Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:14]([NH:15][C:16]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[O:17])=[CH:13][N:12](C4CCCCO4)[N:11]=3)[NH:7][C:6]=2[CH:30]=1>ClCCl.FC(F)(F)C(O)=O>[F:1][C:2]1[C:3]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:14]([NH:15][C:16]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[O:17])=[CH:13][NH:12][N:11]=3)[NH:7][C:6]=2[CH:30]=1
Reactant: O=C(Nc1cn(C2CCCCO2)nc1-c1nc2cc(OCCCCN3CCCCC3)c(F)cc2[nH]1)N1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1c[nH]nc1-c1nc2cc(OCCCCN3CCCCC3)c(F)cc2[nH]1)N1CCCCC1
Yield: 77.7 %

Procedure:
A solution of 130 mg of piperidine-1-carboxylic acid [3-[6-fluoro-5-(4-piperidin-1-ylbutoxy)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide in 2 mL of dichloromethane and 500 μL of trifluoroacetic acid are stirred for 72 hours at ambient temperature. After evaporation of the solvent under vacuum in a rotary evaporator, the reaction crude is purified by flash chromatography on an Analogix RS-12 cartridge with an eluent of 100% dichloromethane to 90/10 dichloromethane/methanol. 86 mg of N-{3-[6-fluoro-5-(4-piperidin-1-ylbutoxy)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}piperidine-1-carboxamide in the form of a trifluoroacetate salt are obtained in the form of a yellow solid. 1H NMR (300 MHz, DMSO-d6, δ in ppm): for this batch, we observe a 60%-40% resolution of tautomers with: from 1.20 to 1.94 (broad m, 16H); from 2.70 to 3.43 (m partially masked, 6H); 3.50 (m, 4H); 4.11 (m, 2H); 7.11 (d, J=7.5 Hz, 0.6H); 7.27 (d, J=11.0 Hz, 0.4H); 7.37 (d, J=7.5 Hz, 0.4H); 7.51 (d, J=11.0 Hz, 0.6H); 8.01 (broad s, 1H); 8.94 (broad m, 1H); 9.83 (s, 0.4H); 9.87 (s, 0.6H); 12.95 (s, 0.4H); 13.0 (s, 0.6H); 13.05 (s, 1H).
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14](OC)=[O:15])[CH2:3]1.[Li+].[BH4-]>O1CCCC1.CCOC(C)=O>[F:18][C:2]1([F:1])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([CH2:14][OH:15])[CH2:3]1
Reactant: COC(=O)[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Into a solution of 1-tert-butyl 2-methyl (2S)-4,4-difluoropyrrolidine-1,2-dicarboxylate (900 mg, 3.39 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) was added LiBH4 (200 mg, 9.1 mmol, 2.7 equiv) in batches at 0° C. The resulting solution was stirred overnight at room temperature, then was diluted with EtOAc and washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give 0.8 g of tert-butyl (2S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate as reddish oil.
Reaction SMILES: Br[C:2]1[N:11]2[C:5]([CH2:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10]2)=[N:4][N:3]=1.[O-:16][CH2:17][CH3:18].[Na+]>>[CH2:17]([O:16][C:2]1[N:11]2[C:5]([CH2:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10]2)=[N:4][N:3]=1)[CH3:18]
Reactant: CC[O-]
Reactant: Brc1nnc2n1C=Cc1ccccc1C2
Agent: [Na+]
Product: CCOc1nnc2n1C=Cc1ccccc1C2

Procedure:
The reaction of 3-bromo-11H-s-triazolo[3,4-b][3]benzazepine with sodium ethoxide yielded 3-ethoxy-11H-s-triazolo[3,4-b][3]benzazepine. Colorless needles (as recrystallized from acetone), melting point: 143°-144° C. Infrared absorption spectrum of this compound was identical with that of the products obtained in Examples 35 and 36.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH:10]1([C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]3)=[N:17][CH:18]=2)[CH2:12][CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([O:9][CH:22]2[CH2:23][CH2:24][N:19]([C:16]3[N:15]=[CH:14][C:13]([CH:10]4[CH2:12][CH2:11]4)=[CH:18][N:17]=3)[CH2:20][CH2:21]2)=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1
Reactant: OC1CCN(c2ncc(C3CC3)cn2)CC1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(OC2CCN(c3ncc(C4CC4)cn3)CC2)c(Cl)c[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 30.2 %

