Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:26][O:27][CH2:28][CH3:29])[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O-:23])=[O:22])=[C:15]([CH2:18][O:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:31]([O:34][CH2:35][CH3:36])(=[O:33])C.CN(C)[C:39](=[O:41])[CH3:40]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:26][O:27][CH2:28][CH3:29])[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O:23][CH:39]([O:41][C:31]([O:34][CH2:35][CH3:36])=[O:33])[CH3:40])=[O:22])=[C:15]([CH2:18][O:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)N(C)C
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC)CS[C@H]12)c1csc(N)n1
Reactant: CCOC(C)=O
Agent: [Na+]
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)OC(=O)OCC)=C(COC)CS[C@H]12)c1csc(N)n1

Procedure:
To a solution of 500 mg of sodium 7-[2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate in 5 ml of N,N-dimethylacetamide were added, with ice-cooling, 395 mg of 1-iodoethyl ethylcarbonate, and then the mixture was stirred at room temperature for 30 minutes. At the end of this time, 50 ml of ethyl acetate were added to the reaction mixture, which was then washed with, in turn, 20 ml of water, 20 ml of a saturated aqueous solution of sodium bicarbonate and 20 ml of an aqueous solution of sodium chloride. The mixture was then dried over anhydrous magnesium sulphate and the solvent was removed by distillation under reduced pressure, giving a residue, which was chromatographed through 20 g silica gel eluted with ethyl acetate, to afford 460 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[CH2:17][OH:18].Cl[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[CH2:17][O:18][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: OCc1nc2c(N3CCOCC3)ccnn2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1c(COc2ccc3ccccc3n2)nc2c(N3CCOCC3)ccnn12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of compound 83a (1 g, 3 mmol) and 2-chloroquinoline (780 mg, 4.76 mmol) in N,N-dimethylformamide (20 mL), 60% sodium hydride (200 mg, 5.00 mmol) was added in portions. The reaction mixture was stirred overnight at 80° C. and quenched by the addition of 20 mL of water. The solids were collected by filtration to afford compound 83b as a white solid. Mass Spectrum (LCMS, ESI pos.) Calcd. For C20H18BrN5O2: 440.1 (M+H). Found 440.2.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([C@@H:13]2[C@H:18]([NH:19][C@@H](C3C=CC(OC)=CC=3)C)[CH2:17][CH2:16][S:15][CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH3:3].FC(F)(F)C(O)=O>CC(O)C.Cl>[ClH:1].[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([C@@H:13]2[C@H:18]([NH2:19])[CH2:17][CH2:16][S:15][CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH3:3]
Reactant: CCOc1cc([C@H]2CSCC[C@H]2N[C@H](C)c2ccc(OC)cc2)ccc1OC
Agent: Cl
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc([C@H]2CSCC[C@H]2N)ccc1OC
Temperature: 25 °C

Procedure:
A mixture of (3R,4R)-3-(3-Ethoxy-4-methoxy-phenyl)-N-[(1R)-1-(4-methoxy-phenyl)-ethyl]-tetrahydro-2H-thiopyran-4-amine hydrochloride (1.0 g; compound C14) and trifluoroacetic acid (2 ml) is stirred at reflux temperature for 30 min yielding a dark red solution. Cooled to RT the solution is evaporated, the dark viscous residue is dissolved in a mixture of diethylether (5 ml) and water (5 ml) and the pH of the solution is increased up to 10 by adding some drops of a 40% aqueous solution of sodium hydroxide. The mixture is extracted with diethylether, the organic phase is washed with a saturated aqueous solution of NaHCO3 and then extracted two times with a 20% aqueous solution of citric acid. The pH of the collected aqueous acid solutions of about 2.4 is increased up to 10 by adding a 40% NaOH solution and the basic mixture is extracted with diethylether. The organic phase is washed two times with water, dried over sodium sulfate and then evaporated to give an oily residue. This is dissolved in 2-propanol (10 ml) and to the stirred solution a 5-6 M solution of hydrogen chloride in 2-propanol (1 ml) is added dropwise at RT inducing a spontaneous crystallization. The slurry is concentrated to about half of the volume and stirred for 15 h at RT. The crystals are filtered off, washed with 2-propanol (2 ml), dried in vacuo at 40° C. to give the title compound. M.p. 233° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C@@H:12]3[CH2:16][CH2:15][NH:14][CH2:13]3)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C@@H:12]3[CH2:16][CH2:15][N:14]([CH2:26][CH2:27][CH:28]=[C:29]4[C:35]5[CH:36]=[CH:37][CH:38]=[N:39][C:34]=5[CH2:33][O:32][C:31]5[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]4=5)[CH2:13]3)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: O=C1CN([C@@H]2CCNC2)Cc2ccc(Cl)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CC[C@@H](N3CC(=O)Nc4cc(Cl)ccc4C3)C1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 48 h
Yield: 28.7 %

