Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:3](=[O:24])[CH2:4][CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=[CH:10][C:9]=1[N+:21]([O-])=O.S1C=CC=C1.[H][H]>[Pd].CO>[NH2:21][C:9]1[CH:10]=[CH:11][C:12]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][C:8]=1[CH2:7][NH:6][CH2:5][CH2:4][C:3]([N:2]([CH3:1])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24]
Reactant: [H][H]
Reactant: CN(C(=O)CCNCc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: CN(C(=O)CCNCc1cc(Oc2ccccc2)ccc1N)c1ccccc1

Procedure:
A mixture of N-methyl-3-(2-nitro-5-phenoxy-benzylamino)-N-phenyl-propionamide (2 g, 0.0049 mol), 10% palladium on carbon (1 g), and thiophene solution (1 mL) in 150 mL of MeOH was hydrogenated until 3 equivalents of hydrogen were consumed. The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography on a Biotage. The product containing fractions were collected and concentrated to yield a residue.
Reaction SMILES: Cl[P:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[C:15]([CH:16]3[CH2:21][CH:20]=[CH:19][CH:18]=[CH:17]3)[C:4]=2[O:3]1.[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC1C=CC=CC=1C.C(OCC)C>[C:22]1([P:2]([C:4]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:5]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[OH:3])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Br[Mg]c1ccccc1
Reactant: ClP1Oc2c(cccc2C2C=CC=CC2)-c2ccccc21
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: Oc1c(-c2ccccc2)cccc1-c1ccccc1P(c1ccccc1)c1ccccc1
Temperature: 120 °C
Yield: 185.8 %

Procedure:
23.5 g (0.1 mol) of 6-chloro-6H-4-phenyl-dibenz[c,e][1,2]-oxaphosphorine in 120 ml of anhydrous o-xylene at 80° C. are introduced, in an argon atmosphere with stirring, and a solution of 0.25 mol of phenylmagnesium bromide in 100 ml of diethyl ether is added dropwise. Diethyl ether is distilled off and the temperature slowly increased to 120° C. in the course of this. The mixture is then stirred for 3 hours at 120° C., cooled to room temperature and 100 ml of water are added. The mixture is neutralized with dilute hydrochloric acid, the organic phase is separated off, dried with sodium sulfate and concentrated under reduced pressure. 40.0 g of colorless viscous oil are obtained.
Reaction SMILES: OC(C(F)(F)F)=O.I[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:21]=[N:20][C:19]=1[O:30][CH3:31].[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH3:31][O:30][C:19]1[N:20]=[N:21][C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:23][C:18]=1[C:10]1[NH:11][C:12]2[C:17]([C:9]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: COc1nnc(-c2ccncc2)cc1-c1[nH]c2ccccc2c1I
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: COCCOC
Product: COc1nnc(-c2ccncc2)cc1-c1[nH]c2ccccc2c1-c1ccccc1

Procedure:
Argon is passed for 30 min through a suspension of 270 mg 3-Iodo-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-1H-indole TFA salt, 73 mg phenylboronic acid, 220 mg potassium carbonate and 52.4 mg triphenylphosphine in 2 ml DME and 1 ml water. 11.2 mg palladium (II) acetate is added and the mixture stirred under reflux for 5 h. The product is isolated by extraction with ethyl acetate and purified by chromatography on silica gel.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11]([NH:15][CH2:16][CH2:17][OH:18])[C:12]=3[F:14])[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[C:26]1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCOCC)C.C(#N)C>C(Cl)(Cl)Cl>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11]([N:15]4[CH2:16][CH2:17][O:18][CH2:26]4)[C:12]=3[F:14])[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(NCCO)c(F)cc2c1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCOCC
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CCOC3)c(F)cc2c1=O
Reaction time: 3 h

