Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]([NH:8]S(C(C)(C)C)=O)[CH3:7])[N:3]=[N:2]1.[ClH:15]>CO>[ClH:15].[NH:1]1[CH:5]=[C:4]([CH:6]([NH2:8])[CH3:7])[N:3]=[N:2]1
Reactant: CC(NS(=O)C(C)(C)C)c1c[nH]nn1
Agent: Cl
Solvent: CO
Product: CC(N)c1c[nH]nn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
Racemic-N-(1-(1H-1,2,3-triazol-4-yl)ethyl)-2-methylpropane-2-sulfinamide (Preparation 63, 1.09 g, 5.04 mmol) was dissolved in methanol (10 mL). 4M HCl in MeOH (10 mL) was added and the mixture was stirred at room temperature for 5 hours. The reaction was concentrated in vacuo and triturated with TBME (50 mL), diethyl ether (20 mL) and finally with acetonitrile (20 mL). The remaining gum was azeotroped with methanol (10 mL) followed by toluene (10 mL) to afford the title compound as a pale yellow gum (780 mg, 100%).
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10]N2C(=O)CCC(N3CC4C(=CC=C(CNC(NC5C=CC(C)=C([Cl:39])C=5)=O)C=4)C3=O)C2=O)=[O:8])[CH2:3][CH2:2]1.Cl>CCOCC>[ClH:39].[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1
Reactant: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)N(COC(=O)C4CCN(C(=O)OC(C)(C)C)CC4)C2=O)C3=O)cc1Cl
Agent: Cl
Solvent: CCOCC
Product: COC(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 360.6 %

Procedure:
To 1-tert-butyl 4-(3-(5-((3-(3-chloro-4-methylphenyl)ureido)methyl)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl piperidine-1,4-dicarboxylate (300 mg, 0.44 mmol, obtained as described in previous example) was added 2 N HCl in Et2O (15 mL). The slurry was vigorously stirred for 2 h at rt. The solid was filtered, washed with copious Et2O, and dried in a vacuum oven overnight to give (3-(5-(3-(3-chloro-4-methylphenyl)ureido)methyl)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl piperidine-4-carboxylate Hydrochloride as a white solid (285 mg, 105% yield): HPLC:Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 3.26 min (98.2%); mp: 234-236° C.; 1H NMR (DMSO-d6) δ 1.62-1.81 (m, 2H, CHH, CHH), 1.87-2.01 (m, 2H, CHH, CHH), 2.02-2.16 (m, 1H, CHH), 2.16-2.29 (m, 3H, CH3), 2.32-2.47 (m, 1H, CHH), 2.59-2.76 (m, 1H, CHH), 2.77-2.99 (m, 3H, CHH, CHH, CHH), 3.00-3.28 (m, 3H, CHH, CHH, CHH), 4.15-4.66 (m, 4H, CH2, CH2), 5.26 (dd, J=4.9, 13.2 Hz, 1H, CH), 5.55-5.80 (m, 2H, CH2O), 7.02 (t, J=5.9 Hz, 1H, NH), 7.09-7.29 (m, 2H, Ar), 7.45 (d, J=7.9 Hz, 1H, Ar), 7.53 (s, 1H, Ar), 7.62-7.82 (m, 2H, Ar), 8.41-8.96 (m, 2H, NH, NH), 9.09 (s, 1H, NH); 13C NMR (DMSO-d6) δ 18.73, 21.46, 24.31, 31.24, 37.30, 42.00, 42.73, 47.20, 52.09, 63.40, 116.31, 117.50, 121.91, 122.99, 126.97, 127.27, 130.09, 130.99, 132.96, 139.69, 142.38, 144.94, 155.21, 167.96, 170.19, 171.29, 172.20; LCMS: MH=582, 584; Anal Calcd for C29H33C12N5O6+1.6 H2O+0.6HCl+0.2 Et2O+0.4 tBuCl: C, 53.35; H, 6.05; N, 9.91; Cl, 13.04. Found: C, 53.13; H, 6.06; N, 9.70; Cl, 13.25.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[NH:4][C:5]([C:22](F)([F:24])[F:23])=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]([CH:14]2[CH2:16][CH2:15]2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C1CCN2C(=NCCC2)CC1>C1COCC1>[F:24][CH:22]([F:23])[C:5]1[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([CH:14]2[CH2:15][CH2:16]2)[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:3]([C:2]([F:27])([F:1])[F:26])[N:4]=1
