Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2C(=O)C3=CNC4C=CC=CC=4C3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:33])=[C:29]([F:32])[CH:30]=2)[N:25]=[C:24]([CH3:34])[C:23]=1[C:35]([O:37]CC)=O.C1(NN)C=CC=CC=1>>[F:33][C:28]1[C:29]([F:32])=[CH:30][C:31]2[C:22]3[C:23]([C:35](=[O:37])[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)=[C:24]([CH3:34])[NH:25][C:26]=2[CH:27]=1
Reactant: CCOC(=O)c1c(C)nc2cc(F)c(F)cc2c1Cl
Reactant: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccccc1
Solvent: NNc1ccccc1
Product: Cc1[nH]c2cc(F)c(F)cc2c2nn(-c3ccccc3)c(=O)c1-2

Procedure:
The title compound was synthesized following the procedure described in synthesis of 4a using 3i and phenyl hydrazine. 1H NMR (DMSO-d6) δ (ppm): 2.80 (3H, s), 6.87 (1H, m), 7.19 (1H, m), 7.34 (1H, m), 7.42 (1H, m), 7.61 (1H, m), 8.17 (1H, m). m/z 312.2 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]([CH3:12])[CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1.[C:13]([NH:18][NH2:19])([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>O>[C:13]([NH:18][NH:19][C:2]1[N:3]=[N:4][C:5]([N:8]([CH3:12])[CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1)([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CN(CCO)c1ccc(Cl)nn1
Reactant: CCOC(=O)NN
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)NNc1ccc(N(C)CCO)nn1
Temperature: 155 °C

Procedure:
A mixture of 1.87 g (0.01 moles) 3-chloro-6-[N-(2-hydroxyethyl)-methylamino]-pyridazine and 2.08 g (0.02 moles) monocarbethoxyhydrazine is warmed up to 155° C and kept at this temperature for half an hour. The product is cooled and dissolved in water, alkalinized by addition of solid potassium carbonate and the aqueous solution saturated by adding sodium chloride. A flocky precipitate separates which is subsequently collected by filtration and crystallized from ethanol, to give with good yields 3-(2-carbethoxyhydrazino)-6-[N-(2-hydroxyethyl)methylamino] -pyridazine melting at 131°-133° C. I.R. Spectrum (mineral oil, cm-1); 3320-3080 (OH and NH), 1715 (C=O carbamate), 1500 (pyridazinic ring), 840 (two ortho aromatic hydrogens).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:17]1[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][OH:23])=[CH:19][CH:18]=1.[OH-].[K+].C1C2C(CCCC2)CCC1>[Cu].C(Cl)(Cl)Cl>[OH:23][CH2:22][CH2:21][C:20]1[CH:24]=[CH:25][C:17]([N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[CH:18][CH:19]=1
Reactant: OCCc1ccc(I)cc1
Reactant: C1=Cc2ccccc2Nc2ccccc21
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1CCC2CCCCC2C1
Product: OCCc1ccc(N2c3ccccc3C=Cc3ccccc32)cc1
Temperature: 200 °C
Reaction time: 40 h
Yield: 29.8 %