Procedure:
A mixture of 0.70 g of ethyl 1-cyclopropyl-6,8-difluoro-7-(2-hydroxyethylamino)-1,4-dihydro-4-oxoquinoline-3-carboxylate, 0.08 g of p-toluenesulfonic acid, 2.08 g of diethoxymethane and 20 ml of acetonitrile was stirred for 3 hours under reflux. The reaction mixture was allowed to cool down, followed by the addition of 100 ml of chloroform. The resultant mixture was washed successively with 5% aq. sodium carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and then concentrated.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[NH:8][CH:7]=1)=[O:5])C.Cl>[OH-].[Na+]>[NH:13]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[C:11]([C:9]2[NH:8][CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=2)=[N:12]1
Reactant: CCOC(=O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
A mixture of 5-(1H-pyrazolo[3,4-b]pyridin-3-yl)-1H-pyrrole-3-carboxylic acid ethyl ester (200 mg, 0.78 mmol) (from Example 11) and 10% NaOH (10 mL) was stirred at room temperature for one hour, at 40° C. for 2 hours and at room temperature for overnight. The reaction was adjusted to pH 6–7 with concentrated HCl. The precipitate was collected by vacuum filtration, washed with water and dried to give 140 mg (79%) of the titled compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.Br[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[C:28]([N+:36]([O-:38])=[O:37])[CH:27]=1>>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:34])[CH3:35])=[C:28]([N+:36]([O-:38])=[O:37])[CH:27]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:16][CH:17]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Reactant: CC(C)Oc1ccc(Br)cc1[N+](=O)[O-]
Product: CC(C)Oc1ccc(-n2c(C(=O)O)cc3cc(-c4ccc(C(C)(C)C)cc4)ccc32)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared in accordance with Example 1(b) from 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester (see Example 1(a)) and 4-bromo-1-isopropoxy-2-nitrobenzene (see step (a) above), followed by ester hydrolysis in accordance with the procedure described in Example 35, Method 3, step (b).
Reaction SMILES: [C:1]1([S:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N-]>C1(C)C(C)=CC=CC=1>[C:1]1([S:7][CH:8]2[CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]2([CH3:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)=CSc1ccccc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)C1C(Sc2ccccc2)C1(C)C
Reaction time: 1 h

Procedure:
Alternately, when no catalyst is used, the reaction is carried out at a higher temperature (approx. 150° ) for thermal decomposition. Xylene is heated to reflux and a mixture of 2-methyl-1-propenyl phenyl sulfide and ethyl diazoacetate is added dropwise over 2 hr. Reflux is continued an additional 1 hr or until nitrogen evolution has ceased. The reaction is then filtered, dried and solvent is removed, giving ethyl 3-phenylthio-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:17][CH2:18][C@@H:19]([C:21]1[CH:22]=[CH:23][C:24]([OH:32])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=1)[OH:20]>>[OH:20][C@H:19]([C:21]1[CH:22]=[CH:23][C:24]([OH:32])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=1)[CH2:18][NH:17][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(C(=O)O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 4-(4-oxo-piperidine-1-yl)-benzoic acid (which was obtained in Example 151) and N-[5-((1R)-2-amino-1-hydroxy- ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 179 as a white solid; ; mp >85° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.80-1.95 (m, 2H), 2.60-3.00 (m, 5H), 2.92 (s, 3H), 3.75-3.85 (m, 2H), 4.53 (dd, J=8.3, 4.0 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H), 6.92 (d, J=8.9 Hz, 2H), 7.01 (dd, J=8.3, 2.0 Hz, 1H), 7.19 (d, J=2.0 Hz, 1H), 7.73 (d, J=8.9 Hz, 2H); MS (ES) m/z: 449.9 (MH+); HRMS Calcd. for C21H26N3O6S(M−H)−: 448.1549. Found: 448.1541.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:17]C(=O)C)=[CH:4][CH:3]=1.[H-].[Na+].[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[NH:32][C:33]([C:35]1[CH:36]=[CH:37][CH:38]=[C:39]2[C:44]=1[CH2:43][N:42]([C:45]1[S:46][C:47]([CH2:55][CH2:56][CH2:57]I)=[C:48]([C:50]([O:52]CC)=[O:51])[N:49]=1)[CH2:41][CH2:40]2)=[O:34].[OH-].[Na+].Cl>CN(C=O)C>[NH2:17][C:9]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:57][CH2:56][CH2:55][C:47]3[S:46][C:45]([N:42]4[CH2:41][CH2:40][C:39]5[C:44](=[C:35]([C:33](=[O:34])[NH:32][C:24]6[S:23][C:27]7[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=7[N:25]=6)[CH:36]=[CH:37][CH:38]=5)[CH2:43]4)=[N:49][C:48]=3[C:50]([OH:52])=[O:51])=[CH:7][CH:6]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCI
Reactant: CC(=O)Nc1nc2ccccc2n1-c1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc2ccccc2n1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31 %

