Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[Si:38](Cl)([CH2:43][CH3:44])([CH2:41][CH3:42])[CH2:39][CH3:40]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:26][Si:38]([CH2:43][CH3:44])([CH2:41][CH3:42])[CH2:39][CH3:40])([C:18]([F:19])([F:20])[F:21])[C:22]([F:25])([F:23])[F:24])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: OC(c1ccc2c(ccn2Cc2ccccc2)c1)(C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC[Si](CC)(CC)OC(c1ccc2c(ccn2Cc2ccccc2)c1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
A solution of 6.72 g (18 mmol) 2-(1-benzyl-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (example 16) in DMF was treated with 4.03 mL (27.0 mmol) of DBU and at 0° C. then dropwise with 4.12 mL (27 mmol) TESCl. The mixture was stirred for 2 hrs at RT and the solvent was evaporated. Column chromatography on silicagel with n-heptane/EtOAc 6:1 yielded 7.7 g (88%) of 1-benzyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-1H-indole, light yellow oil, MS: 489 (MH+).
Reaction SMILES: C(OC(N[C@@H]1CCNC[C@@H]1C(OC)=O)=O)C1C=CC=CC=1.C(N(CC)C(C)C)(C)C.BrCCO.[CH2:35]([O:42][C:43]([NH:45][C@@H:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][OH:54])[CH2:48][C@@H:47]1[C:55]([O:57][CH3:58])=[O:56])=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:42][C:43]([NH:45][C@@H:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][OH:54])[CH2:48][C@H:47]1[C:55]([O:57][CH3:58])=[O:56])=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)[C@H]1CN(CCO)CC[C@H]1NC(=O)OCc1ccccc1
Agent: COC(=O)[C@H]1CNCC[C@H]1NC(=O)OCc1ccccc1
Agent: OCCBr
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CN(CCO)CC[C@H]1NC(=O)OCc1ccccc1
Yield: 60 %

Procedure:
Methyl(3S,4R)-4-{[(benzyloxy)carbonyl]amino}piperidine-3-carboxylate (WO 2005/066176) (2.0 g, 6.84 mmol), N,N-diisopropylethylamine (1.8 mL, 10.26 mmol) and 2-bromoethanol (0.63 mL, 8.9 mmol) were reacted as described for Intermediate 37 to give 1.38 g (60%) of the product as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:10]2)[N:3]=1.C([O-])(=[O:23])C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][C@@H:9]([NH:8][C:4]3[N:5]=[CH:6][NH:7][C:2](=[O:23])[N:3]=3)[CH2:10]2)=[CH:15][CH:16]=1
Reactant: CC(=O)[O-]
Reactant: Fc1ccc(N2CC[C@@H](Nc3ncnc(Cl)n3)C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=c1nc(N[C@@H]2CCN(c3ccc(F)cc3)C2)nc[nH]1
Yield: 15 %

Procedure:
To (R)-4-chloro-N-[1-(4-fluorophenyl)pyrrolidin-3-yl]-1,3,5-triazin-2-amine synthesized in Reference Synthesis Example 337, sodium acetate (153 mg, 1.11 mmol), acetic acid (2.0 mL), and water (0.40 mL) were added and the resultant mixture was stirred at 90° C. for 5 hours. After completion of the reaction, the reaction solution was added to saturated sodium bicarbonate aqueous solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure and the obtained solid was washed with ethyl acetate to obtain the title compound (65.0 mg, two step yield 15%).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:14]=2[CH:15]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.O1CCOCC1>[Br:20][C:17]1[CH:18]=[CH:19][C:13]2[O:12][C:11]([CH:3]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[OH:10])=[CH:15][C:14]=2[CH:16]=1
Reactant: O=C(c1ccccc1)c1cc2cc(Br)ccc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OC(c1ccccc1)c1cc2cc(Br)ccc2o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4 g of sodium borohydride dissolved in the minimum quantity of water are slowly added at ambient temperature to 8.5 g of 2-benzoyl-5-bromobenzofuran in 50 ml of dioxane. When the addition is finished, the mixture is kept stirring at ambient temperature for a further 3 hours. The solvent is removed under reduced pressure, the residue is redissolved in 50 ml of water, and extracted with ethyl ether. The ether phase is dried with anhydrous sodium sulphate, evaporated to dryness, and leaves a residue which on crystallising from cyclohexane has a M.P. of 56°-58° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[I:9]Cl.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][N:4]=1
Reactant: ClI
Reactant: CNc1ccccn1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CNc1ccc(I)cn1
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
2-(N-Monomethylamino)pyridine (98, 1.00 g, 5.55 mmol) was dissolved in dichloromethane (20 mL) and a 1 M iodine monochloride (ICl, 6.10 mL, 6.10 mmol) dichloromethane solution was slowly added at 0° C., and stirred for 30 minutes. To the reaction mixture was added a 10% aqueous solution of sodium sulfite (Na2S2O3) and organic compounds were extracted with dichloromethane and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 2-(N-monomethylamino)-5-iodopyridine (99, 800 mg, 62%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][C:10]1([C:41]1[CH:46]=[C:45]([CH:47]([C:49]2[CH:54]=[CH:53][C:52]([Br:55])=[CH:51][CH:50]=2)O)[C:44]([CH3:56])=[CH:43][C:42]=1[O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C(#N)C>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][C@H:10]1[C:41]1[CH:46]=[C:45]([CH2:47][C:49]2[CH:50]=[CH:51][C:52]([Br:55])=[CH:53][CH:54]=2)[C:44]([CH3:56])=[CH:43][C:42]=1[O:57][CH2:58][C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCc2ccccc2)c(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C(O)c1ccc(Br)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CCOCC
Product: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 50.9 %

