Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22](OC4C=CC=CC=4)=[O:23])[CH2:18][CH2:17]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:34][CH3:35])[CH:3]=1.ClC(OC1C=CC=CC=1)=O.[CH3:46][NH2:47]>C(O)C>[NH2:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:23])[NH:47][CH3:46])[CH2:18][CH2:17]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:34][CH3:35])[CH:3]=1
Reactant: CN
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCN(C(=O)Oc3ccccc3)CC2)CC1
Agent: O=C(Cl)Oc1ccccc1
Solvent: CCO
Product: CNC(=O)N1CCC(CN2CCC(NC(=O)c3cc(Cl)c(N)cc3OC)CC2)CC1
Temperature: 110 °C

Procedure:
To 4-amino-5-chloro-2-methoxy-N-[1-(1-phenoxycarbonyl-4-piperidinylmethyl)-4-piperidinyl]benzamide (880 mg), which is prepared in a similar manner as in Example 1 except that phenyl chloroformate is used instead of dimethylcarbamoyl chloride, is added a 30% solution of methylamine in ethanol (20 ml), and the mixture is heated at 110° C. for 8 hours in a sealed tube. The mixture is concentrated to dryness under reduced pressure, and to the residue is added chloroform. The solution is washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform:methanol=20:110:1) to give the desired compound (200 mg) as amorphous.
Reaction SMILES: [C:1]([C:5]1[CH:39]=[CH:38][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:32][CH2:33][CH2:34][CH2:35][C:36]#[N:37])[CH2:20][CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N:44]=[N+:45]=[N-:46])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:39]=[CH:38][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:32][CH2:33][CH2:34][CH2:35][C:36]2[NH:46][N:45]=[N:44][N:37]=2)[CH2:20][CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCCCC#N)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCCCc2nnn[nH]2)cc1
Temperature: 80 °C

Procedure:
A solution of 200 mg (0.38 mmol) of methyl 4-[3-((E)-2-{2-[(4-tert-butylbenzyl)oxy]phenyl}vinyl)-7-cyanoheptyl)benzoate in 3 ml of toluene is mixed with 660 mg (5.73 mmol) of trimethylsilyl azide and 142.6 mg (0.57 mmol) of di-n-butyltin oxide and heated to 80° C. for 12 hours. After cooling to room temperature, the mixture is washed with saturated sodium bicarbonate solution. The organic phase is separated off, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate is concentrated to dryness. The resulting crude product is purified by chromatography on a silica gel column (mobile phase: cyclohexane/ethyl acetate 1:1). 103 mg (0.18 mmol, 46% of theory) of a white foam are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[F:34][C:35]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[CH:37][C:36]=1[N:50]1[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:34][C:35]1[CH:40]=[C:39]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:12]=[N:13][N:14]([CH2:16][C:17]5[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=5)[CH:15]=4)=[CH:9][N:8]([S:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=4)(=[O:25])=[O:26])[C:5]3=[N:6][CH:7]=2)[CH:38]=[CH:37][C:36]=1[N:50]1[CH2:51][CH2:52][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:54][CH2:55]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Yield: 68.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of Step-i of example 9) (160 g, 0.304 mmol) was coupled with tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (intermediate 69) (216 mg, 0.530 mmol) using sodium carbonate (97 mg, 0.912 mmol) and Pd(PPh3)2Cl2 (11 mg, 0.015 mmol) in DME/water (5/2 mL). This afforded 150 mg (68.10% yield) after purification by column (Silica gel 60/120) using 25% ethyl acetate in hexane as eluent. MS: m/z=725.3 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[C:40]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:45]=[CH:44][C:43]([C:46](Cl)=[O:47])=[CH:42][CH:41]=1>>[C:40]1([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:41]=[CH:42][C:43]([C:46]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:29][CH2:30]5)(=[O:26])=[O:27])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:47])=[CH:44][CH:45]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NC1CCCOCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: CC(C)(C)OC(=O)NC1CCCOCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccc(-c4ccccc4)cc3)CN2C1=O
Yield: 26.6 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-10-oxatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 4-biphenylcarbonyl chloride (113 mg, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 35 mg (27%) of 18-(4-biphenylcarbonyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-10-oxatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.9% pure (HPLC), MS m/z 749 (M−H)−, HRMS: calcd. 751.3013 and found 751.3008 (M+H)+, mp 160-162° C.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[S:30](Cl)(=[O:32])=[O:31].C(N(CC)C(C)C)(C)C>ClCCl>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[S:30]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)(=[O:32])=[O:31]
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1c(Cl)cccc1Cl

