Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-:1].[Br:2]CC[CH2:5][N+:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]CCCCCC)([CH3:8])[CH3:7].[OH-].[Na+]>CO>[Br-:2].[Br:1][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N+:6]([CH3:5])([CH3:7])[CH3:8]
Reactant: CCCCCCCCCCCC[N+](C)(C)CCCBr
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[N+](C)(C)CCCCCCBr
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Six percent crosslinked poly(allylamine) was made as stated in Example 82. To a flask were added the crosslinked poly(allylamine) (12.5 grams; 6% crosslinked; ground to ~30 mesh), (3-bromopropyl)dodecyldimethylammonium bromide (17.5 grams; made by reaction of 1,3-dibromopropane and N,N-dimethyl-1-aminododecane in diethyl ether), and methanol (334 mL). The mixture was heated to 65° C. with stirring. Upon reaching 65° C., aqueous sodium hydroxide (1.14 grams of 50% solution) was added and the stirring continued at 65° C. for 2 hours. Two additional aliquots of aqueous sodium hydroxide (1.14 grams of 50% solution) were sequentially added and the stirring continued at 65° C. for an additional 2 hours for each aliquot. Aqueous sodium hydroxide (1.14 grams of 50% solution) was then added and the stirring continued at 65° C. for an additional 12 hours. The mixture was then allowed to cool to room temperature.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[NH:6][C:7]2[C:8](=[CH:10][CH:11]=[C:12]([C:18]([O:20][CH3:21])=[O:19])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])[N:9]=1.IC.[C:24](=O)(O)[O-].[Na+]>CO.O1CCCC1.Cl>[CH3:24][N:9]1[C:8]2=[CH:10][CH:11]=[C:12]([C:18]([O:20][CH3:21])=[O:19])[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:7]2[N:6]=[C:5]1[CH3:4]
Reactant: O=C([O-])O
Reactant: COC(=O)c1ccc2nc(C)[nH]c2c1C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(nc(C)n2C)c1C(=O)OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium methoxide (1.98 g, 36.6 mmol) is added to a solution of dimethyl 2-methyl-4,5-benzimidazoledicarboxylate (7.44 g, 33.3 mmol) in methanol and tetrahydrofuran. After 5 minutes, iodomethane (2.18 mL, 35.0 mmol) is added and the mixture is stirred for 24 hours at room temperature. Additional sodium methoxide (1.80 g, 33.3 mmol) and iodomethane (2.07 mL, 33.3 mmol) are added and stirring is continued for another 15 hours. The reaction mixture is concentrated in vacuo to give a residue which is dispersed in dilute hydrochloric acid, and treated with sodium bicarbonate to pH 8 and extracted with chloroform. The combined organic extracts are dried (MgSO4) and concentrated in vacuo to give a residue which is recrystallized from ethyl acetate to afford the title product as an orange solid, mp 205°-208° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18]C(OC(C)(C)C)=O)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:27]>CCOC(C)=O>[ClH:27].[CH2:1]([O:8][C:9](=[O:26])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][NH2:18])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCc1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
A solution of [4-(tert-butoxycarbonylamino-methyl)-phenyl]-carbamic acid benzyl ester (1.25 g, 3.51 mmol) in EtOAc (20 mL) was cooled on an ice-bath and 4 M hydrogen chloride in EtOAc (20 mL) was added. The mixture was stirred at ambient temperature for 20 min. The precipitate was collected by filtration, washed with EtOAc, and dried under reduced pressure to give (4-aminomethyl-phenyl)-carbamic acid benzyl ester hydrochloride (957 mg, 93%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].[CH3:20][N:21]([CH:23]=[O:24])[CH3:22]>>[Cl:1][C:2]1[C:3]([CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[C:4]([CH2:8][O:9][C:23](=[O:24])[N:21]([CH3:22])[CH3:20])[CH:5]=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: OCc1cncc(Cl)c1COC1CCCCO1
Agent: [H-]
Agent: [Na+]
Product: CN(C)C(=O)OCc1cncc(Cl)c1COC1CCCCO1
Reaction time: 8 h

