Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-])=O)=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]([C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][N:20]=1)=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl.[Pd]>[CH3:15][O:16][C:17]([C:19]1[CH:24]=[C:23]([O:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([NH2:12])=[CH:4][CH:3]=2)[CH:22]=[CH:21][N:20]=1)=[O:18]
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Reactant: COC(=O)c1cc(O)ccn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cc(Oc2ccc(N)c3ccccc23)ccn1
Temperature: 100 °C
Reaction time: 5 h
Yield: 51.9 %

Procedure:
To a solution of 1-fluoro-4-nitro-naphthalene (1.0 g, 5.24 mmol) in dry DMF (22 mL) was added 4-hydroxy-pyridine-2-carboxylic acid methyl ester (0.993 g, 5.24 mmol) and K2CO3 (7.24 g, 52.4 mmol). The resulting yellow suspension was stirred at 100° C. under argon for five h. After cooling to room temperature, the solution was diluted with CH2Cl2 (62 mL) and 10% Pd/C (1 g) was added. The suspension was stirred under a H2 balloon for 72 h. The reaction was then filtered through a plug of diatomaceous earth and rinsed with EtOAc (150 mL) and extracted with H2O (3×100 mL), brine (1×100 mL) and dried over MgSO4. The solvent was removed via rotary evaporation and the resulting oil was applied to a flash silica column eluting with MeOH:CH2Cl2 (2:98) to provide the title compound (800 mg, 52%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1.[C:12]1([CH:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[CH3:11][C:8]1[N:6]2[N:7]=[C:2]([N:19]3[CH2:20][CH2:21][CH2:22][CH:18]3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: c1ccc(C2CCCN2)cc1
Reactant: Cc1nnc2ccc(Cl)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1nnc2ccc(N3CCCC3c3ccccc3)nn12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 7.9 %

Procedure:
A mixture of 6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine (200 mg, 1.19 mol), 2-phenylpyrrolidine (200 mg, 1.36 mmol) and K2CO3 (350 mg, 2.5 mmol) in acetonitrile (20 mL) was heated at 100° C. under microwave and stirred for 30 mins. After cooled to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuum. The residue was purified by prep-TLC (silica-gel, DCM: MeOH=20:1) to give product 3-methyl-6-(2-phenylpyrrolidin-1-yl)-[1,2,4]triazolo[4,3-b]pyridazine (Compound 10) as a white solid (30 mg, 12%). 1H NMR (300 MHz, CD3OD) δ 7.73-7.77 (d, 1H, J=10.2 Hz), 7.22-7.34 (m, 5H), 6.84-6.87 (d, 1H, J=10.2 Hz), 5.14-5.18 (m, 1H), 3.92-3.98 (m, 1H), 3.71-3.81 (m, 1H), 2.57 (s, 3H), 2.50-2.54 (M, 1H), 2.03-2.13 (m, 3H); LRMS (M+H+) m/z: calcd 279.15; found 279.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[C:4]([Cl:10])[C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C[S-].[Na+]>CN(C=O)C>[Cl:10][C:4]1[CH:5]=[C:6]([OH:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: COc1cc(Cl)c(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(Cl)cc(O)cc2Cl)CC1
Yield: 25.3 %

Procedure:
This compound was prepared in a manner analogous to that of Example 2 Step B, by the reaction of 3.7 grams (0.01 mole) of tert-butyl 4-(2,6-dichloro-4-methoxyphenyl)piperazinecarboxylate and 1.8 grams (0.025 mole) of sodium methanethiolate in 150 mL of DMF. The crude reaction product was purified with column chromatography on silica gel using 50% hexane in methylene chloride, 100% methylene chloride and finally 20% methanol in methylene chloride as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.88 gram of the subject compound. The NMR spectrum was consistent with the proposed structure. The reaction was repeated to obtain additional material for the next reactive step.
Reaction SMILES: CS([N:5]1[C:27]2[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=2)[C:7]2([CH2:11][CH2:10][N:9]([CH2:12]/[CH:13]=[CH:14]/[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:8]2)[CH2:6]1)(=O)=O.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1(C)C=CC=CC=1>[Cl:28][C:24]1[CH:23]=[C:22]2[C:7]3([CH2:11][CH2:10][N:9]([CH2:12]/[CH:13]=[CH:14]/[C:15]4[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=4)[CH2:8]3)[CH2:6][NH:5][C:27]2=[CH:26][CH:25]=1
Reactant: CS(=O)(=O)N1CC2(CCN(C/C=C/c3ccc(Cl)cc3)C2)c2cc(Cl)ccc21
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ccc(/C=C/CN2CCC3(CNc4ccc(Cl)cc43)C2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A solution of 1-methanesulfonyl-5-chloro-1′-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,3′-pyrrolidine] obtained in Step D (256 mg) in toluene (25 ml) under argon was treated with sodium bis(2-methoxyethoxy)aluminium hydride (Red-Al, 65% in toluene, 0.67 ml) and the reaction mixture was stirred at 100° C. for 1 hour, cooled to room temperature, quenched by addition of ethyl acetate (10 ml), stirred for 15 min and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent ethyl acetate:methanol 95:5) to afford 5-chloro-1′-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,3′-pyrrolidine] (157 mg) as a yellow oil, which was characterised by its mass and NMR spectra.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 70 %