Reactant: CCOC(=O)C1=C(C(F)(F)F)NC(C(F)(F)F)=C(C(=O)OCC)C1C1CC1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1C1CC1
Yield: 85 %

Procedure:
To a solution of 40 g (0.0916 mole) of diethyl 2,6-bis(trifluoromethyl)-2,6-dihydroxy-4-cyclopropyl-tetrahydropyran-3,5-dicarboxylate in 200 ml of THF is introduced 55.5 g (3.26 moles) of ammonia. The reaction mixture is concentrated to give 38.5 g (96.7%) of a solid. A portion (28 g) of this material is stirred with 27.08 g (0.129 mole) of trifluoroacetic anhydride for one day. The reaction mixture is concentrated and diluted with ether. The ether solution is washed with saturated sodium bicarbonate, dried (MgSO4), and concentrated to give 21 g (81.3%) of an oil, nD25 1.4460. This oil is identified as diethyl 2,6-bis(trifluoromethyl)- 4-cyclopropyl-1,4-dihydro-pyridine-3,5-dicarboxylate. A portion (18 g) of this oil and 150 ml of THF is treated with 6.82 g (0.0449 mole) of DBU. The reaction mixture is held at reflux for 24 hours and concentrated. The residue is stirred with water and extracted with ether. The ether extract is washed with diluted HCl, dried (MgSO4), and concentrated. The residue is crystallized to give 13 g (76.0%) of crude product. A portion (2.0 g) of this product is recrystallized from petroleum ether at low temperature to give 1.17 g (85%) of desired product, m.p. 30°-32° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32]C)=[O:31])=[CH:25][C:24]=2[O:34][CH3:35])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([CH3:36])[NH:17]2)(=[O:11])=[O:10].[OH-].[Li+].Cl>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][C:24]=2[O:34][CH3:35])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([CH3:36])[NH:17]2)(=[O:11])=[O:10]
Reactant: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C)cc3c2NS(=O)(=O)c2ccc(Cl)cc2Cl)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(CC(=O)O)ccc1Oc1ccc2[nH]c(C)cc2c1NS(=O)(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a room temperature solution of 1.4 (1.00 g, 1.82 mmol) dissolved in a mixture of methanol (5 mL) and water (5 mL) was added lithium hydroxide (190 mg, 7.90 mmol). The reaction mixture was stirred at room temperature for 1 h then poured into aqueous 1N hydrochloric acid solution. The aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were washed twice with water then brine, stirred over magnesium sulfate, filtered and the filtrate concentrated in vacuo on a rotary evaporator to afford a yellow solid. The product was isolated by semi-preparative reversed phase HPLC to afford a colorless solid. LC-MS ESI (neg.) m/z: 533.0 (M−H). 1H NMR (400 MHz) (d6-DMSO) δ 12.30 (br s, 1H); 10.95 (s, 1H); 9.73 (s, 1H); 7.63 (d, J=8.4 Hz, 1H); 7.52 (d, J=2 Hz, 1H); 7.30 (dd, J=2.0 & 8.5 Hz, 1H); 7.09 (d, J=8.6 Hz, 1H); 6.87 (d, J=1.4 Hz, 1H); 6.57 (d, J=8.3 Hz, 1H); 6.31 (d, J=8.6 Hz, 1H); 6.22 (d, J=8.0 Hz, 1H); 6.13 (s, 1H); 3.69 (s, 3H); 3.50 (s, 2H); 2.37 (s, 3H) ppm.
