Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[C:18](=[O:24])[C:17]([CH3:26])([CH3:25])[CH2:16]2.[NH4+].[Cl-]>C1COCC1>[OH:24][C:18]1([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[C:19]2[C:15](=[CH:14][C:13]([O:12][CH3:11])=[C:21]([O:22][CH3:23])[CH:20]=2)[CH2:16][C:17]1([CH3:26])[CH3:25]
Reactant: COc1cc2c(cc1OC)C(=O)C(C)(C)C2
Reactant: COc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2(O)c3cc(OC)c(OC)cc3CC2(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A small portion of 4-bromoanisole is added to a suspension of magnesium (72 mg, 3 mmol) in 6 ml of anhydrous THF. The mixture is heated at gentle reflux to initiate the reaction, then the remainder of the brominated derivative (0.56 g, 3 mmol), in solution in 5 ml of THF, is added dropwise over the course of 15 min. After reflux for 1 h, the magnesium has been consumed. 5,6-Dimethoxy-2,2-dimethylindan-1-one (0.66 g, 3 mmol) is added in small portions. The solution is stirred for 1 h at room temperature, then heated at reflux for 4 h. 10 ml of saturated aqueous NH4Cl solution are added at 0° C. The mixture is extracted with AcOEt. The organic phases collected are washed with saturated aqueous NaCl solution, dried over MgSO4 and evaporated to give a yellow oil (1.20 g). Purification by chromatography (eluent: AcOEt/hexane=1:5) enables the isolation of the expected product (0.65 g, 66%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[N:12](O)=[O:13]>>[N:12]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]=[CH:10]2)=[O:13]
Reactant: Oc1cccc2ccncc12
Reactant: O=NO
Product: O=Nc1ccc(O)c2cnccc12

Procedure:
The 8-hydroxyisoquinoline is reacted with nitrous acid to form 5-nitroso-8-hydroxyisoquinoline. The nitrous acid is generated in situ by the action of mineral acid, such as hydrochloric, sulfuric, and the like, on sodium nitrite usually under cold temperature conditions.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([N+:11]([O-:13])=O)=[C:8]([CH:10]=1)[NH2:9])[CH3:2].[N:14]#[C:15][NH2:16].[CH]Cl.[OH-].[Na+]>O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[N+:11]([O-:13])=[N:14][C:15]([NH2:16])=[N:9][C:8]=2[CH:10]=1)[CH3:2]
Reactant: CCOc1ccc([N+](=O)[O-])c(N)c1
Reactant: N#CN
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1ccc2c(c1)nc(N)n[n+]2[O-]
Temperature: 50 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
A mixture of 5-ethoxy-2-nitroaniline (15) (1.63 g, 9.0 mmol) and cyanamide (1.50 g, 35.8 mmol) were mixed together at 100° C., cooled to 50° C., cHCl (15 mL) added carefully and the mixture heated at 100° C. for 4 h. The mixture was cooled to 50° C., 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100° C. for 3 h. The mixture was cooled, diluted with water (100 mL), filtered, washed with water (3×20 mL), washed with ether (3×5 mL) and dried. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give amine 16 (1.26 g, 68%) as a yellow powder, mp (MeOH) 268-271° C.; 1H NMR [(CD3)2SO] δ 8.02 (d, J=9.4 Hz, 1 H, H-8), 7.19 (brs, 2 H, NH2), 6.92 (dd, J=9.4, 2.6 Hz, 1 H, H-7), 6.83 (d, J=2.6 Hz, 1 H, H-5), 4.17 (q, J=7.0 Hz, 2 H, CH2O), 1.37 (t, J=7.0 Hz, 3 H, CH3); 13C NMR [(CD3)2SO] δ 163.9, 160.7, 151.2, 124.8, 121.4, 117.1, 104.2, 64.2, 14.1. Anal. Calcd for C9H10N4O2: C, 52.4; H, 4.9; N, 27.2. Found: C, 52.4; H, 4.8; N, 27.0%.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]=2[CH:10]=[CH:9][CH:8]=1.B(O)(O)O.S(=O)(=O)(O)O>>[C:1]([CH2:2][CH2:3][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]=2[CH:10]=[CH:9][CH:8]=1)([OH:5])=[O:4]
Reactant: C=CC(=O)O
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Agent: O=S(=O)(O)O
Agent: OB(O)O
Product: O=C(O)CCNc1cccc2c1C(=O)c1ccccc1C2=O
Reaction time: 12 h
Yield: 91.5 %

