Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1.C([O-])(=O)C.C(=O)([O-])[O-].[K+].[K+]>>[F:27][C:26]([F:28])([F:29])[C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:21][CH:22]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(F)(F)c1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 100 °C

Procedure:
A mixture of 0.511 g (2 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.746 ml (6 mmol) 4-aminobenzotrifluoride is heated for 2.5 h at 100° C. The reaction mixture is then distributed between acetate and 20% aqueous potassium carbonate solution. The title compound is obtained after further processing as described in Example 7; m.p. 205-206° C.; ESI-MS: (M+H)+=381.
Reaction SMILES: C([CH:3]([CH2:14][CH3:15])[C:4](=O)[C:5](=[CH:9][O:10][CH2:11][CH3:12])[C:6](O)=O)C.C([O:18]C=C(CC)C(CC(OCC)=O)=O)C.[Cl:31][C:32]1[CH:37]=[C:36]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[N:35]=[C:34]([NH:48][NH2:49])[N:33]=1>>[Cl:31][C:32]1[CH:37]=[C:36]([NH:38][CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=2)[N:35]=[C:34]([N:48]2[C:4]([CH2:3][CH2:14][CH3:15])=[C:5]([C:9]([O:10][CH2:11][CH3:12])=[O:18])[CH:6]=[N:49]2)[N:33]=1
Reactant: CCOC=C(C(=O)O)C(=O)C(CC)CC
Reactant: COc1ccc(CNc2cc(Cl)nc(NN)n2)cc1
Reactant: CCOC=C(CC)C(=O)CC(=O)OCC
Product: CCCc1c(C(=O)OCC)cnn1-c1nc(Cl)cc(NCc2ccc(OC)cc2)n1
Yield: 141 %

Procedure:
Using 1.11 g of ethyl 2-(ethoxymethylene)butyrylacetate (ethyl 2-ethoxymethylene-3-oxohexanoate) and 1.32 g of 4-chloro-2-hydrazino-6-(4-methoxybenzyl)aminopyrimidine, the same reaction and after-treatment of Example 83-(1) were carried out to obtain 1.57 g of the title compound as a milk white solid.
Reaction SMILES: Br[C:2]([CH3:14])([CH3:13])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=[O:21].[In]>C1COCC1>[OH:21][C:16]1([C:2]([CH3:14])([CH3:13])[C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH2:17][CH2:18][CH2:19][CH2:20][O:15]1
Reactant: O=C1CCCCO1
Reactant: CC(C)(Br)C(=O)OCc1ccccc1
Agent: [In]
Solvent: C1CCOC1
Product: CC(C)(C(=O)OCc1ccccc1)C1(O)CCCCO1

