Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[C:20]([C:32]4[CH:33]=[C:34]([NH:38]C(=O)C5C(F)=CC=CC=5F)[CH:35]=[CH:36][CH:37]=4)=[N:21][N:22]4[CH:27]=[C:26](C(F)(F)F)[CH:25]=[CH:24][C:23]=34)[CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1.ClCCO[C:54]1[CH:55]=C(NC2N=C(C3C(C4C=C(NC(=O)C(F)(F)F)C=CC=4)=NN4C=CC=CC=34)C=CN=2)C=C[CH:59]=1.CNCC=C>>[NH2:38][C:34]1[CH:33]=[C:32]([C:20]2[C:19]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH2:55][CH:54]=[CH2:59])[CH:7]=4)[N:18]=3)=[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]3[N:21]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4cc(C(F)(F)F)ccc34)n2)c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCCl)c3)n2)c1)C(F)(F)F
Agent: C=CCNC
Product: C=CCN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)c1

Procedure:
The title compound was obtained by treating N-(3-{3-[2-({3-[(2-chloroethyl)oxy]phenyl}amino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)-2,2,2-trifluoroacetamide with N-methyl-2-propen-1-amine in a manner similar to Example 136 to give the product, ES-LCMS m/z 492 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:7]2[CH2:6][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([C:13](O)=[O:14])[CH2:4][C:3]1=2.CSC.B.CO>C1COCC1>[CH3:12][C:8]1([CH3:11])[CH2:9][CH2:10][C:2]([CH3:1])([CH3:21])[C:3]2[CH2:4][C:5]([CH2:13][OH:14])([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:6][C:7]1=2
Reactant: CCCCCC1(C(=O)O)CC2=C(C1)C(C)(C)CCC2(C)C
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCC1(CO)CC2=C(C1)C(C)(C)CCC2(C)C
Reaction time: 2 h
Yield: 87 %

Procedure:
3.5 g of 4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carboxylic acid were dissolved in 35 ml of THF and treated dropwise at room temperature with a solution of 1.4 ml of borane methylsulfide in 10 ml of THF. The reaction mixture was stirred for 2 hours, then treated dropwise with 13 ml of methanol and evaporated. The yellow, oily residue was purified with flash chromatography (silica gel, hexane/ethyl acetate=5:1) to yield 2.9 g of (4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-inden-2-yl)-methanol as colorless oil.
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].[NH2:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C@H:14]([C:16]2[N:20]([CH:21]3[CH2:23][CH2:22]3)[C:19]3[C:24]([C:28]([NH:30][CH3:31])=[O:29])=[CH:25][CH:26]=[CH:27][C:18]=3[N:17]=2)[CH3:15])[C:8]=1I.CNCCNC.CS(C)=O>CCOC(C)=O.[O-]S(C(F)(F)F)(=O)=O.[Cu+2].[O-]S(C(F)(F)F)(=O)=O>[NH2:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C@H:14]([C:16]2[N:20]([CH:21]3[CH2:23][CH2:22]3)[C:19]3[C:24]([C:28]([NH:30][CH3:31])=[O:29])=[CH:25][CH:26]=[CH:27][C:18]=3[N:17]=2)[CH3:15])[C:8]=1[S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CNC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3I)n(C3CC3)c12
Reactant: CS(=O)[O-]
Agent: [Cu+2]
Agent: CNCCNC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CNC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3S(C)(=O)=O)n(C3CC3)c12
Temperature: 110 °C
Reaction time: 18 h

Procedure:
To a mixture of copper(II) triflate (7.6 mg, 0.021 mmol), sodium methanesulfinate (25.7 mg, 0.251 mmol), (S)-2-(1-(6-amino-5-iodopyrimidin-4-ylamino)ethyl)-1-cyclopropyl-N-methyl-1H-benzo[d]imidazole-7-carboxamide (prepared in Example 21, 100 mg, 0.210 mmol) under N2, N,N′-dimethylethylenediamine (4.52 μL, 0.042 mmol) and DMSO (1 mL) were added. The mixture was placed in a 110° C. oil bath. After stirring for 18 h at 110° C., the mixture was cooled to rt, diluted with EtOAc, and filtered through a pad of silica gel. The filtrate was washed with water, brine, dried and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using 0 to 10% gradient of MeOH in DCM-EtOAc (1:1) 0.2% NH4OH as eluent to give 2-((1S)-1-((6-amino-5-(methylsulfonyl)-4-pyrimidinyl)amino)ethyl)-1-cyclopropyl-N-methyl-1H-benzimidazole-7-carboxamide: 1H NMR (400 MHz, CDCl3) 8.02-7.97 (m, 2H), 7.65 (d, J=8 Hz, 1H), 7.22 (d, J=8 Hz, 1H), 7.12 (dd, J=8, 8 Hz, 1H), 6.01-5.92 (m, 2H), 3.45-3.40 (m, 2H), 3.16 (s, 3H), 3.01 (d, J=4 Hz, 3H), 1.61 (d, J=4 Hz, 3H), 1.22-1.10 (m, 2H), 1.04-0.96 (m, 1H), 0.80-0.73 (m, 1H); LC-MS (ESI) m/z 430.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])([O-])=O>CN(C=O)C.[Pd]>[NH2:1][C:4]1[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1cccc(C(N)=O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(C(N)=O)c1N
