Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[S:15][C:8]=23)=[C:4]([F:31])[CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[C:44](=[O:45])[C:43]([C:46](O)=[O:47])=[CH:42][CH:41]=[N:40]2)=[CH:35][CH:34]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:46]([C:43]2[C:44](=[O:45])[N:39]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)[N:40]=[CH:41][CH:42]=2)=[O:47])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[S:15][C:8]=12
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)CC1
Temperature: 25 °C
Yield: 40.6 %

Procedure:
A round-bottomed flask was charged with tert-butyl 4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)piperidine-1-carboxylate (144.5 mg, 0.326 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (228.9 mg, 0.977 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (312.3 mg, 1.63 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (220.1 mg, 1.63 mmol), N-ethyl-N-isopropylpropan-2-amine (421.1 mg, 3.26 mmol) and DMF (10 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (87.3 mg, 40.62%). LRMS (APCI pos): >95% purity, 254 nm, m/e 660 (M+1). 1H NMR (400 MHz, CD3Cl) δ 11.83 (s, 1H), 8.45 (d, 1H), 8.42 (d, 1H), 8.24 (d, 1H), 7.95 (dd, 1H), 7.37-7.68 (m, 5H), 7.21-7.28 (m, 2H), 6.48 (d, 1H), 4.24 (m, 2H), 3.08 (m, 1H), 2.89 (m, 2H), 2.07 (m, 2H), 1.75 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH3:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:25]=[C:24]([CH3:26])[S:23][C:13]=2[N:14]=1
Reactant: Cc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: Cc1cc2c(NCc3ccc(F)cc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(4-fluorobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [O:1]=[C:2]1[C@@H:5]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][O:3]1.[NH:17]1[CH:21]=[CH:20][CH:19]=[N:18]1>CC#N>[CH2:9]([O:8][C:7]([NH:6][C@@H:5]([CH2:4][N:17]1[CH:21]=[CH:20][CH:19]=[N:18]1)[C:2]([OH:3])=[O:1])=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(N[C@H]1COC1=O)OCc1ccccc1
Reactant: c1cn[nH]c1
Solvent: CC#N
Product: O=C(N[C@@H](Cn1cccn1)C(=O)O)OCc1ccccc1
Temperature: 50 °C
Yield: 37.7 %

Procedure:
A suspension of (S)-benzyl 2-oxooxetan-3-ylcarbamate (0.67 g, 3.03 mmol), and pyrazole (0.22 g, 3.29 mmol) in CH3CN (12 mL) was heated at 50° C. for 24 h. The mixture was cooled to rt overnight and the solid filtered to afford (S)-2-(benzyloxycarbonylamino)-3-(1H-pyrazol-1-yl)propanoic acid (330.1 mg). The filtrate was concentrated in vacuo and then triturated with a small amount of CH3CN (ca. 4 mL) to afford a second crop (43.5 mg). Total yield 370.4 mg (44%). m.p. 165.5-168° C. lit m.p. 168.5-169.5 [Vederas et al. J. Am. Chem. Soc. 1985, 107, 7105]. 1HNMR (400 MHz, CD3OD) δ 7.51 (d, J=2.0, 1H), 7.48 (s, J=1.5 Hz, 1H), 7.24-7.34 (m, 5H), 6.23 m, 1H), 5.05 (d, 12.7H, 1H), 5.03 (d, J=12.7 Hz, 1H), 4.59-4.66 (m, 2H), 4.42-4.49 (m, 1H). LCMS: Anal. Calcd. for C14H15N3O4: 289. found: 290 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:21])=[C:6]([CH:10]=[C:11]2[C:15](=[O:16])[NH:14][N:13]=[C:12]2[O:17][CH:18]([CH3:20])[CH3:19])[NH:7][C:8]=1[CH3:9])([OH:3])=[O:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH3:33][N:34]([CH2:36][CH2:37]O)[CH3:35]>ClCCl>[CH3:33][N:34]([CH3:35])[CH2:36][CH2:37][O:2][C:1]([C:4]1[C:5]([CH3:21])=[C:6]([CH:10]=[C:11]2[C:15](=[O:16])[NH:14][N:13]=[C:12]2[O:17][CH:18]([CH3:19])[CH3:20])[NH:7][C:8]=1[CH3:9])=[O:3]
Reactant: Cc1[nH]c(C=C2C(=O)NN=C2OC(C)C)c(C)c1C(=O)O
Reactant: CN(C)CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1[nH]c(C=C2C(=O)NN=C2OC(C)C)c(C)c1C(=O)OCCN(C)C
Reaction time: 24 h

Procedure:
