Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].N[C@H](C(OC(C)(C)C)=O)CC(O)=O.C(OC(=O)[C@@H](N[C:40](=[O:45])[CH2:41][CH2:42][CH:43]=[CH2:44])CC(O)=O)(C)(C)C>>[C:11]([O:10][C:8](=[O:9])[C@@H:2]([NH:1][C:40](=[O:45])[CH2:41][CH2:42][CH:43]=[CH2:44])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])([CH3:14])([CH3:13])[CH3:12]
Reactant: C=CCCC(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Agent: CC(C)(C)OC(=O)[C@@H](N)CC(=O)O
Product: C=CCCC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C

Procedure:
A mixed crude product B (9.28 g, 100%) of (S)-5-(tert-butoxy)-5-oxo-4-(pent-4-enamido)pentanoic acid (Compound 1b-II) and pent-4-enoic acid (1:0.8) was obtained using (S)-4-amino-5-(tert-butoxy)-5-oxopentanoic acid (Compound 1a-II, 5.00 g, 24.2 mmol) in place of (S)-3-amino-4-(tert-butoxy)-4-oxobutanoic acid (Compound 1a-I) under the same conditions as in the preparation example for Compound 1b-I.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:10]=1)=[O:5].[CH3:27][Mg]I.Cl>C1COCC1.CCOCC>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([N:9]2[CH:10]=[C:6]([C:4](=[O:5])[CH3:27])[N:7]=[C:8]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:16][CH:15]=1
Reactant: C[Mg]I
Reactant: CON(C)C(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Yield: 97 %

Procedure:
A solution of 1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1H-imidazole-4-carboxylic acid methoxy-methyl-amide I-7e (1.64 g, 3.99 mmol) in THF (16 ml) was cooled to 0° C., and methylmagnesium iodide (4.4 ml of a 3.0 M solution in Et2O, 9.9 mmol) was added dropwise via syringe. The resultant solution was stirred at 0° C. for 1 h, and then the reaction mixture was poured into cold 1N HCl (100 ml). The mixture was extracted with ethyl acetate (2 85-ml portions), and the combined extracts were washed with saturated aqueous sodium chloride (100 ml). The organics were dried over anhydrous magnesium sulfate and were concentrated to afford 1-[1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1H-imidazol-4-yl]-ethanone I-7f (1.41 g, 97%) that was used in the next reaction without any further purification.
Reaction SMILES: [CH:1]1([CH2:4]Br)[CH2:3][CH2:2]1.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13]>>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:4][CH:1]1[CH2:2][CH2:3]1
Reactant: Oc1ccccc1Br
Reactant: BrCC1CC1
Product: Brc1ccccc1OCC1CC1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
Prepared from cyclopropylmethyl bromide and 2-bromophenol by the method of Example 42 (b) except that the reaction mixture was stirred at 75° C. for 4 h. This gave the product as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7](N1C=CN=C1)(N1C=CN=C1)=[O:8].[CH3:19][C:20]1[C:21]([CH2:27][N:28]([CH2:35][C:36]2[C:41]([CH:42]([CH3:44])[CH3:43])=[CH:40][CH:39]=[CH:38][N:37]=2)[CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1>C(Cl)Cl.CC#N>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][C:7]([N:32]1[CH2:33][CH2:34][CH:29]([N:28]([CH2:27][C:21]2[C:20]([CH3:19])=[CH:25][C:24]([CH3:26])=[CH:23][N:22]=2)[CH2:35][C:36]2[C:41]([CH:42]([CH3:44])[CH3:43])=[CH:40][CH:39]=[CH:38][N:37]=2)[CH2:30][CH2:31]1)=[O:8]
Reactant: Nc1nccs1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cnc(CN(Cc2ncccc2C(C)C)C2CCNCC2)c(C)c1
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cnc(CN(Cc2ncccc2C(C)C)C2CCN(C(=O)Nc3nccs3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.3 %

