Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]3[CH2:16][CH2:15][O:14][C:13](=[O:17])[NH:12]3)[CH2:7][CH2:6]2)[O:4]CC1.C(#N)C.Cl.C(=O)(O)[O-].[NH4+]>O>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[CH2:16][CH2:15][O:14][C:13](=[O:17])[NH:12]2)[CH2:7][CH2:6]1
Reactant: O=C1NC(C2CCC3(CC2)OCCO3)CCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: O=C1CCC(C2CCOC(=O)N2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A 250 mL round bottom flask was charge with 4-(1,4-dioxaspiro[4.5]decan-8-yl)-1,3-oxazinan-2-one (1.39 g, 5.76 mmol) and acetonitrile (96 mL). A solution of concentrated HCl (6.4 mL) in water (19 mL) was added to the mixture. The mixture was stirred at room temperature for 20 h. Saturated aqueous ammonium bicarbonate was added until the pH was >7. The mixture was extracted with ethyl acetate. Dry organic layer with MgSO4, filter, and concentrate in vacuo to give the target material as a clear oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[CH:9]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:7]=2)[CH:3]=[N:2]1.[CH3:27]C1NN=CC=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[CH3:27][C:5]1[C:4]([C:6]2[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[CH:9]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:7]=2)=[CH:3][NH:2][N:1]=1
Reactant: c1cn2c(-c3cn[nH]c3)nc(-c3ccc(N4CCOCC4)cc3)cc2n1
Reactant: Cc1[nH]ncc1B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1n[nH]cc1-c1nc(-c2ccc(N3CCOCC3)cc2)cc2nccn12
Temperature: 100 °C
Yield: 48.1 %

Procedure:
4-(4-(5-Chloroimidazo[1,2-c]pyrimidin-7-yl)phenyl) morpholine (Example 113, Step D) (0.120 g, 0.381 mmol), 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.119 g, 0.572 mmol) and potassium carbonate (0.158 g, 1.144 mmol) were suspended in a mixture of DME (5 mL) and water (2 mL) and de-gassed with Ar(g). Tetrakis(triphenylphosphine)palladium (0) (0.0220 g, 0.0191 mmol) was added and the reaction sealed and heated at 100° C. for 4 hours. The reaction mixture was diluted with water and filtered. The solids were washed with acetone and dried under high vacuum to afford 4-(4-(5-(3-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-7-yl)phenyl)morpholine (0.0660 g, 0.1831 mmol, 48.0% yield). MS (apci) m/z=361.1 (M+H).
Reaction SMILES: [C:1]([C:5]1[C:14]2[CH:13]=[C:12]([NH:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)[CH:11]=[CH:10][C:9]=2[C:8]([CH3:28])([CH3:27])[CH2:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:35](Br)[CH:36]=[CH2:37].CC(N(C)C)=O>CCOCC>[C:1]([C:5]1[C:14]2[CH:13]=[C:12]([N:15]([CH2:37][CH:36]=[CH2:35])[C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=3)[CH:11]=[CH:10][C:9]=2[C:8]([CH3:27])([CH3:28])[CH2:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C(C)(C)C)=CCC3(C)C)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: C=CCN(c1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C(C)(C)C)=CCC2(C)C
Temperature: 75 °C

Procedure:
A mixture of ethyl 4-(8-t-butyl-5,5-dimethyl-5,6-dihydronaphthalen-2-ylamino)-benzoate (Compound 84, 170 mg, 0.45 mmol), K2CO3 (900 mg), allyl bromide (1 mL) and dimethylacetamide (5 mL) was heated to 75° C. in a sealed tube for 7 days. The mixture was diluted with ether (70 mL), washed with brine, dried and the solvent was removed. Silica gel flash chromatography gave the title compound.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([F:11])[C:3]=1[NH2:4].[N:12]([O-])=O.[Na+].Cl.C(O)(=O)C>S(=O)(=O)(O)O>[F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([F:11])[C:3]=1[NH:4][NH2:12]
Reactant: O=N[O-]
Reactant: Nc1c(F)cc(F)c(F)c1F
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: NNc1c(F)cc(F)c(F)c1F
Yield: 61 %

