Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH2:6])[CH2:3][CH2:2]1.C([O:9][C:10]([C:12]1[S:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])[CH2:19][CH2:18]2)=[N:15][N:16]=1)=O)C>>[CH:1]1([CH2:4][CH2:5][NH:6][C:10]([C:12]2[S:13][C:14]([N:17]3[CH2:18][CH2:19][N:20]([C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH2:21][CH2:22]3)=[N:15][N:16]=2)=[O:9])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Reactant: NCCC1CC1
Product: O=C(NCCC1CC1)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 2-cyclopropylethylamine in place of isoamylamine to react with 5-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl][1,3,4]thiadiazole-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid (0.90 g, 83% yield). 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J=7.8 Hz, 1H), 7.64 (dd, J=7.5, 7.5 Hz, 1H), 7.57 (dd, J=7.5, 7.5 Hz, 1H), 7.35 (d, J=7.5 Hz, 1H), 7.19 (t, J=5.8 Hz, 1H), 4.04-4.10 (m, 1H), 3.86-3.92 (m, 1H), 3.64-3.75 (m, 2H), 3.49-3.56 (m, 4H), 3.33-3.37 (m, 2H), 1.51 (dt, 2H, J=7.0, 7.0 Hz), 0.68-0.75 (m, 1H), 0.46-0.51 (m, 2H), 0.08-0.12 (m, 2H). MS (ES+) m/z 454.2 (M+1).
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:12][CH:13]1[CH2:15][CH2:14]1>>[CH:13]1([CH2:12][S:1][C:2]2[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=2)[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: O=C(O)c1ccc(S)nc1
Product: O=C(O)c1ccc(SCC2CC2)nc1
Yield: 77.3 %

Procedure:
6-[(Cyclopropylmethyl)sulfanyl]pyridine-3-carboxylic acid was prepared from 6-sulfanylpyridine-3-carboxylic acid (0.5 g, 3.22 mmol) and (bromomethyl)cyclopropane (0.44 g, 3.22 mmol) according to the method described for Intermediate 276 to afford the title compound (0.521 g, 61%). Method B HPLC-MS: MH+ requires m/z=210 Found: m/z=210, Rt=1.77 min (79%).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[NH:10][N:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:7]=2)[CH2:3]1.C(N(CC)CC)C.[C:24]1([C:30]2[C:31]([C:39]3[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][CH:40]=3)=[N:32][C:33]3[N:34]([CH:36]=[CH:37][N:38]=3)[CH:35]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.CN(C=O)C>[C:24]1([C:30]2[C:31]([C:39]3[CH:40]=[CH:41][C:42]([CH2:43][N:2]4[CH2:5][CH:4]([C:6]5[N:7]=[C:8]([C:11]6[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=6)[NH:9][N:10]=5)[CH2:3]4)=[CH:45][CH:46]=3)=[N:32][C:33]3[N:34]([CH:36]=[CH:37][N:38]=3)[CH:35]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc(-c2n[nH]c(C3CNC3)n2)nc1
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: c1ccc(-c2cn3ccnc3nc2-c2ccc(CN3CC(c4n[nH]c(-c5ccccn5)n4)C3)cc2)cc1
Yield: 71.5 %

Procedure:
274 mg (1 mmol) 2-(5-azetidine-3-yl-[1,2,4]triazol-3-yl)-pyridine hydrochloride salt were dissolved in 5 mL methanol. After addition of 0.28 mL (2 mmol) triethylamine, 250 mg (0.84 mmol) 4-(6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde dissolved in 5 mL DMF, 0.13 mL (2.20 mmol) acetic acid and 356 mg (1.68 mmol) NaBH(OAc)3, the reaction mixture was stirred at room temperature. Two additional portions of 2 equivalents NaBH(OAc)3 each were added after 1.5 and 3 hours. After 4 hours the solvent was removed by evaporation. Evaporation was repeated after addition of toluene. The residue was purified by chromatography on silica gel (dichloromethane/methanol) to yield 291 mg of the desired product.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[CH3:7][C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1>C(#N)C>[Cl:1][CH2:2][C:3]1[N:14]=[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:7])[N:13]2[CH:5]=1
Reactant: O=C(CCl)CCl
Reactant: Cc1cccc(N)n1
Solvent: CC#N
Product: Cc1cccc2nc(CCl)cn12
Yield: 41.9 %