Procedure:
To a solution of [5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridin-3-yl]-methanol (0.11 g, 0.43 mmol) and NaH (17 mg, 0.86 mmol) in DMF (3 mL) dimethylcarbamyl chloride (0.39 μL, 2.15 mmol) was added and stirring was continued at RT overnight. Solvents were concentrated in vacuo and the residue was partitioned between EA (10 mL) and saturated NaCl solution (10 mL). After extraction of the aqueous layer with EA (2×10 mL) the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 328.9 [M+H+].
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.[OH-].[Na+].S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>>[CH:3]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)=[CH2:2]
Reactant: ClCCOC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: C=COC1CCCCO1
Reaction time: 1 h

Procedure:
A mixture of 1.52 mol of 2-(2-chloroethoxy)-tetrahydro-2H-pyran, 93 g of sodium hydroxide reduced to a powder and 25 g of tetrabutylammonium monosulphate is stirred for 1 hour and then distilled at 50° C. and 20 torr. The distillate is then dried over sodium sulphate, allowing the expected product to be isolated.
Reaction SMILES: C(N(CC)CC)C.C=O.C(=O)C(C)C.[OH:15][CH2:16][C:17]([CH3:28])([CH3:27])[C:18]([O:20][CH2:21]C(C)(C)CO)=[O:19]>CO.C[O-].[Na+]>[OH:15][CH2:16][C:17]([CH3:28])([CH3:27])[C:18]([O:20][CH3:21])=[O:19]
Reactant: CC(C)(CO)COC(=O)C(C)(C)CO
Agent: C=O
Agent: CC(C)C=O
Agent: C[O-]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)CO
Yield: 88.3 %

Procedure:
120 g (1.18 mol) of triethylamine were added with vigorous stirring under reflux to a hot mixture at 50° C. of 975 g (12 mol) of 37% strength formaldehyde solution and 865 g (12 mol) of isobutyraldehyde, and the mixture was allowed to rise to 92° to 94° C. in the course of 10 minutes. Triethylamine and water were then distilled off at from 150 to 30 mbar in the course of from 15 to 20 minutes and at a maximum bottom of column temperature of from 70° to 75° C. The remaining mixture was then heated under atmospheric pressure to 160° C. in the course of 15 minutes, during which, essentially, further residues of water came off, and was stirred at that temperature for a further 160 minutes. Distillation of the mixture gave 180 g of a fraction of boiling range 80°-95° C. at 8-10 mbar, which contained 119 g (1.17 mol) of hydroxypivalinaldehyde, corresponding to 9.75%, based on the starting materials. This left a residue of 305 g which, according to analysis by gas chromatography, comprised 96% (869 g; 4.26 mol) of 2,2-dimethylpropane-1,3-diol hydroxypivalate, corresponding to a 71% yield, based on the starting materials (overall selectivity 80.75%). The residue was taken up in 1,100 ml of methanol, 15 g (0.28 mol) of sodium methanolate were added, and the mixture was stirred at room temperature for 15 hours. Neutralization with acetic acid and fractional distillation gave 496.5 g (3.76 mol) of methyl hydroxypivalate, corresponding to 88.34% yield, based on esterdiol III, and also 375.4 g (3.68 mol) of 2,2-dimethyl-1,3-propanediol, corresponding to an 86.4% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.BrCCBr.[Mg].Br[CH2:17][C:18]([CH3:20])=[CH2:19]>O1CCCC1>[CH3:19][C:18](=[CH2:17])[CH2:20][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: C=C(C)CBr
Reactant: Brc1ccc2c(c1)CCO2
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: C=C(C)Cc1ccc2c(c1)CCO2
Temperature: 30 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of 5-bromo-2,3-dihydrobenzofuran (50 grams, 0.251 mole), and 1,2-dibromoethane (2.2 ml) in tetrahydrofuran (250 ml) was added dropwise to a stirred suspension of magnesium turnings (7.5 grams, 0.31 gram-atoms) in tetrahydrofuran (50 ml) over a period of 45 minutes. During the addition the reaction temperature was maintained at 30° C. The solution was cooled in an ice-bath and 3-bromo-2-methylpropene was added all at once. After stirring overnight, the reaction was quenched with cold 2% hydrochloric acid and the mixture was extracted with ether. Evaporation of solvent gave 5-(2-methylallyl)-2,3-dihydrobenzofuran as an oil (43.4 grams, 99%). M+ 174.
Reaction SMILES: N(OCCC(C)C)=[O:2].[CH3:9][N:10]([CH3:27])[S:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](N)=[O:19])=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=1)(=[O:13])=[O:12].O>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:9][N:10]([CH3:27])[S:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:2])=[O:19])=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=1)(=[O:13])=[O:12]
Reactant: CN(C)S(=O)(=O)c1ccc(C(N)=O)c(C(F)(F)F)c1
Reactant: CC(C)CCON=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(C(=O)O)c(C(F)(F)F)c1

