Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH3:6][O:7][C:8](=[O:18])[CH2:9][N:10]1[CH:14]=[C:13]([CH2:15][CH2:16][NH2:17])[N:12]=[CH:11]1.[CH:19]1(O)[CH2:24][CH2:23]C[CH2:21][CH2:20]1>S(=O)(=O)(O)O>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH:6]1([O:7][C:8](=[O:18])[CH2:9][N:10]2[CH:14]=[C:13]([CH2:15][CH2:16][NH2:17])[N:12]=[CH:11]2)[CH2:23][CH2:24][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)Cn1cnc(CCN)c1
Reactant: OC1CCCCC1
Agent: O=S(=O)(O)O
Product: NCCc1cn(CC(=O)OC2CCCCC2)cn1
Temperature: 110 °C

Procedure:
[4-(2-Amino-ethyl)-imidazol-1-yl]-acetic acid methyl ester sulphate (1 g, 3.6 mmol) is suspended in cyclohexanol (50 ml) and treated with concentrated sulphuric acid (5 drops). The reaction mixture is heated to 110° C. for 4 hours and concentrated in vacuo. The residue is dissolved in saturated sodium bicarbonate solution and the mixture is concentrated in vacuo. The resulting solid is triturated with methanol, filtered and the filtrate is reduced in vacuo. The crude solid is dissolved in water, washed with DCM and the aqueous portion is concentrated in vacuo to yield the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 89.6 %

Procedure:
To a solution of 3,5-dichlorobenzoic acid (50 g, 0.26 mol) in sulfuric acid (250 mL) at 0° C. was added nitric acid (18 g, 0.28 mol) dropwise, and the mixture warmed slowly to ambient temperature. After 5 hours the mixture was poured onto ice, and the white precipitate collected by filtration. The solid was washed with water (3×30 mL), and dried in vacuo to afford 55 g (90% yield) of 3,5-dichloro-2-nitrobenzoic acid; NMR (CDCl3) 8.3 (s, 1), 8.0 (s, 1) ppm.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9](=[O:21])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[C:7]1[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=1[S:5]2.[CH:26]1([CH2:29][O:30][C:31]2[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:32]=2[CH:33]=O)[CH2:28][CH2:27]1.[O-]CC.[Na+]>C(O)C>[CH2:27]1[CH2:28][CH:26]1[CH2:29][O:30][C:31]1[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:32]=1/[CH:33]=[CH:1]/[C:2]1[N:3]=[C:4]2[S:5][C:6]3[CH:25]=[CH:24][CH:23]=[CH:22][C:7]=3[N:8]2[C:9](=[O:21])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=1
Reactant: COc1cccc(C=O)c1OCC1CC1
Reactant: Cc1nc2sc3ccccc3n2c(=O)c1-c1ccc(C(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sc4ccccc4n3c(=O)c2-c2ccc(C(F)(F)F)cc2)c1OCC1CC1
Yield: 42.3 %

Procedure:
The title compound was synthesized by condensation of Intermediate 23 (250 mg, 0.690 mmol) with 2-Cyclopropylmethoxy-3-methoxybenzaldehyde (200 mg, 0.970 mmol) in presence of sodium ethoxide (94 mg, 1.380 mmol) in ethanol (15 ml) according to the procedure outlined in Example 24 to give 160 mg of the desired product as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.28-0.30 (m, 2H), 0.51-0.53 (m, 2H), 0.90-1.01 (m, 1H), 3.69 (d, J=7.5 Hz, 2H), 3.77 (s, 3H), 6.92 (d, J=15.6 Hz, 2H), 6.98-7.00 (m, 2H), 7.56-7.64 (m, 4H), 7.84-7.86 (m, 2H), 8.06-8.08 (m, 1H), 8.22 (d, J=15.6 Hz, 1H), 8.84-8.86 (m, 1H); ESI-MS (m/z) 549.36 (M+H)+.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>C1(C)C=CC=CC=1>[OH:26][CH2:25][CH2:27][NH:28][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1
Reactant: NCCO
Reactant: COC(=O)c1ccc(/C=C/c2c(-c3ccccc3)noc2C)nc1
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccccc2)c1/C=C/c1ccc(C(=O)NCCO)cn1
Temperature: 35 °C
Yield: 71.6 %