Procedure:
2,3,4,6-Tetrafluoroaniline (27.5 g) was diazotised with sodium nitrite (12.5 g) in a mixture of concentrated hydrochloric acid (580 ml) and glacial acetic acid (110 ml). The filtered diazonium salt solution was reduced by the addition of a solution of stannous chloride dihydrate (108 g) in concentrated sulphuric acid (108 ml) at 0°-10° C. The resulting hydrazine hydrochloride solution was evaporated to dryness and the residue was dissolved in water and basified by the addition of aqueous ammonia solution (S.G. 0.880). The precipitated solid was filtered off and the filter pad was well washed with diethyl ether. The ethereal washings were combined with ether extracts of the filtrate, dried over sodium sulphate, filtered and evaporated to dryness. Trituration of the residue with hexane gave 2,3,4,6-tetrafluorophenylhydrazine (18.3 g), m.p. 74°-76° C., in the form of off-white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:19]=[C:13]3CN(C)[CH2:16][CH2:17][N:12]3[N:11]=2)[C:5](=[O:8])[NH:6][N:7]=1.[CH2:20](N1C=CC(N)=N1)C.BrC1C(=O)NN=C(Cl)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:19]=[CH:13][N:12]([CH2:17][CH3:16])[N:11]=2)[C:5](=[O:8])[N:6]([CH3:20])[N:7]=1
Reactant: CN1CCn2nc(Nc3cc(Cl)n[nH]c3=O)cc2C1
Reactant: CCn1ccc(N)n1
Agent: O=c1[nH]nc(Cl)cc1Br
Product: CCn1ccc(Nc2cc(Cl)nn(C)c2=O)n1
Yield: 94 %

Procedure:
Using the same general procedure as described for the preparation of 101m, reaction of 1-ethyl-3-amino-1H-pyrazole (500 mg, 4.50 mmol) with 4-bromo-6-chloropyridazin-3(2H)-one (1.00 g, 4.50 mmol) afforded 102g in 94% yield (1.07 g) as an amorphous yellow solid: mp 173-175° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 7.71 (s, 1H), 7.64 (d, J=2.4 Hz, 1H), 6.19 (d, J=2.4 Hz, 1H), 4.10 (q, J=7.2 Hz, 2H), 3.65 (s, 3H), 1.37 (t, J=7.2 Hz, 3H); MS (ESI+) m/z 254.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][C:3]=1[CH3:11].ClN1C(=O)CCC1=O.[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([C:29]([F:32])([F:31])[F:30])=[CH2:28])[CH:24]=[C:23]([Cl:33])[CH:22]=1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH2:28][C:27]([C:25]3[CH:24]=[C:23]([Cl:33])[CH:22]=[C:21]([Cl:20])[CH:26]=3)([C:29]([F:30])([F:32])[F:31])[O:8][N:7]=2)=[CH:4][C:3]=1[CH3:11]
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: Cc1cc(C=NO)ccc1Br
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Temperature: 70 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a solution of 4-bromo-3-methyl-benzaldehyde oxime (2.600 g, 12.15 mmol) from example S.1 in DMF (40 mL) was added N-chloro succinimide (1.700 g, 12.73 mmol) and the mixture was heated at 70° C. (bath temperature) for 1 h. After cooling to 0° C., a solution of 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (2.900 g, 12.03 mmol) in DMF (8 mL), followed by triethylamine (2.00 g, 2.75 mL, 19.8 mmol) was added. After 1 h at this temperature, the cooling bath was removed and the mixture was stirred over night. The mixture was separated between MTBE and aqueous NH4Cl solution. The organic layer was separated and the solvent was removed in vacuum. Column chromatography on SiO2 with heptane/CH2Cl2 gave the title compound (2.95 g, 54%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[H-].[Na+].[CH:12]1[C:22]2[CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[CH2:18][N:17]([C:27]([C:29]3[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=3)=[O:28])[C:16]=2[CH:15]=[CH:14][CH:13]=1>O1CCCC1>[CH:12]1[C:22]2[CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[CH2:18][N:17]([C:27]([C:29]3[CH:30]=[CH:31][C:32]([C:33]([O:5][CH2:4][C:3]4[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=4[CH3:1])=[O:34])=[CH:36][CH:37]=3)=[O:28])[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: Cc1ccccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1COC(=O)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reaction time: 1 h
Yield: 32 %

