Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23][CH:24]5[CH2:29][CH2:28][N:27](C(C)(C)CO)[CH2:26][CH2:25]5)=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[C:35]([O:39][C:40](N1CCC(S)CC1)=[O:41])([CH3:38])([CH3:37])[CH3:36].CCN(C(C)C)C(C)C.BrC1C=CC2OCCN3C(=NC(C4N(C(C)C)N=CN=4)=C3)C=2C=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(Cl)Cl>[C:35]([O:39][C:40]([N:27]1[CH2:28][CH2:29][CH:24]([S:23][C:20]2[CH:21]=[CH:22][C:15]3[O:14][CH2:13][CH2:12][N:11]4[C:17](=[N:18][C:9]([C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=5)=[CH:10]4)[C:16]=3[CH:19]=2)[CH2:25][CH2:26]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)(C)CO)CC3)ccc1OCC2
Reactant: CC(C)(C)OC(=O)N1CCC(S)CC1
Agent: [Pd]
Agent: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCN(C(=O)OC(C)(C)C)CC3)ccc1OCC2
Temperature: 120 °C
Yield: 931.5 %

Procedure:
A mixture of 9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 1 (100 mg, 0.267 mmol), 4-mercaptopiperidine-1-carboxylic acid tertbutyl ester (87 mg, 0.401 mmol), Pd2(dba)3 (13 mg, 5 mol %), XantPhos (15 mg, 10 mol %) and DIPEA (0.19 mL) in dioxane (3 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. The same process was repeated using a mixture of 9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (400 mg, 1.068 mmol), 4-mercaptopiperidine-1-carboxylic acid tertbutyl ester (348 mg, 1.604 mmol), Pd2(dba)3 (50 mg, 5 mol %), XantPhos (61 mg, 10 mol %) and DIPEA (0.745 mL) in dioxane (10 mL). The two crude reaction mixtures were combined into DCM (200 mL) and purified by column chromatography (Si-PCC, gradient 0-7% MeOH in DCM) affording the title compound as an orange gum (1.27 g, quantitative). LCMS: RT 4.15 min [M+H]+ 511.3. (110174852)
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][CH:20]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:20][CH2:19][CH2:18][C:9]2[CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:31][CH2:30]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: O=CCCc1cc(-c2ccccc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccccc1N1CCN(CCCc2cc(-c3ccccc3)n(-c3ccccc3)n2)CC1

Procedure:
74 mg (83%) of target compound was obtained by using a method same as in Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (55 mg, 0.199 mmol), 1-(2-fluorophenyl)piperazine (0.026 mL, 0.166 mmol), DIPEA (35 mL, 0.199 mmol) and NaBH(OAc)3 (148 mg, 0.697 mmol).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22]>>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]3[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[C:11]=3[CH:10]=[N:9][CH:8]=2)=[CH:19][CH:18]=1)#[N:17]
Reactant: N#Cc1ccc(-c2cncc3c2CCCC3N)cc1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)NC1CCCc2c(-c3ccc(C#N)cc3)cncc21
Yield: 63 %

Procedure:
In analogy to the procedure described for the preparation of example 8, (rac)-4-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)benzonitrile (example 1) was reacted with isobutyryl chloride to give the title compound as a off-white powder in 63% yield. MS: 320.2 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][CH:20]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([NH2:26])=[O:27])=[CH:21][CH:20]=3)=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Oc3ccc(C(N)=O)cc3)ccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCNC3)cc1
Reaction time: 24 h
Yield: 71.1 %

