Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:9]([N:10](S(CC)(=O)=O)[S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])=[CH:8][C:7]([C:21]2[C:25]([CH3:26])=[C:24]([C:27]#[N:28])[N:23]([CH3:29])[N:22]=2)=[C:6]([F:30])[CH:5]=1>O1CCOCC1>[Cl:3][C:4]1[C:9]([NH:10][S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])=[CH:8][C:7]([C:21]2[C:25]([CH3:26])=[C:24]([C:27]#[N:28])[N:23]([CH3:29])[N:22]=2)=[C:6]([F:30])[CH:5]=1
Reactant: CCS(=O)(=O)N(c1cc(-c2nn(C)c(C#N)c2C)c(F)cc1Cl)S(=O)(=O)CC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCS(=O)(=O)Nc1cc(-c2nn(C)c(C#N)c2C)c(F)cc1Cl
Temperature: 22 °C
Reaction time: 1 h

Procedure:
6.5 ml of 2N sodium hydroxide solution are added dropwise to a solution of 2.93 g of 3-(4-chloro-2-fluoro-5-[(N,N-bisethanesulfonyl)amino]phenyl)-4-methyl-5-cyano-1-methyl-[1H]-pyrazole (Example H10) in 15 ml of dioxane and the mixture is stirred for 1 hour at 22° C. The mixture is subsequently poured into ice/water mixture and extracted with ethyl acetate. The combined organic phases are washed with water and dried over sodium sulfate. After the mixture has been filtered and concentrated, 2.31 g (90.6% of theory) of the desired product are obtained.
Reaction SMILES: [C:1]1([N:7]2[C:11]([S:12][C:13]3[C:14](=[O:28])[C:15]([C:20]([CH3:27])([CH3:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:16][C:17](=[O:19])[CH:18]=3)=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]1([SH:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO>[C:1]1([N:7]2[C:11]([S:12][C:13]3[C:18]([S:35][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:17]([OH:19])[CH:16]=[C:15]([C:20]([CH3:27])([CH3:26])[CH2:21][C:22]([CH3:23])([CH3:25])[CH3:24])[C:14]=3[OH:28])=[N:10][N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)CC(C)(C)C1=CC(=O)C=C(Sc2nnnn2-c2ccccc2)C1=O
Reactant: Sc1ccccc1
Solvent: CO
Product: CC(C)(C)CC(C)(C)c1cc(O)c(Sc2ccccc2)c(Sc2nnnn2-c2ccccc2)c1O
Temperature: 0 °C

Procedure:
15g of 2-(1-phenyl-5-tetrazolylthio)-6-(1,1,3,3-tetramethylbutyl)-p-benzoquinone was added to 150ml of methanol and the mixture was cooled to 0°C while stirring. Then a solution of 4.5g of thiophenol in 25ml of methanol was added dropwise to this mixture. After the addition, the mixture was stirred at 0°C for 3 hours. The resulting crystals were separated by filtration and recrystallized from a solvent mixture of n-hexane and ethyl acetate (n-hexane/ethyl acetate = 5/1 by volume). Thus 7.5g of 2-(1-phenyl-5-tetrazolylthio)-3-phenylthio-6-(1,1,3,3-tetramethylbutyl)-hydroquinone having a melting point of 147°C was obtained.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][OH:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:14][CH2:13][CH2:12][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:25])=[O:24]
Reactant: OCCOc1cccc2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1cccc2ccccc12

Procedure:
To a solution of 18.8 g of 2-(1-naphthyloxy)ethanol and 15.1 g of triethylamine in 425 ml of dichloromethane is added 12.6 g of methanesulfonyl chloride as described in Example 1 to give the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10](NO)[CH:9]=2)=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][OH:25])=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][O:25][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:12][N:11]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: ONc1cc(-c2ccc(Cl)cc2)on1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(Cl)cc2)on1
Yield: 74 %

Procedure:
5-(4-Chlorophenyl)-3-hydroxyaminoisoxazole (0.58 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.48 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 1(a) to obtain the title compound (0.69 g, 68%) as colorless crystals.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[C:11]([C:18](=[O:37])/[N:19]=[C:20]4/[S:21][C:22]5[CH:36]=[CH:35][CH:34]=[CH:33][C:23]=5[N:24]/4[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[N:5][C:4]=1[C:38]([O:40][CH3:41])=[O:39])=[O:2].[BH4-].[Na+]>CO.C1COCC1>[OH:2][CH2:1][C:3]1[S:7][C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[C:11]([C:18](=[O:37])/[N:19]=[C:20]4/[S:21][C:22]5[CH:36]=[CH:35][CH:34]=[CH:33][C:23]=5[N:24]/4[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[N:5][C:4]=1[C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4/sc5ccccc5n4COCC[Si](C)(C)C)c3C2)sc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4/sc5ccccc5n4COCC[Si](C)(C)C)c3C2)sc1CO
Temperature: 70 °C
Yield: 89 %