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with 2,6-dichlorophenylsulfonyl chloride in presence of N,N-diisopropyl ethyl amine in dichloromethane to give 2,6-dichloro-N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as a colorless oil. MS: 549.3 ([M+NH4]+)
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[C:41]([Cl:43])[C:40]([O:44][CH3:45])=[CH:39][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH:27]3C(OC(C)(C)C)=O)=[CH:12][C:13]=2[O:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=[CH:7][N:6]=1.FC(F)(F)C(O)=O>>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:42]=[C:41]([Cl:43])[C:40]([O:44][CH3:45])=[CH:39][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)=[CH:12][C:13]=2[O:15][CH:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[N:8]=[CH:7][N:6]=1
Reactant: COc1cc(Nc2ncnc3cc(OCCCN4CCNCC4C(=O)OC(C)(C)C)cc(OC4CCOCC4)c23)c(Cl)cc1Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2ncnc3cc(OCCCN4CCNCC4)cc(OC4CCOCC4)c23)c(Cl)cc1Cl
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 292 %

Procedure:
A mixture of 4-(2,4-dichloro-5-methoxyanilino)-7-[3-(tert-butoxycarbonylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazoline (0.12 g) and trifluoroacetic acid (2 ml) was stirred at ambient temperature for 2 hours. The mixture was evaporated and the residue was triturated under diethyl ether. The resultant solid was isolated and dried under vacuum. The solid was dissolved in diethyl ether and 6M hydrogen chloride gas in diethyl ether (0.5 ml) was added. The resultant solid was isolated, washed with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.112 g); NMR Spectrum: (DMSOd6 and CF3CO2H) 1.9-2.1 (m, 2H), 2.15 (d, 2H), 2.28-2.4 (m, 2H), 3.4 (m, 2H), 3.4-3.9 (m, 10H), 3.92 (s, 3H), 3.95 (m, 2H), 4.39 (t, 2H), 5.2 (m, 1H), 7.0 (d, 1H), 7.2 (d, 1H), 7.78 (s, 1H), 7.82 (s, 1H), 8.9 (s, 1H); Mass Spectrum: M+H+ 562 and 564.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:31]([O-])=O)=[C:6]([NH:8][C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH3:24])[N:15]3[CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:11]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[N:10]=2)[CH:7]=1.C(O)(=O)C.O.[OH-].[NH4+]>[Fe].C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH3:24])[N:15]3[CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:11]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[N:10]=2)[C:5]([NH2:31])=[CH:4][CH:3]=1
Reactant: Cc1nc2c(-c3ccncc3)nc(Nc3cc(Cl)ccc3[N+](=O)[O-])nc2n1C1CCOCC1
Agent: [Fe]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc2c(-c3ccncc3)nc(Nc3cc(Cl)ccc3N)nc2n1C1CCOCC1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To a vial containing N-(5-chloro-2-nitrophenyl)-8-methyl-6-(pyridin-4-yl)-9-(tetrahydro-2H-pyran-4-yl)-9H-purin-2-amine (16.3 mg, 0.035 mmol) was added glacial acetic acid (1 mL), water (2.5 mL) and ethanol (5 mL), followed by iron powder (20 mg, 0.35 mmol, 10 equiv.) and the resulting mixture heated at 90° C. for 15 min (HPLC monitoring). The reaction mixture was left to cool down to room temperature, concentrated ammonium hydroxide solution was added to bring the pH to basic, and the mixture was stirred for 10 min. The aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with brine, dried (anhydrous Na2SO4), and the solvent removed in vacuo to give the desired product as a pale yellow solid (yield quantitative). This material was used in the next step without further purification. MS (EI) m/z 436.4 (MH)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[N:23]1[C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=[CH:25][C:24]=1[C:32]([OH:34])=[O:33].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:29]([C:28]3[N:23]=[C:24]([C:32]([OH:34])=[O:33])[CH:25]=[CH:26][CH:27]=3)=[O:30])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: O=C(O)c1cccc(C(=O)O)n1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1

