Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([CH2:12][C:13]([OH:15])=O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:28]1([C:31](=[N:33]O)[NH2:32])[CH2:30][CH2:29]1.O>CN(C=O)C>[CH:28]1([C:31]2[N:33]=[C:13]([CH2:12][N:9]3[C:7](=[O:8])[C:5]4=[CH:6][CH:1]=[CH:2][CH:3]=[C:4]4[C:10]3=[O:11])[O:15][N:32]=2)[CH2:30][CH2:29]1
Reactant: NC(=NO)C1CC1
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1nc(C2CC2)no1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
N-Phthaloylglycine (90.7 g, 442 mmol) was dissolved in portions (because of clumping) in DMF (500 mL). 1,1′-Carbonyldiimidazole (78.9 g, 486 mmrol) was added in portions (attention CO evolution). The resulting suspension was heated at 80° C. for 20 min. and then cooled to rt, then cyclopropanecarboxamidoxime 1 added and then heated at 110° C. for 2 h. The solution was cooled to rt, then poured into water (4 L), stirred for 15 min, filtered, washed with water (400 mL) and (fried. Yield: 104 g (87%). Mp 115° C. m/z 269 (M).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[N:5]=[C:4]([NH2:18])[N:3]=1.CO.O1CCCC1.C(OCC)(=O)C>[OH-].[Pd+2].[OH-].[C].CCCCCC>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:7]=[CH:2][N:3]=[C:4]([NH2:18])[N:5]=2)=[CH:10][CH:11]=1
Reactant: Nc1nc(Cl)cc(Oc2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CO
Product: Nc1ccc(Oc2ccnc(N)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 340.9 %

Procedure:
After suspending 4-chloro-6-(4-nitrophenoxy)pyrimidin-2-ylamine (1.60 g, 1.32 mmol) in a methanol (30 ml)—tetrahydrofuran (30 ml) mixed solvent, palladium hydroxide-carbon (300 mg) was added and the mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere. The catalyst was filtered off by celite filtration, and after washing with ethanol, the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent—ethyl acetate:hexane=3:1), and the fraction containing the target substance was concentrated to obtain the title compound (910 mg, 4.50 mmol, 75%) as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[O-]S([O-])(=O)=O.[Mg+2].[C:12]1([CH3:18])[CH:17]=CC=C[CH:13]=1>>[CH:12]([CH:18]1[NH:1][CH2:2][CH2:3][CH2:4][O:5]1)([CH3:17])[CH3:13]
Reactant: NCCCO
Reactant: Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CC(C)C1NCCCO1
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of 3-aminopropanol (91 g, 65.4 mmol) in toluene (100 mL) was added isobutraldehyde (9.0 mL, 99.1 mmol, 1.5 equiv.) and MgSO4 (7.5 g) to generate an exotherm. The slurry was stirred for 30 min. and an additional portion of MgSO4 was added (7.5 g), and the slurry was stirred overnight. The resulting mixture was filtered and concentrated under reduced pressure. The condensate was again concentrated under reduced pressure and the two residues were combined to afford 2isopropyltetrahydro-1,3-oxazine as a colorless oil (5.18 g, 61%) 1H NMR (CDCl3) δ0.84-0.88 (m, 6H), 1.24-1.29 (m, 1H), 1.51-1.66 (m, 3H), 2.77-2.87 (m, 1H), 3.07-3.13 (m, 1H), 3.60-3.76 (m, 2H), 4.00-4.05 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([NH2:15])[C:9]=2[C:16]2[CH:17]=[N:18][C:19]([O:22]C)=[CH:20][CH:21]=2)[CH:5]=[CH:6][CH:7]=1.Br.[OH-].[Na+]>C(O)(=O)C>[NH2:14][C:12]1[N:11]=[C:10]([NH2:15])[C:9]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[NH:18][CH:17]=2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:13]=1
Reactant: COc1ccc(-c2c(N)nc(N)nc2-c2cccc(F)c2)cn1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1nc(N)c(-c2ccc(=O)[nH]c2)c(-c2cccc(F)c2)n1
Yield: 70.2 %

