Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:5]1.[C:22]([O-:33])(=O)[C:23]1[C:24](=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:25]([O-])=[O:26].[K+].[K+].C[N:37](C=O)C>O>[C:16]1([S:13]([C:6]2[C:7]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[N:4]([CH2:3][CH2:2][N:37]3[C:25](=[O:26])[C:24]4[C:23](=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:22]3=[O:33])[CH:5]=2)(=[O:15])=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C([O-])c1ccccc1C(=O)[O-]
Reactant: O=S(=O)(c1ccccc1)c1cn(CCCl)c2ncccc12
Reactant: CN(C)C=O
Agent: [K+]
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCn1cc(S(=O)(=O)c2ccccc2)c2cccnc21
Temperature: 115 °C

Procedure:
A solution of 1-(2-chloroethyl)-3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (3.84 g, 12.0 mmol) in DMF is treated with potassium phthalate (2.78 g, 15.0 mmol, heated at 115° C. for 16 h, cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is crystallized from CH2Cl2/hexane to afford the title compound as a white solid, 4.54 g, characterized by HNMR analysis.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[S:17][CH:18]=[C:19]([CH:21]=O)[N:20]=3)[CH:13]=[CH:12][N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C1COCC1.II.Cl.O.[NH3:32]>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[S:17][CH:18]=[C:19]([C:21]#[N:32])[N:20]=3)[CH:13]=[CH:12][N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(Nc2nccc(-c3nc(C=O)cs3)n2)c1
Reactant: N
Agent: Cl
Agent: II
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)cc(Nc2nccc(-c3nc(C#N)cs3)n2)c1
Reaction time: 1 h

Procedure:
To a stirring solution of the crude aldehyde 9a (35 mg, 0.11 mmol) in 1 mL of ammonia water 28% solution and 0.1 mL of THF at rt was added iodine (32 mg, 0.12 mmol). The dark solution became colorless after 1 h of stirring. The reaction mixture was neutralized with 0.5 mL of a 1M aqueous solution of HCl and extracted with ether. Concentrated in vacuo and passed through a short pad of silica gel (30% ethyl acetate/70% hexanes) to give 20 mg (59%) of pure 10.
Reaction SMILES: C[O-].[Na+].C(O)(=O)C.[CH:8]([NH2:10])=[NH:9].Cl.[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([C:25](OCC)=[O:26])[C:21](=O)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C>CO.O>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]2[C:25](=[O:26])[NH:10][CH:8]=[N:9][C:21]=2[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N=CN
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]cnc2c1CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.4 %

Procedure:
Part A: To a solution of sodium methoxide (25 wgt-% in methanol) (67.6 mL, 296 mmol) and methanol (70 mL) at 25° C. was added formamidine acetate (11.00 g, 106 mmol) and then ethyl N-benzyl-3-oxo-4-piperidine carboxylate hydrochloride (25.16 g, 84 mmol). The resulting mixture was stirred at 25° C. for 20 h. The mixture was cooled to 0° C. Water (90 mL) was added, followed by the dropwise addition of acetic acid (6.05 mL, 106 mmol), and the reaction mixture was stirred at 25° C. for another 3 h. The mixture was reduced in volume under vacuum until most of the methanol had been removed. The suspension was filtered. The solids were washed with water and then dried under vacuum to afford 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (16.10 g, 79%) as an off-white solid; Mass Spec.: m/e: 242.06 (M+H)+ [calc'd: 242.12]; 1H NMR (500 MHz, CDCl3) δ 12.61 (br s, 1H), 7.99 (s, 1H), 7.38-7.26 (m, 5H), 3.73 (m, 2H), 3.50 (m, 2H), 2.74 (m, 2H), 2.66 (m, 2H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:14][C:15]1[C:16]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:17][C:18]2[O:22][C:21]([CH2:24][NH2:25])([CH3:23])[CH2:20][C:19]=2[C:26]=1[C:27]([CH3:30])([CH3:29])[CH3:28])(=O)C.O>C1(C)C=CC=CC=1>[NH2:25][CH2:24][C:21]1([CH3:23])[CH2:20][C:19]2[C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])=[C:15]([OH:14])[C:16]([C:31]([CH3:32])([CH3:33])[CH3:34])=[CH:17][C:18]=2[O:22]1
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CN)O2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(CN)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 14 h
Yield: 70.9 %