Procedure:
To compound 45C (2.08 g, 3.42 mmol) in MeOH (50 mL) and THF (20 mL) was added NaBH4 (0.259 g, 6.83 mmol). The reaction mixture was heated at 70° C. for 2 hours. The solvent was removed, and the residue was partitioned between EtOAc and water. The organic layer was isolated, and the aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with 1:1/hexanes:EtOAc to provide 1.86 g of the desired product: 1H NMR (DMSO-d6): δ 8.24-8.26 (m, 1H), 7.94 (d, J=7.67 Hz, 1H), 7.70 (d, J=8.20 Hz, 1H), 7.52-7.56 (m, 1H), 7.34-7.42 (m, 3H), 6.00 (s, 2H), 5.77 (t, J=5.52 Hz, 1H), 5.13 (s, 2H), 4.83 (d, J=5.52 Hz, 2H), 3.67-3.75 (m, 7H), 3.03 (t, J=5.98 Hz, 2H), 0.87-0.91 (m, 2H), −0.18 (s, 9H). MS (ESI(+)): m/z 611 (M+H).
Reaction SMILES: I[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.[CH3:15][NH:16][C:17]([NH:19][C:20]1[S:21][C:22]2[CH:28]=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=[CH:25][C:23]=2[N:24]=1)=[O:18].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[NH2:11][C:9]1[C:10]2[C:2]([C:27]3[CH:26]=[CH:25][C:23]4[N:24]=[C:20]([NH:19][C:17]([NH:16][CH3:15])=[O:18])[S:21][C:22]=4[CH:28]=3)=[CH:3][N:4]([CH:12]([CH3:14])[CH3:13])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CNC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: CC(C)n1cc(I)c2c(N)ncnc21
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: CNC(=O)Nc1nc2ccc(-c3cn(C(C)C)c4ncnc(N)c34)cc2s1
Temperature: 25 °C
Yield: 58.4 %

Procedure:
A mixture of 5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (302) (200 mg, 0.66 mmol), 1-methyl-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)urea (J-2) (333 mg, 1.5 eq, 1.0 mmol), Pd(PPh3)4 (76 mg, 0.1 eq, 0.066 mmol) and Na2CO3 (2 N, 2 mL) in DME (10 mL) was stirred at reflux for 30 min under Ar. The mixture was cooled to room temperature, and then concentrated in vacuo. Brine (10 mL) was added to the residue and then extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine (10 mL), dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography eluting with MeOH/DCM (1/30) to afford the desired product, 1-(6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-methylurea (303) (147 mg 58% yield) as a white solid ESI-MS m/z: 382.00 [M+H]+.
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[C:7]([C:9]([OH:11])=O)[N:8]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:33]([Si:37]([CH3:54])([CH3:53])[O:38][CH:39]([C:41]1[O:42][C:43]([CH2:46][N:47]2[N:51]=[C:50]([NH2:52])[CH:49]=[N:48]2)=[CH:44][N:45]=1)[CH3:40])([CH3:36])([CH3:35])[CH3:34]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[C:33]([Si:37]([CH3:54])([CH3:53])[O:38][CH:39]([C:41]1[O:42][C:43]([CH2:46][N:47]2[N:51]=[C:50]([NH:52][C:9]([C:7]3[N:8]=[C:4]([CH3:3])[O:5][C:6]=3[C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)=[O:11])[CH:49]=[N:48]2)=[CH:44][N:45]=1)[CH3:40])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ncc(N)n2)o1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3cnc(C(C)O[Si](C)(C)C(C)(C)C)o3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid (34 mg, 0.16 mmol) in CH2Cl2 (1.0 mL) was treated at rt with HOBt (25 mg, 0.19 mmol), EDC (74 mg, 0.38 mmol), DMAP (5 mg, 0.04 mmol) and the resulting mixture was stirred at rt for 30 min. 2-{2-[1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl}-2H-[1,2,3]triazol-4-ylamine (50 mg, 0.16 mmol) in CH2Cl2 (0.6 mL) was then added and the resulting mixture was stirred at rt for 16 h. CH2Cl2 (20 mL) followed by water (15 mL) were added and the aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with water, brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a brown oil. LC-MS-conditions 02: tR=1.23 min, [M+H]+=523.56.
Reaction SMILES: [CH2:1]([CH:3]1[CH:6]([CH2:7][CH3:8])[NH:5][C:4]1=[O:9])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:21][C:22]#[N:23].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH2:7]([CH:6]1[CH:3]([CH2:1][CH3:2])[C:4](=[O:9])[N:5]1[CH2:21][C:22]#[N:23])[CH3:8]
Reactant: CCC1NC(=O)C1CC
Reactant: N#CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1C(=O)N(CC#N)C1CC
Temperature: 0 °C

