Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Br:16][C:17]1[CH:29]=[CH:28][C:20]([O:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[Br:16][C:17]1[CH:29]=[CH:28][C:20]([O:21][CH:22]2[CH2:23][CH2:24][N:25]([C:13]([CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)=[O:14])[CH2:26][CH2:27]2)=[CH:19][CH:18]=1
Reactant: Brc1ccc(OC2CCNCC2)cc1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCN(c2ccncc2)CC1)N1CCC(Oc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.4 %

Procedure:
A suspension of 1-(4-pyridyl)piperidine-4-carbonyl chloride (0.94 g) in dichloromethane (20 ml) was added slowly to a stirred solution of 4-(4-bromophenoxy)piperidine (1.0 g) and triethylamine (1.09 ml) in dichloromethane (10 ml) at 5° C. under an atmosphere of argon. The mixture was stirred at ambient temperature for 16 hours, and then the solvent was removed by evaporation. The residue was triturated with water. The resulting solid was collected by filtration and recrystallised from ethanol (10 ml) to give 4-(4-bromophenoxy)-1-[1-[4-pyridyl]piperidin-4-ylcarbonyl]piperidine (0.58 g) as an off-white solid, m.p. 127-130° C.;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:5]([C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=1)[O:1][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:6])[NH2:7]
Reactant: CCOC(=O)CBr
Reactant: NC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc(C(N)=O)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of 3-hydroxybenzamide (300 mg, 2.19 mmol) in MeCN (5 mL) was added ethyl bromoacetate (545 mg, 3.29 mmol) and K2CO3 (907 mg, 6.57 mmol). The mixture was stirred at 80° C. for 4 hours. The mixture was filtered and the filtrate concentrated. The residue was directly for the next step. LCMS (m/z): 224.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[C:4]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[S:26][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[F:33])=[N:24][CH:23]=3)[CH2:17][CH2:16]2)=[O:12])[CH:3]=1.[CH:34]([OH:37])([CH3:36])[CH3:35]>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:37][CH:34]([CH3:36])[CH3:35])[N:5]=[C:4]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[S:26][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[F:33])=[N:24][CH:23]=3)[CH2:17][CH2:16]2)=[O:12])[CH:3]=1
Reactant: N#Cc1c(N)cc(C(=O)NCC2CCN(Cc3cnc(-c4ccccc4F)s3)CC2)nc1Cl
Reactant: CC(C)O
Product: CC(C)Oc1nc(C(=O)NCC2CCN(Cc3cnc(-c4ccccc4F)s3)CC2)cc(N)c1C#N

Procedure:
According to the same procedure described in Example 204, using the compound prepared in Example 393 instead of the compound prepared in Example 215 and isopropanol instead of 1-cyclopropylethanol, the title compound having the following physical data was obtained.
Reaction SMILES: CS[C:3]([C:5]1[NH:6][C:7]([Cl:11])=[C:8]([Cl:10])[N:9]=1)=[O:4].[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C(O)C>[C:12]1([NH:18][NH:19][C:3]([C:5]2[NH:6][C:7]([Cl:11])=[C:8]([Cl:10])[N:9]=2)=[O:4])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CSC(=O)c1nc(Cl)c(Cl)[nH]1
Reactant: NNc1ccccc1
Solvent: CCO
Solvent: O
Product: O=C(NNc1ccccc1)c1nc(Cl)c(Cl)[nH]1
Yield: 49.8 %

Procedure:
21.1 g (0.1 mol) of 4,5-dichloro-imidazole-2-thiocarboxylic acid S-methyl ester were boiled with 10.8 g (0.1 mol) of phenylhydrazine in 150 ml of ethanol for 4 hours under reflux. The cooled reaction mixture was mixed with 500 ml of water and the crystals which had separated out were filtered off and dried. 13.5 g (50% of theory) of 4,5-dichloro-imidazole-2-carboxylic acid N'-phenyl-hydrazide with a melting point of 229°-230° C. (from ethyl acetate) were obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.Br[CH2:13][C:14](=[N:19][OH:20])[C:15]([O:17][CH3:18])=[O:16]>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]23[CH2:11][CH2:10][CH2:9][CH:8]2[CH2:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[N:19][O:20]3)[CH2:3][CH2:2]1
Reactant: COC(=O)C(CBr)=NO
Reactant: C1CCC(N2CCOCC2)C1
Product: COC(=O)C1=NOC2(N3CCOCC3)CCCC2C1
Yield: 70.8 %