Procedure:
Under a nitrogen atmosphere, 13.2 ml of 1M diisobutyl aluminum hydride solution in toluene was added dropwise to a solution of 1.0 g of 5-acetoxy-2-aminomethyl-4,6-di-t-butyl-2-methyl-2,3-dihydrobenzofuran in 30 ml of toluene at room temperature. After stirring at room temperature for 14 hours, the mixture was combined with water and extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by recrystallization from a mixed solvent of ethyl acetate and hexane to give 0.62 g of 2-aminomethyl-4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran as a white crystal (yield 71%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14](=[O:16])[CH3:15])=[CH:11][C:12]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)Cc1ccc(F)cc1
Product: CC(=O)Cc1ccc(F)c(S(=O)(=O)Cl)c1
Temperature: 25 °C

Procedure:
To chlorosulfonic acid (25 ml, excess) cooled at −10° C. is added dropwise 4-fluorophenyl acetone (1.0 g, 6.57 mmol). The temperature is kept below 0° C. throughout the addition. The reaction mixture is then left to warm up to room temperature overnight. The reaction mixture is poured carefully onto ice (1500 ml). Once ice is melted, the aqueous layer is extracted with DCM (3×250 ml). The combined organic layers are dried over MgSO4, filtered and concentrated to afford the titled compound as an off-white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:11]([NH:12][C:13]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].CC(C)([O-])C.[K+].COCCOC.Br[CH2:34][CH:35]1[CH2:37][CH2:36]1>C1(C)C=CC=CC=1.O>[CH:35]1([CH2:34][N:12]([C:11]2[C:3]([CH2:1][CH3:2])=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)[C:13]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[CH2:37][CH2:36]1
Reactant: CCc1nn2ccccc2c1NC(=O)C1CCOCC1
Reactant: BrCC1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: COCCOC
Product: CCc1nn2ccccc2c1N(CC1CC1)C(=O)C1CCOCC1
Reaction time: 4 h
Yield: 92.5 %

Procedure:
A mixture of N4-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)tetrahydro-2H-4-pyrancarboxamide (272 g, 915 mmol), potassium tert-butoxide (144 g, 1.28 mol) and 1,2-dimethoxyethane (1750 mL) was heated and stirred at an external temperature of 40° C. (Bromomethyl)cyclopropane (161 g, 1.19 mol) was then added dropwise to the reaction mixture keeping the internal temperature below 50° C. After heating and stirring for 4 hours, water (1250 mL) and toluene (3750 mL) were added to the reaction mixture. The aqueous layer was removed, and then the organic extract was washed with 10% brine (1250 mL) and water (1250 mL×2 times) in that order, and concentrated under reduced pressure to afford 277 g of the title compound as a brown oil (92.6% yield).
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3]([O:5][CH3:6])=[O:4].[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2OC(=O)[S:22][N:21]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]>C(OCC)(=O)C>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:1]([C:7]([O:9][CH3:10])=[O:8])[S:22][N:21]=2)=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: O=c1oc(-c2ccc([N+](=O)[O-])cc2)ns1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CCOC(C)=O
Product: COC(=O)c1snc(-c2ccc([N+](=O)[O-])cc2)c1C(=O)OC
Yield: 25.2 %