Procedure:
Isoamyl nitrite (150 ml) was added to a stirred mixture of 4-(N,N-dimethylaminosulphonyl)-2-trifluoromethylbenzamide (15.1 g) in acetic acid and concentrated sulphuric acid while maintaining the temperature at 70°-80° C. It was cooled, poured into water and extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered to give 4-(N,N-dimethylaminosulphonyl)-2-trifluoromethylbenzoic acid (11.2 g) as a white solid, m.p. 188.9°-189.4° C.
Reaction SMILES: CS(C)=O.[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]([C:21]([OH:23])=[O:22])=[CH:16][N:11]3[C@@H:12]([CH3:15])[CH2:13][O:14][C:9]([C:10]=23)=[C:8](F)[C:7]=1[F:25].C(OC([NH:33][C:34]12[CH2:39][CH:38]1[CH2:37][NH:36][CH2:35]2)=O)(C)(C)C>C(N(CC)CC)C>[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]([C:21]([OH:23])=[O:22])=[CH:16][N:11]3[C@@H:12]([CH3:15])[CH2:13][O:14][C:9]([C:10]=23)=[C:8]([N:36]2[CH2:37][CH:38]3[C:34]([NH2:33])([CH2:39]3)[CH2:35]2)[C:7]=1[F:25]
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Reactant: CC(C)(C)OC(=O)NC12CNCC1C2
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@H]1COc2c(N3CC4CC4(N)C3)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 62.9 %

Procedure:
To a dimethyl sulfoxide (5 ml) solution of 8-amino-9,10-difluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (200 mg, 0.68 mmol) were added 1-tert-butoxycarbonylamino-3-azabicyclo[3.1.0]hexane (Fr. 1; 270 mg, 1.36 mmol) and triethylamine (1 ml), and the mixture was heated at 100° C. for 24 hours. After evaporation of the solvent under a reduced pressure, the thus obtained residue was mixed with chloroform (50 ml), the resulting solution was washed with 10% citric acid (20 ml×2) and dried over sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained residue was mixed with concentrated hydrochloric acid (5 ml) and stirred at room temperature for 5 minutes, and the mixture was washed with chloroform (30 ml×3), alkalified by adding 20% sodium hydroxide aqueous solution, then, adjusted to pH 7.2 with concentrated hydrochloric acid and extracted with chloroform (50 ml×3). The extract was dried over sodium sulfate, and the solvent was evaporated under a reduced pressure to yield 201 mg of the crude title compound. By recrystallizing this from 28% ammonia aqueous solution-ethanol, 160 mg (63%) of the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][NH2:9])[CH:3]=1.[C:10](O)(=O)[CH3:11]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:10]([CH3:11])=[N:9][N:8]=[C:4]2[CH:3]=1
Reactant: NNc1cc(Br)ccn1
Reactant: CC(=O)O
Product: Cc1nnc2cc(Br)ccn12
Temperature: 125 °C