Procedure:
A mixture of 8.7 g (45 mmol) of 5H-dibenz[b,f]azepine, 12.4 g (50 mmol) of p-iodophenethyl alcohol, 2.8 g (50 mmol) of potassium hydroxide, 4.8 g (75 mmol) of copper powder, and 20 ml of decalin was heated at an external temperature of 200° C. while stirring in a nitrogen stream for 40 hours. The reaction mixture was cooled nearly to room temperature, chloroform was added thereto, followed by filtration using Celite to remove any insoluble matter. The filtrate was concentrated. To remove decalin, n-hexane was added to the residue, followed by filtration. The filter cake was reprecipitated in methanol, and the resulting crude product was purified by silica gel column chromatography to give 4.2 g (30%) of 5-(4-(2-hydroxyethyl)phenyl)-5H-dibenz[b,f]azepine.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[O:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=2)=[CH:9][N:10]=1>ClCCl>[Br:5][C:6]1[O:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)=[CH:9][N:10]=1
Reactant: COc1cccc(-c2cnc(Br)o2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(-c2cnc(Br)o2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
Boron tribromide (5.0 mL, 13.25 g, 53 mmol) was added dropwise to a stirred solution of 2-bromo-5-(3-methoxyphenyl)-1,3-oxazole (2.1 g, 10 mmol) in dry dichloromethane (50 mL) at RT under Nitrogen. The reaction mixture was stirred for about 1 h and then carefully poured over ice. After the ice melted, the mixture was extracted with ethyl acetate (2×250 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was collected by filtration and dried under vacuum to afford a light brown solid (1.13 g, 47%). 1H NMR (400 MHz, d6-DMSO): δ 6.74 (dd, J1=8.1, J2=2.2, 1H), 6.99 (d, J=2, 1H), 7.05 (d, J=7.9, 1H), 7.21 (t, J=7.9, 1H), 7.64 (s, 1H), 9.48 (bs, 1H).
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]([CH3:35])[C@@H:8]([NH:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=1)[C:9]1[O:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[N:12][N:13]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:11]2[O:10][C:9]([C@H:8]([NH:22][C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([C:31]([F:32])([F:34])[F:33])[CH:24]=3)[C@H:7]([OH:6])[CH3:35])=[N:13][N:12]=2)=[CH:19][CH:18]=1)#[N:21]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)c1nnc(-c2ccc(C#N)cc2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a pre-cooled (−55° C.) solution of 4-((1R,2R)-2-(tert-butyldimethyl-silyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-(trifluoromethyl)benzo-nitrile (790 mg, 1.50 mmol) in THF (100 mL) was added TBAF (1.80 mL, 1.80 mmol, 1 M solution in THF) over 10 min. Upon complete addition the reaction mixture was allowed to warm to 0° C. over 1 h, then stirred at 0° C. for a further 30 min and quenched with sat. aq. NH4Cl (100 mL). The resulting mixture was partitioned between H2O (50 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (150 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel (50-80% EtOAc in hexanes) to provided the title compound as a colourless amorphous solid (610 mg, 98%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.20 (dm, J=8.8 Hz, 2H), 8.00 (dm, J=8.8 Hz, 2H), 7.73 (d, J=8.6 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.17 (dd, J=2.5, 8.8 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 5.17 (dd, J=5.7, 8.8 Hz, 1H), 4.45 (pentet, J=6.1 Hz, 1H), 1.42 (d, J=6.4 Hz, 3H).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=2)[CH2:5][CH2:4]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[S:39]1[CH:43]=[C:42]([C:44]2[C:53]3[N:52]=[CH:51][CH:50]=[N:49][C:48]=3[C:47]([C:54](O)=[O:55])=[CH:46][CH:45]=2)[C:41]2[CH:57]=[CH:58][CH:59]=[CH:60][C:40]1=2.S1C2C=CC=CC=2C(B(O)O)=C1>C(Cl)Cl.CO>[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:54]([C:47]3[C:48]4[N:49]=[CH:50][CH:51]=[N:52][C:53]=4[C:44]([C:42]4[C:41]5[CH:57]=[CH:58][CH:59]=[CH:60][C:40]=5[S:39][CH:43]=4)=[CH:45][CH:46]=3)=[O:55])=[N:14][CH:15]=2)[CH2:5][CH2:4]1
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Reactant: O=C(O)c1ccc(-c2csc3ccccc23)c2nccnc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(NC(=O)c3ccc(-c4csc5ccccc45)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture at rt overnight and using 2 equiv of 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride (Example 31), TBTU (2 equiv) and 8-benzo[b]thiophen-3-yl-quinoxaline-5-carboxylic acid. The carboxylic acid was synthesized as described in Steps 1.2-1.7 but using benzothiophene-3-boronic acid in Step 1.4. Title compound: ESI-MS: 494.9 [M+H]+; tR=3.77 min (System 1); TLC: Rf=0.17 (DCM/MeOH, 9:1).
Reaction SMILES: [O:1]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[Br:13]Br>C(OCC)C>[Br:13][CH:4]1[C:5](=[O:8])[CH2:6][CH2:7][O:1][C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]1=2
Reactant: BrBr
Reactant: O=C1CCOc2ccccc2C1
Solvent: CCOCC
Product: O=C1CCOc2ccccc2C1Br
Yield: 70 %

Procedure:
To a solution of 2,3-dihydro-5H-benzo[b]oxepin-4-one (1 eq, 1.6 mmol, 260 mg,), in anhydrous diethyl ether (10 ml), bromine was added dropwise (1.1 eq, 1.76 mmol, 90 ul), and the reaction allowed to stir for an hour. The reaction was absorbed onto silica and purified on the ISCO companion running a gradient from 0% ethyl acetate/petrol to 15% ethyl acetate/petrol, with the product seen at 9% ethyl acetate. This gave 5-bromo-2,3-dihydro-5H-benzo[b]oxepin-4-one as an oil (270 mg, yield 70%).
Reaction SMILES: [CH:1]1([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([C:25]1([C:28](O)=[O:29])[CH2:27][CH2:26]1)#[N:24]>>[C:23]([C:25]1([C:28]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:17][CH:18]=2)=[O:29])[CH2:27][CH2:26]1)#[N:24]
Reactant: N#CC1(C(=O)O)CC1
Reactant: Nc1ccc(CCCCCCCOCC2CCCCC2)cc1
Product: N#CC1(C(=O)Nc2ccc(CCCCCCCOCC3CCCCC3)cc2)CC1
Yield: 95.8 %

