Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:16])[NH:10][NH:11][C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:24][C:25](ON1C(=O)CCC1=O)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.C(OCC)(=O)C>CN(C)C=O>[CH2:17]([O:24][C:25]([N:11]1[C:12]([CH:13]([CH3:14])[CH3:15])=[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:16])[NH:10]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1c(Cc2ccccc2)c(=O)[nH]n1C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 35.5 %

Procedure:
4-Benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (2.00 g) was dissolved in N,N-dimethylformamide (5 mL) at room temperature. N-(Benzyloxycarbonyloxy)succinimide (2.42 g) was added to the solution. The mixture was heated to 50° C. and then stirred for 16 hours. After the addition of water (20 mL) and ethyl acetate (20 mL) to the reaction mixture, the aqueous layer was separated, and the organic layer was washed with water. The obtained organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate/dichloromethane=1/3 to 1/1) to give 1-benzyloxycarbonyl-4-benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (1.15 g).
Reaction SMILES: [NH2:1][C@@:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[C:12]=2[CH:16]2CC2)[CH:7]=1)([CH3:5])[CH2:3][OH:4].C([C@H]1CC[C@H](OC2C(C)=C3C(=CC=2)C=C([C@]2(C)COC(=O)N2)C=C3)CC1)(C)(C)C>>[NH2:1][C@@:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:19][C@H:20]3[CH2:21][CH2:22][C@H:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:24][CH2:25]3)[C:12]=2[CH3:16])[CH:7]=1)([CH3:5])[CH2:3][OH:4]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2C2CC2)CC1
Agent: Cc1c(O[C@H]2CC[C@H](C(C)(C)C)CC2)ccc2cc([C@]3(C)COC(=O)N3)ccc12
Product: Cc1c(O[C@H]2CC[C@H](C(C)(C)C)CC2)ccc2cc([C@@](C)(N)CO)ccc12

Procedure:
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-methylnaphthalen-2-yl)propan-1-ol was synthesized as per (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-cyclopropylnaphthalen-2-yl)propan-1-ol (Example 215) in 64% yield using (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-methylnaphthalen-2-yl)-4-methyloxazolidin-2-one as starting material. MS: m/z=353.44 [M−16]+. 1H NMR (MeOD) δ: 8.06 (d, J=9.0 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.58 (dd, J=9.0, 2.3 Hz, 1H), 7.40 (d, J=9.0 Hz, 1H), 4.21-4.31 (m, 1H), 3.95 (d, J=11.5 Hz, 1H), 3.84 (d, J=11.5 Hz, 1H), 2.53 (s, 3H), 2.17-2.26 (m, 2H), 1.87-1.95 (m, 2H), 1.80 (s, 3H), 1.42-1.56 (m, 2H), 1.10-1.28 (m, 3H), 0.93 (s, 9H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11]([C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+].O.C(Cl)Cl>O1CCOCC1>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([C:17]3[CH:18]=[C:13]([CH:14]=[CH:15][CH:16]=3)[CH:11]=[O:12])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: O=Cc1cccc(-c2ccc3[nH]ccc3c2)c1
Temperature: 100 °C
Yield: 57 %

Procedure:
A mixture of 5-bromo-indole (8.7 g, 44.4 mmol), 3-formylbenzeneboronic acid (10 g, 66.7 mmol), cesium carbonate in water (2M, 88.8 mL, 178 mmol) in 450 mL of dioxane was degassed (evacuate in vacuo and pressurize with nitrogen, 3 times) PdCl2(dppf).DCM (1.1 g, 1.3 mmol) was added and the mixture degassed one more time as described above. The resulting mixture was heated at 100° C. for 3 h, then it was allowed to cool to room temperature and partitioned between diethyl ether and water. The aqueous phase was extracted with diethyl ether and the combined organic phases were washed with water, brine, dried over MgSO4, filtered and evaporated to give the crude product. Chromatography on silica gel (elution with ethyl acetate/heptane) afforded 5.6 g of the desired product.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][N:9]([CH2:22][CH2:23][CH2:24][OH:25])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[C:12]=2[Cl:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:33]1[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=1)[C:36]([O:38]C)=[O:37].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[ClH:21].[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][N:9]([CH2:22][CH2:23][CH2:24][O:25][C:33]2[CH:42]=[CH:41][CH:40]=[C:35]([C:36]([OH:38])=[O:37])[CH:34]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[C:12]=2[Cl:21])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cl
Product: O=C(O)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Reaction time: 18 h
Yield: 50.4 %

