Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:20]=[C:19]([OH:29])[CH:18]=2)=[CH:6][CH:5]=1)(C)C.CC1C=CC(C=O)=CC=1>>[CH3:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]2[N:22]=[C:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:20]=[C:19]([OH:29])[CH:18]=2)=[CH:8][CH:9]=1
Reactant: CC(C)c1ccc(-c2ccccc2Cc2cc(O)nc(-c3ccccc3)n2)cc1
Agent: Cc1ccc(C=O)cc1
Product: Cc1ccc(-c2ccccc2Cc2cc(O)nc(-c3ccccc3)n2)cc1

Procedure:
Compound 7 was prepared using the synthetic route for Compound 6 using 4-methylbenzaldehyde in procedure 5. Purification was accomplished using column chromatography to provide the title compound as a solid (mp 210-214° C.). 1H-NMR (CDCl3) δ 8.1 (m, 2H); 7.5 (m, 3H); 7.3-7.2 (m, 5H); 7.1 (s, 4H); 6.2(s, 1H), 5.4 (s, 1H); 2.3 (s,3H). 13C-NMR (CDCl3) δ 170.9; 165.6; 156.5; 141.4; 138.2; 136.6; 132.1; 132.0; 129.4; 129.32; 129.29; 129.0; 128.5; 127.9; 126.9; 112.5; 58.4; 20.9. Mass spec (MH+ 353). Analysis for C24H20N2O; calculated, C 81.79, H 5.72, N 7.95; found C 81.43, H 5.91, N 7.75.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][CH:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:32]3([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[C:31](=[O:38])[NH:30][CH2:29]2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH:6]([NH:5][CH2:4][CH2:3][N:35]2[CH2:34][CH2:33][C:32]3([N:28]([C:25]4[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=4)[CH2:29][NH:30][C:31]3=[O:38])[CH2:37][CH2:36]2)[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(C(NCCCl)c2ccc(F)cc2)cc1
Reactant: O=C1NCN(c2ccc(F)cc2)C12CCNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=C1NCN(c2ccc(F)cc2)C12CCN(CCNC(c1ccc(F)cc1)c1ccc(F)cc1)CC2

Procedure:
A mixture of 8 parts of N-(2-chloroethyl)-4-fluoro-α-(4-fluorophenyl)benzenemethanamine hydrochloride, 5.7 parts of 1-(4-fluorophenyl)-1,3,8-triazaspiro[4,5]decan-4-one, 10 parts of sodium carbonate, 0.1 parts of potassium iodide and 80 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. The reaction mixture is taken up in water and after stirring for a while, the precipitated product is filtered off. The product is washed with 4-methyl-2-pentanone, dried and crystallized from 4-methyl-2-pentanone (activated charcoal). It is filtered off and dried, yielding 4 parts of 8-[2-{[bis(4-fluorophenyl)methyl]amino}ethyl]-1-(4-fluorophenyl)-1,3,8-triazaspiro[4,5]decan-4-one; mp. 193° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[O:8][CH2:9][C:10](=[O:17])[C:11]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:2]1.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][N:25]=2)[C:20]([CH:27]=O)=[CH:19]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:18]1[C:26]2=[N:25][CH:24]=[CH:23][CH:22]=[C:21]2[C:20]([CH:27]=[C:9]2[O:8][C:7]([NH:6][C:3]3[CH:4]=[CH:5][NH:1][N:2]=3)=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]2=[O:17])=[CH:19]1
Reactant: CCOC(=O)C1=C(Nc2cc[nH]n2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2cc[nH]n2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 42.1 %

