Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[O:5][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:7][N:8]=1.C([Li])CCC.[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22]>C1COCC1.CCCCCC>[CH2:28]([Sn:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:24][CH2:25][CH2:26][CH3:27])[C:2]#[C:3][C:4]1[O:5][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:7][N:8]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CC(C)(C)c1cnc(C=C(Br)Br)o1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](C#Cc1ncc(C(C)(C)C)o1)(CCCC)CCCC
Reaction time: 0.5 h
Yield: 109.3 %

Procedure:
To a stirred solution of 1,1-dibromo-2-(5-t-butyl-oxazol-2-yl)ethylene (6.0 g, 19 mmole) in anhydrous THF (80 mL) at −78 deg C. under argon atmosphere. was added with 1.6 M n-butyllithium (32 mL, 51 mmole) in hexane dropwise over 20 min., the reaction mixture, stirred at −78 deg C. for 30 min and treated with tributyltin chloride (5.5 mL, 20 mmole). The reaction mixture was stirred for 30 min, warmed to 0 deg C., stirred at 0 deg C. for 30 min, and then at room temperature for 45 min. The mixture was passed through a short column of silica gel (deactivated with 2% triethylamine in hexane), and eluted with 10% EtOAc in dichloromethane to obtain crude product of 1-tributylstannyl-2-(5-t-butyl-oxazol-2-yl)acetylene as a brown oil (9.10 g).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:27])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][C:19]([CH:21]3[CH2:23][CH2:22]3)=[C:18]([C:24]([OH:26])=O)[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].CC[N:30](C(C)C)C(C)C.N.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:7]([CH3:27])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][C:19]([CH:21]3[CH2:22][CH2:23]3)=[C:18]([C:24]([NH2:30])=[O:26])[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nc2cccc(-c3cc(C(=O)O)c(C4CC4)[nH]3)c2nc1NC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc(C(N)=O)c(C4CC4)[nH]3)c2nc1NC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
A mixture of 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2-cyclopropyl-1H-pyrrole-3-carboxylic acid (418c) (0.15 g, 0.412 mmol), 0-(-7-azabenzotriazol-1-yl)-n,′n,′n,′n′-tetramethyluronium-hexafluorophosphate (GenScript Corporation, 0.196 g, 0.514 mmol), DIPEA (Sigma Aldrich, 0.179 ml, 1.029 mmol), in DMF (2.058 mL) was stirred at RT for 5 min before addition of ammonia (2.0 M solution in MeOH, 0.412 mL, 0.823 mmol). Reaction mixture was stirred at RT overnight. Additional aliquots of HATU and DIPEA were added to the reaction mixture which was stirred at RT overnight. Reaction mixture was diluted with DCM and washed with water and brine to remove DMF. Purification by Biotage (0-10% MeOH/DCM) produced 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2-cyclopropyl-1H-pyrrole-3-carboxamide (418) (0.028 g, 0.078 mmol, 19% yield). 1H NMR (300 MHz, MeOH-d4) δ ppm 0.82-0.92 (m, 2H) 0.98-1.08 (m, 2H) 1.65 (s, 9H) 2.30-2.45 (m, 1H) 2.57 (s, 3H) 6.93-6.99 (m, 1H) 7.26-7.39 (m, 1H) 7.56-7.65 (m, 1H) 7.75-7.85 (m, 1H). m/z (ESI, +ve) 364.