Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)[CH:19]=3)=[C:13]([CH3:30])[N:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:31]([O-])([O-])=O.[Cs+].[Cs+].IC>CC(C)=O>[C:1]([C:5]1[N:9]([CH3:31])[C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)[CH:19]=3)=[C:13]([CH3:30])[N:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(-n2nc(C(C)(C)C)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Agent: [Cs+]
Solvent: CI
Solvent: CC(C)=O
Product: Cc1nc(-n2nc(C(C)(C)C)n(C)c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.7 %

Procedure:
A suspension of Example 7 (0.050 g, 0.12 mmol) in acetone (2.5 mL) was treated with Cs2CO3 (0.080 g, 0.25 mmol) and iodomethane (0.02 mL, 0.32 mmol) and the mixture was stirred at RT for 12 h. The solvent was removed in vacuo and the residue was dissolved in DCM (3 mL) and washed with water (3 mL). The aqueous phase was extracted with DCM (4×5 mL) and the combined organics were dried (MgSO4) and concentrated in in vacuo. The residue was triturated with Et2O (2 mL) and sonicated for 5 min, which lead to the precipitation of an off white solid. Solid was isolated by filtration and washed with Et2O (3×1 mL). The solid was dried under high vacuum for 3 h, and was then dissolved in MeCN and water, frozen to −78° C., and lyophilized to afford 3-(tert-butyl)-4-methyl-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.024 g, 46.4%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.37 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 6.65 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 3.39 (s, 3H), 2.34 (s, 3H), 1.37 (s, 9H); MS (ESI) m/z: 420.2 (M+H+).
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[S:13]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[CH2:22][CH2:23][CH2:24]O)(=[O:15])=[O:14]>CN(C=O)C.O>[Br:2][CH2:24][CH2:23][CH2:22][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][N:16]1[S:13]([C:7]1[C:8]([CH3:12])=[CH:9][CH:10]=[CH:11][C:6]=1[Cl:5])(=[O:15])=[O:14]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)N1CCCCC1CCCO
Reactant: BrP(Br)Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(Cl)c1S(=O)(=O)N1CCCCC1CCCBr
Reaction time: 0.5 h
Yield: 25 %

Procedure:
PBr3 (3.8 mmol, 1.5 eq) was added dropwise to a solution of 3-(1-(2-chloro-6-methylphenylsulfonyl)piperidin-2-yl)propan-1-ol (2.53 mmol, 1 eq) in DMF (6 ml) at 0° C. and the mixture was stirred for 30 min. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (2×20 ml). The combined organic phases were washed with water (30 ml) and saturated sodium chloride solution (20 ml), dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (30% ethyl acetate in hexane). Yield: 25%
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C([O:10][C:11]1[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][N:15]2[CH:25]1[CH2:27][CH2:26]1)(=O)C>CCO>[CH:25]1([N:15]2[C:16]3[C:12](=[C:11]([OH:10])[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=3)[CH:13]=[CH:14]2)[CH2:26][CH2:27]1
Reactant: CCOC(=O)c1cc(OC(C)=O)c2ccn(C3CC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cc(O)c2ccn(C3CC3)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
K2CO3 (69.6 g) was added to a solution of ethyl 4-acetoxy-1-cyclopropyl-1H-indole-6-carboxylate (72.3 g) in EtOH (360 ml) placed in a 2 L flask and the mixture was stirred at room temperature for 4 h. EtOH was evaporated and the redisue was diluted with EtOAc. The mixture was washed with water and brine, dried over Na2SO4. After filteration and concentration, the residue was triturated with toluene and hexane to give intended compound as a pale tan solid.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].Cl(O)(=O)(=O)=O.[OH-].[Na+].C(O[C:21]([CH3:24])([CH3:23])[CH3:22])(=O)C>O>[O:6]=[C:5]1[NH:1][C@H:2]([C:7]([O:9][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:8])[CH2:3][CH2:4]1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
129 g of L-pyroglutamic acid were suspended in 2 l of tert-butyl acetate. 30 ml of a 70% strength solution of perchloric acid in water were added thereto. The mixture was then stirred at room temperature for 12 h. It was cooled to 0° C. and the pH of the solution was adjusted to 7 by cautious addition of a 2N NaOH solution. The phases were separated and the organic phase was washed twice with 300 ml of a saturated sodium chloride solution each time. The organic phase was then dried with sodium sulfate. The solvents were removed in vacuo, and the residue was stirred with heptane. The solid obtained in this way was filtered off with suction. The mother liquor was concentrated in vacuo, and the solid obtained in this way was also filtered off with suction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])=[N:8][C:7](=O)[C:6]=2[CH:20]=1.Cl.[CH3:22][N:23]([CH3:33])[C:24]1[CH:32]=[CH:31][C:27]([CH2:28][NH:29][NH2:30])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])[N:29]([CH2:28][C:27]3[CH:31]=[CH:32][C:24]([N:23]([CH3:33])[CH3:22])=[CH:25][CH:26]=3)[N:30]=2)[CH:20]=1
Reactant: O=c1nc(-c2cc(Cl)ccc2O)oc2ccc(Cl)cc12
Reactant: CN(C)c1ccc(CNN)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(Cn2nc(-c3cc(Cl)ccc3O)nc2-c2cc(Cl)ccc2O)cc1