Procedure:
A stirred suspension of benzyl 2-bromo-2-methylpropanoate (0.748 g, 2.91 mmol), tetrahydro-2H-pyran-2-one (0.260 g, 2.60 mmol) and indium (0.341 g, 2.97 mmol) in THF (3 mL) was sonicated for 6 h. The reaction was quenched with sat. NaHCO3 and extracted with ether, then concentrated. The residue was purified by silica gel flash chromatography to afford benzyl 2-(2-hydroxytetrahydro-2H-pyran-2-yl)-2-methylpropanoate. 1H NMR (500 MHz, CDCl3) δ ppm 7.30-7.43 (5H, m), 5.18 (2H, s), 3.51-3.61 (2H, m), 2.41 (2H, t, J=7.10 Hz), 1.56-1.66 (2H, m), 1.35-1.47 (8H, m). Benzyl 2-(2-hydroxytetrahydro-2H-pyran-2-yl)-2-methylpropanoate was dissolved in triethylsilane (0.415 mL, 2.60 mmol) and treated with TFA (0.200 mL, 2.60 mmol) and the reaction mixture was stirred at rt for 16 h, then evaporated to dryness to yield benzyl 2-methyl-2-(tetrahydro-2H-pyran-2-yl)propanoate. 1H NMR (500 MHz, CDCl3) δ ppm 7.30-7.41 (5H, m), 5.22 (1H, d, J=12.66 Hz), 5.10 (1H, d, J=12.51 Hz), 3.91-4.01 (1H, m), 3.53 (1H, dd, J=11.22, 1.75 Hz), 3.39 (1H, td, J=11.56, 2.37 Hz), 1.82-1.92 (1H, m), 1.44-1.59 (4H, m), 1.30-1.41 (1H, m), 1.19-1.25 (3H, m), 1.11-1.19 (3H, m). A stirred suspension of 10% Pd—C (16.63 mg) and benzyl 2-methyl-2-(tetrahydro-2H-pyran-2-yl)propanoate (82 mg, 0.313 mmol) in EtOAc (5 mL) was stirred under H2 for 6 h, and then filtered and concentrated to yield Cap P-23 (54 mg). 1H NMR (500 MHz, CDCl3) δ ppm 4.09-4.19 (1H, m), 3.48-3.57 (1H, m), 3.33-3.42 (1H, m), 1.88-1.97 (1H, m), 1.71 (1H, d, J=13.12 Hz), 1.47-1.65 (3H, m), 1.29-1.40 (1H, m), 1.23-1.27 (3H, m), 1.14-1.20 (3H, m).
Reaction SMILES: [N:1]1[N:5]2[CH2:6][CH2:7][NH:8][CH2:9][C:4]2=[CH:3][C:2]=1[C:10]([O:12]CC)=[O:11].F[C:16](F)(F)C([O-])=O>>[CH3:16][N:8]1[CH2:7][CH2:6][N:5]2[N:1]=[C:2]([C:10]([OH:12])=[O:11])[CH:3]=[C:4]2[CH2:9]1
Reactant: CCOC(=O)c1cc2n(n1)CCNC2
Reactant: O=C([O-])C(F)(F)F
Product: CN1CCn2nc(C(=O)O)cc2C1

Procedure:
Prepared analogously to Example 45b starting from 2-ethyl 4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine-2-carboxylate (as the trifluoroacetate salt).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[CH2:7][C:8]3[C:9]([N:28]=[CH:29][N:30]=3)=[CH:10][C:11]=2[C:12]=1[N:13]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)C=O)#[N:2].C(=O)([O-])[O-].[K+].[K+]>CO.O.CC(O)=O>[CH3:27][O:26][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([O:22][CH3:23])[C:19]=1[O:24][CH3:25])[NH:13][C:12]1[C:11]2[CH:10]=[C:9]3[N:28]=[CH:29][N:30]=[C:8]3[CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: COc1cc(N(C=O)c2c(C#N)cnc3c2C=C2N=CN=C2C3)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(Nc2c(C#N)cnc3c2C=C2N=CN=C2C3)cc(OC)c1OC
Yield: 68.4 %

Procedure:
A suspension of 138.6 mg (0.34 mmol) of 7-cyanoimidazo[4,5-g]quinolin-8-yl(3,4,5-trimethoxyphenyl)formamide and 229.1 mg (1.66 mmol) of potassium carbonate in 10 mL of methanol is refluxed for 2 hours. After cooling, the solution is diluted with water and neutralized to pH 7 with AcOH. The precipitate is collected by filtration and washed with water, diethyl ether and ethyl acetate. After drying in vacuo, this yields a crude product. Purification of the crude product by flash chromatography (elution with 95:5 methylene chloride/methanol) yields 87.3 mg (68.5%) of the final product as a yellow solid, mp>260° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH2:9][O:10][CH:11]2[CH2:20][CH2:19][C:14]3(OCC[O:15]3)[CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1.O>C(O)(=O)C>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:4]=[C:5]([CH2:9][O:10][CH:11]2[CH2:12][CH2:13][C:14](=[O:15])[CH2:19][CH2:20]2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(COC2CCC3(CC2)OCCO3)c1
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCC(OCc2cccc(C(F)(F)F)c2)CC1

