Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:28]1[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=1)[C:9]1[CH:10]=[C:11]([C:16]2[S:20][C:19]([CH2:21][C@@H:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[N:18][CH:17]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[Li+].[CH3:41][Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:1]([O:5][C:6]([N:8]([C:28]1[N:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[CH:30][N:29]=1)[C:9]1[CH:10]=[C:11]([C:16]2[S:20][C:19]([CH2:21][C:22]([CH3:41])([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[N:18][CH:17]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)[C@H](C)Cc1ncc(-c2cc(C)cc(N(C(=O)OC(C)(C)C)c3nccc(C(F)(F)F)n3)c2)s1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Cc1ncc(-c2cc(C)cc(N(C(=O)OC(C)(C)C)c3nccc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
The product from Step 1 (700 mg, 1.305 mmol) and methyl iodide (926 mg, 6.52 mmol) were taken up in THF (18 mL) at room temperature, and LHMDS (1.0 M in THF, 6.52 mL, 6.52 mmol) was added dropwise. After stirring for 1 h at room temperature, the reaction was quenched with saturated NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. Flash chromatography (0-50% ethyl acetate in hexanes) afforded methyl 3-[5-(3-{(tert-butoxycarbonyl)[4-(trifluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1,3-thiazol-2-yl]-2,2-dimethylpropanoate (324 mg, 45%) as a yellow gum. MS ESI: [M+H]+ m/z 551.1.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Br[C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=1>>[CH3:22][C:21]1[C:16]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cccnc1Br
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1cccnc1C#Cc1c(-c2ccccc2)noc1C
Yield: 66 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-3-methylpyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 91 mg, 66%) which was obtained as a light yellow solid. MS: m/e=275.2 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOCC.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH:9]=[O:10])[CH2:3][CH2:2]1
Reactant: OCCCC1CCOCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCCC1CCOCC1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
To a solution of 3-(tetrahydro-pyran-4-yl)-propan-1-ol (11.8 g, 0.0825 mol) in CH2Cl2 (200 mL) was added Dess-Martin periodinane (70.27 g, 0.165 mol). The mixture was stirred at rt. When the reaction was complete, the solution was poured into Et2O (300 mL) and anhydrous K2CO3 (19.84 g, 0.165 mol) was added. The mixture was filtered. The filtrate was dried over Na2SO4, and concentrated under vacuum to give the crude product, which was purified by column chromatography to give 3-(tetrahydro-pyran-4-yl)-propionaldehyde (8.59 g, 83%). 1H NMR (CD3OD) δ 1.1-1.3 (m, 4H), 1.4-1.6 (m, 5H), 2.4-2.5 (t, 2H), 3.2-3.3 (m, 2H), 3.8-3.97 (m, 2H), 9.7-9.8 (s, 1H).
Reaction SMILES: OCC1C(N2CCN3C4CCCCC=4C=C3C2=O)=NC=CC=1C1C=C(NC2C=C3CN(C)CCN3N=2)C(=O)N(C)C=1.C([O:45][CH2:46][C:47]1[C:48]([N:80]2[CH2:92][CH2:91][N:83]3[C:84]4[CH2:85][CH2:86][CH2:87][CH2:88][C:89]=4[CH:90]=[C:82]3[C:81]2=[O:93])=[N:49][CH:50]=[CH:51][C:52]=1[C:53]1[CH:58]=[C:57]([NH:59][C:60]2[CH:65]=[CH:64][C:63]([N:66]3[CH2:71][C@@H:70]([CH3:72])[N:69]([CH:73]4[CH2:76][O:75][CH2:74]4)[CH2:68][C@@H:67]3[CH3:77])=[CH:62][N:61]=2)[C:56](=[O:78])[N:55]([CH3:79])[CH:54]=1)(=O)C.[OH-].[Li+]>>[CH3:77][C@H:67]1[CH2:68][N:69]([CH:73]2[CH2:76][O:75][CH2:74]2)[C@H:70]([CH3:72])[CH2:71][N:66]1[C:63]1[CH:64]=[CH:65][C:60]([NH:59][C:57]2[C:56](=[O:78])[N:55]([CH3:79])[CH:54]=[C:53]([C:52]3[CH:51]=[CH:50][N:49]=[C:48]([N:80]4[CH2:92][CH2:91][N:83]5[C:84]6[CH2:85][CH2:86][CH2:87][CH2:88][C:89]=6[CH:90]=[C:82]5[C:81]4=[O:93])[C:47]=3[CH2:46][OH:45])[CH:58]=2)=[N:61][CH:62]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4C[C@@H](C)N(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)cc2C1
Agent: [Li+]
Agent: [OH-]
Product: C[C@@H]1CN(c2ccc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Yield: 18.9 %

