Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])C=CC=CC=1.FC(F)(F)S(O[CH2:26][CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])(=O)=O.[ClH:37]>C1COCC1>[ClH:37].[F:33][C:28]([F:34])([C:29]([F:32])([F:31])[F:30])[CH2:27][CH2:26][C@@H:9]([C:10]([O:12][CH3:13])=[O:11])[NH2:8]
Reactant: O=S(=O)(OCCC(F)(F)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)[C@@H](N)CCC(F)(F)C(F)(F)F
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
Under argon, 132 g (521.0 mmol) of methyl N-(diphenylmethylene)glycinate [described in: WO2010/123792 A1, 2010, 11-13; additionally: commercially available] were initially charged in 1000 ml of THF (anhydrous) and cooled to −40° C. 625.2 ml (625.2 mmol) of bis(trimethylsilyl)lithium amide (1 M in THF) were added dropwise over 30 min. After 10 min, the cooling bath was replaced by a water/ice bath, and the internal temperature was allowed to increase to 0° C. over a period of 35 min. At 0° C., 192.86 g (651.25 mmol) of 3,3,4,4,4-pentafluorobutyl trifluoromethanesulphonate from Example 132A, dissolved in 400 ml of THF, were added dropwise to the reaction solution. After 10 min, the cooling bath was removed and the mixture was stirred at RT for 3 days. The reaction mixture was then cooled to 0° C., and 410 ml (1.33 mol) of 3 N hydrochloric acid were added dropwise. The cooling bath was removed and the reaction solution was stirred at RT for 2 hours. The mixture was then concentrated. This gave 141.5 g of the target compound as a crude mixture which was used without any further purification for the next step.
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]N)=[CH:7][CH:6]=1.[N:15]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[C:18](=O)[CH2:17][CH2:16]2.Cl.O1CCOCC1>C(O)(=O)C>[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]2[NH:11][C:18]3[CH:19]4[CH2:22][CH2:23][N:15]([CH2:16][C:17]=3[C:7]=2[CH:6]=1)[CH2:21][CH2:20]4
Reactant: O=C1CCN2CCC1CC2
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: FC(F)(F)Oc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Temperature: 150 °C

Procedure:
In a 30 ml, microwave reaction tube were combined 4-(trifluoromethoxy)phenyl-hydrazine hydrochloride (1143 mg, 5.0 mmol; Alfa Aesar), 1-azabicyclo[3.2.2]nonan-4-one (696 mg, 5.0 mmol; Example 2A), 4 N HCl in dioxane (2.5 mL, 10.0 mmol; Aldrich), and acetic acid (15 mL). The reaction mixture was heated in a microwave to 150° C. (Biotage Personal Chemistry, maximum 300 W) for 15 minutes, then cooled to room temperature. The solvent was removed, and the residue was basified with 5 N sodium hydroxide and extracted with ethyl acetate (3×50 mL). The combined organic phases were concentrated in vacuo and purified by reverse-phase HPLC [Waters XBridge RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 20 minutes] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.08 (td, J=7, 4 Hz, 4H), 2.99-3.13 (m, 3H), 3.23 (dd, J=14, 7 Hz, 2H), 4.21 (s, 2H), 6.92 (ddd, J=9, 2, 1 Hz, 1H), 7.16 (d, J=1 Hz, 1H), 7.28 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 297 (M+H)+.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=C[CH:10]=[C:9](N)[CH:8]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.CI.ClCCl.[CH3:31][N:32]([CH:34]=O)[CH3:33]>>[C:1]([NH:4][CH:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:34]([N:32]([CH3:31])[CH3:33])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc(N)c1)NC(C)=O
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CI
Product: CCOC(=O)C(Cc1cccc(N(C)C)c1)NC(C)=O
Temperature: 30 °C

