Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:28])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:27])([CH3:26])[O:18][C:19]=3[C:20]([C:22]([O:24]C)=O)=[CH:21][C:11]=2[N:10]=1.[CH:29]1([C:32]2[CH:33]=[CH:34][C:35]([F:39])=[C:36]([CH:38]=2)[NH2:37])[CH2:31][CH2:30]1.C[Al](C)C>C1(C)C=CC=CC=1>[CH:29]1([C:32]2[CH:33]=[CH:34][C:35]([F:39])=[C:36]([NH:37][C:22]([C:20]3[C:19]4[O:18][C:17]([CH3:27])([CH3:26])[CH2:16][C:15]=4[C:12]4[N:13]([CH3:14])[C:9]([NH:8][C:7]5[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=5[Cl:28])=[N:10][C:11]=4[CH:21]=3)=[O:24])[CH:38]=2)[CH2:31][CH2:30]1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)n(C)c2c2c1OC(C)(C)C2
Reactant: Nc1cc(C2CC2)ccc1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cn1c(Nc2c(Cl)cncc2Cl)nc2cc(C(=O)Nc3cc(C4CC4)ccc3F)c3c(c21)CC(C)(C)O3
Yield: 31.7 %

Procedure:
The title compound was prepared following the procedure described for Example-143 by using methyl 2-((3,5-dichloropyridin-4-yl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Intermediate-60, 0.100 g, 0.245 mmol), 5-cyclopropyl-2-fluoroaniline (Intermediate-47, 0.080 g, 0.529 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) to afford 0.042 g of the desired product. 1HNMR (DMSO-d6): δ 0.62 (d, J=5.4 Hz, 2H), 0.94 (d, J=8.4 Hz, 2H), 1.59 (s, 6H), 1.93 (m, 1H), 3.51 (s, 2H), 3.59 (s, 3H), 6.82 (m, 1H), 7.18 (t, J=8.7 Hz, 1H), 7.29 (s, 1H), 8.18 (d, J=7.2 Hz, 1H), 8.47 (s, 2H), 9.99 (br s, 1H), 10.92 (br s, 1H); MS [M]+: 540.20.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([NH2:9])[S:6][C:7]=1[CH3:8])[CH3:2].[Cl:10][C:11]1[C:12]([CH3:21])=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1>>[Cl:10][C:11]1[C:12]([CH3:21])=[C:13]([S:17]([NH:9][C:5]2[S:6][C:7]([CH3:8])=[C:3]([CH2:1][CH3:2])[N:4]=2)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1
Reactant: CCc1nc(N)sc1C
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: CCc1nc(NS(=O)(=O)c2cccc(Cl)c2C)sc1C
Yield: 12 %

Procedure:
The title compound was prepared from 4-ethyl-5-methyl-1,3-thiazol-2-ylamine (METHOD I) and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A, yellowish foam, 40 mg (12% yield): HRMS Calcd (found) for C13H15ClN2O2S2 m/z 330.0263 (330.0271).
Reaction SMILES: CC1C=C(C)C=C(C)C=1O.[OH-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1O.[C:22]1([NH:28]C(=O)CCl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.C1(C)C=CC=CC=1.CN(C)C=O>[C:22]1([NH:28][C:15]2[C:14]([Cl:13])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(CCl)Nc1ccccc1
Reactant: Oc1c(Cl)cccc1Cl
Agent: Cc1cc(C)c(O)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1cccc(Cl)c1Nc1ccccc1
Yield: 91 %