Reaction time: 16 h
Yield: 78 %

Procedure:
A mixture of 2-nitro-isophthalamide (6 g, 0.028 mol) and Pd/C (0.6 g) in DMF (100 mL) was hydrogenated at RT under hydrogen bladder pressure for 16 h. The reaction mixture was filtered through celite bed, washed with DMF and filtrate was evaporated under vacuum to afford the title compound as a brown solid (yield 78%). LC-MS [178 (M−H)], 1H NMR (400 MHz, DMSO-d6): δ 7.97 (s, 2H), 7.84 (brs, 2H), 7.65 (d, J=7.76 Hz, 2H), 7.22 (brs, 2H), 6.49 (t, J=7.76 Hz, 1H).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>O1CCOCC1>[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:16][N:17]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
4N HCl in 1,4-dioxane (1 mL) was added to a mixture of 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (462 mg, 1.03 mmol) in 1,4-dioxane (10 mL) at ambient temperature. The mixture was stirred at ambient temperature overnight. The mixture was charged with additional 4N HCl in 1,4-dioxane (1 mL), and stirred at ambient temperature overnight. The mixture was then charged with TFA (2 mL), and stirred at ambient temperature for 4 h. The mixture was concentrated, diluted with water, basified with saturated NaHCO3, and extracted with EtOAc. The organics were dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by reverse-phase preparative HPLC using CH3CN:H2O gradient (5:95 to 75:25) with 0.05% TFA as a modifier to give 107 mg (23%) of 2-[4-(methylsulfonyl)phenyl]-5-[(4-piperidinylmethyl)oxy]pyridine trifluoroacetate as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.59-8.50 (m, 1H), 8.44 (d, 1H, J=2.9 Hz), 8.28 (d, 2H, J=8.6 Hz), 8.08 (d, 1H, J=8.8 Hz), 8.00 (d, 2H, J=8.6 Hz), 7.55 (dd, 1H, Ja=8.8 Hz, Jb=3.0 Hz), 4.04 (d, 2H, J=6.2 Hz), 3.40-3.25 (m, 2H), 3.25 (s, 3H), 3.00-2.86 (m, 2H), 2.16-2.06 (m, 1H), 2.05-1.90 (m, 2H), 1.56-1.40 (m, 2H); LRMS (ESI), m/z 347 (M+H).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)[C:8]2[N:13]=[N:12][N:11]([CH2:14]C)[C:9]=2[N:10]=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].ClCC1N(C)N=NN=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[N:35]=[N:34][N:33]([CH2:8][C:9]3[N:11]([CH3:14])[N:12]=[N:13][N:10]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Agent: Cn1nnnc1CCl
Product: Cn1nnnc1Cn1nnc2c(N3CC4(COC4)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-tetrazole and isolated as white solid. MS (m/e): 371.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[O:6][CH2:7][CH2:8][NH:9][C:10](=O)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1.O=P(Cl)(Cl)Cl.[BH4-].[Na+].O>CC#N.C(Cl)Cl.CO>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[O:18][CH3:19])[CH2:11][CH:10]1[C:23]2[CH:24]=[C:25]([O:26][CH3:27])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:6][CH2:7][CH2:8][NH:9]1
Reactant: COc1ccc(CC(=O)NCCOc2ccc(OC)c(OC)c2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1ccc(CC2NCCOc3cc(OC)c(OC)cc32)cc1OC
Temperature: 0 °C
Yield: 33.2 %

Procedure:
To a stirred solution of N-[2-(3,4-dimethoxy-phenoxy)-ethyl]-2-(3,4-dimethoxy-phenyl)-acetamide (3.6 g, 9.56 mmol) in dry CH3CN (20 ml), was added POCl3 (2.62 ml, 28.6 mmol). The resulting mixture was stirred at reflux for 3 h under nitrogen. After cooling, the reaction mixture was concentrated in vacuo and the residue was dissolved in MeOH (80 ml). The solution was cooled to 0° C. and NaBH4 (2.53 g, 67.0 mmol) was added portionwise. The resulting pale yellow suspension was stirred at RT for 16 h under nitrogen. The reaction mixture was poured into H2O and extracted three times with CH2Cl2. The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (CH2Cl2/MeOH: 9/1) gave the title product (1.14 g, 33%) as a viscous brown oil.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[C:1]1([C:7]#[C:8][CH2:9][CH2:10][CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCC#Cc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCCC#Cc1ccccc1
