Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16]C(=O)CC)[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[CH2:38]([O:45][CH2:46][C:47](Cl)=[O:48])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([O:45][CH2:46][C:47]([NH:16][C@H:14]1[CH2:15][C@@H:11]([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([Cl:1])=[N:3][C:4]=3[NH:23][CH2:24][CH:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:12]([OH:22])[C@@H:13]1[OH:21])=[O:48])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(Cl)COCc1ccccc1
Product: O=C(COCc1ccccc1)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Intermediate AA) by replacing cyclopropanecarboxylic acid propionyl chloride with benzyloxy-acetyl chloride.
Reaction SMILES: S([O-])([O-])(=O)=O.[Ca+2].[CH2:7]([O:9][C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])=[O:11])[CH3:8].[C:21]([NH:24][C@@H:25]1[C@@H:30]([O:31]C(=O)C)[C@H:29]([O:35]C(=O)C)[C@@H:28]([CH2:39][O:40]C(=O)C)[O:27][C@@H:26]1Cl)(=[O:23])[CH3:22].O.NN>C1C=CC=CC=1.ClCCl>[C:21]([NH:24][C@@H:25]1[C@@H:30]([OH:31])[C@H:29]([OH:35])[C@@H:28]([CH2:39][OH:40])[O:27][C@H:26]1[O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:10]([O:9][CH2:7][CH3:8])=[O:11])(=[O:23])[CH3:22]
Reactant: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H]1Cl
Reactant: CCOC(=O)CCCCCCCCO
Agent: NN
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)CCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Mercuric cyanide (31.8 g, 126 mmol) and anhydrous calcium sulfate were added to a solution of 8-ethoxycarbonyl-1-octanol (25 g, 124 mmol) in 100 ml of dry benzene. The mixture was protected from moisture while stirring for 1 h at room temperature prior to addition of 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-glucopyranosyl chloride (25 g, 68 mmol). The mixture was efficiently stirred for 4 days at room temperature. Dichloromethane (400 ml) was added, the solids were removed by filtration, and the filtrate was sequentially washed with 10% aqueous sodium chloride solution (50 ml), once with saturated aqueous sodium bicarbonate solution (25 ml), and twice with water (50 ml). In each case, the aqueous layer was back-extracted with a little dichloromethane. After drying over magnesium sulfate, the solvents were removed to leave a syrup which crystallized from a mixture of diethyl ether and n-hexane. The crude yield of 8-ethoxycarbonyloctyl 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranoside was 28.9 g (80%). A recrystallized sample showed mp 112°, [α]D20 -12.2° (c 2.4, chloroform). De-O-acetylation of this compound with triethylamine (27 ml) in methanol (500 ml) at 0°-5° for 18 h gave after evaporation of the solvent compound 2 as a chromatographically homogeneous powder which resisted crystallization and was therefore characterized as its hydrazide derivative mp 200°-201°, [α]D26 -22.5° (c 1, water), prepared by treating 2 with an 85% solution of hydrazine hydrate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[N:7]=1.C(Cl)[Cl:15].C(Cl)(=O)C(Cl)=O.CN(C=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([Cl:15])=[O:13])[N:10]=2)[N:7]=1
Reactant: O=C(O)c1cn2nc(Cl)ccc2n1
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 250-mL, round-bottomed flask was added 6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid (2.0 g, 10 mmol, Maybridge, Cornwall, UK) and CH2Cl2 (40 mL). To the mixture was added oxalyl chloride (20 mL, 40 mmol, 2 M in CH2Cl2) and DMF (8.0 μL, 0.10 mmol). The mixture was stirred for 1.5 h at 25° C. Toluene (10 mL) was added and the mixture was concentrated to afford the title compound which was taken on to the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][CH3:18])[C:8]2[CH:9]=[C:10]([B:13]([OH:15])[OH:14])[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:16])[O:4]1)[CH3:2].[H-].[Na+].[CH3:21]I>C1COCC1>[CH2:17]([C:3]1([CH2:1][CH3:2])[C:8]2[CH:9]=[C:10]([B:13]([OH:14])[OH:15])[CH:11]=[CH:12][C:7]=2[N:6]([CH3:21])[C:5](=[O:16])[O:4]1)[CH3:18]
Reactant: CCC1(CC)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC1(CC)OC(=O)N(C)c2ccc(B(O)O)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
To a stirred solution of 4,4-diethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-ylboronic acid (4.85 g, 19.50 mmol) in THF (100 mL) at 0° C. was added sodium hydride (3.12 g-60%, 78 mmol). After 10 minutes, methyl iodide (9.7 mL, 156.0 mmol) was added and the reaction was allowed to warm to room temperature After one week the reaction was quenched with ammonium chloride solution (sat.) and extracted with ethyl acetate several times. The organic layers were washed with brine, dried over magnesium sulfate and concentrated. Trituration with ether gave 4,4-diethyl-1-methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-ylboronic acid as a yellow solid (3.97 g, 77%). 1H NMR (DMSO-d6): δ 8.03 (s, 2H), 7.78 (dd, J=8.2, 1.3 Hz, 1H), 7.60 (d, J=1.3 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 3.28 (s, 3H), 1.99 (m, 4H), 0.78 (t, J=7.4 Hz, 6H). MS (ESI) m/z 264 ([M+H]+); MS (ESI) m/z 262 ([M−H]−); Anal. calcd for C13H18BNO4: C, 59.35; H, 6.90; N, 5.32. Found: C, 58.97; H, 6.98; N, 4.73.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C([Li])CCC.[O:14]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Cl:1][C:2]1[N:3]=[C:4]([CH2:8][C:15]2([OH:14])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(O)(Cc2cccc(Cl)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.22 ml of 2-chloro-6-methylpyridine in 12.5 ml of tetrahydrofuran was added 1.4 ml of a hexane solution containing 1.58 M n-butyl lithium at 0° C., followed by stirring the reaction mixture at 0° C. for 30 minutes. After cooling down to −78° C., a solution of 403.7 mg of tert-butyl 4-oxo-1-piperidinecarboxylate in 1 ml of tetrahydrofuran was added to the solution, followed by gradually warming up the reaction mixture to −40° C. To the reaction mixture was added saturated aqueous ammonium chloride solution, followed by extracting with chloroform. The resulting chloroform layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=20/1−3/2) to give the title compound as a pale yellow oil.
Reaction SMILES: O1CCOCC1.Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2.[CH2:18]([OH:21])[CH:19]=[CH2:20].CN(C1CCCCC1)C1CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C(OC)(C)(C)C>[N:14]1[C:15]2[C:10](=[CH:9][C:8]([CH2:20][CH2:19][CH:18]=[O:21])=[CH:17][CH:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: C=CCO
Reactant: Brc1ccc2ncccc2c1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: O=CCCc1ccc2ncccc2c1
Temperature: 55 °C
Reaction time: 10 h
Yield: 52.7 %

