Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[C:12](O)([CH3:15])([CH3:14])[CH3:13].OS(O)(=O)=O.O>C(O)(C(F)(F)F)=O>[C:12]([C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:8]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)O
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.3 %

Procedure:
2-Trifluoromethyl-phenol (2.98 g, 18.3 mmol) was dissolved in 12 mL TFA and t-butanol (1.43 g, 19.3 mmol) and H2SO4 (0.24 mL) were added. The reaction was stirred at rt for 48 hrs, after which water was added and the compound was extracted into DCM. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (2/1 Hex/EtOAc) to yield 2.01 g of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13].C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:17][N:18]([CH:20]=[C:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[C:8]1=[O:13])[CH3:19]
Reactant: CCOC(OCC)N(C)C
Reactant: COc1cccc2c1CCCC2=O
Product: COc1cccc2c1CCC(=CN(C)C)C2=O

Procedure:
The 3,4-dihydro-2-(dimethylaminomethylene)-5-methoxy-1(2H)-naphthalenone starting material was prepared from 5-methoxy-1-tetralone (5.0 g, 28.4 mmol) and N,N-dimethylformamide diethyl acetal (25 g, 170.2 mmol) to give the desired product as brown needles (5.27 g). m.p. 108-110°. MS (ES+) 232 (MH+, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([OH:15])[CH:9]=2)=[O:5])[CH3:2].[CH:16]([N:19]1[CH2:23][CH2:22][CH:21](O)[CH2:20]1)([CH3:18])[CH3:17].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH:21]1[CH2:22][CH2:23][N:19]([CH:16]([CH3:18])[CH3:17])[CH2:20]1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(C)N1CCC(O)C1
Reactant: CCOC(=O)c1cc2ccc(O)cc2[nH]1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(OC3CCN(C(C)C)C3)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.9 %

Procedure:
A mixture of 1 g (4.8 mmol) ethyl-6-hydroxyindole-2-carboxylate (Journal of the American Chemical Society (1967), 89(13), 3349-50), 0.81 g (6.3 mmol) 1-isopropyl-3-pyrrolidinol, 2.83 ml (11 mmol) tri-n-butyl-phosphine and 2.56 g (9.75 mmol) 1,1′azodicarbonyl-dipiperidine in 50 ml THF was stirred at room temperature for 16 h. The suspension was filtered and the filtrated evaporated to dryness. The residue was purified with column chromatography on silica eluting with a gradient from DCM/2N NH3 in MeOH 99/1 to 19/1. The product containing fractions were combined and evaporated to dryness to yield a brown oil which was crystallized from diethyl ether and heptane to afford 0.5 g of brownish crystals (MS (m/e): 317.1 (MH+, 100%)). and after evaporation of the filtrate 0.6 g of slightly impure product which was used without further purification in the consecutive step.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[S:5].[Cl:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:18][CH:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][C:2]([CH3:1])([CH3:17])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[S:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=S)CC(C)(C)CCc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=S)CC(C)(C)CC(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.06 g (3.09 mmol) of ethyl 3,3-dimethyl-5-phenylthiopentanoate in 10 mL of carbon tetrachloride was added to 590 mg (4.4 mmol) of 1-chloro-2,5-pyrrolidinedione, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered, and the filtrate concentrated to give ethyl 5-chloro-3,3-dimethyl-5-phenylthiopentanoate as an oil. The product was used without further purification in the reaction described in Example 3 below.
Reaction SMILES: COC(=O)[CH2:4][NH:5][CH2:6][C@H:7]([NH:14][C:15]([O:17]CC1C=CC=CC=1)=O)[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.N#N>CO.C(Cl)Cl.[Pd]>[CH:8]1([C@H:7]2[NH:14][C:15](=[O:17])[CH2:4][NH:5][CH2:6]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)CNC[C@H](NC(=O)OCc1ccccc1)C1CCCCC1
Agent: [Pd]
Agent: N#N
Solvent: ClCCl
Solvent: CO
Product: O=C1CNC[C@@H](C2CCCCC2)N1
Reaction time: 18 h
Yield: 128.3 %