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].N[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[Cl:14]>O.Cl>[Cl:14][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:6]=1[N+:1]([O-:3])=[O:2])[C:10]#[N:11]
Reactant: N#Cc1ccc(N)c(Cl)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Sodium nitrite (6.78 g in water (40 mL) at 0° C.) was slowly added to a solution of 4-amino-3-chloro-benzonitrile (10.5 g) in water (30 mL) and concentrated hydrochloric acid (30 mL) also at 0° C. After 10 minutes the solution was poured onto a suspension of cuprous oxide (3.48 g) and sodium nitrite (31.69 g) in water (100 mL) at 0° C. The ensuing mixture was stirred at 0° C. for 1 hour then at 23° C. for 1 hour. The resulting mixture was extracted with dichloromethane and the organic layer washed with saturated sodium chloride. The separated organic layer was dried over sodium sulfate and then concentrated to give 3-chloro-4-nitro-benzonitrile (11.31 g).
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([S:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[F:17])([CH3:7])[CH3:6])C.C[Si](C)(C)[O-].[K+]>C1COCC1>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([S:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:18])=[O:3])=[C:10]([F:17])[CH:11]=1)#[N:16]
Reactant: CCOC(=O)C(C)(C)Sc1ccc(C#N)cc1F
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(Sc1ccc(C#N)cc1F)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 106 %

Procedure:
To a solution of 1.1 g (4.1 mmol) of 2-(4-cyano-2-fluoro-phenylsulfanyl)-2-methyl-propionic acid ethyl ester in THF (50 mL) were added 1.58 g (12.3 mmol) of potassium trimethylsilanolate. The reaction was stirred at room temperature for 3 h. The solvent was removed under reduced pressure. The residue was partitioned between DCM (50 mL) and water (50 mL). The aqueous layer was acidified with 1 M aqueous HCl solution and extracted with DCM (4×50 mL). The combined organic extracts were dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to afford 1.04 g of 2-(4-cyano-2-fluoro-phenylsulfanyl)-2-methyl-propionic acid.
Reaction SMILES: OS(O)(=O)=O.N([O-])=O.[Na+].N[C:11]1[C:12]([Cl:20])=[C:13]([C:16]([Cl:19])=[CH:17][CH:18]=1)[C:14]#[N:15].[BrH:21]>C(O)(=O)C>[Br:21][C:11]1[C:12]([Cl:20])=[C:13]([C:16]([Cl:19])=[CH:17][CH:18]=1)[C:14]#[N:15]
Reactant: N#Cc1c(Cl)ccc(N)c1Cl
Reactant: Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1c(Cl)ccc(Br)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 1 mL of conc. H2SO4 was portionwise added sodium nitrite (1.38 mmol). After complete dissolution, a solution of 3-amino-2,6-dichlorobenzonitrile (1.24 mmol) in 2.5 mL glacial acetic acid was added at 0° C. After 30 min at 0° C., a precooled solution of CuBr (2.76 mmol) in 0.5 mL HBr (48% in H2O) was slowly added. The reaction was stirred at 0° C. for 45 min and then at RT for 45 min. The mixture was quenched with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give the desired product as brown solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[N:10]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH:22]([CH:26]([C:39]([NH2:41])=[O:40])[C:27]2[CH:38]=[CH:37][C:30]([C:31]([O:33][CH2:34][CH2:35][OH:36])=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:24][CH3:25])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(Cl)Cl.C(N(CC)CC)C>[N:10]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH:22]([CH:26]([C:39]([NH2:41])=[O:40])[C:27]2[CH:38]=[CH:37][C:30]([C:31]([O:33][CH2:34][CH2:35][O:36][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=3)=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:24][CH3:25])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCCC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)OCCO)cc1
Reactant: O=C(Cl)c1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)OCCOC(=O)c2cccnc2)cc1
Temperature: 20 °C

Procedure:
A solution of 0.7 gm (4.68 m mol) of nicotinic acid chloride in 20 ml of methylene chloride was rapidly added dropwise to a stirred solution of 2.0 gm (4.56 m mol) of 2-hydroxyethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate in 40 ml of methylene chloride and 0.7 ml (4.81 m mol) of triethylamine. The resulting mixture was stirred at 20° C. for two and one-half hours and then extracted with water, and the organic phase was subsequently dried, filtered, and evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel [toluene/acetone (5:1)].