Procedure:
A 22 L flask was charged with tris(dibenzylideneacetone)dipalladium(0) (70.0 g, 0.076 mol, 0.015 equiv), tri-tert-butylphosphonium tetrafluoroborate (44 g, 0.152 mol, 0.03 equiv), and dioxane (12 L) at room temperature. The resulting solution was then degassed with a steady stream of nitrogen for 20 min before 6-bromoquinoline (8, 1055 g, 5.07 mol, 1.0 equiv), allyl alcohol (588 g, 10.1 mol, 2.0 equiv), and N-methyl-N-cyclohexylcyclohexylamine (1186 g, 6.08 mol, 1.2 equiv) were added at room temperature. The resulting reaction mixture was stirred at 50- to 55° C. for 8-12 h. When TLC and LC/MS showed that the reaction was deemed complete, the reaction mixture was cooled to room temperature before methyl tert-butyl ether (MTBE, 10 L) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 10 min before being filtered through a plug of celite. The filtrate was concentrated under the reduced pressure and the residue was purified by flash column chromatography (SiO2, 20-80% ethyl acetate in heptane gradient elution) to afford 3-(quinolin-6-yl)propanal (9, 495 g, 939.1 g theoretical, 52.7%) as a yellow oil, which solidified partially upon standing at 0-5° C. For 9: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.75 (t, 1H, J=1.24 Hz), 8.83 (dd, 1H, J=4.15 Hz, 1.66 Hz), 8.25 (dd, 1H, J=8.3, 1.03 Hz), 7.93 (d, 1H, J=8.71 Hz), 7.76 (d, 1H, J=1.45 Hz), 7.64 (dd, 1H, J=8.72 Hz, 2.08 Hz), 7.48 (dd, 1H, J=8.30 Hz, 4.36 Hz), 3.05 (t, 2H, J=7.26 Hz), 2.89 (t, 2H, J=7.26 Hz); C12H11NO (MW 185.22), LCMS (EI) m/e 186 (M++H).
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][O:22]S(C)(=O)=O)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[O:27]1[C:35]2[CH:34]=[CH:33][N:32]=[CH:31][C:30]=2[CH:29]=[C:28]1[CH2:36]O>C1COCC1>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][O:22][CH2:36][C:28]2[O:27][C:35]3[CH:34]=[CH:33][N:32]=[CH:31][C:30]=3[CH:29]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Reactant: OCc1cc2cnccc2o1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCOCc2cc3cnccc3o2)CC1
Temperature: 20 °C

