Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21](C(OCC)C)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1COCC1.[OH-].[Na+]>Cl>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(C)n1cc(-c2ncnc3c2ccn3COC(=O)C(C)(C)C)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cn[nH]c3)ncnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
To a solution of crude {4-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (4) in THF (1 L, 12.3 mol), a 4 N aqueous HCl solution (500 mL) was added at room temperature. The resulting reaction mixture was subsequently stirred at room temperature for 5 h. When the reaction was deemed complete as confirmed by TLC and LCMS, the reaction mixture was cooled to 0-5° C. before pH was adjusted to 9-10 with a 1 M aqueous sodium hydroxide (NaOH) solution (2 L). The mixture was concentrated under reduced pressure to remove most of THF and the resulting suspension was stirred at room temperature for 2 h. The solids were collected by filtration, washed with water (3×500 mL), and dried in vacuum to afford crude[4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (5, 157.5 g, 204.43 g theoretical, 77% yield for three steps) as white to off-white solids, which was found to be sufficiently pure (>98 area % by HPLC) to do the subsequent reaction without further purification. For 5: 1H NMR (DMSO-d6, 400 MHz) δ ppm 13.42 (br s, 1H), 8.76 (s, 1H), 8.67 (s, 1H), 8.33 (s, 1H), 7.68 (d, 1H, J=3.8 Hz), 7.11 (d, 1H, J=3.8 Hz), 6.21 (s, 2H), 1.06 (s, 9H); 13C NMR (DMSO-d6, 100 MHz) δ ppm 177.74, 152.31, 152.09, 151.91, 139.52, 130.39, 120.51, 113.93, 101.91, 67.26, 38.98, 27.26; C15H17N5O2 (MW, 299.33), LCMS (EI) m/e 300 (M++H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([CH:8](C(OCC)=O)[C:9]([O:11]CC)=[O:10])[CH:7]=1.Cl>C(O)(=O)C.O.CC#N>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(C)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: Cc1ccc([N+](=O)[O-])c(CC(=O)O)c1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
Diethyl 2-(5-methyl-2-nitro-phenyl)propanedioate (9.50 g, 32.2 mmol) was suspended in glacial acetic acid (40 mL) and warmed until it had dissolved. Hydrochloric acid (40 mL of 6 M solution, 240.0 mmol) was added dropwise and the solution heated at reflux for 24 h. After cooling to room temperature the reaction was diluted with water and extracted with ether. The ether was dried over Na2SO4, filtered, and concentrated in vacuo to afford a light orange solid. The solid was dissolved in minimal CH3CN and added dropwise to stirring 0.05 N HCl (300 mL) resulting in a beige precipitate. The suspension was cooled in an ice bath, filtered, and washed with water to obtain 2-(5-methyl-2-nitro-phenyl)acetic acid as a beige crystalline solid (5.30 g, 84% yield). LC/MS m/z 391.4 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 12.51 (s, 1H), 8.01 (d, J=8.9 Hz, 1H), 7.36 (m, 2H), 3.95 (s, 2H), 2.40 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH2:10][CH3:11])[C:3]=1[CH:12]=[O:13].[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([NH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH2:10][CH3:11])[C:3]=1[CH:12]=[O:13])(=[O:16])[CH3:15]
Reactant: CCc1cc(N)c(C=O)c(CC)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCc1cc(NC(C)=O)c(C=O)c(CC)n1