Procedure:
Compound 77B (32 mg, 0.12 mmol) in DMF (1 ml) was treated with NaH (60% oil dispersion) (12 mg, 0.3 mmol). After stirring at ambient temperature for 5 minutes, compound 2C (63 mg, 0.1 mmol) was added and stirring was continued for 1 hour. Additional NaH (60% oil dispersion) (12 mg, 0.3 mmol) was added and the mixture was stirred at ambient temperature overnight. NaOH (4 N aq.) (0.25 ml, 1 mmol) was added and the mixture was stirred at ambient temperature for 4 hours. HCl (4N in dioxane) (2.5 ml, 10 mmol) was added and the mixture was heated at 70° C. for several hours. When the reaction was shown to be complete by LCMS, the reaction mixture was concentrated, 1N HCl was added to induce any further precipitation of the product. The solid was filtered and rinsed with water. The solid was slurried in Et2O, filtered and rinsed with additional Et2O. The solid was dissolved in 1:1 DMSO/MeOH, filtered via syringe filter to remove undissolved salts and impurities and purified by HPLC (Preparative reverse phase HPLC was performed on an automated Gilson HPLC system, using a SymmetryPrep Shield RP 18 prep cartridge, 250 mm×21.20 mm i.d., 10 um, and a flow rate of 25 mL/min; λ=214, 245 nm; mobile phase A, 0.1% TFA in H2O; mobile phase B, CH3CN; linear gradient 20-90% of B in 40 min) to provide the title compound 77 in 31% yield as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 12.90 (1H, s), 12.83 (1H, s), 8.44 (2H, s), 8.02 (1H, d), 7.79 (1H, d), 7.68 (1H, d), 7.41 (8H, m), 7.17 (3H, m), 6.93 (1H, d), 4.84 (2H, s), 4.10 (2H, t), 3.74 (2H, t), 3.23 (2H, m), 3.04 (2H, t), 2.07 (2H, m). MS (ESI(+)) m/e 702 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Clc1nccc2ccccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-c2nccc3ccccc23)cc1
Reaction time: 8 h
Yield: 51.1 %

Procedure:
In a 200 ml-three-necked flask, 3.40 g (25.0 mmole) of 4-methylphenyl-boronic acid (made by Aldrich Co.), 4.09 g (25.0 mmole) of 1-chloroisoquinoline, 25 ml of toluene, 12.5 ml of ethanol and 25 mol of 2M-sodium carbonate aqueous solution were placed and stirred at room temperature under nitrogen stream, and 0.98 g (0.85 mmole) of tetrakis(triphenylphosphine)-palladium (0) was added thereto. Thereafter, reflux under stirring was performed for 8 hours under nitrogen stream. After completion of the reaction, the reaction product was cooled and extracted by addition of cold water and toluene. The organic layer was washed with saline water and dried on magnesium sulfate, followed by removal of the solvent under a reduced pressure to provide dry solid. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to obtain 2.80 g (yield=51.1%) of 1-(4-methylphenyl)isoquinoline.
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[N:9][C:8]=2[CH2:12]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:34]>CC#N>[Br:34][CH2:12][C:8]1[N:9]=[CH:10][S:11][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ncsc1-c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: BrCc1ncsc1-c1ccccc1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
Prepare a cold (0° C.) solution of (5-phenyl-thiazol-4-yl)-methanol (1.4 g, 7.3 mmol) in CH3CN (50 mL). Add PPh3 (2.6 g, 9.7 mmol) and CBr4 (3.2 g, 9.7 mmol). Stir the reaction at 0° C. for 3 hours, allow to warm to room temperature and then concentrate in vacuo to an oil. Chromatograph (silica gel, 4:1 Hex/ethyl acetate) to afford the title compound (400 mg). 1H NMR (CDCl3) δ 8.80 (s, 1H), 7.40-7.60 (m, 5H), 4.65 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[C:16]([F:24])[CH:15]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[N:31]=[C:32]([Si:35]([CH3:38])([CH3:37])[CH3:36])[S:33][CH:34]=1)CCC>>[F:24][C:16]1[CH:15]=[C:14]([C:9]2[N:10]=[C:11]([CH3:13])[O:12][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([C:30]3[N:31]=[C:32]([Si:35]([CH3:38])([CH3:37])[CH3:36])[S:33][CH:34]=3)=[CH:3][CH:4]=2)[CH:19]=[CH:18][C:17]=1[S:20]([NH2:23])(=[O:22])=[O:21]
Reactant: Cc1nc(-c2ccc(S(N)(=O)=O)c(F)c2)c(-c2ccc(Br)cc2)o1
Reactant: CCCC[Sn](CCCC)(CCCC)c1csc([Si](C)(C)C)n1
Product: Cc1nc(-c2ccc(S(N)(=O)=O)c(F)c2)c(-c2ccc(-c3csc([Si](C)(C)C)n3)cc2)o1

