Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][NH:18][C:19]([CH3:21])([CH3:20])[C:12]2=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:19]([CH3:21])([CH3:20])[C:12]2=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1(C)NCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCn2c(nc(C(=O)NCc3ccc(F)cc3)c(OCc3ccccc3)c2=O)C1(C)C
Temperature: 45 °C

Procedure:
A mixture of 3-(benzyloxy)-N-(4-fluorobenzyl)-9,9-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrazino[1,2-a]pyrimidine-2-carboxamide (prepared as described in Example 3, Step 1) (1 eq.), K2CO3 (2 eq.) and tert-butyl bromoacetate (3 eq.) in DMF was heated for 24 hours at 45° C. and then cooled to room temperature. Solvent was removed under reduced pressure and the residue was taken up in EtOAc and washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to yield the ester. MS (ES) C30H35FN4O5 requires 550. Found: 551 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH:19]=1)[CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].O[CH2:22][C:23]1[O:27][N:26]=[C:25]([CH3:28])[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:22][C:23]2[O:27][N:26]=[C:25]([CH3:28])[CH:24]=2)=[C:6]([CH:19]=1)[CH2:7][N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17]
Reactant: Cc1cc(CO)on1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(Cl)ccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(Cl)cc2CN2C(=O)c3ccccc3C2=O)on1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.2 %

Procedure:
To a mixture of 2-[5-chloro-2-hydroxy benzyl]isoindole-1,3-dione (800 mg, 2.78 mmol), 5-hydroxymethyl-3-methyl-isoxazole (373 mg, 3.3 mmol), and triphenylphosphine (1.0 g, 4.2 mmol) in anhydrous THF (10 mL) was added diethylazodicarboxylate (0.657 mL, 4.7 mmol). The solution was stirred for 15 h at room temperature under anhydrous conditions. The solvent was then removed by rotary evaporation and the product was preadsorbed onto silica gel and purified by flash chromatography to afford the title compound (555 mg, 52%).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[N:10][C:9]=1[NH:20][NH2:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OCC)(=O)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:1]([C:8]1[C:9]2[N:10]([C:22]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:21][N:20]=2)[N:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: NNc1nnc(-c2ccccc2)cc1Cc1ccccc1
Product: CCOC(=O)Cc1nnc2c(Cc3ccccc3)cc(-c3ccccc3)nn12

Procedure:
In a manner analogous to that described in Example 1, by the ring condensation of 4-benzyl-3-hydrazino-6-phenyl-pyridazine [Indian J. Chem., 15B, 352 (1977)] with diethyl malonate there is obtained ethyl 8-benzyl-6-phenyl-s-triazolo[4,3-b]pyridazine-3-acetate, MS: 372 (M)+, which is saponified with a base to the above acid, MS: 316 (M-CO)+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:22][S:19]([C:5]1[CH:4]=[CH:3][C:2]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:7][C:6]=1[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)(=[O:21])=[O:20]
Reactant: C1CNCCN1
Reactant: CS(=O)(=O)c1ccc(F)cc1Nc1cccc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(N2CCNCC2)cc1Nc1cccc2ccccc12
Yield: 18.5 %

