Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.[C:33]([N:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[C:41](O)=[O:42])(=[O:35])[CH3:34].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[C:33]([N:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[C:41]([N:25]1[CH2:24][CH2:23][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:8]3[CH:7]=[C:6]([NH:5][CH2:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)=[O:42])(=[O:35])[CH3:34]
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Reactant: CC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCC[C@H]1C(=O)N1CCC(c2ccc(Nc3cc(NCc4cccc(F)c4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Yield: 100.9 %

Procedure:
The mixture of compound 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (50 mg, 0.11 mmol), (S)-acetyl-pyrrolidine-2-carboxylic acid (35 mg, 0.22 mmol), DIEA (180 μL, 1.1 mmol) in 4 mL NMP was stirred at RT. To it was added BOP (210 mg, 0.55 mmol). The mixture was stirred for overnight, quenched with TFA, and subjected to reverse phase preparative HPLC to isolate the title compound (64 mg). MS found for C31H34F2N6O3 as (M+H)+ 577.5. UV: λ=259 nm. 1H NMR (a pair of rotomers): (CD3OD) δ 8.13 (with 8.15, 1H, s), 7.36 (with 7.32, 2H, d, J=8.8 Hz), 7.25 (1H, m), 7.16 (1H, m), 7.13-7.07 (3H, m), 5.83 (with 5.79, 1H, s), 4.95 (1H, m), 4.65 (1H, m), 4.56 (with 4.55, 2H, s), 4.20 (1H, m), 3.66 (2H, m), 3.30 (1H, m), 2.92 (1H, m), 2.79 (1H, m), 2.27 (1H, m), 2.12 (with 2.10, 3H, s), 2.07-1.85 (5H, m), 1.68 (2H, m) ppm.
Reaction SMILES: [CH:1]1[C:6]2[C:7](=O)[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:7]1[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Nc2ccccc2Sc2ccccc21
Product: ClC1=Nc2ccccc2Sc2ccccc21

Procedure:
A solution of dibenzo[b,f][1,4]thiazepin-11(10H)-one, prepared as described in the previous step, (14.6 g, 64 mmol) in phosphorus oxychloride (20 mL) was heated to reflux for 2 hours. The mixture was concentrated to provide the crude product which was used directly without further purification. ESI-MS (M+1): 246 calc. for C13H8ClNS 245.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[OH:22].Cl.Cl[CH2:25][C:26]1[N:30]([CH3:31])[N:29]=[CH:28][N:27]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([C:18]([F:19])([F:20])[F:21])=[N:13]3)=[CH:4][C:3]=1[O:22][CH2:25][C:26]1[N:30]([CH3:31])[N:29]=[CH:28][N:27]=1
Reactant: Cn1ncnc1CCl
Reactant: Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Agent: Cl
Product: Cn1ncnc1COc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Yield: 58.6 %

Procedure:
2-Fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenol (50.0 mg, 0.16 mmol) was alkylated with 5-chloromethyl-1-methyl-1H-[1,2,4]triazole hydrochloride (prepared as described in WO 0023449, 30.4 mg, 0.20 mmol) as described in Example 47, affording 5-[4-fluoro-3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)phenyl]-2-trifluoromethyl-[1,8]naphthyridine (37.8 mg, 58%). δH (360 MHz, CDCl3) 4.06 (3H, s), 5.39 (2H, s), 7.08-7.12 (1H, m), 7.28-7.36 (2H, m), 7.51 (1H, d, J 4.2), 7.82 (1H, d, J 8.8), 7.87 (1H, s), 8.43 (1H, d, J 8.4), 9.27 (1H, d, J 4.6). m/z (ES+) 404 [MH]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[CH2:12][NH:11][C:10]3[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[N:18][C:9]2=3)[CH2:4][O:3]1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1([CH3:21])[O:3][CH2:4][CH:5]([N:8]2[C:13](=[O:14])[CH:12]=[N:11][C:10]3[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[N:18][C:9]2=3)[CH2:6][O:7]1
Reactant: COc1ccc2c(n1)N(C1COC(C)(C)OC1)C(=O)CN2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(C3COC(C)(C)OC3)c2n1
Yield: 69.1 %

