Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH3:17][NH2:18]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6]([NH:18][CH3:17])=[O:7]
Reactant: CN
Reactant: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1OC
Solvent: ClCCl
Product: CNC(=O)c1cc(OC)c(OC)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a stirred solution of 3,4-dimethoxy-5-nitro-benzoyl chloride (0.50 g, 2.04 mmol) in dichloromethane (10 mL) at 0° C., was added dropwise methylamine (1.02 mL, 2.04 mmol, 2 M in THF). The reaction mixture was stirred at room temperature till all starting material disappeared, then diluted with dichloromethane and washed with water. The organic phase was dried over anhydrous magnesium sulphate, filtered and evaporated to dryness to leave a crude residue that was recrystallised from a dichloromethane/isopropanol mixture to afford 3,4-dimethoxy-N-methyl-5-nitro-benzamide, 0.44 g (89%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:11][C:12]1[N:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]3[C:24]([C:27]([NH:29][C:30]4[CH:35]=[C:34]([C:36](=[O:47])[NH:37][CH2:38][C:39]5[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=5)[CH:33]=[CH:32][C:31]=4[F:48])=[O:28])=[CH:25][N:26]=[C:20]3[CH:19]=2)=[CH:14][CH:13]=1.Cl>C1(C)C=CC=CC=1.CO.C(OCC)C>[ClH:11].[F:46][C:41]1[CH:40]=[C:39]([CH:44]=[CH:43][C:42]=1[F:45])[CH2:38][NH:37][C:36]([C:34]1[CH:33]=[CH:32][C:31]([F:48])=[C:30]([NH:29][C:27]([C:24]2[N:21]3[CH:22]=[CH:23][C:18]([C:15]4[CH:16]=[N:17][C:12]([O:8][CH2:7][CH2:6][N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[CH:13][CH:14]=4)=[CH:19][C:20]3=[N:26][CH:25]=2)=[O:28])[CH:35]=1)=[O:47]
Reactant: OCCN1CCCC1
Reactant: O=C(NCc1ccc(F)c(F)c1)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccc(Cl)nc4)ccn23)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOCC
Product: O=C(NCc1ccc(F)c(F)c1)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccc(OCCN5CCCC5)nc4)ccn23)c1
Temperature: 60 °C

Procedure:
A solution of 2-(pyrrolidin-1-yl)ethanol (30.5 mg, 0.265 mmol) and sodium hydride (6.36 mg, 0.265 mmol) in toluene (442 μl) was stirred at RT for 30 mins and treated with 7-(6-chloropyridin-3-yl)-N-(5-(3,4-difluorobenzylcarbamoyl)-2-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (step 1). The reaction mixture was heated at 60° C. for 1 hour and the reaction was quenched with wet MeOH. Purification of the mixture by chromatography on silica eluting with 0-20% (2M NH3 in MeOH)/DCM afforded a yellow solid. The solid was dissolved in MeOH and treated with 2M HCl in diethyl ether (1 eq). The solvent was removed in vacuo and purification of the crude product by chromatography on silica eluting with 2M NH3 in MeOH/TBME afforded a solid. The solid was treated again with 2M HCl in diethyl ether and concentrated in vacuo to afford the title compound;
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH2:32]1[C:42]2=[C:43]3[C:38](=[CH:39][CH:40]=[CH:41]2)[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[C:34]3[CH2:33]1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:33]1[C:34]2=[C:43]3[C:38](=[CH:37][CH:36]=[CH:35]2)[C:39]([C:2]2[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[N:3]=2)=[CH:40][CH:41]=[C:42]3[CH2:32]1
Reactant: CC1(C)OB(c2ccc3c4c(cccc24)CC3)OC1(C)C
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc2c3c(cccc13)CC2
Yield: 36.1 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.081 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 g; 0.025 mmol), N,N-diisopropylethylamine (0.172 mL; 1.00 mmol) and 2-(1,2-dihydroacenaphthylen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.105 g; 0.375 mmol) in DME-water (1 mL) for 20 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-10%) in heptane furnished 0.040 g (36%) of the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH:13]1([C:16]2[C:17]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=2)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:26]2[CH2:27][CH2:28][N:23]([C:17]3[C:16]([CH:13]4[CH2:15][CH2:14]4)=[CH:21][C:20]([CH3:22])=[CH:19][N:18]=3)[CH2:24][CH2:25]2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: Cc1cnc(N2CCNCC2)c(C2CC2)c1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C2CC2)c1
Yield: 54.6 %

