Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]([S:9][CH3:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6].[NH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1>C1(C)C=CC=CC=1>[C:5]([C:4](=[C:3]([S:9][CH3:10])[NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:7]#[N:8])#[N:6]
Reactant: Nc1cccnc1
Reactant: CSC(SC)=C(C#N)C#N
Solvent: Cc1ccccc1
Product: CSC(Nc1cccnc1)=C(C#N)C#N
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of 11 g (64.6 mmol) of 3,3-bis-methylmercapto-2-cyano-acrylonitrile, 6 g (63.75 mmol) of 3-amino-pyridine and 50 ml of toluene is stirred at 60° C. for 18 hours. Filtration of the reaction mixture while still warm and washing of the filter residue with toluene yield 2-cyano-3-methylmercapto-3-(3-pyridylamino)-acrylonitrile; m.p. 180-181° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:29][C:30]([NH:32][C@@H:33]([CH3:37])[C:34](O)=O)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:21]=[C:37]2[C@@H:33]([NH:32][C:30]([O:29][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:31])[CH3:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccccc2N)C1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccccc2n1[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.4 %

Procedure:
A mixture of (R)-3-(2-aminophenylamino)piperidine-1-carboxylic acid tertbutyl ester (2.25 g, 7.72 mmol), (S)-2-benzyloxycarbonylaminopropionic acid (1.9 g, 8.49 mmol), HOAt (1.16 g, 8.49 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.63 g, 8.49 mmol) and 4-methylmorpholine (1.87 mL, 16.98 mmol) in anhydrous DCM (50 mL) was stirred at RT for 1.5 h. The reaction mixture was diluted with DCM (200 mL) and washed with a 10% citric acid solution, followed by a saturated solution of NaHCO3 and then brine. The organic layer was then dried and concentrated in vacuo. The resulting residue was dissolved in AcOH (20 mL) and heated at 70° C. for 20 h and then at 80° C. for 2 h. After cooling to RT, volatiles were then removed in vacuo and the residue was dissolved in EtOAc (200 mL) and washed with a saturated solution of NaHCO3 (100 mL×2). The organic layer was then washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) affording (R)-3-[2-((S)-1-Benzyloxycarbonylaminoethyl)benzoimidazol-1-yl]piperidine-1-carboxylic acid tertbutyl ester as a white foam (2.75 g, 74%). LCMS: RT 3.16 min [M+H]+ 479.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.CCCCCC.Cl[C:16]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]=[C:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:17]=1>O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]=[C:18]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:17]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Brc1ccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
1,4-Dibromobenzene 2.64 g (11.2 mmol) was dissolved in 30 mL of dried tetrahydrofuran and cooled down to −70° C. A hexane solution (1.6M) 7.4 mL (11.8 mmol) was dropwise added slowly to the above solution and stirred at −70° C. for 30 minutes. A tetrahydrofuran solution of 2-chloro-4,6-diphenyl-1,3,5-triazine 3.00 g (11.2 mmol) was dropwise added to the above mixture at −70° and stirred at −70° C. for 30 minutes, and then the solution was heated slowly up to room temperature and stirred further for 1.5 hour. The mixture thus obtained was extracted with ethyl acetate, and the organic layer was washed in order with water and a saturated saline solution and dried on anhydrous magnesium sulfate. Then, the solvent was removed by distillation, and the residue was refined by silica gel chromatography to thereby obtain 1.48 g (yield: 34%) of 2-(4-bromophenyl)-4,6-diphenyl-1,3,5-triazine.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[CH:9][C:8]([C:11]#[CH:12])=[CH:7][N:6]=2)[CH2:3][CH2:2]1.I[C:14]1[CH:15]=[C:16]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([CH2:30][N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[CH:28]=[CH:29][C:23]=3[N:22]=2)[CH:17]=[CH:18][C:19]=1[CH3:20]>>[CH:1]1([NH:4][C:5]2[N:6]=[CH:7][C:8]([C:11]#[C:12][C:14]3[CH:15]=[C:16]([C:21]4[NH:25][C:24]5[CH:26]=[C:27]([CH2:30][N:31]6[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]6)[CH:28]=[CH:29][C:23]=5[N:22]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])=[CH:9][N:10]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1cnc(NC2CC2)nc1
Reactant: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1I
Product: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1C#Cc1cnc(NC2CC2)nc1

