Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:17][C:18]1[N:23]=[C:22]([S:24]([NH:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])(=[O:26])=[O:25])[CH:21]=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:31]([C:30]4[CH:29]=[C:28]([NH:27][S:24]([C:22]5[CH:21]=[CH:20][CH:19]=[C:18]([CH3:17])[N:23]=5)(=[O:25])=[O:26])[CH:36]=[CH:35][CH:34]=4)=[O:32])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: Cc1cccc(S(=O)(=O)Nc2cccc(C(=O)O)c2)n1
Reactant: Clc1ccc2nc(N3CCNCC3)sc2c1
Product: Cc1cccc(S(=O)(=O)Nc2cccc(C(=O)N3CCN(c4nc5ccc(Cl)cc5s4)CC3)c2)n1

Procedure:
Compound 12 is prepared using synthesis method 2 using intermediates 3g and 5b (yield: 15%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[CH:5]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])[CH2:6][O:7][CH3:8].[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21]>C1COCC1>[CH3:1][O:2][C:3](=[O:19])[C:4]([CH3:17])([CH3:18])[CH:5]([N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:20]1=[O:21])[CH2:6][O:7][CH3:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COCC(Nc1ccccc1N)C(C)(C)C(=O)OC
Solvent: C1CCOC1
Product: COCC(n1c(=O)[nH]c2ccccc21)C(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
To a solution of 3-(2-amino-phenylamino)-4-methoxy-2,2-dimethyl-butyric acid methyl ester (550 mg, 2.1 mmol) in THF (25 mL) was added 1,1′-carbonyldiimidazole (500 mg, 3.1 mmol). The solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated. The resulting residue was purified by CombiFlash with 75% EtOAc in Hexane as the eluent to afford the desired 4-methoxy-2,2-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-butyric acid methyl ester (420 mg, 70%).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)=[N+:2]=[N-:3].[Li+].[CH3:22][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[N:1]([CH2:4][C@@H:5]([N:13]([CH3:22])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)=[N+:2]=[N-:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])C[C@H]1CCCOC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(C(=O)OC(C)(C)C)[C@H](CN=[N+]=[N-])C[C@H]1CCCOC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of tert-butyl (S)-1-azido-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate (30 mg, 0.11 mmol) in anhydrous THF (4 mL) at −78° C. was added 1.0 M LHMDS solution in THF (253 μL, 0.25 mmol), then stirred at this temperature for 30 min. To this mixture was added MeI (125 μL, 0.22 mmol), then the temperature was allowed to warm to 0° C., and stand for 12 hr in the refrigerator. The reaction mixture was quenched with saturated aq. NH4Cl, extracted with EtOAc (30 mL), the separated organic phase was washed with H2O (2×10 mL), brine, and dried (Na2SO4), and filtered. The filtrate was concentrated, the resulting slurry was purified through flash chromatography on silica gel (eluted with gradient system, 0-30% EtOAc in hexane) to afford tert-butyl (S)-1-azido-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-yl(methyl)carbamate 31 mg, yield 100%. MS ESI+ve m/z 321 (M+Na).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:24]([NH:26][C:27](=[O:33])[N:28]([CH2:30][CH2:31][CH3:32])[NH2:29])[CH3:25]>C1COCC1>[CH2:24]([NH:26][C:27](=[O:33])[N:28]([CH2:30][CH2:31][CH3:32])[NH:29][C:6](=[O:8])[C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[CH3:25]
Reactant: O=C(O)c1ccsc1
Reactant: CCCN(N)C(=O)NCC
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCN(NC(=O)c1ccsc1)C(=O)NCC
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 2.62 g (20.5 mmol) of thiophene-3-carboxylic acid and 2.8 mL (20.0 mmol) of triethylamine in 20 mL of THF was cooled to 5° C. and 2.6 mL (20.0 mmol) of isobutyl chloroformate was added dropwise over 5 minutes. The mixture was stirred at 5° C. for 5 minutes and added to a suspension of the 4-ethyl-2-propyl semicarbazide prepared above in 20 mL of THF at 5° C. This mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated to remove most of the solvent, taken up in 75 mL of water and extracted with two 100 mL portions of ethyl acetate. The combined ethyl acetate extracts were washed with 50 mL of 5% aqueous HCl and 50 mL of saturated aqueous sodium bicarbonate (NaHCO3), and dried over MgSO4. Removal of the solvent left 5.30 g of crude 4 -ethyl-2-propyl-1-(3-thenoyl) semicarbazide as an oil.
Reaction SMILES: [CH3:1][N:2]([C:10]([CH3:16])([CH2:12][CH2:13][CH:14]=O)[CH3:11])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[N+](=[C:19](P(=O)(OC)OC)C(=O)C)=[N-].C([O-])([O-])=O.[K+].[K+]>CO.O>[CH3:1][N:2]([C:10]([CH3:16])([CH2:12][CH2:13][C:14]#[CH:19])[CH3:11])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: CN(C(=O)OC(C)(C)C)C(C)(C)CCC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#CCCC(C)(C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To 150 mg of 12e in 3 ml of methanol was added 250 mg of dimethyl 1-diazo-2-oxopropylphosphonate and 250 mg of K2CO3. The mixture was stirred at RT overnight. Then reaction was diluted with water and the product was extracted with ether. The extract was washed once with sat. NaCl, dried, concentrated and filtered over a short silica column, using a pentane-ether gradient as eluent, to give 130 mg of 12f as colorless oil; Rf 0.55 (heptane/ether 3/1). NMR (CDCl3) δ 1.33 (s, 3, 2×CH3), 1.48 (s, 9, tertC4H9), 1.92 (t, 1, acetylene-H), 2.10 (m, 4, CH2CH2), 2.88 (s, 3, NCH3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-])=O)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([NH2:21])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])cnc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1cc(N)cnc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 9 h
Yield: 96.4 %

