Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11]1.[C:25]([O:29][C:30]([NH:32][C@@H:33]([CH3:37])[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:25]([O:29][C:30]([NH:32][C@@H:33]([CH3:37])[C:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:11]1)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)C(=O)OCCN1CCC[C@H](Nc2cc(F)ccc2N)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1N[C@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Temperature: 0 °C
Yield: 93 %

Procedure:
To an ice-cooled mixture of 2,2-dimethylpropionic acid 2-[(S)-3-(2-amino-5-fluorophenylamino)piperidin-1-yl]ethyl ester (1.464 g, 4.34 mmol), (S)-2-tert-butoxycarbonylaminopropionic acid (0.904 g, 4.77 mmol) and HOAt (0.591 g, 4.34 mmol) in DCM (40 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.0 g, 5.21 mmol) portion wise over 10 min. The reaction mixture was stirred in the ice bath for 2 h, then diluted with DCM, washed with 2M Na2CO3 then water. The organic fractions were dried (Na2SO4) then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 40-70% EtOAc in cyclohexane) affording the title compound as a dark red gum (2.054 g, 93%). LCMS (Method B): RT 2.46 min [M+H]+ 509.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22]Br)([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[CH:26]2[CH:30]=[CH:31][CH2:32][CH2:33][CH:25]12.[Na]>CN(C)C=O>[C:24]1(=[O:34])[N:28]([CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22][N:28]2[C:27](=[O:29])[CH:26]3[CH:30]=[CH:31][CH2:32][CH2:33][CH:25]3[C:24]2=[O:34])([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:27](=[O:29])[CH:26]2[CH:30]=[CH:31][CH2:32][CH2:33][CH:25]12
Reactant: O=C1NC(=O)C2CCC=CC12
Reactant: O=C(c1ccccc1)C(OCCBr)(OCCBr)c1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1C2C=CCCC2C(=O)N1CCOC(OCCN1C(=O)C2C=CCCC2C1=O)(C(=O)c1ccccc1)c1ccccc1
Yield: 87.6 %

Procedure:
Benzil-di-(β-bromoethyl)ketal (13.26 g) and 11.42 g of sodium 1,2,5,6-tetrahydrophthalimide were dissolved in 100 ml of N,N-dimethylformamide, and reacted and worked up in the same way as in Example 4. There was obtained 15.3 g (yield 85.9%) of benzil-di-(β-1,2,5,6-tetrahydrophthalimidoethyl)ketal.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:17][CH2:16][N:15]3[C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][N:20]=[C:14]3[CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7](Cl)[C:6]=12.[NH3:25].CC(O)C>>[Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:17][CH2:16][N:15]3[C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][N:20]=[C:14]3[CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:25])[C:6]=12
Reactant: N
Reactant: FC(F)(F)c1nnc2n1CCC(c1nc(Br)c3c(Cl)nccn13)C2
Solvent: CC(C)O
Product: Nc1nccn2c(C3CCn4c(nnc4C(F)(F)F)C3)nc(Br)c12
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 7-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine (335 mg, 0.978 mmol) in NH3-iPrOH (50 mL) was heated at 100° C. for 24 hours in a sealed tube. The reaction was completed by LC-MS, then cooled to room temperature. Remove the solvent in vacuo to give 1-bromo-3-(3-(trifluoro methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)imidazo[1,5-a]pyrazin-8-amine as a yellow solid (0.39 g, yield 99%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=O)[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH2:31][CH3:32]>CC(C)=O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][N:13]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[CH2:30][CH2:31][CH3:32])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(CCNC(=O)Cc2cccc(OC)c2)c1
Reactant: CCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCN(CCc1cccc(OC)c1)CCc1cccc(OC)c1
Yield: 97.3 %

