Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[N:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[N:8]=[C:7]1[C:16]([F:19])([F:18])[F:17])(=O)=O.[I-].[Na+].CCOCC.C(=O)(O)[O-]>CC(C)=O>[Cl:15][C:12]1[CH:13]=[C:14]2[NH:6][C:7]([C:16]([F:17])([F:18])[F:19])=[N:8][C:9]2=[N:10][CH:11]=1
Reactant: CS(=O)(=O)On1c(C(F)(F)F)nc2ncc(Cl)cc21
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: FC(F)(F)c1nc2ncc(Cl)cc2[nH]1
Yield: 71.2 %

Procedure:
1-(Methylsulfonyloxy)-6-chloro-2-(trifluoromethyl)-1H-imidazo [4,5-b] pyridine (20 milligrams) in 0.5 milliliter of acetone was treated with 0.1 gram of sodium iodide in 0.5 milliliter of acetone. The reaction mixture was shaken with ether and bicarbonate solution. The ether portion was dried over magnesium sulfate and evaporated, yielding 10 milligrams (about 73 percent) of 6-chloro-2-(trifluoromethyl)-1H-imidazo [4,5-b] pyridine.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[C:29]=1[C:30](Cl)=[O:31]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:30]([C:29]4[C:33]([O:37][CH3:38])=[CH:34][CH:35]=[CH:36][C:28]=4[O:27][CH3:26])=[O:31])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: COc1cccc(OC)c1C(=O)Cl
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4c(OC)cccc4OC)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2,6-dimethoxybenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([CH3:13])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:16][CH3:17])=[C:8]([O:14][CH3:15])[CH:9]=2)[N:4]=1.C(=O)([O-])[O-:19].[Na+].[Na+].C(O)C>O>[OH:19][CH2:2][C:3]1[C:12]([CH3:13])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:16][CH3:17])=[C:8]([O:14][CH3:15])[CH:9]=2)[N:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc2nc(C)c(CBr)nc2cc1OC
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc2nc(C)c(CO)nc2cc1OC

Procedure:
8.9 g (30 mmols) of 2-(bromomethyl)-6,7-dimethoxy-3-methyl-quinoxaline are suspended in a mixture of 158 g (1.5 mols) of sodium carbonate, 350 ml of water and 100 ml of ethanol. The suspension is boiled under reflux for four hours. 300 ml of water are then added and the resulting mixture is extracted with three times 120 ml of chloroform. The organic phase is dried over magnesium sulphate. The solvent is evaporated in vacuo. The solid residue is recrystallised from methanol. This gives 3.5 g (50%) of a white powder. Melting point: 176° to 177° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH2:16][CH2:17][O:18][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:10](=[O:14])[NH:9][C:8]([NH2:15])=[N:7][C:6]1=2.[C:36](Cl)(=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53].CO.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.ClCCl>[C:36]([O:1][CH2:2][C@H:3]([CH2:16][CH2:17][O:18][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:10](=[O:14])[NH:9][C:8]([NH2:15])=[N:7][C:6]1=2)(=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CC(C)(C)[Si](OCC[C@@H](CO)Cn1cnc2c(=O)[nH]c(N)nc21)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Reaction time: 1 h

Procedure:
(R)-9-[2-Hydroxymethyl 4-(t-butyldiphenylsilyloxy)butyl]guanine (2.31 g, 5 mmole) was coevaporated with dry pyridine twice and dissolved in pyridine (20 ml). To the solution was slowly added dropwise stearoyl chloride (1.86 ml, 5.5 mmole, technical grade) in dichloromethane (2 ml) at -5° C. The reaction was kept at the same temperature for 1 hr and then at 5° C. for 2 hr. The reaction was monitored by TLC. Additional stearoyl chloride (0.29 ml) at -5° C. was added due to incompletion of reaction. After 30 min at 5° C., methanol (3 ml) was added and the reaction mixture stirred for 20 min. It was then poured into aqueous sodium hydrogen carbonate solution, and extracted with dichloromethane. The organic phase was dried and the product purified by silica ge column chromatography with stepwise increasing MeOH, eluting with 3.5% MeOH in CH2Cl2 (Yield 2.7 g).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][O:4]1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>Cl>[C:10]1([NH:9][CH2:2][CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][O:4]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCC1CCCCO1
Reactant: Nc1ccccc1
Agent: Cl
Product: c1ccc(NCC2CCCCO2)cc1
Temperature: 100 °C
Yield: 73.6 %