Procedure:
1,3-Dichloroacetone (17.6 g, 138.3 mmol) was added to a solution of 6-methylpyridin-2-amine (10 g, 92.5 mmol) in acetonitrile (200 ml). The mixture was heated at reflux for 14 h (the reaction was monitored by TLC). The mixture was concentrated under reduced pressure, the residue was diluted with water, and the pH was adjusted to 7.5 with sodium bicarbonate solution. The mixture was extracted with EtOAc, the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 10% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 2-(chloromethyl)-5-methylimidazo[1,2-a]pyridine (7.0 g, 70.7%,) as a pale yellow solid. 1H NMR: 200 MHz, CDCl3: δ 8.15 (s, 1H), 7.6 (dd, 2H), 7.1 (t, 1H), 6.8 (t, 1H), 4.95 (s, 2H), 2.6 (s, 3H). MS: [M+H]+: m/z=181.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@@:8]2([F:24])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21]O)[C:9]2=[O:23])[CH:7]=1.C(Cl)[Cl:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@@:8]2([F:24])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:19])([F:20])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21][Cl:28])[C:9]2=[O:23])[CH:7]=1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(CO)c2cc(C(F)(F)F)ccc21
Reactant: ClCCl
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(CCl)c2cc(C(F)(F)F)ccc21
Reaction time: 0.5 h

Procedure:
To a solution of (S)-3-(5-chloro-2-methoxy-phenyl)-3-fluoro-1-hydroxymethyl-6-trifluoromethyl-1,3-dihydro-indol-2-one ((S)-IV) (64.5 g, 0.166 mol) in CH2Cl2 (700 mL) was added PCI3 (2.0 M in CH2Cl2, 255.0 mL, 0.510 mol) dropwise at 0° C. under N2 over a period of 50 minutes. The resultant mixture was warmed to room temperature and the stirring continued overnight (16 h). The mixture was quenched with ice at 0° C. and the resultant mixture was stirred vigorously for 30 minutes. The organic layer was separated and the aqueous layer was washed with CH2Cl2. The combined organic layer was washed with brine and dried over Na2SO4. Chromatography (silica gel, EtOAc/Hexanes) provided the title compound as a white dry foam (42.0 g, 62% yield). 1H NMR (CDCl3): δ 3.55 (s, 3H), 5.39 (d, J=10.5 Hz, 1H), 5.95 (d, J=11.0 Hz, 1H), 6.76 (dd, J=1.5, 9.0 Hz, 1H), 7.28 (m, 2H), 7.35 (dd, J=1.5, 9.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.78 (dd, J=1.0, 2.5 Hz, 1H).
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.[CH2:15](Br)[C:16]#[CH:17]>>[CH2:17]([N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:1][CH:2]=[CH:3][C:4](=[O:14])[C:5]1=2)[C:16]#[CH:15]
Reactant: C#CCBr
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Product: C#CCn1c2ccccc2c2sccc(=O)c21

Procedure:
By the same method as described in Example 7, 4.8 g of thiopyrano[3,2-b]indol-4(5H)-one is alkylated with propargyl bromide to give 5.0 g of product, mp 144° C. after recrystallization from methylene chloride-ether.
Reaction SMILES: C[S:2][C:3]1[C:8]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C:10]2([CH3:19])[CH3:18])=[CH:7][N:6]=[CH:5][N:4]=1.C[S-].[Na+].Cl>CN(C)C=O>[SH:2][C:3]1[C:8]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C:10]2([CH3:19])[CH3:18])=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: CSc1ncncc1C1c2ccccc2CC1(C)C
Agent: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2ccccc2C1c1cncnc1S
Reaction time: 1.5 h

Procedure:
A mixture of 1.0 g (0.004 mol) of 4-methylthio-5-(2,2-dimethylindan-1-yl)pyrimidine and 1.4 g of sodium methanethiolate in 10 mL of N,N-dimethylformamide was prepared and heated to reflux with stirring for 1.5 hr. The mixture was cooled and was then added to 20 mL of 2N aqueous hydrochloric acid with stirring. The mixture obtained was extracted with 30 mL of ethyl acetate and the resulting organic solution was washed with water and then saturated aqueous sodium chloride. It was then dried over sodium sulfate and concentrated by evaporation under reduced pressure to obtain an oil. The oil was low pressure liquid chromatographed on silica gel eluting first with hexane to remove impurities and then with a 50:50 by volume mixture of ethyl acetate and hexane. The fractions containing the major component of the mixture were concentrated by evaporation under reduced pressure and the oil that was obtain solidified. The resulting 0.66 g (70 percent of theory) solids was the title compound melting at 184°-186° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH3:12])=[N:6][N:5]2[CH:13]=1.[Cl:14][S:15](O)(=[O:17])=[O:16].C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>ClCCCl.O>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH3:12])=[N:6][N:5]2[C:13]=1[S:15]([Cl:14])(=[O:17])=[O:16]
Reactant: CCCc1ccc2nc(Cl)cn2n1
Reactant: O=S(=O)(O)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCCc1ccc2nc(Cl)c(S(=O)(=O)Cl)n2n1
Temperature: 25 °C