Procedure:
37.6 g of 2,4,6-trimethyl phenol and 11 g of sodium hydroxide were dissolved in 30 ml of water and mixed with 150 ml of toluene. The toluene recovered from heating was mixed with 139 ml of N,N-dimethylformamide to obtain a N,N-dimethylformamide solution. 40 g of 2,6-dichlorophenol was dissolved in 130 ml of toluene, followed by the addition of 9.8 g of sodium hydroxide in 20 ml of water, 41.5 g of N-phenyl chloroacetamide and 8.7 ml of N,N-dimethylformamide, and refluxed in a oil bath at 140°-150° C. for 15 h. The toluene was recovered from the reflux, and mixed with the above N,N-dimethylformamide solution and reacted for 3 h. Recovering N,N-dimethylformamide from the reacted mixture with distillation under reduced pressure (145°-150° C., 8 mm Hg) resulted in the formation of 53 g of N-phenyl 2,6-dichloroaniline and the product yield was 90.75%.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]1=[CH:8][C:7](=[O:23])[CH2:6][CH2:5]2.[BH4-].[Na+].C(O)(=O)C>CO.O>[CH3:1][O:2][CH2:3][C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C@@H:16]([OH:22])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]1=[CH:8][C@@H:7]([OH:23])[CH2:6][CH2:5]2
Reactant: COC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COC[C@]12CC[C@H](O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
19-Methoxyandrost-4-ene-3,17-dione is dissolved in methanol and the solution cooled to 0° C. Sodium borohydride is added over a period of fifteen minutes and stirring continued for an additional two hours. The solution is poured into water containing a few drops of acetic acid. The white precipitate which forms is collected by filtration, dried and crystallized from acetone to yield the desired 19-methoxy-androst-4-ene-3β,17β-diol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][CH:15]=[N:16][C:17]=2[C:18]([O:33]C(C2C=CC=CC=2)C2C=CC=CC=2)=[C:19]2[C:23](=[O:24])[N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][C:20]=12)=[O:10].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][CH:15]=[N:16][C:17]=2[C:18]([OH:33])=[C:19]2[C:23](=[O:24])[N:22]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:21][C:20]=12)=[O:10]
Reactant: O=C(NCc1ccccn1)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccccn1)c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Temperature: 25 °C
Yield: 56.3 %

Procedure:
Carboxamide 231 (0.225 g, 0.355 mmol) was dissolved in 1 mL of dichloromethane. To this was added 0.5 mL of triethylsilane and 0.25 mL of trifluoroacetic acid. Stirred at room temperature and after ten minutes complete by TLC. Concentrated off volatiles, azeotroped with toluene to give crude. Triturated twice with 1:1 diethyl ether/hexanes to give 7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid (pyridin-2-ylmethyl)-amide 232 (0.11 g, 0.20 mmol, 56%.) 1H NMR (CD3SOCD3) δ 9.18 (s, 1H), 8.96 (d, 1H), 8.65 (dd, 2H), 8.09 (dd, 1H), 7.76 (dd, 1H), 7.64 (dd, 1H), 7.36 (dd, 2H), 7.22 (dd, 2H), 4.70 (s, 4H), 4.54 (s, 2H). 19F NMR: −75.37 MS: 443 (M+1), 441 (M−1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:35]1[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[N:39][CH:40]=1>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([O:22][C:35]3[CH:40]=[N:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc([N+](=O)[O-])nc3)c2)CC1
Yield: 78.9 %

Procedure:
Following the procedure of Example 69(b) {4-[3-(4-cyanophenoxy)-5-hydroxy-benzoylamino]cyclohexyl}carbamic acid tert-butyl ester 1.2 g (2.65 mmol) and 5-chloro-2-nitro-pyridine (0.84 g, 5.31 mmol) were used to afford 1.2 g of the required product. 1H NMR (DMSO-d6): δ 1.28 (3H, m), 1.4 (10H, s), 1.8 (5H, m), 3.20 (1H, m), 3.7 (1H, m), 6.75 (1H, d), 7.25 (2H, d), 7.35 (1H, d), 7.5 (2H, s), 7.8 (1H, dd), 7.9 (2H, d), 8.35 (2H, d), 8.5 (1H, s).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:8]3[N:9]([C:13]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[N:24]=4)=[C:14]([C:16]4[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=4)[N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:41](Br)[CH:42]=[CH2:43].CCOCC>CN(C)C=O.O>[CH2:43]([O:22][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:8]3[C:7]([NH:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:12][CH:11]=[CH:10][N:9]3[C:13]=2[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:24]=2)[CH:21]=[CH:20][CH:19]=1)[CH:42]=[CH2:41]
Reactant: Oc1cccc(-c2nc3c(NC4CCCC4)cccn3c2-c2ccnc(NC3CCCC3)n2)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: C=CCOc1cccc(-c2nc3c(NC4CCCC4)cccn3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
To a solution of 3-{8-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]imidazo[1,2-α]pyridin-2-yl}phenol (12 mg, 0.03 mmol) in N,N-dimethylformamide was added cesium carbonate (11 mg, 0.04 mmol) followed by allyl bromide (0.1 mL, 1.15 mmol). The resulting mixture was stirred at room temperature for 5 hours. Ether was added followed by water. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (2:1 hexanes:ethyl acetate) provided 2-[3-(allyloxy)phenyl]-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]imidazo[1,2-α]pyridin-8-amine (10 mg, 77%) as an oil. 1H NMR (CDCl3): δ 8.87 (broad, 1H), 8.01 (d, 1H), 7.30 (t, 1H), 7.20–7.17 (m, 2H), 6.95 (m, 1H), 6.78 (t, 1H), 6.38 (d, 1H), 6.28 (d, 1H), 6.03 (m, 1H), 30 5.43–5.24 (m, 4H), 4.54 (d, 2H), 4.34 (m, 1H), 3.91 (m, 1H), 2.12–2.04 (m, 4H), 1.82–1.55 (m, 12H); MS m/z 495 (M+1). This material was treated with anhydrous hydrochloric acid in ether to provide the corresponding hydrochoride salt as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:25])C=1>C(Cl)Cl>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:25])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)CS(=O)Cc1ccc(F)cc1
Solvent: ClCCl
Product: CCOC(=O)CS(=O)(=O)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of ethyl 2-(4-fluorobenzylsulfinyl)acetate (370 mg, 1.52 mmol) in DCM (5.0 mL) was added m-CPBA (77%, 450 mg, 2.0 mmol). The mixture was stirred at room temperature for 2 h and was then quenched with polymer bound diethylene triamine (1.5 g). The reaction mixture was filtered and concentrated in vacuo to give ethyl 2-(4-fluorobenzylsulfonyl)acetate (360 mg, 91% yield). MS(ESI+): m/z 283.10 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1>COCCOC.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:15][C:16]1[CH:21]=[C:20]([C:2]2[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Nc1cccnc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Nc1cccnc1-c1cccc(Cl)c1

