Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[N+:14]([O-])=O)[CH2:3][CH2:2]1>C(O)C>[CH:1]1([CH2:4][NH:5][C:6]2[C:7]([NH2:14])=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(NCC2CC2)c([N+](=O)[O-])c1
Solvent: CCO
Product: COc1ccc(NCC2CC2)c(N)c1
Temperature: 10 °C
Reaction time: 2.5 h

Procedure:
N-(Cyclopropylmethyl)-4-methoxy-2-nitroaniline (8-1, 175 g) was dissolved in ethanol (1750 mL) and was added to a 4.0 L Hast ‘C” Shaker can. The mixture was cooled to 10° C. and treated with 3% Pt/0.6% VG/C, deGussa (4.5 g). The vessel was sparged under nitrogen and then sparged three times with hydrogen at a setting of 40 psi and agitated for 2.5 hours. To a pre-washed solka-flok with ethanol, the reaction mixture was filtered through solka-flok through a sintered glass funnel to have about a ½ inch depth of solka-flok. The solka-flok was then washed with 1 L ethanol and concentrated in vacuo, providing the titled compound 8-2.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25]([NH:27][CH:28]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:29](OC)=O)=[O:26])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.ClCCl>[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[CH:29]=[C:28]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[NH:27][C:25]2=[O:26])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C(NC(=O)NC1CCN(Cc2ccccc2)CC1)c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=c1[nH]c(-c2ccc(F)cc2)cn1C1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
Diisobutylaluminum hydride (1 M, 1.18 mL, 1.18 mmol) was added to a solution of methyl ({[(1-benzylpiperidin-4-yl)amino]carbonyl}amino)(4-fluorophenyl)acetate (430 mg, 1.08 mmol) in toluene (5 mL) and dichloromethane (5 mL) at −78° C. and stirred for 30 min and then warmed to 0° C. After 20 min at 0° C., the reaction was quenched with 1 N saturated potassium sodium tartrate solution (20 mL) and the mixture was extracted with ethyl acetate (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude material was treated with 4 N HCl in dioxane (4 mL), and stirred for 5 min. The mixture was concentrated, dissolved in dichloromethane and extracted with saturated sodium bicarbonate (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (silica gel, 0 to 7% {1% ammonium hydroxide/methanol} in methylene chloride gradient elution), gave the title compound (150 mg). MS 400.29 (M+1)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[C:12](OC)([N:14]([CH3:16])[CH3:15])[CH3:13]>>[CH3:15][N:14]([CH3:16])[C:12]([CH3:13])=[CH:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: COC(C)(OC)N(C)C
Reactant: CC(=O)c1cccnc1
Product: CC(=CC(=O)c1cccnc1)N(C)C

Procedure:
A mixture of 40.0 g of 3-acetylpyridine and 50.0 ml of dimethylacetamide dimethylacetal was heated on a steam bath for 6 hours under argon. The volatile components were then removed in vacuo and hexane was added to the resultant thick syrup to crystallize the product. Filtration gave 33.5 g of the desired product as red-brown crystals, mp 62°-64° C.
Reaction SMILES: Cl[C:2]([C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]1)=[O:3].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([NH:17][CH3:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([N:17]([CH3:18])[C:2]([C:4]2([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]2)=[O:3])=[CH:15][CH:14]=1
Reactant: CNc1ccc(Br)cc1
Reactant: CCOC(=O)C1(C(=O)Cl)CC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(=O)N(C)c2ccc(Br)cc2)CC1
Yield: 50 %

Procedure:
Ethyl 1-chlorocarbonylcyclopropanecarboxylate (3.11 grams, 0.02 mole), prepared in Example XVIII, 4-bromo-N-methylaniline (3.00 grams, 0.02 mole) and triethylamine (1.63 grams, 0.02 mole) were reacted in a manner similar to that described in Example III to give 3.79 grams (0.01 mole) of ethyl 1-[N-(4-bromophenyl)-N-methylaminocarbonyl]cyclopropanecarboxylate isolated as a colorless oil.
Reaction SMILES: [C:1]12([C:11](O)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br.[O:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH2:26][CH2:27][N:28]3[C:32]([CH3:33])=[C:31]([CH3:34])[S:30][C:29]3=[NH:35])[C:19]=2[O:18][CH2:17][CH2:16]1>>[O:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH2:26][CH2:27][N:28]3[C:32]([CH3:33])=[C:31]([CH3:34])[S:30][C:29]3=[N:35][C:11]([C:1]34[CH2:8][CH:7]5[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]5)[CH2:2]3)[CH2:10]4)=[O:12])[C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: Cc1sc(=N)n(CCOc2cccc3c2OCCO3)c1C
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: Br
Product: Cc1sc(=NC(=O)C23CC4CC(CC(C4)C2)C3)n(CCOc2cccc3c2OCCO3)c1C
Yield: 195.6 %

