Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[I:34][C:35]1[S:36][CH:37]=[CH:38][C:39]=1[C:40]([OH:42])=O.[CH3:43][CH:44]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[NH2:55])[CH2:45][CH:46]([CH3:48])[CH3:47]>C(#N)C.O>[CH3:43][CH:44]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[NH:55][C:40]([C:39]1[CH:38]=[CH:37][S:36][C:35]=1[I:34])=[O:42])[CH2:45][CH:46]([CH3:47])[CH3:48]
Reactant: CC(C)CC(C)c1ccccc1N
Reactant: O=C(O)c1ccsc1I
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)CC(C)c1ccccc1NC(=O)c1ccsc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 21.3 %

Procedure:
Under protective gas (argon), 0.56 ml (3.38 mmol) of N,N-diisopropylethylamine and 1.18 g (2.5 mmol) of bromotrispyrrolidinophosphonium hexafluorophosphate (PyBrop) are added to a solution of 516 mg (2.0 mmol) of 2-iodothiophene-3-carboxylic acid and 300 mg (1.7 mmol) of 2-(1,3-dimethylbutyl)phenylamine in 10 ml of acetonitrile. The reaction mixture is stirred at room temperature for 24 hours and, for work-up, added to water, extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. Column chromatography (cyclohexane/ethyl acetate gradient) gives 150 mg (21% of theory) of N-[2-(1,3-dimethylbutyl)phenyl]-2-iodothiophene-3-carboxamide [log P (pH 2.3)=4.14].
Reaction SMILES: [CH2:1]1[C@@H:6](N)[C@H:5](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](N)[C@H]2O)[C@@H:4](O)[C@H:3](O[C@H]2O[C@H](CN)[C@@H](O)C[C@H]2N)[C@H:2]1N.[Cl:33][C:34](OC(=O)C1C=CC=CC=1)=[O:35].C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl.N1C=CC=CC=1>[C:34]([Cl:33])(=[O:35])[C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](N)C[C@@H]1O
Reactant: O=C(Cl)OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1

Procedure:
When the requisite 5-O-thioformyl intermediate is prepared by reacting tobramycin with an excess of benzoyl chloroformate and potassium carbonate in aqueous methanol in a manner similar to that described in Preparation 1A(1) followed by reaction of the thereby formed 1,3,2',6',3"-penta-N-benzyloxycarbonyltobramycin with benzoyl chloride in pryidine in the manner of Preparation 1C(1) thence reaction of the resulting 1,3,2',6',3"-penta-N-benzyloxycarbonyl-4',2",4",6"-tetra-O-benzoyltobramycin with N,N-dimethyl-α-chloroformimidinium chloride in methylene chloride in pyridine followed by treatment with dry hydrogen sulfide in a manner similar to that described in Preparation 1D(1) whereby is obtained 1,3,2',6',3"-penta-N-benzloxycarbonyl-5-O-thioformyl-4',2",4",6"-tetra-O-benzoyltobramycin.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[C:48](Cl)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:48]([N:43]1[CH2:44][CH2:45][CH:40]([CH2:39][C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:46])[CH2:41][CH2:42]1)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(Cl)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2ccccc2)CC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 58 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and benzoyl chloride as starting materials in 58% yield. LCMS for C32H32ClN6O2 (M+H)+: m/z=567.2.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH3:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[CH3:22][C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15]
Reactant: CC(C)(c1ccccc1)N1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(c1ccccc1)N1CCNCC1