Procedure:
In a third alternate process for preparing the above named compound, 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (0.1 mmol) and 2,6-pyridinedicarboxylic acid (0.1 mmol) was dissolved in DCM (3 mL), and HOBt was added (1.0 eq, 14.0 mg) along with EDC (1.0 eq, 19.0 mg). The resultant solution was stirred overnight. The solution was purified by preparative HPLC (Gilson) to yield 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid. This compound was dissolved in 3 mL of DCM along with 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (41.3 mg, 0.1 mmol), followed by the addition of HOBt (1.0 eq, 14.0 mg) and EDC (1.0 eq, 19.0 mg). The resultant solution was stirred overnight and product was purified by preparative HPLC (Gilson) to give 1,1-dimethylethyl (2S)-4-[(5′-{[({6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate. This compound was then dissolved in 2 mL of dioxane:MeOH (3:1). Three drops of HCl (concentrated) were added to the resultant solution and it was heated at 60° C. for 1 h. The solution was applied to the amine column, rinsed with 10 mL of dioxane:MeOH (3:1) to afford 2.2 mg (2.9%) of the above named product. LC-MS m/z 749 (M+H)+, 1.32 min (ret time).
Reaction SMILES: ClC1C=C(Cl)C=CC=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:7].O=C1C(C(O)=O)=CC(C2C=CN=CC=2)=NN1.C(Cl)(=O)C(Cl)=O.[Cl:48][C:49]1[CH:50]=[C:51]([CH:54]=[C:55]([Cl:57])[CH:56]=1)CN>C(N(CC)CC)C.CN(C)C=O.ClCCl>[Cl:48][C:49]1[CH:50]=[C:51]([CH:54]=[C:55]([Cl:57])[CH:56]=1)[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)[CH:13]=1)=[O:7]
Reactant: NCc1cc(Cl)cc(Cl)c1
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1cc(Cl)cc(Cl)c1)c1cc(-c2ccncc2)n[nH]c1=O

Procedure:
Working as in example 2 for the preparation of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide, but starting with 0.3 g of 3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxylic acid, 10 cm3 of dichloromethane, 0.02 cm3 of dimethylformamide, 0.12 cm3 of oxalyl chloride, 0.19 cm3 of 3,5-dichlorobenzylamine and 0.19 cm3 of triethylamine, 0.025 g of N-(3,5-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a white solid melting above 260° C.
Reaction SMILES: [CH2:1]([O:6][CH:7]([CH3:11])[C:8](O)=[O:9])[CH2:2][CH2:3][CH2:4][CH3:5].S(Cl)([Cl:14])=O>>[CH2:1]([O:6][CH:7]([CH3:11])[C:8]([Cl:14])=[O:9])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOC(C)C(=O)O
Reactant: O=S(Cl)Cl
Product: CCCCCOC(C)C(=O)Cl

Procedure:
10 ml of thionyl chloride was added to 2.0 g of α-pentyloxypropionic acid and the mixture was refluxed under heat for 2 hours. Excess of thionyl chloride was distilled off to obtain α-pentyloxypropionic acid chloride. 20 ml of dry pyridine was added thereto, and 7.0 g of 5-decyl-2-(4-hydroxyphenyl)pyrimidine dissolved in 50 ml of dry benzene was further added dropwise. After the addition, the mixture was refluxed under heat, charged into ice water and extracted with benzene. The extract was purified with a silica gel column chromatography to obtain 5-decyl-2-(4'-α-pentyloxypropanoyloxyphenyl)pyrimidine.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[CH:9])[CH3:5])[CH3:2].C([Li])CCC.Cl[C:16]1([CH:23]=[CH:22][CH:21]=[CH:20][CH2:19]1)[CH:17]=[O:18].[Cl-:24].[NH4+]>O1CCCC1>[CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][CH:17]([C:16]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[OH:18])[CH3:5])[CH3:2]
Reactant: [Cl-]
Reactant: O=CC1(Cl)C=CC=CC1
Reactant: C#CCOC(C)OCC
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(C)OCC#CC(O)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
A solution of 6 g (47 mmol) of 1-(1-ethoxyethoxy)-2-propyne in 100 ml of tetrahydrofuran was treated at -78° under argon with 29.2 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -40° for 30 minutes and then a solution of 6.6 g (47 mmol) of 1-chlorobenzaldehyde in 11 ml of tetrahydrofuran was added within 10 minutes. The reaction mixture was warmed to 0°, stirred at 0° for a further 1 hour and then treated with 80 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over magnesium sulphate and concentrated. The residue was purified by flash chromatography on 500 g of silica gel (elution agent ether/ hexane 1:1. There was obtained 4-(1-ethoxyethoxy)-1-(4 -chlorophenyl) 2 -butyn-I ol as an oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[C:27]([C:29]1[CH:37]=[CH:36][C:32](C(Cl)=O)=[CH:31][CH:30]=1)#[N:28].[C:38]1([CH2:48][NH2:49])[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1>>[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:10][C@H:9]2[C:24]([NH:49][CH2:48][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[CH:40][CH:39]=2)=[O:26])=[O:7])=[CH:31][CH:30]=1)#[N:28]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Reactant: NCc1cccc2ccccc12
Product: N#Cc1ccc(C(=O)N2CC(=NOCc3ccc(Cl)c(Cl)c3)C[C@H]2C(=O)NCc2cccc3ccccc23)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, 4-cyanobenzoyl chloride, and 1-naphthylmethylamine the title compound was obtained in 39% purity by LC/MS. MS(ESI+): m/z=571.6.
Reaction SMILES: Cl[C:2]1[C:3](I)=[CH:4][C:5]2[N:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=2[CH:22]=1.[C:24]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.C(#N)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:24]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:29]=[CH:28][C:27]([C:3]2[CH:2]=[CH:22][C:6]3[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])=[N:9][C:5]=3[CH:4]=2)=[CH:26][CH:25]=1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(I)c(Cl)cc21
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(-c3ccc(-c4ccccc4)cc3)ccc21
Temperature: 150 °C

