Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:15][N:16]([CH2:20][CH2:21]Cl)[CH2:17][CH2:18]Cl.Cl>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:9]([O:11][CH3:12])=[O:10])[CH2:21][CH2:20][N:16]([CH3:15])[CH2:17][CH2:18]2)=[CH:6][CH:7]=1
Reactant: CN(CCCl)CCCl
Reactant: COC(=O)Cc1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1(c2ccc(F)cc2)CCN(C)CC1
Reaction time: 8 h
Yield: 30.3 %

Procedure:
Methyl 4-fluorophenylacetate (24.4 g) was dissolved in dry dimethyl sulphoxide (150 ml) and added dropwise to sodium hydride (15.7 g of an 80% dispersion in oil) under nitrogen. After 20 minutes mechlorethamine hydrochloride (24 g) in dry dimethyl sulphoxide (125 ml) was added over a period of 20 minutes. The reaction was poured onto ice (200 ml) and left overnight. The mixture was extracted with diethyl ether (50×250 ml) and the combined organic solutions were extracted with 5N HCl (100 ml). The aqueous solution was treated with potassium carbonate and extracted with ethyl acetate (3×250 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford a brown oil. The oil was purified by flash chromatography eluting with ethyl acetate graduated to 8% methanol in ethyl acetate, to afford the title compound (9.5 g). 1H NMR (360 MHz, CDCl3) δ 1.9-2.03 (2H, m), 2.07-2.19 (2H, m), 2.27 (3H, s), 2.51-2.62 (2H, m), 2.72-2.86 (2H, m), 3.65 (3H, s), 6.98-7.06 (2H, m), 7.27-7.39 (2H, m). MS (Cl+) 224 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:15])[NH:4][CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH:7]=1.[CH3:16]I>>[CH3:16][N:4]1[CH:5]=[C:6]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)[CH:7]=[C:2]([CH3:1])[C:3]1=[O:15]
Reactant: CI
Reactant: Cc1cc(C2CCC(=O)CC2)c[nH]c1=O
Product: Cc1cc(C2CCC(=O)CC2)cn(C)c1=O

Procedure:
The title compound was prepared as a white solid from the methylation of 3-methyl-5-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in Example 44, Step C) with MeI using the procedure described in Step B of Example 38.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:3]2([CH2:8][CH2:7][CH:6]([CH:9]=[C:10](Br)Br)[CH2:5][CH2:4]2)[O:2]1.C([Li])CCC>O1CCCC1.CCCCCC>[C:9]([CH:6]1[CH2:5][CH2:4][C:3]2([O:2][CH2:1][CH2:14][O:13]2)[CH2:8][CH2:7]1)#[CH:10]
Reactant: BrC(Br)=CC1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#CC1CCC2(CC1)OCCO2
Temperature: 20 °C
Yield: 91.1 %

Procedure:
A solution of 14 g of 1,1-ethylenedioxy-4-(2,2-dibromovinyl)cyclohexane in 70 ml of tetrahydrofuran was cooled to -20° C. and treated slowly at this temperature with 76.62 ml of a 1.4M solution of butyl lithium in hexane (exothermic reaction). The cooling bath was removed and the mixture was left to warm to 20° C. within about 20 minutes. The mixture was subsequently treated with 150 ml of water and extracted three times with diethyl ether. The organic phases were washed twice with water and the wash-water was back-extracted with diethyl ether. The organic phases were dried over magnesium sulphate, filtered and evaporated. Low-pressure chromatography of the resulting, yellow liquid (8 g) on silica gel with ethyl acetate/petroleum ether (vol. 7:93) gave 6.5 g (91%) of 4-ethynyl-1,1-ethylenedioxycyclohexane as a clear liquid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[Cl-].[N:30]1([CH2:35][CH2:36][NH2:37])[CH2:34][CH2:33][CH2:32][CH2:31]1>COCCOC>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([NH:37][CH2:36][CH2:35][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)O)c3)nc12