Procedure:
3.0 g of 6-chloro-2-(5-chloro-2-hydroxyphenyl)benz[e][1,3]oxazin-4-one are boiled under reflux for 4 h with 2.2 g of 4-dimethylaminobenzylhydrazine hydrochloride and 3 ml of triethylamine in 50 ml of ethanol. The crystals precipitating on cooling are washed with ethanol. After drying, 3,5-bis(5-chloro-2-hydroxyphenyl)-1-(4-dimethylaminobenzyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 205-207 C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][OH:14].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=O>[CH2:19]([O:14][CH2:13][C:9]1[N:8]([CH2:7][C:6]2[CH:15]=[C:16]([Cl:18])[CH:17]=[C:4]([Cl:3])[CH:5]=2)[CH:12]=[CH:11][N:10]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCc1nccn1Cc1cc(Cl)cc(Cl)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1cc(Cl)cc(Cn2ccnc2COCc2ccccc2)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 5 %

Procedure:
To NaH in DMF, was added [1-(3,5-dichloro-benzyl)-1H-imidazol-2-yl]-methanol (see Example 1) in DMF. The reaction mixture was stirred at 40° C. for 30 min and benzyl bromide was dropwise added. The reaction mixture was stirred at 40° C. for another 3 h. The mixture was diluted with EtOAc and washed with water, 1N HCl and saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using CH2Cl2:MeOH 98:2 as an eluent to afford the title compound (7 mg, 5%); MS m/z 347 [C18H16Cl2N2O+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[C:20]([C:21](=[O:29])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][N:18]=[C:17](S(C)(=O)=O)[N:16]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=1)[NH2:40]>CC(N(C)C)=O>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[C:20]([C:21](=[O:29])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][N:18]=[C:17]([NH:40][C:39]3[CH:41]=[CH:42][CH:43]=[C:37]([O:36][CH3:35])[CH:38]=3)[N:16]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2nc(S(C)(=O)=O)ncc2C(=O)Nc2ccccc2)c1
Solvent: CC(=O)N(C)C
Product: COc1cccc(Nc2ncc(C(=O)Nc3ccccc3)c(Oc3cccc(NC(=O)OC(C)(C)C)c3)n2)c1
Temperature: 90 °C
Yield: 27.4 %

Procedure:
The 2-methylsulfone of 7 (1.0 g, 1.9 mmol) was mixed with 3-methoxyaniline (420 mg, 3.4 mmol) in DMA and the mixture was heated at 90° C. for 24 hours. Workup was done in a manner similar to that for Step-5 in Example 57 to give 9 (300 mg, 0.52 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]=[C:4](O)[CH:3]=1.O=P(Cl)(Cl)[Cl:17]>C1(C)C=CC=CC=1>[Cl:17][C:4]1[CH:3]=[C:2]([CH3:1])[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(C)c2c(C)cc(O)nc12
Solvent: Cc1ccccc1
Product: Cc1ccc(C)c2c(C)cc(Cl)nc12
Yield: 85 %

