Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][CH:5]([C:7]([OH:9])=O)[CH2:4][O:3]1.[NH2:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[C:16]([NH2:18])[CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.N1C=CC=CC=1.C(OCC)(=O)C>[NH2:18][C:16]1[CH:17]=[C:12]([NH:11][C:7]([CH:5]2[CH2:4][O:3][C:2]([CH3:1])([CH3:10])[O:6]2)=[O:9])[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=1
Reactant: CC1(C)OCC(C(=O)O)O1
Reactant: Nc1cc(N)cc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C)OCC(C(=O)Nc2cc(N)cc([N+](=O)[O-])c2)O1
Reaction time: 72 h
Yield: 68.4 %

Procedure:
To a solution of 0.5 g (2.9 mmole) of 2,2-dimethyl-1,3-dioxolane-4-carboxylic acid in 2 ml of methylene chloride, at 0° C., was added a solution of 0.216 g of 3,5-diaminonitrobenzene (1.3 mmole) in 2 ml of methylene chloride and 1 ml of pyridine, followed by 0.61 g (3.0 mmole) of dicyclohexylcarbodiimide. The mixture was stirred 72 hours, diluted with ethyl acetate, filtered and the filtrate evaporated to dryness in high vacuum. The residue was chromatographed over silica gel; elution with 9:1 chloroform-ethyl acetate gave two fractions. The first fraction, 170 mg was the bis-acylated material. The second fraction was evaporated to dryness to give 250 mg of N-(3-amino-5-nitrophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxamide.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][C:15]1[CH:16]=[C:17](O)[CH:18]=[CH:19][CH:20]=1>>[C:15]1([CH3:14])[CH:16]=[CH:17][CH:18]=[C:19]([O:13][CH:10]2[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)[CH:20]=1
Reactant: Cc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Product: Cc1cccc(OC2CCN(C(=O)OC(C)(C)C)C2)c1
Yield: 107.4 %

Procedure:
The title compound (D38) (1.59 g) was prepared according to the experimental procedure described in Description 34 starting from 1-Boc-3-pyrrolidinol (1 g, 5.34 mmol) and 3-Methylphenol (0.558 ml, 5.34 mmol).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([OH:13])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:16][NH:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C)C=O.O>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8](/[CH:9]=[CH:10]/[C:11](=[O:13])[N:17]([CH3:16])[CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)(=[O:3])[CH3:2]
Reactant: CNCc1cccnc1
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1
Agent: CCP(=O)(C#N)CC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Oc1ccc(/C=C/C(=O)N(C)Cc2cccnc2)cc1
Yield: 96.8 %

Procedure:
1.03 g of 4-acetoxycinnamic acid and 0.61 g of 3-(methylaminomethyl)pyridine were dissolved in 5 ml dimethylformamide, and then stirred with 0.90 ml diethylphosphoryl cyanide and subsequently with 0.75 ml triethylamine on ice for 2 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, washed with brine, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was then purified via column chromatography on silica gel (dichloromethane:methanol=30:1) to provide 4[(E)-2-[N-methyl-N-(3-pyridylmethyl)carbamoyl]ethenyl]phenyl acetate (1.50 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14](Br)[CH2:15][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[N+:29]([O-:31])=[O:30].C(OCC)(=O)C.O>CS(C)=O.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.[Cu]>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[N+:29]([O-:31])=[O:30])[CH2:15][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Reactant: BrC1=Cc2ccc(OCc3ccccc3)cc2CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C2=Cc3ccc(OCc4ccccc4)cc3CC2)c([N+](=O)[O-])c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
The title compound was synthesized by referring to Tetrahedron Lett., 1993, 34 (21), 3421. A suspension of 7-benzyloxy-3-bromo-1,2-dihydronaphthalene (38 g), 4-bromo-3-nitroanisole (59 g), dichlorobis(triphenylphosphine)palladium (II) (4.5 g) and copper (32 g) in dimethyl sulfoxide (400 ml) was stirred under a nitrogen atmosphere at 120° C. for 1 hour. Ethyl acetate and water was added thereto, the solution was filtered through celite pad, extracted with ethyl acetate, then sequentially washed with aqueous ammonia, water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (19 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:33]=1[NH2:34].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:34][C:33]3[CH:35]=[CH:36][C:37]([CH3:39])=[CH:38][C:32]=3[F:31])=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Reactant: Cc1ccc(N)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(NC(=O)c2cc3nc(Nc4c(F)cccc4Cl)[nH]c3c3c2OC(C)(C)C3)c(F)c1
Yield: 51.8 %