Procedure:
Dimethyl acetylenedicarboxylate (85.26 g, 0.6 mol) and 5-(p-nitrophenyl)-1,3,4-oxathiazol-2-one (33.63 g, 0.15 mol) were heated as given above for 15 hours. Crystallization of the brown solid from methanol (2×) gave little improvement in purity. The brown solid was decolorized in ethyl acetate solution and recrystallized (3×) to give 12.2 g (0.0378 mol, 25.2%) of dark gold solid, m.p. 142°-143°.
Reaction SMILES: Br[CH:2]([C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=1)=O)[C:3]([O:5][CH3:6])=[O:4].[C:17]([NH2:25])(=[S:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[C:18]1([C:17]2[S:24][C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=3)[N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(=S)c1ccccc1
Reactant: COC(=O)C(Br)C(=O)c1cccc(C#N)c1
Solvent: CCO
Product: COC(=O)c1sc(-c2ccccc2)nc1-c1cccc(C#N)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 91 %

Procedure:
To a solution of methyl 2-bromo-3-(3-cyanophenyl)-3-oxopropionate from Example 7, Part C (0.51 g, 1.8 mmol) in 20 mL of absolute ethanol was added thiobenzamide (0.25 g, 1.8 mmol). The resulting mixture was stirred at 80° C. for 24 h. The reaction was allowed to cool and then was filtered. The solid was washed with ethanol and dried in vacuo to yield 0.53 g (91%) of the title compound. MS (ESI) 321.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[NH:10][C:9]3=[CH:12][C:13]([C:15](O)=[O:16])=[N:14][N:8]3[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:21]1C=CN=C1)=O.FC(F)(F)C1C2C(=O)N3N=C(C(N)=O)C=C3NC=2C=CC=1>CN(C)C=O.CCOCC.C(Cl)Cl>[CH3:1][C:2]1[C:11]2[NH:10][C:9]3=[CH:12][C:13]([C:15]([NH2:21])=[O:16])=[N:14][N:8]3[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c(=O)n3nc(C(=O)O)cc3[nH]c12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: NC(=O)c1cc2[nH]c3cccc(C(F)(F)F)c3c(=O)n2n1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cccc2c(=O)n3nc(C(N)=O)cc3[nH]c12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 4,9-dihydro-5-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid (4.86 g; 0.02 mole) in dimethylformamide (50 ml) is added 1,1'-carbonyldiimidazole (4.86 g; 0.03 mole). The reaction mixture is heated at 100° C. for 12 min, then cooled and diluted with ether (75 ml) and methylene chloride (25 ml). The tan solid is filtered off and suspended in cold (0° C.) DMF (50 ml). Annydrous ammonia is bubbled through for 10 min and the resulting solution is allowed to stand at room temperature overnight. The dimethylformamide solution is evapoated to dryness under reduced pressure and the residue is washed with methylene chloride and ether and dried. Yield 3.0 g; mp 340°-345° C. (d). By the same procedure, starting with the corresponding 8-trifluoromethyl compound, the product obtained is 4,9-dihydro-8-trifluoromethyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxamide.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([S:8]([NH:11][C:12]2[S:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:2]=1.C[Al](C)C.[Si:21]([O:38][C@@H:39]1[CH2:43][CH2:42][O:41][C:40]1=[O:44])([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[Si:21]([O:38][C@H:39]([CH2:43][CH2:42][OH:41])[C:40]([NH:7][C:6]1[CH:1]=[CH:2][C:3]([S:8](=[O:10])(=[O:9])[NH:11][C:12]2[S:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:5]=1)=[O:44])([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)[Si](O[C@@H]1CCOC1=O)(c1ccccc1)c1ccccc1
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](O[C@H](CCO)C(=O)Nc1ccc(S(=O)(=O)Nc2nccs2)cc1)(c1ccccc1)c1ccccc1
Yield: 94.8 %