Reaction SMILES: [Si:1]([C:8]1[N:9]([S:13](=[O:18])(=[O:17])[N:14]([CH3:16])[CH3:15])[CH:10]=[CH:11][N:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:10]1[N:9]([S:13](=[O:18])(=[O:17])[N:14]([CH3:15])[CH3:16])[C:8]([Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[N:12][CH:11]=1
Reactant: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C
Reactant: BrCCCCCCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1c(CCCCCCCCBr)cnc1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A solution of 2-(tert-butyldimethylsilyl)-1-(N,N-dimethylsulfamoyl) imidazole (Example 29 step a) (2.62 g, 9.05 mmol) in dry tetrahydrofuran (30 ml) was cooled under an atmosphere of argon to -78° C. n-Butyl lithium (1.5M in hexanes) (7.25 ml, 10.9 mmol) was added over 15 min and the solution stirred for a further 30 min. A solution of 1,8-dibromooctane (2.55 ml 13.6 mmol) in dry tetrahydrofuran (5 ml) was added over 10 min. The solution was stirred for 2 h, allowed to warm to room temperature and stirred for 18 h. Saturated ammonium chloride solution (30 ml) and diethyl ether (30 ml) were added and the ethereal extract was washed with brine and dried over sodium sulfate. Filtration, evaporation of the filtrate and purification by flash column chromatography (silica; 20%; ethyl acetate/hexane) to afford the product (Rf 0.43) as a white solid (2.36 g, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[C:4]([F:11])[CH:3]=1.[C:12](Cl)(=[O:15])[CH2:13][CH3:14].CCN(C(C)C)C(C)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:12](=[O:15])[CH2:13][CH3:14])[CH3:9])=[C:4]([F:11])[CH:3]=1
Reactant: CCC(=O)Cl
Reactant: CC(N)c1ccc(Br)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)NC(C)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
61 mg (1 eq, 0.24 mmol) of 1-(4-bromo-2-fluorophenyl)ethanamine from Stage 1 were dissolved in 4 ml of dichloromethane, and 24 mg (1.1 eq, 23 μl, 0.264 mmol) of propanoyl chloride and 70 mg (2.2 eq, 90 μl) of Hünig's base were added. The mixture was stirred at room temperature for 5 h and then concentrated. The crude product was dissolved in ethyl acetate and washed 1× with 1M HCl, 1× with sat. sodium carbonate solution and then with water, and dried over magnesium sulphate. After concentrating under reduced pressure, the resulting crude product was purified by means of chromatography on silica gel (eluent: cyclohexane/ethyl acetate). 50 mg (67%) of N-[1-(4-bromo-2-fluorophenyl)ethyl]propanamide were obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.BrC1[CH:8]=[C:9]2[C:26](=CC=1)[O:25][C:12]1([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[CH2:11][C:10]2=[O:29]>[C-]#N.[C-]#N.[Zn+2].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.CN(C=O)C>[C:5]([C:4]1[CH:3]=[C:2]2[C:26](=[CH:9][CH:8]=1)[O:25][C:12]1([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:16][CH2:17]1)[CH2:11][C:10]2=[O:29])#[N:1]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(C#N)ccc1O2
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 5-bromo-2-hydroxyacetophenone (104.35 g, 485.26 mmol), N-Boc-piperidin-4-one (98.62 g, 494.96 mmol), 20 mL of pyrrolidine (17.26 g, 242.63 mmol) and 261 mL of MeOH was heated under reflux until the reaction was complete. The mixture was cooled, then 87 mL of H2O were added, and the mixture was filtered and dried to give tert-butyl 6-bromo-4-oxospiro-[chroman-2,4′-piperidine]-1′-carboxylate. Alternatively, 10 mL of pyrrolidine (121.31 mmol) may be used in this procedure. To a solution of tert-butyl 6-bromo-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (6593 g, 16.6 