Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([CH2:6][C:7](=[O:22])[C:8]([NH:11][C:12](=[O:21])[C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=1)([CH3:10])[CH3:9])(=[O:5])=[O:4])[CH3:2].[Br:23]Br>C(Cl)Cl.BrBr>[CH2:1]([S:3]([CH:6]([Br:23])[C:7](=[O:22])[C:8]([NH:11][C:12](=[O:21])[C:13]1[CH:14]=[C:15]([Cl:20])[CH:16]=[C:17]([Cl:19])[CH:18]=1)([CH3:10])[CH3:9])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CC(=O)C(C)(C)NC(=O)c1cc(Cl)cc(Cl)c1
Reactant: BrBr
Solvent: ClCCl
Product: CCS(=O)(=O)C(Br)C(=O)C(C)(C)NC(=O)c1cc(Cl)cc(Cl)c1
Yield: 66.6 %

Procedure:
N-(3'-Ethylthio-1',1'-dimethylacetonyl)-3,5-dichlorobenzamide (5.0 gm, 0.015 m) was taken in chloroform (200 ml) and meta-chloroperbenzoic acid (7.8 gm, 0.045 m) was added with stirring at room temperature for about 16 hours. The reaction mixture was transferred, with the use of ether (200 ml) as a rinse, to a separatory funnel. The organic solution was washed sequentially with sodium sulfite (2×100 ml), sodium bicarbonate (200 ml), water (100 ml) and brine (200 ml). The solvent was removed after drying over anhydrous sodium sulfate. Recrystallization using ethyl acetate and hexane (1:4) afforded 4.3 gm of 3-(3',5'-dichlorobenzoylamino)-2-oxo-3-methylbutyl ethyl sulfone. A portion of this sulfone (1.00 gm, 0.0027 mole)was taken in methylene chloride (50 ml) and bromine (0.13 ml, 0.003 mole) was added in one portion. Another 2-3 drops of bromine were added and the mixture was heated to reflux for about 1 hour. The solvent was removed and the resulting oil was recrystallized from hexane to obtain 800 mg of the desired product.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[N:26]=[C:27]2[N:31]([C:32]=1[C:33](O)=[O:34])[CH:30]=[CH:29][S:28]2>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:32]2[N:31]3[C:27]([S:28][CH:29]=[CH:30]3)=[N:26][C:25]=2[Cl:24])=[O:34])=[O:10])[N:12]=1
Reactant: O=C(O)c1c(Cl)nc2sccn12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(Cl)nc3sccn23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 6-Chloro-imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.90 min; [M+H]+=511.9.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Cl:14][C:15]1[C:20]([CH3:21])=[C:19](Cl)[N:18]=[CH:17][N:16]=1>C1COCC1.CC(C)([O-])C.[K+]>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][C:19]2[C:20]([CH3:21])=[C:15]([Cl:14])[N:16]=[CH:17][N:18]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1c(Cl)ncnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (6.26 g, 33.4 mmol) and 4,6-dichloro-5-methyl-pyrimidine (5.45 g, 33.4 mmol) in 100 mL THF, 1M potassium tert-butoxide in THF (40 mL, 40 mmol) were added slowly by syringe pump. After 1 hour, everything had been added and mixture was concentrated. Residue was extracted with methylene chloride and water. Organic phases were dried over magnesium sulfate, filtered, and concentrated to give 4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester as a pale yellow solid (10.3 g, 98%). 1H NMR (CDCl3, 400 MHz) δ 1.22-1.24 (d, 6H), 1.74-1.81 (m, 2H), 1.95-2.04 (m, 2H), 2.24 (s, 3H), 3.40-3.45 (m, 2H), 3.74-3.81 (m, 2H), 4.90-4.98 (m, 1H), 5.31-5.37 (m, 1H), 8.40 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.N1C=CC=CC=1.Cl>C(Cl)Cl>[N+:13]([C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=1)([O-:15])=[O:14]
Reactant: COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
A flask containing 1-Methoxy-3-nitro-5-trifluoromethyl-benzene (10 g) and hydrochloride pyridine (10 eq, 52.0 g) was heated to 210 C and stirred for 12 h. Once complete, the reaction was cooled and the residue was dissolved in CH2Cl2 and washed twice with water (100 mL). The organic layer was concentrated under vacuum and then set in the freezer overnight. The resulting crystalline product was filtered off and washed with ether and used as is.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH2:12][CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C.[Pd]>[CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C=CCC1CCCCc2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCC1CCCCc2ccccc21
Reaction time: 3 h
Yield: 97.4 %

