Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:25]([S:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])=[O:29])[CH2:26][CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:34]3[CH2:33][CH2:32][N:31]([S:28]([CH2:25][CH2:26][CH3:27])(=[O:29])=[O:30])[CH2:36][CH2:35]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: CCCS(=O)(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: CCCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Yield: 27.4 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (50 mg, 0.15 mmol), 1-propanesulfonyl-piperazine hydrochloride (52 mg, 0.23 mmol) and sodium triacetoxyborohydride (48 mg. 0.23 mmol) to afford 21 mg (27%) of the desired product after purification.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([C:25](O)=[O:26])[N:15]([CH3:24])[C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:8][CH:7]=1>>[CH2:1]([NH:4][C:25]([C:14]1[N:15]([CH3:24])[C:16]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[C:12]([C:9]2[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][CH:10]=2)[N:13]=1)=[O:26])[CH2:2][CH3:3]
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Reactant: CCCN
Product: CCCNC(=O)c1nc(-c2ccc(C)cc2)c(-c2ccc(C)cc2)n1C

Procedure:
Using essentially the same procedure as Example 9, Step B, but using n-propylamine (0.015 mL), 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Example 9, Step A was converted to the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C(N(CC)CC)C.O>C1COCC1>[CH:5]1([C:3](=[O:4])[CH2:2][S:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COc1ccc(S)cc1
Reactant: O=C(CCl)C1CCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(SCC(=O)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The intermediate 2-Chloro-1-cyclopentyl-ethanone from Step 1 (1 g, 6.81 mmol), was combined with 4-methoxy-benzenethiol (1.05 g, 7.50 mmol), in THF (20 mL) and treated with Triethylamine (1.05 mL, 7.50 mmol). The mixture was stirred for 1 hour at room temperature then poured into water (50 mL) and extracted with EtOAc (2×50 mL). The organics were then washed with 0.5N HCl (2×50 mL), 2N NaOH (2×50 mL), water (2×50 mL) and brine (1×50 mL) the organics were dried over Na2SO4, filtered and concentrated. The residue was used without further purification (1.65 g, 97%).
Reaction SMILES: C(NC(C)C)(C)C.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([Li])CCC.[F:27][C:28]([F:52])([F:51])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([N:38]2[CH2:42][CH:41]([CH3:43])[C:40]([C:44]3[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=3)=[N:39]2)=[O:37])=[CH:31][CH:30]=1.C([O:56][CH2:57][CH3:58])(=O)C>O1CCCC1.CCCCCC>[F:52][C:28]([F:27])([F:51])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([N:38]2[CH2:42][C:41]([CH3:43])([C:57](=[O:56])[CH3:58])[C:40]([C:44]3[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=3)=[N:39]2)=[O:37])=[CH:31][CH:30]=1
Reactant: CC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC(=O)C1(C)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Temperature: -70 °C
Reaction time: 0.67 h

Procedure:
To 14 ml (102 mmole) of diisopropyl amine and 1 mg of phenanthroline in 150 ml of tetrahydrofuran cooled to -30° C. was added 40 ml (100 mmole) of 2.5M n-butyllithium in hexane. After stirring for 5 minutes a solution of 15 g (39 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide (U.S. Pat. No. 4,663,341, see experimental for compound 149) in 25 ml of tetrahydrofuran was added while maintaining the internal temperature between -30° C and -40° C. After stirring for 40 minutes the mixture was cooled to -70° C. and 20 ml of ethyl acetate was added. After stirring for 15 minutes the mixture was quenched with 20 ml of acetic acid, warmed to 0° C. and 25 ml of water was added. The organic layer was separated, concentrated in vacuo, dissolved in 200 ml of diethyl ether, washed with dilute aqueous hydrochloric acid, dilute aqueous sodium hydroxide, and brine. The mixture was dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and crystallized from diethyl ether yielding 6.5 g of the title compound containing a small amount of starting material.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[C:14]([O-])([O-])=O.[Cs+].[Cs+].IC.O>CN1C(=O)CCC1>[Br:1][C:2]1[C:11]([O:12][CH3:14])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc2ccc(Br)c(O)c2n1
Agent: [Cs+]
Solvent: CI
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1c(Br)ccc2ccc(C)nc12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 98.1 %