Procedure:
7 g (30.56 mmol) of ethyl 4-bromobenzoate are dissolved in 60 ml of 1,2-dimethoxyethane and, under argon, 6.96 g (36.67 mmol) of 4-trifluoromethylphenylboronic acid, 271 mg of bis(triphenylphosphine)palladium(II) chloride and 40.7 ml of a 2 M aqueous sodium carbonate solution are added. The reaction mixture is then stirred under reflux for 12 hours. The mixture is then cooled, filtered through 1 g of Extrelute, washed with dichloromethane and concentrated. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/dichloromethane 2:1). 6.31 g (21.4 mmol, 70% yield) of a colourless solid are obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([F:8])=[CH:6][N:7]=1.[O:11]1CCCC1>Cl>[F:1][C:2]1[C:3]([C:9]([NH2:10])=[O:11])=[N:4][C:5]([F:8])=[CH:6][N:7]=1
Reactant: C1CCOC1
Reactant: N#Cc1nc(F)cnc1F
Agent: Cl
Product: NC(=O)c1nc(F)cnc1F
Temperature: 32.5 °C
Reaction time: 6.5 h

Procedure:
In a mixture of 570 mL of 12 mol/L hydrochloric acid and 57 mL of tetrahydrofuran was suspended 57.3 g of 3,6-difluoro-2-pyrazinecarbonitrile. The suspension was stirred at 30-35° C. for 6.5 hours. The reaction mixture was concentrated to dryness under reduced pressure, 100 mL of ethanol was added, and then the solvent and hydrochloric acid were removed under reduced pressure. The residue thus obtained was washed with ethanol and diisopropyl ether to obtain 53.7 g of 3,6-difluoro-2-pyrazinecarboxamide as a colorless solid product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](B(O)O)=[CH:8]2.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[C:25]2[CH3:29])[N:20]=[N:21][CH:22]=1>>[ClH:16].[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([C:17]1[CH:18]=[C:19]([CH2:23][N:24]3[CH:28]=[CH:27][N:26]=[C:25]3[CH3:29])[N:20]=[N:21][CH:22]=1)=[CH:8]2
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: COc1cccc2c1CCC(B(O)O)=C2
Product: COc1cccc2c1CCC(c1cnnc(Cn3ccnc3C)c1)=C2
Product: Cl

Procedure:
The title compound, MS: m/e=333.3 (M+H+), was prepared from 5-methoxy-3,4-dihydro-naphthalene-2-boronic acid and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.F[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)[CH:23]=[CH:22][N:21]=2)=[C:12]([O:36][CH3:37])[CH:11]=1.ClC1C(C2C3C(=CC=CC=3)N(C)C=2)=NC(NC2C=C([N+]([O-])=O)C(F)=CC=2OC)=NC=1>FC(F)(F)CO>[CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]([CH3:35])[CH:27]=4)[CH:23]=[CH:22][N:21]=3)=[C:12]([O:36][CH3:37])[CH:11]=2)[CH2:4]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Agent: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Solvent: OCC(F)(F)F
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 140 °C
Yield: 87 %