Procedure:
A solution of N-(2,2-diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-hydroxypropylamine (186 mg, 0.42 mmol) and methyl 3-hydroxybenzoate (63 mg, 0.42 mmol) in 15 mL of THF was treated with Ph3P (110 mg, 0.42 mmol) and diisopropylazodicarboxylate (93 mg, 0.46 mmol). The reaction was stirred for 18 h, diluted with H2O, and extracted with Et2O. The extracts were washed with H2O, dried, and the solvent evaporated. The residue was purified via silica gel column chromatography eluted with 10% EtOAc:hexane to yield the titled product, (64 mg, 26%). MS (ESI) 583 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:35][CH2:34][C:18]2[N:19]=[C:20]([NH:23][C:24](=[O:33])[C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)[N:21]=[CH:22][C:17]=2[CH2:16]1)=O)(C)(C)C.C(N(CC)CC)C.[S:43]1[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44]1>C(Cl)Cl>[CH2:31]([C:28]1[CH:27]=[CH:26][C:25]([C:24]([NH:23][C:20]2[N:21]=[CH:22][C:17]3[CH2:16][N:15]([S:48]([C:45]4[CH:46]=[CH:47][S:43][CH:44]=4)(=[O:50])=[O:49])[CH2:35][CH2:34][C:18]=3[N:19]=2)=[O:33])=[CH:30][CH:29]=1)[CH3:32]
Reactant: O=S(=O)(Cl)c1ccsc1
Reactant: CCc1ccc(C(=O)Nc2ncc3c(n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(C(=O)Nc2ncc3c(n2)CCN(S(=O)(=O)c2ccsc2)C3)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 66.9 %

Procedure:
Trifluoroacetic acid 7.3 ml (96 mmol) was added to a solution of 2-(4-ethyl-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 567 mg (1.48 mmol) in CH2Cl2 (10 ml) under nitrogen as inert gas and stirring was performed for 1.5 h at RT. After removal of the solvent, the intermediate (4-ethyl-N-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-benzamide trifluoroacetate) was dissolved in CH2Cl2 (10 ml). After the addition of triethylamine 1150 μl (8.20 mmol), the solution was cooled to 0° C. and 3-thiophene sulfonyl chloride 253 mg (1.39 mmol) was added. The reaction mixture was stirred for 1 h at 0° C. and then overnight at RT. After removal of the solvent, purification was performed by means of column chromatography and the product 4-ethyl-N-[6-(thiophene-3-sulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-benzamide 400 mg (0.93 mmol, 63% of theoretical) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.Cl[CH2:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH2:22]1)=[O:20]>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:18][C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH2:22]3)=[O:20])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Reactant: CC1CCN(C(=O)CCl)CC1
Solvent: C1CCOC1
Product: CC1CCN(C(=O)Cn2c3c(c4cc(Cl)ccc42)CCN(C)CC3)CC1
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
To this solution 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.1 g, 0.43 mmol) in THF was added dropwise at 0° C. Then the reaction mixture was stirred for 0.5 h. The solution of 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (89 mg, 0.51 mmol) in THF was added dropwise in reaction mixture. Then the reaction mixture was stirred at RT for 2 h. The reaction monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water. THF was evaporated and aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The crude compound was washed with hexane and diethyl ether for removal of color impurities then recrystallized by using methanol to gives 95 mg of desired compound, which was stirred with ethanolic HCl to give the HCl salt of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-methylpiperidin-1-yl)ethanone.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[CH2:9]([NH2:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>COCCO>[CH2:9]([NH:15][C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCOC(=O)CC#N
Reactant: CCCCCCN
Solvent: COCCO
Product: CCCCCCNC(=O)CC#N
Reaction time: 1.5 h

