Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@@H:12]2[C@@H:15]([OH:17])[CH3:16])[C:9]=1[C:19]([O-:21])=[O:20])(=[O:3])[CH3:2].[Na+].[C:23]([Si:27](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:26])([CH3:25])[CH3:24]>O1CCCC1.C1OCCOCCOCCOCCOC1>[C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@@H:12]2[C@@H:15]([OH:17])[CH3:16])[C:9]=1[C:19]([O:21][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(=O)N/C=C/SC1=C(C(=O)[O-])N2C(=O)[C@H]([C@H](C)O)[C@H]2C1
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N/C=C/SC1=C(C(=O)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)N2C(=O)[C@H]([C@H](C)O)[C@H]2C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 24.3 %

Procedure:
Sodium (5R,6S)-3-[(E)-2-acetamidoethenylthio]-6-[(S)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e64) (50 mg, 50% pure material) in dry tetrahydrofuran (THF) (5 ml) containing 15-crown-5 crown ether (2 drops) and 3 A molecular sieves was treated with tert-butylchlorodiphenylsilane (80 mg). After stirring at r.t. for 20 hr., the THF was evaporated in vacuo and the mixture loaded onto a silica gel column (10 g) and the column eluted with chloroform (10 ml) followed by a chloroform/ethanol mixture (4:1). The fractions containing the ester were combined and evaporated to give tert-Butyldiphenylsilyl (5R,6S)-3-[(E)-2-acetamidoethenylthio]-6-[(S)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e65) as an oil (20 mg), νmax (CH2Cl2) 1785, 1700, 1685, 1625 cm-1. δ(CDCl3) 1.13 (9H,s,C(CH3)3), 1.27 (3H,d,J 6 Hz, CH3CH), 1.77 (3H,s,CH3CO), 2.7-3.2 (2H,m, 4--CH2), 3.22 (1H, m, sharpens to dd on D2O exchange, J1 approx. 5 Hz, J2 approx. 3 Hz, 6--CH), 3.6 (1H, broad, exchanges D2O, OH), 3.9-4.3 (2H,m, 5--CH, 8--CH), 5.60 (1H,d,J 14 Hz, S CH=), 7.02 (1H,dd,J1 14 Hz, J2 10 Hz,d,J 14 Hz on D2O exchange, CH=CH NH), 7.3-7.8 (10H, Ar--H), 8.34 (1H, broad d, exchange D2O, NH) p.p.m. The UV spectrum showed a maximum at about 328 nm.
Reaction SMILES: [N:1]1([C@H:10]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[C@H:11]([OH:14])[CH2:12]O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N:31]1C=CC=C[CH:32]=1>C(OCC)(=O)C.CN>[N:1]1([C@H:10]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[C@H:11]([OH:14])[CH2:12][NH:31][CH3:32])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: OC[C@@H](O)[C@@H](c1cccs1)n1ccc2ccccc21
Reactant: c1ccncc1
Agent: CN
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Product: CNC[C@@H](O)[C@@H](c1cccs1)n1ccc2ccccc21
Reaction time: 2 h

Procedure:
(2S,3S)-3-(1H-indol-1-yl)-3-thien-2-ylpropane-1,2-diol (250 mg, 0.91 mmol) was dissolved in pyridine (3 mL), para-toluenesulfonyl chloride (216 mg, 1.13 mmol) was added and the mixture was stirred for 2 hours. The mixture was diluted with ethyl acetate and washed with water, a saturated aqueous solution of copper sulfate, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 0%-100% ethyl acetate in hexane) to afford 360 mg that was immediately dissolved in methylamine (8M solution in ethanol, 15 mL) and stirred for 16 hours. The mixture was concentrated in vacuo and purified via flash column chromatography (silica, gradient 2%-10% methanol saturated with ammonia in chloroform) to give 180 mg of (1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-thienyl)propan-2-ol as a colorless oil. The freebase was dissolved in ether (5 mL) and treated with a 1N ethereal solution of hydrochloric acid (0.63 mL, 0.63 mmol, 1 equivalent). The white precipitate was collected and dried under vacuum to give 193 mg (60%) of (1S,2R)-1(1H-indol-1-yl)-3-(methylamino)-1-(2-thienyl)propan-2-ol hydrochloride. HRMS: calcd for C16H18N2OS+H+, 287.12126; found (ESI, [M+H]+), 287.1204
