Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][NH:8][C:9]2[C:14]([F:15])=[C:13](Cl)[N:12]=[C:11]([CH3:17])[N:10]=2)[N:6]=1.O.[NH2:19][NH2:20]>CS(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][NH:8][C:9]2[N:10]=[C:11]([CH3:17])[N:12]=[C:13]([NH:19][NH2:20])[C:14]=2[F:15])[N:6]=1
Reactant: Cc1nc(Cl)c(F)c(NCc2csc(N)n2)n1
Reactant: NN
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(NN)c(F)c(NCc2csc(N)n2)n1
Reaction time: 8 h
Yield: 28 %

Procedure:
N-[(2-Amino-1,3-thiazol-4-yl)methyl]-6-chloro-5-fluoro-2-methyl-4-pyrimidinamine (450 mg, 1.56 mmol) was dissolved in 5 ml of DMSO and 5 ml of hydrazine monohydrate was added. The mixture was stirred overnight and was purified by RP-HPLC to provide 6-{[(2-amino-1,3-thiazol-4-yl)methyl]amino}-5-fluoro-4-hydrazino-2-methylpyrimidine (125 mg, 28%). LCMS: (M+H)+: 284.1.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Li+].CC([N-]C(C)C)C.[CH2:19]1[O:21][CH2:20]1>C1COCC1>[Cl:1][C:2]1[C:9]([CH2:19][CH2:20][OH:21])=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: C1CO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(F)c(CCO)c1Cl
Reaction time: 5 h
Yield: 66.2 %

Procedure:
To a solution of 2-chloro-4-fluorobenzonitrile (20.0 g, 128.6 mmol) in THF (200 mL) was added LDA (28% wt in THF, 71.0 mL, 142.0 mmol) at −78° C. After addition, the mixture was stirred at the same temperature for 5 h, then ethylene oxide (9.7 ml, 194.2 mmol) was added. The reaction mixture was allowed to warm to R. T. gradually and stirred overnight. The reaction was quenched by adding saturated aqueous NH4Cl solution and extracted with EtOAc (400 mL). The EtOAc extracts were washed with water, brine and dried over Na2SO4. After the solvent was removed, the residue was purified by SiO2 column to give 2-chloro-4-fluoro-3-(2-hydroxyethyl)benzonitrile (17.0 g, 66%). 1H NMR (400 MHz, CDCl3, δ in ppm) 7.58 (dd, J=5.5, 8.6 Hz, 1H), 7.10 (t, J=8.6 Hz, 1H), 3.88 (m, 2H), 3.13 (t, J=6.8 Hz, 2H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[B:25]1(B2OC(C)(C)C(C)(C)O2)[O:29]C(C)(C)C(C)(C)[O:26]1.CC([O-])=O.[K+].B(O)O>O1CCOCC1.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:21]([O:20][C:18]([N:14]1[CH2:15][CH2:16][CH2:17][C@H:13]1[C:11]1[O:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([B:25]([OH:29])[OH:26])=[CH:3][CH:4]=2)=[N:9][N:10]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nnc(-c2ccc(I)cc2)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: OBO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nnc(-c2ccc(B(O)O)cc2)o1
Temperature: 100 °C
Yield: 21.6 %

Procedure:
A mixture of (S)-tert-butyl 2-(5-(4-iodophenyl)-1,3,4-oxadiazol-2-yl)pyrrolidine-1-carboxylate (24) (0.574 g, 1.30 mmol), bis(pinacolato)diboron (0.665 g, 2.62 mmol), KOAc (0.641 g, 6.53 mmol) and Pd(PPh3)4 (0.076 g, 0.0658 mmol) in dioxane (5 mL) was degassed with a stream of Ar for 15 minutes. The mixture was then heated at 100° C. for 12 hours, cooled to room temperature and poured into ethyl acetate/H2O. The layers were separated, the aqueous phase was re-extracted with ethyl acetate (2×) and the combined organic layers were washed (H2O, brine) and dried (Na2SO4) and filtered. The solvent was removed in vacuo and the residue purified by flash chromatography (hexane:ethyl acetate, 1:1) to give a mixture of the title boronate ester (25) and boronic acid (26). This mixture was repurified by prep HPLC (CH3CN:H2O:TFA) to afford (S)-4-(5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1,3,4-oxadiazol-2-yl)phenylboronic acid 26 as a colorless solid (0.101 g, 22%). 1HNMR (400 MHz, DMSO-d6) δ 8.31 (s, br, 2H), 7.94-8.00 (m, 4H), 5.03-5.10 (m, 1H), 3.37-3.42 (m, 2H), 2.31-2.40 (m, 1H), 1.92-2.04 (m, 3H). 1.38 (s, 3H), 1.18 (s, 6H); LCMS: Anal. Calcd. for C17H22BN3O5: 359. found: 360 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([N:6]3[C:11](=[CH:12]2)[C:10](=[O:15])[NH:9][CH2:8][CH2:7]3)=[N:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][Cl:20]>>[Cl:20][CH2:19][CH2:18][CH2:17][O:1][C:2]1[CH:14]=[C:13]2[C:5]([N:6]3[C:11](=[CH:12]2)[C:10](=[O:15])[NH:9][CH2:8][CH2:7]3)=[N:4][CH:3]=1
Reactant: ClCCCBr
Reactant: O=C1NCCn2c1cc1cc(O)cnc12
Product: O=C1NCCn2c1cc1cc(OCCCCl)cnc12
Yield: 80 %

