Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:30])[NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([C:24]4([CH3:29])OCC[O:25]4)[CH2:20][CH2:19]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>O>[C:24]([CH:21]1[CH2:20][CH2:19][CH:18]([NH:17][C:16](=[O:30])[O:15][CH2:14][CH:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:23][CH2:22]1)(=[O:25])[CH3:29]
Reactant: CC1(C2CCC(NC(=O)OCC3c4ccccc4-c4ccccc43)CC2)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)C1CCC(NC(=O)OCC2c3ccccc3-c3ccccc32)CC1

Procedure:
13.10 g (32 mmol) of 9H-fluoren-9-ylmethyl[4-(2-methyl-[1,3]dioxolan-2-yl)cyclohexyl]carbamate (cis/trans mixture) and 1.30 g of p-toluenesulfonic acid are refluxed in 25 mL of water and 500 mL of acetone for 16 hours with stirring. Then the reaction mixture is concentrated by evaporation and the residue is dissolved in ethyl acetate and extracted with water. The organic phase is dried and evaporated to dryness. The residue is extracted with diisopropylether and suction filtered. Yield: 7.77 g (89%) of cis compound; NMR: LH201628.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH:13]=O.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[NH:16][NH2:17]>C(O)C.C(O)(=O)C>[CH2:20]([O:19][C:15](=[O:18])[NH:16][N:17]=[CH:13][C:3]1[N:4]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:6][C:2]=1[CH3:1])[CH3:21]
Reactant: Cc1[nH]c(-c2ccccc2)nc1C=O
Reactant: CCOC(=O)NN
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)NN=Cc1nc(-c2ccccc2)[nH]c1C
Temperature: 0 °C

Procedure:
A mixture of 10.25 gm. of 5-methyl-2-phenyl-4-imidazolecarboxaldehyde and 5.72 gm. of ethyl carbazate in 30 ml. of ethanol containing one drop of acetic acid is boiled for 30 minutes. The mixture is cooled to 0° C. and concentrated under an air stream on a steam bath. A 50 ml. portion of carbon tetrachloride is added and the mixture is cooled to 0° C. overnight. The solid is collected giving the desired product, m.p. 209°-211° C.
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][C:5]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]>CCOCC.C1COCC1>[OH:4][C:5]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH3:3])=[O:8]
Reactant: Cc1ccc(C(=O)O)c(O)n1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)nc1O
Reaction time: 2 h

Procedure:
Excess diazomethane in ether was added portionwise over 15 mins to 9.58 g (~60 mmoles) of 2-hydroxy-6-methyl nicotinic acid in 900 mL of THF at 0°. After stirring 2 hours, excess diazomethane was removed in vacuo. The resulting white solid was filtered and washed with hexane and dried. This fluffy solid was the required methyl ester. The filtrate was concentrated. The resulting solid was redissolved in a minimum amount of THF and hexane was added until no further precipitation was observed. Solid was filtered and washed with hexane and dried to provide more of the desired compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH:47]1([C:52](Cl)=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48]1.C(N(CC)CC)C>O1CCCC1>[CH:47]1([C:52]([NH:46][C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([C:16]5[N:20]=[CH:19][N:18]([C:21]([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)([C:22]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)[C:34]6[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:17]=5)[CH:11]=4)[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=3)[CH:41]=2)=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C(Cl)C1CCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C1CCCC1

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added cyclopentanecarbonyl chloride (0.060 mL, 0.496 mmol), followed by triethyl amine (0.173 mL, 1.24 mmol). Completion of the reaction necessitated the addition of 2 more equivalents of reagents and a total reaction time of 48 hours at room temperature. The reaction mixture was then partitioned between ethyl acetate and water. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 699 [M+H]+.
Reaction SMILES: C(N[C@H](C(O)=O)CC1C=CC(O)=CC=1)(=[O:3])C.C(#N)C.ON1C(=O)CCC1=O.[CH:28]1([N:34]=[C:35]=[N:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(OCC)(=O)C>[C:35]([NH:34][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)([NH:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)=[O:3]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C