Reaction time: 2.5 h

Procedure:
A solution of 5-phenylpent-4-yn-1-ol (250 mg) in dry CH2Cl2 (2 ml) was added to a suspension of pyridinium chlorochromate (520 mg) in dry CH2Cl2 (3 ml). The mixture was stirred for 2.5 hours and diluted with ether, and the organic solution was decanted off. The oily residue was treated with ether (5×20 ml) and the extracts were washed successively with 5% NaHCO3, water and brine. After drying, the solvent was removed to yield 5-phenylpent-4-ynal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[C:4]([CH2:22]O)[CH:3]=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]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:8]1([CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:12][CH2:13]1)[O:21][CH2:22]2
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2CO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)OCc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
A solution of tert-butyl 4-(4-chloro-2-(hydroxymethyl)phenyl)-4-hydroxypiperidine-1-carboxylate (1.3 g, 3.80 mmol) and triphenylphosphine (1.496 g, 5.70 mmol) in THF (20 mL) was treated with DEAD (0.903 mL, 5.70 mmol), and the mixture was stirred overnight at room temperature. The mixture was concentrated in-vacuo, and the residue was purified over silica gel, eluting with ethyl acetate/hexanes (5%-25% ethyl acetate), to yield the title compound (1.19 g, 3.67 mmol, 97% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:42])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([O:29][CH2:30][C:31]([O:33]CC3C=CC=CC=3)=[O:32])[C:26]3[C:21](=[CH:22][C:23]([CH3:41])=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]>C(O)C.CN(C=O)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:42])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([O:29][CH2:30][C:31]([OH:33])=[O:32])[C:26]3[C:21](=[CH:22][C:23]([CH3:41])=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)OCc3ccccc3)c3ccc(C)cc3n2)CC1
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)O)c3ccc(C)cc3n2)CC1
Reaction time: 4 h

Procedure:
To a solution of 5 g 4-{2-[(4-Benzyloxycarbonylmethoxy-7-methyl-quinoline-2-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester in 50 ml ethanol and 150 ml DMF were added under argon 732 mg Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (5 bar) for 4 h. The suspension was filtered over a plug of Celite® and washed with ethanol and DMF. The crude product was obtained after evaporation of the solvent. Yield: 4.1 g.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:60][O:61]C(C)(OC)C)[C:27]([NH:29][CH:30]2[C:58](=[O:59])[N:32]3[C:33]([C:42]([O:44][CH:45]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])=[C:34]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CC(C)=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:60][OH:61])[C:27]([NH:29][CH:30]2[C:58](=[O:59])[N:32]3[C:33]([C:42]([O:44][CH:45]([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])=[C:34]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: CC(C)=O
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2.775 g of the product of Step C, 14 ml of acetone and 4.5 ml of N hydrochloric acid was stirred for 2 hours at room temperature and the acetone was evaporated under reduced pressure. 20 ml of ethyl acetate were added thereto and the mixture was stirred and decanted. The organic phase was washed 4 times with 10 ml of slightly salted water and the wash waters were extracted with 5 ml of ethyl acetate. The combined organic phases were dried and vacuum filtered and the filter was rinsed with ethyl acetate. The filtrate was evaporated to dryness under reduced pressure and the residue was taken up in ether. Crystallization and efflorescence occured and the mixture was vacuum filtered. The product was rinsed with ether and dried to obtain 1.88 g of the syn isomer of diphenylmethyl 7-[2-(2-tritylamino-4-thiazolyl)-2-hydroxyimino-acetamido]-3-acetoxymethyl-ceph-3-eme-4-carboxylate with Rf=0.5 (ether containing 20% of acetone).