Procedure:
A mixture of 4-amino-2,6-diethylpyridine-3-carbaldehyde (2.0 g) and acetic anhydride (10 ml) in pyridine (20 ml) was heated at reflux for 3 hours. Volatile material was removed by evaporation and the residue was dissolved in ethyl acetate. The solution as washed with aqueous sodium carbonate solution, followed by saturated sodium chloride solution and then dried (MgSO4). Volatile material was removed by evaporation to give an oil which was purified by flash chromatography, eluting with ethyl acetate/petroleum ether (1:1 v/v) to give 4-acetylamino-2,6-diethylpyridine-3-carboxaldehyde as a yellow solid (0.9 g); m.p. 91°-92° C.; NMR (CDCl3): 1.3(t, 3H), 1.35(t, 3H), 2.26(s, 3H), 2.8(q, 2H), 3.14(q, 2H), 8.38(s, 1H), 10.4(s, 1H), 11.7(broad, 1H); mass spectrum (CI): 221 (M+H)+ ; microanalysis, found: C, 65.3; H, 7.3; N, 12.3%; C12H16N2O2 requires: C, 65.4; H, 7.3; N, 12.7%.
Reaction SMILES: [CH2:1]([CH2:6][NH2:7])[CH2:2][C:3]([OH:5])=[O:4].[CH2:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O=S(Cl)[Cl:18]>C(OCC)C>[ClH:18].[CH2:8]([O:4][C:3](=[O:5])[CH2:2][CH2:1][CH2:6][NH2:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCc1ccccc1
Reactant: O=S(Cl)Cl
Reactant: NCCCC(=O)O
Solvent: CCOCC
Product: Cl
Product: NCCCC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
GABA (4 g, 38.8 mmol) was suspended in 50 ml (0.48 mol) of benzyl alcohol. The reaction mixture was stirred, with cooling on an ice bath, while 20 ml SOCl2 was added dropwise over a 30 minute period. The mixture was slowly brought to the reflux temperature and refluxed for 4 hours. The resultant pink viscous solution was cooled to room temperature. Addition of 50 ml of ethyl ether and refrigeration overnight produced white crystals which were collected by filtration, recrystallized from a mixture of ethyl ether and ethanol and dried, m.p. 115°-116° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][N:7]=1.[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH2:27])[CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:18][S:17][C:13]1[N:12]=[C:11]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH:27][CH2:26][CH2:25][N:22]4[CH2:23][CH2:24][O:19][CH2:20][CH2:21]4)[C:3]3=[N:10][CH:9]=2)[CH:16]=[CH:15][N:14]=1
Reactant: NCCN1CCOCC1
Reactant: CSc1nccc(-c2cnc3c(Cl)nccn23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CSc1nccc(-c2cnc3c(NCCN4CCOCC4)nccn23)n1

Procedure:
To a solution of 8-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine (from Example 44 supra) (400 mg, 1.44 mmol) in iPrOH (20 mL) was added 2-morpholino-ethanamine (244 mg, 1.88 mmol) followed by diisopropylethylamine (242 mg, 1.88 mmol). The reaction mixture was stirred at reflux for 15 hours and the solvent was removed under reduced pressure. The residue was extracted with dichloromethane (150 mL) and washed with water (3×25 mL), dried over anhydrous sodium sulfate and concentrated to afford [3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine. (Yield 410 g, 76.8%). LC-MS: [M+H]+ 372.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([OH:14])(=[O:13])[CH2:9]C(O)=O.C([O-])(=O)C.[NH4+:19]>C(O)C>[NH2:19][C:1]1([CH2:9][C:8]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: O=C(O)CC(=O)O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC1(CC(=O)O)CCCCC1

Procedure:
Cyclohexanone (49 g), malonic acid (52 g), and ammonium acetate (77 g) were heated at reflux for six hours in 95% ethanol (150 ml.). The solution was allowed to cool, the crude product (47 g) collected by filtration and recrystallised from 95% ethanol to yield (1-aminocyclohexyl) acetic acid [(40 g) m.p. 240° C.: (found C, 61.0; H, 9.7; N, 8.9; C8H15NO2 requires C, 61:1; H, 9.6; N, 8.9%) n.m.r. δppm (D2O) 1.5-1.8 (b.s., 10H), 2.5 (s, 2H), i.r.νmax (mull) 2150 cm-1 (s, -NH3(+) overtone), 1610 and 1495 cm-1 (s,s, - NH3(+), 1560 cm-1 (b.s. -CO2(-))].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]([N:23]([CH3:25])[CH3:24])=[O:22].[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][N:28]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:24][N:23]([CH3:25])[C:21]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:31]([C:30]1[CH:29]=[N:28][C:27]([Cl:26])=[CH:35][CH:34]=1)=[O:32])=[CH:10][CH:9]=[C:8]([Cl:14])[CH:7]=2)=[O:22]
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CN(C)C(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1c(CNC(=O)c2ccc(Cl)nc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 3-(aminomethyl)-7-chloro-N,N-dimethyl-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxamide (intermediate C, 200 mg, 0.562 mmol), 6-chloronicotinoyl chloride (109 mg, 0.618 mmol), triethylamine (0.157 mL, 1.13 mmol) and methylene chloride (30 mL) was stirred at room temperature. The crude material was purified by flash chromatography (10% ethyl acetate in hexanes ramped to 70% ethyl acetate in hexanes) to give 7-chloro-3-{[(6-chloro-pyridine-3-carbonyl)-amino]-methyl}-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[C:5]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[Cl:20])=[CH:17][C:16]([CH:21]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[CH:15][CH:14]=2)([O:7][CH2:8][CH3:9])=[O:6]>CO.C(O)C>[ClH:20].[C:5]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[S:3][C:2](=[NH:4])[NH2:1])=[CH:17][C:16]([CH:21]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[CH:15][CH:14]=2)([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cnc2ccc(C3CCCCCC3)cc2c1Cl
Reactant: NC(N)=S
Solvent: CO
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(C3CCCCCC3)cc2c1SC(=N)N
Product: Cl
Reaction time: 48 h

