Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(CN2C(=O)C3NC(C4C=CC(COCCOCCOCCOCCOCCOCCOCCOCCOCCOC)=CC=4)=NC=3N(CC3CCCCC3)C2=O)CCCCC1.[CH:62]1([CH2:68][N:69]2[C:77](=[O:78])[C:76]3[N:75]=[C:74]([C:79]4[CH:89]=[CH:88][C:82](/[CH:83]=[CH:84]/[C:85]([OH:87])=[O:86])=[CH:81][CH:80]=4)[NH:73][C:72]=3[N:71]([CH2:90][CH:91]3[CH2:96][CH2:95][CH2:94][CH2:93][CH2:92]3)[C:70]2=[O:97])[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1.C(=O)([O-])[O-].[K+].[K+].CO>C(#N)C>[CH3:1][O:86][C:85](=[O:87])/[CH:84]=[CH:83]/[C:82]1[CH:81]=[CH:80][C:79]([C:74]2[NH:73][C:72]3[N:71]([CH2:90][CH:91]4[CH2:92][CH2:93][CH2:94][CH2:95][CH2:96]4)[C:70](=[O:97])[N:69]([CH2:68][CH:62]4[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]4)[C:77](=[O:78])[C:76]=3[N:75]=2)=[CH:89][CH:88]=1
Reactant: O=C(O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCc1ccc(-c2nc3c([nH]2)c(=O)n(CC2CCCCC2)c(=O)n3CC2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: COC(=O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
In the manner of Example 36, part (b), (E)-4-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6dioxo-9H-purin-8-yl]cinnamic acid was converted to (E)-1,3-bis(cyclohexylmethyl)-8-(3-(2-(1H-imidazol-1yxlcarbonyl)vinyl)phenyl)-9H-purin-2,6(1H,3H)-dione as a yellow powder. Such a sample (2.50 g, 4.62 mmol) was stirred at reflux in acetonitrile (75 ml) with potassium carbonate (1.28 g, 9.25 mmol) and methanol, (10 ml) for 24 hours. The mixture was cooled to room temperature and filtered and the filtrate-wash was adjusted to pH˜3 by addition of 6N hydrochloric acid. The resulting precipitate was filtered and washed with methanol and dried to give (E)-4-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]cinnamic acid methyl ester (1.70 g, 74%) as a white solid. 1H-NMR (300 MHz, DMSO-d6) δ: 8.16 (d, J=8.2 Hz, 2H, phenylCH), 7.83 (d, J=8.4 Hz, 2H, 2 phenylCH), 7.63 (d, J=15.9 Hz,1H, CH═), 6.70 (d, J=15.9 Hz, 1H, CH—), 3.95 (d, J=7.0 Hz, 2H, CH2N), 3.75 (d, J=6.8 Hz, 2H, CH2N), 3.70 (s, 3H, CH3), 2.0-1.50 and 1.20-0.80 (m, 22H, 2C6H11).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH3:22][C:23]1[CH:24]=[CH:25][C:26](O)=[N:27][CH:28]=1>COCCOC>[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[N:27][CH:28]=1
Reactant: Cc1ccc(O)nc1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Solvent: COCCOC
Product: Cc1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)nc1