Reaction SMILES: C(OP(/[C:9](=[CH:15]\[CH3:16])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH3:19][C:20]1[S:21][C:22]([CH:25]=O)=[CH:23][N:24]=1.O>O1CCCC1.CCOCC>[CH3:19][C:20]1[S:21][C:22]([CH:25]=[CH:16][CH:15]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:23][N:24]=1
Reactant: C/C=C(/C(=O)OCC)P(=O)(OCC)OCC
Reactant: Cc1ncc(C=O)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C=CC=Cc1cnc(C)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
A solution of 12.5 g of ethyl diethylphosphonocrotonate in 25 ml of tetrahydrofuran was added with stirring to a mixture of 100 ml of anhydrous tetrahydrofuran and 3 g of sodium hydride in 46% of an oil cooled to 0°C and the mixture was stirred for 30 minutes at 0°C. Then, a mixture of 6.4 g of 2-methyl-5-thiazolecarboxaldehyde in 25 ml of tetrahydrofuran was added to the mixture at 0°C and 250 ml of ice and 250 ml of water were added. The mixture was extracted with methylene chloride and the organic extracts were washed with water, dried and filtered. The filtrate was evaporated to dryness under reduced pressure to obtain 13 g of raw product which was dissolved in ether and the ether solution was stirred in the presence of Florosil and then with activated carbon. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to obtain 11 g of ethyl 5-(2-methyl-5-thiazolyl)-2,4-pentadienoate in the form of a pale yellow oil.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=2)[N:7]=[CH:6][C:5]=1[C:19]([O:21]CC)=[O:20]>C(O)C>[NH2:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=2)[N:7]=[CH:6][C:5]=1[C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)c1cnn(-c2ccc(C(F)(F)F)cn2)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(C(=O)O)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
10 ml of 45% strength aqueous sodium hydroxide solution are added to 18 g (0.06 mole) of 5-amino-1-(5-trifluoromethyl-pyrid-2-yl)-4-ethoxycarbonyl-pyrazole in 100 ml of 50% strength aqueous ethanol solution and the mixture is stirred at 80° C. for 4 hours. For working up, the solvent is removed in vacuo, the residue is taken up in 50 ml of water and the mixture is stirred into a solution of 20 ml of concentrated hydrochloric acid and 50 ml of water. The precipitate is filtered off with suction, washed with a little dilute hydrochloric acid and dried at 50° C. in vacuo. 15.4 g (94.4% of theory) of 5-amino-1-(5-trifluoromethyl-pyrid-2-yl)-pyrazole-4-carboxylic acid of melting point 196° C. (decomposition) are obtained.