Procedure:
A solution of 6.3 g of thiourea in 300 ml of methanol is added to a solution of 25 g of 3-carboethoxy-4-chloro-6-cycloheptyl-quinoline in 200 ml of ethanol and the mixture is left to stand for 2 days at room temperature. The crude 3-carboethoxy-4-amidinothio-6-cycloheptyl-quinoline-hydrochloride formed, of melting point 280°C (decomposition), is then filtered off.
Reaction SMILES: CC1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4]N=1.[C:23]([O:27][C:28](=[O:38])[NH:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Br)=[CH:32][N:31]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:40][C:41]1[O:42]C(C(F)(F)F)=CC=1>>[O:22]=[C:14]1[C:13]2([C:8]3[C:9](=[CH:10][C:5]4[O:4][CH2:40][CH2:41][O:42][C:6]=4[CH:7]=3)[O:11][CH2:12]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]1[CH2:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:28](=[O:38])[O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:31][CH:32]=1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Product: CC(C)(C)OC(=O)Nc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cn1

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and tert-butyl[5-(bromomethyl)pyridin-2-yl]carbamate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, tert-butyl {5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridin-2-yl}carbamate was obtained (74%) as a colorless solid: mp 238-239° C.; 1H NMR (300 MHz, DMSO-d6) δ9.81 (s, 1H), 8.30-8.27 (m, 1H), 7.79-7.73 (m, 1H), 7.73-7.66 (m, 1H), 7.31-7.24 (m, 1H), 7.20-7.14 (m, 1H), 7.12-6.99 (m, 2H), 6.52 (s, 1H), 6.06 (s, 1H), 4.89 (ABq, J=22.9, 15.5 Hz, 2H), 4.74 (ABq, J=44.4, 9.3 Hz, 2H), 4.23-4.05 (m, 4H), 1.45 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ 176.7, 154.6, 152.6, 151.8, 146.9, 144.1, 141.8, 137.8, 137.2, 131.6, 128.7, 126.2, 123.6, 123.1, 121.1, 112.2, 110.8, 109.3, 98.8, 79.5, 79.3, 64.1, 63.5, 57.2, 27.9; MS (ES+) m/z 502.1 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[C:34]2[CH:39]=[CH:38][C:37](I)=[CH:36][CH:35]=2)=[CH:18]/[CH2:19][O:20][C:21]2[CH:32]=[CH:31][C:24]([O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:23]([CH3:33])[CH:22]=2)=[CH:13][CH:12]=1>O1CCCC1.C(N(CC)CC)C.C1C=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.[Cu]I>[Cl:10][C:11]1[CH:12]=[CH:13][C:14](/[C:17](/[C:34]2[CH:35]=[CH:36][C:37]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[CH:38][CH:39]=2)=[CH:18]/[CH2:19][O:20][C:21]2[CH:32]=[CH:31][C:24]([O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:23]([CH3:33])[CH:22]=2)=[CH:15][CH:16]=1
Reactant: C#CCN1CCOCC1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(I)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#CCN3CCOCC3)cc2)cc1C
Temperature: 0 °C
Reaction time: 72 h