Procedure:
1-Benzyl-4-(1-methyl-1-phenyl-ethyl)-piperazine (290 mg, 1.0 mmol) was dissolved in ethanol (3 ml), and the solution was mixed with 10% palladium-carbon (60 mg) and stirred at room temperature for 15 hours in an atmosphere of hydrogen. The catalyst was removed by filtering the reaction solution, and the solvent was removed by evaporation under a reduced pressure to obtain crude 4-(1-methyl-1-phenyl-ethyl)-piperazine. The thus obtained crude 4-(1-methyl-1-phenyl-ethyl)-piperazine, 2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (310 mg, 1.0 mmol) and potassium carbonate (210 mg, 1.5 mmol) were stirred at room temperature for 14 hours in anhydrous N,N-dimethylformamide (3 ml). The reaction solution was mixed with ethyl acetate and washed with water and saturated brine, the solvent was removed by evaporation under a reduced pressure and then the thus obtained residue was dissolved in dichloromethane. The dichloromethane solution was washed with water and saturated brine and dried with anhydrous sodium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 33 mg (0.076 mmol, 7.7% in yield) of the title compound.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH2:7]([OH:9])[CH3:8].Cl[C:11]1[CH:16]=[C:15]([C:17]2[N:21]3[CH:22]=[C:23]([NH:26][CH:27]4[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]4)[CH:24]=[CH:25][C:20]3=[N:19][CH:18]=2)[CH:14]=[CH:13][N:12]=1>CS(C)=O.O>[CH2:7]([O:9][C:13]1[CH:14]=[C:15]([C:17]2[N:21]3[CH:22]=[C:23]([NH:26][CH:27]4[CH2:28][CH2:29][CH:30]([OH:33])[CH2:31][CH2:32]4)[CH:24]=[CH:25][C:20]3=[N:19][CH:18]=2)[CH:16]=[CH:11][N:12]=1)[CH3:8]
Reactant: OC1CCC(Nc2ccc3ncc(-c4ccnc(Cl)c4)n3c2)CC1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1cc(-c2cnc3ccc(NC4CCC(O)CC4)cn23)ccn1
Temperature: 120 °C

Procedure:
Cs2CO3 (5 eq, 1.45 mmol, 480 mg) and 4A molecular sieves (400 mg) are stirred in a mixture of DMSO (5 ml) and ethanol (5 eq 0.8 ml). To this suspension is added [4-[3-(2-chloro-pyridin-4-yl)-imidazo[1,2-a]pyridin-6-ylamino]-cyclohexanol (Example 2.1) (1 eq, 100 mg, 0.29 mmol). The reaction is heated at 120° C. for 16 hours. The mixture is diluted with H2O (20 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo to give a blue oil. The residue is purified by flash chromatography on silica eluting with 0-10% methanol in EtOAc The resulting residue is loaded onto a SCX-2 cartridge (resin loading 0.67 mmol/g) eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+=353
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:21])=O)=[N:17][CH:18]=3)[CH:12]=[C:6]2[C:5]=1[NH:22][C@H:23]1[C@@H:27]([CH3:28])[CH2:26][N:25]([C:29]([C:31]2([C:34]#[N:35])[CH2:33][CH2:32]2)=[O:30])[CH2:24]1)(=[O:3])[NH2:2].C[CH2:37][N:38](C(C)C)[CH:39](C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CNC.C1COCC1>CN(C=O)C>[C:34]([C:31]1([C:29]([N:25]2[CH2:26][C@H:27]([CH3:28])[C@H:23]([NH:22][C:5]3[C:6]4[N:7]([CH:10]=[C:11]([C:13]5[CH:18]=[N:17][C:16]([C:19](=[O:21])[N:38]([CH3:39])[CH3:37])=[CH:15][CH:14]=5)[CH:12]=4)[N:8]=[CH:9][C:4]=3[C:1]([NH2:2])=[O:3])[CH2:24]2)=[O:30])[CH2:32][CH2:33]1)#[N:35]
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@H]1CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(C(=O)O)nc3)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@H]1CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(C(=O)N(C)C)nc3)cc12
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To solution of 5-(3-carbamoyl-4-((3S,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methylpyrrolidin-3-ylamino)pyrrolo[1,2-b]pyridazin-6-yl)picolinic acid (15 mg, 0.026 mmol), DIPEA (0.018 mL, 0.102 mmol) and BOP (16.94 mg, 0.038 mmol) in DMF (0.3 mL) was added a 2 M solution of dimethylamine in THF (0.026 mL, 0.051 mmol) and the resulting mixture was stirred for 1 h. The mixture was concentrated to remove the THF and was purified by preparative LC/MS with the following conditions: column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-100% B over 15 minutes, then a 7-minute hold at 100% B; Flow: 25 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 7.2 mg of the title compound. LCMS (method H) retention time=1.78 min. (MH+501.2). 1H NMR (500 MHz, METHANOL-d4, appeared as rotomers) δ 9.06 (dd, J=7.9, 1.5 Hz, 1H), 8.40-8.29 (m, 2H), 8.22 (dd, J=11.1, 1.7 Hz, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.47-7.34 (m, 1H), 5.28-5.04 (m, 1H), 4.58-4.42 (m, 2H), 4.13-3.87 (m, 2H), 3.64-3.52 (m, 1H), 3.34-3.26 (m, 6H), 3.09-2.89 (m, 1H), 2.01-1.83 (m, 1H), 1.80-1.59 (m, 3H), 1.51-1.35 (m, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[CH2:7]1)[CH3:3].[H-].[Na+].[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][Cl:25])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.O>[ClH:25].[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:16][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[CH2:7][CH:6]([CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])[CH2:15][CH2:14]3)=[CH:22][CH:21]=1
Reactant: CN(C)CCC1CCc2cc(O)ccc2C1
Reactant: ClCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)CCC1CCc2cc(OCc3ccc(Br)cc3)ccc2C1
Product: Cl
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a suspension of (+)-2-[2-(N,N-dimethylamino)ethyl]-6-hydroxytetralin (9.2 g) in toluene (180 ml) was added sodium hydride (60% in oil, 2.0 g). After stirring at 50° C. for 30 min, a solution of 4-bromobenzyl chloride (9.7 g) in toluene (45 ml) was added to the reaction mixture, which was heated under reflux for one hr. The reaction mixture was diluted with water and concentrated. The residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried, and concentrated. The residue was dissolved in solvent mixture of ethyl acetate/hexane (1:4) and the precipitate was filtered off. The filtrate was concentrated and the residue was purified by alumina column chromatography (eluent:ethyl acetate:hexane=1:50 to 1:4) and converted into its hydrochloride. The crystals were washed with diisopropyl ether to obtain the titled compound (17.0 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH:20]=[CH:19][N:18]=[N:17]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:17]2[N:18]=[CH:19][CH:20]=[N:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:16]2[CH:20]=[CH:19][N:18]=[N:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1c[nH]nn1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Product: CC(C)(C)OC(=O)N1CCC(Cn2ccnn2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Cn2nccn2)CC1