Procedure:
To 4-(3-methyl-5-nitropyridin-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (5.0 g) were added 1,4-dioxane (50 ml) and 10% palladium carbon (containing about 50% water, 2.0 g), stirred at room temperature for 9 hours under hydrogen atmosphere, then 10% palladium carbon (containing about 50% water, 1.5 g) was additionally added thereto, and stirred at 40° C. for 8.5 hours under hydrogen atmosphere. The reaction solution was filtered through Celite, and then the solvent was evaporated in vacuo to give 4-(5-amino-3-methylpyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (4.4 g) as a yellow oil.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[CH2:7]([N:14]1[CH2:19][CH2:18][C:17](=O)[CH:16]([CH3:21])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH4+].[Cl-]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][C:17](=[CH2:1])[CH:16]([CH3:21])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C1CCN(Cc2ccccc2)CC1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Potassium tert-butylate (2.1 g, 18.8 mmol, dissolved in 20 ml abs. THF) was added within 30 min to a suspension of methyltriphenylphosphonium bromide (7.5 g, 21 mmol) in dry THF (20 ml) under argon at 0° C. The reaction mixture was stirred for 30 min at 0° C. before 1-benzyl-3-methylpiperidin-4-one (3.05 g, 15 mmol, dissolved in abs. THF (20 ml)) was added dropwise within 30 min at 0° C. The reaction mixture was stirred for 30 min at 0° C. and brought to RT within 1 h and stirred for a further 15 h. For working up, the mixture was added to sat. NH4Cl solution (50 ml) and then extracted with EtOAc (3×20 ml). The desired product S was converted into the corresponding hydrochloride by extraction with 2 N HCl solution (20 ml). The organic phase was washed with water (3×20 ml) and the combined aqueous phases were basified with K2CO3. The product S was obtained in the form of a layer of oil and was separated off by reextraction with EtOAc (3×20 ml). After drying of the combined organic phases over Na2SO4 and removal of the solvent, the desired product S was present in a sufficiently pure form (2.50 g, 83%).
Reaction SMILES: [C:1](OCC)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH:9][C@@H:10]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:26]2[C:25](=[O:31])[CH2:24][C@@:23]2([CH3:32])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C:20](=[O:22])[CH3:21])[CH2:11]1.[H-].[Na+].CO>CS(C)=O>[C:1]([CH2:21][C:20](=[O:22])[C@@H:19]1[C@:23]2([CH3:32])[C@H:16]([C@H:15]3[C@H:26]([C:25](=[O:31])[CH2:24]2)[C@:27]2([CH3:30])[C@H:12]([CH2:11][C@H:10]([OH:9])[CH2:29][CH2:28]2)[CH2:13][CH2:14]3)[CH2:17][CH2:18]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: CCCC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: CCCC(=O)CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 4 h