Procedure:
The title compound was prepared according to the procedure of Example 153 (step 4) using 4-[5-(4-Bromophenyl)-2-methyl-1,3-oxazol-4-yl]-2-fluorobenzenesulfonamide instead of 2-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole and using 4-(tributylstannyl)-2-trimethylsilylthiazole instead of 4-(tributylstannyl)thiazole. The crude product was used next reaction without further purification.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>C(O)C>[Br:13][C:14]1[CH:15]=[C:16]([NH:17][C:4]2[C:5](=[O:12])[C:6](=[O:11])[C:7]=2[O:8][CH2:9][CH3:10])[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(Br)c1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2cccc(Br)c2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.7 g of 3,4-diethoxy-3-cyclobuten-1,2-dione in 25 mL of absolute ethyl alcohol was added 1.7g of 3-bromoaniline, the reaction mixture was stirred at room temperature for 20 hours, then 0.4 g of 3-bromoaniline was added and the reaction mixture was stirred for 48 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([N:6]([C:8]2[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=2[NH:10][C:11](=O)[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH3:7])=[CH:4][CH:3]=1.C(N1CCC(C(NC2C=CC=CC=2)=O)CC1)(OCC1C=CC=CC=1)=O>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([CH3:7])[C:8]3[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=3[N:10]=[C:11]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:4]=2[CH:3]=1
Reactant: CN(c1ccc(Cl)cc1)c1ccccc1NC(=O)C1CCNCC1
Agent: O=C(Nc1ccccc1)C1CCN(C(=O)OCc2ccccc2)CC1
Product: CN1c2ccccc2N=C(C2CCNCC2)c2cc(Cl)ccc21

Procedure:
The compound 2'-(p-chloro-N-methylanilino)isonipecotanilide, prepared by hydrolysis of the corresponding 1-carbobenzoxyisonipecotanilide, is cyclized by the procedure of Example 1 and, after isolation and purification of the product, 2-chloro-5-methyl-11-(4-piperidyl)-5H-dibenzo[b,e][1,4]-diazepine is thereby obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[C:73]([O:74][CH3:75])=[CH:72][C:67]([C:68]([O:70][CH3:71])=[O:69])=[C:66]([F:76])[CH:65]=1>>[CH3:71][O:70][C:68](=[O:69])[C:67]1[CH:72]=[C:73]([O:74][CH3:75])[C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][C:66]=1[F:76]
Reactant: COC(=O)c1cc(OC)c(N)cc1F
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(OC)c(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1F
Yield: 23.9 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (150 mg, 0.259 mmol), was reacted with diisopropylethylamine (171 mg, 1.32 mmol), diphenylphosphinic chloride (155 mg, 0.656 mmol), then reacted with methyl 4-amino-2-fluoro-5-methoxybenzoate (Aldrich, 55 mg, 0.274 mmol,) to give rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-2-fluoro-5-methoxy-benzoic acid methyl ester (40 mg, 24%). MS (ES+) m/z [(M+H)+]: 646
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][S:5](=[O:17])(=[O:16])[NH:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([F:14])=[CH:9][C:8]=1[F:15].[OH-].[Na+]>O1CCOCC1>[F:15][C:8]1[CH:9]=[C:10]([F:14])[CH:11]=[C:12]([F:13])[C:7]=1[NH:6][S:5]([CH2:4][C:3]([OH:18])=[O:2])(=[O:17])=[O:16]
Reactant: COC(=O)CS(=O)(=O)Nc1c(F)cc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CS(=O)(=O)Nc1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.37 g (4.8 mmol) of 2-[N-(2,4,6-trifluorophenyl)sulfamoyl]-acetic acid methyl ester is dissolved in 15 ml of dioxane, 7.5 ml of 2N sodium hydroxide solution is added and it is stirred for one hour at room temperature. The solution is then evaporated to dryness, the residue is dissolved in water, the solution is acidified with 2N hydrochloric acid and extracted twice with ethyl acetate. The ethyl acetate extract is dried on magnesium sulfate, filtered and evaporated to dryness. The residue is crystallized from diethyl ether. 1.12 g (4.16 mmol)=86.68% of the theoretical yield is obtained. Melting point 126-127° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N+:15]([O-:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C(C1C=CC=CC=1)O.[CH3:36][C@H:37]1[CH2:42][CH2:41][CH2:40][NH:39][CH2:38]1.Cl>CN(C)C=O.C(O)C.C(N(CC)CC)C>[ClH:1].[CH3:36][C@H:37]1[CH2:42][CH2:41][CH2:40][N:39]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][N+:15]([O-:18])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:38]1
Reactant: C[C@H]1CCCNC1
Reactant: [O-][n+]1ccc(-c2ccc(OCCCCl)cc2)cc1
Agent: Cl
Agent: O=C(O)C(O)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@H]1CCCN(CCCOc2ccc(-c3cc[n+]([O-])cc3)cc2)C1
Reaction time: 8 h
Yield: 23.6 %

