Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[C:13]([CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[C:25]([F:28])([F:27])[F:26])=[O:16])=[C:12]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:11]2[C:6](=[CH:7][C:8]3[C:37](=[O:38])[CH2:36][CH2:35][C:9]=3[CH:10]=2)[O:5]1.CO.Cl>COCCOC>[F:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[CH2:14][C:13]2[C:4](=[O:3])[O:5][C:6]3[C:11]([C:12]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:10][C:9]2[CH2:35][CH2:36][CH:37]([OH:38])[C:8]=2[CH:7]=3)=[C:19]([C:25]([F:28])([F:26])[F:27])[CH:20]=1
Reactant: O=C(Cc1c(-c2ccccc2)c2cc3c(cc2oc1=O)C(=O)CC3)Nc1ccc(F)cc1C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Product: O=C(Cc1c(-c2ccccc2)c2cc3c(cc2oc1=O)C(O)CC3)Nc1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.4 %

Procedure:
A suspension of NaBH4 (30 mg) in DME (2 ml) was combined with 2-(2,8-dioxo-4-phenyl-2,6,7,8-tetrahydrocyclopenta[g]chromen-3-yl)-N-[4-fluoro-2-(trifluoromethyl)phenyl]-acetamide (Example 88) (170 mg) with cooling in ice, and further combined with methanol, and stirred at room temperature for 10 minutes. The reaction solution was poured into diluted hydrochloric acid, which was then extracted with ethyl acetate. The extract was washed with water, and then dried over magnesium sulfate, and concentrated under reduced pressure to obtain the title compound as a colorless crystal (110 mg, yield: 65%). An aliquot was recrystallized from ethyl acetate to measure a melting point. Melting point: 217-218° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:32]3[C:23](=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[N:27][CH:26]=[CH:25]4)[NH:22][C:21](=[O:33])[CH2:20][C:19]2=[O:34])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[C:3]([C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:32]4[C:23](=[C:24]5[C:29](=[CH:30][CH:31]=4)[CH:28]=[N:27][CH:26]=[CH:25]5)[NH:22][C:21](=[O:33])[CH2:20][C:19]3=[O:34])=[CH:14][CH:13]=2)=[O:6])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2cnccc32)cc1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3cccnc3Cl)cc2)c2ccc3cnccc3c2N1
Yield: 87.4 %

Procedure:
By using 2-chloronicotinic acid (32 mg, 0.2 mmol), and 5-(4-aminophenyl)-1H-[1,4]diazepino[2,3-f]isoquinoline-2,4(3H,5H)-dione (6 mg, 0.02 mmol), the title compound (8 mg, yield 85%) was obtained as pale brown powder in the same manner as that of Example 149.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[C:16](Cl)[CH:15]=3)[N:11]([CH2:21][CH:22]([OH:25])[CH2:23][CH3:24])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:26]([NH2:28])[CH3:27]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:28][CH2:26][CH3:27])[CH:15]=3)[N:11]([CH2:21][C@@H:22]([OH:25])[CH2:23][CH3:24])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(O)Cn1nc(Nc2cccc(Cl)c2)nc1-c1ccnc(Cl)c1
Reactant: CCN
Solvent: CO
Product: CCNc1cc(-c2nc(Nc3cccc(Cl)c3)nn2C[C@@H](O)CC)ccn1
Temperature: 160 °C
Reaction time: 16 h