Procedure:
To an acetonitrile solution (60 mL) of 2,3,4,6-tetra-O-benzyl-1-C-[2-(benzyloxy)-5-[(4-bromophenyl)(hydroxy)methyl]-4-methylphenyl]-D-glucopyranose (5.50 g, 5.96 mmol) were added under nitrogen atmosphere at −10° C. Et3SiH (2.90 mL, 17.8 mmol) and BF3.Et2O (1.90 mL, 14.9 mmol), and the mixture was stirred for 15 minutes at the same temperature and the mixture was stirred for 2.5 hours at room temperature. To the reaction solution cooled in ice was added a saturated sodium bicarbonate aqueous solution and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=15:1 to 10:1) to obtain the title compound (2.70 g, 51%) as a pale yellow oily compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH:9]([CH3:28])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:14]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[B:30]1(B2OCC(C)(C)CO2)[O:35]CC(C)(C)C[O:31]1.CC([O-])=O.[K+].CS(C)=O>O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH3:8][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:29])[CH:9]([CH3:28])[C:10]([NH:12][C:13]1[N:14]=[C:15]([C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]([B:30]([OH:35])[OH:31])=[CH:17][CH:18]=1)=[O:11]
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Reactant: CC(C(=O)Nc1ccc(Br)c(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C(=O)Nc1ccc(B(O)O)c(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 39 h

Procedure:
A mixture of tert-butyl-N-[1-[[5-bromo-6-(2-phenylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]-N-methylcarbamate C2a (2.5 g, 5.45 mmol), bis(neopentyl glycolato)diboron (2.46 g, 10.9 mmol), KOAc (1.61 g, 16.4 mmol), 1,1′-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (399 mg, 0.55 mmol) and DMSO (20 ml) is stirred under argon atmosphere for 39 h at 65° C. The mixture is diluted with water and extracted with DCM. The combined organic layers are dried over MgSO4, concentrated in vacuo and the product purified by RP HPLC. Yield: 1.73 g (75%). HPLC-MS: M+H=424; tR=1.59 min (*Method—5).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]12[CH2:14][N:13]([S:15]([C:18]3[CH:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH2:12][CH2:11][C:10]1=[CH:9][C:8]1[N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[N:26]=[CH:27][C:7]=1[CH2:6]2)=[O:4].[NH:35]1[CH2:38][CH2:37][CH2:36]1>>[CH3:1][O:2][C:3]([C@@:5]12[CH2:14][N:13]([S:15]([C:18]3[CH:19]=[N:20][C:21]([N:35]4[CH2:38][CH2:37][CH2:36]4)=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH2:12][CH2:11][C:10]1=[CH:9][C:8]1[N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[N:26]=[CH:27][C:7]=1[CH2:6]2)=[O:4]
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reactant: C1CNC1
Product: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCC3)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 4b using (R)-6-(6-chloropyridine-3-sulfonyl)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triazacyclopenta[b]na-phthalene-4a-carboxylic acid methyl ester and azetidine. LCMS (Method B): 524 (M+H)+, Retention time 3.5 minutes.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6](=[O:15])[N:5]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:4](=[O:23])[C:3]=1[N:24]=O.C1(CN2C(N)=C(N)C(=O)N(CC3CCCCC3)C2=O)CCCCC1.[CH:50]([C:52]1[CH:53]=[C:54]([CH:60]=[CH:61][CH:62]=1)[CH:55]=[CH:56][C:57]([OH:59])=[O:58])=O>>[CH:17]1([CH2:16][N:5]2[C:4](=[O:23])[C:3]3[N:24]=[C:50]([C:52]4[CH:53]=[C:54]([CH:60]=[CH:61][CH:62]=4)/[CH:55]=[CH:56]/[C:57]([OH:59])=[O:58])[NH:1][C:2]=3[N:7]([CH2:8][CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[C:6]2=[O:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Nc1c(N=O)c(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Reactant: O=Cc1cccc(C=CC(=O)O)c1
Agent: Nc1c(N)n(CC2CCCCC2)c(=O)n(CC2CCCCC2)c1=O
Product: O=C(O)/C=C/c1cccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)c1
Yield: 49 %