Procedure:
A mixture of 2-(bromomethyl)tetrahydro-2H-pyran (100 g, 0.558 mol) and aniline (155.96 g, 1.67 mol) was heated at 100° C. under nitrogen overnight and cooled to room temperature. A 3N hydrochloric acid solution (400 mL) was added and the aqueous layer was washed three times with isopropyl ether. The aqueous layer was made basic with 50% sodium hydroxide solution, and the product was extracted three times into isopropyl ether. The combined organic extracts were washed once with water and evaporated under reduced pressure. The resulting oil was poured into water (1400 mL) and stirred. The water was decanted and water (1500 mL) was again added. The aqueous layer was again decanted and the oil was triturated again in water (1500 mL) to give a solid, which was recrystallized from methanol/water and dried under high vacuum to give 78.5 g of product containing one mole of water (67% yield). A 2.0 g portion was recrystallized from methanol/water and dried under high vacuum to give 0.71 g, mp 55°-58° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:12][S:13](O)(=[O:15])=[O:14].C(Cl)(=O)C(Cl)=O.CN(C=O)C>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:8][CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: ClCCCOc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(OCCCCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 52.75 g (0.265 mol) of (3-chloro-propoxy)-benzene in 100 ml of CH2Cl2, a solution of 19.4 ml (0.292 mol) of chlorosulfonic acid in 100 ml of CH2Cl2 is added dropwise at 0-5° C. under N2 atmosphere. The mixture is allowed to warm to ambient temperature and stirred for 2 hours. To the mixture, 29.6 ml (0.345 mol) of oxalyl chloride and 4 ml (0.052 mol) of DMF are added dropwise at r.t. and the mixture is stirred for 18 h at r.t. The reaction mixture is poured into ice-water, extracted with CH2Cl2. The combined extracts are dried over MgSO4 and concentrated under reduced pressure to give 58.5 g of 4-(3-chloropropoxy)benzenesulfonyl chloride; NMR (CDCl3): 2.26-2.36 (m, 2H), 3.76 (t, 2H, J=6.04 Hz), 4.24 (t, 2H, J=6.04 Hz), 7.06 (d, 2H, J=9.08 Hz), 7.98 (d, 2H, J=9.08 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br-].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][Zn+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:36][C:35]5[CH:38]=[CH:39][CH:40]=[C:33]([O:32][CH3:31])[CH:34]=5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Reactant: COc1cccc(C[Zn+])c1
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Br-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3cccc(OC)c3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-methoxy-benzylzinc bromide following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 8): tR=1.30 min; Mass spectrum (ESI+): m/z=535 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]3[N:10]=[C:11]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]4[C:18](=[O:20])[C:19]=3[C:6]=2[CH2:5][CH2:4][C:3]=1[CH:21]=[O:22].[CH2:23]([O:25][C:26](C1CCN2C(=O)C3C4CCCC(=O)C=4SC=3N=C2CC1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([CH:15]1[CH2:14][CH2:13][N:12]2[C:18](=[O:20])[C:19]3[C:6]4[CH2:5][CH2:4][C:3]([CH:21]=[O:22])=[C:2]([Cl:1])[C:7]=4[S:8][C:9]=3[N:10]=[C:11]2[CH2:17][CH2:16]1)=[O:27])[CH3:24]
Reactant: CCOC(=O)C1CCc2nc3sc4c(c3c(=O)n2CC1)CCCC4=O
Reactant: O=CC1=C(Cl)c2sc3nc4n(c(=O)c3c2CC1)CCCCC4
Product: CCOC(=O)C1CCc2nc3sc4c(c3c(=O)n2CC1)CCC(C=O)=C4Cl
Reaction time: 192 h