Procedure:
Ethyl cyanoacetate (113 g., 1.0 mole), n-hexylamine (101 g., 1.0 mole) and methyl cellosolve (200 ml.) are refluxed with stirring for 1.5 hours and the solvent is removed under reduced pressure to give N-(n-hexyl) cyanoacetamide.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1O)[CH2:2][CH2:3][CH3:4].Br[CH2:13][CH2:14][CH2:15][Br:16].[C:17](=[O:20])([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Br:16][CH2:15][CH2:14][CH2:13][C:6]1[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:10]([O:20][C:17]2[CH:3]=[CH:2][CH:1]=[C:5]([CH2:13][CH2:14][CH2:15][Br:16])[C:6]=2[CH2:7][CH2:8][CH2:9][CH3:10])[CH:9]=[CH:8][CH:7]=1
Reactant: BrCCCBr
Reactant: O=C([O-])[O-]
Reactant: CCCCc1ccccc1O
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCc1c(CCCBr)cccc1Oc1cccc(CCCBr)c1CCCC

Procedure:
A solution of 30 parts of o-n-butylphenol in 150 parts of dry acetone was added dropwise over 5 hours to a stirred refluxing suspension of 80.8 parts of 1,3-dibromopropane, 27.6 parts of anydrous potassium carbonate and 0.5 parts of potassium iodide in 170 parts of dry acetone.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(NC(C)C)(C)C.[Li].[N:15]1([C:19]2[C:28]3[C:23](=[N:24][C:25](Cl)=[C:26]([Cl:29])[N:27]=3)[N:22]=[C:21]([Cl:31])[N:20]=2)[CH2:18][CH2:17][CH2:16]1.O>O1CCCC1>[N:15]1([C:19]2[C:28]3[C:23](=[N:24][C:25]([O:1][C@@H:2]4[CH2:6][CH2:5][O:4][CH2:3]4)=[C:26]([Cl:29])[N:27]=3)[N:22]=[C:21]([Cl:31])[N:20]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: Clc1nc(N2CCC2)c2nc(Cl)c(Cl)nc2n1
Reactant: O[C@@H]1CCOC1
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: Clc1nc(N2CCC2)c2nc(Cl)c(O[C@@H]3CCOC3)nc2n1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
a)+b) 111 μl (1.38 mmol) (R)-3-hydroxytetrahydrofuran are dissolved in 5 ml of tetrahydrofuran and under protective gas at −10° C. mixed with 688 μl (1.38 mmol) of a 2 molar solution of lithium diisopropylamine in tetrahydrofuran. The mixture is stirred for 30 minutes at −10° C., then for one hour at ambient temperature. The mixture is cooled to −10° C. again and combined with a suspension of 400 mg (1.38 mmol) 4-azetidin-1-yl-2,6,7-trichloro-pteridine in 10 ml of tetrahydrofuran. The mixture is stirred for one hour at −10° C., slowly allowed to come up to ambient temperature and stirred for approx. another 16 hours. The reaction mixture is mixed with water and extracted with dichloromethane. The organic phase is dried on sodium sulphate and the solvent is eliminated in vacuo. The residue is stirred with diethyl ether, the precipitated solid is suction filtered, washed with diethyl ether and dried. 290 mg (R)-4-azetidin-1-yl-2,6-dichloro-7-(tetrahydrofuran-3-yl-oxy)-pteridine is obtained, which is dissolved in 13 ml dioxane and slowly added dropwise to a solution of 365 mg (4.24 mmol) piperazine in 12 ml dioxane at a temperature of 80° C. The mixture is stirred for approx. another 16 hours at 80° C., cooled to ambient temperature and water is added to the reaction mixture. It is extracted with dichloromethane, the organic phase is dried on sodium sulphate and purified by chromatography. Yield 170 mg (51% of theoretical)
Reaction SMILES: CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.[C:22]1([C:28]#[C:29][P:30](=[O:35])([OH:34])[O:31][CH2:32][CH3:33])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:36]([C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=1)#[CH:37]>[Au].ClC(Cl)C>[CH2:32]([O:31][P:30]1(=[O:34])[CH:29]=[C:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:37]=[C:36]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[O:35]1)[CH3:33]
Reactant: CCOP(=O)(O)C#Cc1ccccc1
Reactant: C#Cc1ccc(C)cc1
Agent: [Au]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC(Cl)Cl
Product: CCOP1(=O)C=C(c2ccccc2)C=C(c2ccc(C)cc2)O1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.9 %