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:67])[NH:4][C@@H:5]([CH:64]([CH3:66])[CH3:65])[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[NH:38][C:37]([C@@H:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:63])[C@@H:45]([NH:52]C(OCC6C=CC=CC=6)=O)[CH:46]6[CH2:51][CH2:50][S:49][CH2:48][CH2:47]6)=[N:36][CH:35]=5)=[CH:30][CH:29]=4)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=[O:7].Br>C(#N)C.CC(O)=O>[NH2:52][C@@H:45]([CH:46]1[CH2:47][CH2:48][S:49][CH2:50][CH2:51]1)[C:44]([N:40]1[CH2:41][CH2:42][CH2:43][C@H:39]1[C:37]1[NH:38][C:34]([C:31]2[CH:32]=[CH:33][C:28]([C:23]3[CH:24]=[C:25]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[C:18]([C:15]3[NH:14][C:13]([C@@H:9]5[CH2:10][CH2:11][CH2:12][N:8]5[C:6](=[O:7])[C@@H:5]([NH:4][C:3](=[O:67])[O:2][CH3:1])[CH:64]([CH3:65])[CH3:66])=[N:17][CH:16]=3)[CH:27]=[CH:26]4)=[CH:29][CH:30]=2)=[CH:35][N:36]=1)=[O:63]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OCc6ccccc6)C6CCSCC6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: Br
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@@H](N)C6CCSCC6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To (S)-1-((S)-2-(5-(6-(4-(2-((S)-1-((S)-2-(benzyloxycarbonylamino)-2-(tetrahydro-2H-thiopyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester (46 mg, 0.05 mmol) in ACN (0.4 mL) was add 33% HBr in HOAc (0.1 mL) and reaction mixture was cooled to 0° C. and then stirred for 2 hours. After concentrated to afford title compound as white solid (33 mg, 85%). MS (ESI) m/z 790 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[CH3:12][C:13]([O:16][C:17](/[N:19]=[N:20]/[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:18])([CH3:15])[CH3:14]>C1COCC1>[CH3:11][O:10][C:3]1[C:2]([N:19]([C:17]([O:16][C:13]([CH3:15])([CH3:14])[CH3:12])=[O:18])[NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[CH:7][N:6]=[C:5]([S:8][CH3:9])[N:4]=1
Reactant: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Reactant: COc1nc(SC)ncc1Br
Solvent: C1CCOC1
Product: COc1nc(SC)ncc1N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of 5-bromo-4-methoxy-2-(methylthio)pyrimidine (25.3 g, 108 mmol) in THF (250 mL) was added under argon isopropylmagnesium chloride LiCl in THF (108 mL, 140 mmol) at 0° C. The mixture was allowed to warm up to rt and stirred for 1 h. di-tert-butylazodicarboxylate (24.8 g, 108 mmol) was added and the mixture was stirred 1 h at rt, quenched by addition of a saturated aqueous solution of ammonium chloride (250 mL) then extracted with EtOAc. The organic layer was washed with a saturated aqueous solution of ammonium chloride, dried (Na2SO4), filtered and concentrated. The crude material was purified by silica gel column chromatography (hexane/EtOAc, 100:0→75:25) to afford 37.2 g of the title compound as a white solid. tR: 1.17 min (LC-MS 4); ESI-MS: 387.3 [M+H]+ (LC-MS 4), Rf=0.79 (hexane/EtOAc, 1:1).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19].Cl>N1C=CC=CC=1>[C:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Acetic anhydride (550 ml) was added to a mixture of 4-hydroxy-3-nitrobenzoic acid (100 g) and pyridine (119.82 ml), and stirred for 3 hours at 25° C. The reaction solution was poured into a cooled hydrochloric acid solution, and the thus-precipitated crystals were filtered and washed with cold water. The crystals were recrystallized from ethyl acetate/hexane, thereby giving 85.45 g of the desired compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH3:12])=[C:7]([NH:9][NH2:10])[CH:8]=1.[CH3:13][CH2:14][O:15][C:16]([CH:18]([C:22]([CH3:24])=O)[C:19]([CH3:21])=O)=[O:17]>>[CH2:14]([O:15][C:16]([C:18]1[C:19]([CH3:21])=[N:10][N:9]([C:7]2[CH:8]=[C:3]([Cl:2])[CH:4]=[CH:5][C:6]=2[O:11][CH3:12])[C:22]=1[CH3:24])=[O:17])[CH3:13]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: COc1ccc(Cl)cc1NN
Agent: Cl
Product: CCOC(=O)c1c(C)nn(-c2cc(Cl)ccc2OC)c1C
Yield: 38 %