Procedure:
Compound 21 was synthesized by the method described for 4a using compound 19 as a starting material, with the exception that the reaction mixture was stirred for 8 days.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1.C([Li])(C)(C)C.[CH3:19][C:20]12[CH:29]([CH:30]=[O:31])[CH2:28][CH2:27][CH:26]=[C:25]1[CH2:24][C:23]1([S:35][CH2:34][CH2:33][S:32]1)[CH2:22][CH2:21]2>CCOCC>[CH3:19][C:20]12[CH:29]([CH:30]([C:2]3[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=3)[OH:31])[CH2:28][CH2:27][CH:26]=[C:25]1[CH2:24][C:23]1([S:32][CH2:33][CH2:34][S:35]1)[CH2:22][CH2:21]2
Reactant: COc1cc(Br)cc(OC)c1OC
Reactant: CC12CCC3(CC1=CCCC2C=O)SCCS3
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: COc1cc(C(O)C2CCC=C3CC4(CCC32C)SCCS4)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 73.1 %

Procedure:
A solution 5-bromo-1,2,3-trimethoxy-benzene (276 mg, 1.12 mmol) dissolved in 6 mL anhydrous ether is cooled to −78° C. and tert-butyllithium (1.7 M in pentane, 1.32 mL, 2.24 mmol) is added. The mixture was stirred at −78° C. for 15 minutes, then at room temperature for 3 hours. Aldehyde 241 (100 mg, 0.373 mmol) was added dropwise over 10 minutes in 10 mL ether at −30° C. The mixture was stirred for 0.5 hours and the reaction quenched with dropwise addition of saturated aqueous NH4+Cl−. The phases were separated and the aqueous phase was extracted with ether (4×10 mL). The pooled organic extracts were washed with saturated aqueous NaHCO3, brine, dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by flash chromatography over silica gel (25% ethyl acetate-hexanes) to yield 243 (119 mg, 73%).
Reaction SMILES: [CH3:1][C:2]([NH2:6])([CH3:5])[CH2:3][NH2:4].[S:7](Cl)([CH3:10])(=[O:9])=[O:8].C(N(CC)CC)C>C(Cl)Cl>[NH2:6][C:2]([CH3:5])([CH3:1])[CH2:3][NH:4][S:7]([CH3:10])(=[O:9])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(N)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(N)CNS(C)(=O)=O
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
2-Methyl-propane-1,2-diamine (2.00 g, 22.7 mmol, 2.38 mL, 1.1 eq.) was placed in CH2Cl2 (100 mL). Mesyl chloride (2.35 g, 20.7 mmol, 1.59 mL, 1.0 eq.) was added over a period of five minutes followed by triethylamine (6.27 g, 62.1 mmol, 8.71 mL, 3.0 eq.). The reaction was stirred for 30 minutes and then concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-15% MeOH/CH2Cl2 as the eluting solvent to obtain N-(2-amino-2-methyl-propyl)-methanesulfonamide as a white solid (1.15 g, 33%). LCMS (m/e) 167 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 2.98 (s, 3H), 2.95 (s, 2H), 1.17 (s, 3H), 1.16 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[Br:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(N(CC)CC)C>ClCCl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:32][CH:31]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)cc3)S(C)(=O)=O)c(C3CC3)cc12
Reaction time: 48 h
Yield: 26 %

Procedure:
A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide (500 mg, 1.244 mmol), 4-bromophenylboronic acid (1.5 g, 7.464 mmol), copper(II) acetate monohydrate (372 mg, 1.866 mmol), triethylamine (252 mg, 2.488 mmol), and 4 Å molecular sieves (1 g) in dichloromethane (160 mL) was stirred for 2 days. The solution was filtered, concentrated to dryness, and purified by column chromatography to afford 6-(N-(4-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (180 mg, 0.323 mmol, 26% yield) as a brown solid. LCMS (m/z, ES+)=557, 559 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10](=[O:12])[NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([Cl:13])[CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(Cl)c1
Reaction time: 5 h
Yield: 86.3 %