Procedure:
15 Parts of acrylic acid are gradually added to a mixture of 22.3 parts of 1-aminoanthraquinone, 6.2 parts of boric acid and 120 parts of 100% sulphuric acid at 30°-35° C, and the mixture is then stirred for 12 hours at 90° - 95° C. The reaction mixture is then processed as described in Example 1 to give 27 parts (91.5%) of 1-(β-carboxyethylamino)anthraquinone.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[C@@H:8]([CH2:15][CH3:16])[N:7]([C@@H:17]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]3)[C:6]=2[N:5]=1.[CH3:24]I>CC(N(C)C)=O>[Cl:3][C:4]1[N:13]=[CH:12][C:11]2[N:10]([CH3:24])[C:9](=[O:14])[C@@H:8]([CH2:15][CH3:16])[N:7]([C@@H:17]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]3)[C:6]=2[N:5]=1
Reactant: CI
Reactant: CC[C@@H]1C(=O)Nc2cnc(Cl)nc2N1[C@@H]1CCC(F)(F)C1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1[C@@H]1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
60% sodium hydride in mineral oil (22.41 mg, 0.56 mmol) was added to a mixture of (R)-2-chloro-8-((R)-3,3-difluorocyclopentyl)-7-ethyl-7,8-dihydropteridin-6(5H)-one (169 mg, 0.53 mmol) and methyl iodide (36.54 μL, 0.59 mmol) in dimethylacetamide (1.7 mL). The reaction mixture was stirred at room temperature for 1 hour. Ice was added to the reaction mixture. A solid crashed out and was filtered off, rinsing with water. The solid was dried in a pistol under vacuo at 70° C. The compound was obtained as a white solid (165 mg, 94% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=[O:21])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.[CH3:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28]>>[CH2:19]([O:21][C:12]1([O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C:18]1[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:6][CH2:7]3)[CH2:20][CH2:3][CH2:4][CH2:5][CH3:18]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CCCCCCO
Product: CCCCCCOC1(OCCCCCC)CC[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@@]21C

Procedure:
5 g of 3-methoxy-estra-1,3,5(10)-trien-17-one is reacted according to example 1a. N-hexanol is used as alcohol. The reaction mixture was used in the next step without a preceding working up.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[OH-].[K+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([O:21][CH3:22])[CH:13]=1.Cl>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[CH3:22][O:21][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[N+:18]([O-:20])=[O:19])[O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: OCCN1CCCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: Cl
Agent: [Cl-]
Product: COc1cc(OCCN2CCCC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
1-(2-Hydroxyethyl)pyrrolidine (1.6 g, 14 mmol) was added to a mixture of powdered KOH (0.78 g, 14 mmol) and Aliquat 336 (0.56 g, 1.4 mmol) and the resulting mixture was stirred for 5 minutes at 80° C. Then 4-fluoro-2-methoxy-1-nitrobenzene (2.0 g, 12 mmol) was added, and stirring proceeded at this temperature for 30 minutes. The mixture was cooled and partitioned between methylene chloride (75 mL) and water (75 mL), and the organic phase was washed with water (75 mL) and extracted with dilute aqueous HCl (3×60 mL). The combined aqueous phases were washed with methylene chloride (3×75 mL), basified (3N NaOH), and extracted with methylene chloride (3×75 mL). The combined organic extracts were washed with water (3×100 mL), dried (MgSO4), and evaporated, providing 2.4 g, in 76% yield; 1H NMR of the HCl salt (DMSO-d6) δ 1.83-2.01 (m, 4H), 3.04-3.19 (m, 4H), 3.58 (t, J=5.0 Hz, 2H), 3.94 (s, 3H), 4.51 (t, J=5.0 Hz, 2H), 6.74 (dd, J=9.0 Hz, J=2.4 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 7.99 (d, J=9.0 Hz, 1H), 10.97 (br, 1H).
Reaction SMILES: [NH2:1][CH:2]([CH:7]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C:3]([O:5][CH3:6])=[O:4].[C:25]1([CH:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32](O)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:35]1([CH:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:32]([NH:1][CH:2]([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[C:3]([O:5][CH3:6])=[O:4])=[O:33])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(N)C(Sc1cccc(OC)c1)c1cccc(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(NC(=O)C(c1ccccc1)c1ccccc1)C(Sc1cccc(OC)c1)c1cccc(OC)c1