Procedure:
t-BuOK (45 mg, 401 μmol) and 4-(2-methanesulfonyloxyethyl)piperidine-1-carboxylic acid tert-butyl ester (134 mg, 436 μmol) were added to a stirred solution of furo[3,2-c]pyridin-2-ylmethanol (Preparation 4, 50 mg, 336 μmol) in anhydrous THF (5 mL). The reaction was heated under reflux for 6 h, before being cooled to 20° C. and quenched with saturated aqueous NH4Cl. The mixture was extracted twice with EtOAc, then the combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by column chromatography (EtOAc-MeOH, 1:0 to 50:1) to furnish the title compound: RT=2.86 min; m/z (ES+)=361.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][N:3]=1.Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[F:8][C:6]1[CH:5]=[CH:4][N:3]2[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:1]=[C:2]2[CH:7]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1cc(F)ccn1
Product: CCOC(=O)c1cn2ccc(F)cc2n1
Yield: 59 %

Procedure:
[step 1] Using 2-amino-4-fluoropyridine (3.2 g, 28.5 mmol) and ethyl bromopyruvate (4.3 ml, 34.3 mmol), and in the same manner as in Reference Example 8A, step 1, ethyl 7-fluoroimidazo[1,2-a]pyridine-2-carboxylate (3.5 g, 59%) was obtained.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2N=N1.[C:34]1([S:40]([NH:43][C:44]2[N:48]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[N:47]=[C:46]([C:55]3[CH:63]=[CH:62][C:58]([C:59]([OH:61])=O)=[CH:57][CH:56]=3)[CH:45]=2)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)C(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.CN(C1C=CN=CC=1)C.O>[C:12]1([NH:8][C:59](=[O:61])[C:58]2[CH:62]=[CH:63][C:55]([C:46]3[CH:45]=[C:44]([NH:43][S:40]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)(=[O:42])=[O:41])[N:48]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[N:47]=3)=[CH:56][CH:57]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:11]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)c1ccc(-c2cc(NS(=O)(=O)c3ccccc3)n(-c3ccccc3)n2)cc1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1ccc(-c2cc(NS(=O)(=O)c3ccccc3)n(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzotriazol-1-yloxytripyrrolid inophosphonium hexafluorophosphate (0.136 g, 0.26 mmol) was added to a solution of 4-(5-benzenesulfonylamino-1-phenyl-1H-pyrazole-3-yl)-benzoic acid (0.10 g, 0.24 mmol) and N,N-diisopropylethylamine (0.062 ml, 0.36 mmol) in N,N-dimethylformamide (2 ml). 1-Hydroxybenzotriazole hydrate (30 mg, 0.24 mmol) and 4-(N,N-dimethylamino)pyridine (catalytic) were added and the resulting solution was stirred at room temperature for 3 hours. Water (7 ml) was added, and a precipitate was collected by filtration and washed with water. The solid was purified by preparative thin layer silica gel chromatography, using 2% methanol in dichloromethane as the eluant, to yield N-Phenyl-4-[1-phenyl-5-[(phenylsulfonyl)amino]-1H-pyrazol-3-yl]benzamide as a colorless solid.
Reaction SMILES: [C:1]([C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([NH:14][C:15]#[C:16][Si](C)(C)C)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CN(C=O)C.[Cu]I>[C:1]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[NH:14][CH:15]=[CH:16]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(NC#C[Si](C)(C)C)cc1[N+](=O)[O-]
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2cc[nH]c2cc1[N+](=O)[O-]
Temperature: 135 °C
Yield: 69.3 %