Procedure:
To a solution of 2-aminothiazole (48 mg, 0.45 mmol) in CH2Cl2 (5 mL) was added 1,1′-carbonyldiimidazole (90 mg, 0.55 mmol) and the reaction was stirred at room temperature for 4 h. The reaction mixture was concentrated and dried in vacuo. The tan residue was dissolved in a solution of the (3,5-dimethyl-pyrdin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-piperidine-4-yl-amine (80 mg, 0.23 mmol) in CH3CN (5 mL) and warmed to 60° C. After 2 h at 60° C., the mixture was cooled and diluted with CH2Cl2/saturated NaHCO3 (1:1, 60 mL). The aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic layer was dried (MgSO4), filtered, and concentrated to afford a yellow oil. Purification by radial chromatography on silica gel (1 mm plate; using CH2Cl2/MeOH/NH4OH; 100:1:1→25:1:1) afforded the product as a yellow oil (40 mg, 19%). 1H NMR (CDCl3) δ 0.94 (d, 6H, J=6.0 Hz), 1.63 (br m, 2H), 1.96 (d, 2H, J=12.0 Hz), 2.16 (s, 3H), 2.28 (s, 3H), 2.74-2.82 (m, 4H), 3.77 (s, 2H), 3.83 (s, 2H), 4.17 (s, 1H), 4.21 (s, 1H), 6.86 (d, 1H, J=3.0 Hz), 7.11-7.17 (m, 1H), 7.26 (s, 1H), 7.33 (d, 1H, J=3.0 Hz), 7.51(d, 1H, J=9.0 Hz), 8.19 (s, 1H), 8.33 (d, 1H, J=3.0 Hz), 9.16 (br s, 1H). 13C NMR (CDCl3) δ 18.30, 18.47, 23.61, 27.44, 27.50, 30.09, 44.86, 53.85, 54.30, 113.09, 122.38, 123.26, 132.39, 133.25, 133.96, 135.57, 136.72, 139.16, 144.45, 146.06, 146.63, 153.93, 154.34, 156.16, 162.92. ES-MS m/z 479 [M+H]+. Anal. Calcd. for C26H34N6−SO.0.7CH2Cl2.0.7CH3CN: C, 59.54; H, 6.67; N, 16.56; S, 5.66. Found: C, 59.40; H, 6.91; N, 16.49; S, 5.46.
Reaction SMILES: Cl[C:2]1[N:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=[S:8])=[O:5].C1(C)C=CC=CC=1>O>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]2[S:8][C:2]3[N:20]=[CH:19][CH:18]=[CH:17][C:3]=3[C:4](=[O:5])[N:6]=2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(NC(=S)NC(=O)c2cccnc2Cl)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Yield: 94.1 %

Procedure:
5.66 g of 1-(2-chloronicotinoyl)-3-(4-methylphenyl)thiourea and 30 mf of toluene were put in a 100 ml flask. To the flask were then connected a Dean-Stark water separator and a Dimroth condenser. The mixture was then heated under reflux for 4 hours. The reaction mixture was then allowed to cool. The resulting precipitate was collected by filtration, washed with toluene, and then dried under reduced pressure to obtain 4.69 g of 2-(4-methylanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([F:17])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].Br[CH2:20][CH2:21][F:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:20][CH2:21][F:22])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2cc(F)c(F)cc2c1=O
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(CCF)c2cc(F)c(F)cc2c1=O
Yield: 70 %

Procedure:
6,7-Difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester (10.0 g, 39.5 mmol), 1-bromo-2-fluoroethane (25.1 g, 197.5 mmol) and potassium carbonate (10.9 g, 79 mmol) were combined in dimethylformamide (200 ml) and heated to 90° for 20 hours. The reaction mixture was poured into cold water (1.5 l), and the copious precipitate was filtered. The precipitate was washed with cold water and recrystallized from ethyl acetate to provide the title product as light brown needles, m.p. 178°-180° (8.22 g, 27.5 mmol, 70% yield).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C@@H:17]([O:23][C:24](=[O:27])[CH2:25]I)[CH2:16][C@@:15]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>>[CH2:29]([N:31]([CH2:25][C:24]([O:23][C@H:17]1[CH2:16][C@@:15]2([CH3:28])[C@@H:8]([CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[C@H:7]2[C@H:18]1[C@:19]1([CH3:22])[C@@H:4]([CH2:5][CH2:6]2)[CH2:3][C@H:2]([OH:1])[CH2:21][CH2:20]1)=[O:27])[CH2:32][CH3:33])[CH3:30]
Reactant: CCNCC
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@@H](OC(=O)CI)C[C@]12C
Product: CCN(CC)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(C)=O)CC[C@H]2[C@@H]2CC[C@H]3C[C@H](O)CC[C@]3(C)[C@H]21