Procedure:
To a solution of (R)-8-chloro-4-pyrrolidin-3-yl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.198 g, 0.58 mmol) in acetonitrile/water (8:2) (5.8 mL) was added K2CO3 (0.655 g, 4.6 mmol) and 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.183 g, 0.48 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated down and partitioned between EtOAc/H2O, extracted with EtOAc (3×). The organics were collected together dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (5% methanol/95% methylene chloride to 10% methanol/90% methylene chloride to 15% methanol/85% methylene chloride) to yield the title compound (0.077 g, 28%). 1H-NMR (CDCl3): δ 1.55 (s, 6H), 1.74 (septet, 1H), 2.01 (sextet, 1H), 2.32–2.60 (m, 6H), 2.76 (t, 1H), 3.26 (pentet, 1H), 3.43 (d, 1H), 3.46 (s, 2H), 3.74 (s, 2H), 5.27 (bs, 2H), 6.12 (t, 1H), 6.78 (d, 1H), 6.96 (s, 1H), 7.06 (dd, 1H), 7.13 (d, 1H), 7.19–7.27 (m, 2H), 7.44 (d, 1H), 7.55 (dd, 1H), 8.47 (dd, 1H), 8.49 (s, 1H). ESI-MS m/z: 559 (M+1), retention time 1.24.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([C:12]#N)[CH:9]=[C:8]([CH3:14])[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C1C[O:25]CC1>[Zn].CS(O)(=O)=O>[N:1]1([C:6]2[N:11]=[C:10]([C:12](=[O:25])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]=[C:8]([CH3:14])[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)CBr
Reactant: C1CCOC1
Reactant: Cc1cc(C#N)nc(-n2ccnc2)n1
Agent: CS(=O)(=O)O
Agent: [Zn]
Product: CCOC(=O)CC(=O)c1cc(C)nc(-n2ccnc2)n1
Temperature: 67 °C
Reaction time: 1 h

Procedure:
Methanesulfonic acid (200 μL, 3.08 mmol) was added dropwise to a suspension of zinc powder (70.4 g, 1.08 mol) in anhydrous THF (228 mL) and the mixture was heated to 67° C. After 1 hour, a solution of 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carbonitrile (20.0 g, 108 mmol) in THF (120 mL) was added followed by subsequent dropwise addition of ethyl 2-bromoacetate (90.8 g, 540 mmol) over a period of 1.5 h. The mixture was stirred for an additional 30 minutes at 67° C. then cooled to rt. The inorganic solids were removed by vacuum filtration, washed with THF (200 mL), and the filtrate was brought to pH=1 with 3 M hydrochloric acid (200 mL). The solution was stirred for 30 minutes at rt prior to removal of the solvent under vacuum. Ethyl 3-(2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)-3-oxopropanoate (14.3 g) was obtained as yellow solid and was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[O:4][N:3]=1.[C:23]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH:23]1([N:18]2[CH2:19][CH2:20][C:21]3=[CH:22][N:13]([C:10]4[CH:11]=[CH:12][C:7]([C:5]5[O:4][N:3]=[C:2]([CH3:1])[N:6]=5)=[CH:8][CH:9]=4)[N:14]=[C:15]3[CH2:16][CH2:17]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCC1
Reactant: Cc1noc(-c2ccc(-n3cc4c(n3)CCNCC4)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1noc(-c2ccc(-n3cc4c(n3)CCN(C3CCCC3)CC4)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Description 35) (31 mg, 0.10 mmol) in dichloromethane (4 ml) was added cyclopentanone (35 mg, 0.42 mmol) and acetic acid (3 drops). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (89 mg, 0.42 mmol) was added and stirring continued overnight. The resulting crude mixture was diluted with methanol and then purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo to afford the title compound (E27). MS (ES+) m/e 364 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:19]([CH:25]4[CH2:27][CH2:26]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:3]=1.[CH3:32][O:33][CH2:34][C@@H:35]1[CH2:39][O:38][C:37](=[O:40])[NH:36]1>>[CH:22]1([C:21]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:36]5[C@H:35]([CH2:34][O:33][CH3:32])[CH2:39][O:38][C:37]5=[O:40])=[CH:3][C:4]=4[S:28]([CH3:31])(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=[C:19]([CH:25]3[CH2:27][CH2:26]3)[CH:20]=2)[CH2:24][CH2:23]1
Reactant: COC[C@@H]1COC(=O)N1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)c(S(C)(=O)=O)c1
Yield: 31.5 %