Procedure:
By a similar manner to Reference Example 29, 1-tert-butoxycarbonyl-piperidin-4-methanol (1.08 g, 5.0 mmol) was reacted with 1H-1,2,3-triazole (1.04 g, 15 mmol) to give 1-tert-butoxycarbonyl-4-(2H-1,2,3-triazol-2-ylmethyl)piperidine as pale yellow solid substance (168 mg, 13%) and 1-tert-butoxycarbonyl-4-(1H-1,2,3-triazol-1-ylmethyl)piperidine as pale yellow solid substance (1.04 g, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].C(N([CH2:17][CH3:18])CC)C.Cl[S:20]([CH2:23][C:24]([O:26]C)=[O:25])(=[O:22])=[O:21]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][S:20]([CH2:23][C:24]([O:26][CH2:17][CH3:18])=[O:25])(=[O:22])=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COC(=O)CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Reactant: COc1ccc(N)cc1OC
Solvent: ClCCl
Product: CCOC(=O)CS(=O)(=O)Nc1ccc(OC)c(OC)c1
Reaction time: 2 h
Yield: 109.2 %

Procedure:
To a solution of 3,4-dimethoxyaniline (0.740 g, 4.83 mmol) and triethylamine (0.587 g, 5.80 mmol) in dry DCM (10 ml), a solution of methyl 2-(chlorosulfonyl)acetate (1 g, 5.36 mmol) in dry DCM (5 ml) was added dropwise at RT. The mixture was stirred for 2 hours, then the solvent was removed under vacuum; the residue was dissolved in EtOAc, washed with HCl 1N, NaHCO3 sat. sol, and brine, dried over Na2SO4, filtered and evaporated to give 1.6 g of a dark oil. After trituration with iPrOH (8 ml) and filtration, the desired product was obtained (0.74 g, 2.440 mmol, 50.5% yield, MS/ESI+ 311.9 [MNa]+) and used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1([CH2:7]O)[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.O=S(Cl)Cl.[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]=[S:26].CN1CCOCC1>ClCCCl>[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]1[S:26][CH2:7][C:2]2([CH2:6][CH2:5][CH2:4][CH2:3]2)[NH:1]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: NC1(CO)CCCC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Temperature: 100 °C
Yield: 81.1 %