Procedure:
A solution of 4,5,8-trimethylquinolin-2-ol (2.40 g, 12.8 mmol) and 1.4 mL (1.2 eq) of POCl3 in toluene was reacted as outlined in Scheme 1 above to yield the desired title compound (2.2 g, 85%). Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 2.68 (s, 3 H) 2.82 (s, 3 H) 2.85 (s, 3 H) 7.12 (s, 1 H) 7.18 (d, J=7.33 Hz, 1 H) 7.39 (d, 1 H).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]([O:11][B:12](OC(C)C)[O:13][CH:14]([CH3:16])[CH3:15])([CH3:10])[CH3:9].C(Cl)(=O)C>>[C:1]1([B:12]([O:13][CH:14]([CH3:16])[CH3:15])[O:11][CH:8]([CH3:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: [Li]c1ccccc1
Solvent: CC(=O)Cl
Product: CC(C)OB(OC(C)C)c1ccccc1

Procedure:
Following the procedure of Example 9, phenyllithium (17 mL, 30.6 mmol) and triisopropoxyborane (5.6 g, 30 mmol) were reacted, and the reaction quenched with acetyl chloride (2.1 mL, 30 mmol) to yield after distillation 5.2 g (25.2 mmol, 84%).
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[C:10]1([CH3:17])[C:11](Cl)=[CH:12][CH:13]=[CH:14][CH:15]=1.Cl>[OH-].[Na+].C1COCC1>[C:10]1([CH3:17])[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: NC(CC(=O)O)C(=O)O
Reactant: Cc1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccccc1N[C@@H](CC(=O)O)C(=O)O
Reaction time: 0.5 h
Yield: 74 %

Procedure:
20 g of DL-aspartic acid (Aldrich) are dissolved in 210 ml of a 2.5N aqueous sodium hydroxide solution (120 ml)/THF (90 ml) mixture in a 500 ml, three-necked, round-bottomed flask equipped with a pHmeter and two dropping funnels containing, on the one hand, a 2.5N aqueous sodium hydroxide solution and, on the other hand, o-toluyl chloride. The o-toluyl chloride is added drop-wise while maintaining the pH above 9 by simultaneous addition of the 2.5N sodium hydroxide solution. The reaction mixture is kept stirring for 2 h 30 minutes after the end of the addition of the acid chloride before being acidified with a concentrated hydrochloric acid solution. The mixture is then exhaustively extracted with ethyl acetate. The organic phase is washed, dried and concentrated to dryness to provide 27.9 g (non-optimized yield 74%) of N-(ortho-toluyl)aspartic acid, used as is in the second stage.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=O)[NH:14][C:12]2=[O:13])[CH:8]=[CH:7]1)(=[O:3])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>N1C=CC=CC=1>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[S:21])[NH:14][C:12]2=[O:13])[CH:8]=[CH:7]1)(=[O:3])[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(=O)OC[C@@H]1C=C[C@H](n2cc(C)c(=O)[nH]c2=O)O1
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H]1C=C[C@H](n2cc(C)c(=S)[nH]c2=O)O1

Procedure:
MS: m/z 266 (C12H14N2O6, M+), 141 (C7H9O3, sugar group), 126 (C5H6N2O2, base+H). The 1-(5-O-acetyl-2,3-dideoxy-β-D-glycero-pent-2-enofuranosyl)-thymine is dissolved in 25 mL of absolute pyridine and refluxed for 48 hours with 2 g of phosphorus pentasulfide. After cooling, the solution is decanted from the insolubles and evaporated to dryness under vacuum. The resulting residue is fractionated by column chromatography on Kieselgel 40 with chloroform as eluent. From the fractions containing the product, 265 mg of 1-(5-O-acetyl-2,3-dideoxy-β-D-glycero-pent-2-enofuranosyl)-4-thiothymine is obtained after recrystallization from methanol.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([S:9]([OH:12])(=[O:11])=[O:10])[C:5]([O:7][CH3:8])=[O:6].[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C>[N:13]([CH2:2][CH2:3][CH:4]([S:9]([OH:12])(=[O:11])=[O:10])[C:5]([O:7][CH3:8])=[O:6])=[N+:14]=[N-:15]
Reactant: COC(=O)C(CCBr)S(=O)(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCN=[N+]=[N-])S(=O)(=O)O
Yield: 95 %