Procedure:
A solution of ethyl 4-(6,7,8,9-tetrahydro-5H-5-benzocycloheptenyl)-2-butenoate (0.544 g) in ethyl acetate (10 ml) was added with 10% palladium/carbon (0.054 g), and the mixture was stirred for 3 hours under a hydrogen flow. The reaction mixture was filtered through Celite, and then the solvent of the filtrate was concentrated under reduced pressure to obtain the title compound (0.534 g, yield: 97%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].O[CH2:11][NH:12][C:13](=[O:15])[CH3:14]>FC(F)(F)C(O)=O>[C:13]([NH:12][CH2:11][C:5]1[S:1][C:2]([CH2:6][C:7]([OH:9])=[O:8])=[CH:3][CH:4]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)NCO
Reactant: O=C(O)Cc1cccs1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCc1ccc(CC(=O)O)s1

Procedure:
1.42 g of 2-thienylacetic acid are added in portions to a solution, kept at 0°-5° C., of 1.34 g of N-hydroxymethyl acetamide (Einhorn, Ann. Chem., volume 343, page 264 (1905)) in 10 ml of trifluoroacetic acid, whilst stirring. The mixture is stirred for 2 hours at 0°-5° C. and the trifluoroacetic acid is distilled off under reduced pressure. 30 ml of water are added to the residue and the mixture is extracted with twice 50 ml of ethyl acetate. The organic extracts are washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate, concentrated under reduced pressure and filtered through silica gel. The residue is crystallised from ethyl acetate and gives 2-(5-acetylaminomethyl-2-thienyl)-acetic acid, thin layer chromatogram (silica gel): Rf=0.61 (system: butanol/acetic acid/water, 45:45:10); infrared absorption spectrum (mineral oil): characteristic bands at 2.95μ, 5.82μ, 6.23μ and 6.38μ.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](O)=[O:20])[CH:17]=2)[N:12](C2CCCCO2)[N:11]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:52]([NH2:56])[CH:53]([CH3:55])[CH3:54]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:56][CH2:52][CH:53]([CH3:55])[CH3:54])=[O:20])[CH:17]=2)[NH:12][N:11]=1
Reactant: O=C(O)c1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Reactant: CC(C)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)CNC(=O)c1ccc2[nH]nc(-c3cc4ccccc4o3)c2c1
Yield: 19 %

Procedure:
The title compound was prepared as described in Example 277 using of 3-benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylic acid (200 mg, 0.55 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (231 mg, 0.61 mmol) and isobutylamine (60 μL, 0.61 mmol); (71 mg, 19% yield). 1H NMR (DMSO-d6) δ 13.8 (s, 1H), 8.7–8.8 (m, 2H), 8.0 (d, 1H), 7.6–7.8 (m, 4H), 7.3–7.5 (m, 2H), 3.2 (m, 2H), 2.0 (m, 1H), 1.0 (d, 6H), ES-MS (m/z) 334 [M+1]+.
Reaction SMILES: [C:1]([C:5]1[O:9][CH:8]=[N:7][C:6]=1[CH:10]=[C:11](O)[C:12]([NH:14][C@H:15]([C:23](=[O:25])[NH2:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[O:9][CH:8]=[N:7][C:6]=1/[CH:10]=[C:11]1/[C:12](=[O:13])[NH:14][C@@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23](=[O:25])[NH:24]/1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ocnc1C=C(O)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ocnc1/C=C1\NC(=O)[C@H](Cc2ccccc2)NC1=O

