Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:46]([O:45][C:44]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:2]1[CH:3]=[C:4]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1)=[O:50])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(NC3(c4cccc(Br)c4)CC3)nc(OCC(F)(F)F)n2)cc1
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCNc1cccc(C2(Nc3nc(Nc4ccc(C(=O)OC(C)(C)C)cc4)nc(OCC(F)(F)F)n3)CC2)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 27.6 %

Procedure:
To a mixture of tert-butyl 4-(4-(1-(3-bromophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (116 mg, 0.2 mmol),tert-butyl 4-aminobutylcarbamate (37.7 mg, 0.200 mmol), 2-(Di-t-butylphosphino)biphenyl (0.020 mmol), Pd2(dba)3 (18.31 mg, 0.020 mmol), K3PO4 (34.8 mg, 0.200 mmol) in a microwave tube in DME (Volume: 2 mL) was stirred for 3 h at 85° C. The reaction mixture was diluted with CH2Cl2, filtrated through a celite plug washing with CH2Cl2, concentrated to give a residue that was purified by Biotage eluting with 20%-50% ethyl acetate in hexane to give 38 mg (28%) of the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][CH:6]([CH3:8])[CH2:5][CH:4]([CH2:9][C:10](O)=[O:11])[CH2:3]1.P(Cl)(Cl)[Cl:15]>CCOCC>[CH3:1][C:2]1([CH3:13])[CH2:7][CH:6]([CH3:8])[CH2:5][CH:4]([CH2:9][C:10]([Cl:15])=[O:11])[CH2:3]1
Reactant: CC1CC(CC(=O)O)CC(C)(C)C1
Reactant: ClP(Cl)Cl
Solvent: CCOCC
Product: CC1CC(CC(=O)Cl)CC(C)(C)C1
Yield: 264.4 %

Procedure:
114 g of 3,3,5-trimethyl-cyclohexylacetic acid in 350 ml of dry ether in a round flask which is fitted with a thermometer, stirrer, reflux condenser and dropping funnel are treated rapidly with 32.8 g of phosphorus trichloride and the mixture is subsequently held at reflux temperature for a further 4 hours. The phosphorous acid is decanted off and the ether is evaporated in vacuo. There are obtained 128 g (yield: quantitive) of crude 3,3,5-trimethyl-cyclohexylacetyl chloride.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:9]N)[CH:5]=[C:6]([I:8])[CH:7]=1.[CH3:11][CH:12]([CH3:16])[C:13](=O)[CH3:14]>C(O)(=O)C>[I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]2[C:3]=1[C:12]([CH3:16])([CH3:11])[C:13]([CH3:14])=[N:9]2
Reactant: NNc1cc(I)cc(I)c1
Reactant: CC(=O)C(C)C
Solvent: CC(=O)O
Product: CC1=Nc2cc(I)cc(I)c2C1(C)C
Yield: 61.9 %

Procedure:
2 g of 3,5-diiodophenylhydrazine (5.5 mmol), and 1 mL (9.3 mmol) of 3-methyl-2-butanone were refluxed in 15 mL of acetic acid for 20 hours. The acetic acid was evaporated and the residue was dissolved in ether. Insoluble precipitate was filtered off, and the etheric solution was washed with aqueous solutions of NaHCO3, followed by Na2S2O3 and water. The organic layer was dried with CaCl2 and ether was removed under reduced pressure by a rotary evaporator to give 1.4 g of 4,6-diiodo-2,3,3-trimethyl-3H-indole. 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 7.92 (1H, d, 1.1 Hz, arom.), 7.79 (1H, d, 1.1 Hz, arom.), 2.22 (3H, s, 2-CH3), 1.32 (6H, s, C(CH3)2).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:23]2[O:24][CH:25]=[CH:26][N:27]=2)(=O)=O)C=CC=CC=1.[OH-].[K+].CO>O>[O:24]1[CH:25]=[CH:26][N:27]=[C:23]1[C:11]1[NH:10][C:14]2=[N:15][CH:16]=[C:17]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:18]=[C:13]2[CH:12]=1
Reactant: CS(=O)(=O)c1cnc2c(c1)cc(-c1ncco1)n2S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1cnc2[nH]c(-c3ncco3)cc2c1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
A mixture of 1-benzenesulfonyl-2-(oxazol-2-yl)-5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine (0.359 g), potassium hydroxide (0.34 g) and methanol (30 ml) was stirred at 15 to 30° C. for 30 minutes. To the reaction mixture was added water, the resulting mixture was extracted with dichloromethane, washed with a saturated aqueous NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate 1:1) to obtain 0.19 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[Si]([N:23]=[N+:24]=[N-])(C)(C)C>CC#N>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:7]=1)=[N+:23]=[N-:24]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(N)cc2)cc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)Nc2ccc(N=[N+]=[N-])cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
Following the procedure of Moses and coworkers (K. Barral, A. D. Moorhouse, J. E. Moses, Org. Lett. 2007, 9, 1809-1811). N-(4-aminophenyl)-4-methylbenzene-1-sulfonamide (1.00 g, 3.81 mmol) was dissolved in anhydrous CH3CN (6 mL), and the resulting solution was placed under Ar(g) and cooled to 0° C. To this was added t-BuONO (0.68 mL, 5.71 mmol) followed by TMSN3 (0.60 mL, 4.57 mmol) dropwise. The resulting solution was allowed to warm to room temperature and stirred for 2 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with 10% EtOAc/hexanes, to give aryl azide 7 (1.02 g, 3.54 mmol, 93% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[OH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([NH:1][C:29](=[O:30])[C:28]4[CH:27]=[CH:26][C:25]([N:22]5[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][CH2:21]5)=[CH:33][CH:32]=4)=[CH:3][CH:4]=3)[NH:8][N:7]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccc(-c2n[nH]c3cc(N)ccc23)cc1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Product: Nc1ccc(-c2n[nH]c3cc(NC(=O)c4ccc(N5CCC(O)CC5)cc4)ccc23)cc1