Procedure:
4 g of ethyl (RS)-N-acetyl-3-aminophenylalaninate, prepared as described in Example 35-8, in 15 ml of DMF are placed in a three-necked flask under a nitrogen atmosphere, and 5.5 ml of triethylamine, and then 2.5 ml of methyl iodide and 4 ml of dichloromethane, are added while maintaining the temperature in the region of 30° C. using an icebath. The mixture is then warmed at 35° C. for 18 h. 1 ml of methyl iodide dissolved in 1 ml of DMF is then added slowly while maintaining the temperature in the region of 30° C.; 2.2 ml of triethylamine are then added and the mixture is subsequently warmed for a further 5 h at 35° C. The mixture is brought to room temperature and then extracted with 100 ml of ethyl acetate and 150 ml of distilled water. The aqueous phase is separated off after settling and then rewashed with 2 times 70 ml of ethyl acetate. The organic phases are combined, washed with 2 times 80 ml of distilled water and then with 50 ml of distilled water which is saturated with NaCl. The organic phase is separated off after settling, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure in order to yield 2.4 g of a product which is purified by flash chromatography (dichloromethane, MeOH 90/10). 0.72 g (16%) of ethyl (RS)-3-N-acetyl-3-dimethylamino phenylalaninate is thus obtained in the form of yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl[CH2:14][CH:15]([OH:36])[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1.CC([O-])(C)C.[K+]>>[C:30]1([CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]2[CH2:19][CH2:18][N:17]([CH2:16][CH:15]([OH:36])[CH2:14][O:1][C:2]3[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]4[C:3]=3[CH:4]=[CH:5][CH:6]=[N:7]4)[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1ccc(O)c2cccnc12
Reactant: OC(CCl)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1ccc(OCC(O)CN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2cccnc12

Procedure:
Following the same procedure as in Example 23-(c), reaction and treatment were carried out using 360 mg of the above synthesized 5-hydroxy-8-methylquinoline, 1.39 g of 4-(3-chloro-2-hydroxypropyl)-1-diphenylmethylpiperazine and 300 mg of t-BuOK in order to obtain 120 mg of 5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]-8-methylquinoline.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9](Cl)[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])[CH3:2].[CH2:16]([O:23][C:24](=[O:36])[CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:29]([O:28][C:26](=[O:27])[CH:25]([C:9]1[CH:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:10]=1)[C:24]([O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: CCOC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Product: CCOC(=O)c1cc(C(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)ccc1[N+](=O)[O-]

Procedure:
The 5-chloro-2-nitrobenzoic acid ethyl ester (4.40 g) obtained in Example 9-4b) and malonic acid dibenzyl ester were subjected to reactions similar to those in Example 1-3a) to give the title compound (4.61 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[O:18][CH3:19])[CH2:7][CH2:8][CH3:9].[C:20]([O-])(=[O:22])C.[Na+]>CN(C)C=O>[CH3:19][O:18][C:11]1[CH:12]=[C:13]([CH3:17])[C:14]([CH:20]=[O:22])=[C:15]([CH3:16])[C:10]=1[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CC(=O)[O-]
Reactant: CCCCc1c(C)cc(C)cc1OC
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCc1c(OC)cc(C)c(C=O)c1C

Procedure:
5.5 ml. of phosphorous oxychloride are added dropwise while stirring to 4.6 ml. of dimethylformamide. The temperature rises to 30° C. The mixture is treated dropwise with 9.6 g. of 2-butyl-3,5-dimethylanisole, poured onto ice water after the addition of 30 to 35 percent aqueous solution of sodium acetate, stirred for 1 hour and extracted with benzene. The benzene extract is washed with water, dried over sodium sulfate and evaporated. There is obtained 4-methoxy-3-butyl-2,6-dimethyl-benzaldehyde, which is purified by absorption on silica gel, using hexane/methylene chloride 1:1 parts by volume as the eluent, before the condensation with 1-ethoxycarbonyl-2,6-dimethyl-hepta-1,3,5-trien-7-triphenylphosphonium bromide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=3)[N:19]=2)=[CH:12][N:11]([CH:26]2[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]2)[N:10]=1.FC1C=C(F)C=CC=1C1N(C2CCN(C(OC(C)(C)C)=O)C2)N=CC=1C1C=CC2N(C(C(C)C)=NN=2)N=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:24])[CH3:25])=[N:21][N:22]=3)[N:19]=2)=[CH:12][N:11]([CH:26]2[CH2:30][CH2:29][NH:28][CH2:27]2)[N:10]=1
Reactant: CC(C)c1nnc2ccc(-c3cn(C4CCN(C(=O)OC(C)(C)C)C4)nc3-c3ccc(F)cc3F)nn12
Agent: CC(C)c1nnc2ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)C4)c3-c3ccc(F)cc3F)nn12
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)c1nnc2ccc(-c3cn(C4CCNC4)nc3-c3ccc(F)cc3F)nn12
Temperature: 85 °C
Yield: 74 %

