Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH:9]=1.FC1C=CC=CC=1C1CCC(=O)C=C1.[H][H]>[Pd].C(OC(=O)C)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: O=C1CC=C(c2ccccc2F)CC1
Agent: [Pd]
Agent: O=C1C=CC(c2ccccc2F)CC1
Solvent: CCOC(C)=O
Product: O=C1CCC(c2ccccc2F)CC1

Procedure:
To a suspension of palladium on carbon (1.1 g) in 100 mL ethylacetate was added the mixture of 4-(2-Fluoro-phenyl)-cyclohex-3-enone and 4-(2-Fluorophenyl)-cyclohex-2-enone (5.1 g) under argon. The suspension was placed under 50 psi hydrogen for 36 h, filtered through celite, concentrated in vacuo, and passed through silica (10% ethylacetate, hexane) to give 4-(2-fluorophenyl)-cyclohexanone (3.5 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]([CH3:32])[C:6]([C:8]1[N:9]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]([C:21]([F:24])([F:23])[F:22])=[C:11]([CH3:20])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[O:7].CCN(CC)CC.[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:40]([NH:2][CH2:3][CH2:4][N:5]([CH3:32])[C:6]([C:8]1[N:9]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:10]([C:21]([F:23])([F:24])[F:22])=[C:11]([CH3:20])[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[O:7])(=[O:42])[CH3:41]
Reactant: CC(=O)Cl
Reactant: Cc1c(-c2ccc(Cl)cc2)c(C(=O)N(C)CCN)n(Cc2ccccc2)c1C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCN(C)C(=O)c1c(-c2ccc(Cl)cc2)c(C)c(C(F)(F)F)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of N-(2-aminoethyl)-1-benzyl-3-(4-chlorophenyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide hydrochloride (150 mg, 0.308 mmol) in DCM (2 mL) were added dropwise Et3N (0.094 mL, 0.679 mmol) and acetyl chloride (0.024 mL, 0.339 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM and saturated aqueous NaHCO3. The layers were separated using a phase separator and the solvents were evaporated. The product was purified by flash column chromatography (silica, gradient heptane/EtOAc, 1:2→0:1) to afford 106 mg (70%) of SC-37.
Reaction SMILES: Cl[CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[N-:14]=[N+:15]=[N-:16].[Na+]>CS(C)=O>[N:14]([CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])=[N+:15]=[N-:16]
Reactant: O=C1Nc2ccccc2CCC1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC1CCc2ccccc2NC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-chloro-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (15.9 g, 0.08 mol) and sodium azide (6.36 g, 0.10 mol) in dimethylsulfoxide (320 ml) was maintained at 80° C. under an atmosphere of nitrogen for 3 hours. At this time, the IR spectrum of an aliquot showed a strong peak at 2150 cm-1 characteristic of the azide group. The reaction mixture was poured into 1000 ml of ice/water and the suspension was stirred for 30 min. The solid was filtered off, washed with water (250 ml) and dried to give 3-azido-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 142°-5°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:11]=[N:10][CH:9]=[CH:8][C:5]=1[C:6]#N.C([O-])(O)=[O:13].[Na+]>Cl>[C:6]1(=[O:13])[C:5]2[CH:8]=[CH:9][N:10]=[CH:11][C:4]=2[CH2:3][CH2:2][O:1]1
Reactant: O=C([O-])O
Reactant: N#Cc1ccncc1CCO
Agent: Cl
Agent: [Na+]
Product: O=C1OCCc2cnccc21
Yield: 15.29 %

Procedure:
3-(2-Hydroxyethyl) isonicotinonitrile (I-67d: 650 mg, 4.362 mmol) was heated with concentrated HCl (10 mL) at 100° C. overnight. The reaction mass was neutralized with NaHCO3 solution, extracted using DCM and the organic layer was concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 100 mg of the product (15.29% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1CCC[CH2:6][N:5]1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:11]=1.ClC1N=CN=C(N[C:36]2[CH:37]=[C:38]([CH2:42]S(N)(=O)=O)C=C[CH:41]=2)N=1.N[C:48]1C=C(CCS(N)(=O)=O)C=C[CH:53]=1>>[O:2]([CH2:3][C@H:4]1[CH2:53][CH2:48][CH2:6][N:5]1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:25])=[O:26])[CH:20]=[CH:21][CH:22]=2)[N:11]=1)[C:1]1[CH:42]=[CH:38][CH:37]=[CH:36][CH:41]=1
Reactant: Nc1cccc(CCS(N)(=O)=O)c1
Reactant: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCC[C@@H]3COc3ccccc3)n2)c1

