Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru](=O)([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Agent: O=[Ru](=O)(=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Reaction time: 0.17 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-3-hydroxymethylpiperidine (3741 mg, 17.4 mmol, Aldrich) in dry CH2Cl2 (250 mL) was added 4 angstrom molecular sieves (500 mg) and N-methyl-morpholine oxide (3054 mg, 26.1 mmol, Aldrich). After 10 min, tetrapropylammonium perruthenate oxide (305 mg, 0.87 mmol, Aldrich) and the reaction was stirred for 2 h. The reaction was filtered through a pad of silica gel and the silica gel was washed with EtOAc. The organic layers were and conc. in vacuo to a colorless oil which was used without further purification. MS (ESI) 214 (M+H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl.O>[S:16]([O:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CO)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution of (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (1.0 equiv.), tosyl chloride (1.10 equiv.), triethylamine (1.40 equiv.) and N,N-dimethylpyridin-4-amine (0.1 equiv.) in dichloromethane (0.1 M) at RT. The resulting mixture was stirred at RT for 2 hours. The reaction mixture was then diluted with water and the aqueous layer was separated and washed sequentially with NaOH (1 M), water, brine dried over sodium sulfate then concentrated in vaccuo to yield (S)-tert-butyl 2-((tosyloxy)methyl)morpholine-4-carboxylate as a pale yellow oil in 99% yield. LCMS (m/z) (M+H)=390.2, Rt=0.84 min.
Reaction SMILES: [CH3:1][C:2]1([OH:18])[CH:9]2[CH2:10][CH:5]3[CH2:6][C:7]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[O-]Cl.[Na+].[OH-].[K+]>CC(O)=O.C1COCC1.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[C:12]1([C:7]23[CH2:6][CH:5]4[CH2:10][CH:9]([CH2:8]2)[C:3]([C:2](=[O:18])[CH3:1])([CH2:4]4)[CH2:11]3)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC1(O)C2CC3CC1CC(c1ccccc1)(C3)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)C12CC3CC1CC(c1ccccc1)(C3)C2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 251.9 %

Procedure:
2-Methyl-5-phenyl-adamantan-2-ol (20 g, 82.6 mmol) obtained in step III, (86 g, 355.4 mmol), dissolved in a mixture of AcOH (76.3 mL) and THF (360 mL) was added dropwise via an addition funnel to the ice bath cooled NaOCl (4%, 3.5 L) solution over a period of 15 minutes. Solid n-Bu4NI (13.1 g, 35.6 mmol) was added and the reaction mixture was stirred for 1.5 h. The two layers were separated, the aqueous layer was extracted with diisopropylether and the combined organic layer was washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was dissolved in methanol (165 mL), KOH (39.8 g, 300 mmol) was added, and the mixture was refluxed for 1 h. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography to yield compound 1-(1-phenyltricyclo[3.3.1.03,7]non-3-yl)ethanone (50.0 g) in 59% yield as viscous liquid. m/z (M+1) 241; IR (cm−1): 2924, 2867, 1697, 1445, 1356, 1223, 757, 699. 1H NMR (CDCl3) 300 MHz δ 7.38-7.19 (m, 5H), 2.86-2.80 (m, 1H), 2.59-2.50 (m, 1H), 2.32-2.25 (m, 1H), 2.23 (s, 3H), 2.10-1.99 (m, 4H), 1.90-1.79 (m, 4H), 1.78-1.71 (m, 1H). 13C NMR (CDCl3) 75 MHz δ, 211.7, 146.7, 128.2 (2C), 125.7 (2C), 124.7, 61.9, 50.2, 49.0, 47.9, 45.7, 42.4, 42.3, 37.6, 26.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][OH:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20](=[O:29])[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>ClCCl.O=[Mn]=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20](=[O:29])[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3[nH]c2=O)cc2cc(CO)ccc21
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3[nH]c2=O)cc2cc(C=O)ccc21
Temperature: 45 °C
Reaction time: 1 h