Procedure:
The title compound was prepared following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.150 g, 0.400 mmol), thionyl chloride (2.0 mL), 2-fluoro-4-methylaniline (0.075 g, 0.600 mmol), THF (5.0 mL) and DIPEA (3 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.100 g of the desired product. 1HNMR (DMSO-d6): δ 1.54 (s, 6H), 2.29 (s, 3H), 3.17 (s, 2H), 7.00 (d, J=8.4 Hz, 1H), 7.16 (d, J=12.3 Hz, 1H), 7.30 (s, 2H), 7.40 (m, 1H), 7.51 (s, 1H), 8.33 (t, J=8.4 Hz, 1H), 10.02 (s, 1H), 11.12 (s, 2H); MS [M+H]+: 483.17.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:11][CH2:10][N:9]([CH2:12][CH3:13])[CH2:8][CH2:7]1)=[O:5])C>CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:8][CH2:7][C:6]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:21][CH:22]=2)(=[O:16])=[O:15])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1)[CH3:13]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(CC)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CC)CC2)cc1

Procedure:
1-Ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine4-carboxylic acid ethyl ester (7.94 g, 20 mmol) dissolved in methanol (300 ml) and 10N NaOH (35 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 6.5 g (88%); white solid; mp 162° C.; MS: 370 (M+H)+
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7](\[C:13]2[CH:26]=[CH:25][C:24]3[S:23](=[O:28])(=[O:27])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH3:29])[C:15]=3[CH:14]=2)/[C:8]([O:10]CC)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1(/[CH:6]=[C:7](\[C:13]2[CH:26]=[CH:25][C:24]3[S:23](=[O:28])(=[O:27])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH3:29])[C:15]=3[CH:14]=2)/[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)/C(=C/C1CCCC1)c1ccc2c(c1)N(C)c1ccccc1S2(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1c2ccccc2S(=O)(=O)c2ccc(/C(=C\C3CCCC3)C(=O)O)cc21

Procedure:
1.58 g of ethyl(E)-3-cyclopentyl-2-(10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)acrylate are dissolved in 130 ml of methanol, and 13.44 ml of 2 M NaOH solution are added. The reaction mixture is heated at the boil under reflux for two hours. The methanol is removed under reduced pressure, and the reaction mixture is adjusted to pH 4 by addition of 2N hydrochloric acid. The precipitated solid is filtered off with suction and dried under high vacuum. This gives 1.46 g of (E)-3-cyclopentyl-2-(10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)acrylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=O)[CH2:9]2)=[CH:4][C:3]=1[O:23][CH3:24].COC1C=C(N2CCC[C@@H](CN3CCN(C)CC3)C2)C=CC=1[N+]([O-])=O>>[CH3:24][O:23][C:3]1[CH:4]=[C:5]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)[CH2:9]2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: COc1cc(N2CCC[C@H](C(=O)N3CCN(C)CC3)C2)ccc1N
Agent: COc1cc(N2CCC[C@@H](CN3CCN(C)CC3)C2)ccc1[N+](=O)[O-]
Product: COc1cc(N2CCC[C@@H](CN3CCN(C)CC3)C2)ccc1N

Procedure:
2-Methoxy-4-[(S)-3-(4-methyl-piperazin-1-ylmethyl)-piperidin-1-yl]-phenylamine was prepared in an analogous fashion to [(S)-1-(4-Amino-3-methoxy-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone of Example 460c replacing [(S)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone with 1-[(S)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-ylmethyl]-4-methyl-piperazine. (160 mg, 97%). LC/MS (E/I+) 319.21 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17].[Br:18]N1C(=O)CCC1=O>C1C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3]1[C:8]([CH2:9][Br:18])=[CH:7][CH:6]=[CH:5][C:4]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17]
Reactant: COc1c(C)cccc1Oc1ccccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COc1c(CBr)cccc1Oc1ccccc1F
Yield: 114.2 %

