Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:19][NH:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH2:24][CH2:23]1)[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:18])[C:9]=2[CH:8]=[CH:7][CH:6]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[OH:1][C@@H:2]([CH2:19][NH:20][CH2:21][CH:22]1[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][C:30]([F:33])([F:31])[F:32])[CH2:26][CH2:27]1)[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([OH:18])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=C1c2ccccc2-c2c(OCC(O)CNCC3CCN(CCC(F)(F)F)CC3)cccc21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OC1c2ccccc2-c2c(OC[C@@H](O)CNCC3CCN(CCC(F)(F)F)CC3)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A solution of 4-(2-hydroxy-3-{[1-(3,3,3-trifluoro-propyl)-piperidin-4-ylmethyl]-amino}-propoxy)-fluoren-9-one (0.060 g, 0.13 mmol) in 4 mL THF was treated with LAH (0.010 g, 0.26 mmol) and stirred at ambient temperature overnight. Heated to reflux and cooled. The excess LAH was decomposed by the sequential addition of 0.01 mL of each of water and 1 N NaOH, 0.03 mL of water and 0.5 g Na2SO4. The solids were filtered and the filtrate concentrated in vacuo to give 0.045 g of the title compound as a yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:38])[N:8]([C:15]1([CH2:23][CH2:24][CH2:25][CH2:26][NH:27]C(=O)OCC3C=CC=CC=3)[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:9]2=[O:14])(=[O:3])[CH3:2].[H][H].[ClH:41]>C(O)C.[Pd]>[ClH:41].[NH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:15]1([N:8]2[C:7](=[O:38])[C:6]3[C:10](=[CH:11][CH:12]=[CH:13][C:5]=3[NH:4][C:1](=[O:3])[CH3:2])[C:9]2=[O:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22]
Reactant: CC(=O)Nc1cccc2c1C(=O)N(C1(CCCCNC(=O)OCc3ccccc3)CCC(=O)NC1=O)C2=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(=O)Nc1cccc2c1C(=O)N(C1(CCCCN)CCC(=O)NC1=O)C2=O
Reaction time: 2 h
Yield: 12 %

Procedure:
To a solution of 15 (0.02 g, 0.038 mmol) in 2% HCl in ethanol (2.0 mL) was added palladium on activated charcoal (0.004 g) under an atmosphere of argon. The mixture was subsequently saturated with hydrogen using a hydrogen balloon. After 2 h, the mixture was flushed with argon, filtered and concentrated. Preparative HPLC afforded 16 (0.002 g, 12%). 1H NMR (400 MHz, D2O) δ 8.37 (s, 2H), 8.16 (d, J=8.5 Hz, 1H), 7.76 (dd, J=12.9, 5.5 Hz, 1H), 7.60 (d, J=7.4 Hz, 1H), 2.95 (t, J=7.6 Hz, 2H), 2.73 (m, 3H), 2.61-2.47 (m, 1H), 2.41-2.10 (m, 4H), 1.80-1.59 (m, 2H), 1.43 (d, J=39.6 Hz, 3H). MS (ESI) m/z calcd for C19H23N4O5 [M-Cl]+387.4, found 387.7.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Na+].S(=O)(=O)(O)O>>[OH:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: O=C([O-])c1cc2ccccc2cc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1cc2ccccc2cc1O
Temperature: 160 °C
Yield: 90 %