Procedure:
4-Propargylmorpholine (320 mg, 2.4 mmol) was added under nitrogen atmosphere to a degassed solution of methyl (Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (450 mg, 0.82 mmol; prepared as described in example 7) in a mixture of tetrahydrofuran (10 mL) and triethylamine (8 mL) The solution was cooled to 0° C. and tetrakis(triphenylphosphine)palladium (85 mg, 0.073 mmol) and copper(I) iodide (22 mg, 0.115 mmol) were added. The reaction mixture was stirred at ambient temperature for 72 h, diluted with benzene (100 mL) and washed with water (2×50 mL). The organic solution was dried with anhydrous potassium carbonate and subsequently evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene/ethyl acetate 1:0-0:1) yielding methyl (E)-[4-[3-(4-chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-allyloxy]-2-methylphenoxy]acetate contaminated with ca. 20% of 1,6-bis(morpholin-4-yl)-2,4-hexadiyne.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]2)[N:3]=1.C(N(CC)CC)C.Br[CH2:36][CH2:37][OH:38]>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH:27][CH2:36][CH2:37][OH:38])[CH2:23][CH2:22]2)[N:3]=1
Reactant: OCCBr
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](N)CC2)nc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](NCCO)CC2)nc1N

Procedure:
To a stirred solution of trans-[4-amino-2-(4-amino-cyclohexylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (100 mg, 0.27 mmol, Example 120) and triethylamine (200 uL) in tetrahydrofuran (3 mL), 2-bromoethanol (20 uL, 0.28 mmol, Aldrich) was added and the mixture was stirred at reflux for 5 hours. The reaction was quenched with water and the mixture was extracted with ethyl acetate (3×10 mL) and the extracts were dried with sodium sulfate. Removal of solvent gave a yellow solid which was purified by reverse phase HPLC to give a pale yellow solid. 86 mg, 75%. MS (ES) MH+=422. CDK4 IC50=0.020 μM; CDK1 IC50=0.018 μM; CDK2 IC50=0.005 μM; HCT 116 IC90=0.179 μM.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13](CC2C=CC(OC)=CC=2OC)[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:32][C:33]1[CH:40]=[C:39]([OH:41])[CH:38]=[C:37]([Cl:42])[C:34]=1[C:35]#[N:36]>>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)(=[O:11])=[O:12])[CH:6]=[CH:7][C:8]=1[O:41][C:39]1[CH:38]=[C:37]([Cl:42])[C:34]([C:35]#[N:36])=[C:33]([Cl:32])[CH:40]=1)#[N:2]
Reactant: N#Cc1c(Cl)cc(O)cc1Cl
Reactant: COc1ccc(CN(c2ccc(F)cn2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Product: N#Cc1cc(S(=O)(=O)Nc2ccc(F)cn2)ccc1Oc1cc(Cl)c(C#N)c(Cl)c1

Procedure:
The title compound was prepared according to the method described for Method Variation 5 using 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(5-fluoropyridin-2-yl)benzenesulfonamide (Preparation 18) and 2,6-dichloro-4-hydroxybenzonitrile, and then purified using preparative HPLC.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][CH:39]([OH:41])[CH3:40]>>[OH:41][CH:39]([CH3:40])[CH2:38][NH:37][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:29]=1
Reactant: CC(O)CN
Reactant: O=C(O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Product: CC(O)CNC(=O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 82.8 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 46 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:14][S:15]([O:13][CH:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1)(=[O:17])=[O:16]
Reactant: OC1CCN(Cc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)OC1CCN(Cc2ccccc2)C1

Procedure:
Thus, for example, when 1-benzyl-3-pyrrolidinol is reacted with methanesulfonyl chloride in the presence of sodium hydroxide using a mixed solvent composed of toluene and water as the reaction solvent and the reaction mixture is obtained in the form of a two-phase system composed of a toluene phase and an aqueous phase, it is possible to obtain 1-benzyl-3-pyrrolidinol methanesulfonate as a concentrate by removing the solvent by concentrating, under reduced pressure, from the toluene solution obtained by phase separation of the reaction mixture, after or without washing the toluene phase with water.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14][CH2:15][CH2:16][CH2:17]Br.[H-].[Na+]>C1COCC1.O.C(O)C>[Br:14][CH2:15][CH2:16][CH2:17][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: BrCCCn1c2ccccc2c2ccccc21
Temperature: 78 °C
Reaction time: 40 h
Yield: 29.8 %