Reactant: NCCN1CCCC1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)NCCN4CCCC4)c3)nc12
Reaction time: 1 h

Procedure:
3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-5-fluoro-benzoic acid 3 (110 mg, 0.39 mmol) in DME (2 mL) was treated with triethylamine (0.11 mL, 0.77 mmol) and cooled in ice bath with salt, methanolsulfonyl chloride (0.05 mL, 0.58 mmol) was added, and continue stirred for 1 hour in ice bath, then 2-pyrrolidin-1-ylethanamine (CAS 7154-73-6) (0.07 mL, 0.58 mmol) was added, the reaction was stirred overnight. The reaction mixture was purified with prep HPLC to give pure 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-5-fluoro-N-(2-(pyrrolidin-1-yl)ethyl)benzamide 13. LC/MS (ESI+): m/z 381 (M+H). 1H NMR (400 MHz, DMSO) δ 8.75 (t, J=5.6 Hz, 1H), 8.66-8.49 (m, 3H), 8.44 (s, 1H), 8.29 (s, 1H), 8.20 (t, J=4.4 Hz, 2H), 8.05 (s, 1H), 7.73 (d, J=9.4 Hz, 1H), 3.62-3.39 (m, 2H), 2.65 (t, J=7.0 Hz, 2H), 2.54 (s, 4H), 1.82-1.59 (m, 4H).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]([CH2:13][CH3:14])[C@H:5]([OH:12])[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7].[N+](CCCC)#[C-:16]>>[ClH:1].[ClH:1].[NH2:3][C@@H:4]([CH2:13][CH3:14])[C@H:5]([OH:12])[C:6]([NH:8][CH2:9][CH2:11][CH2:10][CH3:16])=[O:7]
Reactant: [C-]#[N+]CCCC
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Agent: Cl
Product: CCCCNC(=O)[C@@H](O)[C@@H](N)CC

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide dihydrochloride, Representative Procedure A, using 1-isocyanobutane in the third step (A3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([OH:25])=O)=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN(C=O)C.[CH3:54][C:55]1([CH3:62])[CH2:60][CH2:59][CH2:58][CH:57]([NH2:61])[CH2:56]1>C1COCC1>[Cl:26][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([NH:61][CH:57]3[CH2:58][CH2:59][CH2:60][C:55]([CH3:62])([CH3:54])[CH2:56]3)=[O:25])=[CH:14][C:12]=2[N:13]=1
Reactant: CC1(C)CCCC(N)C1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1(C)CCCC(NC(=O)c2cc3nc(Nc4c(Cl)cncc4Cl)[nH]c3c3c2OC(C)(C)C3)C1
Yield: 11.2 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-3, 0.070 g, 0.178 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.114 g, 0.355 mmol), TEA (1.0 mL), DMF (1.0 mL), THF (5.0 mL) and 3,3-dimethylcyclohexanamine (0.100 g, 0.787 mmol) to afford 0.010 g of the desired product. 1HNMR (DMSO-d6): δ 0.93 (s, 6H), 1.07-1.11 (m, 2H), 1.23-1.29 (m, 2H), 1.33 (s, 6H), 1.49-1.54 (m, 2H), 1.80 (s, 2H), 3.00 (s, 2H), 3.80 (m, 1H), 7.20 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 8.43 (s, 2H), 10.89 (s, 1H), 11.41 (s, 1H); MS [M+H]+: 502.31.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5]CC)=O.[C:12]1([NH:18][NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO.C[O-].[Na+]>C(O)CCC>[C:20]1([N:19]2[C:1](=[O:9])[CH2:2][C:3](=[O:5])[N:18]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: c1ccc(NNc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CO
Product: O=C1CC(=O)N(c2ccccc2)N1c1ccccc1
Temperature: 100 °C
Yield: 68.7 %

Procedure:
Three point six five (3.65) grams (22.8 mmol) of diethyl malonate and 4.00 g (21.7 mmol) of 1,2-diphenylhydrazine were dissolved in 10 ml of n-butanol, then 4.61 g (23.9 mmol) of a 28% methanol solution of sodium methoxide was added thereto, and the reaction system was heated at 100° C. for 10 hours. Subsequently the solvent was distilled off under reduced pressure, 10 ml of water was added thereto and stirred, and then the reaction solution was filtered. An activated carbon was added to the recovered filtrate and stirred for 30 minutes. After stirring, the solution was filtered again to recover the filtrate. Four (4) ml of hydrochloric acid was added to the filtrate, and the precipitated solid was recovered by filtration. Thus, 3.76 g (yield: 60%) of 1,2-diphenyl-3,5-pyrazolidinedione was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:31](=[O:38])[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>>[CH3:36][CH:35]([O:34][C:32]([C:31](=[O:38])[NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[O:33])[CH3:37]
Reactant: CC(C)OC(=O)C(=O)Cl
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(=O)OC(C)C)c1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (53 mg, 0.14 mmol) and isopropyl 2-chloro-2-oxoacetate (0.035 mL, 0.27 mmol) [prepared according to G. Bucher at al, Eur J Org Chem, 545-552 (2001); b.p. 54-55° C., 30 mmHg]. Yield 54 mg (79%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2([CH2:24][OH:25])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:10]2=[O:23])=[C:4](O)[CH:3]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[C:9]3([CH2:24][O:25][C:4]=2[CH:3]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:10]3=[O:23]
Reactant: CCCCCN1C(=O)C(CO)(c2cc(F)c(Cl)cc2O)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: CCCCCN1C(=O)C2(COc3cc(Cl)c(F)cc32)c2ccccc21
Yield: 44 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using 3-(4-chloro-5-fluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 44% yield: 1H NMR (300 MHz, CDCl3) δ 7.34 (td, 1H), 7.14 (dd, 1H), 7.06 (td, 1H), 6.98 (d, 1H), 6.93 (d, 1H), 6.50 (d, 1H), 4.96 (d, 1H), 4.70 (d, 1H), 3.87-3.63 (m, 2H), 1.81-1.65 (m, 2H), 1.47-1.29 (m, 4H), 0.91 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 176.2, 156.9, 154.8, 151.6, 142.5, 131.5, 129.4, 128.6, 123.7, 121.7, 121.9, 111.2, 108.9, 80.6, 57.9, 40.5, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 360 (M+1).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[N:7][N:6]=1>CO>[CH:11]1[CH:12]=[CH:13][C:14]2[C:9](=[CH:8][N:7]=[N:6][C:5]=2[NH:2][NH2:3])[CH:10]=1
Reactant: Clc1nncc2ccccc12
Reactant: NN
Solvent: O
Solvent: CO
Product: NNc1nncc2ccccc12
Temperature: 2.5 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
A 2 L, 3-necked, round-bottomed flask fitted with a temperature probe and condenser, and was charged 375 mL of hydrazine hydrate; the solution was then cooled to 0 to 5° C. About 75 g of 1-chlorophthalazine salt was added in portions at a rate to maintain the solution temperature at 0 to 5° C. After addition, the solution was stirred at 20 to 25° C. for about 24 hrs. The reaction mixture was then cooled to 0 to 5° C. and 150 mL of methanol was added, the solution stirred for 3 hrs, and the resulting solid material was filtered, washed with 150 mL of cold methanol, and dried under vacuum at 35° C. Yield 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:35]2[NH:39][C:38]([C:40]3[CH:45]=[N:44][CH:43]=[CH:42][N:41]=3)=[CH:37][CH:36]=2)[CH2:13][C@H:14]2[CH2:34][CH2:33][C:16]3(O[C@H](C4C=CC=CC=4)[C@@H](C4C=CC=CC=4)[O:17]3)[CH2:15]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].Cl.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:35]2[NH:39][C:38]([C:40]3[CH:45]=[N:44][CH:43]=[CH:42][N:41]=3)=[CH:37][CH:36]=2)[CH2:13][C@H:14]2[CH2:34][CH2:33][C:16](=[O:17])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)c2ccc(-c3cnccn3)[nH]2)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC(=O)C2)c2ccc(-c3cnccn3)[nH]2)cc1Cl