Procedure:
Adamantane-1-carboxylic acid (0.78 g, 0.12 mmol) and the product of Example 81A (0.15 g, 0.39 mmol) were processed according to the method of Example 77B. Purification by column chromatography (SiO2, 0-15% methanol/methylene chloride gradient) afforded 0.11 g (60%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 1.68-1.79 (m, 6H), 1.96 (d, J=2.4 Hz, 6H), 2.04 (d, J=5.4 Hz, 3H), 2.17 (s, 3H), 2.29 (s, 3H), 4.18-4.30 (m, 4H), 4.36 (t, J=5.3 Hz, 2H), 4.51 (s, 2H), 6.44-6.58 (m, 2H), 6.72 (t, J=8.1 Hz, 1H); MS (DCI/NH3) m/z 469 (M+H)+. Anal. Calculated for C26H32N2O4S: C, 66.64; H, 6.88; N, 5.98. Found: C, 66.36; H, 6.80; N, 5.87.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[NH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[NH:7][C:6](=O)[C:5]=2[CH:4]=[N:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].N>C1COCC1>[CH3:1][N:2]1[C:11]2[NH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[NH:7][CH2:6][C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2c1Nc1ccccc1NC2=O
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cn1ncc2c1Nc1ccccc1NC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To a suspension of 3-methyl-4,9-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-10-one from Example E11.3 (3.01 g, 14.1 mmol) in anhydrous THF (100 ml) at 0° C. was added lithium aluminium hydride (2.13 g, 56.2 mmol), and the resulting suspension was heated at reflux for 18 h, then allowed to cool to room temperature. The mixture was cooled to 0° C., 35% ammonia solution (10 ml) was added dropwise over 15 min and the mixture was stirred at room temperature for 30 min. The resulting suspension was filtered through Celite® filter agent and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 2% methanol:chloroform rising to 5% methanol:chloroform) to yield the title compound (1.60 g, 57%).
Reaction SMILES: C([O:5][C:6]1[CH:35]=[CH:34][CH:33]=[CH:32][C:7]=1[CH2:8][N:9]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)(C)(C)C>CCOC(C)=O.Cl>[C:19]1([CH:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][CH2:10][N:9]([CH2:8][C:7]3[CH:32]=[CH:33][CH:34]=[CH:35][C:6]=3[OH:5])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH2:18][CH2:17]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)Oc1ccccc1CN(CCCN1CCC(c2ccccc2)CC1)Cc1ccccn1
Agent: Cl
Solvent: CCOC(C)=O
Product: Oc1ccccc1CN(CCCN1CCC(c2ccccc2)CC1)Cc1ccccn1
Reaction time: 3 h
Yield: 92 %