Procedure:
4-(2,2-Dimethyl-1,3-dioxan-5-yl)-6-(methyloxy)-1,4-dihydropyrido[2,3-b]pyrazin-3(2H)-one (25.37 g) and activated manganese dioxide (120 g) were stirred in DCM (500 ml) at room temperature for 2 h. The mixture was filtered with suction and the solids were washed with DCM (2×100 ml). The combined filtrate plus washings were evaporated under reduced pressure to give a brown foam; this was purified by column chromatography on silica (eluting with 0%-100% EtOAc in petroleum ether (40-60°)). Appropriate fractions were combined and evaporated under reduced pressure to give the title compound as a light tan solid (17.40 g, 69%).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8]([O-:12])(=[O:11])(=[O:10])=[O:9].CS[C:15]1[S:19][CH:18]=[CH:17][S+:16]=1>CC(C)=O.C(OCC)C>[Cl:8]([O-:12])(=[O:11])(=[O:10])=[O:9].[S:16]1[CH:17]=[CH:18][S:19][C:15]1=[N+:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1scc[s+]1
Reactant: C1CCCNCC1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: CC(C)=O
Product: c1csc(=[N+]2CCCCCC2)s1

Procedure:
0.25 g of hexahydroazepine and 0.5 g of 2-methylthio-1,3-dithiolium perchlorate were teated in the same manner as in Example 26, and the product was recrystallized from acetone-ethyl ether, whereby 0.31 g (yield: 52.0%) of 1-(1,3-dithiol-2-ylidene)hexahydroazepinium perchlorate (Compound No. 37) was obtained as crystals having a melting point of from 86° to 88° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]([C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[CH:17]=3)=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH:26]([C@H:28]([C:30]1[CH:40]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=1)[CH3:29])[NH2:27].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[CH:17]=4)[N:26]([C@H:28]([C:30]3[CH:40]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=3)[CH3:29])[N:27]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COc1ccc2cc(C(=O)C#Cc3cc(Cl)cc(Cl)c3)cnc2c1
Reactant: CCOC(=O)c1ccc([C@H](C)NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2cnc3cc(OC)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the intermediate from step F (118 mg, 0.33 mmol) in DMF was added the ethyl 4-[(1S)-1-hydrazinoethyl]benzoate hydrochloride (89 mg, 0.36 mmol) and triethyl amine (55 μL, 0.39 mmol). After stirring the reaction mixture at room temperature for 18 hours it was concentrated in vacuo. The residue was diluted with water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 25% ethyl acetate-hexanes. This material was then re-purified with 3% acetonitrile-dichloromethane to give the desired compound. 1H NMR (500 MHz, CDCl3): 8.76 (d, J=2.0 Hz, 1H), 8.04 (d, J=8.2 Hz, 2H), 7.92 (1.8 Hz, 1H), 7.85 (d, J=1.8 Hz, 2H), 7.68 (d, J=8.9 Hz, 1H), 7.5 (d, J=2.1 Hz, 1H), 7.36 (t, J=1.8 Hz, 1H), 7.31 (d, J=8.0 Hz, 2H), 6.76 (s, 1H), 4.42 (q, J=7.0 Hz, 1H), 4.03 (s, 3H), 2.04 (s, 3H), 2.01 (t, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H). LC-MS: 4.28 min; (M+H)=546.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][CH:8]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH3:9])=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl>[OH:58][C:51]1[C:50]([CH2:49][NH:48][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([CH:8]([O:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH3:9])=[CH:18][CH:17]=2)=[C:55]([CH3:56])[CH:54]=[C:53]([CH3:57])[N:52]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(Oc1ccncc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccncc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
A mixture of 4-(1-(pyridin-4-yloxy)ethyl)benzoic acid (127 mg, 0.5 mmol), N-hydroxybenzotriazole (101.25 mg, 0.75 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg, 0.75 mmol) and triethylamine (151 mg, 1.5 mmol) in dichloromethane (50 mL) was stirred for 30 minutes at room temperature. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added. The resultant mixture was stirred at room temperature for 12 hours. The mixture was washed with water (10 mL×3). The organic layer was concentrated to give a residue and the residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-(pyridin-4-yloxy)ethyl)benzamide (57 mg, 30%). LRMS (M+H+) m/z: calcd 377.17. found 377. HPLC purity (214 nm): 99%. 1H NMR (300 MHz, CD3OD): δ 8.23 (d, J=5.1 Hz, 2H), 7.78 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 6.93-6.91 (m, 2H), 6.08 (s, 1H), 5.62 (q, J=6.3 Hz, 1H), 4.47 (s, 2H), 2.34 (s, 3H), 2.23 (s, 3H), 1.64 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5]([C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH2:10][NH:11]C(=O)OC(C)(C)C)(=[O:7])=[O:6].O1CCOCC1.[ClH:29]>C(OCC)(=O)C>[ClH:29].[CH3:1][O:2][CH2:3][CH2:4][S:5]([C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH2:10][NH2:11])(=[O:6])=[O:7]
Reactant: COCCS(=O)(=O)c1ccccc1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COCCS(=O)(=O)c1ccccc1CN
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(Step 4) tert-Butyl {2-[(2-methoxyethyl)sulfonyl]benzyl}carbamate obtained in Step 3 (15.0 g) was dissolved in ethyl acetate (91 ml), and 4N hydrogen chloride-1,4-dioxane solution (34.2 ml) was added at 0° C. The mixture was stirred at room temperature for 12 hr, and the precipitated crystals were collected by filtration, and washed with ethyl acetate to give 1-{2-[(2-methoxyethyl)sulfonyl]phenyl}methanamine hydrochloride (10.0 g).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:5]=[CH:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[C:9]=2[C:10](=[O:12])[CH:11]=1.[I:17]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[I:17][C:11]1[C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[S:3][C:2]=1[CH3:1]
Reactant: Cc1cc(=O)c2c(ccc3ccccc32)s1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: Cc1sc2ccc3ccccc3c2c(=O)c1I
Temperature: 60 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
3-Methyl-1H-benzo[f]thiochromen-1-one (1.0 mmol, 176 mg), iodine (1.2 mmol, 305 mg) and ceric ammonium nitrate (1.1 mmol, 603 mg) were dissolved in acetonitrile (4.0 mL), and the solution was stirred under a nitrogen atmosphere at 60° C. for 4 hours. After the disappearance of the starting materials was confirmed by thin-layer chromatography, the reaction solution was poured into a solution of a 10% saturated aqueous sodium thiosulfate solution under ice-cooling to terminate the reaction. The organic substances were extracted with methylene chloride, the obtained organic layer was dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and the title compound (0.74 mmol, 260 mg) was obtained in a 74% yield.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:9](=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]2[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=2)[CH:21]=1>CS(C)=O>[CH3:2][N:3]1[C:9](=[O:10])[CH2:8][CH2:7][N:6]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]3[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=3)[CH:21]=2)[CH2:5][CH2:4]1
Reactant: N#Cc1cnc(Nc2cc(CCl)ccn2)s1
Reactant: CN1CCNCCC1=O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2ccnc(Nc3ncc(C#N)s3)c2)CCC1=O
Reaction time: 20 h