Procedure:
Combine 6-(4-Carbamoyl-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (4.0 g, 10.83 mmol), CH2Cl2 (100 ml), and TFA (25 ml) at room temperature. After the reaction stirred for 24 hours followed by the addition of 11K2CO3 (aq), extract the product out of the aqueous layer with several washings of ethyl acetate/THF. Concentrate the organic phase under reduced pressure and add to 2, 10 g SCX Columns pre-treated with 5% AcOH/MeOH. After several washings of the SCX Columns with MeOH, the elute the product using 1N NH3-MeOH solution to afford 2.00 g, 7.7 mmol (71% yield) of the title compound as a white foam: 1H NMR (500 MHz, DMSO); 2.9-3.1 (2H, m), 3.10-3.25 (1H, m), 3.3-3.5 (2H, m), 4.1-4.3 (2H, m), 7.0-7.2 (3H, m), 7.2-7.4 (1H, m), 7.4-7.6 (1H, m), 8.0-8.1 (1H, m), 8.2-8.4 (1H, m), 8.5-8.65 (1H, m), 9.2-9.4 (2H, m); MS m/z 269 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([NH:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([Cl:16])=[CH:9][CH:8]=3.[OH-].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27]>CO>[F:27][C:26]([F:29])([F:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([NH:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([Cl:16])=[CH:9][CH:8]=3
Reactant: O=c1c2ccc(O)cc2[nH]c2cc(Cl)ccc12
Reactant: FC(F)(F)CCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=c1c2ccc(Cl)cc2[nH]c2cc(OCCCCCC(F)(F)F)ccc12
Temperature: 70 °C

Procedure:
3-hydroxy-6-chloroacridone (594 mg) was stirred in 10 ml of methanol, and 5 ml of methanolic KOH (30 mg/ml) was added (1 equiv. base), whereupon complete dissolution occurred. 1-Bromo-5-trifluoromethylpentane (2.03 g, 3 equiv.) was added and the solution heated at 70° C. overnight, forming a fine solid precipitate; after cooling, 0.35 g of pale yellow powder was collected by filtration. When the filtrate is heated another 2 days, the same quantity of product may be isolated in addition. The crude product was crystallized from methanol. Analogous procedures can be applied for preparation of compounds with the O(CH2)3CF3, O(CH2)4CF3, O(CH2)7CF3, and O(CH2)10CF3— side chains and including aromatic ketone derivatives bearing O(CH2)C2F5 and O(CH2)C3F7 side chains.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.CCN=C=NCCCN(C)C.Cl.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:44]([O:51][C:52](=[O:56])[CH2:53][CH2:54][NH2:55])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([NH:8][C@H:9]([C:17]([NH:55][CH2:54][CH2:53][C:52]([O:51][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:56])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: NCCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCCC(=O)OCc1ccccc1
Reaction time: 0.67 h