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 5-methyl-2-pyridinol, using dry DME as reaction solvent: MS (APCI) m/z 404 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1.[CH3:15][C:16](=O)[CH3:17].C(O)(=O)C.[BH3-]C#N.[Na+].[OH-].[Na+]>C1COCC1.O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH:16]([CH3:17])[CH3:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: CC(C)=O
Reactant: Brc1ccc(CN2CCNCC2)nc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CCN(Cc2ccc(Br)cn2)CC1
Temperature: 45 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
1-(5-Bromopyridin-2-ylmethyl)piperazine (10 g, 39.04 mmol) was dissolved in THF (65 ml), water (0.6 mL), propanone (4.5 g, 78.08 mmol) and acetic acid (7.5 g, 125 mmol) was mixed. Then 1M NaCNBH3 in THF (3.68 g, 58 mmol) (58 mL) was added. The reaction mixture was then heated and 21eq. water was added in order to solve the rest of material in the mixture. The reaction mixture was stirred overnight at 45° C. The reaction mixture was added DCM (150 mL) and water (100 mL). pH was adjusted to pH=10 with 4N NaOH. The water phase was extracted with DCM (2×25 mL). The combined DCM phase was washed with water (2×25 mL), brine (2×25 mL) finally dried MgSO4, filtered and evaporated in vacuo giving 7.56 g (65%) of a thick oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:17]([C:22]([O:24][CH3:25])=[O:23])[C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:17]([C:22]([O:24][CH3:25])=[O:23])[C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)C(Cl)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1ccc(OCc2ccccc2)cc1)C(=O)OC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
4-Benzyloxyphenol (1.0 g, 4.99 mmol), dimethyl 2-chloromalonate (998.2 mg, 5.99 mmol), cesium carbonate (3.25 g, 9.99 mmol) and potassium iodide (41.45 mg, 0.25 mmol) were stirred in 50 ml of DMF at 60° C. for 1.5 h. Addition of 200 μl of dimethyl 2-chloromalonate was followed by stirring at 60° C. for 1 h and at 80° C. for 1 h and concentration, and the residue was taken up in ethyl acetate and water. The organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 477 mg (29%), M+H+: 331.18.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[O:13][C:9]1([CH2:12][CH2:11][CH2:10]1)[CH2:8][C:7]2=O.[OH2:18]>O1CCCC1.CO>[Cl:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[O:13][C:9]1([CH2:12][CH2:11][CH2:10]1)[CH2:8]/[C:7]/2=[CH:8]\[C:9]([O:13][CH2:14][CH3:6])=[O:18]
Reactant: O
Reactant: O=C1CC2(CCC2)Oc2ccc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)/C=C1\CC2(CCC2)Oc2ccc(Cl)cc21

Procedure:
Triethyl phosphonoacetate (4.03 g, 17.897 mmol) was added over 15 min to a stirred and cooled mixture of sodium hydride (431 mg, 17.897 mmol) in anhydrous tetrahydrofuran (25 ml). The reaction mixture was stirred for 30 min and then added 6-Chlorospiro[chromene-2,1′-cyclobutan]-4(3H)-one (2 g, 8.948 mmol) in anhydrous tetrahydrofuran. The reaction mixture was stirred at the same temperature under nitrogen for 24 h. The reaction mixture was diluted with methanol and water and the product was extracted into ethyl acetate (3×100 ml). The organic layer was washed with water (100 ml), brine, dried (Na2SO4) and concentrated to give 3.54 g of the crude product which was used as such for the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17]C(C(F)(F)F)=CC=3)[C:8]2=[O:23])[S:4][C:3]=1[C:24]([OH:26])=O.C1(CN2CCN(C3SC(C(O)=O)=C(C)C=3)C2=O)CC1.[NH2:46][CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1>>[CH:13]1([CH2:12][N:9]2[CH2:10][CH2:11][N:7]([C:5]3[S:4][C:3]([C:24]([NH:46][CH2:47][C:48]4[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=4)=[O:26])=[C:2]([CH3:1])[CH:6]=3)[C:8]2=[O:23])[CH2:18][CH2:17]1
Reactant: Cc1cc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1cc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(CC3CC3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 59 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 59% yield: mp 157-159° C.; 1H NMR (300 MHz, CDCl3) δ 8.51 (s, 1H), 8.50 (d, J=4.1 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.28-7.21 (m, 1H), 6.14 (t, J=5.6 Hz, 1H), 6.06 (s, 1H), 4.57 (d, J=5.6 Hz, 2H), 3.85-3.77 (m, 2H), 3.70-3.63 (m, 2H), 3.14 (d, J=7.1 Hz, 2H), 2.48 (s, 3H), 0.99-0.84 (m, 1H), 0.58-0.50 (m, 2H), 0.25-0.19 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 163.6, 155.8, 149.2, 148.8, 142.8, 141.8, 135.5, 134.2, 123.5, 118.6, 112.1, 48.8, 42.9, 42.1, 41.2, 16.1, 9.0, 3.4; MS (ES+) m/z 371.3 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:18])[CH2:12][CH:13]([OH:17])[C:14]([OH:16])=[O:15])=[C:6]([O:19][CH3:20])[CH:5]=1)[CH:2]=[CH2:3].[C:21]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C>[CH3:21][O:15][C:14](=[O:16])[CH:13]([OH:17])[CH2:12][C:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH:2]=[CH2:3])=[CH:5][C:6]=1[O:19][CH3:20])=[O:18]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1ccc(OC(=O)CC(O)C(=O)O)c(OC)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCc1ccc(OC(=O)CC(O)C(=O)OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of 2-Hydroxy-succinic acid 4-(4-allyl-2-methoxy-phenyl)ester (0.1 g, 0.35 mmol) in dry DMF (2.0 mL) was added dry K2CO3 followed by methyl iodide (0.024 mL) at 0° C. and the reaction mixture was stirred at room temperature (25° C.) over a period of 60 min. The resulting mixture was diluted with ethyl acetate (50.0 mL) and filtered. The filtrate was washed with water (4×200 mL) and dried over sodium sulphate. The crude product obtained upon evaporation of volatiles was purified by column chromatography to obtain orange colour viscuss liquid (0.05 g, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.C([Li])CCC.[F:19][C:20]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:21]=1[CH2:22]Br>O1CCCC1>[CH3:1][O:2][C:3]1[C@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[C@@H:7]([CH2:22][C:21]2[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:20]=2[F:19])[N:8]=1
Reactant: Fc1cc(F)c(CBr)cc1F
Reactant: COC1=N[C@@H](C(C)C)C(OC)=NC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC1=N[C@H](Cc2cc(F)c(F)cc2F)C(OC)=N[C@H]1C(C)C
Reaction time: 0.33 h