Procedure:
Ethyl butyrate (0.84 ml) was added to a mixture of 3α-hydroxy-5α-pregnane-11,20-dione (665 mg) and sodium hydride (150 mg.) in dry dimethyl sulphoxide (10 ml.). The mixture was stirred, under N2, for 13/4 hrs. The reaction mixture was treated with methyl alcohol to destroy excess sodium hydride, then poured into 2N-hydrochloric acid. The product was extracted with ethyl acetate and the combined extracts were washed with water, dried and evaporated. Preparative t.l.c. of the residue (859 mg.) gave two fractions. The more polar fraction was title compound (244 mg.) [α]D + 74.0°, λmax. 278 nm (ε 12,980).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:23]([OH:25])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.[CH3:55][NH:56][O:57][CH3:58]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:23](=[O:25])[N:56]([O:57][CH3:58])[CH3:55])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNOC
Reactant: COc1ccc(CS[C@@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(CS[C@@H]2C[C@@H](C(=O)N(C)OC)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
A solution of 5 g (13.6 mmol) (2S,4R)-4-(4-Methoxy-benzylsulfanyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 20-5620 in 150 ml CH2Cl2 was treated with 10.5 ml (95.2 mmol) N-methylmorpholine, 0.37 g (2.72 mmol) 1-hydroxybenzotriazole, 6.26 g (32.64 mmol) EDCI and 2.92 g (29.92 mmol) N,O-dimethylhydroxylamine hydrochloride. The reaction was stirred over night at room temperature and partitioned between aqueous 10% KHSO4/EtOAc (3×). The organic phases were washed with aqueous saturated NaCl and dried over Na2SO4. Purification by flash-chromatography on silica gel (Hexane/EtOAc 1:1) gave 3.6 g (62%) of (2S,4R)-4-(4-methoxy-benzylsulfanyl)-2-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, MS: 411 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[C:7]([F:32])=[C:8]([CH:29]=[CH:30][CH:31]=1)[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[CH:18]=2)[N:13]=[CH:12][N:11]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([N:23]1[CH2:24][CH2:25][CH2:26][CH:21]([O:20][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][C:16]=2[O:27][CH3:28])[N:13]=[CH:12][N:11]=[C:10]3[NH:9][C:8]2[CH:29]=[CH:30][CH:31]=[C:6]([Cl:5])[C:7]=2[F:32])[CH2:22]1)(=[O:3])[CH3:2]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCNC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(C(C)=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.3 %

Procedure:
Acetyl chloride (27 mg) was added to a solution of 4-(3-chloro-2-fluoroanilino)-6-(piperidin-3-yloxy)-7-methoxyquinazoline (starting material described in Example 22; 134 mg) and diisopropylethylamine (65 mg) in methylene chloride (5 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was adsorbed onto silica and purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 95/5). The fractions containing the required product were combined and evaporated to give the title product (0.07 g); 1H NMR Spectrum: (DMSO d6 at 373K) 1.52-1.62 (m, 1H), 1.80-1.94 (m, 2H), 2.00 (s, 3H), 2.06-2.15 (m, 1H), 3.43-3.64 (m, 3H), 3.82-4.04 (m, 4H), 4.58 (m, 1H), 7.20-7.29 (m, 2H), 7.42 (t, 1H), 7.59 (t, 1H), 7.93 (s, 1H), 8.40 (s, 1H), 9.30 (s, 1H); Mass Spectrum: (M+H)+ 445.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4].C([O-])([O-])=O.[Na+].[Na+].[Cl:21][CH2:22][C:23](Cl)=[O:24]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([NH:14][C:23](=[O:24])[CH2:22][Cl:21])[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1cc2ccc(N)cc2s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2ccc(NC(=O)CCl)cc2s1
Reaction time: 18 h

Procedure:
To a mixture of 6-amino-benzo[b]thiophene-2-carboxylic acid methyl ester (1.0 g, 4.83 mmol) and Na2CO3 (2.05 g, 19.3 mmol) in DMF (10 mL) was added chloroacetylchloride (460 μL, 5.79 mmol.). After stirring for 18 h, the mixture was diluted with EtOAc, filtered and concentrated. The residue was purified by column:chromatography (2:8; EtOAc:hexanes) to give a pale-white solid. MS (EI): cal'd (MH+) 284.01, exp (MH+) 284.15. Also retained ˜50.5% of impure fractions.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1ccc(C(=O)CCCCCBr)cc1OC
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C(=O)CCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1OC
Yield: 35.5 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.1 g) as starting compound, potassium carbonate (2.0 g) and 6-bromo-1-(3,4-dimethoxyphenyl)-1-hexanone (1.0 g) were reacted and treated in the same manner as in Example 172 to give 0.56 g of 4-amino-5-chloro-N-((1-(6-(3,4-dimethoxyphenyl)-6-oxohexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[Mg].[S:12](Cl)(Cl)=[O:13]>C1COCC1>[CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([S:12]([C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:10])[CH3:1])=[CH:4][CH:5]=2)=[O:13])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(Br)cc1
Reactant: O=S(Cl)Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CN(C)c1ccc(S(=O)c2ccc(N(C)C)cc2)cc1
Yield: 33 %

