Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[K+].[NH2:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]#N)=[CH:14][C:13]=2[O:21][CH3:22])=[C:6]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:5]=1.C[OH:30]>>[NH2:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:30])=[O:1])=[CH:14][C:13]=2[O:21][CH3:22])=[C:6]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:5]=1
Reactant: CO
Reactant: [OH-]
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1OC
Agent: [K+]
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1OC
Temperature: 65 °C
Reaction time: 15 h

Procedure:
A 5M aqueous solution of potassium hydroxide (5 mL) was added to a solution of the product from step (vii) (0.60 g) in MeOH (10 mL). The resulting mixture was stirred at 65° C. for 15 h. The mixture was allowed to cool and the solvent evaporated under reduced pressure. The resulting aqueous mixture was neutralised with 2M HCl and extracted with EtOAc. The combined organic phase was dried, filtered and evaporated to give the subtitle compound as a colourless solid 0.329 g that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:34][CH2:33][C:20]4([N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:23][N:22]([CH3:31])[C:21]4=[O:32])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:68][N:69]([CH3:73])[CH2:70][CH2:71][NH2:72]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:34][CH2:33][C:20]4([N:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:23][N:22]([CH3:31])[C:21]4=[O:32])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH:72][CH2:71][CH2:70][N:69]([CH3:73])[CH3:68])=[O:14])=[CH:4][CH:3]=1
Reactant: CN1CN(c2ccccc2)C2(CCN(C(=O)c3cn(CC(=O)O)c4cc(Cl)ccc34)CC2)C1=O
Reactant: CN(C)CCN
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: CN(C)C=O
Product: CN(C)CCNC(=O)Cn1cc(C(=O)N2CCC3(CC2)C(=O)N(C)CN3c2ccccc2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of [6-chloro-3-(3-methyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decane-8-carbonyl)-indol-1-yl]-acetic acid in DMF was treated sequentially with 1 eq. of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 1 eq. of N,N-diisopropylethylamine and 1 eq. of N,N-dimethylethylenediamine. The mixture was shaken at room temperature for 12 h, concentrated and purified by prep. HPLC to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:28]=[C:11]3[N:12]=[C:13]([CH3:27])[C:14]([C@H:17]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19])=[C:15](I)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:29]([N:32]1[CH2:37][CH2:36][O:35][C:34]2[CH:38]=[CH:39][C:40](B3OC(C)(C)C(C)(C)O3)=[C:41]([Cl:42])[C:33]1=2)[CH:30]=[CH2:31].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:29]([N:32]1[CH2:37][CH2:36][O:35][C:34]2[CH:38]=[CH:39][C:40]([C:15]3[N:10]4[N:9]=[C:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=5)[CH:28]=[C:11]4[N:12]=[C:13]([CH3:27])[C:14]=3[C@H:17]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19])=[C:41]([Cl:42])[C:33]1=2)[CH:30]=[CH2:31]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1I
Reactant: C=CCN1CCOc2ccc(B3OC(C)(C)C(C)(C)O3)c(Cl)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(Br)c5)nn34)c(Cl)c21
Temperature: 90 °C
Yield: 49.8 %

