Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH:25]([CH3:27])[CH3:26])[C:9](/[CH:18]=[CH:19]/[C:20](OCC)=[O:21])=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:5]2=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH:25]([CH3:27])[CH3:26])[C:9](/[CH:18]=[CH:19]/[CH2:20][OH:21])=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1c(C(C)C)nn2c(Cl)ccc2c1-c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)c1nn2c(Cl)ccc2c(-c2ccc(F)cc2)c1/C=C/CO
Temperature: -10 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a solution of ethyl (2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propenoate (50 mg) in toluene was added dropwise 1.5 M diisobutylaluminum hydride (0.277 mL) in toluene (24 mL) in a dryice-acetone bath. After addition, the mixture was stirred for 2 hours (−10° C.). The reaction mixture was quenched with sodium, potassium-tartarate and was filtered through Celite. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 40 mL) eluted with hexane-ethyl acetate=10-1, 5-1, and 3-1 to give (2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propen-1-ol as an yellow solid (30 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:33](=[CH:34][CH:35]=2)[O:32][C:31]([CH3:37])([CH3:36])[C:27]2([CH2:30][O:29][CH2:28]2)[C:14]23[CH2:18][O:17][C:16]([NH:19]C(=O)OC(C)(C)C)=[N:15]2)=[O:9])=[N:6][CH:7]=1>C1(C)C=CC=CC=1>[NH2:19][C:16]1[O:17][CH2:18][C:14]2([N:15]=1)[C:27]1([CH2:28][O:29][CH2:30]1)[C:31]([CH3:36])([CH3:37])[O:32][C:33]1[C:13]2=[CH:12][C:11]([NH:10][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:9])=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)NC1=NC2(CO1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1OC(C)(C)C21COC1
Solvent: Cc1ccccc1
Product: CC1(C)Oc2ccc(NC(=O)c3ccc(Cl)cn3)cc2C2(COC(N)=N2)C12COC2
Temperature: 120 °C
Reaction time: 1.33 h
Yield: 81.9 %

Procedure:
A mixture of tert-butyl (6′-{[(5-chloropyridin-2-yl)carbonyl]amino}-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl)carbamate (217 mg, 0.410 mmol), silica gel (neutral; 651 mg), and toluene (4 mL) was stirred for 80 minutes at 120° C. The reaction mixture was cooled down to ambient temperature and concentrated at reduced pressure. Purification of the residue with column chromatography on silica gel (eluted with EtOH/CHCl3=0/100 to 20/80) afforded N-(2-amino-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-6′-yl)-5-chloropyridine-2-carboxamide (144 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].CS(O[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[O:1][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:5]
Reactant: O=Cc1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C=O)CC1
Temperature: 75 °C
Reaction time: 18 h
Yield: 27.4 %

Procedure:
A mixture containing 2-hydroxybenzaldehyde (25; 4.2 g, 34.5 mmol), tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (24; 15.0 g, ˜41 mmol), K2CO3 (7.15 g, 51.7 mmol) and tetrabutyl ammonium iodide (500 mg, cat) in DMF (100 mL) was stirred at 70-80° C. for 18 h. The solvent DMF was removed by concentration under reduced pressure. The resulting residue was diluted with EtOAc (100 mL) and washed with water (50 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (pentane/EtOAc=1:10) to give tert-butyl 4-(2-formylphenoxy)piperidine-1-carboxylate 26 as a yellow oil (2.89 g, 27%).
Reaction SMILES: [C:1]([C:4]1([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:15]>C(Cl)Cl>[Cl:15][C:1]([C:4]1([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[CH2:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(=O)C1(C(C)=O)CCCCC1
Solvent: ClCCl
Product: C=C(Cl)C1(C(=O)OC)CCCCC1

Procedure:
23.5 g of methyl 1-acetyl-1-cyclohexyl-carboxylate dissolved in 100 cm3 of dry methylene chloride were heated under reflux for 6 hours in the presence of 30 g of phosphorus pentachloride. The mixture was then poured on to ice. The methylene chloride solution was separated off and washed with water and then with bicarbonate. After drying over magnesium sulphate, the solution was concentrated and methyl 1-(1'-chlorovinyl)-1-cyclohexyl-carboxylate was then distilled; this product was in the form of a colourless liquid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:13](Cl)(Cl)=[O:14].C(N(CC)CC)C>C(Cl)Cl>[O:14]=[C:13]1[NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH:6]=[CH:7][CH:8]=[N:9][C:10]=3[C:11]=2[O:12]1
Reactant: Nc1ccc2cccnc2c1O
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccc3cccnc3c2o1
Reaction time: 8 h
Yield: 91 %