Procedure:
A Grignard reagent was conventionally prepared using 4-dimethylaminophenyl bromide, magnesium, and THF and further reacted with thionyl chloride, obtaining bis(4-dimethylaminophenyl) sulfoxide in a yield of 33%. A solution of 7.0 g (0.024 mol) of the thus obtained bis(4-dimethylaminophenyl) sulfoxide in 100 g of methylene chloride was cooled at -70° C. in a dry ice/methanol bath whereupon with stirring, 6.0 g (0.027 mol) of trimethylsilyl triflate was added dropwise thereto at less -60° C.
Reaction SMILES: [C:1]([NH:4][C:5]([CH:26]1[CH2:32][C@H:31]2[NH:33][C@H:28]([CH2:29][CH2:30]2)[CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[Cl:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][C:42]=1[Cl:43])[CH:38]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([NH:4][C:5]([CH:26]1[CH2:32][C@H:31]2[N:33]([CH2:38][C:37]3[CH:40]=[CH:41][C:42]([Cl:43])=[C:35]([Cl:34])[CH:36]=3)[C@H:28]([CH2:29][CH2:30]2)[CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:22])([CH3:23])[C:19]([CH3:24])([CH3:25])[O:18]1)[C:6]([NH:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1C[C@H]2CC[C@@H](C1)N2
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1C[C@H]2CC[C@@H](C1)N2Cc1ccc(Cl)c(Cl)c1
Reaction time: 24 h

Procedure:
A solution of 2-acetamido-2-{(1R,5S)-8-azabicyclo[3.2.1]octan-3-yl}-N-tert-butyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-hexanamide (170 mg, 0.37 mmol) and 3,4-dichlorobenzaldehyde (129 mg, 0.74 mmol) and acetic acid (44 mg, 41 μL, 0.74 mmol) in 1,2-dichloroethane (1 mL) was stirred at room temperature for 30 minutes then treated with sodium triacetoxyborohydride (196 mg, 0.93 mmol). After 24 hours, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL), diluted with saturated aqueous sodium chloride (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic phase was collected, dried over MgSO4, filtered and concentrated to give 2-acetamido-N-tert-butyl-2-{(1R,5S)-8-(3,4-dichlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-hexanamide as a pale yellow oil which was used immediately in the next step; m/z for C32H50BCl2N3O4 expected 621.3. found 644.5 (M+Na(35Cl))+, 622.1 (M+H(35Cl))+,
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][N:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[O:30][C:29]([CH3:32])([CH3:31])[O:28][C:27](=[O:33])[C:26]=2[CH:34]=1>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[N:14]=[CH:15][C:16]([CH2:17][NH:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][C:29]([CH3:31])([CH3:32])[O:28][C:27](=[O:33])[C:26]=4[CH:34]=3)=[CH:19][CH:20]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1(C)OC(=O)c2cc(N)ccc2O1
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cn2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cn2)cc1