Procedure:
N-(5-Fluoro-2-(methylsulfonyl)phenyl)naphthalen-1-amine (0.56 g, 1.7 mmol), piperazine (0.46 g, 5.3 mmol), N,N-diisopropylethylamine (0.89 g, 6.8 mmol) were stirred at 80° C. in dry acetonitrile (5 mL) for 48 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 10% methanol in dichloromethane to afford the title compound (120 mg, 18% yield). 1H NMR (400 MHz, CDCl3): δ 8.10 (s, 1H), 7.89 (d, 1H), 7.83 (d, 1H), 7.66 (d, 1H), 7.62 (m, 1H), 7.39 (m, 4H), 6.35 (d, 1H), 6.26 (s, 1H), 3.09 (s, 3H), 2.98 (m, 4H), 2.79 (m, 4H); MS (ESI) m/z: Calculated for C21H24N3O2S: 382.2; Observed: 382.4 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]#[N:11].[S:12]([OH:16])(=[O:15])(=[O:14])[CH3:13].[CH2:17]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])[CH3:18]>ClC1C=CC=CC=1>[S:12]([OH:16])(=[O:15])(=[O:14])[CH3:13].[CH2:17]([C:19]1[CH:20]=[C:21]([NH:22][C:10]([NH:9][C:3]2[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[Cl:1])=[NH:11])[CH:23]=[CH:24][CH:25]=1)[CH3:18]
Reactant: CCc1cccc(N)c1
Reactant: N#CNc1cc(Cl)ccc1Cl
Agent: CS(=O)(=O)O
Solvent: Clc1ccccc1
Product: CCc1cccc(NC(=N)Nc2cc(Cl)ccc2Cl)c1

Procedure:
A mixture of 2,5-dichlorophenylcyanamide (1.02 g, 5.5 mmol), 3-ethylaniline mesylate (1.1 g, 5 mmol), and chlorobenzene (15 mL) were combined in a dry round bottom flask equipped with a water cooled condenser under nitrogen and placed in a preheated oil bath (150-160° C.). The reaction mixture was heated for 2 hours. After cooling, the crude reaction product was purified by crystallization from chlorobenzene/diethylether. The resulting crystals were collected by filtration, washed with diethylether, and dried in a vacuum oven (40° C., 15 hours) to yield the title compound, N-(3-ethylphenyl)-N'-(2,5-dichlorophenyl)guanidine mesylate, as a white solid (1.5 g, 75% yield).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH3:8][C:9]1[C:17]([OH:18])=[CH:16][C:15]([CH3:19])=[C:14]2[C:10]=1[CH2:11][CH2:12][NH:13]2>C(O)=O>[OH:18][C:17]1[C:9]([CH3:8])=[C:10]2[C:14](=[C:15]([CH3:19])[CH:16]=1)[N:13]([CH:1]=[O:3])[CH2:12][CH2:11]2
Reactant: Cc1cc(O)c(C)c2c1NCC2
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: Cc1cc(O)c(C)c2c1N(C=O)CC2
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
Acetic anhydride (25 ml, 264 mmol) was added at room temperature to formic acid (75 ml) and stirred for 30 minutes. To the solution, 2,3-dihydro-4,7-dimethyl-1H-indol-5-ol (14.4 g, 88 mmol) was added and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a chloroform methanol solution and washed: with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was washed with saturated brine and dried over sodium sulfate, and then the solvent was removed under reduced pressure. The resultant residue was washed with diisopropyl ether to obtain 6.2 g of the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](Cl)=[O:7])(=[O:3])[CH3:2].[C:9]1([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)=[CH:18][C:17]([CH2:30][CH2:31][NH2:32])=[C:16]2[CH3:33])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]([NH:32][CH2:31][CH2:30][C:17]1[CH:18]=[C:19]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=2)[N:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:16]=1[CH3:33])=[O:7])(=[O:3])[CH3:2]
Reactant: Cc1c(CCN)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccccc1
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCC(=O)NCCc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TEA (0.29 g, 0.296 mmol) and acetoxyacetyl chloride (0.323 g, 0.00237 mol) are added, at 0° C., to a solution of 2-[1-phenyl-2-methyl-5-(4-methylsulphonylphenyl)-1H-pyrrol-3-yl]-ethanamine (W2008014821), (0.7 g, 0.00197 mol), in CH2Cl2 (10 mL). It is stirred at RT for 2 h. Then it is poured into water and extracted with CH2Cl2, washed with NaHCO3 s.s., and then with H2O, dried and concentrated. The solid obtained (0.85 g, 95.5%) is used as it is for the next step.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:23][O:24][C:25](=[O:45])[CH:26]([NH2:44])[CH2:27][CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]([CH3:43])[C:37]2[N:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[CH:32][CH:31]=1.[Cl:46][C:47]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:48]=1[C:49](O)=[O:50].Cl>ClCCl>[CH3:23][O:24][C:25](=[O:45])[CH:26]([NH:44][C:49](=[O:50])[C:48]1[C:52]([F:56])=[CH:53][CH:54]=[CH:55][C:47]=1[Cl:46])[CH2:27]/[CH:28]=[CH:29]/[C:30]1[CH:31]=[CH:32][C:33]([N:36]([CH3:43])[C:37]2[N:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[CH:34][CH:35]=1
Reactant: COC(=O)C(N)CC=Cc1ccc(N(C)c2ncccn2)cc1
Reactant: O=C(O)c1c(F)cccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)C(C/C=C/c1ccc(N(C)c2ncccn2)cc1)NC(=O)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 28 h