Procedure:
To a mixture of 248 mg of 2-methylbenzyl alcohol in 4 ml of anhydrous tetrahydrofuran is added 80 mg of sodium hydride (60% in mineral oil) and the mixture stirred for 1 hour. To the mixture is added 430 mg of 4-[(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]benzoyl chloride and the mixture is stirred for 18 hours. The tetrahydrofuran is evaporated in vacuo to a residue which is partitioned between methylene chloride and water. The organic layer is separated and washed with 1N HCl, water, 1M NaHCO3, and brine. The organic layer is dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate and hexane added at the boil to give 170 mg of the desired product, m.p. 140°-142° C.
Reaction SMILES: [CH:1]1([CH:6]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][N:26]=2)[C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([N:14]3[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[N:15]3)=[C:9]([CH3:23])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:35]([O:37][C:38](=[O:42])[CH2:39][CH2:40][NH2:41])[CH3:36].ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH:1]1([CH:6]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([NH:41][CH2:40][CH2:39][C:38]([O:37][CH2:35][CH3:36])=[O:42])=[O:30])=[CH:27][N:26]=2)[C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([N:14]3[CH:18]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:16]=[N:15]3)=[C:9]([CH3:23])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C(Nc2ccc(C(=O)O)cn2)C2CCCC2)cc(C)c1-n1cc(C(F)(F)F)cn1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(C)c(-n3cc(C(F)(F)F)cn3)c(C)c2)C2CCCC2)nc1
Reaction time: 70 h

Procedure:
To a mixture of (+/−)-6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methyl)amino)nicotinic acid (731 mg, 1.59 mmol), β-alanine ethyl ester hydrochloride (516 mg, 3.19 mmol), and 1-hydroxy-7-azabenzotriazole (336 mg, 2.39 mmol) in dichloromethane (15.9 mL) was added triethylamine (0.782 mL, 5.58 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (465 mg, 2.39 mmol). After 70 hours, the mixture was diluted with dichloromethane (50 mL) and washed with water (3×50 mL) and sat. aq sodium chloride (50 mL). The organic layer was dried (Na2SO4) and filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (ethyl acetate/heptane) followed by chiral SFC (Cellulose-2 column, 21 mm×250 mm, 35% methanol/carbon dioxide eluent) gave ethyl 3-(6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methyl)amino)nicotinamido)propanoate, Isomer 1 (SFC retention time 2.71 min) and ethyl 3-(6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methyl)amino)nicotinamido)propanoate, Isomer 2 (SFC retention time 3.43 min). 1H NMR (400 MHz, CDCl3, δ): 8.45 (d, J=2.0 Hz, 1H), 7.91 (s, 1H), 7.81-7.72 (m, 2H), 7.09 (s, 2H), 6.84 (t, J=5.7 Hz, 1H), 6.41-6.27 (m, 1H), 6.26 (d, J=9.0 Hz, 1H), 4.33 (t, J=7.6 Hz, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.65 (q, J=6.0 Hz, 2H), 2.59 (t, J=6.0 Hz, 2H), 2.33-2.19 (m, 1H), 1.98 (s, 6H), 1.96-1.85 (m, 1H), 1.74-1.37 (m, 6H), 1.34-1.21 (m, 4H). MS (M+1): 558.5.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:11]2[CH2:16][CH2:15][C@@H:14]([NH2:17])[C@H:13]([OH:18])[CH2:12]2)[C:9]=1[Cl:10])[C:5]#[N:6].C([O-])(=O)C.[K+].[Cl:24][CH2:25][C:26](Cl)=[O:27]>CC(C)=O.O>[NH2:1][C:2]1[C:9]([Cl:10])=[C:8]([N:11]2[CH2:16][CH2:15][C@@H:14]([NH:17][C:26](=[O:27])[CH2:25][Cl:24])[C@H:13]([OH:18])[CH2:12]2)[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1
Reactant: N#Cc1cc(N)c(Cl)c(N2CC[C@@H](N)[C@H](O)C2)c1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1cc(N)c(Cl)c(N2CC[C@@H](NC(=O)CCl)[C@H](O)C2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 47.4 %