Procedure:
To a 1 L autoclave, 800 g of aqueous solution containing 100 g of sodium 2-hydroxynaphthalene-3-carboxylate prepared by means of the Kolbe-Schmitt method was fed and heated to 160° C. An aqueous sulfuric acid solution (72%) was added dropwise to the solution over 50 minutes to adjust the pH of the mixture to 3.5. Then, the mixture was cooled to 80° C. at the rate of 0.4° C./min. At the same temperature, the mixture was filtrated to give 80.6 g of crystalline 2-hydroxynaphthalene-3-carboxylic acid.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH:10]([CH:12]([OH:14])[CH3:13])[CH2:9][C@H:8]1[CH2:15][OH:16])=[O:6])[CH:2]=[CH2:3].CC(C)=[O:19].OS(O)(=O)=O.O=[Cr](=O)=O.CC(O)C>CC(C)=O>[C:12]([CH:10]1[CH2:11][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C@H:8]([C:15]([OH:19])=[O:16])[CH2:9]1)(=[O:14])[CH3:13]
Reactant: CC(C)=O
Reactant: C=CCOC(=O)N1CC(C(C)O)C[C@H]1CO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: C=CCOC(=O)N1CC(C(C)=O)C[C@H]1C(=O)O
Reaction time: 3 h

Procedure:
To a solution of (2S)-1-allyloxycarbonyl-4-(1-hydroxyethyl)-2-hydroxymethylpyrrolidine (30 g) in acetone (300 ml) was added dropwise Jones' Reagent (2.67N, 245 ml) at 0° C. After stirring for 3 hours, to the reaction mixture was added dropwise 2-propanol (500 ml), and the mixture was stirred at 0° C. for 1 hour. The precipitate was filtered off and the filtrate was evaporated to give a residual oil, which was extracted with ethyl acetate and the organic layer was separated, washed with brine, dried over magnesium sulfate. Evaporation of the solvent gave (2S)-4-acetyl-1-allyloxycarbonylpyrrolidine-2-carboxylic acid (26.56 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[C:4]([CH3:16])[N:3]=1.[CH3:17][CH:18]([OH:21])[C:19]#[CH:20].[H-].[Na+].O>CN(C)C=O>[CH3:16][C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[CH:7]=[C:2]([O:21][CH:18]([CH3:17])[C:19]#[CH:20])[N:3]=1
Reactant: Cc1nc(Cl)cc(-c2cccc(F)c2F)n1
Reactant: C#CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CC(C)Oc1cc(-c2cccc(F)c2F)nc(C)n1
Temperature: 25 °C
Reaction time: 9 h
Yield: 86 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 255 mg of 4-chloro-2-methyl-6-(2,3-difluorophenyl)pyrimidine and 97 mg of 3-butyn-2-ol, to which 56 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 9 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 250 mg of 2-methyl-4-(2,3-difluorophenyl)-6-(1-methyl-2-propynyloxy)pyrimidine (the present compound (161)).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([NH:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:19])[CH2:13][CH2:12]2)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>CCO.[Pd]>[CH2:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([NH:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:19])[CH2:13][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC#Cc1ccc2c(c1)CCN2C(=O)NCCC(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCc1ccc2c(c1)CCN2C(=O)NCCC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A mixture of the product of Step C (0.1 g; 0.27 mmol) and 10% Pd/C (0.1 g) in EtOH (15 ml) was stirred at room temperature for 1 h under H2 (balloon). The catalyst was removed by filtration through the Celite pad, washed with CH2Cl2 (2×10 ml) and combined filtrates were evaporated to dryness under reduced pressure to give a title compound (0.09 g; 90%), as colourless solid. 1H-NMR (CDCl3) 7.71 (d, 1H, J=8.8 Hz); 6.94 (d, 1H, J=8.8 Hz); 6.93 (s, 1H); 5.29 (m, 1H); 4.14 (q, 2H, J=7 Hz); 3.82 (t, 2H, J=8.8 Hz); 3.57 (q, 2H, J=5.9 Hz); 3.11 (t, 2H, J=8.6 Hz); 2.59 (t, 2H, J=5.7 Hz); 2.51 (t, 2H, J=7.7 Hz); 1.57 (m, 2H); 1.26 (m, 13H); 0.86 (t, 3H, J=7 Hz).
Reaction SMILES: C([O:5][NH:6][C:7](=[O:34])[CH:8](NS(C1C=CC(OCC#CC)=CC=1)(=O)=O)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][CH:10]=1)(C)(C)C>C(O)(C(F)(F)F)=O>[OH:5][NH:6][C:7](=[O:34])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][CH:10]=1
Reactant: C#CCOc1ccc(C(NS(=O)(=O)c2ccc(OCC#CC)cc2)C(=O)NOC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: C#CCOc1ccc(CC(=O)NO)cc1