Procedure:
Under an argon atmosphere, EDC hydrochloride (39 mg) and HOBT (3 mg) were added to a solution of 2-amino-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (51 mg) and 2-chloro-6-fluorobenzoic acid in dichloromethane (1.5 ml), and the resulting mixture was stirred at room temperature for 28 hours. To the reaction solution, 1N hydrochloric acid was added, and the resulting mixture was extracted with ethyl acetate. Organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by thin layer chromatography (silica gel, developing solvent: hexane/ethyl acetate=1/2) to obtain (E)-2-(2-chloro-6-fluorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (39 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[CH:10]=1.[CH2:11]([CH:13]([C:16]1[C:17]2[N:18]([C:23](I)=[C:24]([CH3:26])[N:25]=2)[N:19]=[C:20]([CH3:22])[CH:21]=1)[CH2:14][CH3:15])[CH3:12]>>[CH2:11]([CH:13]([C:16]1[C:17]2[N:18]([C:23]([C:10]3[N:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]4=[N:3][C:2]=3[CH3:1])=[C:24]([CH3:26])[N:25]=2)[N:19]=[C:20]([CH3:22])[CH:21]=1)[CH2:14][CH3:15])[CH3:12]
Reactant: Cc1cn2ccccc2n1
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4ccccn34)c(C)nc12
Yield: 20.5 %