Procedure:
N-Acetyl-L-tyrosine (1.68 g, 7.53 mmol) was taken up in 94 mL of ethyl acetate/26 mL of acetonitrile and stirred at room temperature. N-Hydroxysuccinimide (NHS, 0.87 g, 7.56 mmol) was added and the resulting solution cooled to 0° C. under N2 (g) in an ice-water bath. To the cold, stirring solution was then added dicyclohexylcarbodiimide (DCC, 1.55 g, 7.52 mmol) predissolved in 3 mL of ethyl acetate. The reaction mixture was stirred at 0° C. for 2 hours and then allowed to warm to room temperature overnight with continued stirring. The insoluble dicyclohexylurea (DCU) was removed by filtration and the resulting filtrate concentrated to a solid residue under reduced pressure. Trituration of this residue with warm ethyl acetate and subsequent storage at 4° C. then afforded a white solid. This was isolated by vacuum filtration, washed with cold ethyl acetate and dried in vacuo to yield the product in greater than theoretical yield (due to contamination with residual DCU). 1H-NMR (300 MHz, CDCl3): δ 2.00 (s, 3H); 2.87 (s, 4H); 3.22 (m, 2H); 4.05 (m, 1H); 5.80 (d, 1H, J=7.2 Hz); 6.96 (AB quartet, 4H, J=8.4 Hz).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].I[CH3:12].O>CN(C=O)C>[Br:1][C:2]1[C:7]([O:8][CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CI
Reactant: Oc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccnc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To a solution of 2-bromo-pyridin-3-ol (10.0 g, 57.8 mmol) in DMF (100 ml) was added NaH (4.2 g, 110 mmol) at 0° C. and the reaction mixture was stirred at 0° C. for 0.5 h. Then iodomethane (4.0 mL, 64 mmol) was added dropwise at 0° C. and the resulting solution was stirred at ambient temperature for 2 h. The mixture was poured into water. The organic layer was separated. The aqueous phase was extracted with EtOAc (80×3 mL). The combined organic layers were dried over anhydrous Na2SO4 and distilled under reduced pressure to give a residue, which was purified by chromatography on silica gel (5% ethyl acetate in petroleum ether) to give 2-bromo-3-methoxypyridine (7.0 g, 65%). 1H NMR (400 MHz, CDCl3) δ 7.99 (dd, J=4.8, 1.6, 1H), 7.23 (dd, J=8.0, 4.8, 1H), 7.16 (d, 1H, J=4.8, 1.6), 3.92 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.C(N)(=O)C.C(O[CH:21]1[O:38][CH2:37][C@@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]1[O:23][C:24](=[O:26])[CH3:25])(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)(=O)C.C(#N)C>[Br:1][C:2]1[N:3]([C@@H:37]2[O:38][CH2:21][C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:32]2[O:33][C:34](=[O:36])[CH3:35])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)OC1OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Clc1cc2nc(Br)[nH]c2cc1Cl
Agent: CC(N)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Reaction time: 1.5 h
Yield: 25.5 %