Procedure:
The pre-activated MnO2 (34.5 g, 15 equiv) and the alcohol (1-8, 10.32 g, 1.0 equiv) were weighed into a 1-liter flask and suspended in dry dichloromethane (500 mL). The reaction mixture was heated to 45° C. and was complete by thin layer chromatography after 1 hour. The mixture was allowed to cool to ambient temperature and the manganese oxide(s) were removed by vacuum filtration. The resulting pad of oxides on the filter were triturated with hot THF and the solvent filtered through under vacuum to remove any product from the oxides. The resulting filtrate was concentrated in vacuo to afford the crude aldehyde as a yellow solid. The solid was triturated with methanol (10 mL) and ethyl acetate (15 mL) followed by vacuum filtration to isolate the pure product. The light-yellow aldehyde was dried under vacuum (1-9). 1H NMR (500 MHz, DMSO-d6) δ 12.15 (s, 1H), 10.08 (s, 1H), 8.26 (d, 1H, J=1.5 Hz), 8.24 (d, 1H, J=8.5 Hz), 8.15 (s, 1H), 7.90 (dd, 1H, J=8.5, 1.5 Hz), 7.77 (d, 1H, J=7.5 Hz), 7.55 (m, 1H), 7.37 (d, 1H, J=8.5 Hz), 7.24 (m, 1H), 7.01 (s, 1H).
Reaction SMILES: Cl[CH:2]([C:8]([C:10]([F:13])([F:12])[F:11])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:14]([NH2:17])(=[S:16])[CH3:15].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:15][C:14]1[S:16][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]([F:13])([F:12])[F:11])[N:17]=1
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Reactant: CC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(C)nc1C(F)(F)F
Yield: 56.4 %

Procedure:
6.00 g of ethyl 2-chloro-4,4,4-trifluoroacetoacetate and 2.06 g of thioacetamide were dissolved in 30 ml of acetic acid and the mixture was refluxed for 6 hours with stirring. The resulting solution was neutralized with aqueous sodium bicarbonate solution, then extracted with ethyl acetate and the organic layer was concentrated. The residue was chromatographed on silica gel (eluent; n-hexane:chloroform:tetrahydrofuran=6:2:1 V/V) to obtain 3.7 g of ethyl 2-methyl-4-trifluoromethylthiazole-5-carboxylate (yield 56%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][CH:8]=2)[NH:5][CH:6]=1>CC(O)=O.Br>[Br:1][C:2]1[N:3]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=2)[NH:5][CH:6]=1
Reactant: COc1ccc(-c2nc(Br)c[nH]2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(-c2nc(Br)c[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
A suspension of 10 (2.6 g, 0.0091 mol) in AcOH (10 ml) and 48% HBr (40 ml) was heated at reflux for 10 hours. After stirring overnight at room temperature the solution was concentrated to dryness and the residue stirred overnight with saturated NaHCO3. The mixture was filtered to yield 1.36 g (65%) of 11.
Reaction SMILES: [O-]CC.[Na+].[CH3:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7].[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(O)(=O)C>C(O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:10]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.9 %

Procedure:
To a solution of sodium ethoxide (4.4 g, 64.6 mmol) in absolute ethanol (60 mL) was added 4-chloroacetophenone (5.0 g, 32.3 mmol) and the reaction mixture was stirred for five minutes at room temperature. Diethyl oxalate (7.0 mL, 51.7 mmol) in absolute ethanol (10 mL) was added and the reaction mixture was heated to reflux for 4 hours. After cooling to room temperature, acetic acid (7.0 mL) was added and the resulting light yellow solid was filtered, washed with ethanol and dried in vacuo to obtain ethyl 4-(4-chlorophenyl)-2,4-dioxobutanoate (8.3 g, 32.6 mmol).
Reaction SMILES: [CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10](I)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C@@:20]12[O:28][CH2:27][O:26][N:22]([CH2:23][C@H:24]1[CH3:25])[C:21]2=[O:29].C(=O)([O-])[O-].[K+].[K+].N>CN1CCCC1=O.[Cu](I)I.C(OCC)(=O)C>[CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10]([N:22]2[CH2:23][C@:24]3([O:26][CH2:27][O:28][C@@:20]3([CH3:19])[C:21]2=[O:29])[CH3:25])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN2OCO[C@@]1(C)C2=O
Reactant: COCOc1ccc(I)nc1Cc1ccccc1
Agent: I[Cu]I
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COCOc1ccc(N2C[C@@]3(C)OCO[C@@]3(C)C2=O)nc1Cc1ccccc1
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 54.5 %