Procedure:
A suspension of 8.75 g of the product of Step A, 17.5 g of calcined neutral potassium carbonate, 17.5 g of propyl iodide and 180 ml of acetone was refluxed for 61/2 hours under nitrogen and the mixture was then filtered. The filtrate was evaporated to dryness and the residue was taken up in ether. The ether solution was washed with water, dried and evaporated to dryness to obtain 8.3 g of 3-methoxy-N-[2-(3-methoxyphenyl)-ethyl]-N-propyl-benzene-ethanamine which was used as is for the next step.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7](O)=[O:8].C(Cl)(=O)C([Cl:14])=O>C1COCC1.CN(C=O)C>[ClH:14].[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7]([Cl:1])=[O:8]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)C/C=C/C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
A well stirred suspension of 4-dimethylaminocrotonic acid hydrochloride (5.0 g, 30 mmol) in cold (0° C.) THF (40 mL) and DMF (2 pipet drops) is treated with oxalyl chloride (3.15 mL, 36 mmol). Stirring at 20–25° C. for 3 hours is followed by cooling to 0° C. and holding for 30 minutes. Solids are collected on a Buchner funnel (under a blanket of nitrogen) and the cake is washed with cold (0° C.) THF (3×5 mL). The solid is dried under vacuum (˜1 torr) at 40–50° C. for 3 hours to give 4.0 g of 4-dimethylaminocrotonoyl chloride hydrochloride. This material is characterized as its methyl ester by treatment of the solid with methanol.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]([CH:10]2[CH2:12][CH2:11]2)[CH2:8][CH3:9])=[C:4]([CH3:15])[CH:3]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:10]1([N:7]([CH2:8][CH3:9])[CH2:6][C:5]2[CH:13]=[CH:14][C:2]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[CH:3][C:4]=2[CH3:15])[CH2:12][CH2:11]1
Reactant: CCN(Cc1ccc(Br)cc1C)C1CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCN(Cc1ccc(C#C[Si](C)(C)C)cc1C)C1CC1
Temperature: 70 °C
Yield: 98.6 %

Procedure:
Using General Procedure D; (4-bromo-2-methyl-benzyl)-cyclopropyl-ethyl-amine (Intermediate 159, 620.0 mg, 2.31 mmols) in triethylamine (8 mL) was treated with copper(I)iodide (44.0 mg, 0.23 mmol) and then sparged with argon for 15 minutes. Trimethylsilylacetylene (1.04 g, 10.6 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (162.0 mg, 0.23 mmol). The resulting reaction mixture was heated to 70° C. for 5 days. The title compound (650.0 mg, 98%) was isolated by chromatography (1-4% EtOAc-hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([F:29])=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26](O)=[O:27])=[CH:21][CH:20]=[CH:19]2.S(Cl)([Cl:32])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([F:29])=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([Cl:32])=[O:27])=[CH:21][CH:20]=[CH:19]2
Reactant: O=S(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc4c(C(=O)O)cccc4c3F)c2cc1OC
Product: COc1cc2nccc(Oc3ccc4c(C(=O)Cl)cccc4c3F)c2cc1OC