Procedure:
Using 4-bromo-2-fluorobenzoyl chloride (2.6 g) and 1-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine hydrochloride (2.8 g) described in Preparation Example 85 and by the reaction and treatment in the same manner as in Preparation Example 108, the title compound (2.5 g) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:54])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH:35]([CH2:41][CH2:42]OS(C4C=CC(C)=CC=4)(=O)=O)[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].CC(C)([O-])C.[K+].Cl>O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2[C:17](=[O:54])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][C:35]4([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:42][CH2:41]4)[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:13][CH:14]=1)#[N:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(CCOS(=O)(=O)c3ccc(C)cc3)C(=O)OCC)CC2)c2ncnn12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC3(C(=O)OCC)CC3)CC2)c2ncnn12
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
A mixture of ethyl 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-4-{[(4-methylphenyl)sulfonyl]oxy}butanoate (0.45 g), potassium tert-butoxide (0.26 g) and tetrahydrofuran (20 mL) was stirred at −10° C. for 10 min. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was 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, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.19 g, 55%).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]([C:11]2[N:12]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=3)=[CH:9][CH:10]=1)=[O:5])C.Cl>O1CCOCC1.[OH-].[Li+]>[C:4]([C:6]1[O:7][C:8]([C:11]2[N:12]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=3)=[CH:9][CH:10]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(-c2cc3cc(S(C)(=O)=O)ccc3n2Cc2ccc(F)cc2)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc2c(c1)cc(-c1ccc(C(=O)O)o1)n2Cc1ccc(F)cc1
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a solution of the compound obtained in Example 29 (4) (0.0306 g) in 1,4-dioxane (0.5 ml), 10% lithium hydroxide aqueous solution (0.5 ml) was added at −5° C. under argon atmosphere and the mixture was stirred for 2 hours. To the reaction solution was then added 10% hydrochloric acid and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 0.0285 g of the desired product as a white powder.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](CC)([O-])=O.[N+](C)([O-])=O>[F:8][C:9]1[CH:15]=[CH:14][C:12]2[NH:13][C:6](=[O:7])[NH:5][S:2](=[O:4])(=[O:3])[C:11]=2[CH:10]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: CC[N+](=O)[O-]
Product: O=C1Nc2ccc(F)cc2S(=O)(=O)N1
Temperature: -80 °C
Reaction time: 0.17 h

Procedure:
After dissolving chlorosulfonyl isocyanate (3.29 mL, 37.8 mmol) in nitroethane (45 mL), the mixture was cooled to −80° C. A solution of 4-fluoroaniline (3.50 g, 31.5 mmol) in nitromethane (5 mL) was then added dropwise thereto over a period of 10 minutes. The reaction mixture was heated to 0° C., and aluminum chloride (5.33 g, 40.0 mmol) was added. After heating to reflux for 30 minutes, the reaction mixture was cooled to room temperature and then poured into ice water (120 mL). The precipitated crystals were filtered out and dried to obtain 7-fluoro-2H,4H-benzo[e]1,2,4-thiadiazine-1,1,3-trione.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]([OH:15])=O)[CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1([NH2:25])[CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.CO.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:13](=[O:15])[NH:25][C:22]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=3)[CH2:24][CH2:23]2)[CH2:10][O:11][CH2:12]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)COC1
Reactant: NC1(c2ccccn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(=O)NC2(c3ccccn3)CC2)COC1
Yield: 104.2 %