Procedure:
3α-Hydroxy-11β-iodoacetoxy-5α-pregnan-20-one (50 mg) in the appropriate solvent (see Table 4) was treated with diethylamine (0.2 ml) and the resulting mixture was kept at room temperature.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:17][C:7]2[C:8]3[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][C:9]=3[S:10][C:6]=2[CH2:5][CH2:4]1.C(O)(C(F)(F)F)=O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:2]([CH:3]1[CH2:17][C:7]2[C:8]3[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][C:9]=3[S:10][C:6]=2[CH2:5][CH2:4]1)=[O:1]
Reactant: N#Cc1ccc2sc3c(c2c1)CC(CO)CC3
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2sc3c(c2c1)CC(C=O)CC3
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
To a room temperature suspension of 8-(hydroxymethyl)-6,7,8,9-tetrahydrodibenzo[b,d]thiophene-2-carbonitrile (0.24 g, 1 mmol) in 4 mL CH2Cl2 was added TFA (0.5 mL). To the resulting homogeneous solution was added Dess-Martin periodinane (0.243 g, 1 mmol). Precipitates were formed after reaction mixture was stirred for 10 minutes. The resulting suspension was cooled in ice water, and diluted with EtOAc (15 mL), then was treated with 10 mL of 1.25 N NaOH (aq.) solution. After stirring for a few minutes, the organic layer was collected, washed with water, then brine, then was dried over MgSO4), filtered, and concentrated. Purification by chromatography on silica gel (25% EtOAc in hexane) afforded 0.14 g (58%) of the title compound as a white solid: mp 172-173° C.; MS (ES) m/z=241 [M]+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[O:19]=[CH:20][C:21]1[CH:29]=[CH:28][C:26]([OH:27])=[C:23]([O:24][CH3:25])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:20]([C:21]1[CH:29]=[CH:28][C:26]([O:27][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])=[C:23]([O:24][CH3:25])[CH:22]=1)=[O:19]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCOC(=O)c1ccc(-c2nc(CCl)c(C)o2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2nc(COc3ccc(C=O)cc3OC)c(C)o2)s1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 5-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)thiophene-2-carboxylate (5.0 g), vanillin (2.66 g), anhydrous potassium carbonate (2.42 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration, and washed with diethyl ether. The obtained crystals were recrystallized from acetone-hexane to give ethyl 5-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}thiophene-2-carboxylate as colorless prism crystals (5.75 g, yield 82%). melting point: 155-156° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@@H:13]([N:15]([CH3:33])[C:16]([N:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][C@@H:19]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[CH3:32])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(O[BH-](O[C:46](=[O:48])[CH3:47])OC(=O)C)(=O)C.[Na+].[C:50](#[N:52])[CH3:51]>C(=O)([O-])O.[Na+]>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@@H:13]([N:15]([CH3:33])[C:16]([N:18]2[CH2:23][CH2:22][C@H:21]([N:52]3[CH2:50][CH2:51][N:15]4[CH2:13][CH2:5][CH2:4][C@H:47]4[C:46]3=[O:48])[CH2:20][C@@H:19]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[CH3:32])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:34])([F:1])[F:35])[CH:8]=1
Reactant: CC#N
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cc(F)ccc1[C@H]1CC(=O)CCN1C(=O)N(C)[C@@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(F)ccc1[C@H]1C[C@@H](N2CCN3CCC[C@H]3C2=O)CCN1C(=O)N(C)[C@@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Intermediate 13a (250 mg) was added to a solution of intermediate 5b (449 mg) in anhydrous acetonitrile (9 mL) under a Nitrogen atmosphere. The solution was stirred at r.t. for 1 hour, then sodium triacetoxyborohydride (282 mg) was added. The mixture was stirred at 23° C. for 16 hours. The solution was diluted with a 5% sodium hydrogen carbonate solution (10 mL) and extracted with AcOEt (3×30 mL). The combined organic extracts were washed with brine (10 mL), dried and concentrated in vacuo to a residue which was purified by flash chromatography (AcOEt/MeOH 8:2) to give three fractions:
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C1(C)C(C)=CC=CC=1.Cl>[CH3:10][CH:9]([NH:8][C:7]1[C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:3][CH:4]=[CH:5][N:6]=1)[CH3:11]
Reactant: CC(C)Nc1nccnc1Cl
Reactant: C1CNCCN1
Agent: Cl
Solvent: Cc1ccccc1C
Product: CC(C)Nc1nccnc1N1CCNCC1

