Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C(O)(C(F)(F)F)=O.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(N2CCCNCC2)ccc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(N2CCCN(S(C)(=O)=O)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-[3-(methyloxy)-4-nitrophenyl]hexahydro-1H-1,4-diazepine (as the TFA salt) (1.0 g, 2.08 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (0.87 mL, 6.25 mmol). Methanesulfonyl chloride (0.24 mL, 3.12 mmol) was added slowly and stirred at rt for 30 min. At this time the reaction mixture was diluted with dichloromethane and washed with a saturated bicarbonate solution, water and a saturated sodium chloride solution, dried over Na2SO4 and filtered. Solvents were removed under reduced pressure to afford 1-[3-(methyloxy)-4-nitrophenyl]-4-(methylsulfonyl)hexahydro-1H-1,4-diazepine. (0.737 g, 2.24 mmol) as a yellow/brown solid. ESIMS (M+H)+=330.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[CH:6]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].BrC[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([O:11][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[CH:8]=[C:7]([O:12][C:22]2[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(O)cc(O)c1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Oc2ccc(C#N)cc2)cc(Oc2ccc(C#N)cc2)c1
Temperature: 35 °C
Yield: 83 %

Procedure:
To a solution of 3,5-dihydroxy benzoic acid ethyl ester 1.2 g (6.58 mmol), dissolved in 10 ml DMF, was added K2CO3 3.63 g (26.32 mmol) followed by 4-bromomethyl-benzonitrile 5.16 g (26.32 mmol) in 5 ml of DMF at 20° C. The reaction mixture was allowed to attain RT and then heated to 35° C. for 8 h. The solvent was removed under reduced pressure and the residue was dissolved in 200 ml of ethyl acetate. The organic layer was washed with brine and water. Organic phase was dried over anhydrous sodium sulphate and solvent was removed under reduced pressure. The crude product was subjected to column chromatography and eluted using hexane:ethyl acetate (8:2) to afford 2.1 g of purified product. 1H NMR (DMSO-d6): 1.3 (3H, t), 4.3 (2H, q), 5.3 (4H, s), 7.0 (1H, s), 7.18 (2H, s), 7.64 (4H, d), 7.86 (4H, d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.ClCCl.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O>[CH3:21][S:22]([O:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1cccc(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 112.6 %

Procedure:
To a cooled (0° C.) mixture of 46.2 g of 3-fluorobenzenethanol, 40 ml of N,N-diethylethanamine and 500 ml of dichloromethane, there were added dropwise 41.2 g of methanesulfonyl chloride, keeping the temperature below 5° C. After stirring for 18 hours at room temperature, the reaction mixture was diluted with water and extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 81 g (100%) of 2-(3-fluorophenyl)ethanol methanesulfonate (ester) (interm. 34).
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])CC1N=CNC=1.[NH2:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14]>>[NH2:12][C@H:13]([C:15]([OH:17])=[O:16])[CH2:14][C:9]([OH:11])=[O:10].[NH2:1][CH2:2][C:9]([OH:11])=[O:10]
Reactant: C[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Product: NCC(=O)O
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
To study the effect of other amino acid residues at the ligation junction in exSAL, the glycopeptide-peptide thioester pairs shown below were examined. Glycopeptides containing N-terminal histidine and aspartic acid residues were synthesized by SPPS (Fmoc strategy). These were reacted with peptide thioesters containing C-terminal glycine, histidine and alanine residues under the mixed solvent system. The ligation between glycopeptide 44 and the peptide thioester 49 bearing a C-terminal glycine gave an isolated yield of 86% (entry 1 above). The peptide thioester containing a C-terminal histidine residue ligated in good yield (70%, entry 2 below) in accord with the previously reported SAL method. By increasing the steric bulk of the C-terminal amino acid of the thioester component, the ligation efficiency substantially decreased (44% for Ala-Gly, entry 3 below). Remarkable ligation yields were achieved for glycopeptides which bear an N-terminal aspartic acid residue. The isolated ligation yield which utilized this glycopeptide exceeded those for the glycine glycopeptide 44 (64-91% yield, entries 7-9 below). Suprisingly, even sterically challenging ligation junctions such as His-His (73%, entry 5 below), Ala-His (77%, entry 6 below) and His-Asp (91%, entry 8 below) gave excellent yields.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1.O.[OH-].[Li+].CO>C1COCC1>[CH3:21][C:19]1[CH:18]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cc(C)cc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)cc(CC2CCc3[nH]c(C(=O)O)cc32)c1