Procedure:
A solution of (S)-methyl 2-(2-(3-bromophenyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.160 g, 0.287 mmol) and 4-allyl-5-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.096 g, 0.287 mmol) in DMF (3 mL) was treated with 2.0 M aq. Na2CO3 (0.358 mL, 0.717 mmol), sparged with N2 for 10 min, treated with Pd(Ph3P)4 (0.033 g, 0.029 mmol), sparged for 5 min, then sealed and heated (90° C.) for 16 h. The reaction was cooled, diluted with EtOAc (20 mL) and washed with 1:1 water/brine (2×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by biotage column chromatography (4 g Isco SiO2, 0% (5 CV), 0%-80% (15 CV), EtOAc/hexanes) to afford semi-purified product (0.122 g, 0.143 mmol, 49.9% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.98 (t, J=1.7 Hz, 1H), 7.76 (dt, J=7.8, 1.2 Hz, 1H), 7.44 (ddd, J=8.0, 2.0, 1.1 Hz, 1H), 7.24 (t, J=7.9 Hz, 1H), 6.99-7.03 (m, 1H), 6.93-6.97 (m, 1H), 6.85 (s, 1H), 5.99-6.10 (m, 1H), 5.36 (dd, J=17.2, 1.6 Hz, 1H), 5.26 (dd, J=10.2, 1.5 Hz, 1H), 5.05 (s, 1H), 4.23-4.32 (m, 2H), 3.69 (dd, J=12.1, 6.0 Hz, 2H), 3.65 (s, 3H), 3.17-3.29 (m, 2H), 2.84 (s, 3H), 1.17 (s, 9H). LCMS (M+H)=641.2.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)([O-:3])=O.[C:13]([C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)#[CH:14].N(C1C=CC=CC=1)=C=O.O>C(#N)C>[O:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[O:6][CH2:5][C:4]1[CH:14]=[C:13]([C:15]2[CH:16]=[C:17]([C:25]([F:26])([F:27])[F:28])[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=2)[O:3][N:1]=1
Reactant: O=[N+]([O-])CCOC1CCCCO1
Reactant: C#Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CC#N
Solvent: O=C=Nc1ccccc1
Solvent: O
Product: FC(F)(F)c1cc(-c2cc(COC3CCCCO3)no2)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
To a solution of 2-[(2-nitroethyl)oxy]tetrahydro-2H-pyran (483 μL, 3.15 mmol) and 1-ethynyl-3,5-bis(trifluoromethyl)benzene (3.0 g, 12.6 mmol) in dry acetonitrile (15 mL) were added TEA (4.4 ml, 31.5 mmol) and isocyanatobenzene (3.4 mL, 31.5 mmol) at rt. The reaction is stirred at 50° C. for 5 h. Water was added and the mixture was extracted with Et2O three times. The combined organic layers were then washed with brine once, dried over MgSO4 and concentrated in vacuo. The residue was purified by radial chromatography (0-40% EtOAc-hexanes gradient) to afford the title compound (0.51 g, 41% yield): MS (ES) m/z 418 (M+Na+).
Reaction SMILES: [OH-].[Na+].Cl.[SH:4][CH2:5][CH2:6][NH2:7].Cl.N1C=CC=CC=1.Cl[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>C(O)C>[N:20]1[CH:21]=[CH:22][C:17]([CH2:16][S:4][CH2:5][CH2:6][NH2:7])=[CH:18][CH:19]=1
Reactant: ClCc1ccncc1
Reactant: NCCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccncc1
Product: NCCSCc1ccncc1
Temperature: 25 °C

Procedure:
34.1 g of sodium hydroxide was dissolved in 500 ml of ethanol under an argon atmosphere and 48.6 g of 2-mercaptoethanamine hydrochloride and 35 g of 4-chloromethylpyridine pyridine hydrochloride were added with ice bath cooling. The reaction mixture was allowed to warm to room temperature over 2 hours, was concentrated, diluted with 300 ml of water and was extracted with 3×150 ml of dichloromethane. The combined organic layers were washed with 100 ml of saturated brine, dried over potassium carbonate and were evaporated to a dark oil which was distilled. The fractions bp 120°-130° C./0.1 mm amounted to 30.68 g (85%) of 2-[[(4-pyridyl)methyl]thio]ethanamine.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:9]([C:17]1[C:22]([F:23])=[C:21](Cl)[N:20]=[C:19]([Cl:25])[N:18]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[O:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[CH2:45][NH:46][CH3:47]>C1COCC1.O>[CH3:31][C:29]([O:28][C:26]([N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:1])[CH3:3])=[O:7])[N:9]([C:17]1[C:22]([F:23])=[C:21]([N:46]([CH2:45][C:41]2[O:40][CH:44]=[CH:43][CH:42]=2)[CH3:47])[N:20]=[C:19]([Cl:25])[N:18]=1)[C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[O:27])([CH3:32])[CH3:30]
Reactant: CNCc1ccco1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1ccco1)c1nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Reaction time: 8 h
Yield: 101.4 %