Procedure:
To a solution of 4-[4-(3-chloropropoxy)phenyl]pyridine 1-oxide (231 mg) and triethylamine (366 μL) in N,N-dimethylformamide (5 mL) are added potassium carbonate (363 mg) and (3S)-3-methylpiperidine mandelate (264 mg). The mixture is stirred at a temperature close to 60° C. for four hours. An additional amount of (3S)-3-methylpiperidine mandelate (100 mg) is added and heating is continued overnight. The suspension is filtered and the precipitate washed with ethyl acetate. The combined organic phases are concentrated under reduced pressure. The residue is purified twice by column chromatography over silica gel using a gradient dichloromethane/methanol/triethylamine from 100/0/0 to 95/5/0.1. Fractions containing the expected product are pooled and concentrated under reduced pressure to give 90 mg of the crude base which is converted to the hydrochloride with an ethereal solution of hydrogen chloride in ethanol to give 75 mg of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide, hydrochloride melting at 74° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([NH:11][C@H:12]([C@@H:27]([OH:29])[CH3:28])[C:13]([NH:15][NH:16][C:17](=O)[C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)=[O:14])=[CH:9][CH:8]=[C:7]([C:30]#[N:31])[C:4]=2[S:5][CH:6]=1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.CO>C1COCC1>[Cl:1][C:2]1[C:3]2[C:10]([NH:11][C@@H:12]([C:13]3[O:14][C:17]([C:18]4[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=4)=[N:16][N:15]=3)[C@@H:27]([OH:29])[CH3:28])=[CH:9][CH:8]=[C:7]([C:30]#[N:31])[C:4]=2[S:5][CH:6]=1
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c2scc(Cl)c12)C(=O)NNC(=O)c1ccc(C#N)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2scc(Cl)c12)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.4 %

Procedure:
To a solution of N′-((2R,3S)-2-(3-chloro-7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)-4-cyanobenzohydrazide (0.83 g, 1.83 mmol) in THF (150 mL) was added PS-BEMP (2.5 g, 5.50 mmol, ˜2.2 mmol/g) and p-TsCl (383 mg, 2.00 mmol) at room temperature. The mixture was stirred at room temperature overnight, then methanol (5 mL) was added to quench the reaction. The resin was filtered and washed with MeOH (400 mL). The combined filtrate was concentrated to give a residue, which was purified by flash chromatography to afford the title compound 3-chloro-4-((1R,2S)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)benzo[b]thiophene-7-carbonitrile (75.2 mg, 9%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.20 (d, J=8.3 Hz, 2H), 8.00 (d, J=8.3 Hz, 2H), 7.75 (s, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 5.28 (dd, J=2.4, 8.2 Hz, 1H), 4.93 (d, J=4.3 Hz, 1H), 4.72 (m, 1H), 1.50 (d, J=6.3 Hz, 3H).