Procedure:
The title compound was synthesized from methyl 4-(3,5-dimethylbenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.066 g, 0.23 mmol) and lithium hydroxide monohydrate (0.049 g, 1.16 mmol), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF was used. The resulting product was purified by chromatography over silica gel (gradient 0 to 100% EtOAc in heptane over 20 min) to afford the title compound. 30 mg. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.06 (ddt, J=12.47, 8.52, 6.03, 6.03 Hz, 1H), 2.26 (s, 6H), 2.44-2.70 (m, 5H), 3.17-3.26 (m, 1H), 6.31 (s, 1H), 6.79 (s, 2H), 6.82 (s, 1H). LCMS m/e 270 (M+H) and 97% pure by HPLC.
Reaction SMILES: O1CCC(C2N=C3C=CC=C(N)N3N=2)[CH2:2]1.[Br:16][C:17]1[N:31]=[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([NH:25][C@@H:26]3[CH2:30][CH2:29][O:28][CH2:27]3)[N:19]2[N:18]=1.[H-].[Na+].IC>COCCOC.C(OCC)(=O)C>[Br:16][C:17]1[N:31]=[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([N:25]([CH3:2])[C@@H:26]3[CH2:30][CH2:29][O:28][CH2:27]3)[N:19]2[N:18]=1
Reactant: Brc1nc2cccc(N[C@@H]3CCOC3)n2n1
Reactant: Nc1cccc2nc(C3CCOC3)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: COCCOC
Product: CN(c1cccc2nc(Br)nn12)[C@@H]1CCOC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71.2 %

Procedure:
(R)-2-Bromo-N-methyl-N-(tetrahydrofuran-3-yl-[1,2,4]triazolo[1,5-a]pyridin-5-amine. (R)-2-Bromo-N-(tetrahydrofuran-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-amine (500.0 mg, 1.766 mmol) was suspended in 1,2-dimethoxyethane (8.83 mL) and cooled to 0° C. The reaction was purged with nitrogen followed by the addition of sodium hydride (89.0 mg, 3.53 mmol, 95%). The mixture was allowed to stir for 10 min. Iodomethane (330.0 μL, 5.30 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature and stir for 16 h. Ethyl acetate was added to the reaction and allowed to stir for 1 min followed by an extraction with ethyl acetate and water. The organics were washed with brine and dried with magnesium sulfate. Organic volatiles were removed under reduced pressure and purified using silica gel chromatography on an Emrys Biotage SP1 (10-100% ethyl acetate in hexanes) over 1.2 L. The desired fractions were combined and organic volatiles removed under reduced pressure to afford (R)-2-bromo-N-methyl-N-(tetrahydrofuran-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-amine (373.8 mg, 1.258 mmol, 71.2% yield). MS (ESI) m/z 297.1 [M]+, 299.1 [M+2]+.
Reaction SMILES: Br[CH2:2][C:3](=[O:17])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)C(C)C)(C)C.[CH2:27]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[CH2:42][NH:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[O:51][CH3:52])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[CH2:27]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[CH2:42][N:43]([CH2:2][C:3](=[O:17])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[O:51][CH3:52])=[O:36])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccccc1CNC[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: O=C(CBr)C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1CN(CC(=O)C(c1ccccc1)c1ccccc1)C[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.1 %

Procedure:
3-Bromo-1,1-diphenyl-2-propanone (12.7 g) and N,N-diisopropylethylamine (15.7 ml) were added successively to a solution of (2S)-2-[(2-methoxybenzylamino)methyl]pyrrolidine-1-carboxylic acid benzyl ester (15.6 g) in tetrahydrofuran (156 ml) at 0° C. After being stirred at room temperature for 2 hours, the mixture was poured into ice-water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (3:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give a colorless syrup of (2S)-2-[[N-(2-oxo-3,3-diphenylpropyl)-N-(2-methoxybenzyl)amino]methyl]pyrrolidine-1-carboxylic acid benzyl ester (1.51 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[Cl:32])[CH2:28][CH:27]([NH:33][CH3:34])[CH2:26][CH2:25]2>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:33]([CH3:34])[CH:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][C:31]([Cl:32])=[C:22]([Cl:21])[CH:23]=4)[CH2:28]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNC1CCc2cc(Cl)c(Cl)cc2C1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C1CCc3cc(Cl)c(Cl)cc3C1)CC2

Procedure:
The title compound is prepared from 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-chloropropane and 6,7-dichloro-2-methylamino-1,2,3,4-tetrahydronaphthalene analogously to Example 1. Mp.: 130° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:9]=[C:10]([NH2:12])[N:11]=2)[C:7]=1Cl.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:9]=[C:10]([NH2:12])[N:11]=2)[C:7]=1[NH:19][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Nc1nc2ccc(Br)c(Cl)n2n1
Reactant: NC1CCCCC1
Product: Nc1nc2ccc(Br)c(NC3CCCCC3)n2n1