Procedure:
B28 was prepared following the procedure reported for B4 using the intermediates A1 and A3. It was obtained as a white crystalline powder; yield: 140 mg (35%). MS (ES) C21H24N6O3S requires: 440. found: 441 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[C:8]([C:9]([O:11]CC)=[O:10])=[C:7]([CH2:14][CH3:15])[C:6]([C:16]([O:18]CC)=[O:17])=[C:5]([C:21]([F:24])([F:23])[F:22])[N:4]=1.CO.[OH-].[K+]>O>[F:25][CH:2]([F:1])[C:3]1[N:4]=[C:5]([C:21]([F:24])([F:22])[F:23])[C:6]([C:16]([OH:18])=[O:17])=[C:7]([CH2:14][CH3:15])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1CC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1c(C(=O)O)c(C(F)F)nc(C(F)(F)F)c1C(=O)O
Yield: 52.3 %

Procedure:
A 1-liter flask is charged with 60 g (0.163 mole) of the product of Example 12 and 200 ml of methyl alcohol. In another flask, 150 ml of water and 21.52 g (0.326 mole) of potassium hydroxide are combined. The aqueous KOH is poured into the 1-liter flask and the mixture is heated to reflux overnight. The reaction mixture is cooled and extracted once with ethyl ether. The aqueous layer is acidified with concentrated hydrochloric acid and extracted with ethyl ether. The organics are dried on anhydrous magnesium sulfate, filtered, and concentrated to yield 26.72 g (52%) of the desired product, m.p. 237°-239° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:46]([N+:50]1[N:54]=[C:53]([CH3:55])[S:52][C:51]=1[CH3:56])[CH2:47][CH2:48][CH3:49]>>[CH2:46]([N:50]1[N:54]=[C:53]([CH3:55])[S:52]/[C:51]/1=[CH:56]\[C:4]([C:3]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=1[Cl:1])=[O:6])[CH2:47][CH2:48][CH3:49]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2,5-dichlorobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.27-1.35 (m, 2 H) 1.67-1.76 (m, 2 H) 2.50 (s, 3 H) 4.16 (t, 2 H) 6.25 (s, 1 H) 7.46-7.53 (m, 2 H) 7.55-7.57 (m, 1 H); MS (ESI) m/z 343 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[Na+].[C:7]([O:12]C)(=O)[CH:8]([CH3:10])[CH3:9].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:24][C:25]1[C:30](Cl)=[N:29][CH:28]=[CH:27][N:26]=1>C(OCC)C>[Cl:24][C:25]1[C:30]([C:8]([CH3:9])([CH3:10])[C:7]([O:4][C:2]([CH3:5])([CH3:3])[CH3:1])=[O:12])=[N:29][CH:28]=[CH:27][N:26]=1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C(C)C
Reactant: Clc1nccnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C(C)(C)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
Sodium tert-butoxide (7.2 g, 74.9 mmol) was suspended in diethyl ether (2500 mL) under argon. Methyl isobutyrate (6.0 ml, 58.7 mmol) was added and the mixture stirred at room temperature for 3 hours. The suspension was filtered through a pad of neutral alumina and concentrated under reduced pressure to −50 mL. The crude product was placed under argon and bromo[tri-tert-butylphosphine]dipalladium(1)dimer (0.282 g, 0.363 mmol) was added. The solution was cooled in an ice/acetone bath and lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 55 ml, 55.0 mmol) was added. The solution was stirred for minutes. 2,3-Dichloropyrazine (5.0 ml, 48.0 mmol) was added neat and after another 5 minutes the mixture was heated at 50° C. for 40 hours. The mixture was cooled and partitioned between water (400 mL), saturated ammonium chloride (100 mL) and ethyl acetate (400 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude product was purified using silica chromatography (hexane to ethyl acetate gradient) to give tert-butyl 2-(3-chloropyrazin-2-yl)-2-methylpropanoate (8.51 g, 33.1 mmol, 69.0% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][N:10]([CH3:14])[C:11](Cl)=[O:12]>N1C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:11](=[O:12])[N:10]([CH3:14])[CH3:9])[CH:3]=[N:4][CH:5]=1
Reactant: Nc1cncc(Br)c1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: CN(C)C(=O)Nc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