Procedure:
Following the procedures as described for compound 113, hydrolysis of 122f (464 mg, 0.66 mmol) with lithium hydroxide afforded 122 as a white solid (83 mg, 20%). LCMS: [M+H]+ 665. 1H NMR (500 MHz, CDCl3) δ 8.69 (d, J=2.5, 1H), 8.51 (d, J=5.0, 1H), 8.03 (d, J=2.5, 1H), 7.88 (s, 1H), 7.86 (d, J=2.5, 1H), 7.38 (d, J=5.0, 2H), 6.90 (s, 1H), 6.82 (d, J=9.0, 1H), 5.07 (s, 1H), 4.77-4.72 (m, 2H), 4.68-4.61 (m, 3H), 4.52 (s, 1H), 4.33 (s, 1H), 4.17-4.11 (m, 2H), 3.88 (s, 1H), 3.76 (s, 1H), 3.73 (s, 3H), 3.19 (s, 1H), 2.93-2.90 (m, 1H), 2.73 (s, 2H), 2.63-2.57 (m, 4H), 2.48 (s, 1H), 1.99-1.90 (m, 3H), 1.80 (s, 2H), 0.91 (t, J=5.5, 6H)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([N:7]=[C:8]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:10]2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:5]1.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46](O)=[O:47])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[C:11]3[C:6](=[N:5][N:4]([CH2:3][CH2:2][NH:1][C:46]([CH:43]4[CH2:44][CH2:45][N:40]([C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[CH2:41][CH2:42]4)=[O:47])[CH:12]=3)[N:7]=[C:8]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCCn2cc3c(-c4ccc(F)cc4)c(-c4ccncc4)c(-c4ccc(F)cc4)nc3n2)CC1

Procedure:
Following a similar procedure to that described in example 48, but starting from 2-(2-aminoethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (obtained in example 90) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid, the desired compound was obtained.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[C:7]2[C:16]([C:17](=[O:21])[C:18]([NH2:20])=[O:19])=[C:15]([CH2:22][CH3:23])[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:8]=2[N:9]=[C:10]([S:12][CH3:13])[N:11]=1.[OH-].[Na+]>C(O)C>[CH3:13][S:12][C:10]1[N:11]=[C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])[C:7]2[C:16]([C:17](=[O:21])[C:18]([NH2:20])=[O:19])=[C:15]([CH2:22][CH3:23])[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:8]=2[N:9]=1
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)nc(SC)nc2n1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)nc(SC)nc2n1Cc1ccccc1
Temperature: 65 °C
Yield: 80.9 %