Procedure:
A suspension of 6-(6,7-dimethoxyquinolin-4-yloxy)-5-fluoro-1-naphthoic acid (1.23 g, 3.12 mmol) in thionyl chloride (3 mL, excess) was refluxed for 1.5 h. The reaction mixture was concentrated in-vacuo and azeotroped with toluene (×2) to give the title compound as a brown solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[C:13]([C:25]#[C:26][CH:27]2[CH2:29][CH2:28]2)([C:21]([F:24])([F:23])[F:22])[O:12][C:11]1=[O:30])(C)(C)C.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[NH2:7][CH2:8][CH2:9][N:10]1[C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[C:13]([C:25]#[C:26][CH:27]2[CH2:29][CH2:28]2)([C:21]([F:22])([F:24])[F:23])[O:12][C:11]1=[O:30]
Reactant: CC(C)(C)OC(=O)NCCN1C(=O)OC(C#CC2CC2)(C(F)(F)F)c2cc(Cl)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCN1C(=O)OC(C#CC2CC2)(C(F)(F)F)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2.5 mg of 7 was added 500 μL of dichloromethane and 500 μL of trifluoroacetic acid. The mixture was allowed to stir at room temperature for 30 minutes and concentrated under reduced pressure to give 3 mg of 8 as a thick oil (M+H, 359).
Reaction SMILES: [Cl:1][C:2]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([N+:17]([O-:19])=[O:18])=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][OH:9])=[O:5].[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([N+:17]([O-:19])=[O:18])=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][O:9][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][O:20]1)=[O:5]
Reactant: C1=COCCC1
Reactant: O=C(NCCO)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=C(NCCOC1CCCCO1)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 12b (0.6 g, 2.14 mmol) in CH2Cl2 was cooled in an ice-bath, and 3,4-dihydro-2H-pyran (2.0 mL) and p-toluenesulfonic acid (0.1 g) were added. The reaction mixture was stirred for 2 h, then concentrated under reduced pressure. Chromatography of the residue on silica gel, eluting with EtOAc/petroleum ether (from 1:2 to 2:1), gave 2-chloro-3,5-dinitro-N-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]benzamide (12c) (0.8 g, 100%): as an oil;
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[N:13][C:14]([Br:17])=[CH:15][CH:16]=1)(C)(C)C.[ClH:19]>C(O)C.C(OCC)(=O)C>[ClH:19].[ClH:19].[Br:17][C:14]1[N:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][NH2:7])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(Br)nc1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: NCCOc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of tert-butyl(2-((6-bromopyridin-3-yl)oxy)ethyl)carbamate obtained in Reference Example 4 (1.20 g) in ethanol (25 mL) was added a 4M solution of hydrogen chloride in ethyl acetate (10 mL) at room temperature. The mixture was stirred at room temperature for 3 days, and the solvent was evaporated under reduced pressure. To the residue was added ethanol, the solvent was evaporated under reduced pressure, and the precipitated solid was collected by filtration to give the title compound (1.09 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]1[C:12](=[O:28])[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH:15]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[C:5]2=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]1[C:12](=[O:28])[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:14]=[C:15]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[C:5]2=1
Reactant: CN(C)C(=O)C1CN(Cc2ccccc2)C(=O)c2c1c1cc(F)ccc1n2C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: CN(C)C(=O)c1cn(Cc2ccccc2)c(=O)c2c1c1cc(F)ccc1n2C
Yield: 52 %

Procedure:
A solution of 2 g (5 mmol) of (±)-6-fluoro-N,N,9-trimethyl-1-oxo-2-(phenylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxamide and of 1.6 g (7 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 250 ml of dichloromethane is stirred for 1 h. The organic phase is washed and dried over sodium sulphate. The solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ethyl acetate. The product is crystallized from diethyl ether. 1 g (2.6 mmol) of product is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[C:22]([CH3:39])[CH:21]=4)[CH:18]=3)[N:13]([S:40]([C:43]3[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[CH:12]=2)[CH:8]=[N:7]1.CO.[ClH:55]>O1CCOCC1>[ClH:55].[F:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[C:22]([CH3:39])[CH:21]=4)[CH:18]=3)[N:13]([S:40]([C:43]3[CH:44]=[CH:45][C:46]([CH3:47])=[CH:48][CH:49]=3)(=[O:41])=[O:42])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)c(C)c4)cnc32)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)c(C)c4)cnc32)cc1
Yield: 95.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methylphenyl)piperazine-1-carboxylate (210 mg, 0.291 mmol) was deprotected in methanol/HCl in dioxane (5/10 ml) to afford 172 mg (95.5% yield) of the titled compound. MS: m/z=621.3 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH:6]([OH:7])[CH2:5][CH:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[CH:3]1[CH2:19][CH2:20][CH:21]([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[OH-].[Na+]>C(O)C>[OH:1][CH:2]1[CH:6]([OH:7])[CH2:5][CH:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:3]1[CH2:19][CH2:20][CH:21]([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCC(O)CCC1C(CCCCCCC(=O)OCC)CC(O)C1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC(O)CCC1C(CCCCCCC(=O)O)CC(O)C1O
Yield: 45.6 %