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 2, using 7.9 grams (0.025 mole) of 8-(3-trifluoromethylphenylmethoxy)-1,4-dioxaspiro[4.5]decane. and 25 mL of water in 50 mL of acetic acid, yielding 4-(3-trifluoromethylphenylmethoxy)cyclohexanone.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:12]1[CH:14]([CH2:15][O:16][CH3:17])[CH2:13]1>>[CH2:1]([N:8]1[CH2:9][CH2:10][O:12][CH:14]([CH2:15][O:16][CH3:17])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC1CO1
Reactant: OCCNCc1ccccc1
Product: COCC1CN(Cc2ccccc2)CCO1
Temperature: 50 °C
Reaction time: 16 h
Yield: 58.2 %

Procedure:
N-Benzylethanolamine (459 g) is mixed with 1,2-epoxy-3-methoxypropane (422 g) and the mixture is stirred at 50° C. for 16 hours and thereafter the excess 1,2-epoxy-3-methoxypropane is distilled off under reduced pressure. The residue is dissolved in 1,4-dioxane (3 liters) and thereto are added powdery potassium hydroxide (692.5 g) and tris(3,6-dioxaheptyl)amine (11.4 g). To the mixture is added dropwise with stirring a solution of p-toluenesulfonyl chloride (809.4 g) in 1,4-dioxane (2 liters) over a period of 1.5 hour, during which the temperature of the reaction mixture raises and the solvent is refluxed. After the dropwise addition, the mixture is stirred for 2 hours, and the undissolved materials are filtered off and washed with ethyl acetate. The filtrate and the washing liquid are combined and distilled under reduced pressure to remove the solvent. To the residue are added water (600 ml) and conc. hydrochloric acid (300 ml) to make acidic. The aqueous layer is washed with ethyl acetate, made strongly basic by adding sodium hydroxide (160 g) under ice cooling and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline solution, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The obtained residue is distilled under reduced pressure to give the title compound (391.3 g) as colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:16][OH:17])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].ClC(Cl)(Cl)C(=N)O[CH2:23][CH:24]=[CH2:25]>C(Cl)Cl.C1CCCCC1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:16][O:17][CH2:25][CH:24]=[CH2:23])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: COC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Solvent: C1CCCCC1
Solvent: ClCCl
Product: C=CCOC[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve N-(benzyloxycarbonyl)-L-serine methyl ester (63 mmol) in methylene chloride/cyclohexane (1:1, 600 mL). Add allyl trichloroacetimidate (26 g, 128 mmol) and trifluroromethanesulfonic acid (5 mL, 56.6 mmol). Stir at room temperature under a nitrogen atmosphere for 5 hours and dilute with methylene chloride. Wash with saturated aqueous sodium hydrogen carbonate, water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography to give N-(benzyloxycarbonyl)-O-2-propenyl-L-serine methyl ester.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[CH:3]=1.[Br:13]N1C(=O)CCC1=O.C([O-])([O-])=O.[K+].[K+].[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30]Br>C(Cl)Cl.CN(C=O)C>[Br:13][C:3]1[C:4](=[O:12])[NH:5][C:6]2[C:11]([C:2]=1[O:1][CH2:30][C:29]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:28]=1[F:27])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=c1cc(O)c2ccccc2[nH]1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2c(OCc2ccc(F)cc2F)c1Br
Reaction time: 1 h