Procedure:
To a 2.0 L round bottom flask containing a solution of ((R)-2-Benzyloxycarbonylamino-2-cyclohexyl-ethylamino)-acetic acid methyl ester (27 g, 77 mmol) in MeOH (300 mL) under a stream of N2 was added Pd (10% on carbon, 4.1 g, 0.05 equiv). The mixture was stirred under 1.0 atm of H2 for 18 hours. The mixture was diluted with 100 mL of CH2Cl2 and filtered through Celite. The filtrate was concentrated to give crude product (R)-6-Cyclohexyl-piperazin-2-one 18 g (127%). The product, which contained impurity and solvent, was continued to the next step with no further purification.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][CH2:13][OH:14])[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH2:13][O:14][C:23](=[O:25])[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCN(CCO)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OCCN(Cc2ccccc2)CCO1
Yield: 227.6 %

Procedure:
The procedure of Example 1 was followed using N-benzyl diethanolamine (16.4 g, 83.9 mmol), triethylamine (24.0 mL, 167.8 mmol), dry THF (600 mL) and triphosgene (8.3 g, 28.8 mmol). The filtrate was concentrated yielding a yellow oil product (14.5 g, 78%).
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[NH:11][CH:10]=[N:9][C:8]=2[N:7]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>CC(C)=O>[CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([S:27]([CH3:26])(=[O:29])=[O:28])[CH:10]=[N:9][C:8]=2[N:7]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCn1c(=O)c2c(ncn2S(C)(=O)=O)n(CCCC)c1=O
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To 500 mg (1.89 mmol) of 1,3-dibutyl-3,7-dihydro-purine-2,6-dione in 30 mL of acetone at 23° C. was added 1.04 g (7.56 mmol) of potassium carbonate followed by 0.15 mL (216 mg, 1.89 mmol) of methanesulfonyl chloride. After stirring at 23° C. for 30 min, the reaction mixture was filtered, the filtrate collected and evaporated to give a white solid. This solid was then triturated with 30 mL of petroleum ether to give 500 mg (1.46 mmol, a 77% yield) of the title compound as a white crystalline solid. mp: 98-100° C.; 1H NMR (300 MHz, CDCl3); δ 0.93-0.99 (m, 6H), 1.42-1.49 (m, 4H), 1.55-1.58 (m, 2H), 1.60-1.70 (m, 2H), 3.85 (s, 3H), 3.99-4.04 (m, 2H), ), 4.05-4.16 (t, 2H), 8.17 (s, 1H), 8.55; IR (KBr, cm−1): 3144w, 2965m, 2938m, 2876w, 1715s, 1663s, 1537s, 1442m, 1397s, 1182s, 1131,m, 761m, 670m; MS (ES) m/z (relative intensity): 343 (M++H, 100).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N:8]([CH2:10][CH2:11][OH:12])[CH3:9].[C:13]1([CH:23]2[CH2:25][O:24]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.[ClH:26]>CC(C)=O.C(OCC)(=O)C>[ClH:26].[CH3:7][N:8]([CH2:10][CH2:11][O:12][CH2:25][CH:23]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[OH:24])[CH3:9]
Reactant: c1ccc2c(C3CO3)cccc2c1
Reactant: CN(C)CCO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CN(C)CCOCC(O)c1cccc2ccccc12