Procedure:
A solution of 6-(3-fluorophenyl)-5-(6-methoxy-3-pyridyl)-2,4-pyrimidinediamine (5.00 g, 16.1 mmol) in acetic acid (30 ml)/concentrated hydrobromic acid (50 ml) was stirred at 100° C. for 1.5 hours. After cooling as it was, the reaction mixture was adjusted to pH 12 to 13 with 5N sodium hydroxide and washed with ethylacetate. The aqueous layer was neutralized with 5N hydrochloric acid. The resulting solid was collected by filtration, to give the title compound (3.36 g, 70%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH:4]=[CH:5][CH:6]=1.C([O:9][CH:10]=[C:11](C(OCC)=O)[C:12](OCC)=O)C.C(O)C.C1(OC2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[NH:1]1[C:10](=[O:9])[CH:11]=[CH:12][N:3]2[CH:4]=[CH:5][CH:6]=[C:2]12
Reactant: Nc1ccc[nH]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCO
Product: O=c1ccn2cccc2[nH]1

Procedure:
In Reaction Scheme D, heteroaryl ketone (vb) is modified by treatment with a brominating reagent such as copper(II) bromide, bromine, or the like in an organic solvent such as chloroform, ethyl acetate, ether or mixture thereof at a temperature of 25-100° C., preferably at reflux in a mixture of chloroform and ethyl acetate, for a period of 2-12 hours gives the corresponding alpha-bromoketon (vib). Alternatively, heteroaryl ketone (vb) may be treated with N-bromosuccinamide, or bromine in an inert solvent such as carbon tetrachloride or chloroform with a radical initiator such as AIBN, at reflux to give the bromoketone (vib). The bromoketone (vib) is substituted by treatment with a azide salt such sodium azide, potasium azide or the like in an inert solvent such as DMF, tetrahydrofuran, ether, water or mixture thereof at 0-50° C. for a period of 2-12 hours. The azido group is converted to an amino group when it is dissolved in an appropriate solvent, such a ethanol or methanol with hydrochloric acid, and (a) to the solution is added palladium-carbon or Raney Nickel as the catalyst and the mixture is reacted at room temperature for one to 12 hours under hydrogen atmosphere, or (b) to the solution is added triethyl phorsphite and the mixture is reacted at 0-25° C. for 1-24 hours to provide the amino ketone hydrochloride (viib). The amino ketone (viib) is cyclized with malononitrile upon treatment with a strong base such as sodium hydroxide or potassium hydroxide in an inert solyent such as acetonitrile, water, ethanol or mixture thereof at 25-100° C. for 2-24 hours to give the aminopyrrole (viiib). The aminopyrrole (viiib) is condensed with a biselectrophilic reagent such as diethyl ethoxymethylenemalonate in an inert solvent such as ethanol or dioxane at a temperature of 25-100° C. for 12-24 hours, then cyclized in a high boiling solvent such as phenyl ether at 200-265° C. for 0.5-2 hours to provide pyrrolo[1,2-a]pyrimidone (ixb).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:3]=1.[CH2:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1)[CH3:17]>>[CH2:16]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:4]3[CH:3]=[C:2]([F:1])[N:7]=[CH:6][N:5]=3)=[CH:10][CH:11]=2)=[O:26])=[CH:20][CH:19]=1)[CH3:17]
Reactant: CCc1ccc(N=C=O)cc1
Reactant: Nc1ccc(Oc2cc(F)ncn2)cc1
Product: CCc1ccc(NC(=O)Nc2ccc(Oc3cc(F)ncn3)cc2)cc1
Reaction time: 4 h

Procedure:
The title compound is prepared as described in Example 102 but using 4-(6-fluoro-pyrimidin-4-yloxy)-phenylamine (Example 111) and 4-ethyl-phenyl-isocyanate. The reaction mixture is stirred for 4 h. The title compound is obtained as a white solid: ES-MS: 353.0 [M+H]+; single peak at tR=8.61 min (System 2); Rf=0.14 (CH2Cl2/Et2O, 90/10).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:13][C:12]([CH3:14])=[C:11]([C:15]([O:17]CC)=[O:16])[CH:10]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:13][C:12]([CH3:14])=[C:11]([C:15]([OH:17])=[O:16])[CH:10]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2OC)oc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1-c1cc(C(=O)O)c(C)o1
Yield: 106.5 %