mol) and DMF (33 L) was added Zn(CN)2 (1947 g, 16.6 mol) and Pd(PPh3)4 (192 g, 0.17 mol). The slurry was heated to 90° C. for 3 hours, then cooled to room temperature and filtered. Water (16 L) was added to the filtrate. The resulting slurry was cooled to 5° C., stirred for 1 hour and filtered. The solid was washed with DMF/water (2:1) and dried under vacuum to give tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate. A solution of 23 g of tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (67.17 mmol), 13.10 g sodium azide (201.52 mmol), 27.74 g of triethylamine hydrochloride (201.52 mmol), and 460 mL of dry DMF was stirred under a nitrogen atmosphere at 100° C. for 12 hours. After cooling to room temperature, 506 mL of EtOAc were added, followed by 322 mL of 1M HCl (322 mmol). Alternatively, 0.5M HCl maybe added until pH=3. The resulting layers were separated, the organic layer was washed with water/methanol (115 mL/46 mL), and then concentrated to give tert-butyl 4-oxo-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate. A solution of 5.08 g of tert-butyl 4-oxo-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate (13.18 mmol), 8.8 mL of 12 M HCl (105.44 mmol) and 8 mL of methanol was heated to 50° C. until the reaction was complete. The resulting slurry was filtered, washed with 25 mL of methanol at room temperature, and dried to give 6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-4-one hydrochloride salt.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][O:11][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](COc1ncccc1[N+](=O)[O-])C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a stirring solution of N-t-butyloxycarbonyl-L-serine (2.26 g) in N,N-dimethylformamide (15 mL) under argon at −20° C. was slowly added sodium hydride (60% oil dispersion, 0.88 g gross weight). The resulting mixture was warmed to 0° C. for 1 h, then recooled to −20° C. before a solution of 2-chloro-3-nitropyridine (1.6 g) in N,N-dimethylformamide (10 mL) was added over 10 min. The resulting red solution was stirred at −20° C. for 1 h. Water (100 mL) was then added, and the mixture was washed with diethyl ether (30 mL twice). The aqueous layer was adjusted to pH 7 with 1.0 M aqueous hydrochloric acid and extracted with ethyl acetate (30 mL three times). The combined extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:2) to obtain N-t-butyloxycarbonyl-O-(3-nitro-2-pyridyl)-L-serine (2.46 g).
Reaction SMILES: [K].[SH:2][C:3]1[O:4][C:5]([CH3:8])=[N:6][N:7]=1.BrCCl.[CH4:12].[I-:13].[Na+]>CC#N.CCOCC>[I:13][CH2:12][S:2][C:3]1[O:4][C:5]([CH3:8])=[N:6][N:7]=1
Reactant: [I-]
Reactant: Cc1nnc(S)o1
Reactant: C
Agent: ClCBr
Agent: [K]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: Cc1nnc(SCI)o1
Yield: 87.3 %

Procedure:
A suspension of 2-mercapto-5-methyl-1,3,4-oxadiazole potassium salt (33.0 g, 214 mmol) in CH3CN (330 mL) was stirred at R.T. for 24 h in the presence of BrCH2Cl (130 g, 1 mol). Then the solvent was evaporated and the residue partitioned between H2O and EtOAc. The organic phase was separated, dried (MgSO4) and evaporated. The residue thus obtained was redissolved in Et2O; the etheral solution was treated with charcoal and filtered through a pad of Celite. Evaporation of the filtrate left 29.4 g of a colorless oil. The crude oil was dissolved in acetone (350 mL), and sodium iodide (134 g, 894 mmol) was added. The resulting mixture was refluxed for 24 h, diluted with Et2O and washed with H2O. The aqueous phase was reextracted with Et2O. The organic extracts were combined, washed with H2O and brine, dried (MgSO4), treated with charcoal, filtered and finally evaporated to give 40.0 g (87.3%) of the title compound as a yellowish oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=4[Cl:28])[C:22](O)=[O:23])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:60][CH2:61][C@H:62]([OH:64])[CH3:63]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:20]=[C:21]([C:22](=[O:23])[NH:60][CH2:61][C@H:62]([OH:64])[CH3:63])[CH:25]=[CH:26][C:27]=4[Cl:28])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1