Procedure:
Boc-L-phenylalanine (1.32 g, 5.00 mmol) was dissolved in dichloromethane (50 mL) and treated with HoBt.H2O (1.53 g, 2.00 mmol) followed by WSCDI (water soluble carbodiimide) (1.00 g, 5.24 mmol). After stirring for 40 minutes, β-alanine benzyl ester tosylate (1.85 g, 5.27 mmol) was added, followed by DIPEA (diisopropylethylamine) (1.29 g, 10 mmol). Stirring was continued overnight, then the solvent removed. The residue was dissolved in ethyl acetate (30 mL) and washed with water, 10% sodium bicarbonate solution, then 10% citric acid solution. The organic layer was dried (MgSO4) and evaporated to a white solid--a single component by TLC, 1.74 g, 82% of (32). NMR (CDCl3) δ 1.41 (9H, s), 2.47 (2H, m), 3.01 (2H, m), 3.45 (2H, m), 4.25 (1H, br.q), 5.00 (1H, br.s), 5.07 (2H, s), 6.21 (1H, br.t), 7.15-7.38 (10H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[N:18][C:19]#[N:20])OC2C=CC=CC=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(#N)C>[C:19]([NH:18][C:10]([NH:26][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[N:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)#[N:20]
Reactant: NC1CCCC1
Reactant: N#CN=C(Nc1cc(Cl)cc(Cl)c1)Oc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#CNC(=Nc1cc(Cl)cc(Cl)c1)NC1CCCC1
Temperature: 82 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a solution of N-(3,5-dichlorophenyl)-N'-cyano-O-phenylisourea (0.8 mmol, 250 mg) in dry acetonitrile (2 ml), cyclopentylamine (0.9 mmol, 0.089 ml) and triethylamine (0.125 ml) were added. The mixture was stirred for 21/2 h at 82° C. under nitrogen. After concentration the residue was purified by flash chromatography (ethyl acetate/heptane 1:2) to give the title compound (160 mg, 66%) as crystals. Mp 147.5-148.5° C.; 1H-NMR (CDCl3): δ 1.45 (m, 2H), 1.65 (m, 4H), 2.05 (m, 2H), 4.11 (sextet, 1H), 5.1 (br, 1H), 7.2 (m, 3H), 8.02 ppm (br, 1H); EI SP/MS: 296 (M+), 298 (M+2), 300 (M+4). MA calc for C13H14Cl2N4 : C, 52.54%; H, 4.75%; N, 18.85%. Found: C, 52.17%; H, 4.71%; N, 18.50%.
Reaction SMILES: Cl.[C:2]1([C:8]2[N:9]=[C:10]([S:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=3N)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(OCCC(C)C)=O>Cl>[C:13]1([C:12]2[N:11]=[C:10]([S:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:24][CH:25]=3)[NH:9][C:8]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cc(C(F)(F)F)ccc1Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: CC(C)CCON=O
Agent: Cl
Product: FC(F)(F)c1ccc(Sc2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
2.24 g of 4,5-diphenyl-2-(2-amino-4-trifluoromethylphenylthio)imidazole hydrochloride is dissolved in 100 ml of methanolic hydrochloric acid and combined at 0° with 0.586 g of isoamyl nitrite. The mixture is agitated for 30 minutes, then heated to boiling for 2 hours and the solution evaporated under vacuum to dryness. The residue is distributed between ethyl acetate and sodium bicarbonate solution. The organic solution is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is crystallized from ether/chloroform, thus obtaining 1.61 g of 4,5-diphenyl-2-(4-trifluoromethylphenylthio)imidazole, mp 227°-229°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.[C:13]([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)(N1C=CN=C1)=O>>[CH2:21]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:13][N:20]1[CH2:24][CH2:23][NH:22][C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)=[O:12]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1n[nH]c2ccccc12
Product: O=C(NCCN1CCc2ccccc2C1)c1n[nH]c2ccccc12
Yield: 185.2 %

Procedure:
Same procedure followed as described in Example 5. The following amounts were used: 1H-indazole-3-carboxylic acid (1.49 g, 9.2 mmol), 1,1'-carbonyldiimidazole (1.49 g, 9.2 mmol) and the intermediate from Preparation 5 (1.62 g, 9.2 mmol). The ethyl acetate extracts were evaporated to a solid. Addition of cyclohexane and filtration provided 2.73 g of solid. Mass spectrum, m+ =321.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11](OC)=[O:12])[CH:8]=[C:7]([F:15])[C:5]=2[N:6]=1.C1COCC1.CC(C[Al]CC(C)C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[C:7]([F:15])[C:5]=2[N:6]=1
Reactant: COC(=O)c1cc(F)c2nc(Br)sc2c1
Agent: CC(C)C[Al]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1cc(F)c2nc(Br)sc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
To a solution of methyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate 0.335 g, 1.15 mmol) in toluene (10 mL) and THF (5 mL) was added Dibal-H (4.8 mL, 4.8 mmol) at −78° C. over 10 min. The resulting mixture was allowed to warm to rt and stirred at rt for 3 hr before it was poured into ice cold water (100 mL). The mixture was stirred at rt for 30 min and then filtered through Celite® 545. The organic layer was separated and the aqueous layer was extracted twice with AcOEt. The combined organic phase was dried over anhydrous MgSO4 and concentrated under vacuum. Evaporation of solvent under vacuum gave the title compound (0.269 g, 89% yield) as a white solid.
Reaction SMILES: [CH:1]([CH:4]1[CH:10]([NH:11]C(=O)C(F)(F)F)[C:9](=[O:18])[NH:8][C:7]2[CH:19]=[CH:20][CH:21]=[CH:22][C:6]=2[S:5]1)([CH3:3])[CH3:2].[OH-].[Na+]>CO>[NH2:11][CH:10]1[C:9](=[O:18])[NH:8][C:7]2[CH:19]=[CH:20][CH:21]=[CH:22][C:6]=2[S:5][CH:4]1[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)C1Sc2ccccc2NC(=O)C1NC(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C1Sc2ccccc2NC(=O)C1N
Temperature: 0 °C
Yield: 80.2 %