Procedure:
Ethyl 5-(2-methoxyphenyl)-2-methylfuran-3-carboxylate (1.00 g, 3.84 mmol) prepared in the Step 20-1-2 was dissolved in ethanol (8 ml), and a 1 mol/ml sodium hydroxide aqueous solution (8 ml) was added thereto. The mixture was heated under reflux for about 40 minutes. After being allowed to cool, the mixture was adjusted to weak acidity with 2 mol/ml hydrochloric acid, and the precipitate was filtered. The residue was washed with water and dried to give the title compound (0.95 g, quantitative) as a white powder.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH3:8].[CH3:9][N:10]([CH3:19])[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>C(O)(=O)C>[CH3:9][N:10]([CH3:19])[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[N:2][N:3]2[CH:7]=[CH:6][N:5]=[C:4]2[CH3:8])=[CH:13][CH:12]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Cc1nccn1N
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nccn1N=Cc1ccc(N(C)C)cc1

Procedure:
1.3 g of 1-amino-2-methylimidazole hydrochloride and 2.2 g of p-(dimethylamino)benzaldehyde are stirred at room temperature for 16 hours in 100 ml of glacial acetic acid. The mixture is evaporated, whereupon the residue is treated four times with ethanol and again evaporated each time. The crystalline residue is washed with ether and then treated with saturated sodium hydrogen carbonate solution. The mixture is extracted with methylene chloride, the extract is dried over sodium sulfate and evaporated, and the material obtained is recrystallized from methylene chloride/petroleum ether. There is obtained 1-[[p-(dimethylamino)benzylidene]amino]-2-methylimidazole of melting point 166°-167°.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][CH2:9][C:10]1[N:14]=[C:13]([C:15]2[CH:20]=[N:19][C:18]3[N:21]([CH2:24][CH3:25])[N:22]=[CH:23][C:17]=3[C:16]=2[NH:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[O:12][N:11]=1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:8][CH2:9][C:10]1[N:14]=[C:13]([C:15]2[C:16]([NH:26][CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[C:17]3[CH:23]=[N:22][N:21]([CH2:24][CH3:25])[C:18]3=[N:19][CH:20]=2)[O:12][N:11]=1)=[O:6]
Reactant: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CN)no3)cnc21
Reactant: O=C(Cl)CCCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CNC(=O)CCCCl)no3)cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.5 %

Procedure:
4-chlorobutanoyl chloride (0.12 mmol) was added to a stirred solution of Intermediate 118 (0.1 mmol) and diisopropylethylamine (0.3 mmol) in chloroform (1 ml) at room temperature. After stirring at room temperature for 16 h, the reaction mixture was applied to a SPE cartridge (aminopropyl, 2 g) and the cartridge was eluted sequentially with chlororm, ethyl acetate and methanol. Fractions containing the desired product were combined and blown down under nitrogen. The resulting residue was further purified on a SPE cartidge (silica, 1 g) eluting with a gradient of 30-100% ethyl acetate in petroleum ether to afford Intermediate 119 as a white solid (45 mg).). LCMS showed MH+=448, TRET=2.77 min.
Reaction SMILES: [OH-].[K+].[CH3:3]I.[CH2:5]([N:8]1[C@H:22]2[C@@H:12]([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]4[C:23]=3[C:20]([CH2:21]2)=[CH:19][NH:18]4)[CH2:11][C@H:10]([NH:24][C:25]2[CH:26]=[CH:27][C:28]3[O:32][CH2:31][CH2:30][C:29]=3[CH:33]=2)[CH2:9]1)[CH2:6][CH3:7].O>CS(C)=O>[CH3:3][N:18]1[C:17]2[C:23]3[C:20]([CH2:21][C@@H:22]4[C@@H:12]([C:13]=3[CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]([NH:24][C:25]2[CH:26]=[CH:27][C:28]3[O:32][CH2:31][CH2:30][C:29]=3[CH:33]=2)[CH2:9][N:8]4[CH2:5][CH2:6][CH3:7])=[CH:19]1
Reactant: CI
Reactant: CCCN1C[C@@H](Nc2ccc3c(c2)CCO3)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCN1C[C@@H](Nc2ccc3c(c2)CCO3)C[C@@H]2c3cccc4c3c(cn4C)C[C@H]21
Reaction time: 5 h