Procedure:
To a room temperature solution of 4-hydroxy-1,2-dihydroquinolin-2-one (500 mg, 3.10 mmol) in CH2Cl2 (10.0 mL) was added portion-wise solid N-bromosuccinimide (551.5 mg, 3.10 mmol). The reaction was stirred vigorously for 1.0 h, followed by the sequential addition of K2CO3 (540 mg, 3.90 mmol), DMF (4.0 mL), and 2,4 difluorobenzyl bromide (0.430 mL, 3.30 mmol). The resulting suspension was stirred for 4.5 hours until complete formation of desired product was seen by LCMS analysis. The reaction was then diluted with ethyl acetate (400 mL) and brine washed (3×200 mL). The resulting organic extract was Na2SO4 dried, filtered, and concentrated in vacuo to a residue that was subjected to SiO2 chromatography with ethyl acetate/hexanes/methanol (60:35:5) to furnish a solid (529 mg, 47%). 1H NMR (300 MHz, d6-DMSO) δ 12.23 (s, 1H), 7.68 (app q, J=7.5 Hz, 1H), 7.64 (app q, J=8.5 Hz, 1H), 7.54 (app q, J=8.3 Hz, 1H), 7.38-7.27 (m, 2H), 7.20 (app t, J=7.4 Hz, 1H), 7.13 (app dt, J=8.4, 2.6 Hz, 1H), 5.25 (s, 2H); LC/MS C-18 column, tr=2.64 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 366 (M+H). ES-HRMS m/z 365.9967 (M+H calcd for C16H11BrF2NO2 requires 365.9936). Step 2: Preparation of methyl 4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-2-oxoquinolin-1(2H)-yl]methyl}benzoate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=[CH:5]2.C([Li])CCC.[NH:20]1[CH:24]=[C:23]([C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[N:22]=[CH:21]1.[Cl-].[NH4+]>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH3:14][O:13][C:7]1[C:8]([CH3:12])=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:25]([C:23]1[N:22]=[CH:21][NH:20][CH:24]=1)([OH:29])[CH:26]([CH3:28])[CH3:27])[CH:11]=[CH:10]2
Reactant: CC(C)C(=O)c1c[nH]cn1
Reactant: COc1ccc2cc(Br)ccc2c1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 52.8 %

Procedure:
6-Bromo-2-methoxy-1-methylnaphthalene (0.95 g) was dissolved in THF (15 ml). The solution was cooled to −78° C. To the reaction mixture was added dropwise a solution of n-butyllithium in hexane (1.6M, 3 ml), and the mixture was stirred for 15 min. To the mixture was added a solution of 1-(1H-imidazol-4-yl)-2-methyl-1-propanone (0.155 g) in THF (10 ml), and the temperature of the mixture was elevated to room temperature. To the reaction mixture were added aqueous solution of ammonium chloride and ethyl acetate and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The extracts were combined, dried and concentrated. The residue was purified by silica gel chromatography (eluent, dichloromethane:methanol=20:1) to give the titled compound (0.184 g) as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:10])[CH2:6][CH2:7][CH2:8][NH2:9].C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[C:27]([Cl:29])[CH:28]=1)[CH2:25][N:24]([CH3:30])[CH2:23][CH:22]2[C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>C(Cl)Cl>[NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:10])[CH2:6][CH2:7][CH2:8][NH:9][S:37]([C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([CH:22]2[C:21]3[C:26](=[C:27]([Cl:29])[CH:28]=[C:19]([Cl:18])[CH:20]=3)[CH2:25][N:24]([CH3:30])[CH2:23]2)[CH:32]=1)(=[O:39])=[O:38]
Reactant: CN(CCCN)CCCN
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCCN)CCCNS(=O)(=O)c1cccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of N1-(3-aminopropyl)-N1-methylpropane-1,3-diamine (560 mg, 3.85 mmol) dissolved in DCM (20 mL), was added triethylamine (300 mg, 2.96 mmol) and 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (300 mg, 0.77 mmol). The resulting solution was stirred for 3 h at room temperature. After removing the solvent, the resulting residue was diluted with EtOAc (50 mL), washed with water (2×10 mL) and dried over anhydrous sodium sulfate. The crude product was purified by Flash-Prep-HPLC with H2O:MeOH (1:4) to afford 300 mg (74%) of N-(3-((3-aminopropyl)(methyl)amino)propyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as a yellow oil.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-])=O)[N:3]=1.O.NN>C(O)C.[C].[Pd]>[NH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[CH:2][N:3]=1
Reactant: COc1ccc([N+](=O)[O-])nc1Br
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(N)nc1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
55.6 g (corresponding to 0.239 mol) of 2-bromo-3-methoxy-6-nitropyridine was dissolved in 1700 mL of ethanol, and 37.3 g (50% wet) of 10% palladium-carbon was added thereto under argon stream. To the mixture, 283 mL of hydrazine monohydrate was then added dropwise. After the reaction mixture was heated under reflux for 70 minutes, the reaction solution was cooled down to room temperature. Then, after palladium-carbon was filtered off, the residue was washed with ethanol, and the washings were combined with the filtrate. The combined solution was concentrated under reduced pressure. Then, 1300 mL of water and 130 mL of conc. aqueous ammonia were added to the concentrate, and the resulting mixture was extracted eight times with chloroform. The combined chloroform layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was distilled under reduced pressure to obtain 26.2 g (corresponding to 0.211 mol) of 2-amino-5-methoxypyridine (FIG. 3, Step 3).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[NH:30]1[C:34]2[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:33]=2[N:32]=[CH:31]1.C([O-])([O-])=O.[K+].[K+]>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>[NH:30]1[C:34]2[CH:35]=[C:36]([C:2]3[S:3][C:4]4[C:10]([C:11]5[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=5)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=4[N:6]=3)[CH:37]=[CH:38][C:33]=2[N:32]=[CH:31]1
Reactant: OB(O)c1ccc2nc[nH]c2c1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
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
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4nc[nH]c4c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A microwave vial was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (78 mg, 0.16 mmol), (1H-benzo[d]imidazol-6-yl)boronic acid (44 mg, 0.27 mmol), then Pd(PPh3)4 (22 mg, 0.02 mmol). The vial was flushed with argon, diluted with dioxane (1.5 mL) and to this was added 2M aqueous K2CO3 (0.25 mL, 0.5 mmol). The vial was sealed, heated to 100° C. for 2 hours, and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-20% MeOH/CH2Cl2 gradient) to afford the desired product. LCMS-ESI+: calc'd for C29H29ClN3O3S: 534.2 (M+H+); Found: 534.3 (M+H+).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][CH2:17][CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C1(C)C=CC=CC=1.O>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:18][CH2:17][O:16][CH3:15])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCCCl
Reactant: Oc1ccc(Sc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(Sc2ccccc2)cc1
Reaction time: 16 h
Yield: 101 %