Procedure:
In analogy to the procedure described in Example 38A], (5-chloro-2-methoxy-phenyl)-hydrazine hydrochloride and ethyl diacetoacetate gave, after precipitation (CH2Cl2/n-pentane), the title compound in 38% yield as light brown solid. MS: 309.1 (MH+, 1 Cl).
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:8]Cl)[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:10]([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]=[S:24])[CH2:11][CH3:12]>>[CH2:10]([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]1[S:24][CH2:8][C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[NH:2]1)[CH2:11][CH3:12]
Reactant: NC1(CCl)CCCC1
Reactant: CCCc1cc([N+](=O)[O-])ccc1N=C=S
Agent: Cl
Product: CCCc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1

Procedure:
2-n-Propylaniline was converted to 2-n-propylacetanilide according to Method A2a, Step 1. The acetanilide was converted to 2-n-propyl-4-nitroacetanilide according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 2-n-propyl-4-nitroaniline. The aniline was converted to 2-n-propyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-n-propyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(2-n-propyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(2-n-propyl-14-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH2:12]Br)=[O:5])[CH3:2].[CH2:14]([O:16][C:17](=[O:31])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH2:12][N:19]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:31])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Reactant: CCOC(=O)c1sc(Br)nc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.8 %

Procedure:
2-Bromo-4-bromomethyl-thiazole-5-carboxylic acid ethyl ester (22.1 g, 67.3 mmol) was dissolved in 169 mL of dry N,N-dimethylformamide. N-(2,4-dimethoxy-benzyl)glycine ethyl ester (17.1 g, 67.3 mmol) and potassium carbonate (10.2 g, 74.0 mmol) were added and the reaction was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-70% ethyl acetate in hexanes to produce 19.5 g of a light yellow solid. MS: (+) m/z 501.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>ClCCl>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)=[O:6]
Reactant: O=C(O)c1cc(F)c(F)cc1Br
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(F)c(F)cc1Br)N1CCOCC1
Reaction time: 2 h
Yield: 96.8 %

Procedure:
2-Bromo-4,5-difluorobenzoic acid (2.00 g, 8.44 mmol), DIPEA (2.18 g, 16.88 mmol) and HATU (3.85 g, 10.13 mmol) were stirred at room temperature for 20 min in dichloromethane (120 mL). Morpholine (0.88 g, 10.13 mmol) was added then the reaction was stirred for 2 hours. The dichloromethane was removed and the resulting residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were passed through a phase separation cartridge and concentrated. The resulting residue was purified via silica gel column chromatography (0-100% ethyl acetate/isohexane) to afford (2-Bromo-4,5-difluorophenyl)(morpholino)methanone (2.5 g, 97%). 1H NMR (400 MHz, CDCl3): δ 7.44 (dd, J=9.42, 6.99 Hz, 1H), 7.14 (dd, J=9.57, 7.88 Hz, 1H), 3.88-3.69 (m, 5H), 3.64-3.57 (m, 1H), 3.33-3.17 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[C:4]([Cl:10])[N:3]=1.O.[CH:12](O)=[O:13]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:12]=[O:13])=[C:4]([Cl:10])[N:3]=1
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Reactant: O=CO
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1nc(Cl)c(NC=O)c(Cl)n1
Temperature: 52.5 °C
Reaction time: 3 h

Procedure:
2,5-Diamino-4,6-dichloropyrimidine (0.01 mol; 2.0 g) and water (0.25 mol; 4.55 ml) were stirred at room temperature. 98% strength formic acid (0.4 mol; 18.27 g; 14.97 ml) was then added to the reaction. The reaction was subsequently heated to 50-55° C. and kept at this temperature for 3 h. Toluene (0.38 mol; 34.6 g; 40 ml) was then added for the azeotropic distillation under high vacuum at 50° C. (toluene was added twice to guarantee a good distillation, i.e. a total of 80 ml).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH:11]=[C:10](I)[CH:9]1[CH2:8][N:7]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:6]2)=[O:4].[S:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO.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>[CH3:1][O:2][C:3]([C:5]12[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH:11]=[C:10]([C:30]3[CH:31]=[CH:32][S:28][CH:29]=3)[CH:9]1[CH2:8][N:7]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:6]2)=[O:4]
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2c1ccccc1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(c1ccsc1)=CCC2c1ccccc1
Yield: 90.9 %

Procedure:
By carrying out the reaction as in Stage C of Example 45, but from 1.2 g of methyl(3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate in 30 cm3 of toluene, from 150 mg of tetrakis(triphenylphosphine)palladium, from 0.35 g of 3-thienylboronic acid in 15 cm3 of methanol and from 28 cm3 of a 2N aqueous sodium carbonate solution at reflux for three hours, 0.99 g (93%) of methyl(3aRS,4SR,7aRS)-2-benzyl-4-phenyl-7-(3-thienyl)-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate was obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and ethyl acetate (85/15 by volume), in the form of a yellow oil, the characteristic of which was as follows:
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[Cl:5][C:6]1[C:7]([F:37])=[C:8]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:35][CH3:36])=[C:20]([CH2:23][N:24]([CH3:34])[C:25]4([C:31]([NH2:33])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>S1(=O)(=O)CCCC1>[Cl:5][C:6]1[C:7]([F:37])=[C:8]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:35][CH3:36])=[C:20]([CH2:23][N:24]([CH3:34])[C:25]4([C:31]([NH2:33])=[O:32])[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][OH:4])[CH2:27][CH2:26]4)[CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCNCC1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCN(CCO)CC1
Temperature: 90 °C
Yield: 15.7 %

