Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[O:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1cc(F)ccc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3cc(F)ccc3F)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2,5-difluorophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (2.70 mg, 40.1% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.40-7.30 (m, 4H), 7.20 (m, 2H), 7.17 (s, 1H), 6.97 (m, 2H), 6.58 (m, 1H), 6.51 (m, 1H), 5.27 (apparent dd, 1H, J=5.1, 8.2 Hz), 3.13 (apparent d, J=9.7 Hz, 2H), 2.64 (m, 2H), 2.51 (m, 2H), 2.34 (apparent sept, partially hidden, J=7.1 Hz, 1H), 2.17 (m, 3H), 1.90-1.80 (m, 4H), 1.25 (d, 6H, J=7.1 Hz); ESMS m/e: 493.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:7]([N+:13]([O-:15])=[O:14])=[CH:8][C:9]=1[CH2:10][CH:11]=[CH2:12])[CH2:5][OH:6].[C:16](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:16][O:1][C:2]1[CH:3]=[C:4]([C:7]([N+:13]([O-:15])=[O:14])=[CH:8][C:9]=1[CH2:10][CH:11]=[CH2:12])[CH2:5][OH:6]
Reactant: C=CCc1cc([N+](=O)[O-])c(CO)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCc1cc([N+](=O)[O-])c(CO)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
4.68 g of 3-hydroxy-6-nitro-4-(2-propenyl)benzylalcohol was dissolved in 90 ml of N,N-dimethylformamide. Thereafter, 3.71 g of potassium carbonate and 3.81 g of iodomethane were added to the reaction solution, and the obtained mixture was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate, and then washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was then purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain 3.93 g of the subject compound.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][N:13]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:14]([NH:16][CH2:17][CH2:18][CH:19]([OH:26])[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(OCC)(=O)C.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl.O>[C:1]12([CH2:11][CH2:12][N:13]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:14]([NH:16][CH2:17][CH2:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[O:15])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCC(O)c1ccncc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H-one (221 mg, 0.520 mmol) was added to a solution of 1-[2-(1-adamantyl)ethyl]-3-[3-hydroxy-3-(4-pyridyl)propyl]-1-pentylurea (100 mg, 0.234 mmol) in anhydrous dichloromethane (2 ml) under ice-cooling, the temperature was raised to room temperature, and the mixture was stirred for one hour. The reaction mixture was cooled with ice again, ethyl acetate (10 ml), a saturated aqueous sodium sulfite solution (5 ml) and a saturated aqueous sodium hydrogencarbonate solution (5 ml) were added to the reaction mixture, and the whole was stirred for 15 minutes. The reaction mixture was distributed with ethyl acetate (50 ml) and water (10 ml), and the organic layer was washed with a saturated aqueous sodium sulfite solution (5 ml), a saturated aqueous sodium hydrogencarbonate solution (5 ml) and a saturated aqueous sodium chloride solution (25 ml) successively. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 87.3 mg (87.8%) of the titled compound as colorless crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)[CH3:4].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>O1CCCC1>[CH2:3]([O:5][C:6](=[O:16])[CH:7]=[CH:22][C:21]1[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=1)[CH3:4]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85.5 %

Procedure:
Sodium hydride (2.11 g, 48.4 mmol) was suspended in anhydrous tetrahydrofuran (60 ml), and diethylphosphonoacetic acid ethyl ester (10.84 g, 48.4 mmol) was added dropwise thereto in an ice bath followed by stirring for 10 minutes. To this mixture solution, a solution of 4-fluorobenzaldehyde (5.00 g, 40.3 mmol) in anhydrous tetrahydrofuran (60 ml) was added dropwise at the same temperature. The reaction solution was stirred for 3 hours, and poured into ice-cold water (150 ml), and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated in vacuo, and then the residue was purified by flash chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=10:1-3:1) to give 4-fluorocinnamic acid ethyl ester (6.69 g, 86% yield) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=[C:5]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:3]=1[C:4]=23.Cl[CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][O:30][C:29]1=[O:33]>C(Cl)(Cl)Cl>[CH2:14]([N:13]([CH2:16][CH3:17])[CH2:12][CH2:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([NH:1][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][O:30][C:29]3=[O:33])=[C:3]3[S:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[C:5]([C:4]=23)=[N:6]1)[CH3:15]
Reactant: O=C1OCCN1CCCl
Reactant: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1ccccc1-2
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCn1nc2c3c(c(NCCN4CCOC4=O)ccc31)Sc1ccccc1-2
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A mixture of 5.8 g 0.017 mol) of 5-amino-N,N-diethyl-2H[1]benzothiopyrano[4,3,2-cd]indazole-2-ethanamine and 5.1 g (0.034 mol) of 3-(2-chloroethyl)-2-oxazolidinone was stirred at 150° C. for two hours, dissolved in 100 ml of CHCl3 and washed twice with 2N NaOH. The solution was dried (MgSO4) and concentrated in vacuo to dryness. The residue was flash chromatographed over silica gel, eluting with a CHCl3 /MeOH (4/1) mixture. The appropriate fractions were combined and concentrated to dryness in vacuo. The residue was treated with 20 ml of acetone and the resulting suspension was treated with 150 ml of Et2O. The resulting precipitate was collected and dried to give 4.9 g of product, mp 90°-94° C.
Reaction SMILES: N([C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:6]=[N:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])N>C(O)C.[Hg]=O>[N:17]1[CH:18]=[CH:19][C:14]([C:5]2[N:6]=[N:7][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][N:4]=2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1nnc(-c2ccncc2)nc1NN
Agent: O=[Hg]
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccncc2)nn1
Yield: 52 %