Procedure:
To a solution of 7-bromo-2-methylquinolin-8-ol (4.10 g, 14.64 mmol) and Cs2CO3 (11.92 g, 36.59 mmol) in NMP (20 mL) was added iodomethane (1.01 mL, 16.10 mmol) at 0° C. The reaction was warmed to ambient temperature and stirred at ambient temperature for 40 minutes. Water (30 mL) was and added and extracted with DCM (30 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM) to give 7-bromo-8-methoxy-2-methylquinoline (3.62 g, 91.23%) as an oil.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH2:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:32]>>[CH2:31]([N:33]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:26]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:25])[CH3:32]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCNc1ccccc1
Product: CCN(C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O)c1ccccc1

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and ethyl-phenyl-amine. MS (ESI): 462.4 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[C:16]2[C:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][C:12]([CH3:20])([CH3:19])[C:11]=2[CH:10]=[C:9]([O:21][CH3:22])[C:8]=1/[CH:23]=[CH:24]/[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.C(N(CC)CC)C.O>O1CCCC1>[C:1]([NH:30][CH2:29][C:28]1[CH:27]=[CH:26][C:25](/[CH:24]=[CH:23]/[C:8]2[C:9]([O:21][CH3:22])=[CH:10][C:11]3[C:12]([CH3:19])([CH3:20])[CH2:13][CH2:14][C:15]([CH3:18])([CH3:17])[C:16]=3[C:7]=2[O:6][CH3:5])=[CH:32][CH:31]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1cc2c(c(OC)c1/C=C/c1ccc(CN)cc1)C(C)(C)CCC2(C)C
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(c(OC)c1/C=C/c1ccc(CNC(C)=O)cc1)C(C)(C)CCC2(C)C
Reaction time: 1 h

Procedure:
1 ml of acetyl chloride in 5 ml of absolute tetrahydrofuran was added dropwise, at 20° C., to a solution of 3 g (8 millimoles) of the benzylamine derivative from Example 30, 1.6 g (16 millimoles) of triethylamine and 50 mg of DMAP (4-N,N-dimethylaminopyridine) in 25 ml of absolute tetrahydrofuran. After 1 hour at 0° C., the mixture was poured onto 100 ml of water and extracted with methylene chloride. The organic phase was dried and evaporated down, and the oily residue was heated with heptane. The mixture was cooled, the supernatant heptane phase was decanted, and the process was repeated several times. Finally, 0.8 g of the title compound of melting point 126°-127° C. crystallized out from the heptane solution and was filtered off under suction.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25](Cl)=[O:26]>ClCCl>[NH2:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([C:25]([C:24]3[C:23]([Cl:22])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:32])=[O:26])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1cccc(C2CCNCC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1cccc(C2CCN(C(=O)c3c(Cl)cccc3Cl)CC2)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 46.9 %

Procedure:
To an ice-cooled solution of 4-(3-aminophenyl)-piperidine hydrochloride (250.2 mg, 1.0 mmol) and triethylamine (1 mL) in dichloromethane (6 mL) is added 2,6-dichlorobenzoic chloride (0.15 mL, 1.0 mmol). The reaction mixture is stirred at 0° C. for 6 hours. After removal of solvent, the residue is purified on a silica gel chromatography with ethyl acetate-hexanes to provide a white solid (163.9 mg, 46.9% yield, ES+(m/z) 349.1 [M+H]).
Reaction SMILES: [NH2:1][CH:2]=[CH:3][CH3:4].[C:5]1([CH2:11][CH:12]2[O:14][CH2:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[CH2:2]([NH:1][CH2:13][CH:12]([OH:14])[CH2:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:3]=[CH2:4]
Reactant: CC=CN
Reactant: c1ccc(CC2CO2)cc1
Solvent: CO
Product: C=CCNCC(O)Cc1ccccc1
Temperature: 25 °C
Yield: 101.7 %