Procedure:
To a solution of ethyl 2-[(3-pyrazolyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.30 g, 1.3 mmol) which similarly prepared according to the procedure described in the Example 4, First step, and 7-azaindole-3-carboxaldehyde (0.19 g, 1.3 mmol) in ethanol (6.0 mL), L-proline (0.015 g, 0.13 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.20 g, y. 35%).
Reaction SMILES: CC1C(C2CCCC(C3C(C)=CC=CN=3)N2)=NC=CC=1.[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27](CBr)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.485 g, 1.81 mmol), 4-bromomethyl-benzoic acid methyl ester (0.642 g, 2.80 mmol), KI (64 mg, 0.38 mmol), and DIPEA (0.65 mL, 3.73 mmol) in DMF (9 mL) was heated at 60° C. for 23 hours. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.67 g (89%) of 4-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester as a white solid. 1H NMR (CDCl3) δ 1.54-1.72 (m, 3H), 2.02-2.08 (m, 1H), 2.20-2.34 (m, 2H), 2.40 (s, 6H), 3.58 (s, 2H), 3.83 (s, 3H), 4.12 (d, 2H, J=11.4 Hz), 6.57 (d, 2H, J=7.8 Hz), 6.96 (dd, 2H, J=7.5, 4.5 Hz), 7.23 (d, 2H, J=7.5 Hz), 7.53 (d, 2H, J=7.8 Hz), 8.26 (d, 2H, J=4.5 Hz); ES-MS m/z 416 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]([F:44])([F:43])[C:33]1[CH:34]=[C:35]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[CH:36]=[CH:37][CH:38]=1.CCN(C(C)C)C(C)C>C1COCC1.C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:42][C:39]3([C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([F:31])([F:43])[F:44])[CH:34]=4)[CH2:41][CH2:40]3)=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)O)c3c(c2[nH]1)CC(C)(C)O3
Reactant: NC1(c2cccc(C(F)(F)F)c2)CC1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)NC3(c4cccc(C(F)(F)F)c4)CC3)c3c(c2[nH]1)CC(C)(C)O3
Yield: 5.4 %

Procedure:
The title compound was prepared following the procedure described for Example-108 using 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-35, 0.150 g, 0.403 mmol), thionyl chloride (2.0 mL), 1-(3-(trifluoromethyl)phenyl)cyclopropanamine (Intermediate-44, 0.121 g, 0.604 mmol), benzene (4 mL), THF (6.0 mL) and DIPEA (4 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.012 g of the desired product. 1HNMR (DMSO-d6): δ 1.33-1.56 (m, 4H), 1.51 (s, 6H), 2.23 (s. 1H), 3.07 (s, 2H), 7.29-7.42 (m, 4H), 7.49-7.53 (m, 3H), 8.40 (s, 1H), 8.93 (s, 1H), 10.86 (s, 1H); MS [M+H]+: 555.29.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:52])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@@H:16]([CH2:47][C:48]([NH2:51])([CH3:50])[CH3:49])[CH2:15]2)=[CH:10][CH:9]=1.CCN(CC)CC.[C:60](Cl)(=[O:62])[CH3:61]>C(Cl)Cl.O>[CH3:1][O:2][CH2:3][C@H:4]([CH3:52])[CH2:5][O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=3)(=[O:39])=[O:38])[C@@H:16]([CH2:47][C:48]([NH:51][C:60](=[O:62])[CH3:61])([CH3:49])[CH3:50])[CH2:15]2)=[CH:12][CH:13]=1
Reactant: CC(=O)Cl
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(C)(C)N)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(C)(C)NC(C)=O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reaction time: 1 h

Procedure:
To a solution of 1.0 mmol of 2-[(2R,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-1,1-dimethyl-ethylamine, 3.0 mmol of Et3N in 10 ml of CH2Cl2 are added 1.5 mmol of acetyl chloride at 0° C. and the resulting mixture is stirred for 1 h. The reaction mixture is diluted with water and extracted with CH2Cl2. The organic phases are combined, dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound which is identified based on its Rf-value.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][NH2:8].[CH3:9][NH:10][S:11]([C:14]1[CH:15]=[C:16]([C:24](Cl)=[O:25])[C:17]2[O:22][CH2:21][CH2:20][O:19][C:18]=2[CH:23]=1)(=[O:13])=[O:12]>>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][NH:8][C:24]([C:16]1[C:17]2[O:22][CH2:21][CH2:20][O:19][C:18]=2[CH:23]=[C:14]([S:11](=[O:13])(=[O:12])[NH:10][CH3:9])[CH:15]=1)=[O:25]
Reactant: CN1CCCC1CN
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Product: CNS(=O)(=O)c1cc2c(c(C(=O)NCC3CCCN3C)c1)OCCO2
Yield: 77 %