Procedure:
696 mg finely powdered KOH and 0.77 ml methyliodide are added to 4.1 g 6-n-propyl-8α-(2,3-dihydro-5-benzofuranylamino)-ergoline (example 9) in 25 ml dimethylsulfoxide. The reactive mixture is stirred for 5 hours, poured onto 150 ml H2O, extracted with ethyl acetate, dried over Na2SO4 and concentrated. The residue is chromatographed on 100 g silica gel using methylene chloride/methanol (98:2) as eluant. M.P.=137°-138° C.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[C:7]([C:15](=[O:20])C(F)(F)F)=[CH:6]1)[CH2:2][CH2:3][CH3:4].[OH-:21].[Na+]>O>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[C:7]([C:15]([OH:20])=[O:21])=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CCCCn1cc(C(=O)O)c2ccc(Cl)cc21
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A mixture of 1-(1-butyl-6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (283.7 mg, 0.81 mmol) in a 20% aqueous sodium hydroxide solution (2.7 mL) was heated under reflux for 17 h. At this time, the reaction was cooled to 25° C. and was diluted with water (75 mL). This mixture was extracted with diethyl ether (1×50 mL). The aqueous layer was acidified to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (1×75 mL). The combined organic layers were washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 1-butyl-6-chloro-1H-indole-3-carboxylic acid (141.4 mg, 69.6%) as a pale orange solid: mp 149-151° C.; EI-HRMS m/e calcd for C13H14ClNO2 (M+) 251.0713, found 251.0721.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[C:7]2[C:12]=1[N:11]([CH2:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[C:10](=[O:20])[CH2:9][CH2:8]2.[O:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCN(C(C)C)C(C)C>C(O)(=O)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[C:7]2[C:12]=1[N:11]([CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([CH:32]3[CH2:33][CH2:34][O:29][CH2:30][CH2:31]3)[CH2:18][CH2:19]1)[C:10](=[O:20])[CH2:9][CH2:8]2
Reactant: O=C1CCOCC1
Reactant: COc1ccc(CC2SC(=O)NC2=O)c2c1N(CC1CCNCC1)C(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc(CC2SC(=O)NC2=O)c2c1N(CC1CCN(C3CCOCC3)CC1)C(=O)CC2
Reaction time: 8 h
Yield: 30 %

Procedure:
To 5-(8-methoxy-1-piperidin-4-ylmethyl-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl)thiazolidine-2,4-dione (20 μmol, 1.0 eq.) was added a DMF (200 μl) solution of tetrahydropyran-4-one (24 μmol, 1.2 eq.) and acetic acid (10 μl). MP-sodium triacetoxy borohydride was added further. After this solution was shaken for several minutes, DIEA (30 μl) was added and a reaction was carried out at 60° C. overnight. The resin was removed by filtration and washed with methylene chloride. The solvent was distilled off with nitrogen gas, and the residue was purified by HPLC (UV-trigger, column:CAPCELL PAK C18, UG 120 S-5, 20 mm×50 mm, 0.05% trifluoroacetic acid-H2O, 0.05% trifluoroacetic acid-CH3CN). The structure was confirmed by LC-MS, and freeze-drying was conducted, giving 5-{8-methoxy-1-[1-(tetrahydropyran-4-yl)piperidin-4-yl]methyl-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl}thiazolidine-2,4-dione in 30% yield.
Reaction SMILES: CS([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[CH:8]=[C:7]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[N:6]=1)(=O)=O.[C:28]([O:32][C:33](=[O:52])[NH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:51])[NH:43][C:44]2[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=2)=[CH:38][CH:37]=1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33](=[O:52])[NH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:51])[NH:43][C:44]2[CH:45]=[CH:46][C:47]([NH:50][C:5]3[N:10]4[N:11]=[CH:12][CH:13]=[C:9]4[CH:8]=[C:7]([C:14]4[CH:15]=[C:16]([C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=5)[CH:17]=[CH:18][CH:19]=4)[N:6]=3)=[CH:48][CH:49]=2)=[CH:38][CH:37]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COc1ccc(-c2cccc(-c3cc4ccnn4c(S(C)(=O)=O)n3)c2)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(N)cc2)cc1
Product: COc1ccc(-c2cccc(-c3cc4ccnn4c(Nc4ccc(NC(=O)c5ccc(CNC(=O)OC(C)(C)C)cc5)cc4)n3)c2)cc1
Temperature: 130 °C