Procedure:
In 200 ml of methanol is dissolved 10 g of 2-isopropyl 3-trifluoroacetamido-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, whereto 75 ml of a 4 N aqueous solution of sodium hydroxide is added at room temperature. The reaction mixture is poured into ice water 2.5 hours later, and the precipitated organic substance is extracted with chloroform. The chloroform layer is washed with water and dried over magnesium sulfate. Thereafter, the solvent is distilled off under reduced pressure. Isopropyl ether is added to the residue, and the resulting crystals are collected by filtration to give 5.7 g of 3-amino-2-isopropyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, m.p. 180°-183° C.
Reaction SMILES: BrC1C=CC=C[N:3]=1.C([Li])CCC.S(Cl)(Cl)(=O)=O.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([NH2:27])(=[O:26])=[O:25]>CCCCCC.CO.C(OCC)C>[NH3:3].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([NH2:27])(=[O:26])=[O:25]
Reactant: Brc1ccccn1
Agent: NS(=O)(=O)c1ccccn1
Agent: [Li]CCCC
Solvent: CO
Solvent: CCOCC
Solvent: CCCCCC
Product: N

Procedure:
According to Reference Example 9-8, by use of 2-bromopyridine (500 mg, 3.2 mmol), diethyl ether (5 mL), n-butyllithium (a 1.56 mol/L solution in hexane, 2.5 mL, 3.8 mmol), sulfuryl chloride (0.28 mL, 3.5 mmol) and a 7 mol/L solution of ammonia in methanol (2 mL), pyridine-2-sulfonamide (Compound FI) (77 mg, yield: 15%) was obtained.
Reaction SMILES: [Br:1]/[CH:2]=[CH:3]/[CH:4]([OH:14])[C:5]([CH3:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].CCOCC.N1C=CN=C1.[CH3:25][Si:26](Cl)([CH3:28])[CH3:27]>O1CCCC1>[Br:1]/[CH:2]=[CH:3]/[CH:4]([O:14][Si:26]([CH3:28])([CH3:27])[CH3:25])[C:5]([CH3:6])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:13]
Reactant: CC(C)(c1ccccc1)C(O)/C=C/Br
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(c1ccccc1)C(/C=C/Br)O[Si](C)(C)C

Procedure:
A solution of 7.8 g. of 1-bromo-4-methyl-4-phenyl-trans-1-pentene-3-ol in a mixture of 45 ml. of ether and 15 ml. of tetrahydrofuran was treated with 4.2 g. of imidazol under N2. After imidazol dissolved completely, the solution was treated at 0° with 5 ml. of trimethylsilyl chloride and stirred for one hour. The solvents were evaporated at 25° and the residue was diluted with n-pentane. After passing through an alumina column, the n-pentane filtrate was evaporated at 25° to afford 9.0 g. of the title product as a colorless liquid, λmaxfilm 3.45, 6.15, 6.65, 6.90, 7.20, 7.30, 7.98, 8.90, 9.10, 9.22, 10.60, 11.30, 11.85, 13.14 and 14.25 μ.
Reaction SMILES: C([O:4][CH2:5]/[CH:6]=[C:7](\[F:16])/[S:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:9])(=O)C.[OH-].[Na+]>CO.O>[F:16]/[C:7](/[S:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:9])=[CH:6]\[CH2:5][OH:4]
Reactant: CCCCCCS(=O)/C(F)=C/COC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCS(=O)/C(F)=C/CO
Reaction time: 0.5 h