Procedure:
2-Bromo-5,6-dichlorobenzimidazole (0.25 g, 0.94 mmol), N,O-bis(trimethylsiyl) acetamide (Aldrich, 1.4 ml, 5.6 mmol), and acetonitrile (Aldrich Sure Seal, 20 ml) were combined and magnetically stirred under a nitrogen atmosphere for 1.5 h. To the silylated base was added 0.30 g (0.94 mmol) 1,2,3,4-tetra-O-acetyl-xylopyranose (Aldrich, Milwaukee) followed by stannic chloride (1.4 mmol, 0.12 ml, Aldrich, Milwaukee). The solution stirred under nitrogen overnight, and additional stannic chloride (0.35 ml, 4.1 mmol) was added the following day. One hour after the second addition of stannic chloride, the reaction was poured into saturated aqueous sodium sulfate, and filtered through a celite pad which was washed with chloroform and water. The filtrate layers were separated. The chloroform layer was washed with 2×150 ml saturated aq. sodium bicarbonate then with 1×150 ml of water. The organic layer was dried with magnesium sulfate (anhyd), filtered, and evaporated. The crude residue was purified on a silica gel column (2.5×20 cm, 230-400 mesh) with hexanes and a step gradient from 0 to 25% ethyl acetate to give the product, 2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-beta-D-xylopyranosyl)-1H-benzimidazole (0.13 g, 0.24 mmol, 26%); 1H NMR (DMSO-d6) δ8.47-8.42 (bs,1H), 7.91 (s, 1H), 6.07-6.02 (bs, 1H), 5.66-5.54 (bs, 3H), 4.18-4.13 (m, 1H), 3.95-3.89 (m, 2H), 2.02 (s, 3H), 1.99 (s, 3H), 1.77 (bs, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][N:5]=[CH:4][N:3]=1.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=1.[H-].[Na+]>CC(N(C)C)=O>[F:15][C:16]([F:25])([F:26])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:22][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:6][N:5]=[CH:4][N:3]=2)=[CH:19][CH:18]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: Clc1ncncc1Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1ccc(COc2ncncc2Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
To a solution of 4-chloro-5-phenoxypyrimidine (0.4 g, 1.9 mmol) described in JP-A-49-92080 and 4-trifluoromethylbenzylalcohol (0.36 g, 2.0 mmol) in dimethylacetamide (7 m) was added sodium hydride (0.093 g, 2.3 mmol) at 0° C., and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4-(4-trifluoromethylbenzyloxy)-5-phenoxypyrimidine (0.60 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc([N+](=O)[O-])cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-Nitro-indole-1-carboxylic acid t-butyl ester (1 eq) was dissolved in methanol (0.1M), to this solution was added palladium on carbon (0.1 eq) in methanol under nitrogen. A hydrogen atmosphere was then inserted and resulting mixture allowed to stir for 3 hours at room temperature. The reaction mixture was then filtered through celite and solvent removed in vacuo to afford 6-Amino-2,3-dihydro-indole-1-carboxylic acid t-butyl ester as a white solid. MS: MH+ 235
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]2[C:4](O)([CH:5]3[CH2:13][CH2:12][CH2:11][CH:6]3[NH:7]2)[C:3]=1[F:15].C(=O)([O-])O.[Na+]>ClCCl.FC(F)(F)C(O)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][CH2:13][C:5]=3[C:4]=2[C:3]=1[F:15]
Reactant: OC12C(F)=C(F)C=CC1NC1CCCC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc2[nH]c3c(c2c1F)CCC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.6 %