Procedure:
Under an inert gas atmosphere at 130° C. bath temperature is heated neat a mixture of 7-methanesulfonyl-5-(4′-methoxy-biphenyl-3-yl)-pyrazolo[1,5-c]pyrimidine and [4-(4-amino-phenylcarbamoyl)-benzyl]-carbamic acid tertbutyl ester (compound B3) overnight. The crude product is purified by silica gel flash chromatography.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]4[N:20]([CH:22]=[CH:23][N:24]=4)[CH:21]=3)=[CH:13][N:14]=2)[N:11]=1.[F-].[K+]>CN1C(=O)CCC1.CCOC(C)=O>[N:24]1[CH:23]=[CH:22][N:20]2[CH:21]=[C:16]([CH2:15][C:12]3[N:10]4[N:11]=[C:6]([NH:4][CH2:3][CH2:1][OH:2])[CH:7]=[CH:8][C:9]4=[N:14][CH:13]=3)[CH:17]=[CH:18][C:19]=12
Reactant: Clc1ccc2ncc(Cc3ccc4nccn4c3)n2n1
Reactant: NCCO
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: OCCNc1ccc2ncc(Cc3ccc4nccn4c3)n2n1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
Ethanolamine (277 μL, 4.55 mmol) was added to a solution of (6-Chloro-3-imidazo[1,2-a]pyridin-6-ylmethyl-imidazo[1,2-b]pyridazine (Example 74, 65 mg, 0.228 mmol) and KF (67 mg, 1.138 mmol) in NMP (1.5 mL). The RM was stirred at 180° C. for 2 h. The mixture was diluted with EtOAc and washed with 1 M Na2CO3 (1×) and water (3×). The aqueous layer was extracted with EtOAc (×2). The combined organic layer was dried over Na2SO4, filtered and concentrated. The aqueous phase was further extracted with DCM (4×). The organic layer was then dried over Na2SO4, filtered and concentrated. The combined residues were purified by preparative LCMS to afford the title compound as a yellow oil (tR 2.62 min (conditions 4), MH+=309.1, 1H-NMR in DMSO-d6: 8.84 (s, 1H); 8.28 (d, 1H); 8.16 (d, 1H); 7.95 (m, 3H); 7.86 (s, 1H); 7.72 (m, 1H); 7.16 (d, 1H); 4.40 (s, 2H); 3.52 (t, 2H); 3.32 (m, 2H)).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.[CH2:15]([N:17]([CH2:20]C)[CH2:18]C)[CH3:16]>>[CH3:18][N:17]([CH3:20])[CH2:15][CH2:16][N:2]1[CH:3]=[C:4]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]2)[CH:5]=[N:1]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCN(CC)CC
Product: CN(C)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 90 °C

Procedure:
The title compound was prepared from pyrazole-4-boronic acid pinacol ester and 2-chloro-N,N-(dimethyl)ethylamine hydrochloride according to Method AC (heating to 90° C. for 6 days before addition of further 2-chloro-N,N-(dimethyl)ethylamine hydrochloride and triethylamine, then heating to 90° C. for a further 3 days) and was isolated as a brown oil (43%). LCMS (ES+) 266 (M+H)+, RT 1.73 minutes (Method 1).
Reaction SMILES: [F:1][CH:2]1[CH2:8][N:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:6][CH2:5][CH:4]([NH:18]C(=O)OC(C)(C)C)[CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=O)(C)(C)C.CO.C(Cl)Cl.N>CO>[NH2:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:7]1[CH2:6][CH2:5][C@H:4]([NH2:18])[CH2:3][C@H:2]([F:1])[CH2:8]1)=[O:48]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(NC(=O)OC(C)(C)C)CC(F)C1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CC[C@H](N)C[C@H](F)C1