3-Amino-5-bromo pyridine (XX) (1.0 g, 5.78 mmol) was dissolved in pyridine and cooled to 0° C. before adding dimethyl carbamyl chloride (XXI) (0.683 g, 6.35 mmol). The reaction mixture was stirred at room temperature for 2 h and then heated overnight at 60° C. under argon. The solution was cooled to room temperature, poured into ice water and extracted with EtOAc. The organic extract was dried over MgSO4, filtered and concentrated to a residue to afford 3-(5-bromopyridin-3-yl)-1,1-dimethylurea (XXII) as a brown solid, (1.24 g, 5.09 mmol, 88% yield). 1H NMR (DMSO-d6) δ ppm 8.67-8.64 (m, 2H), 8.23 (d, J=7.8 Hz, 1H), 2.93 (s, 6H); ESIMS found for C8H10BrN3O m/z 245.05 (M+H).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].[H-].[Na+].CS(C)=O.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>O1CCCC1.O>[C:2](=[N:4][O:5][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)([CH3:3])[CH3:1]
Reactant: CC(C)=NO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)=NOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of propanone oxime (30 g, 0.4 mole) in dry tetrahydrofuran (300 ml) was added slowly to a suspension of sodium hydride (10.8 g, 0.45 mole) in dry tetrahydrofuran (50 ml). After gas evolution was complete, dimethylsulphoxide (100 ml) and 4-fluoronitrobenzene (57.85 g, 0.41 mole) were added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into water and extracted three times with ether. The combined ether extracts were washed with water, dried (MgSO4) and evaporated to give the title compound which was granulated in hexane and filtered, yield 67 g. A sample (7 g) was recrystallised from ethanol, yield 5 g, m.p. 104°-106°.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:19])[NH:6][C:7]1[N:8]([CH2:16][CH2:17][OH:18])[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:33]2[CH:34]=[C:35]([O:38][C@H:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[C@@H:42]([NH2:49])[CH2:41][CH2:40]3)[CH:36]=[CH:37][C:32]2=[N:31][N:30]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:49][C@@H:42]2[C:43]3[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@H:39]([O:38][C:35]3[CH:36]=[CH:37][C:32]4[N:33]([C:29]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[Cl:22])=[N:30][N:31]=4)[CH:34]=3)[CH2:40][CH2:41]2)=[O:19])[N:8]([CH2:16][CH2:17][OH:18])[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCO)n1
Reactant: N[C@H]1CC[C@@H](Oc2ccc3nnc(-c4ccccc4Cl)n3c2)c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(-c5ccccc5Cl)n4c3)c3ccccc32)n(CCO)n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
A mixture of Intermediate 26a (340 mg, 0.95 mmol), Intermediate 31c (372 mg, 0.95 mmol), and DIPEA (248 μL, 1.43 mmol) in dioxane (5 mL) was stirred at 70° C. for 18 h. After cooling to RT, the reaction mixture was partitioned between DCM and water. The organic layer was dried through a phase separator and then concentrated in vacuo. The resultant residue was purified by FCC, using 0-10% MeOH in DCM to afford the title compound (536 mg, 94%) as a brown solid. An aliquot of the compound thus obtained (100 mg) was further purified by MDAP (Method 7) to afford the title compound (45 mg). LCMS (Method 5): Rt 4.08 min, m/z 600 [MH+]. 1H NMR (400 MHz, DMSO): 1.20 (9H, s), 1.81-2.19 (4H, m), 3.66 (2H, d, J=6.1 Hz), 3.93 (2H, t, J=6.0 Hz), 4.78-4.84 (1H, m), 4.98 (1H, br s), 5.51 (1H, t, J=4.3 Hz), 6.05 (1H, s), 7.06 (1H, d, J=8.6 Hz), 7.23-7.30 (1H, m), 7.32-7.38 (4H, m), 7.60 (1H, td, J=7.5, 1.3 Hz), 7.68 (1H, td, J=7.7, 1.9 Hz), 7.73 (2H, td, J=7.5, 1.3 Hz), 7.82-7.92 (2H, m), 8.17 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[NH:10][N:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[C:23](=O)([O-])[O-].[Cs+].[Cs+].C([CH:31]1[O:33][CH2:32]1)Cl>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]([CH3:23])[N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH:32]3[CH2:31][O:33]3)[N:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: CC(=O)N1CCc2[nH]nc(-c3ccc(Cl)c([N+](=O)[O-])c3)c2C1
Reactant: O=C([O-])[O-]
Reactant: ClCC1CO1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)c([N+](=O)[O-])c3)nn2C2CO2)C1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.5 %