Procedure:
Methyl 4-bromo-2-sulfo-butyrate (1.07 g, 4.11 mmol) and sodium azide (0.70 g (10.7 mmol) in DMF (50 ml) was stirred overnight. The mixture was evaporated and purified by SiO2 chromatography and eluted with 1:5:0.01 CH3OH/CH2Cl2/HAc and crystallized with CH3OH/Toluene/Hexane to afford 1.00 g (95%) of the title compound. m.p=267-272° C. (decomp). 1H NMR (DMF-d7): 12.06 (br, 1H), 3.65 (s, 3H), 3.59 (dd, 1H, J=5.4, 8.9 Hz), 3.47 (m, 2H), 2.24 (m, 2H). 13C NMR 171.10, 64.29, 52.24, 50.64, 21.35. ESI MS m/z+ 267.9 (M+2Na—H), m/z− 222.0 (M−H). HRMS m/z− (C5H9N3O5S—H) calcd 222.0185. found 222.0179.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:16][N:15]=[C:10]1[CH2:11][CH2:12][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCC(c2ccccc2)CC1
Temperature: 70 °C
Yield: 97 %

Procedure:
A mixture of 4-phenylcyclohexanone (28.7 mmol), hydroxylamine hydrochloride (36.0 mmol), and sodium acetate (60.95 mmol) in ethanol and water was heated at 70° C. overnight. Ethanol was removed, and the residue was dissolved in water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried, and concentrated to give 1-(hydroxyimino)-4-phenylcyclohexane (97%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:24])=[CH:21][CH:20]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(Cl)c1ccc(Br)cc1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(Br)cc4)cc3c2C1
Yield: 19 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 14.7 mg (0.051 mMol) 4-bromobenzoyl chloride, 3.6 mg (20%) of the title compound were recovered as a light beige solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=1)[N:9]=[C:8]2[NH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[N:31]=[CH:30]2)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[N:9]=[C:8]2[NH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[N:31]=[CH:30]2)(=[O:3])[CH3:2]
Reactant: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OC(C)=O
Agent: [Pd]
Solvent: CO
Product: COc1cc2nc(-c3cccc(N)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OC(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of tert-butyl 5-(6-acetoxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.40 g, 0.70 mmol) in MeOH (100 mL) was added Pd/C (0.15 g) under an atmosphere of N2. The mixture was then stirred under an atmosphere of H2 (balloon pressure) for 48 h at RT. The mixture was filtered through a pad of Celite® washing with MeOH. The filtrate was concentrated in vacuo to give the desired product tert-butyl 5-(6-acetoxy-2-(3-aminophenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate. (0.23 g, 0.43 mmol, 61%). HPLC retention time 5.748 mins.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:19]([O-:21])=[O:20])[C:10]=1[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].Cl.[N:23]([O-])=O.[Na+].[H+].[B-:28]([F:32])([F:31])([F:30])[F:29]>O>[F:29][B-:28]([F:32])([F:31])[F:30].[C:11]([C:10]1[C:9]([N+:19]([O-:21])=[O:20])=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[N+:1]#[N:23])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=N[O-]
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: O
Product: N#[N+]c1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 3-amino-4-benzoyl-5-nitrobenzoic acid (57.2 g) and conc. hydrochloric acid (250 ml) is heated on a steam bath for 10 minutes. After cooling, the amine is diazotized by the dropwise addition of a solution of sodium nitrite (16 g) in water (80 ml), while stirring at -5° C to 0° C. After additional stirring at this temperature for 10 minutes, 50% aqueous hydrofluoboric acid (220 ml) is added during about 5 minutes. The mixture is left for 1 hour, keeping the temperature below 0° C by external cooling. The precipitate formed is then collected by filtration and washed with two portions of icecold water (each portion 25 ml). The material is suspended in acetone (200 ml) and stirred for 15 minutes. It is collected by filtration, washed with acetone, followed by diethyl ether and dried to give 2-benzoyl-5-carboxy-3-nitrobenzenediazonium tetrafluoroborate.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([OH:11])=O)=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:9]([C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=2)=[O:11])=[CH:15][CH:14]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1ccc(F)cc1)c1n[nH]cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
4-Nitropyrazole-3-carboxylic acid (10 g; 63.66 mmol) was added to a stirred solution of 4-fluoroaniline (6.7 ml; 70 mmol), EDC (14.6 g; 76.4 mmol), and HOBt (10.3 g; 76.4 mmol) in DMF (25 ml), then stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure and the residue triturated with ethyl acetate/saturated brine solution. The resultant yellow solid was collected by filtration, washed with 2M hydrochloric acid, then dried under vacuum to give 15.5 g of the title compound. (LC/MS: Rt 2.92 [M+H]+ 250.89).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.BrCC(C1C(C)=C(SCC)C=CN=1)=O.C([O-])([O-])=O.[K+].[K+]>>[N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][CH:2]=1
Reactant: Clc1nc2ccccc2[nH]1
Agent: CCSc1ccnc(C(=O)CBr)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc2[nH]cnc2c1