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A mixture of 13.2 g of potassium tert-butoxide and 47.2 ml of 2-(N,N-dimethylamino)ethanol was heated to 80° C. Thereto was dropwise added 40.0 g of 2-(1-naphthyl)oxirane in 3.5 hours. The resulting mixture was stirred for 1.5 hours at 80°-85° C. The reaction mixture was cooled and added to a mixture of 100 ml of ethyl acetate and 100 ml of ice water. The resulting mixture was adjusted to pH 11.5 with 6N hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with 50 ml of ethyl acetate. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was subjected to distillation to obtain a fraction having a boiling point of 152°-163° C./0.6-0.8 mmHg. The oily product obtained was dissolved in 200 ml of acetone. Into the solution was blown hydrogen chloride gas with ice cooling. The resulting crystals were collected by filtration, washed with acetone, and dried to obtain 22.7 g of 2-[2-(N,N-dimethylamino)ethoxy]-1-(1-naphthyl)ethanol hydrochloride (compound No. 228).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH2:13]>C(#N)C>[CH:5]1[C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=[C:9]2[C:4]=1[C:3]1[C:2]([NH:1]2)=[C:2]2[NH:1][C:9]3[CH:8]=[CH:7][C:6]([C:10]([OH:13])=[O:13])=[CH:5][C:4]=3[C:3]2=[C:2]2[NH:1][C:9]3[CH:8]=[CH:7][C:6]([C:10]([OH:12])=[O:11])=[CH:5][C:4]=3[C:3]=12
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: O
Solvent: CC#N
Product: O=C(O)c1ccc2[nH]c3c4[nH]c5ccc(C(=O)O)cc5c4c4c5cc(C(=O)O)ccc5[nH]c4c3c2c1
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
10 ml of acetonitrile were placed in a 200 ml three-mouth flask followed by dissolving 1.42 g of indole-5-carboxylic acid. On the other hand, preparation of the oxidizing agent solution was carried out by dissolving 16.2 g of anhydrous ferric chloride and 5.4 g of water in 40 ml of acetonitrile and stirring for 10 minutes. Next, after dropping in the prepared oxidizing agent solution into the aqueous indole-5-carboxylic acid solution over the course of 30 minutes, the solution was stirred for 10 hours at 60° C. The reaction solution changed from a pale yellow color to a light green color while generating a small amount of heat, and its pH was 1 or less. Following completion of the reaction, the reaction solution was aspiration filtered with a Kiriyama funnel, washed with acetonitrile and then methanol and dried to obtain 1.12 g of light green 6,11-dihydro-5H-diindolo[2,3-a:2′,3′-c]carbazole-2,9,14-tricarboxylic acid (indole-5-carboxylic acid trimer) (yield: 79%).
Reaction SMILES: [OH:1][C:2]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:20])=[C:12]2[C:3]=1[C:4](=O)[C:5]1[CH:6]=[C:7]([C:25]([OH:27])=[O:26])[C:8]([C:22]([OH:24])=[O:23])=[CH:9][C:10]=1[C:11]2=[O:21].[CH:29]([C:32]1[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]([CH3:41])[CH3:40])[C:33]=1[NH2:34])([CH3:31])[CH3:30].ClC1C=CC=CC=1Cl>O>[CH:39]([C:35]1[CH:36]=[CH:37][CH:38]=[C:32]([CH:29]([CH3:31])[CH3:30])[C:33]=1[N:34]=[C:4]1[C:3]2[C:12](=[C:13]([OH:20])[C:14]3[C:19]([C:2]=2[OH:1])=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[O:21])[C:10]2[CH:9]=[C:8]([C:22]([OH:24])=[O:23])[C:7]([C:25]([OH:27])=[O:26])=[CH:6][C:5]1=2)([CH3:41])[CH3:40]
Reactant: O=C(O)c1cc2c(cc1C(=O)O)C(=O)c1c(c(O)c3ccccc3c1O)C2=O
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: O
Solvent: Clc1ccccc1Cl
Product: CC(C)c1cccc(C(C)C)c1N=C1c2cc(C(=O)O)c(C(=O)O)cc2C(=O)c2c1c(O)c1ccccc1c2O
Reaction time: 18 h
Yield: 49.3 %