Procedure:
A solution of 1-aminopropylene (10.6 grams, 0.186 mol) in methanol was added to a methanolic solution of 3-phenylpropyleneoxide (5.07 grams, 0.037 mol) and the mixture heated to reflux for 30 minutes. The mixture was allowed to warm to room temperature and concentrated in vacuo to yield 7.2 grams (99%) of N-allyl-3-phenyl-2-hydroxypropylamine. 1H NMR (CDCl3, dTMS) 7.34-7.18 (5H, m, Ar-H), 5.84 (1H, ddt, 3JHH =17.1 Hz, 3JHH =10.2 Hz, 3JHH =6 Hz, CH2CH), 5.2-5.0 (2H, m, CH=CH2), 3.86 (1H, m, CHOH), 3.19 (2H, m, NCH2 CH=CH2), 2.76-2.66 (3H, m, NCH2CH(OH)(CHHPh), 2.50 (1H, dd 2JHH =12 Hz, 3JHH =9 Hz). 13C NMR (CDCl3) 138.4, 136.5, 129.3, 128.4, 126.3, 116.0, 70.6, 54.0, 51.9, 41.7.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5](Br)=[CH:6][CH:7]=1.[Cu][C:11]#[N:12].CN(C)C=O.O>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]#[N:12])=[N:4][C:3]=1[CH3:9]
Reactant: Cc1nc(Br)ccc1Br
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(C#N)ccc1Br
Temperature: 110 °C
Yield: 48.8 %

Procedure:
3,6-Dibromo-2-methylpyridine (4.9 g, 19.53 mmol), copper(I)cyanide (1.75 g, 19.53 mmol) and N,N-dimethylformamide (20 mL) were combined in a sealable vessel with a stirbar. The resulting mixture was sealed, stirred vigorously and heated at 110° C. for 4 h. The resulting mixture was diluted with ethyl acetate, poured into a separatory funnel containing water and the layers were separated. The water layer was extracted with ethyl acetate twice. The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by silica gel chromatography (10% ethyl acetate in hexanes) to give the title compound as a white solid (1.88 g, 9.54 mmol, 49% yield). MS (ESI) m/z 197.3 [M]+.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:28]=[C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)[S:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:42]1([S:48]([N:51]2[C:59]3[CH:58]=[CH:57][N:56]=[C:55](Br)[C:54]=3[CH:53]=[CH:52]2)(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCOCC1.S1C=CC=C1C([O-])=O.[Cu+]>[C:42]1([S:48]([N:51]2[C:59]3[CH:58]=[CH:57][N:56]=[C:55]([C:11]4[N:12]=[C:7]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[C:8]5[N:28]=[C:27]([CH2:29][N:30]6[CH2:35][CH2:34][N:33]([C:36]([CH3:40])([CH3:41])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]6)[S:26][C:9]=5[N:10]=4)[C:54]=3[CH:53]=[CH:52]2)(=[O:50])=[O:49])[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C(N)=O)CC3)sc2n1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)nccc21
Agent: [Cu+]
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: CC(C)(C(N)=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(-c4nccc5c4ccn5S(=O)(=O)c4ccccc4)nc3s2)CC1
Temperature: 25 °C