Procedure:
(3RS,4RS)-3,4-diethylazetidin-2-one (step 2) (100 mg, 0.786 mmol) in dry THF (5 ml) was cooled to −78° C. and was treated with lithium bis(trimethylsilyl)amide (0.786 ml, 0.786 mmol) [1M in THF]. The solution was allowed to warm to 0° C. then re-cooled to 0° C. before adding bromoacetonitrile (0.060 ml, 0.865 mmol). The mixture was allowed to warm to RT overnight. 10% Aqueous citric acid (30 ml) was added and the mixture was extracted with ether (4×40 ml). The combined organic layers were dried MgSO4, filtered and evaporated to dryness. Purification by chromatography on silica eluting with 0-100% Et2O in iso-hexane afforded the title compound;
Reaction SMILES: NCCCCCC(O)=O.S(Cl)([Cl:12])=O.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26].Cl.[NH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C(N(CC)CC)C>ClCCl.C(O)C>[ClH:12].[NH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].[N+:25]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:15]=1[NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:23][CH:22]=[CH:21][CH:20]=2)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: O=S(Cl)Cl
Agent: CCOC(=O)CCCCCN
Agent: Cl
Agent: NCCCCCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCCCCNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
Ethyl 6-aminocaproate hydrochloride was prepared from 6-aminocaproic acid, thionyl chloride, and ethanol by the general method of C. Temple, Jr., R. D. Elliott, and J. A. Montgomery, J. Med. Chem., 1988, 31, 697-700. The general method described in Step 1 of Example 1 was used to react 4-chloro-3-nitroquinoline (41.7 g, 200 mmol), ethyl 6-aminocaproate hydrochloride (46.9 g, 240 mmol) and triethylamine (50.6 g, 500 mmol) in dichloromethane for 15 hours to provide ethyl 6-(3-nitroquinolin-4-ylamino)hexanoate (60.6 g) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Br[CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>COCCOC>[S:3]1[CH:4]=[CH:5][N:6]2[CH:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:1]=[C:2]12
Reactant: Nc1nccs1
Reactant: CCOC(=O)C(=O)CBr
Solvent: COCCOC
Product: CCOC(=O)c1cn2ccsc2n1

Procedure:
To the cold solution of 2-aminothiazole (0.5 g, 4.99 mmol) in 10 mL of DME was added ethyl bromopyruvate (0.783 mL, 6.24 mmol). The resultant mixture was stirred at RT for 30 min. The yellow precipitate obtained was filtered. The solid residue was dissolved in 20 mL of ethanol and refluxed for 8 h. After the completion of the reaction as evidenced by LC-MS, the solvent was removed under vacuum. Residue was added to DCM and washed with sodium bicarbonate solution. The organic solvent was evaporated and the crude product was purified by Combiflash. Yield 0.285 g. 1H NMR (400 MHz; CDCl3): δ 1.42 (t, 3H), 4.41 (q, 2H), 6.98 (d, 1H), 7.47 (d, 1H), 8.09 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[S:9][C:10]([C:13]([F:16])([F:15])[F:14])=[N:11][N:12]=2)[CH2:3][CH2:2]1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]3[S:9][C:10]([C:13]([F:16])([F:14])[F:15])=[N:11][N:12]=3)[CH2:3][CH2:2]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: FC(F)(F)c1nnc(NC2CCNCC2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: Fc1ccc(CN2CCC(Nc3nnc(C(F)(F)F)s3)CC2)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
A mixture of piperidin-4-yl-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-amine (D4) (0.040 g, 0.16 mmol), 4-fluorobenzyl chloride (0.023 ml, 0.19 mmol) and diisopropylethylamine (0.042 ml, 0.24 mmol) in acetonitrile (3 ml) was stirred at 120° C. for 30 min., under microwave irradiation. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and extracted with a 10% solution of ammonium chloride (25 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 0-3% ammonia in methanol (7M)/dichloromethane) to yield E4 (0.042 g, 73%) as a solid. C15H16F4N4S requires 360. Found 361 (MH+).
Reaction SMILES: Cl.[N:2]1([C:8]2[C:13](/[CH:14]=[C:15]3/[C:16](=[O:21])[NH:17][C:18](=[O:20])[S:19]/3)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:22]([O:26][C:27]([NH:29][CH2:30][CH2:31][C:32](O)=[O:33])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[O:20]=[C:18]1[NH:17][C:16](=[O:21])/[C:15](=[CH:14]/[C:13]2[C:8]([N:2]3[CH2:7][CH2:6][N:5]([C:32](=[O:33])[CH2:31][CH2:30][NH:29][C:27](=[O:28])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:4][CH2:3]3)=[N:9][CH:10]=[CH:11][CH:12]=2)/[S:19]1
Reactant: O=C1NC(=O)/C(=C/c2cccnc2N2CCNCC2)S1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCN(c2ncccc2/C=C2\SC(=O)NC2=O)CC1
Temperature: 50 °C