Procedure:
To a solution of 3.42 g (18.5 mmol) of commercially available (2S)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine in 100 mL of tetrahydrofuran at −70° C. was added 12 mL (19 mmol) of a 1.6M solution of butyllithium in hexanes. After stirring at this temperature for 20 min, 5 g (22.3 mmol) of 2,4,5-trifluorobenzyl bromide in 20 mL of tetrahydrofuran was added and stirring was continued for 3 h before warming the reaction to ambient temperature. The reaction was quenched with water, concentrated in vacuo, and extracted with ethyl acetate. The combined organic phase was washed with brine, dried, and concentrated in vacuo. Purification by flash chromatography (silica gel, 0-5% ethyl acetate in hexanes) afforded the title compound.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](OCC)=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Mg+2].C(OCC)(=O)C>O1CCCC1>[Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][OH:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OC1CN(c2nc(CO)cs2)C1)(c1ccccc1)c1ccccc1
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
A solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (5.0 g, 10.7 mmol) (obtained as described in Reference Example 2(1)) in anhydrous tetrahydrofuran (100 ml) was added dropwise to a solution of lithium aluminum hydride (1.22 g, 32.1 mmol) in anhydrous tetrahydrofuran (250 ml) in an ice bath under an atmosphere of nitrogen and the mixture was stirred for 1.5 hours under the same conditions. After checking the completion of the reaction, magnesium sulfate decahydrate was gradually added to the reaction mixture in an ice bath. After termination of foaming, the resulting mixture was stirred at room temperature for 1 hour. Ethyl acetate was gradually added to the reaction mixture. The resulting mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (3:1→1:2) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-hydroxymethyl-1,3-thiazol-2-yl)azetidine (3.88 g, yield 86%) as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[OH-].[Na+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[C:18]([CH:20]=O)=O.Cl.C>CO.C(Cl)Cl.CO>[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[F:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[C:18]1[N:2]=[CH:3][C:4](=[O:5])[NH:6][CH:20]=1
Reactant: COc1ccc(F)c(C(=O)C=O)c1
Agent: Cl
Agent: NCC(N)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(F)c(-c2c[nH]c(=O)cn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An aqueous solution of glycinamide (0.027 mol, 3.03 g), which was prepared by neutralizing glycinamide hydrochloride with one equivalent of 10N NaOH, was slowly added to a stirring solution of 2-fluoro-5-methoxyphenyl glyoxal (0.027 mol, 5.42 g) in MeOH (35 mL) at 0° C. One equivalent of 10N NaOH (2.74 mL) was then added slowly to the resulting clear orange solution. After stirring overnight at room temperature the solution was acidified to pH~3 with 12N HCl and the methanol was evaporated under reduced pressure. The residue was partitioned between CH2Cl2 and water and the aqueous phase was extracted (5×) with CH2Cl2. The combined CH2Cl2 portions were dried (Na2SO4) and concentrated under reduced pressure to give a dark solid. The solid was dissolved in CH2Cl2 /MeOH, heated for five minutes with decolorizing charcoal and filtered through 2 inches of silica gel (5% MeOH/CH2Cl2 eluent). Evaporation of the solvents under reduced pressure afforded 5-(2-fluoro-5-methoxyphenyl)-pyrazin-2-one.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15]([CH3:17])[N:16]=1>CN(C=O)C>[CH2:1]([NH:8][C:9](=[O:10])[NH:11][C:12]1[S:13][C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15]([CH3:17])[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCOC(=O)c1sc(N)nc1C
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(NC(=O)NCc2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.05 ml of benzyl isocyanate are added to a solution of 5.0 g of ethyl 2-amino-4-methyl-thiazole-5-carboxylate in 50 ml of DMF. The reaction mixture is stirred at RT overnight, evaporated on a rotary evaporator and the residue is suspended in methylene chloride:methanol 1:1. The insoluble material is filtered off and dried. There are obtained 4.6 g of colorless ethyl 2-(3-benzyl-ureido)-4-methyl-thiazole-5-carboxylate, MS: 320 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([CH3:30])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:29]=[C:28]([CH3:30])[S:27][C:17]=2[N:18]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Cc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: Cc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([C:5]1([CH3:32])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=[C:15]3[CH:14]=[C:13]([CH3:25])[C:12]=2[C@H:26]([OH:31])[C:27]([O:29][CH3:30])=[O:28])[CH2:7][CH2:6]1)[CH2:2][CH:3]=[CH2:4].C(Cl)Cl.C([O-])(O)=O.[Na+]>C(OC(C)=O)(C)(C)C>[CH2:1]([C:5]1([CH3:32])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=[C:15]3[CH:14]=[C:13]([CH3:25])[C:12]=2[C@H:26]([O:31][C:5]([CH3:10])([CH3:6])[CH3:1])[C:27]([O:29][CH3:30])=[O:28])[CH2:7][CH2:6]1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCC1(C)CCN(c2c([C@H](O)C(=O)OC)c(C)cc3nc(C(=O)OCC)cn23)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)OC(C)(C)C
Product: C=CCCC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(C(=O)OCC)cn23)CC1
Reaction time: 1 h
Yield: 56.8 %