Procedure:
Intermediate 1-[3-(3-chloro-phenylamino)-5-(2-chloro-pyridin-4-yl)-[1,2,4]triazol-1-yl]-butan-2-ol (prepared according to description 4) (1.15 g; 3.04 mmol) was dissolved in CH3OH (20 ml) and then ethylamine (3 g) was added. The reaction mixture was stirred for 16 hours at 160° C. under pressure (until the reaction had proceeded to completion). The solvent was then evaporated in vacuo. The residue was purified by reversed-phase high-performance liquid chromatography (Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8 μm, 250 g, I.D. 5 cm). A gradient with 2 mobile phases was applied (phase A: a 0.25% NH4HCO3 solution in water; phase B: CH3CN). The desired fractions were collected, worked-up and finally the residue was crystallized from diisopropyl ether. Yield: 0.1595 g of compound E2 (S-enantiomer).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH2:13][C:14]2(C(F)(F)F)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].ClC1C(OCC2CCCCC2)=C[C:28](F)=[C:29]([CH:33]=1)[C:30](O)=O>>[Cl:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([O:9][C:29]([CH3:33])([CH3:30])[CH3:28])=[O:8]
Reactant: O=C(O)c1cc(Cl)c(OCC2CCCCC2)cc1F
Reactant: O=C(O)c1cc(Cl)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 158 step 2 and making variations as required to replace 5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)benzoic acid with 5-chloro-4-(cyclohexylmethoxy)-2-fluorobenzoic acid, the title compound was obtained as a colorless oil (15.37 g, 43%): MS (ES+) m/z 381.2 (M+39).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])[C:15]#[N:16]
Reactant: CC(C)(C)OC(=O)NCc1cc(C#N)cc(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)c(F)c(CN)c1
Reaction time: 8 h

Procedure:
To a solution of (3-chloro-5-cyano-2-fluoro-benzyl)-carbamic acid tert-butyl ester (645 mg, 2.27 mmol) in CH2Cl2 (15 mL) was added TFA (1.75 mL, 22.7 mmol), and stirring was continued at RT overnight. Volatiles were removed under reduce pressure, water was added and the mixture was washed with EtOAc. The aqueous layer was basified to pH=12 by addition of 4M NaOH solution and extracted twice with EtOAc. The combined organics were dried (phase separator) and evaporated to afford the title compound as a beige solid. MS (LC/MS): 185.0 [M+H]+; tR (HPLC conditions c): 2.62 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[O:27]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[CH2:37][CH2:38][NH2:39])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:18])[NH:39][CH2:38][CH2:37][C:36]3[CH:40]=[CH:41][CH:42]=[C:34]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:35]=3)=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NCCc1cccc(Oc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4cccc(Oc5ccccc5)c4)cc3)c(Cl)cc21
Reaction time: 24 h
Yield: 91.2 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (51.6 mg, 0.137 mmol), in 1:1 DCM:DMF (0.1 M) was sequentially treated with 3-phenoxyphenethylamine (32.1 mg, 0.151 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31.5 mg, 0.164 mmol), and 1-hydroxy-7-azabenzotriazole (5.59 mg, 0.0411 mmol) at ambient temperature. After 24 hours the reaction was applied directly to a silica gel column and eluted with a gradient (15% to 60%) of ethyl acetate-hexanes to provide the title compound (71.6 mg, 0.125 mmol, 91.4% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:12]=2[OH:13])=[CH:5][CH:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[C:26]([C:28]1[CH:29]=[C:30]([S:35]([NH:38][C:39]2[S:43][N:42]=[CH:41][N:40]=2)(=[O:37])=[O:36])[CH:31]=[CH:32][C:33]=1F)#[N:27].Cl>CN(C)C=O>[C:26]([C:28]1[CH:29]=[C:30]([S:35]([NH:38][C:39]2[S:43][N:42]=[CH:41][N:40]=2)(=[O:37])=[O:36])[CH:31]=[CH:32][C:33]=1[O:13][C:12]1[CH:11]=[CH:10][C:9]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][C:7]=1[C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1)#[N:27]
Reactant: Cn1nccc1-c1cc(-c2ccccc2)ccc1O
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(-c2ccccc2)ccc1Oc1ccc(S(=O)(=O)Nc2ncns2)cc1C#N
Temperature: 100 °C
Yield: 99.4 %