Procedure:
Using a procedure analogous to Example 16B, 2-methyl-imidazo[1,2-a]pyridine (Chem. Ber. 1926; 59, 2054), (0.38 g, 2.92 mmol) and 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (1.00 g, 2.92 mmol) give the title compound (0.21 g, 0.60 mmol, 21%). 1H NMR (CDCl3): δ 0.91 (t, J=7.5 Hz, 3H), 0.92 (t, J=7.5 Hz, 3H), 1.80-1.95 (m, 4H), 2.42 (s, 3H), 2.43 (s, 3H), 2.45 (s, 3H), 3.34-3.42 (m, 1H), 6.73 (s, 1H), 6.74 (dt, J=6.6, 0.9 Hz, 1H), 7.21-7.25 (m, 1H), 7.52 (d, J=6.6 Hz, 1H), 7.64 (d, J=6.6 Hz, 1H) ppm. ES-MS (m/z): calcd for C21H25N5 (M+H)+: 348.5. found: 348.2.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([C:33]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH2:44][CH3:45])[CH:36]=2)=O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH3:23].O>C1COCC1>[CH2:44]([O:43][C:37]1[CH:36]=[C:35]([C:33]([C:27]2[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:25]([O:24][CH2:22][CH3:23])[CH:26]=2)=[CH:9][C:10]#[N:11])[CH:40]=[CH:39][C:38]=1[O:41][CH3:42])[CH3:45]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCOc1cc(C(=O)c2ccc(OC)c(OCC)c2)ccc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C(=CC#N)c2ccc(OC)c(OCC)c2)ccc1OC
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of cyanomethylphosphonic acid diethyl ester (7.0 mL, 44.4 mmol) in anhydrous THF (20 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 44.4 mL, 44.4 mmol) at 0° C. and stirred for 30 min followed by addition of bis-(3-ethoxy-4-methoxy-phenyl)-methanone (7.34 g, 22.2 mmol) and refluxed for 3 h. The reaction mixture was poured into water (100 mL), extracted with CH2Cl2 (2×100 mL). The combined organic phases were washed with brine (100 mL), dried over MgSO4, and purified via flash column chromatography (EtOAc/Hexane) to give 3,3-bis-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile as a white solid (3.92 g, 50% yield): 1H NMR (DMSO-d6) δ 1.31 (t, J=7 Hz, 6H, 2CH2CH3), 3.79 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.94-4.04 (two q, J=7 Hz, 4H, 2CH2CH3), 6.11 (s, 1H, CH), 6.77-7.09 (m, 6H, Ar); 13C NMR (DMSO-d6) δ 14.6, 14.6, 55.5, 55.5, 63.8, 92.6, 111.3, 111.5, 112.3, 113.8, 118.9, 122.3, 122.4, 129.3, 130.6, 147.3, 147.8, 150.1, 151.0, 161.4; Anal. Calcd for C21H23NO4: C, 71.37; H, 6.56; N, 3.96. Found: C, 71.42; H, 6.42; N, 3.97.
Reaction SMILES: [Na].[CH3:2][OH:3].Cl[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8]>O>[CH3:2][O:3][C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: CO
Reactant: N#Cc1cccnc1Cl
Agent: [Na]
Solvent: O
Product: COc1ncccc1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
4.98 g (217 mmol) of sodium is added to 80 ml of anhydrous methanol. The reaction medium is stirred at room temperature for 10 minutes and then 10 g (72.2 mmol) of 2-chloronicotinonitrile is added at 0° C. The reaction medium is stirred at 25° C. for 16 hours. The reaction is hydrolyzed by slowly adding water at 0° C. After returning to room temperature, the precipitate obtained is filtered, rinsed with water and then dried at 50° C. to yield 7.85 g (81%) of 2-methoxy-nicotinonitrile in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:28][CH2:27][CH2:26][N:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: CN1CCN(CCN)CC1
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Product: COc1ccc2nc3cc(Cl)ccc3c(NCCN3CCN(C)CC3)c2c1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-2-methoxyacridine and 2-(4-methylpiperazin-1-yl)ethanamine, the title compound was obtained; MS (Found M+1=385).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:20][CH2:19]2)[CH2:11]3)=[CH:4][N:3]=1.Cl[CH:22]([C:25]1([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[N:34]=[CH:33][CH:32]=[CH:31]3)[CH2:27][CH2:26]1)[CH:23]=O>C(O)(C)C>[CH:18]1([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([C:5]4[CH:4]=[N:3][C:2]5[N:7]([C:22]([C:25]6([C:28]7[CH:29]=[C:30]8[C:35](=[CH:36][CH:37]=7)[N:34]=[CH:33][CH:32]=[CH:31]8)[CH2:27][CH2:26]6)=[CH:23][N:1]=5)[CH:6]=4)[CH:9]=3)[C:13]2=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1ncc(-c2ccc3c(c2)CN(C2CC2)C3=O)cn1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Solvent: CC(C)O
Product: O=C1c2ccc(-c3cnc4ncc(C5(c6ccc7ncccc7c6)CC5)n4c3)cc2CN1C1CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(2-aminopyrimidin-5-yl)-2-cyclopropylisoindolin-1-one (20 mg, 0.075 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (18 mg, 0.075 mmol) in isopropyl alcohol (0.5 mL) was stirred at 90° C. overnight. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=458.1.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:10]([F:11])=[CH:9][C:8]([Br:12])=[CH:7][C:6]=1[F:13])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[Br:12][C:8]1[CH:7]=[C:6]([F:13])[C:5]([CH2:4][NH2:1])=[C:10]([F:11])[CH:9]=1
Reactant: [N-]=[N+]=NCc1c(F)cc(Br)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1c(F)cc(Br)cc1F
Temperature: 55 °C