Procedure:
2-Chlorobenzimidazole is reacted with 2-bromoacetyl-4-ethylthio-3-methylpyridine in the presence of K2CO3 to give 2-chloro-1-[2-[4-ethylthio-3-methylpyridyl])-2-oxoethyl]benzimidazole. This is reacted with thiourea and treated with NH4OH to give 2-mercapto-1-(2-(2-(4-ethylthio-3-methylpyridyl))-2-oxoethyl)benzimidazole
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[N:18]=[CH:17]3)[CH:10]([NH2:12])[CH3:11])[CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.[NH4+].[Cl-]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[N:18]=[CH:17]3)[CH:10]([NH:12][S:39]([CH:36]2[CH2:38][CH2:37]2)(=[O:41])=[O:40])[CH3:11])[CH:6]=[CH:5][N:4]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: COc1cc(C(Oc2ccc3c(cnn3-c3cccnc3)c2)C(C)N)ccn1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(Oc2ccc3c(cnn3-c3cccnc3)c2)C(C)NS(=O)(=O)C2CC2)ccn1
Reaction time: 20 h

Procedure:
To a stirred solution of 1-[2-methoxypyridin-4-yl]-1-[1-(pyridin-3-yl)indazol-5-yl]oxypropan-2-amine (41 mg, 110 μmol) in dichloromethane (4 ml) was added triethylamine (36 μl), followed by cyclopropanesulfonic acid chloride (23 mg, i 60 μmol) and DMAP (1.3 mg, 11 μmol).The stirring was continued for 20 h at room temp. The reaction mixture was poured into sat. NH4Cl solution and extracted with dichloromethane then the solvent was removed i.vac., and the product purified by chromatography on silica gel. Yield 4 mg (7.6%) as a racemic mixture of one diastereomer.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.Cl>C(COC)OC.O.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)CCCOc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(C(=O)c2ccc(OCCCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
41 g of methyl 4-[4-(4-methoxybenzoyl)phenoxy]butyrate from Example 2 are dissolved in 600 ml of dimethoxyethane/water 4:1, and 63 ml of 2N sodium hydroxide solution are added. The mixture is stirred at room temperature for 4 hours, then acidified to pH 3 with 3N hydrochloric acid, and the organic solvent is removed in vacuo. The acid which has separated out is filtered off and dried over phosphorus pentoxide in vacuo.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[CH3:8][NH:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[C:12]([N+:19]([O-:21])=[O:20])[CH:11]=1>C(O)=O>[N+:16]([C:14]1[CH:15]=[C:10]([CH:11]=[C:12]([N+:19]([O-:21])=[O:20])[CH:13]=1)[N:9]([CH3:8])[CH:5]=[O:7])([O-:18])=[O:17]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: O=CO
Product: CN(C=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of formic acid (10 ml.) and acetic anhydride (5 ml.) was stirred at room temperature for 30 minutes. N-methyl-3,5-dinitroaniline (5.0 g.) was then added and the reaction mixture was heated on a steam bath for 10 minutes. The mixture was allowed to cool to room temperature during 40 minutes, then poured into ice-water and the precipitate was filtered off. Recrystallisation from methanol gave 3',5'-dinitro-N-methylformanilide (2.2 g.), m.p. 93°-94°C.