Procedure:
A solution of 0.94 g (2.7 mmol) of (R,S; R,S)-2-amino-3-(3-methoxyphenyl)-3-(3-methoxyphenyl-sulfanyl)propionic acid, methyl ester of Example 32, 15 mL of methylene dichloride, 0.69 g (3.2 mmol) of diphenylacetic acid, 0.62 g (3.2 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDAC), and 0.02 g (0.16 mmol) of 4-dimethylaminopyridine (DMAP) is stirred at room temperature for 18 hours. The reaction solution is diluted with 100 mL of methylene dichloride, washed with 80 mL of 1N sodium hydroxide and then 80 mL of 1N hydrochloric acid, dried (magnesium sulfate), and evaporated. The residue is purified via silica gel chromatography eluting with 25% ethyl acetate-hexane to give the product as an inseparable mixture of diastereomers; wt 1.10 g (90%);
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:8](=[O:12])(=[O:11])([OH:10])O>ClC1C=CC=CC=1Cl>[NH2:1][C:2]1[C:7]([S:8]([OH:12])(=[O:11])=[O:10])=[CH:6][C:5]([S:8]([OH:10])(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=S(=O)(O)O
Solvent: Clc1ccccc1Cl
Product: Nc1ccc(S(=O)(=O)O)cc1S(=O)(=O)O

Procedure:
186.2 g (2 mols) of aniline are initially introduced into 500 ml of 1,2-dichlorobenzene and 208.3 g (2.04 mols) of 96% strength sulphuric acid are added dropwise. The mixture is heated for 8 hours at the boil under a water separator, during which period distillate passes over at a rate of 700 ml per hour, cooled and filtered with suction. After it has been dried, the precipitate weighs 338.5 g and contains 86.1% of p-sulphanilic acid (84.2% of the theoretical yield) and 11.2% of aniline-2,4-disulphonic acid (7.5%, relative to aniline).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14](Cl)=[O:15])=[C:12]([CH3:17])[O:11][N:10]=1.[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)[CH3:19].C(N(CC)CC)C>ClCCl>[CH3:17][C:12]1[O:11][N:10]=[C:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:13]=1[C:14]([NH:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([O:20][CH2:18][CH3:19])=[O:29])=[O:15]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(NC(=O)c2c(-c3c(F)cccc3Cl)noc2C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(2-Chloro-6-fluorophenyl)5-methylisoxaz-4-oyl chloride (7.9 g, 29.0 mmol) was added in portions to a stirred solution of ethyl-3-aminobenzoate (4.0 g, 29.0 mmol) and triethylamine (4.04 mL, 29.0 mmol) in dry dichloromethane at 0° C. Following the final addition, the mixture was allowed to warm to ambient temperature and stir for 1 hour. The solution was washed with 0.5M aqueous hydrochloric acid, brine, aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and evaporated to a foam which was used in subsequent reactions without further purification.
Reaction SMILES: C(O)(=O)C.O.O1CCCC1.C1COCC1.[O:16]=[C:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1/[CH:31]=[CH:32]/[CH:33]=[CH:34]/[CH:35]([O:44]C1CCCCO1)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]>C1COCC1>[OH:44][CH:35]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])/[CH:34]=[CH:33]/[CH:32]=[CH:31]/[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:17](=[O:16])[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: CCCCCCCCC(/C=C/C=C/c1ccccc1C(=O)CCCC(=O)OC)OC1CCCCO1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCCCCC(O)/C=C/C=C/c1ccccc1C(=O)CCCC(=O)OC
Reaction time: 16 h
Yield: 60.9 %