Procedure:
To a stirring mixture of 5-chloro-4-hydroxypyridin-2(1H)-one (212 mg, 1.46 mmol), 1-(5-cyclopropylpyrimidin-2-yl)piperidin-4-ol (320 mg, 1.459 mmol, prepared according to procedures described in Example 173 Step A substituting 2-chloro-5-cyclopropylpyrimidine for 2-chloro-5-propylpyrimidine) and triphenylphosphine (574 mg, 2.19 mmol) in DMF (10 mL) at 0° C. was added diisopropyl azodicarboxylate (0.43 mL, 2.2 mmol). The reaction was stirred under Ar at room temperature for 2 days and then H2O was added. The resulting mixture was concentrated in vacuo to a yellow oil. The oil was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2 and then SiO2, 0 to 10% MeOH in CH2Cl2) to yield 153 mg of desired product as a white solid. MS (ESI) 347 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[C:33]([C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=1)#[N:34]>>[C:33]([C:35]1[CH:36]=[C:37]([O:41][C:2]2[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]4)=[CH:13][CH:12]=3)=[O:9])=[CH:4][CH:3]=2)[CH:38]=[CH:39][CH:40]=1)#[N:34]
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Cl)nc3)cc2)CCN1C(=O)OC(C)(C)C
Reactant: N#Cc1cccc(O)c1
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4cccc(C#N)c4)nc3)cc2)CCN1C(=O)OC(C)(C)C
Reaction time: 24 h

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D54) and 3-cyanophenol in a similar manner to that described for D55 in Description 55 although the reaction temp./time was 130° C. for 24 h and purification was carried out by column chromatography. This gave the title compound as a colourless oil (0.184 g). MS (ES): MH+ 542.3.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)([OH:3])=O.C1[CH2:29][CH2:28][N:27]2[C:22](=[N:23][CH2:24][CH2:25][CH2:26]2)[CH2:21]C1.ClC(OCC(C)C)=O.C(NC1C=CC=CN=1)C>C(Cl)(Cl)Cl>[CH2:28]([N:27]([C:22]1[CH:21]=[CH:26][CH:25]=[CH:24][N:23]=1)[C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)=[O:3])[CH3:29]
Reactant: O=C(O)CCCOc1ccc2[nH]c(=O)ccc2c1
Reactant: C1CCC2=NCCCN2CC1
Agent: CC(C)COC(=O)Cl
Agent: CCNc1ccccn1
Solvent: ClC(Cl)Cl
Product: CCN(C(=O)CCCOc1ccc2[nH]c(=O)ccc2c1)c1ccccn1
Reaction time: 1 h

Procedure:
Into 300 ml of chloroform were added 9.9 g of 6-(3-carboxypropoxy)carbostyril and 6.5 ml of DBU. The outside of the reaction vessel containing the abovementioned mixture was ice-cooled and 5.7 ml of isobutyl chloroformate was added dropwise under stirring condition. After the addition operation, stirring was continued for 1 hour at a room temperature and 5.4 g of 2-ethylaminopyridine was added dropwise, then the reaction was continued for 5 hours under stirring condition. The reaction mixture was washed with a diluted NaHCO3 aqueous solution and water, and was concentrated. The residue thus obtained was treated by a silica-gel column chromatography (solvent used was a mixture of chloroform:methanol=20:1) and the elute thus obtained was concentrated then was recrystallized from methanol, to obtain 4.5 g of 6-{3-[N-ethyl-N-(2-pyridyl)aminocarbonyl]propoxy}carbostyril in the form of colorless needle-like crystals. Melting point: 148°-149° C.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH:31]1[CH2:39][OH:40].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:40][CH2:39][CH:31]1[CH2:32][C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]1[C:27]([C:23]1[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[CH2:12][C:4]2([C:5]4[C:6](=[N:7][CH:8]=[CH:9][CH:10]=4)[NH:11][C:3]2=[O:2])[CH2:19]3)[CH:22]=1)=[O:28]
Reactant: OCC1Cc2ccccc2N1
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1c2ccccc2CC1CO