Procedure:
To a solution of (E)-3-fluoro-3-hexylsulfinyl-2propenyl acetate (3.0 g, 12.0 mmol) in 20 ml of methanol under N2 is added aqueous sodium hydroxide (3.0 g, 37.5 mmol). After 30 min. at RT, the solution is diluted with water and extracted with ether. The aqueous phase is diluted with saturated brine and extracted again with ether. The combined ether extracts are dried over Na2SO4 and stripped to give (E)-3-fluoro-3-hexylsulfinyl-2-propenol (cpd. 2, Table A).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([C:12]1[CH:13]=[C:14]([C:28]2[N:33]=[C:32]([CH3:34])[N:31]=[C:30]([NH2:35])[N:29]=2)[C:15]([NH:18][C:19]2[CH:20]=[N:21][C:22]([O:26][CH3:27])=[C:23]([F:25])[CH:24]=2)=[N:16][CH:17]=1)[CH3:11])(C(C)(C)C)(C)C>C1COCC1>[NH2:35][C:30]1[N:31]=[C:32]([CH3:34])[N:33]=[C:28]([C:14]2[CH:13]=[C:12]([CH:10]([CH3:11])[CH2:9][OH:8])[CH:17]=[N:16][C:15]=2[NH:18][C:19]2[CH:20]=[N:21][C:22]([O:26][CH3:27])=[C:23]([F:25])[CH:24]=2)[N:29]=1
Reactant: COc1ncc(Nc2ncc(C(C)CO[Si](C)(C)C(C)(C)C)cc2-c2nc(C)nc(N)n2)cc1F
Solvent: C1CCOC1
Product: COc1ncc(Nc2ncc(C(C)CO)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
Tetra(N-butyl)ammonium fluoride (1.0M in THF) (Fluka, St. Louis, Mo.; 1.206 mL, 1.206 mmol) was added to an orange solution of 4-(5-(1-(tert-butyldimethylsilyloxy)propan-2-yl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (241.0 mg, 0.482 mmol) in THF (5.0 mL) at 25° C., and the resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was subsequently concentrated onto silica gel and chromatographically purified (silica gel, 0 to 100% EtOAc/hexanes) to provide 2-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)propan-1-ol (139.0 mg, 0.361 mmol, 74.8% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 11.88 (s, 1H), 8.66 (d, J=2.5 Hz, 1H), 8.41 (d, J=2.2 Hz, 1H), 8.35-8.40 (m, 1H), 8.25 (d, J=2.5 Hz, 1H), 7.88 (br. s., 1H), 7.74 (br. s., 1H), 4.70 (br. s., 1H), 3.93 (s, 3H), 3.49 (d, J=6.5 Hz, 2H), 2.83 (sxt, J=6.9 Hz, 1H), 2.44 (s, 3H), 1.22 (d, J=7.0 Hz, 3H). 19F NMR (376 MHz, d6-DMSO) δ −139.83 (d, J=13.0 Hz, 1 F). m/z (ESI, +ve) 386.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][CH2:20][O:21][CH2:22][CH3:23])[CH2:16][CH:15]2[C:24](=[O:33])[N:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=C)[CH3:26])=[O:13])[CH2:8][CH:7]1[CH:9]=C)=[O:5])[CH3:2]>ClC(Cl)C>[CH2:1]([O:3][C:4]([C:6]12[CH2:8][CH:7]1[CH:9]=[CH:31][CH2:30][CH2:29][CH2:28][CH2:27][N:25]([CH3:26])[C:24](=[O:33])[CH:15]1[CH:14]([CH2:18][CH:17]([O:19][CH2:20][O:21][CH2:22][CH3:23])[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCN(C)C(=O)C1CC(OCOCC)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Solvent: CC(Cl)Cl
Product: CCOCOC1CC2C(=O)NC3(C(=O)OCC)CC3C=CCCCCN(C)C(=O)C2C1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A degassed solution of dialkene (114)(1.83 g, 3.93 mmol) in dichloroethane (1.8 L, stored over 4 Å molecular sieves before use) was added Howeyda-Grubbs 1st generation catalyst (0.165 g, 0.27 mmol), then shortly degassed and stirred at approximately 85° C. bath temperature overnight (monitored by LC-MS). The reaction mixture was then allowed to cool somewhat after which solid phase catalyst scavenger (1.3 g, MP-TMT, Argonaut Technologies) and stirred additional 1.5 h, then filtered and concentrated. Flash chromatography of the residue (YMC-GEL silica) using stepwise gradient elution (ethyl acetate in hexane, 50-100%) and concentration of the appropriate fractions gave the title compound as a brown syrup which crystallized upon standing (1.33 g, 77%, purity approx. 90%). This material was crystallized from 4:1 ethyl acetate (40 ml) giving a brown solid (0.79 g, 1.8 mmol) and chromatography of the mother liqure gave additional product (0.36 g, 0.81 mmol). LR-MS: Calcd for C23H37N2O6: 437. Found: 437 [M+H].
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])[N:5]=[CH:4][N:3]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[F:8][C:7]1[C:2]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:3][CH:4]=[N:5][C:6]=1[O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14]
Reactant: CCC#CCOc1ncnc(Cl)c1F
Reactant: C1CCNCC1
Product: CCC#CCOc1ncnc(N2CCCCC2)c1F
Reaction time: 3 h
Yield: 97.8 %