Procedure:
To a solution of N-tert-butoxycarbonyl glycine (0.5 g, 2.85 mmol) in dichloromethane (25 ml) at rt was added 3-chloroaniline (0.43 g, 3.42 mmol), HOBt (0.58 g, 4.28 mmol), EDC (1.10 g, 5.7 mmol) and N-methyl morpholine (0.43 g, 4.28 mmol). The reaction was stirred for 5 h and then washed with 1M KHSO4, 10% NaHCO3 solution and brine. The organic phase was separated, dried (Na2SO4), filtered and concentrated under reduced pressure to give [(3-chloro-phenylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (0.7 g, 86%). HPLC-MS 284, 286 [M+1]+.
Reaction SMILES: C(OC(=O)NC1C=C[CH:11]=[C:10]([CH2:14][N:15]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:40])[C@@H:22]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31]([Cl:39])[CH:30]=3)[CH2:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:16]2)[CH:9]=1)(C)(C)C.C(Cl)(=O)[C:43](Cl)=[O:44].COC(C)(C)CN1C=CC(N)=N1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[Cl:39][C:31]1[CH:30]=[C:29]([C@@H:22]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[C:21]([NH:20][C:17]2[CH:18]=[CH:19][N:15]([CH2:14][C:10]([O:44][CH3:43])([CH3:11])[CH3:9])[N:16]=2)=[O:40])[CH:34]=[CH:33][C:32]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Agent: COC(C)(C)Cn1ccc(N)n1
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(C)(C)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
In a round bottom flask, 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 165 mg, 0.50 mmol) was dissolved in methylene chloride (5 mL) and N,N-dimethylformamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 270 μL, 0.53 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (5 mL) and added dropwise into a solution of 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (prepared in Example 94, 85 mg, 0.50 mmol), 2,6-lutidine (130 μL, 1.00 mmol) and methylene chloride (5 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1.5 h. After this time, the reaction was quenched with a small amount of methanol. This was then diluted with ethyl acetate with a very small amount of methanol (<10%) and the organics washed with a saturated 1N aqueous hydrochloric acid solution and a saturated aqueous brine solution it was dried over sodium sulfate, filtered and concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes) to afford (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (211 mg, 90%) as a white foam: [α]31589=−3.04° (c=0.23, methanol); ES-HRMS m/e calcd for C23H32N3O4SCl (M+H)+ 482.1875, observed 482.1873; 1H NMR (300 MHz, DMSO-d6) δ 1.04 (s, 3H, CH3), 1.05 (s, 3H, CH3), 1.11 (m, 2H, CH2), 1.36-1.80 (m, 8H, 4×CH2), 2.09 (m, 1H, CH), 3.13 (s, 3H, OCH3), 3.33 (s, 3H, SO2CH3), 3.92 (m, 1H, ArCHCO), 3.97 (s, 2H, NCH2), 6.45 (d, J=2.2 Hz, 1H, Ar), 7.74 (d, J=2.2 Hz, 1H, Ar), 7.59 (dd, Jm=1.5 Hz, Jo=8.2 Hz, 1H, Ar), 7.70 (d, Jm=1.5 Hz, 1H, Ar), 8.00 (d, Jo=8.2 Hz, 1H, Ar), 10.80 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1N.S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Cc1cc(Cl)c(N)c([N+](=O)[O-])c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(Cl)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a stirred mixture of 2-chloro-4-methyl-6-nitroaniline (7.39 g, 39.7 mM) and concentrated sulfuric acid (6.2 mL) in absolute ethanol (50 mL) at 0°-5° C. was slowly added a solution of sodium nitrite (6.85 g, 99.3 mM) in water (6 mL). The temperature of the reaction mixture was not allowed to exceed 5° C. during the addition. After the addition was completed, the reaction mixture was stirred at room temperature for 0.5 hr and then at reflux until the evolution of gas from the reaction mixture ceased. The reaction mixture was allowed to cool and was concentrated. The residue was slurried with ether and then filtered to remove the solids. The filtrate was concentrated and the residue chromatographed (eluant: diethyl ether/hexane; 1/9) to provide (6.25 g, 92%) the title compound as a yellow crystalline solid, mp 60.5-61° C.; MS(CI): 172 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:21](I)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[Cl:1][C:2]1[C:21]([C:27]2[CH:28]=[N:23][CH:24]=[N:25][CH:26]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(I)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cncnc2)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A mixture of 6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 223.2, 5.7 g, 12.75 mmol), pyrimidine-5-boronic acid (2.5 g, 19.77 mmol), PdCl2(dppf)-(CH2Cl2) (0.625 g, 0.765 mmol), Na2CO3 (19.13 mL, 38.3 mmol) and DME (100 mL) was stirred at 80° C. for 2.5 h under argon atmosphere. The RM was filtered through Hyflo®, diluted with EtOAc (100 mL), washed with a sat. aq. solution of NaHCO3 and with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Biotage Silica gel column, 120 g, n-hexane/EtOAc from 20% to 60% EtOAc) to give the title compound product as a pink crystalline solid. UPLC-MS (Condition 3) tR=1.01 min, 393.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.42 (d, J=8.99 Hz, 2H) 7.88 (d, J=9.38 Hz, 2H) 8.56 (d, J=2.35 Hz, 1H) 9.03 (d, J=2.35 Hz, 1H) 9.10 (s, 2H) 9.32 (s, 1H) 10.69 (s, 1H).
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].Cl[C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([Cl:15])[N:7]=1.O>C1(C)C(C)=CC=CC=1>[Cl:15][C:8]1[N:7]=[C:6]([O:2][CH3:1])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: COc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.8 %