Procedure:
To a solution of 4-tert-butyl-5-nitro-2-trimethylsilanylethynyl-phenylamine (25 g, 86 mmol) in DMF (100 mL) was added CuI (8.2 g, 43 mmol) under a nitrogen atmosphere. The mixture was heated at 135° C. in a sealed pressure flask overnight, cooled down to room temperature and filtered through a short plug of Celite. The filter cake was washed with EtOAc. The combined filtrate was washed with water, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (10-20% ethyl aetate/hexane) to provide 5-tert-butyl-6-nitro-1H-indole as a yellow solid (13 g, 69%).
Reaction SMILES: C(NC(C)C)(C)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=1.CN(C)[CH:20]=[O:21]>O1CCCC1>[Br:8][C:9]1[C:10]([CH:20]=[O:21])=[C:11]([F:17])[C:12]([O:15][CH3:16])=[CH:13][CH:14]=1
Reactant: COc1ccc(Br)cc1F
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(Br)c(C=O)c1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
A solution of anhydrous tetrahydrofuran (50 mL) and diisopropylamine (11 mL) was cooled to 0° C. and had 1.6 M n-butyl lithium/hexanes (47 mL) added drop wise under nitrogen balloon. The mixture was stirred for 10 minutes at 0° C. and was then cooled to −78° C. with an acetone dry ice bath. A mixture of 4-bromo-2-fluoro-1-methoxybenzene (7.9 mL, 61 mmol) in anhydrous tetrahydrofuran (50 mL) was added drop wise, under nitrogen balloon, to the reaction. The mixture was then allowed to stir for 30 minutes at −78° C. N,N-dimethylformamide (7.5 mL) was added drop wise at −78° C. under a nitrogen balloon. The reaction was stirred for 1 hour at room temperature under a nitrogen balloon. Half of the solvent from the solution was removed under reduced pressure and the solution was extracted using ethyl acetate, water (300 mL), and 1 M HCl (65 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was crystallized by washing with hexanes. The solid was collected via filtration and dried under reduced pressure to give 6-bromo-2-fluoro-3-methoxybenzaldehyde (8.21 g, 58% yield).
Reaction SMILES: O.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1C=CC=CC=1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([NH:2][C:27]([NH:26][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:28])[CH2:4][CH2:5]2)=[CH:12]1
Reactant: O=C=NC1CCCCC1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: O
Solvent: c1ccccc1
Product: O=C(NC1CCCCC1)NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reaction time: 18 h
Yield: 102.7 %

Procedure:
4-Amino-1-[2-(3-indolyl)ethyl]piperidine, hydrate (1.307 g, 0.005 mole) in benzene (50 ml.) was treated with cyclohexyl isocyanate (0.688 g, 0.0055 mole) and the mixture stirred for 18 hrs. Filtration afforded the title compound as colourless prisms (1.893 g), m.p. 203.8°.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].Br[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].CN1CCOCC1>O1CCOCC1>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH:6][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](NCC(=O)OCc1ccccc1)C(C)C
Yield: 21.9 %

Procedure:
A solution of 2.12 g (12.6 mmol) of L-valine methyl ester hydrochloride, 2.0 ml (12.6 mmol) of benzyl bromoacetate, and 3.5 ml (31 mmol) of 4-methylmorpholine in 100 ml of dioxane was heated at reflux for 4 h. After being allowed to cool, the solution was concentrated in vacuo and partitioned between ether and water. The organic layer was dried over MgSO4 and concentrated in vacuo. Chromatography on silica gel using 20% ethyl acetate in hexane provided 0.77 g (22%) of the desired compound as a colorless oil (Rf 0.24, 20% ethyl acetate in hexane. 1H NMR δ 0.95 (d, J=7 Hz, 6H), 1.96 (br, 1H), 1.98 (octet, J=7 Hz, 1H), 3.08 (d, J=6 Hz, 1H), 3.43 (AA', 2H), 3.71 (s, 3H), 5.16 (s, 2H), 7.36 (m, 5H).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24](=[O:26])(=[O:25])[NH:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: NCc1ccccc1S(=O)(=O)Nc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1ccccc1S(=O)(=O)Nc1ccccc1
Yield: 71.2 %