Procedure:
0.2 g of 4-chloro-5-fluoro-6-(2-pentynyloxy)pyrimidine and 0.24 g of piperidine were mixed and left for 3 hours at room temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.24 g of 5-fluoro-4-piperidino-6-(2-pentynyloxy)pyrimidine (hereinafter, referred to as Compound (12)).
Reaction SMILES: COC1C=C(OC)C=CC=1CN1C(=O)CNS1(=O)=O.C1CCN2C(=NCCC2)CC1.[CH3:31][Si:32]([CH3:46])([CH3:45])[CH2:33][CH2:34][O:35][C:36]([C:38]1[S:39][C:40](CBr)=[CH:41][CH:42]=1)=[O:37]>C(Cl)Cl>[CH3:31][Si:32]([CH3:46])([CH3:45])[CH2:33][CH2:34][O:35][C:36]([C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)=[O:37]
Reactant: C[Si](C)(C)CCOC(=O)c1ccc(CBr)s1
Agent: COc1ccc(CN2C(=O)CNS2(=O)=O)c(OC)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of the title B compound in Example 9, 2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (7.00 g, 24.4 mmol) and DBU (3.71 g, 24.4 mmol) in CH2Cl2 (200 mL) is treated with the title B compound, 5-bromomethyl-thiophene-2-carboxylic acid 2-trimethylsilanyl-ethyl ester (8.25 g, 25.7 mmol). The mixture is stirred at RT for 3 h and the solvent is evaporated. The residue is chromatographed over silica gel using 20%-50% EtOAc in hexane as the eluent to afford 5-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5]thiadiazolidin-2-ylmethyl]-thiophene-2-carboxylic acid 2-trimethylsilanyl-ethyl ester as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([C:26]([OH:28])=O)=[CH:23]2)=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C.[Cl:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42]>CN(C=O)C.C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([C:26]([NH:42][C:41]3[CH:43]=[CH:44][CH:45]=[C:39]([Cl:38])[CH:40]=3)=[O:28])=[CH:23]2)=[CH:18][CH:17]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COc1cc2nccc(Oc3ccc4ccc(C(=O)O)cc4c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc4ccc(C(=O)Nc5cccc(Cl)c5)cc4c3)c2cc1OC
Reaction time: 2 h

Procedure:
A slurry of 7-(6,7-dimethoxyquinolin-4-yloxy)-2-naphthoic acid (0.54 g, 1.44 mmol) in 10 mL of C2O2Cl2 and 2 drops of DMF was stirred at RT. After 2 h, the solution was concentrated to dryness and placed under high vacuum overnight. A portion of the crude residue (0.075 g, 0.191 mmol) was dissolved in 1 mL of CH2Cl2. To the resulting solution was added DIPEA (0.133 mL, 0.764 mmol), 3-chloroaniline (0.024 mL, 0.229 mmol) and a catalytic amount of DMAP. The reaction was stirred under a N2 atmosphere for 16 h. The reaction was diluted with EtOAc, and washed with saturated aqueous NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated. The residue was passed through a medium-pressure silica gel column (solvent gradient: 95:5 CH2Cl2:MeOH; 90:10 CH2Cl2:MeOH) to afford the desired crude compound. The fractions were concentrated to dryness to afford a solid residue. The residue was triturated with Et2O/Hexanes to afford the desired compound as a pale yellow solid. MS (ESI, pos. ion) m/z: 485.0 (M+1). Mass Calc'd for C28H21ClN2O4: 484.937.