Procedure:
A 50 mL vial was charged with a magnetic spin bar, (Z)-5-((2-(piperazin-1-yl)pyridin-3-yl)methylene)thiazolidine-2,4-dione hydrochloride (Example 89) (0.125 g, 0.38 mmol), 3-(tert-butoxycarbonylamino)propanoic acid (0.109 g, 0.57 mmol), DMF (1.912 ml), and diisopropylethylamine (0.334 ml, 1.91 mmol). With stirring, HATU (0.291 g, 0.76 mmol) was added and the reaction was warmed to 50° C. for 3 h. The reaction was then diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic extract was dried with MgSO4, filtered through a bed of Celite, and conc. in vacuo to yield the product which was purified via silica gel chromatography (80 g) using ethyl acetate/hexanes (1:1) as eluent to provide the title compound as an off white solid. (0.080 g, 45.3%); m/z 462.
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6]C=[CH:4][CH:3]=1.OC1C=C[N:25]=CC=1>>[C:17]([O:16][C:14]([N:10]1[CH2:11][CH2:12][CH2:13][CH:9]1[CH2:8][O:1][C:2]1[CH:7]=[CH:6][N:25]=[CH:4][CH:3]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: Oc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC1COc1ccncc1
Yield: 47 %

Procedure:
2-(Pyridin-4-yl-oxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (22) was prepared according to the same procedure for compound 9, except using 4-hydroxypyridine. The crude product was purified with ethyl acetate to afford 1.31 g (47%) of 22 as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.42 (m, 2H), 6.87 (m, 2H), 4.15 (m, 3H), 3.43 (m, 2H), 1.98 (m, 4H), 1.50 (s, 9H).
Reaction SMILES: [OH-].[Na+].[NH:3]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:4]([C:9]([NH:11][C@H:12]([C:17]([O:19]C)=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[CH2:5][CH:6]([CH3:8])[CH3:7]>O.CC(C)=O>[NH:3]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:4]([C:9]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 1 h

Procedure:
A solution of NaOH (1.34 g, 33.5 mmol) in water (15.0 g) was added dropwise over 10 min to the solution of Boc-Leu-Leu-OMe (10.0 g, 27.9 mmol) in acetone (20.0 g) and water (50.0 g) at 18-22° C. The reaction mixture was stirred at this temperature for 1 h and then analyzed by HPLC. When the methyl ester is under 5%, the reaction stirred for an additional 0.5 h. A white turbidity formed by the end of the reaction which was removed by filtration and rinsed with water (5.0 g). The clear filtrate was treated with formic acid (ca 0.8 g) to form a cloudy solution followed by immediate crystallization of product. Additional formic acid (1.5 g) was added (to pH 4.0-4.5) and the resulting product was collected by filtration then was washed by a mixture of acetone (10.0 g) and water (40.0 g). The solid product was suspended in a mixture of acetone (14.0 g) and water (56.0 g) for 15 min. The solid was collected by filtration and washed with a mixture of acetone (7.5 g) and water (30.0 g) and dried in vacuo at 45° C. Yield: 8.6-8.8 g (89.6-91.7%).
Reaction SMILES: Br.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:14])[S:12][CH:13]=2)=[CH:5][CH:4]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.Cl>N1C=CC=CC=1>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([NH:14][S:21]([C:18]3[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=3)(=[O:23])=[O:22])[S:12][CH:13]=2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2ccc(Br)cc2)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc(Br)cc3)cs2)cc1