Procedure:
The title compound was synthesized in analogy to example 2, intermediate, from 7-hydroxy-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one (example 84, intermediate a) and 1-bromo-3-chloropropane, to give the desired product as a light yellow solid (80%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:14]=[N:13][C:12](O)=[CH:11][CH:10]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:12]1[N:13]=[N:14][C:9]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])=[CH:10][CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc(C)c1-c1ccc(O)nn1
Product: Cc1cccc(C)c1-c1ccc(Cl)nn1
Temperature: 80 °C

Procedure:
A mixture of 6-(2,6-dimethyl-phenyl)-pyridazin-3-ol in POCl3 is heated at 80° C. for 2 h. The volatile material is evaporated under reduced pressure and the residue is partitioned between EtOAc and diluted NaOH aqueous solution. The organic layer is separated and the aqueous layer is extracted with EtOAc once. The combined organic extract is washed with brine, dried and concentrated in vacuo. The crude product is purified by flash column (Hexanes/EtOAc 4:1) to give 3-chloro-6-(2,6-dimethyl-phenyl)-pyridazine. 1H NMR: (CDCl3) 7.59 (d, 1H), 7.38 (d, 1H), 7.25 (m, 1H), 7.14 (d, 2H), 2.06 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=3)[N:13]=[C:12]([C:23]([F:26])([F:25])[F:24])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:14]([C:15]3[CH:16]=[CH:17][C:18]([S:21]([CH3:22])=[O:35])=[CH:19][CH:20]=3)[N:13]=[C:12]([C:23]([F:26])([F:24])[F:25])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(SC)cc2)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)=O)cc2)cc1F
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a solution of 5-(3-fluoro-4-methoxyphenyl)-1-(4-methylsulfanylphenyl)-3-trifluoromethyl-1H-pyrazole (compound No. 14) (790 mg) in chloroform (25 mL), m-chloroperbenzoic acid (55-75%, 464 mg) was added in one portion at −40° C. and stirred at the same temperature for one hour. The reaction mixture was diluted with chloroform (50 mL), washed with saturated solution of aqueous sodium bicarbonate (30 mL), water (2×30 mL), dried over calcium chloride and evaporated under reduced pressure. The product obtained was chromatographed over silicagel using 7:3 ethyl acetate: petroleum ether as eluent to afford 600 mg of product as a thick liquid.
Reaction SMILES: C([O:5][N:6]=[C:7]([C:9]1[N:10]=[CH:11][C:12]([NH:15][C:16](=[O:35])[C@@H:17]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[C:26]([Cl:34])[CH:25]=2)[CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[N:13][CH:14]=1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[Cl:34][C:26]1[CH:25]=[C:24]([C@@H:17]([CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]([NH:15][C:12]2[CH:11]=[N:10][C:9](/[C:7](=[N:6]\[OH:5])/[CH3:8])=[CH:14][N:13]=2)=[O:35])[CH:29]=[CH:28][C:27]=1[S:30]([CH3:33])(=[O:32])=[O:31]
Reactant: CC(=NOC(C)(C)C)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: C/C(=N/O)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
A solution of N-[5-(1-tert-butoxyimino-ethyl)-pyrazin-2-yl]-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (195.5 mg, 0.38 mmol) in methylene chloride (1.4 mL) was treated with trifluoroacetic acid (2.8 mL). The resulting reaction mixture was stirred at 25° C. for 2 h, at which time, thin layer chromatography still indicated the presence of starting material. The reaction was then heated at 40° C. where it was stirred overnight. At this time, thin layer chromatography again still indicated the presence of starting material. The reaction mixture was then heated at 60° C. where it was stirred for a second night. The reaction mixture was then allowed cool to 25° C. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic layer was washed with a saturated aqueous sodium bicarbonate solution (2×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 1/2 ethyl acetate/hexanes) afforded the 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(1(Z)-hydroxyimino-ethyl)-pyrazin-2-yl]-propionamide (110.0 mg, 63%) as an off-white powdery solid: mp 94.2–102.5° C. (foam to gel); (ES)+-HRMS m/e calcd for C21H25ClN4O4S (M+H)+ 465.1358, found 465.1363.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([Cl:33])[C:17]=1[NH:18][C:19]1[C:28]2[C:23](=[C:24]([OH:31])[C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[O:22][C:21](=[O:32])[CH:20]=1>>[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([Cl:33])[C:17]=1[NH:18][C:19]1[C:28]2[C:23](=[C:24]([O:31][CH2:2][CH2:3][CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[O:22][C:21](=[O:32])[CH:20]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: BrCCCc1ccccc1
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCc1ccccc1