Procedure:
2-Chloro-6-n-propylimidazo[1,2-b]pyridazine (5.00 g, 25.6 mmol) was dissolved in 1,2-dichloroethane (30.0 ml), and chlorosulfonic acid (3.40 ml, 51.1 mmol) was added to the solution at room temperature. The mixture was heated for 8.5 hours under reflux, and then cooled to room temperature, and triethylamine (7.84 ml, 56.2 mmol) and phosphorus oxychloride (5.24 ml, 56.2 mmol) were added thereto and heated for 4 hours under reflux. Cold water was added to the reaction mixture which was then extracted with chloroform. The extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrated residues were purified by silica gel column chromatography (ethyl acetate:hexane=3:7) to give the title compound as pale yellow crystals. The yield was 7.40 g (98.4%).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[NH2+]1CCCCC1.[CH:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH3:18].C(O)(=O)CC(O)=O.O>CS(C)=O.N1CCCCC1.C(O)(=O)C.CCOCC>[C:1]([OH:4])(=[O:3])[CH2:2]/[CH:18]=[CH:17]/[CH2:16][CH2:15][CH2:14][C:13]#[C:12][CH3:11]
Reactant: CC#CCCCCC=O
Reactant: CC(=O)[O-]
Agent: C1CC[NH2+]CC1
Agent: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC#CCCC/C=C/CC(=O)O
Yield: 42 %

Procedure:
At room temp., a piperidinium acetate solution, freshly prepared by mixing piperidine (110 μL, 1.10 mmol) and acetic acid (65.0 μL, 1.10 mmol) in dimethyl sulfoxide (5.00 mL), was injected into a stirred solution of the prepared oct-6-ynal (6.70 g, 54.0 mmol) and malonic acid (11.2 g, 108 mmol) in dimethyl sulfoxide (200 mL). After refluxing the reaction mixture for 4 h, water (50 mL) and ether (100 mL) were added at room temp., and the layers were separated. The aqueous layer was extracted with ether (3×100 mL), and the combined organic extracts were washed with water (100 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude material (GC, Δ3:Δ2=70:30) was purified by chromatography on silica gel [200 g; pentane-Et2O (4:1); Rf=0.24 in pentane-Et2O (5:1)] and subsequent Kugelrohr distillation at 160° C./13 mbar to afford (3E)-dec-3-en-8-ynoic acid (3.79 g, 42%) as a colourless crystalline solid (mp, 40-43° C.).
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][N:5]2[C:6](=[O:21])[C@@H:7]([CH2:11][C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][CH:13]=3)[NH:8][C:9](=[O:10])[C@@H:4]2[CH2:3]1.N1C=CN=C1.[C:28]([Si:32](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:31])([CH3:30])[CH3:29]>CN(C)C=O>[Si:32]([O:1][C@H:2]1[CH2:22][N:5]2[C:6](=[O:21])[C@@H:7]([CH2:11][C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][CH:13]=3)[NH:8][C:9](=[O:10])[C@@H:4]2[CH2:3]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1N[C@H](Cc2c[nH]c3ccccc23)C(=O)N2C[C@H](O)C[C@@H]12
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](O[C@@H]1C[C@H]2C(=O)N[C@H](Cc3c[nH]c4ccccc34)C(=O)N2C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of (3R,7R,8aS)-7-hydroxy-3-(1H-indol-3-ylmethyl)-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (2.5 g) in dimethylformamide (30 mL) was added imidazole (1.7 g) and tert-butyl-chloro-diphenylsilane (4.35 mL). The resulting mixture was stirred overnight at room temperature and then partitioned between water and ethyl acetate. The organic layer was dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, EtOAc) to afford (3R,7R,8aS)-7-(tert-butyl-diphenylsilanyloxy)-3-(1H-indol-3-ylmethyl)-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (4.6 g, 99%) (intermediate 7).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18](O)(=[O:21])[CH2:19][CH3:20]>>[C:18]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)(=[O:21])[CH2:19][CH3:20]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CCC(=O)O
Product: CCC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 91.1 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 8 μL (0.1 mMol) 1-propanoic acid, 13.0 mg (91%) of the title compound were recovered.
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([CH:6]=O)[O:3][CH:2]=1.C(O)(=O)[CH2:9][C:10]([OH:12])=[O:11].N1CCCCC1.Cl>N1C=CC=CC=1.O>[O:3]1[CH:2]=[CH:1][CH:5]=[C:4]1[CH:6]=[CH:9][C:10]([OH:12])=[O:11]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccco1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccco1
Temperature: 100 °C
Reaction time: 5 h
Yield: 81.1 %