Procedure:
A mixture of 4.0 g of 4-(4-bromophenyl)-thiazol-2-ylamine hydrobromide with 2.5 g of p-toluenesulfonyl chloride was stirred overnight with 15 ml of pyridine. The resulting, red colored suspension was poured into 180 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and chromatographed on 100 g of Kieselgel 60 with diethyl ether/hexane/methylene chloride (1:1:1) as the eluent. The product-containing fractions were concentrated and the residue was recrystallized twice from 60% ethanol. 0.8 g of N-[4-(4-bromo-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide separated as colorless crystals upon cooling.
Reaction SMILES: [NH2:1][C:2]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[F:15])([CH:5]([F:7])[F:6])[CH2:3]O.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17].C(=O)([O-])O.[K+]>C(#N)C>[Br:14][C:12]1[CH:11]=[CH:10][C:9]([F:15])=[C:8]([C:2]2([CH:5]([F:7])[F:6])[CH2:3][N:1]2[S:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N+:16]([O-:18])=[O:17])(=[O:26])=[O:27])[CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NC(CO)(c1cc(Br)ccc1F)C(F)F
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CC1(c1cc(Br)ccc1F)C(F)F
Temperature: 80 °C
Yield: 37.2 %

Procedure:
2-Amino-2-(5-bromo-2-fluoro-phenyl)-3,3-difluoro-propan-1-ol (13.04 g, 45.9 mmol) [examples 42 step d)] was dissolved in 261 mL acetonitrile, 2-nitrobenzenesulfonyl chloride (22.38 g, 101 mmol) and potassium hydrogencarbonate (13.79 g, 138 mmol) were added. The mixture was heated to 80° C. and stirred over night. After this period, the reaction mixture was cooled down and partitioned between saturated aqueous NaHCO3 solution and TBME. The layers were separated, washed with brine and TBME. The combined organic layers were dried over MgSO4.H2O and evaporated. The crude product was purified on a silica gel column by eluting with hexane/dichloromethane 2/1->1/2 to give 7.71 g of the title compound as white crystals.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11](=[O:41])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].O>C(O)(=O)C>[CH2:3]([NH:10][C:11](=[O:41])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCN2CCOCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 2.4 %

Procedure:
630 mg (1.56 mmol, 2 eq) of sodium hydroxide are added to a solution of 420 mg (0.78 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-(2-morpholin-4-ylethoxy)biphenyl-4-yl]propanoate in 8 ml of 8/1/1 tetrahydrofuran/methanol/water. The reaction mixture is stirred for 4 hours at room temperature. The reaction medium is hydrolyzed with water and acetic acid and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (40/60 heptane/ethyl acetate) and then on preparative HPLC. 10 mg of 3-[3′-(3-heptyl-1-methylureido)-2-(2-morpholin-4-ylethoxy)biphenyl-4-yl]propanoic acid are obtained in oil form. Yield=2%
Reaction SMILES: [CH:1]([NH:3][NH2:4])=O.Cl.C(N(CC)CC)C.C1(C)C(C)=CC=CC=1.Cl[C:22]1[N:27]=[N:26][C:25]([CH3:28])=[C:24]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH:23]=1>O>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([C:24]2[C:25]([CH3:28])=[N:26][N:27]3[CH:22]=[N:4][N:3]=[C:1]3[CH:23]=2)=[CH:30][CH:31]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2C)cc1
Reactant: NNC=O
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc3nncn3nc2C)cc1
Yield: 20.8 %

Procedure:
135 mg (2.25 mmol) of formohydrazide and 310 mg (2.25 mmol) of triethylamine hydrochloride were added to a xylene solution (5 ml) of 352 mg (1.5 mmol) of the obtained 6-chloro-4-(4-methoxyphenyl)-3-methyl-pyridazine, and stirred under reflux for 2 hours. Water was added to the reaction liquid, extracted with ethyl acetate, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=1/2) to obtain 75 mg (yield: 21%) of 7-(4-methoxyphenyl)-6-methyl-[1,2,4]triazolo[4,3-b]pyridazine.