Procedure:
3.6 g of 2-benzyl-3-methoxymethyloxy-6-iodopyridine (Production Example 3), 1.5 g of (3R,4R)-3,4-dimethylmethylenedioxy-2-pyrrolidinone synthesized by the known method as described in the literature document (J. Org. Chem., 1969, 34, 675.), 1.1 g of copper iodide (I), and 3.3 g of potassium carbonate were suspended in 20 ml of 1-methyl-2-pyrrolidone, followed by heating under stirring in an oil bath at 140° C. for 20 minutes under nitrogen atmosphere. After standing to cool, ethyl acetate and aqueous ammonia were added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography with 20–50% ethyl acetate/hexane, to give 2 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(N2CCCC2=O)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(=O)O)cc(N2CCCC2=O)c1
Reaction time: 3 h
Yield: 107.3 %

Procedure:
A mixture of 3-nitro-5-(2-oxopyrrolidin-1-yl)-benzoic acid (D5) (2.86 g) and 10% Pd—C (0.7 g) in methanol (450 ml) water (50 ml) was hydrogenated at atmospheric pressure for 3 hrs. The mixture was filtered through Celite and concentrated to give 3-amino-5-(2-oxopyrrolidin-1-yl)-benzoic acid (2.70 g).
Reaction SMILES: CN1CCOCC1.ClC(OCC)=O.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH:27]=[CH2:28])[C:23](O)=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[OH:24][CH2:23][C@@H:22]([NH:21][C:19](=[O:20])[O:18][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:26][CH:27]=[CH2:28]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=CC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
N-methylmorpholine (15.25 ml) and ethyl chloroformate (12.60 ml) were added to a solution of (S)-2-((tert-butoxycarbonyl)amino)pent-4-enoic acid (25.0 g) in THF (250 ml) at −15° C. After stirring the mixture at −15° C. for 15 minutes, the generated insoluble matter was filtered off. A solution of sodium borohydride (3.23 g) in water (32 ml) was added to the filtrate at −15° C., and the mixture was stirred at −15° C. for 1 hour. A saturated aqueous ammonium chloride solution was added thereto, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate was added thereto to separate the organic layer. The organic layer was washed with a 0.5 N aqueous potassium hydrogensulfate solution, water, a 0.5 N aqueous sodium hydroxide solution, and a saturated sodium chloride solution; and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a light-yellow, oily substance (11.93 g).
Reaction SMILES: Br[C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)O1>>[N:27]1([C:24]2[N:25]=[CH:26][C:21]([C:2]3[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=3)=[CH:22][CH:23]=2)[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: NC(=O)c1cc(Br)sc1[N+](=O)[O-]
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Product: NC(=O)c1cc(-c2ccc(N3CCOCC3)nc2)sc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 5-bromo-2-nitrothiophene-3-carboxamide (Intermediate 10, Step 4) (2.50 g, 9.96 mmol) and 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]morpholine (2.89 g, 9.96 mmol) according to the general procedure described in Intermediate 10, Step 5.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH3:16][C:17]1[C:18](B(O)O)=[CH:19][S:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH3:16][C:17]1[C:18]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[C:12]([F:15])([F:14])[F:13])=[CH:19][S:20][CH:21]=1
Reactant: COC(=O)c1ccc(Br)c(C(F)(F)F)c1
Reactant: Cc1cscc1B(O)O
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2cscc2C)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
A mixture of methyl 4-bromo-3-(trifluoromethyl)benzoate (3.5 g; 12.4 mmol; 1 eq.), 4-methyl-3-thiopheneboronic acid (1.93 g; 13.6 mmol; 1.1 eq.), potassium carbonate (8.54 g; 61.8 mmol; 5 eq.) and Pd(PPh3)4 (1.43 g; 1.24 mmol; 0.1 eq.) in toluene (17.5 mL) and water (17.5 mL) was refluxed for 24 h whereupon 4-methyl-3-thiopheneboronic acid (0.88 g; 6.2 mmol; 0.5 eq.) was added. The reaction mixture was stirred for a further 3 hours then cooled down to room temperature and filtered through a pad of Celite® which was washed with toluene (200 mL). The filtrate was concentrated in vacuo and the residue taken up in ethyl acetate (300 mL). The organic layer was washed with sat. aq. NaHCO3 (100 mL), water (100 mL) and brine (100 mL), dried over magnesium sulphate and concentrated in vacuo to afford the title compound (3 g, 81%) as a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1O>[N+](C1C=CC=CC=1)([O-])=O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[O:7][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1O
Reactant: O=Cc1ccc(O)cc1
Solvent: O=[N+]([O-])c1ccccc1
Product: Oc1ccc(-c2nc3ccccc3o2)cc1
Yield: 64 %