Procedure:
2-Bromoethanol (47 μl, 0.66 mmol) was added to a stirred suspension of 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-4-carboxamide (250 mg, 0.53 mmol) (Example 16) and anhydrous potassium carbonate (150 mg, 1.08 mmol) in tetrahydrothiophene 1,1-dioxide (Sulfolane) (5 ml). The mixture was heated at 90° C. for 3 hours and partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic phase was washed with brine and evaporated. The residues were purified by column chromatography on silica, eluting with 7M ammonia in methanol/methylene chloride (16/84). Fractions containing the desired product were combined and evaporated to a foam. This was triturated with diethyl ether to give the title product as a white solid (43 mg, 16%); 1H NMR Spectrum: (DMSO-d6+CD3COOD) 2.13-2.21 (m, 2H), 2.25 (s, 3H), 2.26-2.33 (m, 2H), 3.13-3.17 (t, 2H), 3.17-3.25 (m, 2H), 3.42-3.49 (m, 2H), 3.71-3.77 (m, 4H), 3.94 (s, 3H), 7.18-7.22 (m, 1H), 7.23 (s, 1H), 7.33-7.38 (m, 1H), 7.58-7.63 (m, 1H), 8.28 (s, 1H), 8.39 (s, 1H); Mass Spectrum: (M+H)+ 517.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:23])/[CH:19]=[CH:20]/[CH2:21][CH3:22])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:23])/[CH:19]=[CH:20]/[CH2:21][CH3:22])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N+:3]=1[O-:32]
Reactant: CC/C=C/C(=O)N1CCN(c2cc(C)nc3ccccc23)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC/C=C/C(=O)N1CCN(c2cc(C)[n+]([O-])c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18.5 %

Procedure:
(E)-1-[4-(2-Methyl-4-quinolyl)piperazin-1-yl]pent-2-en-1-one (30.9 mg, 0.1 mmol) was dissolved in anhydrous dichloromethane, meta-chloroperbenzoic acid (mCPBA) was added (44.6 mg, 0.2 mmol) and the mixture was stirred at room temperature for 15 minutes. The mixture was evaporated to dryness under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 6 mg of a solid (0.0185 mmol, 18.5%). MS (APCI): m/z=325.8 [M+1]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:8][CH:7]=1)[CH2:2][C:3]#[CH:4].[CH2:20]([O:22][C:23](=[O:42])[C@@H:24]([O:40][CH3:41])[CH2:25][C:26]1[CH:31]=[CH:30][C:29](OS(C(F)(F)F)(=O)=O)=[CH:28][CH:27]=1)[CH3:21]>>[CH2:20]([O:22][C:23](=[O:42])[C@@H:24]([O:40][CH3:41])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:4]#[C:3][CH2:2][CH2:1][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:13])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:7]=2)=[CH:28][CH:27]=1)[CH3:21]
Reactant: CCOC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)OC
Reactant: C#CCCOc1ccc(C(=O)c2ccccc2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(C#CCCOc2ccc(C(=O)c3ccccc3)cc2)cc1)OC