Procedure:
As in part (d) of Example, 1, 6-amino 1,3-bis(cyclohexylmethyl)-5-nitrosouracil (from step (c) example 1, 2.79 g, 8.00 mmol) was reduced to 1,3-bis(cyclohexylmethyl)-5,6-diaminouracil, and condensed with 3-Formylcinnamic acid (T. Higa, A. J. Krubsack, J. Org. Chem. 1975, 40: 3037–3045, 1.424 g) to give (E)-3-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]cinnamic acid as an off-white solid (1.947 g, 49%), m.p. >350° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6].[C:15]1([CH3:27])[CH:20]=[CH:19][C:18]([S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:15]1([CH3:27])[CH:16]=[CH:17][C:18]([S:21]([NH:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=2)[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6])=[O:26])(=[O:22])=[O:23])=[CH:19][CH:20]=1
Reactant: CCCCOC(=O)c1cccc(N)c1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: Cc1ccccc1
Product: CCCCOC(=O)c1cccc(NC(=O)NS(=O)(=O)c2ccc(C)cc2)c1

Procedure:
In a three-necked flask equipped with a dropping funnel, a thermometer and a reflux condenser 15.4 g of n-butyl 3-aminobenzoate was placed and 150 ml of toluene was added thereto with stirring to dissolve n-butyl 3-aminobenzoate therein. With stirring the resultant mixture by a magnetic stirrer, 17.3 g of p-toluenesulfonylisocyanate was added dropwise to the mixture through the dropping funnel at room temperature. Continuous stirring of the reaction mixture caused an exothermic reaction, thereby precipitating a large amount of white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([NH:24][CH2:25][CH:26]=[CH2:27])[C:20](OC)=[O:21])=[CH:15][CH:14]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:20](=[O:21])[CH:19]([C:16]3[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=3)[N:24]([CH2:25][CH:26]=[CH2:27])[C:10]2=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: C=CCNC(C(=O)OC)c1ccc(O)cc1
Solvent: C1CCOC1
Product: C=CCN1C(=O)N(c2ccc(Cl)c(Cl)c2)C(=O)C1c1ccc(O)cc1
Yield: 54 %

Procedure:
1.1 equivalent of 3,4-dichlorophenyl isocyanate is added to a solution of 3.5 g of methyl 2-(4-hydroxyphenyl)-2-(2-propenyl)aminoacetate in 50 mL of anhydrous THF in a 50 mL flask equipped with a magnetic stirrer, under nitrogen. After heating under reflux for 4 hours, the product is concentrated then crystallised in isopropyl ether. The solid is filtered and washed with isopropyl ether to yield 3.2 g of white powder (Yd=54%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH:7]([CH2:10][CH3:11])[CH2:8][OH:9])[CH2:4][OH:5])[CH3:2].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:12]([O:9][CH2:8][CH:7]([CH2:10][CH3:11])[CH2:6][CH:3]([CH2:1][CH3:2])[CH2:4][OH:5])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCBr
Reactant: CCC(CO)CC(CC)CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CCCCCCCCCOCC(CC)CC(CC)CO
Temperature: 75 °C
Reaction time: 6 h