Procedure:
To a stirred solution of 3-(1-methyl-1H-pyrazol-5-yl)biphenyl-4-ol (Preparation 28, 44.1 mg, 0.176 mmol) and potassium carbonate (30.4 mg, 0.22 mmol) in N,N-dimethylformamide (1 mL) was added 3-cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 47, 50.0 mg, 0.176 mmol) and the reaction mixture was stirred at 100° C. After stirring for 24 hours, the reaction mixture was cooled to room temperature. A 1M aqueous solution of hydrogen chloride (10 mL) was added to the reaction mixture and the mixture was extracted with dichloromethane (3×10 mL). The combined organic layer was concentrated in vacuo to obtain the title compound (90 mg, 99%).
Reaction SMILES: [Br:1][C:2]([N+:7]([O-:9])=[O:8])([CH2:5][OH:6])[CH2:3][OH:4].[CH3:10][C:11]([CH3:13])=O.B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>>[Br:1][C:2]1([N+:7]([O-:9])=[O:8])[CH2:5][O:6][C:11]([CH3:13])([CH3:10])[O:4][CH2:3]1
Reactant: CC(C)=O
Reactant: O=[N+]([O-])C(Br)(CO)CO
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC1(C)OCC(Br)([N+](=O)[O-])CO1
Reaction time: 8 h
Yield: 40 %

Procedure:
To a 100 ml. 3-necked flask equipped with magnetic stirring was added 20 g. (0.1 mole) of 2-bromo-2-nitropropane-1,3-diol and 30 ml. (0.5 mole) of acetone. After solution was complete, the temperature was 15° C. Then 13 ml. (0.1 mole) of boron trifluoride etherate was added to the reaction mixture from a dropping funnel over a period of about 2 minutes. The temperature rose to 47° C. and then dropped to 35° C. over a period of 10 minutes. The reaction mixture was then poured into 150 ml. of a saturated sodium bicarbonate solution and stirred for 15 minutes. The solids were filtered and washed with 200 ml. acetone, dried and an IR showed a reaction had occurred. About 18 g. of crude material was dissolved in 150 ml. of hot hexane and filtered. On cooling and standing overnight 9.0 g. (40% yield) of 5-bromo-2,2-dimethyl-5-nitro- 1,3-dioxane was obtained as pure white needles. An NMR and IR confirmed the structure. An elemental analysis disclosed the following percentage composition:
Reaction SMILES: Br[C:2]1[C:11]2[O:10][C@@H:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:11]2[O:10][C@@H:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)Cc2scc(-c3ccccc3F)c2O1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A mixed solution of tert-butyl (2S)-8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (681 mg) obtained in Example 12, steps 1-4, (2-fluorophenyl)boronic acid (356 mg), dichlorobis(triphenylphosphine)palladium (68 mg) and potassium carbonate (809 mg) in DME-water (1:1, 20 mL) was stirred at 85° C. for 4 hr under a nitrogen stream. The reaction solution was cooled to room temperature, and water was added. The mixture was filtered through celite, and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 5→15% ethyl acetate/hexane) to give the title compound (694 mg, 98%) as a colorless oil.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([OH:10])=[C:4]2[CH:3]=[N:2]1.[Br:11]Br>O>[Br:11][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[OH:10])[NH:1][N:2]=1
Reactant: Oc1ncnc2[nH]ncc12
Reactant: BrBr
Solvent: O
Product: Oc1ncnc2[nH]nc(Br)c12
Temperature: 91 °C
Yield: 9.5 %

Procedure:
1H-pyrazolo[3,4-d]pyrimidin-4-ol (10 g, 73.5 mmol) was suspended in 700 ml of water. Bromine (10 ml, 194 mmol) was added and the resulting reaction mixture was heated to 91° C. overnight. After cooling on ice-water, the solid was collected by filtration to give 1.508 g of 3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-ol as light yellow solid. 1H NMR (DMSO) 8.06 (s 1H), 12.25(bs, 1H), 14.06 (bs, 1H).
Reaction SMILES: [ClH:1].C([O:9][N:10]1[C:14](=[O:15])[CH2:13][C:12]2([CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[C:11]1=[O:22])C1C=CC=CC=1.[H][H]>CO.O.[Pd]>[ClH:1].[OH:9][N:10]1[C:14](=[O:15])[CH2:13][C:12]2([CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)[C:11]1=[O:22]
Reactant: CN1CCC2(CC1)CC(=O)N(OCc1ccccc1)C2=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CN1CCC2(CC1)CC(=O)N(O)C2=O
Yield: 93 %