Procedure:
To a stirred solution of 6-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-nicotinic acid methyl ester (200 mg, 0.62 mmol) in toluene (0.5 mL) was added ethanolamine (46 mg, 0.75 mmol) and TBD (26 mg, 0.10 mmol), then the reaction mixture was warmed to 35° C. After 3 h the reaction mixture was concentrated. Purification by chromatography (silica, dichloromethane:methanol 100:0 to 93:7) afforded the title compound (155 mg, 71%) as a white solid after trituration with hexane/ethyl acetate. MS: m/e=350.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:29](I)[CH3:30]>C(#N)C>[CH2:29]([O:20][C:6]1[C:5]([O:21][CH3:22])=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[CH:8][C:7]=1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[O:14][CH2:13]2)[CH3:30]
Reactant: CCI
Reactant: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(OCC)c1OC
Temperature: 75 °C
Yield: 60.9 %

Procedure:
To a stirring solution of 5-(4-ethoxy-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (30 mg, 0.1 mmol) in acetonitrile (5 mL) was added potassium carbonate (41 mg, 0.30 mmol) and ethyl iodide (62 mg, 0.40 mmol) and the resultant reaction mixture was heated to 75° C. for 2 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded the title compound as a solid (20 mg, 61%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([C:20]([F:23])([F:22])[F:21])[C:14]([C:18]#[N:19])=[CH:15][CH:16]=3)[CH:11]=[C:10]2[CH3:24])[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[CH3:24][C:10]1[N:9]([CH2:8][C:4]2[CH:3]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=3)[CH:7]=[CH:6][CH:5]=2)[C:17]2[C:12]([CH:11]=1)=[C:13]([C:20]([F:23])([F:22])[F:21])[C:14]([C:18]#[N:19])=[CH:15][CH:16]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cccc(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cccc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
Synthesized as described in Example 310D using 1-[(3-bromophenyl)methyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 318A) and [4-(trifluoromethyl)phenyl]boronic acid: MS (ES) m/z 459 (M+1).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][O:4][N:3]=1.COC(=O)[C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[N:12][CH:11]=1.[OH-].[Li+].O1CCCC1>O1CCCC1.O>[N:12]1[CH:11]=[CH:10][CH:15]=[C:14]([O:16][C:2]2[CH2:6][CH2:5][O:4][N:3]=2)[CH:13]=1
Reactant: BrC1=NOCC1
Reactant: COC(=O)c1cncc(O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: c1cncc(OC2=NOCC2)c1

Procedure:
The enantiomers of 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole III-74a and III-74b were prepared in 2 steps according to the following procedures: racemic 3-bromo 4,5-dihydroisoxazole III-66 was reacted with 5-hydroxynicotinic acid methyl ester using Method 5. The resulting ester (1.0 equiv) was dissolved in 1:1 tetrahydrofuran/water (0.06 M) and lithium hydroxide (8.0 equiv) was added. The reaction was allowed to stir at room temperature for 1 h after which point the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified to pH<2 with 1N HCl to provide the racemic desired acid III-74 as a white solid which was isolated via vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=395.5 m/z. Activity: A
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([O:25]CC)[N:14]([CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>CO.O1CCOCC1>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([OH:25])[N:14]([CH2:15][CH2:16][NH2:17])[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOc1nc2c(N)nc3cccnc3c2n1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCCn1c(O)nc2c(N)nc3cccnc3c21
Temperature: 25 °C
Yield: 89.6 %

Procedure:
A solution of tert-butyl 2-(4-amino-2-ethoxy-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethylcarbamate (6 g, 16 mmol) in methanol (25 mL) was combined with a solution of hydrogen chloride in dioxane (102 mL of 4N). The reaction mixture was allowed to stir over night at ambient temperature and was then concentrated under reduced pressure to provide crude product as an orange solid. The solid was loaded onto a silica gel column. The column was eluted with 47.5% methanol/2.5% ammonium hydroxide in dichloromethane. The fractions were combined and concentrated under reduced pressure to provide an orange solid. The solid was triturated with hot acetonitrile and methanol and then allowed to cool. The solid was isolated by filtration and then washed sequentially with acetonitrile and diethyl ether to provide 3.5 g of 4-amino-1-(2-aminoethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-ol.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][C:14](OB(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(OCC)(=O)C>[N:11]1[CH:16]=[CH:15][C:14]([C:2]2[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)Oc1ccncc1
Reactant: COC(=O)c1ccc(Br)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccncc2)o1
Yield: 17.2 %