Procedure:
In a similar manner to that of the above example, 71 g of levorotatory 1-methyl-2-aminomethyl-pyrrolidine was reacted with 180.5 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride to give 415 g of levorotatory-N-(1-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide (M.P.: 187°-187.5° C.; yield: 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[C:12](/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)\[C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:21][C:18]1[CH:17]=[CH:16][C:15](/[C:12](/[C:13]#[N:14])=[CH:11]/[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:20][CH:19]=1)(=[O:24])[CH3:23]
Reactant: COc1ccc(/C=C(\C#N)c2ccc(O)cc2)cc1OC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(/C=C(\C#N)c2ccc(OC(C)=O)cc2)cc1OC
Yield: 94 %

Procedure:
Compound 48 (1.41 g) was acetylated with acetic anhydride and pyridine in accordance with a customary method, to thereby produce the target product (1.52 g, yield: 94%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.O[N:15]=[C:16]([CH:18]1[CH2:20][CH2:19]1)[NH2:17].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2([C:11]3[O:13][N:17]=[C:16]([CH:18]4[CH2:20][CH2:19]4)[N:15]=3)[CH2:9][CH2:10]2)[CH:3]=1
Reactant: O=C(O)C1(c2cncc(Br)c2)CC1
Reactant: NC(=NO)C1CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Brc1cncc(C2(c3nc(C4CC4)no3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the title compound from Example 72 Step A (45 mg, 0.19 mmol), N′-hydroxycyclopropanecarboximidamide (22 mg, 0.22 mmol) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (116 mg, 0.223 mmol) in N,N-dimethylformamide (0.93 mL) was added triethylamine (26 μl, 0.19 mmol). The reaction stirred at room temperature overnight. It was then diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was then diluted with toluene and heated to reflux overnight. Purification by flash chromatography on silica gel (10-100% ethyl acetate in hexanes) provided the title compound: LCMS m/z 307.85 [M+2+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:36])[NH:15][C:16]2[CH:17]=[C:18]3[C:34](=[O:35])[NH:33][N:32]=[CH:31][C:20]4=[C:21]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[NH:22][C:23]([CH:24]=2)=[C:19]34)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[O:35]=[C:34]1[C:18]2[C:19]3[C:20](=[C:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[NH:22][C:23]=3[CH:24]=[C:16]([NH:15][C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:36])[CH:17]=2)[CH:31]=[N:32][NH:33]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc3c4c(c(-c5ccccc5)[nH]c4c2)C=NNC3=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NN=Cc2c(-c3ccccc3)[nH]c3cc(NC(=O)C4CCNCC4)cc1c23
Yield: 97 %