Procedure:
4-Methyl-[1,4]diazepan-5-one hydrochloride (0.394 g, 2.39 mmol) was dissolved in 3 mL DMSO. Triethylamine (0.33 mL, 2.4 mmol) was added followed by the addition of 2-(4-chloromethyl-pyridin-2-ylamino)-thiazole-5-carbonitrile (0.200 g, 0.798 mmol). The solution as stirred for 20 h. The reaction mixture was purified directly by loading the solution onto a reverse phase preparative column. The fractions containing pure product were concentrated and the white solid that resulted was characterized as the TFA salt. 1H NMR (CD3OD) δ 8.47 (d, 1H, J=5.1 Hz), 8.02 (s, 1H), 7.09 (s, 1H), 7.07 (d, 1H, J=5.0 Hz), 3.78 (bs, 2H), 3.61 (bs, 2H), 2.98 (s, 3H), 2.83-2.67 (bs, 6H). [M+H]+=343.2.
Reaction SMILES: CN([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14]([O:16][CH3:17])=[O:15])C.C(Br)C.[C-:21]#[N:22].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[CH3:17][O:16][C:14]([C:6]1[NH:7][C:8]2[C:13]([C:5]=1[CH2:4][C:21]#[N:22])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:15]
Reactant: [C-]#N
Reactant: COC(=O)c1[nH]c2ccccc2c1CN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CCBr
Solvent: CS(C)=O
Product: COC(=O)c1[nH]c2ccccc2c1CC#N
Reaction time: 0.17 h