Procedure:
To a solution of 1-amino-1-(hydroxymethyl)cyclopentane (Method B1c; 20.7 g, 180 mmol) and HCl (4M in p-dioxane, 400 mL) was added SOCl2 (15.7 mL, 216 mmol) and the resulting solution was heated at 100° C. for 18 h. The reaction mixture was concentrated under reduced pressure, then treated with 2-methyl4-nitrophenyl isothiocyanate (31.4 g, 162 mmol) and 1,2-dichloroethane (400 ml), followed by N-methylmorpholine (49 mL, 449 mmol). The resulting mixture was heated at 70° C. for 18 h, cooled to room temp. and concentrated under reduced pressure. The residue was treated with hot EtOAc, filtered and concentrated under reduced pressure. The residue was recrystallized (MeOH) to yield 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane (38.3 g, 81%): TLC (25% EtOAc/hex) Rf0.27.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[N:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)CCC>C1(C)C=CC=CC=1.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>[F:23][C:22]1[C:17]([C:13]2[N:12]([CH2:11][C:6]3[C:7]([CH2:8][CH2:9][CH3:10])=[C:2]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[N:3]=[CH:4][N:5]=3)[CH:16]=[CH:15][N:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: CCCc1c(Cl)ncnc1Cn1ccnc1-c1ncccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCc1c(Cn2ccnc2-c2ncccc2F)ncnc1-c1ccncc1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-chloro-6-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-pyrimidine (268 mg, 0.81 mmol), 4-tributylstannanyl-pyridine (1.21 mmol), Pd(PPh3)4 (0.08 mmol, 93 mg) in toluene (10 mL) is degassed. The mixture is then heated at 100° C. overnight. Saturated KF aqueous solution (8 mL) is added and the mixture is stirred for 15 minutes. The layers are separated and the aqueous layer is extracted with EtOAc (10 mL). The combined extracts are washed with brine (15 mL), dried (Na2SO4), and evaporated. Preparative TLC (5% methanol in DCM) purification of the residue provides the title product. 1H NMR (CDCl3) 8.95 (s, 1H), 8.65 (d, 1H), 8.26 (d, 1H), 7.77-7.84 (m, 2H), 7.49 (t, 1H), 7.34 (t, 1H), 7.30 (s, 1H), 7.19-7.22 (m, 1H), 7.14 (s, 1H), 5.92 (s, 2H), 2.87-2.91 (m, 2H), 1.46-1.52 (m, 2H), 0.81 (t, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].[C:7](Cl)(Cl)=[O:8].C1(C)C=CC=CC=1.[CH:18]([N:21]([CH:24]([CH3:26])C)CC)([CH3:20])C.N1CCCC1>ClCCl>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([N:21]1[CH2:18][CH2:20][CH2:26][CH2:24]1)=[O:8]
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1nccs1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: O=C(Nc1nccs1)N1CCCC1
Temperature: -60 °C
Reaction time: 0.33 h

Procedure:
Thiazol-2-amine (7.01 g, 10.0 mmol) was dissolved into dichloromethane (700 mL) and cooled to −60° C. The resulting suspension was treated with 20% phosgene in toluene (54 mL, 103 mmol) over 5 minutes and stirred for 10 minutes more before the addition of diisopropylethylamine (24 mL, 138 mmol). After the mixture was stirred for another 20 minutes near −60° C., pyrrolidine (17.5 mL, 210 mmol) was added, and after a few minutes the cold bath was removed. The mixture was warmed to 10° C. over a period of more than an hour, and then was quenched with concentrated aqueous ammonium hydroxide (100 mL) and stirred thoroughly. The aqueous phase was separated and extracted with dichloromethane, and the combined organic phases were washed twice with water; each aqueous phase was back-extracted with dichloromethane. The combined organic phases were concentrated to a slurry and diluted with 2:1 hexanes/ethyl acetate (30 mL). The solids were collected by filtration, rinsed with more 2:1 hexanes/ethyl acetate, slurried and rinsed in 2:1 hexanes/dichloromethane, and dried under vacuum to give the title compound.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][C:25]([CH3:30])([CH3:29])[CH2:26][CH2:27]O.COC(C)(C)CC=O.Cl.[OH:40][NH2:41]>C(OCC)(=O)C.N1C=CC=CC=1.C(Cl)(Cl)Cl>[OH:40][N:41]=[CH:27][CH2:26][C:25]([O:24][CH3:23])([CH3:30])[CH3:29]
Reactant: COC(C)(C)CCO
Reactant: NO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: COC(C)(C)CC=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(C)(C)CC=NO
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.2 %