Procedure:
General procedure E was used to convert 0.616 mmol of 13 and 0.924 mmol of 1-cyanocyclopropanecarboxylic acid to 0.590 mmol (96%) of the title compound.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH2:27][O:28][CH3:29])=[C:21]([CH3:30])[C:20]=2[CH3:31])=[CH:14][C:13]=1[N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].[O:41]=[C:42]1[NH:46][C:45](=[O:47])[CH:44]([CH2:48][C:49]2[CH:59]=[CH:58][C:52]([O:53][CH2:54][C:55](O)=[O:56])=[CH:51][CH:50]=2)[S:43]1.C(N(CC)CC)C>O1CCCC1>[O:41]=[C:42]1[NH:46][C:45](=[O:47])[CH:44]([CH2:48][C:49]2[CH:50]=[CH:51][C:52]([O:53][CH2:54][C:55]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH2:27][O:28][CH3:29])=[C:21]([CH3:30])[C:20]=4[CH3:31])=[CH:14][C:13]=3[N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:56])=[CH:58][CH:59]=2)[S:43]1
Reactant: COCOc1c(C)cc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)c(C)c1C
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCOc1c(C)cc(Oc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)c(C)c1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 75.9 %

Procedure:
7.34 g of diethyl cyanophosphonate were added to a mixture of 18.7 g of t-butyl N-[2-amino-5-(4-methoxymethoxy-2,3,5-trimethylphenoxy)phenyl]-N-methylcarbamate, 12.6 g of 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid, 4.55 g of triethylamine and 300 ml of anhydrous tetrahydrofuran. The resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated by evaporation. Water was then added to the concentrate. After extraction with ethyl acetate, the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography through a silica gel column (eluting solvent: n-hexane/ethyl acetate=1/1), whereby 23.1 g of the desired compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:9]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)[CH2:10]Br)=[CH:4][CH:3]=1.[P:25]([O:30]C)([O:28][CH3:29])[O:26][CH3:27]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:9]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)[CH2:10][P:25](=[O:30])([O:28][CH3:29])[O:26][CH3:27])=[CH:4][CH:3]=1
Reactant: COP(OC)OC
Reactant: Cn1nnnc1C(CBr)=C(c1ccc(F)cc1)c1ccc(F)cc1
Product: COP(=O)(CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C)OC
Temperature: 25 °C

Procedure:
A slurry of 3,3-bis-(4-fluorophenyl)-1-bromo-2-(1-methyl-1H-tetrazol-5-yl)-2-propene (1.17 g, 3.0 mmol) and trimethyl phosphite (0.41 g, 3.3 mmol) was heated at 100° C. for 5 minutes. After cooling to ambient temperature, excess trimethylphosphite was removed in vacuo to give a light yellow solid. This solid was recrystallized from ethyl-acetate/hexane mixture to give the title compound as a pure white solid; m.p.=140°-141° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:8]=1)#[N:2].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[NH2:45][C@@H:46]([CH3:63])[CH2:47][N:48]1[CH:52]=[CH:51][C:50]([C:53]2[CH:60]=[C:59]([F:61])[C:56]([C:57]#[N:58])=[C:55]([Cl:62])[CH:54]=2)=[N:49]1>C(Cl)Cl.CN(C=O)C>[Cl:62][C:55]1[CH:54]=[C:53]([C:50]2[CH:51]=[CH:52][N:48]([CH2:47][C@@H:46]([NH:45][C:12]([C:10]3[N:11]=[C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]4[CH:9]=3)=[O:14])[CH3:63])[N:49]=2)[CH:60]=[C:59]([F:61])[C:56]=1[C:57]#[N:58]
Reactant: N#Cc1ccc2nc(C(=O)O)cn2c1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn2cc(C#N)ccc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.4 %