Procedure:
4.6 g (30 mmol) of morpholinocyclopentane are reacted with 1.75 g (10 mmol) of methyl 3-bromohydroxyiminopropionate by following the method of Example 1(a). 1.9 g of a colorless oil are obtained.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl.[NH2:29][OH:30]>>[OH:30][NH:29][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([CH:18]2[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[NH:27]
Reactant: NO
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC(C2CCN(C#N)CC2)C3)CC1
Agent: Cl
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC(C2CCN(C(=N)NO)CC2)C3)CC1

Procedure:
The title compound is prepared from 4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridine-2-yl]-piperidine-1-carbonitrile and hydroxylamine hydrochloride following a procedure analogous to that described for Intermediate 11. LC (method 5): tR=0.54 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:54])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH2:29]CCS(C)(=O)=O)[CH2:25][CH2:24]3)=[O:22])[C:10]([C:36]3[C:37]([O:51][CH2:52][CH3:53])=[CH:38][C:39]([Cl:50])=[C:40]([S:42]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:44])=[O:43])[CH:41]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:55][O:56][C:57]([C@@H]1CNCCN1C)=[O:58]>>[CH3:55][O:56][C:57]([C@@H:25]1[CH2:24][N:23]([C:21]([N:11]2[C@@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[C@@:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH3:54])[N:9]=[C:10]2[C:36]2[CH:41]=[C:40]([S:42](=[O:44])(=[O:43])[NH:45][C:46]([CH3:48])([CH3:49])[CH3:47])[C:39]([Cl:50])=[CH:38][C:37]=2[O:51][CH2:52][CH3:53])=[O:22])[CH2:28][CH2:27][N:26]1[CH3:29])=[O:58]
Reactant: COC(=O)[C@@H]1CNCCN1C
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1
Product: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)[C@H](C(=O)OC)C1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(5-tert-butylsulfamoyl-4-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 45) was reacted with (S)-1-methyl-piperazine-2-carboxylic acid methyl ester to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C37H45N5O6SCl3 [(M+H)+] 792.2151, observed 792.2148.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:15])[N:3]=1.[H-].[Na+].[N:18]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1CCCCC1>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([O:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:3]=[C:4]([CH3:15])[N:5]=2)=[CH:9][CH:10]=1
Reactant: OCCCCCN1CCCCC1
Reactant: Cc1nc(Cl)cc(-c2ccc(F)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCCCC1
Product: Cc1nc(OCCCCCN2CCCCC2)cc(-c2ccc(F)cc2)n1

Procedure:
13.8 kg of 4-chloro-6-(4-fluorophenyl)-2-methylpyrimidine, 4.8 kg of 60% sodium hydride, 130 kg of cyclohexane and 10.6 kg of 5-piperidino-1-pentanol were stirred under reflux for 4 hours.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O1CCOCC1.Cl[C:14]1[C:19]([N:20]2[N:24]=[CH:23][CH:22]=[N:21]2)=[CH:18][C:17]([N+:25]([O-:27])=[O:26])=[CH:16][N:15]=1>O>[N+:25]([C:17]1[CH:18]=[C:19]([N:20]2[N:24]=[CH:23][CH:22]=[N:21]2)[C:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[N:15][CH:16]=1)([O-:27])=[O:26]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cnc(Cl)c(-n2nccn2)c1
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnc(N2CCOCC2)c(-n2nccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Morpholine (0.5 ml) was added to a 1,4-dioxane solution (1 ml) containing 2-chloro-5-nitro-3-(2H-1,2,3-triazol-2-yl)pyridine (30 mg), followed by stirring at room temperature for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and a yellow solid of 5-nitro-2-morpholino-3-(2H-1,2,3-triazol-2-yl)pyridine (33 mg) was thus obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([O:19]C(=O)C)[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([OH:19])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)c(OC(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCOC(=O)c1ccc(OCc2ccccc2)c(O)c1
Reaction time: 2 h

Procedure:
The compound of step 1 (10 g, 31.8 mmol) was dissolved in methanol, potassium carbonate (88 mg, 0.636 mmol) was added and the mixture was stirred for 2 h under reflux. After evaporation to dryness, the residue was used without further purification in the subsequent step.
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=1)(=O)[CH3:2].[OH:20][CH2:21]CCO.S(=O)(=O)(O)O>O>[C:14]1([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([O:4][CH2:1][CH2:2][CH2:21][OH:20])=[CH:6]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCCO
Reactant: CC(=O)Oc1cn(-c2ccccc2)c2ccccc12
Agent: O=S(=O)(O)O
Solvent: O
Product: OCCCOc1cn(-c2ccccc2)c2ccccc12
Temperature: 80 °C