Procedure:
To a round bottom flask was added tert-butyl 3-(3-(2,4-difluorophenyl)-4-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate and tert-butyl 3-(5-(2,4-difluorophenyl)-4-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (0.446 g, 0.875 mmol, Preparation #X.1.1.1) as a mixture of regioisomers followed by 1,4-dioxane (10 mL) and concentrated hydrochloric acid (3.50 mL, 17.5 mmol). The reaction mixture was heated to about 85° C. for about 20 min. The reaction mixture was partitioned between saturated aqueous NaHCO3 and DCM (50 mL). The organic layer was isolated and the aqueous layer extracted with DCM (2×50 mL). The combined organic layers were dried with MgSO4, filtered and concentrated in vacuo. The reaction mixture was purified by flash chromatography (40 g RediSep® silica gel; DCM/MeOH with 5% 2.0 M ammonia in EtOH gradient from 1:0 to 80:20) to give the title compound (0.265 g, 74%): LC/MS (Table 1, Method g) Rt=1.75 min; MS m/z: 410.3 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]#[C:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH3:20])=[C:14]([O:21][CH3:22])[CH:13]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.C(O)(=O)C.[Pd]>[CH:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH3:20])=[C:14]([O:21][CH3:22])[CH:13]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc2cc(C#CC3CCCCC3)cnc2cc1OC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc2cc(CCC3CCCCC3)cnc2cc1OC

Procedure:
To 3-cyclohexylethynyl-6,7-dimethoxyquinoline (215 mg; 0.73 mmol) in 10 mL CH3OH and 20 mL glacial acetic acid is added 22 mg 10% Pd/C. H2 is bubbled through the reaction mixture and then filtered, evaporated to dryness and diluted with distilled water. This is then neutralized with Na2CO3, extracted with EtOAc, washed with brine, dried (MgSO4), evaporated to dryness and chromatographed with 8:2/hexane: EtOAc to obtain 3-cyclohexylethyl-6,7-dimethoxyquinoline.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](C)[S:8][C:9]=1[C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1)=[O:4].[NH2:18]C(N)=S.C(N)(=S)C>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH2:18])[S:8][C:9]=1[C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1)=[O:4]
Reactant: COC(=O)c1nc(C)sc1-c1cccc(C)c1
Reactant: NC(N)=S
Agent: CC(N)=S
Product: COC(=O)c1nc(N)sc1-c1cccc(C)c1

Procedure:
This compound was synthesised as 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid methyl ester but using thiourea instead thioacetamide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Product: O=c1[nH]nc(N2CCN(Cc3ccccc3)CC2)c2ccccc12

Procedure:
4-Chlorophthalazin-1-one and 1-benzylpiperazine were processed using a method similar to that described in Example 1A to afford the title compound. MS (APCI+) M/Z 321 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)=[O:20])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][C:21]=1[C:19]([NH:18][C:14]1[CH:13]=[C:12]([NH:11][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=1)=[O:20]
Reactant: Nc1cccc(NC(=O)c2ccc3ccccc3c2)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(Nc1cccc(Nc2ncccc2[N+](=O)[O-])c1)c1ccc2ccccc2c1
Yield: 50.1 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (0.87 g), N-(3-aminophenyl)-2-naphthalenecarboxamide (1.31 g) and potassium carbonate (1.0 g) in 1,4-dioxane (20 ml) was stirred under reflux for 20 hours. After cooling, insoluble materials were removed by filtration and the filtrate was concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-[3-(2-naphthoylamino)phenylamino]-3-nitropyridine (961 mg) as an orange solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:30][C:31]1[O:35][C:34]([C:36](O)=[O:37])=[N:33][N:32]=1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:36]([C:34]4[O:35][C:31]([CH3:30])=[N:32][N:33]=4)=[O:37])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: Cc1nnc(C(=O)O)o1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)c2nnc(C)o2)C3)cc1