Procedure:
100 mg (0.24 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 45 mg (0.30 mmol) (2,3-dihydro-1H-indol-2-yl)-methanol, 0.10 mL (0.71 mmol) TEA and 88 mg (0.27 mmol) TBTU in 1.0 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and the solvent was evaporated down by about half. The precipitate formed was suction filtered and dried.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[CH2:6]([NH:13][CH2:3][CH2:2][C:1]([NH2:5])=[O:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCc1ccccc1
Reactant: C=CC(N)=O
Solvent: CCO
Product: NC(=O)CCNCc1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of acrylamide (32 g) in ethanol (450 mL) was added benzylamine (59 mL), and the mixture was stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1-dichloromethane/methanol=50/1) to give the title compound (73.2 g).
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[N:11]([C:14]3[C:15]([CH3:20])=[N:16][N:17]([CH3:19])[CH:18]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33](B(O)O)=[CH:32][N:31]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:10]2[C:5]3[N:6]([CH:7]([CH3:9])[CH3:8])[C:2]([C:33]4[C:34]([O:36][CH3:37])=[N:35][C:30]([O:29][CH3:28])=[N:31][CH:32]=4)=[CH:3][C:4]=3[C:12](=[O:13])[N:11]2[C:14]2[C:15]([CH3:20])=[N:16][N:17]([CH3:19])[CH:18]=2)=[CH:22][CH:23]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: Cc1nn(C)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(Cl)cc2)N(c2cn(C)nc2C)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-6-(4-chloro-phenyl)-5-(1,3-dimethyl-1H-pyrazol-4-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate AY) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a white solid. tR: 1.06 min (HPLC 3); ESI-MS: tR=1.01 min, [M+H]+ 507/509 (LC-MS 1); TLC: Rf=0.22 (9:1 CH2Cl2/MeOH).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH3:14])[C:6]=1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li]CCCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>C1COCC1>[CH3:14][N:5]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:2]([B:20]([OH:25])[OH:21])[CH:3]=[N:4]1
Reactant: Cn1ncc(I)c1Oc1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1ncc(B(O)O)c1Oc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
4-Iodo-1-methyl-5-phenoxy-1H-pyrazole (862 mg; 2.75 mmol) is dissolved in 15 ml THF extra dry and cooled down to −78° C. Afterwards n-BuLi (1.80 ml; 2.88 mmol; 1.6 mol/l in Hexane) and Triisopropyl borate (982.28 mg; 5.22 mmol) are added. It is stirred for 1 hour. The reaction mixture is quenched with 1 ml water and purified with reversed phase chromatography under basic conditions.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[CH2:12]([NH2:18])[C:13]1[O:17][CH:16]=[CH:15][CH:14]=1.COC(OC)OC.[BH4-].[Na+]>CO.CC(O)=O>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:18][CH2:12][C:13]2[O:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C=O)cc1
Reactant: NCc1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: COC(OC)OC
Product: CCOc1ccc(CNCc2ccco2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.9 %

Procedure:
4-Ethoxy benzaldehyde (5 g, 33 mmol) and furfuryl amine (4.2 g, 43 mmol.) in a mixture of methanol (50 mL), trimethylorthoformate (10 mL) and AcOH (1 mL) were stirred at room temperature, under an atmosphere of nitrogen for 16 hours. Sodium borohydride (1.4 g, 35 mmol) was added, in 4 portions, over a period of 30 minutes (exothermic reaction). The reaction was stirred for an additional 2 hours at room temperature. The solvent was removed under vacuum and the residue taken up in ethyl acetate (150 mL). The organic phase was washed with H2O (200 mL) and aqueous phase was back extracted with ethyl acetate (2×, 100 mL). The combined organic layers were concentrated and the residue was purified on silica gel (70% ethyl acetate in hexanes with ˜0.5% triethylamine) to afford N-(4-ethoxybenzyl)-1-(furan-2-yl)methanamine (6.1 g, 80%) as a clear oil. NMR (CDCl3, 400 MHz): δ 1.40 (t, J=7.2 Hz, 3H), 3.71 (s, 2H), 3.76 (s, 2H), 4.02 (q, J=7.2 Hz, 2H), 6.17 (d, J=4 Hz, 1H), 6.31 (m, 1H), 6.84 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.8 Hz, 2H), 7.36 (m, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:11]2)=[CH:6][CH:5]=1.[Na:18].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([S:14]([OH:17])(=[O:15])=[O:16])=[CH:11]2)=[CH:6][CH:5]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Na:18]
Reactant: BrCc1ccccc1
Reactant: O=S(=O)(O)c1ccc2ccc(O)cc2c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: O=S(=O)(O)c1ccc2ccc(OCc3ccccc3)cc2c1
Reaction time: 2 h