Procedure:
Compound 20 (0.15 g, 0.31 mmol) was dissolved in 25 mL EtOAc saturated with HCl and stirred for 3 hr. The solvent was evaporated to dryness. The residue was purified on a silica gel TLC plate that was developed in 8% methanolic NH3 (7 M NH3 in methanol/92% CH2Cl2. The product was obtained as white solid (92%). 1H NMR (CDCl3) δ 8.589 (dd, 1H, Ar), 7.675 (ddd, 1H, Ar), 7.332 (d, 1H, Ar), 7.289 (ddd, 3H, Ar), 7.189 (m, 5H, Ar), 7.009 (dd, 1H, Ar), 6.854 (dd, 1H, Ar), 6.780 (ddd, 1H, Ar), 3.843 (s, 2H, —CH2—), 3.798, (s, 2H, —CH2—), 2.974 (d, 2H, —CH2—), 2.633 (t, 2H, —CH2—), 2.458 (m, 1H, —CH—), 2.333 (m, 2H, —CH2—), 2.000 (m, 2H, —CH2—), 1.782 (m (br), 6H). Mass Spec.=416.27 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[NH:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)=[O:11]
Reactant: Clc1nc2ccccc2o1
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CN)c(-c2ccc(F)cc2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CNc2nc3ccccc3o2)c(-c2ccc(F)cc2)s1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of rac-cis-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone, 2-chlorobenzoxazole, and DIPEA in CH2Cl2 was stirred at 60° C. overnight. The reaction mixture was concentrated in vacuo to leave a near colorless solid. This solid was triturated with Et2O/hex to leave the title compound as a colorless solid homogeneous by HPLC analysis. MS (ESI) 465.03 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1.S(Cl)([Cl:14])=O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Br)cc1Cl
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To a mixture of 15 g of 4-bromo-2-chlorobenzoic acid in 25 ml DMF is added 10 ml thionyl chloride at room temperature and the reaction mixture is stirred for 16 h at 75° C. Excess of thionyl chloride is removed under reduced pressure to give 4-bromo-2-chlorobenzoyl chloride as crude material that is used for the next step without further purification.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)=[O:8])[CH3:3].[BH4-].[Na+].C(Cl)(Cl)Cl>C(O)C.C(Cl)(Cl)(Cl)Cl>[CH2:2]([N:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:11][CH:10]=1)[OH:8])[CH3:3]
Reactant: CCCCCCCN(CC)CCC(=O)c1ccc(NS(C)(=O)=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCCCCCCN(CC)CCC(O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The crude mixture containing N-[4-[3-(ethylheptylamino)-1-oxopropyl]phenyl]methanesulfonamide hydrochloride from Preparation 16 (1.0 g, 2.6 mmol) is transferred to a reaction flask in ethanol-carbon tetrachloride, concentrated, treated with benzene and concentrated again in vacuo. The residue in 18 ml of ethanol, under nitrogen, is cooled in an ice bath and treated with powdered NaBH4 (0.23 g, 0.006 mol) in portions (foaming) over 20 min. The mixture is stirred for 15 min in the cold and for 2.5 hrs at room temperature. It is then treated with 20 ml of ice-water in portions over 5 min. Chloroform (10 ml) is added to the resultant suspension; the mixture is stirred 5 min; and, the layers are separated. The aqueous phase is extracted with additional chloroform (3×50 ml). (Each extract is backwashed with 5 ml of H2O). The pooled organic extract is washed with brine, dried (Na2SO4) and concentrated to give 0.85 g of crude material (two main spots by TLC). This material is chromatographed over 250 ml of silica gel with 0.5% NH4OH/7.5% MeOH/CHCl3 ; 16 ml fractions are collected. Fractions at approximately 36-54 give the title compound which is crystallized from ether-pentane; m.p. 74°-75° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[Br:16]Br>CC(O)=O>[Br:16][C:7]1[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.8 %

Procedure:
To a solution of 2,4-di-t-butylphenol (Aldrich, 2.0 g, 9.7 mmol) in 2 ml of HOAc was added Br2 (0.5 ml, 9.7 mmol). The reaction mixture was stirred at room temperature for 12 hours. Solvent was removed under reduced pressure and the residue was purified by column chromatography (ethyl acetate/hexane 1/20) to yield the desired product (2.54 g) as a white solid. 1H NMR δ 7.33 (d, J=2.3 Hz, 1H), 7.24 (d, J=2.3 Hz, 1H), 1.41 (s, 9H), 1.29 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[C:18]([O:24][CH3:25])=[CH:19][CH:20]=[C:21](C=1)[NH2:22]>CC(O)C>[CH3:25][O:24][C:18]1[CH:19]=[CH:20][C:21]([NH:22][C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=3[CH:5]=[CH:4][N:3]=2)=[N:16][CH:17]=1
Reactant: COC(=O)c1cccc2c(Cl)nccc12
Reactant: COc1ccc(N)cc1N
Solvent: CC(C)O
Product: COC(=O)c1cccc2c(Nc3ccc(OC)cn3)nccc12
Temperature: 90 °C
Yield: 60.1 %

Procedure:
Methyl 1-chloroisoquinoline-5-carboxylate (0.5 g, 2.26 mmol) obtained in Step (1) above was dissolved in 2-propanol (5 mL), and added with 5-amino-p-methoxyaniline (0.33 g, 2.74 mmol) at room temperature. The reaction solution was sealed and stirred for 4 hours or more at 90° C. The reaction mixture was cooled to room temperature, and the solvent was distilled under reduced pressure. The concentrated solid was added with diethyl ether, the solid thus obtained was filtered under reduced pressure. The resulting solid was dried with warm wind in an oven (40° C.) for 3 hours or more to obtain the title compound (0.42 g, 61%).
Reaction SMILES: [C:1](=[O:24])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:2][C:3]1[C:8]2[NH:9][C:10](=[O:12])[S:11][C:7]=2[C:6]([C:13](=[O:15])[CH3:14])=[CH:5][CH:4]=1.[Br-:25].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1.O>[C:1](=[O:24])([O:2][C:3]1[C:8]2[NH:9][C:10](=[O:12])[S:11][C:7]=2[C:6]([C:13](=[O:15])[CH2:14][Br:25])=[CH:5][CH:4]=1)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)c1ccc(OC(=O)OCc2ccccc2)c2[nH]c(=O)sc12
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)Oc1ccc(C(=O)CBr)c2sc(=O)[nH]c12
Temperature: 80 °C
Yield: 86.5 %