Procedure:
A degassed solution of 2-[4-(7-morpholin-4-yl-5-(tributylstannanyl)thiazolo[5,4-d]pyrimidin-2-ylmethyl)piperazin-1-yl]isobutyramide (250 mg, 0.36 mmol), 1-benzenesulfonyl-4-bromo-1H-pyrrolo[3,2-c]pyridine (130 mg, 0.39 mmol), PdCl2{PtBu2(Ph-p-Nme2)}2 (26 mg, 0.036 mmol) and copper(I) thiophene-2-carboxylate (14 mg, 0.07 mmol) in 1,4-dioxane (4 mL) was subjected to microwave irradiation at 140° C. for 20 minutes. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated to give 2-{4-[5-(1-benzenesulfonyl-1H-pyrrolo[3,2-c]pyridin-4-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]piperazin-1-yl}isobutyramide as a crude oil. Aqueous NaOH (12.5 M, 0 4 mL) was added to a solution of 2-{4-[5-(1-benzenesulfonyl-1H-pyrrolo[3,2-c]pyridin-4-yl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl]-piperazin-1-yl}isobutyramide in 1,4-dioxane (4 mL) and IMS (4 mL). The reaction mixture was stirred at ambient temperature for 45 min, then concentrated in vacuo. The residue was dissolved in MeOH then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated to afford a solid. The solid was purified by flash chromatography (Si—PPC, DCM:MeOH, 100:0 to 98:2 to 96:4) followed by reversed phase HPLC (Phenomenex Luna C-18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 95:5 to 2:98) to afford 169 as a yellow solid (43 mg, 23%). LCMS (method E): RT=5.03 min, [M+H]+=522.2. 1H NMR (CDCl3, 400 MHz) δ 8.55 (d, J=5.6 Hz, 1 H), 7.45-7.40 (m, 2 H), 7.38 (d, J=3.3 Hz, 1 H), 7.11 (d, J=5.3 Hz, 1 H), 5.25 (d, J=5.3 Hz, 1 H), 4.53-4.42 (m, 4 H), 3.90 (m, 6 H), 2.68 (m, 4 H), 2.62 (m, 4 H), 1.25 (s, 6 H)
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[Br:11]Br>C(O)(=O)C>[Br:11][CH2:9][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1cccc(Br)n1
Solvent: CC(=O)O
Product: O=C(CBr)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A solution of 1-(6-bromopyridin-2-yl)ethanone (9.2 g, 46.0 mmol) in acetic acid (25 mL) was heated to 70° C. and bromine (2.4 mL, 46.0 mmol) was added dropwise over 30 minutes. After 75 minutes, the solution was cooled to room temperature and a yellow solid precipitated which was collected by filtration and washed with acetic acid (3×10 mL) The solid was then dissolved in a mixture of ethyl acetate (150 mL), hexanes (50 mL), and saturated aqueous sodium bicarbonate (75 mL). The layers were separated and the organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel chromatography (10-50% dichloromethane/hexanes) to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=[N:11][C:10]=2[CH3:23])=[CH:4][C:5](F)=[N:6][CH:7]=1.[C@H:24]1([NH2:31])[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1>CS(C)=O>[Cl:1][C:2]1[C:3]([C:9]2[C:10]([CH3:23])=[N:11][CH:12]=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:14]=2)=[CH:4][C:5]([NH:30][C@H:27]2[CH2:28][CH2:29][C@H:24]([NH2:31])[CH2:25][CH2:26]2)=[N:6][CH:7]=1
Reactant: Cc1ncc(NCC2CCOCC2)nc1-c1cc(F)ncc1Cl
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CS(C)=O
Product: Cc1ncc(NCC2CCOCC2)nc1-c1cc(N[C@H]2CC[C@H](N)CC2)ncc1Cl
Temperature: 100 °C

Procedure:
To a scintillation vial containing 6-(5-chloro-2-fluoropyridin-4-yl)-5-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (7 mg, 0.021 mmol) was added DMSO and trans-cyclohexane-1,4-diamine (23.73 mg, 0.208 mmol). The homogenous reaction mixture was capped and heated to 100° C. in an oil bath for 4 hr. The crude solution was purified by reverse phase preparative HPLC to yield trans-N1-(5-chloro-4-(3-methyl-6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazin-2-yl)pyridin-2-yl)cyclohexane-1,4-diamine (1.1 mg, 2.018 μmol, 9.71% yield), LCMS (m/z): 431.2 (MH+), retention time=0.47 min as a TFA salt after lypholyzing.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:38](Br)[C:39]#[CH:40].O>CN(C)C=O>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:40][C:39]#[CH:38])[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: C#CCBr
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(C)c(C)c2)C1
Reaction time: 1 h

Procedure:
To a stirred mixture of (2R)-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (943 mg) and potassium carbonate (880 mg) in dimethylformamide (10 ml) was added propargyl bromide (0.2 ml) at room temperature. After 1 hour, the reaction mixture was poured into water (100 ml) and extracted with ethyl acetate. The extract was washed with brine and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel using a mixture of hexane and ethyl acetate (5:1) as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-propargylpiperazine (1.09 g) as an oil.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15]([OH:17])=O)[N:13]=1)=[O:7].[CH3:31][N+:32]([CH3:35])=[CH:33][Cl:34].[Cl-].C[Si](CC(N)=O)(C)C.[NH2:45][CH:46]1[C:56](=[O:57])[N:48]2[C:49]([C:53]([OH:55])=[O:54])=[CH:50][CH2:51][S:52][C@H:47]12>C(OCC)(=O)C.O.CN(C)C=O>[CH3:31][N+:32]([CH3:35])=[CH:33][Cl:34].[Cl-:3].[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15]([NH:45][CH:46]2[C:56](=[O:57])[N:48]3[C:49]([C:53]([OH:55])=[O:54])=[CH:50][CH2:51][S:52][C@H:47]23)=[O:17])[N:13]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)NCCCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reactant: O=P(Cl)(Cl)Cl
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Reaction time: 0.5 h