Temperature: 50 °C
Reaction time: 24 h
Yield: 68.4 %

Procedure:
To a solution of 2-(5-{1-[3-chloro-4-(methylsulfonyl)phenyl]-2-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]ethyl}-1H-pyrrol-2-yl)pyrazine (94.3 mg) in tetrahydrofuran (1 mL) was added 1M hydrochloric acid (1 mL), and the mixture was stirred at 50° C. for 24 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (44.7 mg, yield 68%) was obtained as a white amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio). MS: 444 (MH+).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)C1C=CC=CC=1.[H-].[Na+].[CH3:16][O:17][CH2:18]Cl.[OH-].[Na+]>C1COCC1.O>[CH3:16][O:17][CH2:18][O:13][C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCO[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 178.7 %

Procedure:
To a stirred solution of N-benzyl-3-(S)-hydroxypyrrolidine (4.785 g, 27 mmol) in THF (50 ml) was added sodium hydride (60% oil suspension, 1.12 g, 28 mmol) by portions under nitrogen at room temperature. The suspension mixture was then refluxed for 1 h. To this reaction mixture was added chloromethyl methyl ether (2.3 ml, 30 mmol) and refluxing was continued for 13 h. After cooling down to room temperature, water (10 ml) was added to the reaction mixture to give a solution mixture, which was basified with 1N NaOH aqueous solution, extracted with ethyl acetate (30 ml×3), and dried (Na2SO4). Evaporation of the solvent gave 6.33 g of brown oil, which was purified by column chromatography (silica gel: 150 g, CH2Cl2 /MeOH: 20/1 as eluent) to afford 5.09 g (85%) of clear brown oil. A suspension mixture of this oil (5.09 g, 23 mmol) and Pearlman's catalyst (2.00 g) in MeOH (100 ml) was stirred under hydrogen atmosphere at room temperature for 15 h. After removal of the catalyst by Celite filtration, the filtrate was concentrated to give an oil and water mixture, which was dried in vacuo to afford 2.76 g (91.4%) of orange color oil.
Reaction SMILES: Br[CH2:2][C@@H:3]([CH3:6])[CH2:4][CH3:5].FC(F)(F)S(O[C:13]1[C:18]([F:19])=[CH:17][C:16]([CH:20]2[CH2:25][CH2:24][Si:23](CCCCC)([C:26]3C=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)=[CH:15][C:14]=1[F:37])(=O)=O>>[CH2:26]([Si@H:23]1[CH2:24][CH2:25][C@H:20]([C:16]2[CH:17]=[C:18]([F:19])[C:13]([CH2:2][C@@H:3]([CH3:6])[CH2:4][CH3:5])=[C:14]([F:37])[CH:15]=2)[CH2:21][CH2:22]1)[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CC[C@H](C)CBr
Reactant: CCCCC[Si]1(c2ccccc2)CCC(c2cc(F)c(OS(=O)(=O)C(F)(F)F)c(F)c2)CC1
Product: CCCCC[Si@H]1CC[C@H](c2cc(F)c(C[C@@H](C)CC)c(F)c2)CC1

Procedure:
The general procedure of Example 18 was repeated using (S)-1-bromo-2-methylbutane and (2,6-difluoro-4-(4-n-pentyl-4-phenyl-4-silacyclohexyl)phenyl) trifluoromethanesulfonate, thereby obtaining the intended compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=[O:4])=[O:3].ON1C2C=CC=CC=2N=N1.[CH3:24][C:25]([CH3:46])([CH3:45])[CH2:26][CH2:27][NH:28][C:29](=[O:44])[C@H:30]([CH3:43])[CH2:31][C@H:32]([OH:42])[C@@H:33]([NH2:41])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C=O)C>[CH2:34]([C@H:33]([NH:41][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=1)[C@@H:32]([OH:42])[CH2:31][C@H:30]([C:29](=[O:44])[NH:28][CH2:27][CH2:26][C:25]([CH3:24])([CH3:45])[CH3:46])[CH3:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NCCC(C)(C)C