Procedure:
A solution of 1-[3-(4-chloro-3-nitro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (6.4 g, 20.0 mmol) in DMF (60 mL) was treated with cesium carbonate (13.0 g, 40 mmol) and epichlorohydrin (15.6 mL, 200.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for an additional 24 h before it was diluted with ethyl acetate (350 mL) and water (50 mL). The organic layer was separated, washed with water (2×50 mL), brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 10% acetone/CH2Cl2) to provide 7.5 g (83%) of a light yellow powder. MS (electrospray): m/z 377.0 (377.0, calculated for C17H17ClN4O4, [M+H]+). 1H NMR (CDCl3, 400 MHz, a mixture of two rotamers): 8.15-8.05 (m, 1H), 7.75-7.65 (m, 1H), 7.55-7.45 (m, 1H), 4.80-4.65 (m, 1.2H), 4.60 (s, 0.8H), 4.45-4.35 (m, 1H), 4.08-4.02 (m, 1H), 3.92-3.80 (m, 1H), 3.70-3.63 (m, 1H), 3.30-3.20 (m, 1H), 2.90-2.67 (m, 3H), 2.55-2.48 (m, 1H), 2.15 (s, 1.7H), 2.10 (s, 1.3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:26][NH:27][O:28][CH3:29]>C(Cl)Cl.CCOCC>[CH3:29][O:28][N:27]([CH3:26])[C:10](=[O:12])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CNOC
Reactant: CSc1ccc(CC(=O)O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: ClCCl
Product: CON(C)C(=O)Cc1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.8 %

Procedure:
To a solution of 4-(methylthio)phenylacetic acid (18.3 g, 0.100 mol) in methylene chloride (200 mL) was added 1,1'-carbonyldiimidazole (16.3 g, 0.100 mol) portionwise. The mixture was stirred at room temperature for 20 minutes, and N,O-dimethylhydroxylamine hydrochloride (9.8 g, 0.100 mol) was added. The reaction mixture was stirred overnight at room temperature, diluted with ether (500 mL) and washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo to give 20.9 g of N-methoxy-N-methyl-4-(methylthio)-benzeneacetamide as a clear oil (93%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][C@H:6]([OH:8])[C@@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.C(N(CC)CC)C.[O:19]=[P:20](Cl)([Cl:22])[Cl:21]>C1(C)C=CC=CC=1>[P:20]([Cl:22])([Cl:21])([O:8][CH:6]1[CH:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:7]1)=[O:19]
Reactant: CC(C)[C@H]1CC[C@H](C)C[C@@H]1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1CCC(C(C)C)C(OP(=O)(Cl)Cl)C1
Temperature: 25 °C
Reaction time: 23 h
Yield: 99 %

Procedure:
A solution of 7.5 g (48 mmol) of (1S, 2R, 5S)-(+)-menthol (Aldrich) and 4.86 g (48 mmol) of triethylamine in 20 ml of toluene was dropped into 7.36 g (48 mmol) of POCl3 at 0° C. The entire solution was stirred for 23 hours at room temperature. The insoluble triethylamine hydrochloride was filtered and the solvent was evaporated. Yield 99%, 31P NMR δ 6.76 (CDCl3). (lit. T. Milobedzki, W. Janczak, Roczniki Chemji 11, 840 (1931)).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.Cl.[CH3:14]COC(C)=O>CO>[Cl:1][C:2]1[C:3]([C:10]([O:12][CH3:14])=[O:11])=[N:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1
Reactant: Cn1nc(C(=O)O)c(Cl)cc1=O
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CO
Product: COC(=O)c1nn(C)c(=O)cc1Cl
Temperature: 25 °C
Yield: 17 %

Procedure:
A solution of 4-chloro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (390 mg, 2.07 mmol) and conc. HCl (0.10 mL) in MeOH (6 mL) was refluxed for 8 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude material that was redissolved into EtOAc. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (100% hexanes to 10 to 20 to 30 to 50% EtOAc in hexanes) to afford 72 mg (17%) of the desired product.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[CH2:31]([O:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][CH:18]=3)[CH2:8][CH2:7]2)(=[O:22])=[O:23])=[CH:25][CH:26]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(C#N)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(C#N)cc3)CC2)cc1