Procedure:
A solution of 2-chloro-3-(1-methylethylamino)pyrazine (PREPARATION 6, 1.6 g) and piperazine (4.3 g) in xylene (10 ml) is refluxed for 26 hr. The mixture is cooled to 0° and diluted with concentrated hydrochloric acid (8 ml). The xylene is decanted and ether is added and also decanted from the salts. The salts are diluted with excess aqueous sodium hydroxide (5%) and dichloromethane. The phases are separated. The aqueous phase is extracted three more times with dichloromethane. The combined organic extracts are dried over sodium sulfate and concentrated to give a liquid mixture which is flash chromatographed on silica gel eluting with methano/chloroform (5/95). The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 1.27, 1.83, 3.04, 4.12, 4.78, 7.49 and 7.72 δ.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][O:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:4])=[O:3].FC(F)(F)C(O)=O.N>ClCCl.CO>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][O:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2COCc2ccc(S(C)(=O)=O)cn2)CC1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CS(=O)(=O)c1ccc(COC[C@@H]2C[C@@H]2C2CCNCC2)nc1

Procedure:
The product of step D (207 mg, 0.488 mmol) was dissolved in dichloromethane (1.63 mL) and trifluoroacetic acid (1.62 mL, 21.0 mmol) was added. At 1.75 h the volatiles were removed to yield an oil, which was dissolved in 1 mL of MeOH and 1.5 mL of 7 M NH3 in MeOH. After 30 min all volatiles were removed. The free base was used without further purification. 1H NMR (500 MHz, CDCl3) δ 9.10 (d, 1H), 8.26 (dd, 1H), 7.68 (d, 1H), 4.78 (d, 1H), 4.71 (d, 1H), 3.89-3.84 (m, 1H), 3.53-3.49 (m, 1H), 3.46-3.41 (m, 1H), 3.15 (s, 3H), 2.93-2.81 (m, 2H), 2.19-2.12 (m, 1H), 2.02-1.94 (m, 1H), 1.80-1.68 (m, 2H), 1.80-1.68 (m, 2H), 1.38-1.30 (m, 1H), 1.19-1.09 (m, 1H), 0.89-0.22 (m, 2H), 0.11-0.06 (m, 1H). MS (ESI) m/z 437 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[Si:10]([O:17][C@@H:18]1[C@H:22]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:21][C@@H:20]([NH2:32])[CH2:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C>C(O)C>[Si:10]([O:17][C@@H:18]1[C@H:22]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27])[CH2:21][C@@H:20]([NH:32][C:2]2[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=2)[CH2:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](N)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: Fc1c(Cl)ncnc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Nc2ncnc(Cl)c2F)C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 77.6 %

Procedure:
A solution of 4,6-dichloro-5-fluoropyrimidine (102 mg, 0.61 mmol), (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopentanamine (200 mg, 0.56 mmol), and triethylamine (0.16 mL, 1.11 mmol) in ethanol (2.00 mL) was heated in a sealed tube under microwave irradiation at 140° C. for 1 h. The reaction mixture was concentrated under vacuum, and the residue was purified by flash chromatography (0 to 15% ethyl acetate/hexanes) to afford the title compound (213 mg, 70%) as a light yellow solid. LC/MS: Rt=2.60 min, ES+ 490.5 (AA standard).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[N-:11]=[N+]=[N-].[Na+].[C:15]([O:22]C(OC(C)(C)C)=O)(=O)[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C.C(OCC)(=O)C.O>[C:17]([O:16][C:15](=[O:22])[NH:11][CH2:2][CH2:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C(CCCl)C1CCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCC(=O)C1CCCC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
To a solution of 3-chloro-1-cyclopentyl-propan-1-one (2.913 g, 18.1 mmol) from Step 1 above in DMF (40 mL) was added sodium azide (1.77 g, 27.2 mmol). The reaction was heated to 70° C. for 3 hours. The reaction was cooled to room temperature, and then diluted with 100 mL of ethyl acetate and 100 mL of water. The layers were separated, and the aqueous was extracted with 2×50 mL of ethyl acetate. The organic layer was then washed with 2×50 mL of water. The organic layer was dried over sodium sulfate, filtered, and concentrated to an oil. The oil was then dissolved in ethanol (75 mL) and TFA was added (3 mL). To this solution was added 10% Pd/C (300 mg). The slurry was stirred under a hydrogen atmosphere for 2 hours. The solids were removed by filtration, and the organic was concentrated by rotary evaporation to a black oil. The black oil was dissolved in THF (100 mL) and TEA (7.5 mL) and di-tert-butyl pyrocarbonate (1 M in THF, 40 mL, 40 mmol) were added. The reaction was stirred at room temperature for 18 hours, and then concentrated by rotary evaporation. The crude oil was purified by flash chromatography to yield the product (1.677 g, 38%).
Reaction SMILES: Br[C:2]1[C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:38])[C@@H:18]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH2:19][N:20]([CH:28]([CH3:30])[CH3:29])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13][CH2:12]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:45][N:46]1[CH:50]=[C:49](B2OC(C)(C)C(C)(C)O2)[CH:48]=[N:47]1>O1CCOCC1.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>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C@H:18]([C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:3]3[C:2]([C:49]4[CH:48]=[N:47][N:46]([CH3:45])[CH:50]=4)=[CH:7][N:6]=[C:5]4[NH:8][CH:9]=[CH:10][C:4]=34)[CH2:16][CH2:15]2)=[O:38])[CH2:19][N:20]([CH:28]([CH3:29])[CH3:30])[C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[CH:32][CH:33]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
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: O
Solvent: C1COCCO1
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(-c3cnn(C)c3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 150 °C
Yield: 9.9 %