Procedure:
To a solution of methyl 5-bromo-2-furancarboxylate (820 mg), 4-pyridyl boric acid (500 mg), tetrakistriphenyl-phosphine palladium(0) (250 mg) in dimethoxyethane (15 ml) was added 2 M sodium carbonate solution (4 ml) and the solution was heated for 15 hours under reflux. The reaction solution was diluted with ethyl acetate, and the organic layer was separated, washed with water, extracted with 1 N hydrochloric acid. The extract was made alkaline with sodium hydroxide solution, extracted with ethyl acetate, dried and concentrated to give a colorless solid of methyl 5-(4-pyridyl)-2-furancarboxylate (126 mg). 1H-NMR (CDCl3) δ: 3.94 (3H, s), 6.96 (1H, d, J=3.8 Hz), 7.27 (1H, d, J=3.8 Hz), 7.64 (2H, d, J=6.2 Hz), 8.68 (2H, d, J=6.2 Hz). IR (KBr): 1727, 1608, 13.7, 1145 cm−1.
Reaction SMILES: [Mg].[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[CH3:11][N:12]([CH3:25])[C:13]1(C#N)[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1.[Cl-].[NH4+]>C(OCC)C>[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][C:13]2([N:12]([CH3:25])[CH3:11])[CH2:22][CH2:21][C:16]3([O:20][CH2:19][CH2:18][O:17]3)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C1(Cc2ccc(F)cc2)CCC2(CC1)OCCO2
Reaction time: 1 h

Procedure:
925 mg magnesium were stirred into 19 ml analytical grade diethyl ether under a nitrogen atmosphere and approximately one third of the solution of 4.95 g 4-fluorobenzyl chloride in 19 ml analytical grade diethyl ether was added. The remainder of the solution was rapidly added dropwise after the Grignard formation had started, and when the addition had ended the mixture was subsequently stirred for one hour, a solution of 4.00 g 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile in 25 ml analytical grade diethyl ether was then added dropwise and the reaction mixture was stirred overnight. For working up, 29 ml ammonium chloride solution (20 per cent by weight) were added, while cooling with ice, the phases were separated, the aqueous phase was extracted twice with 50 ml diethyl ether each time and the combined organic phases were washed successively with 20 ml water and 20 ml saturated sodium chloride solution. The crude [8-(4-fluorobenzyl)-1,4-dioxaspiro[4.5]dec-8-yl]dimethylamine obtained (5.76 g of yellow solid) was stirred, without further purification, with a mixture of 14 ml conc. hydrochloric acid (32 per cent by weight) and 8 ml water for 24 hours at room temperature. The reaction mixture was then first washed three times with 30 ml diethyl ether each time and then adjusted to pH 9 by addition of aqueous ammonia (25 per cent by weight), while cooling with ice, and extracted three times with 40 ml methylene chloride each time, the combined methylene chloride extracts were dried over sodium sulfate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. 4.70 g 4-dimethylamino-4-(4-fluorobenzyl)cyclohexanone were obtained as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[S:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]2)=[S:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C)cc1NC(=S)Oc1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(C)c(C)cc1NC(=S)N1CCN(c2cc(C)cc(C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate(200 mg, 0.7 mmol) and 1-(3,5-dimethylphenyl)piperazine(154 mg 0.7 mmol) were dissolved in anhydrous tetrahydrofuran and DBU(106 mg) was added thereto. The mixture was stirred at room temperature for 2 hours and concentrated under the reduced pressure to remove the solvent. The concentrate was purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].Cl.[Cl:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Cl.[OH-].[Na+]>C1(C)C(C)=CC=CC=1.CN1C(=O)CCC1>[ClH:11].[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[N:4]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: ClCCNCCCl
Reactant: Nc1cc(F)ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1C
Product: Fc1ccc(F)c(N2CCNCC2)c1
Temperature: 130 °C