Procedure:
A stirred solution of 7,8-difluoro-1,2,3,3a,4,8a-hexahydro-8a-hydroxy-cyclopent[b]indole (1.1 g, 5.2 mmol), in dichloromethane (150 mL) was cooled to 0° C. Trifluoroacetic acid (20 drops) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured onto saturated sodium hydrogen carbonate solution (20 mL) and extracted with dichloromethane (3×50 mL). The organic extracts were combined, dried (magnesium sulfate), filtered, concentrated in vacuo and purified by column chromatography [SiO2; ethyl acetate-heptane (1:5)]to give the product (0.78 g, 78%) as a white crystalline solid. IR νmax (Nujol)/cm−1 3467, 2925, 2854, 1565, 1515, 1450, 1348, 1327, 1244, 1053, 1025, 977, 857, 783, 630 and 516; NMR δH (400 MHz, CDCl3) 2.49-2.58 (2H, m), 2.79-2.87 (2H, m), 2.9-2.96 (2H, m), 6.81-6.95 (2H, m), and 7.83 (1H), br s).
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9])[CH:5]([CH3:7])[CH3:6].C(N(CC)CC)C.[C:30](Cl)(=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([C:30]([NH:3][C@@H:4]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)[CH2:12][CH2:11]2)=[O:9])[CH:5]([CH3:6])[CH3:7])=[O:39])=[CH:32][CH:33]=1
Reactant: CC(C)[C@@H](N)C(=O)N1CCC(C2CCN(C)CC2)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N[C@@H](C(=O)N2CCC(C3CCN(C)CC3)CC2)C(C)C)cc1
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
1-D-Valinyl-4-(1-methylpiperidin-4-yl)piperidine dihydrochloride (15.6 g, 44.1 mmol) is slurried in anhydrous CH2Cl2 (400 mL); and to the slurry is added triethylamine (19.7 mL, 141.0 mmol), followed by p-anisoyl chloride (7.9 mL, 52.9 mmol). The reaction is allowed to stir for about 30 min and then quenched with the addition of saturated NaHCO3 (300 mL), followed by the separation of the phases. The organic layer is washed with saturated NaHCO3 (2×300 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by chromatography over silica gel, eluting with 2.5% (2 M NH3 in MeOH)/CHCl3 to give 16.3 g (89%) of the title compound as a white foam.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].C(N(CC)CC)C.Cl.[N:40]12[CH2:48][C:44]([CH2:49][NH:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([CH2:45][CH2:46][CH2:47]1)[CH2:43][CH2:42][CH2:41]2>C(Cl)Cl>[N:40]12[CH2:48][C:44]([CH2:49][N:50]([CH:18]=[C:17]3[C:16]4[C:15]([CH3:30])([C:14]5[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]6([CH3:31])[CH:8]([C:13]=5[C:21](=[O:22])[C:20]=4[OH:19])[CH2:9][CH2:10][CH:11]6[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]3=[O:24])[CH2:51][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)([CH2:43][CH2:42][CH2:41]1)[CH2:45][CH2:46][CH2:47]2
Reactant: c1ccc(CNCC23CCCN(CCC2)C3)cc1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN(Cc2ccccc2)CC23CCCN(CCC2)C3)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin and triethylamine (65 μL, 0.46 mmol) in 2 mL CH2Cl2 is added (1-aza-bicyclo[3.3.1]non-5-ylmethyl)-benzyl-amine hydrochloride (114 mg). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 676 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:20])[C:11]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[N:7]=1.C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>ClC(Cl)C>[F:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([F:19])[C:12]=1[C:11]1[C:10](=[O:20])[CH:9]=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:29]=1[F:28])=[N:7]2
Reactant: Nc1ccc2c(-c3c(F)cccc3F)c(=O)ccn2n1
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: O=C(Nc1ccc2c(-c3c(F)cccc3F)c(=O)ccn2n1)c1ccc(F)cc1F
Temperature: 80 °C

Procedure:
To a solution of 2-amino-5-(2,6-difluorophenyl)-6H-pyrido[1,2-b]pyridazin-6-one (50 mg, 0.18 mmol) dissolved in dichloroethane (2 mL) was added triethyl amine (0.079 mL, 0.55 mmol) and 2,4-difluorobenzoyl chloride (49 mg, 0.28 mmol). The mixture was heated to 80° C. for 2 hrs until no further progress was observed. Concentrated reaction to an oil and the crude residue was purified via silica gel chromatography (CH2Cl2/MeOH) to yield the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[C:5]2[N:15]([CH2:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]3)[C:16]([CH:18]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH3:19])=[N:17][C:4]=2[CH:3]=1.[CH3:35][N:36](C=O)C>[C-]#N.[Zn+2].[C-]#N>[Cl:14][C:12]1[CH:13]=[C:8]([C:6]2[C:5]3[N:15]([CH2:27][C@H:28]4[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]4)[C:16]([CH:18]([C:20]4[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=4)[CH3:19])=[N:17][C:4]=3[CH:3]=[C:2]([C:35]#[N:36])[N:7]=2)[CH:9]=[N:10][CH:11]=1
Reactant: CC(c1ncccc1F)c1nc2cc(Cl)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(c1ncccc1F)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 140 °C

Procedure:
To a stirred solution of 6-chloro-4-(5-chloropyridin-3-yl)-2-[1-(3-fluoropyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (400 mg, 0.80 mmol) in DMF (16 mL) was added zinc cyanide (37.7 mg, 0.32 mmol), and the reaction was deoxygenated by purging with nitrogen for 10 minutes. 1,1-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (65.5 mg, 0.08 mmol) was added, and the reaction mixture was again deoxygenated for 5 minutes. The reaction was heated to 140° C. for 5 h under a nitrogen atmosphere. The reaction was then cooled to room temperature, diluted with water (25 mL), and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with water (1×25 mL) and brine (1×25 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chormatography (eluting with 35% EtOAc/petroleum ether) to yield 4-(5-chloropyridin-3-yl)-2-[1-(3-fluoropyridin-2-yl)ethyl]-3[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ES/APCI calcd. for C27H26ClFN6 [M+H]+ 489. found 489.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[O:37][CH3:38].CN(C)C=O>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=4[O:37][CH3:38])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCN(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 90 °C
Yield: 106.6 %