Procedure:
Compound 976 was prepared according to the procedure described in Scheme IV from 6-amino-3-(4-aminophenyl)-1H-indazole, and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C25H25N5O2: 428.20; found 428.07.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH3:18])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1)[CH3:2].[CH2:20](I)[CH2:21][CH2:22][CH3:23].N1C(C)=CC=CC=1C>>[CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH3:18])[N:6]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1)[CH2:20][CH2:21][CH2:22][CH3:23])[CH3:2]
Reactant: CCOC(=O)[C@H](C)Nc1ccc(CCC(=O)O)cc1
Reactant: CCCCI
Solvent: Cc1cccc(C)n1
Product: CCCCN(c1ccc(CCC(=O)O)cc1)[C@@H](C)C(=O)OCC
Temperature: 135 °C

Procedure:
N-(4-Carboxyethylphenyl)alanine ethyl ester (2.6 g, 0.01 mol), n-butyl iodide (1.8 g, 0.01 mol) and 2,6-lutidine (1.5 g, 0.04 g) were sealed in a glass tube. The contents of the tube were heated at 135° C. for 48 h. The tube was then cooled and the contents were partitioned between 200 mL ethyl acetate and 200 mL brine. The organic layer was separated, dried over anhyd. sodium sulfate and concentrated at reduced pressure. The resulting oil was charged onto a silica gel column, and eluted with heptane:THF (4:1). The desired ester was isolated as a light yellow oil (0.5 g, 16%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[CH2:9][CH2:10][CH:11](C(NC2C=CC(F)=CC=2)C2C=CC(O[Si](C)(C)C)=CC=2)[C:12]([N:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)COC2=O)=[O:13])=[CH:4][CH:3]=1>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC.[Ag-]=O.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:14]2[CH:18]([C:19]3[CH:20]=[CH:21][C:22]([O:46][Si:47]([CH3:50])([CH3:49])[CH3:48])=[CH:23][CH:24]=3)[CH:11]([CH2:10][CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[O:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:12]2=[O:13])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Oc1ccc(C(Nc2ccc(F)cc2)C(CCC(O[Si](C)(C)C)c2ccc(F)cc2)C(=O)N2C(=O)OCC2c2ccccc2)cc1
Agent: O=[Ag-]
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CCOCC
Product: C[Si](C)(C)Oc1ccc(C2C(CCC(O[Si](C)(C)C)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
3-{5-(4-Fluorophenyl)-2-[(4-fluorophenylamino)-(4-trimethylsilanyloxy-phenyl)methyl]-5-trimethylsilanyloxypentanoyl}-4-phenyloxazolidin-2-one (10 mg) is suspended in MTB ether (1 ml) under argon while cooling in ice. N,O-Bistrimethylsilylacteamide (20.75 μl) is added, followed by tetrabutylphosphonium chloride (4.2 mg) and silver(I) oxide (3.2 mg). The mixture is stirred at room temperature. A reaction to give 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-trimethylsilanyloxypropyl]-4-(4-trimethylsilanyloxyphenyl)azetidin-2-one is found by means of thin-layer chromatography and LC/MS comparison (M+H,-TMS,-HOTMS: 392).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH2:4][CH2:5][CH3:6].C1C=CC2N(O)N=[N:23]C=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH3:42][CH2:43][C@@:44]1([OH:97])[CH2:55][N:53]2[CH2:54][C@@H:46]([CH2:47][C@:48]([C:93]([O:95][CH3:96])=[O:94])([C:63]3[CH:68]=[C:67]4[C:69]56[C@@H:80]([N:81]([CH3:82])[C:66]4=[CH:65][C:64]=3[O:91][CH3:92])[C@@:79]([OH:87])([C:83]([O:85][CH3:86])=[O:84])[C@H:78]([OH:88])[C@:74]3([CH2:89][CH3:90])[CH:75]=[CH:76][CH2:77][N:72]([C@H:73]53)[CH2:71][CH2:70]6)[C:49]3[NH:62][C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[C:50]=3[CH2:51][CH2:52]2)[CH2:45]1.[NH2:98][CH2:99][CH2:100][CH2:101][NH-:102].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:42][CH2:43][C@@:44]1([OH:97])[CH2:55][N:53]2[CH2:54][C@@H:46]([CH2:47][C@:48]([C:93]([O:95][CH3:96])=[O:94])([C:63]3[CH:68]=[C:67]4[C:69]56[C@@H:80]([N:81]([CH3:82])[C:66]4=[CH:65][C:64]=3[O:91][CH3:92])[C@@:79]([OH:87])([C:83]([O:85][CH3:86])=[O:84])[C@H:78]([OH:88])[C@:74]3([CH2:89][CH3:90])[CH:75]=[CH:76][CH2:77][N:72]([C@H:73]53)[CH2:71][CH2:70]6)[C:49]3[NH:62][C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[C:50]=3[CH2:51][CH2:52]2)[CH2:45]1.[NH2:98][CH2:99][CH2:100][CH2:101][NH-:102].[NH2:1][C@H:2]([C:7]([NH2:23])=[O:9])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC[C@]1(O)C[C@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@@H]3C45CCN4CC=C[C@](CC)([C@H]45)[C@@H](O)[C@]3(O)C(=O)OC)C2)C1
Agent: [NH-]CCCN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC[C@H](N)C(N)=O
Reaction time: 0.5 h