Procedure:
Ethyl 7-[3,4-dihydroxy-2-(3-hydroxyoctyl)-cyclopentyl]heptanoate (2.6 g.) [prepared as described in (p) above], ethanol (50 ml.) and 2N aqueous sodium hydroxide solution (50 ml.) were heated together at reflux for 18 hours. The ethanol was removed in vacuo, water (25 ml.) was added and the mixture was washed with diethyl ether. The aqueous phase {which was a solution of sodium 7-[3,4-dihydroxy-2-(3-hydroxyoctyl)cyclopentyl]heptanoate} was acidified to pH 1 by the dropwise addition of concentrated hydrochloric acid, extracted with diethyl ether, and the ethereal extract dried over magnesium sulphate and evaporated in vacuo to give 7-[3,4-dihydroxy-2-(3-hydroxyoctyl)cyclopentyl]heptanoic acid (1.1 g.). Elemental analysis: found: C, 67.2; H, 10.3%. C20H38O5 requires C, 67.0; H, 10.7%.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15]CC(C)(C)N=3)=[C:10]([CH2:21][CH2:22][CH3:23])[CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:26])C>>[C:2]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:15])=[O:26])=[C:10]([CH2:21][CH2:22][CH3:23])[CH:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: CCCc1cc(-c2ccccc2)ccc1C1=NC(C)(C)CO1
Agent: Cl
Product: CCCc1cc(-c2ccccc2)ccc1C(=O)O

Procedure:
To a mixture of conc. hydrochloric acid (30 ml) and glacial acetic acid (10 ml) is added 2-(4-phenyl-2-n-propylphenyl)-4,4-dimethyl-2-oxazoline (2.70 g), and the mixture is refluxed for three days (nine hours×3). The reaction solution is concentrated to about half volume thereof under reduced pressure, and cooled over an ice-bath. The precipitated crystals are collected by filtration, and purified by silica gel column chromatography (solvent; dichloromethane→dichloromethane:methanol=50:1). The desired fractions are combined, evaporated to remove the solvent, and the crystalline residue is recrystallized from n-hexane to give 4-phenyl-2-n-propylbenzoic acid (1.67 g) as colorless needles.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>C1COCC1>[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH:41][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([S:16]([N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:8]3)(=[O:17])=[O:18])=[CH:20][CH:21]=2)=[CH:38][CH:37]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Reactant: NCc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Reaction time: 1 h
Yield: 75.8 %

Procedure:
In a 100 ml RBF combine 4-(3-phenyl-indole-1-sulfonyl)-benzoic acid (2.5 g, 6.62 mmol) and THF (25 ml). Cool the solution in an ice water bath and add 4-methylmorpholine (0.73 ml, 7.29 mmol) follow by the portion wise addition of CDMT (1.16 g, 7.29 mmol). Stir the solution in an ice water bath for one hour. Add dropwise, a solution of 4-fluorobenzylamine (0.83 ml, 7.29 mmol) in THF (8 μl) to the reaction at 0° C. Stir the solution at 0° C. for five hours, and quench with 1N HCl (50 ml). Extract the reaction MTBE (2×50 ml), filter and wash with saturated aqueous sodium chloride (50 ml). Dry the organics over magnesium sulfate, filter and concentrate to give N-(4-fluoro-benzyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide (2.43 g) as a white solid. HPLC=95.5%, MS (ESI) m/z observed 485.1334 calculated 485.1335 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:17][CH2:18][CH2:19][OH:20])=[CH:6][C:7]([F:16])=[C:8]([CH:10]([O:14][CH3:15])[C:11]([OH:13])=O)[CH:9]=1)[CH3:2].[NH2:21][CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[C:22]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:11](=[O:13])[CH:10]([C:8]2[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[C:5]([O:17][CH2:18][CH2:19][OH:20])=[CH:6][C:7]=2[F:16])[O:14][CH3:15])=[CH:25][CH:24]=1)#[N:21]
Reactant: CCOc1cc(C(OC)C(=O)O)c(F)cc1OCCO
Reactant: N#Cc1ccc(CN)cc1
Product: CCOc1cc(C(OC)C(=O)NCc2ccc(C#N)cc2)c(F)cc1OCCO