Procedure:
A suspension of 7-amino-8-hydroxyquinoline (3.2 g, 20.0 mmol) in methylene chloride (50 ml) was treated with 25 ml of 1.6M phosgene gas in methylene chloride. Triethylamine (12 ml) was slowly added and the reaction was stirred overnight. The reaction mixture was partially concentrated and water was added. After treating the resulting mixture with aqueous ammonium hydroxide a precipitate formed which was filtered and dried giving 3.4 g (91% yield) of solid. M.P. >300° C.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[NH:11][CH:10]=[N:9][N:8]=1.O1CCCC1.[Li]CCCC.[Cl:22][C:23]1[CH:34]=[CH:33][C:26]([C:27](N(OC)C)=[O:28])=[CH:25][CH:24]=1.[Cl-].[NH4+].O>>[Cl:22][C:23]1[CH:34]=[CH:33][C:26]([C:27]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]2[NH:11][CH:10]=[N:9][N:8]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: Brc1ccsc1-c1nnc[nH]1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1ccsc1-c1nnc[nH]1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To a solution of 3-(3-bromo-2-thienyl)-4H-1,2,4-triazole (15.05 g, 65.41 mmol) in Tetrahydrofuran (500 mL, 6000 mmol) was added dropwise 2.5M BuLi in hexanes (104 mL, 262 mmol) at −70° C. (internal temperature) and the solution was stirred for 30 min at −78° C. A solution of 4-chloro-N-methoxy-N-methylbenzamide (41.24 g, 206.6 mmol) in tetrahydrofuran (80 mL, 1000 mmol) was then added dropwise into the suspension. The resulting mixture was stirred for 60 min at −78° C. Ammonium chloride (17.49 g, 327.0 mmol) in water (100 mL, 6000 mmol) was added to the mixture at −78° C. and the mixture was stirred for 15 min before being warmed to rt. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, and then filtered to remove drying agent. The solvent was evaporated and the residue was purified by chromatography to afford (4-chlorophenyl)[2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanone as white solid (16.8 g, 88.5%). LCMS: (FA) ES+ 289.9, 291.8
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(Cl)[Cl:11]>>[Cl:11][CH:8]([CH3:9])[C:2](=[O:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: ClCCl
Reactant: CCC(=O)CC(=O)OC
Product: COC(=O)CC(=O)C(C)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-oxopentanoic acid, methyl ester (Aldrich, 26.0 mL, 207.2 mmol) in methylene chloride (300 mL) was added in portions, N,N,N-trimethyl(phenyl) methanaminium dichloroiodanuide (75.71 g, 217.5 mmol). The reaction mixture was stirred at room temperature (rt) for 2 h, then washed with saturated sodium thiosulfate, brine, dried over magnesium sulfate and concentrated. The crude product was used directly in next step (23 g, 67.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][Mg]Cl.CCOCC.[C:16](#[N:18])[CH3:17].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][CH:16]([NH2:18])[CH3:17])[CH:8]=[CH:9][CH:10]=1
Reactant: Cl[Mg]Cc1cccc(Cl)c1
Reactant: CC#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(N)Cc1cccc(Cl)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 11.2 %