Procedure:
A suspension of 99.5 mg (0.225 mmol) of [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester in 8.0 mL of ethanol was treated with 0.175 mL of 2 M sodium hydroxide and the mixture heated to 65° C. for 1 hour. The reaction mixture was cooled to ambient temperature and concentrated under vacuum to a white solid. The solid was dissolved in 12 mL of water and the product precipitated upon the addition of 0.40 mL of 1 M HCl. The solids were collected by filtration, washed with 10 mL of water, then dried in vacuo (40° C., 10 torr) to provide 78 mg (81%) of [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid as a white solid. nmr (500 MHz, dmso-d6) δ1.00 (t, J=7.4 Hz, 3H), 2.49 (s, 3H), 2.91 (q, J=7.4 Hz, 2H), 4.89 (s, 2H), 5.52 (s, 2H), 7.15 (d, J=7.2 Hz, 2H), 7.32 (m, 3H), 7.55 (s, 1H), 7.97 (s, 1H), 13.02 (bs, 1H)
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[O:9][CH2:8][N:7]([C:10]([CH3:15])([CH3:14])[C:11](O)=[O:12])[C:6](=[O:16])[C:5]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[F:23][C:24]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:25]=1[NH2:26].O>CN(C)C=O.C(OCC)(=O)C>[F:23][C:24]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:25]=1[NH:26][C:11](=[O:12])[C:10]([N:7]1[C:6](=[O:16])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([CH2:3][S:2][CH3:1])[O:9][CH2:8]1)([CH3:14])[CH3:15]
Reactant: CSCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O)CO1
Reactant: Nc1cc(F)ccc1F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CSCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2cc(F)ccc2F)CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 7.7 %

Procedure:
A solution of dicyclohexylcarbodiinide (10.04 g) in N,N-dimethyeformaeide was added to a stirred solution of 2-(2,3-dihydro-6-methylthiomethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoic acid (13.00 g) in N,N-dimethylformamide at 20° C. 2,5-Difluoroaniline (7.84 g) was added to the solution at 20° C. and the solution was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with ethyl acetate then added to water and the fine suspension removed by filtration. The organic layer was washed in turn with 0.5M hydrochloric acid, brine, 1.0M sodium carbonate and brine and then dried (magnesium sulphate). The organic solution was evaporated under reduced pressure and the residue was purified by chromatography on silica gel, eluting with dichioromethane to give N-(2,5-difluorophenyl)-2-(2,3-dihydro-6-methylthiomethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (Compound 3, 1.35 g) as a yellow solid, NMR (CDCl3) 1.68(s,6H), 2.10(s,3H), 3.22(s,2H), 5.30(s,2H), 6.64-6.76(m,1H), 6.95-7.05(m,1H), 7.25-7.38(m,5H), 8.11-8.21(m,2H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]([CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7][C:6]1=[O:21])=[O:4].C[O-].[Na+].I[CH2:26][CH3:27]>CO>[CH3:1][O:2][C:3]([C:5]1([CH2:26][CH3:27])[CH2:10][CH:9]([CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7][C:6]1=[O:21])=[O:4]
Reactant: CCI
Reactant: COC(=O)C1CC(CCOCc2ccccc2)CCC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC1(C(=O)OC)CC(CCOCc2ccccc2)CCC1=O
Reaction time: 48 h

Procedure:
A mixture of 5-(2-benzyloxy-ethyl)-2-oxo-cyclohexanecarboxylic acid methyl ester in anhydrous MeOH (10 mL) was reacted with NaOMe solution (16.6 mL, 8.28 mmol) at rt for 15 min. Iodoethane (2.76 mL, 34.5 mmol) was added via syringe and the mixture was stored at rt for 48 h. Another portion of NaOMe (8.3 mmol) and EtI (35 mmol) was added and the mixture was allowed to react until the starting material was not present (by TLC). The solution was quenched with an aqueous work-up and the resultant residue was purified by chromatography to yield 5-(2-benzyloxy-ethyl)-1-ethyl-2-oxo-cyclohexanecarboxylic acid methyl ester (Intermediate K2, 1.87 g (86%). The keto-ester (Intermediate K2) was heated at 90° C. in 10% KOH (100 mL) for 10 h, then 6 h at rt. The mixture was cooled to 0° C. and acidified with HCl. The solution was warmed to 40° C. for 15 min. and then stored at rt for 2 h. The mixture was neutralized to pH 7 with NaOH and the organic material was recovered by extraction with chloroform. The resulting 4-(2-benzyloxy-ethyl)-2-ethyl-cyclohexanone (Intermediate K3) was isolated by standard work-up and used without further purification (88%). Intermediate K3 (1.36 g, 5.24 mmol) was dissolved in THF (75 mL) and treated with MeMgBr (2.62 mL, 7.9 mmol) at 0° C. and reacted at rt for 1 h. The organic material was isolated from an aqueous, acidic work-up and purified by chromatography to give 4-(2-benzyloxy-ethyl)-2-ethyl-1-methyl-cyclohexanol 1.36 g (94%). 4-(2-benzyloxy-ethyl)-2-ethyl-1-methyl-cyclohexanol (1.39 g, 5.04 mmol) and TsOH—H2O (0.48 g, 2.52 mmol) were heated to reflux in benzene (˜100 mL) for 18 h in the presence of MgSO4 (˜250 mg). After an aqueous work-up and chromatographic purification, the product [2-(3-ethyl-4-methyl-cyclohex-3-enyl)-ethoxymethyl]-benzene (Intermediate K4) was isolated as a pale yellow oil 0.912 g (71%).
Reaction SMILES: O[C:2]1([CH3:16])[C:10]2[C:5](=[C:6]([N+:11]([O-])=O)[CH:7]=[CH:8][CH:9]=2)[C:4](=[O:14])[N:3]1[CH3:15].[H][H]>[Pd].CC(O)=O>[NH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[C:4](=[O:14])[N:3]([CH3:15])[CH:2]2[CH3:16]
Reactant: CN1C(=O)c2c([N+](=O)[O-])cccc2C1(C)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1c2cccc(N)c2C(=O)N1C
Yield: 50.4 %