Procedure:
By reaction and treatment in the same manner as in Example 111 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (400 mg) described in Preparation Example 89 and (R)-4-methoxymethyloxazolidin-2-one (104 mg) described in Preparation Example 38, the title compound (138.6 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH2:20][CH2:21][C:22]#[N:23])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C:24](=[O:29])[C@@H:25]([O:27][CH3:28])[CH3:26])[N:10]=1.Cl.Cl.[O:32]([NH2:34])[CH3:33].C(N(CC)CC)C>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH2:20][CH2:21][C:22](=[N:34][O:32][CH3:33])[NH2:23])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C:24](=[O:29])[C@@H:25]([O:27][CH3:28])[CH3:26])[N:10]=1
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCC#N)c1ccccc1
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CON=C(N)CCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)[C@H](C)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 25 %

Procedure:
To cooled (0° C.) solution of 3-(5-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propanenitrile (0.052 g, 0.13 mmol, Example 14, Step C) in ethanol (0.5 mL) was added 9.8 M ethanolic HCl (0.5 mL, 4.9 mmol). After stirring at room temperature for 6 hours, the mixture was concentrated under reduced pressure. To the residue was added methoxylamine hydrochloride (0.021 g, 0.21 mmol), absolute ethanol (0.5 mL) and triethylamine (0.087 mL, 0.63 mmol). After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure. The residue was diluted with 10% Na2CO3 (30 mL) and extracted with dichloromethane. The combined organics were dried, filtered and concentrated under reduced pressure. The residue was chromatographed (40% ethyl acetate in hexanes) to afford the product as a mixture of diastereomers (14 mg, 25% yield). MS ESI (+) m/z 463 (M+1) detected; 1H NMR (4001 MHz, CDCl3) δ 7.50 (m, 2H), 7.38 (m, 8H), 7.30 (m, 2H), 7.13 (m, 4H), 4.78 (q, 1H, J=6.3 Hz), 4.72 (q, 1H, J=6.3 Hz), 4.64 (br. s, 4H), 3.77 (s, 6H), 3.54 (m, 2H), 3.41 (s, 3H), 3.36 (s, 3H), 2.68 (m, 4H), 2.18 (m, 2H), 1.51 (d, 3H, J=6.3 Hz), 1.49 (d, 3H, J=7.0 Hz).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16].O>CN(C)C=O>[F:16][C:15]([F:18])([F:17])[CH2:14][CH2:13][CH:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: FC(F)(F)CCBr
Reactant: N#CCC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
27.6 g of malononitrile was dissolved in 50 ml of N,N-dimethylformamide and 27.6 g of potassium carbonate was added thereto, followed by stirring for 1 hour at room temperature. To the solution was added the mixture of 17.7 g of 1-bromo-3,3,3-trifluoropropane and 20 ml of N,N-dimethylformamide and stirred for 1 hour. Then, the reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to give 11.3 g of 2-(3,3,3-trifluoropropyl)malononitrile.
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4].Cl.ClC1C=C(C(=O)C(NC(C)(C)C)C)C=CC=1.C(N(CC)CC)C.[NH2:41][S:42]([C:45]1[C:46]([Cl:63])=[CH:47][C:48]([NH:56][CH2:57][C:58]2[O:59][CH:60]=[CH:61][CH:62]=2)=[C:49]([CH:55]=1)[C:50]([O:52][CH2:53]Cl)=[O:51])(=[O:44])=[O:43]>C(#N)C>[NH2:41][S:42]([C:45]1[C:46]([Cl:63])=[CH:47][C:48]([NH:56][CH2:57][C:58]2[O:59][CH:60]=[CH:61][CH:62]=2)=[C:49]([CH:55]=1)[C:50]([O:52][CH2:53][N:12]([C:13]([CH3:15])([CH3:14])[CH3:16])[CH:2]([CH3:1])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4])=[O:51])(=[O:43])=[O:44]
Reactant: CC(NC(C)(C)C)C(=O)c1cccc(Cl)c1
Reactant: NS(=O)(=O)c1cc(C(=O)OCCl)c(NCc2ccco2)cc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C(=O)c1cccc(Cl)c1)N(COC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1)C(C)(C)C