Procedure:
A stirred mixture of 6-fluoro-3-(1-piperazinyl)-1H-indazole (2.3 g, 100 mmol), K2CO3 (1.5 g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (2.8 g, 11 mmol), several crystals of KI and dimethylformamide (60 ml) was heated at 90° C. for 16 hours. The reaction was poured into H2O, and the aqueous suspension was extracted with ethyl acetate. The ethyl acetate was washed (H2O), dried (MgSO4) and concentrated to afford 5.0 g of a yellow oil. The oil was chromatographed on a Waters Prep 500 utilizing silica gel columns and eluting with methylene chloride/methanol (7%). Concentration of the desired fractions yielded 2.0 g (46%) of an off-white solid. This sample was combined with 1.0 g of a previous sample, and this was recrystallized from toluene to afford 2.6 g of 1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]-propoxy]-3-methoxyphenyllethanone as a white solid, m.p.=135°-137° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([OH:16])=O)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:16])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCCc1ccccc1
Reactant: C1CCNC1
Solvent: ClCCl
Product: O=C([C@@H]1CCCN1C(=O)CCCc1ccccc1)N1CCCC1
Temperature: 25 °C

Procedure:
When the reaction was over, the mixture was extracted twice with ethyl ether to remove the unreacted acid chloride. The water phase was acidified by addition of hydrochloric acid. The resulting precipitate was extracted three times with ethyl acetate and the solvent was removed under vacuum, whereby N-(γ-phenyl)butyryl-L-proline was obtained. N-(γ-phenyl)butyryl-L-proline (1 equivalent) was then dissolved in dry methylene chloride (ca. 100 ml) together with pyrrolidine (1 equivalent), WSCD (1 equivalent) was added thereto and the mixture was continuously stirred at room temperature for one whole day and night. After the reaction, the product was washed successively with 1N hydrochloric acid, brine, saturated sodium bicarbonate and brine in that order and was then dried over anhydrous magnesium sulfate. The solvent was distilled off under vacuum and the residue was purified by column chromatography on silica gel, whereby the titled compound was obtained.
Reaction SMILES: CO[CH2:3][N:4]([CH2:12][Si](C)(C)C)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:17]1([O:22][C:23]2[CH:24]=[C:25](/[CH:31]=[CH:32]/[C:33]([O:35][CH3:36])=[O:34])[CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:21][CH2:20][CH2:19][CH2:18]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:17]1([O:22][C:23]2[CH:24]=[C:25]([C@H:31]3[C@H:32]([C:33]([O:35][CH3:36])=[O:34])[CH2:3][N:4]([CH2:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:12]3)[CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)/C=C/c1ccc(OC)c(OC2CCCC2)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Reaction time: 12 h
Yield: 85.5 %

Procedure:
To a solution of N-methoxymethyl-N-(phenylmethyl)trimethylsilylmethylamine (2.84 g, 12 mmol) and (E)-methyl 3-(3-cyclopentoxy-4-methoxyphenyl)prop-2-enoate (2.76 g, 10 mmol) in 20 mL of CH2Cl2 cooled to 0° C. was added a 1 mL of a 1M solution of trifluoroacetic acid. Stirring was continued for 12 hr, and the solution was partitioned between ether and sat. NaHCO3. The layers were separated and the aqueous layer was extracted ethyl acetate (2×). The combined organic layers were dried (K2CO3), filtered, and concentrated under reduced pressure to a pale yellow oil. Chromatography on silica gel (3:1, hexanes:ethyl acetate) provided trans-3-(3-cyclopentoxy-4-methoxyphenyl)-4-methoxycarbonyl-1-(phenylmethyl)pyrrolidine (3.5 g, 86%) as a colorless oil. 1H-NMR (300 MHz): δ 2.74-3.09 (m, 5), 3.67 (s, 3), 3.81 (s, 3), 4.75 (m, 1).