Procedure:
To a solution of 7-acetyl-2-oxo-2,3-dihydro-1,3-benzothiazol-4-yl benzyl carbonate (280 mg) in dry THF (20 ml) stirring under nitrogen, was added phenyltrimethylammonium tribromide (330 mg). The mixture was heated at 80° C. for 2 h and then diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered, and evaporated in vacuo. The residue was purified on a 40 g silica biotage cartridge and eluted with 20% ethyl acetate-cyclohexane to give the title compound (186 mg). LCMS RT=3.43 min.
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[C:21]([CH3:31])=[C:22]([CH:27]=[CH:28][C:29]=3[CH3:30])[C:23]([O:25]C)=[O:24])=[O:18])[C:14]([CH3:32])=[CH:13][CH:12]=2)[CH2:6]1>C1COCC1>[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[C:21]([CH3:31])=[C:22]([CH:27]=[CH:28][C:29]=3[CH3:30])[C:23]([OH:25])=[O:24])=[O:18])[C:14]([CH3:32])=[CH:13][CH:12]=2)[CH2:6]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2nc(N3CCCC(CO)C3)ccc2C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(N2CCCC(CO)C2)nc1C(=O)Nc1c(C)ccc(C(=O)O)c1C
Reaction time: 12 h

Procedure:
A solution of aqueous 2N NaOH (3.00 ml) is added to a stirred solution of methyl 3-[[6-[3-(hydroxymethyl)-1-piperidyl]-3-methyl-pyridine-2-carbonyl]amino]-2,4-dimethyl-benzoate (0.18 g, 0.437 mmol) in THF (8 ml). After 12 hours at ambient temperature, the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 4 with citric acid, and extracted with ethyl acetate. The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting residue is purified by preparative HPLC to afford the title compound as off white solid (57 mg, 14%). Mass spectrum (m/z): 398.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26](O)=[O:27])#[N:2].C(Cl)(=O)C(Cl)=O.[CH2:35]([NH2:39])[CH2:36][CH2:37][CH3:38].C(N(CC)CC)C>C1COCC1.O.CN(C=O)C>[CH2:35]([NH:39][C:26](=[O:27])/[CH:25]=[CH:24]/[C:4]1[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:6]2=[N:7][C:8]([CH3:13])=[CH:9][C:10]([CH3:12])=[C:11]2[C:3]=1[C:1]#[N:2])[CH2:36][CH2:37][CH3:38]
Reactant: CCCCN
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCNC(=O)/C=C/c1c(C#N)c2c(C)cc(C)nc2n1[C@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of butylamine (70.8 mg, 0.968 mmol), triethylamine (0.451 ml, 3.24 mmol) and THF (2 ml), and the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the objective product as a solid material.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:10]>CN(C=O)C>[C:2]1([C:1]2[S:8][C:3]3[CH2:4][NH:10][CH2:6][CH2:7][C:2]=3[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: NC(=S)c1ccccc1
Solvent: CN(C)C=O
Product: c1ccc(-c2nc3c(s2)CNCC3)cc1
Reaction time: 6 h

