Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:7]=[CH:6]2.CN(C)P(=O)(N(C)C)N(C)C.[O:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1.[Cl-].[NH4+]>O1CCCC1.C([Li])CCC>[OH:38][C:35]1([C:7]2[N:8]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:13])=[O:14])[C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([S:2][CH3:1])=[CH:11][CH:10]=3)[CH2:36][CH2:37][O:32][CH2:33][CH2:34]1
Reactant: CSc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: O=C1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)cc(C1(O)CCOCC1)n2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-methylthio-1-benzenesulfonylindole (200 mg ) in tetrahydrofuran (5 ml), n-butyl lithium (0.49 ml, 1.61 M) was added at −78° C. under nitrogen atmosphere and the mixture was stirred at −78° C. for 30 minutes, followed by addition of hexamethylphosphoric triamide (0.23 ml), and the mixture was stirred for 15 minutes. Subsequently, tetrahydro-4H-pyran-4-one (0.12 ml) was added thereto and the mixture was stirred at −78° C. for 15 minutes and heated to 15 to 30° C. The reaction solution was then poured into a saturated aqueous ammonium chloride solution, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate=1:1) and (methanol:chloroform=1:20) to obtain 39 mg of the desired product as a colorless oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](=O)[CH3:11])=[N:2]1.Cl.[NH2:14][OH:15].N1C=CC=CC=1>C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](=[N:14][OH:15])[CH3:11])=[N:2]1
Reactant: CC(=O)c1noc2ccccc12
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=NO)c1noc2ccccc12
Temperature: 0 °C

Procedure:
A mixture of 1.4 g of 1-(1,2-benzisoxazol-3-yl)ethanone, 0.7 g of hydroxylamine hydrochloride and 10 ml of pyridine is refluxed for 1 h. The reaction mixture is then poured onto a mixture of ice/water and the precipitated product is isolated by filtration. The product is dissolved in ethyl acetate, the solution is washed once with water, then twice with a saturated solution of sodium chloride and finally dried over sodium sulfate. The solvent is stripped off under vacuum, to give pure 1-(1,2-benzisoxazol-3-yl)ethanone oxime having a melting point of 193°-195° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[CH3:21][O:22][C:23](=[O:28])[CH2:24][C:25](Cl)=[O:26]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]([C:25](=[O:26])[CH2:24][C:23]([O:22][CH3:21])=[O:28])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)CC(=O)Cl
Reactant: COC(=O)c1cc(Cl)cn1NCc1ccc(OC)cc1
Product: COC(=O)CC(=O)N(Cc1ccc(OC)cc1)n1cc(Cl)cc1C(=O)OC

Procedure:
Prepared according to the acylation condition used in Example 2 step f) from 4-chloro-1-(4-methoxy-benzylamino)-1H-pyrrole-2-carboxylic acid methyl ester and chlorocarbonyl-acetic acid methyl ester (1.5 eq.). ESI (m/z): 395 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([OH:23])[CH2:20][C@H:19]1[CH2:24][O:25][C:26](=[O:36])[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)C(C)C)(C)C>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:22][C:21](=[O:23])[CH2:20][C@H:19]1[CH2:24][O:25][C:26](=[O:36])[C:27]1[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1COC(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1COC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (23.5 ml, 246 mmol) in dichloromethane (400 ml), which was cooled to −75° C., dimethyl sulfoxide (35 ml, 492 mmol) in dichloromethane (60 ml) was added in 20 minutes. After 30 minutes at −70° C., a solution of (2S,4R)-4-hydroxy-2-(4-nitro-benzoyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 55, 45 g, 123 mmol) in dichloromethane (300 ml) was added dropwise. After 2 hours at −70° C., N,N-diisopropylethylamine (60 ml) was added in 10 minutes. After 25 minutes at −60° C. and 30 minutes at room temperature dichloromethane (200 ml) was added. The organic solvent was washed with 0.5N HCl (500 ml), water (500 ml) and brine (500 ml), dried (Na2SO4) and evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether/ethyl acetate from 5/1 to 3/1). (S)-2-(4-Nitro-benzoyloxymethyl)-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester was obtained as white solid (28.5 g, yield: 70%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:12]([O:27][CH:28]([CH3:30])[CH3:29])[CH:11]=2)[C:6](=[O:31])[CH2:5]1.O.[Cl-].[Na+]>C(O)C.C(OCC)(=O)C>[OH:31][CH:6]1[CH:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:12]([O:27][CH:28]([CH3:29])[CH3:30])[CH:11]=2)[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5]1
Reactant: CC(C)Oc1cc(C2CCN(C)CC2=O)ccc1NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(C2CCN(C)CC2O)ccc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 26 %