Procedure:
Dess-Martin reagent (15.0 g) was added to a chloroform solution (35 ml) of 3-methoxy-3-methyl-1-butanol (3.3 g) under ice cooling and stirred at room temperature for 5 hours. Chloroform was added to the reaction mixture and the organic layer was washed with an aqueous solution of 20 wt. % sodium thiosulfate, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure, thereby obtaining a crude product containing 3-methoxy-3-methylbutanal. Hydroxyamine hydrochloride (3.5 g) was added to a pyridine solution of the obtained crude product (30 ml) under ice cooling and stirred at room temperature overnight under nitrogen atmosphere. Ethyl acetate was added to the reaction mixture and the organic layer was washed with water, 1M-hydrochloric acid aqueous solution and saturated brine. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (KP-Sil, Biotage, ethyl acetate/n-hexane=10 to 50%), thereby obtaining (N-hydroxy-3-methoxy-3-methylbutan-1-imine (1.4 g) as a colorless oily substance.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][O:16][C:15]=2[CH2:19]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[Cl:37][C:38]1[CH:39]=C(O)C=[CH:42][CH:43]=1.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>CC#N>[Cl:37][C:38]1[CH:39]=[C:15]([CH:19]=[CH:42][CH:43]=1)[O:16][CH2:17][C:18]1[CH:47]=[CH:45][O:46][C:14]=1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]
Reactant: Cc1ccc(S(=O)(=O)OCc2occc2C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(OCc2ccoc2C2CCNCC2)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4-[2-(Toluene-4-sulfonyloxymethyl)furan-3-yl]piperidine-1-carboxylic acid t-butyl ester (65 mg, 0.15 mmol was dissolved in MeCN (770 μL) and added to a mixture of potassium carbonate (32 mg, 230 mmol, 1.6 eq.) and 3-chlorophenol (28.8 mg, 224 μmol, 1.5 eq.). The resulting mixture was shaken at 50° C. overnight. The mixture was then cooled and the solids removed. The supernatant was combined with TFA (12 μL, 160 mmol, 1.0 eq.) and the resulting mixture was shaken overnight at room temperature. The solution was concentrated using an evaporator, then dissolved in 1:1 AcOH:H2O (5.0 mL) then an additional 2.0 ml AcOH, filtered, and purified by preparative HPLC to yield the title compound as a TFA salt (4.3 mg, 98% purity). MS m/z: [M+H]+ calcd for C16H18ClNO2, 292.10. found 292.0.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:11]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Brc1cccnc1
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1cccnc1

Procedure:
Following the general method as outlined in Example 10, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 3-bromopyridine (Fluka), the title compound was obtained as an off-white solid after purification by preparative HPLC.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([CH:17]1[CH2:22][O:21][CH2:20][CH2:19][O:18]1)=[O:16].[CH:23](=[O:25])[CH3:24]>O1CCCC1>[CH3:13][O:14][C:15]([C:17]1([CH:23]([OH:25])[CH3:24])[CH2:22][O:21][CH2:20][CH2:19][O:18]1)=[O:16]
Reactant: CC=O
Reactant: COC(=O)C1COCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(C(C)O)COCCO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
A solution of N,N-diisopropylamine (1.67 g, 2.3 mL, 16.5 mmol) in anhydrous tetrahydrofuran (10 mL) was stirred at −78° C. under nitrogen. n-Butyllithium (6.6 mL, 16.5 mmol, 2.5 M solution in hexane) was added dropwise and the reaction mixture was stirred at −78° C. for 30 minutes. A solution of [1,4]dioxane-2-carboxylic acid methyl ester (1.61 g, 11 mmol) in tetrahydrofuran (10 mL) was added and the reaction mixture was stirred at −78° C. for 30 minutes. Acetaldehyde (1.45 g, 1.8 mL, 33 mmol) was added in one portion. The cooling bath was removed and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 5° C. and ice-cold 1 M hydrochloric acid was added to acidify the reaction mixture to pH 2. Sodium chloride was added to saturate the solution and the mixture was extracted with diethyl ether (4×). The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 1:1 to 0:1 to afford the title compound (1.49 g, 71%), as an oil, and as a 3:1 mixture of diastereoisomers. LCMS (m/z) 213.2 [M+H], Tr=0.62 min.