Procedure:
Equal molar quantities of p-hydroxybenzaldehyde and o-aminophenol in excess nitrobenzene was refluxed for 5 hours. The nitrobenzene was removed and the product extracted from the residue with xylene. 2-(4-Hydroxyphenyl)benzoxazole, m.p. 253°, was isolated in 64% yield.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[S:5](Cl)([C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1)(=[O:7])=[O:6]>N1C=CC=CC=1>[C:11]1([CH3:12])[CH:13]=[CH:14][C:8]([S:5]([CH:1]([OH:4])[CH:2]([OH:3])[S:5]([C:8]2[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=2)(=[O:7])=[O:6])(=[O:7])=[O:6])=[CH:9][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)C(O)C(O)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Yield: 75 %

Procedure:
Twenty-eight ml of ethylene glycol and 100 ml of pyridine were added over a 2.5 hour period to a stirred mixture of tosyl chloride (210 g) in pyridine (225 ml), with the mixture being cooled by a water bath. After stirring for several hours, the mixture was shaken with one liter of ice water for about ten minutes and then filtered. The residue was washed with ether, dilute sulfuric acid, water, and finally ether. (Each of the washed liquids was ice cold.) The residue was then dried by vacuum pumping and recrystallized from boiling acetonitrile. The recrystallized residue, yield 75%, had a melting point of 123° to 125° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH2:11])=[C:4]([CH3:12])[CH:3]=1.[C:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])[CH3:14].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:11][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]([N:19]2[CH2:20][CH2:21][N:16]([C:13](=[O:15])[CH3:14])[CH2:17][CH2:18]2)=[CH:3][C:4]=1[CH3:12]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2cc(C)c(N)c([N+](=O)[O-])c2)CC1
Temperature: 100 °C
Yield: 69.9 %

Procedure:
A mixture of 4-bromo-2-methyl-6-nitro-phenylamine (5 g, 21.64 mmol), 1-acetylpiperazine (4.2 g, 32.46 mmol), palladium acetate (244 mg, 1.08 mmol), tri-tert-butylphosphine (440 mg, 2.16 mmol) and sodium tert-butoxide (4.2 g, 43.29 mmol) in toluene (70 mL) was heated to 100° C. for 14 h under nitrogen. The reaction mixture was cooled to room temperature and diluted with EtOAc. After extraction, the combined organic layers were washed with water, brine, dried over Na2SO4. Concentration gave a brownish residue which was purified by flash column chromatography (10% MeOH/CH2Cl2) to yield the title compound (4.21 g, 70%). 1H NMR (400 MHz, CD3OD) δ 7.42 (1H, d, J=2.8 Hz), 7.23 (1H, d, J=2.8 Hz), 3.71 (2H, t, J=5.1 Hz), 3.67 (2H, t, J=5.1 Hz), 3.04 (2H, t, J=5.2 Hz), 2.98 (2H, t, J=5.2 Hz), 2.24 (3H, s), 2.13 (3H, s). LCMS (M+H)+ m/z 279 (t=1.46 min.).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1([CH2:16][CH2:17][CH2:18][OH:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl.O>[CH:11]1([CH2:16][CH2:17][CH:18]=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OCCCC1CCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CCCC1CCCC1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 83.3 %