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12]([C:15]3[CH:16]=[C:17]([C:21]4(O)[C:34]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[C:28]([C:36]5[CH:41]=[CH:40][CH:39]=[C:38]([C:42]6[C:43]7[C:48]([C:49]8[CH:50]=[CH:51][CH:52]=[CH:53][C:54]=8[CH:55]=6)=[CH:47][CH:46]=[CH:45][CH:44]=7)[CH:37]=5)(O)[C:27]5[C:22]4=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH:18]=[CH:19][CH:20]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.I.[PH2](O)=O>C(O)(=O)C>[CH:1]1[C:14]2[CH:13]=[C:12]([C:15]3[CH:16]=[C:17]([C:21]4[C:22]5[C:27]([C:28]([C:36]6[CH:41]=[CH:40][CH:39]=[C:38]([C:42]7[C:43]8[C:48]([C:49]9[CH:50]=[CH:51][CH:52]=[CH:53][C:54]=9[CH:55]=7)=[CH:47][CH:46]=[CH:45][CH:44]=8)[CH:37]=6)=[C:29]6[C:34]=4[CH:33]=[CH:32][CH:31]=[CH:30]6)=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH:18]=[CH:19][CH:20]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OC1(c2cccc(-c3cc4ccccc4c4ccccc34)c2)c2ccccc2C(O)(c2cccc(-c3cc4ccccc4c4ccccc34)c2)c2ccccc21
Agent: I
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: c1cc(-c2c3ccccc3c(-c3cccc(-c4cc5ccccc5c5ccccc45)c3)c3ccccc23)cc(-c2cc3ccccc3c3ccccc23)c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
9,10-bis(3-(9-Phenanthryl)phenyl)-9,10-dihydroxy-9,10-dihydroanthracene (5.2 g, 7.3 mmole) was suspended in acetic acid (120 ml). To the resultant suspension, a 57% hydroiodic acid (10 ml, 77 mmole, 10 eq) was added and the obtained mixture was stirred at 100° C. for 6 hours. To the reaction mixture, a 50% aqueous solution of hypophosphorous acid (40 ml) was added. The formed solid was separated by filtration and washed with water, methanol and acetone and a white solid (5.0 g, quant.) was obtained.
Reaction SMILES: Cl[Si](C)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:13][C:14]1[CH:21]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[C:18]([B:29]2[O:33][C:32](C)(C)C(C)(C)[O:30]2)[C:15]=1C=O>C1COCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][CH:32]1[O:33][B:29]([OH:30])[C:18]2[CH:19]=[C:20]([O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:21]=[C:14]([CH3:13])[C:15]1=2)[CH3:12]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(Oc2ccccc2)cc(B2OC(C)(C)C(C)(C)O2)c1C=O
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ccccc3)cc(C)c21
Temperature: 55 °C
Reaction time: 0.08 h
Yield: 45.6 %

Procedure:
A suspension of zinc dust (1.26 g, 19.30 mmol) in THF (8 mL) was treated with chlorotrimethylsilane (0.30 mL, 2.40 mmol) at 40° C. The mixture was heated at 55° C. for 15 minutes, the cooled to 37° C. Ethyl bromoacetate (1.68 mL, 17.70 mmol) was added dropwise (refluxed gently upon addition), then stirred for 5 min. The suspension was allowed to settle at room temperature. The Reformasky reagent (approximately 1.7 M stock solution, 1.5 mL, 2.55 mmol) was transferred via syringe to a dry flask, then cooled to 0° C. 2-Methyl-4-phenoxy-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (0.50 g, 1.48 mmol) in THF (5 mL) was added dropwise to the reagent, then stirred at 0° C. for 4 h. The mixture was quenched with saturated NH4Cl, extracted with EtOAc, dried (Na2SO4), filtered and concentrated to a yellow oil. The oil was purified by column chromatography (SiO2, EtOAc/hexanes; 1:5 to 1:1 gradient) to afford (1-hydroxy-4-methyl-6-phenoxy-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.22 g, 46%), as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 7.40 (t, J=7.42 Hz, 2H), 7.16 (t, J=7.42 Hz, 1H), 7.07 (d, J=2.35 Hz, 1H), 7.02-6.97 (m, 3H), 5.51 (dd, J=9.33, 2.34 Hz, 1H), 4.05 (q, J=7.03 Hz, 2H), 3.14 (dd, J=15.63, 2.74 Hz, 1H), 2.89 (s, 3H), 2.33-2.26 (m, 1H), 1.14 (t, J=7.03 Hz, 3H); MS (ES) m/z: 325 (M−1).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[C:15]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=3)[CH:16]=[CH:17][C:18]=2[Cl:19])=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:29])[CH3:30])[CH:23]=3)[CH:16]=[CH:17][C:18]=1[Cl:19])[N:10]=2