Procedure:
The title compound was synthesized from N-cyclopropyl-5-ethynylpyrimidin-2-amine (as prepared above) and 2-(3-iodo-4-methylphenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole (as prepared in Example 1) in a manner similar to that described for in Example 1. The title compound was obtained as a brown solid. Mp: 136-137° C.; 1H NMR (300 MHz, CDCl3) δ: 8.40 (2 H, s), 8.21 (1 H, s), 7.96-7.99 (1 H, d, J=9.0 Hz), 7.52-7.55 (1 H, d, J=9.0 Hz), 7.49-7.52 (1 H, d, J=9.0 Hz), 7.23-7.26 (1 H, d, J=9.0 Hz), 7.15-7.18 (1 H, d, J=9.0 Hz), 5.81 (1 H, s), 5.28 (1 H, s), 3.57 (2 H, s), 2.78 (1 H, s), 2.55 (8H, brs), 2.46 (3 H, s), 2.32 (3 H, s), 0.83-0.87 (2 H, m), 0.56 (2 H, brs). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C29H32N7: 478.2714. found: 478.2718.
Reaction SMILES: O.[OH-].[Na+].[CH3:4][C:5]1([CH3:20])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15](Cl)=[CH:16]C=O)[CH:13]=2)[S:8][CH2:7][CH2:6]1>O1CCOCC1>[CH3:4][C:5]1([CH3:20])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[CH:16])[CH:13]=2)[S:8][CH2:7][CH2:6]1
Reactant: CC1(C)CCSc2ccc(C(Cl)=CC=O)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C#Cc1ccc2c(c1)C(C)(C)CCS2
Yield: 87.68 %

Procedure:
In a 250 ml 4-necked round bottom flask fitted with a mechanical stirrer and reflux condenser, water (41.3 ml) and sodium hydroxide (5.22 g, 0.1305M) are added and heated to a temperature in the range of from about 80° C. to about 90° C. The reaction mixture is stirred, and a solution of 3-[4,4-dimethylthiochroman-6-yl]-3-chloro-2-propene-1-al (3.0 gm, 0.0113 M) is added dropwise in 1,4-dioxane (52.2 ml) under vigorous stirring. The reaction mixture is maintained at a temperature in the range of from about 80° C. to about 90° C. for about 2 hours. After completion of the reaction as determined by TLC, the solvents are distilled off and the product is extracted with ether (15 ml×3). The ether layer is washed with brine (15 ml×3). The organic layer is dried over sodium sulfate, and the solvent is distilled off to get an oily residue. The resulting crude oil is distilled under high vacuum and the vapors are collected at a temperature of about 126° C./0.2 mm as the main product. The main fraction appears as red viscous oil, which upon standing crystallized. Net wt of about 2.00 g, yield of about 87.68%; m.p. in the range of from about 69° C. to about 72° C., purity of about 98% (HPLC). The IR (neat) shows the following absorptions: 3200 cm−1 (C—H-str), 2950 cm−1 (—C═C—H str), 2100 cm−1 (—C═C—). The 1H-NMR (CDCl3), TMS as internal standard shows the following signals δ 1.35 (6H, s), 1.92-1.98 (2H, m), 3.02-3.08 (3H, m), 7.13 (1H, d 8.6 Hz), 7.58 (1H, dd, J 8.6 Hz, 2 Hz), 7.99 (1H, d, J 2 Hz). The CI/MS shows m/z 202 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:8]([CH:12]=O)=[CH:9][S:10][CH:11]=1)=[O:5])[CH3:2].[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C1(C)C=CC=CC=1.[BH4-].[Na+]>O>[CH3:26][C:24]([CH3:27])([O:23][C:21]([N:18]1[CH2:17][CH2:16][CH:15]([NH:14][CH2:12][C:8]2[C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][S:10][CH:9]=2)[CH2:20][CH2:19]1)=[O:22])[CH3:25]
Reactant: CCOC(=O)Nc1cscc1C=O
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)Nc1cscc1CNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
A mixture of 28.2 g (0.142 mol) of 4-(ethoxycarbonyl-amino)-thiophene-3-carboxaldehyde, 28.2 g (0.141 mol) of 4-amino-1-(1,1-dimethyl-ethoxycarbonyl)piperidine and 300 ml of toluene was refluxed using a water separator until water formation had ceased. The solvent was removed in vacuo, the residue was dissolved in 300 ml of methanol and at room temperature combined batchwise with 5.5 g (0.145 mol) of sodium borohydride. The mixture was stirred for a further hour at room temperature, then evaporated down in vacuo and the residue was distributed between water and tert. butyl-methylether. The organic phase was dried over sodium sulphate and freed from solvent in vacuo. The oily residue was further processed without purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:19](=[O:20])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C)C=O>[CH3:21][C:22]1[N:23]([CH2:2][CH2:3][CH2:4][CH:5]2[C:19](=[O:20])[C:9]3[C:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:11][O:12][C:8]=3[CH2:7][CH2:6]2)[CH:24]=[CH:25][N:26]=1
Reactant: Cc1ncc[nH]1
Reactant: O=C1c2c(-c3ccccc3)noc2CCC1CCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nccn1CCCC1CCc2onc(-c3ccccc3)c2C1=O
Temperature: 76 °C
Yield: 40.2 %