Procedure:
To a DMF solution (1 ml) of Boc-Nle (22 mg, 0.095 mmol) was added 318 μl of a 1M solution of HOBT (in NMP) followed by 280 μl of a 1M solution of DCC (in NMP). After 30 min., intermediate (11) (0.0624 mmol) was added in a 3.5 ml DMF. The pH of the reaction was adjusted ~7.5 with diisopropylethylamine. After stirring for 18 hrs the reaction was concentrated to an oil and the Boc protecting group removed by treating the oil with a 1:1 solution of TFA: CH2Cl2 (20 ml). After 5 min. the reaction was concentrated to dryness. Purification was achieved by preparative HPLC on a C-18 reverse phase support (Waters, Delta Pak). Buffer A=0.1% TFA-H2O; B=0.1% TFA-CH3CN. The crude product was loaded in 100% A buffer (100 ml) and a step gradient of 100% A to 30% A was used at a flow rate of 75 ml/min. Homogeneous product fractions were pooled and freeze-dried to yield (12).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[C:4]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[CH3:17][S:18](=S)(OC)=O.C(N(SC)C(C1SC=CC=1[Si](C)(C)C)=O)C>>[Cl:1][C:2]1[S:6][C:5]([C:7]([N:9]([S:18][CH3:17])[CH2:10][CH:11]=[CH2:12])=[O:8])=[C:4]([Si:13]([CH3:14])([CH3:16])[CH3:15])[CH:3]=1
Reactant: C=CCNC(=O)c1sc(Cl)cc1[Si](C)(C)C
Reactant: COS(C)(=O)=S
Agent: CCN(SC)C(=O)c1sccc1[Si](C)(C)C
Product: C=CCN(SC)C(=O)c1sc(Cl)cc1[Si](C)(C)C

Procedure:
The compound of Example 262 (1.1 g) was reacted with 0.52 g of methyl methanethiosulfonate using procedure described for the preparation of the compound of Example 272. The title compound (0.6 g) was purified by flash chromatography with 2% ethyl acetate-hexane and recovered as a colorless oil nD25 1.5698.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[NH2:8][C:6]1[N:7]=[C:2]([N:12]2[CH2:13][CH2:14][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:11]2)[CH:3]=[CH:4][CH:5]=1
Reactant: Nc1cccc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(N)n2)CC1
Temperature: 140 °C
Yield: 27.6 %