Procedure:
The 75 mg (0.154 mmol) sample of ′N-(tert-butoxy)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-[4-(2-propynyloxy)phenyl]acetamide was stirred in neat TFA at room temperature for 72 h. TFA was removed in vacuo. The residue was chromatographed on prep. TLC eluting with 1% HOAc in 10% MeOH/CH2Cl2 to provide 11.1 mg (17%) of (2-butynyloxy)phenyl]sulfonyl}amido)-N-hydroxy-2-[4-(2-propynyloxy)phenyl]acetamide as a white solid was obtained. High Resolution Mass Spec 429.11155 (M+H)+; Calc'd for C21H21N2O6S 429.11149.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=[N:29]2)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[C:32]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]5[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=5)=[CH:9][N:10]=4)[CH:7]=3)=[CH:31][CH:30]=[N:29]2)=[CH:26][CH:27]=1
Reactant: FC(F)(F)c1ccc(-c2cnc3ccc(Br)cn23)cc1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(F)cc2)OC1(C)C
Product: Fc1ccc(-n2nccc2-c2ccc3ncc(-c4ccc(C(F)(F)F)cc4)n3c2)cc1

Procedure:
The title compound, off-white solid (87 mg, 70%), MS (ISP) m/z=423.5 [(M+H)+], mp 172° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (intermediate M) (0.1 g, 0.29 mmol) and 1-(4-fluoro-phenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate A) (0.11 mg, 0.38 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6](=[O:12])[C:5]2([NH:20][C:21](=[O:30])[CH2:22][N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[H-].[Na+].[C:33]1([C:39](Cl)=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C=O)C>[C:39]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[C:10]([Cl:11])[CH:9]=2)[C:5]([NH:20][C:21](=[O:30])[CH2:22][N:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]2)([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:6]1=[O:12])(=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCN(CC(=O)NC2(c3ccc(Cl)cc3)C(=O)Nc3cc(Cl)c(Cl)cc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(CC(=O)NC2(c3ccc(Cl)cc3)C(=O)N(C(=O)c3ccccc3)c3cc(Cl)c(Cl)cc32)CC1

Procedure:
0.14 g of the compound of Example 1 is placed in 9 ml of DMF in a round-bottomed flask equipped with a magnetic stirrer, and under a stream of nitrogen. 0.01 g of 60% NaH is added, at 0° C. PhCOCl is then added dropwise and the mixture is left to react at room temperature for 2 hours. The reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is dried over Na2SO4, filtered and evaporated under vacuum. 120 mg of oil are obtained, which product is purified on a column by flash chromatography, eluting with 95/5 ethyl acetate/methanol, to isolate 20 mg of white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F-].[Cs+].CN(C=O)C>CC([O-])=O.CC([O-])=O.[Pd+2].O>[F:12][C:4]1[CH:3]=[C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(Br)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2)cc1F
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 96.1 %