Procedure:
Following the procedure for Example 101, Intermediate 20, tert-butyl 6-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 gave, after silica gel column chromatography (0-10% MeOH/DCM, 1% 7 N ammonia in MeOH), a white solid (93 mg, 7% over three steps). Compound 122 was obtained as a single enantiomer from SFC chiral separation of the racemic mixture. 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.88 (s, 1H), 7.38-7.28 (m, 2H), 7.08-6.98 (m, 3H), 6.18-6.07 (m, 2H), 4.83-4.66 (m, 1H), 4.30-4.21 (m, 1H), 4.16-4.09 (m, 1H), 3.74 (s, 3H), 3.40-3.16 (m, 3H), 3.11 (m, 1H), 2.98-2.89 (m, 1H), 1.95-1.76 (m, 2H). LCMS (ES+) m/z 466 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:7]=[C:6](C2SC=CC=2)[NH:5][C:4]=1[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)#[N:2]>C1COCC1>[C:1]([C:3]1[C:7]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][NH:5][C:4]=1[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)#[N:2]
Reactant: N#Cc1cc(-c2cccs2)[nH]c1-c1cccs1
Solvent: C1CCOC1
Product: N#Cc1c(-c2cccs2)c[nH]c1-c1cccs1
Yield: 106.6 %

Procedure:
To a stirred solution of 0.8 g (3 mmol) of 3-cyano-2,5-dithienylpyrrole (XVII) in 20 mL of dry THF was added 8 mL of a 1M solution of borane-tetrahydrofuran complex in THF. After the initial exothermic reaction subsided, the mixture was heated to reflux under an inert (argon gas) atmosphere overnight. The solvents then were evaporated in vacuo and the residue partitioned between CHCl3 and a 3N hydrochloric acid (HCl) solution. The CHCl3 layer then was extracted three times with 10 mL portions of 3N HCl dried over sodium sulfate, filtered, and concentrated in vacuo to give 410 mg of unreacted 3-cyanodithienylpyrrole (XVII).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:10])([CH3:9])[C:5]([CH3:8])([OH:7])[CH3:6].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18](=O)[O:19]C1C=CC=CN=1>C1COCC1.CCOC(C)=O>[C:18](=[O:19])([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=1)[O:7][C:5]([CH3:8])([C:4]([F:10])([F:3])[CH3:9])[CH3:6]
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Reactant: CC(C)(O)C(C)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(F)(F)C(C)(C)OC(=O)Oc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.8 %

Procedure:
To a suspension of sodium hydride, 60% in mineral oil (0.652 g, 16.31 mmol) in THF (25 mL) was added 3,3-difluoro-2-methylbutan-2-ol (1.84 g, 14.82 mmol) at 0° C. After stirring 30 min, the solution was transferred to a solution of di(pyridin-2-yl)carbonate (3.20 g, 14.82 mmol) in THF (25 mL) through a cannula. The formed slurry was stirred at 0° C. for 30 min. The slurry was warmed to rt and stirred for 2 h. The reaction was diluted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated to give a residue that was purified by Biotage eluting with 10-50% EtOAc in hexanes to afford the desired product 3,3-difluoro-2-methylbutan-2-yl pyridin-2-yl carbonate (500 mg, 13.76%) as an oil that later crystallized to a white solid upon standing. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.43 (ddd, J=4.9, 2.0, 0.7 Hz, 1H), 7.95-7.75 (m, 1H), 7.31-7.24 (m, 1H), 7.15 (dt, J=8.2, 0.8 Hz, 1H), 1.72 (s, 6H), 1.77-1.66 (m, 3H).