A mixture of 4-[(4-carboxy-3,5-dimethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one (200 mg, 0.68 mmol) in dichloromethane (20 ml) and a drop of DMF, was treated with oxalyldichloride (0.2 ml). The stirring was continued for 24 h and a solution of dimethylaminoethanol (0.6 g, 6.7 mmol) in dichloromethane (5 ml) was added. The stirring was continued for 24 h. The solvent was evaporated to dryness, the solid residue was treated with NaHCO3 (5%) and extracted with dichloromethane. The solid obtained after elimination of the solvent was recrystallized from n-heptane.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[CH2:23][CH2:24][NH2:25].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:25][CH2:24][CH2:23][C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[F:20])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Reactant: NCCc1ccccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3ccccc3F)cc2F)cn1
Reaction time: 8 h
Yield: 74.9 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.650 g, 2.50 mmol), 2-fluorophenethylamine (0.382 g, 2.75 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (12 mL), cap and stir overnight. Add NaBH4 (slight excess) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 10% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound (0.718 g, 75%): TOF MS ES+ 384.2 (M+H)+, HRMS calcd for C21H20N3O2F2 387.2032 (M+H)+, found 387.2032, time 0.52 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% Over 18], tR=11.4 min, 100% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:15][C:14]=3[F:25])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>CN(C=O)C.CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:35][S:36]([O:24][CH2:23][CH2:22][CH2:21][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([F:25])[CH:15]=1)[N:12]=[CH:11][C:10]([C:8]([NH:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:27][CH:26]=1)=[O:9])=[C:19]2[OH:20])(=[O:38])=[O:37]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CCCO)cc2c1O
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide from Example No. 110 (0.13 g) in 10 mL DMF is added NEt3 (0.05 mL) and a spatula tip of DMAP. Methanesulfonyl chloride (0.030 mL) is added dropwise and the reaction is allowed to stir at room temperature overnight. The reaction is partitioned between EtOAc and H2O. The aqueous layer is extracted 3× with EtOAc. The organics are combined, dried over MgSO4, filtered, and concentrated under reduced pressure to give a yellow liquid. The residue is dissolved in CH2Cl2, adsorbed onto silica and chromatographed on a Biotage Flash 40S column (eluent 1% MeOH:CH2Cl2 (1 L) followed by 3% MeOH:CH2Cl2 (2 L)) to afford the desired product as a white solid which is further purified by recrystallization with CH2Cl2 /hexanes. (0.045 g, 0.097 mmol, 29%).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH2:4][S:5][CH3:6].CN(C)C=O.[NH2:22][C@H:23]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(N(CC)CC)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:22][C@H:23]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:9])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCSC)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
6.225 g. (25 mole) of BOC-L-Met was dissolved in 160 ml. of degassed dimethylformamide and cooled under nitrogen to 0° C. 4.55 g. (25 mmole) of L-Leu-OMe was dissolved in 80 ml. of dimethylformamide and set aside. To the BOC-L-Met was added 5.38 ml. of diphenylphosphorylazide in 10% excess followed by 3.48 ml. of triethylamine in 10% excess, followed by the L-Leu-OMe. The reaction mixture was stirred at 0° C. for 3 hrs., then at room temperature for 16 hrs. The solution was concentrated and treated with 3:1 dimethylformamide/ water and mixed bed resin, whereupon it crystallized out on the resin. The resin and crystals were filtered and the resin washed with dimethylformamide to isolate the product. The filtrate was then concentrated and recrystallized from ethyl acetate/hexane. 7.74 g. of product was obtained.