Procedure:
Combine methyl 4-bromo-2-fluorobenzoate (9.3 g, 40.0 mmol), phenylboronic acid (9.75 g, 80.0 mmol), and cesium fluoride (32.6 g, 100.1 mmol), DMF (190 mL) and deionized water (50 mL). Heat to 80° C. and add Pd(OAc)2 (303 g, 4.0 mmol). After 20 min, cool to room temperature, filter through HyFlo with the aid of 100 mL ethyl acetate, extract the filtrate with 2×100 mL 5% aqueous lithium chloride, 2×50 mL 1.0 M aqueous sodium hydroxide, and 2×100 mL brine. Separate the organic phase, dry over MgSO4, filter, and evaporate in vacuo to yield 8.85 g (96%) of methyl 3-fluorobiphenyl-4-carboxylate as a white solid. 1H NMR (CDCl3, 300 MHz) 8.01 (t, J=7.8 Hz, 1H), 7.58-7.62 (m, 2H), 7.41-7.51 (m, 4H), 7.37 (m, 1H), 3.96 (s, 3H); IR (cm−1, KBr): 3033, 2954, 1721, 1622, 1437, 1409, 1298, 1289, 1266, 1097; Anal calc'd for C14H11FO2: C 73.03, H 4.82; Found: C 73.06, H 4.86.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:12]([C:13](=[O:29])[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:16][CH:15]=3)=[C:11]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)[S:10][C:9]=2[CH:37]=1)=[O:4].Cl.Cl[CH2:40][CH2:41][N:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[Na+]>CN(C=O)C.C1COCC1.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:12]([C:13](=[O:29])[C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)=[CH:18][CH:19]=3)=[C:11]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH2:40][CH2:41][N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:34][CH:35]=3)[S:10][C:9]=2[CH:37]=1)=[O:4]
Reactant: ClCCN1CCCC1
Reactant: COC(=O)c1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(O)cc3)sc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Temperature: 60 °C
Yield: 75.9 %

Procedure:
To a solution of 1.5 g (2.9 mmol) of 2-(4-hydroxyphenyl)-3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]benzo[b]thiophene-6-carboxylic acid methyl ester (Part C) and 544 mg (3.2 mmol) of 1-(2-chloroethyl)pyrrolidine hydrochloride in 20 mL of anhydrous DMF was added 2.37 g (7.3 mmol) of cesium carbonate at room temperature under a nitrogen atmosphere. The reaction mixture was heated at 60° C. for 4 h and then cooled to room temperature and diluted with 125 mL of THF and 75 mL of water. The aqueous layer was saturated with sodium chloride and extracted twice with 50 mL portions of THF. The combined organic layers were washed with brine, dried with anhydrous sodium sulfate, and concentrated at reduced pressure. The residue was purified on silica gel (1:1 MeOH/TEA (10%) in THF) to give 1.26 g (2.2 mmol, 77%) of an orange-brown foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:34][O:35][C:36](=[O:42])[C@H:37]([C@@H:39]([CH3:41])[OH:40])[NH2:38].C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]([NH:38][CH:37]([C:36]([O:35][CH3:34])=[O:42])[CH:39]([OH:40])[CH3:41])=[O:11])[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(NC(=O)[C@H](CCCC1CCCCC1)CC(=O)OC(C)(C)C)C(C)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.1 %

Procedure:
An ice-cooled solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 168) (6.40 g, 21.45 mmol) in dichloromethane (75 ml) was treated sequentially with 1-hydroxybenzotriazole hydrate (3.19 g, 23.60 mmol), threonine methyl ester hydrochloride (4.00 g, 23.60 mmol), N,N-diisopropylethylamine (7.85 ml, 45.10 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (4.52 g, 23.58 mmol) and the mixture was stirred for 17 hours being allowed to warm to room temperature over this time. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate then washed sequentially with water, aqueous citric acid solution (10% w/v), a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was dissolved in diethyl ether (100 ml) and treated with pentane (150 ml) to produce a white precipitate. This was filtered off and washed with pentane to afford the title compound as a white powder (6.48 g).
Reaction SMILES: [NH2:1]C1C2C(=CC=C(S(O)(=O)=O)C=2)C=CC=1.C1C2C(=CC=CC=2)C=CC=1.[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[S:36]([OH:39])(=[O:38])=[O:37]>[Fe]>[NH2:1][C:31]1[C:30]2[C:35](=[CH:26][C:27]([S:36]([OH:39])(=[O:38])=[O:37])=[CH:28][CH:29]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: O=S(=O)(O)c1ccc2ccccc2c1
Reactant: Nc1cccc2ccc(S(=O)(=O)O)cc12
Agent: [Fe]
Solvent: c1ccc2ccccc2c1
Product: Nc1cccc2cc(S(=O)(=O)O)ccc12