Procedure:
A mixture of 2-fluorophenyl 2-methoxy-3-methylphenyl ether (11.5 g), N-bromosuccinimide (9 g) and azobisisobutyronitrile (0.9 g) in benzene (100 ml) was treated in a similar manner to that of Example 5-(3) to give oily 2-fluorophenyl 2-methoxy-3-bromomethylphenyl ether (17.6 g).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:2]2.C(N(CC)CC)C.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.O>C(Cl)(Cl)Cl>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:2]2[CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]3[CH2:7][CH:1]2[CH2:6][CH2:5]3)=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1NC2CCC1C2
Reactant: COc1ccc(CCl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C1C2CCC(C2)N1Cc1ccc(OC)cc1
Yield: 85.8 %

Procedure:
To a solution of ethyl 2-azabicyclo[2.2.1]heptane-3-carboxylate (231 mg, 1.37 mmol) in chloroform (5 ml) were added triethylamine (0.20 ml, 1.43 mmol) and 4-methoxybenzyl chloride (0.19 ml, 1.43 mmol) while being cooled with ice. After a reaction at 60° C. for 20 hours, the reaction mixture, with water added thereto, was extracted with chloroform. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (1% methanol/chloroform), to give ethyl 2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (340 mg, 86%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[Cl:15][C:16]1[CH:17]=[C:18]2[N:24]([CH:25]([CH3:27])[CH3:26])[C:23](=[O:28])[N:22]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=3)[C:19]2=[N:20][CH:21]=1.[H-].[Na+]>CN(C=O)C.CO>[Cl:15][C:16]1[CH:17]=[C:18]2[N:24]([CH:25]([CH3:27])[CH3:26])[C:23](=[O:28])[N:22]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:3]4[N:2]([CH3:1])[C:6]5=[N:7][CH:8]=[CH:9][CH:10]=[C:5]5[N:4]=4)=[CH:31][CH:30]=3)[C:19]2=[N:20][CH:21]=1
Reactant: CC(C)n1c(=O)n(-c2ccc(O)cc2)c2ncc(Cl)cc21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)n1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncc(Cl)cc21
Temperature: 180 °C
Yield: 58.3 %