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[C:9]([NH2:10])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:11]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[CH:14]=[CH:13][C:12]=1[OH:21].CN1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28]>>[O:28]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:2]1[N:1]=[C:5]2[CH:6]=[C:7]([O:21][C:12]3[CH:13]=[CH:14][C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=4[CH:11]=3)[CH:8]=[C:9]([NH2:10])[N:4]2[N:3]=1
Reactant: Oc1ccc2c(c1)CCCC2
Reactant: CN1CCCC1=O
Reactant: Nc1cccc2ncnn12
Product: Nc1cc(Oc2ccc3c(c2)CCCC3)cc2nc(-c3ccco3)nn12

Procedure:
A mixture of 1 eq. 7-bromo-2-furan-2-)yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine, 5 eq. 5,6,7,8-tetrahydro-naphthalen-2-ol and a catalytic amount of CS2CO3 in 200 μl N-methyl-pyrrolidon was heated for 2 h to 160°. The mixture was, after filtration, purified with reversed phase column chromatography eluting with an acetonitrile/water gradient yielding the title compound, MS m/e (%): 346 M+H+ (100%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]2[S:9][CH:10]=[C:11]([C:12](O)=[O:13])[C:7]=2[CH:6]=1)(=[O:3])[CH3:2].CN(C)C=O.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]2[S:9][CH:10]=[C:11]([C:12]([Cl:24])=[O:13])[C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc2scc(C(=O)O)c2c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2scc(C(=O)Cl)c2c1

Procedure:
A mixture of 1,349 mg of the above obtained 5-acetoxybenzo[b]thiophene-3-carboxylic acid (4), a drop of dimethylformamide, 1.22 ml of (17.13 mmol) of thionyl chloride and 25 ml of toluene was refluxed for 1.5 hours and then concentrated under reduced pressure to give 1,454 mg of the objective compound (5).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:12])[CH2:8][CH2:9][CH2:10][NH2:11])([CH3:5])([CH3:4])[CH3:3].[Cl:13][C:14]1[CH:15]=[C:16]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH2:17][N:18]1[CH2:23][CH2:22][O:21][C@@H:20]([CH2:24][NH:25][C:26](=O)[O:27]C2C=CC([N+]([O-])=O)=CC=2)[CH2:19]1.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:13][C:14]1[CH:15]=[C:16]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH2:17][N:18]1[CH2:23][CH2:22][O:21][C@@H:20]([CH2:24][NH:25][C:26]([NH:11][CH2:10][CH2:9][CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:12])=[O:27])[CH2:19]1
Reactant: O=C(NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)CCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCNC(=O)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 22 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
4-Aminobutyric acid tert-butyl ester hydrochloride (0.235 g) was added to a stirred solution of Intermediate 13 (0.440 g) and N,N-diisopropylethylamine (0.42 ml) in dry dichloromethane (20 ml) under nitrogen, and the mixture was stirred at 22° C. for 18 h. The mixture was treated with saturated aqueous potassium carbonate (20 ml) and stirred for 5 min. The layers were separated and the organic layer applied to a silica gel cartridge (10 g Varian Bond Elut). Elution with dichloromethane, ether, ethyl acetate, and acetone gave the crude product (0.357 g). Further purification by chromatography on silica gel (10 g Varian Bond Elut cartridge), eluting with dichloromethane (1 column volume), ether (4 column volumes) and ethyl acetate (8 column volumes) gave the title compound as a gum (0.345 