Procedure:
0.03 Mol of 2,5-difluoroaniline and 0.03 mol of bis-(2-chloroethyl)amine hydrochloride are suspended in 50 mL of xylene and 15 mL of NMP. The mixture is heated at 130° C. for 25 h while stirring, then cooled to RT and the solvents are evaporated. The residue is dissolved in water and 1 equivalent of 2N aqueous sodium hydroxide (NaOH) is added. The mixture is extracted with dichloromethane (DCM), and the organic layer is dried over anhydrous MgSO4, filtered and evaporated to dryness in vacuo. The residue is dissolved in acetone and 1 equivalent of HCL in diethyl ether (Et2O) is added. The precipitated product is collected by filtration and recrystallized from isopropanol to afford 1-(2,5-difluorophenyl)piperazine hydrochloride: m.p. 195° C. LC/MS (M+1=199.1). 1H NMR (DMSO-d6, 400 MHz) δ 3.22 (m, 4H), 3.28 (m, 4H), 6.83 (m, 1H), 6.97 (m, 1H), 7.22 (m, 1H), 9.46 (br s, NH).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][CH2:12][NH:11][C:10](=[O:14])[C@H:9]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>N1C=CC=CC=1>[S:22]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][CH2:12][NH:11][C:10](=[O:14])[C@H:9]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:4][CH:3]=1)([CH3:21])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1NCC[C@@H](c2ccc(O)cc2)[C@@H]1c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Oc1ccc([C@@H]2CCNC(=O)[C@H]2c2ccccc2)cc1
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 1.34 g (0.005 mol) of 27 in 10 cm3 of anhydrous pyridine, 1.14 g (0.01 mol; 0.77 cm3) of methanesulfonyl chloride are added under an atmosphere of nitrogen at 0° C. The mixture is stirred for 1 hour at between 0° and 3° C. before being poured into 70 cm3 of cold water. This mixture is extracted with methylene chloride and washed to neutrality. After evaporation and recrystallization in methanol, 29 is obtained in 61% yield. M.p. 199° C.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:34]=[CH:33][C:18]([O:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[C:17]([O:35][CH3:36])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:36][O:35][C:17]1[CH:16]=[C:15]([CH:34]=[CH:33][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26])[CH2:14][O:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=1
Reactant: COC(=O)Cc1cn(C)nc1O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(C)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 57.2 %

Procedure:
A mixture of methyl (3-hydroxy-1-methyl-1H-pyrazol-4-yl)acetate (340 mg), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (687 mg), potassium carbonate (553 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 5 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-methyl-1H-pyrazol-4-yl]acetate (546 mg, yield 57%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[N+:10]([C:13]1[C:26]2[C:25](=[O:27])[C:24]3[C:19](=[C:20]([N+:28]([O-])=O)[CH:21]=[CH:22][CH:23]=3)[C:18](=[O:31])[C:17]=2[CH:16]=[CH:15][CH:14]=1)([O-:12])=[O:11].S(=O)(=O)(O)[OH:33]>O>[OH:33][C:23]1[C:24]2[C:25](=[O:27])[C:26]3[C:17](=[CH:16][CH:15]=[CH:14][C:13]=3[N+:10]([O-:12])=[O:11])[C:18](=[O:31])[C:19]=2[C:20]([NH2:28])=[CH:21][CH:22]=1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2cccc([N+](=O)[O-])c21
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Product: Nc1ccc(O)c2c1C(=O)c1cccc([N+](=O)[O-])c1C2=O
Reaction time: 3 h