Procedure:
To a solution of 3-chlorobenzylmagnesium chloride (0.1 mol) in anhydrous ether (100 mL) (prepared from 3-chlorobenzyl chloride (16.1 g, 0.1 mol) and magnesium turnings (2.4 g, 0.1 mol) in anhydrous ether (100 mL)) was added anhydrous acetonitrile (4.1 g, 0.1 mol) dropwise at room temperature. When the reaction mixture was stirred at 60° C. for 3 hours, it was cooled to 0° C. followed by addition of THF (50 mL). Lithium aluminum hydride (4.2 g, 0.1 mol) was then added cautiously into the above reaction mixture and it was heated to reflux temperature for 3 hours. Ice-water was added to quench the reaction. After partitioning between ether and H2O, the separated organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo. Flash column chromatography separation (silica gel, 180 g, 5% methanol in DCM) then yielded the title compound as yellowish oil (1.9 g, 11%). MS: 170.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][S:6][CH2:7][C:8]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][C:13]2=[O:19].[N:24]1([CH2:29][C@@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)O)[CH:28]=[CH:27][N:26]=[CH:25]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][S:6][CH2:7][C:8]1[C:17]([O:18][C@@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][C:13]2=[O:19]
Reactant: O[C@@H](Cn1ccnc1)c1ccccc1
Reactant: O=C1CCCc2c1ccc(O)c2CSCc1ccc(Cl)c(Cl)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCCc2c1ccc(O[C@H](Cn1ccnc1)c1ccccc1)c2CSCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
5-(3,4-Dichloro-benzylsulfanylmethyl)-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (256 mg, 0.69 mmol), (R)-2-imidazol-1-yl-1-phenyl-ethanol (144 mg, 0.75 mmol), and triphenylphosphine resin (1.46 g, loading 1.41 mmol/g) were combined in dry tetrahydrofuran (10 mL) and treated with diisopropyl azodicarboxylate (271 μL, 2.0 mmol). The resulting orange-brown heterogeneous mixture was allowed to stir at ambient temperature overnight. The spent triphenylphosphine resin was removed by filtration, washing sequentially with ethyl acetate, methanol, and chloroform. The filtrate was concentrated in vacuo and the crude material was purified by silica gel chromatography (hexanes/ethyl acetate/triethylamine 28:70:2) to give 280 mg (75%) of the desired product as a colorless solid: (LC-MS, APCI) m/z 553/555 [M+H]+.
Reaction SMILES: [N:1]1([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH2:2]1.[O:20]=[C:21]1[N:27]([CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C@@H:37]([C:48](O)=[O:49])[CH2:38][C:39]3[CH:44]=[C:43]([CH3:45])[C:42]([OH:46])=[C:41]([CH3:47])[CH:40]=3)=[O:35])[CH2:30][CH2:29]2)[CH2:26][CH2:25][C:24]2[CH:51]=[CH:52][CH:53]=[CH:54][C:23]=2[NH:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:20]=[C:21]1[N:27]([CH:28]2[CH2:29][CH2:30][N:31]([C:34]([O:36][C@H:37]([CH2:38][C:39]3[CH:40]=[C:41]([CH3:47])[C:42]([OH:46])=[C:43]([CH3:45])[CH:44]=3)[C:48]([N:17]3[CH2:16][CH2:15][CH:14]([N:1]4[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:6]4)[CH2:19][CH2:18]3)=[O:49])=[O:35])[CH2:32][CH2:33]2)[CH2:26][CH2:25][C:24]2[CH:51]=[CH:52][CH:53]=[CH:54][C:23]=2[NH:22]1
Reactant: CCOC(=O)CCC1CCN(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Reaction time: 2 h

Procedure:
410 mg (1.20 mmol) ethyl 3-[1,4′]bipiperidinyl-4-yl-propionate (used as the bis-hydrochloride salt) were added at RT to a solution of 500 mg (1.04 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1h), 385 mg (1.20 mmol) TBTU and 0.48 mL (3.40 mmol) triethylamine in 10 mL DMF and the mixture was stirred for 2 h. The reaction mixture was purified by HPLC without any further working up. The fractions containing the product were combined, concentrated by evaporation i.vac. and the residue was stirred with saturated NaHCO3 solution. The precipitate formed was filtered off and dried.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][CH3:12])[CH:8]=[CH:7][C:6]=1I.[Br:16][C:17]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([F:25])[C:18]=1[NH2:19]>>[CH3:1][N:2]([CH3:15])[C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][CH3:12])[CH:8]=[CH:7][C:6]=1[NH:19][C:18]1[C:20]([F:25])=[CH:21][C:22]([Cl:24])=[CH:23][C:17]=1[Br:16]
Reactant: CCc1ccc(I)c(CC(=O)N(C)C)c1
Reactant: Nc1c(F)cc(Cl)cc1Br
Product: CCc1ccc(Nc2c(F)cc(Cl)cc2Br)c(CC(=O)N(C)C)c1