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cccc(S(C)(=O)=O)c1)C(=O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
To a solution of 3-methanesulfonyl benzoic acid (77 mg, 0.39 mmol) and 1-hydroxybenzotriazole (52 mg, 0.39 mmol) in 2:1 dichloromethane/DMF (3.0 ml) was added (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (3,3-dimethylbutyl)-amide (D2) (100 mg, 0.32 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol). The resulting solution was stirred at room temperature overnight and then evaporated to dryness. The residue was partitioned between ethyl acetate and 1M hydrochloric acid. The organic phase was separated and washed with further 1M hydrochloric acid, dil. aq. NaHCO3 and brine. It was dried over MgSO4, filtered and evaporated to afford the crude product which was triturated with ether to afford the title compound (63 mg, 39%).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH:15]1([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][C:19]=2[F:26])[CH2:17][CH2:16]1>>[CH:15]1([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:1][C:2]3[N:6]([C:7]4[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=4)[N:5]=[CH:4][CH:3]=3)=[CH:20][C:19]=2[F:26])[CH2:17][CH2:16]1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(C2CC2)c(F)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(C3CC3)c(F)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-cyclopropyl-3-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 0.71-0.75 (2H, m), 0.96-1.02 (2H, m), 2.06-2.10 (1H, m), 5.17 (2H, s), 5.72 (1H, d, J=1.6 Hz), 6.88-6.92 (1H, m), 7.07-7.10 (2H, m), 7.40 (1H, dd, J=1.6 Hz, 5.2 Hz), 7.55 (1H, d, J=2.0 Hz), 8.02 (1H, s), 8.70 (1H, d, J=5.2 Hz). [M+H] Calc'd for C19H15FN4O, 335. Found, 335.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][C:18]=2[O:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:6].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>C(#N)C.CC(C)=O>[C:23]([C:21]1[CH:20]=[CH:19][C:18]([O:25][C:26]2[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=2)=[C:17]([S:14]([N:11]2[CH2:10][CH2:9][CH:8]([NH:7][C:5]([NH:4][CH2:3][CH2:2][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[O:6])[CH2:13][CH2:12]2)(=[O:15])=[O:16])[CH:22]=1)#[N:24]
Reactant: C1COCCN1
Reactant: N#Cc1ccc(Oc2cc(Cl)cc(Cl)c2)c(S(=O)(=O)N2CCC(NC(=O)NCCCl)CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC#N
Product: N#Cc1ccc(Oc2cc(Cl)cc(Cl)c2)c(S(=O)(=O)N2CCC(NC(=O)NCCN3CCOCC3)CC2)c1
Reaction time: 3 h
Yield: 65.5 %

Procedure:
1-(2-chloroethyl)-3-(1-(5-cyano-2-(3,5-dichlorophenoxy)-phenylsulfonyl)piperidin-4-yl)urea (838 mg), potassium carbonate (655 mg, 3.0 eq.) and morpholine (413 mg, 3.0 eq.) were dissolved in acetonitrile (25 mL) and heated to reflux. After three hours, the reaction was complete (confirmed by HPLC). The mixture was then concentrated in vacuo, the solid triturated with dichlormethane and isopropyl ether to obtain a white powder. The powder was suspended in hot acetone, cooled in an ice bath, filtered, and washed with water to obtain the product as a white powder (601 mg, 65% yield, 97% purity).