Procedure:
To the solution of 2-bromopyridin-3-amine in DME (0.1M) were added 2M aqueous Na2CO3 solution (2 eq.) and (3-chlorophenyl)boronic acid (1.1 eq). The mixture was degassed and placed under an argon atmosphere. PdCl2(dppf) (0.02 eq) were added and the reaction was heated at reflux overnight under argon. After cooling the reaction was diluted with EtOAc and washed with water and brine, then dried and evaporated under reduced pressure to afford the titled compound which was used as such in the next step. MS (ES+) C11H9ClN2 requires 204, 206, found: 205, 207 (M+H)+.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:4]([O:6]N1C(=O)CCC1=O)=O)[CH3:3].[NH2:24][C@H:25]([C:31]([OH:33])=[O:32])[CH2:26][CH2:27][C:28](=[O:30])[NH2:29]>O1CCCC1.O.C(N(CC)CC)C>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[C@H:2]([C:4]([NH:24][C@H:25]([C:31]([OH:33])=[O:32])[CH2:26][CH2:27][C:28](=[O:30])[NH2:29])=[O:6])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: NC(=O)CC[C@H](N)C(=O)O
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 73.5 %

Procedure:
To a solution of 4.80 g of Z-Ala-OSu in 60 ml of tetrahydrofuran was added a solution of 2.19 g of H-Gln-OH in 40 ml of water and 2.10 ml of triethylamine and the mixture was stirred at a room temperature for 20 hours. Tetrahydrofuran and water were removed by distillation and the residue thus obtained was extracted with n-butanol. The n-butanol extract was washed with a 2%-acetic acid and butanol was removed by distillation. The precipitated substance thus obtained was collected by filtration and reprecipitated with methanol-ethyl acetate to obtain 3.87 g of Z-Ala-Gln-OH.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21]OS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([NH:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:29]([CH3:31])[CH3:30]>O1CCOCC1>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][N:32]([CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Reactant: CC(C)CNCC(C)C
Solvent: C1COCCO1
Product: Cc1[nH]c2ccc(CCN(CC(C)C)CC(C)C)cc2c1C(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a solution of 5-(2-methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (360 mg, 0.93 mmol, Example 56, Step D) in dioxane (10 mL) was added diisobutylamine (1.62 mL, 9.3 mmol). The mixture was stirred at 100° C. overnight and then partitioned between methylene chloride and water. The organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a solid residue, which was purified by chromatography (20% ethyl acetate in hexanes) to give 303 mg (77%) of the desired product as a white solid: mp 134-135° C.; MS(APCI+): m/z 421.3 (MH+); Anal. Calcd for C27H36N2O2: C, 77.10; H, 8.63; N, 6.66. Found: C, 76.94; H, 8.75; N, 6.55.
Reaction SMILES: [P:1]([O:13][CH2:14][CH2:15][N:16]([CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([NH:35][C:36]3[CH:40]=[C:39]([CH2:41][C:42]([NH:44][C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=4)=[O:43])[NH:38][N:37]=3)=[N:30][CH:31]=[N:32]2)=[CH:27][CH:26]=1)[CH2:17][CH2:18][O:19][CH3:20])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].O1CCOCC1.Cl>O1CCOCC1>[P:1]([OH:8])([OH:3])([O:13][CH2:14][CH2:15][N:16]([CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([NH:35][C:36]3[CH:40]=[C:39]([CH2:41][C:42]([NH:44][C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=4)=[O:43])[NH:38][N:37]=3)=[N:30][CH:31]=[N:32]2)=[CH:27][CH:26]=1)[CH2:17][CH2:18][O:19][CH3:20])=[O:2]
Reactant: COCCN(CCCOc1ccc2c(Nc3cc(CC(=O)Nc4cccc(F)c4)[nH]n3)ncnc2c1)CCOP(=O)(OC(C)(C)C)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COCCN(CCCOc1ccc2c(Nc3cc(CC(=O)Nc4cccc(F)c4)[nH]n3)ncnc2c1)CCOP(=O)(O)O
Yield: 108 %