Procedure:
A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was added thereto. After stirring at room temperature for 5 minutes, ethyl hydrogen phenylethynylphosphonate (63.0 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto. Then 1-ethynyl-4-methylbenzene (174 mg, 1.5 mmol) was put thereinto, followed by stirring at 30° C. for 16 hours, and when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-phenyl-6-p-methylphenyl-1,2-oxaphosphorin 2-oxide (33.2 mg, 34%) which is a title compound.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:17]1[CH:18]=[CH:19][C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2ccncc2)sc2ccccc12
Yield: 30.7 %

Procedure:
Methyl thiosalicylate (2.0 g, 11.9 mM) and 4-cyanopyridine (1.2 g, 11.5 mM) were dissolved in toluene (5 ml), and triethylamine (2 ml) was added to the solution. After heating for 22 hours under reflux, the same procedures as in REFERENCE EXAMPLE 1 were carried out to give the title compound as crystals (850 mg, 30.7%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][CH3:23].[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][CH2:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:31]([NH:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:32])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C=Nc1ccccc1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)Nc1ccccc1
Yield: 54.4 %

Procedure:
Using the general method of Example 145, except that the reaction was run at ambient temperature, 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.2 mmol) was reacted with phenyl isocyanate (0.35 mL, 3.2 mmol) to provide 0.75 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea as white needles, m.p. 185-187° C. Analysis: Calculated for C25H30N6O. H2O: %C, 66.94; %H, 7.19; %N, 18.74; Found: %C, 67.31; %H, 7.20; %N, 18.70.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH:12][C:13]1[N:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1)=[CH:7]2.[CH3:21][O:22][CH2:23][CH2:24][C:25](O)=[O:26].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[C:19]([C:16]1[N:17]=[CH:18][C:13]([NH:12][C:8]2[N:9]=[CH:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1][C:25](=[O:26])[CH2:24][CH2:23][O:22][CH3:21])=[N:14][CH:15]=1)#[N:20]
Reactant: N#Cc1cnc(Nc2cc3cccc(N)c3cn2)cn1
Reactant: COCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCC(=O)Nc1cccc2cc(Nc3cnc(C#N)cn3)ncc12
Temperature: 40 °C
Reaction time: 48 h
Yield: 11.4 %

