3.Et2O (0.4 ml, 0.48 mol)) were added under vigorous stirring. The solution was left stirring for 3 hours. After adding of triethylamine (TEA) (2 mL), the solvent was evaporated under vacuum and the crude diluted in a saturated solution of Na2HCO3 (30 ml) and extracted with EtOAc (3×30 ml). The collected organic extracts were washed with brine (2×25 mL), dried over Na2SO4 and evaporated under vacuum to give the intermediate 5-(4-hydroxyphenyl)-2,2-dimethyl-1,3-dioxolan-4-one (10.21 g) as yellow oil, pure enough to be used in the further step without any purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[CH3:9].Br[C:36]1[CH:41]=[CH:40][C:39]([CH:42]([CH2:46][CH3:47])[C:43]([OH:45])=[O:44])=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11]([NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:36]2[CH:41]=[CH:40][C:39]([CH:42]([CH2:46][CH3:47])[C:43]([OH:45])=[O:44])=[CH:38][CH:37]=2)=[CH:20][CH:19]=1)=[O:34])[CH3:9]
Reactant: CCC(C(=O)O)c1ccc(Br)cc1
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl
Product: CCC(C(=O)O)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3Cl)cc2)cc1

Procedure:
Prepared as described in Example 36, Step 6 using {3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester and 2-(4-bromophenyl)butanoic acid.
Reaction SMILES: [CH2:1]([O:3]C(Cl)=O)C.[Cl:7][C:8]1[CH:9]=[C:10]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[O:11][C:12]1[C:13]([CH2:24][CH3:25])=[N:14][N:15]([CH2:19][C:20](=[NH:23])[NH:21][OH:22])[C:16]=1[CH2:17][CH3:18]>N1C=CC=CC=1.O1CCCC1.[OH-].[Na+].Cl>[Cl:7][C:8]1[CH:9]=[C:10]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[O:11][C:12]1[C:13]([CH2:24][CH3:25])=[N:14][N:15]([CH2:19][C:20]2[N:23]=[C:1]([OH:3])[O:22][N:21]=2)[C:16]=1[CH2:17][CH3:18]
Reactant: CCc1nn(CC(=N)NO)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCc1nn(Cc2noc(O)n2)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.2 %

Procedure:
Ethylchloroformate (0.30 ml, 3.08 mmol) was added to a stirred solution of the amidoxime of Example 8 (500 mg, 1.39 mmol) in pyridine (8 ml) at 0° C. under nitrogen and the resulting solution was stirred for 10 minutes. The mixture was concentrated under reduced pressure and the residue was dissolved in a mixture of water (4 ml), tetrahydrofuran (4 ml) and 1M aqueous sodium hydroxide solution (2 ml). The mixture was heated under reflux for 1 hour, cooled to room temperature and stirred for a further 2 days. The resulting solution was diluted with 2M aqueous hydrochloric acid (20 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (50 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to leave a yellow oil. The oil was purified by flash column chromatography on silica gel eluting with pentane:ethyl acetate (50:50, by volume) to yield a white solid. The solid was dissolved in a mixture of tetrahydrofuran (1 ml) and 1M aqueous sodium hydroxide solution (10 ml) and then heated under reflux for 24 hours. The resulting solution was diluted with 2M hydrochloric acid (20 ml) and extracted with dichloromethane (2×50 ml). The combined organic layers were washed with brine (50 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to give the title compound (113 mg) as a white solid m.p. 94-96° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:14]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1>C(O)C.O1CCOCC1.ClCCl>[Cl:1][C:2]1[C:3]([CH:14]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)(=[O:25])=[O:24])[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1
Reactant: COC(=O)/C=C/c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Solvent: ClCCl
Solvent: CCO
Solvent: C1COCCO1
Product: COC(=O)CCc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
A Raney nickel suspension (“R-100”, product of Nikko Rika Corporation) was washed sequentially with water and ethanol to give a corresponding ethanol suspension. The resulting ethanol suspension (2 ml) was added to a solution of methyl(E)-3-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]acrylate (770 mg, 1.55 mmol) in a mixture of ethanol (10 ml) and 1,4-dioxane (5 ml). Under a hydrogen atmosphere of 1 atmospheric pressure, the resulting mixture was stirred vigorously for 30 minutes. After the reaction mixture was filtered, the filtrate was concentrated under reduced pressure. The residue thus obtained was dissolved in dichloromethane (15 ml). The resulting solution was dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (720 mg, 1.44 mmol, 93%) as a white powder.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1(=O)[O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[C:16]([O-])(=O)C=C>>[CH2:4]1[CH2:5][CH2:6][C:1]([OH:7])([C:13]([C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:16]=2)=[O:14])[CH2:2][CH2:3]1
Reactant: C=CC(=O)[O-]
Reactant: O=C1CCCCC1
Reactant: O=C1CCCCCO1
Product: O=C(c1ccccc1)C1(O)CCCCC1

Procedure:
10 Parts by mass of cyclohexanone, 95 parts by mass of partially caprolactone-modified polyfunctional acrylate (DPCA-20, produced by Nippon Kayaku Co., Ltd.), and 5 parts by mass of a photopolymerization initiator (Irgacure 184, produced by Ciba Specialty Chemicals Corp.) were added to 90 parts by mass of methyl ethyl ketone (MEK). The resulting mixture was stirred and then filtered through a polypropylene-made filter having a pore size of 0.4 μm to prepare Coating Solution (HCL-1) for Hardcoat Layer.
Reaction SMILES: ClC1N=NC(Cl)=[C:4]2[CH:9]=[N:10][C:11](C3C=CC(O)=CC=3)=[CH:12][C:3]=12.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:51]=[CH:50][C:43]3=[C:44](Cl)[N:45]=[N:46][C:47](Cl)=[C:42]3[CH:41]=2)=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:51]=[CH:50][C:43]3=[C:44]([N:10]4[CH2:11][CH2:12][CH2:3][CH2:4][CH2:9]4)[N:45]=[N:46][C:47]([N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[C:42]3[CH:41]=2)=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Oc1ccc(-c2cc3c(Cl)nnc(Cl)c3cn2)cc1
Reactant: Clc1nnc(Cl)c2cc(-c3ccc(OCc4ccccc4)cc3)ncc12
Reactant: C1CCNCC1
Product: c1ccc(COc2ccc(-c3cc4c(N5CCCCC5)nnc(N5CCCCC5)c4cn3)cc2)cc1

Procedure:
In a procedure similar to (1) in Example 2, 7.0 g. of piperidine instead of morpholine is reacted with 1.7 g. of 7-(4-benzyloxyphenyl)-1,4-dichloropyrido(3,4-d)pyridazine, whereby 1.2 g. of 7-(4-benzyloxyphenyl)-1,4-dipiperidinopyrido(3,4-d)pyridazine is obtained.