Procedure:
Di-tert-butyl 2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl](2-methoxyethyl)amino]ethyl phosphate (200 mg, 0.3 mmol) was solubilised in dioxane (7 ml) and treated with a mixture of dioxane/hydrochloric acid (4.0 N, 0.5 ml) at 20° C. overnight. A light yellow solid was recovered by filtration and dried in vacuo (55° C., 12 h) to yield 2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl](2-methoxyethyl)amino]ethyl dihydrogen phosphate (200 mg, 85% yield) as a pale yellow solid:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.O=[CH:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]>[Na].C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: COC(=O)CCC=O
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na]
Solvent: ClCCl
Product: COC(=O)CCCN1C[C@@H]2COCCN2c2nc(Cl)ncc21

Procedure:
The title compound was prepared in a manner similar to PREPARATION x63 using (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 250 mg, 1.103 mmol), methyl 4-oxobutanoate (128 mg, 1.103 mmol), titanium(IV) chloride in CH2Cl2 (1M, 1.654 mL, 1.654 mmol) and sodium triacetoxyhydroborate (514 mg, 2.427 mmol) in CH2Cl2 (8 mL) (164 mg, 46%). ESI-MS m/z [M+H]+ calc'd for C14H19ClN4O3, 327.12. found 327.2.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]1[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>>[C:4]([C:3]1[CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=[CH:9][C:2]=1[O:21][C:19]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([F:12])[CH:20]=1)#[N:5]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: N#Cc1ccc(O)cc1F
Product: N#Cc1ccc(Oc2ccc(C=O)cc2C#N)cc1F

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 2-fluoro-4-hydroxybenzonitrile.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH3:2].C([Li])CCC.CCCCCC.CON(C)[C:24]([CH:26]1[CH2:28][CH2:27]1)=[O:25]>C1COCC1>[CH:26]1([C:24](=[O:25])[C:6]#[C:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])[CH2:28][CH2:27]1
Reactant: CON(C)C(=O)C1CC1
Reactant: C#CC(OCC)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(C#CC(=O)C1CC1)OCC
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
3,3-Diethoxy-1-propyne (10 mL, 70 mmol) was dissolved under argon in THF (150 mL) and cooled to −70° C. Then a 1.6 M solution of n-butyllithium in hexane (48 mL, 77 mmol) was added slowly at −70° C., then allowed to warm to −30° C. and stirred at −30° C. for 30 min, then cooled again to −70° C. Cyclopropanecarboxylic acid methoxy-methyl-amide (10 g, 77 mmol) was added at once at −70° C. (the temperature rose to −50°) then stirred without cooling until 0° C. was reached, then quenched with sat. NH4Cl solution (20 mL). Extraction: 2×AcOEt, 1× sat. NH4Cl, 1× sat. NaCl. The crude brown oil (15 g) was purified by chromatography on silica gel in heptane/ethyl acetate 10:1. One obtained 6 g (43%) of a yellowish oil. MS: m/z=151(M).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[CH:25]=[CH2:26].CCOC(C)=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][CH2:26][CH:25]=[CH2:24])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCBr
Reactant: O=Cc1cc(O)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(OCc2ccccc2)c(C=O)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of the product from Step A (75.4 mmol) in 100 mL of DMF was added potassium carbonate (20.8 g, 150.7 mmol), followed by allyl bromide (11.7 mL, 135 mmol). The reaction was warmed to 60° C. and stirred for one hour. The solution was poured into EtOAc and washed with water, saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was purified by silica gel chromatography (20-30% EtOAc/hexane) to provide the titled product, along with unreacted starting material (4.39 g, 26%).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH:5]1[CH2:9][CH2:8][C:7]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:6]1)(=O)=O.Cl.[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[C:42]3[CH:43]=[CH:44][C:45]([Cl:47])=[CH:46][C:41]=3[NH:40][C:39]2=[O:48])[CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:8][CH2:9][CH:5]([N:32]3[CH2:33][CH2:34][CH:35]([N:38]4[C:42]5[CH:43]=[CH:44][C:45]([Cl:47])=[CH:46][C:41]=5[NH:40][C:39]4=[O:48])[CH2:36][CH2:37]3)[CH2:6]2)=[CH:15][CH:14]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)C2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(C2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)C2)CC1
Temperature: 70 °C
Reaction time: 52 h