Procedure:
To a vial flushed with argon was added 4-bromo-2-hydrazinylpyridine (1.88 g, 10 mmol) and acetic acid (2.5 mL). The mixture was refluxed at 125° C. under argon for 16 hours. After cooling to room temperature, acetic acid was distilled off, and to the residue was added saturated NaHCO3 (150 mL) and DCM (150 mL). The aqueous layer was extracted with DCM, the organic extracts were combined, dried over MgSO4, and concentrated to give the product. 1H NMR (400 MHz, CDCl3) δ 7.95-7.90 (m, 1H), 7.73 (d, J=7.3 Hz, 1H), 6.94 (dd, J=7.3, 1.7 Hz, 1H), 2.74 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8]C2C=CC3OC(=O)NC=3C=2)[C:5]([CH3:19])=[CH:4][N:3]=1.Cl.CS(C1C=C([NH2:31])C=CC=1)(=O)=O.C(O)(C(F)(F)F)=O>CC(O)C>[CH3:19][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH2:31])=[N:3][CH:4]=1
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: Cc1cnc(Cl)nc1Nc1ccc2oc(=O)[nH]c2c1
Agent: Cl
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(N)nc1N
Temperature: 87.5 °C
Reaction time: 40 h
Yield: 49 %

Procedure:
To a vial with 5-(2-chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one (138.3 mg, 0.5 mmol) and 3-(methylsulfonyl)benzenamine hydrochloride (207.7 mg, 1.0 mmol), i-PrOH (10 mL) was added, followed by TFA (116 μL, 1.5 mmol). The vial was tightly closed, and the reaction mixture was stirred at 85-90° C. for 40 h. The solvent was removed in vacuo, and the crude product was purified by RP-HPLC. N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(3-methylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine was obtained as a mono-trifluoroacetate salt: an off-white solid, 129 mg (49% yield); 1H NMR (300 MHz, DMSO) δ 11.60 (s, 1H), 9.43 (s, 1H), 8.43 (s, 1H), 8.20 (s, 1H), 8.11 (br d, J=7.5, 1H), 7.96 (d, J=0.8, 1H), 7.49-7.33 (m, 4H), 7.27 (d, J=8.5, 1H), 3.13 (s, 3H), 2.16 (s, 3H); LCMS (M+) m/z 412.47.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:21]2[CH2:22][CH2:23][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Fc1ccc2c(c1)NCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-fluoroindoline (9.36 g, 68 mmol) in CH2Cl2 (100 mL) was added 1-Boc-4-piperidone (13.6 g, 68 mmol). The resulting mixture was stirred at room temperature for 1 h and NaBH(OAc)3 (18 g, 85 mmol, 1.25 equiv) was added. The resulting mixture was stirred at room temperature for 24 h and was then poured slowly to a vigorously stirred Na2CO3(aq). After 30 min stirring, the layers were separated. The aqueous layer was extracted with CH2Cl2 (100 mL). The combined organic layer was washed with brine (100 mL), dried (Na2SO4), and filtered. The solvent was removed by roto-evaporator, Et2O (10 mL) and then hexane (150 mL) were added to the resulting residue. The mixture was allowed to stand, resulting in the formation of a white solid, which was collected and washed with 5% Et2O/hexane and then dried. This was repeated to yield three crops of tert-butyl 4-(6-fluoroindolin-1-yl)piperidine-1-carboxylate as a white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClCl.[CH:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:15]Br>ClCCCl>[Br:15][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH:7]=[O:14]
Reactant: O=Cc1ccccc1
Reactant: BrBr
Agent: ClCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=Cc1cccc(Br)c1
Reaction time: 2 h
Yield: 149.7 %