Procedure:
In ethanol (5 ml) was suspended ethyl 5-hydrazino-3-(pyridin-4-yl)-1,2,4-triazine-6-carboxylate (50 mg). To the resulting suspension, mercury (II) oxide (98 mg) was added and the resulting mixture was heated under reflux for 9 hours. After completion of the reaction, the insoluble matter was removed through Celite filtration. The filtrate was concentrated and the concentrate was separated into layers by the addition of ethyl acetate and water. The organic layer thus obtained was dried over anhydrous magnesium sulfate. The filtrate was concentrated, whereby a crudely purified product of the title compound (23 mg, pale yellow powder) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:45][N:46]([CH3:60])[CH2:47][CH2:48][CH2:49][O:50][C:51]1[CH:57]=[CH:56][C:54]([NH2:55])=[CH:53][C:52]=1[O:58][CH3:59]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:55][C:54]2[CH:56]=[CH:57][C:51]([O:50][CH2:49][CH2:48][CH2:47][N:46]([CH3:60])[CH3:45])=[C:52]([O:58][CH3:59])[CH:53]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: COc1cc(N)ccc1OCCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)ccc1OCCCN(C)C

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (250 mg, 0.71 mmol), 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (126 mg, 0.33 mmol) and 4-(3-dimethylaminopropoxy)-3-methoxy-aniline as in step B of 207 (298 mg, 0.78 mmol). The title compound was obtained as a yellow solid (50.0 mg, 13% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.45 (1H, s), 9.32 (1H, br), 9.01 (2H, m), 8.67 (1H, s), 7.33 (1H, m), 7.20 (1H, m), 4.02 (2H, m), 3.74 (3H, s), 3.21 (2H, m), 2.83 (6H, s), 2.07 (2H, m). MS m/z: 557.30, 559.29 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:29])([S:25](F)(=[O:27])=[O:26])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[CH2:37]([NH2:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>O>[CH2:37]([NH:47][S:25]([C:2]([F:29])([F:1])[C:3]([F:23])([F:24])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:17])([F:18])[C:7]([F:15])([F:16])[C:8]([F:13])([F:14])[C:9]([F:11])([F:12])[F:10])(=[O:27])=[O:26])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCCCCN
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
50.21 g (100.0 mmol) of perfluorooctanesulfonyl fluoride is added in drops to a mixture of 10.62 g (105.0 mmol) of triethylamine and 15.73 g (100.0 mmol) of decylamine at 80° C. while being stirred vigorously. It is stirred for 2 days at 80° C., the reaction mixture is mixed with 300 ml of water and extracted three times with ethyl acetate. The combined organic extracts are dried on sodium sulfate, filtered and concentrated by evaporation. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol=4/1).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH2:6]([C:13]1[S:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:22](Cl)(=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.C(=S)=S>O>[CH2:6]([C:13]1[S:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[C:14]=1[C:22]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:31])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(Cc2cc3ccccc3s2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: S=C=S
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)sc3ccccc23)cc1
Reaction time: 6 h
Yield: 81.8 %