Procedure:
The compound No. 1 (2-benzyloxy-8-methyl-2,8-diazaspiro[4,5]decane-1,3-dione hydrochloride (6.4 g), listed in Table 1 in Example 4) was dissolved in 50 ml of methanol-water (1 to 1, v/v), and this was followed by catalytic hydrogen reduction for about 1 hour in the presence of palladium catalyst. The resulting solid was recrystallized from ethanol to obtain 4.3 g of a colorless crystal having a melting point of from 284° to 286° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:5]2=[N:4][CH:3]=1.[CH3:22][O-:23].[Na+]>CO>[CH3:22][O:23][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:5]2=[N:4][CH:3]=1
Reactant: COc1ccc(COc2ccc3ncc(Br)nc3n2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(COc2ccc3ncc(OC)nc3n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59 %

Procedure:
3-Bromo-6-({[4-(methyloxy)phenyl]methyl}oxy)pyrido[2,3-b]pyrazine (1.19 g, 3.44 mmol) was suspended in methanol and a solution of sodium methoxide (25% in methanol, 10.1 mL) was added at room temperature under argon. After 20 min all the solid went into solution, the reaction was stirred overnight at rt. The solvent was removed and the residue partitioned between water (250 mL) and 10% MeOH/DCM (200 mL). The aqueous phase was extracted with 10% MeOH/DCM (2×100 mL). The combined organic phases were dried, evaporated and subjected to column chromatography on silica gel eluting with DCM to afford 0.6 g of the title compound (59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:29][C:30]([O:32]C)=[O:31])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]2[C:17]([C:25]([F:28])([F:27])[F:26])=[N:18][O:19][C:20]=2[C:21]=1[CH2:22][CH2:23][CH3:24].[OH-].[Li+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:29][C:30]([OH:32])=[O:31])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]2[C:17]([C:25]([F:28])([F:26])[F:27])=[N:18][O:19][C:20]=2[C:21]=1[CH2:22][CH2:23][CH3:24]
Reactant: CCCc1c(OCCCNc2ccc(CC(=O)OC)cc2Cl)ccc2c(C(F)(F)F)noc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCc1c(OCCCNc2ccc(CC(=O)O)cc2Cl)ccc2c(C(F)(F)F)noc12
Temperature: 0 °C

Procedure:
A solution of Methyl 3-chloro-4-(3-(3-trifluoromethyl-7-propyl-6-benz-[4,5]-isoxazoloxy)propylamino)-phenylacetate (Step C, 0.113 grams) in methanol (1.5 mL) was treated with a solution of lithium hydroxide in water (1.01 M; 0.362 mL). The reaction was refluxed 1 hour. The reaction mixture was partitioned between isopropyl acetate and 0.1N HCl. The organic was dried over magnesium sulfate, filtered and concentrated to a solid. The solid was suspended in methylene chloride/cyclohexane (1:1; 2 mL). The mixture was refluxed briefly and cooled to 0° C. The title compound was isolated by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:28])[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[C:29]([O:33]C)(=[O:32])[CH:30]=[CH2:31]>CO.C(COC)OC>[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([CH:14]=[CH:13][CH2:12][C:11]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:10](=[O:28])[CH:9]=[CH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:31][CH2:30][C:29]([OH:33])=[O:32])=[CH:20][CH:19]=1
Reactant: Cc1ccc(C=CCC(C(=O)C=Cc2ccc(Cl)cc2)c2ccccc2)cc1
Reactant: C=CC(=O)OC
Solvent: CO
Solvent: COCCOC
Product: Cc1ccc(C=CCC(CCC(=O)O)(C(=O)C=Cc2ccc(Cl)cc2)c2ccccc2)cc1
Reaction time: 36 h