Reaction SMILES: [CH2:1](OC(=NOCCN(C)C[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2C)[C@H](O)[C@@H]1O)C)C.[C:31]([CH2:36][CH2:37][N:38]([CH3:58])[CH2:39][C@H:40]1[O:44][C@@H:43]([N:45]2[C:54]3[N:53]=[CH:52][N:51]=[C:49]([NH2:50])[C:48]=3[N:47]=[C:46]2[CH3:55])[C@H:42]([OH:56])[C@@H:41]1[OH:57])([O:33][CH2:34][CH3:35])=[O:32].CNC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2CC)[C@H](O)[C@@H]1O.ClCCC(OCC)=O.CCN(C(C)C)C(C)C>CN(C=O)C>[C:31]([CH2:36][CH2:37][N:38]([CH3:58])[CH2:39][C@H:40]1[O:44][C@@H:43]([N:45]2[C:54]3[N:53]=[CH:52][N:51]=[C:49]([NH2:50])[C:48]=3[N:47]=[C:46]2[CH2:55][CH3:1])[C@H:42]([OH:56])[C@@H:41]1[OH:57])([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(C)=NOCCN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reactant: CCOC(=O)CCN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Agent: CCOC(=O)CCCl
Agent: CCc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CNC)[C@@H](O)[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C)C[C@H]1O[C@@H](n2c(CC)nc3c(N)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 33b was prepared by the same procedure as described for the preparation of 6a and 33a using 4b (260 mg, 0.84 mm), ethyl 3-chloropropionate (138 mg, 1.0 mm), DIEA (53 mg, 0.07 ml, 0.41 mm), and DMF (4 ml). After column chromatography (elution with 7:1:0.1 chloroform:methanol:NH4OH), a glassy sticky solid was obtained: yield 153 mg (44%), MS: m/z 409 (M+H)+; 1HNMR (DMSO-d6) δ 8.08 (s, 1H, H-2), 7.10 (bs, 2H, 6-NH2), 5.71 (d, 1H, H-1′, J1′,2′=5.5 Hz), 5.32 (bd, 1H, OH-2′, J2′-2′OH=5.0 Hz), 5.16 (bd, 1H, OH-3′, J3′-3′OH=5.1 Hz), 5.12 (ddd, 1H, H-2′, J1′,2′=5.5 Hz, J2′,3′=5.7 Hz, J2′-2′OH=5.0 Hz), 4.14 (ddd, 1H, H-3′, J2′,3′=5.7 Hz, J3′,4′=4.1 Hz, J3′-3′OH=5.1 Hz), 4.01 (q, 2H, CH3—CH2), 3.91-3.98 (m, 1H, H-4′), 2.87 (q, 2H, CH2 of 8-Et), 2.71-2.79 (m, 1H, 5′-CH2), 2.51-2.65 (m, 3H, 5′-CH2, CO—CH2), 2.38 (t, 2H, NCH3—CH2), 2.16 (bs, 3H, N—CH3), 1.30 (t, 31-1, CH3 of 8-Et), 1.15 (t, 3H, OCH2—CH3).
Reaction SMILES: C1(C)C=CC=CC=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].[C:22]([O:26][C:27](=[O:58])[NH:28][CH2:29][C:30]#[C:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[CH:37][N:36]=[C:35]2[NH:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][C:50]2[CH:51]=[N:52][C:53]([CH3:56])=[CH:54][CH:55]=2)=[C:45]([Cl:57])[CH:44]=1)([CH3:25])([CH3:24])[CH3:23]>O1CCCC1>[C:22]([O:26][C:27](=[O:58])[NH:28][CH2:29]/[CH:30]=[CH:31]/[C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[CH:37][N:36]=[C:35]2[NH:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][C:50]2[CH:51]=[N:52][C:53]([CH3:56])=[CH:54][CH:55]=2)=[C:45]([Cl:57])[CH:44]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(C#CCNC(=O)OC(C)(C)C)cc34)cc2Cl)cn1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(/C=C/CNC(=O)OC(C)(C)C)cc34)cc2Cl)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a solution of 7.53 mL of a 65% weight toluene solution of sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al, 24.2 mmol) in 90 mL of tetrahydrofuran at 0° C. was added 5.0 g of (3-{4-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-carbamic acid tert-butyl ester as a solid. The reaction was stirred at 0° C. for 2 hours, quenched with 10% aqueous potassium carbonate and extracted with ethyl acetate. The combined organics were dried and evaporated. The crude material was purified on 115 g of silica gel, eluting with 80% ethyl acetate/hexanes to afford 4.42 g of E-(3-{4-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-carbamic acid tert-butyl ester. 1H NMR (CDCl3): δ 8.66 (s, 1), 8.24 (m, 1), 8.03 (m, 2), 7.77-7.65 (m, 3), 7.13 (m, 2), 6.97 (d, J=8.7 Hz, 1), 6.54 (d, 1), 6.35 (m, 1), 4.90 (m, 1) 3.90 (m, 2), 2.52 (s, 3), 1.46 (s, 9).