Procedure:
(S)-tert-Butyl 3-(4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate (0.05 g, 0.083 mmol, see Example 4) was placed in dioxane (1 mL) and Na2CO3 (aq., 0.087 g, 0.82 mmol) in H2O (0.3 mL). 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.034 g, 0.16 mmol) and PS-Pd(PPh3)4 (0.075 g, 0.1 g/mmol) were then added. The reaction was heated to 150° C. in a microwave for 1 hour. The reaction was then diluted with water and extracted with DCM. The organic fractions were dried, filtered, and concentrated. Purification of the crude residue (500:10 to 500:20 DCM:MeOH) gave (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (0.005 g, 9.9% yield).
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.Br[CH:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][N:2]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22])=[CH:14][CH:13]=1)[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1
Reactant: CN(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)Oc1ccc(N(C)c2nc3ccccc3[nH]2)cc1
Temperature: 100 °C
Yield: 64.5 %

Procedure:
A mixture of 4-[N-methyl-N-(2-benzimidazolyl)amino]phenol (1.14 g), methyl 2-bromopropionate (0.80 g), anhydrous potassium carbonate (0.72 g) and dimethylformamide (25 ml) was heated for 4 hours at a temperature of 100° C. with vigorous stirring. After cooling, the mixture was poured into water and the aqueous solution was extracted with dichloromethane. The organic extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography over silica gel with dichloromethane elution to give methyl 2-{4-[N-methyl-N-(2-benzimidazolyl)amino]phenoxy}propionate (1.0 g) as a colourless oil. The pmr spectrum of the compound was consistent with the assigned structure (CDCl3 ; chemical shift δppm): 1.50, d, 3H; 3.35, s, 3H; 3.70, s, 3H; 4.60, q, 1H; 6.50-7.60, m, 9H.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.[CH2:31]=O>C(O)=O>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:24]5[CH2:25][CH2:26][N:27]([CH3:31])[CH2:28][CH:29]=5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: C=O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(C3=CCNCC3)cc2c1=O
Solvent: O=CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(C3=CCN(C)CC3)cc2c1=O

Procedure:
N-Cyclopropyl-4-methyl-3-[4-oxo-6-(1,2,3,6-tetrahydropyridin-4-yl)quinazolin-3(4H)-yl]benzamide (0.293 g) and 38% aqueous formaldehyde (0.577 ml) were stirred in formic acid (6 ml) at 90° C. for 3.5 hours and then concentrated. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was washed with brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting with 10% methanol/ethyl acetate followed by 10% methanol/ethyl acetate+1% aqueous ammonia solution to give N-cyclopropyl-4-methyl-3-[6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (AZ12285777) (0.257 g) as a white foam solid; NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.70 (m, 2H), 2.15 (s, 3H), 2.30 (s, 3H), 2.59 (m, 4H), 2.85 (m, 1H), 3.08 (s, 2H), 6.40 (s, 1M), 7.52 (d, 1H), 7.74 (d, 1H), 7.85 (s, 1H), 7.91 (d, 1H), 8.06 (d, 1H), 8.14 (s, 1H), 8.29 (s, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 415.