Procedure:
Methanol (3.3 g, 103 mmol) in xylene (100 mL) was added dropwise to a stirred suspension of sodium hydride (60% in mineral oil, 2.72 g, 113 mmol) in xylene (300 mL) at 0° C. under an argon atmosphere. After 20 minutes, 2,6-dichloro-3-nitropyridine (20.0 g, 103 mmol) in xylene (300 mL) was added dropwise then the reaction was warmed to ambient temperature and stirred overnight. Water (200 mL) was then added and the two phases were separated. The organic layer was washed with water and brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography (10:1 hexanes/ethyl acetate) to give the title compound (15.3 g, 78%) as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8](=[O:19])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][NH2:18])=[CH:11][CH:10]=1.N1C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[CH3:6][O:7][C:8](=[O:19])[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][NH:18][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(OCCN)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OCCNS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.4 %

Procedure:
Methanesulfonyl chloride (144 mg, 1.27 mmol) was added to a solution of 4-(2-amino-ethoxy)-benzoic acid methyl ester (266 mg, 1.15 mmol) and pyridine (255 mg, 2.52 mmol) in CH2Cl2 (10 mL) at 0° C. The solution was warmed to room temperature and was stirred for 24 h. EtOAc was added and the organic solution was washed with HCl (1N, 2×) followed by brine. The organic solution was dried (Na2SO4), filtered, and concentrated to yield the title compound as a white solid (240 mg). 1H NMR (400 MHz, CDCl3) δ 7.99 (dd, 2H), 6.90 (dd, 2H), 4.77 (m, 1H), 4.15 (t, 2H), 3.88 (s, 3H), 3.58 (m, 2H), 3.02 (s, 3H); MS 274 (M+1).
Reaction SMILES: [N:1]([CH2:4][C:5](=O)[C:6]([OH:8])=[O:7])=[N+:2]=[N-:3].[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[N:19]=[C:20]([NH:23][NH2:24])[S:21][CH:22]=2)[CH:14]=[CH:15][C:16]=1[Cl:17]>C(O)(=O)C.C(O)C>[N:1]([CH2:4]/[C:5](=[N:24]\[NH:23][C:20]1[S:21][CH:22]=[C:18]([C:13]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([Cl:10])[CH:12]=2)[N:19]=1)/[C:6]([OH:8])=[O:7])=[N+:2]=[N-:3]
Reactant: NNc1nc(-c2ccc(Cl)c(Cl)c2)cs1
Reactant: [N-]=[N+]=NCC(=O)C(=O)O
Solvent: CC(=O)O
Solvent: CCO
Product: [N-]=[N+]=NC/C(=N\Nc1nc(-c2ccc(Cl)c(Cl)c2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
KY-757 3-azido-2-oxopropanoic acid, KY-740 (100 mg, 0.77 mmol) in 5% acetic acid 162 ul was added in to solution of [4-(3,4-Dichloro-phenyl)-thiazol-2-yl]-hydrazine (0.2 gr, 0.77 mmol) in ethanol 2 ml. the reaction mixture was stirred at room temperature for 5 h. and then cooled to room temperature. The yellow solid was precipitated out, filtered and washed by water. Yield 0.1 gr (35%). MS+(ESI) m/z 371.91, calcd mass 371.2.