Procedure:
The title compound was prepared from (3-bromopropyl)benzene and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, CDCl3): δ 8.61 (s, 2H), 7.39 (d, 1H), 7.35-7.15 (m, 5H), 6.97 (d, 1H), 6.54 (s, 1H), 5.14 (s, 1H), 4.19 (t, 2H), 3.98 (s, 3H), 2.91 (t, 2H), 2.15 (m, 2H); MS (ESI): 470.9.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:26]1[CH:31]=[C:30]([C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=2)[CH:29]=[N:28][CH:27]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:36](=[O:37])[C:35]4[CH:34]=[CH:33][C:32]([C:30]5[CH:29]=[N:28][CH:27]=[N:26][CH:31]=5)=[CH:40][CH:39]=4)=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=C(Cl)c1ccc(-c2cncnc2)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(-c5cncnc5)cc4)cc3)cc2C1=O
Yield: 37 %

Procedure:
The compound of example 652 was prepared analogous to the compound of example 640 by reaction of compound of example 6 with commercially available 4-(pyrimidin-5-yl)benzoyl chloride.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([I:13])[CH:11]=2)[N:6]=[CH:5][N:4]=1.O1CCOCC1.Cl.[CH2:22]([O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[ClH:2].[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([NH:34][C:3]2[C:12]3[C:7](=[CH:8][C:9]([F:14])=[C:10]([I:13])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[CH:35][CH:36]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: Fc1cc2ncnc(Cl)c2cc1I
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Fc1cc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2cc1I
Temperature: 110 °C
Yield: 79.1 %

Procedure:
Prepared according to Procedure A from 4-chloro-6-iodo-7-fluoro-quinazoline hydrochloride (4.02 grams, 11.65 mmoles), anhydrous dioxane (70 ml), dichloromethane (20 ml) and 4-benzyloxyaniline hydrochloride (2.83 grams, 12 mmoles). The mixture was stirred and heated to 110° C. (oil bath temperature) for 16 hours. The mixture was cooled to room temperature and filtered to remove the precipitated solids. The solids were washed with cold anhydrous dioxane (100 ml) followed by cold anhydrous diethyl ether. The yellowish solid was collected and dried under vacuum at room temperature to yield 4.68 grams (79%) of the title compound. δH (400 MHz, DMSO-d6): 11.2(s, 1H), 9.3(d, 1H), 8.79(s, 1H), 7.64(d, 1H), 7.58(d, 2H), 7.44(d, 2H), 7.38(m, 2H), 7.31(m, 1H), 7.09(d, 2H), 5.14(s, 2H) ESI-MS m/z 472(M+1).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:13]3[CH:18]=[C:17]([C:19](=[NH:22])[NH:20][OH:21])[CH:16]=[CH:15][N:14]=3)[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:23][C:24]([O:26]CC)=[O:25])[O:3]1.Cl>[OH-].[Na+]>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:13]3[CH:18]=[C:17]([C:19](=[NH:22])[NH:20][OH:21])[CH:16]=[CH:15][N:14]=3)[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:23][C:24]([OH:26])=[O:25])[O:3]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cc(C(=N)NO)ccn3)cc(C)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(Oc2cc(C(=N)NO)ccn2)cc2c1C(CC(=O)O)OB2O