Procedure:
(+/−)-3-amino-5-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-4-chlorobenzonitrile (prepared from Example 171D) (1.0 g, 3.75 mmol) and potassium acetate (0.736 g, 7.50 mmol) were dissolved in acetone (20 ml)+water (6 mL). The solution was cooled to 0° C. under nitrogen. Chloroacetic chloride (0.373 ml, 4.69 mmol) was added dropwise and the mixture stirred at 0° C. for 10 minutes, then at room temperature for 60 minutes. The reaction mixture was partitioned between EtOAc and aq. NaHCO3 solution. The organic layer was washed with brine and dried over MgSO4. MgSO4 was removed by filtration and volatiles evaporated in vacuum to afford (+/−)-N-((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)-2-chloroacetamide (0.61 g,); The material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:31])([C@H:16]([S:18][C@@H:19]1[CH2:24][O:23][C@@H](C2C=CC=CC=2)[O:21][CH2:20]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:31])([C@H:16]([S:18][CH:19]([CH2:20][OH:21])[CH2:24][OH:23])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](S[C@H]1CO[C@H](c2ccccc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
In 3.5 ml of methanol were dissolved 253 mg of (2R,3R)-2-(2,4-difluorophenyl)-3-[[trans-2-phenyl-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol as described in Example 40, and 0.35 ml of a 4N HCl-dioxane solution were added to the solution, followed by stirring of the resulting mixture at room temperature for 30 minutes. To the reaction mixture were added 250 mg of a NaHCO3 powder, and the mixture was stirred for 10 minutes, followed by filtration of the reaction mixture and concentration of the filtrate under reduced pressure. The thus obtained oil was subjected to column chromatography using 5 g of silica gel and eluted with 10% methanol-ethyl acetate to obtain 179 mg (yield: 88%) of the title compound as a viscous oil.
Reaction SMILES: [NH2:1][C:2]1([CH2:17][CH3:18])[C:7](=[O:8])[N:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5](=[O:15])[NH:4][C:3]1=[O:16].N(C1(CC)C(=O)N(C2CCCCC2)C(=O)NC1=O)=[N+]=[N-].[C:39]1(=O)[O:44][C:42](=[O:43])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12>C(O)(=O)C>[CH:9]1([N:6]2[C:7](=[O:8])[C:2]([CH2:17][CH3:18])([N:1]3[C:42](=[O:43])[C:41]4=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]4[C:39]3=[O:44])[C:3](=[O:16])[NH:4][C:5]2=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCC1(N)C(=O)NC(=O)N(C2CCCCC2)C1=O
Agent: CCC1(N=[N+]=[N-])C(=O)NC(=O)N(C2CCCCC2)C1=O
Solvent: CC(=O)O
Product: CCC1(N2C(=O)c3ccccc3C2=O)C(=O)NC(=O)N(C2CCCCC2)C1=O
Temperature: 25 °C
Yield: 61.3 %

Procedure:
A mixture of about 500 mg (about 2 mmol) of 5-amino-1-cyclohexyl-5-ethylbarbituric acid available from 5-azido-1-cyclohexyl-5-ethylbarbituric acid as described in Guetschow, M. et al., Synthesis, 1999, 410-414 (incorporated herein by reference) and about 300 mg (about 2 mmol) of phthalic anhydride and about 20 mL of glacial acetic acid was refluxed for about 5 hours. The mixture was cooled to room temperature and the precipitate was filtered off. The precipitate was next washed with H2O and dried to give about 470 mg of 1-cyclohexyl-5-ethyl-5-phthalimidobarbituric acid (a yield of about 61%). The 1-cyclohexyl-5-ethyl-5-phthalimidobarbituric acid had a melting point of about 248 to about 253° C.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]#[N:12].[CH2:13](N)[CH2:14][NH2:15]>>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]1[NH:15][CH2:14][CH2:13][N:12]=1
Reactant: NCCN
Reactant: Cc1ccc(F)c(CC#N)c1F
Product: Cc1ccc(F)c(CC2=NCCN2)c1F