Procedure:
A solution of bupropion[1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride (700), (U.S. Pat. No. 3,819,706 and U.S. Pat. No. 3,885,046) (0.025 mole), triethylamine (0.055 mole) and acetonitrile (30 mL) is stirred with cooling on an ice bath. A solution of chloromethyl 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoate (15) (0.025 mole) in acetonitrile (30 mL) is added dropwise. After the addition is complete, the reaction is heated to reflux for 2 hours. The reaction is cooled, the volatiles removed by spin evaporation, and the residue partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The organic layer is washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that may be recrystallized to give 2-[(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethyl)(1,1-dimethylethyl)amino]-1-(3-chlorophenyl)-1-propanone (720). See eg., U.S. Pat. No. 5,104,870 and Sandler, et al., Organic Functional Group Preparations, p. 324 (1968).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:28][C:17]3=[CH:18][N:19]=[C:20]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:29]([S:32](Cl)(=[O:34])=[O:33])([CH3:31])[CH3:30].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:28][C:17]3=[CH:18][N:19]=[C:20]([N:22]4[CH2:23][CH2:24][N:25]([S:32]([CH:29]([CH3:31])[CH3:30])(=[O:34])=[O:33])[CH2:26][CH2:27]4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(N4CCNCC4)ncc3O2)CC1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N1CCN(c2cc3c(cn2)OC(C2CCN(C(=O)OC(C)(C)C)CC2)C3)CC1

Procedure:
The title compound is prepared by treatment of 4-(5-piperazin-1-yl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester with isopropylsulfonyl chloride in dichloromethane in the presence of triethylamine. LC (method 10): tR=1.48 min; Mass spectrum (ESI+): m/z=495 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[Cl:19][C:20]1[N:25]2[N:26]=[C:27]([CH3:29])[CH:28]=[C:24]2[N:23]=[C:22]([NH2:30])[C:21]=1[CH3:31]>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:30][C:22]2[C:21]([CH3:31])=[C:20]([Cl:19])[N:25]3[N:26]=[C:27]([CH3:29])[CH:28]=[C:24]3[N:23]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[N:25]2[N:26]=[C:27]([CH3:29])[CH:28]=[C:24]2[N:23]=[C:22]([NH:30][C:9](=[O:10])[CH3:8])[C:21]=1[CH3:31]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Cc1cc2nc(N)c(C)c(Cl)n2n1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)Nc1nc2cc(C)nn2c(Cl)c1C
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)C)cc3)c(C)c(Cl)n2n1
Temperature: 100 °C
Yield: 9 %
Yield: 31 %

Procedure:
7-Chloro-2,6-dimethylpyrazolo[1,5-a]pyrimidin-5-amine (5E, 1.0 equivalent) and 4-t-butylbenzoic acid chloride (2.0 equivalents) were dissolved in DMA (0.5 M with respect to 5E) and were heated to 100° C. for 18 h. After cooling to room temperature, saturated NaHCO3 was added and the mixture was extracted with EtOAc. Combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by chromatography (SiO2) to give 4-tert-butyl-N-(7-chloro-2,6-dimethylpyrazolo[1,5-a]pyrimidin-5-yl)benzamide (5F, 31%) and N-(7-chloro-2,6-dimethylpyrazolo[1,5-a]pyrimidin-5-yl)acetamide (5G, 9%) as white solids.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:6])=[O:5].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O.C(O)C>[C:8]1(/[CH:7]=[CH:3]/[C:4](=[O:5])/[CH:6]=[CH:7]/[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1