Procedure:
2-(ethyl 2-(1-hydroxy-6-(4-(N-hydroxycarbamimidoyl)pyridin-2-yloxy)-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (150 mg) was treated with NaOH solution (200 mg in 10 ml water) for one hour at room temperature. The reaction mixture was acidified to pH 5 with 6 N HCl and then concentrated. HPLC purification gave product as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.5 (b, 1H), 9.20 (b, 1H), 8.23 (d, J=5.2 Hz, 1H), 7.04 (dd, J=5.2, 1.2 Hz, 1H), 7.34 (s, 1H), 7.23 (s, 1H), 7.06 (d, J=1.6 Hz, 1H), 5.53 (dd, J=9.6, 2.4 Hz, 1H), 3.10 (dd, J=15.6, 2.4 Hz, 1H), 2.50 (s, 3H), 2.28 (dd, J=10, 9.6 Hz, 1H). 3 protons assumed to be exchanged with solvents. MS (ESI) m/z=358 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([N:26]3[CH2:31][CH2:30][CH:29]([CH:32](OC)[O:33]C)[CH2:28][CH2:27]3)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:15])=[C:8]([F:37])[CH:7]=1.[I-].[Na+].ClC([SiH3])(Cl)Cl>>[CH3:1][O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([S:23]([N:26]3[CH2:31][CH2:30][CH:29]([CH:32]=[O:33])[CH2:28][CH2:27]3)(=[O:24])=[O:25])=[CH:21][CH:22]=2)=[O:15])=[C:8]([F:37])[CH:7]=1
Reactant: COC(=O)COc1ccc(CNC(=O)Nc2ccc(S(=O)(=O)N3CCC(C(OC)OC)CC3)cc2)c(F)c1
Agent: [I-]
Agent: [Na+]
Agent: [SiH3]C(Cl)(Cl)Cl
Product: COC(=O)COc1ccc(CNC(=O)Nc2ccc(S(=O)(=O)N3CCC(C=O)CC3)cc2)c(F)c1

Procedure:
The title compound was prepared from (4-{3-[4-(4-dimethoxymethyl-piperidine-1-sulfonyl)-phenyl]-ureidomethyl}-3-fluoro-phenoxy)-acetic acid methyl ester (0.274 g, 0.5 mmol), sodium iodide (0.185 g, 1.2 mmol), and trichloromethylsilane (0.118 mL, 1.0 mmol) according to the procedure used for example 84 (Step D) and used directly in the next step
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].[C:21](=[NH:34])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:28]1([C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:34][C:2]2[CH:7]=[C:6]([N:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][N:3]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CCCN(CCC)c1ccnc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCN(CCC)c1ccnc(N=C(c2ccccc2)c2ccccc2)c1
Temperature: 85 °C
Yield: 75.8 %

Procedure:
A mixture of 0.52 g (2.4 mmol) of 2-chloro-N4,N4-dipropylpyridin-4-amine, 0.076 g (0.12 mmol) of racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (BINAP), 0.33 g (3.4 mmol) of sodium tert-butoxide and 0.027 g (0.12 mmol) of palladium (II) acetate in 25 mL of toluene was treated with 0.49 mL (2.9 mmol) of benzophenone imine and heated to 85° C. for 18 h. The crude reaction mixture was diluted with ethyl acetate, filtered through a pad of celite and purified by flash chromatography eluting with a 33% hexanes/ethyl acetate mixture to give 0.65 g (75%) of the title compound as a golden oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[O:38]1[CH2:42][CH2:41][CH2:40][CH:39]1[CH2:43][NH2:44]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:44][CH2:43][CH:39]3[CH2:40][CH2:41][CH2:42][O:38]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: NCC1CCCO1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NCC3CCCO3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and C-(tetrahydro-furan-2-yl)-methylamine according to conditions described in general procedure C.
Reaction SMILES: [CH2:1]([N:5]([CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[K+].O.Cl>CS(C)=O>[CH2:1]([N:5]([CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCc1ccccc1)S(=O)(=O)c1ccc(OC)c([N+](=O)[O-])c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCN(CCCc1ccccc1)S(=O)(=O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 100.7 %