Procedure:
(3R)—N,N-Dimethylpyrrolidin-3-amine (107 mg, 0.94 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 129; (which may be prepared by the method described for Intermediate 87), 0.372 mL, 2.13 mmol) in 2,2,2-trifluoroethanol (5 mL) and the mixture was heated in a microwave at 140° C. for 1 h. The cooled mixture was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M methanolic ammonia and appropriate fractions were combined and concentrated in vacuo onto silica. Purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 gave the title compound (364 mg, 87%) as an orange solid; 1H NMR: 1.74-1.87 (1H, m), 2.11-2.22 (1H, m), 2.21 (6H, s), 2.70-2.81 (1H, m), 3.10-3.21 (2H, m), 3.21-3.28 (1H, m), 3.47 (1H, td), 3.87 (3H, s), 3.95 (3H, s), 6.56 (1H, s), 7.10 (1H, t), 7.18 (1H, d), 7.21-7.27 (1H, m), 7.51 (1H, d), 8.07 (1H, s), 8.29 (1H, d), 8.32 (1H, s), 8.36 (1H, d), 8.54 (1H, s); m/z: ES+ MH+ 488.31.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH:12]1[C:17]2[CH2:18][NH:19][CH2:20][CH2:21][S:22][C:16]=2[CH:15]=[CH:14][CH:13]=1>>[S:22]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:17]=2[CH2:18][N:19]([C:2]2[N:3]=[C:4]([NH:3][CH2:4][CH2:5][CH2:6][NH2:7])[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=2)[CH2:20][CH2:21]1
Reactant: c1ccc2c(c1)CNCCS2
Reactant: Clc1nc(Cl)c2sccc2n1
Product: NCCCNc1nc(N2CCSc3ccccc3C2)nc2ccsc12

Procedure:
The title compound was prepared in analogy to Example 1-1 in Scheme 1 by using 2,4-dichlorothieno[3,2-d]pyrimidine and propane-1,3-diamne) and 6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptene. MS obsd. (ESI+) [(M+H)+] 372, 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.71 (d, J=5.3 Hz, 1H), 7.65 (d, J=7.1 Hz, 1H), 7.50 (d, J=7.1 Hz, 1H), 7.17-7.25 (m, 1H), 7.10-7.16 (m, 1H), 7.09 (d, J=5.6 Hz, 1H), 5.01 (s, 2H), 4.35 (br. s., 2H), 3.72 (t, J=6.6 Hz, 2H), 2.92-2.96 (m, 2H), 2.87-2.92 (m, 2H), 1.92-2.01 (m, 2H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].C(O)C[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CCCCO.CCCCO.CCCCO.CCCCO.[Ti].C(O)C>[Si:5]([CH2:4][CH2:3][CH2:2][SH:1])([O:12][CH2:13][CH2:14][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])([O:6][CH2:7][CH2:8][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[O:9][CH2:10][CH2:11][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17]
Reactant: CCO[Si](CCCS)(OCC)OCC
Reactant: CCCCCCCCCCCCCCCCO
Agent: [Ti]
Solvent: CCO
Solvent: CCCCO
Product: CCCCCCCCCCCCCCCCO[Si](CCCS)(OCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCC
Temperature: 105 °C

Procedure:
2002.6 g of 3-mercaptopropyl(triethoxy)silane are mixed with 6108.5 g of hexadecanol as well as with 2 g of tetrabutyl orthotitanate and heated at 95-115° C. for 360 minutes in a 10 liter flask in a distillation apparatus. Ethanol formed in the transesterification is distilled off in vacuo at 15-600 mbar. After cooling, 7022 g of a colourless, solid product are obtained. As can be shown by 1H-NMR and 29Si-NMR, 92% of the EtO—Si groups are replaced by R—O—Si. In the transesterification more than 80 mole % of the ethanol-free compound [(C16H33O)3Si—C3H6—SH is formed, as can be shown for example by 1H-NMR and 29Si-NMR.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[C:36](=[O:37])[N:5]2[C:6]([C:25]([O:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[O:26])=[C:7]([CH2:10][S:11][C:12]3[N:17]4[N:18]=[C:19]([CH2:21][O:22][CH3:23])[N:20]=[C:16]4[N:15]=[C:14]([CH3:24])[CH:13]=3)[CH2:8][S:9][C@H:4]12.[NH2:38][C:39]1[S:40][CH:41]=[C:42](/[C:44](=[N:58]/[O:59][CH3:60])/[C:45](OSC2SC3C=CC=CC=3N=2)=[O:46])[N:43]=1>C(Cl)Cl.C(O)C>[ClH:1].[NH2:38][C:39]1[S:40][CH:41]=[C:42]([C:44](=[N:58][O:59][CH3:60])[C:45]([NH:2][CH:3]2[C:36](=[O:37])[N:5]3[C:6]([C:25]([O:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:33])([CH3:32])[CH3:34])=[O:26])=[C:7]([CH2:10][S:11][C:12]4[N:17]5[N:18]=[C:19]([CH2:21][O:22][CH3:23])[N:20]=[C:16]5[N:15]=[C:14]([CH3:24])[CH:13]=4)[CH2:8][S:9][C@H:4]23)=[O:46])[N:43]=1
Reactant: CO/N=C(\C(=O)OSc1nc2ccccc2s1)c1csc(N)n1
Reactant: COCc1nc2nc(C)cc(SCC3=C(C(=O)OCOC(=O)C(C)(C)C)N4C(=O)C(N)[C@H]4SC3)n2n1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: COCc1nc2nc(C)cc(SCC3=C(C(=O)OCOC(=O)C(C)(C)C)N4C(=O)C(NC(=O)C(=NOC)c5csc(N)n5)[C@H]4SC3)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
In 100 ml of methylene chloride was dissolved 11.8 g of pivaloyloxymethyl 7-amino-3-[(2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate.hydrochloride, and 5.82 g of benzthiazolylthio 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyiminoacetate was added to the solution and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with 100 ml of a 5% sodium acetate aqueous solution and further washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. 100 ml of isopropanol containing 1.5 ml of conc. hydrochloric acid was added to the residue, and the mixture was thoroughly stirred and further stirred by adding 150 ml of ether. Then, precipitates were collected by filtration, washed with water and dried to obtain powder. This was dissolved in 50 ml of ethanol and filtered and the filtrate was added dropwise into 300 ml of ether. Precipitates were collected by filtration, washed with ether and dried to obtain 7.91 g of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH:5]=[O:6])[CH3:2].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:12]([C:7]1[CH:8]=[C:9]([O:11][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[C:3]([CH2:1][CH3:2])[C:4]=1[CH:5]=[O:6])[CH3:13]
Reactant: CCc1cc(O)cc(CC)c1C=O
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1cc(Oc2ccccc2)cc(CC)c1C=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.6 %