Procedure:
Preparation of example 31 from the title compound of Example 29 (20 mg, 0.041 mmol) and 45% TFA in CH2Cl2 (1 mL) was carried out analogously to Example 20. Isolation, also in an analogous manner, afforded the title compound (20 mg, 0.040 mmol) as a yellow powder in 97% yield.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH2:4][CH2:3]1.Cl.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][NH2:32].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[OH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:10]=2[C:11]([NH:32][CH2:31][CH2:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([F:22])([F:33])[F:34])=[O:13])[CH2:6][CH2:7]1
Reactant: NCCc1ccccc1C(F)(F)F
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N[C@H]1CC[C@@H](O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCCc1ccccc1C(F)(F)F)c1cc([N+](=O)[O-])ccc1N[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (120 mg), [2-(trifluoromethyl)phenyl]ethylamine hydrochloride (111 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (86.4 mg) and 1-hydroxybenzotriazole (81.0 mg) in anhydrous dimethylformamide (3 mL) was stirred for 18 hours at ambient temperature. The mixture was partitioned between water and ethyl acetate. The separated organic layer was washed with IN-hydrochloric acid, water, an aqueous saturated sodium bicarbonate solution and brine, successively, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by a preparative silica gel thin layer chromatography with a mixture of hexane and ethyl acetate (2:1). The obtained product was recrystallized from a mixture of petroleum ether and diethyl ether to give 2-(cis-4-hydroxycyclohexylamino)-5-nitro-N-{[2-(trifluoromethyl)phenyl]ethyl}benzamide (157 mg) as yellow powders.
Reaction SMILES: ClC(CC1C=C2C(=CC=1)N=CC=C2)C=O.BrC1C=NC(N)=NC=1.[Br:24][C:25]1[CH:26]=[N:27][C:28]2[N:29]([CH:31]=[C:32]([CH2:34][C:35]3[CH:36]=[C:37]4[C:42](=[CH:43][CH:44]=3)[N:41]=[CH:40][CH:39]=[CH:38]4)[N:33]=2)[CH:30]=1>CC(O)(CC)C>[Br:24][C:25]1[CH:26]=[N:27][C:28]2[N:33]([C:32]([CH2:34][C:35]3[CH:36]=[C:37]4[C:42](=[CH:43][CH:44]=3)[N:41]=[CH:40][CH:39]=[CH:38]4)=[CH:31][N:29]=2)[CH:30]=1
Reactant: Brc1cnc2nc(Cc3ccc4ncccc4c3)cn2c1
Agent: Nc1ncc(Br)cn1
Agent: O=CC(Cl)Cc1ccc2ncccc2c1
Solvent: CCC(C)(C)O
Product: Brc1cnc2ncc(Cc3ccc4ncccc4c3)n2c1

Procedure:
A solution of 2-chloro-3-(quinolin-6-yl)propanal (1.0 g, 2.54 mmol) and 5-bromopyrimidin-2-amine (0.53 g, 3.05 mmol) in 2-methyl-butan-2-ol (10 mL) was stirred at 135° C. for 12 h. After cooling, the solvent was removed in vacuo and the residue was purified by flash chromatography in silica gel eluting with a CH2Cl2/MeOH gradient to afford a mixture of the title compound and 6-(6-bromo-imidazo[1,2-a]pyrimidin-2-ylmethyl)quinoline (250 mg, 29%) as brown solid. LCMS (method E): [MH]+=339/341, tR=3.51 min.
Reaction SMILES: [CH:1]([O:3][CH:4]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=O.C(O)[CH2:42][CH:43]([OH:48])[CH2:44][CH2:45][CH2:46][OH:47].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:5]([C:4]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[O:48][CH:43]([CH2:44][CH2:45][CH2:46][OH:47])[CH2:42][CH2:1][O:3]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC=O
Reactant: OCCCC(O)CCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCC1(CCCCCCCC/C=C\C/C=C\CCCCC)OCCC(CCCO)O1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A mixture of dilinoleyl ketone (III, 1.80 g, 3.4 mmol), 1,3,6-hexanetriol (II, 0.50 g, 3.7 mmol) and pyridinium p-toluenesulfonate (100 mg, 0.40 mmol) in 120 mL of toluene was refluxed under argon for 3 hours with a Dean-Stark tube to remove water. The resulting mixture was cooled to room temperature. The organic phase was washed with water (2×50 mL), brine (50 mL), and dried over anhydrous Na2SO4. Evaporation of the solvent resulted in pale oil (2.0 g). The crude product was purified by column chromatography on silica gel (230-400 mesh, 50 mL) with 0-3% methanol gradient in dichloromethane as eluent. This afforded 0.90 g (41%) of pure IV as colourless oil.
Reaction SMILES: [CH3:1][C:2]([N+:16]([O-])=O)([CH3:15])[CH2:3][O:4][C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1>CO>[NH2:16][C:2]([CH3:15])([CH3:1])[CH2:3][O:4][C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1
Reactant: CC(C)(COc1ccc(O)c(C(N)=O)c1)[N+](=O)[O-]
Solvent: CO
Product: CC(C)(N)COc1ccc(O)c(C(N)=O)c1