Procedure:
Tin tetrachloride (9.0 mL, 76.91 mmol) was added dropwise over a 25 minute period to a stirred solution of 2-benzyl-benzo[b]thiophene (14.87 g, 96.79 mmol), p-anisoyl chloride (11.75 g, 68.87 mmol) and carbon disulfide (75 mL) under a dry nitrogen atmosphere. After 6 hours, the reaction mixture was added to water and extracted with dichloromethane. The dichloromethane extract was washed with sat. aq. sodium bicarbonate and brine. The solvent was removed and the resultant solid was triturated with pet. ether to give the title compound as a white solid (20.2 g, 85%): mp 135-137° C.: NMR (CDCl3); δ 7.85 (dm, J=9 Hz, 2H), 7.73 (dm, 1H), 7.42 (dm, 1H), 7.18-7.30 (m, 7H), 6.93 (dm, J=9 Hz, 2H), 4.21 (s, 2H, CH2), 3.88 (s, 3H, CH3): IR (KBr, cm-1): 1650; MS (EI): 358 (100%, MI), 343 (15%), 327 (75%); Anal. Calc. for C23H18O2S: C, 77.07, H, 5.06, N, 0.00. Found: C, 76.91, H, 5.02, N, -0.12.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][C:7]([O:9]C)=O)[CH2:2]1.[NH2:11][NH2:12].O>CO>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][C:7]([NH:11][NH2:12])=[O:9])[CH2:2]1
Reactant: COC(=O)CC1CCOC1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)CC1CCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a round-bottom flask was added a solution of methyl 2-(tetrahydrofuran-3-yl)acetate (compound 130.3, 1.50 g, 10.4 mmol, 1.00 equiv) and NH2NH2. H2O (1.04 g, 20.8 mmol, 2.00 equiv) in methanol (15 mL). The resulting mixture was stiffed overnight at 80° C. in an oil bath. After cooling to ambient temperature, the mixture was concentrated in vacuo to yield 1.20 g (80%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Br[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1>CN(C=O)C>[Br:15][C:13]1[CH:14]=[C:9]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:10]=[N:11][CH:12]=1
Reactant: Brc1cncc(Br)c1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cncc(Br)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
2-Methoxyethanol (2.7 ml; 33.8 mmol) is added dropwise to a suspension of NaH (55% suspension; 1.62 g; 37.14 mmol) in DMF (60 ml). After stirring for 30 minutes, 3,5-dibromopyridine (4.0 g; 16.88 mmol) is introduced and the mixture heated to 50° C. for 1 hour. The reaction mixture is poured on water and extracted with ethyl acetate three times, the organic phases are combined, dried over Na2SO4 and evaporated to dryness. Chromatography (SiO2; Hexanes/acetone 85:15) yields the title compound as yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH:26]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)([C:14](=[O:25])[NH:15][C:16]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:26])([C:14](=[O:25])[NH:15][C:16]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCC2c3ccccc3-c3ccccc32)(C(=O)NC2(c3ccccn3)CC2)CC1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N)(C(=O)NC2(c3ccccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of crude 4-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(1-pyridin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester in DMF (0.5 mL) was added piperidine (0.2 mL). The mixture was stirred at room temperature. After 1 h, the solution was diluted with EtOAc (20 mL) and washed with water (4×20 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified via flash chromatography on silica gel (10% MeOH in CH2Cl2 containing 0.1% NH4OH) to afford 74 mg of 4-amino-4-(1-pyridin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH3:2].Cl[CH2:13][CH2:14][O:15][CH2:16][CH2:17]Cl>>[CH2:1]([O:3][C:4]([C:5]1([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])[CH3:2]
Reactant: ClCCOCCCl
Reactant: CCOC(=O)Cc1cccs1
Product: CCOC(=O)C1(c2cccs2)CCOCC1

Procedure:
Thiophen-2-yl-acetic acid ethyl ester (1) was dialkylated as described in Example 1, Step 1, using 1-chloro-2-(2-chloroethoxy)ethane to obtain the title compound (37).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[N:36]2[CH:40]=[CH:39][CH:38]=[N:37]2)[C:24]([Cl:41])=[CH:23][N:22]=1>>[Cl:41][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[N:36]2[CH:40]=[CH:39][CH:38]=[N:37]2)=[N:26][C:21]([NH:1][C:2]2[C:3]([O:18][CH3:19])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:22][CH:23]=1
Reactant: CCN1CC(=O)N(CC)c2cc(N)c(OC)cc2C1
Reactant: COc1ccc(Nc2nc(Cl)ncc2Cl)c(-n2cccn2)c1
Product: CCN1CC(=O)N(CC)c2cc(Nc3ncc(Cl)c(Nc4ccc(OC)cc4-n4cccn4)n3)c(OC)cc2C1

