Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=2[N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6][CH:5]1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].Br[CH2:31][C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33]>CN(C)C=O>[C:34]([C:32]([CH2:31][N:10]1[C:9]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=2[N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6][CH:5]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:4]1=[O:3])=[O:33])([CH3:37])([CH3:36])[CH3:35]
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2c1ccccc1
Reactant: CC(C)(C)C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(NC(=O)OC(C)(C)C)CN2c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
60% Sodium hydride (33 mg) was suspended in anhydrous N,N-dimethylformamide (10 ml), under ice-cooling 2-oxo-3-tert-butoxycarbonylamino-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (200 mg) obtained from Referentioal Example 5, and the mixture was stirred for one hour at room temperature. Subsequently, bromomethyl-tert-butylketone (147 mg) was added, stirred for one hour at room temperature. Ice-water was added to the reaction mixture, extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, diisopropyl ether was added to the residue for crystallization, crystals so precipitated were collected by filtration, to thereby obtain 140 mg of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24](O)=[O:25])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=[C:37]([C:46]([N:48]3[CH2:52][C:51](=[O:53])NC3)=O)C=2)C=C(F)C=1.N1CCOCC1>>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([N:48]3[CH2:46][CH2:37][O:53][CH2:51][CH2:52]3)=[O:25])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Solvent: C1COCCN1
Product: O=C(c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1)N1CCOCC1

Procedure:
75 mg (0.20 mmol) of the compound of Example 34A is reacted analogously to the synthesis of the compound of Example 1 with 0.02 ml (0.23 mmol) of morpholine. 80 mg (90% of theory) of the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:22])[N:16]([CH2:18][C:19]([NH2:21])=[O:20])[CH:17]=2)=O)=[C:4]([CH3:33])[CH:3]=1.Cl.[NH2:35][OH:36].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:25][CH:24]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:22])[N:16]([CH2:18][C:19]([NH2:21])=[O:20])[CH:17]=2)=[N:35]\[OH:36])=[C:4]([CH3:33])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(CC(N)=O)c1)c1ccc(S(C)(=O)=O)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(CC(N)=O)c1)c1ccc(S(C)(=O)=O)cc1

Procedure:
In analogy to example 151, step 3, 2-(5-(3-(4-chloro-2-methylphenyl)-3-(4-(methylsulfonyl)phenyl)propanoyl)-2-oxopyridin-1(2H)-yl)acetamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as an off-white solid, MS (ESI−): m/z=500.1 [M−H]−.
Reaction SMILES: [Mg].Cl[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([O:10][CH3:11])[CH2:8][CH3:9].Cl[CH:13]1[CH2:17][CH2:16][CH:15]=[CH:14]1.[Cl-].[NH4+]>O1CCCC1>[CH3:11][O:10][CH:7]([CH2:8][CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH:17]1[CH2:16][CH2:15][CH:14]=[CH:13]1
Reactant: CCC(CCCCCl)OC
Reactant: ClC1C=CCC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CCCCC1C=CCC1)OC
Temperature: -25 °C
Yield: 89.7 %

Procedure:
A three-neck, round-bottomed flask containing magnesium metal turnings (7.2 g, 0.299 moles), is equipped with a Friedrich condenser and kept under a nitrogen atmosphere. Tetrahydrofuran (300 ml) is added and the contents are allowed to stir. A solution of 1-chloro-5-methoxyheptane (48.1 g, 0.292 moles) is added in small portions and refluxed. The mixture is allowed to stir for 3 hours. The resultant dark yellow solution is cooled to -25° C., and the condenser is removed and replaced with a dry ice addition funnel. A solution of 3-chlorocyclopentene (29.9 g, 0.292 moles) is added over a period of one hour. The viscous solution is poured into two liters of saturated ammonium chloride, extracted with ether, and dried over anhydrous sodium sulfate. Distillation yields 3-(5-methoxyheptyl)cyclopentene (51.5 g, 0.262 moles) as a clear, colorless oil boiling at about 90° C. at 0.3 mm and 54° C. at 0.1 mm.
Reaction SMILES: [CH3:1][CH:2]([N:4]([CH2:9][C@@H:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)[S:5]([CH3:8])(=[O:7])=[O:6])[CH3:3].Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:3][CH:2]([N:4]([CH2:9][C@@H:10]1[N:15]([C:24]2[N:25]=[CH:26][C:27]([C:30]([OH:39])([C:31]([F:32])([F:33])[F:34])[C:35]([F:37])([F:38])[F:36])=[CH:28][N:29]=2)[CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:11]1)[S:5]([CH3:8])(=[O:6])=[O:7])[CH3:1]
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)N(C[C@H]1CN(C(=O)OC(C)(C)C)CCN1)S(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)N(C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)S(C)(=O)=O
Temperature: 100 °C
Yield: 83.6 %