Procedure:
(3) Hill and Barbaro, Experiments in Organic Chemistry. Contemporary Publishing Co. of Raleigh, Inc., Raleigh, 1996. 5 g of sodium hydroxide, dissolved in 25 ml of water and 25 ml of 95% ethanol, was cooled to 20 to 25° C. 2.9 g (50 mmol) of acetone and 10.6 g (100 mmol) of benzaldehyde were added, and a yellow precipitate formed. After 20 minutes the solution was filtered, and the solid was recrystallized from ethyl acetate to afford 10.1 g (86.3%) of bright-yellow platelets: mp 111.9-112.5° C. (lit. mp 112° C., Hill and Barbaro, supra). 1H NMR (250 MHz) δ 7.79-7.73 (d, 1H), 7.65-7.61 (m, 4H), 7.44-7.41 (t, 6H), 7.13-7.07 (d, 1H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CC(C)=O>[CH2:21]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2)[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: O=C1NCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(c1)CCNC2=O

Procedure:
To a solution of 6-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline (23.8 g, 146 mmol) in acetone (350 mL) is added K2CO3 (34.6 g, 219 mmol) and allyl bromide (19.3 g, 161 mmol). The reaction mixture is then heated to reflux for 24 hours. After this time the solution is filtered and subsequently concentrated in vacuo. The resulting material is washed with hexanes (1×200 mL) and Et2O (1×100 mL) to give 6-allyloxy-l,2,3,4-tetrahydroisoquinolin-1-one as a tan solid, m.p. 105°-107°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[C:11]1([P:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:18]C)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>ClC1C=CC=CC=1Cl>[C:11]1([P:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:2]2[CH:7]=[C:6]([P:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)([C:28]3[CH:27]=[CH:26][CH:31]=[CH:30][CH:29]=3)=[O:18])[N:5]=[C:4]([S:9][CH3:10])[N:3]=2)=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCCCC
Reactant: COP(c1ccccc1)c1ccccc1
Reactant: CSc1nc(Cl)cc(Cl)n1
Solvent: Clc1ccccc1Cl
Product: CSc1nc(P(=O)(c2ccccc2)c2ccccc2)cc(P(=O)(c2ccccc2)c2ccccc2)n1

Procedure:
To a stirred refluxing solution of 5.00 g of 4,6-dichloro-2-methylthiopyrimidine in 150 ml of o-dichlorobenzene under nitrogen was added dropwise 15.00 g of methyl diphenylphosphinite over 35 minutes. The mixture was refluxed for 5.5 hours after the addition was completed and then allowed to cool, at which time it was added to 850 ml of n-hexane. The resulting solid was separated by filtration, washed with n-hexane, and recrystallized from 100 ml of ethanol to give 11.00 g of 4,6-bis(diphenylphosphinyl)-2-methylthiopyrimidine as white crystals, mp 221°-222° C. Anal. Calcd for C29H24N2O2P2S: C, 66.15; H, 4.59; N, 5.32. Found: C, 65.59, 65.59; H, 4.54, 4.75; N, 5.04, 5.01.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CN1CCC[C@@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@H]5CCCN5C)n4c3)c3ccccc32)cc1

Procedure:
A solution of Intermediate 60b (123 mg, 0.339 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 140 mg, 0.346 mmol) in 1,4-dioxane (4 mL) and DIPEA (91 μL, 0.52 mmol) was stirred at 93° C. for 3.25 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-20% MeOH in DCM, to give the impure product. Further purification by HPLC (C, 18 X-select column, 25-70% MeCN in H2O, 0.1% formic acid) gave the title compound as a white powder after freeze-drying (118 mg, 56%). LCMS (Method 5): Rt 3.67 min, m/z 619.2 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.80-2.27 (1H, m), 2.31-2.40 (4H, m), 3.11-3.18 (1H, m), 3.98 (1H, t, J 8.2), 4.78-4.86 (1H, m), 5.42 (1H, t, J 4.3), 6.32 (1H, s), 7.09 (1H, d, J 8.5), 7.26-7.42 (9H, m), 7.75 (1H, dd, J 9.7, 1.0), 8.03 (1H, s), 8.28 (1H, d, J 1.0).