Procedure:
This compound was prepared from (4-but-3-ynyloxy-phenyl)-phenylmethanone and (2S)-2-Methoxy-3-(4-trifluoromethane-sulfonyloxy-phenyl)-propionic acid ethyl ester (Example 1, Step A) following the procedure described in Example 38, Step C (66%). 1H-NMR (200.15 MHz, CDCl3): δ 37.85–7.73 (m, 4H), 7.57–7.43 (m; 3H), 7.34 (d, 2H, J=8.1), 7.16 (d, 2H, J=8.3), 7.00 (d, 2H, J=8.6), 4.25 (t, 2H, J=7.0), 4.18 (q, 2H, J=7.0), 3.92 (dd, 1H, J=7.3, 5.6), 3.34 (s, 3H), 3.01 (s, 1H), 2.98 (d, 1H, J=3.5), 2.93 (t, 2H, J=7.0), 1.23 (t, 3H, J=7.3).
Reaction SMILES: [CH3:1][N:2]1[C:9](=O)[CH2:8][C:6](=[O:7])[N:5]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]1=[O:4].O.P(Cl)(Cl)([Cl:20])=O>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:9]([Cl:20])=[CH:8][C:6](=[O:7])[N:5]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]1=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN1C(=O)CC(=O)N(C2CCCCC2)C1=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cn1c(Cl)cc(=O)n(C2CCCCC2)c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
35 g of 1-methyl-3-cyclohexylbarbituric acid is admixed with 15 ml of water and, then, 150 ml of phosphorus oxychloride is added. The reaction mixture is boiled for 1 hour, after which it is poured in ice-water, whereupon 35 g (dry weight) of yellow crystals are obtained. The crystals are dissolved in a small amount of chloroform and chromatographed on a column of silica gel (400 g). The first fraction is collected and concentrated to dryness. By the above procedure is obtained 14 g of 1-methyl-3-cyclohexyl-6-chlorouracil as colorless crystals, melting point: 132°-133° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:23])[CH2:11][N:10]([C:12]3[NH:13][C:14](=[O:22])[C:15]4[CH:20]=[CH:19][N:18]([CH3:21])[C:16]=4[N:17]=3)[CH2:9]2)=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:21][N:18]1[C:16]2[N:17]=[C:12]([N:10]3[CH2:9][C:8]([CH3:23])([C:5]4[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=4)[CH2:11]3)[NH:13][C:14](=[O:22])[C:15]=2[CH:20]=[CH:19]1
Reactant: Cn1ccc2c(=O)[nH]c(N3CC(C)(c4ccc(Br)cc4)C3)nc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1ccc2c(=O)[nH]c(N3CC(C)(c4ccccc4)C3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
A mixture of 2-(3-(4-bromophenyl)-3-methylazetidin-1-yl)-7-methyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (100.3 mg, 269 μmol) in ethyl acetate (2.7 mL) and methanol (2.8 mL) was treated with 10% palladium on carbon (9.2 mg, ˜10% weight of starting material used). The flask was capped with a rubber septum and a hydrogen balloon was attached. The reaction was stirred at room temperature overnight. At this time, the reaction was concentrated in vacuo onto Celite®. Flash chromatography (24 g silica gel column, 20-100% ethyl acetate/hexanes) afforded 7-methyl-2-(3-methyl-3-phenyl-azetidin-1-yl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one as an off-white solid (43.2 mg, 54.6%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.61 (s, 3H) 3.53 (s, 3H) 4.10 (d, J=8.67 Hz, 2H) 4.24 (d, J=8.29 Hz, 2H) 6.23 (d, J=3.01 Hz, 1H) 6.73 (d, J=3.20 Hz, 1H) 7.13-7.50 (m, 5H) 10.90 (s, 1H). LC-MS calcd. for C17H19N4O [(M+H)+] 295, obsd. 295.1.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([C:17]4[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=4)[N:15]=3)[NH:10][C:9]2=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(CN2C3C(=N[CH:39]=[C:40]([C:43]4C=CC(C(OC)=O)=CC=4)[N:41]=3)NC2=O)CCCCC1>[OH-].[Li+].O1CCCC1>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([C:17]4[CH:18]=[CH:19][C:20]([C:21]([NH:41][CH:40]([CH3:43])[CH3:39])=[O:22])=[CH:24][CH:25]=4)[N:15]=3)[NH:10][C:9]2=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(-c2cnc3[nH]c(=O)n(CC4CCCCC4)c3n2)cc1
Reactant: COC(=O)c1ccc(-c2cnc3[nH]c(=O)n(CC4CCCCC4)c3n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1ccc(-c2cnc3[nH]c(=O)n(CC4CCCCC4)c3n2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 90 %

Procedure:
4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoic acid. A solution of methyl 4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoate (See Example 56.A) (350 mg, 0.95 mmol) in 1N lithium hydroxide (4.5 mL) and tetrahydrofuran (4.5 mL) was allowed to stir at rt for 19 h. Upon completion of the reaction, the volatiles were removed under reduced pressure. The residue was treated with 1N hydrochloric acid and sonicated. The resulting precipitate was collected by vacuum filtration, and dried under high vacuum to afford the title compound (300 mg, 90% yield) as a tan solid. MS (ESI) m/z 353.3 [M+1]+.