Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[N:16]1([CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]([N:19]1[CH2:18][CH2:17][N:16]([CH2:22][C:23](=[O:24])[N:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:21][CH2:20]1)=[O:15]
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1C(=O)N1CCN(CC(=O)N2CCCC2)CC1
Temperature: 25 °C

Procedure:
5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), piperazine acetic acid pyrrolidid (42.4 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H26N4O3: 382.2005, found 382.2016.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][CH3:23].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][CH2:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1-(4-Aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.6 mmol) was combined with pyridine (50 mL) and heated to 50° C. Benzoyl chloride (0.22 g, 1.6 mmol) was added via a pipette. After 1 hour analysis by HPLC indicated that all of the starting material was gone and that several products had formed. The reaction mixture was concentrated under vacuum. The residue was combined with dichloromethane and aqueous sodium bicarbonate. The organic layer was separated and then concentrated under vacuum. The residue was dissolved in dichloromethane and placed on a silica gel column. The column was eluted with 5% methanol in dichloromethane and then with 10% methanol in dichloromethane. The 10% methanol in dichloromethane fractions were combined and concentrated under vacuum to provide N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzamide as a solid, m.p. 174-175° C. 1H NMR (500 MHz, DMSO-d6) δ 8.48 (t, J=6.0 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.60 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 7.39 (t, J=8.0 Hz, 1H), 7.18 (t, J=8.0 Hz, 1H), 6.50 (broad s, 2H), 4.54 (t, J=7.0 Hz, 2H), 3.32 (m, 2H), 2.91 (t, J=7.0 Hz, 2H), 1.86 (quintet, J=7.0 Hz, 2H), 1.77 (quintet, J=7.0 Hz, 2H), 1.70 (quintet, J=7.0 Hz, 2H), 1.41 (sextet, J=7.0 Hz, 2H), 0.91 (t, J=7.0 Hz, 3H); MS (CI) m/e 416 (M+H).
Reaction SMILES: I[C:2]1[CH:15]=[C:14]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Cu][C:17]#[N:18].[I-]>CN1CCCC1=O>[CH3:12][N:11]([CH2:10][CH2:9][C:8]1[C:14]2[C:5](=[CH:4][CH:3]=[C:2]([C:17]#[N:18])[CH:15]=2)[NH:6][CH:7]=1)[CH3:13]
Reactant: N#C[Cu]
Reactant: CN(C)CCc1c[nH]c2ccc(I)cc12
Agent: [I-]
Solvent: CN1CCCC1=O
Product: CN(C)CCc1c[nH]c2ccc(C#N)cc12
Temperature: 180 °C
Yield: 82.4 %

Procedure:
A flask with mechanical stirrer is charged with 5-iodo-dimethyltryptamine (179 g of 75% purity, 0.427 mol), copper (I)cyanide (90 g, 1.0 mol), and N-methylpyrrolidone (1.5 l). The pink suspension is heated at 180° C. under a nitrogen atmosphere and vigorously stirred, until the iodide is completely consumed (7 h). After cooling to ambient temperature ammonia (2 l 25% solution in water) is added, and the resulting mixture is stirred over night. The mixture is then extracted with TBME (6*1.5 l), and the combined organic layers are washed with water (3*3 l), and brine (1*3 l), and dried (sodium sulfate). Removal of the solvent leaves 75 g (82%) of the product which is >95% pure by HPLC (other properties cf. Reference Example 3).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([CH3:19])([CH3:18])[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15].[NH2:22][C:23](=[N:37]O)[C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][N:28]2[CH2:33][C:34]([NH2:36])=[O:35].CC(C)N=C=NC(C)C>O1CCOCC1>[F:20][C:2]([F:1])([F:21])[C:3]([CH3:18])([CH3:19])[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[O:11][N:37]=[C:23]([C:24]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:25]=3[CH:26]=[CH:27][N:28]4[CH2:33][C:34]([NH2:36])=[O:35])[N:22]=2)=[CH:7][C:6]=1[C:14]([F:16])([F:15])[F:17]
Reactant: NC(=O)Cn1ccc2c(C(N)=NO)cccc21
Reactant: CC(C)(Oc1ccc(C(=O)O)cc1C(F)(F)F)C(F)(F)F
Agent: CC(C)N=C=NC(C)C
Solvent: C1COCCO1
Product: CC(C)(Oc1ccc(-c2nc(-c3cccc4c3ccn4CC(N)=O)no2)cc1C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.9 %