Procedure:
Carbazole (15.00 g, 89.71 mmol) and 1,3-dibromopropane (45.5 mL, 450 mmol) were dissolved in ˜200 mL dry THF and stirred under argon in a 500 mL rbf. Sodium hydride (3.23 g, 134.56 mmol) was added and the mixture was brought to reflux (˜78° C.) and allowed to do so for 40 hours. After cooling the mixture was diluted in ˜800 mL water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated by rotary evaporation to leave an orange oil and light brown solid. This was distilled under high vacuum (0.05 Torr) at 100° C. for 2 hours to remove excess dibromo compound. A tlc in 30:1 hexanes:ethyl acetate showed 6 spots. A column was run in 30:1 hexanes:ethyl acetate and the third spot was isolated as a thick yellow oil. This oil was dissolved in hot ethanol and put in the −20° C. freezer overnight to yield a white solid (7.70 g, 30% yield). This compound is reported in the literature and the 1H NMR is consistent with the structure.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C([O-])(O)=O.[Na+].C(=O)([O-])OC1C([C@@H](C)CCCCCCC)=CC=CN=1.[CH3:33][C@H:34]([O:42][C:43](N1C=CC=CC1=O)=[O:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>O.C1COCC1>[OH:4][C@@H:3]([CH3:5])[C@@H:2]([NH:1][C:43]([O:42][C@@H:34]([CH3:33])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:44])[C:6]([OH:8])=[O:7]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: CCCCCCC[C@H](C)OC(=O)n1ccccc1=O
Agent: CCCCCCC[C@H](C)c1cccnc1OC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCC[C@H](C)OC(=O)N[C@@H](C(=O)O)[C@H](C)O
Reaction time: 15 h
Yield: 60.8 %

Procedure:
To a stirred mixture of D-threonine (0.150 g, 1.25 mmol) and NaHCO3 (0.158 g, 1.89 mmol) in water (3 mL), the crude mixture containing [(1S)-1-methyloctyl]-2-pyridyl carbonate and [(1S)-1-methyloctyl]-2-oxopyridine 1-carboxylate (0.501 g, 1.88 mmol) in THF (3 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2M HCl solution to pH 2-3 and subsequently extracted with AcOEt (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.220 g, 62%) as transparent oil, which was used in the next step without further purification. MS (ESI) m/z: 290 [M−H]+; (ESI) m/z: 288 [M−H]−. 1H NMR (DMSO-d6): δ 0.87 (t, J=6.8 Hz, 3H), 1.09 (d, J=6.4 Hz, 3H), 1.15 (d, J=6.2 Hz, 3H), 1.21-1.34 (m, 10H), 1.40-1.57 (m, 2H), 3.92 (dd, J=3.4, 9.0 Hz, 1H), 4.01-4.11 (m, 1H), 4.60-4.70 (m, 1H), 6.55 (d, J=9.0 Hz, 1H), 12.49 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20].N1C=CC=CC=1.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(Cl)Cl>[S:35]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])([C:32]1[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=1)(=[O:37])=[O:36]
Reactant: COC(=O)CCCCCCCCCCCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 16 h
Yield: 84.9 %

Procedure:
In 50 ml of methylene chloride, methyl 18-hydroxyoctadecanoate (4.5 g, 14.3 mmoles) was dissolved. To the obtained solution was added pyridine (4.53 g, 57.2 mmoles), and then was gradually added p-toluenesulfonyl chloride (5.46 g, 28.6 mmoles) with ice-cooling over a period of 1 hour. Thereafter, reaction was carried out for 16 hours in a refrigerator. The reaction mixture was washed with a 10% aqueous hydrochloric acid solution, water, saturated aqueous sodium hydrogen carbonate solution, water and aqueous sodium chloride solution in this order, dried, and then concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (eluent: benzene) to give methyl 18-tosyloxyoctadecanoate (5.69 g, 85%) having the following properties.