Procedure:
A mixture of 300 parts of 28% strength oleum and 30 parts of 1,5-dinitroanthraquinone are stirred for 3 hours at 50° to 60° C. After the addition of 85.5 parts of 78% strength sulphuric acid and 165 parts of water with cooling the reaction mixture is stirred for 6 hours at room temperature and then left to stand overnight. The mixture is added to 1,000 parts of water, and the product is filtered off with suction and washed with water until neutral. After drying, 23.3 parts of crude 1-hydroxy-4-amino-8-nitroanthraquinone are obtained, which can be purified by recrystallisation from dimethylformamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[C:15]([C:21]([OH:23])=O)[NH:16]2.[NH2:24][CH:25]1[CH2:30][CH2:29][C:28]([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][C@H:37]([OH:40])[C@@H:36]([CH3:41])[CH2:35]2)([OH:31])[CH2:27][CH2:26]1>>[OH:31][C:28]1([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][C@H:37]([OH:40])[C@@H:36]([CH3:41])[CH2:35]2)[CH2:29][CH2:30][CH:25]([NH:24][C:21]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[C:12]([O:11][CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:26][CH2:27]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: COc1ccccc1CCOc1cccc2[nH]c(C(=O)O)cc12
Product: COc1ccccc1CCOc1cccc2[nH]c(C(=O)NC3CCC(O)(CCN4CC[C@H](O)[C@@H](C)C4)CC3)cc12

Procedure:
This compound is synthesized analogously to example 1 from 4-[2-(2-methoxy-phenyl)-ethoxy]-1H-indole-2-carboxylic acid 16j and amine 14.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[NH2:5].Cl[C:24]1[N:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[N:28][CH:29]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:1][CH:2]([CH3:22])[CH2:3][CH:4]([NH:5][C:24]1[N:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[N:28][CH:29]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: CC(C)CC(N)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: COC(=O)c1cnc(Cl)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)c1cnc(NC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Temperature: 25 °C
Yield: 52 %

Procedure:
A solution of 3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butan-1-amine (0.200 g, 0.651 mmol), methyl 5-chloropyrazine-2-carboxylate (124 mg, 0.716 mmol), and diisopropylethylamine (168 mg, 1.30 mmol) in 2-propanol (5 mL) was heated in a microwave reactor at 100° C. for 2 h. The mixture was cooled to room temperature and concentrated. The mixture was concentrated and purified by column chromatography to give methyl 5-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)pyrazine-2-carboxylate (150 mg, 52%). 1H NMR (400 MHz, CDCl3, δ): 8.75 (s, 1H), 7.87 (s, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 5.46 (s, 1H), 5.04 (t, 1H), 4.12 (s, 3H), 1.87-1.80 (m, 1H), 1.80-1.60 (m, 2H), 1.02 (d, J=6.4 Hz, 3H), 0.98 (d, J=6.4 Hz, 3H).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[N:23][C:24](S(C)(=O)=O)=[N:25][CH:26]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.CN1CCCC1=O.[F:38][C:39]1[CH:44]=[CH:43][C:42]([C@@H:45]([NH2:47])[CH3:46])=[CH:41][CH:40]=1.[OH-].[K+]>C(O)(=O)C>[Cl:19][C:17]1[CH:18]=[C:13]2[C:12]([CH2:20][C:21]3[CH:26]=[N:25][C:24]([NH:47][C@H:45]([C:42]4[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=4)[CH3:46])=[N:23][CH:22]=3)=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1
Reactant: CS(=O)(=O)c1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Reactant: C[C@H](N)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: C[C@H](Nc1ncc(Cc2c[nH]c3ncc(Cl)cc23)cn1)c1ccc(F)cc1

Procedure:
In a microwave vial, 1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (132, 12 mg, 0.026 mmol) was mixed with 600 μL of N-methylpyrrolidinone and (S)-1-(4-fluoro-phenyl)-ethylamine (133, 25.2 mg, 0.18 mmol). The reaction was irradiated at 200° C. for 40 minutes in microwave, then potassium hydroxide (500 μL, 4.00 M in water) was added and the reaction irradiated at 90° C. for 10 minutes in microwave. The reaction was neutralized with the addition of 120 μL of acetic acid, solvents were removed under vacuum, and the resulting material was dissolved in 400 μL of dimethyl sulfoxide for purification by HPLC. The desired compound was purified on Phenomenex C18 column (50 mm×10 mm ID) with mobile phase A of 0.1% trifluoroacetic acid in water, mobile phase B of 0.1% trifluoroacetic acid in acetonitrile, 20-100% B over 16 minutes at a flow rate of 6 mL/min. Appropriate fractions were collected and solvents removed under vacuum to provide the desired compound. MS (ESI) [M+H′]′=381.9.