Reaction SMILES: [OH:1][C:2]12[CH2:35][CH2:34][C@:33]3([CH3:36])[C:28](=[C:29]([CH3:37])[CH2:30][CH2:31][CH2:32]3)[C@@H:3]1[O:4][C:5](=[O:27])[CH:6]2[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[C:16]=2[CH2:25][OH:26])[CH2:10][CH2:9]1.[K+].[Br-].CC1(C)N([O])C(C)(C)CCC1.[O-]Cl.[Na+].Cl.[O-:55]Cl=O.[Na+]>O.C(OCC)(=O)C>[OH:1][C:2]12[CH2:35][CH2:34][C@:33]3([CH3:36])[C:28](=[C:29]([CH3:37])[CH2:30][CH2:31][CH2:32]3)[C@@H:3]1[O:4][C:5](=[O:27])[CH:6]2[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[C:16]=2[C:25]([OH:55])=[O:26])[CH2:10][CH2:9]1
Reactant: COc1cc(CN2CCN(CC3C(=O)O[C@H]4C5=C(C)CCC[C@]5(C)CCC34O)CC2)c(CO)c(OC)c1
Reactant: [O-][Cl+][O-]
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: Cl
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(CN2CCN(CC3C(=O)O[C@H]4C5=C(C)CCC[C@]5(C)CCC34O)CC2)c(C(=O)O)c(OC)c1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
Ethyl acetate (10 mL) was added to a mixture of compound of example 38 (150 mg, 0.29 mol) and KBr in water (0.5 M, 0.24 mL), followed by addition of TEMPO (3.12 mg, 0.02 mmol). A solution of 12% NaClO in water (27 mg, 0.36 mmol) was added dropwise to the mixture over 30 minutes at 5° C. at pH of 8.0-10.0. Stirring was continued for 30 minutes at room temperature (25° C.). Then, the pH was adjusted to 5.0 by addition of 35% hydrochloric acid, followed by addition of 25% NaClO2 in water (32.8 mg, 0.36 mmol) over 30 minutes maintaining the temperature of 27-33° C. Stirring was continued for 3 hours at room temperature (25° C.). The product was extracted with ethyl acetate (3×50 mL), washed with brine, followed by concentration to obtain the title compound.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=4Cl)[CH:23]=[C:22]([CH3:34])[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.[Cl:42]CCl>>[Cl:42][C:28]1[CH:27]=[C:26]([C:24]2[CH:23]=[C:22]([CH3:34])[N:21]=[C:20]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[CH:19]=3)[N:25]=2)[CH:31]=[CH:30][C:29]=1[Cl:32]
Reactant: Cc1cc(-c2ccc(Cl)cc2Cl)nc(-c2ccnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 5 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-(2,4-dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butylamide (0.22 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried. Further purification by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane) yielded the title compound as a white solid (0.024 g, 5%). MS (ISP) 477.1 [(M+H)+]; mp 267° C.
Reaction SMILES: C(OC([N:8]1[CH2:34][CH2:33][C:11]2([CH2:14][N:13]([C@H:15]3[C:23]4[C:18](=[CH:19][C:20]([C:24]5[CH:29]=[CH:28][C:27]([C:30](=[O:32])[NH2:31])=[CH:26][CH:25]=5)=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35]>CCOC(C)=O.O1CCOCC1>[ClH:35].[CH2:14]1[C:11]2([CH2:10][CH2:9][NH:8][CH2:34][CH2:33]2)[CH2:12][N:13]1[C@H:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([NH2:31])=[O:32])=[CH:28][CH:29]=3)=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(-c4ccc(C(N)=O)cc4)ccc31)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)cc1
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of 2-[(R)-5-(4-carbamoyl-phenyl)-indan-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (4-1a, 124 mg, 0.27 mmol) in EtOAc (10 mL) was added 3 mL of 4N HCl in dioxane, resulting in the immediate precipitation of solids. The reaction was stirred for 3 hours. The reaction was concentrated and the residue was coevaporated with diethylether (3×) to provide 4-[(R)-1-(2,7-diaza-spiro[3.5]non-2-yl)-indan-5-yl]-benzamide hydrochloride as a white solid (102 mg, 95%). This material was used without further purification in the next reaction. MS (ES+) 362.5 (M+H)+. 1H NMR (CD3OD) δ 2.12-2.27 (m, 4H), 2.51 (dd, 1H), 2.95-3.03 (m, 1H), 3.13-3.24 (m, 4H), 3.31 (d, 3H), 4.08 (d, 1H), 4.19 (s, 2H), 4.43 (d, 1H), 5.05 (br s, 2H), 7.51-7.62 (m, 2H), 7.64-7.83 (m, 3H), 7.89-7.96 (m, 2H).