Procedure:
Triton B (1 ml., 40% in MeOH) is added to a stirred suspension of 1-(p-chlorophenyl)-4-phenyl-7-(p-methylphenyl)-1,6-heptadien-3-one (14.55 g., 0.038 mole) in glyme (150 ml.) followed by addition of methyl acrylate (3.87 g., 0.045 mole) in glyme (25 ml.). The mixture is warmed slightly to obtain solution then is stirred for 24 to 48 hours. The solvent is removed under reduced pressure and water (1000 ml.) and dilute hydrochloric acid is added to the residue. The organic material is extracted into ether and these extracts are washed with water, saturated brine and dried (MgSO4). After removal of the solvent the residue is heated with a solution of 20% sodium hydroxide (20 ml.) in methanol (800 ml.) on the steam bath for 24 hours. The methanol is removed in vacuo and the residue is dissolved in a large volume of water. Extraction with ether removes unreacted ketone. Ether is expelled from the aqueous phase by warming and dilute hydrochloric acid is added. The solid that separates is collected, washed well with water, and air-dried, yield 10.43 g., m.p. 170°-180°C. Recrystallization from acetonitrile gives material with m.p. 182°-185°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].ClCCl.C([Zn][CH2:28][CH3:29])C>CCCCCC>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:12][CH:13]1[CH2:14][CH:15]1[CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:28][CH3:29]
Reactant: CC[Zn]CC
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OC
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCC1CC1CC1CC1CCCCCCCC(=O)OC
Reaction time: 1 h

Procedure:
To a mixture of linoleic acid methyl ester (2.5 g) and dichloromethane (50 ml), a 0.99M solution of diethylzinc (103 ml) in n-hexane was added under a nitrogen atmosphere. The mixture was cooled in an ice-water bath (−5° C. to 0° C.) and stirred for 1 hour at this temperature. Diodomethane (16.4 ml) was added to the mixture, and the mixture was stirred at ambient temperature overnight. After evaporation in vacuo of the solvent, the reacting mixture was dissolved in a mixture of ethyl acetate (EA) and a saturated aqueous solution of ammonium chloride. The separated organic layer was washed with water and dried over magnesium sulfate. After filtration, the filtrate was concentrated in vacuo. The obtained residue was purified by chromatography on silica gel (eluted with 1% EA in n-hexane). The fractions including 8-(2-((2-pentyl-cyclopropan-1-yl)methyl)cyclopropyl)octanoic acid methyl ester were collected and concentrated in vacuo to give 8-(2-((2-pentylcyclopropan-1-yl)methyl)cyclopropyl)octanoic acid methyl ester (2.81 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH2:15][CH3:16])[C:13]4[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH3:26][O:27][C:28]([CH3:32])([CH3:31])[CH2:29][NH2:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:26][O:27][C:28]([CH3:32])([CH3:31])[CH2:29][NH:30][C:21]([C:19]1[CH:18]=[CH:17][C:13]2[N:14]([CH2:15][CH3:16])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:25]=[CH:24][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:20]=1)=[O:23]
Reactant: COC(C)(C)CN
Reactant: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC(C)(C)OC)ccc21
Yield: 39.6 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid (2-methoxy-2-methyl-propyl)-amide (73.0 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzo-imidazole-5-carboxylic acid (150.0 mg), 2-methoxy-2-methyl-propylamine (61.0 mg), HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 459; and 1H NMR (DMSO-d6, 400 MHz): δ 8.18-8.16 (1H, m), 8.08 (1H, m), 7.92-7.91 (1H, m), 7.79-7.77 (1H, m), 7.67-7.65 (1H, m), 7.54-7.52 (1H, m), 7.40-7.37 (1H, m), 4.21-4.20 (2H, m), 3.37-3.35 (2H, d), 3.18 (3H, s), 1.34-1.30 (3H, t), 1.14 (6H, s), —NH proton signal was not observed.
Reaction SMILES: C([Si]([C:8]1[C:13]([F:14])=[C:12]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][N:16]=2)[N:11]=[C:10]([N:24]2[CH2:29][CH2:28][NH:27][C@H:26]([C@:30]([CH3:39])([O:34][Si](C)(C)C)[CH:31]([CH3:33])[CH3:32])[CH2:25]2)[C:9]=1[F:40])(C)C)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[F:40][C:9]1[C:10]([N:24]2[CH2:29][CH2:28][NH:27][C@H:26]([C@:30]([OH:34])([CH:31]([CH3:32])[CH3:33])[CH3:39])[CH2:25]2)=[N:11][C:12]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][N:16]=2)=[C:13]([F:14])[CH:8]=1
Reactant: CC(C)[C@@](C)(O[Si](C)(C)C)[C@@H]1CN(c2nc(-c3n[nH]c4ncccc34)c(F)c([Si](C)(C)C(C)(C)C)c2F)CCN1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)[C@@](C)(O)[C@@H]1CN(c2nc(-c3n[nH]c4ncccc34)c(F)cc2F)CCN1
Reaction time: 8 h
Yield: 84.1 %