Procedure:
0.5 g (1.32 mmoles) of 6,11-Dihydroxy-naphthacene-5,12-dione-2,3-dicarboxylic acid (product of Example 8), 0.28 g (1.58 mmoles) of 2,6-diisopropylaniline, and 25 ml of o-dichlorobenzene are refluxed for 4 h with azeotropic removal of the reaction water. The mixture is filtered while hot, and the filtrate is kept at 25° for 18 h. The precipitate is washed with hot hexane and dried to give 0.35 g (51%) of red crystals, m.p. 328-330°.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:35]1([CH2:41][C:42](Cl)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[C:13]([N:15]1[CH2:20][CH2:19][C@H:18]([N:21]2[CH2:26][CH2:25][N:24]([C:42](=[O:43])[CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:23][CH2:22]2)[C@H:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16]1)=[O:14]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Reactant: O=C(Cl)Cc1ccccc1
Product: O=C(Cc1ccccc1)N1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccccc2)CC1

Procedure:
The title compound, MS: m/e=604.1 (M+H+), was prepared in accordance with the general method of example 38 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone and phenylacetylchloride.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:22]=2)[C:11]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].Br[CH2:35][CH:36]1[CH2:38][CH2:37]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=3)[CH:22]=2)[C:11]([NH:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:35][CH:36]3[CH2:38][CH2:37]3)[CH2:18][CH2:19]2)=[O:12])=[CH:32][CH:33]=1)#[N:2]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCNCC3)c2)cc1
Reactant: BrCC1CC1
Product: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCN(CC4CC4)CC3)c2)cc1
Yield: 71.2 %

Procedure:
Following procedure of Example 11(e) 3,5-bis-(4-cyano-phenoxy)-N-piperidin-4-yl-benzamide 0.5 g (1.14 mmol) and bromomethyl-cyclopropane (0.231 g, 1.71 mmol) were used to afford 0.4 g of the required product. Percentage purity (LCMS): 45.0%, (M+1)=492.2+1
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[C:20]1[S:21][CH:22]=[CH:23][N:24]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CCOC(C)=O>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[CH:9]=[C:4]([CH:3]=[C:2]([O:1][C:20]3[S:21][CH:22]=[CH:23][N:24]=3)[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[N:13][CH:14]=1
Reactant: Brc1nccs1
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1cc(Oc2nccs2)cc(-c2ccc(C)cn2)c1
Temperature: 135 °C

Procedure:
A stirred mixture of methyl 3-hydroxy-5-(5-methylpyridin-2-yl)benzoate (290 mg, 1.2 mmol), 2-bromothiazole (410 mg, 2.5 mmol), potassium carbonate (346 mg, 2.5 mmol), and dimethyl sulfoxide (5 mL) was heated at 135° C. overnight. The reaction mixture was then cooled to room temperature and diluted with EtOAc. The organic phase was washed with aq. NaHCO3 (sat.), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-30% EtOAc/hexane) to afford the title compound.
Reaction SMILES: B.C1COCC1.[Br:7][CH2:8][C:9]([C:11]1[CH:22]=[CH:21][C:14]2[O:15][C:16]([CH3:20])([CH3:19])[O:17][CH2:18][C:13]=2[CH:12]=1)=[O:10].CO>C1COCC1>[Br:7][CH2:8][C@@H:9]([C:11]1[CH:22]=[CH:21][C:14]2[O:15][C:16]([CH3:19])([CH3:20])[O:17][CH2:18][C:13]=2[CH:12]=1)[OH:10]
Reactant: CC1(C)OCc2cc(C(=O)CBr)ccc2O1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H](O)CBr)ccc2O1
Reaction time: 1 h
Yield: 84.3 %

Procedure:
A solution R-diphenylprolinol (75 mg) in THF (2 ml) was treated with borane-THF (1M, 20.5 ml) over 20 min at 20° C. under nitrogen. After the addition was complete the solution was kept between 30 and 35° C. for 1 h and then cooled in ice and 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone (DE3513885) (3.9 g) in THF (10 ml) was added over 1.5 h keeping the temperature below 5° C. The mixture was stirred under nitrogen for a further 0.5 h and then methanol (4 ml) was added at 0° C. The solvent was removed under reduced pressure and the residue was purified by chromatography on flash silica gel eluting with ethyl acetate-cyclohexane (1:4) to give the title compound (3.31 g) δ (CDCl3) 7.15 (1H, dd, J 8, 2 Hz), 7.03 (1H, br s), 6.82 (1H, d, J 8 Hz), 4.85 (3H, s and m), 3.61 (1H, dd, J 10, 4 Hz), 3.50 (1H, 9 Hz), 1.54 (6H, s).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43]C)=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[NH2:45][C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=1)[CH2:49][OH:50].NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:45][C:46]4[CH:53]=[CH:52][CH:51]=[C:48]([CH2:49][OH:50])[CH:47]=4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: Nc1cccc(CO)c1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(NC(=O)Nc5cccc(CO)c5)cc4)nc32)CC1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 3-aminobenzylalcohol as the aniline component. (12%, MS=613.3 (M+H))
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10](Br)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1)=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:14]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:10]2[CH:9]=[N:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:12][CH:11]=2)=[CH:27][N:26]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23]
Reactant: CCCCCCCCC=COc1ccc(B(O)O)cn1
Reactant: Brc1cnc(-c2ccccc2)nc1
Product: C=CCCCCCCCCOc1ccc(-c2cnc(-c3ccccc3)nc2)cn1