Procedure:
To a solution of (S)-ethyl 5-(4-(but-3-en-1-yl)-4-methylpiperidin-1-yl)-6-(1-hydroxy-2-methoxy-2-oxoethyl)-7-methylimidazo[1,2-a]pyridine-2-carboxylate (0.50 g, 1.13 mmolo, 1 equiv) in t-BuOAc (18 mL) was added 70% HClO4 (0.48 mL, 5.64 mmol, 5 equiv). A white precipitate formed. DCM (5 mL) was added to aid solubility. After 1 h, the reaction was carefully added to saturated aqueous NaHCO3 and extracted with DCM (×3). The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc/hex) to provide the product (0.16 g, 28%) as a white foam. In addition, starting material (0.38 g) was recovered. 1H NMR (400 MHz, CDCl3) [note: major rotamer transcribed, 3:2 mixture of rotamers] δ8.23 (s, 1H), 7.33 (s, 1H), 6.06 (s, 1H), 5.97-5.81 (m, 1H), 5.17-4.97 (m, 2H), 4.53-4.42 (m, 2H), 3.71 (s, 3H), 3.69-3.64 (m, 1H), 3.57-3.50 (m, 1H), 3.17-3.07 (m, 1H), 2.88 (d, J=12.0 Hz, 1H), 2.46-2.44 (m, 3H), 2.18-2.08 (m, 2H), 1.71-1.58 (m, 6H), 1.48-1.43 (m, 3H), 1.25 (s, 9H), 1.16 (s, 3H); LCMS (ESI, M+1): 500.35.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[N:6][CH:7]=1.CO.[C:19]1([CH3:28])[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Si:10]([C:9]#[C:8][C:5]1[CH:4]=[CH:3][C:2]([C:22]2[CH:23]=[CH:24][C:19]([CH3:28])=[CH:20][CH:21]=2)=[CH:7][N:6]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)[Si](C)(C)C#Cc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc(C#C[Si](C)(C)C(C)(C)C)nc2)cc1

Procedure:
4.6 g (15.00 mmol) 5-bromo-2-((tert-butyldimethylsilyl)ethynyl)pyridine are added to 12 mL methanol and 50 mL 1,4-dioxane. Then the mixture is charged with 2.40 g (17.3 mmol) p-tolyl-boronic acid, 0.1 g (0.15 mmol) bis(triphenyphosphine)-dichloropalladium and 16.5 mL (33.0 mmol) of a 2N aq. Na2CO3 solution. The reaction mixture is stirred at reflux for 2 h. Then the solvent is removed in vacuo to some extent and the residue is diluted with EtOAc and water. The organic layer is sequently washed with 50 mL half sat. Na2CO3 solution (1×) and 50 mL water (1×). The organic layer is dried with MgSO4 and the solvent is removed in vacuo. The residue is treated with DIPE and PE to receive a precipitate which is filtered and dried to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][C:6]=2[CH:13]=1.[CH3:14][NH:15][CH2:16][CH:17]=[O:18]>C1C=CC=CC=1>[CH3:14][N:15]([CH2:16][CH:17]=[O:18])[C:11]([NH:10][C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:13][C:6]=2[N:7]=1)=[O:12]
Reactant: CNCC=O
Reactant: Cc1ccc2sc(N=C=O)nc2c1
Solvent: c1ccccc1
Product: Cc1ccc2sc(NC(=O)N(C)CC=O)nc2c1
Reaction time: 1 h