Procedure:
It is known that 1-amino-naphthalene-7-sulphonic acid can be prepared, for example, by sulphonating naphthalene, nitrating the resulting 2-naphthalenesulphonic acid and subsequently reducing this with iron (Beilstein H XIV, 765 and Ullmann, volume 12, 625 (1960)). 1-Amino-naphthalene-6-sulphonic acid is always formed as a by-product in this preparation and must be separated off.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:7](=O)[C:8](OC)=[O:9])[C:3]([O:5][CH3:6])=[O:4].[F:14][C:15]1[CH:35]=[CH:34][CH:33]=[CH:32][C:16]=1[CH2:17][N:18]1[C:22]2=[N:23][C:24]([CH3:27])=[N:25][CH:26]=[C:21]2[C:20]([C:28](=[NH:31])[NH:29][NH2:30])=[N:19]1>C(O)C>[F:14][C:15]1[CH:35]=[CH:34][CH:33]=[CH:32][C:16]=1[CH2:17][N:18]1[C:22]2=[N:23][C:24]([CH3:27])=[N:25][CH:26]=[C:21]2[C:20]([C:28]2[N:29]=[N:30][C:7]([C:2]([CH3:13])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])=[C:8]([OH:9])[N:31]=2)=[N:19]1
Reactant: COC(=O)C(=O)C(C)(C)C(=O)OC
Reactant: Cc1ncc2c(C(=N)NN)nn(Cc3ccccc3F)c2n1
Solvent: CCO
Product: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccccc3F)c3nc(C)ncc23)nc1O
Yield: 19.1 %