Procedure:
2-(2,6-Difluoro-3-methyl-benzyl)-4,5-dihydro-1H-imidazole was prepared from (2,6-difluoro-3-methyl-phenyl)-acetonitrile and ethylene diamine in analogy to Example 19 b): colourless powder; MS (ISP): 210.1 ((M+H)+.).
Reaction SMILES: CO[N:3]([CH2:12][OH:13])[C:4]1[N:9]=[C:8]([NH2:10])[N:7]=[C:6]([NH2:11])[N:5]=1.O>CC(O)C>[CH2:12]([NH:3][C:4]1[N:5]=[C:6]([NH2:11])[N:7]=[C:8]([NH2:10])[N:9]=1)[OH:13]
Reactant: CON(CO)c1nc(N)nc(N)n1
Solvent: CC(C)O
Solvent: O
Product: Nc1nc(N)nc(NCO)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
This example demonstrates the chemical solution 2 which was prepared as follows. In a 1-liter measuring flask were placed 100 g of methoxymethylolmelamine (“cymel 370” from Mitsui Cyanamide), 780 g of pure water, and 40 g of IPA. They were mixed with stirring at room temperature for 6 hours. Thus there was obtained around 10 wt % aqueous solution of methylolmelamine. This solution was incorporated with N-methylpyrrolidone as a swelling promoter.
Reaction SMILES: [CH3:1][C@@H:2]([OH:6])[C@H:3]([OH:5])[CH3:4].O.[H-].[Na+].[Br:10][C:11]1[C:12](Cl)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[NH:26])=[O:25])=[CH:20][CH:19]=2)=[N:15][CH:16]=1>CS(C)=O>[Br:10][C:11]1[C:12]([O:5][C@H:3]([CH3:4])[C@H:2]([OH:6])[CH3:1])=[N:13][C:14]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[NH:26])=[O:25])=[CH:22][CH:23]=2)=[N:15][CH:16]=1
Reactant: CS(=N)(=O)c1ccc(Nc2ncc(Br)c(Cl)n2)cc1
Reactant: C[C@@H](O)[C@@H](C)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@@H](O)[C@@H](C)Oc1nc(Nc2ccc(S(C)(=N)=O)cc2)ncc1Br
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 674 mg (7.5 mmol) of (R,R)-(−)-2,3-butanediol in 6 ml of DMSO is mixed while being cooled with water in portions with 330 mg of sodium hydride (55-60%), and then stirred for 45 minutes at room temperature. The batch is mixed with 196 mg (0.54 mmol) of (RS)—S-{4-[(5-bromo-4-chloropyrimidin-2-yl)amino]phenyl}-S-methyl sulfoximide in 0.5 ml of DMSO and stirred overnight. It is mixed again with 191 mg (0.53 mmol) of (RS)—S-{4-[(5-bromo-4-chloropyrimidin-2-yl)amino]phenyl}-S-methyl sulfoximide in 0.5 ml of DMSO and stirred for another two hours. Finally, it is mixed with 190 mg of (RS)—S-{4-[(5-bromo-4-chloropyrimidin-2-yl)amino]phenyl}-S-methyl sulfoximide (0.53 mmol) in 0.5 ml of DMSO and stirred for one hour. The batch is added to ice water and extracted from ethyl acetate (4×). The combined organic phases are washed with NaCl solution, filtered through a Whatman filter and concentrated by evaporation. The remaining residue is purified by chromatography (DCM/EtOH 9:1). 166 mg (0.41 mmol, corresponding to 25% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:5][C:4]2([CH2:14][C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[C:10](/[CH:16]=[CH:17]/[C:18](O)=[O:19])[CH:11]=3)[O:6]2)[CH2:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:35][O:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][O:38]1>C(Cl)Cl>[CH3:1][N:2]1[CH2:3][C:4]2([CH2:14][C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[C:10](/[CH:16]=[CH:17]/[C:18]([NH:35][O:36][CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][O:38]4)=[O:19])[CH:11]=3)[O:6]2)[CH2:5]1
Reactant: CN1CC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1CC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Yield: 70.8 %