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][N:9]2[C:13]3=[N:14][CH:15]=[N:16][C:17]([NH2:18])=[C:12]3[C:11](I)=[N:10]2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:20][O:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[NH:37][C:38]([C:40]1[N:41]([CH3:49])[C:42]2[C:47]([CH:48]=1)=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[NH2:18][C:17]1[N:16]=[CH:15][N:14]=[C:13]2[N:9]([CH2:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[N:10]=[C:11]([C:26]3[CH:25]=[CH:24][C:23]([NH:37][C:38]([C:40]4[N:41]([CH3:49])[C:42]5[C:47]([CH:48]=4)=[CH:46][CH:45]=[CH:44][CH:43]=5)=[O:39])=[C:22]([O:21][CH3:20])[CH:27]=3)[C:12]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: Nc1ncnc2c1c(I)nn2CCCn1ccnc1
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: COCCOC
Product: COc1cc(-c2nn(CCCn3ccnc3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 80 °C
Reaction time: 24 h
Yield: 49.4 %

Procedure:
A suspension of 1-[3-(1H-1-imidazolyl)propyl]-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.086 g, 0.233 mmol) in ethylene glycol dimethyl ether (4 mL) was treated with N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (0.104 g, 0.256 mmol), tetrakis(triphenylphosphine)palladium (0.016 g, 0.014 mmol), and a solution of sodium carbonate (0.059 g, 0.56 mmol) in water (2 mL). The reaction mixture was stirred for 24 h at 80° C. The organic solvent was removed under reduced pressure and dichloromethane (25 mL) was added. The layers were partitioned and the aqueous layer was extracted with dichloromethane (100 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a step-wise gradient of 5% methanol in dichloromethane to 50% methanol in dichloromethane on a 10 g ISCO column. The column afforded 0.06 g (49%) of pure N2-(4-{4-amino-1-[3-(1H-1-imidazolyl)propyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide. 1H NMR (DMSO-d6, 400 MHz) δ 9.443 (s, 1H), 8.278 (s, 1H), 8.1324-8.1121 (d, 1H, J=8.12 Hz), 7.744-7.699 (m, 2H), 7.6-7.579 (d, 1H, J=8.4 Hz), 7.365-7.283 (m, 5H), 7.172-7.135 (m, 1H), 6.939 (s, 1H), 4.36-4.326 (m, 2H), 4.079-4.019 (m, 5H), 3.964 (s, 3H), 2.324-2.309 (m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.25 min (100%), MH+ 522.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].N1C=CC=CC=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl.CN(C)C1C=CN=CC=1>[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: COc1ccccc1CCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccccc1CCOCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The solution of 7.50 g of 2-[2-(2-methoxyphenyl)ethoxy]ethanol in 75 ml of dichloromethane is admixed successively with 8.5 ml of pyridine, 0.519 g of 4-dimethylaminopyridine and 9.10 g of p-toluenesulphonyl chloride, and stirred at room temperature over 16 hours. The reaction mixture is washed with brine (2×200 ml). The organic phase is dried with sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.26 (1:2 EtOAc-heptane); Rt=5.02.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)C.O.O[Li].O>C1COCC1>[CH2:13]([O:12][C:10]1[CH:11]=[C:6]([CH2:5][C:4]([OH:30])=[O:3])[CH:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][CH:21]=2)[CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
To a solution of (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (120 g, 0.29 mol) in THF (1.2 L) was added water (240 mL), LiOH.H2O (16 g, 0.32 mol) and the resulting mixture was stirred at room temperature for 16 h. The solution was filtered and concentrated in vacuo to remove THF. The resulting thick liquid was acidified to pH 2 by adding 2N aqueous HCl solution and the white suspension was mechanically stirred for 1 h at room temperature. The wet white product was recovered after filtration and dissolved in EtOAc (500 mL). The organic layer was separated from water, dried (MgSO4) and concentrated in vacuo to obtain (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (105 g, 94%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[Li]CCCC.[CH:12]([O:15][B:16]1[O:20][C:19](C)(C)[C:18]([CH3:24])([CH3:23])O1)(C)C>C1COCC1.[NH4+].[Cl-]>[CH3:24][C:18]1([CH3:23])[CH2:12][O:15][B:16]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[O:20][CH2:19]1