Procedure:
To a solution of 1.50 g (8.42 mmol) 2,6-diethyl-4-hydroxy-benzaldehyde in 60 ml dichloromethane were added 1.64 g (13.5 mmol) phenylboronic acid, 2.29 g (12.6 mmol) copper(II) acetate, 30 g 4 Å molecular sieves and 4.06 ml (50.5 mmol) pyridine. The reaction mixture was stirred at room temperature for 72 h and then filtered through celite. The filtrate was extracted with 1 N aqueous hydrochloric acid, the phases were separated, and the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate/heptane gradient) to afford 1.64 g (77%) of the title compound as a yellow oil. 1H-NMR (CDCl3): 1.22 (6H, t, CH3), 2.95 (4H, q, CH2), 6.69 (2H, s, ArH), 7.08 (2H, d, ArH), 7.20 (1H, t, ArH), 7.39 (2H, dd, ArH), 10.5 (1H, s, CHO).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[C:22]([C:26]1[O:30][N:29]=[C:28]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C>[C:22]([C:26]1[O:30][N:29]=[C:28]([NH:31][C:32]([NH:1][C:2]2[CH:21]=[CH:20][CH:19]=[C:4]([O:5][C:6]3[C:15]4[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=4)[N:9]=[CH:8][N:7]=3)[CH:3]=2)=[O:33])[CH:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1O
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 4-(3-aminophenoxy)-7-methoxyquinazolin-6-ol (2.0 g, 0.0070 mol) in DMF (10 mL), phenyl 5-tert-butylisoxazol-3-ylcarbamate (1.74 g, 0.0067 mol) was added. The reaction mixture was stirred at 60° C., overnight. The solvent was evaporated under vacuum and the residue was sonicated in the presence of ethyl ether (60 mL). The solid was filtered and washed with ethyl ether to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)urea (2.75 g, 87.5% yield). 1HNMR (DMSO-d6): δ 10.53 (s, 1H), 9.57 (s, 1H), 8.99 (s, 1H), 8.50 (s, 1H), 7.52 (d, 2H), 7.37 (m, 2H), 7.25 (d, 1H), 6.95 (d, 1H), 6.18 (s, 1H), 4.00 (s, 3H), 1.30 (s, 9H); LC-MS (ESI) m/z 450 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Br:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].[OH-].[Na+].CCOCC>C1(C)C=CC=CC=1>[Br:14][C:8]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[Cl:15])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: NCc1ccccc1Cl
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1NCc1ccccc1Cl
Yield: 61.5 %