Procedure:
A suspension of (E)-3-[1′-methyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (400 mg, 1.29 mmol) in DCM (16 ml) was treated with TEA (0.30 ml, 2.2 mmol) and then with EDC (420 mg, 2.20 mmol), HOBt (297 mg, 2.20 mmol) and NH2OTHP (204 mg, 1.75 mmol) following the procedure described in Example 30, Step B, giving (E)-3-[1′-methyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (340 mg) as a light yellow solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:18])C(=O)C1.O>CN(C=O)C>[Br:18][C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][CH2:2][CH2:1]2)=[CH:5][C:6]=1[OH:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1ccc2c(c1)CCC2
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cc2c(cc1Br)CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-indanol (6.32 g, 47 mmol) in DMF (20 mL) is added NBS (8.38 g, 47 mmol) and the mixture is stirred at ambient temperature for 1 h. Water is added and the mixture is then extracted with EtOAc. The organic layer is washed with 1N HCl solution and brine, dried with NaSO4 and concentrated to give the title compound and it is used in the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](=[O:44])[CH2:25][N:26]1[C:35](=[O:36])[C:34]2[N:33]([CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])[C:32](Cl)=[N:31][C:30]=2[N:29]([CH3:43])[C:27]1=[O:28])([O-:17])=[O:16].C(=O)([O-])[O-].[Na+].[Na+].O>CS(C)=O>[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](=[O:44])[CH2:25][N:26]1[C:35](=[O:36])[C:34]2[N:33]([CH2:37][CH:38]=[C:39]([CH3:40])[CH3:41])[C:32]([N:11]3[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]3)=[N:31][C:30]=2[N:29]([CH3:43])[C:27]1=[O:28])([O-:17])=[O:16]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: CC(C)=CCn1c(Cl)nc2c1c(=O)n(CC(=O)c1ccccc1[N+](=O)[O-])c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)=CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1[N+](=O)[O-])c(=O)n2C
Temperature: 65 °C
Reaction time: 16 h

Procedure:
2.20 g of 3-tert-butyloxycarbonylaminopiperidine is added at 65° C. to 4.40 g of 1-[2-(2-nitrophenyl)-2-oxoethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloroxanthine and 1.30 g of sodium carbonate in 50 mL of dimethylsulfoxide. The reaction mixture is stirred for approximately 16 hours at 65° C. After cooling to ambient temperature, it is poured onto a mixture of 600 mL of water and 100 g of ice. The precipitate formed is suction filtered and washed with water. The filter cake is dissolved in diethyl ether, and the solution is dried and evaporated down. The brown resinous flask residue is brought to crystallization with diisopropylether. Yield: 3.30 g (54% of theory); Rf value: 0.52 (silica gel, cyclohexane/ethyl acetate (3:7)); mass spectrum (ESI+): m/z=596 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:13][C:12]=1[C:22]1[CH:23]=[CH:24][C:25]2[O:30][CH2:29][CH2:28][CH2:27][C:26]=2[CH:31]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C.O>[C:1]([O:5][CH:6]([C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:13][C:12]=1[C:22]1[CH:23]=[CH:24][C:25]2[O:30][CH2:29][CH2:28][CH2:27][C:26]=2[CH:31]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1cc(-c2ccccc2)sc1-c1ccc2c(c1)CCCO2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(C(=O)O)c1cc(-c2ccccc2)sc1-c1ccc2c(c1)CCCO2
Yield: 84.6 %

Procedure:
A solution of methyl 2-(tert-butoxy)-2-[2-(3,4-dihydro-2H-1-benzopyran-6-yl)-5-phenylthiophen-3-yl]acetate (11j) (57 mg, 0.13 mmol) and potassium hydroxide (64 mg, 0.52 mmol) in a mixture of ethanol (2 mL) and water (6 mL) was refluxed for 4 hours. The mixture was concentrated in vacuo. Water (5 mL) was added and the aqueous layer was washed with diethyl ether (5 mL), then extracted with dichloromethane (5 mL). The organic layer was washed with 1N hydrochloric acid (5 mL), dried over sodium sulfate and evaporated to dryness to provide the desired acid (45 mg, 0.11 mmol, 81%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.Cl[CH2:16][C:17]#[N:18]>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6](=[CH:5][CH:4]=1)[NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH:12][CH2:16][C:17]#[N:18]
Reactant: N#CCCl
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Solvent: CCN(CC)CC
Product: COc1ccc2[nH]cc(CCNCC#N)c2c1

Procedure:
Using the procedure of Step A of Example 25, 25 g of 5-methoxytryptamine, 10 ml of chloroacetonitrile and 37 ml of triethylamine were reacted to obtain 20.9 g of the expected product.