Procedure:
11.5 g of 5-(2-methyl-2-nitropropoxy)salicylamide are hydrogenated in 150 ml of methanol at 40°-50° and 80 bar over 5 g of Raney nickel until hydrogen absorption ceases. By filtration and concentration of the filtrate by evaporation, crude 5-(2-amino-2-methylpropoxy)salicylamide is obtained, which, after standing for a relatively long period, crystallises from isopropanol and melts at 115°-117°.
Reaction SMILES: C1(=O)CCCCC1.C(OC(=O)NN)(C)(C)C.C([BH3-])#N.[Na+].Cl.Cl.[CH:23]1([NH:29][NH2:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C[O-].[Na+].C(O[CH2:37][CH:38]([C:41]#[N:42])[C:39]#[N:40])C>CCCCCC.C(O)C>[NH2:42][C:41]1[N:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[N:30]=[CH:37][C:38]=1[C:39]#[N:40]
Reactant: CCOCC(C#N)C#N
Reactant: NNC1CCCCC1
Agent: CC(C)(C)OC(=O)NN
Agent: C[O-]
Agent: Cl
Solvent: CCO
Solvent: CCCCCC
Solvent: O=C1CCCCC1
Product: N#Cc1cnn(C2CCCCC2)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
Alternate Synthesis of Compound 8: Cyclohexanone (Acros, 19.6 g, 200 mmol) and tert-butylcarbazate (Acros, 26.4 g, 200 mmol) were combined in 350 mL dry hexane and stirred under argon for ½ hour. The mixture was then subjected to reflux temperature for 1.5 hours and permitted to cool to room temperature. A white solid formed on cooling which was removed by filtration and dried in vacuo—40.31 g (95%): mp 147-149° C.; MS (ES+ calculated: 212.29; found: 235.05 M+Na). 1H NMR (400 MHz, DMSO-d6) δ 9.47 (br s, 1H), 2.27 (m, 2H), 2.16 (m, 2H), 1.52 (m, 2H), 1.59 (m, 4H), 1.42 (s, 9H). t-Butylcarboxycyclohexanone hydrazone generated above (40.02 g, 189 mmol) was dissolved in a mixture of 175 mL tetrahydrofuran and 225 mL anhydrous methanol. Sodium cyanoborohydride (Acros, 14.3 g, 227 mmol) was added in portions over ten minutes and the mixture was stirred under argon overnight at room temperature. 135 mL of 6N hydrochloric acid were then added dropwise and the mixture was refluxed for one hour. The reaction was permitted to cool to room temperature and a white solid was removed by filtration. The mother liquor was concentrated and residual water was removed by azeotroping with ethanol on a rotary evaporator (3×100 mL). The mixture was concentrated to dryness and was taken up into hot isopropanol (˜300 mL). The solid that was present was removed by filtration and the mother liquor was concentrated to ½ volume at which point an equal volume of ethyl ether was added. This caused cyclohexylhydrazine hydrochloride to precipitate as a white solid. Yield (20.0 g, 93%). To cyclohexylhydrazine hydrochloride (7.52 g, 50 mmol) generated above in 500 mL absolute ethanol was added sodium methoxide (Aldrich, 2.7 g, 50 mmol). The mixture was stirred briefly and ethoxymethylmalononitrile (Acros, 6.11 g, 50 mmol) was added in small portions over twenty minutes. The reaction mixture was then heated at 70° C. under argon overnight. On cooling, the reaction was concentrated and subjected to flash chromatography on silica gel (1:1 hexane: ethyl acetate) affording 6.3 g (66%) of a light brown solid. Compound 8: mp 99-103° C.; MS (ES+ calculated: 190.25; found: 191.15 M+H). HPLC (97% purity, retention time 11.135 minutes—Method A); 1H NMR (400 MHz, DMSO-d6) δ 7.50 (s, 1H), 6.49 (br s, 2H), 4.02 (m, 1H), 1.80-1.10 (m, 10 H).
Reaction SMILES: [NH2:1][C:2](=[O:33])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[C:15]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[N:14]=[C:13]3[CH2:30][CH2:31][CH2:32][C:12]=23)=[CH:6][CH:5]=1.[ClH:34]>CO>[ClH:34].[N:17]1([C:15]2[N:14]=[C:13]3[CH2:30][CH2:31][CH2:32][C:12]3=[C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([CH2:3][C:2]([NH2:1])=[O:33])=[CH:5][CH:6]=3)[CH:16]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Nc3ccc(CC(N)=O)cc3)c3c(n2)CCC3)CC1
Agent: Cl
Solvent: CO
Product: NC(=O)Cc1ccc(Nc2cc(N3CCNCC3)nc3c2CCC3)cc1
Temperature: 65 °C