Procedure:
A suspension of 2,5-dibromo-3-nitrobenzoic acid (10.76 g, 0.0331 mol) in toluene (100 mL) was placed under argon, treated with 2-chlorobenzylamine (14.06 g, 0.0993 mol) and the mixture was brought to reflux. A clear, red solution resulted and the solution was refluxed for 24 hours, cooled, poured into 5% sodium hydroxide solution (600 mL) and ether (100 mL). The insoluble material was filtered off, the layers separated and the aqueous phase was added to the insoluble material and acidified with 10% hydrochloric acid solution. The separated crystalline product was collected, washed with water and the solid was crystallized from a large volume of methanol to provide 7.85 g (61.5%) of the yellow crystalline 5-bromo-2-[(2-chlorophenyl)methyl]amino-3-nitrobenzoic acid; mp 159°-161° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:18][C:19]1[CH:20]=[C:21]([NH2:28])[C:22](=[CH:26][CH:27]=1)[C:23](O)=[O:24].C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]2[C:23](=[O:24])[O:17][C:14]3([NH:28][C:21]=2[CH:20]=1)[CH2:15][CH2:16][N:11]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=1)[CH2:12][CH2:13]3
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: CS(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(N2CCC3(CC2)Nc2cc(Cl)ccc2C(=O)O3)cc1
Yield: 94 %

Procedure:
A mixture of 5.82 g (0.023 mol) of the compound of (B), 4 g (0.023 mol) of 4-chloroanthranilic acid, 75 ml of toluene, and 0.1 of p-toluenesulfonic acid is stirred at reflux with the azeotropic removal of water for 5 hours. After cooling, the resulting precipitate is collected, and washed with cold toluene to give 8.8 g (94%) of title compound: m.p. 193°-194° C.; IR (KBr) 3350, 1695, and 1600 cm-1 ; NMR (DMSO-d6) δ 7.84-7.70 (m, 2H), 7.76 (d, 2H), 7.16 (d, 2H), 6.90-6.84 (m, 1H), 3.78-3.66 (m, 2H), 3.48-3.36 (m, 2H), 3.12 (s, 3H), 2.18-2.08 (m, 2H) and 1.96-1.82 (m, 2H); MS m/e 487 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[SH:10].[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1)([O-:13])=[O:12].Cl>N1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Cc1cc(O)c(S)c(=O)o1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(O)c(SCc2ccc([N+](=O)[O-])cc2)c(=O)o1
Temperature: 90 °C

Procedure:
To a solution of 8.00 g. (0.0510 mole) of 4-hydroxy-3-mercapto-6-methyl-2-pyrone in 50 ml. of pyridine was added 11.0 g. (0.0510 mole) of p-nitrobenzyl bromide portionwise, keeping the temperature of the reaction mixture below 35°C. by means of an ice bath. After the addition was complete the reaction mixture was heated at 90°C. on the steam bath for two hours and 15 minutes. The mixture was then poured into ice and 100 ml. of concentrated hydrochloric acid. The cream colored solid precipitate was collected on a filter, washed with water and dried; m.p. 156°-160°C. (dec.), weight 12.2 g. (81 percent). Recrystallization from ethanol gave the pure 4-hydroxy-6-methyl-3-(4-nitrobenzylthio)-2-pyrone as tan crystals, m.p. 178°C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>CO.C1COCC1.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1Oc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccccc1Oc1ccccc1N
Yield: 61.8 %

Procedure:
To a solution of 1-tert-butyl-2-(2-nitrophenoxy)benzene (˜20 g, crude) in MeOH/THF (1:1, 200 mL) was added 10% Pd/C (2 g). The mixture was hydrogenated under 75 psi overnight. The mixture was filtered through Celite® cake and the filtrate was evaporated to give the crude product as a black oil. Purification by flash chromatography (0-30% EtOAc/hexane) provided 135a (11 g) as a brown solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7]C(=NC#N)OC2C=CC=CC=2)[CH:2]=1.[C:19]1([C@H:25]([CH2:27][OH:28])[NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C[N:30]1CCOCC1.C(O)(C)C>CO.C(Cl)(Cl)Cl>[C:19]1([C@@H:25]2[CH2:27][O:28][N:30]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[NH:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN1CCOCC1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: N#CN=C(Nc1cccnc1)Oc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(C)O
Product: c1ccc([C@@H]2CON(Nc3cccnc3)N2)cc1

Procedure:
A stirred mixture of N-(3-pyridyl)-N'-cyano-O-phenylisourea (see, Example 5 for procedure) (3.00 g, 0.0126 mol), (R)-2-phenylglycinol (1.9 g, 0.0130 mol), N-methylmorpholine (30 mL), and isopropanol (20 mL) was refluxed, under nitrogen, for 2 hours; the reaction was complete by TLC with 10% MeOH-CHCl3. The mixture was concentrated and the residue was chromatographed on silica gel with 1-6% MeOH-CHCl3. The first product eluted from the column was crystallized from MeOH-EtOAc to give 261 mg of (R)-4,5-dihydro-4-phenyl-2-(3-pyridyl)aminooxadiazole: mp 125°-130° C.