Procedure:
486 mg of NaBH4 are added, in portions, to a suspension of 700 mg of benzyl [4-(1-methyl-3-oxopiperidin-4-yl)-2-(propan-2-yloxy)phenyl]carbamate in 35 ml of ethanol brought to 5° C. The reaction medium is stirred at ambient temperature for 50 minutes. 4 ml of water, 15 ml of a saturated aqueous sodium chloride solution and 40 ml of ethyl acetate are added. The two phases are separated, and the aqueous phase is washed with twice 20 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and evaporated. Purification is carried out by flash chromatography on silica gel (40-63 μm), elution being carried out with a mixture of dichloromethane and (MeOH+10% NH4OH) (99/1 to 90/10). 183 mg of benzyl [4-(3-hydroxy-1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]carbamate (trans diastereoisomers) and 183 mg of benzyl [4-(3-hydroxy-1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]carbamate (cis diastereoisomers) are obtained.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:20](/B(O)O)=[CH:21]\[CH3:22].C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=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.O>[CH:20](/[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[CH:21]\[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: C/C=C/B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: C/C=C/c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Temperature: 95 °C
Reaction time: 12 h
Yield: 96.3 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (400 mg, 1.22 mmol), trans-1-propen-1-ylboronic acid (157 mg, 1.82 mmol), ethanol (1.4 ml), 2N aqueous sodium carbonate solution (5 ml), and tetrakis(triphenylphosphine)palladium(0) (170 mg, 0.147 mmol) in toluene (10 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (340 mg, 97.1%) as an oil.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:14]2[NH:15][C:16](=O)[O:17][C@H:13]2[CH2:12][C@H:11]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:29]([CH3:37])S(C(F)(F)F)(=O)=O.[CH2:38]([NH2:40])[CH3:39]>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@H:14]2[N:15]=[C:16]([NH:40][CH2:38][CH3:39])[O:17][C@H:13]2[CH2:12][C@H:11]([CH2:19][O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:37]1[OH:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: O=C1N[C@@H]2[C@@H](OCc3ccccc3)[C@H](O)[C@@H](COCc3ccccc3)C[C@@H]2O1
Reactant: CCN
Solvent: ClCCl
Product: CCNC1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](O)[C@@H](COCc3ccccc3)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.3 %