Procedure:
A mixture of 3-acetyloxy-1-phenylindole (24 g), 1,3-dihydroxypropane (240 ml), and conc. sulfuric acid (10 ml) was heated to 80° C. for 2 h. Water was added followed by extraction with ether. The ether phase was dried over magnesium sulfate followed by removal of solvent in vacuo giving 3-(1-phenyl-3-indolyloxy)-1-propanol, sufficiently pure for use in the next step.
Reaction SMILES: CO.[O:3]1CCCC1.[CH3:8][C:9]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([S:23][CH3:24])[CH:18]=3)[NH:13][C:12]=2[N:11]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:10]=1.I([O-])(=O)(=O)=O.[Na+]>O>[CH3:8][C:9]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([S:23]([CH3:24])=[O:3])[CH:18]=3)[NH:13][C:12]=2[N:11]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:10]=1
Reactant: C1CCOC1
Reactant: CSc1ccc2[nH]c3c(c(C)nn3-c3ccccn3)c(=O)c2c1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: Cc1nn(-c2ccccn2)c2[nH]c3ccc(S(C)=O)cc3c(=O)c12
Temperature: 25 °C
Yield: 61 %

Procedure:
A solution in a mixed solvent of methanol (40 mL), tetrahydrofuran (10 mL) and water (10 mL) of 3-methyl-6-(methylsulfanyl)-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one (1.00 g, 3.10 mmol) and sodium periodate (0.66 g, 3.10 mmol) was heated under reflux for 2 hours. The solution was allowed to cool to room temperature, and concentrated under reduced pressure. The residue was poured into water, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform to chloroform:methanol=98:2) to give the title compound (0.63 g, 61% yield).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.[CH3:29][N:30]1[C:34](=[O:35])[N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:32]([C:44]2[CH:49]=[CH:48][C:47](B3OC(C)(C)C(C)(C)O3)=[CH:46][CH:45]=2)=[N:31]1>>[CH3:29][N:30]1[C:34](=[O:35])[N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:41])[CH3:42])[C:32]([C:44]2[CH:45]=[CH:46][C:47]([C:2]3[N:6]4[N:7]=[CH:8][CH:9]=[C:10]([N:11]5[CH2:16][CH2:15][O:14][CH2:13][CH2:12]5)[C:5]4=[N:4][C:3]=3[CH2:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:48][CH:49]=2)=[N:31]1
Reactant: Brc1c(CCc2ccc3ccccc3n2)nc2c(N3CCOCC3)ccnn12
Reactant: Cn1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)n(COCC[Si](C)(C)C)c1=O
Product: Cn1nc(-c2ccc(-c3c(CCc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cc2)n(COCC[Si](C)(C)C)c1=O

Procedure:
Compound 46a was subjected to Suzuki coupling conditions with compound 51d as described in Example 38, Step A to obtain compound 51e as a light yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C36H42N8O3Si: 663.3 (M+H). Found: 663.4.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.CC1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N+:10]=1[O-].[OH-].[Na+].ClCCl>O>[CH3:15][C:12]1[CH:13]=[CH:14][C:6]([CH2:5][OH:7])=[N:10][CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(C)[n+]([O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(CO)nc1
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
To acetic anhydride (1.61 L) at 90° C. was added 2,5-dimethyl-pyridine 1-oxide (1000 g) dropwise over 3 hours, maintaining a temperature between 90-100° C. The reaction was stirred at 90° C. for 1.5 hours, and then cooled with stirring overnight. The mixture was slowly poured into aqueous 25% sodium hydroxide (3 L) over 4 hours, and then dichloromethane (8 L) and water (8 L) were added, and the mixture was allowed to separate for 2 days. The aqueous layer was separated and extracted separately with dichloromethane and ethyl acetate, and the combined organic layers were concentrated to dryness. The crude material was applied to the top of a pad of silica (˜1 kg) and eluted with ethyl acetate until no product was observed in the eluant. The filtrate was concentrated under vacuum to give the desired product (320 g).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[NH:21][C:20](=[O:23])[CH:19]=[CH:18]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:24]O>>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[NH:21][C:20](=[O:23])[CH:19]=[CH:18]3)=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: O=c1ccc2cccc(OCCCCSc3ccccc3)c2[nH]1
Product: O=c1ccc2cccc(OCCCCS(=O)c3ccccc3)c2[nH]1