Procedure:
A solution of 3-tert-butoxycarbonylamino-oxetane-3-carboxylic acid (82 mg, 0.38 mmol), 1-pyridin-2-yl-cyclopropylamine (56 mg, 0.42 mmol), HATU (215 mg, 0.57 mmol), and triethylamine (77 μL, 0.57 mmol) in DMF (0.5 mL) was stirred at room temperature for 29 h. Water (0.2 mL) and MeOH (1 mL) were added, and the resulting clear solution was purified directly by reverse phase HPLC to give [3-(1-pyridin-2-yl-cyclopropylcarbamoyl)-oxetan-3-yl]-carbamic acid tert-butyl ester as a tan solid (132 mg, >100%) after lyophilization, m/z 334.8 [M+1]+, that was carried on without further purification.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])C.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[O:3]=[CH:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CCOC(=O)CC1CCCN1C(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1CC=O
Temperature: -80 °C
Reaction time: 2 h

Procedure:
Into a 3,000 ml 3-necked roundbottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of tert-butyl 2-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate (119 g, 463 mmol) in dichloromethane (1,200 ml). The solution was cooled to −80° C. and diisobutylaluminum hydride (362 g, 510 mmol) was added dropwise, while maintaining an internal temperature of −80° C. (3 hours total addition time). The resulting solution was allowed to stir for 2 hours while the temperature was maintained at −80° C. The reaction mixture was then quenched by the adding 500 ml of methanol. After warming to ambient temperature, the mixture was washed with 1,000 ml of NaOH (20% w/w aqueous) and 6 times with 1,000 ml of water. The organic layer was dried over sodium sulfate, filtered and concentrated to afford tert-butyl 2-(2-oxoethyl)pyrrolidine-1-carboxylate, which was used without additional purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1.B(F)(F)F.[CH3:17][CH2:18][O:19]CC.C(OCC)(=O)C>ClCCl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH2:17][CH2:18][OH:19])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(COCCO)cc1
Temperature: -5 °C
Reaction time: 0.58 h
Yield: 60329.8 %

Procedure:
To a flame-dried 2-neck flask was added a solution of methyl-4-(hydroxymethyl)benzoate (2.5 g, 15 mmol) in dichloromethane (30 mL). The reaction was purged with nitrogen and brought to −5° C. A dewar condenser (also flame-dried) containing a dry ice/acetone bath (−78° C.) was affixed to the flask and ethylene oxide-tetradeuterate was added (˜55 drops). Then BF3.Et2O (510 μL, 0.0041 mmol) was added dropwise and the reaction stirred at −5° C. for 35 minutes under nitrogen atmosphere. Monitoring by TLC (100% ethyl acetate) showed complete consumption of the starting material. The reaction was warmed to room temperature and vented to remove any excess ethylene oxide gas. The reaction was then diluted with brine and extracted with dichloromethane (2 times). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude oil. Purification by flash column chromatography (4:1 pentane:ethyl acetate) provided the product as a clear oil (520 mg, 16% yield). 1H NMR (600 MHz, CDCl3) δ 8.02 (d, 2H, J=8.2 Hz), 7.41 (d, 2H, J=8.1 Hz), 4.62 (s, 2H), 3.92 (s, 3H); 13C NMR (150 MHz, CDCl3167.1, 143.5, 130.8) δ 129.9, 127.5, 72.8, 52.4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[CH2:18][CH2:17]2)=[O:15])=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30].C(=O)(O)[O-].[Na+]>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.COCCOC>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:38]=[CH:39][C:40]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C:14]([N:16]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[CH3:28])[CH2:18][CH2:17]4)=[O:15])=[CH:6][CH:7]=3)=[CH:41][CH:42]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: Cc1ccccc1N1CCN(C(=O)c2c(C)noc2-c2ccc(Br)cc2)CC1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)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: COCCOC
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)N4CCN(c5ccccc5C)CC4)cc3)cc2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-(4-o-tolyl-piperazin-1-yl)-methanone (0.156 g, 0.36 mmol), 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester (0.168 g, 0.53 mmol), tetrakis(triphenylphosphine)palladium(0) (0.042 g, 0.04 mmol), and sodium bicarbonate (0.076 g, 0.90 mmol) were combined in 3:1 DME:H2O, and the mixture was purged with N2 (g). The reaction was stirred at 80° C. for 1 hour and then cooled and concentrated. The crude material was purified by silica gel chromatography (0-40% EtOAc in hexanes) to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([Cl:15])=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:10]=1)=[O:4].[CH3:16][CH:17]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(=O)CC>[Cl:15][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH2:2][N:26]([CH:17]([CH3:16])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:10][C:9]=1[S:11]([NH2:14])(=[O:13])=[O:12]
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Reactant: CC(CCc1ccccc1)NCc1ccccc1
Solvent: CCC(C)=O
Product: CC(CCc1ccccc1)N(Cc1ccccc1)CC(O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reaction time: 0.5 h