Procedure:
To a solution of 4-(2,2,2-trifluoro-1,1-dimethylethoxy)-3-(trifluoromethyl)benzoic acid (118 mg) and 2-{4-[amino(hydroxyimino)methyl]-1H-indol-1-yl}acetamide (104 mg) in dioxane (5 ml) was added DIC (69 μl), followed by stirring at room temperature for 3 hours, and then heating under reflux for 20 hours. The reaction solution was concentrated, and then to the residue was added water (15 ml), followed by extraction with chloroform (15 ml). The organic layer was washed with a saturated aqueous NaHCO3 solution and saturated brine, dried over anhydrous MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: CAPCEL PAK, C18, MG, S-5, 30×50 mm; solvent: 50-90% acetonitrile/10 mM ammonium carbonate-ammonia (pH 9.2); 40 ml/min), and crystallized with diisopropyl ether to obtain 2-(4{5-[4-(2,2,2-trifluoro-1,1-dimethylethoxy)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)acetamide (40 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]=[C:10]([C:13]([OH:15])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]1[C@H:25]2[C@@H:20]([CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:19][CH2:18][NH:17]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]=[C:10]([C:13]([N:17]3[CH:16]4[CH:25]([CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:20][CH2:19][CH2:18]3)=[O:15])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1csc(-c2ccc(F)nc2)c1
Reactant: C1CC[C@H]2CNCC[C@@H]2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1csc(-c2ccc(F)nc2)c1)N1CCCC2CCCCC21
Yield: 19.8 %

Procedure:
5-(6-Fluoro-pyridin-3-yl)-thiophene-3-carboxylic acid (0.05 g, 0.22 mmol) was dissolved in acetonitrile (1 mL) together with cis, trans-decahydroisoquinoline (0.134 mL, 0.90 mmol), triethylamine (80 μL, 0.60 mmol) and HATU (0.085 g, 0.22 mmol) and the resulting mixture was stirred over the weekend. The crude material was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were evaporated to give the title compound as a pink oil (0.015 g). LCMS m/z 345.23 [M+H]+ R.T.=11.76 min (Analytical Method 2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC#N.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH:20]([CH3:22])[CH3:21])[CH2:15][CH2:16][O:17][CH3:18])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Br
Reactant: COCCNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: COCCN(C(C)C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C

Procedure:
Amine preparation: A mixture of 4-(2-methoxy-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester (see preparation of 121) (300 mg) and 2-bromopropane (1.20 mL) in MeCN (3 mL) with potassium carbonate (192 mg) were heated at 60° C. in a sealed tube for 7 days. The reaction mixture was cooled down, diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to yield 4-[isopropyl-(2-methoxy-ethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as an oil (131 mg). Treatment of this compound with HCl in DCM/MeOH and basic wash with aqueous sodium bicarbonate yielded the desired amine.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=O.[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:25]>C(O)C>[NH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][N:7]=2)[C:3]([CH:1]=[C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[C:17]([S:21]([OH:24])(=[O:22])=[O:23])[CH:16]=3)[NH:12][C:13]2=[O:25])=[CH:4]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: O=C1Cc2cc(S(=O)(=O)O)ccc2N1
Solvent: CCO
Product: O=C1Nc2ccc(S(=O)(=O)O)cc2C1=Cc1c[nH]c2ncccc12
Temperature: 0 °C
Yield: 70 %