Procedure:
Prepared analogous to Example 88 from 8-(4-phenylmercapto-butoxy)-carbostyril by oxidation with hydrogen peroxide.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[C:12]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21](F)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1.Cl.Cl.[CH3:41][N:42]([CH3:47])[CH:43]1[CH2:46][NH:45][CH2:44]1.CN(C)C1CNC1>CC(N(C)C)=O>[Cl:10][C:11]1[C:12]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([N:45]3[CH2:46][CH:43]([N:42]([CH3:47])[CH3:41])[CH2:44]3)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1
Reactant: CN(C)C1CNC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 102.7 %

Procedure:
DIPEA (0.341 mL, 1.96 mmol) was added to a mixture of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 20, 254 mg, 0.61 mmol) and N,N-dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 106 mg, 0.61 mmol) in DMA (4 mL) and the mixture was heated to 100° C. for 0.5 h. Further N,N-dimethylazetidin-3-amine (35 mg, 0.19 mmol) was then added and the mixture was heated at 100° C. for a further 2 h and was then left at r.t. overnight. The mixture was purified directly by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M methanolic ammonia and was concentrated in vacuo onto silica. Purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 gave the title compound (310 mg, 102%) as an orange solid, which was used without further purification; 1H NMR: 2.14 (6H, s), 3.08-3.18 (1H, m), 3.76 (2H, dd), 3.89 (3H, s), 4.02-4.11 (2H, m), 6.28 (1H, s), 7.12 (1H, td), 7.30-7.39 (1H, m), 8.12 (1H, s), 8.37 (1H, br s), 8.42 (1H, s), 8.68 (1H, s), 8.83 (1H, d), 8.94 (1H, d); m/z: ES+ MH+ 495.56.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=2)[NH:8][C:7](=[O:20])[C:6]1=[O:21].CI.[C:29](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=2)[N:8]([CH3:29])[C:7](=[O:20])[C:6]1=[O:21]
Reactant: CCOC(=O)c1ccc2[nH]c(=O)c(=O)n(Cc3ccc(Cl)cc3Cl)c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)c1ccc2c(c1)n(Cc1ccc(Cl)cc1Cl)c(=O)c(=O)n2C
Yield: 90.1 %

Procedure:
A mixture of 1-(2,4-dichlorobenzyl)-7-(ethoxycarbonyl)quinoxaline-2,3-dione (0.90 g), methyl iodide (0.49 g) and potassium carbonate (0.63 g) in acetone (20 ml) was heated under reflux for 2 hr. After cooling, the reaction mixture was concentrated. The residue was washed with water (150 ml) and methyl t-butyl ether (100 ml) and dried to give the object compound (0.84 g) as white crystals.
Reaction SMILES: [OH:1][CH:2]([CH2:5][C@H:6]1[CH2:17][CH2:16][C:15]2[S:14][C:13]3[N:12]=[CH:11][N:10]=[C:9]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH2:21][CH2:20]4)[C:8]=3[C:7]1=2)[C:3]#[N:4].[CH3:31][C:32]([Si:35](Cl)([CH3:37])[CH3:36])([CH3:34])[CH3:33].N1C=CN=C1>ClCCl.CN(C)C1C=CN=CC=1.O>[Si:35]([O:1][CH:2]([CH2:5][C@H:6]1[CH2:17][CH2:16][C:15]2[S:14][C:13]3[N:12]=[CH:11][N:10]=[C:9]([O:18][CH:19]4[CH2:20][CH2:21][CH:22]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH2:23][CH2:24]4)[C:8]=3[C:7]1=2)[C:3]#[N:4])([C:32]([CH3:34])([CH3:33])[CH3:31])([CH3:37])[CH3:36]
Reactant: N#CC(O)C[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(C#N)C[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
A 100-mL round-bottom flask was charged with a solution of 2-hydroxy-3-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanenitrile (290 mg, 0.68 mmol, 1.00 equiv) in dichloromethane (10 mL). TBSCl (153 mg, 1.02 mmol, 1.51 equiv), imidazole (92 mg, 1.35 mmol, 2.00 equiv) and 4-dimethylaminopyridine (17 mg, 0.14 mmol, 0.21 equiv) were added successively at 0° C. under nitrogen. The resulting mixture was stirred overnight at room temperature. After completion, the resulting solution was diluted with water, extracted with 3×30 mL of dichloromethane, dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel with ethyl acetate/petroleum ether (1:1) to afford the desired 2-[(tert-butyldimethylsilyl)oxy]-3-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-3-yl]propanenitrile (350 mg, 95%) as a yellow oil. MS (ES): m/z 543 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:27]=[CH:26][C:18](/[CH:19]=[CH:20]/[C:21](=[O:25])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1.[CH2:28](O)[CH3:29].S(=O)(=O)(O)O>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:27]=[CH:26][C:18](/[CH:19]=[CH:20]/[C:21](=[O:25])[C:22]([O:24][CH2:28][CH3:29])=[O:23])=[CH:17][CH:16]=1
Reactant: CCO
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(/C=C/C(=O)C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C(=O)/C=C/c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Yield: 86 %