Procedure:
A mixture of 5-(2-bromoacetyl)-2-chlorobenzenesulphonamide (3.13 g) in butanone (50 ml) and N-(1-methyl-3-phenylpropyl)-N-(phenylmethyl)amine (4.8 g) was heated under reflux for 30 minutes. The solvent was removed under reduced pressure and the residue triturated with dry ether and filtered. The ether solution was evaporated to dryness and the product dissolved in ethanol (50 ml) and treated with sodium borohydride (0.3 g). The mixture was stirred for 30 minutes and a further aliquot of sodium borohydride (0.3 g) was added. The reaction mixture was acidified with 2N hydrochloric acid and the ethanol removed under reduced pressure. The concentrate was bastified with 5N sodium hydroxide and the mixture extracted with ethyl acetate (2 × 50 ml). The extracts were washed with water (2 × 50 ml), dried (MgSO4) and evaporated to dryness to give the product as a yellow oil, 4.6 g. This oil was purified by chromatography on preparative chromatographic plates (silica, CHCl3 /5% MeOH) and converted into a hydrochloride salt m.p. 120-125°.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:1]1([C@H:7]2[CH2:8][CH2:9][C@H:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C=C1CCC(c2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C[C@H]1CC[C@H](c2ccccc2)CC1
Reaction time: 2 h

Procedure:
The product of Example 1A (6.00 g, 24.7 mmol) was dissolved in 60 mL of ethanol and 10% Pd/C was added (600 mg). The reaction mixture was placed in a Par shaker at 60 psi for 2 h. After this time, the catalyst was filtered, and the solvents evaporated to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.05-1.22 (m, 2 H), 1.22-1.30 (m, 3 H), 1.43-1.59 (m, 2 H), 1.64-1.75 (m, 2 H), 1.86-1.96 (m, 3 H), 2.24 (d, J=6.44 Hz, 2 H), 2.40-2.49 (m, 1 H), 4.15 (q, J=7.35 Hz, 2 H), 7.17-7.23 (m, 3H): 7.24-7.33 (m, 2 H): MS (ESI) m/z 247 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:36]=[CH:35][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[O:34]=[S:30]1(=[O:33])[CH2:31][CH2:32][N:27]([CH2:26][C:25]2[CH:35]=[CH:36][C:22]([NH:20][C:18]3[N:19]=[C:12]4[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)=[CH:16][CH:15]=[CH:14][N:13]4[N:17]=3)=[CH:23][CH:24]=2)[CH2:28][CH2:29]1
Reactant: O=S1(=O)CCN(Cc2ccc(Br)cc2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(CN5CCS(=O)(=O)CC5)cc4)nc23)cc1