Procedure:
To a stirred solution of 0.73 g N-butyl-N-(3'-phenylpropyl)-4-methoxy-3-nitrobenzensulfonamide in 10 ml dimethyl sulfoxide was added 10 ml of a 50% aqueous potassium hydroxide solution and the mixture was heated and stirred at 80° C. for 4 hours. The mixture was poured into water, acidified to pH 4-5 with 20% aqueous hydrochloric acid and extracted into chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed to give 0.71 g N-butyl-N-(3'-phenylpropyl)-4-hydroxy-3-nitrobenzenesulfonamide.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH2:17][CH2:16][O:15][CH:14]1[C:18]1[CH:19]=[CH:20][C:21]([F:24])=[N:22][CH:23]=1.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>C1COCC1>[O:13]1[CH2:17][CH2:16][O:15][CH:14]1[C:18]1[CH:19]=[C:20]([B:25]([OH:30])[OH:26])[C:21]([F:24])=[N:22][CH:23]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(C2OCCO2)cn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OB(O)c1cc(C2OCCO2)cnc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
Diisopropylamine (4.60 mL, 32.5 mmol) was dissolved in THF (80 mL) and cooled in an ice water bath. Then, n-butyllithium solution (1.6 M in hexanes, 21.0 mL, 33.6 mmol) was added via syringe. After 30 minutes, the reaction was cooled to −78° C. and 5-(1,3-dioxolan-2-yl)-2-fluoropyridine (3.73 g, 22.1 mmol) was added as a solution in THF (12 mL) dropwise over 5 minutes via syringe, followed by a THF (4 mL) rinse. The reaction was stirred at −78° C. under nitrogen for 1 hour, and then triisopropyl borate (Fluka 98+%, 8.0 mL, 34.9 mmol) was added via syringe, and the reaction was allowed to warm up to room temperature. After 4.5 hours, the reaction was quenched with 1 N NaOH (75 mL). The layers were separated, and the aqueous phase was treated with 5 N HCl to lower the pH to between 6 and 7. The aqueous phase was extracted with 10:1 DCM/MeOH. 5 N HCl was added to the aqueous phase to lower the pH to about 5, and extraction was continued with 10:1 DCM/MeOH. The organic extracts were combined, concentrated and dried under high vacuum to give 5-(1,3-dioxolan-2-yl)-2-fluoropyridin-3-ylboronic acid (3.165 g, 91% purity, 61% yield over 2 steps). MS (ESI pos. ion) m/z 214 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]([C:21]1[N:30]([CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[C:24]2[N:25]=[C:26](Cl)[N:27]=[CH:28][C:23]=2[CH:22]=1)=[O:20].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:17][O:18][C:19]([C:21]1[N:30]([CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[C:24]2[N:25]=[C:26]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:9][CH2:10][N:11]([C:14](=[O:16])[CH3:15])[CH2:12][CH2:13]4)=[CH:6][CH:7]=3)[N:27]=[CH:28][C:23]=2[CH:22]=1)=[O:20]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: CCC(CC)n1c(C(=O)OC)cc2cnc(Cl)nc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCC(CC)n1c(C(=O)OC)cc2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Temperature: 100 °C
Yield: 40.2 %

Procedure:
To a solution of 1-[4-(4-amino-phenyl)-piperazin-1-yl]-ethanone (12.1 mg, 0.055 mmol) in 1,4-dioxane (0.5 mL) is added a solution of 2-chloro-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester (13 mg, 0.046 mmol) in 1,4-dioxane (0.6 mL), Pd2(dba)3 (2.2 mg, 0.0023 mmol), Xantphos (2.7 mg, 0.046 mmol) and Cs2CO3 (22.5 mg, 0.069 mmol). The mixture is degassed, and heated at 100° C. for 3 h. The mixture is cooled to room temperature, diluted with EtOAc, and filtered through a pad of Celite. The filtrate is concentrated under reduced pressure. The crude product is purified by preparative HPLC to give 8.6 mg of 2-[4-(4-acetyl-piperazin-1-yl)-phenylamino]-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester as a pale white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH:8][C:9]([NH2:11])=[O:10].[CH2:12](O)[CH3:13]>C(C(CC)(CC)C([O-])([O-])[O-])C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:12]([CH3:13])=[N:11][C:9]([OH:10])=[N:8]1
Reactant: CCO
Reactant: NC(=O)NNc1ccccn1
Agent: CCC(CC)(CC)C([O-])([O-])[O-]
Product: Cc1nc(O)nn1-c1ccccn1

Procedure:
A reaction mixture was prepared by suspending 457.6 g (3 m) of 2-pyridinyl-hydrazine carboxamide in 2600 ml of triethylorthoacetate and the mixture refluxed for about 9 hours. The ethanol by-product formed was continuously removed by distillation allowing the reaction temperature to stay at 125°-130° C. The 1-(2-pyridinyl)-5-methyl-1H-1,2,4-triazol-3-ol product was recovered by filtration in a yield of 116 g (66 percent of theoretical) and was washed with chloroform. The product melted at 194°-195° C. and upon analysis was found to have carbon hydrogen and nitrogen contents of 53.87, 4.55 and 31.95 percent, respectively, as compared with the theoretical contents of 54.53, 4.57 and 31.80 percent, respectively, calculated for the above named compound.