Procedure:
A mixture of 3-hydroxy-2,3-dimethyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (Compound 1578, 500 mg), AcOH (12 mL), and 5% Pd/C (60 mg) was hydrogenated for 14 h under 1 atm hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated, residue was purified by column chromatography to afford 200 mg of the title compound (yield: 50%). 1H NMR (CDCl3, 300 MHz): δ=1.43 (d, J=6.8 Hz, 3 H), 3.04 (s, 3 H), 4.33 (q, J=6.3 Hz, 1 H), 5.20 (s, br, 2 H), 6.55 (d, J=8.1 Hz, 1 H), 7.21-7.26 (m, 2 H).
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].[Cl-].[NH4+]>CN(C)C=O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=1
Reactant: CCOC(=O)Cl
Reactant: CC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)N(C(C)=O)c1ccc(OCc2nc3ccccc3s2)cc1
Reaction time: 0.08 h
Yield: 81 %

Procedure:
28 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 187 mg of N-[4-(benzothiazol-2-ylmethoxy)phenyl]acetamide (prepared as described in Example 1 above) in 4 ml of dimethylformamide cooled in an ice-water bath. The resulting mixture was stirred for 5 minutes at the same temperature, after which 0.066 ml of ethyl chloroformate were added, the temperature of the resulting mixture was elevated to room temperature and the mixture was stirred for 5 hours. At the end of this time, the reaction mixture was added to a saturated aqueous ammonium chloride solution and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed consecutively with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give a crude crystalline solid which was purified by column chromatography through silica gel using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 25.6 mg (yield 81%) of the title compound as a solid having a melting point of 155° to 160° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[N+]([O-])(O)=O.[N:18]#[C:19][NH2:20].C(OCC)C>C(O)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:19]([NH2:20])=[NH:18])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(N)cc1
Reactant: N#CN
Solvent: O=[N+]([O-])O
Solvent: CCOCC
Solvent: CCO
Product: Cc1nccn1-c1ccc(NC(=N)N)cc1
Reaction time: 2 h
Yield: 75.6 %