Procedure:
Under nitrogen stream, to a 2-L reactor provided with a stirrer, thermometer, condenser and gas inlet tube, 320 g (2 mol) of 2,4-diethyl-1,5-pentanediol, 311 g (1.5 mol) of n-nonylbromide and 12 g of tetrabutylammonium bromide were put, to which 532 g of 52 mass/volume % aqueous sodium hydroxide was added and heated at 70 to 80 degrees C. for six hours with stirring. After the reaction, the mixture was cooled and left still overnight to deposit white crystal. A liquid layer is transferred to a separating funnel by decantation. The white crystal was washed with 20 mL of hexane. The washing liquid of hexane was added to the liquid layer.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:6]=1[CH2:22][N:23]([CH2:34][C:35]([O:37][CH3:38])=[O:36])S(C1C=CC(C)=CC=1)(=O)=O)=O.C[O-].[Na+].Cl>CO>[CH3:38][O:37][C:35]([C:34]1[C:3]([OH:2])=[C:5]2[C:6](=[CH:22][N:23]=1)[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:8](=[O:12])[C:9]([Br:11])=[CH:10]2)=[O:36]
Reactant: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccc(OC)cc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
5-Bromo-1-(4-methoxy-benzyl)-2-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2.03 g, 3.34 mmol) was dissolved in 80 mL of MeOH and placed in ice bath. NaOMe solution (2.3 mL, 10.0 mmol, 4.375 M in MeOH) was added and the mixture was stirred for 16 h at r.t. 0.1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-20% EtOAc/CH2Cl2) to give 1.02 g of the title compound as an off-white solid. MS: (+) m/z 419.19, 421.14 (M+1, 79/81Br).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[C:20]([C:22]1[O:26][C:25]([C:27](Cl)=[O:28])=[CH:24][CH:23]=1)#[N:21].CCN(C(C)C)C(C)C>>[CH3:12][S:9]([N:8]([CH3:13])[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:27]([C:25]2[O:26][C:22]([C:20]#[N:21])=[CH:23][CH:24]=2)=[O:28])=[C:3]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[CH:4]=1)(=[O:11])=[O:10]
Reactant: CN(c1ccc(N)c(N2CCCCC2)c1)S(C)(=O)=O
Reactant: N#Cc1ccc(C(=O)Cl)o1
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccc(NC(=O)c2ccc(C#N)o2)c(N2CCCCC2)c1)S(C)(=O)=O
Yield: 23 %

Procedure:
Using a procedure similar to Example 23, step (a), N-methyl-N-(4-nitro-3-piperidin-1-yl-phenyl)-methanesulfonamide (89 mg, 0.28 mmol) was stirred with 5% Pd—C (55 mg) under H2 to afford 72 mg (91%) of N-(4-Amino-3-piperidin-1-yl-phenyl)-N-methyl-methanesulfonamide as an oil. Using a procedure similar to Example 4, step (c), N-(4-amino-3-piperidin-1-yl-phenyl)-N-methyl-methanesulfonamide was coupled to 5-cyano-furan-2-carbonyl chloride (77 mg, 0.49 mmol) in the presence of DIEA (107 μL, 0.55 mmol) to afford 26.2 mg (23%) of the title compound as a yellow powder. 1H-NMR (DMSO-d6, 400 MHz): δ 9.66 (s, 1H), 8.10 (d, 1H, J=8.7 Hz), 7.81 (d, 1H, J=3.8 Hz), 7.52 (d, 1H, J=3.7 Hz),), 7.26 (d, 1H, J=2.8 Hz), 7.21-7.19 (m, 1H), 3.23 (s, 3H), 2.95 (s, 3H), 2.84-2.82 (m, 4H), 1.72 (br s, 4H), 1.57 (br s, 2H); Mass spectrum (ESI, m/z): Calcd. for C19H22N4O4S, 403.1 (M+H), found 403.1.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]([OH:17])=O>C1(C)C=CC=CC=1>[CH3:5][C:6]1[CH:14]=[CH:13][C:12]2=[N:11][N:10]3[C:9]([C:15](=[O:17])[N:10]4[N:11]=[C:12]5[C:8]([CH:7]=[C:6]([CH3:5])[CH:14]=[CH:13]5)=[C:9]4[C:15]3=[O:17])=[C:8]2[CH:7]=1
Reactant: Cc1ccc2[nH]nc(C(=O)O)c2c1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1ccc2nn3c(=O)c4c5cc(C)ccc5nn4c(=O)c3c2c1
Yield: 135.5 %