Procedure:
A solution was prepared by combining 10 g of 4-hydroxyphenyl phenyl sulfide which had been synthesized according to the well-known formulation, 5 g of 2-chloroethyl methyl ether, 7.4 g of potassium carbonate, and 20 g of DMF. The solution was aged at 80° C. for 16 hours. The aged solution was cooled to room temperature, to which 20 g of water was added to quench the reaction. To the solution, 40 g of toluene was added for extraction. The organic layer was separated and washed with sodium hydroxide aqueous solution and water in sequence. The organic layer was concentrated in vacuum, obtaining 13 g of the target compound, 4-(2-methoxyethoxy)phenyl phenyl sulfide as oily matter. Yield 93%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:28])=[C:6]([CH:27]=1)[C:7]([NH:9][C:10]1[C:11]([C:23]([O:25]C)=[O:24])=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[F:22])[S:13][CH:14]=1)=[O:8].[OH-].[Li+]>O1CCCC1.CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:28])=[C:6]([CH:27]=1)[C:7]([NH:9][C:10]1[C:11]([C:23]([OH:25])=[O:24])=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[F:22])[S:13][CH:14]=1)=[O:8]
Reactant: COC(=O)c1c(NC(=O)c2cc(F)ccc2O)csc1-c1ccc(C)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2scc(NC(=O)c3cc(F)ccc3O)c2C(=O)O)c(F)c1
Yield: 65 %