Procedure:
Using a Dean-Stark trap whose trap part was filled with molecular sieves 3A, a solution of the compound from Example 7 (50 mg, 0.14 mmol) in toluene (20 mL) was refluxed in the presence of p-TsOH (0.8 mg, 0.0042 mmol) for 18 h. After removal of the solvent, the residue was purified by HPLC to obtain the title compound: yield 11.5 mg (23%), mp 52-56° C., 1H NMR (300 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.60 (s, 1H), 8.47 (s, 1H), 7.24-7.13 (m, 5H), 6.37 (s, 1H), 4.52 (m, 1H), 3.20 (dd, J=3.7, 13.6 Hz, 1H), 2.95 (dd, J=5.0, 13.6 Hz, 1H), 1.31 (s, 9H); HRMS (EI): m/z 339.1584 (M+) (calcd for C19H21N3O3: 339.1583); [α]D25−128.9 (c=0.27, DMSO). Enantiomeric excess was determined to be 98% using chiral HPLC with a CHIRALCEL OD column.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[I:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1I
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc([N+](=O)[O-])ccc1I
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
29.30 g (100 mmol) of 2-iodo-5-nitrobenzoic acid are suspended in a mixture of 200 ml of DCM and 1 ml of DMF as solvent. 19.04 g (150 mmol, 1.5 equivalents) of oxalyl chloride are slowly added dropwise at room temperature. The mixture is then stirred at room temperature for two hours and at 30° C. for 30 min. This is followed by evaporation in a rotary evaporator, and the resulting crude product is employed in the following stage.
Reaction SMILES: [N+:1]([C:4]1[CH:71]=[CH:70][C:7]([CH2:8][C:9]([CH2:60][C:61]2[CH:66]=[CH:65][C:64]([N+:67]([O-])=O)=[CH:63][CH:62]=2)([CH2:36][C:37](=[O:59])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][O:43][C:44]2[CH:49]=[CH:48][C:47]([C@H:50]3[CH2:55][CH2:54][C@H:53]([CH2:56][CH2:57][CH3:58])[CH2:52][CH2:51]3)=[CH:46][CH:45]=2)[C:10]([C:13](=[O:35])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C@H:26]3[CH2:31][CH2:30][C@H:29]([CH2:32][CH2:33][CH3:34])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)([OH:12])[OH:11])=[CH:6][CH:5]=1)([O-])=O>[Zn]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]([CH2:60][C:61]2[CH:66]=[CH:65][C:64]([NH2:67])=[CH:63][CH:62]=2)([CH2:36][C:37](=[O:59])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][O:43][C:44]2[CH:45]=[CH:46][C:47]([C@H:50]3[CH2:51][CH2:52][C@H:53]([CH2:56][CH2:57][CH3:58])[CH2:54][CH2:55]3)=[CH:48][CH:49]=2)[C:10]([C:13](=[O:35])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C@H:26]3[CH2:27][CH2:28][C@H:29]([CH2:32][CH2:33][CH3:34])[CH2:30][CH2:31]3)=[CH:22][CH:21]=2)([OH:11])[OH:12])=[CH:70][CH:71]=1
Reactant: CCC[C@H]1CC[C@H](c2ccc(OCCCCCC(=O)CC(Cc3ccc([N+](=O)[O-])cc3)(Cc3ccc([N+](=O)[O-])cc3)C(O)(O)C(=O)CCCCCOc3ccc([C@H]4CC[C@H](CCC)CC4)cc3)cc2)CC1
Agent: [Zn]
Product: CCC[C@H]1CC[C@H](c2ccc(OCCCCCC(=O)CC(Cc3ccc(N)cc3)(Cc3ccc(N)cc3)C(O)(O)C(=O)CCCCCOc3ccc([C@H]4CC[C@H](CCC)CC4)cc3)cc2)CC1

Procedure:
Preparation can be carried out analogously to Synthetic Example 1 using 0.975 g (1.00 mmol) 2,2-bis(4-nitrobenzyl)-1,3-di{6-[4-(trans-4-propylcyclohexyl) phenoxy]hexanoyl}propanediol, 1.62 g (6.00 mmol) Ferric chloride hexahydrate and 0.65 g (10.00 mmol) Zinc powder yield 2,2-bis(4 -aminobenzyl)-1,3-di{6-[4-(trans-4-propylcyclohexyl)phenoxy]hexanoyl}propanediol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([SH:24])=[N:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:16][CH:17]=1)=[O:11].II>>[C:18]1([C:15]2[N:14]=[C:13]3[S:24][N:9]([CH2:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[C:10](=[O:11])[C:12]3=[CH:17][N:16]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(NCCc1ccccn1)c1cnc(-c2ccccc2)nc1S
Agent: II
Product: O=c1c2cnc(-c3ccccc3)nc2sn1CCc1ccccn1
Yield: 91.3 %