Procedure:
To a solution of tert-butyl 4-(4-((4-(2-amino-2-oxoethyl)phenyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)piperazine-1-carboxylate in methanol (3 mL) was added HCl (6 M, 0.1 mL). The mixture was heated to 65° C. for 16 h. The Boc group was removed, however, the amide function was replaced with a methyl ester group. The mixture was concentrated and following general procedure C, desired product was obtained after forming the hydrochloride salt (0.015 g, 50%) as an orange-brown solid. MW=424.37. 1H NMR (DMSO-d6, 500 MHz) δ 13.26 (s, 1H), 9.40-9.28 (m, 3H), 7.53 (s, 1H), 7.34 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H), 6.91 (s, 1H), 6.07 (s, 1H), 3.64-3.57 (m, 4H), 3.41 (s, 2H), 3.20 (br s, 4H), 3.02 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.5 Hz, 2H), 2.15 (quin, J=7.5 Hz, 2H); APCI MS m/z, 352 [M+H]+.
Reaction SMILES: [H-].[Na+].Br[C:4]1[C:9]([N:10]([CH3:22])[C:11]([C:13]2[C:14]([NH:19][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[CH:8][CH:7]=[C:6]([O:23][CH3:24])[N:5]=1>C1(C)C(C)=CC=CC=1>[CH2:20]([N:19]1[C:14]2[N:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:11](=[O:12])[N:10]([CH3:22])[C:9]2[CH:8]=[CH:7][C:6]([O:23][CH3:24])=[N:5][C:4]1=2)[CH3:21]
Reactant: CCNc1ncccc1C(=O)N(C)c1ccc(OC)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCN1c2ncccc2C(=O)N(C)c2ccc(OC)nc21
Yield: 47.7 %

Procedure:
Sodium hydride (0.9 g of a 50% dispersion in mineral oil) was added to a solution of N-(2-bromo-6-methoxy-3-pyridinyl)-2-ethylamino-N-methyl-3-pyridinecarboxamide (1.4 g) in xylene (20 ml) and the mixture refluxed for 2 hours. After cooling, the mixture was quenched with methanol, diluted with ethyl acetate, and washed with water. The organic phase was dried (anhydrous magnesium sulfate), concentrated, and purified on a silica gel column (ethyl acetate/hexane, 1:4) to give fairly pure product, which was then recrystallized twice from ethyl acetate/hexane to give 0.52 g of pure 5,11-dihydro-11-ethyl-2-methoxy-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one, m.p. 116°-118° C.