Procedure:
To a solution of (3aS,4R,5R,6R,7aS)-4-(benzyloxy)-6-((benzyloxy)methyl)-5-hydroxyhexahydrobenzo[d]oxazol-2(3H)-one (Tetrahedron Lett. 1993, 34, 1525-1528) (235 mg, 0.614 mmol) in dry DCM (1.5 mL) under N2 at 0° C. was added methyl triflate (0.135 mL, 1.23 mmol) dropwise. The mixture was stirred at room temperature for 18 h. The reaction was cooled to 0° C. and ethylamine (0.40 mL, 6.14 mmol) was added. The mixture was stirred at 0° C. for 5 h. The mixture was diluted with aqueous satd. NaHCO3 (15 mL), extracted with DCM (2×15 mL). The extracts were dried (K2CO3) and concentrated to give the crude product (197 mg). This was purified by silica gel chromatography, eluted with 40-60% EtOAc in hexanes to recover the starting material (107 mg, recovery 46%). Further eluted the column with 92:6:2 DCM-MeOH—NH4OH to give the product (3aS,4R,5R,6R,7aS)-4-(benzyloxy)-6-((benzyloxy)methyl)-2-(ethylamino)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazol-5-ol (46 mg, 18%). 1H NMR (600 MHz, CDCl3) δ 7.38-7.27 (m, 10H), 4.89 (d, J=11.6, 1H), 4.72-4.69 (m, 1H), 4.69 (d, J=8.2, 1H), 4.53 (s, 2H), 3.99 (t, J=6.8, 1H), 3.61-3.54 (m, 3H), 3.46 (t, J=6.4, 1H), 3.29-3.20 (m, 2H), 2.11 (dt, J=14.8, 3.0, 1H), 1.94-1.88 (m, 1H), 1.78 (ddd, J=15.7, 12.4, 4.0, 1H), 1.18 (t, J=7.2, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C@H:8]2[CH2:9][C@@H:3]1[CH2:4][CH2:5][C:6]2=[O:7].S([O-])(OCCCCCCCCCCCC)(=O)=O.[Na+].[F:29][B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2.F[B-](F)(F)F>O>[F:29][C@@H:5]1[CH2:4][C@H:3]2[CH2:9][C@H:8]([C:2]2([CH3:10])[CH3:1])[C:6]1=[O:7]
Reactant: F[B-](F)(F)F
Reactant: CC1(C)[C@H]2CCC(=O)[C@@H]1C2
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [Na+]
Solvent: O
Product: CC1(C)[C@H]2C[C@@H](F)C(=O)[C@@H]1C2
Temperature: 80 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of (+)-nopinone (Aldrich, 1.0 g, 7.2 mmol) in water (35 mL), was added sodium dodecyl sulfate (Aldrich, 2.1 g, 7.2 mmol). The mixture was heated to 80° C. and then 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane tetrafluoroborate (Alfa-aesar, 2.8 g, 8.0 mmol) was added in two portions with one hour interval and stirred at 80° C. overnight. The reaction mixture was cooled and extracted with diethyl ether (3×30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-20% of ethyl acetate in hexanes) to obtain 0.4 g of the title compound. MS (DCI/NH3) m/z 174 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][N:4]=[C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[N:8]([CH:15]3[CH2:20][CH2:19][CH2:18][CH:17]([C:21](O)=[O:22])[CH2:16]3)[C:7](=[O:24])[C:6]=12.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH2:56]([NH2:63])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>CN(C)C=O>[CH2:56]([NH:63][C:21]([CH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[N:11][CH:10]=3)[C:5]3=[N:4][O:3][C:2]([CH3:1])=[C:6]3[C:7]2=[O:24])[CH2:16]1)=[O:22])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(C(=O)O)C1)c1cnccc21
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc2c1c(=O)n(C1CCCC(C(=O)NCc3ccccc3)C1)c1cnccc21
Yield: 96 %

Procedure:
Combine 3-(3-methyl-4-oxo-5H-2-oxa-1,5,7-triaza-cyclopenta[a]naphthalen-5-yl)-cyclohexanecarboxylic acid (50 mg, 0.15 mmol) with 1-[3-(dimethyl-amino)propyl]-3ethylcarbodiimide hydrochloride (32 mg, 0.17 mmol), 1-hydroxy-7-azabenzo-triazole (23 mg, 0.17 mmol), N,N-diisopropylethyl amine (44 mg, 3.4 mmol), and benzylamine (18 mg, 0.17 mmol) in N,N-dimethyl-formamide (4 mL) and stir overnight at ambient temperature. Concentrate in vacuo and take up in water and extract with dichloromethane. Dry the combined extracts over sodium sulfate. Concentrate and elute over silica gel using methanol/dichloromethane to give 60 mg (94%) of the desired product as a white solid. MS(ES): (M+1)+ 417.3, 418.3 m/z.
Reaction SMILES: [CH2:1]([C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[O:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=O.[OH:21][CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)[CH2:23][NH2:24].O.Cl>C1C=CC=CC=1>[ClH:31].[Cl:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH:22]([OH:21])[CH2:23][NH:24][CH:2]([CH3:4])[CH2:1][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[O:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(Oc2ccc(CC(C)=O)cc2)o1
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(Oc2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 5-[4-acetonylphenoxy]furan-2-carboxylate (1.04 g) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (0.65 ) in dry benzene (100 ml) was heated under reflux, with azeotropic removal of water, for 1 hr. the solvent was evaporated and the residue dissolved in methanol (100 ml), cooled, and treated with sodium borohydride (0.4 g), in portions. The reaction mixture was stirred at ambient temperature for 2 hr. The solvent was evaporated and the residue partitioned between water and chloroform. The organic layer was dried (MgSO4) and evaporated to an oil which was purified by column chromatography on silica gel. Elution with 4% methanol:chloroform gave a colourless oil. An ethereal solution of the free base was treated with hydrogen chloride gas to give methyl 5-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyl]phenoxy]furan-2-carboxylate, hydrochloride as a 65:35 mixture of diastereoisomers, m.p. 148°-150° C. (ethylacetate-ether).
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[C:22]([Cl:38])=[CH:21][N:20]=1>>[Cl:38][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCCc2cc(N)c(OC)cc21
Product: CCN1C(=O)CCCc2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)c(OC)cc21