Procedure:
Synthesized according to General procedure 3. The reaction was set up with sulfathiazole (122 g, 477 mmol), CH2Cl2 (1.5 L), trimethylaluminum (2.0 M in hexanes, 239 mL, 477 mmol), and (R)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one (125 g, 367 mmol) in CH2Cl2 (250 mL). The reaction was purified via silica gel using 10% MeOH in CH2Cl2 to obtain the desired amide as a white solid (207 g, 348 mmol, 95% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.76 (dd, J=1.8, 7.0 Hz, 1H), 7.74 (s, 1H), 7.59-7.53 (m, 4H), 7.44-7.28 (m, 8H), 7.09 (d, J=4.6 Hz, 1H), 6.46 (d, J=4.6 Hz, 1H), 4.34 (dd, J=4.1, 6.7 Hz, 1H), 3.64-3.59 (m, 1H), 3.54 (dd, J=6.1, 11.4 Hz, 1H), 1.99-1.91 (m, 1H), 1.81-1.70 (m, 1H), 1.10 (s, 9H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=596.5; tR=1.93 min.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][CH:2]1[CH2:10][C:11]([OH:13])=O.S(Cl)(Cl)=O.C[N:19]([CH:21]=O)C>C1(C)C=CC=CC=1>[S:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH:2]1[CH2:10][C:11]([NH:19][C:21]1[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1)=[O:13]
Reactant: CN(C)C=O
Reactant: O=C(O)CC1Sc2ccccc2S1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(CC1Sc2ccccc2S1)Nc1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(benzo[1,3]dithiol-2-yl)acetic acid (1.35 g) in toluene (30 mL) were added thionyl chloride (0.600 mL) and DMF (catalytic amount) at room temperature, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added acetonitrile (30 mL), and then was added dropwise a solution of aniline (1.54 g) in acetonitrile (10 mL) under ice-cooling. The mixture was stirred at the same temperature for 1 hour and then at room temperature for 3 hours, and then concentrated under reduced pressure. To the residue was added 1N hydrochloric acid (50 mL), and the mixture was stirred at room temperature for 0.5 hour. The formed crystals were collected by filtration, washed with water, filtered, and then dried to obtain 2-(benzo[1,3]dithiol-2-yl)-N-(phenyl)acetamide (1.83 g) as a white crystal.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH2:15][N:14](C(O)=O)[CH2:13][CH2:12]2)[O:8][N:7]=1.[ClH:20].C(OCC)C>C(O)C.O1CCOCC1>[ClH:20].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH2:15][NH2+:14][CH2:13][CH2:12]2)[O:8][N:7]=1
Reactant: O=C(O)N1CCC(c2nc(-c3cccs3)no2)CC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Solvent: CCOCC
Product: c1csc(-c2noc(C3CC[NH2+]CC3)n2)c1
Temperature: 50 °C

Procedure:
11 g of the tert-butyl ester of 4-(3-thiophen-2-yl[1,2,4]-oxadiazol-5-yl)piperidine-1-carboxylic acid (32.8 mmol) were placed in a 250 ml round-bottomed flask and dissolved in 66 ml of absolute ethanol. A solution of hydrogen chloride in dioxane (4N) (10 ml) was then added. The reaction medium was heated at 50° C. for 2 hours. The solution was then cooled and 100 ml of diethyl ether were added. The product was then filtered off. 9.56 g of a beige-colored powder were obtained.
Reaction SMILES: C[Si](Cl)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:13]([O:20][C:21]1[CH:28]=[C:27]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH:26]=[C:25]([B:36]2CC(C)(C)C(C)(C)C2)[C:22]=1[CH:23]=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1C[O:48]CC1>[Zn]>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][CH:23]1[O:24][B:36]([OH:48])[C:25]2[CH:26]=[C:27]([O:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)[CH:28]=[C:21]([O:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:22]1=2)[CH3:12]
Reactant: C1CCOC1
Reactant: CCOC(=O)CBr
Reactant: CC1(C)CB(c2cc(OC3CCCCO3)cc(OCc3ccccc3)c2C=O)CC1(C)C
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Product: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(OCc3ccccc3)c21
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 48 %