Procedure:
6-Cyanoimidazo[1,2-a]pyridine-2-carboxylic acid (0.770 mmol, 0.144 g), HOBt (0.770 mmol, 0.104 g) and DIPEA (1.539 mmol, 0.199 g) were dissolved in DCM (5 ml) and DMF (1 ml). EDCI (0.770 mmol, 0.148 g) was added and the resulting mixture was stirred for 10 min at RT. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.592 mmol, 0.22 g) dissolved in small amount of DCM was added and the reaction mixture was stirred overnight at RT. The mixture was diluted with DCM, washed with 1M Na2CO3 and water. The organic phase was dried, filtered and evaporated. The crude product was purified by trituration from ACN. 0.054 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.15 (d, 3H), 4.31-4.45 (m, 2H), 4.46-4.57 (m, 1H), 7.00 (d, 1H), 7.61-7.66 (m, 1H), 7.72-7.77 (m, 1H), 7.86-7.92 (m, 2H), 7.93-7.96 (m, 1H), 8.35-8.37 (m, 1H), 8.69 (d, 1H), 9.34-9.37 (m, 1H).
Reaction SMILES: [C:1](=[S:3])=[S:2].OS(O[CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][NH:11]1)(=O)=O.Cl>[OH-].[Na+]>[CH2:9]1[C@@H:10]2[N:11]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:19]2)[C:1](=[S:3])[S:2]1
Reactant: S=C=S
Reactant: O=S(=O)(O)OC[C@H]1Cc2ccccc2CN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: S=C1SC[C@H]2Cc3ccccc3CN12
Reaction time: 1 h
Yield: 97.3 %

Procedure:
Carbon disulphide (14 g.) is added dropwise, with vigorous stirring, to a solution of (R)-3-hydroxysulphonyloxymethyl-1,2,3,4-tetrahydroisoquinoline (33.9 g.) in 0.6N sodium hydroxide solution (1,000 cc.). After one hour at a temperature of about 20° C., a precipitate appears; stirring is continued for 15 hours. The mixture is neutralised by adding 4N hydrochloric acid. The crystals formed are filtered off and washed with water and then with ethanol. (R)-1,5,10,10a-Tetrahydrothiazolo[3,4-b]isoquinoline-3-thione (30.0 g.) is thus obtained in the form of white crystals melting at 150° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].[C:10]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:10][O:8][C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: O=C(O)c1cnccn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cnccn1
Reaction time: 72 h
Yield: 7.7 %

Procedure:
To pyrazine-2-carboxylic acid (15.0 g, 121 mmol) in DMF (150 mL) were added K2CO3 (50 g, 363 mmol) and MeI (9.0 mL, 145 mmol). After stirring for 3 days, the reaction mixture was filtered and then concentrated. The residue was dissolved in ethyl acetate, washed with water (3 times) and brine, dried over anhydrous Na2SO4, filtered and concentrated. Purification by flash column chromatography eluted with 10-30% ethyl acetate in hexanes gave the title product (1.28 g, 8%).
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([CH:34]([CH3:36])[CH3:35])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([CH:34]([CH3:36])[CH3:35])[N:27]=2)[CH:6]=1
Reactant: COc1ccc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)nc1C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)nc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-isopropyl-5-methoxypyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (100 mg, 200 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (456 mg, 308 μL, 4.00 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated in vacuo then 25% aqueous NH4OH solution added. This was then diluted with dichloromethane and water, the phases separated, and the organic phase washed twice with water. The organic layer was dried over anhydrous magnesium sulfate then purified by chromatography (silica, 0 to 15% methanol in dichloromethane) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-isopropyl-5-methoxypyridin-2-ylamino)pyridazine-3-carboxamide (43 mg, 108 μmol, 54%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.45 (s, 1H), 8.31 (s, 1H), 7.69 (s, 1H), 7.58 (s, 1H), 7.42 (d, J=8.7 Hz, 1H), 6.85 (d, J=8.7 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 3.80 (s, 3H), 3.42 (m, 1H), 3.15 (s, 1H), 1.52-1.69 (m, 8H), 1.32 (m, 2H), 1.24 (d, J=6.4 Hz, 6H); MS (EI/CI) m/z: 400.3 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25](=[O:27])[CH3:26])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[O:29][CH3:28])([OH:27])[CH3:26])[CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(-c2cccc(C(C)(C)C)c2OCc2ccccc2)c1
Reactant: COc1ccccc1[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1C(C)(O)c1cccc(-c2cccc(C(C)(C)C)c2OCc2ccccc2)c1
Reaction time: 3 h