Procedure:
2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.31 g), 2-(aminomethyl)-N-phenylbenzenesulfonamide hydrochloride (2.0 g) and potassium carbonate (1.93 g) were stirred in ethanol (20 ml) at 90° C. for 20 hr. The reaction mixture was poured into 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate→ethyl acetate:methanol=9:1). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (3 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized to give the title compound (0.90 g).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6](Br)[CH3:7])(=[O:3])[CH3:2].[CH3:9][N:10]([CH3:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1>>[C:1]([O:4][CH2:5][CH2:6][CH2:7][O:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]([CH3:18])[CH3:9])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(C)Br
Reactant: CN(C)c1ccc(O)cc1
Product: CC(=O)OCCCOc1ccc(N(C)C)cc1

Procedure:
3-(4-(Dimethylamino)phenoxy)propyl acetate (47A) was prepared following a similar procedure as that described in example 39, except 2-bromopropyl acetate was used instead of 2-bromoethyl acetate and 4-(dimethylamino)phenol was used instead of 3-(dimethylamino)phenol in step 1 of example 39.
Reaction SMILES: [CH3:1][NH:2][NH2:3].C(OCC)(=O)C.O.[CH:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](/[CH:26]=[CH:27]/[C:28]3[O:32][CH:31]=[CH:30][CH:29]=3)=O)=[CH:20][CH:19]=2)=[CH:13][CH:12]=1>CS(C)=O>[O:32]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:27]1[N:2]([CH3:1])[N:3]=[C:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][C:14]3[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=3)=[CH:19][CH:20]=2)[CH:26]=1
Reactant: CNN
Reactant: O=C(/C=C/c1ccco1)c1ccc(Oc2ccccc2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1nc(-c2ccc(Oc3ccccc3)cc2)cc1-c1ccco1
Temperature: 85 °C

Procedure:
In an open vial, 3-furan-2-yl-1-(4-phenoxy-phenyl)-propenone (0.4 g) was dissolved in dimethylsulfoxide (10 mL). Methylhydrazine (1.0 g) was added and the reaction mixture was heated to 85° C. for 3 days. The reaction mixture was cooled to room temperature and ethyl acetate (100 mL) and water (50 mL) were added. The organic layer was washed twice with water (25 mL), then separated and dried over sodium sulfate. The solvent was removed after filtering away the drying agent. Purification by column chromatography (silica, eluted with ethyl acetate-hexanes, 1:9) gave the desired pyrazole in moderate yield (0.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[F:9][C:10]1[CH:11]=[C:12]([OH:17])[CH:13]=[CH:14][C:15]=1[F:16].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][C:12]2[CH:13]=[CH:14][C:15]([F:16])=[C:10]([F:9])[CH:11]=2)=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: Oc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1ccc(Oc2ccc(Br)cn2)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To a solution of 5-bromo-2-fluoropyridine (19 g, 108 mmol) and 3,4-difluorophenol (14.05 g, 108 mmol) in dimethyl sulfoxide (DMSO) (150 mL) was added potassium carbonate (26.9 g, 194 mmol). The reaction mixture was stirred at 80° C. for 2 hr, then H2O (200 ml) and EtOAc (200 ml) were added. The organic layer was separated, and then concentrated under reduced pressure. The crude product was purified by a silica gel chromatography eluting with Hex/EtOAc (10:1) to provide 5-bromo-2-(3,4-difluorophenoxy)pyridine (19 g, 55.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([CH3:32])OCC[O:28]2)=[CH:23][CH:22]=1.Cl>CO>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][C:3]2[C:4]3[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[CH2:7][CH2:6][C:5]=3[CH:17]=[CH:18][C:2]=2[Cl:1])=[CH:26][CH:25]=1)(=[O:28])[CH3:32]
Reactant: CC1(c2ccc(CNc3c(Cl)ccc4c3CCN(C(=O)C(F)(F)F)CC4)cc2)OCCO1
Agent: Cl
Solvent: CO
Product: CC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
Dissolve 7-chloro-6-[4-(2-methyl-[1,3]dioxolan-2-yl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (150 mg, 0.32 mmol) in methanol (5 mL) and add 1N aqueous HCl (1 mL). Stir the solution at room temperature for 2 h. Remove the solvent, dissolve the residue in DCM and wash with saturated aqueous NaHCO3. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1, 17:3 and 4:1) to obtain the title compound as an oil (107 mg, 79%). GC-MS m/z: 424 (M+).