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Cl)c(Oc3ccc(N)cn3)c2)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Cl)c(Oc3ccc4nc(N)sc4n3)c2)c1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
Potassium thiocyanate (1.33 g, 13.7 mmol) was suspended in acetic acid (30 mL), and the mixture was stirred at room m temperature for 10 min. N-{3-[(5-Aminopyridin-2-yl)oxy]-4-chlorophenyl}-3-(1-cyano-1-methylethyl)benzamide (1.40 g, 3.44 mmol) was added to the obtained solution, and the mixture was further stirred at room temperature for 10 min. A solution of bromine (576 mg, 3.61 mmol) in acetic acid (10 mL) was slowly added dropwise to the obtained solution. After the completion of the dropwise addition, the mixture was stirred at room temperature for 12 hr. The yielded yellow insoluble material was filtered off, and washed with acetic acid. The filtrate and the washing fluid were combined, and concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate (200 mL), and the solution was washed with saturated aqueous sodium hydrogen carbonate solution (200 mL×2), water (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate), and the obtained solution was concentrated under reduced pressure to give the title compound (1.58 g, 99%) as a yellow amorphous substance.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=2[N:12]=1)[CH2:9][CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:16]1([N:15]2[C:14]3[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=3[N:12]=[C:11]2[C@@H:8]([NH2:7])[CH2:9][CH3:10])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1nc2ccccc2n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](N)c1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of [(S)-1-(1-phenyl-1H-benzoimidazol-2-yl)propyl]carbamic acid tertbutyl ester (1.76 g) in DCM (10 mL) was added TFA (7.5 mL) and the mixture was stirred at RT for 4 h. Volatiles were removed under reduced pressure and the resulting residue was dissolved in DCM and washed with a saturated solution of NaHCO3. The two phase system was stirred for 20 min, then the organic layer was dried (Na2SO4) and concentrated in vacuo affording (S)-1-(1-Phenyl-1H-benzoimidazol-2-yl)propylamine as a brown oil (1.1 g, 81% over three steps). LCMS: RT 2.02 min [M+H]+ 252.2
Reaction SMILES: [C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Ni:9].C([Br:13])C=C.[CH:14]([C-:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1)([CH3:16])[CH3:15].[Na+:22]>C1COCC1>[CH:14]([C-:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1)([CH3:16])[CH3:15].[Na+:22].[CH2:15]([Ni:9][Br:13])[CH:14]=[CH2:17]
Reactant: C=CCBr
Reactant: [Ni]
Agent: CC(C)[c-]1cccc1
Agent: [C-]#[O+]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[Ni]Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium isopropylcyclopentadienide is prepared in THF as described in Preparation A. Then dimeric allyl nickel bromide is prepared by reacting 70 g of nickel carbonyl and 50 ml of allyl bromide in 200 ml of THF. The final solution is added dropwise onto the solution of sodium isopropylcyclopentadienide and allowed to stir at room temperature for two hours. The mixture becomes violet immediately and NaBr precipitates. The solution containing isopropylcyclopentadienyl nickel allyl is