Procedure:
To a mixture of the crude azide (330 mg, 1.33 mmol) in THF (12 mL) were added polymer-supported Ph3P (2.0 eq.) and water (2 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was extracted with EA and the combined org. extracts dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a yellow solid. LC-MS-conditions 02: tR=0.54 min; [M+CH3CN+H]+=263.45.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24](NC(=O)/C(/C4N=C(NC(OC(C)(C)C)=O)SC=4)=N\OC(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:64][S:65][C:66]2[N:67]=[N:68][NH:69][CH:70]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1.[N+](C)([O-])=O>[NH:69]1[CH:70]=[C:66]([S:65][CH2:64][C:18]2[CH2:19][S:20][C@@H:21]3[CH2:24][C:23](=[O:63])[N:22]3[C:17]=2[C:15]([OH:14])=[S:16])[N:67]=[N:68]1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=S)OC(c4ccccc4)c4ccccc4)=C(CSc4c[nH]nn4)CS[C@H]23)cs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Product: O=C1C[C@H]2SCC(CSc3c[nH]nn3)=C(C(O)=S)N12
Reaction time: 1 h
Yield: 148.1 %

Procedure:
To a suspension of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol -4- yl)-2-trityloxyiminoacetamido]-3-(1,2,3-triazol-4-yl) thiomethylthio-3- cephem-4-carboxylic acid diphenylmethyl ester (9.2 g: 9 mMol.) in a mixture of anisole (18 ml) and nitromethane (72 ml) is added dropwise a solution of aluminum chloride (9.6 g: 72 mMol.) in anisole (31 ml) at -30° C. After stirring for 1 hour at the same temperature, the reaction mixture is quenched with ethanol (25 ml), stirred for several minutes, diluted with 1N-hydrochloric acid (75 ml) and water (500 ml), and washed with ethyl acetate. The aqueous layer was separated, concentrated to remove the organic solvents, and passed through a column of styrene- divinylbenzene copolymer adsorbent. The product is eluted with a mixture of methanol and water (4:1) to give 7β-(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1,2,3-triazol-4-yl)thiomethylthio -3-cephem-4-carboxylic acid as pale yellow powder (4.19 g). Yield: 90%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.Cl.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:27])[CH2:22][CH2:21]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(O)C>C(N(CC)CC)C>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([N:28]3[CH2:29][CH2:30][N:31]([C:6]4[N:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)[CH2:32][CH2:33]3)=[O:27])[CH2:22][CH2:21]2)(=[O:18])=[O:19])=[CH:15][CH:16]=1
Reactant: O=C(N1CCNCC1)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reactant: Cc1cc(Cl)ncn1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCN(C(=O)N3CCN(S(=O)(=O)c4ccc(Br)cc4)CC3)CC2)ncn1
Yield: 45.7 %

Procedure:
4-Methyl-6-chloropyrimidine (0.51 g) was added to a stirred mixture of 1-(4-bromophenylsulphonyl)-4-(1-piperazinylcarbonyl)piperazine hydrochloride (1.50 g) and ethanol (35 ml). Triethylamine (2.2 ml) was added and the mixture was heated at reflux for 6 hours. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel using a gradient of 0% to 10% methanol in dichloromethane as eluent to give a foam. This was crystallised from methyl tert-butyl ether to give 1-(4-bromophenylsulphonyl)-4-[1-(4-methylpyrimidin-6-yl)piperazin-4-ylcarbonyl]piperazine as a solid (0.77 g); m.p. 215-216° C.; NMR (CDCl3): 8.5 (s, 1H), 7.7 (m, 2H), 7.6 (m, 2H), 6.35 (s, 1H), 3.6 (m, 4H), 3.4 (m, 4H), 3.3 (m, 4H), 3.05 (m, 4H), 2.33 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[Br:11][C:12]1[CH:13]=[CH:14][C:15]([OH:21])=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:2][C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[C:5]#[N:6])=[C:16]([CH:20]=1)[C:17]([O:19][CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])=[O:18]
Reactant: N#Cc1ccccc1CBr
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccccc1COC(=O)c1cc(Br)ccc1OCc1ccccc1C#N
Temperature: 55 °C
Reaction time: 16 h