Procedure:
40.6 g Product from (b) were dissolved in 300 ml DMSO and 14.5 ml ethylbromide were added. After 10 minutes, 11.4 g KCN were added and the mixture was stirred for 48 hours. The reaction mixture was poured into citric acid and extracted with CH2Cl2. The solvent was evaporated to give 26 g yellow residue.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:8]1[O:12][CH:11]([N:13]2[CH:18]=[CH:17][C:16]([N:19]=[CH:20][N:21]([CH3:23])[CH3:22])=[N:15][C:14]2=[O:24])[C:10]([OH:26])([CH3:25])[CH:9]1[OH:27])([CH3:4])([CH3:3])[CH3:2].[C:40]([NH:47][C@H:48]([C:52](O)=[O:53])[CH:49]([CH3:51])[CH3:50])([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([SiH2:5][O:6][C:7]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH:8]1[CH:9]([O:27][C:52](=[O:53])[CH:48]([NH:47][C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[CH:49]([CH3:51])[CH3:50])[C:10]([OH:26])([CH3:25])[CH:11]([N:13]2[CH:18]=[CH:17][C:16]([N:19]=[CH:20][N:21]([CH3:22])[CH3:23])=[N:15][C:14]2=[O:24])[O:12]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=Nc1ccn(C2OC(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)C(O)C2(C)O)c(=O)n1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OC1C(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2ccc(N=CN(C)C)nc2=O)C1(C)O

Procedure:
The next steps in this process comprise reacting (3) with Me2NCH(OMe)2 in DMF to form (4), N-[1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine, which is the amino-protected form of (3); reacting (4) with TBDPSCl and imidazole in DCM to provide the 5′-silyl-protected form of (4) as N′-{1-[5-(tert-butyl-diphenyl-silanyloxymethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yl]-2-oxo-1,2-dihydro-pyrimidin-4-yl}-N,N-dimethyl-formamidine (5), where the use of DCM provides the advantage of having greater control over disilyl by-product formation; reacting (5) with N-Boc-L-valine, EDC and DMAP in DCM at room temperature to form 2-tert-butoxycarbonylamino-3-methyl-butyric acid 2-(tert-butyl-diphenyl-silanyloxy-methyl)-5-[4-(dimethylamino-methyleneamino)-2-oxo-2H-pyrimidin-1-yl]-4-hydroxy-4-methyl-tetrahydro-furan-3-yl ester (6); removing the silyl and amino-protecting groups by reacting (6) with NH4F in MeOH in the presence of approximately 10 mole equivalents of ethyl acetate to prevent cleavage of the 3′-O-valinyl ester by liberated ammonia, and refluxing the mixture to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester to provide (7); and finally, reacting (7) with HCl in EtOH to provide 2-amino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester, dihydrochloride salt (8) as a final product.
Reaction SMILES: [N:1]([C:4]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:13]([CH3:15])[CH3:14])=[C:2]=[O:3].[C:16]1([S:22]([C:25]2([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[C:16]1([S:22]([C:25]2([CH2:30][NH:31][C:2]([NH:1][C:4]3[C:5]([CH:13]([CH3:15])[CH3:14])=[CH:6][CH:7]=[CH:8][C:9]=3[CH:10]([CH3:11])[CH3:12])=[O:3])[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:23])=[O:24])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: NCC1(S(=O)(=O)c2ccccc2)CCCC1
Solvent: ClCCl
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NCC1(S(=O)(=O)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.6 %

Procedure:
In a tube, under nitrogen, 157 mg (0.77 mmol) of 2-isocyanato-1,3-diisopropylbenzene is added to a solution of 168 mg (0.7 mmol) of C-(1-benzenesulfonyl-cyclopentyl)-methylamine in 3.5 ml of dichloromethane. The reaction mixture is stirred at RT for 3 h. The solvent is evaporated with a nitrogen stream. The paste obtained is taken up in heptane (5 mL) for crystallization. The white powder obtained is chromatographed on silica gel (dichloromethane then dichloromethane/methanol, 98/2, v/v). The oil obtained is crystallized from heptane. After filtration and drying, 135 mg of 1-(1-benzenesulfonylcyclopentylmethyl)-3-(2,6-diisopropyl-phenyl)-urea is obtained in the form of a white powder (m.p.=124° C., Yield=44%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1.[NH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(NC(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1
Reactant: CCOC(=O)CCCN
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(Cl)ncn1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CCCNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(6-chloropyrimidine-4-carboxamido)-3-methylbenzene-1-sulfonyl chloride (Intermediate 30, 1.2g; 3.47 mmol) in THF (100 ml) was treated with ethyl 4-aminobutanoate (720 mg; 4.34 mmol) and diisopropylamine (2 ml; 14.3 mmol). After stirring at RT for 18 hours the solvent was removed in vacuo and the residue redissolved in DCM and washed with water. The organic extracts were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc. The title product was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[ClH:12].[CH2:13]([OH:15])[CH3:14]>>[ClH:12].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=[NH:11])[O:15][CH2:13][CH3:14]
Reactant: CCO
Reactant: N#CCc1ccc(F)cc1F
Agent: Cl
Product: CCOC(=N)Cc1ccc(F)cc1F