Procedure:
To 1,2-dichloroethane (1,2-dichloroethane: 143.8 g, 1-bromo-2-chloroethane: 60.5 g, 1,2-dibromoethane: 4.8 g) recovered from Example 2 was added fresh 1,2-dichloroethane (41.5 g), and 98% aluminum chloride (0.65 mol, 88.6 g) was mixed. Into this was blown chlorine (0.25 mol, 17.8 g) at °C., and 97% benzaldehyde (0.50 mol, 54.6 g) was added over 1 hour at 40° C. After bromine (0.30 mol, 48.0 g) was added dropwise to this mixture over 2 hours at 40° C., the resulting mixtures were stirred for 2 hours at that temperature. The post-treatment was carried out by the similar procedure to that in Example 1. As a result, 83.1 g of 3-bromobenzaldehyde were obtained.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[OH:17])[C:7](=[O:18])[C:6]=2[CH:5]=[C:4]([C:19]2[NH:23][N:22]=[N:21][N:20]=2)[CH:3]=1.S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[C:2]([O:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[O:17][C:14](=[O:16])[CH3:13])[C:7](=[O:18])[C:6]=2[CH:5]=[C:4]([C:19]2[NH:23][N:22]=[N:21][N:20]=2)[CH:3]=1)(=[O:1])[CH3:3]
Reactant: O=C1c2cccc(O)c2C(=O)c2c(O)cc(-c3nnn[nH]3)cc21
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cccc2c1C(=O)c1c(OC(C)=O)cc(-c3nnn[nH]3)cc1C2=O
Reaction time: 0.17 h

Procedure:
5-(9,10-Dihydro-4,5-dihydroxy-9,10-dioxoanthracen-2-yl)tetrazole (160.0 g) was coated with concentrated sulphuric acid (300 g) and then acetic anhydride (6 liters) added. The mixture was stirred under a nitrogen purge at room temperature for 3 hours. The solid present was isolated by filtration and pulled dry. The isolated solid was then slurried in ice for 10 minutes. The material was re-isolated, washed with water and then pulled dry. The yellow/green solid was then dried in vdcuo at 25° C., m.p. 189°-190° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]([CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[CH2:25][CH2:26][CH3:27])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:6][CH:7]=1.C([O:38]C(N1CCC(N(CC2C=CC=C(C3C=CN=C(Cl)N=3)C=2)CCC)CC1)=O)(C)(C)C.FC1C=C(C=CC=1)CCN>>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]([CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[CH2:25][CH2:26][CH3:27])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[OH:38]
Reactant: CCCN(Cc1cccc(-c2ccnc(NCCc3cccc(F)c3)n2)c1)C1CCNCC1
Reactant: CCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: NCCc1cccc(F)c1
Product: CCCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(F)c3)n2)c1)C1CCNCC1

Procedure:
[2-(3-Fluoro-phenyl)-ethyl-(4-{3-[(piperidin-4-yl-propyl-amino)-methyl]-phenyl}-pyrimidin-2-yl)-amine: Intermediate 93 was coupled with 3-fluorophenethylamine following procedure F. The resulting product was deprotected following procedure G. The product was purified by HPLC. LC-MS showed the product had the expected M+H+ of 448. 1H NMR (Varian 300 MHz, DMSO, shifts relative to the solvent peak at 2.50 ppm) δ 8.3 (d, 1H), 8.0 (s, 1H), 7.9 (d, 1H), 7.4 (m, 2H), 7.3 (m, 2H), 7.1 (d, 2H), 7.0 (d, 1H), 3.6 (s, 2H), 3.5 (d, 2H), 3.2 (d, 2H), 2.9 (m, 4H), 2.8 (m, 1H), 2.5 (d, 2H), 1.8 (m, 4H), 1.3 (m, 2H), 0.96 (t, 3H).
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][NH:13][CH:14]=2)[S:7][C:6]=1[C:15]([NH2:17])=[O:16].C([O-])(O)=O.[Na+].[C:23]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.CC1C=CC(S(O)(=O)=O)=CC=1.[O-]S([O-])(=O)=O.[Mg+2]>CN(C=O)C.CCOC(C)=O>[CH3:3][N:4]1[C:5]2[CH:9]=[C:8]([C:10]3[CH:14]=[N:13][NH:12][CH:11]=3)[S:7][C:6]=2[C:15](=[O:16])[NH:17][C:23]21[CH2:27][CH2:26][CH2:25][CH2:24]2
Reactant: O=C1CCCC1
Reactant: CNc1cc(-c2cn[nH]c2)sc1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1c2cc(-c3cn[nH]c3)sc2C(=O)NC12CCCC2
Yield: 53.3 %