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (46 mgs) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide (68 mgs) were converted to the title compound (64 mgs as a tan solid). 1H-NMR (CDCl3, 400 MHz): 9.82 (s, 1H), 8.95 (broad s, 1H); 8.41 (d, J=8.4 Hz, 1H), 8.10 (s, 1H), 7.92 (d, J=7.8 Hz, 1H); 7.83 (s, 1H); 7.53 (t, J=7.6 Hz, 1H); 7.34 (t, J=7.8 Hz, 1H), 6.78 (s, 1H), 3.91 (s, 3H); 3.5 (s, 2H), 2.78 (s, 6H), 2.65-2.0 (broad m, 6H), 1.17 (t, 7.1 Hz, 3H); LC/MS: found (M+H)+=545.21; MP: 147-153° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC#N>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Yield: 89.1 %

Procedure:
15.01 g (89.9 mmol) 4-nitrobenzoic acid are suspended in 500 mL MeCN and then combined with 15.03 g (108.7 mmol, 1.2 eq) potassium carbonate. 15.4 g (90.4 mmol, 1.01 eq) benzylbromide are added dropwise with stirring and the reaction mixture is heated for 5 h with stirring at 60° C. It is combined with 750 mL distilled water, extracted 4 times with 250 mL of EE and after the organic phases have been combined dried on sodium sulphate. After all the volatile constituents have been eliminated in vacuo the crude product is suspended twice in succession in toluene and evaporated down in vacuo. 20.6 g (80.1 mmol) benzyl 4-nitrobenzoate are obtained, which is used in the next step without any further purification.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[S:25](Cl)(Cl)=[O:26]>C(Cl)Cl>[C:12]([C@H:9]1[CH2:10][O:11][S:25](=[O:26])[N:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)[C@@H](CO)NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[C@H]1COS(=O)N1Cc1ccccc1
Reaction time: 1 h
Yield: 88.9 %

Procedure:
(S)-2-(Benzylamino)-3,3-dimethylbutan-1-ol (5.77 g, 27.8 mmol) in dry DCM (100 mL) was cooled down to −20° C., DIEA (19.39 ml, 111 mmol) was added, followed by thionyl chloride (2.228 ml, 30.6 mmol) in DCM (10 mL). The reaction mixture was stirred for 1 h at this temperature, then concentrated. The residue was purified by column chromatography to give the title compound (6.26 g) as a diastereomeric mixture. LCMS m/z=254.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][C:18]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([CH2:33][N:34]([CH3:41])[CH:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[CH:29][CH:28]=4)=[O:25])=[CH:17][C:16]=3[CH:42]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:43][I:44]>CN(C=O)C>[I-:44].[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][C:18]([C:24]([NH:26][C:27]4[CH:28]=[CH:29][C:30]([CH2:33][N+:34]([CH3:43])([CH3:41])[CH:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[CH:31][CH:32]=4)=[O:25])=[CH:17][C:16]=3[CH:42]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Reactant: CI
Solvent: CN(C)C=O
Product: CCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C[N+](C)(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Product: [I-]
Reaction time: 18 h