Procedure:
To CH2Cl2 (100 mL) at −78° C. were added oxalyl chloride (4.1 mL, 46.8 mmol, Aldrich) and dry DMSO (5.5 mL, 78.0 mmol, Aldrich), dropwise. After 5 min, 3-cyclopentylpropan-1-ol (5.0 g, 39.0 mmol, Aldrich) in 5 mL of CH2Cl2 was added. The mixture was stirred for an additional 0.5 hr at −78° C., and triethylamine (27.2 mL, 195.0 mmol) was added. The mixture was then allowed to warm to room temperature over 0.5 hr. After stirring for 3 hr, 100 mL of water was added. The phases were separated, and the aqueous phase was extracted with diethyl ether (3×100 mL). The combined organic extracts were washed successively with 50 mL of aqueous 1% HCl, 50 mL of water, 50 mL of aqueous 5% NaHCO3 and 50 mL of saturated aqueous NaCl. The organic layer was dried (MgSO4), filtered and concentrated to provide 4.1 g (83%) of the title compound. MS (ESI+) m/z 144 (M+NH4)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:21])[CH3:20]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)Oc1ccccc1
Temperature: 25 °C
Yield: 103 %

Procedure:
Phenol (24.28 g, 0.25 mol), potassium carbonate (39.2 g 0.28 mol), and ethyl 2-bromoproionate (46.7 g, 0.25 mol) were combined in acetone (200 mL) and stirred at room temperature over night. The acetone was removed in vacuo, the residue was purified in silica to provide a golden oil (50 g, 90%), Rf=0.80 in 10:1 ethyl acetate: petroleum ether.
Reaction SMILES: ClC[O:3][C:4]1[C:5]([OH:15])=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH:11]=1)[CH:9]=[O:10].[Al+3].[Cl-].[Cl-].[Cl-].ClC(Cl)C.Cl>N1C=CC=CC=1>[OH:15][C:5]1[C:4]([OH:3])=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1
Reactant: O=Cc1cc(OCCl)c(O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: O=Cc1cc(O)c(O)cc1[N+](=O)[O-]
Temperature: 47 °C
Yield: 68.1 %

Procedure:
To a stirred, cooled (0° C.) dispersion of 1.52 g (0.00658 mol) of 5-chloromethoxy-4-hydroxy-2-nitrobenzaldehyde (10), 1 g AlCl3, and 10 ml dry dichloroethane, 2.4 ml of dry pyridine are added. During addition, the reaction mixture is protected from atmospheric moisture, and the temperature is kept below 35° C. When addition is complete, the temperature is raised to 47° C., and maintained for 18 hours. 6N HCl is added, keeping the temperature at 30°-35° C., until the mixture is acidic to Congo Red indicator paper. The acidic solution is extracted with diethyl ether, and the combined ether extracts are dried over Na2SO4. After filtration, the ether is removed at reduced pressure, giving 0.82 g (68%) of (1): mp 201°-202°° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:10][N:11]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[CH:13]=2)[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][N:3]=1.C(OC([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([NH2:39])[CH:37]=2)[C:32](=[O:40])[NH:31]1)=O)(C)(C)C>C(O)CCC>[CH:14]1([C:12]2[CH:13]=[C:9]([NH:8][C:6]3[C:5]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][N:3]=[C:2]([NH:39][C:36]4[CH:37]=[C:38]5[C:33]([C:32](=[O:40])[NH:31][NH:30]5)=[CH:34][CH:35]=4)[N:7]=3)[NH:10][N:11]=2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2ccc(N)cc21
Reactant: Clc1ncc(-c2ccccc2)c(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CCCCO
Product: O=c1[nH][nH]c2cc(Nc3ncc(-c4ccccc4)c(Nc4cc(C5CC5)n[nH]4)n3)ccc12
Temperature: 95 °C
Reaction time: 12 h

Procedure:
To ((2-Chloro-5-phenyl-pyrimidin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (75 mg, 0.241 mmol), was added 6-Amino-3-oxo-2,3-dihydro-indazole-1-carboxylic acid tert-butyl ester (180 mg, 0.72 mmol) in n-butanol and the solution was heated to 95° C. in a sealed tube. After 12 hr, the solution was concentrated and the title compound was isolated by preparative HPLC as a white solid (5.2 mg, 5% yield) HNMR (500 MHz, MeOH d-6). 7.82-7.80 (2H, m), 7.59-7.50 (6H, m), 7.19-7.17 (1H, m), 6.08 (1H, s), 2.65 (1H, m), 0.91-0.89 (2H, m), 0.45 (2H, m); LCMS m/e: 1.9 min, 425.1 (M+H), 423.1 (M-H).