Procedure:
To a solution of 5-(8-aminoisoquinolin-3-ylamino)pyrazine-2-carbonitrile (36 mg, 0.14 mmol), 3-methoxypropionic acid (34 mg, 0.32 mmol), N-hydroxybenzotriazole hydrate (64 mg, 0.42 mmol) and diisopropylethylamine (78 mg, 0.60 mmol) in DMF (1 mL), was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (78 mg, 0.42 mmol). The reaction mixture was stirred at 40° C. for 48 hours and then concentrated to dryness. Preparative HPLC gave the title compound (5.7 mg, 0.016 mmol, 12%). 1H NMR (d6-DMSO, 400 MHz) δ 11.05 (br s, 1H), 10.20 (s, 1H), 9.32 (s, 1H), 8.82 (d, 1H, J=1.2 Hz), 8.71 (d, 1H, J=1.2 Hz), 8.49 (s, 1H), 7.65-7.75 (m, 3H), 3.71 (t, 2H, J=6.1 Hz), 3.32 (s, 3H, obscured by water signal), 2.75 (t, 2H, J=6.1 Hz). LC-MS (2) Rt=2.10 min; m/z (ESI+) 349 (M+H).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[N:5][CH:4]=1)=[O:2].Cl.[NH2:14][CH2:15][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]([O:19][CH3:20])=[O:18].ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>>[C:25]([O:24][C:22]([NH:21][C@@H:16]([CH2:15][NH:14][C:10](=[O:12])[CH2:9][NH:8][C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][N:5]=1)[C:17]([O:19][CH3:20])=[O:18])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=Cc1cnc(NCC(=O)O)s1
Reactant: COC(=O)[C@H](CN)NC(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: COC(=O)[C@H](CNC(=O)CNc1ncc(C=O)s1)NC(=O)OC(C)(C)C
Yield: 41.5 %

Procedure:
Following the general procedure as described in Example 24, except using 2-((5-formylthiazol-2-yl)amino)acetic acid, 1.00 HCl (150 mg, 0.674 mmol), (S)-methyl 3-amino-2-((tert-butoxycarbonyl)amino)propanoate (see U.S. Publication No. 2007/93414 A1, 164 mg, 0.751 mmol), -1-hydroxy-7-azabenzotriazole (45 mg, 0.331 mmol), CH2C2 (5 mL), N-methylmorpholine (128 μL, 1.164 mmol), EDC (128 mg, 0.667 mmol) and stirring at room temp for 1 h, 108 mg (41.5%) of the title compound is isolated as an orange/red solid. Purification is done by BIOTAGE® Silica gel chromatography on a 20 g Thompson Single Step silica cartridge using a linear gradient from 100% CH2Cl2 to 100% EtOAc over 10 column volumes. LC/MS (Condition A): ret. T=2.54 min, (M+Na) 409.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][NH:15]2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[C:38](Cl)(Cl)=[O:39].Cl.[CH2:43]([NH2:49])[CH2:44]CCC=C>>[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:21]=3)[CH2:16][N:15]2[C:38](=[O:39])[NH:49][CH2:43][CH3:44])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1)C(=O)OCC
Reactant: O=C(Cl)Cl
Reactant: C=CCCCCN
Agent: Cl
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NCC)C(=O)OCC
Yield: 86.8 %