Procedure:
A solution of 3-formyl-7-azaindoie (1.46 g, 0.010 mol) and 2-oxindole-5-sulfonic acid (2.55 g, 0.012 mol) in absolute ethanol (10 ml) was heated to reflux for 1 h. The reaction mixture was chilled with ice water, the precipitate filtered, the residue washed with ice-cooled ethanol and dried under vacuum. Almost pure titie compound was obtained in about 70% yield (2.389 g).
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36](O)=[O:37])=[CH:26][CH:25]=1)[CH3:23]>>[CH2:22]([C:24]1[CH:25]=[CH:26][C:27]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:37])=[CH:28][CH:29]=1)[CH3:23]
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Reactant: CCc1ccc(-c2sc(C)nc2C(=O)O)cc1
Product: CCc1ccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)cc1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(4-ethyl-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]2)=[CH:11][CH:10]=1.[NH2:26][C:27]1[CH:36]=[C:35]2[C:30]([CH2:31][CH2:32][C:33](=[O:37])[NH:34]2)=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:26][C:27]3[CH:36]=[C:35]4[C:30]([CH2:31][CH2:32][C:33](=[O:37])[NH:34]4)=[CH:29][CH:28]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: Nc1ccc2c(c1)NC(=O)CC2
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4c(c3)NC(=O)CC4)nn12

Procedure:
Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (0.080 g, 0.21 mmol) and 7-Amino-3,4-dihydro-1H-quinolin-2-one (0.043 g, 0.27 mmol) were reacted in an analogous manner to Example 908D at 50° C. for 16 h. Upon completion, the product was triturated and washed with acetone. LC/MS: 386 (M+H); HPLC: 2.920 minutes, 99% purity, MP: 310-313° C. 1H NMR (400 MHz, CDCl3 , 6, ppm): 8.56 (s, 1H), 7.97 (d, J=8.6 Hz, 1H), 7.65 (dd, J=7.8, 8.3 Hz, 1H), 7.47 (s, 1H), 7.23-7.16 (m, 3H), 7.07 (d, J=8.0 Hz, 1H), 7.02 (s, 1H), 6.96 (d, J=5.9 Hz, 1H), 3.88 (s, 3H), 2.93 (t, 2H), 2.64 (t, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:34])[C:18](=[O:33])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:34])[C:18](=[O:33])[NH:19][N:20]=2)[CH2:11]1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4)c(NC4CNC4)cc3N21
Yield: 65 %

Procedure:
A solution of 3-(4(R)-methyl-3-oxo-7-phenyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (enantiomer 1, SFC (Table 1, Method 1), Rt=3.374 min., 0.281 g, 0.61 mmol) in TFA (4 mL) and DCM (24 mL) was stirred at ambient temperature for 3 h. The solvent was removed in vacuo to give 6-(azetidin-3-ylamino)-4(R)-methyl-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (Example #1-1, Enantiomer 1, SFC (Table 1, Method 1), Rt=4.541 min., 0.192 g, 65%) as yellow solid. LC/MS (Table 1, Method 5) Rt=2.074 min.; MS m/z: 364 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11]CC2C=CC=CC=2)=[C:7]([CH2:19][O:20][CH3:21])[CH:6]=1)=[O:4].[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37]CC2C=CC=CC=2)=[CH:25][CH:24]=1>C1COCC1>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:19][O:20][CH3:21])[CH:6]=2)[OH:4])=[CH:27][CH:28]=1
Reactant: Fc1ccc(CCOCCCCCNCc2ccccc2)cc1
Reactant: COCc1cc(C(=O)CBr)ccc1OCc1ccccc1
Solvent: C1CCOC1
Product: COCc1cc(C(O)CNCCCCCOCCc2ccc(F)cc2)ccc1O
Yield: 49.9 %