Procedure:
To a mixture of (E)-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylidenepyruvic acid (1.3 g) and ethanol (50 ml) was added conc. sulfuric acid (0.1 ml). The mixture was heated for 8 hours under reflux, then the reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), followed by distilling off the solvent. The residue was subjected to a silica gel column chromatography. From the fractions eluted with ethyl acetate-hexane (1:3, v/v), ethyl (E)-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylidenepyruvate (1.2 g, 86%) was obtained. Recrystallization from ethyl acetate-hexane gave pale yellow prisms. Melting point: 110-111° C.
Reaction SMILES: [CH2:1]1[CH:23]2[NH:24][CH:3]([CH:4](C3C=CC(C(O)=O)=CC=3)[CH:5]3[NH:9][CH:8]([CH:10](C4C=CC(C(O)=O)=CC=4)[CH:11]4[NH:15][CH:14]([CH:16](C5C=CC(C(O)=O)=CC=5)[CH:17]5[NH:21][CH:20]([CH:22]2C2C=CC(C(O)=[O:32])=CC=2)[CH:19]=[CH:18]5)[CH2:13][CH2:12]4)[CH:7]=[CH:6]3)[CH2:2]1.[O-2:61].[O-2].[Ti+4:63].C1(C)C(C)=CC=CC=1>C(O)CCC>[C:5]12[CH:4]=[C:3]3[N:24]=[C:23]([CH:1]=[CH:2]3)[CH:22]=[C:20]3[NH:21][C:17]([CH:18]=[CH:19]3)=[CH:16][C:14]3=[N:15][C:11]([CH:12]=[CH:13]3)=[CH:10][C:8]([NH:9]1)=[CH:7][CH:6]=2.[O-2:32].[Ti+4:63].[O-2:61]
Reactant: O=C(O)c1ccc(C2C3C=CC(N3)C(c3ccc(C(=O)O)cc3)C3CCC(N3)C(c3ccc(C(=O)O)cc3)C3C=CC(N3)C(c3ccc(C(=O)O)cc3)C3CCC2N3)cc1
Agent: [Ti+4]
Agent: [O-2]
Solvent: Cc1ccccc1C
Solvent: CCCCO
Product: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3

Procedure:
An invented undercoat layer dispersion was prepared as follows: a porphine/titanium oxide/phenolic resin/melamine resin dispersion was prepared by ball milling 0.25 grams of meso-Tetraphenylporphine-4,4′,4″,4′″-tetracarboxylic acid (commercially available from Frontier Scientific, Inc., Logan, Utah), 15 grams of titanium dioxide (MT-150W, Tayca Company), 8 grams of the phenolic resin (VARCUM 29159, OxyChem Company, Mw of about 3,600, viscosity of about 200 cps) and 7.5 grams of the melamine resin (CYMEL 323, CYTEC) in 7.5 grams of 1-butanol, and 7.5 grams of xylene with 120 grams of 1 millimeter diameter sized ZrO2 beads for 5 days. The resulting titanium dioxide dispersion was filtered with a 20 micrometer pore size nylon cloth, and then the filtrate was measured with HORIBA CAPA 700 Particle Size Analyzer, and there was obtained a median TiO2 particle size of 50 nanometers in diameter and a TiO2 particle surface area of 30 m2/gram with reference to the above Porphine/TiO2/VARCUM/CYMEL dispersion. 0.5 grams of methyl ethyl ketone were added into the dispersion to obtain the coating dispersion. An aluminum drum, cleaned with detergent and rinsed with deionized water, was then coated with the above generated coating dispersion, and subsequently dried at 160° C. for 40 minutes, which resulted in the TUC8 layer deposited on the aluminum and comprised of TiO2/VARCUM/CYMEL with a weight ratio of about 60/16/24 and a thickness of 5.5 microns.