Procedure:
A 20-mL vial was charged with tert-butyl (3R)-3-(((1-methylethyl)(methylsulfonyl)amino)methyl)-1-piperazinecarboxylate (0.315 g, 0.939 mmol, step 1), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.287 g, 1.02 mmol, Intermediate D), DIPEA (0.492 mL, 2.82 mmol) and 1,4-dioxane (5 mL). The vial was sealed and heated at 100° C. for 12 h. The reaction mixture was allowed to cool to room temperature and additional 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.082 g, 0.29 mmol, Intermediate D) was added. The mixture was heated at 100° C. for an additional 12 h. After allowing the reaction to cool to room temperature, the mixture was partitioned between water (50 mL) and EtOAc (40 mL). The aqueous phase was extracted with EtOAc (40 mL). The combined organic extracts was washed with saturated aqueous NaCl (60 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50 g of silica gel, 0 to 50% EtOAc in hexanes) to afford tert-butyl (3R)-3-(((1-methylethyl)(methylsulfonyl)amino)methyl)-4-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-1-piperazinecarboxylate (0.455 g) as a light yellow foam.
Reaction SMILES: S(Br)([Br:3])=O.[C:5]([OH:14])(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>O>[C:5]([Br:3])(=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCC(=O)O
Reactant: O=S(Br)Br
Solvent: O
Product: CCCCCCCC(=O)Br
Temperature: 50 °C

Procedure:
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 10.07 ml (130 mmol) of thionyl bromide, and a water condenser, is placed 10.30 ml (65 mmol) of octanoic acid. Addition of the thionyl bromide is completed with heating to about 50° C. over the course of about 50 minutes. When addition of the thionyl bromide is complete the mixture is heated and stirred for an additional hour. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl bromide, octanoyl bromide. This acyl bromide, 4.88 g (30 mmol), is put into a dry separatory funnel and combined with 25 ml of dry dichloromethane for use in the next step of the reaction.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[CH2:32][CH:33]1[CH2:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH:33]1([CH2:32][N:17]([CH2:16][C:14]2[S:15][C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=3)=[CH:12][CH:13]=2)[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])[CH2:36][CH2:35][CH2:34]1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Reactant: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1cccc(-c2ccc(CN(CC3CCC3)S(=O)(=O)c3ccccc3C(F)(F)F)s2)c1

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with (bromomethyl)-cyclobutane and cesium carbonate in N,N-dimethylacetamide to give N-cyclobutylmethyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide as a light yellow semi-solid. MS: 560.7 ([M+NH4]+)
Reaction SMILES: C(N(CC)CC)C.[N:8](=[C:10]1[S:14][C:13]([CH3:16])([CH3:15])[N:12]=[C:11]1[CH3:17])[OH:9].[CH3:18][N:19]([S:23][N:24]([CH3:28])[C:25](F)=[O:26])[C:20]([F:22])=[O:21]>C1(C)C=CC=CC=1>[CH3:18][N:19]([S:23][N:24]([CH3:28])[C:25]([O:9][N:8]=[C:10]1[S:14][C:13]([CH3:16])([CH3:15])[N:12]=[C:11]1[CH3:17])=[O:26])[C:20]([F:22])=[O:21]
Reactant: CN(SN(C)C(=O)F)C(=O)F
Reactant: CC1=NC(C)(C)SC1=NO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1=NC(C)(C)SC1=NOC(=O)N(C)SN(C)C(=O)F
Temperature: -50 °C