Procedure:
To a solution consisting of 5-(3-chloropropyl)-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (5.80 g) and dimethylformamide (57.0 ml) was added 2-methylimidazole (3.30 g), diisopropylethyl amine (10.5 ml) and sodium iodide (9.04 g) at room temperature with stirring. The reaction was flushed with nitrogen and warmed at 76° C. for 1 hour. Upon cooling to room temperature, dilute aqueous sodium bicarbonate and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous layer extracted twice with ethyl acetate and once with ether. The combined organic layers were washed with brine and concentrated to give the crude product. Drying was accomplished by azeotroping with benzene. Purification via flash column chromatography (silica gel, 2% triethylamine/0-20% methanol/ether) afforded 2.70 g (40%) of 6,7-dihydro-5-[3-(2-methyl-1H-imidazol-1-yl)-propyl]-3-phenyl -1,2-benzisoxazol-4(5H)-one. Recrystallization from dichloromethane/ether/pentane gave the product, m.p. 97°-99° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:3]=1.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CO
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CCl
Yield: 101.3 %

Procedure:
A solution of 1.33 g (4.96 mmol) [4-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol and 0.72 ml (9.92 mmol) thionylchloride in 30 ml dichloromethane was stirred for 1 h at RT. The reaction mixture was concentrated under reduced pressure to give 1.44 g of pure 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine.
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:11][C:10]2=O.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[N:29]1([C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[CH3:28])[CH:8]=3)[N:13]=[C:12]([N:17]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]3)[N:11]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(-c4ccccc4C)cc3c(=O)[nH]2)c1
Reactant: C1CCNC1
Product: Cc1ccccc1-c1ccc2nc(-n3cc(C(=O)O)cn3)nc(N3CCCC3)c2c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(o-tolyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI/CI): predicted mass C23H21N5O2, 399.2.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]([CH3:16])[CH:12]([NH2:15])[CH2:13][NH2:14])=[CH:3][CH:2]=1.N.Cl[CH2:19]Cl>>[NH:14]1[CH2:13][CH:12]([CH:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)[CH3:16])[N:15]=[CH:19]1
Reactant: ClCCl
Reactant: CC(c1ccnc2ccccc12)C(N)CN
Agent: N
Product: CC(c1ccnc2ccccc12)C1CNC=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To 3-Quinolin-4-yl-butane-1,2-diamine (1.54 g, 7.16 mmol) in 5 ml of dichloromethane, formidic acid ethyl ester hydrochloride (1.57 g, 14.3 mmol) was added. The reaction mixture was stirred overnight at room temperature. Aqueous ammonia (2 ml) was added to the reaction mixture and was partitioned between EtOAc (2×5 ml) and water. The organic layer was dried, filtered and concentrated to give 1.16 g (73%) of the product as a syrup which was used for the subsequent step.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[CH:36]([NH2:39])([CH3:38])[CH3:37].O>C1COCC1>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:39][CH:36]([CH3:38])[CH3:37])[N:3]=3)[N:25]=2)=[CH:34][CH:33]=1
Reactant: CC(C)N
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Nc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At RT, 60 mg (0.11 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.011 ml (0.13 mmol) of isopropylamine were stirred in 1.5 ml of THF for 60 min. Another 11 μl (0.13 mmol) of isopropylamine were then added, and the mixture was stirred at RT for another 60 min. About 10 ml of water were added to the reaction mixture, and the precipitate formed was filtered off, washed with water and dried under high vacuum. This gave 35 mg (56% of theory) of the desired target compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:18]=[CH:19]/[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][N:21]=2)=[C:7]([NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:11])[CH:8]=1.S(=O)(=O)(O)O.[CH3:34]O>>[NH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](/[CH:19]=[CH:18]/[C:6]2[CH:5]=[CH:4][C:3]([CH2:2][O:1][CH3:34])=[CH:8][C:7]=2[NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:11])=[N:21]1
Reactant: Cc1ccsc1C(=O)Nc1cc(CO)ccc1/C=C/c1n[nH]c2ccccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COCc1ccc(/C=C/c2n[nH]c3ccccc23)c(NC(=O)c2sccc2C)c1
Yield: 61 %