Procedure:
A mixture of 3-(methylamino)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide dihydrochloride (145 mg, 0.491 mmol), saturated aqueous NaHCO3 (50 mL) and EtOAc (50 mL) was shaken well. The organic layer was collected, dried over MgSO4, filtered and concentrated under reduced pressure. This residue was mixed with cyclopentanone (2.00 mL, 22.6 mmol), PTSA (9.34 mg, 0.049 mmol), MgSO4 (118 mg, 0.982 mmol) and DMF (2 mL). This mixture was stirred at 80° C. overnight. The mixture was poured into saturated aqueous NaHCO3 and extracted with 3:1 EtOAc/THF (100 mL), and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc then to 90:10 EtOAc/MeOH) to afford a yellow solid. This solid was triturated with EtOAc, and the precipitate was collected by filtration to afford the title compound (75.4 mg, 53%) as a yellow solid:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[S:13][CH:12]=[C:11]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])[CH:10]=1>C(Cl)Cl>[CH3:8][C:9]1[S:13][CH:12]=[C:11]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])[CH:10]=1
Reactant: Cc1cc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reaction time: 0.75 h

Procedure:
Trifluoroacetic acid (2.5 mL) was added to a solution of tert-butyl 4-(5-methylthiophene-3-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 104, step a) (0.34 g) in DCM (10 mL) and the resulting mixture was stirred for 45 minutes and allowed to stand overnight. The solvent was evaporated in vacuo. Toluene (3×25 mL) was added and the mixture evaporated in vacuo. The residue was dissolved in methanol (20 mL) and applied to a SCX cartridge pre-wetted with methanol. The cartridge was washed with methanol (40 mL) and eluted with 2M ammonia in methanol solution (20 mL). The eluent was evaporated in vacuo to give the subtitled compound as a colourless oil. Yield 0.25 g.
Reaction SMILES: CN(P(N(C)C)(N(C)C)=O)C.CN(C)P(N(C)C)(N(C)C)=O.CS(Cl)(=O)=O.C[C:29]([N:31]([CH3:33])[CH3:32])=[O:30].CNC>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C1COCC1.O1CCCC1>[CH3:32][N:31]([CH:29]=[O:30])[CH3:33].[CH3:32][N:31]([CH3:33])[CH:29]=[O:30]
Reactant: CC(=O)N(C)C
Agent: Cl[Pd]Cl
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CN(C)C=O

Procedure:
TEA - triethylamine; HMPA - hexamethylphosphoramide; THF - tetrahydrofuran; MSC - methanesulphonyl chloride; BTPC - bis(triphenylphosphine)palladium (II) chloride; DMA - dimethylamine; IMS - industrial methylated spirits; SPC - Short path chromatography carried out on silica (Merck 7747) unless otherwise stated. FCC - Flash column chromatography carried out on silica (Merck 9385). `Dried` refers to drying using sodium sulphate or magnesium sulphate unless otherwise stated.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]=[O:14])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].Cl.O>O1CCCC1.C(O)(C)C>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][OH:14])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)COC1(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@H](CO)COC1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To an ice cold mixture of (S)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid t-butyl ester (2.00 g, 8.72 mmol) in tetrahydrofuran (15 mL) and isopropanol (15 mL) was added sodium borohydride (0.99 g, 26.17 mmol). After addition was complete the mixture was stirred at 0° C. for 1 h. Upon completion of the reaction 1N aqueous hydrochloric acid (10 mL) was slowly added. The mixture was poured into water and extracted with ethyl acetate (3×30 mL). The combined organic fractions were washed with a saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained (R)-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid t-butyl ester (1.88 g, 93%) as a colorless oil and was used without further purification: LR-ES-MS m/z calculated for C11H21NO4 [M]+ 231, observed 232 [M+H]+.