Procedure:
Ester 385 (61 mg, 151 μmol) and lithium hydroxide (21.7 mg, 907 μmol) in tetrahydrofuran:methanol:water (3:2:1, 0.8 mL) was stirred at 60° C. for 2 h. The mixture was cooled, quenched with 2 M HCl (0.7 mL) and diluted with water (2 mL). The precipitate that formed was filtered and washed with methanol:water (1:2, 1 mL) and dichloromethane (1 mL) to provide 386 (38.2 mg, 65%) as a solid: LRESIMS m/z 390.1 [M+H]+, calcd. for C19H14F2N1O4S1 390.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:31](O)=[O:32])[C:18]3[C:23]([CH3:24])=[N:22][N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:19]=3[N:20]=2)=[C:11]([F:34])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][CH2:36][N:37]([CH:41]([CH3:43])C)[CH:38]([CH3:40])C>ClC(Cl)C>[CH2:41]([N:37]1[CH2:36][CH2:35][C:15]([NH:20][C:31]([C:17]2[C:18]3[C:23]([CH3:24])=[N:22][N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:19]=3[N:20]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11]=3[F:34])[CH:16]=2)=[O:32])([C:12]2[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=2)[CH2:40][CH2:38]1)[C:43]1[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)O)c12
Solvent: CC(Cl)Cl
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)NC3(c4ccccc4)CCN(Cc4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59 %

Procedure:
A mixture of 6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (304 mg), amine (200 (200 mg), DIPEA (340 μL) and BEP (190 mg) in dichloroethane (6.5 mL) was stirred at r.t. for 90 min. The solvent was distilled off in vacuo, the residue was re-dissolved in ethyl acetate (20 mL) and washed twice with water, twice with saturated sodium bicarbonate solution and with brine, then dried over magnesium sulfate. After evaporation of the solvents, the residue was purified by flash chromatography (silica, heptane/ethyl acetate gradient) giving 278 mg (59%) of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10]([OH:12])=O)=[C:8]([CH3:13])[N:7]=[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16](C(F)(F)F)[CH:15]=3)[N:5]=2)[CH2:3][CH2:2]1.Cl.[F:25][C:26]([F:38])([F:37])[O:27]C1C=C(C=CC=1)C(N)=N.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:63]1([CH:68]2[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]2)[CH2:67][CH2:66][CH2:65][CH2:64]1>CN(C=O)C.C(N(CC)CC)C>[CH:1]1([C:4]2[C:9]([C:10]([N:71]3[CH2:72][CH2:73][CH:68]([N:63]4[CH2:67][CH2:66][CH2:65][CH2:64]4)[CH2:69][CH2:70]3)=[O:12])=[C:8]([CH3:13])[N:7]=[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:27][C:26]([F:38])([F:37])[F:25])[CH:15]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)nc(C2CC2)c1C(=O)O
Reactant: N=C(N)c1cccc(OC(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(OC(F)(F)F)c2)nc(C2CC2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for intermediate 2,4-cyclopropyl-6-methyl-2-(3-trifluoromethoxy-phenyl)-pyrimidine-5-carboxylic acid [prepared in analogy to the preparation of 4-cyclopropyl-6-methyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (intermediate 7), by using 3-trifluoromethoxy-benzamidine hydrochloride instead of 3-trifluoromethyl-benzamidine hydrochloride in the reaction step analogous to the preparation of intermediate 7A] was reacted with HATU, triethylamine and 4-pyrrolidin-1-yl-piperidine in DMF. Subsequent purification by preparative HPLC afforded the title compound as a gum. MS: 475.3 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.[C:19]([O-:22])(=[O:21])[CH3:20].[K+]>CN(C=O)C>[C:19]([O:22][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)(=[O:21])[CH3:20]
Reactant: CC(=O)[O-]
Reactant: BrCCCCn1c2ccccc2c2ccccc21
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCCn1c2ccccc2c2ccccc21
Temperature: 110 °C
Reaction time: 12 h
Yield: 93.5 %

Procedure:
Compound 8 (40.1 g, 0.133 mol) and potassium acetate (19.5 g, 1.99 mol) were mixed in 300 mL of DMF under an argon atmosphere. The reaction mixture was stirred for 12 hours at 110° C. The organic phase was separated and extracted with ethyl acetate. The collected organics were then combined and dried over Na2SO4 and filtered. The solvent was evaporated to give the crude product. The resulting product was purified by silica gel column chromatography (eluent: ethyl acetate:methylene chloride=1:30 v/v) to yield 35 g (93%) of 4-(9H-carbazol-9-yl)butyl acetate (Compound 9).