Procedure:
Reaction of compound 12 (330 mg, 0.66 mmol), phosgene (1.6 ml, 1.9 M in toluene, 3 mmol) and hex-5-enylamine hydrochloride (500 mg, 3.68 mmol) following the procedure described in Example 120 gave the pure title product (328 mg, 80%), MS (M+H+) 627.
Reaction SMILES: [Cl-].C[O:3]CP(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:34][C@H:35]1[CH2:40][C:39](=O)[CH2:38][CH2:37][O:36]1.[CH2:42]1[CH2:46][O:45]C[CH2:43]1>>[CH3:34][C@H:35]1[CH2:40][CH:39](/[CH:43]=[CH:42]/[C:46]([OH:45])=[O:3])[CH2:38][CH2:37][O:36]1
Reactant: COC[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@H]1CC(=O)CCO1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Product: C[C@H]1CC(/C=C/C(=O)O)CCO1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a suspension of (methoxymethyl)triphenyl phosphine chloride (32 g) in anhydrous THF (160 ml), cooled to −10° C., was added dropwise sodium bis(trimethylsilyl) amide (46.7 ml of 2M solution in THF). The reaction mixture was stirred for 1 hour and then a solution of (2S)-2-methyltetrahydro-4H-pyran-4-one (7.1 g) in anhydrous THF (20 ml) was added over 5 minutes. The resulting mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched with water (50 ml) and extracted with diethyl ether (3×100 ml). The organics were dried and evaporated to dryness. The resulting gum was treated with diethyl ether and filtered. The organics were evaporated to dryness and the resulting residue was purified by chromatography on silica eluting with ethyl acetate/isohexane (1:9) to give the title compound (˜1:1 E/Z mixture of isomers) as an oil. Yield 6.22 g. NMR CDCl3 1.1 (dd, 3H), 1.45-2.1 (m, 3H), 2.4-2.55 (m, 1H), 3.2 (m, 2H), 3.4 (s, 3H), 3.85 (m, 1H) 5.7 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]4)[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[NH3:25]>C(O)(C)C>[NH2:25][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]4)[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: N
Reactant: CC(=O)N1CCN(C2CC(c3nc(I)c4c(Cl)nccn34)C2)CC1
Solvent: CC(C)O
Product: CC(=O)N1CCN(C2CC(c3nc(I)c4c(N)nccn34)C2)CC1
Temperature: 110 °C

Procedure:
1-{4-[3-(8-Chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutyl]-piperazin-1-yl}-ethanone (13.2 g, 0.029 mol) was dissolved in isopropyl alcohol (100 mL) into a Parr pressure reactor. The vessel was cooled to −78° C. and saturated with ammonia gas and sealed. The reaction was heated for 19 h at 110° C., at which point the reaction was cooled and the solvent concentrated in vacuo. The crude product was purified via silica gel chromatography eluting with 5-10% MeOH (7M NH3): CH2Cl2 to yield the title compounds as an off white solid; MS (ES+): m/z 440.89 (100) [MH+], 441.89 (20) [MH+]; HPLC: tR=0.46 min (OpenLynx, polar—5 min); 1H NMR (CDCl3, 400 MHz) δ 2.09 (s, 3H) 2.28-2.48 (m, 6H) 2.54-2.71 (m, 2H) 2.80-2.99 (m, 1H) 3.27-3.43 (m, 1H) 3.43-3.54 (m, 2H) 3.56-3.70 (m, 2H) 7.02 (d, J=5.05 Hz, 1H) 7.16 (d, J=5.05 Hz, 2H).
Reaction SMILES: Br[CH:2]1[CH2:5][CH2:4][CH2:3]1.[CH3:6][O:7][C:8](=[O:19])[C:9]1[CH:14]=[C:13]([CH:15]=[O:16])[CH:12]=[C:11]([CH3:17])[C:10]=1[OH:18].O>CN(C=O)C.[I-].[K+]>[CH3:6][O:7][C:8](=[O:19])[C:9]1[CH:14]=[C:13]([CH:15]=[O:16])[CH:12]=[C:11]([CH3:17])[C:10]=1[O:18][CH:2]1[CH2:5][CH2:4][CH2:3]1
Reactant: BrC1CCC1
Reactant: COC(=O)c1cc(C=O)cc(C)c1O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C=O)cc(C)c1OC1CCC1
Temperature: 110 °C
Yield: 93.9 %

Procedure:
To a mixture of bromocyclobutane (1.39 g, 10.3 mmol), potassium iodide (43 mg, 5 mol %), and CsCO3 (3.84 g, 11.84 mmol) in DMF (18 mL) is added 5-formyl-2-hydroxy-3-methyl-benzoic acid methyl ester (1.0 g, 5.15 mmol). The reaction is placed in the microwave reactor and heated at 110° C. for 6 h. Water (50 mL) is added to the reaction and the solution is extracted with EtOAc (3×40 mL). The combined organic layers are dried over anhydrous MgSO4 and concentrated in vacuo to give product (282) as orange-yellow oil (1.20 g, 94%).