Procedure:
A mixture of 6-chloropyridin-2-amine (10 g, 78 mmol) and tert-butyl piperazine-1-carboxylate (29 g, 156 mmol) was refluxed at 140° C. for 3 days. The reaction mixture was purified by silica gel column chromatography (elute: petroleum ether/ethyl acetate=2:1) to give tert-butyl 4-(6-aminopyridin-2-yl)piperazine-1-carboxylate (6 g, 28%). LCMS (M+H) m/z: calcd 278.17. found 279.
Reaction SMILES: C(C1NC=CC=1)(OC(C)(C)C)=O.[C:13]([O:17][C:18]([NH:20][C:21]1[CH:22]=[C:23]([C:27]([NH:29][C:30]2[CH:31]=[C:32]([C:36]([O:38]C)=[O:37])[N:33]([CH3:35])[CH:34]=2)=[O:28])[N:24]([CH3:26])[CH:25]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[OH-].[Na+]>CO>[C:13]([O:17][C:18]([NH:20][C:21]1[CH:22]=[C:23]([C:27]([NH:29][C:30]2[CH:31]=[C:32]([C:36]([OH:38])=[O:37])[N:33]([CH3:35])[CH:34]=2)=[O:28])[N:24]([CH3:26])[CH:25]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)c1cc(NC(=O)c2cc(NC(=O)OC(C)(C)C)cn2C)cn1C
Agent: CC(C)(C)OC(=O)c1ccc[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(NC(=O)c2cc(NC(=O)OC(C)(C)C)cn2C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.6 %

Procedure:
A stirred solution of Boc pyrrole dimer (3) (0.805 g, 2.1 mmol) in MeOH (40 mL) was treated with 1M NaOH solution (25 mL). The reaction mixture was stirred at room temperature for 18 hours. The volume was reduced in vacuo and the aqueous solution extracted with EtOAc (50 mL). The solvent was removed from the EtOAc fraction and the residue was treated with 1M NaOH solution (10 mL) for a further 3 hours. This was combined with the previous aqueous fraction and acidified to pH2-3 with 1M HCl solution and the suspension extracted with EtOAc (3×75 mL). The organic fractions were combined, dried over MgSO4 and concentrated in vacuo to give a yellow foam 0.781 g (100%). 1H NMR d6-DMSO δ 12.07 (1H, bs, OH), 9.81 (1H, s, N—H), 9.08 (1H, s, N—H), 7.40 (1H, d, J=1.9 Hz, Py-H), 6.88 (1H, s, Py-H), 6.84 (1H, s, Py-H), 6.83 (1H, s, Py-H), 3.81 (3H, s, N—CH3), 3.80 (3H, s, N—CH3), 1.45 (9H, s, Boc-H); 13C NMR d6-DMSO δ 171.9, 161.9, 158.3, 152.8, 122.6, 122.3, 120.2 (CH), 119.4, 117.0 (CH), 108.3 (CH), 103.7 (CH), 78.3, 36.1 (CH3), 36.1 (CH3), 28.1 ([CH3]3).
Reaction SMILES: [I-:1].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N+](C)(C)C)=[N:3]1.[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OCC)C>CN(C=O)C>[I-:1].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][P+:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:3]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C[N+](C)(C)Cc1n[nH]c2ccccc12
Agent: [I-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
(1H-indazol-3-ylmethyl)trimethylammonium iodide (45.0 g, 142 mmol) obtained in Step 3 was dissolved in DMF (220 mL), and the solution was mixed with triphenylphosphine (44.7 g, 170 mmol), followed by heating under reflux for 2.5 hours. After cooling to room temperature, the reaction mixture was added with diethyl ether and was stirred overnight. The resulting precipitates were collected by filtration to obtain (1H-indazol-3-ylmethyl)triphenylphosphonium iodide (68.3 g, 92%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1>CO.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1ccc([N+](=O)[O-])c(N)n1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(N)c(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 111.7 %