Procedure:
To a solution of 7-(4-butoxyphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) in DMF (7 ml) was added at room temperature methyl iodide (63 μl), and the mixture was stirred for 18 hours and concentrated under reduced pressure. To the residue was added ethyl acetate, and the resulting crystals were collected by filtration and recrystallized from ethanol to give pale yellow of crystals N-[4-[[7-(4-butoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carbonyl]amino]benzyl]-N,N-dimethyltetrahydro-2H-pyran-4-aminium iodide (Compound 149) (290 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=2[CH2:11]1.N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C)C=O>[Si:26]([O:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[NH2:1])[CH2:19][CH2:18]2)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C2CCc3cc(O)ccc3C2)c(N)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(C2CCc3cc(O[Si](C)(C)C(C)(C)C)ccc3C2)c(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
To a solution of 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (850 mg) in N,N-dimethylformamide (10 ml) were sequentially added imidazole (500 mg) and tert-butyldimethylsilyl chloride (480 mg), and the solution was stirred for 1 hour at room temperature. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (805 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[CH:26]=[C:25]([N:27]([CH3:51])[C:28]([N:30]([C:39]4[C:44]([Cl:45])=[C:43]([O:46][CH3:47])[CH:42]=[C:41]([O:48][CH3:49])[C:40]=4[Cl:50])[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:29])[N:24]=[CH:23][N:22]=3)=[C:16]([N+:52]([O-])=O)[CH:15]=2)=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.ClC1C=CC=CC=1.O=[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[CH:26]=[C:25]([N:27]([CH3:51])[C:28]([N:30]([C:39]4[C:40]([Cl:50])=[C:41]([O:48][CH3:49])[CH:42]=[C:43]([O:46][CH3:47])[C:44]=4[Cl:45])[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:29])[N:24]=[CH:23][N:22]=3)=[C:16]([NH2:52])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(Nc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3[N+](=O)[O-])ncn2)c1Cl
Agent: O=[Pt]=O
Solvent: Clc1ccccc1
Solvent: CO
Product: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N)ncn2)c1Cl
Reaction time: 8 h
Yield: 35.4 %

Procedure:
To a solution of tert-butyl-4-(4-(6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)ureido)pyrimidin-4-ylamino)-3-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (380 g, 0.473 mmol) in MeOH (10 mL) was added PtO2 (38 mg, 10% wt) and one drop of chlorobenzene at room temperature, the resulting mixture was stirred under hydrogen atmosphere (1 atm) overnight. The reaction was filtered and concentrated. The residue was purified by flash chromatography on silica to obtain the title compound (130 mg, yield: 37%). MS (ESI): 776 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:13]1C=NC=C(Br)C=1)[C@@H:3]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1F)[OH:4].[Cl:20][C:21]1[N:26]=C[N:24]=[C:23]([C@@H](NC(=O)OC(C)(C)C)[C@@H](C2C=CC=C(F)C=2)O)[CH:22]=1.O.C(O)(C(F)(F)F)=O>CC#N>[ClH:20].[ClH:20].[NH2:1][C@H:2]([C:13]1[N:26]=[C:21]([Cl:20])[CH:22]=[CH:23][N:24]=1)[C@@H:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([F:11])[CH:10]=1)[OH:4]
Reactant: CC(C)(C)OC(=O)N[C@H](c1cc(Cl)ncn1)[C@H](O)c1cccc(F)c1
Reactant: N[C@H](c1cncc(Br)c1)[C@H](O)c1cc(F)ccc1F
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N[C@H](c1nccc(Cl)n1)[C@H](O)c1cccc(F)c1

Procedure:
Prepared according to the same procedure as (1R,2R)-2-amino-2-(5-bromopyridin-3-yl)-1-(2,5-difluorophenyl)ethanol, starting with tert-butyl (1R,2R)-1-(6-chloropyrimidin-4-yl)-2-(3-fluorophenyl)-2-hydroxyethylcarbamate. Analytical HPLC method: Phenomenex LUNA C18, 50×2 3μ, A=90% H2O/10% CH3CN, B=90% CH3CN/10% H2O, Modifier 0.1% TFA, 0.00 min=0% B, 4.0 min=100% B, 5.0 min=100% B, Flow rate=0.8 mL/min., TR=1.823 min, Mass spec.: 268.1