Procedure:
The titled compound was prepared following the procedure A using 6-[(4-butylphenyl)ethynyl]nicotinaldehyde and 6-amino-2,2-dimethyl-benzo[1,3]dioxin-4-one as a yellow powder (22%). 1H NMR (CDCl3, 300 MHz) δ 8.61 (s, 1H), 7.66 (m, 1H), 7.48 (m, 3H), 7.16 (m, 3H), 6.87-6.76 (m, 2H), 4.36 (s, 2H), 2.61 (t, J=7.7 Hz, 2H), 1.69 (s, 6H), 1.66-1.54 (m, 2H), 1.41-1.28 (m, 2H), 0.92 (t, J=7.2 Hz, 3H). M− (ESI): 439.1; M+ (ESI): 441.4. HPLC, Rt: 4.55 min (Purity: 85.3%).
Reaction SMILES: CC(C)([O-])C.[K+].C(S)CC.[CH:11]1([CH2:17][C@@H:18]([NH2:34])[CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32]C)[CH2:22][CH2:21]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CN(C=O)C>[CH:11]1([CH2:17][C@@H:18]([NH2:34])[CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[OH:32])[CH2:22][CH2:21]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1ccccc1N1CCN(C[C@H](N)CC2CCCCC2)CC1
Agent: CC(C)(C)[O-]
Agent: CCCS
Agent: [K+]
Solvent: CN(C)C=O
Product: N[C@H](CC1CCCCC1)CN1CCN(c2ccccc2O)CC1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Potassium t-butoxide is added portionwise to a stirred solution of propanethiol in dry DMF under an argon atmosphere. After 0.5 h, a solution of {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-amine in dry DMF is added and the mixture is heated at 100° C. overnight. A further quantity of potassium t-butoxide and propanethiol is then added and the mixture heated at 100° C. for another 24 h. The cooled mixture is partitioned between water and ethyl acetate. The combined organic layers are washed with brine, dried and concentrated on a rotary evaporator to yield the desired product, which is purified by chromatography on alumina.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]1[C:18]2[C:13](=[C:14]([O:19][CH3:20])[N:15]=[CH:16][CH:17]=2)[N:12]([CH3:21])[CH:11]=1.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[OH:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[O:30][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]1[C:18]2[C:13](=[C:14]([O:19][CH3:20])[N:15]=[CH:16][CH:17]=2)[N:12]([CH3:21])[CH:11]=1
Reactant: Oc1ccc(F)cc1F
Reactant: COc1nccc2c(-c3cc(C=O)ccc3F)cn(C)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1nccc2c(-c3cc(C=O)ccc3Oc3ccc(F)cc3F)cn(C)c12
Yield: 88 %

Procedure:
A mixture of Example 95A (3.26 g, 11.47 mmol), 2,4-difluorophenol (1.492 g, 11.47 mmol) and cesium carbonate (4.11 g, 12.61 mmol) in dimethyl sulfoxide (40 mL) was heated at 100° C. for 3 hours. The reaction mixture was partitioned with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride twice, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 20 to 40% ethyl acetate in heptanes) to provide the title compound (3.98 g, 88%).
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N+:7]([O-:32])=[N:8][C:9]([O:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH3:5].C=O.O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[ClH:1].[CH2:2]([C:6]1[N+:7]([O-:32])=[N:8][C:9]([O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH3:36])[CH2:28][CH2:27]2)=[CH:10][C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:16][CH:17]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1c(-c2ccc(OC3CCCCC3)cc2)cc(OC2CCNCC2)n[n+]1[O-]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCc1c(-c2ccc(OC3CCCCC3)cc2)cc(OC2CCN(C)CC2)n[n+]1[O-]
Reaction time: 1.33 h
Yield: 89.9 %

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine 2-oxide hydrochloride (0.162 mmol, 74.8 mg) in DCM (1.5 mL) was added formaldehyde solution in water (37%, 0.5 mmol, 0.372 mL), and 1 drop of acetic acid. It was stirred for 80 min. and sodium triacetoxyborohydride (0.65 mmol, 145 mg, 95%) was added. The reaction mixture was stirred at room temperature for 80 min. and partitioned between ethyl acetate (8 mL) and saturated aq. sodium bicarbonate solution (8 mL). The ethyl acetate layer was separated and dried over sodium sulfate. The organic solvent was removed in vacuo and the residue was dissolved in DCM and treated with 4 N HCl in dioxane. The organic solvents were removed in vacuo and the residue was triturated with anhydrous diethyl ether and hexanes. The off-white solid was dried overnight under high vacuum to provide the title compound (69.3 mg). LCMS: m/z 441 [M+1] 1H NMR (400 MHz, CD3OD) δ 7.28-7.32 (2H, m), 7.05-7.07 (2H, m), 6.79 and 6.88 (1H, s), 5.15-5.34 (1H, m), 4.38-4.43 (1H, m), 3.23-3.65 (4H, m), 2.92 (3H, s), 2.80-2.84 (2H, m), 2.47-2.56 (1H, m), 2.38 (1H, d), 2.08-2.21 (1H, m), 1.89-2.05 (3H, m), 1.81 (2H, m), 1.21-1.66 (10H, m) 0.82 (3H, t).