Procedure:
8.3 ml of triethylamine are added dropwise to a suspension of 8.59 g of 5-oxo-2,2,4-trimethyl-3-thiazoline oxime in a solution of 10.0 g of bis-(N-methyl-N-fluorocarbonylamino)sulfide in 100 ml of absolute toluene, cooled to -50° C. The resulting clear solution is allowed to warm slowly to 0° C. during 11/2 hours, during which time a crystalline product is precipitated. The reaction mixture is poured into ice-cold brine and extracted with ethyl acetate. After drying the organic phase over anhydrous sodium sulfate and evaporating it, the resulting residue is purified by chromatography on silica gel (eluent:ethyl acetate/n-hexane 1:1). Crystallization from ethyl acetate/n-hexane yields 5-oxo-2,2,4-trimethyl-3-thiazoline O-[N-(N-methylfluoroformamidothio)-N-methylcarbamoyl]oxime, m.p. 77°-79° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[C:17]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:26]3[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=3)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=2)=[CH:9][CH:10]=1)([CH3:16])[CH3:15]
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: CC(C)c1ccc(-c2ccnc(Cl)c2)cc1
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: CC#N
Product: CCOC(=O)c1cccc(-c2cc(-c3ccc(C(C)C)cc3)ccn2)c1
Yield: 70 %