Procedure:
(RS)-[5-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-2-methoxy-acetamide. Light yellow oil. MS 403.4 ([M+H]+)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[CH:21][CH:20]=4)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[CH2:40]([S:44](Cl)(=[O:46])=[O:45])[CH2:41][CH2:42][CH3:43]>ClCCl>[N:28]1([CH2:27][CH2:26][O:25][C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:16]3[N:17]=[C:13]4[CH:12]=[CH:11][CH:10]=[C:9]([C:5]5[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=5)[CH2:2][NH:1][S:44]([CH2:40][CH2:41][CH2:42][CH3:43])(=[O:46])=[O:45])[N:14]4[N:15]=3)=[CH:20][CH:21]=2)[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: NCc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Reactant: CCCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)NCc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of [5-(3-aminomethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.03 g, 0.070 mmol) in dichloromethane (1 ml) was added triethylamine (13 μl, 0.091 mmol) followed by butanesulfonyl chloride (11 μl, 0.084 mmol). The mixture was stirred for 18 hours at room temperature, then filtered and concentrated in vacuo. The product was purified by preparatory HPLC to provide the desired product. LCMS RT: 2.66 min, MI: 549, Method: 2; 1H NMR (DMSO, 300 MHz): 9.43 (s, 1H), 8.18 (s, 1H), 8.03 (d, 1H), 7.65 (m, 6H), 7.16 (d, 1H), 6.90 (d, 2H), 4.27 (d, 2H), 4.05 (t, 2H), 2.93 (t, 2H), 2.70 (s, 4H), 2.45 (dd, 2H), 1.74 (s, 4H), 1.59 (m, 2H), 1.28 (m, 2H), 0.82 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([OH:26])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34].C1(N=C=NC2CCCCC2)CCCCC1>COCCOC>[O:34]=[C:29]1[CH2:30][CH2:31][C:32](=[O:33])[N:28]1[O:25][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)[CH2:19]1)=[O:26]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)ON3C(=O)CCC3=O)C2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 108.2 %

Procedure:
To (3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidine-3-carboxylic acid (1.91 g, 5.18 mmol) in 1,2-dimethoxyethane (13.5 mL) was added N-hydroxysuccinimide (0.60 g, 5.18 mmol) and 1,3-dicyclohexyl carbodiimide (1.18 g, 5.7 mmol). The solution was stirred for 4 hours at room temperature while a precipitate formed. The mixture was then cooled to 0° C. filtrated and the solid washed with diethyl ether. The filtrate and the diethyl ether wash were combined and concentrated to yield 2.61 g of raw tert-butyl 4-{3-[(3R)-3-{[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O.[NH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>>[NH2:20][C:4]1[N:3]=[C:2]([NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[N:19]=[C:18]2[C:5]=1[N:6]=[CH:7][NH:8]2
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CC(C)(C)OC(=O)NCCN
Product: CC(C)(C)OC(=O)NCCNc1nc(N)c2nc[nH]c2n1
Temperature: 120 °C

Procedure:
To a microwave tube containing 2-chloroadenosine (Aldrich Chemical) is added tert-butyl N-(2-aminoethyl)carbamate (AK Scientific, 10-fold molar excess). The mixture is heated in a microwave for 20 minutes at 120° C. under nitrogen. Workup of the reaction mixture, purification, and isolation of the title intermediate is carried out in a manner similar to that of Example 4, ROUTE 1, Step 3 used for Compound 16A.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][NH2:11]>C(O)C>[OH:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:11][CH3:10])[CH:7]=1
Reactant: OCc1ccnc(Cl)c1
Reactant: CN
Solvent: CCO
Product: CNc1cc(CO)ccn1
Temperature: 200 °C
Yield: 46 %

Procedure:
A mixture of 2-chloro-4-hydroxymethylpyridine (1.0 g, 7 mmol), (prepared as described for the starting material in Example 58), and methylamine (30 ml of a 30% solution in ethanol) was heated in a Carius tube for 16 hours at 200° C. The mixture was allowed to cool and the mixture partitioned between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was separated, dried (MgSO4) and the volatiles removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate to give 4-hydroxymethyl-2-(methylamino)pyridine (440 mg, 46%) as a yellow oil.