Procedure:
The synthesis was carried out analogously to Example 27 from 2-phenyl-5-bromopyrimidine and 2-decenyloxypyridine-5-boronic acid.
Reaction SMILES: [C:1]([NH:6][C@H:7]([C:29]([OH:31])=O)[CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.[C:33]([S:38][CH2:39][CH2:40][NH2:41])(=[O:37])[CH:34]([CH3:36])[CH3:35]>>[C:1]([NH:6][C@H:7]([C:29]([NH:41][CH2:40][CH2:39][S:38][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])=[O:31])[CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)SCCN
Reactant: CC(C)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: Cl
Product: CC(C)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCSC(=O)C(C)C
Yield: 75 %

Procedure:
The coupling reaction of 13 (3.93 mmol) with S-isobutyrylcysteamine hydrochloride is carried out according to method B described in the first synthetic route (example 1). After the various treatments, the expected compound is isolated by flash chromatography on a silica gel column (eluent: AcOEt/petroleum ether 65%). 15 is collected in the form of a colorless foam with a yield of 75%. Rf (AcOEt/petroleum ether, 5/5): 0.6. [α]D20=+7.9° (c 1.27, CHCl3).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[N:7]=[C:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11]2.CC1(C)C(C)(C)OB([C:46]2[CH:51]=[CH:50][C:49]([CH2:52][C:53]([O:55][CH2:56][CH2:57][F:58])=[O:54])=[CH:48][CH:47]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:32]([O:31][C:30]([NH:29][C:8]1[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:25])([CH3:27])[CH3:26])([CH3:22])[CH3:23])[CH2:14][CH2:15][CH3:16])=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:46]3[CH:47]=[CH:48][C:49]([CH2:52][C:53]([O:55][CH2:56][CH2:57][F:58])=[O:54])=[CH:50][CH:51]=3)=[CH:37][C:6]=2[N:7]=1)=[O:36])([CH3:33])([CH3:34])[CH3:35]
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Reactant: CC1(C)OB(c2ccc(CC(=O)OCCF)cc2)OC1(C)C
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: CCOC(C)=O
Solvent: CC#N
Product: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCCF)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Temperature: 100 °C

Procedure:
tert-butyl (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate, 2-fluoroethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (1.5 equiv), tetrakis(triphenylphosphine)palladium(0), 2M aqueous potassium carbonate (3 equiv) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) afforded 2-fluoroethyl 2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH2:11][CH2:12][CH2:13][OH:14].[Br:15][C:16]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:17]=1[CH2:18]Br>C(#N)C>[Br:15][C:16]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:17]=1[CH2:18][NH:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: NCCCO
Reactant: Fc1ccc(Br)c(CBr)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: OCCCNCc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Hunig's base (1.3 eq) and 3-aminopropan-1-ol (1.3 eq) were added to a solution of 2-bromo-5-fluoro-benzyl bromide (1 eq) in acetonitrile (0.6 M) and the resulting mixture stirred at RT under nitrogen for 12 h. Concentrated in vacuo to give 3-(((2-bromo-5-fluorophenyl)methyl)amino)propan-1-ol as a clear oil. EI-MS m/z 262, 264 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[OH:15])[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:16]I.[OH-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)COc1ccc(O)c(Cl)c1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.4 %

Procedure:
Ethyl 4 hydroxyphenoxyacetate(l.5 g, 7.6 mmol) was reacted with SO2Cl2 (1.5 mL) to give ethyl 3-chloro-4-hydroxyphenoxyacetate (700 mg, ~80% pure) as a white powder. To a solution of ethyl 3-chloro-4-hydroxyphenoxyacetate (700 mg, 3.0 mmol) and MeI(0.280 mL, 4.5 mmol) in DMF(5 mL) at 0° C. was added 10M aq.NaOH(0.320 mL, 3.2 mmol). The mixture was stirred at r.t. for 12 h, then diluted with H2O and extracted with EtOAc to give ethyl 3-chloro-4 methoxyphenoxy-acetate (700 mg).