Procedure:
The title compound was prepared following procedure described for intermediate A9 but starting from 6-bromo-5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-amine (3.0 g; 12.1 mmol; 1.0 eq.) and cyclohexylamine (12.0 mL; 104.9 mmol; 8.65 eq.) to give the title compound as a dark foam (2.5 g, 66%). HPLC, Rt: 3.21 min. (purity 76.6%). LC/MS, M+(ESI): 310.0.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1.C([O:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:39]=[C:40]([CH:43]=[C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:45]=1)[CH:41]=O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>O1CCCC1>[OH:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:39]=[C:40]([CH:43]=[C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:45]=1)[CH2:41][NH:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(N)nc3ccccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)OCCCCOc1cc(C=O)cc(-c2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCCOc1cc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 30.1 %

Procedure:
2-Amino-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1H-benzimidazole (0.20 g) and 3-(4-acetoxybutoxy)-5-phenylbenzaldehyde (0.19 g) were suspended in tetrahydrofuran (3 mL), and the mixture was stirred at room temperature for 13 hours. To the reaction mixture was added sodium triacetoxyborohydride (0.21 g), and the mixture was stirred at room temperature for 24 hours. After adding water to the reaction mixture, the mixture was concentrated under reduced pressure. The obtained residue was dissolved in methanol (2 mL). To the reaction mixture was added 5 mol/L aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added acetic acid (1 mL), and the mixture was concentrated under reduced pressure. The obtained residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELL PAC C18UG80, 5 μm, 20×50 mm, flow rate 30 mL/minutes linear gradient, water/methanol=70/30-10/90) to give the title compound (0.08 g).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[N+:14]([O-])([O-:16])=[O:15].[K+]>OS(O)(=O)=O>[CH3:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1)=[O:8]
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc([N+](=O)[O-])c2[nH]c(=O)oc(=O)c2c1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
6.9 g (40 mmol) of the above 5-Methylisatoic anhydride was suspended in 40 mL of conc. H2SO4 at −10° C. and cooled to −20° C. Next, 1.05 eq of potassium nitrate dissolved in 12 mL of sulfuric acid and cooled to 0° C., was then added dropwise. The reaction mixture was stirred 20° C. for 15 min then kept between −5° C. and 0° C. for 3 h. The mixture was poured into a beaker containing ice. The resulting solid was collected, washed with cold water and dried to give 3.9 g (44%) of 5-methyl-3-nitroisatoic anhydride as a solid.
Reaction SMILES: [C:1]1([N:7]=[N:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33]>O>[CH2:33]([O:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]=[N:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:10][CH:11]=1)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=[CH2:23]
Reactant: Oc1ccc(N=Nc2ccccc2)cc1
Reactant: C=CCCCCCCCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: C=CCCCCCCCCCOc1ccc(N=Nc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
4-(phenyldiazenyl)phenol (2.100 g; 10.60 mmol) and potassium tert-butoxide (1.247 g; 11.13 mmol) were placed in a dry, two-neck, round-bottom flask equipped with a magnetic stirring bar, a reflux condenser, and a rubber septum. The flask was evacuated and purged with dry argon, then 25 mL of anhydrous N,N-dimethylformamide was added while stirring. As soon as the solids disappeared, 11-bromo-1-undecene (2.44 mL; 2.595 g; 11.13 mmol) was added and the solution was quickly heated, and allowed to reflux for 10 min. Formation of white precipitate was observed, and the color of the solution changed from deep red to bright orange. After 10 min, the heating was discontinued, and the flask was allowed to cool down. The reaction mixture was poured into a separatory funnel containing 100 mL of water, and extracted with four 50 mL portions of hexane. Hexane fractions were combined and dried over magnesium sulfate. Hexane was removed on a rotary evaporator, and the residue was purified by column chromatography (ethyl acetate:hexane 1:20) to give 2.95 g (79.5%) of analytically pure product.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H]>[Pt].C(N(CC)CC)C>[F:1][C:2]([F:11])([F:12])[CH:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: [H][H]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: [Pt]
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(O)C(F)(F)F
Temperature: 40 °C
Reaction time: 6 h
Yield: 95.9 %