Procedure:
5-Methylbenzothiazol-2-yl isocyanate dimer (0.1 mole), the dimethyl acetal of 2-methylaminoacetaldehyde (0.2 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at ambient temperatures for a period of about one hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-methylbenzothiazol-2-yl)ureido]acetaldehyde as the residue.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]3[N:16]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:17]=[CH:18][C:13]3=[C:12]([N:24]3[CH:29]4[CH2:30][CH2:31][CH2:32][CH:25]3[CH2:26][O:27][CH2:28]4)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.C12OC(CC1)CN(C1N=C(C3C=CC(N)=CC=3)N=C3N(CC(F)(F)F)N=CC=13)C2.Cl.C12OC(CC1)CNC2>>[CH:25]12[N:24]([C:12]3[N:11]=[C:10]([C:7]4[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=4)[N:15]=[C:14]4[N:16]([CH2:19][C:20]([F:21])([F:23])[F:22])[N:17]=[CH:18][C:13]=34)[CH:29]([CH2:30][CH2:31][CH2:32]1)[CH2:28][O:27][CH2:26]2
Reactant: O=[N+]([O-])c1ccc(-c2nc(N3C4CCCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Agent: C1CC2CNCC1O2
Agent: Cl
Agent: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(CC(F)(F)F)c3n2)cc1
Product: Nc1ccc(-c2nc(N3C4CCCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1

Procedure:
4-(4-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline was prepared from 9-(6-(4-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-oxa-9-azabicyclo[3.3.1]nonane according to the method used for 4-[4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenylamine, except in step 5,3-oxa-9-azabicyclo[3.3.1]nonane hydrochloride replaced 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH:10]([F:12])[F:11])=[CH:4][N:3]=1.C[C:14]([N:16](C)C)=O>O.[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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]>[F:11][CH:10]([F:12])[O:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([C:14]#[N:16])=[N:3][CH:4]=1
Reactant: CC(=O)N(C)C
Reactant: Cc1cc(OC(F)F)cnc1Cl
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: Cc1cc(OC(F)F)cnc1C#N
Temperature: 110 °C
Yield: 49.8 %

Procedure:
A mixture of 2-chloro-5-(difluoromethoxy)-3-methylpyridine (12.4 g, 64.1 mmol), zinc cyanide (4.07 mL, 64.1 mmol), 1,1′-bis(diphenylphosphino)ferrocene (2.5 g, 4.51 mmol) and tris(dibenzylideneacetone)dipalladium(0) (2.1 g, 2.93 mmol) in DMA (50 mL) was heated to 110° C. under N2 for 18 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase obtained was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 0-70% EtOAc/hex to give 5-(difluoromethoxy)-3-methylpicolinonitrile (5.88 g, 31.9 mmol, 49.8% yield). MS m/z: 185.0 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[C:24]([Cl:31])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:23])=[C:9]([CH:22]=1)[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:11]>CCO.CCOC(C)=O.[Pd]>[NH2:28][C:26]1[CH:25]=[C:24]([Cl:31])[C:3]([O:4][C:5]2[CH:6]=[CH:7][C:8]([OH:23])=[C:9]([CH:22]=2)[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:11])=[C:2]([Cl:1])[CH:27]=1
Reactant: CCCCCCCCCNC(=O)c1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCCCCNC(=O)c1cc(Oc2c(Cl)cc(N)cc2Cl)ccc1O
Reaction time: 1.5 h
Yield: 72.7 %

Procedure:
To a solution of 5-(2,6-dichloro-4-nitro-phenoxy)-2-hydroxy-N-nonyl-benzamide (168 mg, 0.36 mmol) in a mixture of EtOH (3 ml) and EtOAc (3 ml) was added catalyst (10% Pd/C, 100 mg). The resulting mixture was hydrogenated at 55 psi for 1.5 h at RT. The mixture was filtered through Celite® and concentrated to give the title compound of Step E (115 mg) as a tan solid. The title product of Step E was used without further purification in the next step. MS (APCl+) Calc.: 438.1. Found: 439.3 (M+1).