transferred to another flask and solvent is removed by pumping at or below room temperature. The product is removed by vacuum distillation at 10-2 torr in the range of 30°-40° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][C:14]2[N:15]=[C:16]([CH2:35][CH2:36][CH3:37])[N:17]([CH2:24][C:25]3[C:33]([Cl:34])=[CH:32][C:28]4[O:29][CH2:30][O:31][C:27]=4[CH:26]=3)[C:18]=2[C:19]([O:21]CC)=[O:20])=[CH:8][CH:7]=1)([OH:3])=[O:2]>C(O)C>[C:1]([CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([S:12][CH2:13][C:14]2[N:15]=[C:16]([CH2:35][CH2:36][CH3:37])[N:17]([CH2:24][C:25]3[C:33]([Cl:34])=[CH:32][C:28]4[O:29][CH2:30][O:31][C:27]=4[CH:26]=3)[C:18]=2[C:19]([OH:21])=[O:20])=[CH:10][CH:11]=1)([OH:3])=[O:2]
Reactant: CCCc1nc(CSc2ccc(CCC(=O)O)cc2)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Solvent: CCO
Product: CCCc1nc(CSc2ccc(CCC(=O)O)cc2)c(C(=O)O)n1Cc1cc2c(cc1Cl)OCO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
540 mg of the ester obtained in Example 63 is dissolved in 20 ml of ethanol and 10 ml of 2N soda and the solution is agitated for 5 hours at ambient temperature. The solvent is evaporated off under reduced pressure, the aqueous phase is filtered off, it is acidified using acetic acid, the precipitate is separated off, washed with water, dried at 50° C. under reduced pressure. The residue is taken up in isopropyl ether, dried and 420 mg of expected product is obtained. M.p.=171° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH2:18][C:19]([O-:21])=O)=[N:16][N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[Li+].CCN=C=NCCCN(C)C.[CH:34]1[CH:35]=C[C:37]2[N:42](O)N=[N:40][C:38]=2[CH:39]=1.CCN(CC)CC.NC1C=NC=CC=1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH2:18][C:19]([NH:40][C:38]4[CH:37]=[N:42][CH:35]=[CH:34][CH:39]=4)=[O:21])=[N:16][N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: O=C([O-])Cc1nnc2ccc(Nc3cccc(Cl)c3)nn12
Agent: CCN=C=NCCCN(C)C
Agent: Nc1cccnc1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Cc1nnc2ccc(Nc3cccc(Cl)c3)nn12)Nc1cccnc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Lithium 2-(6-(3-chlorophenylamino)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)acetate (50 mg, 0.16 mmol) is taken up in DMF (3 ml) and EDCI (45 mg, 0.24 mmol), HOBt (32 mg, 0.24 mmol), Et3N (30 ul, 0.32 mmol), and 3-aminopyridine is added. The reaction mixture is stirred at 60° C. overnight. The reaction mixture is diluted with ethyl acetate, washed with water, and the organic layer concentrated to dryness. Purification by reversed-phase HPLC yields the product, 2-(6-(3-chlorophenylamino)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-N-(pyridin-3-yl)acetamide.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]#[CH:14])[C:6]=2[CH:15]=1.C(N(CC)C1C=CC=CC=1)C.Cl[C:29]([O:31][CH3:32])=[O:30]>ClCCCl>[F:16][C:3]1[C:2]([NH:1][C:29]([O:31][CH3:32])=[O:30])=[CH:15][C:6]2[N:7]([CH2:12][C:13]#[CH:14])[C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: COC(=O)Cl
Reactant: C#CCN1C(=O)COc2cc(F)c(N)cc21
Solvent: ClCCCl
Solvent: CCN(CC)c1ccccc1
Product: C#CCN1C(=O)COc2cc(F)c(NC(=O)OC)cc21
Yield: 75.4 %

Procedure:
A mixture of 6-amino-7-fluoro-4-propargyl-2H-1,4-benzoxazin-3(4H)-one (2.1 g), N,N-diethylaniline (1.5 g) and methyl chloroformate (1.0 g) was dissolved in 1,2-dichloroethane (10 g), and the resultant mixture was heated under reflux for 3 hours. After cooling, the reaction mixture was washed with water, and the organic layer was concentrated. The residue was washed with methanol to give 7-fluoro-6-methoxycarbonylamino-4-propargyl-2H-1,4-benzoxazin-3(4H)-one (2.0 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]2[CH:34]=[C:33]([CH3:35])[C:28]3[NH:29][C:30](=[O:32])[O:31][C:27]=3[CH:26]=2)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.CN(C=O)C>[CH3:35][C:33]1[C:28]2[NH:29][C:30](=[O:32])[O:31][C:27]=2[CH:26]=[C:25]([NH:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C:15]5[C:10](=[N:11][CH:12]=[CH:13][CH:14]=5)[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH:19]=2)[CH:34]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1cc(Nc2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: Cc1cc(Nc2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2oc(=O)[nH]c12
Temperature: 25 °C

Procedure:
276 mg (1.26 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 350 mg (0.987 mmol) 6-(6-chloro-pyrimidin-4-ylamino)-4-methyl-3H-benzoxazol-2-one and 350 mg (2.53 mmol) potassium carbonate in 2 mL NMP were stirred for 2 h at 130° C. After cooling to RT the reaction mixture was diluted with DMF and purified by preparative HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[C:6]([C:8]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=1[C:10](O)=[O:11])=O.O.[NH2:25][NH2:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[C:8]3[C:9](=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:10](=[O:11])[NH:26][N:25]=2)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: NN
Reactant: COc1cc(OC)cc(C(=O)c2ccc(OC)cc2C(=O)O)c1
Solvent: O
Product: COc1cc(OC)cc(-c2n[nH]c(=O)c3cc(OC)ccc23)c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 2-(3,5-dimethoxybenzoyl)-5-methoxybenzoic acid with hydrazine hydrate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.Cl.[CH3:10][C:11]1[C:15]([CH2:16][N:17]2[CH:21]=[C:20]([NH2:22])[CH:19]=[N:18]2)=[C:14]([CH3:23])[O:13][N:12]=1>>[CH3:10][C:11]1[C:15]([CH2:16][N:17]2[CH:21]=[C:20]([NH:22][C:6]([C:2]3[NH:1][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH:19]=[N:18]2)=[C:14]([CH3:23])[O:13][N:12]=1
Reactant: O=C(O)c1ccc[nH]1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(NC(=O)c2ccc[nH]2)cn1
Yield: 18 %

Procedure:
Prepared as in Example 4-8 from 1H-pyrrole-2-carboxylic acid and 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a). Yield 18%.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.[C:17]([C:19]1[CH:30]=[C:29]([CH3:31])[C:22]2[NH:23]C(=O)[O:25][C:26](=O)[C:21]=2[CH:20]=1)#[N:18].N1C=CC=C(C)C=1.CS(Cl)(=O)=O>C(#N)C.O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:9][C:26](=[O:25])[C:21]3[CH:20]=[C:19]([C:17]#[N:18])[CH:30]=[C:29]([CH3:31])[C:22]=3[N:23]=2)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: Cc1cc(C#N)cc2c(=O)oc(=O)[nH]c12
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: Cc1cccnc1
Solvent: O
Product: Cc1cc(C#N)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
A mixture of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (97.9% purity, 3.09 g, 10.0 mmol), 6-cyano-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (96.3% purity, 2.10 g, 10.0 mmol) and 3-picoline (3.30 mL, 3.16 g, 34 mmol) in acetonitrlle (65 mL) was cooled to about −5° C. Then methanesulfonyl chloride (1.0 mL, 1.5 g, 13 mmol) in acetonitrile (3 mL) was added dropwise at −5 to 0° C. After 15 minutes at −5 to 0° C., the reaction mixture was heated to 50° C. for 4 hours. The reaction mixture was then cooled to room temperature, water (4 mL) was added dropwise, and the reaction mixture was stirred 15 minutes. The mixture was filtered, and the solids were washed sequentially with 4:1 acetonitrile-water (2×2 mL) and acetonitrile (3×2 mL), and dried under nitrogen to afford the title product as a pale green powder, 3.71 g (94.2% purity by HPLC, 82.0% yield calculated based on the purity), melting at 263-267° C.