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (100 mg) was added to a solution of 6-chloro-3-(4-hydroxyphenyl)-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (148 mg) and NaH (20.83 mg) in DMF (3 mL) at room temperature. The mixture was heated at 180° C. for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-50% EtOAc in hexane) to give 6-chloro-1-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (120 mg) as white crystals.
Reaction SMILES: N#N.Br[C:4]1[S:8][C:7]([CH2:9][C:10]#[N:11])=[CH:6][CH:5]=1.CC1(C)C(C)(C)OB([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH2:26])O1>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:4]1[S:8][C:7]([CH2:9][C:10]#[N:11])=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(Br)s1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Agent: [Pd]
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: N#CCc1ccc(-c2ccccc2N)s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
(The following reaction is done in an oxygenfree N2 atmosphere.) Dissolve tetrakis-(triphenylphosphine)-palladium(0) (29 mg, 2.5 mol %) and nitrile (83) (101 mg, 0.50 mmol) in DME (3.7 mL). The reaction mixture is degassed 5 times and flooded with N2 again. Add 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (84) (120 mg, 0.55 mmol), rinse with DME (0.5 mL), add aqu. 1M NaHCO3, degas again (5 times) and stir the reaction solution 2 h at 90° C. (reflux). After cooling to rt partition the reaction mixture between EtOAc and brine (1+1) and extract the separated aqueous layer 3 times with EtOAc. Wash combined organic layer with brine and dry with Na2SO4. Remove solvent under reduced pressure and purify the crude product by preparative radial chromatography (silica gel 60 PF, CyH/EtOAc 2+1) to obtain [5-(2-amino-phenyl)-thiophen-2-yl]-acetonitrile (85) as a brownish oil (84 mg, 78%). 1H NMR (400 MHz, CDCl3): 3.89 (br.s, 2H); 5.20-6.50 (br.s, 2H); 6.92 (t, 1H; J=7.6 Hz); 6.95-7.00 (m, 1H); 6.99 (d, 1H; J=3.8 Hz); 7.11 (d, 1H; J=3.8 Hz); 7.21 (dd, 1H; J1=7.6 Hz, J2=1.3 Hz); 7.27 (dd, 1H; J1=7.6 Hz, J2=1.3 Hz).
Reaction SMILES: CC1(C)[CH2:7][CH2:6][CH2:5][C:4](C)(C)[NH:3]1.C([Li])CCC.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([OH:24])=[O:23].O=C1CCN(C(OC(C)(C)C)=O)C1>CCCCCC.C1COCC1>[NH:3]1[CH2:4][CH2:5][C:6]2([C:18]3[C:17](=[N:16][CH:21]=[CH:20][CH:19]=3)[C:22](=[O:24])[O:23]2)[CH2:7]1
Reactant: O=C(O)c1ccccn1
Reactant: CC1(C)CCCC(C)(C)N1
Agent: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1OC2(CCNC2)c2cccnc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2,2,6,6-tetramethyl-piperidine (0.820 mL, 0.00486 mol) in tetrahydrofuran (5 mL, 0.06 mol) at −75 Celsius was added to 1.600 M of n-butyllithium in hexane (4.05 mL). After the mixture was stirred for 15 min, a solution of 2-pyridinecarboxylic acid (199 mg, 0.00162 mmol) was added. The resulting mixture was stirred at −75 Celsius for 10 minutes, then at −20 Celsius for 30 minutes. A solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (250 mg, 0.0013 mol) in THF (2 mL) was then added to the above mixture. The reaction mixture continued to be stirred at −20 Celsius for 20 minutes, then was warmed up to r.t. and then stirred for additional 1 hour. The reaction mixture was quenched with water, then concentrated to remove THF, and then acidified to pH ˜1 using 6M aqueous HCl solution, and then stirred at r.t. overnight. The resulting mixture was extracted with methylene chloride. The aqueous layer was concentrated and the residue was directly purified by flash chromatography on silica gel column with 10% methanol in methylene chloride to give the desired compound. MS (ESI): 190.9 (M+H+).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[C:15](=O)[NH:16][CH2:17][C:18]1[N:19]=[C:20]2[CH:26]=[CH:25][N:24]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:21]2=[N:22][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:80])=CC=1>O1CCOCC1.CCOC(C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[C:15](=[S:80])[NH:16][CH2:17][C:18]1[N:19]=[C:20]2[CH:26]=[CH:25][N:24]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:21]2=[N:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)[C@@H]4CN(C(=O)OC(C)(C)C)CC[C@@H]4C)cnc32)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=S)[C@@H]4CN(C(=O)OC(C)(C)C)CC[C@@H]4C)cnc32)cc1
Temperature: 80 °C
Yield: 90 %