Reactant: Cn1cccn1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1nccc1B1OCC(C)(C)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 1-methylpyrazole (4.1 g, 50 mmole) in THF (100 mL) at 0° C. was added n-BuLi (2.2M in THF, 55 mmole). The reaction solution was stirred for 1 hour at RT and then cooled to −78° C. [J. Heterocyclic Chem. 41, 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.3 mL, 60 mmole). After 15 min at −78° C., the reaction was allowed to warm to 0° C. over 1 hour. The reaction was diluted with saturated NH4Cl solution and extracted with DCM. The organic fractions were washed with H2O (2×100 mL), dried over Na2SO4 and concentrated under vacuum to afford a tan solid (8.0 g, 77%) which was used without further purification. LCMS (ES) m/z 127 (M+H)+for [RB(OH)2]; 1H NMR (CDCl3, 400 MHz) δ 7.57 (s, 1H), 6.75 (s, 1H), 4.16 (s, 3H), and 1.41 (s, 12H).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1.[Cl:17][S:18](O)(=[O:20])=[O:19]>>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:18]([Cl:17])(=[O:20])=[O:19])[CH:15]=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1nc2c(c(=O)[nH]1)-c1ccccc1CC2
Product: Cc1nc2c(c(=O)[nH]1)-c1cc(S(=O)(=O)Cl)ccc1CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 41 %

Procedure:
1,2,5,6-tetrahydro-3-methyl-1-oxobenzo[f]quinazoline (5 g, 0.024 mole) was added to chlorosulfonic acid (50 ml, Aldrich) and stirred for 12 hours at room temperature. The reaction mixture was poured over ice (750 g), and the dark brown solid collected by filtration. The solid was washed with water, suspended in water (500 ml), and the pH of the suspension adjusted to 5.00 by addition of sodium bicarbonate. The suspension was filtered, the product washed with H2 0 and dried under high vacuum at room temperature to give 1,2,5,6-tetrahydro-3-methyl- oxobenzo[f]quinazolin-9-sulfonyl chloride as a light brown solid (3.054 g, 41%). 1H NMR (DMSO-d6, 300 MHz) δ: 2.60 (s, 3H, CH3); 2.90 (s, 4H, Ar CH2); 7.22 (d, J=9Hz, 1H, Ar); 7.53 (d, J=9Hz, 1H, Ar); 8.75 (s, 1H, Ar).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[N:14]1([CH2:19][CH2:20][NH2:21])[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N+:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:21][CH2:20][CH2:19][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[S:3][C:4]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Reactant: NCCN1CCCC1
Product: O=[N+]([O-])c1ccc2nc(NCCN3CCCC3)sc2c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 20.6 %

Procedure:
A mixture of 2-chloro-6-nitrobenzothiazole (250 mg, 1.16 mmol) and 2-pyrrolidin-1-yl-ethylamine (0.59 mL, 4.66 mmol) was heated at 100° C. for 4 hours then at 60° C. for 16 hours. After this time, the reaction mixture was filtered and the precipitate was washed with 2×5 mL of H2O. The solid was subjected to silica gel column chromatography (7.5% MeOH:92.5% CH2Cl2) to give the title compound as a yellow residue. Yield: 20.6%, 1H-NMR (DMSO-d6): δ 8.80 (br s, 1H); 8.70 (d, 1H, J=2.4 Hz); 8.11 (dd, 1H, J=6.8, 2.4 Hz); 7.47 (d, 1H, J=8.8 Hz); 3.58 (m, 2H); 2.60 (m, 6H); 1.73 (m, 2H).