Procedure:
Vilsmeier reagent was prepared from N,N-dimethylformamide (0.6 g.) and phosphoryl chloride (1.2 g.) in an usual manner. 2-(2-Formamidothiazol-4-yl)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetic acid (syn isomer, 2.6 g.) was added to a stirred suspension of the Vilsmeier reagent in ethyl acetate (30 ml.) under ice-cooling and stirred at the same temperature for 30 minutes [hereinafter referred to solution A]. Trimethylsilylacetamide (5.5 g.) was added to a stirred suspension of 7-amino-3-cephem-4-carboxylic acid (1.4 g.) in ethyl acetate (20 ml.), and the mixture was stirred at 40° C. for 30 minutes. The solution A was added to the solution at -10° to -30° C. and stirred at the same temperature for an hour. Water and ethyl acetate (100 ml.) were added to the reaction mixture at -10° C. and the ethyl acetate layer was separated. Water was added to the ethyl acetate layer, and adjusted to pH 7.5 with a sodium bicarbonate saturated aqueous solution. The aqueous solution was separated and ethyl acetate was added thereto. The mixture was adjusted to pH 2.8 with 10% hydrochloric acid under ice-cooling. The ethyl acetate layer was separated, washed with a sodium chloride saturated aqueous solution and dried over magnesium sulfate. The solution was concentrated in vacuo, and the residue was pulverized with diisopropyl ether to give 7-[2-(2-formamidothiazol-4-yl)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.2 g.)
Reaction SMILES: O[CH2:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[ClH:15].[Cl:15][CH2:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccnc(CO)c1OC
Solvent: ClC(Cl)Cl
Product: COc1ccnc(CCl)c1OC
Product: Cl

Procedure:
2-Hydroxymethyl-3,4-dimethoxypyridine was reacted with thionyl chloride in chloroform to give 2-chloromethyl-3,4-dimethoxypyridine hydrochloride, m.p. 158°-9° (decomp), which was reacted with cysteamine hydrochloride and sodium ethoxide in ethanol to give 2-(3,4-dimethoxy-2-pyridylmethylthio)ethylamine.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]1[C:10]2=[CH:11][C:12]3[CH:13]=[CH:14][CH:15]=[N:16][C:17]=3[N:9]2[CH2:8][CH2:7]1.[OH-].[Na+].CC1C=CC([CH2:27][O:28]C(NNC(C2C=NC=CN=2)=O)=O)=CC=1>CN(C)C=O>[CH2:6]1[C:10]2=[C:11]([CH:27]=[O:28])[C:12]3[CH:13]=[CH:14][CH:15]=[N:16][C:17]=3[N:9]2[CH2:8][CH2:7]1
Reactant: c1cnc2c(c1)cc1n2CCC1
Reactant: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c2n(c3ncccc13)CCC2
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 46 %

Procedure:
Phosphorus oxychloride (3.85 ml) was added dropwise to N,N-dimethylformamide (25 ml) cooled in an ice-bath. The mixture was stirred 10 min before the addition of 2,3-dihydro-1H-3a,4-diaza-cyclopenta[a]indene (4.40 g) in N,N-dimethylformamide (7 ml). The mixture was stirred 45 min at 40° C., cooled to room temperature and concentrated aqueous sodium hydroxide added dropwise to pH10. The mixture was heated at 50° C. 10 min, cooled to room temperature and poured onto crushed ice. The organics were extracted with ethyl acetate (2×), the combined organic phases washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/hexane 1:1 to 1:0) to afford 2,3-dihydro-1H-3a,4-diaza-cyclopenta[a]indene-8-carbaldehyde (2.4 g, 46%) as a light orange oil which solidified on standing. Mp. 137-141; MS (EI): 187 (M+H)+, 143, 100; 1H NMR (δ, CDCl3) 10.01 (s, 1H), 8.45 (dd, 1H, J=1,8 Hz), 8.32 (dd, 1H, J=1,5 Hz), 7.23 (dd, 1H, J=5,8 Hz), 4.31 (t, 2H, J=6 Hz), 3.38 (t, 2H, J=8 Hz), 2.76 (dt, 2H, J=6,8 Hz) ppm.