Procedure:
A round bottom flask was charged with cis-tert-butyl 4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate (5.62 g, 10.6 mmol, prepared using O from 4-methylnicotonic acid, M, H from Example #5, Step C, HATU and DIEA) and Lawesson's reagent (3.0 g, 7.4 mmol) in 1,4-dioxane (100 mL). The reaction was heated at about 80° C. for about 1 h, cooled to ambient temperature, and concd under reduced pressure. The crude product was dissolved in EtOAc (200 mL) and washed with saturated aqueous NaHCO3 (3×100 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to afford cis-tert-butyl 4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)piperidine-1-carboxylate (5.2 g, 90%): LC/MS (Table 1, Method b) Rt=2.65 min; MS m/z: 544 (M+H)+. A round bottom flask was charged with cis-tert-butyl 4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)piperidine-1-carboxylate (2.6 g, 4.8 mmol) and mercury (II) trifluoroacetate (2.1 g, 4.8 mmol) in 1,4-dioxane (72 mL) and stirred at ambient temperature for about 1 h. The reaction mixture was filtered through a pad of Celite®. The Celite® pad was rinsed with DCM (30 mL) and EtOAc (30 mL). The filtrate was concd under reduced pressure. The residue was dissolved in DCM (50 mL) and washed with saturated aqueous sodium thiosulfate (10 mL), and saturated aqueous NaHCO3 (25 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to afford cis-tert-butyl-4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate (2.2 g, 90%): LC/MS (Table 1, Method b) Rt=2.57 min; MS m/z: 510 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][C:5]1[N:6]=[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)[N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12.[F:31][C:32]([F:37])([F:36])[CH2:33][CH2:34][NH2:35]>CN1C(=O)CCC1>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][C:5]1[N:6]=[C:7]([C:14]2[N:15]=[C:16]([NH:35][CH2:34][CH2:33][C:32]([F:37])([F:36])[F:31])[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)[N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12
Reactant: NCCC(F)(F)F
Reactant: CC1(C)C(=O)Nc2nc(-c3nc(Cc4ccccc4F)c4ncccn34)nc(I)c21
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)Nc2nc(-c3nc(Cc4ccccc4F)c4ncccn34)nc(NCCC(F)(F)F)c21
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
Under an argon atmosphere, 200 mg (purity 69%, 0.27 mmol) of 2-[8-(2-fluorobenzyl) imidazo[1,5-a]pyrimidin-6-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 52A) was suspended in 3.2 ml of absolute NMP and 607 mg (5.37 mmol) of 3,3,3-trifluoropropan-1-amine was added. The mixture was stirred for 1.5 h at 150° C. in the microwave. The reaction solution was filtered and purified by preparative HPLC (eluent: acetonitrile/water with 0.1% hydrochloric acid, gradient 20:80→100:0). 41 mg (31% of theor.) of the target compound was obtained.
Reaction SMILES: C([O:4][CH2:5][C:6]1([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[C:15]=2[C:21]#[N:22])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)(=O)C.O=[C:24]([CH3:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:29]([O:28][C:26]([C:25]1[C:24]([CH3:31])=[N:20][C:16]2[C:15]([C:21]=1[NH2:22])=[C:14]([O:13][CH2:12][C:6]1([CH2:5][OH:4])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)[CH:19]=[CH:18][CH:17]=2)=[O:27])[CH3:30]
Reactant: CC(=O)OCC1(COc2cccc(N)c2C#N)CCCCC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC3(CO)CCCCC3)c2c1N

Procedure:
Prepared as in Example 2a from (1-((3-amino-2-cyanophenoxy)methyl)cyclohexyl)-methyl acetate (Tachdjian, C. et al. PCT Inn. Appl. 2008, WO 2008154221) and ethyl 3-oxobutanoate as an off-white solid (60%). MS 373 (MH+).
Reaction SMILES: [CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[O:21])[CH2:13][CH2:12]3)[C:10](=[O:29])[N:9]([CH2:30][C:31]3[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=3)[C:34]([O:36]C(C)(C)C)=[O:35])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:44]>O1CCOCC1>[ClH:44].[CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[O:21])[CH2:13][CH2:12]3)[C:10](=[O:29])[N:9]([CH2:30][C:31]3[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=3)[C:34]([OH:36])=[O:35])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCN(CCCC(=O)c4ccc(F)cc4)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cccc(CN2CN(C3CCCCC3)C3(CCN(CCCC(=O)c4ccc(F)cc4)CC3)C2=O)c1
Yield: 75 %

Procedure:
tert-butyl 3-((1-cyclohexyl-8-(4-(4-fluorophenyl)-4-oxobutyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.39 g, 0.659 mmol) and 4M hydrochloric acid/1% triethylsilane in 1,4-dioxane (6 mL) were stirred at room temperature for 4 hours. The reaction was evaporated and the residue purified by PTLC (10% methanol/dichloromethane). The product obtained from PTLC was redissolved in 4M hydrochloric acid in dioxane and evaporated. The residue was dissolved in acetonitrile (5 mL) and water (5 mL) and lyophilized to give product as a white solid (0.28 g, 75%); HPLC rt 10.92 min; NMR (DMSO-d6); δ1.02-1.08 (m, 1H); 1.18-1.28 (m, 4H); 1.28-1.40 (m, 1H); 1.45-1.65 (m, 2H); 1.65-1.78 (m, 3H); 1.85-2.10 (m, 3H); 2.33-2.50 (m, 2H); 3.10 (m, 2H); 3.22 (t, J=6.8 Hz, 2H); 3.49-3.56 (m, 5H); 4.52 (s, 2H); 7.35-7.40 (m, 2H); 7.50 (m, 2H); 7.85-7.86 (m, 2H); 8.05-8.09 (m, 2H); 10.6 (br s, 1H); 13.0 (br s, 1H); MS for C31H38FN3O4 m/z 536 (M+H)+.