Procedure:
The title compound was prepared from 8-Amino-1,4-diethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(4-methoxy-2-pyrazol-1-yl-phenyl)-amine in an analogous manner to example 730 (0.044 g, 36%). Mp 97-100° C. LCMS (m/e) 563 (M); 1H-NMR (DMSO, 400 MHz) δ 9.85 (s, 1H), 8.24 (S, 1H), 8.12 (s, 1H), 7.97-7.95 (d, 1H, J=8.84 Hz), 7.90 (s, 2H), 7.82 (s, 1H), 7.16 (s, 1H), 7.04 (s, 1H), 6.83-6.81 (d, 1H, J=8.59 Hz), 6.53 (s, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.60-3.50 (m, 1H), 3.49 (s, 2H), 2.95 (s, 2H), 1.10-1.00 (t, 3H, J=7.32 Hz), 0.93-0.83 (t, 3H, J=6.82 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].CO>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[F:21])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4ccccc4F)c3C2=O)C(=O)N1
Yield: 94.9 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and 2-fluorobenzoyl chloride (1.0 mL, 8.4 mmol) in THF (40 mL) was heated to reflux for 15 h. To the mixture was added methanol (10 mL) to give a suspension. The suspension was filtered and washed with methanol (20 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-fluoro-benzamide as a white solid (1.5 g, 93% yield): mp, 300–302° C.; 1H NMR (DMSO-d6) δ 2.05–2.12 (m, 1H, CHH), 2.45–2.65 (m, 2H, CH2), 2.83–2.97 (m, 1H, CHH), 5.18 (dd, J=5.5, 12.9 Hz, 1H, NCH), 7.40–7.49 (m, 2H, Ar), 7.67–7.76 (m, 2H, Ar), 7.88–7.98 (m, 1H, Ar), 8.01–8.05 (m, 1H, Ar), 8.76 (d, J=8.4 Hz, 1H Ar), 10.56 (d, JN-F=10 Hz, 1H, NH), 11.17 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.96, 30.92, 48.97, 116.48, 116.97 (d, JC-F=14 Hz), 118.82, 120.87 (d, JC-F=12 Hz), 125.32 (d, JC-F=1.5 Hz), 125.74, 131.32, 131.39, 134.88 (d, JC-F=9 Hz), 136.22, 136.48, 159.75 (d, JC-F=252 Hz), 161.76 (d, JC-F=7 Hz), 166.58, 168.04, 169.70, 172.71; Anal Calcd for C20H14N3O5F: C, 60.76; H, 3.57; N, 10.63; F, 4.81. Found: C, 60.70; H, 3.64; N, 10.64; F, 4.91.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:28]1([S:31](Cl)(=[O:33])=[O:32])[CH2:30][CH2:29]1.C(O)(C(F)(F)F)=O.C(N(CC)CC)C>N1C=CC=CC=1.O.CC#N>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][S:31]([CH:28]4[CH2:30][CH2:29]4)(=[O:33])=[O:32])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@H](NS(=O)(=O)C1CC1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Temperature: 0 °C
Yield: 34.2 %

Procedure:
(1R,2S)-1-[1-(4-Fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-amine (1a, 16 mg, 0.044 mmole) was dissolved in dry pyridine (2 mL) and cooled to 0° C. Cyclopropanesulfonyl chloride (16 μl, 0.056 mmole) was added and the mixture was stirred at room temperature for 45 mm. The progression of the reaction was followed by HPLC (R.P C-18, 20-90% gradient of CH3CN in water, 0.1% TFA). After 45 and 75 mm additional portions of cyclopropanesulfonyl chloride (5 and 6 μl respectively) were added. As the reaction proceeded very slowly, triethylamine (27 μl, 0.2 mmol) was added after a total of 2.5 h of stirring. The stirring was continued at ambient temperature for additional 18.5h and the reaction mixture was then partitioned between ethyl acetate and aqueous hydrochloric acid (1.7M). The organic phase was washed twice with aqueous hydrochloric acid (1.7M), then with water and finally with brine. Evaporation and flash chromatography (SiO2, gradient of 0-50% EtOAc in heptane) and finally lyophilization from dioxane gave the title compound (7 mg, 33%) containing 15 mol % of dioxane.
Reaction SMILES: [BH4-].[Na+].[OH:3][CH:4]([CH:10]1[CH2:14][CH2:13][O:12][CH:11]1[O:15][CH:16]([CH3:18])[CH3:17])[C:5](OCC)=[O:6].Cl.N(CCO)CCO>C(O)C.O>[CH:16]([O:15][CH:11]1[CH:10]([CH:4]([OH:3])[CH2:5][OH:6])[CH2:14][CH2:13][O:12]1)([CH3:18])[CH3:17]
Reactant: CCOC(=O)C(O)C1CCOC1OC(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: OCCNCCO
Solvent: CCO
Solvent: O
Product: CC(C)OC1OCCC1C(O)CO
Temperature: 25 °C
Reaction time: 19 h

Procedure:
In a 2 L round bottom flask charged with 600 mL of ethanol and NaBH4 (12.55 g, 0.33 mol, 1.1 eq.) at 0° C., ethyl hydroxy-(2-isopropoxytetrahydro-3-furanyl)acetate (70 g, 0.3 mol, 1 eq.) dissolved in 400 mL of ethanol was added dropwise over 1 hour at 0° C. The mixture was allowed to warm up at room temperature and stirred for 19 hours. After cooling at 0° C., diethanolamine hydrochloride (46.7 g, 0.33 mol, 1.1 eq.) dissolved in 100 mL of water was added over 10 min. and stirred for 8 hours. The solvent was evaporated under reduced pressure to afford a clear yellow solid. After dilution with 300 mL of ethylacetate, the heterogeneous mixture was filtered over dicalite. The mixture was used directly in the next step.