Procedure:
4-(2-Methylimidazol-1-yl)phenylamine (10 g, 57.73 mmol) was dissolved in ethanol (100 mL). Nitric acid (3.96 mL, 57.73 mmol) was carefully added followed by cyanamide (2.427 g, 57.73 mmol). The reaction mixture was heated to reflux overnight. Extra cyanamide (1.942 g, 46.19 mmol) and nitric acid (2.98 mL, 46.19 mmol) were added and then the reaction mixture was refluxed for 16 hours. The reaction mixture was allowed to reach room temperature and ethyl ether (100 mL) was added. The mixture was refrigerated for 2 h and the solid obtained was filtered off and washed with ethyl ether yielding 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (9.40 g, 76%).
Reaction SMILES: NC1N=C(N)C2C(=NC=C(CN(C3C=CC=CC=3)C3C=CC=CC=3)N=2)N=1.[CH:27]1[C:37]2[CH:36]=[CH:35][C:34]3[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=3[NH:32][C:31]=2[CH:30]=[CH:29][CH:28]=1.[H-].[Na+].Br.[NH2:45][C:46]1[N:47]=[C:48]([NH2:58])[C:49]2[N:55]=[C:54]([CH2:56]Br)[CH:53]=[CH:52][C:50]=2[N:51]=1>>[NH2:45][C:46]1[N:47]=[C:48]([NH2:58])[C:49]2[N:55]=[C:54]([CH2:56][C:38]3[C:34]4[CH:35]=[CH:36][C:37]5[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=5[NH:32][C:33]=4[CH:41]=[CH:40][CH:39]=3)[CH:53]=[CH:52][C:50]=2[N:51]=1
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: Nc1nc(N)c2nc(CBr)ccc2n1
Agent: Br
Agent: Nc1nc(N)c2nc(CN(c3ccccc3)c3ccccc3)cnc2n1
Agent: [H-]
Product: Nc1nc(N)c2nc(Cc3cccc4c3C=Cc3ccccc3N4)ccc2n1

Procedure:
9-[(2,4-Diaminopyrido[3,2-d]pyrimidin-6-yl)methyl]dibenz[b,f]azepine (Formula I: Ar=2,4-diaminopyrido[3,2-d]pyrimidin-6-yl; W=CH2; X=N; Z=CH═CH; m=n=0) is prepared similarly to N-[(2,4-diaminopteridin-6-yl)methyl]-N,N-diphenylamine as disclosed above by using dibenz[b,f]azepine (154 mg, 0.8 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-6-bromomethylpyrido[3,2-d]pyrimidine hydrobromide (100 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[NH2:12][C:13]1[C:14]([C:30](O)=[O:31])=[N:15][C:16]([N:19]2[CH2:24][CH2:23][N:22]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])[CH2:21][CH2:20]2)=[CH:17][N:18]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C.CCOC(C)=O.O>[NH2:12][C:13]1[C:14]([C:30]([NH:2][CH2:3][C:4](=[O:5])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:31])=[N:15][C:16]([N:19]2[CH2:20][CH2:21][N:22]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])[CH2:23][CH2:24]2)=[CH:17][N:18]=1
Reactant: NCC(=O)c1ccccc1
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)O)n2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)NCC(=O)c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
2-amino-1-phenyl-ethanone hydrochloride (136.1 mg, 0.7928 mmol) was added to a solution of 3-amino-6-(4-ethylsulfonylpiperazin-1-yl)pyrazine-2-carboxylic acid (250 mg, 0.7928 mmol) and DIPEA (512.3 mg, 690.4 μL, 3.964 mmol) in CH2Cl2 (3.332 mL) and DMF (833.2 μL) and the resulting solution stirred at room temperature for 1 hour. The reaction was diluted with EtOAc/water and the layers separated. The aqueous layer was extracted further with EtOAc (2×) and the combined organics washed with water (3×), dried (MgSO4) and concentrated in vacuo. The mixture was purified on silica gel by flash column chromatography (100% EtOAc) to afford the product (229 mg, 67% Yield). 1H NMR (CDCl3) d 1.28 (3H, t), 3.06 (2H, q), 3.51-3.53 (4H, m), 3.56-3.59 (4H, m), 4.95 (2H, d), 6.2 (2H, br s), 7.56 (2H, m), 7.68 (1H, m), 8.05 (3H, m), 8.65 (1H, m) ppm; MS (ES+) 433.0
Reaction SMILES: [BH4-].[Na+].[C:3]1([C:9]2([CH:14]=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[C:3]1([C:9]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=CC1(c2ccccc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
NaBH4 (3.2 g, 86.2 mmol) was added portion wise to a cooled (ice bath) solution of 1-phenyl-cyclopentanecarbaldehyde (7.5 g, 43.1 mmol) in methanol (100 ml) and then stirred for 16 h at RT. After completion of the reaction, it was quenched with saturated ammonium chloride solution and the methanol under reduced pressure. The mixture was diluted with water, extracted with EtOAc, washed with water, brine, dried (Na2SO4) and evaporated to dryness under reduced pressure. Chromatography (15% EtOAc in hexanes) provided (1-phenyl-cyclopentyl)-methanol as a white solid (6 g, 79.8%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20]OCC)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11]>>[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20][NH:9][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1ccc(N)nc1C
Product: CCOC(=O)C(=CNc1ccc(C)c(C)n1)C(=O)OCC
Yield: 88.7 %