Reactant: C[C@@H](O)CN
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)O)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)CNC(=O)c1ccc(Cl)c(N(C)C(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c1
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a mixture of 3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoic acid (3 g, 6.09 mmol) in THF (50 mL) was added EDCI (2.34 g, 12.18 mmol), HOBt (1.23 g, 9.13 mmol), DIPEA (5 mL) and (R)-1-amino-propan-2-ol (0.69 g, 9.13 mmol) by sequence under nitrogen atmosphere at room temperature. The reaction mixture was stirred overnight, diluted with water. The resulting precipitate was washed with water and EtOAc to give 8-bromo-N-(2-chloro-5-((R)-2-hydroxypropylcarbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (2.7 g, yield 81%). 1H NMR (DMSO-d6, 400 MHz): δ8.62 (t, J=5.2 Hz, 1H, NH), 8.11-6.11 (m, 7H, ArH), 4.77 (d, J=4.4 Hz, 1H, OH), 4.18 (br s, 2H, CH2), 3.81-3.75 (m, 1H, CH), 3.32 (s, 3H, NCH3), 3.19 (br s, 2H, CH2), 2.94 (br s, 2H, CH2), 1.05 (d, J=6.0 Hz, 3H, CH3). LC-MS: (ESI, m/z)=549 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:26]=[CH:25][C:16]4[C:17]([C:21]([NH:23][CH3:24])=[O:22])=[C:18]([CH3:20])[O:19][C:15]=4[CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:28][CH:29]1[CH2:31][O:30]1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH3:24][NH:23][C:21]([C:17]1[C:16]2[CH:25]=[CH:26][C:13]([O:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([O:1][CH2:28][CH:29]5[CH2:31][O:30]5)=[CH:3][CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:14][C:15]=2[O:19][C:18]=1[CH3:20])=[O:22]
Reactant: CNC(=O)c1c(C)oc2cc(Oc3ccnc4cc(O)ccc34)ccc12
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CNC(=O)c1c(C)oc2cc(Oc3ccnc4cc(OCC5CO5)ccc34)ccc12
Yield: 93.8 %

Procedure:
A solution of 6-[(7-hydroxyquinolin-4-yl)oxy]-N,2-dimethyl-1-benzofuran-3-carboxamide 123-A (1 g, 2.9 mmol), 2-(bromomethyl)oxirane (467 mg, 3.4 mmol) and Cs2CO3 (1.4g, 4.2 mmol( in CH3CN (25 ml) was heated to 65° C. for 3 hours. The solution was extracted with EtOAc. N,2-dimethyl-6-{[7-(oxiran-2-ylmethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide 123-B (1.1 g) was isolated by a silica gel column using 1-5% MeOH in CH2Cl2 To a solution of 123-B (150 mg, 0.35 mmol) in THF (5 ml) was added a solution of methylamine in MeOH (1 N, 1 ml). The solution was heated to 65° C. for 2 hours. The crude product was purified by HPLC (10-40% CH3CN/H2O over 30 min.) to give 6-({7-[2-hydroxy-3-(methylamino)propoxy]quinolin-4-yl}oxy)-N,2-dimethyl-1-benzofuran-3-carboxamide 123.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[F:19]C1C=CC([N+]([O-])=O)=CC=1.FC1C=CC(CO)=CC=1>>[F:19][C:18]1[CH:17]=[CH:16][C:4]([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)cc1
Agent: OCc1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)cc1
Yield: 86 %

Procedure:
The title compound is prepared in analogy to 1-(3-fluorobenzyloxy)-4-nitro-benzene, starting from 4-fluoro nitrobenzene and 4-fluoro benzyl alcohol. Yield: 86% of a slightly yellow solid. Mp.=124-126°.