Procedure:
tert-butyl-[2-[(3S)-3-[(1R)-1,2-dimethyl-1-trimethylsilyloxy-propyl]piperazin-1-yl]-3,5-difluoro-6-(1H-pyrazolo[3,4-b]pyridin-3-yl)-4-pyridyl]-dimethyl-silane (60 g, 101.9 mmol) was dissolved in THF (216.0 mL) at room temperature. TBAF in THF (214.0 mL of 1 M, 214.0 mmol) was added dropwise via cannula to the brown solution over 45 minutes. The reaction was stirred overnight, after which time the deprotection was complete by Lc/Ms. The mixture was diluted with EtOAc (600 ml) and washed with saturated aqueous NaHCO3 (100 ml then 2×200 ml). The organic phase was further washed with a 2:3 mixture of saturated brine:water (100 ml) until no remaining Bu4N+ salts were observed Lc/Ms analysis. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a brown solid. The solid was triturated with diethyl ether, filtered and dried to give a orange brown solid (34.5 g, 84%). The solid was recrystallised from isopropanol. This afforded the title compound as a beige solid (23 g); 1H NMR (d6-DMSO) 0.84 (3H, d), 0.90 (3H, d), 1.06 (3H, s), 1.83 (2H, m), 2.74 (2H, d), 2.85 (2H, d), 3.09 (1H, d), 3.78 (1H, d), 4.04 (1H, d), 4.13 (1H, s), 7.30 (1H, dd), 7.92 (1H, dd), 8.60 (1H, dd), 8.77 (1H, dd), 13.99 (1H, brs); 19F NMR (decoupled) −128.5, −124.1; MS ES(+) 403.0 (M+1).
Reaction SMILES: [H-].[Li+].[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[F:14])[NH:10][C:9](=[O:15])[CH:8]=[N:7]2.Br[CH2:17][CH2:18][CH:19]1[O:23][CH2:22][CH2:21][O:20]1.O>CN(C)C=O>[O:20]1[CH2:21][CH2:22][O:23][CH:19]1[CH2:18][CH2:17][N:10]1[C:11]2[C:6](=[CH:5][C:4]([F:3])=[C:13]([F:14])[CH:12]=2)[N:7]=[CH:8][C:9]1=[O:15]
Reactant: BrCCC1OCCO1
Reactant: O=c1cnc2cc(F)c(F)cc2[nH]1
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cnc2cc(F)c(F)cc2n1CCC1OCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
Lithium hydride (52 mg, 6.5 mmol) was added to a solution of 6,7-difluoroquinoxalin-2(1H)one (1 g, 5.4 mmol) in N,N-dimethylformamide (10 ml) under cooling on ice and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was cooled on ice again, a solution of 2-(2-bromoethyl)-1,3-dioxolane (0.8 ml, 6.5 mmol) in N,N-dimethylformamide (2 ml) was gradually added thereto and the obtained mixture was stirred for 4 hours. Water was gradually added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 0.6 g (39%) of the title compound.