Procedure:
Experimental conditions analogous to those described for Step 1 of Example 60 were used with 5 g (40.93 mmol) of 5,6-Dimethyl-pyridin-2-ylamine and 8.2 mL (40.93 mmol) of 2-ethoxymethylene malonic acid diethyl ester to afford 10.61 g of 2-[(5,6-Dimethyl-pyridin-2-ylamino)-methylene]-malonic acid diethyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:16][CH2:17][OH:18]>CC#N.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:16][CH2:17][OH:18])[CH:8]=1)([O-:3])=[O:2]
Reactant: OCCBr
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: O=[N+]([O-])c1cnn(CCO)c1
Temperature: 80 °C

Procedure:
To a solution of 4-nitro-1H-pyrazole (6.09 g, 52.20 mmol) in MeCN (80 mL), Cs2CO3 (18.71 g, 57.42 mmol) and 2-bromoethanol (4.59 mL, 62.64 mmol) was added. The resulting mixture was refluxed (80° C.) for 3.5 h, then the reaction mixture was allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM and the filtrate was concentrated in vacuo. The residue was partitionned between water and EtOAc, the org. layer was separated and the aq. layer was extracted with EtOAc (1×). The combined org. layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification was performed by FC (EtOAc/hept 7:3 to EtOAc/MeOH 9:1) to obtain 2-(4-nitro-1H-pyrazol-1-yl)ethanol as a white solid. LC-MS conditions A: tR=0.44 min, [M+H]+=no ionization.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18]([Cl:26])[CH:17]=1)[CH2:5][CH:6]1[CH2:15][CH2:14][C:9]2(OCC[O:10]2)[CH2:8][CH2:7]1.Cl>CC(C)=O.O>[CH3:1][O:2][C:3](=[O:27])[CH:4]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18]([Cl:26])[CH:17]=1)[CH2:5][CH:6]1[CH2:15][CH2:14][C:9](=[O:10])[CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCC2(CC1)OCCO2)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C(CC1CCC(=O)CC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.6 %

Procedure:
A solution of 2-(3-chloro-4-methylsulfonyl-phenyl)-3-(1,4-dioxa-spiro[4.5]dec-8-yl)-propionic acid methyl ester (667 mg, 1.60 mmol) in acetone (15 mL) was treated with a 10% aqueous hydrochloric acid solution (1.8 mL). The reaction mixture was stirred at 25° C. for 24 h. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford pure 2-(3-chloro-4-methylsulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid methyl ester (600 mg, 100%) as a colorless gum which was used without further purification: EI-HRMS m/e calcd for C17H21ClO5S (M+Na)+ 395.0690, found 395.0692.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[C:4]([CH2:11][O:12][Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:9])[OH:10])=[C:4]([CH2:11][OH:12])[CH:3]=1
Reactant: CC(C)[Si](OCc1cc(F)ccc1B(O)O)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OCc1cc(F)ccc1B(O)O
Temperature: 23 °C
Reaction time: 16 h
Yield: 50.4 %

Procedure:
To a solution of 2.60 g (7.97 mmol) (4-fluoro-2-{[(triisopropylsilyl)oxy]methyl}phenyl)boronic acid which was prepared according to intermediate example 299b in 10 mL dichloromethane were added 6.14 mL trifluoroacetic acid and the mixture was stirred for 16 hours at 23° C. The solvent was removed and the residue crystallized from n-hexane to give 682 mg (50%) of the title compound.