Procedure:
Ullmann condensation of N,N-dimethyl-5-ethyl-2-iodo-phenylacetamide with 2-bromo-4-chloro-6-fluoroaniline according to the procedure described in Example 1 yields N,N-dimethyl-5-ethyl-2-(2′-bromo-4′-chloro-6′-fluoroanilino)phenylacetamide.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[NH:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][S:10]1(=[O:20])=[O:19].O.CCOC(C)=O>CN(C=O)C>[Br:8][C:17]1[CH:16]=[CH:15][C:14]2[NH:9][S:10](=[O:19])(=[O:20])[CH2:11][CH2:12][C:13]=2[CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=S1(=O)CCc2ccccc2N1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S1(=O)CCc2cc(Br)ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
NBS (1.5 g, 8.2 mmol) was added to a solution of 3,4-dihydro-1H-benzo[c][1,2]thiazine 2,2-dioxide (1.5 g, 8.2 mmol) in DMF (15 mL). The reaction mixture was stirred overnight at ambient temperature followed by addition of water (200 mL) and EtOAc (100 mL). The two layers were separated and the aqueous phase was extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine (200 mL×3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane=1:3) to afford 6-bromo-3,4-dihydro-1H-benzo[c][1,2]thiazine 2,2-dioxide (1.7 g, 79% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C@@H:19]([NH:28][C:29](=[O:42])[CH2:30][C:31]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([CH3:33])[CH3:32])[C:18]2=[O:43])=[CH:12][CH:11]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C@@H:19]([NH:28][C:29](=[O:42])[CH2:30][C:31]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([CH3:33])[CH3:32])[C:18]2=[O:43])=[CH:14][CH:15]=1
Reactant: [H][H]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3[N+](=O)[O-])cc2)C1=O)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3N)cc2)C1=O)NC(=O)OC(C)(C)C
Yield: 89.9 %

Procedure:
A solution of 7.79 g (13.23 mmol) of the intermediate obtained in Step A in 200 mL of methanol containing 0.9 g of 5% palladium on carbon was hydrogenated at 40 psi. When the uptake of hydrogen was complete, the catalyst was removed by filtration through Celite. The filtrate was concentrated under vacuum to yield 6.6 g (11.9 mmol, 90%) of product. FAB-MS: calculated for C33H4N4O4 556; found 557(M+H). 1H NMR (400 MHz, CDCl3): 1.32 (s, 6H), 1.39 (s, 9H), 1.87 (m, 1H), 2.51 (dd, 1H), 2.59 (m, 1H), 4.51 (m, 1H), 4.89 (d, 1H), 5.15 (d, 1H), 5.32 (br s, 1H), 6.71 (d, 1H), 6.81 (s, 1H), 7.21 (m, 10H).
Reaction SMILES: [NH2:1][C:2]1([C:5]2[CH:6]=[C:7]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([Cl:19])[CH:12]=3)[CH:8]=[N:9][CH:10]=2)[CH2:4][CH2:3]1.[CH2:20]([S:22](Cl)(=[O:24])=[O:23])[CH3:21]>C(Cl)Cl>[Cl:19][C:13]1[CH:12]=[C:11]([C:7]2[CH:6]=[C:5]([C:2]3([NH:1][S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[CH2:3][CH2:4]3)[CH:10]=[N:9][CH:8]=2)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1ccc(-c2cncc(C3(N)CC3)c2)cc1Cl
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCS(=O)(=O)NC1(c2cncc(-c3ccc(C#N)c(Cl)c3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-(1-aminocyclopropyl)pyridin-3-yl)-2-chlorobenzonitrile (70 mg, 0.26 mmol) in DCM (3 mL) at room temperature was added TEA (0.109 mL, 0.779 mmol) and EtSO2Cl (74 μL, 0.779 mmol) dropwise, and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, re-dissolved in DMF (3 mL) and filtered. The filtrate was purified by Xbridge Phenyl followed by Xbridge C18 eluting with 20-80% ACN-water gradient to give N-(1-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)cyclopropyl)ethanesulfonamide. HRMS: (ESI) m/z 362.0712 [(M+H)+ Calcd for C17H96ClN3O2S 362.0725]. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.3 Hz, 3H), 1.32-1.38 (m, 2H), 1.49-1.54 (m, 2H), 2.90 (q, J=7.4 Hz, 2H), 7.60 (dd, J=8.1, 1.8 Hz, 1H), 7.74 (d, J=1.8 Hz, 1H), 7.79 (d, J=8.1 Hz, 1H), 8.01 (t, J=2.3 Hz, 1H), 8.67 (d, J=2.3 Hz, 1H), 8.72 (d, J=2.3 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=3)[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:29]([NH:33][S:34]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)(=[O:36])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([NH:33][S:34]([C:37]1[CH:38]=[C:39]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[C:16]([CH3:24])[CH:15]=4)[CH:11]=[C:10]([C:25]([F:28])([F:26])[F:27])[N:9]=3)[CH:3]=2)[CH:40]=[CH:41][CH:42]=1)(=[O:36])=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(-c4cccc(S(=O)(=O)NC(C)(C)C)c4)c3)n2)ccc1C(F)(F)F