Procedure:
A solution of 36 (0.8 g, 2.23 mmol) in anhydrous tetrahydrofuran (8 mL) was stirred under nitrogen at room temperature and 1M ortho-methoxyphenyl magnesium bromide in tetrahydrofuran (3 mL, 1.35 equiv.) was slowly added. Stirring was continued at room temperature for 30 min and at 60° C. for 3 hr. After cooling, the reaction mixture was poured on saturated ammonium chloride (120 mL) and extracted with ethyl acetate (150 mL). The organic extract was washed with water (2×50 mL), dried over sodium sulfate and filtered. The solvent was removed in a rotary evaporator and the crude 37 thus obtained was used in the next step without further purification.
Reaction SMILES: C1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])C=CC=CC=1.[CH:14]1[C:27]2[C:18](=[CH:19][C:20]3[C:25]([C:26]=2[CH2:28][OH:29])=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][CH:15]=1.C(C1C=CC=CC=1C=C)=C.COCCOC>COC.CCCCCC>[C:8]1([OH:13])[CH:9]=[CH:10][CH:11]=[CH:12][CH:7]=1.[CH:17]([C:18]1[CH:19]=[CH:20][CH:25]=[CH:26][C:27]=1[CH:14]=[CH2:15])=[CH2:16].[CH:24]1[C:25]2[C:20](=[CH:19][C:18]3[C:27]([C:26]=2[CH2:28][OH:29])=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:21]=[CH:22][CH:23]=1
Reactant: Oc1ccccc1-c1ccccc1
Agent: C=Cc1ccccc1C=C
Agent: COC
Agent: OCc1c2ccccc2cc2ccccc12
Solvent: CCCCCC
Solvent: COCCOC
Product: Oc1ccccc1
Temperature: 140 °C
Reaction time: 0.17 h

Procedure:
A solution was prepared consisting of 12.76 g (0.075 mol) 2-phenylphenol, 15.62 g (0.075 mol) 9-Anthracene Methanol, 9.76 (0.075 mol) divinylbenzene dissolved in 25 g cyclopepentyl methyl ether (CPME) and 90 g diethylelene glycol dimethyl ether (DEGME) and the mixture was stirred for 5 minutes in a 250 mL, 4 neck flask equipped with an overhead mechanical stirrer, condenser, thermo watch, Dean Stark trap and a nitrogen purge. After this time, 1.14 g of triflic acid was added to the stirred mixture and it was stirred for another 10 minutes. The temperature of the stirred mixture was then raised to 140° C. and heated for 3 hours. After cooling the reaction mixture and diluting it with 250 mL of CPME, it was transferred to a separating funnel, and washed with two aliquots of deionized (DI) water (2×200 mL). The polymer was precipitated by drowning into hexane and was filtered, washed and dried under vacuum. The polymer was dissolved in THF and isolated using hexane to remove all monomer and oligomers. The weight average molecular weight of the polymer was 1859, PD was 1.40.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][Br:13])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1ncc(Br)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ncc(Br)cc1CBr
Temperature: 80 °C
Reaction time: 5 h
Yield: 48.7 %

Procedure:
To a solution of methyl 5-bromo-3-methylpyridine-2-carboxylate (1.01 g, 4.39 mmol) in carbon tetrachloride (30.0 mL) was added N-bromosuccinimide (8.60E2 mg, 4.83 mmol) and 2,2′-azo-bis-isobutyronitrile (14.4 mg, 0.0877 mmol). The reaction mixture was stirred at 80° C. for 5 h. The reaction mixture was filtered and the filtrate was concentrated to afford 0.66 g (49% yield) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19](=[O:27])OC4C=CC=CC=4)[CH:13]=3)[CH:9]=2)[N:4]([C:28]([NH:30][CH3:31])=[O:29])[CH:3]=1.[CH2:32]([N:34]([CH2:39][CH3:40])[CH2:35][CH2:36][CH2:37][NH2:38])[CH3:33].CN(C)C=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:31][NH:30][C:28]([N:4]1[C:5]2[C:10](=[CH:9][C:8]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([NH:38][CH2:37][CH2:36][CH2:35][N:34]([CH2:39][CH3:40])[CH2:32][CH3:33])=[O:27])[CH:13]=3)=[CH:7][CH:6]=2)[C:2]([Cl:1])=[CH:3]1)=[O:29]
Reactant: CNC(=O)n1cc(Cl)c2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Reactant: CCN(CC)CCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)CCCNC(=O)Nc1cc(Oc2ccc3c(c2)c(Cl)cn3C(=O)NC)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.6 %

Procedure:
Phenyl N-(4-(3-chloro-1-(methylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate (160 mg), 3-(diethylamino)propylamine (120 mg), N,N-dimethylformamide (5 ml) were mixed together and stirred at room temperature for 10 minutes. After the addition of aqueous sodium hydrogencarbonate, extraction was performed with ethyl acetate. The purification by silica gel column chromatography (Fuji Silysia NH, ethyl acetate and sequentially ethyl acetate:methanol=10:1) to yield the title compound as a white solid (86 mg).