Procedure:
The mixture of 2-furfural (15 g, 0.15 mol), malonic acid (17.9 g, 0.17 mol) and piperidine(1.5 ml, 0.016 mol) in 80 ml of pyridine was stirred for 5 hours at 100° C. and then refluxed for 20 min, which was cooled down to room temperature and poured into water (180 ml), and resultant mixture was acidified with concentrated HCl. The generated precipitate was collected by filtration and dried under the reduced pressure to give 3-(furan-2-yl)-acrylic acid (16.8 g). 1H NMR (400 MHz, DMSO-d6) ppm 12.44 (brs, 1H), 7.83 (d, J=1.8 Hz, 1H), 7.40 (d, J=15.9 Hz, 1H), 6.93 (d, J=3.3 Hz, 1H), 6.63 (dd, J=1.8, 3.3 Hz, 1H), 6.17 (d, J=15.7 Hz, 1H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]CC.[Na+].Br[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(O)C>[CH2:25]([O:24][C:22]([C:21]1[C:10]2[C:11](=[O:13])[CH2:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][C:9]=2[O:14][CH:20]=1)=[O:23])[CH3:26]
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Reactant: CCOC(=O)C(=O)CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1coc2c1C(=O)CC(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-phenylcyclohexane-1,3-dione (0.94 g) in ethanol (15 ml) was added sodium ethoxide (0.37 g), and the mixture was stirred, under argon atmosphere, at room temperature for 15 minutes. To the mixture was added ethyl bromopyruvate (0.83 ml), and the mixture was stirred, under argon atmosphere, at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added xylene (15 ml), and the mixture was stirred, under argon atmosphere, at 150° C. for 4 hours. The reaction solution was cooled, and to the mixture was added ice-water. The mixture was extracted with ethyl acetate. The upper layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate/hexane to give 3-ethoxycarbonyl-6-phenyl-4,5,6,7-tetrahydrobenzofuran-4-one (1.04 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[O:5][C:6]1[CH:21]=[CH:20][C:9]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)=[O:11])=[CH:8][C:7]=1[NH:22][C:23]1[C:24]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[N:29][C:25]=2[N:26]=[CH:27][N:28]=1.[C:39]([O:43][C:44]([NH:46][CH2:47][C:48](O)=[O:49])=[O:45])([CH3:42])([CH3:41])[CH3:40].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[C:39]([O:43][C:44](=[O:45])[NH:46][CH2:47][C:48](=[O:49])[NH:1][C:2]1[CH:38]=[CH:37][CH:36]=[C:4]([O:5][C:6]2[CH:21]=[CH:20][C:9]([C:10](=[O:11])[NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[CH:8][C:7]=2[NH:22][C:23]2[C:24]3[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[N:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH:3]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4cccc(Br)c4)ccc3Oc3cccc(N)c3)ncnc2n1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4cccc(Br)c4)ccc3Oc3cccc(NC(=O)CNC(=O)OC(C)(C)C)c3)ncnc2n1
Reaction time: 16 h
Yield: 68.8 %

Procedure:
A mixture of the product of Example 109 (0.068 g, 0.1 mmol), tert-Butoxycarbonylamino-acetic acid (0.023 g, 0.13 mmol), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.025 g, 0.13 mmol), 1-Hydroxybenzotriazole hydrate (0.015 g, 0.11 mmol) and N,N-diisopropylethylamine (0.029 g, 0.22 mmol) in N,N-dimethylformamide (2 mL) was stirred for 16 hours, poured into water and extracted with ethyl acetate (3×15 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated under vacuum to provide a residue which was purified by chromatography on silica eluting with 96:4 dichloromethane/methanol to provide the title compound (50 mg, 69%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.31 (d, J=6.62 Hz, 6 H), 1.38 (s, 9 H), 3.13-3.27 (m, 1 H), 3.68 (d, J=5.88 Hz, 2 H), 6.63-6.71 (m, 1 H), 7.04 (t, J=6.43 Hz, 1 H), 7.08 (d, J=8.46 Hz, 1 H), 7.24 (d, J=4.78 Hz, 2 H), 7.26-7.37 (m, 2 H), 7.49 (s, 1 H), 7.58 (d, J=8.46 Hz, 1 H), 7.72-7.79 (m, 1 H), 7.92 (dd, J=8.64, 2.02 Hz, 1 H), 8.11 (s, 1 H), 8.19 (d, J=1.47 Hz, 1), 8.59 (s, 1 H), 8.76 (d, J=8.46 Hz, 1 H), 10.00 (s, 1 H), 10.05 (s, 1 H), 10.39 (s, 1 H).
Reaction SMILES: C(O)(=O)C.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([CH:18]([NH2:20])[NH2:19])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1)=O.C(OCC)(=O)C>CN(C=O)C>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[NH:19][CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=3)[N:20]=2)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(Cl)c3)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20 %