Reaction SMILES: [CH:1]1([CH:4]([CH:6]2[CH2:8][CH2:7]2)[OH:5])[CH2:3][CH2:2]1.[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][O:5][CH:4]([CH:6]1[CH2:8][CH2:7]1)[CH:1]1[CH2:3][CH2:2]1)[CH3:16]
Reactant: OC(C1CC1)C1CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)COC(C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.1 %

Procedure:
To a solution of dicyclopropylmethan-1-ol (1.5 mL, 12.7 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (1.26 mL, 12.0 mmol). The reaction mixture is stirred at rt for 48 h. The reaction mixture is diluted with heptane, and filtered. The filtrate is evaporated, and the residue is vacuum distilled at 170° C. to give 1.24 g of the product 448.
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([C:18](=[O:20])[NH2:19])=[CH:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[C:18]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[N:8]([CH2:7][C:6]([OH:21])=[O:5])[CH:9]=1)(=[O:20])[NH2:19]
Reactant: CC(C)(C)OC(=O)Cn1cc(C(N)=O)c2cc(Cl)ccc21
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cn(CC(=O)O)c2ccc(Cl)cc12
Reaction time: 2 h

Procedure:
To a solution of (3-carbamoyl-5-chloro-indol-1-yl)-acetic acid tert-butyl ester (455 mg, 0.973 mmol) in CH2Cl2 (6.0 mL) was added TFA (3.0 mL) at RT and stirring was continued for 2 h. Methanol was then added to the reaction mixture and volatiles were removed in vacuo. The residue was taken up in methanol and concentrated again under reduced pressure. The residue was dissolved in 1N aqueous NaOH and washed with CH2Cl2 (3×). The water phase was acidified to pH 2 by adding 6N aqueous HCl to form a white suspension. The precipitate was filtered off, washed with water and dried in vacuo to afford the crude title compound as a white solid. MS (LC/MS): 253 [M+H]+, 505 [2M+H]+; tR (HPLC conditions b): 3.99 min. The product was used in the next reaction step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[N:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[N:26][C:21]2=[N:20][CH:19]=1)CCC>>[N:8]1([C:4]2[N:3]=[C:2]([C:18]3[N:22]4[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:29])[F:30])=[N:26][C:21]4=[N:20][CH:19]=3)[CH:7]=[CH:6][CH:5]=2)[CH:12]=[N:11][CH:10]=[N:9]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Brc1cccc(-n2cncn2)n1
Product: FC(F)(F)c1ccn2c(-c3cccc(-n4cncn4)n3)cnc2n1
Yield: 31.3 %

Procedure:
2-Bromo-6-(1H-[1,2,4]triazol-1-yl)pyridine (0.25 g, 1.13 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.13 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with ethyl acetate on a gradient of methanol (0-10%) and trituration with ethyl acetate gave 3-[6-(1H-[1,2,4]triazol-1-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine (117 mg) as a pale yellow solid: δH (400 MHz, CDCl3) 7.44 (1H, d, J 7), 7.84 (1H, d, J 8), 7.90 (1H, d, J 8), 8.07 (1H, dd, J 8 and 8), 8.19 (1H, s), 8.59 (1H, s), 9.12 (1H, s), 10.16 (1H, d, J 7); m/z (ES+) 331 (M++H).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][C:24]=1[CH:25]=O>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:25][C:24]2[CH:27]=[C:28]([O:31][C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:30][C:23]=2[O:22][CH3:21])[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: COc1ccc(OC(F)(F)F)cc1C=O
Product: COc1ccc(OC(F)(F)F)cc1CN1C(=O)C(C)CC1c1c(OC)cccc1OC

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 2-methoxy-5-(trifluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.92 min.; [M+H]+: 440.07 g/mol.