Procedure:
4.5 g of the product of step a) are charged to a round-bottomed flask with 34 ml of DMF and 2.6 g of thiobenzamide. Heating is carried out at a temperature of 60° C. for 6 hours. An aqueous ammonia solution is added until a basic pH is obtained and evaporation is carried out under vacuum.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([S:5]([C:8]2[CH:31]=[CH:30][C:11]3[N:12]([CH2:20][CH:21]4[CH2:26][CH2:25][N:24]([C:27](=[O:29])[CH3:28])[CH2:23][CH2:22]4)[C:13]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:14][C:10]=3[CH:9]=2)(=[O:7])=[O:6])[CH2:2]1.C[Si]([N:36]=[C:37]=[O:38])(C)C>>[C:27]([N:24]1[CH2:25][CH2:26][CH:21]([CH2:20][N:12]2[C:11]3[CH:30]=[CH:31][C:8]([S:5]([CH:3]4[CH2:4][N:1]([C:37]([NH2:36])=[O:38])[CH2:2]4)(=[O:7])=[O:6])=[CH:9][C:10]=3[N:14]=[C:13]2[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:22][CH2:23]1)(=[O:29])[CH3:28]
Reactant: CC(=O)N1CCC(Cn2c(CC(C)(C)C)nc3cc(S(=O)(=O)C4CNC4)ccc32)CC1
Reactant: C[Si](C)(C)N=C=O
Product: CC(=O)N1CCC(Cn2c(CC(C)(C)C)nc3cc(S(=O)(=O)C4CN(C(N)=O)C4)ccc32)CC1

Procedure:
The title compound was prepared according to the procedure described in STEP D of Example 6 using 1-(4-((5-(azetidin-3-ylsulfonyl)-2-neopentyl-1H-benzo[d]imidazol-1-yl)methyl)piperidin-1-yl)ethanone (STEP D) and trimethylsilyl isocyanate instead of methanesulfonyl chloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.[F-].[K+]>C1COCC1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Yield: 98.2 %

Procedure:
4-Chloronitrobenzene (164 mg, 1.04 mmol) reacted with p-methoxyphenylboronic acid (200 mg, 1.32 mmol) using 1/2 mol % of Pd(OAc)2/Ph5FcP(t-Bu)2 and KF (182 mg, 3.00 mmol) in THF solvent at 50° C. for 17 h to give the title compound (234 mg, 98%) as a solid: 1H-NMR (400 MHz, CDCl3): δ 8.27 (d, 2H, J=8.76 Hz), 7.69 (d, 2H, J=8.76 Hz), 7.59 (d, 2H, J=8.70 Hz), 7.03 (d, 2H, J=8.71 Hz), 3.88 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 160.40, 147.15, 146.47, 130.99, 128.52, 127.01, 124.10, 114.56, 55.39. GC/MS(EI): m/z (M+).
Reaction SMILES: ClCl.[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-])=O.[C]=O.[C:14]1([N:20]=C=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[Pd].C12C=C3N=C(C=C3)C=C3NC(C=C3)=CC3=NC(C=C3)=CC(N1)=CC=2.[Pd].ClC1C=CC=CC=1Cl>[N:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:3][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Pd]
Agent: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3
Agent: ClCl
Solvent: Clc1ccccc1Cl
Product: c1ccc(N=Nc2ccccc2)cc1
Temperature: 230 °C

Procedure:
The chemical analysis indicates a content of 14.8% of palladium and a content of chlorine less than 0.5%. 2.0 grams of palladium porphyrin and 30 grams of nitrobenzene are charged into the autoclave previously described and the total volume is completed to 100 ml with orthodichlorobenzene. A stream of nitrogen is passed in at atmospheric pressure, then it is compressed with carbon monoxide until the pressure reaches 200 bars at 20° C. The autoclave is isolated and heated to 230° C., which brings the pressure of 340 bars. The mixture is allowed to react for 7 hours while maintaining it under agitation, then allowed to cool and analyzed. The O.C.R. of the nitrobenzene is 25.4% and the selectivity to phenylisocyanate is 94.8%. No azobenzene is formed.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:11][CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[C:7]2[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:6]1=2)=[O:4].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.CN(C)C=O>>[CH3:12][C:8]1([CH3:13])[CH2:9][CH2:10][CH2:11][N:5]([C:3](=[O:4])[CH2:2][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:6]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:7]1=2
Reactant: C1CCNC1
Reactant: CC1(C)CCCN(C(=O)CCl)c2cc([N+](=O)[O-])ccc21
Solvent: CN(C)C=O
Product: CC1(C)CCCN(C(=O)CN2CCCC2)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Chloro-1-(5,5-dimethyl-8-nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone (0.494 g, 0.00166 mol), pyrrolidine (0.310 mL, 0.00371 mol) and N,N-dimethylformamide (5.0 mL, 0.064 mol) were combined in a round bottom flask and stirred at room temperature for 18 hours. The reaction was concentrated under reduced pressure. The residue was dissolved in methylene chloride and washed with water and then brine. The organic phase was dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with ether to yield a crude orange solid, 1-(5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-2-pyrrolidin-1-yl-ethanone. LCMS: m/z=332.33 (M+H+).