Procedure:
To Compound 108 (50.0 mg, 0.13 mmol), methanol (1.00 mL) and sulfuric acid (0.07 mL, 1.30 mmol) were added and the mixture was reacted in a microwave reaction vessel at 100° C. for 5 minutes to obtain Compound 121 (31.6 mg, 61%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C@H:11]([CH2:14][OH:15])[O:10][C:9]=2[CH:16]=1)(=[O:4])=[O:3].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:15][CH2:14][C@@H:11]2[O:10][C:9]3[CH:16]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=3[O:13][CH2:12]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CS(=O)(=O)c1ccc2c(c1)O[C@@H](CO)CO2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1

Procedure:
Preparation according to Preparation 10 using [[(2S)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (1.2 g, 5.0 mmol), DCM (25 ml), p-toluenesulfonyl chloride (1.4 g, 7.5 mmol), TEA (1.0 ml, 12.8 mmol) and 4-DMAP (0.6 g, 5.0 mmol). Yield: 1.8 g. MS m/z (rel. intensity, 70 eV) 398 (M+, 49), 226 (bp), 225 (24), 213 (30), 91 (68).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH2:17][CH2:18][OH:19]>CC#N>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:16][CH2:17][CH2:18][OH:19])[CH:8]=1)([O-:3])=[O:2]
Reactant: OCCCBr
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnn(CCCO)c1
Temperature: 75 °C
Reaction time: 6 h
Yield: 92.6 %

Procedure:
To a stirred solution of 4-nitro-1H-pyrazole (27) (1.0 g, 8.9 mmol) in MeCN (15 mL) was added K2CO3 (1.8 g, 13.2 mmol) and 3-bromo-propanol (880 μL, 9.7 mmol). The mixture was stirred at 75° C. for 6 hours. The solvent was evaporated in vacuo and the residue partitioned between H2O (15 mL) and EtOAc (15 mL). The layers were separated and the aqueous phase extracted with EtOAc (2×15 mL). The combined organics were dried (MgSO4), filtered and the solvent evaporated in vacuo to afford the title compound as a pale yellow oil (1.41 g, 93%); LCMS, Rt=1.31 min (MeOH-FA method), m/z 172 (MH+).
Reaction SMILES: [CH:1]1([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7](I)=[N:6]2)[CH2:4][CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)C4)=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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>[CH:1]1([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[N:23]4)=[CH:28][CH:27]=3)=[N:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)nn2C1CCC1
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: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nn2C1CCC1
Temperature: 80 °C