Procedure:
To 1 ml of a 3:1:1 solution of acetic acid, water, and tetrahydrofuran THF) was added 20mg (0.041 mmol) of the titled product of Example 10 and the reaction mixture was allowed to stir 16 hr. After this time, some insoluble oil was still present and approximately 50μl of THF was added to the reaction mixture and it was stirred for an additional 2 hours. The volatile components were removed in vacuo and the residue was flash chromatographed. Elution with 1:1 diethylether-hexane produced b 10 mg of the desired product.
Reaction SMILES: C(O[C:4]([C:6]1[S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[N:14]=1)=[O:5])C.[C:15]1([C@H:21]([NH2:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[Al](C)C.CCCCCC>ClCCl>[C:15]1([C@H:21]([NH:23][C:4]([C:6]2[S:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:13]=3[N:14]=2)=[O:5])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1nc2ccncc2s1
Reactant: C[C@@H](N)c1ccccc1
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1nc2ccncc2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of thiazolo [5,4-c]pyridine-2-carboxylic acid ethyl ester (16 mg, 0.08 mmol) and 1(R)-phenyl ethyl amine (0.03 mL, 0.23 mmol) in dichloromethane(0.3 mL)was added a solution of trimethylaluminum in hexane(0.115 mL, 2.0 M., 0.23 mmol). The solution was then stirred for 5 hours at room temperature. After usual work-up, the product was purified by flash chromatography (CH2Cl2/EtOAc 1:1)and triturated in hexane to give 14 mg of the thiazolo derivative.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][NH:11][C:12](=[O:22])[C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:44][CH2:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([C:54](=[O:65])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=2[C:61]([F:64])([F:63])[F:62])[CH2:50][CH2:49]1)=[O:47].Cl>CN(C=O)C.O>[CH3:10][NH:11][C:12](=[O:22])[C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:44][CH2:45][C:46](=[O:47])[N:48]2[CH2:49][CH2:50][N:51]([C:54](=[O:65])[C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=3[C:61]([F:64])([F:62])[F:63])[CH2:52][CH2:53]2)=[O:18])=[CH:15][CH:14]=1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: CNC(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.74 %

Procedure:
DIPEA (165 mg, 0.2 mL, 1.2 mmol) was added drop wise to N-methyl-terephthalamic acid (80 mg, 0.4 mmol) in DMF (5 mL). EDCI (100 mg, 0.5 mmol) and HOBT (67 mg, 0.5 mmol) were added consecutively and, after 10 minutes, 2-Amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone in its HCl salt form (150 mg, 0.4 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using basic alumina and 10% MeOH in CHCl3 as eluent) to afford 30 mg (15.74% yield) of N-methyl-N′-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-terephthalamide. LCMS Purity: 97.3%. 1H NMR (CDCl3): δ 8.7 (d, 2H), 8.2 (d, 2H), 7.8 (m, 1H), 7.7 (m, 3H), 7.2 (m, 2H), 4.4 (m, 2H), 4.1 (s, 1H), 3.8 (s, 3H), 3.4 (m, 4H).
Reaction SMILES: C(OC([NH:8][C:9]1[O:10][C:11]([CH3:22])=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]=1)=O)(C)(C)C.[C:23]1(B(O)O)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C([O-])(=O)C.[K+]>O1CCOCC1>[CH3:22][C:11]1[O:10][C:9]([NH2:8])=[N:13][C:12]=1[C:31]1[C:32]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Cc1oc(NC(=O)OC(C)(C)C)nc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cccc2ccccc12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1oc(N)nc1-c1cccc2ccccc12
Temperature: 180 °C
Reaction time: 1 h
Yield: 13.9 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 2-tert-butoxycarbonylamino-5-methyl-oxazol-4-yl ester (100 mg), 1-naphthaleneboronic acid (61 mg) palladium (0) tetrakis(triphenylphosphine) (17 mg), potassium acetate (85 mg) and 1,4-dioxane (5 mL) was heated at 180° C. for 24 hours. The solvent was removed under reduced pressure and to the resulting yellow oil was added dichloromethane (18 mL) and trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 1 hour and then the solvent was removed under reduced pressure, the resulting oil was diluted with ethyl acetate and washed with a saturated solution of sodium hydrogen carbonate, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to afford a brown oil. Purification by column chromatography afforded 5-methyl-4-naphthalen-1-yl-oxazol-2-ylamine (30) (9 mg, 14%) as a white solid. 1H NMR (DMSO-D6): 2.15 (3H, s), 6.5 (2H, br s), 7.4-7.5 (4H, m), 7.85-7.90 (2H, m), 8.2 (1H, m). Mass Spectrum (m/z): 225 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][CH2:9]Cl)[CH3:6])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(O)(=O)C>C1COCC1>[CH2:1]([O:3][C:4]([C:5]1([CH3:6])[CH2:9][CH2:8][N:7]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:18])[CH3:2]
Reactant: CCOC(=O)C(C)N(CCCl)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCN1Cc1ccccc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of 2-[benzyl-(2-chloro-ethyl)-amino]-propionic acid ethyl ester (1 eq.) in dry THF was cooled to −78° C. under nitrogen. KHMDS (15% w/w in toluene) (1.25 eq.) was slowly added so that temperature was kept below −65° C. The reaction was stirred for 1 h at −70° C. Then acetic acid (0.3 eq.) was added. The reaction was warmed to 20° C. and stirred for 10 min, then quenched with a saturated aqueous solution of NaHCO3 and partially concentrated under reduced pressure. The crude was extracted twice with DCM. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc 1/0 then 95/5) to afford 1-benzyl-2-methyl-azetidine-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[OH:15].Br[CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.CN(C)C=O>O1CCCC1.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30]
Reactant: COc1cc2nccc(O)c2cc1OC
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(OCCCN3C(=O)c4ccccc4C3=O)c2cc1OC
Yield: 14.4 %