Procedure:
3′-[4-(3-methyl 4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.49) (0.46 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as white foam (0.52 g), which was subsequently deprotected.
Reaction SMILES: Br[C:2]1[S:6](=[O:8])(=[O:7])[C:5]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:4]=2[C:3]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1.[BH4-].[Na+]>CO.CS(C)=O>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:3]2[C:4]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:5]=3[S:6](=[O:8])(=[O:7])[CH:2]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc2c(c1)S(=O)(=O)C(Br)=C2Oc1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: COc1ccc2c(c1)S(=O)(=O)C=C2Oc1ccc(Br)cc1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-3-(4-bromophenoxy)-6-methoxy-benzo[b]thiophene 1,1-dioxide (180 g, 403 mmol) in MeOH (150 mL) and DMSO (1300 mL) at 0° C. (internal temperature was at 5° C.) was added the first portion of NaBH4 (15 g, 396.5 mmol). Internal temperature rose quickly to 40° C. and H2 gas release was observed. The mixture was stirred in an ice bath for 30 min (internal temperature cooled down to 10° C.). The second portion of NaBH4 (15.5 g, 409.7 mmol) was added. The resulting mixture was stirred for 30 minutes after which time the reaction was quenched with water (2000 mL) over 1 hour. The resulting precipitate was collected, air dried over 18 hours, then washed with heptane to afford 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide as an off white solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ ppm=3.85 (s, 3 H), 5.38 (s, 1 H), 7.02-7.08 (m, 3 H), 7.22 (d, J=2.53 Hz, 1 H), 7.47-7.60 (m, 3 H).
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].N(C(OC(C)(C)C)=O)[C@H:29](C(OC)=O)CCCCNC(OCC1C=CC=CC=1)=O>>[CH2:21]([O:20][C:18]([NH:1][C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:15]([O:17][CH3:29])=[O:16])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1

Procedure:
The title compound was prepared from Z-L-Lys(Boc)OH by following the procedure described for example 4, intermediate 31. Intermediate 49 was characterized by the following spectroscopic data: 1H NMR (DMSO-d6, 300 MHz) δ (ppm) 7.47 (m, 5H), 6.76 (t, 1H), 5.09 (s, 2H), 4.51 (m, 1H), 3.68 (s, 3H), 3.18 (m, 2H), 1.90 (m, 2H), 1.55 (m, 2H), 1.38 (s, 9H), 1.25 (m, 2H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=O)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>O1CCCC1>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[S:31])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCN1S(=O)(=O)c1ccc(N2CCCCC2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(N2CCCCC2)cc1)N1CCCC1=S

Procedure:
A mixture comprising 9.1 g of 1-[4-(1-piperidyl)benzenesulphonyl]-2-pyrrolidinone, prepared as in Example 10 of the European Patent published under No. 0,033,578, and 5.96 g of Lawesson reagent (or 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulphide) in 180 cm3 of tetrahydrofuran is heated to reflux for 48 hours. The mixture is allowed to return to room temperature and is evaporated to dryness, and the residue is chromatographed on silica (eluant: benzene). 4.6 g of product are recovered. M.p. 195°-200° C. After crystallization in a chloroform/n-hexane mixture, 4.4 g of expected product are obtained. M.p. 209°-211° C.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[N:37]([CH3:38])[N:36]=[C:35]([CH3:39])[C:34]=1[S:40](Cl)(=[O:42])=[O:41]>N1C=CC=CC=1>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:34]4[C:35]([CH3:39])=[N:36][N:37]([CH3:38])[C:33]=4[Cl:32])(=[O:41])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Solvent: c1ccncc1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4c(C)nn(C)c4Cl)cc3)nc21
Temperature: 23 °C
Reaction time: 3 h

Procedure:
8-(4-Amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione (20 mg, 0.047 mmol) was dissolved in pyridine (0.5 ml) and treated with 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (Maybridge, 16 mg, 0.07 mmol). The reaction was stirred at 23° C. for 3 h. The solvent was removed and the residue was purified by reverse phase HPLC. LCMS, m/z (M+H)=615.2.