Procedure:
Using the procedure of Example 20, 14.0 g (41.6 mmol) of 4-mercapto-2-phenyl-pyrimidine-5-carboxylic acid (2-pyridin-2-yl-ethyl)-amide were treated with 10.6 g (41.7 mmol) of iodine to give 12.7 g of the title compound after recrystallization from ethanol, mp 132°-133° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[CH3:19][O:20][C:21](OC)(OC)OC>O1CCCC1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH3:19][O:20][C:21]1[O:12][C:11]2[C:10]3[CH:9]([CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH2:8][CH2:7][C:6]=3[CH:5]=[CH:4][C:3]=2[N:2]=1
Reactant: COC(OC)(OC)OC
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1nc2ccc3c(c2o1)C(CCNC(C)=O)CC3
Yield: 57.7 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (100 mg, 0.369 mmol) and tetramethoxymethane (151 mg, 1.11 mmol) were heated under reflux in tetrahydrofuran (3.7 mL) for 2 hr. The reaction solution was diluted with ethyl acetate and saturated aqueous sodium hydrogencarbonate solution, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→95/5) to give the title compound (58.4 mg, yield 58%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:28][S:29]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)(=[O:31])=[O:30]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[O:9])=[CH:6][N:5]=[C:4]([NH:38][CH:35]2[CH2:36][CH2:37][N:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:33][CH2:34]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2ccc(C)cc2)c(N)n1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)c2cnc(NC3CCN(S(C)(=O)=O)CC3)nc2N)cc1

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-p-tolyl-methanone (Example 354) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-p-tolyl-methanone. MS (M+H)+, 390
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>CO.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10]
Reactant: N#CCc1ccccc1I
Reactant: OB(O)c1cccc(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: Cc1ccccc1
Product: N#CCc1ccccc1-c1cccc(F)c1F

Procedure:
To a suspension of (2-iodo-phenyl)-acetonitrile (Aldrich, 2.4 g, 10 mmol) and 2,3-difluorophenylboronic acid (Aldrich, 2.4 g, 15 mmol) in anhydrous methanol (10 mL) and toluene (20 mL) was added Cs2CO3 (9.8 g, 30 mmol). The mixture was degassed with nitrogen, followed by the addition of tetrakis(triphenylphosphine)palladium (1.2 g, 1 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[CH:7]=1.I[CH2:28][C:29]1([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:9]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:10][N:11]([CH2:28][C:29]3([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30]3)[N:12]=2)[CH:7]=1
Reactant: OC1(CI)CCCC1
Reactant: COc1ccc(Cl)cc1-c1[nH]ncc1NC(=O)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(CC2(O)CCCC2)cc1NC(=O)c1cnn2cccnc12
Temperature: 140 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
To a solution of N-(5-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (prepared as described for Example 14, 115.4 mg, 0.313 mmol) in 3 mL DMF is added 1-(iodomethyl)cyclopentanol (195.4 mg, 2.762 mmol) and cesium carbonate (339.2 mg, 3.327 mmol). The reaction was stirred in a sealed vessel at 140° C. for 18 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The crude product was separated from the other regioisomeric product and purified by reverse phase HPLC and lyophilized to give 32.1 mg (22%) of N-(3-(5-chloro-2-methoxyphenyl)-1-((1-hydroxycyclopentyl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=467.1; 1H NMR (400 MHz, DMSO-d6) δ: 9.68 (s, 1H), 9.33 (dd, J=7.0, 1.6, 1H), 8.77 (dd, J=4.2, 1.6, 1H), 8.64 (s, 1H), 8.33 (s, 1H), 7.49 (dd, J=8.9, 2.7, 1H), 7.39 (d, J=2.7, 1H), 7.32-7.25 (m, 2H), 4.67 (s, 1H), 4.19 (s, 2H), 3.84 (s, 3H), 1.61 (m, 8H).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)([CH3:5])[C:3]#[N:4].C[N:14](C=O)C>O.[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:3]([C:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[N:14])=[CH:10][CH:11]=1)([CH3:1])[CH3:5])#[N:4]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(C)(C)C#N)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(C)(C#N)c1ccc(C#N)cc1
Temperature: 100 °C
Yield: 85 %