Procedure:
Suspend 4-Diaminomethyl-piperidine-1-carboxylic acid tert-butyl ester acetic acid salt (685 mg; 1.00 equiv; 2.38 mmoles) in dimethylformamide (10 mL; 129.33 mmoles) and add powdered potassium carbonate (1400 mg; 10.13 mmoles). Stir 10 minutes at room temperature then add 2-Bromo-1-(3-chloro-phenyl)-ethanone (1400 mg; 6.00 mmoles) dissolved in 4 mL DMF dropwise to the amidine at room temperature. After 3 h, dilute the reaction with ethyl acetate and wash with 50% aq. sodium bicarbonate. Dry the organic layer over sodium sulfate, filter and concentrate to a crude oil. Purify using ISCO chromatography over a biotage 40M column, eluting with a gradient of DCM to 6% MeOH/DCM. Concentrate the appropriate fractions to give a 20% yield of 4-[4-(3-Chloro-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester. MS (ES): m/z=262.0 [M+H].
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][NH2:13])[CH:10]=2)[C:5]([NH2:14])=[N:4][CH:3]=1.[C:15]([CH:18]1[C:23](=[O:24])[CH2:22][C:21]([CH3:26])([CH3:25])[CH2:20][C:19]1=O)(=O)[CH3:16]>CCO.C(O)(=O)C>[NH2:14][C:5]1[C:6]2[C:11](=[CH:10][C:9]([N:12]3[C:19]4[CH2:20][C:21]([CH3:25])([CH3:26])[CH2:22][C:23](=[O:24])[C:18]=4[C:15]([CH3:16])=[N:13]3)=[CH:8][CH:7]=2)[C:2]([Br:1])=[CH:3][N:4]=1
Reactant: NNc1ccc2c(N)ncc(Br)c2c1
Reactant: CC(=O)C1C(=O)CC(C)(C)CC1=O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nn(-c2ccc3c(N)ncc(Br)c3c2)c2c1C(=O)CC(C)(C)C2
Yield: 80.6 %

Procedure:
A suspension of 4-Bromo-6-hydrazino-isoquinolin-1-ylamine (0.097 g, 0.38 mmol) and 2-acetyl-5,5-dimethyl-1,3-cyclohexanedione (0.074 g, 0.41 mmol) in EtOH/Acetic acid (3:1, 7 mL) is microwaved at 150° C. for 20 min. The solvent is evaporated and the residue is dried under vacuum. Purification of the crude material using a Biotage column (0-10% MeOH/CH2Cl2) afforded 0.1223 g (80%) of 1-(1-Amino-4-bromo-isoquinolin-6-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indazol-4-one. LC/MS m/z=400 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH2:45][CH3:46])=[CH:42][C:43]=2[CH3:44])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH2:45][CH3:46])=[CH:42][C:43]=2[CH3:44])[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CCc1cc(C)c(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnc(CC)cc3C)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(6-ethyl-4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K35) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous red substance (184 mg, 42%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][OH:11].Cl[C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1
Reactant: OCCc1ccc(F)cc1F
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCCc1ccc(F)cc1F)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E11 starting from 2-(2,4-difluorophenyl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:3][CH2:4]2)=[CH:11]1
Reactant: CS(=O)(=O)Cl
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC1CCN(CCc2c[nH]c3ccccc23)CC1
Yield: 105.7 %

Procedure:
To 3-[2-(4-Amino-1-piperidyl)ethyl]indole (1.307 g.) suspended in a solution of triethylamine (2 mls.) in dichloromethane (10 mls.) at room temperature with stirring was added methane sulphonyl chloride (0.570 g.) in dichloromethane (5 mls.). After stirring for 18 hours the solution was washed with water and the organic phase separated, dried and evaporated to yield the title compound (1.690 g.) as an oil. This was recrystallized from ethanolic hydrogen chloride as the hydrochloride salt (0.560 g., m.p. 241°-242° C.).