Procedure:
Tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (6.22 g, 12.54 mmol) was dissolved in THF (15 mL). To this solution was added triethylamine (2.1 mL, 15.0667 mmol), followed by commercially available (2-furanylmethyl)methylamine (1.394 g, 12.32 mmol) which was dissolved in THF (3 mL). The reaction was left to stir overnight. Then the reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate. The organics were dried (Na2SO4) and concentrated to produce tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(2-furanylmethyl)(methyl)amino]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate as a beige solid (7.1439 g). LCMS: (M+H)+=572.3.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30](S(C1C=CC(C)=CC=1)(=O)=O)[CH:29]=[C:28]2[C:44]1[CH:49]=[N:48][CH:47]=[C:46](Cl)[N:45]=1.Cl>CN(C=O)C.CCOC(C)=O.O>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[C:44]1[N:45]=[C:46]([O:3][C@@H:4]2[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]2)[CH:47]=[N:48][CH:49]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(Cl)n3)c3cc(-c4c(F)cccc4Cl)ccc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3c[nH]c4ccc(-c5c(F)cccc5Cl)cc34)n2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.7 %

Procedure:
To a slurry of NaH 60% in mineral oil (0.047 g, 1.171 mmol) in 2 mL DMF at 0° C. was added (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (0.236 g, 1.171 mmol). The reaction was warmed to RT. After 10 min, solid 5-(2-chloro-6-fluorophenyl)-3-(6-chloropyrazin-2-yl)-1-tosyl-1H-indole (0.200 g, 0.390 mmol) was added and the reaction became dark brown. After 30 min, the reaction was sealed and heated to 80° C. overnight. Additional NaH 60% in mineral oil (0.047 g, 1.171 mmol) and (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (0.236 g, 1.171 mmol) were added, the reaction was sealed, and heated to 120° C. for 1 h. The reaction was cooled and treated with ice, water, and EtOAc, and the aqueous layer was acidified with 1N aqueous HCl. The aqeuous layer was extracted 2×EtOAc, and the combined organics were washed 1× water, 1× brine, dried over Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (40 g column) using 0-60% EtOAc/hexane. The product-containing fractions were concentrated to afford (R)-tert-butyl 3-(6-(5-(2-chloro-6-fluorophenyl)-1H-indol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (0.077 g, 0.147 mmol, 37.7% yield) as a light-yellow oil. MS (ESI, pos. ion) m/z: 523 (M+1).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH3:13][O:14][C:15]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:16]=1[CH2:17][NH:18][C:19]1[C:20]([CH2:25][NH:26][CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[N:21][CH:22]=[CH:23][CH:24]=1>CN(C)C=O.O>[CH3:13][O:14][C:15]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:16]=1[CH2:17][N:18]1[C:19]2[CH:24]=[CH:23][CH:22]=[N:21][C:20]=2[CH2:25][N:26]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)[C:1]1=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CNc2cccnc2CNC2CCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2C(=O)N(C3CCN(C(=O)OC(C)(C)C)CC3)Cc3ncccc32)c(OC)c1
Temperature: 150 °C

Procedure:
Carbonyldiimidazole (1.22 g, 7.53 mmol) was added to a solution of the material from Step C in dimethylformamide (20 mL) and the reaction was heated to 150° C. overnight. The reaction was diluted with water and extracted with dichloromethane, and the organic phase dried over sodium sulfate. The crude product was purified by chromatography (silica gel, 30 to 100% ethyl acetate in methylene chloride gradient elution), which gave the title compound (0.10 g). MS 483.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:13][C:14]([CH3:19])=[CH:15][C:16](Cl)=[O:17].N1C=CC=CC=1.Cl>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:9]([CH:10]([CH3:12])[CH3:11])[C:16](=[O:17])[CH:15]=[C:14]([CH3:19])[CH3:13])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(C)=CC(=O)Cl
Reactant: Cc1ccc(NC(C)C)cc1Br
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)=CC(=O)N(c1ccc(C)c(Br)c1)C(C)C
Temperature: 0 °C
Reaction time: 5 h

Procedure:
(3-Bromo-4-methyl-phenyl)-isopropyl-amine (Compound 41, 36.78 g, 161.2 mmol) was dissolved in dichloromethane (200 mL) and the solution was cooled to 0° C. and treated with 3,3-dimethylacryloyl chloride (28.6 g, 241.8 mmol) and then pyridine (36 mL). The solution was stirred at 0° C. for 1 hour and at room temperature for 5 hours. The mixture was poured into separatory funnel containing dichloromethane and 10% aqueous HCl. The layers were separated and the aqueous layer extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried with MgSO4, filtered, and concentrated under reduced pressure to give the title compound, which was used directly for the next reaction without further purification, as a solid: Rf=0.48, 20% ethyl acetate in hexane:
Reaction SMILES: [H][H].[CH3:3][C:4]([CH3:6])=O.[CH:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O>[CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[CH3:3]
Reactant: c1ccccc1
Reactant: CC(C)=O
Reactant: [H][H]
Solvent: O
Product: CC(C)c1ccccc1