Procedure:
To a suspension of powdered zinc dust (3.3 g, 51 mmol) in THF (20 mL) was added trimethylsilyl chloride at room temperature. The reaction mixture was stirred at 40° C. for 20 min and ethyl bromoacetate (5.59 g, 33.0 mmol) was slowly added, the reaction mixture was stirred at 40° C. for an additional 30 min. To a solution of 2-(benzyloxy)-4-(tetrahydro-2H-pyran-2-yloxy)-6-(3,3,4,4-tetramethylborol-1-yl)benzaldehyde (2.8 g, 6.4 mmol) in THF (15 mL) was added dropwise the above prepared zinc reagent at −78° C. The reaction mixture was stirred at room temperature for 1 h and quenched by saturated aqueous NH4Cl. The resulting mixture was extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a light yellow oil (1.3 g, yield: 48%).
Reaction SMILES: [Br:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[CH:19]=2)=[N:14]1.CN(C=O)C.C(Cl)Cl>O>[Br:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[CH:19]=3)=[N:14]2)=[O:9])[N:6]=1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1c[nH]c(Br)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1c[nH]c(Br)n1
Yield: 2.3 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 2-bromo-1H-imidazole-4-carboxylic acid (5.75 mmol, 1.099 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (3.84 mmol, 1 g) using DMF (10 ml) as the solvent. DCM and water were added, the phases were separated and the water phase was extracted with DCM. The combined organics were washed three times with water. The DCM phase was dried, filtered and evaporated. The crude product was purified by flash chromatography and preparative HPLC, respectively. 37.8 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.09 (d, 3H), 4.23-4.48 (m, 3H), 6.95 (d, 1H), 7.64 (s, 1H), 7.82 (d, 1H), 7.94-8.05 (m, 2H), 8.08 (s, 1H), 8.21 (d, 1H), 13.22 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[NH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C(N(CC)CC)C>CC(O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[N:3]=1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: NCCc1ccc(O)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(Cl)nc21
Reaction time: 4 h

Procedure:
2,6-dichloro-9-isopropyl-9H-purine (500 g) was added in portions to a stirred mixture of tyramine (593 g), triethylamine (262 g), and i-PrOH (5.0 L) at 50° C. The mixture was stirred at that temperature for 4 hr, then the reaction mixture was concentrated. The residue was taken up in isopropyl acetate (6.0 L) and was washed with 20% citric acid solution (2.0 L) and water (2.0 L). The organic layer was concentrated to dryness, then was taken up in ethanol (2.0 L) and again concentrated to dryness. The crude solid was crystallized from ethanol (3.2 L) to provide the title compound as a solid.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.C(N[CH2:9][CH3:10])C.[C:11](O)(=O)[CH3:12].O>CO.CCCCC>[CH:11](=[C:2]1[CH:1]=[CH:5][CH:4]=[CH:3]1)[CH2:12][CH2:9][CH3:10]
Reactant: C1=CCC=C1
Reactant: CC(=O)O
Reactant: CCNCC
Solvent: CO
Solvent: O
Solvent: CCCCC
Product: CCCC=C1C=CC=C1
Reaction time: 2 h
Yield: 96 %

Procedure:
2.5 eq. (20.47 g, 0.31 mol) of cyclopentadiene and diethylamine (7.44 g, 1.102 mol) were added to butylaldehyde (8.93 g, 0.124 mol). The reactant solution was incubated in 80 ml of methanol and then at room temperature for 2 hours. 15.1 ml of acetic acid was added, and the result was stirred for 10 minutes. The resultant solution was then diluted with 200 ml of pentane and treated with 100 ml of water to remove methanol. To remove residual diethylamine, the resultant solution was washed with 200 ml of 1 N HCl for 30 seconds and neutralized with 200 ml of saturated sodium bicarbonate. An organic layer was washed with a NaCl solution, subjected to solvent removal in a rotary evaporator, and distilled at 40° C., to give 5-butylidene-cyclopenta-1,3-diene (yield: 96%).
Reaction SMILES: [CH3:1][N:2]([CH3:48])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:47])[C@H:18]([NH:27][C:28]([C@@H:30]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][N:31]2C(OC(C)(C)C)=O)=[O:29])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:13][CH2:12]1)=[O:4].Cl>CCOC(C)=O>[CH2:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:39][C@@H:30]([C:28]([NH:27][C@H:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:3]([N:2]([CH3:1])[CH3:48])=[O:4])[CH2:16][CH2:15]2)=[O:47])=[O:29])[NH:31]1
Reactant: CN(C)C(=O)c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1