Procedure:
A solution of 2-bromo-1-[3-(methoxymethyl)-4-(phenylmethoxy)phenyl]ethanone (1.0 g), N-[5-(2-(4-fluorophenyl)ethoxy]pentyl]benzenemethanamine (0.91 g), and DEA (0.77 g) in THF (15 ml) was left at room temperature for 18 h, filtered and evaporated. The residue was hydrogenated over 10% Pd-C (0.5 g) and 5% Pt-C (0.5 g), filtered and evaporated. The resulting oil was purified by FCC eluting with System C (80:20:1) to give the title compound as a white solid (0.58 g) m.p. 86°-87°, t.l.c. (System C 80:20:1) Rf 0.25.
Reaction SMILES: [C:1](OC)([O:5][CH3:6])([O:3]C)[CH3:2].[CH3:9][C:10]([CH3:14])=[CH:11][CH2:12]O.C1(O)C=CC=CC=1>CO>[CH3:9][C:10]([CH3:14])([CH:11]=[CH2:12])[CH2:2][C:1]([O:5][CH3:6])=[O:3]
Reactant: CC(C)=CCO
Reactant: COC(C)(OC)OC
Solvent: CO
Solvent: Oc1ccccc1
Product: C=CC(C)(C)CC(=O)OC
Yield: 39.9 %

Procedure:
A mixture of trimethyl orthoacetate (120 g; 1 mole), 3-methylbut-2-enol (21.5 g; 0.25 mole) and phenol (1.4 g; 0.015 mole) was placed in a flask equipped with a stirrer and a 10 cm fractionating column packed with Fenske rings. The mixture was heated, with stirring, to a temperature of 95°-110° C. and maintained at this temperature for a period of 2 hours while the methanol formed was collected by distillation. The excess trimethyl orthoacetate was distilled from the reaction mixture over a period of 1 hour during which time the temperature of the reaction mixture was raised to 140°-145° C. The mixture was heated, with stirring, at a temperature of 140°-145° C. for a period of 20 hours and then the product was distilled to give methyl 3,3-dimethylpent-4-enoate (14.2 g; 40%), bp 95°-99° C. at 140 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([NH:17][C:18]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[C:34]([Cl:39])[CH:35]=5)[CH:30]=4)(=[O:28])=[O:27])[CH2:22][CH2:21]3)=[O:19])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.[C:44](OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([N:17]([CH3:44])[C:18]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[C:34]([Cl:39])[CH:35]=5)[CH:30]=4)(=[O:27])=[O:28])[CH2:22][CH2:21]3)=[O:19])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCc2sc(NC(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In N,N-dimethylformamide (10 ml), 1-[N-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbamoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine (147 mg) was dissolved. To the resulting solution, sodium hydride (60% in oil, 22 mg) was added, followed by stirring at room temperature for 30 minutes. After methyl iodide (0.023 ml) was added to the reaction mixture and the resulting mixture was stirred at room temperature for 90 minutes, the residue obtained by the concentration of the reaction mixture under reduced pressure was added with ethyl acetate. The resulting mixture was washed with water and saturated aqueous NaCl solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=2:1), whereby the title compound (43 mg) was obtained.
Reaction SMILES: [C:1]([O:7][C:8]1[C:13](=[O:14])[N:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]2=[N:10][C:9]=1[C:19]([O:21][CH3:22])=[O:20])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1C(=O)N([Br:30])C(=O)C1>C(#N)C.C(O)(=O)C>[Br:30][C:16]1[CH:17]=[CH:18][C:11]2[N:12]([CH:15]=1)[C:13](=[O:14])[C:8]([O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[C:9]([C:19]([O:21][CH3:22])=[O:20])[N:10]=2
Reactant: COC(=O)c1nc2ccccn2c(=O)c1OC(=O)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)c1nc2ccc(Br)cn2c(=O)c1OC(=O)C(C)(C)C
Reaction time: 96 h