Procedure:
4(4Butoxy-benzenesulfonyl)-1-(4cyanobenzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-carboxylic ethyl ester (10.0 g, 124 mmol) dissolved in THF:Methanol (75:50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 0.7 g (11%); off white solid; MS: 456.0 (M+H)+
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Br:10])=[C:5]([Br:9])[C:6]=1[C:7]#[N:8].CC(C)([O-])C.[K+].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>O1CCCC1.O.C(OCC)(=O)C>[Br:1][C:2]1[N:3]([C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([Cl:17])=[CH:19][CH:20]=2)[C:4]([Br:10])=[C:5]([Br:9])[C:6]=1[C:7]#[N:8]
Reactant: N#Cc1c(Br)[nH]c(Br)c1Br
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1c(Br)c(Br)n(C(=O)c2ccc(Cl)cc2)c1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2,4,5-tribromopyrrole-3-carbonitrile (5.0 g, 0.015 mol) and potassium t-butoxide (2.0 g, 0.018 mol) in dry tetrahydrofuran is stirred for 10 minutes at room temperature, treated dropwise with a solution of p-chlorobenzoyl chloride (3.25 g, 0.018 mol) in tetrahydrofuran, heated at reflux temperature for 3 hours, cooled and diluted with a mixture of water and ethyl acetate. The organic phase is separated, washed with brine, dried over Na and concentrated in vacuo to afford a tan solid residue. Recrystallization from benzene gives the title compound as a cream colored solid, 2.9 g (41.4%), mp 154°-157° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](=[O:29])[O:12][C:13]2C(C=1)=CC=C(N1CCN(CCO)CC1)C=2.C(N(C(C)C)CC)(C)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:13][O:12][C:11](=[O:29])[CH2:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: O=c1oc2cc(N3CCN(CCO)CC3)ccc2cc1-c1nc2ccccc2s1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Cc1nc2ccccc2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
10 mg (0.025 mmol) 3-benzothiazol-2-yl-7-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-chromen-2-one are dissolved in 3 mL dichloromethane with 2.5 mg (0.8 eq.) 4-dimethylaminopyridine and 0.013 mL (3 eq.) diisopropylethylamine, and cooled to 0° C. 5.7 mg (1.2 eq.) tosyl chloride are added and the reaction mixture stirred for one hour before being allowed to reach room temperature. After an additional two hours stirring, the reaction mixture is evaporated, the residue taken up in tetrahydrofurane and treated with 0.2 mL tetrabutylammonium fluoride (1M in THF). After stirring for 30 minutes, the solution is evaporated and the desired product obtained as a yellow powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:26])[CH:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]3)[CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.Cl.[CH3:29][N:30]1[CH:34]=[C:33]([NH2:35])[CH:32]=[N:31]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:27][C:5]1[C:6]([N:8]([CH3:26])[CH:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:14]3)[CH2:10]2)=[N:7][C:2]([NH:35][C:33]2[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: CN(c1nc(Cl)ncc1Cl)C1CCC2(CCCN(C(=O)OC(C)(C)C)C2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CCCN(C(=O)OC(C)(C)C)C2)C1
Temperature: 150 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To a suspension of tert-butyl 2-((2,5-dichloropyrimidin-4-yl)(methyl)amino)-7-azaspiro[4.5]decane-7-carboxylate (470 mg, 1.13 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (235.7 mg, 1.76 mmol) in n-BuOH (5 mL) was added DIPEA (482.6 g, 3.74 mmol). The reaction mixture was stirred at 150° C. in a sealed tube overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/1) to give the title compound as a white solid (280 mg, 52.0%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[C:3]([CH2:4][OH:5])=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1c(O)cccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1c(O)cccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a solution of 2-bromo-6-hydroxybenzaldehyde (3.8 g, 18.91 mmol, 1 eq.) in a mixture of THF and MeOH (4/1, 25 mL) was added NaBH4 (1.4 g, 37.81 mmol, 1.5 eq.) at rt portion-wise. Upon the completion of addition, the mixture was continued to stir at rt for 30 min. The mixture was quenched with HCl (4 N) and extracted with EtOAC twice. The combined organic layer was dried over Na2SO4, concentrated, and purified on silica gel using 25% EtOAc/hexanes as eluent to give 3-bromo-2-(hydroxymethyl)phenol (2.3 g, 60%) as a colorless oil.