Procedure:
6,7-Dimethoxy-4-hydroxyquinoline (4.0 g, 19.5 mM), N-(3-bromopropyl)phthalimide (5.8 g, 21.5 mM), potassium carbonate (5.4 g, 39 mM) and DMF dimethylformamide (20 ml) were stirred at 60° C. for 1.5 hours. Water, ethyl acetate and tetrahydrofuran were added to the reaction solution for extraction. The solid which precipitated after standing for a period was filtered out to obtain N-(3-(6,7-dimethoxyquinolin-4-yloxy)propyl)phthalimide (1.1 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Cl>CO.CC(OC)(C)C.Cl[Pd]Cl.O.C(Cl)Cl>[F:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: OB(O)c1cc(F)c(F)cc1F
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccnc(-c2cc(F)c(F)cc2F)c1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 33.1 %

Procedure:
Methyl 2-chloroisonicotinate (3.25 g, 18.94 mmol), 2,4,5-trifluorophenylboronic acid (5.00 g, 28.41 mmol), potassium carbonate (3.93 g, 28.41 mmol) and PdCl2 (dppf) (0.411 g, 0.57 mmol) were mixed in methanol (20 mL) in two 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. The reaction mixture was suspended in methanol, filtered and the filtrate evaporated to yield a dark red slurry. DCM and water were added and the phases separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield a brown solid. The crude brown solid was dissolved in MTBE (120 mL) and solids filtered off. Hydrogen chloride (4 M in dioxane, 4.74 mL, 18.94 mmol) was added dropwise and a suspension was formed. The suspension was stirred at room temperature for 45 min. The solid was collected by filtration and washed with MTBE. MTBE and satd NaHCO3 were added. The organic phase was dried over Na2SO4, filtered and evaporated to yield methyl 2-(2,4,5-trifluorophenyl)isonicotinate (1.676 g, 33%) as a beige solid. The MTBE-filtrate was washed with satd NaHCO3, dried over Na2SO4, filtered and evaporated to yield a brown solid. The residue was purified via Biotage (0=>20% EtOAc in heptane, 6 CV; Biotage® KP-SIL 100 g column) to yield methyl 2-(2,4,5-trifluorophenyl)-isonicotinate (0.86 g, 17%) as a white solid. 1H NMR (600 MHz, cdcl3) δ 3.97 (s, 3H), 7.00-7.07 (m, 1H), 7.81 (dd, 1H), 7.90-7.97 (m, 1H), 8.32-8.33 (m, 1H), 8.83 (dd, 1H). MS m/z 268 (M+H)+