Procedure:
A 60% dispersion of sodium hydride (0.37 g, 9.22 mmol) in mineral oil is washed with hexanes twice and suspended in 40 mL of DMF. To this mixture is added slowly via an addition funnel 7-hydroxynaphthalene-2-sulfonic acid, sodium salt (1.25 g, 5.08 mmol) in 25 mL of DMF at room temperature. The reaction mixture is stirred for 2 hours during which time mild bubbling is observed (H2 evolution). The mixture is treated with benzyl bromide (1.5 mL, 12.6 mmol) and stirred for 18 hours at room temperature. Ice is added to decompose the excess NaH and the resultant mixture is concentrated in vacuo. The residue is suspended in acetone and concentrated in vacuo two times and then is dried under high vacuum. The solid is suspended in acetone, filtered and dried to yield the crude 7-benzyloxynaphthalene-2-sulfonic acid, sodium salt as a beige solid. A mixture of the sulfonic acid, sodium salt (2.47 g) in 8 mL of thionyl chloride is heated at 80° C. for 4 hours. A drop of DMF is added with vigorous bubbling resulting and the mixture is heated for an additional 30 minutes. The mixture is allowed to cool to room temperature and concentrated in vacuo. The residue is diluted in EtOAc and washed successively with water (2×), saturated NaHCO3 solution and saturated NaCl. The organic layer is dried over anhydrous MgSO4, filtered and concentrated to yield the title compound as a beige solid (1.26 g, 3.78 mmol). The crude product is of sufficient purity to be used in subsequent reactions.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[I-].[K+]>O.CN(C)C=O>[OH:10][CH2:9][C:2]1[O:3][CH:4]=[C:5]([O:8][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[C:6](=[O:7])[CH:1]=1
Reactant: O=c1cc(CO)occ1O
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1coc(CO)cc1=O
Temperature: 90 °C
Reaction time: 10 h

Procedure:
A mixture of 56.8 g (0.4 mole) kojic acid, 55,3 g (0.4 mole) potassium carbonate, 133.3 g (0.4 mole) 1-octadecyl bromide, 1 g potassium iodide and 450 mL anhydrous dimethylformamide is stirred for 10 hours at 90° C. After cooling, the mixture is mixed with 1.5 L of water, the precipitate formed is filtered off, well stirred up once with ethyl acetate, filtered off and recrystallized from propan-2-ol with the addition of active charcoal. There is obtained a colorless product: m.p. 71°-73° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[O:18]1CCOCC1>>[CH3:17][C:13]1[N:12]=[C:11]([C:9]2[CH:8]=[CH:7][NH:6][C:5](=[O:18])[N:10]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: C1COCCO1
Reactant: Cc1cccc(-c2ccnc(S(C)(=O)=O)n2)n1
Product: Cc1cccc(-c2cc[nH]c(=O)n2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
2-Methanesulfonyl-4-(6-methyl-pyridin-2-yl)-pyrimidine (625 mg, 2.51 mmol) was dissolved in dioxane (20 ml) and then 2N NaOHaq (12.5 ml, 25 mmol) was added. After stirring at room temperature for 1 hour, the solution was acidified with 37% HClaq. The mixture was evaporated and the residue redissolved in DCM-MeOH—NH4OH (95-5-0.5) and evaporated. The crude was purified by Flash chromatography with DCM-MeOH (9-1) to give 400 mg of the title compound. (85% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[C:17](Br)[CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:27]([N:34]1[CH:42]=[C:41]2[C:36]([CH:37]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:39]=[CH:40]2)=[N:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[C:17]([C:38]3[CH:39]=[CH:40][C:41]4[C:36]([CH:37]=3)=[N:35][N:34]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:42]=4)[CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2cc(Br)c3c(N)ncnn23)c1
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: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Temperature: 150 °C