Procedure:
The first fraction (containing hydrogen) is re-used in the reaction step with acetone and benzene, the second fraction (containing water) is removed from the process, the third fraction (containing benzene) is partly re-used in the reaction step with acetone and hydrogen and partly in a subsequent reaction step, called transalkylation step, where it is reacted with the fifth fraction (containing polyisopropylbenzenes) to produce again the desired product isopropylbenzene.
Reaction SMILES: C(N[C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:26][CH3:27])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:8]([NH2:28])[N:7]=1)CCC.FC(F)(F)C(O)=O.[CH3:36][C@H:37]([O:41]C1NC(N)=C2C(N=1)=NC(OC)=N2)[CH2:38][CH2:39][CH3:40].BrCCCCCl.N1CCCCCC1>>[N:19]1([CH2:18][CH2:17][CH2:16][CH2:15][N:12]2[C:11]([O:26][CH3:27])=[N:10][C:9]3[C:13]2=[N:14][C:6]([O:41][C@@H:37]([CH3:36])[CH2:38][CH2:39][CH3:40])=[N:7][C:8]=3[NH2:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCCCN3CCCCCC3)c2n1
Agent: C1CCCNCC1
Agent: ClCCCCBr
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCN3CCCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 36 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate, 1-bromo-4-chlorobutane, and hexahydro-1H-azepine but with three sequential MDAPs using Method B followed by Method A (×2).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[S:8])[NH:6][NH2:7])[CH:2]=[CH2:3].[Cl:9][CH2:10][C:11](=O)[CH3:12]>>[ClH:9].[CH3:12][C:11]1[N:4]([CH2:1][CH:2]=[CH2:3])[C:5](=[N:6][NH2:7])[S:8][CH:10]=1
Reactant: CC(=O)CCl
Reactant: C=CCNC(=S)NN
Product: C=CCn1c(C)csc1=NN
Product: Cl

Procedure:
From 4-(2-propenyl)-3-thiosemicarbazide and chloroacetone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])/[N:7]=[C:8](/[C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[F:19])\[CH:9]([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([Mg]Cl)[CH:22]=[CH2:23]>C1COCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]([C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[F:19])([CH:9]([F:10])[F:11])[CH2:23][CH:22]=[CH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)/N=C(/c1cc(Br)ccc1F)C(F)F
Reactant: C=CC[Mg]Cl
Solvent: C1CCOC1
Product: C=CCC(NC(=O)OC(C)(C)C)(c1cc(Br)ccc1F)C(F)F