Procedure:
A 2 mL Biotage™ microwave vial was charged with 6-chloro-5-iodo-2-methanesulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (Intermediate 5, 49.0 mg, 0.100 mmol), biphenyl-4-boronic acid (24.0 mg, 0.120 mmol) and Pd(PPh3)4 (5.8 mg, 5 mol %) following by dioxane (1.0 mL) and 1M aqueous K2CO3 (120 uL). The resulting suspension was heated in a microwave synthesizer (Biotage Initiator™) at 150° C. for 10 min. The microwave procedure was repeated two more times, before each irradiation additional Pd(PPh3)4 (2.9 mg, 2.5 mol %) was added. The reaction mixture was then diluted with EtOAc (5 mL), filtered and the resulting solution was evaporated to dryness in vacuo to give brown oil. The oil was dissolved in ACN and passed through a Thiol StratoSphere™ SPE cartridge (Polymer Labs). The solvent was evaporated to dryness in vacuo to give crude product as colorless oil which was used in the next step without further purification. LR-MS (API-ES): calculated C26H29ClN2O3SSi 512.1, observed m/e 513.0 (M+H)+, 485.0, 455.0 (Rt 3.91 min).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>C(OCC)(=O)C>[CH3:26][S:27]([O:1][CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]1)(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC(OCCCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(OCCCOS(C)(=O)=O)CC1

Procedure:
To a solution of 4-(3-hydroxypropyloxy)-N-t-butyloxycarbonylpiperidine (3.82 g) in ethyl acetate (40 ml) were added triethylamine (4.1 ml) and methanesulfonyl chloride (1.37 ml) with stirring under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture were added water (50 ml) and ethyl acetate (50 ml) with stirring. The organic layer was separated, washed twice with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 ml) eluting with a mixture of n-hexane and ethyl acetate (1:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give 4-[3-(methanesulfonyloxy)propyloxy]-N-t-butyloxycarbonylpiperidine (3.77 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]3[C:15]([C:18]([OH:20])=O)=[CH:16][N:17]=[C:11]3[CH:10]=2)[CH2:4][O:3]1.C(Cl)(=O)C(Cl)=O.[CH3:28][C:29]1[C:37]2[C:36]([NH2:38])=[CH:35][CH:34]=[CH:33][C:32]=2[N:31]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[N:41]=2)[N:30]=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O>[CH3:21][C:2]1([CH3:1])[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]3[C:15]([C:18]([NH:38][C:36]4[CH:35]=[CH:34][CH:33]=[C:32]5[C:37]=4[C:29]([CH3:28])=[N:30][N:31]5[CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[N:41]=4)=[O:20])=[CH:16][N:17]=[C:11]3[CH:10]=2)[CH2:4][O:3]1
Reactant: Cc1cccc(Cn2nc(C)c3c(N)cccc32)n1
Reactant: CC1(C)OCC(COc2ccn3c(C(=O)O)cnc3c2)O1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(OCC6COC(C)(C)O6)ccn45)cccc32)n1
Reaction time: 8 h
Yield: 9.9 %

Procedure:
7-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (66 mg, 0.23 mmol) was dissolved in dichloromethane (1 mL) and 2 M oxalyl chloride in dichloromethane (0.12 mL, 0.25 mmol) was added with a drop of dimethylformamide. The mixture was stirred at ambient temperature for 1 hour before addition of 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (57 mg, 0.23 mmol) and diisopropylethylamine (0.08 mL, 0.46 mmol), and then the mixture was stirred overnight. The crude mixture was purified using preparative thin layer chromatography (silica, 20×20 cm, 1 mm) developed in a chamber with 10% methanol/dichloromethane to give 7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (12 mg).