Procedure:
To a solution of [3-(4-amino-5-bromo-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzyl]-carbamic acid tert-butyl ester (2.65 g, 6.1 mmol) in DMF (20 mL), 2-benzyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole (3.26 g, 9.8 mmol), Pd(PPh3)4 (700 mg, 0.6 mmol) and 2 N Na2CO3 (12 mL) were added. The mixture was degassed for 20 min and was then heated to 150° C. in microwave reactor for 10 min. After cooling, the mixture was partitioned between EtoAc/H2O and the organic layer was separated and dried. Biotage® chromatography (50-100% EtOAc) provided the title product as off white solid 2.6 g (76%). NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 4.10 (d, 2 H), 0.9 (s, 9 H); ES-MS m/z 561.34 [M+H]+, HPLC RT (min) 4.06.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([CH:12]=[O:13])[C:9]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C.CN(C)C=O>[OH:13][CH2:12][C:10]1[C:9]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[N:8][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=1
Reactant: O=Cc1cn(-c2ccccc2)nc1-c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: OCc1cn(-c2ccccc2)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
80 grams 1-phenyl-3-(p-chlorophenyl)-pyrazol-4-aldehyde were dissolved in a mixture of 800 milliliters ethanol and 1200 milliliters dimethylformamide. To the solution thus obtained, 5.5 grams 95% sodium borohydride were added in small portions at 20°-25° C. The mixture was then stirred for one hour at room temperature. Thereafter, the reaction mixture was evaporated and the residue was taken up, with rubbing, with ethanol and water were thereafter added. The precipitate formed thereby was separated, dispersed and stirred in warm water, the precipitate was filtered off by suction, dried and recrystallized from benzene. 75 grams 4-hydroxymethyl-1-phenyl-3-(p-chlorophenyl)-pyrazol, melting at 141°-142° C., were obtained, representing a yield of 93%.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:9]=[N:8][NH:7][C:6]=1[NH2:10])([O-:4])=[O:3].C(O[CH:14]=[CH:15][C:16]#[N:17])C>C(O)(=O)C>[ClH:1].[N+:2]([C:5]1[CH:9]=[N:8][N:7]2[C:16]([NH2:17])=[CH:15][CH:14]=[N:10][C:6]=12)([O-:4])=[O:3]
Reactant: Nc1[nH]ncc1[N+](=O)[O-]
Reactant: CCOC=CC#N
Agent: Cl
Solvent: CC(=O)O
Product: Nc1ccnc2c([N+](=O)[O-])cnn12
Temperature: 40 °C
Yield: 93 %

Procedure:
50 g of 4-nitro-2H-pyrazole-3-ylamine hydrochloride (prepared according to H. Dorn and H. Dilcher, Liebigs Ann. Chem., 707, 141, 1967) 35 g of β-ethoxyacrylonitrile and 250 cc of acetic acid were introduced into a 500 cc three-necked round-bottomed flask fitted with a mechanical stirrer and equipped with a condenser and a thermometer. The medium was refluxed for 4h30'. The mixture was cooled to about 40° C. and the precipitate was then filtered off. This precipitate was taken up in 300 cc of ethyl ether with stirring. The precipitate was filtered off again, washed on the filter with 100 cc of ethyl ether and the product was dried under vacuum over phosphorus pentoxide. 61.3 g of 3-nitropyrazolo[1,5-a]pyrimidin-7-ylamine hydrochloride were obtained in the form of a yellow powder. (Yield=93%).
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].CS(C)=O.[H-].[Na+].S(OCC1CCC=CC1)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=O)=O>O>[CH2:1]([O:11][CH2:25][CH:24]1[CH2:26][CH2:27][CH2:21][CH:22]=[CH:23]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Cc1ccc(S(=O)(=O)OCC2CC=CCC2)cc1
Reactant: CCCCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCOCC1C=CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 500 mL round bottom flask equipped with a mechanical stirrer was charged with 23.7g (0.15 mol) decyl alcohol, and 150 mL of DMSO. Sodium hydride (4.22 g, 95% in purity; 0.167 mol) was slowly added to above mixture in an ice bath over 20 min. After the above mixture was reacted at room temperature for 3 hrs, the reaction mixture was cooled to room temperature. 3-Cyclohexene-1-methanol tosylate (39.9 g, 0.15 mol) was slowly added to the above mixture over 20 min. The reaction was carried at room temperature overnight, then 80° C. for 3 hrs. The reaction mixture was added to water (150 mL), and then extracted with chloroform (3×150 niL), washed to water (2×100 mL) and dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.