Procedure:
2-Amino-6-methyl-3-nitropyridine (754 mg, 4.92 mmol) was suspended in MeOH, and 10% Pd/C was added. The mixture was stirred briskly at RT under H2 (balloon). After 4 h, the reaction was filtered through Celite®, and the filtrate was concentrated under vacuum to afford the title compound (677 mg, quantitative): 1H NMR (250 MHz, CD3OD) δ 6.82 (d, 1H), 6.36 (d, 1H), 2.25 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[C:23]12([C:33](O)=[O:34])[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[CH2:24]1)[CH2:30]2.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:33]([C:23]23[CH2:32][CH:27]4[CH2:26][CH:25]([CH2:31][CH:29]([CH2:28]4)[CH2:30]2)[CH2:24]3)=[O:34])=[CH:20][CH:21]=1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)C45CC6CC(CC(C6)C4)C5)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 16.5 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) and commercially available adamantanecarboxylic acid (110 mg) were dissolved in N,N-dimethylformamide (2 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (107 mg) was added, and the admixture was stirred at room temperature for 15 hours. The reaction mixture was purified in the same manner as described in Example 51 to obtain 13 mg of the title compound (yield: 17%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[CH2:26]([O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([NH:36]N)[CH:31]=1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([N:36]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:31]=1)[CH3:27]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: CCOC(=O)c1ccnc(NN)c1
Product: CCOC(=O)c1ccnc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 2-hydrazino-isonicotinic acid ethyl ester (described in Anales Real Soc. Espan. Fis. Quire. (Madrid) Ser. B (1963), 59(3), 179-84) according to example 43 gave the desired product. MS: M=454.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:17])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[C:18]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:17])[CH2:9][CH:10]([CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]([O:26][CH2:27][CH3:28])=[O:25])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(C=Cc1ccccc1)c1cccc(Cl)c1
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1cccc(Cl)c1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(3-chlorophenyl)-3-phenylprop-2-en-1-one and diethyl malonate, diethyl 2-[3-(3-chlorophenyl)-3-oxo-1-phenylpropyl]malonate was obtained as colourless solid.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:7])[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:41][C:42]([C:44]([F:47])([F:46])[F:45])=[O:43].[F:48][CH:49]([F:78])[CH2:50][NH:51][C:52]1[N:53]=[C:54]2[CH2:76][CH:75]([CH3:77])[NH:74][CH2:73][C:55]2=[N:56][C:57]=1[N:58]1[CH2:63][CH2:62][CH:61]([O:64][C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][C:66]=2[F:72])[CH2:60][CH2:59]1>CN(C=O)C>[F:78][CH:49]([F:48])[CH2:50][NH:51][C:52]1[N:53]=[C:54]2[CH2:76][CH:75]([CH3:77])[N:74]([C:4](=[O:6])[C@H:3]([O:2][CH3:1])[CH3:7])[CH2:73][C:55]2=[N:56][C:57]=1[N:58]1[CH2:59][CH2:60][CH:61]([O:64][C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][C:66]=2[F:72])[CH2:62][CH2:63]1.[C:42]([OH:43])([C:44]([F:47])([F:46])[F:45])=[O:41]
Reactant: CO[C@H](C)C(=O)O
Reactant: CC1Cc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CO[C@H](C)C(=O)N1Cc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc2CC1C
Reaction time: 2 h

Procedure:
A solution of (R)-2-methoxypropanoic acid (1.9 mg, 0.018 mmol), DIPEA (7.0 mg, 0.054 mmol), and HATU (6.9 mg, 0.018 mmol) in DMF (90 μL) was stirred for 10 min at room temperature then treated with N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (10 mg, 0.018 mmol). The resulting reaction mixture was stirred for 2 h. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (5 mg) as a white solid. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) 6 ppm 1.17 (t, J=6.6 Hz, 1.4H), 1.27 (dd, J=6.7, 2.7 Hz, 1.6H), 1.33 (dd, J=11.6, 6.8 Hz, 1.4H), 1.38 (dd, J=6.7, 2.7 Hz, 1.6H), 1.92-2.03 (m, 2H), 2.09-2.18 (m, 2H), 2.53-2.68 (m, 1H), 2.94-3.05 (m, 2H), 3.08-3.10 (m, 0.5H), 3.12-3.14 (m, 0.5H), 3.35 (s, 3H), 3.37-3.42 (m, 2H), 3.78 (td, J=14.5, 4.2 Hz, 2H), 4.03 (t, J=18.8 Hz, 1H), 4.30-4.41 (m, 1H), 4.43-4.51 (m, 1H), 4.70-4.82 (m, 1H), 5.03-5.14 (m, 0.5H), 5.18-5.23 (m, 0.5H), 5.90-6.22 (m, 1H), 6.85-6.91 (m, 1H), 6.99 (ddd, J=11.3, 8.5, 2.9 Hz, 1H), 7.18 (td, J=9.2, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 525.9.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].O>C(Cl)Cl>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(C)c1ccc(OCOC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Ethyl 2-(4-(methoxymethoxy)phenyl)propanoate (485 mg, 2.04 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (5 mL) at 0° C. The mixture was stirred for 40 minutes at 0° C. and then slowly added solid sodium bicarbonate (7.14 g) and water (100 mL) at 0° C. The mixture was extracted with methylene chloride. The organic layer was dried with MgSO4. The organic layer was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with n-Hexane/EtOAc=4/1.