Procedure:
Part D. A solution of 2-chloro-4-(4-isopropyl-phenyl)-pyridine (110 mg, 0.48 mmol) in acetonitrile-water (1 mL/0.5 mL) is treated with 3-carboethoxybenzeneboronic acid (186 mg, 0.96 mmol), sodium carbonate (153 mg, 1.44 mmol) and tetrakis(triphenylphosphine)palladium (cat. amount). The mixture is heated to reflux for 12 h., then cooled and partitioned between water and ethyl acetate. The organic phase is washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue is separated by column chromatography to afford ethyl 3-[4-(4-isopropyl-phenyl)-pyridin-2-yl]-benzoate (116 mg, 70%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:52])[NH:4][C@H:5]([C:19](=[O:51])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C@H:25]([N:36]([S:41]([C:44]1[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=1)(=[O:43])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:26][O:27][P:28]([O:33]CC)([O:30]CC)=[O:29])[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[Si](Br)(C)C>ClCCl>[CH3:1][O:2][C:3](=[O:52])[NH:4][C@H:5]([C:19](=[O:51])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C@H:25]([N:36]([S:41]([C:44]1[CH:45]=[CH:46][C:47]([NH2:50])=[CH:48][CH:49]=1)(=[O:42])=[O:43])[CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:26][O:27][P:28]([OH:33])([OH:30])=[O:29])[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOP(=O)(OCC)OC[C@H](CCCCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)NCCCC[C@@H](COP(=O)(O)O)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of step G prepared above (152 mg) was dissolved in anhydrous dichloromethane (3.0 mL). Trimethylsilyl bromide (0.5 mL) was added at 0° C. The mixture was stirred during 1 h at this temperature and overnight at room temperature. The solvent was evaporated and 0.2 mL water was added to the residue. 3 mL EtOH was added mixed and evaporated. This step was repeated three times and the residue dried in vacuo. Yields 98 mg 70% of the title derivatives of this first example.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH:14]=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].[Cl:32]CCl.Cl>C(O)C>[ClH:32].[CH:25]1[C:20]2[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[C:15](=[CH:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCC=C2c3ccccc3CCc3ccccc32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCC=C2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
The above ester (4.4 g, 11 mmol) was dissolved in ethanol (40 ml) and 4N sodium hydroxide (8.3 ml) was added. The mixture was stirred vigorously at ambient temperature for 7 h. Dichloromethane (700 ml) was added followed by 2.5N hydrochloric acid until pH 1. The phases were separated, the organic phase dried (MgSO4) and the solvent was evaporated in vacuo. The residue was re-evaporated twice with acetone and then triturated with a mixture of acetone and diethyl ether. The solid was isolated by filtration and dried in air to give 2.2 g of the title compound as a solid.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([C:19]([OH:21])=O)[C:12]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[CH:18]=1.ClC(OCC)=O.[NH2:28][CH2:29][C@@H:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][C@H:31]1[O:41][CH2:42][CH3:43]>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([C:19]([NH:28][CH2:29][C@@H:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][C@H:31]2[O:41][CH2:42][CH3:43])=[O:21])[C:12]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[CH:18]=1
Reactant: O=C(O)c1cc(Cl)cc2c1OCCO2
Reactant: CCOC(=O)N1CC[C@@H](CN)[C@H](OCC)C1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CC[C@@H](CNC(=O)c2cc(Cl)cc3c2OCCO3)[C@H](OCC)C1
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
At a temperature below 10° C., triethylamine (0.01 mol) was added to 7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylic acid (0.01 mol) in chloroform (40 ml). Ethyl chloroformate 01 mol) was added at a temperature below 10IC and the mixture was stirred for 30 minutes at a temperature below 10° C. This mixture was added to a solution of intermediate (14) (0.01 mol) in chloroform (20 ml), at a temperature below 10° C. The reaction mixture was stirred for 30 minutes then washed with a 5% HCl solution, with water, dried, filtered and the solvent was evaporated, yielding 4 g of (trans)-ethyl 4-[[[(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)carbonyl]-amino]methyl]-3-ethoxy-1-piperidinecarboxylate (intermediate 15).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[CH2:15]([CH2:17][NH2:18])[OH:16].CCN(CC)CC>CO>[OH:16][CH2:15][CH2:17][N:18]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14]
Reactant: NCCO
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Solvent: CCN(CC)CC
Solvent: CO
Product: O=c1c2cccc([N+](=O)[O-])c2ccn1CCO
Temperature: 70 °C
Reaction time: 2 h

Procedure:
5-Nitro-isochromen-1-one (3.60 g, 0.0170 mol) was suspended in MeOH (40 mL), ethanolamine (3.11 g, 0.0508 mol) was added and the reaction mixture was stirred at 70° C. for 2 h under an atmosphere of nitrogen. Cooled to room temperature and Et3N (5 mL) was added and the reaction mixture was stirred at room temperature for 2 days. Solid thus formed was filtered out (yellow solid was obtained as the desired product, 0.9 g). Filtrate was concentrated and the residue was dissolved in EtOAc, washed by water and brine, dried over Na2SO4, solvent was removed, to give the product as a yellow solid (1.3 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([N+]([O-])=O)[CH:11]=[C:12]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:5]=2[CH2:4][CH2:3]1.S(S([O-])=O)([O-])=[O:24].[Na+].[Na+]>>[OH:24][C:10]1[CH:11]=[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:8][CH2:7][C:6]=2[CH:9]=1
Reactant: O=S([O-])S(=O)[O-]
Reactant: CN1CCc2cc([N+](=O)[O-])cc(Sc3ccccc3)c2CC1
Agent: [Na+]
Product: CN1CCc2cc(O)cc(Sc3ccccc3)c2CC1