Procedure:
Ethyl 4,4,4-trifluoroacetoacetate (50 g), under a blanket of nitrogen gas, was heated to 40° C. and treated with platinum (0.1 g of 5% Pt/C, 0.01% load) and triethylamine (1.5 g, 2.9% load). Hydrogen was charged to a pressure of 5 bars, and the mixture agitated at 40° C. for 6h. After filtration to remove the catalyst, 48.5 g (96% yield) of ethyl 4,4,4-trifluoro-3-hydroxybutyrate was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:43]=[CH:44][C:45]=1[OH:46])[O:7][CH2:8][CH2:9][N:10](CC1C=CC=CC=1)[CH2:11][CH:12]([C:14]1[CH:19]=[C:18]([O:20]CC2C=CC=CC=2)[CH:17]=[C:16]([O:28]CC2C=CC=CC=2)[CH:15]=1)[OH:13])(=[O:3])[NH2:2].[H][H]>CO.[Pd]>[C:1]([C:4]1[CH:5]=[C:6]([CH:43]=[CH:44][C:45]=1[OH:46])[O:7][CH2:8][CH2:9][NH:10][CH2:11][CH:12]([OH:13])[C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([OH:28])[CH:15]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)ccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cc(OCCNCC(O)c2cc(O)cc(O)c2)ccc1O

Procedure:
A solution of 31 g of crude N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-N-[2-(3,5-dibenzyloxyphenyl)-2-hydroxy-ethyl]-benzylamine in 300 ml of methanol is hydrogenated under normal conditions over 6 g of palladium-on-charcoal catalyst (5%) until 3 mol equivalents of hydrogen have been taken up. The catalyst is filtered off, the filtrate is evaporated and the residue is dissolved in 200 ml of isopropanol. Filtering through silica gel and evaporating the filtrate yields α-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]aminomethyl]-3,5-dihydroxy-benzyl alcohol in the form of a brownish foam. After recrystallisation from ethylacetate/methanol the compound is obtained in pure state with a melting point of 203°-205°, and contains 1/4 mol of crystal-water. The compound is characterised by the following signals in the proton nuclear magnetic resonance spectrum in hexadeuterodimethylsulfoxide as the solvent:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[N+:13]([O-])([OH:15])=[O:14].N>S(=O)(=O)(O)O>[N+:13]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:4]=1[O:3][C:2]([F:11])([F:12])[F:1])[NH2:8])([O-:15])=[O:14]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Product: Nc1ccc(OC(F)(F)F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 63 %

Procedure:
20 g (112.9 mmol) of 4-trifluoromethoxyaniline were dissolved in 50 ml of concentrated sulfuric acid at a temperature of 0 to 5° C., treated with 30 ml of a 4/1 mixture of sulfuric acid and nitric acid. The mixture was stirred for 5 hours at 0° C. and then poured into an ice-cold water mixture and made alkaline with 200 ml of concentrated aqueous ammonia solution. Extraction with EE, drying with sodium sulfate, evaporation to dryness and recrystallization from ethyl acetate/heptane gave 15.5 g (63%) of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][N:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:25]4[N:24]([CH3:23])[CH:28]=[CH:27][CH:26]=4)[CH:3]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cn1cccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
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: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3cccn3C)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a degassed solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 1-methyl-2-pyrroleboronic acid pinacol ester (96.8 mg, 0.56 mmol) and K2CO3 (116 mg, 0.84 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.014 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(1-methyl-1H-pyrrol-2-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) δ (ppm): 7.61 (dd, 1H), 7.57 (d, 1H), 7.4 (s, 1H), 7.37 (m, 2H), 7.17 (d, 1H), 7.07 (d, 1H), 6.8 (d, 1H), 6.21 (d, 1H), 6.1 (dd, 1H), 4.76 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.7 (m, 3H), 3.57 (m, 1H), 3.2 (m, 4H), 3.03 (m, 1H), 2.42 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:28])[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cccnc2c1-c1cccc(F)c1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(3-fluorophenyl)quinolin-7-yl]ethanone (76 mg, 0.25 mmol) and ammonium acetate (195 mg, 2.54 mmol) in methanol (1.4 mL) and acetonitrile (1.4 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling, sodium cyanoborohydride (31.9 mg, 0.507 mmol) was added to the resultant mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature, quenched with saturated sodium bicarbonate, and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and then evaporated to dryness. The residue was used directly in next step (52 mg, 68%). LCMS calculated for C17H15ClFN2(M+H)+: m/z=301.1; found: 301.0.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]#N)[CH:5]=[CH:4][C:3]=1[CH3:10].[OH-:11].[Na+].[OH2:13]>>[Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:13])=[O:11])[CH:5]=[CH:4][C:3]=1[CH3:10]
Reactant: [OH-]
Reactant: Cc1ccc(C#N)nc1Br
Reactant: O
Agent: [Na+]
Product: Cc1ccc(C(=O)O)nc1Br
Temperature: 120 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
6-Bromo-5-methyl-pyridine-2-carbonitrile (1.0 g, 5.0 mmol) was added to a solution of sodium hydroxide (0.3 g, 7 mmol) in water (20 mL), the mixture was stirred at 120° C. overnight. Subsequently, the mixture was adjusted to pH=3 and extracted with ethyl acetate (2×15 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the product (0.7 g, 63.8%); MS (EI): m/e 216.0 [M+H]+.