Procedure:
A mixture of 13.5 g of 3,3-bis(p-fluorophenyl)cyclopentyl tosylate (nD20 1.5691), 7.5 g of 1-(4-piperidyl)-5-chloro-2-benzimidazolinone hydrochloride, 8.6 g of potassium carbonate and 70 ml of dimethylformamide is stirred at 70° C for 52 hours. The reaction mixture is poured into ice water, and the aqueous layer is removed by decantation. The precipitated semi-solid is dissolved in chloroform. The solution is washed with water and dried over sodium sulfate, and the solvent is removed. The crude crystals are recrystallized from a mixture of chloroform and ethanol (20:1) to give 1-[1-(3,3-bis(p-fluorophenyl)cyclopentyl)-4-piperidyl]-5-chloro-2-benzimidazolinone as white crystals, melting at 131°-134° C.
Reaction SMILES: N1C=CC=CC=1.[Br:7][CH2:8][C:9](Br)=[O:10].[C:12]1([C:18]([OH:21])([CH3:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[Br:7][CH2:8][C:9]([O:21][C:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:20])[CH3:19])=[O:10]
Reactant: CC(C)(O)c1ccccc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(OC(=O)CBr)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
Pyridine (3.84 mL, 47.7 mmol) followed by bromoacetyl bromide (4.16 mL, 47.7 mmol) was added to a solution of 2-phenylpropan-2-ol (5.00 g, 36.7 mmol) in dichloromethane (100 mL) at 0° C., warmed to r.t. and stirred overnight. The reaction mixture was washed with water (3×100 mL), saturated aqueous sodium bicarbonate (3×100 mL), water (2×100 mL), dried (Na2SO4) and concentrated. The crude residue was purified by silica gel flash column chromatography (neutralized with TEA, heptanes) to afford the title compound (2.8 g (non-optimized), 30%) as a colorless oil. 1H NMR (300 MHz, ((CD3)2CO) δ: 7.44 (d, J=7.2 Hz, 2H), 7.34 (t, J=7.2 Hz, 2H), 7.25 (t, J=7.2 Hz, 1H), 4.01 (s, 2H), 1.78 (s, 6H).
Reaction SMILES: [O:1]=[C:2]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH:26]=2)[CH2:21][CH2:20]1)[C@@H:3]([NH:11]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:11][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH:26]=2)[CH2:21][CH2:20]1)=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCc2ccc(-c3ccncc3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)C(=O)N1CCc2ccc(-c3ccncc3)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 25 ml flask was added (S)-tert-butyl 1-oxo-3-phenyl-1-(6-(pyridin-4-yl)indolin-1-yl)propan-2-ylcarbamate 50.D (300 mg, 0.68 mmole) 10 ml of CH2Cl2, and 5 ml of TFA. The reaction was stirred at room temperature for 3 hour at which time the solvent was removed with a stream of nitrogen. The crude was resuspended and the solvent was removed as before. This procedure was repeated one more time to give (S)-2-amino-3-phenyl-1-(6-(pyridin-4-yl)indolin-1-yl)propan-1-one 50.E of as a light yellow oil (300 mg, 21% yield).
Reaction SMILES: [C:1]([C:5]#[CH:6])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH:12]([CH:14]=[CH2:15])=[O:13]>>[CH3:2][C:1]([CH3:4])([CH3:3])[C:5]#[C:6][CH:12]([OH:13])[CH:14]=[CH2:15]
Reactant: C#CC(C)(C)C
Reactant: C=CC=O
Agent: [Li]CCCC
Product: C=CC(O)C#CC(C)(C)C

Procedure:
Reacting t-butylacetylene at −40° C. or less with butyllithium, cooling the reaction mixture at −40° C. or less with acrolein further aging the reaction mixture at −50° C. for 30 minutes to give 6,6-dimethylhept-1-en-4-yn-3-ol.