Procedure:
Following the procedures outlined in Examples 9 and 10, the 3-methyl-8-nitro-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine is reduced with sodium hydrosulfite and the corresponding 8-amino derivative is diazotized and then heated with cuprous sulfate/sulfuric acid to yield 8-hydroxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C@H:3]([OH:16])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:6]1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:21]>>[C:20](=[O:21])([O:22][C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1)[O:16][C@H:3]([CH2:4][N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:6]1)[C:2]([CH3:18])([CH3:17])[CH3:1]
Reactant: CC(C)(C)[C@H](O)Cn1ccc(-c2cccnc2)n1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Product: CC(C)(C)[C@@H](Cn1ccc(-c2cccnc2)n1)OC(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
(2S)-3,3-Dimethyl-1-[3-(3-pyridinyl)-1H-pyrazol-1-yl]-2-butanol was treated with p-nitrophenyl chloroformate as previously described in example 1g to provide the title compound as a solid foam. 1H-NMR (DMSO-d6): δ 8.97 (s, 1H), 8.46 (d, J=4 Hz, 1H), 8.13 (d, J=9 Hz, 2H), 8.10 (d, J=8 Hz, 1H), 7.9 (d, J=2 Hz, 1H), 7.38 (dd, J=7 Hz, J=4 Hz, 1H), 7.22 (d, J=9 Hz, 2H), 6.83 (d, J=2 Hz, 1H), 4.90 (d, J=9 Hz, 1H), 4.62 (d, J=14 Hz, 1H), 4.35 (dd, J=14 Hz, J=9 Hz, 1H), 1.03 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([S:14]([CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)(=[O:16])=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C.[NH:37]1[CH:41]=[C:40]([C:42](O)=[O:43])[CH:39]=[N:38]1>ClCCl>[CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([S:14]([CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([C:42]([C:40]4[CH:41]=[N:37][NH:38][CH:39]=4)=[O:43])[CH2:22][CH2:23]3)(=[O:16])=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:24][C:25]([CH3:26])([CH3:28])[CH3:27]
Reactant: O=C(O)c1cn[nH]c1
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)CC3CCNCC3)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)CC3CCN(C(=O)c4cn[nH]c4)CC3)ccc21
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a solution of N,N-dimethyl-2-(2-neopentyl-5-(piperidin-4-ylmethylsulfonyl)-1H-benzo[d]imidazol-1-yl) ethanamine (STEP C, 687 mg, 1.63 mmol) in dichloromethane (8 mL) were added triethylamine (230 microL, 1.63 mmol), 1H-pyrazole-4-carboxylic acid (201 mg, 1.80 mmol) and O-benzo-triazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (638 mg, 1,68 mmol) at room temperature. After 2 h, the mixture was diluted with dichloromethane (80 mL) and washed with sodium bicarbonate aqueous solution and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by amine gel column chromatography (ethyl acetate-methanol, gradient) to give the title compound (757 mg, 90%) as a pale yellow grease.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH:19]=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21](COCC[Si](C)(C)C)[N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH:19]=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:21][N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:32])=[O:33])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc(NC2CCN(S(C)(=O)=O)CC2)c2nc(-c3c(F)cccc3F)c3cc(C=O)ccc3c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(C=O)ccc23)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A 10 ml round-bottomed flask is charged with 54 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde, prepared in step 5 of example 2, in 5 ml of DCM. After cooling to 0° C. using an ice bath, 0.3 ml of TFA is added and the mixture is stirred at RT for 16 h. It is concentrated under RP and the solid obtained is taken up in 5 ml of saturated aqueous NaHCO3 solution. It is extracted with AcOEt, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a mixture of DCM/AcOEt (50/50 by vol.). This gives 9 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde (yellow solid). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.68 (m, 2 H) 2.11 (m, 2 H) 2.88 (s, 3 H) 2.90 (m, 2 H) 3.57 (m, 2 H) 3.81 (m, 1 H) 6.16 (broad m, 1 H) 7.36 (t, J=7.8 Hz, 2 H) 7.71 (m, 1 H) 8.23 (broad s, 1 H) 8.34 (broad d, J=8.5 Hz, 1 H) 8.57 (d, J=8.2 Hz, 1 H) 10.10 (s, 1 H) 13.02 (broad s, 1 H). LC-MS-DAD-ELSD: 486 (+)=(M+H)(+).