Procedure:
615 mg (3.27 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate were initially charged in 13 ml of ethanol and heated to reflux. Subsequently, 652 mg (2.18 mmol) of 1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidohydrazide suspended in 13 ml of ethanol were added and the mixture was boiled under reflux overnight. After cooling, the mixture was filtered, the filtercake was washed with a little ethanol and the filtrate was concentrated. The residue was purified by means of preparative HPLC (eluent: acetonitrile/water, gradient 30:70→100:0). 182 mg of the target compound were obtained (19% of theory).
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=2)=[N:11][CH:12]=1.C(N(C(C)C)C(C)C)C.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(Cl)Cl>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:21][CH:22]=2)=[N:11][CH:12]=1
Reactant: OCc1ccc(CCC#Cc2ccc(Br)cn2)cc1
Reactant: C1COCCN1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Brc1ccc(C#CCCc2ccc(CN3CCOCC3)cc2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
36 μL (0.46 mmol) methanesulphonic acid chloride are added to a solution, cooled to 0° C., of 120 mg (0.38 mmol) {4-[4-(5-bromo-pyridin-2-yl)-but-3-ynyl]-phenyl}-methanol (Example 2.20a) in 5 mL DCM. A solution of 78 μL (0.46 mmol) ethyldiisopropylamine in 1 mL DCM is slowly added dropwise, the mixture is stirred for a further 30 min at 0° C., then 80 μL (0.92 mmol) of morpholine are added, the mixture is allowed to come up to RT and kept at RT for 2 h. The mixture is evaporated down i. vac., the residue is combined with 20 mL EtOAc and 10 mL water, acidified with 1 M HCl and the phases are separated. The aqueous phase is combined with 2 M Na2CO3 solution, extracted with 20 mL EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the product is obtained.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH:25]1([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][N:31]=2)[CH2:27][CH2:26]1.O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH:25]1([CH2:28][O:29][C:30]2[N:31]=[CH:32][C:33]([C:2]3[N:7]4[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]4[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=4)[CH:3]=3)=[CH:34][CH:35]=2)[CH2:26][CH2:27]1
Reactant: CC1(C)OB(c2ccc(OCC3CC3)nc2)OC1(C)C
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc(OCC4CC4)nc3)n2n1
Temperature: 110 °C
Yield: 40.5 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 100 mg, 0.290 mmol), 2-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (104 mg, 0.377 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21 mg, 29 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.966 mL of 1,4-dioxane and 0.483 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (75-75% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (53.7 mg, 41%). 1H NMR (DMSO-d6) δ: 11.19 (s, 1H), 8.90 (d, J=2.5 Hz, 1H), 8.40 (dd, J=8.8, 2.5 Hz, 1H), 8.01 (d, J=8.6 Hz, 2H), 7.98 (s, 1H), 7.61 (d, J=8.6 Hz, 2H), 7.07 (d, J=8.8 Hz, 1H), 6.38 (s, 1H), 5.19 (br. s., 1H), 4.22 (d, J=7.1 Hz, 2H), 2.40 (s, 3H), 1.45 (s, 6H), 1.25-1.36 (m, 1H), 0.52-0.62 (m, 2H), 0.30-0.42 (m, 2H); ESI-MS: m/z 458.3 (M+H)+.
Reaction SMILES: [C:1]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:9]([C:27](O)=[O:28])[CH2:8]2)=[CH:3][CH:2]=1.[NH2:41][C@:42]1([C:49]([NH:51][S:52]([CH:55]2[CH2:57][CH2:56]2)(=[O:54])=[O:53])=[O:50])[CH2:44][C@H:43]1[CH2:45][CH:46]([F:48])[F:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CO>[C:1]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24])[C:14]([CH3:17])([CH3:15])[CH3:16])[C@H:9]([C:27](=[O:28])[NH:41][C@:42]3([C:49](=[O:50])[NH:51][S:52]([CH:55]4[CH2:57][CH2:56]4)(=[O:53])=[O:54])[CH2:44][C@H:43]3[CH2:45][CH:46]([F:47])[F:48])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1CC(F)F
Reactant: CCCCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)N[C@]2(C(=O)NS(=O)(=O)C3CC3)C[C@H]2CC(F)F)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.7 %

Procedure:
To a solution of (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(butylthio)pyrrolidine-2-carboxylic acid (15 mg, 0.026 mmol), (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-(2,2-difluoroethyl)cyclopropanecarboxamide (8.84 mg, 0.029 mmol), and HATU (15.03 mg, 0.040 mmol) in DMF (1 mL) was added N,N-Diisopropylethylamine (0.014 mL, 0.079 mmol). The formed light yellow solution was stirred at room temperature for 5 h. Diluted with MeOH, purified by prep-HPLC to yield the desired product tert-butyl (S)-1-((2S,4R)-4-(biphenyl-4-yl)-4-(butylthio)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-(2,2-difluoroethyl)cyclopropylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (14 mg, 0.015 mmol, 58.3% yield) as a white solid. 1H NMR (500 MHz, MeOD) ppm 0.83 (t, J=7.17 Hz, 3H), 1.09-1.12 (m, 10H), 1.22-1.45 (m, 7H) 1.47-1.52 (m, 10H), 1.66 (s, 2H), 2.07-2.38 (m, 4H), 2.37-2.51 (m, 1H), 2.76-2.87 (m, 1H), 2.91-3.04 (m, 11H), 3.85-4.06 (m, 2H), 4.51 (d, J=9.77 Hz, 1H), 5.05 (d, J=11.29 Hz, 1H), 5.73-6.09 (m, 1H), 7.37 (t, J=7.02 Hz, 1H), 7.46 (t, J=7.48 Hz, 2H), 7.54-7.64 (m, 4H), 7.68 (d, J=8.24 Hz, 2H). LC-MS (retention time: 3.48 min, method B), MS m/z 819 (M+H).