Procedure:
Compound fa was prepared according to the procedure described in Example 213 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 5-methyl-1,3,4-oxadiazole-2-carboxylic acid. LC-MS: m/z=+507 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][C:32]2[NH:33][CH:34]=[CH:35][N:36]=2)[CH2:24][C:25]2[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])(C)(C)C.Cl.O1CCOCC1.[OH-].[Na+]>CO>[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][C:32]2[NH:36][CH:35]=[CH:34][N:33]=2)[CH2:24][C:25]2[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=2)=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: Cn1ccnc1CN(Cc1ccc(S(=O)(=O)NCCCCNC(=O)OC(C)(C)C)cc1)Cc1ncc[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Cn1ccnc1CN(Cc1ccc(S(=O)(=O)NCCCCN)cc1)Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 8.5 h
Yield: 115.3 %

Procedure:
The compound (902.3 mg) obtained in Example 102-3 was dissolved in methanol (4.0 ml) and added with a 4 mol/l hydrogen chloride/dioxane solution (4.0 ml), followed by stirring at room temperature for 8.5 hours. After the reaction, the solvent was dissolved off. The residue was added with a 1 mol/l sodium hydroxide aqueous solution (7 ml) and subjected to extraction with chloroform. Then, the extract was dried with magnesium sulfate and the solvent was dissolved off. The residue was then purified through a solid-phase extraction column (ODS type), thereby obtaining the subject compound (844.3 mg) as a brown viscous solid.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@H:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][C@H:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:29]=[CH:30][C:31]([CH2:34][CH3:35])=[CH:32][CH:33]=3)[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: CCc1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: CCOC(=O)[C@@H](Cc1ccc2[nH]ccc2c1)OCC
Product: CCO[C@H](Cc1ccc2c(ccn2Cc2nc(-c3ccc(CC)cc3)oc2C)c1)C(=O)O
Yield: 60 %

Procedure:
Starting from (R)-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-(4-ethyl-phenyl)-5-methyl-oxazole, the title compound was obtained in 60% yield as a pale yellow solid. AS: (M−H)− 431.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH:23]([CH3:24])[CH2:22][C:21]4[C:16](=[CH:17][C:18]([C:25]5[CH:29]=[CH:28][NH:27][N:26]=5)=[CH:19][CH:20]=4)[CH2:15]3)[N:11]=[C:10]([NH2:30])[N:9]=2)[CH2:4][CH2:3]1.[C:31](#[N:34])[CH:32]=[CH2:33].N12CCCN=C1CCCCC2>C(#N)C>[NH2:30][C:10]1[N:11]=[C:12]([N:14]2[CH:23]([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][C:18]([C:25]4[CH:29]=[CH:28][N:27]([CH2:33][CH2:32][C:31]#[N:34])[N:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)[CH:13]=[C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[N:9]=1
Reactant: C=CC#N
Reactant: CC1Cc2ccc(-c3cc[nH]n3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1Cc2ccc(-c3ccn(CCC#N)n3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 50 °C