Procedure:
2-methyl-2-(4-methylphenyl)propanenitrile (3.51 g, 15.7 mmol) is dissolved in dry DMF (10 mL). Zn(CN)2 (2.02 g, 17.2 mmol) and Pd(PPh3)4 (906 mg, 5 mol %) are added and the mixture heated at 100° C. for 3 hours. The reaction mixture is diluted with water and the solid recovered by filtration. The solid residue is dissolved in methanol, filtered to remove insoluble impurities, concentrated under vacuo and purified by normal phase MPLC (SiO2, hexane to EtOAc), giving 4-(1-cyano-1-methylethyl)benzonitrile (2.28 g, 13.4 mmol, 85%) as a white solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.70 (s, 6H) 7.73 (dt, J=8.64, 2.03 Hz, 2H) 7.92 (dt, J=8.69, 2.00 Hz, 2H).
Reaction SMILES: [N:1]1([C:6]2[CH:27]=[CH:26][C:9]([CH2:10][C:11]3[C:12](OC)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][C:15]=4C)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>CN(C=O)C.CCOC(C)=O>[N:1]1([C:6]2[CH:27]=[CH:26][C:9]([CH2:10][C:11]3[C:12]([N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1nc2c(C)cc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: CCNCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)c1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 115 °C

Procedure:
A mixture of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline (1.44 g, 3.33 mmol, Intermediate 6, step c) and diethylamine (6.91 mL, 66.5 mmol) in DMF (10 mL) in a sealed tube was heated in a 115° C. oil bath for 23 hours. The mixture was diluted with EtOAc and extracted with water (5×, saturated aqueous NaCl added as needed to achieve phase separation). The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, dry loading, 2-10% EtOAc-Heptane first column, 0-4% EtOAc-Heptane second column) to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:11])[CH2:7][C:6]=2[C:5]([Br:17])=[CH:4][CH:3]=1.Cl[C:19](OC(Cl)(Cl)Cl)=[O:20]>C1(C)C=CC=CC=1>[Br:17][C:5]1[C:6]2[CH2:7][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:11])[O:9][C:10]=2[C:2]([N:1]=[C:19]=[O:20])=[CH:3][CH:4]=1
Reactant: CCOC(=O)C1(C)Cc2c(Br)ccc(N)c2O1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(C)Cc2c(Br)ccc(N=C=O)c2O1
Yield: 104.2 %

Procedure:
By the method of Example 1, Step F, 1.6 grams (0.005 mole) of 7-amino-4-bromo-2-ethoxycarbonyl-2,3-dihydro-2-methylbenzofuran and 1.0 gram (0.005 mole) of trichloromethyl chloroformate were reacted in 60 mL of toluene, yielding about 1.7 grams of 4-bromo-2-ethoxycarbonyl-2,3-dihydro-2-methylbenzofuran-7-yl isocyanate. The product was taken to the next step without further characterization.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].C(N(CC)CC)C.Cl[S:19]([C:22]1[N:26]=[CH:25][NH:24][N:23]=1)(=[O:21])=[O:20].Cl>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][S:19]([C:22]1[N:26]=[CH:25][NH:24][N:23]=1)(=[O:21])=[O:20]
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: O=S(=O)(Cl)c1nc[nH]n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(OS(=O)(=O)c2nc[nH]n2)c(C)c1

Procedure:
4.1 g of 2,4,6-trimethylphenol was dissolved in 15 ml of dichloromethane, and 4.2 ml of triethylamine was added while stirring the solution. Further, 4.6 g of 3-chlorosulfonyl-1,2,4-triazole was gradually added while being cooled with ice and stirred. Then, the solution was stirred at room temperature for 14 hours. After that, 2N hydrochloric acid was added to separate the components. The organic layer was washed with water, and then it was dried with magnesium sulfate. Then, the solvent was removed by distillation, so that coarse crystals were obtained. The coarse crystals were recrystallized from n-hexane/ethyl acetate, so that 3.0 g of the titled compound was obtained.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[C:26](Cl)=[N:25][CH:24]=[CH:23][N:22]=1>C(#N)C>[Cl:20][C:21]1[C:26]([N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)=[N:25][CH:24]=[CH:23][N:22]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Temperature: 100 °C
Reaction time: 40 h
Yield: 99.6 %

Procedure:
A mixture of N-Boc-piperazine (11.47 g, 61.5 mmol), K2CO3 (8.5 g, 61 mmol) and 2,3-dichloropyrazine (9.20 g, 61.7 mmol) in acetonitrile (100 mL) was stirred at 100° C. for 40 h. The reaction mixture was concentrated, dissolved in toluene, washed with water, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel using toluene/EtOAc (7:3) as eluent to give 18.3 g (100%) of the title product. HRMS m/z calcd for C13H19N4O2(M)+298.1197, found 298.1206.