Procedure:
To a well stirred suspension of thiomorpholine 1,1-dioxide (0.36 g, 2.7 mmol) and potassium carbonate (0.37 g, 2.7 mmol) in acetone (5 mL) was added 1-bromo-4-chloromethyl-benzene (0.50 g, 2.4 mmol). The mixture was stirred for 48 hours at room temperature. The mixture was filtered and the volatiles were evaporated. The residue was suspended in ether (100 mL), filtered and evaporated to a solid. The material was purified via chromatography utilizing an ISCO automated purification apparatus (24 g silica gel column 10%→100% ethyl acetate in hexane). 4-(4-Bromo-benzyl)-thiomorpholine 1,1-dioxide was isolated as a white solid (0.72 g, 97%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.47 (d, J=7.6 Hz, 2H), 7.19 (d, J=7.7 Hz, 2H), 3.60 (s, 2H), 3.08-2.94 (m, 8H). MS=304, 306 (MH)+. 114b) N-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-8-[4-(methylsulfonyl)phenyl][1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 4-(4-bromo-benzyl)-thiomorpholine 1,1-dioxide (90.0 mg, 0.296 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.039 g, 29%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.50 (d, J=6.7 Hz, 1H), 8.23 (d, J=7.4 Hz, 2H), 8.09 (d, J=8.0 Hz, 2H), 7.67 (d, J=6.9 Hz, 1H), 7.56 (d, J=7.2 Hz, 2H), 7.29 (d, J=7.8 Hz, 2H), 7.04 (t, J=7.2 Hz, 1H), 6.94 (s, 1H), 3.62 (s, 2H), 3.10 (s, 3H), 3.08-3.03 (m, 4H), 3.02-2.97 (m, 4H). MS=512 (MH)+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCC(C(O)=O)CC1.Cl.N[C@H](C(C)C)C(N[C:40]1[CH:41]=[N:42][C:43]([O:46]C2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[CH:44][CH:45]=1)=O.NC1C=CC(OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=NC=1.NC1C=CC=NC=1>>[C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH:24][C:43]([CH:44]5[CH2:45][CH2:40][CH2:41][NH:42]5)=[O:46])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: CC(C)[C@@H](N)C(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Agent: Cl
Agent: Nc1cccnc1
Agent: O=C(O)C1CCNCC1
Product: O=C(Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1)C1CCCN1

Procedure:
Pyrrolidine-2-carboxylic acid [6-(2-phenylchroman-6-yloxy)pyridin-3-yl]amide and its derivatives were prepared as described for piperidine-4-carboxylic acid [6-(2-phenylchroman-6-yloxy)pyridine-3-yl]amine in Example 19 a) and b) but replacing N-(tert-butoxycarbonyl)isonipecotic acid with (S),(R) or (R,S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and 5-amino-2-(2-phenylchroman-6-yloxy)-pyridine by an appropriate 5-aminopyridine derivatives.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]([O:9][C:10](=[O:32])[NH:11][CH2:12][C@H:13]([OH:31])[CH2:14][NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([F:25])[CH:24]=1)[N:21]([CH2:26][CH:27]1[CH2:29][CH2:28]1)[C:20](=[O:30])[CH2:19]2)([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>ClCCl>[C:5]([O:9][C:10](=[O:32])[NH:11][CH2:12][C@@H:13]1[O:31][C:1](=[O:2])[N:15]([C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([F:25])[CH:24]=2)[N:21]([CH2:26][CH:27]2[CH2:28][CH2:29]2)[C:20](=[O:30])[CH2:19]3)[CH2:14]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC[C@H](O)CNc1cc(F)c2c(c1)CC(=O)N2CC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H]1CN(c2cc(F)c3c(c2)CC(=O)N3CC2CC2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Phosgene (20% solution in toluene, 1.50 ml, 14.1 mmol) is added to (R)-[3-(1-cyclopropylmethyl-7-fluoro-2-oxo-2,3-dihydro-1H-indol-5-ylamino)-2-hydroxy-propyl]-carbamic acid tert-butyl ester (0.74 g, 1.88 mmol) and triethylamine (0.95 ml, 9.41 mmol) in dichloromethane (15 ml) at 0° C. and then stirred at 0° C. for 20 minutes. The mixture is diluted with dichloromethane, washed with water and brine, dried (Na2SO4) and evaporated. The residue is purified by flash column chromatography (70% ethyl acetate/hexane) to give the title compound as a white solid. HPLC r.t. 5.39 min; MS for C21H26FN3O5 m/z 420.1 (M+H)+.