Procedure:
A mixture of 4-(4-methylpiperazin-1-yl)-6-[3-methyl-7-(1H-pyrazol-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine (10.0 mg, 0.0247 mmol), 2-propenenitrile (50.0 uL, 0.761 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.0 uL, 0.033 mmol) in acetonitrile (0.15 mL) was heated at 50° C. for 2 h. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=458.3.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11]([O:13][C:14](=[O:33])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:33])[CH2:15][C:16]1[CH:17]=[C:18]([C:2]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=2[CH:4]=[O:5])[C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH3:12]
Reactant: O=Cc1cc(F)ccc1Br
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 2-bromo-5-fluorobenzaldehyde and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][N:25]4[CH:29]=[CH:28][N:27]=[CH:26]4)=[CH:18][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1)#[N:2].[N-:30]=[N+:31]=[N-:32].[Na+].[Cl-].[NH4+].Cl>O.CN(C)C=O>[N:25]1([CH2:24][CH2:23][CH2:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:12]3[N:13]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]5[NH:32][N:31]=[N:30][N:2]=5)=[CH:4][CH:5]=4)[O:10][CH:11]=3)=[CH:17][CH:18]=2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: N#Cc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: c1cn(CCCc2ccc(OCc3coc(-c4ccc(-c5nnn[nH]5)cc4)n3)cc2)cn1
Reaction time: 24 h
Yield: 32.1 %

Procedure:
A mixture of 2-(4-cyanophenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole (700 mg), sodium azide (585 mg), ammonium chloride (480 mg) and N,N-dimethylformamide (20 ml) was stirred for 24 hours at temperatures ranging from 130 to 135° C. The reaction mixture was poured into water, which was neutralized with 1N hydrochloric acid. The resulting crystalline precipitate was collected by filtration. The filtrate was subjected to extraction with ethyl acetate-tetrahydrofuran. The organic layer was washed with water, dried (MgSO4), and concentrated to leave a crystalline product. Both crystalline products were combined and recrystallized from methanol to give 5-[4-[4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-oxazolyl]phenyl]-1H-tetrazole (250 mg, 33%) as colorless prisms, mp 273-275° C. (decomp.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C1CCNCC1
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-cyanobenzenesulfonyl chloride (0.51 g, 2.5 mmol) and piperidine (0.60 mL, 517 mg, 6.04 mmol) in 10 mL methylene chloride was stirred overnight at ambient temperature. The organic layer was washed successively with water, 5% HCl and brine, dried (Na2SO4) and concentrated. The resulting white solid (0.61 g, 96%) was used with no further purification.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([O:15][CH2:16][CH3:17])=O.[OH-].[K+]>C1COCC1.C(O)C.O>[CH3:12][CH2:11][CH2:10][CH2:9][CH2:8]/[CH:7]=[CH:6]\[CH2:5][CH2:4][CH2:3][CH:16]([OH:15])[CH2:17][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCOC=O
Reactant: CCCCC/C=C\CCCBr
Agent: [K+]
Agent: [Mg]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCCCC/C=C\CCCC(O)CCC/C=C\CCCCC
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
To a suspension of magnesium turnings (1.4 g, 55.1 mmol) in anhydrous THF (6 mL) under nitrogen was slowly added a solution of (Z)-1-bromodec-4-ene 3 (11.5 g, 52.5 mmol) in THF (12 mL). The reaction mixture was stirred at 45° C. for 30 minutes under nitrogen. The solution was cooled to 0° C. and a solution of ethyl formate (4.1 g, 55.1 mmol) in THF (12 mL) was added dropwise to over 5 minutes. The solution was stirred at room temperature for 2 hours then cooled to −15° C. and quenched slowly with water (10 mL) followed by 5M hydrochloric acid (15 mL). Once the magnesium had completely dissolved, the solution was diluted with water (50 mL) and extracted with hexanes (3×75 mL). The combined extracts were dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue obtained was dissolved in ethanol (40 mL) and a solution of potassium hydroxide (4.4 g, 78.7 mmol)) in water (10 mL) was added. The reaction mixture was stirred vigorously for 30 minutes then concentrated in vacuo to remove ethanol. The solution was then made acidic with 5M hydrochloric acid (15 mL) and extracted with hexanes (3×75 mL). The combined hexanes extracts were dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The crude product was purified by column chromatography (100% hexanes to 2.5% ethyl acetate in hexanes) to afford (6Z,15Z)-henicosa-6,15-dien-11-ol 4 as a pale yellow oil (5.6 g, 35%). Rf 0.4 (10% EtOAc-Hexanes).