Procedure:
Nitrogen was bubbled into a mixture of 1-cyclobutyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (60.0 mg, 0.190 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline (64.4 mg, 0.194 mmol), Na2CO3 (50.5 mg, 0.476 mmol), and Pd(PPh3)4 (13.7 mg, 0.0119 mmol) in DMF (4 mL)/water (1 mL) for 5 min, then the mixture was heated under nitrogen to 80° C. (bath temp.) for 17 h. The solvents were evaporated, water was added, the mixture was extracted with CH2Cl2 (3×20 mL), and the combined extracts were washed with brine and dried over MgSO4. MgSO4 was filtered off, and the filtrate was concentrated and chromatographed on an SCX column (1 g/6 mL barrel). The amine-containing fraction was adsorbed onto Hydromatrix and chromatographed on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH2Cl2 (1-11)→1% MeOH in CH2Cl2 (12-28)→2% MeOH in CH2Cl2 (29-46)], yielding the title compound as off-white solid. 1H NMR (CDCl3, 400 MHz): δ=1.87-2.04 (m, 2H), 2.48-2.58 (mc, 2H), 2.86-2.98 (mc, 2H), 5.50 (quint, J=8.0 Hz, 1H), 5.57 (brs, 2H), 7.47-7.52 (m, 1H), 7.53-7.58 (m, 2H), 7.96 (dd, J=1.6, 8.3 Hz, 1H), 7.97 (d, J=8.6 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 8.19-8.23 (m, 2H), 8.31 (d, J=8.6 Hz, 1H), 8.42 (s, 1H), 8.49-8.52 (m, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=14.99 (−), 29.91 (2C, −), 50.61 (+), 98.68 (Cquart), 119.59 (+), 126.53 (+), 126.97 (Cquart), 127.56 (2C, +), 128.66 (+), 128.79 (2C, +), 129.00 (+), 129.53 (+), 134.83 (Cquart), 136.53 (+), 139.14 (Cquart), 143.40 (Cquart), 148.22 (Cquart), 154.00 (Cquart), 155.53 (+), 157.92 (Cquart), 158.18 (Cquart). MS (ES+): m/z 393.1 (53) [MH+]. HPLC: tR=3.1 min (OpenLynx, nonpolar—5 min), 3.6 min (OpenLynx, polar—5 min).
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.Cl.[CH3:13][O:14][C:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[N:21][CH:22]=1)=[O:16].Cl.C(=O)([O-])[O-].[K+].[K+]>>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:19]2[CH:20]=[N:21][CH:22]=[C:17]([CH:18]=2)[C:15]([O:14][CH3:13])=[O:16])=[CH:6][CH:5]=1
Reactant: COC(=O)c1cncc(B(O)O)c1
Reactant: FC(F)Oc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cncc(-c2ccc(OC(F)F)cc2)c1

Procedure:
10.0 g (44.8 mmol) of 4-(difluoromethoxy)bromobenzene were reacted according to General Method 3A with 14.6 g (67.3 mmol) of [5-(methoxycarbonyl)pyridin-3-yl]boronic acid hydrochloride. The release of the hydrochloride was achieved by additional addition of 6.80 g (49.3 mmol) of potassium carbonate. Yield: 8.6 g (67% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH2:19][CH3:20].O>CN(C)C=O>[CH2:19]([O:6][C:5](=[O:7])[C:4]1[C:8]([F:11])=[CH:9][N:10]=[C:2]([Br:1])[CH:3]=1)[CH3:20]
Reactant: CCI
Reactant: O=C(O)c1cc(Br)ncc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Br)ncc1F
Reaction time: 24 h
Yield: 49.5 %

Procedure:
To a solution of 2-bromo-5-fluoroisonicotinic acid (5.2 g) in N,N-dimethylformamide (100 mL) were added potassium carbonate (9.8 g) and iodoethane (7.4 g) at room temperature, and this mixture was stirred at same temperature for 24 hours. This reaction mixture was poured into water, and this mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (2.9 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[C:13]([CH3:25])[S:12][C:11]=2[CH:26]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[CH3:25][C:13]1[S:12][C:11]2[CH:26]=[C:7]([O:6][CH2:5][CH2:4][NH2:1])[CH:8]=[CH:9][C:10]=2[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=1
Reactant: Cc1sc2cc(OCCN=[N+]=[N-])ccc2c1-c1ccc(C(F)(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1sc2cc(OCCN)ccc2c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.3 %

Procedure:
0.230 g (0.610 mmol) 6-(2-Azido-ethoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophene and 0.484 g (1.83 mmol) of triphenylphosphin were dissolved in 1.6 ml of tetrahydrofuran. After stirring of the reaction mixture for 15 minutes at room temperature, 0.1 ml of water were added and the reaction mixture heated to 60° C. for 16 hours. It was then evaporated under reduced pressure, poured into 50 ml of water and extracted 3 times with 10 ml of dichloromethane. The combined dichloromethane phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 9:1 v/v mixture of dichloromethane and methanol as the eluent giving 0.200 g (93.4%) 2-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethylamine as colorless oil, MS: 352 (MH+).