Procedure:
2-(Bromomethyl)benzonitrile (397 mg, 2.027 mmol) was added in one charge to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (200 mg, 0.92 mmol) and potassium carbonate (255 mg, 1.84 mmol) in acetone (40 ml) under nitrogen at 20° C. The reaction mixture was stirred at 55° C. for 16 h. The organic phase was evaporated and the residue was washed with water (25 ml), extracted with ethyl acetate (100 ml) and evaporated in vacuo to yield the title compound as an off-white solid. 350 mg.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:27][C@@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33](=[O:37])[CH2:34][C:35]#[N:36])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][C:12]=3[F:26])[C:3]=12.[CH:38]1([CH:41]=O)[CH2:40][CH2:39]1.N1CCCCC1>CCO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:27][C@@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33]([C:34](=[CH:41][CH:38]3[CH2:40][CH2:39]3)[C:35]#[N:36])=[O:37])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][C:12]=3[F:26])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Reactant: O=CC1CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Reaction time: 0.33 h
Yield: 26.8 %

Procedure:
A solution of 3-((S)-2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (304.2 mg, 0.60 mmol, 1.00 equiv), cyclopropanecarbaldehyde (210 mg, 3 mmol, 5 equiv), piperidine (102 mg, 1.20 mmol, 2 equiv) in EtOH (20 mL) was stirred overnight at rt. The resulting mixture was concentrated under vacuum. Then concentrated and purified on Prep-HPLC. Conditions: (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm. This resulted in 90 mg (22.3%) of the title compound as a white solid. MS (ESI, pos. ion) m/z: 560 (M−TFA+1) H-NMR (400 MHz, CDCl3, ppm): 11.94 (brs, 1H), 8.27 (s, 1H), 7.62-7.58 (m, 1H), 7.19-7.13 (m, 2H), 7.04-6.98 (m, 2H), 6.91 (d, J=111.2 Hz, 1H), 6.81 (d, J=11.2 Hz, 1H), 6.01 (brs, 1H), 4.96-4.86 (m, 1H), 4.76-4.62 (m, 2H), 3.71-3.62 (m, 1H), 3.61-3.45 (m, 1H), 2.12-1.82 (m, 5H), 1.30-1.28 (m, 2H), 0.94-0.89 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[CH:9]1([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12][CH2:11][CH2:10]1>CN(C=O)C>[CH:9]1([N:14]2[CH2:15][CH2:16][N:17]([C:2]3[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=3)[CH2:18][CH2:19]2)[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: C1CCC(N2CCNCC2)C1
Reactant: Nc1ccnc(Cl)n1
Solvent: CN(C)C=O
Product: Nc1ccnc(N2CCN(C3CCCC3)CC2)n1
Temperature: 70 °C
Yield: 51 %

Procedure:
A mixture of 0.5 g (3.86 mmol) 2-chloro-4-pyrimidinylamine (commercially available) and 1-cyclopentyl-piperazine (commercially available) in 1 mL DMF was heated to 70° C. for 16 h. The residue after filtration washed with diethyl ether and dried to yield 0.49 g (51%) of the title compound (intermediate 1) as white solid. MS (m/e): 284.3 (MH+).
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>>[O:1]([CH2:8][C:9]([Cl:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COc1ccccc1
Product: O=C(Cl)COc1ccccc1

Procedure:
Phenoxyacetic acid shown by formula (26) is reacted with thionyl chloride by a conventional method to obtain phenoxyacetyl chloride shown by formula (27).