Procedure:
Thionyl chloride (11 ml; 0.151 mol) was added to a suspension of 5-methyl-1H-indazole-3-carboxylic acid (12.2 g; 0.056 mol), prepared as described in J. Heterocyclic Chem. 1964, Vol. 1 (5) 239-241, in toluene (130 ml), and the reaction mixture was refluxed for 4 hours. The solvent was removed by evaporation under reduced pressure and the residue was taken up twice in toluene to give 12 g of the desired product.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[C:22]([C:34]3[O:38][N:37]=[C:36]([C:39]4[CH:44]=[CH:43][C:42]([CH2:45][NH:46][CH3:47])=[CH:41][CH:40]=4)[CH:35]=3)[C:23]([NH:26]C(=O)OC(C)(C)C)=[N:24][CH:25]=2)=[N:18][CH:19]=1)(=[O:13])=[O:12])([CH3:10])[CH3:9]>C(Cl)Cl>[CH:8]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[C:22]([C:34]3[O:38][N:37]=[C:36]([C:39]4[CH:40]=[CH:41][C:42]([CH2:45][NH:46][CH3:47])=[CH:43][CH:44]=4)[CH:35]=3)[C:23]([NH2:26])=[N:24][CH:25]=2)=[N:18][CH:19]=1)(=[O:12])=[O:13])([CH3:10])[CH3:9]
Reactant: CNCc1ccc(-c2cc(-c3cc(-c4ccc(S(=O)(=O)C(C)C)cn4)cnc3NC(=O)OC(C)(C)C)on2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1ccc(-c2cc(-c3cc(-c4ccc(S(=O)(=O)C(C)C)cn4)cnc3N)on2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
TFA (1 mL, 12.98 mmol) was added to a stirred suspension of tert-butyl N-[5-(5-isopropylsulfonyl-2-pyridyl)-3-[3-[4-(methylaminomethyl)phenyl]isoxazol-5-yl]-2-pyridyl]carbamate (105 mg, 0.1863 mmol) in DCM (5 mL) and the reaction stirred at ambient temperature overnight. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The reaction mixture was passed through a 2 g SCX-2 cartridge and washed with MeOH/DCM. The product was eluted by washing the cartridge with 2M NH3 in MeOH. The fractions were collected, concentrated in vacuo and the residue freeze-dried to give the title compound as a cream solid (30 mg, 35% Yield). NMR (400.0 DMSO) δ 1.22 (d, J=6.9 Hz, 6H), 2.30 (s, 3H), 3.56 (sept, 1H), 3.73 (s, 2H), 7.06 (br s, 2H), 7.51 (d, 2H), 7.63 (s, 1H), 7.93 (d, 2H), 8.24-8.31 (m, 2H), 8.74 (d, 1H), 8.99 (dd, 1H) and 9.02 (d, 1H) ppm; MS (ES+) 464.1.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1)[CH3:2].C(O)(=O)C.[I:13]Cl>C(Cl)Cl>[CH2:1]([C:3]1[N:4]=[C:5]([NH2:8])[S:6][C:7]=1[I:13])[CH3:2]
Reactant: CCc1csc(N)n1
Reactant: ClI
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc(N)sc1I
Reaction time: 1 h

Procedure:
4-Ethyl-thiazol-2-ylamine (0.960 g, 7.49 mmol) was dissolved in 17 mL of CH2Cl2 and 3.5 mL of acetic acid and treated at 0° C. with iodine monochloride (7.86 mL of 1M in CH2Cl2, 1.05 eq.) and kept at this temperature for 1 h. Pouring onto crashed ice/Na2CO3, twofold extraction with ethyl acetate, washing with water and brine, drying over sodium sulfate, and evaporation to dryness afforded 1.67 g of the title compound as almost black viscous oil, sufficiently pure to be used for the next step.
Reaction SMILES: O[Li].O.C([O:6][C:7](=[O:24])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])[O:14][N:13]=1)C.Cl>O.O1CCOCC1>[OH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[O:14][N:13]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][C:7]([OH:24])=[O:6])[CH:16]=1
Reactant: CCOC(=O)CCCCc1cc(-c2ccccc2O)on1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCCCc1cc(-c2ccccc2O)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
Add a solution of LiOH.H2O (2.87 g, 68.4 mmol) in water (60 mL) to a rapidly stirred solution of 5-[5-(2-hydroxy-phenyl)-isoxazol-3-yl]-pentanoic acid ethyl ester (3.96 g, 13.7 mmol) in dioxane (120 mL) and stir at room temperature overnight. After 1 hour, acidify to pH 1 with 5N HCl solution and concentrate to remove the majority of the dioxane. Add water to residue and place in refrigerator overnight. Filter out solids, wash with water, dry in a 50° C. vacuum oven for 6 hours to afford the title compound (3.11 g, 87%). MS (IS) 262 (M+1)+.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([CH3:51])[CH2:47][CH2:46]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]2[CH2:50][CH2:49][CH:48]([CH3:51])[CH2:47][CH2:46]2)=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CC1CCN(C(=O)CCl)CC1
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCC(C)CC2)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 4 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (0.8 mg) was obtained.