Procedure:
Methyl 3-[(pivaloyl)oxy]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylate (see Example 1, Step 2a) and NBS (5 eqs.) were dissolved in a 3:1 mixture of acetonitrile and acetic acid. The solution was left standing at 5° C. with occasional shaking for 4 days. The solvents were removed under reduced pressure and the residue was suspended in chloroform. The precipitate was removed by filtration and the solution concentrated under vacuum. The residue was dissolved in dichloromethane, and triethylamine (7 eqs.) was added. The mixture was stirred for 1.5 hours at room temperature, the solvent removed under vacuum, and the residue partitioned between EtOAc and 1N aqueous HCl. The organic phase was washed with 1N aqueous HCl and the combined aqueous phases extracted with EtOAc. The combined organic phases were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was isolated by flash chromatography (SiO2, eluant: PE/EtOAc, 4.5:5.5). The product was obtained as a light yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].Cl>C1COCC1.O>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(-c2ccccc2)n[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a solution of methyl 3-phenyl-1H-pyrazole-5-carboxylate (6.02 g, 29.8 mmol) in THF and H2O (3:1, 140 mL) was added LiOH (3.42 g, 142.8 mmol) and the mixture was stirred overnight at room temperature. It was poured into 2N HCl solution (150 mL) and extracted with ethyl acetate. After extration, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated at reduced pressure to afford product (3.2 g, 57.1%): MS (EI) for C10H8N2O2: 189.26 (MH+).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25]>>[C:1]([O:20][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CN(C)CCO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN(C)C
Temperature: 150 °C
Reaction time: 4 h

Procedure:
(a″-1) was synthesized by a dehydrating esterification reaction between oleic acid and N-hydroxyethyl-N,N-dimethylamine. Specifically, a four-neck flask equipped with a stirrer, a temperature gage and a dewatering pipe was charged with 132 g of N-hydroxyethyl-N,N-dimethylamine and 400 g of oleic acid and the mixture was raised to 150° C. The mixture was heated under stirring at this temperature for 4 hours while distilling generated water. The resulting mixture was raised to 180° C. and continuously heated with stirring for 10 hours while 66 g of 2-dimethylaminoethanol was added dropwise. After that, the reaction mixture was cooled to 120° C., unreacted amine was distilled under reduced pressure and the reaction mixture was subjected to distillation to obtain 350 g of the target N-oleoyloxyethyl-N,N-dimethylamine (a″-1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21].[NH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[C:28]([NH:30][CH2:31][CH2:32][O:33][CH3:34])=O.C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:22][CH2:23][CH2:24][C:25]2[CH:37]=[CH:36][CH:35]=[C:27]([CH2:28][NH:30][CH2:31][CH2:32][O:33][CH3:34])[CH:26]=2)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21]
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: COCCNC(=O)c1cccc(CCN)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCCNCc1cccc(CCNc2nc(Cl)c(C)n(CC(=O)OCc3ccccc3)c2=O)c1
Temperature: 25 °C
Reaction time: 56 h

Procedure:
Benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (400 mg, 1.22 mmol) [see preparation 17] was added to a solution of 3-(2-aminoethyl)N-(2-methoxyethyl)benzamide (260 mg, 1.25 mmol) (see preparation 41] and triethylamine (0.34 ml, 2.4 mmol) in ethyl acetate (5 ml). The reaction mixture was heated to reflux for 4 hrs, after which time the mixture was cooled to room temperature and stirred for a further 56 hrs, the mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was washed with water (2×20 ml), brine (20 ml) and dried over MgSO4 the solvent was evaporated under reduced pressure. The crude product was purified by trituration with diethyl ether to afford the title compound, 365 mg, (60%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[C:17]([O-])([O-])=O.[K+].[K+]>C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:16]=[CH:17][N:8]([CH2:9][CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1NCCN1CCCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Product: Brc1cnc2c(c1)ncn2CCN1CCCC1

Procedure:
A solution of 470 mg (1.65 mmol) 5-bromo-N2-(2-pyrrolidin-1-yl-ethyl)-pyridine-2,3-diamine in 10 mL formic acid is refluxed for 1.5 h. The mixture is made alkaline with saturated K2CO3 solution and extracted with 40 mL EtOAc. The organic phase is dried over Na2SO4 and the solvent is eliminated i.vac.