Procedure:
[2-(4-{(2R)-2-[((3S)(3-1,2,3,4-Tetrahydro-isoquinolyl)) carbonylamino]-3-(4-chlorophenyl)-propanoyl}piperazinyl)phenyl]-N,N-dimethylcarboxamide was prepared according to the procedure described in Preparation XVI by using tert-butyl 3-[N-((1R)-2-{4-[2-(N,N-dimethylcarbamoyl)-phenyl]piperazinyl}-1-[(4-chlorophenyl) methyl]-2-oxoethyl)carbamoyl](3S)-1,2,3,4-tetrahydro-isoquinoline-2-carboxylate (Step 6) (156 mg, 0.23 mmol) and a satd soln of HCl in EtOAc (5 mL). The title compound was isolated by filtration as a white solid, and purified by preparative HPLC (TFA buffer) (125 mg). MS (ESI, pos. ion) m/z: 574 (M+H). Calc'd for C32H36ClN5O3: 573.25.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C[CH2:24][N:25]([CH:29]([CH3:31])C)[CH:26]([CH3:28])C.[NH2:32][C:33]1[C:42]([C:43]([NH:45][C:46]2[CH:47]=[N:48][CH:49]=[CH:50][C:51]=2[CH:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)=[O:44])=[C:36]2[N:37]=[CH:38][C:39]([F:41])=[CH:40][N:35]2[N:34]=1.NC1[C:70]([C:71](ON2C3C=CC=CC=3N=N2)=[O:72])=C2N=CC(CC#N)=CN2N=1>CN1C(=O)CCC1>[NH2:32][C:33]1[C:42]([C:43]([NH:45][C:46]2[CH:47]=[N:48][CH:49]=[CH:50][C:51]=2[CH:52]2[CH2:57][CH2:56][N:55]([C:71]([CH:70]3[CH2:28][CH2:26][N:25]([CH3:24])[CH2:29][CH2:31]3)=[O:72])[CH2:54][CH2:53]2)=[O:44])=[C:36]2[N:37]=[CH:38][C:39]([F:41])=[CH:40][N:35]2[N:34]=1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)Nc1cnccc1C1CCNCC1
Reactant: CCN(C(C)C)C(C)C
Reactant: N#CCc1cnc2c(C(=O)On3nnc4ccccc43)c(N)nn2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCCC1=O
Product: CN1CCC(C(=O)N2CCC(c3ccncc3NC(=O)c3c(N)nn4cc(F)cnc34)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TBTU (154.5 mg, 0.4812 mmol) and DIPEA (82.92 mg, 111.8 μL, 0.6416 mmol) were added to a solution of 2-amino-6-fluoro-N-[4-(4-piperidyl)-3-pyridyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (114 mg, 0.3208 mmol) and 1-methylpiperidine-4-carboxylic acid (Hydrochloric Acid (1)) (69.16 mg, 0.3850 mmol) in NMP (2.280 mL) and the resulting solution stirred at RT for 2 h. Passed through an SCX cartridge flushing the desired product with 2M ammonia in methanol and the filtrate concentrated in vacuo. The residue was purified by fractionlynx HPLC and the product fractions combined and freeze dried to leave 2-amino-6-fluoro-N-(4-(1-(1-methylpiperidine-4-carbonyl)piperidin-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow crystalline solid. MS (ES+) 481.3.