Procedure:
To a solution of [1-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-eth-(Z)-ylidene]-carbamic acid tert-butyl ester (9.61 g, 27.3 mmol) in 114 ml THF at −75° was added dropwise allylmagnesium chloride solution 2 mol/L in THF (15.0 ml, 30 mmol). The reaction temperature was not allowed to exceed −60° C. After 10 minutes the reaction was quenched with 10% aqueous NH4Cl and extracted with TBME. The organic phase was washed with brine, dried with Na2SO4 and evaporated. The crude product was chromatographed on silica gel with 1-5% TBME/hexane to give 10.39 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([OH:10])=O)[N:6]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[NH2:28][C@@H:29]1[C:57](=[O:58])[N:31]2[C:32]([C:45]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=3)=[O:46])=[C:33]([C@@H:36]3[CH2:40][CH2:39][C@H:38]([C:41]([O:43][CH3:44])=[O:42])[O:37]3)[CH2:34][S:35][C@H:30]12>CN(C)C=O.N1C=CC=CC=1>[CH3:44][O:43][C:41]([C@@H:38]1[O:37][C@H:36]([C:33]2[CH2:34][S:35][C@@H:30]3[C@H:29]([NH:28][C:8](=[O:10])/[C:7](/[C:5]4[N:6]=[C:2]([NH2:1])[S:3][CH:4]=4)=[N:11]\[O:12][CH3:13])[C:57](=[O:58])[N:31]3[C:32]=2[C:45]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=2)=[O:46])[CH2:40][CH2:39]1)=[O:42]
Reactant: COC(=O)[C@H]1CC[C@@H](C2=C(C(=O)OCc3ccc(OC)cc3)N3C(=O)[C@@H](N)[C@H]3SC2)O1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C([C@@H]3CC[C@H](C(=O)OC)O3)CS[C@H]12)c1csc(N)n1
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
A stirred solution of 2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetic acid (20.1mg) and N,N-diisopropylethylamine (0.0176ml) in dimethylformamide (0.3ml) was cooled to -55 to -60° C. and methanesulphonyl chloride (0.0081ml) was added. The mixture was stirred at the same temperature for 0.5h and then a solution of 4-methoxybenzyl (6R,7R)-7-amino-3-[(2S,5R)-5-methoxycarbonyltetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (41mg) in dimethylformamide (0.3ml) was added followed by pyridine (0.0073ml). The mixture was then stored at 0° C. for 1h and then at room temperature for 0.5h. The reaction mixture was partitioned between ethyl acetate and aqueous citric acid solution and the organic phase washed with water and brine. The solution was dried over magnesium sulphate and evaporated, and the title compound (31mg) isolated by column chromatography of the residue (silica gel, ethyl acetate as eluent); vmax (CHCl3) 3496, 3397, 1784, 1733 and 1684cm-1.
Reaction SMILES: C(S[C:4](=[O:23])[CH:5]([C:19]([F:22])([F:21])[F:20])[CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)C.O.[NH2:25][NH2:26]>CCO>[F:20][C:19]([F:22])([F:21])[CH:5]1[CH2:6][C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:26][NH:25][C:4]1=[O:23]
Reactant: NN
Reactant: CCSC(=O)C(CC(=O)c1ccc(C(F)(F)F)cc1)C(F)(F)F
Solvent: CCO
Solvent: O
Product: O=C1NN=C(c2ccc(C(F)(F)F)cc2)CC1C(F)(F)F
Temperature: 23 °C
Yield: 99.1 %

Procedure:
A mixture of 4-oxo-2-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-thiobutyric acid S-ethyl ester (example C.26 step 4) (16.0 g, 45 mmol) and hydrazine monohydrate (2.39 mL, 49 mmol) in EtOH (250 mL) was refluxed for 18 h under nitrogen atmosphere. Cooled to 23° C., the solvents were evaporated to leave the title compound as a brown solid (13.83 g, 100%), which was used without further purification [according to Synthesis 2003, (3), 436.]. MS (ISP) 311.1 [(M+H)+]; mp 135–136° C.
Reaction SMILES: [CH3:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:13].[H-].[Na+].[F:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.O>CN(C=O)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][N:12]3[C:5]4[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=4[C:3]([CH3:13])=[C:2]3[CH3:1])=[CH:25][CH:24]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: Cc1[nH]c2cnn(C)c(=O)c2c1C
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C)n(Cc2ccc(C(=O)c3ccc(F)cc3)cc2)c2cnn(C)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
A solution of 2,3,5-trimethyl-1H-pyrrolo[2,3-d]-pyridazin-4(5H)-one (354 mg) in DMF (30 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (8 ml) on an ice-water bath. The mixture was stirred at room temperature for 1 hour, after which a solution of 4-(4-fluorobenzoyl)benzyl bromide (645 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 2 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:1) to provide the title compound as white powder (628 mg, yield 81%).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[Cu](C#N)[C:31]#[N:32].N>CS(C)=O>[C:31]([C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:3]=1[CH3:29])#[N:32]
Reactant: N#C[Cu]C#N
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Agent: N
Solvent: CS(C)=O
Product: Cc1c(C#N)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Yield: 81.6 %

Procedure:
A solution of N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (0.5 g, 1.09 mmol) obtained in Example 35 and copper cyanide (300 mg 3.27 mmol) in dimethylsulfoxide (30 mL) was heated at 180° C. for 14 hours. To the reaction solution was added aqueous ammonia and the product was extracted with ethyl acetate. The extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 3:1) to obtain 360 mg (yield: 82%) of the title compound. Melting point: 135-136° C. (hexane-ethyl acetate).