Procedure:
Commercially available 2-(2,4-difluorophenyl)acetonitrile (Aldrich), HCl gas and ethanol were processed using the method described for Example 3A to obtain the titled compound except that the reaction time was 72 hours. MS (ESI+) m/z 200 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=2)[C:4]1=[O:14].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(NC(C)C)(C)C.Cl>ClCCl>[CH3:13][O:12][C:7]1[CH:6]=[C:5]2[C:10]([CH2:11][CH:3]([NH:2][C:16](=[O:17])[O:18][CH2:19][CH3:20])[C:4]2=[O:14])=[CH:9][CH:8]=1
Reactant: COc1ccc2c(c1)C(=O)C(N)C2
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CCOC(=O)NC1Cc2ccc(OC)cc2C1=O
Temperature: 25 °C

Procedure:
To a suspension of 2-amino-6-methoxy-2,3-dihydro-1H-inden-1-one hydrochloride (15.4 g, 72.1 mmol) in dichloromethane was added ethyl chloroformate (10.38 ml, 108 mmol) followed by dropwise addition of a solution of diisopropylamine (25.2 ml, 144 mmol) in 10 ml dichloromethane. The reaction mixture was stirred at room temperature over night. Added 1N hydrochloric acid, diluted with dichloromethane, separated organic layer and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed subsequently with water, sodium bicarbonate and brine, dried, filtered and evaporated to obtain the product (ethyl 6-methoxy-1-oxo-2,3-dihydro-1H-inden-2-ylcarbamate) as a purple solid. m=16.4 g (95%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]([CH2:19][O:20][CH3:21])[CH2:17][CH3:18])[C:10]=2[NH2:22])=[C:5]([CH3:23])[CH:4]=1.[C:24](OC)(=[O:28])[C:25]([CH3:27])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[N:22]=[C:25]([CH3:27])[C:24](=[O:28])[N:15]([CH:16]([CH2:19][O:20][CH3:21])[CH2:17][CH3:18])[C:11]=3[N:12]=[CH:13][CH:14]=2)=[C:5]([CH3:23])[CH:4]=1
Reactant: COC(=O)C(C)=O
Reactant: CCC(COC)Nc1nccc(-c2ccc(OC)cc2C)c1N
Product: CCC(COC)n1c(=O)c(C)nc2c(-c3ccc(OC)cc3C)ccnc21
Yield: 3.3 %

Procedure:
4-(4-Methoxy-2-methyl-phenyl)-N2-(1-methoxymethyl-propyl)-pyridine-2,3-diamine (0.08 g, 0.25 mmol) and methyl pyruvate (33 μL, 0.38 mmol) were treated substantially as in Part E of Example 67a to give 3.0 mg of 8-(4-methoxy-2-methyl-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 74a): 1H NMR (400 MHz, CDCl3) δ ppm 8.46 (d, J=4.89 Hz, 1 H), 7.15 (d, J=8.31 Hz, 1 H), 7.12 (d, J=4.40 Hz, 1 H), 6.85 (d, J=6.60 Hz, 1 H), 6.83 (d, J=12.23 Hz, 1 H), 5.89 (m, 1 H), 4.38 (m, 1 H), 3.86 (s, 3 H), 3.77 (m, 1 H), 3.32 (s, 3 H), 2.46 (s, 3 H), 2.11 (s, 3 H), 1.77 (m, 2 H), 0.86 (t, J=7.34 Hz, 2 H). MS (EI) 368.30 [(M+H)+, 100]
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][NH2:11])[CH3:8].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28][CH2:29]Cl>CS(C)=O.O>[CH2:7]([CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][NH:11][CH2:29][CH2:28][CH2:27][O:26][C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)[CH3:8]
Reactant: CCCCC(CC)CN
Reactant: ClCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCC(CC)CNCCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and 2-ethyl-n-hexylamine (0.35 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(2-ethyl-n-hexyl)-(3-(naphthalen-2-yloxy) propyl)amine solid, m.p. 97° C., (yield 0.6 gm, 84.8%).